Microwave oven synthesis of esters promoted by imidazole

Article abstract of DOI:10.1016/S0040-4039(03)00104-7

Using imidazole as promotion agent, primary, secondary and phenolic alcohol compounds were esterified with aliphatic and aromatic carboxylic acid anhydrides. Heating a ternary mixture of alcohol, anhydride and imidazole in an unmodified microwave oven produced esters in low to high yields, depending on the steric bulk of the alcohol.

Full text of DOI:10.1016/S0040-4039(03)00104-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1831–1833
Microwave oven synthesis of esters promoted by imidazole
Takuji Hirose,† Benjamin G. Kopek,‡ Zhao-Hui Wang,† Ritsuko Yusa† and Bruce W. Baldwin*
Department of Chemistry, Spring Arbor University, Spring Arbor, MI 49283 USA
Received 22 November 2002; revised 9 January 2003; accepted 10 January 2003
Abstract—Using imidazole as promotion agent, primary, secondary and phenolic alcohol compounds were esterified with aliphatic
and aromatic carboxylic acid anhydrides. Heating a ternary mixture of alcohol, anhydride and imidazole in an unmodified
microwave oven produced esters in low to high yields, depending on the steric bulk of the alcohol. © 2003 Elsevier Science Ltd.
All rights reserved.
Esterification between alcohol and acid is a most
important organic reaction and a large number of
reactions have been developed. In these days, catalyzed
esterification is a currently active area of research.
Among them, the stoichiometric reactions between
alcohol and acid reported by Yamamoto1 et al. and
Tanabe2 et al. are superior especially from atom eco-
nomical viewpoint. On the other hand, microwave acti-
vation of a large number of organic synthetic3 and
metal catalyzed4 reactions have recently appeared,
attracting attention due time economy. Lidstro¨m et al.,
conveniently reviewed microwave assisted experiments
reported between 1994 and 2000.5 Although these
reports include a number of esterification reactions, the
scope of the individual reactions is rather narrow. This
report further expands the microwave oven assisted
synthesis of esters,6 preparing them from a wide range
of alcohol and carboxylic acid residues using imidazole
carboxylic acids and are therefore less toxic and less
persistent than either acid chlorides or silica gel sup-
port. The promotion agent used here, imidazole, is also
lower in toxicity than some esterification catalysts like
4-dimethylaminopyridine (DMAP). This lowers the risk
to the individual experimentalist and reduces the toxic-
ity of the waste stream from these experiments. The
side-products of this reaction method are relatively
benign, imidazole and a carboxylic acid. In contrast to
esterification with carboxylic acid chlorides, which pro-
duce HCl and SO2 in their preparation as well as HCl
in their use, anhydride/imidazole provides an attractive
alternative. This method allows a wide range of alcohol
and carboxylic acid moieties to be incorporated into the
industrially important chemical class of esters.
Another area requiring new experiments easily carried
out in undergraduate laboratories is chemical educa-
tion.10 Using environmentally friendly reagents protects
the students and reduces the amount of waste gener-
ated. Undergraduate students easily carry out the
microwave oven esterification technique reported
here.11
as promotion agent,
a proven microwave oven
amidation7 and imidation8 agent.
The reagents used have relatively low toxicity and are
environmentally friendly. Although there are
microwave oven esterification reports that use car-
boxylic acid and alcohol, silica gel, a persistent waste
material, is necessary as a solid support.9 Carboxylic
acid anhydrides are less reactive than the widely used
carboxylic acid chlorides and easily break down into
Using a ternary mixture of alcohol, anhydride and
imidazole, a wide range of compounds were conve-
niently and efficiently esterified (Scheme 1). The ternary
mixture was simply measured into a test tube and
irradiated in the microwave oven at full power for three
* Corresponding author: Fax: 517-750-2108; e-mail: bbaldwin@
arbor.edu
† Cooperating research center: Department of Applied Chemistry,
Faculty of Engineering, Saitama University, 255 Shimo-ohkubo,
Saitama, 338-8570, Japan.
‡ Current address: Program in Cellular and Molecular Biology, Uni-
versity of Wisconsin-Madison, 1525 Linden Dr., Madison, WI
53706-1596, USA.
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00104-7

