Synthetic Communications1, 44: 23862392, 2014

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.875210

EFFICIENT MICROWAVE-ASSISTED ESTERIFICATION

REACTION EMPLOYING METHANESULFONIC ACID
SUPPORTED ON ALUMINA AS CATALYST

Lucas Fabian,1 Matas Gomez,1 Juan A. Caturelli Kuran,1

Graciela Moltrasio,2 and Albertina Moglioni1
1
Departamento de Farmacologa, Facultad de Farmacia y Bioqumica,
Universidad de Buenos Aires, Buenos Aires, Argentina
2
Departamento de Qumica Organica, Facultad de Farmacia y Bioqumica,
Universidad de Buenos Aires, Buenos Aires, Argentina

GRAPHICAL ABSTRACT

Abstract A rapid and efcient protocol assisted by microwave irradiation for the synthesis
of esters using methanesulfonic acid (CH3SO3H) supported on Al2O3 (AMA) as catalyst
and free of solvent is described. The products were obtained in good yields and purity, with
reduced reaction time, and the process is simple and environmentally benign.

Keywords AMA catalyst; microwave irradiation; solvent-free; synthesis of esters

INTRODUCTION
Esterication between an alcohol and an acid, catalyzed by mineral acids, is a
very important reaction in organic synthesis and a large number of experimental
conditions have been developed for this reaction. Stoichiometric reactions between
an alcohol and an acid reported by Ishihara et al.[1] and Wakasugi et al.[2] are among
the best, especially from the atom-economy viewpoint.
In the past few years, chemistry using microwave-assisted protocols has been
under intense study with signicant benets in the area of organic synthesis.[3]
There has been growing interest in microwave-assisted reactions since 1986,
when pioneering investigations were performed.[4] Microwave activation of a large
number of organic synthetic- and metal-catalyzed reactions[5] have appeared in the

Received October 31, 2013.

Address correspondence to Albertina Moglioni, Departamento de Farmacologa, Facultad de
Farmacia y Bioqumica, Universidad de Buenos Aires, Junn 956, Buenos Aires, C1113AAD,
Argentina. E-mail: [email protected]

2386
 AMA-CATALYZED MICROWAVE-ASSISTED ESTERIFICATION 2387

past decade, attracting attention because of short reaction times. Lidstrom et al.[6]
and Bodgal and Loupy[7] reviewed microwave-assisted experiments reported between
1994 and 2007. Although these reports include a number of esterication reactions,
the scope of the individual reactions is rather narrow. Simple and efcient esteri-
cation methods are needed in pharmaceutical chemistry and organic synthesis.
Recently several authors described examples of microwave-assisted syntheses
employing supported reagents with excellent results.[8]
The synthesis of esters from carboxylic acids and alcohols using
CH3SO3H-supported Al2O3 (AMA) as catalyst under classical reaction conditions
is well documented, especially for the selective synthesis of monoesters obtained
from diols.[9] Our experience showed that this synthesis involves very large quantities
of AMA (15 mmol of CH3SO3H=3 mmol of Al2O3=1 mmol of carboxylic acid), mak-
ing it difcult to separate the catalyst from the reaction product.
Herein we report our results on the use of AMA as an inorganic acid catalyst in
microwave-induced esterication reactions. With these conditions we were able to
reduce the proportion of AMA=carboxylic acid (1=1.6 mol) and get cleaner
reactions, with good yields and reduced reaction times.

RESULTS AND DISCUSSION

Using a ternary mixture of alcohol (methanol, ethanol, n- and isopropanol),
aromatic and aliphatic carboxylic acid and AMA, previously prepared from
CH3SO3H (2 mol) and Al2O3 (3 mol) (called by us AMA 2:3), a wide range of acids
were conveniently and efciently converted into esters (Table 1). The ternary mixture
was simply loaded into a sealed reaction vessel equipped with magnetic stirring and
irradiated in an Anton Paar MW 300 microwave oven at 80
C for 8 min or at 120
C
for 20 min. These protocols were selected after several experiments at different tem-
peratures and=or times of reaction. The compounds chosen for these experiments
(see Table 1) are important in a wide range of applications.
Given the good results obtained in the preparation of these derivatives from
several carboxylic acids with very different reactivities, extension of the developed
methodology to the synthesis of some a-amino acid esters was assayed.
Amino acid esters are important intermediates in organic synthesis because
they have been used in various areas such as peptide synthesis [17] and medicinal
chemistry[18,19] and as chiral sources[2023] and polymer materials.[24,25] A variety of
reagents have been reported for the transformation of amino acids into amino acid
esters, which include protic acids[26,27] (gaseous hydrochloric acid, sulfuric acid, and
p-toluenesulfonic acid), thionyl chloride,[28] and ion-exchange resins.[29] There are
other methods that require multistep reactions to obtain the products, such as the
sequence of N-protection, esterication, and deprotection.[19] Although some of
them are widely used, they still have several disadvantages, including tedious workup
procedures, safety, waste disposal problems, and harsh reaction conditions.
The use of AMA 2:3 employing microwave irradiation as an energy source
showed the applicability of this methodology for the preparation of methyl, ethyl,
n- and isopropyl esters of some a-amino acids with excellent yields (6995%) at
120
C and short reaction times (20 min) (Table 2). Some of these compounds were
isolated as base and others as the ammonium cations.
2388 L. FABIAN ET AL.

