Economical,Green, and Safe Route Towards Substituted Lactones by Anodic Generation of Oxycarbonyl Radicals

A new electrochemical methodology has been developed for the generation of oxycarbonyl radicals under mild and green conditions from readily available hemioxalate salts. Mono‐ and multi‐functionalised γ‐butyrolactones were synthesised through exo‐cyclisation of these oxycarbonyl radicals with an alkene, followed by the sp³–sp³ capture of the newly formed carbon‐centred radical. The synthesis of functionalised valerolactone derivatives was also achieved, demonstrating the versatility of the newly developed methodology. This represents a viable synthetic route towards pharmaceutically important fragments and further demonstrates the practicality of electrosynthesis as a green and economical method to activate small organic molecules.     

Photoinduced Remote Functionalisations by Iminyl Radical Promoted C−C and C−H Bond Cleavage Cascades

A photoinduced cascade strategy leading to a variety of differentially functionalised nitriles and ketones has been developed. These reactions rely on the oxidative generation of iminyl radicals from simple oximes. Radical transposition by C(sp³)−(sp³) and C(sp³)−H bond cleavage gives access to distal carbon radicals that undergo S_H2 functionalisations. These mild, visible‐light‐mediated procedures can be used for remote fluorination, chlorination, and azidation, and were applied to the modification of bioactive and structurally complex molecules.     

An Interrupted Pummerer/Nickel‐Catalysed Cross‐Coupling Sequence

An interrupted Pummerer/nickel‐catalysed cross‐coupling strategy has been developed and used in the elaboration of styrenes. The operationally simple method can be carried out as a one‐pot process, involves the direct formation of stable alkenyl sulfonium salt intermediates, utilises a commercially available sulfoxide, catalyst, and ligand, operates at ambient temperature, accommodates sp‐, sp²‐, and sp³‐hybridised organozinc coupling partners, and delivers functionalised styrene products in high yields over two steps. An interrupted Pummerer/cyclisation approach has also been used to access carbo‐ and heterocyclic alkenyl sulfonium salts for cross‐coupling.     

Regioselective Vinylation of Remote Unactivated C(sp3)−H Bonds: Access to Complex Fluoroalkylated Alkenes

Regioselective incorporation of a particular functional group into aliphatic sites by direct activation of unreactive C?H bonds is of great synthetic value. Despite advances in radical‐mediated functionalization of C(sp³)?H bonds by a hydrogen‐atom transfer process, the site‐selective vinylation of remote C(sp³)?H bonds still remains underexplored. Reported herein is a new protocol for the regioselective vinylation of unactivated C(sp³)?H bonds. The remote C(sp³)?H activation is promoted by a C‐centered radical instead of the commonly used N and O radicals. The reaction possesses high product diversity and synthetic efficiency, furnishing a plethora of synthetically valuable E alkenes bearing tri‐/di‐/mono‐fluoromethyl and perfluoroalkyl groups.     

γ‐Functionalizations of Amines through Visible‐Light‐Mediated,Redox‐Neutral C−C Bond Cleavage

Cleavage of unstrained C−C bonds under mild, redox‐neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible‐light‐mediated, γ‐functionalization of amines. In situ generated C‐centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp³)−C(sp³), C(sp³)−H and C(sp³)−Br bonds, respectively.     

Homolytic,Heterolytic, Mesolytic ‐ As You Like It: Steering the Cleavage of a HC(sp3)−C(sp3)H Bond in Bis(1H‐2,1‐benzazaborole) Derivatives

A set of (3,3′)‐bis(1‐Ph‐2‐R‐1H‐2,1‐benzazaborole) compounds, in which R=tBu (Bab‐tBu)₂ , R=Dipp (Bab‐Dipp)₂ or R=tBu and Dipp (Bab‐Dipp)(Bab‐tBu) , was synthesized and fully characterized using ¹H, ¹¹B, ¹³C, and ¹⁵N NMR spectroscopy as well as single‐crystal X‐ray diffraction analysis. The central HC(sp³)?C(sp³)H bond with restricted rotation at the junction of both 1H‐2,1‐benzazaborole rings displayed an intriguing reactivity. It was demonstrated that this bond is easily mesolytically cleaved using alkali metals to form the respective aromatic 1Ph‐2R‐1H‐2,1‐benzazaborolyl anions M⁺(THF) _n (Bab‐tBu)^? (M=Li, Na, K) and K⁺(THF) _n (Bab‐Dipp)^? . Furthermore, the central HC(sp³)?C(sp³)H bond of bis(1H‐2,1‐benzazaborole)s is also homolytically cleaved either by heating or photochemical means, giving corresponding 1Ph‐2R‐1H‐2,1‐benzazaborolyl radicals (Bab‐tBu)^. and (Bab‐Dipp)^., which rapidly self‐terminate. Nevertheless, their formation was unambiguously established by NMR analysis of the reaction mixtures containing products of the self‐termination of the radicals after heating or irradiation. (Bab‐Dipp)^. radical was also characterized using EPR spectroscopy. Importantly, it turned out that the essentially non‐polarized HC(sp³)?C(sp³)H bond in (Bab‐tBu)₂ is also cleaved heterolytically with 2 equiv of MeLi, giving the mixture of Li⁺(SOL) _n (Bab‐tBu)^? (SOL=THF or Et₂O) and lithium methyl‐substituted borate complex Li⁺(SOL) _n (Bab‐tBu‐Me)^? in a diastereoselective fashion.     

