Synthesis of polyfunctionally substituted thiophene, thieno[2,3-b]pyridine and thieno[2,3-d]pyrimidine derivatives

Article abstract of DOI:10.1080/104265090889422

The thiophne derivatives 4a-c were prepared according to the Gewald procedure. Their reactivity towards a variety of chemical reagents was studied to give thienopyridines and pyrimidines. Biological investigations were carried on the newly synthesized pro

Full text of DOI:10.1080/104265090889422

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Synthesis of Polyfunctionally
Substituted Thiophene,
Thieno[2,3-b]pyridine and
Thieno[2,3-d]pyrimidine
Derivatives
Wagnat W. Wardakhan a , Hoda Z. Shams b & Hosam
E. Moustafa b
a National Organization for Drug Control &
Research , Cairo, Egypt
b Department of Chemistry, Faculty of Science,
Helwan University , Cairo, Egypt
Published online: 18 Aug 2006.
To cite this article: Wagnat W. Wardakhan , Hoda Z. Shams & Hosam E. Moustafa
(2005) Synthesis of Polyfunctionally Substituted Thiophene, Thieno[2,3-b]pyridine and
Thieno[2,3-d]pyrimidine Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, 180:8, 1815-1827, DOI: 10.1080/104265090889422
To link to this article: http://dx.doi.org/10.1080/104265090889422
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Phosphorus, Sulfur, and Silicon, 180:1815–1827, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090889422
Synthesis of Polyfunctionally Substituted Thiophene,
Thieno[2,3-b]pyridine and Thieno[2,3-d]pyrimidine
Derivatives
Wagnat W. Wardakhan
National Organization for Drug Control & Research, Cairo, Egypt
Hoda Z. Shams
Hosam E. Moustafa
Department of Chemistry, Faculty of Science, Helwan University,
Cairo, Egypt
The thiophne derivatives 4a–c were prepared according to the Gewald procedure.
Their reactivity towards a variety of chemical reagents was studied to give thienopy-
ridines and pyrimidines. Biological investigations were carried on the newly syn-
thesized products.
Keywords Bactericidal; fungicidal; thieno[2,3-d]pyrimidine; thienopyridine[2,3-b]-
pyridine; thiophene
Recently, there has been an increasing interest in the chemistry of
thiophenes because of their biological activities. Many of them have
been widely investigated for therapeutic uses, especially as anti-
fungal,1,2 antibacterial,3 anti-inflammatory,4 anticonvulsant,5 anti-
asthmatic6 and analgesic7 agents. They also were known to show
antiHIV,8 antiproliferative9 activities. Our research group has stud-
ied the reactivity of thiophene derivatives as precursors for the syn-
thesis of a vast variety of fused thiophene derivatives with potential
biological activity.10−13 As a continuation of this study we aimed to de-
sign new systems of polyfunctionally substituted thiophene derivatives
starting from readily available reagents. The key precursors for such
synthetic approach are the aryl thiophene systems 4a–c.
Received June 6, 2004; accepted September 7, 2004.
Address correspondence to Wagnat W. Wardakhan, National Organization for Drug
Control & Research, PO Box 29, Cairo, Egypt. E-mail: wagnatward@hotmail.com
1815

