831 CHAPTER 21 ESTER ENOLATES Y ou have already had considerable experience with carbanionic compounds and their applications in synthetic organic chemistry. The first was acetylide ion in Chapter 9, followed in Chapter 14 by organometallic compounds—Grignard reagents, for example—that act as sources of negatively polarized carbon. In Chapter 18 you learned that enolate ions—reactive intermediates generated from aldehydes and ketones—are nucleophilic, and that this property can be used to advantage as a method for carbon–carbon bond formation. The present chapter extends our study of carbanions to the enolate ions derived from esters. Ester enolates are important reagents in synthetic organic chemistry. The stabilized enolates derived from H9252-keto esters are particularly useful. A proton attached to the H9251-carbon atom of a H9252-keto ester is relatively acidic. Typical acid dissociation constants K a for H9252-keto esters are H1101510 H1100211 (pK a 11). Because the H9251- carbon atom is flanked by two electron-withdrawing carbonyl groups, a carbanion formed at this site is highly stabilized. The electron delocalization in the anion of a H9252-keto ester is represented by the resonance structures H9252-Keto ester: a ketone carbonyl is H9252 to the carbonyl group of the ester. C C ORH11032R OO CH 2 H9252 H9251 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website We’ll begin by describing the preparation and properties of H9252-keto esters, proceed to a discussion of their synthetic applications, continue to an examination of related species, and conclude by exploring some recent developments in the active field of synthetic car- banion chemistry. 21.1 THE CLAISEN CONDENSATION Before describing how H9252-keto esters are used as reagents for organic synthesis, we need to see how these compounds themselves are prepared. The main method for the prepa- ration of H9252-keto esters is a reaction known as the Claisen condensation: On treatment with alkoxide bases, esters undergo self-condensation to give a H9252-keto ester and an alcohol. Ethyl acetate, for example, undergoes a Claisen condensation on treat- ment with sodium ethoxide to give a H9252-keto ester known by its common name ethyl ace- toacetate (also called acetoacetic ester): The systematic IUPAC name of ethyl acetoacetate is ethyl 3-oxobutanoate. The presence of a ketone carbonyl group is indicated by the designation “oxo” along with the appro- priate locant. Thus, there are four carbon atoms in the acyl group of ethyl 3-oxobutanoate, C-3 being the carbonyl carbon of the ketone function. The mechanism of the Claisen condensation of ethyl acetate is presented in Fig- ure 21.1. The first two steps of the mechanism are analogous to those of aldol addition (Section 18.9). An enolate ion is generated in step 1, which undergoes nucleophilic addi- tion to the carbonyl group of a second ester molecule in step 2. The species formed in this step is a tetrahedral intermediate of the same type that we encountered in our dis- cussion of nucleophilic acyl substitution of esters. It dissociates by expelling an ethox- ide ion, as shown in step 3, which restores the carbonyl group to give the H9252-keto ester. Steps 1 to 3 show two different types of ester reactivity: one molecule of the ester gives rise to an enolate; the second molecule acts as an acylating agent. Claisen condensations involve two distinct experimental operations. The first stage concludes in step 4 of Figure 21.1, where the base removes a proton from C-2 of the H9252-keto ester. Because this proton is relatively acidic, the position of equilibrium for step 4 lies far to the right. Ethyl acetate 2CH 3 COCH 2 CH 3 O Ethyl acetoacetate (75%) (acetoacetic ester) CH 3 CCH 2 COCH 2 CH 3 O O Ethanol CH 3 CH 2 OHH11001 1. NaOCH 2 CH 3 2. H 3 O H11001 Ester 2RCH 2 CORH11032 O H9252-Keto ester RCH 2 CCHCORH11032 O R O Alcohol RH11032OHH11001 1. NaORH11032 2. H 3 O H11001 C C ORH11032R O H O H11002 C R C C ORH11032 O O H C H11002 R C C ORH11032 O O H C H11002 Principal resonance structures of the anion of a H9252-keto ester 832 CHAPTER TWENTY-ONE Ester Enolates Ludwig Claisen was a Ger- man chemist who worked during the last two decades of the nineteenth century and the first two decades of the twentieth. His name is associated with three reac- tions. The Claisen–Schmidt reaction was presented in Section 18.10, the Claisen condensation is discussed in this section, and the Claisen rearrangement will be intro- duced in Section 24.13. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.1 The Claisen Condensation 833 X X ±± X X Overall reaction: Step 1: Proton abstraction from the H9251 carbon atom of ethyl acetate to give the corresponding enolate. 2 CH 3 COCH 2 CH 3 O CH 3 CCH 2 COCH 2 CH 3 H11001 CH 3 CH 2 OH Ethyl acetate 1. NaOCH 2 CH 3 2. H 3 O H11001 Ethyl 3-oxobutanoate (ethyl acetoacetate) Ethanol OO CH 3 CH 2 O H11002 Ethoxide H11001 H±CH 2 C OCH 2 CH 3 O Ethyl acetate CH 3 CH 2 OH Ethanol H11001 CH 2 C OCH 2 CH 3 O Enolate of ethyl acetate H11002 CH 2 ? C OCH 2 CH 3 O H11002 Step 2: Nucleophilic addition of the ester enolate to the carbonyl group of the neutral ester. The product is the anionic form of the tetrahedral intermediate. CH 3 COCH 2 CH 3 Ethyl acetate O H11001 Enolate of ethyl acetate CH 2 ? C OCH 2 CH 3 CH 3 CCH 2 COCH 2 CH 3 H11002 O OCH 2 CH 3 Anionic form of tetrahedral intermediate Step 3: Dissociation of the tetrahedral intermediate. O CH 3 CCH 2 COCH 2 CH 3 H11002 O OCH 2 CH 3 Anionic form of tetrahedral intermediate O CH 3 CCH 2 COCH 2 CH 3 O Ethyl 3-oxobutanoate H11001 H11002 OCH 2 CH 3 Ethoxide ion Step 4: Deprotonation of the H9252-keto ester product. O CH 3 CCHCOCH 2 CH 3 O Ethyl 3-oxobutanoate (stronger acid) H11001 H11002 OCH 2 CH 3 Ethoxide ion (stronger base) H O CH 3 CCHCOCH 2 CH 3 O Conjugate base of ethyl 3-oxobutanoate (weaker base) H11001 Ethanol (weaker acid) H11002 HOCH 2 CH 3 O XXX X XX XX XX —Cont. O H11002 FIGURE 21.1 The mechanism of the Claisen condensation of ethyl acetate. