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Comprehensive Summary: Cross‐electrophile couplings (XEC), a crucial subset of cross‐coupling reactions, center on the formation of robust C—C bonds through the union of two electrophiles. Usually, such reactions have primarily been catalyzed by transition metals. However, with the steady advancements in photochemical and electrochemical technologies, XEC reactions have significantly progressed and broadened their scope, allowing for the utilization of a wider array of tolerable functional groups, thus revealing vast application prospects. This review aims to systematically summarize the current prevalent types of electrophiles and delve into their specific application examples within XEC reactions involving electrophiles with identical functional groups. Specifically, XECs between the same type of halides have received considerable attention, whereas carboxylic acids and alcohols are still in the early stages of investigation. Furthermore, certain other common electrophiles remain unexplored in this context. Moreover, this review underscores the remarkable contributions of photochemistry and electrochemistry in the field of XEC reactions, aiming to provide valuable insights and inspiration for researchers. Also, this review hopes to spark further interest in XEC reactions, thereby fueling the continuous development and advancement of this exciting area of research. Key Scientists: Since the 1960s, advancements in the XEC reaction have been substantial, driven primarily by the application of transition metal catalysts. In this area, many distinguished scientists have contributed their wisdom and efforts. Particularly noteworthy is that, during the systematic study of XEC reactions with the identical functional groups, in 2016, MacMillan achieved a photocatalytic XEC reaction between aryl bromides and alkyl bromides; in 2020, Weix successfully realized a nickel‐catalyzed XEC reaction between aryl chlorides and alkyl chlorides. Concurrently, contributions from researchers such as Mei, Wolf, Sevov, Lin, Shen, Browne, Zhang, and Qiu have expanded the scope of XEC reactions to various halides. By 2022, MacMillan and Baran achieved a significant milestone in the XEC between carboxylic acids, further broadening the scope of research in this area. Also, advancements in the XEC of alcohols have been noted, with researchers including Weix, Lian, Tu, and Stahl conducting pioneering work and successfully executing the XEC of protective groups. It is foreseen that the ongoing research endeavors will primarily concentrate on the expansion of diverse electrophiles. [ABSTRACT FROM AUTHOR]

In the present manuscript, we reported the first visible‐light‐enabled direct C3−H alkylation/arylation of quinoxalin‐2(1H)‐ones with unactivated alkyl/aryl chlorides under metal‐free conditions. A wide range of unactivated alkyl and aryl chlorides containing different functionalities are coupled with a variety of quinoxalin‐2(1H)‐one derivatives under mild reaction conditions to afford the C3‐alkyl/aryl substituted quinoxalin‐2(1H)‐ones in moderate to good yields. [ABSTRACT FROM AUTHOR]

We describe a nickel-catalyzed three-component sulfonylation of readily available non-activated alkyl chlorides. A wide range of alkyl aryl sulfones can be synthesized from alkyl chlorides, aryl boronic acids, and potassium metabisulfite, a cheap, efficient, and commercially available SO2 source under simple and easy-to-handle reaction conditions. High selectivity can be achieved with a slight excess of phenylboronic acid and a sulfur dioxide source. [ABSTRACT FROM AUTHOR]

Palladium‐catalyzed couplings of silicon enolates with aryl electrophiles are of great synthetic utility, but often limited to expensive bromide substrates. A comparative experimental study confirmed that none of the established ligand systems allows to couple inexpensive aryl chlorides with α‐trimethylsilyl alkylnitriles. In contrast, ylide functionalized phosphines (YPhos) led to encouraging results. A statistical model was developed that correlates the reaction yields with ligand features. It was employed to predict catalyst structures with superior performance. With this cheminformatics approach, YPhos ligands were tailored specifically to the demands of Hiyama couplings. The newly synthesized ligands displayed record‐setting activities, enabling the elusive coupling of aryl chlorides with α‐trimethylsilyl alkyl nitriles. The preparative utility of the catalyst system was demonstrated by the synthesis of pharmaceutically meaningful α‐aryl alkylnitriles, α‐arylcarbonyls and biaryls. [ABSTRACT FROM AUTHOR]

