Xiang Lyu

A ligand-free, iron-catalyzed aerobic oxidative coupling of unprotected primary arylamines is reported. Utilizing inexpensive FeCl₃ and ambient air as the terminal oxidant, this protocol enables chemoselective ortho–ortho C(sp²)–C(sp²) bond formation while bypassing traditional N-protection requirements. The method accommodates regioselective homo- and cross-coupling of primary arylamines, alongside heterocoupling with phenolic substrates, providing a protection-free platform for constructing complex biaryls directly from primary anilines.

Transition-metal hydride (TMH) catalysis has become a powerful strategy for hydroamination reactions, enabling direct C–N bond formation from simple alkenes and alkynes under mild conditions. In conventional TMH-catalyzed hydroamination, a metal hydride first engages a π system through hydrometalation or related hydrogen-atom-transfer processes to generate organometallic intermediates, wherein stabilization of the incipient carbon center dictates regioselectivity. As a consequence, subsequent coupling with a nitrogen electrophile intrinsically favors C–N bond formation at electronically activated positions. Accordingly, regioselectivity patterns such as α-amination adjacent to electronically polarizing substituents, directing-group-controlled sites, or sterically accessible terminal positions following migration are well-established, whereas complementary β-selective amination remains challenging to achieve. This Account summarizes our efforts to merge TMH catalysis with nitrenoid transfer chemistry and, in doing so, to uncover two distinct and mechanistically orthogonal hydroamidation regimes governed by the ordering of elementary steps. Using bench-stable dioxazolones as acyl nitrenoid precursors, we first established a canonical TMH manifold in which hydrometalation precedes inner-sphere nitrenoid transfer. In this regime, regioselectivity is programmed at the metal hydride insertion stage and can be predictably controlled across a wide range of TMH catalytic systems, enabling regioselective hydroamidation of alkynes and alkenes with broad scope and high functional-group compatibility. A conceptual turning point emerged from mechanistic studies of NiH catalysis, where an unexpected β-selective intramolecular hydroamidation exposed a fundamentally different reaction manifold. Rather than initiating with hydrometalation, NiH was found to activate the nitrenoid precursor first, generating a Ni-amido intermediate that subsequently engages the alkene through polarity-matched amidonickelation. This transposed hydroamidation regime inverts the selectivity-determining step, shifting control from alkene hydrometalation to C–N bond formation. As a result, regioselectivity patterns inaccessible under conventional TMH logic, including β-lactam formation, intermolecular β-amidation of conjugated carbonyls, and homobenzylic hydroamidation of vinylarenes, become attainable with high enantioselectivity. Together, these studies establish step order as a central design parameter in TMH-catalyzed hydroamidation. By deliberately choosing whether hydride delivery or nitrenoid generation occurs first, complementary regio- and stereochemical outcomes can be accessed from the same classes of unsaturated substrates. Beyond nitrenoid chemistry, extension of this transposed logic to carbene transfer processes further underscores its generality. We anticipate that continued mechanistic elucidation and expansion of this framework will transform TMH–nitrenoid synergy from a collection of reactions into a predictive platform for precision C–N bond construction.

We report a nickel-catalyzed asymmetric carboacylation of alkenes using acyl chlorides as bifunctional carbon and carbonyl sources. The reaction proceeds via a functional group transfer mechanism, enabling efficient access to enantioenriched ketones without the use of toxic CO gas. Precise control of CO extrusion and reinsertion affords broad substrate scope and high enantioselectivity, with good tolerance of functional groups commonly found in drug-like molecules. Mechanistic studies, including radical inhibition experiments, isotopic labeling, and DFT calculations, support a Ni⁰/Ni^II/Ni^III/Ni^I catalytic cycle involving reversible CO transfer and stereocontrolled migratory insertion.

