Imidazole 2 PDF

4.
02
Imidazoles
N. Xi, Q. Huang, and L. Liu
Amgen, Inc., Thousand Oaks, CA, USA
ª 2008 Elsevier Ltd. All rights reserved.
4.02.1 Introduction 145

4.02.2 Theoretical Methods 146
4.02.3 Experimental Structural Methods 152
4.02.3.1 X-Ray Diffraction 152
4.02.3.2 Proton and Carbon NMR spectroscopy 156
4.02.3.2.1 Aromatic systems 156
4.02.3.2.2 Nonaromatic systems 160
4.02.3.3 NMR Involving Other Nuclei 162
4.02.3.3.1 Aromatic systems 162
4.02.3.3.2 Nonaromatic systems 164
4.02.3.4 Ultraviolet Spectroscopy 165
4.02.3.5 IR Spectroscopy 167
4.02.3.6 Mass Spectrometry 167
4.02.3.7 Electron Spin Resonance 169
4.02.3.8 Photoelectron Spectra 170
4.02.3.9 CD Spectra 170
4.02.4 Thermodynamic Aspects 171
4.02.4.1 Intermolecular Forces 171
4.02.4.1.1 Melting points 171
4.02.4.1.2 Solubility 171
4.02.4.1.3 Chromatography 172
4.02.4.2 Thermochemistry 172
4.02.4.2.1 Aromatic Stability 172
4.02.4.2.2 Other thermodynamic aspects 174
4.02.4.2.3 Conformations 175
4.02.4.3 Tautomerism 176
4.02.4.3.1 Annular prototropic tautomerism 176
4.02.4.3.2 Substituent prototropic tautomerism 178
4.02.4.3.3 Ring-chain isomerism 180
4.02.5 Reactivity of the Fully Conjugated Rings 182
4.02.5.1 Unimolecular Thermal and Photochemical Reactions 182
4.02.5.1.1 Fragmentation 182
4.02.5.1.2 Rearrangements 182
4.02.5.2 Electrophilic Attack at Nitrogen 184
4.02.5.2.1 Introduction 184
4.02.5.2.2 Proton acids: Basicity and acidity of imidazoles and benzimidazoles 184
4.02.5.2.3 Metal ions 184
4.02.5.2.4 Alkyl halides and related compounds: Imidazoles without a free NH group 184
4.02.5.2.5 Alkyl halides and related compounds: Imidazoles with a free NH group 186
4.02.5.2.6 Aryl halides and related compounds: Imidazoles with a free NH group 187
4.02.5.3 Electrophilic Attack at Carbon 191
143
144 Imidazoles
4.02.5.3.1 Reactivity and orientation 191

4.02.5.3.2 Nitration 191
4.02.5.3.3 Lithium–halogen exchange followed by electrophilic attack 191
4.02.5.3.4 Halogenation 194
4.02.5.3.5 Friedel–Crafts type alkylation and acylation 197
4.02.5.3.6 Diazo coupling 198
4.02.5.3.7 Silylation 198
4.02.5.3.8 Oxidation 198
4.02.5.4 Nucleophilic Attack at Carbon 201
4.02.5.4.1 Hydroxide and O-nucleophiles 201
4.02.5.5 Nucleophilic Attack at Hydrogen 203
4.02.5.5.1 Metallation at a ring carbon atom 203
4.02.5.5.2 Nitrogen carbanion and SRN1 reactions 203
4.02.5.5.3 C-Acylation via deprotonation 204
4.02.5.5.4 Transition metal catalyzed coupling reactions 204
4.02.5.6 Reactions with Radicals and Electron-Deficient Species 211
4.02.5.6.1 Carbenes 211
4.02.5.6.2 Free-radical attack at ring carbon atoms 211
4.02.5.6.3 Electrochemical reactions and reactions with free electrons 214
4.02.5.6.4 Catalytic hydrogenation and reduction by dissolving metals 215
4.02.5.7 Reactions with Cyclic Transition States 216
4.02.5.7.1 Diels–Alder reactions and 1,3-dipolar additions 216
4.02.5.7.2 Photochemical cycloadditions 222
4.02.6 Reactivity of Nonconjugated Rings 223
4.02.6.1 Isomers of Aromatic Derivatives 223
4.02.6.1.1 Compounds not in tautomeric equilibrium with aromatic isomers 223
4.02.6.2 Dihydro Compounds 223
4.02.6.2.1 Tautomerism and interconversions 223
4.02.6.2.2 Aromatization 224
4.02.6.2.3 Ring fission 226
4.02.6.2.4 Other reactions 228
4.02.6.3 Tetrahydro Compounds 236
4.02.6.3.1 Ring fission 236
4.02.6.3.2 Aromatization 237
4.02.6.3.3 Other Reactions 238
4.02.7 Reactivity of Substituents Attached to Ring Carbon Atoms 240
4.02.7.1 Reactions of Substituents Involving Ring Transformations 240
4.02.7.2 Fused Benzene Rings 242
4.02.7.3 Alkyl Groups 242
4.02.7.4 Substituted Alkyl Groups 244
4.02.7.4.1 Vinyl and arylalkyl 244
4.02.7.4.2 Activated alkyl 245
4.02.7.4.3 Heteroatom substituted alkyl 246
4.02.7.5 Other C-Linked Substituents 248
4.02.7.5.1 Unsaturated alkyl 248
4.02.7.5.2 Alkylidene 251
4.02.7.5.3 Aryl 256
4.02.7.5.4 Imine and nitrile derivatives 257
4.02.7.5.5 Carbonyl derivatives 259
4.02.7.6 Amino and Related Groups 261
4.02.7.7 Oxygen-Linked Substituents 264
Imidazoles 145
4.02.7.8 Sulfur-Linked Substituents 265

4.02.7.9 Halogen Atoms 269
4.02.7.10 Metals and Metalloid-Linked Substituents 271
4.02.8 Reactivity of Substituents Attached to Ring Heteroatoms 273
4.02.8.1 Aryl Groups 273
4.02.8.2 Alkyl Groups 273
4.02.8.3 Alkenyl Groups 277
4.02.8.4 Acyl and Aroyl Groups 278
4.02.8.5 Nitrogen Functions 280
4.02.8.6 Silicon, Phosphorus, and Related Groups 280
4.02.8.7 Sulfur Groups 280
4.02.8.8 Oxygen Groups 280
4.02.9 Ring Syntheses from Acyclic Compounds Classified by Number of Ring Atoms
Contributed by Each Component 281
4.02.9.1 Formation of One Bond 281
4.02.9.1.1 Formation of the 1,2- (or 2,3-) bond 281
4.02.9.1.2 Formation of the 1,5- (or 3,4-) bond 287
4.02.9.1.3 Formation of the 4,5-bond 294
4.02.9.2 Formation of Two Bonds 295
4.02.9.2.1 From [4þ1] carbon fragments 295
4.02.9.2.2 From [3þ2] carbon fragments 307
4.02.9.3 Formation of Three or Four Bonds 323
4.02.9.3.1 Formation of the 1,2-, 2,3-, and 3,4-bonds 323
4.02.9.3.3 Formation of the 1,2-, 2,3- and 4,5-bonds 327
4.02.9.3.5 Formation of four bonds 328
4.02.10 Ring Syntheses by Transformations of Another Ring 332
4.02.10.1 Ring Expansions 332
4.02.10.2 Transformations of Other Five-Membered Rings 336
4.02.10.3 Ring Contractions 340
4.02.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the
Various Routes Available 342
4.02.11.1 Imidazole and Benzimidazole Oxides and Radicals 342
4.02.11.2 Nitroimidazoles 344
4.02.11.3 Fluoroimidazoles 345
4.02.11.4 Selenoimidazoles 346
4.02.12 Applications and Importance 347
References 348
4.02.1 Introduction
Imidazole 1 is a five-membered aromatic molecule containing two annular nitrogen atoms. One nitrogen behaves like a
pyrrole-type nitrogen and the other one shows a close resemblance to a pyridine-type nitrogen. The systematic name of
this structure is 1,3-diazole, which is rarely used in the chemical literature. As in the earlier editions CHEC(1984) and
CHEC-II(1996), this chapter covers the following ring structures: imidazole 1 and benzimidazole 2, 2H- 3 and 4H-
imidazole 4, the imidazolines 5–7, imidazolidine 8, imidazo-2-yldiene 9, and imidazolidin-2-ylidene 10 (Figure 1).
146 Imidazoles
Figure 1 Ring structures covered in this chapter.
Reviews on the chemistry of imidazole-related molecules since 1996 include: synthesis of imidazole-containing
natural products <2006SL965, 2003S1753>, fluorinated imidazoles <2004JFC(125)501>, N-halogenated imidazoles
<1999AHC(75)1>, and nitroimidazoles <B-1998MI(2)547>; imidazole derivatives as biologically important mole-
cules <2003TRH19, 2005CTM987, 2003MI945, 1999BOC8>; the aromaticity of imidazole and related molecules
<2001CRV1421, 2001CRV1385>; synthesis, physicochemical properties, structures and applications of imidazolium-
based ionic liquids <2005JPO275, 1999CR2071, 2002CRV3667>; and characterization and applications of imidazo-2-
yldienes and imidazolidin-2-ylidenes <1999ACR913, 2000AGE4036, 2000CR39>.
4.02.2 Theoretical Methods

Over the decade 1995–2005, ab initio quantum chemistry has become an important tool in studying imidazole
derivatives. Two highly productive approaches are often utilized for the calculations: the wave function-based
methods (e.g., Hartree–Fock theory and second-order Moller–Plesset perturbation theory (MP2)) and the density
functional theory (DFT) based methods (e.g., gradient-corrected (BLYP) and hybrid (B3LYP) methods).
For simple imidazole derivatives in gas phase and solution, ab initio quantum-chemical calculations can provide
results approaching benchmark accuracy, and they are used routinely to complement experimental studies
<2004JA814, 1996JPC6484, 2005JA12544>. A wide variety of molecular properties, including structures and ener-
getics <1996JMT(366)227, 1998JMT(422)197, 1998JMT(432)41, 1998PCA7885>, acidity <2004JA814>, tautomer
equilibria <1997ANA431, 1998PCA7885, 2001JST(565)107, 2001JMT(574)221, 2001PCP3569, 1996JMT(366)227>,
thermochemistry profiles <1996PJC795, 1998PJC1054>, and spectroscopic quantities of various types
<2003PCA7827, 1996JPC6484, 2005JST(734)51, 2001JPC10249>, have been investigated.
The DFT method has become increasingly popular in computing molecular properties of imidazole analogues
since the publication of CHEC-II(1996). For example, Gallouj and co-workers employed the DFT method based on
the B3LYP formalism to compute the vibrational modes of 4-ethylimidazole with the 6-31G(df, p)-(5d, 7f) basis set
<1997JRS909>. Toyama and co-workers investigated the molecular vibrations of two tautomers of 4(5)-methylimi-
dazole using the DFT approach <2002PCA3403>. Hasegawa and co-workers performed a systematic vibrational
analysis on four possible protonated forms of 4-methylimidazole employing the B3LYP-DFT method with 6-31G(df,
p) basis set <2000PCB4253>. Maes and co-workers demonstrated that the DFT/B3LYP/6-31þþG** method yielded
the most accurate vibrational frequency predictions for monomeric imidazole among three levels of theory (the RHF
and MP2 methods and the parametrized DFT method) <1997PCA2397>. Mó and co-workers calculated the
enthalpies of formation of N-substituted imidazoles using the B3LYP/6-311* G(3df, 2p)//6-31G(d) approach
<1999PCA9336>.
For molecular properties of complex systems, especially those in solution, ab initio quantum-chemical calculations
may not be able to provide accurate results. For example, the acidity of imidazole in the gas phase can be calculated to
provide equivalent or greater accuracy than that obtained experimentally; however, the determination of its pKa value
Imidazoles 147
in solution is less satisfactory <2004JA814, 1997PCA10075, 2005PCB5884>. This is mostly due to the difficulty in
quantitatively calculating solvation energies with adequate accuracy. A few approaches have been investigated to deal
with the solvation effects required for evaluation of acidity/basicity in solution. Using a PCM (polarized continuum
model) solvation method, the pKa value of imidazole in DMSO has been calculated to be 17.6 (MP2) and 17.1
(B3LYP), as compared to the experimental result of 18.6. <2004JA814>. At the B3LYP/6-311þG(d,p) level of theory,
the computed pKa values of several substituted imidazoles in solution are within 0.8 pKa units <1997PCA10075>.
Better results are obtained with various force field models. Thus, calculation with fixed-charges force field model
reproduces the aqueous pKa value of imidazole at 6.4 (vs. the experimental 7.0), while the polarizable force field
model yields an even more accurate pKa value at 6.96 <2005PCB5884>.
The pKa values of complexed imidazole derivatives are not predicted accurately by ab initio or semiempirical
calculations, even when combined with semiempirical solvation models. Thus, for a series of imidazol-1-ylalkanoic
acid derivatives, the calculations are unable to describe the zwitterionic structure of the carboxylic monoacids series as
the most stable form determined experimentally in solution (Figure 2) <2004JMT(684)121>. Likewise, the effect of an
imidazole substituent on the pKa of phenol is not well reproduced using DFT/B3LYP/6-311þG(2d, 2p) and DFT/
B3LYP/6-31G(d) calculations (Scheme 1). The computed pKa values are higher than the experimental values by ca. 4
log units. Nonetheless, the trend of increasing acidity along the series is reproduced by the calculations <2005OL2735>.
Figure 2 Imidazol-1-ylalkanoic acid derivatives (R1, R2 ¼ H or Et).
Scheme 1
Characterized by its unique pKa value in aqueous solution, the protonation of imidazole ring plays an important role
in biological systems and has been investigated by combinations of dielectric, quantum mechanical, and computer
simulation methods <1997PCA10075, 1996JPC4466, 2000JA6989>. The species involved in the protonation process,
that is, imidazole and the imidazolium ion, are characterized as both individual and complexed identities. For
example, the electronic spectra of imidazole and the imidazolium ion have been computed with the complete active
space self-consistent field method and multireference second-order perturbation theory <1996JPC6484>. The
solvation free energies of imidazole and the imidazolium ion have been investigated using the Ewald method and
equilibrium fluctuations of electrostatic potentials <1998PCA7885>. In addition, the imidazole–imidazolium com-
plex, a strongly hydrogen-bonded system formed in the equilibrium, has also been the subject of many theoretical
calculations <2004PCA7038, 2003PCA7827, 2004PCB13874>. Thus, the vibrational spectra of the imidazole–
imidazolium complex have been computed at the B3LYP/6-311þþG** level of theory <2003PCA7827>. Similar
calculations have been extended to the pyrazole–imidazole system, which also forms an extensive H-bonded complex
<2005JMT(724)167>.
Histamine, a biologically important imidazole derivative, is in multiple acid–base and tautomeric equilibria in
aqueous solution. Tautomeric and basic center preferences for isolated neutral and monoprotonated histamine have
been studied by ab initio calculations (HF, MP2, and DFT), and the polarizable continuum model (PCM) has been
148 Imidazoles
used to investigate the variations of the tautomeric and basicity center preferences in histamine on going from the gas
phase to aqueous solution <2003JPO783, 2003JMT(666)143, 2002PJC1027>. Tautomeric equilibria and vibrational
spectra of histamine in solution have also been computed by quantum-mechanical calculations <2003JA2328,
2000PCA2120>.
Two possible histamine conformations, that is, essential and scorpio forms, have been investigated at different
semiempirical (CNDO, INDO, MINDO/3, MNDO, AM1, and PM3) and ab initio (RHF/STO-3G//STO-3G, RHF/
STO-4G//STO-4G, RHF/3-21G//3-21G, RHF/6-31G//6-31G, RHF/6-31G* //6-31G, RHF/6-31G* //6-31G* , RHF/6-
31þþG** //6-31G* , RHF/6-311þþG** /6-31G* , RHF/6-31G** //6-31G** , RHF/31þþG** //6-31þþG** , MP2/6-31G* //
6-31G* and MP2/6-31G** //6-31G** ) levels of theory. The results indicate that the so-called ‘essential’ (trans, T1) and
‘scorpio’ (gauche, T2) conformations of the neutral histamine tautomers equilibrate through the monoprotonated
histamine tautomer (MP) (see Scheme 2) <2001JPO770>. Calculations using the AM1 method have also been
carried out on isolated neutral and ring-N-protonated forms of histamine and model 4(5)-alkylimidazoles
<2001JMT(574)221, 2003TRH167>. Theoretical investigations on the conformers of more complex imidazoles,
such as the dipeptides HisGly and GlyHis, have been carried out with a combination of Monte Carlo search with the
Amber force field and local geometry optimization at the ab initio HF/6-31G(d) level <2005PCP3744>.
Scheme 2 Acid–base and tautomeric equilibria of histamine.
Theoretical calculations have been employed to study the unique structural features of the imidazole ring. The
characteristic annular tautomerism of imidazoles with unsubstituted nitrogen is a fast process, leading to usually
inseparable tautomeric pairs <2000AHC(76)157>. Computed at the IEF-PCM/B3LYP/6-31G* level of theory, the
1,3-tautomerization is predicted to be feasible through the formation of an intermolecular imidazole chain in
nonprotic solvents, while the 1,2-prototropic shift, as an intramolecular tautomerization path, is disfavored
<2005PCB22588>. The preference of one tautomer form over another is governed by four different effects: s-
and/or p-electron donating and/or withdrawing effects, as indicated in the theoretical studies on C-5-substituted
imidazoles at the MP2/6-311þþG** level (Scheme 3) <2001JST(565)107>. Similar results have also been obtained
from semiempirical AM1 and PM3 calculations <1998JMT(425)249>.
Scheme 3 Tautomerism of C-5-substituted imidazoles.

Imidazoles 149
Imidazole derivatives undergo ring-substituent prototropic tautomerization, which is often mediated by a solvent-
assisted mechanism. A systematic investigation of the proton transfer in the tautomerization of 2-thioimidazolone
using DFT theory indicates that the barrier height for non-water-assisted intramolecular proton transfer is very high
(175.8 kJ mol1) <2005JMT(730)199>.
Enol/ketone and thiol/thione prototropic tautomerism in 2-imidazolone and 2-thioimidazolone has been investi-
gated by ab initio methods in terms of thermodynamic stability (Scheme 4) <2003JPO47>. Semiempirical methods
(AM1, PM3, and MNDO) have been used to evaluate the tautomerism of 2-, 4-, and 5-imidazolones and their thio- or
azo-analogues in the gas phase <1996JMT(366)227>.
Scheme 4 Tautomerism in 2-imidazolone and 2-thioimidazolone.
Molecules such as 2-(2-hydroxyphenyl)benzimidazole (shown in Scheme 5), 2-(3-hydroxy-2-pyridyl)benzimida-

zole, 2-(2-hydroxy-3-pyridyl)benzimidazole and 4,5-dimethyl-2-(2-hydroxyphenyl)imidazole are characterized by
having a proton donor (the OH) group and a proton acceptor (the -NT) site connected by an intramolecular hydrogen
bond in the ground state. Tautomerism of these molecules has been investigated by HF/CIS/D95** , semiempirical
(AM1), DFT/B3LYP/6-31þG* methods, as well as Monte Carlo simulations, continuum model, and the Onsager,
SCI-PCM, and COSMO methods based on both ab initio and semiempirical Hamiltonians calculations
<1999PCA4525, 2002JST(604)87, 1998PCA1560, 1998JCF2775, 2005JST(734)51, 2001PCP3569>.
Scheme 5
The structures of substituted imidazolines such as the antihypertensives Clonidine and Moxonidine have been
studied with B3LYP/6-31þG(d,p) and BP86/TZ2P DFT methods (Scheme 6) <2006BMC1715>.
1,3-Dialkylimidazolium-based ionic liquids (ILs) are a class of novel solvents with very interesting properties. The
structures and conformational properties of 1-alkyl-3-methylimidazolium halide ionic liquids have been studied with
a B3LYP parameter functional method with 6-31G* , 6-31þþG** , and 6-311þþG** basis sets. The calculated results
indicate imidazolium cations can form hydrogen bond interactions with halide anions <2005JCP174501>. Similarly, in
the structures of the 1-alkyl-3-methylimidazolium hexafluorophosphate or tetrafluoroborate, hydrogen-bonding inter-
actions between the fluorine atoms of the PF6 or BF4 anion and the C-2-hydrogen on the imidazolium ring are also
predicated by DFT (B3LYP) and RHF calculations <2004PCB13177, 2006JML(124)84>.
150 Imidazoles
Scheme 6
Ab initio calculations at the B3LYP, MP2, and CCSD(T) levels on the gas-phase ion pairs of 1-butyl-3-methylimi-
dazolium chloride indicate that the most stable conformers are essentially degenerate and have the chloride
H-bonding to, or lying above, the C-2-H bond <2006PCA2269>. The ethyl side-chain in 1-ethyl-3-methylimidazo-
lium ion had been predicted to exist in an equilibrium between planar and nonplanar Et groups versus the
imidazolium ring plane, in its liquid form <2005JPC(A)8976>. The local structure of ionic liquid 1,3-dimethylimi-
dazolium chloride has been investigated by density-functional-based Car–Parrinello molecular dynamics (CPMD)
simulations. The specific CH Cl hydrogen bonds are characterized in terms of donor–acceptor interactions between
lone pairs on Cl and antibonding s* CH orbitals <2005PCB18591>.
Imidazol-2-ylidene and related carbenes 9 and 10 are remarkably stable, and many theoretical studies have been
carried out to investigate the special stabilities (see also Section 4.02.4.2.1) <2000CPL(322)83, 1996TL149,
1996JA2091>. According to theoretical predictions at the B3LYP level, the activation energy of the 1,2-hydrogen
shift of 9 to imidazole is very high <1997AGE1478, 1998EJO1517>. Ab initio calculations at the MP4/6-311G(d,p)//
MP2/6-31G(d) level suggest that the higher stability of 9 than that of 10 is caused by the enhanced pp–pp
delocalization. Nevertheless, both carbenes (9 and 10 in Figure 1) are strongly stabilized by electron donation
from the nitrogen lone pairs into the formally ‘empty’ pp orbital <1996JA2039>. On the other hand, the prototype
carbenes, that is, structures with hydrogen atoms on the nitrogens (e.g., 9), have not been isolated as stable
compounds. Calculations at B3LYP/aug-cc-pVDZ level of theory suggest that two molecules of imidazol-2-ylidene
could form the hydrogen-bonded complex 11 initially. Complex 11 would then dimerize to form imidazole dimer 13
through transition state 12 with a low activation energy value of 4.8 kcal mol1 (Scheme 7) <2001TL3897>.
Scheme 7 Species involved in the intermolecular hydrogen transfer and dimerization of 2,3-dihydroimidazol-2-ylidene.
The gas-phase proton affinity of 1-ethyl-3-methylimidazol-2-ylidene indicates that the carbene is one of the
strongest bases reported thus far. DFT calculations have been carried out at the B3LYP/6-31þG(d) level to
rationalize this strong basicity <2005OL3949>. Interestingly, dilithiated imidazole 14 and benzimidazole 15,
Imidazoles 151
displaying similar structures to those of N-heterocyclic carbenes, are potentially accessible, as predicted by B3LYP/
6-31G* and B3LYP/6-311þG** calculations. In these structures, the p orbitals on the central carbons are only
partially occupied, as are also observed in the related carbenes, for example, imidazol-2-ylidene (Figure 3)
<2001OL1249>.
Figure 3 Dilithiated imidazole 14 and benzimidazole 15.
Theoretical computations have been used to study the reactions that involve imidazole or benzimidazole analogues
<2006PCA7621, 2006T5474, 2006JA3543, 2002JA4944>. For example, the ring-closure reactions of 2,4-diazapenta-
dienyl anions and the corresponding dipoles have been investigated by quantum-chemical model calculations (RHF,
MP2, SCS-MP2, G3, and DFT) (Scheme 8) <2004EJO2567>, and the reactions of various functionalized imines
with nitrosoalkenes giving imidazoles and imidazole N-oxides have been investigated by theoretical calculations at
the semiempirical AM1 and ab initio HF/6-31G* levels of computational analysis (Scheme 9) <2006T5474>.
Scheme 8
Scheme 9
The mechanism of imidazole-2-ylidene-catalyzed transesterification has been studied using B3LYP DFT
(Scheme 10). The reaction is predicted to involve neutral tetrahedral intermediates, TS1 and ATS1, in which
the catalyst imidazol-2-ylidene facilitates proton transfer from alcohol to the carbonyl oxygen by forming the
tetrahedral intermediate TD <2005TL6265, 2005OL2453>.
152 Imidazoles
Scheme 10
The reaction of azathioprine, an immunosuppressive drug, with hydroxide anion has been investigated by means of
quantum chemistry <B-2000MI233>. The reaction of azathioprine with cysteine in aqueous solution has also been
studied using solvation model SM5.4 with PM3 Hamiltonian. The calculations suggest that the reaction involves
nucleophilic attack by the COO of cysteine on the C-5 atom of the imidazole ring, followed by a subsequent
intramolecular attack by the SH group of the cysteine residue (Scheme 11) <2001JA6404>.
Scheme 11
4.02.3 Experimental Structural Methods

4.02.3.1 X-Ray Diffraction
X-Ray crystallography has become ever more accessible and, as a result, routine inclusion of crystal structures of
imidazoles and their metal complexes have often appeared in the literature since the publication of CHEC-II(1996).
Particularly, transition metal complexes containing imidazole ligands are increasingly used in, and their X-ray
structural studies are reported for, important organic reactions such as Heck (N,N9-di-(2,4,6-trimethylphenyl)imida-
zolidine-2-thione/PdCl2 <2004OL1577>), Suzuki–Miyaura (1,3-bis(2,6-diisopropylphenyl)imidazolidine/Pd(0)
<2004TL3511>), Pauson–Khand (N-heterocyclic carbene (NHC)/Co <2003OM5374, 2004SL2103>), and olefin
metathesis (NHC/Ru <2003JA2546>). Earlier work on the characterization of NHCs has been summarized in a
review <1999ACR913>. In contrast to the commonly observed NHC C-2-metal complexes, major products from the
reactions of pyridine-functionalized imidazoles and IrH5(L)2 (L ¼ Ph3P; R ¼ mesityl, i-Pr) shows abnormal ligand
binding at the C-4/5 position of imidazolium salts. The structures of these complexes have been unequivocally
established from X-ray structural analyses (16, 18, Figure 4). The hydrogenated intermediate 17 has also been
isolated and characterized in the solid state <2002JA10473, 2001CC2274>.
Imidazoles 153
Figure 4 Abnormal Ir-imidazolium complexes.
1-Methyl-2,4,5-trinitroimidazole was first reported in 1970 but its structure in the solid state was determined only
in 2001. The 2-, 4-, and 5-nitro groups are twisted out of the imidazole plane by 24.2 , 9.8 , and 39.5 , respectively
<2001JHC141>.
The mechanism of nucleophilic addition to 4-nitroimidazoles under basic conditions is supported by the isolation
and structure confirmation of intermediate oximes such as 19 (Scheme 12) and their ring transformed products
<2003JHC523>.
Scheme 12
In the synthesis of anionic amido-N-heterocyclic carbene complexes of lanthanides (22, Ln ¼ Sm, Y;

N9 ¼ (TMS)2N)) from the bridged imidazolium complex 20 via carbene 21, a typical increase in the length of the
C–N bond and a decrease in the N–C–N angle were observed going from 20 to 21 <2003AGE5981>. The Sm–
Ccarbene distance of 2.588(2) Å is the shortest recorded compared to those reported for monodentate Sm–NHC
complexes (2.62–2.83 Å).
In the solid state, 4(5)-nitro-5(4)-methoxyimidazole exists as a 1:1 mixture of the two prototropic annular tautomers
<2004AXB191>. However, in histidine-dipeptides, the tautomer equilibrium (N1-H vs. N"2-H) has been found to
vary depending on the nature of the peptide structures <2005JA12544>.
The strongly fluorescent crystals of 23 (Figure 5) show efficient amplified spontaneous emission (ASE) associated
with an excited-state intramolecular proton transfer (ESIPT) process <2005JA10070>. From the X-ray crystal-
lographic analysis and semiempirical molecular orbital calculation, it has been found that the four aromatic groups
attached to the imidazole ring of 23 provide a positive steric effect towards improved fluorescence emission by
limiting the excessive tight-stacking responsible for the intermolecular vibrational coupling and relevant nonradiative
relaxation. The methyl group in 2-(4-methylpyridin-2-yl)-1H-benzimidazole derivative 24 assumes an anti-config-
uration, while significant delocalization of the charge in salt 25 is manifested in a decreased N(1)–C(2) vs. C(2)–N(3)
bond length differences. The dihedral angles about C-2–C-29 correlate well with relative UV-visible properties
154 Imidazoles
<2003JHC129>. In the solid state the cyclic peptide based on dipeptidyl imidazole 26 organizes to a rigid molecule
in which all lone pairs of the imidazole nitrogens and the hydrogens of the secondary amides point toward the center
of the macrocycle. The valine side-chains all lie on the same face of the molecule and adopt axial positions. The
imidazole moieties form a cone-like structure <2002TL6335>.
Figure 5
In the crystal structures of nitronyl nitroxide 27 and iminyl nitroxide 28 (Figure 6), magnetic linear chains along
the c-axis have been observed when R is H. These solids exhibit strong antiferromagnetism. In contrast, Cl
substitutions in both radicals result in a less favorable geometry for intermolecular spin interactions <1997JOC8854>.
Figure 6
The 10-E-3 hypervalent adducts from imidazo-thione/selenone and bromine (29, X ¼ Se; 30, X ¼ S, Se; Figure 7)
assume T-shaped bonding with an almost linear Br–X–Br array roughly perpendicular to the average plane of the
imidazole ring. These adducts are arranged in parallel planes, showing graphite-like stacking <2001CEJ3122>.
Similar bonding geometries have also been observed in the X-ray structures of bisimidazolines with the mixed
halogen IBr <2001AGE4229>.
Figure 7
Macrocyclic imidazolylboranes can exist in various structural types depending on the substituents of both the
imidazole and borane component. In the crystal structure of pentameric 31, all imidazole rings are almost perpendi-
cular to the plane of the molecule. The average N–B–N angle of 109.3(6) is very close to that of a perfect pentagon.
The tetramer 32 shows that the two opposite imidazole rings lie in the plane of the molecule while the other two are
perpendicular to it <2000AGE547>.
Imidazoles 155
The nitrogen atoms of imidazoles are excellent H-bond acceptors. As a result, hydrates of these molecules form
extended H-bonded networks (see also Section 4.02.2). One-dimensional water chains have been observed in the
hydrates of 33, 34 (Figure 8) <2003AGE5452>, and even 35 in which a strong electron-withdrawing nitro group is
present <2003AXB487> . Diverse H-bond networks have also been reported in the hydrates of oligo(thiophenes)
capped with imidazole <2005T6056>, 2,29-dimethyl-4,49-biimidazole <2003T6027>, and human isozyme (hCA II)
complex with L-histidine <2005BML5136> or histamine <1997B10384>. Not surprisingly, Baccatin III forms a 2:1
crystalline complex with imidazole which utilizes N(1)–H in the HB to the Ac(10) group of one Baccatin and N-3 in
the HB to the HO(7) of another Baccatin molecule <2000OL3269>.
Figure 8
In the structure of 1,3-dihydroxy-4,4,5,5-tetramethylimidazoline (36, Figure 9), the imidazolidine ring is highly
distorted (>0.27 Å off the mean plane). The hydroxyl groups form intermolecular hydrogen bonds with the nitro
group <2001CEJ2007>. The complexes between tris(4,5-dihydroimidazol-2-yl)benzene and either TFA (37,
R ¼ CF3) <1998CC1085> or tetrazole <1999JOC6425> form C3-symmetrical H-bond networks. The molecular
network in 38 features a twisted dicarboxylate (79.5 ) bridging coplanar bisimidazolines <1997TL1933>.
Figure 9
The ethylene-bridged imidazolium chloride 39 (Figure 10) crystallizes in the monoclinic space group P21/c with
an antiparallel arrangement of the two halves. The chloride anions interact with hydrogen atoms at C-2 and C-19 of
the bridge. In contrast, the naphthalene analogue 40 crystallizes in the triclinic space group P1̄ with syn relationship of
the imidazole rings. The water molecule forms extensive hydrogen contacts bridging both the cations and the
chloride anions <2004T5807>.
Figure 10
156 Imidazoles
N-heterocyclic carbenes (NHCs) catalyze the amidation of unactivated esters with amino alcohols (see Section 4.04.2).
The X-ray structure of N,N9-bis(mesityl)imidazolylidene–methanol complex (41, Figure 11) reveals a nearly linear (174 )
hydrogen bonding interaction within the plane defined by the imidazolidine ring <2005OL2453>. This observation, along
with solution 1H NMR, 13C NMR, and IR studies, led to the proposal of a new mode of catalysis for stable carbenes. Similar
solid-state hydrogen-bonding interaction between an NHC and diphenylamine was reported earlier <2002AGE1432>.
Together these represent a unique type of hydrogen bond involving a carbon-based acceptor: X-H C.
Figure 11
Cross-linking between the imidazole ring of histidines and side-chains of another residue have been identified by
X-ray structure studies in enzymes such as the green fluorescent protein (GFP) with a Y66L variant (His-148 to Leu-
66) <2005B8303> and the O2 binding site of cytochrome c oxidase (Tyr244-His240) <2003JA6028>. In the latter
case, copper(I) complexes of Tyr-His model structures have been shown to mimic the Tyr244-His240 crosslink.
4.02.3.2 Proton and Carbon NMR spectroscopy

4.02.3.2.1 Aromatic systems
A review on 1H NMR of Cu(II) complex with histidine-containing peptides has appeared <2003MRC877>.
Typical examples of proton and carbon chemical shifts are given in Table 1 for compounds 42, 43, and 44
<2001J(P1)3054>.
1
Table 1 H and 13C NMR chemical shifts of 1,2-dimethylimidazole derivatives at 80 C in [d8]-THF
Atom
H-1 2.95 3.54

H-3 1.6-1.2 (br) 2.25
H-4 5.99 6.64
H-5 6.06 6.88
C-1 32.42 32.62 32.3
C-2 166.7 145.1 164.1
C-3 22.16 (br) 13.10 12.93
C-4 110.8 121.0 112.7
C-5 123.7 127.4 122.9
C-6 45.50
C-7 76.83
C-8 148.9
C-9 71.16
C-10 54.1-54.3
Imidazoles 157
In biaryl systems containing an imidazole ring, the 1H chemical shifts of the other ring can vary over a large range
depending on the conformation and resonance interactions in the imidazole ring. For example, the aromatic proton
located ortho to the aryl–heteroaryl axis in the seven-membered cyclic ether 45 (Figure 12) experiences a far greater
downfield shift than the analogous proton in the rotationally less restricted eight-membered cyclic ether 46
<2003OL4795>. N-Methyl isomers of 47a and 47b show very different chemical shifts for the pyridine protons due
to different canonical forms induced by the N-methyl imidazoles. The signals for the protons on the pyridine ring in 47a
appear over a broad range ( ¼ 2.06 ppm) compared to those for 47b ( ¼ 0.87 ppm) <2003JOC4527>. In m-xylene-
bridged imidazolium receptor 48, the C-2 proton signal of imidazolium moiety shifts downfield (9.2–10.7 ppm) when
the free receptor 48a becomes complexed with anions such as Br 48b in MeCN <2005OL3993>.
Figure 12
Metalloporphyrins having an imidazolyl group at the meso position can form a complementary dimer, where each
imidazolyl group is coordinated to the metal ion of the other porphyrin in a slipped cofacial arrangement. Imidazole
protons of the free ligand H2Piv3ImP were observed at 7.8 ppm as a broad single peak due to free rotation of the
imidazole. In the presence of a metal ion, as in (Co(III)Piv3ImP)2, the imidazole protons were observed as two peaks,
because rotation was inhibited by coordination of N-6 to the cobalt of another porphyrin <2004T3097>. Based on the
1
H NMR spectrum of 2-(1H-imidazol-2-yl)-pyridine-Ru2þ complex, the mer/fac isomer ratio was determined to be
close to the statistic ratio (3:1) due to the C3-symmetry associated with the fac isomer <2005HCA487>.
The solution NMR spectrum of 1-hydroxy-2,4,5-triphenyl-1H-imidazole 3-oxide 49 at 300 K corresponds to
prototropic equilibrium between tautomers (49a, 49b, Scheme 13). Addition of a small amount of TFA increases
tautomerization, leading to narrower, averaged signals ascribed to 49c. At 233 K, the signals were assigned as cited in
Table 2 <2003HCA1026>. The average of signals obtained at 233 K is very close to the values measured in the
presence of TFA. The 13C NMR spectrum of 49 also suggests that there is no tautomerization at 233 K, slow
prototropy at 300 K (broad signals), and rapid exchange in the presence of TFA (Table 3). However, in the solid state
13
C NMR (with the nonquaternary suppression NQS experiment), the imidazole ring signals are similar to either the
233 K or the averaged spectra, casting doubts on the structural interpretation (see 15N NMR).
Scheme 13
158 Imidazoles
1
Table 2 H NMR chemical shifts of 1-hydroxy-2,4,5-triphenyl-1H-imidazole 3-oxide 49
2-Ph 4-Ph 5-Ph

400 MHz
CDCl3 OH ortho meta para ortho meta para ortho meta para
233 K 11.91 8.22 7.33 7.45 7.62 7.45 7.45 6.44 7.07 7.25
Average 8.22 7.33 7.45 7.03 7.26 7.35 7.03 7.26 7.35
300 K 8.31 7.33 7.44 7.61 7.44 7.44 6.60 7.08 7.23
CF3COOH 7.98 7.34 7.42 7.06 7.25 7.32 7.06 7.25 7.32
13
Table 3 Selected C NMR chemical shifts of 1-hydroxy-2,4,5-triphenyl-1H-imidazole 3-oxide 49
100 MHz, CDCl3 C-2 C-4 C-4
233 K 135.4 129.5 126.4

Average 135.4 128.0 128.0
300 K 135.7 n.o. n.o.
CF3COOH 135.5 126.3 126.3
CPMAS, 300 K 132.5 128.6 126.6
In the 13C MAS NMR spectra of histidine-dipeptides, the 13C chemical shifts for C and C span a large range (up
to 13 ppm) and are highly influenced by the tautomer effect and intermolecular interactions <2005JA12544>. The
imidazole ring 13C chemical shifts of 50 (158.6, 123.8 (2JCF ¼ 36.0), 131.0 ppm, Scheme 14) resemble more closely
those of 1-methyl-5-(p-tolyl)-4-trifluoromethyl-1H-imidazole (137.6, 128.8 (2JCF ¼ 37.4 Hz), 133.0 ppm). Based on
this observation, it was proposed that in the solid state 50 most likely assumes the tautomeric form 50a rather than
50b <2001JHC773>.
Scheme 14
The 13C chemical shifts of 2-lithiated imidazoles in THF-d8 range from 195.9 ppm to 216.1 ppm for compounds
51–54 (Figure 13). Simple imidazoles such as 51–53 exist as the ring form even at 20 C, whereas benzimidazole
exists as a mixture of ring 54a and chain 54b, C2 158.4 ppm) tautomers. The nature of the lithiated species
(carbene, carbenoid, or simple carbanion) is not easily discerned based on the 13C chemical shifts <1997CB1213>.
Figure 13
Quaternization of imidazoles (55, Figure 14) to imidazolium salts 56 leads to low-field shifts of all the imidazole
carbon signals except that of C-4, which is shielded probably by steric compression resulting from N-3 substitution. In
contrast, the corresponding imidazole 1-oxides 57 show a high-field shift for all the imidazole carbons. This high-field
Imidazoles 159
shift is due to increased negative charge accumulated at the carbon atoms (as reflected by the resonance structures).
N-Oxidation also leads to a significant increase in the one-bond C–H coupling constant (1J) and a decrease in the
differences between long-range coupling constants (3J), as a result of increased delocalization <1998MRC296>.
Figure 14
The complex [Y(L){N(SiMe3)2}2] (L ¼ 1-tert-butyl-3-(2-tert-butylaminoethyl)imidazol-2-ylidene) showed a

13
CC(carbene) resonance at 186 ppm with a 1J 89Y–C(carbene) coupling of 54.7 Hz, larger than any 1JYC value reported
for an s-bound yttrium alkyl or an yttrium–NHC adduct <2003AGE5981>. In comparison, the 1JYC value for
Y[N(SiHMe2)2]3(N,N9-dimethyl-NHC) was 49.6 Hz <1997OM682>.
Analyses of 13C NMR of N-heterocyclic carbenes (Figure 15) seem to suggest that the chemical shift of the
carbene carbon correlates to the NCN bond angle in the solid state (Table 4).
Figure 15
Table 4 Selected 13C chemical shifts of N-herocyclic carbenes and bond

angles in the solid state <2003AGE5243, 1999CEJ1931>
Carbene ( ppm) at C-2 N-(1)–C-(2)–N-(3) angle ( )
58 211.4 102.2
59 219.7 101.4
60 213.7 101.5
61 244.5 104.7
62 238.2 106.4
63 231.4 103.5; 104.3
64 240 n.a.
The rate of deuterium exchange at C-2 of substituted imidazolium cations in buffered D2O was measured by
monitoring the disappearance of the C-2 proton signal. These data enabled calculation of carbon acid pKa values of
1,3-dimethylimidazolium (23.0), 1,3-dimethylbenzimidazolium (21.6), and 1,3-bis((S)-1-phenethyl)benzimidazolium
(21.2) <2004JA4366>. Solid-state 1H CRAMPS (combined rotation and multiple pulse spectroscopy) and 13C NMR
studies of lyophilized L-histidine at various pH values provided valuable insights into the acid–base and tautomeric
equilibria. Calculated pKa values from solid-state acid-to-base ratios (r) are similar to those measured in solution
<2002JA2025>. Dynamic 1H NMR measurement of line broadening of intramolecularly hydrogen-bonded amide
NH at different temperatures predicts that the strength of hydrogen bonds in N,N9-disubstituted imidazole-4,5-
dicarboxamides 65 is 14 kcal mol1 <2005OL135> (Figure 16).
160 Imidazoles
Figure 16
In studies of the 1H NMR spectra of N-glucosylimidazoles, analyses of both J4,59 from the sugar ring
<2001JOC1097> and chemical shifts of the imidazolyl H-2 <1999JA6911> upon protonation discount the previously
proposed reverse anomeric effect of electropositive groups at C-1 of pyranoses.
Dipolar coupling of H-2 and H-4 protons of the histidine residue in L-carnosine (ß-alanyl-L-histidine) has been
observed in human tissues using an in vivo 1H NMR technique <2003MR256>.
4.02.3.2.2 Nonaromatic systems

The 1H and 13C NMR chemical shifts of the aldose reductase inhibitor 4(S)-2,3-dihydro-6-fluoro-2(R)-methylspiro-
[chroman-4,49-imidazoline]-29,59-dione (methylsorbinil, 66, Figure 17) and its seven synthetic intermediates have
been completely assigned on the basis of DEPT, COSY, g-HSQC and g-HMBC. All the J-values for C-F (1–4 bonds),
H-F (1–4 bonds), and H-H (3–4 bonds) have been determined <2005MRC1008>.
Figure 17
13
C NMR spectra of a series of imidazolidines with different substitution patterns have been reported based on
HMQC single bond and HMBC long-range H-C correlations. For 1,3-dialkyl (or dibenzyl)imidazolidines, 1JC–H
constants reflect relative orientation to the nitrogen lone pair: C–H bonds trans to a lone pair have lower values (1JC–H
135 Hz) whereas C–H bonds cis to a lone pair have higher values (1JC–H 144–154 Hz) <2003H(60)2103>. In the
1
H NMR spectra of N-benzyl imidazolidines, protons trans to nitrogen lone pair have upfield chemical shifts based on
the notion that trans lone pair or cis-alkyls have shielding effects on the protons <2003H(60)89>. This trend also
holds for the C-2 protons of N,N9-diaryl imidazolidines <2001JHC849>.
Conformations of 1,3-dihydroxy-4,4,5,5-tetramethyl-2-pyridinylimidazolidines (67–69, Figure 18) have been stu-
died using both 1H and 13C NMR techniques and HF/6-31G(d) calculations. All three molecules adopt a conforma-
tion with the OH groups trans to the pyridinyl groups at lower temperature. At T > 300 K, 69 can also adopt another
conformation where intramolecular H-bonding (N-OH) is no longer viable <1997T16911, 2004HCA425>. cis-N,N9-
Dialkyl-4,5-diaryl imidazolinium 70 shows symmetrical 1H and 13C NMR resonances, indicating a planar conforma-
tion of the N-CTN moiety. The large coupling constant between the two benzylic protons (J4,5 ¼ 12–12.90 Hz)
suggests a small dihedral angle (0–15 ) <2004JME915>. 1JC–H couplings are directly proportional to the fraction of s-
character in a given C–H bond. In the 13C NMR spectrum of monolithiated chiral imidazoline 71 at 69 C, a single
set of well-resolved signals with C ¼ 40.2 ppm (t, 1JC–H ¼ 125 Hz) is consistent with the expected N-lithiation.
Further lithiation of (C) affords a single unsymmetrical product whose 13C NMR spectrum at 69 C shows
C ¼ 64.2 ppm (d, 1JC–H ¼ 157 Hz), in agreement with N,C-bislithiated structure 72. Both the (downfield) chemical
shift and the increase in 1JC–H are indications of partial delocalization at the C of 72. Overall, this center is
pyramidalized and renders a high degree of diastereoselectivity in alkylation reactions <1998JOC8107>.
Imidazoles 161
Figure 18
During the C-5 lithiation–substitution of 73 (Scheme 15), it was found that the reaction yields never exceeded
50%, and that a significant amount of starting material was always recovered. Both 1H and 13C NMR measurements
indicated that 73 exist as a 1:1 mixture of rotamers about the NBOC amide bond at 78 C. Upon addition of s-BuLi,
only one of the rotamers undergoes deprotonation. Presumably only the conformer in which the carbonyl oxygen is cis
to C-5 of the imidazolidine ring undergoes directed lithiation. Based on line coalescence of the NMR signals at
various temperatures, the half-life for rotation was determined to be >100 h at 78 C and 10 min at 40 C
<2001OL3799>. H/D substitution rates (kdeut) of 5-monosubstituted imidazolidine-2,4-diones were determined by
1
H NMR spectroscopy. In conjunction with the rates of racemization (krac), as determined by chiral HPLC methods,
it was postulated that the deuteration and racemization of chiral 5-monosubstituted hydantoins follow general base
catalysis and that the deuteration occurs with inversion of configuration <1996HCA767>.
Scheme 15
The reactions of 2-amino-2-deoxy-D-glucopyranose with 2-halo-phenyl isothiocyanates in ethanol–water produced

the corresponding (4R,5R)-1-aryl-5-hydroxy-4-(D-arabino-tetritol-1-yl)imidazolidinone-2-thiones (74, Scheme 16)
with J4,5 2.2 Hz. On the other hand, reaction with 2-methoxyphenyl isothiocyanate gave rise to the (4R, 5S)-
epimer 77 with J4,5 7.4 Hz. The 5(S)-epimer undergoes rapid epimerization in DMSO giving 78, as evidenced by
1
H NMR measurements. Per-O-acetylation of the OH groups was achieved in Ac2O-pyridine (1:1) at 15 C without
altering the C-5 configuration. Rapid elimination of the 5-OAc in the (5R) epimer 75 led to the formation of the
corresponding imidazoline 76. Variable-temperature 1H NMR analyses revealed that the (5S)-epimer also undergoes
elimination but via the (5R)-epimer. It was concluded that the elimination reaction follows a pericyclic pathway
<1999T4377>. Dynamic NMR techniques as well as molecular mechanics were employed for the study of atrop-
isomerism of 74–76, 78–80. The naphthylthiones 79, 80 showed the highest barrier of rotation about the C(Ar)–N
bond (17 kcal mol1) and existed as mixtures of atropisomers at room temperature <1999T4401>.
162 Imidazoles
Scheme 16
4.02.3.3 NMR Involving Other Nuclei

4.02.3.3.1 Aromatic systems
Spectroscopic properties of both imidazole and benzimidazole are difficult to define due to the annular tautomerism.
A compilation of solid state and solution 13C and 15N NMR data at both rt and low temperature was reported along
with comparisons with, and attempted correlations to, calculated absolute shieldings <2001H(55)2109>. Chemical
shift principle values for imidazole have been reported and compared with calculated values. The 15N chemical shift
tensors are very sensitive to the hybridization of the nitrogen atoms <1997JA9804>. A 2D–15N exchange NMR study
of protonic conduction in 15N-labeled imidazole provided little support to the Grotthus mechanism <1999JA11486>.
The 22 tensor value is a good indicator of hydrogen bond length in cationic imidazole species such as histidine
<1999JA10389>. Magic-angle spinning solid-state 2D 15N NMR with the rotor synchronized sequence R1852 applied
at the 1H Larmor frequency allowed for an estimate of hydrogen bond length in crystalline [U-13C, 15N]-L-
histidine?HCl?H2O [15N(1)-H: 109 pm; 15N("2)-H: 105 pm] <2001JA11097>.
Computed chemical shifts (s 1H, 15N, 195Pt, 99Ru, 103Rh) of transition-metal (M ¼ Zn, Pd, Pt, Ru, Rh)
complexes with a prototypical nitro-imidazole-based radiosensitizer, 1,2-dimethyl-5-nitro-1H-imidazole, were
reported at the GIAO-BP86 and B3LYP levels for BP86/ECP1-optimized geometries <2005HCA2705>.
1
H–15N heteronuclear multiple bond correlation NMR (HMBC) is a convenient method for locating the position of
imidazole-protecting groups <2003JOC7521>. A modified accordion-based sequence with an accordion delay of
3–10 Hz was used to optimize 1H-15N long-range correlations. In general, stronger correlations were observed from
protons to pyrrole-like nitrogens than to the pyridine-type nitrogens of imidazoles <2003MRC307>. In N-alkylated
imidazoles, the ‘pyridine-type’ nitrogen resonates at higher frequency (higher ) compared to the substituted
‘pyrrole-type’ nitrogen (>60 ppm) <2002JST(605)199>. Hence in the 1H–15N HMBC spectrum the cross peak
between the b-protons of the histidine side-chain and the p-nitrogen would coincide with the higher nitrogen in a
-protected compound (81, Figure 19). Similarly, a correlation with the lower nitrogen would indicate a p-protected
compound 82. This method was applied to C-4-linked imidazole ribonucleoside 83 where the location of the POM
group at the t-nitrogen was established (a 1H(C10)/15N(p) cross-peak in 1H–15N HMBC signals [ (ppm) 15N (t)
176.1, 15N (p) 247.1, and 1H (C10) 4.66]) <2005T11976>.
Imidazoles 163
Figure 19
The first solid-state cross-polarization magic angle spinning 15N-CPMAS/NMR was recorded for 1-hydroxy-2,4,5-
triphenyl-1H-imidazole 3-oxide (84, Scheme 17). Two signals at 170.4 and 166.2 ppm (300 K) were observed.
Based on GIAO/B3LYP/6-31G* calculations, the signals were attributed to the presence of two independent
molecules with an averaged structure 1c in the asymmetric unit <2003HCA1026>.
Scheme 17
The 19F NMR chemical shift sensitivity of fluoroimidazoles as a function of pH near the region of the pKa of the
substrate was studied in an effort to develop potential probes for intracellular pH determination. As shown in
Table 5, the maximum chemical shift BHþ/B (chemical shift difference between acid (HBþ) and base (B)
forms) varies as a function of the F-substitution, with the 1-(4-fluorophenyl)imidazole 87 showing the largest shift.
Interestingly, in 86 the 19F resonance moves downfield with increasing pH while that of 85 moves in the opposite
direction <1997T8211>.
19
Table 5 Acidity and F NMR/pH property of 1-substituted fluoroimidazoles
Structure
pKa 5.18 6.52 5.78

BHþ/B 0.46 0.22 3.94
164 Imidazoles
4.02.3.3.2 Nonaromatic systems

For a leading reference containing multinuclei NMR data for RCM catalysts containing NHC ligands, see
<2003JA2546>.
Multiple-nuclei (13C, 15N, 77Se) solid-state CPMAS/NMR spectra of 1,3-imidazolidine-2-selenones have been
reported <2003MRC1026>. Effects of substituents and hydrogen bonding on 14N and 17O chemical shifts in
3-imidazoline 3-oxides were shown to vary over a range of 155 and 110 ppm, respectively <2005CHE1134>.
2-Methyl-5-nitroimidazoles were studied by 14N NMR–NQR double resonance spectrometry to evaluate the effect
of substitutions on electron density distributions <1999MRC878>.
Through studies of 6Li and 15N NMR spectra of 88 and 89 in various proportions, the formation of the mixed dimer
90 was identified as the catalyst responsible for enantioselective epoxide rearrangements to chiral allylic alcohols
<2001J(P1)3054> (Scheme 18).
Scheme 18
The structure confirmation of dimethyl 1-(4-chlorophenyl)-2-methyl-5-oxo-2-imidazoline-4,4-dicarboxylate 91,

synthesized via a 1,3-dipolar cycloaddition reaction between an azomethine ylide and an isocyanate, was based on
an nOe (7.5%) between the 2-methyl group and the 29-aromatic H, and the fact that there was one sp2 nitrogen at
72 ppm (N3) in the 14N NMR and one sp3 nitrogen at 212 ppm (N1) in the 15N MMR <1997T6351> (Figure 20).
Figure 20
The characterization of transient intermediates during photosensitized oxidation of 2-13C-4,5-diphenylimidazole

was made possible by following the change of the 2-13C label as a function of temperature. The 13C and 15N spectra
data for the intermediates are shown in Table 6 <2002JA9629>.
Lithiation of 1,2,2,5,5-pentamethyl-3-imidazoline 3-oxide 92 leads to the formation of the dipole-stabilized
organolithium 93 (Scheme 19). Compared with 92, both C-4 and C-5 resonate at higher frequency, whereas N-3
resonates at lower frequency (Table 7). The 7Li NMR resonance appears significantly lower in frequency relative to
that of s-BuLi (0.34 ppm), indicating more covalent character of the C–Li bond in 93 <2001MRC681>.
Imidazoles 165
Table 6 Chemical shifts of transient intermediates formed during the reaction of 2-13C-4,5-diphenylimidazole with singlet
oxygen
13 15
C ( ppm) N ( ppm)
Temperature ( C ) Transient intermediates C-2 C-4 C-5 N-1 N-3
100 102.2 172.6 100.3 111.1 307.0
88 117.5 167.0 167.0 356.6 356.6
80 177.8 181.4 181.4 308.6 308.6
80 127.3 162.9 162.9 364.2 304.2
30 163.7 100.6 189.1 44.9 288.3
Scheme 19
Table 7 Selected 14N (MeNO2), 13C (TMS), and 7Li (LiClO4) chemical
shifts for 92 and 93 (ppm)
14 13 13 7
Compound N-3 C-4 C-5 Li
92 74 132.1 60.5 n.a.

