Late-stage gem-difluoroallylation of phenol in bioactive molecules and peptides with 3,3-difluoroallyl sulfonium salts.

An efficient method for the late-stage selective O-fluoroalkylation of tyrosine residues with a stable yet highly reactive fluoroalkylating reagent, 3,3-difluoroallyl sulfonium salts (DFASs), has been developed. The reaction proceeds in a mild basic aqueous buffer (pH = 11.6) with high efficiency, high biocompatibility, and excellent regio- and chemoselectivity. Various oligopeptides and phenol-containing bioactive molecules, including carbohydrates and nucleosides, could be selectively O-fluoroalkylated. The added vinyl and other functional groups from DFASs can be valuable linkers for successive modification, significantly expanding the chemical space for further bioconjugation. The synthetic utility of this protocol has been demonstrated by the fluorescently labeled anti-cancer drug and the synthesis of O-link type 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid-tyrosine3-octreotate (DOTA-TATE), showing the prospect of the method in medicinal chemistry and chemical biology.

Reductive Catalytic Difluorocarbene Transfer via Palladium Catalysis.

A palladium-catalyzed reductive difluorocarbene transfer reaction that tames difluorocarbene to couple with two electrophiles has been developed, representing a new mode of difluorocarbene transfer reaction. The approach uses low-cost and bulk industrial chemical chlorodifluoromethane (ClCF2 H) as the difluorocarbene precursor. It produces a variety of difluoromethylated (hetero)arenes from widely available aryl halides/triflates and proton sources, featuring high functional group tolerance and synthetic convenience without preparing organometallic reagents. Experimental mechanistic studies reveal that an unexpected Pd0/II catalytic cycle is involved in this reductive reaction, wherein the oxidative addition of palladium(0) difluorocarbene ([Pd0 (Ln )]=CF2 ) with aryl electrophile to generate the key intermediate aryldifluoromethylpalladium [ArCF2 Pd(Ln )X], followed by reaction with hydroquinone, is responsible for the reductive difluorocarbene transfer.

Copper-catalysed difluorocarbene transfer enables modular synthesis.

The use of metal catalysts to produce and control the reactivity of carbenes has long offered a powerful approach to organic synthesis; however, difluorocarbene transfer catalysed by metal is an outlier and remains a substantial challenge. In that context, copper difluorocarbene chemistry has been elusive so far. Here we report the design, synthesis, characterization and reactivity of isolable copper(I) difluorocarbene complexes, which enable the development of a copper-catalysed difluorocarbene transfer reaction. The method offers a strategy for the modular synthesis of organofluorine compounds from simple and readily available components. This strategy facilitates a modular difluoroalkylation by coupling difluorocarbene with two inexpensive feedstocks, silyl enol ethers and allyl/propargyl bromides, in a one-pot reaction via copper catalysis, providing a diversity of difluoromethylene-containing products without laborious multistep synthesis. The approach enables access to various fluorinated skeletons of medicinal interest. Mechanistic and computational studies consistently reveal a mechanism involving nucleophilic addition to an electrophilic copper(I) difluorocarbene.

3,3-Difluoroallyl Sulfonium Salts: Practical and Bench-Stable Reagents for Highly Regioselective gem-Difluoroallylations.

The site-selective introduction of the difluoromethylene group into organic molecules has important applications in producing pharmaceuticals and agrochemicals. However, the general and efficient methods that can construct both C(sp2 )-CF2 R and C(sp3 )-CF2 R bonds remain challenging. Here, we disclose a new type of practical and bench-stable difluoroalkylating reagent 3,3-difluoroallyl sulfonium salt (DFAS) that can be practically prepared from inexpensive and bulk chemical feedstock 3,3,3-trifluoropropene. This reagent allows highly regioselective gem-difluoroallylation of various organozinc reagents, including aryl, primary, secondary, and tertiary alkyl zinc reagents, via copper catalysis under mild reaction conditions with high efficiency. The reaction can also be extended to a series of substituted DFASs. Application of the approach leads to the short synthesis of complex analogs, showing the prospect of DFASs in medicinal chemistry.

(Fluoro)alkylation of alkenes promoted by photolysis of alkylzirconocenes.

