Cocaine has been prepared by a sequence beginning with a Mannich reaction between dimethyl acetonedicarboxylate, methylamine, an
d butanedial. The mechanism involves the following steps: 1. Following initial protonation of the carbonyl oxygen, nucleophilic attack by the amine forms carbinolamine 1; 2. Proton transfer and elimination of water forms iminium ion 2; 3. The enol form of the dicarboxylate ester attacks the iminium ion to form adduct 3; 4. Adduct 3 tautomerizes to form enol 4; 5. Following protonation of the aldehyde, cyclization occurs as protonated carbinolamine 5 is formed; 6. Proton transfer and elimination of water lead to iminium ion 6; 7. The enol attacks the iminium ion in a second cyclization reaction to form bicyclic ion 7; 8. Deprotonation leads to the final product. Write out the mechanism on a separate sheet of paper and then draw the structure of protonated carbinolamine 1.
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