Myers C!

N Bond-Forming Reactions: Reductive Amination Chem 115

Reviews:
Reducing Agents
Abel-Magid, A. F.; Mehrman, S. J. Org. Proc. Res. Devel. 2006, 10, 971–1031.
Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, • Common reducing agents: NaCNBH3, Na(OAc)3BH, H2/catalyst

61, 3849-3862.
Bhattacharyya, S. Tetrahedron Lett. 1994, 35, 2401–2404.
Hutchins, R. O.; Hutchins, M. K., Reduction of CdN to CHNH by Metal Hydrides. In Comprehensive
Organic Synthesis; Trost, B. N., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8.
• Iminium ions are reduced selectively in the presence of their carbonyl precursors. Reagents
such as sodium cyanoborohydride and sodium triacetoxyborohydride react selectively with
iminium ions and are frequently used for reductive aminations.

Overview:
Reduction with Sodium Cyanoborohydride:
• The reductive amination of aldehydes and ketones is an important method for the synthesis of
primary, secondary, and tertiary amines.
• Borch and co-workers showed that sodium cyanoborohydride and lithium cyanoborohydride
are acid-stable reagents capable of rapidly reducing carbonyl compounds to alcohols at pH
• Reductive amination is a powerful and reliable strategy for the formation of C–N bonds, and
3–4, presumably via a protonated carbonyl cation.
can avoid the problem of overalkylation that often accompanies direct alkylation of amines
with alkyl halides.

NaBH3CN
O OH
Mechanism: CH3OH
Ph CH3 Ph CH3
• Reductive amination involves a one- or two-step procedure in which an amine and a carbonyl pH 3, 23 °C, 1 h
93% (±)
compound condense to afford an imine or iminium ion that is reduced in situ or subsequently
to form an amine product.

Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904.
R3 R4 H+ (cat.) R3 R4
O N R3 R4 hydride N
R3 R4 N
+ N • At pH 7, reduction of carbonyl compounds with lithium cyanoborohydride is very slow, even
R1 R2 H R1 R2 R2
source R1 R2 at reflux in methanol.
HO R1 H
R1, R2, R3, R4 = H, alkyl, aryl
!H2O
R4 = H R3 hydride,
N
proton source
R1 R2 LiBH3CN
O OH
CH3OH
Ph CH3 Ph CH3
pH 7, reflux, 72 h
• relative rates of reductive amination: 36% (±)

H
N
H2NR > > HNR2 > H2NAr
n Borch, R. F.; Durst, H. D. J. Am. Chem. Soc. 1969, 91, 3996–3997.
n = 1, 2 Jonathan William Medley, Fan Liu

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Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115
• With care to maintain a pH of 6–7, a mixture of a ketone or aldehyde reactant, an amine, and Reduction with Sodium Triacetoxyborohydride:
sodium cyanohydride provides products of reductive amination selectively, without • Sodium triacetoxyborohydride has been found to be a highly selective reducing agent for
competitive reduction of the carbonyl substrate. reductive amination; acetic acid is frequently employed as a proton donor.
• Though the conditions of the Borch reduction are mild, sodium cyanoborohydride is highly • This protocol is generally high yielding, highly functional group tolerant, and proceeds without
toxic, as are its byproducts. release of cyanide salts. The substrate scope includes aromatic and aliphatic aldehydes,
ketones, and primary and secondary amines. Ammonia can be employed successfully if used
in large excess as its acetate salt.
NaBH3CN
R3 R4
O R3 R4 CH3OH N R3 R4
+ N O NaHB(OAc)3 N
R3 R4
R1 R2 + N
H pH 6–8,a 23 °C R1 R2
H R1 R2 H Method R1 R2
H

carbonyl compound amine product isolated yield (%) carbonyl compound amine methoda product yield (%)

O Ph Ph
N N
O O O
II 96
N N
79
N N
H
H

O H
EtO N
NH2 II 88
O NHCH3 OEt EtO
OEt
H3C CH3NH2 H3C 90
Ph Ph
CH3 CH3 NH4OAc
cycloheptanone
(10 equiv) IIb cycloheptylamine 80c

O H OH CH3 CH3
N N N
H2NOH 66
PhNH2 I 96

O NHPh
O NHPh
H3C PhNH2 H3C 78 COOEt COOEt
H H OHC
CH3 CH3 H II 95
N N
N
N

O NH2
O N(i-Pr)2
HO OH NH3 HO OH 51
H (i-Pr)2NH II 88
O O O O (±)

aThe pH was maintained by addition of HCl and/or KOH as needed using bromocresol green as an
aMethod
I: ClCH2CH2Cl, AcOH (1!2 equiv), NaBH(OAc)3 (1.3!1.6 equiv). Method II: ClCH2CH2Cl,
indicator. NaBH(OAc)3 (1.3!1.6 equiv). bEt3N (1.5!2.0 equiv) added. cyield of HCl salt.

Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904. Jonathan William Medley

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Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115
Reaction with Weakly Nucleophilic Amines: Reduction with Sodium Borohydride:

• Reductive amination of carbonyl compounds with primary amines can be complicated by

overalkylation. In these cases, formation and isolation of the imine followed by reduction can prove
NaHB(OAc)3 R3 R4
O R3 R4 N to be a superior alternative.
+ N
R1 R2 H Method R1 R2
H
• It was found that the use of methanol as solvent allows for rapid (< 3h) and nearly quantitative imine
formation from aldehydes without the need for dehydrating reagents.

carbonyl compound amine methoda product yield (%)

R3 R3 R4
Br O CH3OH N NaBH4 N
+ R3 NH2
O Br !H2O 10!15 min
H R1 R2 R1 R2 R1 R2
III N 89b H
H2N

aldehyde amine product yield (%)a

Cl Cl O
Ph
O H3CO N
Cl Cl H H PhNH2 84
N H
IV 95 Cl
H2N

H N 89
H2N H
Cl Cl
O H
N
H IV 95
H2N NO2 O
NO2 Ph
PhNH2 N 90
H
H

O S H S
H2N IV N 60 O
t-Bu
Ph H N Bn N N
H t-BuNH2 83
H
O H
H2N Ts IVc N Ts 80
Ph H Bn Ph H
BnNH2 Ph NHBn 85
O

aproducts isolated as HCl salts.

aMethod III: ClCH2CH2Cl, AcOH (1 equiv), NaBH(OAc)3 (1.4 equiv). Method IV: ClCH2CH2Cl,
AcOH (2!5 equiv), carbonyl compound (1.5!2 equiv), NaBH(OAc)3 (2.0!2.8 equiv). byield of HCl Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem.
salt. cEt3N (2.0 equiv) added. 1996, 61, 3849!3862. Jonathan William Medley

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Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115
Examples in Synthesis

O
CH3
OTBS O
AcO CH3 Na(AcO)3BH, Sn(OTf)2 CH3
H3C + H3C H N(CH3)2 NaBH3CN
CHO O 4 Å MS, ClCH2CH2Cl, 0 °C O HO
N HO OCH2 CH3 O O OH
O CH3 CH3OH,
H H OCH3
O
CH3
CH3O
66% Et O OH O OH NH
CH3 O

tylosin 79%

OTBS
AcO CH3
H3C N
O O
H O
CH3 N
Hosokawa, S.; Sekiguchi, K.; Hayase, K.; Hirukawa, Y.; Kobayashi, S. Tetrahedron Lett. 2000, CH3
41, 6435-6439. H3C N(CH3)2
O HO
HO OCH2 CH3 O O
O O CH3 OH
OCH3 CH3
CH3O
Et O OH O OH
CH3
Ph Ph Ph Ph
O O
NaBH3CN
N H N H
H CH3 CH2O Matsubara, H.; Inokoshi, J.; Nakagawa, A.; Tanaka, H.; Omura, S. J. Antibiot. 1983, 36, 1713-1721.
H3C CH3
84%

Jacobsen, E. J.; Levin, J.; Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4329-4336. H CO2Bn H CO2Bn CO2Bn H CO2Bn H CO2Bn
OHC NaBH3CN H
• Formic acid can also be used as a hydride donor: N OTHP N N OTHP
CO2t-Bu CH3OH CO2t-Bu

+ 59%
H H3C
1. H2, Pd/C, EtOH,
N CH3 N CH3 CO2Bn
H3C H3C H H2O, HCl
HO OH HO OH 2. TFA
H3C H3C NH•TFA
OH CH3 N(CH3)2 OH CH3 N(CH3)2
H3C H3C HO H3C H3C HO
O O O CH3 O O O CH3
CH2O, HCO2H CO2H H CO2H H CO2H
O O OCH3 O O OCH3 H
N N OH
CH3 CH3 CHCl3, 65 ºC CH3 CH3 H
O OH 71% O OH
CH3 CH3
2'-deoxymugineic acid

Ohfune, Y.; Tomita, M.; Nomoto, K. J. Am. Chem. Soc. 1981, 103, 2409-2410.
Dokic, S.; Kobrehel, G.; Lopotar, N.; Kamenar, B.; Nagl, A.; Mrvos, D. J. Chem. Res (S). 1988, 152.
Mark G. Charest, Fan Liu

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Myers C!N Bond-Forming Reactions: Reductive Amination Chem 115
• A regioselective reductive amination using sodium triacetoxyborohydride was employed in • In a complex transformation, a tryptamine derivative and an enantioenriched dialdehyde
the construction of the pyrrolidine ring of (!)-communesin A: were combined to give a cyclic bis-hemiaminal interemediate; electrophilic activation with
trifluoroacetic anhydride initiated a Mannich/Sakurai cascade. Subsequent iminium reduction
H3C CH3 H3C CH3 with sodium cyanoborohydride afforded a pentacyclic diamine en route to (!)-aspidophytine.
OH
O O O HN
H3C N NH4OAc
H3C N
H3C O NaHB(OAc)3
H3C O
OH
NH CH3OH, >92%
NH OHC
N N NH2 N
CH3CN
CH3 CH3 OHC HO
N H3CO N R
H3CO R TMS
4 steps OCH3 CH3 TMS OCH3 CH3
R = CH2COOi-Pr
TFAA (2 equiv)
H3C Ac !TFA
CH3
N
O N

