Aromatic nucleophilic displacement aniline

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]. 

Nucleophilic displacements on unsubstituted aromatics usually do not occur since H is not a good leaving group. However, an example of nucleophilic aromatic substitution of hydrogen (NASH) has been reported on reacting aniline and azobenzene in the presence of base under aerobic conditions to generate 4-(phenylazo)diphenylamine, 9 (equation 13)115. 

Other general reactions of amines would be nucleophilic displacement, electrophilic aromatic substitution in anilines and substitution via diazonium salts. 

Interestingly, a substance somewhat closely related to flunixin, triflocin (30), is a diuretic rather than an antiinflammatory agent. It can be prepared by nucleophilic aromatic displacement on 4-chloronicotinic acid (29) with m-trifluoromethyl-aniline.8... 

One of the earlier second-generation quinolones indeed includes fluorine at the 6 position and a basic function at the 7 position, characteristic of the more potent drugs that also feature a broader spectmm of antibacterial activity. The starting material (39-3) for one of these agents is prepared by application of the same scheme as above to the substituted aniline (39-1). Nucleophilic aromatic displacement with A-methylpiperazine (39-4) proceeds at the 7 position due to activation by the carbonyl group para to the chlorine (39-5). Saponification of the displacement product leads to pefloxacin (39-6) [46]. 

The general scheme is sufficiently flexible to permit the interchange of the order of some of the steps. Thus alkylation of aniline thioether (30-3) with 3-chloro-l-diethylaminopropane leads to the intermediate (31-1). Ring closure as above by nucleophilic aromatic displacement leads to the antipsychotic dmg chlorproethazine (31-2) [32]. 

A byproduct from the reductive ring closure was often the corresponding 2-aminodiphenylamine, arising from direct reduction of the nitro group without ring formation. Competing nucleophilic aromatic substitution by this new aniline of a displaceable ortho substituents normally leads to byproduct for-... 

Acid catalysis in nucleophilic aromatic displacements with amines has been observed only with heterocyclic substrates. Banks (86) has shown that the reaction rates of 2-chloro-4,6-diamino-s-triazene and of 2-amino-4-chloropyrimidine with aniline and with ring-substituted anilines in aqueous solution or suspension are accelerated by an increase in the hydrogen ion concentration. This catalysis is due to conversion of the substrate to its conjugate acid, since the heterocyclic nitrogen is a better activating group for the displacement reaction in the ammonium form than in the amino form. 

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