Alkynylation of N-(3-iodopyridin-2-yl)sulfonamide under Pd/C–Cu catalysis: a direct one pot synthesis of 7-azaindoles and their pharmacological evaluation as potential inhibitors of sirtuins

Abstract

The Pd-mediated alkynylation of N-(3-iodopyridin-2-yl)sulfonamide was investigated in the presence of 2-aminoethanol as a base. The combination of Pd/C–Cu catalysts and 2-aminoethanol facilitated the reaction to proceed via a coupling-cyclization sequence in a single-pot. Unlike earlier Pd-mediated two-step process the present reaction proceeds via a tandem C–C and C–N bond forming reaction affording a direct synthesis of 2-substituted-7-azaindole derivatives. A variety of novel 2-substituted-7-azaindoles were prepared by using this one-pot method. The methodology was explored for a formal synthesis of a Variolin B analogue. When tested in vitro some of the compounds synthesized showed promising sirtuin inhibiting properties in yeast without showing significant cell toxicities. Docking studies using the active molecules were carried out to understand the nature of their interactions with Sir2 protein.