Reaction of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo-[b]thiophene with ethyl acetoacetate: Novel syntheses of pyridines, pyrazoles, and their fused derivatives

Article abstract of DOI:10.1002/hc.1079

The reaction of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene 1 with ethyl acetoacetate 2 gave compound 3. The reactivity of the latter produce toward a variety of chemical reagents was studied to give fused thiophene derivatives of potential pharmaceutical interest.

Full text of DOI:10.1002/hc.1079

Heteroatom Chemistry
Volume 12, Number 6, 2001
Reaction of 2-Amino-3-Cyano-4,5,6,7-
Tetrahydrobenzo-[b]Thiophene with Ethyl
Acetoacetate: Novel Syntheses of
Pyridines, Pyrazoles, and Their Fused
Derivatives
Rafat M. Mohareb and Mona H. Mohamed
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
Received 10 January 2001; accepted 2 April 2001
RESULTS AND DISCUSSION
ABSTRACT: The reaction of 2-amino-3-cyano-4,5,
6,7-tetrahydrobenzo[b]thiophene 1 with ethyl acetoac-
etate 2 gave compound 3. The reactivity of the lat-
ter product toward a variety of chemical reagents was
studied to give fused thiophene derivatives of potential
C
In this article, we report the reaction of 2-amino-3-
cyano-4,5,6,7-tetrahydrobenzo-[b]thiophene 1 with
ethyl acetoacetate (2) in an oil bath at 140 C to give
the acyclic amide derivative 3. The structure of 3
was elucidated on the basis of analytical and spectral
data. Thus, the IR spectrum of the reaction prod-
pharmaceutical interest.
2001 John Wiley & Sons, Inc.
Heteroatom Chem 12:518–527, 2001
1
uct showed an NH stretching at 3455–3340 cm ,
1
a CN group stretching at 2223 cm and two C
O
1
1
groups stretching at 1705 and 1687 cm . The H
NMR spectrum showed, besides the expected multi-
ples corresponding to the four CH2 groups, a singlet
at 2.23 for the CH3 group, a singlet at 5.55 for a
CH2 group and a singlet (D2O exchangeable) at 8.81
for an NH group. Further confirmation for structure
3 was obtained through its reactivity toward chem-
ical reagents. Thus, the reaction of 3 with benzene-
diazonium chloride gave the hydrazone derivative 4.
Compound 3 underwent ready cyclization when
heated in sodium ethoxide solution to give the
3-acetyl-4-amino-2-hydroxytetrahydrobenzo[b]thie-
nopyridine derivative 5, not the tautomeric acetyl-
4-amino-2-oxotetrahydrobenzo-[b]thienopyridine 6.
The structure of compound 5 was established on the
basis of its 13C NMR spectrum which showed the
presence of 25.9 (CH3), 23.3, 23.9 (cyclohexene
C-2, C-3), 29.3, 30.1 (cyclohexene C-1, C-4), 121.3,
122.4, 123.8, 124.0, 132.2, 133.0, 139.8 (thiephene
INTRODUCTION
Despite fairly intense research on the synthesis
and the evaluation of biological properties of com-
pounds containing thiophenes and the thienoazine
moiety [1–9], very few perianellated systems with
the thienoazine skeleton are known [10–12], and,
to our knowledge, a relatively small amount of
work has been done on the chemistry of tetrahy-
drobenzo[b]thiophene derivatives. In earlier arti-
cles [13–15], our research group described the uses
of 4,5,6,7-benzo[b]thiophene derivatives in hetero-
cyclic syntheses to give azole and azine derivatives
containing the benzothiophene moiety. The impor-
tance of these compounds is due to their diverse
pharmaceutical activities [16–19].
c
2001 John Wiley & Sons, Inc.
518

Reaction of 2-Amino-3-Cyano-4,5,6,7-Tetrahydrobenzo-[b]Thiophene with Ethyle Acetoacetate 519
C, pyridine C), 180.3 (C O). The presence of
an acetyl group ortho to the hydroxyl group in
the pyridine ring showed interesting reactivity
toward active methylene reagents. Thus, with
either malononitrile (7a) or ethyl cyanoacetate
(7b) in ammonium acetate and with heating in
an oil bath at 130 C, compound 5 gave the tetra-
hydrobenzo[b]thieno[2,3:b]pyrido[2,3-d]pyridine
derivatives 9a and 9b respectively. Formation of
the latter products took place via the intermediate
formation of 8a and 8b, respectively. The structures
of compounds 9a,b were based on analytical and
spectral data: thus, the 13C NMR spectrum of 9a
the amide derivative 3 with malononitrile under a
variety of conditions. Thus, conducting the reac-
tion in ethanolic sodium, ethoxide solution gave
the pyridine derivative 10. The latter product un-
derwent ready cyclization when heated in ethano-
lic sodium hydroxide to give the tetrahydrobenzo[b]
thieno[5,4:4,5]-pyrimidine[2,1:1,2]pyridine deriva-
tive 11. The reaction of compound 3 with mal-
ononitrile in ethanolic piperidine solution gave
two products. Their separation depended on the
far greater solubility of one of them in ethanol
over the other. The ethanol soluble product was
identified to be the acyclic product 12, and the
ethanol insoluble product was identified to be
the 6-oxopyridine derivative 13, which underwent
ready cyclization when heated in sodium ethox-
ide solution to give the tetrahydrobenzo[b]thieno-
[5,4:4,5]pyrimidine-[2,1:1,2]pyridine derivative 14
(Scheme 2). Structures of compounds 10–14 were
identified on the basis of analytical and spectral data
(see Experimental section).
showed the presence of
24.2 (CH3), 23.2, 23.5
(cyclohexene C-2, C-3), 29.0, 30.4 (cyclohexene C-1,
C-4), 119.6 (CN), 121.1, 122.2, 123.5, 124.2, 132.5,
133.1, 134.6, 139.7, 148.7 (thiophene C, pyridine C)
(Scheme 1).
