International Journal of Modern Organic Chemistry, 2012, 1(2): 96-114

International Journal of Modern Organic Chemistry ISSN: 2166-0174

Journal homepage: www.ModernScientificPress.com/Journals/IJOrgChem.aspx Florida, USA
Article
3-Iminobutanenitrile as Building Block for the Synthesis of
Substituted Pyrazolo[1,5-a]pyrimidines with Antitumor and
Antioxidant Activities
M. A. Metwally 1, M. A. Gouda 1, 2, *, Ammar N. Harmal 1, A. M. Khalil 1
1
Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
2
Current correspondence address: Department of Chemistry, Faculty of Science and Arts, Ulla,
Taibah University, KSA.

* Author to whom correspondence should be addressed; E-Mail: dr_mostafa_chem@yahoo.com; Tel.:

+2050-6432235; Fax: +2050-2246781.

Article history: Received 8 July 2012, Received in revised form 11 August 2012, Accepted 12 August
2012, Published 12 August 2012.

Abstract: Iminopropanehydrazonoyl cyanide 4 was obtained by diazotization of

antipyrinyl diazonium salt 2 and 3-iminobutanenitrile (3) in EtOH/AcONa. 3-
Aminopyrazole 5 was obtained by reaction of 4 with hydrazine hydrate in 1,4-dioxane.
Diazodization of 5 afforded the diazonium salt 12 which coupled with pyrazole 7 to give
pyrazolo-pyrimidine 15. Furthermore, compound 5 was used as a key intermediate for the
synthesis of pyrazolopymidines 9-11, 15, 19, 22a, b, 24, 27 and 33-37 via its reaction with
1,3-diketone, halocarbonyl, aryledines and DMF-DMA followed by reaction with active
methylene components. Newly synthesized compounds were screened for their antitumor
and antioxidant activities. The obtained results showed clearly that most of compounds
exhibited good antitumor activities and weak antioxidant activities, while compounds 4 and
22a exhibited broad spectrum of antitumor and antioxidant activities.

Keywords: iminobutanenitrile; antipyrine; pyrazole; pyrazolopyrmidine; antitumor

activity; antioxidant activity.

1. Introduction
It is well known that nitriles are widely used as intermediates for a large number of
heterocyclic compounds. 3-Aminopyrazole compounds can be readily obtained by reaction of nitrile
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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 97

derivatives with hydrazine hydrate [1-5]. 3-Aminopyrazoles are versatile reagents, and extensively
used as synthetic intermediates for the synthesis of poly-substituted fused pyrazolopyrimidine of
potential biological activity [1,6-10]. Antipyrine derivatives are important intermediates that possess
biological and pharmacological activities [11-15]. Moreover, several pyrazole ring systems are
associated with diverse biological activities [16-18], and the biological importance of
pyrazolopyrimidine ring systems is well documented [19-22]. Therefore, it was thought of interest to
combine the above mentioned boilable rings together in a molecular framework to investigate the
additive effect of these rings towards antioxidant and antitumor activities.

2. Materials and Methods

2.1. Instruments

All melting points are in degree centigrade (uncorrected), and determined on Gallenkamp
electric melting point apparatus. The IR spectra were recorded (KBr) on a Mattson 5000 FTIR
Spectrophotometer at the Microanalytical Unit at Faculty of Science, Mansoura University. The 1H-
NMR spectra were carried out on a Varian Spectrophotometer at 300 MHz, using TMS as an internal
reference and DMSO-d6 as solvent at the Microanalytical Center, Cairo University. The mass spectra
were recorded on Shimadzu Qp-2010 plus at the Microanalytical Center, Cairo University. Elemental
analyses (C, H and N) were carried out at the Microanalytical Center of Cairo University, Egypt, and
the results were found to be in good agreement with the calculated values. Biological activity was
carried out in Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Egypt.

2.2. Synthesis

Synthesis of N'-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-imino-propane-
hydrazonoyl cyanide (4)
A well stirred solution of 1 (1.02 g, 5 mmol) in conc. HCl (3 mL) and H2O (2 mL) was
cooled in ice-bath and diazotized with the solution of NaNO2 (0.35 g, 5.1 mmol in 5 mL H2O). The
cold diazonium solution was added dropwise to a well stirred solution of 3 (0.41 g, 5 mmol) in ethanol
(20 mL) containing sodium acetate (1.64 g, 20 mmol). The reaction mixture was stirred for further 2 h
and left to stand overnight at refrigerator. The crude product was filtered off, dried well and
recrystallized from a mixture of ethanol/benzene to give 4. Orange crystals, Yield, 78%, mp: 218-220
o
C; IR (KBr): νmax, cm-1: 3299, 3203 (2NH), 2190 (CN), 1646 (CO), 1612 (C=N), 1490 (N=N); 1H
NMR (DMSO-d 6) δ (ppm): 2.23 (s, 3H, CH3-pyrazole), 2.29 (s, 3H, CH3-C=N), 3.22 (s, 3H, CH3-N),
7.32-7.54 (m, 5H, Ar-H), 7.64 (br, 1H, C=NH), 7.97 (br, 1H, NH-hydrazo); MS (EI, 70 ev) (m/z, %):
298 (M++2, 2.1), 297 (M++1, 8.9), 296 (M+, 1.1), 254 (5.1), 226 (0.5), 214 (0. 6), 202 (9.2), 188 (1.0),

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 98

173 (0. 8), 158 (1.0), 145 (0.8), 130 (0.7), 119 (5.2), 109 (1.7), 91 (10.8), 83 (43.0), 77 (10.3), 56
(100.0), 55 (8.1). Anal. Calcd. For C15H16N6O (296.33): C, 60.80; H, 5.44; N, 28.36%. Found: C,
60.86; H, 5.52; N, 28.46%.

