Heterocyclic synthesis using nitrilimines: Part 14. Synthesis of new pyrazole derivatives

Article abstract of DOI:10.3906/kim-0910-30

A new series of 1, 3, 4, 5-tetrasubstituted pyrazoles have been synthesized by the 1, 3-dipolar cycloaddition of suitable nitrilimines to 3-propylidene and 3-benzylidene-phthalide. Both analytical and spectroscopic data of all the synthesized compounds are in full agreement with the proposed structures. tuebitak.

Full text of DOI:10.3906/kim-0910-30

Turk J Chem
34 (2010) , 529 – 535.
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ꢀ TUBITAK
doi:10.3906/kim-0910-30
Heterocyclic synthesis using nitrilimines: part 14.
Synthesis of new pyrazole derivatives
Hany M. DALLOUL
Department of Chemistry, Faculty of Applied Science, Alaqsa University of Gaza,
P.O.Box 4051, Gaza 76888, PALESTINE
e-mail: hmdalloul60@yahoo.com
Received 12.10.2009
A new series of 1,3,4,5-tetrasubstituted pyrazoles have been synthesized by the 1,3-dipolar cycloaddition
of suitable nitrilimines to 3-propylidene and 3-benzylidene-phthalide. Both analytical and spectroscopic data
of all the synthesized compounds are in full agreement with the proposed structures.
Key Words: Nitrilimines, 1,3-dipolar cycloaddition, phthalides, pyrazoles
Introduction
In recent years, 1,3-dipolar cycloaddition reactions have received considerable attention because they have
been shown to be an efficient synthetic tool for the preparation of a wide variety of heterocyclic compounds.1
The reactions of nitrilimine 1,3-dipoles with dipolarophiles provide an option for the construction of substi-
tuted pyrazoles.1,2 The stereochemistry of the formation of pyrazoles from nitrilimines was reported in many
studies.3−9 The pyrazole ring comprises the core structure of a number of drugs,10−13 including the widely
r
r
prescribed Celebrex (Celecoxib),14 Viagra,15 and Rimonabant (Acompliaꢀ or Zimultiꢀ), a high-potency
cannabinoid type-1 (CB1) receptor inverse agonist that has recently been approved in the European Union as a
treatment for obesity.5 Furthermore, recent reports indicate the pyrazole chemotype as the structural motif of
a number of highly potent inhibitors of coagulation factor Xa.13 Among them, Rivaroxaban and Apixaban were
selected for clinical development for the prevention and treatment of thrombotic diseases.16 A huge number of
pyrazole derivatives have antimicrobial,17 antiviral,17,18 herbicidal,19 hypoglycemic,20 hypolipidemic,19,21 and
anticancer21,22 activities. Some of them were identified as selective antagonists of subtype 1 PGE2 receptors
(EPI),22,23 and showed efficacy in numerous preclinical models of pain, including allodynia and neuropathic pain,
and are expected to be devoid of the gastrointestinal effects associated with non-steroidal anti-inflammatory
drugs (NSAIDS)24 and the cardiovascular side effects typical of COX-2 selective inhibitors.25 In view of these
529

Heterocyclic synthesis using nitrilimines: part 14...., H. M. DALLOUL
facts and in continuation of our studies on the use of hydrazonoyl halides as useful precursors for the synthesis
of various heterocycles,26 we report here the synthesis of new pyrazole derivatives via reaction of nitrilimines
with 3-propylidenephthalide and 3-benzylidenephthalide.
Experimental
Melting points were determined on an A. Kru¨ss Melting Point Meter and are uncorrected. The IR spectra
were measured as potassium bromide pellets using a Satellite 3000 Mid infrared spectrophotometer. The 1 H-
NMR and 13 C-NMR spectra were recorded on a Bruker AM 300 MHz spectrometer at room temperature in
DMSO-d6 solution using tetramethylsilane (TMS) as internal reference. Chemical shifts were recorded as δ
values in parts per million (ppm) downfield from internal TMS. Electron impact (EI) mass spectra were run on a
Shimadzu GCMS-QP1000 EX spectrometer at 70 eV. Elemental analyses were performed at the Microanalytical
Center of Cairo University, Egypt. The hydrazonoyl halides 127−29 and 3-benzylidenephthalide30 were prepared
according to literature procedures. 3-Propylidenephthalide, benzene, and triethylamine were purchased from
Avocado Research Chemicals, England, and used without further purification.
