Synthesis and antitumor activity of some novel pyrazole and thienopyrimidine derivatives

Article abstract of DOI:10.1080/10426500902758410

The novel thiosemicarbazide derivative was prepared by hydrazinolysis of isothiocyanatosulfonamide with hydrazine hydrate. It was used as a starting material for the synthesis of some novel pyrazolosulphaphenazole, phthalazine, thiourea, and 1,2,4-triazolbenzenesulfonamide derivatives. Isothiocyanato sulfonamide was cyclized with sulfanyl acetic acid to furnish the novel 2-thioxothiazolidine derivative. Treatment of p-substituted sulfamoylphenyl isothiocyanate derivatives with various O-aminoesters of thiophene derivatives yielded dimethyl thiophene-carboxylate, methylthiophene carboxylate, and thienopyrimidine derivatives. Some of synthesized compounds were evaluated for one cell line. Compounds 3, 9, 15a, 15b, and 18 exhibited remarkable antitumor activity against MCF7 (breast) human cells. Supplemental materials are available for this article. Go to the publisher′s online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426500902758410

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Synthesis and Antitumor Activity
of Some Novel Pyrazole and
Thienopyrimidine Derivatives
Hala M. Aly a
a Department of Chemistry, Faculty of Science (Girls), Al-Azhar
University, Nasr City, Cairo, Egypt
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To cite this article: Hala M. Aly (2009): Synthesis and Antitumor Activity of Some Novel Pyrazole
and Thienopyrimidine Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:1,
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Phosphorus, Sulfur, and Silicon, 185:211–221, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902758410
SYNTHESIS AND ANTITUMOR ACTIVITY OF SOME
NOVEL PYRAZOLE AND THIENOPYRIMIDINE
DERIVATIVES
Hala M. Aly
Department of Chemistry, Faculty of Science (Girls), Al-Azhar University,
Nasr City, Cairo, Egypt
The novel thiosemicarbazide derivative was prepared by hydrazinolysis of isothiocyanatosul-
fonamide with hydrazine hydrate. It was used as a starting material for the synthesis of some
novel pyrazolosulphaphenazole, phthalazine, thiourea, and 1,2,4-triazolbenzenesulfonamide
derivatives. Isothiocyanato sulfonamide was cyclized with sulfanyl acetic acid to fur-
nish the novel 2-thioxothiazolidine derivative. Treatment of p-substituted sulfamoylphenyl
isothiocyanate derivatives with various O-aminoesters of thiophene derivatives yielded
dimethyl thiophene-carboxylate, methylthiophene carboxylate, and thienopyrimidine deriva-
tives. Some of synthesized compounds were evaluated for one cell line. Compounds 3, 9,
15a, 15b, and 18 exhibited remarkable antitumor activity against MCF7 (breast) human
cells.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Antitumor activity; dimethyl thiophenecarboxylate; methylthiophene carboxylate;
thienopyrimidine; thiosemicarbazide; 2-thioxothiazolidine
INTRODUCTION
Pyrazole1 and 1,2,5-thiadiazole2,3 derivatives are biologically important compounds.
Substituted 1,2,5-thiadiazoles were found to be efficient muscarine4 receptor agonists as
well as inhibitors of HIV-1 replication.5 For example, 1-(1,1-di-methylethylamino)-3-(4-
morpholino-1,2,5-thiadiazol-3-yloxy)-2-propanol (timolol) is one of the most important
medicines for the treatment of glaucoma.6,7 Furthermore, antibacterial,8 antifungal,9 in-
sulin releasing,10 carbonic anhydrase inhibitory,11 anti-inflammatory,12 and antitumor13
properties of the sulfamoyl moiety have been described. With these facts, and in continu-
ation of my efforts to synthesize biologically active heterocyclic compounds from readily
available starting materials,14–17 the synthesis and antitumor activity of some novel pyrazole
and 1,2,5-thiadiazole derivatives containing sulfamoyl moiety are reported here.
Received 25 October 2008; accepted 19 January 2009.
Address correspondence to Hala M. Aly, Department of Chemistry, Faculty of Science (Girls), Al-Azhar
University, Nasr City, Cairo, Egypt. E-mail: hala mali@yahoo.com
211

212
H. M. ALY
Scheme 1
RESULTS AND DISCUSSION
Isothiocyanate derivatives are useful and widely used building blocks in the synthesis
of nitrogen, sulfur, and oxygen heterocyclic compounds and organometallic compounds of
academic, pharmaceutical, and industrial interest.18,19 Isothiocyanatosulfonamides (2a,b)
were synthesized by the treatment of sulfonamide derivatives (1a,b) with thiophosgene
in the presence of dilute hydrochloric acid at room temperature in quantitative yields
(Scheme 1).
In the IR spectra of compound (2a), the NH and N C S bands were observed in the
3460–3445 cm−1 and 2030 cm−1 regions, respectively. The 1H NMR spectrum of compound
(2a; DMSO-d6) exhibited the following signals: 5.5, 6.6 (2s, 2H, pyrazole-H), 7.5–7.71 (m,
9H, Ar-H), and 10.5 ppm (s, H, NHSO2). Also, its mass spectrum displayed a molecular
ion peak at m/z 356 (M+, 17.49%), and the base peak was found in the spectrum at m/z
158 (100%), where mass spectral fragmentation of (2a) was in agreement with its structure
(Chart 1, available online in the Supplementary Materials). The IR spectrum of (2b) revealed
1
the absorption bands at 3330–3226 (NH), 2100 (NCS), 1332, 1162 cm−1(SO2). The H
NMR spectrum of compound (2b; DMSO-d6) exhibited the following signals: 3.98 (s, 3H,
OCH3), 7.4–7.7 (m, 4H, Ar-H), 10.2 (s, H, NHSO2). Also, its mass spectrum revealed a
molecular ion peak m/z at 328 (M+, 17.40%), with a base peak at 134 (100%). The reaction
of isothiocyanate derivative (2a) with some nitrogen, sulfur, and carbon nucleophiles was
investigated. The strategic starting material N-(4-(N-(1-phenyl-1H-pyrazol-5yl) sulfamoyl)
phenyl)hydrazinecarbothioamide (3) was obtained in good yield via hydrazinolysis of the
corresponding isothiocyanate derivative (2a) with hydrazine hydrate in refluxing ethanol at
room temperature (Scheme 1).
The structure of (3) was established by elemental analysis and spectral data (Table I).
Its infrared spectrum showed the absence of N C S band and exhibited the following
absorption bands: 3356, 3190 (NH2), 1628 (C N), and 1338, 1160 cm−1 (SO2). The
1H NMR spectrum of (3; in DMSO-d6) showed the following signals: 5.7, 6.5 (2s, 2H,

PYRAZOLE AND THIENOPYRIMIDINE DERIVATIVES
213
Table I Spectral data of the newly synthesized compounds (2a–18)
Compd. no.
IR/max (cm−1
)
1H NMR (DMSO-d6) (δ/ppm)
2a
2b
3
3445 (NH), 300 (CH- arom.), 2030 (NCS), 5.5, 6.6 (2s, 2H, pyrazole-H), 7.5–7.71 (m, 9H,
1586 (C N), 1345, 1163 (SO2). Ar-H), 10.5 (s, H, NHSO2).
3226 (NH), 3099 (CH arom.), 2100 (NCS), 3.98 (s, 3H, OCH3), 7.4–7.7 (m, 4H, Ar-H),
1332, 1162 (SO2). 10.2 (s, H, NHSO2).
3356, 3190 (NH2), 3068 (CH-arom.), 1628 5.7, 6.5 (2s, 2H, pyrazole-H), 7.42–7.71 (m,
(C N) and 1338, 1160 (SO2).
11H, Ar-H+2 NH), 10.6 (s, H, NHSO2),
11.3 (s, H, NH2).
4
3380, 3200 (2NH), 3055 (CH-arom.), 2927, 1.2 (s, 3H, CH3), 1.3 (s, 3H, CH3), 5.4, 5.9, 6.5
2898 (2CH-aliph.), 1654(C N), 1384,
1153 (SO2), 1088 (C S).
(3s, 3H, 2pyrazole-H cyclic), 7.42–7.68 (m,
9H, Ar-H), 9.8 (s, H, NH), 10.3 (s, H,
NHSO2).
