New synthesis of 3-aryl-5-amino-1H-pyrazoles

Article abstract of DOI:10.1007/s11178-005-0053-x

A new efficient procedure has been proposed for the synthesis of 3-aryl-5-amino-1H-pyrazoles by reaction of α-chloro-β- arylacrylonitriles with hydrazine hydrate.

Full text of DOI:10.1007/s11178-005-0053-x

Russian Journal of Organic Chemistry, Vol. 40, No. 10, 2004, pp. 1518–1520. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 10, 2004,
pp. 1566–1568.
Original Russian Text Copyright © 2004 by Nenaidenko, Golubinskii, Lenkova, Shastin, Balenkova.
Dedicated to Full Member of the Russian Academy of Sciences
O.N. Chupakhin on His 70th Anniversary
New Synthesis of 3-Aryl-5-amino-1H-pyrazoles
V. G. Nenaidenko1, I. V. Golubinskii1, O. N. Lenkova1,
A. V. Shastin2, and E. S. Balenkova1
1 Faculty of Chemistry, Lomonosov Moscow State University, Vorob'evy gory 1, Moscow, 119992 Russia
e-mail: nen@acylium.chem.msu.ru
2 Institute of Chemical Physics Problems, Russian Academy of Sciences, Chernogolovka, Moscow oblast, Russia
Received February 28, 2004
Abstract—A new efficient procedure has been proposed for the synthesis of 3-aryl-5-amino-1H-pyrazoles by
reaction of α-chloro-β-arylacrylonitriles with hydrazine hydrate.
Reactions of olefins in which the double bond is
activated by two electron-acceptor groups on the same
carbon atom are used in the synthesis of various
heterocyclic compounds [1]. However, preparation of
3-aryl-5-aminopyrazoles from α-chloro-β-arylacrylo-
nitriles has not been reported, although reactions of
α-haloacrylonitriles with hydrazines are known to
afford the corresponding aminopyrazoles in good
yields [1]. Some 3-aryl-5-aminopyrazoles and their
derivatives exhibit high biological activity and are
used as intermediate products in the synthesis of fused
pyrazolo[1,5-a]heterocycles [2].
thiosemicarbazones [6] and semicarbazones [7, 8],
reaction of β-amino-β-arylacrylonitrile [9] or α,β-di-
chloropropionitrile [10] with hydrazines, and decar-
boxylation of 5-amino-3-arylpyrazole-1-carboxylic
acids [3].
We previously reported on the catalytic olefination
of hydrazones derived from aromatic aldehydes and
ketones with trichloroacetonitrile, which opened
a simple and accessible synthetic route to α-chloro-β-
arylacrylonitriles II [11]. This reaction was used to
obtain a series of compounds II. In the present work
we also synthesized naphthalene-containing and
heterocyclic analogs IIg–IIi. The structure of the
products was determined by comparing the 13C–1H
coupling constant between the carbon atom of the
cyano group and proton at the double bond (3JCH) with
our previous data [11]. Reactions of nitriles IIg–IIi
with hydrazine gave the corresponding aminopyrazoles
III in good yields. Despite the presence of three elec-
trophilic centers in molecules II, the reactions occurred
with high selectivity.
The most widely used procedure for the synthesis
of aminopyrazoles is based on reaction of β-oxo
nitriles with hydrazine [3, 4]. β-Oxo nitriles are pre-
pared in turn by reaction of halo ketones with sodium
or potassium cyanide. An obvious drawback of this
method is the necessity of using toxic cyanides.
Hartmann and Liebscher [5] proposed a procedure for
the synthesis of aminopyrazoles via reaction of hydra-
zine with β-aryl-β-chloroacrylonitriles. Other known
methods for the preparation of aminopyrazoles are
based on intramolecular cyclization of acetophenone
Thus, the described two-step procedure (catalytic
olefination and reaction of the resulting nitriles with
R
CCl3CN, Et3N
CuCl
N2H4 ·H2O
EtOH
R
H
Cl
N2H4 ·H2O
N
R
CHO
R
CH
N
NH2
NH2
N
CN
H
Ia–Ii
IIa–IIi
IIIa–IIIi
R = 4-ClC6H4 (a), 4-MeOC6H4 (b), 4-Me2NC6H4 (c), 4-NO2C6H4 (d), 3-NO2C6H4 (e), 2,4-Me2C6H3 (f), 2-naphthyl (g),
1-naphthyl (h), 2-thienyl (i).
