Reaction of 3-Cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene with enaminonitriles

Article abstract of DOI:10.1007/s00706-002-0494-7

2-Amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene with ethyl β-amino-α-cyano-γ-ethoxycarbonylcrotenoate yields the corresponding amide derivative. That compound reacts with benzenediazonium chloride to give the phenyl hydrazone derivative. This type of compounds was cyclized to give pyridazine and pyridine derivatives, respectively. Chemical reactivities of the latter were studied to give fused heterocyclic compounds with antimicrobial activities.

Full text of DOI:10.1007/s00706-002-0494-7

Monatshefte f€ur Chemie 133, 1443–1452 (2002)
DOI 10.1007/s00706-002-0494-7
Reaction of 3-Cyano-2-amino-4,5,6,7-
tetrahydrobenzo[b]thiophene
with Enaminonitriles
Rafat M. Mohareb1;ꢀ, Fatma A. Al-Omran2, and Jonathan Z. Ho3
1
Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
2
Chemistry Department, Faculty of Science, Kuwait University, 13060 Kuwait
3
Merck Research Laboratories, Merck & Co. Inc., Rahway NJ 07065-0900, USA
Received February 8, 2002; accepted (revised) March 28, 2002
Published online September 2, 2002 # Springer-Verlag 2002
Summary. 2-Amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene with ethyl ꢀ-amino-ꢁ-cyano-ꢂ-
ethoxycarbonylcrotenoate yields the corresponding amide derivative. That compound reacts with
benzenediazonium chloride to give the phenyl hydrazone derivative. This type of compounds was
cyclized to give pyridazine and pyridine derivatives, respectively. Chemical reactivities of the latter
were studied to give fused heterocyclic compounds with antimicrobial activities.
Keywords. Thiophene; Thiazole; Pyridazine; Pyridine.
Introduction
In pharmacological studies of azines and derivatives it has been shown that they
possess a variety of activities including antihelmintic [1] and antimicrobial [2–4].
Thiophenes and their fused derivatives have shown diverse pharmacological activ-
ities including antibacterial [3], immunomodulatory [4] antiflammatory [5], anti-
diabatic [6, 7], antiplatele-activating factor [8], and antiviral activities [9, 10].
Therefore, it was thought to be of interest to combine two of the above-mentioned
rings together in a molecular framework to give heterocyclic products with high
pharmaceutical potentiality.
Results and Discussion
In our earlier publications [11–13] we reported some biologically active
4,5,6,7-tetrahydrobenzo[b]thiophene derivatives. In this article, we report the
reaction of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (1) with ethyl
ꢀ
Corresponding author. E-mail: rmmohareb@hotmail.com

1444
R. M. Mohareb et al.
ꢀ-amino-ꢁ-cyano-ꢂ-ethoxycarbonylcrotenoate (2) to form an amide derivative
capable for cyclization into azine derivatives incorporating the thiophene ring with
anticipated biological activity. Thus, the reaction of 1 with 2 in 1,4-dioxane solu-
tion gave the amide derivative 3. The structure of 3 was established on the basis of
Scheme 1

Reaction of 3-Cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene
1445
analytical and spectral data. The 1H NMR spectrum of the reaction product showed
a triplet at ꢃ ¼ 1.16 ppm corresponding to a CH3 group, two multiplets at 2.22,
2.67 ppm for four CH2 groups, a quartet at 4.24 ppm for the ester CH2 group, a
singlet at 4.52 ppm (D2O exchangeable) for NH2, a singlet at 5.67 ppm for CH2
group, a singlet at 8.86 ppm for the NH group. The 13C NMR spectrum showed
resonances at ꢃ ¼ 26.8 (CH3), 33.6, 34.2, 34.5 (4 CH2), 55.9, 66.13 (2 CH2), 108.9,
110.1 (C¼C), 119.2, 120.2 (2 CN), 126.5, 125.4, 135.1, 140.0 (thiophene-C), and
finally 179.5, 180.2 (2 C¼O) ppm.
