TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9059–9060
A new reagent for the methylation of carboxyl groups
Bina S. Siddiqui,* Firdous and Sabira Begum
H.E.J. Research Institute of Chemistry, University of Karachi, Karachi 75270, Pakistan
Received 21 March 2001; revised 25 September 2001; accepted 5 October 2001
Abstract—A new reagent for the preparation of methyl esters of carboxylic acids is described. The reaction involves treatment of
acids with methanesulfonyl chloride in pyridine at 0°C. © 2001 Published by Elsevier Science Ltd.
Although methyl esters, which are the most simple
esters can be prepared by numerous methods and a
great variety of methods for their preparation is well
documented,6 our procedure offers the use of new and
inexpensive reagent, mildness and simplicity. The scope
of reagent can be gauged from the wide range of
substrates entered in Table 1. In all cases mild condi-
tions have been used.
Methanesulfonyl chloride finds a general applicability
in organic synthesis. It is used to prepare mesylates of
alcohols in the presence of pyridine.1 In 1976 Japanese
chemists reported examples of an abnormal conversion
of allylic alcohols into chlorides with inversion of
configuration by treatment with methanesulfonyl chlo-
ride in pyridine.2 For Beckmann fragmentations of
oximes3 and fragmentation of oxoalkane nitriles,4
methanesulfonyl chloride is used in refluxing pyridine.
In the present paper we report the methylation of
carboxylic acids with mesyl chloride in pyridine at 0°C.
Prior to this, the general applicability of this reagent for
methylation has not been reported and in only one
publication,5 formation of methyl esters of carboxylic
acid was noted during the synthesis of hindered a-dia-
zoketones via acyl mesylates. The reaction was done in
triethylamine. In an attempt to prepare 3-O-mesyl
derivative of ursolic acid, we obtained its carbomethoxy
derivative in addition to the required O-mesyl
derivative.
The methylation of the carboxy group of ursolic acid 1
is representative. A solution of the acid (100 mg, 0.219
mmol) in anhydrous pyridine (2 ml, 0.3 mmol) was
treated with methanesulfonyl chloride (0.041 ml, 0.54
mmol) at 0°C and the reaction was monitored by TLC.
Evolution of SO2 gas was observed and confirmed by
collecting the gas through a delivery tube in a test tube
containing H2O. The sulfurous acid thereby formed
turned blue litmus paper red. The gas also decolorized
a dilute solution of KMnO4. After 60 min, 1 was almost
completely consumed and the reaction mixture was
partitioned between ethyl acetate and H2O. The organic
phase was washed, dried (anhydrous Na2SO4) and the
solvent was removed under reduced pressure. Purifica-
tion of the reaction mixture by column chromatogra-
phy using hexane–EtOAc (7.5:2.5) as eluent, afforded a
mixture of 3b-mesyloxyursolic acid 1A and methyl 3b-
mesyloxyursolate 1B in a 40:60 ratio and an 83%
overall yield (99.7 mg). Their ratio was determined by
1H NMR spectroscopy and they were separated into 1A
and 1B through thick layer chromatography (silica gel,
hexane–EtOAc, 7.5:2.5)
RCOOH+MsClPy, 0°CRCOOMe
On further elaboration of the reaction to various classes
of carboxylic acids (entries 2–8, Table 1), the general
applicability of the reaction was observed. In each case
a solution of the acid (1 mmol) in anhydrous pyridine
(1.2 mmol) was treated with methanesulfonyl chloride
(1.2–2.5 mmol) at 0°C (except entry 7). The reaction
time required for completion of the reaction was
variable.
Keywords: methylation; carboxylic acid; methanesulfonyl chloride.
* Corresponding author. Tel.: 92-21-9243199; fax: 92-21-9243190/
9243191; e-mail: bina@khi.comsats.net.pk
Further studies on this new procedure are in progress
and will be reported shortly.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01888-3
Siddiqui, Bina S.
