Imidazoles Mannich reaction

N-Unsubstituted pyrazoles and imidazoles add to unsaturated compounds in Michael reactions, for example acetylenecarboxylic esters and acrylonitrile readily form the expected addition products. Styrene oxide gives rise, for example, to 1-styrylimidazoles (76JCS(P1)545). Benzimidazole reacts with formaldehyde and secondary amines in the Mannich reaction to give 1-aminomethyl products. 

Pyrazoles and imidazoles exist partly as anions (e.g. 108 and 109) in neutral and basic solution. Under these conditions they react with electrophilic reagents almost as readily as phenol, undergoing diazo coupling, nitrosation and Mannich reactions (note the increased reactivity of pyrrole anions over the neutral pyrrole species). 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

The dimethylaminomethyl group (entry 9) is easily introduced by a Mannich reaction, and lithiation occurs readily at -78°C (88JOC5685). After reaction with a variety of electrophiles, hydrolysis can be performed directly with aqueous acid to give 2-substituted imidazoles in good yield. However, the 2-lithio anion 47 was found to be quite basic, despite the base-weakening effect of coordination with the amino substituent, and thus it was capable of deprotonating the 2-butyl derivative 48 as it was formed by reaction with 1-bromobutane (Scheme 42). No such side-reac-... 

The 1,3 relationship between C-N and C-O suggests a Mannich reaction to add the imidazole ling (Chapter 27), and that disconnection reveals an indole with an unsymmetrical right-hand side, having an extra ketone group. Fischer disconnection will reveal a diketone as partner for phenylhy-drazine. We shall leave aside for the moment when to add the methyl group to the indole nitrogen. 

Heterocyclic substrates, such as pyrrole and imidazole derivatives 68, may undergo selective Mannich reactions. C-Aminomethylation is favored by acidic conditions, whereas N-Mannich bases are produced when free amine and formaldehyde, or N,0-acetals in anhydrous solvents, are employed. Heterocyclic N-Mannich bases, however, are not particularly stable and may therefore behave as aminomethylation agents (see,... 

Ishiwata, S. and Shiokawa, Y.. Benzimidazoles and related compounds. III. Inna-molecular Mannich reaction of 2-alkylumi-nomethylben/imidazoles. Client. Phann. Bull. Tokyo. 18, 1245, 1970. 

The related Mannich reaction is not common. Under the usual acidic reaction conditions TV-substitution occurs, but this is a reversible reaction in the presence of base. Therefore, in basic medium, C- substituted products accumulate, and all positions can be substituted. 2-Methylimidazole gives 1,4,5-tri, 4,5-di- and 4-mono-substituted products. The observation that with formaldehyde and hydrochloric acid histamine gave (98) is at variance with the apparent requirement for basic medium. Since 1-substituted imidazoles do not react it is likely that the imidazole conjugate base is the reactive species. Unless imidazoles contain activating substituents they are not very susceptible to reaction with aldehydes (except HCHO) and ketones. An exception appears to be the product (99) of interaction between imidazole and hexane-2,4-dione. An activated compound such as 4-methylimidazoline-2-thione gives the 5-dimethylamino compound (100) imidazoline-2-thione gave only the (V-hydroxymethyl product under the same reaction conditions. Imidazolin-4-ones with a free 5-position readily form benzylidene derivatives (B-76MI40701). 

Mannich reactions of imidazole-4-carboxylic or the 4,5-dicarboxylic acid gave mixtures of 5-dimethylaminomethylimidazole-4-carboxylic acid and 2,4,5-tris(dimethylaminomethyl)imidazole depending on the reagent ratio. 4-Nitroimidazole-5-carboxylic acid is, however, inert to these aminomethylation conditions. It is more likely that the Mannich reaction involves ipw-replacement of carboxy than prior thermal decarboxylation (cf. (pio-hydroxymethylation <83JHC1417 <89CHE165>. 

Mannich reaction. A complex derived from (r-BuOjaHf, imidazole and 6,6 -dibromo-BINOL is air-stable. It is capable of asymmetric induction in catalyzing the Mannich reaction (80-90% ee). ... 

By analogy to imidazoles, alkylation by haloalkanes of benzimidazoles on the N-atom occurs in neutral and in basic media. 1-Alkylbenzimidazoles are obtained from benzimidazole, sodium hydroxide and bromoalkanes. Benzimidazoles unsubstituted in the 1-position undergo the Mannich reaction ... 

Tmidazo[2,l-Z)]thiazole has been shown by n.m.r, spectroscopy to protonate on the N-atom of the imidazole ring, whilst the mass spectra of some 2-alkyl-substituted imidazo[2,l-6]thiazoles have been correlated with their structures. Compound (69) is brominated in the vacant imidazole ring position by bromine in acetic acid or with sodium hypobromite, but bromination with bromine in chloroform occurs preferentially in the vacant a-position of the furan ring, and in this case a mixture of mono- and di-bromo-compounds is obtained. Compound (69) undergoes the Mannich reaction preferentially in the vacant imidazole ring position the products undergo further substitution e.g. nitration) in the a-position of the furan ring. ... 

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