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. We developed the first mechanochemical annulation of 6‐amino uracil with tert‐propargyl alcohols by milling with p‐TSA/HFIP. This regioselective annulation proceeds through the allenylation of uracil and subsequent 6‐endo‐trig cyclization. Interestingly, sec‐propargyl alcohols furnished the propargylation of amino uracil.