5
6
3367, 3254 (2NH), 3066 (CH-arom.),
1751,1740 (2C O), 1681 (C N), 1384,
1154 (SO2), 1070 (C S).
5.8 (s, 2H, CH2CO pyrazoline), 5.5, 6.6 (2s,
2H, pyrazole-H), 7.35–7.95 (m, 10H, Ar-H),
9.4 (s, 1H, NH) and 10.5 (s, 1H, NHSO2).
3310, 3230 (2NH), 3055 (CH-arom.), 2980 1.23 (s, 3H, CH3), 5.8 (s, 2H, CH2CO
(CH-aliph.), 1670 (C O), 1545 (C N),
1380, 1150 (SO2), 1093 (C S).
pyrazoline), 5.54, 6.68 (2s, 2H, pyrazole-H),
7.22–7.55 (m, 9H, Ar-H), 8.9 (s, H, NH),
9.9 (s, 1H, NHSO2).
7
8
3210 (NH), 1740, 1733 (2C O), 1378,
1168 (SO2), 1089 (C S).
3300, 3330 (NH, NH2), 1378, 1165 (SO2), 5.3, 6.5 (2s, 2H, pyrazole-H), 7.42–8.0 (m,
5.5, 6.7 (2s, 2H, pyrazole-H), 7.5–8.3 (m, 15H,
Ar-H+NH), 10.3 (s, H, NHSO2).
1067, 1089 (2C S).
10H, Ar-H+NH), 9.8, 9.9(2s, 2H, 2NH),
10.6 (s, H, NHSO2), 11.0 (s, H, NH2).
9
3200 (NH),1358, 1167 (SO2), 1058 (C S). 5.3, 6.4 (2s, 2H, pyrazole-H), 7.6–8.2 (m, 10H,
Ar-H+NH), 10.5 (s, H, NHSO2).
10
3222 (NH), 3120 (CH-arom.) and 1740
cm−1 (C O; thiazolidinone), 1376, 1168
(SO2), and 1093 (C S).
4.2 (s, 2H, CH2 thiazolidinone), 5.3, 6.6 (2s,
2H, pyrazole-H), 7.2–8.1 (m, 10H,
Ar-H+SO2NH).
12a
12b
15a
3330, 3243, 3236 (3NH), 3165 (CH-arom.), 0.87, 1.2 (2s, 6H, 2CH3), 1.3 (t, 3H, CH3), 4.0
2987 (CH-aliph.), 1775 (C O), 1545
(C N), 1350, 1165 (SO2), 1063 (C S).
(q, 2H, CH2), 5.6, 6.6 (2s, 2H, pyrazole-H),
7.5–7.9 (m, 10H, Ar-H+NH), 8.0(s, H,
NH), 11.1 (s, H, NHSO2).
3494, 3242, 3105 (3NH), 2985 (CH-aliph.), 0.9, 1.1(2s, 6H, 2CH3), 1.30 (t, 3H, CH3), 4.10
1759(C O), 1534 (C N), 1321, 1155
(SO2), 1069 (C S).
(s, 3H, OCH3), 4.2 (q, 2H, CH2), 7.1–7.5
(m, 5H, Ar-H+NH), 8.0 (s, H, NH), 9.9 (s,
H, NHSO2).
3330, 3207, 3199 (3NH), 3168 (CH-arom.), 0.89 (s, 3H, CH3), 1.2 (t, 3H, CH3), 3.3 (s, 3H,
2996 (CH-aliph.), 1775, 1696 (2C O),
1598 (C N), 1376, 1166 (SO2), 1059
(C S).
COCH3), 4.1 (q, 2H, CH2), 5.8, 6.4 (2s, 2H,
pyrazole-H), 7.4–7.9 (m, 11H, Ar-H+2NH),
10.9 (s, H, NHSO2).
15b
18
3384–3204 (br, 3NH), 3015 (CH arom.),
2976 (CH-aliph.), 1736, 1685 (2C O),
1311, 1146 (SO2), and 1067 (C S).
3243 (NH), 3134 (CH-arom.), 2976
(CH-aliph.), 1715 (C O), 1565 (C N),
1366, 1145 (SO2), 1057 (C S).
