A novel synthetic approach towards pyrazole-4-carboxamides using N-(3-(dimethylamino)-2-formylacryloyl)formamide

Article abstract of DOI:10.1007/s00706-010-0290-8

A novel synthesis of pyrazole-4-carboxamides is reported. The reaction of N-(3-(dimethylamino)-2-formylacryloyl)formamide, an intermediate obtained by Vilsmeier-Haack formylation of acetonitrile, with hydrazine hydrate or monosubstituted hydrazines provid

Full text of DOI:10.1007/s00706-010-0290-8

Monatsh Chem (2010) 141:569–576
DOI 10.1007/s00706-010-0290-8
ORIGINAL PAPER
A novel synthetic approach towards pyrazole-4-carboxamides
using N-(3-(dimethylamino)-2-formylacryloyl)formamide
•
Madhukar N. Jachak Maruti G. Ghagare Dilip R. Birari Ramhari V. Rote
•
•
•
•
Muddassar A. Kazi Sanjay M. Jachak Raghunath B. Toche
•
Received: 20 December 2009 / Accepted: 27 February 2010 / Published online: 16 April 2010
Ó Springer-Verlag 2010
Abstract A novel synthesis of pyrazole-4-carboxamides
is reported. The reaction of N-(3-(dimethylamino)-2-
formylacryloyl)formamide, an intermediate obtained by
Vilsmeier–Haack formylation of acetonitrile, with hydra-
zine hydrate or monosubstituted hydrazines provides such
compounds in good yields. This method has advantages
over other methods for construction of such ring systems
previously described in the literature.
rarely been explored. The reported procedure for prepara-
tion of pyrazole-4-carboxamides consisted in the synthesis
of 4-methylpyrazole [12–19] which was oxidized to pyra-
zole-4-carboxylic acid [20] using KMnO4, followed by
reaction with thionyl chloride to give corresponding acid
chloride [21, 22]. Subsequently, the acid chloride was
quenched with aqueous ammonia solution leading to pyr-
azole-4-carboxamides. Unfortunately, this method was
limited owing to drastic reaction conditions, laborious
workup, and a multistep reaction procedure. As a conse-
quence, the introduction of new methods and/or further
work on technical improvements to overcome the limita-
tions is still an important experimental challenge.
Keywords Hydrolysis Á Cyclization Á
Nucleophilic substitution Á N-Alkylation
Introduction
Pyrazole-4-carboxamides have found widespread appli-
cations because of their cannabinoid CB1 receptor [23],
herbicidal [24, 25], and anti-platelet [26] activity. Pyra-
zole-4-carboxamides bearing an aromatic substituent at the
N1 position have immunosuppressant activity [27] equiv-
alent to that of leflunomide and brequinar. As part of a
campaign to develop libraries based on this template, we
now report that pyrazole-4-carboxamides with a range of
different substituents at N1 can be conveniently prepared
from N-(3-(dimethylamino)-2-formylacryloyl)formamide 1
and hydrazine hydrate or monosubstituted hydrazines.
The first primary synthesis of 1-phenyl-3-methyl-5-pyr-
azolone from ethyl acetoacetate and phenyl hydrazine was
carried out by Knorr in 1883 [1]. His interest in quinine led
to tests of the antifebrile activity of this and related com-
pounds and resulted in the discovery of antipyrine [2],
probably the first antipyretic pyrazole derivative. This
stimulated interest in pyrazole chemistry and since then
several pyrazole derivatives have been synthesized using
different synthetic routes [3–11]. However, methods deal-
ing with the synthesis of pyrazole-4-carboxamides have
Results and discussion
M. N. Jachak (&) Á M. G. Ghagare Á D. R. Birari Á
R. V. Rote Á M. A. Kazi Á R. B. Toche
In connection with our previous work [28], we decided to
elaborate the reaction of 1 with hydrazine hydrate and
substituted hydrazines as an attractive procedure leading to
pyrazole-4-carboxamides. Thus our study began with
compound 1, which was reacted with 1.05 equiv. hydrazine
hydrate (2) via nucleophilic substitution in ethanol in
the presence of a catalytic amount of AcOH at room
Department of Chemistry, Organic Chemistry Research Centre,
K.T.H.M. College, Gangapur Road, Nashik 422002,
Maharashtra, India
e-mail: mn_jachak@hotmail.com
S. M. Jachak
National Institute of Pharmaceutical Education and Research,
S.A.S. Nagar, Mohali 160062, Punjab, India
123

570
M. N. Jachak et al.
Scheme 1
O
H2N
N
N
H
25-30 °C
EtOH/H+
N
N
O
O
H
3
H
N
O
EtOH/H+
H
+
NH2NH2.H2O
N
O
1
2
H2N
75-80 °C
EtOH/H+
N
N
H
4
Table 1 Optimization of the reaction conditionsa
temperature to give compound 3 in 40% yield (Scheme 1,
entry 1). However the same reaction at 75–80 °C led
selectively to 4 in 38% isolated yield (Table 1, entry 4).