The reaction of 3 with benzaldehyde (4) in ethanol=piperidine solution gave the
benzal derivative 5. The reaction of 5 with malononitrile (6) gave a single product
Scheme 2

1446
R. M. Mohareb et al.
with the molecular formula C27H22N6SO3. Two possible isomeric structures 8 and 9
were assigned for this formula. Both of these structures were assumed on the basis of
the intermediate formation of 7. Structure 9 was established for the reaction product
on the basis of the 1H NMR spectrum which showed, beside the expected peaks, a
singlet at 5.45 ppm corresponding to one NH2 group, a singlet at 6.21 ppm corre-
sponding to CH group, and a singlet at 8.91 ppm for the NH group.
Scheme 3

Reaction of 3-Cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene
1447
The reaction of 3 with benzenediazonium chloride in alcoholic sodium acetate
solution at 0ꢁC gave the phenylhydrazono derivative 10. The latter underwent read-
ily cyclization when heated in ethanolic sodium hydroxide solution to give the
pyridazine derivative 11. Similar pyridazine formations have been reported in Refs.
[14, 15]. Cyclization of 3 in EtOH=NaOH gave the pyridine derivative 12. The
reaction of the latter product with either 16 or 13 gave 14a and 14b, respectively.
The reaction of 12 with benzenediazonium chloride gave the 4-phenylazote-
trahydrobenzo[b]thieno[5,4:4,5]-1,3-oxazino[2,3:6,1]-pyridine derivative 16. For-
mation of the latter product was based on the intermediate formation of 15
followed by cyclization. Analytical and spectral data are consistent with the as-
signed structure (see Exp.). The reaction of 12 with bromine in hot acetic acid
solution gave the 5-bromopyridine derivative 17. The ꢁ-oxohalo moiety present in
17 showed an interesting reactivity towards thioamides to form pyridothiazole
derivatives of potential biological activities. Thus, 17 reacted with either thiourea
(18a) or cyanothioacetamide (18b) to give the thiazolo[4,5-b]pyridine derivatives
19a and 19b. Structures of the latter products were based on analytical and spectral
data (see Exp.). The Reaction of 19b with 4 gave the benzal derivative 20, the latter
reacted with either 6 or 13 to give the pyrido[6,1:2,3]thiazolo[4,5:2,3]pyridine
derivatives 22a and 22b. Formation of 22a and 22b took place through the inter-
mediate formation of 21a and 21b. The analytical and spectral date are consistent
with the assigned structures (see Exp.). The latter products were obtained through
another reaction route. Thus, the reaction of 19b with either ꢁ-cyanocinnamonitrile
(23a) or ethyl ꢁ-cyanocinnamate (23b) gave the same products 22a and 22b.
Table 1. In vitro bactericidal activity of some of the newly synthesized compounds
Compound
No.
Bacillus cereus
Staph. aureus
E. coli
K. pneumonia
(Gram positive)
(Gram positive)
(Gram negative)
(Gram negative)
5
þþþ
þþ
þþ
þþþ
þþ
þþþ
þþ
þþþ
þ
þþþ
þþ
þ
9
þþþ
þþþ
þþ
þþþ
þ
10
þþ
þþþ
þ
11
þ
16
17
þþþ
þþþ
þ
þþþ
þ
19a
19b
20
þþ
þ
þþ
þþþ
þþ
þ
þþþ
þþ
þþ
þþ
þþþ
þþ
þ
þþþ
þþþ
þþ
22a
22b
25
þþ
þþþ
þ
þþþ
þ
þþþ
þ
27a
27b
28a
28b
þþ
þ
þþþ
þþþ
þþ
þþþ
þþ
þþ
þþþ
þþ
þþþ
þþ
þ
þþ
þ
Slight inhibition þ, moderate inhibition þþ, strong inhibition þþþ; rating percent control: no
inhibition 0, slight inhibition 10, 20, 30, moderate inhibition 40, 50, 60, strong inhibition 70, 80, 90,
complete inhibition 100

1448
R. M. Mohareb et al.
On the other hand the reaction of 19b with salicyladehyde (24) gave the 6-cou-
marin-3-yl-thiazolo[4,5:b]pyridine derivative 25.
