Synthesis and reactions of N-methyl-4-(methylthio)thieno[2,3-d]- pyrimidinium salts

Article abstract of DOI:10.1002/jhet.5570450543

(Chemical Equation Presented) Two methods for the preparation of N-methyl-4-(methylthio)thieno[2,3-d]pyrimidinium salts 6a,b and 13a,b are described. Treatment of 6a,b and/or 13a,b with active methylene compounds such as malononitrile and ethyl cyanoaceta

Full text of DOI:10.1002/jhet.5570450543

Sep-Oct 2008
1503
Synthesis and Reactions of N-Methyl-4-(methylthio)thieno[2,3-d]-
pyrimidinium Salts
Hiroshi Maruoka,* Fumi Okabe and Kenji Yamagata
Faculty of Pharmaceutical Sciences, Fukuoka University
8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
E-mail: maruoka@fukuoka-u.ac.jp
Received December 24, 2007
C(CN)R2
SMe
N
S
I
CH2(CN)R2
Me
R1
Me
Me
N
MeI
MeI
N
N
R1
R1
N
S
S
N
S
S
N
S
C(CN)R2
N
SMe
N
CH2(CN)R2
R1
R1
R1
N
S
N
S
N
I
Me
Me
Me
R1 = Me, Ph
R2 = CN, CO2Et
Two methods for the preparation of N-methyl-4-(methylthio)thieno[2,3-d]pyrimidinium salts 6a,b and
13a,b are described. Treatment of 6a,b and/or 13a,b with active methylene compounds such as
malononitrile and ethyl cyanoacetate in the presence of sodium methoxide caused nucleophilic addition
followed by elimination of methanethiol, giving the corresponding N-methyl-4-ylidenethieno[2,3-d]-
pyrimidines 7a,b, 8a,b, 14a,b and 15a,b.
J. Heterocyclic Chem., 45, 1503 (2008).
INTRODUCTION
-thienopyrimidines (type A) [23]. On the other hand, to
the best of our knowledge, there are relatively few
methods in the literature describing the preparation
[24ꢀ27] of 4-ylidene-containing fused pyrimidines such
as types C, D and E, even though they may have
biological activity. Therefore we studied the reaction of
malononitrile derivative 1 with a series of alkylating
reagents. Although treatment of 1 with excess of methyl
iodide and 1.1 equivalent of sodium hydride in N,N-
dimethylformamide gave ꢂ-methylated malononitrile
derivative 2 in 74% yield, the desired N-methyl-4-
ylidenethieno[2,3-d]pyrimidine 7b or 14b was not
obtained at all [21] (Scheme 1). This result indicates that
the synthesis of N-alkylated 4-ylidenethieno[2,3-d]-
pyrimidines is not easy. In continuation and in order to
extend the scope of the method, we aimed to examine the
possibility of synthesis a series of N-methyl-4-ylidene-
The fused pyrimidine ring system is a commonly
encountered structural core in a number of natural and
synthetic molecules with a wide range of biological
activities [1ꢀ9]. In this context, the synthesis of
compounds containing this ring system continues to
attract attention and provides an interesting challenge
[10ꢀ19]. For these reasons, we have been interested in the
development of the methods for the synthesis of fused
pyrimidine derivatives.
CH(R2)R3
N
C(R2)R3
NH
C(R2)R3
N
R1
N
R1
N
R1
N
H
X
X
X
X
X
A
D
B
E
C
C(R2)R3
C(R2)R3
N
R4
N
X = O, S
R1
R1
N
N
Scheme 1
R4
Me C(CN)2
Figure 1 Five Different [d]Fused Pyrimidines
N
C(CN)2
S
S
N
Ph
In our previous papers [20ꢀ22] we discussed the
synthesis of 4-substituted furo(and thieno)[2,3-d]-
pyrimidines through a nucleophilic addition of various
nucleophiles to heterocyclic ꢁ-enaminonitriles (types A
and B in Figure 1). More recently, we have also
demonstrated the one-pot synthesis of 4-alkoxy-furo and
MeI
2
NH
C(CN)2
Me
C(CN)2
N
S
N
Ph
1
N
or
X
N
S
N
Ph
Ph
7b
14b Me

1504
H. Maruoka, F. Okabe and K. Yamagata
Vol 45
Scheme 2
thieno[2,3-d]pyrimidines by the reaction of N-methyl-4-
(methylthio)thieno[2,3-d]pyrimidinium salts with active
methylene compounds.
O
S
O
Me
R1
Me
P2S5
MeI
NH
R1
N
N
R1
S
N
S
N
S
N
RESULTS AND DISCUSSION
3a,b
5a,b
4a,b
MeI
Initially, we examined the synthesis of 3-methyl-4-
ylidenethieno[2,3-d]pyrimidines 7a,b and 8a,b starting
from thieno[2,3-d]pyrimidin-4(3H)-ones 3a,b, which
were prepared from 2-acylamino-4,5-dihydro-3-thio-
phenecarbonitrile [20,21]. Thus, the reaction of 3a,b with
methyl iodide in the presence of sodium methoxide in
methanol gave the corresponding 3-methylthieno[2,3-d]-
pyrimidin-4(3H)-ones 4a,b (70,61%) together with 4-
methoxylthieno[2,3-d]pyrimidine 4c [23] (10%) as a
minor product (Scheme 2). After treating 4a,b with
phosphorous pentasulfide in pyridine, 3-methylthieno[2,3-
d]pyrimidin-4(3H)-thiones 5a,b were isolated in 73 and
79% yield, respectively. Subsequently, the alkylation
reaction of 5a,b with methyl iodide provided the
corresponding 3-methyl-4-(methylthio)thieno[2,3-d]-
pyrimidinium salts 6a,b (97,75%). Treatment of 6a,b with
malononitrile or ethyl cyanoacetate in the presence of
sodium hydride caused nucleophilic addition followed by
elimination of methanethiol to afford 3-methyl-4-ylidene-
thieno[2,3-d]pyrimidines 7a,b (51,68%) or 8a,b
(69,84%), respectively. It makes us believe that since
nucleophilic addition of activated methylene compounds
to the 4-position of 6a,b would easily occur, 7a,b and
8a,b could be obtained.