In the past, our research group studied the reac-
tion of acetoacetanilide derivatives with malononi-
trile under different conditions to give either acyclic
products or pyridine derivatives [20]. In continua-
tion of this work, we studied here the reaction of
The reaction of compound 3 with benzaldehyde
in the presence of a catalytic amount of piperidine
CN
CN
140 o
C
CH3-CO-CH2-COOEt
+
NH-CO-CH2-CO-CH3
S
NH2
S
2
CN
3
1
NH-CO-C-CO-CH3
NaOEt
S
N-NH-Ph
X
NC
4
C
NH2
C-CH3
OH
NH2
CH2CN
NH2
COCH3
COCH3
X
7a, X = CN
OH
O
b,
X = COOEt
N
N
NH
S
S
S
8a, X = CN
b, X = COOEt
6
5
X
NH2
CH3
OH
N
9a X = CN
b, X = COOEt
N
S
SCHEME 1

520 Mohareb and Mohamed
O
CN
CN
HN
NaOEt
NH
CH2(CN)2
CH3
+
3
S
10
EtOH/piperidine
CN
O
CN
CN
CN
NH2
NC
H2N
CN
CH3
+
N
N
NH-CO-CH2-C-CH3
S
S
O
CH3
N
13
12
S
11
H2N
N
CN
CH3
N
S
O
14
SCHEME 2
gave the benzal derivative 15. The latter product
showed high reactivity toward hydrazines. Thus,
with either hydrazine hydrate 16a or phenylhy-
drazine 16b, the pyrazole derivatives 17a and 17b
were formed, respectively. Moreover, the reaction of
15 with either malononitrile (7a) or ethyl cyanoac-
etate (7b) gave, in each case, a single product with
molecular formulas C23H18N4O2S and C25H23N3O4S,
respectively. Two possible isomeric structures were
considered: the benzene derivatives 18a and b or
the pyridine derivatives 19a and b. Structures 18a
(mixed m.p. tests and comparison of IR spectra)
(Scheme 3).
The reaction of compound 3 with bromine in
the presence of acetic acid at 60 C gave the ω-bromo
derivative 21. Compound 21 showed interesting re-
activity toward potassium cyanide and potassium
thiocyanate to give the corresponding cyano and
thiocyano derivatives 22a and 22b, respectively. The
reaction of 22a and 22b with malononitrile gave the
corresponding pyridine derivatives 24a and 24b, re-
spectively. Formation of the latter products took
place via the intermediate formation of 23a and b,
followed by cyclization (Scheme 4).
The reactions of compounds 24a and 24b with
benzenediazonium chloride in ethanolic sodium hy-
droxide solution gave the hydrazo derivatives 25a
and 25b, respectively, not the azo derivatives 26a
and b. Confirmations of the structures of the latter
products were based on 13C NMR data of the reaction
products (see Experimental section). Further confir-
mations of the structures 25a and b were obtained
via the ready cyclization of these products, when
1
and b were ruled out on the basis of the H NMR
spectra of the reaction products, which showed the
absence of any NH group. Moreover, the presence
of singlets at 2.78 and 2.68, respectively, corre-
sponding to CH3 of an acetyl group which con-
firms structures 19a and b. Further confirmations
of structures 19a and b were obtained through
their syntheses via another reaction route. Thus,
the reaction of 3 with either -cyanocinnamonitrile
(20a) or -ethoxycarbonyl cinnamonitrile (20b)
gave the same products 19a and 19b, respectively

Reaction of 2-Amino-3-Cyano-4,5,6,7-Tetrahydrobenzo-[
b]Thiophene with Ethyle Acetoacetate 521
CH2-CN
X
X= CN
X = COOEt
CN
CN
NH-CO-C-CO-CH3
NH--CO-CH-CO-CH3
3
+
Ph-CHO
S
S
CN
CH-CH
Ph
CH-Ph
X
15
R-NH-NH2
16a, R = H
b, R = Ph
-H2
CN
O
OH
CN
NH-CO
S
CN
COCH3
Ph
N
CH3
N
S
NHCO
Ph
NH2
H2N
S
X
18a, x = CN
b, X = COOEt
X
19a, x = CN
b, X = COOEt
N
R
Ph
17a, R = H
b, R = Ph
CN
X
Ph-CH=C
3
+
20a, X = CN
b, X = COOEt
SCHEME 3
heated in ethanolic sodium hydroxide solution, to
give the pyrido[4,3-d]pyridazine derivatives 26a and
26b, respectively (Scheme 5).
was heated, and the formed solid product was col-
lected by filtration.
Compound 3: Yellow crystals (from ethanol),
1
yield 80% (2.09 g), m.p. 165 C. IR ( /cm ) = 3455–
3340 (NH), 2990, 2885 (CH3, CH2), 2223 (CN), 1705,
1687 (2 C O), 1638 (C C). 1H NMR = 2.23 (s, 3H,
CH3), 2.22, 2.64 (2m, 8H, 4CH2), 5.55 (s, 2H, CH2),
8.81 (s, 1H , NH). C13H14N2O2S (262.32): Calcd: C,
59.52; H, 5.38; N, 10.68; S, 12.22%. Found: C, 59.27;
H, 5.59, N, 9.87; S, 12.38%.
EXPERIMENTAL
All melting points were uncorrected. IR spectra were
recorded (KBr) on a Pye Unicam Sp-1000 spec-
1
trophotometer. H NMR and 13C NMR spectra were
measured on a Varian EM-390 90 MHz spectrom-
eter in DMSO-d6 as solvent with tetramethylsilane
(TMS) as an internal reference. Chemical shifts were
expressed as . Analytical data were determined at
the Microanalytical Data Unit at Cairo University.
