Acetanilide, reduction

Production is by the acetylation of 4-aminophenol. This can be achieved with acetic acid and acetic anhydride at 80°C (191), with acetic acid anhydride in pyridine at 100°C (192), with acetyl chloride and pyridine in toluene at 60°C (193), or by the action of ketene in alcohoHc suspension. 4-Hydroxyacetanihde also may be synthesized directiy from 4-nitrophenol The available reduction—acetylation systems include tin with acetic acid, hydrogenation over Pd—C in acetic anhydride, and hydrogenation over platinum in acetic acid (194,195). Other routes include rearrangement of 4-hydroxyacetophenone hydrazone with sodium nitrite in sulfuric acid and the electrolytic hydroxylation of acetanilide [103-84-4] (196). 

The resulting acetyl compound is usually hydrolyzed with aqueous alkaU to give the free amine. Other A/-acyl derivatives may be used, particularly for the less soluble succinyl and phthaloyl products. The use of -nitrobenzenesulfonyl chloride, followed by reduction of the nitro to an amino function, is much more expensive and is rarely used. A/-Acetylsulfanilyl chloride [121 -60-8] is obtained by the chlorosulfonation of acetanilide [103-84-4] which is the basic material for most of the sulfonamides. 

From Table 3, it can be seen that the reactivity of acyl acetanilide, such as BAA or AAA, is higher than that of the other reductant reported from our laboratory, i.e., acetanilide (AA), N-acetyl-p-methylaniline (p-APT), acetylacetone (AcAc), and ethyl acetoacetate (EAcAc). Moreover, the promoting activities of derivatives of acetoacetanilide were affected by the ortho substituent in benzene ring, and the relative rate of polymerization Rr) decreased with the increase of the bulky ortho substituent to the redox reaction between Ce(IV) ion and substituted acetoacetanilide. 

Aniline, 4,4 -azodi-, 40,18 Aniline, reaction with hexachlotoace-tone to form a, ,a-trichloro-acetanilide, 40, 103 reaction with maleic anhydride, 41,94 Anisoin, reduction to deoxyanisoin by tin and hydrochloric add, 40, 16... 

Compounds containing two primary amino groups attached to a benzene ring can be prepared by the reduction of dinitro compounds and of nitroanilines, usually with tin or stannous chloride and hydrochloric acid or with iron and very dilute hydrochloric acid. Pam-diamines may also be obtained by the reduction of aromatic amino-azo compounds (e.g., p-aminodimethylaniline from methyl orange, see Section IV,78). p-Phenylenediamine may also be prepared from p-nitroacetanilide reduction with iron and acid yields p-amino-acetanilide, which may be hydrolysed to the diamine. 

To get a complex set of substituents by direct derivatization of benzotriazole is not feasible. In such situations, it is better to have all the substituents in place first and later construct the heterocyclic ring. High reactivity of anilines and their well-developed chemistry makes them good stating materials. In an example shown in Scheme 215, acetanilide 1288 is nitrated to afford nitro derivative 1289 in 73% yield. Catalytic reduction of the nitro group provides methyl 4-acetylamino-3-amino-5-chloro-2-methoxybenzoate 1290 in 96% yield. Nitrosation of compound 1290 in diluted sulfuric acid leads to intermediate 1291, which without separation is heated to be converted to 7-chloro-4-methoxy-l//-benzotriazole-5-carboxylic acid 1292, isolated in 64% yield <2002CPB941>. 

The electrochemical measurements were carried out in the presence of one equivalent of a weak acid (acetanilide) to ensure protonation of the electrogenerated terf-butoxy anion. This was necessary to avoid the interference of the father-son reaction between t-BuO and the perbenzoate, leading to the corresponding ester. The initial one-electron reduction proceeds with 0—0 bond cleavage leading to the formation of t-BuO and ArCOO according to a stepwise (equations 71, 72) or concerted (equation 73) mechanism. At the working potentials, f-BuO is reduced (equation 74) to the anion t-BuO (E° = —0.23 V)and thus the overall process is a two-electron reduction. 

