Preparation of Monofluorinated Compounds

Three strategies are used to prepare a monofluorinated compound  

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Bromofluoro compounds are themselves useful starting materials for the preparation of monofluorinated compounds. For example, reduction of 1-bromo-2-fluorocyclododecanes with tributyltin hydride gives fluorocyclododecane, while other methods to produce this compound have been unsuccessful.15 The elimination of hydrogen bromide from vicinal bromofluorides also gives vinyl fluorides in good yields,10 16 as is illustrated by the recent synthesis of several substituted a-fluorostyrenes for studies related to [4+2]-cycloadditions.17... 

In many cases, di- and polyfluoropyridines can be prepared using the same reactions for preparation of monofluorinated analogues. The degree of fluorination in some cases can be controlled, however, often leading to mixmres of polyfluorinated compounds. Some polyfluoropyridines can be reduced back to di- or monofluor-opyridines, which can be successfully used for a selective synthesis of these compounds. 

Initial attempts at the direct fluorination of carbonyl compounds such as acetone,72 butane-one,73 and butyric acid74 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.75,7<1 and other pyruvate derivatives, e.g. I,77 are reported to be selectively monofluorinated with dilute elemental fluorine at — 10"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.77 Direct fluorination of acyclic 1,3-dicarbonyl compounds in formic acid or acetonitrile at room temperatures results in the formation of 2-fluoro-1,3-dicarbonyl compounds in good to excellent yield.78,79 Although in these systems the keto form predominates, there are significant concentrations of the enol form which undergoes fluorination (Table 5).78,79 The fluorination of 1,3-dicarbonyl compounds with acetyl hypo-fluorite is only successful when there are significant concentrations of the enol form compounds which have low concentrations of the enol form are successfully fluorinated by preparation of their metal cnolates followed by fluorination with acetyl hypofluorite (see Section 1.1.2.5.).95... 

Monofluorination of Enolates. /V Fluorosultam (1) has been successfully used to prepare a-fluorocarbonyl compounds by electrophilic fluorination starting, for example, from disubstituted enolates derived from ketones, esters, and -dicarbonyl compounds (eqs 13). The related /V-fluorosulfonamide reagents ... 

Several typical synthetic methodologies for the preparation of fluorinated isoquinoline derivatives emeiged in the 1950s and 1960s. Fundamental reactivities and properties of such compounds were also concomitantly reported. In 1951, Roe and Teague reported the first synthesis of monofluorinated isoquinolines (Scheme 1) [9]. They successfully prepared 1-, 3-, 4-, and 5-fluoroisoquinolines via heating diazonium intermediates... 

The first section of this chapter describes the preparation and several synthetic applications of a-fluoroalkyl P-sulfmyl enamines and imines the second deals with the chemistry of di- and trifluoropyruvaldehyde A, 5-ketals, stereochemically stable synthetic equivalents of P-di and P-trifluoro a-amino aldehydes, which can be prepared from the corresponding p-sulfinyl enamines the third overviews the preparation of chiral sulfinimines of trifluoropyruvate and their use to prepare a library of a-trifluoromethyl (Tfm) a-amino acids the fourth section is mainly dedicated to the asymmetric synthesis of monofluorinated amino compounds, using a miscellany of methods such as MifstmobuAike azidation of P-hydroxy sulfoxides, ring opening of fluoroalkyl epoxides with nitrogen-centered nucleophiles and 1,3-dipolar cycloadditions with chiral fluorinated dipolarophiles. 

Hydrazones are known to be alternative precursors to gem-di-fluoromethylene compounds. Oxidative gg/n-difluorination of hydra-zones has been performed with fluorine gas, in situ prepared IF from I2 and Fj, or in situ generated BrF from A -bromosuccininiide/Py(HF) . In contrast, anodic oxidation of hydrazones in the presence of fluoride ions provides monofluorinated products predominantly along with smaller amounts of ge/ra-difluorinated products (Scheme 52). ... 

The reactions described in this paper have shown that a number of different molecules can be prepared by the use of the monofluoroxenonium hexafluorometalates. These salts are extremely mild and regioselective agents for oxidative fluorination. Thus, the synthetic potential of XeF+MF6" (M = As, Sb) offers the possibility to obtain monofluorinated onium salts as well as compounds containing an E-XeF element bond or even polyhalonium cations. It is clear that many unexpected results remain to be discovered in this area. 

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