One-pot synthesis of functionalized 3-aryl-1-phenyl-1H-pyrazoles from hydrazonoyl chlorides and acetylenic esters in the presence of Ph3P

Article abstract of DOI:10.1002/hlca.200900246

The zwitterionic 1 :1 intermediates generated by addition of Ph ₃P to acetylenic esters is trapped by 1-[(aryl)chloromethylene]-2- phenylhydrazines (=N-phenylarenecarbohydrazonoyl chlorides) to yield functionalized 3-aryl-1-phenyl-1H-pyrazoles

Full text of DOI:10.1002/hlca.200900246

Helvetica Chimica Acta – Vol. 93 (2010)
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One-Pot Synthesis of Functionalized 3-Aryl-1-phenyl-1H-pyrazoles from
Hydrazonoyl Chlorides and Acetylenic Esters in the Presence of Ph3P
by Issa Yavari*, Gholamhossein Khalili, and Anvar Mirzaei
Chemistry Department, Tarbiat Modares University, P. O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-82883465; fax: þ 98-21-82883455; e-mail: yavarisa@modares.ac.ir)
The zwitterionic 1:1 intermediates generated by addition of Ph3P to acetylenic esters is trapped by 1-
[(aryl)chloromethylene]-2-phenylhydrazines (¼ N-phenylarenecarbohydrazonoyl chlorides) to yield
functionalized 3-aryl-1-phenyl-1H-pyrazoles in good yields.
Introduction. – Pyrazoles have occupied a unique position in the design and
synthesis of novel biologically active agents that exert remarkable anticancer activities.
In fact, pyrazoles have been studied for over a century as an important class of
heterocyclic compounds and still continue to attract considerable attention due to the
broad range of biological activities they possess [1 – 4]. Among these, N-arylpyrazoles
are an interesting class of heterocycles with remarkable pharmacological activities such
as antibacterial-antifungal [5], tumor-necrosis inhibitor [6], antimicrobial [7], hypo-
glycemic [8], hypolipidemic [9], and anti-inflammatory [10][11].
Results and Discussion. – As a part of our current studies on the development of
new routes in heterocyclic synthesis [12 – 15], we report the results of our studies
involving the reaction of the zwitterionic intermediates derived from triphenylphos-
phine (Ph3P) and acetylenic esters 1 with 1-[(aryl)chloromethylene]-2-phenylhydra-
zines (¼ N-phenylarenecarbohydrazonoyl chlorides) 2 [16 – 18], which constitutes a
synthesis of functionalized 3-aryl-1-phenyl-1H-pyrazoles (3) in good yields (Scheme 1).
1
The structures of compounds 3a – 3j were deduced from their IR, H-NMR, and
13C-NMR spectra. For example, the 1H-NMR spectrum of 3a exhibited two ss (d 3.87
1
and 3.90) for the MeO groups, along with ms for the Ph groups. The H-decoupled
13C-NMR spectrum of 3a showed 15 distinct resonances that confirm the proposed
structure. The IR spectrum of 3a displayed characteristic C¼O bands (1726 and
1725 cmꢀ1). The NMR spectra of 3b – 3j were similar to those for 3a, except for the aryl
and ester moieties, which exhibited characteristic resonances in appropriate regions of
the spectra. The 1H-NMR spectra of 3e – 3j exhibited a s at d ca. 8.50 for the pyrazole
CH group, which confirms the proposed structures.
Although the mechanistic details of the reaction are not known, a plausible
rationalization may be advanced to explain the product formation. Presumably, the
zwitterionic intermediate [19 – 21] 4, formed from Ph3P and 1, adds to the hydrazonoyl
chloride 2 to produce 5 (Scheme 2). This intermediate undergoes a cyclization reaction
to afford 6, which is converted to 3 by elimination of Ph3P.
