Radical-radical Cross-coupling Research Articles

Two-in-One Role of Benzophenone in Photoinduced C(sp3)-H Monofluoralkenylation: Hydrogen-Atom Transfer and Single-Electron Transfer.

A new protocol for monofluoralkenylation of C(sp3)-H bonds with gem-difluoroalkenes was reported. In this protocol, benzophenone serves as a photocatalyst with dual roles of hydrogen-atom transfer and single-electron transfer. The excited state of benzophenone abstracts a hydrogen atom from a C(sp3)-H bond to generate a corresponding carbon radical, which subsequently undergoes a radical addition/SET/β-F elimination process rather than radical-radical cross-coupling of previous work. This reaction shows high regioselectivity for the α-carbon atoms of ethers, thioethers, and amines, enabling the preparation of monofluoroalkenes.

Redox-neutral electrochemical decontamination of hypersaline wastewater with high technology readiness level.

Industrial hypersaline wastewaters contain diverse pollutants that harm the environment. Recovering clean water, alkali and acid from these wastewaters can promote circular economy and environmental protection. However, current electrochemical and advanced oxidation processes, which rely on hydroxyl radicals to degrade organic compounds, are inefficient and energy intensive. Here we report a flow-through redox-neutral electrochemical reactor (FRER) that effectively removes organic contaminants from hypersaline wastewaters via the chlorination-dehalogenation-hydroxylation route involving radical-radical cross-coupling. Bench-scale experiments demonstrate that the FRER achieves over 75% removal of total organic carbon across various compounds, and it maintains decontamination performance for over 360 h and continuously treats real hypersaline wastewaters for two months without corrosion. Integrating the FRER with electrodialysis reduces operating costs by 63.3% and CO2 emissions by 82.6% when compared with traditional multi-effect evaporation-crystallization techniques, placing our system at technology readiness levels of 7-8. The desalinated water, high-purity NaOH (>95%) and acid produced offset industrial production activities and thus support global sustainable development objectives.

Masters of Mediation: MN(SiMe3)2 in Functionalization of C(sp3)-H Latent Nucleophiles.

Organoalkali compounds have undergone a far-reaching transformation being a coupling partner to a mediator in unusual organic conversions which finds its spot in the field of sustainable synthesis. Transition-metal catalysis has always been the priority in C(sp3)-H bond functionalization, however alternatively, in recent times this has been seriously challenged by earth-abundant alkali metals and their complexes arriving at new sustainable organometallic reagents. In this line, the importance of MN(SiMe3)2 (M = Li, Na, K & Cs) reagent revived in C(sp3)-H bond functionalization over recent years in organic synthesis is showcased in this minireview. MN(SiMe3)2 reagent with higher reactivity, enhanced stability, and bespoke cation-π interaction have shown eye-opening mediated processes such as C(sp3)-C(sp3) cross-coupling, radical-radical cross-coupling, aminobenzylation, annulation, aroylation, and other transformations to utilize readily available petrochemical feedstocks. This article also emphasizes the unusual reactivity of MN(SiMe3)2 reagent in unreactive and robust C-X (X = O, N, F, C) bond cleavage reactions that occurred alongside the C(sp3)-H bond functionalization. Overall, this review encourages the community to exploit the untapped potential of MN(SiMe3)2 reagent and also inspires them to take up this subject to even greater heights.

Generation and Radical-Radical Cross-Coupling of Alkenyloxy Radical.

Alkene-attached oxygen radicals are rarely used, as highly reactive oxygen radicals are incompatible with the alkene moiety. The direct radical-radical cross-coupling of O radicals is also challenging (limited to N-O bond formation) because of the lack of suitable persistent radical species. This study demonstrated the feasibility of using Breslow intermediate radical (BIR) as a persistent radical to capture unstable π-conjugated O radicals and allow the C-O radical-radical cross-coupling.

Electrochemical Synthesis of Selenosulfonates from Diselenides and Sulfonyl Hydrazides.

The electrochemical oxidative radical-radical cross-coupling of sulfonyl hydrazides with diselenides for the synthesis of selenosulfonates was successfully accomplished. The method is applicable to a wide range of aromatic/aliphatic sulfonyl hydrazides and diselenides, providing products in good to excellent yields. Notably, this protocol stands out for its green and sustainable nature, as it does not rely on transition metals and oxidizing agents, and the starting materials are cost-effective and readily available.

Visible-Light-Induced Decarboxylative Aminosulfonylation of (Hetero)aryl Carboxylic Oxime Esters.

Sulfonamides are important structures in pharmaceuticals, agrochemicals, and organocatalysts, yet the rapid and benign synthesis of these compounds is still a great challenge. Herein we report a photoinduced method for synthesizing sulfonamides from (hetero)aryl carboxylic acid oxime esters. This reaction proceeds via one-pot cascade radical-radical cross-coupling by energy-transfer-mediated photocatalysis. A wide substrate scope including (hetero)aryl substrates and late-stage modification of pharmaceutical molecular entities reveal its generality.

