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C(sp3)–H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp3)–H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C–H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2′-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, and N-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C–H functionalization/cross-coupling in drug discovery., A copper-based catalyst system composed of commercially available reagents enables C–H isocyanation with exquisite (hetero)benzylic site selectivity, enabling high-throughput access to pharmaceutically relevant ureas via coupling with amines.

Over the past two decades, there have been major developments in transition metal-catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon-nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event., National Institutes of Health (U.S.) (Award GM58160), National Institutes of Health (U.S.) (Award RO1-GM078201-05), National Institutes of Health (U.S.) (Award GM113311)

Over the past two decades, there have been major developments in transition metal–catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon–nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event.

Bicyclic guanidines are able to catalyze the protonation reactions of 2-phthalimidoacrylates with thiols in excellent yields and enantioselectivities. The protonation reaction of itaconimides with secondary phosphine oxides is also known. Herein, the tandem conjugate addition-enantioselective protonation of N-substituted itaconimides with thiols catalyzed by chiral bicyclic guanidine is investigated. The rotational barrier of the C-N axis of N-2-tert-butyl phenylitaconimide is also studied, both experimentally and computationally.