Copper-Catalyzed Chemo- and Enantioselective Radical 1,2-Carbophosphonylation of Styrenes

The copper-catalyzed enantioselective radical difunctionalization of alkenes from readily available alkyl halides and organophosphorus reagents possessing a P−H bond provides an appealing approach for the synthesis of α-chiral alkyl phosphorus compounds. The major challenge arises from the easy generation of a P-centered radical from the P−H-type reagent and its facile addition to the terminal side of alkenes, leading to reverse chemoselectivity. We herein disclose a radical 1,2-carbophosphonylation of styrenes in a highly chemo- and enantioselective manner. The key to the success lies in not only the implementation of dialkyl phosphites with a strong bond dissociation energy to promote the desired chemoselectivity but also the utilization of an anionic chiral N,N,N-ligand to forge the chiral C(sp³)−P bond. The developed Cu/N,N,N-ligand catalyst has enriched our library of single-electron transfer catalysts in the enantioselective radical transformations.     

Photocatalytic Dehydrogenative Cross‐Coupling of Alkenes with Alcohols or Azoles without External Oxidant

Direct cross‐coupling between alkenes/R‐H or alkenes/RXH is a dream reaction, especially without external oxidants. Inputting energy by photocatalysis and employing a cobalt catalyst as a two‐electron acceptor, a direct C−H/X−H cross‐coupling with H₂ evolution has been achieved for C−O and C−N bond formation. A new radical alkenylation using alkene as the redox compound is presented. A wide range of aliphatic alcohols—even long chain alcohols—are tolerated well in this system, providing a new route to multi‐substituted enol ether derivatives using simple alkenes. Additionally, this protocol can also be used for N ‐vinylazole synthesis. Mechanistic insights reveal that the cobalt catalyst oxidizes the photocatalyst to revive the photocatalytic cycle.     

Bis(1-Methyl-ortho-Carboranyl)Borane

The Lewis superacid, bis(1-methyl-ortho-carboranyl)borane, is rapidly accessed in two steps. It is a very effective hydroboration reagent capable of B−H addition to alkenes, alkynes, and cyclopropanes. To date, this is the first identified Lewis superacidic secondary borane and most reactive neutral hydroboration reagent.     

Remote Radical Desaturation of Unactivated C−H Bonds in Amides

Desaturation of inert aliphatic C−H bonds in alkanes to form the corresponding alkenes is challenging. In this communication, a new and practical strategy for remote site-selective desaturation of amides via radical chemistry is reported. The readily installed N-allylsulfonylamide moiety serves as an N radical precursor. Intramolecular 1,5-hydrogen atom transfer from an inert C−H bond to the N-radical generates a translocated C-radical which is subsequently oxidized and deprotonated to give the corresponding alkene. The commercially available methanesulfonyl chloride is used as reagent and a Cu/Ag-couple as oxidant. The remote desaturation is realized on different types of unactivated sp³-C−H bonds. The potential synthetic utility of this method is further demonstrated by the dehydrogenation of natural product derivatives and drugs.     

An environmentally benign synthesis of isoxazolines and isoxazoles mediated by potassium chloride in water

An effective and environmentally benign procedure for the synthesis of isoxazolines and isoxazoles has been developed by a cycloaddition of nitrile oxides with alkenes or alkynes in water. In this approach, potassium chloride is first oxidized into chlorine in water by the environmentally friendly oxidant Oxone®, then aldoximes are oxidized into nitrile oxides by the in situ generated hypochlorous acid, finally a 1,3-dipolar cycloaddition between nitrile oxides and alkenes or alkynes occurs to provide the corresponding isoxazolines and isoxazoles in good yields.     

