Fluorination nucleophilic displacement

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. 

In the general preparation of quinolones by forming the nitrogen aryl bond a in the ring closure, typical precursors are prepared as shown in Figure 2. The ring closure involves nucleophilic displacement of a halogen, usually a chlorine or fluorine (76) eg, (29) and (30) lead to (31) [86483-54-7] and (32) [123942-15-4] respectively. 

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. 

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

Interestingly, the photolysis of methyl 3-azido-2.6-difluorobenzoate (61) in diethylamine yields, in addition to the two expected 3//-azepines 62 and 63, a third azepine 64 formed by nucleophilic displacement of allylic fluorine from the 3-position by diethylamine.188 Displacement of allylic halogen from haloazepines has been noted previously.177... 

Considerable interest has been focused on the efficient and rapid synthesis of 2-deoxy-2-[ F]fluoro-D-gIucose, a popular imaging agent for positron-emission tomography (see Section III, 1). However, introduction of a fluorine atom at C-2 by nucleophilic displacement is generally not easy on account of the weak nucleophilic character of the fluoride ion. One possible... 

Selective nucleophilic displacement of the C-10 fluorine atom of 158 was achieved with secondary amines iV-methylpiperazine, 4-methylpiperidine, or 1,2,3,4-tetrahydroisoquinoline affording the product 159 in low to moderate yield <2000JHC297>. 

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... 

Fluorobenzene-type compounds have been used as functional groups in homobifunctional crosslinking agents (Chapter 4, Section 4). Their reaction with amines involves nucleophilic displacement of the fluorine atom with the amine derivative, creating a substituted aryl amine bond (Reaction 9). Detection reagents incorporating reactive aryl chemistry include 2,4-dinitrofluorobenzene and trinitrobenzenesulfonate (Eisen et al., 1953). These compounds form... 

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>. 

An alternative procedure for the introduction of the fluorine substituent in secondary positions of carbohydrates consists in nucleophilic displacement of sulfonic esters. Walden inversion always accompanies such displacements, and the success of this method may be attributed to two factors. 

Nucleophilic displacement using [ F] fluoride works well in aUphatic systems where reactive haUdes or sulfonates esters can undergo substitution at unhindered sites. In order to introduce a F fluorine atom in a secondary or tertiary position, a two steps strategy was developed. It involves a F-bromofluorination of alkenes, followed by reductive debromination (n-BujSnH, AIBN). [ F]BrF is usually generated in situ from [ F]potassium fluoride and l,3-dibromo-5,5-dimethylhydantoin (DBH) in sulfuric acid. This methodology was successfully applied to label steroids at the 11 and 6a positions [245] (Scheme 60) and to prepare [ F]fluorocyclohexanes [246]. 

Chemical methods for determining the amino acid sequence of a peptide or protein have been developed, and the normal approach is to exploit the properties of the amino group at the Al-terminus. A long-established procedure for identifying the N-terminal amino acid is use of the Sanger reagent 2,4-dinitrofluorobenzene. This reacts with an amine by nucleophilic displacement of the fluorine. 

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). 

Fluorination in the electrophilic 2-, 4-, and 6-positions is effected by substitutions of other halides, and this is normally performed by nucleophilic displacement with fluoride ion <1994HC(52)1>. Hydrofluoric acid can also be used, and in the case of 2,4-dichloro-5-trichloromethylpyrimidine 111, replacement of all five chlorine atoms occurred, to give 2,4-difluoro-5-trifluoromethylpyrimidine 112, which was subsequently hydrolyzed to give 5-tri-fluoromethyluracil 113 <1996JFC(77)93>. 

While the explanation is of a qualitative nature, it is consistent with the patterns that are observed by icr. This approach constitutes an initial point of view which needs further exploration. There remain some very pertinent unanswered questions relating to the fact that these reactions seem to involve primarily fluorinated benzenes. Furthermore, fluoride ion itself is seldom observed as a product of aromatic nucleophilic displacement. 

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. 

Diazotization routes are mainly suited to the production of fluoroaromatics with only one or two fluorine atoms in the same ring. Two Or more fluorine atoms are often introduced via the nucleophilic displacement of chlorine atoms in an activated , i.e. electron-deficient, ring by fluoride ions. For example, the reaction of 2,4-dichloro-l-nitrobenzene with potassium fluoride has been used in the manufacture of 2,4-difluoro-l-nitrobenzene, an intermediate for the antiinflammatory aspirin derivative diflunisal (7). 

The activated bromine atom in bromomethyl phenyl ketone (1) can be replaced by fluorine by refluxing with sodium fluoride in methanol for several hours,12 but besides fluoromethyl phenyl ketone (2), the product of nucleophilic displacement by methoxide ion, methoxymethyl phenyl ketone (3) is also formed. 

The nucleophilic displacement of halogens by fluorine can be successfully carried out by reaction with potassium fluoride under several conditions. Primary and secondary alkyl halides 1 are converted to the corresponding fluorides 2 by heating with a saturated aqueous solution of potassium fluoride in the presence of catalytic amounts of hexadecyltributylphosphonium bromide.56 Small amounts of the corresponding alcohol and the olefinic elimination product are formed as side products. While neopentyl bromide does not react at all, polyhaloalkanes give only products of elimination or hydrolysis. Chlorocyclohexane gives only the elimination product.56... 

The nucleophilic displacement of halogens in aromatic compounds by fluorine is aided by utilizing an appropriate catalyst. Polymer-supported aminopyridinium salts have been found to be versatile catalysts for the synthesis of aryl fluorides. The advantage of the catalyst is that it can be recycled and used again. l-Chloro-4-nitrobenzene (3) is converted to l-fluoro-4-nitrobenzene (4) in 71 % isolated yield using this method. The catalyst used has the structure 5.91... 

Analogous to aromatic halides, heterocyclic halides can be transformed to the corresponding fluorides by nucleophilic displacement with fluoride ions. Fluorinated heterocyclic compounds are also biologically interesting and several technical applications are also known.116... 

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