The reaction of 12 with either hydrazine hydrate (26a) or phenyl hydrazine
(26b) gave the 6-hydrazinopyridine derivatives 27a and 27b. The latter products
underwent cyclization in sodium ethoxide solution to give the pyrido[6,1-b]pyrim-
idine derivatives 28a and 28b. Structures of the latter products were based on
analytical and spectral data. Thus, the IR spectrum of 28a showed only one CN
group stretching at ꢄ ¼ 2220 cmꢂ 1 and its 13C NMR spectrum showed resonances
at 33.8, 34.2, 34.5 (4 CH2), 118.9, 119.2 (2 CN), 122.6, 124.6, 138.2, 140.0
(pyridine, pyrimidine and thiophene-C), 177.3 (C¼O), and 179.9 (C¼N) ppm.
Bactericidal activity
The diverse biological activities of thiophenes and their fused derivatives prompted
us to test and study the biological activities of some of the newly synthesized
products. Their bactericidal activities were measured applying the literature pro-
cedure [16, 17]. The results are compiled in Table 1.
Experimental
All melting points are uncorrected. IR spectra were recorded for KBr discs on a Pye Unicam SP-1000
1
spectrophotometer. H NMR and 13C NMR spectra were measured on a Varian EM-390-200MHz in
CD3SOCD3 as solvent and using TMS as internal standard.
2-Acetylamino-ꢁ-(Ethyl ꢁ-cyano-ꢀ-aminoacrylate)-3-cyano-4,5,6,7-
tetrahydrobenzo[b]thiophene (3, C17H18N4SO3)
To a solution 1.78g of the 4,5,6,7-tetrahydrobenzo[b]thiophene derivative 1 (0.01 mol) in 30cm3 DMF,
2.26g 2 (0.01 mol) was added. The reaction mixture was heated under reflux for 3 h and then poured
into ice=water mixture containing few drops of HCl. Yield 80%; m.p. 130–133ꢁC (ethanol); IR:
ꢄꢀ¼ 3465 ꢂ 3435 (NH2, NH), 2988, 2895 (CH3, CH2), 2225, 2220 (2 CN), 1720, 1695 (2 C¼O),
1
1633 (C¼C) cmꢂ 1; H NMR ꢃ ¼ 1.16 (t, J ¼ 7 Hz, CH3), 2.22, 2.67 (2m, 4 CH2), 4.24 (q, J ¼ 7 Hz,
CH2), 4.52 (s, NH2), 5.67 (s, CH2), 8.86 (s, NH) ppm. 13C NMR (DMSO-d6) ꢃ ¼ 26.8 (CH3), 33.6,
34.2, 34.5 (4 CH2), 55.9, 66.13 (2 CH2), 108.9, 110.1 (C¼C), 119.2, 120.2 (2 CN), 126.5, 125.4, 135.1,
140.0 (thiophene-C), 179.5, 180.2 (2 C¼O) ppm.
2-Benzalacetylamino-ꢁ-(Ethyl ꢁ-cyano-ꢀ-aminoacrylate)-3-cyano-4,5,6,7-
tetrahydrobenzo[b]thiophene (5, C24H22N4SO3) and
4-Amino-3-cyano-6-benzalcyano-methyleno-1-(3-cyano-4,5,6,7-
tetrahydrobenzo[b]thiophene-2-yl)-2-oxo-thiazolo[4,5-b]pyridine (20, C25H16N6S2O)
To a solution of either 3.58 g 3 (0.01 mol) or 3.92g 19b (0.01 mol) in 50cm3 1,4-dioxane containing
0.5 cm3 piperidine, 1.08g benzaldehyde (0.01 mol) was added. The reaction mixture, in each case, was
heated under reflux for 3 h and then poured into ice=water containing a few drops of HCl. The formed
solid product was collected by filtration.
