An Auto-Tandem Palladium Catalysis Strategy 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.