1.0 (s, 3H, 2CH3), 1.2 (t, 3H, CH3), 3.4 (s, 3H,
COCH3), 4.14 (s, 3H, OCH3), 4.2 (q, 2H,
CH2), 7.4–7.9 (m, 7H, Ar-H+3NH).
0.89, 1.1 (2s, 6H, 2CH3), 3.4 (s, 3H, COCH3),
5.54, 6.59 (2s, 2H, pyrazole-H), 7.5–7.9 (m,
10H, Ar-H+NH), 10.5 (s, H, NHSO2).
pyrazole-H), 7.42–7.71 (m, 11H, Ar-H+2 NH), 10.6 (s, H, NHSO2), and 11.3 ppm (s,
H, NH2). Its mass spectrum revealed a molecular ion peak corresponding to the for-
mula C16H16N6O2S2 (387, M-1), and the base peak was found in the spectrum at m/z 77
(100%), which is characteristic for phenyl group (see Chart 1, Supplemental Materials).

214
H. M. ALY
Scheme 2
Thiosemicarbazide derivative (3) was exploited as starting material for further function-
alization and heterocyclization. It was planned to investigate the reactivity of thiosemi-
carbazide derivative (3) toward an active methylene compound, where the pyrazole ring
system has important and versatile biological activities.20,21 Thus, when thiosemicarbazide
derivative (3) reacted with acetylacetone, diethylmalonate, and/or ethylacetoacetate, the
dimethylpyrazoline (4), pyrazolindione (5), pyrazolinone (6) derivatives were obtained
(Scheme 2). The structures of pyrazolosulphaphenazole (4–6) were elucidated by elemen-
tal analysis and spectral data. The infrared spectrum of all compounds (4–6) exhibited the
1
disappearance of characteristic bands for NH2 group of the hydrazide (3). The H NMR
spectrum of (4; DMSO-d6) showed new resonances assigned to the 2CH3; proton at δ 1.2
and δ 1.3 provided evidence for 3,5-dimethylpyrazole formation. The infrared spectrum
of (5) showed the following bands: 1751, 1740 (2C O), 1681 (C N), 1384, 1154 (SO2),
and 1070 cm−1(C S). Also, its 1H NMR spectrum (in DMSO-d6) revealed the following
signals: 5.8 (s, 2H, CH2CO pyrazoline), 9.4 (s, 1H, NH), and 10.5 ppm (s, 1H, NHSO2).
The infrared spectrum of compound (6) exhibited the following absorption bands:
3310, 3230 (2NH), 1670 (C O), 1380, 1150 (SO2), and 1093 cm−1 (C S). The 1H NMR
spectrum of (6; DMSO-d6) showed a singlet at δ 1.23 assigned to the CH3 group and singlet
at δ 5.8 assigned to the CH2CO pyrazoline and 5.54, 6.68 (2s, 2H, pyrazole-H), 7.22–7.55
(m, 9H, Ar-H), 8.9 (s, H, NH), 9.9 ppm (s, 1H, NHSO2). The phthalazine derivative (7)
was obtained in a good yield via reaction of thiosemicarbazide derivative (3) with phthalic
anhydride (Scheme 3). The structure of (7) was established via analytical and spectral data
(Table I). Its spectrum showed the following absorption bands: 3210 (NH), 1740, 1733
cm−1(2C O). 1H NMR spectrum of (7) (in DMSO-d6) showed the following signals: 5.5,
6.7 (2s, 2H, pyrazole-H), 7.5–8.3 (m, 15H, Ar-H+NH), and 10.3 ppm (s, H, NHSO2).
