Synthesis and transformations of 3-ethoxycarbonyl-2-(N-R-thioreido)thiophenes

Article abstract of DOI:10.1023/B:COHC.0000003515.53486.4d

3-Ethoxycarbonyl-2-N-R-thioureido)-4,5,6,7-tetrahydrobenzo[b]thiophenes were obtained by the reaction of 2- amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene with isothiocyanates and of 3-ethoxycarbonyl-2-isothiocyanato-4,5,6,7-tetrahydrobenzo[b]

Full text of DOI:10.1023/B:COHC.0000003515.53486.4d

Chemistry of Heterocyclic Compounds, Vol. 39, No. 8, 2003
SYNTHESIS AND TRANSFORMATIONS
OF 3-ETHOXYCARBONYL-
2-(N-R-THIOUREIDO)THIOPHENES
L. Yu. Chumakova1, A. M. Demchenko1, A. N. Krasovsky2, T. V. Dolishnyak2,
and M. O. Lozinskii3
3-Ethoxycarbonyl-2-(N-R-thioureido)-4,5,6,7-tetrahydrobenzo[b]thiophenes were obtained by the
reaction of 2-amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene with isothiocyanates and of
3-ethoxycarbonyl-2-isothiocyanato-4,5,6,7-tetrahydrobenzo[b]thiophene with primary and secondary
amines. The cyclization paths of the products leading to derivatives of thieno[2,3-d]pyrimidine and
thieno[2,3-d]-1,3-thiazine were studied. The corresponding S-substituted derivatives were obtained by
the alkylation of 3-R-2-thioxo-3,4,5,6,7,8-hexahydrobenzo[b]thieno[2,3-d]pyrimidin-4-ones.
Keywords: isothiocyanate, pyrimidine, thiazine, thiophene, alkylation, cyclization.
Compounds containing a condensed pyrimidine ring are of interest in the search for biologically active
compounds [1-5]. It is known that the reaction of 2-amino-3-ethoxycarbonylthiophenes (1) [6] with
isothiocyanates stops at the intermediate 3-ethoxycarbonyl-2-(N-R-thioureido)thiophenes (2) [1-3, 7, 8]
(method A).
We have developed alternative paths for the synthesis of compounds 2, involving the reaction of
3-ethoxycarbonyl-2-isothiocyanato-4,5,6,7-tetrahydrobenzo[b]thiophene (3) with primary and secondary amines
of the aliphatic, aromatic, and heterocyclic series (method B) (Scheme 1). This method makes it possible to
insert various types of substituents into the thiourea fragment of the products 2, since the range of appropriate
isothiocyanates is restricted (method A), and also to obtain compounds of type 4.
2-(2-Benzothiazolylamino)-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (5) was isolated
when compound 3 was heated with o-aminothiophenol.
The cyclization of compounds 2 depends on the pH of the medium and leads to substances with various
structures [7, 8]. Thus, when the thiophenes 2a-o were heated in an alkaline medium the potassium salts of
3-R-mercapto-3,4,5,6,7,8-hexahydrobenzo[b]thieno[2,3-d]pyrimidin-4-ones 6a-o were isolated, and their
acidification gave compounds 6'a-g respectively (Scheme 2). In an acidic medium compounds 2e,k are
converted into derivatives of 2-(R-amino)-4(H)-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]-1,3-thiazin-4-one 7a,b
(Scheme 2).
__________________________________________________________________________________________
1
T. G. Shevchenko Chernigov State Pedagogical University, Chernigov 14013, Ukraine; e-mail:
2
lyuda_chumakova@chemdiv.com. Chernigov State Technological University, Chernigov 14027, Ukraine.
3 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail:
iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1152-1163,
August, 2003. Original article submitted February 26, 2001. Revision submitted November 28, 2001.
