Reaction of 3-cyano-2-diazo-4,5,6,7-tetrahydrobenzo[b]thiophene with 3-imino-butyronitrile: Synthesis of pyridazines, thiophenes and their fused derivatives

Article abstract of DOI:10.1080/10426500307831

The reaction of the 3-cyano-2-diazo-4,5,6,7-tetrahydrobenzo[b]thiophene 1 with 3-imino-butyronitrile 2 gave the azo derivative (3). The reactivity of the latter product toward different reagents was studied to give fused derivatives with potential biologi

Full text of DOI:10.1080/10426500307831

Phosphorus, Sulfur, and Silicon, 178:1667–1680, 2003
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390225614
REACTION OF 3-CYANO-2-DIAZO-4,5,6,7-
TETRAHYDROBENZO[b]THIOPHENE WITH
3-IMINO-BUTYRONITRILE: SYNTHESIS OF
PYRIDAZINES, THIOPHENES AND THEIR
FUSED DERIVATIVES
K. M. H. Hilmy,a R. M. Mohareb,b
A. El-Torgman,a and Y. M. Sharawya
Minofiya University, Shebin Elkom, Egypt;a and
Cairo University, Giza, Egyptb
(Received September 30, 2002; accepted October 31, 2002)
The reaction of the 3-cyano-2-diazo-4,5,6,7-tetrahydrobenzo[ b]thio-
phene 1 with 3-imino-butyronitrile 2 gave the azo derivative (3). The
reactivity of the latter product toward different reagents was studied to
give fused derivatives with potential biological activities.
Keywords: 3-Imino-butyronitrile; 4,5,6,7-tetrahydrobenzo[b]thio-
phene; pyridazines
During recent years we have maintained a comprehensive pro-
gram aimed at investigation of the reaction of 2-diazo-4,5,6,7-
terahydrobenzo[b]thiophene-3-carboxylate with active methylene
reagents followed by heterocyclization of the resultant azo derivatives
with simple, available regents. Such a synthetic route has been proved
to be an easy facile and sole approach for the synthesis of either to
unreported derivatives of polyfunctionally substituted thiophenes,
2,3-dihydrothiazoles and thiazolidine.1,3
The importance of such compounds is due to their diverse
pharmacological activities including antibacterial,4 immunodulatory,5
antiflammatory,6 antidiabatic,7,8 antiplatelet activating factor,9 and an-
tiviral activities.10,11
Address correspondence to Khalid M. H. Hilmy, PO Box 73, Shoubra, Misr, Cairo,
Egypt. E-mail: khaledhilmy@hotmail.com
1667

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K. M. H. Hilmy et al.
RESULTS AND DISCUSSION
In continuating of our previous work, we report here in the uses of
3-cyano-2-diazo-4,5,6,7-tetrahydrobenzo[b]thiophene 112 for the syn-
thesis of a variety of azole, azine, or azoloazine derivatives incorpora-
tion a tetrahydrobenzo[b]thiophene moiety with anticipated biological
activity.
The reaction of 3-cyano-2-diazo-4,5,6,7-tetrahydrobenzo[b]thio-
phene 1 with a cold solution (0–5◦C) of 2-imino-butyronitrile 213 in
ethanol containing sodium acetate gave a single product with molecular
formula C13H13N5S. Three possible isomeric structures were proposed
for this formula, 3, 4, and 5. Structures 4 and 5 were ruled out on the
basis of the 1H NMR spectrum of the reaction product that showed the
presence of two singlets (D2O exchangeable) at δ 8.97 and 9.23 ppm,
corresponding to two NH groups together with the absence of any sin-
glet due to a CH group or any NH2 group stretching through the IR
spectrum of the reaction product, which might be expected to appear if
neither structure 4 or 5 were considered. The analytical and spectral
data are in agree with structure 3. Further conformation for structure
3 was obtained through studying its reactivity toward various chemical
reagents. Thus, heating compounds in refluxing acetic/hydrochloric acid
solution gave the 3-cyno-2-hydrazono (3-oxo-butyronitril-2-yl)-4,5,6,7-
tetrahydrobenzo[ b]thiophene (6). The structure of compound 6 was
based on analytical and spectral data. The oxo-group in compound 6
showed interesting reactivity toward cyano methylene reagents. Thus,
the reaction of 6 with malononitrile in the presence of ammonium
acetate gave the corresponding Knoevenagel condensation product 7.
The structure of 7 was established on the basis of IR spectrum, which
showed the presence of four CN group stretching at 2225–2210 cm−1
and 13C NMR data, which showed the presence of δ 23.2, 23.8 (cyclochex-
ene C-2, C-3), 28.2 (CH3), 29.7, 30.2 (cyclochexene C-1, C-4), 118.4,
118.6, 119.6, 120.9 (4 CN), 121.0, 122.6 (C C),∗ 126.8, 132.2, 133.0,
138.2 (thiophene-C), 158.3 (C N) ppm. Compound 7 underwent ready
cyclization when heated under reflux in sodium ethoxide solution to give
9. The latter product is formed through the intermediate formation of
the 6-iminopyridazine 8 by Micheal addition and hydrolysis (Scheme 1).
The structure of compound 9 was confirmed on the basis of analyt-
ical and spectral data. Thus, the IR spectrum of the reaction product
showed the presence of two CN group stretching at 2225, 2220 cm−1
moreover the H NMR spectrum revealed, beside the two multiplets
characteristic for the two CH2 groups of the cyclohexene moiety, the
;
1
∗The C C group appears at low field due to its conjugation with C N and C
N .

