Large scale microwave-accelerated esterification of carboxylic acids with dimethyl carbonate

Article abstract of DOI:10.1016/S0040-4039(02)01116-4

An environmentally friendly process for the esterification of carboxylic acids with dimethyl carbonate can be accelerated by employing a combined strategy: using 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) as the catalyst (chemical means) and microwave as the energy source (physical means). This approach provides synthetic advantages, niches, and upscalability.

Full text of DOI:10.1016/S0040-4039(02)01116-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5607–5609
Large scale microwave-accelerated esterification of carboxylic
acids with dimethyl carbonate
Wen-Chung Shieh,* Steven Dell and Oljan Repicˇ
Chemical and Analytical Development, Novartis Institute for Biomedical Research, One Health Plaza, East Hanover, NJ 07936,
USA
Received 29 April 2002; accepted 11 June 2002
Abstract—An environmentally friendly process for the esterification of carboxylic acids with dimethyl carbonate can be
accelerated by employing a combined strategy: using 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) as the catalyst (chemical means)
and microwave as the energy source (physical means). This approach provides synthetic advantages, niches, and upscalability.
©
2002 Published by Elsevier Science Ltd.
5
The transformation of carboxylic acids into the corre-
sponding methyl esters is a popular and fundamental
process in organic synthesis and has been thoroughly
temperature (90°C) without the use of autoclaves
(175°C).
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1
documented in the literature. Protection of amino
In recent years, microwave-assisted transformations
have become popular in promoting organic reactions.
7
–13
acids as their methyl esters is also an important strategy
for peptide synthesis because of its simple deprotection
A microwave-induced esterification for acetic acid is
2
14
conditions. The reported procedures for the synthesis
reported by Kabza. However, most of these applica-
of methyl esters require the use of strong acids (e.g.
sulfuric acid, hydrochloric acid), toxic chemicals
tions utilize domestic microwave ovens that lack scale-
up capability. This constraint restricts the use of this
valuable technology for large-scale synthesis. We report
herein a microwave-accelerated esterification of car-
boxylic acids using a commercial continuous-flow reac-
tor that is capable of processing large quantities
(
(
methyl iodide or dimethyl sulfate) or unsafe reagents
diazomethane). Esterification of sterically-hindered
acids is also difficult, due to increased steric hindrance
in their transition states. Considering the impacts of
toxic and hazardous reagents on ecology and human
beings, as well as the need for a more efficient method
for the formation of sterically-hindered methyl esters,
exploration of alternative syntheses to overcome these
issues is a compelling task. Several advanced method-
ologies with improved process efficiency have been
introduced recently. However, the consequences of
toxic reagents and wastes are not properly addressed by
these new processes. Recently, we discovered that ester-
ification of carboxylic acids with dimethyl carbonate
15
(hundred grams) of substrates.
This microwave reactor has an in-line thermal sensor,
which is able to monitor the temperature profile of the
reaction mixture. The reactor also has an in-line pres-
sure control valve, which enables volatile DMC be
processed safely at temperatures above its boiling point
(90°C). In a typical procedure, a solution containing a
carboxylic acid (5 g), DBU (1 equiv.), DMC (50 mL)
3,4
and CH CN (50 mL) is circulated by a pump through
3
(
DMC), an environmentally friendly process that gener-
the microwave reactor pre-heated to 160°C at 20 bar by
microwave irradiation. Under these conditions, the
esterification rate can be accelerated from hours to
minutes, which represents a rate increase of approxi-
mately 80 folds (Table 1). Since quantitative conver-
sions are achieved in many cases, clean products can be
isolated after performing aqueous acid and base washes
and evaporating solvents.
ates methanol and CO as by-products, can be pro-
moted by DBU under mild conditions. We found that
2
5
DBU functions as a nucleophilic catalyst and reacts
with DMC to form a more activated alkylating reagent,
which enables the esterification to proceed at a lower
Keywords: microwave-accelerated reaction; DBU; nucleophilic cata-
lyst; methylation; dimethyl carbonate; phase-transfer reagent.
Employing the microwave protocol, benzoic acid was
converted to its methyl ester in 12 min. For substituted
*
Corresponding author. E-mail: wen.shieh@pharma.novartis.com
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01116-4

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W.-C. Shieh et al. / Tetrahedron Letters 43 (2002) 5607–5609
Table 1. Esterification of carboxylic acids with DMC and DBU
benzoic acids, such as sterically-hindered 2,6-dimethoxy
and unactivated 2,6-dichlorobenzoic acid, transforma-
tion into the esters was achieved in 12 and 24 min,
respectively (entries 2 and 3). A clean regioselectivity
was observed for the preparation of methyl ester of
phenylacetic acid (entry 5). Although ester 5 contains
an activated methylene carbon, no a-methylated
product 4 was generated under the microwave condi-
lated ester 6. The microwave protocol (160°C, 20 bar)
was also applied to the synthesis of an epimerization-
sensitive amino ester, N-a-Cbz-N-methylphenylalanine
methyl ester (7), and afforded the product in 12 min
(97% yield, 58% ee) (entry 7). In comparison, when
thermal conditions (90°C, 16 h) were utilized, a nearly
total epimerization (2% ee) was observed for the iso-
lated ester 7. These results suggest that ester 7 is
1
6
tions. For a Boc-protected amino acid, the esterifica-
epimerization-sensitive in the presence of DBU (pK =
a
17
tion yield was excellent (entry 6). The isolated
12). The degree of epimerization presumably depends
more on reaction time than on reaction temperature.
Indeed, by increasing the reaction temperature to 190°C
by microwave irradiation in the presence of a phase
transfer catalyst, tetrabutylammonium iodide (TBAI),
synthesis of 7 can be accomplished in 2 min (99%) with
N-a-t-Boc- -proline methyl ester (6) was essentially
L
epimerization-free as determined by a chiral HPLC
analysis. In comparison, when the thermal protocol
(
90°C, 16 h) was employed for the same esterification,
5
partial epimerization (3.5%) was detected in the iso-

