Synthesis of Pyrrolotriazoloisoquinoline Frameworks by Intramolecular Cu-Mediated or Free Radical Arylation of Triazoles

The cyclization of (2-bromophenyl)pyrrolyl-1,2,4-triazoles via copper-mediated intramolecular direct C-arylation of 1,2,4-triazoles was first accomplished under triazole-NHC control to give unknown fused heterocyclic skeletons, pyrrolo[3,2-c][1,2,4]triazolo[5,1-a] or [3,4-a]isoquinolines. The primary products underwent a triazole ring opening under the basic arylation conditions, providing N-(1H-pyrrolo[3,2-c]isoquinolin-5-yl)cyanamides. The formation of the cyanamides from isomeric pyrrolo[3,2-c][1,2,4]triazolo[3,4-a]isoquinolines involves, besides the triazole ring opening, the unusual migration of the cyano group. Cyanamides can be easily reduced to 1H-pyrrolo[3,2-c]isoquinolin-5-amines, the first NH2-substituted derivatives of 1H-pyrrolo[3,2-c]isoquinoline. An insight into the mechanism of the triazole ring cleavage was achieved by performing a DFT study at the B3LYP/6-31G+(d,p) level. Free radical cyclization of (2-bromophenyl)pyrrolyl-1,2,4-triazoles with TTMSS/AIBN under neutral conditions allows obtaining pyrrolo[3,2-c][1,2,4]triazolo[5,1-a] and [3,4-a]isoquinolines, as well two more new heterocyclic systems, pyrrolo[3,4-c][1,2,4]triazolo[5,1-a] and [3,4-a]isoquinolines, in good yields without triazole ring cleavage. The developed cyclizations provide a concise, atom-economical route to novel fluorescent fused polyheterocycles containing pyrrole and 1,2,4-triazole moieties.