We have seen that the alpha carbon atom of an enamine can

Identify which of the following compounds are expected to have pKa<20. For each compound with pKa<20, identify the most acidic proton in the compound. O H O O OH O O

One of the compounds from the previous problem has pKa<10. Identify that compound and explain why it is so much more acidic than all of the other compounds.

Draw resonance structures for the conjugate base that is produced when each of the following compounds is treated with sodium ethoxide: (a) OEt O O (b) OEt O O (c) CN O

Rank the following compounds in terms of increasing acidity: O O O O O O O OH

Draw the enol of each of the following compounds and identify whether the enol exhibits a significant presence at equilibrium. Explain. O (a) O O (b) O O (c) O (d)

Ethyl acetoacetate has three enol isomers. Draw all three.

Draw the enolate that is formed when each of the following compounds is treated with LDA: H O (a) O (b) OEt O (c) O (d)

When 2-hepten-4-one is treated with LDA, a proton is removed from one of the gamma (g) positions. Identify which g position is deprotonated and explain why the g proton is the most acidic proton in the compound.

When optically active (S)-2-methylcyclopentanone is treated with aqueous base, the compound loses its optical activity. Explain this observation and draw a mechanism that shows how racemization occurs.

The racemization process described in the previous problem also occurs in acidic conditions. Draw a mechanism for the racemization process in aqueous acid.

Draw all four b-hydroxyaldehydes that are formed when a mixture of acetaldehyde and pentanal is treated with aqueous sodium hydroxide.

Identify all of the different b-hydroxyaldehydes that are formed when a mixture of benzaldehyde and hexanal is treated with aqueous sodium hydroxide.

Propose a plausible mechanism for the following isomerization and explain the driving force behind this reaction. In other words, explain why the equilibrium favors the product. OH O O OH H3O+

The isomerization in the previous problem can also occur in basic conditions. Draw a mechanism for the transformation in the presence of catalytic hydroxide.

Draw the product obtained when each of the following compounds is heated in the presence of a base to give an aldol condensation: O (a) H O (b) H O (c)

Trimethylacetaldehyde does not undergo an aldol reaction when treated with a base. Explain why not.

Identify the reagents necessary to make each of the following compounds with an aldol condensation: O (a) O (b) H O (c) O (d)

When acetaldehyde is treated with aqueous acid, an aldol reaction can occur. In other words, aldol reactions can also occur in acidic conditions, although the intermediate is different than the intermediate involved in the base-catalyzed reaction. Draw a plausible mechanism for the acid- catalyzed process. H O OH H O H3O+

Diethyl malonate (the starting material for the malonic ester synthesis) reacts with bromine in acid- catalyzed conditions to form a product with molecular formula C7H11BrO4. (a) Draw the structure of the product. (b) Draw a mechanism of formation for the product. (c) Would you expect this product to be more or less acidic than diethyl malonate?

Cinnamaldehyde is one of the primary constituents of cinnamon oil and contributes significantly to the odor of cinnamon. Starting with benzaldehyde and using any other necessary reagents, show how you might prepare cinnamaldehyde. H O Cinnamaldehyde

Draw the condensation product that is expected when each of the following esters is treated with sodium ethoxide followed by acid workup: OEt O (a) OEt O (b)

Starting with diethyl malonate and using any other reagents of your choice, show how you would prepare each of the following compounds: Ph OH O (a) OH O (b) COOH Ph Ph (c

Starting with ethyl acetoacetate and using any other reagents of your choice, show how you would prepare each of the following compounds: Ph O (a) O (b) COCH3 Ph (c)

Propose a plausible mechanism for the following transformation: O OH H3O+

Draw the condensation product obtained when the following compound is heated in the presence of aqueous sodium hydroxide: O O C12H12O NaOH, H2O Heat + H2O

Identify the reagents you would use to convert 3-pentanone into 3-hexanone.