Direct C(sp3)-H Arylation of Unprotected Benzyl Anilines and Alkylarenes by Organocatalysis under Visible Light.

Reported herein is direct C(sp3)-H arylation of unprotected benzyl anilines and alkylarenes via consecutive photoinduced electron transfer by visible light irradiation. Reductive quenching cycles and radical-radical cross-coupling were involved, and electron paramagnetic resonance experiments provide evidence for the formation of radical intermediates formed in situ. The protocol highlights transition metal free, external oxidant free, broad substrate scope, and high efficiency (>60 examples, up to 96%).

Direct C-H alkylation of 3,4-dihydroquinoxaline-2-ones with N-(acyloxy)phthalimides via radical-radical cross coupling.

We present an organophotoredox-catalyzed direct Csp3-H alkylation of 3,4-dihydroquinoxalin-2-ones employing N-(acyloxy)pthalimides to provide corresponding products in good yields. A broad spectrum of NHPI esters (1°, 2°, 3°, and sterically encumbered) participates in the photoinduced alkylation of a variety of 3,4-dihydroquinoxalin-2-ones. In general, mild conditions, broad scope with good functional group tolerance, and scalability are the salient features of this direct alkylation process.

Difunctionalization of gem-difluoroalkenes for amination and heteroarylation via metal-free photocatalysis.

gem-Difluoroalkenes are widely used building blocks in fluorine chemistry. Herein, a metal-free photocatalytic amination and heteroarylation method of gem-difluoroalkenes with heteroaryl carboxylic acid oxime esters as substrates is reported. This environmentally benign reaction proceeds via radical-radical cross-coupling in energy-transfer-mediated photocatalysis and can be used in the rapid construction of heteroaryl difluoroethylamine scaffolds and late-stage modification of complex pharmaceutical structures.

Photoredox-catalyzed radical-radical cross coupling of ketyl radicals with unstabilized primary alkyl radicals.

Herein, a novel protocol dealing with the preparation of sterically hindered alcohols has been successfully developed via radical-radical coupling reactions enabled by mild and redox-neutral photocatalysis. With alkylsilicates as the radical precursors, a range of primary alkyl radicals bearing various functional groups could couple with a range of phthalimides and activated ketones.

Photoredox-Catalyzed Radical-Radical Cross-Coupling of α-Ketoesters with Ethers: Access to Sterically Hindered α-Hydroxy Esters.

We describe a photoredox catalysis method for synthesizing sterically hindered α-hydroxy esters from α-ketoesters and ethers through a radical-radical cross-coupling reaction. This approach utilizes commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst and inexpensive and readily available nBu4NBr as a hydrogen atom transfer catalyst. Unactivated tetrahydrofuran and other ethers effectively react with various α-ketoesters to yield the desired products. The efficiency of this reaction is highlighted by its broad substrate scope, good functional group tolerance, and mild reaction conditions.

Dual visible-light and NHC-catalyzed radical relay trifunctionalization of unactivated alkenes

Radical trifunctionalization of unactivated alkenes remains rare and challenging, although they can provide a robust tool for the construction of molecules with high added value from simple materials. This work presents the relay dual N-heterocyclic carbene organocatalytic and visible-light photocatalytic multi-component trifunctionalization of alkyl alkenes via the merger of remote 1,4-cyano migration and alkylacylation. The method features a broad substrate scope and good compatibility of diverse functional groups. Density functional theory calculations were also carried out to rationalize the origin of this reaction. The cooperative N-heterocyclic carbene and photoredox catalysis enabled reductive single-electron transfer reaction of acyl azolium species and subsequent radical-radical cross-coupling, allowing for the facile construction of three new C−C bonds in one-pot reactions with high regioselectivity.

Access to Trifluoromethylketones from Alkyl Bromides and Trifluoroacetic Anhydride by Photocatalysis.

Aliphatic trifluoromethyl ketones are a type of unique fluorine-containing subunit which plays a significant role in altering the physical and biological properties of molecules. However, catalytic methods to provide direct access to aliphatic trifluoromethyl ketones is highly desirable yet remains underdeveloped, partially due to the high reactivity and instability of trifluoroacetyl radical. Herein, we report a photocatalytic synthesis of trifluoromethyl ketones from alkyl bromides with trifluoroacetic anhydride. The reaction features a dual catalysis of visible-light and XAT reaction, followed by an enabling radical-radical cross-coupling of alkyl radical with a stabilized trifluoromethyl radical. The reaction provides the first straightforward access to aliphatic trifluoromethyl ketones from easily-available and cost-effective alkyl halides and TFAA.

Photoredox-Catalyzed Radical-Radical Cross-Coupling of Sulfonyl Chlorides with Trifluoroborate Salts.

Sulfones are widely found in natural products and drug molecules. Here, we disclose a strategy for direct synthesis of sulfone compounds with diverse structures by visible-light-catalyzed radical-radical cross-coupling of sulfonyl chlorides and trifluoroborate salts. Allyl, benzyl, vinyl, and aryl trifluoroborates can be successfully cross-coupled with (hetero)aryl and alkyl sulfonyl chlorides, respectively. This strategy features redox neutrality, good substrate generality, simple operation, and benign reaction conditions.

