Synthesis of fully substituted pyrano[2,3-c]pyrazole derivatives via a multicomponent reaction of isocyanides Ahmad Shaabani * , Afshin Sarvary, Ali Hossein Rezayan, Sajjad Keshipour Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran article info Article history: Received 4 November 2008 Received in revised form 25 January 2009 Accepted 13 February 2009 Available online 24 February 2009 Keywords: Multicomponent reaction Isocyanide Pyranopyrazole derivatives abstract The three-component reaction of the zwitterions generated from dialkyl acetylenedicarboxylate and isocyanides with 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one is described. The reaction afforded the cor- responding special type of fully substituted pyrano[2,3-c]pyrazole derivatives in good yields without using any catalyst and activation. Ó 2009 Published by Elsevier Ltd. 1. Introduction Multicomponent reactions (MCRs) are special types of syn- thetically useful organic reactions in which three or more differ- ent starting materials react to a final product in an onepot procedure. 1 Such reactions are atom-efficient processes by incorporating the essential parts of the starting materials into the final product. MCRs are powerful tools in the modern drug discovery process and allow the fast, automated, and high- throughput generation of organic compounds. 2 In the past years the pharmaceutical industry has focused more and more on diversity-oriented and biased combinatorial libraries. 3,4 Further- more, the discovery of novel MCRs can be considered as an in- teresting topic for academic research that also satisfies a practical interest of applied science. 5–9 Dihydropyrano[2,3-c]pyrazoles play an essential role in bi- ologically active compounds and therefore represent an interesting template for medicinal chemistry. They have been widely used as medicine intermediates due to their useful biological and phar- macological properties, such as antimicrobial, 10 insecticidal, 11 and anti-inflammatory. 12 Furthermore dihydropyrano[2,3-c]pyrazoles showed molluscicidal activity 13,14 and was identified as a screening hit for Chk1 kinase inhibitor. 15 Over the last years, the chemistry of dihydropyrano[2,3-c]- pyrazoles has received great interest. The first approach to synthesize of these substances was undertaken by Otto, 16 in which he initiated the reaction sequence by the base-catalyzed cyclization of 4-aryliden-5-pyrazolone. In a further report, this same group showed that weak bases can also be used for a Michael-type cyclization. 17 Extending the work of Otto, Klokol and colleagues performed the direct conversion of 3-methyl-3-pyrazolin-5-one with malo- nonitrile in the presence of a weak base. 18 Recent methods for the synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles include synthesis based on the procedure of Klokol, 19 water or ethanol media, 20–25 under microwave irradiation, 26 and under solvent-free conditions. 27 As part of our continuing interest in the development of new synthetic methods in heterocyclic chemistry and our interest in isocyanide based multicomponent reactions, 28–33 herein we de- scribe an efficient synthesis of fully substituted pyrano[2,3-c]pyr- azoles 4 via the reaction of an isocyanide 1 with an dialkyl acetylenedicarboxylate 2 and 3-methyl-1-phenyl-1H-pyrazol- 5(4H)-one 3 in high yields without using any catalyst at ambient temperature (Scheme 1). R 1 N C r.t., 12 h + + C C CO 2 R 2 CO 2 R 2 CH 3 CN N N O O N N CO 2 R 2 CO 2 R 2 NH R 1 Ph Ph 1 2 3 4a-l Scheme 1. Synthesis of pyrano[2,3-c]pyrazoles via a three-component reaction. * Corresponding author. Fax: þ98 21 22403041. E-mail address: a-shaabani@cc.sbu.ac.ir (A. Shaabani). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.tet.2009.02.035 Tetrahedron 65 (2009) 3492–3495 Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet