Xiao-Qiang Hu

Exploration of Visible-Light Photocatalysis in Heterocycle Synthesis and Functionalization: Reaction Design and Beyond

Visible-light photocatalysis has recently received increasing attention from chemists because of its wide application in organic synthesis and its significance for sustainable chemistry. This catalytic strategy enables the generation of various reactive species, frequently without stoichiometric activation reagents under mild reaction conditions. Manipulation of these reactive intermediates can result in numerous synthetically useful bond formations in a controllable manner. In this Account, we describe our recent advances in the rational design and strategic application of photocatalysis in the synthesis of various synthetically and biologically important heterocycles. Our main research efforts toward this goal can be classified into four categories: formal cycloaddition and cyclization reactions, radical-mediated olefin functionalization/cyclization cascades, photocatalytic generation and cyclization of N-centered radicals, and photocatalytic functionalization of heterocycles by visible-light-induced dual catalysis. Inspired by the wide application of tertiary amines as reductive additives in photoredox catalysis, we exploited a series of readily accessible or rationally designed tertiary amines with reactive sites in a range of photocatalytic formal cycloaddition and cyclization reactions, providing efficient access to diverse nitrogen heterocycles. Employing various photogenerated radical species, we further developed a series of radical-mediated olefin functionalization/cyclization cascade reactions to successfully assemble various five- and six-membered heterocycles. We have also achieved for the first time the direct catalytic conversion of recalcitrant N-H bonds into neutral N-centered radicals through a visible-light-photocatalytic oxidative deprotonation electron transfer. Using this generic strategy, we have devised several types of radical cyclizations of unsaturated hydrazones, leading to the construction of diversely functionalized pyrazoline and pyridazine derivatives in good yields and selectivity. Moreover, we have demonstrated that this photocatalysis can serve as a mild and highly selective tool for direct functionalization of heterocycles because of its powerful capability to controllably generate diverse reactive intermediates under mild reaction conditions. Guided by the fundamental principles of photocatalysis and the redox properties of the photocatalysts, we successfully developed an array of dual-catalyst systems by combining the photocatalysts with palladium, nickel, or amine, enabling efficient and selective coupling reactions. An intriguing phototandem catalytic system using a single photocatalyst was also identified for the development of cascade reactions. Notably, some of the newly developed methodologies have also been successfully utilized for late-stage modification of biologically active natural compounds and complex molecules and as key steps for formal synthesis of natural products. This Account presents a panoramic view and the logic of our recent contributions to the design, development, and application of photocatalytic systems and reactions that provide not only methods for the efficient synthesis of heterocycles but also useful insights into the exploration of new photochemical reactions.

Photocatalytic Generation of N‐Centered Hydrazonyl Radicals: A Strategy for Hydroamination of β,γ‐Unsaturated Hydrazones

A visible-light photocatalytic generation of N-centered hydrazonyl radicals has been accomplished for the first time. This approach allows efficient intramolecular addition of hydrazonyl radical to terminal alkenes, thus providing hydroamination and oxyamination products in good yields. Importantly, the protocol involves deprotonation of an N-H bond and photocatalytic oxidation to an N-centered radical, thus obviating the need to prepare photolabile amine precursors or the stoichiometric use of oxidizing reagents.

Photocatalytic Radical Trifluoromethylation/Cyclization Cascade: Synthesis of CF3-Containing Pyrazolines and Isoxazolines

A general visible light induced photoredox-catalyzed radical trifluoromethylation/cyclization cascade of β-aryl-β,γ-unsaturated hydrazones and oximes is described. The protocol enables an efficient access to various densely functionalized and biologically important CF3-containing dihydropyrazoles and isoxazolines with generally high yields.

Catalytic N-radical cascade reaction of hydrazones by oxidative deprotonation electron transfer and TEMPO mediation

Compared with the popularity of various C-centred radicals, the N-centred radicals remain largely unexplored in catalytic radical cascade reactions because of a lack of convenient methods for their generation. Known methods for their generation typically require the use of N-functionalized precursors or various toxic, potentially explosive or unstable radical initiators. Recently, visible-light photocatalysis has emerged as an attractive tool for the catalytic formation of N-centred radicals, but the pre-incorporation of a photolabile groups at the nitrogen atom largely limited the reaction scope. Here, we present a visible-light photocatalytic oxidative deprotonation electron transfer/2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediation strategy for catalytic N-radical cascade reaction of unsaturated hydrazones. This mild protocol provides a broadly applicable synthesis of 1,6-dihydropyradazines with complete regioselectivity and good yields. The 1,6-dihydropyradazines can be easily transformed into diazinium salts that showed promising in vitro antifungal activities against fungal pathogens. DFT calculations are conducted to explain the mechanism.

Controllable Remote C−H Bond Functionalization by Visible-Light Photocatalysis

Remote control: New strategies for the activation of remote C(sp3 )-H bonds by photoredox-catalyzed (PC) radical translocation via O- and N-centered radicals have recently been described. These methods enable the controlled and site-selective functionalization of inert C(sp3 )-H bonds and provide new opportunities for reaction design (HAT=hydrogen atom transfer).

Organophotocatalytic Generation of N- and O-Centred Radicals Enables Aerobic Oxyamination and Dioxygenation of Alkenes.

A cooperative TEMPO and photoredox catalytic strategy was applied for the first time to the direct conversion of N-H and O-H bonds into N- and O-centred radicals, enabling a general and selective oxidative radical oxyamination and dioxygenation of various β,γ-unsaturated hydrazones and oximes. In the reaction, O2 was employed not only as a terminal oxidant but also as the oxygen source. This protocol provided efficient access to the synthesis of various synthetically and biologically important pyrazoline, pyridazine and isoxazoline derivatives under metal-free and mild reaction conditions. Mechanistic studies revealed that the cooperative organophotocatalytic system functions through two single-electron-transfer (SET) processes.

A visible-light photocatalytic N-radical cascade of hydrazones for the synthesis of dihydropyrazole-fused benzosultams

An efficient visible light photocatalytic and external oxidant-free N-radical 5-exo cyclization/addition/aromatization cascade of β,γ-unsaturated hydrazones is described, which provides a practical route to various biologically interesting dihydropyrazole-fused benzosultams in satisfactory yields.

Metal-containing carbonyl ylides: versatile reactants in catalytic enantioselective cascade reactions.

New players in town: In situ generated transition-metal-containing carbonyl ylides are a unique class of reagents which have found wide applications in catalytic asymmetric cascade reactions. Recent advances in reaction design are likely to lead to more novel developments with these reactive species.