Synthesis of 4-((3-amino-5-methyl-1H-pyrazol-4-yl)diazenyl)-2,3-dimethyl-1-phenyl-1,2-
dihydropyrazol-5-one (5)

To a solution of 4 (1.48 g, 5 mmol) in 1,4-dioxane (20 mL) and hydrazine hydrate (0.25 g;
98%, 5 mmol) was added. The reaction mixture was refluxed for 4 h then left to cool at room
temperature. The separated solid product was filtered off, dried and recrystallized from a mixture of
DMF/ethanol to give 5. Orange powder, Yield, 90%, mp: 288-290 oC; IR (KBr): νmax, cm-1: 3451,
3262, 3201 (NH2, NH), 1641 (CO), 1610 (C=N), 1484 (N=N); 1H NMR (DMSO-d 6) δ (ppm): 2.29 (s,
3H, CH3, antipyrine), 2.33 (s, 3H, CH3, pyrazole), 3.19 (s, 3H, CH3, antipyrine), 6.08 (br., 2H, NH2),
7.35-7.56 (m, 6H, Ar-H, NH-pyrazole); MS (EI, 70 ev) (m/z, %): 312 (M++1, 7.1), 311 (M+, 37), 296
(2.1), 282 (0.2), 268 (0.3), 251 (0.1), 227 (0.2), 215 (1), 202 (1.1), 191 (1.8), 177 (1.0, 158 (0.7), 137
(0.7), 119 (5.5), 77 (9.2), 56 (100). Anal. Calcd. For C15H17N7O (311.34): C, 57.87; H, 5.50; N,
31.49%. Found: C, 57.96; H, 5.57; N, 31.53%.

General procedure for the synthesis of pyrazolo[1,5-a]pyrimidine derivatives 9-11

A solution of 5 (1.56 g, 5 mmol) and 6 (0.5 g, 5 mmol), 7 (1.1 g, 5 mmol) or 8 (0.96 g, 5 mmol)
in a mixture of pyridine (20 mL) and DMF (10 mL) was refluxed for 14, 24 and 24 h. The reaction
mixture was left to stand overnight at room temperature. The separated solid product was filtered off,
dried and recrystallized from a mixture of ethanol/benzene to give 9-11, respectively.

2,3-Dimethyl-1-phenyl-4-((2,5,7-trimethylpyrazolo[1,5-a]pyrimidin-3-yl)diazenyl)-1,2-
dihydropyrazol-5-one (9)

Yellow crystals, Yield, 75.0%, mp: 172-4 oC; IR (KBr): νmax, cm-1: 1643 (CO), 1629 (C=N); 1H
NMR (DMSO-d 6) δ (ppm): 2.50 (s, 3H, CH3), 2.57(s, 3H, CH3), 2.59 (s, 3H, CH3-antipyrine), 2.62 (s,
3H, CH3-pyrazole), 3.27 (s, 3H, CH3-N), 6.9 (s, 1H, pyrimidine, H-6), 7.33-7.52 (m, 5H, Ar-H); MS
(EI, 70 ev) (m/z, %): 377 (M++2, 3.5), 376 (M++1, 9.7), 375 (M+, 51.0), 360 (5.7), 344 (6.3), 334 (7.6),
314 (6.3), 309 (1.1), 302 (9.4), 294 (1.9), 291 (7.1), 271 (5.4), 264 (7.4), 243 (9.2), 235 (6.0), 206
(7.3), 195 (7.3), 175 (9.9), 162 (7.0), 153 (50.9), 133 (63.5), 121 (5.3), 107 (7.8), 97 (5.7), 81 (7.8), 56
(100.0), 55 (9.4). Anal. Calcd. for C20H21N7O (375.43): C, 63.98; H, 5.64; N, 26.12%. Found: C,
64.07; H, 5.71; N, 26.18%.

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 99

2,3-Dimethy-1-phenyl-4-((2,6-dimethyl-8-phenyl-1H-dipyrazolo[1,5-a:4',3'-e]pyrimidin-3-
yl)diazenyl-1,2-dihydropyrazol-5-one
(10)
Brown crystals, Yield, 67.0%, mp: 176-8 oC; IR (KBr): νmax, cm-1: 1662 (CO), 1621 (C=N),
1496 (2N=N); 1H NMR (DMSO-d6) δ (ppm): 2.55 (s, 3H, CH3-antipyrine), 2.60 (s, 3H, CH3-
phenylpyrazole), 2.62 (s, 3H, CH3-pyrazole), 3.17 (s, 3H, CH3-N), 7.32-8.07 (m, 10H, Ar-H), 8.71 (s,
1H, N=CH); MS (EI, 70 ev) (m/z, %): 478 (M++1, 14.7), 477 (M+, 22.4), 466 (2.3), 450 (21.0), 431
(17.0), 406 (24.7), 372 (22.1), 350 (25.2), 343 (18.4), 327 (17.9), 316 (23.2), 311 (17.0), 303 (19.8),
297 (6.8), 283 (33.4), 268 (21.0), 264 (27.5), 244 (21.0), 234 (20.7), 219 (29.1), 206 (25.2), 181 (19.8),
164 (21.0), 149 (46.7), 136 (28.3), 115 (9.1), 105 (19.0), 96 (13.3), 77 (13.9), 68 (100.0), 54 (90.1).
Anal. Calcd. for C26H23N9O (477.52): C, 65.40; H, 4.85; N, 26.40%. Found: C, 65.48; H, 4.93; N,
26.45%.

2,3-Dimethy-1-phenyl-4--((2-methyl-6,7-dihydrobenzo[h]pyrazolo[1,5-a]quinazolin-3-yl)diazenyl)-
1,2-dihydropyrazol-5-one
(11)

Orange crystals, Yield, 67.0%, mp: 246-8 oC; IR (KBr): νmax, cm-1: 1648 (CO), 1592 (C=C),
1490 (N=N); 1H NMR (DMSO-d6) δ (ppm): 2.57 (s, 3H, CH3-antipyrine), 2.65 (s, 3H, CH3-pyrazole),
2.85-2.95 (m, 4H, 2CH2), 3.18 (s, 3H, CH3-N), 7.33-7.63 (m, 9H, Ar-H), 8.61 (s, 1H, CH=N-
pyrimidine); MS (EI, 70 ev) (m/z, %): 451 (M++2, 16.9), 450 (M++1, 14.1), 449 (M+, 40.5), 448 (7.1),
429 (9.2), 401 (6.3), 390 (2.2), 366 (6.8), 354 (7.4), 331 (13.1), 311 (34.1), 303 (8.8), 292 (7.4), 288
(9.2), 273 (9.3), 258 (11.0), 249 (27.3), 235 (17.8), 214 (3.9), 207 (65.4), 182 (38.2), 181 (31.8), 154
(11.7), 152 (6.2), 127 (20.3), 119 (35.6), 110 (2.3), 93 (43.1), 77 (33.1), 56 (13.1), 50 (7.5). Anal.
Calcd. for C26H23N7O (449.51): C, 69.47; H, 5.16; N, 21.81%. Found: C, 69.41; H, 5.09; N, 21.78%.