[Display omitted] • The continuous flow microreactor were used for the synthesis of chlorides. • The fluid model was proposed based on kinetic parameters. • Catalytic experiments validated the reliability of the fluid model. • The chloride achieved yields of up to ∼98 % with excellent reusability. The efficient and safe synthesis of chlorides is attractive in pharmaceutical chemicals yet presents challenges. Herein, a novel route has been developed for the conversion of alcohols into the corresponding alkyl chlorides in continuous flow microreactor. Meanwhile, the system utilizes deep eutectic solvents (DESs) hydrochloride solutions (DESs/HCl) as both solvents and catalysts for this reaction. The results suggest that the premixed mode continuous flow microreactor using DESs/HCl can significantly improve the harsh reaction conditions in the synthesis reaction of chlorides. Furthermore, tuning the HCl concentration under 383 K and 30 min conditions significantly increased the yields of n -Butanol chloride and Benzyl chloride to 86 % and 98 %, respectively. This work shows the great application potential of the continuous flow microreactor combined with DESs/HCl to convert alcohols into corresponding alkyl chlorides or aryl chlorides. Besides, the fluid model and HCl absorption kinetics were established based on the calculated diffusion coefficients (D R), Damköhler number (Da), Bodenstein number (Bo), residence time (τ), and experimental results. The flow model of the mixture of DESs/HCl and alcohols in the microreactor was a plug flow, which is beneficial for improving the efficiency of this reaction. [ABSTRACT FROM AUTHOR]

A photoredox and copper‐catalyzed sulfonylphosphorothiolation of alkenes has been developed. With the use of readily available aryl or alkyl sulfonyl chlorides as radical precursors and (RO)2P(O)SH as coupling partners, a wide range of decorated β‐sulfonyl phosphorothioates could be obtained in 37–98% yields with good functional group tolerance. Importantly, this three‐component reaction can be conveniently extended to late‐stage modification of bioactive molecules and gram‐scale synthesis. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The asymmetric reductive arylation and alkenylation of benzylic chloride under photoredox/nickel dual catalysis using chiral biimidazoline (BiIm) ligand is reported to access 1,1‐diaryl alkanes and aryl allylic compounds with good yield as well as stereo‐ and enantioselectivities. This protocol uses more commercially available and less expensive C(sp2)‐Br as the electrophile coupling partner. A primary result using alkenyl chloride and alkyl chloride is also reported. Various functional groups are tolerated and the applications of this method are investigated by late‐stage functionalization and gram‐scale reaction. [ABSTRACT FROM AUTHOR]

Electrochemical catalytic reductive cross couplings are powerful and sustainable methods to construct C−C bonds by using electron as the clean reductant. However, activated substrates are used in most cases. Herein, we report a general and practical electro-reductive Ni-catalytic system, realizing the electrocatalytic carboxylation of unactivated aryl chlorides and alkyl bromides with CO2. A variety of unactivated aryl bromides, iodides and sulfonates can also undergo such a reaction smoothly. Notably, we also realize the catalytic electrochemical carboxylation of aryl (pseudo)halides with CO2 avoiding the use of sacrificial electrodes. Moreover, this sustainable and economic strategy with electron as the clean reductant features mild conditions, inexpensive catalyst, safe and cheap electrodes, good functional group tolerance and broad substrate scope. Mechanistic investigations indicate that the reaction might proceed via oxidative addition of aryl halides to Ni(0) complex, the reduction of aryl-Ni(II) adduct to the Ni(I) species and following carboxylation with CO2. Electrochemistry is a promising approach to make existing chemical protocols milder, but many simple transformations of feedstocks are still out of reach. Here, the authors transform unactivated aryl and alkyl (pseudo)halides into carboxylic acids, via nickel catalysis and electricity, using atmospheric CO2 as the carbon source. [ABSTRACT FROM AUTHOR]

Although iron catalyzed cross-coupling reactions show extraordinary promise in reducing the environmental impact of more toxic and scarce transition metals, one of the main challenges is the use of reprotoxic NMP (NMP = N-methylpyrrolidone) as the key ligand to iron in the most successful protocols in this reactivity platform. Herein, we report that non-toxic and sustainable N-butylpyrrolidone (NBP) serves as a highly effective substitute for NMP in iron-catalyzed C(sp2)–C(sp3) cross-coupling of aryl chlorides with alkyl Grignard reagents. This challenging alkylation proceeds with organometallics bearing β-hydrogens with efficiency superseding or matching that of NMP with ample scope and broad functional group tolerance. Appealing applications are demonstrated in the cross-coupling in the presence of sensitive functional groups and the synthesis of several pharmaceutical intermediates, including a dual NK1/serotonin inhibitor, a fibrinolysis inhibitor and an antifungal agent. Considering that the iron/NMP system has emerged as one of the most powerful iron cross-coupling technologies available in both academic and industrial research, we anticipate that this method will be of broad interest. [ABSTRACT FROM AUTHOR]

