New synthesis of ethyl 6-amino-4-aryl-5-cyano-1,4-dihydropyrano[2,3-c] pyrazole-3-carboxylates

Article abstract of DOI:10.1134/S1070428014050121

Ethyl 6-amino-4-aryl-5-cyano-1,4-dihydropyrano[2,3-c]pyrazol-3-carboxylates were synthesized by a reaction of diethyloxalacetate sodium salt with aromatic aldehyde, hydrazine hydrate, and malononitrile in the presence of acetic acid.

Full text of DOI:10.1134/S1070428014050121

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 5, pp. 691–693. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © V.L. Gein, T.M. Zamaraeva, I.V. Kozulina, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 5, pp. 703–705.
New Synthesis of Ethyl 6-Amino-4-aryl-5-cyano-1,4-
dihydropyrano[2,3-с]pyrazole-3-carboxylates
V. L. Gein, T. M. Zamaraeva, and I. V. Kozulina
Perm State Pharmaceutical Academy, Polevaya ul. 2, Perm, 614000 Russia
е-mail: geinvl48@mail.ru
Received October 25, 2013
Abstract—Ethyl 6-amino-4-aryl-5-cyano-1,4-dihydropyrano[2,3-с]pyrazol-3-carboxylates were synthesized
by a reaction of diethyloxalacetate sodium salt with aromatic aldehyde, hydrazine hydrate, and malononitrile in
the presence of acetic acid.
DOI: 10.1134/S1070428014050121
One of the most promising methods of heterocycles
synthesis in organic chemistry is multicomponent
reactions [1].
Compounds Iа–If are colorless crystalline
substances soluble in DMF, DMSO, chloroform,
ethanol, insoluble in water. IR spectra of compounds
Iа–If contain the absorption bands of stretching
vibrations in the groups COOEt (1720 cm–1), CN
(2248–2288 cm–1), NH (3216–3288 cm–1), NH2 (3320–
3550 cm–1), and С=С (1604–1628 cm–1).
The characteristic signals in the 1Н NMR spectra of
compounds Iа–If alongside the signals of aromatic
protons and the groups attached to the aromatic ring
are the resonances of the ester group (1.14 and
4.15 ppm), a singlet of the proton Н4 (4.67 ppm),
singlets of protons of groups NH2 (6.80 ppm) and NH
(13.45 ppm).
A four-component reaction between aromatic
aldehydes, malononitrile, acetylenedicarboxylate, and
hydrazine hydrate was described as a convenient
preparative method for the synthesis of 6-amino-4-
aryl-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-
carboxylates [2]. 2-Amino-4Н-pyrans and fused
heterocycles on their basis attract the interest as a
heterocyclic class of organic substances exhibiting a
fairly wide range of biologic action [3–5].
Aiming at the preparation of new fused pyranes we
examined the reaction of diethyloxalacetate sodium
salt with malononitrile, aromatic aldehyde, and
hydrazine hydrate. The reaction proceeds at short
boiling of the mixture in ethanol affording ethyl 6-
amino-4-aryl-5-cyano-1,4-dihydropyrano[2,3-с]pyra-
zole-3-carboxylates Iа–If (Scheme 1).
The 13С NMR spectrum of compound Ib contains
chemical shifts of carbon atoms from the ester group
(160.17 ppm), CH3O (55.00 ppm), СН (38.98 ppm)
groups, and also the signals of aromatic carbons
(111.4–159.11 ppm).
Scheme 1.
R = H (а), 3-MeO (b), 4-Cl (c), 3-NO2 (d), 3-F (e), 4-Pr-i (f).
691