1816
W. W. Wardakhan et al.
RESULTS AND DISCUSSION
Compounds 4a–c were synthesized via the condensation of acetophe-
none derivatives 1a–c with malononitrile 2 in benzene containing
glacial acetic acid and ammonium acetate to give the condensa-
tion product 3a–c. The reaction of compounds 3a–c with sulfur in
ethanol containing a catalytic amount of triethyl amine gave the thio-
phene derivatives 4a–c (Scheme 1), according to the Gewald’s thio-
phene synthesis.14,15 Structures of the latter products were estab-
lished on the basis of analytical and spectral data. Compound 4a
was previously reported.16 On the other hand, the IR spectrum of
4b showed two stretching modes at υ 3577–3476 and 2205 cm−1 cor-
responding to NH2 and CN groups, respectively. Moreover, it’s 1H
NMR spectrum showed a singlet at δ 2.21 corresponding to a CH3
group, a singlet at δ 4.37 for an NH2 group, a singlet at δ 6.30
for a thiophene H-5 proton, and a mutiplet at δ 7.25–7.30 for C6H4
protons.
The reactivity of 4a, b (as representatives) towards active methy-
lene reagents, namely malononitrile (2) and ethyl cyanoacetate (5), was
studied. Thus, the reaction of 4a, b with either 2 or 5 gave the thieno[2,3-
b]pyridine derivatives 6a–d. Structures of the latter products were es-
tablished on the basis of analytical and spectral data. Thus, the IR
spectra of 6a, b showed the presence of stretching modes at υ 3433,
3205 cm−1 region corresponding to NH2 functions and at 2206 cm−1 for
CN groups. 1H NMR spectra displayed singlets at δ 4.19, 5.30 (2H each),
and at δ 4.95, 5.82 (2H each), and (D2O exchangeable) corresponding to
NH2 protons for compounds 6a and 6b, respectively. Singlets at δ 6.05,
6.36 (1H each) for thiophene H-2 protons, two multiplets at δ 7.37–7.61
(5H), and at 6.96–7.29 (4H) corresponding to phenyl moieties of 6a and
6b respectively are also ditinguished. Compound 6b exhibited a singlet
at δ 3.49 (3H) indicating CH3 protons. Further confirmation of the as-
signed thienopyridine structures 6a–d was achieved via coupling with
benzenediazonium chloride to give the corresponding azo derivatives
7a–d (Scheme 2). The latter products were synthesized using another
reaction route. Thus, the reaction of either 4a or 4b with benzenediazo-
nium chloride gave the phenylazo derivatives 8a and 8b, respectively.
The reaction of the latter products with either malononitrile (2) or ethyl
cyanoacetate (5) gave the same products 7a–d (fingerprint IR, m.p., and
mixed m.p., are identical).
The reaction of 8a with either acetylactone (9a) or ethyl acetoac-
etate (9b) gave the thieno[2,3-b]pyridine derivatives 10a and 10b, re-
spectively. Structures of the latter products were based on the analyt-
1
ical and spectral data. Thus, the H NMR spectrum of 10a exhibited

Polyfunctionally Substituted Thiophene Derivatives
1817
SCHEME 1

1818
W. W. Wardakhan et al.
SCHEME 2
two singlets at δ 2.51 and 3.36 (3H each) corresponding to two methyl
groups and a D2O exchangeable singlet at δ 5.67 (2H) for resonating
1
NH2 groups. The H NMR spectrum of 10b showed a singlet at δ 2.63
(3H) corresponding to methyl function, a D2O exchangeable singlet at
δ 5.55 (2H), 7.98 corresponding to resonating NH2, and a singlet at δ
10.31 (1H) corresponding to OH proton.

Polyfunctionally Substituted Thiophene Derivatives
1819
Recently, our research group was interested in studying the reac-
tions of active methylene reagents with phenyl isothiocyanate in basic
dimethylformamide followed by a reaction with α-halocarbonyl com-
pounds to give either thiophene or thiazole derivatives.17,18 As an ex-
tension of this work, we studied the reactivity of 4a, b towards phenyl
isothiocyanate to give the intermediate potassium sulfide salts 12a, b.
The latter products underwent heterocyclization through reaction with
phenacyl bromide 13 to give the thiophene derivatives 14a and 14b, re-
spectively (Scheme 2). Structures of the latter products were confirmed
on the basis of analytical and spectral data (see Experimental section).
Similarly, the reaction of 12a, b with ethyl bromoacetate (15) gave the
thieno[2,3-b]pyrimidine derivatives 17a and 17b, respectively. Forma-
tion of the latter products took place via the intermediate formation of
16a and 16b, respectively (Scheme 3). Structures of 17a and 17b were
1
based on analytical and spectral data. Thus the H NMR spectra of
17a and 17b exhibited the ethyl ester CH3 triplets at δ 1.22; 1.26 (3H
each) and CH2 quartets at δ 4.23, 4.28 (2H each); singlets at δ 5.35 and
5.22 (2H each) due to methylene sulfide moiety; singlets at δ 6.91 and
6.26 (1H each) exhibiting thieno H-6 protons, and D2O exchangeable
singlets at δ 8.23 and 8.09 (1H each) corresponding to imino functions.
Compound 17b showed a singlet at δ 2.36 (3H) revealing a methyl group
in the aromatic moiety. In a similar manner, the reaction of 12a with
ethyl bromocyanoacetate (18) gave the thieno[2,3-d]pyrimidine deriva-
tive 19. The latter product is formed through the hydrolysis of the ethyl
carboxylate group and cyclization. Structure of the latter product was
confirmed on the basis of analytical and spectral data (see Experimen-
tal section). Further confirmation was obtained through the synthesis
of 19 via another reaction route. Thus, the reaction of 12a with bro-
moacetonitrile (20) gave the product 19 (finger print IR, m.p., & mixed
m.p.).
Antimicrobial Activity
The diverse biological activities of azole and azine derivatives prompted
us to test and study the biological activities of some of the newly synthe-
sized products.19,20 The culture medium was the nutrient agar for bac-
teria and Czapek’s Dox agar medium for fungi. The sterile medium was
inoculated with the test organism so that each 100 mL of the medium
received 1 mL of a 24-hour culture of bacterium or a 7-day-old culture of
spore suspension of the fungus. The solutions of the tested compounds
at 25 µg/mL in dimethylformamide (DMF) were placed separately in
the cup (8 mm diameter) through the disc and the compound diffused
from the disc into the medium. The culture was examined for areas of

