A tandem coupling-ketooxygenation reaction of readily accessible enediyne-carboxylic compounds with inner alkynes has been developed that utilizes the PdCl2/CuBr2 catalytic system under an O2 atmosphere and assembles a class of isoindolinones and o-acylbenzoic acids. The two oxygen atoms are regioselectively incorporated into enediyne units at the 1- and 6-positions from atmospheric molecular oxygen and H2O, respectively, during the present process. This study uncovered a formal [4C + 2C] benzannulation-diketonization of enediynes and alkynes via a coupling and decoupling strategy.