0-Nitrodiphenylamines, reduction

Amination of aromatic nitro compounds is a very important process in both industry and laboratory. A simple synthesis of 4-aminodiphenyl amine (4-ADPA) has been achieved by utilizing a nucleophilic aromatic substitution. 4-ADPA is a key intermediate in the rubber chemical family of antioxidants. By means of a nucleophibc attack of the anilide anion on a nitrobenzene, a o-complex is formed first, which is then converted into 4-nitrosodiphenylamine and 4-nitrodiphenylamine by intra- and intermolecular oxidation. Catalytic hydrogenation finally affords 4-ADPA. Azobenzene, which is formed as a by-product, can be hydrogenated to aniline and thus recycled into the process. Switching this new atom-economy route allows for a dramatic reduction of chemical waste (Scheme 9.9).73 The United States Environmental Protection Agency gave the Green Chemistry Award for this process in 1998.74... 

Some time ago, Holliman and co-workers illustrated a method for synthesizing polysubstituted phenazines by reductive cyclization of o-nitrodiphenylamine. However, the yield was poor when competitive cyclizations occurred <70CC1423>. Recently, Kamikawa and co-workers reported a more efficient method to synthesize phenazines using sequential aniline arylation, which was first introduced by Buchwald <97JOC1264>. Regioselective bromination of o-nitrodiphenylamine 226 with bromine in the presence of sodium bicarbonate yielded 227 which was subjected to the Buchwald conditions to provide the desired phenazine 228 and the eliminated product 229 <00TL355>. The former compound is a proposed intermediate for the synthesis of the radical scavenger benthocyanin A. 

An example of the method described is the synthesis of saphenic acid (47) that has recently been reported by Nielsen et al. [81]. Starting from properly substituted aromatic precursors 92 and 93, the naturally occurring 1,6-disub-stituted phenazine was synthesized in racemic form. Here, the first major step involves an intermolecular nucleophilic aromatic substitution that, due to the substitution pattern, has proved to be relatively unproblematic and after hydrolysis of the acetal yields the o-nitrodiphenylamine 94. Much more difficult is the ring formation leading to the final phenazine, which can best be achieved through a high excess of NaBH4, accompanied by reduction of the methyl ketone. But at 32%, the yield is still rather poor. 

Quite recently, the structure of pelagiomicins B (60) and C (61) was confirmed by a synthesis starting from griseoluteic acid (62) [60]. In the first synthesis of 62, Holliman et al. employed the reductive cyclization of o-nitrodi-phenylamines using NaBH4 to yield phenazines [84]. To this end, 3-amino-4-methoxybenzyl alcohol (99) was treated with methyl 2-bromo-3-nitrobenzoate (100) to yield the o-nitrodiphenylamine 101, which by reductive cyclization... 

That the second option can also be successfully used has recently been revealed by our synthesis of 2-methoxyphenazine (117) [90]. The reduction of o-bromo-o -nitrodiphenylamine 132 accessible via intermolecular Pd-catalyzed JV-arylation provides the o-amino-o -bromodiphenylamine 133, which can then be cyclized to give 117 in a Pd-catalyzed intramolecular AT-arylation by employing Pd2(dba)3 as the Pd complex and 134 as the phosphine ligand. It should be noted that the outcome of both the intermolecular and the intramolecular AT-arylations heavily depends on the appropriate choice of the Pd complex as well as the phosphine. Ether cleavage leads to 2-hydroxyphenazine (9). 

Preferential reduction of a nitro group in the presence of a carbonyl group in 4-nitroacetophenone ISD, intramolecular rearrangements of o-nitro-benzanilides 32) intramolecular cyclizations of o-nitro-ferf-anilines to benzimidazol-1-oxides 153,154) cyclizations of acylated 2-nitrodiphenylamines to phenazine-l-oxides i ), intramolecular additions of nitro groups to double bonds 156) remarkably ef-... 

Arylbenzotriazoles (797) are prepared via 2-nitro- and 2-amino-diphenylamines (Scheme 161). The 2-nitrodiphenylamines (796) are prepared from the appropriate aniline by reaction with 2-fluoronitrobenzene in the presence of KF <808215,85JCS(Pl)2725>. Azo-coupling of 2-amino-1-cyano-azulene (798) with p-tolyldiazonium chloride gives (799) (Scheme 162). Catalytic reduction of (799) quantitatively yields the diamino derivative (800), which on diazotization affords 9-cyano-azuleno[l,2-J]triazole (801) in 77% yield <85TL335>. 