Synthesis of Pyridazines, Thiophenes and their Fused Derivatives
1669
SCHEME 1
presence of only a singlet at δ 2.19 ppm characteristic for a CH3
group.
The reaction of compound 7 with elemental sulfur in the presence of a
catalytic amount of triethylamine gave the thiophene derivative 10.14,15
The latter underwent ready cyclization when refluxed in dimethylfor-
mamide containing triethylamine to give 11. The structure of 11 was
1
established on the basis of analytical and spectral data. Thus, the H
NMR spectrum of the reaction product showed the presence of two
multiplets at δ 2.23–2.27 and 2.42–2.47 ppm due to two CH2 group
of the cyclohexene ring, a singlet at δ 5.38 ppm (D2O exchangeable)
corresponding to an NH2 group and a singlet at δ 6.99 ppm due to

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K. M. H. Hilmy et al.
the thiophene H-5 proton, moreover, the 13C NMR spectrum, showed
δ 23.1, 23.7 (cyclohexene C-2, C-3), 29.6, 30.8 (cyclohexene C-1, C-4),
119.6, 120.3 (2CN), 126.7, 132.2, 133.6, 139.8, 142.1 (pyridazine-C,
thiophene-C), 178.40 (CO) ppm. Compound 11 showed an interesting
reactivity toward cycloaddition reactions.16 Thus, 11 reacted with ei-
ther acrylonitrile 12a or ethyl acrylate 12b to give the phthalazine
derivatives 14a and 14b respectively (Scheme 2). Formation of the
SCHEME 2

Synthesis of Pyridazines, Thiophenes and their Fused Derivatives
1671
latter products is explained in terms of the intermediate formation
of 13a and 13b followed by elimination of hydrogen sulphide. Struc-
tures 14a and 14b were based on analytical and spectral data (see
Experimental).
The reaction of compound 7 with either benzaldehyde 15a or
4-chlorobenzaldehyde 15b gave the corresponding arylidene deriva-
tives 16a and 16b, respectively, the analytical and spectral data of
which are in agree with the proposed structures. The reaction of 16a
with either malononitrile or ethyl cyanoacetate in the presence of tri-
ethylamine gave the corresponding benzo[d]pyridiazine derivatives 18a
and 18b respectively. Formation of the latter products was explained
in terms of the intermediate formation of 17a and 17b, respectively,
followed by Michael addition of NH to CN group, hydrolysis, and elimi-
nation of hydrogen cyanide. The structures of 18a and 18b were based
on analytical and spectral data. Further conformation for the proposed
structures was obtained through their synthesis via another reaction
route. Thus, the reaction of 7 with cinnamonitrile derivatives 19a and
19b gave the same products 18a and 18b respectively (identical m.p.
and mixed m.p.) (Scheme 3).
The reaction of compound 6 with ethyl cyanoacetate gave the pyri-
dazine derivative 20; its structure was based on analytical and spectral
data. The latter product reacted with elemental sulfur to give a single
product with molecular formula C16H11N5S2O. Two possible isomeric
structures were considered, 11 and 21. The reaction product was shown
to be identical in all respects with compound 11 previously obtained (see
Experimental).
The reaction of 20 with benzene diazomium chloride gave the phenyl-
hydrazo derivative 22. The latter product underwent ready cyclization
when heated under reflux in ethanolic/sodium hydroxide solution to
give the pyridazo[4,5-d]pyridazine derivative 24 via the intermediate
formation of 23.
The presence of the 1,3-dicarbonyl moiety in compound 24 showed
an interesting reactivity characteristic for such a series of compounds.
Thus, the reaction of compound 24 with hydrazine hydrate afforded 25.
Moreover, with either urea or thiourea, compound 24 gave 26a and 26b,
respectively; their structures were confirmed on the basis of analytical
and spectral data (Scheme 4).
EXPERIMENTAL
All melting points are uncorrected, the NMR spectra were recorded on a
Varian Em-390 (90 MHz), and chemical shifts were expresed as δ values

