Synthesis of new pyrazole derivatives from benzylidenemalononitrile

Full text of DOI:10.1134/S107042800903021X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 3, pp. 463–465. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © S.B. Nosachev, N.A. Shchurova, E.A. Tyrkova, A.G. Tyrkov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 3,
pp. 473–474.
SHORT
COMMUNICATIONS
Synthesis of New Pyrazole Derivatives
from Benzylidenemalononitrile
S. B. Nosachev, N. A. Shchurova, E. A. Tyrkova, and A. G. Tyrkov
Astrakhan State University, pl. Shaumyana 1, Astrakhan, 414000 Russia
e-mail: tyrkov@rambler.ru
Received November 9, 2007
DOI: 10.1134/S107042800903021X
1
1,3-Dipolar cycloaddition of diazoalkanes to acety-
lenes [1] or styrenes [2] activated by electron-with-
drawing substituents underlies a traditional procedure
for the synthesis of pyrazoles. For example, 1-bromo-
1-nitro-2-phenylethene reacts with diazomethane in
diethyl ether to give 5-bromo-5-nitro-4,5-dihydro-1H-
pyrazole, and treatment of the latter with hydrochloric
acid or a solution of sodium hydrogen carbonate leads
to the formation of 5-bromo- or 5-nitro-4-phenyl-1H-
pyrazole, respectively [3].
With a view to study competing effects of func-
tional groups in an analog of 1-nitro-2-phenylethene,
benzylidenemalononitrile (I), we examined its reac-
tions with diazomethane (II) and diazoethane (III).
The cycloaddition of diazoalkanes II and III to di-
polarophile I occurred under mild conditions (in di-
ethyl ether at –5 to 5°C), and the products were the
corresponding 4-phenyl-1H-pyrazole-5-carbonitriles
IV and V (Scheme 1).
signal appeared in their H NMR spectra as a broad-
ened singlet at δ 10.8–10.9 ppm. The presence of
a labile hydrogen atom on the nitrogen in molecules
IV and V opens prospects in further functionalization
of these compounds, e.g., via alkylation of the corre-
sponding potassium salts VI and VII. The latter were
prepared in situ by treatment of 4-phenyl-1H-pyrazole-
5-carbonitriles IV and V with potassium ethoxide. The
alkylation of potassium salts VI and VII with chloro-
methyloxirane, phenacyl bromide, and 4-toluenesul-
fonyl chloride resulted in the formation of previously
unknown alkylation products VIII–XI and N-sulfonyl
derivatives XII and XIII (Scheme 2) whose structure
was confirmed by spectral data and elemental analyses.
The IR spectra of X and XI contained an absorption
band at 1705 cm–1 due to stretching vibrations of the
carbonyl group, while compounds XII and XIII dis-
played absorption bands at 1150 and 1300 cm–1 be-
longing, respectively, to antisymmetric and symmetric
Scheme 1.
Scheme 2.
CN
R
Ph
+
RCHN2
EtOK
Ph
IV, V
K+
CN
N
CN
VI, VII
Ph
I
II, III
N
R
Ph
Et2O
R
+
HCN + N2
N
R'Hlg, Me2CO, Δ
CN
N
H
N
CN
N
IV, V
R'
II, IV, R = H; III, V, R = Me.
VIII–XIII
In the IR spectra of compounds IV and V we
observed an absorption band at 3550 cm–1 due to
stretching vibrations of the NH group, and the NH
VI, VIII, X, XII, R = H; VII, IX, XI, XIII, R = Me; VIII,
IX, R′ = oxiran-2-ylmethyl; X, XI, R′ = PhCOCH2; XII,
XIII, R′ = 4-MeC6H4SO2; Hlg = Cl, Br.
463