93 115 213.1 72.0 0.69
4.02.3.4 Ultraviolet Spectroscopy

In MeOH, 2-(1H-imidazol-2-yl)pyridine shows two p–p* bands at 272 and 292 nm. Upon complexation with Co2þ or
Ni2þ, these two bands show slight red shifts along with a new, weaker band around 340 nm (" 8000 dm3 mol1
cm1) <2005HCA487>. The UV-visible spectra of 94–98 (Figure 21) show broad and intense maxima (max) in the
range of 250–340 nm (log " > 4). Quaternization at the picoline ring 96, 97 generally led to bathochromic effects
relative to the neutral compounds 94, 95, in agreement with increased charge transfer. A hypo-hypsochromic shift was
observed from 96 ! 98, reflecting two opposing effects: charge transfer and deviation from planarity of the rings
around C(2)–C(29) <2003JHC129>.
166 Imidazoles
Figure 21
By analyzing the UV spectra of 4-(imidazol-1-yl)phenol complexed with b-cyclodextrin (CD) under different
conditions, it was concluded that the imidazole moiety was buried deep inside the cavity of CD <2004SAA2295>.
The 2-(2-pyridylmethylsulfinyl)benzimidazole structure present in proton pump inhibitors is responsible for acid-
activated formation of a reactive intermediate that is responsible for covalent binding to the cysteine 813 residue of
the pump. The effect of the pKa of either the imidazole or the pyridine moiety on the half-life of these inhibitors was
studied using pH-dependent UV spectroscopy <2004JA7800>. UV-Vis spectroscopy as well as X-ray crystallography
was employed to delineate the mechanism of the green fluorescent protein (GFP) chromophore formation
<2005B8303>. The hydride transfer reaction from 2-[furyl and thienyl]-1,3-dimethylbenzimidazoline derivatives
100 to pyridinium or isoquinolinium salts giving 99 (Figure 22) has been studied in i-PrOH–H2O (4:1) using UV
spectroscopy. The results were rationalized by the Marcus theory supporting the notion of a one-step hydride transfer
mechanism <1998JOC7275>.
Figure 22
Hydrolysis of 2,4,5-triphenyl-N-acylimidazoles, as followed by UV-Vis measurements, was found to proceed

through a concerted pathway that was accelerated by steric crowding around the N-acyl bond <1997JOC2872>.
The pKa values were determined based on the kinetic data of the hydrolysis of 5-methyl-3,5-diarylimidazolidine-2,4-
dione 101 yielding 102 <2005JHC899> (Scheme 20).
Scheme 20
Binding of metal ions Cu2þ and Zn2þ to calixarene containing fluorophore and imidazole ionophore causes opposite
responses to the fluorescence emission at 404 nm <2003TL4751>.
Imidazoles 167
4.02.3.5 IR Spectroscopy
Acetylation of (4R,5R)-1-aryl-5-hydroxy-4-(D-arabino-tetritol-1-yl)imidazolidinone-2-thiones 74 first gives the OAc
derivatives showing NH stretching at 3300 cm1 and then the NAc derivative, prepared by per-acetylation at 80 C,
showing an amide stretch at 1700 cm1 <1999T4377>. 4-Cyanoimidazolium-5-olate (103, Figure 23) can exist in
eight different tautomeric forms (three keto-, four enol-, and one enoate). The IR spectrum of this compound shows
CH and NH stretching in the 3200–2300 cm1 region. The absence of carbonyl stretching around 1700 cm1 and CO
stretching around 3400 cm1 suggests the mesoionic structure 103 <1997JOC7037>.
Figure 23
Triphenylimidazole on a Ag surface gives rise to Raman enhanced lines at 928, 1009, 1097, and 1380 cm1. The
first three bands were assigned to ring breathing of the imidazole ring oriented perpendicular to Ag <1999SAA2393>.
4.02.3.6 Mass Spectrometry

The farnesyl transfer inhibitor 104 (Scheme 21) undergoes a complicated rearrangement and fragmentation upon
collision-induced dissociation in the gas phase. An intramolecular SN2 reaction followed by fragmentations expels the
methylene–imidazole (m/z 81), and the m/z 326 fragment <2001JMP911>.
Scheme 21
Structures of both imidazol-2-ylidene 105 and imidazol-4-ylidene 106 (Scheme 22) were generated as the
corresponding ions 105?þ and 106?þ by neutralization–reionization (NR) and charge-stripping (CS) mass spectro-
metry from 2-formylimidazole and 4,5-bis(methoxycarbonyl)imidazole, respectively. Relative to imidazole, the
collision-induced dissociation (CID) mass spectrum of 105?þ shows an intense peak at m/z 42 that is attributed to
the loss of acetylene, thus supporting the 2-carbene ion structure. The CID spectra of 106?þ show a strong peak at
m/z 29 and a weak peak at m/z 16 <1997AGE1478>.
During photosensitized oxidation of N(1)–H, C(2)–H imidazoles with molecular oxygen, the formation of CO2 was
detected by GC-MS analyses of the reaction atmosphere <2002JA9629>.
Electron impact mass spectrometry studies of 1,3-di- and 1,2,3-tri-substituted imidazolines show ionization pre-
ferences depending on the substitution pattern (Scheme 23). Ions corresponding to R1Nþ were detected for all
substrates (path 2). In 2-substituted 1,3-diarylimidazolidines, loss of substituents at C-2 ([M-R]þ, path 3) is favored
over the loss of hydrogen (path 4). In 1,2,3-trisubstituted compounds, azirinium ions (c, path 4A) were abundant,
especially when R ¼ aryl. 2-Phenylimidazolidines fragment to the characteristic tropylium ion (C7H7þ, m/z 91).
1-Aryl-3-benzylimidazolidines readily lose a benzyl group as radical or cation ([M-benzyl]þ, path 1) <2000JHC57>.
168 Imidazoles
Scheme 22
Scheme 23
Imidazoles 169
N-Substituted 2-(2-bromophenyl)benzimidazoles form palladacycles by reaction with Pd(dba)2. These complexes

were characterized by mass spectrometry <2005TL661>. Cold spray ionization (CSI) mass spectrometry of tris(imi-
dazoline) 107 (Figure 24) and tris(oxazoline) 108 in dichloromethane indicated the formation of heterodimer
predominantly [m/z 614.0, (107þ108)þ] <2004T1339>.
Figure 24
4.02.3.7 Electron Spin Resonance

A series of 2-imidazoline nitroxides linked to a pyrazole either directly or through a phenylethynylic bridge show the
ESR characteristics of the 2-imidazoline nitroxide moiety. An unexpected strong temperature dependence of
magnetic moment eff(T) for solid 109 was discovered that agrees with the Bleaney–Bowers model for isolated
two-center exchange cluster with spin 1=2 (Figure 25). In single crystals of 109, packing by pairs of molecules was
observed although there were no intermolecular contacts within the range of 3 Å <1998MC216>. The ESR spectrum
of hydroxamic acid 110 showed a quintuplet with a high nitrogen coupling constant (aN ¼ 8.71 G) <2004T99>. Both
solid and solution ESR of nitronyl biradicals have been reported <1997JOC8854>.
Figure 25
2-(Nitrenophenyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole 3-oxide 1-oxyls (111 and 112, Figure 26), gener-

ated from the corresponding azido derivatives in frozen solution, show S ¼ 3/2 state ESR spectra with zero-field splitting
jD/hcj 0.277 cm1, jE/hcj 0.002 cm1 for 111 and jD/hcj 0.352 cm1, jE/hcj 0.006 cm1 for 112 <2004JOC5247>.
These results suggest that quinonoid delocalization in the case of 111 does not result in exchange of the nitreno radical.
Figure 26
170 Imidazoles
A series of 2-imidazoline-1-oxyl derivatives with the general structure A-Sp-R (A: charge acceptor, luminophor; Sp:
spacer; R: imidazoline) were studied in a three-spin system using optically detected magnetoresonance OD ESR and
level-crossing Mary spectroscopy. In the most favorable case 113, a spin triad with 100 ns lifetime was observed and
the exchange integral for the biradical anion derived from 113 was estimated to be 103 G <2004JA2807>.
Upon irradiation with a Xe lamp (100 W), the typical five-line spectrum characteristic of the nitronyl nitroxide
radical 114 (g ¼ 2.0066) was progressively transformed into a seven-line spectrum characteristic of an imino nitroxide
radical (Scheme 24). It was proposed that during the irradiation, selective deoxygenation of the radical 114 to the
radical 115 had occurred <2003S2145>.
Scheme 24
Copper(II) ions are involved in antiferromagnetic exchanges in the ESR of imidazole-bridged Cu(II)–Cu(II)
complexes with ethylenediamine <2005SAA1893, 2002SAA2961, 2000SAA2791>. The ESR spectra of 3-imidazoline
nitroxides show that the spin density localizes mostly at the NO fragment with a dominant triplet at N-1 with splitting
of 14.1 G (in toluene) <2006T4597>. pH-Dependent spin probes such as N,N-disubstituted 4-amino-2,2,5,5-
tetramethyl-3-imidazoline 1-oxyls with pKa values ranging from 3.5 to 6.2 have been reported <2005JOC9702>.
The peak-to-peak line width of the ESR spectra in the presence of paramagnetic broadening agent K3Fe(CN)6 was
used to determine the pKa values of carboxyl groups remote to the nitroxide moiety.
Bis-imidazole complexes of a series of Fe(III)-porphyrinates show EPR spectra with g values increasing as a function
of the dihedral angles between the axial imidazole ligands: ‘large gmax’ signals are observed (3.61–3.27) for nearly
perpendicular ligand plane arrangement <2003JA15986>. In the mixed-spin ferric heme cytochrome-c system, the
nitrogen ENDOR reveals larger hyperfine coupling to the histidine nitrogen and smaller hyperfine coupling to the
heme nitrogen than found in high-spin ferric heme systems <2005JA9485>.
4.02.3.8 Photoelectron Spectra

Mössbauer electronic structure studies of imidazole ligated iron(II) porphyrinates suggest that they form a distinctly
different set of electronic configurations than iron(II) porphyrinates with other axial ligands, as reflected in opposite
signs for zero-field splitting constant (D) and quadrupole splitting (Eq) <2005JA5675>.
4.02.3.9 CD Spectra
CD spectroscopy is useful in determining the absolute configuration of chiral imidazolines. In methanol, 116 shows a
positive Cotton effect, whereas 117 shows a negative Cotton effect at 370 nm (Figure 27) <1997T5359>.
Figure 27
Imidazoles 171
4.02.4 Thermodynamic Aspects

4.02.4.1 Intermolecular Forces
4.02.4.1.1 Melting points
It is well known that N-unsubstituted imidazoles have higher melting and boiling points than their N-substituted
analogues. The N-H group presented in N-unsubstituted imidazoles is able to form a strong hydrogen bond, resulting
in highly crystalline solids. Destroying the hydrogen-bonding network as in N-substituted imidazoles effectively
lowers the melting and boiling points. Thus, imidazole and 1-methylimidazole boil at 256 C and 199 C, respectively.
A dramatic decrease of the melting point (mp) is observed when 2-(4-methylpyridin-2-yl)-1H-benzimidazole 94
(mp ¼ 225–226 C ) <1977JHC937> is N-methylated to give 95 (mp 80–82 C) <2003JHC649>, due not only to the
removal of hydrogen bonding but also an altered conformation (Figure 28).
Figure 28
Room temperature (rt) ionic liquids are salts composed of large organic cations and a variety of anions, and usually
having a melting point at or below room temperature <1999CRV2071, 2000AGE3772, 2002CRV3667>. In particular,
1,3-dialkylimidazoliums have been widely used as cations in rt ionic liquids. The influence of structure variation in
these cations on the melting point has been extensively investigated <1999JCD2133, 2001GC156, 2001CC1466,
2000JA7264, 2004CEJ6581, 2005CC868>. Qualitatively, low symmetry, weak ion interactions, and effective charge
distribution over the cation and/or anion tend to reduce the crystal lattice energy of the salts, thus resulting in low-
melting salts <2004EJO6581>. Hence, the crystalline 1-n-butyl-3-methylimidazolium 3,5-dinitro-1,2,4-triazolate
(Figure 29), which contains an aromatic charge delocalized anion, that is, the nitro-substituted triazole, has a low
melting point of 35 C <2005CC868>.
Figure 29
4.02.4.1.2 Solubility
Imidazole derivatives generally have good solubility in protic solvents. Simple imidazole derivatives, such as 1H-
imidazole, 2-methyl-1H-imidazole, and 1,2-dimethylimidazole, have very high solubility in water. Their solubility in
alcohol is lower than that in water and decreases with increasing molecular weight of the alcohols <2002CED8>. The
solubility of imidazoles in ethers is lower than that in alcohols and decreases with increasing chain length of the ethers
<2003CED557>. In contrast, the solubility of benzimidazoles in alcohols (C3–C6) is higher than in water and
generally decreases with an increase of the alkyl chain length of the alcohols. The solubility of 2-methylbenzimid-
azole in alcohols (C3–C6) is higher than that of benzimidazole <2003CED951>. Both benzimidazole and 2-methyl-
benzimidazole have much higher solubility in octan-1-ol than in water <2002CED456>.
Simple imidazoles are much less soluble in nonpolar solvents. For example, 1H-imidazole, 2-methyl-1H-imidazole,
benzimidazole, 2-methylbenzimidazole, 2-phenylimidazole, 4,5-diphenylimidazole, and 2,4,5-triphenylimidazole
have very low solubility in chloroalkanes (dichloromethane, 1-chlorobutane), toluene and 2-nitrotoluene. Among
them, the solubility of phenylimidazoles is significantly lower than that of 1H-imidazole or benzimidazoles in all of
the solvents <2004CED1082>.
172 Imidazoles
Imidazolium-based ionic liquids are characteristically soluble in water <2005GC83>. For the ionic liquids contain-
ing butylmethylimidazolium as the cation, octanol–water partition coefficient (KOW ¼ concentration in octanol/con-
centration in water) values range from 0.003 to 11.1, depending on the choice of anion. The KOW values increase with
increasing alkyl chain length on the cation. Nonetheless, imidazolium-based ionic liquids are polar molecules and are
more soluble in low-molecular-weight alcohols. Thus, the solubility of 1-dodecyl-3-methylimidazolium chloride in
primary alcohols, such as ethanol, 1-butanol, 1-hexanol, 1-octanol, 1-decanol, and 1-dodecanol, decreases with the
increase in the molecular weight of the alcohol (C6 to C12) <2003PCB1858>.
4.02.4.1.3 Chromatography
Reverse-phase high-pressure liquid chromatography (RP-HPLC) has become a widely applicable method for
analyzing and purifying mixtures containing imidazole derivatives <1998JCH(716)239, 2003JME5445>. Moreover,
separation and analysis of racemic imidazole derivatives have been achieved using HPLC with chiral stationary
phases (CSPs) <2002JCH(942)107, 1997JCH(769)231, 1996JCH(729)1, 2003JME5445>. For example, HPLC with
chiral columns containing carbamate of cellulose and amylase was employed to analyze and separate a mixture
containing racemic becliconazole and its synthetic precursors 118, 119, and imidazole (Figure 30). The HPLC
method gives good performance from both qualitative and quantitative standpoints, allowing the enantiomeric ratio
of becliconazole and its impurities to be determined <1997JCH(769)231>.
Figure 30 Becliconazole and precursors to it.
4.02.4.2 Thermochemistry
4.02.4.2.1 Aromatic Stability
Aromatic stability, also referred to as ‘aromaticity’, is not a directly measurable quantity, but rather is generally
evaluated on the basis of energetic, geometric, and magnetic criteria <2003T1657, 1996JA6317>. Different aspects of
aromaticity, such as aromatic stabilization energies (ASE), resonance energies (RE), nucleus-independent chemical
shifts (NICS), magnetic susceptibility exaltation (), harmonic oscillator model of aromaticity (HOMA), etc., have
been fully reviewed <2001CRV1421, 2001CR1385, 2001CRV1115>. The absolute numerical values for these criteria
are not meaningful; instead, they are useful in comparable terms <2003T1657, 2002JOC1333, 1998JOC5228>. For
example, ASE, arguably the most used operational criterion, gives 25.2 kcal mol1 for imidazole in one calculation
<1998JOC5228>, while it is 16.18 kcal mol1 in another <2003T1657>. Nonetheless, under the same calculation
criteria, the ASE value can be used to evaluate the relative aromaticity of different ring system. Thus, ASE has been
calculated to be 25.2 kcal mol1 for imidazole, 26.7 kcal mol1 for benzene, 19.8 kcal mol1 for furan, and 25.5 kcal
mol1 for pyrrole <1998JOC5228>.
The aromatic stability of imidazolyl carbene has been evaluated according to thermodynamic, magnetic, and
structural criteria <1999ACR913, 2000CR39>. Theoretical calculations indicate that there is cyclic electron deloca-
lization in imidazole-2-ylidene 9 (Figure 1), although its aromatic character is less pronounced as compared to
benzene or the imidazolium cation <1996JA2091>. In fact, the computed aromatic stabilization energy for carbene 9
is comparable to that of furan and pyrrole <1996TL149>.
The aromaticity of 4H-imidazoles 120a–d and their derivatives has been investigated in detail (Scheme 25). The
electronic absorption of compounds 120a–d show bathochromic shifts of about 150 nm upon protonation, attributed
to transformation of the cyclic mero-polymethine-type chromophore in 4H-imidazoles 120 into the polymethinic
p-bond system of the iminium salt 121. The iminium salt 121 can also be regarded as an anti-aromatic 1,3-diazacyclo-
pentadienylium salt 1219. Based on nucleus-independent chemical shift (NICS) calculations, the structure of
compound 120 is considered to possess weak anti-aromatic bonding character <1997JPR729, 2000EJO1661>.
Imidazoles 173
Scheme 25
The weak anti-aromaticity character of compound 120 is also demonstrated in their single crystal structures. In the
crystal structures of compound 120a–c, the C–N bond lengths in the heterocyclic ring are in the range of 1.34–1.37 Å.
Interestingly, the C(4)–C(5) bond lengths in compounds 120a–d (1.493–1.511 Å) are considerably longer than typical
Csp2–Csp2 bonds found in conjugated systems (in imidazole, the length of Csp2–Csp2 is 1.358 Å). Theoretical calculations
[DFT RB3LYP/6-311þG** and ab initio G2(MP2)] predict a planar 5-aminoimidazol-4-imide parent structure, in
which the C–C bond of the 5-membered ring is exceedingly long (1.53 Å), in agreement with the X-ray data
<1997JPR735>.
Compounds 120 can also be oxidized regioselectively to afford aminonitrones 122. The X-ray structural analysis of
122 (Ar ¼ p-MeC6H4) shows an unexpected tautomeric fixation of the hydrogen atom and indicated that the
resonance structures 1229 and 1220 participate in the stabilization of the nitrone 122. Thus, compounds 122 are
unusually stable due to the contributions of anionic as well as cationic delocalized mesomeric structures (Scheme 26)
<2000JPR245, 1999H(51)763>.
Scheme 26
Aromaticity can be assessed by comparing the relative reactivities of imidazole derivatives and their analogues. For
example, the aromatic stability of imidazolone 123 has been evaluated by the rate of base-catalyzed deuterium
exchange and condensation with hexadeuteroacetone. Three compounds were used in both studies: 1-methyl-2-
phenyl-5(4H)-imidazolone 123, 2-phenyl-5(4H)-oxazolone 124 and 3,3-dimethyl-2-phenyl-4(3H)-pyrrolone 125
(Scheme 27). The order of the reactivity in these kinetic surveys was the same: 123 > 124 > 125. This result is
explicable on the basis of the stabilization of the derived anions (e.g., 1239) by aromaticity. The higher reactivity of
123 versus 124 would arise from the lower aromaticity of oxazole relative to imidazole. In addition, the N-Me 1H
NMR signal in the imidazolone 126 shows a discernible downfield shift of 0.1 ppm relative to the parent 123. This
deshielding seems to indicate the presence of a ring current in 126, most likely a consequence of its aromaticity
<2006TL5763>.
174 Imidazoles
Scheme 27
Imidazoles are generally considered to be electron-rich and stable aromatic compounds. However, with certain
substituents attached to the imidazole ring, aromatic stability may alter greatly. For example, during the reaction of 2-
(1-chloro-2,2-dimethylpropyl)-1-methyl-1H-imidazole hydrochloride 127 with excess of N,N-dimethylamine, an
addition product, 4,5-bis(N,N-dimethylamino)-1-methyl-2-(2,2-dimethylpropyl)-2-imidazoline 129, was obtained in
74% yield together with a normal SN2 product, 2-(1-N,N-dimethylamino-2,2-dimethylpropyl)-1-methyl-1H-imidazole
128 in 15% yield (Scheme 28). Compound 129 may result from a serial double nucleophilic addition of the secondary
amine to the imidazole nucleus, even though it is otherwise a stable aromatic ring structure <2000TL7503>.
Scheme 28
4.02.4.2.2 Other thermodynamic aspects

Accurate experimental enthalpies of formation of N-substituted imidazoles were measured using static bomb
combustion calorimetry, the ‘vacuum sublimation’ drop method, and the Knudsen-effusion method
<1999PCA9336>.
The enthalpies of combustion, heat capacities, enthalpies of sublimation, and enthalpies of formation of 2-tert-
butylbenzimidazole and 2-phenylimidazole have been reported and the experimental results compared with theore-
tical estimates of the enthalpies of formation, obtained in single-point calculations at the B3LYP/6-311þþG(d,p)
level on B3LYP/6-31G* optimized geometries <2006PCA2535>.
Crystalline imidazole (mp 361–364 K) fuses autogenously after making contact at room temperature with methanol
(mp 316 K) as a consequence of the hydrogen bond network alternation.
Conditions have been established to grow single crystals of ionic liquids, and the structures of several commercially
available low-melting ionic liquids have been determined <2005JA16792>.
Imidazoles 175
Thermodynamic properties of imidazolium-based ionic liquids, such as densities, heat capacities, and enthalpies of
fusion of [bmim] [PF6] and [bmim] [NTf2] have been determined and a critical analysis of the effect of impurities on
the measured thermodynamic properties has been carried out <2006CED1856>.
4.02.4.2.3 Conformations
Like fully conjugated imidazoles, some 2-imidazoline, hydantoin, and imidazolone ring structures adopt planar
conformations. Thus, 4,5-bis(4-hydroxy/methoxyphenyl)-2-imidazolines 130a–b have a symmetric planar ring in
spite of being formally asymmetric due to the typical amidine structure (Figure 31). In the 1H NMR spectra of
130a–b, only one set of signals for the aromatic protons and a singlet resonance of the benzylic protons are observed.
The same effect also shows in the 13C spectrum of 130b (MeO compound) with seven signals. Such spectra can only
be rationalized with a symmetric heterocyclic ring with partially sp2-hybridized nitrogens and a delocalization of the
proton between the nitrogen atoms <2002JME3356>.
Figure 31
X-Ray structural analysis of 3-alkyl-5-arylimidazolindinedione 131 indicates that the central hydantoin ring is
planar, with the N and C atoms adopting sp2 hybridization. Bond lengths within the ring are intermediate between
single and double bond, implying electronic delocalization in the system <2002JME1748> (Figure 32). Similarly,
the crystal structure of 4,4-diphenyl-5-imidazolone 132 revealed that the imidazole ring is planar (including also O-6
and H-1 and H-2) while the phenyl rings are almost mutually perpendicular. The double bond is localized between
C-2 and N-3, as shown in Figure 32 <1997JOC7037>.
Figure 32
A fully saturated imidazolidine usually adopts a nonplanar geometry. Semiempirical studies on 2-methyl-1,3-
dihydroxy-4,4,5,5-tetramethylimidazolidine 133 suggested that the imidazolidine ring assumes a half-chair
conformation, as shown in Figure 33. The calculated results are in agreement with the experimental observations
for 2-aryl-1,3-dihydroxy-4,4,5,5-tetramethylimidazolidines 134. Thus, the 1H NMR spectra of 134 indicated that the
two methyl groups are situated in magnetically distinct environments, which means the molecule has a nonplanar
conformation <1997T16911>.
X-Ray structural analysis of ethyl N-(5,5-diphenyl-4-oxo-2-imidazolidyl)glycinate 135 showed that the five-mem-
bered imidazolone ring has an open-envelope conformation with C-4 departing from the [N(3)–C(2)–N(1)–C(5)] plane
by 0.044 Å (Scheme 29). The deviation of the imidazolone ring from planarity is caused by the sp3 hybridization of C-5.
The guanidine fragment is flat and the p-electrons in this system are delocalized between all three C–N bonds. The two
N-hydrogens more likely reside on N-1 and N-6, as depicted in tautomer 135b (cf. Section 4.02.2) <1998JST(447)89>.
176 Imidazoles
Figure 33
Scheme 29
Interesting conformational features were discovered in 1-methyl-2-(4-methylpyridin-2-yl)-1H-benzimidazole 95,

two rotamers of which have the methyl group in a syn- or anti-configuration relative to g-picoline ring (Figure 34).
X-Ray analysis of compound 95 revealed that the benzimidazole ring, the g-picoline ring, and the methyl group lie on
a plane, thus allowing extensive electron delocalization in the molecule. Additionally, the X-ray data indicate the
existence of C–H N hydrogen bonds <2003JHC129>.
Figure 34
4.02.4.3 Tautomerism
4.02.4.3.1 Annular prototropic tautomerism
4,5-Disubstituted 1H-imidazoles are classic examples of prototropic annular tautomerism. Depending on the nature
of substituents, one tautomer may predominate over the other, as in the case of trifluoromethyl-substituted imidazole
50, where form 50A is the major component in solution in DMSO or CH3CN. In an unusual case, the two tautomers,
4-nitro-5-methoxyimidazole 136A and 5-nitro-4-methoxyimidazole 136B, were found as a 50:50 mixture in the
crystal structure (Scheme 30) <2004AXB191>.
Intramolecular hydrogen bonding can greatly influence the prototropic annular tautomerization. 4,29-Bi-imidazole
nucleosides can exist in four roto-tautomers due to the restricted rotation about the conjoining bond (Scheme 31).
With different R groups, one roto-tautomer may be favored over the other. Thus, for R ¼ CH2OH, roto-tautomer
137a dominates, while for R ¼ CH3, the 137a and 137d roto-tautomers are very close in energy, as indicated by both
experimental and computational (DFT at the B3LYP/6-31G(d,p) level of theory) results. The electronic influence on
N-39 by the R group affects the strength of the hydrogen bond and can thus have a marked influence on the overall
energy of the structure <2005JPO240>.
Imidazoles 177
Scheme 30
Scheme 31
The prototropic equilibrium of a series of benzimidazole derivatives 138 with intramolecular H-bonding potential has
also been investigated by NMR and IR techniques and theoretical methods. For example, tautomer 138-I, particularly
structure 138-IA is found to be more stable in amide analogues (R ¼ NH2), while tautomer 138-II is predominant for
esters (R ¼ OEt) (Scheme 32). The stability of tautomer 138-II over tautomer 138-I in esters could be attributed to
intramolecular hydrogen bonding between the NH of the benzimidazole ring and the carbonyl group <2001T6745>.
Scheme 32
178 Imidazoles
4-Cyanoimidazolium-5-olate 139 is a 5(4)-substituted imidazole-4(5)-one derivative and therefore can exist in eight
different tautomeric forms because of both annular and keto–enol tautomerism as shown in Scheme 33.
Spectroscopic studies (X-ray single crystal structure, NMR, IR) suggested mesoionic character (as exemplified in
139h and 139i) in solid-state and in solution (DMSO). The bond lengths indicated a p-delocalization in the ring
involving also the substituents, with values in keeping with those reported for imidazole <1997JOC7037>.
Scheme 33
4.02.4.3.2 Substituent prototropic tautomerism

Heteroatom-substituted imidazole derivatives have the opportunity to undergo ring-substituent prototropic tauto-
merization. For example, structural characterization of 1-mesityl-1,3-dihydroimidazole-2-selone by X-ray diffraction
and NMR spectroscopic methods demonstrated that the compound exists as the selone rather than the selenol
tautomer, a result that was confirmed by DFT calculations (Scheme 34). Specifically, the hydrogen atom attached to
nitrogen was located and refined in the X-ray diffraction. The C–Se bond length of 1.845 Å is intermediate between
the values predicted by the respective sum of the single- and double-bond covalent radii of carbon and selenium:
d(C–Se) ¼ 1.94 Å and d(CTSe) ¼ 1.74 Å. As such, the structural data are consistent with the notion that an important
resonance contributor is the zwitterionic form with a C–Se single covalent bond <2006JA12490>.
Scheme 34
Aminonitrone-N-hydroxyaminoimine tautomerism in 2-substituted 1-hydroxy-4,4,5,5-tetramethyl-4,5-dihydro-1H-

imidazole 140 is considered to be an acid–base equilibrium with the ratio between the forms dictated by the ratio of
their acidity constants. A substituent with a positive mesomeric and/or inductive effect stabilizes the nitrone form
140A more effectively than the N-hydroxyaminoimino form 140B (Scheme 35) <2004JST(697)49> .
Imidazoles 179
Scheme 35
In contrast, the tautomerization of benzimidazole N-oxide derivatives is greatly influenced by the hydrogen
bonding abilities of the N-hydroxy/N-oxide moiety through either intramolecular or intermolecular modes. Thus,
n-butyl-5-nitrobenzimidazole-2-carboxamide 3-oxide 141 in CHCl3 or DMSO is a mixture of tautomers, the N-oxide
being the predominant one. On the other hand, ethyl 5-nitrobenzimidazole-2-carboxylate 3-oxide 142 exists in the
solid phase as the N-hydroxy tautomer, unambiguously identified by an X-ray diffraction experiment. The tautomer
is stabilized by a strong and linear intermolecular hydrogen bond (O–H- - -N-39) <2004PCA11241> (Scheme 36).
Scheme 36
An acidic side-chain in imidazole derivatives produces a form in which the imidazole ring is protonated. This is
exemplified in (S)-2-hydroxy-3-(1H-imidazol-5-yl)propanoic acid hydrate 143, which has a fully extended lactic acid
side-chain oriented nearly perpendicular to the imidazole plane. The imidazole ring is protonated, and the carbox-
ylate group deprotonated, presenting a zwitterionic structure (Scheme 37) <1999AXC217>.
Scheme 37
Ring-substituent prototropic tautomerism is predicted to exist in 3-amino-1-(2-aminoimidazol-4-yl)-prop-1-ene

144. According to the calculations at the 6-316* level of theory, the conjugated CTC bond would migrate along the
side-chain, leading to four possible tautomers, as shown in Figure 35. The computed energy differences between the
four tautomers are relatively small (<1.40 kcal mol1), suggesting their possible coexistence <2004OL3933>.
180 Imidazoles
Figure 35 Tautomerism of 3-amino-1-(2-aminoimidazol-4-yl)-prop-1-ene.
4.02.4.3.3 Ring-chain isomerism

Ring–chain isomerism can be observed in some imidazolidine derivatives. This is the specific case of equilibrium
between an imine and an aminol. Substituent influence on this isomerization has been investigated by various
spectroscopic methods.
1
H NMR spectroscopic studies on N-substituted-2-arylimidazolidines 145 indicate that these molecules undergo
ring–chain transformation in CDCl3. The ratios of the open and ring-closed forms are influenced not only by the
electronic effect of the substituent X on the aryl group, but also by the substituent on the N atom of the imidazoline
ring. In addition, the ring–chain ratios are also influenced by the polarity and hydrogen-bonding abilities of the
solvent. Thus, 1-phenyl-imidazolines are preferred in CDCl3, while the corresponding open forms are preferred in d6-
DMSO (Scheme 38) <1998T13639>.
Scheme 38
In the related 1,2-diaryl-substituted imidazolidines 146, ring–chain mixtures are observed in CDCl3. Both 1- and
2-aryl groups exert significant electronic effects on the equilibrium. Generally, a more electron-donating substituent
Y (e.g., Y ¼ p-NMe2) on the N-aryl group and a more electron-withdrawing substituent (e.g., X ¼ p-NO2) on the C-aryl
group produce a higher ring/chain ratio (Scheme 39) <1999H(51)2431>.
Scheme 39
Ring–chain isomerism between 1-[alkylidene(or arylidene)amino]-2-aminoethanes and imidazolidines has been

investigated by NMR spectroscopic methods. Compounds 147 with R ¼ H; R1 ¼ Me, Et, n-Pr exist only in the cyclic
form 147B, whereas with R ¼ H; R1 ¼ Ph exist only in the linear form 147A. Both linear and cyclic forms are
detectable in solution when R ¼ Me; R1 ¼ Me, Et, n-Pr, and R ¼ H, R1 ¼ i-Pr (Scheme 40) <1998OPP109>.
Imidazoles 181
Scheme 40
Most imidazoline, imidazolone, and imidazole derivatives are stable ring structures and usually exist only in the
cyclic forms. For example, in the reaction of methyl 2-deoxy-2-isothiocyanato-a-D-glucopyranoside 149 with
D-glucosamine 148, a-deoxy-2-(3-substituted thioureido)-D-aldose, 150, is presumably the reaction intermediate.
However, the ring-chain tautomeric equilibrium of 150 shifts towards the cyclic form to yield 151 which is the only
detectable form by NMR analysis (Scheme 41) <1999TA3011>.
Scheme 41
Imidazole ring–chain equilibrium may be involved in some reaction intermediates, as in the ring contraction
reaction of 5-bromo-29-deoxyuridine to an imidazoline nucleoside (see also Section 4.02.10.3). During the reaction,
the b-anomer 152 is obtained as the major product in good yield (75–86%) with minor a-anomer 153 (6–11% yield).
The formation of a-anomer 153 is unusual, and is explained by a mechanism involving the attack of hydroxide ion on
C-5 of the b-anomer 152, as depicted in Scheme 42. This base-catalyzed ring–chain tautomerization is facilitated by
the presence of the electron-withdrawing group (4-carboxylate) on the imidazolinone ring. <2005T5081>.
Scheme 42
182 Imidazoles
4.02.5 Reactivity of the Fully Conjugated Rings

Reactivity of imidazoles was fully covered in CHEC(1984) and CHEC-II(1996). A number of reviews on the
chemistry of imidazole since the release of CHEC-II(1996) have summarized the recent progress <2006SL965>,
especially in the field of transition metal-catalyzed transformations <2006EJO3283, 2005T2245>.
4.02.5.1 Unimolecular Thermal and Photochemical Reactions

4.02.5.1.1 Fragmentation
Imidazoles are relatively stable thermally (CHEC(1984) and CHEC-II(1996)). However, fragmentation in mass
spectrometry has been reported (see also 4.02.3.6). Imidazole amidoxime 154 undergoes loss of hydroxylamine
followed by acetonitrile to give 2H-azirinium nitrile 156. Alternatively, imidazole amidoximes undergo loss of
ammonia to give rise to a nitrile oxide 157 which further loses formaldehyde and then hydrogen cyanide to give
the same final product, 2H-azirinium nitrile 156 (Scheme 43) <2006RCM1071>.
Scheme 43
Diazoimidazoles were reported to be light sensitive (CHEC-II(1996)). Stepwise controlled fragmentation photo-
lysis in carbon monoxide-doped argon matrices of 4-diazo-4H-imidazole was reported, and FT-IR characterization of
each fragmentation step in Scheme 44 was in accord with theoretical calculations [B3LYP/6-3111G(d,p)]
<2000EJO2535>.
4.02.5.1.2 Rearrangements
Photochemical rearrangements of imidazoles starting from photoaffinitive nitro-substituted imidazoles were thor-
oughly covered in CHEC-II(1996).
Under microwave irradiation, sceptrin in water rearranges to ageliferin in good yields (Scheme 45)
<2004AGE2674>. Retention of configuration is observed, which is in contrast to what is expected via a 1,3-
sigmatropic rearrangement. In fact, formation of [D2]-sceptrin 169 in CD3OD via microwave irradiation is a result
of tautomerization of the aminoimidazole ring. This suggests that tautomerization might also be the starting point for
the conversion of 167 into 168 in water via a tandem mechanism, although it is also possible that the cyclobutane ring
undergoes an ionic cleavage followed by tautomerization and closure of an open-chain system. Microwave irradiation
of 170, resulting only in 171, also suggested that the amino substitution at the 2-position of the imidazole might have
played a vital role in the rearrangement of 167 into 168. It is unlikely that this transformation involves a homolytic
cleavage mechanism.
Imidazoles 183
Scheme 44
Scheme 45
184 Imidazoles
4.02.5.2 Electrophilic Attack at Nitrogen

4.02.5.2.1 Introduction
The nature of electrophilic reactions at nitrogen in imidazole and benzimidazole was reviewed in CHEC(1984),
including the relative order of reactivity. The influence of substituents on the imidazole involves both electronic and
steric effetcs.
4.02.5.2.2 Proton acids: Basicity and acidity of imidazoles and benzimidazoles

The basicity of imidazole was thoroughly covered in CHEC(1984) and CHEC-II(1996). The ambivalent acid–base
properties of imidazole play an important role in the biochemical activity of the histidine unit.
Experimental gas-phase acidities of pyrrole and imidazole reveal that there is a free-energy exchange of
rxnG298 ¼ 9.3 0.6 kcal mol1 for deprotonation of imidazole by anionic pyrrole (Equation 1) <2005JPCA11504>.
ð1Þ
The acidity of the free NH group of imidazole and benzimidazole was reviewed in CHEC-II(1996) in great detail.
4.02.5.2.3 Metal ions

Coordination between imidazole and a transition metal was reviewed in CHEC(1984) and CHEC-II(1996).
Progress on the effect of exchange rates between free and metal-bound forms of the ligand on detection of
paramagnetic relaxation rate NMR studies of Cu(II) complexes with histidine-containing peptides has been reviewed
<2003MRC877>. These data can be used to determine the structure of the complexes (and thus the donor set to the
metal) and to distinguish between the binding of copper(II) to either N-1 or N-3 of the imidazole ring of histidine in
an effort to understand the effect of copper redox activity to its host proteins such as b-amyloid precursor protein and
prion protein, which are associated with Alzheimer’s disease and Creutzfeldt–Jakob disease, respectively.
N-Substituted 2-(2-bromophenyl)benzimidazoles form complexes with palladium (e.g., Figure 36). The palladium
complexes are used to catalyze Heck reactions to give coupled products in good yields <2005TL661>.
Figure 36
Also, due to coordination with metal, imidazole has been used as an anticorrosion agent for copper, iron, and zinc
<2001JMT(571)139>.
4.02.5.2.4 Alkyl halides and related compounds: Imidazoles without a free NH group
4.02.5.2.4(i) General
Quaternization of imdazoles with alkyl halides to form imidazolium ions was reviewed in detail in CHEC-II(1996).
During the past decade, a great deal of chemistry has been reported on the formation of imidazolium ions, with the
majority focusing on the utility of imidazolium ions. There are two major areas of chemistry that were, in large part,
Imidazoles 185
directly derived from imidazolium chemistry, namely N-heterocyclic carbene (NHC) chemistry (for reviews see
<1991AGE674, 1997AGE2162, 2004AGE5896>), and the chemistry of ionic liquids or room-temperature ionic
liquids (RTILs) <1999CRV2071, 2003ACSSS(856), 2004CCR2459, 2001AIJ2384, 2004AJC113, 2006CC1905,
2005ACSSS(902), 2006BCJ1665, 2006PCP2101, 2002CTO157>.
4.02.5.2.4(ii) Ionic liquids

Performing chemistry in an environmentally friendly manner, so-called ‘green chemistry’, has been increasingly
reported in the field of ionic liquids <2000PAC1391, 2002MI(819)10, 2002MI(818)90, 2002MI177, 2000PAC2275,
2002MI(818)2, 2003MI(856)2>. Quaternization of an imidazole was successfully performed in environmentally
benign supercritical CO2 as solvent <2005GC701>. Preparation of imidazolium-containing ionic liquids, in the
desired product ionic liquid as a solvent, is a virtually solvent-free, one-pot process proceeding in good to excellent
yields <2003S2626>. Microwave-assisted, solvent-free processes for the preparation of imidazolium-based ionic
liquids have been developed <2001CC643, 2003GC181>. Solvent-free preparation of 1-alkyl-3-methylimidazolium
halides was reported with ultrasonic agitation to facilitate the reaction <2002OL3161>. Using renewable feed stock
such as fructose 172 as a starting material for the synthesis of RTILs is an environmentally friendly alternative
(Scheme 46) <2003OL2513>.
Scheme 46
4.02.5.2.4(iii) Imidazolin-2-ylidene carbenes

Breslow first hypothesized the involvement of a thiazol-2-ylidene carbene in the catalytic cycle of vitamin B1
<1957CIL893>. The hypothesis was supported by deuterium exchange at the C-2 position of a thiazolium salt
<1957JA1762>. Imidazolidin-2-ylidene carbene 178 was first described by Wanzlick in 1960 (Figure 37)
<1960AG494>, prepared by deprotonation of the correspondent imidazolium salt. But the carbene was not isolated,
rather trapped with mercury <1970LA176>. The first isolation and characterization via X-ray analysis of 1,3-bis(1-
adamantyl)imidazolin-2-ylidene 176 was reported by Arduengo (Scheme 47) <1991JA361>.
Scheme 47
It is evident that the large sizes of the two adamantyl groups in 176 and the two mesityl groups in 178 provide
steric shielding which stabilizes carbenes 176 and 178. The isolation of tetramethyl-imidazolin-2-ylidene carbene
177 demonstrated the intrinsic electronic stability of imidazol-2-ylidene carbenes <1992JACS5523>. Carbene 179
was isolated and reported to be air stable, presumably due to the electron-withdrawing effects of the two chlorine
atoms (Figure 37) <1997JA12742>.
186 Imidazoles
Figure 37
4.02.5.2.5 Alkyl halides and related compounds: Imidazoles with a free NH group
The mechanism of alkylation of N-unsubstituted imidazoles and benzimidazole was discussed in CHEC(1984). Both
CHEC(1984) and CHEC-II(1996) had extensive reviews on the topic, which are still relevant. A summary of
improved Ullman coupling reactions is given in Table 9.
When K2CO3 was used as base in DME, trisubstituted imidazole 180 was alkylated by benzyl bromide 181 with a
2:1 ratio in favor of 182 (Scheme 48) <2003JOC5168>.
Scheme 48
It was believed that electrophilic attack by a bulky reagent such as tosyl or trityl halides led selectively to the least
hindered substitution products, such as 186 (Scheme 49) <2003H(60)1>. It was later found that the mixture of
Scheme 49
Imidazoles 187
products 189 and 190 from benzylation would convert to a single product 189 upon heating in DMF at 70 C. This is
interpreted as further benzylation of 190 followed by debenzylation of the bisalkylated product to form the less
sterically constrained 189 <2004TL5529>. This isomerization approach was generalized to a number of alkylating
reagents, such as MOMCl, SEMCl, BnCl, and MeI, to form exclusively 1,4-disubstituted imidazoles <2004TL5529>.
Simply heating compound 191 with imidazole 1 in dichloroethane gave product 193. It is believed that imidazole
trapped carbocation 192 (Scheme 50) <2000JOC7399>.
Scheme 50
4.02.5.2.6 Aryl halides and related compounds: Imidazoles with a free NH group
In the last decade or so, transition metal-mediated N–C bond formation has received great attention. A number of transition
metals have been utilized as catalysts in this transformation. These direct carbon-to-carbon, and carbon-to-heteroatom
bond-forming mechanisms have greatly simplified the synthesis of N-aryl imidazoles and N-aryl benzimidazoles.
4.02.5.2.6(i) Copper-catalyzed N-arylation of imidazoles and benzimidazoles

The century-old Ullmann reaction is usually carried out under rather harsh conditions. Classical Ullmann reactions use
stoichiometric amounts of copper metal to mediate the N-arylation of an amine. Due to its eco-friendly nature and low
cost, relative to most other transition metals, copper-catalyzed reactions have received great attention since 1995.
Buchwald and co-workers first reported the use of (CuOTf)2-benzene as catalyst, with addition of 1,10-phenanthroline
(Phen) 213 or dibenzylideneacetone (dba) 217 (Figure 38) as ligands, to facilitate the N-arylation of imidazoles or
benzimidazoles with aryl bromides or iodides (Scheme 51) <1999TL2657>. When substrates are not sterically hindered,
both bromo- and iodo-benzenes arylate imidazole and benzimidazole and give high yields, though bromobenzene
requires a higher temperature (125 C for aryl bromide vs. 110 C for aryl iodide). However, using a sterically hindered
aryl bromide or 2-methylimidazole as one of the coupling partners, the reaction yields go down from >90% to 62%.
It was suggested that the addition of 1,10-phenanthroline or dba as ligands to the copper salt creates a soluble, stable,
and more active copper catalyst species in situ, which in turn improves the turnover rate of the reaction and lowers the
activation barrier, in comparison to the classical Ullmann-type catalysis. Though only a catalytic amount of copper is
needed, a stoichiometric amount of 1,10-phenanthroline (relative to aryl halide) is required to provide efficient catalysis.
Later, it was reported by the same laboratory that racemic trans-1,2-cyclohexyldiamines 211 and 212 are effective
ligands (in catalytic amounts, i.e., 10% with respect to aryl halide) for the catalytic copper (1% CuI, with respect to aryl
halide) mediated N-arylation of cyclic and acyclic amides with aryl bromides and aryl iodides, and N-arylation of
nitrogen heterocycles, including imidazole, with aryl iodides <2001JA7727, 2004JOC5578>. This class of 1,2-diamines
211 and 215 was also reported to be able to assist copper in catalyzing arylation of imidazole even between sterically
hindered coupling partners, though yields were low (Scheme 52) <2005EJO1637>. Imidazole and benzimidazole were
arylated by arylboronic acids when catalyzed with the same catalyst system, the Chan–Evans–Lam protocol.
188 Imidazoles
Figure 38 Ligands for copper-mediated imidazole N-arylation.
Scheme 51
Imidazoles 189
Scheme 52
Salicylaldehyde Schiff bases and analogues were reported to form highly active copper catalysts with Cu2O for
Ullmann-type coupling reactions. Ligands such as salicylaldoxime 208 (Salox), salicylaldhydrazone 209, and pyr-
idine-carbaldehyde Schiff base 210 (Chxn-Py-Al) were very effective for N-arylation of imidazole and benzimidazole
<2004CEJ5607>. The catalysts are so active that copper-catalyzed arylation of imidazole with an aryl iodide can be
performed at 50 C when Salox 208 was used as ligand, giving a nearly quantitative yield. Aryl bromides were also
effective coupling partners when compound 209, which is commercially available, was used as the ligand at 80 C.
The difference in reactivity between an aryl bromide and an aryl iodide offers a control feature in designing a
synthetic route toward a particular desired target, such as 201 (Scheme 53) <2004CEJ5607>.
Scheme 53
Amino acids such as L-proline 218 and N,N-dimethylglycine 219 were very effective in assisting CuI-catalyzed
arylation of imidazole and benzimidazole by aryl bromides and aryl iodides <2005JOC5164>. Both electron-rich and
-poor aryl iodides coupled with imidazole in excellent yields, when catalyzed by CuI (10%, with respect to imidazole)
with L-proline 218 (20%, with respect to imidazole) as ligand, in the presence of K2CO3 (2 equiv) as base. This
catalyst system was also very effective in mediating the coupling between electron-poor aryl bromides (>90% yields
in most cases) and imidazole, while electron-rich aryl bromides gave lower yields, though still fairly good (80% yields
in most cases). However, N,N-dimethylglycine 219 worked well as a ligand in CuI-catalyzed arylation with electron-
rich aryl bromides of imidazole and benzimidazole. L-Proline 218 was also reported to promote copper(I) iodide-
catalyzed Ullmann type coupling between imidazole or benzimidazole and various alkenyl bromides to give
N-alkenyl imidazole and benzimidazole in ionic liquids as solvent <2005CC2849>.
Common bases of choice for Ullmann type reactions are K2CO3 and Cs2CO3 that are effective in most cases.
However, an organic-soluble base, tetramethylammonium carbonate (TEAC) was found to be more effective than
Cs2CO3 when 8-hydroxyquinoline 221 <2005JOC10135> was used with CuI for N-arylation of imidazole by aryl
bromides and iodides. Aryl bromides reacted efficiently with imidazole when CuI (10%) and 8-hydroxyquinoline 221
(10%) were used. The use of TEAC as base created a near homogeneous reaction system which was very effective in
forming the C–N bond between aryl halides and imidazole or benzimidazole. This catalyst system was also effective
in catalyzing the coupling between aryl chlorides and imidazole or benzimidazole, though in lower yields (40–50%).
Pyrrolidine-2-phosphonic acid phenyl monoester (PPAPM) 216a is readily accessible and is very effective as a
ligand in copper-mediated C–O, C–N, and C–P bond formation <2006CEJ3636>. Though both bromobenzene and
iodobenzene were effective in arylating imidazole, by controlling reaction temperature and time, selectivity was
achieved for iodobenzene over bromobenzene (Table 8).
190 Imidazoles
Table 8 N-Arylation of imidazole
Temperature ( C ) Time (h) Yield (%)
100 24 86
110 30 85
95 24 89
Under solvent-free conditions, imidazole and benzimidazole were efficiently arylated by aryl/heteroaryl chloride or
bromide, catalyzed by copper(I) bromide in the presence of 2-amino-4,6-dihydroxypyrimidine 220 as a ligand and TBAF
as a base <2006JOC8324>. Even sterically crowded 2-methylimidazole and 2-methylbenzimidazole were efficiently
arylated with high yields. However, arylation of 2-phenylimidazole with 2-chloropyrimidine gave only a trace of product
while arylation of 2-methylimidazole with the same aryl chloride afforded the product in quantitative yield.
When polyethyleneglycol (PEG) was used as co-solvent, 4,7-dimethoxy-1,10-phenanthroline 214 was found to be
effective in copper-catalyzed N-arylation of imidazole by aryl bromides or iodides <2006OL2779>. A critical part of
this catalytic system is the inclusion of PEG. It is believed that PEG acts as a phase transfer reagent, when Cs2CO3 is
used as base. Besides the much expanded scope in coupling partners, one major improvement of 4,7-dimethoxy-1,10-
phenanthroline over 1,10-phenanthroline <1999TL2657> is that only a catalytic amount of the ligand is needed, and
the reactions can be carried out at 80–120 C. A variety of sterically hindered imidazoles and aryl halides were coupled
in good to excellent yields. Intrinsic reactivity differences between aryl halides enabled coupling of aryl iodides
selectively in the presence of substrates containing bromine, chlorine, or fluorine. Imidazole was selectively arylated
in the presence of a free hydroxyl or an amino group.
Phosphoramidite 216b was reported as an effective ligand for copper to catalyze C–N bond formation in N-
arylation of imidazole or benzimidazole with aryl iodides <2006T4435>. The reaction could be carried out at 90 C
and produced moderate to high yields (65–90%).
Preformed, stable copper catalysts, such as aminoarenethiolate copper(I) are also effective catalysts for mediating
N-arylation of imidazole and benzimidazole (Figure 39) <2005OL5241>.
Figure 39 Aminoarenethiolate–Cu(I) complexes as active catalysts for Ullmann-type couplings.

