Efficient Difluoromethylation of Alcohols Using TMSCF<sub>2</sub>Br as a Unique and Practical Difluorocarbene Reagent under Mild Conditions

Xie, Qiqiang; Ni, Chuanfa; Zhang, Rongyi; Li, Lingchun; Rong, Jian; Hu, Jinbo

doi:10.1002/anie.201611823

Cited by 130 publications

(54 citation statements)

References 44 publications

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“…TMSCF 2 Br, a difluorocarbene precursor developed by us,‐ is now commercially available and is one of the most versatile difluorocarbene reagents . It has been applied in the difluoromethylation of (thio)phenols, alcohols, thiols, and amines, as well as the cyclopropanation or cyclopropenation of alkenes and alkynes, among other applications –. In continuation of our effort to develop TMSCF 2 Br as a versatile and robust difluorocarbene reagent, we report herein our recent success in the difluoromethylation of carbon acids with TMSCF 2 Br (Scheme c).…”

Section: Methodsmentioning

confidence: 99%

A General Protocol for C−H Difluoromethylation of Carbon Acids with TMSCF₂Br

Xie

Zhu

et al. 2019

Angew Chem Int Ed

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An efficient method for the selective C‐difluoromethylation of carbon acids with the reagent TMSCF2Br has been developed. A variety of structurally diverse sp3‐ and sp‐hybridized carbon nucleophiles, including esters, amides, fluorenes, terminal alkynes, β‐ketoesters, malonates, and other activated C−H nucleophiles, could be efficiently and selectively transformed into the corresponding C‐difluoromethylated products under mild conditions. This protocol is also effective for the late‐stage difluoromethylation of pharmaceutically relevant molecules and can be readily scaled up. Moreover, ambident substrates with more than one reactive site towards difluorocarbene can be difluoromethylated orthogonally using TMSCF2Br.

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Section: Methodsmentioning

confidence: 99%

A General Protocol for C−H Difluoromethylation of Carbon Acids with TMSCF₂Br

Xie

Zhu

et al. 2019

Angew Chem Int Ed

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“…Hu and collaborators have reported in 2017 a convenient difluoromethylation reaction of alcohols employing TMSCF 2 Br, KHF 2 as additive (or NaOH, or KAOc), in CH 2 Cl 2 /H 2 O as solvent, at room temperature. The reaction mainly proceeds through direct interaction between a neutral alcohol and difluorocarbene, which is different from the difluoromethylation of phenols.…”

Section: Late‐stage Introduction Of Cf2h and Cf2y Groups Into Organicmentioning

confidence: 99%

“…The authors have also accomplished the difluoromethylation reaction of bioactive compounds, such as idebenone and estradiol benzoate, affording products 224 , and 239 , in 97 and 93 % yields, respectively (Scheme ). The yields of difluoromethylated ethers obtained from alcohols are comparable or even better than those reported by Shen and colleagues, from Scheme and Scheme .…”

Section: Late‐stage Introduction Of Cf2h and Cf2y Groups Into Organicmentioning

confidence: 99%

“…The yields of difluoromethylated ethers obtained from alcohols are comparable or even better than those reported by Shen and colleagues, from Scheme and Scheme . For instance, in the case of idebenone, Hu and co‐workers have obtained an almost quantitative yield of product 224 (cf. Schemes and Scheme ).…”

Section: Late‐stage Introduction Of Cf2h and Cf2y Groups Into Organicmentioning

confidence: 99%

“…Schemes and Scheme ). Another difference found in the methodology of Hu and co‐workers is that the protocol can be applied to tertiary alcohols and substrates with olefinic moieties (i.e., product 233 ).…”

Section: Late‐stage Introduction Of Cf2h and Cf2y Groups Into Organicmentioning

confidence: 99%

See 2 more Smart Citations

Difluoromethylation Reactions of Organic Compounds

Yerien

Barata‐Vallejo

Postigo

2017

Chemistry A European J

404

153

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

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