General procedure for synthesis of pyrazole derivatives 5a-p.
Triethylamine (10 mmol) was added to a stirred mixture of phthalides 3 (5 mmol) and the appropriate
hydrazonoyl halides 1 (5 mmol) in benzene (50 mL) and the reaction mixture was heated under refluxing
condition. The reaction was controlled by TLC and continued until the starting substrates were completely
consumed (10-12 h); it was then left to cool to room temperature. The solvent was then evaporated under
reduced pressure and the residual solid was washed with water (2 × 25 mL) and in a few cases the gummy
products were triturated with ethanol or methanol (10 mL). The crude solid product was collected and
recrystallized from ethanol to give the desired compounds.
The following compounds were synthesized using this method:
2-[3-Acetyl-1-(4-chlorophenyl)-4-ethyl-1H-pyrazol-5yl]benzoic acid (5a): Yield 54%; mp 176-
178 ◦ C; 1 H-NMR (DMSO-d6)δ 12.45 (1H, s, OH), 7.76-7.21 (8H, m, arom. H), 2.69 (2H, q,J 7.5, CH2),
2.56 (3H, s, COCH3), 1.09 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 192.3, 166.7, 147.6, 146.3, 142.2,
137.9, 135.3, 133.1, 131.8, 129.8, 129.4, 128.9, 128.2, 124.3, 118.7, 25.6, 16.8, 13.6; IR (KBr) ν 2525 (br OH),
1720 (C=O acid), 1690 (C=O acetyl), 1621 (C=N) cm−1 ; MS: m/z = 368/370 [M+ ]; Analysis (% Calculated/
found) for C20 H17 ClN2 O3 (Mw 368.82) C: 65.13/65.45, H: 4.65/4.50, N: 7.60/7.45.
2-[3-Acetyl-4-ethyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]benzoic acid (5b): Yield 56%; mp 156-
158 ◦ C; 1 H-NMR (DMSO-d6) δ 12.50 (s, 1H, OH), 7.75-7.23 (8H, m, arom. H), 2.73 (3H, s, p-CH3), 2.66 (2H,
q,J 7.5, CH2), 2.54 (3H, s, COCH3), 1.10 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 192.3, 166.7, 147.8,
146.3, 142.2, 136.9, 135.4, 133.0, 130.8, 129.3, 128.6, 128.3, 125.3, 123.2, 118.7, 25.6, 21.7, 16.8, 13.6; IR (KBr)
ν 2520 (br OH), 1720 (C=O acid), 1692 (C=O acetyl), 1622 (C=N) cm−1 ; MS: m/z = 348 [M+ ]; Analysis (%
Calculated/found) for C21 H20 N2 O3 (Mw 348.41) C: 72.40/72.15, H: 5.79/5.90, N: 8.04/7.95.
2-[3-Acetyl-1,4-diphenyl-1H-pyrazol-5-yl]benzoic acid (5c): Yield: 57%; mp 160-162 ◦ C; 1 H-
NMR (DMSO-d6)δ 12.50 (s, 1H, OH), 7.75-7.21 (14H, m, arom. H), 2.54 (3H, s, COCH3); 13 C-NMR (DMSO-
530

Heterocyclic synthesis using nitrilimines: part 14...., H. M. DALLOUL
d6)δ 192.1, 166.7, 147.6, 146.3, 142.3, 139.7, 136.4, 134.8, 133.3, 129.8, 129.2, 128.8, 128.5, 128.3, 127.2, 126.3,
124.8, 123.7, 118.7, 25.6; IR (KBr) ν 2525 (br OH), 1718 (C=O acid), 1690 (C=O acetyl), 1620 (C=N) cm−1
;
MS: m/z = 382 [M+ ]; Analysis (% Calculated/found) for C24 H18 N2 O3 (Mw 382.42) C: 75.38/75.65, H:
4.74/4.60, N: 7.33/7.21.
