Trifluoromethyl 3-amino alcohol

Though not available commercially, trifluoronitroethane shows some interesting chemistry consistent with the powerful electron-withdrawing effect exerted by the nitro group. Fluoride-mediated nitroaldol reactions were reported [144] with aldehydes affording a valuable entry to trifluoromethyl amino alcohols... 

Bravo and co-workers report asymmetric syntheses of fluoroalkylamino compoimds via chiral sulfoxides and the stereoselective synthesis of p-fluoroalkyl-p-amino alcohol units using chiral sulfoxides and the Evans aldol reaction. Begde and colleagues discuss the stereoselective and enantioselective synthesis of trifluoromethyl amino alcohols and fluoroalkyl isoserinates. Hoffman reports the aysmmetric fluorination of a-aminoketones, while... 

So, we were able to prepare selectively syn and anti trifluoromethyl amino alcohols. The next step was a search for a chiral approach to these compounds. Two approaches have been investigated to obtain chiral anti amino alcohols first we performed the reaction of epoxy ethers 3 with the chiral dimethylaluminum amide, prepared from the fi -phenethylamine and MeaAl (Scheme 5). From 3a, the reaction was effective leading, after reduction to the anti diastereoisomers 8a and 9a stereoselectively (Scheme 5). However, the chiral amine induced no selectivity anti amino alcohols 8a and 9a were obtained in a 50/50 mixture. Their separation was performed by crystallisation of the mandelate salts. Although this access to homochiral anti amino alcohols is somehow tedious, it is general since oxirane ring opening is efficient whatever the R substituent, and since epoxy ethers, substituted with various fluoroalkyl groups, are available. ... 

Fluoroform (CHF3) efficiently trifluoromethylates aromatic aldehydes to the corresponding alcohols when deprotonated by potassium DMSylate in DMF. This is surprising, as species such as KCF3 have carbenoid character, and tend to be unstable. However, the reaction fails for solvents such as THF, and appears to depend on a highly specific role for DMF. It is proposed that CFs is trapped in situ by the solvent to form the gem-amino alcoholate (70), which acts as a stable, masked form of the anion, which then attacks the aldehyde, regenerating DMF. 

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. 

J. Joubert, S. Roussel, C. Christophe, T. Billard, B.R. Langlois, T. Vidal, Trifluoroa-cetamides from amino alcohols as nucleophilic trifluoromethylating reagents, Angew. Chem. Int. Ed. 42 (2003) 3133-3136. 

It has recently been shown that when the tetrahedral intermediate of the reaction is cyclic, it is a better donor of nucleophilic CF3. These cyclic intermediates can be generated intramolecularly from trifluoroacetamides or trifluorosulfmamides derived from (9-silylated ephedrine. These reagents are able to trifluoromethylate aldehydes and ketones, even in the case of enolizable substrates, as a strong base is not required (Figure 2.34). However, while the source of CF3 is chiral, there is no chirality transfer to the addition product, and the replacement of ephedrine by other chiral amino alcohols did not show any improvement. " Similar to asymmetric trifluoromethylation with the Ruppert reagent, only the use of a fluoride salt of cinchonine can increase the enantioselectivity. " " ... 

Imines and (Af,(9)-acetals from fluoral are useful precursors of trifluoromethyl nitrogen-containing molecules amines, amino alcohols, amino acids, peptidomimetic units, heterocycles, and so on (Figure 2.50). These simple Af-derivatives of fluoral are easily prepared from the hydrate or the hemiacetal. Imines of fluoral react in [2 + 1 ]... 

Another powerful approach to prepare a-amino acids bearing an aromatic or unsaturated side chain in /I (but also many other compounds) is based on the reactivity of 5-fluoro-4-trifluoromethyloxazole, a starting material easily accessible from hexafluoroacetone. The fluorine atom in the 5 position is easily displaced by an allylic or benzylic alcohol. Then, the obtained ethers spontaneously undergo a Claisen rearrangement to afford, after acidic hydrolysis, an a-trifluoromethyl amino acid... 

Trifluoromethyl /1-thioalkyls and /1-amino alcohols are often good reversible inhibitors of esterases and proteases, respectively. Depending on the enzymes (serine or aspartyl enzymes), fluorinated alcohols are often less efficient inhibitors than the corresponding ketones, which act as analogues of the transition state (vide infra). Nevertheless, fluoroalcohols inhibit hydrolytic enzymes with high inhibition constants (Figure 7.25)." ... 

The Henry nitro-aldol condensation involves the use of P-amino alcohols as the building blocks of fluoromethyl ketones. Although this method has been used extensively in the synthesis of monofluoropeptides (Table 2),19-121 it is more widely utilized as a method for synthesizing trifluoromethyl ketones and the details of the reaction will be discussed in Section 15.1.4.3.2. 

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. 

Asymmetric hydrogenation of either a carbonyl or an imino group to a hydroxyl group or an amino group has frequently been employed for the introduction of chirality in amino acid syntheses. Corey s catecolborane-oxazaborolidine protocol enables transformation of difluoromethyl ketone 1 into alcohol 2 with excellent enantioselectivity. The reaction of diastereoselective amination of a-hydroxyaldehyde 3 with A,A-diallylamine and 2-furyl-boronic acid provides furyl amino alcohol 4 in good chemical yield along with excellent diastereoselectivity. This protocol is applicable for the preparation of amino acids and amino alcohols with a trifluoromethyl group by the combination of /V,/V-diallyl or N,N-dibenzyl amine and aromatic, heteroaromatic and alkenyl boronic acids [7]. The usual chemical transformations as shown in steps 5 to 8 in Scheme 9.1 lead to (2S,3R) difluorothreonine 5 [8]. 

Huguenot, F. and Brigaud, T. (2006) Concise synthesis of enantiopure a-trifluoromethyl alanines, diamines, and amino alcohols via the Strecker-type reaction.. /. Org. Chem., 71, 7075-7078. 

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. 

Table 6.2. Variation of the amines in the 1,3-amino alcohol synthesis by using 4-trifluoromethyl-benzal-dehyde as constant building block...

A synthetic route to the protected trifluoromethyl P-amino alcohol 3 (8) required for the preparation of the trifluoromethyl ketone II is shown in Scheme 1. 2-... 

Cyclohexylpropionic acid was deprotonated with 2.2 equivalent of lithium diisopropylamide and the resulting dianion was condensed with trifluoroacetaldehyde which was generated in situ from its ethyl hemiacetal. The P-hydroxy acid 1 was isolated as a racemic mixture of two diastereomers. Silylation with tert-butyldimethylsilyl triflate was followed by ester hydrolysis to give the acid 2. A Curtius rearrangement with diphenylphosphoryl azide in the presence of benzyl alcohol afforded the protected P-amino alcohol 3 which was used in the preparation of the trifluoromethyl alcohol I. Oxidation using the Dess-Martin periodinane reagent (9) yielded the trifluoromethyl ketone II as a mixture of diastereomers. The signal for the carbonyl carbon in the 13C-NMR spectrum of this ketone appeared at 94.5 ppm and this is consistent with the hydrated form of the trifluoromethyl ketone. 

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