Facile preparation of polymer-supported methyl sulfonate and its recyclable use for methylation of carboxylic acids and amines

Article abstract of DOI:10.1055/s-2005-862348

A simple and efficient one-pot procedure for the preparation of polymer-supported methyl sulfonate from the reaction of polymer-supported sulfonic acid with trimethyl orthoacetate was achieved, and it could be successfully used for efficient methylation of carboxylic acids, phosphonic acids, sulfinic acids, amines, thiol, and phenol. Moreover, the polymer reagent could be recovered, regenerated, and reused easily for the same reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-862348

LETTER
517
Facile Preparation of Polymer-Supported Methyl Sulfonate and its Recyclable
Use for Methylation of Carboxylic Acids and Amines
Preparation of
P
o
olymer-Sup
m
ported Methyl
S
ulfo
o
nate nori Yoshino,a Hideo Togo*a,b
a
Graduate School of Science and Technology, Chiba University, Yayoi-cho 1-33, Inage-ku 263-8522, Japan
Department of Chemistry, Faculty of Science, Chiba University, Yayoi-cho 1-33, Inage-ku 263-8522, Japan
E-mail: togo@faculty.chiba-u.jp
b
Received 25 October 2004
the preparation of polymer-supported methyl sulfonate by
the reaction of polymer-supported sulfonyl chloride with
methanol in the presence of a base, effective introduction
of the methyl sulfonate groups is not easy, since the
Abstract: A simple and efficient one-pot procedure for the prepa-
ration of polymer-supported methyl sulfonate from the reaction of
polymer-supported sulfonic acid with trimethyl orthoacetate was
achieved, and it could be successfully used for efficient methylation
of carboxylic acids, phosphonic acids, sulfinic acids, amines, thiol, formed methyl sulfonate groups may further react with
and phenol. Moreover, the polymer reagent could be recovered,
regenerated, and reused easily for the same reactions.
methanol in the presence of the base to provide sulfonate
salt groups and methyl ether. Practically, in our work, an
Key words: polymer-supported methyl sulfonate, trimethyl
orthoacetate, methylation, carboxylic acid, phosphonic acid, amine,
environmentally benign
effective conversion of sulfonyl chloride groups to methyl
sulfonate groups in polymer-supported sulfonyl chloride
with methanol and triethylamine was unsuccessful, and
we observed that most of the sulfonyl chloride groups
were converted to the corresponding sulfonate groups,
and so it did not work as an effective methylation reagent
for carboxylic acid. Here, as a part of our study on envi-
ronmentally benign organic synthesis with polymer-sup-
ported reagents,7 we would like to report an operationally
simple and efficient one-pot preparation of polymer-sup-
ported methyl sulfonate from commercially available
polymer-supported sulfonic acid with trimethyl orthoace-
tate, and its synthetic use for methylation of carboxylic ac-
ids, phosphonic acids, amines, and phenol. Previously, we
reported an operationally simple and efficient esterifica-
tion of various carboxylic acids with triethyl orthoacetate
and trimethyl orthoacetate under neutral conditions in a
room temperature ionic liquid.8 Triethyl orthoacetate and
trimethyl orthoacetate are also an excellent reagent for the
esterification of sulfonic acids.9 Based on these results, we
studied a novel preparation of polymer-supported methyl
sulfonate from polymer-supported sulfonic acid with tri-
methyl orthoacetate. Polymer-supported methyl sulfonate
1a was easily prepared by the reaction of polymer-sup-
ported sulfonic acid [macroporous poly(styrene-co-divi-
nylbenzene); loading rate of SO3H: 4.07 mmol/g], with
trimethyl orthoacetate (4.4 equiv) without a solvent at
room temperature (Equation 1). Polymer reagent 1a was
simply obtained by the filtration of the reaction mixture.
Loading rate of the methyl sulfonate group was deter-
mined by both elemental analysis and IR, to be ca. 4.0
mmol/g. Then, various carboxylic acids such as aromatic
carboxylic acids, aliphatic carboxylic acids, were treated
with polymer reagent 1a in the presence of K2CO3 to pro-
vide the corresponding methyl esters in high yields as
shown in Table 1. Here, simple filtration of the reaction
mixture and removal of the solvent gave methyl esters
with high purity (>98%). Polymer-supported ethyl sul-
fonate 1b (loading rate of ethyl sulfonate; ca. 3.1 mmol/g)
was also prepared from the reaction of polymer-supported
Alkylation of carboxylic acids and other protic com-
pounds to the corresponding esters or ethers is important
for organic transformation.1 Generally, methyl iodide, di-
azomethane, dimethyl sulfate, and methyl p-toluene-
sulfonate are typically used for the methylation. However,
it is well known that the former three reagents are highly
toxic, and, moreover, diazomethane is explosive. Today,
from the environmental point of view, it is important to
avoid these toxic reagents and troublesome operation in-
volved in organic synthesis. Therefore, alternative safe
methylation reagents have been long desired. O-Methyl-
isourea is an efficient methylation reagent2 because of its
low toxicity. Polymer-supported methylation reagents,
which can be easily handled, recovered, and reused, are
very attractive and practically useful from the environ-
mental point of view. Polymer-supported O-methyl-
isourea, prepared via one step from commercially
available resin, can be used for methylation of carboxylic
acids.3 Polymer-supported triazenes, which are prepared
via 4 steps from commercially available resin, alkylate
various carboxylic acids.4 Polymer-supported sulfonate
esters have been used in the alkylation of amines and thi-
ols at high temperature.5 Generally, polymer-supported
sulfonate esters are prepared from the reaction of poly-
mer-supported sulfonyl chloride with alcohols in the pres-
ence of a base, and polymer-supported sulfonyl chloride is
prepared from the reaction of polymer-supported sulfonic
acid with SOCl2 or PCl5, or the reaction of polystyrene
with ClSO3H.6 So, the preparation of polymer-supported
methyl sulfonate from commercially available polymer-
supported sulfonic acid requires two steps. Moreover, in
SYNLETT 2005, No. 3, pp 0517–0519
1
6.
0
2.
2
0
0
5
Advanced online publication: 17.01.2005
DOI: 10.1055/s-2005-862348; Art ID: U29304ST
© Georg Thieme Verlag Stuttgart · New York