1070-4280/04/4010-1518 © 2004 MAIK “Nauka/Interperiodica”

NEW SYNTHESIS OF 3-ARYL-5-AMINO-1H-PYRAZOLES
1519
hydrazine) ensures preparation of various 3-aryl-5-
aminopyrazoles from the corresponding aromatic and
heteroaromatic aldehydes.
tals, Rf 0.6 (hexane–methylene chloride, 1:2). IR spec-
trum: ν(CN) 2220 cm–1. 1H NMR spectrum (CDCl3), δ,
ppm: E isomer: 8.07 s (1H, CH), 7.98–7.81 m (4H,
Harom), 7.62–7.51 m (3H, Harom); Z isomer: 8.02 s (1H,
CH) (the other signals were overlapped by those of the
EXPERIMENTAL
13
major isomer). C NMR spectrum (CDCl3), δC, ppm:
The IR spectra were recorded on a UR-20 spec-
trometer from samples prepared as thin films (liquids)
E isomer: 143.3, 140.5, 133.2, 131.4, 127.7, 127.3,
126.8, 126.5, 125.1, 122.9, 122.7, 114.6 (CN), 102.6
(CCl). Found, %: C 71.71; H 3.42. C13H8ClN. Calcu-
lated, %: C 73.08; H 3.77.
1
or dispersed in mineral oil (solid substances). The H
and 13C NMR spectra were measured from solutions
in CDCl3 and DMSO-d6 on a Varian VXR-400 spec-
trometer (400 MHz for 1H and 100 MHz for 13C) using
TMS as internal reference. Thin-layer chromatography
was performed on Kieselgel 60 F254 plates (Merck),
and silica gel (63–200 mesh, Merck) was used for
column chromatography.
2-Chloro-3-(2-thienyl)acrylonitrile (IIi). Yield
25%. A 1.2:1 mixture of E and Z isomers, yellow
crystals, Rf 0.58 (hexane–methylene chloride, 1:2).
1
IR spectrum: ν(CN) 2230 cm–1. H NMR spectrum
(CDCl3), δ, ppm: E isomer: 7.53 d (1H, Harom, J =
5.3 Hz), 7.49 d (1H, Harom, J = 3.5 Hz), 7.42 s (1H,
CH), 7.11 t (1H, Harom, J = 5.3, 3.5 Hz); Z isomer:
7.65 d (1H, Harom, J = 5.3 Hz), 7.55 s (1H, CH), 7.47 d
(1H, Harom, J = 3.5 Hz), 7.15 d.d (1H, Harom, J = 5.3,
β-Aryl-α-chloroacrylonitriles IIg–IIi (general
procedure). A solution of 5 mmol of aldehyde Ia–Ii in
10 ml of DMSO was added dropwise under stirring to
a solution of 0.12 ml (5 mmol) of hydrazine hydrate
in 5 ml of DMSO. The mixture was stirred for 2–4 h
until the initial aldehyde disappeared (TLC), 3.5 ml
(25 mmol) of triethylamine and 50 mg (10 mol %) of
freshly purified copper(I) chloride were added to the
resulting hydrazone solution, and a solution of 2.5 ml
(25 mmol) of trichloroacetonitrile in 5 ml of DMSO
was then added dropwise over a period of 2 min, main-
taining the mixture at room temperature by cooling
with a water bath. The mixture was stirred for 2 h,
treated with 200 ml of 0.1 M hydrochloric acid, and
extracted with methylene chloride. The combined
extracts were dried over sodium sulfate, the solvent
was distilled off, and the product (E/Z isomer mixture)
was isolated by column chromatography using
hexane–methylene chloride (1:1) as eluent.
13
3.5 Hz). C NMR spectrum (CDCl3), δC, ppm: E iso-
mer: 138.0, 134.6, 132.7, 130.5, 127.9, 115.0 (CN),
97.0 (CCl). Found, %: C 50.32; H 2.38. C7H4ClNS.
Calculated, %: C 49.56; H 2.38.
