Visible-Light-Induced Oxidative Decarboxylative Coupling of Phenylacetic Acid Derivatives Using SF6 as an Oxidant.

A visible-light-mediated decarboxylative coupling reaction of phenylacetic acid derivatives, featuring sulfur hexafluoride (SF6) as the oxidant, has been developed. This metal-free method allows for the synthesis of a series of bibenzyl derivatives and complex all-carbon skeletons, facilitating efficient utilization and degradation of the greenhouse gas SF6.

Photoredox Catalyzed Synthesis of gem-Difluoroalkenes and Monofluorinated Cyclooctenes via 1,5-HAT Process.

gem-Difluoroalkenes and monofluorinated cycloalkenes have emerged as basic structural units in a variety of bioactive molecules and natural products. Thus, developing straightforward and efficient methods for synthesizing fluorinated alkene compounds is of considerable significance. Herein, we disclose a visible-light-induced defluorination of 2-trifluoromethyl-1-alkene via a 1,5-HAT process using N-alkoxyphtalimides as both radical precursor and potential nucleophile. The mild and stepwise reaction leads to a variety of structurally diverse gem-difluoroalkenes and monofluorinated cyclooctenes with high efficiency, respectively.

Nickel-Catalyzed Hydrotrifluoroalkylation of Alkynes to Construct Allylic Trifluoromethyl Terminal Alkenes.

Herein, we describe a nickel-catalyzed hydrotrifluoroalkylation of terminal alkyne for the synthesis of a manifold allylic trifluoromethyl terminal alkene. The combination of nitrogen and phosphine ligands, especially electron-rich ones, plays an indispensable role in the course of the reaction, promoting the reactivity to a remarkable level, demonstrating high efficiency, broad substrate scope, and favorable functional group compatibility. The strategy provides a facile method for the synthesis of diversified allylic CF3-containing drugs and bioactive molecules.

Asymmetric construction of allylicstereogenic carbon center featuring atrifluoromethyl group via enantioselective reductive fluoroalkylation.

Emerging as a powerful tool for lead optimization in pharmaceutical research and development, to develop the facile, general protocols that allows the incorporation of fluorine-containing motif in drug candidates has accumulated enormous research interest in recent years. Among these important motifs, the incorporation of strategic motif CF3 on aliphatic chain especially with the concomitant construction of trifluoromethylated alkanes bearing a CF3-substituted stereogenic carbon, is of paramount importance. Herein, we disclose an asymmetric nickel-catalyzed reductive trifluoroalkylation of alkenyl halides for enantioselective syntheses of diverse α-trifluoromethylated allylic alkanes, offering a general protocol to access the trifluoromethyl analogue to chiral α-methylated allylic alkanes, one of the most prevalent key components among natural products and pharmaceuticals. Utilities of the method including the application of the asymmetric trifluoroalkylation on multiple biologically active complex molecules, derivatization of transformable alkenyl functionality were demonstrated, providing a facile method in the diversity-oriented syntheses of CF3-containing chiral drugs and bioactive-molecules.

Development of Axially Chiral Styrene-Type Carboxylic Acid Ligands via Palladium-Catalyzed Asymmetric C-H Alkynylation.

A weakly coordinated carboxylate-directed palladium-catalyzed atroposelective C-H alkynylation method for the development of novel axially chiral styrene-type carboxylic acids is disclosed. This transformation exhibits good yields (up to 85%), excellent enantiocontrol (up to 99% ee), and mild conditions. Notably, the synthetic utility of the resulting alkynyl carboxylic acid derivatives was demonstrated by various derivatizations as well as their potential as chiral ligands in asymmetric C-H activations.

Facile synthesis of axially chiral styrene-type carboxylic acids via palladium-catalyzed asymmetric C-H activation.

A novel method by a one-step introduction of axial chirality and sterically hindered group has been developed for facile synthesis of axially chiral styrene-type carboxylic acids. With the palladium-catalyzed C-H arylation and olefination of readily available cinnamic acid established, this transformation demonstrated excellent yield, excellent stereocontrol (up to 99% yield and 99% ee), and broad substrate scope under mild conditions. The axially chiral styrene-type carboxylic acids produced have been successfully applied to Cp*CoIII-catalyzed asymmetric C-H activation reactions, indicating their potential as chiral ligands or catalysts in asymmetric synthesis.

Copper-catalyzed monochloromethylazidation to access transformable terminal alkyl chlorides using stoichiometric BrCH2Cl.

Efficient copper-catalyzed 1,2-difunctionalization of alkenes with commercially available BrCH2Cl as a chloromethylating source was carried out, in which mild conditions, high reactivity, excellent functional-group tolerance, and late-stage modification of a bioactive molecule are demonstrated. This strategy offers a solution for the diverse syntheses of nitrogen-containing terminal alkyl chlorides, a common synthetic handle that is promising for multiple derivatizations. Mechanistic studies indicate that a chloromethyl radical is involved in the catalytic cycle.

Copper-Catalyzed Intramolecular Amination of C(sp3)-H Bond of Secondary Amines to Access Azacycles.

