Versatile synthesis of N,S-heterocycles containing the antipyrine moiety

Article abstract of DOI:10.1080/104265090969054

A series of novel sulfide derivatives of expected biological activity were synthesized via the reaction of 4-(chloroacetyl)antipyrine (1) with several sulfur nucleophiles. The quantitatively available 2-aminothiazole derivatives 10 and 11 were coupled wit

Full text of DOI:10.1080/104265090969054

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Versatile Synthesis of N,S-
Heterocycles Containing the
Antipyrine Moiety
E. Abdel-Latif a
a Chemistry Department, University of Mansoura,
Mansoura, Egypt
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Containing the Antipyrine Moiety, Phosphorus, Sulfur, and Silicon and the Related
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Phosphorus, Sulfur, and Silicon, 181:125–139, 2006
Copyright © Taylor & Francis LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090969054
Versatile Synthesis of N,S-Heterocycles Containing
the Antipyrine Moiety
E. Abdel-Latif
University of Mansoura, Chemistry Department, Mansoura, Egypt
A series of novel sulfide derivatives of expected biological activity were synthesized
via the reaction of 4-(chloroacetyl)antipyrine (1) with several sulfur nucleophiles.
The quantitatively available 2-aminothiazole derivatives 10 and 11 were coupled
with pyrazolopyridinyl and aromatic diazonium salts to furnish a new series of
the corresponding pyrazolopyridinylazo and arylazo-thiazole dyes 12 and 13. The
reaction of 4-(cyanoacetyl)antipyrine (14) with phenyl isothiocyanate afforded the
nonisolable adduct 15, which was used as a precursor for the synthesis of poly-
functionally substituted ketene N,S-acetal, dihydrothiazole, and thiazolidinone ring
systems.
Keywords Antipyrine; sulfur nucleophiles; aminothiazole; ball-milling; azo coupling;
phenyl isothiocyanate; ketene N,S-acetal; dihydrothiazole; thiazolidin-5-one
INTRODUCTION
Several classes of organic sulfur compounds are of widespread use
in medicine1−3 and pharmacology (for example, antibacterial4 or
antiinflammatory5 applications). Diverse pharmacological properties
have been associated with antipyrine derivatives. These include
antiinflammatory,6 analgesic,7,8 antidepressant,9 and antipyretic10
properties. It appeared interesting to prepare new sulfur compounds
containing the antipyrine moiety with expected biological activity.
In continuation of our previous studies11,12on the synthesis of a vari-
ety of thiazole derivatives from the readily obtainable and inexpensive
starting materials for the dyeing of polyester fabrics, we report on the
reactivity of 4-(chloroacetyl)-antipyrine (1)13,14 towards various sulfur
and/or nitrogen nucleophiles, including different thiourea derivatives.
The work also involved the addition of 4-(cyanoacetyl)-antipyrine (14)14
to phenyl isothiocyanate and has resulted in the formation of a variety
Received October 16, 2004; in final form January 19, 2005.
Address correspondence to E. Abdel-Latif, University of Mansoura, Chemistry
Department, Faculty of Science, Mansour, Egypt. E-mail:ehabattia00@gmx.net
125

126
E. Abdel-Latif
of ketene N,S-acetal, dihydrothiazole, and thiazolidinone derivatives in
which the antipyrine moiety is incorporated.
RESULTS AND DISCUSSION
Compound 1 was reacted with various sulfur nucleophile derivatives,
e.g., O-ethyl xanthic acid potassium salt, 4,5-dihydrothiazole-2-thiol,
and pyrimidine-2-thiol in acetone in the presence of anhydrous potas-
sium carbonate as a catalyst to afford the corresponding sulfide deriva-
tives 2, 3, and 4, respectively. The structure of the latter products was
confirmed on the basis of their correct elemental analysis and spectral
data (Scheme 1).
SCHEME 1
Similarly,
compound
1
reacted
with
4,6-dimethyl-2-
mercaptonicotinonitrile to yield the corresponding sulfide derivative
5 in good yield. The structure of compound 5 was assigned by means

Versatile Synthesis of N,S-Heterocycles
127
of its elemental analysis and spectral properties. Also, compound 5
underwent cyclization on heating in a solution of ethanol containing
sodium ethoxide to afford the corresponding thieno[2,3-b]pyridine
derivative 6. The structure of 6 was established on the basis of
itselemental analysis and spectral data.
Compound 1 was allowed to react with 2-aminobenzothiazole in boil-
ing ethanol to give the imidazo[2,1-b]benzothiazole derivative 7. Com-
pound 7 was assigned as the reaction product in accordance with its
elemental analysis and spectral data.
2-Aminothiazoles are useful precursors for the synthesis of many
important heterocyclic compounds, e.g., thiazole-pyrimidinones and –
imidazoles as well as more involved polycondensed N,S-heterocycles.
The chemistry (syntheses and reactions) of 2-aminothiazole derivatives
was covered by our recent review.15
The syntheses of 2-amino-4-substituted-thiazoles are most easily ac-
cessible by various approaches, and even waste-free, solid-state re-
actions have been developed.16,17 The waste-free, solid-state reaction
could be applied to 4-(chloroacetyl) antipyrine (1) and various thiourea
derivatives 8 and 9. The aminothiazole products 10 and 11 could
be obtained with a 100% yield from stoichiometric reactions by ball-
milling, followed by washings with Na2CO3 solutions (Scheme 2). This
remarkable 3-cascade reaction of substitution, cyclization, and dehy-
dration proceeds again16 in the solid state.
SCHEME 2