2-[1-(4-Chlorophenyl)-4-ethyl-3-methoxycarbonyl-1H-pyrazol-5-yl]benzoic acid (5d): Yield:
51%; mp 171-173 ◦ C; 1 H-NMR (DMSO-d6)δ 12.51 (1H, s, OH), 7.72-7.28 (8H, m, arom. H), 3.75 (3H, s,
OCH3), 2.67 (2H, q,J 7.5, CH2), 1.12 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 166.7, 164.3, 147.1, 146.3,
142.2, 137.9, 134.9, 133.0, 131.8, 130.4, 129.7, 128.7, 128.2, 124.8, 118.7, 47.9, 16.8, 13.6; IR (KBr) ν 2530
(br OH), 1712 (C=O acid), 1705 (C=O ester), 1624 (C=N) cm−1 ; MS: m/z = 384/386 [M+ ]; Analysis (%
Calculated/found) for C20 H17 ClN2 O4 (Mw 384.82) C: 62.42/62.20, H: 4.45/4.55, N: 7.28/7.40.
2-[3-Benzoyl-1-(4-chlorophenyl)-4-ethyl-1H-pyrazol-5-yl]benzoic acid (5e): Yield: 47%; mp
196-198 ◦ C; 1 H-NMR (DMSO-d6)δ 12.52 (1H, s, OH), 7.77-7.26 (13H, m, arom. H), 2.61 (2H, q,J 7.5, CH2),
1.10 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 185.3, 166.7, 147.8, 146.3, 144.3, 142.2, 137.8, 134.9, 133.1,
132.2, 131.6, 129.9, 129.7, 129.1, 128.8, 128.5, 127.9, 124.6, 118.7, 16.8, 13.6; IR (KBr) ν 2520 (br OH), 1714
(C=O acid), 1654 (Ar-C=O), 1619 (C=N) cm−1 ; MS: m/z = 430/430 [M+ ]; Analysis (% Calculated/found)
for C25 H19 ClN2 O3 (Mw 430.89) C: 69.69/69.45, H: 4.44/4.60, N: 6.50/6.65.
2-[3-Benzoyl-1-(4-chlorophenyl)-4-phenyl-1H-pyrazol-5-yl]benzoic acid (5f): Yield: 44%; mp
189-191 ◦ C; 1 H-NMR (DMSO-d6)δ 12.52 (1H, s, OH), 7.71-7.26 (18H, m, arom. H); 13 C-NMR (DMSO-d6)δ
185.2, 166.7, 147.8, 146.3, 143.6, 141.9, 137.8, 136.9, 134.6, 133.4, 132.6, 131.8, 130.7, 129.7, 129.4, 129.1, 128.8,
128.6, 128.2, 127.6, 124.6, 123.7, 118.7; IR (KBr) ν 2527 (br OH), 1715 (C=O acid), 1656 (Ar-C=O), 1620
(C=N) cm−1 ; MS: m/z = 478/480 [M+ ]; Analysis (% Calculated/found) for C29 H19 ClN2 O3 (Mw 478.94) C:
72.73/72.95, H: 4.00/3.85, N: 5.85/5.71.
2-[4-Ethyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazol-5-yl]benzoic acid (5g): Yield: 49%; mp
165-167 ◦ C; 1 H-NMR (DMSO-d6)δ 12.50 (1H, s, OH), 9.80 (1H, s, NH), 7.76-7.17 (14H, m, arom. H), 2.60
(2H, q,J 7.5, CH2), 1.09 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 159.5, 166.7, 146.8, 145.7, 142.2, 139.8,
138.1, 134.4, 133.1, 130.2, 129.6, 129.0, 128.7, 128.1, 127.7, 126.6, 124.6, 123.4, 121.8, 16.8, 13.6; IR (KBr)
ν 2525 (br OH), 1710 (C=O acid), 1665 (Ar-C=O), 1613 (C=N) cm−1 ; MS: m/z = 411 [M+ ]; Analysis (%
Calculated/found) for C25 H21 N3 O3 (Mw 411.46) C: 72.98/73.25, H: 5.14/4.92, N: 10.21/10.05.
2-[1-(4-Chlorophenyl)-4-ethyl-3-phenylcarbamoyl-1H-pyrazol-5-yl]benzoic acid (5h): Yield:
47%; mp 157-158 ◦ C; 1 H-NMR (DMSO-d6)δ 12.51 (1H, s, OH), 9.85 (1H, s, NH), 7.79-7.16 (13H, m, arom.
