Iodine-Mediated Synthesis of Novel Pyrazole Derivatives

Article abstract of DOI:10.1055/s-0035-1560553

The reaction between N,2-diarylhydrazinecarbothioamide (generated from arylhydrazines and aryl isothiocyanates) and malononitrile in the presence of iodine/triethylamine in N,N-dimethylformamide at 80 °C afforded novel pyrazoles, 5-amino-1-aryl-3-(arylami

Full text of DOI:10.1055/s-0035-1560553

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
paper
A
M. Mahdavi et al.
Paper
Synthesis
Iodine-Mediated Synthesis of Novel Pyrazole Derivatives
Mohammad Mahdavia
Mahsa Khoshbakhtb
Mina Saeedic,d
Mehdi Asadia
Mohammad Bayatb
Alireza Foroumadia
Abbas Shafiee*a
CN
H2N
S
Y
NC
I2, Et3N
DMF, 80 °C, 1–2 h
CN
H
N
N
N
H
N
N
N
Y
H
H
X
X
13 examples
62–90%
X = H, F, Br, OMe
Y = H, 2-F, 2-Cl, 2-Br, 4-Me, 4-MeO
a Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran
ashafiee@ams.ac.ir
b Department of Chemistry, Imam Khomeini International
University, Qazvin, Iran
c Medicinal Plants Research Center, Faculty of Pharmacy, Tehran
University of Medical Sciences, Tehran, Iran
d Persian Medicine and Pharmacy Research Center, Tehran
University of Medical Sciences, Tehran, Iran
Received: 30.09.2015
Accepted after revision: 09.11.2015
Published online: 07.01.2016
vestigated and compared with another desulfurizing agent
(e.g., HgCl2).9b Also, iodine has been reported as a useful re-
agent for the preparation of cyanamides from dithiocarba-
mate salts.9c
DOI: 10.1055/s-0035-1560553; Art ID: ss-2015-n0572-op
Abstract The reaction between N,2-diarylhydrazinecarbothioamide
(generated from arylhydrazines and aryl isothiocyanates) and malono-
nitrile in the presence of iodine/triethylamine in N,N-dimethylform-
amide at 80 °C afforded novel pyrazoles, 5-amino-1-aryl-3-(arylamino)-
1H-pyrazole-4-carbonitriles, in good yields. In this strategy, iodine
served as a versatile desulfurizing agent, efficiently promoting the cy-
clization reaction.
Pyrazole derivatives are a key structural motif in a vari-
ety of biologically active molecules. Some derivatives have
been considered at a clinical level and they are commercial-
ly available pharmaceuticals; apixaban, antipyrine, celecox-
ib, fipronil, novalgine, phenylbutazone, pyrazofurin ram-
ifenazone, and rimonabant are examples in this area.10
Apart from these pharmaceutical agents, various medicinal
properties of pyrazoles, such as analgesic and anti-inflam-
matory,11 antibacterial,12 anticonvulsant,13 antimalarial,14
antifungal,15 antimycobacterial,16 antioxidant,17 antitumor-
al,18 insecticidal,19 leishmanicidal,20 antiglaucoma,21 and
hypoglycemic22 activity, have been frequently described in
the literature. It is clear that new methods for the construc-
tion of pyrazole derivatives are still required.
