Copper-Catalyzed Tandem Dehydrocyanation and [3+2] Cyclo-addition Reactions of Phenacylmalononitriles: Regioselective Synthesis of Functionalized 4-Benzoyl-5-cyanopyrazoles under Mild Conditions

Article abstract of DOI:10.1055/s-0039-1691591

A novel copper-catalyzed [3+2] cycloaddition reaction with concomitant in situ generation of benzoylacrylonitriles and nitrile imines from phenacylmalononitriles and hydrazonoyl chlorides, respectively, is reported. The reaction was performed using copper(I) chloride as catalyst and N-methylimidazole as a clean complexing agent/weak base to afford the functionalized 4-benzoyl-5-cyanopyrazoles in moderate to good yields and excellent regioselectivity under ambient conditions. This method provides rapid access to a wide range of highly functionalized 4-benzoyl-5-cyanopyrazoles.

Full text of DOI:10.1055/s-0039-1691591

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–H
paper
A
en
I. Yavari, O. Khaledian
Paper
Synthesis
Copper-Catalyzed Tandem Dehydrocyanation and [3+2] Cyclo-
addition Reactions of Phenacylmalononitriles: Regioselective
Synthesis of Functionalized 4-Benzoyl-5-cyanopyrazoles under
Mild Conditions
Issa Yavari*
0
0
0
0-0
0
0
1-7
8
9
6-
9
2
8
2
N
N
N
N
–
Omid Khaledian
CN
Ar1
NPh
N+
Ph
N
CuCl
H
Ar1
H
N
Department of Chemistry, Tarbiat Modares University,
PO Box 14115-175, Tehran, Iran
O
+
– HCl
– HCN
yavarisa@modares.ac.ir
Cl
Ar2
O
NC
CN
Ar2
[3+2]
Ph
N
Ph
N
CN
CN
O
N
air oxidation
– H2
N
Excellent regioselectivity
Mild conditions
Simple substrates
Ar1
Ar1
Ar2
O
Ar2
Moderate to good yields
16 examples
37–80% yield
In situ generation of acrylonitriles
Received: 14.11.2019
Accepted after revision: 14.01.2020
Published online: 06.02.2020
reported herbicidal activities of substituted 4-benzoyl-
pyrazoles.5 The benzoyl moiety can be a useful precursor to
a wide range of functional groups such as benzyl alcohols,
imines, oximes, and alkenes, thus providing facile access to
structurally diverse pyrazoles.6
DOI: 10.1055/s-0039-1691591; Art ID: ss-2019-n0348-op
Abstract A novel copper-catalyzed [3+2] cycloaddition reaction with
concomitant in situ generation of benzoylacrylonitriles and nitrile
imines from phenacylmalononitriles and hydrazonoyl chlorides, respec-
tively, is reported. The reaction was performed using copper(I) chloride
as catalyst and N-methylimidazole as a clean complexing agent/weak
base to afford the functionalized 4-benzoyl-5-cyanopyrazoles in moder-
ate to good yields and excellent regioselectivity under ambient condi-
tions. This method provides rapid access to a wide range of highly func-
tionalized 4-benzoyl-5-cyanopyrazoles.
O
NH2
O
O
O
N
O
N
EtO2C
N
HN
anticancer agent
nNOS and iNOS inhibitor
N
Key words 4-benzoyl-5-cyanopyrazoles, copper catalysis, [3+2] cyclo-
addition, phenacylmalononitrile, hydrazonoyl chloride
HN
O
The pyrazole structural unit, whether free or fused with
other heterocycles, is an active pharmacophore in many bi-
ologically important molecules including those possessing
antimalarial,1a analgesic,1b antimicrobial,1c anti-inflamma-
tory,1d and antidiabetic1e properties. Among the commer-
cially available N-heterocyclic drugs, celecoxib, sul-
faphenazole, lonazolac, mepiprazole, and rimonabant are
pyrazole-based compounds. Pyrazole-derived ligands have
been employed in transition-metal-catalyzed cross-
coupling reactions.2 Moreover, various substituted pyra-
zoles have been used as chelating and extracting reagents
for many metal ions.3
N
N
CN
N
N
N
O
N
O
H2N
Acumapimod: MAP kinase inhibitor
Ocinaplon: anxiolytic drug
Figure 1 Examples of bioactive benzoylpyrazoles
Among substituted cyanopyrazoles used as pharmaceu-
ticals and agrochemicals7 are Fipronil, Pyriprole, Pyra-
fluprole, and Ethiprole as insecticide,8 Zaleplon as sedative-
hypnotic,9 and Lorlatinib as ALK/ROS1 inhibitor.10 The cya-
no group can be converted into acids, ketones, imines, alde-
hydes, amines, amides, and even triazoles and tetrazoles.11
Benzoylpyrazoles, due to their usefulness as pharma-
ceutical and agrochemical agents,4 have attracted much
attention in recent years (Figure 1). Several patents have
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
I. Yavari, O. Khaledian
Paper
Synthesis
In view of the important applications of pyrazoles, new
synthetic strategies for their preparation are currently in
demand.
