A novel synthesis of 5-aryl-3-phenylpyrazole from 2-aryl-3-benzoyl-1,1- cyclopropanedicarbonitrile and hydrazine

Article abstract of DOI:10.1002/jhet.5570430237

A new process for synthesis of 5-aryl-3-phenylpyrazole is achieved. The regioselective ring-opening reaction of 2-aryl-3-benzoyl-1,1- cyclopropanedicarbonitrile with hydrazine plays a crucial role in the described process.

Full text of DOI:10.1002/jhet.5570430237

Mar-Apr 2006
495
A Novel Synthesis of 5-Aryl-3-Phenylpyrazole from 2-Aryl-3-
Benzoyl-1,1-cyclopropanedicarbonitrile and Hydrazine
Zhongjiao Ren *a, Weiguo Cao a, b, Jie Chen a, Yu Wang a, Weiyu Ding a
[a] Department of Chemistry, Shanghai University, Shanghai, 200444, P. R. China
[b] State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, 200032, P. R. China
Received June 6, 2005
H
Ph
CN
CN
H
.
+NH2NH2 H2O
N
DME
reflux 3h
Ar
Ar
N
H
COPh
2
3
1
Yield: 55-75%
A new process for synthesis of 5-aryl-3-phenylpyrazole is achieved. The regioselective ring-opening
reaction of 2-aryl-3-benzoyl-1,1-cyclopropanedicarbonitrile with hydrazine plays a crucial role in the
described process.
J. Heterocyclic Chem., 43, 495 (2006).
Pyrazoles have found wide uses in pharmaceuticals and
agrochemistry [1]. The importance of this class of
compounds led to extensive effort towards the
development of methods for preparation of pyrazole [2].
Pyrazoles are usually prepared by the reaction between
hydrazine with ꢀ-difunctional compounds and 1,3-dipolar
cycloadditions of diazo compounds [3]. Although these
methods are very frequently used, a mixture of regio-
isomeric pyrazoles is produced when the unsymmetrically
substituted compounds are used as substrates [4]. In
general, the regioselectivity in the synthesis of the
substituted pyrazole is still a problem. Much effort has
been devoted to the development of regioselective
synthesis of pyrazole [5].
A survey of the literature reveals that the methods for
regioselective synthesis of the 5-aryl-3-phenylpyrazole
were seldom reported in the past, such as the preparation of
5-aryl-3-phenylpyrazole by ꢀ-tosylhydrazone phosphonates
[5d] or dilithiophenyl hydrazones [5e]. These processes
suffered from harsh conditions, poor availability of starting
material and lack of generality. The facts mentioned above
prompted us to develop a general regioselective process for
preparation of 5-aryl-3-phenylpyrazole.
broad range of valuable products [6]. We have reported
some reactions of electron deficient cyclopropane with
oxygen [7] and nitrogen nucleophiles [8]. These processes
are regio-and stereoselective.
It was reported that the reaction of ꢁ,ꢀ-unsaturated
carbonyl compound with hydrazine afforded pyrazole
derivates [5b,9]. It is well known that the chemistry of the
cyclopropane C-C single bond resembles that of carbon-
carbon double bond [6]. We think that the reactivity of the
cyclopropane with carbonyl group is similar to that of
a,b-unsaturated carbonyl compound. A natural exten-
sion of our work was to examine the reaction of cyclo-
propyl ketone with hydrazine. Here we reported a
successful process for synthesis of 5-aryl-3-phenylpyra-
zoles from 2-aryl-3-benzoyl-1,1-cyclopropanedicarbo-
nitriles with hydrazine (Scheme 1).
Scheme 1
H
Ph
CN
CN
H
+
NH2NH2•H2O
N
DME reflux
Ar
Ar
N
H
COPh
2
1
3
For some years, our group has engaged in the nucleo-
philic addition reaction of cyclopropanes because these
compounds can undergo regio- and stereoselective ring-
opening reactions with various nucleophiles to yield a
In a typical general experimental procedure, the mixture
of 2-aryl-3-benzoyl-1,1-cyclopropanedicarbonitrile (1
mmol) and hydrazine hydrate (85%) (120 mg, 2 mmol) in
Table 1
Synthesis of Pyrazole from Cyclopropane and Hydrazine
Entry
Product
Ar
Yield %
Entry Product Ar
Yield %
1
2
3
4
3a
3b
3c
3d
C6H5
58
74
69
70
5
6
7
8
3e
3f
2-ClC6H4
75
70
69
55
4-FC6H4
4-BrC6H4
4-ClC6H4
2,4-(Cl)2C6H3
4-CH3C6H4
4-CH3OC6H4
3g
3h