1002
0009-3122/03/3908-1002$25.00©2003 Plenum Publishing Corporation

Scheme 1
Method A
COOEt
Method B
COOEt
NCS
HS
NH2
COOEt
S
H2N
S
S
H2NR
R
RNCS
1
S
3
HN
N
COOEt
S
H
O
N
5
COOEt
S
S
N
H
N
H
2a–r
O
S
N
H
N
4
2 a R = CH2CH=CH2; b R = Ph; c R = C6H4Me-4; d R = C6H4Me-2; e R = C6H4Br-4;
f R = C6H3Cl2-2,4; g R = C6H4OMe-4; h R = C6H4OMe-2; i R = C6H4OCHF2-4; j R = Bn;
k R = C6H4NHCOMe-4; l R = N=CHC6H4F-4; m R = 5-chloro-2-pyridyl; n R = 2,3-dimethyl-1-phenyl-5-oxo-4-pyrazolyl;
o R = 4,6-di(ethylamino)-1,3,5-triazin-2-ylamino; p R = C6H4OH-3; q R = NHPh; r R = NHCOC6H4Br-4
Compounds 6a-n enter readily into reaction with alkylating reagents in an alkaline medium, and the
corresponding S-substituted 3-R-2-alkyl(aryl)thio-3,4,5,6,7,8-hexahydrobenzo[b]thieno[2,3-d]pyrimidin-4-ones
8a-b' are formed (Scheme 2). An attempt at a single-stage synthesis of substances with structure 8 by the
Scheme 2
O
O
_
R
S
[H+]
[OH ]
S
[H+]
N
2a–r
S
N
N
H
R
S
N
6a–o
K
7a,b
O
BrCH2COC6H4CMe3-4
R
XR1
N
COOEt
S
O
S
N
H
6'a–g
S
R
S
N
N
-4
N
1
C6H4CMe3
R
S
N
S
C6H5
8a–z, a', b'
9
6a R = CH2CH=CH2; 6'a, 6b R = Ph; 6c R = C6H4Me-4; 6d R = C6H4Me-2; 6e R = C6H4Br-4; 6f R = C6H3Cl2-2,4;
6g, 6'b R = C6H4OMe-4; 6h R = C6H4OMe-2; 6i, 6'c R = C6H4OCHF2-4; 6j, 6'd R = Bn; 6k R = C6H4NHCOMe-4;
6l, 6'e R = N=CHC6H4F-4; 6m R = 5-chloro-2-pyridyl; 6n, 6'f R = 2,3-dimethyl-1-phenyl-5-oxo-4-pyrazolyl;
6o, 6'g R = 4,6-di(ethylamino)-1,3,5-triazin-2-ylamino; 7 a R = C6H4Br-4; b R = C6H4NHCOMe-4; 8 a R = CH2CH=CH2,
R1 = CH2COPh; b R = Ph, R1 = CH2COBu-t; c R = Ph; R1 = CH2COC6H4Br-4; d R = Ph, R1 = CH2COC6H4OCHF2-2;
e R = Ph, R1 = CH2COC6H4Ph-4; f R = Ph, R1 = CH2CONPhCHMe2; g R = C6H4Me-4, R1 = CH2COPh; h R = C6H4Me-2,
R1 = CH2CONPhCHMe2; i R = C6H4Me-2, R1 = Me; j R = C6H4Br-4, R1 = C6H3(NO2)2-2,4; k R = C6H4Br-4, R1 = CH2COC6H4Cl-4;
l R = C6H3Cl2-2,4, R1 = CH2CONPhCHMe2; m R = C6H4OMe-2, R1 = CH2COC6H4Br-3; n R = C6H4OMe-4; R1 = CH2COC6H4-t-Bu-4;
o R = C6H4OMe-4, R1 = CH2COC6H4Cl-4; p R = C6H4OCHF2-4, R1 = CH2COC6H4F-4; q R = C6H4OCHF2-4, R1 = CH2COC6H4Cl-4;
r R = C6H4OCHF2-4, R1 = CHMeCOC6H4Cl-4; s R = C6H4OCHF2-4, R1 = CH2COC6H4OCHF2-4; t R = C6H4OCHF2-4,
R1 = CH2COC6H4(OCH2)2-3,4; u R = Bn, R1 = CH2COC6H4Cl-4; v R = Bn, R1 = CH2CONPhCHMe2; w R = C6H4NHCOMe-4,
R1 = C6H3(NO2)2-2,4; x R = C6H4NHCOMe-4, R1 = CH2COC6H4F-4; y R = C6H4NHCOMe-4, R1 = CH2CONPhCHMe2;
z R = N=CHC6H4F-4, R1 = CH2CONPhCHMe2; a' R = 5-chloro-2-pyridyl; R1 = CH2CONPhCHMe2;