Synthesis of 2,3-Dimethy-1-phenyl-4-((3-(2-(3-amino-5-oxo-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-
5-methyl-1H-pyrazol-4-yl)diazenyl)diazenyl)- 1,2-dihydropyrazol-5-one(14)

To a well stirred cooled solution of 5 (1.56 g, 5 mmol) in a mixture of acetic acid (10 mL) and
conc. HCl (3 mL), a solution of NaNO2 (0.35 g, 5.1 mmol in 5 mL H2O) was added dropwise. The
above cooled diazonium solution was added slowly to a well stirred solution of 3-amino-1H-pyrazol-
5(4H)-one (13) (0.49 g, 5 mmol) and the reaction mixture was stirred for further 2 h. The crude
product was filtered off, dried well and crystallized from the ethanol/benzene to give compound 14.
Orange crystals, Yield, 77%, mp: 270-2 oC; IR (KBr): νmax, cm-1: 3407, 3382, 3261, 3216 (OH, NH2,
2NH), 1631 (br, C=O); 1H NMR (DMSO-d6) δ (ppm): 2.41 (s, 3H, CH3, antipyrine), 2.71 (s, 3H, CH3 -
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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 100

pyrazole), 3.28 (s, 3H, CH3-N), 5.75 (br, 2H, NH2), 7.34-7.50 (m, 5H, Ar-H), 10.62 (br., 1H, NH-
pyrazole), 12.23 (br., 1H, NH-pyrazolone), 12.44 (br, 1H, NH-hydrazone); MS (EI, 70 ev) (m/z, %):
421 (M+, 22.6), 406 (23.6), 404 (0.6), 374 (25.5), 363 (2.1), 341 (22.6), 323 (24.7), 307 (28.9), 284
(22.0), 271 (21.3), 264 (8.4), 242 (22.2), 224 (26.4), 220 (10.3), 195 (23.6), 168 (22.0), 157 (8.3), 152
(27.6), 137 (10.7), 114 (4.2), 105 (7.7), 93 (100.0), 73 (7.5), 66 (46.0), 50 (2.7). Anal. Calcd. for
C18H19N11O2 (421.42): C, 51.30; H, 4.54; N, 36.56%. Found: C, 51.37; H, 4.61; N, 36.63%.

Synthesis of 3-(2-(4-((2,3-dimethyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)diazenyl)-5-methyl-
1H-pyrazol-3-yl)hydrazono)-3,3a,6,7-tetrahydrobenzo[h] pyrazolo[1,5-a]quinazolin-2(1H)-one (15)

A solution of compound 5 (0.77 g, 2.5 mmol) and 1-chloro-3,4-dihydronaphthalene-2-

carbaldhyde (8) (0.48 g, 2.5 mmol) in pyridine (20 mL) and DMF (10 mL) was refluxed for 24 h The
reaction mixture was left to stand at room temperature overnight, and the separated was filtered and
crystallized from a mixture of DMF/ethanol to give compound 15. Brown powder, Yield, 66%, mp:
246-7 oC; IR (KBr): νmax, cm-1: 3401, 3266, 3206 (2NH), 1635 (br, C=O); 1H NMR (DMSO-d6) δ
(ppm): 2.38 (s, 3H, CH3, antipyrine), 2.51-2.58 (m, 4H, CH2CH2), 2.69 (s, 3H, CH3-pyrazole), 2.85 (s,
3H, CH3-N), 7.27-7.51 (m, 10H, Ar-H), 7.91 (br, 1H, NH-pyrazole), 8.06 (s, 1H, CH=N), 8.31 (br, 1H,
NH-pyrazolone), 8.87 (br, NH-hydrazone); MS (EI, 70 ev) (m/z, %): 578 (M++H2O, 13.1), 565 (12.6),
533 (13.3), 523 (1.5), 451 (13.7), 433 (15.1), 415 (12.2), 391 (16.1), 372 (9.5), 350 (27.5), 341 (37.9),
330 (23.6), 311 (19.0), 298 (14.2), 282 (26.1), 279 (16.2), 258 (17.5), 244 (14.0), 236 (40.0), 220
(17.8), 208 (71.8), 182 (81.5), 181 (46.7), 160 (19.3), 152 (39.8), 130 (39.2), 121 (21.0), 109 (22.1), 91
(41.9), 77 (31.6), 56 (100.0), 53 (31.7). Anal. Calcd. for C29H27N11O2 (561.6): C, 62.02; H, 4.85; N,
27.43%. Found: C, 62.07; H, 4.92; N, 27.46%.

4-((3-((4-Chlorobenzylidene)amino)-5-methyl-1H-pyrazol-4-yl)diazenyl)-2,3-dimethyl-1-phenyl-1,2-
dihydropyrazol-5-one (17)

A solution of 5 (1.56 g, 5 mmol) and 16 (0.70 g, 5 mmol) in a mixture of pyridine (20 mL) and
DMF (10 mL) was refluxed for 12 h. The reaction mixture was left to stand at room temperature
overnight. The separated solid product was filtered off, dried and crystallized from a mixture of
ethanol/benzene to give 17. Yellow crystals, Yield, 77%, mp: 180-2 oC; IR (KBr): νmax, cm-1: 3257
(NH), 1646 (CO), 1490 (N=N); 1H NMR (DMSO-d6) δ (ppm): 2.46 (s, 3H, CH3-antipyrine), 2.69 (s,
3H, CH3-pyrazole), 3.16 (s, 3H, CH3-N), 7.32-7.52 (m, 9H, Ar-H), 7.91 (s, 1H, N=CH), 9.97 (s, 1H,
NH-pyrazole); MS (EI, 70 ev) (m/z, %): 409 (M+-N2, 16.9), 408 (100.0), 398 (74.6), 381 (11.6), 373
(14.5), 359 (92.2), 344 (9.4), 330 (15.8), 308 (12.6), 304 (78.7), 292 (80.1), 277 (23.1), 263 (20.4), 251
(42.6), 230 (37.8), 223 (13.7), 200 (59), 195 (53), 180 (25.5), 160 (17.8), 151 (42.3), 133 (39.4), 114

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(16.4), 100 (20.3), 74 (94.3), 61 (33.7), 59 (5.5). Anal. Calcd. for C22H20ClN7O (433.89): C, 60.90; H,
4.65; N, 22.60%. Found: C, 60.97; H, 4.73; N, 22.64%.

