Direct Synthesis of Thioesters from Feedstock Chemicals and Elemental Sulfur.

The development of a mild, atom- and step-economical catalytic strategy that effectively generates value-added molecules directly from readily available commodity chemicals is a central goal of organic synthesis. In this context, the thiol-ene click chemistry for carbon-sulfur (C-S) bond construction has found widespread applications in the synthesis of pharmaceuticals and functional materials. In contrast, the selective carbonyl thiyl radical addition to carbon-carbon multiple bonds remains underdeveloped. Herein, we report a carbonyl thiyl radical-based thioester synthesis through three-component coupling from feedstock aldehydes, alkenes, or alkynes and elemental sulfur by direct photocatalyzed hydrogen atom transfer. This method represents an orthogonal strategy to the conventional thiol-based nucleophilic substitution and exhibits a remarkably broad substrate scope ranging from simple commodity chemicals such as ethylene and acetylene to complex pharmaceutical molecules. This protocol can be easily extended to the synthesis of thiolactones, oligomer/polymers, and thioacids. Its synthetic utility has been demonstrated by a two-step synthesis of the drug esonarimod. Mechanistic studies indicate that the use of elemental sulfur to trap acyl radicals is both thermodynamically and kinetically favored, illustrating its great potential for the synthesis of sulfur-containing molecules.

Deoxygenative Arylation of Carboxylic Acids by Aryl Migration.

An unprecedented deoxygenative arylation of aromatic carboxylic acids has been achieved, allowing the construction of an enhanced library of unsymmetrical diaryl ketones. The synergistic photoredox catalysis and phosphoranyl radical chemistry allows for precise cleavage of a stronger C-O bond and formation of a weaker C-C bond by 1,5-aryl migration under mild reaction conditions. This new protocol is independent of substrate redox-potential, electronic, and substituent effects. It affords a general and promising access to 60 examples of synthetically versatile o-amino and o-hydroxy diaryl ketones under redox-neutral conditions. Furthermore, it also brings one concise route to the total synthesis of quinolone alkaloid, (±)-yaequinolone A2, and a viridicatin derivative in satisfying yields.

Deoxygenative Deuteration of Carboxylic Acids with D2 O.

We report a general, practical, and scalable means of preparing deuterated aldehydes from aromatic and aliphatic carboxylic acids with D2 O as an inexpensive deuterium source. The use of Ph3 P as an O-atom transfer reagent can facilitate the deoxygenation of aromatic acids, while Ph2 POEt is a better O-atom transfer reagent for aliphatic acids. The highly precise deoxygenation of complex carboxylic acids makes this protocol promising for late-stage deoxygenative deuteration of natural product derivatives and pharmaceutical compounds.

Photoredox-Catalyzed Deoxygenative Intramolecular Acylation of Biarylcarboxylic Acids: Access to Fluorenones.

An efficient deoxygenative radical cyclization reaction has been reported for the synthesis of fluorenones by employing various biarylcarboxylic acids via photoredox catalysis. Attractive features of this process include generation of acyl radical, which quickly underdone intramolecular radical cyclization. This method marks the first photocatalytic intramolecular acyl radical coupling for constructing carbon-carbon bond, which further synthesizes the valuable fluorenone products with mild conditions, good yields, and good functional-group compatibility.

Domino-Fluorination-Protodefluorination Enables Decarboxylative Cross-Coupling of α-Oxocarboxylic Acids with Styrene via Photoredox Catalysis.

Domino-fluorination-protodefluorination decarboxylative cross-coupling of α-keto acids with styrene has been developed via photoredox catalysis. The critical part of this strategy is the formation of the carbon-fluorine (C-F) bond by the capture of a carbon-centered radical intermediate, which will overcome side reactions during the styrene radical functionalization process. Experimental studies have provided evidence indicating a domino-fluorination-protodefluorination pathway with α-keto acid initiating the photoredox cycle. The present catalytic protocol also affords a novel approach for the construction of α,ß-unsaturated ketones under mild conditions.

Silyl Radical as an Isocyanide Transfer Agent for Giese-Type Reactions Involving Aliphatic Amines.

Herein we report silyl radicals serve as isocyanide transfer agents for Giese-type reaction from aliphatic amines and electron-deficient olefins. α-Primary, α-secondary, and sterically encumbered α-tertiary primary amines could be easily converted into isocyanides for coupling with electron-deficient olefins by employing latent silyl radicals under visible light irradiation. Notably, the abstraction of silane-mediated isocyanide not only enables voltage-independent activation of strong C-N bonds but also represents a mechanistic alternative Giese-type reaction in which single electron reduction and protonation processes are replaced by direct hydrogen atom transfer. This transformation occurs under photoinduced catalyst-free conditions and exhibits excellent functional group compatibility and mild reaction conditions.

Photocatalyzed regioselective hydrosilylation for the divergent synthesis of geminal and vicinal borosilanes.

