Amides, Hofmann reaction preparation

Our recent studies on effective bromination and oxidation using benzyltrimethylammonium tribromide (BTMA Br3), stable solid, are described. Those involve electrophilic bromination of aromatic compounds such as phenols, aromatic amines, aromatic ethers, acetanilides, arenes, and thiophene, a-bromination of arenes and acetophenones, and also bromo-addition to alkenes by the use of BTMA Br3. Furthermore, oxidation of alcohols, ethers, 1,4-benzenediols, hindered phenols, primary amines, hydrazo compounds, sulfides, and thiols, haloform reaction of methylketones, N-bromination of amides, Hofmann degradation of amides, and preparation of acylureas and carbamates by the use of BTMA Br3 are also presented. 

This reaction then is exactly analogous to Hofmann s preparation of the corresponding chloro compound from chloroacet-amide.2 Toxicity by injection into mice showed a l.d. 50 of about 60 mg. /kg. 

The above procedure is essentially that of Ullmann and Bleier.2 2-Aminobenzophenone has also been prepared by reduction of 2-nitrobenzophenone,3 by the Hofmann reaction of the amide of o-benzoylbenzoic acid with sodium hypobromite,4 by the action of an excess of benzoyl chloride on aniline at 220°,6 and by hydrolysis of the acetyl derivative which is obtained by the action of phenylmagnesium bromide on 2-methyl-3,l,4-benzoxaz-4-one (from anthranilic acid and acetic anhydride).6 Various methods for the preparation of 2-aminobenzophenones have been summarized critically by Simpson, Atkinson, Schofield, and Stephenson.7... 

For the preparation of anthranilic acid the starting material is phthalimide, the cyclic imide ring of which is opened by alkaline hydrolysis in the first step of the reaction to give the sodium salt of phthalimidic acid (the half amide of phthalic acid). The intermediate undergoes the Hofmann reaction in the manner outlined on p. 783 yielding o-aminobenzoic acid (anthranilic acid). 

Answer Procedures XI-3, which requires an amide and Hint (lie desired amine contains the grouping N-CHa-, and procedure XI-4, which is the Hofmann reaction. Let us use procedure XI-3. The student may prepare Xl b via procedure XI-4 as an exercise. 

The Hofmann and Curtius reactions as applied to both the mono-and diamides and hydrazides have been reported. Marquardt found that a low yield of the amine can be obtained in the Hofmann reaction of l,2,5-thiadiazole-3-carboxamide. The main side reaction was hydrolysis of the electron-deficient amide to the carboxylic acid. Under the same conditions the dicarboxamide (78) formed the amino acid (16b). Attempts to prepare diaminothiadiazole via the Hofmann reaction of the amino amide (16a) resulted only in amide hydrolysis and the formation of the same amino acid. 

Amides react with alkaline hypochlorite or hypobromite solutions to form primary amines having one less carbon atom. The reaction involves the hydrolysis of an isocyanate, which is seldom isolated. Isocyanates are also intermediates in the Curtius and Lossen rearrangements (methods 447 and 448). Although diese methods have a common mechanism and intermediate, they involve three separate and distinct types of starting materials and are, therefore, treated individually. A comparison of these reactions has been made. A detailed discussion of the Hofmann reaction, which includes conditions, typical procedures, and compounds prepared thereby, has been presented. ... 

The intermediate in the Gabriel-Posner synthesis of quinazolin-2(lH)-one (fusion of o-aminobenzaldehyde with excess of urea), was found to be o-ureidobenzylidene urea (19), which then cyclized on heating, or in the presence of acid, with elimination of urea. The intermediate reacted with aniline, iV-methylaniline, and N,V-dimethylaniline to form 4-p-aminophenyl, 4-p-methylaminophenyl, and 4-p-dimethylaminophenyl quinazolin-2(lH)-ones in an unusual manner. Several quinazolin-2(li/)-ones were prepared by converting o-acylanilines into o-ureidophenyl ketones followed by cycli-zation in acetic acid medium for long periods at 55°C. A novel modification of this cyclization involved a Curtius or Hofmann reaction on 2 -benzoyl-oxanilic acid chlorides (20 = Cl) or amides (20 = NH2), respectively. 

The Curtius, Hofmann (see p. 267), and Schmidt (see p. 307) reactions are in that order decreasingly mild, decreasingly flexible, and increasingly expeditious. The last-named quality varies somewhat with the available starting material, whether the free acid or the ester. The Curtius reaction lends itself to the preparation of isocyanates, sym-and 08-ureas, amides, urethans, and amines at will, and provides a wide choice of experimental conditions. For synthetic purposes the Hofmann reaction can be used only to prepare sym-ureas, urethans, and amines directly, and halting the reaction at a desired intermediate is often not possible. The variety of experimental conditions is narrower and more limited. The Schmidt reaction on carboxylic acids or derivatives has been applied as a preparative method only to the production of amines although urethans and isocyanates have been prepared occasionally by this reaction, it can hardly be considered a preparative method for them. Amides can be prepared by the Schmidt reaction only from ketones. The choice of experimental conditions employable in the Schmidt reaction is narrow. 

Hofmann rearrangement In this reaction, amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous sodium or potassium hydroxide (NaOH or KOH). 

Amides are the least reactive of the carboxylic acid derivatives, and undergo acid or base hydrolysis to produce the parent carboxylic acids, and reduction to appropriate amines (see Section 4.3.10). They can also be dehydrated to nitriles, most commonly with boiling acetic anhydride, (AcO)20, sulphonyl chloride (SOCI2) or phosphoms oxychloride (POCI3) (see Section 4.3.18). Amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous NaOH or KOH. This reaction is known as Hofmann rearrangement (see Section 4.3.10). 

HOFMANN S REACTION. Reaclion used lor preparation of a primary amine from an amide by treatment with a halogen (usually bromine) and caustic soda. The resulting amine has one fewer carhon atom than the amide used. 

An interesting and general reaction for the preparation of primary amines is the Hofmann degradation, in which an unsubstituted amide is converted to an amine by bromine (or chlorine) in sodium hydroxide solution ... 

Arnido . or imido " hydrogen atoms ate easily replaced in the Cold by the positive bromine atom of alkali hypobtomites. The reaction is the first step in the Hofmann degradation of acid amides (method 446) and, as such, has been extensively studied. The N-bromoamides are sometimes isolated. Excellent directions are given for the preparation of N-btomoacetamide (51%). ... 

Phenyleyclopentylamine has also been prepared from 1-phenylcyclopentanecarboxylic acid by means of the Hofmann degradation of the intermediate amide and from the intermediate carboxylic acid chloride by the Curtins reaction. In the method described, using the mixed carboxylic-carbonic anhydride, improved yields of the amine are obtained. 

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