Stereocontrolled Synthesis of 1,4‐Dicarbonyl Compounds by Photochemical Organocatalytic Acyl Radical Addition to Enals

We report a visible‐light‐mediated organocatalytic strategy for the enantioselective acyl radical conjugate addition to enals, leading to valuable 1,4‐dicarbonyl compounds. The process capitalizes upon the excited‐state reactivity of 4‐acyl‐1,4‐dihydropyridines that, upon visible‐light absorption, can trigger the generation of acyl radicals. By means of a chiral amine catalyst, iminium ion activation of enals ensures a stereoselective radical trap. We also demonstrate how the combination of this acylation process with a second catalyst‐controlled bond‐forming event allows to selectively access the full matrix of all possible stereoisomers of the resulting 2,3‐substituted 1,4‐dicarbonyl products.     

On the Role of Pre‐ and Post‐Electron‐Transfer Steps in the SmI2/Amine/H2O‐Mediated Reduction of Esters: New Mechanistic Insights and Kinetic Studies

The mechanism of the SmI₂‐mediated reduction of unactivated esters has been studied using a combination of kinetic, radical clocks and reactivity experiments. The kinetic data indicate that all reaction components (SmI₂, amine, H₂O) are involved in the rate equation and that electron transfer is facilitated by Brønsted base assisted deprotonation of water in the transition state. The use of validated cyclopropyl‐containing radical clocks demonstrates that the reaction occurs via fast, reversible first electron transfer, and that the electron transfer from simple Sm(II) complexes to aliphatic esters is rapid. Notably, the mechanistic details presented herein indicate that complexation between SmI₂, H₂O and amines affords a new class of structurally diverse, thermodynamically powerful reductants for efficient electron transfer to carboxylic acid derivatives as an attractive alternative to the classical hydride‐mediated reductions and as a source of acyl‐radical equivalents for C?C bond forming processes.     

A Visible‐Light‐Driven Iminyl Radical‐Mediated C−C Single Bond Cleavage/Radical Addition Cascade of Oxime Esters

A room‐temperature, visible‐light‐driven N‐centered iminyl radical‐mediated and redox‐neutral C?C single bond cleavage/radical addition cascade reaction of oxime esters and unsaturated systems has been accomplished. The strategy tolerates a wide range of O‐acyl oximes and unsaturated systems, such as alkenes, silyl enol ethers, alkynes, and isonitrile, enabling highly selective formation of various chemical bonds. This method thus provides an efficient approach to various diversely substituted cyano‐containing alkenes, ketones, carbocycles, and heterocycles.     

Photo‐Organocatalytic Enantioselective Radical Cascade Reactions of Unactivated Olefins

Radical cascade processes are invaluable for their ability to rapidly construct complex chiral molecules from simple substrates. However, implementing catalytic asymmetric variants is difficult. Reported herein is a visible‐light‐mediated organocatalytic strategy that exploits the excited‐state reactivity of chiral iminium ions to trigger radical cascade reactions with high enantioselectivity. By combining two sequential radical‐based bond‐forming events, the method converts unactivated olefins and α,β‐unsaturated aldehydes into chiral adducts in a single step. The implementation of an asymmetric three‐component radical cascade further demonstrates the complexity‐generating power of this photochemical strategy.     

A Rhodium Catalyst Superior to Iridium Congeners for Enantioselective Radical Amination Activated by Visible Light

A bis‐cyclometalated rhodium(III) complex catalyzes a visible‐light‐activated enantioselective α‐amination of 2‐acyl imidazoles with up to 99 % yield and 98 % ee. The rhodium catalyst is ascribed a dual function as a chiral Lewis acid and, simultaneously, as a light‐activated smart initiator of a radical‐chain process through intermediate aminyl radicals. Notably, related iridium‐based photoredox catalysts reported before were unsuccessful in this enantioselective radical C?N bond formation. The surprising preference for rhodium over iridium is attributed to much faster ligand‐exchange kinetics of the rhodium complexes involved in the catalytic cycle, which is crucial to keep pace with the highly reactive and thus short‐lived nitrogen‐centered radical intermediate.     

Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones by the Decarboxylative Arylation of α‐Oxo Acids

The direct decarboxylative arylation of α‐oxo acids has been achieved by synergistic visible‐light‐mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone architectures from simple α‐oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners. This mild decarboxylative arylation can also be utilized to efficiently access medicinal agents, as demonstrated by the rapid synthesis of fenofibrate.     

