The fields of C-H functionalization and photoredox catalysis have garnered enormous interest and utility in the past several decades. Many different scientific disciplines have relied on C-H functionalization and photoredox strategies including natural product synthesis, drug discovery, radiolabeling, bioconjugation, materials, and fine chemical synthesis. In this Review, we highlight the use of photoredox catalysis in C-H functionalization reactions. We separate the review into inorganic/organometallic photoredox catalysts and organic-based photoredox catalytic systems. Further subdivision by reaction class-either sp2 or sp3 C-H functionalization-lends perspective and tactical strategies for use of these methods in synthetic applications.

Photoredox-Catalyzed C-H Functionalization Reactions.

Over the past decade, the landscape of molecular synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C–H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C–H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programmes. This Review highlights the significant advances achieved in the late-stage C–H functionalization of drugs and drug-like compounds, and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examined and classified by mechanistic patterns involving directed or innate C–H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small molecules are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new molecules of interest. Late-stage C–H functionalization of complex molecules has emerged as a powerful tool in drug discovery. This Review classifies significant examples by reaction manifold and assesses the benefits and challenges of each approach. Avenues for future improvements of this fast-expanding field are proposed.

Late-stage C-H functionalization offers new opportunities in drug discovery

Vicinal alkene carboamination is a highly efficient and practical synthetic strategy for the straightforward preparation of diverse and valuable amine derivatives starting from simple compounds. During the last decade that approach has found continuous research interests and various practical methods have been developed using transition-metal catalysis. Driven by the renaissance of synthetic radical chemistry, intermolecular radical alkene carboamination comprising a C-C bond and a C-N bond forming step has been intensively investigated recently culminating in novel strategies and improved protocols which complement existing methodologies. Radical alkene carboamination can be achieved via three different reaction modes. Such cascades can proceed through N-radical addition to an alkene with subsequent C-C bond formation leading to 2,1-carboamination products. Alternatively, the C-C bond can be installed prior to the C-N bond via initial C-radical addition to the alkene with subsequent β-amination resulting in 1,2-carboamination. The third mode comprises initial single electron oxidation of the alkene to the corresponding alkene radical cation that gets trapped by an N-nucleophile and the cascade is terminated by radical C-C bond formation. In this review, the three different conceptual approaches will be discussed and examples from the recent literature will be presented. Further, the reader will get insights into the mechanism of the different transformations.

Intermolecular radical carboamination of alkenes.

Pyridinium salts are valuable building blocks, which have been widely applied in various organic transformations during the past few decades. In particular, N-functionalized pyridinium salts have b...

Recent Advances in Pyridinium Salts as Radical Reservoirs in Organic Synthesis

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.

Metal-free, visible-light-induced site-selective heteroarylation of remote C(sp3 )-H bonds has been accomplished through the design of N-alkoxyheteroarenium salts serving as both alkoxy radical precursors and heteroaryl sources. The transient alkoxy radical can be generated by the single-electron reduction of an N-alkoxypyridinium substrate by a photoexcited quinolinone catalyst. Subsequent radical translocation of the alkoxy radical forms a nucleophilic alkyl radical intermediate, which undergoes addition to the substrate to achieve remote C(sp3 )-H heteroarylation. This cascade strategy provides a powerful platform for remote C(sp3 )-H heteroarylation in a controllable and selective manner and is well suited for late-stage functionalization of complex bioactive molecules.

Visible‐Light‐Induced Pyridylation of Remote C(sp3)−H Bonds by Radical Translocation of N‐Alkoxypyridinium Salts

The development of intermolecular alkene aminopyridylation has great potential for quickly increasing molecular complexity with two valuable groups. Here we report a strategy for the photocatalytic aminopyridylation of alkenes using a variety of N-aminopyridinium salts as both aminating and pyridylating reagents. Using Eosin Y as a photocatalyst, amino and pyridyl groups are simultaneously incorporated into alkenes, affording synthetically useful aminoethyl pyridine derivatives under mild reaction conditions. Remarkably, the C4-regioselectivity in radical trapping with N-aminopyridinium salt can be controlled by electrostatic interaction between the pyridinium nitrogen and sulfonyl group of β-amino radical. This transformation is characterized by a broad substrate scope, good functional group compatibility, and the utility of this transformation was further demonstrated by late-stage functionalization of complex biorelevant molecules. Combining experiments and DFT calculations on the mechanism of the reaction is investigated to propose a complete mechanism and regioselectivity.

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Visible light induced alkene aminopyridylation using N-aminopyridinium salts as bifunctional reagents.

By employing an N-heterocyclic carbene (NHC) catalyst, we developed a versatile catalytic system that enables deaminative cross-coupling reactions of aldehydes with redox-active pyridinium salts. Katritzky pyridinium salts behave as single-electron oxidants capable of generating alkyl radicals enabled by the redox properties of the enolate form of Breslow intermediates. The resultant alkyl radical undergoes efficient recombination with the NHC-bound aldehyde-derived carbonyl carbon radical for the formation of a C–C bond. The mild and transition metal-free reaction conditions tolerate a broad range of functional groups, and its utility has been further demonstrated by the modification of a series of peptide feedstocks and application to the three-component dicarbofunctionalization of olefins.

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N-Heterocyclic carbene-catalyzed deaminative cross-coupling of aldehydes with Katritzky pyridinium salts

Direct Phosphonation of Quinolinones and Coumarins Driven by the Photochemical Activity of Substrates and Products.

The selective installation of phosphinoyl and carbamoyl moieties on the pyridine scaffold is an important transformation in synthetic and medicinal chemistry. By employing quinolinone as an efficient organic photocatalyst, we developed a catalytic system driven by visible light that forms phosphinoyl and carbamoyl radicals, which react with various heteroarenium derivatives under mild, transition-metal-free conditions. This straightforward and environmentally friendly synthetic method represents a new approach to site-divergent pyridine functionalization that offers considerable advantages in both simplicity and efficiency. Ambient temperature is sufficient for the formation of the reactive radicals, and the site-selectivity can be switched from C2 to C4 by changing the radical coupling sources. Under standard reaction conditions, phosphinoyl radicals give access to C4 products, while carbamoyl radicals selectively give C2 products. We found that the carbamoyl radical overcomes the intrinsic preference for forming the ortho-product by allowing the oxo functionality of the carbamoyl radical to electrostatically engage the nitrogen of the pyridinium substrate, which preferentially gives the ortho-product. The phosphinoyl radical cannot engage in the same interaction, because the phosphorus is too large. This novel synthetic route tolerates a broad range of substrates and provides a convenient and powerful synthetic tool for accessing the core structures of numerous privileged scaffolds.

Inwon Kim

Papers

Visible‐Light‐Induced Pyridylation of Remote C(sp3)−H Bonds by Radical Translocation of N‐Alkoxypyridinium Salts

Visible light induced alkene aminopyridylation using N-aminopyridinium salts as bifunctional reagents.

N-Heterocyclic carbene-catalyzed deaminative cross-coupling of aldehydes with Katritzky pyridinium salts

Direct Phosphonation of Quinolinones and Coumarins Driven by the Photochemical Activity of Substrates and Products.

Site-Selective Functionalization of Pyridinium Derivatives via Visible-Light-Driven Photocatalysis with Quinolinone.