Uses of 2-diazo-4,5,6,7-tetrahydrobenzo[b]thiophene derivatives in the synthesis of azoles, azines, and their fused derivatives

Article abstract of DOI:10.1002/hc.10003

The reactions of 2-Diazo-4,5,6,7-tetrahydrohydrobenzo[b]thiophene derivatives in the synthesis of azoles, azines, and their fused derivatives were studied. The reactivity of the products towards various chemical reagents was analysed. Results showed high

Full text of DOI:10.1002/hc.10003

Heteroatom Chemistry
Volume 13, Number 2, 2002
Uses of 2-Diazo-4,5,6,7-tetrahydrobenzo-
[b]thiophene Derivatives in the Synthesis
of Azoles, Azines, and Their Fused Derivatives
Wagnat W. Wardakhan1 and Daisy H. Fleita2
1Department of Chemistry, University of California, Berkeley, California 94720
2Chemistry Department, American University in Cairo, 113 Kaser El-Eini Street, Cairo, Egypt
Received 3 April 2001; revised 2 July 2001
vity against platelet aggregation, and antidiabetic
ABSTRACT: The reactions of 2-diazo-4,5,6,7-tetrahy-
activity [4–15]. In addition, they have proved to be
drobenzo[ b]thiophene derivatives with dimeric add-
convenient candidates for chemical transforma-
ucts 2a and 2b gave the hydrazone derivatives 3a and
tions into various fused heterocyclic ring systems.
3b, respectively. The reactivity of the latter products
Prompted by our earlier promising results, we have
towards various chemical reagents was studied in or-
extended our work to include the reactions of
der to provide azole and azine derivatives incorpo-
ethyl 2-diazo-4,5,6,7-tetrahydrobenzo[b]thiophene-
rating the thiophene ring, and most of them showed
3-carboxylate (1) with dimeric adducts, namely 3-
C
high antimicrobial activity.
2002 Wiley Periodicals,
amino-2,4-dicyanocroteno-nitrile (2a) and diethyl-
3-amino-2-cyanopenten-1,5-dicarboxylate (2b) to
give azo derivatives capable of heterocyclic transfor-
mations.
Inc. Heteroatom Chem 13:108–115, 2002; Published on-
line in Wiley Interscience (www.interscience.wiley.com).
DOI 10.1002/hc.10003
INTRODUCTION
RESULTS AND DISCUSSION
The reactivity of 2-diazo-4,5,6,7-tetrahydrobenzo[b]
thiophene derivatives towards active methylene re-
agents, with subsequent in situ heterocyclization of
the resulting adducts with various reagents has
been recently studied by our research group [1–3]
to make available a variety of polyfunctionaly sub-
stituted thiazole, pyridine, and pyrazole derivatives.
These types of compounds are of interest because
of their wide spectrum of biological properties and
applications. They have been used as dihydrofolate
reductase inhibitors, as well as antitumor agents.
Some of them have shown diuretic properties, acti-
The reaction of 1 with either of the dimeric adducts
2a or 2b gave the corresponding hydrazone deriva-
tives 3a and 3b, respectively (Scheme 1). The struc-
tures of the latter products were based on analyt-
ical and spectral data. Thus, the IR spectrum of
3a (as an example) showed NH2 and NH stretch-
1
ing at = 3470–3320 cm , four CN group stretch-
1
1
ings at = 2225–2220 cm , and the H NMR spec-
trum showed two multiplets at = 2.22 and 2.87
for four CH2 groups of the cyclohexene ring, a sin-
glet at = 4.89 for the NH2 group, and a singlet at
= 8.69 for the NH group. Moreover, the 13C NMR
spectroscopic data showed = 29.5, 30.2 (cyclohex-
ene C-1, C-4); 23.8, 24.9 (cyclohexene C-2, C-3); 58.4
(C N); 102.9, 104.3 (C C); 119.3, 119.8, 120.2, 120.7
(4 CN); 126.4, 132.0, 134.2, 138.7 (thiophene-C). The
Correspondence to: Wagnat W. Wardakhan; e-mail: wagnatward
@hotmail.com.
c
2002 Wiley Periodicals, Inc.
108

2-Diazo-4,5,6,7-tetrahydrobenzo[b]thiophene Derivatives Used to Synthesize Azoles, Azines, and Their Derivatives 109
SCHEME 1
1H NMR spectrum of 3b showed, besides the cyclo-
hexene CH2 protons, two triplets at = 1.34 and 1.46
for two CH3 groups, two quartets at = 4.20 and 4.24
for two CH2 groups, a singlet at = 5.31 for NH2, and
a singlet at = 9.24 for an NH group.
tion of compound 9 in sodium ethoxide solution gave
a single product of molecular formula C15H15N9S.