C(CN)R2
SMe
N
I
Me
CH2(CN)R2
Me
N
R1
N
R1
S
S
N
7a,b
8a,b
6a,b
OMe
N
R1
R2
3ꢀ8
a
b
7
8
CN
CO2Et
Me
Ph
S
N
Ph
4c
Scheme 3
O
O
O
MeNH2 HCl
NH2
NH2
NH2
NHMe
NH2
NMe
S
S
S
9
10
R1COCl or (R1CO)2O
O
SMe
N
S
P2S5
MeI
N
N
R1
R1
R1
S
N
S
N
S
N
I
Me
Me
Me
11a,b
13a,b
12a,b
CH2(CN)R2
We next tried the synthesis of 1-methyl-4-ylidene-
thieno[2,3-d]pyrimidines 14a,b and 15a,b (Scheme 3).
First the construction of 1-methylated thieno[2,3-d]-
pyrimidin-4(1H)-ones was investigated and second the
preparation of 1-methylated 4-(methylthio)thieno[2,3-d]-
pyrimidinium salts was examined. The reaction of 2-
amino-4,5-dihydro-3-thiophenecarboxamide (9), prepared
commonly from 2-amino-4,5-dihydro-3-thiophenecarbo-
nitrile according to our earlier work [28], with methyl-
amine hydrochloride gave 4,5-dihydro-2-(methylamino)-
3-thiophenecarboxamide (10) in 75% yield. Treatment of
10 with acetic anhydride or benzoyl chloride in pyridine
caused N-acylation of methylamino group and subsequent
cyclocondensation with dehydration to yield 1-methyl-
thieno[2,3-d]pyrimidin-4(1H)-ones 11a,b (68, 77%). The
reaction of compounds 11a,b with phosphorous
pentasulfide by the procedure described above provided
C(CN)R2
N
O
R1
R2
CN
11–15
NH2
a
b
Me 14
Ph 15 CO2Et
R1
N
S
S
N(Me)COMe
16
Me
14a,b
15a,b
These products 4ꢀ8 and 10ꢀ15 gave satisfactory
elemental analyses and spectroscopic data (1H nmr, 13C
nmr and mass) consistent with their assigned structures.
For example, the ir spectrum of 4a displays a carbonyl
band at 1650 cm-1, whereas that of 11a shows at 1615
1
cm-1; the H nmr spectrum of 4a exhibits a three-proton
singlet at ꢁ 2.50 attributable to the 2-methyl protons and a
three-proton singlet at ꢁ 3.49 due to the N-methyl protons,
whereas that of 11a shows a three-proton singlet at ꢁ 2.47
attributable to the 2-methyl protons and a three-proton
singlet at ꢁ 3.57 due to the N-methyl protons; the 13C nmr
spectrum of 4a shows a signal at ꢁ 30.7 due to the N-
methyl carbon and a signal at ꢁ 158.4 due to the carbonyl
carbon, whereas that of 11a exhibits a signal at ꢁ 38.9 due
to the N-methyl carbon and a signal at ꢁ 166.2 due to the
carbonyl carbon. Mass spectra and elemental analyses of
4a and 11a point to the same molecular ion and elemental
composition C8H10N2OS (see experimental section). In
1-methylthieno[2,3-d]pyrimidin-4(1H)-thiones
12a,b
(66,84%), which were treated with methyl iodide to form
1-methyl-4-(methylthio)thieno[2,3-d]pyrimidinium salts
13a,b (94,91%). Compounds 13a,b reacted with
malononitrile or ethyl cyanoacetate to afford 1-methyl-4-
ylidenethieno[2,3-d]pyrimidines 14a,b (44,43%) or 15a,b
(73,88%), respectively.

Sep-Oct 2008
Synthesis and Reactions of N-Methyl-4-(methylthio)thieno[2,3-d]pyrimidinium Salts
1505
5,6-Dihydro-3-methyl-2-phenylthieno[2,3-d]pyrimidin-
4(3H)-one (4b). This compound was obtained as colorless
needles (1.48 g, 60%), mp 156ꢁ158 ˚C (acetoneꢁpetroleum
ether); ir (potassium bromide): ꢂ 1650 cm-1 (C=O); 1H nmr
(deuteriochloroform): ꢀ 3.29ꢁ3.33 (m, 2H, 5-H), 3.41ꢁ3.45 (m,
2H, 6-H), 3.42 (s, 3H, 3-Me), 7.47ꢁ7.49 ppm (m, 5H, aryl H);
13C nmr (deuteriochloroform): ꢀ 30.85 (C-5), 30.87 (C-6), 34.1
(3-Me), 117.1 (C-4a), 128.0, 128.8, 130.4, 134.6 (C aryl), 158.7
(C-4), 160.4 (C-2), 170.0 ppm (C-7a); ms: m/z 244 [M+]. Anal.
Calcd. for C13H12N2OS+0.2H2O: C, 62.98; H, 5.04; N, 11.30.
Found: C, 62.95; H, 5.09; N, 11.29.
order to understand better the formation of 11a,
compound 10 was allowed to react with acetyl chloride
under the milder conditions to furnish N-acetylated
carboxamide derivative 16 in 64% yield. Upon heating,
compound 16 was cyclized to 1-methylthieno[2,3-d]-
pyrimidin-4(1H)-one 11a in 97% yield. The melting point
and ir spectrum of this compound coincided with those of
an authentic sample prepared from 10 and acetyl chloride.
Interestingly, in deuteriochloroform or dimethyl
sulfoxide-d6, the nmr spectra indicated that compounds
8a,b and 15a,b existed as a geometrical single isomer of
E- or Z-configuration but their configuration was not
confirmed by nmr spectroscopy.
In conclusion, we have developed a convenient method
for the construction of N-methyl-4-ylidenethieno[2,3-d]-
pyrimidines 7, 8, 14 and 15 by the reaction of N-methyl-
4-(methylthio)thieno[2,3-d]pyrimidinium salts 6 and 13
with active methylene compounds. It is worth noting that
very little study [29] has thus far been devoted to fused
pyrimidinium salts such as compounds 6 and 13. This
methodology offers significant advantages with regard to
the supply of ylidene-containing fused pyrimidines, which
according to the literature may exhibit biological activities
such as anti-inflammatory, anthelmintic, analgesic and
anticonvulsive activities.
