Trifluoromethyl alcohols, activated

Table V Diastereoselective Cyclopropanation with Trifluoromethylated Optically Active Ally lie Alcohols...

Using the same experimental approach, a family of enantiomerically pure oxonium ions, i.e., O-protonated 1-aryl-l-methoxyethanes (aryl = 4-methylphenyl ((5 )-49) 4-chlorophenyl ((5)-50) 3-(a,a,a-trifluoromethyl)phenyl ((5)-51) 4-(a,a,a-trifluoromethyl)phenyl ((S)-52) 1,2,3,4,5- pentafluorophenyl ((/f)-53)) and 1-phenyl-l-methoxy-2,2,2-trifluoroethane ((l )-54), has been generated in the gas phase by (CH3)2Cl -methylation of the corresponding l-arylethanols. ° Some information on their reaction dynamics was obtained from a detailed kinetic study of their inversion of configuration and dissociation. Figs. 23 and 24 report respectively the Arrhenius plots of and fc iss for all the selected alcohols, together with (/f)-40) of Scheme 23. The relevant linear curves obey the equations reported in Tables 23 and 24, respectively. The corresponding activation parameters were calculated from the transition-state theory. 

The chiral compounds (/ )- and (5)-bis(trifluoromethyl)phenylethanol are particularly useful synthetic intermediates for the pharmaceutical industry, as the alcohol functionality can be easily transformed without a loss of stereospecificity and biological activity, and the trifluoromethyl functionalities slow the degradation of the compound by human metabolism. A very efficient process was recently demonstrated for the production of the (5)-enantiomer at >99% ee through ketone reduction catalyzed by the commercially available isolated alcohol dehydrogenase enzyme from Rhodococcus erythropolis (Figure 9.1). The (7 )-enantiomer could be generated at >99% ee as well using the isolated ketone reductase enzyme KRED-101. 

Trifluoromethylation can be achieved with the use of imidazolylidene carbene 1 [159], Song and co-workers found this transformation is tolerant of both electron-rich and electron-poor aldehydes (Table 26). Even enolizable aldehydes undergo trifluoromethylation in 81% yield (entry 3). Selective reaction occurs with an aldehyde in the presence of a ketone in the substrate (entry 5). The use of activated ketones as acceptors leads to tertiary alcohols in good yields (entries 7 and 8). 

Ricci and co-workers introduced a new class of amino- alcohol- based thiourea derivatives, which were easily accessible in a one-step coupling reaction in nearly quanitative yield from the commercially available chiral amino alcohols and 3,5-bis(trifluoromethyl)phenyl isothiocyanate or isocyanate, respectively (Figure 6.45) [307]. The screening of (thio)urea derivatives 137-140 in the enantioselective Friedel-Crafts reaction of indole with trans-P-nitrostyrene at 20 °C in toluene demonstrated (lR,2S)-cis-l-amino-2-indanol-derived thiourea 139 to be the most active catalyst regarding conversion (95% conv./60h) as well as stereoinduction (35% ee), while the canditates 137, 138, and the urea derivative 140 displayed a lower accelerating effect and poorer asymmetric induction (Figure 6.45). The uncatalyzed reference reaction performed under otherwise identical conditions showed 17% conversion in 65 h reaction time. 

Esterases of the Juvenile Hormone of Insects Many works have been dedicated to the inhibition of esterases of the juvenile hormone of insects. The purpose of these works is to control insect populations by ehminating their metamorphosis. Among the numerous trifluoromethyl ketones that have been synthesized, thioalkyl derivatives of trifluoroacetone have been shown to be the most active ones. Curiously, the corresponding alcohols are also excellent inhibitors. Trifluoromethyl ketones can also inhibit other insect esterases antenna esterases and esterases that are involved in the release of pheromones (Figure 7.33). The inhibition of these latter ones can also be interesting for insect control purposes. 

Trifluoromethyl ketones and alcohol derivatives of squalene have been prepared in order to inhibit squalene epoxycyclase. This important enzyme regulates the biosynthesis of cholesterol. It bears a cysteine in its active site. Although these compounds have been shown to be good inhibitors, the involved mechanism is different from what was expected. Indeed, they do not inhibit squalene epoxycyclase, but they are substrates of this enzyme and are transformed into fluorohydroxysterols. The repression of the expression of HMG-CoA reductase is responsible for the observed inhibition of cholesterol biosynthesis. This repression comes from the back-regulation that is exerted by fluorohydroxysterols. Indeed, these compounds induce an important diminution of the cell activity of HMG-CoA reductase (Figure 7.66). °... 

Verevkin, S.R et al.. Thermodynamic properties of mixtures containing ionic liquids. Vapor pressures and activity coefficients of n-alcohols and benzene in binary mixtures with l-methyl-3-butyl-imidazolium bis(trifluoromethyl-sulfonyl)imide. Fluid Phase Equilib., 236, 222, 2005. 

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. 

Fluorinated aromatic chlorides " or bromides are substrates for nucleophilic substitutions however, fluorine is preferentially substituted. This is demonstrated by the formation of compound 19j in good yield. - The trifluoromethyl and the trifluorometliylsulfonate groups are activating groups that are not readily displaced. Again, chlorine. - i5i.is4 bromine, or iodine are readily substituted by alcoholates. 

Synthesis of trifluoromethylated compounds 152 has been achieved via ester-enolate [2,3]-Wittig and [3,3]-lreland-Claisen rearrangements. Perfluorocyclo-butane phosphonium ylides, e.g. 153, have been used as a masked fluoride anion source in their reactions with alcohols and carboxylic acids which lead to alkyl-and acyl-fluorides. Ylides 153 are also reported to cleave Si-C and Si-O bonds, cause dimerisation of fluoro-olefins, and also react with acid chlorides or other activated aromatic compounds under halogen exchange. ... 

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