A copper-catalyzed [3 + 2 + 1] oxidative cyclization to access functionalized pyridines was descripted. Employing ethyl tertiary amine as a C2 source, alcohol as a C1 source, and easily handled enamines, one new C-N bond and two new C-C bonds are sequentially constructed by the effective functionalization of multiple C(sp3)-H bonds. Besides the readily available raw materials, mild reaction conditions, broad substrate scope, and effective bond-forming strategy, the present approach offers a viable strategy for preparing functionalized pyridines in future organic synthesis.

The aza-Michael reaction is a fundamental transformation for carbon–nitrogen bond formation, providing efficient access to β-amino carbonyl compounds, nitriles, and related nitrogen-containing building blocks of broad importance in medicinal chemistry and organic synthesis. Over the past two decades, ionic liquids (ILs) have attracted considerable attention as alternative reaction media, promoters, and catalysts for aza-Michael reactions, owing to their distinctive physicochemical properties and tunable structures. This review presents a comprehensive and critical overview of ionic-liquid-mediated aza-Michael reactions, emphasizing the evolution of IL design from early imidazolium-based systems to modern task-specific, supported, and bio-derived ionic liquids. Conventional room-temperature ionic liquids are discussed as non-innocent solvents capable of stabilizing charged intermediates and enhancing electrophilicity, thereby enabling catalyst-free or metal-assisted aza-Michael additions. Subsequent sections focus on task-specific ionic liquids incorporating Brønsted acidic, basic, hydrogen-bond-donating, or bifunctional motifs, highlighting how rational structural design translates into improved activity, selectivity, and substrate scope. Particular attention is devoted to guanidine-, DABCO-, and DBU-based ionic liquids, where mechanistic studies reveal cooperative activation modes rather than simple acid–base catalysis. Recent advances in supported and polymeric ionic liquids are also reviewed, demonstrating effective strategies to combine IL-like reactivity with enhanced recyclability and operational simplicity. Overall, this review clarifies the diverse roles of ionic liquids in aza-Michael chemistry and outlines current challenges and future perspectives toward more sustainable and efficient C–N bond-forming methodologies.

Organic synthesis often relies on readily available and versatile scaffolds that can be efficiently modified into diverse functional molecules. In many cases, reactions that are difficult to perform under conventional conditions can be successfully achieved using suitable catalysts. In recent years, organic catalysis has gained increasing attention because it frequently offers milder conditions, improved selectivity, and environmentally safer alternatives compared to traditional reagent-based methods. Among the various reagents explored for this purpose, s-trichlorotriazine (TCT), also known as cyanuric chloride, has emerged as an inexpensive and highly effective scaffold in synthetic chemistry. Due to its remarkable chemoselectivity, operational simplicity, and reduced formation of toxic by-products, TCT has been widely applied in numerous organic transformations. This review summarizes the reported literature on the synthetic applications of s-trichlorotriazine, highlighting its importance as both a catalyst and a reagent in modern organic synthesis.

Although chiral α-alkenyl quaternary amino acid derivatives have been extensively utilized in organic synthesis, the catalytic asymmetric synthesis of such compounds remains elusive. In this report, we present a highly efficient method for the direct introduction of an alkenyl group at the α carbon of an NH2-unprotected amino acid ester through a three-component reaction involving readily available aryl (alkenyl) bromide and allyl acetate, facilitated by chiral aldehyde/palladium co-catalysis. A diverse array of α-alkenyl quaternary amino acid esters featuring unconjugated π systems are generated in commendable yields and excellent enantioselectivities, and some of them are used for the synthesis of valuable building blocks.

