Methyleneimmonium salts

Apart from rare exceptions, preformed reagents (Fig. 19) are intermediate derivatives having the structure of methyleneimmonium salts (31), X-aminomethyl compounds (32, X = heteroatom see Table 5, below) and imines (33), produced by different routes and capable of readily giving Mannich reactions with the appropriate substrate. 

Methyleneimmonium salts 31 are conveniently prepared from mcihylene-bis-amines, formaldehyde-N,0-acetals, or methylene halogenides. Electrochemical reactions on various alkylamines have also been used to generate methyleneimmonium salts, and trimethylamine N-oxide 34 (Fig. 20) is reported as a source of the corresponding methyleneimmonium salt by reaction with trifluoroacetic anhydride. ... 

The nature of the counterion in methyleneimmonium salts derives from the preparation method, as in the abovementioned examples however chloride or iodide anions are actually mostly reported. It is worth noting that morpholinomethyl fluoride, as distinct from the other halogenides, is a distillable liquid that does not exhibit salt behavior, due... 

Aminomethylation Reactions with Preformed Methyleneimmonium Salts 31 ... 

The anion of methyleneimmonium salts may assume a remarkable relevance, as in some cases it affects the manipulation of the reagent and product as well as the chemo-or regioselectivity of the Mannich reaction. - - ... 

Methyleneimmonium salts have been succe,s,sfully used in Mannich reactions on a high number of different substrates, as reported in Table 4. However, the reactions are frequently performed on substrates such as, in particular, alkyl-caihonyl derivatives, esters and lactones included, previously activated as described above (Refs. 39-42, 59, 65, 69, and 71 in Table 4). 

In addition to their use in Mannich reactions, methyleneimmonium salts can be employed as aminomethylating agents of organometallic derivatives, - - - especially organo-tin compounds, and as dienophiles in aqueous solution. ... 

Table 6 confirms that the Mannich reaction is usually quite. simple to achieve. The use of methyleneimmonium salts (condition E in Table 6), however, requires rather accurately controlled conditions, such as anhydrous solvents or a very low reaction temperature. - These reagents can be prepared in situ with good results - employing, for example, formaldehyde N,0-acetals in the presence of trimethylsilyl halide. The most frequently used solvent is acetonitrile, followed by dichloromethane, but it is important to remember that the type of solveni" -" - - - as well as the concentration of reactants may be critical for reaction yield or selectivity. 

Aminomcthylation of hctcroatoms (X-aminomcthylation in Table 6) is generally the easiest, whereas C-aminomethylation requires a great variety of experimental conditions. Indeed, the C—H moiety bound to a carboxyl group is among the less reactive systems, so that alkyl ketones require conditions A alkyl esters, which would be unstable under such conditions, have to be allowed to react with methyleneimmonium salts. Alkenes, as well as ferrocenyl derivatives, are also barely reactive. By contrast, the nitro group of nitroalkanes behaves as a very good activator of aminomcthylation, and phenols are readily aminomethylated. 

Alkyl vinyl ketones having the general structure 67 (X = H, Table 8) exhibit different reactive sites, depending on the nature of the substituents and the steric requirements. Vinyl ketobases (for the analogous styryl derivatives see Refs. 353 and 354) are obtained by attack of type A on acyclic or exocyclic unsaturated substrates in acidic medium, or with preformed methyleneimmonium salts. Vinylogous Mannieh bases are... 

Other cationic structures have been proposed for the aminomethylating species. In the reactions of N,0-acetals catalyzed by trimethylsilyl derivatives MejSiX, the reactive agent is claimed to be the oxonium cation 50 (sec also Refs. 210 and 211). Moreover, the intermediate hydrochloride 51 could be formed by the action of anhydrous hydrogen chloride " on hexahydrotriazines 32b, although more recent studies suggest the formation, under the same conditions, of equimolecular amounts of methyleneimmonium chloride and the halogenatcd salt 52. 

In the presence of transition metal complexes, such as those of Ir3+ (Scheme 24), Rh3+ and Ru3+, the proton sponge 1 behaves as a hydride donor from one of its methyl groups51,186. The methyleneimmonium cation 157 thus formed undergoes immediate cyclization to a l,l,3-trimethyl-2,3-dihydroperimidinium salt 158. 

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