Tetrahydrofurans, fluorination

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. 

Phenyllithium caimot be formed from fluoroben2ene. Instead, the electronegativity of fluorine makes the ortho hydrogen sufficiently acidic to permit reaction with / -butyUithium in tetrahydrofuran at —50°C to give 2-fluorophenyllithium [348-53-8]. An isomer, 4-fluoropheny11ithium [1493-23-8] was reported to be explosive in the soHd state (167). 

Properties have been determined for a series of block copolymers based on poly[3,3-bis(ethoxymethyl)oxetane] and poly [3,3-bis(methoxymethyl)oxetane]- (9-tetrahydrofuran. The block copolymers had properties suggestive of a thermoplastic elastomer (308). POX was a good main chain for a weU-developed smectic Hquid crystalline state when cyano- or fluorine-substituted biphenyls were used as mesogenic groups attached through a four-methylene spacer (309,310). Other side-chain Hquid crystalline polyoxetanes were observed with a spacer-separated azo moiety (311) and with laterally attached mesogenic groups (312). 

The enamines, enol ethers and enol acetates of A -3-keto steroids provide important substrates for fluorination with FCIO3. Reaction of such A -enol ethers and acetates (6) with perchloryl fluoride results in 6a- and 6jff-fluoro-A -3-ketones (7) and (8), the latter representing the more abundant isomer. Tetrahydrofuran or dioxane-water mixtures appear to be particu-... 

Hydrogen fluoride adds to more complex molecules, such as unsaturated steroids, to give fluorinated derivatives [/, 8] Low temperatures and inert diluents, such as tetrahydrofuran or methylene chloride, are generally employed. With bicyclic unsaturated terpenes, rearrangements often accompany addition to the double bond [/]. 

Mixtures of anhydrous hydrogen fluoride and tetrahydrofuran are successfully used as fluorinating agents to convert 1,1,2-trifluoro-l-allcen-3-ols, easily prepared from bromotrifluoroethene via lithiation followed by the reaction with aldehydes or ketones, to 1,1,1,2-tetrafluoro-2-alkenes The yields are optimal with a 5 1 ratio of hydrogen fluoride to tetrahydrofuran The fluorination reaction involves a fluonde lon-induced rearrangement (Sf,j2 mechanism) of allylic alcohols [65] (equation 40)... 

A variety of media have been used for the Wallach fluorination reaction anhydrous hydrogen fluoride alone or with cosolvents such as methylene chloride, benzene, or tetrahydrofuran and hydrogen fluoride-pyridine alone or with co solvents such as benzene, glyme, or acetic acid [42,43, 46 50] Solutions of cesium fluoride, tetraethylammonium fluoride, or tetrabutylammonium fluoride in strong acids such as methanesulfonic acid or trifiuoroacetic acid with numerous cosolvents have also been studied [48, 49]... 

Reductive removal of fluorme from alk I fluorides requires a potent reducing agent and so is not noimally encountered However, hydrogenolysis of an unacuvated carbon-fluorine bond in, for example, 3 (3-fluorocholestane has been efficiently accomplished in 88% yield with a solution of potassium and dicyclohexyl 18 crown-6 in toluene at 25 C [/] Similarly, sodium naphthaiene in tetrahydrofuran converts 6 tluorohexene-1 and 1-fluorohexane to hydrocarbons in 50% yield at 25 C over a 7-h penod [2]... 

The spectral properties of pentafluorophenylcopper te-tramer are as follows infrared (Nujol) cm. 1630 medium 1391 medium 1353 medium 1275 medium 1090,1081, and 1071 strong triplet 978 strong 785 medium fluorine magnetic resonance (tetrahydrofuran with trichlorofluoromethane as internal reference) 8 (multiplicity, number of fluorines, assignment, coupling constant J in Hz.) 107.2 (20-line multiple , 2, ortho F), 153.4 (triplet of triplets, 1, para F, J= 1.3 and 20), 162.3 (17-line multiplet, 2, meta F). Absorptions at 820-900, 1100-1125, and 1290 cm.- in the infrared spectrum and at 8 3.05 in the proton magnetic resonance spectrum indicate that dioxane is still present. 