GEIN et al.
692
Scheme 2.
R
N
N
R
O
H
O
R
N
O
N
N
A
N
O
N
H
O
N
O
O
O
CH3COOH
O
_
NH2-NH2
H2O
C
Na+
N
H
-CH3COONa
NH
O
O
O
B
R
R
R
O
O
O
O
O
O
N
N
N
N
N
N
N
N
H
HN
O
N
H
H2N
O
H
HO
N
E
Ia-If
D
In the mass spectrum of compound Ia the peak of
the ion [M]+ (m/z 310) is observed and also peaks of
fragment ions [M – C2H5OCO – C6H5]+ (m/z 160), [Ph]+
(m/z 77) confirming the assumed structure.
13С NMR spectra were taken in DMSO-d6 on a
spectrometer Bruker-300 (operating frequency 75 MHz).
The assignment of carbon atoms in СН, СН2, СН3
groups and quaternary carbon atoms was carried out
applying Dept experiment. Mass spectrum was
obtained on a Finnigan MАT INCOS-50 instrument
(ionizing electrons energy 70 eV). Elemental analysis
was performed on a Perkin Elmer 2400 analyzer.
Melting points were measured on a M-565 instrument.
Apparently in the first stage two parallel reactions
proceed of malononitrile with the aromatic aldehyde
and of the diethyloxalacetate sodium salt with
hydrazine hydrate in the presence of acetic acid
leading to the formation of intermediate
arylidenemalonodinitrile
А
and pyrazolone
B
Ethyl 6-amino-4-phenyl-5-cyano-1,4-dihydro-
pyrano[2,3-с]pyrazole-3-carboxylate (Iа). A mixture
of 0.66 g (0.01 mol) of malononitrile, 1 mL (0.01 mol)
of benzaldehyde in ethanol was boiled for 1 h, then a
mixture was added of 2.10 g (0.01 mol) of
diethyloxalacetate sodium salt with 0.5 mL (0.01 mol)
of hydrazine hydrate in the presence of 2 mL of acetic
acid. The reaction mixture was boiled for 0.5 h, and on
cooling the precipitate was filtered off and
recrystallized from ethanol. Yield 2.51 g (81%), mp
217–219°С (EtOH). IR spectrum, ν, cm–1: 3320–3472
(NH2), 3240 (NH), 2288 (CN), 1720 (COOEt), 1616
(C=C). 1Н NMR spectrum, δ, ppm: 1.14 t (3Н,
respectively. In the second stage the intermediates А
and B react with each other to provide intermediate C
whose isomerization into compound D followed by a
cyclization through a 6-imino derivative E gives
finally compounds Iа–If (Scheme 2).
EXPERIMENTAL
IR spectra were recorded on a Specord M-80 from
1
mulls in mineral oil. Н NMR spectra were registered
on a spectrometer Bruker 500 (operating frequency
500.13 MHz) in DMSO-d6, internal reference TMS.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014