b' R = 2,3-dimethyl-1-phenyl-5-oxo-4-pyrazolyl, R1 = C6H3(NO2)2-2,4; X = Hal
1003

TABLE 1. The Characteristics of Compounds 2a-r, 4, 5, and 9
Found, %
1Н NMR spectrum, δ, ppm (J, Hz)
——————
Com-
Empirical
formula
Yield,
%
Calculated, %
mp, °С
pound
OCH2 (q),
(СН2)4,
N
3
S
4
NH (s)
6
R
9
СН3 (t)
(br. d, br. s)
1
2
5
7
8
10
C15H20N2O2S2
C18H20N2O2S2
8.48
8.64
19.54
19.75
148-149
178-180
82
88
2a
2b
7.38
17.92
10.90; 11.80
4.23 (J = 7.2); 2.65 (J = 35.8);
2.96 (J = 7.2) 1.73
5.53-5.72 (5H, m, С6Н5)
7.77
17.79
C19H22N2O2S2
C19H22N2O2S2
C18H19BrN2O2S2
7.10
7.49
16.86
17.11
175-176
170-171
182-183
89
84
86
2c
2d
2e
7.12
17.48
7.49
6.08
6.38
17.11
14.22
14.58
11.10; 12.50
10.90; 11.80
10.60; 11.70
10.60; 11.70
10.70; 11.80
9.89; 11.60
4.15 (J = 7.0); 2.64 (J = 36.1);
1.20 (J = 7.0) 1.71
4.23 (J = 7.2); 2.70 (J = 36.6);
1.29 (J = 7.2) 1.71
4.21 (J = 7.1); 2.65 (J = 34.8);
1.25 (J = 7.1) 1.71
4.21 (J = 7.2); 2.65 (J = 32.7);
1.25 (J = 7.2) 1.71
4.22 (J = 7.1); 2.65 (J = 30.5);
1.25 (J = 7.1) 1.72
4.26 (J = 7.2); 2.65 (J = 39.3);
1.30 (J = 7.2) 1.70
7.90 (d, J = 8.7); 7.80 (4H, d, J = 8.7, С6Н4)
C18H18Cl2N2O2S2
C19H22N2O3S2
C19H22N2O3S2
C19H20F2N2O3S2
C19H22N2O2S2
6.36
14.62
157-158
163-164
161-162
172-173
120-121
7.76 (1H, s); 7.48-7.56 (2H, m, C6H3)
85
89
86
89
81
2f
2g
2h
2i
6.52
14.93
6.84
7.17
16.62
16.42
7.31 (d, J = 8.9); 6.97 (4H, d, J = 8.9, С6Н4);
3.77 (3H, s, ОСН3)
6.96-7.81 (4Н, m, С6Н4); 3.78 (3Н, s, ОСН3)
7.42
16.08
7.17
16.42
6.22
6.57
15.40
15.04
7.20-7.40 (5H, m, C6H4–OCHF2-4)
7.18
17.0
7.28-7.35 (5H, m, С6Н5); 4.68 (2H, br. s, СН2)
2j
7.48
17.11

TABLE 1 (continued)
1
2
3
4
5
6
7
8
9
10
C20H23N3O3S2
C19H20FN3O2S2
C17H18ClN3O2S2
10.42
10.07
15.65
15.34
203-204
230-231
216-217
81
68
73
2k
10.26
16.10
2l
10.37
10.36
10.61
15.80
16.46
16.20
11.30; 15.20
9.77; 12.0
4.32 (J = 7.2); 2.67 (J = 33.3);
1.30 (J = 7.2) 1.73
4.15 (J = 7.1); 2.63 (J = 28.9);
1.23 (J = 7.1) 1.70
4.21 (J = 7.2); 2.69 (J = 21.3);
1.19 (J = 7.0) 1.70
8.21 (d, J = 2.5); 7.94 (q, J = 8.7);
7.22 (d, J = 8.7, Py)
2m
C23H26N4O3S2
C19H28N8O2S2
12.12
14.0
211-212
191-192
7.39-7.52 (5H, m, С6Н5); 3.32 (3H, s, NCH3);
82.5
67
2n
2o
11.90
13.63
2.19 (3H, s, CH3)
24.38
24.12
13.56
10.12; 12.20
8.86 (1H, s, NH); 8.66 (1H, s, NH);
7.00 (1H, s, NH); 3.45 (br. s);
1.06 (10Н, br. s, Et2)
13.80
C18H20N2O3S2
C18H21N3O2S2
C19H20BrN3O3S2
C16H22N2O3S2
C18H18N2O2S2
7.66
7.44