128
E. Abdel-Latif
The reactivity of thiazolyl amine derivatives 10a–d was tested to-
wards a coupling reaction with 4,6-dimethylpyrazolo[3,4-b]pyridine-
3-diazonium nitrate hydrate18 to afford the corresponding 5-
(dimethylpyrazolo[3,4-b]pyridin-3-yl-azo)thiazole-2-yl amines 12a–d.
Moreover, thiazol-2-yl amine 11a, when coupled with a variety of aro-
matic diazonium salts in ethanol buffered with sodium acetate, yielded
the corresponding 5-arylazo-thiazol-2-yl amines 13a–c in good yields.
The molecular structures of 12a–d and 13a–c were secured by spectral
data.
4-(Cyanoacetyl)antipyrine (14) was prepared previously by the treat-
ment of 1 with sodium cyanide in ethanol as a polar solvent.14 The ad-
dition of 14 to an equimolar amount of phenyl isothiocyanate in DMF
containing potassium hydroxide afforded the potassium sulfide salt 15
that was not isolated. Subsequent treatment of the salt 15 with methyl
iodide afforded the corresponding ketene N,S-acetal 16 (Scheme 3).
SCHEME 3

Versatile Synthesis of N,S-Heterocycles
129
Heterocyclization of 15 was achieved by the reaction with α-
halogenated ketone, e.g., phenacyl bromide. The dihydrothiazole
derivative 17 was obtained. The molecular structure of 17 was con-
firmed by analytical and spectral data.
On the other hand, the in situ cyclization of 15 with chloroacetyl
chloride afforded the corresponding thiazolidin-5-one derivative 18. The
reactivity of the methylene group in compound 18 was tested toward
the azo coupling reaction19 with diazonium salts. Thus, an equimolar
amount of p-tolyl diazonium chloride at 0–5◦C reacted with compound
18 to yield the corresponding monohydrazono derivative 19.
EXPERIMENTAL
Melting points were determined with a Gallenkamp melting point ap-
paratus (capillary method) and were uncorrected. Elemental analyses
were carried out at the Microanalytical Unit of the Faculty of Science,
Cairo University, and all compounds gave satisfactory elemental anal-
yses. IR spectra (KBr) were recorded with a Mattson 5000 FTIR spec-
trometer (not all frequencies are reported). The 1H NMR and 13C NMR
spectra were acquired using a Bruker WP 300 spectrometer at 300
MHz (1H) or 75.5 MHz (13C; in broad-band mode). Mass spectra were
obtained with a Finnigan MAT 212 instrument by an electron impact
at 70 eV.
General Procedure for the Synthesis of Sulfide Derivatives
(2–5)
A mixture of 1 (1.32 g, 5.0 mmol), the corresponding thiol deriva-
tive (5.0 mmol) (namely O-ethyl xanthic acid potassium salt,
4,5-dihydrothiazole-2-thiol, pyrimidine-2-thiol, and 4,6-dimethyl-
2-mercaptonicotinonitrile), and anhydrous potassium carbonate
(0.35 g, 2.5 mmol) in acetone (30 mL) was refluxed for 4 h. The
excess acetone was evaporated under reduced pressure. The residue
was washed with water and recrystallized from the appropriate
solvent.
Dithiocarbonic Acid S-(2-antipyrinyl-2-oxo-ethyl) O-Ethyl Ester
(2)
Yellow crystals, yield 72%, m.p. 95–96◦C (EtOH). IR (cm−1): 3050, 2980,
2924, 1679, 1640, 1593, 1524, 1486, 1455, 1408, 1376, 1313, 1235,
1
1117, 1082, 1044, 763, 717. H NMR (CDCl3) δ/ppm:1.40 (t, J = 7.15
Hz, 3H, CH3), 2.65 (s, 3H, CH3), 3.35 (s, 3H, CH3), 4.65 (q, J = 7.15