CF3COO N CF3COO
NH R TMS N
N !CF3COOTMS
CH3 H3CO N R
N TMS
H3CO
(!)-communesin A OCH3 CH3
OCH3 CH3
Zuo, Z.; Ma, D. Angew. Chem., Int. Ed. 2011, 50,12008!12011.
• Regio- and stereoselective indolenine reduction and reductive methylation of two secondary
amines was achieved using Borch conditions en route to (+)-haplophytine.
N CF3COO N
H R R
N CO2CH3 TFA NaBH3CN
O N HCHO, NaBH3CN
N O AcOH (5 equiv)
MsO N H N H
H3CO H3CO 66%
CH2Cl2, CH3OH
0 " 23 °C OCH3 CH3 OCH3 CH3
O N CH3
55%
CH3 OCH3 N CO2CH3
O N
N O
MsO O

N O N
CH3 O N H R
O 6 steps
N
O N O CH3 OCH3 CH3
N O
HO 1. 1N NaOH, CH3OH, 60 °C. H3CO N H H3CO N H
2. K3Fe(CN)6, NaHCO3, OCH3 CH3 OCH3 CH3
O N H t-BuOH, H2O, 70% (2 steps).
(!)-aspidophytine
CH3 OCH3 CH3

(+)-haplophytine
Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem., He, F.; Bo, Y.; Altom, J.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 6771!6772.
Int. Ed. 2009, 48, 7600!7603. Jonathan William Medley

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 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115
Reviews: Solvent Choices:
• Most general: toluene, THF, DME, dioxane, and tertiary alcohols
Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27–50.
• Water is compatible but rates of reaction are often slower.
Klinkenberg, J. L.; Hartwig, J. F. Angew. Chem. Int. Ed. 2011, 50, 86–95. • DMF, NMP, MeCN, acetone, etc., should be avoided as single solvents, but they can be great co-
solvents, especially for substrates containining potentially chelating functional groups that
Industrial Review of C-N and C-O Coupling: otherwise might inhibit catalysis.
Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599–1626.
Activation

• In order for the catalytic cycle to begin, palladium must be in the Pd(0) oxidation state. One of the
• The Buchwald-Hartwig reaction is the coupling of an amine with an aryl halide mediated by a most common Pd(0) sources is Pd2dba3.
palladium catalyst.

• Pd(II) sources can be used and are more stable, but they require reduction to Pd(0). One of most
R' PdLn R' common activation methods is via reduction of Pd(OAc)2 with PR3, water, and heat.
+ X Ar N Ar
NH
R Base, Solvent R

H2O Pd(0)PR3
Pd(II)(OAc)2 + 2PR3 (R3P)Pd(0)(OAc) + AcOPR3
O=PR3 + 2HOAc
Mechanism:
Activation
LnPd(0) or LnPd(II)
Oxidative
Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 11, 2177–2180
Addition
R R' Ar X Amatore, C.; Carre, E.; Jutand, A.; M'Barki, M. Organometallics 1995, 14, 1818–1826
Reductive N
Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008, 10, 3505–3508.
Elimination Ar
LnPd(0)

• Precatalyst systems allow for lower reaction temperatures.

LnPd(II)(Ar)[N(R)R'] LnPd(II)(Ar)(X) Coordination

NaOtBu
R R' L–Pd(0) +
N NH2 N
Pd dioxane, 23 ºC (active catalyst)
H H
Base-HX H Cl L
R R'
N
Deprotonation Base
LnPd(II)(Ar)(X)
Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686-6687.

The Base (bolded bases are the most commonly used):

• For fast reactions: strong bases such as NaOt-Bu, KOH (uncrushed pellets) K3PO4 L–Pd(0) +
• For substrates bearing sensitive functional groups: weaker bases such as K3PO4, Cs2CO3,
NH2 THF, 23 ºC (active catalyst)
K2CO3 with t-BuOH or t-amyl alcohol Pd N
• For substrates bearing acidic functional groups, use of LiHMDS as base affords lithiates that can Cl L H
prevent catalyst inhibition.

Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073–14075.
Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett. 2002, 4, 2885–2888. Rob Singer, David Bernhardson

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 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115
Oxidative Addition Coordination

• Electron-rich and sterically hindered aryl halides undergo slower oxidative addition. Reactivity • Electron-rich amines are superior substrates due to their enhanced nucleophilicities.
order: I > Br > OTf > Cl > OTs. Deprotonation
• Binding to Pd increases the acidity of the amine, which facilitates deprotonation.

