Iron-Catalyzed Friedel-Crafts Synthesis of Dihydro- and Tetrahydroisoquinolines

Significance

A mild and versatile method for the synthesis of substituted dihydro- and tetrahydro­isoquinolines using an intramolecular Friedel-Crafts reaction of propargylic alcohols is reported. The propargylic alcohols are readily synthesized from aromatic aldehydes, benzyl amines, or benzylic alcohols in 3-4 steps (V. Terrasson et al. Adv. Synth. Catal. 2006, 348, 2063). The cyclization is effected by catalytic amounts of a Lewis acid, a number of which gave comparable yields; the choice for the use of FeCl₃ was based on its low cost. A Brønsted acid, such as p-toluene sulfonic acid (PTSA) did not yield the desired isoquinoline but instead afforded a Meyer-Schuster rearrangement product (an open-ring ene-ketone, see: C. Y. Lorber et al. Tetrahedron Lett. 1996, 37, 853). In general, tetrahydroisoquinolines A were formed in moderate to excellent yields although in two cases the isomerized dihydroisoquinolines B were obtained. The allene products A were isomerized into the dihydroisoquinolines B by treatment with PTSA. The substrate scope was moderately studied but not tested thoroughly in terms of R¹ = EWG effects.