H), 2.63 (2H, q,J 7.5, CH2), 1.11 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 159.2, 166.7, 147.1, 145.9,
142.2, 138.2, 137.6, 134.1, 133.0, 131.8, 130.2, 129.7, 128.6, 128.4, 127.8, 124.6, 123.6, 121.6, 118.7, 16.8, 13.6;
IR (KBr) ν 2525 (br OH), 1712 (C=O acid), 1662 (Ar-C=O), 1616 (C=N) cm−1 ; MS: m/z = 445/447 [M+ ];
Analysis (% Calculated/found) for C25 H20 ClN3 O3 (Mw 445.91) C: 67.34/67.11, H: 4.52/4.70, N: 9.42/9.55.
2-[1-(4-Chlorophenyl)-4-phenyl-3-phenylcarbamoyl-1H-pyrazol-5-yl]benzoic acid (5i): Yield:
45%; mp 171-173 ◦ C; 1 H-NMR (DMSO-d6)δ 12.51 (1H, s, OH), 9.85 (1H, s, NH), 7.74-7.18 (13H, m, arom.
H); 13 C-NMR (DMSO-d6)δ 166.7, 159.4, 147.1, 146.3, 142.3, 141.2, 137.9, 137.5, 136.4, 134.6, 133.4, 131.8,
129.8, 129.4, 129.2, 128.9, 128.6, 128.4, 127.9, 127.3, 124.8, 123.7, 121.6; IR (KBr) ν 2525 (br OH), 1714
(C=O acid), 1660 (Ar-C=O), 1613 (C=N) cm−1 ; MS: m/z = 493/495 [M+ ]; Analysis (% Calculated/found)
531

Heterocyclic synthesis using nitrilimines: part 14...., H. M. DALLOUL
for C29 H20 ClN3 O3 (Mw 493.95) C: 70.52/70.85, H: 4.08/3.90, N: 8.51/8.40.
2-[4-Ethyl-1-(4-flurorophenyl)-3-phenylcarbamoyl-1H-pyrazol-5-yl]benzoic acid (5j): Yield:
43%; mp 181-183 ◦ C; 1 H-NMR (DMSO-d6)δ 12.50 (1H, s, OH), 9.75 (1H, s, NH), 7.76-7.22 (13H, m, arom.
H), 2.60 (2H, q,J 7.5, CH2), 1.10 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 159.2, 166.7, 160.9, 147.4,
146.5, 142.2, 138.1, 135.8, 134.7, 133.2, 130.5, 129.1, 128.8, 128.6, 127.9, 123.8, 121.7, 116.8, 115.7, 16.8, 13.6; IR
(KBr) ν 2525 (br OH), 1713 (C=O acid), 1665 (Ar-C=O), 1618 (C=N) cm−1 ; MS: m/z = 429 [M+ ]; Analysis
(% Calculated/found) for C25 H20 FN3 O3 (Mw 429.45) C: 69.92/70.28, H: 4.69/4.55, N: 9.78/9.65.
2-[1-(4-Methylphenyl)-4-phenyl-3-phenylcarbamoyl-1H-pyrazol-5-yl]benzoic acid (5k): Yield:
46%; mp 193-195 ◦ C; 1 H-NMR (DMSO-d6)δ 12.51 (1H, s, OH), 9.68 (1H, s, NH), 7.72-7.10 (18H, m, arom.
H), 2.73 (3H, s, p-CH3); 13 C-NMR (DMSO-d6) δ 159.5, 166.7, 147.4, 146.7, 142.3, 138.4, 137.1, 136.6, 136.2,
135.7, 134.4, 133.0, 130.4, 129.8, 129.4, 128.7, 128.5, 128.1, 127.8, 127.3, 125.7, 123.7, 121.6, 21.6; IR (KBr)
ν 2525 (br OH), 1711 (C=O acid), 1660 (Ar-C=O), 1615 (C=N) cm−1 ; MS: m/z = 473 [M+ ]; Analysis (%
Calculated/found) for C30 H23 N3 O3 (Mw 473.54) C: 76.09/75.81, H: 4.90/5.10, N: 8.87/9.05.