Structure 10 was indicated for this product on the
basis of analytical and spectral data (see experimen-
tal section).
Compound 3a reacted with malononitrile (11)
to give the pyrimidine derivative 12, which under-
went ready cyclization in sodium ethoxide solution
to give the pyrimido[5,4-d]pyridazine derivative 13
(Scheme 3). The structure of compound 13 was
based on 13C NMR data, which showed = 29.2,
30.0 (cyclohexene C-1, C-4); 23.1, 24.5 (cyclohexene
C-2, C-3); 62.2 (CH2); 118.2, 119.0, 120.5 (3 CN);
124.4, 131.0, 133.6, 134.2, 134.9, 138.7, 138.9, 140.9,
144.1 (thiophene-C, pyridazine-C, and pyrimidine-
C); 180.5 (C O). Compound 13 reacted with ace-
tophenone (14) in the presence of benzene/AcOH
containing ammonium acetate to give the conden-
sate product 15 (Scheme 3). The latter product re-
acted with sulfur in the presence of triethylamine
to give the thiophene derivative 16 (Scheme 4). The
structure of 16 was based on analytical and spectral
data; thus, the IR spectrum of the reaction product
Compounds 3a and 3b were cyclized when
heated under reflux in basic ethanol solution to give
annulated derivative 5 and the pyridazine derivative
6, respectively (Scheme 1). Formation of 5 can be
explained by the formation of 4 as an intermediate
followed by cyclization and hydrolysis of the newly
formed C NH group to give the C O group. Struc-
tures of compounds 5 and 6 were based on analytical
and spectral data (see the Experimental section).
The reactions of 3a and 3b with phenyl isothio-
cyanate gave the 1,2,3-triazine derivatives 7a and 7b,
respectively (Scheme 2). Compound 7a underwent
ready cyclization when heated in sodium ethoxide
solution to give the corresponding pyrido[2,3-e]-1,2,
4-triazine derivative 8. The structure of 8 was es-
tablished on the basis of spectral data. Thus, the IR
spectrum showed NH2, NH stretchings at = 3465–
3355 cm 1 and two CN groups stretching at = 2225
1
1
1
showed two NH2 stretchings at = 3472–3363 cm ,
and 2220 cm . Moreover, the H NMR spectrum
showed two multiplets at = 2.24 and 2.36 for four
CH2 groups of the cyclohexene ring, a singlet at
= 4.98 for an NH2 group, and a singlet at = 9.38
for an NH group.
two CN groups stretchings at = 2225 and 2220
1
cm , and the 1H NMR spectrum showed two multi-
plets at = 2.33 and 2.39 for four CH2 groups of the
cyclohexene ring, two singlets at = 4.75 and 5.21
for two NH2 groups, and a singlet at = 6.98 for the
thiazole H-5 proton.
The reaction of 3a with hydrazine hydrate gave
the pyrazole derivative 9 (Scheme 2). The cycliza-

110 Wardakhan and Fleita
SCHEME 2
SCHEME 3

2-Diazo-4,5,6,7-tetrahydrobenzo[b]thiophene Derivatives Used to Synthesize Azoles, Azines, and Their Derivatives 111
SCHEME 4
The reaction of 4a with ethyl cyanocetate
intermediate formation of 21. The structure of
the latter product was confirmed on the basis of
analytical and spectral data (see Experimental
section) (Table 1).
(17) gave the pyridazine derivative 18 (Scheme 4).
Compound 18 underwent ready cyclization in
sodium ethoxide solution to give the pyrido[2,1-
c]pyridazine derivative 19. Structures of compounds
18 and 19 were based on analytical and spectral data
(see Experimental section).
ANTIMICROBIAL ACTIVITY
The diverse biological activities of azole and azine
derivatives prompted us to test and study the bio-
logical activities of some of the newly synthesized
products. Their bactericidal and antifungal activi-
ties [16,17] were measured. A disc of blotting paper
was impregnated with a known volume and an ap-
propriate concentration of a compound to be tested,
which was then placed on a sensitivity testing agar
plate that was inoculated with the test organism. The
compound diffused from the disc into the medium.