3-Cyano-2-( -oxo-␣-phenylhydrazobutyramido-
N-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene 4
To a cold solution (0–5 C) of 3 (2.62 g, 0.01 mol)
in ethanol (40 mL), a cold solution of benzenedi-
azonium chloride (0.01 mol) (prepared by adding
cold sodium nitrite solution [0.7 g, 0.01 mol] to a
cold suspension [0–5 C] of aniline [0.92 g, 0.01 mol]
in concentrated hydrochloric acid [8 mL] with stir-
ring) was added with continuous stirring. The whole
reaction mixture was left at room temperature for
3-Cyano-2-( -oxobutyramido-N-yl)-4,5,6,7-
tetrahydrobenzo[b]thiophene 3
General procedure: To dry solid 1 (1.78 g, 0.01 mol),
ethyl acetoacetate (1.52 g, 0.01 mol) was added. The
reaction mixture was heated in an oil bath at 140 C
for 2 hours, then left to cool. Ethanol (50 mL, 95%)
was added to the reaction mixture, the whole mixture

522 Mohareb and Mohamed
CN
+
Br2
3
NH-CO-CH2-CO-CH2Br
KCN
or
S
KSCN
21
CN
CN
NC
NH-CO-CH2-C-CH2X
CN
CH2(CN)2
NH-CO-CH2-CO-CH2X
S
S
23a, X = CN
b, X = SCN
22a, X = CN
b, X = SCN
CN
H2N
N
CN
CH2X
S
O
24a, X = CN
b, X = SCN
SCHEME 4
CN
_
H2N
N
CN
+
Ph-N NCl
EtOH
NaOH
24a,b
C-X
S
N-NH-Ph
O
25a, X = CN
b, X = SCN
Ph
N
O
CN
H2N
N
N
O
X
S
26a, X = CN
b, X = SCN
SCHEME 5

Reaction of 2-Amino-3-Cyano-4,5,6,7-Tetrahydrobenzo-[b]Thiophene with Ethyle Acetoacetate 523
(s, 2H, NH2), 10.56 (s, 1H, OH). 13CNMR = 24.2
(CH3), 23.2, 23.5 (cyclohexene C-2, C-3), 29.0, 30.4
(cyclohexene C-1, C-4), 119.6 (CN), 121.1, 122.2,
123.5, 124.2, 132.5, 133.1, 134.6, 139.7, 148.7 (thio-
phene C, pyridine C). C16H14N4OS (310.97): Calcd:
C, 61.74; H, 4.50; N, 18.01; S, 10.29%. Found: C,
61.53; H, 4.30, N, 17.99; S, 9.87%.
4 hours, and the formed solid product was collected
by filtration.
Compound 4: Red crystals (from ethanol), yield
1
80% (2.92 g), m.p. 95 C. IR ( /cm ) = 3466–3320
(NH), 2980, 2970 (CH3, CH2), 2220 (CN), 1705, 1685
(2 C O), 1640 (C C). 1H NMR = 2.24 (s, 3H, CH3),
2.25, 2.76 (2m, 8H, 4CH2), 7.30–7.44 (m, 5H, C6H5),
8.90, 9.87 (2s, 2H , 2NH). C19H18N4O2S (366.44):
Calcd: C, 62.22; H, 4.91; N, 15.28; S, 8.73%. Found:
C, 62.46; H, 4.87, N, 14.95; S, 8.77%.
Compound 9b: Orange crystals (from ethanol),
1
yield 72% (2.77 g), m.p. 166–169 C. IR ( /cm ) =
3555–3345 (OH, NH2), 2988, 2865 (CH3, CH2), 1695
(C O), 1658 (C N), 1644 (C C). 1H NMR = 1.16
(t, 3H, CH3), 2.42 (s, 3H, CH3), 2.25, 2.73 (2m, 8H,
4CH2), 4.22 (q, 2H, CH2), 4.77 (s, 2H, NH2), 10.31 (S,
1H, OH). C18H19N3O3S (357.41): Calcd: C, 60.43; H,
5.31; N, 11.75; S, 8.95%. Found: C, 60.19; H, 5.44,
N, 11.61; S, 8.49%.
4-Amino-3-acetyl-2-hydroxy-4,5,6,7-
tetrahydrobenzo[b]thieno[5,4:2,3]pyridine 5
A solution of compound 3 (2.62 g, 0.01 mol) in
sodium ethoxide (0.01 mol) (prepared by dissolving
sodium metal [0.23 g, 0.01 mol] in absolute ethanol
[40 mL]) was heated in a boiling water bath for 8
hours and then left to cool. The solid product formed
upon pouring the mixture into ice/water containing
hydrochloric acid (to pH 6) was collected by filtra-
tion.
2-Amino-N(3-cyano-4-methyl-6-oxopyridine-
6-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene 10
General procedure: To a suspension of 3 (2.62 g, 0.01
mol) in sodium ethoxide solution (prepared by dis-
solving sodium metal [0.46 g, 0.02 mol] in absolute
ethanol [60 mL]), malononitrile was added. The re-
action mixture was heated in a boiling water bath
for 5 hours and then poured into ice/water contain-
ing hydrochloric acid (to pH 6). The formed solid
product was collected by filtration.