Cationic Iridium-Catalyzed Asymmetric Decarbonylative Aryl Addition of Aromatic Aldehydes to Bicyclic Alkenes

We report an unprecedented catalytic protocol for the enantioselective decarbonylative transformation of aryl aldehydes. In this process, the decarbonylation of aldehydes catalyzed by chiral iridium complexes enabled the formation of asymmetric C−C bonds through the formation of an aryl−iridium intermediate. The decarbonylative aryl addition to bicyclic alkenes was fluidly performed without a stoichiometric aryl−metal reagent, such as aryl boronic acid, with a cationic iridium complex generated in situ from Ir(cod)₂(BAr^F₄) and the sulfur-linked bis(phosphoramidite) ligand ((R,R)-S−Me−BIPAM). This reaction has broad functional group compatibility, and no waste is generated, except carbon monoxide.     

Ruthenium‐Catalyzed para‐Selective C−H Alkylation of Aniline Derivatives

The para ‐selective C−H alkylation of aniline derivatives furnished with a pyrimidine auxiliary is herein reported. This reaction is proposed to take place via an N−H‐activated cyclometalate formed in situ. Experimental and DFT mechanistic studies elucidate a dual role of the ruthenium catalyst. Here the ruthenium catalyst can undergo cyclometalation by N−H metalation (as opposed to C−H metalation in meta ‐selective processes) and form a redox active ruthenium species, to enable site‐selective radical addition at the para position.     

O-Isocyanates as Uncharged 1,3-Dipole Equivalents in [3+2] Cycloadditions

1,3-Dipoles are commonly used in [3+2] cycloadditions, whereas isoelectronic uncharged dipole variants remain underdeveloped. In contrast to conventional 1,3-dipoles, uncharged dipole equivalents form zwitterionic cycloadducts, which can be exploited to build further molecular complexity. In this work, the first cycloadditions of oxygen-substituted isocyanates (O-isocyanates) were studied experimentally and by DFT calculations. This unique cycloaddition strategy provides access to a novel class of heterocycle aza-oxonium ylides through intramolecular and intermolecular cycloadditions with alkenes. This allowed a systematic study of the reactivity of the transient aza-oxonium ylide intermediate, which can undergo N−O bond cleavage followed by nitrene C−H insertion, and the formation of β-lactams or isoxazolidinones upon varying the structure of the alkene or O-isocyanate reagents.     

Silylated Cyclohexadienes in Radical Chain Hydrosilylations

A new method for the mild radical hydrosilylation of alkenes and alkynes is described. Silylated cyclohexadienes that can be readily prepared on large scale are used as radical hydrosilylating reagents. Non‐activated alkenes and alkynes are hydrosilylated in high yields. The reaction can be combined with C C bond formation, as demonstrated for the preparation of silylated cycloalkanes from the corresponding dienes. Furthermore, radical hydrosilylations in combination with β‐fragmentation reactions for the synthesis of allylsilanes and hydrosilylations of aldehydes and ketones providing protected alcohols can be readily performed by this strategy.     

Frontispiece: Photocatalytic Terminal C−C Coupling Reaction Inside Water Soluble Nanocages

Developing methods that activate C−H bonds directly with high selectivity for C−C bond formation in complex organic synthesis has been a major chemistry challenge. Recently it has been shown that photoactivation of weakly polarized C−H bonds can be carried out inside a cationic water-soluble nanocage with visible light-mediated host-guest charge transfer (CT) chemistry. Using this novel photoredox activation paradigm, here we demonstrate C−C bond formation to photo-generate 1,3-diynes at room temperature in water from terminal aromatic alkynes for the first time. The formation of cavity-confined alkyne radical cation and the proton-removed neutral radical species highlight the unique C−C coupling step driven by supramolecular preorganization.     