The culture was examined for areas of no growth
around the disc (zones inhibition) after overnight in-
cubation. Growth of bacterial strains sensitive to a
compound is inhibited at certain distances from the
center of the disc whereas resistant strains grow up
to the edge of the disc.
The reaction of 3a with ␣-cyanocinnamonitrile
(20) gave the pyrido[2,3-c]pyridazine derivative 22
(Scheme 5). The reaction took place through the
EXPERIMENTAL
All melting points are uncorrected. IR spectra were
recorded for KBr disc on a Pye Unicam SP-1000
SCHEME 5

112 Wardakhan and Fleita
TABLE 1 In Vitro Bactericidal and Fungicidal Activity of Some of the Newly Synthesized Compounds
Bacillus cerceus
(Gram Positive)
Staphylococcus aureus
(Gram Negative)
Escherichia coli
(Gram Negative)
K. pneumonia
(Gram Negative)
Compound No.
3a
3b
5
+++
+
++
+++
++
+++
++
+
++
+
+++
++
++++
+++
++
6
++
+++
++
++
++
++
++
+
7a
7b
8
+++
++
+
++
++
+++
++
+++
++
+
9
+
10
12
13
15
16
18
19
22
+++
++
++
+++
+++
++
+++
++
+++
++
++
+++
++
+++
+++
++
++
+
+++
+
+++
+++
++
+++
++
++
+++
++
+
++
1
spectrophotometer. H NMR and 13C NMR spectra
were measured on a Varian EM390-300 MHz in
CD3SOCD3 as solvent, using TMS as an internal stan-
dard, and chemical shifts are expressed as . Ana-
lytical data were obtained from the Microanalytical
Data Unit at Cairo University, Giza, Egypt.
NH)); 2975, 2890 (CH3, CH2); 2225, 2220 (2 CN);
1705, 1680 (2 C O); 1660 (C N); 1638 (C C). H
1
NMR = 1.34, 1.46 (2t, 6H, 2CH3); 2.20, 2.862 (m,
8H, 4CH2); 4.20, 4.24 (2q, 4H, 2CH2); 5.31 (s, 2H,
NH2); 9.24 (s, br, 1H, NH). C19H21N5O4S (415.47) =
Calcd: C, 54.93; H, 5.10; N, 16.86; S, 7.72%, found:
C, 56.46; H, 5.49; N, 16.54; S, 7.87%.
3-Cyano-2-hydrazono-N-(a-cyano-b-aminocro-
tononitrile-y-ylideno)-4,5,6,7-tetrahydrobenzo-
[b]thiophene (3a) and 3-Cyano-2-hydrazono-N-
(a-cyano-b-ethoxycarbonyl-ethyl crotonate-y-
ylideno)-4,5,6,7-tetrahydrobenzo[b]-thiophene
(3b)
2,4-Dicyano-3-amino-6-oxo-(4,5,6,7-tetrahydro-
benzo[b]thieno[2,3:6,5]-pyridazino[6,1-a]pyri-
midine (5) and 4-Amino-5-cyano-1-(3-cyano-
4,5,6,7-tetrahydrobenzo[b]thieno-2-yl)-
3-ethoxycarbonyl-6-oxopyridazine (6)
General Procedure. To a clear solution of the di-
azonium salt of compound 1 [prepared by adding a
cold solution of sodium nitrite (0.7 g, 0.01 mol in
10 ml water) to a cold solution of 1 in hydrochlo-
ric acid (10 ml) containing acetic acid (20 ml) with
continuous stirring] either 2a or 2b was added. The
reaction mixture in each case was stirred at 0 C for
3 h and the formed solid product, in each case, was
collected by filtration.
General Procedure. A solution of either 3a (3.2 g,
0.01 mol) or 3b (4.2, 0.01 mol) in ethanol (40 ml)
containing sodium hydroxide (0.8 g, 0.02 mole) was
heated under reflux for 2 h and then evaporated in
vacuum. The remaining solid product was triturated
with diethyl ether and then collected by filtration.
