A SYNTHESIS OF MONOMETHOXY-1,2,3,4-TETRAHYDROISOQUINOLINE AND DIMETHOXY-1,2,3,4-TETRAHYDROISOQUINOLINE VIA PUMMERER REACTION - EFFECTS OF METHOXYL GROUPS ON INTRAMOLECULAR CYCLIZATION

A synthesis of 1,2,3,4-tetrahydroisoquinolines (TIQs) (23) with one an d two methoxyl groups at various positions of the benzene ring was ach ieved via the intramolecular cyclization of N-(aryl)methyl-2-(phenylsu lfinyl)ethylamines (9) using the Pummerer reaction as a hey step. The reaction was carried out by using trifluoroacetic anhydride (TFAA) (me thod A) or TFAA-BF3.Et2O (method B), The cyclization to 4-SPhTIQs (11) proceeded effectively when the reaction center at the benzene ring wa s electronically activated by a methoxyl group, In the reaction of the sulfoxide (9e) having two OMe groups at orthro- and para-positions a different cyclization reaction leading to a benzothiazepine (12) was o bserved, indicating that the high nucleophilicity of the benzene ring caused the unexpected reaction prior to the cyclization to 4-SPhTIQ (1 1e), The route starting from methoxylated benzaldehydes (5) was proved to provide an efficient and convenient method of TIQ synthesis which should be complementary to the well known Pictet-Spengler method.