The starting materials (i.e., phenacylmalononitriles 1a–d)
were prepared according to a reported procedure (Scheme
2A).20 Hydrazonoyl chlorides 2a–d were also obtained from
commercially available benzoyl chlorides and phenylhydra-
zine according to standard reported procedures (Scheme
2B).21
On the pallet of organic reactions that are used in het-
erocyclic synthesis, dipolar cycloadditions possess a promi-
nent position, since they are efficient methods for creating
new five-membered heterocycles with control of stereo-
chemistry.12 The 1,3-dipolar cycloaddition, also referred as
the Huisgen cycloaddition, is a classical and fundamental
organic reaction, which consists of the reactions of dipoles
(e.g., nitrile imines) with olefinic dipolarophiles, resulting
in formation of various highly substituted pyrazoles and
pyrazolines in a regio- and stereoselective manner.13 How-
ever, there have been only a few cases of performing the
substituted pyrazole synthesis with the dipolarophile gen-
erated in situ.14
O
O
CN
i
+
NC
CN
Br
A.
Ar1
Ar1
CN
1a–d
Cl
O
O
H
N
H
ii
iii
H
N
+
Ar2
N
Ph
N
B.
H2N
Ph
Ar2
Cl
Ar2
N
Ph
H
2a–d
i) NaOH, EtOH, rt; ii) Py, CH2Cl2, 0 °C to rt; iii) CCl4, PPh3, CH3CN, rt.
Scheme 2 Synthesis of the starting materials
Unsaturated cyanocarbonyl compounds provide an at-
tractive entry into electron-deficient dienophiles employed
in Diels–Alder cycloadditions.15 To prepare these valuable
substrates, several synthetic methodologies have been re-
ported, including Wittig type olefination of glyoxal deriva-
tives, palladium-catalyzed four-step procedure from alke-
nals, dehydrohalogenation of suitable substituted precur-
sors, or five-step chemical modification of trans-
styrylacetic acid.16 These approaches are frequently long
and cumbersome. To our knowledge, there is no report re-
garding either in situ generation of benzoylacrylonitriles, or
describing their use as a dipolarophile in 1,3-dipolar cyclo-
addition reactions.
Table 1 Optimization of Reaction Conditions for the Synthesis of Pyra-
zole 3aa
Ph
O
CN
O
CN
N
Ph
Ph
CN
Ph
N
1a
3a
cat., base
solvent
+
+
CN
Cl
H
N
NH2
O
Ph
N
Ph
Ph
Dehydrocyanation of substituted nitriles was first intro-
duced by Hauser and Brasen, wherein 2,2,3-triphenyl-
propionitrile (I) undergoes -elimination to form triphenyl-
ethylene (II) (Scheme 1).17
2a
4a
Entry
Catalyst
Base
imidazole
Solvent
3a (%)b
3a/4ac
1
none
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
CuI
EtOH
trace
37
1:1
H
C
H
Ph
C
KNH2, liq. NH3
– HCN
Ph
Ph
H
2
imidazole
NMId
NMI
EtOH
6:1
Ph
CN
C
C
Ph
3
EtOH
53
13:1
15:1
18:1
8:1
Ph
4e
5
MeOH
MeOH
MeOH
MeCN
MeCN
MeOH
MeOH
MeOH
MeOH
61
I
II
Scheme 1 The first reported dehydrocyanation of nitriles
NMI
69
6f
7
NMI
56
NMI
21
1:1.5
1:19<
9:1
As can be inferred from Scheme 1, strong alkaline con-
ditions are required for the dehydrocyanation process when
leading to an olefinic target. This type of reaction might be
more facile if a more stable aromatic product is formed.18
Since the use of a strong, or even a moderate base such as
Et3N in the methodology investigated causes side reactions,
we previously conceived that a weak base (e.g., N-me-
thylimidazole in the presence of a catalytic amount of cop-
per mono halides as Lewis acid) might lead to the desired
outcome.
In line with the studies conducted in our research group
focused on the synthesis of different substituted pyra-
zoles,19 we decided to carry out the synthesis of multiply
substituted pyrazoles with the concomitant in situ genera-
tion of both the dipole and the dipolarophile.
8
Et3N
NMI
NDg
47
9
10
NMI
36
5:1
11h
12
CuCl2
Cu(OAc)2
NMI
ND
ND
–
NMI
–
a Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), catalyst (10 mol%),
base (2.5 equiv), solvent (1 mL), r.t., under an atmosphere of air.
b Yield of isolated product.
c The selectivity for 3a/4a was determined by 1H NMR spectroscopic analysis
of the reaction mixtures.
d N-Methylimidazole.
e CuCl (5 mol%) was used.
f The reaction was allowed stirred for 24 h.
g Not detected.
h A complex mixture was obtained.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

C
I. Yavari, O. Khaledian
Paper
Synthesis
Initially we chose phenacylmalononitrile (1a), and hy-
drazonoyl chloride 2a, as model substrates to optimize the
conditions for the [3+2] cycloaddition reaction. Initially, the
reaction was carried out in EtOH at room temperature in
the presence of imidazole as base, as Garve et al. used in
their work with hydrazonoyl chlorides,22 resulting a trace
amount of both 3a and the by-product 4a (Table 1, entry 1).
