Fluorination p-ketoester

Ethoxycarbonylmethenyltriphenylphosphorane reacts with fluorinated nitriles to form intermediate R, which is hydrolyzed to the fluorinated p-ketoester S. Explain the sequence of reactions leading to these products. 

It should be noted that the reaction outcome depended strongly on the solvent. In particular, a mixture of 716 and 717 was obtained by healing the starting materials in EtOH instead of AcOH, 717 still being the major isomer (717 716=70 30) [419]. These data show that the structures of the products in the reactions of fluorinated P-diketones 699 with amino azoles should be checked carefully in each particular case, especially for the early reports in this area. It is interesting to note, that opposite regioselectivity (confirmed by X-Ray) was observed in the case of fluorinated p-ketoesters (Table 34, Entries 13-15) [432]. 

Cinchona-based organocatalysts with a guanidine functionality were studied by Lu and coworkers [93] and by the group of Park [94]. In the former study, several guanidines derived from quinidine were synthesized and observed to catalyze the asymmetric amination reaction of a-fluorinated P-ketoesters (Scheme 6.44). 

The fluorination of P-diketones and p-ketoesters with N-/luorobis(trifluo-romethanesulfonyl)imide (Table 3a, B) can be controlled to give either mono-fluorination or difluorination. Monofluorination occurs when the strong acid, bis(trifluoromethanesulfonyl)imide, a reaction product, is removed by addition of water, which prevents further enolization and fluormation of the monofluoro adduct [83] (equation 38)... 

This microflow processing was also demonstrated using other P-keto esters such as ethyl 2-chloro-3-oxobutanoate [309,273] or ethyl 2-methyl-3-oxobutanoate [273]. Five-and six-ring P-ketoester derivatives such as 3-acetyl-3,4,5-trihydrofuran-2-one (1) [273], 2-acetyl cyclohexanone [273] and ethyl 2-oxocydohexane carboxylate (2) [273] were directly fluorinated as well. 

Fluorination of -Ketoester Enolates. (+)-N-Fluoro-2,10-(3,3-dichlorocamphorsultam) (1) is reactive towards the enolates generated from p-ketoesters. Thus, treatment of the sodium enolate of 8 with (+)-l afforded the desired product 9 in 95% isolated yield and 46% ee with undetermined stereochemistry (eq 4). Reduced yields and enantioselectivities were noted under similar conditions for (-)-N-fluoro-2,10-camphorsultam (28% yield, 25% ee). ... 

The importance of a-fluoro-p-ketoesters stems from their use as synthons in the preparation of biologically active monofluorinated heterocycles(45) and fluorinated isoprenyl derivatives (46) which have found application as hyperlipidemic drugs (47), as hormone substitutes (48), and in cancer chemotherapy (49). 

Several routes to this class of compounds have been reported, such as (a) crossed Claisen condensation reactions (50-53) (b) acylation of the anion derived from ethyl fluoroacetate (54) or self-condensation of the anion derived from ethyl bromofluoroacetate (55) (c) electrophilic fluorination of the anion of p-ketoesters (56,57) (d) acylation-hydrolysis of fluoroolefins (58) and (e) acylation of fluorine-containing ketene silyl acetals (Easdon, J.C., University of Iowa, unpublished data). The limitations associated with these methods and the success achieved in the alkylation-hydrolysis of a-fluoro phosphorus ylides prompted us to examine acylation-hydrolysis of these a-fluoro ylides as a general route to 2-fluoro-3-oxoesters. 

Fluorides. This stable, crystalline reagent (1) is derived from the artificial . v eetener Acesulfam. It fluorinates enolates of P-ketoesters and malonic esters, as well as pnol acetates and anisoles. 

Using the same catalytic system, the electrophilic fluorination of aromatic P-ketoesters was also reported [154]. After optimization of the reaction conditions, the prodncts conld be isolated with ees up to 74%, the (R) enantiomer being in excess. 

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. 

Akiyama developed an enantioselective fluorination of indanone-derived p-ketoesters 63 with Af-fluorobis(phenylsulfonyl)amine (NFSI, 64) with the use of ehiral phosphorie acid 62 and Na2COs (Scheme 2.38). The simultaneous formation of the sodium enolate from 63 and chiral sodium phosphate from 62 under basie eonditions was the key to achieving high yield... 

Scheme 2.38 Enantioselective a-fluorination of p-ketoesters with the use of chiral sodium(i) phosphate.

Using chiral palladium enolates (143) as key intermediates, efficient catalytic enantioselective fluorination reactions of P-ketoesters and P-ketophosphonates (144) gave fluorinated products (145) (Scheme 51). ... 

