N -Mesyl-Enabled Cu 2 O Catalysis: Synthesis of ( E )-3-Alkylideneisoindolin-1-ones and 3,4-Unsubstituted Isoquinolones via Sequential Alkynylation/Annulation

A highly regio- and stereoselective synthesis of (E)-3-alkylideneisoindolin-1-ones has been developed via a Cu2O-catalyzed ligand- and base-free Sonogashira alkynylation/5-exo-dig cyclization of o-iodo-N-mesylbenzamides with terminal alkynes. In this process, the N-mesyl group serves as a dual directing and activating group, ensuring the exclusive formation of the (E)-exocyclic double bond in good-to-excellent yields with broad functional group tolerance. The mesyl group can be subsequently removed with TBAF to afford NH-free 3-alkylideneisoindolin-1-ones. When TIPS-acetylenes were used as the terminal alkyne, the reaction stopped at the Sonogashira intermediate due to steric hindrance; however, a subsequent TBAF-mediated deprotection of both TIPS and mesyl groups triggered a 6-endo-dig cyclization. This divergent approach provides an efficient route to 3,4-unsubstituted isoquinolin-1(2H)-ones. Operationally simple and scalable, this method avoids expensive additives and offers a practical, selective entry to two privileged heterocyclic scaffolds.