5: Pale yellow crystals (from acetic acid), yield
1
62% (2.0 g), m.p. > 300 C. IR ( /cm ) = 3460, 3380
(NH2); 2895 (CH2); 2220, 2215 (2 CN); 1695 (C O);
1
3a: Buff crystals (from 1,4-dioxane), yield 72%
1670 (C N); 1645 (C C). H NMR = 2.23, 2.76
1
(2.3 g), m.p. 110 C. IR ( /cm ) = 3470–3320 (NH2,
(2m, 8H, 4CH2); 5.51 (s, 2H, NH2). C15H10N6OS
(322.34) = Calcd: C, 55.89; H, 3.13; N, 26.07; S,
9.95%, found: C, 56.43; H, 3.45; N, 26.31; S,
9.62%.
NH); 2960 (CH2); 2225–2220 (4 CN); 1650 (C N);
1625 (C C). 1H NMR = 2.22, 2.87 (2m, 8H, 4CH2);
4.89 (s, 2H, NH2); 8.69 (s, br, 1H, NH). 13C NMR
= 29.5, 30.2 (cyclohexene C-1, C-4); 23.8, 24.9 (cy-
clohexene C-2, C-3); 58.4 (C N); 102.9, 104.3 (C C);
119.3, 119.8, 120.3, 120.7 (4 CN); 126.4, 132.0, 134.2,
138.7, (thiophene-C). C15H11N7S (321.36) = Calcd: C,
56.06; H, 3.45; N, 30.51; S, 9.98%, found: C, 56.46;
H, 3.87; N, 30.99; S, 9.55%.
6: Pale yellow crystals (from acetic acid), yield
1
59% (2.2 g), m.p. 185 C. IR ( /cm ) = 3465–3380
(NH2); 2970, 2885 (CH2, CH3); 2225, 2220 (2 CN);
1
1705, 1685 (2 C O); 1670 (C N); 1660 (C C). H
NMR = 1.36 (t, 3H, CH3); 2.24, 2.84 (2m, 8H, 4CH2);
4.25 (q, 2H, CH2); 5.30 (s, 2H, NH2). C17H15N5O3S
(369.41) = Calcd: C, 55.13; H, 3.98; N, 18.91; S,
8.66%, found: C, 55.54; H, 3.98; N, 19.25; S, 8.98%.
3b: Buff crystals (from 1,4-dioxane), yield 69%
1
(2.9 g), m.p. 120 C. IR ( /cm ) = 3480–3325 (NH2,

2-Diazo-4,5,6,7-tetrahydrobenzo[b]thiophene Derivatives Used to Synthesize Azoles, Azines, and Their Derivatives 113
(CH3, CH2); 2225, 2220 (2 CN); 1670 (exocyclic
N); 1638 (C C); 1200–1190 (C S). 1H NMR
6-( -Cyano-b-aminoacrylonitrilo- -yl)-5-imino-
4-phenyl-3-thioxo-2-(3-cyano-4,5,6,7-tetra-hydro-
benzo[b]thieno-2-yl)-1,2,4-triazine (7a) and
6-(Ethyl -cyano- -amino-acrylat- -yl)-5-oxo-
4-phenyl-3-thioxo-2-(3-cyano-4,5,6,7-tetra-
hydrobenzo[b]thieno-2-yl)-1,2,4-triazine (7b)
C
= 2.24, 2.36 (2m, 8H, 4CH2); 4.98 (s, 2H, NH2); 7.32–
7.39 (m, 5H, C6H5); 9.38 (s, br, 1H, NH). C22H16N8S2
(456.54) = Calcd: C, 57.88; H, 3.53; N, 24.54; S,
14.10%, found: C, 57.39; H, 3.21; N, 24.67; S, 14.45%.
10: Orange crystals (from acetic acid), yield 66%
General Procedure. To a solution of either 3a
(3.2 g, 0.01 mol) or 3b (4.2 g, 0.01 mole) in ethanol
(50 ml) containing triethylamine (0.5 ml), phenyl
isothiocyanate was added. The reaction mixture was
heated under reflux for 6 h. The solid product,
formed in each case, upon cooling was collected by
filtration.
1
(2.3 g), m.p. 230 C. IR ( /cm = 3490, 3345 (3 NH2);
2890 (CH2); 2220 (CN); 1655 (C N); 1634 (C C);
1580 (N N). 1H NMR = 2.26, 2.66 (2m, 8H, 4CH2),
4.35, 4.98–5.09 (3s, 6H, 3NH2); 6.99 (s, 1H, pyridine
H-3). C15H15N9S (353.35) = Calcd: C, 50.99; H, 4.28;
N, 35.68; S, 9.07%, found: C, 50.76; H, 4.58; N, 35.46;
S, 9.45%.