Difluoroalkylated compounds have important applications in pharmaceutical, agrochemical, and materials science. However, efficient methods to construct the alkylCF2-alkyl bond are very limited, and the site-selective introduction of a difluoromethylene (CF2) group into an aliphatic chain at the desired position remains challenging. Here, we report an unprecedented example of alkylzirconocene promoted difluoroalkylation of alkyl- and silyl-alkenes with a variety of unactivated difluoroalkyl iodides and bromides under the irradiation of visible light without a catalyst. The resulting difluoroalkylated compounds can serve as versatile synthons in organic synthesis. The reaction can also be applied to activated difluoroalkyl, trifluoromethyl, perfluoroalkyl, monofluoroalkyl, and nonfluorinated alkyl halides, providing a general method to controllably access fluorinated compounds. Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway induced by a Zr(iii) species is involved in the reaction, in which the Zr(iii) species is generated by the photolysis of alkylzirconocene with blue light.

Coupling of Heteroaryl Halides with Chlorodifluoroacetamides and Chlorodifluoroacetate by Nickel Catalysis.

A nickel-catalyzed cross-coupling of heteroaryl halides with chlorodifluoroacetamides and chlorodifluoroacetate has been developed. The combination of NiCl2 ⋅ DME with 4,4'-diNon-bpy, co-ligand PPh3 , and additive LiCl renders the catalytic system efficient for the synthesis of medicinal interest heteroaryldifluoroacetamides. The application of the method leads to short and highly efficient synthesis of biologically active molecules, providing a facile route for applications in medicinal chemistry and agrochemistry.

Decarboxylative and Deaminative Alkylation of Difluoroenoxysilanes via Photoredox Catalysis: A General Method for Site-Selective Synthesis of Difluoroalkylated Alkanes.

A general method for site-selective difluoroalkylation of alkyl carboxylic redox esters with difluoroenoxysilanes through photoredox-catalyzed decarboxylative reaction has been developed. The reaction can also be extended to aliphatic amine derived pyridinium salts. This method has the advantages of high efficiency, mild reaction conditions, and broad substrate scope, including primary, secondary, and sterically hindered tertiaryl alkyl substrates, providing a general and practical route for applications in organic synthesis and pharmaceutical studies.

Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium.

Difluoromethylated aromatic compounds are of increasing importance in pharmaceuticals, agrochemicals and materials. Chlorodifluoromethane (ClCF2H), an inexpensive, abundant and widely used industrial raw material, represents the ideal and most straightforward difluoromethylating reagent, but introduction of the difluoromethyl group (CF2H) from ClCF2H into aromatics has not been reported. Here, we describe a direct palladium-catalysed difluoromethylation method for coupling ClCF2H with arylboronic acids and esters to generate difluoromethylated arenes with high efficiency. The reaction exhibits a remarkably broad substrate scope, including heteroarylboronic acids, and was used for difluoromethylation of a range of pharmaceuticals and biologically active compounds. Preliminary mechanistic studies revealed that a palladium difluorocarbene intermediate is involved in the reaction. Although numerous metal-difluorocarbene complexes have been prepared, the catalytic synthesis of difluoromethylated or difluoromethylenated compounds involving metal-difluorocarbene complexes has not received much attention. This new reaction therefore also opens the door to understand metal-difluorocarbene complex catalysed reactions.

Tandem Difluoroalkylation-Arylation of Enamides Catalyzed by Nickel.

A nickel-catalyzed three-component reaction for the synthesis of difluoroalkylated compounds through tandem difluoroalkylation-arylation of enamides has been developed. The reaction tolerates a variety of arylboronic acids and widely available difluoroalkyl bromides, and even the relatively inert substrate chlorodifluoroacetate. The significant advantages of this protocol are the low-cost nickel catalyst, synthetic convenience, excellent functional-group compatibility and high reaction efficiency.

Nickel-Catalyzed Difluoroalkylation of (Hetero)Arylborons with Unactivated 1-Bromo-1,1-difluoroalkanes.

A nickel-catalyzed cross-coupling between (hetero)arylborons and unactivated 1-bromo-1,1-difluoroalkanes has been developed. The use of two ligands (a bidentate bipyridine-based ligand, 4,4'-ditBu-bpy, and a monodentate pyridine-based ligand, DMAP) offers a highly efficient nickel-based catalytic system to prepare difluoroalkylated arenes which have important applications in medicinal chemistry.

Access to Difluoromethylated Arenes by Pd-Catalyzed Reaction of Arylboronic Acids with Bromodifluoroacetate.

An unprecedented example of Pd-catalyzed difluoromethylation of aryl boronic acids with bromodifluoroacetate is described. The reaction proceeds under mild reaction conditions with hydroquinone and Fe(acac)3 as additives. Preliminary mechanistic studies reveal that a difluorocarbene pathway is involved in the reaction, which is unusual compared to the most traditional approaches. This reaction has advantages of high efficiency and excellent functional group compatibility, even toward bromide and hydroxy group, thus providing a useful protocol for drug discovery and development.