1820
W. W. Wardakhan et al.
SCHEME 3
no growth around the disc (zones of inhibition) after overnight incuba-
tion. Growth of bacterial strains sensitive to a compound was inhibited
at certain distances from the center of the disc whereas resistant stains
grew up to the edge of the disc.
The results showed in Table I indicated that most of the prepared
compounds were active against the test organisms. The most toxic

Polyfunctionally Substituted Thiophene Derivatives
1821
TABLE I In Vitro Bactericidal and Fungicidal Activity of Some of the
Newly Synthesized Compoundsa
Compound
no.
Bacillus cereus
(Gram positive)
Staph. Aureus
(Gram positive)
E. Coli
K. Pneumonia
(Gram negative) (Gram negative)
4a
4b
6a
6b
7a
8a
8b
10a
10b
14a
14b
17a
17b
19a
+
++
+ + +
++
+ + +
++
++
++
+ + +
++
+
+ + +
++
++
+ + +
+ + +
++
−
+ + +
++
++
+ + +
+
+ + +
++
−
++
++
+
+ + +
++
+ + +
+ + +
++
+
+
+
+
+ + +
++
+
+ + +
++
+
+ + +
+ + +
+
+
++
+
++
++
++
+ + +
++
++
aSlight inhibition, +; moderate inhibition, ++; Strong inhibition, + + +; rating
percent control: no inhibition, 0; slight inhibition, 10, 20, 30; moderate inhibition, 40,
50, 60; strong inhibition, 70, 80, 90; complete inhibition, 100.
compounds against bacterial and fungal isolates were 4b, 6a, 8b, and
14a followed by 6b, 8a, 10a, 10b, 17a, 19a, and 14b. Compounds 4a,
7a, and 17b were less toxic to the test organisms.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded (KBr) on
1
a Pye Unicam SP-1000 spectrophotometer. H NMR spectra were ob-
tained on a Varian EM-390 90 MHz spectrophotometer in DMSO-d6 as
solvent and TMS as internal reference. Chemical shifts δ are expressed
in ppm.
2-Amino-3-cyano-4-phenylthiophene (4a),
2-Amino-3-cyano-4-(4-methyl- phenyl)thiophene (4b) and
2-Amino-3-cyano-4-(4-methoxy-phenyl)thiophene (4c)
General Procedure
Equimolar amount of α-cyano-β-phenyl crotononitrile (3a) (1.68 g,
0.01 mol), or α-cyano-β-(4-methylphenyl) crotononitrile (3b) (1.82
g, 0.01 mol) or α-cyano-β-(4-methoxyphenyl) crotnonitrile (3c)
(1.98 g, 0.01 mol) and sulfur (0.32 g, 0.01 mol) in absolute ethanol