Imidazoles 191
It was found that N-arylation reactions could be carried out in solventless conditions with all the six catalysts 222–
227. However, with the presence of a little NMP (1 ml at a 5 mmol scale), reaction yields were higher in all cases. In
the presence of NMP, the yields were 77–100%, wheareas for the neat case, the yields were 56–68% (Scheme 54).
Scheme 54
While the catalysts discussed above are all homogeneous systems, zeolite- and FAP-supported copper complexes
were developed as heterogeneous catalytic systems, and are also rather effective in catalyzing the N-arylation of
imidazole and benzimidazole <2006SL2195, 2006TL3897> with no additional organic ligands added. Other ligand-
less catalysts for Ullmann type reactions used CuO or Cu2O–Cu nanoparticles <2003OL4847, 2004CC778>. Not
only could the insoluble catalyst be easily removed via filtration after the reaction, it could also be recycled and
reused with ease. The catalytic efficacy remained high after three cycles. A protocol of ligandless and solventless
copper(I) bromide mediated N-arylation of imidazole and benzimidazole by aryl bromide or aryl iodide was reported
<2006JOC8324>.
4.02.5.3 Electrophilic Attack at Carbon

4.02.5.3.1 Reactivity and orientation
The reactivity and orientation displayed by imidazole and benzimidazole toward electrophilic attack at carbon were
reviewed in detail in CHEC(1984) and CHEC-II(1996).
4.02.5.3.2 Nitration
Most widely used protocols for nitration of imidazoles still use HNO3 in conc. H2SO4 <2003SC1977>; fuming HNO3
and conc. H2SO4 <1998JOC9448, 1998JHC607>; fuming HNO3, conc. H2SO4 with addition of Ac2O
<2004JOC8151>. Yields of nitration reactions are generally low to moderate. Mostly, nitration proceeds at C-4 of
an imidazole. However, a mixture of 4- and 5-nitroimidazoles was also observed with a near 1:1 ratio <1998JHC607>.
Though nitration of some imidazoles goes readily at ambient temperature, a trifluoromethyl substituent on the
imidazole ring has a profound deactivating influence. Nitration of compound 230 did not take place at 80 C; at
100 C, nitration did not stop at mono-nitro-derivative 231 – a mixture of mono- and dinitration products (with near
1:1 ratio) was formed. Thus, a nitro substituent at C-4 does not seem to be a strong deactivating factor, since
compound 231 could be completely converted into 232. On the other hand, nitration of 4-trifluoromethylimidazole
233 was much slower when compared with compound 230, taking 24 h to complete the reaction in 86% yield.
A methyl group at C-2 resulted in a substantial increase in reactivity: only 4 h were needed to complete the nitration
of 235 to 236 (Scheme 55) <1998JOC9448>.
Ozone-mediated nitration (Kyodai nitration) of imidazole under neutral condition gave poor yields of 4-nitroimi-
dazole. However, the yield improved dramatically with the addition of methanesulfonic acid. The combination NO2–
O3 is a much more reactive electrophilic reagent since a reaction temperature of 0 C was sufficient (Scheme 56),
<1996JCM244>. The 4-nitro product 238 could also be converted into 1,4-dinitroimidazole 239 over a long period.
4.02.5.3.3 Lithium–halogen exchange followed by electrophilic attack

The 2-chloroimidazole 240 undergoes chlorine–lithium exchange to give the 2-lithiated species which could then be
quenched by an electrophile: with benzyl chloroformate 241 the imidazole-2-carboester 242 was obtained
(Scheme 57) <2005BML1441>.
N-1-Protected 2,4,5-triiodoimidazole 243 was selectively lithiated at the 2-position via iodine–lithium exchange
(Scheme 58) (2005S136>. The lithiated species was then quenched by a number of aryl aldehydes 244 to give
unsymmetrical diarylmethyl alcohols 245 in high yields. The high yields of these reactions indicated that the iodine–
lithium exchange of this triiodoimidazole is efficient and selective.
Table 9 N-arylation/alkenylation of imidazole and benzimidazole via improved Ullmann-type coupling reactions
Substrates Halides
1 2 Ar/Vna X CuX Ligand Base Solvent Temp.( C) Time (h) Reference
þ Ar B(OH)2 Cu(OAc)2 DCM rt 24 1998TL2941

þ þ Ar B(OH)2 [Cu(OH) TMEDA]2Cl2 DCM rt 16 2000OL1233
þ Ar B(OH)2 CuCl, CuBr, CuI, CuCl2, MeOH Reflux 3–12 2004CC188
CuClO4, Cu(OAc)2, Cu(NO3)2
þ þ Ar B(OH)2, (BF3)Kþ CuI, Cu(OAc)2 211 and 216a Cs2CO3 DCM rt 48 2005EJO1637
þ þ Ar Pb(OAc)3 Cu(OAc)2 DCM-DMF 90–100 4–6 1992TL659
þ þ Ar Br, I (CuOTf)2-PhH 213 and 217 Cs2CO3 xylene 110–125 24–48 1999TL2657
þ þ Ar2 IþBF4 Cu(acac)2 K2CO3 DCM 50 6 2000SL1022
þ Ar Pb(OAc)3 Cu(OAc)2 DCM rt 3–14 2000OL3055
þ þ Ar I CuI 211 K3PO4 Dioxane 110 24 2001JA7727
þ Ar Br CuO K2CO3 DMSO 150 48 2003OL4847
þ þ Ar Cl Cu2O-Cu Cs2CO3 DMSO 150 18 2004CC778
þ Ar Br, I (CuOTf)2–TolH 213 and 217 Cs2CO3 DMF-xylene 115 48 2004BMCL1637
þ Ar Br, I Cu2O 208–210 Cs2CO3 MeCN 82 24–100 2004CEJ5607
þ þ Ar I CuI 212 and 213 Cs2CO3 Dioxane,DMF 110 24 2004JOC5578
þ Ar Br (CuOTf)2-TolH 213 and 217 Cs2CO3 xylene 110 71 2005JOC3997
þ þ Ar Br, I CuI 218 and 219 K2CO3 DMSO 60–110 34–65 2005JOC5164
þ þ Ar Cl, Br, I CuI 221 TEAC DMF 110–130 10–64 2005JOC10135
þ þ Ar Br, I CuI 211 and 216a Cs2CO3 DMF,dioxane 95–170 24–48 2005EJO1637
þ Ar B(OH)2 Cu(OAc)2 pyridine DCM rt 48 2005JME6632
þ þ Vn Br CuI 218 IL 90–110 20–36 2005CC2849
þ Ar Br CuSR* K2CO3 NMP, Neat 160 16 2005OL5241
þ Ar Br, I Cu2O 214 Cs2CO3 n-PrCN,NMP 80–120 3–48 2006OL2779
þ þ Ar Br CuI 213 KF/Al2O3 xylene 130–140 15–18 2006TL5203
þ Ar Br, I CuI 215 K3PO4 DMF 95–110 24–30 2006CEJ3636
þ þ Ar Br, I CuBr 216b Cs2CO3 DMF 95 24 2006T4435
þ Ar Br (CuOTf)2-PhH 213 and 217 Cs2CO3 Xylene 110 71 2006EJOC693
þ Ar Cl, Br, I Cu(II)-NaY K2CO3 DMF 120 20–48 2006SL2195
þ þ Ar Br, I CuFAP K2CO3 DMSO 110 2–15 2006TL3897
þ Vn Br CuI 210 Cs2CO3 MeCN 50 30 2006CEJ5301
þ þ Ar Br, Cl CuBr TBAF No 145–150 24 2006JOC8324
a
Ar ¼ aryl, heteroaryl; Vn ¼ vinyl.
Imidazoles 193
Scheme 55
Scheme 56
Scheme 57
194 Imidazoles
Scheme 58
4.02.5.3.4 Halogenation
Benzimidazole was iodinated at the 2-position to form a copper-benzimidazole complex 246 by treatment with CuI
and KI in aqueous ammonium hydroxide (Scheme 59) <2005CEO514>.
Scheme 59
Iodination of a benzimidazole was also achieved via treating a 1-alkylated benzimidazole with a strong base such as
LDA or alkyllithium at low temperature then quenching with 1,2-diiodoethane, or iodine <2003TL8967,
2003OL3209>. NBS brominates benzimidazole at the 2-position <1996H(43)1375>. Treatment of benzimidazole
with BuLi followed by quenching with carbon tetrabromide, carbon tetrachloride, or oxalyl chloride, gave
2-bromobenzimidazole or 2-chlorobenzimidazole, respectively <1999JOM(588)155, 2000JOM(601)233>.
Oxidative iodination was first reported for iodination of arylamines using iodine and urea hydrogen peroxide (UHP)
as an oxidant in moderate yields <2002MOL867>. A modified oxidative iodination with iodine and ortho-periodic
acid was found to be effective in iodination of imidazole at C-2 giving 247 in 72% yield <2005MOL401>; 5–8% of
another regioisomer was observed via NMR and TLC. It was proposed that iodine was oxidized by ortho-periodic
acid [I (VII)] to an Iþ species, which is capable of iodinating arenes, including imidazole (Scheme 60). It is worth
noting that the only by-product of this reaction is water.
Scheme 60
Imidazoles 195
Aromatic nucleophilic substitution (SNAR) of a haloimidazole or halobenzimidazole with an appropriate halogen

salt, that is, halogen exchange, is also a promising way of making halogenated imidazoles and benzimidazoles,
especially fluoro derivatives. The 2-bromoimidazole 248 was converted in good yield into 2-fluoroimidazole 249
by treating with spray-dried KF in the presence of a catalytic amount of 18-crown-6 in diglyme under reflux
(Scheme 61) <1996JOC6666>. Likewise, compound 248 was converted into 250 by treatment with CuCl in
diglyme under reflux in good yield. When LiCl was used as the chloride source, compound 250 was formed at
150 C and could be dealkylated to give 251 upon intense heating, with an overall yield of 72% from 248 to 251.
Scheme 61
Cesium fluoride in 18-crown-6 as solvent converted 2-chlorobenzimidazole 252 into 2-fluorobenzimidazole 253
quantitatively. The fluorine could then be displaced in situ by alkylamine 254 at room temperature with a good yield
<1999TL6875>. It was also found that a catalytic amount of cesium fluoride coupled with triethyleneglycol
monomethyl ether (TGME) was effective in promoting the amination of 252 with amine 254 to give 255 in high
yield (Scheme 62) <1999TL6875>.
Scheme 62
When treated with TBAF in DMF, 2-bromobenzimidazole was converted into 2-fluorobenzimidazole (24% yield)
<2001JBS417>. TBAF in DMSO was found to be very efficient in converting electron-deficient aryl and heteroaryl
chlorides, including 2-chlorobenzimidazole 252, into their fluoro analogues, even at room temperature, in high yields
(Scheme 63) <2006AGE2720>.
196 Imidazoles
Scheme 63
Sandmeyer reaction was effective in converting an aminoimidazole into a fluoroimidazole. Zinc reduction of
4-nitroimidazole 256 followed by treatment with aqueous NaNO2 in HBF4, in one-pot, gave 4-fluoroimidazole 257
(Scheme 64) <2006JOC5000>.
Scheme 64
Chlorination of imidazole and benzimidazole at C-2 has mainly been accomplished by deprotonation of an
imidazole or benzimidazole with BuLi or LDA followed by quenching with a perchloroalkane <2005H(65)2721,
2004JOC8115, 2004SL1306>. 2-Chlorobenzimidazole can also be obtained by chlorodehydration of benzimidazol-2-
one by heating in POCl3 <2006JME3719 and 2005BML719>.
Using N-chlorosuccinimide (NCS), 4,5-disubstituted imidazoles afford 2-chloro substituted imidazoles. However,
if other positions are available, chlorination goes preferentially at C-5 first, then C-4, and lastly, C-2. Selective
chlorination (or halogenation in general) at the 2-position can be achieved via deprotonation using LDA, at the
2-position, followed by quenching with NCS or NBS (Scheme 65) <2003JME3463>.
Scheme 65
Imidazoles 197
Under basic conditions, a 1,3-disubstituted imidazole 264 was selectively brominated with benzyltrimethylammo-
nium tribromide (BTMA Br3) in the presence of calcium carbonate to give the 5-bromoimidazole 265 in good yield
(Scheme 66) <2006JOC3159>.
Scheme 66
4-(1H-Imidazol-1-yl)benzenamine 266 was selectively brominated only on the phenyl ring with BTMA Br3 and Ca2CO3
(Scheme 67) <2003JOC10158>, though generally speaking imidazoles are much more electron-rich than benzenes.
Scheme 67
4.02.5.3.5 Friedel–Crafts type alkylation and acylation

Ordinarily, direct Friedel–Crafts alkylation and acylation do not take place on imidazoles due to deactivation of
imidazole ring after coordination to a Lewis acid catalyst (CHEC-II(1996)). Most alkylations and acylations of imidazoles
have been realized via quenching of an imidazole lithium derivative with a corresponding electrophile (CHEC-II(1996)).
However, the following are examples of direct electrophilic alkylation of imidazole. A two-step synthesis of marine
natural product ageladine A 271 started from the commercially available histamine 269 and the pyrrole-2-carbox-
aldehyde 268. The entire skeleton of the alkaloid was built in one step via a Pictet–Spengler type condensation. The
reaction was accelerated by Lewis acid scandium triflate, although the reaction did proceed without a catalyst but at a
slower pace (Scheme 68) <2006OL4083>.
Scheme 68
198 Imidazoles
Likewise, electrophilic condensation of an imidazole via a Mannich protocol occurred when an imidazole 272 was
aminomethylated at C-4 to give 275 in aqueous acetic acid at room temperature (Scheme 69) <2003MI132>.
Scheme 69
The synthesis of a cyclopentadienyl-annulated imidazolium salt 282 was accomplished through a Nazarov-type
cyclization as a key transformation. This annulation step was affected by toluenesulfonic acid via protonation–
dehydration of the tertiary allylic alcohol 278 to form a three-centered carbocation, which was then annulated, in
an electrophilic fashion, onto the C-4 position of the imidazole to form 279. The formation of the alcohol 278 was
achieved via lithiation of imidazole 276 and then quenching with ketone 277 to give the 1,2-addition product
(Scheme 70) <2005TL6847>.
Scheme 70
4.02.5.3.6 Diazo coupling

The coupling of diazotized p-aminoacetophenone (DPAAP) with imidazole forms the basis of the differential pulse
adsorption stripping voltammetry (DPASV) method for detection of histidine and its metabolites. The absorption of
azo-histidine was found to obey Frumkin absorption isotherm <1999TAL319>.
4.02.5.3.7 Silylation
Silylation at carbon can be achieved via quenching an imidazole anion with a silylating agent such as trimethylsilyl
chloride, as discussed in CHEC-II(1996).
4.02.5.3.8 Oxidation
The mechanism of the oxidation of imidazoles by singlet oxygen was studied via isotope-labeled imidazole deriva-
tives. Singlet oxygen reacts with 4,5-diphenylimidazole 283 via a [4þ2] cycloaddition to form a 2,5-endoperoxide
284. Upon warming, the 2,5-endoperoxide decomposed to form the hydroperoxide 285, which then decomposed via
two pathways (Scheme 71). The hydroperoxide 285 lost water to form 286, which was rehydrated to 287. In the
other pathway, the formation of carbon dioxide and benzyl diimine suggested that the oxidative decomposition went
through the following mechanism: the hydroperoxide 285 was deprotonated at C-2 followed by 1,2-shift then
protonation to form diol 289. The diol rearranged to amino-oxazolinone 291 by opening and reclosing the five-
membered ring. Amino-oxazolinone 291 decomposed to benzil diimine 292 and CO2 <2002JA9629>.
Imidazoles 199
Scheme 71
An NH in the imidazole is required for the decomposition of the initially formed endoperoxide. Otherwise the
endoperoxide decomposes back to starting material. The endoperoxide product 294 from N-methylimidazole 293
was stable up to 28 C. However, it only decomposed to give back starting material 293 upon warming. On the other
hand, 2,5-endoperoxide 296 of 2,4,5-triphenylimidazole gave rise to hydroperoxide 297, which was rearranged to 4,5-
endoperoxide 298. The latter converted to diacylamidine 299 (Scheme 72), <2002JA9629>.
Scheme 72
200 Imidazoles
Oxidative rearrangements of tetrahydrobenzimidazoles 300–304 on treatment with dimethyldioxirane (DMDO)

provided spiro-5-imidazolones 305–311 selectively in good yields. Moderate to excellent stereoselectivity was
achieved via preferential oxidation at the less sterically hindered face (Scheme 73) <2004OL735>.
Scheme 73
One of the notable features of this rearrangement is the exclusive formation of 5-imidazolones 315 rather than the
isomeric 4-imidazolones (Scheme 74). These results were attributed to two causes. Sterically, the 5-imidazolone
is less crowded than the isomeric 4-imidazolone since the spirocyclopentyl ring is further away from the
Imidazoles 201
N-1-substituent. Second, the carbocation 314 (or electron-deficient carbon) leading to the 5-imidazolone is more
stabilized than the corresponding carbocation which would lead to the 4-imidazolone.
Scheme 74
However, from substrate tetrahydrobenzimidazol-2-carbamates 316a and 316b, no spiro rearrangement products
were observed. Instead, diols 317a and 317b were found to be major products, along with oxidative coupling products
318a and 318b. Less sterically congested methyl carbamate gave much better conversion than its t-butyl counterpart.
Davis’ reagent (N-sulfonyloxaziridine), on the other hand, was also able to bring about oxidative rearrangement of
tetrahydrobenzimidazole 319 to spiro-5-imidazolone 320 in good yield (Scheme 75) <2006SL965>.
Scheme 75
4.02.5.4 Nucleophilic Attack at Carbon

4.02.5.4.1 Hydroxide and O-nucleophiles
4.02.5.4.1(i) Neutral imidazoles
Cyclocondensation of 2-halobenzimidazole 322 (or 2-haloimidazoles) with 2-hydroxybenzyl alcohol 321 in the melt
gave 85-91% of 2H-benzimidazo[2,1-b][1,3]benzoxazine 323 (Scheme 76) <2005CHE1201>.
Hydrazonoyl halide 325 reacted with 2-methylthiobenzimidazole 324 to furnish benzimidazo[1,2-d]-1,2,4-oxadi-
azole derivative 326 (Scheme 77) <2004HAC432>. This reaction proceeded in a [2þ3] fashion.
202 Imidazoles
Scheme 76
Scheme 77
4.02.5.4.1(ii) Acidity of C-2 hydrogen of imidazolium cation

Position C-2 of an imidazole is usually electrophilic. However, a 1,3-disubstituted imidazolium cation can easily be
deprotonated at C-2, thus converting the carbon atom into a nucleophilic centre (Scheme 78). Sodium hydride
deprotonates 1,3-dimesitylimidazolium chloride; quenching with an electrophile such as isobutyl chloroformate then
formed imidazolium-2-carboester 328 in good yield <2005JA17624>. Dimethyl carbonate N-methylated 1-methyl-
imidazole, then an electrophilic substitution at C-2 gave imidazolium-2-carboxylate 331 (Scheme 78)
<2005JA17624>.
Scheme 78
Imidazoles 203
4.02.5.5 Nucleophilic Attack at Hydrogen

4.02.5.5.1 Metallation at a ring carbon atom
N-Methylimidazole was converted into the 2-lithio-imidazole upon treatment with a stoichiometric amount of lithium
in the presence of isoprene as catalyst (20 mol%) in THF at room temperature with near quantitative yield
<2005T11148>. The same lithioimidazole was obtained in high yield when butyllithium <2005H(66)263> or
methyllithium <2002EJI2015> were used as lithiating reagents (Schemes 79 and 80).
Scheme 79
Scheme 80
Lithiated imidazoles are good nucleophiles and can easily be converted into other species by treatment with an
appropriate electrophile. For example N-methylimidazole was converted into 332. Sec-butyllithium was then used to
deprotonate at the 5-position for reaction with 333 leading to 334. Removal of the silyl group followed by installation
of the second alkyl group at C-2, using n-butyllithium and 336, then gave the 1,2,5-trisubstituted imidazole 337
(Scheme 80) <2005H(66)263>.
4.02.5.5.2 Nitrogen carbanion and SRN1 reactions

Direct C–C bond formation at the 2-position of imidazole and benzimidazole was reported when imidazole was
deprotonated with potassium t-butoxide in liquid ammonia via electrochemically induced SRN1. Coupling products
340 and 341 were isolated in a 4:1 ratio when the reaction started from 4-methylimidazole 338. Only one product 343
was obtained when 2-methylimidazole was used. It was proposed that delocalization of the negative charge of 345
resulted in some carbanion character (resonance contributors 346–348), and thus subsequent SRN1 reaction with an
electron deficient aryl chloride at carbon (Scheme 81) <1995JOC8015>.
204 Imidazoles
Scheme 81
4.02.5.5.3 C-Acylation via deprotonation

Direct acylation of N-protected imidazole involves formation of an N-acyl azolium salt, which is then deprotonated
at C-2 followed by rearrangement of the acylazolium ylide to the 2-acylated imidazole (for mechanism and a
number of applications, see CHEC-II(1996)). An example is shown in Scheme 82: N-acylation of imidazole 350
followed by 2-deprotonation of the azolium cation, then migration of the acyl group to C-2 gives product 351
<2005JME2154>.
Scheme 82
4.02.5.5.4 Transition metal catalyzed coupling reactions

4.02.5.5.4(i) Palladium mediated coupling of N-protected imidazole halides
4.02.5.5.4(i)(a) Heck coupling
Few Heck couplings were reported associated with halogenated imidazoles. Multisubstituted 4-iodoimidazoles
<2003TL7115, 2004TL1869> and 4-bromoimidazole <2004SPH15> were cross-coupled with methyl acrylate in
high yields catalyzed by Pd(OAc)2 with PPh3 in the presence of TEA in DMF. Iodoimidazole 352 was cross-coupled
with methyl acrylate to give product 353 under the usual Heck conditions in high yield (Scheme 83)
<2003HCA3482>. This iodoimidazole was also cross-coupled with styrene under similar conditions.
Imidazoles 205
Scheme 83
4.02.5.5.4(i)(b) Stille coupling

Imidazole-2-stannanes reacted with substituted bromobenzene in the presence of PdCl2(PPh3)2 in good yields
<1996TL7611>. Imidazole-2-stannane 354 was cross-coupled with alkenyl bromide 355 (Scheme 84)
<2005HCA707>. However, under the same coupling conditions, imidazole-2-stannane 354 with alkenyl iodide
357 resulted in a poor yield. It was also noted that an E-configured coupling product 359 resulted from a Z-configured
alkenyl bromide 358.
Scheme 84
Arylstannanes reacted with 2-iodoimidazole under Stille conditions gave rise to cross-coupled products. The
imidazole modified tetrathiafulvalene 362, synthesized via Stille coupling, formed a charge transfer complex with
chloranil, which displayed metal like conductivity for the first time in a purely organic material (Scheme 85)
<2004AGE6343>.
Scheme 85
The 5-bromoimidazole 363 cross-coupled with an allylstannane 364 with Pd(0) as the catalyst to give allylated
product 365 in good yield (Scheme 86) <2006JOC3159>.
206 Imidazoles
Scheme 86
Sometimes, the role of the coupling partner is important for the success of a coupling reaction. Imidazole stannane
367 reacted with iodoimidazolopyridine 366 under the common Stille conditions to give product 368 in good yields.
However, under the same conditions, iodoimidazole 370 and stannane 369 only produced traces of the desired
product 368 (Scheme 87) <2003HCA3461>.
Scheme 87
4.02.5.5.4(i)(c) Negishi coupling

Imidazole zinc reagent 372 was made from 2-iodoimidazole 371 with activated zinc dust. The organozinc reagent was
cross-coupled with aryl iodides and alkenyl iodides, in good yields (Scheme 88), <1997T7237>.
Scheme 88
Imidazole zinc reagent 376 was made via transmetallation of the 2-lithioimidazole with zinc chloride. This zinc
reagent underwent Negishi cross-coupling with pyridinone triflate 377 to give the highly substituted pyridinone 378
in 51% yield (Scheme 89) <1999TL4069>.
4.02.5.5.4(i)(d) Sonogashira coupling

2-Iodoimidazole 371 coupled efficiently with TMS-acetylene 379 to produce 2-alkynyl-imidazole 380 in the
presence of CuI and PdCl2(PPh3)2 at only 35 C (Scheme 90) <2006JA4119>.
Imidazoles 207
Scheme 89
Scheme 90
When 2-iodoimidazole 381 was treated with 382 bearing both a terminal alkene and a terminal alkyne, in the
presence of copper and palladium as catalysts, only the Sonogashira product was obtained in high yield (Scheme 91)
<2006T3798>.
Scheme 91
Iodination of 384 via a Sandmeyer reaction followed by palladium-catalyzed cross-coupling with TMS acetylene
and subsequent in situ treatment with ammonia in methanol in a sealed tube furnished the annulation product 387
(Scheme 92) <2006JA4453>.
208 Imidazoles
Scheme 92
4.02.5.5.4(i)(e) Suzuki coupling

Aryl boronic ester 389 was cross-coupled with 2-iodobenzimidazole 388 under Suzuki conditions to give 2-arylbenz-
imidazole 390 in good yield (Scheme 93) <2003TL8967>.
Scheme 93
1-Substituted-2-iodoimidazole 391 also coupled with an arylboronic acid 392 under conventional Suzuki condi-
tions forming 393 (Scheme 94) <2005H(65)2721>.
Scheme 94
Imidazoles 209
N-1-Substituted iodoimidazoles behave normally with arylboronic acids to give cross-coupled products
<2005T6056>. N-1-Substituted-2-bromoimidazoles also coupled efficiently with aryl boronic acids and alkenyl
boronic acids to give cross-coupled products in high yields (Scheme 95) <2004JOC8829>.
Scheme 95
4.02.5.5.4(i)(f) Copper-mediated cross-coupling of iodoimidazoles with allzylzinc reagents

The iodocarboxamide 397 with CuBr cross-coupled with the zinc reagent BrZnCF2CO2Et, cyclization occurred
in situ to give the tetracyclic product 399 (Scheme 96) <2005JOC4897>.
Scheme 96
4.02.5.5.4(i)(g) Palladium-mediated aminocarbonylation

The disubstituted imidazole 400 was brominated to give 5-bromoimidazole 401, which underwent direct aminocar-
bonylation in the presence of palladium acetate and 1,3-bis(diphenylphosphino)propane (1,3-DPPP) to give carbox-
amide 402, a selective H1 antagonist as a potential treatment for allergy (Scheme 97) <2005JME2154>.
Scheme 97
4.02.5.5.4(ii) Palladium-mediated coupling of 2-H-imidazole or 2-H-benzimidazole with aryl halides

It was reported for the first time that direct palladium-catalyzed C–C bond formation could be achieved between
azoles (including N-methylimidazole) and an aryl halide. Palladium-catalyzed cross-coupling with selectivity for the
more electron-rich C-5 position, gave monoarylated product 403. When C-5 was already arylated, then C-2 was
preferred for arylation to give 404. However, when only CuI was used in a stoichiometric amount to mediate the
reaction, the cross-coupling reaction went specifically at the 2-position to give 405, although the yield was poor.
When both palladium and copper were used, a mixture of 2-phenylimidazole and 2,5-diphenylimidazole were
obtained in a nearly 1:1 ratio. N-Methylbenzimidazole 407 was arylated by various aryl iodides at the 2-position
when catalyzed by copper(I) iodide to give excellent yields (Scheme 98) <1998BCJ467>.
210 Imidazoles
Scheme 98
1-Methylimidazole was arylated only once with solid phase bound (chloromethyl polystyrene as solid phase
precursor) aryl iodide 409. Depending on the choice of catalyst, 1-methylimidazole coupled with solid phase
bound aryl iodide in 67% yield at the 5-position when Pd(OAc)2 and PPh3 were used as the catalyst system.
However, when CuI was added to the above catalyst system, the only product isolated was the 2-arylated imidazole
411 in 49% yield. No diarylation product was found using either reaction system (Scheme 99) <2000OL3111>.
Scheme 99
Imidazoles 211
1-Hydroxylimidazole, bound to a Wang resin under Mitsunobu conditions, was selectively lithiated at the 2-
position by butyllithium at 50 C and then transmetallated with zinc chloride to give resin bond imidazolylzinc
chloride. This resin bound imidazolylzinc reagent was cross-coupled with aryl iodides under palladium catalysis to
give 2-arylimidazoles (upon cleavage from resin) in moderate yields <2001S909>. When catalyzed by copper,
imidazole itself was arylated at N-1 to give 413, a structure confirmed by X-ray crystallography. A second copper-
mediated cross-coupling could then be achieved at the 2-position to give 1,2-diarylimidazole 415 (Scheme 100)
<2002JME1697>.
Scheme 100
Rhodium-catalyzed C-2 arylation of benzimidazole and a number of other azoles with aryl iodides was reported
<2004OL35>. Scheme 101 shows the reaction and its proposed mechanism. Benzimidazoles can undergo cross-
coupling with aryl halides, though most efficiently aryl iodides, when catalyzed by a rhodium catalyst in the presence
of tricyclohexylphosphine with moderate yields. It is believed that the reaction proceeds through an N-heterocyclic
carbene (NHC) intermediate <2002JA3202>. A number of other coupling partners, including phenylboronic acid,
phenyltrimethylstannane, and phenyl triflate, were investigated as well. Only phenylboronic acid gave 10% conver-
sion in cross-coupled products; the other potential coupling partners did not react at all <2004OL35>.
4.02.5.6 Reactions with Radicals and Electron-Deficient Species

4.02.5.6.1 Carbenes
Diazafulvene 424 reacts with alkenylcarbenes 425 through a formal [6þ3] heterocyclization in a regio- and stereo-
selective manner to afford dihydroimidazo[1,2-a]pyridines 426. When enyne carbenes are treated with diazafulvene
424, consecutive and diastereoselective [6þ2]/cyclopentannulation cyclization reactions take place affording new
polycyclic complex systems 429 that can be appropriately demetallated to the corresponding imidazole-based fused
systems. Finally, enyne carbenes undergo consecutive [6þ2]/[5þ1] cyclization reactions with diazafulvene 424 and
tert-butyl-NC to yield tetracyclic adducts 432 (Scheme 102) <2006CEJ3201>.
4.02.5.6.2 Free-radical attack at ring carbon atoms

Imidazoles normally undergo free-radical reactions at the 2-position. For example, homolytic free-radical alkylation of
histidines and histamines yields 2,3-disubstituted histidines and histamines. In these reactions, the free radical was
generated via silver-catalyzed oxidative decarboxylation of acids with peroxydisulfate 433 (Scheme 103)
<2001BML1133>.
The imidazol-5-yl radical 437, on the other hand, has been generated from 5-bromo-1,2-dimethylimidazole 436
using Bu3SnH and an azo-initiator such as AIBN or 1,19-azobis(cyclohexanecarbonitrile) (ACN). The addition of the
212 Imidazoles
Scheme 101
imidazol-5-yl radical onto aromatic rings becomes a favorable process by keeping the concentration of Bu3SnH low
during the course of the reaction. Thus, 5-arylimidazoles 439 and 440 are obtained from the nonchain reaction of
imidazol-5-yl radical 436 with benzene. The reaction of 437 with 2,6-lutidine leads to the exclusive isolation of the
3-substituted isomer 441 in 35% yield (Scheme 104) <2004T8065>.
Intramolecular imidazole free-radical reactions usually afford good to excellent yields and have been used to
synthesize cyclic imidazole derivatives. For example, imidazoles and benzimidazoles undergo intramolecular radical
cyclization to give [1,2-a] fused derivatives. In the intramolecular homolytic substitution, N-(o-alkyl) radicals are
generated using Bu3SnH from N-(o-phenylselanyl)alkyl side-chains. Phenylselanyl groups are used as radical leaving
groups to avoid problems of N-alkylation (Scheme 105) <1999T4109>.
Imidazoles 213
Scheme 102
Scheme 103
Xanthate 446 undergoes cyclization in the presence of camphorsulfonic acid via a radical chain reaction initiated by
a small amount of lauroyl peroxide to give pyrroloimidazoles 449 in 56% yield. The use of an acid and anhydrous
medium inhibits nucleophilic attack of the basic heterocycles at the xanthate moiety and allows radical reactions to
occur. Fused heteroaromatic compounds can also be prepared directly from benzimidazole carrying an N-alkenyl
substituent and xanthates by a tandem radical addition/cyclization to provide, for example, pyrrolobenzimidazole 453
in 57% yield (Scheme 106) <2002OL4345>.
Cyclization reactions of allylic b-imidazolinonyl-b-ketoesters 454, 456 were carried out in a Mn(III)-promoted
radical cascade. The reaction pathway (5-exo/6-endo or 5-exo/5-exo) can be directed to construct the cyclohexenyl 455
and central cyclopentyl 457 core skeletons with regioselectivity. In the cyclization, two C–C bonds and three or four
contiguous stereogenic centers are established in one step, as shown in products 462 and 464. A plausible mechanism
is depicted in Scheme 107 <2006AGE4345>.
The use of the Sonogashira reaction for cross-coupling between 1-iodo-2-(phenylethynyl)benzene 465 and 1-(2-
propynyl)-1H-imidazole 466 followed by treatment of the resulting adduct with KO-t-Bu gives an indeno-fused
imidazo[1,2-a]pyridine 468 in 98% yield. Presumably the reaction proceeded through a 1,3-prototropic rearrangement
to form benzannulated enyne-allenes, which then undergo either a concerted Diels–Alder reaction or a two-step
process involving a Schmittel cyclization reaction to form a biradical followed by an intramolecular radical–radical
coupling and prototropic rearrangement (Scheme 108) <2005JOC6647>.
214 Imidazoles
Scheme 104
Scheme 105
4.02.5.6.3 Electrochemical reactions and reactions with free electrons

Indirect electrochemical reduction of perfluoroalkyl halides, by means of an aromatic anion mediator, in the presence of
imidazole derivatives yields the corresponding C-perfluoroalkylated imidazole analogues by an SRN1 mechanism. The
reaction is triggered by dissociative electron transfer and, therefore, does not involving the intermediacy of the anion
radical of the substrate. Some fluoro arenes, such as 1-iodo-2-(trifluoromethyl)benzene, also react with imidazole-
derived ions to give the corresponding 4-(fluorinated-aryl) imidazole analogues (Scheme 109) <1996JOC1331>.
Imidazoles 215
Scheme 106
Regioselective Michael addition of imidazole to levoglucosenone 475 is effectively catalyzed by cathodic electro-
lysis. The electrochemical conditions are milder and provide higher yields as compared to the base-catalyzed
reactions (Scheme 110) <1996JOC8786>.
The reversibility of the two-electron reduction of tetraazafulvalenes 478 has been confirmed by employing
cyclovoltammetric measurements, although attempts to oxidize these systems electrochemically or by chemical
oxidizing agents failed. On the other hand, treatment of the systems 481 with sodium dithionite provided a new
entry to quinomethides 482, which represents the SEM form of this four-step redox system and thus can finally be
reduced to yield the tetraamino-substituted bisimidazoles 483 (Scheme 111) <2006T8586>.
4.02.5.6.4 Catalytic hydrogenation and reduction by dissolving metals

Naphthalene-catalyzed lithiation of 1,3-dimethyl-2-phenylimidazolidine leads to cleavage of the benzylic carbon–
nitrogen bond, with formation of an intermediate dianion. The dianion could be trapped with several electrophiles,
including primary and secondary alkyl halides, as well as enolizable and nonenolizable carbonyl derivatives, affording
diamines 485 in satisfactory yields (Scheme 112) <2005T3177>.
216 Imidazoles
Scheme 107
4.02.5.7 Reactions with Cyclic Transition States

4.02.5.7.1 Diels–Alder reactions and 1,3-dipolar additions
Imidazoles are electron-rich heterocycless and can undergo inverse electron demand Diels–Alder reactions.
Particularly, amino-substituted imidazoles are good dienophiles and cyclize with electron-poor counterparts to
provide cycloadducts. For example, intermolecular cycloadditions of 2-substituted imidazole 486 with various
Imidazoles 217
Scheme 108
Scheme 109
Scheme 110
218 Imidazoles
Scheme 111
Scheme 112
1,2,4-triazines 487 produces both imidazo[4,5-c]pyridines (3-deazapurines) 490 and pyrido[3,2-d]pyrimidin-4-ones (8-
deazapteridines) 491. The product distribution was controlled by reactant substituents and influenced by reaction
temperature <2003JOC4345, 1997TL7495>. Reaction of 2-substituted imidazole 492 with 1,2,4,5-tetrazine-3,6-
dicarboxylate 493 produces imidazo[4,5-d]pyridazine 494 in good yield, even at low reaction temperature
(Scheme 113) <2001T5497>.
Reaction of 5-amino-1-benzyl-4-imidazolecarboxylic acid 495 with 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine 496 at 80 C
in DMF led to 9-benzyl-2,6-bis(ethoxycarbonyl)purine 501 in 83% yield. Presumably, 5-amino-1-benzyl-4-imidazole 497
is generated in situ from the acid and is highly reactive for the cycloaddition. The cycloadduct 498 then spontaneously
undergoes retro Diels–Alder reaction with the loss of ethyl cyanoformate 499 followed by the loss of ammonia and
aromatization to produce the purine in a regioselective manner (Scheme 114) <1999JA5833, 2005JOC998>.
Imidazole and 2-phenylimidazole undergo intramolecular Diels–Alder reaction with 1,2,4-triazines tethered
between an imidazole nitrogen and the triazinyl C-3 position to produce tetrahydro-1,5-naphthyridines. The reaction
proceeds by a cycloaddition with subsequent loss of N2, followed by a presumed stepwise loss of a nitrile. Addition of
antioxidant BHT inhibits aromatization to greatly improve the yield of tetrahydronaphthyridine 504 (Scheme 115)
<2004JOC7171, 1997TL7499>.
Vinylimidazoles participate in Diels–Alder reactions with a wide variety of dienophiles <2006SL965>. Thus,
cycloadduct 508 is obtained at room temperature on reaction of compound 506 with N-phenylmaleimide 507 in 91%
yield. A similar reaction occurs between natural product oroidin 509 and maleimide 510 to give cycloadduct 512 with
catalysis by Y(OTf)3 511 (Scheme 116) <2006OL819>.
Homonuclear Diels–Alder dimerization of various 5-ethenyl-2-phenylsulfanyl-1H-imidazole 513 provides a novel
highly regio- and stereoselective route to the preparation of multifunctionalized 4,5,6,7-tetrahydrobenzimidazoles,
514/515 as illustrated in Scheme 117 <2006T10182, 2002TL4377>.
Imidazoles 219
Scheme 113
Scheme 114
220 Imidazoles
Scheme 115
Scheme 116
Scheme 117
Imidazoles 221
Reaction of a sulfonamide-protected 5-vinylimidazole 516 with 4-phenyl-1,2,4-triazoline-3,5-dione 517 in metha-

nol gave the Diels–Alder adduct 518 in 85% yield, subequent aromatization to form the imidazole ring in 519 was
achieved quantitatively by DBU treatment (Scheme 118) <1998TL4561, 2001OL1319>.
Scheme 118
The use of the p-toluenesulfonyl (Ts) and tosylvinyl (Tsv) groups as nitrogen masking groups imparts high
regioselectivity in Diels–Alder reactions. The electron-withdrawing Tsv group is utilized as an electronically
adjustable nitrogen-protecting group as subsequent hydrogenation provides the more electron-rich tosylethyl (Tse)
group. This electronic adjustment strategy provides the desired regioisomer in good yield (Scheme 119)
<2005OL1679>.
Scheme 119
222 Imidazoles
Compound 526 undergoes an intramolecular Diels–Alder reaction providing the expected cycloadduct 527 in 48%
yield, along with the aromatized congener 528 in 28% yield (Scheme 120) <2006T10555>.
Scheme 120
4.02.5.7.2 Photochemical cycloadditions

Irradiation of a series of 4,5-bis(alkyn-1-yl)imidazoles (R ¼ Me, Bu, Ph) (450 W low-pressure Hg) induced Bergman
cycloaromatization reactions providing benzimidazole derivatives. The cyclized product (R ¼ Ph) was obtained in
highest yields (26–64%) with the best result obtained in THF (Scheme 121) <2005TL1373>.
Scheme 121
When a solution of 29,39-O-isopropylidenebredinin 529 in 0.1 M AcOH was irradiated with a high-pressure Hg
lamp, an imidazole ring-cleavage reaction occurred to give the 2-aminomalonamide riboside 534 in 71% yield
(Scheme 122) <2000J(P1)3603>.
Scheme 122
Imidazoles 223
4.02.6 Reactivity of Nonconjugated Rings

4.02.6.1 Isomers of Aromatic Derivatives
4.02.6.1.1 Compounds not in tautomeric equilibrium with aromatic isomers
4.02.6.1.1(i) 2H-Imidazoles
The anion 536 from a-lithiation of nitrone 535 is stabilized by the dipolar functional group. In the absence of
electrophiles, 536 undergoes oxidative coupling to form dimer 537 (Scheme 123); with aldehydes or ketones,
alcohols are formed in high yields. The initial alcohol 539 undergoes an intramolecular 1,3-dipolar cycloaddition
process leading to the formation of the tricyclic structure 540 <2000T4071, 1998HCO261>.
Scheme 123
4.02.6.1.1(ii) 4H-Imidazoles
5-Imino-4,4-bis(trifluoromethyl)imidazoline 542, obtained from amide 541, undergoes Dimroth rearrangement upon
basic work-up giving the less congested isomer 543 that is also stabilized due to extended conjugation (Scheme 124)
<1996T11153>.
Scheme 124
4.02.6.2 Dihydro Compounds

4.02.6.2.1 Tautomerism and interconversions
2-Alkyl-2-imidazolines 544 are in equilibrium with the enediamine tautomers 545 through which carbon-bound
diazenium diolates 546 are formed upon reaction with nitric oxide (Scheme 125) <2005JOC7647>.
Due to the electron-withdrawing nature of the pyridine rings, isomerization of cis-2,4,5-tripyridylimidazoline 547 to
548 occurs under milder conditions than those reported for non-heterocycle-substituted imidazolines (Scheme 126)
<1998TL4785>.
224 Imidazoles
Scheme 125
Scheme 126
4.02.6.2.2 Aromatization
4,4-Bis(trifluoromethyl)imidazoline 549, which contains a hydroxyl group at the 5-position, undergoes detrifluoro-
methylation under basic conditions to give 4-trifluoromethyl-imidazoles 551. The reaction is believed to proceed
through ring opening to 550, which was isolated under milder basic conditions and subsequently converted into 551
(Scheme 127), <1997JOC2550>.
Scheme 127
Dehydrogenation of 2-imidazolines to the corresponding imidazoles can be achieved with trichloroisocyanuric acid
<2004SL2803>, KMnO4 absorbed on supports such as silica gel <2004TL8687>, alumina <2004BML6079>, or
Montmorillonite K-10 (552, R9 ¼ H, Me) <2005CJC110> (Scheme 128). It is possible to achieve chemoselectivity
during oxidation of 2-imidazolines: 2-alkylimidazolines (R ¼ alkyl) are selectively oxidized in the presence of
2-arylimidazolines (R ¼ aryl) under heterogeneous conditions. In contrast, 2-arylimidazolines are readily oxidized in
DMSO at 120 C while 2-alkylimidazolines remained unchanged <2000S1814>. This method is particularly useful
for 2-arylimidazolines containing halogens where classical Pd/C dehydrogenation failed to give satisfactory results
<1990SC2483>. 2-Arylimidazolines can be oxidized with molecular oxygen in the presence of activated carbon in
Imidazoles 225
xylene <2007T2414> O-Iodoxybenzoic acid (IBX) <2003AGE4077> and (diacetoxyiodo)benzene <2006SL227>

can also be used for the synthesis of electron-rich imidazole derivatives (cf. 553). Magtrieve in combination with
microwave irradiation offers an efficient and convenient oxidation of 2-substituted imdazolines 554 <2006T5868>. A
comparison of methods for the oxidative aromatization of 2-(2-alkoxyphenyl)-1H-imidazoles 555 was reported
<2006JHC835>.
Scheme 128
Substituted 2-imidazolines, especially with steric congestion at the sp3 centers, can be oxidized by air to imidazoles
<2005JOC3542, 2005OL39>. Other conventional oxidations of imidazolines include BrCCl3/DBU and MnO2
<2004OL1681>. In a recent synthesis of 13C-labeled midazolam and 19-hydroxymidazolam, MnO2 was used for
the oxidation of midazoline 556 (Scheme 129) <2005TL2087>.
Scheme 129
5-Aminoimidazoles 560 were selectively synthesized from trans-4,5-bisamino-1-methyl-2-alkyl-2-imidazoline 558

by heating (Scheme 130). Isotope exchange experiments suggest that the reaction proceeds through a tele-elimina-
tion mechanism via intermediate 559 (Scheme 130) <2004T6639>.
226 Imidazoles
Scheme 130
2-[Furyl/thienyl]-1,3-dimethylbenzimidazoline derivatives can be oxidized by 1-benzyl-3-carbamoylpyridinium

ion or 1-benzyl-5-nitroisoquinolinium ion through a one-step hydride transfer mechanism <1998JOC7275>.
4.02.6.2.3 Ring fission

Hydrolysis in aqueous ethanol of 2-methyl imidazolines 561, derived from C2-symmetric diamines and the Pinner
salt, leads to mono-protected 1,2-diamines 562. The latter are readily converted into N,N-disubstituted 1,2-diamines
(Scheme 131) <2000TL8431>. N-protected 3-imidazolines are readily hydrolyzed under milder conditions. Thus
peptidyl trifluoromethyl ketones 564 were prepared through hydrolysis of 563 <1996JA8485>.
Scheme 131
The unique resonance structure of the dihydroimidazolium cation has been studied in the context of the
one-carbon transfer function of coenzyme N(5),N(10)-methenyl tetrahydrofolic acid. Reaction of 2-methyl-4,5-
dihydro-1H-imidazolium salt 565 with amines or water results in the formation of N,N,N9-trisubstituted
ethylenediamines (566, 567) (Scheme 132). By choosing groups at N-1 and N-3 with different electronic
properties, ring opening at the imidazolium carbon occurs regiospecifically as a result of protonation of the
more basic nitrogen <2000SC3307, 2002SC1447>. Carbon acids such as malononitrile add to 568 to give
enamines <2004SC3535>. The hydroxylamine adduct 569 undergoes a Beckmann rearrangement upon acid
treatment <2000JHC1329>.
Compound 570 was hydrolyzed to the bisindole 571 in high yield (Scheme 133) <1996HCO305>.
Ring opening of imidazoline under nitrosation is regiospecific giving nitrosoamide that is further converted to the
bis-N-nitroso derivative 573. Presumably the initial product, N-nitrosoimidazolinium cation 572, undergoes hydration
followed by ring opening in such a way that the NMe group is cleaved from the tetrahedral intermediate
(Scheme 134). <1998TL1845>.
Imidazoles 227
Scheme 132
Scheme 133
Scheme 134
Under basic conditions, attempts to achieve C-5-alkylation of 574 (Scheme 135) led instead to the N-alkylated
product 576 after hydrolysis. Presumably a putative initial anion underwent electrocyclic ring opening reaction to
generate the more stable N-complex 575 before alkylation took place <1997TL4359>.
228 Imidazoles
Scheme 135
Imidazolines are often converted into the corresponding tetrahydroimidazoles prior to ring opening reactions in situ.
For example, reduction of 577 with sodium offers a practical process for the conversion of carboxylic acids into the
corresponding aldehydes (Scheme 136) <1997SC2701>. The reduction of dihydroimidazolium salts requires mild
conditions and is applicable to complex structures. Methylation of 578 (to 579) followed by reduction with NaBH4
led to the quaternary aldehyde after work-up <1998TL8979>. Similarly, reductive ring opening of sulfonyl
dihydroimidazolium salt 580 provides trisubstituted ethylenediamine derivatives 581 <2002SC1447>.
Scheme 136
4.02.6.2.4 Other reactions

4.02.6.2.4(i) 2-Imidazolines
N-Alkylation of 2-methyl-2-imidazoline can be achieved under phase transfer catalysis. The reaction works best with
mixed bases in the absence of a solvent (Scheme 137; R: Et, Pr, Bu, C7H15, C12H25; yields: 60–96%) <1999SC3025>.
Imidazoles 229
Scheme 137
When imidazolinium salts lacking a 2-substituent such as 1-(3-nitrobenzenesulfonyl)-3,4-dimethylimidazolinium

iodide 582 reacted with the sodium salt of indole, 583 was formed <2005H(65)2893>. In contrast, 1,3-diacetylimi-
dazolium acetate, which is derived from compound 584, reacts at the indole 3-position to give 585 (Scheme 138)
<1996HCO305>.
Scheme 138
Direct C–H activation of 2-imidazolines in the addition to alkenes has been observed under rhodium catalysis as
shown for the formation of 586 (Scheme 139) <2004OL1685>. The proposed intermediate was thought to be similar
to that involved in metal-N-heterocyclic carbene (NHC) complexes <2002AGE1290>.
Scheme 139
Difenchyl imidazolinium salt 587 when treated with a strong base (to form the putative carbene) followed by the
addition of copper(II) triflate, gave the unexpected piperazin-2-one 589 and urea 588 (Scheme 140)
<2006OL3049>. The formation of 589 was confirmed by X-ray structural analyses and probably results via
dimerization following deprotonation of 587. The putative carbene intermediate has not been isolated.
Imidazolinium salt 590 reacted with propiolate and an aromatic aldehyde to give the cyclic three-component
adduct, furan 593 (Scheme 141). This reaction involves conjugate addition of the carbene to the alkyne to form 591,
which undergoes cycloaddition with an aldehyde. The resulting spiroaminal 592 isomerizes to the more stable
aminofuran 593 <2005OL2297>.
230 Imidazoles
Scheme 140
Scheme 141
Homochiral 4,5-dihydroimidazolium ylides 595 derived from chiral 1-benzyl-4-phenyl-2-imidazoline 594, undergo
diastereoselective endo 1,3-dipolar cycloaddition with a range of alkene dipolarophiles to form hexahydropyrrolo[1,2-a]-
imidazoles 596. These reactions are best carried out in one pot by refluxing a mixture of 594, bromoacetate, and a
dipolarophile in the presence of DBU (Scheme 142) <1996TL1707, 1998J(P1)2061>. Bicyclic adducts 596 are readily
converted into enantiopure pyrrolidines in a two-step procedure <1996TL1711>. An intramolecular system (597 to
598) provided a rapid assembly of 2,3,4-trisubstituted pyrrolidines <1997TL1647>.
Scheme 142
Imidazoline 3-oxides (which are nitrones) such as 599 (Scheme 143) react with dipolarophiles in an exo fashion
<2006JHC277>. Depending on the substitution pattern, the adducts from electron-deficient alkynes 600 undergo a
further 1,5-(C,N)-H shift 601 to form a ketone 602 or aldehyde 603. Alkene dipolarophiles react with 599 with high
Scheme 143
232 Imidazoles
regio- and diastereoselectivity, giving rise to bicyclic (604, 605) or tricyclic (606, 607) adducts in modest yields
<2000JHC481>. Interestingly, the reaction with methacrylate ester gave the regioisomeric 5-substituted isoxazol-
idines in low yield <2000SL967>.
The imine bond in 2-imidazolines reacts with Fisher carbenes under irradiation (Scheme 144). Low yields were
obtained with monosubstituted imidazolines 608a–c due to thermal decomposition of the substrates under the
reaction conditions. Optically active 4,4-disubstituted 2-imidazolines 608d–e form azapenams (609d, 610e, 611)
with (methoxymethylcarbene)chromium complex in good yields and high diastereoselectivity. The electronic nature
of R1/R2 clearly influences the sense of diastereoselectivity (609 vs. 610, 611) <1977JOC3586>.
Scheme 144
The Zwitterionic nitrogen-bonded complex 613 formed from 4,6-dinitrobenzofuroxan and imidazoline 612
(Rf ¼ (CH2)6F), undergo base-catalyzed isomerization to 613a which then undergoes a 1,3-allylic rearrangement of
the N-oxide to form 613b. Extrusion of the imidazoline completes the catalytic cycle. The overall conversion is an
unusual case of a formal intramolecular oxygen transfer (Scheme 145) <2001TL4499>.
Reductions of 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazolyl nitronyl nitroxides are discussed in Section 4.02.8.8.
One of the emerging applications of imidazole-based compounds is in the area of metal complexes for novel organic
transformations. 2-Imidazolines have been extensively studied as chiral auxiliary in asymmetric syntheses, such as in
Scheme 146 palladium-catalyzed CO/styrene copolymerization 614 <2004CEJ3747>, ruthenium catalyzed Diels–
Alder reaction 614 <2001J(P1)1500 2006JOM(691)3445> diethylzinc addition to aldehydes 615 <2003SL102>,
palladium-catalyzed allylation 616 <1997SUL783>, asymmetric intramolecular Heck reaction 617 <2003OL595>,
ruthenium-catalyzed epoxidation <2005OL3393> and Ir-catalyzed hydrogenation of imines 618 <2004TA3365>
and styrenes 619 <2002OL4713>. The complex of Cu(OTf)2 with N-tethered-bis(imidazoline) 620 has been shown
to catalyze asymmetric benzoylation of 1,2-diols (48% ee) and the cyclopropanation of styrenes by ethyl diazoacetate
(75–83% ee) <2005SL2670>. Compared to the corresponding oxazolines, higher enantioselectivity is often observed
in imdazoline-based systems. Substitution at the N-1 position offers the opportunity to fine-tune both the electronic
and the steric properties of the imidazoline ring. Highly enantioselective and efficient aza-Claisen rearrangements of
N-4-methoxyphenyl trifluoroacetimidates occur with the FIP catalyst 621 <2006AGE5694>.
Imidazoles 233
Scheme 145
Scheme 146
4.02.6.2.4(ii) 3-Imidazolines
Metallation of 1,2,2,5,5-pentamethyl-3-imidazoline-3-oxide 622 with s-BuLi leads to the dipole-stabilized organolithium
intermediate 623 that reacts with electrophiles HgCl2, Me3SiCl, Et3GeCl, nBu3SnBr, Ph2P(O)Cl, and TsCl to give
a-heteroatom substituted nitrones 624 (R ¼ HgCl, Me3Si, n-Bu3Sn, Ph2P(O), or Cl) (Scheme 147) <2002TL2445>.
Scheme 147
234 Imidazoles
An internal redox process took place when the alcohol 625 was treated with piperidine (but not with Et3N), leading
to the formation of ketone 626 (Scheme 148) <2000T4071>.
Scheme 148
A highly exo-selective alkylation on the amidine function of 627, possibly as a result of steric hindrance, leads to
628 the amide of which is then converted to pH-sensitive spin probe 629 via an oxidative N-demethylation
(Scheme 149) <2005JOC9702>.
Scheme 149
The reactions between 3-imidazoline 3-oxides (630, Scheme 150) and maleimides give rise to a mixture of endo-
and exo-adducts. The endo selectivity is higher in toluene than in benzene, CH2Cl2, or THF. The reaction is slower
when a 2-substituent (R1) is present <2006T1351>. Similarly, cycloadditions with isocyanate <1997T13873>,
styrene <1998H(48)537>, alkenes <2001TA1463>, and alkynes <2004SC1617> give 631–634. These compounds
are prone either to retro cycloaddition or fragmentations leading to the formation of imidazoles.
Scheme 150
Imidazoles 235
Homochiral dihydroimidazol-4-one 635 was efficiently oxidized to 2-tert-butyl-3-methyl-2,3-dihydroimidazol-4-

one N-oxide 636 which adds to functionalized olefins to afford the adducts 637 with high diastereoselectivity
(Scheme 151) <2004OL1653>. This is an efficient method for the synthesis of chiral glycine analogues 638.
Scheme 151
4.02.6.2.4(iii) 4-Imidazolines
Under irradiation conditions, imidazolines are excellent hydrogen donors. For example 1,3-dimethyl-2-phenylben-
zyimidazoline 639 reduces a,b-epoxy ketones in the presence of proton donors (Scheme 152) <2001S1248>).
Scheme 152
Compound 639 also promotes the photoinduced reduction of ketones whereas 2-(29-hydroxyphenyl)-1,3-dimethyl-
benzimidazoline 640 promotes benzpinacol formation (Scheme 153) <2005JOC9632>. Photoinduced single elec-
tron transfer (SET) followed by regiospecific proton transfer (PT) led to the formation of either benzhydrol or
benzpinacol, depending on the 2-aryl substituent.
Scheme 153
236 Imidazoles
4.02.6.3 Tetrahydro Compounds

4.02.6.3.1 Ring fission
N-Alkyl and N-phenyl-2-arylimidazolidines display ring–chain tautomerism in CDCl3. The ring/chain ratios were
determined based on 1H NMR spectra. Electron-withdrawing groups on the aryl ring favor the ring tautomers,
whereas bulky N-substituents favor the chain tautomers. The electronic effects of the 2-aryl substituents were shown
to correlate with the Hammett–Brown constants þ (log Kx ¼ þþlog KH) <1998T13639>. Variable temperature 1H
NMR studies of 2-isopropyl-1,3-imidazolidine in d6-DMSO-D2O revealed that the ring–chain equilibrium free
energy G6¼ 62 kJ mol1 <1997J(P2)169>.
Reductive cleavage of imidazolidines 641 was implicated in the one-pot synthesis of N,N,N9-trisubstituted
ethylenediamines 643 from N,N9-disubstituted ethylene diamines and an aldehyde R2CHO. Presumably the inter-
mediate iminium ion 642 is reduced by NaBH4 (Scheme 154) <2003SC3193>. Naphthalene-catalyzed lithiation of
1,3-dimethyl-2-phenylimidazoline 644 leads to benzylic C–N bond cleavage. The intermediate dianion can be
trapped with electrophiles (H2O, alkyl halides, ketones, and aldehydes) to afford diamines 645 <2005T3177>.
Scheme 154
The aminal function embedded in hexahydropyrrolo[1,2-a]imidazoles 646 (Scheme 155) renders them prone to
equilibration and eliminations under basic conditions. For example 646 (E ¼ CN, CO2Me) undergoes epimerization
647 upon storage or exposure to basic alumina. In the case of chloronitrile 648, a 2,4-disubstituted pyrrole is readily
formed under mild conditions <1998J(P1)2061>.
Scheme 155
Imidazoles 237
N-Sulfinylimidazolidines 649 are reduced to the N-benzyl-N-sulfinyldiaminoalcohols 650 with regioselective

cleavage of the aminal center. The regioselectivity is presumably due to initial reduction of the ester group and
chelation of Al to both the resulting alkoxide function and the nearby aminal nitrogen atom (Scheme 156)
<1999SL1543, 2003CEJ2867>. Acidic hydrolysis at the aminal center leads to either b-sulfinate 651 or a-benzyl-
amine 652, depending on the reaction conditions <2004JOC1542>.
Scheme 156
In the synthesis of chiral 1,2-diamines, selective hydrolysis of the aminal function group of 653 was achieved with
malonic acid to give the BOC-protected diamine 654. In the presence of TFA, both aminal and BOC were cleaved to
give 655 (Scheme 157) <2001OL3799>.
Scheme 157
4.02.6.3.2 Aromatization
Ethyl 2,3-a-diphenyl-5-p-tolyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazole-3-carboxylate 656 undergoes base or ther-
mally-induced fragmentation (formally a double cis-elimination) to imidazole 657 (Scheme 158) <2000TL5407,
2001T3413>.
Scheme 158
238 Imidazoles
4.02.6.3.3 Other Reactions

4,4,5,5-Tetramethylimidazolidines 658 are oxidized to the corresponding nitronylnitroxides 659 (78%, R ¼ Ph), via a
1,3-dihydroxy intermediate (Scheme 159) <2001CEJ2007>. KMnO4 effects C–H oxidation of the derivative 660 to
give the imidazolidinone 661 <2004SC1617>.
Scheme 159
Hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-diones such as 662, (Scheme 160), in the presence of a

secondary amine, undergo a formal retro-[3þ2] cycloaddition to give 3-imidazoline 664 via the bisamide intermediate
663 <2006T1351>.
Scheme 160
Unlike an N,N9-disubstituted imidazoline-2-thione, the reaction of imidazolidine-2-thione 665 itself with