130
E. Abdel-Latif
Hz, 2H, CH2), 4.70 (s, 2H, CH2), 7.35–7.55 (m, 5H, Ar-H). 13C NMR
(CDCl3)δ/ppm: 12.36, 13.64, 33.40, 44.98, 69.99, 104.84, 126.75 (2C),
128.83, 129.58 (2C), 133.39, 155.34, 163.61, 187.84, 213.95. Anal. calcd.
for C16H18N2O3S2 (350.46): C, 54.83; H, 5.18; N, 7.99. Found: C, 54.92;
H, 5.22; N, 7.94.
4-[2-(4,5-Dihydrothiazol-2-ylsulfanyl)acetyl]antipyrine (3)
Yellow crystals, yield 70%, m.p. 184–185◦C (EtOH). IR (cm−1): 3042,
2917, 1652, 1635, 1568, 1490, 1455, 1410, 1374, 1339, 1306, 1264,
1
1156, 1087, 969, 920, 766, 720. H NMR (CDCl3) δ/ppm: 2.65 (s, 3H,
CH3), 3.35 (s, 3H, CH3), 3.40 (t, J = 8.20 Hz, 2H, CH2), 4.20 (t, J =
8.20 Hz, 2H, CH2), 4.65(s, 2H, CH2), 7.2–7.50 (m, 5H, Ar-H). 13C NMR
(CDCl3) δ/ppm: 12.39, 33.42, 35.68, 42.19, 64.34, 104.67, 126.66 (2C),
128.72, 129.54 (2C), 133.46, 155.57, 163.59, 164.74, 188.61. Anal. calcd.
for C16H17N3O2S2 (347.46): C, 55.31; H, 4.93; N, 12.09. Found: C, 55.21;
H, 4.86; N, 12.03.
4-[2-(Pyrimidin-2-ylsulfanyl)acetyl]antipyrine (4)
White crystals, yield 82%, m.p. 235–236◦C (EtOH-DMF mixture, 2:1).
IR (cm−1): 3059, 2908, 1656, 1641, 1593, 1562, 1547, 1525, 1489, 1455,
1416, 1377, 1329, 1318, 1239, 1213, 1189, 1143, 1087, 997, 890, 823, 768,
749, 721. 1H NMR (CDCl3/CF3COOD) δ/ppm: 2.65 (s, 3H, CH3), 3.40 (s,
3H, CH3), 4.75 (s, 2H, CH2), 7.05 (t, 1H, Ar-H), 7.30–7.55 (m, 5H, Ar-H),
8.55 (d, 2H, Ar-H). 13C NMR (CDCl3/CF3COOD) δ/ppm: 12.24, 32.92,
40.71, 104.68, 116.70, 128.35 (2C), 130.00 (2C), 130.54, 131.78, 153.10,
157.01 (2C), 163.08, 170.80, 188.59. MS m/z (%): 340 (M+, 94), 307 (18),
244 (9), 215 (100), 189 (38), 125 (14), 106 (22), 56 (61). Anal. calcd. for
C17H16N4O2S (340.40): C, 59.98; H, 4.74; N, 16.46. Found: C, 59.85; H,
4.79; N, 16.40.
2-[2-Antipyrinyl-2-oxo-ethylsulfanyl]-4,6-
dimethylnicotinonitrile (5)
Yellow crystals, yield 78%, m.p. 187–188◦C (EtOH). IR (cm−1): 3063,
2894, 2218, 1666, 1641, 1578, 1510, 1493, 1409, 1367, 1264, 1087, 988,
1
872, 770, 723, 616. H NMR (CDCl3) δ/ppm: 2.40 (s, 6H, 2CH3), 2.65
(s, 3H, CH3), 3.35 (s, 3H, CH3), 4.80 (s, 2H, CH2), 6.75 (s, 1H, pyridine
H-5), 7.30–7.55 (m, 5H, Ar-H). 13C NMR (CDCl3) δ/ppm: 12.41, 20.00,
24.53, 33.49, 39.64, 104.72, 105.31, 115.19, 119.78, 126.68 (2C), 128.75,
129.60 (2C), 133.63, 151.61, 155.64, 161.06, 161.53, 163.83, 189.38. MS
m/z (%): 392 (M+, 8), 271 (22), 215 (100), 189 (11), 106 (14), 77 (21), 56

Versatile Synthesis of N,S-Heterocycles
131
(51). Anal. calcd. for C21H20N4O2S (392.47): C, 64.27; H, 5.14; N, 14.28.
Found: C, 64.18; H, 5.07; N, 14.21.
Synthesis of 3-Amino-2-(antipyrinylcarbonyl)-4,6-dimethyl-
thieno [2,3-b] pyridine (6)
The nicotinonitrile derivative 5 (1.96 g, 10.0 mmol) was added to a
solution of sodium ethoxide (from 0.23 g Na, 10.0 mmol) in absolute
ethanol (30 mL). The solution was refluxed for 2 h, left to cool, and
diluted with cooled water (50 mL). The solid obtained was filtered and
recrystallized from ethanol.
Yellow crystals, yield 66%, m.p. 254–255◦C (EtOH). IR (cm−1): 3406,
3327, 2975, 1641, 1620, 1588, 1555, 1471, 1445, 1376, 1354, 1302, 1267,
1244, 1110, 1017, 966, 849. 1H NMR (CDCl3/CF3COOD) δ/ppm: 2.40 (s,
6H, 2CH3), 2.65 (s, 3H, CH3), 3.35 (s, 3H, CH3), 6.90 (s, 1H, pyridine H-
5), 7.40–7.60 (m, 5H, Ar-H). 13C NMR (CDCl3/CF3COOD) δ/ppm: 12.48,
20.20, 23.28, 33.66, 95.72, 107.43, 121.98, 122.33, 127.21 (2C), 129.43,
129.79 (2C), 132.84, 144.66, 149.30, 154.58, 160.34, 160.87, 163.83,
186.47. Anal. calcd. for C21H20N4O2S (392.47): C, 64.27; H, 5.14; N,
14.28. Found: C, 64.36; H, 5.21; N, 14.18.
Synthesis of 2-Antipyrinyl-imidazo[2,1-b]benzothiazole (7)
A mixture of 1 (1.32 g, 5.0 mmol) and 2-aminobenzothiazole (0.75 g,
5.0 mmol) was refluxed in absolute ethanol (30 mL) for 8 h. The pre-
cipitate upon cooling was collected by filtration and recrystallized from
ethanol.
White crystals, yield 74%, m.p. 216–217◦C (EtOH). IR (cm−1): 3041,
2939, 1644, 1591, 1595, 1457, 1311, 1268, 1213, 1134, 755, 719. 1H NMR
(DMSO-d6) δ/ppm: 2.70 (s, 3H, CH3), 3.30 (s, 3H, CH3), 7.30–7.55 (m,
10H, 9Ar-H and olefin C CH). 13C NMR (DMSO) δ/ppm: 12.35, 33.29,
104.72, 123.87 (2C), 124.79, 126.89 (2C), 127.31, 129.05, 129.67 (2C),
133.21, 135.46, 141.22, 144.71, 152.73, 155.21, 157.52, 163.37. MS m/z
(%): 360 (M+, 100), 215 (48), 174 (22), 150 (82), 119 (56), 93 (60), 77
(90), 56 (78). Anal. calcd. for C20H16N4OS (360.43): C, 66.65; H, 4.47; N,
15.54. Found: C, 66.54; H, 4.41; N, 15.47.
Synthesis of Aminothiazole Derivatives (10) and (11)
A mixture of 1 (2.0 mmol) and thiourea derivative 8 or 9 (2.0 mmol) was
ball-milled at 70◦C for 60 min. After drying at 0.01 bar at 80◦C, quan-
titative yields of 10.HCl or 11.HCl were obtained. The free bases 10
and 11 were obtained by washing the fine powder of the hydrochloride