1822
W. W. Wardakhan et al.
(20 mL) containing triethylamine (0.5 mL) were heated under reflux
for 3 h. The solid product, in each case, thus formed upon dilution with
water containing few drops of hydrochloric acid, which was collected by
filtration.
4a. Yellow crystals (from ethanol), yield 80% (3.19 g), m.p. 96–100◦C.
IR υ (cm−1) = 3855–3567 (NH2), 3050 (CH aromatic), 2205 (CN), 1626
(C C). 1H NMR δ = 4.94 (s, 2H, NH2, D2O exchangeable), 6.35 (s, 1H,
thiophene H-5), 7.40–7.65 (m, 5H, C6H5). Anal. Calcd. for C11H8N2S
(M/e = 200): C, 65.97; H, 4.03; N, 13.98; S, 16.01; found: C, 66.08; H,
3.88; N, 14.06; S, 15.88%.
4b. Canary-yellow crystals (from ethanol), yield 85% (1.81 g), m.p.
95◦C. IR υ (cm−1) = 3577–3476 (NH2), 3055 (CH aromatic), 2987 (CH3),
1
2210 (CN), 1638 (C C). H NMR δ = 2.21 (s, 3H, CH3), 4.37 (s, 2H,
NH2, D2O exchangeable), 6.30 (s, 2H, thiophene H-5), 7.25–7.30 (m,
4H, C6H5). Anal. Calcd for C12H10N2S (M/e = 214): C, 67.26; H, 4.70;
N, 13.07; S, 14.96; found: C, 67.09; H, 4.90; N, 12.89; S, 15.35%.
4c. Yellowish brown crystals (from ethanol/dioxane), yield 85% (1.95
g), m.p. 105◦C. IR υ (cm−1) = 3567–3436 (NH2), 3052 (CH aromatic),
2988 (CH3), 2215 (CN), 1632 (C C). 1H NMR δ = 2.88 (s, 3H, CH3), 4.43
(s, 2H, NH2, D2O), 6.30 (s, 1H, thiazole H-5), 7.21–7.35 (m, 4H, C6H4).
Anal. Calcd. for C12H10N2OS (230.28): C, 62.58; H, 4.37; N, 12.16; S,
13.92; found: C, 62.81; H, 4.53; N, 11.88; S, 14.30%.
4,6-Diamino-5-cyano-3-phenylthieno[2,3-b]pyridine (6a),
4,6-Diamino-5-cyano-3-(4-methylphenyl)thieno[2,3-b]pyridine
(6b), 4-Amino-5-cyano-6-hydroxy-3-phenylthieno[2,3-b]
pyridine (6c) and 4-Amino-5-cyano-6-
hydroxy-3-(4-methylphenyl) Thieno[2,3-b]pyridine (6d)
General Procedure
To a solution of either 4a (2.00 g, 0.01 mol) or 4b (2.14 g, 0.01 mol) in
absolute ethanol (25 mL) containing a catalytic amount of triethylamine
(0.5 mL) either malononitrile (2) (0.66 g, 0.01 mol) or ethyl cyanoacetate
(5) (1.13 g, 0.01 mol) was added. The reaction mixture was heated under
reflux for 2 h then poured onto ice water mixture containing a few
drops of hydrochloric acid. The solid product, formed in each case, was
collected by filtration.
6a. Yellowish brown crystals (from ethanol), yield 70% (1.82 g), m.p.
85◦C. IR υ (cm−1) = 3426, 3205 (2 NH2), 3048 (CH aromatic), 2206 (CN),
1627 (C C). 1H NMR δ = 4.19, 5.30 (m, 4H, 2NH2, D2O exchangeable),
6.05 (s, 1H, thiophene H-5), 7.37–7.61 (m, 5H, C6H5). Anal. Calcd. for