Compound 5: Pale yellow crystals (from acetic
acid), yield 77% (2.02 g), m.p. 220–222 C. IR (
/
1
cm ) = 3580–3314 (OH, NH2), 2985, 2880 (CH3,
1
CH2), 1680 (C O), 1660 (C N), 1642 (C C). H
NMR = 2.26, 2.69 (2m, 8H, 4CH2), 2.41 (s, 3H,
CH3), 4.94 (s, 2H, NH2), 9.86 (s, 1H, OH). 13C NMR
= 25.9 (CH3), 23.3, 23.9 (cyclohexene C-2, C-3),
29.3, 30.1 (cyclohexene C-1, C-4), 121.3, 122.4, 123.8,
124.0, 132.2, 133.0, 139.8 (thiephene C, pyridine C),
180.3 (C O). C13H14N2O2S (262.32): Calcd: C, 59.52;
H, 5.38; N, 10.68; S, 12.22%. Found: C, 59.69; H,
5.30, N, 10.99; S, 11.87%.
Compound 10: Buff crystals (from ethanol),
1
yield 81% (2.51 g), m.p. 271–274 C. IR ( /cm ) =
3460–3345 (2 NH), 3035 (pyridine CH), 2979, 2880
(CH3, CH2), 2225, 2220 (2 CN), 1693 (C O), 1665
(C N), 1638 (C C). 1H NMR = 2.39 (s, 3H, CH3),
2.29, 2.68 (2m, 8H, 4CH2), 4.99 (s, 2H, NH2), 7.43 (s,
1H, pyridine H-3). C16H14N4OS (310.37): Calcd: C,
61.92; H, 4.55; N, 18.05; S, 10.33%. Found: C, 61.72;
H, 4.11, N, 17.68; S, 10.09%.
5-Amino-4-cyano-2-hydroxy-3-methyl-4,5,6,7-
tetrahydrobenzo[b]thieno[5,4:2,3]pyridino
[4,5:2,3]pyridine 9a and 5-Amino-4-
ethoxycarbonyl-2-hydroxy-3-methyl-4,5,6,7-
tetrahydrobenzo[b]thieno[5,4:2,3]pyridino
[4,5:2,3]pyridine 9b
6-Amino-4-cyano-3-methyl-5-oxo-4,5,6,7-
tetrahydrobenzo[b]thieno[5,4:4,5]pyrimidino
[2,1:1,2]pyridine 11
To dry solid compound 5 (2.62 g, 0.01 mol), ammo-
nium acetate (0.77 g, 0.01 mol) was added followed
by addition of either malononitrile (0.66 g, 0.01 mol)
or ethyl cyanoacetate (1.13 g, 0.01 mol). The reac-
tion mixture, in each case, was heated in an oil bath
at 130 C for 0.5 hours and then left to cool. The
solid product formed after triturating with ethanol
was collected by filtration.
A suspension of 10 (3.10 g, 0.01 mol) in sodium eth-
oxide solution (prepared by dissolving sodium metal
[0.46 g, 0.02 mol] in absolute ethanol [60 mL]) was
heated in a boiling water bath for 7 hours. The solid
product, so formed upon pouring the mixture into
ice/water containing hydrochloric acid (to pH 6) was
collected by filtration.
Compound 11: Pale yellow (from DMF), yield
1
Compound 9a: Yellow crystals (from 1,4-dio-
70% (2.17 g), m.p. 189–191 C. IR ( /cm ) = 3480,
xane), yield 82% (2.64 g), m.p. 188–190 C. IR (
/
3700 (NH2), 3050 (pyridine CH), 2988, 2892 (CH3,
CH2), 2223 (CN), 1688 (C O), 1660 (C N), 1645
(C C). 1H NMR = 2.41 (s, 3H, CH3), 2.27, 2.71 (2m,
8H, 4CH2), 5.32 (s, 2H, NH2), 7.31 (s, 1H, pyridine
1
cm ) = 3570–3385 (OH, NH2), 2980, 2877 (CH3,
CH2), 2225 (CN), 1660 (C N), 1638 (C C). 1H NMR
= 2.38 (s, 3H, CH3), 2.28, 2.71 (2m, 8H, 4CH2), 4.89

524 Mohareb and Mohamed
H-3). 13C NMR = 34.1 (CH3), 23.1, 23.9 (cyclohex-
ene C-2, C-3), 29.5, 31.2 (cyclohexene C-1, C-4), 120.7
(CN), 122.1, 122.0, 123.9, 124.7, 132.2, 134.9, 135.6,
139.7, 148.7 (thiophene C, pyridine C, pyrimidine C),
178.7 (C O). C16H14N4OS (310.37): Calcd: C, 61.92;
H, 4.55; N, 18.05; S, 10.33%. Found: C, 61.66; H,
4.42, N, 18.27; S, 10.27.
3462, 3380 (NH2), 2965, 2872 (CH3, CH2), 2220 (CN),
1678 (C O), 1642 (C C). 1H NMR = 2.39 (s, 3H,
CH3), 2.26, 2.63 (2m, 8H, 4CH2), 4.72 (s, 2H, NH2),
7.09 (s, 1H, pyridine H-3). C16H14N4OS (310.37):
Calcd: C, 61.92; H, 4.55; N, 18.05; S, 10.33%. Found:
C, 62.31 H, 4.79, N, 17.72; S, 10.08%.
3-Cyano-2-( -benzal-␣-oxobutyramido-N-yl)-4,
5,6,7-tetrahydrobenzo[b]thiophene 15
2-Aminocarbonyl[␣-cyano- -methyl-
crotononitril-␥-yl]-4,5,6,7-tetrahydrobenzo[b]
thiophene 12 and 3-Cyano-2-[2-amino-3-cyano-
4-methyl-6-oxopyridine-1-yl]-4,5,6,7-
tetrahydrobenzo[b]thiophene 13
To a solution of 3 (2.62 g, 0.01 mol) in 1,4-dioxane (50
mL) containing piperidine (0.5 mL), benzaldehyde
(1.10 mL, 0.01 mol) was added. The reaction mixture
was heated under reflux for 2 hours and then evap-
orated in a vacuum, and the remaining semisolid
product was triturated with ethanol. The solid prod-
uct was collected by filtration.
