Heterocyclic synthesis with thiophene-2-carboxamide

Article abstract of DOI:10.1080/10426500701557005

3-Amino-4-cyano-N-phenylaminothiophene-2-carboxamide (2) was prepared by reacting 2-(1,1-dicyanomethylene)-3-N-phenyl-1,3-thiazolidin-4-one (1) with ammonia. The carboxamide when reacted with benzaldehyde, formic acid, phenylisothiocyanate, cyclohexanone, cyclopentanone, ethylchloroformate and carbon disulfide yield. The pyrimidinone derivatives (3, 4, 5, 6, 7, 8, and 9), respectively. The biological activity of all synthesized compounds were studied as antibiotics and against Gram positive and Gram negative bacteria. The purpose of this article is synthesis of new antibiotic and antibacterial drugs.

Full text of DOI:10.1080/10426500701557005

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Heterocyclic Synthesis with
Thiophene-2-Carboxamide
Gamal A. Ahmed a
a Zagazig University, Faculty of Science, Chemistry
Department, Zagazig, Egypt
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Phosphorus, Sulfur, and Silicon, 183:74–81, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701557005
Heterocyclic Synthesis with Thiophene-2-Carboxamide
Gamal A. Ahmed
Zagazig University, Faculty of Science, Chemistry Department,
Zagazig, Egypt
3-Amino-4-cyano-N-phenylaminothiophene-2-carboxamide (2) was prepared by re-
acting 2-(1,1-dicyanomethylene)-3-N-phenyl-1,3-thiazolidin-4-one (1) with ammo-
nia. The carboxamide when reacted with benzaldehyde, formic acid, phenylisoth-
iocyanate, cyclohexanone, cyclopentanone, ethylchloroformate and carbon disulfide
yield. The pyrimidinone derivatives (3, 4, 5, 6, 7, 8, and 9), respectively. The biolog-
ical activity of all synthesized compounds were studied as antibiotics and against
Gram positive and Gram negative bacteria. The purpose of this article is synthesis
of new antibiotic and antibacterial drugs.
Keywords Tetrahydrothienopyrimidinone; dihydrothienopyrimidine; thienopyrim-
idinedione; oxazinone
INTRODUCTION
Thienopyrimidines still attract considerable attention of many research
groups due to their wide applications in medicinal chemistry. Sev-
eral of these compounds were used as analgecics,1 antipyreties,2 and
anti-inflammatory agents.3,4 In this part, preparation of thieno[3,2-
d]pyrimidines was accomplished starting from thiophene. So, a num-
ber of thieno[3,2-d]pyrimidines were synthesized employing 3-amino-
4-cyano-5-N-phenylaminothiophene-2-carboxamide (2), which was in
turn synthesized from 2-(1-dicyano)-3-phenylthiazolidin-4-ones (1)5
and ammonia.
When compound (2), was allowed to react with benzalde-
hyde, it afforded the 7-cyano-6-N-phenylamino-2-phenyl-1,2,3,4-
tetrahydrothieno-[3,2-d]pyrimidin-4-one (3) in good yield (Scheme 1).
Also, compound (2) easily reacted with formic acid and gave the
7-carboxamide-6-N-phenylamino-3,4-dihydrothieno[3,2-d]pyrimidine
(4). The structure of (4) was elucidated from its correct spectral data.
Received 5 May 2007; accepted 5 June 2007.
Address correspondence to Gamal A. Ahmed, Zagazig University, Faculty of Science,
Chemistry Department, Zagazig, Egypt. E-mail:yehia 3@yahoo.com
74

Synthesis with Thiophene-2-Carboxamide
75
SCHEME 1
Furthermore, when compound (2) was allowed to react with
phenyl isothiocyanate in refluxing acetic acid afforded the 7-cyano-
2-mercapt-3-phenyl-6-N-phenylaminothieno[3,2-d]pyrimidin-4-one (5)
(Scheme 2).
Compound (2) reacted with cyclohexanone and cyclopeantanone in
refluxing acetic acid and yielded compounds (6) and (7) (Scheme 1).
The structures of these compounds were confirmed from their correct
analytical data.
Furthermore, compound (2) reacted with ethylchloroformate in re-
fluxing acetic acid yielded the dione compound (8) (Scheme 2).
A very interesting reaction occurred when compound (2) was allowed
to react with carbon disulphide in pyridine. This produce the tricyclic
compound (9) (Scheme 2). The structure of compound (9) was confirmed
from its correct spectral data.
Finally, 2-methyl-4-cyano-5-(N-acetyl-N-phenyl)aminothieno[3,2-d]
oxazine-7-one (10) was obtained instead of the expected pyrimidinone,
when the carboxamide (2) was allowed to react with acetic anhydride
at reflux temperature (Scheme 2).
The biological activity of the tested compounds have been evaluated
using filter paper disc method6,7 (Table II).
EXPERIMENTAL
Melting points are uncorrected. IR spectra were recorded on Unicam
SP-1200 infrared spectrophotometer using KBr. 1H NMR spectra were
recorded on varianEM300 spectrometer at 60 MHz in DMSO-d6, (chem-
ical shift in ppm). 13C NMR spectra were carried out on a Bruker Avance
75 MHz in DMSO-d6 (chemical shift δ ppm).

