Substitution Reactions of Carbonyl Compounds at the α Carbon

Question: (a) Identify intermediates A–C in the following stepwise conversion of p-isobutyl benzaldehyde to the analgesic ibuprofen.

(b) Direct alkylation of D by treatment with one equivalent of LDA and CH3I does not form ibuprofen. Identify the product of this reaction and explain how it is formed.

Question: A key step in the synthesis of the narcotic analgesic meperidine (trade name Demerol) is the conversion of phenyl acetonitrile to X. (a) What is the structure of X? (b) What reactions convert X to meperidine?

Question: Clopidogrel is the generic name for Plavix, a drug used to prevent the formation of blood clots in patients that have a history of heart attacks or strokes. A single enantiomer of clopidogrel can be prepared in three steps from the chiral α-hydroxy acid A. Identify B and C in the following reaction sequence, and designate the configuration of the enantiomer formed by this route as R or S

Question: What reaction conditions—base, solvent, and temperature—are needed to convert ketone A to either B or C by an intramolecular alkylation reaction?

Question: Although ibuprofen is sold as a racemic mixture, only the S enantiomer acts as an analgesic. In the body, however, some of the R enantiomer is converted to the S isomer by tautomerization to an enol and then protonation to regenerate the carbonyl compound. Write a stepwise mechanism for this isomerization.

Question: Draw a stepwise mechanism showing how two alkylation products are formed in the following reaction.

Question: Draw a stepwise mechanism for the following reaction.

Question: Treatment of α, β-unsaturated carbonyl compound X with base forms the diastereomer Y. Write a stepwise mechanism for this reaction. Explain why one stereogenic center changes configuration but the other does not.

Question: Draw stepwise mechanisms illustrating how each product is formed.

Question: A key step in the synthesis of β-vetivone, a major constituent of vetiver, a perennial grass found in tropical and subtropical regions of the world, involved the reaction of compound A and dihalide B with two equivalents of LDA to form C. Draw a stepwise mechanism for this reaction. β-Vetivone contains a spiro ring system—that is, two rings that share a single carbon atom.

Question:

(a) Draw two different haloketones that can form A by an intramolecular alkylation reaction.

(b) How can A be synthesized by an acetoacetic ester synthesis?

Question: Synthesize each compound from cyclohexanone and organic halides having $\le$4  C’s. You may use any other inorganic reagents.

a.

b.

c.

Question: Bupropion, sold under the trade name of Zyban, is an antidepressant that was approved to aid smoking cessation in 1997. Devise a synthesis of bupropion from benzene, organic compounds that have fewer than five carbons, and any required inorganic reagents.

Question: Devise a synthesis of anastrozole, a drug used to reduce the recurrence of breast cancer (Section 22.18), from the given compounds. You may use any other needed organic compounds or inorganic reagents.

Question: Synthesize (Z)-hept-5-en-2-one from ethyl acetoacetate (CH₃COCH₂CO₂Et ) and the given starting material. You may also use any other organic compounds or required inorganic reagents.

Question: Treatment of ketone A with LDA followed by CH₃CH₂  did not form the desired alkylation product B. What product was formed instead? Devise a multistep method to convert A to B, a synthetic intermediate used to prepare the anticancer drug tamoxifen (Section 23.8C and the chapter-opening molecule).

Question: Capsaicin, the spicy component of hot peppers, can be prepared from amine X and acid chloride Y. Devise a synthesis of Y from (E)-6-methylhept-4-en-1-ol  [(CH₃)₂ CHCH=CH(CH₂)₃OH],CH₂(CO₂Et)₂ , and any required inorganic reagents.

Question: Treatment of W with CH₃Li, followed by CH₃l, affords compound Y (C₇H₁₄O ) as the major product. Y shows a strong absorption in its IR spectrum at  , and its 1 H NMR spectrum is given below. (a) Propose a structure for Y. (b) Draw a stepwise mechanism for the conversion of W to Y.

Question: Explain why H_a  is much less acidic than H_b . Then draw a mechanism for the following reaction.

Question: Devise a stepwise mechanism for the following reaction.

Question: The last step in the synthesis of β-vetivone (Problem 23.61) involves treatment of C with  CH₃Li to form an intermediate X, which forms β-vetivone with aqueous acid. Identify the structure of X and draw a mechanism for converting X to β-vetivone.

Question: Keeping in mind the mechanism for the dissolving metal reduction of alkynes to trans alkenes in Chapter 12, write a stepwise mechanism for the following reaction, which involves the conversion of an α,β-unsaturated carbonyl compound to a carbonyl compound with a new alkyl group on the α carbon.

Question: (–)-Hyoscyamine, an optically active drug used to treat gastrointestinal disorders, is isolated from Atropa belladonna, the deadly nightshade plant, by a basic aqueous extraction procedure. If too much base is used during isolation, optically inactive material is isolated. (a) Explain this result by drawing a stepwise mechanism. (b) Explain why littorine, an isomer isolated from the tailflower plant in Australia, can be obtained optically pure regardless of the amount of base used during isolation.