Trifluoromethylation of aldehydes

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

The reactions appear to be similar to organometallic synthesis, where the reduction is performed by the metal instead of electricity. However, these reactions have been shown to be essentially different from the corresponding organometallic reactions. This method has valuable advantages. As the anode reaction is controlled, an undivided cell can be used, the reaction occurs in one-step, the conditions are quite simple, and so on. Sibille and Perichon et al. have found that the sacrificial zinc anode is quite effective for trifluoromethylation of aldehydes to form trifluoromethylated alcohols in almost quantitative yields (Eq. 6) [19]. The reaction proceeds via the reduction of Zinc(II) salts, followed by a chemical reaction between the reduced metal, CF3Br, and aldehyde. 

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 been shown that the tetrahedral oxyanion formed on addition of the conjugate base of fluoroform to solvent DMF acts as a masked form of FsC with which to effect trifluoromethylation of aldehydes. " ... 

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. 

Iseki, Nagai, and Kobayashi prepared cinchonine-derived 4f and 4g from the corresponding bromides by the method B (Scheme 9.5), and realized the asymmetric trifluoromethylation of aldehydes and ketones with trifluoromethyltrimethylsilane (Me3SiCF3) catalyzed by these ammonium fluorides (Schemes 9.9 and 9.10) [19]. Although the enantioselectivities are not sufficiently high, this reaction system should offer a new access to various chiral trifluoromethylated molecules of analytical and medicinal interests through appropriate modifications. 

A procedure for alkylation of C=0 double bonds in the presence of (metal-free) organocatalysts and non-metallic nucleophiles has been reported by the Iseki group for trifluoromethylation of aldehydes and ketones [185]. On the basis of a previous study of the Olah group [186, 187] which showed the suitability of non-chiral phase-transfer catalysts for trifluoromethylation of carbonyl compounds, Iseki et al. investigated the use of N-benzylcinchonium fluoride, 182, as a chiral catalyst. The reaction has been investigated with several aldehydes and aromatic ketones. Trifluoromethyltrimethylsilane, 181, was used as nucleophile. The reaction was, typically, performed at —78 °C with a catalytic amount (10-20 mol%) of 182, followed by subsequent hydrolysis of the siloxy compound and formation of the desired alcohols of type 183 (Scheme 6.82). 

The trifluoromethylation of aldehydes from CF3Br6 can also be well conducted electrochemically in DMF in the presence of a zinc anode (Equation 8.7, Protocol 2). Again yields are higher than those obtained using activated zinc. 

TBAF-assisted Trifluoromethylation, Perfluoroalkylation, and Polyfluoroalkoxylation. TBAF combines with TMSCF3 to form nucleophilic trifluoromethyl anion equivalents. The precise structure of this nucleophile is unknown, although it is likely that a pentacoordinate silicon intermediate is involved. The TBAF/TMSCF3 combination leads to smooth trifluoromethylation of aldehydes,ketones, esters, imines, nitroso compounds, a-ketoesters, Q -ketoamides (eq and... 

Scheme 2.31 Enantioseleetive trifluoromethylation of aldehydes with the use of chiral sodium(i) hinaphtholate and quinidine-derived chiral quaternary ammonium salt.

This scheme can be used in general to describe three catalytic transformations reported by MacMillan the enantioselective a-trifluoromethylation of aldehydes using the Togni reagent, the enantioselective a-aiylation of aldehydes, and the enantioselective ot-vinylation of aldehydes. ... 

Trifluoroacetaldehyde hydrate, F3C-CH(OH)2, has been used as a trifluoromethyl source for nucleophilic trifluoromethylation of aldehydes and ketones, including hindered cases such as adamantanone. Using DMF solvent at -50 C, potassium t-butoxide is used to form the dianion of the hydrate, delivering trifluoromethyl anion, with significant stabilization by the solvent. 

Nagib DA, Scott ME, MacMillan DWC (2009) Enantioselective a-trifluoromethylation of aldehydes via photoredox organocatalysis. J Am Chem Soc 131 10875-10877... 

Table 6.2 Trifluoromethylation of aldehydes with Ruppert s reagent — selected examples.

Scheme 4.10 gives an insight into this reaction mechanism. It is supposed that the electron-rich iridium-complex Ir(ppy)2(dtb-bpy) generates the electrophilic tri-fluoromethyl radical via a single-electron transfer. This trifluoromethyl radical reacts with the enamine of the organocatalyst 7 and enoUzable aldehydes highly enantioselectively. The second catalytic cycle, the photoredox cycle, was reaUzed by oxidation/reduction processes of transition metal complexes with the aid of light, as depicted in Scheme 4.10 for the trifluoromethylation of aldehydes. 

Scheme 4.10 Proposed reaction mechanism for the trifluoromethylation of aldehydes.

Imidazolidinone catalysis was also coupled with Lewis acid catalysis to effect trifluoromethylation of aldehydes (Scheme 15.108). In this instance the Lewis acid was required to activate the trifluoromethyl bearing Togni s reagent, a suitable electrophile for the reaction process. It was found that the best yields and enantiomeric excesses were obtained when copper(i) chloride was used. 

Scheme 15.107 Enantioselective trifluoromethylation of aldehydes mediated by coupled photoredox/organocatalysis.

The trifluoromethylation of aldehydes with CF3Br can also be conducted elec-trochemically in DMF in the presence of a zinc anode. However, it is worth noting that CF3ZnBr and (CF3)2Zn species, which are stable, have been found to show a lower reactivity towards carbonyl compounds (aldehydes and ketones) than the transitory species denoted CF3Zn stemming from the electroreduction of CF3Br in the presence of the substrate (Scheme 15.3) [7]. 

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