Regioselective Synthesis of Cycloalkane-fused Pyrazolo[4,3-e]pyridines through Tandem Reaction of 5-aminopyrazoles, Cyclic Ketones and Electron-rich Olefins

Abstract

Background: Pyrazolopyridines are interesting fused heterocyclic pharmacophores that combine pyrazole and pyridine; two privileged nuclei extensively studied and with a wide range of applications. They can be obtained by a broad variety of synthetic methods among which multicomponent reactions have gained importance, especially from 5-aminopyrazoles and dielectrophilic reagents. However, the search for new approaches more in tune with sustainable chemistry and the use of unconventional heating in three-component synthesis are open and highly relevant study fields. Methods: A novel, practical and efficient three-component synthesis of cycloalkane-fused pyra-zolo[4,3-e]pyridines was developed through a tandem reaction of 5-aminopyrazoles, cyclic ke-tones and electron-rich olefins, using microwave induction in perfluorinated solvent and iodine as catalyst. Results: The microwave-induced three-component approach applied in this work promoted the construction of 10 new pyrazolopyridines with high speed and excellent control of regioselec-tivity, favoring the linear product with good yields; where the versatility of electron-rich olefins in iodine-catalyzed cascade heterocyclizations, granted the additional benefit of easy isolation and the possibility to reuse the fluorous phase. Conclusions: Although pyrazolopyridines have been synthetically explored because of their structural and biological properties, most of the reported synthetic methods use common or even toxic organic solvents and conventional heating or multi-step processes. In contrast, this study applied a multicomponent methodology in a single step by microwave induction and with the versatility provided in this case by the use of perfluorinated solvent, which allowed easy isolation of the final product and recovery of the fluorous phase.