γ‐Functionalizations of Amines through Visible‐Light‐Mediated,Redox‐Neutral C−C Bond Cleavage

Cleavage of unstrained C−C bonds under mild, redox‐neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible‐light‐mediated, γ‐functionalization of amines. In situ generated C‐centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp³)−C(sp³), C(sp³)−H and C(sp³)−Br bonds, respectively.     

Multicomponent Oxyalkylation of Styrenes Enabled by Hydrogen‐Bond‐Assisted Photoinduced Electron Transfer

Herein, we disclose a strategy for the activation of N‐(acyloxy)phthalimides towards photoinduced electron transfer through hydrogen bonding. This activation mode enables efficient access to C(sp³)‐centered radicals upon decarboxylation from bench‐stable and readily available substrates. Moreover, we demonstrate that the formed alkyl radicals can be successfully employed in a novel redox‐neutral method for constructing sp³−sp³ bonds across styrene moieties that gives straightforward access to complex alcohol and ether scaffolds.     

Trifluoromethylation of Alkyl Radicals: Breakthrough and Challenges†

Trifluoromethylation of alkyl radicals is emerging as a powerful tool for C(sp³)–CF₃ bond formations. Based on the hypothesis of CF₃ group transfer from Cu(II)–CF₃ to alkyl radicals, a number of trifluoromethylation reactions have been developed, including trifluoromethylation of alkyl halides, decarboxylative trifluoromethylation of aliphatic carboxylic acids, C(sp³)–H trifluoromethylation, amino‐ and carbo‐trifluoromethylation of alkenes, etc. Challenges in this intriguing field are also discussed.     

Visible‐Light‐Driven Palladium‐Catalyzed Radical Alkylation of C−H Bonds with Unactivated Alkyl Bromides

Reported herein is a novel visible‐light photoredox system with Pd(PPh₃)₄ as the sole catalyst for the realization of the first direct cross‐coupling of C(sp³)−H bonds in N‐aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra‐ and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp³)−C(sp³) and C(sp²)−C(sp³) bonds in moderate to excellent yields. These redox‐neutral reactions feature broad substrate scope (>60 examples), good functional‐group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible‐light photocatalyst and radicals are involved in the process.     

Selective Functionalization of Aromatic C(sp2)−H Bonds in the Presence of Benzylic C(sp3)−H Bonds by Electron‐Deficient Carbenoids Generated from 4‐Acyl‐1‐Sulfonyl‐1,2,3‐Triazoles

A rhodium(II)‐catalyzed reaction of newly prepared 4‐acyl‐1‐sulfonyl‐1,2,3‐triazoles with benzene, and its derivatives, is investigated. Acceptor/acceptor carbenoids generated from 4‐acyltriazoles undergo selective insertion at aromatic C(sp²)−H bonds in the presence of benzylic C(sp³)−H bonds to produce N ‐sulfonylenaminones.     

Donor–Acceptor Complex Enables Alkoxyl Radical Generation for Metal‐Free C(sp3)–C(sp3) Cleavage and Allylation/Alkenylation

The alkoxyl radical is an essential and prevalent reactive intermediate for chemical and biological studies. Here we report the first donor–acceptor complex‐enabled alkoxyl radical generation under metal‐free reaction conditions induced by visible light. Hantzsch ester forms the key donor–acceptor complex with N ‐alkoxyl derivatives, which is elucidated by a series of spectrometry and mechanistic experiments. Selective C(sp³)‐C(sp³) bond cleavage and allylation/alkenylation is demonstrated for the first time using this photocatalyst‐free approach with linear primary, secondary, and tertiary alkoxyl radicals.     

Synthesis of Functionalized [3], [4], [5] and [6]Dendralenes through Palladium-Catalyzed Cross-Couplings of Substituted Allenoates

A mild method for the synthesis of highly functionalized [3]–[6]dendralenes is reported, representing a general strategy to diversely substituted higher homologues of the dendralenes. The methodology utilizes allenoates bearing various substitution patterns, along with a wide range of boron and alkenyl nucleophiles that couple under palladium catalysis leading to sp-, sp²-, and sp³-substituted arrays. Regioselective transformations of the newly formed unsymmetrical dendralene derivatives are demonstrated. The use of micellar catalysis, where water is the global reaction medium, and room temperature reaction conditions, highlights the green nature of this technology.     