R Reductive Elimination
I H2N R NH R= H2N 90% • Electron deficient amines undergo slower reductive elimination.
Cl Pd2(dba)3, Xantphos Cl
• Bulky ligands help to accelerate reductive elimination through steric repulsion.
NaOt-Bu, toluene H2N
80 ºC Ph Ph Amine pKa (HNR2) Temp (ºC) Yield (%)
Br Br
96%
Br P Ph R1
Temp N(tolyl)2 25 85 90
Fe Pd Ph N
N R1 1.5 h R2 NHPh 30 25 80
P
R2
Ph Ph NHi-Bu 41 0 64
Larsen, S. B.; Bang-Andersen, B.; Johansen, T. N.; Jorgensen, M. Tetrahedron, 2008, 64, 2938–2950.
Hartwig, J. F. Inorg. Chem. 2007, 46, 1936–1947.

Boc Examples of Ligands

N Ph2P PPh2 Buchwald Hartwig
OCH3
O
Boc Br N CH3
H3CO PCy2
N Pd2(dba)3, Xantphos P(t-Bu)2
PCy2 i-Pr i-Pr P(t-Bu)2 Ph Ph
H3C CH3 Fe
N NaOt-Bu, toluene N i-PrO Oi-Pr PCy2
N Fe Ph Ph
H 100 ºC, 96% Xantphos
Cl Cl Ph
i-Pr

• OTf and OTs may undergo competing hydrolysis. RuPhos BrettPhos Josiphos Q-phos
(for 2º amines) (for 1º amines) CyPFtBu
• Iodides are less frequently used because they tend to be more expensive, dehalogenate more
readily, and tend to form bridged palladium dimers. OCH3 Stradiotto Singer
• Halides in the 2- and 4-positions of 6-membered hetercycles are predisposed towards oxidative
3,5-CF3C6H4
addition. H3CO P 3,5-CF3C6H4
O
Boc i-Pr i-Pr
N
N Ph N
N
Boc Br P(t-Bu)2
P(Ad)2
N Pd2(dba)3, Xantphos i-Pr
Ph N N
N Ph
N P(t-Bu)2
NaOt-Bu, toluene N JackiePhos i-Pr i-Pr
N
H 100 ºC, 95%
Br
Br NH Mor-DalPhos Bippyphos
Pd i-Pr
L Cl tBuXPhos
Ji, J.; Li, T.; Bunnelle, W. H. Org. Lett. 2003, 5, 4611–4614. Pre-Ru: L = RuPhos
Maes, B. U. W.; Loones, K. T. J.; Jonckers, T. H. M.; Lemiere, G. L. F.; Dommisse, R. A.; Haemers, A. Pre-Brett: L = BrettPhos
Synlett, 2002, 1995–1998. Rob Singer, David Bernhardson

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 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115
Nitrogen nucleophiles Secondary Amines vs. Primary Amines

• Ligand choice is important. A catalyst that is too hindered inhibits reactions with secondary
• Listed, in decreasing order, by approximate ease of coupling: anilines, secondary amines, primary amines, while primary amines require a hindered ligand, to avoid double arylation.
amines, amides, sulfamides, five-membered heterocycles (i.e. pyrazole, imidazole, etc.), and ammonia.

Anilines

OR OR
N Ar N
N O N O O O
Br ArNH2, K3PO4, DME, 80oC N
N CH3 N CH3 Br
N N H N N
H H N N H2N CH3 H
CH3 Pd2(dba)3, BINAP CH3 N CH3
O O H n = 2 or 4 n
61-81%
PdL (1 mol%) H3CO PdL (1 mol%)
OTBS OTBS OTBS OTBS H3CO NaOt-Bu, dioxane NaOt-Bu, dioxane H CO
3
100 ºC 100 ºC n = 2 or 4
R = CH2Ph or 4-CN-PhCH2CH2
PdL PdL
Pre-Ru - 99% (GC) Pre-Ru - 30% (GC), n = 7
Meier, C.; Sonja, G. Sylett 2002, 802–804. Pre-Brett - 17% (GC) Pre-Brett - 99% (GC), n = 7
• A selective C–N coupling reaction was used in the synthesis of the core of variolins, a group of marine Pd(dba)2/Qphos - 96% (isolated) Pd(dba)2/Qphos - 85% (isolated), n = 5
natural products with potent cytotoxic activities against murine leukemia cells:

H2N
Cl N Cl
Br Br
Fors, B.; Buchwald, S. L. J. Am. Chem. Soc., 2010, 132, 15914–15917.
(1.2 eq) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5566.
N N Pd(OAc)2 (5 mol%) N N
N JohnPhos (10 mol%) N • The combination of Pd(OAc)2 and CyPFt-Bu is highly effective for monoarylation of primary
Cl HN
NaOt-Bu (1.4eq) amines. While it can be used to effect arylation of secondary amines, the rate is slower and
THF, 70 ºC, 83% higher catalyst loading is required:
N

