Four-component catalyst-free reaction in water: Combinatorial library synthesis of novel 2-amino-4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-4H-chromene-3- carbonitrile derivatives

Article abstract of DOI:10.1039/b913838b

A catalyst-free combinatorial library of novel 2-amino-4-(5-hydroxy-3- methyl-1H-pyrazol-4-yl)-4H-chromene-3-carbonitrile derivatives has been developed by a four-component reaction between hydrazine hydrate (1), ethyl acetoacetate (2), 2-hydroxybenzaldeh

Full text of DOI:10.1039/b913838b

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COMMUNICATION
www.rsc.org/greenchem | Green Chemistry
Four-component catalyst-free reaction in water: Combinatorial library
synthesis of novel 2-amino-4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-4H-
chromene-3-carbonitrile derivatives†
Kandhasamy Kumaravel and Gnanasambandam Vasuki*
Received 10th July 2009, Accepted 30th September 2009
First published as an Advance Article on the web 14th October 2009
DOI: 10.1039/b913838b
A catalyst-free combinatorial library of novel 2-amino-
4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-4H-chromene-3-
carbonitrile derivatives has been developed by a four-
component reaction between hydrazine hydrate (1), ethyl
acetoacetate (2), 2-hydroxybenzaldehydes (3) and malonon-
itrile (4) in water at ambient temperature.
literature.9 The reported procedure focuses on the synthesis
of 4-substituted-2-amino-4H-chromene framework involving a
three-component electrochemical reaction in organic solvent
and pyrazolone has been used as one of the substituents. We are
actively engaged in developing multi-component reaction proto-
cols in water.3,10 Herein, we report for the first time a catalyst-free
four-component reaction for a combinatorial synthesis of novel
highly functionalised 4-pyrazolyl-4H-chromene frameworks in
water at ambient temperature (Scheme 1).
The challenging task of achieving ‘efficiency’ in all aspects
of chemical production, advocated by green chemistry can be
realized by innovative research which comprehensively addresses
the issues of atom economy, economy of steps and avoidance of
auxiliary chemicals.1 Developing a simple, eco-friendly reaction
protocol for the synthesis of compound libraries of medicinal
scaffolds is as an attractive area of research in both academic
and pharmaceutical R&D.2 Multi-component reaction (MCR)
protocols in water will be one of the most suitable strategies,
which will meet the requirements of green chemistry as well as
for developing libraries of medicinal scaffolds.3
The chromene framework,4 particularly 4-aryl/alkyl-2-
aminochromenes, is an important medicinal scaffold. Several
compounds having this framework show pro-apoptotic activity
against cancer cells as a single agent or in combination with
chemo radiotherapy,5 as well as anticoagulant, spasmolytic,
diuretic, insecticidal, and antianaphylactin activity.6 Some of
them can also be employed as cosmetics and pigments,4 and
utilized as potential biodegradable agrochemicals.7
Pyrazolones are important ingredients in many pharmaceuti-
cal preparations, such as analgesics, antipyretics etc. Hetero-
cycle substituted pyrazolones are reported to possess kinase
inhibitory properties, particularly of enzymes which catalyze the
phosphorylation of serine and threonine in proteins. Therefore,
an inhibitor of these protein kinases can be developed as a drug
candidate for treating diseases related to these enzymes, such as
rheumatoid arthritis, psoriasis, septic shock, bone loss, cancers
and other proliferative diseases.8
Scheme 1 Catalyst-free four-component synthesis of 4-pyrazolyl-4H-
chromenes (5a–k).
A four-component reaction between hydrazine hydrate 1,
ethyl acetoacetate 2, 2-hydroxybenzaldehyde 3 and malonon-
itrile 4 in water at ambient temperature resulted in novel
pyrazolyl-4H-chromene derivatives 5 in good to excellent yields.
The reaction is compatible with several 2-hydroxybenzaldehyde