The Preparation of Compound 10 from
9
and
Methylamine Hydrochloride. A mixture of 9 [28] (0.72 g, 5
mmoles) and methylamine hydrochloride (0.68 g, 10 mmoles) in
pyridine (5 mL) was stirred at 130 ˚C for 3 hours in a sealed
tube. After removal of pyridine in vacuo, cold water was added
to the residue. The resulting mixture was extracted with
chloroform (60 mL). The extract was dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was
recrystallized from acetone–petroleum ether to afford 4,5-
dihydro-2-(methylamino)-3-thiophenecarboxamide (10). This
compound was obtained as colorless scales (0.59 g, 75%), mp
125ꢁ126 ˚C; ir (potassium bromide): ꢂ 3400, 3200 (NH), 1665
1
cm-1 (C=O); H nmr (deuteriochloroform): ꢀ 2.44ꢁ2.57 (m, 2H,
4-H), 2.91 (t, J = 7.8 Hz, 0.4H, 3-H), 2.97 (d, J = 4.9 Hz, 0.4H,
5-H), 3.12ꢁ3.30 (m, 1.6H, 5-H), 3.17 (s, 1.2H, NMe), 3.18 (s,
1.8H, NHMe), 3.47ꢁ3.51 (m, 0.6H, NHMe), 4.83 (br. s, 0.4H,
CONH2), 5.72 (br. s, 0.6H, CONH2), 7.76 (br. s, 0.6H, CONH2),
8.56 ppm (br. s, 0.4H, CONH2); 13C nmr (deuteriochloroform): ꢀ
30.02, 30.04 (C-4), 31.1, 33.1 (C-5), 33.3 (C-3), 43.9 (NMe),
53.8 (NHMe), 88.1 (C-3), 168.7, 170.6 (C-2), 173.0 ppm
(C=O); ms: m/z 158 [M+]. Anal. Calcd. for C6H10N2OS: C,
45.55; H, 6.37; N, 17.71. Found: C, 45.38; H, 6.31; N, 17.86.
The Preparation of Compounds 11a,b from 10. A mixture
of 10 (1.58 g, 10 mmoles) and acetic anhydride (10 mL) or
benzoyl chloride (1.55 g, 11 mmoles) in pyridine (20 mL) was
stirred at 80 ˚C (in the case of the preparation of 11a) or 60 ˚C
(in the case of the preparation of 11b) for 2 hours. Further
processing of the resulting mixture is described in the following
paragraphs.
EXPERIMENTAL
All melting points are uncorrected. The ir spectra were
recorded on a JASCO A-302 spectrometer. The 1H and 13C nmr
spectra were recorded on a JEOL JNM-A500 spectrometer at
500 and 125 MHz, respectively. The 1H and 13C chemical shifts
(ꢀ) are reported in parts per million (ppm) relative to
tetramethylsilane as internal standard. The mass (70 eV, electron
impact ionization) spectra were obtained on a JEOL JMS-D300
spectrometer. The elemental analyses were performed on a
YANACO MT-6 CHN analyzer.
(A) After removal of the solvent in vacuo, the residue was
recrystallized from acetone to give 11a.
The Preparation of Compounds 4a,b from 3a,b and
Methyl Iodide. A solution of 3a [20] (1.68 g, 10 mmoles) or 3b
[21] (2.30 g, 10 mmoles), methyl iodide (5.68 g, 40 mmoles) and
sodium (0.25 g, 11 mmoles) in anhydrous methanol (30 mL) was
stirred at 50 ˚C overnight. After removal of the solvent in vacuo,
cold water was added to the residue. The precipitate was isolated
by filtration, washed with water, dried and purified by column
chromatography on silica gel with chloroform–acetone (4:1) as the
eluent to afford 4a,b. In the case of the preparation of 4b, the first
elution with chloroform gave 4c [23] (0.25 g, 10%).
(B) To a reaction mixture was added cold water with stirring.
The resulting mixture was extracted with chloroform (60 mL).
The extract was dried over anhydrous sodium sulfate and
concentrated in vacuo. The residue was recrystallized from
acetone to give 11b.
5,6-Dihydro-1,2-dimethylthieno[2,3-d]pyrimidin-4(1H)-
one (11a). This compound was obtained as colorless prisms
(1.24 g, 68%), mp 196ꢁ200 ˚C; ir (potassium bromide): ꢂ 1615
1
cm-1 (C=O); H nmr (deuteriochloroform): ꢀ 2.47 (s, 3H, 2-Me),
3.28 (t, J = 8.5 Hz, 2H, 5-H), 3.46 (t, J = 8.5 Hz, 2H, 6-H), 3.57
ppm (s, 3H, 1-Me); 13C nmr (deuteriochloroform): ꢀ 22.0 (2-
Me), 32.4 (C-5), 32.5 (C-6), 38.9 (1-Me), 117.4 (C-4a), 157.1
(C-7a), 158.5 (C-2), 166.2 ppm (C-4); ms: m/z 182 [M+]. Anal.
Calcd. for C8H10N2OS: C, 52.72; H, 5.53; N, 15.37. Found: C,
52.73; H, 5.56; N, 15.37.
5,6-Dihydro-1-methyl-2-phenylthieno[2,3-d]pyrimidin-4(1H)-
one (11b). This compound was obtained as colorless needles
(1.87 g, 77%), mp 178ꢁ179 ˚C; ir (potassium bromide): ꢂ 1615
cm-1 (C=O); 1H nmr (dimethyl sulfoxide-d6): ꢀ 3.13 (t, J = 8.4 Hz,
2H, 5-H), 3.41 (s, 3H, 1-Me), 3.52 (t, J = 8.4 Hz, 2H, 6-H),
5,6-Dihydro-2,3-dimethylthieno[2,3-d]pyrimidin-4(3H)-
one (4a). This compound was obtained as colorless columns
(1.27 g, 70%), mp 149ꢁ151 ˚C (acetoneꢁpetroleum ether); ir
(potassium bromide):
ꢂ
1650 cm-1 (C=O); 1H nmr
(deuteriochloroform): ꢀ 2.50 (s, 3H, 2-Me), 3.23 (t, J = 8.4 Hz,
2H, 5-H), 3.38 (t, J = 8.4 Hz, 2H, 6-H), 3.49 ppm (s, 3H, 3-Me);
13C nmr (deuteriochloroform): ꢀ 23.3 (2-Me), 30.7 (3-Me), 30.8
(C-5), 30.9 (C-6), 116.2 (C-4a), 158.4 (C-4), 159.1 (C-2), 169.7
ppm (C-7a); ms: m/z 182 [M+]. Anal. Calcd. for C8H10N2OS: C,
52.72; H, 5.53; N, 15.37. Found: C, 52.62; H, 5.55; N, 15.37.