It of interest to note that the isobutyl group may also be replaced by a heterocyclic ring. The route to this compound, pirprofen (51-6), starts with the direct methylation of unesterihed 4-nitrophenylacetic acid (51-1). The observed selectivity for monoalkylation in this case may reside in the structure of the dianion, whose most stable form is presumably that depicted in (51-2). Catalytic reduction of the product (51-3) gives the corresponding aniline this is then converted to its acetanilide (51-4) with acetic anhydride. Treatment with chlorine followed by hydrolysis gives the chloroaniline (51-5). Double alkylation of this last intermediate with 1,4-dichloro-but-2-ene (depicted as the cis isomer for aesthetic reasons) forms the dihydropyrrole ring. There is thus obtained the NSAID pirprofen (51-6) [52]. 

Iodoaniline has been prepared by the reduction of -nitro-iodobenzene 1 by the hydrolysis of -iodoacetanilide formed by the action of iodine monochloride on acetanilide 2 and by the direct iodination of aniline.3 The method described here is an adaptation of the procedure used by Wheeler/ and by Hann and Berliner 5 for the iodination of the toluidines. 

Another side reaction which occurs is reduction in the reaction the —N2C1 or —N(NO)COCH3 group is replaced by hydrogen. wi-Bromo-toluene was isolated in 6% yield from the reaction between the sodium diazotate from 2-bromo-4-methylaniline and benzene, and in 10% yield in a similar reaction from 2-methyl-4-bromoaniline.4 Some nitrobenzene is obtained in the preparation of 3-nitrobiphenyl from nitroso-w-nitro-acetanilide (p. 250). The source of the hydrogen effecting the reduction has not been determined. f... 

Reduction of acetanilide with tetra-n-butylammonium borohydride in the presence of dichloromethane followed by treatment with HCl gives 74% N-ethylaniline hydrochloride. ... 

Fierz-David and Ziegler (301) first applied this method to azo compounds. Ethyl acetoacetate and various aromatic amines (aniline, o- and p-toluidines, m-xylidine, o-anisidine, and chloroanilines) were convereted to acetoacetanilides and then coupled with diazotized sulfanilic acid. The azo dyes (38) were reduced with stannous chloride in hydrochloric acid to the corresponding aminoaceto-acetanilides (39), which in alkali formed the dihydropyrazines (40). Catalytic reduction of o-hydroxyphenylglyoxal phenylhydrazone in acetic acid over palladium has been shown also to give 2,5-bis(o-hydroxyphenyl)pyrazine (302). Reduction of chemical means has been shown to give... 

Several types of Schmidt reaction merit special mention (a) An interesting consequence of the factors governing migratory aptitudes is that acetanilides are the major (typically >95%) products of rearrangement of acetophenones. This leads to a practical alternative to nitration and reduction as a preparative route to aromatic amines , cf. reaction (24). (b) Product analyses showed that... 

Nitroanilines are employed extensively in dye manufacture. Amination of o-chloronitro-benzene, at 175 °C and 40 atmospheres, affords o-nitroaniline. Partial reduction of m-dinitrobenzene gives the corresponding meta-derivative. The para-isomer 15b is used more extensively than the other nitroanilines in dye manufacture. In addition to amination of p-chloronitrobenzene, it can be made by nitration of acetanilide to yield (21), followed by hydrolysis. 

There are two good routes from 15b to p-phenylenediamine (22), namely reduction with Na2S3 in aqueous solution, and acid/iron reduction. It is also made by the action of ammonia on p-dichlorobenzene under pressure. The p-amino acetanilide (23) is made by reduction of the nitro-precursor 21. 

The commonly used methods for the determination of total nitrogen involve variations of the Dumas or Kjeldahl techniques. The Dumas approach involves oxidation of the nitrogen to elemental or oxide form by combustion of the sample, reduction of nitrogen oxides, and determination of the elemental nitrogen. The Dumas oxidation is usually represented by the following example for acetanilide ... 

Sulfoxide Reduction. Reduction of the sulfoxide of the mercapturic acid of 2-chloro-f+-isopropylacetanilide by Intestinal microflora has been shown in vitFo (9), but has not been demonstrated to occur in tissues. The excretion of this mercapturate sulfoxide, which is excreted into the intestine with the bile, in feces from germfree rats dosed with the acetanilide is vivo evidence for the reductive function of the intestinal microflora (49) in MftP catabolism. This reduction, in addition to deacetylation, is another source for cysteine conjugates which can be translocated to the tissues for metabolism or excretion, or remain in the intestine and further catabolized by the microflora. 

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