Acylated amines and their substitution reactions

Acylation of an aromatic primary or secondary amine may be readily achieved by using an acid chloride in the presence of base however, acetylation is more usually effected with acetic anhydride rather than the more obnoxious acetyl chloride. 

In general, benzoylation of aromatic amines finds less application than acetylation in preparative work, but the process is often employed for the 

The benzoyl compounds frequently occlude traces of unchanged benzoyl chloride, which thus escapes hydrolysis by the alkali it is therefore advisable, wherever possible, to recrystallise the benzoyl derivatives from methanol, ethanol or rectified spirit, since these solvents will esterify the unchanged acid chloride and so remove the latter from the recrystallised material. Sometimes the benzoyl compound does not crystallise well this difficulty may be frequently overcome by the use of p-nitrobenzoyl chloride or 3,5-dinitrobenzoyl chloride (Expt 6.161), which usually give highly crystalline derivatives of high melting point. Benzoyl compounds are readily hydrolysed by heating with about 70 per cent sulphuric acid (alkaline hydrolysis is very slow for anilides). 

Primary amines react readily upon warming with acetic anhydride to yield, in the first instance, the monoacetyl derivative. 

If heating is prolonged and excess of acetic anhydride is employed, variable amounts of the diacetyl derivative are formed. 

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Acylated amines and their substitution reactions (Expts 6.67 and 6.68). 

The phenolic group is activating and ortho-para directing. The electrophilic substitution reactions in the nucleus in (a) nitrosation and nitration (b) halogenation and (c) acylation and alkylation, are therefore particularly facile, and various experimental procedures need to be adopted to control the extent of substitution (cf. substitution reactions of aromatic amines and their acylated derivatives, Sections 6.6.1 and 6.6.2, pp. 906 and 916 respectively). 

Reactions of pyrimido[4,5-3] [l,4]thiazines were discussed in CHEC-II(1996) <1996CHEC-II(7)737> more recently, reported reactions of this system involve nucleophilic substitution in a number of guises. Hemiaminals at C-3 react with ammonium acetate to form aminals (Equation 166) <1999CHE97>. The formation of acyl hydrazides from pyrimido[4,5-3][l,4]thiazine-2-carboxylic acids, along with their subsequent conversion to acyl azides and Curtius... 

The different reactivity of 1,2- and 1,1-acceptor/donor-substituted alkenes is paralleled by the readiness with which these compounds can be prepared. Thus, /3-amino acrylates are often spontaneously formed by mixing amines with /3-keto esters, and these derivatives have been used as protective groups for amines because of their low reactivity. a-Amino acrylates can, similarly, be prepared from a-keto esters [40], but this condensation reaction does not proceed spontaneously and requires chemical or azeotropic removal of water [41—43]. a-Amino acrylates are unstable compounds which must be stored at low temperatures [41] or N-acylated immediately after their generation [43]. 

Displacement of halides by secondary amines and of sulfonyl groups by alkoxides can also take place. Furoxancarboxylic acids are attacked by base to give acyclic products, but their derivatives can undergo nucleophilic acyl substitutions. Likewise nucleophilic addition reactions can be accomplished for ketofuroxans, although ring cleavage is also commonplace. The generation of new heterocyclic systems by reaction with nucleophiles is dealt with in Section 4.22.3.2.5. 

Thioesters and oxoesters are similar in their rates of nucleophilic acyl substitution, except with amine nucleophiles for which thioesters are much more reactive. Many biological reactions involve nucleophilic acyl substitutions referred to as acyl transfer reactions. The thioester acetyl coenzyme A is an acetyl group donor to alcohols, amines, and assorted other biological nucleophiles. 

The preparation of amides by the treatment of amines with acyl haUdes is a very general reaction. When phosgene is the acyl hahde, both aliphatic and aromatic primary amines or their salts give carbamoyl chlorides, which can be regarded as substituted chloroformamides, CICONHR. 

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