Polyfunctionally Substituted Thiophene Derivatives
1823
C14H10N4S (266.32): C, 63.14; H, 3.78; N, 21.04; S, 12.04; found: C, 63.00;
H, 3.45; N, 21.41; S, 11.87%.
6b. Brown crystals (from ethanol/dioxane), yield 65% (1.82 g), m.p.
130◦C. IR υ (cm−1) = 3433, 3209 (2 NH2), 3065 (CH aromatic), 2854
1
(CH3), 2206 (CN), 1655 (C N). H NMR δ = 3.49 (s, 3H, CH3), 4.95,
5.82 (2s, 4H, 2NH2, D2O exchangeable), 6.36 (s, 1H, thiophene H-5),
6.96–7.29 (m, 4H, C6H4). Anal. Calcd. for C15H12N4S (280.35): C, 64.26;
H, 4.31; N, 19.98; S, 11.44; found: C, 64.09; H, 3.95; N, 19.62; S, 11.80%.
6c. Brown crystals (from ethanol), yield 65% (1.73 g), m.p. 133◦C.
IR υ (cm−1) = 3597, 3303 (NH2, OH), 3055 (CH aromatic), 2206 (CN),
1626 (C C). 1H NMR δ = 4.97 (s, 2H, NH2, D2O exchangeable), 6.35 (s,
1H, thiophene H-2), 7.35–7.59 (m, 5H, C6H5), 10.42 (s, 1H, OH). Anal.
Calcd. for C14H9N3OS (267.31): C, 62.90; H, 3.39; N, 15.72; S, 11.99;
found: C, 62.84; H, 3.55; N, 15.43; S, 11.71%.
6d. Yellow crystals (from acetic acid), yield 80% (2.24 g), m.p. 180–
2◦C. IR υ (cm−1) = 3582, 3315 (NH2, OH), 3050 (CH aromatic), 2880
(CH3), 2215 (CN), 1634 (C C). 1H NMR δ = 4.82 (s, 2H, NH2, D2O
exchangeable), 6.30 (s, 1H, thiophene H-2), 7.32–7.49 (m, 5H, C6H5),
10.29 (s, 1H, OH). Anal. Calcd. for C15H11N3OS (281.34): C, 64.04; H,
3.94; N, 14.93; S, 11.39; found: C, 63.88; H, 3.65; N, 15.35; S, 11.52%.
4,6-Diamino-5-cyano-2-phenylazo-3-phenylthieno[2,3-
b]pyridine (7a), 4,6-Diamino-5-cyano-2-phenylazo
-3-(4-methylphenyl)thieno[2,3-b]pyridine (7b), 4-Amino—5-
cyano-6-hydroxy-2-phenylazo-3-phenylthieno[2,3-b]-pyridine
(7c), 4-Amino-5-cyano-6-hydroxy-2-phenylazo-3-(4-methyl-
phenyl)thieno[2,3-b]pyridine (7d),
2-Amino-3-cyano-4-(4ꢀ-methylphenyl)-5-phenylazothiophene
(8a) and 2-Amino-3-cyano-4-phenyl-5-phenylazo-thiophene
(8b)
General Procedure
To a cold solution (0–5◦C) of either 6a (2.66 g, 0.01 mol), 6b (2.80 g,
0.01 mol), 6c (2.67 g, 0.01 mol), 6d (2.81 g, 0.01 mol), 4a (2.0 g, 0.01 mol),
or 4b (2.14 g, 0.01 mol) in ethanol (50 mL) containing sodium acetate
(5.0 g), benzenediazonium chloride (0.01 mol) [prepared by adding a cold
solution of sodium nitrite (0.7 g, 0.01 mol) to a solution of aniline (0.94 g,
0.01 mol) in hydrochloric acid (5 mL) with continuous stirring] was
added. The reaction mixture, in each case, was left at room temperature
for 2 h with stirring and the formed a solid product which was collected
by filtration.

1824
W. W. Wardakhan et al.
7a. Orange crystals (from acetic acid), yield 80% (2.96 g), m.p. 195–
7◦C. IR υ (cm−1) = 3426, 3222 (2 NH2), 3053 (CH aromatic), 2220
(CN), 1633 (C C). 1H NMR δ = 4.20 (m, 4H, 2NH2, D2O exchange-
able), 7.31–7.52 (m, 10H, 2C6H5). Anal. Calcd. for C20H14N6S (370.44):
C, 64.84; H, 3.81; N, 22.68; S, 8.65; found: C, 64.64; H, 4.27; N, 22.41; S,
8.45%.
7b. Orange crystals (from acetic acid), yield 78% (2.99 g), m.p. 232–
4◦C. IR υ (cm−1) = 3445, 3222 (2 NH2), 3053 (CH aromatic), 2220
1
(CN), 1633 (C C). H NMR δ = 2.89 (s, 3H, CH3), 4.20 (m, 4H, 2NH2,
D2O exchangeable), 7.28–7.46 (m, 9H, C6H4, C6H5). Anal. Calcd. for
C21H16N6S (384.46): C, 65.60; H, 4.19; N, 21.86; S, 8.34; found: C, 65.47;
H, 4.38; N, 22.01; S, 8.28%.
7c. Yellow crystals (from 1,4-dioxane), yield 69% (2.55 g), m.p. 236–
8◦C. IR υ (cm−1) = 3546–3230 (OH, NH2), 3045 (CH aromatic), 2215
(CN), 1634 (C C). 1H NMR δ = 4.36 (m, 2H, NH2, D2O exchange-
able), 7.32–7.47 (m, 10H, 2C6H5), 10.20 (s, 1H, OH). Anal. Calcd for
C20H13N5OS (371.41): C, 64.67; H, 3.53; N, 18.85; S, 8.63; found: C,
64.88; H, 3.87; N, 18.67; S, 8.57%.
7d. Orange-red crystals (ethanol), yield 66% (2.54 g), m.p. 280–3◦C.
IR υ (cm−1) = 3450–3211 (OH, NH2), 3051 (CH aromatic), 2209 (CN),
1
1629 (C C). H NMR δ = 2.88 (s, 3H, CH3), 4.30 (m, 2H, NH2, D2O
exchangeable), 7.28–7.45 (m, 9H, C6H4, C6H5), 10.15 (s, 1H, OH). Anal.
Calcd. for C21H15N5OS (385.44): C, 65.44; H, 3.92; N, 18.17; S, 8.32;
found: C, 64.28; H, 4.09; N, 18.04; S, 8.46%.
8a. Red crystals (from ethanol), yield 80% (2.43 g), m.p. 240–4◦C.
IR υ (cm−1) = 3493, 2434 (NH2), 3058 (CH aromatic), 2212 (CN),
1638 (C C). 1H NMR δ = 4.23 (m, 2H, NH2, D2O exchangeable), 7.36–
7.44 (m, 10H, 2C6H5). Anal. Calcd. for C17H12N4S (304.42): C, 67.07;
H, 3.97; N, 18.42; S, 10.53; found: C, 66.87; H, 4.17; N, 18.28; S,
10.46%.
8b. Yellow crystals (from ethanol), yield 75% (2.38 g), m.p. 184–6◦C.
IR υ (cm−1) = 3490, 3380 (NH2), 3056 (CH aromatic), 2985 (CH3), 2209
1
(CN), 1645 (C C). H NMR δ = 2.27 (s, 3H, CH3), 4.48 (m, 2H, NH2,
D2O exchangeable), 6.86–7.33 (m, 9H, C6H4, C6H5). Anal. Cald. for
C18H14N4S (318.40): C, 67.90; H, 4.43; N, 17.59; S, 10.07; found: C,
67.77; H, 4.33; N, 17.68; S, 9.93%.

