Carbonyl compounds fluorination

Numerous fluorinated and perfluorinated alkyl hypochlorites have been synthesized and characterized, eg, CF OCl [22082-78-6] C2F OCl [22675-67-8] /-C F OCl [22675-68-9] and /-C F OCl [22082-78-6]. These nonmetal oxychlorine compounds are much more thermally stable than the corresponding parent compounds and can be prepared by reaction of GIF with the appropriate carbonyl compound or alcohol. 

In the diaziridine field many compounds are known bearing N-YL, A/-alkyl and A-acyl groups, but here no dramatic changes in reactivity are caused by A-substituents. N-Aryldiaziridines are underrepresented. The ring carbon is in the oxidation state of a carbonyl compound or, in the diaziridinones (5) and the diaziridinimines (6) that of carbonic acid. In single cases, diaziridine carbon bears chlorine or fluorine. 

Hypochlorites- are obtained by reaction of fluorinated carbonyl compounds, such as carbonyl lluonde, with an alkali metal fluoride and chlorine fluoride f62, 720]... 

Many fluorinations by electropositive fluorine reagents produce a-fluoro carbonyl compounds as the final result An extensive review exists on the preparation of a-fiuorocarbonyl compounds [101 Also, electropositive reagents are used widely in the preparation of F-labeled radioactive materials required in positron etmssion tomography for biomedical research Excellent reviews are available on fluonne-18 labeling [//, 72]. 

These reactions differ from those of sulfur tetrafluoride with carbonyl compounds in that a formal oxidation-reduction of the sulfur atoms m the thiocarbonyl compound and sulfur tetrafluoride molecule occurs, resulting in the formation of free sulfur and the complete utilization of the fluorine atoms in sulfur tetrafluoride. 

Fluoroolefins may he prepared by the reaction of Wittig reagents and other pho sphorus-containtng y tides with fluorinated carbonyl compounds. (A discussion of the fluorinated Wittig reagents or other fluonnated phosphorus reagents with nonfluorinated carbonyl compounds is on page 581.) Tnphenylphosphoranes, derived from alkyltriphenyl phosphonium salts, react with 1,1,1-trifluoroacetone [3/] or other trifluoromethyl ketones [32, iJ] (equation 26) (Table 10). 

Fluorinated a., -unsaturated carbonyl compounds also are reactive dipo-larophiles Because ol the highly activating carbonyl substituent, these 1,3-dipolar cycloadditions are rapid and regiospecific Good examples are the additions of... 

Polyfluoroalkyl- andperfluoroalkyl-substituted CO and CN multiple bonds as dipolarophiles. Dmzo alkanes are well known to react with carbonyl compounds, usually under very mild conditions, to give oxiranes and ketones The reaction has been interpreted as a nucleophilic attack of the diazo alkane on the carbonyl group to yield diazonium betaines or 1,2,3 oxadiazol 2 ines as reaction intermediates, which generally are too unstable to be isolated Aromatic diazo compounds react readily with partially fluorinated and perfluorinated ketones to give l,3,4-oxadiazol-3-ines m high yield At 25 °C and above, the aryloxa-diazolines lose nitrogen to give epoxides [111]... 

For a review of the preparation of a-fluoro carbonyl compounds, see Rozen, S. Filler, R. Tetrahedron, 1985, 41, 1111. For a monograph, see German, L. Zemskov, S. New Fluorinating Agents in Organic Chemistry Springer NY, 1989. 

As indicated in Chapter 3, compounds with fluorines bound directly to a carbon bearing a hydroxyl group are usually very unstable relative to the carbonyl compound plus HF. Nevertheless trifluoromethanol has been prepared, but it spontaneously loses HF at temperatures above -30 °C. Its fluorine and carbon NMR data are given in Scheme 5.8 and 5.11, and they resemble the respective data of trifluoromethyl ethers. 

The chemical shifts of trifluoromethyl groups at the terminus of a,(3-unsaturated carbonyl compounds are not affected by the presence of the carbonyl group, as is indicated by the examples in Scheme 5.37, and as exemplified by the fluorine NMR of 4,4,4-trifluorocrotonic acid, given in Fig. 5.14. 

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

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... 

Funabiki prepared a-fluoro-/ -phenylacrylaladehyde (92), a particularly useful synthetic intermediate, by an addition elimination strategy (Scheme 34) [81], Electrochemical fluorination of //-phenylsulfenyl-a, S-unsaturated ketones can form a-fluoro-a, S-unsaturated carbonyl compounds (Scheme 35) [82], a-Fluoro- S-thio-a, S-unsaturated ketone (93) was synthesized by the selective nucleophilic... 

M. Essers, C. Muck-Lichtenfeld, G. Flaufe, Diastereoselective diels-alder reactions of a-Fluorinated a, -unsaturated carbonyl compounds Chemical consequences of fluorine substitution, J. Crg. Chem. 67 (2002) 4715-4721. 

D.F. Andres, U. Dietrich, E.G. Laurent, B.S. Marquet, Anodic fluorination of vinyl sulfides - synthesis of a-fluoro- -thio-a, -unsaturated carbonyl compounds. Tetrahedron 53 (1997) 647-658. 

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). 

Since fluoro-carbonyl compounds are such useful and versatile synthetic intermediates, much effort has been devoted to their preparation [124], but only in a few instances has elemental fluorine been used directly. One of the earliest successful direct fluorinations of a simple carbonyl compound was the fluorina-tion of pyruvic acid derivatives which have a high enol content (R = Aryl, Acyl) (Fig. 47) [125] in the solvent being used (mixtures of CF2C1CFC12 and acetonitrile). However, in derivatives where the enol content was low (R = Alkyl), complicated mixtures of products were obtained. 

Attempts to use fluorine in the preparation of simple a-fluoro-carbonyl compounds were not successful initially. Even when derivatives of carbonyl compounds such as enol acetates were treated with fluorine, a complicated mixture of products was obtained from which none of the desired a-fluoro... 

Under similar conditions, the enol acetate and the trimethylsilyl ether of estrone were fluorinated to give the corresponding a-fluoro carbonyl compound (Fig. 54) [135]. 

Trifluoromethyl hypofluorite was first made by Cady by passing methanol [184] or carbon monoxide [185, 186] with fluorine over silver difluoride at elevated temperatures. Later, trifluoromethyl hypofluorite and higher perfluoroalkyl hypofluorites were prepared by treating the appropriate carbonyl compound with fluorine in the presence of dry caesium fluoride at sub-zero temperatures (Fig. 81) [187-189]. 

Similarly, l-bromo-l,l-difluoro-2-alkynes, which were prepared by the reaction of lithium acetylides with CF2ClBr [284] or CF2Br2 [285], also reacted with carbonyl compounds in the presence of zinc to afford the corresponding a,a-difluoropropargyl alcohol [285]. This reaction has been utilized for the preparation of 3-fluoro-2,5-disubstituted furans [286] and other fluorinated biologically active compounds [285,287] (Scheme 99). 

Thus, precursors such as hydrocarbon ethers, amines, carbonyl compounds which are readily protonated tend to be more amenable to ECF than, say, hydrocarbons or halocarbons whose solubilities and conductivities are low. A number of techniques have been developed in the past decade, however, to overcome such problems (see Sect. 4.2). Similarly, advances in methodology of ECF now allow the fluorination of gaseous, liquid, solid, and even polymeric materials [72-77]. 

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