Carboxylic acids are important chemical feedstocks, and direct decarboxylative asymmetric transformation holds significant synthetic value. Herein, we report a copper-catalyzed direct enantioselective decarboxylative cyanation of benzyl carboxylic acids under electrophotocatalytic conditions. Benzylic radicals are efficiently generated via ligand-to-metal charge transfer of copper(II) carboxylate species under irradiation of blue LEDs. Concurrently, the generation of copper(II) cyanide occurred simultaneously at the anode via electro-oxidation, avoiding the use of the stoichiometric amount of chemical oxidants. Then the coupling of benzylic radical and chiral Cu(II) cyanide leads to enantioselective decarboxylative cyanation. This reaction features a broad substrate scope and excellent functional group tolerance, enabling the direct conversion of carboxylic acids into diverse chiral benzyl nitriles.

Asymmetric catalytic hydroamination of alkenes represents one of the most efficient strategies for constructing chiral N-heterocycles. Herein, we realize the asymmetric intramolecular remote hydroamination of internal cis-alkenes via palladium catalysis. The reaction proceeds through sequential alkene aminopalladation, palladium migration, and reduction of terminal alkyl-palladium intermediates. The corresponding nitrogen-containing heterocycles are furnished in good yields with high enantioselectivity, offering a straightforward and robust route to the synthesis of piperidone, pyrrolidone, and oxazolidin-2-one scaffolds. Detailed mechanistic studies disclose that the stereochemical outcome and reversibility of aminopalladation are strongly solvent-dependent. Furthermore, the reduction of the alkyl-Pd(II) bond is highly susceptible to steric hindrance, which enables the achievement of remote asymmetric hydroamination.

Chiral allenes are privileged structural motifs found in numerous natural products and bioactive molecules, consequently, the synthesis of these scaffolds-especially polysubstituted chiral allenes-has garnered significant research interest. Among these methods, direct asymmetric functionalization of allenic sp2 C-H bond has been recognized as a powerful strategy for the modification of allenes, enabling late-stage functionalization (LSF) of allene-containing bioactive compounds. In recent years, Cu(II)-bound nitrogen-centered radicals (NCRs) have been demonstrated to override innate radical preferences to achieve site-selective C-H functionalizations, achieving the site-selective C-H cyanation, arylation and alkynylation of allenes via a copper-catalyzed radical relay process, where the HAA process exclusively occurs at sp2 C-H bonds. Although the enantioselective version has been achieved for the reaction of 1,3-disubstituted allenes, which afforded the chiral trisubstituted allenic nitriles with excellent enantioselectivities, the reactions of trisubstituted allenes exhibited significantly poor enantioselectivity. Herein, we report a copper-catalyzed site- and enantioselective sp2 C-H cyanation of trisubstituted allenes. This reaction was catalyzed by CuOAc and Box ligand L1 in a mixture solvent of tert-amyl alcohol (tAmOH), acetone and (trifluoromethyl)benzene at -40 degrees C. This method efficiently afforded a broad array of tetrasubstituted axially chiral allenic nitriles in good to excellent yields with excellent enantioselectivities.

The first copper-catalyzed enantioselective allylic C-H cyanation of electron-deficient alkenes was established herein. With a sequential catalytic hydrogenation in a one-pot fashion, the current method provides easy access to structurally diverse γ-cyanated carbonyls in good yields with excellent enantioselectivity, which are difficult to synthesize by the previously reported methods. Additional mechanistic investigations of the controlling experiments, kinetic study, isotopic effect, and DFT calculations revealed a new reaction pathway. We found that the previously reported Cu(II)-bound N-centered radical (NCR) undergoes dissociation in polar solvents to generate a free NCR species. This free sulfonamidyl radical, derived from the NF reagent, has a greater hydrogen-atom abstraction (HAA) ability, which is crucial for the successful allylic C-H abstraction of electron-deficient alkenes. Although the off-cycle existed to quench free NCR species by the extra Cu(I) catalyst, this side reaction can be effectively suppressed by reducing the catalyst concentration. Therefore, highly selective and efficient allylic C-H cyanation of electron-deficient alkenes could be achieved by using a low catalyst loading (0.25 mol %). These findings highlight the method to adjust the interaction between the copper(II) intermediate and free NCRs, which opens a window to carry out asymmetric C-H bond functionalization reactions across a range of substrate types.

Transition metal-catalysed enantioselective radical transformations have emerged as powerful tools for the synthesis of chiral molecules, and a range of methods have been developed. However, most of these successful reactions are effective for resonance-stabilized radicals; in sharp contrast, achieving precise stereocontrol over highly reactive, unstabilized alkyl radicals remains a major challenge, with very few successful examples. Here we establish a ligand-mediated radical orientation strategy that enables the highly enantioselective cyanation of such transient intermediates via copper catalysis. The chiral BoxOH ligand engages in dynamic hydrogen bonding with various remote functional groups on the radical species, strategically reshaping the reaction energy landscape and overcoming the inherently barrierless radical coupling process to dictate stereoselectivity. Consequently, this method enables the direct asymmetric cyano-functionalization of unactivated alkenes and inert sp 3 C-H bonds, expanding asymmetric radical reactions beyond stabilized intermediates and providing a platform for the enantioselective functionalization of abundant chemical feedstocks.