Encouraged by these results, we surveyed a series of
reactions using different molar ratios of hydrazine hydrate
and temperature (Table 1). We found that either 3 or 4
could be prepared almost exclusively by varying the stoi-
chiometry and reaction conditions. The yields of pyrazoles
3 and 4 were found to be best when 2.5 equiv. hydrazine
hydrate relative to 1 were used (Table 1, entries 3 and 6).
Use of smaller amounts of hydrazine hydrate was found to
be less effective. An interesting observation was that when
1 was added to hydrazine hydrate in boiling ethanol, the N-
formyl group in 1 was hydrolysed to an amido group in 4.
Noteworthy was that compound 3 heated under reflux
separately in ethanol with a catalytic amount of AcOH
gave pyrazole-4-carboxamide 4 in quantitative yield.
The structure of compound 3 was deduced from its
elemental analysis and spectroscopic data. The mass
spectrum of 3 contained the molecular ion peak at
m/z = 153, which was consistent with the molecular
weight of 3. The IR spectrum of 3 contained absorption
bands of the amide carbonyl and NH2 groups at
1,676 cm-1 and 3,218 cm-1, respectively, and stretching
Entry Equiv. 1 Equiv. 2 Temp. Yield 3 (%)b Yield 4 (%)b
1
2
3
4
5
6
a
1
1
1
1
1
1
1.05
1.50
2.50
1.05
1.50
2.50
rt
40
48
80
–
–
rt
–
rt
–
Reflux
Reflux
Reflux
38
42
75
–
–
All reactions were carried out on approximately 1.46 mmol scale
Isolated yields
b
corresponding to the molecular weight of 4. In the 1H NMR
spectrum of 4, the pyrazole-NH resonated at 13.03 ppm, and
the C3H and C5H appeared at 8.11 and 7.83 ppm. The NH2
protons appeared separately as two broad singlets at 7.50 and
6.95 ppm because of either restricted rotation or hydrogen
bonding between the NH2 group and the amide carbonyl
group. Further 13C NMR spectroscopic analysis showed that
the peak at 163.8 ppm could be assigned to the amide car-
bon. The olefinic carbons resonated at d = 138.8 and
129.7 ppm. The remaining carbon appeared at 117.8 ppm.
The reaction mechanism could be explained by initial
substitution of the dimethylamino group in 1 to give the
enehydrazine intermediate 11. Simultaneously the second
molecule of hydrazine hydrate attacks the electrophilic
carbon of the N-formyl group leading, after condensation
with the aldehyde carbonyl group, to intermediate 12.
Extrusion of one water molecule gives 3. In order to trap
the open-chain intermediate, we carried out reactions of
compound 1 and hydrazine hydrate 2 at -5, -10, -15,
and -20 °C, but the cyclization process was so fast that
in all cases 3 was obtained as the sole product. When the
reaction temperature was 75–80 °C, intermediate 3 was
mainly hydrolysed by water to give intermediate 4
(Scheme 2).
1
of the NH group appeared at 3,311 cm-1. The H NMR
spectrum of 3 contained three broad singlets readily
assigned to an NH2 group and two NH groups (d = 5.62,
10.98, and 11.37 ppm, respectively). The pyrazole moiety
gave rise to characteristic signals (d = 7.96 and 8.99 ppm)
in the aromatic region of the spectrum. In the 13C NMR
spectrum of 3, the amide carbonyl appeared at 165.8 ppm,
the peak at 163.8 ppm corresponded to imine carbon, and
the pyrazole ring carbons C3, C4, and C5 appeared at
d = 163.3, 98.7, and 162.1 ppm, respectively.
The IR spectrum of 4 contained absorption bands of the
amide carbonyl, NH2, and NH groups at 1,670 cm-1
,
3,164 cm-1, and 3,364 cm-1, respectively. The mass spec-
trum of 4 contained the molecular ion peak at m/z = 111,
123

A novel synthetic approach towards pyrazole-4-carboxamides
571
Scheme 2
-
O
O
O
N
O
O
O
H+
O
N
O
N
O
N
H
H
H
NH2
-NH(CH )2
3
N
H
NH-NH2
N
H2N NH2
1
2
11
H2N NH2
O
H
NH2
N
O
H2N
O
O
O
OH
H
N
N
H
HO
N
H2N
N
H
H
H2O
Heat
N
N
N
-H2O
-H2O
N
N
N
N
H
N
H
H
H
4
3
12
With the optimized reaction conditions we attempted the
preparation of a new series of pyrazole-4-carboxamides by
reaction of 1 with substituted hydrazines 5. As expected, in
the substituted hydrazines the unsubstituted nitrogen was
more nucleophilic. The corresponding pyrazole-4-carbox-
ylic acid amide derivatives 6 were obtained in 79–90%
yields without any side reaction. In this case the required
reaction time was longer, probably because of the insuffi-
cient basicity of the substituted hydrazines that underwent
the cyclisation. Here also the N-formyl group in 1 was
hydrolysed to the amido group in 6 (Scheme 3).
