Activation-displacement fluorination

Scheme 15.8 Activation-displacement fluorination by DAST type reagents.

Two closely related indoles fused to an additional saturated ring have been described as CNS agents. The first of these is obtained in straightforward manner by Fischer indole condensation of functionalized cyclohexanone 0 with phenyl hydrazine (19). The product, cyclindole (21) shows antidepressant activity. The fluorinated analogue flucindole (26) can be prepared by the same scheme. An alternate route starting from a somewhat more readily available intermediate involves as the first step Fischer condensation of substituted phenyl hydrazine with 4-hydroxycyclohexanone (23). The resulting alcohol (24) is then converted to its tosylate (25). Displacement by means of dimethyl amine leads to the antipsychotic agent flucindole (26). ... 

Both positions, ortho- and para- to the nitro group, are activated for the replacement by a nucleophile, in this case a sulfide anion. The nucleophilic attack takes place at the position of the lowest electron density. Since the inductive effect of fluorine is much stronger than that of bromine, the electron density is lower in position 4 than in position 2. Therefore, the sulfide anion displaces fluorine and not bromine [100]. 

The fra 5-5,6-ring system existing in phenylmorphans was constructed by the displacement of nitro-activated aromatic fluorine widi a hydroxyl group . 

Molybdenum and Tungsten.— The anion [(7r-CsH6)(CO)2(Ph3P)Mo] displaces fluorine from activated fluoro-aromatic compounds, yielding complexes (215) and (216) with pentafluoropyridine and tetrafluorophthalonitrile, respectively. ... 

The use of transition-metal complexes to activate haloarenes for S Ar reactions has been used as a strategy for important skeletal bond formation steps in a number of syntheses. An example of carbon-carbon bond formation in this way can be found in amino acid synthesis. The Shiffs base nucleophile (Me02C)(Ph2C=N)CH displaces fluorine from (fluorotoluene)Cr(CO)3 [316]. This type of substitution reaction has been applied in a model study for the diaryl ether section of SK F L-94901 (68) using a cationic cyclohexadienyliron complex (see Scheme 14.16)... 

Nucleophilic Displacement Reactions. The presence of activating groups, eg, o,p mX.1.0 groups, makes aromatic fluorine reactive in nucleophilic displacement reactions. This has been demonstrated by deterrnination of the relative fluorine—chlorine displacement ratios from the reaction of halonitroben2enes with sodium methoxide in methanol (137) F is displaced 200—300 times more readily than Cl. 

The formation of ethyl cyano(pentafluorophenyl)acetate illustrates the intermolecular nucleophilic displacement of fluoride ion from an aromatic ring by a stabilized carbanion. The reaction proceeds readily as a result of the activation imparted by the electron-withdrawing fluorine atoms. The selective hydrolysis of a cyano ester to a nitrile has been described. (Pentafluorophenyl)acetonitrile has also been prepared by cyanide displacement on (pentafluorophenyl)methyl halides. However, this direct displacement is always aecompanied by an undesirable side reaetion to yield 15-20% of 2,3-bis(pentafluoro-phenyl)propionitrile. 

These quaternary phosphonium fluorides provide a range of activities for the displacement of halogen by fluorine [30] (Table 3)... 

Triethylbenzylammonium chloride and potassium fluoride containing 1% water can provide chlorine-fluorine exchange of activated halides in the absence of a solvent. This mixture also can displace the chlorine of a chlorodifluoromethyl group to form a trifluoromethyl group [62] (equation 36). 

Polyethylene glycol (molecular weight, 300-6(W) can aid in the displacement of activated halogen by fluorine. Propionyl chloride is converted to propionyl fluoride with potassium fluoride and polyethylene glycol in acetonitrile [63] Treatment of benzyl chloride with a mixture of potassium fluoride and potassium iodide for 5 h in acetonitrile containing polyethylene glycol 200 gives benzyl fluoride in 62% yield [64],... 

This topic has been reviewed [2, pp 94, 100-111, 130-134] All of the standard approaches to the synthesis of a compound like methyl 2-fluorostearate from methyl 2-bromostearate result mall yield of the 2-fluoro ester and the unsaturated esters. Although silver fluoride is not a new reagent, its use moist in wet acetonitrile to convert methyl 2-bromostearate to its fluoro ester is a departure from the traditional set of anhydrous conditions (Procedure 6, p 194) [71] In contrast, silver tetrafluoroborate converts a-chloroketones to their respective fluoroketones under anhydrous conditions. The displacement of less activated halogen groups by silver tetrafluoroborate to form their respective fluorides is novel Although silver tetrafluoroborate could not be used to convert an aliphatic terminal dichloromethyl or trichloromethyl group to its corresponding fluoro derivative, it is an effective fluorine source in other situations [72] (Table 8)... 

