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Volume 14, Number 1, March 2019
Pages 39-47
*Corresponding Author: Mahmoud F. Farhat Email: mf_farhat@yahoo.com
JJC
Jordan Journal of Chemistry
ARTICLE
Utilization of 2-Ylidene-4-Thiazolidinones in the Synthesis
of Heterocyclic Compounds
Part III: Synthesis and In-Vitro Antibacterial Activity
Evaluation of Thienopyrimidinone Derivatives
Mahmoud F. Farhata*, Ahmed M. El-Saghierb, Suhilla Kh. Elnamia,
Nisrin A. Dwayaa, Asma O. Jebrilc, Asma O. Errayesa, Moftah O.
Darwisha and Mohammed S. Ibrahim.d
a Chemistry Department, Faculty of Science, University of Tripoli, Tripoli, Libya
b Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt
c Chemistry Department, Faculty of Education, University of Tripoli, Tripoli, Libya
d General Department, Faculty of Nursing, Sebha University, Sebha, Libya
Received on: 11th Mar. 2019 Accepted on: 19th May 2019
Abstract: 3-Amino-2-thiophenecarboxamides (3a, d-g) were synthesized from 2-(4-oxo-3-
phenyl- thiazolidin-2-ylidene)malononitrile (2) and employed in the synthesis of a variety
of thiophene and thienopyrimidinone derivatives. 3-Amino-2-thiophenecarboxamides (3a,
d, e) on refluxing in acetic acid gave the tetrahydrothienopyrimidinones (6a-m). On the
other hand, the reaction of the 3-amino-2-thiophenecarboxamides (3a, d, e) with
triethylorthoformate or with formic acid produced the dihydrothienopyrimidinones (7a-c).
The synthesized heterocyclic compounds were screened for antibacterial activities using
narrow spectrum against gram-positive and gram-negative bacteria.
Keywords: 3-amino-2-thiophenecarboxamides, dihydrothienopyrimidinones,
tetrahydrothienopyrimidinones, antibacterial activity.
Introduction
Thienopyrimidine derivatives play an
essential role in several biological processes and
have considerable chemical and pharmacological
activities[1-3]. They were also found to possess a
variety of pronounced activities, such as
ulcerogenic[4] as well as antipsychotic[5] and
antioxidant activities[6]. Moreover, some of 2-
alkylthio or 2-alkyl substituted thieno-
pyrimidines show significant antifungal and
antibacterial activities[2], whereas others exhibit
good anticonvulsant properties[7]. In our last
publication, we have reported that 2-(4-oxo-3-
phenylthiazolidin-2-ylidene)malononitrile (2) on
treatment with a variety of amines and alcohols
was successfully converted in a one-pot reaction
into 3-aminothiophene-2-carboxamides (3a-c)
and 3-aminothiophene-2-carboxylates (4a-e),
respectively, (Scheme 1) [11].
In continuation of our investigations on the
transformations of 2-ylidene-4-thiazolidinones
into other heterocyclic compounds[8-11], we report
here the utility of 3-amino-2-thiophenecarbox-
amides derived from 2-(4-oxo-3-phenyl-
thiazolidin-2-ylidene)malononitrile (2) in the
synthesis of a variety of thiophene and thieno-
pyrimidinone derivatives with anticipated
biological activities.
Farhat et al.
40
S
NH2
O
OR
PhHN
N S
O
Ph
NC CN
base
S
NH2
O
NHR
PhHN
NC
RNH
2
ROH
(3a-c) (4a-e)
NC
(2)
Scheme 1: One-pot conversion of 2-(4-oxo-3-phenylthiazolidin-2-ylidene)malononitrile (2) into 3-
aminothiophene-2-carboxamides (3a-c) and 3-aminothiophene-2-carboxylates (4a-e).
Experimental
General Remarks
Melting points were recorded by Koffler
melting points apparatus and are uncorrected.
Infrared spectra were recorded on a Bruker FTIR
spectrometer in the frequency range of 3900-450
cm-1 using KBr discs. Nuclear Magnetic
Resonance (NMR) spectra were recorded on a
Bruker avance of 400 MHz for 1H-NMR and 100
MHz for 13C-NMR using DMSO-d6 as a solvent
and tetramethylsilane (TMS) as an internal
standard. The chemical shift (δ) values are
expressed in parts per million (ppm). Legend: s =
singlet, d = doublet, t = triplet and m = multiplet.
Mass spectra were recorded on Shimadzu QP-
2010 plus mass spectrometer at 70 eV. The
structures and names of all the compounds were
generated using ChemDraw ultra 12.0.
Synthesis
4-Cyano-5-(phenylamino)thiophene-2-carbox-
amide (3a) was synthesized according to a
reported method by treatment of 2-(4-oxo-3-
phenylthiazolidin-2-ylidene)malononitrile (2)
with ammonia[11,12].