The mass spectrum of (7) revealed a molecular ion peak m/z at 518 (M+, 2.77%) with a

PYRAZOLE AND THIENOPYRIMIDINE DERIVATIVES
215
Scheme 3
base peak at 104 (100%). Treatment of thiosemicarbazide derivative (3) with ammonium
thiocyanate in ethanol in the presence of concentrated hydrochloric acid afforded the
thiourea derivative (8) after cooling of the filtrated product, while 1,2,4-triazol benzene-
sulfonamide derivative (9) was separated while hot. The structure of compounds (8) and (9)
are supported by their elemental analysis and spectral data. Infrared spectrum of compound
(8) showed the presence of an absorption band at 3300, 3330 cm−1, which is characteristic
for the NH2 functional group in addition to absorption bands due to NH group, 1378, 1165
(SO2), and 1067, 1089 cm−1 (2C S). 1H NMR spectrum of (8) (in DMSO-d6) showed the
following signals: 5.3, 6.5 (2s, 2H, pyrazole-H), 7.42–8.0 (m, 10H, Ar-H+NH), 9.8, 9.9(2s,
2H, 2NH), 10.6 (s, H, NHSO2), and 11.0 ppm (s, H, NH2). Also, its mass spectrum afforded
a molecular ion peak m/z at 449 (M+2, 24.98%) in addition to the base peak at m/z 56
1
(100%). H NMR spectrum of (9) (in DMSO-d6) showed the following signals: 5.3, 6.4
(2s, 2H, pyrazole-H), 7.6–8.2 (m, 10H, Ar-H+NH), and 10.5 ppm (s, H, NHSO2). Its mass
spectrum furnished a molecular ion peak corresponding to the formula C17H15N7O2S2 at
414 (M+1, 31.7%) and the base peak was found in the spectrum m/z at 104 (100%). The
formation of 1,2,4-triazol benzenesulfonamide derivative (9) is assumed to proceed via the
formation of thiourea derivative (8), followed by intramolecular cyclization through initial
nucleophilic attack of amino group to C S followed by intramolecular cyclization via
elimination of hydrogen sulfide.
Cyclocondensation of isothiocyanate derivative (2a) with 2-mercaptoacetic acid in re-
fluxing acetic acid to furnish 2-thioxothiazolidine derivative (10) (Scheme 4). The structure
of (10) was established via analytical and spectral data. Its spectrum showed the following
absorption bands: 3222 (NH), 1740 cm−1 characteristic for the C O functional group of
thiazolidinone moiety and 1093 cm−1 (C S). Also, its 1HNMR spectrum revealed a signal
at δ 4.2 assigned to the -CH2 of thiazolidinone moiety and multiplet at δ 7.2–8.1 ppm
assigned to aromatic protons and SO2NH. Also, mass spectrum furnished a molecular ion
peak m/z at 430 (M+, 28%), and the base peak was found in the spectrum m/z at 52 (100%).
The formation of thiazolidinone (10) is assumed to proceed through the initial
nucleophilic attack of the mercapto group to the thiocarbanyl moiety of the isothio-
cyanate followed by intramolecular cyclization via dehydration. The reactivity of isoth-
iocyanates (2a,b) towards some nitrogen nucleophiles was investigated. Thus, interaction
of isothiocyanatosulfonamides (2a,b) with 2-amino-4,5-dimethyl-3-thio-phenecarboxylic
acid ethyl ester (11) and 4-acetyl-2-amino-5-methyl-3-thio-phenecarboxylic acid methyl
ester (14) furnished dimethyl thiophenecarboxylate derivative (12a,b) and methylthiophene

216
H. M. ALY
Scheme 4
carboxylate derivative (15a,b) rather than the expected products (13a,b) and (16a,b), which
were ruled out on the basis of analytical and spectral data (Scheme 5). The structures of
