Ketones trifluoromethyl

Geranyl acetoacetate (685) is converted into geranylacetone (686). On the other hand, a mixture of E- and Z-isomers of 688 is obtained from neryl acetoacetate (687). The decarboxylation and allylation of the allyl malonate or cyanoacetate 689 affords the o-allylated acetate or nitriie[447]. The trifluoromethyl ketone 691 is prepared from cinnamyl 4.4,4-trifluoroacetoace-tate (690)[448],... 

Acetamide, af,Q, Q -trifluoro-N,N-dimethyl-trifluoromethyl ketones from, 4, 833-834... 

Trifluoromethyl alkyl ketones also undergo directed aldol condensations under thermodynamic conditions in the presence of piperidine and acetic acid [2, d] Under these reaction conditions, the product suffers a facile dehydration to form the unsaturated trifluoromethyl ketones (equations 2 and 3)... 

Lastly, a-trimetfayisflyl enolates have been added to trifluoromethyl ketones to effect Peterson olefination of the tnfluoromethyl ketones [IS (equation 13)... 

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). 

By analogy, Peterson oleflnation of trifluoromethyl ketones proceeds in 66% yield with an E /Z ratio of 1 1 [34] (equation 27). 

Table 10. Wittig Reactions with Trifluoromethyl Ketones...

Homer-Emmons reagents react with trifluoromethyl ketones to form tnfluo romethylated olefins, however, the double bond can isomerize out of conjugation with the carboxylic acid group with the product olefin that bears a y-proton [37] (equation 30)... 

Dialkylcadmium reagents are often useful alternatives to the more reactive Gngnard reagents in the preparation of ketones from acyl halides However, bis(trifluotomethyl)cadmium glyme is decomposed by acyl halides and does not give trifluoromethyl ketones [, 124] Nevertheless, this reaction can be used as a low-temperature source of difluorocarbene [S, 124] (equation 102)... 

Another reaction that has potential is the intramolecular ene reaction, which preferentially results in five-membered rings Because fluorinated ketones have a propensity for undergoing intermolecular ene reactions [5S], this reaction has tremendous synthetic possibilities Only one example of an ene reaction of an unsaturated trifluoromethyl ketone has been reported, but it indicates the potential of the methodology [59] (equation 59)... 

Table 12 [19, 56.101,102, fOJ],Table 13 [56. 73.104], and Table 14 [56,105, 106] cover six common CF -containing subunits of general interest and utility tnfluoroetbanes, trifluoroacetates, tnfluoroacetamides, tnfluorometbanesuLfon-ates, trifluoromethyl ketones, and trifluorometbyl carbinols. The majority of these data were acquired under uniform conditions (10% solutions in CDCI3 at room temperature [5(5]) to provide for a valid comparison of -NMR values within a narrow range of approximately 10 ppm. Most of these compounds are common,... 

Table 14. NMR Data for Trifluoromethyl Ketones and Corresponding Trifluoromethyl Carbinols...

Trifluoromethyl Ketone F NMR Signal for CFfCOR F NMR Signal for CFjCH(OH)R / Ref... 

Methods for synthesis of a,(3-unsaturated trifluoromethyl ketones and their use in the synthesis of trifluoromethyl-substituted heterocycles 99UK483. 

Tiifluoromethyl derivatives of tetrahydrothiopyran-4-ols result from the Michael addition of hydrosulfide to a, -unsaturated trifluoromethyl ketones <96JOC1986> and tetrahydro-thiopyran-4-ones arise from the reaction of H2S with l,5-diaryl-2-chloropenta-l,4-dien-3-ones <96PS(108)93>. 

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

The first substrate analogue inhibitors of FAAH were reported in 1994. The anandamide analogues prepared represented three elasses of putative transition-state inhibitors a-trifluoromethyl ketones, a-ketoesters and a-ketoamides [62], In the initial sereening studies, it was found that the trifluoromethyl ketone eompounds tested were effeetive inhibitors of AEA hydrolysis. A selected set of a-keto esters also inhibited hydrolysis, while a-keto amides were ineffective. In particular, arachidonyl trifluoromethyl ketone (32), gave almost 100% inhibition of anandamide hydrolysis. A detailed investigation of the structural requirements for FAAH inhibition with a-trifluoromethyl ketones has been carried out by Roger and co-workers [63]. 

This approach has been mainly applied to peptide-based inhibitors of proteases, where the inhibitory molecule is a peptide with a transition state isostere appended to it, and the cognate substrate is simply a peptide of the same amino acid sequence, but lacking the isostere functionality. Examples where good correlations between the free energy of inhibitor binding and the free energy of kcJKM have been found, include peptide-trifluoromethyl ketone inhibitors of human leukocyte elastase (Stein et al., 1987) and peptide-phosphonamidate inhibitors of the metalloprotease ther-molysin (Bartlett and Marlowe, 1983). 

