Efficient methylation of carboxylic acids with potassium hydroxide/methyl sulfoxide and iodomethane

Article abstract of DOI:10.1081/SCC-100104469

Methylation of several carboxylic acids was promoted by potassium hydroxide in methyl sulfoxide and iodomethane to produce corresponding methyl esters in good yield. This method has advantage over other described methods because it uses inexpensive reagents and the reaction is carried out under mild and favorable conditions.

Full text of DOI:10.1081/SCC-100104469

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EFFICIENT METHYLATION OF CARBOXYLIC ACIDS
WITH POTASSIUM HYDROXIDE/METHYL SULFOXIDE
AND IODOMETHANE
a
b
J. Gustavo Avila-Zárraga & Roberto Martínez
a
Facultad de Química, Departamento de Orgánica, Universidad Nacional Autónoma de
México;, Circuito Interior, Ciudad Universitaria, Coyoacán, D.F., 04510, Mexico
b
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior,
Ciudad Universitaria, Coyoacán, D.F., 04510, Mexico
Version of record first published: 09 Nov 2006
To cite this article: J. Gustavo Avila-Zárraga & Roberto Martínez (2001): EFFICIENT METHYLATION OF CARBOXYLIC ACIDS
WITH POTASSIUM HYDROXIDE/METHYL SULFOXIDE AND IODOMETHANE, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 31:14, 2177-2183
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SYNTHETIC COMMUNICATIONS, 31(14), 2177–2183 (2001)
EFFICIENT METHYLATION
OF CARBOXYLIC ACIDS WITH
POTASSIUM HYDROXIDE/METHYL
SULFOXIDE AND IODOMETHANE
1
,
2
J. Gustavo Avila-Za
´
rraga * and Roberto Martı
´
nez
1
Facultad de Quı
Nacional Auto
Circuito Interior, Ciudad Universitaria, 04510
Coyoacan, D.F., Mexico
mica, Universidad Nacional Auto
xico, Circuito Exterior, Ciudad Universitaria, 04510
Coyoacan, D.F., Mexico
´
mica, Departamento de Orga
´
nica, Universidad
´
noma de Mexico,
´
´
2
Instituto de Quı
´
´
noma de
Me
´
´
ABSTRACT
Methylation of several carboxylic acids was promoted by
potassium hydroxide in methyl sulfoxide and iodomethane
to produce corresponding methyl esters in good yield. This
method has advantage over other described methods because
it uses inexpensive reagents and the reaction is carried out
under mild and favorable conditions.
The development of methodology for the methylation of carboxylic
acids has been a challenging goal for organic chemists. Numerous reagents
and procedures have been recommended for this purpose. Many methods
2
3
have been reported using methanol on: sulfuric acid, hydrochloric acid,
*
Corresponding author.
2
177
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
´
´
AVILA-ZARRAGA AND MARTINEZ
2
178
4
amberlyst-15, sulfuric acid plus methyl sulfate, thionyl chloride, phos-
5
6
7
phorus oxychloride, boron trifluoride, phosphorus pentoxide, chlorotri-
8
9
1
0
11
methylsilane,
1
sulfonic acid,
manganese(IV) oxide,
triphenylphosphine and potassium
13
2
14
hydroxide,
iron(III) perchlorate,
nickel(II)
18
chloride, indium(II) iodide, iron(III) sulfate, dimethylthin dichloride,
copper(II) chloride, DCC, DMTMM, TCE. Another important route
is the methylation with diazomethane reagent. However, in this case gen-
eration of diazomethane is hazardous and tedious. A recently proposed
approach uses cesium carbonate in hot methanol/water followed by
1
5
16
17
1
9
20
21
22
2
3
2
4
iodomethane in DMF. Unfortunately many of the methods mentioned
still suffered from some disadvantage, as they require severe conditions,
needing excess of the reagents, use dangerous reagents or employ tedious
work up procedures. To explore further applications of methyl sulfoxide
2
5
in organic synthesis, herein we report an efficient unprecedented methyl-
ation of carboxylic acids using a slurry of potassium hydroxide in methyl
sulfoxide and iodomethane.
DMSO
RCOOH þMeI ꢀꢀꢀꢀ ꢀꢀ ! RCOOMe
1aꢀ1
KOH
2aꢀ1
In a typical experiment, treatment of acid (1 mmol) 1a with
iodomethane (1.48 mmol) in the presence of a mixture of potassium
hydroxide in DMSO at room temperature by 2 hours gave the methyl
ester 2a in 94% yield. Under identical reaction conditions, the aromatic
carboxylic acids (1b–h) afforded the corresponding methyl ester (2b–h)
in good yields. Similar results were also obtained for aliphatic carboxylic
acids 1i–l. The ratio of carboxylic acid/iodomethane (1.0:1.48) proved to be
the optimal system efficient for prepared the representative set of com-
pounds listed in Table 1. When we used a lesser relation than this ratio
the yields and rates of conversion to methyl esters was poor. This behavior
is in accord with the results previously reported for a SN type reaction.
2
This method also was successfully applied for 1–10 g scale and gave identical
yields. This result is very important because methylation of carboxylic
acids constitutes a challenging goal for organic chemist due to the
broad use of methyl esters as reaction intermediates, biologically active
compounds, derivatives more easily separated than natural carboxylic
acids, etc.
The formation of (2a–l) from (1a–l) with iodomethane in the presence
of potassium hydroxide in methyl sulfoxide can be rationalized as shown
below:
MeSðOÞMe þ KOH > KCH SðOÞMe
ð1Þ
2