Synthesis of 7-amino-5-(4-chlorophenyl)-3-((2,3-dimethyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-
4-yl)diazenyl)-2-methyl-4,5-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile (19)

Method A: A solution of 5 (1.56 g, 5 mmol) and 18 (0.94 g, 5 mmol) in a mixture of pyridine

(20 mL) and DMF (10 mL) was refluxed for 24 h. The reaction mixture was left to stand at room
temperature overnight. The separated solid product was filtered off, dried and recrystallized from a
mixture of ethanol/benzene to give 19.
Method B: A solution of compound 17 (1.1 g, 2.5 mmol) and malononitrile (0.16 g, 2.5 mmol)
(20) in a mixture of pyridine (20 mL) and DMF (10 mL) was refluxed for 18 h. The reaction mixture
was left to stand overnight at room temperature. The separated solid product was filtered off, dried and
recrystallized from a mixture of ethanol/benzene to give compound 19. Orange crystals, Yield, (A,
67%; B, 74%), mp: 224-6 oC; IR (KBr): νmax, cm-1: 3377, 3333, 3213 (NH2, NH), 2197 (CN), 1644
(CO), 1624 (C=N); 1H NMR (DMSO-d6) δ (ppm): 2.46 (s, 3H, CH3-antipyrine), 2.68 (s, 3H, CH3-
pyrazole), 2.84 (s, 3H, CH3N), 3.73 (br, 1H, C5- pyrimidine), 7.42-7.90 (m, 11H, Ar-H,NH2), 8.36 (s,
1H, NH), delet 9.06 (br., s, 21H, NH2); MS (EI, 70 ev) (m/z, %): 499 (M++2, 4.37), 498 (M++1, 6.7),
497 (M+, 5.8), 484 (6.2), 474 (6.1), 431 (42.7), 401 (12.3), 378 (10.7), 369 (18.0), 360 (75.4), 345
(22.5), 333 (39.6), 311 (37.3), 296 (10), 284 (30.4), 275 (16.5), 265 (32.5), 249 (28), 230 (18.5), 215
(24.8), 187 (19.1), 174 (28.9), 163 (38.8), 142 (22.3), 138 (49.2), 125 (39.8), 111 (60.4), 89 (35.7), 77
(100), 64 (73.2), 51 (84.9), 50 (18.2). Anal. Calcd. for C25H20ClN9O (497.94): C, 60.30; H, 4.05; N,
25.32%. Found: C, 60.26; H, 4.13; N, 25.36%.

General procedure for the synthesis of 4-((5-substituted-2-methyl-7-phenyl-4,5-dihydropyrazolo

[1,5-a]pyrimidin-3-yl)diazenyl)- 2,3-dimethyl -1-phenyl -1,2-dihydropyrazol-5-ones 22a, b
An equimolecular amounts of 5 (1.56 g, 5 mmol) and 21a (1.25 g, 5 mmol) or 21b (1.21 g, 5
mmol) in DMF (30 mL) containing a catalytic amount of pyridine (1 mL) was refluxed for 5 h. The
reaction mixture was poured onto ice cold water (250 mL), filtered off, washed with petroleum ether
(60-80) and recrystallized from a mixture of ethanol/benzene to give compounds 22a, b, respectively.

1,5-Dimethyl-4-((2-methyl-7-phenyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)di-azenyl)- 2,3-
dimethyl -1-phenyl -1,2-dihydropyrazol-5-one (22a)

Brown crystals, Yield, 69%, mp: 226-228 oC; IR (KBr): νmax, cm-1: 3392 (br., NH), 1646 (CO),
1621 (C=N); 1H NMR (DMSO-d6) δ (ppm): 2.31 (s, 3H, CH3-antipyrine), 2.66 (s, 3H, CH3N), 3.22 (s,

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3H, CH3-N), 4.30 (m, 2H, CH2, C6 -pyrimidine), 5.34 (m, 1H, CH=, C7-pyrimidine), 7.36-7.93 (m,
10H, Ar-H), 9.06 (br., s, 1H, NH); MS (EI, 70 ev) (m/z, %): 427 (M++2, 2.2), 426 (M++1, 7.8), 425
(M+, 24.8), 424 (18.8), 409 (6.4), 396 (6.6), 378 (4.9), 354 (5.8), 341 (5.0), 330 (5.2), 311 (6.9), 297
(7.2), 296 (1.8), 287 (4.2), 279 (8), 259 (5.8), 251 (4.2), 232 (4.3), 223 (2.4), 205 (5), 182 (34.3), 181
(10.2), 155 (8.6), 141 (8.4), 129 (8.9), 115 (8.3), 105 (13.8), 91 (17.8), 77 (31.4), 56 (100). Anal.
Calcd. For C24H23N7O (425.49): C, 67.75; H, 5.45; N, 23.04%. Found: C, 67.83; H, 5.52; N, 23.13%.

4-((5-(4-Chlorophenyl)-2-methyl-7-phenyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-3-yl)diazenyl)- 2,3-
dimethyl -1-phenyl -1,2-dihydropyrazol-5-one (22b)
Brown crystals, Yield, 66%, mp: 110-2 oC; IR (KBr): νmax, cm-1: 3423 (NH), 1656 (CO), 1596
(C=C), 1486 (N=N); 1H NMR (DMSO-d6) δ (ppm): 2.45 (s, 3H, CH3-antipyrine), 2.57 (s, 3H, CH3-
pyrazole), 2.85 (s, 3H, CH3N), 3.73 (br., 1H, CH), 6.85 (m, 1H, CH=, pyrimidine), 7.3-7.8 (m, 14H,
Ar-H), 9.40 (br., 1H, NH); MS (EI, 70 ev) (m/z, %): 537 (M++2, 15), 536 (M++1, 16.2), 535 (M+,
59.8), 519 (18.9), 449 (0.6), 429 (5.0), 415 (3.1), 399 (3.4), 387 (5.3), 365 (5.3), 348 (5.2), 333 (32.4),
313 (2.5), 312 (1.7), 291 (24.6), 263 (7.9), 238 (8.7), 166 (1.8), 157 (60.7), 119 (8.3), 93 (21.0), 83
(20.7), 56 (100), 54 (11). Anal. Calcd. for C25H24N10O2 (496.52): C, 60.47; H, 4.87; N, 28.21%.
Found: C, 60.53; H, 4.94; N, 28.26%.