Once the structure of pyrazole-4-carboxamide 4 was
confirmed, we utilized its NH functionality for the alkylation
to obtain different analogues of pyrazole-4-carboxamides 8.
Thus, compound 4 was subjected to N-alkylation with 1.1
equiv. 7 using K2CO3 in DMF at room temperature to give
N-alkylated pyrazole-4-carboxamides 8 in 78–85% yields
(Scheme 4).
The scope of this reaction was explored by using a
variety of substituted anilides 9 to afford 10 in 85–90%
1
yields (Scheme 5). The H NMR spectrum of 10a con-
tained a broad singlet instead of a triplet at 10.81 ppm for
the –NH proton and a singlet instead of doublet at
5.08 ppm corresponding to the –CH2 group, clearly indi-
cating the N-alkylation at the N1 position and not on the
amide NH2.
O
O
O
In conclusion, we have discovered a simple and scalable
synthesis of pyrazole-4-carboxamides using N-(3-(dimeth-
H2N
Reflux
R
NH2
H
+
O
N
H
N
EtOH/H+
ylamino)-2-formylacryloyl)formamide as
a
convenient
N
H
N
R
precursor. A bidentate nucleophile such as hydrazine
N
1
5a-5h
6a-6h
O
O
H2N
H2N
rt
5, 6
a
R
R-X
+
N
N
DMF/K2CO3
C6H5
N
R
N
H
b
c
-C(=S)NH2
4
7a-7i
8a-8i
4-(CH3NHSO2CH2)C6H4
2,4-di-NO2C6H3
d
e
7, 8
R
7, 8 R
4-(NH2SO2)C6H4
a
b
c
d
e
CH3
CH3CH2
CH3CH2CH2
CH3CH2CH2CH2
(CH3)2CHCH2
f
g
h
i
CH3(CH2)4
Cyclopentyl
CH3CH2OCOCH2
(CH3CH2O)2CHCH2
f
4-( CH3NHSO2(CH2)2)C6H4
g
4-([1,2,4]triazol-1-ylmethyl)phenyl
4-[(1-pyrrolidinylsulfonyl)methyl]phenyl
h
Scheme 3
Scheme 4
123

572
M. N. Jachak et al.
Scheme 5
O
O
H2N
H
H2N
DMF
N
+
Ar
Br
N
K2CO3
N
N
N
O
H
H
N
Ar
4
9a-9d
10a-10d
O
9, 10 Ar
a
b
c
4-Cl-3-(F3C)C6H3
4-MeC6H4
2,4-di-ClC6H3
4-ClC6H4
d
N-(Hydrazonomethyl)-1H-pyrazole-4-carboxamide
(3, C5H7N5O)
hydrate reacted with N-(3-(dimethylamino)-2-formylacry-
loyl)formamide giving two products 3 and 4. At room
temperature exclusive formation of 3 was observed,
whereas compound 4 was obtained as the sole product at
reflux. The NH group at position 1 in 4 could be alkylated to
give different analogues of pyrazole-4-carboxamides. The
method is a facile means of construction of the heteroaro-
matic ring, which could be widely used for synthesis of
biologically active molecules and advanced materials. The
simplicity and very good yields make this method one of the
most attractive approaches towards pyrazole derivatives.
To a solution of 0.5 g 1 (2.93 mmol) and a catalytic amount
of acetic acid (0.05 cm3) in 12.5 cm3 ethanol at room
temperature was added 0.367 g hydrazine hydrate (2,
7.24 mmol). The reaction mixture was stirred at room
temperature for 0.5 h (TLC monitoring, chloroform–meth-
anol, 9.5:0.5), and the solid obtained was isolated by
filtration and washed with ethanol to give 3 as a yellow
solid. This solid was purified by column chromatography
using 95:5 v/v dichloromethane–methanol as eluent. M.p.:
ꢀ
175–178 °C; yield 0.35 g (80%); IR (KBr): m = 3,311,
3,218, 2,994, 1,708, 1,442, 1,403, 1,312, 1,237, 1,128 cm-1
;
Experimental
1H NMR (300 MHz, DMSO-d6): d = 5.62 (bs, 2H, NH2),
7.96 (s, 1H, CH), 8.99 (s, 1H, CH), 9.13 (d, J = 12 Hz, 1H,
CH), 10.98 (bs, 1H, NH), 11.37 (bs, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 98.7, 162.1, 163.3, 163.8,
165.8 ppm; MS (ESI): m/z = 153 [M?].
Melting points were determined on a Buchi model B-545
melting-point apparatus. The 1H (300 MHz) and 13C
(75 MHz) NMR spectra were recorded on a Varian XL-300
spectrometer. Chemical shifts were reported in ppm rela-
tive to tetramethylsilane (TMS), and multiplicities are
given as s (singlet), d (doublet), t (triplet), q (quartet), or m
(multiplet). The solvent for NMR spectra was DMSO-d6
unless otherwise stated. Infrared spectra were taken on a
Thermo Electron Nicolet 380 FTIR instrument in potas-
sium bromide pellets unless otherwise stated. Mass spectra
were recorded on a Shimadzu GC–MS QP 2010A mass
spectrometer with an ionization potential of 70 eV. Ele-
mental analysis was performed on a Hosli CH-Analyzer,
and results were within 0.4% of the theoretical values.
