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The crystal structure of a low melting difluorinated silicon reagent (bromodifluoromethyl)trimethylsilane is described. Hexamethylphosphoramide (HMPA) serves as an efficient Lewis basic activator to decompose the silicon reagent to generate difluorocarbene along with the formation of silyl-capped HMPA cation. The bromide salt with Me3Si-HMPAcation was also obtained by interaction of bromotrimethylsilane with HMPA and was characterized by X-ray analysis. Interaction of silanes with HMPA was evaluated by quantum chemical calculations, which demonstrated that the Lewis base provides a significant decrease of the transition state energy for the generation of difluorocarbene by an attack at the silicon atom.

Cesium carbonate (Cs 2 CO 3 )-mediated decarboxylative fluorination of β -ketoacids using NFSI in the MeCN/H 2 O mixed solvent system affords α-fluoroketones with a broad scope. Both electron-rich and electron-deficient α-non-substituted β -ketoacids are amenable to this protocol. The mechanistic study indicates that the reaction proceeds through electrophilic fluorination followed by decarboxylation, which is different from the decarboxylative fluorination of normal carboxylic acids.

A new strategy for nucleophilic addition to aldehydes with difluoromethyl organometallic reagents has been developed by functionalizing the difluoromethyl moiety with the phenylsulfonyl group (SO 2 Ph). This electron-withdrawing group influences both the thermodynamic stability and the nucleophilicity of difluoromethyl organometallic reagents, which plays an important role in the nucleophilic difluoromethylation of aldehydes.

A diastereoselective nucleophilic monofluoromethylation of tert-butanesulfinyl aldimines with α-fluoro-α-phenylthio-α-phenylsulfonylmethane (FTSM) as the reagent has been developed, which affords α-monofluoromethyl amines in good to excellent yields with excellent stereocontrol on both the monofluoromethylated carbon and the neighboring sulfonyl-bearing fluorinated carbon. The racemic α-fluoro-α-phenylthio-α-phenylsulfonylmethide anions undergo a dynamic thermodynamic resolution due to the reversibility of their addition to the optically pure tert-butanesulfinyl aldimines under the optimized conditions.

Although the chemical oxidation of fluoride ions is generally challenging due to the high electronegativity of fluorine, in the past four years, a number of oxidative fluorination reactions via the reactivity umpolung of substrates or fluorides have been developed. These reactions can introduce fluorine into nucleophilic or electron-neutral systems. This short review provides a summary on the recent developments of oxidative fluorination of arenes, alkanes, and alkenes with fluorides promoted by various oxidants. These newly developed reactions are of high selectivity and efficiency, and provide a pathway for the more efficient use of the abundant, yet less nucleophilic fluorides.

We have made a systematic investigation on the copper(0)-mediated tetrafluoroethylenation of iodobenzene with structurally diverse 2-bromo-1,1,2,2-tetrafluoroethyl compounds. A comparison of this reaction with 1,2,2-trifluoro-1-phenylethylation and the known functionalized difluoroalkylation demonstrates that the substituent R of α,α-difluoroalkyl copper species RCF2Cu plays a crucial role on their reactivity, which is believed to be useful for the development of new fluoroalkylation reactions under the promotion of transition metals.

An efficient radical (2-pyridylsulfonyl)difluoromethylation of terminal alkenes with 2-PySO2CF2I has been successfully achieved by using catalytic amount of Et3B/air as initiating system. This methodology was also further extended to the synthesis of 2-PySO2CF2-substituted alkanes and alkenes.

The reactions between carbonyl compounds and PhSO2CF2H using substoichiometric amount of base in situ generated from N(TMS)(3) and catalytic amount of Me4NF have been investigated. It is found that both enolizable and non-enolizable aldehydes are suitable

A protocol for the synthesis of difluoromethylated tertiary amines by nucleophilic difluoromethylation of N,N-acetals using TMSCF2SO2Ph reagent is developed. The reaction proceeds smoothly in 1,4-dioxane using K2CO3 as the initiator. A key feature of the reaction is that the in situ generated iminiums (from N,N-acetals and CF3COOH) could be fluoroalkylated in an efficient way.

A series of sulfur-, selenium- and tellurium-containing (phenylchalcogen)difluoromethylation reagents PhSCF 2 H ( 1a ), PhSeCF 2 H ( 1b ), and PhTeCF 2 H (1c ) were prepared, and their relative reactivity towards aldehydes, ketones, and imines was investigated. Compared to the former developed (phenylchalcogen)difluoromethylation reagents, these reagents are relatively easily available and more atom-economical in fluoroalkylation reactions. It was found that the efficient nucleophilic (phenylchalcogen)difluoromethylation of aldehydes, ketones, and imines could be achieved with 1a – 1c . Reagents 1a and 1b showed better reactivity than 1c toward carbonyl compounds and imines, and PhOCF 2 H ( 1d ) was found to be unable to undergo similar fluoroalkylation reactions.

