Herein, nickel-catalyzed decyanative reductive cross-coupling of benzyl nitriles with aryl chlorides has been developed. The current protocol features a wide scope, good functional group compatibility, and excellent chemoselectivity, thus providing a powerful alternative to the known methods for the synthesis of diarylmethanes. Mechanistic studies demonstrate the formation of benzyl-nickel species as the key intermediate in the catalytic cycle.

A method is described for the synthesis of α-aryl and allylic sulfones and sulfonamides through CuBr/oxalamide-catalyzed coupling at 40 °C. This transformation involves coupling with (hetero)aryl or vinyl bromides and 2-substituted sulfonylacetates (or amide analogues), proceeding via spontaneous hydrolysis and decarboxylation. The conditions are compatible with various functional groups and heterocycles, allowing for the diverse syntheses of the target compounds.

Aryl C-glycosides are privileged scaffolds in drug discovery, biochemical research, and materials science. Established methods for their synthesis typically involve radical cross-coupling of saccharides. However, the glycosyl donors required in these methods encounter longstanding challenges, including instability and the need for prefunctionalization at the anomeric position. Herein, we report a highly efficient radical cross-coupling approach in which the native hydroxyl group on saccharides is activated in situ by a phosphorus reagent, enabling C - C bond formation with aryl iodides to afford a broad range of aryl C-glycosides. A combination of Zn and I2 is developed for initiating the key β-scission step. Importantly, the glycosyl donors are bench-stable and readily available, addressing the issues associated with previous donors. Furthermore, this method offers an attractive strategy for the direct synthesis of drug-sugar conjugates and therapeutic agents. Mechanistic experiments and density functional theory (DFT) calculations provide strong support for the proposed reaction mechanism.

C,N-Palladacycle based on <em>N,N</em>-dimethyl-<em>N</em>-(diphenylmethyl)amine as an effective phosphine-free (pre)catalyst for the Suzuki-Miyaura cross-coupling

The development of robust, practical, and chemoselective methods for introducing the difluoromethyl (CF₂H) group into organic molecules is highly sought after in the fields of pharmaceutical and agrochemical design. Herein, we report a Fe/Ni dual-transition-metal electrocatalytic strategy for difluoromethylation of (hetero)aryl halides, using difluoroacetate—the most abundant source of the CF₂H group—as an effective difluoromethylating reagent. A diverse array of aryl and heteroaryl halides, bearing synthetically useful functional groups, can be readily converted into the corresponding difluoromethylated products with good efficiency. This difluoromethylation protocol is readily scalable and is successfully applied to the preparation and late-stage functionalization of bioactive molecules.

Transition-metal-catalyzed C-N bond activation has emerged as a powerful yet underdeveloped strategy in synthetic chemistry, largely constrained by the high bond dissociation energy and intrinsic stability of amines. Here, we report a Ni-catalyzed deaminative reductive allylic alkylation and arylation that enables the efficient construction of C-C bonds from readily available arylallylic amines and a broad range of alkyl and aryl halides, providing a robust and stable platform for C-N bond cleavage. This transformation proceeds under mild reductive conditions and displays broad functional group tolerance. Additionally, the reaction is readily scalable to the gram level, and the synthesized products can be subjected to a range of downstream derivatizations.

Abstract The palladium-catalyzed cyanation of aryl halides has been accomplished for the synthesis of aryl nitriles using the electrophilic N–CN reagent as a cyanating reagent. The method utilizes a mild base and a substoichiometric amount of zinc as a promotor and offers a mild cyanation that tolerates various functional groups to afford aryl nitriles in good to excellent yields. Preliminary mechanistic investigation revealed the important role of the methylene linkage and the reductant.

