Microwave-assisted synthesis of amide under solvent-free conditions

Article abstract of DOI:10.1080/00397910701860372

An efficient and environmentally friendly synthetic method for the synthesis of primary amides under microwave irradiation was described, in which the primary amine was directly reacted with acid without any catalytic agents. The reaction took place in 8-12-min, which was much shorter than the traditional synthetic methods, with almost quantitative yields. The influential factor of the reaction was discussed. The tautomerization between the carboxylic acid group and the H atom in α-carbon of L-amino acid was observed, presumably a dehydrated intermediate forming from this tautomerized isomer. Copyright Taylor & Francis Group, LLC.

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Microwave‐Assisted Synthesis of Amide under
Solvent‐free Conditions
Xiao‐Jian Wang a , Qian Yang a , Fei Liu a & Qi‐Dong You a
a Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing, 210009, China
Version of record first published: 12 Mar 2008.
To cite this article: Xiao‐Jian Wang, Qian Yang, Fei Liu & Qi‐Dong You (2008): Microwave‐Assisted Synthesis
of Amide under Solvent‐free Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:7, 1028-1035
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Synthetic Communicationsw, 38: 1028–1035, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701860372
Microwave-Assisted Synthesis of Amide
under Solvent-free Conditions
Xiao-Jian Wang, Qian Yang, Fei Liu, and Qi-Dong You
Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing, China
Abstract: An efficient and environmentally friendly synthetic method for the synthesis
of primary amides under microwave irradiation was described, in which the primary
amine was directly reacted with acid without any catalytic agents. The reaction took
place in 8–12 min, which was much shorter than the traditional synthetic methods,
with almost quantitative yields. The influential factor of the reaction was discussed.
The tautomerization between the carboxylic acid group and the H atom in a-carbon
of L-amino acid was observed, presumably a dehydrated intermediate forming from
this tautomerized isomer.
Keywords: Acylation, dehydrated intermediate, microwave-assisted, primary amine,
tautomerization
INTRODUCTION
Amide compounds have attracted much attention because of their extensive
applications in the pharmaceutical industry: they have been generally used as
a protective group in synthetic routes,[1,2] an amide functional group is
contained in many bioactive compounds or drugs, and amide modification is
an important optimization methodology for new chemical entities in
medicinal chemistry. Furthermore, peptide bonds, a special kind of amide
Received July 3, 2007
Address correspondence to Qi-Dong You, Department of Medicinal Chemistry,
China Pharmaceutical University, Nanjing 210009, China. E-mail: youqidong@
gmail.com
1028

Microwave-Assisted Synthesis of Amide
1029
bond in life science, constitute the backbone of proteins. In the chemical
industry, the structure of amides is involved in many important materials.[3–5]
The formation of an amide bond is generally developed[6–10] in these
ways: the traditional synthetic procedures of the acetamido group
compounds are carried out by primary amino compounds with acyl
halides,[6] acid anhydrides,[7] esters,[8] or acids[9] in different conditions.
However, all these procedures have usage limitations: the acyl halides and
acid anhydrides were hygroscopic and many active acylation agents would
be exothermic and produce unwanted acid during the reaction process, so
they should be treated carefully under well-cooled and anhydrous conditions
in the presence of acid-tricing agents. The ester and acids were low chemically
active acylation agents, so they would take a longer time for the reactions with
lower yields. Some chemical active agents such as N,N0-dicyclohexylcarbo-
diimide
(DCC),[10]
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide
(EDC),[11]and so forth should be added to catalyze the reaction; these
catalytic agents should be treated carefully during the reactions because
they are harmful to body and environment.
During recent years, microwave irradiation has been widely used in
organic synthesis because of its reduction in reaction time and its good
yields its applications in N-acylation amides were also developed,[12–14] but
anhydrides were used to form the amide bonds in anhydrous conditions, and
the diversity of amines was not sufficient to elucidate the influential factor
of the reaction. In this article, we report a more facile strategy for the
formation of an amide bond using acid without other solvents under
microwave irradiation (Scheme 1).
Firstly the benzylamine and acetic acid were put together in a microwave
reaction chamber, and an N-acetylated compound was obtained. In this
reaction, acetic acid was used as acylation agent and solvent. Compared
with the traditional amide synthetic procedure, this method was mild and con-
venient with a short time (a few minutes instead of several hours) and high
yields (more than 90%).
Prompted by these results, we extended this synthetic procedure to several
different primary amines with acid. As shown in Table 1, most primary amines
reacted with acetic acid and gave higher yields, between 90 and 95%. Instead
of acetic acid, benzoic acid was used as an acylation agent and also gave
similarly high yields (1b, 2b). Otherwise, benzoic acid could provide a
steady circumstance for the reaction because it would be liquated at
temperatures greater than 150 8C. Moreover, when the p-aminobenzoic acid
or 2-(p-aminophenyl) acetic acid was treated in acetic acid under
Scheme 1.