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website In general, the equilibrium represented by the sum of steps 1 to 3 is not favorable for condensation of two ester molecules to a H9252-keto ester. (Two ester carbonyl groups are more stable than one ester plus one ketone carbonyl.) However, because the H9252-keto ester is deprotonated under the reaction conditions, the equilibrium represented by the sum of steps 1 to 4 does lie to the side of products. On subsequent acidification (step 5), the anion of the H9252-keto ester is converted to its neutral form and isolated. Organic chemists sometimes write equations for the Claisen condensation in a form that shows both stages explicitly: Like aldol condensations, Claisen condensations always involve bond formation between the H9251-carbon atom of one molecule and the carbonyl carbon of another: PROBLEM 21.1 One of the following esters cannot undergo the Claisen con- densation. Which one? Write structural formulas for the Claisen condensation products of the other two. Unless the H9252-keto ester can form a stable anion by deprotonation as in step 4 of Figure 21.1, the Claisen condensation product is present in only trace amounts at equi- librium. Ethyl 2-methylpropanoate, for example, does not give any of its condensation product under the customary conditions of the Claisen condensation. CH 3 CH 2 CH 2 CH 2 CO 2 CH 2 CH 3 Ethyl pentanoate C 6 H 5 CH 2 CO 2 CH 2 CH 3 Ethyl phenylacetate C 6 H 5 CO 2 CH 2 CH 3 Ethyl benzoate Ethyl propanoate 2CH 3 CH 2 COCH 2 CH 3 O Ethanol CH 3 CH 2 OHH11001 1. NaOCH 2 CH 3 2. H 3 O H11001 Ethyl 2-methyl-3-oxopentanoate (81%) CH 3 CH 2 CCHCOCH 2 CH 3 O O CH 3 Ethyl acetate 2CH 3 COCH 2 CH 3 O NaOCH 2 CH 3 H 3 O H11001 Ethyl acetoacetate CH 3 CCH 2 COCH 2 CH 3 O O Sodium salt of ethyl acetoacetate CH 3 CCHCOCH 2 CH 3 Na H11001 H11002 O O 834 CHAPTER TWENTY-ONE Ester Enolates Step 5: Acidification of the reaction mixture. This is performed in a separate synthetic operation to give the product in its neutral form for eventual isolation. O CH 3 CCHCOCH 2 CH 3 O Conjugate base of ethyl 3-oxobutanoate (stronger base) H11001 H11002 H H O H11001 H Hydronium ion (stronger acid) O CH 3 CCHCOCH 2 CH 3 O Ethyl 3-oxobutanoate (weaker acid) H11001 H H O H Water (weaker base) XX XX FIGURE 21.1 (Continued ) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website At least two protons must be present at the H9251 carbon for the equilibrium to favor prod- uct formation. Claisen condensation is possible for esters of the type RCH 2 CO 2 RH11032, but not for R 2 CHCO 2 RH11032. 21.2 INTRAMOLECULAR CLAISEN CONDENSATION: THE DIECKMANN REACTION Esters of dicarboxylic acids undergo an intramolecular version of the Claisen condensa- tion when a five- or six-membered ring can be formed. This reaction is an example of a Dieckmann cyclization. The anion formed by proton abstraction at the carbon H9251 to one carbonyl group attacks the other carbonyl to form a five-membered ring. PROBLEM 21.2 Write the structure of the Dieckmann cyclization product formed on treatment of each of the following diesters with sodium ethoxide, followed by acidification. (a) (b) CH 3 CH 2 OCCH 2 CH 2 CHCH 2 CH 2 COCH 2 CH 3 O X CH 3 W O X CH 3 CH 2 OCCH 2 CH 2 CH 2 CH 2 CH 2 COCH 2 CH 3 O X O X CH 3 CH 2 OCCH 2 CH 2 CH 2 CH 2 COCH 2 CH 3 O O Diethyl hexanedioate 1. NaOCH 2 CH 3 2. H 3 O H11001 O COCH 2 CH 3 O Ethyl (2-oxocyclopentane)- carboxylate (74–81%) Ethyl 2-methylpropanoate 2(CH 3 ) 2 CHCOCH 2 CH 3 O NaOCH 2 CH 3 (CH 3 ) 2 CH C C OCH 2 CH 3 OO CH 3 H 3 C C Ethyl 2,2,4-trimethyl-3-oxopentanoate (cannot form a stable anion; formed in no more than trace amounts) 21.2 Intramolecular Claisen Condensation: The Dieckmann Reaction 835 H11002CH 3 CH 2 O H11002 C H11002 CHCOCH 2 CH 3 O OCH 2 CH 3 O Enolate of diethyl hexanedioate C CHCOCH 2 CH 3 OCH 2 CH 3 O H11002 O COCH 2 CH 3 H O O Ethyl (2-oxocyclopentane)carboxylate Walter Dieckmann was a German chemist and a con- temporary of Claisen. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (c) SAMPLE SOLUTION (a) Diethyl heptanedioate has one more methylene group in its chain than the diester cited in the example (diethyl hexanedioate). Its Dieckmann cyclization product contains a six-membered ring instead of the five- membered ring formed from diethyl hexanedioate. 21.3 MIXED CLAISEN CONDENSATIONS Analogous to mixed aldol condensations, mixed Claisen condensations involve car- bon–carbon bond formation between the H9251-carbon atom of one ester and the carbonyl carbon of another. The best results are obtained when one of the ester components is incapable of forming an enolate. Esters of this type include the following: The following equation shows an example of a mixed Claisen condensation in which a benzoate ester is used as the nonenolizable component: PROBLEM 21.3 Give the structure of the product obtained when ethyl phenyl- acetate (C 6 H 5 CH 2 CO 2 CH 2 CH 3 ) is treated with each of the following esters under conditions of the mixed Claisen condensation: (a) Diethyl carbonate (c) Ethyl formate (b) Diethyl oxalate 1. NaOCH 3 2. H 3 O H11001COCH 3 O Methyl benzoate (cannot form an enolate) H11001 CH 3 CH 2 COCH 3 O Methyl propanoate CH 3 CCHCOCH 3 O O Methyl 2-methyl-3-oxo- 3-phenylpropanoate (60%) HCOR O Formate esters ROCOR O Carbonate esters ROCCOR OO Oxalate esters COR O Benzoate esters Ester RCOCH 2 CH 3 O Another ester RH11032CH 2 COCH 2 CH 3 O H11001 1. NaOCH 2 CH 3 2. H 3 O H11001 H9252-Keto ester RCCHCOCH 2 CH 3 O O RH11032 Diethyl heptanedioate CH 3 CH 2 OCCH 2 CH 2 CH 2 CH 2 CH 2 COCH 2 CH 3 O X O X 1. NaOCH 2 CH 3 2. H 3 O H11001 O O COCH 2 CH 3 Ethyl (2-oxocyclohexane)- carboxylate CH 3 CH 2 OCCHCH 2 CH 2 CH 2 COCH 2 CH 3 O X CH 3 W O X 836 CHAPTER TWENTY-ONE Ester Enolates Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website SAMPLE SOLUTION (a) Diethyl carbonate cannot form an enolate, but ethyl phenylacetate can. Nucleophilic acyl substitution on diethyl carbonate by the eno- late of ethyl phenylacetate yields a diester. The reaction proceeds in good yield (86%), and the product is a useful one in fur- ther synthetic transformations of the type to be described in Section 21.7. 21.4 ACYLATION OF KETONES WITH ESTERS In a reaction related to the mixed Claisen condensation, nonenolizable esters are used as acylating agents for ketone enolates. Ketones (via their enolates) are converted to H9252-keto esters by reaction with diethyl carbonate. Esters of nonenolizable monocarboxylic acids such as ethyl benzoate give H9252-diketones on reaction with ketone enolates: Intramolecular acylation of ketones yields cyclic H9252-diketones when the ring that is formed is five- or six-membered. 