Synthesis of 2-benzyl-2H-pyrazole-3,4-diamine dihydrochloride

Article abstract of DOI:10.1016/S0040-4039(02)02527-3

This report describes a straightforward, high yield synthesis of a previously inaccessible N-protected diaminopyrazole in five steps starting from acrylonitrile, hydrazine and benzaldehyde.

Full text of DOI:10.1016/S0040-4039(02)02527-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 41–43
Synthesis of 2-benzyl-2H-pyrazole-3,4-diamine dihydrochloride
†
Marcus H. Holschbach,* Walter Wutz and Ray A. Olsson
Institut f u¨ r Nuklearchemie, Forschungszentrum J u¨ lich GmbH, D-52425 J u¨ lich, Germany
Received 5 August 2002; accepted 8 November 2002
Abstract—This report describes a straightforward, high yield synthesis of a previously inaccessible N-protected diaminopyrazole
in five steps starting from acrylonitrile, hydrazine and benzaldehyde. © 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
mediate 3, using readily available and cheap reagents.
Based on a general method for the synthesis of 3-
3
The title compound, 2-benzyl-2H-pyrazole-3,4-diamine
dihydrochloride, 6, is a versatile building block for the
synthesis of 1H-pyrazolo[3,4-b]pyrazines, in which the
aminopyrazoles, hydrazine hydrate was condensed
with acrylonitrile and the resulting 3-hydrazinopropi-
onitrile was reacted with benzaldehyde to give hydra-
1
benzyl group represents a suitable protective group for
pyrazole N-1. Up to now the literature describes the
zone 4. Base-catalyzed cyclization of 4 yielded
1
2-benzyl-2H-pyrazol-3-ylamine, 3. Carrying out this
synthetic sequence as a one-pot procedure without the
isolation of hydrazone 4 gave the amine in a yield of
85%. Amine 3 was converted to its hydrochloride salt,
3a, using HCl gas in diethyl ether. Nitrosation of 3
using 3-methylbutyl nitrite and subsequent reduction of
the resulting unstable 2-benzyl-4-nitroso-2H-pyrazol-3-
synthesis of only one homologue, 2-methyl-2H-pyra-
zole-3,4-diamine dihydrochloride 2, prepared by the
electrophilic nitrosation of 2-methyl-2H-pyrazol-3-
ylamine 1 followed by reduction of the nitroso group
(
Scheme 1).
Compound 3, the benzyl homologue of 1, has been
ylamine hydrochloride, 5, with SnCl in aqueous HCl
2
2
obtained by the same group in a three-step synthesis
completed the synthesis of 6 (Scheme 3).
by condensation of benzylhydrazine with ethoxy-
methylene cyanoacetic acid ethyl ester, followed by
saponification and thermal decarboxylation in an over-
all yield of 90% (Scheme 2).
This strategy can be applied to the synthesis of a variety
of differently 2-substituted 2H-pyrazole-3,4-diamine
salts, which are versatile building blocks in heterocyclic
chemistry.
One of our ongoing projects required larger amounts of
6
and, since benzylhydrazine is very expensive, we
devised a simple procedure for the preparation of inter-
2
. Experimental
Melting points were measured on an Electrothermal™
apparatus and are uncorrected. The Zentralabteilung
f u¨ r chemische Analysen at the Forschungszentrum
J u¨ lich performed elemental analyses, which agreed with
calculated composition within ±0.4%. Thin-layer chro-
matography (TLC) employed precoated sheets of silica
(SIL G-25/UV254) or aluminium oxide (ALOX N/
UV254) (Polygram™, Macherey-Nagel, D u¨ ren, Ger-
Scheme 1. Synthesis of diamine 2 via a nitrosation–reduction
1
sequence. Reagents: (i) C H ONO, HCl; (ii) SnCl .
5
9
2
1
13
many). H and C NMR spectra were obtained at
2
2
2
00.13 and 50.32 MHz, respectively, in a Bruker DPX-
00 spectrometer (Avance 200) in ca. 5% solution at
5°C. Chemical shifts are reported as l ppm based on
Keywords: diaminopyrazole; condensation; nitrosation; reduction.
*
Corresponding author. Tel.: +49-02461-616961; fax: +49-02461-
12535; e-mail: m.holschbach@fz-juelich.de
6
†
Present address: Department of Internal Medicine, University of
South Florida, Tampa, FL 33612, USA.
the proton signals of the deuterated solvents
(lH(CDCl3)=7.30, H(DMSO-d6)=2.52, C(CDCl3)=77.48,
l
l
0
040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02527-3

