Browsing by Author "Roizen, Jennifer L"

The design of synthetic transformations that proceed selectively in the presence of multiple sites of similar chemical reactivity has been a long-standing challenge. Cross-coupling and C–H functionalization processes have gathered significant attention over the past few decades as a result of their ability to rapidly generate molecular complexity. Despite these advances, a chemist’s ability to judiciously, selectively, and predictably perform these synthetic transformations has not yet been fully realized. Herein disclosed are the investigations into new methods for the Suzuki-Miyaura and Hofmann-Löffler-Freytag reactions that proceed with predictable selectivity.

Tactical advances have resulted in the development of selective, serial, and exhaustive cross-coupling transformations of alkyl pinacol boronic esters with polyhalogenated (hetero)arenes. These Suzuki-Miyaura processes facilitate access to a wide variety of alkyl-substituted aromatic compounds, specifically 2-alkylpyridines, which constitute an important class of functional molecules.

Conceptual innovations have established sulfamate esters as a promising manifold for the radical-mediated functionalization of remote, aliphatic C–H bonds. New methods for the synthesis of sulfamate esters have facilitated access to these valuable functional motifs, thereby allowing their use in Hofmann-Löffler-Freytag reactions. Accordingly, the selective, sulfamate ester-guided chlorination of remote C(sp3)–H bonds has been developed. This transformation proceeds with unique site-selectivity and furnishes γ-functionalized masked alcohol derivatives.

Advancements in photocatalysis have enabled access to previously inaccessible intermediates, and have allowed for the development of innovative strategies for bond-formation. By employing a series of metal polypyridyl complexes, chemists have been able to tune reaction conditions to favor productive methodologies for the synthesis of challenging molecular targets. In recent years, photochemically-mediated strategies utilizing this series of privileged metal polypyridal complexes, have overcome significant hurdles when applied to C–H functionalization reactions. C–H functionalization processes take inspiration from the precision of enzymatic reactions in Nature, which are able to transform otherwise indistinguishable and unreactive C(sp3)–H bonds into high value functional groups. A typical strategy employed by chemists for selectively engaging strong C(sp3)–H bonds (BDE = 90 – 105 kcal/mol) involves the use of directing groups that are geometrically disposed to guide reactions at one C–H bond in preference to others. Photoredox-catalyzed platforms have enabled the controlled access to reactive radical intermediates capable of acting as directing groups for the transformation of unreactive C–H bonds under mild conditions.

In addition to allowing access to unprecedented radical intermediates, photosensitizers can also overcome longstanding challenges associated with metal catalyzed cross-coupling reactions. The use of photocatalysts in nickel-catalyzed cross-coupling reactions enables more efficient reductive elimination, and has revolutionized the types of nucleophiles capable of engaging in C–C, C–O, C–S, and C–N coupling reactions. As a result, these photochemically-driven strategies potentiate access to diverse chemical structures, including many underexplored classes of small molecules.

Through this research, we apply photocatalysis to the generation of sulfamyl and sulfamidyl radicals for site-selective carbon–carbon bond formation. These guided alkylation reactions are the first of their kind to generate sulfamyl and sulfamidyl radicals from non-preoxidized or activated sulfamate esters and sulfamides. As directing groups, both sulfamate esters and sulfamides offer modified Hofmann-Löffler Freytag (HLF) position selectivity for late-stage C–H functionalization processes. Additionally, we have applied a dual photochemically driven, nickel-catalyzed reaction manifold to the N-(hetero)arylation of sulfamate esters and sulfamides. We demonstrate that both sulfamates and sulfamides are competent nucleophiles in these dual photochemical and nickel-catalyzed processes. Furthermore, these user-friendly methods improve access to underexplored arylated sulfamate ester and sulfamide small molecules.

Synthetic technologies that enable transformation of typically inert carbon–hydrogen (C–H) bonds into diverse functional groups have streamlined access to complex molecules. These processes, defined as C–H functionalization reactions, remain challenging as traditionally unreactive C–H bonds have high bond dissociation energies (90–105 kcal•mol–1), are not acidic (pKa ≥ 50), and do not incorporate more polarizable and electronically accessible π-orbitals. In addition, the ubiquity of C–H bonds within organic molecules requires methods to predictably and selectivity control the site of functionalization.

Some of the most effective strategies for controlling the position of C–H functionalization employ directing groups to guide a reaction to a particular site within a molecule. Herein disclosed are investigations into position-selective C–H halogenation reactions mediated by sulfamate ester and sulfamide directing groups. We have demonstrated that these substrates guide rare, 1,6-hydrogen-atom transfer (1,6-HAT) processes to dictate the position of halogen installation with specific focus on chlorination and fluorination reactions.

