Four-Component Domino Strategy for the Combinatorial Synthesis of Novel 1,4-Dihydropyrano[2,3‑c]pyrazol-6-amines Selvaraj Kanchithalaivan, † Sathiyamoorthi Sivakumar, † Raju Ranjith Kumar,* ,† Palani Elumalai, ‡ Qazi Naveed Ahmed, § and Anil K. Padala § † Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India ‡ Department of Chemistry, University of Delhi, North Campus, Delhi 110 007, India § CSIR-Indian Institute of Integrative Medicine, Jammu 180 001, India * S Supporting Information ABSTRACT: An efficient one-pot four-component domino protocol for the combinatorial synthesis of novel 1,4- dihydropyrano[2,3-c]pyrazol-6-amines has been achieved. This transformation presumably occurs via cyclization- Knoevenagel condensation-Michael addition-tautomerism- intramolecular O-cyclization-elimination sequence of reac- tions. The significant features of this reaction include expedient one-pot process, short reaction time, no column chromatographic purification, excellent yield, and readily available starting materials. KEYWORDS: 1,4-dihydropyrano[2,3-c]pyrazol-6-amine, (E)-N-methyl-1-(methylthio)-2-nitroethenamine, domino, 2-hydroxy-1,4-naphthoquinone, DIPEA ■ INTRODUCTION Multicomponent domino reactions (MDR) constitute a versatile class of organic chemistry widely employed for the synthesis of complex heterocycles and natural products. 1 According to Tietze, a domino reaction is a process in which two or more bond-forming transformations occur based on functionalities formed in the previous step. Further no additional reagents or catalyst can be added to the reaction vessel, nor can reaction conditions be changed. 1,2 It is noteworthy that MDR are environmentally benign processes as they obey the principles of “Green Chemistry” on the basis of prevention of waste and avoiding time-consuming purification or protection/deprotection steps. In the past few decades investigations pertaining to the development of domino strategies toward the synthesis of novel heterocycles from simple and readily available substrates have received much of the attention of synthetic organic chemists. 3 Pyrano[2,3-c]pyrazole derivatives are known for their wide range of biological activities such as antimicrobial, 4 insecticidal, 5 and anti-inflammatory. 6 Furthermore, compounds containing pyrano[2,3-c]pyrazole moiety have been reported to exhibit enzyme inhibition, 7 anticancer 8 and antifungal 9 activity apart from being significant intermediates for the construction of complex heterocycles. 10 In view of the biological significance, there has been extensive attention toward the development of synthetic routes for the synthesis of compounds containing pyrano[2,3-c]pyrazole core (Figure 1). 11 As a consequence of our continued interest in the synthesis of novel heterocycles employing domino protocols, 12 herein we report for the first time a facile synthesis of a library of novel 1,4-dihydropyrano[2,3-c]pyrazol-6-amines via the one-pot four- component domino reactions of ethyl acetoacetate 1{1}/ethyl benzoylacetate 1{2}/DMAD 1{3} with hydrazines 2, aromatic aldehydes 3, and (E)-N-methyl-1-(methylthio)-2-nitroethen- amine 4 in the presence of DIPEA. Incidentally, the ethenamine 4 is an ambiphilic substrate widely employed in the synthesis of several heterocycles which include the antiulcer drugs ranitidine and nizatidine. 13 Moreover, the present work is the first report on the use of 4 in the synthesis of pyrano[2,3-c]pyrazol-6- amines. ■ RESULTS AND DISCUSSION Initially, to identify the optimum reaction condition, a representative reaction of ethyl acetoacetate 1{1}, phenyl- hydrazine 2{1}, p-chlorobenzaldehyde 3{2}, and (E)-N-methyl- 1-(methylthio)-2-nitroethenamine 4{1} affording 4-(4-chloro- phenyl)-N,3-dimethyl-5-nitro-1-phenyl-1,4-dihydropyrano[2,3- c]pyrazol-6-amine 5{1,1,2,1} was investigated. To begin with, the reaction was performed without base in ethanol at room temperature (Table 1, entry 1), which after 8 h afforded 4-(4- chlorophenyl)-3,5-dimethyl-1,7-diphenyl-4,7-dihydro-1H- Received: July 30, 2013 Revised: October 11, 2013 Published: October 22, 2013 Figure 1. Pyrano[2,3-c]pyrazole derivatives. Research Article pubs.acs.org/acscombsci © 2013 American Chemical Society 631 dx.doi.org/10.1021/co4000997 | ACS Comb. Sci. 2013, 15, 631-638