132
E. Abdel-Latif
with 5% Na2CO3 solution, followed by water and drying at 80◦C in a
vacuum.
2-Amino-4-antipyrinylthiazole (10a)
White crystals, yield 100%, m.p. 235–236◦C; lit.17,20 m.p. 235◦C. IR
1
(cm−1): 3327, 3151, 2956, 1636, 1593. H NMR (DMSO-d6)δ/ppm: 2.70
(s, 3H, CH3), 3.15 (s, 3H, CH3), 6.55 (s, 2H, NH2), 7.15 (s, 1H, thiazole
H-5), 7.25–7.50 (m, 5H, Ar-H). 13C NMR (DMSO) δ/ppm: 10.80, 33.86,
100.44, 102.71, 122.46 (2C), 124.80, 127.31 (2C), 133.58, 141.00, 150.58,
162.26, 165.62. Anal. calcd. for C14H14N4OS (286.35): C, 58.72; H, 4.93;
N, 19.57. Found: C, 58.83; H, 4.99; N, 19.64.
4-Antipyrinyl-2-(methylamino)thiazole (10b)
White crystals, yield 100%, m.p. 182–183◦C. IR (cm−1): 3268, 2890,
1636, 1563, 1494, 1455, 1397, 1329, 1245, 1152, 1066, 907, 831, 788. 1H
NMR (CDCl3) δ/ppm: 2.70 (s, 3H, CH3), 3.00 (s, 3H, CH3), 3.15 (s, 3H,
CH3), 5.25 (s, 1H, NH), 7.30–7.55 (m, 6H, Ar-H and thiazole H-5). 13C
NMR (CDCl3) δ/ppm: 12.53, 31.98, 35.61, 103.22, 105.46, 124.19 (2C),
126.54, 129.04 (2C), 135.25, 143.04, 152.26, 164.44, 169.29. MS m/z (%):
300 (M+, 100), 285 (10), 226 (10), 208 (22), 167 (14), 150 (15), 77 (10), 56
(25). HR-MS calcd. for C15H16N4OS: 300.1044, found 300.1044. Anal.
calcd. for C15H16N4OS (300.38): C, 59.98; H, 5.37; N, 18.65. Found: C,
59.93; H, 5.33; N, 18.69.
4-Antipyrinyl-2-(phenylamino)thiazole (10c)
White crystals, yield 100%, m.p. 252◦C; lit.21 m.p. 247–248 ◦C. IR (cm−1):
3261, 3040, 1618, 1532, 1495, 1446, 1411, 1312, 1251, 844, 749, 696. 1H
NMR (DMSO-d6) δ/ppm: 2.75 (s, 3H, CH3), 3.15 (s, 3H, CH3), 6.90–
7.70 (m, 11H, Ar-H and thiazole H-5), 10.15 (s, 1H, NH). 13C NMR
(DMSO) δ/ppm: 12.17, 35.18, 102.27, 103.06, 116.76 (2C), 121.02, 124.25
(2C), 126.53, 128.87 (2C), 129.01 (2C), 135.01, 141.23, 142.89, 152.09,
162.32, 163.38. Anal. calcd. for C20H18N4OS (362.45): C, 66.28; H, 5.01;
N, 15.46. Found: C, 66.35; H, 5.06; N, 15.42.
4-Antipyrinyl-2-(diphenylamino)thiazole (10d)
White crystals, yield 100%, m.p. 205–206◦C. IR (cm−1): 3146, 3061,
1651, 1593, 1505, 1451, 1408, 1333, 1303, 1233, 1151, 1066, 813, 768. 1H
NMR (CF3COOD) δ/ppm: 2.50 (s, 3H, CH3), 3.45 (s, 3H, CH3), 7.25–7.70
(m, 16H, Ar-H and thiazole H-5). 13C NMR (CF3COOD) δ/ppm: 10.75,

