Synthesis of Non-Symmetrical and Atropisomeric Dibenzo[1,3]diazepines: Pd/CPhos-Catalysed Direct Arylation of Bis-Aryl Aminals

Abstract

Pd/CPhos-catalysis provides direct arylation/cyclisation of methylene-linked bis-anilines to dibenzo[1,3]diazepines v, which are both non-(C2)-symmetrical and axially chiral. Synthesis of the direct arylation substrates commences with substitution of (N-acyl)anilines to methylene methyl sulfide derivatives, followed by halogenation/de-thiomethylation to N-(chloromethyl)anilines. These are substituted with a second aniline derivative, allowing modular preparation of (ortho-halo)aryl-aminal-linked arenes 4. The C–H functionalising direct arylation conditions were adapted from Fagnou and co-workers: substrates and potassium carbonate were heated in dimethylacetamide in the presence of palladium acetate and an electron-rich and sterically hindered biarylphosphine ligand, here CPhos 5. These conditions delivered the C1-(a)symmetric dibenzo[1,3]diazepine targets, which, due to torsion around the axis of the newly formed biaryl bond, are also intrinsically atropisomeric. The axially twisted scaffold is known to impart special properties to ligands/catalysts when the products are further converted into the corresponding seven-membered ring-containing N-heterocyclic carbenes (e.g. xii and xiv).