Furan fluorination

Furan-2-carboxylic acid reacts with sulfur tetrafluoride at 0 °C to give 2-furoyl fluoride, but attempts at further fluorination results in resin formation [222] A second carboxylic group and/or electron withdrawing substiments, such as the nitro or tnfluoromethyl group, stabilize the furan ring Thus, turandicar-... 

Treatment of 2,5 and 2,4-furandicarboxylic acids with sulfur tetrafluonde in an excess of hydrogen fluoride leads simultaneously to conversion of the carboxylic groups into trifluoromethyl groups and addition of two fluorine atoms to the furan ring to give highly fluorinated diastereoisomersof2,5-dihydrofuran [225,226,227] (equations 117 and 118)... 

Irradiation of cyclic ketones having perfluoroalkyl groups causes cleavage of a ring to yield acyclic products [I74 (equation 44) Similarly, perfluonnated ketones undergo decarbonylation when irradiated [775]. Gas-phase photolysis of perfluorodiazoketones, in the presence of a trapping agent, yields fluorinated furan as a major product [176] (equation 45)... 

Direct fluorination of five-membered heterocyles gave products that were dependent on the heterocycle. For example, pyrrole yielded tar, whereas there was predominantly syn 1,4- addition of fluorine to furan (90G749). 

High-valency metal fluoride fluorination of pyridine [82JFC(21)171], quinoline [82JFC(21)413], and 2-methylfurans [91 JFC(51)179] has been reported. With 2-methylfuran a complex mixture of stereoisomers of partially fluorinated oxolans was obtained. These can be dehydrofluorinated to fluorooxolens and no furans have been observed. Conformation and structural group were found to influence the direction and readiness toward dehydrofluorination [91 JFC(52) 165]. 

As was the case for pyrroles, fluorine substituents at the 2-position are greatly deshielded relative to those at the 3-position of furans and benzofurans (Scheme 3.65). 

The pair of difluorofurans given in Scheme 3.66 also exhibits the significant difference in fluorine chemical shift between the 2- and the 3-positions of furan. 

Unlike the nitrogen of pyrroles and the oxygen of furans, the sulfur of thiophenes does not significantly affect fluorine chemical shifts either inductively or as an electron donor. Thus, the fluorine chemical... 

The reaction of benzyne with furan was the first example of a Diels-Alder reaction of benzyne to be studied b. No authenticated examples of arynes are known which fail to give cyclo-adducts with furan i38>. The tetrahalogenobenzynes all form the expected adducts 103, X = F 6), Cl 57>i39)j gr 59) or i 59)). d0 other highly fluorinated arynes i40,i4i>. The isomeric adducts (104) and (105) have been detected by 19F n.m.r. spectroscopy when the dilithio-compound (12) was allowed to decompose in the presence of furan 28 103). 

Hydroxymethyl)furan, Triethylamine Jenzen, A. F. et al., J. Fluorine Chem., 1988, 38, 205-208 Reaction of sulfur tetrafluoride with 2-hydroxymethylfuran in presence of triethylamine at —50°C is explosive in absence of a solvent. 

The development of synthetic methods for the selective introduction of short-chain perfluoroalkyl groups into organic molecules is of interest in drug development [464]. Fluoromodifications often confer unique properties on a molecule, for example in terms of increased metabolic stability and lipophilicity and, as a consequence, the pharmacokinetic profiles are often improved [465]. Burger and coworkers developed a domino process consisting of a SN reaction combined with a Claisen and a Cope rearrangement which allows the transformation of simple fluorinated compounds into more complex molecules with fluoro atoms [466]. Treatment of furan 2-917 with 2-hydroxymethyl thiophene (2-918) in the presence... 

Scheme 2.205. Unusual domino reaction of a fluorinated furan 2-917.

MCP (1) is not known to undergo [4 + 2] cycloadditions. The substitution of two, or more, ring protons with fluorine atoms, however, seems to improve dramatically the dienophilic reactivity of the exocyclic double bond. 2,2-Di-fluoromethylenecyclopropane (5) is a quite reactive dienophile in Diels-Alder cycloadditions. With cyclopentadiene (6) and furan (7), it formed two isomeric adducts (Scheme 1) [9]. In both cases the adduct with the endo CF2 group is the major isomer. 

