Acetanilide, hydrolysis preparation

The synthesis of SFs-substituted phenothiazine was disclosed in a patent from Smith, Kline French Laboratories (63USP3107242). 3-SFs-Acetanilide (120), prepared by acetylation of d-SFs-aniline (39) with acetic anhydride, was first condensed with bromobenzene under basic conditions, in the presence of Cul and copper-bronze powder, and after add hydrolysis provided 3-SFs-diphenylamine (121). This product was then fused with sulfur in the presence of a catalytic amount of iodine to give 2-SFs-phenothiazine (122) in unreported yield (Scheme 34). 

Mono-substitution products of primary amines cannot easUy be prepared by direct action of the appropriate reagent for example, bromination of aniline yields largely the 2 4 6-tribomo derivative and nitration results in much oxidation. If, however, the amino group is protected as in acetanilide, smooth substitution occurs. Thus with bromine, />-bromoacetanilide is the main product the small quantity of the ortlio isomeride simultaneously formed can be easily eliminated by crystallisation. Hydrolysis of p-bromoacetanilide gives/ -bromoaniline ... 

M. Kiese, G. Renner, The Hydrolysis of Acetanilide and Some of Its Derivatives by Enzymes in the Microsomal and Soluble Fraction Prepared from Livers of Various Species , N.-S. Arch. Exp. Path. Pharmakol. 1966, 252, 480-500. 

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. 

Preparation of diazoketones and their rearrangements during hydrolysis (method 271) and alcoholysis (method 295) are discussed elsewhere. Ammonolysis of diazoketones leads to amides of acids containing one more carbon atom than the original acyl halide. Halogen atoms may be present in a remote position on an aliphatic chain. The reaction is carried out by heating the diazoketone in alcohol or dioxane solution with aqueous ammonia in the presence of silver oxide or silver nitrate catalysts. Substituted acetanilides are formed when aniline is used in place of ammonia. ... 

This procedure may be briefly illustrated by one example 109 A mixture of nitric acid id 1.5 23 g), urea (1 g), and glacial acetic acid (23 g) is prepared hot and then cooled. To this a solution of acetanilide (45 g) in acetic anhydride (34 g) and glacial acetic acid (22 g) is slowly added. After 24 hours storage at room temperature precipitation is completed by addition of ice (360 g), and the crude product (52 g, 87 %) is filtered off. This is then rubbed, at 0°, with a 1 4 1 (v/v) mixture of 50% aqueous potassium hydroxide solution, water, and ethanol, which dissolves only the ortho-compound. The /wra-compound is filtered off and washed with water until pure it can be hydrolysed by warm dilute sodium hydroxide to /Miitro-aniline. When the filtrate has been kept for a day at room temperature hydrolysis of the ortho-compound is complete and pure o-nitroaniline has separated in large crystals. The proportion of ortho- to / tfra-compound is about 3 1. 

The following experiments in this sequence outline a novel and efficient procedure for the preparation of this important substance. The chemistry involves the trifluoroacetylation of aniline (Experiment [Cl]), the chlorosul-fonation of the resulting acetanilide (Experiment [C2]), which is followed by concomitant aminolysis and hydrolysis of the sulfonyl chloride intermediate (Experiment [C3]) to produce the final product, sulfanilamide ... 

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