Syntheses of functionalized thieno[3,4-d]imidazoles and thieno[3,2-d]pyrimidines from chlorine-containing enamidonitriles

Article abstract of DOI:10.1134/S1070363206120206

Enamidonitriles of the general formula Cl(X)C=C(CN)NHCOR readily react with methyl sulfanylacetate to give tri-or tetra-substituted thiophenes, which can be converted into new functional derivatives of thieno[3,2-d]pyrimidine and thieno[3,4-d]imidazole.

Full text of DOI:10.1134/S1070363206120206

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 12, pp. 1943 1947.
Pleiades Publishing, Inc., 2006.
Original Russian Text S.V. Popil’nichenko, S.G. Pil’o, V.S. Brovarets, B.S. Drach, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 12,
pp. 2032 2036.
Syntheses of Functionalized Thieno[3,4-d]imidazoles
and Thieno[3,2-d]pyrimidines
from Chlorine-Containing Enamidonitriles
S. V. Popil’nichenko, S. G. Pil’o, V. S. Brovarets, and B. S. Drach
Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine;
e-mail: drach@bpci.kiev.ua
Received April 28, 2006
Abstract Enamidonitriles of the general formula Cl(X)C=C(CN)NHCOR readily react with methyl sul-
fanylacetate to give tri- or tetra-substituted thiophenes, which can be converted into new functional derivatives
of thieno[3,2-d]pyrimidine and thieno[3,4-d]imidazole.
DOI: 10.1134/S1070363206120206
Accessible chlorine-containing enamidonitriles I
were previously used for the preparation of a series of
nonfused azole derivatives; these syntheses were re-
viewed in [1] and also considered in recent publica-
tions [2 4]. In the present work we studied a new way
of using compounds I in the synthesis of functionally
substituted thiophenes and their fused ring derivatives.
As shown in Scheme 1, enamidonitriles I having one
or two labile chlorine atoms reacted with methyl sul-
fanylacetate in the presence of triethylamine to give
initially intermediates II and III which then under-
went intramolecular ring closure involving the triple
C N bond and active methylene group. As a result,
the corresponding functionally substituted thiophenes
IV and V were obtained (Table 1). Analogous base-
catalyzed cyclizations of various compounds posses-
Table 1. Yields, melting points, and elemental analyses of compounds IV IX
Found, %
Calculated, %
mp, C (solvent for
Comp. no. Yield, %
Formula
crystallization)
N
S
N
S
IVa
IVb
IVc
IVd
IVe
Va
64
66
58
70
53
71
65
62
59
68
63
61
68
65
52
59a
61
164 166 (EtOH)
157 159 (EtOH)
138 140 (EtOH)
186 188 (EtOH)
168 171 (EtOH)
130 133 (EtOH)
150 151 (EtOH)
>300 (AcOH)
286 288 (AcOH)
275 277 (AcOH)
240 242 (AcOH)
235 237 (AcOH)
193 195 (EtOH)
182 184 (EtOH)
228 230 (AcOH)
233 235 (EtOH)
237 239 (EtOH)
10.22
9.59
6.95
6.61
6.49
11.45
11.10
16.15
15.28
14.83
16.74
16.23
11.83
11.21
16.35
15.41
14.93
22.45
8.62
C13H12N2O3S
C14H14N2O3S
C20H18N2O3S2
C19H15N2O3S2Cl
C20H17N2S2O3Cl
C16H16N2O5S2
C17H18N2O5S2
C13H9N3O2S
C14H11N3O2S
C20H15N3O2S2
C19H12N3O2S2Cl
C20H14N3O2S2Cl
C10H10N2S2O4
C21H18N4OS
10.14
9.65
7.03
6.69
6.47
11.60
11.04
16.09
15.31
14.81
16.86
16.26
11.82
11.24
16.30
15.49
14.98
22.40
8.56
7.15
7.01
7.36
7.10
Vb
VIa
VIb
VIc
VId
VIe
VII
VIII
IXa
IXb
IXc
15.44
14.69
10.60
10.09
9.79
15.49
14.73
10.68
10.15
9.82
9.81
9.78
14.91
10.34
10.72
10.29
14.96
10.29
10.61
10.36
23.67
16.31
15.78
C9H8N2O4S2
C16H14N3O3S2Cl
C18H19N3O4S2
23.55
16.20
15.81
a
Method a.
1943