1506
H. Maruoka, F. Okabe and K. Yamagata
Vol 45
7.49ꢀ7.60 ppm (m, 5H, aryl H); 13C nmr (dimethyl sulfoxide-d6):
ꢁ 31.75 (C-5), 31.8 (C-6), 40.6 (1-Me), 117.0 (C-4a), 128.27,
128.29, 130.0, 133.6 (C aryl), 157.4 (C-7a), 159.4 (C-2), 164.7
ppm (C-4); ms: m/z 244 [M+]. Anal. Calcd. for C13H12N2OS: C,
63.91; H, 4.95; N, 11.47. Found: C, 64.11; H, 5.11; N, 11.85.
The Preparation of Compounds 5a,b and 12a,b from 4a,b
and/or 11a,b and Phosphorous Pentasulfide. A solution of 4a
(1.82 g, 10 mmoles), 4b (2.44 g, 10 mmoles), 11a (1.82 g, 10
mmoles) or 11b (2.44 g, 10 mmoles) and phosphorous
pentasulfide (2.66 g, 12 mmoles) in pyridine (20 mL) was
refluxed for 6 hours (in the case of the preparation of 5a,b) or
stirred at 70 ˚C for 4 hours (in the case of the preparation of
12a,b). After removal of pyridine in vacuo, cold water was
added to the residue. The precipitate was isolated by filtration,
washed with water, dried and purified by column
chromatography on silica gel with chloroform (in the case of
5a,b) or chloroformꢀacetone (4:1) (in the case of 12a,b) as the
eluent to afford 5a,b and 12a,b.
5,6-Dihydro-2,3-dimethylthieno[2,3-d]pyrimidin-4(3H)-
thione (5a). This compound was obtained as pale yellow
needles (1.45 g, 73%), mp 186ꢀ187 ˚C (acetone); 1H nmr
(deuteriochloroform): ꢁ 2.62 (s, 3H, 2-Me), 3.36ꢀ3.45 (m, 4H,
5- and 6-H), 3.96 ppm (s, 3H, 3-Me); 13C nmr (deuteriochloro-
form): ꢁ 24.7 (2-Me), 29.6 (C-5), 35.6 (C-6), 38.2 (3-Me), 132.9
(C-4a), 159.2 (C-2), 166.4 (C-7a), 177.4 ppm (C-4); ms: m/z
198 [M+]. Anal. Calcd. for C8H10N2S2: C, 48.45; H, 5.08; N,
14.13. Found: C, 48.24; H, 5.06; N, 14.17.
5,6-Dihydro-3-methyl-2-phenylthieno[2,3-d]pyrimidin-4(3H)-
thione (5b). This compound was obtained as pale yellow
needles (2.04 g, 79%), mp 200ꢀ201 ˚C (acetone); 1H nmr
(deuteriochloroform): ꢁ 3.41ꢀ3.46 (m, 2H, 5-H), 3.49ꢀ3.53 (m,
2H, 6-H), 3.83 (s, 3H, 3-Me), 7.26ꢀ7.53 ppm (m, 5H, aryl H);
13C nmr (deuteriochloroform): ꢁ 29.7 (C-5), 35.5 (C-6), 41.8 (3-
Me), 127.9, 128.9, 130.6 (C aryl), 133.6 (C-4a), 135.0 (C aryl),
160.7 (C-2), 166.4 (C-7a), 177.7 ppm (C-4); ms: m/z 259 [M+].
Anal. Calcd. for C13H12N2S2: C, 59.97; H, 4.65; N, 10.76. Found:
C, 59.90; H, 4.76; N, 10.63.
5,6-Dihydro-1,2-dimethylthieno[2,3-d]pyrimidin-4(1H)-
thione (12a). This compound was obtained as yellow columns
(1.31 g, 66%), mp 199ꢀ203 ˚C (acetone–methylene chloride);
1H nmr (deuteriochloroform): ꢁ 2.56 (s, 3H, 2-Me), 3.47 (s, 4H,
5-H), 3.61 ppm (s, 3H, 1-Me); 13C nmr (deuteriochloroform): ꢁ
21.9 (2-Me), 31.3 (C-5), 36.3 (C-6), 39.9 (1-Me), 132.4 (C-4a),
153.4 (C-2), 154.3 (C-7a), 190.1 ppm (C-4); ms: m/z 198 [M+].
Anal. Calcd. for C8H10N2S2: C, 48.45; H, 5.08; N, 14.13. Found:
C, 48.24; H, 5.05; N, 14.11.
6b) was stirred at room temperature overnight. The precipitate
was isolated by filtration, washed with acetone and dried. The
crude products 6a,b and 13a,b was sufficiently pure to be used
without further purification.
5,6-Dihydro-2,3-dimethyl-4-(methylthio)thieno[2,3-d]-
pyrimidinium Iodide (6a). This compound was obtained as
1
yellow needles (3.29 g, 97%), mp 167ꢀ169 ˚C dec.; H nmr
(dimethyl sulfoxide-d6): ꢁ 2.69 (s, 3H, SMe), 2.83 (s, 3H, 2-Me),
3.64ꢀ3.68 (m, 2H, 5-H), 3.71ꢀ3.75 (m, 2H, 6-H), 4.06 ppm (s,
3H, 3-Me); 13C nmr (dimethyl sulfoxide-d6): ꢁ 17.4 (SMe), 24.4
(2-Me), 31.4 (C-5), 32.4 (C-6), 40.9 (3-Me), 136.9 (C-4a), 154.1
(C-4), 164.0 (C-2), 183.1 ppm (C-7a); ms: m/z 213 [M-I]+. Anal.
Calcd. for C9H13N2IS2: C, 31.77; H, 3.85; N, 8.23. Found: C,
31.72; H, 3.86; N, 8.01.