Table 1. Esters prepared from aromatic and aliphatic carboxylic acids

Methanol Ethanol n-Propanol Isopropanol

Time Yield Time Yield Time Yield Time Yield

Entry Acid (min) (%) (min) (%) (min) (%) (min) (%)

1 Salicylic 20 96a 20 96a 20 96b 20 90[10]

2 Palmitic 20 97b 20 97b 20 97[11],c 20 97a
3 Stearic 20 97b 20 97b 20 97[11] 20 97[12],c
4 Decanoic 20 97b 20 97b 20 97b 20 97b
5 Cyclohexylacetic 8 98a 8 98a 8 98 8 98[13]
6 3,5-Dinitrobenzoic 8 89a 8 88[14] 8 88[14] 8 88[14]
7 3,4-Dimethoxyphenylacetic 20 88c 20 90[15] 20 90 20 90[16]
8 Benzoic 8 98a 8 98a 8 98a 8 98[10]
9 Phenylacetic 8 97a 8 97a 8 97a 8 97[13]
10 Succinicd 8 97b 8 97a 8 97c 8 97b

Note. Yields correspond to isolated yield. All compounds were fully characterized by 1H and 13CNMR
spectra.
a
NMR spectra are in accordance with those reported in NMR Catalogues: Poucher and Campbell,
Aldrich Library of NMR Spectra Aldrich NMR Library, and Aldrich Spectral Viewer v 1.1.10.
b
NMR spectra are in accordance with those reported in the Spectral Database for Organic Compounds,
SDBS, by National Institute of Advanced Industrial Science and Technology (AIST), Japan.
c
WSS, spectral data were obtained from Wiley Subscription Services, Inc. (US).
d
Diester derivatives.

Table 2. Esters prepared from a-amino acids

Methanol Ethanol n-Propanol Isopropanol

Amino isolated isolated isolated isolated
Entry acid yield (%) yield (%) yield (%) yield (%)

11 Phenylalanine 90 88 92[30] 72[31]

12 Valine 93 92 88 69
13 Glutamic acida 88 86 70 90[32]
14 Alanine 93 95 88 74

Note. All compounds were fully characterized by 1H and 13

CNMR spectra.
a
Diester derivatives.
 AMA-CATALYZED MICROWAVE-ASSISTED ESTERIFICATION 2389

Scheme 1. Esters prepared from homochiral ketoacids and percentage of isomers by 1HNMR.

This methodology also was assayed in the ester synthesis of homochiral

ketoacids. In this case, the traditional esterication methods, using protic acids, favor
the isomerization of the chiral center bearing the keto group. Therefore, the use of
diazomethane is almost the only suitable method. In this context pinononic and
pinonic acid methyl esters, obtained from ()-verbenone and ()-apinene, were
synthesized by this new methodology (Scheme 1).[33] These esters were obtained in
good yields after irradiation at 70
C for 20 min, but this could not prevent a certain
percentage of isomerisation in both cases (29% for the pinononic acid and 25% for
the pinonic acid).
In summary, a simple and quick method was described for the esterication of a
wide range of carboxylic acids and amino acids with several primary and secondary
alcohols, using AMA 2:3 as heterogeneous catalyst and microwave irradiation. Our
method has several advantages such as simple procedure and very good yields; because
the products are obtained with high purity further purication of the nal products is
not necessary. This method would be of use in research, education, and industry.

EXPERIMENTAL
Reactions were performed on an Anton Parr Monowave 300 reactor and the
reaction mixture temperature was monitored by an infrared (IR) sensor. Elemental
analysis was done for all the new compounds on a PerkinElmer C, H, N,
S-Analyzer 2400. All the isolated compounds were characterized by 1H NMR and
13
C NMR. NMR spectra were recorded on Bruker Advance 500 or Bruker AC
300 spectrometers in deuterated solvents.

Preparation of Methanesulfonic Acid Supported on Al2O3 (AMA)

AMA 2:3 was prepared mixing Al2O3 (3 mol), previously activated in an oven
at 150
C for 72 h, with CH3SO3H (2 mol) in a mortar until homogeneity.

Representative Procedure for Preparation of Aromatic and Aliphatic

Esters (Table 1)
In a typical reaction, AMA 2:3 (332 g, 0.6 mol), the corresponding carboxylic
acid (1 mol), and alcohol (1.52 mol) were mixed in the provided reaction glass tube
equipped with a screw cap and magnetic agitation until a wet mixture was achieved.
The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300
reactor) at 80
C for 8 min or 120
C for 20 min. On cooling, the mixture was diluted
2390 L. FABIAN ET AL.

with dichloromethane (41 mL), ltered under gravity, and washed with dichloro-
methane; then the ltrate was washed with Na2CO3 (ss) and water. The organic layer
was dried over Na2SO4, ltered, and concentrated under reduced pressure to give the
ester.

