Abstract A highly regio- and enantioselective synthesis of chiral 3-allyl-1H-indenes has been developed using a Rh(I)/bisoxazolinephosphine catalyst in combination with 4-dimethylaminopyridine (DMAP). The tridentate NPN* ligand binds tightly to Rh(I), effectively preventing catalyst deactivation by the indene products and enabling high yields with excellent stereocontrol. Mechanistic studies reveal an unconventional pathway involving initial formation of a 1,5-diene intermediate, followed by Rh/DMAP cocatalyzed 1,3-proton migration to yield the thermodynamically favored 1,4-diene products. The method exhibits broad functional group compatibility with both allylic carbonates and indene derivatives, affording the desired products in up to 98% yield, >99% ee, and >20:1 rr.
We present a highly efficient strategy for the assembly of bispidine-isoxazolidine-fused multicyclic structures via [3+2] cycloaddition of alkenes to a nitrone-functionalized bispidine framework. The reaction smoothly delivers diverse hybrid heterocycles featuring complex stereochemistry at the isoxazolidine-bispidine junction point in high yields and good selectivity. This approach opens a straightforward pathway to new synthetic analogues of natural compounds (primarily lupine alkaloids) and may prove to be useful for the discovery of new bioactive molecules and ligands for catalysis.
Abstract We report an unprecedented photoredox-catalyzed four-component cascade reaction of β,γ-unsaturated ketones with bromodifluoroalkyl compounds, nitriles and water. Merging 1,2-carbonyl migration and radical-polar crossover, this protocol delivers a variety of valuable fluorine-containing acetamides and features broad substrate compatibility, including natural product and pharmaceutical skeletons. Gram-scale synthesis, product derivatization and AIE properties are demonstrated. Mechanistic control experiments including radical trapping, deuterium labeling, and luminescence quenching studies collectively support a catalytic cycle involving photoinduced single-electron transfer, intramolecular 1,2-carbonyl migration, and subsequent ionic nucleophilic capture through radical-polar crossover.
Abstract We report a pyridine-to-pyridazine skeletal editing strategy that enables a formal CN-to-NN atom-pair exchange from readily available pyridines. Key to this transformation is hydrazine-mediated ring opening of N-(2,4-dinitrophenyl)pyridinium salts, followed by mCPBA-promoted oxidation to a 5-diazenylpenta-2,4-dienal intermediate that undergoes 6π-electrocyclization and oxidative deformylation to deliver pyridazines. This method features mild reaction conditions, broad substrate scope, late-stage applicability, and gram-scale scalability.
Abstract Fluorinated bicyclo[1.1.1]pentanes (F-BCPs) are valuable three-dimensional bioisosteres in drug discovery, yet methods for the direct construction of bridge-monofluorinated and quaternary F-BCPs remain scarce. Here, we report a fluoroiodocarbene addition to bicyclobutanes under mild conditions, providing 2-fluoro-2-iodobicyclo[1.1.1]pentanes. The C–I bond serves as a versatile radical handle, enabling synthesis of quaternary bridge-fluorinated BCPs, including Giese-type additions to activated alkenes and desulfonylative couplings. This strategy offers a practical, modular entry to bridge-fluorinated BCP architectures of potential interest for medicinal chemistry.
Abstract An electrochemical nickel-catalyzed cross-electrophile coupling reaction of organic halides with cyclosulfonium salts to construct C(sp3)–C(sp3)/C(sp2) bonds is reported. This highly selective synthetic approach demonstrates significant practical utility, as evidenced by its broad substrate scope encompassing C(sp3)–/C(sp2)–iodides, while maintaining excellent functional group tolerance, particularly challenging late-stage functionalization applications. Moreover, density functional theory (DFT) calculations are employed to systematically evaluate the Gibbs free energy profile of key intermediates along the proposed nickel-catalyzed reaction pathway, thereby providing robust theoretical support for the mechanistic feasibility of the transformation.
Abstract This study reports a novel class of bench-stable, oxime ester-derived bifunctional fluorosulfamoyl reagents for photosensitized 1,n-fluorosulfonamidylimination of alkenes. Upon visible-light irradiation, these reagents undergo energy-transfer-mediated homolysis, simultaneously generating a transient fluorosulfonamide radical and a persistent iminyl radical. This dual-radical system enables efficient 1,2- and 1,4-fluorosulfonamidylimination of alkenes, thereby providing direct access to valuable amino-aliphatic sulfamoyl fluorides under mild conditions. The utility of this method is demonstrated by the late-stage modification of bioactive molecules and further diversification of products via SuFEx click chemistry and selective deprotection.