5,6-Dihydro-3-methyl-4-(methylthio)-2-phenylthieno[2,3-d]-
pyrimidinium Iodide (6b). This compound was obtained as
1
yellow needles (3.01 g, 75%), mp 177ꢀ178 ˚C dec.; H nmr
(dimethyl sulfoxide-d6): ꢁ 2.83 (s, 3H, SMe), 3.72ꢀ3.82 (m, 4H,
5- and 6-H), 3.95 (s, 3H, 3-Me), 7.62ꢀ7.72 (m, 3H, aryl H),
7.77ꢀ7.80 ppm (m, 2H, aryl H); 13C nmr (dimethyl sulfoxide-
d6): ꢁ 17.4 (SMe), 31.7 (C-5), 32.3 (C-6), 44.3 (3-Me), 128.8,
129.1, 131.8, 132.5 (C aryl), 136.8 (C-4a), 155.6 (C-4), 162.4
(C-2), 182.9 ppm (C-7a); ms: m/z 275 [M-I]+. Anal. Calcd. for
C14H15N2IS2: C, 41.80; H, 3.76; N, 6.96. Found: C, 41.78; H,
3.90; N, 6.85.
5,6-Dihydro-1,2-dimethyl-4-(methylthio)thieno[2,3-d]-
pyrimidinium Iodide (13a). This compound was obtained as
1
colorless prisms (3.28 g, 94%), mp 195ꢀ196 ˚C dec.; H nmr
(dimethyl sulfoxide-d6): ꢁ 2.70 (s, 3H, 2-Me), 2.80 (s, 3H, SMe),
3.41 (t, J = 8.3 Hz, 2H, 5-H), 3.85 (t, J = 8.3 Hz, 2H, 6-H), 3.88
ppm (s, 3H, 1-Me); 13C nmr (dimethyl sulfoxide-d6): ꢁ 12.5 (2-
Me), 22.3 (SMe), 31.2 (C-5), 34.0 (C-6), 42.4 (1-Me), 128.8 (C-
4a), 160.4 (C-2), 165.7 (C-4), 168.3 ppm (C-7a); ms: m/z 213
[M-I]+. Anal. Calcd. for C9H13N2IS2: C, 31.77; H, 3.85; N, 8.23.
Found: C, 31.67; H, 3.75; N, 8.21.
5,6-Dihydro-1-methyl-4-(methylthio)-2-phenylthieno[2,3-d]-
pyrimidinium Iodide (13b). This compound was obtained as
1
yellow prisms (3.64 g, 91%), mp 191ꢀ192 ˚C dec.; H nmr
(dimethyl sulfoxide-d6): ꢁ 2.69 (s, 3H, SMe), 3.49 (t, J = 8.4 Hz,
2H, 5-H), 3.81 (s, 3H, 1-Me), 3.92 (t, J = 8.4 Hz, 2H, 6-H),
7.63ꢀ7.70 (m, 3H, aryl H), 7.82ꢀ7.84 ppm (m, 2H, aryl H); 13C
nmr (dimethyl sulfoxide-d6): ꢁ 12.7 (SMe), 31.1 (C-5), 34.2 (C-
6), 44.3 (1-Me), 128.7, 129.4 (C aryl), 129.6 (C-4a), 131.2,
131.8 (C aryl), 158.8 (C-2), 165.6 (C-4), 169.2 ppm (C-7a); ms:
m/z 275 [M-I]+. Anal. Calcd. for C14H15N2IS2: C, 41.80; H, 3.76;
N, 6.96. Found: C, 41.75; H, 3.73; N, 6.91.
5,6-Dihydro-1-methyl-2-phenylthieno[2,3-d]pyrimidin-4(1H)-
thione (12b). This compound was obtained as yellow prisms
(2.22 g, 84%), mp 171ꢀ172 ˚C (acetone); H nmr (deuterio-
The Preparation of Compounds 7a,b, 8a,b and/or 14a,b,
15a,b from 6a,b and/or 13a,b and Active Methylene
Compounds. To an ice-cooled and stirred solution of
malononitrile (0.66 g, 10 mmoles) or ethyl cyanoacetate (1.13
g, 10 mmoles) in tetrahydrofuran (30 mL) was added 60%
sodium hydride (0.40 g, 10 mmoles). Stirring was continued
at room temperature until the evolution of gas ceased. To the
obtained solution was added 6a (1.70 g, 5 mmoles), 6b (2.01
g, 5 mmoles), 13a (1.70 g, 5 mmoles) or 13b (2.01 g, 5
mmoles) with stirring and ice-cooling, and then the mixture
was stirred at room temperature for 3 hours. After removal of
the solvent in vacuo, cold water was added to the residue.
Further processing of the resulting mixture is described in the
following paragraphs.
1
chloroform): ꢁ 3.50ꢀ3.57 (m, 4H, 5- and 6-H), 3.53 (s, 3H,
1-Me), 7.44ꢀ7.52 (m, 3H, aryl H), 7.55ꢀ7.57 ppm (m, 2H, aryl
H); 13C nmr (deuteriochloroform): ꢁ 31.3 (C-5), 36.3 (C-6), 41.5
(1-Me), 128.7, 128.8, 130.7, 132.6 (C-aryl), 132.9 (C-4a), 154.5
(C-2), 154.6 (C-7a), 189.9 ppm (C-4); ms: m/z 260 [M+]. Anal.
Calcd. for C13H12N2S2+0.25H2O: C, 58.95; H, 4.76; N, 10.58.
Found: C, 59.02; H, 4.71; N, 10.52.
The Preparation of Compounds 6a,b and 13a,b from 5a,b
and/or 12a,b and Methyl Iodide. A solution of 5a (1.98 g, 10
mmoles), 12a (1.98 g, 10 mmoles) and 12b (2.60 g, 10 mmoles)
in methyl iodide (60 mL) (in the case of the preparation of 6a,
13a and 13b) or 5b (2.60 g, 10 mmoles) and methyl iodide (60
mL) in tetrahydrofuran (60 mL) (in the case of the preparation of
(A) The resulting mixture was extracted with ethyl acetate (60
mL). The extract was dried over anhydrous sodium sulfate and

Sep-Oct 2008
Synthesis and Reactions of N-Methyl-4-(methylthio)thieno[2,3-d]pyrimidinium Salts
1507
concentrated in vacuo. The residue was purified by column
chromatography on silica gel with chloroformꢀacetone (4:1) as
the eluent to afford 7a and 8a.
