Transition metal-free synthesis of primary amides from aldehydes and hydroxylamine hydrochloride

Article abstract of DOI:10.1016/j.tetlet.2014.04.020

Primary aromatic amides can be synthesized from aldehydes and hydroxylamine hydrochloride in the presence of Cs₂CO₃. Various aromatic aldehydes (include some heteroaromatic aldehydes) are able to generate the corresponding aromatic amides in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.04.020

Tetrahedron Letters 55 (2014) 3192–3194
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Transition metal-free synthesis of primary amides from aldehydes
and hydroxylamine hydrochloride
⇑
⇑
Wei Wang, Xue-Mei Zhao, Jing-Li Wang, Xin Geng, Jun-Fang Gong, Xin-Qi Hao , Mao-Ping Song
College of Chemistry and Molecular Engineering, Zhengzhou University, No. 100 of Science Road, Zhengzhou 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Primary aromatic amides can be synthesized from aldehydes and hydroxylamine hydrochloride in the
presence of Cs2CO3. Various aromatic aldehydes (include some heteroaromatic aldehydes) are able to
generate the corresponding aromatic amides in moderate to excellent yields.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 3 December 2013
Revised 21 March 2014
Accepted 8 April 2014
Available online 13 April 2014
Keywords:
Aldehyde
Transition metal-free
Primary amide
Primary amides play an important role in organic and pharma-
ceutical chemistry due to their highly useful applications in acade-
mia and industry.1 A large amount of natural products and
pharmaceuticals were constructed by peptide bond.2 Traditional
construction methods of primary amides usually adopted coupling
of carboxylic acid or its derivatives with ammonia.3 It has attracted
great attention of many synthetic chemists to develop new effective
methods for the synthesis of primary amide.4 In recent years, signif-
icant advancement has been achieved in the synthesis of primary
amides. With this strategy, primary amides were usually prepared
by conversion of benzaldehydes with hydroxylamine5 or catalytic
hydration of organonitriles.6 Transition metals (Ru, Rh, Pd, Pt, Ir,
Au, Fe, Co, Ni, and Cu, etc.) are needed as catalysts for effective con-
version in this system,5,6 nevertheless, nowadays those expensive
and toxic transition-metals are out of fashion in industrial applica-
tions considering the environmental issues.7 Therefore, novel econ-
omy and environment-friendly catalysis systems are rapidly
desired. Bio glycerol-based carbon was used as a recyclable catalyst
for a mild and expeditious synthesis of amides from aldehydes.8 Effi-
cient and practical transition metal-free catalytic hydration of
organonitriles to amides has been developed.9 This significant
advance inspired us to explore appropriate catalytic synthesis
approach of amides from nontoxic substrates and reagents. In this
Letter, a transition-metal-free approach will be described for trans-
formation of aldehydes to primary amides using hydroxylamine
hydrochloride with Cs2CO3 as catalyst.
Initially, benzaldehyde as model substrate was tested to react
with hydroxylamine hydrochloride in various solvents under air
conditions. A rough survey of reaction condition indicated that the
yields of the catalysis products were largely dependent on the vol-
ume ratio of mixed solvent DMSO/H2O and the base (Table 1). A
19% yield of benzamide was obtained in DMSO at 125 °C in the pres-
ence of 1.2 equiv Cs2CO3. By using the same conditions, no product
was generated in aqueous solution. For instance, the yield of benz-
amide increased to 54% in the mixed solvent of DMSO and H2O
(v/v = 1/1). Remarkably, while the appropriate proportion of DMSO
and H2O mixture solvent was equal to 3:1 in volume, the highest
yield reached up to 91%. Meanwhile, several bases were examined
in the following experiments. Under the above conditions, the mod-
erate to good yield of benzamide was obtained by reactions using
Cs2CO3 as base.
Furthermore, the substrate scope of this reaction was screened by
different aromatic aldehydes. Under the optimized conditions, most
substituted aldehydes could transform into the corresponding
amides (Table 2). In all cases, the corresponding primary benzamides
were isolated in moderate to good chemical yields. The substituent
can be an electron-donating group such as Me, MeO, or PhO and also
be an electron-withdrawing group such as Cl, Br, I, or NO2. And it can
be located at the 3- or 4- position (entries 1–12). Furthermore, the
2-naphthaldehyde (entry 13) and the heteroaromatic aldehydes
such as pyridine-2-carbaldehyde (entry 14), furan-2-carbaldehyde
(entry 15), thiophene-2-carbaldehyde (entry 16), and substituted
heteroaromatic aldehydes (entries 17–20) can be extended to het-
eroaromatic amides in excellent yields (93–99% yields).
⇑
Corresponding authors. Tel./fax: +86 371 6776 3866.
E-mail addresses: xqhao@zzu.edu.cn (X.-Q. Hao), mpsong@zzu.edu.cn
When the reaction of benzaldehyde with hydroxylamine was
shortened to 24 h under the optimized conditions, the uncompleted
(M.-P. Song).
http://dx.doi.org/10.1016/j.tetlet.2014.04.020
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