General procedure: To a solution of 3 (2.62 g, 0.01
mol) in absolute ethanol (70 mL) containing piperi-
dine (1.0 mL), malononitrile (0.66 g, 0.01 mol) was
added. The reaction mixture was heated under reflux
for 1 hour, and the formed solid product that precip-
itated from the hot solution was filtered off as com-
pound 13. The filtrate was dropped into ice/water
containing a few drops of hydrochloric acid, and the
formed solid product was filtered off as compound
12.
Compound 15: Colorless crystals (from ethanol),
yield 82% (2.87 g), m.p. 122–124 C. IR ( /cm )
1
= 3455–3340 (NH), 3060 (CH aromatic), 2979, 2868
(CH3, CH2), 2222 (CN), 1696, 1682 (2 C O), 1638
1
(C C). H NMR = 2.44 (s, 3H, CH3), 2.29, 2.74
(2m, 8H, 4CH2), 7.06 (s, 1H, C CH), 7.28–7.35 (m,
5H, C6H5), 8.76 (s, 1H NH). C20H18N2O2S (350.54):
Calcd: C, 68.52; H, 5.17; N, 8.02; S, 9.15%. Found:
C, 68.33; H, 4.85, N, 7.95; S, 8.86%.
Compound 12: Orange crystals (from ethanol),
1
yield 53% (1.64 g), m.p. 188–190 C. IR ( /cm ) =
3440–3320 (NH), 2981, 2895 (CH3, CH2), 2225, 2220,
2217 (3 CN)1686 (C O), 1644 (C C). 1H NMR
=
2-Aminocarbonyl(3-methyl-5-phenylpyrazole-
4-yl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]
thiophene 17a and 2-Aminocarbonyl
(3-methyl-1,5-diphenylpyrazole-4-yl)-3-cyano-4,
5,6,7-tetrahydrobenzo[b]thiophene 17b
2.24 (s, 3H, CH3), 2.27, 2.72 (2m, 8H, 4CH2), 5.46
(s, 2H, CH2), 8.87 (s, 1H, NH). C16H14N4OS (310.37):
Calcd: C, 61.92; H, 4.55; N, 18.05; S, 10.33%. Found:
C, 61.59; H, 4.61, N, 18.31; S, 10.46%.
Compound 13: Orange crystals (from ethanol),
1
yield 40% (1.24 g), m.p. >300 C. IR ( /cm ) =
General procedure: To a solution of 15 (3.50 g, 0.01
mol) in ethanol (70 mL) either hydrazine hydrate
(0.5 mL, 0.01 mol) or phenylhydrazine (1.1 g, 0.01
mol) was added. The reaction mixture, in each case,
was heated under reflux for 5.5 hours, then poured
into ice/water containing a few drops of hydrochlo-
ric acid. The solid product formed was collected by
filtration.
3470, 3340 (NH2), 2977, 2892 (CH3, CH2), 2225,
2218 (2 CN)1682 (C O), 1639 (C C). 1H NMR
= 2.48 (s, 3H, CH3), 2.23, 2.70 (2m, 8H, 4CH2),
4.95 (s, 2H, NH2), 7.09 (s, 1H, pyridine H-3).
C16H14N4OS (310.37): Calcd: C, 61.92; H, 4.55; N,
18.05; S, 10.33%. Found: C, 61.78 H, 4.31, N, 18.28;
S, 10.57%.
Compound 17a: Yellow crystals (from acetic
acid), yield 70% (2.53 g), m.p. 158–160 C. IR (
/
6-Amino-4-cyano-3-methyl-1-oxo–4,5,6,7-
tetrahydrobenzo[b]thieno[5,4:4,5]
pyrimidino[3,2:1,2]pyridine 14
1
cm ) = 3440–3387 (2 NH), 2980, 2872 (CH3, CH2),
1
2225 (CN), 1680 (C O), 1645 (C C). H NMR
= 2.35 (s, 3H, CH3), 2.26, 2.69 (2m, 8H, 4CH2),
7.30–7.42 (m, 5H, C6H5), 8.88, 9.31 (2s, 2H, 2NH).
C20H18N4OS (362.68): Calcd: C, 66.23; H, 5.00; N,
15.51; S, 8.84%. Found: C, 66.09; H, 4.69, N, 15.82;
S, 9.32%.
A suspension of 13 (3.10 g, 0.01 mol) in sodium eth-
oxide solution (prepared by dissolving sodium metal
[0.23 g, 0.01 mol] in absolute ethanol [60 mL]) was
heated in a boiling water bath for 8 hours and left
to cool. The solid product formed upon pouring the
mixture into ice/water containing hydrochloric acid
(to pH 6) was collected by filtration.
Compound 17b: Orange crystals (from acetic
acid), yield 66% (2.39 g), m.p. 186–188 C. IR (
/
1
cm ) = 3442–3325 (NH), 2980, 2878 (CH3, CH2),
1
Compound 14: Pale yellow crystals (from DMF),
yield 78% (2.42 g), m.p. 173–175 C. IR ( /cm ) =
2220 (CN), 1688 (C O), 1640 (C C). H NMR
=
1
2.42 (s, 3H, CH3), 2.28, 2.71 (2m, 8H, 4CH2),

Reaction of 2-Amino-3-Cyano-4,5,6,7-Tetrahydrobenzo-[b]Thiophene with Ethyle Acetoacetate 525
7.26–7.39 (m, 10H, 2C6H5), 8.43 (s, 1H NH).
C26H22N4OS (438.78): Calcd: C, 71.17; H, 5.05; N,
12.82; S, 7.31%. Found: C, 69.93; H, 4.79, N, 13.17;
S, 7.08%.
acetic acid (10 mL) was added dropwise with stir-
ring for 10 minutes. The reaction mixture was al-
lowed to attain room temperature and was poured
into ice/water, and the formed solid product was col-
lected by filtration.
