A synthesis of mono- and dimethoxy-1,2,3,4-tetrahydroisoquinolines via Pummerer reaction: Effects of methoxyl groups on intramolecular cyclization

Article abstract of DOI:10.1248/cpb.46.918

A synthesis of 1,2,3,4-tetrahydroisoquinolines (TIQs) (23) with one and two methoxyl groups at various positions of the benzene ring was achieved via the intramolecular cyclization of N-(aryl)methyl-2- (phenylsulfinyl)ethylamines (9) using the Pummerer reaction as a key step. The reaction was carried out by using trifluoroacetic anhydride (TFAA) (method A) or TFAA-BF₃ · Et₂O (method B). The cyclization to 4-SPhTIQs (11) proceeded effectively when the reaction center at the benzene ring was electronically activated by a methoxyl group. In the reaction of the sulfoxide (9e) having two OMe groups at ortho- and para-positions a different cyclization reaction leading to a benzothiazepine (12) was observed, indicating that the high nucleophilicity of the benzene ring caused the unexpected reaction prior to the cyclization to 4-SPhTIQ (11e). 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.

Full text of DOI:10.1248/cpb.46.918

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