Skeletal Editing to Access Substituted Aminoisoquinolines

Keywords

ruthenium catalysis - sulfoxonium ylides - isoquinolines - [4+2] annulation - C–H acetylation - quinazolinones

Significance

Nitrogen heterocycles have been shown to be present in > 80 % of small-molecule pharmaceuticals, with many recent studies focusing on the development of methods for skeletal editing enabling the facile transformation of heterocyclic systems in a single synthetic step. The current report describes a method for the conversion of 2-arylquinazolinones into 1-aminoisoquinolines through ruthenium-catalyzed [4 + 2] annulation with sulfoxonium ylides. Mechanistically, the reaction is hypothesized to proceed through a cascade involving C–H acetylation, nucleophilic cyclization and alcoholysis, with initial electrophilic ruthenation of the 2-arylquinazolinone to form a five-membered cycloruthenium complex initiating the sequence.

Comment

Model studies on the reaction between 2-phenylquinazolinone (1) and phenyl sulfoxonium ylide 2 allowed identification of the optimal catalyst and additive for the transformation, with the reaction shown to proceed best in ethanol under an air atmosphere at elevated temperatures using a sealed pressure tube. The stoichiometry of the additive was shown to be critical with this species proposed to play a dual role in not only facilitating activation of the catalyst but also accelerating the alcoholysis step. The substrate scope highlighted broad functional group tolerance for both the 2-arylquinazolinones and the sulfoxonium ylides, with both aromatic and aliphatic derivatives exemplified for the latter, while the intermediate 11, arising from C–H activation/tandem cyclization, was isolated during the mechanistic studies.