Polyfunctionally Substituted Thiophene Derivatives
1825
4-Amino-6-methyl-5-acetyl-2-phenylazo-3-phenylthieno[2,3-
b]pyridine (10a) and 4-Amino-6-hydroxy-5-acetyl-2-phenylazo-
3-phenylthieno[2,3-b]pyridine (10b)
General Procedure
To a solution of 8a (3.04 g, 0.01 mol) in absolute ethanol (50 mL)
containing triethylamine (0.5 mL), either acetylacetone (1.0 g, 0.01 mol)
or ethyl acetoacetate (1.30 g, 0.01 mol) was added. The reaction mixture
was heated under reflux for 3 h and then left to cool. The solid product
that was formed; in each case upon pouring onto water containing few
drops of hydrochloric acid, was collected by filtration.
10a. Yellowish brown crystals (from 1,4-dioxane), yield 75% (2.98 g),
m.p. 240–2◦C. IR υ (cm−1) = 3297, 3178 (NH2), 3051 (CH aromatic),
1
1639 (C N), 1511 (N N). H NMR δ = 2.51, 3.36 (2s, 6H, 2CH3), 5.67
(s, 2H, NH2, D2O exchangeable), 7.34–7.72 (2m, 10H, 2C6H5). Anal.
Calcd. for C22H18N4OS (386.47): C, 68.37; H, 4.69; N, 14.49; S, 8.29;
found: C, 68.02; H, 4.37; N, 14.68; S, 8.37%.
10b. Yellowish brown crystals (from ethanol), yield 75% (3.0 g),
m.p. 247–9◦C. IR υ (cm−1) = 3630–3298 (OH, NH2), 3056 (CH aro-
matic), 2926 (CH3), 1639 (C N), 1511 (N N). 1H NMR δ = 2.63 (s,
3H, CH3), 5.55 (s, 2H, NH2, D2O exchangeable), 7.20–7.33 (m, 10H,
2C6H5), 10.31 (s, 1H, OH). Anal. Calcd. for C21H16N4O2S (388.47): C,
64.93; H, 4.15; N, 14.42; S, 8.24; found: C, 65.35; H, 4.29; N, 14.58; S,
8.51 %.
2-(Benzoylmethylthio)-4-imino-3,5-diphenylthieno[2,3-d]-
pyrimidine (14a), 2-(Benzoylmethylthio)-4-imino-5-(4-methyl-
phenyl)-3-phenylthieno[2,3-d]-pyrimidine (14b), 2-(α-ethyl
acetatothio)-4-imino-3,5-diphenylthien-o[2,3-d]pyrimidine
(17a) 2-(α-ethyl acetatothio)-4-imino-5-(4-methylphenyl)-3-
phenylthieno[2,3-d]pyrimidine (17b) 2-(α-acetonitrilo-thio)-
4-imino-3,5-diphenylthieno[2,3-d]pyrimidine 2-(α-acetonitrilo-
thio)-4-imino-5-(4-methylphenyl)-3-phenylthieno[2,3-d]-
pyrimidine (19b)
General Procedure
To a solution of either 4a (2.00 g, 0.01 mol) or 4b (2.14 g, 0.01 mol) in
dimethyl formamide (20 mL), phenylisothiocyanate (1.35 g, 0.01 mol)
and potassium hydroxide (0.57 g, 0.01 mol) were added. The reaction
mixture, in each case, was heated under reflux on a boiling water bath
for 1 h, then either phenacyl bromide (13) (1.99 g, 0.01 mol), ethyl bro-
moacetate (15) (1.67 g, 0.01 mol), or ethyl bromocyanoacetate (18) was

