Halides, acyl reaction with amines

The acetylation of amines with isopropenyl acetate appears to be a transition between the highly exothermic reactions of acyl halides and anhydrides with amines on the one hand and the reaction of amines with more conventional esters on the other. While this reagent is of particular value in the preparation of enol acetate, it has been used for the preparation of amides. One interesting aspect of its use is that acetone forms as a coproduct which may distill off as the reaction proceeds. Isopropenyl acetate and other isopropenyl esters may also be used to Y-acylate amides and imides. By the judicious selection of starting amides and isopropenyl esters, tertiary amides with three different acyl groups may be synthesized. This may very well be one of very few reaction systems which permits the synthesis of this rare group of tertiary amides. 

The Cunius degradation of acyl azides prepared either by treatment of acyl halides with sodium azide or trimethylsilyl azide [47] or by treatment of acyl hydrazides with nitrous acid [f J yields pnmarily alkyl isocyanates, which can be isolated when the reaction is earned out in aptotic solvents If alcohols are used as solvents, urethanes are formed Hydrolysis of the isocyanates and the urethanes yields primary amines. 

Pi peridinobenzimidazole also serves as starting material for the antipsychotic agent halopemide (69). In the absence of a specific reference, one may speculate that the first step involves alkylation with bromochloro-ethane to give halide The chlorine may then be converted to the primary amine by any of several methods such as reaction with phthalimide anion followed by hydrazinolysis. Acylation with j -fluorobenzoyl chloride then gives the desired product. 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

Many of the reactions of amines are familiar from past chapters. Thus, amines react with alkyl halides in S 2 reactions and with acid chlorides in nucleophilic acyl substitution reactions. Amines also undergo E2 elimination to yield alkenes if they are first qualernized by treatment with iodomethane and then heated with silver oxide, a process called the Hofmann elimination. 

The reaction of enamines with ketenes can be conveniently carried out by generating the ketene in situ from an acyl halide and a tertiary amine. 

Ketenes can be prepared by treatment of acyl halides with tertiary amines. The scope is broad, and most acyl halides possessing an a hydrogen give the reaction, but if at least one R is hydrogen, only the ketene dimer, not the ketene, is isolated. However, if it is desired to use a reactive ketene in a reaction with a given compound, the ketene can be generated in situ in the presence of the given compound. ... 

In a similar reaction, aromatic acyl halides are converted to amines in one laboratory step by treatment with hydroxylamine-O-sulfonic acid. " ... 

Acyl halides and anhydrides are the most reactive class of carboxylic acid derivatives, and readily react with amines to give amides. It should be noted that in both cases the leaving group is a conjugate base that, upon protonation during the reaction, will become an... 

Esters also react smoothly with amines, which is a useful reaction if the corresponding acyl halides or anhydrides are not easily available. The reaction proceeds through the anticipated tetrahedral anionic intermediate. There are two possible leaving groups... 

By far the most common method for preparation of amides is the reaction of ammonia or a primary or secondary amine with one of the reactive reagents described in Section 3.4.1. When acyl halides are used, some provision for neutralizing the hydrogen halide is necessary, because it will otherwise react with the reagent amine to form the corresponding salt. Acid anhydrides give rapid acylation of most amines and are convenient if available. The Schotten-Bauman conditions, which involve shaking an amine with excess anhydride or acyl chloride and an alkaline aqueous solution, provide a very satisfactory method for preparation of simple amides. 

The formation of amides can be accomplished by dehydration of the ammonium salts of salicylic acid. The more common method for amines is the reaction of the ester, acyl halide, or anhydride with an amine or ammonia. Each step is fast and essentially irreversible. 

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