4-Cyano-5-(phenylamino)thiophene-2-carbox-
amides (3d-g)
General Procedure: A mixture of 2-(4-oxo-3-
phenylthiazolidin-2-ylidene)malononitrile (2)
2.88g (0.012 mol) in aqueous aliphatic amines;
namely methylamine, ethylamine, dimethyl-
amine or morpholine (30 mL) in the presence of
a few drops of TEA was stirred at certain
temperatures and lengths of time. The
precipitated product was filtered off, dried and
recrystallized from benzene.
3-Amino-4-cyano-N-methyl-5-(phenylamino)-
thiophene-2-carboxamide (3d)
Yield: 66%, (RT, 48h), white crystals, mp.
202-204 °C; νmax (cm-1) 3458-3266 br. (NH2,
NH), 2200 (CN), 1586 (C=O); δH 9.98 (br. 1H,
NH), 7.37-7.10 (m,5H, arom and br,1H,NH),
6.58 (br,2H,NH2), 3.20 (s,3H,CH3); δC (ppm)
164.77 (C=O), 159.95, 151.69, 141.28, 129.86,
124.76, 121.08, 87.03, 83.21 (C arom.), 114.41
(CN), 26.13 (CH3); m/z (ESI) = 272.00.
3-Amino-4-cyano-N-ethyl-5-(phenylamino)thio-
phene-2-carboxamide (3e)
Yield: 54%, (RT, 48h), yellow crystals, mp.
164-166 °C; νmax (cm-1) 3386-3253 (NH2 and
NH), 2207 (CN), 1596 (C=O); δH (ppm) 9.87
(br, 1H, NH), 7.40-7.15 (m, 5H, arom, and br
1H, NH), 6.59 (br. 2H, NH2), 3.20 (q, 2H, CH2),
1.04 (t, 3H, CH3); δC (ppm) 164.16 (C=O),
160.00, 151.84, 141.32, 129.87, 124.75, 121.13,
87.04, 83.19 (C arom), 114.42 (CN), 33.89
(CH2), 15.53 (CH3); m/z (ESI) = 286.10.
3-Amino-4-cyano-N,N-dimethyl-5-(phenylamino)-
thiophene-2-carbox-amide (3f)
Yield: 84%, (Reflux, 3h), pale yellow crystals,
mp. 178-180 °C; νmax (cm-1) 3374-3273 (NH2,
3191 (NH), 2203 (CN), 1598 (C=O), δH (ppm)
Utilization of 2-Ylidene-4-Thiazolidinones in the Synthesis of Heterocyclic Compounds: Part (III):…
41
9.97 (br, 1H, NH), 7.40-6.85 (m, 5H, arom),
6.56 (br. 2H, NH2), 2.95 (s, 6H, 2CH3); δC (ppm)
166.13 (C=O), 160.21, 152.37, 141.12, 129.86,
124.61, 120.76, 86.39, 83.19 (C arom), 114.44
(CN), 37.79 (CH3); m/z (ESI) = 286.85.
4-Amino-5-(morpholine-4-carbonyl)-2-(phenyl-
amino)thiophene-3-carbonitrile (3g)
Yield: 84%, (Reflux,3h), white powder, mp.
238-240 °C; νmax (cm-1), 3440-3340 (NH2), 3247
(NH), 2207 (CN), 1609 (C=O); δH 10.01 (s,1H,
NH), 7.41-6.85 (m, 5H, arom), 6.40 (br,2H,
NH2), 3.57-3.26 (4 CH2 morpholine); δC 165.92
(C=O), 160.65, 151.81, 141.05, 129.87, 124.81,
120.00, 86.8, 83.03 (C arom.), 114.33 (CN); m/z
(ESI) = 328.00.
2-(2-Morpholino-2-oxoethylthio)(phenyl-
amino)methylene)malononitrile (5g)
A mixture of 2-(4-oxo-3-phenylthiazolidin-2-
ylidene)malononitrile (2) (1g, 0.004mol) and
morpholine (0.016 mol,1.3 mL) in dioxane (15
mL) in the presence of a few drops of TEA was
stirred at room temperature for 48 h. The
precipitated product was filtered off and
recrystallized from dioxane.
Yield: 58%, white crystals, mp. 138-140°C;
νmax (cm-1) 3184 (NH), 2202 (CN), 1629 (C=O);
δH 10.74 (br, 1H, NH), 7.44-7.26 (m, 5H, arom),
3.95 (s,2H,CH2-S), 4.37-4.2 (t,3H, H5); δC (ppm)
169.28 (C=O), 166.19 (=C-NPh), 139.09
(=C(CN)2, 129.98, 129.57, 126.97, 124.25 (C
arom.), 115.77 (CN), 66.86 (C morpholine),
46.51 (C morpholine), 35.29 (CH2-S); m/z (ESI)
= 328.85.
