Important Concepts. Problems. Chapter Problems. Cuprate additions followed by enolate alkylations. 15. Michael Addition (Section 18-11)

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1 Problems hapter uprate additions followed by enolate alkylations P 1. R 2uLi, TF 2. RX A A R R N 15. Michael Addition (Section 18-11) D P D R P R A RR 16. Robinson Annulation (Section 18-11) Important oncepts A K 2 1. ydrogens next to the carbonyl group (A-hydrogens) are acidic because of the electron-withdrawing nature of the functional group and because the resulting enolate ion is resonance stabilized. 2. Electrophilic attack on enolates can occur at both the a-carbon and the oxygen. aloalkanes usually prefer the a-carbon. Protonation of the oxygen leads to enols. 3. Enamines are neutral analogs of enolates. Resonance donation of the nitrogen lone pair imparts nucleophilic character on the remote double bond carbon, which can be alkylated to give iminium cations that hydrolyze to aldehydes and ketones on aqueous work-up. 4. Aldehydes and ketones are in equilibrium with their tautomeric enol forms; the enol keto conversion is catalyzed by acid or base. This equilibrium allows for facile a-deuteration and stereochemical equilibration. 5. A-alogenation of carbonyl compounds may be acid or base catalyzed. With acid, the enol is halogenated by attack at the double bond; subsequent renewed enolization is slowed down by the halogen substituent. With base, the enolate is attacked at carbon, and subsequent enolate formation is accelerated by the halogens introduced. 6. Enolates are nucleophilic and reversibly attack the carbonyl carbon of an aldehyde or a ketone in the aldol condensation. They also attack the b-carbon of an a,b-unsaturated carbonyl compound in the Michael addition. 7. a,b-unsaturated aldehydes and ketones show the normal chemistry of each individual double bond, but the conjugated system may react as a whole, as revealed by the ability of these compounds to undergo acid- and base-mediated 1,4-additions. uprates add in 1,4-manner, whereas alkyllithiums normally attack the carbonyl function. Problems 32. Underline the a-carbons and circle the a-hydrogens in each of the following structures ( 3 ) 2 3 [ 3 [ 3 3 [ (e) 3 3 (f )

2 862 hapter 18 Enols, Enolates, and the Aldol ondensation (g) ( 3 ) 3 (h) ( 3 ) Write the structures of every enol and enolate ion that can arise from each of the carbonyl compounds illustrated in Problem What product(s) would form if each carbonyl compound in Problem 32 were treated with alkaline D 2 ; 1 equivalent of r 2 in acetic acid; excess l 2 in aqueous base? 35. Describe the experimental conditions that would be best suited for the efficient synthesis of each of the following compounds from the corresponding nonhalogenated ketone. r A l l l l l 36. Propose a mechanism for the following reaction. (int: Take note of all of the products that are formed and base your answer on the mechanism for acid-catalyzed bromination of acetone shown in Section 18-3.) atalytic l, l 4 S 2 l 2 S 2 l l 37. Give the product(s) that would be expected on reaction of 3-pentanone with 1 equivalent of LDA, followed by addition of 1 equivalent of 3 2 r ( 3 ) 2 l ( 3 ) 2 2 S 3 ( 3 ) 3 l 38. Give the product(s) of the following reaction sequences. 3 N 1., 2. ( 3 ) 2 P 2 l 3., 2 N 1., , 2 2 r N 2 N 39. The problem of double compared with single alkylation of ketones by iodomethane and base is mentioned in Section Write a detailed mechanism showing how some double alkylation occurs even when only one equivalent each of the iodide and base is used. Suggest a reason why the enamine alkylation procedure solves this problem. 40. Would the use of an enamine instead of an enolate improve the likelihood of successful alkylation of a ketone by a secondary haloalkane? 41. Formulate a mechanism for the acid-catalyzed hydrolysis of the pyrrolidine enamine of cyclohexanone (shown in the margin). 42. Write the structures of the aldol condensation products of pentanal; 3-methylbutanal; cyclopentanone. 43. Write the structures of the expected major products of crossed aldol condensation at elevated temperature between excess benzaldehyde and 1-phenylethanone (acetophenone see Section 17-1 for structure); acetone; 2,2-dimethylcyclopentanone. 44. Formulate a detailed mechanism for the reaction that you wrote in of Problem 43.

