Trifluoromethyl ketone reduction

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... 

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. 

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. 

P.V. Ramachandran, A.V. Teodorovic , FI.C. Brown, Chiral synthesis via organobor-anes. 38. Selective reductions. 48. Asymmetric reduction of trifluoromethyl ketones by B-chlorodllsopInocampheylborane In high enantiomeric purity. Tetrahedron 49(9) (1993) 1725-1738. 

Reductive amination. Conversion of ketones or aldehydes to amines is usually accomplished by reduction of the carbonyl compound with sodium cyanoborohydride in the presence of an amine (Borch reduction, 4, 448-449). However, yields are generally poor in reactions of hindered or acid-sensitive ketones, aromatic amines, or trifluoromethyl ketones. Yields can be improved markedly by treatment of the ketone and amine first with TiCl4 or Ti(0-i -Pr)42 in CH2C12 or benzene to form the imine or enamine and then with NaCNBH3 in CH3OH to effect reduction. Note that primary amines can be obtained by use of hexamethyldisilazane as a substitute for ammonia (last example). 

Compounds carrying a trifluoroacetyl group, for example trifluoromethyl ketones and esters of trifluoroacetic acid, can be converted into the corresponding trimethylsilyl difluoroenol ethers [27] or into trimethylsilyldifluoroacetic acid esters [28] by reduction with magnesium metal in the presence of Me SiCl (Scheme 2.195). These readily accessible species are synthetically very useful as nucleophilic difluoromethylene equivalents. The same type of chemistry [29] can also be extended to trifluoromethyl imines [30]. 

Also difluoromethyl ketones can be reduced by magnesium to the corresponding fluorenol ethers [32]. Thus, by application of one or two sequential reduction-desi-lylation steps, trifluoromethyl ketones can be converted into difluoromethyl and fluoromethyl ketones (Scheme 2.198). Deuterodesilylation instead ofthe usual pro-todesilylation enables convenient access to deuterated analogs of these compounds. 

Scheme 2.198 Synthesis of fluoromethyl and difluoromethyl ketones by stepwise reduction of trifluoromethyl ketones with magnesium [32]. This method also enables the simple preparation of deuterated analogs.

The catalytic reduction of trifluoromethyl ketones was successfully realized by using catecholborane as reductant. In the case of the reduction of anthryl trifluoromethyl ketone, one recrystallization of the crude (i )-alcohol (94% ee) afforded the enantiopure carbinol [35]. Trichloromethyl ketones were also reduced... 

Steric bulkiness of substituents in ketones (25), for example, makes it possible to differentiate two pairs of lone-pair electrons (a or b in 25) on carbonyl oxygen for coordinating with the Lewis acidic center of boron in oxazaborolidine (28). The complex (29) formed from 28 with catecholborane binds ketone (32) stereospecifically by using the lone-pair electrons at the less hindered side so as to direct the smaller substituent Rs toward the bulky N-tert-butyl group. The intramolecular hydride transfers to the favorably coordinated carbonyl group as shown in 30, Scheme 1.82, results in asymmetric reduction of ketones. Reduction of trifluoromethyl and methyl ketones (25) (R = CF3 or CH3) by this system afforded the corresponding alcohols (26 or 27) with an opposite stereochemistry (Scheme 1.82). 

Figure 15-34. Asymmetric reduction of trifluoromethyl ketones containing a sulfur functionality by the acetone powder of G. candidumI1831.

The acetone powder of G. candidum (APG4) has also been used for the reduction of sulfur containing trifluoromethyl ketones (Fig. 15-34) 183l This reaction can be scaled up easily without the loss of enantioselectivity. For example, the reduction of trifluoro(2-thienyl)ethanone on the gram scale proceeded quantitatively and yielded the optically pure (R)-alcohol in 88% yield after purification (4.16 g, ee > 99%). The thienyl alcohol can be further transformed into a fluorinated aliphatic alcohol without racemization. 

Carbonyl reduction. Many substrates have been reduced enantioselectively to give alcohols trifluoromethyl ketones, a-acetoxyketones, pyridinophenones, ethyl a-methylacetoacetate, a-keto acid derivatives," and 3-chloro-2-oxoaIkanoic esters a,/3-Epoxy ketones undergo reduction and hydrolytic ring opening/... 

Catalytic synthesis of aryl trifluoromethyl ketone via RC(0)-0Ar bond cleavage is also known. Combination of Pd(OAc)2 with 3 equiv of P Bu3 catalyzes the formation of aryl trifluoromethyl ketone from phenyl trilluoroacetate and arylbo-rane (Eq. 3.12) [69]. This reaction is interpreted by RC(0)-0Ph bond oxidative addition to give (acyl)(phenoxo)palladium(II) complex, followed by metathesis (transmetallation) of phenoxopalladium species with arylborane and reductive elimination of acyl and aryl carbons to form the product. 

This group also employed the Dakin-West reaction to prepare a series of amino alcohols (not shown) by reduction of the trifluoromethyl ketones 85, resulting from treatment of Walkoxycarbonylamino acids 84 with TFAA (Fig. 4.27). 

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). 

Table 18. Asymmetric reduction of aryl trifluoromethyl ketones with PNAH and sodium borohydride.

Baba N, Matsumura Y, Sugimoto T (1978) Asymmetric reduction of aryl trifluoromethyl ketones with an achiral NADH model compound in a chiral hydrophobic binding site of sodium cholate micelle,... 

The asymmetric reduction of trifluoromethyl ketones using 1-propyl-1,4-dihydronicotinamide has been reported. This achiral NADH model compound is oxidized in an aqueous solution of cyclohepta-amylose, which has a... 

The route via racemic carbinol 7 requires its derivatization into a mixture of dia-stereomers, their separation by crystallization and final removal of the derivatizing agent [16]. Moreover, the wrong enantiomer of ferf-alcohol 7 cannot be racemized via oxidation-reduction, a process that was successfully applied in the S5mthetic approach to sertraline, as presented in Chap. 7. At Merck Research Laboratories, the enantioselective alkynylation of trifluoromethyl ketone 5 by cyclopropylacety-lene 6 was therefore studied as the key step in the asymmetric s5mthesis of enan-tiopure efavirenz (5)-l (Scheme 13.2) [16]. The observation that the Li-acetylide of... 

The reaction of (5)-(trifluoromethyl)diphenylsulfonium triflate with Na2S204 or H0CH2S02Na under suitable conditions can generate the CF3 radical without further reduction. Various styrenes react with (5)-(trifluoromethyl)diphenylsulfonium triflate in the presence of H0CH2S02Na-2H20 or Na2S204, furnishing a-trifluoromethylated ketones (eq 4). ... 

Reduction of the L-r/tam o-derived methyl ketone 5 with L-selectride affords the D-rf6o-pentitoI 6. Under similar conditions, the trifluoromethyl ketone 7 affords the L-/yxo-derivative 8. ... 

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