Monofluorination

1 Electrophilic reagent F2, CsS04F, R2NF, CF3OF, RC02F, ArIF, XeF2 

On the mechanism of activation of XeF2 by hydroxy group on glass-wares Ramsden, C.A., and Smith, R.G. (1998) /. Am. Chem. Soc., 120, 6842-6843. 

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Drugs. Ring-fluotinated aromatics have found broad pharmaceutical appHcations, eg, in tranquilizers, hypnotics, sedatives, antibacterial agents (qv), etc. Representative monofluorinated dmgs are Hsted in Table 4. Arprinocid [5579-18-15] is a fluoroaromatic-based veterinary dmg that has found wide acceptance as a coccidiostat for chicken feed. 

Few appHcations for fluoronaphthalenes and related polycycHc stmctures have materialized. The fused-ring bicycHc, suHndac [38194-50-2] a monofluorinated indene-3-acetic acid, is used as an antiinflammatory agent. 

In radical reactions not involving bromine or chlorine on the substrate, rearrangements are much rarer One example is the fluorination of di-tert butyl ketone which produces perfluormated / rt-buty isobutyl ketone [J5] Although isolated yields are poor only the rearranged ketone could be isolated This is perhaps only the second example of a 1,2-acyl shift Low fluorine substrate ratios show that this rearrangement occurs after monofluorination... 

The fluorination of P-diketones and p-ketoesters with N-/luorobis(trifluo-romethanesulfonyl)imide (Table 3a, B) can be controlled to give either mono-fluorination or difluorination. Monofluorination occurs when the strong acid, bis(trifluoromethanesulfonyl)imide, a reaction product, is removed by addition of water, which prevents further enolization and fluormation of the monofluoro adduct [83] (equation 38)... 

The results given in both Table 1 and in the reviews [4, 5 7, 8, I0 show that xenon difluoride reacts with a wide variety of aromatic substrates to produce regioselecuvely monofluorinated aromatics An example is the preparation of 6-fluoro-L DOPA [83] (equation 48)... 

For toluene fluorination, the impact of micro-reactor processing on the ratio of ortho-, meta- and para-isomers for monofluorinated toluene could be deduced and explained by a change in the type of reaction mechanism. The ortho-, meta- and para-isomer ratio was 5 1 3 for fluorination in a falling film micro reactor and a micro bubble column at a temperature of-16 °C [164,167]. This ratio is in accordance with an electrophilic substitution pathway. In contrast, radical mechanisms are strongly favored for conventional laboratory-scale processing, resulting in much more meta-substitution accompanied by imcontroUed multi-fluorination, addition and polymerization reactions. 

GL 1] [R 1] [R 3] [P la-d] Space-time yields higher by order of magnitude were found for the falling film micro reactor and the micro bubble column as compared with the laboratory bubble column [38], The space-time yields for the micro reactors ranged from about 20 000 to 110 000 mol monofluorinated product m h. The ratio with regard to this quantity between the falling film micro reactor and the micro bubble column was about 2. The performance of the laboratory bubble column was of the order of 40-60 mol monofluorinated product m" h. ... 

The above-mentioned space-time yields were referred solely to the reaction volume, i.e. the micro channel volume. When defining this quantity via an idealized reactor geometry, taking into accoimt the construction material as well, natarally the difference in space-time yield of the micro reactors from the laboratory bubble column becomes smaller. Still, the performance of the micro reactors is more than one order of magnitude better [38], The space-time yields for the micro reactors defined in this way ranged from about 200 to 1100 mol monofluorinated product... 

Lateral monofluorination of the p-alkoxyphenyl isocyanide system [XAu (CNC6H40C H2 +i)] (X = C1, Br, I), in ortho-(3-F) (6a) and meta-(2-F) (6b) positions relative to the alkoxy chain was also studied [18]. None of the free fluorinated ligands is a LC, but their gold complexes display mesomorphic properties. This is a typical case of a promesogenic ligand which yields a mesogen upon coordination to a metal. 

Figure 14. Energetics (in kcol/mol) of the ring expansions of fluoro-substituted phenylni-trenes, calculated at the CASPT2(8,8)/cc-pVDZ//CASSCF(8,8)/6-31G level.87-88 (a) Difluo-rinated nitrenes. (b) Monofluorinated nitrenes.