Compound 21: Orange crystals (from acetic
3-Cyano-2-aminocarbonyl(2-amino-5-acetyl-3-
cyano-4-phenyl-6-oxopyridine-1-yl)-4,5,6,7-
tetrahydrobenzo[b]thiophene 19a and
3-Cyano-2-(2-amino-5-acetyl-3-cyano-
4-phenyl-6-oxopyridine-1-yl)-4,5,6,7-
tetrahydrobenzo[b]thiophene 19b
acid), yield 88% (3.0 g), m.p. 171–173 C. IR (
/
1
cm ) = 3445–3315 (NH), 2885 CH2), 2225 (CN),
1700, 1680 (2 C O), 1643 (C C). 1H NMR
=
2.25, 2.69 (2m, 8H, 4CH2), 4.29, 5.58 (2s, 4H, 2CH2),
8.66 (s, 1H , NH). C13H13N2O2SBr (341.42): Calcd: C,
45.73; H, 3.83; N, 8.24; S, 9.39; Br, 23.43%. Found:
C, 45.49; H, 3.67, N, 8.05; S, 9.02; Br, 23.01%.
Method (A): To a solution of 15 (3.5 g, 0.01 mol)
in 1,4-dioxane (50 mL) containing triethylamine
(1.0 mL), either malononitrile (0.66 g, 0.01 mol) or
ethyl cyanoacetate (1.13 g, 0.01 mol) was added. The
reaction mixture was heated under reflux for 4 hours,
evaporated in a vacuum, and the remaining product
was triturated with ethanol. The formed solid prod-
uct, in each case, was collected by filtration.
Method (B): Equimolar amounts of compound
3 (2.62 g, 0.01 mol) and either -cyanocinnamo-
nitrile (1.45 g, 0.01 mol) or -ethoxycarbonylcin-
namonitrile (2.10 g, 0.01 mol) were mixed with 1,
4-dioxane (60 mL) containing triethylamine (1 mL).
The reaction mixture was heated under reflux for
2 hours and then poured into ice/water contain-
ing a few drops of hydrochloric acid. The formed
solid product, in each case, was collected by
filtration.
2-Aminocarbonyl-( -oxobutyronitrilo- -yl)-3-
cyano-4,5,6,7-tetrahydrobenzo[b]thiophene 22a
and 2-Aminocarbonyl-( -oxobutyrothionitrilo-
-yl)-3-cyano-4,5,6,7-tetrahydrobenzo[b]
thiophene 22b
General procedure: To a hot solution (50 C) of 21
(3.41 g, 0.01 mol) in ethanol (40 mL), a solution
(in 5 mL water) of either potassium cyanide (0.76 g,
0.01 mol) or potassium thiocyanide (0.98 g, 0.01 mol)
was added dropwise. The reaction mixture, in each
case, was left at room temperature for 4 hours with
stirring. The solid product, formed in each case,
upon pouring into ice/water containing hydrochlo-
ric acid (to pH 6) was collected by filtration.
Compound 22a: Yellow crystals (from ethanol),
1
yield 72% (2.06 g), m.p. 122 C. IR ( /cm ) = 3465–
Compound 19a: White (from ethanol), yield
3342 (NH), 2877 (CH2), 2225, 2218 (2 CN), 1690,
1
75% (3.10 g), m.p. 233–236 C. IR ( /cm ) = 3455,
1
1675 (2C O), 1634 (C C). H NMR = 2.20, 2.71
3385 (NH2), 3055 (CH aromatic), 2988, 2866 (CH3,
CH2), 2223, 2220 (2 CN), 1693, 1683 (2 C O), 1641
(2m, 8H, 4CH2), 4.77, 5.05 (2s, 4H, 2CH2), 8.41 (s,
1H, NH). C14H13N3O2S (287.33): Calcd: C, 58.52;
H, 4.56; N, 14.62; S, 11.16%. Found: C, 58.31; H,
4.72, N, 14.43; S, 11.07%.
1
(C C). H NMR = 2.78 (s, 3H, CH3), 2.23, 2.74
(2m, 8H, 4CH2), 5.21 (s, 2H, NH2), 7.33–7.40 (m,
5H, C6H5). C23H18N4O2S (414.71): Calcd: C, 66.55;
H, 4.34; N, 13.50; S, 7.71%. Found: C, 66.44; H, 4.39,
N, 13.59; S, 7.50%.
Compound 22b: Orange crystals (from acetic
acid), yield 66% (2.10 g), m.p. 196–199 C. IR (
/
1
cm ) = 3433–3320 (NH), 2890 (CH2), 2220, 2213 (2
Compound 19b: Pale yellow (from acetic acid),
CN), 1693, 1680 (2C O), 1644 (C C). 1H NMR
=
1
yield 59% (2.72 g), m.p. 192–194 C. IR ( /cm ) =
2.22, 2.69 (2m, 8H, 4CH2), 4.70, 4.89 (2s, 4H, 2CH2),
8.38 (s, 1H, NH). C14H13N3O2S2 (319.39): Calcd: C,
52.64; H, 4.10; N, 13.15; S, 20.07%. Found: C, 52.39;
H, 3.88, N, 13.39; S, 19.89%.
3475, 3363 (NH2), 3060 (CH aromatic), 2983, 2869
(CH3, CH2), 2220 (CN), 1690–1680 (3 C O), 1648
(C C). 1H NMR
= 1.36 (t, 3H, CH3), 2.68 (s,
3H, CH3), 2.26, 2.70 (2m, 8H, 4CH2), 4.22 (q, 2H,
CH2), 5.45 (s, 2H, NH2), 7.31–7.38 (m, 5H, C6H5).
C25H23N3O4S (461.51): Calcd: C, 64.90; H, 4.98;
N, 9.11; S, 6.93%. Found: C, 64.85; H, 4.89, N, 9.37;
S, 6.69%.
