Catalyst-Controlled Intermolecular Homobenzylic C(sp³)–H Amination for the Synthesis of β-Arylethylamines

Abstract

The combination of a tailored sulfamate with a C 4symmetrical rhodium(II) tetracarboxylate allows to uncover a selective intermolecular amination of unactivated homobenzylic C(sp 3 )−H bonds. The reaction has a broad scope (>30 examples) and proceeds with a high level of regioselectivity with homobenzylic/benzylic ratio of up to 35:1, thereby providing a direct access to β-arylethylamines that are of utmost interest in medicinal chemistry. Computational investigations evidenced a concerted mechanism, involving an asynchronous transition state. Based on a combined activation strain model and energy decomposition analysis, the regioselectivity of the reaction was found to rely mainly on the degree of orbital interaction between the [Rh 2 ]−nitrene and the C−H bond. The latter is facilitated at the homobenzylic position due to the establishment of specific noncovalent interactions within the catalytic pocket.

Enantioselective Nitrene Transfer to Hydrocinnamyl Alcohols and Allylic Alcohols Enabled by Systematic Exploration of the Structure of Ion-Paired Rhodium Catalysts

“…A continuing challenge in the field is that of developing generally applicable ligand strategies for asymmetric nitrene transfer . An established approach for rhodium paddlewheels involves the replacement of the achiral carboxylate ligands with chiral variants, as demonstrated in early work on amination of benzylic C–H bonds from Hashimoto et al, Müller et al, Davies and Reddy, and Du Bois and Zalatan and followed by recent important intermolecular contributions from Dauban et al (Figure a, left) . Very recently, Miller et al have developed novel peptide-derived carboxylate ligands, which, through a well-defined hydrogen bonding network, form a chiral pocket in which benzylic C–H amination occurs (Figure a, center). − Applied to aziridination, chiral Rh carboxylate complexes have been recently showcased by Dauban and co-workers as being very effective on trisubstituted styrenes and terminal aliphatic alkenes. , Using a distinct approach, Rh(III) Cp* complexes have also been used productively in enantioselective allylic amination and aziridination reactions.…”