Identify the reagents necessary to achieve each of the following transformations: OEt O O OEt O O O O O

Draw the structure of the product that is obtained when acetophenone is treated with each of following reagents: (a) Sodium hydroxide and excess iodine followed by H3O+ (b) Bromine in acetic acid (c) Aqueous sodium hydroxide at elevated temperature

Draw a reasonable mechanism for the following transformation: O O O + NaOH, H2O Heat

6 Predict the major product for each of the following transformations: O O CO2Et CO2Et EtO2C EtO2C C6H8O2 H3O+ Heat (a) CH2CO2Et CH2CO2Et C11H16O3 C8H12O H3O+ Heat 1) NaOEt 2) H3O+ (b) O C5H9BrO Pyridine [H3O+], Br2 C8H16O C5H8O 1) Et2CuLi (c) 2) MeI C9H16O O 1) LDA, 78C 2) EtI (d)

Propose an efficient synthesis for each of the following transformations: EtO O OEt O O (a) O O (b) O O O (c)

The product of an aldol condensation is an a,b-unsaturated ketone which is capable of undergoing hydrogenation to yield a saturated ketone. Using this technique, identify the reagents that you would need in order to prepare rheosmin via a crossed aldol reaction. Rheosmin is isolated from raspberries and is often used in perfume formulations for its pleasant odor. Hint: The presence of a phenolic proton will be problematic during an aldol reaction. (Can you explain why?) Consider using a protecting group (Section 13.7). Rheosmin HO O

Identify the reagents you would use to convert cyclohexanone into each of the following compounds: O (a) O (b) O (c) O (d) O O (e) CO2Et O (f) O (g)

The enolate of a ketone can be treated with an ester to give a diketone. Draw a mechanism for this Claisen-like reaction and explain why an acid source is required after the reaction is complete. O O O 1) LDA 2) OEt O 3) H3O+

Beta-keto esters can be prepared by treating the enolate of a ketone with diethyl carbonate. Draw a plausible mechanism for this reaction. O O OEt O 1) LDA 3) H3O+ 2) O EtO OEt

The enolate of an ester can be treated with a ketone to give a b-hydroxy ester. Draw a mechanism for this aldol-like reaction. EtO O EtO O OH 2) O 1) LDA 3) H3O

Nitriles undergo alkylation at the a position much like ketones undergo alkylation at the a position. CN CN R 1) LDA 2) RX The a position of the nitrile is first deprotonated to give a resonancestabilized anion (like an enolate), which then functions as a nucleophile to attack the alkyl halide. (a) Draw the mechanism described above. (b) Using this process, show the reagents you would use to achieve the following transformation: Br OH O

Identify the Michael donor and Michael acceptor that could be used to prepare each of the following compounds via a Michael addition: O O O (a) OEt O CN O (b) OEt OEt O O NO2 (c) OEt O O CHO (d) (e) O2N NO2

The conjugate base of diethyl malonate can serve as a nucleophile to attack a wide range of electrophiles. Identify the product that is formed when the conjugate base of diethyl malonate reacts with each of the following electrophiles followed by acid workup: Br (a) O (b) Cl O (c) O (d) I (e) (f) CN O O O (g) (h) NO2

Draw the product of the Robinson annulation reaction that occurs when the following compounds are treated with aqueous sodium hydroxide: O + O O

Identify what reagents you would use to make the following compound with a Robinson annulation reaction: O O

Draw a plausible mechanism for the following transformation: NO2 O NO2 + NaOH, H2O Heat

Propose an efficient synthesis for the following transformation: O

For a pair of keto-enol tautomers, explain how IR spectroscopy might be used to identify whether the equilibrium favors the ketone or the enol.