Versatile Synthesis of N,S-Heterocycles
133
32.99, 95.26, 126.04 (4C), 129.12 (2C), 129.94, 130.38, 130.92, 131.28
(2C), 131.37 (2C), 131.90 (4C), 133.42 (2C), 141.44, 147.69, 158.71,
170.92. MS m/z (%): 438 (M+, 100), 346 (8), 289 (10), 219 (20), 77 (12), 56
(15). HR-MS calcd. for C26H22N4OS: 438.1514, found 438.1508. Anal.
calcd. for C26H22N4OS (438.54): C, 71.21; H, 5.06; N, 12.78. Found: C,
71.32; H, 5.13; N, 12.72.
2-(4-Antipyrinyl-thiazol-2-ylamino)-N,N-dimethylacetamide
(11a)
White crystals, yield 100%, m.p. 212–213◦C. IR (cm−1): 3326, 3134,
2936, 1661, 1640, 1594, 1540, 1476, 1408, 1371, 1332, 1255, 1147, 1104,
1067, 1036, 790, 745, 697, 635, 587.1H NMR (CDCl3)δ/ppm: 2.70 (s, 3H,
CH3), 3.00 (s, 6H, 2CH3), 3.10 (s, 3H, CH3), 4.15 (s, 2H, CH2), 6.20 (s, 1H,
NH), 7.20–7.45 (m, 6H, Ar-H and thiazole H-5). 13C NMR (CDCl3)δ/ppm:
12.52, 35.59 (2C), 35.78, 46.01, 103.47, 105.29, 124.16 (2C), 126.53,
129.02 (2C), 135.19, 142.70, 152.18, 164.32, 166.70, 167.88. MS m/z
(%): 371 (M+, 21), 299 (100), 271 (4), 213 (5), 151 (5), 72 (20), 56 (22).
HR-MS calcd. for C18H21N5O2S: 371.1416, found 371.1417. Anal. calcd.
for C18H21N5O2S (371.46): C, 58.20; H, 5.70; N, 18.85. Found: C, 58.06;
H, 5.78; N, 18.80.
2-(4-Antipyrinyl-thiazol-2-ylamino)-N,N-diethylacetamide
(11b)
White crystals, yield 100%, m.p. 165–166◦C. IR (cm−1): 3259, 3120,
3040, 2990, 2936, 1661, 1641, 1593, 1548, 1530, 1489, 1460, 1404, 1349,
1
1318, 1288, 1245, 1152, 1098, 1066, 790, 750, 698, 647, 592. H NMR
(CDCl3) δ/ppm: 1.15 (t, J = 7.00 Hz, 3H, CH3), 1.20 (t, J = 7.00 Hz, 3H,
CH3), 2.70 (s, 3H, CH3), 3.10 (s, 3H, CH3), 3.30 (q, J = 7.00 Hz, 2H, CH2),
3.40 (q, J = 7.00 Hz, 2H, CH2), 4.15 (s, 2H, CH2), 6.20 (s, 1H, NH), 7.20–
7.50 (m, 6H, Ar-H and thiazole H-5). 13C NMR (CDCl3) δ/ppm: 12.54,
12.90, 14.00, 35.58, 40.49, 40.93, 45.94, 103.50, 105.32, 124.18 (2C),
126.55, 129.03 (2C), 135.17, 142.61, 152.16, 164.33, 166.86, 166.96. MS
m/z (%): 399 (M+, 72), 372 (56), 299 (100), 271 (10), 213 (11), 151(6), 77
(16), 56 (64). Anal. calcd. for C20H25N5O2S (399.51): C, 60.13; H, 6.31;
N, 17.53. Found: C, 60.08; H, 6.28; N, 17.55.
Synthesis of 4,6-Dimethylpyrazolo[3,4-b]pyridin-3-ylazo)
thiazoles(12a–d)
A solution of 4,6-dimethylpyrazolo[3,4-b]pyridine-3-diazonium nitrate
hydrate (5.0 mmol, 1.27 g in 10 mL H2O) was added with continuous

