Defluorination, reductive

Irradiation of lomefloxacin 271 in dilute neutral aqueous solution (in which it exists as a zwitter ion) in Pyrex-filtered 500 W medium pressure mercury (Helios Italquartz) at 17°C gave pyrrolo[3,2,l-(/ ]quinoline 272 (99JOC5388). Under this condition, reductive defluorination via a radical anion took place. This study is important because of the phototoxicity of the fluorinated compounds which could be used as antibacterials (Scheme 49). 

The reductive defluorination of perfluorocarbons is an example where the above model helped to resolve a rather complicated mechanism and to rationalize the reactivity pattern.82 The reductive elimination of the three fluorines occurs successively according to the following reaction sequence ... 

From the lithium chemistry point of view, the carbon-fluorine bond cannot be considered as a carbon-halogen bond because alkyl or aryl fluorides are not adequate starting materials in lithiation processes, due to the fact that this bond is the strongest that carbon can form . On the other hand, a possible reductive defluorination process could be important from an environmental point of view due to the difficult degradation of fluoro derivatives in nature . 

A difluorinated analogue of the Danishefsky diene has been prepared by reductive defluorination with Mg(0) of an a,/i-unsaturated trifluoromethylketone. Its use in a hetero-Diels-Alder reaction (including asymmetric version) can lead to oxygen- and nitrogen-containing heterocycles (Figure 2.25)." ... 

Reductive defluorination reactions have also been described in ether, difluoroallylic alkoxides undergo stereoselective reduction (Eq. 138) to the E-mono-fluoro derivatives upon treatment with lithium tetrahydridoaluminate [354]. Sodium borohydride [355] and Red-Al [346] have also been used to achieve this transformation. 

Conversely to their usual stability and chemical inertness, saturated perfluorocarbons can be susceptible to reductive defluorination in one-electron-transfer reactions. Thus, per-fluorodeeahydronaphthalene is converted by sodium benzenethiolate to octakisfphenylsul-fanyl)naphthalene, attacking first the weaker tertiary C — F bond (see Section 3.5.). Independent of the strong C — C bonds, in hydrocarbon-perfluorocarbon copolymers elimination of hydrogen fluoride takes place above 350 C. 

The reductive defluorination of perfluoronaphthalene by the zirconocene-aetivated magnesium system in tetrahydrofuran gives mainly the dihydro product 8 in good yield (for the procedure see Section 2.I.I.I.).159-160 When zinc in aqueous ammonia is used as the reducing agent, the dihydro derivative 8 also results as a main product in ea. 30% yield.164... 

Several methods are employed for the reductive defluorination of 2-fluoro-l-phenyl-ethanones. Electrolytic reduction at a mercury cathode selectively replaces fluorine in 2-fluoro-l -phenylethanone by hydrogen.94 The hydrodefluorination of fluoroacetophenones, e.g. 7, to dithioacetals of the corresponding defluorinated ketones with aluminum chloride and ethanethiol take place readily by stirring the mixture in dichloromethane at 0°C under nitro-... 

Tetracarbonyl(trifluoromethyl)iron(II) iodide reacts with C-C bond formation to give per-fluoroethene. Tetracarbonyl(perfluorohexyl)iron(II) iodide gives several products, but no per-fluorohexene resulting from /1-elimination has been found.148 However, reductive defluorination of perfluoro(methylcyclohexane) has been reported with dicarbonyl(ty5-cyclopcn-tadienyl)iron(III).212 The defluorination is accompanied by substitution of fluorine with the cyclopentadienyl anion and proton abstraction from the solvent, the latter is well known in the chemistry of fluoroaromatics with the cyclopentadienyl anion. 

Reductive defluorination occurs with perfluorocyclohexene (13), forming hexafluorobenzene (14) [26-28] by a series of one-electron transfer steps... 

Tertiary phosphines lead to a variety of reductive defluorinations, e.g. (29) to (31) and coupling reactions, e.g. (29) to (35) and (32) to (34) (Scheme 11) [29,30] the intermediate species in these cases are, however, ylides, i.e. (33) and (30), which then react further giving (34) and (35), respectively. Other examples of ylide formation are described later (Sect. 7). 

Recently a number of groups, most significantly those of Crabtree and Richmond, have devised methods of carrying out reductive defluorination/ functionalization processes of saturated fluorocarbons. It is assumed that these processes involve successive single electron transfer processes [82]. Richmond and... 

In the case of diazirines, both difluorodiaztrine and bis(trifluoromethyl)diazirine have been obtained. Difluorodiazirine was originally prepared by reductive defluorination of bis(difluoroamino)difluoromethane [320, 321], but it can also be obtained by an interesting fluoride-ion-induced rearrangement of difluorocyanamide [322] (Figure 8.125). Bis(trifluoromethyl)diazirine [318, 323] is best obtained by the oxidation of 2,2-diaminohexafluoropropane, prepared from hexafluoroacetone, with sodium hypochlorite (Figure 8.126). 

Electrochemical reduction of polyhalopyridines has been observed the position of H-transfer corresponds with calculated spin and charge densities [179] (Figure 9.75). Reductive defluorination will also occur under relatively mUd conditions, in some circumstances by electron transfer from metals, e.g. zinc [180, 181] (Figure 9.76). 

Lind RC, Gandolfi AJ, Sipes iG, Brown BR, Jr., Waters SJ. Oxygen concentrations required for reductive defluorination of halothane by rat hepatic microsomes. Anesth Anaig 1986 65(8) 835-9. 