2-Aryl-4-oxo-6-(phenylamino)-1,2,3,4-tetra-
hydrothieno[3,2-d]pyrimidine-7-carbonitriles
(6a-m)
General procedure: A solution of 3-amino-4-
cyano-5-(phenylamino)thiophene-2-carboxamide
(3a,d,e) (0.0019 mol) and the aromatic aldehyde
(0.0019 mol) in 15 mL glacial acetic acid was
refluxed for 7 h. The reaction mixture was then
left overnight at room temperature and the
precipitated solid that formed was filtered off
and recrystallized from ethanol.
2-(4-Methoxyphenyl)-3-methyl-4-oxo-6-phenyl-
amino-1,2.3,4-tetrahydro-thieno [3,2-d]pyrimi-
dine-7-carbonitrile (6a)
Yield: 64%, white powder, mp. 258-260 °C;
νmax (cm-1) 3321 (br. 2NH), 2205 (CN), 1596
(C=O); δH (ppm) 10.22 (br,1H, NH), 8.09
(br,1H, NH), 7.42-7.93 (m, 9H, arom.), 5.77 (d,
1H, CH), 3.87 (s, 3H, OCH3), 2.81 (s, 3H,
NCH3); δC (ppm) 164.60 (C=O), 159.68, 159.20,
149.00, 140.20, 131.88, 129.43, 127.83, 127.34,
124.77, 113.77, 89.80, 79.05 (C arom), 113.46
(CN), 71.76 (CH), 55.09 (OCH3), 31.47 (CH3);
m/z (ESI) = 390.70
2-(4-Chlorophenyl)-3-methyl-4-oxo-6-phenyl-
amino-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimi-
dine-7-carbonitrile (6b)
Yield: 66%, pale yellow powder, mp. 254-
256 °C; νmax (cm-1) 3302 br (2NH), 2211 (CN),
1630 (C=O); δH (ppm) 10.26 (br, 1H, NH), 8.21
(br, 1H, NH), 7.16-7.13 (m, 9H, arom) 5.87 (d,
1H, CH), 2.81(s, 3H, CH3),; δC (ppm) 164.23
(C=O), 159.43, 149.40, 140.17, 136.79, 132.64,
129.46, 128.41, 126.16, 124.85, 120.87, 89.94,
78.89 (C arom.), 113.39 (CN), 71.23 (CH), 31.71
(NCH3); m/z (ESI) = 394.75.
3-Methyl-2-(4-nitrophenyl)-4-oxo-6-phenyl-
amino-1,2,3,4-tetrahydrothieno- [3,2-d]pyrimi-
dine-7-carbonitrile (6c)
Yield: 80%, pale brown powder, mp. 234-238
°C; νmax (cm-1) 3320 br. (2NH), 2197 (CN), 1608
(C=O); δH (ppm) 10.20 (br, 1H, NH), 8.43-7.16
(m, 9H, arom + br 1H, NH), 6.04 (d, 1H, CH),
2.94 (s, 3H, CH3); δC (ppm) 164.96 (C=O),
160.73, 159.74, 149.94, 148.00, 140.24, 137.55,
136.74, 129.44, 128.83, 126.64, 121.55, 91.11,
79.62 (C arom), 113.77 (CN), 71.65 (CH), 32.36
(CH3); m/z (ESI) =405.80
3-Methyl-4-oxo-6-phenylamino-2-p-tolyl-1,2,3,4-
tetrahydro-thieno[3,2-d]pyrimidine-7-carbo-
nitrile (6d)
Yield: 75%, yellow powder, mp. 268-270 °C;
νmax (cm-1) 3310 (NH), 3230 (NH), 2207 (CN),
1597 (C=O); δH (ppm) 10.22 (br, 1H, NH), 8.12
(d, 1H, NH), 7.42-7.14 (m, 9H arom), 5.79 (s,
1H, CH) 2.83 (s, 3H, CH3Ph), 2.29 (s, 3H, CH3),;
δC (ppm) 164.02 (C=O), 159.64, 149.42, 140.24,
137.55, 136.74, 129.44, 128.83, 126.64, 121.55,
120.84, 89.88 C arom), 113.44 (CN), 72.63
(NCH3), 71.76 (CH), 20.00 (CH3Ph); m/z (ESI)=
437.70.
2-(4-Chlorophenyl)-3-ethyl-4-oxo-6-phenyl-
amino-1,2,3,4-tetrahydro-thieno [3,2-d]pyrimi-
dine-7-carbonitrile (6e)
Yield: 66%, pale yellow powder, mp. 256-
258 °C; νmax (cm-1) 3297 (br 2NH), 2208 (CN)
1620 (C=O); δH (ppm) 10.25 (s, 1H, NH),8.23 (d,
1H, NH), 7.46-7.13 (m, 5H, arom), 5.91-5.90
(d,1H, CH), 3.86-3.80, (q, 1H, CH2), 2.95-2.88,
Farhat et al.
42
(q,1H, CH2),1.05-1.01 (t, 3H, CH3); δC (ppm)
164.75 (C=O), 159.50, 149.85, 140.68 140.09,
133.22, 129.96, 128.76, 128.66, 125.30, 121.36,
91.21, 79.47 (C arom), 113.90 (CN), 69.58 (CH),
39.30 (NCH2), 14.51 (CH3).