1944
POPIL’NICHENKO et al.
Scheme 1.
H
N
C
R
N
MeOC(O)CH2SH, Et3N
X = H, ArS
MeOC(O)CH2SH, 2Et3N
X = Cl
O
Cl
X
Ia Ig
H
N
H
N
N
C
C
S
R
R
O
N
S
O
O
OMe
OMe
MeO
S
X
O
O
IIa IIe
IIIa, IIIb
Et3N
Et3N
H
H
NH2
O
NH2
O
R
N
R
N
O
O
OMe
OMe
MeO
X
S
S
S
O
IVa IVe
Va, Vb
HC(OEt)3,
HC(O)NH2,
O
N
NH
R
NH
OMe
MeO
N
O
S
S
X
O
O
NH
S
VII
HY
(1) HC(OEt)3,
(2) HY
;
VIa VIe
X = H,
(1) POCl3;
N
R = 4-MeC6H4
NH
(2) 2PhCH2NH2
Y
MeO
O
S
S
O
O
NH
N
4-MeC6H4
IXa IXc
N
S
Ph
HN
VIII
R = Ph (Ia, Ic, Id, If, IIa, IIc, IId, IIIa, IVa, IVc, IVd, Va, VIa, VIc, VId), 4-MeC6H4 (Ib, Ie, Ig, IIb, IIe,
IIIb, IVb, IVe, Vb, VIb, VIe); X = H (a, b), 4-MeC6H4S (c), 4-ClC6H4S (d, e), Cl (f, g); IX: Y = HO (a),
4-ClC6H4CH2NH (b), 4-MeOC6H4CH2CH2NH (c).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 12 2006