All reactions were monitored by thin-layer chromatogra-
phy, carried out on 0.2 mm silica gel 60 F254 (Merck)
plates using UV light (254 and 366 nm) for detection.
Common reagent-grade chemicals are either commercially
available and were used without further purification or
were prepared by standard literature procedures.
1H-Pyrazole-4-carboxamide (4)
To a solution of 0.5 g 1 (2.93 mmol) and a catalytic
amount of acetic acid (0.05 cm3) in 12.5 cm3 ethanol was
added 0.367 g hydrazine hydrate (2, 7.24 mmol). The
reaction mixture was stirred at reflux for 1 h (TLC
monitoring, chloroform–methanol, 9.5:0.5). It was then
cooled to rt, and the solid obtained was isolated by
filtration and washed with ethanol. The crude solid was
recrystallized from ethanol to afford 4 as a yellow
crystalline solid. M.p.: 225–227 °C; yield 0.24 g (75%);
ꢀ
IR (KBr): m = 3,364, 3,164, 1,670, 1,596, 1,560, 1,493,
1,440, 1,336 cm-1 1H NMR (300 MHz, DMSO-d6):
;
d = 6.95 (bs, 1H, NH2), 7.50 (bs, 1H, NH2), 7.83 (s, 1H,
CH), 8.11 (s, 1H, CH), 13.03 (bs, 1H, NH) ppm;
13C NMR (75 MHz, DMSO-d6): d = 117.8, 129.7, 138.8,
163.8 ppm; MS (ESI): m/z = 111 [M?].
123

A novel synthetic approach towards pyrazole-4-carboxamides
573
General procedure for synthesis of 6a–6h
1-[4-(Aminosulfonyl)phenyl]-1H-pyrazole-4-carboxamide
(6e, C10H10N4O3S)
To a solution of 0.5 g 1 (2.93 mmol) and a catalytic
amount of acetic acid (0.05 cm3) in 12.5 cm3 ethanol was
added substituted hydrazine 5 (7.24 mmol). The reaction
mixture was stirred at reflux for 1.5–2.0 h (TLC monitor-
ing, chloroform–methanol, 9.5:0.5). The reaction mixture
was then cooled to rt, filtered, and the residue was re-
crystallized from ethanol to afford 6 in 79–90% yields.
Under reflux for 2 h. Yellow solid, m.p.: 250–252 °C; yield
0.67 g (86%); IR (KBr): ꢀm = 3,395, 3,196, 1,647, 1,619,
1,599 cm-1; 1H NMR (300 MHz, DMSO-d6): d = 7.25 (bs,
1H, NH2), 7.43 (bs, 2H, NH2), 7.73 (bs, 1H, NH2), 7.94 (d,
J = 9.0 Hz, 2H, ArH), 8.03 (d, J = 9.0 Hz, 2H, ArH), 8.16
(s, 1H, C5H), 8.99 (s, 1H, C2H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 118.6, 121.1, 127.2, 129.7, 137.1, 138.2,
140.9, 165.6 ppm; MS (ESI): m/z = 266 [M?].
1-Phenyl-1H-pyrazole-4-carboxamide (6a, C10H9N3O)
Under reflux for 2 h. Colourless solid, m.p.: 235–237 °C
(Ref. [29] 217–220 °C, Ref. [30] 160.3 °C (MeOH)); yield
1-[4-[2-(Methylaminosulfonyl)ethyl]phenyl]-1H-pyrazole-
4-carboxamide (6f, C13H16N4O3S)
ꢀ
0.42 g (79%); IR (KBr): m = 3,238, 3,127, 3,067, 2,922,
Under reflux for 2 h. Yellow solid, m.p.: 176–179 °C; yield
1,722, 1,685, 1,597, 1,553 cm-1 1H NMR (300 MHz,
;
0.81 g (90%); IR (KBr): m = 3,393, 3,309, 3,193, 1,747,
ꢀ
DMSO-d6): d = 7.37–7.87 (m, 5H, ArH), 8.39 (s, 1H, CH-
pyrazole), 9.21 (bs, 1H, NH2), 9.24 (s, 1H, CH-pyrazole),
11.50 (bs, 1H, NH2) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 111.9, 121.5, 132.4, 137.2, 139.3, 144.5, 146.5,
166.7 ppm; MS (ESI): m/z = 187 [M?].