3-Ethyl-2-(4-nitrophenyl)-4-oxo-6-phenylamino-
1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidine-7-
carbonitrile (6f)
Yield: 79 %, brown powder, mp. 228-230 °C;
νmax (cm-1) 3284 br (2NH), 2208 (CN), 1625
(C=O); δH (ppm) 10.27 (br, 1H, NH), 8.42-7.14
(m, 9H, arom and br 1H, NH), 6.07 (d, 1H, CH),
3.92-3.83 (q,1 H,CH2), 3.02-2.96 (q, 1H, CH2),
1.15 (t,3H, CH3); δC (ppm) 164.94 (C=O),
159.23, 149.91, 148.75, 147.80, 140.61, 130.21,
130.08, 129.97, 128.06, 125.47, 124.25, 124.00,
122.12, 121.42, 91.11,79.60 (C arom.), 113.97
(CN), 69.38 (CH),39.30 (NCH2), 14.61 (CH3).
3-Ethyl-2-(4-methoxyphenyl)-4-oxo-6-phenyl-
amino-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimi-
dine-7-carbonitrile (6g)
Yield:74 %, white powder, mp. 262-264 °C;
νmax (cm-1) 3302 (NH), 3175 (NH), 2209 (CN),
1620 (C=O); δH (ppm) 10.20 (br, 1H, NH), 8.08-
6.88 (m, 9H, arom. and br,1H, NH), 5.80(d, 1H,
CH) 3.86 (s, 3H, OCH3), 3.92-3.84 (q, 1H, CH2),
3.02-2.9 (q, 1H, CH2),1.04 (t, 3H, CH3); δC
(ppm) 165.40 (C=O), 159.78, 149.86, 140.87,
132.91, 131.75, 129.90, 128.38, 121.25, 115.34,
114.22, 91.57, 80.01(C arom), 113.97 (CN),
70.47 (CH), 55.63 (OCH3Ph), 39.18 (NCH2),
14.28 (CH3).
3-Ethyl-4-oxo-6-phenylamino-2-p-tolyl-1,2,3,4-
tetrahydro-thieno[3,2-d]-pyrimidine-7-carbo-
nitrile (6h)
Yield: 71 %, yellow powder, mp. 260-262
°C; νmax (cm-1)3301 (br. 2NH), 2210 (CN) 1620
(C=O); δH (ppm) 10.21 (s, 1H, NH), 8.13 (d, 1H,
NH), 7.41-7.13 (m, 5H, arom), 3.84-3.01 (q, 1H,
CH2), 2.90-2.86 (q, 1H, CH2), 2.27 (s, 3H,
CH3Ph), 1.04-0.99 (t, 3H, CH3); δC (ppm) 164.53
(C=O), 159.60, 149.85, 140.75, 137.95, 137.93,
129.94, 129.28, 126.75, 125.38, 121.25, 91.11,
79.60, (C arom), 113.97 (CN), 39.20 (CH), 70.17
(CH2), 21.09 (CH3Ph), 14.43 (CH3).
2-(4-Nitrophenyl)-4-oxo-6-phenylamino-1,2,3,4-
tetrahydrothieno[3,2-d]-pyrimidine-7-carbo-
nitrile (6i)
Yield: 88 %, orange powder, mp. 284-287
°C; νmax (cm-1) 3356 (NH), 3238 (NH), 2214
(CN) 1647 (C=O); δH (ppm) 10.20 (br, 1H,
NHPh), 8.43-7.38 (m, 9H, arom and br,1H, NH),
7.19 (br. 1H, NH), 5.87 (br 1H, CH); δC (ppm)
164.98 (C=O), 160.73, 151.22, 149.41, 147.93,
140.75, 129.75, 128.79, 125.47, 123.83, 121.55,
91.50, 79.62 (C arom), 113.83 (CN), 66.04 (CH).
2-(4-Methoxyphenyl)-4-oxo-6-phenylamino-
1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-7-
carbonitrile (6j)
Yield: 81 %, white powder, mp: 295-297 °C;
νmax (cm-1) 3480 (NH), 3411 (NH), 2217 (CN),
1635 (C=O); δH 10.30 (s, 1H, NH), 7.81 (s, 1H,
NH), 7.71 (s, 1H, NH), 7.45-6.95 (m, 9H,
arom.), 5.70 (s, 1H, CH), 3.76 (s, 3H, OCH3); δC
164.67 (C=O), 161.48, 159.52, 151.66, 140.83,
133.21, 129.93, 128.49, 124.29, 121.34, 91.33,
80.05 (C arom), 113.99 (CN), 67.05 (CH), 55.62
(OCH3).