3 Problems hapter Give the likely products for each of the following aldol addition reactions. 2 2 Na, 2 ( 3 ) 2 Na, 2 Na, 2 3 Na, Rotundone (margin) is the natural product responsible for the peppery aroma in peppers, many herbs, and red wines (p. 846). What cyclic diketone will give rotundone upon intramolecular aldol condensation? 47. Write all possible products of the base-catalyzed crossed aldol reactions between each pair of reaction partners given below. (int: Multiple products are possible in every case; be sure to include thermodynamically unfavorable as well as favorable ones.) utanal and acetaldehyde 2,2-Dimethylpropanal and acetophenone enzaldehyde and 2-butanone 48. For each of the three crossed aldol reactions described in Problem 47, indicate which, if any, of the multiple possible products should predominate in the reaction mixture and explain why. 49. Aldol condensations may be catalyzed by acids. Suggest a role for 1 in the acid-catalyzed version. (int: onsider what kind of nucleophile might exist in acidic solution, where enolate ions are unlikely to be present.) 50. Reaction review. Without consulting the Reaction Road Maps on pp , suggest reagents to convert butanal into each of the following compounds. Rotundone l r r (e) (f) (g) 51. Reaction review II. Without consulting the Reaction Road Maps on pp , suggest reagents to convert acetophenone into each of the following compounds l (e) 6 5 (f) r 52. Reaction review III. Without consulting the Reaction Road Maps on pp , suggest reagents to convert 3-buten-2-one into each of the following compounds. 6 5

4 864 hapter 18 Enols, Enolates, and the Aldol ondensation 4-M Polysantol (e) (f) 53. A number of highly conjugated organic compounds have found use as sunscreens. ne of the more widely used is 4-methylbenzylidene camphor (4-M), whose structure is shown in the margin. This compound is effective in absorbing so-called UV- radiation (with wavelengths between 280 and 320 nm, responsible for most sunburns). Suggest a simple synthesis of this compound using a crossed aldol condensation. 54. The distillate from sandalwood is one of the oldest and most highly valued fragrances in perfumery. The natural oil is in short supply and, until recently, synthetic substitutes have been difficult to prepare. Polysantol (margin) is the most successful of these substitutes. Its synthesis in 1984 involved the aldol condensation shown below. K, 2, 3 This synthetic step, although usable, had a significant drawback that was responsible for its modest yield (60). Identify this problem in detail. A solution that avoids conventional aldol condensation was published in A bromoketone is prepared and, upon reaction with Mg metal, gives a magnesium enolate. This enolate then reacts with the aldehyde selectively to give a hydroxyketone that may be dehydrated to the desired product. Discuss how this approach solves the problem outlined in part. (g) (h) Mgr r 2, 3 2, l 4 Mg, ether r 55. Write the expected major product of reaction of each of the carbonyl compounds (i) (iii) with each of the reagents (h). (i) (ii) 3 P 2, Pd, 3 2 l 2, l 4 (e) 3 Li, ( 3 2 ) 2 (g) N 2 NN 2, D G (iii) 56. Give the expected product(s) of each of the following reactions. LiAl 4, ( 3 2 ) 2 KN, 1, 2 (f) ( ) 2 uli, TF (h) ( ) 2 uli, followed by treatment with 2 P 2 l in TF LDA, TF r, MPA 1. LDA, TF 2. r 2 3

5 Problems hapter ( 3 ) 2 uli, TF l 3 ( 2 ) 4 r LDA, TF 57. Write the products of each of the following reactions after aqueous work-up. LDA, TF P 6 5 ( 3 ) 2 P Na, 2 1. ( 2 P) 2 uli, TF 3 1. ( 3 ) 2 uli, TF 2. 2 P 3 2. ( 3 ) 2 P 3 (e) Write the results that you expect from base treatment of the products of reactions and. 58. Write the final products of the following reaction sequences. 2 P 3 Na 3, 3, P 3 K, 3, 1. LDA, TF 2. q 3 Write a detailed mechanism for reaction sequence. (int: Treat the 3-butyn-2-one reagent as a Michael acceptor in the first step.) 59. Propose syntheses of the following compounds by using Michael additions followed by aldol condensations (i.e., Robinson annulation). Each of the compounds shown has been instrumental in one or more total syntheses of steroidal hormones E Would you expect addition of l to the double bond of 3-buten-2-one (shown in the margin) to follow Markovnikov s rule? Explain your answer by a mechanistic argument. 3 P 2 3-uten-2-one