1,647, 1,617 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 2.54 (t, J = 7.8 Hz, 2H, CH2), 2.60 (d, J = 5.4 Hz,
3H, CH3), 3.31 (t, J = 8.7 Hz, 2H, CH2), 7.00 (q,
J = 5.4 Hz, 1H, NH), 7.17 (bs, 1H, NH2), 7.43 (d,
J = 8.1 Hz, 2H, ArH), 7.67 (bs, 1H, NH2), 7.75 (d,
J = 8.1 Hz, 2H, ArH), 8.07 (s, 1H, C5H), 8.85 (s, 1H, C2H)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 28.6, 34.3,
50.1, 118.6, 120.3, 128.9, 129.5, 135.2, 136.5, 142.3,
165.9 ppm; MS (ESI): m/z = 308 [M?].
1-(Aminothioxomethyl)-1H-pyrazole-4-carboxamide
(6b, C5H6N4OS)
Under reflux for 1.5 h. Yellow solid, m.p.: 190–193 °C;
ꢀ
yield 0.39 g (81%); IR (KBr): m = 3,415, 3,299, 3,017,
1,822, 1,670, 1,594 cm-1; 1H NMR (300 MHz, DMSO-d6):
d = 7.30 (bs, 1H, NHCO), 7.91 (bs, 1H, NHCO), 8.18 (s, 1H,
ArH), 9.18 (s, 1H, ArH), 9.64 (bs, 1H, NH2), 10.14 (bs, 1H,
NH2) ppm; 13C NMR (75 MHz, DMSO-d6): d = 121.4,
135.9, 138.6, 162.1, 176.6 ppm; MS (ESI): m/z = 170 [M?].
1-[4-([1,2,4]Triazol-1-ylmethyl)phenyl]-1H-pyrazole-4-
carboxamide (6g, C13H12N6O)
Under reflux for 2 h. Brown solid, m.p.: 195–197 °C; yield
ꢀ
0.63 g (82%); IR (KBr): m = 3,383, 3,194, 3,102, 1,782, 1,655,
1
1,620 cm-1; H NMR (300 MHz, DMSO-d6): d = 5.45 (s,
2H, CH2), 7.19 (bs, 1H, NH2), 7.42 (d, J = 8.4 Hz, 2H, ArH),
7.68 (bs, 1H, NH2), 7.82 (d, J = 8.4 Hz, 2H, ArH), 7.98 (s, 1H,
CH-pyrazole), 8.09 (s, 1H, CH-pyrazole), 8.67 (s, 1H, CH-
triazole), 8.86 (s, 1H, CH-triazole) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 51.4, 118.8, 120.6, 129.0, 129.1, 134.8, 138.6,
140.5, 142.1, 144.6, 164.9 ppm; MS (ESI): m/z = 268 [M?].
1-[4-[(Methylaminosulfonyl)methyl]phenyl]-1H-pyrazole-
4-carboxamide (6c, C12H14N4O3S)
Under reflux for 2 h. Yellow solid, m.p.: 262–265 °C
ꢀ
(decomp.); yield 0.74 g (87%); IR (KBr): m = 3,434,
3,199, 2,977, 1,915, 1,686, 1,609 cm-1 1H NMR
;
(300 MHz, DMSO-d6): d = 2.58 (d, J = 4.8 Hz, 3H,
CH3), 4.39 (s, 2H, CH2), 6.97 (q, J = 4.8 Hz, 1H, NH2),
7.20 (bs, 1H, NH2), 7.51 (d, J = 8.7 Hz, 2H, ArH), 7.68
(bs, 1H, NH), 7.85 (d, J = 8.7 Hz, 2H, ArH), 8.11 (s, 1H,
C5H), 8.88 (s, 1H, C3H) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 28.9, 55.0, 118.5, 120.6, 129.1, 130.1, 134.8,
138.6, 142.5, 165.9 ppm; MS (ESI): m/z = 294 [M?].
1-[4-[(1-Pyrrolidinylsulfonyl)methyl]phenyl]-1H-pyrazole-
4-carboxamide (6h, C15H18N4O3S)
Under reflux for 2 h. Yellow solid, m.p.: 265–275 °C
ꢀ
(decomp.); yield 0.86 g (88%); IR (KBr): m = 3,386,
1
3,192, 2,970, 1,725, 1,646, 1,613, 1,562 cm-1; H NMR
(300 MHz, DMSO-d6): d = 1.77 (t, J = 6.3 Hz, 4H, 2
CH2), 3.14 (t, J = 6.3 Hz, 4H, 2 CH2), 4.48 (s, 2H, CH2),
7.20 (bs, 1H, NH2), 7.54 (d, J = 8.7 Hz, 2H, ArH), 7.69 (bs,
1H, NH2), 7.84 (d, J = 8.7 Hz, 2H, ArH), 8.10 (s, 1H, CH-
pyrazole), 8.88 (s, 1H, CH-pyrazole) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 118.4, 120.6, 128.6, 129.1,
131.9, 133.7, 137.6, 166.9 ppm; MS (ESI): m/z = 334 [M?].