(4-Chlorophenyl)-4-oxo-6-phenylamino-1,2,3,4-
tetrahydrothieno[3,2-d]-pyrimidine-7-carbo-
nitrile (6k)
Yield: 90 %, pale yellow, mp: 310-312 °C;
νmax (cm-1) 3409 (NH), 3242 (NH), 2214 (CN),
1678 (C=O); δH 10.25 (br, 1H, NH), 7.95 (s, 1H,
NH), 7.80 (s, 1H, NH), 7.50-7.37 (m, 9H,
arom.), 5.70 (s, 1H, CH); δC 164.82 (C=O),
161.13, 151.44, 140.76, 140.56, 133.31, 129.94,
128.99, 128.60, 125.38, 121.44, 121.10, 91.00,
79.85 (C arom), 113.00 (CN), 66.40 (CH).
2-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-6-(phenyl-
amino)-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimi-
dine-7-carbonitrile (6l)
Yield: 74 %, pale yellow, mp: 230-232 °C;
νmax (cm-1) 3417 (NH), 3233 (NH), 2214 (CN),
1641 (C=O); δH 10.30 (br, 1H, NH), 7.90 (br,
1H, NH), 7.80 (br, 1H, NH), 7.40-6.70 (m, 9H,
arom.), 5.70 (s,1H, CH), 6.02 (s, 2H, OCH2); δC
164.71 (C=O), 161.13, 151.53, 147.69, 140.77,
135.20, 129.95, 125.33, 121.33, 120.67, 107.59,
101.58, 91.0, 79.83 (C arom), 113.00 (CN),
66.98 (CH).
4-Oxo-6-phenylamino-2-p-tolyl-1,2,3,4-tetra-
hydrothieno[3,2-d]-pyrimidine-7-carbonitrile
(6m)
Yield: 68%, white powder, mp: 299-300 °C;
νmax (cm-1) 3347 br (2NH), 2214 (CN) 1681
(C=O); δH 10.30 (br, 1H, NH), 7.90 (br, 1H,
NH), 7.80 (br, 1H, NH), 7.19-7.40 (m, 9H,
arom), 5.70 (s,1H, CH), 2.31 (s, 3H, CH3Ph); δC
164.68 (C=O), 161.36, 159.95, 151.55, 140.84,
138.48, 137.97, 129.92, 129.11, 127.05, 125.29,
121.37, 91.38, 80.07 (C arom), 113.97 (CN),
67.04 (CH), 21.43 (CH3).
Utilization of 2-Ylidene-4-Thiazolidinones in the Synthesis of Heterocyclic Compounds: Part (III):…
43
Synthesis of 4-oxo-6-(phenylamino)-3,4-dihy-
drothieno-[3,2-d]pyrimidine-7-carbonitriles
(7a-c)
Method I: General Procedure
A solution of 3-amino-4-cyano-N-alkyl-5-
(phenylamino)thiophene-2-carboxamide (3a,d,e)
(0.0018 mol) and triethylorthoformate (0.5 mL)
in glacial acetic acid (20 mL) was refluxed for 3
h. The reaction mixture was cooled and the
precipitated solid was filtered off and
recrystallized from glacial acetic acid.
Method II: General Procedure:
A solution of 3-amino-4-cyano-N-alkyl-5-
(phenylamino)thiophene-2-carboxamide (3a,d,e)
(0.002 mol) in formic acid (15 mL) was refluxed
for 5 h. The reaction mixture was then cooled
and the precipitated solid was filtered off and
recrystallized from glacial acetic acid.
4-Oxo-6-(phenylamino)-3,4-dihydrothieno[3,2-
d]pyrimidine-7-carbonitrile (7a)
Yield: method I; 55%, method II; 34%, light
brown powder, mp. 295-298 °C; νmax (cm-1) 3219
(NH), 3129 (NH), 2214 (CN), 1641 (C=O), 1586
(C=N); δH (ppm) 12.54 (br. 1H, NH), 10.67 (br.
1H, NH), 8.16 (s, 1H, CH), 7.48-7.23 (m, 5H,
arom); δC (ppm) 165.26 (C=O), 157.97, 155.96,
149.11, 140.43, 130.28, 126.10, 122.08, 108.09,
84.43, [(C arom.) and (C=N)], 114.04 (CN); m/z
(ESI) = 268.85.
3-Methyl-4-oxo-6-(phenylamino)-3,4-dihydro-
thieno[3,2-d]pyrimidine-7-carbonitrile (7b)
Yield: method I; 61%, method II; 40%,
yellow powder, mp. 228-230 °C; νmax (cm-1)
3259 (NH), 3129 (NH), 2212 (CN), 1668 (C=O),
1578 (C=N); δH (ppm) 10.67 (br. 1H, NH), 8.16
(s, 1H, CH), 7.48-7.23 (m, 5H, arom.); δC (ppm)
164.89 (C=O), 156.84, 155.96, 151.42, 140.43,
131.81, 129.64, 125.78, 121.60, 106.84, 83.52,
[(C arom) and (C=N)], 113.47 (CN),33.54
(CH3); m/z (ESI) = 285.75.
