Three-component synthesis of 5-aryl-3-amino-1H-pyrazole-4-carbonitriles and 3-amino-1,2-diazaspiro[4.5]dec-3-ene-4-carbonitriles

Article abstract of DOI:10.1134/S1070363217100322

A multicomponent method of the synthesis of 5-aryl-3-amino-1H-pyrazole-4-carbonitrile and 3-amino-1,2-diazaspiro[4.5]dec-3-ene-4-carbonitriles with thermal and microwave activation was developed.

Full text of DOI:10.1134/S1070363217100322

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 10, pp. 2477–2480. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © M.A. Ivonin, O.Yu. Bychok, N.V. Safarova, V.V. Sorokin, 2017, published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 10,
pp. 1728–1731.
LETTERS
TO THE EDITOR
Three-Component Synthesis
of 5-Aryl-3-amino-1H-pyrazole-4-carbonitriles
and 3-Amino-1,2-diazaspiro[4.5]dec-3-ene-4-carbonitriles
M. A. Ivonin*, O. Yu. Bychok, N. V. Safarova, and V. V. Sorokin
Chernyshevskii Saratov National Research State University, ul. Astrakhanskaya 83, Saratov, 410012 Russia
*
e-mail: ivonin.m@list.ru
Received June 26, 2017
Abstract—A multicomponent method of the synthesis of 5-aryl-3-amino-1H-pyrazole-4-carbonitrile and
-amino-1,2-diazaspiro[4.5]dec-3-ene-4-carbonitriles with thermal and microwave activation was developed.
3
Keywords: 5-aryl-3-amino-1H-pyrazole-4-carbonitrile, 3-amino-1,2-diazaspiro[4.5]dec-3-ene-4-carbonitriles,
microwave activation, multicomponent reaction
DOI: 10.1134/S1070363217100322
Pyrazole derivatives are scaffolds for the creation
of important pharmaceutical preparations and other
biologically active compounds with anti-inflammatory,
antimicrobial, antimycobacterial activity [1, 2].
ponent condensation of hydrazine hydrate, malonic
acid dinitrile, and aromatic aldehydes (benzaldehyde,
salicylaldehyde) in the presence of catalytic amounts
of triethylamine under microwave or thermal activa-
tion (Scheme 1, Table 1).
Pyrazoles containing amino and cyano groups are
of interest both for applied research and for the
synthesis of other fused polyheterocyclic systems [3].
The use of microwave irradiation does not change
the direction of the three-component condensation, but
it allows a significant decrease in the reaction time and
an increase in the yield of the target compounds. In
addition, the proposed method is environmentally
friendly due to the use of water as a solvent.
Synthesis of 5-aryl-3-amino-1H-pyrazole-4-carbo-
nitrile has been previously carried out in two stages by
reacting 3-oxo-3-phenylpropanenitrile with trichloro-
acetonitrile and subsequent condensation with hyd-
razine [4, 5]. Here we report on the synthesis of pyra-
zole and pyrazoline type aminocyanides through one-
step three-component condensation.
Physicochemical characteristics of compound 1
completely coincided with those of the product ob-
tained by the two-stage synthesis [4, 5].
5
-Aryl-3-amino-1H-pyrazole-4-carbonitriles 1–3
The composition and the structure of compounds 2
and 3 were confirmed by the elemental analysis, H
l
described previously [4] were obtained by three-com-
Scheme 1.
MW, H O
2
N
NH2
HN
(
Et) N
3
CN
CHO
R
H C
+
+
NH2__NH2
CN
2
CN
H OH
R
Δ, C2
5
(
Et) N
3
1_
3
R = H (1), OH (2), NO
2
(3).
2
477

