Chloronitrobenzene, aniline derivatives

The reaction of aniline and aniline derivatives with p-chloronitrobenzene is the critical coupling reaction practiced by Bayer and Monsanto for the manufacture of 4-nitrodiphenylamine, 2. Hydrogenation of 2 produces 4-aminodiphenylamine (4-ADPA), 3, which is a key intermediate in the p-phenylenediamine class of antioxidant used in rubber products (Figure 8). 

Finally, replacement of the methylene bridge by a sulfur bridge leads to compoxmds such as 117 and 123 which are major tranquilizers. Thus, Ullmann condensation of thiosalicylic acid 112 with ortho-chloronitrobenzene affords thioether 113 the nitro group is then reduced to the aniline (114). Cycliza-tion as above leads to the lactam 115, which is then converted to the iminochloride derivative (116). Condensation with N-methylpiperazine affords clothiapine... 

Alkoxy derivatives of aniline are manufactured for use in dye and pharmaceutical production. Thus the action of methanol and sodium hydroxide on o-chloronitrobenzene, followed by reduction, yields o-anisidine (o-methoxyaniline) (24a). The para-isomer 24b is prepared in a similar way. Both are used for azo dyes and azoic intermediates. The ethoxy derivatives, o-phenetidinc (24c) and p-phenetidine (24d), are used in dye manufacture. The amine 24d is also used to make Phenacetin (acetophenetidine) (25). 

Derivation (1) From p-chloronitrobenzene, (2) from aniline by nitration after acetylation, (3) from acetanilide. 

A number of tetrahydroquinoxalines (23) have been derived from o-amino-7V-(2-hydroxyethyl)anilines (21) by cyclization with concentrated hydrobromic or hydrochloric acid " " and alternatively by reduction of A-2 -chloroethyl-o-nitroanilines (22). The starting materials 21 and 22 are generally obtained from the appropriate o-chloronitrobenzene. 

Most derivatives of aniline are not obtained from aniline itself, but are prepared by hydrogenation of their nitroaromatic precursors. The exceptions, for example, N-alkylanilines, N-arylanilines, sulfonated anilines, or the N-acyl derivatives, can be prepared from aniline and have been discussed. Nitroanilines are usually prepared by ammonolysis of the corresponding chloronitrobenzene. Special isolation methods may be required for some derivatives if the boiling points are close and separation by distillation is not feasible. Table 6 Hsts some of the derivatives of aniline that are produced commercially. 

The selective removal of the chloride in the presence of a readily hydrogenated aromatic nitro group was also reported (Scheme 58). ° Acetonitrile was used as the solvent along with triethylamine as the base for the hydrogenolysis of the chloro group in chloronitrobenzene derivative 187. In EtOAc, however, the nitro group was concomitantly reduced to give aniline 189 in 80% yield. 

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