2-phenyloxirane in the presence of BF3 leads to the formation of 1,3-bis[(E)-2-phenylethen-1-yl]imidazolidine-2-thione
666 (Scheme 161) <2005HCA3253>. This unusual mode of reaction is presumably due to a Lewis-acid-catalyzed
rearrangement of oxirane to aldehyde followed by an ene-like reaction with the iminothiol.
Scheme 161
Imidazoles 239
Substituted imidazolidin-4-ones can be viewed as protected glycine derivatives, thus offering versatile reactivity
profiles. For example, spontaneous intramolecular reductive amination occurs upon Cbz deprotection of 667
(Scheme 162) <2006OL239>. C-Alkylation of imidazolidinone 668 resulted in 4,4-disubstituted imidazolidinone
669 in high diastereo- and enantioselectivity (Scheme 163) <2003OL4249>. Chiral imidazolidinone organocatalysts
such as 670 form iminium intermediates 671 with enals that participate in a variety of directed enantioselective
organic reactions (see Section 4.02.8.3) <2006ALD79>.
Scheme 162
Scheme 163
The C-2 proton of 1,3-di-(tert-butoxycarbonyl)imidazolidine 672 is abstracted under controlled conditions with sec-
BuLi (2.2 equiv) and the resulting anion can be quenched with various electrophiles to give 2-substituted products
673 in modest yields and, in the case of chiral 672, with low diastereoselectivity (Equation 2). Depending on the
nature of substituents at C-4 and C-5, deprotonation under this protocol leads to mixture of 2- and 4-anions
<1998T14255>. In contrast to the bis-N-Boc derivative, mono-N-BOC-protected imidazolidine 674 undergoes
deprotonation exclusively at the 5-position. In the presence of ()-sparteine, asymmetric lithiation occurred at the
pro-S hydrogen and quenching with electrophiles (RX: Bu3SnCl, Me3SiCl, Ph2MeSiCl, Ph2CTO, MeI) afforded 675
in high optical purity (Equation 3) <2001OL3799>; however, with allyl bromide as electrophile a racemic product
was produced. The modest yield of the reaction is a result of hindered rotation about the Boc amide bond that was
shown to control the extent of the deprotonation (see Section 4.02.3.3 for NMR studies).
240 Imidazoles
ð2Þ
ð3Þ
4.02.7 Reactivity of Substituents Attached to Ring Carbon Atoms

4.02.7.1 Reactions of Substituents Involving Ring Transformations
Rarrangement of N-alkoxycarbonylimidazole acyl azides 676 led to the formation of two products (Scheme 164).
Imidazo[1,5-c]pyrimidinone 677 was formed when R was either Me or Et, although it was not clear how the alkyl
transfer from imidazole to the pyrimidone occurred. With higher R groups (Pr or Ph), the anticipated imidazo[4,5-
c]pyridinone 678 was formed <2002TL5879>.
Scheme 164
A vinyl cyclobutane rearrangement of sceptrin 679 to ageliferin 680 under microwave irradiation has been reported
(Scheme 165). This reaction appeared to be specific to the 2-aminoimidazole substituted cyclobutane as a nonsub-
stituted model compound failed to yield any product <2004AGE2674>.
Scheme 165
Imidazoles 241
The electron-withdrawing benzimidazole group activates nitro- or fluoro-arenes in SNAr reactions. Thus 2-(2-
nitrophenyl)-1H-benzimidazoles such as 681 undergo high-yielding intramolecular displacement of nitrite with
N-pendant alkoxides to give tetracyclic 6,7-dihydro-5-oxa-7a,12-diazadibenzo[a,e]azulene 682 under mild conditions
(Scheme 166). At elevated temperatures and in the presence of excess NaH, the initially formed product
was converted into the corresponding N-vinyl-substituted 2-(2-hydroxyphenyl)-1H-benzimidazole 683 via base-
catalyzed isomerization<2003OL4795>.
Scheme 166
Imidazolones 684, Fc ¼ ferrocenyl and hydantoins 686 were converted into the bicyclic 1-({9-(tert-butoxycarbonyl)-
3-oxo-8,9-dihydro-3H-imidazo[1,2-a][1,3]diazepin-2(5H)-ylidene}methyl)ferrocene 685 <2002EJO3801> and 1,8-
diazabicyclo[4.3.0]non-3-ene-7,9-diones 687 <1997TL2065>, respectively, with the first-generation Grubbs’ olefin
metathesis catalyst (Scheme 167). Studies on the ring-closing metathesis of substituted imidazoles were limited by
the concern that N-3 ligation and the formation of stable carbene complexes from the vinylimidazole moiety
potentially deactivate the catalyst. The nature of protecting groups at N-1 was not relevant to successful RCM
reactions. When N-3 was protonated with TsOH, RCM with [(1,3-Mes2Im)(PCy3)Ru(CHPh)Cl2] could be applied to
diallyl or vinyl allyl imidazoles 688–690, but not 4,5-allyl vinyl systems 691 <2003TL1379>.
Scheme 167
242 Imidazoles
4.02.7.2 Fused Benzene Rings

4,49-Dibromo-2,29-bisbenzimidazoles 692 react with aryl zincates under Negishi coupling conditions to give 4,49-
bisaryl-2,29-bisbenzimidazoles 693 (Scheme 168). Lower yields were obtained with heteroaryl zincates (2- or 3-
pyridyl) <2006OL4989>. Cross-coupling of bromides 694 with phosphonites provided an efficient synthesis of
phosphonates 695 <1998TL2797>.
Scheme 168
4.02.7.3 Alkyl Groups

Due to the acidic nature of the 4-methyl group, 3-hydroxyimidazoline 1-oxyl 696 condenses readily with aldehydes to
give aldol products such as 697 (Scheme 169). Acetylide coupling of 697 with concurrent radical formation at N-1
results in the formation of 698 <2006T4597, 2004TL7741>. Similarly, 4H-imidazole N-oxide 699, R ¼ Ph, 2-Py, 3-
O2NC6H4, Et) undergoes nitrosation with isopropyl nitrite to give oximes 700 in high yield. Treatment of 700 with
TsCl yielded 4H-imidazole-5-carbonitrile 3-oxides 701 <2003S871>.
Scheme 169
Azolium formation from 2-alkyl imidazoles 702 renders the C-29 proton sufficiently acidic that under mild
conditions the resulting anion 703 can be formed and adds to imines to form 704 (Scheme 170) <2005TL4789>.
Imidazoles 243
Scheme 170
Addition of the 1-benzyl-2-lithiomethyl-4,5-dihydroimidazole 705 to aldehydes or ketones, and the subsequent

‘retro–ene’ reaction to revert back to the starting material, was discussed in <CHC(II)3.02.6.2.3)> (Scheme 171).
The reaction of 705 with nitriles results in the formation of b-amino a,b-unsaturated imidazoline 706 after in situ
isomerization <1999T2695>.
Scheme 171
Lithiated imidazoles (such as 707 (Scheme 172) are used as bulky bases in the rearrangement of cyclic epoxides to
allylic alcohols in the presence of chiral lithium amides. During this process, epoxide opening by the lithiated
imidazole <1997MCR123> (to give, e.g., 708) can be a competing or even an exclusive reaction pathway
<2005TL8315>. The later reaction is highly sensitive to steric factors imposed by the C-2 alkyl substituents.
Scheme 172
Lateral metallation at C-2(a) of 1-tert-butoxycarbonyl-2-methylimidazoline 709 (Scheme 173) with sec-BuLi

results in the formation of a bright yellow lithiated intermediate that reacts with alkyl halides, diphenyldiselenide,
and phosphoryl chlorides to give 710. In the case of reaction with esters, the conjugated ketones 711 are formed
<2000T2061>. In the case of acylation with esters, conjugated enamino-ketones were the tautomer isolated. Further
alkylation is also possible under similar conditions, to give 712.
2-Alkyl-2-imidazoline can exist as the enediamine tautomer, which will react with electrophiles such as nitric oxide
<2005JOC7647> (see Section 4.02.6.2.1).
244 Imidazoles
Scheme 173
4.02.7.4 Substituted Alkyl Groups

4.02.7.4.1 Vinyl and arylalkyl
When the C-2(a) bears an aromatic group 713, 715 (Scheme 174), deprotonation at this center is rapid due to the
benzylic stabilization, so that it is possible to alkylate, including alkylative THF ring opening with electrophilic
assistance from 9-BBN(OTf) 716, the dianions from unprotected imidazolines <1998CC331>. Support for the N,C-
dianion species is evident from the reaction with a dihalide giving 714 and from low temperature 13C NMR studies of
the dilithium intermediate <1998JOC8107>. With chiral imidazolines, a high level of 1,4-stereoinduction has been
observed for the formation of benzylic quaternary carbon centers 716 <1998CC331>. In the presence of an oxidant
such as TEMPO, the initially formed dianion of 717 (R ¼ Me, 4-butenyl, 5-pentenyl) undergoes electron transfer to a
configurationally stable radical that further reacts with TEMPO to give chiral alcohol 735 in 80% de. When TEMPO
is added slowly to the dianion, dimers of 718 are formed <1999TL4035>.
Scheme 174
Imidazoles 245
A sequential lithiation–alkylation based on the dianion chemistry was utilized in an efficient synthesis of
()-mesembrine (Scheme 175 <1998TL8979>.
Scheme 175
4.02.7.4.2 Activated alkyl

In a vinylogous fashion, 2-o-tolyl-4,5-dihydro-1H-imidazole 719 (Scheme 176) undergoes ‘imidazole directed’
lithiation, subsequent trapping with electrophiles giving 720 and 721. The product distribution (bis- vs. mono-)
can be modulated by reaction temperature and the nature/amount of base <2004SC3455>.
Scheme 176
Under basic conditions, nitrile 722 undergoes Diels–Alder [4þ2] cycloaddition with 1,3,5-triazine followed by
fragmentation and concurrent deblocking of the acetate to give1-[4-(4-aminopyrimidin-5-yl)imidazol-1-yl]-1-
-D-
ribofuranose-2,3,5-triol 723 (Scheme 177) <2005OL63>. Direct cross-coupling approaches as between the corre-
sponding 4-iodoimidazole and pyrimidines were less successful <2005JOC1612>.
Scheme 177
246 Imidazoles
Electrophilic fluorination of 5-(cyanomethyl)imidazole-4-carboxamide 724 gives good yields of diastereoisomers 725,

which were further transformed into a series of 3-fluoro-3-deazaguanosine analogues 726 (Scheme 178) <2005SL1586>.
Scheme 178
4.02.7.4.3 Heteroatom substituted alkyl

The anions of the 2-phosphoryl derivatives from 727 and 729 undergo Wadsworth–Emmons reactions with aldehydes
or ketones to give 2-alkenyl imidazolines 728 and 730 (Scheme 179) <1997T1111>. An alternative olefination
involves alkylation of phenylselenyl derivative 731. Deprotection of 732 followed by oxidative elimination afforded
N-1-unsubstituted 2-alkenyl imidazolines 733 <2000T2061>.
Scheme 179
The Horner–Wadsworth–Emmons reagent 735 (Scheme 180) prepared through Michaelis–Becker reaction of
4-(chloromethyl)-1-tritylimidazole 734 with lithium diethyl phosphonate reacts with aldehydes or ketones to give
4-vinylimidazoles 736 <2002S1072>.
Scheme 180
Imidazoles 247
3-Hydroxymethyl imidazoline 737 (Scheme 181) undergoes Mitsunubo reaction with phenols and activated
amines to give 738 in high yields. Due to the instability of the imidazoline ring, coupling reactions with the
corresponding bromide 739 are not successful <2003TL9111>.
Scheme 181
1-Methyl-2-(1-hydroxyalkyl)-1H-imidazole 740 is easily converted into the corresponding chloride 741

(Scheme 182). The latter undergoes SN2 reaction with less bulky nucleophiles, such as thioates, alcohols, phenols,
and simple primary amines to give 742. With secondary amines or diamines as nucleophiles, tele-substitution at the
imidazole ring becomes dominant, resulting in a serial double nucleophilic addition to the imidazole nucleus
<2004T6639, 2000TL7503>. Similarly, diethyl 2-methylmalonate anion adds to 741 to give direct displacement
product 743, tele-, and double tele-adducts 744, 745 <2004JHC335>. The tele-reaction can be explained by the
formation and subsequent reactions of intermediate 746. The carbamoyl group in 747 is replaced with soft nucleophiles
under solvolysis conditions to give 748 (Nuc-H: H2O, MeOH, EtOH, AcNH2, MsNH2) <2002OL4017, 2001OL157>.
Scheme 182
Oxidation of 2-aminomethyl-substituted imidazole 749, R ¼ Me, with either singlet oxygen or mCPBA (>2 equiv)
leads to the formation of 4,4-bis(trifluoromethyl)imidazolines 750 in high yields (69–76%) (Scheme 183).
Presumably chemoselective cleavage of the imidazole CTC bond (via 1,2-addition of 1O2) followed by acid-catalyzed
dehydrocyclization gives rise to the rearranged product. However, when R ¼ H, 1,4-addition of singlet oxygen results
in the formation of imidazolone 751, 42%) <1996H(43)937>.
248 Imidazoles
Scheme 183
Allylic alcohol 752 undergoes a formal 1,3-allylic rearrangement upon acetylation to give 753 (Scheme 184)
<1997SC415>.
Scheme 184
4.02.7.5 Other C-Linked Substituents

4.02.7.5.1 Unsaturated alkyl
The unsaturated ester function in furanosyl imidazoles 754 can be converted into the corresponding aldehyde 755
either through ozonolysis or dihydroxylation/diol cleavage (Scheme 185) <1999JOC7158>.
Scheme 185
Addition of ‘FBr’ to 1-trityl-4-vinyl-1H-imidazole 756 occurs with Markovnikov regioselectivity to produce 757
(Scheme 186). Elimination of HBr (giving 758) followed by fluorobromination provides 759. The bromide is
converted into azide 760, which is reduced to b,b-difluorohistamine 761. In contrast, functionalization of 1-trityl-4-
formyl-1H-imidazole (cyanohydrin/DAST; MeNO2) does not yield useful intermediates for the preparation of 761
<2001JOC4687>. The ‘FBr’ addition/HBr elimination is compatible with hydroxyl (but not carboxyl) group 762,
which is employed in the synthesis of 763 en route to b-fluorourocanic acids 764 <2002JOC3468>.
The CTC bonds in sulfamoyl-protected imidazoles 765, 767 are electrophilic in nature and can be functionalized
either through thiol radical addition 766 or palladium-catalyzed hydride reduction 768 (Scheme 187)
<2005HCA707>. In the case of 768, both CTC and CTO functions are reduced.
2-Alkenyl imidazolines such as 769 (Scheme 188) behave as a,b-unsaturated esters and undergo exclusive
conjugate addition of both hard (producing e.g. 770) and soft carbon nucleophiles (giving e.g. 771). In conjunction
with the cleavage of dihydroimidazoles <1984J(P1)2559, 1986J(P1)205, 1986J(P1)1995>, these reactions constitute a
synthesis of b-substituted carboxylic acids and ketones <1997T1111>.
Imidazoles 249
Scheme 186
Scheme 187
Scheme 188
250 Imidazoles
Intramolecular cyclization of allylic amide 772 in the presence of strong acid gives oxazoline 773 in high yield.
Hydrolysis of 773 in aqueous acid leads to the formation of 774 (Scheme 189) <2000OL3443>.
Scheme 189
2-(29-Alkenyl) substituted arylimidazoles 776 (n ¼ 1,2) undergo iodocyclization to form fused imidazoles 775, 777
(Scheme 190). The extent of iodination on the imidazole core depends on the nature of the reagents used
<2003T6759>.
Scheme 190
2-Alkynyl-4,4,5,5-tetramethylimidazolidine-1,3-diol 778 (Scheme 191), prepared from 2,3-di(hydroxyamino)-2,3-

dimethylbutane and an aldehyde, is prone to rearrangement to (E)-2-(1-hydroxy-4,4,5,5-tetramethylimidazolidin-2-
ylidene)-ketone 779 <2000T10075>. The trimethylsilane-stabilized derivative 778 (R ¼ SiMe3) is isolable
<2006EJO2695>.
Scheme 191
Alkyne-substituted nitronyl nitroxide 780 reacts with diazomethane to give either 3- 782 or 4- 781 -pyrazolyl
nitronyl nitroxide (Scheme 192), depending on the steric environment of the alkyne group <2006EJO2695>.
Imidazoles 251
Scheme 192
Heterocycle-bridged enynes react with a Fischer carbene offering an easy benzannulation process. Unlike furan- or
thiophene-bridged enynes, imidazole-bridged enyne 783 give a lower yield of the product 784 (Scheme 193). It has
been suggested that coordination of the imidazole nitrogen to the Cr center might compete with the annulation
pathway <2005TL2211>.
Scheme 193
N-Aryl and N-alkyl substituted imidazole-fused enediynes 785 undergo thermally promoted Bergman cycloaro-
matization to the benzimidazoles 786 at 145 C (Scheme 194). Kinetic data indicate that N-aryl substitution
enhances the rate by up to sevenfold <2004TL3621>. 4,5-Bis-(alkyn-1-yl)imidazoles also undergo photoinduced
Bergman cycloaromatization <2005TL1373>.
Scheme 194
4.02.7.5.2 Alkylidene
Alkylidene imidazoles are best described as either ketene acetals or enamines, depending on the positions of
substitution. 2-(2-Propylidene)imidazoles such as 787 (Scheme 195) react with azides to form spiroheterocycles
788. The reaction rates vary widely depending on the hybridization of C(4)–C(5) bond of the dipolarophiles:
dihydroimidazoles react in days while imidazoles take only hours <2005HCA1589>.
Scheme 195
252 Imidazoles
The nucleophilic properties of the enaminoester or heterocylic keteneaminal in 789 can be utilized in annulation
reactions with bis-electrophiles to form imidazo[1,2-a]pyridones Table 10. The reaction is thought to proceed with
initial N-acylation at N-1 with either acid chloride or acylimidazolides generated in situ, followed by subsequent
conjugate C-addition of the ketene acetal. With less active unsaturated esters, the reaction sequence may be reversed
(e.g., azaene pathway) as supported by the isolation of a conjugated ester (entry 4). Ketoesters may lead to
regioisomers (entries 5,6) while malonate or 1,3-diketones are not reactive toward 789 <1998T6191>. Diethyl
oxalate reacts with 789 to give dioxopyrrolo[1,2-a]imidazole (entry 8). In contrast to substituted aldehydes (entry
7), propenal adds to 789 to give the cyclohexene derivative in quantitative yield (entry 9, yield based on the
aldehyde).
Table 10 Reactions between 805 and various nucleophiles
Entry Electrophile Product Yield
a, R ¼ H, 98%
1 b, R ¼ Me, 89%
c, R ¼ Ph, 98%
2 93%
3 82%
4 95%
R ¼ Me, 79%
5
R ¼ Ph, 72%
6 21%
(Continued)
Imidazoles 253
Table 10 (Continued)
Entry Electrophile Product Yield
R1 ¼ H, R2 ¼ Me, 62%
R1 ¼ R2 ¼ Me, 32%
7
R1 ¼ Me, R2 ¼ H, 32%
R1 ¼ H, R2 = Ph, 27%
8 EtO2C–CO2Et 50%
9 60%
The N,N-ketene acetal function in fused systems such as 790 (R ¼ H, Me (Scheme 196) undergoes easy hydration
on chromatography to afford the saturated system 791 (see also 787).
Scheme 196
Bromination of enamine ketone 792 leads to the formation of 793 (Scheme 197). The Br in 793 can be replaced
with hydrazine to give 2-(1-hydrazino-1,2-oxopropylidene)imidazoline 794. Cyclization between the nitrogen termini
in 810 with aldehyde or acid chlorides affords 795, imidazo[2,1-d][1,2,4]triazine 796 and imidazo[2,1-d][1,2,4]triaze-
pines 797 and 798, respectively <1997SC2433>.
C-Benzylation of 799 with ethyl 2-(bromomethyl)benzoate affords 800 (Scheme 198), readily converted into
azepinone 801 in the presence of base <2002S523>.
C-Alkylated ketene aminals 802 (R ¼ phenyl, vinyl; Ar ¼ phenyl, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4) react with
diethyl azodicarboxylate to give the quaternary carbon-containing adducts 803. Upon prolonged heating in THF, the
latter undergo sequential intramolecular cyclization, fragmentation, and ring-fusion to yield 804, 805, and 806
(Scheme 199) <2002T7791>.
(5Z)-1-Acyl-3-methyl-5-(cyanomethylidene)imidazolidine-2,4-diones such as 807 readily undergo 1,3-dipolar
cycloadditions with various 1,3-dipoles. The final products depend both on the nature of the dipoles and the
dipolarophiles. Thus, spirohydantoins 808 and 809 are formed under neutral conditions with diazomethane or a
nitrile oxide whereas further isomerization occurs under either basic or acidic conditions leading to acylureas such as
811 via 810 (Scheme 200) <2001HCA3403>.
The exocyclic methylene in thiohydantoins 812 reacts with O,O-diethyl S-hydrogen phosphorodithioate to give the
conjugate adduct 813 (Scheme 201). Base-induced intramolecular cyclization, fragmentation, and ring formation
gives 3,5-diaryl-3,5-dihydrothieto[2,3-d]imidazole-2(1H)-thiones 814 <2003S1079>.
254 Imidazoles
Scheme 197
Scheme 198
Scheme 199
During the design of steroid mimics as potential ACAC inhibitors, the exocyclic enone functions in 2-[4,4-
bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-1H-imidazol-5-ylidene]-1-(4-fluorophenyl)-1-ethanones 815 are
selectively reduced with zinc dust to the imidazolines 816 in high yields (Scheme 202) <1996T11153>.
Imidazoles 255
Scheme 200
Scheme 201
Scheme 202
256 Imidazoles
4.02.7.5.3 Aryl
Reductive cyclization of 2-(ortho-nitro)phenyl imidazoles 817, 819 (Scheme 203) in the presence of an orthoester or
a ketone is promoted by a low-valent titanium reagent TiCl4-Zn to afford imidazo[1,2-c]quinazolines 818 and 5,6-
dihydroimidazo[1,2-c]quinazolines 820 <2005JHC173>. Notably, halogens are not reduced under these conditions.
Scheme 203
Reductive metallation of 1,3-dimethyl-2-(4-substituted phenyl)imidazoles 821 (Scheme 204) with Li metal in the
presence of naphthalene (5%) leads to either dehalogenation or benzylic dealkylation. The resulting anions are trapped with
electrophiles (H2O, alkyl halides, ketones, and aldehydes) to afford diamines 822 <2005T3177>. Cross-coupling of iodide
823 with phosphines under the conditions of Kraatz <2000TA1617> afforded the BIPI ligands 824 for asymmetric Heck
reactions <2003OL595>. SNAr reactions of the corresponding fluoride or bromide have been reported <2004TA3365>.
Scheme 204
Imidazolines are excellent directing groups in the metallation of aromatic rings. The diastereoselectivity 826/827
of ortho-metallation of chiral ferrocenyl imidazolines 825 showed a remarkable influence of LDA as an additive
<2005OL4137> (Table 11).
Imidazoles 257
Table 11 ortho-Lithiation of 825
Product t-BuLi (equiv) LDA (equiv) EX 815/816 (1H NMR) Yield (%) (isolated )
825a 1.10 0.00 MeI 5: 1 61

825a 0.95 1.50 MeI 1: 12 66
825a 1.10 0.00 Ph2CO 4: 1 34
825a 0.95 1.50 Ph2CO 1: 12 50
825b 1.00 0.00 MeI 1: 3
825b 0.95 1.00 MeI 1: 31 41
825b 1.00 0.00 Ph2CO 1: 2
825b 0.95 1.00 Ph2CO 1: 21 41
The directing function of the nitrogen atom of imidazolines makes it possible to prepare metallocycles of chiral
imidazoline-based ligands. Cycloplatination of the Phebim ligand 828 (Scheme 205) leads to the formation of pincer
complexes 829 through directed C–H bond activation <2006TL5033>. Similarly, cyclopalladation of ferrocenyl
imidazolines 830 affords the FIP complexes 831 <2006AGE5694>. Metallation of 2-phenylimidazoline with Pd(II)
or Pt(II) reagents leads to the formation of cyclometallated complexes in which the a C–H of the phenyl ring was
replaced with a C–Pd or C–Pt bond <1996JOM(506)149>.
Scheme 205
4.02.7.5.4 Imine and nitrile derivatives

1,3-Dipolar addition of the 1,3-dipole derived from aldoxime 832 with various alkenes affords 3-(-2-butyl-4-chloro-
1H-imidazolyl)-substituted d-2-isoxazolines in high yields with the 5-substituted isoxazolines 833 as the major
products (Scheme 206). These compounds are potent antifungal agents <2003BMC4539>.
Scheme 206
258 Imidazoles
In the presence of sulfur, ethylene diamine adds to 4,5-dicyanoimidazole 834 (Scheme 207) to form bis-imidazo-
line 835 using microwave heating <2006T5868>. In contrast, 4H-imidazole-5-carbonitrile 3-oxides 836 react with
primary or secondary amines at the 5-position resulting in displacement of the activated CN group 837 <2003S871,
1997RJO1302>.
Scheme 207
In 4-cyanoimidazole 838, the nitrile group undergoes addition to Grignard reagents to afford 4-acyl-1H-imidazoles
840, presumably via intermediate 839 <2003S677>. Controlled reduction of the nitrile group on an imidazole ring
841, 842 to an aldehyde function is achieved either by LiAlH(OEt)3, generated in situ from LAH and EtOAc in THF
<2001S2393>, or by hydrogenation in dilute sulfuric acid (Scheme 208) <1997JHC107>.
Scheme 208
a-Iminocarbonyl derivatives of 2,5-dihydro-1H-imidazole nitroxides 843 undergo heterocyclization reactions in the

presence of a base to give oxazoles 847. In the presence of an amidine, 1,3,5-triazines 846 are formed as well. These
reactions have been shown to proceed through the homodimer 844 that under basic conditions fragments to
intermediate 845. Cyclization of 845 leads to the formation of the oxazole. On the other hand, addition of amidine
to intermediate 845 followed by extrusion of PhCHO and subsequent oxidative cyclisation, perhaps by air, leads to
triazines (Scheme 209) <2003EJO4432>.
The reactions of 1-aryl-5-amino-4-cyanoformimidoyl imidazoles 848 can take different courses depending on the
nature of the reagents and the sites of reaction at the cyanoformimidyl function. Methyl cyanoacetate reacts at the
imidyl carbon to give intermediates 849 which then cyclize to 3-aryl-6,7-dicyanoimidazo[4,5-b]pyridine-5-one 851 as
the salt form 850 (Scheme 210) <2005SL2429>. The high chemoselectivity of this reaction is presumably due to
intramolecular hydrogen bonding that leads to the initial intermediate 849. Compound 851 is a strong acid such that
neutralization of the salt 850 requires strong acids like TFA (pKa 0.23). Similarly, 853 reacts with ethoxymethyl-
enemalononitrile to give 854 <2004OBC2340>. Acetylacetone, which has similar pKa to methyl cyanoacetate, reacts
Imidazoles 259
Scheme 209
with 848 at the imine nitrogen under similar conditions to give, after a series of rearrangements, 6-carbamoyl purine
852 <2003JOC276>. Isocyanates react at the imine nitrogen of 5-amino--imino-1H-imidazole-4-acetonitriles 853
via intermediates 855 and 857 to give either 4,49-bi-1H-imidazol-2-ones 856 or 2-oxopurines 858, depending on the
nature of the isocyanates: tosyl isocyanate favors the formation of 858 <2001J(P1)1241>, whereas alkyl and aryl
isocyanates favor 856 <2002JOC5546>.
The ambident 1,3-dipolar 2-arylthiocarbamoyl imidazolium salts 859 are readily prepared from the corresponding
carbenes and phenyl isothiocyanate as crystalline solids. Reaction of 859 with DMAD leads to the formation of
spiro[imidazoline-2,39-dihydrothiophenes] 860, indicating that 859 acts as a C–C–S dipole. In contrast, the reaction of
859 with ethyl propiolate proceeds slowly to form spiro[imidazoline-2,39-dihydropyrroles] 861, indicating a C–C–N
dipolar reaction being thermodynamically driven (Scheme 211) <2006CC1215>.
4.02.7.5.5 Carbonyl derivatives

In the Schmidt rearrangement of imidazolyl aryl ketone 872, Ar ¼ 4-FC6H4), the reaction appears to favor the
imidazolyl migration 864 over the aryl migration 863 (Scheme 212) <1997JOC2550>. A Baylis–Hillman product
865 has been observed for 2-formylimidazole with excess methyl acrylate in the presence of DABCO <1997SC415>.
In situ protection of the vinylogous ester-aldehyde of imidazole 866 as triazine 867 allows for the selective conversion
of the ester group into amide 881 <2005TL6005>.
An improved dissymmetrization of imidazole-4,5-dicarboxylic acid 869 for the synthesis of N,N9-disubstituted
dicarboxamides 872 involves the preparation of pyrazine-dione diphenyl ester 870. Selective amide formation at the
pyrazine carbonyl at low temperatures affords the mixed amide ester 871, which is subsequently converted into 872
(Scheme 213) <2002JOC7151>.
Electron-rich heterocycles (Ar-H: indoles, furans, and pyrroles) react with a,b-unsaturated 2-acyl imidazoles 873,
R ¼ alkyl and aryl) with high enantioselectivity under (pybox)-Sc(OTf)3 catalysis to give 2-acylimidazoles 874
(Scheme 214) <2005JA8942>. It is interesting to note that the enantioselectivity is inversely proportional to the
molar percentage of catalyst loading. 2-Acylimidazoles 874 can be converted into a variety of carbonyl derivatives 875,
Nuc: OR, NR2, H, Ph) upon activation of the imidazole ring <1997CPB1254, 1991J(P1)2691>. In the absence of
external nucleophiles, the pyrrole ring in 876 cyclizes upon activation to give 877 which serves as a precursor in the
synthesis of heliotridane <2006OL2249>. Sodium pyruvate (carbonyl anion equivalent), in the presence of a thiazolium
catalyst, adds to 878 to provide 1,4-diketone 879. This reaction works best with b-aryl substituted 2-acyl imidazoles.
2-Acyl imidazole 879 is activated by MeOTf and converted into esters or amides such as 880 <2005JA14675>.
Cerium(IV)-pybox catalysts promote [3þ2] cycloaddition of nitrones to 873 to give 881 in high ee <2006OL3351>.
260 Imidazoles
Scheme 210
Scheme 211
Imidazoles 261
Scheme 212
Scheme 213
4.02.7.6 Amino and Related Groups

The chemistry of 2-aminoimidazole derivatives in the synthesis of pyrrole-imidazole alkaoids has been reviewed
<2006SL965, 2003S1753, 2001EJO237>.
4-Amino-5-alkoxycarbonylimidazoles 882 react with isocyanates <2002JOC188, 2002CPB1379> or, more
conveniently, with carbamates in the presence of a hindered potassium base to give 1-substituted xanthines
which are further alkylated to 1,3-disubstituted xanthines 883 (Scheme 215) <2004OL2237>. The chemo-
and regioselectivities of 2-aminobenzoimidazole adding to unsaturated nitriles are highly dependent on the nature
of the substrates. A modest yield of adduct 884 is obtained as a result of exo-(NH2)-b-addition to benzylidenemalo-
nonitrile <2005JHC1111>. A 1:1 mixture of regioisomers 886, 887 is obtained in the Boc protection of 885
<1996T11153>.
262 Imidazoles
Scheme 214
Scheme 215
Imidazoles 263
Diazonium salts of imidazoles have been discussed in CHEC-II(1996) <1996CHEC-II(3)168>. Recent examples
of Sandmeyer reactions include conversion of amine 888 into iodide 889 <1999JOC7158> and conversion of 890 to
891 (Scheme 216) <2003JHC159>.
Scheme 216
The reaction of 4-nitroimidazoles 892 with nucleophiles involves initial addition 893 and formation of nitroso 894
that can lead to ring transformations. For example, reaction of 4-amino-1,2,4-triazole and 892 under basic conditions
results in the formation of oxadiazole 895 or isourea 896, depending on the substitution pattern of 892. Oxime 897 is
isolated in the reaction between phenylacetonitrile and 892 (Scheme 217) <2003JHC523>.
Scheme 217
In a study of the synthesis of marine 2-aminoimidazole alkaloids, the aminal C–N bond of bicyclic 898 was cleaved
regioselectively to form the allylic amine 899. Deuterium exchange results in H-1, H-2, and H-5, but not H-7
exchange, although the C(6)–C(7) double bond underwent isomerization 901. This is atributed to the assistance of
the carbamoyl group that formed the oxazoline 900. Hydrolysis of the carbamate group of 899 under basic conditions
affords either pyrrole 902 or pyridine 903 (Scheme 218) <2004OL3933>.
264 Imidazoles
Scheme 218
4.02.7.7 Oxygen-Linked Substituents

In the bicyclic imidazo[2,1-b]oxazole 904, acid-mediated ether bond cleavage occurs selectively at the oxazole carbon to
give either sulfide 905 or iodide 906 <2003S659>. Substitution of an enol phosphate 907 with an iodine function is
achieved with NaI in the presence of HI generated in situ (908, Ar ¼ 3,5-dichlorophenyl) (Scheme 219) <2003TL6509>.
Scheme 219
When a-protons are present in the side-chain of the substituted aminal function of imidazolines such as 909,
isomerizations become easy under acidic conditions, leading to rearrangement products 910 through a sequence of
dehydration, isomerization, and solvolysis (Scheme 220) <1998JOC1248>.
Imidazoles 265
Scheme 220
The carbonyl group in 1-methyl-3-trimethylsilylparabanic acid 911 is activated, relative to the nonsilylated parent,
to undergo addition of primary amines readily. For example, addition of naamine C 912 affords pyronaamidine 913 in
good yield (Scheme 221) <2003H(60)583>.
Scheme 221
4.02.7.8 Sulfur-Linked Substituents

In the presence of BF3, imidazolidine-2-thione reacts with 2-phenyloxirane at the nitrogen to give 1,3-bis[(E)-2-
phenylethen-1-yl]imidazolidine-2-thione (Section 4.02.6.3.3). However, in the presence of SiO2, 1,3-dimethylimida-
zolidine-2-thione 914 reacts with the oxiranes 915 and 918 to give the 1,3-dimethylimidazolidin-2-one 916 and
thiiranes 917 and 919. This S-transfer reaction is highly stereoselective: in the case of (R)-918, the corresponding
thiirane 919 is formed with complete inversion at the chiral center (Scheme 222) <2005HCA3253>.
Scheme 222
266 Imidazoles
Imidazole-2-thiones 920 reacts with a-chlorosulfanyl chloride 921 (n ¼ 0) or a-chlorodisulfanyl chloride (n ¼ 1) to

form di- or trisulfanes 922. Owing to the unfavorable strains introduced by having an sp2 center in a four-membered
ring, these chlorosulfanes are stable to purification and characterization by NMR and X-ray analyses (Scheme 223).
<2003HCA2272>.
Scheme 223
5-Methyl-2-mercaptobenzimidazole 923 is oxidized with ozone to afford mainly sulfonic acid 924 at low tempera-
ture (Table 12, entry 1). The formation of desulfurized product 924 is most likely a result of partial oxidation,
followed by intermolecular reduction by 923. At higher temperatures and in the presence of nucleophiles, substitu-
tion of the sulfonic acid group takes place <1996SC3241>. 2-Mercaptoimidazoline reacts similarly under these
conditions.
Table 12 Ozonolysis of 923
Entry Method Products 924 Yield (%)
1 A (C) a 86 (77)
2 A (C) b 11 (15)
3 B c 67
4 D, NH3 d 63
5 D, MeNH2 e 79
6 D, Et2NH f 71
7 D, Piperidine g 88
Method A: DCM, 25 C; method B: DCM/MeOH (1:1 v/v), 25 C; method

C: DCM/MeOH (1:1 v/v), 0 C; method D: DCM, amine (1.8 equiv/mol), 25 C.
Imidazoline-2-thiones are oxidized with H2O2 (mediated by Na2MoO4-2H2O) to the corresponding sulfonic acid
reproducibly, provided the internal temperature is kept at approximately 4 C <1996JME3533>. Oxidation of
1,3-dihydroimidazole-2-thiones 925 with hydrogen peroxide in an acidic medium affords 1H-imidazole-2-sulfinic
acids 926 as the major products and the desulfurized imidazoles 927 as the minor products (Scheme 224). In a
neutral medium in ethanol the desulfurized imidazoles 927 are the major products and the ethyl esters of
1H-imidazole-2-sulfinic acids 928a–d are the minor products <2004S116>. Oxidative dethionation of 1-benzylimi-
dazole-2-thiones 929 with hydrogen peroxide affords 930, R ¼ CN, NO2, Br, OMe, H cleanly in HOAc
<2003JHC229>.
Imidazoles 267
Scheme 224
In the context of natural product synthesis, sulfide 931 was oxidized with Stang’s reagent to a Pummerer
intermediate that underwent sequential cyclizations to the tetracyclic product 932 (Scheme 225). The latter was
further transformed into the sponge metabolite dibromophakellstatin 933 under oxidative hydrolysis conditions
<2005OL929>.
Scheme 225
4,5-Diphenyl-2-mercaptoimidazole 934 reacts with ketones, in HOAc and in the presence of small amount of
H2SO4 (conc.), to afford the sulfide 935 which, upon treatment with Ac2O, forms 5,6-diphenylimidazo[2,1-b]thiazole
936 (Scheme 226). It has been proposed that disulfide 937 is formed in the ‘acidified’ acetic acid, which then
undergoes thiolation on the enol form of the ketone. Overall, this sequence bypasses the preparation of a-haloketones
for the synthesis of 935. The reaction has rather general scope as exemplified in the Table shown in Scheme 226
<2000JHC943>.
Like 2-haloimidazoles, direct displacement of 2-sulfanyl or even 2-sulfonyl imidazoles with external nucleophiles
is generally a slow process. In contrast, intramolecular ipso-substitution of 2-sulfonylimidazoles 938 (Scheme 227) is
an effective reaction for the synthesis of 2,3-dihydroimidazo[2,1-b][1,3]oxazoles 939, R ¼ Ph, 4-ClC6H4; R ¼ Me, Ph)
<2002S2691, 1999S1613>.
268 Imidazoles
Scheme 226
Scheme 227
Reduction of imidazole thiones 940 with Na/K in THF leads to carbenes 941 (Scheme 228) <2003AGE5243>.
Under similar conditions, imidazoline 943 is formed from 942 <1999CEJ1931>. The carbene 944 can be obtained if
the reaction is conducted in toluene. The intermediacy of a carbene has been proposed for the reaction of 4,4,5,5-
tetramethylimidazolidine-2-thione and ()-valine in the presence of C60 fullerene that leads to the formation of an
open [5,6] adduct <1997TL6613>.
Scheme 228
Imidazoles 269
Displacements of an imidazoline 2-methylthio function by arylamines 946, 948 are generally accomplished by
either reacting 1-acyl-2-thioether 945 under acidic conditions giving 947 <2000T6563> or displacing the sulfonic
acid group 949 which is easily formed under careful oxidation conditions (H2O2, Na2MoO4-H2O, NaCl, 10 to
5 C) 950 (Scheme 229) <1996JME3533>.
Scheme 229
4.02.7.9 Halogen Atoms

Direct displacement reactions of 2-bromoimidazoles with nucleophiles are very difficult. For example, 1-methyl-
2,4,5-tribromoimidazole fails to react with NaOMe <2003S659>. However, intramolecular ipso substitution reactions
such as during the synthesis of 2,3-dihydroimidazo[2,1-b][1,3]oxazoles 952 (Scheme 230) via 951 work well
<2002S2691>.
Scheme 230
2-Haloimidazolidines are commonly generated in situ for the preparation of heteroatom-substitutions at the
2-position. Recent examples include the synthesis of a potent a-adrenergic antagonist 953 (Scheme 231)
<2005BML4691> and a modified dechloroamination procedure using dimethyl chlorophosphate giving 954
<2005SC2633>.
The reaction between heteroaromatic N-oxides and 2-chloro-4,5-dihydroimidazole 955 results in a formal ureida-
tion of the heteroaryls. This reaction was extended to 2- and 4-picoline N-oxides for the synthesis of 956 and 957,
respectively (Scheme 232) <2002JHC911>. The 2-bromine of nitronyl nitroxide 958 is easily displaced with sodium
azolides to give spin-labeled azoles (imidazole, pyrazole, triazole) 959 which are prone to hydrolysis to hydroxamide
acid anion 960 <2004T99>.
Anions derived from halogenated imidazoles are frequently utilized in the formation of C-heteroatom bonds.
Bromolithium exchange of 961 (Scheme 233) followed by azidation 962 and reduction leads to 2-aminoimidazole
963 (PMB ¼ p-methoxybenzyl) <2003H(60)583>. The Mg-imidazolide intermediate from I/Mg exchange of 964,
PBB ¼ p-bromobenzyl) reacts with sulfur dioxide for the synthesis of sulfonamide 965 <2003TL6509>.
270 Imidazoles
Scheme 231
Scheme 232
Scheme 233
Imidazoles 271
Halogenated imidazoles are commonly used in Stille, Heck <1999JOC7158, 2006SL965> 966 to 967
(Scheme 234), Sonogashira <2004TL3621> 968 to 969, and Suzuki reactions with high regioselectivities 970 to
971, 972 <1998H(48)1887, 2005H(65)1975>.
Scheme 234
Early studies of metal–halogen exchange reactions were discussed in CHEC-II(1996). Since then, a number of new
methodologies have emerged <2003TL7115, 2003SL1533, 2000CEJ767>. Sequential halogen–magnesium exchange
reactions <2003AGE4302> of 2,4,5-tribromoimidazole 973 occur regioselectively to give the di- and mono-bromides
974 and 975 in good yields. Earlier studies seem to suggest that chelation through the protecting group at N-1 led to
the observed selectivity (Scheme 235) <2000JOC4618, 2000SL345>. However, iodine at the 5-position 976 can be
exchanged for MgX and subsequently reacted with electrophiles (including Hþ) to give 977 regardless of the nature
of the N-1 protecting groups (MOM, SO2NMe2, SEM, Bn, Me) <2001OL1319, 2003H(60)1, 2005TL2211> 978.
When the 2-position of the imidazole is nonsubstituted, the nature of the N-1 protecting group and the solvent during
the halogen exchange reaction can have noticeable effect on the C-5/C-4 ! C-2 anion isomerization <1997T14481>.
Selective I–Mg exchange of diiodide 979 followed by Pd-catalyzed phosphonylation resulted in the synthesis of (D)-
manno- or gluco-tetrahydroimidazopyridine-2-phosphonates 979 to 980 <2004HCA3035, 2003TL3667>.
2-Substituted 4,5-diiodoimidazoles are converted into the corresponding 4,5-dimagnesioimidazoles upon treatment
with i-PrMgCl (2.4 equiv) in THF at 0–5 C. There are no synthetically useful differences in reactivity between the
two carbanions. It is found that the dilithioimidazoles are rather difficult to form under lithium exchange conditions
<2002JOC2699>.
4.02.7.10 Metals and Metalloid-Linked Substituents

Stille reactions of imidazolyl stannanes such as 981 with 2-bromocinnamyl aldehyde occur in the presence of Ag2O as
a promoter (Scheme 236) <2005HCA707>. An in situ generated stannane from 6,7-dihydro-5H-pyrrolo[1,2-a]imi-
dazole 982 reacted with a heterocyclic iodide under standard Stille conditions to give 983 <2005BML4666>. An
anomalous Stille reaction of 5-stannylimidazole 984 with 3-iodoindole has been reported to give both the ipso-985
and the cine-986 substituted products <1998H(48)11>.
272 Imidazoles
Scheme 235
Scheme 236
Imidazoles 273
Imidazolyl-zinc reagent 987 added to a chiral ketoester with high diasteroselectivity (>10:1) to give 988
(Scheme 237) <2005T4419>.
Scheme 237
4.02.8 Reactivity of Substituents Attached to Ring Heteroatoms

4.02.8.1 Aryl Groups
Directed metallation at the ortho position of the N-phenyl imidazoles 989 during lithiation at imidazole C-2 in the
presence of excess BuLi and TMEDA results in the formation of a dianion which was captured as the bis
diphenylphosphine 990 or 991 <2004T10365>. The traditional Pictet–Spengler reaction has been extended to
arylamines linked to the N-1 position of substituted imidazoles. Thus, polymer-supported 2-imidazol-1-yl aniline 992
was converted into imidazoquinoxaline 993 under mild conditions (Scheme 238) <2005JCO317>. The homolog
triazabenzoazulene 994 was prepared in a similar way <2005JOC4889>.
Scheme 238
4.02.8.2 Alkyl Groups

N-Methylimidazole is efficiently N-demethylated when it is passed through layers of H2O2, sodium salt of 4,6-
dichloro-2-hydroxy-[1,3,5]triazine, and then basic alumina in a column <2004OL541>.
274 Imidazoles
Intramolecular cycloaddition of nitrones 996, derived from aldehydes 995, to the N-tethered olefin leads to the
formation of two regioisomers, 997 and 998. The product distribution depends on the nature of the substituent (R)
(Scheme 239) <2004TA3181>.
Scheme 239
Aldehydes react with imidazole and TBDMSCl to form a rather stable aminal 999 that can be deprotected with HF
in MeCN (Scheme 240) <2001SL1925>. O-tert-Butyldimethylsilylimidazolyl aminals 1000 react with 2 equiv of
organolithium reagents (R9 ¼ Me, n-Bu, Ph, Ar, t-Bu) as if to the parent aldehydes to give the alcohols 1003. The
reaction probably proceeds via the 2-lithioimidazole intermediate 1001, which undergoes a ‘retro-Brook’ rearrange-
ment (to 1002) to generate the aldehyde. In fact, with 1 equiv of R9Li only the aldehyde RCHO is isolated. Blocking
the 2-position of the imidazole results in complete resistance toward R9Li <2003SL1451>.
Scheme 240
The CH2 group of o-imidazol-1-yl)acetophenone 1004 is sufficiently activated by the carbonyl and the imidazole
group that it readily reacts with aldehydes, aromatic diazonium salts (to form diazo compounds) and acrylonitrile. The
reaction of 1004 with phenyl isothiocyanate in the presenceof KOH results in the formation of adduct 1005 that is not
isolated but further condensed with phenacyl bromide to afford thienylimidazole 1006 in 87% yield (Scheme 241)
<2003SC153>. In the presence of a 2-sulfanyl group 1007, the enolate of a-imidazolyl acetophenone 1008 no longer
reacts with aldehydes or even alkyl halides except for MeI 1009 <2002S2691>.
1-(o-Bromoalkyl) imidazole-4-aldehydes 1010 undergo intramolecular oxidative radical cyclization to give the [1,2-c]-
fused imidazole 1011 in moderate yields (Scheme 242). This cyclization is highly regiospecific for [1,2-c] (vs. [1,2-a])
formation. When such a mode of cyclization is blocked as in 1010, only reduction of bromide is operative 1012,
suggesting that nucleophilic addition of the alkyl radical is the rate-limiting step. However, when imidazole-2-
aldehyde 1010 is subjected to the reaction, deformylation product 1013 is isolated <1997TL7937>. This result
suggests that pathways involving the formation of a C-2 radical are competing against oxidative cyclizations.
Imidazoles 275
Scheme 241
Scheme 242
Formation of [1,2-a]-fused imidazoles 1015, 1017 is achieved through having sulfur substituents at the 2-position
as, for example, in 1014, 1016 that serve as radical leaving groups (Scheme 243) <1997TL3793, 1999T4109,
1999T8111>. Alternatively, xanthate 1018 undergoes regioselective radical cyclization in the presence of a stoichio-
metric amount of CSA to promote formation of the [1,2-a]-fused product 1019 <2002OL4345>.
2-Alkyl-1-bromodifluoromethylimidazoles 1020 react with aryl aldehydes in the presence of tetrakis(dimethyl-
amino)ethene as the reducing agent to give 2-alkyl-1-(29-aryl-19,19-difluoro-29-hydroxyethyl)imidazoles 1021
(Scheme 244) <2000TL2265>. A more efficient generation of a heteroaryl-N-difluoromethyl anion is based on
heteroaryl-N-difluoromethyltrimethylsilanes such as 1023, readily prepared from bromide 1022. In the presence of
Me4NF, 1023 reacts with aldehydes or ketones (the latter require stoichiometric Me4NF) to give 1024 or 1025 in
high yields <2001SL374>.
(1-Imidazolyl)methyl benzotriazole or 5-phenyltetrazoles 1026 are double-alkylated to give the heteroaminals
1027 which, under basic conditions, undergo elimination to give N-cycloalkenylimidazoles 1028 (Scheme 245)
<2002JOC8230>.
276 Imidazoles
Scheme 243
Scheme 244
Scheme 245
Imidazoles 277
4.02.8.3 Alkenyl Groups

As a potentially useful protecting group, the vinyl group in N-vinylimidazoles 1029, R ¼ H, SMe, CH(OH)Me,
CH2OH, CHO) is readily cleaved with ozone in the presence of Me2S (Scheme 246) <1997TL4647>. N-Vinyl-
nitroimidazoles <2004JHC701> are reasonably reactive toward 1,3-dipoles for the construction of potential nucleo-
side precursors. For example, 4-nitro-1-vinyl imidazole 1030 reacts with THP-OCH2CNO generated in situ to give
1031 in good yield after deprotection <2005S2695>.
Scheme 246
Radical addition of xanthate to alkenylimidazoles 1032 in anhydrous acidic medium (to ‘neutralize’ the basicity of
the heteroatoms) yields 1033 that can be further functionalized into more complex structures (Scheme 247)
<2002OL4345>.
Scheme 247
Thermolysis of azaene-diyne, 2-ethynyl-1-phenylethynylimidazole, in neat 1,4-cyclohexadiene leads to the forma-

tion of cyclopentapyrazine 1034 and the related cyclopropane 1035. In chlorobenzene, the reaction gives rise to
imidazo[1,2-a]pyridine 1036. These results contrast with traditional enediyne rearrangements in that other reaction
pathways after the Bergman rearrangement are operating in the case of aza-enediynes (Scheme 248)
<2002OL4543>.
Scheme 248
278 Imidazoles
Chiral imidazolidinone organocatalysts such as 1037 form iminium intermediates 1038 with enals that participate
in a variety of directed enantioselective organic reactions including Diels–Alder, 1,3-dipolar cycloadditions, and
Friedel–Crafts alkylations. Conjugate additions such as (hydrido)a-fluorinations/a-chlorinations and intramolecular
Michael additions as well as epoxidations, transfer hydrogenations, and organo-cascade reactions of nonsubstituted
aldehydes in the presence of 1037 are highly efficient processes (Scheme 249) <2006ALD79>. (4R,5R)-4,5-
Diphenylimidazolidine catalyzes enantioselective a-chlorination of ketones <2004AGE5507>.
Scheme 249
4.02.8.4 Acyl and Aroyl Groups

Imidazole and benzimidazole esters are quite reactive towards lithium enolates of ketones. Kinetic studies show that
the reaction involves primarily monomers of the enolates <1999OL145>. This is in contrast to reactions of aryl esters
where both monomers and aggregates of the enolates participate in the reaction. Although (thio)carbonylimidazole
esters are normally formed between alcohols and 1,19-carbonyldiimidazole or 1,19-(thiocarbonyl)diimidazole 1039,
transfer of the imidazole group has been reported in reactions with activated alcohols to give, for example, 1040
(Scheme 250) <1997JOC7319>.
Scheme 250
Di(imidazol-1-yl)methanimine 1041 behaves like cyanogen halides in that both can serve as a nitrile cation equiva-
lents. However, 1041 is a solid and reacts with nucleophiles with high chemoselectivity. Thus, dinucleophiles react with
1041 in refluxing THF to give heterocycles 1042–1046 (Table 13) <2003JHC191>. Sequential treatment of 1041 or
1047 with two different amines affords guanidines 1049 via the intermediate 1048 (Scheme 251) <2002JOC7553>.
Table 13 Dinucleophiles and the products from reactions with 1041
1042, 28–94% 1043, 34% 1044, 61% 1045, 83% 1046, 47%
Imidazoles 279
Scheme 251
Carbamoylimidazolium salts 1050 are versatile electrophiles that react with amines, alcohols, phenols, or thiols to
give the corresponding ureas (Scheme 252) <1998TL6267>, carbamates or thiocarbamates 1051 <1999TL2669>.
Furthermore, salts 1050 react with carboxylic acids in the presence of amines to afford amides 1052, including
Weinreb amides <2003TL7485>.
Scheme 252
Imidazole carboxylic esters of secondary or tertiary alcohols, such as 1053 and 1054, , form carbonates exclusively
with primary alcohols (Scheme 253). Thus, 1054 is a useful reagent for the BOC-protection of primary hydroxyl groups
<1999OL933>. In some cases, 1054 offers better selectivity than pivaloyl chloride in the protection of carbohydrates
<1998S1787>. Similarly, 1-(methyldithiocarbonyl)imidazole 1055 and its methyl triflate salt convert alcohols to
S-methyldithiocarbonates <1997SL1279> and amines to S-methyldithiocarbamates or thioureas <2000T629>.
Scheme 253
Deprotection of the N-alloc group of 3-imidazoline 1056 with Pd(PPh3)4 catalyst gives cleanly the desired
product 1075 if a basic allyl acceptor is used. In contrast, a mixture of 1057 and 1058 is formed when the acidic
allyl acceptor dimedone is used (Scheme 254) <1997TL4359>.
Scheme 254
280 Imidazoles
4.02.8.5 Nitrogen Functions

N-Aminoimidazole 1059 reacts with 2-ethoxybenzoyl chloride to give imidazo[5,1-f ][1,2,4]triazinone 1060, which is
the precursor to the PDE5 inhibitor vardenafil (Levitra) (Scheme 255) <2005JOC7331>.
Scheme 255
4.02.8.6 Silicon, Phosphorus, and Related Groups

Tris- and tetrakis(imidazol-1-yl)silanes are effective dehydrating reagents for the formation of carboxylic acid
derivatives via 1-acylimidazole intermediates <2005CL734>.
4.02.8.7 Sulfur Groups

N-Sulfonyl protecting groups on imidazoles (Scheme 256) are readily cleaved with thiols. For example, the dilithium
salt of thioglycolic acid in DMF removes the tosyl group of 1061 to 2-phenylimidazole in 88% yield at rt in 2.5 h
<2004TL599>. 2-Nitrobenzensulfonamide 1062 reacts with perfluorinated thiol (C8F17C2H4SH) to release imid-
azole in 76% yield after solid-phase extraction through perfluorinated silica <2004TL7991>.
Scheme 256
4.02.8.8 Oxygen Groups

