Microwave-assisted modified synthesis of C8-analogues of naturally occurring methylxanthines: Synthesis, biological evaluation and their practical applications

An efficient, microwave-assisted, oxidant-interceded, transition-metal-free, cross-dehydrogenative Csp(2)-C-sp(3) coupling of C-8-Caffeine 2/Theobromine 3/theophylline 4 with substituted aliphatic alcohols 11a-1 via C-H bond activation for the preparation of series of substituted C-8-(hydroxymethyl) Caffeine 12a-1/theobromine 13a-c/ theophylline 14a-b has been developed using microwave irradiation upto 98% yield. The reaction proceeds smoothly in the presence of tert-butyl hydroperoxide (TBHP) under solvolysis condition at 120 degrees C for 20 min to corresponding substituted C-8-(hydroxymethyl)-methylxanthine derivatives in good to excellent yields. The good substrate scope, control experiments, gram-scale synthesis, and practical synthetic transformations further highlights the practicality of this methodology. These C-8-(hydroxymethyl) Caffeine 12a-1, 13a-c and 14a-b have been found to show promising in vitro antioxidant as well as antiplatelet activities.