6 866 hapter 18 Enols, Enolates, and the Aldol ondensation 61. Using the following information, propose structures for each of these compounds. 5 10, NMR spectrum A, UV l max (e) 5 280(18) nm; 5 8, NMR spectrum, UV l max (e) 5 220(13,200), 310(40) nm; 6 12, NMR spectrum, UV l max (e) 5 189(8,000) nm; 6 12, NMR spectrum D, UV l max (e) 5 282(25) nm. (See the next page for spectrum D.) ( 3 ) 4 Si 1 1 ( 3 ) 4 Si A Mz 1 NMR spectrum ppm ( δ ) 300-Mz 1 NMR spectrum ppm ( δ ) Next, for each of the following reactions, name an appropriate reagent for the indicated interconversion. (The letters refer to the compounds giving rise to NMR spectra A through D.) (e) A y ; (f) y D; (g) y A Mz 1 NMR spectrum ppm ( δ)

7 Problems hapter ( 3 ) 4 Si D Mz 1 NMR spectrum ppm ( δ ) 62. Treatment of cyclopentane-1,3-dione with iodomethane in the presence of base leads mainly to a mixture of three products. Na, 3 I, A Give a mechanistic description of how these three products are formed. Reaction of product with a cuprate reagent results in loss of the methoxy group. For example, 1. ( ) 2 uli, TF 2., D Suggest a mechanism for this reaction, which is another synthetic route to enones substituted at the b-carbon. (int: See Exercise ) 63. A somewhat unusual synthesis of cortisone-related steroids includes the following two reactions.

8 868 hapter 18 Enols, Enolates, and the Aldol ondensation 3 ( 3 ) 3 ( 3 ) 3 A r ( 3 ) 3 K, benzene 3 ( 3 ) 3 ( 3 ) 3 3 I, ( 3 ) 3 K, benzene 3 ( 3 ) 3 3 ( 3 ) 3 Propose mechanisms for these two transformations. e careful in choosing the initial site of deprotonation in the starting enone. The alkenyl hydrogen, in particular, is not acidic enough to be the one initially removed by base in this reaction. Propose a sequence of reactions that will connect the carbons marked by arrows in the third structure shown to form another six-membered ring. 64. The following steroid synthesis contains modified versions of two key types of reactions presented in this chapter. Identify these reaction types and give detailed mechanisms for each of the transformations shown. 3 K ( 3 ) 3, TF K 2 3, 3 ) 2 3 ) Devise reasonable plans for carrying out the following syntheses. Ignore stereochemistry in your strategies. 3, starting from cyclohexanone N 3 3 3, starting from 2-cyclohexenone (int: Prepare in your first step.) 3 2

9 Problems hapter Write reagents (a, b, c, d, e) where they have been omitted from the following synthetic sequence. Each letter may correspond to one or more reaction steps. This sequence is the beginning of a synthesis of germanicol, a naturally occurring triterpene. The diol used in the step between and provides selective protection of the more reactive carbonyl group. [int: See Problem 63 when formulating.] 3 3, Li, liquid N 3 * (e) Team Problem Germanicol When 2-methylcyclopentanone is treated with the bulky base triphenylmethyllithium under the two sets of conditions shown, the two possible enolates are generated in differing ratios. Why is this so? Li Li 3 ( 6 5 ) 3 Li 3 3 onditions A: Ketone added to excess base onditions : Excess ketone added to base 6 94 To tackle this problem, you have to invoke the principles of kinetic versus thermodynamic control (review Sections 11-6, 14-6, and 18-2); that is, which enolate is formed faster and which one is more stable? Divide your team so that one group considers conditions A and the other conditions. Use curved arrows to show the flow of electrons leading to each enolate. Then assess whether your set of conditions is subject to enolate equilibration (thermodynamic control) or not (kinetic control). Reconvene to discuss these issues and draw a qualitative potential-energy diagram depicting the progress of deprotonation at the two a sites. *An electron-transfer process (compare alkyne reduction, Section 13-6) that is the equivalent of adding hydride, : 2, to the b-carbon. The product is the enolate of the saturated ketone.

10 870 hapter 18 Enols, Enolates, and the Aldol ondensation Preprofessional Problems 68. When 3-methyl-1,3-diphenyl-2-butanone is treated with excess D 2 in the presence of catalytic acid, some of its hydrogens are replaced by deuterium. ow many? ne; two; three; six; (e) eight. 69. ow would you best classify the following reaction? Wittig reaction; cyanohydrin formation; conjugate addition; aldol addition. E N 2 PPN N 2 PN The aqueous hydroxide-promoted reaction of the compound shown in the margin with ( 3 ) 3 yields exclusively one compound. Which one is it? 3 ( 3 ) 3 f P i 3 A 3 3 A 3 ( 3 ) 3 P 3 ( 3 ) 3 P The 1 NMR spectrum of 2,4-pentanedione indicates the presence of an enol tautomer of the dione. What is its most likely structure? 3 E E PP 3