1030
X.-J. Wang et al.
Table 1. Microwave-assisted synthesis of amides
Product (acetic acid
or benzoic acid)
Yield
Mp (8C) Lit. mp (8C) (%)
Compound
Substrate
1
61
61
95
94
105–107
106–107
2
Oil
93
90
60–61
59–60
3
113
111–115
98
4
5
6
167–169
260–261
100–101
167
259–260
101
92
91
95
7
8
149–150
60–62
149–151
65–67
97
94
9
10
11
107
109–110
129–132
139–145
98
97
97
127–129
138–141
12
13
137–139
92–93
138
75
67
93–94
(continued)

Microwave-Assisted Synthesis of Amide
1031
Table 1. Continued
Product (acetic acid
or benzoic acid)
Yield
Mp (8C) Lit. mp (8C) (%)
Compound
Substrate
14
128–131
178
130–132
177–179
78–80
75
48
33
15
16
79–82
17
18
213–214
215–217
36
No reaction
19
153–155
202–203
151–152
202–204
44
40
20
21
No reaction
22
23
204
142
206
95
93
140.5–141
24
25
26
150–152
146
155
146
118
94
92
94
115–117
[a]2D0 ¼ 69.2 [a]2D0 ¼ 64.2
microwave irradiation, only an N-acetylated product was obtained (4, 5),
which means that the carboxylic acid group in the substrate did not react
with the amino group under this condition. Encouraged by these results, we
use this method to form an amide bond in amino acid. Perhaps it would be
a promising method for the selective N-terminal protection or N-acylation
of compounds.

1032
X.-J. Wang et al.
EXPERIMENTAL SECTION
Melting points were determined with a micromelting-point apparatus: XT-4.
1H NMR spectra were recorded on a Brucker AMX 300-MHz spectrometer,
using deuteriochloroform as solvent. Chemical shifts are reported in parts
per million (d) relative to TMS as an internal standard. DMSO was
employed to confirm exchangeable protons (ex.). Mass spectra (EI) were
obtained on a Shimadzu GCMS-QP2010. Optical rotations were measured
on a Perkin-Elmer model 241 polarimeter in a glass microcell (100-mm
path length, 1-mL volume) with an Na gas discharge lamp as the light
source. Reagents, solvents, and starting materials were purchased from
standard sources and purified using literature procedures.
General Procedure
All of the experiments were carried out in a Discover microwave synthesizer
from CEM Corporation. Primary amino compounds 1–21 (200 mg) were
added to acetic acid (2 mL) or benzoic acid (800 mg) under microwave
irradiation (200 W, 150 8C) for 6–8 min. The reaction mixture was poured
into a mixture of acetic ether and cyclohexane (1:50), then stored for some
time in a refrigerator. The white crystals or the oil that separated were
washed free of acid with water and then allowed to dry. The results for the
preparation of a series of amides of substrates possessing a variety of poten-
tially labile groups and their melting points are shown in Table 1 (1–21).
Primary amino compounds 22–26 (200 mg) were treated with acetic acid
(2 mL) at 200 W, 150 8C, in the microwave machine for 10–12 min. The
product was separated by column chromatography. The results for the prep-
1
aration of a series of amides are in Table 1. The MS data and H NMR data
of some representative compounds and new compounds are shown in Table 2.
RESULTS AND DISCUSSION
During the experimentation, some L-amino acids, such as L-phenylalanine
(23), L-leucine (24), and L-valine (25), were used as substrates to react with
acetic acid in the same conditions; they all produced the corresponding
N-acylation products. Unfortunately, these L-amino acids were converted to
a racemic mixture of dl N-acetated enantiomers after the reaction (23,
24, and 25). It is presumed that there is a tautomerization between the car-
boxylic acid group and the H atom in the a-carbon of L-amino acid and a dehy-
drated intermediate forming from this tautomerized isomer (Scheme 2). When
this acylation reaction was used for another chiral amino-alcohol compound
(26), a chiral product with both N-Ac and O-Ac was obtained. The result