SYNTHESES OF FUNCTIONALIZED THIENO[3,4-d]IMIDAZOLES
Table 2. IR and 1H NMR spectral parameters of compounds IV IX
1945
Comp.
no.
1
IR spectrum, , cm (KBr)
1625 (
1H NMR spectrum, , ppm (DMSO-d6)
IVa
IVb
IVc
), 1645 (NC=O), 1690 (OC=O), 3.76 s (3H, OCH3), 6.55 br.s (2H, NH2), 7.52 m (3Harom), 7.85 s
NH2
3050 3250 (NH as.), 3370, 3450 (NH2) (1H, C5H), 7.93 m (2Harom), 9.81 s (1H, NH)
1610 ( ), 1645 (NC=O), 1690 (OC=O), 2.41 s (3H, CH3), 3.76 s (3H, OCH3), 6.53 br.s (2H, NH2), 7.30 d
NH2
3350, 3440 (NH, NH2)
(2Harom), 7.82 s (1H, C5H), 7.83 d (2Harom), 9.70 s (1H, NH)
1645a (NC=O,
), 1685 (OC=O), 3170, 2.31 s (2H, CH3), 3.69 s (3H, OCH3), 6.36 br.s (2H, NH2), 7.22 d
(2Harom), 7.37 d (2Harom), 7.53 m (3Harom), 8.00 d (2Harom), 9.83 s
(1H, NH)
NH2
3225 (NH, NH2)
IVd
IVe
Va
1605 (
), 1650 (NC=O), 1675 (OC=O), 3.72 s (3H, OCH3), 6.33 br.s (2H, NH2), 7.37 s (4Harom), 7.53 m
NH2
3250, 3380, 3490 (NH, NH2)
1620 ( ), 1640 (NC=O), 1690 (OC=O), 2.40 s (3H, CH3), 3.72 s (3H, OCH3), 6.30 br.s (2H, NH2), 7.27 d
3180 3250 (NH as.), 3340, 3430 (NH2) (2Harom), 7.37 s (4Harom), 7.86 d (2Harom), 9.74 s (1H, NH)
1640 (NC=O), 1675 (OC=O), 1745
(OC=O), 3250, 3400 (NH, NH2)
1640 (NC=O), 1675 (OC=O), 1745
(OC=O), 3200, 3450 (NH, NH2)
(3Harom), 7.97 d (2Harom), 9.81 s (1H, NH)
NH2
3.66 s (3H, OCH3), 3.75 s (5H, CH2, OCH3), 6.28 br.s (2H, NH2),
7.50 m (3Harom), 8.02 d (2Harom), 9.75 s (1H, NH)
2.41 s (3H, CH3), 3.66 s (3H, OCH3), 3.72 s (2H, CH2), 3.76 s (3H,
OCH3), 6.19 br.s (2H, NH2), 7.30 d (2Harom), 7.91 d (2Harom),
9.64 s (1H, NH)
Vb
VIab 1670a (C=O), 2800 3500 (NH as.)
7.55 m (3Harom), 7.99 d (2Harom), 8.20 s, 8.35 s (2H, C6H, C2H),
9.80 s (1H, NH), 12.53 br.s (1H, NH)
VIc
1675a (C=O), 2800 3400 (NH as.)
2.34 s (3H, CH3), 7.21 d (2Harom), 7.40 d (2Harom), 7.53 m
(3Harom), 8.02 d (2Harom), 8.08 d (1H, C2H, 3JHH 2.4 Hz), 10.19 s
(1H, NH), 12.52 br.s (1H, NH)
VId
VId
1685a (C=O), 2800 3450 (NH as.)
1680a (C=O), 2750 3180 (NH as.)
7.43 m (7Harom), 8.00 d (2Harom), 8.12 d (1H, C2H, 3JHH 2.8 Hz),
10.24 s (1H, NH), 12.58 br.s (1H, NH)
2.41 s (1H, CH3), 7.30 d (2Harom), 7.41 d.d (4Harom), 7.91 d
3
(2Harom), 8.12 d (1H, C2H, JHH 3.0 Hz), 10.18 s (1H, NH),
12.61 br.s (1H, NH)
VIIc
VIII
1700 (OC=O), 1740 (OC=O), 3050 3130 3.63 s (3H, OCH3), 3.83 s (2H, CH2), 3.94 s (3H, OCH3), 8.25 s
(NH as.)
1660 (C=O), 3250 3400 (NH as.)
(1H, C4H), 12.51 br.s (1H, NH)
2.42 s (3H, CH3), 4.77 d (2H, CH2, 3JHH 6.0 Hz), 7.35 m (7Harom),
7.89 d (2Harom), 8.27 s, 8.46 s (2H, C6H, C2H), 8.50 t (1H, NH),
9.60 s (1H, NH)
IXa
IXb
1695a (C=O), 2400 3200 (NH as., OH as.) 3.86 s (3H, OCH3), 3.88 s (2H, CH2), 9.00 s (1H, C4H), 9.24 br.s
(2H, NH, OH)
1650 (NC=O), 1695 (OC=O), 3050 3140 3.83 s (3H, OCH3), 3.89 s (2H, CH2), 4.24 d (2H, CH2), 7.17 d
(NH as.)
(2Harom), 7.32 d (2Harom), 8.65 s (1H, C4H), 8.67 t (1H, NH),
12.63 br.s (1H, NH)
IXc
1645 (NC=O), 1690 (OC=O), 3070 3160 2.61 t (2H, CH2), 3.20 s (3H, OCH3), 3.24 m (2H, CH2), 3.71 s
(NH as.)
(3H, OCH3), 3.82 s (2H, CH2), 6.75 d (2Harom), 7.03 d (2Harom),
8.13 t (1H, NH), 8.21 s (1H, C4H), 12.49 br.s (1H, NH)
a
b
+
c
+
A band with a shoulder.
Mass spectrum: m/z 271 (M ).
Mass spectrum: m/z 286 (M ).
sing an O=C CH2 S C=C C N fragment have been
studied in sufficient detail [5, 6]. The disappearance of
C N bond and active methylene group and formation
of a primary amino group in the transformations II
formations into fused heterocycles VI and VII, res-
pectively (Scheme 1). The transformation IV VI
occurring by the action of formamide indicates that
the methoxycarbonyl and amino groups in the initial
compound are located at the neighboring carbon
atoms of the thiophene ring. Numerous examples of
analogous pyrimidine ring fusion were reported pre-
viously [7 9]. Examples of fusion of an imidazole
1
IV and III V were confirmed by the IR and H NMR
data (Table 2). The structure of new thiophene-2-
carboxylic acid derivatives IV and V is consistent
with spectral data; it was also proved by their trans-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 12 2006