The synthesis of covalent organic frameworks (COFs) is still largely driven by chemists' literature-informed intuition and iterative trial-and-error, which can be difficult to scale and reproduce. Here we present a chemist-guided human-AI workflow that digitizes this reasoning loop─search, hypothesis formation, and iteration─by coupling a structured literature knowledge base with retrieval-augmented large language models and experiment-aware updates. We first construct a COF synthesis knowledge base containing 2709 protocols extracted from over 800 publications. Given an unseen linker combination, the workflow retrieves a Top-K neighborhood and assembles evidence through stratified sampling and context permutation, generating a range-type synthesis prior over solvent system, catalyst, temperature, time, and stoichiometry. A diagnosis module then interprets macroscopic observations together with powder X-ray diffraction (PXRD) files using a failure taxonomy and proposes targeted updates and next-round experiments. In leave-one-out benchmarks on 60 held-out COFs, the best context-assembly and self-consensus settings improve solvent-catalyst hit rates from baseline levels to up to 0.83, supporting robust transfer beyond individual case studies. We demonstrate the workflow by synthesizing two fluorinated COFs, TAPPy-4F and TAPPy-8F, both exhibiting crystallinity and permanent porosity. By simulating the chemist's reasoning loop, this human-AI system integrates expert knowledge with model-driven exploration, offering a generalizable and scalable paradigm for the rational design of complex reticular materials.

Subnano and nanometric metal clusters are ultrasmall aggregates in which most atoms are exposed on the surface, directly interacting with reactants and enabling highly efficient catalysis. However, metal carbonate clusters have been barely prepared and used in catalysis. Here, we report the synthesis of ultrasmall, ligand-free MgCO3 clusters formed via CO2 capture with MgCl2, with an average composition of [MgCO3]5·3H2O. These clusters exhibit catalytic activity in various nucleophilic alcohol addition reactions, showing a 5-fold enhancement compared to bulk MgCO3 and CaCO3-triethylamine clusters. These results pave the way for synthesis of ultrasmall alkaline metal carbonate clusters beyond Ca, which can be employed as efficient catalysts in organic synthesis.

The construction of C-C bonds is a pivotal transformation in organic synthesis. Traditional Ullmann type and Hurtley reactions for constructing C(sp3)-C(sp2) bonds rely on organometallic reagents or substrates with active methylene units. These requirements significantly limit their practical applicability. Herein, employing two readily available organic halides, we report a ligand-enabled, electrochemical copper-catalyzed cross-electrophile coupling. Although Cu is the first metal reported for C-C bond construction, cross-electrophile coupling nowadays is dominated by Ni. This work demonstrates that efficient cross-electrophile coupling can be realized by electrochemical Cu catalysis. Our protocol is applicable to a wide range of propargyl bromides and (hetero)aryl iodides or bromides, delivering the desired products in good yields with high cross-selectivity. The use of an orthodimethylamine-substituted diamine ligand is crucial for promoting the reaction and suppressing cathodic Cu deposition. We attribute this effect to an intramolecular H···N H-bonding, which facilitates hyperconjugation between the NMe2 moiety and the nitrogen atom coordinated to the Cu center. Mechanistic studies indicate that the reaction follows a radical pathway, contrasting with the SN2 pathway reported previously. This work establishes a foundation for electrochemical Cu-catalyzed cross-electrophile coupling and provides a new paradigm for Cu-catalyzed C-C bond formation via radical intermediates.

Comprehensive Summary Transition‐metal‐catalyzed carbene transfer reactions have emerged as a robust and versatile strategy in organic synthesis. Conventional carbene transfer processes primarily encompass C–H bond insertion, cyclopropanation, and ylide formation, which have found extensive applications both in academic research and industrial settings. A prominent example includes the Rh(II)‐catalyzed intramolecular N–H insertion employed in the synthesis of β‐lactam antibiotics such as thienamycin, as well as asymmetric cyclopropanation utilized in the production of chrysanthemate‐based insecticides. Over the past decade, a novel class of transition‐metal‐catalyzed transformations involving carbene precursors has gained significant attention. In these reactions, diazo compounds—or their precursors such as N ‐tosylhydrazones—serve as cross‐coupling partners for the construction of C–C single or C=C double bonds. The transformations developed thus far in this field are summarized in the accompanying figure. These processes typically proceed via metal–carbene intermediates followed by migratory insertion steps, enabling efficient bond formation under either redox‐neutral or oxidative conditions. The broad compatibility of various carbene precursors and coupling partners has greatly enhanced the synthetic utility of this approach. This carbene‐based coupling strategy has demonstrated wide applicability, with numerous transition metals—including Pd, Cu, Rh, Ni, Co, and Ir—proving effective as catalysts. Moreover, the substrate scope has expanded beyond diazo compounds to include other carbene sources, and diverse cascade processes have been designed based on carbene migratory insertion. In addition, this methodology has been integrated with C–H functionalization, fluorine chemistry, and more recently, metal‐hydride‐mediated transformations. Its utility extends from the synthesis of complex molecules to the development of functional polymeric materials. Concurrently, asymmetric versions of carbene cross‐coupling reactions are being actively explored, although considerable challenges remain in this area. This review summarizes the historical development and recent advances in transition‐metal‐catalyzed carbene transfer reactions, with a focus on emerging coupling strategies and their synthetic applications. Key Scientists

