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Tetrahedron Letters
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Article history: Isoxazole is an important pharmacophore that is critical for biological activity. The isoxazole ring ranks
Received 27 December 2017 33rd in frequency among the 351 ring systems found in marketed drugs, thus suggesting a great deal of
Revised 7 February 2018 interest in the synthesis of functional isoxazoles. In recent years, various approaches have been devel-
Accepted 8 February 2018
oped for the synthesis and functionalization of isoxazoles. This comprehensive survey summarizes the
Available online 10 February 2018
recent new synthetic approaches to functionalized isoxazoles, with particular focus on the last three
years with regard to the following reaction types: (1) 1,3-dipolar cycloaddition, (2) condensation, (3)
Keywords:
cycloisomerization, and (4) direct functionalization.
Isoxazole
Cycloaddition
Ó 2018 Elsevier Ltd. All rights reserved.
Condensation
Cycloisomerization
Functionalization
Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159
1,3-Dipolar cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1160
Condensation reactions using 1,3-dicarbonyl derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
Cycloisomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1166
Intramolecular nitro group addition to unsaturated CAC bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1167
Direct functionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1168
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170
https://doi.org/10.1016/j.tetlet.2018.02.020
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
1160 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171
R N O
F
R
NOH NCS F
O 5
F F N
CHCl3, rt N O
F F F
4a 2b R F
NR'2 R
6
N O N O N O
F F OH F
CO2Et O
F F F BocN
Fig. 1. Synthetic approaches of functionalized isoxazoles.1b 5a, 73% 5b, 67% 5c, 48%
N O N O N O
F F F
1,3-Dipolar cycloaddition
F CO2Et F CN F
O
One of the best established routes to isoxazole synthesis is the 6a, 80% 6b, 34% 6c,47%
1,3-dipolar cycloaddition of nitrile oxides to alkynes/alkenes. The
reaction of nitrile oxides with alkynes proceeds under thermal con- Scheme 2. Synthesis of 3-difluoromethyl isoxazoles 5 and 6.
ditions; however, the regioselectivity is very poor because of the
high activation energy to the reaction.2 Fokin et al.3 reported a cop-
per-catalyzed 1,3-dipolar cycloaddition of alkynes with nitrile oxi-
des generated from oxime halides under basic conditions in 2005.
This strategy enabled the synthesis of functionalized isoxazoles in
high yields and regioselectivities under mild conditions. Nowa-
days, both metal-catalyzed and metal-free 1,3-dipolar cycloaddi-
tions have been developed under mild conditions to access
functionalized isoxazoles.
The synthesis of (per)fluoroalkyl isoxazoles has been developed
vigorously because of the biological importance of fluorinated
compounds. For example, Ley et al.4 reported the synthesis of 3-tri-
fluoromethylisoxazoles. They prepared hydroximoyl bromide 1a as
a precursor to nitrile oxide 2a from a commercially available triflu-
oromethylated hemiacetal in two steps. Bromide 1a was readily
converted into the corresponding nitrile oxide under basic condi-
tions for reacting with terminal alkynes to yield the corresponding
3-trifluoromethyl-5-substituted isoxazoles 3 in good to high yields
Scheme 3. One-pot synthesis of 3-trifluoromethyl-4-iodoisoxazole 7.
(Scheme 1). The combination of base/solvent affected the 1,3-dipo-
lar cycloaddition yields greatly: trimethylamine/toluene was suit-
able for aromatic alkynes, whereas Na2CO3/H2O was suitable for
aliphatic alkynes. Furthermore, difluoromethyl-substituted isoxa- the isoxazoles 9. By contrast, 3-chloro-4-iodoisoxazoles were
zoles were synthesized through the 1,3-dipolar cycloaddition of synthesized from dichloroaldoxime 1c (Scheme 4).7 The use of cop-
difluoromethyl nitrile oxides generated from oxime 4a to alkynes per acetylide was the key to preventing the dimerization of the
and enamines (Scheme 2).5 nitrile oxide. The combination of alkynylcopper(I) and molecular
The one-pot synthesis of 3-trifluoromethyl-4-iodoisoxazoles iodine was used as a synthetic equivalent to 1-iodoalkyne. The tri-
from trifluoromethylated oxime 1b and alkynes was demonstrated ple bond of 1-iodoalkyne was activated by coordination to CuI and
by Wu et al.6 The reaction of 1b with phenylacetylene proceeded at reacted with a-chloronitrile oxide to yield 3-chloro-4-iodoisoxa-
room temperature to afford 4-iodo-5-phenyl-3-(trifluoromethyl) zoles 11 as a novel building block with a broad substrate scope.
isoxazole (7), a useful building block for further functionalization Hamme II et al.8 prepared a series of 4-bromo spiroisoxazolines
at the C4 position (Scheme 3). The proposed isoxazole ring 14 containing various aliphatic and aromatic substituents at the
construction of the mechanistic studies did not occur through
1,3-dipolar cycloaddition; however, a stepwise bond formation
mechanism was invoked. The resulting intermediate reacted with
N-iodosuccinimide (NIS) to install iodine at the C-4 position of
OH
R1 N
X OH R
Cl
N Br3 R1
R1 O N
n R R1 H O
X X
R1 R
NEt3, CH2Cl2 N OH K2CO3, CH2Cl2 Br R1
n
O n
12 13 Cl 14
n = 1, 2 O N 16 examples
X = H2, O O (61-80%)
Br Cl
14a
Scheme 12. Generation of nitrile oxide 2 using isoamyl nitrite 33. Scheme 13. Generation of nitrile oxide from aldoxime 4a using PhI(OAc)2.
