Transition-Metal-Free Multicomponent Reaction of Quinoxalinones with Alkenes and Zhdankin Reagent through Photoredox Catalysis

A photo-induced three-component coupling reaction of quinoxalinones with unactivated alkenes and azidobenziodoxolone (ABX, Zhdankin reagent) was developed. The protocol provides an efficient approach for the synthesis of various bioactive organoazides with quinoxalinone scaffold in moderate to good yields under mild conditions. This reaction is environmentally friendly avoiding the use of expensive transition-metal photocatalysts and stoichiometric oxidants.     

Electro-reductive C-H cyanoalkylation of quinoxalin-2(1H)-ones

Herein, we report a practical electro-reductive protocol for the direct C–H cyanoalkylation of quinoxalin-2(1H)-ones via iminyl radical-mediated ring opening. These mild reactions proceed under metal-, reductant-, and reagent-free conditions to provide synthetically useful cyanoalkylated quinoxalin-2(1H)-ones.     

Visible light/Ir(III) photocatalytic initiation of xanthate-based radical-chain reactions: Xanthate group transfer and oxidative addition to aromatic systems

A photocatalyzed redox generation of radicals from O-ethyl xanthates to generate electrophilic radicals under photoredox catalysis, using Ir(ppy)₃ and blue LEDs irradiation is described. The protocol can be used in classical xanthate-based inter- and intra-molecular group transfer reactions and oxidative radical addition to several heteroaromatic systems. The process does not require high temperature and reactions are cleaner compared with the traditional peroxide initiation. In the oxidative addition to aromatic systems, the oxidation process is part of the catalytic cycle and does not require a stoichiometric oxidant such as DLP which is particularly difficult to separate from the product.     

Traceless polymer-supported divergent synthesis of quinoxalinones by microwave irradiation

A novel protocol for rapid assemble of quinoxalinones framework has been demonstrated. This method incorporated with soluble polymer support provides a convenient approach for diversification of heterocyclic compounds and for easy purification via facile precipitation from reaction matrix. The key transformation of this study involves in situ reduction of aromatic nitro compound, tandem lactamization concomitant with traceless cleavage of the polymer support under microwave irradiation in a one-pot fashion. Moreover, forward synthetic routes were introduced to maximize complexity of the master intermediate on which further chemical elaboration was applied. The strategy is envisaged to apply for establishment of drug-like small-molecule libraries for high-throughput screening.     

Enantioselective α‐Alkylation of Aldehydes by Photoredox Organocatalysis: Rapid Access to Pharmacophore Fragments from β‐Cyanoaldehydes

The combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective α‐cyanoalkylation of aldehydes. This synergistic catalysis protocol allows for the coupling of two highly versatile yet orthogonal functionalities, allowing rapid diversification of the oxonitrile products to a wide array of medicinally relevant derivatives and heterocycles. This methodology has also been applied to the total synthesis of the lignan natural product (?)‐bursehernin.     

Iron(II)-catalyzed direct CH cyanoalkylation of 2H-indazoles and coumarins via radical CC bond cleavage

An iron-catalyzed C-3 cyanoalkylation of 2H-indazole and coumarin derivates with cyclobutanone oxime esters has been accomplished, which proceeds efficiently in a high regioselective manner to construct diverse alkylated 2H-indazole and coumarin derivates in moderate to good yields. Preliminary mechanistic studies reveal that a distal cyanosubstituted alkyl radicals intermediate would be formed through radical-involved CC bond cleavage of cyclobutanone oximes ester.     

CuCl2-Catalyzed α-Chloroketonation of Aromatic Alkenes via Visible-Light-Induced LMCT

Here we report a copper-catalyzed protocol for the synthesis of α-chloroketones from aromatic alkenes including electron-deficient olefins under visible-light irradiation. Preliminary mechanistic studies show that the peroxo Cu(II) species is the key intermediate and hydroperoxyl (HOO⋅) and chlorine (Cl⋅) radicals can be generated by ligand-to-metal charge transfer (LMCT).     

铜催化烯烃氰烷基化成环合成含氰吲哚酮

发展一种简单、高效的铜催化活泼烯烃氰烷基化成环合成吲哚酮的方法。 在CuI/DTBP(叔丁基过氧化物)催化作用下, N-芳基丙烯酰胺类化合物与α-氰基偶氮试剂发生自由基环化反应, 高效地合成了一系列含α-氰基季碳中心的吲哚酮, 并探讨了其反应机理。 该方法底物适用范围较广、反应体系温和, 催化体系廉价。     

The coupling of alkylboronic acids and esters with Baylis–Hillman derivatives by Lewis base/photoredox dual catalysis

Utilizing Lewis base/photoredox dual catalysis, carbon radicals generated from either alkylboronic acids or esters were coupled with Baylis–Hillman derivatives under visible light irradiation. This protocol provides a mild and operationally simple method for the synthesis of a variety of α,β-unsaturated carbonyl compounds in a broad scope of the substrates. The mechanism of Lewis base activation and reductive quenching cycle was probably involved.     