Through this research, we have developed methods to prepare sulfamate esters and sulfamides from readily available starting materials via activation of sulfamic acid salts. Additionally, we have utilized these substrates to guide position-selective chlorine- and fluorine-transfer reactions, enabling access to alkyl halide products with complementary selectivity to that achieved with other known halogenation technologies.

Synthetic technologies that enable transformation of typically inert carbon–hydrogen (C–H) bonds into diverse functional groups have streamlined access to complex molecules. These processes, defined as C–H functionalization reactions, remain challenging as traditionally unreactive C–H bonds have high bond dissociation energies (90–105 kcal•mol–1), are not acidic (pKa ≥ 50), and do not incorporate more polarizable and electronically accessible π-orbitals. In addition, the ubiquity of C–H bonds within organic molecules requires methods to predictably and selectivity control the site of functionalization.

Some of the most effective strategies for controlling the position of C–H functionalization employ directing groups to guide a reaction to a particular site within a molecule. Herein disclosed are investigations into position-selective C–H halogenation reactions mediated by sulfamate ester and sulfamide directing groups. We have demonstrated that these substrates guide rare, 1,6-hydrogen-atom transfer (1,6-HAT) processes to dictate the position of halogen installation with specific focus on chlorination and fluorination reactions.

Through this research, we have developed methods to prepare sulfamate esters and sulfamides from readily available starting materials via activation of sulfamic acid salts. Additionally, we have utilized these substrates to guide position-selective chlorine- and fluorine-transfer reactions, enabling access to alkyl halide products with complementary selectivity to that achieved with other known halogenation technologies.

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.

Research towards highly efficient, position-selective atom-transfer technologies is described. At the outset of this study, it was envisioned that a pendant directing group on organic substrates would direct functionalization of a vicinal position by employing one of two strategies: (1) the directing group would chelate to an early transition metal catalyst and thereby position a pendant atom-transfer agent, or (2) the directing group itself would geometrically constrain the site of C–H abstraction to dictate the site of functionalization.

Investigations into complexes of iron-cyclohexanediamine and iron-dipyrrolidine demonstrated that this class of complex was capable of affecting nitrogen-atom transfer to styrenes to produce aziridines. Utilizing sterically hindered iron complexes, limiting quantities of various styrenes could be transformed into diverse aziridines in moderate to good yields; however, due to the narrow substrate scope, the system did not allow for opportunities to evaluate position-selective, chelate-guided aziridination. Mechanistic studies provided limited support that the hypothesized iron-imido intermediate was capable of carrying out single electron oxidation of electron rich olefins but did not evidence single electron transfer from electron deficient alkenes.

Using a complementary approach, we provided the first evidence that sulfamides could direct exogenous atom-transfer processes by developing a sulfamide-guided chlorine-transfer technology. Utilizing sulfamides as masked amines, it was possible to induce g-selective chlorine transfer from N-chlorosulfamides to an appended alkyl chain, with position selectivity postulated to be a result of the elongated S–N bonds of the sulfamide motif. Quantum yield studies demonstrated that this transformation proceeded by an intermolecular radical chain propagation mechanism as opposed to an intramolecular process.

Recent advances in photo-driven reactions have dramatically expanded thescope of transformations no longer exclusively dependent on thermal energy to drive cross-coupling activity of transition metal catalysts. Of these catalysts, nickel has emerged as one of the most versatile due, in part, to its flexibility in adopting all integer oxidation states from 0 to +4, as well as its lower cost and higher abundance in comparison to precious metal catalysts. Carbon–heteroatom and carbon–carbon cross-couplings are areas of particularly resurgent expansion in photo-driven reaction development. These classes of couplings are essential in the production of innumerable compounds including fine chemicals and natural product synthesis, as well as pharmaceuticals and agrochemicals. Disclosed herein are investigations into dual photo-/nickel-catalyzed reactions for C–N and C–C cross-coupling with (hetero)aryl bromides in sulfamides and sulfamate esters, respectively. The reactivity demonstrated in the N-(hetero)arylation of sulfamides is complementary to that previously demonstrated in traditional, palladium-catalyzed processes. Moreover, the radical C(sp2)–C(sp3) cross-coupling guided by a 1,6-HAT process in sulfamate esters is the first example of this type of nickel-/photocatalyzed reaction and has been long sought after by pioneers of the field. This represents the first plank in a new platform for internally guided, nickel-catalyzed cross-coupling reactions. The development of these complementary technologies constitutes a substantive advancement in access to chemically diverse sulfamides and C–H functionalization technologies, respectively.