3-Ethyl-4-oxo-6-phenylamino-3,4-dihydro-
thieno[3,2-d]pyrimidine-7-carbonitrile (7c)
Yield: method I; 70%, method II; 44%, white
crystals, mp. 264-266 °C; νmax (cm-1) 3239 (NH),
2214 (CN), 1660 (C=O), 1592 (C=N); δH (ppm)
10.59 (br 1H, NH), 8.47 (s, 1H, CH), 7.48-7.26
(m, 5H, arom), 3.98 (q, 2H, CH), 1.30 (t, 3H,
CH3); δC (ppm) 165.24 (C=O), 157.29, 155.28,
151.32, 140.43, 122.20, 107.89, 84.40 [(C arom)
and (C=N)], 113.83 (CN) 41.79 (CH2), 15.19
(CH3); m/z (ESI) = 296.85.
Results and Discussion
2-(4-Oxo-3-phenylthiazolidin-2-ylidene)ma-
lononitrile (2) was synthesized according to our
reported method[8] by the reaction of ethyl
chloroacetate with ketene-N,S-acetal (1) which
was prepared from malononitrile, phenyl-
isothiocyanate and potassium hydroxide. The
reaction of 2-(4-oxo-3-phenylthiazolidin-2-
ylidene)malononitrile (2) with ammonia[12] and a
number of amines; namely, methyl amine, ethyl
amine, diethylamine and morpholine gave the
corresponding 3-amino-4-cyano-5-(phenyl-
amino)thiophene-2-carboxamides (3a, d-g) in a
similar fashion to our reported method[10]. The
assignment of these carboxamides (3a, d-g) was
based on their spectral analysis. IR spectra
showed bands at ν 3458-3353, 3340-3253 and
3266-3185 cm-1 representing NH2, NHPh and
amidic NH groups, respectively. The 1H-NMR
spectrum for each carboxamide lacked the CH2
signal which is characteristic of 4-thiazolidinone
ring. It also revealed new D2O-exchangable
signals at δ 10.01-9.80 and δ 6.58-6.40 ppm
representing NHPh and NH2 protons,
respectively. The NH amidic protons and
aromatic protons appeared as multiplets at δ
7.40-7.15 ppm. Their 13C-NMR spectra did not
also show any signals for the methylene carbons
which are characteristic of the starting
thiazolidinone rings when DEPT135 technique
was performed but revealed new signals at δ
165.92-164.16 ppm which were assigned to the
amidic carbonyl carbons. The molecular ion
peaks in the mass spectra of these compounds
(3d-g) gave (m/z) = 272.00, 286.10, 286.85 and
328.00, respectively. This amination reaction is
similar to our previously proposed mechanism
and involves ring opening of the thiazolidinone
ring to give the intermediates (5a-e) followed by
intramolecular cyclization producing the
thiophene-2-carboxamides (3a, d-g) (Scheme 2).
The mechanism shown in Scheme 3 was
supported by the isolation of the intermediate 4e.
This intermediate (4e) was refluxed in dioxane in
the presence of morpholine, which acts as a
Lewis base accelerating the formation of the
carbanion that attacks the cyano group causing
cyclization into the expected thiophene-2-
carboxamide (3g).
Farhat et al.
44
PhNCS, KOH
dioxane / 0-5
o
C
NC CN
SKPhHN
NS
CNNC
O
Ph
ClCH
2
CO
2
Et
(2)
(1)
CNNC
S
NH
2
NC
PhHN
NR
1
R
2
O
NO
d)R
1
= H, R
2
= CH
3
e)R
1
= H, R
2
= C
2
H
5
f)R
1
= R
2
= (CH
3
)
2
g)R
1
, R
2
=
(3a, d-g)
SPhHN
O
NR
1
R
2
NC CN
(5a-e)
NHR
1
R
2
a)R
1
= R
2
= H
TEA
Dioxan e
Dio xane
Scheme 2. Synthesis of thiophene-2-carboxamides (3a,d-g).
(2)
N S
NC CN
O
Ph
S
NH
2
NC
PhHN
N
O
N
H
OCNNC
PhHN
O
SN
O
O
reflux
+
(5e)
(3g)
reflux
RT
Morpholine
Scheme 3. Proposed mechanism of the formation of 4-amino-5-(morpholine-4-carbonyl)-2-
phenylaminothiophene-3-carbonitrile (3g).
The IR spectrum of compound (5e) showed
bands at ν 3184, 2202 and 1629 cm-1
representing NHPh, cyano and amidic carbonyl
groups, respectively. The 1H-NMR spectrum of
compound (5e) exhibited a new D2O-
exchangable signal at δ 10.74 ppm for NHPh
group and a singlet at δ 4.20 ppm representing
CH2-S-, in addition to a set of signals at δ 3.58-
3.20 ppm for the morpholine CH2 protons. The
13-CNMR spectrum also confirmed the proposed
structure of this intermediate. It showed a signal
at 169.28 ppm which was assigned to amidic
(C=O) carbon with the presence of two bands at
66.86 and 42.79 ppm for the methylene carbons
(4CH2) of the morpholine ring and the methylene
group (CH2-S) at 35.29 ppm. These signals were
clearly confirmed when DEPT technique was
used.