3-Aryl-5-aminopyrazoles IIIa–IIIi (general
procedure). Hydrazine hydrate, 0.15 ml (0.03 mol),
was added to a solution of 0.01 mol of nitrile IIa–IIi in
20 ml of ethanol. The mixture was heated for 4 h under
reflux (TLC) and poured into 50 ml of water, and
the precipitate was filtered off and recrystallized from
aqueous ethanol. Compounds IIIe, IIIf, and IIIh, were
isolated as the corresponding hydrochlorides, and IIIi,
as hydrogen oxalate.
5-Amino-3-(4-chlorophenyl)-1H-pyrazole (IIIa).
Yield 78%. Colorless crystals, mp 172–175°C;
published data [4]: mp 173–175°C; Rf 0.55 (aceto-
1
nitrile–aqueous ammonia, 20:1). H NMR spectrum
2-Chloro-3-(2-naphthyl)acrylonitrile (IIg). Yield
50%. A 2:1 mixture of E and Z isomers, yellow crys-
tals, Rf 0.6 (hexane–methylene chloride, 1:2). IR spec-
(DMSO-d6), δ, ppm: 7.65 d (2H, Harom, J = 8.6 Hz),
7.40 d (2Harom, J = 8.6 Hz), 5.74 s (1H, CH).
1
trum: ν(CN) 2230 cm–1. H NMR spectrum (CDCl3),
5-Amino-3-(4-methoxyphenyl)-1H-pyrazole
(IIIb). Yield 79%. Colorless crystals, mp 140–142°C;
published data [4]: mp 141–143°C; Rf 0.50 (aceto-
δ, ppm: E isomer: 8.07 s (1H, Harom), 7.90–7.80 m
(4H, Harom), 7.60–7.51 m (2H, Harom), 7.49 s (1H, CH);
Z isomer: 8.20 s (1H, Harom), 7.47 s (1H, CH) (the
other signals were overlapped by those of the major
isomer). 13C NMR spectrum (CDCl3), δC, ppm:
E isomer: 145.2, 134.2, 132.8, 130.1, 128.9, 128.7,
128.4, 128.0, 127.7, 127.0, 123.9, 115.2 (CN), 99.9
(CCl). Found, %: C 72.08; H 3.45. C13H8ClN. Calcu-
lated, %: C 73.08; H 3.77.
1
nitrile–aqueous ammonia, 20:1). H NMR spectrum
(DMSO-d6), δ, ppm: 7.56 d (2H, Harom, J = 8.7 Hz),
6.92 d (2H, Harom, J = 8.7 Hz), 5.67 s (1H, CH), 3.75 s
(3H, OMe).
5-Amino-3-(4-dimethylaminophenyl)-1H-pyra-
zole (IIIc). Yield 67%. Yellow crystals, mp 203–
205°C; Rf 0.45 (acetonitrile–aqueous ammonia, 20:1).
1H NMR spectrum (DMSO-d6), δ, ppm: 7.44 d (2H,
Harom, J = 8.9 Hz), 6.70 d (2H, Harom, J = 8.9 Hz), 5.61 s
2-Chloro-3-(1-naphthyl)acrylonitrile (IIh). Yield
38%. A 2:1 mixture of E and Z isomers, yellow crys-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004

NENAIDENKO et al.
1520
(1H, CH), 2.89 s (6H, NMe2). 13C NMR spectrum
(DMSO-d6), δC, ppm: 154.1, 149.7, 144.8, 125.7,
119.4, 112.2, 86.9, 40.0. Found, %: C 64.46; H 6.60.
C11H14N4. Calculated, %: C 65.32; H 6.98.
143.8, 133.3, 130.3, 129.9, 128.6, 127.8, 127.3, 126.5,
126.1, 125.4, 124.4, 96.9. Found, %: C 61.26; H 4.83.
C13H12ClN3·1/2H2O. Calculated, %: C 61.30; H 5.14.
5-Amino-3-(2-thienyl)-1H-pyrazolium hydrogen
oxalate (IIIi). Yield 53%. Pink crystals, mp 193–
195°C; Rf 0.55 (acetonitrile–aqueous ammonia, 20:1).
1H NMR spectrum (DMSO-d6), δ, ppm: 7.70–7.66 m
(2Harom.), 7.17 d.d (1H, Harom, J = 5.1, 3.76 Hz) 6.25 s
(1H, CH). 13C NMR spectrum (DMSO-d6), δC, ppm:
162.4 (COO–), 150.7, 142.6, 135.5, 127.7, 124.9,
123.7, 87.0. Found, %: C 46.15; H 3.80. C8H8N3O2S.
