Dual relay Rh-/Pd-catalysis enables β-C(sp3)-H arylation of α-substituted amines

Abstract

A dual relay catalytic protocol, built on reversible dehydrogenation of amines by Rh catalysis and C-H functionalisation of transient imines by Pd catalysis, is reported to enable regioselective arylation of amines at their unactivated β-C(sp³)-H bond. Notably, the new strategy is applicable to secondary anilines and N-PMP-protected primary aliphatic amines of intermediate steric demands, which is in contrast to the existing strategies that involve either free-amine-directed C-H activation for highly sterically hindered secondary aliphatic amines or steric-controlled migrative cross-coupling for unhindered N-Boc protected secondary aliphatic amines. Regioselectivity of the reaction is imposed by the electronic effects of transient imine intermediates rather than by the steric effects between specific starting materials and catalysts, thereby opening the uncharted scope of amines. In a broader sense, this study demonstrates new opportunities in dual relay catalysis involving hydrogen borrowing chemistry, previously explored in the functionalisation of alcohols, to execute otherwise challenging transformations for amines, commonly present in natural products, pharmaceuticals, biologically active molecules, and functional materials.

Fig. 1. Context & the current work.

Scheme 1. Design of β-arylation of amines in a dual-catalytic relay, building on reversible dehydrogenation of amines by [cat.HB] and arylation of transient imines by [Pd].

Fig. 2. Reaction development – effect of different catalysts and conditions. Yields determined by ¹H NMR analysis of reaction mixtures with an internal standard (1,3,5-trimethoxybenzene). ^aYield of isolated material reported in parentheses. ^bYield of 4aa with (tBu₃P)₂Pd (<5% for other entries).

Fig. 3. Scope of (hetero)aryl bromides and α-substituted amines. Both spectroscopic and isolated yields (in parenthesis) are reported; yields of isolated material are in some cases substantially lower than spectroscopic yields due to the difficulty of separating target products from remaining starting materials. ^a2 mol% Pd, 10 mol% Rh. ^bStandard conditions reported in Fig. 3, top.

Fig. 4. Control mechanistic experiments. ^aStandard conditions reported in Fig. 3. ^bYield of imine-3ah was measured upon HCl-mediated hydrolysis to a ketone derivative; for details, see the ESI.