1. NaOCH 3 2. H 3 O H11001CH 3 CH 2 CCH 2 CH 2 COCH 2 CH 3 O O Ethyl 4-oxohexanoate CH 3 OO 2-Methyl-1,3-cyclopentanedione (70–71%) COCH 2 CH 3 O Ethyl benzoate H11001 O CH 3 C Acetophenone 1. NaOCH 2 CH 3 2. H 3 O H11001 CCH 2 C O O 1,3-Diphenyl-1,3- propanedione (62–71%) 1. NaH 2. H 3 O H11001CH 3 CH 2 OCOCH 2 CH 3 O Diethyl carbonate H11001 O Cycloheptanone COCH 2 CH 3 O O Ethyl (2-oxocycloheptane)- carboxylate (91–94%) CH 3 CH 2 O C C 6 H 5 CH COCH 2 CH 3 O H11002 O OCH 2 CH 3 C OCH 2 CH 3 C 6 H 5 CH O C OCH 2 CH 3 O Diethyl 2-phenylpropanedioate (diethyl phenylmalonate) 21.4 Acylation of Ketones with Esters 837 Sodium hydride was used as the base in this example. It is often used instead of sodium ethoxide in these reactions. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEM 21.4 Write an equation for the carbon–carbon bond-forming step in the cyclization reaction just cited. Show clearly the structure of the enolate ion, and use curved arrows to represent its nucleophilic addition to the appropriate carbonyl group. Write a second equation showing dissociation of the tetrahedral intermediate formed in the carbon–carbon bond-forming step. Even though ketones have the potential to react with themselves by aldol addition, recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18.9). On the other hand, acylation of ketone enolates gives products (H9252-keto esters or H9252-diketones) that are converted to stabilized anions under the reaction conditions. Consequently, ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base in the presence of esters. 21.5 KETONE SYNTHESIS VIA H9252-KETO ESTERS The carbon–carbon bond-forming potential inherent in the Claisen and Dieckmann reac- tions has been extensively exploited in organic synthesis. Subsequent transformations of the H9252-keto ester products permit the synthesis of other functional groups. One of these transformations converts H9252-keto esters to ketones; it is based on the fact that H9252-keto acids (not esters!) undergo decarboxylation readily (Section 19.17). Indeed, H9252-keto acids, and their corresponding carboxylate anions as well, lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation. Thus, 5-nonanone has been prepared from ethyl pentanoate by the sequence CH 3 CH 2 CH 2 CH 2 COCH 2 CH 3 O Ethyl pentanoate 1. NaOCH 2 CH 3 2. H 3 O H11001 1. KOH, H 2 O, 70–80°C 2. H 3 O H11001 CH 3 CH 2 CH 2 CH 2 CCHCOCH 2 CH 3 O O CH 2 CH 2 CH 3 Ethyl 3-oxo-2-propylheptanoate (80%) CH 3 CH 2 CH 2 CH 2 CCH 2 CH 2 CH 2 CH 3 O 5-Nonanone (81%) 70–80°C H11002CO 2 3-Oxo-2-propylheptanoic acid (not isolated; decarboxylates under conditions of its formation) CH 3 CH 2 CH 2 CH 2 CCHCOH O O CH 2 CH 2 CH 3 R C O CH 2 RH11032 Ketone heat H11002CO 2 H9252-Keto acid R C C O OO HRH11032 H C Enol form of ketone C RH11032 R O H C H 838 CHAPTER TWENTY-ONE Ester Enolates Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The sequence begins with a Claisen condensation of ethyl pentanoate to give a H9252-keto ester. The ester is hydrolyzed, and the resulting H9252-keto acid decarboxylates to yield the desired ketone. PROBLEM 21.5 Write appropriate chemical equations showing how you could prepare cyclopentanone from diethyl hexanedioate. The major application of H9252-keto esters to organic synthesis employs a similar pat- tern of ester saponification and decarboxylation as its final stage, as described in the fol- lowing section. 21.6 THE ACETOACETIC ESTER SYNTHESIS Ethyl acetoacetate (acetoacetic ester), available by the Claisen condensation of ethyl acetate, has properties that make it a useful starting material for the preparation of ketones. These properties are 1. The acidity of the H9251 proton 2. The ease with which acetoacetic acid undergoes thermal decarboxylation Ethyl acetoacetate is a stronger acid than ethanol and is quantitatively converted to its anion on treatment with sodium ethoxide in ethanol. The anion produced by proton abstraction from ethyl acetoacetate is nucleophilic. Adding an alkyl halide to a solution of the sodium salt of ethyl acetoacetate leads to alkylation of the H9251 carbon. The new carbon–carbon bond is formed by an S N 2-type reaction. The alkyl halide must therefore be one that is not sterically hindered. Methyl and primary alkyl halides work best; secondary alkyl halides give lower yields. Tertiary alkyl halides react only by elim- ination, not substitution. Saponification and decarboxylation of the alkylated derivative of ethyl acetoacetate yields a ketone. H11001 NaX Sodium halide H 3 C C C OCH 2 CH 3 O O HR C 2-Alkyl derivative of ethyl acetoacetate H 3 C C C OCH 2 CH 3 O O C Na H11001 H11002 HRX Sodium salt of ethyl acetoacetate; alkyl halide 21.6 The Acetoacetic Ester Synthesis 839 H11001 H 3 C C C OCH 2 CH 3 O O HH C Ethyl acetoacetate (stronger acid) K a 10 H1100211 (pK a 11) NaOCH 2 CH 3 Sodium ethoxide (stronger base) Sodium salt of ethyl acetoacetate (weaker base) H 3 C C C OCH 2 CH 3 OO H11002 C H Na H11001 H11001 CH 3 CH 2 OH Ethanol (weaker acid) K a 10 H1100216 (pK a 16) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website This reaction sequence is called the acetoacetic ester synthesis. It is a standard procedure for the preparation of ketones from alkyl halides, as the conversion of 1- bromobutane to 2-heptanone illustrates. The acetoacetic ester synthesis brings about the overall transformation of an alkyl halide to an alkyl derivative of acetone. We call a structural unit in a molecule that is related to a synthetic operation a synthon. The three-carbon unit is a synthon that alerts us to the possibil- ity that a particular molecule may be accessible by the acetoacetic ester synthesis. PROBLEM 21.6 Show how you could prepare each of the following ketones from ethyl acetoacetate and any necessary organic or inorganic reagents: (a) 1-Phenyl-1,4-pentanedione (c) 5-Hexen-2-one (b) 4-Phenyl-2-butanone SAMPLE SOLUTION (a) Approach these syntheses in a retrosynthetic way. Iden- tify the synthon and mentally disconnect the bond to the H9251-carbon atom. The synthon is derived from ethyl acetoacetate; the remainder of the molecule originates in the alkyl halide. Disconnect here CCH 2 O CH 2 CCH 3 O H9251 1-Phenyl-1,4-pentanedione X CCH 2 O Required alkyl halide H11001 CH 2 CCH 3 H11002 O Derived from ethyl acetoacetate ±CH 2 CCH 3 O X ±CH 2 CCH 3 O X ±CH 2 CCH 3 O X Primary or secondary alkyl halide RX H9251-Alkylated derivative of acetone R CH 2 CCH 3 O H 3 C C C OCH 2 CH 3 O O HR C 2-Alkyl derivative of ethyl acetoacetate H 3 C C C OH O O HR C 2-Alkyl derivative of acetoacetic acid 1. HO H11002 , H 2 O 2. H H11001 heat H11002CO 2 Ketone CH 3 CCH 2 R O 840 CHAPTER TWENTY-ONE Ester Enolates CH 3 CCH 2 COCH 2 CH 3 O O Ethyl acetoacetate CH 3 CCH 2 CH 2 CH 2 CH 2 CH 3 O 2-Heptanone (60%) 1. NaOCH 2 CH 3 , ethanol 2. CH 3 CH 2 CH 2 CH 2 Br 1. NaOH, H 2 O 2. H H11001 3. heat H11002CO 2 CH 3 CCHCOCH 2 CH 3 O O CH 2 CH 2 CH 2 CH 3 Ethyl 2-butyl-3- oxobutanoate (70%) E. J. Corey (page 557) in- vented the word “synthon” in connection with his efforts to formalize synthetic planning. