S-methylation of N-containing heterocyclic thiols with conjugated acids of methoxy groups

Article abstract of DOI:10.3987/COM-09-11859

2-Mercaptopyridine-3-carboxylic acid reacts with methanol under acidic conditions to afford the corresponding S-methylated methyl ester, methyl 2-methylthiopyridine-2-carboxylate. Such S-methylation occurred for various N-containing heterocyclic thiols wi

Full text of DOI:10.3987/COM-09-11859

HETEROCYCLES, Vol. 81, No. 2, 2010
413
HETEROCYCLES, Vol. 81, No. 2, 2010, pp. 413 - 420. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd October, 2009, Accepted, 30th November, 2009, Published online, 1st December, 2009
DOI: 10.3987/COM-09-11859
S-METHYLATION OF N-CONTAINING HETEROCYCLIC THIOLS
WITH CONJUGATED ACIDS OF METHOXY GROUPS
a
b
a
Masao Shimizu,* Teruaki Shimazaki, Yoshihiro Kon, and Takeo
b
Konakahara
a
National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1
b
Higashi, Tsukuba, Ibaraki 305-8565, Japan;
Faculty of Science and
Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba
78-8510, Japan
2
Abstract – 2-Mercaptopyridine-3-carboxylic acid reacts with methanol under
acidic conditions to afford the corresponding S-methylated methyl ester, methyl
2
-methylthiopyridine-2-carboxylate. Such S-methylation occurred for various
N-containing heterocyclic thiols with acidic methanol. The reaction proceeded
by the attack of mercapto groups on the conjugated acid of methanol. Therefore,
the sulfur atom of pyridine-2-thiol was also methylated with acidic methyl ethers
or methyl esters.
A convenient method for esterification of carboxylic acids is heating them in alcoholic solvent in the
1
presence of sulfuric acid. Methyl thiosalicylate, for example, is synthesized by heating thiosalicylic
2
acid in methanol in the presence of sulfuric acid. In the same way, it was reported that methyl
2
2
-mercaptopyridine-3-carboxylate, an aza-analogue of methyl thiosalicylate, is prepared from
3
-mercaptopyridine-3-carboxylic acid (1). However, this esterification was unexpectedly troublesome
4
according to the later report; N-methylation occurred under these conditions to afford
3
-methoxycarbonyl-1-methyl-2-pyridinethione.
The N-methylation usually occurs under basic
5
conditions with methylating reagents such as methyl halides or dimethyl sulfates. Therefore, we were
interested in the mechanism for this type of methylation of 1 with methanol under acidic conditions.
We first re-examined esterification of 1. When 1 was refluxed in methanol for 8 h in the presence of
1
13
sulfuric acid, a product that had two methyl groups, according to H and C NMR spectra (at  2.54 and
1
13
3
.94 ppm in H NMR,  14.0 and 52.4 ppm in C NMR), was obtained as the main product, and methyl

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HETEROCYCLES, Vol. 81, No. 2, 2010
2
3
-mercaptopyridine-3-carboxylate was not isolated. If this main product was the N-alkylated product,
4
1
-methoxycarbonyl-1-methyl-2-pyridinethione, as reported in the literature, the H NMR peak at 2.54
ppm, assignable to an N-methyl group, appeared rather high upfield. By comparing spectral data of
6
N-methyl and S-methyl pyridinethiol derivatives reported in the literature, we deduced the structure of
the product as methyl 2-methylthiopyridine-3-carboxylate (2). S-Methylation of 1 occurred in acidic
methanol. It was reported that the methyl group on methyl 2-mercaptobenzoate migrates to the
7
mercapto group to form (2-methylthio)benzoic acid. Therefore, it is probable that 2 was produced by
esterification of 2-methylthiopyridine-3-carboxylic acid which was formed by migration of the methyl
group
on
-mercaptopyridine-3-carboxylic acid (3) with sulfuric acid in methanol refluxing for 8 h gave methyl
-methylthiopyridine-3-carboxylate (4) in 68% yield. This result showed that the carboxyl group
methyl
2-mercaptopyridine-3-carboxylate.
However,
the
reaction
of
6
6
neighboring the thiol group did not affect methylation of the mercapto group. These methylations were
then applied to pyridine-2-thiol (5), which had no carboxylic acid group.
O
O
MeOH, H SO
OH
2
4
OMe
reflux, 8 h
N
SH
N
SMe
1
2
: 64%
O
O
OH
2
MeOH, H SO4
OMe
reflux, 8 h
HS
N
MeS
N
3
4
: 68 %
Scheme 1. Esterification of mercaptopyridine-3-carboxylic acids
Pyridine-2-thiol (5) was refluxed in methanol for 8 h in the presence of sulfuric acid. As a result,
2
-methylthiopyridine (6, 62%) and 2,2’-dipyridyl sulfide (7, 2%) were isolated from the reaction mixture.
Methylation certainly occurred to the sulfur atom. We tried methylation with various acids (Table 1).
Methanol in the presence of sulfonic acids methylated 5 (Entries 3 and 4). Hydrochloric acid or a Lewis
acid can be substituted for sulfuric acid (Entries 5 and 6); however, acetic acid did not work for this
methylation (Entry 7). The formation of 6 in good yield required an excess amount of strong acid.
Other heterocyclic thiols, such as quinoline (8), benzimidazole (10), imidazole (12), and thiazoline
derivatives (14), were treated as substrates with acidic methanol under the same reaction conditions for
pyridinethiol methylation: the corresponding methylated products were obtained (Table 2). On the
contrary, the sulfur atom of 4-t-butylbenzenethiol was not methylated under these conditions, and the
starting material was recovered.

