Nitro groups, aromatic with cyclizations

Since most anilines are derived from nitro intermediates the reduction of the aromatic nitro group followed by cyclization of the aniline in situ has offered a direct approach to the synthesis of quinolines. The ort/io-nitro cinnamic acid derivatives 28 undergo cyclization, where R corresponds to R , respectively, when treated with zinc in near-critical water at 250 °C... 

The resin-bound phenylene diamine intermediates 3 are then generated by nitro group reduction with tin(II) chloride in NMP and cyclization/ aromatization with a wide variety of aldehydes gave the resin-bound benzimidazole intermediates 4. The treatment of this intermediate with 50% TFA/DCM liberates the substituted 3-(benzoimidazol-l-yl)-propionic acid derivative 4a. Analysis of this intermediate by HPLC and LC-MS gave a measure of the purity of the resin-bound product and enabled the optimization of conditions for the incorporation of the Rl-nitroarenes and R2-aldehydes by an iterative process. 

Perhaps the most reliable method for the reductive cyclization of a nitro ester to a hydroxamic acid is that which involves treatment with sodium horohydride in the presence of palladium on charcoal. Although under these conditions aromatic nitro compounds are reduced to amines, o-nitro esters such as 53, in which the ester group is suitably oriented with respect to the nitro group, give good yields of cyclic hydroxamic acids (54). Coutts and his co-... 

In a similar vein, the amino group in sulfide 14 (obtained presumably by an aromatic displacement reaction) is first converted to the bromide by Sandmeyer reaction to give 25. Reduction of the nitro group (16) followed by cyclization gives the substituted phenothiazine. Alkylation with the familiar halide (3) affords dimethothiazine (18). ... 

Nucleophilic aromatic substitution of the anthranilic acid derivatives, 72, on ortho-bromonitrobenzene affords the diphenyl-amine, 73. The ester is then saponified and the nitro group reduced to the amine (74). Cyclization of the resulting amino acid by heat affords the lactam (75). Alkylation on the amide nitrogen with 2-dimethylaminoethyl chloride by means of sodium amide affords dibenzepine (76). ... 

Chakrabarti and coworkers at Eli Lilly in the United Kingdom have reported the initial discovery and synthesis of olanzapine (Schemes 5 and,6). The thiophene 22 was synthesized by adding a DMF solution of malononitrile to a mixture of sulfur, propionaldehyde and triethylamine in DMF. The anion of amino thiophene 22 underwent a nucleophilic aromatic substitution with 2-fluoronitrobenzene to provide 23. The nitro group was reduced with stannous chloride and the resulting anihne cyclized with the cyano group to form amidine 24. Finally, a mixture of N-methylpiperazine and 24 were refluxed in DMSO/toluene to afford olanzapine (2). 

Another important synthesis involves the reductive cyclization of 4-ethoxyalkylidinehydrazino-5-nitropyrimidines of type (372), which are obtained readily by reaction of 4-hydrazino-5-nitro-pyrimidines (371) with ortho esters. Catalytic reduction of the nitro group in (372) affords the 5-aminopyrimidine intermediate (373), which cyclizes in situ to the dihydro product (374). This may be oxidized without isolation to give the fully aromatic product (375). These reactions are shown in... 

An interesting reaction has been described by Simonov and his colleagues [371], Studying the reaction of some aromatic rnt/zo-dinitro- and trinitrocompounds with benzylamine they have discovered that under special conditions the reaction of substitution of the nitro group with the benzylamine group is accompanied by reduction of the second nitro group and cyclization into 2-phenylbenzimidazole derivatives. In this case benzyl alcohol forming from benzylamine serves as a reducer. By the way it was obtained 4,5-dimethoxy-7-nitro-2-phenylbenzimidazole in 89% yield from 3,4,5-trinitroveratrole [371],... 

With -diarylthioureas the cyclization direction is determined by the character of substituents, and the introduction of a nitro group or other electron-withdrawing substituents decreases the reactivity of the aromatic ring [179], This can be illustrated by the following Scheme 2.99. 

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