Abstract A visible light-induced palladium catalyzed intramolecular and intermolecular C(sp3)–C(sp2) cross-coupling reaction has been established. This synthetic method exhibits broad functional group tolerance and a wide substrate scope including bioactive molecules, pharmaceutical scaffolds, and peptides, enabling access to structurally novel β,γ-unsaturated amides, benzazepine derivatives as bioisosteres of sedative–hypnotic 1,4-benzodiazepine drugs, and heterocyclic acetamides. Moreover, it offers a direct route to commercially relevant pharmaceuticals such as zolpidem and alpidem. Notably, the successful synthesis of key inhibitors─including those targeting KDM5B, JNK1, and PDE10A─highlights the practical significance and broad applicability of this method. The reaction mechanism was explored using control experiments, Stern–Volmer fluorescence quenching experiments, light on/off experiments, and density functional theory (DFT) calculations.
Abstract Medium-ring lactams are important structural motifs in many scientific fields but are difficult to synthesize due to unfavorable entropic/enthalpic effects and transannular interactions. Herein, an efficient strategy for accessing highly functionalized borylated 9- to 11-membered lactams is established, relying on photocatalytic cascade ring expansion of unstrained cyclic amines with N-heterocyclic carbene (NHC)-borane. Notably, this methodology features mild conditions, excellent functional group tolerance, and great downstream transformations, providing a powerful and practical platform for constructing diverse medium-ring lactams. Mechanistic studies support a radical mechanism involving nucleophilic NHC-boryl radical formation, radical ipso-cyclization, and subsequent 1,4-aryl migration from N-to-C atom to release the desired ring-expanded lactams.
Rifamycins display structural diversity and broad bioactivities, with the intrinsic reactivity of their polyketide chain and quinone ring providing a foundation for photochemical reactions. Herein, we constructed the mutant strain Δrif-orf3_16::rifR+rif-orf19 by deleting post-PKS modification genes of rifamycin, yielding 34a-deoxyrifamycin W (1a) and its derivatives (2a-4a). Subsequent sunlight irradiation of these compounds triggered an intramolecular Paternò-Büchi reaction coupled with Michael addition, producing oxetane-rifamycins A-D (1b-4b). They feature a unique 4/6/6/6/6/17 hexacyclic scaffold and exhibit potent anti-MRSA activity. Density functional theory (DFT) calculations elucidated the formation mechanism of the oxetane-rifamycin scaffold.
A modular, metal-free, cascade cyclization of functionalized enynes provides rapid access to structurally diverse boron-doped polycyclic aromatic hydrocarbons. The method simultaneously constructs the polycyclic framework and B-O, B-N, or C-B bonds while allowing straightforward boron functionalization. The alkene substitution pattern dictates the cyclization pathway, enabling selective formation of five- or six-membered rings. Photophysical studies reveal how structural variations govern the optical and fluorescence properties of these π-conjugated materials.
An efficient tandem amidyl-radical cyclization/alkyl radical Heck reaction for the construction of allylated γ-lactams has been developed under visible-light-induced palladium catalysis. The reaction proceeds via an amidyl radical/Pd(I) hybrid species generated through photoexcited Pd(0)-mediated N-O bond cleavage of N-acyloxyamides, followed by intramolecular cyclization to form an alkyl-Pd(I) intermediate. This intermediate subsequently undergoes an intermolecular alkyl radical Heck reaction with vinyl arenes, furnishing N-alkyl allylated γ-lactams bearing diverse functional groups under mild conditions. Furthermore, successful late-stage functionalization of bioactive molecules and downstream transformations of the products underscore the utility of this method.
We report a ruthenium-catalyzed regioselective and stereospecific hydrostannation of terminal alkynes in a switchable solvent system under ambient conditions. This method exhibits excellent selectivity and functional group tolerance, enabling controlled Markovnikov and anti-Markovnikov addition of tributyl tin hydride to the C(sp)-C(sp) bond. The stereospecific formation of (E)-β-vinylstannane from (Z)-β-vinylstannane by isomerization at high temperatures was verified through a detailed NMR study. We also demonstrated the utility of this method by synthesizing an organotin-containing boronic ester that can be used for sequential cross-coupling reactions as a nucleophilic partner.