There are various methods for the synthesis of pyra-
zoles23 using different synthetic strategies such as the cy-
clocondensation of arylhydrazines with various monothio-
1,3-diketones,24 four-component coupling of a terminal
alkyne, hydrazine/hydroxylamine, carbon monoxide, and
an aryl iodide in the presence of a palladium catalyst,25 re-
action of diarylhydrazones and vicinal diols,26 reaction of
vinyl azide, aldehyde, and tosylhydrazine in the presence of
base,27 and acid-catalyzed propargylation of N,N-diprotect-
ed hydrazines followed by base-mediated 5-endo-dig cy-
clization.28
Key words pyrazoles, molecular iodine, heterocycles, isothiocya-
nates, malononitrile
Molecular iodine has been well documented as an effec-
tive Lewis acid catalyst for the promotion of organic trans-
formations1 as well as polymer synthesis.2 It is inexpensive,
user-friendly, resistant to air and moisture, readily avail-
able, and nontoxic. Hence, it is a preferred replacement for
toxic and expensive acid catalysts. The application of iodine
has been reported in various organic strategies, such as the
synthesis of a wide spectrum of heterocycles,3 the iodina-
tion of organic compounds,4 protection-deprotection of
functional groups,5 Michael additions,6 Prins-related reac-
tions,7 and oxidation reactions.8 Recently, iodine has at-
tracted much attention as an expedient reagent for the syn-
thesis of heterocyclic as well as acyclic compounds starting
from isothiocyanates, thioamides, or dithiocarbamates
through a desulfurization process.9 Shibahara et al. report-
ed the synthesis of 2-azaindolizines via iodine-promoted
cyclization of N-(2-pyridylmethyl)thioamides.9a A study by
Patel et al. reported the regioselective synthesis of tetra-
zoles from isothiocyanates; the efficiency of iodine was in-
Herein, in continuation of our research program on the
synthesis of novel heterocycles,29 we describe an efficient
procedure to access novel pyrazoles, 5-amino-1-aryl-3-
(arylamino)-1H-pyrazole-4-carbonitrile
derivatives
5,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
M. Mahdavi et al.
Paper
Synthesis
CN
S
H2N
Ar1
H
Ar2
Et2O, r.t., 2 h
Et3N
4
CN
NC
I2, Et3N
DMF, 80 °C, 1–2 h
N
Ar2
Ar1
Ar1
N
N
NHNH2
+
Ar2
NCS
N
H
H
N
H
N
1
2
3
5
Scheme 1 Synthesis of 5-amino-1-aryl-3-(arylamino)-1H-pyrazole-4-carbonitriles 5
through iodine-promoted reaction of N,2-diarylhydrazine-
carbothioamides 3 (prepared from arylhydrazines 1 and
aryl isothiocyanates 2)30 and malononitrile 4 in N,N-di-
methylformamide at 80 °C (Scheme 1).
mmol) in N,N-dimethylformamide yielding only the ex-
pected product, compound 5a (entries 2 and 3); the best re-
sults were obtained at 80 °C furnishing product 5a in 85%
yield. Conducting the model reaction in the presence of dif-
ferent desulfurizing reagents, such as copper(I) iodide, cop-
per(I) bromide, mercury(II) chloride, and dicyclohexylcar-
bodiimide (entries 8–11) resulted in an inefficient reaction
that gave several byproducts in addition to 5a.
With these results in hand, in order to obtain insight
into the role of electronic effects on the reaction, it was per-
formed using various N,2-diarylhydrazinecarbothioamide
derivatives 3a–m possessing various substituents, includ-
ing electron-withdrawing and electron-donating groups
(Table 2). All of them reacted with malononitrile (4) in one
to two hours to give 5-amino-1-aryl-3-(arylamino)-1H-
pyrazole-4-carbonitriles 5a–m. It should be noted that
compounds 3a–m possessing electron-donating groups
(methoxy and methyl) requires a longer reaction time and
lower yields of the corresponding product were obtained
compared with the other derivatives.
Table 1 Optimization of the Reaction Conditionsa
S
CN
H
H2N
Ph
N
various conditions
Ph
N
N
H
H
N
N
F
F
H
N
3a
5a
Entry
Solvent
Reagent
Temp (°C)
Yieldb (%)
1
2
DMF
I2
r.t.
–
DMF
I2
80
85
85
60
80
45
30
20
35
70
trace
3
DMF
I2
100
reflux
reflux
reflux
reflux
80
4
EtOH
MeCN
CH2Cl2
I2
5
I2
6
I2
7
toluene
DMF
I2
8
CuI
CuBr
HgCl2
DCC
Table 2 Synthesis of 5-Amino-1-aryl-3-(arylamino)-1H-pyrazole-4-
carbonitriles 5
9
DMF
80
10
11
DMF
80
CN
S
Ar1
NHNH2
H2N
Ar1
NC
CN
H
Ar2
DMF
80
Et2O
4
N
Ar2
1
Ar1
N
N
+
N
a Reaction conditions: 3a (1 mmol), malononitrile (4, 1 mmol), reagent (1
equiv), Et3N (1 equiv), solvent (8 mL), 2 h.
b Isolated yield.
r.t., 2 h
I2, Et3N
DMF, 80 °C
8–12 h
N
H
H
Ar2
H
NCS
2
N
3
5
Entry
Ar1
Ar2
Product
Yielda (%)
Initially, N,2-diarylhydrazinecarbothioamide derivatives
3 were easily prepared by the reaction of various arylhydra-
zines 1 and aryl isothiocyanates 2 in dry diethyl ether in the
presence of triethylamine at room temperature (Scheme 1).