Ethoxyvinyl trifluoromethyl ketone 243 reacts slowly at elevated temperature with aryl and benzyl azides to provide triazoles 245 in good yield (51-88%). The reactions, carried out neat, are completed usually in 2-3d(days). However, a longer reaction time (6 d) is required for 2-methylphenyl azide due to its steric hindrance. 5-Ethoxytriazolines 244, the expected intermediates in this process, readily eliminate ethanol under the reaction conditions and cannot be isolated (Scheme 34) <2002JFC(116)81 >. 

Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

Besides the above-mentioned catalytic asymmetric hydrogenation method for preparing fluorine-containing compounds, other reactions such as asymmetric reduction of achiral fluorine-containing ketones are also feasible methods for preparing chiral fluorinated compounds. For example, the oxazabor-olidine system, which has been discussed in Chapter 6, can also be employed in the catalytic reduction of trifluoromethyl ketones. Scheme 8 40 depicts some examples.85... 

In Scheme 8 40, the reaction of 9-anthryl trifluoromethyl ketone 103 and mesityl trifluoromethyl ketone 104 with catecholborane 106 in the presence of 10 mol% of chiral catalyst 107 (CBS) provides (R)-carbinol 108 and 109 with 94% and 100% ee, respectively. When methyl ketone instead of trifluoromethyl ketone is used in the reaction, product 110 is obtained with ( -configuration in 99.7% ee with over 95% yield. 

Perfiuoroolefins, 0-substituted, from a-trifluoromethyl ketones, 48,119 Periodate oxidation of thioanisole, 46, 78... 

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. 

By analogy to the initial work on trifluoromethyl ketones as ZBGs in their hydrated forms [34], as in compounds 12, silanol versions 13 have been developed. HDAC1 and 8 assays are mentioned in the patent application, but activities are not stated, nor is there any indication of whether the compounds suffer similar metabolic liabilities [35]. 

Two convenient methods have been developed for the preparation of trifluoro-methyl-substituted alkoxyallenes. Reductive elimination of allylic acetates 30 with samarium diiodide leads to 31 (Scheme 8.11) [38], whereas reaction of Wittig cumu-lene 32 with phenyl trifluoromethyl ketone (33) and thermolysis of the intermediate 34 provides 35 (Scheme 8.12) [39]. 

Reduction of phenyl trifluoromethyl ketone by 119 generally leads to the (S)-carbinol (Table 15, entry 28). One would expect that conformational changes in the favored transition states would occur. However, the degree of asymmetric induction in these cases is quite low, and the (/ )-carbinol was in fact formed in toluene at 110°C (Table 15, entry 29), suggesting a rather delicate balance of competing interactions. 

When trifluoroacetaldehyde ethyl hemiacetal [F3CCH(OH)OEt] is treated with enamines in hexane at room temperature, it provides a source of the aldehyde under mild conditions. Subsequent reaction with the enamine can be used to prepare -hydroxy-/ -trifluoromethyl ketones, F3CCH(OH)CH2COR. The enamine plays successive roles as base, ammonium counterion, and then carbon nucleophile as the sequence proceeds. 

Under Dakin-West reaction conditions (trifluoroacetic anhydride-MeCN/80 °C/5 h), At-methoxycarbonylproline (128 R = Me) yielded Af-methoxycarbonyl-4-trifluoro-acetyl-2,3-dihydropyrrole (129 R = Me) and none of the expected Dakin-West product, the trifluoromethyl ketone (127). A possible mechanism proposed by the authors involves initial formation of a mesoionic l,3-oxazolium-5-olate (130 R = Me), but the pathway to the iV-methoxycarbonyl-2,3-dihydropyrrole (131 R = Me) and thence the final product (129 R = Me) was unexplained. ... 

Enol trimethylsilyl ethers were trifluoromethylated with S -salt 17 in the presence of an equimolar amount of pyridine to give trifluoromethyl ketones in good yields (Eqs. 21, 22). 

An enamine was trifluoromethylated with 5-salt 17 (1 equivalent) in the presence of an equimolar amount of 4-(dimethylamino)pyridine to give mono(trifluoromethyl) and di(trifluoromethyl) ketones (Eq. 23). 

Concurrently, Glorius and co-workers reported the synthesis of y-butyrolactones under similar reaction conditions [122, 123], Glorius has extended this reactivity to include trifluoromethyl ketones (Scheme 36). In addition to intermolecular reactions, intramolecular homoenolate additions are possible in modest yield Eq. 21 [123],... 

Scheme 36 Synthesis of y-butyrolactones from trifluoromethyl ketones and enals...

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