We have investigated the different chlorodifluoromethyl aryl ketones 1a – 1g and sulfones 2a – 2h as difluorocarbene reagents for O - and N -difluoromethylations. It was found that the sulfone reagents 2 were generally more efficient in difluoromethylation than the ketone reagents 1 . Furthermore, while the different substituents on ketone reagents 1 did not show a remarkable impact on the difluoromethylation reaction, the substituent effect on the sulfone reagents 2 was much more significant. Finally, we found that p -chlorophenyl chlorodifluoromethyl sulfone 2d and p -nitrophenyl chlorodifluoromethyl sulfone 2h were among the most powerful difluorocarbene reagents in this category for O -difluoromethylations.

Selective incorporation of a fluoroalkyl moiety to modulate the properties of an organic molecule has become a frequently used strategy in life science- and materials science-related applications. In this context, selective introduction of a (phenylsulfonyl)difluoromethyl group (PhSO 2 CF 2 ) into organic molecules has attracted much attention, since the PhSO 2 CF 2 group can be regarded as a “chemical chameleon” that can be readily transformed into difluoromethyl (CF 2 H), difluoromethylene (–CF 2 –), and difluoromethylidene ( CF 2 ) functionalities. This article overviews the recent development of (phenylsulfonyl)difluoromethylation reactions from 2003, including the nucleophilic (phenylsulfonyl)difluoromethylations with PhSO 2 CF 2 H, PhSO 2 CF 2 SiMe 3 and PhSO 2 CF 2 Br reagents, free radical (phenylsulfonyl)difluoromethylations with PhSO 2 CF 2 I reagent, and electrophilic (phenylsulfonyl)difluoromethylations with a hypervalent iodine(III)-CF 2 SO 2 Ph reagent.

A facile and highly efficient nucleophilic (phenylthio)difluoromethylation of alkyl halides has been achieved via fluoride ion-mediated substitution reaction using [difluoro(phenylthio)methyl]trimethylsilane (Me 3 SiCF 2 SPh). The reaction proceeds well with primary alkyl bromides (or alkyl iodides) in DME solvent when CsF/15-crown-5 was used as the fluoride source/additive. The PhSCF 2 -containing products can be readily transformed into CF 2 H-containing compounds via a free-radical desulfurization method.

We have successfully achieved nucleophilic (phenylsulfinyl)difluoromethylation of both enolizable and non-enolizable aldehydes and ketones by using difluoromethyl phenyl sulfone (1) as the fluoroalkylating agent. Although the chemical yields of the reactions are good to excellent, the observed diastereoselectivity is poor (dr = 1:1.04-2.03). The present synthetic methodology provides a convenient alternative for the preparation of alpha-(phenylsulfinyl)difluoromethylated carbinols that were previously synthesized via a two-step procedure. (C) 2007 Elsevier B.V. All rights reserved.

1,1-Difluoroethysilanes (R3SiCF2CH3, R = Me or Et) were synthesized from 1,1-difluoroethyl phenyl sulfone and chlorosilanes using magnesium metal via reductive 1,1-difluoroethylation. It was confirmed that 1,1-difluoroethylsilanes were effective 1,1-difluoroethylating reagents for carbonyl compounds.

A new solid acid/superacid catalyzed microwave assisted synthesis of trifluoromethyl-imines is described. Various α,α,α-trifluoromethylketones react readily with primary amines to produce the corresponding imines. Two different strategies have been employed; one is the application of microwave irradiation coupled with solvent-free solid acid catalysis. The other method, for highly deactivated substrates includes the use of a pressure vessel at 175 °C temperature, with solid superacid catalysis. Using the solid acid K-10 montmorillonite or the superacidic perfluorinated resinsulfonic acid Nafion-H, a wide variety of trifluoromethylated imines have been synthesized using the above methods. The products have been isolated in good to excellent yields and high selectivities. This new environmentally friendly synthetic methodology provides significantly higher yields than traditional methods during relatively short reaction times for the preparation of the target compounds.

Tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective electron-transfer agent that promoted the reactions of bromodifluoromethyl phenyl sulfone with aldehydes to give structurally diverse (benzenesulfonyl)difluoromethylated alcohols in good yield, which can be further transformed into difluoromethyl alcohols and 1,1-difluoro-1-alkenes via reductive desulfonylation and Julia olefination, respectively.

Chlorodifluoromethanesulfonic acid (1) was prepared using a new procedure starting from perchloromercaptan, which is readily obtained from chlorination of CS2. Modified Swarts reaction transformed N,N-diethyl trichloromethanesulfenamide into N,N-diethyl chlorodifluoromethanesulfenamide, and the latter species was further oxidized and hydrolyzed into chlorodifluoromethanesulfonic acid. The preparations of other two new α,α-difluoroalkanesulfonic acids, phenyl difluoromethanesulfonic acid (2) and 2-phenyl-1,1,2,2,-tetrafluoroethanesulfonic acid (3), are also disclosed. The acids 2 and 3 are stable in the forms of sodium (lithium) salts or in aqueous solutions; however, the pure forms of 2 and 3 can readily undergo defluorinations. 1–3 and their salts have potential applications as superacid catalysts and lithium battery electrolytes.

Di- and monofluoromethyl ketones were prepared from the readily available trifluoromethyl ketones in high yields. Magnesium metal mediated reductive defluorination readily generates fluorinated enol silyl ethers, which upon fluoride or acid assisted hydrolysis give the respective ketones in good to excellent yields.