NEW SYNTHESIS
693
3-СН3СH2O, J 7.12 Hz), 4.08 q (2Н, 3-СН3СH2O, J
7.12 Hz), 4.67 s (1Н, Н4), 6.90 br.s (2H, 6-NH2) 7.06–
7.25 m (5Н, С6Н5), 13.75 s (1Н, N1Н). Found, %: С
61.84, 62.05; Н 4.46, 4.63; N 17.95, 18.16.
C16H14N4O3. Calculated, %: С 61.93; Н 4.55; N 18.05.
6-NH2), 7.48–8.79 m (4Н, NO2С6Н4), 13.59 s (1Н, N1Н).
Found, %: С 53.97, 54.21; Н 3.58, 3.79; N 19.59, 19.84.
C16H13N5O5. Calculated, %: С 54.09; Н 3.69; N 19.71.
Ethyl 6-amino-4-(3-fluorophenyl)-5-cyano-1,4-
dihydropyrano[2,3-с]pyrazole-3-carboxylate (Ie).
Yield 3.01 g (92%), mp 220–222°С (EtOH). IR
spectrum, ν, cm–1: 3350–3550 (NH2), 3150 (NH), 2288
(CN), 1720 (COOEt), 1604 (C=C). 1Н NMR spectrum,
δ, ppm: 1.13 t (3Н, 3-СН3СH2O, J 6.5 Hz), 4.09 q (2Н,
3-СН3СH2O, J 6.5 Hz), 4.73 s (1Н, Н4), 6.76 br.s (2H,
6-NH2) 6.81–7.27 m (4Н, FС6Н4), 13.57 s (1Н, N1Н).
Found, %: C 58.43, 58.63; Н 3.92, 4.06; N 16.97,
17.19. C16H13FN4O3. Calculated, %: С 58.54; Н 3.99;
N 17.07.
Compounds Ib–If were prepared similarly.
Ethyl 6-amino-4-(3-methoxyphenyl)-5-cyano-
1,4-dihydropyrano[2,3-с]pyrazole-3-carboxylate
(Ib). Yield 2.41 g (71%), mp 205–207°С (EtOH). IR
spectrum, ν, cm–1: 3360–3472 (NH2), 3216 (NH), 2288
(CN), 1720 (COOEt), 1628 (C=C). 1Н NMR spectrum,
δ, ppm: 1.07 t (3Н, 3-СН3СH2O, J 6.9 Hz), 3.71 s (3Н,
3-CH3O), 4.11 q (2Н, 3-СН3СH2O, J 6.9 Hz), 4.75 s
(1Н, Н4), 6.65 d (1Н, Н6aryl, J 6.9 Hz), 6.66 s (1Н,
Н2aryl, J 6.9 Hz), 6.76 d.d (1Н, Н5aryl, J 6.9, 2.1 Hz),
7.05 br.s (2H, 6-NH2), 7.21 d (1Н, Н4aryl, J 7.8 Hz),
13.77 с (1Н, N1Н). 13С NMR spectrum, δ, ppm: 13.80
(3-СН3), 38.98 (4-СН), 55.00 (СН3О), 57.81 (С–С≡N),
60.90 (СН2), 103.55 (СAr), 111.47, 113.68, 119.52
(3СAr), 120.33, 129.11 (2СAr), 129.45 (СAr), 146.55,
155.66, 158.24, 159.11 (4СAr) 160.17 (CO). Found, %:
С 59.89, 60.13; Н 4.67, 4.83; N 16.34, 16.57.
C17H16N4O4. Calculated, %: С 60.00; Н 4.74; N 16.46.
Ethyl 6-amino-4-(4-isopropylphenyl)-5-cyano-
1,4-dihydropyrano[2,3-с]pyrazole-3-carboxylate
(If). Yield 2.67 g (76%), mp 222–224°С (EtOH). IR
spectrum, ν, cm–1: 3328–3472 (NH2), 3216 (NH), 2288
(CN), 1720 (COOEt), 1612 (C=C). 1Н NMR spectrum,
δ, ppm: 1.18 d.d [6Н, (CH3)2CHС6Н4], 1.02 t (3Н,
3-СН3СH2O, J 7.11 Hz), 2.80 m [1Н, (CH3)2CHС6Н4],
4.09 q (2Н, 3-СН3СH2O, J 7.11 Hz), 4.70 s (1Н, Н4),
6.83 br.s (2H, 6-NH2), 6.99–7.17 m [4Н, С6Н4], 13.70
s (1Н, N1Н). Found, %: С 64.64, 64.89; Н 5.66, 5.80;
N 15.78, 16.01. C19H20N4O3. Calculated, %: С 64.76;
Н 5.72; N 15.90.
Ethyl 6-amino-4-(4-chlorophenyl)-5-cyano-1,4-
dihydropyrano[2,3-с]pyrazole-3-carboxylate (Ic).
Yield 2.90 g (84%), mp 224–226°С (EtOH). IR
spectrum, ν, cm–1: 3368–3488 (NH2), 3288 (NH), 2248
(CN), 1720 (COOEt), 1608 (C=C). 1Н NMR spectrum,
δ, ppm: 1.12 t (3Н, 3-СН3СH2O, J 7.4 Hz), 4.16 q (2Н,
3-СН3СH2O, J 7.4 Hz), 4.70 s (1Н, Н4), 6.89 br.s (2H,
6-NH2), 7.07–8.56 m (4Н, ClС6Н4), 13.51 s (1Н, N1Н).
Found, %: С 55.64, 55.87; Н 3.71, 3.90; N 16.16, 16.36.
C16H13ClN4O3. Calculated, %: С 55.74; Н 3.80; N 16.25.
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Ethyl 6-amino-4-(3-nitrophenyl)-5-cyano-1,4-
dihydropyrano[2,3-с]pyrazole-3-carboxylate (Id).
Yield 3.16 g (89%), mp 221–223°С (EtOH). IR
spectrum, ν, cm–1: 3376–3456 (NH2), 3168 (NH), 2288
(CN), 1720 (COOEt), 1620 (C=C). 1Н NMR spectrum, δ,
ppm: 1.14 t (3Н, 3-СН3СH2O, J 7.4 Hz), 4.09 q (2Н,
3-СН3СH2O, J 7.4 Hz), 4.92 s (1Н, Н4), 7.01 br.s (2H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 5 2014