1-(2,4-Dinitrophenyl)-1H-pyrazole-4-carboxamide
(6d, C10H7N5O5)
Under reflux for 2 h. Yellow solid, m.p.: 258–260 °C; yield
ꢀ
0.69 g (85%); IR (KBr): m = 3,471, 3,371, 3,107, 1,760,
1,667, 1,596 cm-1 1H NMR (300 MHz, DMSO-d6):
;
d = 7.34 (bs, 1H, NH2), 7.81 (bs, 1H, NH2), 8.15 (d,
J = 8.7 Hz, 1H, ArH), 8.18 (s, 1H, C5H), 8.64 (dd,
J = 2.7, 8.7 Hz, 1H, ArH), 8.87 (d, J = 2.7 Hz, 1H, ArH),
8.88 (s, 1H, C2H) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 121.0, 121.7, 126.0, 128.0, 132.6, 135.3, 138.4, 140.7,
143.7, 164.1 ppm; MS (ESI): m/z = 277 [M?].
General procedure for synthesis of 8a–8i
To a stirred suspension of 0.5 g 4 (4.5 mmol) and 0.622 g
K2CO3 (4.5 mmol) in 5 cm3 DMF at room temperature
123

574
M. N. Jachak et al.
1,658, 1,615, 1,564, 1,425, 1,295 cm-1
;
1H NMR
was added 7 (5.3 mmol) dropwise within 10 min. The
reaction mixture was then stirred at room temperature for
4–5 h (TLC monitoring, chloroform–methanol, 9.5:0.5).
The reaction mass was quenched in ice-cold water and
extracted with ethyl acetate (3 9 5 cm3). The combined
organic layer was then dried over sodium sulfate and
concentrated to a residue which was recrystallized from
ethanol to afford compound 8.
(300 MHz, DMSO-d6): d = 1.29 (d, J = 6.9 Hz, 6H,
CH3), 2.55 (m, 1H, CH), 4.33 (d, J = 6.9 Hz, 2H, CH2),
7.38 (bs, 1H, NH2), 7.92 (bs, 1H, NH2), 8.22 (s, 1H, CH),
8.49 (s, 1H, CH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 19.7, 29.1, 58.7, 118.1, 131.8, 138.7, 163.6 ppm; MS
(ESI): m/z = 167 [M?].
1-Pentyl-1H-pyrazole-4-carboxamide (8f, C9H15N3O)
At rt for 4.5 h. Colourless crystals, m.p.: 133–136 °C; yield
1-Methyl-1H-pyrazole-4-carboxamide (8a, C5H7N3O)
At rt for 4 h. White solid, m.p.: 168–170 °C; yield 0.45 g
ꢀ
0.66 g (83%); IR (KBr): m = 3,395, 3,210, 2,956, 1,650,
ꢀ
1,607, 1,558, 1,418, 1,306, 1,135 cm-1 1H NMR
;
(82%); IR (KBr): m = 3,370, 3,157, 1,676, 1,624, 1,562,
1,415, 1,316, 1,283, 1,133 cm-1
;
1H NMR (300 MHz,
(300 MHz, DMSO-d6): d = 0.86 (t, J = 7.0 Hz, 3H,
CH3), 1.29 (m, 2H, CH2), 1.32–1.34 (m, 2H, CH2), 1.70–
1.79 (m, 2H, CH2), 4.09 (t, J = 6.7 Hz, 2H, CH2), 6.95 (bs,
1H, NH2), 7.49 (bs, 1H, NH2), 7.79 (s, 1H, CH), 8.09 (s,
1H, CH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 14.0,
21.8, 28.2, 29.5, 51.5, 118.1, 131.3, 138.6, 163.6 ppm; MS
(ESI): m/z = 181 [M?].
DMSO-d6): d = 3.82 (s, 3H, NCH3), 6.95 (bs, 1H, NH2),
7.49 (bs, 1H, NH2), 7.79 (s, 1H, CH), 8.07 (s, 1H, CH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 38.8, 118.4,
132.1, 138.7, 163.5 ppm; MS (ESI): m/z = 125 [M?].
1-Ethyl-1H-pyrazole-4-carboxamide (8b, C6H9N3O)
At rt for 4 h. Colourless crystals, m.p.: 135–137 °C; yield
ꢀ
1-Cyclopentyl-1H-pyrazole-4-carboxamide
(8g, C9H13N3O)
0.52 g (85%); IR (KBr): m = 3,386, 3,200, 2,984, 1,650,
1,608, 1,560, 1,424, 1,358, 1,300 cm-1 1H NMR
;
At rt for 5 h. Colourless crystals, m.p.: 123–126 °C; yield
(300 MHz, DMSO-d6): d = 1.38 (t, J = 7.3 Hz, 3H,
CH3), 4.15 (q, J = 7.3 Hz, 2H, CH2), 6.95 (bs, 1H,
NH2), 7.49 (bs, 1H, NH2), 7.79 (s, 1H, CH), 8.10 (s, 1H,
CH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 15.3, 46.4,
118.1, 130.6, 138.5, 163.5 ppm; MS (ESI): m/z = 139
[M?].