The cross-coupling of C-N bond directly from inert C-H bonds is an ideal approach to synthesize saturated azacycles due to its high efficiency and atom economy. In this article, a copper-catalyzed intramolecular amination via the cross coupling of C(sp3)-H and N-H bonds of secondary amine has been reported, which exhibit excellent chemo- and regioselectivity, extensive substrate scope, and functional group tolerance in good to excellent yield, offering an efficient pathway to build nitrogen-containing heterocycle skeletons.

Enantioselective Copper-Catalyzed Remote C(sp3)-H Alkynylation of Linear Primary Sulfonamides.

The highly efficient copper-catalyzed enantioselective alkynylation of the remote C(sp3)-H bond on linear primary sulfonamides is presented here using a radical relay strategy. The chiral box-copper complex, which is used to recapture the in-situ-generated alkyl radical via a 1,5-HAT strategy, is the key to success, affording the chiral alkynes after a following reductive elimination. A general substrate scope, mild conditions, and excellent regio- and enantioselective control are demonstrated in this method.

Enantioselective Copper-Catalyzed Cyanation of Remote C(sp3)-H Bonds Enabled by 1,5-Hydrogen Atom Transfer.

The direct functionalization of C(sp3)-H bonds has led to the development of methods to access molecules or intermediates from basic chemicals in an atom- and step-economic fashion. Nevertheless, achieving high levels of chemo-, regio-, and enantioselectivity in these reactions remains challenging due to the ubiquity and low reactivity of C(sp3)-H bonds. Herein, we report an unprecedented protocol for enantioselective cyanation of remote C(sp3)-H bonds. With chiral Box-Cu complex as the catalyst, the reaction of N-fluorosulfonamide furnishes the corresponding products in excellent yields and high enantiomeric excess (ee) under mild reaction conditions. A radical relay pathway involving 1,5-hydrogen atom transfer (1,5-HAT) of N-center radicals followed by enantioselective cyanation of the in situ-formed benzyl radicals is proposed. This enantioselective copper-catalyzed cyanation thus offers insights into an efficient way for the synthesis of bioactive molecules for drug discovery.

Highly stereoselective nickel-catalyzed difluoroalkylation of aryl ketones to tetrasubstituted monofluoroalkenes and quaternary alkyl difluorides.

A nickel-catalyzed difluoroalkylation of α-C-H bonds of aryl ketones to furnish highly stereo-defined tetrasubstituted monofluoroalkenes or quaternary alkyl difluorides from secondary or tertiary ketones, respectively, has been established. Mechanistic investigations indicated that these C-H fluoroalkylations proceed via a Ni(i)/Ni(iii) catalytic cycle. An obvious fluorine effect was observed in the reaction, and this reaction has demonstrated high stereoselectivity, mild conditions, and broad substrate scopes, thus enabling the late-stage fluoroalkylation of bioactive molecules. This method offers a solution for expedient construction of monofluoroalkenes from readily available materials, and provides an efficient approach for the synthesis of bioactive fluorinated compounds for the discovery of lead compounds in medicinal chemistry.

Copper-Catalyzed Dichloromethylazidation of Alkenes Using BrCCl2H as a Stoichiometric Dichloromethylating Reagent.

A copper-catalyzed dichloromethylazidation of alkenes using commercially available BrCCl2H as a stoichiometric dichloromethylating reagent has been reported. Mechanistic studies indicated that a dichloromethyl radical was involved in the catalytic cycle. This transformation has demonstrated mild conditions, high reactivity, excellent functional-group tolerance, and a broad substrate scope, and thus it has offered a new solution for difunctionalization of alkenes to make diverse transformable dichloromethylated molecules.

Nickel-Catalyzed Heck-Type Monofluoroacetation of Styrenes for Facile Synthesis of Allylic Fluorides.

An efficient nickel-catalyzed Heck-type reaction between styrenes and fluoroalkyl iodine has been developed. This novel transformation has demonstrated a broad substrate scope, mild reaction conditions and excellent E-stereoselectivity. This efficient synthetic method has been applied to the late-stage monofluoroacetation of biologically active molecules. Mechanistic investigations indicate that a monofluoroalkyl radical is involved in the catalytic cycle.

Novel and facile synthesis of 1-benzazepines via copper-catalyzed oxidative C(sp3)-H/C(sp2)-H cross-coupling.

A novel and facile synthetic strategy for the construction of 1-benzazepines has been developed via copper-catalyzed oxidative C(sp3)-H/C(sp2)-H cross-coupling directly from two inert C-H bonds. This transformation represents an atom- and step-economical way to synthesize biologically important seven-membered benzo-heterocycles compared with the known methods.

Copper-catalyzed oxidative C(sp3)-H/C(sp2)-H cross-coupling en route to carbocyclic rings.

Copper-catalyzed selective coupling of C(sp3)-H bonds with C(sp2)-H bonds has been developed. An aniline module was used as a directing group to generate an aminyl radical, which selectively cleaves the secondary and tertiary C(sp3)-H bonds via a 1,5-HAT process to forge six-membered carbocyclic rings.