Fluorinated 7-isomers

All of the possible ring-fluorinated isomers of 1,2,4-trioxolane are known and these can be prepared by ozonolysis of the corresponding vinyl fluorides 3-fluoro-1,2,4-trioxolane <79JOC3i8i> cis- and rani-3,5-difluoro derivatives <77JA7239> and 1,1-difluoro-1,2,4-trioxolane <83JA5047>. 

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... 

One example of the relevance of this in pharmaceutical chemistry are the two isomers 2-fluoro (2-F-NE) and 6-fluoronorepinephrine (6-F-NE) [21]. The modes of binding of these two different fluorinated isomers to their receptor are, unexpectedly, fundamentally different - 6-F-NE has agonistic a-adrenergic activity whereas 2-F-NE acts as a /i-agonist. This can be explained by the stabilization of two different preferred conformations by internal hydrogen bridges between the aliphatic hydroxy group and the aromatic fluorine (Scheme 4.15). 

The dodecyl sulfate (Y=Ci2H25SO ) salts formed mesophases and showed unusual behavior. A rich polymorphism is found N, SmA, SmC and cubic phases [20]. The single crystal X-ray structure of the methoxy homologue has been determined [16], This rich and varied polymorphism in these ionic systems may have some electrochemical applications. This mesomorphism is disturbed by lateral fluorination of the ligand 3-fluorinated isomers promote smectic phases and suppress the cubic phase while the 2-fluorinated isomers promote both the nematic and the cubic mesophase [17]. 

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). 

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-... 

Several flaoraza reagents shown in Tables 3a and 3b (B, C, E, F, J, and K) are reactive enough to fluorinate an aromatic ring (Table 1). The ortho isomer predominates in the o/mlp mixture Reagent K has been used to prepare fluorinated derivatives of tyrosine and estradiol [77 (equation 35) (Table 1, entry 10)... 

An ipso attack on the fluorine carbon position of 4-fIuorophenol at -40 °C affords 4-fluoro-4-nitrocyclohexa-2 5-dienone in addtion to 2-nitrophenol The cyclodienone slowly isomenzes to the 2-nitrophenol Although ipso nitration on 4-fluorophenyl acetate furnishes the same cyclodienone the major by-product is 4 fluoro-2,6-dinitrophenol [25] Under similar conditions, 4-fluoroanisole pnmar ily yields the 2-nitro isomer and 6% of the cyclodienone The isolated 2 nitro isomer IS postulated to form by attack of the nitromum ion ipso to the fluorine with concomitant capture of the incipient carbocation by acetic acid Loss of the elements of methyl acetate follows The nitrodienone, being the keto tautomer of the nitrophenol, aromatizes to the isolated product [26] (equation 20) Intramolecular capture of the intermediate carbocation occurs in nitration of 2-(4-fluorophenoxy)-2-methyIpropanoic acid at low temperature to give the spiro products 3 3-di-methyl-8 fluoro 8 nitro-1,4 dioxaspiro[4 5]deca 6,9 dien 2 one and the 10-nitro isomer [2d] (equation 21)... 

Miller et al. [9] hypothesized rules on the regioselectivity of addition from the study of the base-catalyzed addition of alcohols to chlorotnfluoroethylene. Attack occurs at the vinylic carbon with most fluorines. Thus, isomers of dichloro-hexafl uorobutene react with methanol and phenol to give the corresponding saturated and vinylic ethers The nucleophiles exclusively attack position 3 of 1,1-dichloro-l,2,3,4,4,4-hexafluoro-2-butene and position I of 4,4-dichloro-l,l,2,3,3,4-hexafluoro-1-butene [10]. In I, l-dichloro-2,3,3,4,4,4-hexafluoro-l-butene, attack on position 2 is favored [J/] (equation 5) Terminal fluoroolefms are almost invariably attacked at tbe difluoromethylene group, as illustrated by the reaction of sodium methoxide with perfluoro-1-heptene in methanol [/2J (equation 6). 

