Copper‐Catalyzed Regioselective [3+3] Annulations of Alkynyl Ketimines with α‐Cyano Ketones: the Synthesis of Polysubstituted 4H‐Pyran Derivatives with a CF3‐Containing Quaternary Center. Issue 23 (18th March 2022) - Sheng, Cheng
Abstract: Regioselective [3+3] annulation of alkynyl ketimines with α ‐cyano ketones for the synthesis of polysubstituted 4 H ‐pyran derivatives with a quaternary CF3 ‐containing center has been realized by using Cu(OAc)2 as the catalyst. The novel strategy tolerates a wide range of α ‐CF3 alkynyl ketimines and α ‐cyano ketones with both aryl and alkyl substitutents. A preliminary asymmetric synthesis of chiral product 3 has been attempted by using copper and chiral thiourea as the cocatalyst with excellent yields (86‐99 %) and good enantioselectivities (71–78 % ee ). Furthermore, product 3 aa could be obtained on a gram‐scale reaction with 75 % yield and 99 % ee after recrystallization. Several products were also transformed readily. Control experiments indicate that the reaction involves a process with a base‐catalyzed or chiral thiourea‐catalyzed Mannich‐type reaction followed by a highly regioselective copper‐catalyzed ring‐closing reaction on the alkynyl moiety in a 6 ‐endo ‐ dig fashion. Abstract : A regioselective [3+3] annulation of alkynyl ketimines with α ‐cyano ketones for the synthesis of polysubstituted 4 H ‐pyran derivatives with a quaternary CF3 ‐containing center has been realized by using Cu(OAc)2 as a catalyst, providing the desired products in up to 99 % yield. The method tolerates some variations in the α ‐CF3 alkynyl ketimines and α ‐cyano ketones scope. The products could be synthesized on a gram‐scale and several products were conveniently transformed.