1672
K. M. H. Hilmy et al.
SCHEME 3
against SiMe4 as internal standard. IR spectra were recorded as KBr
pellets on a Pye Unicam spectrometer.
3-Cyano-2-hydrazono(3-imino-butyronitril-2-yl)-
4,5,6,7-tetrahydrobenzo[ b]thiophene (3)
To a cold solution of compound 2 (0.82 g, 0.01 mol), in ethanol (50 ml),
sodium acetate (0.82 g, 0.01 mol) and a cold solution of diazonium salt
1 (0.01 mol) (which was prepared by adding NaNO2 [0.7 g, 0.01 mol]
solution to a cold solution of the amine precursor 1 [1.47 g, 0.01 mol]
in acetic acid [20 ml], HCl [5 ml]) was added dropwise with stirring
for 1 h at 0–5◦C. The formed solid product was collected by filtration,
washed with water, dried, and crystallized from acetic acid, in 80%

Synthesis of Pyridazines, Thiophenes and their Fused Derivatives
1673
SCHEME 4

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K. M. H. Hilmy et al.
yield; m.p. 180–181◦C. IR (KBr) cm−1: 3564–3430 (2NH), 2972–2840
1
(CH3, CH2), 2225, 2220 (2CN); H NMR (DMSO-d6) ppm: 2.21–2.26
(2m, 4H, 2CH2), 2.30–2.34 (2m, 4H, 2CH2), 3.21 (s, 3H, CH3), 8.97,
9.23 (2s, 2H, 2NH). Anal. Calcd. for C13H13N5S (271.00): C, 57.56; H,
4.97; N, 25.83; S, 11.80. Found: C, 57.50; H, 4.80; N, 25.81, S, 11.80.
3-Cyano-2-hydrazono(3-oxo-butyronitril-2-yl)-
4,5,6,7-tetrahydrobenzo[ b]thiophene (6)
A solution of compound 3 (2.71 g, 0.01 mol) in acetic acid (40 ml) con-
taining HCl (5 ml) was heated under reflux for 4 h and then poured into
an icewater mixture containing NaOH (to PH6). The formed solid prod-
uct was collected by filtration, washed with cold water several times,
dried, and crystallized from acetic acid in 68% yield; m.p. 186–187◦C. IR
(KBr) cm−1: 3480–3420 (NH), 2980, 2873 (CH3, CH2), 2225, 2220 (2CN),
1690 (CO); 1H NMR (DMSO-d6) ppm: 2.23–2.26 (2m, 4H, 2CH2), 2.33–
2.38 (2m, 4H, 2CH2), 3.02 (s, 3H, CH3), 8.90 (s, 1H, NH). Anal. Calcd.
for C13H12N4OS (272): C, 57.35; H, 4.41; N, 20.58; S, 11.76. Found: C,
53.12; H, 4.11; N, 20.32, S, 11.56.
3-Cyano-2-hydrazono(3,3-dicyano-carbonylideno-butyro-
nitril-2-yl)-4,5,6,7-tetrahydrobenzo[ b]thiophene (7)
To compound 6 (2.88 g, 0.01 mol), malononitrile (0.66 g, 0.01 mol) and
amonium acetate (0.77 g, 0.01 mol) were added. The reaction mixture
was heated in an oil bath at 140◦C for 1 h and left to cool. The solidi-
fied product washed with ethanol and collected by filtration, dried, and
crystallized from ethanol in 96% yield; m.p. 210–211◦C. IR(KBr) cm−1
:
1
3440–3360 (NH), 2990, 2875 (CH3, CH2), 2225–2210 (4CN); H NMR
(DMSO-d6) ppm: 2.23–2.25 (m, 4H, 2CH2), 2.36–2.38 (m, 4H, 2CH2),
8.96 (s, 1H, NH); 13C NMR (DMSO-d6) ppm: 23.2,23.8 (cyclohexene
C-2, C-3), 28.2 (CH3), 29.7, 30.2 (cyclohexene C-1, C-4), 118.4, 118.6,
119.6, 120.9 (4CN), 121.0, 122.6 (C C), 126.8, 132.2, 133.0, 138.2
(thiophene-C) 158.3 (C N). Anal. Calcd. for C16H12N6S (320): C, 60.00;
H, 3.75; N, 26.25; S, 10.00. Found: C, 59.85; H, 3.59; N, 25.39; S, 10.17.
3,5-Dicyano-4-methyl-8-oxo-4,5,6,7-tetrahydrobenzo[ b]-
thiophene[2,3:5,6]pyrimidino-[1,6-f]pyridazine (9)
A suspension of compound 7 (3.2 g, 0.01 mol), in sodium ethoxide
(which was prepared by adding sodium metal [0.23 g, 0.01 mol] to ab-
solute ethanol [40 ml]) was heated in a boiling water bath for 3 h and
poured into ice-water containing HCl (PH6). The formed solid product
was collected by filtration, dried, and crystallized from DMF in 62%
yield; m.p. 158–159◦C. IR (KBr) cm−1: 2865 (CH3), 2225, 2220 (2CN),
1706 (CO); 1H NMR (DMSO-d6 ) ppm: 2.19 (s, 3H, CH3), 2.24–2.27

