Acylation of aromatic amines

Compensation has recently been observed in the dissociation of bisulfite addition compounds (Blackadder and Hinshelwood, 1958), in the ionization of phenols (Chen and Laidler, 1962), in the alkaline hydrolysis of certain cyclopentyl acetates (Bruice and Fife, 1962), and in the acylation of aromatic amines (Venkataraman and Hinshelwood, 1960). 

In the above equations Ajj, from the work of Jacobson, represents the relative rates of acylation of aromatic amines having substituents X by means of pigeon liver acetyl transferase, e represents the calculated electron densities on the nitrogen atom made by Perault and Pullman. Equation 22 accounts for only 47% of the variance in the data while eq 23 accounts for 99%. Thus it appears that quantum mechanically obtained electron densities can be extremely useful to the medicinal chemist. In this way the relative electron density on each atom in the molecule can be found and through regression analysis the relative importance of this density at one or more points in the molecule can be evaluated. This approach offers, in principle, a great advantage over the use of a. 

There have, of course, been many attempts to moderate the reaction conditions by various additions and to make the process usable for more sensitive substances. For instance, adding small amounts of concentrated sulfuric acid have been recommended for acylation of aromatic amines, or similarly addition of aluminum chloride. Phosphoric oxide has sometimes been added to bind the water formed. In other cases it proved valuable to add the anhydride of the acid in question, but its action is not limited to binding the water because, being a stronger acylating agent than the acid, it must itself perform much of the acylation of the ammonia. 

The remarks made about the acylation of 1,3-dicarbonyl compounds (p. 205) are relevant here. No intermediate has been isolated from reactions of this kind, but it is interesting that cinnamoyl-pyridinium chloride gives with phenol a bright yellow solution. The colour fades slowly, and phenyl cinnamate (80 per cent) results. The acylation of aromatic amines may proceed similarly 37,... 

Ketone formation can also be avoided if one of the functional acyl halogens ia phosgene is blocked. Carbamyl chlorides, readily obtained by the reaction of phosgene with ammonia or amines, are suitable reagents for the preparation of amides ia direct Friedel-Crafts acylation of aromatics. The resulting amides can be hydroly2ed to the corresponding acids (134) ... 

The reverse reaction is an intramolecular acidolysis of amide group by the o-carboxyhc acid to reform anhydride and amine. This unique feature is the result of an ortho neighboring effect. In contrast, the acylation of an amine with ben2oic anhydride is an irreversible reaction under the same reaction conditions. The poly(amic acid) stmcture (8) can be considered as a class of polyamides. Aromatic polyamides that lack ortho carboxylic groups are very... 

Nucleophilic aromatic substitution of the anion from ary lace ton itrile 113 on the dichloroni-trobenzene 114 results in replacement of the para halogen and formation of 115. Reduction of the nitro group gives the corresponding aniline (116). Acylation of the amine with 3,5-diiodoacetylsa-licylic acid 117 by means of the mixed anhydride formed by use of ethyl chloroformate, gives, after alkaline hydroly.sis, the anthelmintic agent closantel (118) [28]. 

Acylation (Sections 16.3,21.4) The introduction of an acyl group, —COR, onto a molecule. For example, acylation of an alcohol yields an ester, acylation of an amine yields an amide, and acylation of an aromatic ring yields an alkyl aryl ketone. 

It has been reported that the ease of A-alkylation of aromatic amines is enhanced by ultrasonics [9], and, predictably, the presence of mesomeric electron-withdrawing substituents at positions ortho or para to the amino function aids the A-alkylation of the aromatic amines [e.g. 10], see also, for example, the phase-transfer catalysed glycosidation of 2-cyanoaniline [11], Generally, the direct /V-monoalkylation of aminoarenes is not particularly satisfactory, but an alternative protocol [12] in which the N-acyl derivatives are alkylated and then hydrolysed leads to enhanced yields (>90%) (see Section 5.2). In a similar manner, a one pot synthesis converts 2-... 

Aromatic and heteroaromatic amines can be linked to insoluble supports using strategies similar to those used for aliphatic amines. Because of the lower basicities of aromatic amines, however, their /V-bcnzyl derivatives will usually be more susceptible to acidolytic cleavage than aliphatic /V-bcnzylamincs. For the same reason, N-acyl derivatives of aromatic amines will generally be more sensitive towards nucleophiles than the corresponding derivatives of aliphatic amines. 

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). 

Electrophilic substitution reactions of substituted 2,1-benziso-thiazoles have already been discussed. The only other functionally substituted compound so far studied in any detail is the 3-amino derivative (87). This compound is readily diazotized and the dia-zonium salt formed (88) couples with tertiary aromatic amines yielding azo dyes.117,119-121 The salt (88) also undergoes the usual Sandmeyer reactions, and other 3-substituted derivatives, such as the cyano compound (89) may be prepared.111 Acylation of the amine (87) yields diacyl derivatives which appear to possess the 3-acylimino structure (90).111... 

We haven t yet discussed amine protection (that will come later in this chapter) but, since it is the amino group s nucleophilicity that is the problem, it makes sense to react it with an acylating agent an amide is much less nucleophilic than an amine because the nitrogen s lone pair is involved in conjugation with the carbonyl group. The same method was used to reduce the nucleophilicity of aromatic amines in bromination (Chapter 22). The carboxylic acid also needs protecting, and it is made into an ethyl ester. 

When (253) reacts with phosgene the 1-acyl chloride product (254) can react with amines to give amides (79LA1756X while in a further transfer reaction with ketones the compounds (255) and (256) are produced (Scheme 146) (80H(14)97). Acylation of aromatic hydrocarbons using 1-acylimidazoles in the presence of trifluoracetic acid gives high yields provided that the aryl compounds are electron rich, e.g. p-dimethoxybenzene, thiophene, anisole <80BCJ1638). 

Reaction of aromatic amines with sulfur monochloride and an acyl chloride in the presence of Zn salts to give 1,3-benzothiazoles (see 1st edition). 

The reactivity of aromatic amines towards halogens is reduced by salt formation (mineral acid medium), A-acylation, or JV-alkylation. Aqueous solutions of the amine hydrohalide are treated with the halogen or glacial acetic acid is used as solvent to which sodium acetate is added to bind the halogen acid formed. As with phenols, the formation of mono- and di-bromin-ated amines is of especial interest. 

Additional examples of oxidations at a nitrogen center inciude the foiiowing the PhI(OAc)2-induced oxidation of aromatic amines to imines appiied for deprotection of protected amino diois [512], N-acylation of 1,3-disubstituted thioureas using PhI(OAc)2 [513], PhI(OAc)2-promoted oxidation of 1,2-dicarbethoxyhydrazine to diethyl azodicarboxylate as a key step in an organocatalytic Mitsunobu... 

The number of reagents that has been used for the identification of primary amines is possibly larger than for any other class of compounds [5], But most of these classical derivatives lie beyond the scope of this chapter. They are covered in other parts of the book acylation in Chapter 3, silylation in Chapter 4 and alkylation in Chapter 5. The different nitrophenyl derivatives are discussed in Chapter 8, and Chapter 9 presents the options for preparing fluorescent derivatives. The only derivatization fitting into the framework of this chapter is the condensation with carbonyls resulting in the formation of Schiff bases or, in the case of aromatic amines, anils. 

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