Transition-Metal (Cu, Pd, Ni)-Catalyzed Difluoroalkylation via Cross-Coupling with Difluoroalkyl Halides

Accounts of Chemical Research, Journal Year: 2018, Volume and Issue: 51(9), P. 2264 - 2278

Published: Aug. 22, 2018

Difluoroalkylated compounds play a remarkably important role in life and materials sciences because of the unique characteristics difluoromethylene (CF2) group. In particular, precise introduction CF2 group at benzylic position can dramatically improve biological properties corresponding molecules. As consequence, difluoroalkylation aromatic has become powerful strategy modulating bioactivities organic However, efficient strategies to selectively synthesize difluoroalkylated arenes had been very limited before 2012. Traditional synthetic methods this regard suffer from either harsh reaction conditions or narrow substrate scope, significantly restricting their widespread applications, particularly for late-stage bioactive To overcome these limitations, straightforward route access valuable skeletons is direct (CF2R) onto rings through transition-metal-catalyzed cross-coupling. instability some metal species, which are prone protonation, dimerization, and/or generation other unknown byproducts, it difficult control catalytic cycle suppress side reactions. context, we proposed use low-cost widely available difluoroalkyl halides as fluoroalkyl sources reactions via Account, summarize our major efforts on copper-, palladium-, nickel-catalyzed difluoroalkylations aromatics with sources. Four modes reactions, including nucleophilic difluoroalkylation, electrophilic radical metal-difluorocarbene coupling (MeDiC), have demonstrated careful modulation systems. Among MeDiC represents new mode fluoroalkylation. These processes enable variety aryl arylboron reagents under mild conditions. A wide range halides, activated (Cl/BrCF2R, R = π system), unactivated (BrCF2R, alkyl, H), especially inert inexpensive industrial chemical chlorodifluoromethane (ClCF2H), applicable providing facile routes diverse (hetero)arenes. halide-based also be applied prepare alkenes, alkynes, alkanes feature impressive advantages over conventional synthesis terms efficiency, functional tolerance, structural diversity. molecules offers good opportunities development medicinal agents without need multistep de novo syntheses.

Language: Английский

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Recent Progress toward the Introduction of Functionalized Difluoromethylated Building Blocks onto C(sp²) and C(sp) Centers

Chemistry - A European Journal, Journal Year: 2015, Volume and Issue: 21(37), P. 12836 - 12865

Published: July 14, 2015

Fluorine chemistry is a field undergoing tremendous expansion. Although much attention has been paid to the introduction of fluorine atom and CF3 group, less interest devoted functionalized fluorinated building blocks, in sharp contrast with high versatility products. In this Minireview, most relevant methods for difluoromethylated blocks are summarized. Access arenes, alkenes, alkynes highlighted special explanation reaction mechanism.

Language: Английский

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A General Synthesis of Fluoroalkylated Alkenes by Palladium‐Catalyzed Heck‐Type Reaction of Fluoroalkyl Bromides

Angewandte Chemie International Edition, Journal Year: 2014, Volume and Issue: 54(4), P. 1270 - 1274

Published: Dec. 2, 2014

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

Language: Английский

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Gold‐Catalyzed Highly Selective Photoredox C(sp²)−H Difluoroalkylation and Perfluoroalkylation of Hydrazones

Angewandte Chemie International Edition, Journal Year: 2016, Volume and Issue: 55(8), P. 2934 - 2938

Published: Jan. 21, 2016

The first gold-catalyzed photoredox C(sp(2) )-H difluoroalkylation and perfluoroalkylation of hydrazones with readily available RF -Br reagents is reported. resulting gem-difluoromethylated perfluoroalkylated are highly functionalized, versatile molecules. A mild reduction the coupling products can efficiently produce β-amino phosphonic acids acid derivatives. In mechanistic studies, a difluoroalkyl radical intermediate was detected by an EPR spin-trapping experiment, indicating that pathway operating.

Language: Английский

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Tandem Difluoroalkylation‐Arylation of Enamides Catalyzed by Nickel

Angewandte Chemie International Edition, Journal Year: 2016, Volume and Issue: 55(40), P. 12270 - 12274

Published: Sept. 8, 2016

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

Language: Английский

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Where Does the Fluorine Come From? A Review on the Challenges Associated with the Synthesis of Organofluorine Compounds

Organic Process Research & Development, Journal Year: 2020, Volume and Issue: 24(4), P. 470 - 480

Published: March 5, 2020

Fluorinated organic molecules are increasingly being prepared for a variety of applications, including pharmaceutical products. However, the supply chain to access necessary raw materials, which originate primarily from calcium fluoride, is often not considered, may be difficult at commercial scale, and has become destabilized as more stringent environmental policies justifiably enforced. This manuscript presents an overview preparation use simple organofluorinated intermediates reagents challenges associated with them.

Language: Английский

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Recent progress on selective deconstructive modes of halodifluoromethyl and trifluoromethyl-containing reagents

Chemical Society Reviews, Journal Year: 2020, Volume and Issue: 49(24), P. 9197 - 9219

Published: Jan. 1, 2020

Halodifluoromethyl and trifluoromethyl-containing compounds can act various rolesviaselective cleavage modes to access more valuable fluorinated or nonfluorinated molecules.

Language: Английский

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Nickel‐CatalyzedDicarbofunctionalization of Alkenes^†

Chinese Journal of Chemistry, Journal Year: 2020, Volume and Issue: 38(11), P. 1371 - 1394

Published: June 16, 2020

As a straightforward strategy for rapidly increasing molecular complexity, dicarbofunctionalization of alkenes has attracted substantial interests organic synthesis, medicine chemistry, and materials science. Nickel‐catalyzed cascade dicarbofunctionalizations have been flourished in this area recently, nickel‐mediated radical pathways particularly offer new opportunities conjunctive cross‐couplings with alkyl coupling partners. Herein, we give comprehensive review nickel‐catalyzed through historical perspective, including intermolecular three‐component reactions intramolecular reactions. Among the discussed review, carbometallation/cross‐coupling process addition/cross‐coupling are two major alkenes. The oxidative cyclization 1,2‐metallate shift processes also selectively discussed. These methods overcome limitations associated using noble metals field, providing an efficient access to structurally diversified molecules.

Language: Английский

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

Organic Letters, Journal Year: 2015, Volume and Issue: 18(1), P. 44 - 47

Published: Dec. 14, 2015

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

Language: Английский

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Difluoromethylation of (hetero)aryl chlorides with chlorodifluoromethane catalyzed by nickel

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: March 15, 2018

Relatively low reactivity hinders using chlorodifluoromethane (ClCF2H) for general difluoromethylation with organic molecules, despite its availability as an inexpensive industrial chemical. To date, transformations of ClCF2H are very limited and most them involve difluorocarbene intermediate. Here, we describe a strategy aromatics through nickel-catalyzed cross-coupling readily accessible (hetero)aryl chlorides. The reaction proceeds under mild conditions high efficiency features synthetic simplicity without preformation arylmetals broad substrate scope, including variety heteroaromatics commercially available pharmaceuticals. reliable practicability scalability the current process has also been demonstrated by several 10-g scale reactions loss efficiency. Preliminary mechanistic studies reveal that starts from oxidative addition aryl chlorides to Ni(0) difluoromethyl radical is involved in reaction, providing route applications synthesis related chemistry.

Language: Английский

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