Solution-Phase Synthesis of a Diverse Isocoumarin Library

Abstract

The solution-phase synthesis of a 167-member library of isocoumarins is described. The key intermediates for library generation, 4-iodoisocoumarins, are easily prepared by iodocyclization of the corresponding 2-(1-alkynyl)arenecarboxylate esters. The 4-iodoisocoumarins undergo palladium-catalyzed Sonogashira, Suzuki−Miyura, and Heck reactions to yield a diverse set of isocoumarins. Alternatively, isocoumarins, bearing hydroxyl or bromine functionalities, have been prepared by ZnCl₂- and Pd(PPh₃)₄-mediated cyclization of the corresponding o-iodobenzoic acid and appropriate terminal alkynes. The resulting isocoumarins were further diversified by derivatization of the hydroxyl or bromine groups. A small set of isoquinolinones were also prepared from the corresponding isocoumarins.