O
O
P(t-Bu)2 N Cl
n-C8H17 NH2 n-C8H17 H
H N
N
Johnphos Pd(OAc)2 (1 mol%) N Pd(OAc)2 (0.005 mol%)
CyPFt-Bu (1 mol%) CyPFt-Bu (0.005 mol%) N
N
NaOt-Bu, DME, 90 ºC NaOtBu, DME, 90 ºC
69% (isolated) 100% (GC)
• The selectivity in this case is attributed to the directing effects of the neighboring nitrogen atoms. 92% (isolated)

A. Baeza, C. Burgos, J. Alvarez-Builla, J. J. Vaquero, Tetrahedron Lett. 2007, 48, 2597

Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586–6596.
Rob Singer, David Bernhardson

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 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115
Amides as Substrates
Challenging Substrate for Coupling

• Aminopyridines frequently function as chelating ligands with palladium. This effect can be mitigated CH3 CH3
by the use of LiHMDS and hindered, reactive ligands.
[Pd(allyl)Cl]2 (1 mol%)
O Cl HN O JackiePhos (5 mol%) N O
H2N Cs2CO3, 3Å MS
O N H t-Bu
H Br N toluene, 130 ºC, 81% t-Bu
N
PdL (2 mol%) PdL (4 mol%)
N NH2 LiHMDS, 65 ºC N NH2
N NH2 LiHMDS, 65 ºC
PdL PdL Hicks, J. D.; Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L. J. Am. Chem. Soc., 2009, 131, 16720–
Pre-Ru - 79% (isolated) Pre-Ru - 47% (GC) 16734.
Pre-Brett - <10% (GC) Pre-Brett - 78% (isolated)
• Application to the synthesis of an HIV-1 integrase inhibitor:

Perez, F.; Minatti, A. Org. Lett. 2011, 13, 1984–1987.

Selective Coupling of Primary over Secondary Amines H3CO N N

OH N N
N
O 1. Pd(OAc)2, Xantphos N
O
N
NH Cs2CO3, dioxane, 65 ºC N
NH2 NH
Ph NH N Br 2. TMSCl, NaI
Cl H2N F N
H
MeCN, 92% O F
Pre-Brett (1 mol%) 1% Pre-Brett NH H
N O
BrettPhos (1 mol%) 1% BrettPhos
HN Ph NaOt-Bu, dioxane NaOt-Bu, dioxane
80 ºC, 89% 80 ºC, 84%

Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc., 2008, 130, 13552– Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.; Foster, S. A.; Jeffrey,
13554. J. L.; Miller, W. H. Bioorg. Med. Chem. Lett., 2009, 19, 1807–1810.

Large-Scale Amination Ureas as Substrates

• Application to the synthesis of a CNS-Active aminotetralin: • Application to the synthesis of a TRPV1 receptor antagonist:
CH3
CH3
CH3 N N
CH3
H Pd(OAc)2 (0.5 mol%) O
CH3 N BINAP (2 mol%) O
N Ph CH3 Pd2(dba)3 (1 mol%)
+ H HN NH2 N N
N Ph NaOt-Bu, toluene N Bippyphos (2 mol%) HN N
H N H
Br 100 ºC
CH3 K3PO4, DME
"quantitative yield" N
F3C t-Bu Cl 80 ºC, 84%
125-kg scale CH3 F3C t-Bu

Federsel, H.-J.; Hedberg, M.; Qvarnström, F. R.; Tian, W. Org. Process Res. Dev. 2008, 12, 512–521.
Federsel, H.-J.; Hedberg, M.; Qvarnström, F. R.; Sjögren, M. P. T.; Tian, W. Acc. Chem. Res. 2007, Yu, S.; Haight, A.; Kotecki, B.; Wang, L.; Lukin, K.; Hill, D. R. J. Org. Chem., 2009, 74, 9539–9542.
40, 1377–1384. Rob Singer, David Bernhardson

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 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115
Sulfamides as Substrates • Application to the synthesis of an intermediate en route to a tetracycline antibiotic:

• Application to the synthesis of a c-Met Kinase Inhibitor:

CH3 O O O
H2N N O t-BuO NH2
S Br t-BuO NH Br
O O (2.88 kg) CH3 Pd2(dba)3 (5 mol%) CH3 CH3
O N Xantphos (15 mol%) N O N
Cl Br Pd2(dba)3 (6.6 mol%) CH3 O
O H
Xantphos (15 mol%) Cl N N O Br CO2Ph Cs2CO3, dioxane Br CO2Ph t-BuO N CO2Ph
S H
OBn 80 ºC, 62% OBn OBn
N Cs2CO3, THF O O
60 ºC, 69% N
(3.4 kg) (9.6 kg) 4 : 1

Stewart, G. W.; Brands, K. M. J.; Brewer, S. E.; Cowden, C. J.; Davies, A. J.; Edwards, J. S.;
Clark, R. B.; He, M.; Fyfe, C.; Lofland, D.; O'Brien, W. J.; Plamondon, L.; Sutcliffe, J. A.; Xiao, X.-Y. J.
Gibson, A. W.; Hamilton, S. E.; Katz, J. D.; Keen, S. P.; Mullens, P. R.; Scott, J. P.; Wallance, D. J.;
Med. Chem., 2011, 54, 15-11-1528
Wise, C. S. Org. Process Res. Dev, 2010, 14, 849–858