7a: Yellowish brown crystals (from 1,4-dioxane),
13: Yellowish brown crystals (from ethanol),
1
yield 65% (3.0 g), m.p. 140 C. IR ( /cm = 3465,
1
yield 64% (2.4 g), m.p. 240 C. IR ( /cm ) = 3460,
3355 (NH2, NH); 3060 (CH aromatic); 2898 (CH3,
CH2); 2225–2205 (3 CN); 1673 (exocyclic C N); 1635
3345 (NH2); 2895 (CH2); 2225, 2220–2215 (3 CN);
1685 (C O); 1665 (C N); 1645 (C C). 1H NMR
= 2.21, 2.72 (2m, 8H, 4CH2); 3.82 (s, 2H, CH2);
5.48 (s, 2H, NH2). 13C NMR = 29.2, 30.0 (cyclo-
hexene C-1, C-4); 23.1, 24.5 (cyclohexene C-2, C-3);
62.2 (CH2); 118.2, 119.0, 120.5 (3 CN); 124.4,
131.0, 133.6, 134.2, 134.9, 138.7, 138.9, 140.9, 144.1
(thiophene-C, pyridazine-C, and pyrimidine-C);
180.5 (C O). C18H12N8OS (388.41) = Calcd: C, 55.66;
H, 3.11; N, 28.85; S, 8.25%, found: C, 55.22; H, 3.57;
N, 28.34; S, 8.58%.
1
(C C); 1200–1192 (C S). H NMR = 2.26, 2.75
(2m, 8H, 4CH2); 4.84 (s, 2H, NH2); 7.30–7.37 (m, 5H,
C6H5); 9.22 (s, br, 1H, NH). C22H16N8S2 (456.54) =
Calcd: C, 57.88; H, 3.53; N, 24.54; S, 14.10%, found:
C, 57.46; H, 3.49; N, 24.34; S, 14.31%.
7b: Yellow crystals (from 1,4-dioxane), yield 73%
1
(3.7 g), m.p. 130 C. IR ( /cm ) = 3480, 3350 (NH2);
3055 (CH aromatic); 2983, 2890 (CH3, CH2); 2225,
2210 (2 CN); 1703, 1685 (2 C O); 1665 (C N); 1640
1
(C C); 1210–1195 (C S). H NMR = 1.13 (t, 3H,
19: Pale yellow crystals (from ethanol), yield 71%
CH3); 2.25, 2.72 (2m, 8H, 4CH2); 4.29 (q, 2H,
CH2); 4.92 (s, 2H, NH2); 7.34–7.39 (m, 5H, C6H5).
C24H20N6O3S2 (504.34) = Calcd: C, 57.13; H, 4.10; N,
16.66; S, 12.71%, found: C, 57.01; H, 4.49; N, 16.79;
S, 12.32%.
1
(2.8 g), m.p. > 300 C. IR ( /cm ) = 3460, 3340 (2
NH2); 2865 (CH2); 2225–2210 (3 CN); 1687 (C O);
1
1655 (C N); 1638 (C C). H NMR = 2.29, 2.70
(2m, 8H, 4CH2); 4.81, 5.36 (2s, 4H, 2NH2). 13C
NMR data which showed
29.3, 30.7 (cyclohex-
ene C-1, C-4); 23.6, 24.8 (cyclohexene C-2, C-3);
118.7, 119.4, 121.0 (3 CN); 123.9, 131.9, 134.0, 134.2,
134.6, 137.8, 138.4, 140.3, 144.4, 146.6 (thiophene-
C, pyridazine-C, and pyridine-C); 178.9 (C O).
C18H12N8OS (388.41) = Calcd: C, 55.66; H, 3.10; N,
28.85; S, 8.25%, found: C, 55.33; H, 3.29; N, 30.06; S,
8.11%.