HETEROCYCLES, Vol. 81, No. 2, 2010
415
a
Table 1. Methylation of pyridine-2-thiol (5) with acidic methanol
MeOH, H+
reflux
+
SH
S Me
S
N
N
N
N
5
6
7
b
Entry
1
Acid
Equiv.
5.5
Products (Yield )
H
2
SO
4
4
6 (62%), 7 (2%)
2
3
4
5
H
2
SO
8.0
2.0
1.7
2.7
6 (81%), 7 (4%)
6 (74%)
p-TsOH•H O
2
MsOH
HClaq
6 (51%)
6 (54%)
6
7
BF
3
•OEt
2
2.0
4.0
6 (51%)
6 (trace)
AcOH
a
b
5
2.7 mmol, MeOH 30 mL, reflux, 8 h.
Isolated product.
a
Table 2. Methylation of heterocyclic thiols with acidic methaol
b
Entry
Thiol
Product
Yield (%)
SH
SH
N
SMe
SMe
N
1
69
8
9
N
N
N
H
N
2
64
78
H
1
0
11
N
N
3
4
SH
N
SMe
N
Me
1
2
13
Me
N
N
SMe
32
S
SH
S
1
4
15
a
b
Thiol 2.7 mmol, H
2
SO
4
5.5 mmol, MeOH 30 mL, reflux, 8 h.
Isolated product.
8
9
Acidic primary alcohol alkylation of 5 or mercapto azoles can be found in the literature, but no precise
mechanism has been mentioned. The above results were used to formulate the reaction mechanism.
Although it is possible that protonated methanol and dimethyl sulfate generated from the reaction of

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HETEROCYCLES, Vol. 81, No. 2, 2010
sulfuric acid with methanol were the active electrophilic species, the former is suitable as electrophiles
because hydrochloric acid or a Lewis acid could be used in place of sulfuric acid. When pyridine-2-thiol
5
was used as a substrate, the pyridine ring was predominantly protonated, but sufficient nucleophilicity
remained on the mercapto group. Actually, methylation of pyridine-2-thiol 5 with iodomethane also
o
occurred under acidic conditions; in the presence of sulfuric acid in acetone and with heating at 80 C (in
1
0
a sealed tube) for 5 h, 6 was obtained in 54% yield.
electrophiles to produce 2-methylthiopyridine 6.
In this way, protonated 5 can react with
Although alkyloxonium cations that formed from alcohols under acidic conditions operate as alkylating
1
1
agents in symmetrical ether or during alkyl halide synthesis, these cationic species have been applied
only infrequently to other syntheses. Nucleophilic substitution in general was not carried out under
acidic conditions, due to deactivation of the nucleophilic center by protonation. Although alcohols, such
as 2-methyl-2-propanol, that generate stable carbocation species by dehydration under acidic conditions,
1
2
can react with thiols to yield alkylthio derivatives, there appeared to be another reaction mechanism. It
seemed that methylation of heterocyclic thiols by acidic methanol proceeded by an S 2cA mechanism
Scheme 2).
N
(
H+
H+
Me OH
Me OH2
Me OH2
SH
SH
S Me
N
N
N
H
H
Scheme 2. Proposed mechanism for S-methylation under acidic conditions.
Reasoning from the above reaction mechanism, it is possible that an acidic methoxy group could work as
a methylation reagent for heterocyclic thiols. Therefore, we tested the reaction using ethers and esters as
electrophiles instead of methanol. Various kinds of methyl ethers and methyl esters were used for
reagents in the presence of methanesulfonic acid (Table 3). Since methyl esters are in general more
1
3
difficult to protonate than methanol, the yields of 6 were low (Entries 1 and 2). In contrast,
1
4
1
,2-dimethoxymethane is easier to protonate than the other ethers, and methylation of 5 occurred in 58%
yield (Entry 3). Although the yield of S-methylation using acidic methyl acetate was low (Entry 4),
13
owing to difficulty of forming the corresponding conjugated acid, the reaction in dimethyl carbonate
proceeded in 47% yield (Entry 5). The reaction with methyl methanesulfonate proceeded exceptionally
well to afford 6 in good yield (Entry 6).

