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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Difluoromethylation Reactions of Organic Compounds

Chemistry - A European Journal, Journal Year: 2017, Volume and Issue: 23(59), P. 14676 - 14701

Published: June 20, 2017

Abstract The relevance of the ‐CF 2 H moiety has attracted considerable attention from organic synthetic and medicinal chemistry communities, because this group can act as a more lipophilic isostere carbinol, thiol, hydroxamic acid, or amide groups. Being weakly acidic, CF establish hydrogen‐bonding interactions to improve binding selectivity biologically active compounds. Therefore, hydroxyl, amino, thio substituents lead structures are routinely replaced by motif in drug discovery, with great benefits pharmacological activity drugs candidates agrochemicals. Consequently, late‐stage introduction is sought‐after strategy designing bioactive Secondly, but nonetheless relevant meaningful, study pathways introduce −Y (Y≠H, F) into substrates compounds that contain functionality have also found vast applications other areas, such fungicides, insecticides, etc., thus, deserves special attention. Although emphasis made on difluoromethylation strategies functionalize different families compounds, three main methodological protocols will be presented review article for Y moieties substrates: i) metal‐photoredox catalysis; ii) through transition metal‐catalyzed thermal protocols; iii) transition‐metal‐free strategies.

Language: Английский

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Catalytic Defluoroalkylation of Trifluoromethylaromatics with Unactivated Alkenes

Journal of the American Chemical Society, Journal Year: 2017, Volume and Issue: 140(1), P. 163 - 166

Published: Dec. 19, 2017

We describe a new catalytic approach to selective functionalization of the strong C-F bonds in trifluoromethylaromatic (Ar-CF3) systems. In this approach, single electron reduction Ar-CF3 substrates (using photoredox catalyst) results difluorobenzylic radical formation through cleavage mechanism. These radicals undergo efficient intermolecular coupling with simple alkenes defluoroalkylation process where termination is accomplished by polarity reversal catalyst. This mild protocol engages wide range give medicinally relevant fluorinated substructures complete regiocontrol.

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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Selective C–F Functionalization of Unactivated Trifluoromethylarenes

Journal of the American Chemical Society, Journal Year: 2019, Volume and Issue: 141(33), P. 13203 - 13211

Published: Aug. 1, 2019

Fluorinated organic molecules are pervasive within the pharmaceutical and agrochemical industries due to range of structural physicochemical properties that fluorine imparts. Currently, most abundant methods for synthesis aryl–CF2 functionality have relied on deoxyfluorination ketones aldehydes using expensive poorly atom economical reagents. Here, we report a general method aryl–CF2R aryl–CF2H compounds through activation corresponding trifluoromethyl arene precursors. This strategy is enabled by an endergonic electron transfer event provides access radical anions lie outside catalyst reduction potential. Fragmentation these reactive intermediates delivers difluorobenzylic radicals can be intercepted alkene feedstocks or hydrogen provide diverse array difluoalkylaromatics.

Language: Английский

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Nickel-catalyzed difunctionalization of allyl moieties using organoboronic acids and halides with divergent regioselectivities

Chemical Science, Journal Year: 2017, Volume and Issue: 9(3), P. 600 - 607

Published: Oct. 26, 2017

We present herein a nickel-catalyzed dicarbofunctionalization of alkenes using readily available organoboronic acids and organic halides in three-component fashion.

Language: Английский

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Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds

Science, Journal Year: 2018, Volume and Issue: 360(6384), P. 75 - 80

Published: Feb. 19, 2018

A sulfur matchmaker for fluorous coupling Fluorination is a burgeoning technique fine-tuning the properties of pharmaceutical compounds. Unfortunately, cross-coupling reactions widely used to make carbon-carbon bonds in drug research can be tripped up by fluorine substituents. Merchant et al. report class easily prepared, solid sulfone compounds that engage nickel-catalyzed their fluoroalkyl groups with aryl zinc reagents. These sulfones considerably simplify synthetic routes fluorinated analogs would previously have required multistep strategies focused strictly on fluorination protocol. Science , this issue p. 75

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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Visible-Light-Induced Palladium-Catalyzed Selective Defluoroarylation of Trifluoromethylarenes with Arylboronic Acids

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(34), P. 13971 - 13979

Published: Aug. 19, 2021

Selective functionalization of inactive C(sp3)-F bonds to prepare medicinally interesting aryldifluoromethylated compounds remains challenging. One promising route is the transition-metal-catalyzed cross-coupling through oxidative addition bond in trifluoromethylarenes (ArCF3), which are ideal precursors for this process due their ready availability and low cost. Here, we report an unprecedented excited-state palladium catalysis strategy selective defluoroarylation with arylboronic acids. This visible-light-induced palladium-catalyzed proceeds under mild reaction conditions allows transformation a variety acids ArCF3. Preliminary mechanistic studies reveal that ArCF3 palladium(0) via single electron transfer pathway responsible activation.

Language: Английский

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Enantioselective 1,2-Difunctionalization of 1,3-Butadiene by Sequential Alkylation and Carbonyl Allylation

Journal of the American Chemical Society, Journal Year: 2018, Volume and Issue: 140(8), P. 2735 - 2738

Published: Feb. 9, 2018

A highly enantioselective three-component coupling of 1,3-butadiene with a variety fluorinated or nonfluorinated alkyl halides and aldehydes has been achieved relying on Cr/Co bimetallic catalysis system. The strategy established here facilitates straightforward introduction the privileged fluoro functionalities into homoallylic alcohols from bulk feedstock materials in anti-diastereo manner.

Language: Английский

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