The behavior of strained,/Zuorimiret/ methylenecyelopropanes depends upon the position and level of fluorination [34], l-(Difluoromethylene)cyclopropane is much like tetrafluoroethylene in its preference for [2+2] cycloaddition (equation 37), but Its 2,2-difluoro isomer favors [4+2] cycloadditions (equation 38). Perfluoromethylenecyclopropane is an exceptionally reactive dienophile but does not undergo [2+2] cycloadditions, possibly because of stenc reasons [34, 45] Cycloadditions involving most possible combinations of simple fluoroalkenes and alkenes or alkynes have been tried [85], but kinetic activation enthalpies (A/f j for only the dimerizations of tetrafluoroethylene (22 6-23 5 kcal/mol), chlorotri-fluoroethylene (23 6 kcal/mol), and perfluoropropene (31.6 kcal/mol) and the cycloaddition between chlorotnfluoroethylene and perfluoropropene (25.5 kcal/mol) have been determined accurately [97, 98] Some cycloadditions involving more functionalized alkenes are listed in Table 5 [99. 100, 101, 102, 103]... 

Lewis acids promote migration of fluorine m halofluoroalkenes to yield isomers, which can be transformed easily into perfluorinated alkynes [27. 22] (equation 6)... 

Photochemical isomerization of partially fluorinated benzenes also leads to relatively stable Dewar isomers [164, 265], however, at elevated temperatures, they rearrange to benzene derivatives [166]... 

Four fluorinated acrylates are presented in Table 4 [66, 67, 68, 69] to supplement the vmyl fluoride data Perfluoroacrylic acid [70] and methyl per-fluoroaciylate [69, 70] are both reported m the literature. The cts and trans isomers of fluoroethylenes are readily distinguished by the magnitude of their couphng constants, with trans typically more than 3 times the magnitude of cis... 

Sulfanuric halides contain the characteristic group -N=S(0)X- (X = Cl, F). Unlike the isoelectronic cyclophosphazenes (NPClajx (x = 3-17), " only six-membered rings have been well characterized. The sulfanuric halides are colourless solids (X = Cl) or liquids (X = F), which are stable in dry air. Sulfanuric chloride [NS(0)C1]3 is best prepared by treatment of SOCI2 with sodium azide in acetonitrile at -35°C (Eq. 8.16). It may also be obtained as a mixture of a- and yS-isomers in a two-stage reaction from H2NSO3H and PCls. The fluoride [NS(0)F]3 is formed as a mixture of isomers by the fluorination of [NS(0)C1]3 with Sbp3. ... 

The fluoride [NS(0)F]3 is more stable thermally and towards nucleophilic reagents than the corresponding chloride. For example, 8.15a is hydrolyzed by water to NH(S02NH2)2, whereas sulfanuric fluoride is unaffected by cold water. In warm water, however, hydrolysis occurs to give the [N3S304F2] anion. All three fluorine atoms in [NS(0)F]3 can be replaced by primary or secondary amines at 80-90°C in the absence of a solvent. Mono- or diphenyl derivatives can be prepared by treatment of [NS(0)F]3 with PhLi in diethyl ether at -70°C, while the Friedel-Crafts reaction with benzene at reflux in the presence of AICI3 gives two isomers of [NS(0)Ph]3. ... 

Newman projections are helpful in determining the proper dihedral angles for the fluorines and hydrogens. Here are diagrams for the RR isomer, looking down the C-C bond in both directions ... 

The use of nitrogen anions in this process has not been well investigated. Nitrogen anion (36) readily substituted fluorine in perfluoroazaaromatics and the products could be rationalized on the basis of kinetic and thermodynamic control. With tetafluoropyridazine and CsF as a source of F, none of the expected 4,5-isomer was obtained. For 4,5 substitution a less... 

Kirk and Cohen (1969, 1971, 1973 Kirk et al., 1973) successfully applied the photo-fluoro-de-diazoniation method for the introduction of fluorine into imidazole and its derivatives with various substituents (e.g., histidine) 2- and 4-fluoroimi-dazole had not previously been synthesized by other methods. 2-Fluoroimidazole, in contrast to the 4-isomer, is easily hydrolyzed in water (Kirk et al., 1973). 

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