Microwave-assisted esterification of diverse carboxylic acids and chiral amino acids

Article abstract of DOI:10.1080/00397910802279845

A facile and efficient synthetic method of esters from their corresponding carboxylic acids and amino acids is described. The esterification reaction of carboxylic acids and amino acids could be greatly accelerated under microwave irradiation because the reactions described in this article took place in only 5 min with almost quantitative yields, and distinct acidity of catalytic acids was well tolerated. Unlike the racemation problem in microwave-assisted N-acylation reactions, the esters of chiral amino acids could be achieved with retention of configuration under this condition. Copyright Taylor & Francis Group, LLC.

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Microwave-Assisted
Esterification of Diverse
Carboxylic Acids and Chiral
Amino Acids
a
a
a b
Qian Yang , Xiao-jian Wang , Zhi-yu Li
, Li Sun
a
a
&
Qi-dong You
a
Department of Medicinal Chemistry , China
Pharmaceutical University , Nanjing, China
b
Experimental Teaching Center for Pharmacy, China
Pharmaceutical University , Nanjing, China
Published online: 31 Oct 2008.
To cite this article: Qian Yang , Xiao-jian Wang , Zhi-yu Li , Li Sun & Qi-dong You
(2008) Microwave-Assisted Esterification of Diverse Carboxylic Acids and Chiral Amino
Acids, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 38:23, 4107-4115, DOI: 10.1080/00397910802279845
To link to this article: http://dx.doi.org/10.1080/00397910802279845
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1
Synthetic Communications , 38: 4107–4115, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802279845
Microwave-Assisted Esterification of Diverse
Carboxylic Acids and Chiral Amino Acids
1
Qian Yang, Xiao-jian Wang, Zhi-yu Li, Li Sun,
1
1,2
1
1
and Qi-dong You
Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing, China
1
2
Experimental Teaching Center for Pharmacy, China Pharmaceutical
University, Nanjing, China
Abstract: A facile and efficient synthetic method of esters from their correspond-
ing carboxylic acids and amino acids is described. The esterification reaction of
carboxylic acids and amino acids could be greatly accelerated under microwave
irradiation because the reactions described in this article took place in only
5
min with almost quantitative yields, and distinct acidity of catalytic acids was
well tolerated. Unlike the racemation problem in microwave-assisted N-acylation
reactions, the esters of chiral amino acids could be achieved with retention of con-
figuration under this condition.
Keywords: Chiral amino acids, esterification, microwave-assisted, retention of
configuration
INTRODUCTION
The esterification reaction has attracted much attention because of its
extensive applications in the chemical and pharmaceutical industry.
The ester bond is a typical prodrug pattern aimed at reducing the toxi-
city and adverse stimulation of active drugs, for example, flufenamic
Received February 17, 2008.
Address correspondence to Qi-dong You, Department of Medicinal Chemis-
try, China Pharmaceutical University, Nanjing, China. E-mail: youqidong@
gmail.com
4
107

4108
Q. Yang et al.
[1,2]
acid and ibuprofen.
Until now different synthetic methods of ester
bond have been extensively developed; the traditional synthesis method
of esters is carried out by alcohol with carboxylic acids, anhydrides, or
acyl halides. However, the reaction is not environmentally friendly
[
3]
[4]
because Lewis acids,
[
silica chloride
should be added to the reaction system to enhance the electro-
and other synthetic cata-
5–9]
lysts
philicity of the carbonyl group, and it usually takes long time for the
reaction.
In the past decade, the microwave-enhanced organic chemistry
[
10,11]
had made dramatically changes in the synthetic chemistry,
retically all thermally driven chemical reactions can be accelerated
under microwave irradiation.
theo-
[
12,13]
The monomode microwave units
have offered many advantages such as greatly shortening reaction
time and increasing yields for small-scale reactions by using sealed
[
14,15]
glass tubes.
N-acylation reactions of various aniline and amino acids under micro-
Recently our research groups have reported a facile
[
16]
wave irradiation.
In this reaction, acetic acid was used as both acy-
lation agent and solvent; the reaction could complete within 10 min
with high yields. However, the defect of this microwave-accelerated
reaction is that the L-amino acids were all converted to a racemic
mixture of N-acetated enantiomers after 10 min of microwave irradia-
tion. Beside this disadvantage, an interesting phenomenon was
observed: when this acylation method was applied to chiral amino-
alcohol compound, a chiral product with both N-acylation and
O-acylation was obtained. The result showed that there is no selectiv-
ity between the OH and NH group in the acylation reaction under
2
microwave irradiation.
Prompted by this interesting result, we began to explore the ester-
ification reaction of diverse carboxylic acids. Previous investigations
of microwave-assisted synthesis of benzoate were carried out on a stir-
[
17,18]
red tank reactor
microwave apparatus with the prompt removal of water produced dur-
ing the reaction.
and recently been reported on the multimode
[
19]
In our studies, the widely used monomode micro-
wave vessel was applied; as a start point, the reaction time of benzoic
acid and methanol was optimized because we found that the conversion
rate of the reaction was retained at 96% after 5 min under this reaction
condition. The catalytic efficiency was compared: the conversion rate of
this reaction was slightly influenced by the acidity of catalytic acids.
Thereafter, by using 4% equivalent of sulfuric acid as the catalytic acids,
we extended this synthetic methodology to diverse substituted benzoic
acids and alcohols to investigate the electric factor of this reaction
(Table 1); different types of carboxylic acids were also applied for the
investigation (Table 2).

