Gold-catalyzed amide synthesis from aldehydes and amines in aqueous medium

Article abstract of DOI:10.1039/c2cc17689k

An efficient gold-catalyzed amide synthesis from aldehydes and amines in aqueous medium under mild reaction conditions has been developed.

Full text of DOI:10.1039/c2cc17689k

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COMMUNICATION
Gold-catalyzed amide synthesis from aldehydes and amines in aqueous
mediumw
Gai-Li Li, Karen Ka-Yan Kung and Man-Kin Wong*
Received 8th December 2011, Accepted 5th March 2012
DOI: 10.1039/c2cc17689k
An efficient gold-catalyzed amide synthesis from aldehydes and
amines in aqueous medium under mild reaction conditions has
been developed.
only a trace amount of aldehyde conversion was found. In
addition, we conducted a detailed study on reaction parameters
including catalyst loading, reaction temperature, various metal
catalysts, solvent systems and bases toward the reaction of 1a
and 2a, and amide 3a was obtained in up to 85% isolated yield
(Tables S1–S3 in ESIw).
The amide functionality is commonly found in natural products,
proteins, and therapeutic drugs and has significant importance in
organic and biological chemistry.1 The conventional approach for
amide synthesis involves coupling of activated carboxylic acids and
amines that may require extra functional group interconversions
and lead to poor atom and step economy. New developments
include Staudinger ligation,2a hydrative amide synthesis from
terminal alkynes and sulfonyl azides,2b and iodonium-promoted
nitroalkane–amine coupling reaction.2c In 2006, we reported
manganese porphyrin-catalyzed oxidative amide synthesis
from alkynes and amines.3 Transition metal-catalyzed amide
formation from the reaction of aldehydes,4 alcohols,5 and
esters6 with amines has also been reported. However, high
reaction temperature, inert atmosphere, and/or anhydrous
organic solvents are generally required. In particular, synthesis
of tertiary amides from secondary amines remains a challenging
task.7 Thus, the development of new methods for amide synthesis
in aqueous medium under mild reaction conditions would be of
great interest.
Table 1 KAuCl4-catalyzed amide synthesis from aldehydes 1a–1m
and piperidine 2aa
Entry
Aldehyde
Product
Yieldb (%)
1
2
3
4
5
6
X = p-NO2 1a
X = m-NO2 1b
X = p-Cl 1c
X = o-Cl 1d
X = p-Br 1e
X = p-CHO 1f
3a
3b
3c
3d
3e
3f
61 (A), 85 (B)
64 (A), 74 (B)
55 (A), 70 (B)
67 (B)
40 (B)
55 (A), 44 (B)
Gold catalysis has emerged as a frontier research area in
organic chemistry, owing to its excellent reactivity, compatibility
with aqueous medium and mild reaction conditions.8 Recently, a
number of heterogeneous gold catalysts have been used for amide
synthesis from alcohols and amines under aerobic conditions.9
Along with our ongoing research to develop gold catalysis for
organic synthesis,10 we recently found an efficient gold-catalyzed
amide synthesis from aldehydes and amines in aqueous medium
under mild reaction conditions.
6 (A), 15 (B)
7
8
9
10
X = m-CHO 1g
X = o-CHO 1h
X = H 1i
3g
3h
3i
67 (A), 42 (B)
40 (B)
50 (B)
X = o-OH 1j
3j
15 (B)
11
12
24 (B)
The coupling reaction of p-nitrobenzaldehyde 1a (1 equiv.) and
piperidine 2a (2 equiv.) in the presence of KAuCl4 (1 mol%) and
K2CO3 (10 mol%) in CH3CN/H2O (1 : 1) at 60 1C for 12 h was
conducted (Table 1, entry 1, see also Table S1 in ESIw). It was
found that amide 3a was obtained in 61% isolated yield while no
amide product was detected without KAuCl4. Without H2O,
52 (A), 50 (B)
98 (A), 99 (B)
13
a
Conditions A: the reactions were carried out with 1a–1m (1.0 mmol),
2a (2.0 mmol, 2 equiv.), KAuCl4 (1 mol%), K2CO3 (10 mol%) in
CH3CN/H2O (1 : 1, 2 mL) at 60 1C for 12 h. Conditions B: the
reactions were carried out with 1a–1m (0.2 mmol), 2a (0.4 mmol,
2 equiv.), KAuCl4 (10 mol%), K2CO3 (10 mol%) in CH3CN/H2O
State Key Laboratory of Chirosciences and Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon, Hong Kong (China).
