Procedure trifluoromethyl ketones

The procedure illustrates a fairly general method for the preparation of -substituted perfiuoroolefins. The method has been applied to the synthesis of 2-cyclohexyl- (70%), 2-benzyl- (61%), and 2-(/>-fluorophenyl)perfluoropropenes (67%), and it is probably applicable to any a-trifluoromethyl ketone. Olefins containing a perfluoroalkyl group other than trifluoromethyl can be prepared by the same procedure by the substitution of lithium chlorodifluoroacetate for sodium chlorodifluoroacetate.7 Other routes to / -substituted perfiuoroolefins are not general or convenient. Routes to perfiuoroolefins generally yield the a-substi-tuted olefin rather than the /3-substituted olefin. 

Similar to the Dakin-West procedure previously mentioned, the Henry nitro-aldol condensation reaction is most widely used to synthesize trifluoromethyl ketones, although there are many examples of a,a-difluoroalkyl ketones synthesized by this method (Table 6)JU 12271 The method for a,a-difluoroalkyl and trifluoromethyl ketone synthesis is identical except for the final oxidation although fluoroalkyl and a,a-difluoroalkyl ketones are easily oxidized by the Sarett method (Cr03/pyridine),[12 the corresponding trifluoromethyl ketones can only be oxidized under basic conditions (0.3 M NaOH) with KMn04Jul Also, in some of the syntheses of a,a-difluoroalkyl ketones, the nitro alcohol intermediate was protected by si-lylation with /ert-butylchlorodimethylsilane. The silyl group was later removed by TosOH prior to oxidation. The full details of this method are given in Section 15.1.4.3.2. 

One of the most widely used methods for the synthesis of peptidyl fluoromethyl ketones is a modified Dakin-West acylation procedure. Although this reaction is primarily used for the synthesis of trifluoromethyl ketones (see Scheme 4), it is also frequently used to synthesize fluoroalkyl (Section 15.1.4.1.4), difluoroalkyl (Section 15.1.4.2.2), and perfluoroalkyl ketones. This method is extremely versatile however, there are several drawbacks. First, as noted in Section 15.1.4.1.2, several of the reagents used in the Dakin-West acylation are... 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

The reaction of peptide aldehydes with ICF Zn has the obvious advantage that it allows the stereoselective synthesis of trifluoromethyl ketones since it avoids the use of an achiral carbanion in the carbon bond forming step, a requirement for the previously discussed synthetic procedures. In this method, a trifluoromethyl anion equivalent is reacted with a peptide aldehyde, which already contains the chiral a-carbon (Scheme 7). Provided the... 

Trifluoromethyl ketones can also be synthesized from 1-trifluoromethyl-substituted enol ethers, which are readily prepared from aldehydes via a Wittig reaction (Scheme 9). Similar to Ruppert s procedure (Section 15.1.4.3.4), this method has thus far only been used to prepare trifluoromethyl compounds. The a-amino trifluoromethyl ketones produced in the reaction scheme are much less stable than the corresponding a-amino ketones, which leads to the formation of byproducts (a-hydroxy ketones) during attempts to purify the a-amino trifluoromethyl ketones by chromatography on silica gel. 35 ... 

Aryl difluoroenoxysilanes 20 were prepared by Mg-promoted defluorination of trifluoromethyl ketones, according to Uneyama s procedure [60], Their reaction with DHA acetate appeared to be much more critical than any other Lewis acid-catalyzed reaction and the setup was very troublesome. Each difluoroenoxysilane required specific reaction conditions (e.g., Lewis acid and rate of addition) (see Scheme 6.11 and Table 6.4) [61]. For instance, the best conditions found for the preparation of the difluoroketone 21a (SnCh, 0.4 equivalents) provided a completely rearranged artemisinin skeleton when applied to the enoxysilane 20b. Furthermore, the stereochemical outcome of reactions was unusual difluoroketones 21a-c all possess the epf-artemisinin configuration at C-9 (9a-Me). The mechanism of this epimerization at C-9 is not fully understood, but probably... 

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... 

In this section the synthesis of fluoroalkyl (Section 15.1.4.1.3), a,a-difluoroalkyl (Section 15.1.4.2.3), and trifluoromethyl- and perfluoroalkyl ketones are discussed collectively. The second most widely used method for synthesizing peptide fluoromethyl ketones is the Henry nitro-aldol condensation reaction, which involves the use of (3-nitro alcohols to build the fluoromethyl ketones. As with the modified Dakin-West procedure, the Henry reaction has also been used to synthesize mono-, di-, tri-, and extended fluoromethyl ketones, making it another extremely versatile synthetic method.19 12 19 27 29 33 341 However, similar to the Dakin-West procedure, the products of the Henry reaction are not chiral, since an achiral carbanion is involved in the crucial carbon bond forming step. 

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). 

Substituted 4,S-dihydropyridazin-3,6-dione 3-hydrazones were reacted with trifluoroacetic acid to yield 3-trifluoromethyl-s-triazolo[4,3-6]pyri-dazinones (19) [94M1(49)21]. Reaction of catechol derivatives with 3,4,5-tri-chloropyridazine have been shown to afford 4-chloro[l,4]benzodioxino[2,3-c]-pyridazines 20 and 21 [93JHC(30)789]. An efficient procedure for preparing phenyl 3-pyridazinyl ketones 22 has been published [93JHC(30)1685] [94SC(24)773],... 

Trifluoromethyl perfluorohexylethyl ketone is an efficient alternative catalyst for the epoxidation reactions of alkenes. Such reactions were carried out using 1-5 mol% of this fluorous ketone as a catalyst and 1.5 equivalents of the oxone in a mixture of hexafluoroisopropanol and water. Thus, the new procedure circumvents the need for volatile fluorine compounds such as trifluoroacetone and hexafluoroacetone. 

At the same time as discussed in [82], Cheng and coworkers [83] reported the Rh-catalyzed oxidative C-H-activated annulation of benzaldehydes with alkynes to form indenones. In this approach, an acetylhydrazone was formed in situ using acetylhydrazine and acetic acid. Subsequently, the in situ DG removal takes place since ketone hydrazone is more susceptible toward hydrolysis than aldehyde hydrazone. The procedure tolerates a series of functional groups, such as methoxyl, acetylamino, fluoro, trifluoromethyl, methoxycarbonyl, chloro, and bromo groups. 

Reactions with Carhonyl Compounds and Related Derivatives. Since the original procedure for the trifluoromethylation of carbonyl compounds with TMSCF3 was reported (enploying catalytic TBAF as initiator in THF as solvent), several improved protocols have appeared over the years. Thus, removal of residual water by pre-drying the TBAF solution over activated 4 A molecular sieves, in combination with non-polar aprotic solvents, made possible the trifluoromethylation of less reactive substrates such as hindered ketones and aliphatic or aromatic esters (eq 10). Other anhydrous sources of fluoride anions have been successfully applied, including CsF, tetramethylammonium fluoride... 

The treatment of carbonyl compounds with Sml2 and methyl chloroformate in the presence of molecular sieves affords the cyclic carbonates or biscarbonates of pinacols. This one-pot reaction proceeds rapidly even with aliphatic ketones. The stereochemistry of the reaction run by this procedure is different from that of conventional pinacolic couplings. Trifluoromethylated five-membered cyclic carbonates were prepared through the palladium-promoted reaction of tertiary trifluoromethylated propargylic alcohols and sodium carbonate (Scheme 6). ... 

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