First, the reaction of N-(2-fluorophenyl)-2-phenylhydrazin-
ecarbothioamide (3a) with malononitrile (4) was examined
under varying conditions and solvents with a view to ob-
tain the corresponding product, 5-amino-3-[(2-fluorophe-
nyl)amino]-1-phenyl-1H-pyrazole-4-carbonitrile (5a) in
good yield (Table 1). Focusing on the efficiency of iodine in
organic transformations,1 the reaction of compound 3a (1
mmol) and malononitrile (1 mmol) was investigated in the
presence of iodine and triethylamine under various condi-
tions (Table 1). The presence of base was crucial, and one
equivalent of triethylamine was sufficient to obtain the best
result. Our studies revealed that the reaction of compound
3a (1 mmol) and malononitrile (4, 1 mmol) was very clean
in the presence of iodine (1 mmol) and triethylamine (1
1
2
Ph
2-FC6H4
5a
5b
5c
5d
5e
5f
85
75
80
70
70
85
68
70
90
83
80
65
62
Ph
2-ClC6H4
2-BrC6H4
4-MeC6H4
3
Ph
4
Ph
5
Ph
4-MeOC6H4
Ph
6
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-BrC6H4
4-BrC6H4
7
4-MeOC6H4
4-MeC6H4
2-FC6H4
5g
5h
5i
8
9
10
11
12
13
2-FC6H4
5j
2-ClC6H4
4-MeOC6H4
4-FC6H4
5k
5l
4-MeOC6H4
4-MeOC6H4
5m
a Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

C
M. Mahdavi et al.
Paper
Synthesis
I
I
I
I
SI
SI2
S
H
H
H
H
N
CN
NC
Ar2
Ar1
N
C
N
Ar2
N
Ar2
N
Ar2
N
Ar1
N
H
N
Ar1
N
H
N
Ar1
N
N
H
8
H
7
6
3
NEt3
NEt3
CN
CN
Ar1
HN
H2N
Ar1
Ar2
H
Ar2
H
N
N
C
N
Ar2
N
N
N
N
H
Ar1
NEt3
N
H
N
C
CN
N
5
10
9
Scheme 2 Plausible mechanism for the formation of product 5
A plausible mechanism for the formation of 5-amino-1-
aryl-3-(arylamino)-1H-pyrazole-4-carbonitriles 5a–m is
given in Scheme 2. The reaction is initiated by deprotona-
tion of 3 by triethylamine, this is followed by iodination at
sulfur to give intermediate 6 and a second iodination at sul-
fur gives intermediate 7, which liberates sulfur affording
carbodiimide derivative, N-[(2-arylhydrazono)methyl-
ene]aniline 8. Intermediate 8 is attacked by malononitrile
anion to give 9, and finally, intramolecular cyclization of 9
gives intermediate 10 that tautomerizes to furnish product
5.
In continuation of our investigation of the synthesis of
pyrazoles, we conducted the reaction of compound 3a and
ethyl cyanoacetate under the optimized conditions; howev-
er 5a was not obtained and clearly malononitrile showed
higher activity.
5-Amino-1-aryl-3-(arylamino)-1H-pyrazole-4-carbonitriles 5;
General Procedure
A solution of arylhydrazine derivative 1 (1 mmol), isocyanate deriva-
tive 2 (1 mmol), and Et3N (1 mmol) in dry Et2O (8 mL) was stirred at
r.t. for 2 h. After completion of reaction, the precipitated product was
filtered off and dried at 50–60 °C to give pure N,2-diarylhydrazinecar-
bothioamide derivative 3. Then, a mixture of compound 3 (1 mmol),
malononitrile 4 (1 mmol), I2 (1 mmol), and Et3N (1 mmol) in DMF (8
mL) was stirred at 80 °C for 1–2 h. When the reaction was complete
(TLC monitoring), the mixture was filtered off through Celite and the
filtrate was extract using sat. Na2S2O3 solution and EtOAc. The organic
phase was dried (Na2SO4), the solvent was removed under reduced
pressure, and the crude mixture was purified using column chroma-
tography (silica gel, petroleum ether–EtOAc, 5:1) to give pure pyra-
zoles 5. All products were recrystallized (petroleum ether–EtOAc).
5-Amino-3-[(2-fluorophenyl)amino]-1-phenyl-1H-pyrazole-4-
carbonitrile (5a)
In summary, novel 5-amino-1-aryl-3-(arylamino)-1H-
pyrazole-4-carbonitriles were synthesized by reaction of
N,2-diarylhydrazinecarbothioamide (generated from aryl-
hydrazines and aryl isothiocyanates) and malononitrile in
the presence of iodine and triethylamine in N,N-dimethyl-
formamide at 80 °C in a short reaction time (1–2 h). Molec-
ular iodine played important role as a desulfurizing reagent
giving the corresponding products in good yields. Consider-
ing the bioactivity of pyrazoles, we hope that this protocol
will be useful for organic, as well as medicinal, chemists for
the construction of pyrazole-based agents possessing valu-
able medicinal properties.
White crystals; yield: 0.25 g (85%); mp 185–186 °C.
IR (KBr): 3452, 3309, 3211, 2216, 1629, 1553 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 8.09 (s, 1 H, NH), 7.77 (t, J = 7.5 Hz,
1 H, H3′), 7.51–7.36 (m, 5 H, H2–H6), 7.19–7.12 (m, 1 H, H6′), 7.06 (t,
J = 7.5 Hz, 1 H, H5′), 6.89–6.87 (m, 1 H, H4′), 6.70 (s, 2 H, NH2).
