Fluorination, asymmetric

Chiral organofluorine compounds containing a fluorine atom bonded directly to a stereogenic center have been used in a variety of research investigations, including mechanistic studies of enzymes and intermediates in the asymmetric synthesis of bioactive compounds. The development of effechve methodologies for the 

Kim and coworkers reported the asymmehic fluorinahon of P-keto phospho-nates in ionic liquids using palladium complex 46 as a catalyst [74]. The fluorinahon of P-keto phosphonate with NFSI in the presence of 5mol% of 46 in [bmim][BF4] at room temperature produced a fluorinated product in 95% yield with 93% ee. The chemical yield and enantioselechvity were quite similar to those obtained in MeOH (8h, 93%, 97% ee). Moreover, the catalyst immobilized in the ionic liquid layer was recycled seven times without any obvious loss in yield or 

A wide variety of catalytic asymmetric transformations have been achieved in the above investigations, which clearly indicates that quaternary ammonium salts derived from cinchona alkaloids are still powerful reagents, despite their limited structural diversity. Moreover, as PTC chemistry has been recognized as a highly practical approach, further progress should be expected in this area of research. 

3 Shioiri, T. and Arai, S. (2000) Stimulating Concepts in Chemistry (eds F. Vogde, J.F. Stoddart and M. Shibasaki), Wiley-VCH, Germany, pp. 123-143. 

28 Arai, S. Hasegawa, K. Nishida, A. (2004) Tetrahedron Lett. 45, 1023-1026 (2005) Tetrahedron Lett. 46, 6171. 

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The asymmetric fluorination of enolates by means of chiral metal complexes has been reported with Selectfluor in the presence of a chiral Lewis acid derived from TADDOL (TiCl2/TADDOL), or with F-A-sulfonimide (NFSI) with palladium complexes and chiral phosphines. 

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). 

Asymmetric fluorination of the lithium enolate derived from tetralone 307 has been achieved with several new chiral A-fluoro-l,2-benzothiazine reagents (Scheme 44) <2000JOC7583, 2000CPB1954, see also 1999JFC(97)65>. For instance, sulfonamides 149 and 150 afford the opposite enantiomers of fluoroketone 308 in up to 79% yield and 62-70% ee. 

Often, however, there is insufficient molecular mobility in the solid state for asymmetric fluorine placement to significantly increase the dielectric constant. Below the glass transition temperature, only restrained local motions are possible, and below subglass relaxations such as the P relaxation in polyimides, even these limited motions are virtually eliminated, rendering orientation polarization negligible. 

Table 16. Asymmetric Fluorination of Enolates with A -Fluorocamphorsultams 2a-c...

The enantioselective a-fluorination of carbonyl compounds has been highlight- ed.i50- 52 The catalytic asymmetric fluorination of various substrates has also been reviewed.153,154... 

The asymmetric fluorination of /3-keto esters has been performed in the presence of various catalysts, such as CpTiCl3,155 chiral rare earth perfluorinated organophos- phates,156 and chiral palladium complexes.157... 

Interestingly, cyclic / -keto esters, e.g. 69, can be also fhiorinated with enantioselectivity up to 80% ee, although the yield and enantioselectivity depend strongly on the type of substrate. A representative example of asymmetric fluorination of a cyclic ester is shown in Scheme 3.27, Eq. (2). In addition, oxindoles 71 have been successfully fhiorinated, as shown in Scheme 3.27, Eq. (3). Under optimized conditions, the desired 3-substituted 3-fluorooxindole, 72, was obtained in 79% yield and with enantioselectivity of 82% ee. 

A first attempt to realize catalytic asymmetric fluorination under phase transfer conditions goes back to attempts by Cahard et al. [20] Quaternary ammonium salts of cinchona alkaloids were used as catalysts in the presence of TosNFtBu as F-source and 23 was employed as substrate. Unfortunately, enantioselectivities remained rather low. Very recently, Kim and Park have described a closely related system (Scheme 4) [21]. 

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

Steiner DD, Mase N, Barbas CF 3rd (2005) Direct asymmetric—fluorination of aldehydes. Angew Chem Weinheim Bergstr Ger 117 3772-3776 Stetter H (1976) Die katalysierte Addition von Aldehyden an aktivierte Doppel-bindungen-Ein neues Syntheseprinzip. Angew Chem Weinheim Bergstr Ger 88 695... 

A -Fluoro-dihydrobenzo[l,2-i isothiazole is an efficient agent for electrophilic asymmetric fluorination of enolates <1999JOG5708>. A -Fluoro-2,10-camphorsulfonamide 237 (see Section 4.05.6.4.2) is a good asymmetric reagent for a-fluorination of ketones <1998JOG9604>. 

Electroreductive asymmetric alkylation [480,481] and electrooxidative asymmetric fluorination [482,483] of chiral substrates have been reported. 

The asymmetrical, fluorine-containing carbonyl halides, COXF (X = Cl, Br or I) were first prepared and examined by Kwasnik at I.G. Leverkusen (a part of I.G. Farbenindustrie) during World War II. This work was later disclosed by RUdorff [1751], and by Fischer [656a] in the enemy-property confiscation reports, known as the FIAT Reviews of German Science. 

Reviews (a) F. A. Davis, H. Qi, G. Sundarababu, Asymmetric Fluorination in Enantiocontrolled Synthesis of Fluoro-Organic Compounds Stereochallenges and Biomedical Targets (V A. Solosho-nok Ed.), John Wiley and Sons, New York, 1999 (b) G. Resnati, Tetrahedron 1993, 49, 9385. 

Figure 9.4. Polymers with very large dielectric constants caused by asymmetric fluorination. (a) Poly(vinylidene fluoride), where the fluorine substitution is symmetric at a given C atom, but asymmetric (alternating) along the chain, (b) Poly[oxy(methyl y-trifluoropropylsilylene)].

Asymmetrically fluorinated poly(vinyl fluoride) and poly(vinylidene fluoride), whose electrical properties differ qualitatively from general trends for polymers (Section 9.B). 

Asymmetric fluorine-containing /1-diketones (01IZV643, 94JFC(67)87) on interaction with 2-cyanoacetamide in the presence KF give 3-cyano-2-pyridones in useful yields only with short polyfluoroalkyl chains (CF2H, CF3) the yield of the tetrafluoroethyl derivative was only 20%, and the octafluorobutyl —4% (Scheme 44). 

Fluorination of enolates. Asymmetric fluorination is observed in moderate yields and enantiomer excesses with reagent (1). 

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. 

Scheme 16.42 Asymmetric fluorination using new fluorinated Cinchona-derived...

Recently, the Sun group reported that N-heterocyclic carbenes catalysed the asymmetric fluorination of azoliumenolates, which were generated from readily available simple aliphatic aldehydes. The process provided facile... 

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). 

Shibata s Cinchona alkaloid-mediated asymmetric fluorination of oxindoles was used in the first enantioselective synthesis of BMS-204352 (MaxiPost), a potent opener of maxi-K channels developed by Bristol-Myers Squibb Pharmaceutical Research Institute for the treatment of acute ischemic stroke [7]. The Togni group [8] developed a similar method for the asymmetric fluorination of another class of substrates with activated methylene groups, a-nitroesters however, usefiil levels of enantioinduction were not obtained. 

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

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