A number of tetrahydrothieno[3,2-d]pyrimi-
dine-7-carbonitriles, specifically 6a-m, were
synthesized by reacting thiophene-2-carbox-
amides (3a,d,e) with various aromatic aldehydes
in refluxing glacial acetic acid. The 1HNMR of
6a-m spectra lacked any NH2 signals and showed
D2O-exchangable signals of NHPh and
pyrimidinone NH groups at 10.27-10.20 and
8.43-8.07 ppm, respectively. The singlets at
6.08-5.91 ppm were attributed to the pyrimi-
dinone CH protons and the NCH3 protons
appeared at 2.96-2.80 ppm. It is worthy to
mention that the CH2 protons of each ethyl group
of each of tetrahydrothienopyrimidinones (6e-h)
in which R2 = C2H5 appeared as two quartet
signals at δ 3.89-3.77 ppm and at δ 3.03- 2.85
ppm. Each quartet signal represents one of these
two (CH2) protons due to possible hydrogen
bonding with the (C=O) groups as shown in
Figure 1 below. The signals of the methyl
protons of these ethyl groups appeared as triplets
at 1.14-0.99 ppm.
The 13CNMR spectra of compounds 6a-m
showed signals at δ 164.96-164.01 ppm
representing the C=O groups and also new
signals at δ 72.09-66.04 ppm representing the
methine ring carbons. Their mass spectra gave
also the correct molecular weights. Primary and
Utilization of 2-Ylidene-4-Thiazolidinones in the Synthesis of Heterocyclic Compounds: Part (III):…
45
secondary 3-aminothiophene-2-carboxamides
(3a,d,e) when treated with triethylorthoformate
in refluxing glacial acetic acid gave 4-oxo-6-
(phenylamino)-3,4-dihydrothieno[3,2-d]pyrimi-
dine-7-carbonitriles (7a-c) in high yields instead
of the expected condensation intermediates (8a-
c). The same dihydrothienopyrimidinones (7a-c),
although in lesser yields, were successfully
synthesized when formic acid was used instead
of triethylorthoformate probably via the
intermediates (9a-c) (Scheme 5). This last
method gave less yields and purity of the target
compounds 8a-c.
S
N
H
2
O
NR
1
R
2
N
C
ArCHO
S
NC
NR
2
H
NAr
O
glacial acetic acid
(3a, d, e) (6a-m)
PhHN
PhHN
a)R
1
=H, R
2
=H
d)R
1
=H, R
2
=CH
3
e)R
1
=H, R
2
=C
2
H
5
Scheme 4. Synthesis of tetrahydrothienopyrimidinones (6a-m).
S
NC
Ar
N
O
C
H
PhHN
NC
H
H
H
HH
H
Figure 1. Hydrogen bonding between CH2 protons and C=O groups in 6e-h.
Scheme 5. Synthesis of dihydrothienopyrimidinones (7a-c).
Compound R
2
Ar. Comp. R
2
Ar.
6a CH
3
p-OCH
3
C
6
H
4
6h C
2
H
5
p-CH
3
C
6
H
4
6b CH
3
p-ClC
6
H
4
6i H p-NO
2
C
6
H
4
6c CH
3
p-NO
2
C
6
H
4
6j H p-OCH
3
C
6
H
4
6d CH
3
p-CH
3
C
6
H
4
6k H p-ClC
6
H
4
6e C
2
H
5
p-ClC
6
H
4
6l H 5-Piperonyl
6f C
2
H
5
p-NO
2
C
6
H
4
6m H p-CH
3
C
6
H
4
6g C
2
H
5
p-OCH
3
C
6
H
4
- - -
Farhat et al.
46
The IR spectra of compounds (7a-c) indicated
the disappearance of NH2 absorptions and
showed amidic carbonyl bands at ν 1668-1641
cm-1. The 1H-NMR spectra showed new signals
at 8.47-8.16 ppm indicating N=CH protons and
broad D2O-exchangable signals at 10.70-10.59
ppm representing NH protons. The 13C-NMR
and mass spectra of compounds (7a-c) confirmed
their proposed structures.
In-vitro Antibacterial Activity Evaluation
The objective of this part of the present study
was to investigate the antimicrobial activities of
newly synthesized thienopyrimidinones. This
was carried out with the hope of discovering
structures serving as antimicrobial agents. The
synthesized dihydro and tetrahydrothienopyrimi-
dinones were screened using the agar-diffusion
two-fold serial dilution method[13] to evaluate
their in-vitro antibacterial activity. Table 1
summarizes the inhibitory activity of the twelve
most active compounds. Nitrofurantoin, a hetero-
cyclic antibiotic, was used as reference drug. The
bactericidal/bacteriostatic effect was assessed for
all compounds using three concentrations 500,
300 and 150 µg/mL and the diameters of
inhibition zones (DIZ) were recorded.