76
G. A. Ahmed
SCHEME 2
Synthesis of 2-(1,1-Dicyanomethylene)-3-N-phenyl-1,3-
thiazolidin-4-one (1)
A solution of the ketene-N-S-acetyl (4.02 g, 0.02 mol) in distilled water
(20 ml) was stirred at room temperature and ethylchloroacetate (2.44
g, 0.02 mol), in ethanol (25 ml) was added. The reaction mixture was
heated at 60–80◦C for about 2 h. The solid produced was collected and
recrystallized from ethanol to give white powder,5 yield 88%, m.p.: 271–
273◦C.

Synthesis with Thiophene-2-Carboxamide
77
TABLE I Physical and Spectral Data of the Synthesized Compounds
(3–10)
No. M.p./yield%
IR cm−1
1H NMR ppm
13C NMR ppm
3
350–352 66 3314 (νNHCO-),
3252 (νNH), 3162
(νNH-Ph), 2220
(νCN), 1624
δ 5.7(s, 1H,
164, 160, 150, 141,
140, 113, 90, 79,
120-129 (two phenyl
groups, C-Ar)
pyrimidone), 7.8 (s,
1H, NH), 8.1 (s, 1H,
NH-Ph), 10.2–10.5
(broad, 1H,
(νC O)
NH-CO-), 7.2–7.6
(m, 10H, two phenyl)
δ 11.8(s, NH-CO-),
10–10.2 (broad
NH-Ph), 7.7 (s, 2H,
amide), 7.8–8.4 (m,
5H, phenyl)
δ 6.7(s, 1H, NH-CS-),
7.1–7.5 (m, 10H, two
phenyl), 10 (s, 1H,
NH-Ph)
4
5
6
360 85
230 76
260 74
3377 (νNHCO-),
3300-3190 (νNH),
3100 (νNH-Ph),
1674 (νC O)
163, 160, 156, 147,
145, 139, 130, 125,
130, 125, 121, 107,
105
3350 (νNH), 3300
(νNH-Ph), 2205
(νCN), 1706
(νC O), 1456
(νC S)
3373 (νNHCO-), 3114 δ 1.2–2.6(m, 10H,
163, 160, 150, 113, 90,
80, 78, 70, 22, 21.8
(νNH-Ph), 3257
(νNH), 2211 (νCN),
1678 (νC O)
aliphatic), 7.1 (s, 1H,
NH), 7.4 (1H,
NH-Ph), 7.2–7.5 (m,
5H, phenyl), 10.1
(broad, 1H, NH-CO-)
1.2–2.6 (m, 8H,
aliphatic), 6.8 (1H,
NH), 7.1–7.5 (m, 5H,
aromatic), 7.6 (1H,
NH-Ph), 10.2 (1H,
NH-CO-)
7
8
9
230 70
177 88
350 85
3413 (νNHCO-),
3353 (νNH-Ph),
2213 (νCN), 1693
(νC O), 3211
(νNH)
3342 (νNHCO-),
3413 (νNH), 3200
(νNH-Ph), 2213
(νCN), 1691
δ 7.1 − 7.4(m,
5H-aromatic), 7.8
(1H, NH.Ph),
10–10.2 (broad 1H,
NH-CO), 12.1 (1H,
-CO-NH-CO-)
δ 13.1(broad, 1H,
-CO-NH-CS-), 12.4
(s, 1H, NH-CS), 11
(s, 1H, NH),
(νC O)
3329 (νCO-NH-CS),
3150 (νNH-CS-),
3126 (νNH), 1636
(νC O), 1453
(νC S), 1208
7.2-7.6 (m, 5H
(ν-C(S) S)
aromatic)
10 296–298 75 1696 (νCO-O), 1680
3.6 (s, 3H, COCH3),
2.4 (s, 3H, CH3),
7.3-7.8 (m, 5H
(νCO-CH3), 2217
(νCN)
phenyl)

78
G. A. Ahmed
TABLE II Antimicrobial Activity of the Tested Thienopyrimidinone
Derivatives
Diameter of inhibition zone
No.
4
Compound
Solvent
MeOH
S. aureus E. coli P. are
K. spp Pr. Vul
−ve
+ve
+ve
−ve
++ve +++ve ++ve
++ve +++ve +++ve
5
CH3COOEt
6
7
8
Acetone
Acetone
Acetone
+ve
+ve
+ve
−ve
+ve
−ve
+++ve
+ve
+ve
++ve
++ve +++ve
++ve +++ve
++ve
9
Acetone
++ve
+ve + + +ve +++ve +++ve
+ve = 8 mm; ++ve = 12 mm; +++ve = 18 mm; S. aureus = staphylococcus aureus;
E. coli = Escherichia; P. aer = Pseudomonas arugonosa; K. spp = Klebsiella Spp.; Pr.
Vul = Proteus Vulgaris.
Synthesis of 3-Amino-4-cyano-5-phenylaminothiopene-
2-carboxamide (2)
Ammonia solution (30 ml) was added to (1) (2.41 g, 0.01 mol) and the
reaction mixture was stirred at room temperature for 24 h. The solid
produced was collected by filtration and recrystallized from chloroform
to give brown powder, yield 75%, m.p.: 198–200◦C.(5)

