Fluorination of carbonyl compounds

Phloroglucinol, which is regarded as the tri-enol form of cyclohexane-1,3,5-trione, gives the hexahydrate of the corresponding perfluoro-trione upon fluorination in formic acid (Fig. 31) [93] (see 3.1.1.2 for a discussion of the fluorination of carbonyl compounds). 

Table 2. Fluorination of Carbonyl Compounds with Molyb-denum(VI) Hexafluoride and Boron Trifluoride13...

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... 

Initial attempts at the direct fluorination of carbonyl compounds such as acetone, bulan-2-one, and butyric acid with elemental fluorine resulted in the formation of complex mixtures, with only low yields of a-monofluorinated carbonyl compounds formed. However, more recently, methyl 3-phenylpyruvate. and other pyruvate derivatives, e.g. 1," are reported to be selectively monofluorinated with dilute elemental fluorine at — lO C in moderate yield. The success of this reaction is attributed to the fact that the substrate predominantly exists in the enol form and not the keto form." Direct fluorination of acyclic 1,3-dicarbonyl compounds in formic acid or acetonitrile at room temperatures results in the formation of 2-fluoro-... 

The fluorination of carbonyl compounds is facilitated by the formation of a metal enolate prior to fluorination. The fluorination of metal enolates has been successfully achieved using a wide variety of N-F reagents, e.g. A-fluorosulfonamidcs, chiral /V-fluorocamphorsul-tam." A-fluorooxathiazinone dioxides," iV-fluoroperfluoroalkylsulfonamides." 1-fluoropyridinium trifluoromethanesulfonates, " and l-alkyl-4-fluoro-1,4-dia7-oniabicyclo[2.2.2]octane salts" (see Table 8). 

Carbonyl difluoride is a particularly versatile fluorinating agent, and an important material for the synthesis of organofluorine compounds [1079], Its reactions with perfluoroalkenes gives perfluoroacyl fluorides in the presence of a fluoride ion source, and its facile reaction with amines or alcohols results in the formation of carbamoyl fluorides or fluoroformates, respectively. The fluorination of carbonyl compounds, such as aldehydes and ketones, with COF can give gem-difluorides by replacement of the carbonyl oxygen atom with two atoms of fluorine e.g.-. 

Scheme 2.7 Selective direct a-fluorination of carbonyl compounds. Copper salt catalysis supposedly acts via formation of the copper enolate complex [19, 20], The formation of the corresponding copper complex of monofluoromalonate, the precursor of difluorinated products, is energetically disfavored.

Scheme 2.64 Proposed mechanism for fluorination of carbonyl compounds into the corresponding gem-difluoromethylene derivatives [139].

Scheme 4.13 a-Fluorination of carbonyl compounds reduces lipophilicity because stable hydrophilic hydrates (box) can be formed. 

Dicarbonyl compounds are selectively fluorinated a to the two carbonyl groups with 1-fluoro-4.6-bis(trifluoromethyl)pyridinium 2-sulfonate (2) at room temperature. In sharp contrast, the fluorination of carbonyl compounds with l-fluoro-2,4,6-trimethylpyridinium trifluoro-methanesulfonate (3) requires heating and Lewis acid catalysis (Table 6). The reactivity of the pyridinium N-F reagent is dependent on the electronic nature of the substituents on the ring.41 When two equivalents of. V-fluoropyridinium salts were used for the fluorination of 1,3-dicarbonyl compounds, the major product was the 2,2-difluoro derivate (Table 7). 

Catalytic enantioselective a-fluorination of carbonyl compounds using chiral transition metal complexes with heterocyclic ligands 07Y1099. 

The most extensively studied halogenation process is probably the a-fluorination of carbonylic compounds, due to the unique properties of the fluorinated compounds [167]. Imidazolidinones of type 91 (20mol%) could be used to promote the a-fluorination of linear aldehydes (19a, = H) using N-fluorobenzenesulfon-... 

Not only phase transfer catalyst but also proline derivatives can be used as organocatalyst for the fluorination of carbonyl compounds. Thus, the reaction of cyclohexanone with selectfluor (80) in the presence of substoichiometric amounts... 

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