160.4 (C-2), 166.5 (C=O), 175.7 ppm (C-7a); ms: m/z 277 [M+].
Anal. Calcd. for C13H15N3O2S: C, 56.30; H, 5.45; N, 15.15.
Found: C, 56.33; H, 5.54; N, 15.11.
(B) The precipitate was isolated by filtration, washed with
water, dried and recrystallized from an appropriate solvent to
yield 7b, 8b, 14a,b and 15a,b.
Ethyl cyano(5,6-dihydro-3-methyl-2-phenylthieno[2,3-d]-
pyrimidin-4(3H)-ylidene)acetate (8b). This compound was
obtained as yellow needles (1.42 g, 84%), mp 204ꢀ206 ˚C
(acetone); ir (potassium bromide): ꢁ 2190 (CN), 1660 cm-1
(5,6-Dihydro-2,3-dimethylthieno[2,3-d]pyrimidin-4(3H)-
ylidene)propanedinitrile (7a). This compound was obtained as
pale yellow plates (0.59 g, 51%), mp 219ꢀ220 ˚C dec. (acetone);
ir (potassium bromide): ꢁ 2200, 2190 cm-1 (CN); 1H nmr
(deuteriochloroform): ꢂ 2.26 (s, 3H, 2-Me), 3.46 (t, J = 8.4 Hz,
2H, 5-H), 3.68 (t, J = 8.4 Hz, 2H, 6-H), 3.83 ppm (s, 3H, 3-Me);
13C nmr (deuteriochloroform): ꢂ 24.1 (2-Me), 30.4 (C-5), 33.3
(C-6), 42.0 (3-Me), 42.2 [=C(CN)2], 118.4 (CN), 120.9 (C-4a),
155.3 (C-4), 160.2 (C-2), 173.4 ppm (C-7a); ms: m/z 230 [M+].
Anal. Calcd. for C11H10N4S: C, 57.37; H, 4.38; N, 24.33. Found:
C, 57.38; H, 4.42; N, 24.39.
1
(C=O); H nmr (deuteriochloroform): ꢂ 1.34 (t, J = 7.0 Hz, 3H,
OCH2Me), 3.53 (t, J = 8.3 Hz, 2H, 5-H), 3.68 (t, J = 8.3 Hz, 2H,
6-H), 3.69 (s, 3H, 3-Me), 4.24 (q, J = 7.0 Hz, 2H, OCH2Me),
7.35ꢀ7.59 (m, 3H, aryl H), 7.67ꢀ7.69 ppm (m, 2H, aryl H); 13C
nmr (deuteriochloroform): ꢂ 14.7 (OCH2Me), 30.9 (C-5), 33.4
(C-6), 47.1 (3-Me), 60.2 (OCH2Me), 63.3 [=C(CN)CO2CH2Me],
120.8 (CN), 125.6 (C-4a), 129.0, 129.1, 131.8, 133.7 (C aryl),
155.7 (C-4), 161.9 (C-2), 166.5 (C=O), 175.4 ppm (C-7a); ms:
m/z 339 [M+]. Anal. Calcd. for C18H17N3O2S: C, 63.70; H, 5.05;
N, 12.38. Found: C, 63.73; H, 5.22; N, 12.10.
Ethyl cyano(5,6-dihydro-1,2-dimethylthieno[2,3-d]pyrim-
idin-4(1H)-ylidene)acetate (15a). This compound was obtained
as yellow needles (1.01 g, 73%), mp 231ꢀ232 ˚C
(acetoneꢀmethylene chloride); ir (potassium bromide): ꢁ 2190
(5,6-Dihydro-3-methyl-2-phenylthieno[2,3-d]pyrimidin-
4(3H)-ylidene)propanedinitrile (7b). This compound was
obtained as yellow plates (0.99 g, 68%), mp 261ꢀ262 ˚C dec.
(chloroformꢀmethanol); ir (potassium bromide): ꢁ 2200, 2190
1
1
cm-1 (CN); H nmr (deuteriochloroform): ꢂ 3.51 (t, J = 8.5 Hz,
(CN), 1690 cm-1 (C=O); H nmr (dimethyl sulfoxide-d6): ꢂ 1.18
2H, 5-H), 3.76 (t, J = 8.5 Hz, 2H, 6-H), 3.78 (s, 3H, 3-Me),
7.52ꢀ7.56 (m, 2H, aryl H), 7.57ꢀ7.63 ppm (m, 3H, aryl H); 13C
nmr (deuteriochloroform): ꢂ 30.6 (C-5), 33.2 (C-6), 44.3
[=C(CN)2], 46.9 (3-Me), 118.1 (CN), 120.6 (C-4a), 128.9, 129.3,
132.2, 133.2 (C aryl), 156.3 (C-4), 161.7 (C-2), 173.3 ppm (C-
7a); ms: m/z 291 [M+]. Anal. Calcd. for C16H12N4S: C, 65.73; H,
4.14; N, 19.16. Found: C, 65.84; H, 4.22; N, 19.13.
(5,6-Dihydro-1,2-dimethylthieno[2,3-d]pyrimidin-4(1H)-
ylidene)propanedinitrile (14a). This compound was obtained
as pale yellow needles (0.51 g, 44%), mp 293ꢀ294 ˚C dec.
(chloroform); ir (potassium bromide): ꢁ 2195, 2180 cm-1 (CN);
1H nmr (dimethyl sulfoxide-d6): ꢂ 2.48 (s, 3H, 2-Me), 3.49ꢀ3.52
(m, 2H, 5-H), 3.57ꢀ3.61 (m, 2H, 6-H), 3.62 ppm (s, 3H, 1-Me);
13C nmr (dimethyl sulfoxide-d6): ꢂ 21.2 (2-Me), 31.8 (C-5), 32.4
(C-6), 40.0 (1-Me), 48.1 [=C(CN)2], 115.2 (C-4a), 118.0, 119.2
(CN), 157.2 (C-2), 159.7 (C-4), 160.8 ppm (C-7a); ms: m/z 230
[M+]. Anal. Calcd. for C11H10N4S: C, 57.37; H, 4.38; N, 24.33.