Synthesis of N'-(4-((2,3-dimethyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)di-azenyl)-5-methyl-
1H-pyrazol-4-yl)-N,N-dimethylformimidamide (24)

A solution of 5 (1.56 g, 5 mmol) and DMF-DMA (23) (0.59 g, 5 mmol) in pyridine (20 mL) in
DMF (10 mL) was refluxed for 18 h. The reaction mixture was left to stand overnight at room
temperature. The separated solid product was filtered, dried and recrystallized from a mixture of
ethanol/benzene mixture to give 24. Yellow crystals, Yield, 85%, mp: 245-7 oC; IR (KBr): νmax, cm-1:
3266 (NH), 1658 (CO), 1616 (C=N); 1H NMR (DMSO-d6) δ (ppm): 2.46 (s, 3H, CH3-antipyrine), 2.49
(s, 3H, CH3-pyrazole), 3.29 (s, 3H, CH3-N), 3.32 (s, 3H, CH3-N), 3.35 (s, 3H, N-CH3, antipyrine),
7.32-7.52 (m, 5H, Ar-H), 8.91 (s, 1H, CH-N), 12.85 (s, 1H, NH-pyrazole); MS (EI, 70 ev) (m/z, %):
368 (M++2, 9.8), 279 (75.5), 256 (8.7), 167 (40.9), 149 (100), 139 (7.8), 121 (18), 98 (22), 86 (71.1),
70 (41.1), 69 (32.2), 61 (11.2). Anal. Calcd. for C18H22N8O (366.42): C, 59.00; H, 6.05; N, 30.58%.
Found: C, 59.12; H, 6.08; N, 30.64%.

2,3-Dimethyl-4-((3-methyl-5-((3-oxo-3-phenylpropylidene)amino)-1H-pyrazol-4-yl)diazenyl)-1-
phenyl-1,2-dihydropyrazol-5-one (26)

A solution of 24 (1.83 g, 5 mmol) with acetophenone (25) (0.8 g, 5 mmol) in a mixture of

pyridine (20 mL) and DMF (10 mL) was refluxed for 24 h. The reaction mixture was left to stand

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 103

overnight at room temperature. The separated solid product was filtered off, dried and recrystallized
from a mixture of ethanol/benzene to give 26. Brown crystals, Yield, 67%, mp: 226-8 oC; IR (KBr):
νmax, cm-1: 3199 (NH), 1692 (CO), 1608 (C=N); 1H NMR (DMSO-d6) δ (ppm): 2.46 (s, 3H, CH3-
antipyrine), 2.57 (d, 2H, CH2), 2.88 (s, 3H, CH3-pyrazole), 3.16 (s, 3H, CH3-N), 3.28 (s, 1H, CH),
7.34-8.06 (m, 10H, Ar-H), 8.65 (br, 1H, NH-pyrazole); MS (EI, 70 ev) (m/z, %): 443 (M++2, 51.9),
442 (M++1, 66), 441 (M+, 79.3), 433 (76.4), 407 (56.6), 398 (86.8), 378 (82.1), 371 (84), 355 (67), 344
(58.5), 333 (98.6), 311 (16), 310 (74.5), 301 (63.2), 298 (51.9), 284 (100), 273 (59.4), 263 (58.5), 240
(64.2), 230 (69.8), 218 (79.3), 204 (97.3), 187 (92.5), 176 (49.1), 163 (94.4), 151 (82.1), 126 (79.3),
125 (68.0), 101 (37.7), 84 (62.3), 73 (69.8), 67 (71.7), 55 (21.7). Anal. Calcd. for C24H23N7O2
(441.49): C, 65.29; H, 5.25; N, 22.21%. Found: C, 65.21; H, 5.21; N, 22.17%.

Synthesis of 2,3-dimethyl-4-((2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-3-yl)di-azenyl)-1-phenyl-
1,2-dihydropyrazol-5-one (27)

Method A: A solution of compound 26 (1.11 g, 2.5 mmol) in DMF (10 mL) containing POCl3
(1 mL) was refluxed for 24 h. The reaction mixture was poured on ice cold water and neutralized with
ammonia. The separated solid product was filtered off, dried and recrystallized from a mixture of
ethanol/benzene to give 27.
Method B: A solution of 24 (1.83 g, 5 mmol) and 28 (0.88 g, 5 mmol) in DMF (10 mL)
containing pyridine (1 mL) was refluxed for 24 h. The reaction mixture was left to stand overnight at
room temperature. The separated solid product was filtered off, dried and recrystallized from a mixture
of ethanol/benzene to give 27. Orange crystals, Yield, (A, 78%; B, 82%), mp: 258-260 oC; IR (KBr):
νmax, cm-1: 1633 (CO), 1492 (C=N); MS (EI, 70 ev) (m/z, %): 425 (M++2, 4.6), 424 (M++1, 17.3), 423
(M+, 58.4), 409 (1.8), 394 (0.6), 381 (0.5), 368 (0.4), 353 (0.6), 338 (0.7), 331 (0.6), 315 (1.3), 311
(1.0), 303 (6.0), 297 (0.2), 289 (0.8), 277 (1.3), 262 (3.6), 249 (2.6), 223 (8.9), 208 (4.0) 182 (22.1),
181 (77.9), 155 (16.9,) 143 (2.3), 129 (35.9), 119 (16.7), 103 (18.2), 91 (23.1), 77 (25.9), 56 (100), 51
(6.2). Anal. Calcd. for C24H21N7O (423.47): C, 68.07; H, 5.00; N, 23.15%. Found: C, 68.13; H, 5.08;
N, 23.22%.