Carbamates as Substrates
N-Heterocyles as Substrates

H3C

Pd2(dba)3•CHCl3 (3 mol%) H N
Br t-BuXPhos (9 mol%) N O H3C Cl N NH
H2N O H
Ot-Bu N N HCl N
t-Bu Ot-Bu NaOt-Bu, toluene t-Bu N NH2
23 ºC, 76% H N dioxane, 70%
N

Pd2(dba)3 (0.5 mol%)

Xantphos (1.5 mol%)
Bhagwanth, S.; Waterson, A. G.; Adjabeng, G. M.; Hornberger, K. R. J. Org. Chem., 2009, 74, 4634– Na2CO3, dioxane
4637. 70 ºC, 73%

H3C
Pd2(dba)3 (1.5 mol%) H
Br t-BuBrettPhos (3.6 mol%) N O N NH2
NaOCN N
N tBuOH*, 130 ºC, 73% N Ot-Bu
N
O O
t-Bu t-Bu
N

*Other alcohols can be used to make other carbamates

Shen, Z.; Hong, Y.; He, X.; Mo, W.; Hu, B.; Sun, N.; Hu, X. Org. Lett. 2010, 12, 552–555.
Perez, F.; Minatti, A. Org. Lett. 2013, 15, 1394–1397. Rob Singer, David Bernhardson

10
 Myers C–N Bond-Forming Reaction: The Buchwald-Hartwig Reaction Chem 115
Ammonia as a substrate • Application to the synthesis of Vitamin E Amines:

1. NH2
[Pd(cinnamyl)Cl2]2 (1.5 mol%)
Cl Mor-DalPhos (2.25 mol%) NH2
Pd(OAc)2, BINAP
NaOt-Bu, toluene, 80 ºC
N NaOt-Bu, NH3, 1,4-dioxane N
2. Pd/C, HCO2NH4
110 ºC, 79%
MeOH, 65 ºC
67% (2 steps)
CH3
F3C O CH3
S H2N
[Pd(cinnamyl)Cl2]2 (3.0 mol%) O O R
H3C O R
Cl Mor-DalPhos (4.5 mol%) NH2 CH3 1.
CH3 H3C O
CH3
NaOt-Bu, NH3, 1,4-dioxane CH3
t-Bu t-Bu
110 ºC, 69% NH
Pd(OAc)2, BINAP, NaOt-Bu
toluene, 80 ºC

Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M. Angew. Chem. Int. Ed., 2010, 49, 4071– 2. HCl, H2O, THF
4074. 23 ºC, 79% (2 steps)

Ammonia Surrogates CH3 CH3 CH3

R=
• Application to the synthesis of a JAK2 Inhibitor: CH3

1. Mazzini, F.; Netscher, T.; Salvadori, P. Eur. J. Org. Chem. 2009, 2063–2068.
OCH3 OCH3

NH
H3CO O H3CO O CH3
Pd2(dba)3, Xantphos CH3
N Ot-Bu N Ot-Bu N
Cs2CO3, dioxane, 90oC N S
NH
N N S N
N N
N
2. HCl, water, THF, 2 min Pd2(dba)3 (0.25 mol%) NH2
Cl N H2N N Br
23 ºC, 89% BINAP (0.75 mol%)
CH3 CH3
NaOCH3, toluene, 83–87 ºC;
37% HCl, 70–78 ºC;
5N NaOH, 55–65 ºC

PCT Int. Appl., 2011028864, 10 Mar 2011.

14-kg scale, 86%

Liu, Y.; Prashad, M.; Repic, O.; Blacklock, T. J. J. Heterocyclic Chem. 2003, 40, 713–716.
Rob Singer, David Bernhardson

11
 Myers C–N Bond-Forming Reaction: Cu-Catalyzed, Ullmann-Type Couplings Chem 115
Reviews: Typical Ligands:
1,2-diamines (most common), amino acids, 1,3-dicarbonyls, 1,2-amino alcohols, 1,2-diols
Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13–31. • Examples
Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48, 6954–6971.
Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450–1460. O
H3C O
Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400–5449. N
N OH N
CH3 OH
N NH OH
A comparison between Pd- and Cu-catalyzed C–N Bond-Forming Processes:
Beletskaya, I. P.; Cheprakov, A. V. Organometallics 2012, 31, 7753–7808.