13C NMR (75 MHz, DMSO-d6): δ = 152.3 (d, J = 241.3 Hz), 151.1, 150.9,
137.7, 130 (d, J = 10.6 Hz), 129.4, 127.1, 124.4 (d, J = 2.5 Hz), 123.7,
121.1 (d, J = 7.3 Hz), 119.7, 115.1 (d, J = 18.5 Hz), 114.4, 66.0.
Anal. Calcd for C16H12FN5: C, 65.52; H, 4.12; N, 23.88. Found: C, 65.38;
H, 4.31; N, 23.67.
5-Amino-3-[(2-chlorophenyl)amino]-1-phenyl-1H-pyrazole-4-
carbonitrile (5b)
White crystals; yield: 0.23 g (75%); mp 204–205 °C.
IR (KBr): 3455, 3409, 3312, 2210, 1638, 1608 cm–1
.
Melting points were taken on a Kofler hot stage apparatus and are un-
corrected. 1H and 13C NMR spectra were recorded on Bruker FT-500,
400, and 300 using TMS as an internal standard. The IR spectra were
obtained on a Nicolet Magna FTIR 550 spectrophotometer (in KBr).
Mass spectra were documented on an Agilent Technology (HP) mass
spectrometer operating at an ionization potential of 70 eV. The ele-
mental analysis was performed with an Elementar Analysensystem
GmbH VarioEL CHNS mode.
1H NMR (300 MHz, CDCl3): δ = 8.25 (dd, J = 8.0, 1.3 Hz, 1 H, H6′), 7.61–
7.42 (m, 5 H, H2–H6), 7.36 (dd, J = 8.0, 1.3 Hz, 1 H, H3′), 7.14 (t, J = 8.0,
1.3 Hz, 1 H, H5′), 6.88 (td, J = 8.0, 1.3 Hz, 1 H, H4′), 6.79 (s, 1 H, NH),
4.68 (s, 2 H, NH2).
13C NMR (75 MHz, CDCl3): δ = 150.6, 148.9, 137.2, 136.9, 129.9, 129.0,
128.2, 127.7, 123.8, 121.4, 120.5, 117.6, 113.5, 67.2.
Anal. Calcd for C16H12ClN5: C, 62.04; H, 3.90; N, 22.61. Found: C,
61.91; H, 4.15; N, 22.48.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

D
M. Mahdavi et al.
Paper
Synthesis
5-Amino-3-[(2-bromophenyl)amino]-1-phenyl-1H-pyrazole-4-
carbonitrile (5c)
1H NMR (300 MHz, DMSO-d6): δ = 8.38 (s, 1 H, NH), 7.56–7.47 (m, 4 H,
H2, H6, H2′, H6′), 7.32 (t, J = 8.5 Hz, 2 H, H3, H5), 6.79 (d, J = 8.6 Hz, 2
H, H3′, H5′), 6.63 (s, 2 H, NH2), 3.64 (s, 3 H, OMe).
White crystals; yield: 0.28 g (80%); mp 194–196 °C.
13C NMR (75 MHz, DMSO-d6): δ = 160.5 (d, J = 242.5 Hz), 153.0, 151.5,
151.2, 135.4, 134.3 (d, J = 2.6 Hz), 126.1 (d, J = 8.8 Hz), 118.2, 116.1 (d,
J = 22.7 Hz), 114.7, 113.8, 64.1, 55.1.
IR (KBr): 3450, 3415, 3300, 2220, 1630, 1615 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.25 (dd, J = 8.0, 1.2 Hz, 1 H, H3′), 7.56–
7.53 (m, 5 H, H2–H6), 7.44 (dd, J = 8.0, 1.2 Hz, 1 H, H6′), 7.29 (td,
J = 8.0, 1.2 Hz, 1 H, H5′), 6.81–6.85 (m, 2 H, NH, H4′), 4.71 (s, 2 H, NH2).
Anal. Calcd for C17H14FN5O: C, 63.15; H, 4.36; N, 21.66. Found: C,
63.28; H, 4.42; N, 21.80.
13C NMR (100 MHz, CDCl3): δ = 150.7, 148.9, 138.0, 137.2, 132.3,
129.9, 128.5, 128.2, 123.8, 121.9, 117.7, 114.1, 111.2, 67.1.
5-Amino-1-(4-fluorophenyl)-3-(p-tolylamino)-1H-pyrazole-4-car-
bonitrile (5h)
Anal. Calcd for C16H12BrN5: C, 54.25; H, 3.41; N, 19.77. Found: C,
54.08; H, 3.52; N, 19.58.
White crystals; yield: 0.21 g (70%); mp 216–218 °C.
IR (KBr): 3440, 3338, 3224, 2920, 2820, 2201, 1640, 1602, 1576 cm–1
.
