Synthesis of 3-methylthio-4-aryl-3-pyrroline-2,5-diones and 3-arylpyrolidine-2,5-diones by reaction of nitroketene dithioacetal with arylacetonitriles

Article abstract of DOI:10.3987/COM-01-9336

The reaction of nitroketene dithioacetal (1a), i.e., 2,2-bis(methylthio)-1-nitroethylene, with arylacetonitriles (2a-I) in the presence of the base like sodium hydroxide gave 4-nitrobut-2-enenitriles (3a-I) which were convened into 5-hydroxyimino-4-methylthio-3-phenyl-3-pyrrolin-2-ones (4a-i) under refluxing in methanol. Title compounds (5a-i) were readily obtained by the treatment of 4a-i with hydrochloric acid and were finally led to N-methylated products (6a-I) with methyl iodide. The reduction of maleimides (4 - 6) with zinc dust in acetic acid afforded the corresponding 3-arylpyrrolidine-2,5-diones (7a-i) that can be convened to pharmacologycally active compounds like mesembrines.

Full text of DOI:10.3987/COM-01-9336

HETEROCYCLES, Vol. 55, No. 12, 2001, pp. 2257 - 2260, Received, 3rd September, 2001
SYNTHESIS OF 3-METHYLTHIO-4-ARYL-3-PYRROLINE-2,5-DIONES
AND
3-ARYLPYROLIDINE-2,5-DIONES
BY
REACTION
OF
NITROKETENE DITHIOACETAL WITH ARYLACETONITRILES
Yasuhiro Shigemitsua and Yoshinori Tominaga*b
aIndustrial Technology Center of Nagasaki, 2-1303-8 Ikeda, Omura, Nagasaki
b
856-0026, Japan; Center of Instrumental Analysis, Nagasaki University, 1-14,
Bunkyo-machi, Nagasaki 852-8521, Japan
Abstract
—
The reaction of nitroketene dithioacetal (1a), i.e.,
2,2-bis(methylthio)-1-nitroethylene, with arylacetonitriles (2a-I) in the presence
of the base like sodium hydroxide gave 4-nitrobut-2-enenitriles (3a-I) which were
converted into 5-hydroxyimino-4-methylthio-3-phenyl-3-pyrrolin-2-ones (4a-i)
under refluxing in methanol. Title compounds (5a-i) were readily obtained by the
treatment of 4a-i with hydrochloric acid and were finally led to N-methylated
products (6a-I) with methyl iodide. The reduction of maleimides (4 – 6) with zinc
dust in acetic acid afforded the corresponding 3-arylpyrrolidine-2,5-diones (7a-i)
that can be converted to pharmacologycally active compounds like mesembrines.
It is considered useful and significant to newly exploit an efficient synthetic route to afford
3-arylpyrrolidine-2,5-diones, very important starting materials of some natural products like mesembrine
which is isolated from Mesembryanthemum tortuosum.1,2 We previously reported the synthesis of
4-methylthiomaleimides (3-methylthio-3-pyrroline-2,5-diones) bearing a cyano or a methoxycarbonyl
group as an electron-withdrawing group via the reaction of ketene dithioacetal3 with nitromethane in the
presence of appropriate base.4 With their high electrophilic nature, 4-methylthiomaleimides serve as key
intermediates for the preparation of some heterocycles like pyridazine derivatives with
chemiluminescence and are also applicable to the synthesis of other heterocycles. Following the similar
strategy for preparing 4-methylthiomaleimides, we now wish to report the convenient synthesis of
3-methylthio-4-aryl-3-pyrroline-2,5-diones by using the reaction of nitroketene dithioacetal5 with aryl

