The asymmetric Bischler–Napieralski reaction: preparation of 1,3,4-trisubstituted 1,2,3,4-tetrahydroisoquinolines

Abstract

The Bischler–Napieralski reaction, which is used to prepare dihydroisoquinolines from phenylethylamides, is demonstrated by the reaction of (S)-1-alkyl-1,2-diphenylethylamides with POCl3–P2O5. The reaction generated 3-alkyl-4-phenyl-1,2-dihydroisoquinolines with stereochemical selectivities of 80–91% de depending on the alkyl and the acetamide substituents. These are the first examples of the asymmetric Bischler–Napieralski reaction where cyclisation discriminates between two identical diastereotopic aryl groups. Reduction of the resultant dihydroisoquinoline products with LiAlH4 generated the corresponding 1,2,3,4-tetrahydroisoquinolines in a stereoselective manner, carrying three stereogenic centres at C(1), C(3) and C(4).