Robinson’s tropinone synthesis

In 1917 Robert Robinson prepared tropinone, the skeleton of atropine and cocaine, in a single step under near-physiological conditions: water, room temperature and a pH close to 7. It is one of the most elegant syntheses in organic chemistry and the first example of a “biomimetic” synthesis.

Methylamine forms a cyclic iminium ion with succinaldehyde, to which the enol of acetonedicarboxylic acid adds (a Mannich reaction); a second, intramolecular iminium ion and a second Mannich reaction close the bicyclic system. The carboxyl groups, which make the CH₂ hydrogens more acidic, are then lost by decarboxylation.