Aminomethylation, of phenols

Aliphatic aldehydes and ketones react with aziridines to form relatively stable half aminals, eg, aziridine reacts with formaldehyde to form Ai-hydroxymethylaziridine [20276-43-1]. Half aminals can be converted to full aminals by reaction with a further secondary amine, isomerized to oxazolidines by the action of heat or used in a Mannich reaction for the ring aminomethylation of phenols, although this reaction gives only moderate yields (218-227). 

Hydrogen chloride Aminomethylation with hexahydro-l,3,5-triazines p-Aminomethylation of phenols... 

Richardson et al.y as part of a study of the reactions of metal ions with vitamins, have determined the structures of the bis chelates of pyridoxamine (PM) with Cu1111 and Zn11.12 In each case the pyridoxamine molecule behaves as an N—O bidentate in bonding through the 4-(aminomethyl) and phenolate groups. The PM molecules are zwitterionic, with the heterocyclic N atoms protonated. 

The selective aminomethylation of either reactive center has been also achieved.- - - In tetracycline it has been shown that aminomethylation occurs at the amide N atom and not at the phenolic D ring, in accordance with the higher reactivity of the amide N—group as compared with that of the C atom in ortho position to the phenolic hydroxy group. ... 

The possibility of regiosclcctive reaction arises when aminomethylation may occur on different sites of a substrate, such as, for example, the unequivalent a or a positioas of a nonsymmetrical ketone, the ortho or para positions of phenol, the different. sites of a heterocyclic compound, and so on. 

Deaminomethylation of Mannich bases may also occur in the presence of electrophilic species, capable of replacing the aminomethyl group linked to the substrate moiety, such as, for example, diazonium salts acting on Mannich bases of phenols and indoles, or alcohols acting on cyclic O-Mannich bases. The deaminomethylation reaction is also prc.sent in. several equilibria afforded by aminomethyl derivatives of benzotriazole (sec 209, Chap. 1, C.6). 

Macromolecular phenol derivatives have been extensively studied, and the ami-nomethylation reaetion is performed even on crosslinked substrates."- Aminomethylation of lignin for the purpose of produeing complexing agents should also be included in this erouD of reactions, as it is likely to occur on the phenolic moieties abundantly... 

Finally, crosslinked structures of type VII may result from the hardening, for instance, of phenolic resins (503) through reaction of novolacs with hexamethylenetetramine, which is a preformed aminomethylating agent (see Table 31, Chap. III). 

So far as the aminomethylation of di- or poly-hydroxy phenolic substrates is concerned, it has been discovered " "" that the reaction always occurs in the ortho position with respect to one hydroxy group, in accordance with the orienting properties of the substituents. 

As in the case of antibiotics, this group of substrates may be readily functionalized by aminomethylation due to the presence of phenolic rings, which permit preparation of pnxlucts with basic properties. Flavonoids such as rutin " and silymarin pos.sess two hydroxylated aromatic nuclei, both of which may undergo aminomethylation, thus preventing the clear detection of the site of attack however, the products obtained usually maintain the pharmacological activity of the initial material. In the case of arctigenin, aminomethylation can lake place only in the ortho position with respect to the hydroxy group, and chrysin (487, Fig. 180) reacts at position 8. 

The classical Mannich reaction converts phenols to aminomethylated phenols. The reaction involves the addition of phenols to C=N bonds of imines or iminium salts formed from formaldehyde and primary or secondary amines, respectively . Recent modifications employ the reaction of an aminal in the presence of SO3, which gives a sulfonate ester, followed by o-aminomethylation (equation Sc(OTf)3 catalyzed... 

Nitrogen Content of Phenol and Methylphenol Novolacs Produced by Mannich Reaction as a Function of the Ratio of Aminomethylating Mixture (Methanal and Dimethylamine) to Novolac (data from ref [91])... 

Anhydrous HCl introduced at -30° into a soln. of 1,3,5-tri-n-propylhexahydro-triazine in anhydrous acetonitrile, then a soln. of phenol in acetonitrile added, and allowed to stand 24 hrs. at room temp. p-(n-propylaminomethyl)phenol. Y 56%. - p-Substitution is favored by this method in contrast to conventional aminomethylating agents, whidi favor o-substitution. F. e. s. D. D. Reynolds and B.C. Cossar, J. Heterocyclic Chem.5,605(1971) 3,4-dihydro-2H-l,3-benzoxazmes cf. ibid. 8, 611. 

Electrophiles attack on nitrogen in protonation, alkylation, and N-oxidation reactions. Electrophihc substitutions at carbon are not observed in the parent compound. Donor substituents (e.g., OH or NH2) increase the SsAr reactivity of the pyrimidine system (two substituents lead to an S Ar reactivity corresponding to benzene, three to that of phenol) and enable nitration, nitrosation, aminomethylation, and azo-coupHng to take place at the 5-position, for example ... 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

Phenols, secondary and tertiary aromatic amines, pyrroles, and indoles can be aminomethylated by treatment with formaldehyde and a secondary amine. Other aldehydes have sometimes been employed. Aminoalkylation is a special case of the Mannich reaction (16-15). When phenols and other activated aromatic compounds are treated withA-hydroxymethylchloroacetamide, amidomethylation takes place " ... 

For the synthesis of perfectly dendronized sohd-phase polymers (Fig. 7.4) various dendritic structures were prepared based on amide connections [6]. For example, the naturally occurring amino acid lysine was used as a building block in creating a dendritic scaffold [33]. The synthesis of symmetrical tri-branching den-drimers on aminomethyl polystyrene macrobeads was also described in literature [34]. Recently, aryl ether dendrimers were prepared on hydroxymethyl polystyrene using a Mitsunobu reaction with 3,5-bis(acetoxymethyl)phenol [35]. 

In a closely related example, a Mannich reaction of the somewhat more complex phenol (20-1) with formaldehyde and fert-butylamine gives the aminomethylated product (20-2). Hydrolysis of the acetamide protecting group then affords the corresponding aniline (20-3). Alkylation with the quinoline (17-6) in this case also proceeds on aniline nitrogen. The selectivity over the more basic secondary side nitrogen can probably be ascribed to steric hindrance about the latter. There is thus obtained tebuquine (20-4) [22]. 

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