Upon further examination, it was found that in the pres-
ence of a catalytic amount of a copper compound, the effi-
ciency of the reaction increased (entry 2). Additionally, N-
methylimidazole (NMI) was found to be more effective than
imidazole (entry 3). A change of solvent to MeOH was
shown to be effective (entry 4), wherein CuCl (10 mol%)
proved to be the best catalyst, resulting in a 69% yield of the
cycloadduct (entry 5). Increasing the reaction time resulted
in a considerable decrease in the yield of 3a (entry 6). Run-
ning the reaction in MeCN showed that product 1a tends to
undergo intramolecular cyclization to form the by-product
2-amino-5-phenylfuran-3-carbonitrile (4a) especially in
aprotic solvents (entry 7). When using Et3N, the reported
base of choice to generate nitrile imines,23 compound 4a
was dominant while 3a was not detected (entry 8). Running
the reaction with a catalytic amount of other copper mono
halides (CuBr and CuI) decreased the amount of product 3a
formed (entries 9 and 10). When using CuCl2 or Cu(OAc)2 as
catalyst, a complex mixture was obtained (entries 11 and
12).
With the optimal conditions in hand, a range of hydra-
zonoyl chlorides and phenacylmalononitriles were exam-
ined. In particular, a number of N′-arylbenzohydrazonoyl
chlorides with various substituents on the aryl fragments
were tested, and most afforded moderate to good yields of 3
(Table 2). The method worked well especially for methyl
and methoxy derivatives, and moderate yields were ob-
tained for 4-chloro- and 4-fluoro-N-phenylbenzohydrazo-
noyl chlorides. An electron-releasing functional group at
the para-position of phenacylmalononitrile (e.g., 4-me-
thoxy-, and 4-methyl-) showed higher efficiency compared
Table 2 Scope of the Reaction with Respect to 4-Benzoyl-5-cyanopyrazolesa
Ar1
O
NH2
CN
Ar1
Ph
CuCl, NMI
O
CN
Cl
O
O
NC
CN
H
+
+
+
Ar1
N
Ar1
CN
Ar2
N
Ph
MeOH, rt, 5 h
under an atmosphere
of air
N
Ar2
N
Ar2
Ph
N
N
1a–d
2a–d
3a–p
not observed
4a–d
Ph
Ph
Ph
Ph
O
O
O
O
O
F
Cl
O
Ph
Ph
CN
CN
CN
CN
CN
CN
N
N
N
N
N
N
N
N
N
N
Ph
N
N
Ph
Ph
Ph
Ph
Ph
3a, 69%
3a/4a, 18:1b
3b, 75%
3b/4a, 19:1
3c, 44%
3c/4a, 13:1
3d, 49%
3d/4a, 12:1
3e, 70%
3e/4b, 17:1
3f, 79%
3f/4b, >19:1
OMe
OMe
OMe
O
O
O
O
O
CN
CN
CN
CN
Ph
CN
Ph
Cl
F
N
N
N
N
N
N
N
N
Cl
N
N
Ph
Ph
Ph
Ph
3g, 55%
3g/4b, 15:1
3h, 58%
3h/4b, 16:1
3i, 73%
3i/4c, >19:1
3j, 80%
3j/4c, >19:1
3k, 60%
3k/4c, 17:1
Cl
Cl
OMe
Cl
Cl
O
O
O
O
O
CN
Ph
CN
CN
CN
CN
Cl
F
F
N
N
N
N
N
N
N
N
N
Ph
N
Ph
Ph
Ph
Ph
3l, 67%
3l/4c, 15:1
3m, 53%
3m/4d, 11:1
3n, 57%
3n/4d, 13:1
3o, 37%
3o/4d, 8:1
3p, 39%
3p/4d, 9:1
a Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), CuCl (0.05 mmol, 10 mol%), N-methylimidazole (1.25 mmol, 2.5 equiv), MeOH (3 mL), r.t., under an atmo-
sphere of air, 5 h.
b The selectivity for 3/4 was determined by 1H NMR spectroscopic analysis of the reaction mixtures.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

D
I. Yavari, O. Khaledian
Paper
Synthesis
to 4-chloro-phenacylmalononitrile. The highest yield of
80%, was achieved for 4-(4-methoxybenzoyl)-1-phenyl-3-
NH
CN
[1,3]
H-shift
O
NH2
O
Ar1
Ar1
(p-tolyl)-1H-pyrazole-5-carbonitrile,
having
electron-
CN
CN
donating groups at the para-positions of both aryl moieties
of the initial materials. In contrast, 4-(4-chlorobenzoyl)-3-
(4-chlorophenyl)-1-phenyl-1H-pyrazole-5-carbonitrilewas
obtained only in 37% yield. In addition to the low reactivity
of 4-halo-N-phenylbenzohydrazonoyl chlorides in this 1,3-
dipolar cycloaddition reaction, the higher tendency of 4-
chloro-phenacylmalononitrile to partake in the side reac-
tion resulting the by-product 4, could presumably be a rea-
son for these observations (Scheme 3). It is noteworthy that
10–25% of the hydrazonoyl chloride substrates always re-
mained unreacted, whereas in all reactions the phenacyl-
malononitrile substrates 1a–d were completely consumed.