2-[1-(4-Chlorophenyl)-4-ethyl-3-(furan-2-yl)-1H-pyrazol-5-yl]benzoic acid (5l): Yield: 51%;
mp 172-173 ◦ C; 1 H-NMR (DMSO-d6)δ 12.53 (1H, s, OH), 8.12-7.28 (11H, m, arom. H), 2.67 (2H, q,J 7.5,
CH2), 1.11 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 173.4, 166.7, 149.5, 147.1, 146.6, 143.7, 142.2,
137.8, 134.1 132.9, 131.2, 130.9, 129.7, 128.7, 128.3, 124.8, 123.5, 121.2, 115.7, 16.8, 13.6; IR (KBr) ν 2525
(br OH), 1715 (C=O acid), 1655 (Ar-C=O), 1622 (C=N) cm−1 ; MS: m/z = 420/422 [M+ ]; Analysis (%
Calculated/found) for C23 H17 ClN2 O4 (Mw 420.86) C: 65.64/65.45, H: 4.07/3.90, N: 6.66/6.85.
2-[1-(4-Chlorophenyl)-4-ethyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl]benzoic acid (5m): Yield:
53%; mp 167-169 ◦ C; 1 H-NMR (DMSO-d6)δ 12.52 (1H, s, OH), 8.21-7.27 (11H, m, arom. H), 2.69 (2H,
q,J 7.5, CH2), 1.12 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 176.6, 166.7, 147.8, 146.3, 144.3, 142.0,
137.6, 135.9, 134.4, 133.7, 133.2, 131.4, 130.2, 129.6, 129.2, 128.7, 128.4, 124.3, 123.6, 16.8, 13.6; IR (KBr) ν
2525 (br OH), 1715 (C=O acid), 1665 (Ar-C=O), 1624 (C=N) cm−1 ; MS: m/z = 436/438 [M+ ]; Analysis (%
Calculated/found) for C23 H17 ClN2 O3 S (Mw 436.92) C: 63.23/63.50, H: 3.92/4.10, N: 6.41/6.25.
2-[1-(4-Chlorophenyl)-4-ethyl-3-(2-naphthoyl)-1H-pyrazol-5-yl]benzoic acid (5n): Yield: 47%;
mp 197-199 ◦ C; 1 H-NMR (DMSO-d6)δ 12.45 (1H, s, OH), 8.41-7.22 (15H, m, arom. H), 2.56 (2H, q,J 7.5,
CH2), 1.08 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 183.5, 166.7, 147.3, 146.1, 142.2, 139.1, 137.9, 134.7,
133.1, 132.6, 132.3, 131.7, 131.0, 130.6, 129.7., 129.1, 128.8, 128.3, 128.1, 127.9, 127.5, 126.9, 125.1, 124.6, 123.4,
16.8, 13.6; IR (KBr) ν 2525 (br OH), 1710 (C=O acid), 1645 (Ar-C=O), 1610 (C=N) cm−1 ; MS: m/z =
481/483 [M+ ]; Analysis (% Calculated/found) for C29 H22 ClN2 O3 (Mw 481.96) C: 72.27/72.56, H: 4.60/4.50,
N: 5.81/5.66.
2-[1-(4-Chlorophenyl)-3-(2-naphthoyl)-4-phenyl-1H-pyrazol-5-yl]benzoic acid (5o): Yield: 49%;
mp 170-172 ◦ C; 1 H-NMR (DMSO-d6)δ 12.45 (1H, s, OH), 8.45-7.24 (20H, m, arom. H); 13 C-NMR (DMSO-
d6)δ 183.6, 166.7, 147.1, 146.3, 141.7, 139.0, 137.8, 136.6, 134.3, 133.2, 132.8, 132.6, 131.8, 130.9, 130.2, 129.6,
129.3, 129.1, 128.8, 128.6, 128.4, 128.2, 127.9, 127.7, 127.3, 126.7, 124.6, 124.2, 123.4; IR (KBr) ν 2525 (br
OH), 1712 (C=O acid), 1647 (Ar-C=O), 1615 (C=N) cm−1 ; MS: m/z = 528/530 [M+ ]; Analysis (% Calcu-
lated/found) for C33 H21 ClN2 O3 (Mw 529.00) C: 74.93/75.25, H: 4.00/3.85, N: 5.30/5.43.
