Bismuth radical catalysis in the activation and coupling of redox-active electrophiles

Abstract

Radical cross-coupling reactions represent a revolutionary tool to make C(sp³)-C and C(sp³)-heteroatom bonds by means of transition metals and photoredox or electrochemical approaches. However, the use of main-group elements to harness this type of reactivity has been little explored. Here we show how a low-valency bismuth complex is able to undergo one-electron oxidative addition with redox-active alkyl-radical precursors, mimicking the behaviour of first-row transition metals. This reactivity paradigm for bismuth gives rise to well-defined oxidative addition complexes, which could be fully characterized in solution and in the solid state. The resulting Bi(III)-C(sp³) intermediates display divergent reactivity patterns depending on the α-substituents of the alkyl fragment. Mechanistic investigations of this reactivity led to the development of a bismuth-catalysed C(sp³)-N cross-coupling reaction that operates under mild conditions and accommodates synthetically relevant NH-heterocycles as coupling partners.

Fig. 1. Unlocking single-electron oxidative-addition processes for bismuth.

a, Merging pnictogen reactivity (left: polar, two-electron pathways dominate) with first-row transition-metal behaviour (right: radical, one-electron processes dominate) to unveil the oxidative addition of redox-active alkyl-radical precursors to bismuth(I) via SET. b, Development of a bismuth-catalysed C–N cross-coupling reaction through the study of the radical behaviour of alkyl-bismuth(III) complexes. OA, oxidative addition; RE, reductive elimination; Boc, tert-butoxycarbonyl; Ts, 4-toluenesulfonyl; Pn, pnictogen. R = tert-butyl.

Fig. 2. Oxidative additions to bismuth(I).

a, Evaluating electronically different (polar, E_p/2 < –2.0 V, versus radical, E_p/2 > –2.0 V) oxidative additions to bismuthinidene 1 (left). Cyclic voltammetry of 1 (right). b, Stable oxidative-addition complexes accessed via S_N2 (5–8 and 14) or SET (9–13) mechanisms. c, Evidence for alkyl-radical formation after oxidative addition. ^a Cyclic voltammetry recorded in MeCN, potential in V versus Fc^0/+. ^b Cyclic voltammetry recorded in MeCN (ref. ); potential in V versus Fc^0/+ converted from V versus saturated calomel electrode (−2.13 V). ^c Yields and conversions determined by ¹H NMR, unless noted otherwise. Ts, 4-toluenesulfonyl; MsO, mesylate.

Fig. 3. Divergent reactivity of an unbiased alkyl-bismuth complex and an α-amino alkyl-bismuth complex.

a, Stable unbiased alkyl-bismuth(III) intermediates displaying typical alkyl-radical reactivity (left) and unstable α-amino alkyl-bismuth(III) complexes that evolve into iminium ion intermediates upon release of bismuth(I) (right). b, Development of a bismuth-catalysed C–N cross-coupling reaction based on the oxidation of α-amino alkyl radicals. ^aStandard reaction conditions: 22 (1 equiv.) and 25 (3 equiv.) in the presence of bismuthinidene 1 (10 mol%) in DMA (0.033 M) at 25 °C for 2 h. Yields determined by ¹H NMR using diphenylmethane as internal standard. Ts, 4-toluenesulfonyl; Boc, tert-butoxycarbonyl.

Fig. 4. Proposed mechanistic rationale.

The C–N cross-coupling reaction of α-amino and α-oxo acids via bismuth(I)-catalysed SET. The graph shows EPR analysis of 23. R³R⁴NH, NH-heterocycle; OA, oxidative addition; Boc, tert-butoxycarbonyl.