Auto-tandem palladium catalysis for unsymmetrical cyclooctatetraenes: modular synthesis and mechanistic elucidation

Abstract

The synthesis of fully substituted, unsymmetrical cyclooctatetraenes (COTs) has long been constrained by multi-step sequences and inefficient cross-couplings of pre-formed COT fragments. We report an auto-tandem palladium catalysis strategy that represents a paradigm shift from traditional coupling approaches to a cascade logic in COT synthesis. This single catalytic system orchestrates a sequence of cyclization, double carbopalladation, and C–H activation in one pot, converting simple alkynone O-methyl oximes and alkynes into a diverse range of previously inaccessible COT derivatives (17 examples, up to 95% yield) under mild conditions. Beyond synthesis, integrated experimental and DFT studies provide a complete mechanistic map: they delineate the full catalytic cycle, identify the origin of regioselectivity, and reveal the subtle kinetic competition between carbopalladation and C–H activation that dictates product selectivity. This work establishes tandem catalysis as a general platform for COT synthesis and delivers a mechanistic blueprint for designing cascade processes to construct other complex molecular architectures.