Synthesis of Pyridazines, Thiophenes and their Fused Derivatives
1675
(m, 4H, 2CH2), 2.35–2.38 (m, 4H, 2CH2). Anal. Calcd. for C16H11N5OS
(321): C, 59.81; H, 3.43; N, 21.81; S, 9.97. Found: C, 59.64; H, 3.31; N,
21.90; S, 9.81.
3-Cyano-2-hydrazono[(2-amino-3-cyanothiophen-4-yl)ace-
tonitrilo-ylideno]-4,5,6,7-tetrahydrobenzo[ b]thiophene
(10)
To a solution of compound 7 (3.2 g, 0.01 mol), in dioxane (30 ml), Et3N
(0.5 ml) and elemental sulfur (0.32 g, 0.01 mol) was added. The reaction
mixture was heated under reflux for 4 h and left to cool. The formed solid
product upon pouring into ice-water, was collected by filtration, washed
with water, dried, and crystallized from ethanol in 63% yield; m.p. 190–
191◦C. IR (KBr) cm−1: 3480, 3420 (NH2, NH), 2855 (CH2), 2225, 2220,
2215 (3 CN); 1H NMR (DMSO-d6) ppm: 2.20–2.24 (m, 4H, 2CH2), 2.34–
2.36 (m, 4H, 2CH2), 5.55 (s; 2H, NH2), 6.89 (s, 1H, thiophene H-5), 8.84
(s, 1H, NH). Anal. Calcd. for C16H12N6S2 (352): C, 54.54; H, 3.41; N,
23.86; S, 18.18. Found: C, 54.41; H, 3.32; N, 23.78; S, 18.20.
3-Cyano-2-(6-amino-3-cyano-7-oxo-thieno[3,4-d]pyrida-
zine)-4,5,6,7-tetrahydrobenzo[ b]thiophene (11)
A solution of either compound 10 (3.52 g, 0.01 mol) in DMF
(30 ml) containing Et3N (0.5 ml), or compound 20 (3.21 g, 0.01 mol)
in DMF (30 ml) containing Et3N (0.5 ml) and elemental sulfur (0.32 g,
0.01 mol) was heated under reflux for 12 h and then evaporated in
vacuum. The remaining product was triturated with diethyl ether and
the formed solid product was collected by filtration, dried, and crystal-
lized from dioxane in 51% yield; m.p. >300◦C. IR (KBr) cm−1: 3470,
3350 (NH2), 2975 (CH2), 2225, 2220 (2CN), 1700 (CO), 1655 (C N),
1644 (C C); 1H NMR (DMSO-d6) ppm: 2.23–2.27 (m, 4H, 2CH2), 2.42–
2.47 (m, 4H, 2CH2), 5.38 (s, 2H, NH2), 6.99 (s, 1H, thiophene H-5);
13C NMR (DMSO-d6) ppm: 23.1, 23.7 (cyclohexene C-2, C-3), 29.6, 30.8
(cyclohexene C-1, C-4), 119.6, 120.3 (2CN), 126.7, 132.2, 133.6, 139.8,
142.1 (pyridazine-C and thiophene-C), 178.4 (CO). Anal. Calcd. for
C16H11N5OS2 (353): C, 54.54; H, 3.41; N, 19.86; S, 18.18. Found: C,
54.43; H, 3.35; N, 19.72; S, 18.12.
Benzo[d]pyridazine Derivatives (14a,b)
(General Procedure)
Equimolecular amounts of compound 11 (3.53 g, 0.01 mol) and ei-
ther acrylonitrile 12a (0.53 g, 0.01 mol), or ethyl acrylate 12b (1.14 g,
0.01 mol) in dioxane (40 ml) containing Et3N (0.5 ml) were heated under