Calculated, %: C 45.70; H 3.84.
5-Amino-3-(4-nitrophenyl)-1H-pyrazole (IIId).
Yield 72%. Brown crystals, mp 248–252°C [4]; Rf 0.50
1
(acetonitrile–aqueous ammonia, 20:1). H NMR spec-
trum (DMSO-d6), δ, ppm: 8.20 d (2H, Harom, J = 7.9 Hz),
7.91 d (2H, Harom, J = 7.9 Hz), 5.87 s (1H, CH).
5-Amino-3-(3-nitrophenyl)-1H-pyrazole hydro-
chloride (IIIe). Yield 63%. Yellow crystals, mp 192–
195°C. Rf 0.44 (acetonitrile–aqueous ammonia, 20:1).
1H NMR spectrum (DMSO-d6), δ, ppm: 8.68 s (1H,
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 03-03-32052a).
Harom), 8.31 d (1H, Harom, J = 7.9 Hz), 8.23 d (1H,
Harom, J = 8.2 Hz), 7.76 t (1H, Harom, J = 8.2, 7.9 Hz),
13
6.77 s (1H, CH). C NMR spectrum (DMSO-d6), δC,
REFERENCES
ppm: 148.3, 144.9, 143.1, 132.0, 130.7, 130.1, 123.5,
120.0, 94.5. Found, %: C 45.66; H 3.80. C9H8N4O2.
Calculated, %: C 44.92; H 3.77.
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5-Amino-3-(2,4-dimethylphenyl)-1H-pyrazole
hydrochloride (IIIf). Yield 86%. Colorless crystals,
mp 194–195°C; Rf 0.60 (acetonitrile–aqueous am-
monia, 20:1). H NMR spectrum (DMSO-d6), δ, ppm:
1
7.32 d (1H, Harom, J = 7.8 Hz), 7.13 s (1H, Harom),
7.08 d (1H, Harom, J = 7.8 Hz), 6.12 s (1H, CH), 2.30 s
(3H, Me), 2.28 s (3H, Me). 13C NMR spectrum
(DMSO-d6), δ, ppm: 145.4, 145.0, 139.0, 135.6, 131.6,
129.0, 126.8, 125.0, 95.3, 20.7, 20.2. Found, %:
C 54.93; H 6.06. C11H14ClN3·H2O. Calculated, %:
C 54.66; H 6.67.
3. Cusmano, S. and Sprio, V., Gazz. Chim. Ital., 1982,
5-Amino-3-(2-naphthyl)-1H-pyrazole (IIIg).
Yield 73%. Colorless crystals, mp 129–130°C; Rf 0.50
vol. 82, p. 373.
4. Fomum, Z.T., Landor, S.R., Landor, F.D., and
Mpango, G.W., J. Chem. Soc., Perkin Trans. 1, 1981,
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1
(acetonitrile–aqueous ammonia, 20:1). H NMR spec-
trum (DMSO-d6), δ, ppm: 8.15 s (1H, Harom), 7.90–
7.84 m (4H, Harom), 7.50–7.43 m (2H, Harom), 5.89 s
(1H, CH). 13C NMR spectrum (DMSO-d6), δC, ppm:
152.8, 145.9, 133.2, 132.3, 129.8, 128.1, 127.9, 127.6,
126.4, 125.8, 123.6, 122.9, 87.5 (CH, pyrazole).
Found, %: C 74.04; H 5.49. C13H11N3. Calculated, %:
C 74.62; H 5.30.
5. Hartmann, H. and Liebscher, J., Synthesis, 1984, p. 276.
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5-Amino-3-(1-naphthyl)-1H-pyrazole hydro-
chloride (IIIh). Yield 72%. Colorless crystals, mp 177–
179°C; Rf 0.50 (acetonitrile–aqueous ammonia, 20:1).
1H NMR spectrum (DMSO-d6), δ, ppm: 8.08–7.98 m
(3H, Harom), 7.67–7.60 m (4H, Harom), 6.38 s (1H, CH).
13C NMR spectrum (DMSO-d6), δC, ppm: 144.9,
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Lenkova, O.N., and Balenkova, E.S., Izv. Ross. Akad.
Nauk, Ser. Khim., 2004, p. 218.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 10 2004