1826
W. W. Wardakhan et al.
added. The reaction mixture, in each case, was left stirring at room tem-
perature overnight. The solid product which was formed in each case
upon pouring into ice/water containing hydrochloric acid, was collected
by filtration.
14a. Yellow crystals (from acetic acid), yield 73% (3.30 g), m.p. 228–
30◦C. IR υ (cm−1) = 3390–3317 (NH), 3055 (CH aromatic), 1728–1695
(CO), 1540 (C N). 1H NMR δ = 4.41 (s, 2H, CH2), 6.84 (s, 1H, thiophene
H-5), 7.14–7.77 (m, 15H, 3C6H5), 7.99 (s, 1H, NH, D2O exchangeable).
Anal. Calcd. for C26H19N3OS2 (453.59): C, 68.85; H, 4.22; N, 9.26; S,
14.14; found: C, 68.72; H, 4.44; N, 9.56; S, 14.38%.
14b. Yellowish-brown crystals (from acetic acid), yield 70% (3.26 g),
m.p. 180–182◦C. IR υ (cm−1) = 3395–3320 (NH), 3050 (CH aromatic),
1
1720–1695 (CO), 1542 (C N). H NMR δ = 2.29 (s, 3H, CH3), 4.38 (s,
2H, CH2), 6.81 (s, 1H, thiophene H-5), 7.28–7.57 (m, 14H, 2C6H5, C6H4),
7.96 (s, 1H, NH, D2O exchangeable). Anal. Calcd. for C27H21N3OS2
(467.61): C, 69.37; H, 4.53; N, 8.98; S, 13.71; found: C, 69.58; H, 4.50; N,
9.27; S, 14.09%.
17a. Yellowish crystals (from ethanol), yield 65% (2.73 g), m.p. 76◦C.
IR υ (cm−1) = 3340–3305 (NH), 3055 (CH aromatic), 1695 (CO), 1634
1
(C C). H NMR δ = 1.22 (t, 3H, CH3), 4.23 (q, 2H, CH2), 5.35 (s, 2H,
CH2), 6.91 (s, 1H, thiophene H-5), 7.30–7.44 (m, 10H, 2C6H5), 8.23 (s,
1H, NH, D2O exchangeable). Anal. Calcd. for C22H19N3O2S2 (421.54):
C, 62.68; H, 4.54; N, 9.97; S, 15.21; found: C, 62.79; H, 4.44; N, 9.56; S,
14.86%.
17b. Pale yellow crystals (from ethanol), yield 60% (2.52 g), m.p.
89◦C. IR υ (cm−1) = 3325–3120 (NH), 3060 (CH aromatic), 1728 (CO),
1660 (C N). 1H NMR δ = 1.26 (t, 3H, CH3), 2.36 (s, 3H, CH3), 4.28 (q,
2H, CH2), 5.22 (s, 2H, CH2), 6.26 (s, 1H, thiophene H-5), 7.16–7.48 (m,
9H, C6H5, C6H4), 8.09 (s, 1H, NH, D2O exchangeable). Anal. Calcd. for
C23H21N3O2S2 (435.57): C, 63.42; H, 4.86; N, 9.65; S, 14.72; found: C,
62.99; H, 4.74; N, 9.68; S, 14.91%.
19a. Yellow crystals (from ethanol), yield 65% (2.43 g), m.p. 128◦C.
IR υ (cm−1) = 3317–3209 (NH), 3055 (CH aromatic), 2222 (CN), 1656
(C N). 1H NMR δ = 5.21 (s, 2H, CH2), 7.03 (s, 1H, thiophene H-5), 7.19–
7.45 (m, 10H, 2C6H5), 8.49 (s, 1H, NH, D2O exchangeable). Anal. Calcd.
for C20H14N4S2 (374.48): C, 64.14; H, 3.76; N, 14.96; S, 17.12; found: C,
64.00; H, 4.08; N, 14.82; S, 16.78%.
19b. Orange crystals (from ethanol), yield 70% (2.71 g), m.p. 223–
225◦C. IR υ (cm−1) = 3332–3197 (NH), 3062 (CH aromatic), 2215 (CN),
1
1660 (C N). H NMR δ = 2.24 (s, 3H, CH3), 5.18 (s, 2H, CH2), 7.04 (s,

