Asymmetric Fluorination Reaction

29 indicated even higher enantioselectivity than its nonfluorinated cousins. The catalyst could be recovered by fluorous solid-phase extraction and reused for up to five times without significant loss of yield and enantioselectivity. 

Gladysz, J.A., Curran, D.P., and Horvdth, I.T. (2004) Handbook of Fluorous Chemistry, Wiley-VCH Verlag GmbH, Weinheim. 

Dordonne, S., Crousse, B., Bonnet-Delpon, D., and Legros, ). (2011) Chem. Commun., 47, 5855-5857. 

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The first asymmetric fluorination reaction using catalytic quantities of an organo-catalyst was reported by Kim in 2002 (Scheme 13.5) [13]. The enantioselective... 

It is noteworthy that Toste and coworkers described the new concept of an anionic phase-transfer catalyst, whereby a chiral phosphate catalyst was used in the asymmetric fluorination reactions. They used selectfluor as a versatile cationic fluorinating agent, which would normally be insoluble in nonpolar organic solvents. 

A fluorous version of the chiral bis-phosphine BINAP has been developed for asymmetric Heck reactions [5], Several fluorous-derivatized binaphthols and BINAP derivatives have been reported, (Scheme 10.4) [6], The silane spacer group present in one of the ligands was used to maximize the percentage fluorine on the molecule. Even so, the partition coefficient1 between FC-72 (see Chapter 3) and benzene was only 2.85, and not surprisingly, the reuse of the catalyst was poor. 

Fluorination of sulfonamides 147 and 148 takes place upon deprotonation with NaH and reaction with perchloryl fluoride, FCIO3, to give products 149 and 150 (Scheme 19) <2000JOC7583, 2000CPB1954>. The resulting A-fluorosultams 149 and 150 have been used for the asymmetric fluorination of aryl ketone enolates (vide infra). 

Both experimental and theoretical studies have been reported of fluoro-denitration and fluoro-dechlorination reactions using anhydrous tetrabutylammonium fluoride in DMSO. The absences of ion pairing and strong solvation are critical in contributing to the reactivity of the fluorinating agent24 Quaternary ammonium salts derived from cinchona alkaloids have been shown to be effective catalysts in an improved asymmetric substitution reaction of /1-dicarbonyl compounds with activated fluoroarenes. The products may be functionalized to yield spiro-oxindoles.25... 

To summarise, the development of novel enantioselective fluorination methods with the aid of either chiral N-fluoro ammonium salts or transition metal catalysts has established truely practical routes towards chiral fluorinated compounds. Despite the current mechanistic uncertaincies it appears that a door has been opened for exciting and promising further development of asymmetric (catalytic) fluorination reactions in the near future [31, 32]. 

Another advantage was conferred by introducing 6,6 -substituents to BINOL. In general, catalytic asymmetric syntheses of fluorine-containing compounds are rather difficult.42 However, an effective asymmetric nitroaldol reaction of the rather unreactive a,ct-difluoro aldehydes proceeded satisfactorily when using the heterobimetallic asymmetric catalysts generated from 6,6 -bis[(triethylsilyl)-ethynyl]BINOL, as shown in Table 5 43 The -configuration of the nitroaldol adduct 71 showed that the nitronate reacted preferentially on the Si face of the... 

Ma JA, Cahard D (2004) Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions. Chem Rev 104 6119... 

The importance of fluorinated organic componnds both in medicinal chemistry and biochemistry has resulted in much recent attention towards efficient carbon fluorine bond formation [30]. The reactions developed include a very successful electrophilic asymmetric mono-fluormation of 1,3-dicarbonyl compounds [31]. A nucleophilic variant was also investigated. In this context, the groups of Togni and Mezzetti have established that ruthenium Lewis acids could efficiently catalyze fluorination reactions [32]. In the presence of [Ru(l,2-bis(diphenylphosphino)ethane)2Cl][PF6] (8) (10 mol%), fert-butyl iodide reacted at room temperature with TIF (1.1 equiv.) to yield fert-butyl fluoride (84% yield). This reaction was extended successfully to a range of organic halides (Entries 1-3, Scheme 10.19). The use of the chiral complex [Ru((lS,2S)-N,N bis[2-diphenylphos-phino)benzylidene]diaminocydohexane))Cl][PF6] (9) showed modest chiral induction at the outset of the reaction (Entry 4, Scheme 10.17). The near-racemic mixture obtained at completion points to an SNl-type process in this nucleophilic halide... 