Deuterium-labeled silanes are of great significance in organic synthesis and drug discoveries, yet obtaining versatile deuterated silanes efficiently and selectively under electrochemical conditions using green deuterium sources remains enormously challenging. Herein, facile and general electrochemical deuteration of silanes using D2O as the economical deuterium source was reported. A variety of alkyl- and aryl-substituted silanes can be smoothly converted into the corresponding products with excellent levels of deuterium incorporation and yields. Furthermore, this protocol enables 10-gram-scale preparation under high current conditions, underscoring the potential in industry applications. Mechanistic studies have revealed that a catalytic amount of nickel may form a pivotal silicon-nickel intermediate, reversing the polarity of silicon and thereby facilitating the subsequent reactions.

Sulfur ylides, first reported by Ingold and Jessop in 1930, have long occupied a central position in organic synthesis owing to their ambiphilic character and diverse reactivity. In recent years, ylide chemistry has progressed beyond classical systems toward the development of mixed ylides, in which two distinct heteroatoms are incorporated within a single ylide framework. Among these, sulfur based mixed ylides have emerged as powerful and versatile intermediates. Their unique electronic structure enables polarity inversion at the α-carbon, allowing this position to exhibit both nucleophilic and electrophilic behavior and thereby granting access to a broad range of reactive intermediates, including carbenes, radicals, carbocations, and carbynes. The discovery of the first sulfur based mixed ylide in 2018 marked a significant milestone, opening new avenues for reactivity and selectivity. This Review summarizes recent advances in sulfur based mixed ylide chemistry, with particular emphasis on their mechanistic features, and applications in diverse organic transformations.

The controlled synthesis of both E- and Z-stereoisomers remains a long-standing challenge in organic synthesis, yet it is important for accessing structurally and functionally diverse enamides. This study demonstrates the synthesis of E- and Z-hydrophenoxylated enamides using a nickel(II)-catalyst alongside phenols. The stereochemical outcome is controlled by the ligand environment and temperature. Ligands promote syn-addition via a keteniminium intermediate to afford the E-isomer, and elevated temperatures enable efficient E→Z isomerization to deliver the Z-isomer with excellent selectivity. This efficient and versatile strategy exhibits a broad substrate scope and functional group tolerance, including acids, bioactive estrone derivatives, sesamol, and related compounds.

The catalytic construction of medium-sized rings, particularly in an enantioselective manner, remains a significant challenge due to inherent entropic penalties and stereocontrol issues, yet it is an area of great interest. Herein, we disclose the development of a general (6 + n) annulation strategy leveraging 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates as versatile precursors for the efficient assembly of medium-sized rings. Through palladium-catalyzed formal (6 + 5) and (6 + 3) cycloadditions with vinylethylene carbonates (VECs) or trimethylenemethanes (TMMs), we have successfully achieved the regioselective construction of 11- and 9-membered heterocycles, respectively. Of particular note, the enantioselective (6 + 3) annulation, facilitated by rational chiral ligand design, afforded enantioenriched 9-membered heterocycles (up to 75% yield and 93% ee). Featuring readily available starting materials, structural modularity, and mild reaction conditions, this methodology represents a robust platform for accessing synthetically valuable medium-sized ring systems, including their enantioselective variants, thereby addressing a long-standing limitation in organic synthesis.