Polyfunctionally Substituted Thiophene Derivatives
1827
1H, thiophene H-5), 7.22–7.39 (m, 9H, C6H5, C6H4), 8.49 (s, 1H, NH,
D2O exchangeable). Anal. Calcd. for C21H16N4S2 (388.51): C, 64.92; H,
4.15; N, 14.42; S, 16.50; found: C, 65.36; H, 4.22; N, 14.02; S, 16.37%.
REFERENCES
[1] F. Bracher and T. Papke, Pharmazie, 50, 525 (1995).
[2] P. Nussbaumer, G. Petranyi, and A. Stutz, J. Med. Chem., 34, 65 (1991).
[3] N. J. Broom, J. S. Elder, P. C. Hannan, J. E. Pons, P. J. O’Hanlon, G. Walker, J. Wilson,
and P. J. Woodall, Antibiotics, 48, 1336 (1995).
[4] M. Nakanishi, H. Imamura, Y. Maruyama, and H. Hoshino, J. Pharm. Soc. Jpn., 90,
272 (1970).
[5] D. Briel, Pharmazie, 45, 236 (1995).
[6] M. Yamaguchi, N. Maruyama, T. Koga, K. Kamei, M. Akima, T. Kuroki, M. Hamana,
and N. Ohi, Chem. Pharm. Bull., 43, 236 (1995).
[7] R. E. Boyd, J. B. Press, C. R. Rasmussen, R. B. Raffa, E. E. Codd, C. D. Connelly,
Q. S. Li, R. P. Martinez, M. A. Lewis, and B. J. Almond, J. Med. Chem., 44, 863
(2001).
[8] R. Pontikis, R. Benhida, A. M. Aubertin, D. S. Grieson, and C. Monneret, J. Med
Chem., 40, 1845 (1997).
[9] P. Diana, P. Barraja, A. Lauria, A. M. Almerico, G. Cirrincione, C. Minnei, S. Longu,
D. Congiu, C. Musiu, and R. La Colla, Anticancer Res, 19, 2127 (1999).
[10] H. Z. Shams, Y. M. Elkholy, R. A. Azzam, R. M. Mohareb, Phosphorus, Sulfur, &
Silicon, 155, 215 (1999).
[11] S. M. Sherif, R. M. Mohareb, H. Z. Shams, and H. M. Gaber, J. Chem. Research (s),
434 (1995).
[12] R. M. Mohareb, Y. M. Elkholy, N. I. Abdel-Sayed, and H. Z. Shams, J. Chin. Chem.
Soc., 39, 181 (1992).
[13] R. M. Mohareb, H. Z. Shams, and Y. M. Elkholy, Phosphorus Sulfur & Silicon, 72,
93 (1992).
[14] K. Gewald, E. Schinke, and H. Bottcher, Chem. Ber., 94, 99 (1966).
[15] H. Schafer, H. Jablohoff, M. Hentschel, and K. Gewald, J. Prakt. Chemie., 326, 916
(1984).
[16] K. Gewald, Chem. Ber., 98, 3571 (1965).
[17] R. M. Mohareb, H. F. Zohdi, S. M. Sherif, and W. W. Wardakhan, Tetrahedron, 50,
5807 (1994).
[18] R. M. Mohareb, W. W. Wardakhan, and F. Z. El-Ablack, J. Chem. Research (s), 126
(1994); J. Chem. Research (M), 0747 (1994).
[19] Y. Z. Gutter, Pflanzenkr Pflanzenschutz, 89, 332 (1982); Chem. Abstr., 97, 143345
(1982).
[20] Y. Shachnai, M. N. Gutter, and A. Dinoor, Bull Merkaz Volcano Minhol Ha-Merchkar
(bet Dogan, Isr.), 189, 64 (1981); Chem. Abstr., 97, 143345 (1982).