• New Cl/F exchange method for the preparation of sulfonyl fluorides was developed. • A stable derivative pyrrolidine-1-sulfinyl fluoride can be used a fluorination agent. • DFT calculations of chlorine/fluorine exchange reactions were studied. The reaction of (2S)-2-(difluoro(methoxy)methyl)pyrrolidine-1-sulfinyl fluoride with aryl, heteryl and alkyl sulfonyl chlorides provides a convenient synthetic route to sulfonyl fluorides. DFT calculations predict negative reaction energy values for the exchange reaction. The S-F bond energy is higher in the sulfonyl fluorides than that in sulfinyl fluorides. The reaction of (2S)-2-(difluoro(methoxy)methyl)pyrrolidine-1-sulfinyl fluoride with aryl, heteryl and alkyl sulfonyl chlorides provides convenient synthetic route to the sulfonyl fluorides. [Display omitted] [ABSTRACT FROM AUTHOR]

Development of practical deuteration reactions is highly valuable for organic synthesis, analytic chemistry and pharmaceutic chemistry. Deuterodehalogenation of organic chlorides tends to be an attractive strategy but remains a challenging task. We here develop a photocatalytic system consisting of an aryl-amine photocatalyst and a disulfide co-catalyst in the presence of sodium formate as an electron and hydrogen donor. Accordingly, many aryl chlorides, alkyl chlorides, and other halides are converted to deuterated products at room temperature in air (>90 examples, up to 99% D-incorporation). The mechanistic studies reveal that the aryl amine serves as reducing photoredox catalyst to initiate cleavage of the C-Cl bond, at the same time as energy transfer catalyst to induce homolysis of the disulfide for consequent deuterium transfer process. This economic and environmentally-friendly method can be used for site-selective D-labeling of a number of bioactive molecules and direct H/D exchange of some drug molecules. Deuterodehalogenation of organic chlorides is a useful strategy to install deuterium atoms at specific positions, however, it has several drawbacks. In this study, the authors report an organophotocatalytic system consisting of an aryl-amine-based photocatalyst and a common disulfide co-catalyst, for efficient deuteration of a wide range of aryl chlorides, alkyl chlorides and other halides, at room temperature in air. [ABSTRACT FROM AUTHOR]

A general, efficient, highly enantio‐ and chemoselective N‐heterocyclic carbene (NHC)/Ni‐catalyzed addition of readily available and stable arylboronic esters to ketones is reported. This protocol provides unexpectedly fast access (usually 10 min) to various chiral tertiary alcohols with exceptionally broad substrate scope and excellent functional group tolerance (76 examples, up to 98 % ee). This process is orthogonal to other known Ni‐mediated Suzuki–Miyaura couplings, as it tolerates aryl chlorides, fluorides, ethers, esters, amides, nitriles, and alkyl chlorides. The reaction is applied to late‐stage modifications of various densely functionalized medicinally relevant molecules. Preliminary mechanistic studies suggest that a rare enantioselective η2‐coordinating activation of ketone carbonyls is involved. This cross‐coupling‐like mechanism is expected to enable other challenging transformations of ketones. [ABSTRACT FROM AUTHOR]

A photocatalytic borylation of alkyl bromides and chlorides in air under visible-light irradiation by graphene-supported Cu-Pd alloy nanoparticles is reported. [Display omitted] • An efficient photocatalytic protocol for borylation of alkyl halides is reported. • A graphene supported Cu/Pd alloy nanoparticles was employed as photocatalyst. • The borylations were conducted at 30 °C in air under visible light. • Primary and secondary alkyl bromides and chlorides were borylated in good yields. • The high activity results from LSPR of Cu and alloy surface charge heterogeneity. A highly efficient photocatalytic protocol for borylation of alkyl bromides and chlorides with graphene supported Cu/Pd alloy nanoparticles as a heterogeneous catalyst is reported. This photocatalytic system operates with visible light in air, providing a wide range of primary and secondary alkyl halides with B 2 pin 2 or B 2 neop 2 in high yields at low temperatures, thereby demonstrating its broad utility and functional group tolerance. The high performance is attributed to a synergistic effect of localized surface plasmon resonance (LSPR) of Cu and charge transfer from Cu to Pd due to the alloy surface charge heterogeneity. Transfer of energetic electrons from Pd to electrophilic alkyl halides lead to the formation of the alkyl radicals, which quickly react with a nucleophilic adduct of a diboron compound with base adsorbed on the positively charged Cu sites to form the corresponding borylation product. [ABSTRACT FROM AUTHOR]