ꢀ
0.68 g (85%); IR (KBr): m = 3,367, 3,188, 2,956, 1,664,
1,614, 1,557, 1,427, 1,302, 1,144 cm-1 1H NMR
;
(300 MHz, DMSO-d6): d = 1.60–1.68 (m, 2H, CH2),
1.71–1.79 (m, 1H, CH2), 1.82–1.93 (m, 2H, CH2), 2.01–
2.09 (m, 2H, CH2), 4.64–4.69 (m, 1H, CH), 6.94 (bs, 1H,
NH2), 7.48 (bs, 1H, NH2), 7.79 (s, 1H, CH), 8.14 (s, 1H,
CH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 23.7,
32.5, 62.2, 117.8, 129.8, 138.5, 163.4 ppm; MS (ESI):
m/z = 179 [M?].
1-Propyl-1H-pyrazole-4-carboxamide (8c, C7H11N3O)
At rt for 4.5 h. Colourless crystals, m.p.: 120–124 °C; yield
ꢀ
0.54 g (80%); IR (KBr): m = 3,409, 3,225, 2,973, 1,651,
1
1,607, 1,561, 1,425, 1,316, 1,295, 1,136 cm-1; H NMR
4-(Aminocarbonyl)-1H-pyrazole-1-acetic acid ethyl ester
(8h, C8H11N3O3)
(300 MHz, DMSO-d6): d = 0.83 (t, J = 7.3 Hz, 3H, CH3),
1.82 (m, 2H, CH2), 4.06 (t, J = 6.9 Hz, 2H, CH2), 6.96 (bs,
1H, NH2), 7.51 (bs, 1H, NH2), 7.80 (s, 1H, CH), 8.09 (s,
1H, CH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 10.8,
23.0, 53.0, 117.9, 131.3, 138.5, 163.5 ppm; MS (ESI):
m/z = 153 [M?].
At rt for 4.5 h. Colourless crystals, m.p.: 131–133 °C; yield
ꢀ
0.44 g (78%); IR (KBr): m = 3,377, 3,199, 2,986, 1,755,
1
1,654, 1,609, 1,562, 1,428, 1,333, 1,215 cm-1; H NMR
(300 MHz, DMSO-d6): d = 1.23 (t, J = 7.0 Hz, 3H, CH3),
4.18 (q, J = 7.2 Hz, 2H, CH2), 5.08 (s, 2H, CH2), 7.03 (bs,
1H, NH2), 7.59 (bs, 1H, NH2), 7.85 (s, 1H, CH), 8.11 (s,
1H, CH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 14.0,
52.6, 61.1, 118.8, 133.0, 139.1, 163.1, 167.7 ppm; MS
(ESI): m/z = 197 [M?].
1-Butyl-1H-pyrazole-4-carboxamide (8d, C8H13N3O)
At rt for 4 h. Colourless crystals, m.p.: 115–117 °C; yield
ꢀ
0.61 g (82%); IR (KBr): m = 3,410, 3,218, 2,958, 1,652,
1,608, 1,562, 1,456, 1,308, 1,138 cm-1 1H NMR
;
(300 MHz, DMSO-d6): d = 0.89 (t, J = 7.3 Hz, 3H,
CH3), 1.27 (m, 2H, CH2), 1.68–1.77 (m, 2H, CH2), 4.10
(t, J = 6.9 Hz, 2H, CH2), 6.95 (bs, 1H, NH2), 7.49 (bs, 1H,
NH2), 7.79 (s, 1H, CH), 8.09 (s, 1H, CH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 13.4, 19.1, 31.6, 51.0, 118.0,
131.2, 138.5, 163.4 ppm; MS (ESI): m/z = 167 [M?].
1-(2,2-Diethoxyethyl)-1H-pyrazole-4-carboxamide
(8i, C10H17N3O3)
At rt for 4.5 h. Colourless crystals, m.p.: 135–137 °C; yield
ꢀ
0.79 g (78%); IR (KBr): m = 3,397, 3,217, 2,979, 1,652,
1
1,606, 1,558, 1,434, 1,351, 1,290, 1,129 cm-1; H NMR
(300 MHz, DMSO-d6): d = 0.97–1.06 (m, 6H, CH3),
3.38–3.43 (m, 2H, CH2), 3.55–3.65 (m, 2H, CH2), 4.17
(d, J = 5.4 Hz, 2H, CH2), 4.78 (t, J = 5.5 Hz, 1H, CH),
6.98 (bs, 1H, NH2), 7.54 (bs, 1H, NH2), 7.81 (s, 1H, CH),
8.07 (s, 1H, CH) ppm; 13C NMR (75 MHz, DMSO-d6):
1-(2-Methylpropyl)-1H-pyrazole-4-carboxamide
(8e, C8H13N3O)
At rt for 4.5 h. Colourless crystals, m.p.: 155–157 °C; yield
ꢀ
0.60 g (80%); IR (KBr): m = 3,396, 3,186, 3,109, 2,955,
123

A novel synthetic approach towards pyrazole-4-carboxamides
575
d = 15.1, 54.0, 62.1, 100.2, 118.3, 132.3, 138.8, 163.3 ppm;
MS (ESI): m/z = 227 [M?].
