C O M M U N I C A T I O N S
Table 3. Copper-Catalyzed Oxidative Amidation of Aldehydes with
Scheme 1. Tentative Mechanism for the Oxidative Amidation of
Aldehydes with Amine HCl Salts
Amine Hydrochloride Saltsa
entry aldehyde
R
amine HCl
R
′
product yield (%)b
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2g
2g
2g
2g
2g
Et
Bn
CH2Bn
3a
3b
3c
3d
3e
3f
3g
3h
3i
91
71
89
73
39
89
91
91
78
81
49
39
cyclohexyl
tBu
CH2CH2Cl
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
In conclusion, we have developed an efficient copper-catalyzed
protocol for the formation of amides from aldehydes and amine
HCl salts using TBHP as an oxidant. Further investigations into
the scope, mechanism, and synthetic application of this reaction
are now in progress.
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
cyclohexyl
10
11
12
3j
3k
3l
Acknowledgment. We thank the Canada Research Chair (Tier
I) foundation (to C.J.L.), the CFI, NSERC, and CIC (AstraZeneca/
Boehringer Ingelheim/Merck Frosst) for support of our research.
a Aldehyde (1.0 equiv), amine HCl (1.5 equiv), CaCO3 (1.1 equiv),
T-HYDRO (1.1 equiv), CuI (1.0 mol %), and AgIO3 (1.0 mol %) in MeCN
(C ) 5.0 M). b Isolated yields were based on the aldehyde.
was switched from decane to water (entry 6).11 The reaction
conditions were further optimized, and the reaction was shown to
be complete in 6 h at 40 °C.
Supporting Information Available: Experimental procedure and
characterization of all new compounds (PDF). This material is available
With the further optimized conditions in hand, we explored the
scope of the oxidative amidation reaction of aldehydes 1a-f with
amine hydrochloride salts 2a-g (Table 3).
References
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(8) For recent examples, see: (a) Lin, Y.-S.; Alper, H. Angew. Chem., Int.
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Generally, the copper-catalyzed amidation reaction proceeds well
to provide the desired amides 3a-l in high yields. Steric effects of
the amine HCl salts may play a role since a bulky group, such as
tBu, provided amide 3e in low yield (entry 5).12 Remarkably, the
amidation occurred even in the presence of other electrophiles, such
as alkyl chloride (entry 6) and ester (entries 7-12). The oxidative
amidation was also compatible with a variety of electron-rich and
electron-poor aryl aldehydes (entries 8-11). When aliphatic alde-
hyde 1f was utilized as a coupling partner, the desired amide 3l
was obtained with a low yield (entry 12). Interestingly, when the
oxidative amidation reaction was applied to optically active amine
ester 2h, the reaction proceeded smoothly in high yield without
racemization (eq 2).
(9) (a) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Synthesis 1983, 474. (b) Naota,
T.; Murahashi, S. Synlett 1991, 693. (c) Tillack, A.; Rudloff, I.; Beller,
M. Eur. J. Org. Chem. 2001, 523.
(10) Yoo, W.-J.; Li, C.-J. J. Org. Chem. 2006, 71, 6266.
(11) T-HYDRO is the trademark name of a tert-butyl hydroperoxide solution
in water (70 wt % in H2O).
(12) Oxidative amidation of aldehydes with secondary amine HCl salts, such
as piperidine HCl, did not occur under the current optimized reaction
conditions.
(13) Analogous to carbinolamine 4, oxidation of hemiacetal intermediates has
been invoked for the oxidative esterification of aldehydes with alcohols.
See: Gopinath, R.; Patel, B. K. Org. Lett. 2000, 2, 577.
(14) The oxidative amidation reaction most likely occurs via a radical
mechanism since radical scavenger, 2,6-di-tert-butyl-4-methylphenol
(BHT), inhibits the reaction. Radical-based mechanisms have been
proposed for the oxidation of alcohols to aldehydes by galactose oxidases.
For recent mechanistic studies, see: (a) Himo, F.; Eriksson, L. A.; Maseas,
F.; Siegbahn, P. E. M. J. Am. Chem. Soc. 2000, 122, 8031. (b) Whittaker,
M. M.; Ballou, D. P.; Whittaker, J. W. Biochemistry 1998, 37, 8426. (c)
Wachter, R. M.; Montague-Smith, M. P.; Branchaud, B. P. J. Am. Chem.
Soc. 1997, 119, 7743.
A tentative mechanism for the oxidative amidation of aldehydes
for amide formation is proposed in Scheme 1. The oxidative
amidation of the aldehyde may be envisioned by the initial
deprotonation of the amine HCl salt to the free amine. Nucleophilic
addition of the free amine to aldehyde would generate carbinolamine
intermediate 4, which then may be oxidized by Cu(I)/TBHP to
generate the desired amide products.13,14 Mechanistically, it is also
plausible that amide formation may arise from a transamidation
reaction with a carboxylic acid derived from the direct oxidation
of the aldehyde. However, when benzaldehyde was replaced with
benzoic acid, the expected amide was not observed under the
optimized reaction conditions.
JA064315B
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J. AM. CHEM. SOC. VOL. 128, NO. 40, 2006 13065