Utilizing the CF
            <sub>2</sub>
            H Moiety As a H-bond-donating Group in Drug Discovery

Zafrani, Yossi; Saphier, Sigal; Gershonov, Eytan

doi:10.4155/fmc-2019-0309

Cited by 73 publications

(42 citation statements)

References 20 publications

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“…Recent studies showed that the hydrogen bonding ability of the CF 2 H group was comparable to that of hydroxyl, thiol, and amine groups [19] . Therefore, the installation of CF 2 H groups has become a commonly used tactic in medicinal chemistry to modulate the lipophilicity and metabolic stability of lead drug candidates [20] …”

Section: Introductionmentioning

confidence: 99%

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

et al. 2021

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The engagement of unactivated alkyl halides in copper‐catalyzed cross‐coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen abstraction ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper‐catalyzed Negishi‐type cross‐coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon–iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi‐type difluoromethylation approach has been applied to the late‐stage modification of densely functionalized pharmaceutical agents and natural products.

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Section: Introductionmentioning

confidence: 99%

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

et al. 2021

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“…[19] Therefore,t he installation of CF 2 Hg roups has become ac ommonly used tactic in medicinal chemistry to modulate the lipophilicity and metabolic stability of lead drug candidates. [20] One of the most straightforward approaches to the synthesis of CF 2 H-containing compounds is the direct difluoromethylation of the corresponding organohalides.A l-though transition metal catalysis has received great success in the difluoromethylation of aryl halides, [21] the analogous reaction with unactivated alkyl halides remains aformidable challenge.P rakash has reported an ucleophilic substitution approach to the conversion of primary alkyl halides to their corresponding difluoromethyl phenyl sulfones,w hich were then transformed to the alkyl difluoromethanes using the sodium/mercury amalgam reduction. [22] Very recently,t he Shen group has reported an elegant Pd-catalyzed approach for the difluoromethylation of primary alkyl halides with TMSCF 2 Ha st he CF 2 Hs ource along with stoichiometric copper iodide.…”

Section: Introductionmentioning

confidence: 99%

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

et al. 2021

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The engagement of unactivated alkyl halides in copper-catalyzed cross-coupling reactions has been historically challenging,d ue to their lowr eduction potential and the slow oxidative addition of copper(I) catalysts.I nt his work, we report an ovel strategy that leverages the halogen abstraction ability of aryl radicals,t herebye ngaging ad iverse range of alkyli odides in copper-catalyzed Negishi-type cross-coupling reactions at room temperature.S pecifically,a ryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon-iodide bonds of alkyl iodides.The alkyl radicals thus generated enter the copper catalytic cycles to couple with ad ifluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products.T his unprecedented Negishi-type difluoromethylation approach has been applied to the latestage modification of densely functionalizedp harmaceutical agents and natural products.

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“…58,59 Therefore, the installation of CF2H groups has become a commonly used tactic in medicinal chemistry to modulate the lipophilicity and metabolic stability of lead drug candidates. 60 One of the most straightforward approaches to the synthesis of CF2H-containing compounds is the direct difluoromethylation of the corresponding organohalides. Although transition metal catalysis has received great success in the difluoromethylation of aryl halides, [61][62][63][64][65][66][67][68][69] the analogous reaction with unactivated alkyl halides remains a formidable challenge.…”

Section: Introductionmentioning

confidence: 99%

Copper-Catalyzed Difluoromethylation of Alkyl Halides Enabled by Aryl Radical Activation of Carbon–Halogen Bonds

Cai

Yan

Liu

2021

Preprint

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The engagement of unactivated alkyl halides in copper-catalyzed cross-coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen abstraction ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper-catalyzed Negishi–type cross-coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon–iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi–type difluoromethylation approach has been applied to the late-stage modification of densely functionalized pharmaceutical agents and natural products.

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Utilizing the CF ₂ H Moiety As a H-bond-donating Group in Drug Discovery

Cited by 73 publications

References 20 publications

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

Copper-Catalyzed Difluoromethylation of Alkyl Halides Enabled by Aryl Radical Activation of Carbon–Halogen Bonds

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Utilizing the CF 2 H Moiety As a H-bond-donating Group in Drug Discovery

Cited by 73 publications

References 20 publications

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

Copper-Catalyzed Difluoromethylation of Alkyl Halides Enabled by Aryl Radical Activation of Carbon–Halogen Bonds

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Utilizing the CF ₂ H Moiety As a H-bond-donating Group in Drug Discovery