E-mail: bcmkwong@inet.polyu.edu.hk; Fax: +852 2364-9932
w Electronic supplementary information (ESI) available: Experimental
details and compounds characterization. See DOI: 10.1039/c2cc17689k
b
(1 : 1, 1 mL) at 40 1C for 12 h. Isolated yield.
c
4112 Chem. Commun., 2012, 48, 4112–4114
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The scope of the amide synthesis reaction was examined by
using a variety of aldehydes. Treatment of a series of aldehydes
1a–1m with piperidine 2a furnished the corresponding amide
products 3a–3m (Table 1). In general, the amide synthesis reactions
were conducted in the presence of 1 mol% KAuCl4 at 60 1C
(conditions A), and/or 10 mol% KAuCl4 at 40 1C (conditions B).
Benzaldehydes 1a–1e bearing electron-withdrawing groups
(ꢀNO2, ꢀCl, and ꢀBr) afforded the corresponding amides
3a–3e in good isolated yields (40–85%) (entries 1–5). For para-
dialdehyde 1f, mono-amide 3f (55% (A)) and diamide 3f0 (6% (A))
were obtained (entry 6). The observation of the corresponding
formylbenzoic acids as byproducts may account for the
slightly reduced yields obtained (entries 6–8). Lower yields
were obtained for benzaldehyde 1i (50%) and ortho-hydroxyl
benzaldehyde 1j with an electron-donating hydroxyl group
(15%) (entries 9 and 10). These results suggested that the
electronic effect of aromatic aldehydes would have influence
on the amide synthesis reaction. The use of 4-(2-pyridinyl)-
benzaldehyde 1k afforded the corresponding amide 3k with the
pyridine ring remaining intact (entry 11). Furthermore, the
present amide synthesis reaction worked for aliphatic aldehyde
1l and formaldehyde 1m (entries 12 and 13).
Scheme 1 KAuCl4-catalyzed amide synthesis from aldehydes 1n and
1o and amines 2a and 2b.
benzylamine and aniline were used as the substrates, only
the corresponding imines were obtained. To demonstrate the
generality of the present amide synthesis reaction, a diversity
of aromatic and aliphatic aldehydes were coupled with various
secondary amines to afford the corresponding amides 5a–5m
in up to 99% isolated yield.
In addition, we further examined the functional group
compatibility of the KAuCl4-catalyzed amide synthesis reaction
(Scheme 1). The reactions of monosaccharides 1n and 1o with
secondary amines 2a and 2b in the presence of KAuCl4 (10 mol%)
and K2CO3 (10 mol%) in CH3CN/H2O (1 : 1) at 40 1C for 12 h
were conducted. The corresponding amide products 6a–6c
with the ketal and trimethylsilyl ether groups remaining intact
were obtained in 53–62% isolated yields. It should be noted
that the ester moieties were also tolerated in the present amide
synthesis reaction, whereas ester–amide exchange reaction was
reported using ruthenium catalyst.6
We further examined the scope of this reaction by employing
various amines (Table 2). Pyrrolidine 2b, 4-methylpiperidine 2c,
3-methylpiperidine 2d, hexamethyleneimine 2e, and hepta-
methyleneimine 2f provided the desired amides 4a–4e in good
isolated yields (52–76%). When primary amines including
Table 2 KAuCl4-catalyzed amide synthesis from aldehydes 1a–1c, 1f,
1k–1m and secondary amines 2b–2fa,b
Oligosaccharides are involved in a wide range of biological
processes and thus important targets for bioconjugation.11
Given the high functional group tolerance and mild aqueous
reaction conditions of the present KAuCl4-catalyzed amide
synthesis reaction, we proceeded to investigate the modification
of an oligosaccharide-based aldehyde bearing polyhydroxyl
groups (Scheme 2). We were pleased to find that the reaction
of unprotected D-raffinose aldehyde 1p (10 mM in H2O) with
amines 2a–2c and 2e and 2f (5 equiv.) in the presence of KAuCl4
(50 mol%) and K2CO3 (10 mol%) in H2O at 40 1C for 12 h gave
7a–7e with the hydroxyl groups remaining intact with up to
90% aldehyde conversion as shown by LC-MS analysis.12
A reaction mechanism for the gold-catalyzed amide synthesis
from aldehydes and amines in aqueous medium is proposed
(Scheme 3). An aminyl radical (A) is generated from the reaction
a
All reactions were carried out with 1a–1c, 1f and 1k–1m (0.2 mmol),
2b–2f (0.4 mmol, 2 equiv.), KAuCl4 (10 mol%), K2CO3 (10 mol%) in
Scheme 2 KAuCl4-catalyzed modification of D-raffinose aldehyde 1p
and secondary amines 2.