Fluorine at the equatorial 6a position also results in an increase in potency. One scheme for the production of such a compound relies on the shift of the double bond from the 4,5 to the 5,6 position, which follows the formation of an acetal at position 3. The scheme starts with the selective reduction of the 11 ketone in the cortisone intermediate (13-2). Epoxidation of the product (18-1) with a peracid takes place selectively at the unconjugated double bond to give the 5a,6a oxirane (18-2). Treatment of that with hydrogen fluoride in tetrahydrofuran leads to fluorohydrin (18-3). (There is evidence to indicate that the reagent involves an HF THF acid base complex since the omission of THF in at least some cases leads to a complex mixture of rearrangement products [15].) The side chain in fluorohydrin (18-3) is then converted... 

Fluorination of bicyclic derivatives, which has been used in prostaglandin synthesis from nor-bornadicne, gives a 1 1 mixture of two isomeric ot-fluoro esters, e.g. 3.18 The reaction is performed in tetrahydrofuran at — 78 °C, while a violent explosion occurs if the reaction is performed at — 40 C (upon quenching the reaction with water). 

Testosterone enol diacetate reacts with perchloryl fluoride in aqueous dioxane to give 6a- and 6/i-fluorotestostcrone 17-acetatc (18 X = a-F, /i-F) as the major products along with 6a- and 6/3-hydroxytestosterone 17-acetate (18 X = a-OH, /j-OH) and also 17/i-hydroxyandrostane-3,6-dione 17-acctate.31 The enamine derivative 3-(pyrrolidin-l-yl)estra-3,5-dien-17/i-ol can be fluorinated in methanol at —25 to — 35 C to provide 4/J-fluoro-3a-methoxycstr-5-ene-3/f 17/ -diol (19),32 while various 2-fluoro-3-oxoestranc derivatives 20 are formed by fluorination of a number of 3-methoxyestrane derivatives in tetrahydrofuran/water mixture with perchloryl fluoride.33... 

In the low-temperature fluorination of benzofuran (39, Y = O) and 1-acetylindole (39. Y = NAc), addition reactions are observed as well as vicinal fluoro trifluoromethoxy adducts 40A and 40B, vicinal difluoridcs 41 are formed.63 Trichloromethiazide is converted into the 5-fluoro derivative 42 in tetrahydrofuran/hydrogen fluoride at 0 C (in dichloromethanc/acetone 42 is accompanied by two nonfluorinated products).64... 

Cesium fluoroxysulfate in acetonitrile medium at 35 C converts primary alcohols and alkyl and aryl aldehydes into acid fluorides in high yields.i" Hammett correlation analysis of the fluorination of various benzene-substituted aldehydes gives the reactivity constant31 q = —0.38. It has been shown that solvent polarity plays an extremely important role in the conversion of aldehydes into fluorides the conversion is almost quantitative in acetonitrile, but completely stopped in dichloromethane, hexane or tetrahydrofuran. The presence of ni-... 

V-Fluorobis(phenylsulfonyl)amine (1 a) can be synthesized in a one-step reaction using commercially available bis(phenylsulfonyl)amine (up to 0.2 mol) and fluorine (10% F2/N2,1 equiv) in the presence of powdered sodium fluoride, either in acetonitrile at — 40 °C in an ambient pressure reactor131 or in trichlorofluoromethane/chloroform, water or a water-miscible organic solvent.133 iV-Fluorobis(phenylsulfonyl)amine (la) is soluble in most organic solvents, e.g. diethyl ether, tetrahydrofuran, dichloromethane. acetonitrile and toluene.131 133... 