1676
K. M. H. Hilmy et al.
reflux for 6 h until all hydrogen sulfide was liberated. The remaining
product, obtained upon evaporating the solution under vacuum, was
triturated with ethanol and the formed solid product was collected by
filtration, dried, and crystallized from the proper solvent to produce
14a,b.
3-Cyano-2-(7-amino-3,5-dicyano-8-oxo-benzo[d]pyrida-
zine)-4,5,6,7-tetrahydrobenzo[ b]thiophene (14a)
14a crystallized from dioxane in 59% yield; m.p. 233–234◦C. IR (KBr)
cm−1: 3480, 3360 (NH2), 2890 (CH2), 2225, 2215, 2210 (3CN), 1703 (CO),
1645 (C N), 1638 (C C); 1H NMR (DMSO-d6) ppm: 2.21–2.26 (m, 4H,
2CH2), 2.30–2.38 (m, 4H, 2CH2), 5.20 (s, 2H, NH2), 7.32–7.41 (m, 2H,
C6H2). Anal. Calcd. for C19H12N6OS (372): C, 61.29; H, 3.22; N, 22.58;
S, 8.60. Found: C, 61.22; H, 3.18; N, 22.43; S, 8.57.
3-Cyano-2-(7-amino-3-cyano-5-ethoxy-carbonyl-8-oxo-
benzo[d]pyridazine)-4,5,6,7-tetrahydrobenzo[ b]thiophene
(14b)
14b crystallized from acetic acid in 69% yield; m.p. >300◦C. IR (KBr)
cm−1: 3480, 3365 (NH2), 2980, 2880 (CH3, CH2), 2225, 2222 (2CN), 1703,
1
1680 (2 CO), 1645 (C N), 1638 (C C); H NMR (DMSO-d6) ppm: 1.66
(t, 3H, J = 6.2 Hz, CH3), 2.21–2.27 (m, 4H, 2CH2), 2.30–2.37 (m, 4H,
2CH2), 4.22 (q, 2H, J = 6.2 Hz, CH2),5.20 (s, 2H, NH2), 7.30–7.38 (m,
2H, C6H2). Anal. Calcd. for C21H17N5O3S (419): C, 60.14; H, 4.07; N,
16.70; S, 7.37. Found: C, 60.10; H, 4.00; N, 16.81; S, 7.29.
4,5,6,7-Tetrahydrobenzo[b]thiophene Derivatives (16a,b)
(General Procedure)
To a solution of compound 7 (3.2 g, 0.01 mol) in DMF (40 ml) con-
taining piperidine (0.5 ml), either benzaldehyde (1.06 g, 0.01 mol) or
4-chlorobenzaldehyde (1.41 g, 0.01 mol) was added. In each case the
reaction mixture was heated under reflux for 4 h and evaporated in
vacuum. The remaining products were collected by filtration and crys-
tallized from the proper solvent to produce 16a,b.
3-Cyno-2-hydrazono(3,3-dicyano-carbonyl-ideno-4-benzal-
butyronitril-2-ylideno)-4,5,6,7-tetrahydrobenzo[ b]-
thiophene (16a)
16a crystallized from ethanol in 80% yield; m.p. 210–211◦C. IR (KBr)
cm−1: 3461–3340 (NH), 2890 (CH2), 2225–2210 (4CN), 1640 (C N);
1H NMR (DMSO-d6) ppm: 2.24–2.27 (m, 4H, 2CH2), 2.30–2.35 (m, 4H,

