Benefiting from the impressive increase in fundamental knowledge, the last 20 years have shown a continuous burst of new ideas and consequently a plethora of new catalytic methods for enantioselective radical reactions. This review aims to provide a complete survey of progress achieved over this latter period. The first part of this review focuses on the use of chiral organocatalysts, and these include catalysts covalently linked to the substrate and those that interact with the substrate by weaker interactions like hydrogen bonds. The second part of the review is devoted to transition-metal redox catalysis which is organized according to increasing atomic number for the first-row transition metals (Ti, Cr, Fe, Mn, Co, Ni, Cu). Bioinspired manganese- and iron-mediated hydroxylations and oxidations are also discussed. A specific section is dedicated to the reactivity of Ru, Rh, and Ir complexes as Lewis acids with a special focus on complexes chiral at metal. Absorption of photons result in different events such as energy transfer, single-electron transfer, and hydrogen-atom transfer facilitating the formation of radicals. Organocatalysis has been successfully combined with photocatalysts, a reactivity which has opened new pathways enlarging the number of radical precursors available. The merger of photocatalysis with organo- or metalla-photocatalysis has brought novelty and allowed for the discovery of a large number of original transformations. The use of enzyme-catalyzed reactions involving radical intermediates which also largely benefit from visible-light irradiation are included in the review. This review provides a comprehensive inventory of progress in enantioselective radical reactions with a goal of detailing the reaction mechanisms involved in these transformations such that any nonspecialist could find their own creativity to invent yet unknown applications.

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Enantioselective Radical Reactions Using Chiral Catalysts.

The chemistry of nitrogen-centered radicals (NCRs) has plentiful applications in organic synthesis, and they continue to expand as our understanding of these reactive species increases. The utility of these reactive intermediates is demonstrated in the recent advances in C-H amination and the (di)amination of alkenes. Synthesis of previously challenging structures can be achieved by efficient functionalization of sp2 moieties without prefunctionalization, allowing for faster and more streamlined synthesis. This Review addresses the generation, reactivity, and application of NCRs, including, but not limited to, iminyl, aminyl, amidyl, and aminium species. Contributions from early discovery up to the most recent examples have been highlighted, covering radical initiation, thermolysis, photolysis, and, more recently, photoredox catalysis. Radical-mediated intermolecular amination of (hetero)arenes can occur with a variety of complex amine precursors, generating aniline derivatives, an important class of structures for drug discovery and development. Functionalization of olefins is achievable in high anti-Markovnikov regioselectivity and allows access to difunctionalized structures when the intermediate carbon radicals are trapped. Additionally, the reactivity of NCRs can be harnessed for the rapid construction of N-heterocycles such as pyrrolidines, phenanthridines, quinoxalines, and quinazolinones.

/pdf/nitrogen-centered-radicals-in-functionalization-of-sp2-13v6mjzs.pdf

Nitrogen-Centered Radicals in Functionalization of sp2 Systems: Generation, Reactivity, and Applications in Synthesis.

The 2,3-dihydrobenzofuran scaffold is widely found in natural products and biologically active compounds. Herein, dearomatizing 2,3-fluoroaroylation of benzofurans with aroyl fluorides as bifunctional reagents to access 2,3-difunctionalized dihydrobenzofurans is reported. The reaction that occurs by cooperative NHC/photoredox catalysis provides 3-aroyl-2-fluoro-2,3-dihydrobenzofurans with moderate to good yield and high diastereoselectivity. Cascades proceed via radical/radical cross-coupling of a benzofuran radical cation generated in the photoredox catalysis cycle with a neutral ketyl radical formed through the NHC catalysis cycle. The redox-neutral transformation exhibits broad substrate scope and high functional group compatibility. With anhydrides as bifunctional reagents, dearomatizing aroyloxyacylation of benzofurans is achieved and the strategy can also be applied to N-acylated indoles to afford 3-aroyl-2-fluoro-dihydroindoles.

https://pubs.acs.org/doi/pdf/10.1021/jacs.2c01735

Aroyl Fluorides as Bifunctional Reagents for Dearomatizing Fluoroaroylation of Benzofurans

Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations

Many organometallic iridium(III) complexes have photoactive excited states with mixed metal-to-ligand and intraligand charge transfer (MLCT/ILCT) character, which form the basis for numerous applications in photophysics and photochemistry. Cobalt(III) complexes with analogous MLCT excited-state properties seem to be unknown yet, despite the fact that iridium(III) and cobalt(III) can adopt identical low-spin d6 valence electron configurations due to their close chemical relationship. Using a rigid tridentate chelate ligand (LCNC), in which a central amido π-donor is flanked by two σ-donating N-heterocyclic carbene subunits, we obtained a robust homoleptic complex [Co(LCNC)2](PF6), featuring a photoactive excited state with substantial MLCT character. Compared to the vast majority of isoelectronic iron(II) complexes, the MLCT state of [Co(LCNC)2](PF6) is long-lived because it does not deactivate as efficiently into lower-lying metal-centered excited states; furthermore, it engages directly in photoinduced electron transfer reactions. The comparison with [Fe(LCNC)2](PF6), as well as structural, electrochemical, and UV–vis transient absorption studies, provides insight into new ligand design principles for first-row transition-metal complexes with photophysical and photochemical properties reminiscent of those known from the platinum group metals.

/pdf/cobalt-iii-carbene-complex-with-an-electronic-excited-state-1rmpcwtw.pdf

Cobalt(III) Carbene Complex with an Electronic Excited-State Structure Similar to Cyclometalated Iridium(III) Compounds

We present here a review of the photochemical and electrochemical applications of multi-site proton-coupled electron transfer (MS-PCET) in organic synthesis. MS-PCETs are redox mechanisms in which both an electron and a proton are exchanged together, often in a concerted elementary step. As such, MS-PCET can function as a non-classical mechanism for homolytic bond activation, providing opportunities to generate synthetically useful free radical intermediates directly from a wide variety of common organic functional groups. We present an introduction to MS-PCET and a practitioner's guide to reaction design, with an emphasis on the unique energetic and selectivity features that are characteristic of this reaction class. We then present chapters on oxidative N-H, O-H, S-H, and C-H bond homolysis methods, for the generation of the corresponding neutral radical species. Then, chapters for reductive PCET activations involving carbonyl, imine, other X═Y π-systems, and heteroarenes, where neutral ketyl, α-amino, and heteroarene-derived radicals can be generated. Finally, we present chapters on the applications of MS-PCET in asymmetric catalysis and in materials and device applications. Within each chapter, we subdivide by the functional group undergoing homolysis, and thereafter by the type of transformation being promoted. Methods published prior to the end of December 2020 are presented.

Photochemical and Electrochemical Applications of Proton-Coupled Electron Transfer in Organic Synthesis.

The accumulation of persistent plastic waste in the environment is widely recognized as an ecological crisis. New chemical technologies are necessary both to recycle existing plastic waste streams into high-value chemical feedstocks and to develop next-generation materials that are degradable by design. Here, we report a catalytic methodology for the depolymerization of a commercial phenoxy resin and high molecular weight hydroxylated polyolefin derivatives upon visible light irradiation near ambient temperature. Proton-coupled electron transfer (PCET) activation of hydroxyl groups periodically spaced along the polymer backbone furnishes reactive alkoxy radicals that promote chain fragmentation through C-C bond β-scission. The depolymerization produces well-defined and isolable product mixtures that are readily diversified to polycondensation monomers. In addition to controlling depolymerization, the hydroxyl group modulates the thermomechanical properties of these polyolefin derivatives, yielding materials with diverse properties. These results demonstrate a new approach to polymer recycling based on light-driven C-C bond cleavage that has the potential to establish new links within a circular polymer economy and influence the development of new degradable-by-design polyolefin materials.

James H. Cox

Papers

Photochemical and Electrochemical Applications of Proton-Coupled Electron Transfer in Organic Synthesis.

Depolymerization of Hydroxylated Polymers via Light-Driven C-C Bond Cleavage.