496
Z. Ren , W. Cao , J. Chen , Y. Wang, W. Ding
Vol 43
EXPERIMENTAL
dimethoxyethane (DME) (4 ml) was refluxed for 3 h to
afford 5-aryl-3-phenylpyrazoles in 55%-75%. The results
were shown in Table 1.
The structures of pyrazoles 3a-h were confirmed by H
NMR, MS, IR, elementary analysis and X-ray (3a).
All reagents and solvents were obtained from commercial
source and used without purification. The 2-aryl-3-benzoyl-1,1-
cyclopropanedicarbonitriles were prepared by methods reported
in the literature [10]. All melting points are uncorrected.
Melting points were determined on WRS-1 digital melting point
apparatus made by Shanghai physical instrument factory
(SPOIF), China. IR spectra were measured in KBr on a PE-580B
1
1
spectrometer. H NMR spectra were recorded using a Bruker
AM-300, with CDCl3 as solvent and TMS as internal reference.
Mass spectra were obtained on the Agilent 5973N spectrometer.
Elemental analyses were measured on the elementar vario EL
III.
General procedure for 5-Aryl-3-Phenylpyrazole.
A mixture of cis-2-aryl-3-benzoyl-1,1-cyclopropanedicarbo-
nitrile (1 mmol) and hydrazine hydrate (85%) (120 mg, 2 mmol)
in DME (4 ml) was refluxed for 3 h. The DME was removed
under reduce pressure and the residue was purified on a silica
gel chromatographic column (petroleum ether/ethyl acetate, 5:1)
to afford 5-aryl-3-phenylpyrazole.
3a
5-Phenyl -3-Phenylpyrazole (3a).
We proposed a reasonable mechanism to account for
this reaction as illustrated in Scheme 2.
This compound was obtained as a colorless solid, mp 199-200
°C (Lit. mp 198-199 °C) [11]; 1H nmr (300 MHz, CDCl3): ꢀ
6.81 (1H, s, =CH), 7.25-7.36 (6H, m, Ph-H), 7.66-7.70 (4H, m,
Ph-H), 10.21 (1H, s, NH); ir (potassium bromide): 3098, 3003,
1572, 1403 cm-1; ms (m/z): 221 (M+ +1, 17), 200 (M+, 100), 191
(23), 189 (13), 165 (7), 89 (6), 77 (10), 51 (7).
In this reaction, the first step, the hydrazone C is
formed by the condensation of carbonyl group on the
cyclopropane A with hydrazine B. The second step, the
intramolecular nucleophilic addition between the cyclo-
propane ring and the free amino group of hydrazone C
generates the pyrazoline D, followed by the easy trans-
formation of pyrazoline D into pyrazoline E. In the step
forming pyrazoline D, the reason for the regioselective
ring-opening reaction is that the carbanion formed in
pyrazoline D is stabilized by two cyano groups. The last
step, the aromatization of pyrazoline E converted to
pyrazole F is achieved by the elimination of malononitrile
in the presence of hydrazine as base.
Anal. Calcd. for C15H12N2: C, 81.79; H, 5.49; N, 12.72. Found:
C, 81.90, H, 5.41, N, 12.78.
5-(4-Fluorophenyl)-3-Phenylpyrazole (3b).
This compound was obtained as a colorless solid, mp 181-182
1
°C; H nmr (300 MHz, CDCl3): ꢀ 6.68 (1H, s, =CH), 6.92-6.98
(2H, t, Ph-H), 7.25-7.31 (3H, q, Ph-H), 7.58-7.62 (4H, q, Ar-H),
10.38 (1H, s, NH); ir (potassium bromide): 3118, 3015, 1606,
1400 cm-1; ms (m/z) : 239 (M+ +1, 17), 238 (M+, 100), 209 (30),
207 (13), 104 (12), 95 (11), 77 (16), 51 (12).
Anal. Calcd. for C15H11FN2: C, 75.62; H, 4.65; N, 11.76.
Found: C, 75.62, H, 4.55, N, 11.75.
Scheme 2
5-(4-Bromophenyl)-3-Phenylpyrazole (3c).
H
CN
CN
H
H
This compound was obtained as a colorless solid, mp 219-220
1
°C; H nmr (300 MHz, CDCl3): ꢀ 6.87 (1H, s, =CH), 7.25-7.44
CN
CN
H
NH2NH2•H2O
B
+
DME reflux Ar
Ph
Ar
(5H, m, Ph-H), 7.51-7.79 (4H, m, Ar-H), 13.78 (1H, s, NH). ir
(potassium bromide): 3142, 3013, 1588, 1400 cm-1; ms (m/z):
301 (M+ +3, 16), 300 (M+ +2, 90), 299 (M+ +1, 19), 298 (M+,
100), 269 (8), 191 (12), 190 (11), 189 (22).
Anal. Calcd. for C15H11BrN2: C, 60.22; H, 3.71; N, 9.36.
Found: C, 60.34, H, 3.70, N, 9.36.
COPh
A
H2NN
C
NH2NH2
H
CN
CN
H
H
H
H
H
CH(CN)2
NH2NH2•H2O
CH(CN)2
Ar
C
Ar
Ar
H2N
HN
HN
Ph
Ph
Ph
N
H
N
E
N
5-(4-Chlorophenyl)-3-Phenylpyrazole (3d).
D
This compound was obtained as a colorless solid, mp 216-217
°C (Lit. mp 216-217 °C) [12]; 1H nmr (300 MHz, CDCl3): ꢀ
6.81 (1H, s, =CH), 7.35-7.44(5H, m, Ph-H), 7.66-7.69 (4H, m,
Ar-H). ir (potassium bromide): 3143, 3099, 1589, 1400 cm-1; ms
(m/z): 257 (M+ +3, 6), 256 (M+ +2, 35), 255 (M+ +1, 19), 254
(M+, 100), 225 (10), 191 (6), 189 (13), 89 (5).
Ar
HN
+
CH2(CN)2
Ph
N
F

