Tandem Prins/Friedel–Crafts cyclization for stereoselective synthesis of heterotricyclic systems

Abstract

Homoallylic substrates such as (E)-6-arylhex-3-enyl alcohols, N-tosylamides, and thiols undergo smooth cross-coupling with various aldehydes in the presence of 10 mol % Sc(OTf)(3) and 30 mol % TsOH to afford the trans-fused hexahydro-1H-benzo[f]isochromenes, N-tosyloctahydrobenzo[f]isoquinolines, and hexahydro-1H-benzo[f]isothiochromenes, respectively. However, the cross-coupling of (Z)-olefins such as 6-arylhex-3-enyl alcohols, N-tosylamides, and thiols with aldehydes affords the corresponding hexahydro-1H-benzo[f]isochromenes, N-tosyloctahydrobenzo[f]isoquinolines, and hexahydro-1H-benzo[f]isothiochromenes with complete cis selectivity via intramolecular Prins-, aza-Prins-, and thia-Prins/Friedel-Crafts cyclizations, respectively. Though the Prins cyclization proceeds smoothly under the influence of Sc(OTf)(3), high conversions and enhanced reaction rates are achieved using a mixture of Sc(OTf)(3) and TsOH (1:3).