(12a,b) and (15a,b) were supported via analytical and spectral data (Table I). The infrared
spectrum of compound (12a) displayed the absence of NCS functional group and showed
the following absorption bands: 3330, 3243, 3236 (3NH), 3165 (CH-arom.), 2987 (CH-
aliph.), 1775 (C O), 1545 (C N), 1350, 1165 (SO2), 1063 cm−1 (C S). Also, its 1H NMR
spectrum (in DMSO-d6) revealed the following signals: 0.87, 1.2 (2s, 6H, 2CH3), 1.3 (t,
3H, CH3), 4.0 (q, 2H, CH2), 5.6, 6.6 (2s, 2H, pyrazole-H), 7.5–7.9 (m, 10H, Ar-H+NH),
8.0 (s, H, NH), and 11.1 ppm (s, H, NHSO2). The infrared spectrum of compound (12b)
exhibited the following absorption bands: 3494, 3242, 3105 (3NH), 2985 (CH-aliph.),
1759(C O), 1534 (C N), 1321, 1155 (SO2), 1069 cm−1 (C S). Its 1H NMR spectrum (in
DMSO-d6) revealed the following signals: 0.9, 1.1(2s, 6H, 2CH3), 1.30 (t, 3H, CH3), 4.10
(s, 3H, OCH3), 4.2 (q, 2H, CH2), 7.1–7.5 (m, 5H, Ar-H+NH), 8.0 (s, H, NH), 9.9 ppm
(s, H, NHSO2). The IR spectrum of (15a) revealed the absorption bands at 3330, 3207,
3199 (3NH), 3168 (CH-arom.), 2996 (CH-aliph.), 1775, 1696 (2C O), 1598 (C N), 1376,
1166 (SO2), 1059 cm−1 (C S). Its 1H NMR spectrum (in DMSO-d6) revealed the follow-
ing signals: 0.89 (s, 3H, CH3), 1.2 (t, 3H, CH3), 3.3 (s, 3H, COCH3), 4.1 (q, 2H, CH2),
5.8, 6.4 (2s, 2H, pyrazole-H), 7.4–7.9 (m, 11H, Ar-H+2NH), 10.9 (s, H, NHSO2). The IR
spectrum of (15b) exhibited absorption bands at 3384–3204 (br, 3NH), 3015 (CH arom.),
2976 (CH-aliph.), 1736, 1685 (2C O), 1311, 1146 (SO2), and 1067 cm−1 (C S). Also,
1
its H NMR spectrum (in DMSO-d6) revealed the following signals: 1.0 (s, 3H, 2CH3),
1.2 (t, 3H, CH3), 3.4 (s, 3H, COCH3), 4.14 (s, 3H, OCH3), 4.2 (q, 2H, CH2), 7.4–7.9
ppm (m, 7H, Ar-H+3NH). Alternatively, treatment of 4-isothiocyanato-N-(1-phenyl-1H-
pyrazol-5-yl)benzene- sulfonamide (2a) with 1,1’-(2-amino-5-methyl-thiophene-3,4-diyl)
diethanone (17) yielded thienopyrimidine derivative (18) and eliminated the other possible
structure (19) on the basis of analytical and spectral data (Scheme 5). Its infrared spectrum
exhibited the following absorption bands: 3243 (NH), 3134 (CH-arom.), 2976 (CH-aliph.),
1
1715 (C O), 1565 (C N), 1366, 1145 (SO2), 1057 cm−1 (C S) (Table I). Its H NMR
spectrum (in DMSO-d6) revealed the following signals: 0.89, 1.1 (2s, 6H, 2CH3), 3.4 (s,
3H, COCH3), 5.54, 6.59 (2s, 2H, pyrazole-H), 7.5–7.9 (m, 10H, Ar-H+NH), 10.5 ppm (s,
H, NHSO2). The mass spectrum of compound (18) showed the molecular ion peak m/z at
537 (M+, 18.60%), and the base peak was found in the spectrum m/z at 130 (100%).

PYRAZOLE AND THIENOPYRIMIDINE DERIVATIVES
217
Scheme 5
Antitumor Evaluation and Discussion
Doxorubicin, the reference drug used in this study, is one of the most effec-
tive antitumor agents that is used to produce regression in acute leukemia, Hodgkin’s
disease, and other lymphomas. The novel synthesized compounds (3,9,15a,15b, and
18) were evaluated in the MCF7 (Breast) cell line (see the Supplemental Materials
online, Table III).
EXPERIMENTAL
All melting points are uncorrected and were determined on a Stuart melting point
apparatus. IR spectrawererecordedonaShimadzu-440IRspectrophotometer using theKBr

218
H. M. ALY
Table II Characterization data for newly synthesized compounds (2a–18)
Elemental Analyses Calculated/(Found).
