Ketones alkyl-trifluoromethyl

Alkyl trifluoromethyl ketones were hydrogenated with [Rh(OCOCF3) (S)-Cy,Cy-oxoProNOP ]2 in toluene under 20 atm of H2 to give the corresponding chiral alcohols in high ee (Scheme 7) [27]. Trifluoromethyl was efficiently differ-... 

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... 

Alkyl trifluoromethyl ketones also undergo directed aldol condensations under thermodynamic conditions in the presence of piperidine and acetic acid. Under thc.se conditions the product... 

In the same way as a,a,(Z-trihalogenated carbonyl compounds are cleaved hydrolytically to produce haloforms, the fluorinated analogs also react by release of trifluoromethane. The fluoroform reaction has been described with aldehydes such as trifluoroacetaldehyde, alkyl trifluoromethyl ketones, and aryl trifluoromethyl ketones, e.g. l-(2,4-dihydroxyphcnyl)-... 

Reduction of Alkyl Fluoroalkyl Ketones. Since 1 reduces non-fluorinated aralkyl ketones in high ee, a better understanding of the effects of fluorine atom in asymmetric induction with this reagent was sought from the reduction of a series of alkyl a-fluoroalkyl ketones. The fact that unhindered prochiral dialkyl ketones are typically reduced by 1 in relatively poor ee added value to this proj t. DBP-CMoride reduced alkyl trifluoromethyl ketones at a rate faster dwn that of the aryl derivatives... 

Figure S. Asymmetric Reduction of alkyl trifluoromethyl ketones with 1...

Support for this concept is provided by H NMR studies which have identified a downfield resonance of the hydrogen-bonded proton in this pair at 18 ppm in chymotrypsinogen and chymotrypsin at low pH and at 14.9-15.5 ppm at high pH values.246 247 Similar resonances are seen in the a-lytic protease,248 in sub-tilisin,249 in adducts of serine proteases with boronic acids250 251 or peptidyl trifluoromethyl ketones,252 in alkylated derivative of the active site histidine,253 and in molecular complexes that mimic the Asp-His pair in the active sites of serine proteases.254... 

A-Benzylimines 14k and I, derived from alkyl fluoroalkyl ketones, are less reactive in the base-catalyzed 1.3-proton shift reaclion. Thus, when 14k is kept in triethylamine solution at room temperature for 2 days, less than 5% conversion is detected.14 Either heating in triethylamine or the use of DBU effects the transformation at a preparatively acceptable rate and in good yield. Reaction of the benzyl trifluoromethyl ketone derivative 14m is expected... 

Experimental results of an unprecedented haloform-type reaction in which 4-alkyl-4-hydroxy-3,3-difluoromethyl trifluoromethyl ketones undergo base-promoted selective cleavage of the CO-CF3 bond, yielding 3-hydroxy-2,2-difluoro acids and fluoro-form, have been rationalized using DFT (B3LYP) calculations.159 The solvent-induced effects on the two pathways, introduced within the SCRF formalism through PCM calculations, do not reverse the predicted preference of the CO-CF3 over the CO-CF2 bond cleavage in the gas phase. 

Similar but smaller effects of hydrogen concentration were observed with other aromatic and alkyl-aromatic trifluoromethyl ketones such as 2 and 3 (Table 2). On the contrary, in the hydrogenation of the aliphatic ketone 4 medium to high hydrogen pressure favoured the enantiodifferentiation. Note that this correlation is typical for the hydrogenation of a-ketoesters and other activated ketones over the Pt-CD system4. 

Various alkyl halides may be used to obtain phosphorus ylides. The dibromodifluoromethane/ triphenylphosphane and sodium ehlorodifluoroacetate/triphenylphosphaiie systems have been employed to synthesize 2-arylpentafluoropropenes 12 from aryl trifluoromethyl ketones. 

The haloform reaction of unsymmetncal perfluoroalkyl and (o-hydroper-fluoroalkyl trifluoromethyl ketones gives the alkane corresponding to the longer alkyl chain [.54] (equation 53) If the methyl group contains chlorine, the reaction can take different pathways, leading to loss of chlorine (equation 54), because of the variable stability of the chlorine-substituted methyl carbanions m alkali. 