General procedure for the synthesis of pyrazolo[1,5-a]pyrimidine derivatives 33-37

A solution of compound 24 (1.85 g, 5 mmol) and 29 (0.56 g, 5 mmol), 20 (0.33 g, 5 mmol), 6
(0.5 g, 5 mmol), 31 (0.87 g, 5 mmol) or 32 (0.66 g, 5 mmol) in a mixture of DMF (10 mL) and
pyridine (2 mL) was refluxed for 24 h. The reaction mixture was left to stand overnight at room

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 104

temperature. The separated solid product was filtered off, dried and recrystallized from a mixture of
ethanol/benzene to give 33-37, respectively.
3-((2,3--Dimethyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)diazenyl)-2-methyl-8,9-
dihydropyrazolo[1,5-a]quinazolin-6(7H)-one (33)

Brown crystals, Yield, 75%, mp: 245-7 oC; IR (KBr): νmax, cm-1: 1643 (br., 2CO), 1494 (N=N); 1H
NMR (DMSO-d6) δ (ppm): 1.77-1.85 (m, 2H, CH2, cyclohexeone,C8-H), 2.46-2.49 (m, 7H, CH3-
antipyrine, 2CH2, cyclohexenone C7-H, C9-H), 2.56 (s, 3H, CH3-pyrazole), 3.34 (s, 3H, CH3-N), 7.33-
7.52 (m, 5H, Ar-H), 8.81(s, 1H, pyrmidine-C5-H); MS (EI, 70 ev) (m/z, %): 416 (M++1, 4), 415 (M+,
11.8), 414 (2.2), 404 (2.7), 369 (1.8), 339 (10.1), 323 (2.0), 311 (11.2), 296 (2.1), 293 (1.9), 263 (2.1),
241 (2.4), 228 (4.6), 216 (18.3), 203 (7.7), 191 (4.2), 174 (14.2), 164 (19), 148 (38.3), 131 (9.2), 119
(19.7), 103 (8.5), 93 (32.8), 77 (26.9), 56 (100), 55 (18.7), 50 (6.2). Anal. Calcd. for C22H21N7O2
(415.45): C, 63.60; H, 5.09; N, 23.60%. Found: C, 63.67; H, 5.13; N, 23.69%.

7-Amino-3-((2,3-dimethyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)diazenyl)-2-
methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (34)
Brown crystals, Yield, 79%, mp: 104-6 oC; IR (KBr): νmax, cm-1: ; 3453, 3295 (NH2), 2199
(CN), 1649 (CO), 1636 (C=C) 1H NMR (DMSO-d6) δ (ppm): 2.46 (s, 3H, CH3, antipyirn), 2.66 (s, 3H,
CH3, pyrazole), 3.28 (s, 3H, NCH3), 6.91-8.05 (m, 7H, Ar-H, NH2); MS (EI, 70 ev) (m/z, %): 369 (M+-
NH3, 3.6), 368 (9.4), 316 (5.4), 265 (12.8), 239 (100), 236 (6.3), 213 (12.4), 198 (14.4), 188 (21.7),
174 (44.5), 159 (6.9), 147 (21.3), 129 (20.8), 120 (83.4), 98 (28.7), 97 (42.0), 73 (74.6), 55 (98.2), 50
(8.8). Anal. Calcd. for C19H17N9O (387.4): C, 58.91; H, 4.42; N, 32.54%. Found: C, 58.96; H, 4.48; N,
32.62%.

4-((6-Acetyl-7-amino-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)diazenyl)-2,3-dimethyl-1-phenyl-1,2-
dihydropyrazol-5-one (35)

Black crystals, Yield, 77%, mp: above 320 oC; IR (KBr): νmax, cm-1: 1633 (br., 2CO), 1492 (N=C);
1
H NMR (DMSO-d 6) δ (ppm): 2.40 (s, 3H, CH3-pyrimidine), 2.53 (s, 3H, CH3-CO), 2.60 (s, 3H, CH3 -
antipyrine), 2.66 (s, 3H, CH3, pyrazole), 3.31 (s, 3H, CH3-N), 7.33-8.01(m, 6H, Ar-H), delet 9.02 (s,
1H, C6-H-pyrimidine); MS (EI, 70 ev) (m/z, %): 405 (M++2, 5.2), 404 (M++1, 5.2), 403 (M+, 18.7),
389 (1.1), 375 (11.6), 353 (3.3), 339 (1.1), 325 (0.5), 311 (2.2), 297 (1.3), 296 (0.4), 285 (2.7), 269
(1.1), 255 (2.3), 236 (2.1), 215 (3.2), 202 (9.7), 188 (0.5), 175 (3.8), 161 (9.7), 146 (21.4), 133 (25.7),
119 (14.8), 98 (8.2), 91 (20.5), 83 (20.0), 56 (100), 55 (24.7), 50 (4.4). Anal. Calcd. for C21H21N7O2
(403.44): C, 62.52; H, 5.25; N, 24.30%. Found: C, 62.60; H, 5.33; N, 24.37%.

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 105

4-((7-Amino-6-(benzo[d]thiazol-2-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)di-azenyl)-2,3-
dimethyl-1-phenyl-1,2-dihydropyrazol-5-one(36 )
Orange crystals, Yield, 76%, mp: 266-4 oC; IR (KBr): νmax, cm-1: 3373 (NH2), 1632 (br., CO,
N=C), 1487 (N=N); 1H NMR (DMSO-d6) δ (ppm): 2.46 (s, 3H, antipyrine), 2.60 (s, 3H, CH3-
pyrazole), 3.22 (s, 3H, CH3-N), 7.21-7.93 (m, 12H, Ar-H, NH2); MS (EI, 70 ev) (m/z, %): 497 (M++2,
19.5), 496 (M++1, 11.6), 495 (M+, 41.8), 481 (21.2), 456 (4.9), 435 (6), 423 (4.9), 414 (7), 392 (7.2),
378 (18), 377 (9.6), 351 (6.1), 336 (8.7), 322 (17), 310 (5.6), 308 (15.3), 296 (71.1), 281 (42.8), 269
(4.6), 253 (86), 248 (8.7), 228 (93), 214 (14.8), 201 (55), 184 (50.6), 174 (37.2), 159 (11), 147 (10.8),
127 (4.2), 119 (41.4), 109 (20.6), 93 (67.8), 77 (40.2), 56 (100), 53 (19.5). Anal. Calcd. for
C25H21N9Os (495.56): C, 60.69; H, 4.27; N, 25.44%. Found: C, 60.73; H, 4.31; N, 25.53%.

