Fluorination ester enolates,

Because of thetr electron deficient nature, fluoroolefms are often nucleophihcally attacked by alcohols and alkoxides Ethers are commonly produced by these addition and addition-elimination reactions The wide availability of alcohols and fliioroolefins has established the generality of the nucleophilic addition reactions The mechanism of the addition reaction is generally believed to proceed by attack at a vinylic carbon to produce an intermediate fluorocarbanion as the rate-determining slow step The intermediate carbanion may react with a proton source to yield the saturated addition product Alternatively, the intermediate carbanion may, by elimination of P-halogen, lead to an unsaturated ether, often an enol or vinylic ether These addition and addition-elimination reactions have been previously reviewed [1, 2] The intermediate carbanions resulting from nucleophilic attack on fluoroolefins have also been trapped in situ with carbon dioxide, carbonates, and esters of fluorinated acids [3, 4, 5] (equations 1 and 2)... 

Equations 36-39 suggest that fluorine substituents at the a position of the ester enolate play a role in favouring the formation of /J-arnino esters. This conclusion is supported by the condensation of the Reformatsky reagent deriving from 20 with imines, the only product being the open-chain adduct 63 (equation 40)123. 

Conjugate addition reactions to the E-alkenoate proceeded fruitfully [293]. Remarkably, ketone enolates added to the alkenoate (Eq. 106) to afford the Michael adducts in the absence of the three fluorine atoms, the retro-Michael reaction dominates, because a ketone enolate is more stable that the ester enolate generated by the conjugate addition process therefore some special driving... 

The reaction of a citronellic ester enolate with electrophilic agents gives open-chain fluorinated products 32 and 33 only.11 The absence of rearranged fluorinated products in this system, a potential precursor to a 5-hexenyl-type radical clock, indicates that free radicals are not intermediates in the path to fluorinated products.12... 

Fluorination of Ester Enolates. (+)-N-Fluoro-2,10-(3,3-dichlorocamphorsultam) (1) also reacts with the enolates generated from esters. For example, treatment of methyl 2-phenylpropionate 6 with NaHMDS in THF followed by addition of (+)-l affords the corresponding a-fluoro ester 7 in 54% yield and 33% ee (eq 3). The absolute configuration was not determined. The enantioselectivity observed with (+)-l is better than (—)-N-fluoro-2,10-camphorsultam i.e., < 10% ee (30% yield). ... 

Unlike the chiral, neutral N-F reagents, the [N-F] ammonium salts of cinchona alkaloids are employed for the fluorination of a number of substrates ketone and ester enolates, (3-keto esters, a-cyano esters, a-nitro esters, a-amino esters, silyl enol ethers, enol acetates, nitrile anions, and... 

It is more reactive than perchloryl fluoride and therefore not without danger. It forms, for instance, a highly explosive product with pyridine. Like perchloryl fluoride it reacts with enol ethers, esters and enamines, but at lower temperature (—78°) to yield the fluorinated ketones as well as addition... 

Trimelhylsilyl enol ethers are effective substrates in fluorination with fluo-roxytrifluoromethanefor the preparation of a-fluoro esters, amides and aldehydes [J7] (equations 13-15)... 

Enolate anions of p-keto esters react with some fluoroolefms, initially by replacement of a vinylic fluorine atom, to give ultimately heterocyclic products [2S, 29] (equation 25). 

The reactions of fluorinated esters and amides to form, respectively, enol ethers [47] and enamines [4S] give high yields and are interesting synthetic transformations (equations 34 and 35) (Table 12)... 

Table 12. Fluorinated Esters and Amides in the Wittig Reaction to Form Enol Ethers [47 and Enamines 48 ...

Importance of enol formation for y keto ester fluorination... 

GL 4] [R 5] [P 5] The rate of the fluorination of y0-keto esters is usually correlated with the enol concentration or the rate of enol formation as this species is actually fluorinated [15, 16]. For the fluorination of ethyl 2-chloroacetoacetate in a micro reactor, much higher yields were found as expected from such relationships and as compared with conventional batch processing which has only low conversion. Obviously, the fluorinated metal surface of the micro channel promotes the enol formation. 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives.134 The acids or their chlorides or anhydrides can be a chlorinated by treatment with CuCl in polar inert solvents (e.g., sulfolane).135 Acyl halides can be a brominated or chlorinated by use of N-bromo- or N-chlorosuccinimide and HBr or HC1.136 The latter is an ionic, not a free-radical halogenation (see 4-2). Direct iodination of carboxylic acids has been achieved with L-Cu(II) acetate in HO Ac.137 Acyl chlorides can be a iodinated with L and a trace of HI.138 Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium N-isopropylcyclohexylamide in THF and treatment of this solution at - 78° with I2138 or with a carbon tetrahalide.139 Carboxylic acids, esters, and amides have been a fluorinated at -78°C with F2 diluted in Ni.,4°... 

Formal replacement of hydrogen by fluorine takes place in the a-position of a ketone by treatment of enol acetates with triethylamine tris(hydrogen fluoride).51-55 The kinetically favored isomers are formed.51,55 Furthermore, benzylic positions bonded with an electron-withdrawing group (ketone, ester, nitrile, sulfonate) can be fluorinated electrochemically.51" 6-58 There are also various examples of the preparation of a-fluorosulfides front sulfides.51... 

Various steroids are fluorinated by conversion into the enolates, followed by fluorination with perchloryl fluoride to give the 16-fluorinated products 16.19 28 The Schiff base of 7-aminodeacetoxyeephalosporanic acid tart-butyl ester is converted into an anion with potassium tm-butoxide,29 while further reaction with perchloryl fluoride diluted with nitrogen at — 50 C gives 7-(benzylideneamino)-7-fluorodeacetoxycephalosporanicacid fer/-butyl ester (17) in high yield. An attempt to prepare 2-fluoropodophyllotoxin by reaction of the enolate with perchloryl fluoride resulted in a violent explosion.30... 

F-Teda BF4 (6) has also been used for the gem-difluorination of active methylene compounds, / -oxo esters and amides.102 The reaction times can be significantly reduced by carrying out the two fluorination steps sequentially and, importantly, with the sodium enolate of the monofluoro intermediate for the second step. 

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