5: Yield 66%; m.p. 165–168ꢁC (ethanol); IR: ꢄꢀ¼ 3466 ꢂ 3420 (NH2), 2986, 2888 (CH3, CH2),
2222, 2220 (2 CN), 1710, 1690 (2 C¼O), 1637 (C¼C) cmꢂ 1
;
1H NMR (DMSO-d6) ꢃ ¼ 1.15

Reaction of 3-Cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene
1449
(t, J ¼ 6 Hz, CH3), 2.26, 2.66 (2m, 4 CH2), 4.23 (q, J ¼ 6 Hz, CH2), 4.55 (s, NH2), 7.01 (s, CH¼C),
7.32–7.38 (m, C6H5), 8.86 (s, NH) ppm.
20: Yield 62%; m.p. 190–193ꢁC (ethanol); IR: ꢄꢀ¼ 3462ꢂ 3339 (2 NH2), 2895 (CH2), 2225, 2220,
1
2218 (3 CN), 1701 (C¼O), 1651 (C¼N), 1637 (C¼C) cmꢂ 1; H NMR (DMSO-d6): ꢃ ¼ 2.26, 2.69
(2m, 4 CH2), 5.21 (s, NH2), 6.78 (s, CH¼C), 7.32–7.40 (m, C6H5) ppm.
3-Cyano-2-aminocarbonyl-(2-amino-3-cyano-4-phenyl-6-ethyl cyanoacetato-ꢁ-
yl-pyridin-5-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene (9, C27H22N6SO3)
Equimolecular amounts of 4.47g 5 (0.01 mol) and 0.66g 6 (0.01 mol) in 40cm3 1,4-dioxane contain-
ing 1.0cm3 triethylamine was heated under reflux for 6 h. After cooling the reaction mixture, the
solution was evaporated in vacuum. The remaining product was triturated in ethanol and the formed
solid product was collected by filtration. Yield 70%; m.p. 220–222ꢁC (1,4-dioxane); IR:
ꢄꢀ¼ 3470 ꢂ 3410 (NH, NH2), 2980, 2750 (CH3, CH2), 2225, 2215, 2210 (3 CN), 1720, 1693 (2
1
C¼O), 1634 (C¼C) cmꢂ 1; H NMR (DMSO-d6): ꢃ ¼ 1.16 (t, J ¼ 7 Hz, CH3), 2.25, 2.66 (2m, 4
CH2), 4.25 (q, J ¼ 7 Hz, CH2), 5.45 (s, NH2), 6.21 (s, CH), 7.30–7.41 (m, C6H5), 8.91 (s, NH) ppm.
3-Cyano-2-amino(ꢁ-phenylhydrazono-ꢁ-(ethyl ꢁ-cyano-ꢀ-aminoacrylato)-
acetyl-4,5,6,7-tetrahydrobenzo[b]thiophene (10, C23H22N6SO3)
and 3-Amino-2-cyano-4-phenylazo-6-imino-4,5,6,7-tetrahydrobenzo[b]thieno-
[5,4:4,5]-1,3-oxazino[3,2:1,2]pyridine (16, C21H16N6SO2)
To a cold solution (0ꢁC) of either 3.58 g 3 (0.01 mol) or 3.12 g 12 (0.01 mol) in 50cmꢂ 1 ethanol
containing 10.0 g sodium acetate benzenediazonium chloride (0.01 mol) was added with continuous
stirring. The reaction mixture was stirred at room temperature for 2 h and the formed solid product, in
each case, was collected by filtration.
10: Yield 84%; m.p. 231–233ꢁC (acetic acid); IR: ꢄꢀ¼ 3455ꢂ 3370 (NH2, 2 NH), 2982, 2776 (CH3,
CH2), 2225, 2212 (2 CN), 1710, 1680 (2 C¼O), 1660 (C¼N), 1640 (C¼C) cmꢂ 1; 1H NMR (DMSO-
d6): ꢃ ¼ 1.15 (t, J ¼ 5 Hz, CH3), 2.24, 2.68 (2m, 4 CH2), 4.22 (q, J ¼ 5 Hz, CH2), 5.23 (s, NH2), 7.32–
7.39 (m, C6H5), 8.72, 9.47 (2s, 2NH) ppm.