Tetrahedral transition state analogues of ester and amide substrates are known to function as efficient enzyme inhibitors of hydrolytic enzymes such as serine and aspartyl proteases as well as metalloproteinases (see Fig. 1.24) [141-144], Although ketals of alkyl or aryl ketones are usually not stable, those of difluroalkyl or trifluoromethyl ketones have considerable stability, as exemplified by their facile formations of the corresponding stable hydrates [145, 146]. Therefore, substrate analogues, containing difluoroalkyl or trifluoromethyl ketone moiety in appropriate positions, have been studied as effective transition state inhibitors of hydrolytic enzymes [141, 147-150],... 

It was already known that amino alcohols of the kind we have just used 78 were good at this kind of asymmetric addition but this particular combination of an acetylenic nucleophile and an aryl trifluoromethyl ketone was uncharted territory. After some exploration, stoichiometric pyrrolidine alcohol 88 prepared by alkylation of norephedrine 87 from the chiral pool (chapter 23) proved the best and the ketone 85 had to be used as its V-4-methoxybenzyl derivative18 89. 

Trifluoromethyl ketones are more electrophilic than the alkyl ketones described above and typically exist in equilibrium with their hydrate forms. Potent inhibitory activity of trifluoromethyl ketones toward metal-dependent proteases has been well documented, which sparked the investigation of compounds bearing this war head in the context of inhibition of HD AC function [71]. Indeed, the alkyl-linked trifluoroketone 17 (Fig. 7) demonstrated submicromolar HD AC inhibitory activity and antiproliferative effects in HT1080 and MDA 435 cell lines. Molecules within... 

Using jS-alkyl- -methoxyvinyl trifluoromethyl ketones allows the preparation of various heterocyclic compounds with a CF3-group (95JHC739, 99JFC(99)177). Often carried out by cyclocondensation with hydroxylamine, semicarbazide, thiosemicarbazide, phenylhydrazine, and urea (Scheme 99). 

The mode of addition of hydrogenphosphonates to fluorinated ketones can also be complex. The addition of dialkyl, diphenyl or bis(trimethylsilyl) hydrogenphosphonates to methyl trifluoromethyl ketones occurs in the expected manner, but this contrasts with the behaviour of aryl perfluoralkyl ketones in the presence of triethylamine at room temperature, when the products, obtained even under such mild conditions, are phosphate esters (reaction 6), a situation which represents lack of stability of the hydroxyphospho-nate rather than novelty of the reaction under identical conditions, the corresponding alkyl aryl ketones fail to react. The same reaction with mixed-halogen ketones is still more involved, and the nature of the products depends on the reaction conditions if these are of a mild nature, and with catalysis by triethylamine or pyridine (depending on the particular ketone), the product is the expected (hydroxyalkyl)phosphonate 177, whereas with... 

Recently, two methods were published that have attracted some interest, because no metal salts are necessary as oxidation reagents. Shi and Xu (1990) found that substituted (trifluoromethyl)-diazoalkanes (CF3CRN2, R = alkyl or aryl) are obtained by refluxing trifluoromethyl ketones and 2,4,6-tri(isopropyl)benzenesulfonyl hydrazone in a methanolic solution of KOH. Kumar (1991) synthesized a-diazocar-bonyl compounds under tri-phase phase-transfer catalysis using a polystyrene-supported (tributyl)(methyl)-ammonium chloride catalyst, methanesulfonyl chloride, NaN3, and methylsulfonyl azide in 1,2-dichloroethane and a carbonyl-activated substrate (69-94% yield). 

Phenyl trifluoromethyl ketone has been used as a standard for comparing stereoselectivities in Meerwein-Ponndorf-type reductions with chiral alkoxyalu-minium and magnesium halides derived from monoterpenoid alcohols, and (24) is one of the few to show high selectivity (77% enantiomer excess). The alkylative addition of butyl-lithium to aldehydes in chiral media has been studied as part of a general programme to develop auxiliaries, based on tartaric acid, for asymmetric synthesis. Optical yields of up to 40% in the butyl carbinol products are obtained at low temperature in solutions containing chiral 1,2-dihetero-ethane derivatives such as (25), which are believed to complex the alkyl-lithium as in (26). 

Linderman RJ, Jamois EA, Tennyson SD (1994) Synthesis of and analysis of thiol additions to p-alkyl-a, p-imsaturated trifluoromethyl ketones. J Oig Chem 59 957-962... 

The Dy(OTf)3-PyBOX ligand-catalyzed Friedel-Crafts alkylation of indoles with a,/3-unsaturated trifluoromethyl ketones represents the only known example of a highly enantioselective reaction that employs Dy(OTf)3 (eq 14). ... 

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