Geminal and vicinal borosilanes are useful building blocks in synthetic chemistry and material science. Hydrosilylation/hydroborylation of unsaturated systems offer expedient access to these motifs. In contrast to the well-established transition-metal-catalyzed methods, radical approaches are rarely explored. Herein we report the synthesis of geminal borosilanes from α-selective hydrosilylation of alkenyl boronates via photoinduced hydrogen atom transfer (HAT) catalysis. Mechanistic studies implicate that the α-selectivity originates from a kinetically favored radical addition and an energetically favored HAT process. We further demonstrate selective synthesis of vicinal borosilanes through hydrosilylation of allyl boronates via 1,2-boron radical migration. These strategies exhibit broad scopes across primary, secondary, and tertiary silanes and various boron compounds. The synthetic utility is evidenced by access to multi-borosilanes in a diverse fashion and scaling up by continuous-flow synthesis.

Photoinduced Defluorinative Branch-Selective Olefination of Multifluoro (Hetero)arenes.

We report a photoredox platform for constructing styrenyl polyfluoro (hetero)arenes with branch selectivity by taking advantage of sulfinate as both a radical-relay precursor and a sacrificial nucleofuge. This protocol merges photoredox catalysis with radical-radical coupling and an elimination process in a one-pot operation and features good functional group tolerance, mild conditions, and a facile method to access polyfluoro (hetero)aryl derivatives of natural products and drugs.

Stepwise on-demand functionalization of multihydrosilanes enabled by a hydrogen-atom-transfer photocatalyst based on eosin Y.

Organosilanes are of vital importance for modern human society, having found widespread applications in functional materials, organic synthesis, drug discovery and life sciences. However, their preparation remains far from trivial, and on-demand synthesis of heteroleptic substituted silicon reagents is a formidable challenge. The generation of silyl radicals from hydrosilanes via direct hydrogen-atom-transfer (HAT) photocatalysis represents the most atom-, step-, redox- and catalyst-economic pathway for the activation of hydrosilanes. Here, in view of the green characteristics of neutral eosin Y (such as its abundance, low cost, metal-free nature, absorption of visible light and excellent selectivity), we show that using it as a direct HAT photocatalyst enables the stepwise custom functionalization of multihydrosilanes, giving access to fully substituted silicon compounds. By exploiting this strategy, we realize preferable hydrogen abstraction of Si-H bonds in the presence of active C-H bonds, diverse functionalization of hydrosilanes (for example, alkylation, vinylation, allylation, arylation, deuteration, oxidation and halogenation), and remarkably selective monofunctionalization of di- and trihydrosilanes.

Iron-mediated ligand-to-metal charge transfer enables 1,2-diazidation of alkenes.

Given the widespread significance of vicinal diamine units in organic synthesis, pharmaceuticals and functional materials, as well as in privileged molecular catalysts, an efficient and practical strategy that avoids the use of stoichiometric strong oxidants is highly desirable. We herein report the application of ligand-to-metal charge transfer (LMCT) excitation to 1,2-diazidation reactions from alkenes and TMSN3 via a coordination-LMCT-homolysis process with more abundant and greener iron salt as the catalyst. Such a LMCT-homolysis mode allows the generation of electrophilic azidyl radical intermediate from Fe-N3 complexes poised for subsequent radical addition into carbon-carbon double bond. The generated carbon radical intermediate is further captured by iron-mediated azidyl radical transfer, enabling dual carbon-nitrogen bond formation. This protocol provides a versatile platform to access structurally diverse diazides with high functional group compatibility from readily available alkenes without the need of chemical oxidants.

Photomediated reductive coupling of nitroarenes with aldehydes for amide synthesis.

In view of the widespread significance of amide functional groups in organic synthesis and pharmaceutical studies, an efficient and practical synthetic protocol that avoids the use of stoichiometric activating reagents or metallic reductants is highly desirable. A straight-forward pathway to access amides from abundant chemical feedstock would offer a strategic advantage in the synthesis of complex amides. We herein disclose a direct reductive amidation reaction using readily available aldehydes and nitroarenes enabled by photo-mediated hydrogen atom transfer catalysis. It avoids the use of metallic reductants and production of toxic chemical waste. While aldehydes represent a classic class of electrophilic synthons, the corresponding nucleophilic acyl radicals could be directly accessed by photo hydrogen atom transfer catalysis, enabling polarity inversion. Our method provides an orthogonal strategy to conventional amide couplings, tolerating nucleophilic substituents such as free alcohols and sensitive functional groups to amines such as carbonyl or formyl groups. The synthetic utilization of this reductive amidation is demonstrated by the late-stage modification of complex biologically active molecules and direct access of drug molecules leflunomide and lidocaine.

Divergent functionalization of aldehydes photocatalyzed by neutral eosin Y with sulfone reagents.