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METHYLATION OF CARBOXYLIC ACIDS
2179
Table 1. Yields and Physical Data for Methyl Esters (2a–l)
Reaction time Yield
(%)
IR
–
(cm )
1
Compound No.
R
(h)
Ref.
a
b
c
d
e
f
3,4,5-triMeOC
6
H
2
2
2
2
2
1
2
2
0.5
2
94
92
88
91
95
98
76
85
81
94
96
54
1714
1720
1725
1706
1722
1730
1720
1732
1716
1737
1742
1735
3i
13/ 23a
23i/ 23a
23a
13
4-BrC
4-FC H
6
H
4
6
4
4-NH
2
C
6
H
4
C
3-NO C H
6
H
5
13
2
6
4
g
h
i
4-ClC
Pyridinyl
6
H
4
23a
23a
2d
2g
2a
C
C H
6
H
5
CH ¼¼ CH
j
2
2
2
6
11
k
l
C
MeO
5
H
11
2
CCH
2
3c
ꢀ
þ
RCOOH þ KCH SðOÞMe . RCOO K
ð2Þ
ð3Þ
2
ꢀ
þ
RCOO K þ MeI ꢀ! RCOOMe
The superbasicity of the KOH/DMSO system, Eq. (1), as a first
2
6
approximation is due to the separation of the base ion-pair and the for-
2
7
mation of a highly basic and poorly solvated dimsyl anion. This anion
could undergo a base-acid reaction with the corresponding carboxylic acid,
Eq. (2). The nucleophilic attack of carboxylate anion on iodomethane
produces the final products (2a–l).
In conclusion, this methylation method using an inexpensive, safe,
and easily handled solvent, methyl sulfoxide, is a simple and efficient pro-
tocol that is applicable to a variety of carboxylic acids. The operation sim-
plicity, rapid reaction rates, and formation of pure products in good yields
at very moderate temperature make this method superior to existing one.
EXPERIMENTAL
All reactions were performed in oven-dried glassware at room pres-
sure. Reaction mixtures were concentrated by using a rotary evaporator
ꢀ
(
ca. 20 C/ 20 Torr). Thin layer chromatography was carried out on Merck
Kieselgel 60 PF254. Commercial grade reagents were used without further

