Difluorine reactions, 445

Many aldehydes and ketones have been converted to g m-difluoro compounds with sulfur tetrafluoride (SF4), " including quinones, which give 1,1,4,4-tetra-fluorocyclohexadiene derivatives. With ketones, yields can be raised and the reaction temperature lowered, by the addition of anhydrous HF. Carboxylic acids, acyl chlorides, and amides react with SF4 to give 1,1,1-trifluorides. In these cases the first product is the acyl fluoride, which then undergoes the ge i-difluorination reaction ... 

The author next tried to stabilize the PGI2 structure by introducing second fluorine atom to the 7-position. However, it had been unknown to make such a difluorovinyl ether unit in the literature. We studied difluorination and Wittig reaction as key steps in the synthetic route of the target difluoro-PGl2 from the Corey lactone. After searching the difluorination reaction, it was found that fluorination with A/-fluorobenzenesulfonimide in the presence of potassium bis(trimethylsilyl) amide and manganese dibromide effectively provided the desired difluoride (Table 7) [106]. 

Depending on the fluonnating agent, diazoalkanes, diazoketones, and diazoesters can undergo hydrofluonnation, halofluonnation, and geminal difluorination reactions... 

However, the current efficiency for this difluorination reaction is extremely low because of competitive oxidation of EtjN-SHF and the starting compound. On the other hand, gm-difluorinated products 64 can be obtained directly from the organic sulfur compounds 41 by using the less oxidizable salt Et4NF4HF as shown in Scheme 50. In these cases, theoretical amounts of electricity must be employed to bring about complete fluorination. 

Although NFSI was successful for the monofluorinations, it was not as active in the difluorination reactions and tended to form mixtures of the mono- and difluorinated compounds. After some experimentation, N-fluoro-2,4,6-trimethylpyridinium triflate was found to be more active in the difluorination reaction and generated moderate to excellent yields of the functionalized compounds (Example 7.18). 

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 extent of mono- versus difluorination of etiolates may also be controlled through the use of N-fluorosultam (Table 3a, G). With a base/W-fIiioro com-pound/substrate ratio of 1.2/1.3-1 6/1, the reaction yields inonofluoro products, but with a ratio of 2.4-3.6/2.6-3 6/1, the difluorinated compounds are obtained [68] (equation 42)... 

A rather complex microwave-assisted ring-opening of chiral difluorinated epoxy-cyclooctenones has been studied by Percy and coworkers (Scheme 6.131) [265]. The epoxide resisted conventional hydrolysis, but reacted smoothly in basic aqueous media (ammonia or N-methylimidazole) under microwave irradiation at 100 °C for 10 min to afford unique hemiacetals and hemiaminals in good yields. Other nitrogen nucleophiles, such as sodium azide or imidazole, failed to trigger the reaction. The reaction with sodium hydroxide led to much poorer conversion of the starting material. 

Dichlorine shortens the induction period of autoxidation of paraffin wax [187] and accelerates the oxidation of hydrocarbons [109]. Difluorine is known as very active initiator of gas-phase chain reactions, for example, chlorination [188,189]. 

Another fast reaction of radical initiation is the difluorine addition to the double bond of the unsaturated compounds [192-194] ... 

In contrast to the cathodic reduction of organic tellurium compounds, few studies on their anodic oxidation have been performed. No paper has reported on the electrolytic reactions of fluorinated tellurides up to date, which is probably due to the difficulty of the preparation of the partially fluorinated tellurides as starting material. Quite recently, Fuchigami et al. have investigated the anodic behavior of 2,2,2-trifluoroethyl and difluoroethyl phenyl tellurides (8 and 9) [54]. The telluride 8 does not undergo an anodic a-substitution, which is totally different to the eases of the corresponding sulfide and selenide. Even in the presence of fluoride ions, the anodic methoxylation does not take place at all. Instead, a selective difluorination occurs at the tellurium atom effectively to provide the hypervalent tellurium derivative in good yield as shown in Scheme 6.12. 

