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

In recent years, radical C–C bond cleavage reactions have been increasingly understood and used to perform transformations that complement traditional ionic processes. However, to date radical C–C bond cleavage/functionalization reactions have not been the subject of a dedicated review. Herein we summarize the most recent and significant developments in the radical activation and functionalization of carbon–carbon bonds, with an emphasis on both synthetic outcomes and reaction mechanisms, and highlight how these radical C–C bond cleavage reactions enable challenging transformations.

Cleavage of carbon-carbon bonds by radical reactions.

The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them.

Visible light photocatalysis in the late-stage functionalization of pharmaceutically relevant compounds.

Just as "Deconstructivism" appeared as a novel movement in architecture in the 1980s, deconstructive approaches have recently emerged as excellent strategies for scaffold hopping modifications in chemistry. The deconstruction and functionalization of cyclic molecules mainly involves the cleavage of the carbon-carbon (C-C) bond followed by the construction of new bonds. The cleavage of inert C-C single bonds, especially in unstrained cycles, and their subsequent functionalization is still one of the most sought-after challenges in chemistry. In this vein, radical-mediated strategies provide an excellent approach for achieving this aim. This minireview is an outline of the history of homolytic cleavage and highlights the recent advances in exploring new chemical space by deconstructive functionalization.

Radical-Promoted C-C Bond Cleavage: A Deconstructive Approach for Selective Functionalization.

Herein, we report a nickel-catalyzed allylic defluorinative alkylation of trifluoromethyl alkenes through reductive decarboxylation of redox-active esters. The present reaction enables the preparation of functionalized gem-difluoroalkenes with the formation of sterically hindered C(sp3)–C(sp3) bonds under very mild reaction conditions, while tolerating many sensitive functional groups and requiring minimal substrate protection. Therefore, this method provides an efficient and convenient approach for late-stage modification of biologically interesting molecules.

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Nickel-catalyzed allylic defluorinative alkylation of trifluoromethyl alkenes with reductive decarboxylation of redox-active esters

A copper-catalyzed system has been introduced for the enantioselective defluoroalkylation of linear 1-(trifluoromethyl)alkenes through C–F activation to synthesize various gem-difluoroalkenes as carbonyl mimics. For the first time, arylboronate-activated alkyl Grignard reagents were uncovered in this cross-coupling reaction. Mechanistic studies confirmed that the tetraorganoborate complexes generated in situ were the key reactive species for this transformation.

Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents.

A series of in situ formed alkenyl diboronate complexes from alkenyl Grignard reagents (commercially available or prepared from alkenyl bromides and Mg) with B2 Pin2 (bis(pinacolato)diboron) react with diverse alkyl halides by a Ru photocatalyst to give various gem-bis(boryl)alkanes. Alkyl radicals add efficiently to the alkenyl diboronate complexes, and the adduct radical anions undergo radical-polar crossover, specifically, a 1,2-boryl-anion shift from boron to the α-carbon sp2 center. This transformation shows good functional-group compatibility and can serve as a powerful synthetic tool for late-stage functionalization in complex compounds. Measurements of the quantum yield reveal that a radical-chain mechanism is operative in which the alkenyl diboronates acts as reductive quencher for the excited state of the photocatalyst.

An Olefinic 1,2-Boryl-Migration Enabled by Radical Addition: Construction of gem-Bis(boryl)alkanes.

A novel rearrangement of cycloketoxime esters to cyano-containing benzoates beyond the traditional Beckmann and Neber rearrangement process has been established in the presence of photocatalysis catalysis. This SET-induced structural reorganization of cycloketoxime esters is perfectly an atom economic process and distinguished by mild and safe reaction conditions that avoid acid, base and toxic cyanide salts.

Photoinduced fragmentation-rearrangement sequence of cycloketoxime esters

An efficient method for photocatalytic perfluoroalkylation of vinyl-substituted all-carbon quaternary centers involving 1,2-aryl migration has been developed. The rearrangement reactions use fac-Ir(ppy)3 , visible light and commercially available fluoroalkyl halides and can generate valuable multisubstituted perfluoroalkylated compounds in a single step that would be challenging to prepare by other methods. Mechanistically, the photoinduced alkyl radical addition to an alkene leads to the migration of a vicinal aryl substituent from its adjacent all-carbon quaternary center with the concomitant generation of a C-radical bearing two electron-withdrawing groups that is further reduced by a hydrogen donor to complete the domino sequence.

Zexian Li

Papers

Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents.

An Olefinic 1,2-Boryl-Migration Enabled by Radical Addition: Construction of gem-Bis(boryl)alkanes.

Photoinduced fragmentation-rearrangement sequence of cycloketoxime esters

Radical Addition Enables 1,2-Aryl Migration from a Vinyl-Substituted All-Carbon Quaternary Center

Diverse strategic approaches en route to Taxol total synthesis