4
2
M. H. Holschbach et al. / Tetrahedron Letters 44 (2003) 41–43
2
Scheme 2. Synthesis of 3 starting from benzylhydrazine. Reagents and conditions: (i) ethoxymethylene cyano acetic acid
ethylester; (ii) (a) NaOH, (b) HCl; (iii) heat.
l
C(DMSO-d6)=40.38). The multiplicity symbols s, d, t and
and formation of product 3, R 0.15. Evaporation of
f
m refer to singlet, doublet, triplet and multiplet, respec-
tively. Solvents and reagents were used as supplied by
the vendors.
the solvent and high vacuum distillation (bp0.04 mbar
115–120°C) gave 3 as a pale yellow oil that solidified on
2
standing. Yield 35 g (98%), mp 71–73°C (lit. 70–72°C,
1
di-n-butyl ether). H NMR (CDCl ): l 3.59 (s , 2H,
3
br
NH ); 5.17 (s, 2H, C H CH ); 5.5 (d, 1H, pyrazole H-4,
2
.1. 3-(N%-Benzylidenehydrazino)propionitrile 4
2
6
5
2
J=1.8 Hz); 7.12–7.16 (m, 2H, phenyl H-2 and H-6);
1
3
7
.28–7.37 (m, 4H, C H -2,3,4 and pyrazole H-5).
C
Hydrazine hydrate (19.4 mL, 0.4 mol) was added over
0 min to a vigorously stirred, cooled (< 20°C, water
6
5
NMR (CDCl ): l 51.82 (C H CH ); 91.99 (pyrazole
1
3
6
5
2
C-4); 127.24, 128.16, 129.08 (C H -2,3,4); 137.17 (C H -
bath) solution of acrylonitrile (27 mL, 0.41 mol) in dry
ethanol (200 mL). After stirring for 24 h at room
temperature the flask was cooled in an ice/water bath
and benzaldehyde (40.15 mL, 0.395 mol) was added at
a rate keeping the reaction temperature below 20°C.
The mixture was stirred in the ice bath for another 10
min and then at room temperature for 5 h, when TLC
6
5
6
5
1
); 139.14 (pyrazole C-5); 145.27 (pyrazole C-3).
2.3. 2-Benzyl-2H-pyrazol-3-ylamine hydrochloride 3a
Bubbling HCl gas through an ice-cooled solution of 3
(35 g, 202 mmol) in dry ethyl ether (300 mL) precipi-
tated 3a as a gum that solidified on standing. The
hydrochloride salt was filtered off, air-dried and tritu-
rated with hot acetone (2×50 mL) to remove colored
impurities. After drying in air the yield of 3a was 42.3
g (100%). Recrystallization from 2-propanol gave an
analytical sample, mp 166°C. TLC on Al O (ethyl
(
ethyl acetate/hexane: 50/50 v/v) showed the absence of
benzaldehyde (R 0.89) and the formation of product
f
(
R 0.70). Evaporation of ethanol and high vacuum
f
distillation gave 4 as a viscous yellow oil that was pure
by TLC. Yield 61.7 g (89%), bp
3
135–138°C (lit.
0
.04 mbar
1
bp0.3 torr 143–146°C). H NMR (CDCl ): l 2.72 (t, 2H,
CH CN); 3.52 (t, 2H, NHCH ); 5.2–5.9 (s , 1H, NH);
7
3
2
3
2
2
br
acetate/hexane: 50/50 v/v) showed a single spot for 3a,
.33–7.40 (m, 3H, 3,4,5-C H ); 7.57–7.61 (m, 2H, 2,6-
R 0.67, while TLC on silica gel caused decomposition
6
5
3
f
1
1
C H ); 7.72 (s, 1H, CHꢀN). C NMR (CDCl ): l 18.83
of both the amine 3 and the hydrochloride salt 3a. H
NMR (DMSO-d ): l 5.77 (s, 2H, C H CH ); 5.78 (d,
6
5
3
(
CH CN); 46.18 (NHCH ); 118.99 (CN); 126.44,
2
2
6
6
5
2
1
29.09, 129.46 (C H -2,3,4); 135.43 (C H -1); 141.09
1H, pyrazole H-4, J=3 Hz) 7.28–7.38 (m, 5H, C H );
6
5
6
5
6 5
(
CHꢀN).
8.02 (d, 1H, pyrazole H-5, J=3 Hz); 7.39–8.62 (s , 3H,
br
+ 13
NH ). C NMR (DMSO-d ): l 49.74 (C H CH );
3
6
6
5
2
2.2. 2-Benzyl-2H-pyrazol-3-ylamine 3
92.06 (pyrazole C-4); 128.51, 129.04, 129.57 (C H -
6 5
2
,3,4); 135.26 (C H -1); 136.26 (pyrazole C-5); 151.43
6 5
Solid NaOH (200 mg, 5 mmol) was added to a solution
of 4 (43.5 g, 0.2 mol) in 1-propanol and the orange
mixture was stirred at 120°C for 5 h, during which the
(pyrazole C-3).
2
.4. 2-Benzyl-4-nitroso-2H-pyrazol-3-ylamine hydro-
solution became deep red. TLC (Al O , ethyl acetate/
2
3
chloride 5
hexane: 25/75 v/v) indicated the absence of 4, R 0.43,
f
Under argon a suspension of finely ground 3·HCl (20.9
g, 100 mmol in dry ethanol (80 mL) and 5N ethanolic
HCl (60 mL, 300 mmol) was stirred in a salt–ice bath
until the flask temperature was <0°C. The addition of
isoamyl nitrite (11.7 g, 13.4 mL, 100 mmol) over 30 min
gave a clear yellow solution from which product precip-
itated. After an additional hour at 0°C the dark yellow
product was filtered off and washed with 25 mL ace-
tone. Drying in air gave 5, 17.2 g, 72%, as a yellow
solid. The product decomposed on heating so was
immediately used in the next step. The presence of four
1
exchangeable protons in the H NMR spectrum of 5
Scheme 3. Synthesis of 3 starting from acrylonitrile and
transformation into 6. Reagents and conditions: (i) N H ·H O;
was evidence for the existence of two tautomers, 5 and
1
5% (Scheme 4). H NMR (DMSO-d ): l 5.33+5.41 (2 s,
2
4
2
6
(
ii) C H CHO; (iii) NaOH, heat; (iv) C H ONO, HCl; (v)
C H CH ); 7.19–7.55 (m, C H ); 8.18+8.55 (s, pyrazole
6
5
2
6
5
6
5
5
9
+
SnCl2.
H-5); 9.64 (s , N-OH); 10.63 (s , NH ).
br br 3