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1
Scheme 2
The formation of a mixture of two regioisomers of 1,3,4-trisubstituted and 1,3,5-
trisubstituted pyrazoles, in a ratio of 1:4, has been reported [22] from the reaction of 1-
[(aryl)chloromethylene]-2-phenylhydrazines with alkyl prop-2-ynolates 1c and 1d in
the presence of Et3N. When we carried out this reaction in the presence of Ph3P, only
one regioisomer, namely the 1,3,4-trisubstituted products 3e – 3j, were obtained in 83 –
92% yields. Structures 3e – 3j were distinguished from the corresponding 1,3,5-
trisubstituted pyrazoles by their NMR spectra. Thus, the methine H-atom of 3e – 3j
showed a s at d > 8.5, whereas the methine signal of the 1,3,5-trisubstituted pyrazoles is
expected at d ca. 7 ppm. Similarly, the 13C-NMR signal of the pyrazole CH group in
compounds 3e – 3j appeared at d > 130, which is a deshielding by more than 10 ppm
compared to the expected resonance for the 1,3,5-trisubstituted isomer.
In conclusion, the zwitterionic 1:1 intermediates generated by addition of Ph3P to
acetylenic esters is trapped by 1-[(aryl)chloromethylene]-2-phenylhydrazines to yield
functionalized 3-aryl-1-phenyl-1H-pyrazoles in good yields. The present method may
be considered as a practical route for the synthesis of pyrazole-ring systems.
Experimental Part
General. Compounds 1 and Ph3P were obtained from Merck and used without further purification.
Compounds 2 were prepared according to [16]. M.p.: Electrothermal-9100 apparatus; uncorrected. IR
Spectra: Shimadzu-IR-460 spectrometer; ˜n in cmꢀ1. 1H- and 13C-NMR Spectra: Bruker-DRX-500-Avance
instrument; in CDCl3 at 500.1 and 125.7 MHz, resp.; d in ppm, J in Hz. MS: Finnigan-MAT-8430 mass
spectrometer, at 70 eV; in m/z (rel. %). Elemental analyses (C, H, N): Heraeus-CHN-O-Rapid analyzer.

Helvetica Chimica Acta – Vol. 93 (2010)
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Compounds 3: General Procedure. To a stirred soln. of Ph3P (0.52 g, 2 mmol) and 1-[(aryl)chloro-
methylene]-2-phenylhydrazine 2 (2 mmol) in MeCN (10 ml) was added the acetylenic ester 1 (2 mmol) at
ꢀ 58. The mixture was allowed to reach r.t. After completion of the reaction (2 – 4 h; TLC (AcOEt/
hexane 2 :1) monitoring), the solvent was evaporated, and the residue was purified by column
chromatography (silica gel (230 – 240 mesh; Merck), hexane/AcOEt 4 :1): pure product.
Dimethyl 1,3-Diphenyl-1H-pyrazole-4,5-dicarboxylate (3a): Yield 0.31 g (93%). Colorless crystals.
M.p. 153 – 1558. IR (KBr): 1726 (C¼O), 1725 (C¼O), 1521, 1487, 1442, 1265, 1227, 1140, 1098, 1015, 786,
752, 688. 1H-NMR: 3.87 (s, MeO); 3.90 (s, MeO); 7.45 – 7.55 (m, 6 CH); 7.57 – 7.59 (m, 2 CH); 7.78 – 7.80
(m, 2 CH). 13C-NMR: 52.1 (MeO); 53.1 (MeO); 114.4 (C); 124.6 (2 CH); 128.2 (2 CH); 128.8 (2 CH);
129.0 (CH); 129.1 (CH); 129.2 (2 CH); 131.4 (C); 136.9 (C); 139.1 (C); 152.0 (C); 160.7 (COO); 163.4
(COO). EI-MS: 336 (75, Mþ), 305 (90), 77 (100), 51 (60). Anal. calc. for C19H16N2O4 (336.34): C 67.85, H
4.79, N 8.33; found: C 67.72, H 4.85, N 8.20.
Dimethyl 3-(4-Methylphenyl)-1-phenyl-1H-pyrazole-4,5-dicarboxylate (3b): Yield 0.31 g (90%).