5-Amino-1-phenyl-3-(p-tolylamino)-1H-pyrazole-4-carbonitrile
(5d)
1H NMR (300 MHz, DMSO-d6): δ = 8.47 (s, 1 H, NH), 7.55 (dd, J = 8.7,
4.5 Hz, 2 H, H2, H6), 7.45 (d, J = 8.5 Hz, 2 H, H2′, H6′), 7.34 (t, J = 8.7
Hz, 2 H, H3, H5), 6.99 (d, J = 8.5 Hz, 2 H, H3′, H5′), 6.65 (s, 2 H, NH2),
2.20 (s, 3 H, OMe).
13C NMR (125 MHz, DMSO-d6): δ = 160.6 (d, J = 242.5 Hz), 151.2,
139.5, 134.3, 128.9, 128.8, 128.2, 126.1 (d, J = 8.7 Hz), 116.8, 116.1 (d,
J = 22.5 Hz), 114.6, 64.4, 20.3.
White crystals; yield: 0.20 g (70%); mp 168–170 °C.
IR (KBr): 3433, 3335, 3220, 2921, 2202, 1595, 1571, 1543 cm–1
1H NMR (500 MHz, DMSO-d6): δ = 8.47 (s, 1 H, NH), 7.52–7.47 (m, 4 H,
H2, H3, H5, H6), 7.45 (d, J = 7.5 Hz, 2 H, H2′, H6′), 7.35 (t, J = 7.7 Hz, 1
H, H4), 7.00 (d, J = 7.5 Hz, 2 H, H3′, H5′), 6.64 (s, 2 H, NH2), 2.20 (s, 3 H,
CH3).
.
Anal. Calcd for C17H14FN5: C, 66.44; H, 4.59; N, 22.79. Found: C, 66.57;
H, 4.68; N, 22.86.
13C NMR (125 MHz, DMSO-d6): δ = 151.2, 151.0, 139.6, 137.9, 129.4,
129.1, 128.9, 128.2, 126.8, 123.4, 116.8, 66.0, 20.3.
Anal. Calcd for C17H15N5: C, 70.57; H, 5.23; N, 24.20. Found: C, 70.41;
H, 5.37; N, 24.34.
5-Amino-1-(4-fluorophenyl)-3-[(2-fluorophenyl)amino]-1H-pyra-
zole-4-carbonitrile (5i)
White crystals; yield: 0.28 g (90%); mp 205–206 °C.
5-Amino-3-[(4-methoxyphenyl)amino]-1-phenyl-1H-pyrazole-4-
carbonitrile (5e)
IR (KBr): 3443, 3363, 3227, 2213, 1650, 1629 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 8.08 (s, 1 H, NH), 7.76 (t, J = 8.0 Hz,
1 H, H3′), 7.55–7.51 (m, 2 H, H2, H6), 7.33 (t, J = 8.2 Hz, 2 H, H3, H5),
7.15 (t, J = 8.0 Hz, 1 H, H5′), 7.06 (t, J = 8.0 Hz, 1 H, H4′), 6.88 (d, J = 8.0
Hz, 1 H, H6′), 6.70 (s, 2 H, NH2).
13C NMR (75 MHz, DMSO-d6): δ = 160.7 (d, J = 243.1 Hz), 152.3 (d,
J = 241.2 Hz), 151.3, 150.9, 134.0 (d, J = 2.7 Hz), 129.9 (d, J = 10.7 Hz),
126.4 (d, J = 8.7 Hz), 124.4 (d, J = 3.3 Hz), 121.2 (d, J = 7.2 Hz), 119.8,
116.2 (d, J = 22.8 Hz), 115.1 (d, J = 18.7 Hz), 114.4, 65.8.
White crystals; yield: 0.21 g (70%); mp 185–186 °C.
IR (KBr): 3441, 3356, 3157, 2923, 2204, 1626, 1600, 1568, 1509 cm–1
1H NMR (500 MHz, DMSO-d6): δ = 8.38 (s, 1 H, NH), 7.75–7.48 (m, 6 H,
H2, H3, H5, H6, H2′, H6′), 7.35 (t, J = 7.0 Hz, 1 H, H4), 6.81 (d, J = 9.0
Hz, 2 H, H3′, H5′), 6.62 (s, 2 H, NH2), 3.68 (s, 3 H, OMe).
.
13C NMR (125 MHz, DMSO-d6): δ = 154.5, 153.0, 151.5, 138.0, 135.5,
129.3, 126.7, 123.3, 118.2, 114.7, 113.8, 64.3, 55.1.
Anal. Calcd for C17H15N5O: C, 66.87; H, 4.95; N, 22.94. Found: C, 66.71;
H, 5.17; N, 23.11.
Anal. Calcd for C16H11F2N5: C, 61.73; H, 3.56; N, 22.50. Found: C, 61.85;
H, 3.67; N, 22.64.