2
478
IVONIN et al.
Table 1. Synthesis of 5-aryl-3-amino-1H-pyrazole-4-carbo-
nitriles 1–3
Table 2. Synthesis of 3-amino-1,2-diazaspiro[4.5]dec-3-ene-
4-carbonitriles 4–6
Comp.
no.
Synthesis
method
Time,
min
Yield,
%
Comp.
no.
Synthesis
method
Time,
min
Yield,
%
R
R
1
2
3
H
Δ
MW
Δ
180
2
31
88
55
90
25
82
4
5
6
H
Δ
MW
Δ
360
4
30
88
41
85
45
92
OH
NO
180
2
Ph-NO
Ph
2
-4
420
6
MW
Δ
MW
Δ
2
240
4
420
5
MW
MW
1
3
1
and C NMR spectra. The H NMR spectra contained
zolines. Thus, when changing the carbonyl component
for cyclohexanone, the reaction proceeded smoothly to
form previously unknown 3-amino-1,2-diazaspiro[4.5]-
dec-3-ene-4-carbonitriles 4–6 (Scheme 3). The use of
microwave irradiation in the synthesis of spiro
compounds also led to a 2–3 times increase in the
products yields and a 70–90 times decrease in the
reaction time (Table 2). The composition and the struc-
ture of compounds 4–6 were confirmed by elemental
the singlets of NH (11.08–11.85 ppm) and NH (6.54–
.98 ppm) groups, the doublets of aromatic protons
6.93–7.88 ppm). In the spectrum of compound 2 there
was a signal of a hydroxy group (4.98 ppm). The C
NMR spectra contained the signals of 9 sp - and 1sp-
hybridized carbon atomsin agreement with the assumed
structure.
2
8
(
1
3
2
The probable formation of pyrazolecarbonitriles 1–3
involves the initial condensation of malonic acid
dinitrile with an aromatic aldehyde and the subsequent
heterocyclization of the intermediate A with the
binucleophilic reagent (Scheme 2).
1
13
1
analysis, H and C NMR spectra. In the H NMR
spectra there were the singlets of NH (8.12–8.81 ppm)
and NH groups (6.24–6.60 ppm), the multiplets of the
2
alicycle (1.08–1.70 ppm). The spectra of compounds 5
and 6 contained also the doublet signals of the
1
3
We have shown that this three-component condensa-
tion can also be used for the synthesis of spiropyra-
aromatic protons (6.95–7.60 ppm). In the C NMR
spectra the characteristic signals of spiro-carbon atoms
Scheme 2.
CHO
NH2
CN
CN
R
NC
CN
H
NH
2
N
C
H N
2
H C
+
HN
2
_
_
R Ph
CN
_
_
R Ph
_
A
1 3
Scheme 3.
R
MW, H O
2
NH2
(
Et) N
3
N
CN
CN
2
3
4
HN
1
_
_
__
H C
+
+
R NH NH
2
2
CN
Δ, C H OH
2
5
O
(
Et) N
3
4_
6
2
R = H (4), Ph-NO -4 (5), Ph (6).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 10 2017

THREE-COMPONENT SYNTHESIS
2479
Scheme 4.
R
NC
CN
NH2
C
N
NH2
NC
2
3
CN
NH2
NH
HN
1
4
R
NH
C
CN
H C
2
+
R
CN
CN
O
_
7
4 6
are observed at 53.25–55.76 ppm. The presence of the
aryl substituent in the position 2 was proved by HMBC
correlation between the signals of the protons of the
secondary and primary amino groups and the carbon
5-(2-Hydroxyphenyl)-3-amino-1H-pyrazole-4-
carbonitrile (2). Yield 0.47 g (55%, method a), 0.77 g
1
(90%, method b), mp 218–221°C. H NMR spectrum,
δ, ppm: 11.08 s (1H, NH), 8.98 s (2H, NH ), 7.30 d
2
3
13
atom C (6.99–7.58 ppm/144.19 ppm).
(4H, C H , J = 8.0 Hz), 4.97 s (1H, OH). C NMR
6
4
7
spectrum, δ , ppm: 162.8 (C≡N), 158.56 (C ), 155.9
C
By the example of compound 6 we performed the
two-stage authentic synthesis by reacting 2-cyclo-
hexylidene malononitrile 7 and phenylhydrazine (re-
fluxing equimolar amounts of the reagents in ethanol).
As a result, the expected 3-amino-2-phenyl-2-
diazaspiro[4.5]dec-3-ene-4-carbonitrile 6 was isolated
in 40% yield (Scheme 4) whose characteristics coin-
cided with the product, obtained by the three-com-
ponent reaction.
3
5
(
1
C ), 143.9 (C ), 128.9, 128.7, 127.6, 119.20, 116.21,
16.05 (C H ), 85.30 (C ). Found, %: C 60.03; H 4.23;
4
6 5
N 28.09. C H N O. Calculated, %: C 59.99; H 4.03; N
1
0
8
4
2
7.99.
5-(2-Nitrophenyl)-3-amino-1H-pyrazole-4-carbo-
nitrile (3). Yield 0.20 g (25%, method a), 0.66 g (82%,
1
method b), mp 201–203°C. H NMR spectrum, δ,
ppm: 11.85 s (1H, NH), 7.65 d (4H, C
H , J = 8.0 Hz),
6
4
6
.54 s (2H, NH ). Found, %: C 52.05; H 3.13; N 30.93.
2
In conclusion, the three-component condensation of
malonic acid dinitrile, hydrazines, and oxo compounds
under microwave irradiation can be used for con-
venient one-pot synthesis of aminocyanides of pyra-
zole and spiropyrazoline series.
C H N O . Calculated, %: C 52.40; H 3.08; N 30.56.
1
0
7
5
2
3-Amino-1,2-diazaspiro[4.5]dec-3-ene-4-carbo-
nitriles (4–6). a. A mixture of 3 mmol of cyclo-
hexanone, 3 mmol of dinitrile, and 0.08 mol % of
triethylamine in ethanol was refluxed for 20 min, then
5-Aryl-3-amino-1H-pyrazole-4-carbonitriles (1–3).
3
mmol of hydrazine was added. The reaction mixture
a. A mixture of 3 mmol of aromatic aldehyde, 3 mmol
of malonic acid dinitrile, and 0.08 mol % of
triethylamine in ethanol was refluxed for 20 min, then
was heated for 360–420 min. The crystals were filtered
off, washed with hexane, and dried in air.
3
mmol of hydrazine hydrate was added. The reaction
b. A mixture of 3 mmol of cyclohexanone, 3 mmol
of dinitrile, 3 mmol of hydrazine, and 0.08 mol % of
triethylamine in water was subjected to microwave
irradiation for 4–6 min. The crystals were filtered off,
washed with water, and dried in a vacuum.
mixture was heated for 180–240 min. After the
reaction completed the crystals were filtered off,
washed with hexane, and dried in air.
b. A mixture of 3 mmol of an aromatic aldehyde,
3
mmol of malonic acid dinitrile, 3 mmol of hydrazine
c. For the preparation of compound 6 a mixture of
1 mmol of 2-cyclohexylidene malononitrile and 1 mmol
of phenylhydrazine in ethyl alcohol was refluxed for
360 min. The crystals were filtered off, washed with
hexane, and dried in air.
hydrate, and 0.08 mol % of triethylamine in water was
subjected to microwave irradiation for 2–4 min. The
crystals were filtered off, washed with water, and dried
in a vacuum.
5-Phenyl-3-amino-1H-pyrazole-4-carbonitrile (1).
3-Amino-1,2-diazaspiro[4.5]dec-3-ene-4-carbo-
Yield 0.19 g (31%, method a), 0.55 g (88%, method
b), mp 200–202°C (mp 200–202°C [4, 5]). Found, %:
C 63.11; H 4.44; N 30.39. C H N . Calculated, %: C
nitrile (4). Yield 0.19 g (30%, method a), 0.56 g
(88%, method b), mp 245–248°C. H NMR spectrum,
δ, ppm: 8.81 s (1H, NH), 8.12 s (1H, NH), 6.24 s (2H,
1
1
0
8
4
6
3.22; H 4.35; N 30.43.
NH ), 1.37–1.08 m [10H, (CH ) ]. Found, %: C 60.25;
2 2 5
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 10 2017