Table 1. The invitro antibacterial activity of thienoprymidinone derivatives.
ENTRY
µg/mL
Diameter of Inhibition Zone (mm)
Gram–positive Gram–negative
S.aur MRSA B. sub E. coli K. pne P. aer
6a
500
300
150
10
-ve
-ve
-
ve
-ve
-ve
15
12
9
15
10
11
17
16
12
11
10
9
6b
500
300
150
10
9
8
-
ve
-ve
-ve
10
-ve
-ve
12
12
-ve
18
17
15
15
14
10
6c
500
300
150
-
ve
-ve
-ve
-
ve
-ve
-ve
10
-ve
-ve
-
ve
-ve
-ve
-
ve
-ve
-ve
11
10
-ve
6d
500
300
150
10
-ve
-ve
-
ve
-ve
-ve
10
-ve
-ve
13
10
-ve
16
11
-ve
13
12
-ve
6e
500
300
150
-
ve
-ve
-ve
-
ve
-ve
-ve
11
-ve
-ve
15
14
-ve
-
ve
-ve
-ve
11
10
-ve
6f
500
300
150
10
10
-ve
10
9
-ve
12
9
-ve
12
-ve
-ve
11
-ve
-ve
11
10
9
6g
500
300
150
-
ve
-ve
-ve
-
ve
-ve
-ve
12
-ve
-ve
13
-ve
-ve
-
ve
-ve
-ve
-
ve
-ve
-ve
6h
500
300
150
-
ve
-ve
-ve
-
ve
-ve
-ve
-
ve
-ve
-ve
16
14
11
-
ve
-ve
-ve
12
-ve
-ve
6i
500
300
150
-
ve
-ve
-ve
-
ve
-ve
-ve
11
9
11
12
11
-ve
-
ve
-ve
-ve
13
10
-ve
7a
500
300
150
-
ve
-ve
-ve
-
ve
-ve
-ve
-
ve
-ve
-ve
12
-ve
-ve
11
-ve
-ve
13
-ve
-ve
7b
500
300
150
-
ve
-ve
-ve
-
ve
-ve
-ve
15
12
-ve
17
11
-ve
11
11
-ve
15
14
-ve
7c
500
300
150
-
ve
-ve
-ve
-
ve
-ve
-ve
12
-ve
-ve
15
12
-ve
17
14
-ve
18
16
-ve
Nitrofurantoin 300 20 21 12 18 19 11
S. aur: Staphylococcus aureus; MRSA: Methicillin-Resistant Staphylococcus; B. sub: Bacillus subtilis, E.coli: Escherichia
coli, K. pne: Klebsiella pneumonia; P. aer: Pseudomonas aeruginosa.
Utilization of 2-Ylidene-4-Thiazolidinones in the Synthesis of Heterocyclic Compounds: Part (III):…
47
The experiments were performed using test
bacterial organisms belonging to Gram-positive
and Gram-negative bacteria, three of each. S.
aureus, MRSA and B. subtilis (Gram-positive)
and E. coli, K. pneumonia and P. aeruginosa
(Gram-negative) were the test organisms
utilized. With a very few exceptions, compounds
6c, 6e, 6g, 6h, 6i and 7b) are inactive against
Gram-positive bacteria. These exceptions, after
all, are of very weak bacterio-static effect (9-
11mm/hole). On the other hand, most tested
compounds are found to be active against most
Gram-negative bacteria. The dihydrothieno-
pyrimidinones 7a, 7b and 7c displayed a better
activity against Gram-negative organisms. The
ring in compounds 7a-c and tetrahydrothieno-
pyrimidinones 6a, 6b, 6d, 6f and 6i seemed to be
responsible for their distinguished activity
against most tested organisms. This might be due
to the presence of pyrimidinone rings which are
carrying different chemically active substituents
like N-methyl, N-ethyl groups and substituted
phenyls, such as p-nitrophenyl-, p-chlorophenyl-
and p-tolyl- and fused with thiophene rings.
Conclusions
1. 3-Aminothiophene-2-carboxamides (3a,d-g)
were successfully synthesized by reacting 2-(4-
oxo-3-phenylthiazolidin-2-ylidene)malononitrile
(2) with a variety of amines (ammonia,
methylamine, ethylamine, dimethylamine and
morpholine).
2. 3-Aminothiophene-2-carboxamides were
successfully employed as useful synthons in
synthesizing dihydrothienopyrimidinones (7a-c)
and tetrahydrothienopyrimidinones (6a-i).
3. In general, the screened thienopyrimidinone
derivatives 6a-i and 7a-c displayed variable
antibacterial activities.
Acknowledgement
We would like to express our sincere thanks
to Prof. Nabil A. Saleh of Ain-Shams University,
Cairo, Egypt for his help in performing the in-
vitro antibacterial activity evaluation.
_____________________________________________________________________
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