16: Yield 72%; m.p. 177–179ꢁC (1,4-dioxane); IR: ꢄꢀ¼ 3465 ꢂ 3350 (NH2, NH), 2223 (CN), 1702
(C¼O), 1668 (C¼N), 1645 (C¼C) cmꢂ 1; 1H NMR (DMSO-d6): ꢃ ¼ 2.24, 2.68 (2m, 4 CH2), 5.52 (s,
NH2), 7.31–7.42 (m, C6H5), 8.37 (s, NH) ppm.
3-Cyano-2-aminocarbonyl-(4-amino-5-cyano-1-phenyl-6-oxopyridazino)-4,5,6,7-
tetrahydrobenzo[b]thiophene (11, C21H16N6SO2) and 3-Cyano-2-(4-amino-3-cyano-
5-hydroxy-6-oxopyridine-1-yl)-4,5,6,7-tetrahydrobenzo[b]-thiophene (12, C15H12N4SO2)
A solution of either 4.62 g 10 (0.01 mol) or 3.58g 3 (0.01 mol) in 60cm3 ethanol containing 0.5g solid
NaOH was heated under reflux for 1 h, then poured into ice=H2O containing a few drops HCl (till
pH¼ 6). The solid product was collected by filtration.
11: Yield 88%; m.p. 234–237ꢁC (acetic acid); IR: ꢄꢀ¼ 3489 ꢂ 3410 (NH2, NH), 2980, 2773 (CH3,
CH2), 2222, 2217 (2 CN), 1705, 1686 (2 C¼O), 1655 (C¼N), 1638 (C¼C) cmꢂ 1; 1H NMR (DMSO-
d6): ꢃ ¼ 2.27, 2.70 (2m, 4 CH2), 5.78 (s, NH2), 7.32–7.38 (m, C6H5), 8.21 (s, NH) ppm.
12: Yield 77%; m.p. 156ꢁC (acetic acid); IR: ꢄꢀ¼ 3580 ꢂ 3340 (OH, NH2), 2987, 2879 (CH3, CH2),
1
2227, 2213 (2 CN), 1698 (C¼O), 1644 (C¼C) cmꢂ 1; H NMR (DMSO-d6): ꢃ ¼ 2.25, 2.68 (2m,
4 CH2), 5.44 (s, NH2), 7.06 (s, pyridine CH), 9.82 (s, OH); 13C NMR (DMSO-d6): ꢃ ¼ 33.5, 34.6, 34.2
(4 CH2), 119.0, 120.6 (2 CN), 124.5, 125.1, 134.8, 138.9, 140.0, 143.2 (thiophene-C, pyridine-C),
179.6 (C¼O) ppm.

1450
R. M. Mohareb et al.
3-Amino-2-cyano-6-dicyanomethino-1-oxo-4,5,6,7-tetrahydrobenzo-
[b]thieno[5,4:4,5]pyrimidino[3,2:1,2]pyridine (14a, C18H12N6SO)
and 3-Amino-2-cyano-1-oxo-6-ethyl cyanoacetato-4,5,6,7-tetrahydrobenzo-
[b]thieno[5,4:4,5]-pyrimidino[3,2:1,2]pyridine (14b, C20H17N5SO3)
Equimolecular amounts of 3.12g 12 (0.01 mol) and either 0.66 g 6 (0.01 mol) or 1.13g 13 (0.01 mol) in
40cm3 1,4-dioxane containing triethylamine (1.00 ml) was heated under reflux for 4 h. The solution
was evaporated under vacuum and the remaining product was triturated with ethanol and the formed
solid product, was collected by filtration.