W. Wang et al. / Tetrahedron Letters 55 (2014) 3192–3194
3193
Table 1
Table 2 (continued)
Optimization of reaction conditions
Entrya
Substrate
Product
Yieldb/%
CHO
CONH2
base
+
NH2OH.HCl
Me
Me
solvent
125 oC, 48 h
O
C
CHO
12
57
NH2
Entrya
Solvent
Base
Yieldb/%
Me
Me
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DMSO
H2O
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
t-BuOK
NaOH
K3PO4ÁH2O
NaHCO3
KOAc
DBU
K3PO4Á3H2O
19
n.r.
54
33
91
58
Trace
30
n.r.
n.r.
n.r.
n.r.
Trace
n.r.
CHO
O
13
14
99
93
NH2
DMSO/H2O (1:1)
DMSO/H2O (1:3)
DMSO/H2O (3:1)
DMSO/H2O (3:1)
DMSO/H2O (3:1)
DMSO/H2O (3:1)
DMSO/H2O (3:1)
DMSO/H2O (3:1)
DMSO/H2O (3:1)
DMSO/H2O (3:1)
DMSO/H2O (3:1)
DMSO/H2O (3:1)
NH2
NH2
NH2
N
O
S
CHO
N
O
15c
16c
17d
>99
>99
>99
CHO
O
S
O
CHO
S
O
S
a
Reaction conditions: benzaldehyde (0.5 mmol), hydroxylamine hydrochloride
(0.6 mmol), base (0.6 mmol), solvent (2.0 mL), T = 125 °C, t = 48 h, under air.
NH2
NH2
Me
Me
CHO
b
Isolated yield.
O
O
18d
19d
>99
98
Me
Br
Me
Br
CHO
CHO
O
O
NH2
S
S
Me
O
Table 2
Synthesis of primary benzamides from various aldehydes10
Me
20e
NH2
95
O
O
O
Cs2CO3
CHO
S
S
+
NH2OH.HCl
DMSO/H2O
Ar
H
Ar
NH2
O
125 oC, 48 h
a
Reaction conditions: aldehyde (0.5 mmol), hydroxylamine hydrochloride (0.6
mmol), Cs2CO3 (0.6 mmol), solvent (2.0 mL), T = 125 °C, t = 48 h, under air.
Entrya
1
Substrate
Product
Yieldb/%
52
b
Isolated yield.
12 h.
14 h.
16 h.
c
Me
CHO
Me
C
NH2
d
e
O
C
NH2
MeO
Cl
CHO
CHO
MeO
Cl
2
3
79
42
reaction liquid was separated by silica gel column chromatography.
GC–MS was used to analyze the composition of the separated prod-
uct. The mass spectroscopy showed the m/z = 103, which is consis-
tent with benzonitrile. On the base of these results, we propose one
possible mechanism to allow that the aldehyde first undergo reac-
tion with hydroxylamine hydrochloride in the presence of base to
give aldoximes that are transformed into amide by dehydration
and hydration processes.5m
O
C
NH2
O
C
CHO
4
5
49
50
47
91
71
56
66
48
NH2
Me
HO
Me
HO
MeO
PhO
Cl
O
C
CHO
CHO
CHO
CHO
CHO
In conclusion,
a simple transition metal-free system was
NH2
explored to synthesize the primary aromatic amides from alde-
hydes and hydroxylamine hydrochloride in the presence of Cs2CO3.
Various aromatic aldehydes are able to generate the corresponding
aromatic amides in moderate to excellent yields. The base Cs2CO3
and the volume ratio of mixed solvent DMSO/H2O were important
factors in this system. We believe that this transition metal-free
system will be useful for the synthesis of primary amides.
O
C
NH2
6
MeO
PhO
O
C
7
NH2
O
C
Acknowledgment
8
NH2
Cl
Br
O
C
Financial support from National Science Foundation of China
(Nos. 21102135, 21272217 and J1210060) is gratefully acknowl
edged.
9
NH2
Br
O
CHO
C
Supplementary data
10
11
NH2
I
I
O
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.04.020.
CHO
NH2
O2N
O2N

3194
W. Wang et al. / Tetrahedron Letters 55 (2014) 3192–3194
Tetrahedron Lett. 1995, 36, 8657; (f) Kaminskaia, N. V.; Kostic´, N. M. J. Chem.
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