Ketones a-fluoro

A special application of heteroaromatic acylation via a modified Dakin-West reaction leads to a-fluoro ketone derivatives [50] (equation 30) Such fluoro ketones have been successfully used as enzyme inhibitors in modern bioorganic chemistry [5, 6]... 

When diazo ketones are treated with HBr or HCl, they give the respective a-halo ketones, but HI does not give the reaction, since it reduces the product to a methyl ketone (10-87). a-Fluoro ketones can be prepared by addition of the diazo ketone to polyhydrogen fluoride-pyridine. This method is also successful for diazoalkanes. 

The use of chiral a-fluoro ketone G can lead to enantioselective epoxidation.106... 

Substituted 2//-azirines are readily transformed into 2,2-difluoroethylamines160168 by treatment with hydrogen fluoride/pyridine to give the products in moderate yield. Depending on the substituents, a-fluoro ketones are also formed in some cases.160169 Increased yields are obtained under similarly mild conditions with a weakened hydrogen fluoride system from 30% hydrogen fluoride/pyridine plus triethylamine.169... 

While fluoroxy compounds react well with enol derivatives, fluorine in general does not. However, there are various reports where such reactions are described and in certain cases even with decent yields. In 1982 it was reported that pyruvates with a dominant enolic form react well with fluorine, to give the corresponding fluoro derivatives l.78 Several silyl enol ethers 2 and 379 including ones made from 1,3-dicarbonyl derivatives 480 react quite satisfactorily with fluorine to give the expected a-fluoro ketones. Steroidal 16-enol acetates react with fluorine to form mainly 16a-fluoro-17-oxo steroids e.g. 5.81... 

Mixtures obtained in reactions of fluorine with acid salts were tested on ( )-stilbene and from one to six products were formed, e.g. formation of 25.12 Various enol acetates can be converted into a-fluoro ketones 26 in a similar manner.2-4... 

Enol acetates, oxo esters, nilroalkenes33 and sodium salts of various esters have been successfully converted into fluoro ketones and esters by acetyl hypofluorite, trifluoroacetyl hypofluorite or mixtures containing acetyl hypofluorite and fluoroxy compounds.3 4 -10-12-13 Examples are the formation of l-fluoro-l,3-diphenylacetone (12), a-fluoro-/i-oxo esters 13, a-fluoro ketones 14 and 15. ethyl l-fluoro-2-oxocyclopentanecarboxylate (16), and 2-fluoromalonate 17. 

Aliphatic a-hydroxy ketones react with sulfur tetrafluoride, generally to provide trifluoroal-kanes. However, under carefully chosen conditions the carbonyl group in hydroxy ketones remains intact while the hydroxy group undergoes selective substitution by fluorine. Thus, 5-hydroxyoctan-4-one reacts with sulfur tetrafluoride (20°C, 3 h) to give a 1 1 mixture of 5-fluorooctan-4-one(l b) and 2-oxo-l-propylpentyl fluorosulfite.63 a-Fluoro ketones 1 are formed in high yield and as the sole product when diethyl ether is used as solvent.64... 

Direct regioselective conversion of a variety of cyclic and acyclic ketones to a-fluoro ketones was achieved in high to excellent yield using NFTh (21) in acetonitrile solution.96 The collected results (Table 10) of this highly effective direct transformation show that a comprehensive range of ketones can be fluorinated a to the carbonyl group, without prior activation. 

Reactions of fluoroxytrifluoromethane with enol ethers, enol acetates, and enamines [/, 2, 3] are very useful, especially for the preparation of steroidal a-fluoro ketones (Table 2, entries 1,3,5, 6, and 7) [1] (equation 12)... 

Scheme 8). For instance, the fluorination at the position a of ketones has been realized by the anodic oxidation of enol acetates (78) in an MeCN/Et3N-3HF/(Pt) system under potential control, giving a-fluoro ketone (79 equation 38). ... 

An alternative approach to an a-fluoro ketone is to convert the parent ketone into the corresponding silyl enol ether which is then fluorinated. 

Treatment of a, -epoxy sulfoxides with tw O equivalents of potassium hydrogen fluoride/ boron trifluoride-diethyl ether complex reagent in chloroform at room temperature gives a-fluoro ketones in moderate to good yield together with some rearranged products.There are no other examples of the use of this reagent. 

Enamines, which are readily obtained from the corresponding ketones, can be converted into a-fluoro ketones by treatment with a reagent capable of delivering electrophilic fluorine ( F ). 

Several cyclic a-fluoro ketones 8 have been obtained from the corresponding cyclic ketones via the enamines 7, using difluorodiazene as the fluorinating agent. 

Due to these safety problems, the search for new, easy-to-handle electrophilic fluorinating agents has become an important area of research. Some of these new reagents have been tested in the fluorination of enamines to give a-fluoro ketones. These include l-fluoropyridin-2(l//)-one (9), A -fiuoroquinuclidinium fluoride (NFQNF, 10), Af-fluoropyridinium salts 11, and A -fluorobis(trifluoromethanesulfonyl)aminc (Tf2NF. 12). ... 

Fluorinations of other functionalities containing C = N bonds, such as 2//-azirines and imines, are included in this section. Certain 2Ff-azirines and imines yield a-fluoro ketones. With other 2Ff-azirines, /i,/(-difluoro amines are the main reaction products. In a strict sense, these reactions cannot be considered as examples of substitution of nitrogen-containing functional groups no substitution takes place when /S. -difluoro amines are the reaction products. However, these methods have been included. 

The reaction of 2//-azirines (e.g.. 1) with hydrogen fluoride in pyridine [pyridinium poly(hy-drogen fluoride). Olah s reagent] gives /f,/f-difluoro amines (e.g., 7) or a-fluoro ketones (e.g., 5) (Table 10). In some cases, pyrazines (e.g.. 9) are the main reaction products (Table IQj 31-35 2//-Azirines arc more reactive than aziridines towards pyridinium poly(hydrogcn... 

In the mechanism proposed to explain the formation of /l,y difluoro amines and a-fluoro ketones, two main, competing pathways are possible, after protonation of the 2//-azirine 1. One pathway leads to the / ,/ -difluoro amine 7 via the intermediates 2 and 6. A second possibility, via 2, 3 and 4, gives the observed a-fluoro ketone 5. Pyrazines are formed by the intermoleciilar reaction of the intermediates corresponding to 3, lo give diprotonated intermediates, e.g. 8. 

Difluoro Amines and a-Fluoro Ketones by the Reaction of 2//-Azirines with Pyridinium Poly(hydrogen fluoride) General Procedure ... 

The reaction of unsaturated steroids with nitrosyl fluoride leads to fluoro-substituted nitrimines 1 which arc hydrolyzed to a-fluoro ketones 2. ... 

Also covered in this section is the fluorination of enamines with electrophilic fluorine ( F+ ). This reaction is not really a substitution of a monovalent nitrogen (amino) group by fluorine, but in this method the enamine group of the substrate is substituted, although in another position, by fluorine in the a-fluoro ketone product. 

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