Found: C, 57.43; H, 4.38; N, 24.37.
(t, J = 7.2 Hz, 3H, OCH2Me), 2.49 (s, 3H, 2-Me), 3.26ꢀ3.30 (m,
2H, 5-H), 3.50 (t, J = 8.2 Hz, 2H, 6-H), 3.64 (s, 3H, 1-Me), 4.30
ppm (q, J = 7.2 Hz, 2H, OCH2Me); 13C nmr (dimethyl sulfoxide-
d6): ꢂ 14.4 (OCH2Me), 21.5 (2-Me), 32.3 (C-5), 34.8 (C-6), 40.1
(1-Me), 58.5 (OCH2Me), 71.7 [=C(CN)CO2CH2Me], 117.5 (C-
4a), 121.2 (CN), 155.6 (C-2), 159.1 (C-4), 161.4 (C-7a), 164.9
ppm (C=O); ms: m/z 277 [M+]. Anal. Calcd. for C13H15N3O2S:
C, 56.30; H, 5.45; N, 15.15. Found: C, 56.33; H, 5.36; N, 15.01.
Ethyl cyano(5,6-dihydro-1-methyl-2-phenylthieno[2,3-d]-
pyrimidin-4(1H)-ylidene)acetate (15b). This compound was
obtained as yellow needles (1.49 g, 88%), mp 187ꢀ188 ˚C
(acetone); ir (potassium bromide): ꢁ 2190 (CN), 1670 cm-1
1
(C=O); H nmr (dimethyl sulfoxide-d6): ꢂ 1.19 (t, J = 7.0 Hz,
3H, OCH2Me), 3.28ꢀ3.52 (m, 2H, 5-H), 3.54 (s, 3H, 1-Me),
3.55ꢀ3.59 (m, 2H, 6-H), 4.05 (q, J = 7.0 Hz, 2H, OCH2Me),
7.54ꢀ7.61 (m, 3H, aryl H), 7.67ꢀ7.69 ppm (m, 2H, aryl H); 13C
nmr (dimethyl sulfoxide-d6): ꢂ 14.4 (OCH2Me), 32.4 (C-5), 34.6
(C-6), 41.7 (1-Me), 58.7 (OCH2Me), 72.7 [=C(CN)CO2CH2Me],
118.0 (C-4a), 121.0 (CN), 128.4, 129.0, 130.6, 132.6 (C aryl),
155.5 (C-2), 158.8 (C-4), 162.1 (C-7a), 164.9 ppm (C=O); ms:
m/z 339 [M+]. Anal. Calcd. for C18H17N3O2S: C, 63.70; H, 5.05;
N, 12.38. Found: C, 63.53; H, 5.11; N, 12.15.
The Preparation of Compound 16 from 10 and Acetyl
Chloride. A mixture of 10 (1.58 g, 10 mmoles) and acetyl
chloride (0.87 g, 11 mmoles) in pyridine (10 mL) was stirred at
40 ˚C for 3 hours, and then cold water was added to the reaction
mixture. The resulting mixture was extracted with chloroform
(60 mL). The extract was dried over anhydrous sodium sulfate
and concentrated in vacuo. The residue was recrystallized from
acetone to afford 4,5-dihydro-2-(N-methylacetamido)-3-thio-
phenecarboxamide (16). This compound was obtained as
colorless prisms (1.28 g, 64%), mp 143ꢀ144 ˚C; ir (potassium
bromide): ꢁ 3320, 3300, 3140 (NH), 1680, 1650 cm-1 (C=O); 1H
nmr (deuteriochloroform): ꢂ 2.14 (s, 3H, COMe), 3.13 (s, 3H,
NMe), 3.17ꢀ3.22 (m, 2H, 4-H), 3.25ꢀ3.29 (m, 2H, 5-H), 5.81
ppm (br. s, 2H, NH2); 13C nmr (deuteriochloroform): ꢂ 21.2
(COMe), 29.5 (C-4), 34.7 (NMe), 35.4 (C-5), 124.5 (C-3), 151.4
(C-2), 136.6, 170.5 ppm (C=O); ms: m/z 158 [M+]. Anal. Calcd.
for C8H12N2O2S: C, 47.98; H, 6.04; N, 13.99. Found: C, 47.99;
H, 6.08; N, 14.16.
(5,6-Dihydro-1-methyl-2-phenylthieno[2,3-d]pyrimidin-
4(1H)-ylidene)propanedinitrile (14b). This compound was
obtained as pale yellow plates (0.63 g, 43%), mp 316ꢀ317 ˚C
dec. (chloroform); ir (potassium bromide): ꢁ 2200, 2180 cm-1
(CN); 1H nmr (dimethyl sulfoxide-d6): ꢂ 3.51 (s, 3H, 1-Me),
3.57ꢀ3.61 (m, 2H, 5-H), 3.64ꢀ3.68 (m, 2H, 6-H), 7.53ꢀ7.59 (m,
3H, aryl H), 7.63ꢀ7.65 ppm (m, 2H, aryl H); 13C nmr (dimethyl
sulfoxide-d6): ꢂ 31.8 (C-5), 32.3 (C-6), 41.6 (1-Me), 48.9
[=C(CN)2], 115.8 (C-4a), 117.8, 118.9 (CN), 128.2, 128.5,
130.5, 132.1 (C aryl), 156.9 (C-2), 159.4 (C-4), 161.4 ppm (C-
7a); ms: m/z 291 [M+]. Anal. Calcd. for C16H12N4S: C, 65.73; H,
4.14; N, 19.16. Found: C, 65.79; H, 4.18; N, 19.12.