Exploiting Imine Photochemistry for Masked N‐Centered Radical Reactivity

This report details the development of a masked N‐centered radical strategy that harvests the energy of light to drive the conversion of cyclopropylimines to 1‐aminonorbornanes. This process employs the N‐centered radical character of a photoexcited imine to facilitate the homolytic fragmentation of the cyclopropane ring and the subsequent radical cyclization sequence that forms two new C?C bonds en route to the norbornane core. Achieving bond‐forming reactivity as a function of the N‐centered radical character of an excited state Schiff base is unique, requiring only violet light in this instance. This methodology operates in continuous flow, enhancing the potential to translate beyond the academic sector. The operational simplicity of this photochemical process and the structural novelty of the (hetero)aryl‐fused 1‐aminonorbornane products are anticipated to provide a valuable addition to discovery efforts in pharmaceutical and agrochemical industries.     

Visible‐Light‐Promoted Iminyl‐Radical Formation from Acyl Oximes: A Unified Approach to Pyridines,Quinolines, and Phenanthridines

A unified strategy involving visible‐light‐induced iminyl‐radical formation has been established for the construction of pyridines, quinolines, and phenanthridines from acyl oximes. With fac‐[Ir(ppy)₃] as a photoredox catalyst, the acyl oximes were converted by 1 e^? reduction into iminyl radical intermediates, which then underwent intramolecular homolytic aromatic substitution (HAS) to give the N‐containing arenes. These reactions proceeded with a broad range of substrates at room temperature in high yield. This strategy of visible‐light‐induced iminyl‐radical formation was successfully applied to a five‐step concise synthesis of benzo[c]phenanthridine alkaloids.     

Visible‐Light‐Promoted Iminyl‐Radical Formation from Acyl Oximes: A Unified Approach to Pyridines,Quinolines, and Phenanthridines

A unified strategy involving visible‐light‐induced iminyl‐radical formation has been established for the construction of pyridines, quinolines, and phenanthridines from acyl oximes. With fac‐[Ir(ppy)₃] as a photoredox catalyst, the acyl oximes were converted by 1 e⁻ reduction into iminyl radical intermediates, which then underwent intramolecular homolytic aromatic substitution (HAS) to give the N‐containing arenes. These reactions proceeded with a broad range of substrates at room temperature in high yield. This strategy of visible‐light‐induced iminyl‐radical formation was successfully applied to a five‐step concise synthesis of benzo[c]phenanthridine alkaloids.     

Visible‐Light‐Mediated Photocatalytic Difunctionalization of Olefins by Radical Acylarylation and Tandem Acylation/Semipinacol Rearrangement

A novel method for the mild photoredox‐mediated tandem radical acylarylation and tandem acylation/semipinacol rearrangement has been developed. The synthesis of highly functionalized ketones bearing all‐carbon α‐ or β‐quaternary centers has been achieved using easily available symmetric aromatic carboxylic anhydrides as the acyl radical source. The method allows for a straightforward introduction of the keto functionality and concomitant construction of molecular complexity in a single operation.     

Visible‐Light‐Promoted Cascade Radical Cyclization: Synthesis of 1,4‐Diketones Containing Chroman‐4‐One Skeletons

A visible‐light‐induced cascade radical cyclization of aroyl chlorides with 2‐(allyloxy)‐benzaldehyde derivatives has been developed. The method takes advantages of unactivated C=C bonds as the acyl radical acceptors and offers a mild and green approach for the synthesis of 1,4‐diketones bearing biologically important chroman‐4‐one skeletons with moderate to good yields.     

光催化甲苯衍生物、环烷烃与无机亚磺酸盐的位点选择性C(sp3)-H砜基化

烃类是最基础的有机分子之一,具有品种丰富、来源广泛、价格低廉等优势,其多样性、选择性转化一直备受合成化学家关注.然而,这些化合物中通常存在多个键能高、极性低、相互间差异性小的C(sp3)-H键,因此,实现高效、选择性C-H官能化极具挑战性.近年来,可见光催化广泛应用于有机合成中,与氢转移催化相结合所发展的可见光氢转移光...     

Nucleophilic Attack of α‐Aminoalkyl Radicals on Carbon?Nitrogen Triple Bonds to Construct α‐Amino Nitriles: An Experimental and Computational Study

A new reactivity pattern of α‐aminoalkyl radicals, involving nucleophilic attack on C?N triple bonds under thermal conditions, has been developed to construct α‐amino nitriles. In contrast to previous C? H functionalization of tertiary amines involving α‐aminoalkyl radicals, this methodology does not require the use of photocatalytic conditions or a transition‐metal catalyst. Inexpensive and nontoxic phenylacetonitrile was chosen as cyano source for this α‐aminonitrile forming reaction. A plausible mechanism is proposed based upon experimental and computational results. An α‐aminoalkyl radical intermediate and benzoyl cyanide have been shown to be key intermediates in this green and mild radical process. Nucleophilic attack of the α‐aminoalkyl radical on the C?N bond of PhCOCN followed by an elimination step forms the desired α‐aminonitrile and an acyl radical.     