Electrochemical Umpolung Enabled Radical–Radical Cross-Coupling Between Electron-Deficient Methylarenes and Aldehydes

Electrochemical Umpolung Enabled Radical–Radical Cross-Coupling Between Electron-Deficient Methylarenes and Aldehydes

Visible-light induced cross-electrophile coupling of imines and anhydrides to synthesize α-amino ketones.

α-Amino ketones are important motifs in synthetic and medicinal chemistry. Efficient methods to directly access these motifs from feasible precursors are, however, limited. Herein, a visible-light mediated reductive cross-electrophile coupling of readily available imines and anhydrides was developed. Under mild reaction conditions, the umpolung reactivity of diverse imines engaged with anhydrides gives a variety of α-amino ketones with good yields and a broad functional group compatibility. Primary mechanistic studies revealed that this transformation might proceed through a radical-radical cross coupling pathway dominantly.

A novel approach for synthesizing α-amino acids via formate mediated hydrogen transfer using a carbon source

We report an unprecedented synthesis of α-amino acid derivatives utilizing HCOO− as a carbon and hydrogen source. This method employs firstly commercially available 2-naphthalenethiol as an organic photocatalyst for radical-radical cross-coupling.

Direct Hydroxylarylation of Benzylic Carbons (sp3/sp2/sp) via Radical-Radical Cross-Coupling Powered by Paired Electrolysis.

Diaryl alcohol moieties are widespread in pharmaceuticals. Existing methods for the synthesis of diaryl alcohols require the use of pre-functionalized benzylic alcohols, aromatic aldehydes, or ketones as starting materials. Herein, the first convergent paired electrochemical approach to the direct hydroxylarylation of unactivated benzylic carbons (sp3/sp2/sp) is proposed. This protocol features direct functionalization of unactivated benzylic C(sp3)-H bonds and benzylic sp2/sp-carbons, mild conditions (open air, room temperature), an environmentally friendly procedure (without any external catalyst/mediator/additive), and direct access to sterically hindered alcohols from inexpensive and readily available alkyl/alkenyl/alkynylbenzenes. Mechanistic studies, including divided-cell experiments, isotope labeling, radical trapping, electron paramagnetic resonance, reaction kinetics, and cyclic voltammetry, strongly support the proposed radical-radical cross-coupling between transient ketyl radicals and persistent radical anions. Gram-scale synthesis and diversification of drug derivatives have visualized the tremendous potential of this protocol for practical applications.

Tuning band structures of Hf-PCN-224(M) for β-Carbonyl C(sp3)-H bond activation and difunctionalization: Tandem C(sp3) radical cross-coupling through photoredox

The construction of C(sp3)-C(sp3) bonds by different C(sp3) radicals coupling reactions is still unexplored due to the high bond dissociation energy of C(sp3)-H bond and the difficulty for selective generating of C(sp3) radical. Benefiting from the precisely regulating for band structures of Hf-PCN-224(M), the β-carbonyl C(sp3)-H bonds are effectively oxidized by photo-generated holes to affording C(sp3) radicals in this work. C(sp3)-C(sp3) and C(sp3)-O bonds are constructed by tandem radical-radical cross-coupling, hydrogen atom transfer (HAT), and radical-radical cross-coupling between two C(sp3)-H bonds, enabling an effective C3-difunctionalization of indolin-2-ones under photo-thermo synergetic catalysis on Hf-PCN-224(Cu). Significantly, OH serves as triple roles: introduced hydroxyl group in situ, HAT abstractor and α-heteroatom for secondary activating C(sp3)-H bonds. Control experiments, EPR spectroscopy and DFT calculation provide insight into the tandem radicals cross-coupling mechanism. This operable strategy opens up a door for the difunctionalization of C(sp3)-H bonds in heterogeneous photoredox manner.

Electrochemical Synthesis of Polysubstituted Sulfonated Pyrazoles via Cascade Intermolecular Condensation, Radical-Radical Cross Coupling Sulfonylation, and Pyrazole Annulation.

Electrochemical synthesis of polysubstituted sulfonated pyrazoles from enaminones and sulfonyl hydrazides was established under metal-free, exogenous-oxidant-free, and mild conditions. By judicious choice of different electrochemical reaction conditions, NH2-functionalized enaminones or N,N-disubstituted enaminones can react with aryl/alkyl sulfonyl hydrazides to afford tetra- or trisubstituted sulfonated pyrazoles in moderate to good yields, respectively. The gram-scale electrochemical transformation demonstrated the efficiency and practicability of this synthetic strategy. In addition, the sulfonated NH-pyrazole can be obtained via the dissociation of the N-tosyl group. Mechanistic studies reveal that the electrochemical cascade reaction synthesis of polysubstituted sulfonated pyrazoles proceeded via the sequence of intermolecular condensation, radical-radical cross coupling sulfonylation, and pyrazole annulation.