HETEROCYCLES, Vol. 81, No. 2, 2010
417
In conclusion, S-methylation of nitrogen containing heterocyclic thiols proceeds with methanol under
acidic conditions. We explain the reaction mechanism as a nucleophilic attack of heterocyclic mercapto
groups on the conjugated acid of methanol. This alkylation is applicable to methyl ethers and methyl
esters.
a
Table 3. Methylation of pyridine-2-thiol (5) with acidic ethers or esters
b
Temp
Time
(h)
9.5
6
Yield (%)
Entry
Solvent
o
(
C)
6
20
7
7
c
1
2
3
4
5
6
Me-O-Cp
reflux
100
24
21
20
12
27
-
Me-O-Ph
MeO(CH OMe
AcOMe
(MeO) C=O
MeSO OMe
2
)
2
reflux
reflux
reflux
100
7
58
6
5
2
8.5
1
47
96
2
a
b
c
5
1.0 mmol, MeSO
3
H 2.0 mmol, solvent 5 mL.
GC yield. Cp = cyclopentyl.
EXPERIMENTAL
1
13
Melting points were determined on a Mettler FP90 microscopic plate and are uncorrected. H and C
NMR spectra were obtained with a JEOL LA-500 spectrometer, and chemical shifts () are reported in
3
parts per million relative to internal tetramethylsilane and CDCl , respectively. IR spectra were
recorded on a JASCO FT IR-4100 spectrophotometer. Gas chromatographic analyses were performed
on Shimadzu GC-14A chromatograph fitted with a Neutrabond-1 column. Silica gel column
chromatography was carried out on Merck silica gel 60 (0.063–0.200 mm). Elemental analysis was
performed by the Analytical Center at the National Institute of Advanced Industrial Science and
Technology.
Typical procedure for the esterification of mercaptopyridine-3-carboxylic acids
To a solution of a mercaptopyridine-3-carboxylic acid (1 or 3, 500 mg, 3.2 mmol) in MeOH (25 mL) was
added H
was extracted with CH
product was obtained after evaporating solvent. Products were isolated by silica gel column
2
SO
4
(98%, 0.5 mL). After reflux for 8 h, aqueous sodium carbonate was added and the product
2
Cl . The organic layer was washed with water and dried over MgSO . Crude
2
4
chromatography with CH
2
Cl
2
: AcOEt (20 : 1) mixture as an eluent.
1
6
Methyl 2-methylthiopyridine-3-carboxylate (2). Mp 59.0 - 59.3 °C (hexane); H NMR (CDCl , 500
3
MHz)  2.54 (3H, s), 3.94 (3H, s), 7.05 (1H, dd, J = 7.7, 4.7 Hz), 8.21 (1H, dd, J = 7.7, 1.8 Hz), 8.59 (1H,