C% H% N%
Compd. No. Mp (◦C) Yield (%) Mol. Formula (Mol. Wt)
2a
2b
3
4
5
6
7
8
9
10
12a
12b
15a
15b
18
118–120
148–150
135–137
158–160
205–207
230–232
194–196
142–144
289–290
158–160
228–230
180–182
210–211
148–150
244–246
85
90
79
77
83
75
80
82
75
83
85
69
81
76
39
C16H12N4O2S2 (356)
10H8N4O3S3 (328)
C16H16N6O2S2 (388)
53.92(53.60) 3.39(3.00) 15.72(15.90)
36.57(36.30) 2.46(2.70) 17.06(17.40)
49.47(49.20) 4.15(4.50) 21.63(21.30)
55.73(55.53) 4.45(4.15) 18.57(18.67)
49.99(50.29) 3.53(3.63) 18.41(18.21)
52.85(52.55) 3.99(4.09) 18.49(18.69)
55.59(55.99) 3.50(3.80) 16.21(16.01)
45.62(45.32) 3.83(3.93) 21.91(21.61)
49.38(49.58) 3.66(3.86) 23.71(23.31)
50.22(50.52) 3.28(3.08) 13.01(13.31)
54.03(53.73) 4.53(4.33) 12.60(12.40)
43.25(43.15) 4.01(3.01) 13.27(12.87)
53.50(53.70) 4.32(4.42) 13.71(14.01)
43.23(43.53) 3.81(4.01) 12.60(12.70)
55.85(55.55) 4.31(4.11) 13.03(13.33)
C
C
C
C
C
C
C
C
C
C
C
C
C
21H20N6O2S2 (452)
19H16N6O4S2 (456)
20H18N6O3S2 (454)
24H18N6O4S2 (518)
17H17N7O2S3 (447)
17H15N7O2S2 (413)
18H14N4O3S3 (430)
25H25N5O4S3 (555)
19H21N5 O5S4 (527)
27H25N5O5S3 (583)
20H21N5O6S4 (555)
25H23N5O3S3 (537)
technique (Shimadzu, Japan). 1H NMR spectra were measured on a Bruker proton NMR-
Avance 300 (300MHz, spectrometer), in DMSO-d6 as a solvent, using tetramethylsilane
(TMS) as an internal standard. The mass spectra were performed by Hewlett Packard Model
MS-5988 spectrometer. Elemental analyses were carried out at the Microanalytical Unit,
Faculty of Science, Cairo University.
4-Isothiocyanato-N-(1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide
(2a) and 4-Isothiocyanato-N-(4-methoxy-1,2,5-thiadiazol-3-yl)
benzenesulfonamide (2b)
Sulfonamide derivative 1a,b (0.01 mol) were dissolved in H2O (200 mL) containing
concentrated HCl (50 mL). To this, CSCl2 (0.012 mol) was added in one portion. Stirring
was begun immediately and continued until all of the red color of CSCl2 had disappeared
(1 h), and the product was precipitated as white crystals. The resulting solid was filtered
off, dried, and recrystallized from acetone to give 2a,b, respectively (Table II).
N-(4-(N-(1-Phenyl-1H-pyrazol-5yl)sulfamoyl)phenyl)
hydrazinecarbothioamide (3)
Hydrazine hydrate and/or phenyl hydrazine (0.01 mol) was added to a solution of 2a
(0.01 mol) in ethanol (50 mL). The reaction mixture was stirred for 3 h, during which time
a white precipitate formed. The product was recrystallized from ethanol to give 3 (Table II).
3,5-Dimethyl-N-(4-(N-(1-phenyl-1H-pyrazol-5-yl)sulfamoyl)phenyl)-
1H-pyrazole-1-carbothioamide (4)
A mixture of 3 (0.01 mol) and acetylacetone (0.01 mol) in absolute ethanol (50 mL)
was heated under reflux for 7 h. The reaction mixture was cooled, and the precipitate formed
was filtered off then recrystallized from ethanol to give 4 (Table II).

PYRAZOLE AND THIENOPYRIMIDINE DERIVATIVES
219
3,5-Dioxo-N-(4-(N-(1-phenyl-1H-pyrazol-5-yl)sulfamoyl)phenyl)pyrazolidine-
1-carbothioamide (5)
A mixture of 3 (0.01 mol) and diethylmalonate (0.01 mol) in absolute ethanol
(50 mL) was heated under reflux for 7 h. The reaction mixture was cooled, and the
precipitate formed was filtered off then recrystallized from ethanol to give 5 (Table II).
