Functionalized 2,5-disubstituted benzazepines: Stereoselective synthesis of 3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-2-carbonitrile and related derivatives

Article abstract of DOI:10.1055/s-2004-825618

A stereoselective synthesis of 2-carbonitrile and 2-aminomethyl-substituted 5-phenylbenzazepine derivatives was developed starting from [4-hydroxy-3-(methyloxy)phenyl]acetic acid. The key step in the synthesis is a stereoselective addition of cyanide to 3-methyl-1-phenyl-2,3-dihydro-1H-3- benzazepine (4) to give a 15:1 trans/cis mixture of 2-carbonitrile-5-phenyl benzazepine diastereomers 5a/5b in 83% yield. The stereochemistry of the major product was deduced by ¹H NMR NOESY analysis. The carbonitrile diastereomers could be separated and further manipulated by reduction to the corresponding aminomethyl derivatives 3a and 3b in a stereoselective manner. The aminomethyl benzazepine template 3 has potential to serve as a handle for the synthesis of a variety of derivatives modified at the 2-position of the benzazepine scaffold, as illustrated by an acylation of the primary amine of 3 followed by mild deprotection of the 7-phenol functionality.