Abstract 1,2-Benzoisoxazol-3-amines are obtained in 52–96% isolated yields directly from 2-fluorobenzonitriles using a combination of hydroxylamine salts and quaternary ammonium hydroxide bases in aqueous media, as opposed to the literature precedent that requires lengthy synthesis or the use of hazardous hydroxylamine derivatives. This streamlined approach improves operational safety and atom economy, simplifying access to medicinally relevant motifs. Mechanistic experiments and DFT calculations support an SNAr-first pathway with rate-limiting substitution followed by rapid cyclization.
Abstract A novel and efficient method to access (1,2b)-syn-2-hydroxy-1-aryl-2-tetrahydroisoquinolin propan-1-ones (±)-3a–3n and (±)-4a–4v has been developed through a micro water-initiated and Cu(OTf)2-catalyzed process from benzo-N,O-acetals and α-diazo ketones. A series of substituted (1,2b)-syn-2-hydroxy-1-aryl-2-tetrahydroisoquinolin propan-1-ones were obtained with moderate to excellent yields and excellent selectivities (syn:anti >19:1). In addition, density functional theory (DFT) calculations were performed to explain the stereochemistry outcome for this novel transformation.
Abstract Catalytic dearomatization offers a powerful strategy for accessing structurally complex partially saturated architectures, yet it remains largely unexplored for BN-embedded aromatics. Herein, we report a B(C6F5)3-catalyzed dearomative hydrosilylation of 2,1-borazaronaphthalenes with hydrosilanes, enabling efficient access to BN-isosteres of 1,2-dihydronaphthalenes under mild, metal-free conditions. The method features broad substrate scope, excellent functional-group tolerance, and gram-scale applicability, providing a versatile platform for constructing partially saturated BN bioisosteres.
Abstract 1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) represent privileged scaffolds in medicinal chemistry as pharmaceutical bioisosteres of benzene rings owing to their enhanced metabolic and pharmacokinetic properties. Herein, we demonstrate an unprecedented and practical photoredox-catalyzed direct C(sp2)-H trifluoromethyl-bicyclopentylation of enamides with bench-stable BCP-thianthrenium salt under environmentally friendly and transition-metal-free conditions, delivering a broad array of geometrically-defined E-configured enamides bearing the pharmaceutically prominent CF3-BCP entity in a regio- and stereoselective manner. The transformation proceeded through the Giese addition of structurally rigid CF3-BCP alkyl radical to electron-rich enamides and the ensuing oxidative radical/polar crossover followed by β-H elimination. The synthetic utility of this methodology was further highlighted by its scalability and its capacity for streamlined late-stage functionalization, enabling access to various synthetically and biologically important organic intermediates and heterocycles.
Abstract Sulfamates and sulfamides are privileged motifs in medicinal chemistry, yet direct methods for assembling their N-(hetero)aryl derivatives remain limited. We report a unified Cu-catalyzed protocol for the N-arylation of sulfamates and sulfamides with aryl- and heteroaryl bromides that is operationally simple, cost-effective, scalable, and broadly applicable to pharmacologically relevant substrates. Copper-catalyzed N-arylations can also be combined with HFIPS sulfamoylations to access N-aryl sulfamates and sulfamides in telescoped or one-pot sequences from alcohol and amine precursors.
Abstract A reagent-controlled divergent reaction of vinyl sulfoxonium ylides with arylideneindane-1,3-diones has been developed. The transformation proceeds through in situ formation and selective cleavage of donor–acceptor cyclopropane intermediates, providing dihydropyranone and indenopyranone scaffolds with excellent regio- and stereoselectivity. B(C6F5)3 affords dihydropyranones, whereas ceric ammonium nitrate (CAN) furnishes indenopyranones. Mechanistic studies identify a common vinyl cyclopropane intermediate and support distinct ionic and radical pathways.
Abstract Herein, we have developed an efficient and highly enantioselective approach for the synthesis of spiro-cyclopropane-pyrazolones via a proline-based secondary amine-catalyzed formal [2 + 1] cycloaddition reaction. The protocol provides access to structurally diverse spiro-cyclopropane-pyrazolone derivatives bearing three contiguous stereogenic centers in good to excellent diastereoselectivities and excellent enantioselectivities. Mechanistic studies support the proposed reaction pathway, while the scalability of the reaction further demonstrates its practical utility.
