A Synthesis of 2,3,4,5-Tetrahydro-1H-3-benzazepines via Pummerer-Type Cyclization of N-(2-Arylethyl)-N-(2-phenylsulfinylethyl)formamides

Abstract

A construction of 2,3,4,5-tetrahydro-1H-3-benzazepine ring system (7) was achieved via Pummerer-type cyclization of N-(2-arylethyl)-N-2-(phenylsulfinylethyl)formamides (6).This route produced the benzazepines ( 10) and ( 11) in six steps starting from readily available 2-arylethylamines (2) and 2-chloroethyl phenyl sulfide.2,3,4,5-Tetrahydro-1H-3-benzazepine derivatives have received considerable attention, in part due to their interesting pharmacological activities observed in the compounds (1), a class of dopamine receptor antagonists and neuroleptics. 1In a series of paper we reported the synthesis of 1,2,3,4-tetrahydroisoquinolines, 2 and 1,2,3,4-tetrahydroquinolines 3 using an aromatic cyclization of the in situ formed thionium ion generated under the acidic conditions from a sulfinyl precursor (Pummerer reaction). 4We now describe a further extension of this method to the synthesis of 2,3,4,5-tetrahydro-1H-3-benzazepines. 5 Preparation of SulfoxidesN-( 2-Arylethyl)-N-(2-phenylsulfinylethyl)formamides (6a-b), substrates of the Pummerer-type cyclization, were prepared from 2-arylethylamines (2a-b) via the route shown in Scheme 1.A mixture of 2a-b and 2-chloroethyl phenyl sulfide in dioxane was heated under reflux for 3 days in the presence of a phase transfer catalyst to afford secondary amines (3a-b) in good yields, although the undesired dialkyl derivatives (4a-b) were accompanied as a minor product.The amines (3a-b) were then treated with formic acid-acetic anhydride to give N-formyl derivatives (5a-b).Oxidation of 5a-b with sodium metaperiodate in aqueous methanol gave sulfoxides (6a-b) in good overall yields.