Selective and sensitive determination of hydroxyl radicals generated from living cells through an electrochemical impedance method

An efficient protocol for selective and sensitive detection of generated hydroxyl radicals was first developed in the photocatalytic system through an electrochemical impedance method and further successfully applied to monitor hydroxyl radicals in the LPS-mediated cellular ROS/RNS burst process.     

Cu‐Catalyzed Selective Oxy‐Cyanoalkylation of Allylamines with Cycloketone Oxime Esters and CO2

The radical‐initiated carboxylative cyclization of allylamines with CO₂ represents an efficient and highly promising strategy to afford valuable 2‐oxazolidinones. However, the radical precursors and pathways to generate radicals in such processes are still limited. Herein, we report the first Cu‐catalyzed selective oxy‐cyanoalkylation of allylamines with cycloketone oxime esters and CO₂ via C—C bond cleavage. Many cyanoalkyl‐substituted 2‐oxazolidinones are obtained in moderate to good yields with high regio‐ and chemo‐selectivities. The utility of this redox‐neutral and cyanide‐free method is demonstrated with mild conditions, broad substrate scope, good functional group tolerance and easy scalability.     

Two-photon chemistry in the laser jet: generation of radical intermidiates and their photochemical transformations

The novel laser jet technique provides sufficiently high photon densities to permit the observation of the photochemistry of photochemically generated radicals (two-photon chemistry) in the liquid phase. Four recent applications of this novel photochemically useful method are presented: these include the photochemistry of hydroxydiphenylmethyl, 9-hydroxyxanthenyl, diphenylmethyl, and benzoyl radicals under laser jet and normal photolysis conditions.

The regioselectivity of cross-coupling reactions of hydroxydiphenylmethyl or 9-hydroxyxanthenyl radicals with solvent-derived radicals changes when these species are electronically excited,i.e. under the high intensity conditions of the laser jet, cross-coupling at the para position (head-to-tail combination) is significantly enhanced relative to the normal coupling mode at the hydroxy-bearing radical site (head-to-head combination). Semiempirical calculations of the spin density distributions for the ground and first excited states of the radicals confirm the change in spin density from the hydroxy-bearing carbon atom to the conjugating benzene rings in these radical species on photoexcitation.

For the diphenylmethyl radical, two reaction pathways have been observed under the high photon densities of the laser jet: the electronically excited diphenylmethyl radical can either abstract a chlorine atom from carbon tetrachloride through an electron transfer process or can be photoionized on further photoexcitation (multiphoton chemistry). The resulting benzhydryl cation was trapped by methanol as the corresponding ether product, which unequivocally demonstrates that carbene formation by photoejection of a hydrogen atom does not take place under laser jet photolysis conditions.

An advantage of the high photon densities produced in laser jet photolysis is the high steady state concentration of short-lived transients that are generated, which enable unprecedented intermolecular reactions to be observed. Thus, about a millimolar concentration of tert-butoxy radicals can be obtained in the laser jet photocleavage of tert-butyl peroxide. When the tert-butoxy radicals are produced in the presence of benzaldehyde, the main product is tert-butyl benzoate. If carbon tetrachloride is also present, chlorobenzene can be detected. This is rationalized as the product derived from chlorine abstraction by phenyl radicals, which are presumably produced by the photodecarbonylation of benzoyl radicals.

An alternative method of obtaining benzoyl radicals is the two-photon cleavage of benzil. The laser jet photolysis of benzil in tert-butyl peroxide yields mainly tert-butyl benzoate, whereas in carbon tetrachloride, benzoyl chloride, chlorobenzene and ,,-trichloroacetophenone are observed. The first two products result from chlorine atom abstraction by the photochemically generated benzoyl and phenyl radicals, and the last product from in-cage cross-coupling between benzoyl and trichloromethyl radicals.

Such product studies provide detailed mechanistic information on the photochemical behaviour of electronically excited, short-lived transients which complements nicely the kinetic and spectral data of time-resolved laser flash studies. Consequently, the laser jet technique constitutes a valuable tool for determining the mechanism of two- photon reactions.     

Cyclisation of α-chiral aminyl radicals

α-Chiral aminyl radicals have been generated from sulfenamides of α-amino acid esters and α-phenylethylamine using Bu₃SnH. The aminyl radicals of α-amino acid esters undergo 5-exo-trig cyclisation reactions onto side chain alkenes to yield proline analogues with reasonable diastereoselectivity. Preliminary studies show urethanyl radicals generated from sulfenamides of alkenyl urethane derivatives of α-amino acid esters and α-phenylethylamine undergo 5-exo-rig cyclisations to providing a protocol for the radical amination of unactivated alkenes. The α-ester of the amino acid or the urethane groups impart electrophilic behaviour to the aminyl radicals and facilitates cyclisation onto alkenes.     