Overview O O O O
CH3
H3C NH HN CH3 OEt N
R' Cu salt R' CH3 O OH
NH + X Ar N Ar
R Base, Solvent R

O
OH
• The Ullman-type reaction involves coupling amines and other nitrogen nucleophiles with an aryl
halide, catalyzed by copper salts.
N N N O
N H
H3C NH HN CH3 OH
N N O
• Copper is highly effective for coupling aryl halides with amides, carbamates, azoles and ureas.
These substrates tend to be problematic in Pd-catalyzed couplings.
• 1,2-Diamines are among the most general supporting ligands in Cu-Catalyzed C-N Couplings: The
• The mechanism may follow the same cycle as with Pd, but is more likely to involve coordination of amine nucleophiles often coordinate to copper to form a stable bis-amine complex which impedes
the amine prior to oxidative addition (Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. catalysis. Diamine chelation suppresses this undesired pathway.
Chem. Soc. 2005, 127, 4120–4121).
Critical Features of Ligand Design:

Mechanism:
Ethylene or cyclohexane
R = CH3 gives highest
backbone is most
reaction rate; larger
effective.
R R' R R' groups impede rate.
N N
Ar LnCu(I)X Coordination R NH HN R
Reductive H
Elimination Further substitution to
R = H leads to ligand arylation.
give tertiary amine, such
as TMEDA, leads to
LnCu(III)X(Ar)[N(R)R'] LnCu(I)X[NH(R)R'] ineffective ligands.

Typical Cu salts:
Oxidative Addition LnCu(I) Base CuI (most common), CuBr, CuOAc, Cu2O.

Ar X N Base-HX Deprotonation Typical Solvents:

R R'
NMP, DMAC, DMSO, DMF, toluene, THF, DME, dioxane.

Typical Bases:
• an alternative mechanism involves oxidative addition prior to coordination. Most general: Cs2CO3. Commonly used: K2CO3, K3PO4.
May be used: KOH, CsF, CsOAc.
Rob Singer, David Bernhardson

12
 Myers C–N Bond-Forming Reaction: Cu-Catalyzed, Ullmann-Type Couplings Chem 115
Preparation of benzimidazoles: • Lactams couple selectively over secondary amines:

Bn H3C NH HN CH3
Et NH O (10 mol%) Bn
Et H3C NH HN CH3 Et HN
R O R NH R N
NH (20 mol%) AcOH N + CuI (5 mol%), K2CO3,
O NH O
+ R' Br toluene, 110 ºC, 78%
R' NH2
I CuI (5 mol%), Cs2CO3, N R' 68–93% N
H
dioxane, 90 ºC

Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 3529–
Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749–4751. 3533.
Selective coupling of pyridazinone in the presence of a sulfonamide and a secondary amide:
Application to the Synthesis of the Natural Product Geldanamycin
O

I N
Oi-Pr
O N O Oi-Pr
S S H3CO
HN HN H3CO
O O O H3C NH HN CH3 O
O H3C NH HN CH3 O
NC NC Br (2 equiv)
+ NH (10 mol%) N
Oi-Pr
N N
CuI (4 mol%)
N H3C H2N O CuI (1 equiv)
H3C Oi-Pr H CH3
K3PO4, DMF, OBn BnO H3CO
H3CO CH3 OCH3 CH3 K2CO3, 110 oC,
H 110 ºC H
N N toluene, 81% H3CO OMOM
CH3 CH3 H3C CH3 CH3
O O OMOM

Schweinitz, A.; Dönnecke, D.; Ludwig, A.; Steinmetzer, P.; Schulze, A.; Kotthaus, J.; Wein, S.; 4 steps
Clement, B.; Steinmetzer, T. Bioorg. Med. Chem. Lett. 2009, 19, 1960–1965.

Preparation of quinolones:
O
H3CO
O
H3C NH HN CH3
O O N
R (20 mol%) R O H
R H3C O CH3
CH3 O CuI (10 mol%) CH3 NaOH
+ HO H3CO O
Br Ph NH2 K2CO3, toluene, NH
dioxane, 110 ºC H3CO O NH2
N Ph
110 ºC O Ph 67–89% H CH3 CH3

Geldanamycin

Qin, H.-Li.; Panek, J. S. Org. Lett. 2008, 10, 2477–2479.

Jones, C. P.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2007, 72, 7968–7973.
Rob Singer, David Bernhardson

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 Myers C–N Bond-Forming Reaction: Cu-Catalyzed, Ullmann-Type Couplings Chem 115
Couplings of Azoles Couplings of Primary Amines:
• Proline is one of few ligands that can facilitate Cu-catalyzed C–N coupling with anilines:
Cu2O (5 mol%)
I (20 mol%) OH H
N NH + I Br N N
Cs2CO3, MeCN Br OCH3 CuI (20 mol%) N
Br N L-proline (40 mol%)
50 ºC, 89%
OH I
H2N K2CO3, DMSO OCH3
OCH3 90 ºC, 97% OCH3
Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607–5622.

Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164–5173.
CuBr (10 mol%) O O
II (20 mol%) • Room-temperature C–N coupling can be achieved using ligand V:
N NH + I N N OEt
Cs2CO3, DMSO
60 ºC, 85%
II
NH2 CuI (5 mol%) O O
Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863–3867. V (20 mol%) H N CH3
+ I Br
Cs2CO3, DMF Br
• Inexpensive amino acids can be used as ligands and demonstrate a broad substrate scope: CH3
23 ºC, 98%
O O V
H
I Bn CuI (10 mol%) N N Bn
N N NH2 L-proline (20 mol%) N
N Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742–8743.
N O N K2CO3, DMSO N O
Bn 80 ºC, 77% Bn
• Couplings of acyclic secondary amines was virtually unprecedented until the discovery of
DMPAO as a supporting ligand:
Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 496–499.
Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164–5173. O
H3C O
Br CuI (10 mol%) N Ph H3C OH
• Ligand III is effective for heterocycles and even activated aryl chlorides:
DMPAO (20 mol%) NH
H3C
N Ph K3PO4, DMSO
CuI (10 mol%) H
N 90 ºC, 86% CH3
III (20 mol%) N
+ Cl OCH3 OCH3
NaOCH3, DMSO N O O DMPAO
N N N
H 110 ºC, 90% N
OH III
• This methodology can also be applied to primary amines and cyclic secondary amines, but not to
Ma, H.-C.; Jiang, X.-Z. J. Org. Chem. 2007, 72, 8943–8946. anilines.
• Couplings catalyzed by Ligand IV proceed under mild conditions and with a low loading of the Zhang, Y.; Yang, X.; Tao, Q.; Ma, D. Org. Lett. 2012, 14, 3056–3059.
copper catalyst:
• DMPAO can also be applied to the synthesis of aryl carbamates:
CuBr (1 mol%) H
IV (2 mol%) Br CuI (20 mol%) N On-Bu
+ N O
NH I N DMPAO (40 mol%)
N Cs2CO3, DMSO N O
+ KOCN
60 ºC, 84% OH n-BuOH, 110 ºC, 80%
O2N O2N Cl Cl
IV

Yang, X.; Zhang, Y.; Ma, D. Adv. Synth. Catal. 2012, 354, 2443–2446.
Yang, K.; Qiu, Y. Q.; Li, Z.; Wang, Z.; Jiang, S. J. Org. Chem. 2011, 76, 3151–3159. Rob Singer, David Bernhardson, Fan Liu

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 Myers C–N Bond-Forming Reaction: Cu-Catalyzed, Ullmann-Type Couplings Chem 115
Ligand-controlled N-Arylation versus O-arylation of amino alcohols Heterocycle formation via tandem coupling and hydroamidation
NH2 OH 1.
H3C NH HN CH3
H2N (20 mol%) H3C NH HN CH3
CuI (5 mol%) CuI (5 mol%) H
Boc N (20 mol%) Boc
L2 (10 mol%) Br I L1 (20 mol%) n-Pr
Br O N Boc n-Pr I NH2Boc
+ Br NH NH H n-Pr N n-Pr
CsCO3, PhCH3 CsCO3, DMF
N
90 ºC, 86% 23 ºC, 97% CuI (5 mol%), Cs2CO3 CuI (5 mol%), Cs2CO3
HO THF, 80 ºC, 84% n-Pr THF, 80 ºC, 84%
20:1 >50:1 n-Pr
2. TFA, CH2Cl2, 23 ºC
CH3
CH3 O O
CH3 Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2006, 45, 7079–7082.
H3C
N
CH3 Cu-catalyzed C–N couplings with boronic acids
N
H3C L2 L1 CH3

Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490–3491. H H3C [Cu(OH)•TMEDA]2Cl2
N (10 mol%)
+
• Chemoselective N-Arylation of 1,2-amino alcohols: the substrate functions as the ligand. The N B(OH)2 CH2Cl2, 23 ºC N
choice of solvent dictates C–N versus C–O bond formation. O2, 98%
N

OH Ph OH Ph
CuI (2.5 mol%), K3PO4 H O Ph
I H2N N O
OH OH
+ ethylene glycol, i-PrOH Et N NH Cu(OAc)2 (1.1 equiv) Et N
CH3 CH3 + N
75 oC, 76%
B(OH)2 air, Et3N, CH2Cl2
Protic solvent favors C-N coupling
4Å MS, 79%
Ph Ph
Ph I + H3CHN CuI (5 mol%) H3CHN
OH OPh
Cs2CO3, n-butyronitrile
Cu(OAc)2 (10 mol%)
CH3 CH3
+
125 ºC, 74% O2, CH2Cl2, 23 ºC
Aprotic solvent favors C-O coupling NH2 B(OH)2
4Å MS, 85% N
H
Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 3703–3706.

• C–N coupling can be facilitated by ortho-chelating groups:

CO2CH3 Cu(OAc)2 (10 mol%) CO2CH3
+
Ph O2, CH2Cl2, 23 ºC Ph
H2N B(OH)2 N
O CuI (5 mol%) O 4Å MS, 90% H
Cs2CO3, DMF, 23 ºC (no epimerization observed)
OH OH
+ n-Hexylamine
96% yield
Br N CH3
(0% yield in the absence of CuI) H Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42,
3415–3418.
Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236.
Diao, X.; Xu, L.; Zhu, W.; Jiang, Y.; Wang, H.; Guo, Y.; Ma, D. Org. Lett. 2011, 13, 6422–6425. Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397–4400. Rob Singer, David Bernhardson

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