Displacement of fluorine

Intramolecular Nucleophilic Displacement of Fluorine Hudlicky, M Isr J Chem 17, 80-91 68... 

Acetylated aniline 21 was reacted under Skraup/Doebner-von Miller conditions in the presence of an arsenic salt to yield quinoline 22 with concurrent displacement of fluorine. ... 

Similarly to the oxadiazine system 158, reaction of 162 with a series of amines was performed. Nucleophilic displacement of fluorine atom only at 10-position occurred when the 9,10-difluoro derivative 162a was treated with various amines (such as pyrrolidine, 4-methylpiperazine, morpholine, 4-ethoxycarbonylpiperazine) in the presence of a catalytic amount of DBU in refluxing acetonitrile or pyridine to give compounds 163. When the... 

Second, metabolism of 6-fluoroBP by rat liver microsomes yields the same BP quinones obtained in the metabolism of BP (23). This suggests that these products are formed by an initial attack of a nucleophilic oxygen atom at C-6 in the 6-fluoroBP radical cation with displacement of the fluoro atom. In fact, when 6-fluoroBP is treated with the one-electron oxidant Mn(0Ac)3, the major products obtained are 6-acetoxyBP and a mixture of 1,6- and 3,6-diacetoxyBP (15), indicating that reaction occurs via an initial attack of acetate ion at C-6 of the 6-fluoroBP radical cation. On the other hand electrophilic substitution of 6-fluoroBP with bromine or deuterium ion shows no displacement of fluorine at C-6, although in both cases substitution occurs at C-l and/or C-3. These results indicate that... 

The small effect on reaction rates of the addition of crown ethers to the lower alcohols was also observed in the reaction of potassium acetate with 1-bromobutane in ethanol (Hirao et al., 1978a,b). The displacement of fluorine in either o-nitro- or p-nitro-fluorobenzene by a methoxy group, by reaction with potassium methoxide in methanol was hardly influenced by the presence of dicyclohexyl-18-crown-6 (Del Cima et al., 1973). Mariani et al. (1978), too,... 

In sharp contrast to the KOCH3/CH3OH system, the KOt-Bu/t-BuOH combination is quite sensitive to the presence of cation-complexing agents, as was shown by Del Cima et al. (1973). Whereas on addition of ([20] + [21]), the rate of displacement of fluorine by reaction with KOt-Bu increased by only a factor of 3 in the case of l-fluoro-2-nitrobenzene, it increased by a factor of 1.4 x 103 for l-fluoro-4-nitrobenzene (Table 23). Consequently, the... 

In the reaction of 1-naphthol with 3-nitro-4-fluorobenzalmalononitrile in ethanol, catalyzed by secondary amines, nucleophilic displacement of fluorine competes with pyran ring closure. Application of a tertiary amine (N-methylmorpholine) leads to the selective formation of the corresponding aminochromene (94H(38)399). 2,3-, 1,8-Dihydrooxynaphthalenes 148 and 149 react with 1 or 2 equiv. of aromatic aldehyde 28 and MN 27a to yield naphthopyrans 150 and 151 or dipyrans 152 and 153 (90IJB885, 02RCB2238) (Scheme 53). 

Alkoxylation in the benzene ring of quinazolines and quinazolinones is readily achieved in the presence of an ortho-nitro group, and even in the absence of a nitro group, displacement of fluorine is still quite facile. Examples of haloquinazolines to have been alkoxylated include 5-chloro-8-nitro-4(3//)-quinazolinone 187 <2005BMC5613>, 7-chloro-6-nitro-4(377)-quinazolinone 188 <1996JME267>, 4-arylamino-7-fluoro-6-nitroquinazolines 189... 

Yet a further variation of this theme consists in the replacement of the bridging methylene group by sulfur to give a thiadiazepine as the central ring. The starting thiophene ether (26-3) is obtained by the nucleophilic aromatic displacement of fluorine in nitrobenzene (26-1) by the anion from imidazole-2-thiol (26-2). The nitro... 

Sadly then, the first attempt to retain a C — F bond in an organic fluoride, whilst a functional group was replaced, failed. A reaction far more significant in organo-fluorine chemistry than the planned one had been hidden by the misinterpretation however. The first recorded nucleophilic displacement of fluorine from an aromatic C —F bond had occurred a process to become of vast importance. 

Diazotization in the presence of boron trifluoride enables diazonium tetrafluoroborates to be isolated from the reaction mixture and purified. Subsequent controlled decomposition produces the required fluoroaromatic. Although explosion hazards and the toxicity of the isolated salts are significant concerns with this process, known as the Balz-Schiemann process, 4,4 -di-fluorobenzophenone (BDF. 6) has been prepared by this route as a monomer for the production of the engineering plastic poly(ether ether ketone) , or PEEK , by condensation with 1,4-dihydroxybenzene in the presence of potassium carbonate. BDF 6 is superior to its chlorine analog because in aromatic systems the nucleophilic displacement of fluorine is more facile than that of chlorine, leading to a shorter polymerization time and a better quality product containing less degradation impurities. 

A consequence of the high C —F bond strength is that fluorine is an especially poor leaving group. Alkyl fluorides are 102-106 less reactive toward nucleophilic displacement than other alkyl halides.8 9 gera-Difluorides and trifluoromethyl groups are essentially unreactive toward nucleophilic displacement of fluorine. 

Several mechanisms are involved in the displacement of fluorine by hydrogen and these can be divided into two groups, namely radical-type and nucleophilic hydrodefluorinations. The most general is a radical mechanism involving reductive cleavage of the fluorine bond. Radical catalytic hydrogenolyses take place at the catalyst surface ... 

In perfluorinated tetraalkylethenes, the displacement of fluorine with hydrogen during catalytic hydrogenation can be accompanied by allylic rearrangement. 

