Trifluoromethyl carbonyl compounds

Trifluoromethyl-Substituted Heterodienophiles Trifluoromethyl Carbonyl Compounds... 

Trifluoromethylation. Carbonyl compounds are converted into the trifluoro-methyl carbinols in excellent yields by this reagent in the presence of a quaternary ammonium fluoride. Moderate asymmetric induction is observed when a chiral catalyst is used. 

Iron-catalysed trifluoromethylation with concomitant 1,2-migration of an aryl group starting from diaryl allyl alcohol has been reported to give a-substituted-j0-trifluoromethyl carbonyl compounds (Scheme 86). ... 

Lithium silylamides react smoothly with tiifluoronitrosomethane to give diazenes Traces ot water initiate the decomposition of the latter with liberation of a trifluoromethyl carbanion, which is trapped by carbonyl compounds [775] (equation 116) Desilylation of trialkyl(trifluoromethyl)silanes by fluoride ion produces also a trifluoromethyl carbanion, which adds to carbonyl carbon atoms [136, 137] (equations 117 and 118)... 

Fluoroolefins may he prepared by the reaction of Wittig reagents and other pho sphorus-containtng y tides with fluorinated carbonyl compounds. (A discussion of the fluorinated Wittig reagents or other fluonnated phosphorus reagents with nonfluorinated carbonyl compounds is on page 581.) Tnphenylphosphoranes, derived from alkyltriphenyl phosphonium salts, react with 1,1,1-trifluoroacetone [3/] or other trifluoromethyl ketones [32, iJ] (equation 26) (Table 10). 

In similar work, CF3CCI2CO2CH3 yields methyl a-trifluoromethyl-a,(i-un-saturated carboxylates when reacted with a zinc-copper couple, aldehydes, and acetic anhydride [67] (equation 55). This methodology gives (Z)-a-fluoro-a- -un-saturated carboxylates from the reaction of carbonyl compounds with CFCI2CO2CH3 and zinc and acetic anhydride [6 ]. 

As indicated in Chapter 3, compounds with fluorines bound directly to a carbon bearing a hydroxyl group are usually very unstable relative to the carbonyl compound plus HF. Nevertheless trifluoromethanol has been prepared, but it spontaneously loses HF at temperatures above -30 °C. Its fluorine and carbon NMR data are given in Scheme 5.8 and 5.11, and they resemble the respective data of trifluoromethyl ethers. 

The chemical shifts of trifluoromethyl groups at the terminus of a,(3-unsaturated carbonyl compounds are not affected by the presence of the carbonyl group, as is indicated by the examples in Scheme 5.37, and as exemplified by the fluorine NMR of 4,4,4-trifluorocrotonic acid, given in Fig. 5.14. 

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). 

Scheme 8-42. Asymmetric trifluoromethylation of carbonyl compounds by chiral quaternary ammonium fluorides.

Trifluoromethyl)trimethylsilane has been prepared by a modification5 of the procedure originally published by Ruppert.4 The optimized yield is 75%. Other less convenient methods are also available for its preparation. (Trifluoromethyl)trimethylsilane acts as an in situ trifluoromethide equivalent under nucleophilic initiation and reacts with a variety of electrophilic functional groups. Carbonyl compounds such as aldehydes, ketones and lactones react rather readily5 7 with (trifluoromethyl)trimethylsilane under fluoride initiation. The reagent also reacts with oxalic esters,8 sulfonyl fluorides,9 a-keto esters,10 fluorinated ketones,11 and... 

Miscellaneous PTC Reactions The field of PTC is constantly expanding toward the discovery of new enantioselective transformations. Indeed, more recent applications have demonstrated the capacity of chiral quaternary ammonium salts to catalyze a number of transformations, including the Neber rearrangement (Scheme 11.19a), ° the trifluoromethylation of carbonyl compounds (Scheme 11.19b), ° the Mannich reaction (Scheme 11.19c), and the nucleophilic aromatic substitution (SnAt)... 

The bioreduction of carbonyl compounds with reductases has been exploited for many years, especially in the case of ketones, with baker s yeast Saccharomyces cerevisiae) being the most popular biocatalyst [45]. For instance, yeast treatment of 3-chloropropiophenone affords the expected (lS)-3-chloro-l-phenylpropan-l-ol, which was treated with trifluorocresol in tertrahydrofuran in the presence of tri-phenylphosphine and diethyl azodicarboxylate at room temperature to give (3R)-l-chloro-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propane and the later reaction with methylamine leads to (R)-fluoxetine that is an important serotonin uptake inhibitor (Scheme 10.19) [46]. 

Reaction of 3-trifluoromethyl-substituted 1,2-oxazine 5 with lithium diisopropylamide (LDA) resulted in smooth deprotonation at C-4 and allowed subsequent alkylation with various electrophiles. Reaction of 5 with Mel furnished the 4-methyl-l,2-oxazine 54 in good yield and with excellent r-diastereoselectivity, whereas carbonyl compounds could not be employed successfully as electrophiles <1996JFC( 80)21 1 reatment of 3,4,6-trisubstituted l,2"Oxazine... 

Trifluoromethyl hypofluorite was first made by Cady by passing methanol [184] or carbon monoxide [185, 186] with fluorine over silver difluoride at elevated temperatures. Later, trifluoromethyl hypofluorite and higher perfluoroalkyl hypofluorites were prepared by treating the appropriate carbonyl compound with fluorine in the presence of dry caesium fluoride at sub-zero temperatures (Fig. 81) [187-189]. 

Interest in linkers for carbonyl compounds has only slowly emerged in recent years. The main driving force for the development of such linkers was the need for methods to prepare peptide aldehydes and related compounds (e.g. peptide trifluoromethyl ketones), which can be highly specific and valuable enzyme inhibitors [700,701], and are potentially useful for the treatment of various diseases. 

Polyfluorooxiranes rearrange to carbonyl compounds in the presence of a wide range of catalysts. The nature of the product carbonyl compound depends on the structure of the epoxide and the catalyst an overview is given in Scheme 8. Monosubstituted perfluorooxiranes generally give acyl fluorides with Lewis bases, and trifluoromethyl ketones with Lewis acids. Symmetrically 2,3-disubstituted perfluorooxiranes give ketones with either Lewis acids or Lewis bases. In the presence of Lewis acids, unsymmetrically 2.3-disubstituted perfluorooxiranes give a 1 1 mixture of the two possible ketones. 

Peptidyl fluoromethyl ketones can readily be synthesized by addition of organometallic reagents to peptide aldehydes and other carbonyl compounds 28 one variation of this reaction is suitable for the stereoselective synthesis of trifluoromethyl ketones. 23,31 ... 

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). 

Oxygenation of 2-substituted adamantanes with methyl(trifluoromethyl)dioxirane showed a reaction constant, p = -2.31, consistent with a strongly electron-demanding transition state. Analysis of the effect of solvents on the rate yielded a positive regression coefficient with Dimroth-Reichardt Ej solvent polarity parameter. A mechanism involving an electrophilic O atom insertion has been postulated for the formation of alcohols and carbonyl compounds.201... 

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