3-Methyl-5-oxo-N-(4-(N-(1-phenyl-1H-pyrazol-5-yl)sulfamoyl)phenyl)-4,
5-dihydro-pyrazole-1-carbothioamide (6)
A mixture of 3 (0.01 mol) and ethyl acetoacetate (0.01 mol) in absolute ethanol
(50 mL) was heated under reflux for 7 h. The reaction mixture was cooled, and the
precipitate formed was filtered off then recrystallized from ethanol to give 6 (Table II).
1,4-Dioxo-N-(4-(N-(1-phenyl-1H-pyrazol-5-yl)sulfamoyl)phenyl)
-3,4-dihydro-phthalazine-2(1H)-carbothioamide (7)
A mixture of 3 (0.01 mol) in acetic acid and phthalic anhydride (0.01 mol) was added.
The reaction mixture was then heated under reflux for 7 h, and the precipitate formed was
filtered off then recrystallized from acetic acid to give 7 (Table II).
N1-(4-(N-(1-Phenyl-1H-pyrazol-5-yl)sulfamoyl)phenyl)hydrazine-1,2-
bis(carbothio-amide) (8) and N-(1-Phenyl-1H-pyrazol-5-yl)-4-(5-thioxo-2,
5-dihydro-1H-1,2,4-triazol-3-ylamino)benzenesulfonamide (9)
A mixture of 3 (0.01mol) and ammonium thiocyanate (0.01mol) in ethanol (50 mL)
containing concentrated hydrochloric acid (4 mL) was refluxed for 13 h. The reaction
mixture was filtered while hot to give compound 9. Compound 8 was obtained after cooling
the filtered reaction mixture and recrystallized from dioxane (Table II).
4-(4-Oxo-2-thioxothiazolidin-3-yl)-N-(1-phenyl-1H-pyrazol-
5-yl)benzenesulfonamide (10)
A mixture of 2a (0.01 mol) and thioglycolic acid (0.01 mol) in dioxane (30 mL)
containing a few drops of triethylamine was heated under reflux for 3 h. The reaction
mixture was then cooled and poured into cold water and acidified with dilute HCl. The
solid product was recrystallized from ethanol to give 10 (Table II).
Ethyl-4,5-dimethyl-2-(3-(4-(N-(1-phenyl-1H-pyrazol-5-yl)sulfamoyl)
phenyl)thio-ureido)thiophene-3-carboxylate (12a) and Ethyl-2-(3-(4-(N-
(4-methoxy-1,2,5-thia-diazol-3-yl)sulfamoyl)phenyl)thioureido)
-4,5-dimethylthiophene-3-carboxylate (12b)
A mixture of isothiocyanatosulfonamides 2a, b (0.01 mol) and ethyl 2-amino-4,5-
dimethylthiophene-3-carboxylate 11 (0.01mol) in dioxane (30 mL) containing a few drops
of triethylamine was heated under reflux for 13 h. The reaction mixture was cooled, and
the solid product was recrystallized from ethanol to give 12a,b, respectively (Table II).

220
H. M. ALY
Ethyl-4-acetyl-5-methyl-2-(3-(4-(N-(1-phenyl-1H-pyrazol-5-yl)sulfamoyl)
phenyl) thioureido)thiophene-3-carboxylate (15a) and Ethyl-4-acetyl-2-
(3-(4-(N-(4-methoxy-1,2,5-thiadiazol-3-yl)sulfamoyl) phenyl) thioureido)
-5-methylthiophene-3-carboxylate (15b)
A mixture of isothiocyanatosulfonamides 2a,b (0.01 mol) and methyl 4-acetyl-2-
amino-5-methylthiophene-3-carboxylate 14 (0.01 mol) in dioxane (50 mL) containing a
few drops of triethylamine was heated under reflux for 15 h. The reaction mixture was then
cooled, and the solid product was recrystallized from ethanol to give 15a, b, respectively
(Table II).
4-(5-Acetyl-4,6-dimethyl-2-thioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3
(4H)-yl)-N-(1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide (18)
A mixture of isothiocyanatosulfonamide 2a (0.01 mol) and 1,1’-(2-amino-5-
methylthiophene-3,4-diyl)diethanone 17 (0.01 mol) in dioxane (50 mL) containing a few
drops of triethylamine was heated under reflux for 13 h. The reaction mixture was cooled,
and the solid product was recrystallized from ethanol to give 18 (Table II).
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