Cross-electrophile coupling (XEC) reactions have emerged as powerful methods for carbon-carbon bond formation and have seen rapid development in recent years. Among these, nickel-catalyzed XEC offers a cost-effective and versatile alternative to palladium-based biaryl synthesis, gaining increasing prominence in organic synthesis. However, despite the advantages of nickel-based systems, the identification of optimal catalytic systems and a comprehensive understanding of the reaction mechanisms involved remain limited due to the complex nature of Ni complexes. Electrochemistry provides a compelling platform for studying nickel-catalyzed reductive coupling reactions. It allows for precise control of redox potentials, eliminates the need for metallic reductants, decouples electrochemical and chemical processes, and enhances scalability, all of which have spurred growing interest in electrochemical approaches. Moreover, electrochemical techniques offer unique mechanistic insights into nickel-mediated transformations.[1] The generally accepted mechanism for reductive nickel-catalyzed coupling of aryl halides involves: (a) reduction of a Ni²⁺ precursor to Ni⁰, (b) oxidative addition of the aryl halide, (c) transmetalation, and (d) reductive elimination. Many of the reactants and intermediates in this catalytic cycle exhibit well-defined redox behavior. Owing to the distinct redox characteristics of these species, electroanalytical methods are well-suited for monitoring concentration profiles and enabling kinetic investigations during the reaction.[2] In this study, we employ cyclic voltammetry (CV) to explore the redox behavior of nickel complexes relevant to XEC reactions. CV provides information on thermodynamic potentials and allows quantification of both the relative and absolute concentrations of nickel species throughout the catalytic cycle. We investigate how variables such as temperature, solvent, ligand electronics, and substrate choice affect nickel speciation and reactivity. In particular, voltammetric techniques are applied to determine the redox potentials, stability, and reactivity of intermediates, especially those formed during the oxidative addition of Ni to aryl and alkyl halides, based on the analysis of voltammetric peak currents and potentials. These data offer valuable kinetic and mechanistic insights into nickel-catalyzed cross-electrophile coupling reactions.[1] M. Rafiee, D.J. Abrams, L. Cardinale, Z. Goss, A. Romero-Arenas, S.S. Stahl, Cyclic Voltammetry And Chronoamperometry: Mechanistic Tools for Organic Electrosynthesis. Chem. Soc. Rev. 2024, 53, 566.[2] Z.M. Su, J. Zhu, D.L. Poole, M. Rafiee, R.S. Paton, D.J. Weix, S.S. Stahl, Selective Ni-Catalyzed Cross-Electrophile Coupling of Heteroaryl Chlorides and Aryl Bromides at 1: 1 Substrate Ratio. J. Am. Chem. Soc. 2025, 147, 353.

In this talk, I will explain how to synchronize AC electrolysis with a Ni catalytic cycle. I will use a Ni-catalyzed C-N cross-coupling reaction as the model reaction. Under AC electrolysis, the reaction exhibits a frequency-dependent selectivity between the C-N cross-coupling product and the C-C homo-coupling product. Our cyclic voltammetric studies reveal that the optimal frequency for selective C-N coupling is dictated by the rate of the oxidative addition of Ni (I) species and aryl bromide substrate. The voltammetric features in their CV scan predict the optimal frequency for different aryl bromide substrates.

Deuterated compounds serve as powerful tools for investigating reaction mechanisms, tracing molecular pathways, as well as enhancing properties in medicinal and materials science. Herein, we report a nickel-catalyzed deutero-dehalogenation of abundant yet inert aryl chlorides, enabling direct access to deuterated (hetero)arenes using D2O as the exclusive, economical deuterium source. This reductive cross-coupling strategy overcomes traditional limitations of aryl chlorides and operates under mild conditions. This protocol delivers products with a high degree of deuterium incorporation across a broad range of (hetero)aryl substrates. It also exhibits excellent functional group tolerance and tolerates various sensitive functional groups including anilines, phenols, and organoboron derivatives. A variety of deuterated products have been efficiently prepared via site-selective chlorination intermediates. Moreover, the method is readily scalable to the kilogram level. Extensive mechanistic studies have been carried out to provide insights into the non-radical NiI/NIII catalytic cycle. The simplicity, cost-effectiveness, and scalability of this approach make it highly attractive for applications in drug discovery, mechanistic studies, and metabolic research.