Synthesis of Pyridazines, Thiophenes and their Fused Derivatives
1677
2CH2), 6.20–6.23 (d, 2H, J = 3.50 Hz, CH CH) 7.32–7.40 (m, 5H, C6H5),
8.75 (s, 1H, NH). Anal. Calcd. for C23H16N6S (408): C, 67.64; H, 3.92;
N, 20.58; S, 7.84. Found: C, 67.81; H, 3.98; N, 20.43; S, 7.72.
3-Cyano-2-hydrazono[3,3-dicyano-carbonyl-ideno-4-
(4-chlorobenzal)-butyronitril-2-ylideno]-4,5,6,7-tetra-
hydrobenzo[ b]thiophene (16b)
16b crystallized from ethanol in 72% yield; m.p. 185–186◦C. IR (KBr)
cm−1: 3520–3330 (NH), 2893 (CH2), 2225–2212 (4CN), 1642 (C N),
1638 (C C); 1H NMR (DMSO-d6) ppm: 2.21–2.25 (m, 4CH, 2CH2), 2.36–
2.39 (m, 4H, 2CH2), 6.23–6.27 (d, 2H, J = 3.50 Hz, CH CH), 7.33–7.40
(m, 4H, C6H4), 8.81 (s, 1H, NH). Anal. Calcd. for C23H15ClN6S (442.5):
C, 62.37; H, 3.38; Cl, 8.02; N, 18.98; S, 7.23. Found: C, 62.28; H, 3.41;
Cl, 8.12; N, 18.81; S, 7.11.
Benzo[d]pyridazine Derivatives (18a,b)
(General Procedure)
Method A. For an equimolecular amounts of compound 16a (4.08 g,
0.01 mol) in dioxane (40 ml) containing Et3N (0.5 ml) either malonitrile
(0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g, 0.01 mol) was added.
The reaction mixture in each case was heated under reflux for 8 h.
The solid product, formed upon pouring into ice-water containing few
drops of HCl, was collected by filtration, dried, and crystallized from
appropriate solvent to produce 18a,b.
Method B. To a solution of compound 7 (3.2 g, 0.01 mol) in dioxane
(50 ml), containing Et3N (0.5 ml), either 19a (1.54 g, 0.01 mol) or 19b
(2.01 g, 0.01 mol) of the cinnamonitrile derivatives was added. The re-
action mixture in each case was heated under reflux for 5 h and poured
into ice-water containing a few drops of HCl. The solid product formed
was collected by filtration, washed with cold water, dried, and crystal-
lized from appropriate solvent to produce 18a,b.
3-Cyano-2-(7-amino-3,6-dicyano-5-phenyl-8-oxo-benzo[d]-
pyridazine)-4,5,6,7-tetrahydrobenzo[ b]thiophene (18a)
18a crystallized from acetic acid in 60% yield; m.p. 158–159◦C. IR
(KBr) cm−1: 3480–3360 (NH2), 2880 (CH2), 2225, 2222, 2217 (3CN),
1
1697 (CO), 1650 (C N); H NMR (DMSO-d6) ppm: 2.25–2.28 (m, 4H,
2CH2), 2.36–2.39 (m, 4H, 2CH2), 5.50 (s, 2H, NH2), 7.30–7.38 (m,
6H, C6H5, benzene CH). Anal. Calcd. for C25H16N6OS (448): C, 66.96;
H, 3.57; N, 18.75; S, 7.14. Found: C, 66.90; H, 3.41; N, 18.91; S,
7.11.

