Aromatic Substitution Approaches to Synthesis

Electrophilic attack in imidazole is usually most facile at an annular nitrogen, and there are many examples of Af-aUcylation, -protonation, -acylation, cyanation, -arylation and -silylation. A-Nitration is much less common A-oxidation is virtually non-existent. When an annular nitrogen becomes substituted, tautomerism in the molecules is blocked, and mixtures of isomers are usually formed with substituted benzimidazoles and 4(5)-substituled imidazoles. 

Other ring carbon positions. Nitro groups analogously activate groups a and Y to themselves to nucleophilic attack. 

In benzimidazole (2), electrophilic substitution occurs most readily in the fused benzene ring, commonly at C-5 a second substituent usually enters at C-6, although in all cases groups already present on the molecules can substantially modify the usual orientation of substitution. Thus, in benzimidazoles, a strongly electron-releasing group at C-5 will direct subsequent attack to C-4 electron-withdrawing substituents lead to subsequent attack at C-4 or C-6. Increased reactivity is achieved if the molecules can be induced to react in their anionic forms.  

In summary, substitution processes on the preformed rings usually lead to 1-, 2-, 4- and 5-substitution in imidazole, and 1-, 2-, 5- and 6-substitution in benzimidazole [2-8]. 

Preston, in Benzimidazoles and Congeneric Tricyclic Compounds (ed. P. N. Preston). Wiley-Intersdence, New York, 1981. 

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Figure 14.6 Nucleophilic approach to synthesis of 6-[18F]fluoroDOPA. The multistep synthesis introduces fluorine-18 in an initial nucleophilic aromatic substitution reaction.

An interesting alternative approach to the synthesis of a cryptand having nitrogen atoms in the bridges was presented by Newkome and coworkers. This group condensed triethanolamine with 2,6-dichloropyridine in a relatively straightforward but low yield (5%) nucleophilic aromatic substitution to form 7, illustrated below in Eq. (8.6). The identity of the compound was confirmed by X-ray structural analysis. 

There have been a number of different synthetic approaches to substituted PTV derivatives proposed in the last decade. Almost all focus on the aromatic ring as the site for substitution. Some effort has been made to apply the traditional base-catalyzed dehydrohalogenation route to PTV and its substituted analogs. The methodology, however, is not as successful for PTV as it is for PPV and its derivatives because of the great tendency for the poly(u-chloro thiophene) precursor spontaneously to eliminate at room temperature. Swager and co-workers attempted this route to synthesize a PTV derivative substituted with a crown ether with potential applications as a sensory material (Scheme 1-26) [123]. The synthesis employs a Fager condensation [124] in its initial step to yield diol 78. Treatment with a ditosylate yields a crown ether-functionalized thiophene diester 79. This may be elaborated to dichloride 81, but pure material could not be isolated and the dichloride monomer had to be polymerized in situ. The polymer isolated... 

The general approaches for the synthesis of poly(arylene ether)s include electrophilic aromatic substitution, nucleophilic aromatic substitution, and metal-catalyzed coupling reactions. Poly(arylene ether sulfone)s and poly(arylene ether ketone)s have quite similar structures and properties, and the synthesis approaches are quite similar in many respects. However, most of the poly(arylene ether sul-fone)s are amorphous while some of the poly(arylene ether)s are semicrystalline, which requires different reaction conditions and approaches to the synthesis of these two polymer families in many cases. In the following sections, the methods for the synthesis of these two families will be reviewed. 

A flexible approach to the synthesis of substituted benzazepines 403 was devised (equation 166). As before, the seven-membered ring was made by the use of a ring-expansion reaction and exclusive migration of the aromatic ring was observed. 

An alternate and more controlled approach to the synthesis of phenothiazines involves sequential aromatic nucleophilic displacement reactions. This alternate scheme avoids the formation of the isomeric products that are sometimes observed to form from the sulfuration reaction when using substituted aryl rings. The first step in this sequence consists of the displacement of the activated chlorine in nitrobenzene (30-1) by the salt from orf/io-bromothiophenol (30-2) to give the thioether (30-3). The nitro group is then reduced to form aniline (30-4). Heating that compound in a solvent such as DMF leads to the internal displacement of bromine by amino nitrogen and the formation of the chlorophenothiazine (30-4). Alkylation of the anion from that intermediate with 3-chloro-l-dimethylaminopropane affords chlorpromazine (30-5) [31]. 

An early approach to suitable dialdehydes made use of a nucleophilic aromatic substitution process which enabled the synthesis of nitro-substituted complexes to be achieved (Scheme 27)159,160 Yery recently, a similar approach has been used to incorporate pyrimidine rings into macrocyclic complex structures (Scheme 28).161... 

Several reactive chloro compounds have been used to attempt to effect the controlled monochlorination of aromatic amines. One such reagent is N-chlorosuccinimide, with which the chlorination of aniline, for example, can be largely restricted to monosubstitution, although a mixture of isomers (orthopara, 1.9 1) is obtained.24 One approach to the achievement of specific ortho chlorination is illustrated by the synthesis of o-chlorobenzanilide (Expt 6.61), readily hydrolysable to o-chloroaniline. The anilide is formed, by a type of Swi mechanism indicated below, when AT-phenylhydroxylamine is benzoylated and the product is treated with thionyl chloride.25 The reaction has been successfully applied to several substituted JV-phenylhydroxylamines, prepared by the controlled reduction of the corresponding substituted nitro compounds (cf. Expt 6.87). 

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