5-Amino-1-(4-fluorophenyl)-3-(phenylamino)-1H-pyrazole-4-car-
bonitrile (5f)
5-Amino-1-(4-bromophenyl)-3-[(2-fluorophenyl)amino]-1H-pyr-
azole-4-carbonitrile (5j)
White crystals; yield: 0.25 g (85%); mp 190–192 °C.
White crystals; yield: 0.31 g (83%); mp 180–182 °C.
IR (KBr): 3427, 3348, 3315, 2198, 1605, 1550 cm–1
.
IR (KBr): 3443, 3397, 3202, 2213, 1639, 1580 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.55–7.47 (m, 4 H, H2, H6, H2′, H6′),
7.30 (t, J = 7.5 Hz, 2 H, H3′, H5′), 7.20 (t, J = 8.0 Hz, 2 H, H3, H5), 6.98 (t,
J = 7.5 Hz, 1 H, H4′), 6.25 (s, 1 H, NH), 4.63 (s, 2 H, NH2).
13C NMR (75 MHz, CDCl3): δ = 161.8 (d, J = 247.5 Hz), 151.4, 149.0,
140.4, 133.3 (d, J = 3.0 Hz), 129.1, 125.9 (d, J = 8.6 Hz), 121.3, 117.0,
116.7, 114.0, 66.5.
1H NMR (300 MHz, DMSO-d6): δ = 8.12 (s, 1 H, NH), 7.76 (t, J = 8.0 Hz,
1 H, H3′), 7.67 (d, J = 7.8 Hz, 2 H, H3, H5), 7.46 (d, J = 7.8 Hz, 2 H, H2,
H6), 7.15 (t, J = 8.0 Hz, 1 H, H5′), 7.06 (t, J = 8.0 Hz, 1 H, H4′), 6.89 (d,
J = 8.0 Hz, 1 H, H6′), 6.78 (s, 2 H, NH2).
13C NMR (75 MHz, DMSO-d6): δ = 160.4 (d, J = 241.0 Hz), 151.3, 151.1,
137.0, 132.2, 129.8 (d, J = 10.9 Hz), 125.6, 124.4, 121.3 (d, J = 7.0 Hz),
120.0, 119.7, 115.1 (d, J = 19.0 Hz), 114.3, 66.1.
Anal. Calcd for C16H12FN5: C, 65.52; H, 4.12; N, 23.88. Found: C, 65.68;
H, 4.23; N, 23.71.
Anal. Calcd for C16H11BrFN5: C, 51.63; H, 2.98; N, 18.82. Found: C,
51.77; H, 3.21; N, 18.67.
5-Amino-1-(4-fluorophenyl)-3-[(4-methoxyphenyl)amino]-1H-
pyrazole-4-carbonitrile (5g)
5-Amino-1-(4-bromophenyl)-3-[(2-chlorophenyl)amino]-1H-pyr-
White crystals; yield: 0.22 g (68%); mp 208–209 °C.
azole-4-carbonitrile (5k)
IR (KBr): 3437, 3351, 3224, 2922, 2834, 2204, 1641, 1608 cm–1
.
White crystals; yield: 0.31 g (80%); mp 234–235 °C.
IR (KBr): 3463, 3411, 3360, 2205, 1630, 1579 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

E
M. Mahdavi et al.
Paper
Synthesis
1H NMR (300 MHz, DMSO-d6): δ = 7.80 (d, J = 8.0 Hz, 1 H, H6′), 7.69 (d,
J = 8.5 Hz, 2 H, H3, H5), 7.57 (s, 1 H, NH), 7.48 (d, J = 8.5 Hz, 2 H, H2,
H6), 7.40 (d, J = 8.0 Hz, 1 H, H3′), 7.24 (t, J = 8.0 Hz, 1 H, H5′), 6.91 (t,
J = 8.0 Hz, 1 H, H4′), 6.86 (s, 2 H, NH2).
(4) Das, B.; Krishnaiah, M.; Venkateswarlu, K.; Reddy, V. S. Tetrahe-
dron Lett. 2007, 48, 81.
(5) Sun, J.; Dong, Y.; Cao, L.; Wang, X.; Wang, S.; Hu, Y. J. Org. Chem.
2004, 69, 8932.
(6) Gao, S.; Tzeng, T.; Sastry, M. N. V.; Chu, C. M.; Liu, J. T.; Lin, C.;
Yao, C.-F. Tetrahedron Lett. 2006, 47, 1889.
(7) Yadav, J. S.; Reddy, B. V. S.; Chaya, D. N.; Kumar, G. G. K. S. N.;
Aravind, S.; Kunwar, A. C.; Madavi, C. Tetrahedron Lett. 2008, 49,
3330.