The development of new synthetic strategies that exploit visible light as a sustainable energy source represents a significant advancement in organic synthesis. Benzylthioethers and benzylsulfones are pivotal structural motifs, widely utilized as synthetic intermediates and functional groups in both organic and medicinal chemistry. In this study, we report a novel photoredox-catalyzed intermolecular approach for the formation of benzylic C-S bonds via direct functionalization of benzylic C(sp3)-H bonds. This methodology facilitates the efficient synthesis of secondary thioether and sulfonylation derivatives through the reaction of secondary benzylic substrates with readily available sodium benzenethiolate and sodium sulfinates under visible-light irradiation. This protocol offers a practical and atom-economical route to accessing diverse sulfur-containing compounds under mild conditions.

Main-group organometallic reagents played a pivotal role in organic synthesis, with numerous applications, ranging from pharmaceutical industries to material science. Especially, functionalized heterocyclic molecules may be prepared using main-group organometallics and have multiple applications due to their electronic and chemical properties. This comprehensive review emphasized the significance of functionalized organo-Li, -Mg, -Zn, -Al, -Mn, -Cu, -B, -Na, -La, -In, -Cd, and -Zr reagents for the selective functionalization of N-heteroaromatic scaffolds. Our major focus was on advanced synthetic methods for the preparation of densely functionalized N-heteroaromatic compounds. In recent years, various leading research groups developed highly reactive, air- and moisture-stable organometallic reagents that permitted a broad range of cross-coupling reactions (C-C, C-N, C-S, and C-X) using various electrophiles. We will describe the various preparations of N-heteroromatic organometallics (direct metal insertions, halogen-metal exchanges, transmetalations or directed metalations), showing the advantages and limitations of each method. Moreover, the use of low-cost and less toxic transition-metal-catalyzed processes with air-stable zinc reagents or TMP bases under sustainable conditions, offered alternative synthetic pathways for the preparation of fused N-heteroaromatic-based natural products and drugs. In this context, this review article points to new approaches for the functionalization of N-heteroaromatic scaffolds using various main-group organometallic reagents published between 2010 and 2024.

The nonenzymatic synthesis of organics from H2-CO2 redox couple forms the foundational basis for prebiotic carbon metabolism. However, constructing comprehensive carbon cycling reaction networks with multiple interlinked subsystems preceding enzymatic catalysis remains challenging. Here, we demonstrate that metallic molybdenum sulfide mimicking Mo-S2-pterin enzyme drives the construction of hydrothermal CO2 reaction networks across five carbon sequestration pathways including acetyl-CoA, reductive tricarboxylic acid, 3-hydroxypropionate-4-hydroxybutyrate, dicarboxylate-4-hydroxybutyrate, and ethylmalonyl-CoA pathways. A total of 32 intermediates and end-products are synthesized from CO2, encompassing five universal metabolic precursors. Spectroscopic and computational studies reveal that molybdenum sulfide containing Mo3+ with vacancy-induced distorted octahedral structure promotes the formation of radicals and enhances their adsorption and coupling in aqueous solutions, leading to CO2 conversion rate of 68.6% and selectivity of up to 70% for C2+ carboxylates. The metal sulfide-catalyzed multiple CO2 reaction networks under extreme conditions could function as a prebiotic precursor to ancient and core metabolic pathways.

ABSTRACT Sulfur ylides (S‐ylides) have long been recognized as versatile reagents and intermediates in organic synthesis. In particular, their role as surrogates for diazo compounds has recently gained considerable attention due to their superior stability, safer handling, and broader functional group tolerance, which make them attractive alternatives in both academic and industrial settings. Beyond classical transformations, S‐ylides have been increasingly applied in skeletal‐editing strategies, such as ring expansion reactions, that provide access to pharmaceutically relevant frameworks. Despite these advances, challenges remain in developing highly enantioselective catalytic protocols and expanding the scope of sustainable photochemical methodologies. This perspective highlights the emerging potential of S‐ylides in skeletal editing, tracing their evolution from fundamental studies to state‐of‐the‐art applications, while offering insights into current limitations and future opportunities that could reshape their role in synthetic chemistry.