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HETEROCYCLES, Vol. 81, No. 2, 2010
1
3
dd, J = 4.7, 1.8 Hz); C NMR (CDCl , 125 MHz)  14.0, 52.4, 118.0, 123.0, 138.8, 152.1, 163.0, 165.9;
3
-
1
IR (KBr): max 1715, 1556, 1397, 1278, 1243, 1130, 1069, 770 cm ; Anal. Calcd for C
8 9 2
H NO S: C,
5
2.44; H, 4.95; N, 7.64. Found: C, 52.61; H, 4.87; N, 7.57.
1
15
Methyl 6-methylthiopyridine-3-carboxylate (4). Mp 56.7 - 57.3 °C (hexane); H NMR (CDCl , 500
3
MHz)  2.61 (3H, s), 3.93 (3H, s), 7.23 (1H, dd, J = 8.5, 0.8 Hz), 8.04 (1H, dd, J = 8.5, 2.2 Hz), 9.02 (1H,
1
3
dd, J = 2.2, 0.8 Hz); C NMR (CDCl , 125 MHz) 13.2, 52.2, 120.7, 121.4, 136.2, 150.7, 165.7, 166.0.
3
-1
IR (KBr): max 1715, 1590, 1434, 1364, 1292, 1122, 767 cm .
Typical procedure for the alkylation of heterocyclic thiols (5, 8, 10, 12, 14)
To a solution of thiol (2.7 mmol) in MeOH (30 mL) was added H
reflux for 8 h, aqueous sodium carbonate was added and the product was extracted with CH
organic layer was washed with water and dried over MgSO Crude product was obtained after
evaporating solvent. A product was isolated by silica gel column chromatography with CH Cl : AcOEt
2
SO
4
(98%, 0.3 mL, 5.5 mmol). After
2
Cl . The
2
4
.
2
2
(
100 : 1) mixture as an eluent.
1
6
1
2
-Methylthiopyridine (6). Bp 106 °C (4.0 kPa) [lit., 94 – 95 °C (4.0 kPa)]; H NMR (500 MHz,
CDCl )  2.57 (3H, s), 6.97 (1H, ddd, J = 7.3, 4.9, 1.0 Hz), 7.18 (1H, dt, J = 8.2, 0.9 Hz), 7.48 (1H, ddd, J
3
1
3
=
8.2, 7.3, 1.8 Hz), 8.44 (1H, ddd, J = 4.9, 1.8, 0.9 Hz); C NMR (125 MHz, CDCl )  13.3, 119.2, 121.6,
3
-
1
1
2
7
35.8, 149.5, 160.1; IR (neat): max 1581, 1556, 1455, 1414, 1126, 756, 733 cm .
1
7
1
,2’-Dipyridyl sulfide (7). Bp 192 °C (120 Pa) [lit., 148 °C (133 Pa)]; H NMR (500 MHz, CDCl ) 
3
.17 (2H, ddd, J = 7.6, 4.9, 0.9 Hz), 7.45 (2H, dt, J = 7.7, 0.9 Hz), 7.62 (2H, td, J = 7.7, 1.9 Hz), 8.54 (2H,
1
3
ddd, J = 4.9, 1.9, 0.9 Hz); C NMR (125 MHz, CDCl )  121.8, 125.9, 137.1, 150.2, 156.8; IR (neat):
3
-1

max 1573, 1559, 1448, 1417, 1113, 758 cm .
1
8
1
2
-Methylthioquinoline (9). Bp 170 °C (227 Pa) [lit., 115 – 117 °C (200 Pa)]; H NMR (500 MHz,
CDCl )  2.71 (3H, s), 7.23 (1H, d, J = 8.5 Hz), 7.42 (1H, ddd, J = 7.9, 7.0, 1.2 Hz), 7.65 (1H, ddd, J =
3
1
3
8
.5, 7.0, 1.5 Hz), 7.72 (1H, dd, J = 7.9, 0.9 Hz), 7.88 (1H, d, J = 8.6 Hz), 7.95 (1H, d, J = 8.6 Hz); C
NMR (125 MHz, CDCl )  12.9, 120.7, 125.2, 125.9, 127.6, 128.0, 129.6, 135.2, 148.4, 159.9; IR
3
-1
(
neat):max 1612, 1594, 1556, 1497, 1419, 1292, 1138, 1091, 815, 779, 748 cm .
1
9
1
2
-Methylthiobenzimidazole (11). Mp 203.0 - 204.0 °C (AcOEt) [lit., 201 °C (AcOEt)]; H NMR
1
3
(
500 MHz, CDCl )  2.72 (3H, s), 7.17 (2H, dd, J = 3.0, 1.5 Hz), 7.44-7.46 (2H, m); C NMR (125 MHz,
3
CDCl )  14.5, 54.1, 122.6, 139.6, 152.8; IR (KBr):max 1441, 1421, 1394, 1361, 1268, 1221, 986, 740
3
-
1
cm .

HETEROCYCLES, Vol. 81, No. 2, 2010
419
20
1
1
-Methyl-2-methylthioimidazole (13). Bp 166 °C (4.0 kPa) [lit., 124 – 125 °C (4.0 kPa)]; H NMR
1
3
(
500 MHz, CDCl )  2.59 (3H, s), 3.59 (3H, s), 6.91 (1H, d, J = 1.2 Hz), 7.04 (1H, d, J = 1.2 Hz); C
3
NMR (125 MHz, CDCl )  16.2, 33.0, 122.0, 129.1, 143.1; IR (neat): max 3388, 1462, 1416, 1279, 1125,
3
-1
7
41, 685 cm .
1
21
2
-Methylthio-2-thiazoline (15). Bp 174°C (4.0 kPa) [lit., 70 – 71 °C (133 Pa)]; H NMR (CDCl ,
3
1
3
5
00 MHz)  2.55 (3H, s), 3.41 (2H, t, J = 7.9 Hz), 4.22 (2H, t, J = 7.9 Hz); C NMR (CDCl , 125 MHz)
3
-1
.