Direct C−C Double Bond Cleavage of Alkenes Enabled by Highly Dispersed Cobalt Catalyst and Hydroxylamine

The utilization of a single-atom catalyst to break C−C bonds merges the merits of homogeneous and heterogeneous catalysis and presents an intriguing pathway for obtaining high-value-added products. Herein, a mild, selective, and sustainable oxidative cleavage of alkene to form oxime ether or nitrile was achieved by using atomically dispersed cobalt catalyst and hydroxylamine. Diversified substrate patterns, including symmetrical and unsymmetrical alkenes, di- and tri-substituted alkenes, and late-stage functionalization of complex alkenes were demonstrated. The reaction was successfully scaled up and demonstrated good performance in recycling experiments. The hot filtration test, catalyst poisoning and radical scavenger experiment, time kinetics, and studies on the reaction intermediate collectively pointed to a radical mechanism with cobalt/acid/O₂ promoted C−C bond cleavage as the key step.     

A Visible‐Light‐Driven Iminyl Radical‐Mediated C−C Single Bond Cleavage/Radical Addition Cascade of Oxime Esters

A room‐temperature, visible‐light‐driven N‐centered iminyl radical‐mediated and redox‐neutral C?C single bond cleavage/radical addition cascade reaction of oxime esters and unsaturated systems has been accomplished. The strategy tolerates a wide range of O‐acyl oximes and unsaturated systems, such as alkenes, silyl enol ethers, alkynes, and isonitrile, enabling highly selective formation of various chemical bonds. This method thus provides an efficient approach to various diversely substituted cyano‐containing alkenes, ketones, carbocycles, and heterocycles.     

Amidinyl Radical Formation through Anodic N−H Bond Cleavage and Its Application in Aromatic C−H Bond Functionalization

We report herein an atom‐economical and sustainable approach to access amidinyl radical intermediates through the anodic cleavage of N−H bonds. The resulting nitrogen‐centered radicals undergo cyclizations with (hetero)arenes, followed by rearomatization, to afford functionalized tetracyclic benzimidazoles in a highly straightforward and efficient manner. This metal‐ and reagent‐free C−H/N−H cross‐coupling reaction exhibits a broad substrate scope and proceeds with high chemoselectivity.     

A Three-Component Arene Difunctionalization: Merger of C(sp3)/(sp2)−H Bond Addition

A tandem three-component C−H bond addition involving the activation of an inert C(sp³)−H bond is reported. The process enables the direct regioselective synthesis of 1,2-difunctionalized arenes with the formation of C(sp³)− and C(sp²)−C(arene) bonds. 2-Iodobenzoic acid derivatives behave as masked bifunctional reagent (BFR) and react with 2-pyridyl-methyl sulfoximine (MPyS) protected aliphatic acids bearing α,α-disubstituted groups, and alkenes to produce β-aryl-δ-alkenyl amide derivatives in a single operation. The transformation involves Pd(II)/Pd(IV) and Pd(II)/Pd(0) catalytic systems. Detailed mechanistic studies, including density functional theory (DFT) calculations, reveal the formation of large T-shaped palladacycles and the onset of a 1,2-palladium migration via decarboxylation.     

Transition-Metal-Free Coupling of 1,3-Dipoles and Boronic Acids as a Sustainable Approach to C−C Bond Formation

The need for alternative, complementary approaches to enable C−C bond formation within organic chemistry is an on-going challenge in the area. Of particular relevance are transformations that proceed in the absence of transition-metal reagents. In the current study, we report a comprehensive investigation of the coupling of nitrile imines and aryl boronic acids as an approach towards sustainable C−C bond formation. In situ generation of the highly reactive 1,3-dipole facilitates a Petasis–Mannich-type coupling via a nucleophilic boronate complex. The introduction of hydrazonyl chlorides as a complementary nitrile imine source to the 2,5-tetrazoles previously reported by our laboratory further broadens the scope of the approach. Additionally, we exemplify for the first time the extension of this protocol into another 1,3-dipole, through the synthesis of aryl ketone oximes from aryl boronic acids and nitrile N-oxides.     