Microwave-Assisted Esterification
4109
Table 1. Esterification of substituted benzoic acids under microwave irradiation
Conver- Measured
bp=mp
Literature
bp=mp
Catalytic sion rate
acid (%)
EI-MS
þ
1
2
ꢀ
ꢀ
Entry
R
R
( C)
( C)
([M] )
1
2
3
4
5
6
H
H
H
H
H
H
CH
CH3 CH SO H 91
3
H
2
SO
4
96 84 (20 mm)
84 (19 mm)
85 (25 mm)
136
3
3
CH
CH CH
CH(CH3)2 H SO
3
p-TsOH
87
2
3
H
2
SO
4
4
4
90 104 (25 mm)
96 100 (20 mm)
95 130 (20 mm)
102 (23 mm)
102 (24 mm)
126–128
150
164
178
2
n-C
H
4 9
H
2
SO
(
20 mm)
110–115
16 mm)
7
2-Cl
CH
3
H
2
SO
4
93 120 (20 mm)
170
(
8
9
0
1
2
3
3-Cl
4-Cl
4-OH
3-OH
3-NO
5-Cl,
CH
CH
CH3
CH
CH
CH3
3
3
H
H
H SO
2
2
SO
SO
4
4
4
4
4
4
95 115 (20 mm)
99 mp: 41–42
114 (18 mm)
mp: 42–44
89 mp: 123–125 mp: 125–128
170
170
152
152
181
215
2
1
1
1
1
3
3
H
H
2
SO
SO
82 mp: 69–71
99 mp: 79–80
98 mp: 51–52
mp: 70–72
mp: 78–80
mp: 48–52
2
2
H SO
2
2-NO
2
RESULTS AND DISCUSSION
As shown in Table 1, distinct acidity of catalytic acids was well tolerated
in the esterification of benzoic acid and methanol (1–3) under microwave
condition, and different alcohols were able to utilize the reaction with
equal conversion rate (4–6). The benzoic acids with electron-donating
group on the phenyl ring would obtain lower yield than the electron-
withdrawing substituted ones (7–13). In Table 2, methyl esterifications
of different carboxylic acids were successfully reacted under the same
condition (14–18), and esters of heterocyclic acid were also obtained with
high yields (19–20). The result showed that the process of esterification
reaction could be greatly accelerated a reasonable combination of micro-
wave power, compress, and heat energy.
Prompted by these results, we investigated the case of microwave-
assisted esterification of racemic piperidine-2-carboxylic acids. The reaction

4
110

4
111

4
112
Q. Yang et al.
took place in 5 min, and the target ester hydrochloride was obtained
with 83% yields. Then the same methodology was applied to chiral amino
acids. It is exciting that, unlike the defect of racemation in microwave-
assisted N-acylation reactions, the ester products were obtained
with retention of configuration because the melting point and optical
[
20]
rotation of each ester were in accordance with the literature
Table 3). Compared with the traditional synthetic method of chiral
(
amino acid esters, the microwave-promoted method could avoid the
release of contaminative HCl gas and reduce the reaction time with a
greatly simplified operation. It could be concluded that amino acids
and their esters could maintain the optical rotations under the combina-
tion of microwave power, compress, and high temperature in acidic
circumstances.
In conclusion, esterification reaction of carboxylic acids could be effi-
ciently achieved in a monomode microwave vessel. The combination of
microwave, compress, and heat energies could promote the equilibrium
reaction to produce the ester product with small amounts of simple cat-
alytic acids. It is significant that this methodology can be applied to the
synthesis of chiral amino acid esters, which could be of great benefit in
biological chemistry and combinatorial chemistry.
EXPERIMENTAL
Melting points (mp) were determined with a XT-4 melting-point appara-
tus. Mass spectroscopes (EI) were obtained on a Shimadzu GCMS-
QP2010. Optical rotations were measured on a Perkin-Elmer model
2
41 polarimeter in a glass microcell (100-mm path length, 1-mL volume)
with a Na gas discharge lamp as the light source. The solvents used in the
detection of optical rotation are in accordance with the literature.
Reagents, solvents and starting materials were purchased from standard
sources and purified to literature procedures. All of the experiments were
carried out in the Discover microwave synthesizer of CEM Corporation.
General Procedure for the Synthesis of Esters
To a solution of different carboxylic acids (200 mg) and alcohols (1 ml),
4
5
% equivalent of catalytic acids was added. The reactions took place in
ꢀ
min under microwave irradiation (70 W, 100 psi, 100 C) in the Discover
microwave synthesizer manufactured by CEM Corporation. In Tables 1
and 2, the esters were separated and characterized by high performance
liquid chromatography (HPLC) and mass spectroscopy. The conversion

4
113

4114
Q. Yang et al.
rate was calculated according to the peak area data of the reactant and
product. In Table 3, the reaction mixture was poured into water and then
basified by sodium bicarbonate. The ester was extracted by CH Cl and
2
2
dried. The CH Cl was evaporated, and a small amount of HCl-saturated
2
2
methanol was added to form ester hydrochloride. Then methanol was
evaporated to obtain the ester hydrochloride solid.
ACKNOWLEDGMENTS
This research was supported by the National ‘‘863’’ Program (Grant No.
2007AA02Z307) and the Innovation Program for the Postgraduates in
Jiangsu Province.
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