Thermal C-C bond cleavage reactions allow the construction of structurally diverse molecular skeletons via predictable and efficient bond reorganizations. Visible light photoredox-catalyzed radical-mediated C-C bond cleavage reactions have recently emerged as a powerful alternative method for overcoming the thermodynamic and kinetic barrier of C-C bond cleavage in diverse molecular scaffolds. In recent years, a plethora of elegant and useful reactions have been invented, and the products are sometimes otherwise inaccessible by classic thermal reactions. Considering the great influence and synthetic potential of these reactions, we provide a summary of the state of art visible light-driven radical-mediated C-C bond cleavage/functionalization strategies with a specific emphasis on the working models. We hoped that this review will be useful for medicinal and synthetic organic chemists and will inspire further reaction development in this interesting area.

Visible Light-Driven Radical-Mediated C-C Bond Cleavage/Functionalization in Organic Synthesis

Radical-radical couplings are mostly nearly diffusion-controlled processes. Therefore, the selective cross-coupling of two different radicals is challenging and not a synthetically valuable transformation. However, if the radicals have different lifetimes and if they are generated at equal rates, cross-coupling will become the dominant process. This high cross-selectivity is based on a kinetic phenomenon called the persistent radical effect (PRE). In this Review, an explanation of the PRE supported by simulations of simple model systems is provided. Radical stabilities are discussed within the context of their lifetimes, and various examples of PRE-mediated radical-radical couplings in synthesis are summarized. It is shown that the PRE is not restricted to the coupling of a persistent with a transient radical. If one coupling partner is longer-lived than the other transient radical, the PRE operates and high cross-selectivity is achieved. This important point expands the scope of PRE-mediated radical chemistry. The Review is divided into two parts, namely 1) the coupling of persistent or longer-lived organic radicals and 2) "radical-metal crossover reactions"; here, metal-centered radical species and more generally longer-lived transition-metal complexes that are able to react with radicals are discussed-a field that has flourished recently.

The Persistent Radical Effect in Organic Synthesis

Advances in nickel-catalyzed cross-coupling reactions have expanded the chemical space of accessible structures and enabled new synthetic disconnections. The unique properties of Ni catalysts facilitate the activation of traditionally inert substrates, tolerate alkyl coupling partners that undergo decomposition via β-hydride (β-H) elimination with Pd, and enable stereoconvergent cross-couplings. The radical pathways accessed by Ni catalysts have been merged with photoredox and electrochemical catalysis to achieve new reactivity. The growing utility of Ni catalysis is, in no small part, due to advances in our fundamental understanding of the properties of Ni catalysts and the mechanisms by which the reactions occur. This review highlights recent important contributions to the field with an emphasis on studies that have afforded mechanistic insight.

Mechanisms of Nickel-Catalyzed Cross-Coupling Reactions

In recent years, visible light-induced transition metal catalysis has emerged as a new paradigm in organic photocatalysis, which has led to the discovery of unprecedented transformations as well as the improvement of known reactions. In this subfield of photocatalysis, a transition metal complex serves a double duty by harvesting photon energy and then enabling bond forming/breaking events mostly via a single catalytic cycle, thus contrasting the established dual photocatalysis in which an exogenous photosensitizer is employed. In addition, this approach often synergistically combines catalyst-substrate interaction with photoinduced process, a feature that is uncommon in conventional photoredox chemistry. This Review describes the early development and recent advances of this emerging field.

Visible Light-Induced Transition Metal Catalysis.

Hantzsch esters were often previously used as reductants in thermal catalytic hydrogenation reactions. Over the last few decades, Hantzsch esters have proven to be a useful class of electron donors and proton sources in photoredox catalyzed processes. Moreover, under photoredox catalytic conditions, alkyl-1,4-dihydropyridines can serve as versatile types of alkylation reagents via oxidative fragmentation mechanisms. This minireview highlights the recent advances in the chemistry of Hantzsch esters in photoredox catalyzed organic synthesis, with particular emphasis placed on reaction mechanisms. We hope that this review will inspire further new reaction design and developments with such a class of readily accessible reagents.

Hantzsch esters: an emerging versatile class of reagents in photoredox catalyzed organic synthesis

DNA-encoded library (DEL) technology is a powerful tool commonly used by the pharmaceutical industry for the identification of compounds with affinity to biomolecular targets. Success in this endeavor lies in sampling diverse chemical libraries. However, current DELs tend to be deficient in C(sp3) carbon counts. We report unique solutions to the challenge of increasing both the chemical diversity of these libraries and their C(sp3) carbon counts by merging Ni/photoredox dual catalytic C(sp2)-C(sp3) cross-coupling as well as photoredox-catalyzed radical/polar crossover alkylation protocols with DELs. The successful integration of multiple classes of radical sources enables the rapid incorporation of a diverse set of alkyl fragments.

Katelyn Billings

Papers

Open-Air Alkylation Reactions in Photoredox-Catalyzed DNA-Encoded Library Synthesis.

Multifunctional Building Blocks Compatible with Photoredox-Mediated Alkylation for DNA-Encoded Library Synthesis.