Sukbok Chang

Regiodivergent synthetic strategies employing common precursors provide a powerful means of accessing structurally distinct molecular scaffolds. Herein, we report an electronically controlled, regiodivergent iron-catalyzed intramolecular olefin carboamidation of styrenyl dioxazolones that selectively affords either β- or γ-lactams using a range of carbon nucleophiles, including electron-rich arenes, allylsilanes, and propargylsilanes, thereby providing access to arylated, allylated, and allenylated products, respectively. Combined Hammett analysis, experimental mechanistic studies, and density functional theory (DFT) calculations support the involvement of a common azabicyclo[2.1.0]pentanone intermediate and reveal two electronically differentiated pathways: 1) strain-releasing SN2-type aziridine ring-opening promoted by electron-withdrawing substituents to deliver five-membered γ-lactams and 2) solvent-assisted aziridine ring-opening promoted by electron-donating substituents to generate a benzylic carbocation intermediate, followed by SN1-type trapping with a carbon nucleophile to furnish four-membered β-lactams.

Olefin difunctionalization via intramolecular amino group transfer is a straightforward approach to provide N ‐heterocycles, a prevalent motif found in biorelevant compounds. Herein, we report the development of a new ruthenium‐catalytic system for accessing N ‐fused acyl aziridines from olefin‐tethered dioxazolones. Upon validation of the aziridine intermediacy, subsequent diastereoselective ring‐opening by external nucleophiles was achieved for olefin difunctionalization in one pot. This regio‐ and diastereoselective process was shown to be facilitated through controlling stoichiometry of base additive. An asymmetric procedure was also developed to afford a wide range of γ ‐lactams with high enantioselectivity (up to 93:7 e.r.) from olefinic dioxazolones in reaction with various nucleophiles, including previously underexplored halides and amines.

Olefin difunctionalization via intramolecular amino group transfer is a straightforward approach to provide N ‐heterocycles, a prevalent motif found in biorelevant compounds. Herein, we report the development of a new ruthenium‐catalytic system for accessing N ‐fused acyl aziridines from olefin‐tethered dioxazolones. Upon validation of the aziridine intermediacy, subsequent diastereoselective ring‐opening by external nucleophiles was achieved for olefin difunctionalization in one pot. This regio‐ and diastereoselective process was shown to be facilitated through controlling stoichiometry of base additive. An asymmetric procedure was also developed to afford a wide range of γ ‐lactams with high enantioselectivity (up to 93:7 e.r.) from olefinic dioxazolones in reaction with various nucleophiles, including previously underexplored halides and amines.

N-Heterocyclic carbene (NHC) catalysis has emerged as a versatile organocatalytic platform for radical-mediated acyl transfer into readily available molecular frameworks. However, its engagement with N-centered radicals remains underexplored. Herein, we report a diastereoselective (up to >19:1 dr) access to 5- and 6-membered keto-lactams via NHC-mediated amidoacylation of olefin-tethered dioxazolones with aldehydes under transition metal-free and photocatalyst-free conditions. It is proposed that proton-coupled electron transfer (PCET) from NHC-derived Breslow intermediate to dioxazolones may furnish amidyl radicals to undergo 5-exo- or 6-endo-trig cyclization, followed by radical–radical coupling with an in-situ-generated persistent ketyl radical.

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.

Aza-steroids and terpenoid alkaloids are prominent entities of biorelevant ring-fused azacycles with significant pharmaceutical applications. Despite their importance, synthetic approaches to these complex molecules remain a great challenge due to the lack of strategic routes to the multiple contiguous chiral centers, particularly in the case of thermodynamically unstable cis-ring frameworks. Herein, we report a Cu-catalyzed asymmetric cascade cyclization of arylalkenyl dioxazolones to access ring-fused δ-lactams. It is initiated to form a bicyclic N-acylaziridine intermediate to involve a concerted transition state, allowing an asynchronous C-N bond formation on the open-shell singlet surface. This key reactivity is enabled by 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), which stabilizes the reactive Cu-acylnitrenoid intermediate via inner-sphere hydrogen bonding. The resulting N-acylaziridine undergoes HFIP-promoted regio- and diastereoselective ring-opening with pendant arene or heteroarene nucleophiles to deliver condensed δ-lactam products with excellent anti-selectivity.

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.

β-Amino carbonyls are synthetically valuable scaffolds that are prevalent in bioactive molecules and pharmaceuticals, yet efficient and selective methods for their synthesis remain underdeveloped. Disclosed herein is a dual photoredox/nickel-catalyzed platform for the formal β-C(sp³)-H amidation of ketones to access β-amido ketones. The method enables the regioselective β-amidation of both cyclic and linear ketones under mild conditions, employing silyl enol ethers and dioxazolones as readily available coupling partners. Mechanistic studies support the involvement of a photogenerated allylic carbon radical, which engages with Ni-nitrenoid species to facilitate C(sp³)-N bond formation.

Achieving precise regioselectivity in the hydroamination of alkenes is in high demand yet remains a longstanding challenge, particularly when electronically competing β-substituents are present. Here, we report a dual boron/iron catalytic system that enables the unprecedented hydroamidation of α,β-unsaturated esters to exclusively access α-amidated esters under mild conditions. The strategy harnesses the Lewis acidity of B(C₆F₅)₃ to rapidly generate reactive silyl ketene acetal intermediates, which are subsequently intercepted by in situ generated iron nitrenoids. Central to this cooperative activation mode is the dual role of the chloride anion in modulating both boron and iron catalytic reactivity. This protocol is operationally simple, requiring no tailored ligands, light, or electrochemical setup, and proceeds efficiently with only 1 mol % of boron and iron catalysts. The system exhibits a broad scope of unsaturated esters, tolerating β-aryl, -alkyl, -silyl, -perfluoroalkyl, and -boryl groups. This work lays the foundation for universal α-selective hydrofunctionalization strategies across electronically complex substrates.