Trifluoromethylation of aldehydes and ketones

A trifluoromethyl anion is also difficult to generate because it easily lose a fluoride ion to form difluoro carbene. Shono and Kashimura et al have similarly achieved the generation of such a species from trifiuoromethane using the electrogenerated a-pyrrolidone anion. The efficient trifluoromethylation of aldehydes and ketones in the presence of hexamethyldisilazane (HMDS) can thus be obtained (Scheme 4.3) [32]. 

Carbonyl Addition Diethylzinc has been added to benzaldehyde at room temperature in the presence of an ephedra-derived chiral quat (8) to give optically active secondary alcohols, a case in which the chiral catalyst affords a much higher enantioselectivity in the solid state than in solution (47 to 48, Scheme 10.6) [30]. Asymmetric trifluoromethylation of aldehydes and ketones (49 to 50, Scheme 10.6 [31]) is accomplished with trifluoromethyl-trimethylsilane, catalyzed by a quaternary ammonium fluoride (3d). Catalyst 3d was first used by the Shioiri group for catalytic asymmetric aldol reactions from silyl enol ethers 51 or 54 (Scheme 10.6) [32]. Various other 1,2-carbonyl additions [33] and aldol reactions [34] have been reported. 

Iseki, Nagai, and Kobayashi prepared cinchonine-derived 4f and 4g from the corresponding bromides by the method B (Scheme 9.5), and realized the asymmetric trifluoromethylation of aldehydes and ketones with trifluoromethyltrimethylsilane (Me3SiCF3) catalyzed by these ammonium fluorides (Schemes 9.9 and 9.10) [19]. Although the enantioselectivities are not sufficiently high, this reaction system should offer a new access to various chiral trifluoromethylated molecules of analytical and medicinal interests through appropriate modifications. 

A procedure for alkylation of C=0 double bonds in the presence of (metal-free) organocatalysts and non-metallic nucleophiles has been reported by the Iseki group for trifluoromethylation of aldehydes and ketones [185]. On the basis of a previous study of the Olah group [186, 187] which showed the suitability of non-chiral phase-transfer catalysts for trifluoromethylation of carbonyl compounds, Iseki et al. investigated the use of N-benzylcinchonium fluoride, 182, as a chiral catalyst. The reaction has been investigated with several aldehydes and aromatic ketones. Trifluoromethyltrimethylsilane, 181, was used as nucleophile. The reaction was, typically, performed at —78 °C with a catalytic amount (10-20 mol%) of 182, followed by subsequent hydrolysis of the siloxy compound and formation of the desired alcohols of type 183 (Scheme 6.82). 

Trifluoroacetaldehyde hydrate, F3C-CH(OH)2, has been used as a trifluoromethyl source for nucleophilic trifluoromethylation of aldehydes and ketones, including hindered cases such as adamantanone. Using DMF solvent at -50 C, potassium t-butoxide is used to form the dianion of the hydrate, delivering trifluoromethyl anion, with significant stabilization by the solvent. 

Iodine-catalysed hydroperoxidation of cyclic and acyclic ketones with aqueous hydrogen peroxide in acetonitrile is an efficient and eco-friendly method for the synthesis of gem -dihydroperoxides and the reaction is conducted in a neutral medium with a readily available low-cost oxidant and catalyst.218 Aryl benzyl selenoxides, particularly benzyl 3,5-bis(trifluoromethyl)phenyl selenoxide, are excellent catalysts for the epoxidation of alkenes and Baeyer-Villiger oxidation of aldehydes and ketones with hydrogen peroxide.219 Efficient, eco-friendly, and selective oxidation of secondary alcohols is achieved with hydrogen peroxide using aqueous hydrogen bromide as a catalyst. Other peroxides such as i-butyl hydroperoxide (TBHP), sodium... 

The impact of a carbonyl group on the chemical shift of a CF3 group somewhat emulates the effect of other electronegative substituents. As indicated by the examples of aldehyde and ketones in Scheme 5.28, when the carbonyl carbon is directly attached to the CF3 group, it causes shielding of the CF3 fluorines. Note that aryl trifluoromethyl ketones are considerably less shielded than are alkyl trifluoromethyl ketones. The fluorine signal of trifluoromethyl ketones of course always appears as a sharp singlet. The spectrum of l,l,l-trifluoromethyl-2-butanone, as... 

Finally, no consideration of the chemistry of a-haloaUqtlsilanes would be complete without mention of Ruppert s reagent (58). In the presence of a source of fluoride (usually tetrabutylammonium fluoride), the reagent will deliver a trifluoromethyl group to carbonyl groups of aldehydes and ketones, esters,and a variety of other functional groups (Scheme 18). The exceptional versatility of the reagent is revealed in an excellent review from Prakash and Yudin.l ... 

Verevkin, S. P. Vasiltsova, T. V. Bich, E. Heintz, A. Thermodynamic properties of mixtures containmg ionic Uquids. Activity coefficients of aldehydes and ketones in l-methyl-3-ethyl-imidazolium bis(trifluoromethyl-sulfonyl) imide using the tianspiration... 

Prakash and co-workers have prepared monofluoro-methyl 3,5-bis(trifluoromethyl)phenyl sulfone and have used it in the fluoroalkenylation of aldehydes and ketones.They employ KOH or CsF as base in DMSO at 20°C. On their side, Hu and co-workers have developed TBTSO2CH2F as a versatile fluoromethylidene synthon. Difluoromethyl 2-pyridyl sulfone has been used for the gem-difluoromethylenation of aldehydes and ketones and was found to be a more efficient difluoromethyfidene synthon than BTSO2CF2H, PTSO2CF2H and TBTS02CF2H. ... 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

The recent discovery of a convenient synthesis of sulfur tetrafluoride from sulfur dichloride and sodium fluoride in acetonitrile invited the application of this reagent in fluorination reactions. Hasek, Smith and Engelhardt showed that carboxylic acids and their derivatives can be converted into trifluoromethyl derivatives and that aldehydes and ketones are converted into 5 em-difluoro compounds. They also observed that the reaction was acid... 

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

Although the sulfur trifluoride compounds are generally useful as selective agents for conversion of carbonyl and carboxyl groups to difluoromethylene and trifluoromethyl groups, variations in reaction conditions are often necessary.7 Thus the reaction of aromatic ketones requires heating at 150°. Since the reaction with aliphatic aldehydes and ketones is exothermic, it is advan-... 

It has recently been shown that when the tetrahedral intermediate of the reaction is cyclic, it is a better donor of nucleophilic CF3. These cyclic intermediates can be generated intramolecularly from trifluoroacetamides or trifluorosulfmamides derived from (9-silylated ephedrine. These reagents are able to trifluoromethylate aldehydes and ketones, even in the case of enolizable substrates, as a strong base is not required (Figure 2.34). However, while the source of CF3 is chiral, there is no chirality transfer to the addition product, and the replacement of ephedrine by other chiral amino alcohols did not show any improvement. " Similar to asymmetric trifluoromethylation with the Ruppert reagent, only the use of a fluoride salt of cinchonine can increase the enantioselectivity. " " ... 

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... 

With regard to carboxylic derivatives, there is generally little difference in chemical shift among the various trifluoroacetic acid derivatives, as exemplified by the examples in Scheme 5.30. Also, the effect of moving the CF3 farther from the carboxylic acid function is similar to that seen with the aldehydes and ketones. Trifluoromethyl ketones will often be in equilibrium with their hydrated form, in which case signals from both the hydrate and water-free ketone will be observed, as is the case for the following pyruvate example. 

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