NOSACHEV et al.
464
1
stretching vibrations of the SO2 group. The H NMR
spectra of VIII–XIII were consistent with the assumed
structures, and they resembled those reported for struc-
turally related compounds [4, 5]. Protons in the oxirane
ring of compounds VIII and IX resonated in the
of 6 mmol of p-toluenesulfonyl chloride in ethanol was
added, and the mixture was heated for 2 h under reflux.
The mixture was then kept for 3 days at 25°C and
evaporated under reduced pressure, the residue was
treated with diethyl ether (3×10 ml), the extract was
evaporated, and the residue was subjected to chroma-
tography in a 500×10-mm column charged with ac-
tivated silica gel (Silicagel, 100–400 μm) using ben-
zene (compounds VIII, IX) or chloroform (X–XIII) as
eluent.
1
1H NMR spectra at δ 2.65–3.07 ppm. The H NMR
spectra of phenacyl and sulfonyl derivatives X–XIII
contained signals typical of methylene protons in the
NCH2CO fragment (δ 6.44–6.45 ppm; compounds X,
XI) or protons in the p-tolyl substituent (XII, XIII).
Thus the described reactions open a synthetic route
to functionally substituted pyrazoles having various
pharmacophoric groups on the nitrogen atom, which
are difficult to obtain by other methods.
1-(Oxiran-2-ylmethyl)-4-phenyl-1H-pyrazole-
5-carbonitrile (VIII). Yield 62 %, mp 105–108°C.
1H NMR spectrum, δ, ppm: 2.65 d (CH2), 3.06 m (CH),
4.23 d (CH2), 7.38 m (Harom), 7.59 s (CH). Found, %:
C 69.10; H 4.68; N 18.51. C13H11N3O. Calculated, %:
C 69.33; H 4.89; N 18.67.
Diazomethane [6], diazomethane [7], and phenacyl
bromide [8] were prepared according to known proce-
dures.
3-Methyl-1-(oxiran-2-ylmethyl)-4-phenyl-1H-
pyrazole-5-carbonitrile (IX). Yield 64%, mp 118–
Reaction of benzylidenemalononitrile (I) with
diazoalkanes II and III (general procedure). A solu-
tion of diazoalkane II or III was added under stirring
to a solution of 8 mmol of benzylidenemalononitrile
(I) in 30 ml of anhydrous diethyl ether at –5 to 5°C
until nitrogen no longer evolved. The mixture was then
kept for 24 h at 25°C and evaporated under reduced
pressure, and the oily residue was subjected to chroma-
tography in a 250×10-mm column charged with ac-
tivated silica gel (Silicagel 100–400 µm) using carbon
tetrachloride as eluent.
1
120°C. H NMR spectrum, δ, ppm: 2.35 s (CH3),
2.64 d (CH2), 3.05 m (CH), 4.21 d (CH2), 7.35 m
(Harom). Found, %: C 70.05; H 5.27; N 17.38.
C14H13N3O. Calculated, %: C 70.29; H 5.44; N 17.57.
1-(2-Oxo-2-phenylethyl)-4-phenyl-1H-pyrazole-
5-carbonitrile (X). Yield 72%, mp 141–143°C. IR
1
spectrum, ν, cm–1: 2230 (CN). 1705 (C=O). H NMR
spectrum, δ, ppm: 6.44 s (CH2), 7.33–7.45 m (Harom),
7.58 s (CH). Found, %: C 75.05; H 4.34; N 14.42.
C18H13N3O. Calculated, %: C 75.26; H 4.53; N 14.63.
4-Phenyl-1H-pyrazole-5-carbonitrile (IV). Yield
44%, mp 154–156°C. IR spectrum, ν, cm–1: 3550
(NH), 2230 (CN). H NMR spectrum, δ, ppm: 7.35 m
(Harom), 7.58 s (CH), 10.9 br.s (NH). Found, %:
C 70.74; H 4.03; N 24.58. C10H7N3. Calculated, %:
C 71.01; H 4.14; N 24.85.
3-Methyl-1-(2-oxo-2-phenylethyl)-4-phenyl-1H-
pyrazole-5-carbonitrile (XI). Yield 74%, mp 152–
153°C. IR spectrum, ν, cm–1: 2230 (CN), 1705 (C=O).
1H NMR spectrum, δ, ppm: 2.34 s (CH3), 6.45 s (CH2),
7.36–7.44 m (Harom). Found, %: C 75.56; H 4.77;
N 13.74. C19H15N3O. Calculated, %: C 75.75; H 4.98;
N 13.95.
1
3-Methyl-4-phenyl-1H-pyrazole-5-carbonitrile
(V). Yield 46%, mp 162–164°C. IR spectrum, ν, cm–1:
1-(4-Methylphenylsulfonyl)-4-phenyl-1H-pyra-
zole-5-carbonitrile (XII). Yield 71%, mp 172–174°C.
IR spectrum, ν, cm–1: 2230 (CN); 1300, 1150 (SO2).
1H NMR spectrum, δ, ppm: 2.32 s (CH3), 7.11–7.52 m
(Harom), 7.57 s (CH). Found, %: C 62.94; H 3.86;
N 12.83. C17H13N3O2S. Calculated, %: C 63.16;
H 4.02; N 13.00.
1
3550 (NH), 2230 (CN). H NMR spectrum, δ, ppm:
2.35 s (CH3), 7.34 m (Harom), 10.8 br.s (NH). Found,
%: C 7.95; H 4.78; N 22.74. C11H9N3. Calculated, %:
C 72.13; H 4.92; N 22.95.
1-Substituted 4-phenyl-1H-pyrazole-5-carboni-
triles VIII–XIII (general procedure). A solution of
6 mmol of compound IV or V in 20 ml of ethanol was
cooled to 0±5°C, 6 mmol of potassium ethoxide was
added, the mixture was kept for 0.5 h at 5°C, and the
precipitate was filtered off, washed with cold ethanol,
and dried. Pyrazole potassium salt VI or VII thus ob-
tained was dispersed in 100 ml of acetone, 6 mmol of
chloromethyloxirane or phenacyl bromide or a solution
3-Methyl-1-(4-methylphenylsulfonyl)-4-phenyl-
1H-pyrazole-5-carbonitrile (XIII). Yield 75%,
mp 180–183°C. IR spectrum, ν, cm–1: 2230 (CN);
1
1300, 1150 (SO2). H NMR spectrum, δ, ppm: 2.32 s
(CH3), 2.35 s (CH3), 7.12–7.54 m (Harom). Found, %:
C 63.86; H 4.27; N 12.31. C18H15N3O2S. Calculated,
%: C 64.09; H 4.45; N 12.46.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009

SYNTHESIS OF NEW PYRAZOLE DERIVATIVES
465
3. Parham, W.E. and Bleasdale, J.L., J. Am. Chem. Soc.,
The IR spectra were recorded on an IKS-29 spec-
trometer from solutions in chloroform with a concen-
tration of 40 mg/ml (cell path length l = 0.1 mm). The
1H NMR spectra were measured from solutions in
acetone-d6 on a Tesla BS-487C spectrometer (80 MHz)
relative to hexamethyldisiloxane as internal reference.
The progress of reactions and the purity of products
were monitored by ascending TLC on Silufol UV-254
plates using acetone–hexane (2 :3) as eluent; spots
were visualized by treatment with iodine vapor.
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