Reductive transformations of substances that are difficult to reduce continue to pose challenges for photoredox catalysis. Promising photoreduction catalysts include flavin and deazaflavin derivatives; however, even their reductive abilities are limited for the range of substrates considered "inert". In this work, we present 5-deazaalloxazines, a new group of deazaflavin analogues that are predisposed to catalyze reductions due to their low reduction potential (down to -1.65V vs. SCE) even in the ground state. We studied three series of 5-deazaalloxazines ([i] 5-unsubstituted, [ii] 5-aryldeazaalloxazines, and [iii] 5-trifluoromethyl-5-deazaalloxazines) to determine their photophysical and electrochemical properties and their ability to participate in model photoreduction reactions. From 31 compounds, we selected 1,3-dimethyl-7,8-dimethoxy-5-(o-tolyl)-5-deazaalloxazine [3a(o-MePh)], as it showed, among other things, the highest efficiency in photodehalogenation of p-fluoroanisole and was photostable and absorbed in the visible light region, thereby allowing photoreactions using a 400nm LED. Practical applicability was demonstrated in the C─P coupling reaction of electron-rich aryl halides (including chloroanisoles and p-fluoroanisole) with trimethyl phosphite, providing an arylation reaction to form dimethyl arylphosphonates, and in the release/deprotection of amines from the corresponding tosyl and triflylamides.

Despite its potential, the radical-mediated 1,2-arylheteroarylation of alkenes for constructing valuable 1,2-arylheteroaryl ethane motifs remains underdeveloped. We herein report an alternative continuous-flow electrochemical approach using alkenes, aryl bromides, and cyanopyridines as coupling partners. This method eliminates the need for sacrificial anodes, catalysts, or chemical oxidants, requires minimal electrolyte, and achieves high regioselectivity. Its utility is underscored by successful applications in the late-stage functionalization of bioactive molecules.

In this work, we elaborate on the configurations, electronic properties, and cross-coupling reaction mechanisms of several (hetero) aryl halides and X-based (X = N, C, O, S) nucleophiles coadsorbed on a novel geminal-Cu sites deposited on the polymeric carbon nitride (Cug/PCN). All reactants undergo an exothermic dynamic bridge-coupling process accompanied by reconstruction of the Cu-Cu sites. The activation barriers of the reaction, following the order of C-N > C-C > C-O > C-S, are positively associated with the degree of dynamic contraction of the Cu-Cu bond distance during the couplings, which aligns well with the experimental conditions. Overall, because of the quantum primogenic effect, the dynamic change of the geminal-Cu distance acts as a driving force, enabling the efficient coupling reactions on the Cug/PCN. Unraveling the structure-activity relationship on Cug/PCN facilitates the development of cross-coupling catalysis.

Abstract Radical chain initiation strategies are fundamental to the synthesis of small molecule drugs and macromolecular materials. Modern methods for initiation through one-electron reduction are largely dominated by photo- and electrochemistry but the large-scale industrial application of these methods is often hampered by scalability challenges. Here we report a general, thermally driven and scalable method for the reductive initiation of radical chains that involves reacting an inexpensive azo initiator with a formate salt to form a carbon dioxide radical anion. Substoichiometric quantities of this initiator system were used to form C( sp 2 )–C( sp 3 ), C( sp 2 )–S, C( sp 2 )–H, C( sp 2 )–B and C( sp 2 )–P bonds from complex (hetero)aryl halides, with high chemoselectivity and under transition-metal-free conditions. The developed initiator system was also used to probe the mechanism of other radical reactions.

Abstract C–H functionalization is unlocking new avenues in molecular design by transforming the inert carbon–hydrogen bond into a versatile handle for creating complex and value-added compounds with remarkable precision. Taking this into account, we have developed a new ruthenium-catalyzed mild, one-step, robust methodology for ortho C−H diarylation of 2-phenyl-2H-indazoles using aryl iodides as an arylating reagent under photo-mediated conditions at room temperature. This approach extends seamlessly to another heteroarene, 1-phenyl-1H-pyrazole. The strategy shows broad substrate scope, an extensive range of functional group compatibility, and moderate to excellent yield formation. Furthermore, gram-scale synthesis demonstrates the practical applicability of the method.

