Amines, acetylation salts

In general, benzoylation of aromatic amines finds less application than acetylation in preparative work, but the process is often employed for the identification and characterisation of aromatic amines (and also of hydroxy compounds). Benzoyl chloride (Section IV, 185) is the reagent commonly used. This reagent is so slowly hydrolysed by water that benzoylation can be carried out in an aqueous medium. In the Schotten-Baumann method of benzoylation the amino compound or its salt is dissolved or suspended in a slight excess of 8-15 per cent, sodium hydroxide solution, a small excess (about 10-15 per cent, more than the theoretical quantity) of benzoyl chloride is then added and the mixture vigorously shaken in a stoppered vessel (or else the mixture is stirred mechanically). Benzoylation proceeds smoothly and the sparingly soluble benzoyl derivative usually separates as a solid. The sodium hydroxide hydrolyses the excess of benzoyl chloride, yielding sodium benzoate and sodium chloride, which remain in solution ... 

Acetoiicetyliition Reactions. The best known and commercially most important reaction of diketene is the aceto acetylation of nucleophiles to give derivatives of acetoacetic acid (Fig. 2) (1,5,6). A wide variety of substances with acidic hydrogens can be acetoacetylated. This includes alcohols, amines, phenols, thiols, carboxyHc acids, amides, ureas, thioureas, urethanes, and sulfonamides. Where more than one functional group is present, ring closure often follows aceto acetylation, giving access to a variety of heterocycHc compounds. These reactions often require catalysts in the form of tertiary amines, acids, and mercury salts. Acetoacetate esters and acetoacetamides are the most important industrial intermediates prepared from diketene. 

The chlorohydrin process (24) has been used for the preparation of acetyl-P-alkylcholine chloride (25). The preparation of salts may be carried out mote economically by the neutralization of choline produced by the chlorohydrin synthesis. A modification produces choline carbonate as an intermediate that is converted to the desired salt (26). The most practical production procedure is that in which 300 parts of a 20% solution of trimethyl amine is neutralized with 100 parts of concentrated hydrochloric acid, and the solution is treated for 3 h with 50 parts of ethylene oxide under pressure at 60°C (27). 

The reactions of (174) with various amines has been studied." " Hydrolysis of the hexamine salt of (174) gave not the symmetric diamine but (184) via a cyclic intermediate. The pyrolysis of 5-methyl-2-thenyltrimethyl ammonium hydroxide (185) is claimed to give (186) through a 1,6 Hofmann elimination reaction. The Bischler-Napieralski cyclization has been applied to acetyl derivatives of 2-(2-thienyl) ethylamine and 2-(3-thienyl) ethylamine for the preparation of sulfur analogs of isoquinoline. ... 

Inclusion of a para acetyl group requires a somewhat different approach to the preparation of these compounds. Reaction of the diazonium salt from p-aminoacetophenone with sulfur dioxide affords the sulfonyl chloride, 203 this is then converted to the sulfonamide, 204, Elaboration via the carbamate with cyclohexyl-amine affords acetohexamide (205). ... 

Iodosobenzene diacetate is used as a reagent for the preparation of glycol diacetates from olefins,9 for the oxidation of aromatic amines to corresponding azo compounds,10 for the ring acetylation of N-arylacetamides,11 for oxidation of some phenols to phenyl ethers,12 and as a coupling agent in the preparation of iodonium salts.13 Its hydrolysis to iodosobenzene constitutes the best synthesis of that compound.14... 

Amines tend to give more complex results. The compound obtained by treating a 5-halofuran-2-carboxaldehyde with aniline is now thought to have a structure resulting from anil formation, halogen displacement, protropy and protonation. The free base is too unstable to be studied easily but acetylation of the salt provides readily recognizable products.182 A related example is discussed later (Section X,A,2). 

Two of these systems were studied as models—the acetylation of choline in brain to give acetyl choline (Hebb, Nachmansohn), and of sulfanilamide (the active component in prontosil, Chapter 3) in liver (Lipmann). Sulfanilamide is rapidly inactivated by acetylation on the p-amino group and then excreted. Sulfanilamide is easily diazotized the diazonium salt formed can be coupled with N-( 1 -naphthyl)ethylenedi-amine dihydrochloride to give a pink derivative (Bratton and Marshall, 1939). This formed the basis for an elegant colorimetric assay. Only the free p-amino group reacts, so that as acetylation proceeded color formation diminished. 

The A-acetyl derivatives of the 2-alkylthio-l,3-thiadiazol-4-imines (124, R = SR, R = Ac) undergo nucleophilic displacement reaction with amines (benzylamine, cyclohexylamine, morpholine, or aniline) giving the 2-amino derivatives (124, R = NRj, R = Ac). The salt (126, R = R = Ph, R = R = H, X = Cl) reacts with aniline at room temperature giving 4-anilino-2-phenyl-l,3-thiazole (128), presumably by a mechanism involving cleavage of the heterocyclic ring. ... 

Acetylation of the stericaUy hindered amine in 40 required treatment with acetic anhydride and sodium acetate at 116°C. The resulting r-butyl acetamide was treated with one equivalent of hydrogen chloride in ethanol followed by filtration of the precipitate to give clean hydrochloride salt 41 in 87% yield. This was the only purification step in the entire... 

The unprotected amine was acetylated with acetic anhydride and the nitrile was converted to the ethyl ester in acidic ethanol with concomitant removal of the Boc group to provide oseltamivir. Finally, salt formation with 85% phosphoric acid in ethanol afforded oseltamivir phosphate (1). 

The first oxidative studies on N-acylglycosylamines were conducted on a preparative scale by Niemann and Hays.65 The N-acetyl-D-glucopyranosylamine (69) obtained by acetylation of D-glucopyranos-ylamine with ketene (or by acetylation of this amine, followed by ammonolysis) was oxidized by way of the dialdehyde 70 to the acid 71, isolated as the strontium salt. Hydrolysis of 71 led to D(+)-glyceric acid (72), thus showing the pyranose structure of 69. 

Lc yel crysts, mp 240° with decompn starts to blacken ca 200° sol in ben acet in sol in ligroin. Was prepd by treating silver salt of hexanitrodi phenyl amine with acetyl chloride. No refs to its expl props... 

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