17.44
17.03
190-191
193-194
209-210
161-162
131-132
9.58; 10.80
10.30; 12.50
11.10; 12.50
12.10
4.22 (J = 7.2); 2.63 (J = 33.9);
1.26 (J = 7.2) 1.71
4.12 (J = 7.2); 2.64 (J = 30.9);
1.17 (J = 7.2) 1.70
4.15 (J = 7.2); 2.64 (J = 29.4);
1.20 (J = 7.2) 1.71
4.38 (J = 7.3); 2.65 (J = 25.9);
1.31 (J = 7.3) 1.72
4.30 (J = 7.2); 2.67 (J = 20.7);
1.31 (J = 7.2) 1.73
6.65-7.20 (4H, m, С6Н4)
90.4
56
2p
2q
2r
4
11.52
17.44
8.34 (1H, s, NH); 6.80-7.40 (5H, m, С6Н5)
11.20
17.07
8.92
8.71
13.50
13.29
10.5 (1H, s, NH); 7.80 (d, J = 8.9);
7.90 (4H, d, J = 8.9, С6Н4)
3.74 (t, J = 9.2); 3.90 (8H, t, J = 9.2, (СН2)4)
87
8.08
18.44
98.8
95
7.91
18.08
7.62
7.82
18.06
17.88
11.36
7.88 (4H, d, J = 11.1); 7.65 (d, J = 11.1);
7.39 (t, J = 11.1 ); 7.23 (4H, t, J = 11.1;
2-benzothiazolyl
5
C30H32N2O2S2·
9.12
9.39
8.94
8.59
114-115
—
4.07 (J = 7.2); 2.62 (br. s);
1.11 (J = 7.2) 1.73
8.60 (2H, s, picric acid); 7.09-7.29 (9H, m, Ar);
65
9
С6Н3N3O7
6.75 (1H, s, CH); 1.20 (9H, s, t-Bu)

TABLE 2. The Characteristics of Compounds 6a,c-f,h,k,m, 6'a, and 7a,b
Found, %
1H NMR spectrum, δ, ppm (J, Hz)
——————
Com-
Empirical
formula
Calculated, %
mp, °С
Yield, %
9
pound
N
3
S
4
NH (s)
6
(CH2)4 (m; m)
7
R
8
1
2
5
C13H13KN2OS2
C16H14N2OS2
8.43
8.85
20.54
20.26
>300
276-277
>300
95
96
94
90
87
93
88
92
6а
6'a
6c
7.86
20.70
13.70
—
2.76; 1.76
2.72; 1.75
2.77; 1.78
2.77; 1.78
2.74; 1.76
2.72; 1.75
2.70; 1.73
7.41-7.59 (5H, m, С6Н5)
8.91
20.39
С17Н15KN2OS2
С17Н15KN2OS2
C16H14BrKN2OS2
C16H11Cl2KN2OS2
C17H16N2O2S2
C17H15KN2O2S2
7.32
7.64
17.97
17.50
7.20 (d; J = 8.4); 7.40 (4H, d, J = 8.1, С6Н4); 2.42 (3H, s, СН3)
7.30 (4H, m, С6Н4); 2.06 (3H, s, СН3)
7.28
17.73
>300
—
6d
6e
7.64
17.50
6.11
6.50
15.21
14.86
>300
—
7.45 (d; J = 8.7); 7.80 (4H, d, J = 8.7; С6Н4)
7.67 (2H, s); 7.97 (1H, s, С6Н3)
6.32
15.47
>300
—
6f
6.65
15.22
8.06
8.13
18.95
18.62
259-260
>300
13.90
—
7.34 (d, J = 8.7); 7.13 (4Н, d, J = 8.7, С6Н4); 3.85 (3H, s, ОСН3)
7.14-7.57 (4H, m, С6Н4); 3.80 (3H, s, ОСН3)
6'b
6h
7.15
16.89
7.32
16.76

TABLE 2 (continued)
1
2
3
4
5
6
7
8
9
C17H14F2N2O2S2
C17H16N2OS2
7.05
7.36
17.08
16.86
>300
>300
13.70
13.69
—
2.68; 1.75
2.70; 1.74
2.64; 1.76
7.24-7.32 (5H, m, C6H4OCHF2-4)
94
96
93
6'c
8.27
19.71
7.28-7.36 (5H, m, C6H5); 5.60 (2H, s, CH2)
6'd
6k
8.53
10.03
10.26
19.52
15.91
15.66
C18H16KN3O2S2
280-281
9.91 (1H, s, NH); 7.50 (d, J = 8.8); 6.86 (4H, d, J = 8.8, C6H4);
2.06 (3H, s, CH3)
C17H14FN3OS2
C15H11ClKN3OS2