14a: Yield 68%; m.p. >300ꢁC (acetic acid); IR: ꢄꢀ¼ 3488 ꢂ 3370 (NH2), 2984, 2888 (CH3, CH2),
1
2225, 2217, 2212 (3 CN), 1703 (C¼O), 1655 (C¼N), 1640 (C¼C) cmꢂ 1; H NMR (DMSO-d6):
ꢃ ¼ 2.29, 2.66 (2m, 4 CH2), 5.61 (s, NH2), 6.12 (s, CH), 7.02 (s, pyridine CH) ppm; 13C NMR (DMSO-
d6): ꢃ ¼ 33.8, 33.9, 34.2, 36.6 (4 CH2), 66.3 (CH), 119.8, 120.9, 121.2 (3 CN), 122.4, 124.5, 125.1,
134.1, 136.9, 141.2, 143.9, 144.8 (thiophene-C, pyrimidine-C, pyridine-C), 178.3 (C¼O) ppm.
14b: Yield 70%; m.p. 280–284ꢁC (acetic acid); IR: ꢄꢀ¼ 3477 ꢂ 3315 (NH2), 2979, 2884 (CH3,
CH2), 2227, 2213 (2 CN), 1702, 1688 (2 C¼O), 1653 (C¼N), 1633 (C¼C) cmꢂ 1; 1H NMR (DMSO-
d6): ꢃ ¼ 1.15 (t, J ¼ 6 Hz, CH3), 2.28, 2.69 (2m, 4 CH2), 4.27 (q, J ¼ 6 Hz, CH2), 5.62 (s, NH2), 7.02 (s,
pyridine CH) ppm.
4-Amino-3-bromo-5-cyano-1-(3-cyano-4,5,6,7-tetrahydrobenzo[b]-thiophene-2-yl)-
2,6-dioxopyridine (17, C15H11N4SO2Br)
A solution of 3.12g 12 (0.01 mol) in 40 cm3 glacial acetic acid was warmed to 60ꢁC then 1.6 g bromine
(0.01 mol) in 10cm3 acetic acid was added dropwise with continuous stirring. The reaction mixture
was stirred for 1.5 h then poured into ice=H2O and the formed solid product was collected by filtration.
Yield 64%; m.p. 188–190ꢁC (acetic acid); IR: ꢄꢀ¼ 3577ꢂ 3315 (OH, NH2), 2890 (CH2), 2225, 2217 (2
1
CN), 1705 (C¼O), 1633 (C¼C) cmꢂ 1; H NMR (DMSO-d6): ꢃ ¼ 2.25, 2.68 (2m, 4 CH2), 5.34 (s,
NH2), 9.79 (s, OH) ppm.
4,6-Diamino-3-cyano-2-oxo-1-(3-cyano-4,5,6,7-tetrahydrobenzo[b]-thiophene-
2-yl)-thiazolo[4,5-b]pyridine (19a, C16H12N6S2O) and 4-Amino-3-cyano-6-
cyanomethyleno-2-oxo-1-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)
thiazolo[4,5-b]pyridine (19b, C18H12N6S2O)
To a solution of 3.91 g 17 (0.01 mol) in 50 cm3 ethanol either 0.76 g 18a (0.01 mol) or 1.00 g 18b
(0.01 mol) was added. The reaction mixture was heated under reflux for 3 h then left to cool. The solid
product, so formed in each case, was collected by filtration.
19a: Yield 75%; m.p. 177–180ꢁC (ethanol); IR: ꢄꢀ¼ 3483ꢂ 3331 (2 NH2), 2887 (CH2), 2223, 2213
1
(2 CN), 1699 (C¼O), 1639 (C¼C) cmꢂ 1; H NMR (DMSO-d6): ꢃ ¼ 2.27, 2.71 (2m, 4 CH2), 4.99,
5.33 (2s, 2NH2) ppm.
19b: Yield 71%; m.p. 245–246ꢁC (acetic acid); IR: ꢄꢀ¼ 3477 ꢂ 3320 (NH2), 2880 (CH2), 2227,
1
2223, 2219 (3 CN), 1702 (C¼O), 1667 (C¼N), 1640 (C¼C) cmꢂ 1; H NMR (DMSO-d6): ꢃ ¼ 2.26,
2.69 (2m, 4 CH2), 4.21 (s, CH2), 5.21 (s, NH2) ppm.
