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 Csp2-Csp3 coupling of C8-Caffeine 2/Theobromine 3/theophylline 4 with substituted aliphatic alcohols 11a-lvia CH bond activation for the preparation of series of substituted C8-(hydroxymethyl) Caffeine 12a-l/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 °C for 20 min to corresponding substituted C8-(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 C8-(hydroxymethyl) Caffeine 12a-l, 13a-c and 14a-b have been found to show promising in vitro antioxidant as well as antiplatelet activities. [Display omitted] •An efficient, microwave-assisted, oxidant-interceded, transition-metal-free, cross-dehydrogenative coupling is reported.•Several substituted C8-(hydroxymethyl) methylxanthines 12a-l, 13a-c and 14a-b were synthesized using this new methodology.•Good substrate scope, control experiments, gram-scale synthesis, and practical synthetic transformations further highlights the practicality of this methodology.•C8-(hydroxymethyl)Caffeine 12a-l, 13a-c and 14a-b showed promising in vitro antioxidant and antiplatelet activities.