Phenazines can be obtained from o-nitrodiphenylamines by reduction or from o-aminodiphenyla-mines by oxidative techniques. The preferred method is that of phenazine 9,10-dioxides from benzofuran, thus benzofuroxans, itself with hydroquinone, gives the 2-hydroxy derivative (Scheme... 

Reduction of 2-nitrochIorobenzene-4-sulfonic acid gives o-chlorometanilic acid which is used in making azo dyes. The real technical value of nitrochlorobenzene-sulfonic acid, however, lies in the ability of its chlorine atom to be replaced by various groups. For example, o-nitrophenol-p-sulfonic acid is obtained by treatment wiui sodium hydroxide, and this product, on reduction, yields o-aminophenol-p-sulfonic acid. An ogously, nitrochlorobenzenesulfonic acid gives o-nitroanisole-p-sulfonic acid by treatment with alcoholic methanol, and from this is obtained o-anisidine-p-sulfonic acid. The action of ammonia on nitrochlorobenzenesulfonic acid produces o-nitroaniline-p>sulfonic acid aniline and its derivatives produce o-nitrodiphenylamine-p Sulfonic acids (cf. Table II). 

After reduction of the substituted 2-nitrodiphenylamines (1 g) two general methods were followed Method A The 2-aminodipbenylamines (a.s obtained on evaporation of the alcoholic solution under N ) were refluxed for 5 h in nitrobenzene (25 mL) containing some 1,3-dinitrobcnzene (0.5 g). 6M HCl (100 mL) was added and the nitrobenzene was removed by steam distillation the crude phenazines were obtained by neutralization of the acidic residue yields 5-67%. 

Diphenylamine-p-arsinic acid inay be produced by the hydrolysis of p-phenylacetylaminophenylarsinic acid or by the direct arsenation of diphenylamine. The nitrodiphenylamine-p-arsinic acids may also be formed by the direct arsenation of nitrodiphenylamines. Direct arsenation of diphenylamine leads to the formation of two by-products, diphenylamine-p-p -diarsinic acid and iisdiphenylaminearsinic acid, the fonner yielding an arseno-compound on reduction. 

Continuing examples of ring closure of diphenylamine arsinic, acids and their derivatives, 2-nitrodiphenylamine-6 -dichloroarsine when boiled in acetic acid solution for three hours is transformed into 10-chloro-4i-nitro-5 lO-dihydropkenarsazine (XIII), and reduction of... 

Derivation From p-nitrodiphenylamine-o-sulfonic acid by reduction with iron and hydrochloric acid. 

The most cited strategy for phenazine synthesis goes via 2-nitrodiphenylamine which, upon reductive ring closure, affords the desired phenazine. 

Scheme 9. General Mechanism for Reductive Cyclization of 2-Nitrodiphenylamines To Form Phenazines...

BusP as ligand.Poor yields in the reductive cyclization method—when competitive cyclization is possible—and also the need for milder reaction conditions in the cyclization step urged Emoto et al. to report an alternative method based on sequential palladium-catalyzed aryl amination (Scheme 10). The substrate for the cyclization was 2-amino-2 -bromo-diphenylamine, obtained by selective bromination and reduction of the well-known 2-nitrodiphenyl-amines or by coupling of 2-bromoaniline with a l-bromo-2-nitrobenzene and subsequent reduction. Treatment of 2-bromo-2 -nitrodiphenylamine with catalytic amounts of palladium(II) and BINAP as ligand afforded the desired phenazines in good yields. ... 

Of the derivatives of p-phenylenediamine, the most effective are the N, N -di-alkyl derivatives, in which the alltyl possesses a branched hydrocarbon chain on the carbon closest to the nitrogen atom [235]. They are usually produced by reductive allq lation of p-nitroaniline, p-phenyl-enediamine, p-nitrodiphenylamine, p-nitrosodiphenylamine, or p-amino-diphenylamine with aldehydes and ketones [236-252] with hydrogen at a temperature of 100-250°C and a pressure from 5 to 200 atm in the presence of catalysts. Copper-chromium catalysts (mixtures of oxides of the metals chromium, copper, barium, etc.) [241, 242, 245-247, 249, 250], iodine in the presence of HCl, HBr, or HI [253, 254], Pt/C [245, 252], and Raney nickel [244] are most often used as the catalysts. 

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