Acrolein is an a,b-unsaturated aldehyde that is used in the production of a variety of polymers. Acrolein can be prepared by treating glycerol with an acid catalyst. Propose a plausible mechanism for this transformation. HO OH OH Glycerol H O Acrolein H2SO4 Heat

Draw the structure of the product with molecular formula C10H10O that is obtained when the compound below is heated with aqueous acid. H3O+ Heat CN O C10H10O

Lactones can be prepared from diethyl malonate and epoxides. Diethyl malonate is treated with a base, followed by an epoxide, followed by heating in aqueous acid: EtO OEt O O HO OH O O OH HO O OH O O H3O+ Heat (CO2) 1) NaOEt 2) O H3O+ Heat EtO OEt O O O [H3O+] @ Using this process, identify what reagents you would need to prepare the following compound: O O

Predict the major product of the following transformation: CO2Et OO H3O+ Heat C10H10O

Consider the structures of the constitutional isomers, compound A and compound B. When treated with aqueous acid, compound A undergoes isomerization to give a cis stereoisomer. In contrast, compound B does not undergo isomerization when treated with the same conditions. That is, compound B remains in the trans configuration. Explain the difference in reactivity between compound A and compound B. O Compound A Compound B O

Propose a plausible mechanism for the following transformation: Ph O OH O Ph OH H3O+

Propose a plausible mechanism for the following transformation: O O NaOH, H2O Hea

This chapter covered many C!C bond-forming reactions, including aldol reactions, Claisen condensations, and Michael addition reactions. Two or more of these reactions are often performed sequentially, providing a great deal of versatility and complexity in the type of structures that can be prepared. Propose a plausible mechanism for each of the following transformations: O O HO O (a) NaOH, EtOH O O O O (b) NaOEt EtOH

The following transformation cannot be accomplished by direct alkylation of an enolate. Explain why not and then devise an alternate synthesis for this transformation. O O

We have seen that the alpha carbon atom of an enamine can function as a nucleophile in a Michael reaction, and in fact, enamines can function as nucleophiles in a wide variety of reactions. For example, an enamine will undergo alkylation when treated with an alkyl halide. Draw the structure of intermediate A and the alkylation product B in the following reaction scheme (J. Am. Chem. Soc. 1954, 76, 20292030): O NH TsOH H2O A 1) CH3I B NH 2) H3O+

Consider the reaction between cyclohexanone and the optically pure amine shown below (J. Org. Chem., 1977, 42, 16631664). (a) Draw the structure of the resulting enamine and discuss how many isomer(s), if any, form in this reaction. (b) When the enamine(s) formed in part a is (are) treated with methyl iodide, followed by aqueous acid, 2-methylcyclohexanone with 83% ee is isolated. Explain the source of the observed enantiomeric excess (as compared with the racemic mixture obtained in Problem 22.110), and identify the enantiomer that predominates. O H H3C N CH3 TsOH H2O +

Predict the product of the following reaction sequence, which was recently used in a synthetic route toward a series of 1,3,6-substituted fulvenes (J. Org. Chem. 2012, 77, 63716376): O O 1) NaOH/H2O, heat 2) PhMgCl, THF 3) conc. H2SO4 C17H14

The natural product ()-N-methylwelwitindolinone C isothiocyanate is isolated from a blue-green algae and has been identified as a promising compound to treat drug-resistant tumors. Compound X (R = protecting group) was utilized as a key synthetic intermediate in the synthesis of the natural product (J. Am. Chem. Soc. 2011, 133, 1579715799). Compound X can be prepared in a ring-forming reaction from compound Y under strongly basic conditions (excess NaNH2). N O H SCN Cl N O H H RO N O OR Br X Y N-methylwelwitindolinone C isothiocyanate Several steps O H (a) Propose a plausible mechanism for conversion of Y into X under basic conditions. (b) When Y is converted into X, a minor side product of the reaction is a constitutional isomer of X which lacks a ketone group. Propose a structure for this side product. (Hint: Recall that enolates are ambident nucleophiles.)

