One-Pot Sequential Aerobic Oxidation/1,3-Dipolar Cycloaddition/α-Iminol Rearrangement of 1-Benzyl-3,4-dihydroisoquinolines with Iso(thio/seleno)cyanates: A Facile Synthesis of Tetrahydroisoquinoline-Fused-(Thio/Seleno)Hydantoin Derivatives
Abstract
High Resolution Image Download MS PowerPoint Slide The synthesis of fully substituted (thio/seleno)hydantoins remains a significant challenge in medicinal chemistry. Herein, we report an efficient one-pot sequential aerobic oxidation/1,3-dipolar cycloaddition/α-iminol rearrangement of diverse 1-benzyl-3,4-dihydroisoquinolines using iso(thio/seleno)cyanate as reagents to afford the corresponding tetrahydroisoquinoline-fused-(thio/seleno)hydantoin derivatives with good functional group tolerance on the periphery of the core in high yields (58 examples, average yield 70%). The discovery of the tert -butyl isocyanate-catalyzed aerobic oxidation of 1-benzyl-3,4-dihydroisoquinolines is reliable for the synthesis of 1-benzoyl-3,4-dihydroisoquinolines in high yields under mild reaction conditions, which are well-suited for other subsequent late-stage transformations. Additionally, the cascade reaction with an excess amount of aryl-, propargyl-, tosyl-, benzoyl-, and trimethylsilyl- iso(thio)cyanate reagents furnishes novel tetrahydroisoquinoline-hydantoin-oxazolidinone fused tetracycles (13 examples, up to 99% yield). Moreover, the late-stage functionalization of the desired (thio)hydantoin products affords structurally diverse (thio)hydantoin scaffolds with increasing complexity in excellent yields (15 examples, average 91%). A plausible reaction mechanism for the 1,3-dipolar cycloaddition/α-iminol rearrangement sequence is proposed, which occurs via a nonconcerted reaction pathway.