A nucleophilic mechanism can be applied in reductions with complex hydrides of highly fluori-nated aliphatic and alicyclic fluoroalkenes with electron-deficient C = C bonds the hydride anion adds as a strong nucleophilic agent to the more electrophilic carbon atom the intermediate anion can then lose a fluoride ion either from the original C = C bond, or from the allylic position finishing an SN2 displacement of the fluorine. Thus, the reductions of vinylic C-F bonds with hydrides proceed by a nucleophilic addition-elimination mechanism. Displacement of fluorine in highly fluorinated aromatic compounds proceeds by the same mechanism ... 

Some unusual reactions involving tris(pentafluorophenyl)methanol (14) occur in strong acids. In concentrated sulfuric acid, displacement of fluorine occurs giving 4-[bis(pentafluorophenyl)-mcthylene]tetrafluorocyclohexa-2,5-dienone (15).48... 

Due to the pharmaceutical importance of their reaction products, a number of fluorinated 4-oxo-l,4-dihydroquinoline-3-carboxylic acid derivatives have been treated with various thiols (Table 8). The displacement of fluorine proceeds under moderate conditions regiosclcctively at C-7 or C5 giving 2 or 3, respectively in the ease of the 5,6,7,8-tetrafluoro derivative, fluorine is replaced at C5 in a nonpolar solvent, e.g. toluene, and at C7 in polar solvents, e.g. ethanol.18... 

Examples of the use of lithium aluminum hydride in stereoselective [75] (equation 9), regioselecuve [76] (equation 10), and product-selective [7 7] (equation 11) displacements of fluorine are available... 

In an unusual example of displacement of fluorine by hydroxyl, hydroxyl radicals attack fluorinated benzenes Hexafluorobenzene is the least reactive The hydroxyl radical generates the pentafluorocyclohexadienonyl radical from it [13] (equation 13) These unstable species are detected spectroscopically Their disap-... 

Pentafluoro-, 2,3,5,6-, 2,3,4,6- and 2,3,4,5-tetrafluorobenzaIdehyde readily form benzylidene derivatives with rhodanine.110 The products are hydrolyzed by base to /3-aryl-a-mercaptoacrylic acids, which cannot be isolated, but which spontaneously cyclize by nucleophilic displacement of fluorine to give 4,5,6,7-tetrafluoro- and 4,5,7-, 4,6,7-and 5,6,7-trifluorobenzo[6]thiophene-2-carboxylic acid, respectively. 

Displacement of fluorine in arenes.3 Attempted demethylationofl withC2H5SNa results also in displacement of the fluorine by SC2H5 to give 2. The fluorine is also partially displaced by Br on demethylation with BBr3 in CH2C12. Demethylation of 1 with Nal and (CH3)3SiCl is not successful. 

Displacement of fluorine from gem-difluoroalkenes has been developed as methodology for fluorine-free synthesis [108] (Scheme 49). 

The pentamer of tetrafluoroethene (66) (Scheme 29) is an unusual example of type (96) and reacts readily with nucleophiles [129] (Scheme 65). In contrast, (66) undergoes a remarkable reaction with aqueous triethylamine, producing the dihydrofuran derivative (101) and the process formally involves a direct intramolecular displacement of fluorine from a saturated site and a mechanism has been advanced (Scheme 66) which accounts for the product formed [126]. Understandably, this process is not easily accepted [3, 130] because it has essentially no precedent. Indeed, it is well established that nucleophilic displacement from saturated sites in fluorocarbons occurs only in exceptional circumstances. Consequently, other mechanisms have been advanced, which seem no more convincing [3, 130]. It should be remembered that the major point in favour of the step (100) to (101) (Scheme 66) is that the nucleophile is generated in close proximity to the reaction centre because of the special geometry of this situation. Consequently, much of the otherwise high energy/entropy barrier has already been overcome in this case. 

Nucleophilic displacement of fluorine from the activated aromatic nucleus in 469 gave 470 (Equation 76) <2003T5259>. 

The first step in the hydrolysis in tert-butyl alcohol is probably nucleophilic displacement of fluorine in the reactive allylic position. Spontaneous elimination of hydrogen fluoride from the geminal fluorohydroxy compound yields perfluorocyclopent-2-en-l-one. 

The reaction in diglyme starts with a nucleophilic displacement of fluorine at the double bond, whose electron density is decreased by the vicinity of strongly electronegative difluoromethylene groups. 

Nucleophilic displacement of fluorine atoms in the reactive allylic position affords an enol of a fluorinated 1,3-diketone, 2H-pentafluoro-cyclopentane-l,3-dione (compound H) [57]. ... 

The electron-deficient double bond in lH-pentafluoropropene reacts easily with nucleophiles such as azide anion to form primarily an addition product l-azido-l,2,3,3,3-pentafluoropropane. In the basic medium, unsaturated l-azido-2,3,3,3-tetrafluoropropene is also formed, either by elimination of hydrogen fluoride from the addition product, or by direct displacement of fluorine by SN2 mechanism [90]. 

However, the addition and displacement of fluorine are such exothermic reactions that they are accompanied by the ring-opening reaction and cleavage of methylene bridges, of which relative amounts are affected by the fluorination temperature. Therefore, in order to restrict the ring-opening reaction, the fluorination must be carried out at relatively low temperatures, for instance, 50°C and 70°C. On... 

Thioazolidinediones have by now achieved a major role in the treatment of Type II, also called adult onset diabetes. A recent example includes a benzimidazole moiety as part of the structure. One of the syntheses for this compound starts by nucleophihc aromatic displacement of fluorine in p-fluorobenzaldehyde (151) by the anion from treatment of the hydroxy-methylbenzimidazole (150) with strong base. The product (152) is then... 

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