acetonitriles followed by their reduction with zinc dust that gives 3-arylpyrrolidine-2,5-diones, i.e.,
arylsuccinimides.
Synthesis of 3-methylthio-4-aryl-3-pyrroline-2,5-diones (arylmaleimides).
A synthesis of arylmaleimides were initially examined by the reaction of ketene dithioacetal (1a) with
nitromethane in the presence of sodium hydroxide in dimethyl sulfoxide (DMSO) in an attempt to
prepare 3-methylthio-4-nitro-2-phenylbut-2-enenitrile (3a).6 Since we found this reaction did not
proceed smoothly, alternative reaction was
MeS
MeS
MeS
Ar
Ar
+
Me NO2
X
CN
H2C
NO2
CN
3a
newly explored to obtain 3a as described in
Scheme 1. The reaction of nitroketene
dithioacetal (1b) with phenylacetonitriles
(2a-i) in the presence of powdered sodium
hydroxide in DMSO at room temperature
smoothly occurred to yield 3a-i that are key
intermediates of the desired maleimides and
were used in next reaction without
purification. Compounds (3a-i) were treated
with methanol under refluxing to yield
5-hydroxyimino-4-methylthio-3-phenyl-3-
pyrrolin-2-ones (4a-i). The outline of reaction
pathway from 3 to 4 is shown in Scheme 2.
Conversion of 4a-i into 5a-i was
1a
MeS
MeS
HC
H
Ar
NO2
+
MeS
MeS
a
Ar
C
CN
Ar CH
CN
NO2
H2
H
CN
O2N
1b
2a-i
b
3a-i
MeS
O
Ar
MeS
Ar
Ar
MeS
d
c
O
O
O
O
HO N
N
N
N
H
Me
H
5a-i
6a-i
4a-i
Ar
a: C6H5
Ar
a: NaOH in DMSO
b: reflux in MeOH
c: reflux in c-HCl and MeOH
d: MeI and K2CO3 in Me2CO
f: C6H4-Cl(2)
g: 1-C10H7
h: 2-thienyl
i: 3-indolyl
b: C6H4-OMe(4)
c: C6H4-OMe(2)
d: C6H3-(OMe)2(3,4)
e: C6H4-Cl(4)
Scheme 1
Table 1 Melting points and yields of 5-aryl-4-methylthiomaleimides
promptly carried out by the
hydrolysis of hydroxyimino group
with conc. hydrochloric acid in
moderate to good yields (74-98%).
mp(°C)
Yield(%)
mp(°C)
Yield(%)
mp(°C)
Yield(%)
Entry
1
5
R
4
6
234-235
84
214-215
85
195-196
77
93-94
91
175-178 6b
6a
C6H5
4a
5a
5b
61-62
94
74-75
94
91-92
94
2
3
C6H4OMe(4) 4b
C6H4OMe(2) 4c
90
131-132 6c
84
5c
We
subsequently
tried
the
202-203
84
250-251
74
200-202
67
250-251
75
182-183
6d
4 C6H3(OMe)2(3,4) 4d
5d
5e
5f
110-111
95
70-71
96
58-59
95
124-125
92
methylation of 5a-i as one of the
simplest alkylations with methyl
iodide in the presence of potassium
carbonate in acetone. This reaction
gave the corresponding methylated
products (6a-i) in good yields as
shown in Table1.
91
134-135 6e
5
6
C6H4Cl(4)
C6H4Cl(2)
4e
4f
84
127-128
98
6f
7
144-145 6g
74
1-naphtyl
4g
5g
8
9
239-241
54
4i 249-251
38
152-153
79
6h
2-tienyl
4h
5h
5i
69-70
92
131-132
92
6i
3-indolyl
185-187
88