When a mixture of conformationally isomeric enamines, shown below, is treated with methyl acrylate, followed by aqueous acid, the expected Stork enamine synthesis product A is isolated in 21% ee (Tetrahedron Lett., 1969, 10, 42334236). Assuming that the two enamine isomers are present in equal concentration, explain why such an enantiomeric mixture of A would result in this case by providing a mechanistic analysis for the Michael reaction possible via each enamine. Based on your analysis, determine whether the R or S enantiomer of A predominates in the product mixture and explain your choice. O O OCH3 N CO2Et 1) EtO2C N O OCH3 + 2) H3O+ (Methyl acrylate) A

The following sequence, beginning with a cyclic hemiacetal (compound A), was part of a recently reported enantiospecific synthesis of a powerful sex pheromone (currently used in pest management) of the mealybug Pseudococcus viburni (Tetrahedron Lett. 2010, 51, 52915293): O RO HO P Ph Ph Ph OEt O Heat B py C TsCl A Me2CuLi RO OEt O RO O D E O F (a) Draw the structures of compounds B and C. (b) Describe in words how the cyclopentyl ring is closed during the conversion of compound C into compound D. (c) Identify the reagents you would use to convert compound D into compound F (in just two steps). Also identify the structure of compound E.

The following synthetic step was utilized as part of a recent synthesis of the polycyclic natural product haouamine B (J. Am. Chem. Soc. 2012, 134, 92919295). In this reaction, the function of the first reagent (triflic anhydride) is to activate the Michael acceptor that is present in the starting compound (rendering it even more electrophilic), so that it can undergo an intramolecular Michael reaction. Draw a mechanism for this reaction and explain the observed stereochemistry of the newly formed chirality center. N O R H MeO MeO N O R H S O S O O CF3 O F3C O S CF3 O O OMe MeO OMe OMe Pyridine

In a recent effort to devise a new synthetic pathway for the preparation of useful building blocks for the synthesis of natural products, compound 2 was prepared by treating compound 1 with diethylmalonate in the presence of potassium carbonate (Tetrahedron Lett. 2010, 51, 69186920). Propose a plausible mechanism for this reaction. N H OO EtS SEt H3C Cl EtO OEt O O O O O K K HN O O SEt H3C Cl EtO2C EtO2C 1 2 ! !

The compound fusarisetin A (isolated from a soil fungus) displays significant anticancer activity without detectable cytotoxicity (toxicity to cells). A key step in a reported synthesis of the enantiomer of fusarisetin A involves a Dieckmann cyclization followed by the intramolecular formation of a hemiacetal under basic conditions (J. Am. Chem. Soc. 2012, 134, 920923). Provide a mechanism consistent with this transformation. H H OH H H O N O O OMe OH H H H H O O N O OH OH NaOMe

Provide a reasonable mechanism to account for the formation of compound 2, including a rationale to explain the observed stereochemistry of the product (Org. Lett. 2012, 14, 47384741). Note that NaHMDS is a strong base, comparable to LDA. (Hint: Consider both resonance structures of the intermediate formed in the first step of the mechanism.) O O Na (NaHMDS) O OH 1) 2) H2O 1 2 N TMS TMS ! @

Gibberellins (named GA1 through GAn in order of discovery, over 120 are known) are plant hormones that regulate growth and influence various developmental processes, such as germination, flowering, etc. The modified gibberellin exo-16,17-dihydro-GA5-13-acetate (1) has considerable promise in reducing the risk of lodging (harmful to a plants growth) in cereal crops such as corn and wheat. O OC OAc CO2H H H 1 When developing a new drug for plant or human use, it is often important to introduce a radiolabel, or an isotope, into the structure so it can be traced as it does its job, and subsequently the metabolites (smaller fragments of the original compound formed as a molecule is metabolized) can be tested for toxicity to the host or environment. For the purpose of compound 1, C3 will be labeled with 14C (illustrated with an asterisk, *), and a key step in the synthesis of this labeled compound involves an intramolecular aldol-type reaction to form a ring (Can. J. Chem. 2004, 82, 293300). Draw a detailed, stepwise mechanism for the transformation of aldehyde 2 to alcohol 3. O C H OAc CO2H H H 2 OHC O 1) 2) HCl KO OK O * O OC OAc CO2H H H 3 3-( HO * 14C)-1 H2O * = 14C-labeled carbon