Tetrahydrofuran is partially fluorinated over cobalt(III) fluoride81 and potassium tetra-fluorocobaltate(III).82 With cobalt(III) fluoride at 100-1 IO C,27 products are obtained with an overall yield of about 50 60%. Most are polyfluorooxolanes 2-4, and the rest (13% of the product mixture) polyfluoropropanes. The major products are 2 (15%), 3 (29%), and 4 (29%) (since the various stereoisomers are equilibrated at the positions next to oxygen in the fluorination process, the total percentages for each set of constitutional isomers are shown, and not the percentages for each stereoisomer). 

Silver(II) fluoride and potassium tetrafluoroargentate(III) are too powerful as fluorinating agents for tetrahydrofuran and no oxygen-containing products are detected."... 

The fluorination of oxathiane is described in Section 25.1.1.3.84 1,4-Dithiane reacts quite differently107 from dioxane and oxathiane over potassium tetrafluorocobaltate(III). The major products (ca. 60 % of the product mixture, itself in ca. 50 % yield) are the result of rearrangement to the 2-methyl-l, 3-dithiolane skeleton, e.g. 1-3. Fluorinated 1,4-dithiancs comprised about 30% of the product the major product is 4. The extent of fluorination, that is the number of fluorine atoms introduced, is much greater than that of dioxane under comparable conditions (tetrahydrothiophene and tetrahydrofuran show a similar contrast). 

The product from the fluorination of thiophene over potassium tetrafluorocobaltate(III) varied, not surprisingly, with temperature.108 At 120 C, virtually the sole product was the dihydrothiophene 5, albeit in low yield (14%) this compound is obviously analogous to 2,2.5,5-tetra-fluoro-2,5-dihydrofuran from tetrahydrofuran and potassium tetrafluorocobaltate(IIl). At 350-370 °C, 5 is still a major product, but now seven others are also present, the main ones being 6-8 and the sulfur extruded product perfluorobutane. 

Aryltriazenes can also be decomposed by hydrogen fluoride in organic solution after extraction from their aqueous mother phase. In this case, hydrogen fluoride can be used in small excess but the nature of the solvent is crucial for example, tetrahydrofuran gives complex mixtures, dichloromethane promotes radical reactions (dimerizations, reductions) and acetic acid favors triazene decomposition before fluorination. Aromatic and haloaromatic compounds seem to be the best solvents.283 Such a technique, especially suited for the rapid introduction of an 18F atom, has been employed to produce [ 8F]haloperidol (3), the specific receptors of which have been localized in the brain by positron emission transaxial tomography.298... 

The mechanism for the cyclization of these perfluoro ketones, proposed by German and coworkers5 and discussed in the review by Krcspan and Petrov.4 involves initial activation of the carbonyl with antimony V) fluoride and a 1.4-fluorine shift from the /1-trifluoromethyl group. The resultant difluoromethylene carbocation then cyclizes with the carbonyl oxygen to give the tetrahydrofuran. 

In a similar structure, both benzylic fluorines in 1,4-difluoro-l, 1,4,4-tetraphenylbutane are easily replaced with hydrogen or deuterium using lithium aluminum hydride or lithium aluminum deuteride, respectively, in refluxing tetrahydrofuran (47 h) in 31 % isolated yield.74... 

The only known method enabling a selective replacement of a-fluorine substituents in aliphatic polyfluorinated esters without affecting the carbonyl group is pholoinduced reduction (e. g., 1 - 2) the reaction yield is dependent on the solvent (hydrogen donor) used, e. g. propan-2-ol > tetrahydrofuran > 1,3-dioxolane.106 The reactivity of fluorinated esters is also dependent on the group attached to the /(-carbon, e. g. 3 > 4 > 5.106... 

Systems containing radical anions are capable of eliminating fluorine efficiently. Sodium/ benzophenone in tetrahydrofuran defluorinates perfluorocycloalkanes (perfluorodecahy-dronaphthalene, perfluorotetradecahydrophenanthrene) to give perfluoroaromatics 4 and 5138 on a preparative scale at ambient temperature. The reactivity of perfluorocyclohexane under these conditions is very low. 

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