Greener and rapid access to bio-active heterocycles: room temperature synthesis of pyrazoles and diazepines in aqueous medium Vivek Polshettiwar and Rajender S. Varma * Sustainable Technology Division, National Risk Management Research Laboratory, US Environmental Protection Agency, 26 West Martin Luther King Drive, MS 443, Cincinnati, OH 45268, USA Received 10 October 2007; revised 31 October 2007; accepted 1 November 2007 Available online 7 November 2007 Abstract—An expeditious room temperature synthesis of pyrazoles and diazepines by condensation of hydrazines/hydrazides and diamines with various 1,3-diketones is described. This greener protocol was catalyzed by polystyrene supported sulfonic acid (PSSA) and proceeded efficiently in water in the absence of any organic solvent within 1–2 min. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction Pyrazoles are an important class of bio-active drug tar- gets in the pharmaceutical industry, as they are the core structure of numerous biologically active compounds, 1 including blockbuster drugs such as Celebrex 2 and Via- gra. 3 They also possess important biological properties such as antitumor cyclin-dependent kinase (CDK) inhibitors, 4 monoamine oxidase-B (MAO-B) inhibitors, and antiinflammatory agents. 5 Recently, they have also emerged as potential atypical antipsychotics. 6 Several syntheses of pyrazoles have been developed and by far the most prevalent method of choice is the reac- tion of 1,3-diketones with hydrazines. 7 Other methods for the synthesis of pyrazoles that do not require 1,3- diketones have been reported. 8 Recently, a few efficient methods have been developed, 9 however, most of these utilize a circuitous route, require longer reaction time, and are often carried out in organic solvents. Compared with the reactions in organic solvents, solventless reac- tions are often rapid, regio- or chemoselective, occur in high yields and have environmental and economic advantages. 10,11 In our continued quest for greener synthetic pathways, 12 herein, we report an expeditious synthesis of pyrazoles by the reaction of 1,3-diketones with hydrazines and hydrazides catalyzed by polystyrene supported sulfonic acid (PSSA), which proceeded efficiently in water in the absence of any organic solvent at room temperature within 1–2 min (Scheme 1). To optimize the reaction conditions, we studied the con- densation of pentane-2,4-dione with phenyl hydrazine, using various acid catalysts: acetic acid, p-toluene sul- fonic acid, and PSSA. Although reaction proceeds in each case, the yield and the rate of reaction is superior in the case of PSSA as compared to other catalyst. The general efficiency of this protocol was then studied for the synthesis of a variety of pyrazoles and the results are summarized in Table 1. 0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2007.11.017 Keywords: Pyrazoles; Diazepines; Polystyrenesulfonic acid (PSSA), Aqueous medium. * Corresponding author. Tel.: +1 513 487 2701; fax: +1 513 569 7677; e-mail: varma.rajender@epa.gov R 2 H N R 1 O O NH 2 X N N R 2 X R 1 PSSA/H 2 O RT, 1-2 min R 1 = Me, OEt R 2 = Ph, 4-ClPh, COPh CO-furyl, CO-thienyl X = H, Et, Cl Scheme 1. PSSA catalyzed pyrazole synthesis in water. Available online at www.sciencedirect.com Tetrahedron Letters 49 (2008) 397–400