13C NMR (75 MHz, DMSO-d6): δ = 151.1, 150.9, 138.1, 136.9, 132.3,
129.3, 127.8, 125.8, 121.9, 121.4, 119.8, 119.0, 114.1, 66.3.
MS: m/z (%) = 391 [M + 4]+ (3), 389 [M + 2]+ (12), 387 [M]+ (9), 354
(61), 337 (13), 273 (33), 246 (20), 155 (23), 119 (16), 75 (26).
Anal. Calcd for C16H11BrClN5: C, 49.45; H, 2.85; N, 18.02. Found: C,
49.69; H, 2.72; N, 17.88.
(8) Mori, N.; Togo, H. Tetrahedron 2005, 61, 5915.
(9) (a) Shibahara, F.; Kitagawa, A.; Yamaguchi, E.; Murai, T. Org. Lett.
2006, 8, 5621. (b) Yella, R.; Khatun, N.; Rout, S. K.; Patel, B. K.
Org. Biomol. Chem. 2011, 9, 3235. (c) Nath, J.; Patel, B. K.; Jamir,
L.; Sinha, U. B.; Satyanarayana, K. V. V. V. Green Chem. 2009, 11,
1503.
(10) Küçükgüzel, Ş. G.; Şenkardeş, S. Eur. J. Med. Chem. 2015, 97, 786.
(11) Maggio, B.; Daidone, G.; Raffa, D.; Plescia, S.; Mantione, L.;
Cutuli, V. M. C.; Mangano, N. G.; Caruso, A. Eur. J. Med. Chem.
2001, 36, 737.
(12) Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Suzuki, K.;
Ueda, T.; Terauchi, H.; Kawasaki, M.; Nagai, K.; Wachi, M.;
Yamagishi, J. Bioorg. Med. Chem. 2004, 12, 5515.
(13) Aragade, P.; Kolhe, S.; Kamble, H.; Baheti, D.; Maddi, V. Int. J.
Drug Discovery 2012, 3, 688.
5-Amino-1-(4-methoxyphenyl)-3-[(4-methoxyphenyl)amino]-1H-
pyrazole-4-carbonitrile (5l)
White crystals; yield: 0.22 g (65%); mp 184–186 °C.
IR (KBr): 3416, 3356, 3225, 2205, 1630, 1601, 1570 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.33 (s, 1 H, NH), 7.48 (d, J = 9.0 Hz,
2 H, H2, H6), 7.40 (d, J = 8.5 Hz, 2 H, H2′, H6′), 7.05 (d, J = 8.5 Hz, 2 H,
H3′, H5′), 6.79 (d, J = 9.0 Hz, 2 H, H3, H5), 6.47 (s, 2 H, NH2), 3.80 (s, 3
H, OMe), 3.67 (s, 3 H, OMe).
13C NMR (125 MHz, DMSO-d6): δ = 158.1, 152.9, 151.2, 150.9, 135.6,
130.8, 125.6, 118.1, 114.9, 114.5, 113.8, 63.7, 55.4, 55.1.
Anal. Calcd for C18H17N5O2: C, 64.47; H, 5.11; N, 20.88. Found: C,
64.58; H, 5.20; N, 20.71.
(14) Dominquez, J. N.; Charris, J. E.; Caparelli, M.; Riggione, F.
Arzneimittelforschung 2002, 52, 482.
(15) Li, Y.; Zhang, H.; Lıu, J.; Yang, X.; Liu, Z. J. Agric. Food Chem. 2006,
54, 3636.
(16) Castagnolo, D.; De Logu, A.; Radi, M.; Bechi, B.; Manetti, F.;
Magnani, M.; Supino, S.; Meleddu, R.; Chisu, L.; Botta, M. Bioorg.
Med. Chem. 2008, 16, 8587.
5-Amino-3-[(4-fluorophenyl)amino]-1-(4-methoxyphenyl)-1H-
pyrazole-4-carbonitrile (5m)
White crystals; yield: 0.20 g (62%); mp 194–195 °C.
IR (KBr): 3417, 3357, 3226, 2206, 1631, 1601, 1570 cm–1
.
(17) Bandgar, B. P.; Gawande, S. S.; Bodade, R. G.; Gawande, N. M.;
Khobragade, C. N. Bioorg. Med. Chem. 2009, 17, 8168.
(18) Anzaldia, M.; Macciò, C.; Mazzeia, M.; Bertolottob, M.;
Ottonellob, L.; Dallegrib, F.; Balbi, A. Chemistry & Biodiversity
2009, 6, 1674.
1H NMR (500 MHz, DMSO-d6): δ = 8.44 (s, 1 H, NH), 7.40 (dd, J = 9.0,
5.0 Hz, 2 H, H2′, H6′), 7.33 (d, J = 8.5 Hz, 2 H, H2, H6), 7.14 (dd, J = 9.0
Hz, 2 H, H3′, H5′), 6.93 (d, J = 8.5 Hz, 2 H, H3, H5), 6.63 (s, 2 H, NH2),
3.77 (s, 3 H, OMe).