Reaction of y,y-difluoro-a, 3-enoate derivatives 42 with Me2CuLi (5 equivalents), followed by aqueous work-up afford the reductive defluorination product 44 without forming the a-methylated product. It is postulated that enolate intermediate 43 reacts with alkyl halide smoothly and regioselectively to give the desired a-alkylated product 45 (see Scheme 10.12) [22, 23]. The reaction proceeded in an excellently Z-selective manner. 

Although Me2CuLi-mediated reductive defluorination of 42, followed by a-alkylation with alkyl halide, gave product 45 in high yield and in Z-selective manner, the relative stereochemistry at C-5 and C-2 was not controlled (see Scheme 10.12). For the stereo-controlled alkylation at C-2, a chiral auxiliary at the carboxyl moiety was used, and relatively high diastereoselectivity was realized in the case of camphorsultam derivative 46 (see Scheme 10.14) [23]. 

A facile synthesis of fluoro-olefins through Pd(0)-catalyzed reductive defluorination of allylic g m-difluorides, in particular y,y-difluoro-a,P-enoates was recently reported (see Scheme 10.16) [26]. Stereoselectivities were moderate to high (.E Z= 1 1-1 9). 

The reductive defluorination-alkylation method shown in Scheme 10.12 was successfully applied to the synthesis of A -Boc-Sta-xF[CF=CH]-Ala ethyl ester 51, which mimics the central Sta-Ala unit of pepstatin, a naturally occurring inhibitor of aspartyl proteases including renin, pepsin, HIV-1 and HIV-2 proteases (see Figure 10.3) [27]. 

As expected, Me2CuLi-mediated reductive defluorination of 56 and subsequent meth-ylation with methyl iodide proceeded smoothly to give methylated product 57 in 96% yield. Regarding the stereoselectivity, a moderate Z-selectivity (Z E = 6.4 1) was observed for the olefin moiety, but the C-2-methylation proceeded in nonselective manner. Fortunately, two diastereomers were readily separable by medium-pressure liquid chromatography (MPLC) as shown in Scheme 10.18. Structural assignments were made based on the x-ray crystallographic analysis of (2S)-57. 

As described above, an organocopper reagent derived from alkyl lithium, such as Me2CuLi, readily reacts with y,y-difluoro-a,P-enoate 42 to form a reductive defluorinated metal species 43, exclusively (see Scheme 10.12). To facilitate the reactivity of fluorine as a leaving group, we also investigated the effects of alkylaluminum on this reaction as... 

Narumi, T., Tomita, K., Inokuchi, E., et al. (2007) Facile synthesis of fluoroalkenes by palladium-catalyzed reductive defluorination of allylic gera-difluorides. Org. Lett., 9, 3465-3468. 

A particularly active reductive defluorination system [64] prepared from Cp2ZrCl2/Mg/HgCl2 is able to attack perfluorocyclohexane, a substrate without tertiary C-F bonds, with 2,3,5,6-tetrafluorobenzene obtained in 35% yield as the final organic product. 

This is the first high yield example of using reductive defluorination to induce C-C bond coupling. Perfluorodiphenyl ether is not an intermediate in this reaction and treatment of perfluorodicyclohexyl affords only perfluorodiphenyl rather than a fused ring system. 

Scheme 2.27 Industrial-scale methods for reductive defluorination—aromatization of perfluorocycloaliphatic precursors, which again are accessible by the cobalt trifluoride process [74].

Scheme 2.28 Reductive defluorination-aromatization under milder reaction conditions suitable for laboratory-scale synthesis of perfluoro-olefins and related products (Hg = photochemically excited mercury) Cp = pentamethylcyclopentadienyl [75. 76].

Ar-X nucleophilic substitution (Halex) Perfluorocycloalkanes reductive defluorination- 46... 

Mitsch, R.A. Organic fluoronitrogens. X. Reductive defluorination-cyclization. J. Org. Chem. 1968, 33, 1847. 

The ability of Al-fluoro amines to undergo reductive defluorination was discovered by Mitsch in 1965. " The treatment of amines 30, 31, and 67 by ferrocene results in the formation of the corresponding cyclic imidoyl fluorides 81, 83, and... 

FIGURE 9.26 Reductive defluorination of cyclic perfluorinated A-fluoroamines. 

The mechanism of the reductive defluorination of perfluorinated N F amines may involve a relatively low laying LUMO of N—F bond. The injection of an electron on this orbital leads to the formation of radical anion D, which can further lose fluoride anion, forming radical E. The reduction of E to azaanion F followed by second fluoride anion elimination may lead to the corresponding cyclic imidoyl fluoride as a result of reductive defluorination (Scheme 9.1). 

SCHEME 9.1 Mechanism of reductive defluorination of cyclic Al-fluoro amines. 

Several methods are available for the preparation of perfluorinated cyclic imidoyl fluorides. For example, reductive defluorination of cyclic A-fluoro compounds... 

A wide variety of perfluorinated cyclic materials has been prepared and a large body of experimental material on the synthesis and chemistry of perfluorinated nonaromatic heterocyclic was accumulated. Despite the fact that the saturated perfluorinated heterocycles are expected to be chemically inert, this group of materials actually have an interesting and unusual chemistry, which can be exemplified by reductive defluorination of cyclic perfluorinated N—F amines under the action of mild reducing agents or cleavage of cyclic amines under the action of strong acids. 

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