Like other heterocyclic N-oxides, imidazole 3-oxides 1063 react with Ac2O to give the corresponding imidazolones
1064 and 1065 (Scheme 257). TMSCN transforms 1063 into imidazole 2-carbonitriles 1066, whereas alkyl thiones
convert 1063 to 1067 <2000HCA728, 1998HCA1585, 2002AGE2290>. The 2-aminoimidazoles 1068, formed from
the reactions with either isocyanate or isothiocyanate, react further with isocyanates to form ureas but are inert toward
thiourea formation. In contrast to nonaromatic imidazole N-oxides (nitrones), oxides 1063 react with DMAD to form
butanedioates 1069, rather than the (putative) [3þ2] adduct <2000T5405>.
Nitronyl nitroxide 1070 is reduced in the presence of thiourea to imino nitroxide 1071, which is further reduced to
2-imidazoline N-oxide 1072 in high yields (Scheme 258) <2003TL6397, 2005TL3599>.
N-Hydroxyimidazoles are normally converted into the corresponding imidazoles by reductive N–O cleavage with
TiCl3 <1999JME2180>. N–O Cleavage of imidazo[1,2-b]isoxazolidine 1073 can be effected using Raney nickel to
afford pyrrolo[1,2-b]imidazolidine 1074 (Scheme 259) <2000JHC481>. Thermal conversion of 1075 into 1076 has
been reported at high temperatures such as are achieved by microwave irradiation <2004OL2473>.
Imidazoles 281
Scheme 257
Scheme 258
Scheme 259
4.02.9 Ring Syntheses from Acyclic Compounds Classified by Number of Ring

Atoms Contributed by Each Component
4.02.9.1 Formation of One Bond
4.02.9.1.1 Formation of the 1,2- (or 2,3-) bond
This classification is illustrated in Scheme 260. Formation of the 1,2- (or 2,3-) bond via the activation of an amide or
urea group is a versatile method to synthesize imidazoles. Many reagents, such as PPh3-CCl4, PCl5, or acids, etc., have
been used for the cyclization process.
282 Imidazoles
Scheme 260
Treatment of N-acylated a-aminonitriles 1077 with PPh3 and a carbon tetrahalide affords 2,4-disubstituted 5-halo-
1H-imidazoles 1078 in good yields. A variety of alkyl and aryl substituents (R1 and R2) are tolerated. A possible
mechanism involves the formation of a novel seven-membered ring intermediate and then elimination of triphenyl-
phosphine oxide, as illustrated in Scheme 261 <2004OL929>.
Scheme 261
Dipeptides 1079 composed of a C-terminal b-amino a-acid residue undergo cyclization to give imidazolines 1080
in the presence of Ph3PO/Tf2O. The reaction is mediated by bis(triphenyl)oxodiphosphonium trifluoromethansulfo-
nate and includes nucleophilic attack of the tosylamino group on the phosphonium-activated amide carbonyl group.
The imidazolines 1080 are obtained in moderate to very good yields, and with excellent enantioselectivity at both
chiral centers (Scheme 262) <2004OL1681>. The method is also utilized to the synthesis of imidazole-containing
peptides on solid support <2006OL2417>.
A method to synthesize substituted imidazoles starts from 1,2-aminoalcohols 1081 via a four-step procedure, as
demonstrated in Scheme 263. Oxidation of acylated alcohol 1082 leads to a ketone 1083, which is transformed into
imine 1084. Activation of the amide bond with dehydrating agent PCl5 leads to intramolecular cyclization, providing
Imidazoles 283
imidazoles 1085 (Scheme 263) <2002TL7687>. Similarly, the acylated 1,2-aminoalcohols 1086 are converted into
a-amino amides 1087, which undergo cyclization to yield imidazolines 1088 under basic conditions. Oxidation of
1088 with MnO2 in toluene leads to imidazoles 1089 <2004BML3721>.
Scheme 262
Scheme 263
284 Imidazoles
In contrast to the process described in Scheme 261, N-acylated aminonitriles can cyclize to afford imidazoles via
three multi-step procedures. The key intermediate is 2-(pentanoyl)amino-3-methylthioprop-2-enoate derivative
1091, which is obtained by the addition of methyl mercaptan to N-acylated a-aminonitrile 1090. Treatment of
compound 1091 with PCl5/DMAP at low temperature promotes an intramolecular cyclization, yielding 1,2,4,5-tetra-
substituted imidazole 1092. The cyclization also proceeds in moderate yields by a two-step procedure via the
corresponding thioamide intermediate prepared using Lawesson’s reagent. Alternatively, the intramolecular cycliza-
tion is achieved in good yields using H2SO4 in DME at ambient temperature (Scheme 264) <1996S1325>.
Scheme 264
Activation of amide bonds with an acid (usually at elevated temperatures) to facilitate the 1,2- (or 2,3-) bond
formation is a useful method to prepare imidazoles and benzimidazoles (see Section 4.02.9.2(i)). For example,
b-ketoester 1093 possessing a diamino acid (diaminobutanoic acid or ornithine) group is activated by AcOH to
form bicyclic imidazole 1094 <2003SL780>. A library of imidazolines, exemplified in Scheme 265, was prepared
from Ugi products under acidic conditions <1999TL7925>.
Urea 1095 undergoes a cyclodehydration process in the presence of Ph3P-CCl4/Et3N to give 2-aminoimidazolones
1096, presumably through a transient carbodiimide that cyclizes spontaneously <2003TL6509>. Thiourea 1115 is
more reactive than urea 1097 and can transform to imidazolone 1098 with the aid of EDC (Scheme 266)
<2004SL2800>.
A widely applicable method to synthesize benzimidazoles starts from acylated or thioacylated o-phenylenediamine
intermediates (see CHEC-II(1996)). Acids, either Brønsted or Lewis acids, are exclusively used for the amide bond
activation. For example, the cyclodehydration of N-acyl-1,2-phenylenediamines (1099, 1101, catalyzed by HOAc or
BF3?OEt2) provides benzimidazoles (1100, 1102) in excellent yields <2003JHC1107, 2004TL4185>. N,N9-Diacyl 1,2-
phenylenediamines 1103 also cyclize to give benzimidazoles 1104 under acidic condition <1997T457>. Thioamides
such as 1105 are routinely activated by HgCl2 or HgO to give 2-aminobenzoimidazoles 1106 <1999TL1103>. N-(2-
Aminoaryl)thioureas 1107 undergo CuCl-promoted intramolecular cyclization to give the corresponding 2-(N-substi-
tuted amino)benzimidazoles 1108 in good to excellent yields (Scheme 267) <2004TL7167>.
Imines 1110 derived from trifluoromethyl aryl ketones and ortho-phenylenediamines 1109 undergo intramolecular
cyclization to afford 2-arylbenzimidazoles 1111. The reaction is carried out under basic conditions and the CF3 group
serves as a leaving group (Scheme 268) <1999TL4119>.
Imidazoles 285
Scheme 265
Scheme 266
286 Imidazoles
Scheme 267
Scheme 268
1,2-Diaminomaleonitrile derivatives 1112 are useful synthons for the synthesis of imidazoles (see CHEC(1984)
and CHEC-II(1996)). For example, imidazolone 1115 is obtained from the reaction of 1,2-diaminomaleonitrile with
isocyanate 1113 via the intermediate N-[(Z)-2-amino-1,2-dicycanovinylcarbamoyl]-p-toluenesulfonamide 1114
(Scheme 269) <2001JHC939>.
Imidazoles 287
Scheme 269
a-Cyano-a-isocyanoalkanoates (1116, R1 ¼ Me, Et, PhCH2, R2 ¼ t-Bu; or R1 ¼ PhCH2, R2 ¼ Et) react with alk-
oxides to give 4-alkoxy-5-alkyl-1H-imidazoles 1117. When compound 1116 reacts with thiolates, 4H-imidazole-4-
carboxylates 1118 are the major product. The by-product 1119 is formed via thiolate addition to the isocyanide group
(Scheme 270) <1999HCA909>.
Scheme 270
-Amino esters 1121 and 1123, obtained by 1,4-addition of sarcosine or glycine ethyl ester to
conjugated azoalkenes 1120, cyclize to yield 4-methoxycarbonyl-5-methyl-1-ureidoimidazole 1122 and 1-ureido-
5-methyl-4-imidazoline 1124, respectively, in the presence of copper salts (Scheme 271) <1997TL2329,
2001T2031>.
Resin-supported a-bromoacetic acid 1125 undergoes amine displacement, urea formation, and intramolecular
cyclization to afford 3-aminohydantoins 1126. A diverse set of 3-aminohydantoins with different substituents at the
1-position was readily prepared (Scheme 272) <2000TL1165>.
4.02.9.1.2 Formation of the 1,5- (or 3,4-) bond

This classification is illustrated in Scheme 273. As described in CHEC(1984) and CHEC-II(1996), N-substituted
amidines, guanidines, ureas, and related structures are used extensively as starting materials for the synthesis of
imidazoles or benzimidazoles in this category of imidazole ring formation. The other participating functional group is
often either a ketone/aldehyde or an acetal. The cyclization step is usually carried out under acidic conditions
<1996JOC2202, 1997SL521, 1998SL1077, 1997JME18>. Thus, 1-aryl-2-aminoimidazoles 1128 are obtained from an
acid-catalyzed reaction of guanidine acetals 1127 <1996JOC2202> and 2-[(methylamino)methyl]-4,5,6,7-tetrahydro-
1H-benzimidazole 1130 from an amidine acetal 1129 (Scheme 274) <1998SL1077>.
288 Imidazoles
Scheme 271
Scheme 272
Scheme 273
Alkylation of amidine 1131 with 1-bromo-2-methoxy-2-propene affords regiospecifically N-alkylated product

1132. Treatment of 1132 with pyridinium p-toluenesulfonate in aqueous THF provides imidazole 1133 in good
yield. In this reaction, 1-bromo-2-methoxy-2-propene is used as a protected form of a-bromoacetone, which itself
leads to poor yields when reacted directly with amidines (Scheme 275) <2000JME3168>.
Reduction of N-(aminocarbonyl)-a-amino esters 1134 and N-(aminothiocarbonyl)-a-amino esters 1135 with
DIBALH affords 4-hydroxyimidazolidin-2-ones 1136 and 4-hydroxyimidazolidine-2-thiones 1137, respectively.
These substances eliminate a water molecule upon acidic work-up to give imidazol-2-ones 1138 and imidazole-2-
thiones 1139 (Scheme 276) <1997SL521>.
Imidazoles 289
Scheme 274
Scheme 275
Scheme 276
a-Diazo-b-ketoesters 1140 undergo N–H insertion with primary ureas 1141 in the presence of dirhodium tetra-
octanoate to yield a-ureido-b-ketoesters 1142. These ureas 1142 cyclize in the presence of TFA to provide
imidazolones 1143 in 72–85% yields. This chemistry is readily translated onto insoluble polymer resins and was
utilized to prepare a small array of imidazolones (Scheme 277) <2003OL511, 2004JOC8829>.
Reaction of diazenes 1144 with 1,3-keto-amides 1145 leads to 2-imidazolin-2-ones 1147 via a two-step procedure.
The first step involves a regioselective attack of the active methylene group on the diazene to yield Michael adduct
1146. The adduct 1146 then undergoes an acid-catalyzed cyclodehydration to form imidazolin-2-one 1147
(Scheme 278) <2003TL5965>.
290 Imidazoles
Scheme 277
Scheme 278
A protocol involving the intermolecular cyclization between acetals and ureas has been developed to synthesize
imidazolones on solid support. Reaction of polymer-bound glycerol 1148 with bromoacetaldehyde diethyl acetal
gives the cyclic acetal bromide 1149. Amination followed by urea formation affords the resin-bound urea acetals
1150. The aldehydes released from the resin upon treatment with TFA immediately cyclize to give 2-imidazolones
1151 in good yields and purity (Scheme 279) <2002TL4571>.
Scheme 279
Imidazoles 291
A similar strategy for the preparation of substituted imidazolidin-2-ones in two steps from readily available
N-allylamines has been developed. Addition of amines 1152 to isocyanates affords N-allylureas 1153, which are
converted to imidazolidin-2-one 1154 with the formation of two bonds and up to two stereocenters when treated with
aryl bromides and catalytic amounts of Pd2(dba)3/Xantphos in the presence of NaOt-Bu. Based on the stereochemical
and regiochemical outcomes, a mechanism for the transformation has been proposed, as illustrated in Scheme 280
<2006OL2531>.
Scheme 280
Oxidative C–H amination of N-trichloroethoxysulfonyl-protected ureas (1155, R1 ¼ H, R1 ¼ Et, H2CTCH, Ph;

R ¼ Me, R1 ¼ Me, Et, etc.), and guanidines (1157, R ¼ H, R1 ¼ n-Pr, Ph; R ¼ Me, R1 ¼ Me, Et, etc.), to 2-imidazo-
lidinones, 1156, and 2-imino-1,3-imidazolidines, 1158, respectively, has been demonstrated to proceed in high yields
for tertiary and benzylic substrates. The success of these reactions is predicated on the choice of the electron-
withdrawing 2,2,2-trichloroethoxysulfonyl (Tces) protecting group, the commercial catalyst Rh2(esp)2 [dirhodium
bis(,,9,9-tetramethyl-1,3-benzenedipropionate)] (1–2 mol%), and toluene as solvent (Scheme 281)
<2006OL1073>.
Transition metal-catalyzed cyclization of (o-bromoaryl)guanidines 1159 generates substituted 2-aminobenzimid-
azoles 1160. Either copper or palladium complexes have been used, although inexpensive copper salts such as CuI
are generally superior to palladium catalysts. Regioselective cyclizations, where R3 ¼ H, are achieved under CuI/1,10-
phenanthroline conditions. Cyclization of the guanidine occurs preferentially from the less sterically encumbered NH
site, and from an NH-aryl rather than NH-alkyl group <2003OL133>. This procedure is readily transferable onto the
polymer resins <2002JCO359>. A similar process for 2-substituted benzimidazoles 1162 via the palladium-catalyzed
intramolecular N-arylation from (o-bromophenyl)amidine precursors 1161 has also been developed (Scheme 282)
<2002TL1893>.
292 Imidazoles
Scheme 281
Scheme 282
Transition metal-catalyzed intramolecular cyclization has also been applied to the formation of imidazoles.
Palladium-mediated amino Heck reactions of O-pentafluorobenzoylamidoximes 1163 afford 1-benzyl-4-methylimid-
azoles 1164 with a range of substituents at the 2-position. This method is particularly suitable for the preparation of
imidazoles with a chiral substituent at the 2-position (Scheme 283) <2005OL609>.
Amidinyl radicals 1166 are readily generated from amidoxime benzoates, for example, 1165, by treatment with a
stannane-diazo initiator or with Ni-AcOH and captured by an internal olefin to give the corresponding imidazoline
1167. Interestingly, the use of allyl tri-n-butylstannane in the case of substrate 1168 results in the clean formation of
allyl imidazoline 1169. As expected, allylation occurs from the least hindered exo face to give the isomer shown
(Scheme 284) <2003CC1870> (ACCN ¼ 1,19-azobis(cyclohexanecarbonitrile)).
Amidines 1170 substituted with electron-rich aromatic rings undergo an oxidative intramolecular cyclization
process to give N-substituted benzimidazoles 1172. The reaction proceeds well in MeCN with CAN or electro-
chemical oxidation and probably involves the cationic intermediate 1171 (Scheme 285) <1996JOC3902>.
Imidazoles 293
Scheme 283
Scheme 284
Scheme 285
Heating 1-aryl-2-acyl-2-cyanohydrazines 1173 in Ph2O yields 2-aminoacylbenzimidazoles 1174 in poor to excel-

lent yields depending on the nature of the aromatic substituents. A hetero-Cope rearrangement results in the
cleavage of N–N bond. Strongly electron-deficient aromatic rings (e.g., structures with R1 ¼ 4-NO2) are poor
substrates for this reaction (Scheme 286) <1997TL3115>.
294 Imidazoles
Scheme 286
Enantiopure 1,4-disubstituted 2-imidazolines 1179 can be prepared from chiral b-amino alcohols 1175. The
acylated alcohols, N-hydroxyethylamides 1176, are reacted with excess thionyl chloride (or with thionyl chloride
followed by phosphorus pentachloride) to yield N-chloroethylimidoyl chlorides 1177. Treatment of 1177 with amines
or anilines produces N-chloroamidines 1178, which were converted into imidazolines 1179 upon work-up with
aqueous hydroxide (Scheme 287) <2002JOC3919>.
Scheme 287
4.02.9.1.3 Formation of the 4,5-bond

This classification is illustrated in Scheme 288. The synthesis of benzimidazoles via the formation of the 4,5-bond is
an uneconomical process because it requires the formation of a benzene ring from a macrocyclic precursor. On the
other hand, examples of imidazoline and imidazole formation under this category are known. One reaction, useful to
prepare cis-diamines via cis-imidazolines, has been investigated extensively. The process starts with ammonium
hydroxide reacting with aromatic aldehydes 1180 to form 2,4-diazapentadienes 1181. Deprotonation of 2,4-diaza-
pentadienes 1181 with a strong base (PhLi) or under thermal conditions results in formation of the transient 2,4-
diazapentadienyl anion that cyclizes in a disrotatory fashion to furnish cis-imidazolines 1182 (Scheme 289)
<1998TL4785, 1997TL8631>. This simple, stereocontrolled and economical synthesis of ()-cis-2,4,5-triarylimida-
zoline can be carried out with diverse forms of NH3, such as silica-supported ammonium hydrogen carbonate,
alumina-ammonium acetate, and HMDS in the presence of alumina. Microwave irradiation facilitates the ring-closure
process <2004S1249, 2003SL1117, 2003S1236, 2005H(65)353>.
Scheme 288
Imidazoles 295
Scheme 289
Electrocyclization is the key step in a route to 4H-imidazoles 1187 and imidazoles 1188. Thus, activation of
N-acylamidines 1183 with trifluoromethanesulfonic anhydride and subsequent condensation with amino compounds
1185 produces 1-amino-2,4-diazapenta-1,3-dienes 1186. Deprotonation of 1186 by the use of strong organic bases
yields the corresponding 4H-imidazoles 1187 or imidazoles 1188 after amine elimination through an anionic 1,5-
electrocyclization reaction. For the cyclization to occur, the amino compound 1185 needs to possess electron-
withdrawing substituents such as alkoxycarbonyl or fluorenyl groups (Scheme 290) <2004EJO2567>.
Scheme 290
4.02.9.2 Formation of Two Bonds

4.02.9.2.1 From [4þ1] carbon fragments
4.02.9.2.1(i) Formation of the 1,2- and 1,5-bonds
This classification is illustrated in Scheme 291. By definition, imidazole synthesis under this classification requires
an amine or its derivatives as one of the starting materials. Enamines, imines, and isonitriles have been used as the
other reactants. Thus, reaction of primary amines with methyl 3-bromo-2-isocyanoacrylates 1189 leads to methyl 1,5-
disubstituted imidazole-4-carboxylates 1190, which can undergo decarboxylation to give 1,5-disubstituted imidazoles
1191 (Scheme 292) <1996JME596>.
296 Imidazoles
Scheme 291
Scheme 292
Reaction between ethyl 3-N,N-dimethylamino-2-isocyanoacrylate 1192 and a primary amine affords 1-alkyl-4-
imidazolecarboxylates 1193 in good yields. The process is applicable to unhindered alkylamine substrates (R-NH2),
including those containing reactive functionalities such as alcohols and secondary and tertiary amines
<2002OL4133>. Solid-phase bound 3-N,N-dimethylamino-2-isocyanoacrylate 1194 undergoes the same cyclization
under microwave conditions (Scheme 293) <2004TL2219>.
Scheme 293
Heteroarylamines, for example 1195, react with (dimethylamino)propenoate 1196 to yield an imidazolecarboxylate
1199. The imidazole ring is formed via the intermediate diaminoalkenoate 1197, which undergoes an intramolecular
Michael addition followed by a retro-aldol-like reaction (Scheme 294) <1998JHC1527>. Similarly, 4-dimethyl-
amino-2-aza-1,3-dienes 1200, serving as g-dielectrophiles, condense with amines or hydrazines neat at 70 C to form
N-substituted imidazole-4-carboxylates 1201 in 60–75% yields (Scheme 294) <1999TL8097>.
Imidazoles 297
Scheme 294
Cyclization of ketoamides with ammonium salts continues to be the method of choice for preparing structurally
diverse imidazoles, which range from monosubstituted to 1,2,4,5-tetrasubstituted (Scheme 295) <2000JOC4736,
1998TL8939, 2003EJO3209, 2001SL218, 2004JME2318, 2004JME5009, 2004BML3721>. For example, N-substi-
tuted imidazoles 1203 are obtained from the reaction of N-(2,2-dimethoxyethyl)formamides 1202 with ammonium
acetate in good yields <2000JOC4736>. Tetrasubstituted imidazoles 1206 are prepared from ketoamides 1205,
which are derived from a-amino alcohols 1204 <1998TL8939>. Imidazole 1208 was synthesized from chiral a-amino
acid-derived ketoamides 1207 without disruption of the chiral center <2003EJO3209>. Notably, the synthesis of 2,4-
disubstituted imidazoles 1210 was achieved by condensing ketoamides 1209 with ammonium acetate under micro-
wave irradiation <2001SL218>.
Thiazolium-catalyzed addition of aldehydes 1211 to acyl imines 1212 generates a-ketoamides 1213, which
condense with amines in situ to give substituted imidazoles 1214 (Scheme 296) <2004OL843>.
298 Imidazoles
Scheme 295
Scheme 296
N-Alkyl-N-(
-keto)amides 1216 have been prepared using a traceless linker strategy starting from resin-bound
benzylamines 1215. The ketoamides 1217 released from the resin react with an ammonium salt to afford 1,2,4-
trisubstituted imidazoles 1218 in good yields and high purities (Scheme 297) <2000OL323>.
Imidazoles 299
Scheme 297
Replacing the carbonyl group in the ketoamides with a cyano group leads to N-acylated a-aminonitriles (see
Section 4.02.9.1(i)). These compounds, such as 1219, react with ammonium acetate at high temperature to give
cyclized products, imidazoline 1220 and 1H-imidazol-5(4H)-imine 1221 (Scheme 298) <1996H(43)937,
1997T5359>.
Scheme 298
a-Amino acid phenylhydrazides 1222 (R1 ¼ H, Ph, CH2SMe, etc.) react with levulinic acid 1223 providing
imidazolidin-4-ones 1224, which undergo a second ring closure to afford the dihydro-1H-pyrrolo[1,2-a]imidazole-
2,5-diones 1225 (Scheme 299) <2003EJO3840, 2004EJO2833>.
4.02.9.2.1(ii) Formation of the 1,2- and 2,3-bonds

This classification is illustrated in Scheme 300. The annelation of o-phenylenediamines with carboxylic acid
derivatives is the most common method for the syntheses of benzimidazoles. As discussed in CHEC(1984) and
CHEC-II(1996), either Brønsted or Lewis acids can be used to promote the cyclization (e.g., Scheme 301; also see
Section 4.02.9.1(i)) <1998TA2245>. Carboxylic acids and their derivatives, such as acid chlorides, imidates, and
phosgene iminium chloride, have been used in these reactions <2005JME8289, 2006BML4994>.
300 Imidazoles
Scheme 299
Scheme 300
Scheme 301
Aldehydes have been used to condense with o-phenylenediamines, o-nitroanilines, or ethylene diamines to afford
benzimidazoles and imidazolines. Either an oxidation or a reduction process may be required during the annelation
depending on the oxidation state of the starting material. To prepare imidazolines or benzimidazoles from aldehydes
and diamines under anaerobic conditions, the system I2/KI/K2CO3/H2O can be used to oxidize a C–N single bond to a
double bond (Scheme 302) <2006TL79>. Oxidant K3Fe(CN)6 has also been used to promote similar processes
Scheme 302
Imidazoles 301
<2005SC2395>. Reaction of o-phenylenediamine and an aryl aldehyde in the presence of a catalytic amount of
scandium triflate Sc(OTf)3 gives 2-(aryl)benzimidazoles in moderate to good yields. In this transformation, oxygen
serves as the oxidant (Scheme 302) <2004H(63)2769>.
o-Nitroanilines are convenient substrates for the synthesis of benzimidazoles since they are readily available from
the corresponding o-fluoronitrobenzenes. Various reducing agents are effective in promoting the cyclization of
o-nitroanilines with aldehydes. For example, heating a DMSO solution of o-nitroaniline and an aldehyde with
aqueous or solid Na2S2O4 provided a series of benzimidazoles (Scheme 303) <2005S47>. Similarly, in situ reduction
of o-nitroaniline with SnCl2 followed by cyclization with carboxylic acids under microwave irradiation generated
2-substituted benzimidazoles in high yields (Scheme 303) <2005TL6741>.
Scheme 303
The chemistry discussed above is readily transferable onto solid-phase. Many procedures are available to prepare
structurally diverse benzimidazoles on solid support <1996TL4887, 1999TL6185, 1998TL6655, 1998T8055,
1999TL7633, 1999TL7247, 1999TL6443, 1999TL2665, 1997TL5099, 1998TL7467, 2001TL2635, 2001TL1627>.
Two examples are illustrated in Scheme 304 <1996TL4887, 1999TL6185>.
Some special methods have been developed to prepare benzimidazoles. For example, N-alkoxy benzimidazoles
1226, 1227 can be prepared in a simple two-step process from 2-fluoro nitroaromatics. The imidazole-forming step
involves tandem heterocyclization and O-alkylation with an in situ alkylating agent (Scheme 305) <2002TL7707>.
Photolysis of dinitrobenzenes or nitroanilines in alcoholic solution in the presence of TiO2 leads to 2-methylbenz-
imidazoles 1228 in excellent yields (Scheme 306) <1997JOC5222>.
Reaction of 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-dienecarboxylic esters 1229 with 2-amino- or 2-aminomethyl-
anilines 1230 produces cis-5-(benzimidazol-2-yl)pyrroline-2-acetic acid esters 1231 from a double Michael addition
process. Substituents on the nitrogen atoms or in the aromatic ring are tolerated as long as they do not strongly reduce
the nucleophilicity of the nitrogen atoms (Scheme 307) <2005S2357>.
2-Substituted imidazolines are readily prepared from the condensations of 1,2-diaminoalkenes with aldehydes,
carboxylic acids and their derivatives, nitriles, and 1,1-dihaloethenes, etc. Further dehydrogenation with suitable
oxidants leads to the corresponding imidazoles. Some examples are illustrated in Schemes 308 and 309. Thus,
pyridinium hydrobromide perbromide (PHPB) acts as an oxidant when aldehydes 1232 are used as a starting material
<2006SL1479>, and AlMe3 and P2S5 serve as activating reagents when ester 1233 and nitrile 1234 are used
<2002JME32, 2003JME1962, 2003JME2169, 1996JME3929>. Nitriles are also activated by a catalytic amount of
sulfur under ultrasonic or microwave irradiation to form 2-imidazolines 1235 when coupling with ethylenediamine.
The advantages of this system include short reaction times, high yields and the ability to carry out reactions on a large
scale <2006TL2129, 2006T5868>. Condensation of arylhydroximoyl chlorides 1236 with ethylenediamine provides
an alternative way to prepare 2-arylimidazolines (Scheme 308) <1998H(47)1043>.
Imidates 1237 undergo cyclization with ethylene-1,2-diamines in alcoholic solution to afford 2-substituted imid-
azolines 1238 in good yields <2001BMC613, 2005BML5211>. Aryl-1,1-dibromoethenes 1239 react with ethylene-
diamine under mild condition to produce various 2-(arylmethyl)imidazolines 1240. The imidazolines could be further
converted into the corresponding imidazoles by Pd-catalyzed dehydrogenation, Swern oxidation or MnO2 treatment
(Scheme 309) <2004T9857, 2005BML5211>.
302 Imidazoles
Scheme 304
Scheme 305
Scheme 306
Imidazoles 303
Scheme 307
Scheme 308
Scheme 309
304 Imidazoles
Optically active imidazolines are generally obtained from enantiopure 1,2-diamines. For example, chiral ferro-
cenylimidazolines are prepared from ferrocenyl carboxylic acid 1241 (Scheme 310). Amide 1242 is activated by
O-alkylation with Et3OþBF4, generating iminium ether tetrafluoroborate salt 1243. The formation of the imidazoline
ring in 1244 is accomplished by condensation of 1243 with the chiral diamine 1245 at room temperature without the
need to isolate the intermediate imidate 1243 <2005OL4137>.
Scheme 310
Reaction of dimethylformamide dimethyl acetal or formamidine with chiral 1,2-diamines provides optically active
imidazolines <1997JOC3586, 1997JMC2931, 2004OL43> (Scheme 311). In these examples, the 2-position in the
imidazolines is unsubstituted.
Scheme 311
Imidazole-2-thione 1249 can be synthesized from sterically hindered diamine 1248, which is derived from the
corresponding diazide 1247 by an oxidative addition of azide to the nucleophilic carbon–carbon double bond of 1246
(Scheme 312) <2004OL3881>.
Reaction of succindialdehyde, benzotriazole, and N-phenylethylenediamine provides 1-phenyl-5-(benzotriazol-1-
yl)hexahydro-1H-pyrrolo[1,2-a]imidazole 1250. Further reaction of compound 1250 with Grignard reagents affords
1-phenyl-5-substituted-hexahydro-1H-pyrrolo[1,2-a]imidazoles 1251 in good to excellent yields (Scheme 313)
<2000JOC3683>.
Imidazoles 305
Scheme 312
Scheme 313
The reaction of diazonium salts with aqueous solutions of 1,2-diaminocyclohexane mixed with
formaldehyde affords the 1-[2-aryl-1-diazenyl]-3-({3-[2-aryl-diazenyl]perhydrobenzo[d]imidazol-1-yl}methyl)perhy-
drobenzo[d]imidazoles 1252 in 23-66% yields (Scheme 314) <2006JHC217>.
Scheme 314
2-Amino-3-azidoacrylates 1253 undergo aza-Wittig reactions with isocyanates to form 4-substituted 2-amino-
imidazoles 1255 (Scheme 315). Presumably, the carbodiimide 1254 is the reactive intermediate that cyclizes to
form the imidazole ring <1996S1459>.
306 Imidazoles
Scheme 315
An unprecedented attack on an azide group by an iminium species, generated in situ under Vilsmeier conditions,
furnishes a novel route to construct the imidazole ring. Thus, N-aryl-5-chloro-2-(dimethylamino)imidazole-4-carbox-
aldehydes 1257 were obtained from the Vilsmeier cyclization of N-aryl-2-azidoacetamides 1256. The possible
mechanism for the reaction is illustrated in Scheme 316 <1998JOC7136>.
Scheme 316
4.02.9.2.1(iii) Formation of the 1,5- and 4,5-bonds

This classification is illustrated in Scheme 317. Imidazole synthesis under this category is uncommon, as noted in
CHEC(1984) and CHEC-II(1996). One example, in which secondary amino-N-carbothioic acid (phenyl-p-tolylimino-
methyl)amides 1258 react with dimethyl acetylenedicarboxylate to form 4-aminoimidazoles 1259, has been reported.
A reaction mechanism including the formation of a seven-membered cyclic intermediate followed by the extrusion of
thioglyoxylic ester has been proposed (Scheme 318) <2004TL8945>.
Scheme 317
Imidazoles 307
Scheme 318
4.02.9.2.2 From [3þ2] carbon fragments

4.02.9.2.2(i) Formation of the 1,5- and 2,3-bonds
This classification is illustrated in Scheme 319. The Marckwald method has been widely used to assemble
functionalized imidazoles <2003JME3230, 1997JME2571, 2003H(60)593> (Scheme 319). The original procedure
provided a synthetic route to 1-substituted imidazole-2-thione from the reaction of isothiocyanates with aminoacetals
or a-aminocarbonyl compounds. For example, substituted 2-mercaptoimidazoles 1261 are obtained by the condensa-
tion of isocyanates with aminoacetaldehyde diethyl acetal followed by cyclization of the resulting thioureas 1260
under acidic conditions. The coupling of isothiocyanates with 2-aminocyclopentanone 1262 gives the hydroxyl
derivatives 1263, which are converted into the 1-substituted 2-mercapto-1,4,5,6-tetrahydrocyclopent[d]imidazoles
1264 by dehydration with PBr3-pyridine (Scheme 320) <1996JME596>.
Many modified Marckwald procedures are available to prepare structurally diverse imidazoles; most of them are
focused on the preparation of an a-aminoketone or its equivalents. For example, a regiospecific synthesis of
trisubstituted imidazoles has been developed. Thus, treatment of BOC-protected a-amino acids 1265 with malonic
monoester leads to a-aminoketones. After removal of the BOC protecting group, the resulted a-aminoketone salt 1266
will condense with isothiocyanates to form thioureas 1267. The intermediates 1285 undergo cyclodehydration under
acidic conditions, yielding imidazole-2-thiones 1268 in good yields. Both reductive and oxidative desulfonation have
been used to convert the imidazole-2-thiones 1268 into imidazoles (1269 or 1270) (Scheme 321) <2005TL7315>.
Another way to form a-aminoketones from a-amino acids is via the Dakin–West reaction, in which amino acids are
treated with aliphatic acid anhydrides to give ketone amides. Thus, reaction of ()-phenylalanine with the appro-
priate aliphatic acid anhydrides followed by acidic hydrolysis afforded keto-amide 1271. Cyclization of 1272 with
potassium cyanate gave 5-alkyl-4-benzyl-1,3-dihydroimidazol-2-ones 1273 (Scheme 322) <2002JHC375>.
In situ formation of a-aminoketones has been achieved from the reaction of a-hydroxy- or a-haloketones with
amines. 1,3-Dihydroxypropan-2-one has been used as a starting material in the Marckwald synthesis
<1997JME3297>. Also, reaction of 4-chloro-N-methyl-3-oxobutanamide 1274 with amines leads to cyclic (E)-N-
methyl-5-(methylimino)-2,5-dihydrofuran-3-amines 1275, which behave as latent a-aminoketones. Treatment of
1275 with isothiocyanates in refluxing EtOH affords imidazole-2-thiones 1276 (Scheme 323) <2005JCO826>.
308 Imidazoles
Scheme 319
Scheme 320
Scheme 321
Thioamides can serve as surrogates for isothiocyanates in the Marckwald synthesis. For example, reaction of
a-amino acetals 1278 with thioamides 1277 in the presence of HgCl2 affords amidine intermediates, which cyclize to
form imidazoles under acidic conditions. This method has been applied to synthesize a variety of sugar imidazoles
(Scheme 324) <2005HCA10, 2004HCA3035, 2004HCA719, 2000TA435>.
Imidazoles 309
Scheme 322
Scheme 323
Condensation of aryl-derived imidate 1279 with a-aminoacetaldehyde dimethyl acetal gives amidine 1280, which
cyclizes in the presence of TiCl4 to yield N-aryl imidazoles 1281 (Scheme 325) <2004BML333>.
A regiospecific synthesis of N-substituted (aminopyridinyl)imidazole 1286 started with ketone 1282 (cf.
Section 4.02.9.2(i)). a-Oximination of ketone 1282 with isoamyl nitrite under basic condition provides oxime
isomers 1283. Both cis- and trans-oximes 1283 participate in the cyclization process when treated with
1,3,5-trimethyl-1,3,5-triazinane, leading to imidazole N-oxide 1284 that is then reduced with 2,2,4,4-treta-
methyl-cyclobutane-1,3-dithione to give 1285 (Scheme 326) <2003JOC4527, 1999JME2180> (see also Section
4.02.9.3(i)).
Amidinylation of a-aminoketones 1287 with cyanamide or activated guanidines such as pyrazole derivative 1288
affords 2-aminoimidazoles 1289. This method has been applied to prepare L-aminohomohistidine, as shown in
Scheme 327 <2004TL2779>.
Treatment of a-azido esters 1290 with triphenylphosphine gives E-phosphazides 1291, which subsequently react
with isothiocyanates to afford thiohydantoins 1292 after aqueous work-up. The cyclization conditions can also be
adapted to hydantoin synthesis when isocyanates are used (Scheme 328) <2004TL1655>.
Reaction of glycine methyl ester with imidate 1293 under optimized conditions affords the rather unstable
imidazolinone 1294 in ca. 90% yield (Scheme 329). Treatment of 1294 with POCl3/DMF followed by aqueous
work-up gives 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde 1295 in good yield <1999JOC8084, 2004S506>.
310 Imidazoles
Scheme 324
Scheme 325
Scheme 326
Imidazoles 311
Scheme 327
Scheme 328
4.02.9.2.2(ii) Formation of the 1,2- and 4,5-bonds

This classification is illustrated in Scheme 330. Imidazole synthesis under this classification consists mainly of two
approaches: 1,3-dipolar cycloaddition and one-pot addition–cyclization involving isocyano derivatives.
a-Silylimines 1297 derived from N-benzylidenebenzylamine 1296 undergo 1,3-dipolar cycloaddition reactions
with trifluoroacetonitrile to give trifluoromethyl-substituted imidazolines 1298. Both benzoyl chloride and benzyl
chloroformate can be used to facilitate the formation of the azomethine ylide. The resulting 3-imidazolines are
easily cleaved with mild acid hydrolysis to yield the amino-protected trifluoromethyl ketones 1299 <1996JA8485>.
a-Silylimine 1300 behaves similarly to give benzyl 2-methyl-2-phenyl-4-(trifluoromethyl)-2H-imidazole-
1(5H)-carboxylate 1301 in 57% yield (Scheme 331) <1997TL4359>.
312 Imidazoles
Scheme 329
Scheme 330
Scheme 331
4,4-Dicarboxyimidazolines 1304 are obtained from the Lewis-acid-catalyzed [3þ2] cycloaddition reaction of
N-malonylimidates 1302 with imines in good to excellent yields. The cycloaddition proceeds optimally at
ambient temperature with a catalytic amount of MgCl2 in CH3CN. The Lewis acid used in the
reaction promotes a 1,2-prototropic shift to give a metal-coordinated azomethine ylide 1303 <2004JOC8537>.
Similarly, the 1,3-dipolar cycloaddition between N-malonylimidates 1302 and 4-chlorophenyl isocyanate or
ethoxycarbonyl isothiocyanate 1305 as dipolarophiles proceeds regioselectively under solvent-free conditions.
Scheme 332 illustrates the cycloadduct 1307 obtained via 1306 when ethoxycarbonyl isothiocyanate is used as
the reactant <1997T6351>.
Imidazoles 313
Scheme 332
Ruthenium(II)-catalyzed cycloaddition reactions of N-sulfonylimines 1308 with methyl isocyanoacetate 1309 gave
trans-2-imidazolines 1310 stereoselectively in 75–90% yields under neutral, mild conditions [R1 ¼ phenyl, substi-
tuted phenyl, 2-furyl, trans-PhCHTCH, tert-Bu; R2 ¼ tosyl, PhSO2] (Scheme 333) <1997JOC1799>. In contrast, the
same reaction catalyzed by 1 mol% AuCl(c-HexNC) provides 4-methoxycarbonyl-5-alkyl-2-imidazolines 1321 with
over 98% cis-selectivity (Scheme 333) <1996TL4969>.
Scheme 333
Cycloaddition of imines to a münchnone intermediate 1312 is the key step in preparing imidazoles on solid-
support with linkers directly attached to the synthesized imidazole rings. In this manner, imidazoles 1313 with
various aromatic substituents (R1 ¼ Ph, 4-FC6H4; R2 ¼ Ph, 4-FC6H4, 4-MeOC6H4; R3 ¼ 3-pyridyl, 4-pyridyl) are
assembled regioselectively from arylglycines, acyl chlorides, and imines (Scheme 334) <1998JOC2800>.
Condensation of pre-formed imines with tosylmethyl isocyanide (TosMIC) has been widely used to produce
polysubstituted imidazoles <1996JME3929>. Examples include the preparation of 2-imidazolines and di- and
trisubstituted imidazoles (CHEC(1984) and CHEC-II(1996)). The three-component reaction involving the cycload-
dition of TosMICs with imines generated in situ is known as the van Leusen three-component reaction (see also
Section 4.02.9.3(iv)).
The condensation of a-substituted TOSMICs with aldehydes and amines bearing various functional groups has
been investigated in detail <2000JOC1516, 2002JME1697, 2003JME3463, 2005JME6632, 2005TL9053,
1998JOC4529, 2005OL3183>. Traditional imine-forming reactions employing virtually any aldehyde and amine
followed by addition of a substituted TosMIC reagent delivers 1,4,5-trisubstituted imidazoles with predictable
314 Imidazoles
Scheme 334
regiochemistry. Thus, an efficient synthesis of alkyne-derived imidazoles 1314 is achieved in a regioselective fashion
with good yields <2005TL9053>. The reaction works quite well with aldehydes bearing O-functional groups in
different oxidation states, for example, using pyruvaldehyde as a starting material leads to a free keto group in the
product imidazole 1315 <2000JOC1516>, and using glyoxylates leads to an ester group in the product 1316
(Scheme 335) <2000TL5453, 2004JOC977>.
Scheme 335
Imidazoles 315
1,4-Disubstituted imidazoles can also be prepared by a simple variant of the van Leusen procedure. Thus, selecting
glyoxylic acid as the aldehyde component leads to 1,4-disubstituted imidazoles 1317 after decarboxylation.
Alternatively, using NH4OH as the amine component in conjunction with a variety of aldehydes delivers 4,5-
disubstituted imidazoles 1318 in moderate to good yields. Employing chiral amines or aldehydes, particularly
those derived from a-amino acids, produces imidazoles 1319 with asymmetric centers appended to N-1 or C-5,
respectively, with excellent retention of chiral purity (Scheme 336) <2000JOC1516>.
Scheme 336
316 Imidazoles
Variants of TosMIC and imines have also been utilized for imidazole synthesis. For example, benzotriazol-1-
ylmethyl isocyanide (BetMIC), 1320, reacts with aldimines 1321, like TosMIC, to form imidazoles 1322. In this case,
the benzotriazolyl group stabilizes the anion formed in the first step and is spontaneously eliminated from the
intermediate imidazoline. BetMIC derivatives are found to be unstable in the presence of strong bases such as LDA,
n-BuLi, and NaH. The most effective conditions for all of these reactions are found to be potassium tert-butoxide in
DMSO or THF (Scheme 337) <1997H(44)67>.
Scheme 337
Reaction of 1,4-benzodiazepinic N-nitrosoamidines 1323, used as synthetic equivalent of imidoyl chlorides, with
the monoanion of tosylmethyl isocyanide 1324 affords 3-(4-tosyl)imidazo[1,5-a][1,4]benzodiazepines 1325
(Scheme 338) <2004S2697>.
Scheme 338
Base-induced cycloaddition of diethyl isocyanomethylphosphonate 1326 to trifluoroacetimidoyl chlorides 1327

produces 1-substituted diethyl 5-trifluoromethylimidazole-4-phosphonates 1328 with high regioselectivity
(Scheme 339) <1996S511>.
Scheme 339
Imidazoles 317
A Cu2O-catalyzed synthesis of 1,4-disubstituted imidazoles 1331 via cross-cycloaddition between two different
isocyanides (i.e., 1329, 1330) has been reported. The reaction is proposed to start with the activation of a C–H bond
of the isocyanide by the influence of Cu2O catalyst, as depicted in Scheme 340 <2006JA10662>.
Scheme 340
4.02.9.2.2(iii) Formation of the 1,5- and 3,4-bonds

This classification is illustrated in Scheme 341. In this classification, the N–C–N scaffold is embedded in nitrogen-
containing precursors, such as amidines, guanidines, ureas, or thioureas, etc. Reaction of a-halocarbonyl compounds
with amidines or guanidines is one of the conventional methods to prepare substituted imidazoles. However, most of
amidines and guanidines, especially the alkyl-substituted ones, are strong bases and often cause various side-reactions
of the a-halocarbonyl compounds, resulting in lower cyclocondensation yields. Thus, reaction of a-bromoaldehyde
1332 with formamidine provided 5-substituted imidazole 1333 in only a modest 39% yield (Scheme 342)
<2005HCA2454, 2000JME3168>.
Scheme 341
Scheme 342
318 Imidazoles
In contrast, condensation of less basic amidines or guanidines such as N-aryl substituted amidines, acyl and carboxy
guanidines, with a-halocarbonyl compounds provides substituted imidazoles in good yields. For example, arylbenz-
amidine 1334 reacts with ethyl 3-bromo-2-oxobutanoate 1335 to yield 1,2-diaryl-1H-imidazole-4-carboxylate 1336 in
70% yield. Subsequent treatment with acid is needed to complete the dehydration step <2005JME1823>. The
process has been used extensively to synthesize 1,2-diaryl substituted imidazoles, for example, 1337 <1997JME1634,
2005JME2638, 2005JME6516, 2004BML1151>. Similarly, both BOC- and acetyl-protected guanidines have been
used to prepare 2-aminoimidazoles, for instance 1338 (Scheme 343) <2005TL8635>.
Scheme 343
Imidazoles 319
Another way to avoid the direct condensation of a-halocarbonyl with basic amidines or guanidines is to use latent
a-halocarbonyl derivatives. Thus, 2-bromo-3-i-propoxy-2-propenal 1340, acting as a latent a-halocarbonyl compound,
reacts with a range of monosubstituted amidines 1339 to provide imidazolecarboxaldehydes (1341, 1342) in moderate
yields. The nature of the R1 substituent, whether alkyl or aryl, does not seem to influence the yield of the imidazole
product. Employing unsubstituted amidines (R1 ¼ butyl, R2 ¼ H) to synthesize imidazolecarboxaldehydes was unsuc-
cessful. Reaction of 2-bromo-3-methoxy-2-propenenitrile 1343 with monosubstituted amidines 1339 leads to analogous
1,2-disubstituted imidazole-5-nitriles (1344, 1345) with good regioselectivity (Scheme 344) <1997JOC8449>.
Scheme 344
Some naturally occurring carbohydrates, for example, D-fructose (or D-glucose), D-galactose, and L-sorbose, can be
condensed with formamidine acetate under microwave irradiation to give imidazoles 1347. Microwave irradiation
clearly brings about a sequential double condensation of formamidine followed by acid-catalyzed cyclization of the
intermediate linear imidazolyltetritols, for example, 1346 (Scheme 345) <1999HCA2015, 1999EJO893>.
Scheme 345
320 Imidazoles
Imidazolines have been prepared starting from amidines and guanidines. Reaction of amidine 1348 with 2-chloro-
acrylonitrile gives the imidazoline 1349 in 79% yield, aromatization giving the imidazole 1350 (Scheme 346)
<2000JME3168>.
Scheme 346
Reaction of BOC-guanidine with dihydropyridine 1351 in the presence of bromine provides the bicyclic
regioisomers 1352. After removal of the Boc-protecting group, the aminal bond in compound 1353 was
regioselectively cleaved in boiling aqueous NaOH solution to yield the 2-aminoimidazole 1354
(Scheme 347) <2004OL3933>.
Scheme 347
Cyclization of 1-aroyl-3-arylthioureas 1355 with a variety of carbonyl compounds bearing an a-H, in the presence of
bromine and triethylamine, provides 1-aroyl-3-aryl-4-substituted imidazole-2-thiones 1356 <2003OL1657>. The
underlying mechanism of this condensation is illustrated in Scheme 348.
a-Tosyloxylation of ketones 1357 with [hydroxyl(tosyloxy)iodo]benzene, followed by treatment of amidines 1358
provides a one-pot procedure for the synthesis of 1H-imidazole derivatives 1359 (Scheme 349) <2001S2075>.
The cycloacylation of benzamidines 1361 with oxalate-derived bisimidoyl chlorides 1360 provides 4H-imidazoles
1362 in good yields. The same products can also be obtained from the displacement of chlorine atoms in compound
1363 with the corresponding anilines in the presence of triethylamine (Scheme 350) <1997JPR729>.
Imidazoles 321
Scheme 348
Scheme 349
Scheme 350
322 Imidazoles
Primary ureas 1365 are good substrates in rhodium-catalyzed N–H insertion reactions with an array of 2-diazo-1,3-
keto esters 1364. The products from the insertion reaction cyclize with the aid of acid to yield imidazolones 1366.
This chemistry has been translated onto insoluble polymer resins and utilized to prepare a small array of imidazolones
(Scheme 351) <2003OL511, 2004JOC8829>.
Scheme 351
Imidazolin-2-ones 1368 are obtained from b-ketoesters for example 1367 upon treatment with tert-butyl nosylox-
ycarbamate and calcium oxide under mild conditions. A possible pathway to explain this unexpected formation of
imidazolin-2-ones is shown in Scheme 352 <2003OL1019>.
Scheme 352
Imidazoles 323
Reaction of ethyl tosyloxycarbamate 1370 with an electron-rich olefin is the key step in the synthesis of the
pyrrole–imidazole alkaloid dibromophakellstatin 1372. The direct annulation of the imidazolinone ring to pyrrolo-
pyrazinone precursor 1371 is achieved by employing an ethoxycarbonylnitrene generated in situ. Samarium diiodide
proved to be the best reducing agent for the chemoselective, stepwise deprotection, resulting intetracycle 1372
(Scheme 353) <2005AGE2295, 2004OL3881>.
Scheme 353
4.02.9.3 Formation of Three or Four Bonds

4.02.9.3.1 Formation of the 1,2-, 2,3-, and 3,4-bonds
Scheme 354 illustrates this classification. Reaction of keto-oximes 1373 (Ar1 ¼ 4-FC6H4, 3-CF3C6H4; Ar2 ¼ 4-pyrimidinyl,
4-pyridyl), ammonium acetate, aldehydes 1374 (R3 ¼ p-tolyl, Et, 4-MeOC6H4, etc.), and glacial acetic acid in a
microwave vial yields N-hydroxyimidazoles 1375. Reduction of the N–O bond with TiCl3 upon microwave
irradiation affords 2,4,5-trisubstituted imidazoles 1376. Increasing the reaction temperature to 200 C induces a
thermal reductive N–O bond cleavage, thus providing the same polysubstituted imidazoles 1378 in good yields in
one step (Scheme 355) <2004OL2473>.
Scheme 354
Scheme 355
324 Imidazoles
An aza-Wittig reaction utilizing isocyanates leads to ferrocene-containing imidazolones. Thus, condensation of b-

ferrocenylvinyliminophosphorane 1377 with isocyanates provides the carbodiimide intermediate 1378, which can
then be reacted with various amines to give the imidazolones 1379 in good yields (Scheme 356) <1996TL7829>
(see Section 4.02.9.2(i)(b)).
Scheme 356
Treatment of arylglyoxal monohydrates 1380 with tetrasulfur tetranitride 1381 in dioxane at reflux affords 2-aroyl-
5-arylimidazoles 1382 and 2-aroyl-5-aryloxazoles 1383 in 10–31% and 17–32% yields, respectively (Scheme 357)
<1999JHC911>.
Scheme 357
The N-unsubstituted nonstabilized azomethine ylides generated from the desilylation of N-[(trimethylsilyl)methyl]-
iminium triflates [1384, R1 ¼ H, R2 ¼ Ph; R1R2 ¼ (CH2)5, (CH2)2O(CH2)2] cycloadd to strongly polarized sulfonyl-
imines 1385 (Ar ¼ Ph, 4-ClC6H4, 4-O2NC6H4) to produce the corresponding 2-imidazolines, for example, 1387,
together with the initial cycloadducts 1386 (Scheme 358) <2001H(55)243>.
Scheme 358
Imidazoles 325

Scheme 359 illustrates this classification. Bredereck’s formamide cyclization continues to be one of the choices for
the synthesis of 4,5-disubstituted or 4(5)-monosubstituted imidazoles <2005JME6632, 2005H(65)2783, 1997S347>.
Typically, the reaction proceeds at high temperature with formamides and a-haloketones as the starting materials.
For instance, monosubstituted imidazole 1389 is prepared from compound 1388 in 25% yield. 4,5-Disubstituted
imidazole 1391 with a hindered side-chain is obtained from 1390 in 48% yield (Scheme 360) <2000JOC8402>.
Scheme 359
Scheme 360
Treatment of a-halo ketones 1392 (X ¼ Br, Cl) with potassium thiocyanate and monosubstituted hydrazines 1393
provides N-aminoimidazoline-2-thiones [1397, R1, R2 ¼ Me, Ph; R1R2 ¼ (CH2)4; R3 ¼ Ph, 4-O2NC6H4, PhCH2, etc.].
The reaction is considered to proceed via the formation of azo-alkenes 1394 and thiocyanic acid 1395. The
intermediates, in turn, undergo a [3þ2] cycloaddition reaction to give azomethine imine cycloadducts 1396, which
proceed to the final products 1397 (Scheme 361) <1997H(45)691, 2003JME1546>.
Scheme 361
326 Imidazoles
A nonoxidative diamination reaction of a,b-unsaturated ketones 1398 or esters 1401 with N,N-dichloro-p-
toluenesulfonamide 1399 (4-MeC6H4SO2NCl2) and MeCN (one of the nitrogen donors) gives polysubstituted
imidazolines 1400, 1402. Several transition metal complexes have been utilized to catalyze this transformation. For
example, rhodium(II) heptafluorobutyrate dimer is effective to facilitate the reaction at elevated temperatures. The
reaction proceeds at 55 C to afford imidazolines in 57–77% yields. A mechanism is proposed in Scheme 362 to
explain the resulting regio- and stereoselectivity <2002TL3809>. The FeCl3-PPh3 complex can also promote the
nonoxidative diamination of electron-deficient alkenes. Under this catalytic system, a,b-unsaturated carboxylic
esters are better substrates than their ketone counterparts. The reaction proceeds at room temperature without the
special protection of inert gases. Modest to good yields (52–84%) and high regio- and stereoselectivity are achieved
<2001AGE4277>.
Scheme 362
The direct electrophilic diamination reaction of electron-deficient alkenes can be carried out without the use of
any metal catalysts. N,N-Dichloro-p-toluenesulfonamide or the combination of 2-NsNH2/NCS functions as the
electrophilic nitrogen source, and alkanenitriles such as MeCN, EtCN, and n-PrCN as the nucleophilic nitrogen
source. The reaction proceeds with good regio- and stereoselectivity and modest to good yields (35–84%)
<2003JOC5742>. It is proposed that 2-NsNHCl is involved with the nitriles via a [2þ3] cycloaddition mechanism,
which is responsible for the excellent regio- and stereoselectivity of the resulting diamination products (Scheme 363)
<2002JOC4777, 2004T12095>.
Electrophilic diamination of nonactivated alkenes (i.e., 1403, 1407) has been achieved with the combination of
N-chlorosaccharin 1404/CH3CN. The reaction is believed to proceed via a Ritter-type mechanism involving the
attack of the saccharin anion 1411 on an intermediate nitrilium ion 1410, which itself is generated from an alkene-
derived chloronium ion 1409. The resulting b-chloro sulfonylamidines 1412 can cyclize to yield imidazolines 1414
in situ by treatment with potassium ethoxide solution followed by NaH in DMF. The sequence is compromised by
the formation of competing aziridine (i.e., 1406) and allylic chloride byproducts (Scheme 364). Nonetheless, this
methodology compliments the diamination reaction with TsNCl2, which has been mainly limited to the reactions of
electron-deficient alkenes <2003OL3313>.
Imidazoles 327
Scheme 363
4.02.9.3.3 Formation of the 1,2-, 2,3- and 4,5-bonds

This classification is illustrated in Scheme 365. The synthesis of imidazoles under this classification is rare mainly
due to the difficulty of C–C bond formation. A palladium-catalyzed coupling of imines 1415, 1417 and acid chloride
1416 to synthesize substituted imidazoles 1418 belongs to this category of ring formation. N-Alkyl and N-aryl imines
can be used, as can imines of aryl and even nonenolizable alkyl aldehydes. A plausible reaction mechanism involving
1,3-dipolar cycloaddition with münchnones is illustrated in Scheme 366 <2006JA6050>.
A similar example to obtain imidazoline carboxylic acids 1422 from a palladium-catalyzed multicomponent
condensation reaction employs an imine 1420, an acid chloride 1421 and CO (Scheme 367). The reaction is also
believed to proceed through a putative münchnone intermediate <2001AGE3228>.

