Regioselective Friedel–Crafts acylation of 2,3,4,5-tetrahydro-1H-2-benzazepine and related nitrogen heterocycles

Abstract

It is revealed that NH-protected 2,3,4,5-tetrahydro-1H-2-benzazepine 4 is acylated on C-8 with greater than 95% regioselectivity. This regioselectivity has been applied to the synthesis of 3-(1-benzylpiperidin-4-yl)-1-(2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl)propan-1-one 3a, an inhibitor of acetylcholinesterase (AChE). The regioselectivities of the acylation of the following nitrogen heterocycles have also been studied: 4-formyl-2,3,4,5-tetrahydro-1,4-benzoxazepine 6, 2,3,4,5-tetrahydro-1H-2-benzazepin-3-one 7, 2,3,4,5-tetrahydro-1H-3-benzazepin-2-one 8, 7,11b,12,13-tetrahydro-5H-isoindolo[2,1-b][2]benzazepin-7-one 9 and 6,7,9,13b-tetrahydro-5H-isoindolo[1,2-a][2]benzazepin-9-one 10. A molecular orbital (MO) calculation on the Lewis acid coordinated substrates has been used for predicting regioselectivity.