We developed SWNT-supported palladium catalysts that enable cross-couplings in water without surfactants or cosolvents. Even water-insoluble solid aryl bromides reacted efficiently with simple stirring. Pyrene-1-sulfonate anchoring ensured high activity, recyclability, and undetectable leaching. Unlike mechanochemical methods, our stirring protocol avoids energy-intensive steps. This strategy highlights the intrinsic advantages of SWNTs in stabilizing reactive metal species, offering a sustainable and versatile platform for advancing redox-active organometallic chemistry in water.

MIL-101(Cr) metal-organic frameworks (MOFs) possess advantageous properties, such as high surface area and porosity, which render them effective as catalytic supports. In this study, MIL-101(Cr) powder was functionalized with putrescine (PUT) via post-synthetic modification (PSM). Subsequently, a novel strategy was employed to incorporate palladium nanoparticles into the functionalized MIL-101(Cr) framework. The resulting Pd-loaded, functionalized MIL-101(Cr) catalysts were assessed for their catalytic efficiency in Suzuki–Miyaura carbon–carbon cross-coupling reactions. In particular, these catalysts were used to couple phenylboronic acid with various aryl halides (Ar–X, where X = I, Br, Cl, F). To maximize catalytic performance, key reaction parameters including the amount of catalyst, the amount and type of solvent, and the reaction time were optimized. The catalyst exhibited excellent reusability and stability, maintaining its efficiency over multiple reaction cycles.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-22375-7.

Insertive cross-coupling reactions provide the option of repurposing widely available coupling partners for the formation of new linkages. By confronting a major limitation of the aminative Suzuki-Miyaura methods we recently reported, we achieve a general method for the Pd-catalyzed aminative coupling of primary and secondary alkyl boronic esters with aryl (pseudo)halides. Introducing a formal nitrene insertion into this Suzuki-Miyaura reaction diverts the outcome from the traditional C(sp2)─C(sp3) products to the C(sp2)─NH─C(sp3) analogues (N-aryl anilines). DFT calculations and experimental mechanistic studies indicate that C─N bond formation from the electrophilic aryl component occurs first, providing further evidence for this previously hypothetical pathway. By comparison of several transition state structures, we find that C─N bond formation likely takes place through an unusual dyotropic rearrangement of a LPd(Ar)NHX complex (X=OPOPh2).

Abstract Insertive cross‐coupling reactions provide the option of repurposing widely available coupling partners for the formation of new linkages. By confronting a major limitation of the aminative Suzuki–Miyaura methods we recently reported, we achieve a general method for the Pd‐catalyzed aminative coupling of primary and secondary alkyl boronic esters with aryl (pseudo)halides. Introducing a formal nitrene insertion into this Suzuki–Miyaura reaction diverts the outcome from the traditional C(sp 2 )─C(sp 3 ) products to the C(sp 2 )─NH─C(sp 3 ) analogues ( N ‐aryl anilines). DFT calculations and experimental mechanistic studies indicate that C─N bond formation from the electrophilic aryl component occurs first, providing further evidence for this previously hypothetical pathway. By comparison of several transition state structures, we find that C─N bond formation likely takes place through an unusual dyotropic rearrangement of a LPd(Ar)NHX complex (X = OPOPh 2 ).

Metal hydride hydrogen atom transfer (MHAT) has emerged as a powerful strategy for alkene hydrofunctionalization, offering exceptional control over regio- and chemoselectivity. However, conventional MHAT reactions with 1,3-enynes remain limited to the 1,2-addition pathway. Herein, we report a regioselective 1,4-hydroarylation of 1,3-enynes with various aryl halides enabled by dual cobalt and nickel catalysis. This transformation proceeds through cobalt(III)-H-mediated HAT to the 1,3-enynes, followed by nickel-catalyzed cross-coupling with aryl halides, delivering a wide range of tetrasubstituted allenes in good to excellent yields. This work expands the scope of Co(III)H-mediated radical hydrofunctionalization reactions and offers a modular strategy for constructing valuable, highly substituted allene building blocks.