derivatives (Table 1). The product is separated from the reaction
mixture and isolated by filtration, and was pure on TLC. Con-
ventional chromatographic purification or recrystallisation was
not required. However, the product was washed with water and
then a small amount of an ethyl acetate/hexane mixture (1:1).
Formation of the product is suggested to involve the tandem
reactions of: (i) reaction between 1 and 2 resulting in instanta-
neous formation of pyrazolone 6, (ii) Knoevenagel condensation
between 2-hydroxybenzaldehyde and malononitrile forming
2-imino-2H-chromene-3-carbonitrile 7 intermediate by 6-exo-
dig cyclization of the hydroxyl group with the cyano group, and
(iii) Michael addition of 6 to 7 and subsequent rearrangement.
The reaction is completed within 5–10 minutes (Scheme 2).
The pyrazolone moiety is present as a hydroxyl tautomer in
the product. A reaction between 2-hydroxybenzaldehyde with
malononitrile to form the 2-imino-2H-chromene-3-carbonitrile
intermediate in water and its reaction with Michael donors have
been reported.11
A molecular skeleton which integrates chromene as well as py-
rozolone moieties might possess properties of both and enhance
the activity. To the best of our knowledge only one compound
possessing such molecular skeleton has been reported in the
Department of Chemistry, Pondicherry University, Puducherry, 605 014,
India. E-mail: vasukig@gmail.com, vasuki.che@pondiuni.edu.in;
Fax: +91 413 2655987; Tel: +91 413 2654498
† Electronic supplementary information (ESI) available: Detailed ex-
perimental procedures, including spectroscopic data for all the new
compounds along with NMR spectra. See DOI: 10.1039/b913838b
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Table 1 Catalyst-free synthesis of 4-pyrazolyl-4H-chromene in water
Table 1 (Contd.)
Entry Salicyaldehyde 3
4-Pyrazoyl-4H-chromenes 5 Yield (%)a
Entry Salicyaldehyde 3
4-Pyrazoyl-4H-chromenes 5 Yield (%)a
1
87
81
5a
5j
10
74
79
2
3
5b
11
5k
a Isolated pure product.
5c
5d
78
83
4
5
90
92
79
5e
5f
6
7
Scheme 2 Proposed reaction pathway.
The four-component catalyst-free reaction protocol devel-
oped in water results in a potential medicinal scaffold. This
reaction protocol conforms to several green chemistry princi-
ples coupled with the potential for developing combinatorial
libraries. Green aspects of this reaction include: (i) highly atom
economic – ethanol and water are the byproducts, (ii) being
a multi-component reaction it is step economic, (iii) water is
being used as the reaction medium, therefore use of conventional
volatile organic solvents is avoided and (iv) avoidance of
catalyst.
5g
5h
8
9
86
76
Experimental
General procedure
Toastirred aqueous mixture of hydrazine hydrate 98% 1 (0.107 g,
2 mmol) and ethyl acetoacetate 2 (0.260 g, 2 mmol), 2-hydroxy
benzaldehyde 3 (2 mmol), malononitrile 4 (0.132 g, 2 mmol)
were added successively at ambient temperature under an open
atmosphere with vigorous stirring for 5–10 min. The precipitated
solid was filtered, washed with water and then with 5 mL of ethyl
5i
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acetate/hexane mixture (1:1). The product obtained was pure by
TLC and spectral techniques.
V. V. Fokin, Chem. Rev., 2009, 109, 725; D. Tejedor and F. Garcia-
Tellado, Chem. Soc. Rev., 2007, 36, 484.
4 G. P. Ellis, The Chemistry of Heterocyclic Compounds: Chromenes,
Chromanes and Chromones, ed. A. Weissberger and E. C. Taylor,
Wiley, New York, ch. II, 1997.
Acknowledgements
5 W. Kemnitzer, J. Drewe, S. Jiang, H. Zhang, J. Zhao, C. Crogan-
Grundy, L. Xu, S. Lamothe, H. Gourdeau, R. Denis, B. Tseng,
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G.V. thanks DST (Ref. No. SR/S5/GC-22/2007) and UGC
(F. No. 32-238/2006 SR), Government of India, for financial
support. K.K. thanks CSIR for the award of CSIR-SRF. The
authors thank the Central Instrumentation Facility (CIF),
Pondicherry University, for high-resolution NMR and FT-IR
facilities.
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