Enantioselective Synthesis of Chiral 2,2-Difluoro-spiro[indene- [1,3,4]oxadiazines] by NHC-Catalyzed [4 + 2] Cyclization Reactions

1,3,4-Oxadiazine derivatives represent an essential class of oxadiazine scaffolds that have demonstrated a wide spectrum of applications in modern drug discovery. However, the efficient and stereoselective construction of chiral 2,2-difluoro-spiro[indene-[1,3,4]oxadiazines] with broad substrate generality remains a significant challenge and has not yet been reported. Herein, we developed the NHC-catalyzed asymmetric enantioselective [4 + 2] cyclization of <i>gem</i>-difluoroalkyl-1,3-indandiones with 2-pyridyl-substituted hydrazones to achieve various chiral 2,2-difluoro-spiro[indene-[1,3,4]oxadiazines] in good to high yields with excellent enantioselectivities. The scalability and practical applicability of this method were demonstrated through large-scale reactions and a variety of subsequent transformations.