C21H20N4O2S2
11.38
17.97
>300
14.00
—
2.75; 1.76
2.79; 1.78
2.80; 1.76
9.20 (1H, s, СН); 7.31-7.46 (4H, m, С6Н4)
91
96
89
6'l
11.69
17.83
11.23
10.83
13.00
13.21
16.77
16.53
15.46
15.09
302-303
224-225
8.72 (s), 8.19 (d, J = 8.7); 7.72 (3H, d, J = 8.7, Py)
7.40-7.76 (5H, m, С6Н5), 2.27 (3H, s, СН3), 3.34 (3H, s, NCH3)
6m
6'f
13.80
C17H22N8OS2
26.34
15.72
242-244
13.56
2.66; 1.76
9.22 (1H, s, NH); 6.82 (1H, s, NH); 6.64 (1H, s, NH);
3.19-3.24 (4H, m); 1.00-1.13 (6H, m, Et2)
92
6'g
26.77
15.32
C16H13BrN2OS2
C18H17N3O2S2
6.85
7.12
16.52
16.28
229-230
238-240
10.60
10.44
2.70; 1.74
2.75; 1.72
7.66 (d, J = 8.7); 7.56 (4H, d, J = 8.7, С6Н4)
67
7а
70
10.98
17.56
9.96 (1H, s, NH); 7.60 (d, J = 8.8); 7.50 (4H, d, J = 8.8, C6H4);
7b
11.32
17.25
2.04 (3H, s, CH3)

TABLE 3. The Characteristics of Compounds 8a-z,a',b'
Found, %
1Н NMR spectrum, δ, ppm (J, Hz)
——————
Com-
Empirical
formula
Yield,
%
Calculated, %
mp, °С
pound
(CH2)4
R
7
R1
8
N
3
S
4
(br. d; br. s)
1
2
5
6
9
C21H20N2O2S2
6.85 16.38
7.06 16.17
143-45
2.76 (J = 27.8);
5.95-6.00 (1H, m, CH); 5.83 (d,
J = 13.0); 5.26 (2H, d, J = 16.0, CH2);
4.86-4.88 (2H, m, CH2)
7.37-8.10 (5H, m, C6H5);
4.62 (2H, s, CH2)
64
8a
1.75
C22H24N2O2S2
C24H19BrN2O2S2
C25H20F2N2O3S2
C30H24N2O2S2
6.46 15.82
6.79 15.54
186-187
225-226
209-210
231-232
2.76 (J = 26.1);
7.41-7.59 (5Н, m, С6Н5)
7.43-7.60 (5Н, m, С6Н5)
7.25-7.43 (5H, m С6Н5)
7.45-7.55 (5H, m, С6Н5)
4.26 (2H, s, СН2); 1.20 (9H, s, t-Bu)
74
65
75
72
8b
8c
8d
8e
1.76
5.16 12.93
2.72 (J = 28.8);
7.94 (d, J = 8.7); 7.77 (4H, d, J = 8.7,
C6H4); 4.67 (2H, s, СН2)
5.48 12.54
1.75
5.36 13.02
5.62 12.86
2.73 (J = 24.3);
7.52-7.75 (5H, m, С6Н4OCHF2-2);
1.75
4.53 (2H, s, CH2)
5.27 12.85
2.72 (J = 32.9);
8.10 (d, J = 8.4); 7.90 (4H, d, J = 8.4,
C6H4); 7.59-7.79 (5H, m, C6H5);
4.75 (2H, s, CH2)
5.51 12.61
1.75
C27H27N3O2S2
8.17 13.46
8.58 13.10
259-260
2..77 (J = 12.3); 7.26-7.38 (5H, m, С6Н5)
7.42-7.57 (5H, m, С6Н5);
69
8f
1.77
4.67-4.76 (1H, m, СН); 3.56 (2H, s,
CH2); 1.02 (6H, d, J = 6.6, (CH3)2)
C25H22N2O2S2
C28H29N3O2S2
6.04 14.73
6.27 14.36
213-214
246-247
2.72 (J = 30.5);
7.40 (d, J = 8.4); 7.30 (4H, d,
7.55-8.00 (5H, m, С6Н5);
71
84
8g
8h
1.75
J = 8.1, С6Н4); 2.42 (3H, s, СН3)
4.70 (2H, s, CH2)
8.07 12.98
2.77 (J = 17.1);
7.24-7.38 (4H, m, С6Н4); 2.06 (3H, s, СН3)
7.40-7.56 (5H, m, С6Н5);
8.34 12.73
1.78
4.75-4.85 (1Н, m, СН); 3.54 (2H, s,
CH2); 1.01 (6H, d, J = 6.0, (CH3)2)