The structures of compounds 3a–p were assigned on
4
intramolecular
cyclization
O
CN
O
CuCl, base
– HCN
Ar1
CN
Ar1
5
1
Cl
H
N
–
+
base
Ar2
N
N
Ph
Ar2
N
Ph
[3+2]
– HCl
6
2
O
O
CN
N
CN
air
Ar1
Ar1
1
the basis of their IR, mass, H NMR, and 13C NMR spectro-
oxidation
N
Ph
Ph
scopic analyses. IR spectra showed a medium absorption at
2230–2250 cm–1 together with a strong absorption at
1630–1655 cm–1 corresponding to the cyano and carbonyl
functional groups, respectively. The mass spectra of prod-
ucts 3 displayed molecular ion peaks at appropriate m/z
values. Unequivocal evidence for the regioselective forma-
tion of 3-(4-chlorophenyl)-4-(4-methoxybenzoyl)-1-phenyl-
1H-pyrazole–5-carbonitrile (3k) was obtained from single-
crystal X-ray analysis (Figure 2).24 The same structures
were assumed for the other derivatives on the basis of their
NMR spectroscopic similarities.
Ar2
N
N
– H2
Ar2
7
3
Scheme 3 Proposed mechanism for the formation of product 3 and
byproduct 4
when using a weak base in a protic solvent, the amount of
the side product is negligible (optimal conditions, Table 1,
entry 5).
In conclusion, we have described an unprecedented cop-
per-catalyzed regioselective synthesis of 4-arylcarboxo-1-
phenyl-3-aryl-1H-pyrazole-5-carbonitriles via a [3+2] cyc-
loaddition reaction between phenacylmalononitriles and
hydrazonoyl chlorides. In situ generation of the dipole and
the dipolarophile, nitrile imine and acrylonitrile, respec-
tively, the mild copper-catalyzed/weak base mediated for-
mation of two new C–C and C–N bonds, excellent regiose-
lectivity, and the retention of the benzoyl group, are the ad-
vantages of this one-pot method. The reaction works well
with a wide range of of hydrazonoyl chloride and phenacyl-
malononitrile substrates. The methodology reported here
may serve as a simple strategy to synthesize a wide variety
of highly functionalized 4-benzoyl-5-cyanopyrazoles.
Figure 2 X-ray crystal structure of compound 3k. Nitrogen atoms are
shown in blue, oxygen atoms in red, chlorine atom in green. Hydrogen
atoms are omitted for clarity.
These observations, together with reported evidence,
led us to propose the mechanism shown in Scheme 3.25 The
phenacylmalononitrile substrate 1 undergoes a dehydrocy-
anation reaction triggered by CuCl as a Lewis acid to gener-
ate the acrylonitrile intermediate 5, the olefinic dipolaro-
phile. Deprotonation of hydrazonoyl chloride and concomi-
tant loss of HCl leads to nitrile imine 6 with a 1,3-dipolar
structure. Then, a regioselective [3+2] cycloaddition be-
tween the dipole 6, and the dipolarophile 5, leads to inter-
mediate 7, which subsequently affords the pyrazole product
as a result of an air oxidation.
All purchased solvents and chemicals were of analytical grade and
used without further purification. Phenacylmalononitriles 1a–d, and
hydrazonoyl chlorides 2a–d, were prepared by reported proce-
dures.20,21 The physical properties of the known compound 4a corre-
sponds to the reported data.26 Melting points were measured with an
Electrothermal 9100 apparatus. IR spectra were recorded with a
Shimadzu-IR 460 spectrophotometer (ύ in cm−1). 1H, 13C, and 19F NMR
spectra were recorded with a Bruker DRX-500 Avance instrument us-
ing CDCl3 as solvent at 500.1, 125.7, and 471 MHz, respectively ( in
ppm, J in Hz). Mass spectra were recorded with a Finnigan-MAT-
8430MS spectrometer at an ionization potential of 70 eV. Elemental
analyses for C, H, and N were performed with a Heraeus CHN-O-Rap-
id analyzer. X-ray crystal structure data were collected with a Marre-
search 345 dtb diffractometer using Mo K radiation (0.71073 Å) at
Compound 1, can undergo an intramolecular cyclization
reaction under alkaline conditions, followed by a 1,3-hy-
drogen shift to yield the by-product 4. As noted above,
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

E
I. Yavari, O. Khaledian
Paper
Synthesis
295 K. The structure was solved by direct methods using SHELXS-97
and the obtained model was refined with SHELXL-97. All non-hydro-
gen atoms were refined anisotropically. Hydrogen atoms were added
at ideal positions and refined using a riding model.
4-Benzoyl-3-(4-fluorophenyl)-1-phenyl-1H-pyrazole-5-carbo-
nitrile (3d)
Yield: 90 mg (49%); colorless solid; mp 101–103 °C.
IR (KBr): 3069, 2238, 1653, 1597, 1496, 1452, 1280, 1180, 1099, 917,
696 cm–1
.
4-Benzoyl-5-cyanopyrazoles; General Procedure
1H NMR (500 MHz, CDCl3):  = 7.90–7.79 (m, 4 H), 7.67–7.50 (m, 6 H),
7.42 (t, J = 7.5 Hz, 2 H), 7.00 (t, J = 8.4 Hz, 2 H).
A mixture of 1 (0.6 mmol), 2 (0.5 mmol), CuCl (5 mg, 10 mol%), and N-
methylimidazole (103 mg, 2.5 equiv) in MeOH (3 mL) was stirred for
5 h at r.t. under an atmosphere of air. Upon completion of the reaction
(TLC monitoring), the solvent was removed under reduced pressure
and the product was purified by silica gel (Merck 230–400 mesh) col-
umn chromatography (n-hexane/EtOAc, 8:1).
