Mannich bases nucleophilic substitutions

Mannich bases (see 16-15) of the type RCOCH2CH2NR2 similarly undergo nucleophilic substitution by the elimination-addition mechanism.The nucleophile replaces the NR2 group. 

The exocyclic amino group of 5-aminotetrazole is reactive in nucleophilic substitution of halogen atoms in halonitrobenzenes. For example, the synthesis of 5-picrylaminotetrazole 406 is based on this process <1999THS(3)467>. Finally, 5-aminotetrazole and l-methyl-5-aminotetrazole 407 undergo a Mannich reaction with formaldehyde and trinitromethane with formation of products 408 (R = H, Me) . 

Tfce preferred synthetic route to these important intermediates is the Mannich reaction (Chapter 27), The compound is stored as the stable Mannich base and the unstable enone released by elimination of a tertiary amine with mild base, The same conditions are right for this elimination and for conjugate addition, Thus the aw-methylene compounds can be formed in the flask for immediate reaction with the enol(ate) nucleophile, The overall reaction from (3-amino carbonyl to 1,5-dicarbonyl appears to be a substitution but the actual mechanism involves elimination and conjugate addition,... 

The electron-dona ting power of thye indole and pyrrole nitrogens is never better demonstrated than in the use to which these Mannich bases (the products of the reaction) are put. You may remember that normal Mannich bases can be converted to other compounds by alkylation and substitution (see p. 758). No alkylation is needed here as the indole nitrogen can even expel the Me2N group when NaCN is around as a base and nucleophile. The reaction is slow and the yield not wonderful but it is amazing that it happens at all. The reaction is even easier with pyrrole derivatives. 

The Robinson annulation is the reaction of alkali metal derivatives of cyclohexanones with a-,p>unsaturated methyl ketones to produce cycloketones and polycycloketones. The standard method for Robinson annulation is exemplified in the mechanism shown above. For the synthesis of the 1,5-diketone side chain, the enolate nucleophile reacts with a Michael acceptor this Michael acceptor is usually a substituted vinyl ketone or the parent methyl vinyl ketone (MVK), although the latter gives low yield due to its propensity to polymerize under the standard reaction conditions. To overcome the drawbacks for using MVK, Robinson, McQuillin and Du Feu introduced the Robinson-Mannich variation of the annulation reaction. This modification uses a quatemized Mannich base formed from the vinyl entity the Maimich base is made in situ and acts as a methyl vinyl ketone precursor after it is converted to its methiodides. The formed methiodides of the Mannich adduct 4-(trimethylamino-2-butanone) is condensed with sodioderivatives of ketones or with the parent ketone in the presence of sodium ethoxide. 

Note that dming the reduction of the keto group in the Mannich base, the IV-benzylic group is contemporaneously hydrogenoUtically removed. In the last step, nucleophilic substitution of chlorine by an alkoxide anion is promoted by an electron-withdrawing trifluoromethyl group in the para-position. 

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