Colorless crystals. M.p. 65 – 678. IR (KBr): 1729 (C¼O), 1706 (C¼O), 1585, 1527, 1490, 1432, 1292, 1261,
1230, 1179, 1110, 1003, 817, 750, 688. 1H-NMR: 2.42 (s, Me); 3.85 (s, MeO); 3.88 (s, MeO); 7.26 (d, 3J ¼
8.0, 2 CH); 7.43 – 7.49 (m, CH); 7.55 (d, 3J ¼ 7.8, 2 CH); 7.67 (d, 3J ¼ 8.0, 2 CH). 13C-NMR: 21.3 (Me); 52.0
(MeO); 53.0 (MeO); 114.1 (C); 124.6 (2 CH); 128.5 (C); 128.7 (2 CH); 128.9 (2 CH); 129.1 (CH); 129.3
(2 CH); 136.8 (C); 138.3 (C); 139.2 (C); 152.0 (C); 160.7 (COO); 163.5 (COO). EI-MS: 350 (75, Mþ),
319 (84), 77 (100), 51 (65). Anal. calc. for C20H18N2O4 (350.37): C 68.56, H 5.18, N 8.00; found: C 68.78, H
5.25, N 8.10.
Diethyl 1,3-Diphenyl-1H-pyrazole-4,5-dicarboxylate (3c): Yield 0.32 g (90%). Pale yellow crystals.
M.p. 52 – 538. IR (KBr): 1716 (C¼O), 1702 (C¼O), 1523, 1489, 1440, 1261, 1227, 1143, 1099, 1011, 756,
691. 1H-NMR: 1.26 (t, 3J ¼ 6.3, Me); 1.31 (t, 3J ¼ 6.3, Me); 4.33 – 4.35 (m, 2 CH2O); 7.44 – 7.48 (m, 4 CH);
7.55 – 7.57 (m, CH); 7.78 – 7.80 (m, CH). 13C-NMR: 13.7 (Me); 14.0 (Me); 61.1 (CH2O); 62.4 (CH2O);
114.4 (C); 124.8 (2 CH); 128.1 (2 CH); 128.7 (CH); 128.8 (2 CH); 128.9 (CH); 129.1 (2 CH); 131.6 (C);
137.1 (C); 139.2 (C); 151.9 (C); 160.2 (COO); 162.9 (COO). EI-MS: 364 (69, Mþ), 319 (85), 77 (100), 51
(55). Anal. calc. for C21H20N2O4 (364.40): C 69.22, H 5.33, N 7.69; found: C 69.30, H 5.40, N 7.80.
Diethyl 3-(4-Methylphenyl)-1-phenyl-1H-pyrazole-4,5-dicarboxylate (3d): Yield 0.33 g (89%). Pale
yellow crystals. M.p. 210 – 2128. IR (KBr): 1728 (C¼O), 1706 (C¼O), 1525, 1488, 1432, 1261, 1229, 1170,
1153, 1109, 1002, 816, 749. 1H-NMR: 1.24 (t, 3J ¼ 7.1, Me); 1.30 (t, 3J ¼ 7.1, Me); 2.40 (s, Me); 4.28 – 4.33
(m, 2 CH2O); 7.24 (d, 3J ¼ 7.9, 2 CH); 7.45 – 7.50 (m, CH); 7.53 – 7.55 (m, 2 CH); 7.66 (d, 3J ¼ 7.9, 2 CH).
13C-NMR: 13.8 (Me); 14.0 (Me); 21.3 (Me); 61.0 (CH2O); 62.3 (CH2O); 114.3 (C); 124.8 (2 CH); 128.6
(C); 128.7 (2 CH); 128.8 (2 CH); 128.9 (CH); 129.0 (2 CH); 136.8 (C); 138.7 (C); 139.3 (C); 152.0 (C);
160.1 (COO); 163.0 (COO). EI-MS: 378 (75, Mþ), 333 (70), 77 (100), 51 (59). Anal. calc. for C22H22N2O4
(378.42): C 69.83, H 5.86, N 7.40; found: C 69.68, H 5.80, N 7.31.