Ligand-to-metal charge-transfer (LMCT) excitation has emerged in recent years as a powerful modality in organic synthesis, namely for the generation of heteroatom-centered radicals through formal metal-ligand bond homolysis from the LMCT excited state. However, the exploitation of alternative LMCT excited state processes has been extremely limited. Here, we describe a general strategy for tuning the reaction course from LMCT excited states of titanium alkoxides. This reactivity paradigm has been exploited for tandem β-scission/Giese addition reactions of both scission-amenable and scission-recalcitrant alcohols under divergent reaction pathways of metal-ligand bond homolysis and excited state β-scission through judicious choice of electronically tuned Ti catalysts. Through intramolecular competition studies, catalyst-controlled scission is shown to facilitate a rate enhancement of up to 103-fold over the intrinsic scission of free alkoxyl radicals, highlighting the impact of accessing the excited state scission paradigm. Computations support the relevance of a scission-promoting LMCT excited state with stereoelectronically aligned alkoxyl radical cation character to enable direct, selective β-scission.

In traditional transition-metal-catalyzed cross-coupling reactions, alkenyl electrophiles typically undergo transformation at the ipso-position of the leaving group, resulting in the formation of a single bond, rather than the installation of two functionalities across a C═C unit. Achieving the direct difunctionalization of alkenyl electrophiles has become increasingly desirable for streamlining the synthesis of complex molecules, which is essential for advancing molecular complexity in organic synthesis. Here, we report an iron-catalyzed cine-reductive carboboration of alkenyl tosylates with alkyl halides, providing a streamlined route to synthetically valuable tetrasubstituted alkenyl boronates. Mechanistic studies support a pathway that involves selective cine-alkylation of alkenyl tosylates followed by borylation, enabling the sequential formation of C(sp3)─C(sp3) and C(sp3)─B bonds, with subsequent elimination affording the desired C(sp2)─C(sp2) and C(sp2)─B bonds. These findings not only provide new mechanistic insights into iron-catalyzed cine-coupling processes but also establish a foundation for the rational design of new transformations of alkenyl electrophiles under iron catalysis.

ortho-Diacylbenzenes serve as versatile precursors for pharmaceutical synthesis, other biological applications, and organic synthesis. The intermolecular cyclization between the alkyl chains of two ketone substrates for the synthesis of ortho-diacylbenzenes offers atom-economical access to ortho-diacylbenzenes. However, intermolecular cyclization between the alkyl chains of two ketone substrates is a challenging chemical transformation. Here, we report that the copper-catalyzed reaction between ketone substrates containing alkyl chains in the presence of TEMPO as the oxidant undergoes dehydrogenation-initiated intermolecular [4 + 2] cyclization between the alkyl chains of two ketone substrates to regioselectively produce the ortho-diacylbenzene with high functional group tolerance. This copper-catalyzed intermolecular cyclization between the alkyl chains of two ketone substrates enables ketone substrates containing diverse molecular scaffolds to serve as efficient substrates for the synthesis of ortho-diacylbenzenes, although butyl-phenyl-ketones containing substituents at the δ-positions of the butyl chains regioselectively produce meta-diacylbenzene products. Consequently, structurally complex ketones generated from natural products or bioactive compounds undergo targeted transformation to efficiently produce ortho-diacylbenzenes. Interestingly, this copper-catalyzed intermolecular cyclization between the alkyl chains of two ketone substrates proceeds through the electrophilic TEMPO-catalyzed unknown [4 + 2] cycloaddition of two electron-poor alkenyl ketone intermediates, which overcomes the general requirement of the Diels-Alder cycloaddition reactions.

N,N-Dimethylformamide (DMF) has been a cornerstone solvent in both peptide and organic synthesis due to its excellent solubilizing properties and chemical stability. However, its use has raised significant health and environmental concerns. DMF is classified as a substance of very high concern (SVHC) by the European Chemicals Agency (ECHA) due to its reproductive toxicity and potential for skin absorption, leading to liver damage upon prolonged exposure. Consequently, restrictions on its use have been introduced, encouraging the scientific community to seek safer, more sustainable alternatives. This review provides a comprehensive analysis of the existing literature on alternative solvents to DMF, identifying current gaps or problems, and offering recommendations for future research.