Bruce Alan Arndtsen

We describe the use of visible light to activate Katritzky salts toward nickel-catalyzed carbonylative coupling reactions. Analysis suggests that this system avoids the classical inhibitory influence of carbon monoxide coordination on nickel catalysis, which has blocked access to this chemistry under thermal conditions, by instead using visible light photoexcitation of electron donor-acceptor adducts between the pyridinium salt and nitrogen donors to mediate carbon-nitrogen bond cleavage for subsequent nickel-mediated coupling. Overall, this opens a mild and versatile strategy to employ Katritzky salts in nickel-catalyzed carbonylation chemistry for the synthesis of esters and amides.

We describe herein a palladium-catalyzed carbonylative route for preparing substituted lactones from aliphatic bromoalcohols. This exploits the ability of photoexcited palladium catalysts to activate C(sp3)–bromides in concert with irreversible thermal reductive elimination to access substituted five-membered lactones under mild conditions, from available reagents, and where regioselectivity is defined by the substrate.

A modular strategy for the synthesis of fused indolizine/isoindole hybrids, pyrido[2,1‐α]isoindoles, via cycloaddition of pyridine‐based mesoionic 1,3‐dipoles with benzyne is described. The method is effective across a broad range of substituted 1,3‐dipoles derived from pyridinyl acid chlorides and imines, enabling the incorporation of aromatic groups bearing electron‐donating or electron‐withdrawing substituents, extended conjugation, or aliphatic substituents onto the heteroaromatic framework from readily available and stable reagents.

We describe a versatile method for using earth-abundant nickel catalysts in carbonylative coupling reactions. In this process, the wavelength-dependent excitation of a Xantphos-ligated nickel in concert with a weakly nucleophilic fluoride anion offers a route to build up acyl fluorides in high yield from classically unreactive C(sp³) bromides. Coupling the formation of the acyl fluorides with subsequent nucleophilic addition can be used to construct a diverse array of amides, esters, and thioesters via carbonylations.

Transition metal-catalyzed carbonylative coupling reactions play a crucial role in the synthesis of functional molecules of use throughout pharmaceutical development, natural products, and material science. This utility is driven by both the efficiency of carbonylation chemistry and the broad presence of the carbonyl functionality in most synthetic materials. Unfortunately, the development of enantioselective carbonylative coupling reactions of alkyl halides and nucleophiles to access the α-chiral motif found in most drugs is, to date, not viable. This has been attributed to the inhibitory influence of carbon monoxide, which blocks the activation of C(sp³)-halides and limits the efficacy of chiral ligand environments in modulating selectivity. Here, we show how this challenge can be addressed via a conceptually alternative approach to such reactions, where the coupling of photoredox and chiral nickel catalysis can be employed to separate reactivity from stereocontrol. This combined strategy has enabled the first asymmetric carbonylative coupling of benzylic and related C(sp³)-halides with amines and the preparation of a diverse array of chiral amides with excellent enantioselectivity. These findings expand the scope of enantioselective catalysis and offer new possibilities for synthesizing chiral carbonyl-containing compounds with wide-ranging implications for drug discovery and synthetic chemistry.

Palladium-catalyzed bond-forming reactions such as carbonylations offer an efficient and versatile avenue to access products from often feedstock reagents. However, the use of catalysts also comes with a cost, as their need to be regenerated after each product-forming cycle requires balancing thermal operations. The latter can lead to high barriers even with catalysts as well as restrict their application to many products. We introduce herein an alternative approach to palladium catalyst design, where instead electrochemical potential can drive catalysis by continual two-electron cycling of the metal oxidation state. The power behind these redox steps offers a route to carry out carbonylation reactions, including the catalytic synthesis of high-energy aroyl halide electrophiles, at unprecedentedly mild ambient temperature and pressure. More generally, analysis suggests this catalyst functions by a distinct multi-electron exchange pathway, where two-electron reduction enables oxidative addition and two-electron oxidation drives product elimination. The combination creates a unique platform where both these reverse operations are favored in the same system and with electrochemical potential energy as the only added energy source.

We describe the development of a nickel‐catalyzed route to prepare aliphatic isocyanates via carbonylation chemistry. Unlike thermal reactions, where the affinity of Ni(0) for carbon monoxide has traditionally limited its use in carbonylations, mechanistic studies suggest that visible light excitation of a Xantphos‐bound nickel catalyst can enable a radical pathway for the carbonylation of alkyl halides, while the CO‐bound nickel drives the formation of a reactive acyl azide product for rapid Curtius rearrangement. Coupling this transformation with subsequent nucleophilic reactions has opened a unique and modular pathway to apply carbonylations to the synthesis of an array of diversely substituted, unsymmetrical ureas and carbamates, including those of relevance to drug design.

We describe the development of a nickel‐catalyzed route to prepare aliphatic isocyanates via carbonylation chemistry. Unlike thermal reactions, where the affinity of Ni(0) for carbon monoxide has traditionally limited its use in carbonylations, mechanistic studies suggest that visible light excitation of a Xantphos‐bound nickel catalyst can enable a radical pathway for the carbonylation of alkyl halides, while the CO‐bound nickel drives the formation of a reactive acyl azide product for rapid Curtius rearrangement. Coupling this transformation with subsequent nucleophilic reactions has opened a unique and modular pathway to apply carbonylations to the synthesis of an array of diversely substituted, unsymmetrical ureas and carbamates, including those of relevance to drug design.

We describe here the development of a new class of palladium catalyzed multicomponent coupling reaction for the assembly of pyrido[2,1-α]isoindoles via the carbonylative coupling of imines, bromopyridines and aryne derivatives.