Free-radical cyclization approach to polyheterocycles containing pyrrole and pyridine rings.

A wide range of derivatives with new pyrido[2,1-a]pyrrolo[3,4-c]isoquinoline skeleton was synthesized by free-radical intramolecular cyclization of o-bromophenyl-substituted pyrrolylpyridinium salts using the (TMS)3SiH/AIBN system. The cyclization provides generally good yields of pyrido[2,1-a]pyrrolo[3,4-c]isoquinoline hydrobromides having no additional radical-sensitive substituents. The free bases can be obtained from the synthesized hydrobromides in quantitative yield by basification at room temperature. The selectivity control of intramolecular arylation was achieved by replacing the halogen: the use of 1-(2-(ortho-bromophenyl)-4-(ortho-iodophenyl)pyrrol-3-yl)pyridinium bromide makes it possible to obtain a monocyclization product, and the bicyclization product from the dibromo derivative. The procedure is also applicable to obtain 3-arylpyrido[2,1-a]pyrrolo[3,2-c]isoquinoline derivatives including 2-unsubstituted skeletons that are inaccessible via Pd-catalyzed cyclization.

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.