Trifluoromethylation nucleophilic

Due to the poor efficiency of trifluoromethylated organometaUic derivatives as trifluoromethylating reagents, nucleophilic trifluoromethylation has remained unattractive for a long time. Indeed, in the absence of stabilization, the trifluoromethyl anion is very unstable and is quickly transformed into difluorocarbene (cf. Chapter 1). When the carbon-metal bond is relatively covalent, the organometaUic species becomes more stable but it is then less reactive toward an electrophile. On the synthetic level, only zinc and copper derivatives have found real applications in 

Some other fluoroalkyl derivatives of silicon (e.g., ArCF2TMS, CICF2TMS, RfTMS, CeFsTMS) have been prepared and used as fluoroalkylating reagents. Unfortunately, their reactivity is much lower than that of CF3TMS, and they have not found important synthetic applications.  

heteroaryl, styryl R =Aryl, heteroaryl, styryl 

Trifluoromethyl phenylsulfone is accessible from fluoroform and diphenyldisul-fide, and it has been proposed as a donor of CF3. However, the reaction must be performed in basic medium (f-BuOK) and is then limited to nonenolizable aldehydes and ketones. But it can also be used as a precursor of the Ruppert reagent. This latter 

It should also be noted that a new reagent for trifluoroethylidenation, trifluor-oethyldiphenylphosphine, can be used in Homer reactions under TBAF activation 

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J. Joubert, S. Roussel, C. Christophe, T. Billard, B.R. Langlois, T. Vidal, Trifluoroa-cetamides from amino alcohols as nucleophilic trifluoromethylating reagents, Angew. Chem. Int. Ed. 42 (2003) 3133-3136. 

Figure 2.31 Nucleophilic trifluoromethylation with Ruppert reagent.

Figure 2.33 Nucleophilic trifluoromethylation with (0,A/)-acetals of fluoral. ...

The trifluoromethyl group has been introduced on every position, except position 5 in the fiiranose series and position 6 in the pyranose series. These reactions can be performed through several pathways by nucleophilic trifluoromethylation with the... 

Tetrakis(dimethylamino)ethylene (TDAE) combines with CF3I to give a nucleophilic trifluoromethylation reagent which is effective with (V-tosylaldimines and (if A-tolylsulfinimines, the latter case being diastereoselective.84... 

The method has been further improved." Trimethyl(perfluoroalkyl)silanes RpTMS (Rp = c, -C, perfluoroaliphatic groups) are prepared by reaction of perfluoroalkyl halides RpX (X = Br, I) with chlorotrimethylsilane in the presence of tris(dialkylamino)phosphanes in acetonitrile. For example, chlorotrimethylsilane was treated with bromotrifluoromethane and tris(diethylamino)phosphane in acetonitrile at — 40"C for 1 hour to give trimethyl(trifluo-romethyl)silane in 90% yield. Bis(dimethylamino)(trifluoromethyl)silane is available from the reaction of chlorobis(dimethylamino)silane with the system bromotrifluoromethane/tris-(diethylamino)phosphane, while trichloro(trifluoromethyl)silane is prepared by nucleophilic trifluoromethylation of tetrachlorosilane with bromotrifluorornethane/tris(diethylamino)phos-phane. " ... 

Nucleophilic trifluoromethylation and introduction of fluorinated moieties in the syntheses of bioactive fluorinated heterocycles 03S185. 

The less stable trifluoromethyl zinc compounds [48] can be used as a source of nucleophilic trifluoromethyl fragments either in the isolated form or generated in situ by sonication of perfluoroalkyl iodides with zinc in DMF or THF. Zinc perfluoroorganyls find application in Barbier-type reactions [49], palladium-catalyzed cross-coupling reactions [50], or hydroperfluoroalkylations of acetylenes or olefins [51] (Scheme 2.119). 

Scheme 2.125 Synthesis of trifluoroacetaldehyde hemiaminal derivatives and their use as nucleophilic trifluoromethylation reagents (TMS = trimethylsilyl) [59].

Scheme 2.127 Mechanism of the nucleophilic trifluoromethylation of carbonyl compounds by Me3SiCF3 [59, 65],...

Scheme 2.130 Nucleophilic trifluoromethylation of artemisinin to the -trimethylsilyl ether as the kinetic primary product and the a-trifluoromethyl hemiketal as the thermodynamic final product after desilylation [76].