TABLE 3 (continued)
1
2
3
4
5
6
7
8
9
C18H18N2OS2
C22H15BrN4O5S2
7.95 18.97
8.18 18.72
171-172
214-215
256-257
226-228
2.77 (J = 23.9);
7.30-7.45 (4H, m, С6Н4); 2.03 (3H, s, CH3)
7.80 (d, J = 8.7); 7.45 (4Н, d, J = 8.7, С6Н4)
7.82 (d, J = 8.7); 7.62 (4H, d, J = 8.4, С6Н4)
7.97 (1H, s, C6H3); 7.67 (2H, s)
2.43 (3H, s, СН3)
77
78
75
71
8i
8j
1.77
9.87 11.87
2.77 (J = 24.3);
8.80 (1Н, s); 8.50 (1H, d, J = 8.8);
8.07 (1Н, d, J = 8.8, С6Н3)
10.02 11.46
1.78
C24H18BrClN2O2S2 4.96 11.92
5.13 11.75
C27H25Cl2N3O2S2
2.73 (J = 28.6);
8.02 (d, J = 8.7); 7.44 (4Н, d, J = 8.7,
8k
8l
1.75
С6Н4); 4.70 (2H, s, CH2)
7.31 11.82
2.74 (br. s);
1.76 (br. t,
J = 5.91)
7.35-7.96 (5H, m, С6Н5);
4.75-4.84 (1H, m, СН);
7.52 11.48
3.60 (2H, q, J = 9.1, CH2);
1.10 (6H, d, J = 6.5, (CH3)2)
C25H21BrN2O3S2
C29H30N2O3S2
5.02
12.0
215-216
189-190
2.70 (J = 26.4);
7.14-7.57 (4H, m, С6Н4); 3.80 (3H, s, ОСН3)
7.94 (d, J = 8.7); 7.78 (4Н, d, J = 8.7,
С6Н4); 4.68 (2H, q, J = 28.6, CH2)
74
69
8m
8n
5.17 11.84
1.73
5.27 12.64
2.72 (J = 32.1);
3.85 (3H, s, ОСН3); 7.34 (d, J = 8.7);
7.13 (4H, d, J = 8.7, C6H4)
7.90 (d, J = 8.7); 7.60 (4H, d,
J = 8.7, С6Н4); 4.70 (2H, s, CH2);
1.32 (9H, s, (CH3)3)
5.40 12.36
1.75
C25H21ClN2O3S2
C25H19F3N2O3S2
5.25 13.15
5.64 12.90
233-234
234-236
2.73 (J = 32.1);
7.30 (d, J = 8.7); 7.10 (4Н, d, J = 8.7, С6Н4);
3.85 (3Н, s, ОСН3)
7.35-7.50 (5H, m, C6H4–OCHF2-4)
8.00 (d, J = 8.4); 7.61 (4Н, d, J = 8.4,
78
79
8o
8p
1.75
С6Н4); 4.64 (2H, s, CH2)
5.18 12.80
2.73 (J = 28.6);
7.51-8.11 (4H, m, С6Н4);
4.70 (2H, s, СН2)
5.42 12.41
1.75
C25H19ClF2N2O3S2 5.02 12.47
5.26 12.03
243-244 2.73 (J = 28.30); 7.50 (d; J = 9.0); 7.40 (5H, d, J = 8.7,
8.03 (d, J = 8.7); 7.66 (4Н, d, J = 8.7,
80
78
8q
8r
C6H4–OCHF2-4)
С6Н4); 4.70 (2H, s, CH2)
1.75
C26H21ClF2N2O3S2 4.96 11.95
5.12 11.72
188-189
2.73 (J = 26.4);
7.20-7.50 (5H, m, C6H4–OCHF2-4)
8.10 (d, J = 8.7); 7.60 (4H, d, J = 8.7,
C6H4); 5.50 (1H, q, J = 23.3, СН);
1.4 (3H, d, J = 7.2, СН3)
1.75
C26H20F4N2O4S2
C27H22F2N2O5S2
4.64 11.75
4.96 11.36
211-213
212-214
2.74 (J = 29.9);
7.20-7.70 (5H, m, C6H4–OCHF2-4)
7.20-7.60 (5H, m, C6H4–OCHF2-4)
7.20-8.10 (5H, m, C6H4OCHF2-4);
81
82
8s
8t
1.74
4.70 (2H, s, CH2)
5.24 11.81
2.75 (J = 26.2);
7.00-7.50 (3H, m, С6Н3);
4.65 (2H, s, CH2);
5.03 11.52
1.76
4.31 (4H, q, J = 11.8, (OCH2)2)

TABLE 3 (continued)
1
2
3
4
5
6
7
8
9
C25H21ClN2O2S2
5.43 13.77
5.82 13.33
190-191
2.73 (br. d,
J = 49.5);