2
480
IVONIN et al.
Yield 0.40 g (60%), mp 172–174°C (mp 173.5–174.5°C
H 7.45; N 31.04. C H N . Calculated, %: C 60.65; H
9
14
4
7
.92; N 31.43.
-Amino-2-(4-nitrophenyl)-2-diazaspiro[4.5]dec-
-ene-4-carbonitrile (5). Yield 0.39 g (41%, method
[6]). Found, %: C 72.99; H 6.93; N 19.79. C
Calculated: C 73.79; H 6.85; N 19.27.
9 10 2
H N .
3
1
13
3
H and C, HSQC, and HMBC NMR spectra were
1
a), 0.81 g (85%, method b), mp 253–255°C. H NMR
spectrum, δ, ppm: 8.05 s (1H, NH), 7.27 d (4H, C H ,
recorded on a Varian 400 spectrometer (400 and
100 MHz, DMSO-d ). Elemental analysis was
6
4
6
J = 8.0 Hz), 6.60 s (2H, NH ), 1.69–1.17 m [10H,
performed on a Vario MICRO cube CHNS analyzer.
For the reactions, an Anton Paar Monowave 300 micro-
wave reactor (constant temperature mode technique)
was used. Temperature control was carried out using a
fiber optic temperature sensor (630 W).
2
1
3
(
CH ) ]. C NMR spectrum, δ , ppm: 162.96 (C≡N),
57.45 (C ), 146.23 (C ), 142.35 (C ), 125.83,
2 5 C
3
11
14
1
1
3
4
5
25.71, 116.30, 115.42 (C H ), 98.65 (C ), 55.76 (C ),
6
5
9.19, 39.15, 24.41, 23.54, 23.52. Found, %: C 60.05;
H 5.73; N 23.43. C H N O . Calculated, %: C 60.19;
1
5
17
5
2
H 5.72; N 23.40.
-Amino-2-phenyl-2-diazaspiro[4.5]dec-3-ene-4-
carbonitrile (6). Yield 0.36 g (45%, method a), 0.75 g
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