Tetrahedron Letters
A novel four-component synthesis of ethyl 6-amino-4-aryl-5-
cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylates
a
b
V. L. Gein a, , T. M. Zamaraeva , P. A. Slepukhin
⇑
a Perm Pharmaceutical Academy, Polevaya Street, 2, Perm, Russia
b Institute of Organic Synthesis, Ural Branch of Russian Academy of Science, Sofya Kovalevskaya Street 22/20, Ekaterinburg, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Ethyl 6-amino-4-aryl-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylates were synthesized via a
four-component reaction of the sodium salt of diethyloxaloacetate, an aromatic aldehyde, hydrazine
hydrate, and malononitrile. The products were obtained in moderate to high yields.
Ó 2014 Published by Elsevier Ltd.
Received 18 February 2014
Revised 18 May 2014
Accepted 19 June 2014
Available online xxxx
Keywords:
Multicomponent reaction
Sodium diethyloxaloacetate
Aromatic aldehydes
Malononitrile
Hydrazine hydrate
Pyrano[2,3-c]pyrazoles
Multicomponent reactions (MCRs) are very promising methods
for the synthesis of heterocyclic compounds in organic
chemistry.1–5 The main advantages of MCRs in comparison with
traditional multistep procedures are high efficiency, experimental
simplicity, low cost, avoidance of large quantities of waste, ready
availability of reagents, and the ability to generate a significant
variety of products.6–10
2-Amino-4H-pyrans and their annelated heterocyclic deriva-
tives have attracted the attention of researchers as they represent
organic substances with a wide spectrum of biological activities,
such as anti-inflammatory,11 analgesic,12 and antihypertensive.13
Many pyranopyrazoles act as antimicrobial,14 antifungal,15
insecticidal,16 and anticancer agents.17,18 Some examples have
found applications in agriculture.19
Pyrano[2,3-c]pyrazoles have been synthesized in one-pot
regimes using hydrazine hydrate, ethyl acetoacetate, malononitri-
le, and aromatic aldehydes in the presence of triethylamine,20 cin-
chona derived alkaloids,21 proline,22 or imidazoles23 as catalysts.
Four-component reactions of aromatic aldehydes, malononitri-
le, dimethyl acetylenedicarboxylate, and hydrazine hydrate have
been performed in water without catalysts for the formation of
new substituted 3-methoxycarbonyl pyranopyrazoles.24
In continuation of the research in this area, and with the aim of
building new condensed heterocyclic compounds by reactions
with aldehydes, malononitrile, and hydrazine hydrate, we have,
for the first time, utilized the sodium salt of diethyloxaloacetate
as a substrate.
We found that the reaction proceeds with the formation of ethyl
6-amino-4-aryl-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-car-
boxylates in good yields (Table 1).
It was found that various aromatic aldehydes containing
electron-donating or electron-withdrawing functional groups at
different positions on the aromatic ring did not influence the
reaction time to any great extent and yields of the products were
similar in each case.
As suggested previously,20–24 a reasonable explanation for the
mechanism is as follows:
Probably, in the first stage, there are two parallel reactions
occurring with the formation of arylidenemalononitrile 6 and
pyrazolone 7 from the reactions of malononitrile (2) and the
aromatic aldehyde (3), and hydrazine hydrate (4) with the sodium
salt of diethyloxaloacetate (1) in the presence of acetic acid. The
two intermediates 6 and 7 undergo intermolecular addition with
the formation of 8. Subsequent cyclization and isomerization give
the product 5 (Scheme 1).
All the structures were confirmed from their 1H NMR, 13C NMR,
and IR spectra, and from elemental analysis. Additionally, the
structure of ethyl 6-amino-4-(3-methoxyphenyl)-5-cyano-2,4-
⇑
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0040-4039/Ó 2014 Published by Elsevier Ltd.