Acetamides, fluorinated

The high reactivity of N-H bonds has also been exploited to produce N-F denvatives without significant substitution on neighbonng C-H bonds, Diethyl-phosphoramidates of ammonia, alkylammes, and a,polar solvents to produce difluoroamine [57], N,N-difluoroalkylamines, and a,to-bis(At,7V-difluoroamino)alkanes [52] Acetamide undergoes fluonnation to give modest yields of N,N difluoroacetatnide and acetyl fluonde when fluorinated... 

The earliest examples of such fluorine-18 labelling are 2- and 6-[ F]fluoronico-tinic acid diethylamide and 2- and 6-[ F]fluoronicotine (Fig. 5). All were obtained in up to 40-50% radiochemical yield from the corresponding 2- and 6-chloro-(or bromo-) pyridine derivatives and [ F]fluoride as its cesium salt, in melted acetamide or DMSO at about 200 °C for 30 min [226-229]. 

The formation of minor quantities of acetamide by-products can be avoided by using sulpholane as solvent however, concomitant fluorination of the aromatic ring is said to occur under these conditions [27,29]. 

It is interesting to note that little work on this process has been conducted outside the laboratories of Phillips Petroleum Company and 3 M Company however, related studies on the fluorinations of formamide and acetamide in molten KH2F3 on amorphous carbon anodes at 120 °C have been reported by Tasaka and co-workers [57]. The amides were said to react with atomic fluorine produced on the (CxF)n [x > 2] film by discharge of fluoride ion, according to the scheme below. 

Various side reactions are possible. The solvent acetonitrile can also react as a nucleophilic agent to form, after hydrolysis, acetamides [R CH(NHAc)R2].23 Methanol as solvent results in a methoxylation product [R CH(OMe)R2].22 The selectivity of partial electrochemical fluo-rination depends on many different parameters, e.g. the type of solvent, the supporting electrolytes, the electrode materials, the electrochemical potential etc. The electrochemical potential can be measured by cyclic voltametry. Partially fluorinated compounds are particularly used in medical fields or as pesticides. 

Perfluoro[AT-fluoro-Af-(4-pyridyl)acetamide], prepared via direct fluorination of the sodium salt of perfluoro[/V-(4-pyridyl)acetamide], readily fluorinates diethyl sodio(phenyl)malonate, 1-morpholinocyclohexene, phenol and anisole under mild conditions.129... 

PhCHBrCOjEt KF, acetamide PhCHFC02Et precursor for the synthesis of biologically active organo-fluorine compounds 47... 

The relative reactivity of a-haloacetates toward protein functionalities is sulfhydryl > imidazolyl > thioether > amine. Among halo derivatives the relative reactivity is I > Br > Cl > F, with fluorine being almost unreactive. The a-haloacetamides have the same trend of relative reactivities, but will obviously not create a carboxylate functional group. The acetamide derivatives typically are used only as blocking reagents. 

DFIT-induced fluoro-Pummerer reactions of N-substituted-2-(phenylsul-fanyl)acetamides have also been reported (Scheme 37) [107]. With some amides, cyclization of the Pummerer intermediate was competitive with fluorination, and in other cases, fluorination was preempted by sulfoxide formation. 

Electrochemical fluorination 168,169> is a commercial process for perfluorina-tion of aliphatic compounds. The reaction is performed in liquid hydrogen fluoride -potassium fluoride at a nickel anode. The mechanism is not known free fluorine cannot be detected during electrolysis, so it seems probable that fluorination is a direct electrochemical reaction. Theoretically, hydrogen fluoride-potassium fluoride should be a very oxidation-resistant SSE, and it might well be that the mechanism is analogous to that proposed for anodic acetamidation of aliphatic compounds in acetonitrile-tetrabutylammonium hexafluorophosphate 44 K... 

Sulfolane is an alternative to acetonitrile or nitromethane as a solvent for anodic reactions in reductions it generally offers no advantages over such solvents as MeCN, DMF, or DMSO, but for anodic fluorination sulfolane might be better than MeCN, as a competing acetamidation is avoided (Chapter 25). 

Laurent and coworkers found that anodic benzylic mono- and difluorination proceeds selectively when the benzylic position is substituted by electron-withdrawing groups (EWG) [Eq. (5)] [29,30]. In these cases, / -methoxy or />-chloro substituents on the benzene ring are necessary for the operation of efficient fluorination. In their absence, benzylic acetamidation becomes a major reaction. The use of sulfolane as a solvent instead of MeCN leads to higher yields of fluorinated products owing to the absence of competing acetamidation [31]. 

Scheme 2.79 Representative syntheses of a variety of OF-reagents and the mechanism proposed for the selective electrophilic ortho fluorination of aromatic acetamides [178].

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