3-Cyano-2-(2-amino-3-cyano-4-cacetonitrilo-6-
oxopyridine-1-yl)-4,5,6,7-tetrahydrobenzo[b]
thiophene 24a and 3-Cyano-2-(2-amino-3-
cyano-4-thioacetonitrilo-6-oxopyridine-1-yl)-
4,5,6,7-tetrahydrobenzo[b]thiophenene 24b
3-Cyano-2-(ω-bromo- -oxobutyramido-N-yl)-
4,5,6,7-tetrahydrobenzo[b]thiophene 21
General procedure: To a solution of either 22a (2.87 g,
0.01 mol) or 22b (3.19 g, 0.01 mol) in dimethyl-
formamide (30 mL) containing piperidine (1.0 mL),
malononitrile (0.66 g, 0.01 mol) was added. The
To a hot solution (60 C) of 3 (2.62 g, 0.01 mol) in
acetic acid (40 mL), bromine (0.5 mL, 0.01 mol) in

526 Mohareb and Mohamed
reaction mixture, in each case, was heated under re-
flux for 5 hours and then poured into ice/water. The
formed solid product, in each case, was collected by
filtration.
8H, 4CH2), 4.59 (s, 2H, NH2), 7.25 (s, 1H, pyridine
H-5), 7.34–7.41 (m, 5H, C6H5), 8.59 (s, 1H, NH).
C23H17N7OS2 (471.52): Calcd: C, 58.58; H, 3.63; N,
20.79; S, 13.60%. Found: C, 58.21; H, 3.19, N, 20.45;
S, 13.38%.
Compound 24a: Yellow crystals (from 1,4-
dioxane), yield 61% (2.04 g), m.p. 156–159 C. IR
1
(
/cm ) = 3455, 3387 (NH2), 3045 (CH pyridine),
3-Cyano-2-(7-amino-3-cyano-5,8-dioxopyrido
[4,3-d]pyridazino-6-yl)-4,5,6,7-tetrahydrobenzo
[b]thiophene 26a and 3-Cyano-2-(7-amino-3-
thiocyano-5,8-dioxopyrido[4,3-d]pyridazino-6-
yl)-4,5,6,7-tetrahydrobenzo[b]thiophene 26b
2877 (CH2), 2225–2218 (3 CN), 1683 (C O), 1646
(C C). 1H NMR = 2.22, 2.68 (2m, 8H, 4CH2), 4.22
(s, 2H, NH2), 5.12 (s, 2H, CH2), 7.29 (s, 1H, pyridine
H-5). C17H13N5OS (335.33): Calcd: C, 60.87; H, 3.91;
N, 20.88; S, 9.56%. Found: C, 60.67; H, 4.11, N,
21.28; S, 9.64%.
A solution of either 25a (4.39 g, 0.01 mol) or 25b
(4.71 g, 0.01 mol) in ethanol (70 mL) contain-
ing sodium hydroxide pellets (0.4 g, 0.01 mol) was
heated under relfux for about 3 hours until all am-
monia gas evolution ceased. The reaction mixture
was left to cool, then poured into an ice/water mix-
ture and hydrochloric acid was added dropwise (to
pH 6). The formed solid product, in each case, was
collected by filtration.
Compound 24b: Yellow crystals (from acetic
acid), yield 70% (2.57 g), m.p. 210–212 C. IR (
/
1
cm ) = 3465, 3375 (NH2), 3060 (CH pyridine), 2890
(CH2), 2225–2215 (3 CN), 1679 (C O), 1639 (C C).
1H NMR = 2.26, 2.74 (2m, 8H, 4CH2), 4.29 (s, 2H,
NH2), 5.08 (s, 2H, CH2), 7.27 (s, 1H, pyridine H-5).
C17H13N5OS2 (367.47): Calcd: C, 55.56; H, 3.56; N,
19.06; S, 17.45%. Found: C, 55.43; H, 3.60, N, 19.35;
S, 17.84%.
Compound 26a: Buff crystals (from 1,4-dio-
1
xane), yield 70% (3.10 g), m.p. >300 C. IR ( /cm )
= 3480, 3339 (NH2)), 3060 (CH aromatic), 2899
3-Cyano-2-(2-amino-3-cyano-4-
(CH2), 2222, 2219 (2 CN), 1690, 1680 (2 C O),
phenylhydrazoacetonitrilo-6-oxopyridine-1-yl)-
4,5,6,7-tetrahydrobenzo[b]thiophene 25a and
3-Cyano-2-(2-amino-3-cyano-4-
phenylhydrazoacetothionitrilo-6-oxopyridine-
1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene 25b
1640 (C C). 1H NMR
= 2.22, 2.74 (2m, 8H,
4CH2), 4.48 (s, 2H, NH2), 7.22 (s, 1H, pyridine H-
5), 7.30–7.38 (m, 5H, C6H5). 13CNMR 23.0, 23.8
(cyclohexene C-2, C-3), 29.2, 30.6 (cyclohexene C-1,
C-4), 119.9, 120.2 (2 CN), 119.2, 120.3, 121.3, 122.7,
123.9, 124.6, 130.9, 132.7, 133.8, 134.9, 135.7, 139.7,
144.6, 148.7 (thiophene C, aromatic C), 178.9, 180.2
(2 C O). C23H16N6O2S (440.52): Calcd: C, 62.72; H,
3.65; N, 19.08; S, 7.28%. Found: C, 62.94; H, 3.74,
N, 18.87; S, 7.00%.
