Aldehydes enantioselective fluorinations

The organocatalyst-based a-functionalisation strategy has been applied with much success to the asymmetric halogenation of aldehydes. The imidazolidi-none salt (5.110) has been used by MacMillan and coworkers, in combination with NFSI, to effect enantioselective fluorination of a range of aldehydes, for example (5.111). ... 

Rovis and co-workers have also extended the intermolecular Stetter reaction to inclnde nitroaUcenes as the electrophilic component. Fluorinated triazolinm precatalyst 155 was effective in catalysing the reaction of a variety of heteroaromatic aldehydes 153 with nitroalkenes 154 to generate P-nitroketones in excellent yields and enantioselectivities. The authors propose that stereoelectronically induced conformational effects on the catalyst skeleton are key to the high selectivities observed with flnorinated catalyst 155 (Scheme 12.33) [69],... 

The heterobimetallic asymmetric catalyst, Sm-Li-(/ )-BINOL, catalyzes the nitro-aldol reaction of ot,ot-difluoroaldehydes with nitromethane in a good enantioselective manner, as shown in Eq. 3.78. In general, catalytic asymmetric syntheses of fluorine containing compounds have been rather difficult. The S configuration of the nitro-aldol adduct of Eq. 3.78 shows that the nitronate reacts preferentially on the Si face of aldehydes in the presence of (R)-LLB. In general, (R)-LLB causes attack on the Re face. Thus, enantiotopic face selection for a,a-difluoroaldehydes is opposite to that for nonfluorinated aldehydes. The stereoselectivity for a,a-difluoroaldehydes is identical to that of (3-alkoxyaldehydes, as shown in Scheme 3.19, suggesting that the fluorine atoms at the a-position have a great influence on enantioface selection. 

Fluorine-containing compounds can also be synthesized via enantioselective Reformatsky reaction using bromo-difluoroacetate as the nucleophile and chiral amino alcohol as the chiral-inducing agent.86 As shown in Scheme 8-41, 1 equivalent of benzaldehyde is treated with 3 equivalents of 111 in the presence of 2 equivalents of 113, providing a,a-difluoro-/ -hydroxy ester 112 at 61% yield with 84% ee. Poor results are observed for aliphatic aldehyde substrates. For example, product 116 is obtained in only 46% ee. 

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). 

Direct enantioselective catalytic a-fluorination of aldehydes has been carried out using jV-fluorobenzenesulfonimide [F-N-(02SPh)2] and a chiral secondary amine (an imidazolidinone) to provide enamine organocatalysis.295... 

In this chapter, we will outline the application of organocatalysis for the enantio-selective a-heteroatom functionalization of mainly aldehydes and ketones. Attention will be focused on enantioselective animation-, oxygenation-, fluorination-, chlorination-, bromination-, and sulfenylation reactions catalyzed by chiral amines. The scope, potential and application of these organocatalytic asymmetric reactions will be presented as the optically active products obtained are of significant importance, for example in the life-science industries. 

Various chiral amines can catalyze the direct enantioselective a-fluorination of aldehydes. Enders and Hiittl have focused on the use of Selectfluor for the a-fluorination of aldehydes and ketones [24a], For the aldehydes, no enantiomeric excess was reported using L-proline as the catalyst. In an attempt to perform direct enantioselective a-fluorination of ketones, cyclohexanone was used as the model substrate and a number of chiral amines were tested for their enantioselective properties however, the enantiomeric excess was rather low and in the range of 0 to 36% ee. 

Scheme 2.33 Direct enantioselective a-fluorination of aldehydes catalyzed by (S)-2-[bis(3,5-bistrifluoro-methylphenyl)trimethyl-silanyloxymethyljpyrrolidine 3b and the salt of imidazolidinone compound 3g.

Beeson TD, MacMillan DWC (2005) Enantioselective organocatalytic alpha-fluorination of aldehydes. J Am Chem Soc 127 8826-8828 Berkessel A, Groger H (2005) Asymmetric organocatalysis. Wiley-VCH, Weinheim... 