6,8-Diamino-3-((2,3-dimethyl-5-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)diazenyl)-2-
methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carbonitrile (37)

A solution of 24 (1.85 g, 5 mmol) and 36 (0.66 g, 5 mmol) in a mixture of pyridine (20 mL)
and DMF (10 mL) was refluxed for 24 h. The reaction mixture was left to stand overnight at room
temperature. The separated solid product was filtered, dried and recrystallized from a mixture of
ethanol/benzene to give 37. Brown crystals, Yield, 83%, mp: 289-290 oC; IR (KBr): νmax, cm-1: 3377,
3314 (2NH2), 2210 (CN), 1649 (CO), 1492 (N=N); 1H NMR (DMSO-d6) δ (ppm): 2.46 (s, 3H, CH3,
antipyrine), 2.59 (s, 3H, CH3, pyrazole), 3.30 (s, 3H, CH3-N), 7.35-7.53 (m, 5H, Ar-H), 8.40 (br., s,
2H, NH2), 8.73 (s, 1H, CH=N, pyrimidine), 10.62 (br, 1H, NH); MS (EI, 70 ev) (m/z, %): 455 (M++2,
1.1), 454 (M++1, 1.4), 453 (M+, 4.8), 435 (0.6), 426 (0.7), 411 (1.2), 392 (1.0), 387 (9.2), 367 (0.7),
352 (0.6), 339 (7.8), 325 (1.2), 311 (7.9), 300 (1.8), 297 (1.0), 286 (1.6), 267 (1.4), 253 (3.1), 240
(21.6), 226 (1.3), 211 (10.3), 202 (4.8), 188 (9.1), 173 (4.1), 159 (4.6), 145 (13.9), 133 (2.2), 119
(14.0), 110 (5.8), 91 (17.8), 77 (24.7), 56 (100.0). Anal. Calcd. for C22H19N11O (453.46): C, 58.27; H,
4.22; N, 33.98%. Found: C, 58.34; H, 4.28; N, 34.03%.

2.3. Antitumor Activity Assay

Different concentrations of the tested compounds were prepared (ED100, ED50 and ED25 μg/
DMSO). The amount of DMSO was adjusted to give a final concentration of 0.1%. Ascites fluid was
obtained from the peritoneal cavity of the donor animal from (National Cancer Institute, Cairo, Egypt)
contain Ehrlich cell was as aseptically aspirated. The cells were grown partially floating and attach in a
suspension culture (RPMI 1660 medium, Sigma Chemical Co. St. Louis, USA), supplemented with
10% foetal bovine serum (GIBCO, UK). They were maintained at 37 oC in humidified atmosphere
with 5% CO2 for 2 h. The viability of the cell used in control experiments (DMSO only without drug)

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 106

exceeded 95% as determined by microscopically examination using a hemocytometer and trypan blue
stain (stain only the dead cells).

2.4. Antioxidant Activity Assay

Antioxidant activities were evaluated from the bleaching of ABTS derived radical cations. The
radical cation was derived from ABTS [2,2'-azino-bis (3-ethyl benzothiazoline-6-sulfonic acid)],
which was prepared by reaction of ABTS (60 μL) with MnO2 (3 mL, 25 mg/mL) in aqueous buffer
solution (pH 7). After shaking the solution for a few minutes, it was centrifuged and filtered.
Absorbance (A control) of the resulting green-blue solution (ABTS radical solution) was
recorded at λmax 734 nm. The absorbance (A test) was measured upon the addition of (20 μL of 1
mg/mL) solution of the tested sample in spectroscopic grade MeOH/buffer (1:1, v/v) to the ABTS
solution. The decrease in the absorbance is expressed as % inhibition which calculated from the
following equation: % Inhibition = [A (control) – A (test)]/A (control)  100. Ascorbic acid (20 μL, 2
mM) solution was used as standard antioxidant (positive control). Blank sample was run using solvent
without ABTS.

3. Results and Discussion

3.1. Chemistry

The synthetic strategies adopted to obtain the target compounds are depicted in Schemes 1-4.
4-((3-Amino-5-methyl-1H-pyrazol-4-yl)diazenyl)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one (5)
was obtained by coupling of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-diazonium
chloride (2) with 3-iminobutanenitrile (3) [23] in ethanol containing sodium acetate followed by
reaction of the formed N'-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H- pyrazol-4-yl)-2-imino-
propanehydrazonoyl cyanide (4) with hydrazine hydrate in 1,4-dioxane. Cyclocondensation of 5 with
acetyl acetone (6) or 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4- carbaldehyde (7) [24] or 1-chloro-
3,4-dihydronaphthalene-2-carbaldhyde (8) [25] in refluxing DMF containing a catalytic amount of
pyridine gave the corresponding pyrazolopyrimidines 9-11, respectively (Scheme 1).
Furthermore, diazotization of 3-aminopyrazole 5 with sodium nitrite in a mixture of acetic acid
and hydrochloric acid afforded the corresponding diazonium salt 12 which coupled with 3-amino-1H-
pyrazol-5(4H)-one (13) in pyridine to give the corresponding hydrazone derivative 14.
Reaction of compound 14 with 1-chloro-3,4-dihydronaphthalene-2-carbaldehyde (8) gave the
corresponding pyrazolopyrimidine derivative 15. Treatment of compound 5 with p-
chlorobenzaldehyde (16) in pyridine/DMF mixture gave the corresponding Schiff base 17 which
afforded the pyrazolopyrimidine derivative 19 upon treatment with malononitrile 20. Furthermore,

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 107

compound 19 was obtained in a good yield via reaction of 5 with 2-(4-chlorobenzylidene)

malononitrile (18) [26] in refluxing pyridine/DMF mixture (Scheme 2).
Moreover, reaction of 1-phenyl-3-(piperidin-1-yl)propan-1-one hydrochloride (21a) [27] or 3-
(4-chlorophenyl)-1-phenylprop-2-en-1-one (21b) [28] with 5 in a mixture of pyridine/DMF afforded 4-
((5-substituted-2-methyl-7-phenyl-4,5-dihydro-pyrazolo [1,5-a]pyrimidin-3-yl)diazenyl)-1,5-dimethyl-
2-phenyl-1H-pyrazol-3(2H)-ones 22a and 22b, respectively. Furthermore, reaction of 5 with DMF-
DMA (23) in DMF furnished N'-(4-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
yl)diazenyl)-5-methyl-1H-pyrazol-3-yl)-N,N-dimethyl formimid-amide (24). 1,5-Dimethyl-4-((2-
methyl-7-phenylpyrazolo[1,5-a]pyrimidin-3-yl)di-azenyl)-2-phenyl-1H-pyrazol-3(2H)-one (27) was
obtained via treatment of 24 with acetophenone (25) in a mixture of pyridine/DMF followed by
cyclization of the formed iminone 26 with POCl3 in DMF. In another rout, compound 27 was obtained
via treatment of 5 with enaminone 28 [29] (Scheme 3).

