Axial stereocontrol in tropos dibenz[c,e]azepines: the individual and cooperative effects of alkyl substituents

Abstract

6,7-Dihydro-5H-dibenz[c,e]azepines, a class of secondary amine incorporating a centre-axis chirality relay, can be prepared from N-(2-bromobenzyl)-N-(1-arylalkyl)methanesulfonamides via Pd-catalysed intramolecular direct arylation, and methylated at C(7) via the 5,7-trans diastereoselective addition of methylmagnesium bromide to the derived N-benzylazepinium tetraphenylborate. Using these methods, the 4,5-dimethylated and 4,5,7-trimethylated homologues 13 and 14 were obtained and shown by ¹H NMR spectroscopy to be axially biased in opposite senses, as defined by the respective pseudoaxial or pseudoequatorial orientation of the 5-substituent in the preferred conformers, while retaining their tropos nature (the Arrhenius activation energy, E_A, for the conformational exchange process in 14 was estimated to be 57 kJ mol⁻¹ using 2D-EXSY NMR spectroscopy at 233–248 K). These results serve to illustrate how substituent effects might be exploited in new designs of bridged biaryl ligand in which tropos dynamics operate in combination with a pre-existing axial stereochemical bias.