Optically active fluorine-containing alcohols (91-93% ee) (entries 12 and 13) and deuterio alcohols (84-94% ee) (entries 14 and 15) are synthesized, respectively, by the enantioselective alkylation of fluorine-containing aldehyde and deuterio aldehyde using DBNE. 

Ohno et al. developed an enantioselective alkylation by the use of a C2-sym-metric disulfonamide as a chiral ligand[ 19,20,21 ]. They designed the chiral catalyst based on the concept that coordination of an electron-withdrawing chiral ligand to the Lewis acid, Ti(0-z-Pr)4, enhances the catalytic activity. Actually, the acidity of the disulfonamide has an influence on the enantioselectivity and fluorine-containing disulfonamides, especially trifluoromethylsulfonamide, were found to be the best choice of chiral catalyst (Scheme 7). It should be noted that a decrease in the amount of chiral ligand from 0.02 equiv. to 0.0005 equiv. has no effect on the yield and ee and the turnover reached 2,000. Also in the alkylation of aliphatic aldehydes, very high enantioselectivities can be attained. 

The LLB type catalysts were also successfully applied in the asymmetric nitroaldol reaction of the quite um-eactive a,a-difluoro aldehydes. In general, catalytic asymmetric syntheses of fluorine-containing compounds are rather difficult [32]. However, catalytic asymmetric nitroaldol reaction of a broad variety of a,a-difluoro aldehydes 20,22,24,26,28, and 30 proceeded satisfactorily when using the heterobimetallic asymmetric catalysts with modified, 6,6 -disubstitut-ed BINOL ligands [33] (Scheme 7). The best results were obtained with the sa-marium(III) complex (5mol%) generated from 6, 6 -bis (triethylsilyl)ethy-nyl BINOL with enantioselectivities up to 95% ee. 

Notably, for linear-chained aldehydes, imidazolidinone-derived catalysts gave the highest enantioselection (88% ee). The use of NFSI provided access to quaternary a-fluoroaldehydes in high yields and modest enantio-selectivies using proline, albeit several other organocatalysts were more promising in accessing enantiopure fluorinated-substrates. 

The 1,2,3-triazole-linked fluorous proline organocatalyst 32 was introduced by Pericas and coworkers in 2013 for the asymmetric aldol reactions of acetone with aromatic aldehydes, giving higher enantioselectivities than other proline derivatives (Scheme 11.27). ° The fluorous tag and the use of a per-fluorinated solvent allowed the easy recycling and reuse of 32, for at least six times. 

The asymmetric electrophilic a-fluorination of aldehydes with 2,5-disub-stituted pyrrolidines was tested independently by Jorgensen and Barbas III, but in these reactions MacMillan s imidazolidinones (Chapter 18) or diatylprolinol silyl ethers (Chapter 8) afforded much better yields and higher enantioselectivities. 

In 2009, the Rovis group disclosed a remarkable study on the asymmetric intermoleeular Stetter reaction with heteroaromatic aldehydes and p-alkyl substituted nitroalkenes in excellent enantioselectivity. With the novel backbone-fluorinated NHC initially developed by their group, the Stetter reaction products were afforded with up to 99% yield and 96% ee. With detailed conformational analysis of the catalyst and DFT calculations, the authors demonstrated that the gawcAe-effect from the fluorine on the five-membered backbone of the catalyst plays a crucial role on increasing the enantioselectivity dramatically (Scheme 7.29). 

Houk, Rovis, and their co-workers later extended the scope of the asymmetric intermolecular Stetter reaction of p-nitrostyrenes to unactivated aliphatic aldehydes, which have rarely been utilized in this reaction due to their relatively lower electrophilicity compared with aryl aldehydes. Comparing to known scaffolds, tert-leucine derived trans-fluorinated catalyst leads to improved reactivity and enantioselectivity in this transformation. Computational studies show that the optimized catalyst is the most stereoselective one because the Re-face attack is stabilized by favorable electrostatic interactions between the phenyl group and the fluorine on the catalyst backbone (Scheme 7.31). 

---