Facile Access to Fluoromethylated Arenes by Nickel-Catalyzed Cross-Coupling between Arylboronic Acids and Fluoromethyl Bromide.

The nickel-catalyzed fluoromethylation of arylboronic acids was achieved with the industrial raw material fluoromethyl bromide (CH2 FBr) as the coupling partner. The reaction proceeded under mild reaction conditions with high efficiency; it features the use of a low-cost nickel catalyst, synthetic simplicity, and excellent functional-group compatibility, and provides facile access to fluoromethylated biologically relevant molecules. Preliminary mechanistic studies showed that a single-electron-transfer (SET) pathway is involved in the catalytic cycle.

Rhodium-Catalyzed ortho-Selective C-F Bond Borylation of Polyfluoroarenes with Bpin-Bpin.

An ortho-selective C-F bond borylation between N-heterocycle-substituted polyfluoroarenes and Bpin-Bpin with simple and commercially available [Rh(cod)2 ]BF4 as a catalyst is now reported. The reaction proceeds under mild reaction conditions with high efficiency and broad substrate scope, even toward monofluoroarene, thus providing a facile access to a wide range of borylated fluoroarenes that are useful for photoelectronic materials. Preliminary mechanistic studies reveal that a Rh(III/V) catalytic cycle via a key intermediate rhodium(III) hydride complex [(H)Rh(III) Ln (Bpin)] may be involved in the reaction.

A general synthesis of fluoroalkylated alkenes by palladium-catalyzed Heck-type reaction of fluoroalkyl bromides.

An efficient palladium-catalyzed Heck-type reaction of fluoroalkyl halides, including perfluoroalkyl bromides, trifluoromethyl iodides, and difluoroalkyl bromides, has been developed. The reaction proceeds under mild reaction conditions with high efficiency and broad substrate scope, and provides a general and straightforward access to fluoroalkylated alkenes which are of interest in life and material sciences.

Palladium-catalyzed difluoroalkylation of aryl boronic acids: a new method for the synthesis of aryldifluoromethylated phosphonates and carboxylic acid derivatives.

The palladium-catalyzed difluoroalkylation of aryl boronic acids with bromodifluoromethylphosphonate, bromodifluoroacetate, and further derivatives has been developed. This method provides a facile and useful access to a series of functionalized difluoromethylated arenes (ArCF2 PO(OEt)2 , ArCF2 CO2 Et, and ArCF2 CONR(1) R(2) ) that have important applications in drug discovery and development. Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway may be involved in the catalytic cycle.

Highly selective gem-difluoroallylation of organoborons with bromodifluoromethylated alkenes catalyzed by palladium.

A first example of Pd-catalyzed gem-difluoroallylation of organoborons using 3-bromo-3,3-difluoropropene (BDFP) in high efficiency with high α/γ-substitution regioselectivity has been developed. The reaction can also be extended to substituted BDFPs and has advantages of low catalyst loading (0.8 to 0.01 mol %), broad substrate scope, and excellent functional group compatibility, thus providing a facile route for practical application in drug discovery and development.

Pd-catalyzed direct arylation of polyfluoroarenes on water under mild conditions using PPh3 ligand.

We report a Pd-catalyzed direct arylation of polyfluoroarenes with aryl iodides. The advantages of this reaction are its high reaction efficiency, excellent functional group compatibility, mild reaction conditions (70 °C), inexpensive PPh(3) ligand, and use of pure water as reaction medium. The usefulness of this reaction has also been demonstrated by rapid preparation of highly functionalized polyfluoroarenes via iterative Pd-catalyzed C-H bond functionalization.

Highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids from chiral imines of trifluoropyruvate.

An efficient method for highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids was developed via indium mediated allylation of (R)-phenylglycinol methyl ether based imines of trifluoropyruvate in good yields with high diastereoselectivities at room temperature; to illustrate the application of this method in organic synthesis, 2-allyl-2-(trifluoromethyl) aziridine was prepared in an efficient manner.

Pd(OAc)(2) catalyzed olefination of highly electron-deficient perfluoroarenes.

An efficient, Pd(OAc)(2) catalyzed method for direct olefination of highly electron-deficient perfluoroarenes was developed. The reaction scope includes a series of activated and nonactivated alkenes in moderate to high yields with moderate to high regio- and stereoselectivities.