Synthesis with Thiophene-2-Carboxamide
79
Synthesis of 7-Cyano-6-N-phenylamino-2-phenyl-1,2,3,
4-tetrahydro-thieno[3,2-d]pyrimidin-4-one (3)
To a solution of (2), (2.58 g, 0.01 mol) in glacial acetic acid (20 ml),
benzaldehyde (1.06 g, 0.01 mol) was added. The reaction mixture was
refluxed for 6 h, the solid produced was collected, dried, and recrystal-
lized from the chloroform, to give brown powder of (3), yield 66%, m.p.:
350–352◦C.
Synthesis of 7-Carboxamide-6-N-phenylamino-3,
4-dihydrothieno[3,2-d]-pyrimidine (4)
In a round-bottom flask with a reflux condenser a mixture of (2), (2.58 g,
0.01 mol) and formic acid (20 ml), were refluxed for 6 h. The precipitate
produced was collected and recrystallized from ethanol to give a yellow
powder of (4), yield 85%, m.p.: 360◦C.
Synthesis of 7-Cyano-2-mercapto-3-phenyl-6-N-
phenylaminothieno[3,2-d]-pyrimidin-4-one (5)
To a solution of (2) (2.58 g, 0.01 mol), phenylisothiocyanate (1.35 g,
0.01 mol), was added, the reaction mixture were refluxed for 5 hours
in acetic acid (20 ml). The precipitate was collected and recrystallized
from ethanol, to give light brown powder of (5), yield 76% m.p.: 230◦C.
Synthesis of 7-Cyano-6-phenylamino-1,3,4-trihydrospyro-
cyclohex-ane-(1‘, 2)-thieno-[3,2-d]pyrimidin-4-one (6)
In a round-bottom flask with a reflux condenser a mixture of compound
(2) (2.58 g, 0.01 mol), cyclohexanone (0.98 g, 0.01 mol) and sodium ac-
etate (3 gm) were refluxed for 5 h in glacial acetic acid (20 ml); the
reaction mixture was concentrated by evaporation under vacuum, the
solid product was collected and recrystallized from chloroform, to give
dark gray crystal of compound (6), yield 74%, m.p.: 260◦C.
Synthesis of 7-Cyano-6-phenylamino-1,3,4-trihydrospyro-
cyclopent-ane(1‘,2)-thieno-[3,2-d]pyrimidin-4-one (7)
In a round-bottom flask with a reflux condenser a mixture of compound
(2) (2.58 g, 0.01 mol), cyclopentanone (0.84 g, 0.01 mol) and sodium
acetate (3 g) were refluxed for 5 h in glacial acetic acid (20 ml), the
reaction mixture was concentrated by evaporation under vacuum, the

80
G. A. Ahmed
solid product was collected and recrystallized from acetic acid, to gave
light gray crystal of compound (7), yield 70%, m.p.: 230◦C.
Synthesis of 7-Cyano-6-phenylamino-1,2,3,4-tetrahydro-
thieno[3,2-d]-pyrimidin-2,4-dione (8)
In a round-bottom flask with a reflux condenser a mixture of compound
(2), (2.58 g, 0.01 mol) and ethylchloroformate (1.08 g, 0.01 mol), were
refluxed for 4 h in pyridine (10 ml) and then allowed to cool. The solid
product formed upon pouring onto ice/hydrochloric acid was collected
by filtration and recrystallized from acetic acid, to give red crystals of
(8), yield 88%, m.p.: 177◦C.
Synthesis of 4-Imino-1-phenyl-2,6-dithia-5,6,7,8-tetrahy-
dropyrimido[5,4-b]-thieno-[5,4-d]-1,3-thiazine-8-one (9)
A mixture of (2), (2.58 g, 0.01 mol), carbon disulfide, (1.56 g, 0.02 mol)
and dry pyridine (20 ml), were refluxed until the evolution of hydro-
gen disulphide ceased (20 h), (until no more yellow coloration of lead
acetate impregnated filter paper took place). The reaction mixture was
allowed to cool, the solid product formed upon pouring in ice cold water
containing few drops of hydrochloric acid (pH = 6) was collected and
recrystallized from DMF, to give yellow powder of compound (9), yield
85%, m.p.: 350◦C.
Synthesis of 2-Methyl-4-cyano-5-(N-acetyl-N-
phenyl)aminothieno[3,2-d]-oxazin-7-one (10)
In a round-bottom flask with a reflux condenser a mixture of (2), (2.58
g, 0.01 mol) and acetic anhydride (20 ml) were refluxed for 6 h. The
precipitate was collected and recrystallized from ethanol to give yellow
crystals of compound (10)5, yield 75%, m.p.: 296–298◦C.
CONCLUSION
This article enabled us to synthesize a new biologically active hetero-
cyclic compounds against Gram (+ve) and Gram (–ve) bacteria.
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Synthesis with Thiophene-2-Carboxamide
81
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