15.5, 35.8, 64.4, 166.6; IR (neat) max 1569, 1000, 979, 958, 917 cm
Typical procedure for the methylation of pyridine-2-thiol with ethers or esters.
To a solution of pyridine-2-thiol (5, 111 mg, 1.0 mmol) in solvent (5 mL) was added methanesulfonic
acid (2.0 mmol). After reflux for 5 – 11 h, aqueous sodium carbonate was added and the product was
2 2 4
extracted with CH Cl . The organic layer was washed with water and dried over MgSO . Yields of the
products were determined by an internal standard technique using the GC method.
REFERENCES AND NOTES
1
.
For examples, L. F. Fieser and M. Fieser, “Reagents for Organic Synthesis,” Wiley, New York, 1967,
p. 678.
2
.
F. J. Baerlocher, M. O. Baerlocher, R. F. Langler, S. L. MacQuarrie, and M. E. Marchand, Aust. J.
Chem., 2000, 53, 1; E. Matsumura, T. Nishinaka, H. Tsujibo, H. Hachiken, Y. Miki, Y. Sakagami,
and Y. Inamori, Biol. Pharm. Bull., 2000, 23. 254.
3.
4.
5.
L. R. Fibel and P. E. Spoerri, J. Am. Chem. Soc., 1948, 70, 3908.
L. Katz, W. Schroeder, and M. Cohen, J. Org. Chem., 1954, 19, 711.
th
A. Schöberl and A. Wagner, Houben-Weyl, 4 ed., Vol. 9, ed. by E. Müller, Thieme, Stuttgart, 1955,
p. 93.
6
.
M. Gelbcke, R. Grimée, R. Lejeune, L. Thunus, and J. V. Dejardin, Bull. Soc. Chim. Belg., 1983, 92,
3
9.
7
.
.
J. C. Grivas and K. C. Navada, J. Org. Chem., 1971, 36 1520.
8
Courtot and Zwilling, In Chem. et Ind. Sonderband 18. Congr. Chim. ind., Nancy, 1938, p. 796
th
(
Beilstein, 4 ed, Vol. 21, p. 374).
9
1
.
N. D. Abramova, G. G. Skvortsova, and B. V. Trzhtsinskaya, Zh. Org. Khim., 1984, 20, 2031; J. Org.
Chem. USSR, 1984, 20, 1854.
0. Under the same reaction conditions, treatment of 4-t-butylbenzenethiol with iodomethane afforded
-t-butylphenyl methyl sulfide in 1% yield and bis(4-t-butylphenyl) disulfide in 80% yield.
4

420
HETEROCYCLES, Vol. 81, No. 2, 2010
1
1
1. G. W. Brown, “The Chemistry of the Hydroxyl Group,” ed. by S. Patai, Wiley, London, 1971, p.
593; H. Feuer and J. Hooz, “The Chemistry of the Ether Linkage,” ed. by S. Patai, Wiley, London,
1
967, p.445.
2. For examples: A. Courtin, H.-R. Tobel, and G. Auerbach, Helv. Chim. Acta, 1980, 63, 1412; T.
Schaefer and G. H. Penner, Can. J. Chem., 1988, 66, 1641; N. C. Cutress, T. B. Grindley, A. R.
Katritzky, and R. D. Topsom, J. Chem. Soc., Perkin Trans. 2, 1974, 263.
3. G. A. Olah, A. M. White, and D. H. O’Brien, Chem. Rev., 1970, 70, 561.
4. O. Tsuge and M. Noguchi, Chem. Lett., 1977, 749.
1
1
1
1
1
1
1
2
5. M. Gelbcke, R. Grimée, R. Lejeune, and L. Thunus, Spectrochim. Acta, 1985, 41A, 567.
6. I. B. Cook, Aust. J. Chem., 1989, 42, 1493.
7. Monsanto Co., FR Patent, 1,503,307 (1967) (Chem. Abstr., 1969, 70, 3549).
8. A. Maslankiewicz, Pol. J. Chem., 1980, 54, 2069.
9. E. Hoggarth, J. Chem. Soc., 1949, 3311.
0. M. Nishida, H. Kimoto, S. Fujii, Y. Hayakawa, and L. A. Kohen, Bull. Chem. Soc. Jpn., 1991, 64,
2
255.
2
1. A. K. Bose, J. L. Fahey, and M. S. Manhas, J. Heterocycl. Chem., 1973, 10, 791.