1678
K. M. H. Hilmy et al.
3-Cyano-2-[7-amino-3-cyano-6-(ethoxy-carbonyl)-5-phenyl-
8-oxo-benzo[d]pyridazine]-4,5,6,7-tetrahydrobenzo[ b]-
thiophene (18b)
18b crystallized from acetic acid in 50% yield; m.p. 222–223◦C. IR
(KBr) cm−1: 3480–3365 (NH2) 2878 (CH2), 2225, 2220 (2 CN), 1685
1
(CO), 1660 (C N), 1640 (C C), 1635 (CO); H NMR (DMSO-d6) ppm:
1.64 (t, 3H, J = 7.0 Hz, CH3), 2.25–2.27 (m, 4H, 2CH2), 2.35–2.39 (m,
4H, 2CH2), 4.24 (q, 2H, J = 7.0 Hz, CH2), 5.42 (s, 2H, NH2), 7.30–7.41
(m, 6H, C6H5, benzene CH). Anal. Calcd. for C27H21N5O3S (495): C,
65.45; H, 4.24; N, 14.14; S, 6.46. Found: C, 65.35; H, 4.12; N, 14.00; S,
6.51.
3-Cyano-2-(3,5,-dicyano-4-methyl-6-oxo-pyridazin-1-yl)-
4,5,6,7-tetrahydrobenzo[ b]thiophene (20)
To a dry solid of compound 6 (2.88 g, 0.01 mol), ethyl cyanoacetate
(1.13 g, 0.01 mol) and ammonium acetate (0.77 g, 0.01 mol) were added.
The reaction mixture was heated in an oil bath at 140◦C for 1 h and
left to cool. The solidified product washed with ethanol and collected
by filtration, dried, and crystallized from dioxane in 65% yield; m.p.
148–149◦C. IR (KBr) cm−1: 2982, 2873 (CH3, CH2), 2225, 2220, 2215
(3CN), 1695 (CO), 1655 (C N), 1640 (C C); 1H NMR (DMSO-d6) ppm:
2.20 (s, 3H, CH3), 2.24–2.26 (2m, 4H, 2CH2) 2.36–2.40 (2m, 4H, 2CH2).
Anal. Calcd. for C16H11N5OS (321): C, 59.81; H, 3.42; N, 21.80; S, 9.96.
Found: C, 59.72; H, 3.37; N, 21.70; S, 9.94.
3-Cyano-2-[3,5,-dicyano-4-(phenylhydrazono-methino)-6-
oxo-pyridazin-1-yl]-4,5,6,7-tetrahydrobenzo[ b]thiophene
(22)
To a cold (0–5◦C) solution of compound 20 (3.21 g, 0.01 mol) in ethanol
(50 ml) containing NaOH solution (10 ml, 10%), a solution of benzene
diazonium chloride (0.01 mol) (which was prepared by NaNO2 [0.79 g,
0.01 mol], in water [2 ml] was added to a cold solution of aniline [0.93 g,
0.01 mol] containing the appropriate amount of HCl with stirring) was
added with continuous stirring. The formed solid product was collected
by filtration, dried, and crystallized from acetic acid in 70% yield; m.p.
198–199◦C. IR (KBr) cm−1: 3460–3330 (NH) 2895 (CH2), 2225, 2220,
1
2215 (3 CN), 1695 (CO), 1655 (C N), 1640 (C C); H NMR (DMSO-
d6) ppm: 2.30–2.34 (m, 4H, 2CH2), 2.38–2.41 (m, 4CH, 2CH2), 6.58 (s,
1H, CH), 7.30–7.38 (m, 5H, C6H5), 8.20 (s, 1H, NH). Anal. Calcd. for
C22H15N7OS (425): C, 62.12; H, 3.53; N, 23.05; S, 7.52. Found: C, 61.98;
H, 3.41; N, 23.00; S, 7.41.