Hypervalent iodine mediated C-H amination of quinoxalinones with heteroaromatic amines under metal-free conditions

An efficient and facile method for C–H amination of quinoxalinones with heteroaromatic amines under metal-free conditions has been described. In the presence of hypervalent PIDA reagent, the desired products with various groups were obtained with moderate to high yields.     

Copper-catalyzed aryldifluoromethylenation of N-arylacrylamides to synthesis of the diheterocyclic compounds linked by gem-difluoromethylene moiety

An efficient method of copper-catalyzed aryldifluoromethylenation of N-arylacrylamides is described to step-economic synthesis of the various biologically important biheterocyclic compounds linked by gem-difluoromethylene moiety through addition of benzo-1,3-azolic (oxa- or thia-)difluoromethyl radicals generated in situ to terminal of C–C double bond of N-arylacrylamides then cyclization cascade. This protocol has demonstrated to have broad substrate scope and excellent functional-group tolerance under mild reaction conditions.     

Catalytic C−H Trifluoromethoxylation of Arenes and Heteroarenes

The intermolecular C?H trifluoromethoxylation of arenes remains a long‐standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a novel trifluoromethoxylating reagent and redox‐active catalysts for the direct (hetero)aryl C?H trifluoromethoxylation. Our approach is operationally simple, proceeds at room temperature, uses easy‐to‐handle reagents, requires only 0.03 mol % of redox‐active catalysts, does not need specialized reaction apparatus, and tolerates a wide variety of functional groups and complex structures such as sugars and natural product derivatives. Importantly, both ground‐state and photoexcited redox‐active catalysts are effective. Detailed computational and experimental studies suggest a unique reaction pathway where photoexcitation of the trifluoromethoxylating reagent releases the OCF₃ radical that is trapped by (hetero)arenes. The resulting cyclohexadienyl radicals are oxidized by redox‐active catalysts and deprotonated to form the desired products of trifluoromethoxylation.     

Liquid phase synthesis of chiral quinoxalinones by microwave irradiation

Single mode microwave-assisted combinatorial synthesis of biologically interesting quinoxalinones is described. Chiral libraries of quinoxalinone were readily assembled utilizing S_NAr reactions, reduction and followed with concomitant cyclization under microwave irradiation. Enantiomeric 1,2,3,4-tetrahydroquinoxalinones were isolated in excellent yield and purity after cleavage.     

Direct vs Indirect Grafting of Alkyl and Aryl Halides

The direct and indirect electrochemical grafting of alkyl and aryl halides (RX, ArX) on carbon, metal and polymer surfaces is examined. Their electrochemical reduction occurs at highly negative potential in organic solvents and very often produces carbanions because the reduction potentials of RX and ArX are more negative than those of their corresponding radicals. Therefore, direct electrografting of alkyl and aryl radicals generated from RX and ArX is not easy to perform. This obstacle is overcome using aryl radicals derived from the 2,6-dimethylbenzenediazonium salt (2,6-DMBD), which do not react on the electrode surface due to their steric hindrance but react in solution by abstracting an iodine or bromine atom from RX (X=I, Br) or ArI to give alkyl or aryl radicals. As a consequence, alkyl and aryl radicals are generated at very low driving force by diverting the reactivity of aryl radicals derived from an aryl diazonium salt; they attack the electrode surface and form strongly attached organic layers. This strategy applies to the chemical modification of polymers (polyethylene, polymethylmethacrylate) by alkyl halides under heating.     

Highly efficient microwave-assisted fluorous Ugi and post-condensation reactions for benzimidazoles and quinoxalinones

The efficiency of an Ugi/de-Boc/cyclization strategy for construction of heterocyclic compounds has been improved through the incorporation of microwave and fluorous technologies. In the synthesis of substituted quinoxalinones and benzimidazoles, a fluorous-Boc protected diamine is employed for the Ugi reactions. Both the Ugi and the post-condensation reaction proceed rapidly under microwave irradiation and the reaction mixtures are purified by solid-phase extraction (SPE) over FluoroFlash^TM cartridges.     

A Redox‐Active Nickel Complex that Acts as an Electron Mediator in Photochemical Giese Reactions

We report a simple protocol for the photochemical Giese addition of C(sp³)‐centered radicals to a variety of electron‐poor olefins. The chemistry does not require external photoredox catalysts. Instead, it harnesses the excited‐state reactivity of 4‐alkyl‐1,4‐dihydropyridines (4‐alkyl‐DHPs) to generate alkyl radicals. Crucial for reactivity is the use of a catalytic amount of Ni(bpy)₃²⁺ (bpy=2,2′‐bipyridyl), which acts as an electron mediator to facilitate the redox processes involving fleeting and highly reactive intermediates.