4-Amino-7-cyano-6-imino-2-(3-cyano-4,5,6,
7-tetra hydrobenzo[b]thieno-2-yl)-4-phenyl-3-
thioxopyrido[2,3-e]-1,2,4-triazine (8), 2,4,5-
Triamino-3-(3-cyano-4,5,6,7-tetrahydrobenzo-
[b]thieno-2-az)-pyrazolo[3,4-b]pyridine (10),7-
Amino-3-cyano-5-cyanomethyleno-1-(3-cyano-
4,5,6,7-tetrahydrobenzo-[b]thieno-2-yl)-8-
oxopyrimidino [4,5-d]pyridazine (13), and
3,5-Diamino-4,7-dicyano-1-(3-cyano-4,5,6,7-
tetrahydrobenzo[b]thieno-2-yl)-8-oxopyridino-
[3,2-c]pyridazine (19)
3-Cyano-2-hydrazono-N-[ -(aminopropiono-
nitrile-a-ylideno)- -(2,5-di-aminopyrazolo-2-
ylidino)]-4,5,6,7-tetrahydrobenzo[b]thiophene
(9)
A suspension of either 7a (4.56 g, 0.01 mol), 9 (3.5 g,
0.01 mol), 12 (3.87 g, 0.01 mol), or 17 (3.8 g, 0.01 mol)
in sodium ethoxide solution [prepared by dissolving
sodium metal (0.46 g, 0.02 mol) in absolute ethanol
(50 ml)] was heated in a boiling water bath for 2 h.
The solid product, formed in each case, upon pour-
ing the reaction mixture into ice/water containing
hydrochloric acid, was collected by filtration.
A solution of 3a (3.2 g, 0.01 mol) in 1,4-dioxane
(70 ml) was treated with hydrazine hydrate (0.5 g,
0.01 mol). The reaction mixture was heated under
reflux for 6 h and then poured into ice/water contain-
ing a few drops of hydrochloric acid. The solid prod-
uct formed upon stirring overnight was collected by
filtration.
8: Yellowish brown crystals (from 1,4-dioxane),
9: Buff crystals (from ethanol), yield 68% (2.3 g),
1
1
yield 65% (3.0 g), m.p. 180 C. IR ( /cm ) = 3465,
m.p. 110 C. IR ( /cm ) = 3468, 3340 (3 NH2, NH);
3355 (NH2, NH); 3050 (CH aromatic); 2983, 2890
2890 (CH2); 2225, 2220 (2 CN); 1660 (C N); 1640

114 Wardakhan and Fleita
(C C). 1H NMR = 2.23, 2.64 (2m, 8H, 4CH2); 4.45,
4.85–5.01 (3s, 6H, 3NH2); 8.99 (s, br, 1H, NH). C15H15
N9S (353.41) = Calcd: C, 51.10; H, 4.28; N, 35.67;
S, 9.07%, found: C, 51.34; H, 4.02; N, 35.29; S, 9.35%.
(2 NH2); 3065 (CH aromatic); 2860 (CH2); 2225, 2220
(2 CN); 1685 (C O); 1660 (C N); 1630 (C C). H
1
NMR = 2.33, 2.39 (2m, 8H, 4CH2); 4.75, 5.21 (2s,
4H, 2NH2); 6.98 (s, 1H, thiazole H-5); 7.32–7.41 (m,
5H, C6H5). C26H18N8OS2 (522.60) = Calcd: C, 59.76;
H, 3.47; N, 21.44; S, 12.27%, found: C, 57.34; H, 3.01;
N, 21.78; S, 12.33%.
3-Cyano-2-hydrazonoacetonitrilo- -(6-amino-5-
cyano-2-cyanomethleno-4-yl)-4,5,6,
7-tetrahydrobenzo[b]thiophene (12)
3-Cyano-2-[5-amino-4-cyano-6-( -cyano-b-
aminoacrylonitrilo- -yl)-3-oxopyridazine-
2-yl] (18)
A solution of 3a (3.2 g, 0.01 mol) in 1,4-dioxane
(50 ml) containing a catalytic amount of triethy-
lamine (0.5 ml) was treated with malononitrile (11)
(0.66 g, 0.01 mol). The reaction mixture was heated
under reflux for 8 h and then left to cool. The formed
solid product was collected by filtration.
A solution of 3a (3.2 g, 0.01 mol) in dimethylfor-
mamide (20 ml) containing a catalytic amount of tri-
ethylamine (0.5 ml) was treated with ethyl cyanoac-
etate (17) (1.13 g, 0.01 mol). The reaction mixture
was heated under reflux for 4 h and then left to cool.
The solid product formed upon pouring the mixture
into ice/water containing a few drops of hydrochloric
acid was collected by filtration.