1832
T. Hirose et al. / Tetrahedron Letters 44 (2003) 1831–1833
minutes. The work-up was accomplished by washing
the diethyl ether diluted mixture successively with
aqueous Na2CO3, water, aqueous 2% citric acid and
water. Further purification was unnecessary as indi-
cated by FTIR and NMR (1H and 13C) spectra.
important in a wide range of applications. The propi-
onate of phenethyl alcohol 1 is a proven octopominer-
gic compound.12 Such compounds are useful in
developing more environmentally friendly insecticides.
The esters of chiral secondary alcohols 4 and 5 are very
useful for studying enzyme catalyzed kinetic
resolutions13 and as chiral building blocks. Simple and
efficient esterification methods are needed to facilitate
this area of study, important in pharmaceutical
chemistry.
A wide range of alcohol functional groups were
esterified (Fig. 1). Primary, secondary and phenolic
groups were esterified in good to excellent yield (Table
1). The compounds chosen for these experiments are
At least eleven synthetically significant carboxylic acid
esters were made under conservative conditions as
defined by an equimolar ternary mixture of alcohol,
anhydride and imidazole (Table 1). This finding
appears to be in opposition to reports of excellent yield
of phenolic esters without catalyst by Kwon et al.14 We
found the use of imidazole was essential to obtain
significant yields of any ester. When benzoic anhydride
was used, a less reactive anhydride, only phenol and
phenethyl alcohol yielded significant esterification
product under these conditions.
Although some of the esterifications worked well with
stoichiometric amounts of reagents, significant yield
enhancement was observed when using alco-
hol:anhydride:imidazole molar ratios of 1:3:1 (Table 2).
Part of these enhanced results were due to imidazole
promotion (Table 2, entries 1 and 2). Using three
equivalents of anhydride allowed synthetically useful
yields for most of the acetylations. Acetate esters are
very useful intermediates. This result compares favor-
ably with the microwave oven acetylation of sugars
described by Limousin et al.15 While increasing the
anhydride ratio we also observed the lack of influence
on reaction yield of microwave oven wattage (Table 2).
Table 2. Esterification using alcohol:anhydride:imidazole
molar ratio of 1:3:1
Entry
Alcohol
Anhydrides yield
(%)
Ac
Pr
1
Phenethyl
Phenethyl
p-Methoxybenzyl
p-Methylbenzyl
sec-Phenethyl
N-(2-Hydroxypropyl)benzamide
(+)-N-(2-Hydroxypropyl)-
benzamide
86a
29
87
83a
73
63
–
92
44
74
74a
84
89
90
2b
3c
4
Figure 1. Alcohol compounds used in this study.
Table 1. Alcohol esterification using carboxylic anhydrides
5
with imidazole promoter under economical conditionsa
6
7d
Entry
Alcohol
Anhydrides yield (%)
8
9
Phenol
74
–
–
66
84
48
0
Ac
Pr
Bz
Methyl 4-hydroxybenzoate
4-Hydroxybenzaldehyde
2-(4%-Methoxyphenyl)-2-hexanol
10
1
2
3
4
5
6
Phenethyl
p-Methoxybenzyl
sec-Phenethyl
N-(2-Hydroxypropyl)benzamide
Phenol
Methyl 4-hydroxybenzoate
65
25
58
5
12
–
86
45
79
43
52
6
72
0
1
2
87
–
11e
0
Irradiation was for three minutes at full power (500 watts).
a Full power was 1,000 watts for these experiments.
b There was no imidazole promoter in these reactions.
c These were irradiated for only two minutes at full power.
d No racemization was observed in esterification or subsequent
hydrolysis. Acetylation was assumed to be similar.
Irradiation was for three minutes at full power (500 watts).
a Alcohol:anhydride:imidazole molar ratios were 1:1:1.
e Approximately 20% olefin and 40% recovered alcohol.

T. Hirose et al. / Tetrahedron Letters 44 (2003) 1831–1833
Table 3. Phenethyl alcohol esterification using propionic
1833
Acknowledgements
anhydride with various promoters under identical condi-
tions with Table 2
This work was supported by Spring Arbor University
(USA) and Saitama University (Japan).
Entry
Promoter
Yield (%)
1
2
3
4
Imidazole
92
95
88
2
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The simple and quick microwave oven method
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lic alcohol compounds to be esterified with a useful
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