Carbonyl compounds electrophilic fluorination

Trifluoromethyl)trimethylsilane has been prepared by a modification5 of the procedure originally published by Ruppert.4 The optimized yield is 75%. Other less convenient methods are also available for its preparation. (Trifluoromethyl)trimethylsilane acts as an in situ trifluoromethide equivalent under nucleophilic initiation and reacts with a variety of electrophilic functional groups. Carbonyl compounds such as aldehydes, ketones and lactones react rather readily5 7 with (trifluoromethyl)trimethylsilane under fluoride initiation. The reagent also reacts with oxalic esters,8 sulfonyl fluorides,9 a-keto esters,10 fluorinated ketones,11 and... 

Fluorinated carbonyl compounds may be employed in condensation reactions to stereo- and regioselectively construct specifically fluorinated materials. The fluorinated reactants may be utilized as either the nucleophilic or electrophilic reaction partners. 

A -FluorohiXtrifluoromethanesulfonyl)imide is one of the most powerful electrophilic fluori-nating agents. It was successfully used to fluorinate diethyl cyanomethylphosphonate in the presence of w-BuLi (1 eq), and the resulting diethyl 1-fluoro-1-cyanomethylphosphonate can be isolated (51% yield) or metallated in situ and reacted with carbonyl compounds in a Homer-Wadsworth-Emmons reaction to give a-fluoroacrylonitriles in 30-58% overall yields (Scheme 3.21). 2 These results aie especially noteworthy because the fluorination of diethyl cyanomethylphosphonate with NFBS in the presence of LiHMDS (2 eq) produces the A -fluoro and not the expected C-fluoro phosphonate. 

One of the first reagents used for electrophilic fluorination ivas xenon difluoride (XeF2) [168], a solid which is easy to handle and which can be used in solvents which are relatively inert toward oxidation, for example acetonitrile and dichloromethane. The reactivity is mostly determined by its strong oxidizing power, rendering its mode of action more oxidative than electrophilic fluorination. With XeF2 not only are typical electrophilic fluorinations of aromatic compounds possible but also the Hunsdiecker-like fluorodecarboxylation of carboxylic acids and fluori-native rearrangements of carbonyl compounds to difluoromethyl ethers [169-171] (Scheme 2.76.). 

Nonfluorinated alkyl hypofluorites (ROF) are mostly unstable and decompose through HF elimination with formation of the corresponding carbonyl compounds. However, tert-butyl [24] and methyl hypofluorites (RO+ F ) [25] can be generated and employed in situ for alkoxy-fluorination of alkenes. The relatively higher stability of both hypofluorites comes from the nonavailability of a-hydrogens which are reactive to the radical hydrogen abstraction [26]. Both of the hypofluorites add to carbon-carbon double bonds regio- and stereoselectively as shown in Scheme 2.48. The anti-addition mode (37-39) is in sharp contrast to the syn-addition mode of electrophilic fluoroalkoxy and acetoxy reactions of fluorinated alkyl and acetyl hypofluorites (RfO F+, 40-41) [27]. 

Many carbonyl addition and substitution reactions are carried out under acidic conditions or in the presence of Lewis acids. Qualitatively, protonation or complexation increases the electrophilicity of the carbonyl group. The structural effects of protonation have been examined for formaldehyde, acetaldehyde, acetone, formamide, and formyl fluoride. These effects should correspond to those in more complex carbonyl compounds. Protonation results in a substantial lengthening of the C=0 bond. The calculated [B3LYP/ 6-31-H-G(phase proton affinities reflect the trend of increasing basicity with donor groups (CH3, NH2) and decreased basicity for fluorine. 

Fluorinated oxetanes can be obtained in decent yield through an electrophilic [2 + 2] cycloaddition of carbonyl compounds and fluoroolefins. The formation of oxetane 2 was first reported by Weinmayr in 1963. The reaction of TFE with paraformaldehyde... 

Many a-fluoro carbonyl compounds, which are intermediates or final products in the design of fluorinated analogs of biologically active compounds, were prepared by electrophilic fluorination this includes fluoro-tribactam antibiotics, 12-fluoroforskohn, 2-(/ )-fluorodehydroquinic... 

The best carbonyl components for these reactions are highly electrophilic compounds such as glyocylate, pyruvate, and oxomalonate esters, as well as chlorinated and fluorinated aldehydes. Most synthetic applications of the carbonyl-ene reaction utilize Lewis acids. Although such reactions may be stepwise in character, the stereochemical outcome is often consistent with a cyclic TS. It was found, for example, that steric effects of trimethylsilyl groups provide a strong stereochemical influence.28... 

On the other hand, in -fluoroalkyl groups (with one uncompensated C-F dipole moment) fluorination usually reduces lipophilicity. Another important instance of fluorine substitution reducing lipophilicity is in compounds with a-fluorocarbonyl groups. In these fluorination can increase the electrophilicity of the carbonyl carbon atom to such an extent that the formation of stable, polar hydrates occurs this again reduces the lipophilicity significantly (Scheme 4.13). In a-fluorocar-boxylic acids and fluorinated phenols the lipophilicity is also reduced by the increased ionization constant which results from the negative inductive —la) effect of fluorine [16]. 

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