13C NMR (126 MHz, CDCl3):  = 187.7, 162.3 (d, 1JCF = 249.6 Hz), 150.6,
136.9, 135.4, 133.2, 129.4 (d, 3JCF = 8.5 Hz), 128.9, 128.8, 127.7, 126.0,
4
2
125.5 (d, JCF = 3.0 Hz), 123.3, 122.3, 115.5, 114.6 (d, JCF = 21.7 Hz),
108.6.
19F NMR (471 MHz, CDCl3):  = –106.4.
4-Benzoyl-1,3-diphenyl-1H-pyrazole-5-carbonitrile (3a)
MS: m/z (%) = 367 (100), 338 (13), 290 (19), 129 (6), 105 (16), 77 (55),
51 (13).
Yield: 121 mg (69%); colorless solid; mp 127–129 °C.
IR (KBr): 3058, 2239, 1650, 1595, 1498, 1453, 1418, 906, 763, 694 cm–1
1H NMR (500 MHz, CDCl3):  = 7.98–7.75 (m, 4 H), 7.75–7.45 (m, 6 H),
7.40 (t, J = 7.3 Hz, 2 H), 7.36–7.28 (m, 3 H).
13C NMR (126 MHz, CDCl3):  = 188.9, 152.6, 138.2, 136.6, 134.1,
130.4, 130.1, 129.9, 129.8, 129.3, 128.7, 128.6, 127.5, 125.6, 123.4,
116.4, 109.8.
.
Anal. Calcd for C23H14FN3O (367.38): C, 75.19; H, 3.84; N, 11.44.
Found: C, 75.56; H, 3.82; N, 11.49.
4-(4-Methylbenzoyl)-1,3-diphenyl-1H-pyrazole-5-carbonitrile
(3e)
Yield: 127 mg (70%); colorless solid; mp 118–120 °C.
IR (KBr): 3068, 2922, 2242, 1636, 1605, 1494, 1425, 1290, 1177, 923,
MS: m/z (%) = 349 (100), 332 (24), 320 (43), 272 (74), 105 (25), 77
(15), 77 (83), 51 (23).
772, 688 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.86 (d, J = 7.2 Hz, 2 H), 7.78 (d, J =
7.3 Hz, 2 H), 7.67–7.46 (m, 5 H), 7.38–7.28 (m, 3 H), 7.21 (d, J = 7.2 Hz,
2 H), 2.40 (s, 3 H).
Anal. Calcd for C23H15N3O (349.39): C, 79.07; H, 4.33; N, 12.03. Found:
C, 79.36; H, 4.35; N, 12.06.
13C NMR (126 MHz, CDCl3):  = 188.5, 152.4, 145.4, 138.2, 134.1,
130.5, 130.3, 129.9, 129.7, 129.5, 129.3, 128.7, 128.5, 127.8, 123.4,
116.1, 109.9, 21.9.
4-Benzoyl-1-phenyl-3-(p-tolyl)-1H-pyrazole-5-carbonitrile (3b)
Yield: 136 mg (75%); colorless solid; mp 143–145 °C.
IR (KBr): 3062, 2923, 2232, 1650, 1617, 1515, 1498, 1449, 1422, 918,
MS: m/z (%) = 363 (100), 347 (81), 334 (25), 271 (28), 119 (23), 91
(34), 77 (41), 51 (14).
768, 696 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.93–7.79 (m, 4 H), 7.66–7.51 (m, 4 H),
7.48 (d, J = 7.4 Hz, 2 H), 7.44–7.35 (m, 2 H), 7.11 (d, J = 7.3 Hz, 2 H),
2.33 (s, 3 H).
Anal. Calcd for C24H17N3O (363.42): C, 79.32; H, 4.72; N, 11.56. Found:
C, 79.03; H, 4.71; N, 11.60.
13C NMR (126 MHz, CDCl3):  = 187.9, 151.5, 138.3, 137.0, 135.0,
133.0, 128.9, 128.7, 128.6, 128.2, 127.6, 127.3, 126.4, 126.2, 122.3,
115.1, 108.8, 20.3.
4-(4-Methylbenzoyl)-1-phenyl-3-(p-tolyl)-1H-pyrazole-5-carbo-
nitrile (3f)
Yield: 149 mg (79%); colorless solid; mp 129–131 °C.
MS: m/z (%) = 368 (100), 346 (17), 334 (26), 286 (49), 105 (20), 77
(69), 51 (14).
IR (KBr): 3059, 2951, 2922, 2232, 1647, 1616, 1609, 1497, 1457, 1175,
919, 764, 624 cm–1
.
Anal. Calcd for C24H17N3O (363.42): C, 79.32; H, 4.72; N, 11.56. Found:
C, 79.65; H, 4.70; N, 11.61.
1H NMR (500 MHz, CDCl3):  = 7.85 (d, J = 7.1 Hz, 2 H), 7.79 (d, J =
7.6 Hz, 2 H), 7.67–7.45 (m, 5 H), 7.23 (d, J = 7.4 Hz, 2 H), 7.13 (d, J =
7.3 Hz, 2 H), 2.41 (s, 3 H), 2.34 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 187.5, 151.3, 144.2, 138.2, 137.1,
133.0, 129.1, 128.9, 128.7, 128.5, 128.4, 128.3, 127.2, 126.4, 122.2,
114.8, 108.8, 20.8, 20.3.