Selective transformation of C-H bonds represents a frontier research area in synthetic chemistry. While the high reactivity of radicals provides an alternative and efficient pathway for C-H bond functionalization, controlling their selectivity─particularly in processes such as site-selective hydrogen atom abstraction (HAA)─remains a long-standing and unresolved challenge in radical chemistry, largely due to the lack of effective regulation strategies. This review deliberately avoids a comprehensive discussion of the field's current state or landmark discoveries in C-H functionalization. Instead, by focusing on recent advances in metal-catalyzed, highly site-selective C-H bond transformations, this Perspective elucidates how metal-bound radicals enable precise hydrogen abstraction for targeted functionalization. This emerging paradigm offers innovative strategies for regulating radical behavior, potentially unlocking novel radical-mediated selective transformations─including but not limited to the precise functionalization of C-H bonds.

Here, we report an efficient method to synthesize enantiomerically enriched propargyl nitriles via copper-catalyzed asymmetric cyanation of propargylic radicals, which are generated from silyl-substituted allenes or alkynes. These reactions proceeded through a highly site-selective hydrogen atom abstraction (HAA) with Cu(II)-bound nitrogen-centered radicals (NCRs). Notably, silyl-substituted allenes demonstrate exceptional allenic sp2 C─H bond activation selectivity, outcompeting alternative reactive sp3 C─H bonds (benzylic, allylic, and heteroatom-adjacent) in HAA processes. This chemo-selectivity profile enables precise enantiocontrol and site-specific functionalization of complex molecular architectures.

Direct C-H bond functionalization has emerged as one of the most powerful and practical strategies for the modification of drug molecules. We have recently disclosed a Cu/NFAS (NFAS = N-fluoroalkyl sufonamide) catalytic system that exhibits high site-, regio-, and enantioselectivity for the direct cyanation of allylic C-H bonds. Here, we present a mechanistic investigation of this catalyst system, including the elucidation of side reactions involved in the transformation. This work focuses on an in-depth analysis of the catalytic cycle based on kinetic studies by NMR spectroscopy and characterization of the catalyst speciation by EPR and UV-vis spectroscopy. These studies indicate that a fraction of NFAS is sacrificed to the side reactions of the Cu(II)-bounded N-centered radical (Cu(II)-NCR) species for the generation of silylated sulfonamides and (CN)2. The data also show a great dependence of the reaction yield and selectivity (hydrogen atom abstraction or HAA over side reactions) on the structure of the Cu(II)-NCR species. Kinetic studies and DFT calculations further reveal that oxidation of the CuCN species by NFAS, HAA process, and cyanation of Cu(II)-NCRs with TMSCN have comparable energy barriers, which collectively determine the rate of the overall C-H cyanation reaction.

Mirror-image isomer blends have been converted into a single isomer by a light-activated copper catalyst — a challenging reaction that prevents the waste of materials. Mirror-image isomer blends have been converted into a single isomer by a light-activated copper catalyst — a challenging reaction that prevents the waste of materials.

Asymmetric allylic C(sp3)-H oxidation of terminal alkenes provides a streamlined process for accessing allylic alcohols and their derivatives; however, it represents a long-standing challenge in the field for several decades. Herein, we disclosed a copper-catalyzed approach for the enantioselective allylic C(sp3)-H oxidation of terminal alkenes, facilitated by introducing a sterically bulky B2Im(C6F5)6 anion. Notably, a wide range of aryl-substituted terminal alkenes were used as limiting reagents, delivering various products with excellent enantioselectivity and regioselectivity (up to 99% ee, >20:1 b/l). Mechanistically, the bulky counteranion was found to be essential for achieving excellent enantioselective control and high catalytic efficiency.

Herein, we established a copper-catalyzed asymmetric alkynylation of the sp2 C-H bond of silylallenes, which was presented as an efficient method for the synthesis of enantioenriched skipped diynes with excellent enantioselectivity. The reaction was initiated by hydrogen atom abstraction of sp2 allenic C-H bonds, in which the resonance forms of allenic and propargylic radicals were chemo- and enantioselectively trapped by chiral alkynyl-Cu(II) species to deliver a variety of skipped diynes. The method features a broad substrate scope and robust functional group tolerance, accommodating both alkynyl silanes and boronic esters. Moreover, the resulting skipped diynes serve as versatile key synthons for incorporating enantiomerically enriched enynes, alkynes, alkanes, and their derivatives, which could be applied in the concise synthesis of several bioactive molecules.