Propyl cyclohexylacetate (5c). Yellow oil; 1H NMR (500 MHz, CDCl3): d

0.94 (m, 5H), 1.15 (m, 1H), 1.28 (m, 2H), 1.64 (m, 3H), 1.71 (m, 4H), 1.78 (m,
1H), 2.18 (d, J 7.1 Hz, 2 H), 4.02 (t, J 6.8 Hz, 3 H); 13C NMR (125 MHz, CDCl3):
d 10.4, 22.0, 26.0, 26.1, 33.0, 34.9, 42.2, 65.7, 173.2. Anal. calcd. for C11H20O2: C,
71.70; H, 10.94. Found: C, 71.69; H, 10.99.

Propyl 3,4-dimethoxyphenylacetate (7c). Yellow oil; 1H NMR (300 MHz,

CDCl3): d 0.75 (t, J 7.4 Hz, 3 H), 1.46 (m, 2 H), 3.39 (s, 2 H), 3,66 (s, 3H), 3,69 (s,
3H), 3,88 (t, J 7.0 Hz, 2 H), 6.66 (d, J 10.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 10.4, 22.0, 40.9, 55.7, 55.8, 66.3, 111.3, 112.5, 121.4, 126.8, 148.2, 149.0, 171.8.
Anal. calcd. for C13H18O4: C, 65.53; H, 7.61. Found: C, 65.40; H, 7.80.

Representative Procedure for Preparation of a-Amino Acids Esters

(Table 2)
In a typical reaction, AMA 2:3 (498 g, 1 mol), the corresponding aminoacid
(1 mol) and alcohol (1.52 mol) were mixed in the provided reaction glass tube
equipped with a screw cap and magnetic agitation until a wet mixture was achieved.
The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300
reactor) at 120
C for 20 min. On cooling, the mixture was diluted with chloroform
(41 mL), ltered with glass frit over celite under vacuum, and washed with chloro-
form; then the ltrate was washed with Na2CO3 (ss) and water. The organic layer
was dried over Na2SO4, ltered, and concentrated under reduced pressure to give
the ester.

L-valine propylester methanesulfonate (12c). Yellow oil; 1H NMR

(500 MHz, CDCl3): d 0.97 (t, 3H), 1.08 (d, 3H), 1.11 (d, 3H), 1.71 (m, 2H), 2.37
(m, 1H), 2.77 (s, 3H, CH3 SO3 ), 4.01 (ca, 1H), 4.16 (m, 2H), 7.757.91 (brs, 3H);
13
C NMR (125 MHz, CDCl3): d 10.3, 17.5, 18.3, 21.7, 29.3, 58.4, 67.7, 169.0. Anal.
calcd. for C9H21NO5S: C, 42.34; H, 8.29; N, 5.49. Found: C, 42.10; H, 8.40; N, 5.30.

L-valine isopropyl ester (12d). Yellow oil;1H NMR (500 MHz, CDCl3): d
0.88 (d, J 6.9 Hz, 3H), 0.96 (d, J 6.9 Hz, 3H), 1.24 (dd, J 6.4 Hz, J0 6.2 Hz,
6H), 2.00 (dd, J 6.9 Hz, J0 5.0 Hz, 1H), 3.22 (d, J 5.0 Hz, 1H), 5.00 (m, 1H);
13
C NMR (125 MHz, CDCl3): d 17.3, 22.1, 32.4, 60.2, 68.3, 175.3. Anal. calcd. for
C8H17NO2: C, 60.35; H, 10.76; N, 8.80. Found: C, 60.20; H, 10.90.; N, 8.71.

L-glutamic acid dipropyl ester (13c). Yellow oil; 1H NMR (300 MHz,
CDCl3):d 0.82 (m, 6H), 1.54 (m, 4H), 1.72 (m, 1H), 1.96 (m, 1H), 2.34 (t, J 7.7 Hz,
Hz, 2H), 3.33 (dd, J 5.1 Hz, J0 8.2 Hz, 1H), 3.94 (m, 4H); 13C NMR (75 MHz,
CDCl3): d 10.1, 21.7, 29.6, 30.3, 53.5, 65.8, 66.3, 172.9, 175.4. Anal. calcd. for
C11H21NO4: C, 57.12; H, 9.15; N, 6.06. Found: C, 56.96; H, 9.20; N, 6.03.
 AMA-CATALYZED MICROWAVE-ASSISTED ESTERIFICATION 2391

ACKNOWLEDGMENT
We thank SANICO S.A.I.&C. (Argentina) because it allocated the Anton Parr
Monowave 300 reactor to check the rst reactions developed in this study.

FUNDING
This work was supported by SECYT=University of Buenos Aires and
CONICET (Argentina). J.A.C.K. is grateful to CONICET for a research fellowship.

SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publishers website.

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