ORDER
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´
´
AVILA-ZARRAGA AND MARTINEZ
2
180
purification except when indicated. All melting points are uncorrected. The
IR spectra were recorded on a Nicolet FT-55X spectrophotometer. The
1
H-NMR spectra were determined on a Varian FT-200 instrument. All
nmr spectra were obtained with the pulse sequence as part of the spectro-
meter’s software and was determined in deuteriochloroform solution con-
taining SiMe as the internal standard with chemical shifts (d) expressed
4
downfield from SiMe . Mass spectra were recorded using Jeol SX-102
mass spectrometer using the direct inlet system with an ionization
4
energy of 70 eV, an emission current of 100 mA and ion source temperature
of 150 C.
ꢀ
1
The structures of compounds 2a–1 were supported by IR, H-NMR
and MS spectral data which are identical to those reported. The purity of
1
compounds was checked by thin layer chromatography and H-NMR.
Preparation of Methyl3-Nitrobenzoate (2f)
Typical Procedure
0.25 g of powered potassium hydroxide 85% (1.26 mmol) and 5 mL
of methyl sulfoxide was vigorously stirred for 30 minutes at room tempera-
ture. To this slurry was added a solution of 0.5 g of 1f (2.99 mmol) in 5 mL
of methyl sulfoxide and the resulting mixture was stirred for 15 minutes
and then cooled with a ice-water bath. After the addition of iodomethane
(
0.63 g, 4.43 mmol) the mixture was stirred for a further 2 hours at room
temperature and then added a mixture of ice-water. The resulting solution
was extracted with ethyl acetate (15 mL Â 3). The organic layer was washed
with a sodium chloride saturated solution (15 mL Â 5) and dried (sodium
sulphate) and concentrated to give 2f as an oil (0.53 g, 98%).
1
þ
H-NMR: d 8.28 (m, 5H), 3.99 (s, 3H); MS: m/z (%), M :181 (58).
1
Methyl 3,4,5-trimethoxybenzoate (2a), H-NMR: d 7.30 (s, 2H),
.91 (s, 12H); MS: m/z (%), M : 226 (100%).
Methyl 4-Bromobenzoate (2b); H-NMR: d 7.24 (AA , BB ; 4H),
.90 (s, 3H). MS: m/z (%), M : 214, 216 (56%).
Methyl 4-fluorobenzoate (2c); H-NMR: d 8.05 (m, 2H), 7.10 (m, 2H),
.91 (s, 3H); MS: m/z (%), M : 154 (35).
þ
3
3
3
4
1
0
0
þ
1
þ
1
0
0
Methyl 4-aminobenzoate (2d); H-NMR: d 7.26 (AA , BB ; 4H),
þ
.0(brs, 2H, exchange with D O), 3.88 (s, 3H): MS m/z (%), M : 151 (42).
1
2
Methyl benzoate (2e); H-NMR: d 7.73 (m, 5H), 3.91 (s, 3H); MS: m/z
þ
(
%), M : 136 (85).
1
0
0
Methyl 4-chlorobenzoate (2g); H-NMR: d 7.96 (AA , BB : 4H),
.91 (s, 3H); MS: m/z (%), M þ2; 172 (8), M ; 170 (25).
þ
þ
3

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METHYLATION OF CARBOXYLIC ACIDS
2181
1
Methyl isonicotinate (2h); H-NMR: d 8.48 (m, 2H), 7.85 (m, 2H),
.96 (s, 3H); MS: m/z (%), M : 137 (100).
þ
3
1
Methyl trans-cinnamate (2i); H-NMR: d 7.70 (d, J ¼ 16 Hz, 1H),
þ
7
.45 (m, 5H), 6.44 (d, J ¼ 16 Hz, 1H), 3.81 (s, 3H); MS: m/z (%), M :
162 (89).
1
Methyl cyclohexanecarboxylate (2j); H-NMR: d 3.66 (s, 3H), 2.30 (m,
H), 1.9–1.2(brs.,11H); MS: m/z (%), M : 142 (30).
þ
1
1
1
Methyl hexanoate (2k); H-NMR: d 3.66 (s, 3H), 2.30 (t, J ¼ 8 Hz, 2H),
þ
.66 (m, 2H), 1.33 (m, 2H), 0.89 (m, 5H); MS: m/z (%), M : 130 (20).
1
Dimethyl malonate (2l); H-NMR: d 3.75 (s, 6H), 3.40 (s, 2H); MS:
m/z (%), M : 132 (34).
þ
ACKNOWLEDGMENTS
This work was generously supported by the Consejo Nacional de
Ciencia y Tecnologıa (CONACYT), Proyect 32633-E and DGAPA,
Proyect IN-206598. We are also grateful to R. Patino, M. A. Pena,
B. Quiroz, H. Rios, W. Matus, L. Velasco and F. J. Perez for their assistance
´
˜
˜
´
´
1
in obtaining the IR, H-NMR and mass spectral data.
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Received in the USA October 19, 2000

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