Catalytic asymmetric halogenation reactions are still rarely studied. Togni et al. developed the efficiency of [Ti(TADDOLato)] complexes 18 in combination with the fluorinating agent Selectfluor in the catalytic fluorination of P-ketoesters. In 2004, this group executed the asymmetric chlorination of P-ketoesters using titanium complexes 18 with (dichloroiodo)toluene to generate enantiomerically enriched a-chlorinated products 19 (Scheme 5) [35]. 

These ligands were initially tested in the nickel(ll)-catalyzed enantioselec-tive fluorination of oxindoles and P-ketoesters, yielding the corresponding products with enantioselectivities of up to >99% ee and high yields. Application of the chiral pincer ligands in the chromium-catalyzed enantioselective Nozaki-Hiyama-Kishi reaction of aldehydes gave the corresponding alcohols with a maximum enantioselectivity of 93% [34]. 

Electrophilic fluorination of 1,3-dicarbonyl compounds, in particular P-ketoesters, has been the focus of several studies [281]. The reaction usually involves the formation of corresponding enol (or enolate) form of the substrate. Substoichiometric amounts of Lewis acid can significantly accelerate product formation, presumably by facilitating the enolization process [281aj. 

Trifluoroacetamidine (585) is most widely used for the principal synthesis of pyrimidines. Compound 585 can be prepared from ethyl trifluoroacetate by ammo-nolysis, followed by dehydration with P2O5 and reaction with ammonia (Scheme 124) [335,336]. Amidine 585 has been introduced into reaction with various p-dicarbonyl compounds and their synthetic equivalents (Table 27), including p-ketoesters (Entries 1-6), in particular p-ketopyruvates (Entry 3) and a-alkoxymethylene-p-ketoesters (Entries 4-6), p-enaminocarbonyl compounds (Entries 7-9), malonic acid derivatives (Entry 10), fluorinated p-diketones (Entry 11), vinamidinium salts (Entry 12), a,p-unsaturated nitriles with leaving group at p position (Entries 13-15) and other bis-electrophiles (Entries 16, 17). Usually, the reaction gives moderate yields of the target 2-CF3-pyrimidines (ca. 50 %). 

More than a third part of all the described principal syntheses of pyrimidines bearing fluorinated alkyl at C-4 atom commences from fluorinated p-dicarbonyl compounds 699. The chemistry of these bis-electrophiles was reviewed recently [411, 412] therefore, their preparation is not discussed herein. This synthesis of pyrimidines is fairly general (Table 34) it allows for introducing aliphatic, alicyclic and aromatic p-diketones (Entries 1-10), p-ketoesters (Entries 11-16), and cyclic P-ketoamides (Entry 17). Presence of some functional groups, such as additional ester moiety (Entry 15), is more or less tolerated, whereas increasing steric hindrance results in lowered yields of the products (Entry 10). A scope of conunon NCN binucleophiles include amidines (Entries 1, 11, 12, 17), (thio)urea and its derivatives (Entries 2-4), guanidines (Entries 5,16) and biguanides (Entry 6). Electron-rich amino heterocycles e.g. aminoazoles and even 2,6-diaminopyridine) are excellent NCN binucleophiles for the principal synthesis of fused pyrimidine derivatives (Entries 7-10, 13-15). 

The method was extended to other classes of fluorinated p-dicarbonyl compounds, including p-ketoesters (Table 42, Entry 1), p-diketones (Entry 2), P-ketosulphones (Entry 3), p-ketosulphamides (Entry 4), and p-ketophosphonates (Entries 5 and 6). It should be noted that in case of some p-diketones (i.e. 1,1,1,5,5,5-hexafluoroacetylacetone), the products of principal pyrimidine synthesis were formed instead of Biginelli adducts under reaction conditions [568]. Apart from urea and thiourea, other classes of NCN binucleophiles were also introduced, including A-alkylureas (Entries 7 and 8, note different stereochemistry of the products), aminotriazoles (Entries 9 and 10), aminotetrazole (Entry 11), and 2-aminobenzimidazole (Entry 12). 

Hara S, Sekiguchi M, Ohmori A, Fukuhara T, Yoneda N (1996) Selective fluorination of P-ketoesters using iodotoluene difluoride and a HF-amine complex. J. Chem. Soc. Chem Comm 16 1899-1900... 

Kawatsura M, Hayashi S, Komatsu Y, Hayase S, Itoh T. Enantioselective a-fluorination and chlorination of p-ketoesters by cobalt catalyst. Chem. Lett. 2010 39(5) 466 67. 

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