Ethyl cyano(5,6-dihydro-2,3-dimethylthieno[2,3-d]pyrim-
idin-4(3H)-ylidene)acetate (8a). This compound was obtained
as yellow columns (0.96 g, 69%), mp 163ꢀ164 ˚C (acetone); ir
1
(potassium bromide): ꢁ 2190 (CN), 1645 cm-1 (C=O); H nmr
(deuteriochloroform): ꢂ 1.31 (t, J = 7.2 Hz, 3H, OCH2Me), 2.68
(s, 3H, 2-Me), 3.47ꢀ3.51 (m, 2H, 5-H), 3.55ꢀ3.59 (m, 2H, 6-H),
3.72 (s, 3H, 3-Me), 4.19 ppm (q, J = 7.2 Hz, 2H, OCH2Me); 13
C
nmr (deuteriochloroform): ꢂ 14.7 (OCH2Me), 24.2 (2-Me), 30.7
(C-5), 33.4 (C-6), 42.3 (3-Me), 60.0 (OCH2Me), 60.4
[=C(CN)CO2CH2Me], 121.0 (CN), 126.3 (C-4a), 155.0 (C-4),

1508
H. Maruoka, F. Okabe and K. Yamagata
Vol 45
[13] Audoux, J.; Plé, N.; Turck, A.; Quéguiner, G. Tetrahedron
2004, 60, 6353.
[14] Briel, D.; Drescher, S.; Dobner, B. J. Heterocycl. Chem. 2005,
42, 841.
[15] Petricci, E.; Radi, M.; Corelli, F.; Botta, M. Tetrahedron Lett.
2003, 44, 9181.
[16] Hurst, D. T. In Second Supplements to the 2nd Edition of Rodd’s
Chemistry of Carbon Compounds, Volume IV: Heterocyclic Compounds
(Parts ꢀꢁJ), Sainsbury, M. Ed, Elsevier Sciences B.V., Amsterdam, The
Netherlands, 2000, pp 71ꢀ98.
The Preparation of Compound 11a from 16. Compound 16
(2.00 g, 10 mmole) was heated at 160 ˚C for 1 hour. The crude
product was recrystallized from acetone to afford 11a (1.76 g,
97%). The melting point and ir spectrum of this compound
coincided with an authentic sample prepared from 10 and acetic
anhydride.
Acknowledgement. We are grateful to Mr. Hiroshi Hanazono
and Ms. Yukiko Iwase for obtaining mass and nmr spectra and
to Ms. Junko Honda for her valuable help with elemental
analyses.
[17] Brown, D. J. In The Chemistry of Heterocyclic Compounds,
Quinazolines: Supplement 1, Brown, D. J. Ed, John Wiley & Sons, New
York, NY, 1996, Vol 55.
[18] Delia, T. J.; Warner, J. C. In The Chemistry of Heterocyclic
Compounds, Part 4, Fused Pyrimidines: Miscellaneous Fused Pyrimidines,
Brown, D. J. Ed, John Wiley & Sons, New York, NY, 1992, Vol 24.
[19] Armarego, W. L. F. In The Chemistry of Heterocyclic
Compounds, Part 1, Fused Pyrimidines: Quinazolines (Vol. 24), Brown, D.
J. Ed, John Wiley & Sons, New York, NY, 1967.
[20] Yamagata, K.; Tomioka, Y.; Yamazaki, M.; Noda, K. Chem.
Pharm. Bull. 1983, 31, 401.
[21] Yamagata, K.; Tomioka, Y.; Yamazaki, M. Chem. Pharm. Bull.
1986, 34, 516.
[22] Maruoka, H.; Yamagata, K.; Yamazaki, M. J. Heterocycl.
Chem. 2001, 38, 269.
REFERENCES
[1] Bannister, M. L.; Williams, A. J. Biochem. Biophys. Res.
Commun. 2004, 317, 397.
[2] Ghafourian, T.; Rashidi, M. R. Chem. Pharm. Bull. 2001, 49,
1066.
[3] Tobe, M.; Isobe, Y.; Tomizawa, H.; Matsumoto, M.; Obara,
F.; Nagashima, T.; Hayashi, H. Bioorg. Med. Chem. Lett. 2001, 11, 545.
[4] D’yakonov, A. L.; Telezhenetskaya, M. V. Chem. Nat.
Comp. 1997, 33, 221.
[5] Harrap, K. R. Cancer Res. 1995, 55, 2761.
[6] Wilson, W. D.; Zhao, M.; Patterson, S. E.; Wydra, R. L.;
Janda, L.; Strekowski, L.; Schinazi, R. F. Med. Chem. Res. 1992, 2, 102.
[7] Bisset, G. M. F.; Pawelczak, K.; Jackman, A. L.; Calvert, A.
H. J. Med. Chem. 1992, 35, 859.
[23] Maruoka, H.; Okabe, F.; Yamagata, K. J. Heterocycl. Chem.
2008, 45, 541.
[24] Partridge, M. W.; Slorach, S. A.; Vipond, H. J. J. Chem. Soc.
1964, 3670.
[8] Martin-Kohler, A.; Widmer, J.; Bold, G.; Meyer, T.; Séquin,
U.; Traxler, P. Helv. Chim. Acta 2004, 87, 956.
[25] Molina, P.; Arques, A.; Cartagena, I.; Valcarcel, M. V. J.
Heterocycl. Chem. 1985, 22, 1189.
[9] Jäschke, H.; Neumann, S.; Moore, S.; Thomas, C. J.; Colson,
A.-O.; Costanzi, S.; Kleinau, G.; Jiang, J.-K,; Paschke, R.; Raaka, B. M.;
Krause, G.; Gershengorn, M. C. J. Biol. Chem. 2006, 281, 9841.
[10] Pyo, J. I.; Lee, S. H.; Cheong, C. S. J. Heterocycl. Chem.
2006, 43, 1129.
[26] Müller, R.; Gebert, L.; Pech, R.; Böhm, R. Pharmazie 1993, 48,
585.
[27] Eshimbetov, A. G.; Tulyasheva, M. A.; Kristallovich, E. L.;
Abdullaev, N. D.; Shakhidoyatov, Kh. M. Chem. Heterocycl. Comp. 2006,
42, 200.
[11] Ikaunieks, M.; Belyakov, S.; Madre, M. J. Heterocycl. Chem.
2006, 43, 943.
[28] Maruoka, H.; Yamagata, K.; Yamazaki, M. Heterocycles 1990,
31, 2011.
[12] Chattopadhyay, S. K.; Dey, R.; Biswas, S. Synthesis 2005,
1083.
[29] Hosni, H. M.; Basyouni, W. M.; EI-Bayouki, K. A. M. Acta
Poloniae Pharm. 1999, 56, 49.