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Analyzing the target molecule in this way reveals that the required alkyl halide is an H9251-halo ketone. Thus, a suitable starting material would be bromomethyl phenyl ketone. Dialkylation of ethyl acetoacetate can also be accomplished, opening the way to ketones with two alkyl substituents at the H9251 carbon: Recognize, too, that the reaction sequence is one that is characteristic of H9252-keto esters in general and not limited to just ethyl acetoacetate and its derivatives. Thus, It’s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a diffi- cult reaction to carry out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of H9252-keto esters, being far less basic than ketone enolates, give a higher substitution–elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. Anions of H9252-keto esters are said to be synthetically equivalent to the enolates of ketones. The anion of ethyl acetoacetate is synthetically equivalent to the enolate of acetone, for example. The use of synthetically equivalent groups is a common tac- tic in synthetic organic chemistry. One of the skills that characterize the most cre- ative practitioners of organic synthesis is an ability to recognize situations in which otherwise difficult transformations can be achieved through the use of synthetically equivalent reagents. 1. NaOCH 2 CH 3 , ethanol 2. NaOH, H 2 O 3. H H11001 4. heat CCH 2 Br O Bromomethyl phenyl ketone H11001 CH 3 CCH 2 COCH 2 CH 3 O O Ethyl acetoacetate 1-Phenyl-1,4-pentanedione CCH 2 CH 2 CCH 3 O O 21.6 The Acetoacetic Ester Synthesis 841 CH 3 CCH CH 2 CH CO 2 CH 2 CH 3 CH 2 O Ethyl 2-allylacetoacetate 1. NaOCH 2 CH 3 2. CH 3 CH 2 I 1. NaOH, H 2 O 2. H H11001 3. heat O CH 2 CH 3 CH 3 CCCO 2 CH 2 CH 3 CH 2 CH CH 2 Ethyl 2-allyl-2-ethyl- acetoacetate (75%) 3-Ethyl-5-hexen- 2-one (48%) O CH 2 CH 3 CH 3 CCHCH 2 CH CH 2 COCH 2 CH 3 H O O Ethyl 2-oxo- cyclohexanecarboxylate COCH 2 CH 3 CH 2 CH CH 2 O O Ethyl 1-allyl-2-oxo- cyclohexanecarboxylate (89%) H CH 2 CH CH 2 O 2-Allylcyclohexanone (66%) 1. NaOCH 2 CH 3 2. CH 2 ?CHCH 2 Br 1. KOH, H 2 O 2. H H11001 3. heat Can you think of how bro- momethyl phenyl ketone might be prepared? The starting material in the example is obtained by alkyl- ation of ethyl acetoacetate with allyl bromide. The starting material in this example is the Dieckmann cyclization product of diethyl heptanedioate (see Problem 21.2a). Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.7 THE MALONIC ESTER SYNTHESIS The malonic ester synthesis is a method for the preparation of carboxylic acids and is represented by the general equation The malonic ester synthesis is conceptually analogous to the acetoacetic ester synthesis. The overall transformation is Diethyl malonate (also known as malonic ester) serves as a source of the synthon in the same way that the ethyl acetoacetate serves as a source of the syn- thon . The properties of diethyl malonate that make the malonic ester synthesis a useful procedure are the same as those responsible for the synthetic value of ethyl acetoacetate. The protons at C-2 of diethyl malonate are relatively acidic, and one is readily removed on treatment with sodium ethoxide. Treatment of the anion of diethyl malonate with alkyl halides leads to alkylation at C-2. H11001 CH 3 CH 2 O C C OCH 2 CH 3 O O HH C Diethyl malonate (stronger acid) K a 10 H1100213 (pK a 13) NaOCH 2 CH 3 Sodium ethoxide (stronger base) Sodium salt of diethyl malonate (weaker base) CH 3 CH 2 O C C OCH 2 CH 3 OO H11002 C H Na H11001 H11001 CH 3 CH 2 OH Ethanol (weaker acid) K a 10 H1100216 (pK a 16) ±CH 2 CCH 3 O X ±CH 2 COH O X Primary or secondary alkyl halide RX H9251-Alkylated derivative of acetic acid R CH 2 COH O RX Alkyl halide H11001 CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate (malonic ester) RCH(COOCH 2 CH 3 ) 2 H9251-Alkylated derivative of diethyl malonate RCH 2 COOH Carboxylic acid NaOCH 2 CH 3 ethanol 1. HO H11002 , H 2 O 2. H H11001 3. heat 842 CHAPTER TWENTY-ONE Ester Enolates Among the methods for preparing carboxylic acids, carboxylation of a Grignard reagent and preparation and hydrolysis of a nitrile convert RBr to RCO 2 H. The malonic ester synthesis converts RBr to RCH 2 CO 2 H. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Converting the C-2 alkylated derivative to the corresponding malonic acid deriva- tive by ester hydrolysis gives a compound susceptible to thermal decarboxylation. Tem- peratures of approximately 180°C are normally required. In a typical example of the malonic ester synthesis, 6-heptenoic acid has been pre- pared from 5-bromo-1-pentene: PROBLEM 21.7 Show how you could prepare each of the following carboxylic acids from diethyl malonate and any necessary organic or inorganic reagents: (a) 3-Methylpentanoic acid (c) 4-Methylhexanoic acid (b) Nonanoic acid (d) 3-Phenylpropanoic acid SAMPLE SOLUTION (a) Analyze the target molecule retrosynthetically by men- tally disconnecting a bond to the H9251-carbon atom. Disconnect here CH 3 CH 2 CH CH 3 CH 2 COH O H9251 3-Methylpentanoic acid H11001 CH 2 COH H11002 O Derived from diethyl malonate Required alkyl halide XCH 3 CH 2 CH CH 3 21.7 The Malonic Ester Synthesis 843 CH 2 CHCH 2 CH 2 CH 2 Br 5-Bromo-1-pentene CH 2 CHCH 2 CH 2 CH 2 CH(COOCH 2 CH 3 ) 2 Diethyl 2-(4-pentenyl)malonate (85%) H11001 CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate NaOCH 2 CH 3 ethanol O COCH 2 CH 3 COCH 2 CH 3 O CH 2 CHCH 2 CH 2 CH 2 CH Diethyl 2-(4-pentenyl)malonate 1. HO H11002 , H 2 O 2. H H11001 3. heat O CH 2 CHCH 2 CH 2 CH 2 CH 2 COH 6-Heptenoic acid (75%) CH 3 CH 2 O C C OCH 2 CH 3 O O HR C 2-Alkyl derivative of diethyl malonate HO C C OH O O HR C 2-Alkyl derivative of malonic acid 1. HO H11002 , H 2 O 2. H H11001 heat H11002CO 2 Carboxylic acid RCH 2 COH O H11001 NaX Sodium halide CH 3 CH 2 O C C OCH 2 CH 3 O O HR C 2-Alkyl derivative of diethyl