7.25-7.34 (5H, m, С6Н5); 5.33 (2H, s, CH2)
8.03 (4H, d, J = 8.7, С6Н4);
81
8u
7.66 (d, J = 8.7); 4.79 (2H, s, CH2)
1.75 (br. d, J = 4.9)
C28H29N3O2S2
8.06 12.95
8.34 12.73
202-203
2.77 (J = 33.9);
7.20-7.35 (5H, m, С6Н5); 5.25 (2H, s, CH2)
7.36-7.55 (5H, m, С6Н5);
84
8v
1.75
4.77 (1H, s, СН); 3.64 (2H, s, CH2);
1.01 (6H, d, J = 6.6, (CH3)2)
C24H19N5O6S2
C26H22FN3O3S2
C29H30N4O3S2
12.87 12.18
13.03 11.92
230-231
272
2.77 (J = 26.0);
10.22 (1H, s, NH); 7.73 (d, J = 8.8);
8.80 (s); 8.47 (d, J = 8.8);
8.10 (3H, d, J = 8.8, С6Н3)
83
85
83
8w
8x
8y
1.76
7.42 (4H, d, J = 8.8, C6H4); 2.20 (3H, s, CH3)
8.00 12.93
2.71 (J = 30.3);
10.22 (1H, s, NH); 7.75 (d, J = 8.7);
7.30-8.10 (4H, m, С6Н4);
8.28 12.62
1.74
7.34 (4H, d, J = 8.7, C6H4); 2.20 (3H, s, CH3) 4.68 (2H, s, CH2)
9.84 11.98
10.26 11.72
173-174
2.63 (br. s);
10.20 (1H, s, NH); 7.70 (d, J = 8.7);
7.30-7.50 (5H, m, С6Н5);
1.77 (br. s)
7.30 (4H, d, J = 8.5, C6H4); 2.10 (3H, s, CH3) 4.79 (1H, s, СН); 3.56 (2H, s, CH2);
1.02 (6H, d, J = 7.7, (CH3)2)
C28H27FN4O2S2
C26H25ClN4O2S2
C27H22N6O6S2
10.05 12.27
10.49 11.98
193-194
185-186
225
2.75 (J = 29.1);
9.20 (1H, s, СН); 7.35-7.42 (4H, m, С6Н4)
7.40-8.00 (5H, m, С6Н5);
81
85
82
8z
1.76
4.82 (1H, s, СН); 3.56 (2H, s, CH2);
1.01 (6H, d, J = 9.9, (CH3)2)
10.31 12.59
10.67 12.21
2.76 (J = 13.2);
8.78 (s); 8,27 (d, J = 8.7);
7.35-7.54 (5H, m, С6Н5);
8'a
8'b
1.79
7.72 (3Н, d, J = 8.7, 5-Cl–Py)
4.78 (1H, s, СН); 3.58 (2H, s, CH2);
1.01 (6H, d, J = 6.6, (CH3)2)
14.02 11.06
14.23 10.86
2.80 (J = 27.0);
7.40-7.76 (5H, m, С6Н5), 3.34 (3H, s, NСН3), 8.86 (s); 8.50 (d, J = 8.8);
2.27 (3H, s, CH3) 8.14 (3H, d, J = 8.8, С6Н3)
1.76

reaction of compound 2b with p-tert-butyl-α-bromoacetophenone led to the formation of the thiazoline
derivative – 3-ethoxycarbonyl-2-[4-(p-tert-butylphenyl)-3-phenyl-2-thiazolinylideneamino]-4,5,6,7-tetrahydro-
benzo[b]thiophene picrate (9).
Di[3-(5-chloro-2-pyridyl)-4-oxo-3H-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-2-ylthio]methane
was isolated in the reaction of compound 6m with methylene chloride (Scheme 3).
Scheme 3
Cl
O
+
N
N
Cl
O
N
S
N
S
N
N
Cl
S
SK
O
N
6m
N
N
S
S
CH2
2
10
The structure of the synthesized compounds was confirmed by data from elemental analysis and
1H NMR spectra (Tables 1-3).
EXPERIMENTAL
1
The H NMR spectra of the synthesized compounds were recorded on a Bruker-300 instrument
(300 MHz) with DMS0-d6 as solvent and TMS as internal standard.