Methyl 1,3-Diphenyl-1H-pyrazole-4-carboxylate (3e): Yield 0.25 g (92%). Pale yellow crystals. M.p.
110 – 1128. IR (KBr): 1692 (C¼O), 1589, 1525, 1433, 1360, 1274, 1221, 1133, 1053, 1007, 753, 680.
3
4
3
1H-NMR: 3.85 (s, MeO); 7.39 (t, J ¼ 6.4, CH); 7.42 – 7.53 (m, 5 CH); 7.81 (dd, J ¼ 1.0, J ¼ 8.5, 2 CH);
7.91 (dd, J ¼ 1.4, J ¼ 8.0, 2 CH); 8.53 (s, CH). 13C-NMR: 50.8 (MeO); 112.8 (C); 119 (2 CH); 126.9
(CH); 127.4 (2 CH); 128.2 (CH); 128.8 (2 CH); 129.0 (2 CH); 131.6 (C); 131.7 (CH); 138.7 (C); 153.5
(C); 162.8 (COO). EI-MS: 278 (70, Mþ), 247 (63), 77 (100), 51 (66). Anal. calc. for C17H14N2O2 (278.31):
C 73.37, H 5.07, N 10.07; found: C 73.50, H 5.10, N 10.15.
4
3
Methyl 3-(4-Methylphenyl)-1-phenyl-1H-pyrazole-4-carboxylate (3f): Yield 0.25 g (86%). Pale
yellow crystals. M.p. 103 – 1058. IR (KBr): 1723 (C¼O), 1587, 1517, 1492, 1443, 1275, 1201, 1108, 1024,
823, 750, 687. 1H-NMR: 2.44 (s, Me); 3.86 (s, MeO); 7.27 (t, 3J ¼ 7.8, 2 CH); 7.37 (t, 3J ¼ 7.5, CH); 7.48 –
7.51 (m, 2 CH); 7.78 – 7.80 (m, 4 CH); 8.51 (s, CH). 13C-NMR: 21.4 (Me); 51.3 (MeO); 113.3 (C); 119.5
(2 CH); 127.4 (CH); 126.6 (2 CH); 128.0 (C); 129.2 (2 CH); 129.5 (2 CH); 132.2 (CH); 138.6 (C); 139.3
(C); 154.1 (C); 163.4 (COO). EI-MS: 292 (72, Mþ), 261 (68), 77 (100), 51 (69). Anal. calc. for
C18H16N2O2 (292.33): C 73.96, H 5.52, N 9.58; found: C 73.90, H 5.60, N 9.64.
Ethyl 1,3-Diphenyl-1H-pyrazole-4-carboxylate (3g): Yield 0.25 g (87%). Pale yellow crystals. M.p.
63 – 648. IR (KBr): 1679 (C¼O), 1525, 1272, 1224, 1143, 1029, 744, 681. 1H-NMR: 1.34 (t, 3J ¼ 7.2, Me);
4.33 (q, 3J ¼ 7.2, CH2O); 7.38 (t, 3J ¼ 7.4, CH); 7.42 – 7.53 (m, 5 CH); 7.81 (d, 3J ¼ 8.3, 2 CH); 7.89 (d, 3J ¼
8.3, 2 CH); 8.53 (s, CH). 13C-NMR: 14.2 (Me); 60.3 (CH2O); 113.8 (C); 119.5 (2 CH); 127.4 (CH); 127.9

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(2 CH); 128.6 (CH); 129.4 (2 CH); 129.6 (2 CH); 132.3 (CH); 138.5 (C); 139.3 (C); 154.0 (C); 162.9
(COO). EI-MS: 292 (74, Mþ), 247 (65), 77 (100), 51 (66). Anal. calc. for C18H16N2O2 (292.33): C 73.96, H
5.52, N 9.58; found: C 73.90, H 5.58, N 9.71.