518
T. Yoshino, H. Togo
LETTER
recovered quantitatively by simple filtration, and poly-
mer-supported sulfonic acid could be regenerated by
treatment with diluted sulfuric acid through a column, and
polymer reagent 1a could be prepared again and reused
for the same reactions without loss of chemical yields of
the methylation products (entries 2–6). Amines, phenol,
thiol, and phosphonic acids were also easily methylated to
give the corresponding methyl esters in good yields as
shown in Table 2. However, sulfinic acids gave a mixture
of the corresponding methyl sulfinate and methyl sulfone
even if the reaction was carried out at room temperature.
CH3C(OR)3
r.t., 24 h
SO3H
SO3R
1a: R = CH3 (4.0 mmol/g)
1b: R = C2H5 (3.1 mmol/g)
loading rate:
4.07 mmol/g
Equation 1
Table 1 Methylation of Carboxylic Acids with Polymer-Supported
Methyl Sulfonate 1a
SO3CH3 (1a) (1.8 equiv)
K2CO3 (1.0 equiv)
RCO2H
RCO2CH3
MeCN, reflux
Table 2 Methylation of other Protic Compounds with Polymer-
Supported Methyl Sulfonate 1a
Entry RCO2H
Time (h) Yield (%)
SO3CH3 (1a) (1.8 equiv)
1
5
96
CO2H
K2CO3 (1.0 equiv)
RXH
RXCH3
MeCN, reflux
2
3
4
5
6
7
4
4
4
4
4
4
99
Entry
1
RXH
Time (h)
72
Yield (%)
75
CO2H
CH3
99a
98b
97c
98d
93e
CH3
H
N
CH3
2
48
83a
NH2
8
5
97
CO2H
3
4
67
24
70
O2N
NO2
(CH2)7CO2H
CH3
OH
9
21
72
CH3(CH2)7
CO2H
82b
OH
10
11
4
4
99
HO
87e
5
6
6
90
CH3
SH
74 (29:45)c
61 (17:44)c
12
13
24
24
89
3
24d
CH3
SO2H
CO2H
67e
92f
7
8
24
O
Cbz
H
HN
P
OH
OH
CO2H
24
91
N
H
O
97f
P
14
3
HO
H
OH
CO2H
a Yield of N,N-dimethyl compound. N-methyl compound was also
obtained in 17% yield.
a With the first regenerated 1a.
b With the second regenerated 1a.
c With the third regenerated 1a.
d With the fourth regenerated 1a.
e Compound 1b was used instead of 1a.
b Yield of 2-(4-methoxyphenyl)ethanol. 4-(2-Methoxyethyl)phenol
was also obtained in 9% yield.
c Ratio of methyl sulfinate:methyl sulfone.
d Reaction was carried out at r.t.
f Optically pure (Daicel Chiralcel OD-H; eluent:
e Compound 1a (3.6 equiv) and K2CO3 (2.0 equiv) were used and the
yield indicated for dimethyl phosphonate.
hexane–i-PrOH = 4:1).
In conclusion, a simple and efficient one-pot preparation
of polymer-supported methyl sulfonate with trimethyl
orthoacetate without any additive, and effective methyl-
ation of carboxylic acids, phosphonic acids, amines, thiol,
and phenol were successfully carried out, and, moreover,
recovery, regeneration, and reuse of the polymer-support-
ed methyl sulfonate were achieved.
sulfonic acid with triethyl orthoacetate (Equation 1), and
it could be used for the ethylation of carboxylic acids un-
der the same conditions (entries 7, 11). Hydroxy acid and
Cbz-protected amino acid could be cleanly methylated to
give the corresponding methyl esters in high yields with-
out any racemization (entries 13, 14). No side reactions
occurred, and polymer-supported sulfonate salt could be
Synlett 2005, No. 3, 517–519 © Thieme Stuttgart · New York

