Mechanochemical Regioselective 3+3 Annulation of 6-Amino Uracil with Propargyl Alcohols Catalyzed by a Brønsted Acid/Hexafluoroisopropanol

A mechanochemistry approach is developed for regioselective synthesis of functionalized dihydropyrido[2,3-d]pyrimidines by milling propargylic alcohols and 6-aminouracils with HFIP/p-TsOH. In the case of tert-propargyl alcohols, this [3+3] cascade annulation proceeded through allenylation of uracil followed by a 6-endo trig cyclization. With sec-propargyl alcohols, the reaction furnished the propargylation of uracil. This atom economy ball milling reaction allows access to a broad range of dihydropyrido[2,3-d]pyrimidine derivatives in excellent yields. We demonstrated the gram scale synthesis of 3 g and post-synthetic modifications to effect the cyclization of 5 to 6.A mechanochemistry approach is developed for regioselective synthesis of functionalized dihydropyrido[2,3-d]pyrimidines by milling propargylic alcohols and 6-aminouracils with HFIP/p-TsOH. In the case of tert-propargyl alcohols, this [3+3] cascade annulation proceeded through allenylation of uracil followed by a 6-endo trig cyclization. With sec-propargyl alcohols, the reaction furnished the propargylation of uracil. This atom economy ball milling reaction allows access to a broad range of dihydropyrido[2,3-d]pyrimidine derivatives in excellent yields. We demonstrated the gram scale synthesis of 3 g and post-synthetic modifications to effect the cyclization of 5 to 6.