13C NMR (125 MHz, DMSO-d6): δ = 159.0 (d, J = 240.0 Hz), 157.6,
155.5, 151.1, 139.2, 136.1, 128.7, 126.5 (d, J = 7.5 Hz), 114.5 (d,
J = 22.5 Hz), 114.2, 113.5, 55.3, 45.2. 55.3.
(19) Dong, W.; Xu, J.; Xıong, L.; Liu, X.; Li, Z. Chin. J. Chem. 2009, 27,
579.
(20) Faria, J. V.; dos Santos, M. S.; Bernardino, A. M. R.; Becker, K. M.;
Machado, G. M. C.; Rodrigues, R. F.; Canto-Cavalheiro, M. M.;
Leon, L. L. Bioorg. Med. Chem. Lett. 2013, 23, 6310.
(21) Kasımoğulları, R.; Bülbül, M.; Arslan, B. S.; Gökçe, B. Eur. J. Med.
Chem. 2010, 45, 4769.
Anal. Calcd for C17H14FN5O: C, 63.15; H, 4.36; N, 21.66. Found: C,
63.28; H, 4.22; N, 21.51.
(22) Cottineau, B.; Toto, P.; Marot, C.; Pipaud, A.; Chenault, J. Bioorg.
Med. Chem. Lett. 2002, 12, 2105.
Acknowledgment
(23) (a) Fustero, S.; Simón-Fuentes, A.; Sanz-Cervera, J. F. Org. Prep.
Proced. Int. 2009, 41, 253. (b) Makino, K.; Kim, H. S.; Kurasawa,
Y. J. Heterocycl. Chem. 1999, 36, 321.
This research was supported by grants from the Research Council of
Tehran University of Medical Sciences and Iran National Science
Foundation (INSF).
(24) Kumar, S. V.; Yadav, S. K.; Raghava, B.; Saraiah, B.; Ila, H.;
Rangappa, K. S.; Hazra, A. J. Org. Chem. 2013, 78, 4960.
(25) Ahmed, M. S. M.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7, 4487.
(26) Panda, N.; Jena, A. K. J. Org. Chem. 2012, 77, 9401.
(27) Zhang, G.; Ni, H.; Chen, W.; Shao, J.; Liu, H.; Chen, B.; Yu, Y. Org.
Lett. 2013, 15, 5967.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560553.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(28) Reddy, C. R.; Vijaykumar, J.; Grée, R. Synthesis 2013, 45, 830.
(29) (a) Mahdavi, M.; Bialam, M.; Saeedi, M.; Jafarpour, F.;
Foroumadi, A.; Shafiee, A. Synlett 2015, 26, 173. (b) Goli-Garm-
roodi, F.; Omidi, M.; Saeedi, M.; Sarrafzadeh, F.; Rafinejad, A.;
Mahdavi, M.; Bardajee, G. R.; Akbarzadeh, T.; Firoozpour, L.;
Shafiee, A.; Foroumadi, A. Tetrahedron Lett. 2015, 56, 743.
(c) Saeedi, M.; Mahdavi, M.; Foroumadi, A.; Shafiee, A. Tetrahe-
dron 2013, 69, 3506. (d) Rasouli, M. A.; Mahdavi, M.; Saeedi, M.;
Ranjbar, P. R.; Shafiee, A.; Foroumadi, A. J. Heterocycl. Chem.
References
(1) Tekale, S. U.; Kauthale, S. S.; Dake, S. A.; Sarda, S. R.; Pawar, R. P.
Curr. Org. Chem. 2012, 16, 1485.
(2) Moulay, S. Des. Monomers Polym. 2014, 17, 501.
(3) Rahimizadeh, M.; Bakavoli, M.; Shiri, A.; Eshghi, H. Bull. Korean
Chem. Soc. 2009, 30, 1699.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

F
M. Mahdavi et al.
Paper
Synthesis
2015, 52, 386. (e) Esmaeili-Marandi, F.; Saeedi, M.; Mahdavi,
M.; Yavari, I.; Foroumadi, A.; Shafiee, A. Synlett 2014, 25, 2605.
(f) Saeedi, M.; Ansari, S.; Mahdavi, M.; Sabourian, R.;
Akbarzadeh, T.; Foroumadi, A.; Shafiee, A. Synth. Commun. 2015,
45, 2311.
(30) (a) Britto, M. M.; Almeida, T. M. G.; Leitão, A.; Donnici, C. L.;
Lopes, M. T. P.; Montanari, C. A. Synth. Commun. 2006, 36, 3359.
(b) Ram, V. J. Indian J. Appl. Chem. 1970, 33, 394.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F