Use of chiral fluoride sources at low reaction temperatures opens - at least in principle - a route to enantioselective nucleophilic trifluoromethylation of pro-chiral carbonyl compounds [77, 78] (Scheme 2.131). Enantiomeric excesses obtained so far by this method are, however, low to moderate only. 

Scheme 2.131 Enantioselective nucleophilic trifluoromethylation of prochiral carbonyl compounds with chiral fluoride sources [78].

Scheme 2.134 Nucleophilic trifluoromethylation of N-tosyl aldimines and chiral sulfinimines [85, 86]. The mechanistic rationalization of the observed stereoselectivity of the addition to chiral sulfinimines is sketched in a box.

By use of a similar synthetic procedure McjSiCFj can also be employed as a reagent for nucleophilic trifluoromethylation of a variety of sulfur electrophiles (Scheme 2.135). The other way around, Prakash and coworkers demonstrated, that trifuoromethyl sulfones can also be used as a source of nucleophilic CFj equivalents when they are treated with alcoholates [69]... 

An alternative route to aromatic trifluoromethylsulfonyl and sulfinyl compounds is based on the nucleophilic trifluoromethylation of sulfonyl or sulfinyl halides with Me3SiCF3 [38[ (Scheme 2.178). 

Scheme 2.178 Conversion of sulfonyl and sulfinyl halides to the corresponding trifluoromethyl sulfones and sulfoxides by nucleophilic trifluoromethylation [38].

Nucleophilic Trifluoromethylation with MejSiCFj A.9.1 Nucleophilic Trifluoromethylation of Ketone 33... 

Nucleophilic trifluoromethylation reactions of organic compounds (in particular, heterocycles) with (trifluoromethyl)trimethylsilane 00T7613. 

The behavior of methyl and halomethyl radicals in their reactions with the fluoro-olefins (Table 1.2), can thus be rationalized hi terms of a more dominant role of polar factors and the nucleophilic or electrophilic character of the radicals involved. Methyl radicals are usually considered to be slightly nucleophilic, trifluoromethyl and trichloromcthyl radicals arc electrophilic (Tabic 1.4). 

Trifluoromethylation. Nascent trifluoromethyl anions are generated when CFjSiMej is in contact with a fluoride ion. Nucleophilic trifluoromethylation of oxazolidinones is for the synthesis of protected a-amino trifluoromethyl ketones. ... 

Shreeve et al. have synthesized a range of new ionic liquids based on oxazoli-dine, morpholine and 1,2,4-triazole. These have been found to be good solvents for the Cu(I)-mediated nucleophilic trifluoromethylation of benzyl bromide [155]. Nucleophilic substitution has also been carried out on alkenes in the form of 2-tosyltropone, where the tosyl group was substituted for a chloride in [BMIM][BF4] [156]. Aminopyridines [157] and aminopyrimidines [158] react with a-halo ketones to form imidazopyridines and imidazopyrimidines. These reactions have been investigated in [Bp4] and [PFs]" ionic liquids and found to give fester reaction rates than in organic solvents [159]. 

TBAF-assisted Trifluoromethylation, Perfluoroalkylation, and Polyfluoroalkoxylation. TBAF combines with TMSCF3 to form nucleophilic trifluoromethyl anion equivalents. The precise structure of this nucleophile is unknown, although it is likely that a pentacoordinate silicon intermediate is involved. The TBAF/TMSCF3 combination leads to smooth trifluoromethylation of aldehydes,ketones, esters, imines, nitroso compounds, a-ketoesters, Q -ketoamides (eq and... 

A short review examines nucleophilic trifluoromethylation of C=N bonds imines, hydrazones, and nitrones, together with iminium cations and azomethine imines, mainly focusing on the Ruppert-Prakash reagent, TMS-CF3. ... 

Another application of trifluoromethyl phenyl sulfone is in the preparation of benzenesulfonic acid (or metal benzenesulfonate) using oxygen nucleophiles. Trifluoromethyl phenyl sulfone is readily transformed into benzenesufonate salt upon treatment with an alkoxide or hydroxide (eq 6). This is particularly useful for the convenient transformation of a polymer-supported trifluoromethyl phenyl sulfone into polymer-supported sulfonic acid (or sufonate) ion-conducting materials. " ... 

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