4-Benzoyl-3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-5-carboni-
trile (3c)
Yield: 84 mg (44%); colorless solid; mp 168–170 °C.
IR (KBr): 3062, 2924, 2231, 1649, 1593, 1500, 1448, 1285, 1198, 1093,
MS: m/z (%) = 377 (100), 362 (70), 348 (22), 286 (21), 119 (23), 91
(38), 77 (33), 65 (5), 51 (8).
1014, 917, 692 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.93–7.76 (m, 4 H), 7.65–7.49 (m, 6 H),
7.44 (t, J = 7.2 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 2 H).
13C NMR (126 MHz, CDCl3):  = 188.7, 151.5, 138.0, 136.6, 135.6,
134.4, 130.0, 130.0, 129.9, 129.9, 129.8, 128.9, 128.9, 127.3, 123.4,
116.6, 109.6.
Anal. Calcd for C25H19N3O (377.45): C, 79.55; H, 5.07; N, 11.13. Found:
C, 79.96; H, 5.09; N, 11.17.
3-(4-Chlorophenyl)-4-(4-methylbenzoyl)-1-phenyl-1H-pyrazole-
5-carbonitrile (3g)
MS: m/z (%) = 383 (100), 368 (13), 354 (19), 306 (49), 129 (25), 105
(73), 77 (63), 51 (5).
Yield: 109 mg (55%); colorless solid; mp 159–161 °C.
IR (KBr): 3062, 2958, 2927, 2235, 1649, 1607, 1499, 1176, 1097, 920,
Anal. Calcd for C23H14ClN3O (383.84): C, 79.97; H, 3.68; N, 10.95.
Found: C, 80.39; H, 3.70; N, 11.00.
768 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

F
I. Yavari, O. Khaledian
Paper
Synthesis
1H NMR (500 MHz, CDCl3):  = 7.84 (d, J = 7.1 Hz, 2 H), 7.78 (d, J =
7.3 Hz, 2 H), 7.68–7.48 (m, 5 H), 7.30 (d, J = 7.9 Hz, 2 H), 7.25 (d, J =
7.2 Hz, 2 H), 2.43 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 187.2, 150.1, 144.6, 136.9, 134.3,
132.9, 129.1, 128.7, 128.7, 128.7, 128.6, 128.5, 127.8, 126.4, 122.2,
115.1, 108.6, 20.8.
MS: m/z (%) = 393 (100), 376 (20), 362 (51), 135 (33), 92 (13), 77 (51),
51 (8).
Anal. Calcd for C25H19N3O2 (393.45): C, 76.32; H, 4.87; N, 10.68.
Found: C, 76.01; H, 4.89; N, 10.70.
3-(4-Chlorophenyl)-4-(4-methoxybenzoyl)-1-phenyl-1H-pyra-
zole-5-carbonitrile (3k)
MS: m/z (%) = 397 (100), 382 (86), 368 (18), 306 (33), 119 (54), 91
(58), 77 (60), 65 (22), 51 (15).
Yield: 124 mg (60%); colorless solid; mp 159–161 °C.
Anal. Calcd for C24H16ClN3O (397.86): C, 72.45; H, 4.05; N, 10.56.
Found: C, 72.86; H, 4.06; N, 10.61.
IR (KBr): 3073, 2974, 2937, 2237, 1642, 1608, 1577, 1498, 1268, 1170,
845, 773 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.98–7.79 (m, 4 H), 7.71–7.51 (m, 5 H),
7.31 (d, J = 8.0 Hz, 2 H), 6.92 (d, J = 8.3 Hz, 2 H), 3.89 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 186.0, 163.4, 149.9, 136.9, 134.3,
131.5, 128.7, 128.7, 128.5, 128.3, 127.9, 127.8, 126.6, 122.2, 114.9,
113.1, 108.6, 54.6.
3-(4-Fluorophenyl)-4-(4-methylbenzoyl)-1-phenyl-1H-pyrazole-
5-carbonitrile (3h)
Yield: 103 mg (58%); colorless solid; mp 102–104 °C.
IR (KBr): 3097, 2927, 2247, 1654, 1607, 1498, 1447, 1226, 1160, 909,
766 cm–1
.
MS: m/z (%) = 413 (100), 396 (19), 382 (57), 135 (27), 91 (29), 77 (44).
1H NMR (500 MHz, CDCl3):  = 7.84 (d, J = 7.5 Hz, 2 H), 7.77 (d, J =
7.5 Hz, 2 H), 7.69–7.51 (m, 5 H), 7.24 (d, J = 7.5 Hz, 2 H), 7.02 (t, J =
8.2 Hz, 2 H), 2.42 (s, 3 H).
Anal. Calcd for C24H16ClN3O2 (413.86): C, 69.65; H, 3.90; N, 10.15.
Found: C, 69.98; H, 3.94; N, 10.28.