4-Amino-3,6,8-tricyano-7-phenyl-9-imino-2-oxo-1-(3-cyano-4,5,6,7-
tetrahydrobenzo[b]thiophen-2-yl)-pyrido[2,1:2,3]thiozolo[4,5:2,3]pyridine
(22a, C28H16N8S2O) and 4-Amino-3,6-dicyano-8-ethoxycarbonyl-7-phenyl-9-
imino-2-oxo-1-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-
pyrido[2,1:2,3]-thiazolo[4,5:2,3]pyridine (22b, C30H21N7S2O3)
Method (A): To a suspension of 3.9g 19b (0.01 mol) in sodium ethoxide solution (0.01 mol) either
0.66g 6 (0.01 mol) or 1.13g 13 (0.01 mol) was added. The reaction mixture, in each case, was heated

Reaction of 3-Cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene
1451
in a boiling H2O bath for 4 h then poured into ice=H2O containing HCl (till pH 6) and left with
continuous stirring for 2 h. The formed solid product was collected by filtration.
Method (B): Equimolecular amounts of 3.9g 19b (0.01 mol) and either 1.4 g 23a (0.01 mol) or
2.03g 23b (0.01 mol) in 50 cm3 DMF containing 1.0 cm3 trimethyl amine was heated under reflux for
2 h. The reaction mixture was left to cool, then poured into H2O and the formed solid product was
collected by filtration.
22a: Yield 75%; m.p. 266–270ꢁC (1,4-dioxane); IR: ꢄꢀ¼ 3495ꢂ 3306 (NH2, NH), 2229,
2220 ꢂ 2215 (4 CN), 1700 (C¼O), 1677 (C¼N), 1638 (C¼C) cmꢂ 1
;
1H NMR (DMSO-d6):
ꢃ ¼ 2.28, 2.71 (2m, 4 CH2), 5.23 (s, NH2), 7.25–7.34 (m, C6H5), 8.78 (s, NH) ppm.
22b: Yield 66%; m.p. 132ꢁC (1,4-dioxane); IR: ꢄꢀ¼ 3488 ꢂ 3328 (NH2, NH), 2227, 2223, 2219 (3
1
CN), 1700, 1694 (2 C¼O), 1673 (C¼N), 1643 (C¼C) cmꢂ 1; H NMR (DMSO-d6): ꢃ ¼ 1.16 (t,
J ¼ 5 Hz, CH3), 2.25, 2.66 (2m, 4 CH2), 4.25 (q, J ¼ 5 Hz, CH2), 5.44 (s, NH2), 7.30–7.35 (m,
C6H5), 8.90 (s, NH) ppm.
4-Amino-3-cyano-6-(coumarin-3-yl)-2-oxo-1-(3-cyano-4,5,6,7-tetrahydro-
benzo[b]thiophene-2-yl)-thiazolo[4,5-b]pyridine (25, C25H15N5S2O3)
To a solution of 3.94 g 19b (0.01 mol) in 40cm3 1,4-dioxane containing 1.0 cm3 piperidine, 1.18g 24
(0.01 mol) was added. The reaction mixture was heated under reflux for 2 h then evaporated in vacuum.
The remaining product was triturated with ethanol and the formed solid product was collected by
filtration. Yield 70%; m.p. 208–211ꢁC (1,4-dioxane); IR: ꢄꢀ¼ 3488ꢂ 3328 (NH2), 2225, 2220 (2 CN),
1
1705, 1688 (2 C¼O), 1660 (C¼N), 1640 (C¼C) cmꢂ 1; H NMR (DMSO-d6): ꢃ ¼ 2.23, 2.70 (2m,
4 CH2), 5.22 (s, NH2), 6.99 (s, coumarin H-4), 7.29–7.39 (m, C6H5) ppm.
4-Amino-3-cyano-6-hydrazino-2-oxo-1-(3-cyano-4,5,6,7-tetrahydrobenzo-
[b]thiophene-2-yl)-pyridine (27a, C15H14N6SO) and 4-Amino-3-cyano-6-phenylhydrazino-
2-oxo-1-(3-cyano-4,5,6,7-tetrahydrobenzo-[b]thiophene-2-yl)-pyridine (27b, C21H18N6SO)
To a solution of 3.94g 12 (0.01 mol) in 30 cm3 1,4-dioxane either 0.5g 26a (0.01 mol) or 1.18g 26b
(0.01 mol) was added. The reaction mixture was heated under reflux for 4 h then poured into ice=water
containing few drops of hydrochloric acid. The formed solid product, in each case, was collected by
filtration.