We present here the first example of NiH-catalyzed homobenzylic hydroalkylation of aryl alkenes mediated by a nickel carbene radical, achieving the elusive β-selectivity with excellent regiocontrol. Mechanistic investigations suggest that this transformation is enabled by the preferential engagement of NiH with bench-stable sulfoxonium ylides, whose unique chelation properties promote carbene activation prior to alkene insertion. The resulting nickel carbene radical is proposed to undergo selective β-addition, followed by intramolecular metal hydride transfer and protodemetalation. The reaction exhibits broad scope across aryl, heteroaryl, and complex bioactive alkene derivatives, as well as diverse sulfoxonium ylides. This work establishes a new mechanistic platform for NiH catalysis, expanding the synthetic repertoire for site-selective alkene functionalization.

Herein, we present a mechanistically distinct approach to the multicomponent difunctionalisation of styrenes with alkyl halides and oxygen by integrating α-aminoalkyl radical-mediated halogen-atom transfer (XAT) with copper catalysis under air-equilibrated conditions. This strategy eliminates the need for external peroxides or photoredox conditions, offering a streamlined and efficient alternative. Mechanism studies uncover a unique role for the copper catalyst: instead of directly activating alkyl halides, inexpensive CuCl₂ oxidizes a tertiary amine to generate an α-aminoalkyl radical, which then drives XAT to release alkyl radicals. These radicals subsequently add to alkenes, facilitating efficient difunctionalisation. This method accommodates a broad range of alkyl radical precursors, including fluoroalkyl- and alkyl halides, and demonstrates compatibility with diverse styrenes, enabling the modular synthesis of β-(fluoro)alkylated ketones with excellent functional group tolerance under mild conditions. Notably, the strategy's practical utility is exemplified through the late-stage functionalisation of biologically active molecules and pharmaceuticals, showcasing its potential for rapid, efficient access to structurally complex molecules.

A nickel-catalyzed intramolecular DKR of racemic azabiaryl triflates achieves axial and central chirality via reductive addition and nickel-mediated inversion, affording versatile chiral heterobiaryls applicable as ligands and organocatalysts.

Herein, we introduce a Ni-catalyzed asymmetric homobenzylic hydroamidation reaction that efficiently addresses the dual challenges of achieving regio- and enantioselectivity in the synthesis of β-(hetero)arylethylamides. By employing a transposed NiH catalysis approach, this method facilitates the formation of key chiral nickel-amido intermediates, enabling asymmetric insertion into alkenes to produce the desired β-arylamide products with excellent enantioselectivity. The reaction exhibits a high functional group tolerance and utilizes readily available starting materials of vinylarenes to react with dioxazolone as a robust amidating source. Notably, this approach was successfully applied to the synthesis of pharmaceutical compounds and natural products, such as Clobenzorex, Direx, Selegiline, Sacubitril, and Cipargamin.

Herein, we introduce a Ni-catalyzed asymmetric homobenzylic hydroamidation reaction that efficiently addresses the dual challenge of achieving regio- and enantioselectivity in the synthesis of β-(hetero)arylethylamides. By employing a transposed NiH catalysis approach, this method facilitates the formation of key nickel-amido intermediates, enabling migratory insertion into alkenes to produce the desired products. The reaction exhibits excellent functional group tolerance and utilizes simple, readily available starting materials, thereby readily accessing pharmaceutical and natural product frameworks. Notably, the approach was applied to the synthesis of pharmaceutical compounds and natural products, such as Sacubitril and Cipargamin, showcasing its potential to streamline the process with high yields and selectivity. This work underscores the transformative role of NiH catalysis in expanding the toolbox of asymmetric hydroamidation.

Herein, we disclose a photoinduced radical cascade cyclization of alkynes with sulfinates via a novel EDA complex for the synthesis of various 3-sulfonylindoles and vinyl sulfone oxindoles, which are crucial motifs in medicinal and biological chemistry. The reaction proceeds under mild, photocatalyst- and transition-metal-free conditions, featuring operational simplicity, broad substrate scope, and easy scalability. Mechanistic studies reveal that the reaction is initiated with a photoinduced intermolecular charge transfer from sulfinates to N-sulfonamides, generating a sulfonyl radical followed by an N-centered radical, thus enabling the cascade cyclization process.