LETTER
Preparation of Polymer-Supported Methyl Sulfonate
519
Typical Experimental Procedures.
References
Preparation of Polymer-Supported Methyl Sulfonate 1a:
Polymer-supported sulfonic acid (2.0 g, Argonaut Tech. Inc.) was
stirred with trimethyl orthoacetate (4.2 mL, 4.4 equiv) at r.t. After
one day, polymer-supported methyl sulfonate (1a) was filtered and
washed with acetone 4 times. Polymer reagent 1a was dried under
reduced pressure with a vacuum pump. IR (KBr): 2930, 1360, 1180,
990 cm–1. Anal. Calcd: C, 56.4; H, 5.6; S, 14.4.
(1) Otera, J. Angew. Chem. Int. Ed. 2001, 40, 2044.
(2) (a) Mathias, L. J. Synthesis 1979, 561. (b) Hugger, U.;
Sharpless, K. B. Tetrahedron Lett. 1995, 36, 6603.
(3) (a) Crosignani, S.; White, P. D.; Linclau, B. Org. Lett. 2002,
4, 1035. (b) Crosignani, S.; White, P. D.; Linclau, B. J. Org.
Chem. 2004, 69, 5897.
(4) Rademann, J.; Smerdka, J.; Jung, G.; Grosche, P.; Schmid,
D. Angew. Chem. Int. Ed. 2001, 40, 381.
(5) Rueter, J. K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.; Reitz,
Methylation of Carboxylic Acid with Polymer-Supported
Methyl Sulfonate 1a:
A. B. Tetrahedron Lett. 1998, 39, 975.
A mixture of 2,4,6-trimethylbenzoic acid (164.4 mg, 1.0 mmol),
polymer reagent 1a (0.45 g), and K2CO3 (138.2 mg, 1.0 mmol) in
MeCN (3 mL) was refluxed for 4 h under an argon atmosphere, until
2,4,6-trimethylbenzoic acid disappeared. After the reaction, the
mixture was filtered and washed with acetone 4 times. Removal of
the solvent from the filtrate provides methyl 2,4,6-trimethylben-
zoate (bp 70 °C/1 mmHg, lit.10 79–84 °C/2 mmHg) in an almost
pure state (178.2 mg, 99% yield).
(6) (a) Rubinstein, M.; Patchornik, A. Tetrahedron Lett. 1972,
2881. (b) Roush, W. R.; Feitler, D.; Rebek, J. Tetrahedron
Lett. 1974, 1391. (c) Hunt, J. A.; Roush, W. R. J. Am. Chem.
Soc. 1996, 118, 9998.
(7) (a) Togo, H.; Nogami, G.; Yokoyama, M. Synlett 1998, 534.
(b) Togo, H.; Abe, S.; Nogami, G.; Yokoyama, M. Bull.
Chem. Soc. Jpn. 1999, 72, 2351. (c) Abe, S.; Sakuratani, K.;
Togo, H. Synlett 2001, 22. (d) Abe, S.; Sakuratani, K.;
Togo, H. J. Org. Chem. 2001, 66, 6174. (e) Sakuratani, K.;
Togo, H. Synthesis 2003, 21. (f) Tashino, Y.; Togo, H.
Synlett 2004, 2010. (g) Review: Togo, H.; Sakuratani, K.
Synlett 2002, 1966.
Acknowledgment
Financial support from a Grant-in-Aid for Scientific Research (No.
16655012) from the Ministry of Education, Science, Sports, and
Culture of Japan is gratefully acknowledged.
(8) Yoshino, T.; Togo, H. Synlett 2004, 1604.
(9) (a) Padmapriya, A. A.; Just, G.; Lewis, N. G. Synth.
Commun. 1985, 15, 1057. (b) Trujillo, J. I.; Gopalan, A. S.
Tetrahedron Lett. 1993, 34, 7355.
(10) Kim, S.; Lee, J. I. J. Org. Chem. 1984, 49, 1712.
Synlett 2005, No. 3, 517–519 © Thieme Stuttgart · New York