134
E. Abdel-Latif
stirring to a cold (0–5◦C) solution of the aminothiazole derivatives 10
(5.0 mmol) in pyridine (30 mL). The reaction mixture was allowed to
rest at (0–5◦C) for 2 h, was diluted with water, and then the solid was
collected by filtration. The pyrazolopyridinylazo-thiazoles 12a–d thus
obtained were dried and recrystallized from ethanol-DMF mixture (3:1).
2-Amino-4-antipyrinyl-5-(4,6-dimethylpyrazolo[3,4-b]pyridin-
3-ylazo)thiazole (12a)
Red crystals, yield 75%, m.p. 241–241◦C. IR (cm−1): 3281, 3180, 3094,
1612, 1592, 1496, 1416, 1305, 1268, 1198, 1142, 830, 750, 695. 1H NMR
(CDCl3/CF3COOD) δ/ppm: 2.80 (s, 3H, CH3), 3.00 (s, 3H, CH3), 3.15
(s, 3H, CH3), 3.60 (s, 3H, CH3), 7.35–7.75 (m, 6H, Ar-H and pyridine-
H). 13C NMR (CDCl3/CF3COOD) δ/ppm: 13.31, 19.87, 20.22, 33.71,
95.41, 114.72, 120.01, 122.07, 128.88 (2C), 129.90, 131.24 (2C), 133.06,
136.14, 139.45, 143.92, 149.97, 151.41, 157.23, 160.52, 170.09. MS m/z
(%): 459 (M+, 10), 342 (18), 310 (20), 272 (20), 228 (45), 198 (25),
184 (52), 162 (100), 155 (15), 70 (40). Anal. calcd. for C22H21N9OS
(459.53): C, 57.50; H, 4.61; N, 27.43. Found: C, 57.66; H, 4.70; N,
27.40.
4-Antipyrinyl-2-(methylamino)-5-(4,6-dimethylpyrazolo[3,4-b]
pyridin-3-ylazo)-thiazole (12b)
Red crystals, yield 72%, m.p. 270–271◦C. IR (cm−1): 3174, 2938, 1646,
1590, 1498, 1456, 1392, 1283, 1192, 1151, 1081, 1036, 826, 744. 1H NMR
(CDCl3/CF3COOD) δ/ppm: 2.75 (s, 3H, CH3), 2.95 (s, 3H, CH3), 3.10 (s,
3H, CH3), 3.30 (s, 3H, CH3), 3.50 (s, 3H, CH3), 7.30–7.75 (m, 6H, Ar-
H and pyridine-H). 13C NMR (CDCl3/CF3COOD) δ/ppm: 12.99, 19.93,
20.05, 33.40, 33.59, 95.05, 114.14, 120.26, 121.60, 128.62 (2C), 129.58,
130.86 (2C), 132.66, 134.98, 140.85, 143.55, 149.76, 151.06, 156.75,
162.42, 170.05. MS m/z (%): 473 (M+, 82), 343 (100), 300 (32), 210 (36),
162 (65), 93 (35), 56 (42). Anal. calcd. for C23H23N9OS (473.55): C, 58.33;
H, 4.90; N, 26.62. Found: C, 58.41; H, 4.94; N, 26.68.
4-Antipyrinyl-2-(phenylamino)-5-(4,6-dimethylpyrazolo[3,4-b]
pyridin-3-ylazo)-thiazole (12c)
Violet crystals, yield 83%, m.p. 291–292◦C. IR (cm−1): 3256, 3077,
1651, 1569, 1489, 1450, 1301, 1260, 1239, 1148, 833, 751. 1H NMR
(CDCl3/CF3COOD) δ/ppm: 2.80 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.05 (s,
3H, CH3), 3.60 (s, 3H, CH3), 7.40–7.80 (m, 11H, Ar-H and pyridine-H).
13C NMR (CDCl3/CF3COOD) δ/ppm: 13.28, 20.14, 20.36, 33.63, 95.49,

Versatile Synthesis of N,S-Heterocycles
135
114.40, 121.61, 123.32 (2C), 128.75 (2C), 129.66, 130.38, 131.04 (4C),
132.89, 135.02, 135.30, 141.64, 143.41, 149.90, 151.71, 156.34, 159.79,
160.18, 168.66. MS m/z (%): 535 (M+, 10), 507 (20), 475 (17), 362 (22),
343 (100), 310 (25), 272 (22), 228 (52), 184 (65), 155 (25), 70 (60). Anal.
calcd. for C28H25N9OS (535.62): C, 62.79; H, 4.70; N, 23.54. Found: C,
62.86; H, 4.76; N, 23.50.
4-Antipyrinyl-2-(diphenylamino)-5-(4,6-dimethylpyrazolo[3,4-
b] pyridin-3-ylazo)-thiazole (12d)
Red crystals, yield 81%, m.p. 264–265◦C. IR (cm−1): 3089, 2919, 1657,
1591, 1479, 1447, 1411, 1305, 1150, 1024, 828, 756, 694. 1H NMR
(CDCl3/CF3COOD) δ/ppm: 2.55 (s, 3H, CH3), 2.65 (s, 3H, CH3), 3.70 (s,
3H, CH3), 3.30 (s, 3H, CH3), 7.00–7.55 (m, 16H, Ar-H and pyridine-
H). 13C NMR (CDCl3/CF3COOD) δ/ppm: 13.50, 20.05, 20.32, 33.60,
96.03, 114.42, 121.46 (2C), 125.76 (4C), 128.89 (2C), 129.40, 131.06 (2C),
131.50 (4C), 133.08 (2C), 136.54, 143.18, 143.79, 150.01, 152.11, 155.91,
159.66, 160.27, 162.33, 162.75, 169.85. MS m/z (%): 611 (M+, 15), 453
(44), 449 (50), 343 (52), 283 (20), 210 (20), 194 (28), 169 (100), 77 (36).
Anal. calcd. for C34H29N9OS (611.72): C, 66.76; H, 4.78; N, 20.61. Found:
C, 66.62; H, 4.69; N, 20.66.
Synthesis of 2-(4-antipyrinyl-5-arylazo-thiazol-2-ylamino)-
N,N-dimethylacetamides (13a–c)
A solution of sodium nitrite (0.70 g in 10 mL water) was gradually
added to a well-cooled (0–5◦C) solution of the aromatic amine (10.0
mmol) in concentrated HCl (3.0 mL). The diazonium salt solution
was added with continuous stirring to a cold (0–5◦C) solution of the
aminothiazole derivative 11a (10.0 mmol) in ethanol (50.0 mL) and
sodium acetate (4.0 g ). The reaction mixture was allowed to stir at
(0–5◦C) for 2 h, and then the solid was collected by filtration. The ary-
lazothiazoles 13a–c thus obtained, were dried and recrystallized from
ethanol.
2-(4-Antipyrinyl-5-phenylazo-thiazol-2-ylamino)-N,
N-dimethylacetamide (13a)
Red crystals, yield 86%, m.p. 233–234◦C. IR (cm−1): 3294, 2955, 1672,
1650, 1613, 1594, 1536, 1492, 1426, 1402, 1343, 1315, 1267, 1200, 1188,
,1087, 752, 692, 641, 608. 1H NMR (CDCl3)δ/ppm: 2.35 (s, 3H, CH3), 3.00
(s, 6H, 2CH3), 3.15 (s, 3H, CH3), 4.20 (s, 2H, CH2), 6.90 (s, 1H, NH), 7.20–
7.50 (m, 8H, Ar-H), 7.70 (d, 2H, Ar-H). 13C NMR (CDCl3) δ/ppm: 12.94,