The use of alkyl chlorides in Pd-catalyzed Mizoroki–Heck coupling reactions remains an unsolved problem despite their significant potential for synthetic utility and applicability. The combination of the high thermodynamic barrier of alkyl chloride activation and kinetic propensity of alkylpalladium complexes to undergo undesired β-hydride elimination provides significant challenges. Herein, a variety of alkyl chlorides, even tertiary chlorides, are shown to efficiently participate in Mizoroki–Heck cross-coupling reactions with excellent functional group compatibility under mild reaction conditions via photoinduced Pd catalysis. The reaction is applied to late-stage functionalizations of diverse biologically significant scaffolds and iterative double Mizoroki–Heck annulations, affording high molecular complexity in a single step. Notably, studies on the kinetic isotope effects in combination with density functional theory (DFT)-computations completely exclude the involvement of a previously proposed β-hydride elimination in the catalytic cycle, revealing that the chlorine atom transfer process is the key catalytic turnover step. This distinctive single-electron transfer mediated reaction pathway resolves a longstanding challenge in traditional two-electron based Pd-catalyzed Mizoroki–Heck cross-coupling with alkyl electrophiles, wherein the β-hydride elimination is involved in the formation of both the desired product and undesired by-products. The use of alkyl chlorides in Pd-catalyzed Mizoroki–Heck coupling reactions remains an unsolved problem despite their significant synthetic potential. Here, the authors show that alkyl chlorides can efficiently participate in Mizoroki–Heck cross-coupling reactions with excellent functional group compatibility via photoinduced Pd catalysis. [ABSTRACT FROM AUTHOR]

We report a C(sp3)−C(sp3) cross‐coupling of alkyl bromides and alkyl chlorides with ethers by dual photoredox‐nickel catalysis. The catalytic system comprises of the organic photocatalyst 1,2,3,5‐tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzene (4‐CzIPN) and bench stable nickel (II) acetylacetonate in the presence of visible‐light, providing the coupling products in up to 92% yield. Preliminary mechanistic studies suggest two catalytic cycles, as well as the photogeneration of bromine or chlorine radicals from halide atoms that are present in the structures of the coupling partners. The halide radical mediates the hydrogen atom transfer event, avoiding the need of an additional HAT catalyst. [ABSTRACT FROM AUTHOR]

• We investigated mechanisms of formation of 1,1-diarylalkanes in enantioselective Ni-catalyzed reductive cross-coupling system. • For the reactant (S)-R 2 to get the products (R, S)-P, the favored way is Path C where the NiI catalyst initially combined with alkyl chloride. • For the reactant (R)-R 2 to get the products (R, S)-P, the favored way is Path A or B where NiI or Ni° catalyst initially combined with aryl bromide. • The formation of (R)-P is dominant over the product (S)-P. The detail mechanisms of enantioselective Ni-catalyzed reductive coupling of 5-bromide-2-methoxypyridine (R 1) and (1-chloropropyl) benzene (R 2) to form 1,1-diarylalkanes (R, S)-P were studied using Density Functional Theory calculations. The overall catalytic cycles include the following basic steps: the oxidative addition, reduction, radical production, radical addition, reductive elimination and the catalyst regeneration. Our calculated results show that the favored way from the reactant (S)-R 2 to get the products (R, S)-P is Path C (the NiI catalyst initially combined with alkyl chloride) where the energy barrier of the rate-determining step is the oxidative addition step with 9.1 kcal/mol (of TS 1b), but the favored path starting from the reactant (R)-R 2 to get the products (R, S)-P is Path A (the NiI catalyst initially combined with aryl bromide) or Path B (the Ni° catalyst initially combined with the aryl bromide) where the energy barrier of the rate-determining step is the radical production step with 12.7 kcal/mol (of (R)-TS 2 ). Our calculated results also indicate that the formation of (R)-P is dominant over the product (S)-P, which meets the experimental results. The ligand effects have also been studied. [Display omitted] [ABSTRACT FROM AUTHOR]

The title reaction proceeds under ambient temperature and low catalyst loading with excellent chemo- and site-selectivities for a broad substrate scope. [ABSTRACT FROM AUTHOR]