This classification is illustrated in Scheme 368. Imidazole synthesis via the van Leusen three-component
reaction, in which an amine, an aldehyde, and TosMIC undergo condensation to give imidazoles, is discussed in
Section 9.02.9.1. Like the van Leusen imidazole synthesis, the three-component condensation between an
amine, an aldehyde, and an a-acidic isocyanide (i.e., 1423, 1425) provides substituted 2-imidazolines 1424,
1426 in 47–91% yields. The methodology is limited by the reactivity of the isocyanide and by the steric bulk
on the imine generated in situ rather than by the presence of additional functional groups on the imine. The
isocyanides used in the condensation require an acidic a-proton, such as 2-phenylisocyanoacetate 1423 or 9-
isocyanofluorene 1425. Reactions with less reactive isocyanides 1427, such as p-nitrobenzyl isocyanide, or less
reactive ketones as the oxo-compounds can be promoted by silver(I) acetate <2003OL3759, 2005JOC3542>
(Scheme 369). Ratios refer to anti:syn; only the major diastereomer is depicted. The spiro-2-imidazoline was
prepared from 9-isocyanofluorene.
328 Imidazoles
Scheme 364
Scheme 365
4.02.9.3.5 Formation of four bonds

This classification is illustrated in Scheme 370. The traditional method of three-component condensation of
dicarbonyl compounds (or a-hydroxyketones), amines (including ammonia) and aldehydes are still widely utilized
to prepare poly-substituted imidazoles. In a special case where glyoxal and ammonia are the reactants, 2-substituted
imidazoles such as 1429, 1430 are the products (Scheme 371) <1997TL1275, 1999JME1587, 2002JME2173>.
Synthesis of 2,4,5-trisubstituted imidazoles 1433 is achieved via the reaction of 1,2-diketones 1431 and aldehydes
1432 in the presence of NH4OAc <1996TL7331>. Reaction of protected benzoins 1434 with ammonium acetate
and an aldehyde in the presence of Cu(OAc)2 leads to substituted imidazoles 1435 <1999JME2180, 1997JME3297>.
Highly substituted imidazole libraries have been prepared on Wang resin via ester or ether linkages in the same
three-component condensation process (Scheme 372) <1996TL835, 1996TL751>.
Imidazoles 329
Scheme 366
Scheme 367
Scheme 368
330 Imidazoles
Scheme 369
Scheme 370
Scheme 371
Imidazoles 331
Scheme 372
This three-component reaction also proceeds with excellent yields under microwave irradiation with the use of
solid-supported reagents. For example, alkyl, aryl, and heteroaryl-substituted imidazoles have been obtained in yields
from 80% to 99% with microwave irradiation <2004OL1453>. A solvent-free, microwave-assisted synthesis of
substituted imidazoles 1436 is achieved as a result of the condensation of a 1,2-dicarbonyl compound with an
aldehyde and an amine. Acidic alumina impregnated with ammonium acetate serves as the solid support in the
reaction <2000TL5031>. Similarly, the condensation of a-hydroxyketone 1437 with an aldehyde and a primary
amine on silica gel or alumina impregnated with ammonium acetate affords tetrasubstituted imidazoles 1438. It is
believed that the imidazoline intermediates are oxidized by O2 in situ to give imidazoles (Scheme 373)
<2004H(63)1613, 2004H(63)87>. The condensation of benzil 1439, benzonitrile derivatives and primary amines
on the surface of silica gel under solvent-free and microwave irradiation conditions provides tetrasubstituted
imidazoles 1440 in high yields (Scheme 373) <2003TL1709>.
Scheme 373
332 Imidazoles
Reaction of N-Cbz-protected a-amino glyoxals 1441 with R1CHO and NH4OAc in MeOH gives imidazoles 1462.
The chirality of the side-chains, originating from a-amino acids or dipeptides, is retained during the cyclization
<2000TL1275>. Alkenyl tricarbonyl esters 1443 undergo a similar reaction with aldehydes and NH4OAc to form
imidazole carboxylic esters 1444 <2002TL3351>. Esters 1445 derived from a-hydroxy acetophenone condense with
NH4OAc at elevated temperature to afford 2,4-disubstituted imidazoles 1446 (Scheme 374) <2004BML3521>.
Scheme 374
3,3,3-Trifluoro-2-oxopropanal 1-(dimethylhydrazone) 1447 is a synthetic equivalent of trifluoropyruvaldehyde.

Like its 1,2-dicarbonyl counterpart, compound 1447 participates in the condensation reaction with aldehydes and
ammonium acetate to afford 4-trifluoromethylimidazoles 1448 in 42–72% yield <2003H(60)1185>. 1,1,1-Trifluoro-
2,3-alkanediones 1449, also 1,2-dicarbonyl equivalents, condense with aldehydes and aqueous ammonia to yield
4-(trifluoromethyl)imidazoles 1450 <2001JHC773>. 3-(Dimethylhydrazono)-1,1,1,4,4,4-hexafluoro-2-butanone
1452, obtained from the reaction of trimethylacetaldehyde dimethylhydrazone 1451 with TFAA, reacts in situ with
aldehydes in aqueous ammonia solution to afford 4,5-bis(trifluoromethyl)-1H-imidazoles 1453 (Scheme 375)
<2000TL9267>.
4.02.10 Ring Syntheses by Transformations of Another Ring

4.02.10.1 Ring Expansions
A wide range of aziridine derivatives undergo Ritter reactions with nitriles in a regio- and stereoselective manner to
yield imidazolines. Various Lewis acids are capable of promoting this ring-opening process. For example, BF3?OEt2
catalyzes the reaction of chiral 2-(1-aminoalkyl)-aziridine 1454 with nitriles to provide enantiopure 2,4,5-trisubsti-
tuted imidazolines 1455. The neighboring amino group facilitates the ring opening step during the reaction
<2004OL4499>. Similarly, silyl groups can assist the process by stabilizing the positive charge on a carbon through
the b-effect of silicon. Thus, 2-tert-butyldiphenylsilylmethyl-substituted aziridines 1456 undergo [3þ2] cycloaddition
with nitriles in the presence of BF3.OEt2 to yield imidazolines 1457 (Scheme 376) <2005JA16366>.
Imidazoles 333
Scheme 375
Scheme 376
334 Imidazoles
N-Tosylaziridines can be transformed to imidazolines without neighboring group assistance. Thus, Lewis acids
such as BF3-OEt2 or ZnBr2 catalyze ring opening of phenyl N-tosylaziridine 1458 with CH3CN to yield imidazolines
1459 in good yields <2004TL1137, 2005TL4103>. Sc(OTf)3 promotes a similar reaction in the absence of organic
solvent to afford the corresponding imidazolines 1460 in good to excellent yields (Scheme 377) <2006TL1509>.
Scheme 377
Aminomethylaziridines 1461 react with triphosgene and NaH to give 5-alkyl- or 5-aryl-4-chloromethylimidazolidin-
2-ones 1463 (Scheme 378). The reaction proceeds through the formation of the aziridium ion intermediate 1462 and
the addition products are obtained in yields of 71–97% regardless of the stereochemistry <2005T9281>.
Scheme 378
Reaction of 2-vinylaziridines 1464 with various heterocumulenes (i.e., 1465, 1467), catalyzed by [Pd(OAc)2] and
PPh3 at room temperature, affords five-membered ring products 1466, 1468 in moderate to high yields. The reaction
is regioselective and involves a Z3–Z1–Z3 interconversion of a (p-allyl)palladium intermediates (Scheme 379)
<2000JOC5887, 1998JOC17>.
This ring transformation also proceeds asymmetrically in the presence of catalyst (Z3-C3H5PdCl)2 and Trost
chiral ligands to form cyclic ureas 1469 in 13–95% yields and 52–99% enantiomeric excesses <2003JA11836>
(Scheme 380). Cycloaddition of aziridines 1472 with isocyanates 1470 also proceeds smoothly in the presence
of a nickel catalyst. The initial imino-oxazolidine products 1473 can be isolated in good yields. A longer
reaction time allows the isomerization of the imino-oxazolidine to the corresponding imidazolidinones 1474.
The best results are obtained when the reaction is carried out in the presence of NiI2 (Scheme 380)
<2006OL379>.
Imidazoles 335
Scheme 379
Scheme 380
336 Imidazoles
4.02.10.2 Transformations of Other Five-Membered Rings

1,3-Dipolar cycloaddition reactions of N-substituted mesoionic oxazolones (or münchnones) with imines provide a
general route for the syntheses of imidazoles and imidazolines <1998JOC2800, 2002OL3533>. For example, TMSCl
promotes the reaction of 2-phenyl-4-methyl-4H-oxazolin-5-one 1475 with imines generated in situ to afford imid-
azolines 1476 with high diastereoselectivity. Only the trans diastereomers (with respect to R2 and R3) of the
imidazolines are observed. A [3þ2] cycloaddition mechanism has been proposed to account for the observed high
diastereoselectivity. Typical products are illustrated in Scheme 381 <2002OL3533, 2005OL5091, 2003S1433,
2004JA12776>.
Scheme 381
Reaction of aldehyde 1477 with TosMIC and NaCN yields tosyl-substituted oxazoline 1478, which is converted
into imidazole 1479 with ammonia at elevated temperature (Scheme 382) (see also van Leusen imidazole synthesis
in Section 4.02.9.2(ii)(b)) <2005JME2100, 2003JME5445, 1999JME1115>.
Imidazoles 337
Scheme 382
A novel ring transformation/desulfurization of substituted 2-methyl-1,2,4-thiadiazolium salts 1481 provides a

versatile entry to imidazoles 1482 with a variety of substituents. The starting 1,2,4-thiadiazolium salts 1481 can be
prepared from N-(thiocarbonyl)-N9-methylamidines 1480 under mild oxidative conditions. Related salts, 1,2,4-
dithiazolium triiodides 1483, also react with amines to form imidazoles 1484 <1997JOC3480>. Alternatively,
N-(thiocarbonyl)-N9-methylamidines 1485 can be transformed into 1-substituted imidazoles 1487 via S-methylation
followed by elimination of methylthiol (Scheme 383) <1997JOC3480>.
Scheme 383
338 Imidazoles
Pyrolysis of 1-aroylamino-4,5-diphenyl-1,2,3-triazole 1488 yields 2-aryl-4,5-diphenylimidazole 1489 as the major

product (Scheme 384) <1998JHC891>.
Scheme 384
Cyclic nitrones 1490 (3-imidazoline 3-oxides) react regioselectively with alkyl phenylpropiolates 1491 (or with
dimethyl acetylenedicarboxylate) to give the corresponding 2-phenyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazole-3-
carboxylic acid alkyl esters 1492. Subsequent thermal, base (piperidine, triethylamine, or alkoxide) induced ring-
opening reactions led to imidazoles 1493 (Scheme 385) <2004SC1617, 2000TL5407>.
Scheme 385
(Z)-1-(59-Methyl-19,39,49-thiadiazol-29-yl)-4-arylidene-4,5-dihydro-2-phenylimidazol-5-ones Z-1496 are prepared

by the condensation of (Z)-4-arylidene-4,5-dihydro-2-phenyloxazol-5-ones 1494 with 2-amino-5-methyl-1,3,4-thia-
diazoles 1495 on basic alumina under microwave irradiation. The E-1496 isomers are also formed as minor products
(Scheme 386) <2001S1509>.
Scheme 386
N-Monosubstituted 1,2-diaminobenzenes 1497 (R ¼ Me, Ph, PhCH2, and 3,4-Me2C6H3CH2) react with 4,5-
dichloro-l,2,3-dithiazolium chloride 1498 in dichloromethane at room temperature to give the corresponding imines
1499 which undergo thermolysis to form 2-cyanobenzimidazoles 1500 in fair to good yields (Scheme 387)
<1998T9639>.
Reaction of N,N-dialkyl dichloromethaniminium chlorides 1501 with 2-aminoacetophenones 1502 provides a
general route to the formation of 5-aryl substituted 2-(dialkylamino)-1,3-oxazolium salts 1503; these can also be
prepared from the corresponding 5-aryl substituted 2-(dialkylamino)-1,3-oxazoles by alkylation with (MeO)2SO2.
Treatment of 1503 with NH4OAc gives 1-substituted 4-aryl-2-(dialkylamino)-1H-imidazoles 1504 (Scheme 388)
<1999HCA1981>.
Imidazoles 339
Scheme 387
Scheme 388
Reduction of 4-nitro-5-amino-2,1,3-benzothiadiazole 1505 with Sn/HCl in the presence of a carboxylic acid having
a C(1)–C(3) chain yields the corresponding 2,5-dialkylbenzo[1,2-d:3,4-d9]diimidazoles 1506 (Scheme 389)
<1998H(48)113>.
Scheme 389
Irradiation of 3-[o-(alkylamino)phenyl]-5-methyl-1,2,4-oxadiazole 1507 leads to concomitant formation of benz-

imidazoles 1509 and indazoles 1508, presumably arising from a common photolytic species, as shown in Scheme 390
<1996JOC8397>.
Scheme 390
340 Imidazoles
A novel singlet oxygen ring cleavage of 4,5-bis(4-fluorophenyl)-,-bis(trifluoromethyl)-1H-pyrrole-2-methanamine

1510 and subsequent acid-catalyzed facile dehydrocyclization gave 4,4-bis(trifluoromethyl)imidazoline 1512
(Scheme 391) <1996T11153>.
Scheme 391
3,5-Dichloro-2H-1,4-oxazin-2-one 1513 reacts with a-amino ketones e.g. 1514 to yield bicyclic imidazo-fused
intermediates 1516 via an intramolecular cyclization reaction. Reaction of lactones such as 1516 with various
nucleophiles generates substituted 1H-imidazoles such as 1517 (Scheme 392) <1999T3987>.
Scheme 392
4.02.10.3 Ring Contractions

5-Acylamino-6-hydroxymethyl-3-phenylpyrimidin-4(3H)-one 1518 undergoes a ring contraction process in basic
alcoholic solution to afford 2-alkyl-5-hydroxymethyl-4-phenylcarbamoyl-1H-imidazole 1519. 5-Amino-6-benzoylxy-
methyl-3-phenylpyrimidin-4(3H)-one 1520 is oxidized with CuCl2 in alcohol to give 2-methoxy-5-alkoxymethyl-4-phe-
nylcarbamoyl-1H-imidazole 1521 in 9% yield, accompanied by 5-amino-6-methoxymethyl-3-phenylpyrimidin-4(3H)-one
1522 as the major product (Scheme 393) <1997JHC761>.
Imidazoles 341
Scheme 393
Mild alkaline treatment of 5-bromo-29-deoxyuridine 1523 results in a ring contraction of the pyrimidine to form the
imidazolinone nucleoside 1524. The a-anomer was isolated after chromatographic purification (Scheme 394)
<2005T5081>.
Scheme 394
Reaction of 2-aminopyrimidines 1525 with a-bromocarbonyl compounds 1526 affords imidazo[1,2-a]pyrimidinium

salts 1528, which undergo a ring-opening process in the presence of hydrazine to yield 2-aminoimidazoles 1529 in
good yields (Scheme 395) <2006OL5781>.
Scheme 395
342 Imidazoles
4.02.11 Synthesis of Particular Classes of Compounds and Critical Comparison

of the Various Routes Available
4.02.11.1 Imidazole and Benzimidazole Oxides and Radicals
Imidazole and benzimidazole N-oxides are invariably prepared via ring-closure processes (CHEC(1984) and CHEC-
II(1996)). The synthetic routes for the preparation of 1H-imidazole N-3-oxides (e.g., 1532, 1536) usually involve
electrophile–nucleophile (such as 1,2-diimine-a-oximineketone) or nucleophile–electrophile (oxime–formaldimine)
synthons. For example, cyclization of 1,2-diimines 1530 with oximes 1531, performed under solvent-free conditions
using silica gel and aluminium oxide as supports and catalysts, gives imidazole N-oxides 1532 <1996H(43)1465,
2004S2678>. Imidazole N-oxides 1536 are obtained as crystalline products in high yields (58–95%) from the reaction
of a-(hydroxyimino)ketones 1534 with 1,3,5-trisubstituted hexahydro-1,3,5-triazines 1533 (Scheme 396)
<1998HCA1585, 2004JME6311>.
Scheme 396
A procedure for 1-alkyl(aryl)-1H-4-methylimidazole N-3-oxides 1539 involves the cyclocondensation of a-amino-

oximes, for example, 1537, and orthoesters 1538. Low yields (6–27%) in the cyclization process are due to the
predominant Z-stereoisomer around the oxime moiety in 1537 (Scheme 397) <2004S2678>.
Scheme 397
Imidazoline N-oxides or radicals can be produced from the oxidation then reduction of the corresponding
N-hydroxy imidazolines. Thus, imidazoline-derived biradicals 1542 and 1543 were prepared from 1,3-di(N-imidazo-
lyl)benzene bis-aldehydes 1540. The 1,3-dihydroxy-4,4,5,5-tetramethyl imidazolidine 1541 was oxidized with NaIO4
to yield 1,3-bis{2-(1-oxyl-3-oxo-4,4,5,5-tetramethylimidazolin-2-yl)imidazol-1-yl}benzene 1542. Reduction of 1542
with NaNO2 in acetic acid affords 1,3-bis{2-(1-oxyl-4,4,5,5-tetramethylimidazolin-2-yl)imidazol-1-yl}benzene 1543 in
85% yield <1997JOC8854>. Oxidation of N,N9-dihydroxyimidazolines 1544 then NaNO2 treatment yields imidazo-
line oxyl 1545; PbO2 can also be used <2004JST(697)49>. Compound 1546 is obtained in a one-pot reaction
(Scheme 398) <1997S1049>.
2-Substituted 1-oxo-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazoles 1548 have been prepared from N-hydroxy
imidazoline 1547, as shown in Scheme 399 <2004JST(697)49>.
Imidazoles 343
Scheme 398
Scheme 399
Treatment of 4H-imidazoles 1549 with dimethyldioxirane resulted in formation of amino-nitrones 1550 regio-
selectively (Ar ¼ 4-MeC6H4, 4-MeOC6H4, 4-t-BuC6H4, naphthyl). Compounds 1550 are unusually stable due to
contributions from anionic as well as cationic delocalized mesomeric structures (Scheme 400) <2000JPR245>.
Scheme 400
344 Imidazoles
Reaction of N-n-butyl-2,6-dinitroaniline 1551 with NaOH in 60% dioxane–water at reflux provided 7-nitro-2-n-
propylbenzimidazole 3-oxide 1552. Two nitro groups ortho to the amine are needed for this transformation to occur
(Scheme 401) <1996TL767>.
Scheme 401
4.02.11.2 Nitroimidazoles
Formation of nitroimidazoles via ring-closure approaches is rare (see CHEC-II(1996)), and most nitroimidazoles have
been prepared from 4(5)-nitroimidazoles and 1,4-dinitroimidazoles <2005JME4378, 2004OL1853, 2005JHC883,
2005SC2259, 2003JHC523, 2003EJO1080, 2002H(57)1689, 2002TL4127, 2002PJC67>. Access to 5-nitroimidazoles
bearing one or more tri- or tetrasubstituted ethylenic double bonds at the 2-position via the versatile SRN1
methodology has been reviewed <B-1998MI(2)547>. In addition, N-alkylation of 4(5)-nitroimidazoles
<2005JHC883, 2005JME4378, 2004OL1853>, nucleophilic substitution of 4-nitro-haloimidazoles <2005SC2259>
and nucleophilic addition-elimination of 1,4-dinitroimidazoles <2004OL1853> have been successfully applied to
prepare other nitroimidazoles. For example, the reaction of 1,4-dinitroimidazoles 1553, 1556 with amines 1554, 1557
proceeds via nucleophilic addition of the amine to the imidazole 5-position, ring opening, and then ring closure with
expulsion of NO2NH2 to yield the N-substituted-4-nitroimidazoles 1555, 1558 (Scheme 402) <2004OL1853,
2003EJO1080>.
Scheme 402
The synthesis of 1-methyl-2,4,5-trinitroimidazole 1564 illustrates a general approach to 4(5)-nitroimidazole and

1,4-dinitroimidazole (Scheme 403). Thus, imidazole is converted in good yield into 4-nitroimidazole 1577 with the
mixed acid comprising 70% nitric acid and concentrated sulfuric acid. Treatment of 4-nitroimidazole with acetyl
nitrate (acetic anhydride and fuming nitric acid in acetic acid) at low temperature afforded 1,4-dinitroimidazole 1560.
Subsequent thermal rearrangement in refluxing chlorobenzene produces 2,4-dinitroimidazole 1561. The third
nitration to 2,4,5-trinitroimidazole 1562 can be performed in mixed acid conditions. The product itself is not stable
enough to be isolated; however, its salt, that is, potassium 2,4,5-trinitroimidazole 1563, can be obtained in good yield
when treated with K2CO3/KCl solution. The N-methylated derivative 1582 is easily obtained from the 2,4,5-
trinitroimidazole salt (Scheme 403) <2001JHC141>.
Imidazoles 345
Scheme 403
4.02.11.3 Fluoroimidazoles
Photochemical Balz–Schiemann reaction of diazonium fluoroborates continues to be the method of choice to prepare
fluoro substituted imidazoles. Thus, 4(5)-fluoroimidazole 1565 is prepared from 4(5)-nitroimidazole 1559 in mod-
erate yield by conversion of the nitro group to the diazonium salt followed by irradiation in aqueous tetrafluoroboric
acid. Sugar-fluoroimidazole derivatives 1566 and 1567 were prepared using an N-silyl derivative of 1565
(Scheme 404).
Scheme 404
4,5-Difluoroimidazole 1571 has been prepared from 5-fluoroimidazole-4-carboxylic acid ethyl ester 1568. The
ester 1586 is converted into the carbonyl azide 1569, which undergoes Curtius rearrangement in tert-butyl alcohol to
produce 4-t-butyloxycarbonylamino-5-fluoroimidazole 1570. In situ diazotization of the resulting amine and irradia-
tion produces 4,5-difluoroimidazole 1571 (Scheme 405) <2001JFC(107)147>.
346 Imidazoles
Scheme 405
Photochemical trifluoromethylation of 4-fluoro-5-methylimidazole 1572 provides the trifluoromethyl derivative

1573 in 53% yield. Similarly, 4-fluoro-2-methylimidazole 1574 gives 4-fluoro-2-methyl-5-(trifluoromethyl)imidazole
1575 in 26% yield (Scheme 406) <1998JOC9448>.
Scheme 406
Fluorination of an imidazole side-chain has been reviewed <2004JFC(125)501>.
4.02.11.4 Selenoimidazoles
1-Mesityl-1,3-dihydroimidazole-2-selone 1576 is prepared in three steps from readily available 1-mesitylimidazole:
(1) deprotonation with n-BuLi, (2) treatment with elemental selenium, and (3) addition of HCl (aq). Diselenide 1577
is obtained via the air oxidation of 1576 (Scheme 407) <2006JA12490>.
Scheme 407
Imidazoles 347
Reaction of isoselenocyanates 1579 with a-lithiated a,a-disubstituted isocyanides 1578 such as a,a-methylbenzyl
isocyanide and diphenylmethyl isocyanide at 78 C for 1 h affords 2-butylseleno-2-imidazoline-5-selones 1580 after
trapping with butyl iodide. The yields for these reactions range from 73% to 97% (Scheme 408) <1997T13667>.
Scheme 408
4.02.12 Applications and Importance

Imidazole analogues, such as histamine and histidine, display many important biological functions, as discussed in
CHEC(1984) and CHEC-II(1996). The applications of imidazoles in pharmaceuticals are also well documented, as
demonstrated in many drugs such as histamine receptor (H2) antagonist Cimetidine and angiotensin II receptor
antagonist Losartan. Figure 40 shows the structures of some marketed imidazole-based drugs.
The imidazole-derived structures such as imidazol-2-ylidene 9 and imidazolidin-2-ylidene 10 (see Figure 1) are
generally referred to as N-heterocyclic carbenes. They exhibit properties strikingly similar and even superior to those
of the electron-rich organophosphanes PR3. Therefore, phosphorus ligands have often been advantageously replaced
by N-heterocyclic carbenes as ligands in transition metal catalysis <2005JOC3542>. NHC-containing organometallic
catalysts are much more effective than conventional catalysts in a number of reactions. One of the most well-
established applications of N-heterocyclic carbenes is the second generation of Grubbs’ ruthenium–NHC complex,
which catalyzes olefin-metathesis reactions <1999OL953> (Figure 41). NHCs have also been shown to be excellent
ligands in complexes which catalyze Heck and Suzuki coupling reactions <2002AGE1290, 1997AGE2162,
2005TL6265>. Chiral NHCs and their transition metal complexes are used as chiral catalysts in asymmetric
transformations <2004CSR619, 2003TA951>. Imidazo-2-ylidene and imidazolidin-2-ylidene derived carbenes are
also strong bases and have been used as catalysts themselves <2005OL3949, 2004AGE5130>.
Figure 40
348 Imidazoles
Figure 41 Grubbs’ catalyst, second generation.
1,3-Disubstituted imidazolium salts belong to a class of novel solvents known as ionic liquids. Imidazolium-based
ionic liquids possess very interesting properties, such as negligible vapor pressure, ability to dissolve organic,
inorganic, and polymeric materials and high thermal stability. Thus, ionic liquids have gained popularity as ‘green’
alternatives to volatile organic solvents, to be applied in electrochemical, synthetic, and separation processes
<1999CRV2071, 2002CRV3667>.
References
1957CIL893 R. Breslow, Chem. Ind., 1957, 893.
1957JA1762 R. Breslow, J. Am. Chem. Soc., 1957, 79, 1762.
1960AG494 H. W. Wanzlick and E. Schikora, Angew. Chem., 1960, 72, 494.
1970LA176 H. Schoenherr and H. Wanzlick, Liebigs Ann. Chem., 1970, 176.
1977JHC937 E. Barni and P. Savarino, J. Heterocyl. Chem., 1977, 14, 937.
1977JOC3586 Y. Hsiao and L. S. Hegedus, J. Org. Chem., 1997, 62, 3586.
1984J(P1)2559 M. W. Anderson, M. J. Begley, R. C. F. Jones, and J. Saunders, J. Chem. Soc., Perkin Trans. 1, 1984, 2559.
1986J(P1)205 M. W. Anderson, R. C. F. Jones, and J. Saunders, J. Chem. Soc., Perkin Trans. 1, 1986, 205.
1986J(P1)1995 M. W. Anderson, R. C. F. Jones, and J. Saunders, J. Chem. Soc., Perkin Trans. 1, 1986, 1995.
1990SC2483 Y. Amemiya, D. D. Miller, and F. L. Hsu, Synth. Commun., 1990, 2483.
1991AGE674 M. Regitz, Angew. Chem., Int. Ed. Engl., 1991, 30, 674.
1991JA361 A. Arduengo, R. Harlow, and M. Kline, J. Am. Chem. Soc., 1991, 113, 361.
1991J(P1)2691 D. H. Davies, J. Hall, and E. H. Smith, J. Chem. Soc., Perkin Trans. 1, 1991, 2691.
1992JACS5523 H. Tokuyama, M. Isaka, and E. Nakamura, J. Am. Chem, Soc., 1992, 114, 5523.
1992TL659 P. López-Alvarado, C. Avendaño, and J. C. Menéndez, Tetrahedron Lett., 1992, 33, 659.
1995JOC8015 M. Chahma, C. Combellas, and A. Thiebault, J. Org. Chem., 1995, 60, 8015.
1996CHEC-II(3)168 M. R. Grimmett; in ‘Comprehensive Heterocyclic Chemistry II’, A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Eds.;
Pergamon, Oxford, 1996, vol. 3, p. 168.
1996H(43)49 J. Zou, Z. Lu, L. Qiu, and K. Chen, Heterocycles, 1996, 43, 49.
1996H(43)937 H.-Y. Li, I. Delucca, S. Drummond, and G. A. Boswell, Heterocycles, 1996, 43, 937.
1996H(43)1375 I. Kawasaki, N. Taguchi, Y. Yoneda, M. Yamashita, S. Ohta, and Kyoto, Heterocycles, 1996, 43, 1375.
1996H(43)1465 J. Alcázar, M. Begtrup, and A. de la Hoz, Heterocycles, 1996, 43, 1465.
1996HCO305 J. Bergman and D. Koch, Heterocycl. Commun., 1996, 2, 305.
1996HCA767 M. Reist, P.-A. Carrupt, B. Testa, S. Lehemann, and J. J. Hansen, Helv. Chim. Acta, 1996, 79, 767.
1996JA2039 C. Boehme and G. Frenking, J. Am. Chem. Soc., 1996, 118, 2039.
1996JA2091 J. O. Link and K. Straub, J. Am. Chem. Soc., 1996, 118, 2091.
1996JA6317 P. v. R. Schleyer, C. Maerker, A. Dransfeld, H. Jiao, and N. J. R. van Eikema Hommes, J. Am. Chem. Soc., 1996, 118, 6317.
1996JA8485 C. W. Derstine, D. N. Smith, and J. A. Katzenellenbogen, J. Am. Chem. Soc., 1996, 118, 8485.
1996JCH(729)1 M. G. Quaglia, E. Bossu, G. C. Porretta, M. Biava, R. Fioravanti, L. Romanelli, and A. Leonardi, J. Chromatogr., A, 1996,
729, 1.
1996JCM244 H. Suzuki and N. Nonoyama, J. Chem. Res. (S), 1996, 244.
1996JME596 M. Yamada, T. Yura, M. Morimoto, T. Harada, K. Yamada, Y. Honma, M. Kinoshita, and M. Sugiura, J. Med. Chem., 1996,
39, 596.
1996JME3533 S. A. Munk, D. Harcourt, G. Ambrus, L. Denys, C. Gluchowski, J. A. Burke, A. B. Kharlamb, C. A. Manlapaz, E. U. Padillo,
et al., J. Med. Chem., 1996, 39, 3533.
1996JME3929 J. C. Boehm, J. M. Smietana, M. E. Sorenson, R. S. Garigipati, T. F. Gallagher, P. L. Sheldrake, J. Bradbeer, A. M. Badger,
J. T. Laydon, J. C. Lee, L. M. Hillegass, D. E. Griswold, J. J. Breton, M. C. Chabot-Fletcher, and J. L. Adams, J. Med. Chem.,
1996, 39, 3929.
1996JMT(366)227 C. Oegretir and S. Yarligan, THEOCHEM, 1996, 366, 227.
1996JOC1331 M. Medebielle, M. A. Oturan, J. Pinson, and J. Saveant, J. Org. Chem., 1996, 61, 1331.
1996JOC2202 R. Bossio, S. Marcaccini, R. Pepino, and T. Torroba, J. Org. Chem., 1996, 61, 2202.
1996JOC3902 M. Kobayashi and K. Uneyama, J. Org. Chem., 1996, 61, 3902.
1996JOC6666 E. Coad, J. Kampf, and P. Rasmussen, J. Org. Chem., 1996, 61, 6666.
1996JOC8397 S. Buscemi, N. Vivona, and T. Caronna, J. Org. Chem., 1996, 61, 8397.
Imidazoles 349
1996JOC8786 A. V. Samet, M. E. Niyazymbetov, V. V. Semenov, A. L. Laikhter, and D. H. Evans, J. Org. Chem., 1996, 61, 8786.
1996JOM(506)149 C. Navarro-Ranninger, F. Zamora, I. Lopez-Solera, A. Monge, and J. R. Masaguer, J. Organomet. Chem., 1996, 506, 149.
1996JPC4466 L. L. Ho, A. D. MacKerell, Jr., and P. A. Bash, J. Phys. Chem., 1996, 100, 4466.
1996JPC6484 L. Serrano-Andres, M. P. Fuelscher, B. O. Roos, and M. Merchan, J. Phys. Chem., 1996, 100, 6484.
1996PJC795 E. D. Raczyńska, Pol. J. Chem., 1996, 70, 795.
1996S511 W. Huang and C. Yuan, Synthesis, 1996, 511.
1996S1325 H. Heitsch, Synthesis, 1996, 1325.
1996S1459 P. Molina, C. Conesa, and V. M. Desamparados, Synthesis, 1996, 1459.
1996SC3241 R. Saladino, C. Crestini, F. Occhionero, and R. Nicoletti, Synth. Commun., 1996, 26, 3241.
1996T11153 H.-Y. Li, S. Drummond, I. DeLucca, and G. A. Boswell, Tetrahedron, 1996, 52, 11153.
1996TL149 R. R. Sauers, Tetrahedron Lett., 1996, 37, 149.
1996TL751 C. Zhang, E. J. Moran, T. F. Woiwoele, K. M. Short, and A. M. Mjalli, Tetrahedron Lett., 1996, 37, 751.
1996TL767 E. B. de Vargas and A. I. Cañas, Tetrahedron Lett., 1996, 37, 767.
1996TL835 S. Sarshar, Tetrahedron Lett., 1996, 37, 835.
1996TL1707 R. C. F. Jones, K. J. Howard, and J. S. Snaith, Tetrahedron Lett., 1996, 37, 1707.
1996TL1711 R. C. F. Jones, K. J. Howard, and J. S. Snaith, Tetrahedron Lett., 1996, 37, 1711.
1996TL4887 G. B. Phillips and G. P. Wei, Tetrahedron Lett., 1996, 37, 4887.
1996TL4969 T. Hayashi, E. Kishi, V. Soloshonok, and Y. Uozumi, Tetrahedron Lett., 1996, 37, 4969.
1996TL7331 X. R. Bu, H. Li, D. Van Derveer, and E. A. Mintz, Tetrahedron Lett., 1996, 37, 7331.
1996TL7611 G. Kennedy and A. Perboni, Tetrahedron Lett., 1996, 37, 7611.
1996TL7829 P. Molina, A. Pastor, M. J. Vilaplana, and M. C. Ramirez de Arellano, Tetrahedron Lett., 1996, 37, 7829.
1997AGE1478 G. A. McGibbon, C. Heinemann, D. J. Lavorato, and H. Schwarz, Angew. Chem. Int. Ed., 1997, 36, 1478.
1997AGE2162 W. A. Herrmann and C. Kocher, Angew. Chem. Int. Ed., 1997, 36, 2162.
1997ANA431 E. D. Raczyńska, Anal. Chim. Acta, 1997, 348, 431.
1997B10384 F. M. Briganti, S. Mangani, P. Orioli, A. Scozzafava, G. Vernaglione, and C. T. Supuran, Biochemistry, 1997, 36, 10384.
1997CB1213 C. Hilf, F. Bosold, K. Harms, M. Marsch, and G. Boche, Chem. Ber./Recl., 1997, 130, 1213.
1997CPB1254 A. Miyashita, Y. Suzuki, I. Nagasaki, C. Ishiguro, K.-I. Iwamoto, and T. Higashino, Chem. Pharm. Bull., 1997, 45, 1254.
1997H(44)67 A. R. Katritzky, D. Cheng, and R. Musgrave, Heterocycles, 1997, 44, 67.
1997H(45)691 J. G. Schantl and I. M. Lagoja, Heterocycles, 1997, 45, 691.
1997JA9804 M. S. Solum, K. L. Altman, M. Strohmeier, D. A. Berges, Y. Zhang, J. C. Facelli, R. J. Pugmire, and D. M. Grant, J. Am.
Chem. Soc., 1997, 119, 9804.
1997JA12742 A. Arduengo, F. Davidson, H. Dias, J. Goerlich, D. Khasnis, W. Marshall, and T. Prakasha, J. Am. Chem. Soc., 1997, 119,
12742.
1997JCH(769)231 R. Ferretti, B. Gallinella, F. La Torre, and L. Turchetto, J. Chromatogr., A, 1997, 769, 231.
1997JHC107 F. Perandones and J. L. Soto, J. Heterocycl. Chem., 1997, 34, 107.
1997JHC761 T. Ueda, S. Asai, K. Oiji, S. Nagai, A. Nagatsu, and J. Sakakibara, J. Heterocyl. Chem., 1997, 34, 761.
1997JME18 S. A. Munk, D. A. Harcourt, P. N. Arasasingham, J. A. Burke, A. B. Kharlamb, C. A. Manlapaz, E. U. Padillo, D. Roberts,
E. Runde, L. Williams, L. A. Wheeler, and M. E. Garst, J. Med. Chem., 1997, 40, 18.
1997JME1634 I. K. Khanna, R. M. Weier, Y. Yu, X. D. Xu, F. J. Koszyk, P. W. Collins, C. M. Koboldt, A. W. Veenhuizen, W. E. Perkins,
J. J. Casler, J. L. Masferrer, Y. Y. Zhang, S. A. Gregory, K. Seibert, and P. C. Isakson, J. Med. Chem., 1997, 40, 1634.
1997JME2571 M. Mor, F. Bordi, C. Silva, S. Rivara, P. Crivori, P. V. Plazzi, V. Ballabeni, A. Caretta, E. Barocelli, M. Impicciatore,
P. A. Carrupt, and B. Testa, J. Med. Chem., 1997, 40, 2571.
1997JME2931 A. A. Cordi, J-M. Lacoste, F. Le Borgne, Y. Herve, L. Vaysee-Ludot, J.-J. Descombes, C. Courchay, M. Laubie, and
T. J. Verbeuren, J. Med. Chem., 1997, 40, 2931.
1997JME3297 Y. z. Ling, J. s. Li, Y. Liu, K. Kato, G. T. Klus, and A. Brodie, J. Med. Chem., 1997, 40, 3297.
1997JOC1799 Y. R. Lin, X. T. Zhou, L. X. Dai, and J. Sun, J. Org. Chem., 1997, 62, 1799.
1997JOC2550 H.-Y. Li, I. DeLucca, S. Drummond, and G. A. Boswell, J. Org. Chem., 1997, 62, 2550.
1997JOC2872 J. P. Lee, R. Bembi, and T. H. Fife, J. Org. Chem., 1997, 62, 2872.
1997JOC3480 A. Rolfs and J. Liebscher, J. Org. Chem., 1997, 62, 3480.
1997JOC3586 Y. Hsiao and L. S. Hegedus, J. Org. Chem., 1997, 62, 3586.
1997JOC5222 H. Wang, R. E. Partch, and Y. Li, J. Org. Chem., 1997, 62, 5222.
1997JOC7037 E. Barni, R. Bianchi, G. Gervasio, A. T. Peters, and G. Viscardi, J. Org. Chem., 1997, 62, 7037.
1997JOC7319 M. J. Totleben, J. P. Freeman, and J. Szmuszkovicz, J. Org. Chem., 1997, 62, 7319.
1997JOC8449 S. C. Shilcrat, M. K. Mokhallalati, J. M. D. Fortunak, and L. N. Pridgen, J. Org. Chem., 1997, 62, 8449.
1997JOC8854 R. Akabane, M. Tanaka, K. Matsuo, N. Koga, K. Matsuda, and H. Iwamura, J. Org. Chem., 1997, 62, 8854.
1997J(P2)169 R. B. Moodie, M. Z. Moustras, G. Read, and J. P. B. Sandall, J. Chem. Soc., Perkin Trans. 2, 1997, 169.
1997JPR729 J. Atzrodt, J. Brandenburg, C. Kaepplinger, R. Beckert, W. Guenther, H. Goerls, and J. Fabian, J. Prakt. Chem., 1997, 339,
729.
1997JPR735 J. Fabian, H. Goerls, R. Beckert, and J. Atzrodt, J. Prakt. Chem., 1997, 339, 735.
1997JRS909 H. Gallouj, P. Lagant, and G. Vergoten, J. Raman Spectrosc., 1997, 28, 909.
1997MCR123 R. J. Sundberg and P. Van Nguyen, Med. Chem. Res., 1997, 7, 123.
1997OM682 W. A. Herrmann, F. C. Munck, G. R. J. Artus, O. Runte, and R. Anwander, Organometallics, 1997, 16, 682.
1997PCA2397 M. K. Van Bael, J. Smets, K. Schoone, L. Houben, W. McCarthy, L. Adamowicz, M. J. Nowak, and G. Maes, J. Phys. Chem.,
1997, 101, 2397.
1997PCA10075 I. A. Topol, G. J. Tawa, S. K. Burt, and A. A. Rashin, J. Phys. Chem. A, 1997, 101, 10075.
1997RJO1302 V. A. Reznikov, O. N. Burchak, L. A. Vishnivetskaya, L. B. Volodarskii, T. V. Rybalova, and Y. V. Gatilov, Russ. J. Org.
Chem., 1997, 33, 1302.
1997S347 B. Miller, J. Altman, and W. Beck, Synthesis, 1997, 347.
1997S1049 T. Kálai, J. Jek, Z. Szabó, L. Párkányi, and K. Hideg, Synthesis, 1997, 1049.
350 Imidazoles
1997SC415 S. E. Drewes and M. B. Rohwer, Synth. Commun., 1997, 27, 415.

