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

Regioselective [3+3] annulation of alkynyl ketimines with alpha-cyano ketones for the synthesis of polysubstituted 4H-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 alpha-CF3 alkynyl ketimines and alpha-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.

Automated summary

This study achieved the regioselective [3+3] annulation of alkynyl ketimines with alpha-cyano ketones using Cu(OAc)(2) as the catalyst, resulting in the synthesis of polysubstituted 4H-pyran derivatives with a quaternary CF3-containing center. The strategy demonstrated excellent tolerance towards a wide range of alpha-CF3 alkynyl ketimines and alpha-cyano ketones with various aryl and alkyl substituents. Moreover, asymmetric synthesis of chiral product 3 was attempted and yielded high yields and enantioselectivities. The research has significant implications in the synthesis of polysubstituted 4H-pyran derivatives.