Synthesis of 3,4-dihydro-1(2H)-isoquinolinones

Approaches toward the preparative-scale synthesis of target 3,4-dihydro-1(2H)-isoquinolinones 1-3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large-scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high-temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)-isoquinolinone (9). Catalytic hydrogenation of 9 provided the desired 3,4-dihydro-5-methyl-1(2H)-isoquinolinone (2) in 65 % overall yield. Similar reduction of a commercially available 5-hydroxy-1(2H)-isoquinolinone precursor 10 followed by an O-alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4-dihydro-1(2H)-isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.