SMe
SMe
SMe
Ar
Ar
H
H
Ar
MeS
O2N
Ar
N+
C
O
H
+
N
+
OH
N
C
C
-O
CN
-O
NH
NH
O
-O
N
H2
MeS
MeS
N
Ar
Ar
MeS
O
Ar
O
MeS
N
Ar
*
O
O
HO
HO
O
NH
N
O
O
N
H
H
Scheme 2 Reaction Mechanism
(* Treatment of 3 with conc. hydrochloric acid gave 3-methylthio-4-arylfuran-2,5-diones.)
Synthesis of Succinimides by the Reduction of Maleimides
Succinimides obtained by the reduction of maleimides derivatives are important as starting materials of
natural products like mesembrine and pharmacologically active compounds like methosuximide.1,2
Desulfurization of 6a with Raney nickel (W-2) in refluxed ethanol gave only 4-phenylsuccinimide
(1-methyl-3-phenylpyrrolidine-2,5-dione) (7e) in 28% yield. Incidentally, zinc in acetic acid is
applicable to a wide range of reduction reactions.5 This reagent has also been chosen to demonstrate
selective reduction in sensitive,
polyfunctional molecules. By using a
general method, the reduction of 5a
employing zinc dust in acetic acid
under refluxing afforded the
corresponding 4-phenylsuccinimide
(7a) in 98% yield. Other succinimide
products (7b-i) were obtained in a
similar way from the corresponding
maleimides (5,6) in good yields as
Table 2. Synthesis of 4-Arylsuccinimides from 4-Arylmaleimides by Zinc Reduction a
No.
mp(°C) Yield(%)
R
Ar
98(28)b
68-69
7a
b
c
H
H
C6H5
C6H4-OMe(4)
128-129
130-131
134-135
92
92
97
Ar
H
Ar
MeS
O
H
H
H
H
C6H4-Cl(4)
Zn
1-Naphthyl
d
e
AcOH
O
O
O
N
R
Me
Me
C6H5
54-55
114-115
93
85
N
R
C H -OMe(4)
f
g
6
4
97-98
97-98
75-76
82
82
83
Me C6H4-Cl(4)
1-Naphthyl
5,6
7a-i
h
i
Me
Me 2-Thienyl
a All reactions were carried out in asystem of 5,6 (1.0 mmol) and zinc dust (5.0 mmol) in
acetic acid (20 mL) under reflux for 1 h.
b This yield was obtained by using Raney nickel.
Table 3. Reduction of 5-Hydroxyimino-4-methylthio-3-phenyl-3-pyrrolin-2-ones with
Zinc Dust a
shown in Table 2.
These
Ar
H
H
succinimides (7a-d) were also
obtained from the corresponding
hydroxyimino compounds (4) in
good yields as shown in Table 3. The
intermediates in this reaction are
thought to be imino compounds and
were readily converted to carbonyl
compounds through hydrolysis. In
H
H
O
Ar
H
HN
N
H
H
O
H
O
Zn
conc.-HCl
4a,b,e,g
in AcOH
reflux in MeOH
+
N
H
Ar
H
H
O
O
N
H
Yield(%)
Ar
C6H5
C6H4-OMe(4)
C6H4-Cl(4)
1-Naphthyl
No.
R
7a
b
H
H
71
74
a All reactions were carried out in a system of
4 (1.0 mmol) and zinc dust (5.0 mmol) in
acetic acid (29 mmol) under reflux for 1 h.
c
H
H
72
91
d

conclusion, 4-aryl- and heteroaryl-3-methylthio-3-pyrroline-2,5-dione derivatives were readily obtained
through the reaction of nitroketene dithioacetal with aryl- or heteroarylacetonitriles. This is a new
synthetic example of nitroktene dithioacetal with active methylene compounds of benzyl types.
REFERENCES
1. a) J. B. P. A. Wijnberg, W. N. Speckamp, and H. E. Schoemaker, Tetrahedron Lett., 1974, 4073; b) J.
B. P. A. Wijnberg, and W. N. Speckamp, Tetrahedron Lett., 1975, 3963; c) M. Y. Kim, J. E. Starrett,
Jr., and S. M. Weinreb, J. Org. Chem., 1981, 46, 5383; d) L. E. Overman and R. M. Burk, Tetrahedron
Lett., 1984, 25, 5739; d) K. Bodendorf and W. Kriegerm, Arch. Pharm., 1957, 290, 441.
2. I. O. Edafiogho and K. R. Scott, “Therapeutic Agents” in “Burger’s Medicinal Chemistry and Drug
Discovery”, Vol. 3, ed. by M. E. Wolff, A Wiley-Intersciences Publication, John Wiley & Sons, New
York, 1996, pp. 175-260.
3. a) W. J. Middleton and V. A. Engelhardt, J. Am. Chem. Soc., 1958, 80, 2829; b) Y. Tominaga, S.
Kohra, H. Honkawa and A. Hosomi, Heterocycles, 1989, 29, 1409
4. a) Y. Tominaga, N. Yoshioka, and S. Kataoka, Heterocycles, 1996, 43, 1597; b) Y. Tominaga, K.
Komiya, S. Itonaga, N. Yoshioka, S. Kataoka, K. Sasaki, and T. Hirota, Heterocylces, 1997, 46, 41; c)
Y. Tominaga, N. Yoshioka, S. Kataoka, Y. Shigemitsu, T. Hirota and K. Sasaki, Heterocycles, 1999,
50, 43
5. a) Y. Tominaga and Y. Matsuda , J. Heterocycl. Chem., 1985, 22, 937; b) Y. Tominaga and Y. Matsuda,
Yuki Gousei Kyoukaishi (J. Synth. Org. Chem. Japan), 1985, 43, 669.
6. J. Sandstrom and I. Wennerbeck, Acta Chem. Scand., 1970, 24, 1191
7. C. A. Batty, M. K. Manthey, J. Kirk, M. Manthey, and R. I. Christopherson, J. Heterocycl. Chem.,
1997, 34, 1355.