Nitrogen-Oxidants Enable Group-Transfer Reactions

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Synthetic technologies can enable transformation of polarizable carbon–carbon (C=C) bonds and typically inert carbon–hydrogen (C–H) bonds into value-added diverse functional groups. Such technologies streamline access to complex molecules. In recent years, nitrogen-centered oxidants have garnered significant attention as a result of their ability to engage in selective and predictable synthetic transformations of these groups. Within this broad class of reactions, herein disclosed are investigations into two complementary approaches to access and utilize nitrogen-centered oxidants. Of these, the first approach advances iron nitrenoids to affect substrate-limited aziridination reactions of carbon–carbon double bonds. Specifically, Chapter two documents a best-in-class method that relies on limiting quantities of electronically varied styrene substrates to furnish synthetically useful aziridines in moderate to good yields under mild conditions. Subsequently, an orthogonal approach is developed – one that demonstrates the viability sulfamate esters as precursors to radical intermediates that template C–H functionalization reactions, with a focus on two group-transfer processes. Through this research, sulfamate esters have been identified as precursors to a modern class of nitrogen-centered oxidants, sulfamyl radicals. To enable broader usage, Chapter three discloses a new general and mild method to access substrates for this approach, employing inexpensive readily available sulfur trioxide sources with a wide range of ubiquitous amine and alcohol starting materials. The method relies on activation of a common intermediate, a sulfamic acid salt, to generate a large variety of N, O-disubstituted sulfamate esters and sulfamides. Studies described in Chapters four and five have resulted in mild strategies to generate sulfamyl radicals from sulfamate esters. These sulfamyl radicals engage in a rare, 1,6-hydrogen-atom transfer processes to affect position-selective C(3)-functionalization of aliphatic C–H bonds. More specifically, in Chapter four, this rare property is harnessed to establish a C(3)-selective xanthylation process. Enabled by visible-light, xanthylation of primary, secondary, and tertiary centers has been demonstrated with exquisite site selectivity. This investigation confirms the scientific insight that N-functionalized sulfamate esters enable complementary site selectivity to the previously known methods employing nitrogen-centered radicals. Additionally, this C(3)-xanthylation reaction can be combined with known technologies to affect formal C(sp3)–H azidation, thiolation, trifluoromethylthiolation, deuteration, allylation, and vinylation to generate molecular diversity from a common intermediate. Building on this foundation, Chapter five documents a photoredox-mediated method to generate the requisite sulfamyl radicals for site-selective carbon-carbon and carbon-oxygen bond forming processes. These investigations are the first of their kind to generate sulfamyl radicals from non-pre-oxidized sulfamate esters. These nitrogen-centered sulfamyl radicals, through the sulfamate-templated 1,6-HAT process, furnish secondary and tertiary carbon-centered radicals which can be trapped by Michael acceptors for a formal C(3)-alkylation. This process yields products with diastereoselectivity when engaging complex small molecules and enantioenriched Michael acceptors. Thereby, photoredox-mediated C(3)-selective alkylation process affords complementary position selectivity to that was achieved using known photoredox–mediated carbon-carbon bond-forming reactions. Finally, Chapter six describes electrochemical methods to generate the key sulfamyl radicals. Through this research, the first example of direct anodic oxidation of sulfamate ester anions is disclosed. The resultant sulfamyl radicals are utilized to affect novel C(3)-hydroxylation reactions. The electrochemical method is further extended to affect N-alkylation of sulfamate esters and sulfamides. Together, conceptual innovations have facilitated mild methods to access the nitrogen-centered oxidants for the functionalization of carbon–carbon (C=C) bond and radical-mediated functionalization of remote C(3)-aliphatic C–H bonds. These investigations enable synthetic disconnections that would be infeasible using previously established methods and provide efficient access to new chemical space.






Ayer, Suraj Kumar (2021). Nitrogen-Oxidants Enable Group-Transfer Reactions. Dissertation, Duke University. Retrieved from


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