27a: Yield 70%; m.p. 196–199ꢁC (DMF); IR: ꢄꢀ¼ 3493 ꢂ 3300 (2 NH2, NH), 2227, 2221 (2 CN),
1
1699 (C¼O), 1633 (C¼C) cmꢂ 1; H NMR (DMSO-d6): ꢃ ¼ 2.23, 2.68 (2m, 4 CH2), 4.87, 5.31 (2s,
2 NH2), 7.08 (s, pyridine H-5), 8.72 (s, br, NH) ppm.
27b: Yield 55%; m.p. 210–214ꢁC (DMF); IR: ꢄꢀ¼ 3460 ꢂ 3300 (NH2, 2 NH), 2225, 2220 (2 CN),
1
1692 (C¼O), 1637 (C¼C) cmꢂ 1; H NMR (DMSO-d6): ꢃ ¼ 2.24, 2.67 (2m, 4 CH2), 5.22 (s, NH2),
6.91 (s, NH), 7.07 (s, pyridine H-5), 7.33–7.39 (m, C6H5), 8.62 (s, br, NH) ppm.
2-Cyano-3,5-Diamino-6-imino-2-oxo-4,5,6,7-
tetrahydrobenzo[b]thieno[5,4:4,5]pyrimidino[2,1:1,2]pyridine (28a, C15H14N6SO)
and 3-Amino-2-cyano-5-phenylamino-6-imino-2-oxo-4,5,6,7-tetrahydrobenzo-
[b]thieno[5,4:4,5]pyrimidino[2,1:1,2]pyridine (28b, C15H14N6SO)
A suspension of either 3.26 g 27a (0.01 mol) or 4.01 g 27b (0.01 mol) in sodium ethoxide solution
(obtained by dissolving, 0.46g Na (0.02 mol) in 40.0cm3 absolute ethanol) was heated in a boiling
water bath for 4 h and then left to cool. The solid product formed upon pouring into ice=H2O was
collected by filtration.
28a: Yield 70%; m.p. 155–157ꢁC (DMF); IR: ꢄꢀ¼ 3486ꢂ 3279 (2 NH2, NH), 2225 (CN), 1703
(C¼O), 1668 (C¼N), 1638 (C¼C) cmꢂ 1; 1H NMR (DMSO-d6): ꢃ ¼ 2.25, 2.70 (2m, 4 CH2), 4.77, 5.30

1452
R. M. Mohareb et al.: Reaction of 3-Cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene
(2s, 2 NH2), 7.08 (s, pyridine H-5), 9.33 (s, br, NH) ppm; 13C NMR (DMSO-d6): ꢃ ¼ 33.8, 34.2, 34.5
(4 CH2), 118.9, 119.2 (CN), 122.6, 124.6, 138.2, 140.0 (pyridine, pyrimidine and thiophene-C), 177.3
(C¼O), 179.9 (C¼N) ppm.
28b: Yield 50%; m.p. 167–169ꢁC (DMF); IR: ꢄꢀ¼ 3465ꢂ 3309 (NH2, 2 NH), 2222 (CN), 1690
(C¼O), 1640 (C¼C) cmꢂ 1; 1H NMR (DMSO-d6): ꢃ ¼ 2.24, 2.67 (2m, 4 CH2), 5.22 (s, NH2), 6.91 (s,
NH), 7.07 (s, pyridine H-5), 7.33–7.39 (m, C6H5), 8.62, 903 (2s, br, 2 NH) ppm.
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