Mikami, K., Itoh, Y. and Yamanaka, M. (2004) Fluorinated carbonyl and olefmic compounds Basic character and asymmetric catalytic reactions. Chemical Reviews, 104(1), 1-16. 

The LLB type catalysts were also successfully applied in the asymmetric ni-troaldol reaction of quite unreactive a,a-difluoro aldehydes. However, catalytic asymmetric nitroaldol reaction of a broad variety of a,a-difluoro aldehydes proceeded satisfactorily when using the heterobimetallic asymmetric catalysts with modified, 6,6 -disubstituted BINOL ligands [22]. The best results were obtained with the samarium (III) complex (5 mol%) generated from 6,6 -bis[(tri-ethylsilyl)ethynyl BINOL with enantioselectivities up to 95% ee. The ( -configuration of one representative nitroaldol adduct showed that the nitronate reacted preferentially on the Si face of aldehyde in the presence of (P)-LLB (20 mol% 74% yield 55% ee). It is noteworthy that the enantiotopic face selection for a,a-difluoro aldehydes is reverse to that for nonfluorinated aldehydes. The stereoselectivity for a,a -difluoro aldehydes is identical with that of P-oxa-aldehydes, suggesting that the fluorine atoms at the a-position have a great influence on enantioface selection. 

Asymmetric aldolization of a-isocyanoacetamide and fluorinated benzaldehydes has been realized with a gold(I) salt and a ferrocenyl amine-phosphine ligand. (Salen)-Ti complexes serve well in catalyzing the condensation of diketene with aldehydes. " A camphor lactam is an adequate chiral auxiliary as its derived imide undergoes asymmetric aldol reactions. 

Fig. 13 DNA-based asymmetric Diels-Alder, Michael, and fluorination reactions...

Nakamura and co-workers synthesized a heavily fluorinated chiral BINAP, (R)-6,6 - bis(tris (1H, 1 H,2 H,2 H-perfluorooctyl) srlyl]-2,2 -bis (diphenylphosphino)-1,1 -binaphthyl ((R)- FJ3BINAP) (F content = 54%, partition coefficient benzene/FC-72 = 26 74, CH3CN/FC-72 = 2 98) and applied it to an asymmetric Heck reaction [12). The reaction between 2,3-dihydrofuran and 4-chlorophenyl triflate was carried out under the same conditions as those of original nonfluorous reaction by using FjjBlNAP in BTF or benzene to provide the corresponding product, 2-(4-chloro-phenyl)-2,3-dihydrofuran, in 59% chemical yield or in 90% ee and 92% ee, respectively (71% chemical yield and 91% ee in the original reaction in benzene [13]) [Eq. (3)]. 

The asymmetric fluorination of 3-ketoesters has been achieved in 62-90% ee using F-TEDA (Selectfluor) as fluorine source in the presence of 0.5 mol% of the chiral nonracemic titanium-based Lewis acid (5.108). ° A greater range of p-ketoesters are fluorinated with higher ee using catalytic quantities of the palladium-BINAP complex (5.109) and N-fluorobenzenesulfonamide (NFSI). ° In both cases the reaction proceeds through the intermediacy of a chiral enolate. 

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. 

Substitution reactions that generally display poor atom economy are omitted from this discussion. For example, guanidine-catalysed asymmetric fluorination or trifluoromethylation are important reactions, but fluorination and trifluorination reagents typically have high negative contributions to atom economy e.g. fluorine constitutes just 5.4% of Selectfluor s molecular weight). 

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