DFT-Aided Modular Synthesis of Aryl- and Heteroaryl-Annulated Carbazoles Catalyzed by Brønsted Acid.

A metal-free, DFT-aided, and modular strategy is reported for the synthesis of seven distinct classes of aryl/heteroaryl-annulated carbazoles and their key intermediates, using ketones bearing hydroxy/halogen leaving groups as versatile synthons. Initial reactions under standard acidic conditions afforded α-indolyl ketones rather than the intended carbazoles, prompting the use of DFT calculations to map free energy profiles. These calculations revealed competing carbonyl/hydroxy pathways, guiding the optimization of reaction conditions (toluene/TsOH, reflux, argon protection) to achieve high-yielding synthesis of benzo[a]carbazoles. The strategy expands the substrate scope to include primary α-hydroxy ketones (previously forming inseparable mixtures), 2-thienylindoles/2-furylindoles (affording pentacyclic analogs), and α-haloketones with electron-donating/sterically bulky substituents. Mechanistic flexibility was uncovered in the reactions of 2,2'-biindole, where nucleophilic and electrocyclic pathways converged to the same indolo[2,3-a]carbazole product. This work addresses critical limitations of existing methods (expensive metal catalysts, residual metal contamination, narrow substrate scope) and provides a practical platform for carbazole synthesis in medicinal and materials chemistry.