Palladium‐Catalyzed Cross‐Coupling of Alkenyl Carboxylates

• Published in: Angewandte Chemie International Edition 2020-09, Vol.59 (39), p.17277-17281
• Main Authors: Becica, Joseph, Heath, Oliver R. J., Zheng, Cameron H. M., Leitch, David C.
• Format: Article
• Language: English
• Subjects: alkenylation; Carboxylates; Catalysis; Chemical reactions; Cross coupling; C−O activation; Esters; heterocycles; Oxidants; Oxidizing agents; Palladium; palladium catalysis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202006586

Carboxylate esters have many desirable features as electrophiles for catalytic cross‐coupling: they are easy to access, robust during multistep synthesis, and mass‐efficient in coupling reactions. Alkenyl carboxylates, a class of readily prepared non‐aromatic electrophiles, remain difficult to functionalize through cross‐coupling. We demonstrate that Pd catalysis is effective for coupling electron‐deficient alkenyl carboxylates with arylboronic acids in the absence of base or oxidants. Furthermore, these reactions can proceed by two distinct mechanisms for C−O bond activation. A Pd0/II catalytic cycle is viable when using a Pd0 precatalyst, with turnover‐limiting C−O oxidative addition; however, an alternative pathway that involves alkene carbopalladation and β‐carboxyl elimination is proposed for PdII precatalysts. This work provides a clear path toward engaging myriad oxygen‐based electrophiles in Pd‐catalyzed cross‐coupling. Carboxylate, activate! Pd catalysis is generally assumed to be ineffective for cross‐coupling with most oxygen‐based electrophiles. It is demonstrated not only that alkenyl carboxylates are able to couple with boronic acids under extremely mild conditions, but that there are two distinct pathways for C−O activation. The result is an operationally simple arylation of many pharmaceutically relevant (hetero)cyclic cores with excellent functional‐group tolerance.