Exploring Superacid-Promoted Skeletal Reorganization of Aliphatic Nitrogen-Containing Compounds

Here we report a method to reorganize the core structure of aliphatic unsaturated nitrogen-containing substrates exploiting polyprotonation in superacid solutions. The superelectrophilic activation of N-isopropyl systems allows for the selective formal C_sp3−H activation/cyclization or homologation / functionalization of nitrogen-containing substrates. This study also reveals that this skeletal reorganization can be controlled through protonation interplay. The mechanism of this process involves an original sequence of C−N bond cleavage, isopropyl cation generation and subsequent C−N bond and C−C bond formation. This was demonstrated through in situ NMR analysis and labelling experiments, also confirmed by DFT calculations.     

Activation of Remote meta‐C−H Bonds in Arenes with Tethered Alcohols: A Salicylonitrile Template

Palladium‐catalyzed activation of remote meta ‐C−H bonds in arenes containing tethered alcohols was achieved with high regioselectivity by using a nitrile template. Computational studies on the macrocyclic transition state of the regioselectivity‐determining C−H activation steps revealed that both the C‐N‐Ag angles and gauche comformations of phenyl ether play an extremely important role in the meta selectivity.     

Computational Study on Chemoselective Difunctionalization of Unactivated Alkenes with Radical-mediated Remote Functional Group Migration

A computational study of the radical-mediated chemoselective difunctionalization of the tertiary alcohol substituted aliphatic alkenes is carried out employing density functional theory (DFT) and high-level coupled-cluster methods, such as coupled-cluster singles and doubles with perturbative triples [DLPNO-CCSD(T)]. Our results indicate that the cyclic vinyl radical plays an important role in the progression of the reactions. Our computations demonstrated that the chemoselective difunctionalization of unactivated alkenes with radical-mediated remote functional group migration is suitable for the 5- and 6-exo-dig cyclization, as opposite to 3- and 4-exo-dig cyclization suffering from cyclic intermediate with high energy. Our results show that the migration of nitrile group is more preferable than that of alkynyl group for the molecules including both cyano group and alkynyl group. For the 5- and 6-exo-dig cyclization, the rate-determining step is the homolysis of the C−C σ-bond in the cyclic intermediate, which results in the hydroxyl alkyl radical.     

New Radical Borylation Pathways for Organoboron Synthesis Enabled by Photoredox Catalysis

Radical borylation using N‐heterocyclic carbene (NHC)‐BH₃ complexes as boryl radical precursors has emerged as an important synthetic tool for organoboron assembly. However, the majority of reported methods are limited to reaction modes involving carbo‐ and/or hydroboration of specific alkenes and alkynes. Moreover, the generation of NHC‐boryl radicals relies principally on hydrogen atom abstraction with the aid of radical initiators. A distinct radical generation method is reported, as well as the reaction pathways of NHC‐boryl radicals enabled by photoredox catalysis. NHC‐boryl radicals are generated via a single‐electron oxidation and subsequently undergo cross‐coupling with the in‐situ‐generated radical anions to yield gem‐difluoroallylboronates. A photoredox‐catalyzed radical arylboration reaction of alkenes was achieved using cyanoarenes as arylating components from which elaborated organoborons were accessed. Mechanistic studies verified the oxidative formation of NHC‐boryl radicals through a single‐electron‐transfer pathway.     

Palladium‐Catalyzed Formal Hydroalkylation of Aryl‐Substituted Alkynes with Hydrazones

We have developed an unprecedented Pd‐catalyzed formal hydroalkylation of alkynes with hydrazones, which are generated in situ from naturally abundant aldehydes, as both alkylation reagents and hydrogen donors. The hydroalkylation proceeds with high regio‐ and stereoselectivity to form (Z)‐alkenes, which are more difficult to generate compared to (E)‐alkenes. The reaction is compatible with a wide range of functional groups, including hydroxy, ester, ketone, nitrile, boronic ester, amine, and halide groups. Furthermore, late‐stage modifications of natural products and pharmaceutical derivatives exemplify its unique chemoselectivity, regioselectivity, and synthetic applicability. Mechanistic studies indicate the possible involvement of Pd‐hydride intermediates.