1997SC2433 A. M. M. El-Saghier, A. A. Maihub, and H. A. Al-Shirayda, Synth. Commun., 1997, 27, 2433.
1997SC2701 Z. Shi and H. Gu, Synth. Commun., 1997, 27, 2701.
1997SL521 J. A. Markwalder, R. S. Pottorf, and S. P. Seitz, Synlett, 1997, 521.
1997SL783 T. Morimoto, K. Tachibana, and K. Achiwa, Synlett, 1997, 783.
1997SL1279 W. Y. Sun, J. Q. Hu, and Y. P. Shi, Synlett, 1997, 1279.
1997SUL225 J. Zou, X. Liu, Z. Lu, and K. Chen, Sulfur Lett., 1997, 20, 225.
1997T457 M. R. DeLuca and S. M. Kerwin, Tetrahedron, 1997, 53, 457.
1997T1111 R. C. F. Jones, J. S. Snaith, M. W. Anderson, and M. J. Smallridge, Tetrahedron, 1997, 53, 1111.
1997T5359 H. Li, I. DeLucca, S. Drummond, and G. Boswell, Tetrahedron, 1997, 53, 5359.
1997T6351 J. M. Lerestif, L. Toupet, S. Sinbandhit, F. Tonnard, J. P. Bazureau, and J. Hamelin, Tetrahedron, 1997, 53, 6351.
1997T7237 A. Prasad, T. Stevenson, J. V. Nyzam, and P. Knochel, Tetrahedron, 1997, 53, 7237.
1997T8211 J. L. Harper, R. A. J. Smith, J. J. Bedfor, and J. P. Leader, Tetrahedron, 1997, 53, 8211.
1997T13667 H. Maeda, K. Nobuaki, N. Sonoda, S. Fujiwara, and T. Shin-ike, Tetrahedron, 1997, 53, 13667.
1997T13873 N. Coskun, Tetrahedron, 1997, 53, 13873.
1997T14481 D. S. Carver, S. D. Lindell, and E. A. Saville-Stones, Tetrahedron, 1997, 53, 14481.
1997T16911 A. F. De, C. Alcantara, D. Pilo-Veloso, H. O. Stumpf, and W. B. De Almeida, Tetrahedron, 1997, 53, 16911.
1997TL1275 L. N. Pridgen, M. K. Mokhallalati, and M. A. McGuire, Tetrahedron Lett., 1997, 38, 1275.
1997TL1647 R. C. F. Jones, K. J. Howard, and J. S. Snaith, Tetrahedron Lett, 1997, 38, 1647.
1997TL1933 O. Félix, M. W. Hosseini, A. D. Cian, and J. Fischer, Tetrahedron Lett., 1997, 38, 1933.
1997TL2065 A. B. Dyatkin, Tetrahedron Lett., 1997, 38, 2065.
1997TL2329 A. Arcadi, O. A. Attanasi, L. De Crescentini, E. Rossi, and F. Scienze, Tetrahedron Lett., 1997, 38, 2329.
1997TL3115 M. Teresa, Tetrahedron Lett., 1997, 38, 3115.
1997TL3793 F. Aldabbagh and W. R. Bowman, Tetrahedron Lett., 1997, 38, 3793.
1997TL4359 C. W. Derstine, D. N. Smith, and J. A. Katzenellenbogen, Tetrahedron Lett., 1997, 38, 4359.
1997TL4647 D. J. Hartley and B. Iddon, Tetrahedron Lett., 1997, 38, 4647.
1997TL5099 J. Thomas, M. Fall, J. Cooper, J. Burgess, and F. Carroll, Tetrahedron Lett., 1997, 38, 5099.
1997TL6613 J.-H. Xu, Y.-L. Li, D.-G. Zheng, J.-K. Yang, Z. Mao, and D.-B. Zhu, Tetrahedron Lett., 1997, 38, 6613.
1997TL7495 Z. Wan and J. Snyder, Tetrahedron Lett., 1997, 38, 7495.
1997TL7499 C. E. Neipp, P. B. Ranslow, Z. Wan, and J. K. Snyder, Tetrahedron Lett., 1997, 38, 7499.
1997TL7937 F. Aldabbagh, W. R. Bowman, and E. Mann, Tetrahedron Lett., 1997, 38, 7937.
1997TL8631 E. J. Corey and F. N. M. Kühnle, Tetrahedron Lett., 1997, 38, 8631.
1998BCJ467 S. Pivsa-Art, T. Satoh, Y. Kawamura, M. Miura, and M. Nomura, Bull. Chem. Soc. Jpn., 1998, 71, 467.
1998CC1085 A. F. Kraft and R. Fröhlich, Chem. Commun., 1998, 1085.
1998CC331 P. I. Dalko and Y. Langlois, Chem. Commun., 1998, 331.
1998EJO1517 G. Maier and J. Endres, Eur. J. Org. Chem., 1998, 1517.
1998H(48)11 T. Choshi, S. Yamada, J. Nobuhiro, Y. Mihara, E. Sugino, and S. Hibino, Heterocycles, 1998, 48, 11.
1998H(48)113 S. Mataka, K. Isomura, T. Sawada, T. Tsukinoki, M. Tashiro, K. Takahashi, and A. Tori-i, Heterocycles, 1998, 48, 113.
1998H(48)537 N. Coskun and M. Ay, Heterocycles, 1998, 48, 537.
1998H(48)1887 I. Kawasaki, H. Katsuma, Y. Nakayama, M. Yamashita, and S. Ohta, Heterocycles, 1998, 48, 1887.
1998H(47)1043 H. Salgado-Zamora, E. Campos, R. Jimenez, and H. Cervantes, Heterocycles, 1998, 47, 1043.
1998HCA1585 G. Mloston, T. Gendek, and H. Heimgartner, Helv. Chim. Acta, 1998, 81, 1585.
1998HCO261 M. A. Voinov, I. A. Grigor’ev, and L. B. Volodarsky, Heterocycl. Commun., 1998, 4, 261.
1998JCF2775 F. Rodriguez-Prieto, J. C. Penedo, and M. Mosquera, J. Chem. Soc., Faraday Trans., 1998, 2775.
1998JCH(716)239 M. K. Handley, W. W. Hirth, J. G. Phillips, S. M. Ali, A. Khan, L. Fadnis, and C. E. Tedford, J. Chromatogr. B, 1998, 716,
239.
1998JHC607 A. Shafiee, N. Rastkary, and A. Foroumadi, J. Heterocycl. Chem., 1998, 35, 607.
1998JHC891 C. P. Hadjiantoniou-Maroulis, A. P. Charalambopoulos, and A. J. Maroulis, J. Heterocycl. Chem., 1998, 35, 891.
1998JHC1527 L. Selic and B. Stanovnik, J. Heterocycl. Chem., 1998, 35, 1527.
1998JMT(422)197 G. Li, M. Ruiz-Lopez, M. Zhang, and B. Maigret, J. Mol. Struct. Theochem, 1998, 422, 197.
1998JMT(425)249 C. Ogretir and S. Yarligan, THEOCHEM, 1998, 425, 249.
1998JMT(432)41 S. Cho, Y. Cheun, and B. Park, J. Mol. Struct. Theochem, 1998, 432, 41.
1998JOC17 H. Maas, C. Bensimon, and H. Alper, J. Org. Chem., 1998, 63, 17.
1998JOC1248 A. Olofson, K. Yakushijin, and D. A. Horne, J. Org. Chem., 1998, 63, 1248.
1998JOC2800 M. T. Bilodeau and A. M. Cunningham, J. Org. Chem., 1998, 63, 2800.
1998JOC4529 J. Sisko, J. Org. Chem., 1998, 63, 4529.
1998JOC5228 A. R. Katritzky, M. Karelson, S. Sild, T. m. Krygowski, and K. Jug, J. Org.Chem., 1998, 63, 5228.
1998JOC7136 V. J. Majo and P. T. Perumal, J. Org. Chem., 1998, 63, 7136.
1998JOC7275 I.-S. H. Lee and E. H. Jeoung, J. Org. Chem., 1998, 63, 7275.
1998JOC8107 P. I. Dalko and Y. Langlois, J. Org. Chem., 1998, 63, 8107.
1998JOC9448 Y. Hayakawa, H. Kimoto, L. Cohen, and K. Kirk, J. Org. Chem., 1998, 63, 9448.
1998J(P1)2061 R. C. F. Jones, K. J. Howard, J. R. Nichols, and J. S. Snaith, J. Chem. Soc., Perkin Trans. 1, 1998, 2061.
1998JST(447)89 J. Karolak-Wojciechowska, A. Mrozek, W. Kwiatkowski, W. Ksiazek, K. Kiec-Kononowicz, and J. Handzlik, J. Mol. Struct.,
1998, 447, 89.
1998MC216 S. F. Vasilevsky, E. V. Tretyakov, O. M. Usov, Y. N. Molin, S. V. Fokin, Y. G. Shwedenkov, V. N. Ikorskii,
G. V. Romanenko, R. Z. Sagdeev, and V. I. Ovcharenko, Mendeleev Commun., 1998, 8, 216.
B-1998MI(2)547 P. Vanelle and M. P. Crozet, in ‘Recent Research Development in Organic Chemistry’, Research Signpost, Trivandram,
India, 1998; vol. 2, p. 547.
1998MRC296 J. Alcazar, A. de la Hoz, and M. Begtrup, Mag. Reson. Chem., 1998, 36, 296.
Imidazoles 351
1998OPP109 K. N. Zelenin and I. V. Ukraintzev, Org. Prep. Proced. Int., 1998, 30, 109.
1998PCA1560 M. A. Rios and M. C. Rios, J. Phys. Chem. A, 1998, 102, 1560.
1998PCA7885 G. Hummer, L. R. Pratt, and A. E. Garcia, J. Phys. Chem. A, 1998, 102, 7885.
1998PJC1054 E. D. Raczyńska, Pol. J. Chem., 1998, 72, 1054.
1998S1787 F. Santoyo-Gonzales, C. Uriel, and J. A. Calvo-Asin, Synthesis, 1998, 1787.
1998SL1077 V. A. Reader, Synlett, 1998, 1077.
1998TA2245 A. Katritzky, D. Aslan, and D. Oniciu, Tetrahedron: Asymmetry, 1998, 9, 2245.
1998T6191 R. C. F. Jones, P. Patel, S. C. Hirst, and M. J. Smallridge, Tetrahedron, 1998, 54, 6191.
1998T8055 K. Bougrin, A. Loupy, and M. Soufiaoui, Tetrahedron, 1998, 54, 8055.
1998T9639 L. Konstantinova, O. Rakitin, C. Rees, S. Sivadasan, and T. Torroba, Tetrahedron, 1998, 54, 9639.
1998T13639 L. Lazar, A. Goblyos, F. Evanics, G. Bernath, and F. Fulop, Tetrahedron, 1998, 54, 13639.
1998T14255 I. Coldham, R. A. Judkins, and D. R. Witty, Tetrahedron, 1998, 54, 14255.
1998TL1845 R. N. Loeppky and W. Cui, Tetrahedron Lett., 1998, 39, 1845.
1998TL2797 C. D. Edlin and D. Parker, Tetrahedron Lett., 1998, 39, 2797.
1998TL2941 P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan, and A. Combs, Tetrahedron Lett., 1998, 39,
2941.
1998TL4561 P. Deghati, M. Wanner, and G. Koomen, Tetrahedron Lett., 1998, 39, 4561.
1998TL4785 M. L. Larter, M. Phillips, F. Ortega, G. Aguirre, R. Somanathan, and P. J. Walsh, Tetrahedron Lett., 1998, 39, 4785.
1998TL6267 R. A. Batey, C. Y. Ishii, and S. D. Taylor, Tetrahedron Lett., 1998, 39, 6267.
1998TL6655 J. P. Mayer, Tetrahedron Lett., 1998, 39, 6655.
1998TL7467 D. Tumelty, M. Schwarz, and M. Needels, Tetrahedron Lett., 1998, 39, 7467.
1998TL8939 C. F. Claiborne, N. J. Liverton, and K. T. Nguyen, Tetrahedron Lett., 1998, 39, 8939.
1998TL8979 P. I. Dalko, V. Brun, and Y. Langlois, Tetrahedon Lett., 1998, 39, 8979.
1999ACR913 A. J. Arduengo, III, Acc. Chem. Res., 1999, 32, 913.
1999AHC(75)1 M. S. Pevzner; in ‘Advances in Heterocyclic Chemistry’, A. R. Katritzky, Ed.; Elsevier, Amsterdam, 1999, vol. 75, p. 1.
1999AXC217 N. Okabe and Y. Adachi, Acta Crystallogr., Sect. C, 1999, 55, 217.
1999BOC8 T. Lindel, H. Hoffmann, and M. Hochgurtel, New Perspectives Bioorg. Chem., 1999, 8.
1999CEJ1931 F. E. Hahn, L. Wittenbecher, R. Boese, and D. Bläser, Chem. Eur. J., 1999, 5, 1931.
1999CRV2071 T. Welton, Chem. Rev., 1999, 99, 2071.
1999EJO893 J. Streith, H. Rudyk, T. Tschamber, C. Tarnus, C. Strehler, D. Deredes, and A. Frankowski, Eur. J. Org. Chem., 1999, 893.
1999H(51)763 J. Atzrodt, R. Beckert, and H. Gorls, Heterocycles, 1999, 51, 763.
1999HCA909 M. Bergemann and R. Neidlein, Helv. Chim. Acta, 1999, 82, 909.
1999HCA1981 T. Moschny and H. Hartmann, Helv. Chim. Acta, 1999, 82, 1981.
1999HCA2015 T. Tschamber, H. Rudyk, and D. Le Nouen, Helv. Chim. Acta, 1999, 82, 2051.
1999JA5833 Q. Dang, Y. Liu, and M. Erion, J. Am. Chem. Soc., 1999, 121, 5833.
1999JA6911 C. L. Perrin, M. A. Fabian, J. Brunckova, and B. K. Ohta, J. Am. Chem. Soc., 1999, 121, 6911.
1999JA10389 Y. Wei, A. C. De Dios, and A. E. McDermott, J. Am. Chem. Soc., 1999, 121, 10389.
1999JA11486 B. S. Hickman, M. Mascal, J. J. Titman, and I. G. Wood, J. Am. Chem. Soc., 1999, 121, 11486.
1999JCD2133 J. D. Holbrey and K. R. Seddon, J. Chem. Soc., Dalton Trans., 1999, 2133.
1999JHC911 Y. Kong and K. Kim, J. Heterocycl. Chem., 1999, 36, 911.
1999JME1115 I. De Esch, R. Vollinga, K. Goubitz, H. Schenk, U. Appelberg, U. Hacksell, S. Lemstra, O. Zuiderveld, M. Hoffmann,
R. Leurs, W. Menge, and H. Timmerman, J. Med. Chem., 1999, 42, 1115.
1999JME1587 G. Le Bihan, F. Rondu, A. Pele-Tounian, X. Wang, S. Lidy, E. Touboul, A. Lamouri, G. Dive, J. Huet, B. Pfeiffer,
P. Renard, B. Guardiola-Lemaitre, D. Manechez, L. Penicaud, A. Ktorza, and J. Godfroid, J. Med. Chem., 1999, 42, 1587.
1999JME2180 N. J. Liverton, J. W. Butcher, C. F. Claiborne, D. A. Claremon, B. E. Libby, K. T. Nguyen, S. M. Pitzenberger,
H. G. Selnick, G. R. Smith, A. Tebben, J. P. Vacca, S. L. Varga, L. Agarwal, K. Dancheck, A. J. Forsyth, D. S. Fletcher,
B. Frantz, W. A. Hanlon, C. F. Harper, S. J. Hofsess, M. Kostura, J. Lin, S. Luell, E. A. O’Neill, and S. J. O’Keefe, J. Med.
Chem., 1999, 42, 2180.
1999JOC1331 X.-T. Zhou, Y.-R. Lin, L.-X. Dai, J. Sun, L.-J. Xia, and M.-H. Tang, J. Org. Chem., 1999, 64, 1331.
1999JOC6425 A. Kraft, F. Osterod, and R. Froehlich, J. Org. Chem., 1999, 64, 6425.
1999JOC7158 N. Minakawa, N. Kojima, and A. Matsuda, J. Org. Chem., 1999, 64, 7158.
1999JOC8084 G. Griffiths, M. Hauck, R. Imwinkelried, J. Kohr, C. Roten, G. Stucky, and J. Gosteli, J. Org. Chem., 1999, 64, 8084.
1999JOM(588)155 C. Boga, E. Del Vecchio, L. Forlani, L. Milanesi, and P. Todesco, J. Organomet. Chem., 1999, 588, 155.
1999MRC878 J. N. Latosinska, J. Seliger, and B. Nogaj, Magn. Reson. Chem., 1999, 37, 878.
1999OL145 A. Streitwieser, S. S. W. Leung, and Y.-J. Kim, Org. Lett., 1999, 1, 145.
1999OL933 S. P. Rannard and N. J. Davis, Org. Lett., 1999, 1, 933.
1999OL953 M. Scholl, S. Ding, C. W. Lee, and R. H. Grubbs, Org. Lett., 1999, 1, 953.
1999PCA4525 M. Fores, M. Duran, M. Sola, M. Orozco, and F. J. Luque, J. Phys. Chem. A, 1999, 103, 4525.
1999PCA9336 O. Mo, M. Yanez, M. Roux, P. Jimenez, J. Davalos, M. Ribeiro da Silva, M. Ribeiro da Silva, M. Matos, L. Amaral,
A. Sanchez-Migallon, P. Cabildo, R. Claramunt, J. Elguero, and J. Liebman, J. Phys. Chem. A, 1999, 103, 9336.
1999S1613 M. Heras, M. Ventura, A. Linden, and J. M. Villalgordo, Synthesis, 1999, 1613.
1999SAA2393 A. C. Testa, Spectrochim. Acta, Part A, 1999, 55, 2393.
1999SC3025 X. Chen, X. Wang, H. Wang, H. Lian, Y. Pan, and Y. Shi, Synth. Commun., 1999, 29, 3025.
1999SL1543 A. Viso, R. Fernandez de la Pradilla, A. Garcia, M. Alonso, C. Guerrero-Strachan, and I. Fonseca, Synlett, 1999, 1543.
1999TA3011 J. G. Fernandez-Bolanos, E. Zafra, O. Lopez, I. Robina, and J. Fuentes, Tetrahedron: Asymmetry, 1999, 10, 3011.
1999T2695 S. Fustero, M. Dolores Diaz, A. Asensio, A. Navarro, J. S. Kong, and E. Aguilar, Tetrahedron, 1999, 55, 2695.
1999T3987 B. P. Medaer and G. J. Hoornaert, Tetrahedron, 1999, 54, 3987.
1999T4109 F. Aldabbagh and W. R. Bowman, Tetrahedron, 1999, 55, 4109.
1999T4377 M. Avalos, R. Babiano, P. Cintas, J. L. Jimenez, J. C. Palacios, G. Silvero, and C. Valencia, Tetrahedron, 1999, 55, 4377.
352 Imidazoles
1999T4401 M. Avalos, R. Babiano, P. Cintas, F. J. Higes, J. L. Jimenez, J. C. Palacios, G. Silvero, and C. Valencia, Tetrahedron, 1999, 55,
4401.
1999T8111 F. Aldabbagh, W. R. Bowman, E. Mann, and A. M. Z. Slawin, Tetrahedron, 1999, 55, 8111.
1999TAL319 C. Nan, W. Ping, D. Ping, and C. Qing, Talanta, 1999, 49, 319.
1999TL1103 J. J. Perkins, Tetrahedron Lett., 1999, 40, 1103.
1999TL2657 A. Kiyomori, J. Marcoux, and S. Buchwald, Tetrahedron Lett., 1999, 40, 2657.
1999TL2665 W. Huang and R. Scarborough, Tetrahedron Lett., 1999, 40, 2665.
1999TL2669 R. A. Batey, C. Y. Ishii, S. D. Taylor, and V. Santhakumar, Tetrahedron Lett., 1999, 40, 2669.
1999TL4035 P. I. Dalko, Tetrahedron Lett., 1999, 40, 4035.
1999TL4069 I. Collins and J. Castro, Tetrahedron Lett., 1999, 40, 4069.
1999TL4119 A. S. Kiselyov, Tetrahedron Lett., 1999, 40, 4119.
1999TL6185 D. Tumelty, M. Schwarz, K. Cao, and M. Needels, Tetrahedron Lett., 1999, 40, 6185.
1999TL6443 Pi. Pan and C. Sun, Tetrahedron Lett., 1999, 40, 6443.
1999TL6875 C. Senanayake, Y. Hong, T. Xiang, H. Wilkinson, R. Bakale, A. Jurgens, M. Pippert, H. Butler, and S. Wald, Tetrahedron
Lett., 1999, 40, 6875.
1999TL7247 C.-M. Yeh and C.-M. Sun, Tetrahedron Lett., 1999, 40, 7247.
1999TL7633 J. Smitha and V. Krchnak, Tetrahedron Lett., 1999, 40, 7633.
1999TL7925 C. Hulme, L. Ma, J. Romano, and M. Morrissette, Tetrahedron Lett., 1999, 40, 7925.
1999TL8097 S. Jouneau and J. Bazureau, Tetrahedron Lett., 1999, 40, 8097.
1999H(51)2431 A. Goblyos, L. Lazar, F. Evanics, and F. Fulop, Heterocycles, 1999, 51, 2431.
2000AGE547 A. Weiss, H. Pritzkow, and W. Siebert, Angew. Chem. Int. Ed., 2000, 39, 547.
2000AGE3772 P. Wasserscheid and W. Keim, Angew. Chem. Int. Ed., 2000, 39, 3772.
2000AGE4036 V. P. W. Böhm and W. A. Herrmann, Angew. Chem. Int. Ed., 2000, 39, 4036.
2000AHC(76)157 J. Elguero and A. R. Katritzky; in ‘Advances in Heterocyclic Chemistry’, A. R. Katritzky, Ed.; Elsevier, Amsterdam, 2000,
vol. 76, p. 157.
2000CEJ767 M. Rottländer, L. Boymond, L. Bérillon, A. Leprêtre, G. Varchi, S. Avolio, H. Laaziri, G. Quéguiner, A. Ricci, G. Cahiez,
and P. Knochel, Chem. Eur. J., 2000, 6, 767.
2000CPL(322)83 M. J. Cheng and C.-H. Hu, Chem. Phys. Lett., 2000, 322, 83.
2000CR39 D. Bourissou, O. Guerret, F. P. Gabbaı̈, and G. Bertrand, Chem. Rev., 2000, 100, 39.
2000EJO1661 J. Atzrodt, R. Beckert, W. Gunther, and H. Gorls, Eur. J. Org. Chem., 2000, 1661.
2000EJO2535 G. Maier and J. Endres, Eur. J. Org. Chem., 2000, 2535.
2000HCA728 G. Mloston, M. Celeda, G. K. S. Prakash, G. A. Olah, and H. Heimgartner, Helv. Chim. Acta, 2000, 83, 728.
2000JA6989 J. Kovalainen, J. Christiaans, R. Ropponen, A. Poso, M. Peraekylae, J. Vepsaelaeinen, R. Laatikainen, and J. Gynther, J. Am.
Chem. Soc., 2000, 122, 6989.
2000JA7264 A. S. Larsen, J. D. Holbrey, F. S. Tham, and C. A. Reed, J. Am. Chem. Soc., 2000, 122, 7264.
2000JHC57 A. Salerno, M. E. Hedrera, N. B. D’Accorso, M. M. Alho, and I. A. Perillo, J. Heterocycl. Chem., 2000, 37, 57.
2000JHC481 R. C. F. Jones, J. N. Martinan, and P. Smith, J. Heterocycl. Chem., 2000, 37, 481.
2000JHC943 Z. A. Hozien, A. E.-W. A. O. Sarhan, H. A. H. El-Sherief, and A. M. Mahmoud, J. Heterocycl. Chem., 2000, 37, 943.
2000JHC1329 C. Xia, Y. Tang, and P. Zhou, J. Heterocycl. Chem., 2000, 37, 1329.
2000JME3168 I. Khanna, Y. Yu, R. Huff, R. Weier, X. Xu, F. Koszyk, P. Collins, J. Cogburn, P. Isakson, C. Koboldt, J. Masferrer,
W. Perkins, K. Seibert, A. Veenhuizen, J. Yuan, D. Yang, and Y. Zhang, J. Med. Chem., 2000, 43, 3168.
2000JOC1516 J. Sisko, A. J. Kassick, M. Mellinger, J. J. Filan, A. Allen, and M. A. Olsen, J. Org. Chem., 2000, 65, 1516.
2000JOC3683 A. R. Katritzky, G. Qiu, H.-Y. He, and B. Yang, J. Org. Chem., 2000, 65, 3683.
2000JOC4618 M. Abarbri, J. Thibonnet, L. Berillon, F. Dehmel, M. Rottlaender, and P. Knochel, J. Org. Chem., 2000, 65, 4618.
2000JOC4736 M. Botta, F. Corelli, F. Gasparrini, F. Messina, and C. Mugnaini, J. Org. Chem., 2000, 65, 4736.
2000JOC5887 D. Butler, G. Inman, and H. Alper, J. Org. Chem., 2000, 65, 5887.
2000JOC7399 K. Laali, T. Okazaki, and M. Coombs, J. Org. Chem., 2000, 65, 7399.
2000JOC8402 Y. Hayashi, S. Orikasa, K. Tanaka, K. Kanoh, and Y. Kiso, J. Org. Chem., 2000, 65, 8402.
2000JOM(601)233 C. Boga, E. Del Vecchio, L. Forlani, and P. Todesco, J. Organomet. Chem., 2000, 601, 233.
2000J(P1)3603 S. Shuto, K. Haramuishi, M. Fukuoka, and A. Matsuda, J. Chem. Soc., Perkin Trans. 1, 2000, 3603.
2000JPR245 J. Atzrodt, R. Beckert, H. Gorls, and Helmar, J. Prakt. Chem., 2000, 342, 245.
B-2000MI233 M. Hoffmann and J. Rychlewski; in ‘Quantum Systems in Chemistry and Physics: Advanced Problems and Complex
Systems’, A. Hernandez-Laguna et al., Ed.; Kluwer Academic Publishers, Dordrecht, 2000, p. 233.
2000OL323 B. Lee and S. Balasubramanian, Org. Lett., 2000, 2, 323.
2000OL1233 J. P. Collman and M. Zhong, Org. Lett., 2000, 2, 1233.
2000OL3055 G. I. Elliott and J. P. Konopelski, Org. Lett., 2000, 2, 3055.
2000OL3111 Y. Kondo, T. Komine, and T. Sakamoto, Org. Lett., 2000, 2, 3111.
2000OL3269 F. S. Gibson, J. Wei, P. Vemishetti, Q. Gao, and J. L. Dillon, Org. Lett., 2000, 2, 3269.
2000OL3443 A. C. B. Sosa, K. Yakushijin, and D. A. Horne, Org. Lett., 2000, 2, 3443.
2000PAC1391 M. Earle and K. Seddon, Pure Appl. Chem., 2000, 72, 1391.
2000PAC2275 K. Seddon, A. Stark, and M. Torres, Pure Appl. Chem., 2000, 72, 2275.
2000PCA2120 J. A. Collado, I. Tuñón, E. Silla, and F. Ramirez, J. Phys. Chem., A, 2000, 104, 2120.
2000PCB4253 K. Hasegawa, T. Ono, and T. Noguchi, J. Phys. Chem. B, 2000, 104, 4253.
2000SAA2791 R. N. Patel, S. Kumar, and K. B. Pandeya, Spectrochim. Acta, Part A, 2000, 56, 2791.
2000S1814 M. Anastassiadou, G. Baziard-Mouysset, and M. Payard, Synthesis, 2000, 1814.
2000SC3307 C. Xia, C. Kang, B. Zhao, J. Chen, H. Wang, and P. Zhou, Synth. Commun., 2000, 30, 3307.
2000SL345 F. Dehmel, M. Abarbri, and P. Knochel, Synlett, 2000, 345.
2000SL967 R. C. F. Jones, J. N. Martin, and P. Smith, Synlett, 2000, 967.
2000SL1022 S. Kang, S. Lee, and D. Lee, Synlett, 2000, 1022.
Imidazoles 353
2000TA435 C. Gasch, M. Pradera, B. Salameh, J. Molina, and J. Fuentes, Tetrahedron Asymmetry, 2000, 11, 435.
2000T629 P. K. Mohanta, S. Dhar, S. K. Samal, H. Ila, and H. Junjappa, Tetrahedron, 2000, 56, 629.
2000T2061 R. C. F. Jones and P. Dimopoulos, Tetrahedron, 2000, 56, 2061.
2000T4071 M. A. Voinov, I. A. Grigor’ev, and L. B. Volodarsky, Tetrahedron, 2000, 56, 4071.
2000T5405 G. Mloston, T. Gendek, and H. Heimgartner, Tetrahedron, 2000, 56, 5405.
2000T6563 S. R. Mundla, L. J. Wilson, S. R. Klopfenstein, W. L. Seibel, and N. N. Nikolaides, Tetrahedron, 2000, 56, 6563.
2000T10075 E. V. Tretyakov, A. V. Tkachev, T. V. Rybalova, Y. V. Gatilov, D. W. Knight, and S. F. Vasilevsky, Tetrahedron, 2000, 56,
10075.
2000TA1617 H.-B. Kraatz and A. Pletsch, Tetrahedron: Asymmetry, 2000, 11, 1617.
2000TL1165 S. Wu and J. Janusz, Tetrahedron Lett., 2000, 41, 1165.
2000TL1275 M. Groarke, M. A. McKervey, and M. Nieuwenhuyzen, Tetrahedron Lett., 2000, 41, 1275.
2000TL2265 L. M. Yagupolskii and D. V. Fedyuk, Tetrahedron Lett., 2000, 41, 2265.
2000TL5031 A. Ya. Usyatinsky and Y. L. Khmelnitsky, Tetrahedron Lett., 2000, 41, 5031.
2000TL5407 N. Coşkun, F. T. Tat, Ö.Ö.Güven, D. Ülkü, and C. Arici, Tetrahedron Lett., 2000, 41, 5407.
2000TL5453 B.-C. Chen, M. S. Bednarz, R. Zhao, J. E. Sundeen, P. Chen, Z. Shen, A. P. Skoumbourdis, and J. C. Barrish, Tetrahedron
Lett., 2000, 41, 5453.
2000TL7503 S. Ohta, T. Osaki, S. Nishio, A. Furusawa, M. Yamashita, and I. Kawasaki, Tetrahedron Lett., 2000, 41, 7503.
2000TL8431 J. M. Mitchell and N. S. Finney, Tetrahedron Lett., 2000, 41, 8431.
2000TL9267 Y. Kamitori, Tetrahedron Lett., 2000, 41, 9267.
2001AGE3228 R. Dghaym, R. Dhawan, and B. Arndtsen, Angew. Chem. Int. Ed., 2001, 40, 3228.
2001AGE4229 M. C. Aragoni, M. Arca, A. J. Blake, F. A. Devillanova, W.-W. du Mont, A. Garau, F. Isaia, V. Lippolis, G. Verani, and
C. Wilson, Angew. Chem. Int. Ed., 2001, 40, 4229.
2001AGE4277 G. Li, H. Wei, S. Kim, and M. Carducci, Angew. Chem. Int. Ed., 2001, 40, 4277.
2001AIJ2384 J. Brennecke and E. Maginn, AIChE J., 2001, 47, 2384.
2001BMC613 T. Prisinzano, H. Law, M. Dukat, A. Slassi, N. MaClean, L. Demchyshyn, and R. Glennon, Bioorg. Med. Chem., 2001, 9, 613.
2001BML1133 S. Narayanan, S. Vangapandu, and R. Jain, Bioorg. Med. Chem. Lett., 2001, 11, 1133.
2001CC643 R. Varma and V. Namboodiri, Chem. Commun., 2001, 643.
2001CC1466 D. M. Bassani, X. R. Sallenave, V. Darcos, and J.-P. Desvergne, Chem. Commun., 2001, 1446.
2001CC2274 S. K. Gruendemann, A. Albrecht, A. Kovacevic, M. Albrecht, J. W. Faller, and R. H. Crabtree, Chem. Commun., 2001, 2274.
2001CEJ2007 C. Hirel, K. E. Vostrikova, J. Pecaut, V. I. Ovcharenko, and P. Rey, Chem. Eur. J., 2001, 7, 2007.
2001CEJ3122 M. C. A. Aragoni, M. Arca, F. Demartin, F. A. Devillanova, A. Garau, F. Isaia, F. Lelj, V. Lippolis, and G. Verani, Chem. Eur.
J., 2001, 7, 3122.
2001CRV1115 P. von R. Schleyer, Chem. Rev., 2001, 101, 1115.
2001CRV1385 T. M. Krygowski and M. K. C. Cyraski, Chem. Rev., 2001, 101, 1385.
2001CRV1421 A. Katritzky, K. Jug, and D. Oniciu, Chem. Rev., 2001, 101, 1421.
2001EJO237 A. A. Mourabit and P. Potier, Eur. J. Org. Chem., 2001, 237.
2001GC156 J. G. Huddleston, A. E. Visser, W. M. Reichert, H. D. Willauer, G. A. Broker, and R. D. Rogers, Green Chem., 2001, 3, 156.
2001H(55)243 O. Tsuge, T. Hatta, H. Tashiro, and H. Maeda, Heterocycles, 2001, 55, 243.
2001H(55)2109 R. M. Claramunt, C. Lopez, D. Sanz, I. Alkorta, and J. Elguero, Heterocycles, 2001, 55, 2109.
2001HCA3403 U. Groselj, A. Drobnic, S. Recnik, J. Svete, B. Stanovnik, A. Golobic, N. Lah, I. Leban, A. Meden, and S. Golic-Grdadolnik,
Helv. Chim. Acta, 2001, 84, 3403.
2001JA6404 M. Hoffmann, J. Rychlewski, M. Chrzanowska, and T. Hermann, J. Am. Chem. Soc., 2001, 123, 6404.
2001JA7727 A. Klapars, J. Antilla, X. Huang, and S. Buchwald, J. Am. Chem. Soc., 2001, 123, 7727.
2001JA11097 X. Zhao, J. L. Sudmeier, W. W. Bachovchin, and M. H. Levitt, J. Am. Chem. Soc., 2001, 123, 11097.
2001JBS417 M. Bastos, J. Barbosa, A. Pinto, W. Kover, Y. Takeuchi, and N. Boechat, J. Braz. Chem. Soc., 2001, 12, 417.
2001JFC(107)147 B. Dolensky, Y. Takeuchi, L. A. Cohen, and K. L. Kirk, J. Fluorine Chem., 2001, 107, 147.
2001JHC141 T. Ueda, N. Yatsuzuka, S.-I. Nagai, K. Okada, E. Takeichi, H. Segi, and J. Sakakibara, J. Heterocycl. Chem., 2001, 38, 141.
2001JHC773 Y. Kamitori, J. Heterocycl. Chem., 2001, 38, 773.
2001JHC849 A. Salerno, G. Buldain, and I. A. Perillo, J. Heterocycl. Chem., 2001, 38, 849.
2001JHC939 A.-S. S. Hamad and H. A. Y. Derbala, J. Heterocycl. Chem., 2001, 38, 939.
2001JMP911 X. Z. Qin, J. Mass Spectrom., 2001, 36, 911.
2001JMT(571)139 G. Bereket, C. Öĝretir, and A. Yurt, J. Mol. Struct. Theochem, 2001, 571, 139.
2001JMT(574)221 E. D. Raczynska, T. Rudka, and M. Darowska, THEOCHEM, 2001, 574, 221.
2001JOC1097 A. R. Vaino and W. A. Szarek, J. Org. Chem., 2001, 66, 1097.
2001JOC4687 B. Dolensky and K. L. Kirk, J. Org. Chem., 2001, 66, 4687.
2001J(P1)1500 A. J. Davenport, D. L. Davies, J. Fawcett, and D. R. Russell, J. Chem. Soc., Perkin Trans. 1, 2001, 1500.
2001J(P1)1241 B. L. Booth, I. M. Cabral, A. M. Dias, A. P. Freitas, A. M. M. Beja, M. F. Proença, and M. R. Silva, J. Chem. Soc., Perkin
Trans. 1, 2001, 1241.
2001J(P1)3054 S. O. N. Lill, D. Pettersen, M. Amedjkouh, and P. Ahlberg, J. Chem. Soc., Perkin Trans. 1, 2001, 3054.
2001JPC10249 M. C. R. Rodrı́guez, M. Mosquera, and F. Rodnı́guez-Prieto, J. Phys. Chem., 2001, 105, 10249.
2001JPO770 E. D. Raczynska, M. Darowska, T. Rudka, and M. Makowski, J. Phys. Org. Chem., 2001, 14, 770.
2001JST(565)107 M. Kurzepa, J. Cz. Dobrowolski, and A. P. Mazurek, J. Mol. Struct., 2001, 565–566, 107.
2001MRC681 M. A. Voinov, G. E. Salnikov, A. M. Genaev, V. I. Mamatyuk, M. M. Shakirov, and I. A. Grigor’ev, Magn. Reson. Chem., 2001,
39, 681.
2001OL157 D. J. Hlasta, Org. Lett., 2001, 3, 157.
2001OL1249 Z.-X. Wang, T. K. Manojkumar, C. Wannere, and P. von. R. Schleyer, Org. Lett., 2001, 3, 1249.
2001OL1319 C. J. Lovely, H. Du, and H. V. R. Dias, Org. Lett., 2001, 3, 1319.
2001OL3799 Coldham, R. C. B. Copley, T. F. N. Haxell, and S. Howard, Org. Lett., 2001, 3, 3799.
2001PCP3569 J. Luis Perez-Lustres, M. Brauer, M. Mosquera, and T. Clark, Phys. Chem. Chem. Phys., 2001, 3, 3569.
354 Imidazoles
2001S909 S. Harez, M. Begtnup, P. Vedsø, K. Anderson, and T. Ruhland, Synthesis, 2001, 909.
2001S1248 E. Hasegawa, N. Chiba, A. Nakajima, K. Suzuki, A. Yoneoka, and K. Iwaya, Synthesis, 2001, 1248.
2001S1509 M. Kidwai, P. Sapra, K. Bhushan, and P. Misra, Synthesis, 2001, 1509.
2001S2075 P.-F. Zhang and Z.-C. Chen, Synthesis, 2001, 2075.
2001S2393 B. L. Booth, R. A. Carpenter, G. Morlock, Z. Mahmood, and R. B. Pritchard, Synthesis, 2001, 2393.
2001SL218 P. M. Fresneda, P. Molina, and M. A. Sanz, Synlett, 2001, 218.
2001SL374 G. Bissky, V. I. Staninets, A. A. Kolomeitsev, and G.-V. Roschenthaler, Synlett, 2001, 374.
2001SL1925 L. G. Quan and J. K. Cha, Synlett, 2001, 1925.
2001T2031 G. Abbiati, A. Arcadi, O. Attanasi, L. Crescentini, and E. Rossi, Tetrahedron, 2001, 56, 2031.
2001T3413 N. Coskun, F. Tirli Tat, and O. Ozel Guven, Tetrahedron, 2001, 57, 3413.
2001T5497 Z. Wan, G. Woo, and J. Snyder, Tetrahedron, 2001, 57, 5497.
2001T6745 M. L. Lopez-Rodriguez, B. Benhamu, A. Viso, M. Murcia, and L. Pardo, Tetrahedron, 2001, 57, 6745.
2001TA1463 N. Coskun, F. T. Tat, and O. O. Guven, Tetrahedron: Asymmetry, 2001, 12, 1463.
2001TL1627 V. Krchák, J. Smith, and J. Vágner, Tetrahedron Lett., 2001, 42, 1627.
2001TL2635 J. Lee, A. Doucette, N. S. Wilson, and J. Lord, Tetrahedron Lett., 2001, 42, 2635.
2001TL3897 M.-J. Cheng and C.-H. Hu, Tetrahedron Lett., 2001, 42, 3897.
2001TL4297 D. Norris, P. Chen, J. Barrish, J. Das, R. Moquin, B. Chen, and P. Guo, Tetrahedron Lett., 2001, 42, 4297.
2001TL4499 F. Terrier, M. Beaufour, J. C. Halle, J. C. Cherton, and E. Buncel, Tetrahedron Lett., 2001, 42, 4499.
2002AGE1290 W. A. Herrmann, Angew. Chem. Int. Ed., 2002, 41, 1290.
2002AGE1432 J. A. Cowan, J. A. C. Clyburne, M. G. Davison, R. L. W. Harris, J. A. K. Howard, P. Kupper, M. A. Leech, and
S. P. Richards, Angew. Chem. Int. Ed., 2002, 41, 1432.
2002AGE2290 S. Laufer, G. Wagner, and D. Kotschenreuther, Angew. Chem. Int. Ed., 2002, 41, 2290.
2002CED8 U. Domanska, M. Kozlowska, and M. Rogalski, J. Chem. Eng. Data, 2002, 47, 8.
2002CED456 U. Domanska, M. K. Kozlowska, and M. Rogalski, J. Chem. Eng. Data, 2002, 47, 456.
2002CPB1379 A. R. Hergueta, M. J. Figueira, C. López, O. Caamaño, F. Fernández, and J. E. Robrı́gues-Borges, Chem. Pharm. Bull., 2002,
50, 1379.
2002CRV3667 J. Dupont, R. de Souza, and P. Suarez, Chem. Rev., 2002, 102, 3667.
2002CTO157 D. Zhao, M. Wu, Y. Kou, and E. Min, Catal. Today, 2002, 74, 157.
2002EJI2015 D. Vagedes, G. Kehr, D. Konig, K. Wedeking, R. Frohlich, G. Erker, C. Muck-Lichtenfeld, and S. Grimme, Eur. J. Inorg.
Chem., 2002, 2015.
2002EJO3801 G. Túrós, A. Csámpai, T. Lovász, A. Györfi, H. Wamhoff, and P. Sohár, Eur. J. Org. Chem., 2002, 3801.
2002H(57)1689 K. Benakli, T. Terme, J. Maldonado, and P. Vanelle, Heterocycles, 2002, 57, 1689.
2002JA2025 B. Henry, P. Tekely, and J.-J. Delpuech, J. Am. Chem. Soc., 2002, 124, 2025.
2002JA3202 K. Tan, R. Bergman, and J. Ellman, J. Am. Chem. Soc., 2002, 124, 3202.
2002JA4944 R. F. R. Jazzar, S. A. Macgregor, M. F. Mahon, S. O. Richards, and M. K. Whittlesey, J. Am. Chem. Soc., 2002, 124, 4944.
2002JA9629 P. Kang and C. S. Foote, J. Am. Chem. Soc., 2002, 124, 9629.
2002JA10473 S. Gruendemann, A. Kovacevic, M. Albrecht, J. W. Faller, and R. H. Crabtree, J. Am. Chem. Soc., 2002, 124, 10473.
2002JCH(942)107 R. Cirilli, R. Costi, R. Di Santo, R. Ferretti, F. La Torre, L. Angiolella, and M. Micocci, J. Chromatogr. A, 2002, 942,
107.
2002JCO359 P. Bendale and C. Sun, J. Comb. Chem., 2002, 4, 359.
2002JHC375 Y. M. Loksha, P. T. Jorgensen, E. B. Pedersen, M. A. El-Badawi, A. A. El-Barbary, and C. Nielsen, J. Heterocycl. Chem., 2002,
39, 375.
2002JHC911 F. Saczewski, A. Bulakowska, and M. Gdaniec, J. Heterocycl. Chem., 2002, 39, 911.
2002JME32 F. Gentili, P. Bousquet, L. Brasili, M. Caretto, A. Carrieri, M. Dontenwill, M. Giannella, G. Marucci, M. Perfumi,
A. Piergentili, W. Quaglia, C. Rascente, and M. Pigini, J. Med. Chem., 2002, 45, 32.
2002JME1697 L. Wang, K. Woods, Q. Li, K. Barr, R. McCroskey, S. Hannick, L. Gherke, R. Credo, Y. Hui, K. Marsh, R. Warner, J. Lee,
N. Zielinski-Mozng, D. Frost, S. Rosenberg, and H. Sham, J. Med. Chem., 2002, 45, 1697.
2002JME1748 F. Ooms, J. Wouters, O. Oscari, T. Happaerts, G. Bouchard, P. Carrupt, B. Testa, and D. M. Lambert, J. Med. Chem., 2002,
45, 1748.
2002JME2173 J. McKenna, F. Halley, J. Souness, I. McLay, S. Pickett, A. Collis, K. Page, and I. Ahmed, J. Med. Chem., 2002, 45,
2173.
2002JME3356 R. Gust, R. Keilitz, K. Schmidt, and M. von Rauch, J. Med. Chem., 2002, 45, 3356.
2002JOC188 R. J. Herr, P. F. Vogt, H. Meckler, M. P. Trova, S. R. Schow, and R. C. Petter, J. Org. Chem., 2002, 67, 188.
2002JOC1333 M. K. Cyranski, T. M. Krygowski, A. R. Katritzky, and P. von. R. Schleyer, J. Org. Chem., 2002, 67, 1333.
2002JOC2699 R. H. J. Butz and S. D. Lindell, J. Org. Chem., 2002, 67, 2699.
2002JOC3468 B. Dolensky and K. L. Kirk, J. Org. Chem., 2002, 67, 3468.
2002JOC3919 N. A. Boland, M. Casey, S. J. Hynes, J. W. Matthews, and M. P. Smyth, J. Org. Chem., 2002, 67, 3919.
2002JOC4777 H.-X. Wei, S. H. Kim, and G. Li, J. Org. Chem., 2002, 67, 4777.
2002JOC5546 A. M. Dias, I. Cabral, M. F. Proenca, and B. L. Booth, J. Org. Chem., 2002, 67, 5546.
2002JOC7151 A. V. Wiznycia and P. W. Baures, J. Org. Chem., 2002, 67, 7151.
2002JOC7553 Y.-Q. Wu, S. K. Hamilton, D. E. Wilkinson, and G. S. Hamilton, J. Org. Chem., 2002, 67, 7553.
2002JOC8230 A. R. Katritzky, R. Maimait, Y.-J. Xu, and Y. S. Gyoung, J. Org. Chem., 2002, 67, 8230.
2002JST(604)87 P. Purkayastha and N. Chattopadhyay, J. Mol. Struct., 2002, 604, 87.
2002JST(605)199 R. M. Claramunt, P. Cornago, D. Sanz, M. D. Santa-Marfa, C. Foces-Foces, I. Alkorta, and J. Elguero, J. Mol. Struct., 2002,
605, 199.
2002MI(818)2 J. Holbrey and R. Rogers; in ‘ACS Symposium Series’, R. D. Rogers and K. R. Seddon, Eds.; American Chemical Society,
Washington, DC, 2002, vol. 818, p. 2.
2002MI(818)90 M. Earle; in ‘ACS Symposium Series’, R. D. Rogers and K. R. Seddon, Eds.; American Chemical Society, Washington, DC,
2002, vol. 818, p. 90.
Imidazoles 355
2002MI(819)10 M. Earle and K. Seddon; in ‘ACS Symposium Series’, M. A. Abraham and L. Moens, Eds.; American Chemical Society,
Washington, DC, 2002, vol. 819, p. 10.
2002MI177 M. Earle, K. Seddon, Proceedings – Electrochemical Society, 2002, No. 19, p. 177.
2002MOL867 M. Sosnowski and L. Skulski, Molecules, 2002, 7, 867.
2002OL3161 V. Namboodiri and R. Varma, Org. Lett., 2002, 4, 3161.
2002OL3533 S. Peddibhotla and J. J. Tepe, Org. Lett., 2002, 4, 3533.
2002OL4017 Y. Deng and D. J. Hlasta, Org. Lett., 2002, 4, 4017.
2002OL4133 C. J. Helal and J. C. Lucas, Org. Lett., 2002, 4, 4133.
2002OL4345 F. Gagosz and S. Z. Zard, Org. Lett., 2002, 4, 4345.
2002OL4543 A. K. Nadipuram, W. M. David, D. Kumar, and S. M. Kerwin, Org. Lett., 2002, 4, 4543.
2002OL4713 F. Menges, M. Neuburger, and A. Pfaltz, Org. Lett., 2002, 4, 4713.
2002PCA3403 A. Toyama, K. Ono, S. Hashimoto, and H. Takeuchi, J. Phys. Chem. A, 2002, 106, 3403.
2002PJC67 J. Wengel and K. Walczak, Pol. J. Chem., 2002, 76, 67.
2002PJC1027 M. Darowska and E. D. Raczynska, Pol. J. Chem., 2002, 76, 1027.
2002S523 Z.-H. Xu, Y.-F. Jie, M.-X. Wang, and Z.-T. Huang, Synthesis, 2002, 523.
2002S1072 S. Harusawa, S. Koyabu, Y. Inoue, Y. Sakamoto, L. Araki, and T. Kurihara, Synthesis, 2002, 1072.
2002S2691 P. Moreno, M. Heras, M. Maestro, and J. M. Villalgordo, Synthesis, 2002, 2691.
2002SAA2961 R. N. Patel, S. Kumar, K. B. Pandeya, and P. V. Khadikar, Spectrochim. Acta, Part A, 2002, 58, 2961.
2002SC1447 C. Xia, H. Wang, B. Zhao, J. Chen, C. Kang, Y. Ni, and P. Zhou, Synth. Commun., 2002, 32, 1447.
2002T7791 M.-X. Zhao, Z.-M. Wang, M. Wang, C.-H. Yan, and Z.-T. Huang, Tetrahedron, 2002, 58, 7791.
2002TL1893 C. T. Brain and S. A. Brunton, Tetrahedron Lett., 2002, 43, 1893.
2002TL2445 M. A. Voinov and I. A. Grigor’ev, Tetrahedron Lett., 2002, 43, 2445.
2002TL3351 H. Wasserman, Y. Long, R. Zhang, and J. Parr, Tetrahedron Lett., 2002, 43, 3351.
2002TL3809 H.-X. Wei, S. Siruta, and G. Li, Tetrahedron Lett., 2002, 43, 3809.
2002TL4127 M. D. Crozet, P. Perfetti, M. Kaafarani, P. Vanelle, and M. P. Crozet, Tetrahedron Lett., 2002, 43, 4127.
2002TL4377 I. Kawasaki, N. Sakaguchi, N. Fukushima, N. Fujioka, F. Nikaido, M. Yamashita, and S. Ohta, Tetrahedron Lett., 2002, 43,
4377.
2002TL4571 J.-F. Cheng, C. Kaiho, M. Chen, T. Arrhenius, and A. Nadzan, Tetrahedron Lett., 2002, 43, 4571.
2002TL5879 Y. Jiao, E. Valente, S. T. Garner, X. Wang, and H. Yu, Tetrahedron Lett., 2002, 43, 5879.
2002TL6335 G. Haberhauer and F. Rominger, Tetrahedron Lett., 2002, 43, 6335.
2002TL7687 K. H. Bleicher, F. Gerber, Y. Wüthrich, A. Alanine, and A. Capretta, Tetrahedron Lett., 2002, 43, 7687.
2002TL7707 J. M. Gardiner, A. D. Goss, T. Majid, A. D. Morley, R. G. Pritchard, and J. E. Warren, Tetrahedron Lett., 2002, 43, 7707.
2003ACSSS(856) Ionic Liquids as Green Solvents: Progress and Prospects, ACS Symposium Series 856, R. D. Rogers, K. R. Seddon, Eds.,
American Chemical Society, Washington DC, 2003.
2003AGE4077 K. C. Nicolaou, C. J. N. Mathison, and T. Montagnon, Angew. Chem. Int. Ed., 2003, 42, 4077.
2003AGE4302 P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I. Sapountzis, and V. A. Vu, Angew. Chem. Int. Ed.,
2003, 42, 4302.
2003AGE5243 F. E. Hahn, M. Paas, D. Le Van, and T. Luegger, Angew. Chem. Int. Ed., 2003, 42, 5243.
2003AGE5452 L. E. Cheruzel, M. S. Pometun, M. R. Cecil, M. S. Mashuta, R. J. Wittebort, and R. M. Buchanan, Angew. Chem. Int. Ed.,
2003, 42, 5452.
2003AGE5981 P. L. Arnold, S. A. Mungur, A. J. Blake, and C. Wilson, Angew. Chem. Int. Ed., 2003, 42, 5981.
2003AXB487 M. Kubicki, T. Borowiak, G. Dutkiewicz, S. Sobiak, and I. Weidlich, Acta Crystallogr., Sect. B, 2003, 59, 487.
2003ASY(856) in ‘ACS Symposium Series’, R. D. Rogers and K. R. Seddon, Eds.; American Chemical Society, Washingdon, DC, 2003, vol.
856, .
2003ASY(856)2 J. Holbrey, M. Turner, and R. Rogers; in ‘ACS Symposium Series’, R. D. Rogers and K. R. Seddon, Eds.; American
Chemical Society, Washington, DC, 2003, vol. 856, p. 2.
2003BMC4539 Basappa, M. P. Sadashiva, K. Mantelingu, S. N. Swamy, and K. S. Rangappa, Bioorg. Med. Chem., 2003, 11, 4539.
2003CC1870 D. Gennet, S. Z. Zard, and H. Zhang, Chem. Commun., 2003, 1870.
2003CED557 U. Domanska and M. K. Kozlowska, J. Chem. Eng. Data, 2003, 48, 557.
2003CED951 U. Domanska and E. Bogel-Lukasik, J. Chem. Eng. Data, 2003, 48, 951.
2003CEJ2867 A. Viso, R. F. de la Pradilla, A. Garcı́a, C. Guerrero-Strachan, M. Alonso, M. Tortosa, A. Flores, M. Martı̀nez-Ripoll,
I. Fonsecac, and A. Rodrı̀guez, Chem. Eur. J., 2003, 9, 2867.
2003EJO1080 J. Suwiński, W. Szczepankiewicz, K. Swierczek, and K. Walczak, Eur. J. Org. Chem., 2003, 1080.
2003EJO3209 G. Haberhauer and F. Rominger, Eur. J. Org. Chem., 2003, 3209.
2003EJO3840 G. Verardo, P. Geatti, P. Martinuzzi, M. Merli, and N. Toniutti, Eur. J. Org. Chem., 2003, 3840.
2003EJO4432 G. A. Roshchupkina, N. V. Pervukhina, T. V. Rybalova, Y. V. Gatilov, A. B. Burdukov, and V. A. Reznikov, Eur. J. Org.
Chem., 2003, 4432.
2003GC181 M. Deetlefs and K. Seddon, Green Chem., 2003, 5, 181.
2003H(60)1 C. J. Lovely, H. Du, and H. V. R. Dias, Heterocycles, 2003, 60, 1.
2003H(60)89 I. A. Perillo, C. de los Santos, and A. Salerno, Heterocycles, 2003, 60, 89.
2003H(60)583 S. Nakamura, I. Kawasaki, M. Yamashita, and S. Ohta, Heterocycles, 2003, 60, 583.
2003H(60)1185 Y. Kamitori, Heterocycles, 2003, 60, 1185.
2003H(60)2103 A. Perillo, G. Buldain, and A. Salerno, Heterocycles, 2003, 60, 2103.
2003HCA1026 A. Sanchez-Migallon, A. de la Hoz, C. Lopez, R. M. Claramunt, L. Infantes, S. Motherwell, K. Shankland, H. Nowell,
I. Alkorta, and J. Elguero, Helv. Chim. Acta, 2003, 86, 1026.
2003HCA2272 A. Majchrzak, A. Janczak, G. Mloston, A. Linden, and H. Heimgartner, Helv. Chim. Acta, 2003, 86, 2272.
2003HCA3461 M. Hervet, I. Thery, A. Gueiffier, and C. Enguehard-Gueiffier, Helv. Chim. Acta, 2003, 86, 3461.
2003HCA3482 M. Terinek and A. Vasella, Helv. Chim. Acta, 2003, 86, 3482.
2003MI132 T. Smirnova, P. Kurapov, E. Vetrova, A. Bass, and N. Nam, Izv. Timiryazevskoi Sel’skokhozyaistvennoi Akad., 2003, 4, 132.
356 Imidazoles
2003JA2328 F. J. Ramirez, I. Tunon, J. A. Collado, and E. Silla, J. Am. Chem. Soc., 2003, 125, 2120.
2003JA2546 T. M. Trnka, J. P. Morgan, M. S. Sanford, T. E. Wilhelm, M. Scholl, T.-L. Choi, S. Ding, M. W. Day, and R. H. Grubbs,
J. Am. Chem. Soc., 2003, 125, 2546.
2003JA6028 K. Kamaraj, E. Kim, B. Galliker, L. N. Zakharov, A. L. Rheingold, A. D. Zuberbuehler, and K. D. Karlin, J. Am. Chem. Soc.,
2003, 125, 6028.
2003JA11836 B. Trost, and D. Fandrick, J. Am. Chem. Soc., 2003, 125, 11836.
2003JA15986 L. A. Yatsunyk, M. D. Carducci, and F. A. Walker, J. Am. Chem. Soc., 2003, 125, 15986.
2003JHC129 G. Gervasio, D. Marabello, C. Barolo, P. Quagliotto, and G. Viscardi, J. Heterocycl. Chem., 2003, 40, 129.
2003JHC159 M. Vuilhorgne, J. Malpart, S. Mutti, and S. Mignani, J. Heterocycl. Chem., 2003, 40, 159.
2003JHC191 Y.-Q. Wu, D. C. Limburg, D. E. Wilkinson, and G. S. Hamilton, J. Heterocycl. Chem., 2003, 40, 191.
2003JHC229 P. E. Maligres, M. S. Waters, S. A. Weissman, J. C. McWilliams, S. Lewis, J. Cowen, R. A. Reamer, R. P. Volante,
P. J. Reider, and D. Askin, J. Heterocycl. Chem., 2003, 40, 229.
2003JHC523 J. Suwinski, K. Swierczek, P. Wagner, M. Kubicki, T. Borowiak, and J. Slowikowska, J. Heterocycl. Chem., 2003, 40, 523.
2003JHC649 E. Barni, C. Barolo, P. Quagliotto, P. Savarino, G. Viscardi, and D. Marabello, J. Heterocycl. Chem., 2003, 40, 649.
2003JHC1107 L.-C. Yang, C.-M. Qi, G.-X. Zhang, and N.-Z. Zou, J. Heterocycl. Chem., 2003, 40, 1107.
2003JME1546 I. Lagoja, C. Pannecouque, A. Van Aerschot, M. Witvrouw, Z. Debyser, J. Balzarini, P. Herdewijn, and E. De Clercq,
J. Med. Chem., 2003, 46, 1546.
2003JME1962 F. Touzeau, A. Arrault, G. Guillaumet, E. Scalbert, B. Pfeiffer, M. Rettori, P. Renard, and J. Merour, J. Med. Chem., 2003,
46, 1962.
2003JME2169 F. Gentili, P. Bousquet, L. Brasili, M. Dontenwill, J. Feldman, F. Ghelfi, M. Giannella, A. Piergentili, W. Quaglia, and
M. Pigini, J. Med. Chem., 2003, 46, 2169.
2003JME3230 S. Laufer, G. Wagner, D. Kotschenreuther, and W. Albrecht, J. Med. Chem., 2003, 46, 3230.
2003JME3463 C. Almansa, J. Alfon, A. De Arriba, F. Cavalcanti, I. Escamilla, L. Gomez, A. Miralles, R. Soliva, J. Bartroli, E. Carceller,
M. Merlos, and J. Garcia-Rafanell, J. Med. Chem., 2003, 46, 3463.
2003JME5445 R. Kitbunnadaj, O. Zuiderveld, I. De Esch, O. Vollinga, C. R. R. Bakker, M. Lutz, A. Spek, E. Cavoy, M. Deltent,
W. Menge, H. Timmerman, and R. Leurs, J. Med. Chem., 2003, 46, 5445.
2003JMT(666)143 I. M. Mandity, G. Paragi, F. Bogar, and I. G. Csizmadia, THEOCHEM, 2003, 666–667, 143.
2003JOC10158 Y. Miura, T. Nishi, and Y. Teki, J. Org. Chem., 2003, 68, 10158.
2003JOC276 M. E. A. Zaki, M. F. Proenca, and B. L. Booth, J. Org. Chem., 2003, 68, 276.
2003JOC4345 B. Lahue, Z. Wan, and J. Snyder, J. Org. Chem., 2003, 68, 4345.
2003JOC4527 G. K. Wagner, D. Kotschenreuther, W. Zimmermann, and S. A. Laufer, J. Org. Chem., 2003, 68, 4527.
2003JOC5168 E. Giorgio, C. Minichino, R. Viglione, R. Zanasi, and C. Rosini, J. Org. Chem., 2003, 68, 5186.
2003JOC5742 D. Chen, C. Timmons, H.-X. Wei, and G. Li, J. Org. Chem., 2003, 68, 5742.
2003JOC7521 S. Zaramella, P. Heinonen, E. Yeheskiely, and R. Stroemberg, J. Org. Chem., 2003, 68, 7521.
2003JPO47 J. G. Contreras and S. T. Madariaga, J. Phys. Org. Chem., 2003, 16, 47.
2003JPO783 E. D. Raczynska, M. Darowska, M. K. Cyranski, M. Makowski, T. Rudka, J.-F. Gal, and P.-C. Maria, J. Phys. Org. Chem.,
2003, 16, 783.
2003MI945 J. A. Murry, Curr. Opin. Drug Discov. Dev., 2003, 6, 945.
2003MR256 L. Schroder and P. Bachert, J. Magn. Reson., 2003, 164, 256.
2003MRC307 M. Kline and S. Cheatham, Magn. Reson. Chem., 2003, 41, 307.
2003MRC877 E. Gaggelli, N. D’Amelio, D. Valensin, and G. Valensin, Magn. Reson. Chem., 2003, 41, 877.
2003MRC1026 M. I. M. Wazeer, A. A. Isab, and H. P. Perzanowski, Magn. Reson. Chem., 2003, 41, 1026.
2003OL133 G. Evindar and R. A. Batey, Org. Lett., 2003, 5, 133.
2003OL511 S.-H. Lee, B. Clapham, G. Koch, J. Zimmermann, and K. D. Janda, Org. Lett., 2003, 5, 511.
2003OL595 C. A. Busacca, D. Grossbach, R. C. So, E. M. O’Brien, and E. M. Spinelli, Org. Lett., 2003, 5, 595.
2003OL1019 S. Fioravanti, F. Marchetti, A. Morreale, L. Pellacani, and P. Tardella, Org. Lett., 2003, 5, 1019.
2003OL1657 R. Zeng, J. Zou, S. Zhi, J. Chen, and Q. Shen, Org. Lett., 2003, 5, 1657.
2003OL2513 S. Handy, M. Okello, and G. Dickenson, Org. Lett., 2003, 5, 2513.
2003OL3209 S. Park and H. Alper, Org. Lett., 2003, 5, 3209.
2003OL3313 K. Booker-Milburn, D. Guly, B. Cox, and P. Procopiou, Org. Lett., 2003, 5, 3313.
2003OL3759 R. S. Bon, C. Hong, M. J. Bouma, R. F. Schmitz, F. J. J. De Kanter, M. Lutz, A. L. Spek, and R. V. A. Orru, Org. Lett., 2003,
5, 3759.
2003OL4249 G. A. Reichard, C. Stengone, S. Paliwal, I. Mergelsberg, S. Majmundar, C. Wang, R. Tiberi, A. T. McPhail, J. J. Piwinski,
and N. Y. Shih, Org. Lett., 2003, 5, 4249.
2003OL4795 T. Fekner, J. Gallucci, and M. K. Chan, Org. Lett., 2003, 5, 4795.
2003OL4847 V. Vargas, R. Rubio, T. Hollis, and M. Salcido, Org. Lett., 2003, 5, 4847.
2003OM5374 S. E. Gibson, C. Johnstone, J. A. Loch, J. W. Steed, and A. Stevenazzi, Organometallics, 2003, 22, 5374.
2003PCA7827 W. Tatara, M. J. Wojcik, J. Lindgren, and M. Probst, J. Phys. Chem. A, 2003, 107, 7827.
2003PCB1858 U. Domanska, E. Bogel-Lukasik, and R. Bogel-Lukasik, J. Phys. Chem. B, 2003, 107, 1858.
2003S659 G. A. Kraus and P. K. Choudhury, Synthesis, 2003, 659.
2003S677 J.-I. Kawakami, K. Kimura, and M. Yamaoka, Synthesis, 2003, 677.
2003S871 I. A. Kirilyuk, T. G. Shevelev, D. A. Morozov, E. L. Khromovskih, N. G. Skuridin, V. V. Khramtsov, and I. A. Grigor’ev,
Synthesis, 2003, 871.
2003S1079 L. D. S. Yadav and R. Kapoor, Synthesis, 2003, 1079.
2003S1236 H. Uchida, T. Shimizu, P. Y. Reddy, S. Nakamura, and T. Toru, Synthesis, 2003, 1236.
2003S1433 S. Peddibhotla and J. J. Tepe, Synthesis, 2003, 1433.
2003S1753 H. Hoffmann and T. Lindel, Synthesis, 2003, 1753.
2003S2145 R. Ziessel and C. Stroh, Synthesis, 2003, 2145.
2003S2626 D. Xu, B. Liu, S. Luo, Z. Xu, and Y. Shen, Synthesis, 2003, 2626.
Imidazoles 357
2003SC153 M. Abdel-Megid, Synth. Commun., 2003, 33, 153.