Scheme 1. Synthesis of 4-((3-amino-5-methyl-1H-pyrazol-4-yl)diazenyl)-1,5-dimethyl-2-phenyl-1H-

pyrazol-3(2H)-one (5) and its reactions with aldehydes and ketone.

On the other hand, pyrazol[1,5-a]pyimidine derivatives 33, 34, 35, 36 and 37 were obtained
through reaction of N,N-dimethylformimidamide 24 with cyclohexane-1,3-dione (29), malononitrile
20, acetyl acetone (6), 2-(benzo[d]thiazol-2-yl)acetonitrile (30) [30] or 2-imino- propane-1,1,3-
tricarbonitrile (32) [31] in refluxing pyridine/DMF mixture, respectively (Scheme 4).

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 108

Scheme 2. Synthesis of pyrazolo[1,5-a]quinazolinone 15 and pyrazolo[1,5-a]pyrimidine 19.

Scheme 3. Synthesis of pyrazolo[1,5-a]pyrimidines 22a, b and 27.

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 109

Scheme 4. Reactions of N,N-dimethylformimidamide 24 with nitrile and diketone derivatives.

3.2. Biological Activities

3.2.1. Antitumor activity

Effects of drugs on the viability of Ehrlich ascites carcinoma cells (EAC) in vitro seventeen
antipyrine derivatives were tested for cytotoxicity against a well known established model EAC in
vitro [32]. Results for the ED100, ED50, ED25 and IC50 values of the active compounds are summarized
in Table 1. The data showed clearly that most of compounds have good activities. Compounds 34, 36
and 37 have moderate activities. Thus, it would appear that introducing of pyrazole, and or pyrimidine
moieties decrease the antitumor properties of N'-(1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H-
pyrazol-4-yl)-2-imino-propanehydrazonoyl cyanide (4) (Fig. 1).
By comparing the results obtained of the investigated compounds to their structures, the
following structure activity relationships (SAR's) were postulated: (i) antipyrine derivative 4 is more
potent than 5-florouracil (5-Fu) which may be attributed to the replacement of pyrimidine moiety with
the antipyrine and presence of iminobutanenitrile moiety. (ii) Compound 5 is less potent than
compound 4 which may be due to conversion of the iminobutanenitrile moiety into pyrazole. (iii) Most
of the derivatives are more potent than the 5-florouracil (5-Fu) which may be attributable to presence
of pyrazole, antipyrine, pyrazolopyrimidine moieties or all of them together.

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 110

Figure 1. Structure activity relationships (SAR's) of the more potent antioxidant compounds.
Table 1. Ehrlich ascites carcinoma cells (EAC) in vitro assay results for the investigated compounds
Compound No. IC50 μg ED100 µg ED50 µg ED25 µg
5-Fu 32.26 98.2 70.1 40
4 0.46 94.9 68.7 49.8
5 1.71 98.8 80 63.3
22a 3.13 99.8 87.1 70.2
22b 29.39 93 64.7 48.2
9 20.56 95 69.3 51
17 24.64 98.6 81.5 66.6
19 31.98 94.2 67 48
10 5.02 94.1 65 44.3
11 6.78 94.7 65 46
24 9.18 98.3 80 63.3
26 -- -- -- --
27 11.52 96 73 55.4
33 14.72 95 71.2 54
34 40.48 93 59 37.3
35 28.33 93 63 48
36 54.29 80.3 50 28
37 52.04 82 50.9 30
Notes: The IC50 is the inhibitive concentration, and ED100, ED50, and ED25 are the effective doses at 25, 50, and 100 μL,
respectively, of the compounds used. The dead % refers to the % of the dead tumor cells and 5-Fu is 5-fluorouracil as a
well known cytotoxic agent.

3.2.2. Antioxidant activity

The antioxidant activities of seventeen pyrazole compounds were evaluated as reported by
Lissi et al. [33]. The data showed clearly that compounds 4 and 22a have good activities, while
compound 24, 27 and 33 exhibited moderate activities. On the other hand, the other compounds
showed weak activities (Table 2). Thus, it would appear because of conversion of iminobutanenitrile
moiety in compound 4 into aminopyrazole moiety in compound 5. Generally, cyclization of
aminopyrazole 5 into pyrazolopyrimidines enhances the biological activity (Fig. 1).

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Int. J. Modern Org. Chem. 2012, 1(2): 96-114 111

Table 2. Antioxidant activities of the investigated compounds

Compound No. ABTS
Absorbance of samples % Inhibition
Control of ABTS 0.507 0.0
Ascorbic Acid 0.039 92.30
4 0.090 80.93
5 0.338 28.38
9 0.321 36.68
10 0.347 31.55
11 0.264 47.92
17 0.135 73.37
19 0.288 43.19
22a 0.041 91.91
22b 0.339 33.13
24 0.168 66.86
26 -- --
27 0.228 55.02
33 0.210 58.57
34 0.393 22.48
35 0.346 31.75
36 0.445 12.22
37 0.429 15.38

4. Conclusions

The objective of the present study was to synthesize and evaluate the antitumor and antioxidant
activity of some novel pyrazolopyrimidine with the hope of discovering new structure leads serving as
antitumor and antioxidant agents. The data showed clearly that most of compounds have good
antitumor activities and weak antioxidant activities, while compounds 4 and 22a exhibited broad
spectrum of antitumor and antioxidant activities.

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crystal structure of 3-{[(1E)-1-(2-hydroxyphenyl)methylidene]amino}-4-cyanopyrazole. Chin. J.
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