2-[4-Ethyl-1-(4-methylphenyl)-3-(2-naphthoyl)-1H-pyrazol-5-yl]benzoic acid (5p): Yield: 45%;
532

Heterocyclic synthesis using nitrilimines: part 14...., H. M. DALLOUL
mp 184-186 ◦ C; 1 H-NMR (DMSO-d6)δ 12.46 (1H, s, OH), 8.43-7.26 (15H, m, arom. H), 2.72 (3H, s, p-CH3),
2.58 (2H, q,J 7.5, CH2), 1.09 (3H, t, J 7.5, CH3); 13 C-NMR (DMSO-d6)δ 183.4, 166.7, 146.5, 145.7, 140.8,
139.0, 136.8, 135.7, 134.5, 133.0, 132.4, 132.1, 130.8, 130.2, 129.7, 129.3, 128.6, 128.5, 128.3, 128.1, 127.7, 126.9,
124.6, 123.2, 21.7, 16.8, 13.6; IR (KBr) ν 2525 (br OH), 1710 (C=O acid), 1645 (Ar-C=O), 1612 (C=N)
cm−1 ; MS: m/z = 460 [M+ ]; Analysis (% Calculated/found) for C30 H24 N2 O3 (Mw 460.54) C: 78.24/77.90,
H: 5.25/5.42, N: 6.08/5.96.
Results and discussion
The required nitrilimines 2 were generated in situ by base-promoted dehydrohalogenation of the corresponding
hydrazonoyl halides 1. Treatment of the resulting non-isolable nitrilimines 2, 1,3-dipole, with phthalides 3 in
refluxing benzene gave in each case a single product that proved to be the respective 1,3,4,5-tetrasubstituted
pyrazoles 5a-p instead of spiropyrazoline derivatives 4. The proposed mechanism involved initial formation of
the spiro intermediates 4 via 1,3-dipolar cycloaddition of nitrilimines 2 to the exocyclic double bond of compound
3. The latter intermediates, which cannot be isolated nor observed by TLC, ultimately underwent ring opening
via 1,3-hydrogen shift to aromatic pyrazole derivatives 5a-p as outlined in the Scheme. It is worth mentioning
that the nitrile oxides generated in situ from the respective hydroxamoyl chlorides with triethylamine as a base
react with 3-benzylidenephthalides to afford isoxazoles.31 The purity of obtained compounds was controlled
by TLC and elemental analysis. Both the analytical and spectral data (IR, 1 H-NMR, 13 C-NMR, and mass
spectra) of the synthesized pyrazoles were in full agreement with the proposed structures.
Ar
-
Cl(Br)
H
N
+
O
N
O
N
N
O
O
N
2
Ar
i
O
N
Ar
1R
ii
1R
+
1R
1
2R
H
O
O
2R
4
3
Ar
CO2H
N
N
i) Et3N, r.t.; ii) Benzene, reflux, 12-16 h.
O
3
Ar = 4-R -C6H4-
1
2
3
R /R /R = 5a: Me/Et/Cl; 5b: Me/Et/CH3; 5c: Me/Ph/H;
1R
2R
5d:MeO/Et/Cl; 5e:Ph/Et/Cl; 5f:Ph/Ph/Cl; 5g:PhNH/Et/H;
5h: PhNH/Et/Cl; 5i: PhNH/Ph/Cl; 5j: PhNH/Et/F;
5k:PhNH/Ph/CH3;5l:2-C4H3O/Et/Cl; 5m: 2-C4H3S/Et/Cl;
5a-p
5n: 2-C10H7/Et/Cl; 5o: 2-C10H7/Ph/Cl; 5p: 2-C10H7/Et/CH3.
Scheme. Synthetic pathway for the preparation of pyrazoles 5a-p.
The characterization data of the synthesized compounds 5a-p are given in the Experimental section. The
electron impact (EI) mass spectra displayed the correct molecular ions (M+.) in accordance with the suggested
533

Heterocyclic synthesis using nitrilimines: part 14...., H. M. DALLOUL
structures. The IR spectra of compounds 5a-p revealed 2 strong absorption bands in the regions 1720-1710
cm−1 (COOH) and 1690-1640 cm−1 (C=O aroyl). The stretching band for C=N of the pyrazole ring appeared
in the region 1620-1610 cm−1 . All these products gave a singlet signal at 12.5 ppm in their 1 H-NMR spectra
assignable to benzoic acid moiety. Their 13 C-NMR spectra showed all the signals of the proposed structures;
in particular the carbon of the carboxyl group was found to resonate at about 167 ppm and the signal at about
147-145 ppm was attributed to C=N of the pyrazole ring. The complete 13 C-NMR data are presented in the
Experimental section.
