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.
All about efficiency: The title reaction tolerates a variety of arylboronic acids and widely available difluoroalkyl bromides, and even the relatively inert substrate chlorodifluoroacetate. The protocol provides a highly efficient method for the catalytic synthesis of difluoroalkylated compounds.
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.
A nickel‐catalyzed cross‐coupling of heteroaryl halides with chlorodifluoroacetamides and chlorodifluoroacetate has been developed. The synthetic simplicity from widely available fluorine sources and heteroaryl halides renders the protocol cost efficient synthesis of biologically active molecules, providing a facile route for applications in medicinal chemistry.
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 (ArCF2PO(OEt)2, ArCF2CO2Et, and ArCF2CONR1R2) 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.
Palladium does it: The palladium‐catalyzed difluoroalkylation of aryl boronic acids with bromodifluoromethylphosphonate, bromodifluoroacetate, and further derivatives has been developed (see scheme). Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway may be involved in the catalytic cycle.
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.
Simplicity is beauty: The title reaction features a broad substrate scope and excellent functional‐group compatibility. Mechanistic studies reveal that the free fluoroalkyl radicals initiated by Pd0Ln through a single‐electron transfer pathway is involved in the Heck‐type catalytic cycle.
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)−CF2R and C(sp3)−CF2R 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.
A new type of bench‐stable yet highly reactive fluoroalkylating reagents, 3,3‐difluoroallyl sulfonium salts (DFASs), has been developed. The reaction of DFASs with aromatic and aliphatic zinc reagents via copper catalysis provides general and practical access to a wide range of versatile gem‐difluoroallylated compounds with high regioselectivity.
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.
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 (ClCF2H) 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 ArCF2Pd(Ln)X, followed by reaction with hydroquinone, is responsible for the reductive difluorocarbene transfer.
A new mode of difluorocarbene transfer reaction that tames difluorocarbene to couple with two electrophiles via palladium catalysis has been developed. This reaction overcomes the intrinsic limitations of electrophilic difluorocarbene and allows difluoromethylation of various aryl bromides and aryl triflates. Experimental mechanistic studies revealed that a palladium(0/II) pathway is responsible for this reductive reaction.
The nickel‐catalyzed fluoromethylation of arylboronic acids was achieved with the industrial raw material fluoromethyl bromide (CH2FBr) 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.
Efficient and straightforward: The title reaction is characterized by synthetic simplicity, employing a low‐cost nickel catalyst and the industrial raw material CH2FBr as a coupling partner. It enables the late‐stage fluoromethylation of biologically relevant molecules. Preliminary mechanistic studies show that a single‐electron‐transfer pathway is involved in the catalytic cycle. DMAP=4‐dimethylaminopyridine, DME=1,2‐dimethoxyethane, phen=1,10‐phenanthroline.
Difluoroalkylated compounds have important applications in pharmaceutical, agrochemical, and materials science. However, efficient methods to construct the alkylCF
2
-alkyl bond are very limited, and ...the site-selective introduction of a difluoromethylene (CF
2
) 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.
An unprecedented example of alkylzirconocene promoted difluoroalkylation of alkyl- and silyl-alkenes with a variety of fluoroalkyl and nonfluoroalkyl halides under the irradiation of visible light has been reported.
Difluoromethylated aromatic compounds are of increasing importance in pharmaceuticals, agrochemicals and materials. Chlorodifluoromethane (ClCF
H), an inexpensive, abundant and widely used industrial ...raw material, represents the ideal and most straightforward difluoromethylating reagent, but introduction of the difluoromethyl group (CF
H) from ClCF
H into aromatics has not been reported. Here, we describe a direct palladium-catalysed difluoromethylation method for coupling ClCF
H 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.
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