Methods for direct enantioselective oxidation of C(sp3)–H bonds will revolutionize the preparation of chiral alcohols and their derivatives. Enzymatic catalysis, which uses key metal-oxo species to facilitate efficient hydrogen atom abstraction, has evolved as a highly selective approach for C–H oxidation in biological systems. Despite its effectiveness, reproducing this function and achieving high stereoselectivity in biomimetic catalysts has proven to be a daunting task. Here we present a copper-based biomimetic catalytic system that achieves highly efficient asymmetric sp3 C–H oxidation with C–H substrates as the limiting reagent. A Cu(II)-bound tert-butoxy radical is responsible for the site-selective C–H bond cleavage, which resembles the active site of copper-based enzymes for C–H oxidation. The developed method has been successfully accomplished with good functional group compatibility and exceptionally high site- and enantioselectivity, which is applicable for the late-stage oxidation of bioactive compounds. The efficiency of enantioselective sp3 C–H bond oxidation using small synthetic catalysts is usually limited. Now a catalytic system involving a Cu(II)-bound tert-butoxy radical for site-selective C–H bond cleavage achieves allylic and propargylic sp3 C–H oxidation with the C–H substrates as the limiting reagent.

A palladium-catalyzed asymmetric 1,n-remote aminoacetoxylation of cis-alkenes has been developed using PhI(OAc)2 as an oxidant, providing the acetoxylated lactams with excellent enantioselectivities under mild reaction conditions. The sterically hindered pyridine-oxazoline (Pyox) L3 with a tert-butyl group in oxazoline ring and propyl group in C6 position of pyridinyl is vital for the reaction, where the former is good for asymmetric aminopalladation step and the latter for the chain walking process. The enantioenriched lactam products were proven to be good building blocks for the synthesis of azabicycles.

Herein, we establish a remote hydrosulfonamidation (HSA) of alkenes using palladium catalysis, where N-fluoro-N-(fluoro-sulfonyl)-carbamate with a sulfur(VI) fluoride moiety is demonstrated as a good amidation reagent. The anti-Markovnikov HSA reaction of terminal alkenes and the remote HSA of internal alkenes are achieved to efficiently yield primary N-alkyl-N-(fluorosulfonyl)-carbamates. In addition, this protocol enables the high-value utilization of alkane by combining the dehydrogenation process. The generated N-alkyl products exhibit a unique reactivity of sulfur(VI) fluorides, which can be directly transferred to N-alkyl sulfamides or amines via the sulfur(VI) fluoride exchange reaction, thereby streamlining their synthesis. Moreover, a (pyridyl) benzazole-type ligand proved to be vital for the excellent chemo- and regioselectivities.

Development of methods for the sp2 C-H transformations of allenes has received much attention, and it presents a powerful tool for the synthesis of complicated allene-containing bioactive molecules. With a copper-catalyzed radical relay, sp2 allenic C-H arylation and alkynylation were established herein, using various aryl boronic acids and trimethoxysilyl-substituted alkynes as carbon nucleophiles and using electrophilic N-F reagents as nitrogen-centered radical precursors. These methods featured excellent site selectivity to deliver fully substituted allenes efficiently. Moreover, with silyl-substituted allenes as substrates, a subsequent dual sp2 C-H functionalization process was established as well, which allowed for the divergent synthesis of multifunctionalized allenes, significantly expanding their chemical spaces.

Alkynes are versatile synthons in organic synthesis, as well as important structural moieties in bioactive molecules. Recently, transition metal-catalyzed hydroalkynylation of alkenes has been developed with reactive alkenes and alkenes bearing directing groups. However, the regioselective hydroalkynylation of simple alkenes is still challenging. Herein, we have developed a palladium-catalyzed Markovnikov hydroalkynylation of unactivated terminal alkenes, which provides an efficient approach for the synthesis of branched alkynyl compounds under mild conditions. This reaction features excellent functional group tolerance, good reaction yields and excellent regioselectivity. Moreover, the asymmetric hydroalkynylation reaction has also been achieved with moderate enantioselectivity by introducing a sterically bulky chiral Pyox ligand.

Compared with the extensively reported hydrogen atom transfer (HAT) at sp3 C-H, abstraction of hydrogen atoms at the sp2 carbon is extremely rare. Here, we communicate the site-selective cyanation of the sp2 C-H bond of allenes using the strategy of copper-catalyzed radical relay. The reactions afford various allenyl nitriles directly from simple allenes with a broad substrate scope and a remarkable functional group compatibility under mild conditions. These reactions exhibit excellent site-selectivity toward sp2 C-H, which can be attributed to the unique pocket created by the Cu-bound nitrogen-centered radical. The favorable HAT on sp2 C-H is due to crucial hydrogen bonding between the fluoride bonded to the Cu(II) center and the hydrogen atom at the allylic position. These features enable the late-stage functionalization of druglike bioactive molecules containing an allene motif.