1946
POPIL’NICHENKO et al.
ring to thiophene via reaction with ethyl orthoformate
are also known [10], though they are fewer in number.
Elimination of the acyl residue during the transforma-
tion V VII was confirmed by the mass spectral data
(Table 2).
7-Acylamino-6-arylsulfanyl-3,4-dihydrothieno-
[3,2-d]pyrimidin-4-ones VIc VIe were synthesized
in a similar way from substituted thiophenes IVc IVe.
Methyl 4-methoxycarbonylmethylsulfanyl-1H-
thieno[3,4-d]imidazole-6-carboxylate (VII). A mix-
ture of 0.002 mol of compound Va or Vb, 8 ml of tri-
ethyl orthoformate, and 1 2 drops of acetic anhydride
was heated for 6 h at the boiling point. The mixture
was cooled, and the precipitate was filtered off and
purified by recrystallization.
Finally, it should be noted that the transformations
VI VIII and VII IX can be regarded as particular
cases of modification of functional substituents in the
thieno[3,2-d]pyrimidine and thieno[3,4-d]imidazole
systems. These reactions attract interest not only from
the viewpoint of confirming the structure of com-
pounds VI and VII but also as synthetic routes to
fused heterocyclic systems which are difficult or
impossible to obtain by other methods; this aspect
will be considered in detail in our further publications.
N-(4-Benzylaminothieno[3,2-d]pyrimidin-7-yl)
4-methylbenzenecarboxamide (VIII). A mixture of
0.01 mol of compound VIb, 5 ml of phosphoryl chlo-
ride, and 0.01 mol of N,N-dimethylaniline was heated
for 5 h under reflux. Volatile substances were re-
moved under reduced pressure, the residue was treated
with water, the precipitate was filtered off, dried, and
dissolved in 30 ml of acetonitrile, 0.022 mol of
benzylamine was added to the solution, the mixture
was heated for 10 h under reflux, the solvent was
removed under reduced pressure, the residue was
treated with water, and the precipitate was filtered off
and purified by recrystallization.
EXPERIMENTAL
The IR spectra were recorded in KBr on a Specord
M-80 spectrometer. The 1H NMR spectra were
measured from solutions in DMSO-d6 relative to
TMS (internal) on a Varian VXR-300 instrument. The
mass spectra were obtained on a Varian MAT-311A
spectrometer.
Methyl 4-acylamino-3-aminothiophene-2-car-
boxylates IVa and IVb (general procedure). Methyl
sulfanylacetate, 0.011 mol, and triethylamine,
0.01 mol, were added to a solution of 0.01 mol of
compound Ia or Ib in 30 ml of anhydrous acetonitrile,
the mixture was heated for 8 h at 60 C, the solvent
was removed under reduced pressure, the residue was
treated with water, and the precipitate was filtered off
and purified by recrystallization.
4-Methoxycarbonylmethylsulfanyl-1H-thieno-
[3,4-d]imidazole-6-carboxylic acid (IXa). A solution
of 0.004 mol of compound VII in 10 ml of sulfuric
acid was heated for 1 min at 110 C. It was then
cooled and poured onto ice, and the precipitate was
filtered off and purified by recrystallization.
Methyl 6-( p-chlorobenzylcarbamoyl)-1H-
thieno[3,4-d]imidazole-4-ylsulfanylacetate (IXb).
a. A mixture of 0.004 mol of compound Va, 8 ml of
triethyl orthoformate, and 0.3 ml of acetic anhydride
was heated for 2 h under reflux, 0.006 mol of p-chlo-
robenzylamine was added, and the mixture was heated
for an additional 2 h under reflux. The precipitate was
filtered off and purified by recrystallization.
Methyl 4-acylamino-3-amino-5-arylsulfanyl-
thiophene-2-carboxylates IVc IVe were synthesized
in a similar way from nitriles Ic Ie.
Methyl 4-acylamino-3-amino-5-(methoxycar-
bonylmethylsulfanyl)thiophene-2-carboxylates Va
and Vb (general procedure). Methyl sulfanylacetate,
0.0082 mol, and triethylamine, 0.0082 mol, were
added to a solution of 0.004 mol of nitrile If or Ig in
30 ml of anhydrous acetonitrile. The mixture was
heated for 10 h under reflux, the solvent was removed
under reduced pressure, and the residue was treated
with water. The product was filtered off and purified
by recrystallization from ethanol.
b. A solution of 0.004 mol of compound VII and
0.008 mol of p-chlorobenzylamine in 10 ml of di-
methylformamide was heated for 3 h at 110 C. The
mixture was cooled, 20 ml of water was added, and
the precipitate was filtered off and recrystallized from
ethanol. Yield 72%; no depression of the melting
point was observed on mixing samples of IXb
prepared according to methods a and b; their IR and
7-Acylamino-3,4-dihydrothieno[3,2-d]pyrimidin-
4-ones VIa and VIb (general procedure). A mixture
of 0.01 mol of compound IVa or IVb and 10 ml of
formamide was heated for 7 h at the boiling point.
The mixture was then treated with water, and the pre-
cipitate was filtered off and recrystallized from acetic
acid.
1H NMR spectra were also identical.
Methyl 6-[2-( p-methoxyphenyl)ethylcarba-
moyl)-1H-thieno[3,4-d]imidazole-4-ylsulfanylace-
tate (IXc) was synthesized as described above for
compound IXb (method a) from substituted thiophene
Va and 2-(p-methoxyphenyl)ethanamine.
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SYNTHESES OF FUNCTIONALIZED THIENO[3,4-d]IMIDAZOLES
1947
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