13C NMR (126 MHz, CDCl3):  = 188.4, 163.4 (d, 1JCF = 249.4 Hz), 151.5,
3-(4-Fluorophenyl)-4-(4-methoxybenzoyl)-1-phenyl-1H-pyra-
zole-5-carbonitrile (3l)
3
145.6, 138.1, 134.1, 130.4 (d, JCF = 8.4), 130.3, 129.9, 129.8, 129.6,
4
2
127.5, 126.7 (d, JCF = 3.2 Hz), 123.4, 116.3, 115.8 (d, JCF = 21.6 Hz),
Yield: 133 mg (67%); colorless solid; mp 125–127 °C.
109.8, 21.9.
19F NMR (471 MHz, CDCl3):  = –106.5.
IR (KBr): 3077, 2932, 2235, 1649, 1596, 1499, 1260, 1165, 909, 842,
762 cm–1
.
MS: m/z (%) = 381 (100), 366 (85), 352 (19), 290 (38), 119 (39), 91
(40), 77 (43), 65 (15), 51 (11).
1H NMR (500 MHz, CDCl3):  = 7.90–7.79 (m, 4 H), 7.67–7.58 (m, 4 H),
7.55 (t, J = 6.9 Hz, 1 H), 7.03 (t, J = 8.2 Hz, 2 H), 6.90 (d, J = 8.2 Hz, 2 H),
3.88 (s, 3 H).
Anal. Calcd for C24H16FN3O (381.41): C, 75.58; H, 4.23; N, 11.02.
Found: C, 75.87; H, 4.25; N, 11.07.
13C NMR (126 MHz, CDCl3):  = 187.2, 164.7, 163.4 (d, 1JCF = 249.5 Hz),
151.3, 138.1, 132.6, 130.4 (d, 3JCF = 8.4 Hz), 129.9, 129.8, 129.7, 129.0,
4
2
4-(4-Methoxybenzoyl)-1,3-diphenyl-1H-pyrazole-5-carbonitrile
(3i)
127.6, 126.7 (d, JCF = 3.0 Hz), 123.4, 115.8 (d, JCF = 21.8 Hz), 114.2,
109.9, 55.7.
Yield: 138 mg (73%); colorless solid; mp 163–165 °C.
19F NMR (471 MHz, CDCl3):  = –106.5.
IR (KBr): 3068, 2965, 2934, 2241, 1641, 1596, 1573, 1501, 1263, 1168,
MS: m/z (%) = 397 (100), 380 (21), 366 (65), 290 (21), 198 (8), 135
(50), 92 (15), 77 (49), 51 (8).
908, 759, 692 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.91–7.81 (m, 4 H), 7.66–7.57 (m, 4 H),
7.55 (t, J = 6.65, 1 H), 7.37–7.29 (m, 3 H), 6.89 (d, J = 7.95 Hz, 2 H), 3.87
(s, 3 H).
Anal. Calcd for C24H16FN3O2 (397.41): C, 72.54; H, 4.06; N, 10.57.
Found: C, 72.13; H, 4.04; N, 10.60.
13C NMR (126 MHz, CDCl3):  = 186.2, 163.4, 151.0, 137.1, 131.5,
129.4, 128.7, 128.5, 128.4, 128.2, 127.6, 127.3, 126.7, 122.2, 114.8,
113.0, 108.8, 54.5.
4-(4-Chlorobenzoyl)-1,3-diphenyl-1H-pyrazole-5-carbonitrile
(3m)
Yield: 101 mg (53%); colorless solid; mp 147–149 °C.
MS: m/z (%) = 379 (100), 362 (23), 348 (62), 336 (6), 272 (17), 190 (8),
135 (40), 92 (15), 77 (59), 64 (8), 51 (12).
IR (KBr): 3080, 3055, 2242, 1652, 1584, 1494, 1418, 1278, 1088, 905,
762, 699 cm–1
.
Anal. Calcd for C24H17N3O2 (379.42): C, 75.98; H, 4.52; N, 11.08.
Found: C, 76.29; H, 4.51; N, 11.12.
1H NMR (500 MHz, CDCl3):  = 7.86 (d, J = 7.35 Hz, 2 H), 7.78 (d, J =
8.1 Hz, 2 H), 7.65–7.43 (m, 5 H), 7.40–7.26 (m, 5 H).
13C NMR (126 MHz, CDCl3):  = 186.4, 151.4, 139.6, 136.9, 133.7,
130.2, 129.1, 128.8, 128.4, 127.9, 127.6, 127.5, 125.9, 123.3, 122.3,
115.4, 108.6.
4-(4-Methoxybenzoyl)-1-phenyl-3-(p-tolyl)-1H-pyrazole-5-carbo-
nitrile (3j)
Yield: 157 mg (80%); colorless solid; mp 156–158 °C.
MS: m/z (%) = 383 (100), 366 (11), 347 (62), 272 (42), 139 (19), 111
(23), 77 (39), 51 (11).
IR (KBr): 3058, 2979, 2917, 2232, 1649, 1616, 1596, 1572, 1501, 1259,
1168, 906, 762 cm–1
.
Anal. Calcd for C23H14ClN3O (383.84): C, 71.97; H, 3.68; N, 10.95.
Found: C, 72.36; H, 3.70; N, 11.98.
