SolutionsThe Mannich reaction
Exercise 1
Write the product of the Mannich reaction of cyclohexanone with formaldehyde and dimethylamine hydrochloride, and the one obtained on treating it with methyl iodide and then with a base.
The Mannich reaction gives 2-[(dimethylamino)methyl]cyclohexanone (as the hydrochloride). With CH3I the trimethylammonium salt forms, which with a base undergoes Hofmann elimination (E1cB, through the enolate) to give 2-methylenecyclohexanone, an exocyclic enone that is a very reactive Michael acceptor.
Exercise 2
Why is the Mannich reaction normally carried out with secondary amines? When is it useful to use a primary amine?
With a primary amine, the Mannich base formed is a secondary amine, which can form a second iminium ion and react again (dialkylation), giving mixtures. That double reaction is useful precisely when a nitrogen-containing ring is to be closed, as in Robinson’s tropinone synthesis, in which methylamine reacts with both carbonyls of succinaldehyde.