Cycloaddition of furans followed by a subsequent transformation is still adopted as a useful strategy to prepare fluorine-containing benzene derivatives and isoquinoline compounds <00SL550>. The cycloaddition adduct can also be converted to a trifluoromethyl substituted cyclohexanone compound via hydrogenation and hydrolysis. Examples of these transformations are illustrated below. 

In the case of the fluorine-substituted allene 85 with Ag(I) catalyst, only the product of a cyclization/elimination process, the furan 86, was produced (Scheme 15.20)... 

Fluorine reacts with N-methylpyrrole and thiophene to give mixtures of mono-fluorinated isomers, consistent with an electrophilic fluorination process (Fig. 58) [152, 153], whilst furan gives a mixture of products largely resulting from addition of fluorine to the ring. The conversions of the reactions reported... 

Similarly, l-bromo-l,l-difluoro-2-alkynes, which were prepared by the reaction of lithium acetylides with CF2ClBr [284] or CF2Br2 [285], also reacted with carbonyl compounds in the presence of zinc to afford the corresponding a,a-difluoropropargyl alcohol [285]. This reaction has been utilized for the preparation of 3-fluoro-2,5-disubstituted furans [286] and other fluorinated biologically active compounds [285,287] (Scheme 99). 

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). 

Furan-2,3.4-tricarboxylic acid,155 2-(trifluoromethyl)furandicarboxylic acids.152 and tris(tri-fluoromethyl)-2-furoic acid.156 even in excess hydrogen fluoride and under forcing reaction conditions, give exclusively the corresponding poly(trifluoromethyl)furans. e.g. formation of 14 no addition of fluorine to the ring carbons occurs. 

Sulfur tetrafluoride fluorination of the methyl group has been reported.253 Thus, the reaction with 2,5-dimethylfuran-3,4-dicarboxylic acid gives, besides the expected acid fluoride 16 and 2,5-dimethyl-3,4-bis(trifluoromethyl)furan (17a), higher fluorinated compounds, 2-(difluoro-methyl)-5-methyl-3,4-bis(trifluoromethyl)furan (17b) and 2-methyl-3,4,5-tris(trifluoromethyl)-furan (17c). Low yields are due to considerable tar formation. 

Furan-2,5-dicarboxylic acid reacts similarly, but a temperature of 150°C is required for the reactions to proceed. Again, reaction in the presence of disulfur dichloride gives exclusively the fluorinated product, 2,5-difluoro-2,5-bis(trifluoromethyl)-2,5-dihydrofuran (21), while in the presence of chlorine a mixture of chlorofluoro derivatives 22 and 23 is formed.245... 

Potassium tetrafluorocobaltate(III) at 200°C reacts with tetrahydrofuran to give82 unsaturated products the major ones are 5 and 6, although the overall yield is poor (< 30%). Furan itself gives no products at all over cobalt(IIl) fluoride it presumably polymerizes. This does not, however, rule furan out as an intermediate in the tetrahydrofuran fluorinations (it could form by desaturation, as does benzene in the fluorination of cyclohexane, vide supra). 2-Methyl-and 2,5-dimethyltetrahydrofuran83 have also been fluorinated with similar results to tetrahydrofuran. 

A large number of fluorinations of partially fluorinated ethers have been successfully carried out. A few examples are fluorination of methyl 2,2,2-trifluoroethyl ether (12),85 1,1,2,2-tetrafluoroethyl 2,2,2-trifluoroethyl ether (13),85 2-(l,l,2,3,3,3-hexafluoropropyl)tetrahydro-furan (14),86 difluoromethyl 2,2,2-trifluoroethyl ether (15),10 and bis(2,2,2-trifluoroethyl) ether (16).10 Manganese(III) fluoride is more reactive than cobalt(III) fluoride in the last two fluorinations. 

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