Amidomethylation reaction

The amidomethylation reaction is suitable for the same purpose, as NH atnide.s, whieh are well-known substrates of Mannich synthesis, can also behave like amine reagents. Thus, the resultant amidomethyl derivative 21 (Fig. 15) can be then subjected to hydrolysis by means of hydrazine to give the primary amine product. - By this method the 6-aminomethyl indole derivative 22 has been obtained. ... 

Since it would hardly be feasible to give a concise, detailed discussion of the mechanisms related to syntheses involving so many different classes of substrates, the main paths of the Mannich reaction are considered in only a general way here. The topic is treated in Refs. 258 and 270 and the mechanism of the analogous amidomethylation reaction is discussed in Refs. 79 and 139. 

Altosaar, H., Christjanson, P and Siimer. K Amidomethylation reactions. XII. Study of phenylamine reactions with 2-pyrrolidonc... 

As far as the biocide properties are concerned, 0-Mannich bases containing extended hydrocarbon chains and used for their combined detcrgent/gcrmicidc action are worth mentioning. A good preserving function is also performed by plywood adhesives, based on urea, melamine, and formaldehyde, which are fixed by suitable iodo-derivatives presumably by amino- and amidomethylation reactions. 

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 " ... 

Fig. 8.3. Hydrolytic reactions in the activation of prodrugs of carboxylic acids that incorporate an aminomethyl (R = H or alkyl, R" = H or alkyl) or amidomethyl group (R = acyl, R" = H or alkyl). Reaction a (chemical and/or enzymatic) liberates the drug RCOOH and a carbinolamine or carbinolamide, which then breaks down to formaldehyde and an amine or...

Thermolysis of the alkylzinc 2-(amidomethyl)pyridines induces an oxidative C—C coupling reaction at the methanide carbon atom. The products 213 ° and 214 (Figure 100) were structurally characterized by X-ray crystallography. These dimers are isostructural with 113, which was obtained from the thermal conversion of the diethylzinc complex of Af-tcrt-butyl-2-pyridylcarbaldimine. Details (Figure 52) are given above (Section in.D). 

A notable application of this reaction is the hydrogenation of the 2-amidomethyl substrate to produce the syn diastereomeric product in... 

In the second alternative method a two-step procedure has been described.15 The first step involves amidomethylation of the aromatic nucleus by reaction with paraformaldehyde and acetamide in the presence of concentrated sulphuric acid. The isolated intermediate is then treated with phosphorus oxychloride in dimethylformamide and xylene and converted into the chloromethylated product [e.g. see 2-(chloromethyl)-4-nitrotoluene, Expt 6.29, for formulation]. The mechanisms of these reactions are currently only speculative. 

S-Acetamidomethyl groups are introduced by reaction of the thiol with l-(acet-amidomethyl)-benzotriazole69 or N-( hydroxy me thyl)acetamide under acidic conditions.62 70 The latter procedure is also used to introduce the S-phenylacetami-domethyl (Phacm) group [Scheme 5.37].71 Thus, the Phacm group can be introduced onto L-cysteine by reaction of yV-(hydroxymethyl)phenylacetamide 37 1 with cysteine hydrochloride in the presence of trifluoromethanesulfonic add. The crude intermediate is then treated with di-/erf-butyl dicarbonate (or... 

The cyclization reaction is also successfully performed through amidomethylation, by using formylatcd amine. ... 

In the reaction on the analogous systems 450 (Fig. 169), the double bond remains in the original position however, an amidomethylation is actually involved in this case, the cycli-zation taking place only when R or R is equal to carbonyl group. 

These reactions have a general relevance in organic synthesis, as they allow the performance of X-methylation reactions such as cyano-, thio-, amidomethylations, etc. starting from hydrogen cyanide, amides, etc. When, in particular, the abovemen-tioned methylol derivatives are allowed to react with amine (R —YH = primary or secondary amine), a Mannich base is produced. 

It is finally worth mentioning that guanidine, melamine, and similar derivatives are frequently used as amine reagents or, sometimes, as preformed reagents.- " The above reactions are related to the analogous, even more commonly applied, amidomethylations (Chap. I, A.2) involving urea derivatives all these compounds have similar chemical features and applications. 

Bis-methylolamide.s achieve crosslinking by reaction with the amino groups of protcic macromolecules, for example, in hairdressing preparations (Fig. 179, Chap. IV). The same compounds can afford amidomethylation of materials that lack amino groups, as in the well-known anticrease treatment of cellulosic fibers. Mcthylol derivatives of the cyclic Mannich bases 498 (Sec. A.l) arc. similarly used with cellulosic fibers. 

An interesting example of template synthesis is the amidomethylation of 2-(hydroxyimino) propanamide in its Niir complex, which gave the carboxamide chelate [Ni(39)] (Equation (2)).50 This is the first example of a ring-closure reaction featuring coordinated amide groups. 

Tscherniac-Einhorn reaction. Introduction of the amidomethyl group into aromatic rings or activated methylene groups in the presence of sulfuric acid. 

An interesting reaction for 5-amidomethylation of indoles unblocked in the 3-position has been reported.5 The conditions are N-hydroxymethyl-phthalimide in concentrated HaSOi, at room temperature and excellent yields are obtained. Jr 0... 

Such is the case also for jV-(halomethyl) carboxamides (R = H or alkyl, R = acyl)721 and iV-(halomethyl) diacylamides (R and R = acyl), which are specific for amidomethylation of / -diketones, a reaction that cannot be effected otherwise) for a review of these reactions see Gross and Hoft679). Amino- and amido-methylation of aromatic carbocyclic and heterocyclic compounds by -halo amines and amides have also been reported.707,722,723... 

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