O- Nitroaniline

Concentrate each of the two solutions (or eluates) to about 20 ml, by distilling off the greater part of the benzene, the distilling-flask being immersed in the boiling water-bath. Then pour the concentrated solution into an evaporating-basin, and evaporate the remaining benzene (preferably in a fume-cupboard) in the absence of free flames, i.e., on an electrically heated water-bath, or on a steam-bath directly connected to a steam-pipe. Wash the dry residue from the first eluate with petrol and then dry it in a desiccator pure o-nitroaniline, m.p. 72°, is obtained. Wash the second residue similarly with a small quantity of benzene and dry pure />--nitroaniline, m.p. 148" , is obtained. Record the yield and m.p. of each component. 

Physical Properties. All solid, sparingly soluble in cold water, freely soluble in hot water. o-Nitroaniline, NO2C6H4NH2, orange, volatile in steam m-nitroaniline, yellow, also volatile in steam />-nitroaniline, yellow, non-volatile in steam. 

Dissolve 34 g. of o-nitroaniline in a warm mixture of 63 ml. of concentrated hydrochloric acid and 63 ml. of water contained in a 600 ml. beaker. Place the beaker in an ice - salt bath, and cool to 0-5° whilst stirring mechanically the o-nitroaniline hydrochloride will separate in a finely-divided crystalline form. Add a cold solution of 18 g. of sodium nitrite in 40 ml. of water slowly and with stirring to an end point with potassium iodide - starch paper do not allow the temperature to rise above 5-7 . Introduce, whilst stirring vigorously, a solution of 40 g. of sodium borofluoride in 80 ml. of water. Stir for a further 10 minutes, and filter the solid diazonium fluoborate with suction on a sintered glass funnel. Wash it immediately once with 25 ml. of cold 5 per cent, sodium borofluoride solution, then twice with 15 ml. portions of rectified (or methylated) spirit and several times with ether in each washing stir... 

Prepare the diazoniuni fluoborate from 34 g. of p-nitroaniline as detailed in Section IV,68 for o-Nitroaniline. 

Experimental details are given for o-phenylenedlamlne, which is conveniently prepared by the reduction of o-nitroaniline in alcoholic sodium hydroxide solution with zinc powder ... 

Feebly basic amines, e.g., the nitroanilines, generally react so slowly with benzenesulphonyl chloride that most of the acid chloride is hydrolysed by the aqueous alkali before a reasonable yield of the sulphonamide is produced indeed, o-nitroaniline gives little or no sulphonamide under the conditions of the Hinsberg test. Excellent results are obtained by carrying out the reaction in pyridine solution ... 

Benzenesulphonyl chloride reacts with primary and secondary, but not with tertiary, amines to yield substituted sulphonamides (for full discussion, see Section IV,100,3). The substituted sulphonamide formed from a primary amine dissolves in the alkaline medium, whilst that produced from a secondary amine is insoluble in alkali tertiary amines do not react. Upon acidifying the solution produced with a primary amine, the substituted sulphonamide is precipitated. The reactions form the basis of the Hinsberg procedure for the separation of amines see Section IV,100,(viii) for details. Feebly basic amines, such as o-nitroaniline, react slowly in the presence of allcali in such cases it is best to carry out the reaction in pyridine solution see Section IV,100,3. ... 

Quinoxaline mono-N-oxides are also available by a direct synthesis from n-nitroaniline derivatives. Condensation of acetyl chloride derivatives with o-nitroaniline followed by treatment with sodium ethoxide in ethanol yields the mono-N-oxides in good yields (Scheme 20) (64JCS2666). 

Perhaps one of the most exciting developments in the chemistry of quinoxalines and phenazines in recent years originates from the American University of Beirut in Lebanon, where Haddadin and Issidorides first made the observation that benzofuroxans undergo reaction with a variety of alkenic substrates to produce quinoxaline di-AT-oxides in a one-pot reaction which has subsequently become known as the Beirut reaction . Many new reactions tend to fall by the wayside by virtue of the fact that they are experimentally complex or require starting materials which are inaccessible however, in this instance the experimental conditions are straightforward and the starting benzofuroxans are conveniently prepared by hypochlorite oxidation of the corresponding o-nitroanilines or by pyrolysis of o-nitrophenyl azides. 

