Functionalized Cycloolefin Ligand as a New Solution to Ortho-Constraint in the Catellani-Type Reaction

The Catellani reaction, i.e., the Pd/NBE catalysis, has been evolved into a versatile approach to multisubstituted arenes via the ortho-functionalization/ipso-termination process of a haloarene. Despite significant advances over the past 25 years, this reaction still suffered from an intrinsic limitation in the substitution pattern of the aryl halide, referred to as “ortho-constraint”. When an ortho substituent is absent, the haloarene substrate often fails to undergo effective mono ortho-functionalization process, and either ortho-difunctionalization products or NBE-embedded byproducts predominate. To tackle this challenge, structurally-modified NBEs (smNBEs) have been developed, which were proved effective for the mono ortho-aminative, -acylative, and -arylative Catellani reactions of ortho-unsubstituted haloarenes. However, the smNBE strategy is incompetent for solving the ortho-constraint in Catellani reactions with ortho-alkylation, and to date there lacks a general solution to this challenging but synthetically useful transformation. Recently, our group developed the Pd/olefin catalysis, in which an unstrained hybrid cycloolefin ligand served as a covalent catalytic module to enable the ortho-alkylative Catellani reaction without an NBE mediator. In this work, we show that this chemistry could afford a new solution to ortho-constraint in the Catellani reaction. A functionalized hybrid cycloolefin ligand bearing an amide group as the internal base was designed, which allowed for mono ortho-alkylative Catellani reaction of iodoarenes suffering from ortho-constraint before. Mechanistic study revealed that the newly designed ligand is capable of both accelerating the C−H activation and inhibiting side reactions, which accounts for its superior performance. The present work showcased the uniqueness of the Pd/olefin catalysis as well as the power of rational ligand design in metal catalysis.