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.

A general and operationally convenient method for intermolecular amination of C(sp )-H bonds is described. This technology allows for efficient functionalization of complex molecules, including numerous pharmaceutical targets. The combination of pivalonitrile as a solvent, Al O as an additive, and phenyl sulfamate as a nitrogen source affords differential reaction performance and substrate scope. Mechanistic data strongly implicate a pathway for catalyst decomposition that initiates with solvent oxidation, thus providing rationale for the marked influence of pivalonitrile on this reaction process.

The preparation of substituted azetidines and larger ring, nitrogen-containing saturated heterocycles is enabled through efficient and selective intermolecular sp 3 -C−H amination of alkyl bromide derivatives. A range of substrates are demonstrated to undergo C−H amination and subsequent sulfamate alkylation in good to excellent yield. N-Phenoxysulfonylprotected products can be unmasked under neutral or mild basic conditions to yield the corresponding cyclic secondary amines. The preparative convenience of this protocol is demonstrated through gram-scale and telescoped multistep procedures. Application of this technology is highlighted in a nine-step total synthesis of an unusual azetidine-containing natural product, penaresidin B.

Ageneral and operationally convenient method for intermolecular amination of C(sp 3 )ÀHbonds is described. This technology allows for efficient functionalization of complex molecules,i ncluding numerous pharmaceutical targets.T he combination of pivalonitrile as asolvent, Al 2 O 3 as an additive, and phenyl sulfamate as an itrogen source affords differential reaction performance and substrate scope.M echanistic data strongly implicate ap athway for catalyst decomposition that initiates with solvent oxidation, thus providing rationale for the marked influence of pivalonitrile on this reaction process.Due to the ubiquity of nitrogen-containing molecules in nature,pharmaceuticals,and agrochemicals,the development of reaction technologies for the construction of C À Nb onds remains ap roblem of central importance. [1a-f] As ag eneral process,t he selective oxidation [2a,b] of CÀHb onds to form amine derivatives offers numerous salient features,n ot the least of which is the ability for late-stage diversification of existing molecular architectures. [3a-r] Arguably,the full potential of this technology has not been realized owing to the limited substrate scope and performance of available intermolecular CÀHa mination reactions.H ere,w ed isclose ag eneral and efficient method for the single-step amination of complex molecules,aprocess that uses one equivalent of substrate,minimal reaction additives,and aconvenient nitrogen source (Figure 1). Mechanistic studies identify al ink between solvent oxidation and catalyst stability,a nd provide ab asis for understanding improved turnover numbers under the new protocol.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

The desire for maximally efficient transformations in complex molecule synthesis has contributed to a surge of interest in C− H functionalization methods development in recent years. In contrast to the steady stream of methodological reports, however, there are noticeably fewer studies comparing the efficacies of different C−H functionalization protocols on a single structurally intricate substrate. Recognizing the importance of heteroatom incorporation in complex molecule synthesis, this report discloses a comparative examination of diverse strategies for C−O, C−N, and C−X bond formation through late-stage C−H oxidation of the tricyclic cyanthiwigin natural product core. Methods for allylic C−H acetoxylation, tertiary C−H hydroxylation, tertiary C−H amination, tertiary C−H azidation, and secondary C−H halogenation are explored. These efforts highlight the robustness and selectivities of many well-established protocols for C−H oxidation when applied to a complex molecular framework, and the findings are relevant to chemists aiming to employ such strategies in the context of chemical synthesis.