2003SC1977 E. Muri, H. Mishra, M. Avery, and J. Williamson, Synth. Commun., 2003, 33, 1977.
2003SC3193 A. Salerno, M. A. Figueroa, and I. A. Perillo, Synth. Commun., 2003, 33, 3193.
2003SL102 M. Casey and M. P. Smyth, Synlett, 2003, 102.
2003SL780 G. Haberhauer and F. Rominger, Synlett, 2003, 780.
2003SL1117 H. Uchida, H. Tanikoshi, S. Nakamura, P. Reddy, and T. Toru, Synlett, 2003, 1117.
2003SL1451 T. Gimisis, P. Arsenyan, D. Georganakis, and L. Leondiadis, Synlett, 2003, 1451.
2003SL1533 C. Montagne, G. Fournet, and B. Joseph, Synlett, 2003, 1533.
2003T1657 M. K. Cyranski, P. v. R. Schleyer, T. M. Krygowski, H. Jiao, and G. Hohlneicher, Tetrahedron, 2003, 59, 1657.
2003T6027 W. Zhang, C. P. Landee, R. D. Willett, and M. M. Turnbull, Tetrahedron, 2003, 59, 6027.
2003T6759 F. Ek, L.-G. Wistrand, and T. Frejd, Tetrahedron, 2003, 59, 6759.
2003TA951 M. C. Perry and K. Burgess, Tetrahedron: Asymmetry, 2003, 14, 951.
2003TL1379 Y. Chen, H. V. R. Dias, and C. J. Lovely, Tetrahedron Lett., 2003, 44, 1379.
2003TL1709 S. Balalaie, M. M. Hashemi, and M. Akhbari, Tetrahedron Lett., 2003, 44, 1709.
2003TL3667 E. Dubost, T. Tschamber, and J. Streith, Tetrahedron Lett., 2003, 44, 3667.
2003TL4751 Y.-D. Cao, Q.-Y. Zheng, C.-F. Chen, and Z.-T. Huang, Tetrahedron Lett., 2003, 44, 4751.
2003TL5965 P. Langer and A. Bodtke, Tetrahedron Lett., 2003, 44, 5965.
2003TL6397 E. Y. Fursova, V. I. Ovcharenko, G. V. Romanenko, and E. V. Tretyakov, Tetrahedron Lett., 2003, 44, 6397.
2003TL6509 R. P. Frutos and M. Johnson, Tetrahedron Lett., 2003, 44, 6509.
2003TL7115 M. R. Dobler, Tetrahedron Lett., 2003, 44, 7115.
2003TL7485 J. A. Grzyb and R. A. Batey, Tetrahedron Lett., 2003, 44, 7485.
2003TL8967 B. Wang and P. Smith, Tetrahedron Lett., 2003, 44, 8967.
2003TL9111 N. Defacqz, T.-T. Van, A. Cordi, and J. Marchand-Brynaert, Tetrahedron Lett., 2003, 44, 9111.
2003TRH19 F. Saczewski and J. Saczewski, Trends Heterocycl. Chem., 2003, 9, 19.
2003TRH167 E. D. Raczynska, M. Darowska, and M. Makowski, Trends Heterocycl. Chem., 2003, 9, 167.
2004AGE2674 P. Baran, D. O’Malley, and A. Zografos, Angew. Chem. Int. Ed., 2004, 43, 2674.
2004AGE5130 V. Nair, S. Bindu, and V. Sreekumar, Angew. Chem. Int. Ed., 2004, 43, 5130.
2004AGE5507 M. Marigo, S. Bachmann, N. Halland, A. Braunton, and K. A. Jorgensen, Angew. Chem. Int. Ed., 2004, 43, 5507.
2004AGE5896 R. Alder, M. Blake, L. Chaker, J. Harvey, F. Paolini, and J. Schuetz, Angew. Chem. Int. Ed., 2004, 43, 5896.
2004AGE6343 T. Murata, Y. Morita, K. Fukui, K. Sato, D. Shiomi, T. Takui, M. Maesato, H. Yamochi, G. Saito, and K. Nakasuji, Angew.
Chem. Int. Ed., 2004, 43, 6343.
2004AJC113 S. Forsyth, J. Pringle, and D. MacFarlane, Aust. J. Chem., 2004, 57, 113.
2004AXB191 M. Kubicki, Acta Crystallogr., Sect. B, 2004, 60, 191.
2004BMCL1637 W. Yue, S. I. Lewis, Y. M. Koen, and R. P. Hanzlik, Bioorg. Med. Chem. Lett., 2004, 14, 1637.
2004BML333 T. Nakamura, H. Kakinuma, H. Umemiya, H. Amada, N. Miyata, K. Taniguchi, K. Bando, and M. Sato, Bioorg. Med. Chem.
Lett., 2004, 14, 333.
2004BML1151 B. Dyck, V. Goodfellow, T. Phillips, J. Grey, M. Haddach, M. Rowbottom, G. Naeve, B. Brown, and J. Saunders, Bioorg.
Med. Chem. Lett., 2004, 14, 1151.
2004BML3521 A. Liberatore, J. Schulz, J. Pommier, M. Barthelemy, M. Huchet, P. Chabrier, and D. Bigg, Bioorg. Med. Chem. Lett., 2004,
14, 3521.
2004BML3721 T. Marsilje, J. Roses, E. Calderwood, S. Stroud, N. Forsyth, C. Blackburn, D. Yowe, W. Miao, S. Drabic, M. Bohane,
J. Daniels, P. Li, L. Wu, M. Patane, and C. Claiborne, Bioorg. Med. Chem. Lett., 2004, 14, 3721.
2004BML6079 M. Abdollahi-Alibeik, I. Mohammadpoor-Baltork, and M. A. Zolfigol, Bioorg. Med. Chem. Lett., 2004, 14, 6079.
2004CC188 J. Lan, L. Chen, X. Yu, J. You, and R. Xie, Chem. Commun., 2004, 188.
2004CC778 S. Son, I. Park, J. Park, and T. Hyeon, Chem. Commun., 2004, 778.
2004CCR2459 T. Welton, Coord. Chem. Rev., 2004, 248, 2459.
2004CED1082 U. Domanska, A. Pobudkowska, and M. Rogalski, J. Chem. Eng. Data, 2004, 49, 1082.
2004CEJ3747 A. Bastero, C. Claver, A. Ruiz, S. Castillón, E. Daura, C. Bo, and E. Zangrando, Chem. Eur. J., 2004, 10, 3747.
2004CEJ5607 H. Cristau, P. Cellier, J. Spindler, and M. Taillefer, Chem. Eur. J., 2004, 10, 5607.
2004CEJ6581 Z.-B. Zhou, H. Matsumoto, and K. Tatsumi, Chem. Eur. J., 2004, 10, 6581.
2004CSR619 V. Cesar, S. Bellemin-Laponnaz, and L. H. Gade, Chem. Soc. Rev., 2004, 33, 619.
2004EJO2567 N. Habersaat, R. Froehlich, and E. Wuerthwein, Eur. J. Org. Chem., 2004, 2567.
2004EJO2833 G. Verardo, P. Geatti, M. Merli, and E. Castellarin, Eur. J. Org. Chem., 2004, 2833.
2004H(63)87 Y. Xu, Y.-Z. Liu, L. Rui, L. Liu, and Q.-X. Guo, Heterocycles, 2004, 63, 87.
2004H(63)1613 Y. Xu, L.-F. Wan, H. Salehi, W. Deng, and Q.-X. Guo, Heterocycles, 2004, 63, 1613.
2004H(63)2769 T. Itoh, K. Nagata, H. Ishikawa, and A. Ohsawa, Heterocycles, 2004, 63, 2769.
2004HAC432 K. Dawood, Heteroatom Chem., 2004, 15, 432.
2004HCA425 A. F. De, C. Alcantara, M. G. F. Vaz, H. O. Stumpf, D. Pilo-Veloso, and W. B. De Almeida, Helv. Chim. Acta, 2004, 87, 425.
2004JA814 Y. Fu, L. Liu, R.-Q. Li, R. Liu, and Q.-X. Guo, J. Am. Chem. Soc., 2004, 126, 814.
2004JA2807 F. B. Sviridenko, D. V. Stass, T. V. Kobzeva, E. V. Tretyakov, S. V. Klyatskaya, E. V. Mshvidobadze, S. F. Vasilevsky, and
Y. N. Molin, J. Am. Chem. Soc., 2004, 126, 2807.
2004JA4366 T. L. Amyes, S. T. Diver, J. P. Richard, F. M. Rivas, and K. Toth, J. Am. Chem. Soc., 2004, 126, 4366.
2004JA7800 J. M. Shin, Y. M. Cho, and G. Sachs, J. Am. Chem. Soc., 2004, 126, 7800.
2004JA12776 S. Peddibhotla and J. J. Tepe, J. Am. Chem. Soc., 2004, 126, 12776.
2004JFC(125)501 B. Dolensky, G. Nam, W.-P. Deng, J. Narayanan, J. Fan, and K. L. Kirk, J. Fluorine Chem., 2004, 125, 501.
2004JHC335 S. Ohta, K. Sato, I. Kawasaki, Y. Yamaguchi, S. Nishio, and M. Yamashita, J. Heterocycl. Chem., 2004, 41, 335.
2004JHC701 R. Clayton and C. A. Ramsden, J. Heterocycl. Chem., 2004, 41, 701.
358 Imidazoles
2004JME915 M. von Rauch, M. Schlenk, and R. Gust, J. Med. Chem., 2004, 47, 915.
2004JME2318 C. A. Blum, X. Zheng, and S. De Lombaert, J. Med. Chem., 2004, 47, 2318.
2004JME5009 H. Breslin, T. Miskowski, B. Rafferty, S. Coutinho, J. Palmer, N. Wallace, C. Schneider, E. Kimball, S. Zhang, J. Li,
R. Colburn, D. Stone, R. Martinez, and W. He, J. Med. Chem., 2004, 47, 5009.
2004JME6311 S. Laufer, W. Zimmermann, and K. Ruff, J. Med. Chem., 2004, 47, 6311.
2004JMT(684)121 E. Soriano, S. Cerdan, and P. Ballesteros, THEOCHEM, 2004, 684, 121.
2004JOC977 B.-C. Chen, R. Zhao, M. S. Bednarz, B. Wang, J. E. Sundeen, and J. C. Barrish, J. Org. Chem., 2004, 69, 977.
2004JOC1542 A. Viso, R. Fernandez de la Pradilla, M. L. Lopez-Rodriguez, A. Garcia, A. Flores, and M. Alonso, J. Org. Chem., 2004, 69,
1542.
2004JOC5247 P. R. Serwinski, B. Esat, P. M. Lahti, Y. Liao, R. Walton, and J. Lan, J. Org. Chem., 2004, 69, 5247.
2004JOC5578 J. Antilla, J. Baskin, T. Barder, and S. Buchwald, J. Org. Chem., 2004, 69, 5578.
2004JOC7171 B. Lahue, S. Lo, Z. Wan, G. Woo, and G. J. Snyder, J. Org. Chem., 2004, 69, 7171.
2004JOC8115 N. Mani, J. Jablonowski, and T. Jones, J. Org. Chem., 2004, 69, 8115.
2004JOC8151 D. Jaramillo, Q. Liu, J. Aldrich-Wright, and Y. Tor, J. Org. Chem., 2004, 69, 8151.
2004JOC8537 R. K. Bowman and J. S. Johnson, J. Org. Chem., 2004, 69, 8537.
2004JOC8829 S.-H. Lee, K. Yoshida, H. Matsushita, B. Clapham, G. Koch, J. Zimmermann, and K. D. Janda, J. Org. Chem., 2004, 69, 8829.
2004PCB13874 S. Yana and Y. Bu, J. Phys. Chem. B, 2004, 108, 13874.
2004JST(697)49 S. A. Popov, R. V. Andreev, G. V. Romanenko, V. I. Ovcharenko, and V. A. Reznikov, J. Mol. Struct., 2004, 697, 49.
2004OBC2340 M. A. Carvalho, M. E. A. Zaki, Y. Álvares, M. F. Proença, and B. L. Booth, Org. Biomol. Chem., 2004, 2, 2340.
2004OL35 J. Lewis, S. Wiedemann, R. Bergman, and J. Ellman, Org. Lett., 2004, 6, 35.
2004OL43 D. D. Diaz and M. G. Finn, Org. Lett., 2004, 6, 43.
2004OL541 T. Rosenau, A. Hofinger, A. Potthast, and P. Kosma, Org. Lett., 2004, 6, 541.
2004OL735 C. Lovely, H. Du, Y. He, and H. Dias, Org. Lett., 2004, 6, 735.
2004OL843 D. Frantz, L. Morency, A. Soheili, J. Murry, E. Grabowski, and R. Tillyer, Org. Lett., 2004, 6, 843.
2004OL929 Y.-L. Zhong, J. Lee, R. A. Reamer, and D. Askin, Org. Lett., 2004, 6, 929.
2004OL1453 S. E. Wolkenberg, D. D. Wisnoski, W. H. Leister, Y. Wang, Z. Zhao, and C. W. Lindsley, Org. Lett., 2004, 6, 1453.
2004OL1577 D. Yang, Y.-C. Chen, and N.-Y. Zhu, Org. Lett., 2004, 6, 1577.
2004OL1653 S. W. Baldwin and A. Long, Org. Lett., 2004, 6, 1653.
2004OL1681 S.-L. You and J. W. Kelly, Org. Lett., 2004, 6, 1681.
2004OL1685 S. H. Wiedemann, R. G. Bergman, and J. A. Ellman, Org. Lett., 2004, 6, 1685.
2004OL1853 C. J. Helal, Z. Kang, J. C. Lucas, and B. R. Bohall, Org. Lett., 2004, 6, 1853.
2004OL2237 I. A. Zavialov, V. H. Dahanukar, H. Nguyen, C. Orr, and D. R. Andrews, Org. Lett., 2004, 6, 2237.
2004OL2473 R. B. Sparks and A. P. Combs, Org. Lett., 2004, 6, 2473.
2004OL2473 R. Sparks and A. Combs, Org. Lett., 2004, 6, 2473.
2004OL3881 R. Chung, E. Yu, C. D. Incarvito, and D. J. Austin, Org. Lett., 2004, 6, 3881.
2004OL3933 R. Abou-Jneid, S. Ghoulami, M.-T. Martin, E. T. H. Dau, N. Travert, and A. Al-Mourabit, Org. Lett., 2004, 6, 3933.
2004OL4499 J. Concellon, E. Riego, J. Suarez, S. Garcia-Granda, and M. Diaz, Org. Lett., 2004, 6, 4499.
2004PCA7038 S. Yan, Y. Bu, Z. Cao, and P. Li, J. Phys. Chem. A, 2004, 108, 7038.
2004PCA11241 M. Boiani, H. Cerecetto, M. Gonzalez, O. Piro, and E. Castellano, J. Phys. Chem. A, 2004, 108, 11241.
2004PCB13177 E. R. Talaty, S. Raja, V. J. Storhaug, A. Doelle, and W. R. Carper, J. Phys. Chem. B, 2004, 108, 13177.
2004S116 Y. M. Loksha, A. A. El-Barbary, M. A. El-Badawi, C. Nielsen, and E. B. Pedersen, Synthesis, 2004, 116.
2004S506 K. Srinivas, C. K. S. Nair, S. Ramesh, and M. Pardhasaradhi, Synthesis, 2004, 506.
2004S1249 B. Kaboudin and F. Saadati, Synthesis, 2004, 1249.
2004S2678 C. L. Francis, N. M. Williamson, and A. D. Ward, Synthesis, 2004, 2678.
2004S2697 C. del Pozo, A. Macias, E. Alonso, and J. Gonzalez, Synthesis, 2004, 2697.
2004SAA2295 P. Chowdhury, S. Panja, and S. Chakravorti, Spectrochim. Acta, Part A, 2004, 60, 2295.
2004SC1617 N. Coskun and B. Yilmaz, Synth. Commun., 2004, 34, 1617.
2004SC3455 E. F. Calderwood, N. E. Forsyth, and A. E. Gould, Synth. Commun., 2004, 34, 3455.
2004SC3535 D. Li, J. Hao, B. Deng, W. Guo, F. Huo, Y. Zhang, and C. Xia, Synth. Commun., 2004, 34, 3535.
2004SL1306 G. Desforges, C. Bossert, C. Montagne, and B. Joseph, Synlett, 2004, 1306.
2004SL2103 A. M. Poulton, S. D. R. Christie, R. Fryatt, S. H. Dale, M. R. J. Elsegood, and D. M. Andrews, Synlett, 2004, 2103.
2004SL2800 X. Wang, Y. Xu, L. Zhang, D. Krishnamurthy, L. Nummy, V. Farina, and C. Senanayake, Synlett, 2004, 2800.
2004SL2803 I. Mohammadpoor-Baltork, M. A. Zolfigol, and M. Abdollahi-Alibeik, Synlett, 2004, 2803.
2004SPH15 T. Erker and N. Handler, Sci. Pharm., 2004, 72, 15.
2004T99 E. V. Tretyakov, G. V. Romanenko, and V. I. Ovcharenko, Tetrahedron, 2004, 60, 99.
2004T12095 C. Timmons, D. Chen, C. Barney, S. Kirtane, and G. Li, Tetrahedron, 2004, 60, 12095.
2004T1339 S. R. Nam, H.-J. Kim, S. Sakamoto, K. Yamaguchi, and J.-I. Hong, Tetrahedron Lett., 2004, 45, 1339.
2004T3097 Y. Inaba and Y. Kobuke, Tetrahedron, 2004, 60, 3097.
2004T5807 H. M. Lee, C. Y. Lu, C. Y. Chen, W. L. Chen, H. C. Lin, P. L. Chiu, and P. Y. Cheng, Tetrahedron, 2004, 60, 5807.
2004T6639 I. Kawasaki, T. Osaki, K. Tsunoda, E. Watanabe, M. Matsuyama, A. Sanai, A. Khadeer, M. Yamashita, and S. Ohta,
Tetrahedron, 2004, 60, 6639.
2004T8065 P. T. F. McLoughlin, M. A. Clyne, and F. Aldabbagh, Tetrahedron, 2004, 60, 8065.
2004T9857 D. Huh, H. Ryu, and Y. Kim, Tetrahedron, 2004, 60, 9857.
2004T10365 N. V. Artemova, M. N. Chevykalova, Y. N. Luzikov, I. E. Nifant’ev, and E. E. Nifant’ev, Tetrahedron, 2004, 60, 10365.
2004TA3181 E. Beccalli, G. Broggini, A. Contini, I. De Marchi, G. Zecchi, and C. Zoni, Tetrahedron: Asymmetry, 2004, 15, 3181.
2004TA3365 E. Guiu, C. Claver, J. Benet-Buchholz, and S. Castillon, Tetrahedron: Asymmetry, 2004, 15, 3365.
2004TL599 C. M. Haskins and D. W. Knight, Tetrahedron Lett., 2004, 45, 599.
2004TL1137 B. Prasad, G. Pandey, and V. Singh, Tetrahedron Lett., 2004, 45, 1137.
2004TL1655 P. M. Fresneda, M. S. Castaneda, A. Miguel, and P. Molina, Tetrahedron Lett., 2004, 45, 1655.
Imidazoles 359
2004TL1869 A. Chittiboyina, R. Reddy, B. Watkins, and M. Avery, Tetrahedron Lett., 2004, 45, 1869.
2004TL2219 B. Henkel, Tetrahedron Lett., 2004, 45, 2219.
2004TL2779 M. Friedel and T. Lindel, Tetrahedron Lett., 2004, 45, 2779.
2004TL3511 K. Arentsen, S. Caddick, F. G. N. Cloke, A. P. Herring, and P. B. Hitchcock, Tetrahedron Lett., 2004, 45, 3511.
2004TL3621 Z. Zhao, Y. Peng, N. K. Dalley, J. F. Cannon, and M. A. Peterson, Tetrahedron Lett., 2004, 45, 3621.
2004TL4185 V. K. Tandon and M. Kumar, Tetrahedron Lett., 2004, 45, 4185.
2004TL5529 Y. He, Y. Chen, H. Du, L. Schmid, and C. Lovely, Tetrahedron Lett., 2004, 45, 5529.
2004TL7167 X.-J. Wang, L. Zhang, Y. Xu, D. Krishnamurthy, and C. H. Senanayake, Tetrahedron Lett., 2004, 45, 7167.
2004TL7741 S. F. Vasilevsky, S. V. Klyatskaya, O. L. Korovnikova, D. V. Stass, S. A. Amitina, I. A. Grigir’ev, and J. Elguero, Tetrahedron
Lett., 2004, 45, 7741.
2004TL7991 C. Christensen, R. P. Clausen, M. Begtrup, and J. L. Kristensen, Tetrahedron Lett., 2004, 45, 7991.
2004TL8687 I. Mohammadpoor-Baltork, M. A. Zolfigol, and M. Abdollahi-Alibeik, Tetrahedron Lett., 2004, 45, 8687.
2004TL8945 A. Marwaha, P. Singh, M. P. Mahajan, and D. Velumurugan, Tetrahedron Lett., 2004, 45, 8945.
2005AGE2295 D. E. N. Jacquot, M. Zoellinger, and T. Lindel, Angew. Chem. Int. Ed., 2005, 44, 2295.
2005ACSSS(902) Ionic Liquids IIIB: Fundamentals, Progress, Challenges, and Opportunities – Transformations and Processes, ACS
Symposium Series 902, R. D. Rogers, K. R. Seddon, Eds., American Chemical Society, Washington DC, 2005.
2005B8303 M. A. Rosenow, H. N. Patel, and R. M. Wachter, Biochemistry, 2005, 44, 8303.
2005BML719 B. Shao, J. Huang, Q. Sun, K. Valenzano, L. Schmid, and S. Nolan, Bioorg. Med. Chem. Lett., 2005, 15, 719.
2005BML1441 C. Plummer, P. Finke, S. Mills, J. Wang, X. Tong, G. Doss, T. Fong, J. Lao, M. Schaeffer, J. Chen, C. Shen, D. Stribling,
L. Shearman, A. Strack, and L. Van der Ploeg, Bioorg. Med. Chem. Lett., 2005, 15, 1441.
2005BML4666 P. G. Piotr, A. Khan, S. B. Gurpreet, V. Palmer, D. Medland, H. Numata, H. Oinuma, J. Catchick, A. Dunne, M. Ellis,
C. Smales, J. Whitfield, J. Neame Stephen, B. Shah, D. Wilton, L. Morgan, T. Patel, R. Chung, H. Desmond, M. S. James,
N. Sato, and A. Inoue, Bioorg. Med. Chem. Lett., 2005, 15, 4666.
2005BML4691 S.-S. Hong, S. A. Bavadekar, S.-I. Lee, P. N. Patil, S. G. Lalchandani, D. R. Feller, and D. D. Miller, Bioorg. Med. Chem. Lett.,
2005, 15, 4691.
2005BML5136 C. Temperini, A. Scozzafava, L. Puccetti, and T. Supuran Claudiu, Bioorg. Med. Chem. Lett., 2005, 15, 5136.
2005BML5211 N. Xi, Y. Bo, E. M. Doherty, C. Fotsch, N. Gavva, N. Han, R. Hungate, L. Klionsky, Q. Liu, R. Tamir, S. Xu, J. S. Treanor,
and M. H. Norman, Bioorg. Med. Chem. Lett., 2005, 15, 5211.
2005CC868 A. R. Katritzky, S. Singh, K. Kirichenko, J. D. Holbrey, M. Smiglak, W. M. Reichert, and R. D. Rogers, Chem. Commun.,
2005, 868.
2005CC2849 Z. Wang, W. Bao, and Y. Jiang, Chem. Commun., 2005, 2849.
2005CEO514 T. Wu, D. Li, and S. Ng, CrystEngComm, 2005, 7, 514.
2005CHE1134 I. A. Grigor’ev, M. A. Voinov, and M. A. Fedotov, Chem. Heterocycl. Compd., 2005, 41, 1134.
2005CHE1201 N. Sidorina and V. Osyanin, Chem. Heterocycl. Compd., 2005, 41, 1201.
2005CJC110 I. Mohammadpoor-Baltork and M. Abdollahi-Alibeik, Can. J. Chem., 2005, 83, 110.
2005CL734 T. Tozawa, Y. Yamane, and T. Mukaiyama, Chem. Lett., 2005, 34, 734.
2005CTM987 S. R. Natarajan and J. B. Doherty, Curr. Top. Med. Chem., 2005, 5, 987.
2005EJO1637 E. Alcalde, I. Dinares, S. Rodriguez, and C. Garcia de Miguel, Eur. J. Org. Chem., 2005, 1637.
2005GC83 L. Ropel, L. Belveze, S. N. V. K. Aki, M. A. Stadtherr, and J. F. Brennecke, Green Chem., 2005, 7, 83.
2005GC701 W. Wu, W. Li, B. Han, Z. Zhang, T. Jiang, and Z. Liu, Green Chem., 2005, 7, 701.
2005H(65)353 B. Kaboudin and F. Saadati, Heterocycles, 2005, 65, 353.
2005H(65)1975 I. Langhammer and T. Erker, Heterocycles, 2005, 65, 1975.
2005H(65)2721 I. Langhammer and T. Erker, Heterocycles, 2005, 65, 2721.
2005H(65)2783 J. Yli-Kauhaluoma, A. Laine, J. Ratilainen, and A. Karjalainen, Heterocycles, 2005, 65, 2783.
2005H(65)2893 Y. Zhang, D. Li, C. Xia, and W. Guo, Heterocycles, 2005, 65, 2893.
2005H(66)263 Y. Ishida, H. Miyauchi, and K. Saigo, Heterocycles, 2005, 66, 263.
2005HCA487 G. Stupka, L. Gremaud, and A. F. Williams, Helv. Chim. Acta, 2005, 88, 487.
2005HCA707 S. Sahli, B. Stump, T. Welti, W. B. Schweizer, F. Diederich, D. Blum-Kaelin, J. D. Aebi, and H.-J. Boehm, Helv. Chim. Acta,
2005, 88, 707.
2005HCA1589 H. Quast, M. Ach, J. Balthasar, T. Hergenroether, D. Regnat, J. Lehmann, and K. Banert, Helv. Chim. Acta, 2005, 88, 1589.
2005HCA2454 P. Magdolen and A. Vasella, Helv. Chim. Acta, 2005, 88, 2454.
2005HCA2705 T. C. Ramalho, M. Buhl, J. D. Figueroa-Villar, and R. Bicca de Alencastro, Helv. Chim. Acta, 2005, 88, 2705.
2005HCA3253 S. Malaschichin, C. Fu, A. Linden, and H. Heimgartner, Helv. Chim. Acta, 2005, 88, 3253.
2005JA5675 C. Hu, A. Roth, M. K. Ellison, J. An, C. M. Ellis, C. E. Schulz, and W. R. Scheidt, J. Am. Chem. Soc., 2005, 127, 5675.
2005JA8942 D. A. Evans, K. R. Fandrick, and H.-J. Song, J. Am. Chem. Soc., 2005, 127, 8942.
2005JA9485 O. M. Usov, P. S. T. Choi, J. P. Shapleigh, and C. P. Scholes, J. Am. Chem. Soc., 2005, 127, 9485.
2005JA10070 S. Park, O.-H. Kwon, S. Kim, S. Park, M.-G. Choi, M. Cha, S. Y. Park, and D.-J. Jang, J. Am. Chem. Soc., 2005, 127, 10070.
2005JA12544 F. Cheng, H. Sun, Y. Zhang, D. Mukkamala, and E. Oldfield, J. Am. Chem. Soc., 2005, 127, 12544.
2005JA14675 M. C. Myers, A. R. Bharadwaj, B. C. Milgram, and K. A. Scheidt, J. Am. Chem. Soc., 2005, 127, 14675.
2005JA16366 V. Yadav and V. Sriramurthy, J. Am. Chem. Soc., 2005, 127, 16366.
2005JA16792 A. R. Choudhury, N. Winterton, A. Steiner, A. I. Cooper, and K. A. Johnson, J. Am. Chem. Soc., 2005, 127, 16792.
2005JA17624 A. Voutchkova, L. Appelhans, A. Chianese, and R. Crabtree, J. Am. Chem. Soc., 2005, 127, 17624.
2005JCO317 B. Kundu, D. Sawant, and R. Chhabra, J. Comb. Chem., 2005, 7, 317.
2005JCO826 S. Bae, H. Hahn, and K. Nam, J. Comb. Chem., 2005, 7, 826.
2005JCP174501 Y. Wang, H. Li, and S. Han, J. Chem. Phys., 2005, 123, 174501.
2005JHC173 D. Shi, C. Shi, J. Wang, L. Rong, Q. Zhuang, and X. Wang, J. Heterocycl. Chem., 2005, 42, 173.
2005JHC883 P. Kowalski, K. Nowak, and B. Szpakiewicz, J. Heterocycl. Chem., 2005, 42, 883.
2005JHC899 M. Sedlak, R. Keder, J. Hanusek, and A. Ruzicka, J. Heterocycl. Chem., 2005, 42, 899.
360 Imidazoles
2005JHC1111 S. A. Komykhov, K. S. Ostras, A. R. Kostanyan, S. M. Desenko, V. D. Orlov, and H. Meier, J. Heterocycl. Chem., 2005, 42,
1111.
2005JME1823 J. Lange, H. van Stuivenberg, H. Coolen, T. Adolfs, A. McCreary, H. Keizer, H. Wals, W. Veerman, A. Borst, W. de Looff,
P. Verveer, and C. Kruse, J. Med. Chem., 2005, 48, 1823.
2005JME2100 R. Kitbunnadaj, T. Hashimoto, E. Poli, O. Zuiderveld, A. Menozzi, R. Hidaka, I. de Esch, R. Bakker, W. Menge,
A. Yamatodani, G. Coruzzi, H. Timmerman, R. Leurs, and Rob, J. Med. Chem., 2005, 48, 2100.
2005JME2154 F. Janssens, J. Leenaerts, G. Diels, B. De Boeck, A. Megens, X. Langlois, K. van Rossem, J. Beetens, and M. Borgers,
J. Med. Chem., 2005, 48, 2154.
2005JME2638 B. Asproni, G. Talani, F. Busonero, A. Pau, S. Sanna, R. Cerri, M. Mascia, E. Sanna, and G. Biggio, J. Med. Chem., 2005, 48,
2638.
2005JME4378 G. De Martino, G. La Regina, A. Di Pasquali, R. Ragno, A. Bergamini, C. Ciaprini, A. Sinistro, G. Maga, E. Crespan,
M. Artico, and R. Silvestri, J. Med. Chem, 2005, 48, 4378.
2005JME6516 T. Wiglenda, I. Ott, B. Kircher, P. Schumacher, D. Schuster, T. Langer, and R. Gust, J. Med. Chem., 2005, 48, 6516.
2005JME6632 M. Voets, I. Antes, C. Scherer, U. Mueller-Vieira, K. Biemel, C. Barassin, S. Marchais-Oberwinkler, and R. Hartmann,
J. Med. Chem., 2005, 48, 6632.
2005JME8289 J. Venable, H. Cai, W. Chai, C. Dvorak, C. Grice, J. Jablonowski, C. Shah, A. Kwok, K. Ly, B. Pio, J. Wei, P. Desai, W. Jiang,
S. Nguyen, P. Ling, S. Wilson, P. Dunford, R. Thurmond, T. Lovenberg, L. Karlsson, N. Carruthers, and J. Edwards,
J. Med. Chem., 2005, 48, 8289.
2005JMT(724)167 Q. Sun, Z. Li, X. Zeng, M. Ge, and D. Wang, THEOCHEM, 2005, 724, 167.
2005JST(734)51 S. K. Dogra, J. Mol. Struct., 2005, 734, 51.
2005JMT(730)199 H.-J. Zhu, Y. Ren, J. Ren, and S.-Y. Chu, THEOCHEM, 2005, 730, 199.
2005JOC998 Z. Yu, Q. Dang, and Y. Wu, J. Org. Chem., 2005, 70, 998.
2005JOC1612 K. L. Seley, S. Salim, L. Zhang, and P. I. O’Daniel, J. Org. Chem., 2005, 70, 1612.
2005JOC3542 R. S. Bon, B. Van Vliet, N. E. Sprenkels, R. F. Schmitz, F. J. J. De Kanter, C. V. Stevens, M. Swart, F. M. Bickelhaupt,
M. B. Groen, and R. V. A. Orru, J. Org. Chem., 2005, 70, 3542.
2005JOC3997 F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi, and S. Viel, J. Org. Chem., 2005, 70, 3997.
2005JOC4889 B. Kundu, D. Sawant, P. Partani, and A. P. Kesarwani, J. Org. Chem., 2005, 70, 4889.
2005JOC4897 Y. Pan, C. Holmes, and D. Tumelty, J. Org. Chem., 2005, 70, 4897.
2005JOC5164 H. Zhang, Q. Cai, and D. Ma, J. Org. Chem., 2005, 70, 5164.
2005JOC6647 W. Dai, J. L. Petersen, and K. K. Wang, J. Org. Chem., 2005, 70, 6647.
2005JOC7331 A. Heim-Riether and J. Healy, J. Org. Chem., 2005, 70, 7331.
2005JOC7647 J. A. Hrabie, M. L. Citro, G. N. Chmurny, and L. K. Keefer, J. Org. Chem., 2005, 70, 7647.
2005JOC9632 E. Hasegawa, T. Seida, N. Chiba, T. Takahashi, and H. Ikeda, J. Org. Chem., 2005, 70, 9632.
2005JOC9702 M. A. Voinov, J. F. Polienko, T. Schanding, A. A. Bobko, V. V. Khramtsov, Y. V. Gatilov, T. V. Rybalova, A. I. Smirnov, and
I. A. Grigor’ev, J. Org. Chem., 2005, 70, 9702.
2005JOC10135 L. Liu, M. Frohn, N. Xi, C. Dominguez, R. Hungate, and P. J. Reider, J. Org. Chem., 2005, 70, 10135.
2005JPCA8976 Y. Umebayashi, T. Fujimori, T. Sukizaki, M. Asada, K. Fujii, R. Kanazaki, and S. Ishiguro, J. Phys. Chem., 2005, 109, 8976.
2005JPCA11504 A. J. Gianola, T. Ichino, R. L. Hoenigman, S. Kato, V. M. Beirbaum, and W. C. Lineberger, J. Phys. Chem. A, 2005, 109,
11504.
2005JPO240 J. Maeki, P. Taehtinen, L. Kronberg, and K. D. Klika, J. Phys. Org. Chem., 2005, 18, 240.
2005JPO275 C. Chiappe and D. Pieraccini, J. Phys. Org. Chem., 2005, 18, 275.
2005MOL401 M. Sosnowski and L. Skulski, Molecules, 2005, 10, 401.
2005MRC1008 M. M. Wang, M. K. Mishra, W. Zhu, and P. F. Kador, Magn. Reson. Chem., 2005, 43, 1008.
2005OL39 K. Illgen, S. Nerdinger, D. Behnke, and C. Friedrich, Org. Lett., 2005, 7, 39.
2005OL929 K. S. Feldman and A. P. Skoumbourdis, Org. Lett., 2005, 7, 929.
2005OL135 J. R. Rush, S. L. Sandstrom, J. Yang, R. Davis, O. Prakash, and P. W. Baures, Org. Lett., 2005, 7, 135.
2005OL63 K. L. Seley, S. Salim, and L. Zhang, Org. Lett., 2005, 7, 63.
2005OL1679 P. J. Dransfield, S. Wang, A. Dilley, and D. Romo, Org. Lett., 2005, 7, 1679.
2005OL2297 V. Nair, V. Sreekumar, S. Bindu, and E. Suresh, Org. Lett., 2005, 7, 2297.
2005OL2453 M. Movassaghi and M. A. Schmidt, Org. Lett., 2005, 7, 2453.
2005OL2735 D. A. Pratt, R. P. Pesavento, and W. A. Van der Donk, Org. Lett., 2005, 7, 2735.
2005OL3183 V. Gracias, A. F. Gasiecki, and S. W. Djuric, Org. Lett., 2005, 7, 3183.
2005OL3393 S. Bhor, G. Anilkumar, M. K. Tse, M. Klawonn, C. Doebler, B. Bitterlich, A. Grotevendt, and M. Beller, Org. Lett., 2005, 7,
3393.
2005OL3949 H. Chen, D. R. Justes, and R. G. Cooks, Org. Lett., 2005, 7, 3949.
2005OL3993 S. In, J. C. Seung, H. L. Kyu, and J. Kang, Org. Lett., 2005, 7, 3993.
2005OL4137 R. Peters and D. F. Fischer, Org. Lett., 2005, 7, 4137.
2005OL5091 V. Sharma and J. Tepe, Org. Lett., 2005, 7, 5091.
2005OL5241 T. Jerphagnon, G. van Link, J. de Vries, and G. van Koten, Org. Lett., 2005, 7, 5241.
2005OL609 S. Zaman, K. Mitsuru, and A. D. Abell, Org. Lett., 2005, 7, 609.
2005PCB5884 G. A. Kaminski, J. Phys. Chem. B, 2005, 109, 5884.
2005PCB18591 M. Buehl, A. Chaumont, R. Schurhammer, and G. Wipff, J. Phys. Chem. B, 2005, 109, 18591.
2005PCB22588 P. I. Nagy, F. R. Tejada, and W. S. Messer, J. Phys. Chem. B, 2005, 109, 22588.
2005PCP3744 K. Catherine and O. Gilles, Phys. Chem. Chem. Phys., 2005, 7, 3744.
2005S47 D. Yang, D. Fokas, J. Li, L. Yu, and C. M. Baldino, Synthesis, 2005, 47.
2005S136 C. Montagne, G. Fournet, and B. Joseph, Synthesis, 2005, 136.
2005S2357 D. Weber, E. Heller, C. Hoenke, S. Hoerer, P. Baeuerle, and V. Austel, Synthesis, 2005, 2357.
2005S2695 R. Clayton and C. A. Ramsden, Synthesis, 2005, 2695.
2005SAA1893 R. N. Patel, N. Singh, K. K. Shukla, and V. L. N. Gundla, Spectrochim. Acta, Part A, 2005, 61, 1893.
Imidazoles 361
2005SC2259 Y. Al-Soud and N. Al-Masoudi, Synth. Commun., 2005, 35, 2259.

2005SC2395 J. Cheng, N. Xiu, X. Li, and X. Luo, Synth. Commun., 2005, 35, 2395.
2005SC2633 W. M. Kan, S.-H. Lin, and C.-Y. Chern, Synth. Commun., 2005, 35, 2633.
2005SL1586 K. Sakthivel and P. D. Cook, Synlett, 2005, 1586.
2005SL2429 M. E. A. Zaki, M. F. Proenca, and B. L. Booth, Synlett, 2005, 2429.
2005SL2670 T. Arai, T. Mizukami, N. Yokoyama, D. Nakazato, and A. Yanagisawa, Synlett, 2005, 2670.
2005T2245 S. Schroeter, C. Stock, and T. Bach, Tetrahedron, 2005, 61, 2245.
2005T3177 U. Azzena, G. Dettori, L. Pisano, and I. Siotto, Tetrahedron, 2005, 61, 3177.
2005T4419 M. J. Rozema, A. W. Kruger, B. D. Rohde, B. Shelat, L. Bhagavatula, J. J. Tien, W. Zhang, and R. F. Henry, Tetrahedron,
2005, 61, 4419.
2005T5081 C. Cadena-Amaro and S. Pochet, Tetrahedron, 2005, 61, 5081.
2005T6056 T. Murata, Y. Morita, and K. Nakasuji, Tetrahedron, 2005, 61, 6056.
2005T9281 H. Y. Noh, S. W. Kim, S. I. Paek, H.-J. Ha, H. Yun, and W. K. Lee, Tetrahedron, 2005, 61, 9281.
2005T11148 R. Torregrosa, I. Pastor, and M. Yus, Tetrahedron, 2005, 61, 11148.
2005T11976 L. Araki, S. Harusawa, M. Yamaguchi, S. Yonezawa, N. Taniguchi, D. M. J. Lilley, Z.-y. Zhao, and T. Kurihara, Tetrahedron,
2005, 61, 11976.
2005TL661 K. R. Reddy and G. G. Krishna, Tetrahedron Lett., 2005, 46, 661.
2005TL1373 Z. Zhao, J. Peacock, D. Gubler, and M. Peterson, Tetrahedron Lett., 2005, 46, 1373.
2005TL2087 Y. Zhang, P. W. K. Woo, J. Hartman, N. Colbry, Y. Huang, and C. C. Huang, Tetrahedron Lett., 2005, 46, 2087.
2005TL2211 Y. Zhang, D. Candelaria, and J. W. Herndon, Tetrahedron Lett., 2005, 46, 2211.
2005TL3599 E. Y. Fursova, V. I. Ovcharenko, G. V. Romanenko, and E. V. Tretyakov, Tetrahedron Lett., 2005, 46, 3599.
2005TL4103 M. Ghorai, K. Das, A. Kumar, and K. Ghosh, Tetrahedron Lett., 2005, 46, 4103.
2005TL4789 C. A. Zificsak and D. J. Hlasta, Tetrahedron Lett., 2005, 46, 4789.
2005TL6005 R. K. Ujjinamatada and R. S. Hosmane, Tetrahedron Lett., 2005, 46, 6005.
2005TL6265 C.-L. Lai, H. M. Lee, and C.-H. Hu, Tetrahedron Lett., 2005, 46, 6265.
2005TL6741 D. S. VanVliet, P. Gillespie, and J. J. Scicinski, Tetrahedron Lett., 2005, 46, 6741.
2005TL6847 A. Arduengo, T. Bannenberg, D. Tapu, and W. Marshall, Tetrahedron Lett., 2005, 46, 6847.
2005TL7315 N. Xi, S. Xu, Y. Cheng, A. S. Tasker, R. W. Hungate, and P. J. Reider, Tetrahedron Lett., 2005, 46, 7315.
2005TL8315 S. J. Oxenford, J. M. Wright, P. O’Brien, N. Panday, and M. R. Shipton, Tetrahedron Lett., 2005, 46, 8315.
2005TL8635 G. Papeo, M. A. Gomez-Zurita, D. Borghi, and M. Varasi, Tetrahedron Lett., 2005, 46, 8635.
2005TL9053 V. Gracias, D. Darczak, A. Gasiecki, and S. Djuric, Tetrahedron Lett., 2005, 46, 9053.
2006AGE2720 H. Sun and S. DiMagno, Angew. Chem. Int. Ed., 2006, 45, 2720.
2006AGE4345 X. Tan and C. Chen, Angew. Chem. Int. Ed., 2006, 45, 4345.
2006AGE5694 M. E. Weiss, D. F. Fischer, Z.-q. Xin, S. Jautze, W. B. Schweizer, and R. Peters, Angew. Chem. Int. Ed., 2006, 45, 5694.
2006ALD79 Lelais, G. MacMillan, and D. W. C. Aldrichim. Acta, 2006, 39, 79.
2006BCJ1665 H. Ohno, Bull. Chem. Soc. Jpn., 2006, 79, 1665.
2006BMC1715 M. Remko, M. Swart, and F. M. Bickelhaupt, Bioorg. Med. Chem., 2006, 14, 1715.
2006BML4994 A. Carpenter, K. Al-Barazanji, K. Barvian, M. Bishop, C. Britt, J. Cooper, A. Goetz, M. Grizzle, D. Hertzog, D. Ignar,
R. Morgan, G. Peckham, J. Speake, and W. Swain, Bioorg. Med. Chem. Lett., 2006, 16, 4994.
2006CC1215 M.-F. Liu, B. Wang, and Y. Cheng, Chem. Commun., 2006, 1215.
2006CC1905 D. MacFarlane, J. Pringle, K. Johansson, S. Forsyth, and M. Forsyth, Chem. Commun., 2006, 1905.
2006CED1856 J. Troncoso, C. A. Cerdeirina, Y. A. Sanmamed, L. Romani, and L. P. N. Rebelo, J. Chem. Eng. Data, 2006, 51, 1856.
2006CEJ3201 J. Barluenga, J. Garcia-Rodriguez, S. Martinez, A. Suarez-Sobrino, and M. Tomas, Chem. Eur. J., 2006, 12, 3201.
2006CEJ3636 H. Rao, Y. Jin, H. Fu, Y. Jiang, and Y. Zhao, Chem. Eur. J., 2006, 12, 3636.
2006CEJ5301 M. Taillefer, A. Ouali, B. Renard, and J. Spindler, Chem. Eur. J., 2006, 12, 5301.
2006EJO3283 M. Schnurch, R. Flasik, A. Khan, M. Spina, M. Mihovilovic, and P. Stanetty, Eur. J. Org. Chem., 2006, 3283.
2006EJO2695 E. Tretyakov, G. Romanenko, A. Podoplelov, and V. Ovcharenko, Eur. J. Org. Chem., 2006, 2695.
2006EJOC693 F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi, and S. Viel, Eur. J. Org. Chem., 2006, 693.
2006JA3543 R. Gordillo and K. N. Houk, J. Am. Chem. Soc., 2006, 128, 3543.
2006JA4119 Y. Nakamura, N. Aratani, H. Shinokubo, A. Takagi, T. Kawai, T. Matsumoto, Z. Yoon, D. Kim, T. Ahn, D. Kim,
A. Muranaka, N. Kobayashi, and A. Osuka, J. Am. Chem. Soc., 2006, 128, 4119.
2006JA4453 M. Erlacher, K. Lang, B. Wotzel, R. Rieder, R. Micura, and N. Polacek, J. Am. Chem. Soc., 2006, 128, 4453.
2006JA6050 A. R. Siamaki and B. A. Arndtsen, J. Am. Chem. Soc., 2006, 128, 6050.
2006JA10662 C. Kanazawa, S. Kamijo, and Y. Yamamoto, J. Am. Chem. Soc., 2006, 128, 10662.
2006JA12490 V. K. Landry, M. Minoura, K. Pang, D. Buccella, B. V. Kelly, and G. Parkin, J. Am. Chem. Soc., 2006, 128, 12490.
2006JHC217 J. F. Glister and K. Vaughn, J. Heterocycl. chem., 2006, 43, 217.
2006JHC277 S. A. Popov, N. V. Chukanov, G. V. Romanenko, T. V. Rybalova, Y. V. Gatilov, and V. A. Reznikov, J. Heterocycl. Chem.,
2006, 43, 277.
2006JHC835 P. Parik, S. Senauerova, V. Liskova, K. Handlir, and M. Ludwig, J. Heterocycl. Chem., 2006, 43, 835.
2006JME3719 V. Ognyanov, C. Balan, A. Bannon, Y. Bo, C. Dominguez, C. Fotsch, V. Gore, L. Klionsky, V. Ma, Y. Qian, R. Tamir,
X. Wang, N. Xi, S. Xu, D. Zhu, N. Gavva, J. Treanor, and M. Norman, J. Med. Chem., 2006, 49, 3719.
2006JML(124)84 N. E. Heimer, R. E. Del Sesto, Z. Meng, J. S. Wilkes, and W. R. Carper, J. Mol. Liq., 2006, 124, 84.
2006JOC3159 C. Sun, X. Lin, and S. Weinreb, J. Org. Chem., 2006, 71, 3159.
2006JOC5000 T. Chandra, X. Zou, E. Valente, and K. Brown, J. Org. Chem., 2006, 71, 5000.
2006JOC8324 Y. Xie, S. Pi, J. Wang, D. Yin, and J. Li, J. Org. Chem., 2006, 71, 8324.
2006JOM(691)3445 A. J. Davenport, D. L. Davies, J. Fawcett, and D. R. Russell, J. Organomet. Chem., 2006, 691, 3445.
2006OL239 D. R. Ijzendoorn, P. N. M. Botman, and R. H. Blaauw, Org. Lett., 2006, 8, 239.
2006OL379 T. Munegumi, I. Azumaya, T. Kato, H. Masu, and S. Saito, Org. Lett., 2006, 8, 379.
2006OL819 C. Poeverlein, G. Breckle, and T. Lindel, Org. Lett., 2006, 8, 819.
362 Imidazoles
2006OL1073 M. Kim, J. V. Mulcahy, C. G. Espino, and J. Du Bois, Org. Lett., 2006, 8, 1073.
2006OL2249 D. A. Evans and K. R. Fandrick, Org. Lett., 2006, 8, 2249.
2006OL2417 E. Biron, J. Chatterjee, and H. Kessler, Org. Lett., 2006, 8, 2417.
2006OL2531 J. A. Fritz, J. S. Nakhla, and J. P. Wolfe, Org. Lett., 2006, 8, 2531.
2006OL2779 R. Altman and S. Buchwald, Org. Lett., 2006, 8, 2779.
2006OL3049 A. S. Pelegri, M. R. J. Elsegood, V. McKee, and G. W. Weaver, Org. Lett., 2006, 8, 3049.
2006OL3351 D. A. Evans, H. J. Song, and K. R. Fandrick, Org. Lett., 2006, 8, 3351.
2006OL4083 S. Shengule and P. Karuso, Org. Lett., 2006, 8, 4083.
2006OL4989 Y. Yasui, D. K. Frantz, and J. S. Siegel, Org. Lett., 2006, 8, 4989.
2006OL5781 D. S. Ermolat’ev’, E. V. Babaev, and E. V. Van der Eyeken, Org. Lett., 2006, 8, 5781.
2006PCP2101 F. Endres and S. Zein El Abedin, Phys. Chem. Chem. Phys., 2006, 8, 2101.
2006PCA2269 P. A. Hunt and I. R. Gould, J. Phys. Chem. A, 2006, 110, 2269.
2006PCA2535 L. Infantes, O. Mo, M. Yanez, M. V. Roux, P. Jimenez, J. Z. Davalos, M. Temprado, M. A. V. Ribeiro da Silva,
M. D. M. C. Ribeiro da Silva, L. M. P. F. Amaral, P. Cabildo, R. Claramunt, and J. Elguero, J. Phys. Chem. A, 2006, 110,
2535.
2006PCA7621 A. Akdag, M. L. McKee, and S. D. Worley, J. Phys. Chem. A, 2006, 110, 7621.
2006RCM1071 L. Oresmaa, P. Aulaskari, and P. Vainiotalo, Rapid Commun. Mass Spectrom., 2006, 20, 1071.
2006SL227 M. Ishihara and H. Togo, Synlett, 2006, 227.
2006SL965 H. Du, Y. He, R. Silvappa, and C. J. Lovely, Synlett, 2006, 965.
2006SL1479 S. Sayama, Synlett, 2006, 1479.
2006SL2195 M. Kantam, B. Rao, B. Choudary, and R. Reddy, Synlett, 2006, 2195.
2006T1351 N. Coskun, H. Mert, and N. Arikan, Tetrahedron, 2006, 62, 1351.
2006T3798 A. Nadipuram and S. Kerwin, Tetrahedron, 2006, 62, 3798.
2006T4435 Z. Zhang, J. Mao, D. Zhu, F. Wu, H. Chen, and B. Wan, Tetrahedron, 2006, 62, 4435.
2006T4597 S. F. Vasilevsky, S. V. Klyatskaya, O. L. Korovnikova, S. A. Amitina, D. V. Stass, I. A. Grigor’ev, and J. Elguero, Tetrahedron,
2006, 62, 4597.
2006T5474 A. Marwaha, P. Singh, and M. P. Mahajan, Tetrahedron, 2006, 62, 5474.
2006T5868 A. de la Hoz, Á. Dı́az-Ortiz, M. Mateo, M. Moral, A. Moreno, J. Elguero, C. Foces-Foces, M. Rodrı́guez, and A. Sánchez-
Migallón, Tetrahedron, 2006, 62, 5868.
2006T8586 M. Matschke, C. Kaepplinger, and R. Beckert, Tetrahedron, 2006, 62, 8586.
2006T10182 I. Kawasaki, N. Sakaguchi, A. Khadeer, M. Yamashita, and S. Ohta, Tetrahedron, 2006, 62, 10182.
2006T10555 P. Krishnamoorthy, S. Rasapalli, H. Du, and C. Lovely, Tetrahedron, 2006, 62, 10555.
2006TL79 P. Gogoi and D. Konwar, Tetrahedron Lett., 2006, 47, 79.
2006TL1509 J. Wu, X. Sun, and H. Xia, Tetrahedron Lett., 2006, 47, 1509.
2006TL2129 V. Mirkhani, M. Moghadam, S. Tangestaninejad, and H. Kargar, Tetrahedron Lett., 2006, 47, 2129.
2006TL3897 M. Kantam, G. Venkanna, C. Sridhar, and K. Kumar, Tetrahedron Lett., 2006, 47, 3897.
2006TL5033 X.-Q. Hao, J.-F. Gong, C.-X. Du, L.-Y. Wu, Y.-J. Wu, and M.-P. Song, Tetrahedron Lett., 2006, 47, 5033.
2006TL5203 R. Hosseinzadeh, M. Tajbakhsh, and M. Alikarami, Trtrahedron Lett., 2006, 47, 5203.
2006TL5763 S. Chandrasekhar and P. Karri, Tetrahedron Lett., 2006, 47, 5763.
2007T2414 S. Haneda, A. Okui, C. Ueba, and M. Hayashi, Tetradedron, 2007, 63, 2414.
Imidazoles 363
Biographical Sketch
Dr. Ning Xi received his B.S. (1984) and M.S. (1987) in chemistry from Beijing University,
Beijing, and his Ph.D. (1996) in organic chemistry from Rice University, Houston, Texas. After
a year stay as a post-doctoral associate at Rice University, he started his drug discovery endeavors
at AMRI, Albany, NY in 1997 and continued at Amgen, Thousand Oaks, CA in 1998. He left
Amgen in 2007 and co-founded Kintor Pharmaceuticals, Inc. Dr. Xi’s research interests include
applications of transition metal-catalyzed reactions, synthesis of bioactive molecules and discov-
ery of drug candidates, especially targeting G-protein coupled receptors and kinases. He has
coauthored more than 55 peer-reviewed publications and patents.
Dr. Longbin Liu Received his B.Sc. in Chemistry from NW University in Xi’an, China, in 1983.
After a short stint as a teaching assistant in NW Agricultural University, he went to Columbia
University in New York City in 1986 where he did his PhD (1991) work on the synthesis of
helicenes in Prof. Thomas J. Katz’s group. He then pursued natural product synthesis in the
laboratories of Prof. Robert E. Ireland (Virginia) and Prof. Gilbert Stork (Columbia). In 1996, he
joined Amgen and is currently a Principal Scientist in the Medicinal Chemistry Department. His
current research interests lie in the areas of anti-cancer drug design and heterocyclic chemistry.
He has coauthored more than 30 publications and patents.
364 Imidazoles
Dr. Qi Huang obtained his B.S. (1986) in medicinal chemistry from Shanghai Medical University
and Ph.D. (1998) in medicinal chemistry from University of Wisconsin-Milwaukee, in Prof. James
M. Cook’s laboratories. During his Ph.D. work, he discovered a GABAA/BzR subtype selective
agonist, which is currently undergoing clinical trials as a selective anxiolytic agent. Dr. Huang has
continued his drug discovery efforts at Amgen since 1998 as a research scientist. His current
research interests focus on discovering novel anti-cancer drugs. He has coauthored more than 30
publications and patents.

Imidazole 2 PDF

Încărcat de

Informații document

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Imidazole 2 PDF

Încărcat de

Drepturi de autor:

Formate disponibile

4.

4.02.1 Introduction 145

4.02.5.3.1 Reactivity and orientation 191

4.02.7.8 Sulfur-Linked Substituents 265

Figure 1 Ring structures covered in this chapter.

4.02.2 Theoretical Methods

Figure 2 Imidazol-1-ylalkanoic acid derivatives (R1, R2 ¼ H or Et).

Scheme 2 Acid–base and tautomeric equilibria of histamine.

Scheme 3 Tautomerism of C-5-substituted imidazoles.

Scheme 4 Tautomerism in 2-imidazolone and 2-thioimidazolone.

Molecules such as 2-(2-hydroxyphenyl)benzimidazole (shown in Scheme 5), 2-(3-hydroxy-2-pyridyl)benzimida-

Figure 3 Dilithiated imidazole 14 and benzimidazole 15.

4.02.3 Experimental Structural Methods

Figure 4 Abnormal Ir-imidazolium complexes.

In the synthesis of anionic amido-N-heterocyclic carbene complexes of lanthanides (22, Ln ¼ Sm, Y;

4.02.3.2 Proton and Carbon NMR spectroscopy

H-1 2.95 3.54

2-Ph 4-Ph 5-Ph

100 MHz, CDCl3 C-2 C-4 C-4

233 K 135.4 129.5 126.4

The complex [Y(L){N(SiMe3)2}2] (L ¼ 1-tert-butyl-3-(2-tert-butylaminoethyl)imidazol-2-ylidene) showed a

Table 4 Selected 13C chemical shifts of N-herocyclic carbenes and bond

Carbene ( ppm) at C-2 N-(1)–C-(2)–N-(3) angle ( )

4.02.3.2.2 Nonaromatic systems

The reactions of 2-amino-2-deoxy-D-glucopyranose with 2-halo-phenyl isothiocyanates in ethanol–water produced

4.02.3.3 NMR Involving Other Nuclei

pKa 5.18 6.52 5.78

4.02.3.3.2 Nonaromatic systems

The structure confirmation of dimethyl 1-(4-chlorophenyl)-2-methyl-5-oxo-2-imidazoline-4,4-dicarboxylate 91,

The characterization of transient intermediates during photosensitized oxidation of 2-13C-4,5-diphenylimidazole

Temperature ( C ) Transient intermediates C-2 C-4 C-5 N-1 N-3

100 102.2 172.6 100.3 111.1 307.0

88 117.5 167.0 167.0 356.6 356.6

80 177.8 181.4 181.4 308.6 308.6

80 127.3 162.9 162.9 364.2 304.2

30 163.7 100.6 189.1 44.9 288.3

92 74 132.1 60.5 n.a.

4.02.3.4 Ultraviolet Spectroscopy

Hydrolysis of 2,4,5-triphenyl-N-acylimidazoles, as followed by UV-Vis measurements, was found to proceed

4.02.3.6 Mass Spectrometry

N-Substituted 2-(2-bromophenyl)benzimidazoles form palladacycles by reaction with Pd(dba)2. These complexes

4.02.3.7 Electron Spin Resonance

2-(Nitrenophenyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole 3-oxide 1-oxyls (111 and 112, Figure 26), gener-

4.02.3.8 Photoelectron Spectra

4.02.4 Thermodynamic Aspects

Figure 30 Becliconazole and precursors to it.

4.02.4.2.2 Other thermodynamic aspects

Interesting conformational features were discovered in 1-methyl-2-(4-methylpyridin-2-yl)-1H-benzimidazole 95,

4.02.4.3.2 Substituent prototropic tautomerism

Aminonitrone-N-hydroxyaminoimine tautomerism in 2-substituted 1-hydroxy-4,4,5,5-tetramethyl-4,5-dihydro-1H-

Ring-substituent prototropic tautomerism is predicted to exist in 3-amino-1-(2-aminoimidazol-4-yl)-prop-1-ene

Figure 35 Tautomerism of 3-amino-1-(2-aminoimidazol-4-yl)-prop-1-ene.

4.02.4.3.3 Ring-chain isomerism

Ring–chain isomerism between 1-[alkylidene(or arylidene)amino]-2-aminoethanes and imidazolidines has been

4.02.5 Reactivity of the Fully Conjugated Rings

4.02.5.1 Unimolecular Thermal and Photochemical Reactions

4.02.5.2 Electrophilic Attack at Nitrogen

4.02.5.2.2 Proton acids: Basicity and acidity of imidazoles and benzimidazoles

4.02.5.2.3 Metal ions

4.02.5.2.4(ii) Ionic liquids

4.02.5.2.4(iii) Imidazolin-2-ylidene carbenes

4.02.5.2.6(i) Copper-catalyzed N-arylation of imidazoles and benzimidazoles

Figure 38 Ligands for copper-mediated imidazole N-arylation.