More mechanistic insight into the C-H functionalization process of arenes is provided by theoretical and experimental studies. Multifluorinated, electron poor, aromatic substrates readily undergo CH activation with coordina-tively unsaturated rhenium complexes, attributed to the stronger C-Re bond in the product, whereas with monofluorinated analogs, the if -complex predominates (Equation (60)).61... 

In a similar way, a monofluorination of various phenylthio derivatives of lactams [212, 213], lactones [214] and diox-olanones [215] was achieved. 

A monofluorination of 2-substituted-l,3-oxathiolan-5-ones (Scheme 116) [216], 2-substituted dithiolanones [217], thi-azolidinones [218], and dihydrochro-manone or thiodihydrochromanone... 

Hydroxypiperidine alkaloids have been synthesized via anodic methoxylation that allowed the regio- and stereoselective introduction of substituents [213]. A highly diastereoselective fluorination was achieved with chiral l,3-oxathiolan-5-ones derived from camphorsulfonamide. In dimethoxyethane containing Et4NF-4HF, the monofluorinated product (9) was obtained as a single diastereomer [214]. 

Monofluorinated Analogues of Polybrominated Diphenyl Ethers as Analytical Standards Synthesis, NMR, and GC-MS Characterization and Molecular Orbital Studies (from Luthe et al., 2006)... 

Luthe, G. Leonards, P. E. G. Reijerink, G. S. Liu, H. Johansen, J. E. Robertson, L. W. Monofluorinated Analogues of Polybrominated Diphenyl Ethers as Analytical Standards Synthesis, NMR, and GC-MS Characterization and Molecular Orbital Studies. Environ. Sci. Technol. 2006, 40, 3023-3029. 

Not unexpectedly by comparison with the monofluorinated 1-deoxynojirimycin derivatives, the 4,4-difluoro derivative 102 (Scheme 26) was found to be inactive with almond (l-glucosidase and the a-glucosidase from yeast.227 Equally inactive with these enzymes was the 3,3-difluoro compound 105 (Scheme 26).228 It is noteworthy that the 4,4-difluoro derivative of 1-deoxymannojirimycin, 103 (pAfa 5.3) turned out a good inhibitor of the (1-glucosidase from almonds (K, 45 pM, at pH 6.8 2 47 pM) and remained unprotonated and active at pH 5 (K, 92 pM 2 Kt 300 pM)227... 

E. Prell and R. Csuk, Amplification of the inhibitory activity of miglitol by monofluorination, Bioorg. Med. Chem. Lett., 19 (2009) 5673-5674. 

The comparison of the olfactory properties of fluoro analogues of citronellol is a significant example (Fig. 1) [11,12]. While monofluorinated compound exhibit only minor changes in olfactory properties, this is quite different for trifluorocitro-nellol. In the absence of other factors envisioned, the important differences observed between citronellol and trifluorocitronellol are very likely due to a different recognition by the olfactory receptors, connected to the bigger size of the CF3 with respect to CH3 [10]. 

G. Haufe, T.C. Rosen, O.G.J. Meyer, R. Frohlich, K. Rissanen, Synthesis, reactions and structural features of monofluorinated cyclopropanecarboxylates, J. Fluor. Chem. 114 (2002) 189-198. 

The synthesis of fluorinated aliphatic compounds is the main topic of this chapter. Indeed, numerous aromatic fluorinated products are available commercially. Moreover, in contrast to aliphatic molecules, their synthesis has not undergone significant evolution in the last few years. The synthesis of highly fluorinated compounds is also not considered here, since these compounds are much more involved in the formulation sciences than in medicinal chemistry. In this chapter, the synthesis of fluorinated compounds is dealt with in the following order monofluorinated, then difluoro-methylated, and finally trifluoromethylated molecules. 

Three strategies are used to prepare a monofluorinated compound ... 

Formation of Carbon-Carbon Bonds Starting from Monofluorinated Synthons... 

The only monofluorinated synthons that are available are monofluoroacetic acid and its derivatives (esters, thioacetate, bromofluoroacetate) and halogenofluoromethanes (CHCI2F). 

Fluorine is found in nature as mineral fluorides, and it is the most abundant halogen in the Earth s crust. Thus, it is rather surprising that less than 15 fluorinated organic molecules have been isolated from plants. They are aU secondary metabolites of fluoroacetate. Among these compounds, all monofluorinated, half are composed of (w-fluorinated homologues of fatty acids. ... 

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