malonate CH 3 CH 2 O C C OCH 2 CH 3 O O C Na H11001 H11002 HRX Sodium salt of diethyl malonate; alkyl halide Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website We see that a secondary alkyl halide is needed as the alkylating agent. The anion of diethyl malonate is a weaker base than ethoxide ion and reacts with secondary alkyl halides by substitution rather than elimination. Thus, the synthesis of 3- methylpentanoic acid begins with the alkylation of the anion of diethyl malonate by 2-bromobutane. As actually carried out and reported in the chemical literature, diethyl malonate has been alkylated with 2-bromobutane in 83–84% yield and the product of that reaction converted to 3-methylpentanoic acid by saponification, acidification, and decarboxylation in 62–65% yield. By performing two successive alkylation steps, the malonic ester synthesis can be applied to the synthesis of H9251,H9251-disubstituted derivatives of acetic acid: PROBLEM 21.8 Ethyl acetoacetate may also be subjected to double alkylation. Show how you could prepare 3-methyl-2-butanone by double alkylation of ethyl acetoacetate. The malonic ester synthesis has been adapted to the preparation of cycloal- kanecarboxylic acids from dihaloalkanes: CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate 1. NaOCH 2 CH 3 , ethanol 2. BrCH 2 CH 2 CH 2 Br Br CH(COOCH 2 CH 3 ) 2 H 2 C CH 2 C CH 2 (Not isolated; cyclizes in the presence of sodium ethoxide) H 2 C CH 2 C CH 2 COOCH 2 CH 3 COOCH 2 CH 3 Diethyl 1,1-cyclobutanedicarboxylate (60–65%) H COOH Cyclobutanecarboxylic acid (80% from diester) 1. H 3 O H11001 2. heat 1. NaOCH 2 CH 3 , ethanol 2. CH 3 Br 1. NaOCH 2 CH 3 , ethanol 2. CH 3 (CH 2 ) 8 CH 2 Br CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate CH 3 CH(COOCH 2 CH 3 ) 2 Diethyl 2-methyl-1,3-propanedioate (79–83%) 1. KOH, ethanol–water 2. H H11001 3. heat Diethyl 2-decyl-2-methyl-1,3-propanedioate C H 3 C CH 3 (CH 2 ) 8 CH 2 COOCH 2 CH 3 COOCH 2 CH 3 C H 3 C CH 3 (CH 2 ) 8 CH 2 H COOH 2-Methyldodecanoic acid (61–74%) 1. NaOCH 2 CH 3 , ethanol 2. NaOH, H 2 O 3. H H11001 4. heat CH 3 CH 2 CHBr CH 3 2-Bromobutane CH 3 CH 2 CHCH 2 COH O CH 3 3-Methylpentanoic acid H11001 CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate 844 CHAPTER TWENTY-ONE Ester Enolates Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The cyclization step is limited to the formation of rings of seven carbons or fewer. PROBLEM 21.9 Cyclopentyl methyl ketone has been prepared from 1,4-dibro- mobutane and ethyl acetoacetate. Outline the steps in this synthesis by writing a series of equations showing starting materials, reagents, and isolated interme- diates. 21.8 BARBITURATES Diethyl malonate has uses other than in the synthesis of carboxylic acids. One particu- larly valuable application lies in the preparation of barbituric acid by nucleophilic acyl substitution with urea: Barbituric acid is the parent of a group of compounds known as barbiturates. The bar- biturates are classified as sedative–hypnotic agents, meaning that they decrease the responsiveness of the central nervous system and promote sleep. Thousands of deriva- tives of the parent ring system of barbituric acid have been tested for sedative–hypnotic activity; the most useful are the 5,5-disubstituted derivatives. These compounds are prepared in a manner analogous to that of barbituric acid itself. Diethyl malonate is alkylated twice, then treated with urea. PROBLEM 21.10 Show, by writing a suitable sequence of reactions, how you could prepare pentobarbital from diethyl malonate. (The structure of pentobar- bital was shown in this section.) H11013H 2 C COCH 2 CH 3 O COCH 2 CH 3 O Diethyl malonate H11001 H 2 N H 2 N CO Urea 1. NaOCH 2 CH 3 2. H H11001 H 2 C C C O O N N H H CO Barbituric acid (72–78%) H O O H O 1 N N 2 3 5 4 6 21.8 Barbiturates 845 H O O H O N N CH 3 CH 2 CH 3 CH 2 5,5-Diethylbarbituric acid (barbital; Veronal) 5-Ethyl-5-(1-methylbutyl)- barbituric acid (pentobarbital; Nembutal) H O O H O N N CH 3 CH 2 CH 2 CH CH 3 CH 2 CH 3 5-Allyl-5-(1-methylbutyl)- barbituric acid (secobarbital; Seconal) H O O H O N N CH 3 CH 2 CH 2 CH CHCH 2 CH CH 3 1. RX, NaOCH 2 CH 3 2. RH11032X, NaOCH 2 CH 3 H 2 NCNH 2 O X CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate C R RH11032 COOCH 2 CH 3 COOCH 2 CH 3 Dialkylated derivative of diethyl malonate H O O H O N N R RH11032 5,5-Disubstituted derivative of barbituric acid Barbituric acid was first pre- pared in 1864 by Adolf von Baeyer (page 98). A historical account of his work and the later development of barbi- turates as sedative–hypnotics appeared in the October 1951 issue of the Journal of Chemical Education (pp. 524–526). Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Barbituric acids, as their name implies, are weakly acidic and are converted to their sodium salts (sodium barbiturates) in aqueous sodium hydroxide. Sometimes the drug is dispensed in its neutral form; sometimes the sodium salt is used. The salt is designated by appending the word “sodium” to the name of the barbituric acid—pentobarbital sodium, for example. PROBLEM 21.11 Thiourea reacts with diethyl malonate and its alkyl derivatives in the same way that urea does. Give the structure of the product obtained when thiourea is used instead of urea in the synthesis of pentobarbital. The anesthetic thiopental (Pentothal) sodium is the sodium salt of this product. What is the structure of this compound? PROBLEM 21.12 Aryl halides react too slowly to undergo substitution by the S N 2 mechanism with the sodium salt of diethyl malonate, and so the phenyl sub- stituent of phenobarbital cannot be introduced in the way that alkyl substituents can. One synthesis of phenobarbital begins with ethyl phenylacetate and diethyl car- bonate. Using these starting materials and any necessary organic or inorganic reagents, devise a synthesis of phenobarbital. (Hint: See the sample solution to Problem 21.3a.) The various barbiturates differ in the time required for the onset of sleep and in the duration of their effects. All the barbiturates must be used only in strict accordance with instructions to avoid potentially lethal overdoses. Drug dependence in some indi- viduals is also a problem. 