Fluorinated malonates

Scheme 17. Microbial decarboxylation of fluorinated malonic acids...

The (R,/J)-Ph-DBFOX/Zn(OAc)2 combination is an effective catalyst to give optically pure 2-fluorinated malonates in a process similar to desymmetrization (Scheme 44.21). Although the malonates are nearly symmetrical and less acidic, the enantioselectivities observed in the desymmetrization-like fluorination reaction are high and superior to the corresponding enzymatic methods. This synthetically useful method was applied to the synthesis of pharmaceutically attractive molecules that include a-ben-zyl- 3-alanine, fiuorinated -lactams, fiuoro-alacepril, and a HIV-1 protease inhibitor. ... 

The introduction of fluorine atoms into the substrates indeed brought about a favorable effect on the reaction, as the fluorine atom is strong electron withdrawing and not bulky group (Table 2) [15]. Moreover, a-fluorinated malonic acid (22g) gave the corre-... 

FLUORINECOMPOUNDS,ORGANIC - FLUORINATED AROMATIC COMPOUNDS] (Volll) -malonate derivative TALONIC ACID AND DERIVATIVES] (Vol 15)... 

Hydrogenolysis (23S) of perchloryl aromatic compounds yields ArH and not ArOH, thus confirming the presence of a —Cl bond. Another useful reaction of FCIO3 involves the replacement of the active hydrogens of methylene compounds by fluorine (145, 262, 284). A typical example is the fluorination of malonic esters ... 

Diketones react more rapidly with fluorine than the corresponding keto-esters, and dialkyl malonates do not react at all under these conditions. However, if dialkyl malonates are first converted into their sodium salts, reaction with fluorine gives the corresponding fluoro-compound (Fig. 50) [128]. 

In the next stage the introduction of a fluorine atom onto the chiral center was examined with some 2-fluoro-2-alkyl malonic acid diesters with lipases. When the hydrolysis of 2-fluoro-2-methyl malonic aicd diester was examined with pig... 

Diethyl phenylmalonate and its sodium salt undergo substitutive fluorination by perfluoro-1-fluoropiperidinc (1) and perfluorinated polymers. The fluorination product is diethyl fluoro(phenyl)malonate, perfluoro-l-fluoropiperidine being a more efficient fluorinating agent than the N-F containing fluoropolymers 5. 

Perfluoro[AT-fluoro-Af-(4-pyridyl)acetamide], prepared via direct fluorination of the sodium salt of perfluoro[/V-(4-pyridyl)acetamide], readily fluorinates diethyl sodio(phenyl)malonate, 1-morpholinocyclohexene, phenol and anisole under mild conditions.129... 

Decarboxylation of (bromodifluoromethyl)malonates (9) reminiscent of Krapcho s deal-koxycarbonylation process, is observed on treatment with potassium fluoride in dimethyl sulfoxide at 170 °C to give 2-(trifluoromethyl)-substituted esters 10.43 The precursors are prepared by reacting diethyl malonates 8 with dibromodifluoromethane in the presence of sodium hydride. The exchange of bromine for fluorine in 9 followed by decarboxylation is an excellent method of introducing a trifluoromethyl group a- to an ester group. 

On the other hand, variable yields of fluorinated 2-alkoxy-2//-pyrans 64 were found108,109 in mixtures formed in the reaction of perfluoroalkenes with dialkyl malonates. 

Unsaturatcd carboxylic acids arc selectively hydroxylated on the double bonds. Pentafluoro-prop-1-enyl)malonate is selectively dihydroxylated by potassium permanganate on the fluorinated carbons. The intermediate geminal fluorohydrins 3 immediately eliminate hydrogen fluoride to give dioxo esters, such as 4, as the final product (vide supra).90... 

Initial C-perfluoroalkylation of p diketones occurs during their UV irradiation in the presence of perfluoroalkyl iodides in liquid ammonia Fluorinated enami-noketones are obtained by subsequent ammonolysis of a difluoromethylene group and removal of the acetyl group [131] C-alkylation of dimethyl malonate takes... 

Multinuclear NMR data for homologous senes of fluoromethylated malo-nates [72] and trimethylsilanes [97] are compiled in Table 11. In both senes, fluoromethyl attachment is to a quaternary site These compounds are readily synthesized using fluorohalomethanes to incorporate the final fluoromethyl moiety All the malonates, except diethyl methyltnfluoromethylmalonate (4) [93], are isopropyl-substituted diethyl esters [72]. The silane data, with the exception of trimethyltrifluoromethylsilane (5) [95], are from reference 97 Chemical shift data are very comparable, with the malonates having higher proton and fluorine chemical shifts but slightly lower carbon values. The magnitudes of cf and 2J jp coupling are similar for both sets of compounds. 

Synthesis of Fluorinated Propane-1,3-diol from Alkyl Malonates. . 160... 

Recently, Fukumoto and coworkers used 2,4,6-trimethyl A-fluoropyridinium triflate for obtaining enantiomerically pure fluorinated building blocks. They employed a methyl menthyl malonate in order to induce a diastereomeric excess and indeed obtained a 3 1 diastereoisomeric mixture, which was separated and then either reduced or partially hydrolyzed (equation 198)342. A somewhat different approach was taken by Differding and Lang who used chiral A-fluorosultams to induce for the first time some chirality around 50% ee, when reacted with 2-carboethoxycyclopentanone enolate (equation 199)343. 

Selective fluorination of a wide variety of carbanions has been carried out very effectively with iV-fluoro-Y-alkyl sulfonamides by Barnette63. Treatment of carbanions of malonates, enolates of ketones, acids and amides, and alkyl and aryl organometallics results in the transfer of fluorine from nitrogen to carbon (equation 43). Yields are fair to... 

Because of the inductive and resonance effects of fluorine, the double bond has a very low electron density, especially at the terminal difluoro-methylene group. Dimethyl malonate adds nucleophilically across the double bond. 

The direct fluorination with elemental fluorine at — 78 "C of trimethylsilyl enol ethers derived from diketones results in the formation of the corresponding monofluoro diketones 11 in moderate yield. The trimethylsilyl ethers from cyclic diketones undergo smooth fluorination to give the enol forms, c.g. 12, and not the keto forms.Higher yields are generally observed for the analogous reactions of silyl derivatives of esters, carboxylic acids, malonates, dimethyl amides and lactones (Table 4). ... 

The synthesis of one of the agents begins with nucleophilic aromatic displacement of bromine by cyanide in the highly fluorinated compound 78. Acid hydrolysis of the nitrile (79), followed by esterification of the newly formed acid, affords ester 80. Base-catalyzed condensation of the intermediate with diethyl malonate leads to the tricarbonyl derivative 81. 

After hydrolysis, fluorinated derivatives of alanine are obtained in both cases because decarboxylation of the substituted malonic acid occurs (equation 109)... 

Fluorination of active-methylene compounds. The Pennsalt groups treated diethyl malonate with two equivalents of sodium ethoxide in ethanol and passed in perchloryl fluoride with cooling and reported isolation of diethyl difluoromalonate in... 

Newer QM/MM simulations of the electrophilic fluorination of a malonate coordinated to a titanium center with a simplified Selectfluor (F-TEDA) analog [189] throw a new light on the electron transfer/fluorine transfer mechanism. During the approach of the electrophilic fluorine toward the carbon nucleophile an electron is transferred from the nucleophile to Selectfluor, then fluorine is transferred to the nucleophile. Interestingly, the transition state for transfer of the fluorine radical is formed only if a polar solvent (acetonitrile) is used. If the simulation is carried out in vacuo, the reaction stops after the initial electron transfer. 

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