Mar-Apr 2006
5-Aryl-3-Phenylpyrazole from 2-Aryl-3-Benzoyl-1,1-cyclopropanedicarbonitrile
497
Acknowledgements.
Anal. Calcd. for C15H11ClN2: C, 70.73; H, 4.35; N, 11.00.
Found: C, 70.74, H, 4.34, N, 10.95.
Thanks are due to the National Natural Science Foundation of
China for financial support (No. 20472047).
5-(2-Chlorophenyl)-3-Phenylpyrazole (3e).
This compound was obtained as a colorless solid, mp 127-128
1
°C; H nmr (300 MHz, CDCl3): ꢀ 6.99 (1H, s, =CH), 7.26-7.48
REFERENCES AND NOTES
(6H, m, Ph-H, Ar-H), 7.68-7.77 (3H, d, Ar-H), 9.81 (1H, s, NH).
ir (potassium bromide): 3205, 3007, 1585, 1398 cm-1; ms (m/z):
257 (M+ +3, 6), 256 (M+ +2, 35), 255 (M+1 +1, 19), 254 (M+,
100), 225 (10), 191 (7), 190 (7), 189 (18).
Anal. Calcd. for C15H11ClN2: C, 70.73; H, 4.35; N, 11.00.
Found: C, 70.68, H, 4.28, N, 10.97.
[*] Corresponding author, e-mail: renrui198229@hotmail.com;
Fax: +86-21-6613-4856.
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This compound was obtained as a colorless solid, mp 181-182
1
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°C; H nmr (300 MHz, CDCl3): ꢀ 6.95 (1H, s, =CH), 7.20-7.25
(1H, m, Ph-H), 7.33-7.46 (4H, m, Ph-H), 7.58-7.60 (1H, d, Ar-
H), 7.67-7.70 (2H, d, d, Ar-H), 9.51 (1H, s, NH). ir (potassium
bromide): 3148, 3026, 1592 1400 cm-1; MS (m/z) (%): 290 (M+
+1, 64), 289 (M+, 6), 288 (M+-1, 100), 190 (15), 189 (36), 187
(18), 94 (27), 77 (26).
Anal. Calcd. for C15H10Cl2N2: C, 62.31; H, 3.49; N, 9.69.
Found: C, 62.52, H, 3.49; N, 9.71.
5-(4-Methylphenyl)-3-Phenylpyrazole (3g).
This compound was obtained as a colorless solid, mp 179-180
°C; 1H nmr (300 MHz, CDCl3): ꢀ 2.38 (3H, s, CH3), 6.80 (1H, s,
=CH), 7.19-7.25 (2H, t, Ph-H), 7.33-7.42 (3H, m, Ph-H), 7.60
(2H, d, J=8.0Hz, Ar-H), 7.74 (2H, d, J=8.2Hz, Ar-H). ir
(potassium bromide): 3129, 3018, 1570, 1400 cm-1; ms (m/z):
235 (M+ +1,19), 234 (M+, 100), 233 (M+-1, 22), 205 (7), 202 (6),
189 (5), 130 (6), 117 (5).
Anal. Calcd. for C16H14N2: C, 82.02; H, 6.02; N, 11.96. Found:
C, 82.15, H, 6.08, N, 11.93.
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This compound was obtained as a colorless solid, mp 160-161
°C; 1H nmr (300 MHz, CDCl3): ꢀ 3.74 (3H, s, CH3O), 6.64 (1H,
s, =CH), 6.76-6.77 (2H, d, Ph-H), 7.22-7.28 (3H, m, Ph-H), 7.55
(2H, d, J=8.3Hz, Ar-H), 7.64 (2H, d, J=8.0Hz, Ar-H), 11.36
(1H, s, NH). ir (potassium bromide): 3132, 3009, 1618, 1400
cm-1; ms (m/z): 251 (M+ +1, 20), 250 (M+, 100), 236 (7), 235
(37), 207 (17), 178 (16), 125 (5), 77 (5).
Anal. Calcd. for C16H14N2O: C, 76.78; H, 5.64; N, 11.19.
Found: C, 76.96, H, 5.56, N, 11.19.