W.-C. Shieh et al. / Tetrahedron Letters 43 (2002) 5607–5609
5609
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higher optical purity (70% ee). To expand the syn-
thetic utility, an acid-sensitive carbohydrate ester 8 was
prepared in excellent yield (95%) under microwave con-
ditions (entry 8). Esterification of 2,3:4,6-di-O-iso-
1989; Chapter 9.
2. Greenstein, J. P.; Winitz, M. Chemistry of the Amino
Acids; Krieger Publishing Company: Malabar, 1984; Vol.
2, Chapter 10.
3. Chakraborti, A. K.; Basak (n e´ e Nandi), A.; Grover, V. J.
Org. Chem. 1999, 64, 8014.
propylidene-2-keto-
L
-gulonic acid (entry 8) and
N-a-t-Boc- -proline (entry 6) demonstrates another
niche for this methodology. These esters, containing
acid-sensitive functionalities, would not survive acid-
L
4. Bryson, T. A.; Dyke, C. A. Tetrahedron Lett. 2001, 42,
3
959.
. Shieh, W.; Dell, S.; Repic, O. J. Org. Chem. 2002, 67,
188.
1
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catalyzed esterification conditions.
5
2
Investigation of the reproducibility and scale-up feasi-
bility of the microwave protocol was also conducted.
To prove the concept, esterification of benzoic acid was
chosen because of its economic advantage. We found
that methyl benzoate could be synthesized at a 10 g
scale with consistent yield and time. Similarly, benzoic
acid at 50 and 100 g scales was regularly converted to
its methyl ester in 20 min (microwave residency time).
6
7
. Thompson, R. B. U.S. Patent 4,513,146, 1985.
. Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48,
1665.
8
9
. Caddick, S. Tetrahedron 1995, 51, 10403.
. Kingston, H. M.; Haswell, S. J. Microwave-Enhanced
Chemistry. Fundamentals, Sample Preparation, and Appli-
cations; American Chemical Society: Washington, DC,
1997; Chapter 8.
1
0. Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; Jayaraman,
M.; Manhas, M. S. Chemtech 1997, 27, 18.
1. Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Mathe, D. Synthesis 1998, 1213.
2. Varma, R. S. Green Chem. 1999, 43.
3. Krstenansky, J. L.; Cotterill, I. Curr. Opin. Drug Discov-
ery Dev. 2000, 3, 454.
In conclusion, the present microwave protocol provides
an efficient method for the esterification of the follow-
ing carboxylic acids: aromatic, sterically-hindered,
amino, and carbohydrate. The notable advantages of
this synthetic strategy are: (a) the use of a cheaper and
1
1
1
‘
green’ methylating reagent (DMC), (b) the efficiency
and applicability to sterically-hindered acids, (c) repro-
ducibility and upscalability, (d) feasibility for acid-sen-
sitive functionality, (e) compatibility with commonly
used amino acid protecting groups, such as Boc and
Cbz, (f) tolerance or minimization of epimerization, (g)
rapid reaction rates (in minutes), and (h) high yields.
1
1
1
4. Kabza, K. G.; Chapados, B. R.; Gestwicki, J. E.;
McGrath, J. L. J. Org. Chem. 2000, 65, 1210.
5. All our microwave operations were performed on a Mile-
stone ETHOS-CFR continuous-flow reactor.
6. For examples of a-methylation with DMC for activated
methylenes see: (a) Bomben, A.; Marques, C. A.; Selva,
M.; Tundo, P. Tetrahedron 1995, 51, 11573; (b) Tundo, P.
Pure Appl. Chem. 2000, 72, 1793; (c) Selva, M.; Marques,
C.; Tundo, P. J. Chem. Soc., Perkin Trans. 1 1994, 1323;
Acknowledgements
(
d) Tundo, P.; Trotta, F.; Moraglio, G. J. Chem. Soc.,
We thank Dr. Juergen Brokatzky and Dr. Thomas
Blacklock for their encouragement in pursuing this
study. We are grateful to Mr. Mauricio Loo for his
assistance in operating the continuous-flow microwave
reactor. We thank Ms. Noela Reel for her help in
developing a chiral HPLC method.
Perkin Trans. 1 1989, 1070.
1
1
7. Granitza, D.; Beyermann, M.; Wenschuh, H.; Haber, H.;
Carpino, L. A.; Truran, G. A.; Bienert, M. J. Chem. Soc.,
Chem. Commun. 1995, 2223.
8. For an example of using phase transfer catalyst to accel-
erate a homogeneous reaction under classical thermal
conditions see: Matsui, M.; Yamamoto, H. Bull. Chem.
Soc. Jpn. 1995, 68, 2663.
9. For an example of acid-catalyzed esterification see:
Nakao, R.; Oka, K.; Fukomoto, T. Bull. Chem. Soc. Jpn.
1981, 54, 1267.
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