136
E. Abdel-Latif
35.40, 35.65, 35.84, 45.38, 105.10, 121.95 (2C), 124.73 (2C), 126.81,
128.88 (2C), 129.08 (2C), 135.01, 141.47, 148.91, 152.84, 154.95, 160.12,
163.17, 167.06, 168.04. MS m/z (%): 475 (M+, 92), 403 (100), 375 (14),
327 (13), 299 (51), 283 (8), 214 (8), 105 (16), 93 (42), 77 (62), 56 (77). Anal.
calcd. for C24H25N7O2S (475.57): C, 60.61; H, 5.30; N, 20.62. Found: C,
60.52; H, 5.34; N, 20.55.
2-(4-Antipyrinyl-5-(p-tolylazo)thiazol-2-ylamino)-N, N-
dimethylacetamide (13b)
Red crystals, yield 88%, m.p. 260–261◦C. IR (cm−1): 3289, 2939, 1674,
1651, 1619, 1596, 1537, 1494, 1456, 1424, 1405, 1335, 1314, 1264, 1210,
1090, 828, 748, 696, 639, 599. 1H NMR (CDCl3/CF3COOD) δ/ppm: 2.30
(s, 3H, CH3), 2.40 (s, 3H, CH3), 2.90 (s, 6H, 2CH3), 3.30 (s, 3H, CH3),
4.10 (s, 2H, CH2), 7.15–7.50 (m, 9H, Ar-H). 13C NMR (CDCl3/CF3COOD)
δ/ppm: 13.06, 21.31, 33.98, 35.62, 35.82, 46.92, 96.42, 122.29 (2C),
127.46 (2C), 129.68 (2C), 129.96 (2C), 132.22, 141.99, 144.78, 148.90,
150.73, 155.76, 161.48, 164.67, 168.14 (2C). MS m/z (%): 489 (M+,
100), 444 (21), 417 (94), 371 (18), 324 (8), 299 (63), 283 (7), 214
(6), 119 (6), 106 (14), 91 (57), 56 (72). Anal. calcd. for C25H27N7O2S
(489.59): C, 61.33; H, 5.56; N, 20.03. Found: C, 61.21; H, 5.47; N,
20.11.
2-(4-Antipyrinyl-5-(p-methoxy-phenylazo)-thiazol-2-ylamino)-
N,N-dimethylacetamide (13c)
Red crystals, yield 77%, m.p. 252–253◦C. IR (cm−1): 3302, 3056, 2935,
1677, 1646, 1619, 1601, 1579, 1531, 1494, 1468, 1421, 1407, 1340,
1
1315, 1253, 1203, 1146, 1088, 1033, 839, 751, 696, 638, 592. H NMR
(CDCl3) δ/ppm: 2.30 (s, 3H, CH3), 2.90 (s, 6H, 2CH3), 3.15 (s, 3H, CH3),
3.80 (s, 3H, CH3), 4.20 (s, 2H, CH2), 6.75 (s, 1H, NH), 6.80 (d, 2H, Ar-H),
7.15–7.40 (m, 5H, Ar-H), 7.60 (d, 2H, Ar-H). 13C NMR (CDCl3)δ/ppm:
12.92, 35.46, 35.63, 35.83, 45.35, 55.43, 105.26, 114.15 (2C), 123.56
(2C), 124.62 (2C), 126.71, 129.06 (2C), 135.08, 141.68, 146.80, 147.16,
154.97, 160.59, 163.26, 167.15, 167.27. Anal. calcd. for C25H27N7O3S
(505.59): C, 59.39; H, 5.38; N, 19.39. Found: C, 59.51; H, 5.44; N,
19.33.
Synthesis of Compounds 16, 17, and 18
To a cold suspension of finely divided KOH (0.56 g, 10.0 mmol) in DMF
(30 mL) were added the cyanoacetyl-antipyrine 14 (2.55 g, 10.0 mmol)
followed by phenyl isothiocyanate (1.20 mL, 0.01 mol). The mixture