Microwave-Assisted Synthesis of Amide
1033
Table 2. Molecule weight and 1H NMR data of some representative compounds and
new compounds
Molecule
weight
Compound
1H NMR data (d)
2a
193.2
N-[2-(3-Methoxyphenyl) ethyl]acetamide
d ¼ 1.96 (3H, s, -COCH3) 2.81 (2H, t, J ¼ 6.9, -CH2-
CH2NH-), 3.53 (2H, dd, J ¼ 6.9, -CH2CH2NH-), 5.56
(1H, s, -CH2CH2NH-), 6.75–6.80 (3H, dt,-ArH), 7.25
(1H, m,-ArH).
4
193.2
207.2
187
[4-(Acetylamino)phenyl]acetic acid
d ¼ 2.04 (3H, s, -COCH3), 3.56 (2H, s,-CH2COOH),
7.13 (2H, dd, J ¼ 8.4, J ¼ 8.5, 2 meta H), 7.27 (2H, d,
J ¼ 8.4, 2 ortho H), 7.48 (1H, d, J ¼ 8.5, -NH-), 9.86
(1H, s, -COOH).
23
24
N-Acylation of L-phenylalanine
d ¼ 2.03 (3H, s, -COCH3), 3.20 (2H, m, J ¼ 14,
-CHCH2Ar), 4.92 (1H, dd, J ¼ 14, J ¼ 7.2, -CH2CH-
), 5.92 (1H, d ¼ 7.2, -NH-), 7.21–7.35 (5H, m,
-ArH).
N-Acylation of L-leucine
d ¼ 0.88 [6H, d, J ¼ 14, -CH(CH3)2], 1.48 (2H, dd,
J ¼ 6.3,-CHCH2CH-), 1.61 [1H, m, J ¼ 6.3, -CH
(CH3)2], 1.83 (1H, s, -COCH3), 4.19 (1H, dd, J ¼ 14,
-CH2CHNH-), 8.05 (1H, d, J ¼ 1.83, -NH-), 12.3
(1H, s,-COOH).
25
26
159.2
221.3
N-Acylation of L-valine
d ¼ 0.99 [6H, d, J ¼ 6.9, -CH(CH3)2], 2.06 (3H, s,
-COCH3), 2.25 [1H, m, J ¼ 6.9, J ¼ 8.5, -CH
(CH3)2], 4.56 (1H, J ¼ 8.5, J ¼ 3.5, -CHNH-), 5.90
(1H, d, J ¼ 3.5-NH-).
(2S)-2-(Acetylamino)-2-phenylethyl acetate
d ¼ 2.02 (3H, s, -OCOCH3), 2.05 (3H, s, -NHCOCH3),
4.23–4.47 (2H, dd, J ¼ 13, -CH2OCOCH3), 5.30
(1H, dt, J ¼ 13, -ArCHCH2-), 6.02 (1H, s, -NH-),
7.25–7.38 (5H, m, -Ar).
showed that there was no selectivity between OH and NH2 groups under this
condition.
When aniline was used as a substrate, a different type of substituted group
on the phenyl ring would influence the yield. If the aniline contained an
electron-withdrawing group on the phenyl ring, such as chloro-, nitro-, or tri-
fluoromethyl group or heterocyclic amine (15–20), the yields of N-acetylation
reached only 33–48%. These groups in the para-position obtained higher
yields than in the othro-position because of the “othro effect,” whereas the
othro-nitro substituted aniline cannot produce the corresponding N-acylation

1034
X.-J. Wang et al.
Scheme 2.
product because of the strong deactivation effect, as did 4,6-dichloro-2-
methylptrimidin-5-amine (21) with an intentsive electron-withdrawing
effect because of the two choro-substitution in othro-position. In contrast,
the anilines with an electron-donating group on the phenyl ring (methyl,
methoxyl group) will obtain a high yield (67–98%) except for 3,5-
dimethyl-substituted aniline (7–14). The substrate with a carboxylic acid or
an ester group on the phenyl ring could also obtain ideal yields (4, 5, and 6).
In conclusion, we have developed a simple, convenient, and efficient
synthetic method for amides using primary amine and acetic acid or
benzoic acid that would be an ideal method for the selective N-terminal pro-
tection or N-acylation of compounds. The new method is easy to handle,
catalyst-free, and environmentally friendly.
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