Aldehydes a-trifluoromethylation

The numerous preparations of mono-, di-, tri-, and hexafluoro derivatives of valine, norvaline, leucine, norleucine, and isoleucine, using classical methods of amino acid chemistry (e.g., amination of an a-bromoacid, " azalactone, Strecker reaction, amidocarbonylation of a trifluoromethyl aldehyde, alkylation of a glycinate anion are not considered here. Pure enantiomers are generally obtained by enzymatic resolution of the racemate, chemical resolution, or asymmetric Strecker reaction. ... 

Conjugate addition reactions to enantiomerically pure tolylsulfinyl trifluoro-propene were used recently to prepare a-trifluoromethyl aldehydes [249]. Conjugate adducts were elaborated by Pummerer rearrangement of the sulfoxyl group to install the aldehydic carbonyl (Eq. 83). 

Furthermore, the group of MacMillan extended the present photocatalytic protocol to the trifluoromethylation using CF3I (2a) as a CF3 source and a strongly reducing Ir photocatalyst, leading to the synthesis of valuable enantioenriched a-trifluoromethylated aldehydes 5 (Scheme 3) [34]. In this reaction, the Ru catalyst, [Ru(bpy)3], also afforded the product but in a lower yield. 

Allen and MacMillan demonstrated the introduchon of a trifluoromethyl group at the a-position of enolizable aldehydes by a simple deployment of the corresponding iodonium salts [41]. Enamines of enolizable aldehydes and chiral imidazolidin-4-ones react with trifluoromethyl-benziodoxole in the presence of catalytic amounts of Lewis acids to give a-trifluoromethylated aldehydes with high degrees of enantioselectivities (Scheme 4.11). 

In similar work, CF3CCI2CO2CH3 yields methyl a-trifluoromethyl-a,(i-un-saturated carboxylates when reacted with a zinc-copper couple, aldehydes, and acetic anhydride [67] (equation 55). This methodology gives (Z)-a-fluoro-a- -un-saturated carboxylates from the reaction of carbonyl compounds with CFCI2CO2CH3 and zinc and acetic anhydride [6 ]. 

To overcome these problems with the first generation Brmsted acid-assisted chiral Lewis acid 7, Yamamoto and coworkers developed in 1996 a second-generation catalyst 8 containing the 3,5-bis-(trifluoromethyl)phenylboronic acid moiety [10b,d] (Scheme 1.15, 1.16, Table 1.4, 1.5). The catalyst was prepared from a chiral triol containing a chiral binaphthol moiety and 3,5-bis-(trifluoromethyl)phenylboronic acid, with removal of water. This is a practical Diels-Alder catalyst, effective in catalyzing the reaction not only of a-substituted a,/ -unsaturated aldehydes, but also of a-unsubstituted a,/ -unsaturated aldehydes. In each reaction, the adducts were formed in high yields and with excellent enantioselectivity. It also promotes the reaction with less reactive dienophiles such as crotonaldehyde. Less reactive dienes such as isoprene and cyclohexadiene can, moreover, also be successfully employed in reactions with bromoacrolein, methacrolein, and acrolein dienophiles. The chiral ligand was readily recovered (>90%). 

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56).135 Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated (i-airiinoalcohols stereoselectively.136 Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57).137 Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58).138 Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

A trifluoromethyl anion is also difficult to generate because it easily lose a fluoride ion to form difluoro carbene. Shono and Kashimura et al have similarly achieved the generation of such a species from trifiuoromethane using the electrogenerated a-pyrrolidone anion. The efficient trifluoromethylation of aldehydes and ketones in the presence of hexamethyldisilazane (HMDS) can thus be obtained (Scheme 4.3) [32]. 

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. " " ... 

Scheme 6 Synthesis of a Trifluoromethyl Ketone by Reaction of an Organometallic Reagent with a Simple Fluorinated Aldehyde 281...

The reaction of peptide aldehydes with ICF Zn has the obvious advantage that it allows the stereoselective synthesis of trifluoromethyl ketones since it avoids the use of an achiral carbanion in the carbon bond forming step, a requirement for the previously discussed synthetic procedures. In this method, a trifluoromethyl anion equivalent is reacted with a peptide aldehyde, which already contains the chiral a-carbon (Scheme 7). Provided the... 

Treatment of trifluoromethyl(trimethyl)silane with fhe fused salt gives the tri-fluoromefhyl anion-equivalent species. This adds to the aldehyde in good yield to form fhe alcohol wifh a trifluoromethyl group (Scheme 2.11). 

An oxidative decarboxylation at ambient temperature is that of the a-hy-droxy, a-trifluoromethyl acids or esters to the corresponding trifluoromethyl-ketones, using bidentate Co-amide catalysts, with yields >80%. Again, these are slow reactions requiring relatively low reactant/catalyst ( 25/1) ratios, and an aldehyde promoter which is partly oxidized itself. 

Nucleophilic attack of t-BuO anion on carbon, sulfur, or silicon conqiounds such as TMSCP3, 4 secondary trifluoroamides and trifluoroacetates, secondary trifluoromethanesulfinamides and trifluoromethanesulfinates, and trifluoromethyl sulfoxides and sulfones allows the transfer of a trifluoromethyl carbanion to various electrophilic acceptors, such as nonenolizable ketones and aldehydes (eq 54). ... 

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