Ethyl 3-(4-Methylphenyl)-1-phenyl-1H-pyrazole-4-carboxylate (3h): Yield 0.26 g (85%). Pale yellow
crystals. M.p. 98 – 1008. IR (KBr): 1682 (C¼O), 1522, 1272, 1220, 1133, 1052, 765, 677. 1H-NMR: 1.34 (t,
3J ¼ 7.1, Me); 2.41 (s, Me); 4.30 (q, 3J ¼ 7.1, CH2O); 7.26 (t, 3J ¼ 7.9, 2 CH); 7.35 (t, 3J ¼ 7.4, CH); 7.47 – 7.50
(m, 2 CH); 7.77 – 7.80 (m, 4 CH); 8.50 (s, CH). 13C-NMR: 14.3 (Me); 21.3 (Me); 60.3 (CH2O); 113.7 (C);
119.5 (2 CH); 127.3 (CH); 128.4 (C); 128.5 (2 CH); 129.3 (2 CH); 129.5 (2 CH); 132.3 (CH); 138.5 (C);
139.3 (C); 154.0 (C); 163.0 (COO). EI-MS: 306 (77, Mþ), 261 (62), 77 (100), 51 (60). Anal. calc. for
C19H18N2O2 (306.36): C 74.49, H 5.92, N 9.14; found: C 74.60, H 5.85, N 9.25.
Methyl 3-(4-Chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxylate (3i): Yield 0.25 g (83%). Pale
yellow crystals. M.p. 1498. IR (KBr): 1692 (C¼O), 1597, 1527, 1501, 1436, 1277, 1222, 1138, 1090, 1061,
1
3
3
1091, 959, 838, 771, 702. H-NMR: 3.84 (s, MeO); 7.37 (t, J ¼ 7.4, CH); 7.42 (d, J ¼ 8.5, 2 CH); 7.50 (t,
3
3
3J ¼ 7.8, 2 CH); 7.77 (d, J ¼ 7.8, 2 CH); 7.87 (d, J ¼ 8.5, 2 CH); 8.50 (s, CH). 13C-NMR: 51.4 (MeO);
113.3 (C); 119.5 (2 CH); 127.6 (CH); 128.1 (C); 129.5 (2 CH); 130.5 (2 CH); 130.6 (2 CH); 132.4 (CH);
134.7 (C); 139.1 (C); 152.8 (C); 163.1 (COO). EI-MS: 312 (70, Mþ), 281 (72), 77 (100), 51 (56). Anal.
calc. for C17H13ClN2O2 (312.74): C 65.28, H 4.20, N 8.95; found: C 65.13, H 4.53, N 8.71.
Ethyl 3-(4-Chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxylate (3j): Yield 0.28 g (86%). Pale yellow
crystals. M.p. 146 – 1488. IR (KBr): 1685 (C¼O), 1596, 1531, 1273, 1225, 1130, 1059, 1030, 953, 839, 770.
1H-NMR: 1.34 (t, 3J ¼ 7.1, Me); 4.31 (q, 3J ¼ 7.1, CH2O); 7.37 (t, 3J ¼ 7.3, CH); 7.42 (d, 3J ¼ 8.4, 2 CH); 7.50
3
3
3
(t, J ¼ 7.9, 2 CH); 7.77 (d, J ¼ 8.1, 2 CH); 7.87 (d, J ¼ 8.4, 2 CH); 8.50 (s, CH). 13C-NMR: 14.2 (Me);
60.4 (CH2O); 113.7 (C); 119.5 (2 CH); 127.5 (CH); 128.0 (C); 129.5 (2 CH); 130.6 (2 CH); 130.7 (2 CH);
132.3 (CH); 134.7 (C); 139.2 (C); 152.8 (C); 162.7 (COO). EI-MS: 326 (71, Mþ), 281 (71), 77 (100), 51
(58). Anal. calc. for C18H15ClN2O2 (326.77): C 66.15, H 4.62, N 8.57; found: C 66.73, H 4.19, N 8.43.
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Received June 29, 2009