In conclusion, we described the 1,3-dipolar cycloadditions of nitrilimines to some exocyclic olefins and
the results demonstrated that the aromatization was the driving force for the formation of aromatic pyrazole
derivatives.
References
1. Caramella, P.; Grunanger, P.; in 1,3-Dipolar Cycloaddition Chemistry; A. Padwa, Ed., Wiley Interscience, New
York, 1984, pp. 291-319.
2. Carruthers, W.; Cycloaddition Reaction in Organic Synthesis, Pergamon Press, New York, 1990; Shawali, A. S.;
Parkanyi, C.; J. Heterocycl. Chem. 1980, 17, 833-854; Tanaka, K.; Maeno, S.; Mitsuhashi, K.; J. Heterocycl. Chem.
1985, 22, 565-568; Shawali, A. S.; Abdelkader, M. H.; Altablawy, F. M.; Tetrahedron 2000, 58, 2875-2880; Shawali,
A. S.; Mosselhi, M. H.; Altablawy, F. M.; Farghaly, T. A.; Tawfik, N. M.; Tetrahedron 2008, 64, 5524-5530; Shawali,
A. S.; Hassaneen, H. M.; Shurrab, N. Kh.; Tetrahedron 2008, 64, 10339-10343; Abunada, N. M.; Hassaneen, H.
M.; Kandile, N, G.; Miqdad, A. O.; Molecules 2008, 13, 1011-1024.
3. Hassaneen, H. M.; Hilal, R. H.; Elwan, N. M.; Harhash, A.; Shawali, A. S.; J. Heterocycl. Chem. 1984, 21, 1013-
1016.
4. Agocs, A.; Benyei, A.; Somogy, L.; Herczegh, P.; Tetrahedron: Asymmetry 1998, 9, 3359-3363.
5. Donohue, S. R.; Halldin, C.; Pike, V. W.; Tetrahedron Lett. 2008, 49, 2789- 2791; Mernyak, E.; Kozma, E.; Hetenyi,
A.; Mark, L.; Schneider, G.; Wolfling, J.; Steroids 2009, 74, 520-525.
6. Kerbal, A.; Tshiamala, K.; Vebrel, J.; Laude, B.; Mercier, M. F.; Bull. Soc, Chim. Belg. 1991, 100, 159-168.
7. Jedlovska, E.; Levai, A.; Toth, G.; Balazs, B.; Fisera, L.; J. Heterocycl. Chem. 1999, 36, 1087-1090.
8. Mishriky, N.; Girgis, A. S.; Ibrahim, Y. A.; J. Chem. Res. S, 2000, 1, 2-3.
9. Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S.; Targets Heterocycl. Syst. 2002, 6, 52-98.
10. Henningfield, J. E.; Fant, R. V.; Buchhalter, A. R.; Stitzer, M. L.; CA Cancer J. Clin. 2005, 55, 281-299.
11. Glass, M.; Van Dellen, A.; Blakemoore, C.; Hannan, A. J.; Faull, R. L.; Neuroscience 2004, 123, 207-212; J. H.
M. Lange, C. G. Kruse, Drug Discovery Today 2005, 10, 693-702.
12. Eriksson, B. I.; Quinlan, D. J.; Drugs 2006, 66, 1411-1429.
13. Oh, L. M.; Tetrahedron Lett. 2006, 47, 7943-7946.
14. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee,
I. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.;
Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C.; J. Med. Chem. 1997, 40, 1347-1365.
534

Heterocyclic synthesis using nitrilimines: part 14...., H. M. DALLOUL
15. Escolar, G.; Villaha, J.; Casals, F.; Bozzo, J.; Serradell, N.; Bolos, J.; Drugs Future 2006, 31, 484-493.
16. Deeb, A.; El-Meriah, F.; Hosny, M.; Bioorg. Med. Chem. Lett. 2004, 14, 5013-5017; Farghaly, A. M.; Soliman, F.
S. G.; El-Semary, M. M. A.; Rostom, Sh. A. F.; Pharmazie 2001, 56, 28-32.
17. Rashad, A. E.; Hegab, M. I.; Abdel-Mageid, R. E.; Mickey, J. A; Abdel-Mageid, F. M. E.; Bioorg. Med. Chem.
2008, 16, 7102-7106.
