Decarboxylative cross-nucleophile coupling via ligand-to-metal charge transfer photoexcitation of Cu(II) carboxylates

Abstract

Reactions that enable carbon-nitrogen, carbon-oxygen and carbon-carbon bond formation lie at the heart of synthetic chemistry. However, substrate prefunctionalization is often needed to effect such transformations without forcing reaction conditions. The development of direct coupling methods for abundant feedstock chemicals is therefore highly desirable for the rapid construction of complex molecular scaffolds. Here we report a copper-mediated, net-oxidative decarboxylative coupling of carboxylic acids with diverse nucleophiles under visible-light irradiation. Preliminary mechanistic studies suggest that the relevant chromophore in this reaction is a Cu(II) carboxylate species assembled in situ. We propose that visible-light excitation to a ligand-to-metal charge transfer (LMCT) state results in a radical decarboxylation process that initiates the oxidative cross-coupling. The reaction is applicable to a wide variety of coupling partners, including complex drug molecules, suggesting that this strategy for cross-nucleophile coupling would facilitate rapid compound library synthesis for the discovery of new pharmaceutical agents.

Fig. 1 |. Common strategies for decarboxylative coupling usually involve prefunctionalizations of either or both reacting partners while the current strategy enables direct decarboxylative coupling.

a, Redox-neutral cross-couplings of carboxylic acid feedstocks. b, Use of redox-active PINO and iodinane esters for formal decarboxylative coupling reactions. c, Proposed design plan for oxidative decarboxylative cross-couplings employing visible-light photoactive Cu(II) carboxylates.

Fig. 2 |. Mechanistic studies.

a, The guiding mechanistic hypothesis for this reaction involves MLCT photoexcitation of a preassembled Cu(II) carboxylate complex, spontaneous decarboxylation of the resulting carboxyl radical, and Cu(II)-mediated oxidative coupling of the corresponding radical. b, Decarboxylative cyclization under Ritter amidation conditions is consistent with a putative radical intermediate. c, Decarboxylative ring-opening of a radical clock substrate. d, UV-vis titration study to interrogate the interaction between the carboxylate derived from 1a and Cu(II). An initial species is formed with λ_max = 304 nm at low carboxylate loadings, which transitions to a blue-shifted species (λ_max = 260 nm) at high carboxylate loadings. The species formed at high carboxylate loadings is photochemically inactive at 427 nm, in line with the empirically optimized conditions. e, UV irradiation at high acid equivalents still leads to radical generation, but chemoselective formation of dimer 78 is observed in lieu of the expected product 2.