An Efficient Multi-component Synthesis of 6-Amino-3-methyl-4-Aryl-2,4- dihydropyrano[2,3-c]Pyrazole-5-carbonitriles

Abstract

Multi-component reactions are effective in building complex molecules in a single step in a\nminimum amount of time and with facile isolation procedures; they have high economy1–7\nand thus have become a powerful synthetic strategy in recent years.8–10 The multicomponent\nprotocols are even more attractive when carried out in aqueous medium. Water\noffers several benefits, including control over exothermicity, and the isolation of products\ncan be carried out by single phase separation technique. Pyranopyrazoles are a biologically\nimportant class of heterocyclic compounds and in particular dihydropyrano[2,3-c]pyrazoles\nplay an essential role in promoting biological activity and represent an interesting template\nin medicinal chemistry. Heterocyclic compounds bearing the 4-H pyran unit have received\nmuch attention in recent years as they constitute important precursors for promising\ndrugs.11–13 Pyrano[2,3-c]pyrazoles exhibit analgesic,14 anti-cancer,15 anti-microbial and\nanti-inflammatory16 activity. Furthermore dihydropyrano[2,3-c]pyrazoles show molluscidal\nactivity17,18 and are used in a screening kit for Chk 1 kinase inhibitor activity.19,20 They\nalso find applications as pharmaceutical ingredients and bio-degradable agrochemicals.21–29\nJunek and Aigner30 first reported the synthesis of pyrano[2,3-c]pyrazole derivatives from\n3-methyl-1-phenylpyrazolin-5-one and tetracyanoethylene in the presence of triethylamine.\nSubsequently, a number of synthetic approaches such as the use of triethylamine,31\npiperazine,32 piperidine,33 N-methylmorpholine in ethanol,34 microwave irradiation,35,36\nsolvent-free conditions,37–39 cyclodextrins (CDs),40 different bases in water,41 γ -alumina,42\nand l-proline43 have been reported for the synthesis of 6-amino-4-alkyl/aryl-3-methyl-\n2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles. Recently, tetraethylammonium bromide\n(TEABr) has emerged as mild, water-tolerant, eco-friendly and inexpensive catalyst. To\nthe best of our knowledge, quaternary ammonium salts, more specifically TEABr, have notbeen used as catalysts for the synthesis of pyrano[2,3-c]pyrazoles, and we decided to investigate\nthe application of TEABr as a catalyst for the synthesis of a series of pyrazole-fused\npyran derivatives via multi-component reactions