СО cat. H + NH2CH3 + H2CO2C CO2CH3 CO CHE Cocaine has been prepared by a sequence beginning with a Mannich reaction between dimethyl acetonedicarboxylate, methylamine, and 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; he 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. 1 pt Write out the mechanism on a separate sheet of paper and then draw the structure of bicyclic ion 7 1 pl 1 p • You do not have to consider stereochemistry,

1. H2C=CHCOCH 2. H2O* 3. NaOH, H2O The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one, followed by enamine hydrolysis and base treatment, yields the product indicated. The mechanism involves the following steps: 1. Michael addition of the enamine to the unsaturated ketone yields carbanion 1; 2. Proton transfer leads to enamine 2: 3. Hydrolysis of the enamine leads to cyclohexanone 3; 4. Deprotonation leads to carbanion 4; 5. Intramolecular aldol addition leads to tetrahedral intermediate 5; 6. Protonation leads to aldol addition product 6; 7. Dehydration leads to the final product. Write out the reaction mechanism on a separate sheet of paper, and then draw the structure of tetrahedral intermediate 5. 2 pt • You do not have to consider stereochemistry • You do not have to explicitly draw Hatoms, . Do not include lone pairs in your answer. They will not be considered in the grading, 2 pt

References This question has multiple parts. Work all the parts to get the most points. For the following reaction: H + HECH NaOH CH3CH, OH a Draw the major organic product, assuming no dehydration of aldol product has occurred. ce- -O0O-

Reference Na Oh н н н н–бсH-CH, Correct

References Draw the organic product of the mechanism step in part (b) above, representing any enolate ions as oxyanions. • Do not include counter-ions, e.g., Na, r, in your answer. Co- O0O-

REDES This question has multiple parts. Work all the parts to get the most points. The Knoevenagel condensation is a reaction involving an active methylene compound (a CH, flanked by two electron withdrawing groups) and an aldehyde or ketone. For the following reaction: CHCOẠNa, CHỊCHO CH,CH20 OCH CH3 + Not Submitted a Write a mechanism for the step below, Arrow-pushing Instructions

b Now draw the product of the step above. • You do not have to consider stereochemistry. • Any enolate ions should be drawn as oxyanions. • Omit counterions, hydroxide ion, acetate ion, or acetic acid. 0- -000 – Not Submitted