Although both cuprous and cupric fluorides have been studied in the past, an active fluorine donor can be formed from cupric oxide and hydrogen fluonde. This donor, in combination with 2,2 -bipyridine, effectively displaces the halogen of... 

Displacement of the sulfhydryl group in primary thiols, like L cysteine and 2-diethylaminoethanethiol, requires elemental fluorine, the most active oxidant Elemental sulfur is the major by-product in those reactions [7] (equation 2)... 

The efficacy of ring fluorination depends on the nature and position of the activating group, Y, m the aromatic ring The relative extent of for N (CH3)3 displacement decreases in the following order for Y p-NOy (71%), p-CN (24%), P-CH3CO (15%), p CHO (<5%) = m NO2 (<5%) This fluorodequaternization technique was subsequently adapted to prepare numerous NC A (no-camer-added) F-labeled aryl fluorides [7J, 74]... 

Ornithine decarboxylase is a pyridoxal dependent enzyme. In its catalytic cycle, it normally converts ornithine (7) to putrisine by decarboxylation. If it starts the process with eflornithine instead, the key imine anion (11) produced by decarboxylation can either alkylate the enzyme directly by displacement of either fluorine atom or it can eject a fluorine atom to produce viny-logue 12 which can alkylate the enzyme by conjugate addidon. In either case, 13 results in which the active site of the enzyme is alkylated and unable to continue processing substrate. The net result is a downturn in the synthesis of cellular polyamine production and a decrease in growth rate. Eflornithine is described as being useful in the treatment of benign prostatic hyperplasia, as an antiprotozoal or an antineoplastic substance [3,4]. 

It is interesting to note that all the new aromatic systems, as described, undergo displacement polymerizations in DMAC solvent by the K2CO3 method, except perfluoroalkylene [10] and amide activated polymerization [9], which were performed in NMP solvent. The displacement polymerization in DMAC solvent was carried out at 155-164°C. poly(aryl ether ketones) require less reaction time (3-6 h) than other aromatic systems for synthesis of polyethers [15]. Synthesis of the fluorinated polyether as reported by Irvin et al. [16] was carried out at room temperature for 16 h (Mw = 75,000), whereas the same polymer by Mercer et al. [17] was synthesized at 120°C for 17 h (Mw = 78,970). 

Fluorination. Attention has been focused on the direct fluorination of isoquinolines activated by conversion into 2-methylisocarbostyril (80). With gaseous fluorine (diluted to 10% with argon) in acetic acid a 54% yield of the 4-fluoro derivative was obtained. (Scheme 40). With methylene chloride as the solvent, only the 4-chloro analogue was formed [82H( 17)429]. Fluoroisoquinolines have also been made by displacement of nitro groups, and from diazonium fluoroborates (87JHC181). Hepta-chloroisoquinoline was converted into a perfluoro derivative by heating it in an autoclave with anhydrous potassium fluoride [66JCS(C)2328]. 

As 2-amino-2-deoxy-D-mannose is tumorstatic and 2-acetamido-2-deoxy-D-mannose 6-phosphate is an obligatory intermediate in the biosynthetic pathway to sialic acid, displacement of the essential OH-6 with a fluorine atom should be interesting from the biological viewpoint. 2-Acetamido-1,3,4-tri-0-acetyl-2,6-dideoxy-6-fluoro-D-mannopyranose (see Table 111 in Section 11,3) and its O- and A,0-deacetyl derivatives were prepared the first compound showed weak anticancer activity. 

Further new competitive AMPA antagonists include the imidazo-fused 23-benzodiazepine derivative 103. This compound showed excellent anticonvulsant activity and other activities indicative of possible therapeutic significance in human stroke and Parkinson k disease <00BMC2127>. An efficient synthesis of fluorine-containing H-1,4-diazepino[6,5-/t]quinolines has been described based on iV,/V-dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine and an aromatic nucleophilic displacement with 1,2-ethylenediamine, followed by cyclocondensation <00S1822>. 

By selection of an appropriate derivative the hydroxyl group can become activated towards displacement (via an 8 2 exchange process) with a suitably chosen nucleophile. Conversion to the sulfonate ester (SO2R) [115] promotes displacement by either an acetate ( OAc) (sequence Dl) or phthalimide nucleophile (Sequence D2), whilst the trimethylsilyl derivative facilitates introduction of fluorine (Sequence E) [116]. 

The selective introduction of fluorine is of continuing interest not only because of the synthetic challenge but also because of the possibility of a dramatic change in biological activity. The fluoride-ion displacement of carbohydrate trifluoromethanesulfonates using tris(dimethylamino)sulfonium... 

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