M. H. Holschbach et al. / Tetrahedron Letters 44 (2003) 41–43
43
min, 2600×g) gave a clear supernatant. Evaporation of
the supernatant and co-evaporation with acetonitrile
(
50 mL) gave crude 6 as a colorless glassy residue (11.5
g, 90%). Shaking a solution of 6 (2.6 g, 10 mmol) in 5
mL water with acetonitrile (100 mL) deposited product
as white crystals. (NOTE: Air and moisture sensitivity
necessitated storage under argon.) The diamine salt
Scheme 4. Tautomers of 5.
1
decomposed upon heating at ±220°C. H NMR
(DMSO-d ): l 5.26 (s, 2H, C H CH ); 5.40–7.20 (s ,
1
3
6
6
5
2
br
The C NMR spectrum shows 16 resonances instead of
the eight expected for compound 5, additional support
for two tautomers, 5 and 5%.
+
6
H, 2 NH ); 7.19–7.32 (m, 5H, C H ); 7.40 (s, 1H,
3 6 5
13
pyrazole H-5).
C
NMR (DMSO-d6):
l
51.76
(
C H CH ); 117.87 (pyrazole C-4); 127.31, 128.42,
6
5
2
1
29.01 (phenyl C H -2,3,4); 137.33 (C H -1); 139.87
6 5 6 5
2
6
.5. 2-Benzyl-2H-pyrazole-3,4-diamine dihydrochloride
(
pyrazole C-5); 142.01 (pyrazole C-3). Elemental analy-
sis (free base, FW 188.23) calcd: C, 63.81; H, 6.43; N,
2
9.77. Found: C, 63.97; H, 6.42; N, 39.92.
A suspension of 5 (11.9 g, 50 mmol) in ethanol (100
mL) acidified with 32% HCl (25 mL, 250 mmol) was
stirred at 60–70°C The addition of a solution of
SnCl ·2H O (24.8 g, 110 mmol) in ethanol (25 mL) over
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then the clear solution was cooled to room temperature
and diluted with water (100 mL). After evaporation of
ethanol and dilution with additional water (250 mL),
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the solution was saturated with H S. Centrifugation (10
2