Nickel-Catalyzed Heteroannulative Route to Isoquinolones

Significance

Reported is an efficient and con­venient Ni-catalyzed annulation route to highly substituted isoquinolones 3 and 4 by reaction of 2-halobenzamides 1 with alkynes 2. After a thorough screening of nickel catalysts, phosphines, bases, and solvents, it was demonstrated that the reaction system required the presence of Et₃N, [Ni(dppe)Br₂] and Zn. The scope of this reaction was extended to a variety of 2-halobenzamides (I, Br and Cl) bearing both EDGs and EWGs and a variety of N-substituents. The present reaction was extended to a variety of alkynes 2 (aliphatic, aryl, symmetrical and unsymmetrical) and applied to the total synthesis of oxyavicine (7) starting with 4 and 5 and proceeding via intermediate 6. A plausible mechanism was proposed for the ­heteroannulative process without evidence.