General procedure: To a cold solution (0 C) of either
24a (2.78 g, 0.01 mol) or 24b (3.67 g, 0.01 mol)
in ethanol (50 mL) containing sodium hydroxide
(1.0 g in water, 5 mL), benzenediazonium chloride
(prepared by adding sodium nitrite solution [0.7 g,
0.01 mol in water 5 mL] to a cold suspension [0 C] of
aniline [0.93 g, 0.01 mol] in hydrochloric acid) was
added with continued stirring. The solid product
formed upon stirring for 3 hours was collected by
filtration.
Compound 26b: Pale brown crystals (from
acetic acid), yield 68% (3.21 g), m.p. >300 C. IR
1
(
/cm ) = 3483, 3365 (NH2)), 3055 ( CH aromatic),
2886 (CH2), 2220, 2213 (2 CN), 1693, 1676 (2 C O),
1635 (C C). 1H NMR = 2.20, 2.70 (2m, 8H, 4CH2),
4.51 (s, 2H, NH2), 7.20 (s, 1H, pyridine H-5), 7.35–
7.42 (m. 5H. C6H5). 13CNMR 23.3, 23.1 (cyclo-
hexene C-2, C-3), 29.0, 31.0 (cyclohexene C-1, C-4),
119.5, 120.4 (2 CN), 119.9, 120.4, 121.0, 122.9,
123.9, 124.3, 130.2, 132.9, 133.2, 134.6, 135.6, 136.3,
142.3, 147.7 (thiophene C, aromatic C), 179.3, 180.0
(2 C O) C23H16N6O2S2 (472.51): Calcd: C, 58.46; H,
3.41; N, 17.79; S, 13.57%. Found: C, 58.28; H, 3.55,
N, 18.01; S, 13.49%.
Compound 25a: Reddish brown crystals (from
ethanol), yield 77% (3.38 g), m.p. 167–169 C. IR (
/
1
cm ) = 3499–3332 (NH2, NH)), 3058 (CH aromatic),
2896 (CH2), 2227–2212 (3 CN), 1684 (C O), 1659
1
(C N), 1644 (C C). H NMR = 2.28, 2.71 (2m,
8H, 4CH2), 4.43 (s, 2H, NH2), 7.29 (s, 1H, pyri-
dine H-5), 7.35–7.42 (m, 5H, C6H5), 8.77 (s, 1H,
NH). C23H17N7OS (439.46): Calcd: C, 62.86; H, 3.89;
N, 22.31; S, 7.30%. Found: C, 62.58; H, 3.99, N,
21,99; S, 7.24%.
Compound 25b: Reddish brown crystals (from
REFERENCES
ethanol), yield 81% (3.81 g), m.p. 222–224 C. IR (
/
1
cm ) = 3471–3338 (NH2, NH)), 3063(CH aromatic),
[1] Taylor, E. C.; Patel, H. H.; Sabitha, G.; Chandari, R.
Heterocycles 1996, 43, 349.
[2] Geies, A. N. J Chem Res 1998 (S), 290; (M) 1248.
2890 (CH2), 2226–2210 (3 CN), 1688 (C O), 1665
1
(C N), 1639 (C C). H NMR = 2.26, 2.70 (2m,

Reaction of 2-Amino-3-Cyano-4,5,6,7-Tetrahydrobenzo-[b]Thiophene with Ethyle Acetoacetate 527
[3] Robba, M.; Laduree, D.; Fossey, C.; Renault, J.;
Jaurdan, F. J. Pharm Belefg 1995, 50, 121.
[4] Hozien, Z. A.; Atta, F. M.; Hassan, K. M.; Abdel-
Wahab, A. A.; Ahmed, S. A. Synth Commun 1996,
26, 3733.
[5] Rosowsky, A.; Papoulis, A. T.; Quaner, S. F. J Med
Chem 1997, 40, 3694.
[6] El-Dean, A. M. K. Monatsh Chem 1998, 129, 523.
[7] Clark, J.; Hitiris G. J Chem Soc Perkin Trans 1, 1984,
2005.
[12] Russel, R. K.; Rampulla, R. A.; Nievelt, C. E.;
Klaubert, D. H. J. Heterocyclic Chem 1990, 27, 1761.
[13] Mohareb, R. M.; Manhi, F. M. Heteroat Chem 2000,
11, 403.
[14] Mohareb, R. M.; El-Omran, F. A.; Ho, J. Heteroat
Chem 2001, 12, 168.
[15] Zodi, H. F.; Wardakhan, W. W.; Doss, S. H.; Mohareb,
R. M. J Chem Res (S), 1996, 440; (M), 1996, 2526.
[16] Wardakhan, W. W. Phosphorus Sulfur Silicon 2000,
162, 275.
[8] Meeson, M. L.; Parsons, M. E.; Theobald, J. C. J Med
Chem 1995, 38, 2763.
[17] Magni, A.; Signorelli, G.; Bochiola, G.; Arzeneim-
Forsch J Drug Res 1994, 44, 1420.
[18] El-Feky, S. A.; Avdel-Samii, Z. K. Pharmazie 1995, 50,
341.
[19] Nanteuil, G. D.; Herve, Y.; Duhault, J.; Espinal, J.;
Boulanger, M.; Ravel, D. Arzeneim-Forsch J Drug Res
1995, 45, 1175.
[20] Habashi, A.; Ibrahim, N. S.; Mohareb, R. M.; Fahmy,
S. M., Liebigs Ann Chem 1986, 1632.
[9] Shishoo, C. J.; Devani, M. B.; Bhadt, V. G.; Jain, K.
S.; Rathod, I. S.; Goyal, R. K.; Gandhi, T. P.; Patel, R.
B.; Nail, G. R. Arzneim-Forsch 1990, 40, 567.
[10] Russel, R. K.; Rampulla, R. A. U. S. Patent
1990/4939/37; Chem Abstr 1990, 113, 212008.
[11] Grinev, A. N.; Kaplina, N. V. Khim Geterotsikl Soedin
1985, 925.