18. Rosinger, C.; Van Den Berg, J.; Geraats, B.; PCT Int. Appl. WO 2006007982, 2006.
19. Seki, K.; Isegawa, J.; Fukuda, M.; Ohki, M.; Chem. Pharm. Bull. 1984, 32, 1568-1577.
20. Cottineau, B.; Toto, P.; Marot, C.; Pipaud, A.; Chenault, I.; Bioorg. Med. Chem. Lett. 2002, 12, 2105-2108.
21. Bouabdallah, I.; Mbarek, L. A.; Zyad, A.; Ramadan, A.; Zidane, I.; Melhaoui, A.; Nat. Prod. Res. 2006, 20,
1024-1030.
22. McKeown, S. C.; Hall, A.; Giblin, G. M. P.; Lorthioir, O.; Blunt, R.; Lewell, X. Q.; Wilson, R. J.; Brown, S. H.;
Chowdhury, A.; Coleman, T.; Watson, S. P.; Chessell, I. P.; Pipe, A.; Clayton, N.; Goldsmith, P.; Bioorg. Med.
Chem. Lett. 2006, 16, 4767-4771.
23. Akrea, U. S.; Curr. Pharm. Des. 2005, 11, 1779-1793.
24. Meagher, E. A.; Curr. Pharm. Des. 2004, 10, 603-611.
25. Dalloul, H. M.; Synthetic Commun. 2009, 39, 1847-1856; Dalloul, H. M.; J. Chin. Chem. Soc. 2009, 56, 196-201;
Dalloul, H. M.; Al-Shorafa, A. Z.; Org. Commun., 2009, 2:1, 20-27; Dalloul, H. M.; Arkivoc, 2008, (xiv), 234-241;
Dalloul, H. M.; Mohamed, E. A. R.; Shorafa, H. Z.; El-Shorafa, A. Z.; Arkivoc 2008, (xiii), 207-217;;alloul, H. M.;
Chem. Heterocycl. Comp. 2004, 40, 1402-1407.
26. Dalloul, H. M.; Boyle, P. H.; Teterocycl. Commun. 2007, 13, 155-160; Dalloul, H. M.; Boyle, P. H.; Turk. J. Chem.
2006, 30, 119-124; El-Abadelah, M. M.; Hussein, A. Q.; Thaher, B. A.; Teterocycles 1991, 32, 1879-1895; Shawali,
A. S.; Abdelhamid, A. O.; Bull. Chem. Soc. Jap. 1976, 49, 321-324; Hassaneen, H. M.; Shawali, A. S.; Elwan, N.
M.; Abounada, N. M.; Sulfur Lett. 1992, 13, 273-285; Hassaneen, H. M.; Shawali, A. S.; Elwan, N. M.; Abounada,
N. M.; Org. Prep. Proced. Int. 1992, 24, 171-175.
27. Frohberg, P.; Drutkowski, G.; Wagner, C.; Eur. J. Org. Chem. 2002, 1654-1663.
28. Shawali, A. S.; Hassaneen, H. M.; Shetta, A.; Osman, A.; Abdel-Galil, F.; Teterocycles 1982, 19, 57-62; Farag, A.
M.; Algharib, M. S. Org. Prep. Proced. Int. 1988, 20, 521-526; El-Abadelah, M. M.; Hussein, A. Q.; Kamal, M.
R.; Al-Adhami, K. H. Heterocycles 1988, 27, 917-924.
29. Vebrel, J.; Msaddek, M.; Djapa, F.; Ciamala, K.; Laude, B.; Eur. J. Org. Chem. 1998, 2855-2863.
30. Mali, R. S.; Massey, A. P.; Talele, M. I. J. Chem. Res-s (S) 1998, 68-69; (M) 1998, 472-500.
31. Howe, R. K.; Shelton, B. R.; Lui, C.; J. Org. Chem. 1985, 50, 903.
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