Heck reaction of ortho-substituted iodobenzenes with α,β-unsaturated nitriles as a key step in the synthesis of tetrahydro-2-benzazepines and hexahydro-3-benzazocines

A novel strategy is reported for the synthesis of tetrahydro-2-benzazepines 2 and hexahydro-3-benzazocines 3 comprising a Heck reaction of ortho-substituted iodobenzenes 6 and 14 with alpha,beta-unsaturated nitriles. Hydrogenation of the resulting alpha,beta-unsaturated nitriles 7, 11, 15, and 16 was followed by reductive cyclization. It was shown that the formation of 2-benzazepines was faster than the formation of 3-benzazocines, which was explained by the higher stability of the aliphatic dimethyl acetals in 17 and 18. The tetrahydro-2-benzazepine 2d with an N-butyl residue reveals very high sigma(1) affinity with a K-i-value of 2.0 nM. (C) 2013 Elsevier Ltd. All rights reserved.