Catalytic reduction of 1,2,4-oxadiazoles also breaks the N—O bond e.g. (264) gives (265). Benzofuroxan can be reduced under various conditions to benzofurazan (266), the dioxime (267) or o-phenylenediamine (268) (69AHC(10)l). Reduction by copper and hydrochloric acid produced o-nitroanilines (Scheme 30) (69AHC(lO)l). 

General Conditions for each step and selectivity of m-substituted anilines As previously mentioned, Hauser and Reynolds reported on factors governing the first step of the Conrad-Limpach reaction but they tvere by no means exhaustive. Other than the conditions reported above for the first step, HClAleOH, CHCI3 or CHCI2 (neat or with acid catalyst), PhMe or PhH with removal of water with or without acid catalyst, or EtOH/AcOH/CaS04 were reported to provide the desired enamino-ester from an aryl amine and 3-keto-ester. Hauser and Reynolds also noted that o-nitroaniline and o-nitro-p-methoxyaniline failed to form the desired enamino-ester under conditions which they reported. 

More importantly, Peet and coworkers reported the reaction of o-nitroaniline 35 with acetylene dicarboxylate 32 to provide fumarate 36. Subsequent cyclization proved difficult under thermal conditions and only a 35% yield of quinolone 37 was isolated. Use of PPA for the cyclization improved the yield of 37 significantly. Using this modification allowed enamino-ester formation with a nitro-group attached to the arylamine. 

Benzofuroxan may be obtained by oxidation of o-quinone dioxime. The first benzofuroxan derivative, 1,2-naphthofuroxan, was obtained by this method. Suitable oxidizing agents include alkaline ferri-cyanide, bromine water, chlorine, and nitric acid. The method is of practical value only when the o-quinone or its monooxime (o-nitrosophenol) is readily available, and since this is not generally the case, other routes, e.g., the oxidation of o-nitroanilines and the thermal decomposition of o-nitrophenyl azides/ are more commonly used. 

The oxidation of o-nitroanilines to benzofuroxans was discovered by Green and Rowe, who used alkaline hypochlorite. Although this method has been used extensively, it occasionally fails to... 

Early attempts to prepare 5-amino- and 5-acylaminobenzofuroxans by hypochlorite oxidation of the corresponding o-nitroanilines met with failure. Pyrolysis of the appropriate azide, however, gives 5-dimetliylamino- and 5-acetamidobenzofuroxan, whereas urethans of type (33) are produced by Curtius degradation of the 5-carboxylic acid. Controlled hydrolysis of the acetamido compound and the... 

The spectral changes which occur in increasingly acid solutions of polyaza-heterocycles may indicate a second ionization. This event, however, can readily be distinguished from dehydration by measuring the spectra in anhydrous dichloroacetic acid, provided that the pKa value for the anhydrous species is above 1. Anhydrous dichloroacetic acid has a Hammett acidity function (Hq) of — 0.9 (as determined using o-nitroaniline as the solute), and the ultraviolet spectrum of a base with a p > 1 would be that of the anhydrous cation in this 2 A. Albert and W. L. F. Armarego, J. Chem. Soc. 4237 (1963). 

Pedras and co-workers (98P1959) isolated a phytoalexin from Wasabi (Wasabia japonica, syn. Eutrema wasabi) and determined its structure to be methyl l-methoxyindole-3-carboxylate (109) (Scheme 38). Compound 109 had already been synthesized by Acheson and co-workers [78JCS(P1)1117] in ten steps from o-nitroaniline. Pedras and co-workers (98P1959) combined our tungstate method and Acheson s work, and synthesized 109 in 9% overall yield but in an impure state. 

An analogous sequence leads to the anthelmintic agent, etibendazole (50). Reaction of the benzophenone 47, which can be obtained by acylation of o-nitroaniline with g-fluorobenzoyl chloride, with ethylene glycol leads to acetal 48. Sequential reduction of the nitro group and cyclization of the resulting diamine (49) with N,N-dicarbomethoxy-S-methylthiourea gives the benzimidazole etibendazole (50) fl6]. 

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