Regioselective, one-pot, multi-component, green synthesis of substituted benzo[c]pyrazolo[2,7]naphthyridines

Abstract

An efficient and environmentally benign synthetic protocol has been developed for the synthesis of benzo[c]pyrazolo[2,7]naphthyridine derivatives through regioselective multi-component “on-water” reaction of isatin, malononitrile and 3-aminopyrazole. The Knoevenagel condensation of isatin with malononitrile resulted in the formation of arylidene, which subsequently underwent Michael addition with 3-aminopyrazole followed by basic hydrolysis, cyclization, decarboxylation and aromatization to give the target naphthyridines in good to excellent yields. The one-pot multi-component protocol was also employed to obtain the said naphthyridines in a lower yield (10–15%) than obtained by basic hydrolysis of spiro-intermediates. The present study shows attractive features such as the use of water as a green solvent, short reaction time, reduced waste products and transition metal free C–C and C–N bond formation. The structures of the synthesized derivatives were established through FTIR, ¹H-NMR, ¹³C-NMR spectroscopy and ESI-mass spectrometry.