Carbonyl Condensation Reactions

Question: In theory, the intramolecular aldol reaction of 6-oxoheptanal could yield the three compounds shown. It turns out, though, that 1-acetylcyclopentene is by far the major product. Why are the other two compounds formed in only minor amounts? Draw a stepwise mechanism to show how all three products are formed.

Question: Draw a stepwise mechanism for the following variation of the aldol reaction, often called a nitro aldol reaction.

Question: Draw a stepwise mechanism for the following Robinson annulation. This reaction was a key step in a synthesis of the steroid cortisone by R. B. Woodward and co-workers at Harvard University in 1951.

 Question: One step in the synthesis of sitagliptin (Problem 17.14, a drug used to treat type 2 diabetes) involves reaction of the mixed anhydride A with B to form C. Draw a stepwise mechanism for this reaction.

Question: Reaction of X and phenylacetic acid forms an intermediate Y, which undergoes an intramolecular reaction to yield rofecoxib. Rofecoxib is a nonsteroidal anti-inflammatory agent once marketed under the trade name Vioxx, now withdrawn from the market because of the increased risk of heart attacks from long-term use in some patients. Identify Y and draw a stepwise mechanism for its conversion to rofecoxib.

Question: Coumarin, a naturally occurring compound isolated from lavender, sweet clover, and tonka bean, is made in the laboratory from o-hydroxybenzaldehyde by the reaction depicted below. Draw a stepwise mechanism for this reaction. Coumarin derivatives are useful synthetic anticoagulants.

Question: When A is treated with aqueous –OH, the major product is compound B, which undergoes ester hydrolysis and decarboxylation to form C. Draw a stepwise mechanism for the conversion of A to B.

Question: One step in a recent short synthesis of a prostaglandin (Section 19.6) involves the conversion of succinaldehyde to the bicyclic hemiacetal X. Draw a stepwise mechanism for this process. (Hint: The mechanism begins with an intermolecular aldol reaction.)

Question: (a) Draw a stepwise mechanism for the reaction of ethyl hexa-2,4-dienoate with diethyl oxalate in the presence of base.

(b) How does your mechanism explain why a new carbon-carbon bond forms on C6?

(c) Why is this reaction an example of a crossed Claisen reaction?

Question: Devise a synthesis of each compound from the given starting material. You may use any other organic compounds or required inorganic reagents

Question: Devise a synthesis of each compound from cyclopentanone, benzene, and organic alcohols having ≤ 3 C's. You may also use any required organic or inorganic reagents.

Question: Devise a synthesis of each compound from $\mathit{C}{\mathit{H}}_{\mathbf{3}}\mathit{C}{\mathit{H}}_{\mathbf{2}}\mathit{C}{\mathit{H}}_{\mathbf{2}}\mathit{C}{\mathit{O}}_{\mathbf{2}}\mathit{E}\mathit{t}$ , benzene, and alcohols having ≤ 2 C's. You may also use any required organic or inorganic reagents.

Question: Devise a synthesis of 2-methylcyclopentanone from cyclohexene. You may also use any required reagents

Question: Octinoxate is an unsaturated ester used as an active ingredient in sunscreens.(a) What carbonyl compounds are needed to synthesize this compound using a condensation reaction?(b) Devise a synthesis of octinoxate from the given organic starting materials and any other needed reagents.

Question: Answer the following questions about 2-acetylcyclopentanone.

a. What starting materials are needed to form 2-acetylcyclopentanone by a Claisen reaction that forms bond (a)?

b. What starting materials are needed to form 2-acetylcyclopentanone by a Claisen reaction that forms bond (b)?

c. What product is formed when 2-acetylcyclopentanone is treated with $\mathit{N}\mathit{a}\mathit{O}\mathit{C}{\mathit{H}}_{\mathbf{2}}\mathit{C}{\mathit{H}}_{\mathbf{3}}$, followed by $\mathit{C}{\mathit{H}}_{\mathbf{3}}\mathit{I}$ ?

d. Draw the Robinson annulation product(s) formed by reaction of 2-acetylcyclopentanone with methyl vinyl ketone $\left(C{H}_2=CHCOC{H}_3\right)$.

e. Draw the structure of the most stable enol tautomer(s).

Question: Draw a stepwise mechanism for the following reaction, which was used in the synthesis of ezetimibe (Section 20.6), a drug used to treat patients with high cholesterol.

Question: Propose a stepwise mechanism for the following reaction of a  $\mathit{\alpha }\mathbf{,}\mathit{\beta }$-keto ester. Suggest a reason why this rearrangement reaction occurs.

Question: Isophorone is formed from three molecules of acetone $[{\left(C{H}_3\right)}_2=\mathrm{CO}]$ in the presence of base. Draw a mechanism for this process.

Question: Devise a stepwise mechanism for the following reaction. (Hint: The mechanism begins with the conjugate addition of $\mathit{O}\mathit{H}$ .)

Question: Draw a stepwise mechanism for the following reaction. (Hint: Two Michael reactions are needed.)

Question: 4-Methylpyridine reacts with benzaldehyde $\left(C_6{H}_{5}CHO\right)$ in the presence of a base to form A.

(a) Draw a stepwise mechanism for this reaction.

(b) Would you expect 2-methylpyridine or 3-methylpyridine to undergo a similar type of condensation reaction? Explain why or why not.

Question: Draw a stepwise mechanism for the following reaction, one step in the synthesis of the cholesterol-lowering drug pitavastatin, marketed in Japan as a calcium salt under the name Livalo.

Question: Devise a stepwise mechanism for the following reaction, a key step in the synthesis of the antibiotic abyssomicin C. Abyssomicin C was isolated from sediment collected from almost 1000 ft below the surface in the Sea of Japan. (Hint: The mechanism begins with a Dieckmann reaction.)