Oxydifluoromethylation of Alkenes by Photoredox Catalysis: Simple Synthesis of CF2H‐Containing Alcohols

We have developed a novel and simple protocol for the direct incorporation of a difluoromethyl (CF₂H) group into alkenes by visible‐light‐driven photoredox catalysis. The use of fac‐[Ir(ppy)₃] (ppy=2‐pyridylphenyl) photocatalyst and shelf‐stable Hu's reagent, N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine, as a CF₂H source is the key to success. The well‐designed photoredox system achieves synthesis of not only β‐CF₂H‐substituted alcohols but also ethers and an ester from alkenes through solvolytic processes. The present method allows a single‐step and regioselective formation of C(sp³)–CF₂H and C(sp³)?O bonds from C=C moiety in alkenes, such as hydroxydifluoromethylation, regardless of terminal or internal alkenes. Moreover, this methodology tolerates a variety of functional groups.     

Three Isostructural 4‐Sulfophthalate‐Based Lanthanide Complexes: Syntheses,Crystal Structures,and Luminescent Properties

Three lanthanide complexes with the ligand 4‐sulfophthalate (sp^3–), [Ln(H₂O)₂(sp)]_n [Ln = Dy ( 1 ), Tb ( 2 ), and Er ( 3 )], were solvo‐/hydrothermally synthesized by changing the rare earth cations, and were characterized structurally and photophysically. Complexes 1 – 3 are isostructural, exhibiting a two‐dimensional layered structure with centrosymmetric dinuclear subunits infinitely extended by 4‐connected sp^3– connectors. Photoluminescence spectra of 1 – 3 demonstrate that anionic sp^3– ligand can serve as a functionalized chromophore to sensitize the luminescent emission of the lanthanide ion, suggesting that the sp^3–‐involved lanthanide complexes can be used as novel optical materials.     

Transition‐metal‐free Chemoselective Oxidative C−C Coupling of the sp3 C−H Bond of Oxindoles with Arenes and Addition to Alkene: Synthesis of 3‐Aryl Oxindoles,and Benzofuro‐ and Indoloindoles

A transition‐metal (TM)‐free and halogen‐free NaOt Bu‐mediated oxidative cross‐coupling between the sp³ C−H bond of oxindoles and sp² C−H bond of nitroarenes has been developed to access 3‐aryl substituted and 3,3‐aryldisubstituted oxindoles in DMSO at room temperature in a short time. Interestingly, the sp³ C−H bond of oxindoles could also react with styrene under TM‐free conditions for the practical synthesis of quaternary 3,3‐disubstituted oxindoles. The synthesized 3‐oxindoles have also been further transformed into advanced heterocycles, that is, benzofuroindoles, indoloindoles, and substituted indoles. Mechanistic experiments of the reaction suggests the formation of an anion intermediate from the sp³ C−H bond of oxindole by tert ‐butoxide base in DMSO. The addition of nitrobenzene to the in‐situ generated carbanion leads to the 3‐(nitrophenyl)oxindolyl carbanion in DMSO which is subsequently oxidized to 3‐(nitro‐aryl) oxindole by DMSO.     

Synthesis,Crystal Structure,and Antibacterial Activity of 1,2,4‐Triazoles and 1,2,4‐Triazol‐3‐one

A straightforward method has been developed for the synthesis of 1,2,4‐triazol‐3‐one 3 and 1,2,4‐triazoles 6a , 6b , 6c , 6d starting from N¹‐substituted‐N¹‐tosylhydrazonates 2 and hydrazine monohydrate. This methodology affords a number of 1,2,4‐triazol‐3‐one 3 and 1,2,4‐triazoles 6a , 6b , 6c , 6d in reasonable yields. The structures of all new compounds were elucidated using infrared, ¹H and ¹³C NMR, high‐resolution mass spectrometry, elemental analysis, and the X‐ray crystallography (for compounds 3 and 6a ). Some of the newly synthesized compounds were screened for their antibacterial activity.     

Synthesis of Pyrrolophenanthridine Alkaloids Based on C(sp3)H and C(sp2)H Functionalization Reactions

Assoanine, pratosine, hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C? H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp³)? H functionalization followed by a Catellani reaction, including C(sp²)? H functionalization. A one‐pot reaction involving both C(sp³)? H and C(sp²)? H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups.     

Direct sp3 C?H Amination of Nitrogen‐Containing Benzoheterocycles Mediated by Visible‐Light‐Photoredox Catalysts

Visible‐light‐mediated direct sp³ C? H amination of benzocyclic amines via α‐aminoalkyl radicals by using photoredox catalysts is described here. The obtained N,N‐acetals were also successfully applied for carbon–carbon bond forming reactions with carbon nucleophiles. The procedure is suitable for a late‐stage modification of C? H bonds to C? C bonds.     

Visible‐Light‐Mediated Remote Aliphatic C−H Functionalizations through a 1,5‐Hydrogen Transfer Cascade

A redox‐neutral, light‐mediated functionalization of unactivated C(sp³)−H bonds via iminyl radicals is presented here. A 1,5‐H transfer followed by the functionalization of a C(sp²)−H bond takes place in aqueous media producing a variety of elaborated fused ketones. Mechanistic investigations have revealed 1,5‐H transfer as the reversible, rate‐determining step in this transformation. Divergent scaffolds are also accessible via C(sp³)−N bond formation upon a careful choice of the reaction additives.