Visible‐Light‐Driven Aza‐ortho‐quinone Methide Generation for the Synthesis of Indoles in a Multicomponent Reaction

A visible‐light‐driven radical‐mediated strategy for the in situ generation of aza‐ortho ‐quinone methides from 2‐vinyl‐substituted anilines and alkyl radical precursors is described. This process enables an efficient multicomponent reaction of 2‐vinylanilines, halides, and sulfur ylides, and has a wide substrate scope and good functional group tolerance. Treatment of the cycloaddition products with a base leads to densely functionalized indoles in a single‐flask operation.     

Polarity Umpolung Strategy for the Radical Alkylation of Alkenes

Free radical mediated alkylation of alkenes is a challenging and largely unmet goal. Disclosed here is a conceptually novel “polarity umpolung” strategy for radical alkylation of alkenes using a portfolio of easily accessed, difunctional alkylating reagents. This strategy is achieved by substituting inherently nucleophilic alkyl radicals with electrophilic sulfone‐bearing surrogates, thus inverting the usual mode of reactivity. Along with alkylation, either an heteroaryl or oximino group is concurrently incorporated into the alkenes by a consecutive docking and migration process, leading to valuable products. The reaction displays a broad functional‐group tolerance under mild reaction conditions. The protocol opens new vistas for the late‐stage modification of complex natural products and drug molecules containing alkene moieties.     

Dual Hypervalent Iodine(III) Reagents and Photoredox Catalysis Enable Decarboxylative Ynonylation under Mild Conditions

A combination of hypervalent iodine(III) reagents (HIR) and photoredox catalysis with visible light has enabled chemoselective decarboxylative ynonylation to construct ynones, ynamides, and ynoates. This ynonylation occurs effectively under mild reaction conditions at room temperature and on substrates with various sensitive and reactive functional groups. The reaction represents the first HIR/photoredox dual catalysis to form acyl radicals from α‐ketoacids, followed by an unprecedented acyl radical addition to HIR‐bound alkynes. Its efficient construction of an mGlu5 receptor inhibitor under neutral aqueous conditions suggests future visible‐light‐induced biological applications.     

Dual Catalysis Sees the Light: Combining Photoredox with Organo‐, Acid,and Transition‐Metal Catalysis

The photoredox activation of organic substrates with visible light is a powerful methodology that generates reactive radical species under very mild conditions. When combined with another catalytic process in a dual catalytic system, novel, visible‐light‐promoted transformations have been realized that do not proceed using either catalyst in isolation. In this minireview, the state of the art in organic reactions mediated by dual catalytic systems merging photoredox activation with organo‐, acid or metal catalysis is discussed.     

Photoredox Imino Functionalizations of Olefins

Shown herein is that polyfunctionalized nitrogen heterocycles can be easily prepared by a visible‐light‐mediated radical cascade process. This divergent strategy features the oxidative generation of iminyl radicals and subsequent cyclization/radical trapping, which allows the effective construction of highly functionalized heterocycles. The reactions proceed efficiently at room temperature, utilize an organic photocatalyst, use simple and readily available materials, and generate, in a single step, valuable building blocks that would be difficult to prepare by other methods.     

N‐Heterocyclic Carbene Catalyzed Photoenolization/Diels–Alder Reaction of Acid Fluorides

The combination of light activation and N‐heterocyclic carbene (NHC) organocatalysis has enabled the use of acid fluorides as substrates in a UVA‐light‐mediated photochemical transformation previously observed only with aromatic aldehydes and ketones. Stoichiometric studies and TD‐DFT calculations support a mechanism involving the photoactivation of an ortho‐toluoyl azolium intermediate, which exhibits “ketone‐like” photochemical reactivity under UVA irradiation. Using this photo‐NHC catalysis approach, a novel photoenolization/Diels–Alder (PEDA) process was developed that leads to diverse isochroman‐1‐one derivatives.     

Polar effects in free‐radical reactions. A novel homolytic acylation of heteroaromatic bases by aerobic oxidation of aldehydes,catalysed by N‐hydroxyphthalimide and Co salts

A new process for the homolytic acylation of protonated heteroaromatic bases is described; an N‐oxyl radical (PINO) generated from N‐hydroxyphthalimide by air oxygen and Co(II) abstracts a hydrogen atom from an aldehyde. The resulting nucleophilic acyl radical adds to a heteroaromatic base, which is then rearo‐matised in a chain process. Quinazoline has an anomalous behaviour, giving 3H‐quinazolin‐4‐one as the only reaction product.