T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171 1163
Scheme 16. Synthesis of 5-acyl-3-cyanoisoxazoles 59. Scheme 17. One-pot synthesis of 5-trifluoromethyl isoxazoles 67.
1164 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171
undergoes intramolecular cyclization followed by the elimination Strong electrophiles, such as oxocarbenium cations, also pro-
of HBr to afford 5-bromoisoxazoles. Alternatively, nitromethane mote the intramolecular cyclization of alkynyl-O-methyl oximes.
was used for the construction of isoxazoles through [3+2] cycload- 4-[Alkoxy(aryl)methyl]-substituted isoxazoles 124 were synthe-
dition with highly electron-deficient cyclopropanes (Scheme 28).34 sized from alkynyl-O-methyl oximes 123 and aromatic acetals
The DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)-promoted ring (Scheme 32).39 The generation of oxocarbenium cations from the
opening of the cyclopropanes afforded the thermodynamically acetals in the presence of boron trifluoride was essential for acti-
stable carbanion species 107. The tautomer of 107 undergoes a for- vating the alkynyl-O-methyl oxime triple bond. The intramolecular
mal 1,3-dipolar cycloaddition with nitromethane to yield the cor- 5-endo dig cyclization was induced to afford the corresponding
responding isoxazole-5-carboxylates through 5-membered isoxazoles. However, the reaction was limited to electron-donating
heterocyclic intermediates. alkoxy groups at R1 of the alkynyl-O-methyl oximes.
Miyata and Ueda et al.40 reported the gold-catalyzed sequential
cyclization/[3,3]-sigmatropic rearrangements of O-allyl hydroxam-
Cycloisomerization ates 125 for the synthesis of 4-allyl-3-hydroxyisoxazoles 126
(Scheme 33). They previously reported the direct synthesis of
Cycloisomerization is a powerful method in terms of the gener- trisubstituted isoxazole 129 through a gold-catalyzed domino
ation of intrinsic atom-economy structural complexity in organic reaction of alkynyl oxime ether 128.41 The similar transformation
synthesis.35 In this section, we cover the recent advances in isoxa- proceeded with O-allyl hydroxamates 125 instead of O-allyl oxime
zole synthesis via cycloisomerization under both metal-catalyzed ether 128 to afford the corresponding isoxazoles 126 along with N-
and metal-free conditions. allylisoxazolones 127. The formation of N-allylisoxazolones
Nakamura et al.36 developed a skeletal rearrangement of O- increased as the R groups became bulkier.
propargylic formaldoximes 112 in the presence of a gold catalyst Blum et al.42 reported intramolecular BAO r-bond additions
for the preparation of 4-methylenated isoxazoline derivatives to the CAC triple bond to form 4-borylated isoxazoles 133,
113 via a unique intermolecular methylene transfer pathway. which are potential building blocks for further functionalization
Thereafter, these isoxazolines underwent isomerization or an ene (Scheme 34). The reaction proceeded with gold catalysts at 50
reaction with maleimide, azodicarboxylate, and glyoxalate to pro- °C or without catalyst at 110 °C, yielding a single regioisomer.
vide the corresponding functionalized isoxazoles114–117 The utility of this reaction was extended for the scaled-up syn-
(Scheme 29). Furthermore, this system can be used for the synthe- thesis of valdecoxib and a valdecoxib analog, a nonsteroidal
sis of chiral isoxazole 120 from enantioenriched O-propargylic anti-inflammatory drug.
oxime 118 through chirality transfer (Scheme 30).37 Interestingly, Ferreira et al.43 developed the regioisomeric synthesis of 3,5-
the chirality of the enantioenriched O-propargylic oxime 118 was disubstituted isoxazoles 137 and 138 from propargylic N-hydroxy-
completely retained during the gold-catalyzed skeletal rearrange- lamines 134 and propargylic amino ethers 135 via a Pt-catalyzed
ment/ene reaction cascade. cyclization (Scheme 35). The reaction mechanism involves the
Thongsornkleeb et al.38 reported the synthesis of 4-chloroisox- intramolecular nucleophilic attack of oxygen or nitrogen to the
azole 122 from (E/Z)-alkynyl-O-methyl oximes 121 via chlorinative Pt-activated alkyne moiety. The 1,2-H shift, isomerization, and R3
cyclization (Scheme 31). The combination of N-chlorosuccinimide group cleavage for aromatization yields the corresponding isoxa-
(NCS) and chlorotrimethylsilane (TMSCl) is essential for generating zoles. The authors extended this methodology for the synthesis
chlorine (Cl2) and HCl in situ. Non-cyclizable (E)-Alkynyl-O-methyl of anti-rhinovirus analogs.
oximes were readily isomerized to the (Z)-isomers under mild
conditions for the desired isoxazole cyclization. 4-Bromo- and
4-iodoisoxazoles were prepared analogously by using N-bromo-
succinimide and NIS.
Scheme 37. Synthesis of isoxazoles 143 from tert-butyl nitrite (142) and aryl
alkynes 141.
Conclusion
Acknowledgment
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