Versatile Synthesis of N,S-Heterocycles
137
was stirred at room temperature overnight, and then was treated with
the appropriate halogenated compound (10.0 mmol). The stirring was
continued at room temperature for 8 h. The reaction mixture was poured
into ice-cold water. The resultant solid product was collected by fil-
tration, washed with water, dried, and recrystallized from the proper
solvent.
2-Antipyrinyl-3-methylsulfanyl-3-phenylaminoacrylonitrile
(16)
Yellow crystals, yield 44%, m.p. 173–174◦C (EtOH). IR (cm−1): 3173,
2964, 2106, 1644, 1599, 1556, 1443, 1337, 1266, 1130, 887, 732. 1H NMR
(CDCl3) δ/ppm: 2.55 (s, 3H, CH3), 2.80 (s, 3H, CH3), 3.25 (s, 3H, CH3),
7.10–7.70 (m, 10H, Ar-H), 10.75 (s, 1H, NH). 13C NMR (CDCl3) δ/ppm:
12.30, 18.78, 33.32, 103.56, 110.23, 114.21, 127.11 (2C), 128.49 (2C),
129.00 (3C), 129.60 (3C), 132.84, 135.11, 154.58, 161.39, 163.31, 179.81.
Anal. calcd. for C22H20N4O2S (404.48): C, 65.33; H, 4.98; N, 13.85.
Found: C, 65.43; H, 5.04; N, 13.93.
3-Antipyrinyl-2-(3,4-diphenyl-3H-thiazol-2-ylidene)
-3-oxopropionitrile (17)
Yellow crystals, yield 66%, m.p. 192–193◦C (EtOH). IR (cm−1): 3060,
2843, 2197, 1631, 1606, 1547, 1474, 1449, 1412, 1363, 1320, 1256,
1
1240, 1221, 1156, 1120, 1051, 971, 895, 866, 768, 703, 590. H NMR
(CDCl3/CF3COOD) δ/ppm: 2.80 (s, 3H, CH3), 3.75 (s, 3H, CH3), 7.10–
7.85 (m, 15H, Ar-H), 8.15 (s, 1H, C CH), 8.35 (d, 2H, Ar-H). 13C
NMR (CDCl3/CF3COOD) δ/ppm: 11.25, 34.01, 86.57, 102.81, 123.98,
125.88, 126.29, 126.59, 128.05 (2C), 129.31 (2C), 129.61 (2C), 130.40
(2C), 131.62 (2C), 131.73 (2C), 132.46, 134.96, 135.15, 135.83, 149.02,
152.88, 153.42, 163.07, 170.95. MS m/z (%): 490 (M+, 100), 387 (19), 356
(12), 105 (62), 77 (20). HR-MS calcd. for C29H22N4O2S: 490.1463, found
490.1455. Anal. calcd. for C29H22N4O2S (490.58): C, 71.00; H, 4.52; N,
11.42. Found: C, 71.11; H, 4.61; N, 11.37.
3-Antipyrinyl-3-oxo-2-(5-oxo-3-phenylthiazolidin-2-ylidene)
propionitrile (18)
Yellow crystals, yield 52%, m.p. 244–245◦C (EtOH-CHCl3 mixture, 3:1).
IR (cm−1): 2965, 2209, 1739, 1662, 1614, 1525, 1485, 1414, 1363, 1318,
1227, 1200, 1170, 1132, 1067, 979, 720, 694. 1H NMR (DMSO-d6) δ/ppm:
2.30 (s, 3H, CH3), 3.15 (s, 3H, CH3), 3.85 (s, 2H, CH2), 7.10–7.40 (m, 10H,
Ar-H). 13C NMR (DMSO-d6) δ/ppm: 9.88, 29.77, 32.35, 86.61, 104.78,

138
E. Abdel-Latif
111.76, 124.53 (2C), 126.15, 127.43 (6C), 128.34, 132.62, 133.37, 153.11,
159.78, 167.81, 171.33, 181.96. MS m/z (%): 430 (M+, 15), 388 (4), 356
(5), 311 (7), 215 (100), 188 (25), 143 (10), 106 (10), 77 (27). Anal. calcd.
for C23H18N4O3S (430.48): C, 64.17; H, 4.21; N, 13.01. Found: C, 64.31;
H, 4.28; N, 13.06.
Synthesis of 3-Antipyrinyl-3-oxo-2-[5-oxo-3-phenyl-4-
(p-tolylhydrazono)-thiazolidin-2-ylidene]-propionitrile (19)
A freshly cooled solution of p-tolyldiazonium chloride (prepared by
adding cold sodium nitrite solution [0.35 g in 10 mL H2O] to a cold
suspension of p-toluidine (0.53 g, 5.0 mmol) in 1.5 mL concentrated
HCl) was added with continuous stirring to a cold (0–5◦C) solution of
the thiazolidinone derivative 18 (2.15 g, 5.0 mmol) in pyridine (25 mL).
The reaction mixture was allowed to stir at (0–5◦C) for 2 h, and then
the solid was collected by filtration. The p-tolylazo derivative 19 thus
obtained was dried and recrystallized from ethanol.
Red crystals, yield 64%, m.p. 210–211◦C. IR (cm−1): 3203, 3040, 2942,
2207, 1728, 1664, 1614, 1538, 1489, 1412, 1362, 1208, 1146, 1084, 984,
866. 1H NMR (CDCl3) δ/ppm: 2.25 (s, 3H, CH3), 2.40 (s, 3H, CH3), 3.20
(s, 3H, CH3), 7.00–7.60 (m, 14H, Ar-H), 10.30 (s, 1H, NH). Anal. calcd.
for C30H24N6O3S (548.61): C, 65.68; H, 4.41; N, 15.32. Found: C, 65.60;
H, 4.47; N, 15.29.
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