21.9 MICHAEL ADDITIONS OF STABILIZED ANIONS Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to H9251,H9252- unsaturated carbonyl compounds. This reaction, called the Michael reaction, has been described for anions derived from H9252-diketones in Section 18.13. The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the H9252-carbon atom of H9251,H9252-unsaturated aldehydes, ketones, and esters. For example, In this reaction the enolate of diethyl malonate adds to the H9252 carbon of methyl vinyl ketone. CH 3 CCH CH 2 O Methyl vinyl ketone H11001 CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate KOH ethanol Ethyl 2-carboethoxy-5-oxohexanoate (83%) CH 3 CCH 2 CH 2 CH(COOCH 2 CH 3 ) 2 O CH 3 CH 2 O O O N H H N 5-Ethyl-5-phenylbarbituric acid (phenobarbital) (H 2 NCNH 2 ) S X 846 CHAPTER TWENTY-ONE Ester Enolates Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The intermediate formed in the nucleophilic addition step abstracts a proton from the solvent to give the observed product. After isolation, the Michael adduct may be subjected to ester hydrolysis and decar- boxylation. When H9251,H9252-unsaturated ketones are carried through this sequence, the final products are 5-keto acids (H9254-keto acids). PROBLEM 21.13 Ethyl acetoacetate behaves similarly to diethyl malonate in its reactivity toward H9251,H9252-unsaturated carbonyl compounds. Give the structure of the product of the following reaction sequence: 21.10 H9251 DEPROTONATION OF CARBONYL COMPOUNDS BY LITHIUM DIALKYLAMIDES Most of the reactions of ester enolates described so far have centered on stabilized eno- lates derived from 1,3-dicarbonyl compounds such as diethyl malonate and ethyl ace- toacetate. Although the synthetic value of these and related stabilized enolates is clear, chemists have long been interested in extending the usefulness of nonstabilized enolates derived from simple esters. Consider the deprotonation of an ester as represented by the acid–base reaction O RCHCORH11032 H Ester H11001 B H11002 Base RCH O H11002 ORH11032 C Ester enolate H11001 HB Conjugate acid of base 1. NaOCH 2 CH 3 , ethanol 2. KOH, ethanol–water 3. H H11001 4. heat H11001 Ethyl acetoacetate CH 3 CCH 2 COCH 2 CH 3 O O 2-Cycloheptenone O CH 3 CCH 2 CH 2 CH 2 COH O O 5-Oxohexanoic acid (42%) Ethyl 2-carboethoxy-5-oxohexanoate (from diethyl malonate and methyl vinyl ketone) CH 3 CCH 2 CH 2 CH(COOCH 2 CH 3 ) 2 O 1. KOH, ethanol–water 2. H H11001 3. heat 21.10 H9251 Deprotonation of Carbonyl Compounds by Lithium Dialkylamides 847 CH 3 CCH 2 CH 2 CH(COOCH 2 CH 3 ) 2 O HCH 2 CH 3 O CH(COOCH 2 CH 3 ) 2 O H11002 CH 3 C CH CH 2 H11001 OCH 2 CH 3 H11002 CH 3 C O CH CH 2 H11001 CH(COOCH 2 CH 3 ) 2 H11002 CH(COOCH 2 CH 3 ) 2 O H11002 CH 3 C CH CH 2 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website We already know what happens when simple esters are treated with alkoxide bases— they undergo the Claisen condensation (Section 21.1). Simple esters have acid dissocia- tion constants K a of approximately 10 H1100222 (pK a 22) and are incompletely converted to their enolates with alkoxide bases. The small amount of enolate that is formed reacts by nucleophilic addition to the carbonyl group of the ester. What happens if the base is much stronger than an alkoxide ion? If the base is strong enough, it will convert the ester completely to its enolate. Under these conditions the Claisen condensation is suppressed because there is no neutral ester present for the enolate to add to. A very strong base is one that is derived from a very weak acid. Refer- ring to the table of acidities (Table 4.2, page 135), we see that ammonia is quite a weak acid; its K a is 10 H1100236 (pK a 36). Therefore, amide ion is a very strong base— more than strong enough to deprotonate an ester quantitatively. Amide ion, however, also tends to add to the carbonyl group of esters; to avoid this complication, highly hindered analogs of are used instead. The most frequently used base for ester enolate for- mation is lithium diisopropylamide (LDA): Lithium diisopropylamide is a strong enough base to abstract a proton from the H9251-carbon atom of an ester, but because it is so sterically hindered, it does not add readily to the carbonyl group. To illustrate, Direct alkylation of esters can be carried out by forming the enolate with LDA fol- lowed by addition of an alkyl halide. Tetrahydrofuran (THF) is the solvent most often used in these reactions. Ester enolates generated by proton abstraction with dialkylamide bases add to aldehydes and ketones to give H9252-hydroxy esters. CH 3 COCH 2 CH 3 O Ethyl acetate CH 2 C OLi OCH 2 CH 3 Lithium enolate of ethyl acetate LiNR 2 THF 1. (CH 3 ) 2 C?O 2. H 3 O H11001 Ethyl 3-hydroxy- 3-methylbutanoate (90%) CH 3 CCH 2 COCH 2 CH 3 OHO CH 3 CH 3 CH 2 CH 2 COCH 3 O Methyl butanoate CH 3 CH 2 CHCOCH 3 O CH 3 CH 2 Methyl 2-ethylbutanoate (92%) CH 3 CH 2 CH C OLi OCH 3 Lithium enolate of methyl butanoate LDA THF CH 3 CH 2 I Lithium diisopropylamide Li H11001 (CH 3 ) 2 CH N H11002 CH(CH 3 ) 2 H 2 N H11002 (H 2 N H11002 ) 848 CHAPTER TWENTY-ONE Ester Enolates CH 3 CH 2 CH 2 COCH 3 O Methyl butanoate (stronger acid) K a 10 H1100222 (pK a 22) H11001 [(CH 3 ) 2 CH] 2 NLi Lithium diisopropylamide (stronger base) CH 3 CH 2 CH C OLi OCH 3 Lithium enolate of methyl butanoate (weaker base) H11001 [(CH 3 ) 2 CH] 2 NH Diisopropylamine (weaker acid) K a 10 H1100236 (pK a 36) Lithium diisopropylamide is commercially available. Al- ternatively, it may be pre- pared by the reaction of butyllithium with [(CH 3 ) 2 CH] 2 NH (see Problem 14.4a for a related reaction). Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Lithium dialkylamides are excellent bases for making ketone enolates as well. Ketone enolates generated in this way can be alkylated with alkyl halides or, as illus- trated in the following equation, treated with an aldehyde or a ketone. Thus, mixed aldol additions can be achieved by the tactic of quantitative enolate for- mation using LDA followed by addition of a different aldehyde or ketone. PROBLEM 21.14 Outline efficient syntheses of each of the following compounds from readily available aldehydes, ketones, esters, and alkyl halides according to the methods described in this section: (a) (c) (b) (d) SAMPLE SOLUTION (a) The H9251-carbon atom of the ester has two different alkyl groups attached to it. The critical carbon–carbon bond-forming step requires nucleophilic substitution on an alkyl halide by an ester enolate. Methyl halides are more reactive than iso- propyl halides in S N 2 reactions and cannot undergo elimination as a competing process; therefore, choose the synthesis in which bond is formed by alkylation. (This synthesis has been reported in the chemical literature and gives the desired product in 95% yield.) 