4-Aminocarbonyl-N-(4-chlorophenyl)-1H-pyrazole-1-
acetamide (10d, C12H11ClN4O2)
At rt for 5 h. White solid, m.p.: 252–255 °C; yield 1.0 g
(87%); IR (KBr):
ꢀm = 3,391, 3,265, 3,187, 1,675, 1,651,
General procedure for the synthesis of 10a–10d
1,618, 1,598, 1,546, 1,492, 1,425, 1,313 cm-1; H NMR
(300 MHz, DMSO-d6): d = 5.03 (s, 2H, CH2), 7.01 (bs,
2H, NH2), 7.35 (d, J = 6.9 Hz, 2H, ArH), 7.38 (d,
J = 6.7 Hz, 2H, ArH), 7.83 (s, 1H, ArH), 8.15 (s, 1H,
ArH), 10.48 (bs, 1H, NH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 54.6, 118.5, 120.5, 127.0, 128.6, 133.2,
137.2, 138.2, 168.2, 170.9 ppm; MS (ESI): m/z = 278
[M?], 280 [M ? 2].
1
To a stirred suspension of 0.5 g 4 (4.5 mmol) and 0.622 g
K2CO3 (4.5 mmol) in 5 cm3 DMF at room temperature
was added 9 (4.9 mmol). The reaction mass was stirred at
room temperature for 4–5 h (TLC monitoring, chloroform–
methanol, 9.5:0.5). The reaction mass was then quenched
in ice-cold water, the solid obtained was isolated by fil-
tration under suction, washed with water, and recrystallized
from ethanol to afford 10 in good yield.
Acknowledgments The authors gratefully acknowledge financial
support of this project by UGC, New Delhi, India. Also we thank
Principal, Dr V. B. Gaikwad, KTHM College, Nashik-02, for facilities.
4-Aminocarbonyl-N-[4-chloro-3-(trifluoromethyl)phenyl]-
1H-pyrazole-1-acetamide (10a, C13H10ClF3N4O2)
At rt for 4.5 h. White solid, m.p.: 222–224 °C; yield 1.43 g
ꢀ
(92%); IR (KBr): m = 3,481, 3,322, 3,281, 3,195, 1,701,
1
1,654, 1,601, 1,556, 1,483, 1,418, 1,320 cm-1; H NMR
References
(300 MHz, DMSO-d6): d = 5.08 (s, 2H, CH2), 7.03 (bs,
1H, NH2), 7.60 (bs, 1H, NH2), 7.66–7.78 (m, 3H, ArH),
7.84 (s, 1H, ArH), 8.16 (s, 1H, ArH), 10.81 (bs, 1H, NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 54.6, 117.7,
120.7, 123.8, 124.3, 126.5, 126.9, 132.1, 133.4, 134.8,
136.2, 166.3, 168.7 ppm; MS (ESI): m/z = 346 [M?], 348
[M ? 2].
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At rt for 4.5 h. Colourless crystals, m.p.: 250–252 °C; yield
ꢀ
0.98 g (85%); IR (KBr): m = 3,393, 3,273, 3,190, 2,943,
1
1,684, 1,652, 1,617, 1,540, 1,515, 1,428, 1,314 cm-1; H
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(s, 2H, CH2), 7.01 (bs, 1H, NH2), 7.10 (d, J = 8.4 Hz, 2H,
ArH), 7.43 (d, J = 8.1 Hz, 2H, ArH), 7.58 (bs, 1H, NH2),
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ppm; 13C NMR (75 MHz, DMSO-d6): d = 20.5, 54.6,
118.5, 119.0, 129.1, 132.5, 133.2, 135.8, 137.0, 166.3,
169.5 ppm; MS (ESI): m/z = 258 [M?].
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4-Aminocarbonyl-N-(2,4-dichlorophenyl)-1H-pyrazole-1-
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At rt for 4.0 h. White solid, m.p.: 220–223 °C; yield 1.21 g
ꢀ
(87%); IR (KBr): m = 3,356, 3,252, 3,190, 2,939, 1,690,
1
1,666, 1,628, 1,566, 1,528, 1,474, 1,432 cm-1; H NMR
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(300 MHz, DMSO-d6): d = 5.15 (s, 2H, CH2), 7.02 (bs,
1H, NH), 7.39 (d, J = 8.7 Hz, 2H, ArH), 7.59 (bs, 2H,
NH2), 7.67 (s, 1H, ArH), 7.76 (d, J = 8.7 Hz, 2H, ArH),
7.85 (s, 1H, ArH), 8.16 (s, 1H, ArH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 54.3, 118.6, 126.4, 126.7,
127.5, 128.9, 129.4, 133.1, 133.3, 135.2, 166.2,
169.6 ppm; MS (ESI): m/z = 313 [M?], 317 [M ? 4].
123

576
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123