In fluorine thermochemistry, two key heat values frequently occur. They are the dissociation energy of difluorine, required for evaluation of fluorine bond energies and the heat of formation of hydrogen fluoride, a product in hydrolysis, hydrogenation, fluorine combustion, or neutralization reactions. These values have been difficult to measure and have changed considerably over the years. A recommended set of values has been reported in recent CODATA bulletins (60) which are collected in Table I together with older values and corrections to update them. 

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)." ... 

Treatment of the symmetrical triaminopyrimidine (50-1) with sulfuryl chloride ties up the two adjacent amines in a thiadiazole ring, protecting those groups from attacks in subsequent reactions. Reaction of the product (50-2) with ortho difluorinated benzylamine (50-3) results in the replacement of the pyrimidine amino group by that in the reagent most hkely by an addition-elimination sequence to afford (50-4). That amino group is then converted to the formamide (50-5) with formic acid. Exposure of the product to Raney nickel leads to a loss of sulfur and the formation of the transient intermediate (50-6). This cyclizes to a purine... 

Reactions with imines also occur under similar conditions leading to the formation of difluorinated /1-lactams [196,197]. Formally, this reaction corresponds to a [2+ 2]-cycloaddition across an imine there is also an isolated report of a difluoroketene reaction, shown in Eq. (63) [198]. Useful chemistry of a silyl difluoroketene acetal was reported recently Eq. (64) shows the efficient asymmetric reaction between this reactive carbon nucleophile and aldehydes catalysed by chiral Lewis acids [199]. 

This effect cannot be explained by simply considering differences in frontier orbital energies. A useful monofluorinated dienophile has been prepared [364] using metallated difluoroenol carbamate chemistry (Eq. 143) cycloaddition occurred smoothly with a range of dienes, and desulfination could be achieved under mild conditions without loss of the fluorine atom. Wakselman and co-workers [365] synthesised a rare competent difluorinated dienophile. Lewis acid catalysed Diels-Alder reaction with furan afforded an acceptable yield of (unfortunately) unstable cycloadduct which decomposed to a phenolic product via a dehydrofluorination reaction, circumscribing its utility (Eq. 144). 

Difluorine is an extremely active reagent and reacts with organic molecules at low (200 and lower) temperatures. Such a high activity of difluorine is due to the very high BDE of the formed hydrogen fluoride molecule (-DF H = 570 kJ mol ) and the relatively low BDE in the difluorine molecule (DF F = 158.7 kJ mol-1). Due to this great difference in the BDE of the reactants and the products, bimolecular reactions of hydrogen atom abstraction... 

F-Teda BF4 (6) has also been used for the gem-difluorination of active methylene compounds, / -oxo esters and amides.102 The reaction times can be significantly reduced by carrying out the two fluorination steps sequentially and, importantly, with the sodium enolate of the monofluoro intermediate for the second step. 

The selective oxidation of C—H bonds in alkanes under mild conditions continues to attract interest from researchers. A new procedure based upon mild generation of perfluoroalkyl radicals from their corresponding anhydrides with either H2O2, m-CPBA, AIBN, or PbEt4 has been described. Oxidation of ethane under the reported conditions furnishes propionic acid and other fluorinated products.79 While some previously reported methods have involved metal-mediated functionalization of alkanes using trifluoroacetic acid/anhydride as solvent, these latter results indicate that the solvent itself without metal catalysis can react as an oxidant. As a consequence, results of these metal-mediated reactions should be treated with caution. The absolute rate constants for H-abstraction from BU3 SnH by perfluorinated w-alkyl radicals have been measured and the trends were found to be qualitatively similar to that of their addition reactions to alkenes.80 a,a-Difluorinated radicals were found to have enhanced reactivities and this was explained as being due to their pyramidal nature while multifluorinated radicals were more reactive still, owing to their electrophilic nature.80... 

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