b
CH3CN/H2O (1 : 1, 1 mL) at 40 1C for 12 h. Isolated yield.
c
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Scheme 3 Proposed reaction mechanism.
between an amine and an Au(III) ion in aqueous medium. The
reaction of A with an aldehyde gives an alkoxy radical (B)
which affords an amide as the product via loss of a hydrogen
radical. Oxygen acts as the oxidant for the re-oxidation of the
Au(I) to the Au(III) ion to complete the catalytic cycle.
Mechanistic studies have been conducted to support the above
reaction mechanism. Addition of TEMPO and diyldibenzene
(radical scavengers) significantly suppressed the coupling reaction
of 1a or 1i with 2a (Schemes S1a and S1b in ESIw), suggesting the
involvement of radical species. Generation of amine radicals
through the reaction of amines with gold ions13 and in gold(III)/
gold(I) redox processes in aqueous medium has been reported.8a,14
Thus, an aminyl radical (A) generated from the reaction between
an amine and an Au(III) ion in aqueous medium is proposed.
The reaction of 1i (34% 18O-incorporation) and 2a was
conducted in H218O (Scheme S1d, ESIw) to give the product
amide 3i with 30% 18O-incorporation as confirmed by ESI-MS
analysis, indicating that the amide carbonyl oxygen atom
originated from the aldehyde. No TEMPO adduct formation
with 1i as observed by 1H NMR and chromatography analysis
suggests that an acyl radical would not be generated under the
reaction conditions (Scheme S1h, ESIw).15 Thus, an alkoxy
radical (B) generated from the reaction of an aminyl radical
(A) and an aldehyde is suggested.
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The reaction between 1i and 2a in air gave 3i in 50% isolated
yield (Scheme S1i, ESIw). When the reaction was carried out
under a N2 atmosphere, 3i was found in 5% isolated yield,
indicating that oxygen in air is important. Under an oxygen
atmosphere (balloon), no amide product was detected. This
would be attributed to the oxidation of aminyl radical species
by oxygen.16 In this regard, oxygen acting as an oxidant for
the oxidation of Au(I) to Au(III) is suggested.17
In conclusion, we have developed an efficient gold-catalyzed
amide synthesis from aldehydes and amines with high
functional group tolerance in aqueous medium under mild reaction
conditions. This method allows an easy access to amides from the
reaction of aromatic, aliphatic and polyhydroxyl oligosaccharide-
based aldehydes with secondary amines.
11 C. Y. Wu and C. H. Wong, Chem. Commun., 2011, 47, 6201.
12 For aldehyde conversion analyzed by LC-MS analysis, see ESIw.
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16 J. H. Horner, F. N. Martinez, O. M. Musa, M. Newcomb and
H. E. Shahin, J. Am. Chem. Soc., 1995, 117, 11124.
We thank the financial support of Hong Kong Research
Grants Council (PolyU 5031/11p) and The Hong Kong
Polytechnic University (PolyU Departmental General Research
Funds, Competitive Research Grants for Newly Recruited
Junior Academic Staff and SEG PolyU01). We also thank Prof.
Jun-Long Zhang of Peking University for helpful discussion on
mechanistic studies.
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Lett., 2001, 42, 7253; (b) A. Corma, I. Domıguez, A. Domenech,
V. Fornes, C. J. Gomez-Garcıa, T. Rodenas and M. J. Sabater,
J. Catal., 2009, 265, 238; (c) J. Xie, H. Li, J. Zhou, Y. Cheng and
C. Zhu, Angew. Chem., Int. Ed., 2012, 124, 1252.
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c
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This journal is The Royal Society of Chemistry 2012