The initial 2-amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (1) and 3-ethoxycarbonyl-2-
isothiocyanato-4,5,6,7-tetrahydrobenzo[b]thiophene (3) respectively were synthesized by the methods described
in [6, 9].
3-Ethoxycarbonyl-2-N-R-thioureido-4,5,6,7-tetrahydrobenzo[b]thiophenes (2a-r, 4). A. To a
solution of 2-amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (2.25 g, 10 mmol) in ethanol (20 ml)
we added the respective isothiocyanate (10 mmol). The reaction mixture was boiled for 3-4 h and cooled, and
the precipitate was filtered off. Compounds 2a-c,g,i,j were obtained
B. To a solution of the respective amine in ethanol (30 ml) we added 3-ethoxycarbonyl-2-
isothiocyanato-4,5,6,7-tetrahydrobenzo[b]thiophene (2.67 g, 10 mmol). The reaction mixture was boiled for
4-6 h and cooled, and the precipitate was filtered off. Compounds 2b-r and 4 were obtained.
2-(2-Aminobenzothiazolyl)-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (5). This
compound was obtained from 3-ethoxycarbonyl-2-isothiocyanato-4,5,6,7-tetrahydrobenzo[b]thiophene and
o-aminothiophenol by method B.
Potassium Salts of 3-R-2-Mercapto-3,4,5,6,7,8-hexahydrobenzo[b]thieno[2,3-d]pyrimidin-4-ones
(6a,c-f,h,k,m). A solution of the respective 2-(N-R-thioureido)-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo-
[b]thiophene (10 mmol) and potassium hydroxide (1.12 g, 20 mmol) in ethanol (20 ml) was boiled for 3-4 h and
cooled, and the precipitate was filtered off.
1011

3-R-2-Thioxo-1,2,3,4,5,6,7,8-octahydrobenzo[b]thieno[2,3-d]pyrimidin-4-ones (6'a-g). A solution of
the respective 3-ethoxycarbonyl-2-(N-R-thioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene (10 mmol) and
potassium hydroxide (1.12 g, 20 mmol) in ethanol (20 ml) was boiled for 3-4 h. The reaction mixture was
poured into water, neutralized with glacial acetic acid, and cooled. The precipitate was filtered off.
2-R-Amino-4(H)-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]-1,3-thiazin-4-ones (7a, b). Compound
2e,k (10 mmol) was dissolved in concentrated sulfuric acid (15 ml), and the solution was left at 18-20°C for
24 h. It was then poured into iced water (100 ml) and neutralized with ammonia. The precipitate was filtered
off.
The Picrate of 3-Ethoxycarbonyl-2-[4-(p-tert-butyl)-3-phenyl-2-thiazolinylideneamino]-4,5,6,7-
tetrahydrobenzo[b]thiophene (9). Compound 2b (3.6 g, 10 mmol) and p-tert-butyl-α-bromoacetophenone
(2.53 g, 10 mmol) were boiled in ethanol (25 ml) for 4 h and cooled. A saturated solution of picric acid was
added, and the precipitate was filtered off.
S-Substituted
3-R-2-Mercapto-3,4,5,6,7,8-hexahydrobenzo[b]thieno[2,3-d]pyrimidin-4-ones
(8a',b'). To a solution of the potassium salt 6 (10 mmol) in ethanol (20-30 ml) [ready prepared or obtained by
dissolving compound 6' (10 mmol) in an alcohol solution (20-30 ml) of potassium hydroxide (0.056 g,
10 mmol)] we added the alkylating agent (10 mmol). The reaction mixture was left at 20°C for 20-24 h, and the
precipitate was filtered off.
Di[3-(5-chloro-2-pyridyl)-4-oxo-3H-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-2-ylthio]-
methane (10). To a solution of methylene chloride (0.85 g, 10 mmol) in ethanol (10 ml) we added dropwise
with stirring a solution of the potassium salt 6m (10 mmol) in aqueous ethanol (20 ml). The mixture was left at
20°C for 24 h and was then boiled for 1 h and cooled. The precipitate was filtered off. Yield 52%;
mp 295-296°C (from DMF). 1H NMR spectrum, δ, ppm (J, Hz): 1.68-1.82 [8H, m, 2 (CH2)4]; 2.65-2.83 [8H, m,
2 (CH2)4]; 4.90 (2H, s, CH2); 7.72 (2H, d, J = 8.7, HPy); 8.70 [2H, s, 6-H (5-Cl-Py)2]. Found %: N 12.0; S 18.46.
C31H24Cl2N6O2S4. Calculated %: N 11.81; S 18.00.
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2.
3.
4.
5.
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1012