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

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 H 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 , for the conformational exchange process in 14 was estimated to be 57 kJ mol 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.