Synthesis of Pyridazines, Thiophenes and their Fused Derivatives
1679
3-Cyano-2-[3-cyano-7,8-dioxo-6-phenyl-pyridazo(4,5-d)
pyridiazin-1-yl]-4,5,6,7-tetrahydrobenzo[ b]thiophene (24)
A solution of compound 22 (4.25 g, 0.01 mol) in ethanol (50 ml) con-
taining NaOH (0.5 g) was heated under reflux for 5 h and poured into
ice-water containing a few drops of HCl. The solid product formed was
collected by filtration, washed with cold water, dried, and crystallized
from dioxane in 60% yield; m.p. 210–211◦C. IR (KBr) cm−1: 2890 (CH2),
2225, 2215 (2CN), 1700, 1685 (2CO), 1660 (C N), 1650 (C C); 1H NMR
(DMSO-d6) ppm: 2.25–2.28 (m, 4H, 2CH2), 2.33–2.36 (m, 4H, 2CH2),
7.30–7.37 (m, 6H, C6H5, and pyridazine H). Anal. Calcd. for C22H14N6
O2S (426): C, 61.97; H, 3.28; N, 19.72; S, 7.51. Found: C, 61.82; H, 3.17;
N, 19.70; S, 7.48.
3-Cyano-2-(3-cyano-7-phenyl-1,2,6,7,9,10,-hexazaace-
napthalen-1-yl)-4,5,6,7-tetrahydrobenzo[ b]thiophene (25)
To a solution of compound 24 (4.26 g, 0.01 mol) in dioxane (30 ml)
hydrazine hydrate (0.52 g, 0.01 mol) was added. The reaction mixture
was heated under reflux for 2 h and poured into ice-water containing a
few drops of HCl. The solid product formed was collected by filtration,
dried, and crystallized from ethanol in 60% yield; m.p. 280–281◦C. IR
(KBr) cm−1: 2893 (CH2), 2225, 2215 (2CN), 1660 (C N), 1635 (C C);
1H NMR (DMSO-d6) ppm: 2.24–2.26 (m, 4H, 2CH2), 2.33–2.38 (m, 4H,
2CH2), 7.31–7.36 (m, 6H, C6H5 and pyridazine H). Anal. Calcd. for
C22H14N8S (422): C, 62.55; H, 3.31; N, 26.54; S, 7.58. Found: C, 62.42;
H, 3.20; N, 26.42; S, 7.52.
3-Cyano-2-(1,2,6,7,9,11-hexazaphenanthren-1-yl)-
4,5,6,7-tetrahydrobenzo[b]thiophene Derivatives (26a,b)
(General Procedure)
To a suspension of compound 24 (4.26 g, 0.01 mol) in sodium ethoxide
(prepared by dissolving sodium metal in absolute ethanol [40 ml]), ei-
ther urea (0.6 g, 0.01 mol) or thiourea (0.76 g, 0.01 mol) was added. The
reaction mixture was heated in boiling water bath for 5 h and poured
into ice-water containing HCl (PH6). The formed solid product in each
case was collected by filtration, dried, and crystallized from appropriate
solvent to produce 26a,b.
3-Cyano-2-(3-cyano-7-phenyl-10-oxo-1,2,6,7,9,11-hexaza-
phenanthren-1-yl)-4,5,6,7-tetrahydrobenzo[ b]thiophene
(26a)
26a crystallized from dioxane in 62% yield; m.p. 210–211◦C. IR (KBr)
cm−1: 2880 (CH2), 2225, 2218 (2CN), 1689 (CO), 1655 (C N), 1640

1680
K. M. H. Hilmy et al.
1
(C C); H NMR (DMSO-d6) ppm: 2.26–2.28 (m, 4H, 2CH2), 2.32–2.36
(m, 4H, 2CH2), 7.28–7.36 (m, 6H, C6H5, and pyridazine H). Anal. Calcd.
for C23H14N8OS (450): C, 61.33; H, 3.11; N, 24.88; S, 7.11. Found: C,
61.16; H, 3.09; N, 24.81; S, 7.10.
3-Cyano-2-(3-cyano-7-phenyl-10-thioxo-1,2,6,7,9,11-hexa-
zaphenanthren-1-yl)-4,5,6,7-tetrahydrobenzo[ b]thiophene
(26b)
26b crystallized from dioxane in 70% yield; m.p. 180–181◦C. IR (KBr)
cm−1: 2880 (CH2), 2220, 2218 (2CN), 1694 (C S), 1650 (C N), 1640
1
(C C); H NMR (DMSO–d6) ppm: 2.27–2.32 (m, 4H, 2CH2), 2.39–2.41
(m, 4H, 2CH2), 7.26–7.35 (m, 6H, C6H5 and pyridazine H). Anal. Calcd.
for C23H14N8 S2 (466): C, 59.22; H, 3.00; N, 24.03; S, 13.73. Found: C,
59.13; H, 2.88; N, 24.00; S, 13.61.
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