Extended fused N-heterocycles are generally accessible through metal-catalyzed C-H bond activation which involve harsh conditions, expensive catalysts and limited functional group tolerance. These synthetic limitations inspired us to search for a simpler and versatile methodology to attain these heterocycles. Herein, we utilized an anionic approach to access multicyclic N-heteroarene isoquinoline 3 and benzazepine 4 via a two-step cyclization of bis-alkynyl amide 1. The first intramolecular cyclization step readily undergoes 5-exo-dig ring closure under anionic conditions and yields the isoindolinone 2. However, the second intramolecular cyclization step to provide the polycyclic products can proceed through one of two pathways: 6-exo-dig to access isoquinoline 3 or 7-endo-dig to access benzazepine 4. The regioselectivity can be controlled to provide either 3 or 4 through diyne 1, notably by variation of the R-substituents at the terminal alkyne position. A combination of stereoelectronic and steric effects provides control over the regioselectivity, where electron-withdrawing R-substituents stabilizes the 6-exo-dig pathway while non-sterically demanding donating groups favour the 7-endo-dig cyclization. Computational experiments were performed to assess the energy profiles for each cyclization pathway, providing insight to the selectivity of the cyclization processes.

Sequential anionic intramolecular cyclization of bis-alkynylarene amides toward polycyclic isoindolo-isoquinolines and -benzazepines: Regioselectivity study

2019 Fall National Meeting

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