1H NMR (500 MHz, CDCl3):  = 7.92–7.76 (m, 4 H), 7.64–7.56 (m, 2 H),
7.56–7.47 (m, 3 H), 7.13 (d, J = 7.1 Hz, 2 H), 6.90 (d, J = 8.5 Hz, 2 H),
3.87 (s, 3 H), 2.34 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 187.5, 164.6, 152.2, 139.3, 138.3,
132.6, 129.8, 129.7, 129.6, 129.4, 128.3, 127.8, 127.7, 123.3, 115.8,
114.1, 110.0, 55.7, 21.4.
4-(4-Chlorobenzoyl)-1-phenyl-3-(p-tolyl)-1H-pyrazole-5-carbo-
nitrile (3n)
Yield: 113 mg (57%); colorless solid; mp 160–162 °C.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

G
I. Yavari, O. Khaledian
Paper
Synthesis
IR (KBr): 3071, 2926, 2243, 1640, 1618, 1591, 1500, 1274, 921,
623 cm–1
1H NMR (500 MHz, CDCl3):  = 7.85 (d, J = 7.6 Hz, 2 H), 7.79 (d, J =
8.2 Hz, 2 H), 7.61 (t, J = 7.2 Hz, 2 H), 7.56 (t, J = 7.0 Hz, 1 H), 7.44 (d, J =
7.7 Hz, 2 H), 7.37 (d, J = 8.2 Hz, 2 H), 7.12 (d, J = 7.6 Hz, 2 H), 2.35 (s,
3 H).
13C NMR (126 MHz, CDCl3):  = 187.7, 152.6, 140.7, 139.7, 138.1,
134.9, 131.4, 129.9, 129.8, 129.5, 129.1, 128.5, 127.4, 124.5, 123.4,
116.4, 109.8, 21.4.
References
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MS: m/z (%) = 397 (100), 382 (13), 362 (42), 286 (31), 139 (23), 111
(28), 77 (45), 51 (11).
Anal. Calcd for C24H16ClN3O (397.86): C, 72.45; H, 4.05; N, 10.56.
Found: C, 72.83; H, 4.06; N, 10.59.
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4-(4-Chlorobenzoyl)-3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-5-
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(5) See for example: (a) Kikugawa, H.; Nagayama, S.; Sano, M. (Ishi-
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H.; Sano, M.; Kitahara, Y.; Kominami, H.; Okita, T. (Ishihara
Sangyo Kaisha Ltd) US Patent 8,030,498, 2011.
Yield: 77 mg (37%); colorless solid; mp 153–155 °C.
IR (KBr): 3092, 2246, 1653, 1498, 1448, 1089, 1015, 907 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.84 (d, J = 7.6 Hz, 2 H), 7.80 (d, J =
8.2 Hz, 2 H), 7.65–7.55 (m, 2 H), 7.53 (d, J = 8.2 Hz, 2 H), 7.42 (d, J =
8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H).
13C NMR (126 MHz, CDCl3):  = 186.3, 162, 150.3, 139.9, 136.8, 134.6,
133.6, 130.2, 128.9, 128.8, 128.7, 128.2, 127.9, 127.6, 122.2, 115.4,
108.4.
MS: m/z (%) = 417 (100), 400 (9), 382 (61), 306 (50), 139 (39), 111
(44), 77 (56), 51 (16).
(6) Carey, F.; Giuliano, R. Aldehydes and Ketones: Nucleophilic Addi-
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Anal. Calcd for C23H13Cl2N3O (418.28): C, 66.05; H, 3.13; N, 10.05.
Found: C, 66.43; H, 3.15; N, 10.09.
4-(4-Chlorobenzoyl)-3-(4-fluorophenyl)-1-phenyl-1H-pyrazole-5-
carbonitrile (3p)
Yield: 78 mg (39%); colorless solid; mp 161–163 °C.
IR (KBr): 3079, 2241, 1652, 1589, 1500, 1450, 1224, 1089, 920, 851,
(8) (a) Caboni, P.; Sammelson, R. E.; Casida, J. E. J. Agric. Food Chem.
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764 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.84 (d, J = 7.9 Hz, 2 H), 7.79 (d, J =
7.5 Hz, 2 H), 7.67–7.48 (m, 5 H), 7.40 (d, J = 7.6 Hz, 2 H), 7.03 (t, J =
7.9 Hz, 2 H).
13C NMR (126 MHz, CDCl3):  = 187.5, 163.5 (d, 1JCF = 250.2 Hz), 151.6,
141.0, 138.0, 134.9, 131.4, 130.6 (d, 3JCF = 8.5 Hz), 129.9, 129.6, 129.2,
4
2
126.7, 126.5 (d, JCF = 2.9 Hz), 124.4, 123.4, 115.9 (d, JCF = 21.9 Hz),
109.6.
19F NMR (471 MHz, CDCl3):  = –105.9.
MS: m/z (%) = 401 (100), 384 (11), 366 (66), 290 (62), 139 (40), 111
(41), 77 (62), 51 (16).
Anal. Calcd for C23H13ClFN3O (401.83): C, 68.75; H, 3.26; N, 10.46.
Found: C, 69.18; H, 3.28; N, 10.48.
Funding Information
We are grateful to the Research Council of Tarbiat Modares University
for support of this work.
T
arb
i
at
M
o
d
ares
U
n
i
v
ersity()
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691591.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

H
I. Yavari, O. Khaledian
Paper
Synthesis
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H