RESUMEN
Amines are centrally important motifs in medicinal chemistry and biochemistry, and indispensable intermediates and linchpins in organic synthesis. Despite their cross-disciplinary prominence, synthetic access to amine continues to rely on two-electron approaches based on reductions and additions of organometallic reagents, limiting their accessible chemical space and necessitating stepwise preassembly of synthetic precursors. We report herein a homogeneous photocatalytic tricomponent decarboxylative radical-mediated amine construction that enables modular access to α-branched secondary amines directly from the broad and structurally diverse chemical space of carboxylic acids in a tricomponent reaction with aldehydes and aromatic amines. Our studies reveal the key role of acridine photocatalysis acting in concert with copper and Brønsted acid catalytic processes in facilitating the previously inaccessible homogeneous photocatalytic reaction and provide a streamlined segue to a wide range of amines and nonproteinogenic α-amino acids.
RESUMEN
Development of photocatalytic systems that facilitate mechanistically divergent steps in complex catalytic manifolds by distinct activation modes can enable previously inaccessible synthetic transformations. However, multimodal photocatalytic systems remain understudied, impeding their implementation in catalytic methodology. We report herein a photocatalytic access to thiols that directly merges the structural diversity of carboxylic acids with the ready availability of elemental sulfur without substrate preactivation. The photocatalytic transformation provides a direct radical-mediated segue to one of the most biologically important and synthetically versatile organosulfur functionalities, whose synthetic accessibility remains largely dominated by two-electron-mediated processes based on toxic and uneconomical reagents and precursors. The two-phase radical process is facilitated by a multimodal catalytic reactivity of acridine photocatalysis that enables both the singlet excited state PCET-mediated decarboxylative carbon-sulfur bond formation and the previously unknown radical reductive disulfur bond cleavage by a photoinduced HAT process in the silane-triplet acridine system. The study points to a significant potential of multimodal photocatalytic systems in providing unexplored directions to previously inaccessible transformations.
RESUMEN
Chemodivergent construction of structurally distinct heterocycles from the same precursors by adjusting specific reaction parameters is an emergent area of organic synthesis; yet, understanding of the processes that underpin the reaction divergence is lacking, preventing the development of new synthetic methods by systematically harnessing key mechanistic effects. We describe herein cesium carbonate-promoted oxadiaza excision cross-coupling reactions of ß-ketoesters with 1,2,3-triazine 1-oxides that form pyridones in good to high yields, instead of the sole formation of pyridines when the same reaction is performed in the presence of other alkali metal carbonates or organic bases. The reaction can be further extended to the construction of synthetically challenging pyridylpyridones. A computational study comparing the effect of cesium and sodium ions in the oxadiaza excision cross-coupling reactions reveals that the cesium-coordinated species changes the reaction preference from attack at the ketone carbonyl to attack at the ester carbon due to metal ion-specific transition state conformational accommodation, revealing a previously unexplored role of cesium ions that may facilitate the development of chemodivergent approaches to other heterocyclic systems.
RESUMEN
Sulfinamides are some of the most centrally important four-valent sulfur compounds that serve as critical entry points to an array of emergent medicinal functional groups, molecular tools for bioconjugation, and synthetic intermediates including sulfoximines, sulfonimidamides, and sulfonimidoyl halides, as well as a wide range of other S(iv) and S(vi) functionalities. Yet, the accessible chemical space of sulfinamides remains limited, and the approaches to sulfinamides are largely confined to two-electron nucleophilic substitution reactions. We report herein a direct radical-mediated decarboxylative sulfinamidation that for the first time enables access to sulfinamides from the broad and structurally diverse chemical space of carboxylic acids. Our studies show that the formation of sulfinamides prevails despite the inherent thermodynamic preference for the radical addition to the nitrogen atom, while a machine learning-derived model facilitates prediction of the reaction efficiency based on computationally generated descriptors of the underlying radical reactivity.