While aldehydes represent a classic class of electrophilic synthons, the corresponding acyl radicals are inherently nucleophilic, which exhibits umpolung reactivity. Generation of acyl radicals typically requires noble metal catalysts or excess oxidants to be added. Herein, we report a convenient and green approach to access acyl radicals, capitalizing on neutral eosin Y-enabled hydrogen atom transfer (HAT) photocatalysis with aldehydes. The generated acyl radicals underwent SOMOphilic substitutions with various functionalized sulfones (X-SO2R') to deliver value-added acyl products. The merger of eosin Y photocatalysis and sulfone-based SOMOphiles provides a versatile platform for a wide array of aldehydic C-H functionalizations, including fluoromethylthiolation, arylthiolation, alkynylation, alkenylation and azidation. The present protocol features green characteristics, such as being free of metals, harmful oxidants and additives; step-economic; redox-neutral; and amenable to scale-up assisted by continuous-flow technology.

A general deoxygenation approach for synthesis of ketones from aromatic carboxylic acids and alkenes.

The construction of an aryl ketone structural unit by means of catalytic carbon-carbon coupling reactions represents the state-of-the-art in organic chemistry. Herein we achieved the direct deoxygenative ketone synthesis in aqueous solution from readily available aromatic carboxylic acids and alkenes, affording structurally diverse ketones in moderate to good yields. Visible-light photoredox catalysis enables the direct deoxygenation of acids as acyl sources with triphenylphosphine and represents a distinct perspective on activation. The synthetic robustness is supported by the late-stage modification of several pharmaceutical compounds and complex molecules. This ketone synthetic strategy is further applied to the synthesis of the drug zolpidem in three steps with 50% total yield and a concise construction of cyclophane-braced 18-20 membered macrocycloketones. It represents not only the advancement for the streamlined synthesis of aromatic ketones from feedstock chemicals, but also a photoredox radical activation mode beyond the redox potential of carboxylic acids.

Selective reduction of carboxylic acids to aldehydes with hydrosilane via photoredox catalysis.

The direct reduction of carboxylic acids to aldehydes with hydrosilane was achieved through visible light photoredox catalysis. The combination of both single electron transfer and hydrogen atom transfer steps offers a novel and convenient approach to selective reduction of carboxylic acids to aldehydes. The method also features mild conditions, high yields, broad substrate scope, and good functional group tolerance, such as alkyne, ester, ketone, amide and amine groups.

[3+2] Cycloaddition of azide with aldehyde hydrazone through an aminyl radical-polar crossover strategy.

A novel approach to obtain functionalized tetrazoles by a [3+2] cycloaddition of azide with aldehyde hydrazone is reported. This reaction features a broad substrate scope and mild reaction conditions through an aminyl radical-polar crossover strategy.

Photoredox-Catalyzed Hydroacylation of Olefins Employing Carboxylic Acids and Hydrosilanes.

A hydroacylation reaction of alkenes has been achieved employing readily available carboxylic acids as the acyl source and hydrosilanes as a hydrogen source via photoredox catalysis. The combination of both single electron transfer and hydrogen atom transfer steps has dramatically expanded new applications of carboxylic acids in organic synthesis. The protocol also features extremely mild conditions, broad substrate scope, and good functional group tolerance, affording a novel and convenient approach to hydroacylation of alkenes.

Visible-light-induced aerobic dearomative reaction of indole derivatives: access to heterocycle fused or spirocyclo indolones.

Oxazolo[3,2-a]indolone and spiro[furan-2,2'-indolin]one are synthesized by the visible-light-induced aerobic dearomative reaction of indoles. The common indole tethered alcohol at the N1 or C2 position reacts in a cascade fashion, providing facile access to diverse indolone scaffolds.

A photoredox catalyzed radical-radical coupling reaction: facile access to multi-substituted nitrogen heterocycles.

Visible light induced photoredox catalysis is an efficient method for radical activation. Herein, we report the photoredox catalysis involving an intramolecular radical-radical coupling reaction that proceeds through a biradical intermediate. This protocol represents a new synthetic route to construct multi-substituted N-heterocycles. Four, five and six-membered N-heterocyclic structures with a quaternary carbon center are accessible under mild conditions.

Cascade Photoredox/Iodide Catalysis: Access to Difluoro-γ-lactams via Aminodifluoroalkylation of Alkenes.

The novel cascade photoredox/iodide catalytic system enables the alkene to serve as a radical acceptor capable of achieving aminodifluoroalkylation of alkenes. Cheap iodide salts play a vital role in this reaction, which could tune carbocation reactivity through reversible C-I bond formation for controlling reaction selectivity, and a series of competitive reactions are completely eliminated in the presence of multiple reactivity pathways. The present dual catalytic protocol affords a very convenient method for direct synthesis of various difluoro-γ-lactams from simple and readily available starting materials under mild reaction conditions.

A Single Electron Transfer (SET) Approach to C-H Amidation of Hydrazones via Visible-Light Photoredox Catalysis.

The reductive single electron transfer (SET) umpolung amination of aldehyde-derived hydrazones has been developed through visible-light-promoted photoredox catalysis. The ideal transformation of hydrazones into the corresponding hydrazonamide through selective carbon-hydrogen (C-H) bond functionalization represents one of the most step- and atom-economical methods. This SET umpolung strategy features mild conditions and a remarkably broad substrate scope, offering an entirely new substrate class to direct C-H amination.