12: Yellowish brown crystals (from ethanol),
1
yield 64% (2.4 g), m.p. 240 C. IR ( /cm ) = 3466,
3320 (NH2, NH); 2888 (CH2); 2225, 2220–2215 (4
1
CN); 1665 (C N); 1645 (C C). H NMR = 2.21,
2.72 (2m, 8H, 4CH2); 3.82 (s, 2H, CH2); 5.48 (s, 2H,
NH2). C18H13N9S (387.38)-Calcd: C, 55.63; H, 3.64; N,
28.83; S, 8.19%, found: C, 55.41; H, 3.91; N, 28.64; S,
8.28%.
18: Yellowish brown crystals (from 1,4-dioxane),
1
yield 65% (3.0 g), m.p. 180 C. IR ( /cm ) = 3460,
3340 (2 NH2); 2865 (CH2); 2225–2215 (4 CN); 1680
(C O); 1655 (C N); 1630 (C C). 1H NMR = 2.27,
2.72 (2m, 8H, 4CH2); 4.99, 5.45 (2s, 4H, 2NH2).
C18H12N8OS (388.41) = Calcd: C, 55.66; H, 3.10; N,
28.85; S, 8.25%, found: C, 55.45; H, 3.35; N, 28.98; S,
8.45%.
7-Amino-3-cyano-5-(b-phenylcrotononitrilo-a-
yl)-1-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thieno-
2-yl)-10-oxopyrimidino[4,5-d]pyridazine (15)
Equimolar amounts of 13 (3.88 g, 0.01 mol) and ace-
tophenone (14) (1.2 g, 0.01 mol) in benzene (50 ml)
containing acetic acid (15 ml) and ammonium ac-
etate (1.40 g, 0.02 mol) were heated under reflux for
5h, the eliminated water was separated, and then
the organic mixture was evaporated in vacuum. The
residual product was triturated with ethanol, and the
formed solid product was collected by filtration.
15: Orange crystals (from ethanol), yield 58%
3-Amino-4,7-dicyano-6-imino-1-(3-cyano-4,5,6,
7-tetrahydrobenzo[b]thieno-2-yl)-8-phenylpyri-
dino[3,2-c]pyridazine (22)
A solution of 3a (3.2 g, 0.01 mol) in dimethylforma-
mide (20 ml) containing a catalytic amount of trie-
thylamine (0.5 ml) was treated with ␣-cyanocinna-
monitrile (26), and the reaction mixture was heated
under reflux for 4 h and then left to cool. The solid
product formed upon pouring the reaction mixture
into ice/water mixture was collected by filtration.
22: Pale brown crystals (from acetic acid), yield
1
(2.9 g), m.p. 220 C. IR ( /cm ) = 3465, 3420 (NH2);
3065 (CH aromatic); 2975, 2880 (CH3, CH2); 2225–
2215 (3 CN); 1685 (C O); 1665 (C N); 1630 (C C).
1H NMR = 2.24, 2.66 (2m, 8H, 4CH2); 2.88 (s, 3H,
CH3); 5.39 (s, 2H, NH2), 7.31–7.38 (m, 5H, C6H5).
C26H18N8OS (490.54) = Calcd: C, 63.66; H, 3.71; N,
22.84; S, 6.26%, found: C, 63.97; H, 3.45; N, 22.67; S,
6.26%.
1
61% (2.7 g), m.p. 110 C. IR ( /cm = 3465, 3360
(NH2, NH); 3058 (CH aromatic); 2890 (CH2); 2225,
2210 (3 CN); 1670 (exocyclic C N); 1638 (C C).
1H NMR = 2.24, 2.70 (2m, 8H, 4CH2); 4.89 (s, 2H,
NH2); 7.32–7.39 (m, 5H, C6H5); 9.38 (s, br, 1H, NH).
C24H16N8S (448.54) = Calcd: C, 64.28; H, 3.57; N,
25.00; S, 7.14%, found: C, 64.50; H, 3.21; N, 24.76; S,
7.24%.
7-Amino-3-cyano-5-(2-amino-4-phenylthieno-3-
yl)-1-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thieno-
2-yl)-8-oxopyrimidino[4,5-d]pyridazine (16)
A mixture of 15 (4.9 g, 0.01 mol) and sulfur (0.32 g,
0.01 mol) in ethanol 950 ml) containing triethy-
lamine (0.5 ml) was heated under reflux for 4 h and
then left to cool. The formed solid product was col-
lected by filtration.
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16: Pale yellow crystals (from ethanol), yield
1
73% (3.8 g), m.p. 190 C. IR ( /cm ) = 3472–3363

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