1. LDA, THF 2. CH 3 I Ethyl 3-methylbutanoate (CH 3 ) 2 CHCH 2 COCH 2 CH 3 O Ethyl 2,3-dimethylbutanoate (CH 3 ) 2 CHCHCOCH 2 CH 3 CH 3 O b Disconnect bond b Disconnect bond a (CH 3 ) 2 CH O CH 3 CHCOCH 2 CH 3 b a CH 3 CHCOCH 2 CH 3 H11002 O H11001(CH 3 ) 2 CHX (CH 3 ) 2 CHCHCOCH 2 CH 3 H11002 O CH 3 X H11001 CH 2 COC(CH 3 ) 3 O OH C 6 H 5 CHCOCH 3 O CH 3 OH CHC 6 H 5 O (CH 3 ) 2 CHCHCOCH 2 CH 3 O CH 3 CH 3 CH 2 CC(CH 3 ) 3 O 2,2-Dimethyl- 3-pentanone CH 3 CH C OLi C(CH 3 ) 3 Lithium enolate of 2,2-dimethyl-3-pentanone 1. CH 3 CH 2 CH 2. H 3 O H11001 O X 5-Hydroxy-2,2,4- trimethyl-3-heptanone (81%) CH 3 CHCC(CH 3 ) 3 O HOCHCH 2 CH 3 LDA THF 21.10 H9251 Deprotonation of Carbonyl Compounds by Lithium Dialkylamides 849 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.11 SUMMARY Sections H9252-Keto esters, which are useful reagents for a number of carbon–carbon 21.1–21.4 bond-forming reactions, are prepared by the methods shown in Table 21.1. Section 21.5 Hydrolysis of H9252-keto esters, such as those shown in Table 21.1, gives H9252- keto acids which undergo rapid decarboxylation, forming ketones. H9252-Keto esters are characterized by K a ’s of about 10 H1100211 (pK a 11) and are quantitatively converted to their enolates on treatment with alkoxide bases. The anion of a H9252-keto ester may be alkylated at carbon with an alkyl halide and the product of this reaction subjected to ester hydrolysis and decarboxylation to give a ketone. Section 21.6 The acetoacetic ester synthesis is a procedure in which ethyl acetoac- etate is alkylated with an alkyl halide as the first step in the preparation of ketones of the type .CH 3 CCH 2 R O X Resonance forms illustrating charge delocalization in enolate of a H9252-keto ester C C ORH11032R O O H11002 CH R C C ORH11032 O O CH H11002 R C C ORH11032 OO CH 2 R C C ORH11032 OO CH H11002 RH11032O H11002 Most acidic proton of a H9252-keto ester H9252-Keto ester RCCH 2 CORH11032 O O H9252-Keto acid RCCH 2 COH O O Ketone RCCH 3 O 1. NaOH, H 2 O 2. H H11001 heat H11002CO 2 850 CHAPTER TWENTY-ONE Ester Enolates CH 3 CCH 2 COCH 2 CH 3 O O Ethyl acetoacetate CH 3 CCH 2 CH 2 CH CHCH 3 O 5-Hepten-2-one (81%) NaOCH 2 CH 3 CH 3 CH?CHCH 2 Br 1. HO H11002 , H 2 O 2. H H11001 3. heat CH 3 CCHCOCH 2 CH 3 O O CH 2 CH CHCH 3 R C C ORH11032 OO CH 2 H9252-Keto ester H11001 RH11033X Alkyl halide NaORH11032 1. HO H11002 , H 2 O 2. H H11001 3. heat Alkylated H9252-keto ester R C C ORH11032 OO CH RH11033 Ketone RCCH 2 RH11033 O Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.11 Summary 851 TABLE 21.1 Preparation of H9252-Keto Esters Reaction (section) and comments Claisen condensation (Sec- tion 21.1) Esters of the type RCH 2 CORH11032 are con- verted to H9252-keto esters on treatment with alkoxide bases. One molecule of an ester is converted to its enolate; a second molecule of ester acts as an acylat- ing agent toward the eno- late. Dieckmann cyclization (Section 21.2) An intramo- lecular analog of the Clais- en condensation. Cyclic H9252- keto esters in which the ring is five- to seven- membered may be formed by using this reaction. Mixed Claisen condensa- tions (Section 21.3) Diethyl carbonate, diethyl oxalate, ethyl formate, and ben- zoate esters cannot form ester enolates but can act as acylating agents toward other ester enolates. Acylation of ketones (Sec- tion 21.4) Diethyl carbo- nate and diethyl oxalate can be used to acylate ketone enolates to give H9252- keto esters. General equation and specific example Ester 2RCH 2 CORH11032 O X H9252-Keto ester RCH 2 CCHCORH11032 W O X O X R RH11032OH Alcohol H11001 1. NaORH11032 2. H H11001 Ethyl 2-ethyl-3-oxohexanoate (76%) CH 3 CH 2 CH 2 CCHCOCH 2 CH 3 W O X O X CH 2 CH 3 1. NaOCH 2 CH 3 2. H H11001 2CH 3 CH 2 CH 2 COCH 2 CH 3 O X Ethyl butanoate 1. NaOCH 2 CH 3 2. H H11001 O COCH 2 CH 3 O Ethyl indan-2-one-1-carboxylate (70%) CH 2 COCH 2 CH 3 CH 2 COCH 2 CH 3 O O X X Diethyl 1,2-benzenediacetate Ester RCOCH 2 CH 3 O X Another ester RH11032CH 2 COCH 2 CH 3 O X H9252-Keto ester RCCHCOCH 2 CH 3 W O X O X RH11032 H11001 1. NaOCH 2 CH 3 2. H H11001 Ketone RCH 2 CRH11032 O X Diethyl carbonate CH 3 CH 2 OCOCH 2 CH 3 O X H9252-Keto ester RCHCRH11032 W O X O ? COCH 2 CH 3 H11001 1. NaOCH 2 CH 3 2. H H11001 Ethyl propanoate CH 3 CH 2 COCH 2 CH 3 O X Diethyl oxalate CH 3 CH 2 OCCOCH 2 CH 3 O X O X Diethyl 3-methyl-2- oxobutanedioate (60–70%) CH 3 CHCOCH 2 CH 3 W X O X C±COCH 2 CH 3 O X O H11001 1. NaOCH 2 CH 3 2. H H11001 4,4-Dimethyl- 2-pentanone (CH 3 ) 3 CCH 2 CCH 3 O X Ethyl 5,5-dimethyl- 3-oxohexanoate (66%) (CH 3 ) 3 CCH 2 CCH 2 COCH 2 CH 3 O X O X H11001 1. NaOCH 2 CH 3 2. H H11001 Diethyl carbonate CH 3 CH 2 OCOCH 2 CH 3 O X O X Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Section 21.7 The malonic ester synthesis is related to the acetoacetic ester synthesis. Alkyl halides (RX) are converted to carboxylic acids of the type RCH 2 COOH by reaction with the enolate ion derived from diethyl mal- onate, followed by saponification and decarboxylation. Section 21.8 Alkylation of diethyl malonate, followed by reaction with urea, gives derivatives of barbituric acid, called barbiturates, which are useful sleep-promoting drugs. Section 21.9 Michael addition of the enolate ions derived from ethyl acetoacetate and diethyl malonate provides an alternative method for preparing their H9251- alkyl derivatives. Section 21.10 It is possible to generate ester enolates by deprotonation provided that the base used is very strong. Lithium diisopropylamide (LDA) is often used for this purpose. It also converts ketones quantitatively to their eno- lates. CH 3 CH 2 CC(CH 3 ) 3 O 2,2-Dimethyl-3-pentanone CH 3 CH CC(CH 3 ) 3 OLi 1. C 6 H 5 CH 2. H 3 O H11001 O X 1-Hydroxy-2,4,4- trimethyl-1-phenyl- 3-pentanone (78%) C 6 H 5 CHCHCC(CH 3 ) 3 OOH CH 3 LDA THF NaOCH 2 CH 3 CH 3 CH 2 OH Triethyl 2-methylpropane- 1,1,3-tricarboxylate (95%) CH 3 CHCH 2 COCH 2 CH 3 O CH(COOCH 2 CH 3 ) 2 CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate H11001 CH 3 CH CHCOCH 2 CH 3 O Ethyl 2-butenoate CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate RCH(COOCH 2 CH 3 ) 2 Alkylated derivative of diethyl malonate RX, NaOCH 2 CH 3 H 2 NCNH 2 O X O O O H H N N R H Alkylated derivative of barbituric acid 852 CHAPTER TWENTY-ONE Ester Enolates CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate CH(COOCH 2 CH 3 ) 2 CH 2 COH O (2-Cyclopentenyl)acetic acid (66%) 1. HO H11002 , H 2 O 2. H H11001 3. heat NaOCH 2 CH 3 Cl Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEMS 21.15 The following questions pertain to the esters shown and their behavior under conditions of the Claisen condensation. (a) Two of these esters are converted to H9252-keto esters in good yield on treatment with sodium ethoxide and subsequent acidification of the reaction mixture. Which two are these? Write the structure of the Claisen condensation product of each one. (b) One ester is capable of being converted to a H9252-keto ester on treatment with sodium ethoxide, but the amount of H9252-keto ester that can be isolated after acidification of the reaction mixture is quite small. Which ester is this? (c) One ester is incapable of reaction under conditions of the Claisen condensation. Which one? Why? 21.16 (a) Give the structure of the Claisen condensation product of ethyl phenylacetate (C 6 H 5 CH 2 COOCH 2 CH 3 ). (b) What ketone would you isolate after saponification and decarboxylation of this Claisen condensation product? (c) What ketone would you isolate after treatment of the Claisen condensation product of ethyl phenylacetate with sodium ethoxide and allyl bromide, followed by saponification and decarboxylation? (d) Give the structure of the mixed Claisen condensation product of ethyl phenylacetate and ethyl benzoate. (e) What ketone would you isolate after saponification and decarboxylation of the product in part (d)? (f) What ketone would you isolate after treatment of the product in part (d) with sodium ethoxide and allyl bromide, followed by saponification and decarboxylation? 21.17 All the following questions concern ethyl (2-oxocyclohexane)carboxylate. (a) Write a chemical equation showing how you could prepare ethyl (2-oxocyclohexane)car- boxylate by a Dieckmann reaction. (b) Write a chemical equation showing how you could prepare ethyl (2-oxocyclohexane)- carboxylate by acylation of a ketone. (c) Write structural formulas for the two most stable enol forms of ethyl (2-oxocyclo- hexane)carboxylate. (d) Write the three most stable resonance forms for the most stable enolate derived from ethyl (2-oxocyclohexane)carboxylate. COCH 2 CH 3 O O Ethyl (2-oxocyclohexane)carboxylate Problems 853 CH 3 CH 2 CH 2 CH 2 COCH 2 CH 3 O X Ethyl pentanoate CH 3 CH 2 CHCOCH 2 CH 3 O X W CCH 3 Ethyl 2-methylbutanoate CH 3 CHCH 2 COCH 2 CH 3 O X W CCH 3 Ethyl 3-methylbutanoate (CH 3 ) 3 CCOCH 2 CH 3 O X Ethyl 2,2-dimethylpropanoate Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (e) Show how you could use ethyl (2-oxocyclohexane)carboxylate to prepare 2-methylcy- clohexanone. (f) Give the structure of the product formed on treatment of ethyl (2-oxocyclohexane)car- boxylate with acrolein in ethanol in the presence of sodium ethoxide. 21.18 Give the structure of the product formed on reaction of ethyl acetoacetate with each of the following: (a) 1-Bromopentane and sodium ethoxide (b) Saponification and decarboxylation of the product in part (a) (c) Methyl iodide and the product in part (a) treated with sodium ethoxide (d) Saponification and decarboxylation of the product in part (c) (e) 1-Bromo-3-chloropropane and one equivalent of sodium ethoxide (f) Product in part (e) treated with a second equivalent of sodium ethoxide (g) Saponification and decarboxylation of the product in part (f) (h) Phenyl vinyl ketone and sodium ethoxide (i) Saponification and decarboxylation of the product in part (h) 21.19 Repeat the preceding problem for diethyl malonate. 21.20 (a) Only a small amount (less than 0.01%) of the enol form of diethyl malonate is present at equilibrium. Write a structural formula for this enol. (b) Enol forms are present to the extent of about 8% in ethyl acetoacetate. There are three constitutionally isomeric enols possible. Write structural formulas for these three enols. Which one do you think is the most stable? The least stable? Why? (c) Bromine reacts rapidly with both diethyl malonate and ethyl acetoacetate. The reaction is acid-catalyzed and liberates hydrogen bromide. What is the product formed in each reaction? 21.21 (a) On addition of one equivalent of methylmagnesium iodide to ethyl acetoacetate, the Grignard reagent is consumed, but the only organic product obtained after working up the reaction mixture is ethyl acetoacetate. Why? What happens to the Grignard reagent? (b) On repeating the reaction but using D 2 O and DCl to work up the reaction mixture, it is found that the recovered ethyl acetoacetate contains deuterium. Where is this deuterium located? 21.22 Give the structure of the principal organic product of each of the following reactions: (a) (b) (c) (d) (e) (f) Product of part (e) 1. NaOH, H 2 O 2. H H11001 3. heat Product of part (c) 1-iodobutaneH11001 NaOCH 2 CH 3 , ethanol Product of part (c) 1. NaOH, H 2 O 2. H H11001 3. heat Ethyl acetoacetate 1-bromobutaneH11001 NaOCH 2 CH 3 , ethanol Product of part (a) 1. NaOH, H 2 O 2. H H11001 3. heat Ethyl octanoate 1. NaOCH 2 CH 3 2. H H11001 (CH 2 ?CHCH) O X 854 CHAPTER TWENTY-ONE Ester Enolates Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (g) (h) (i) (j) (k) (l) (m) 21.23 Give the structure of the principal organic product of each of the following reactions: (a) (b) (c) (d) (e) 21.24 The spicy flavor of cayenne pepper is due mainly to a substance called capsaicin. The fol- lowing sequence of steps was used in a 1955 synthesis of capsaicin. See if you can deduce the structure of capsaicin on the basis of this synthesis. C 8 H 15 Br C 11 H 18 O 4 C 10 H 18 O 2 C 10 H 17 ClOC 18 H 27 NO 3 Capsaicin PBr 3 OH 1. NaCH(CO 2 CH 2 CH 3 ) 2 2. KOH, H 2 O, heat 3. H H11001 heat 160–180°C SOCl 2 HO CH 2 NH 2 CH 3 O Product of part (d) C 6 H 8 O 1. HO H11002 , H 2 O 2. H H11001 3. heat C 9 H 12 O 3 1. NaOCH 2 CH 3 2. H H11001 CH 2 COOCH 2 CH 3 H H CH 2 COOCH 2 CH 3 Product of part (b) C 7 H 10 O 3 H 2 O, H H11001 heat C 12 H 18 O 5 1. NaOCH 2 CH 3 2. H H11001 COOCH 2 CH 3 COOCH 2 CH 3 COOCH 2 CH 3 C 7 H 12 O H 2 O, H 2 SO 4 heat CH 3 CH 2 O COOCH 2 CH 3 COOCH 2 CH 3 tert-Butyl acetate 1. [(CH 3 ) 2 CH] 2 NLi, THF 2. benzaldehyde 3. H H11001 Product of part (k) H 2 O, HCl, heat Diethyl malonate 6-methyl-2-cyclohexenoneH11001 NaOCH 2 CH 3 , ethanol Product of part (i) 1. NaOH, H 2 O 2. H H11001 3. heat Diethyl malonate 1-bromo-2-methylbutaneH11001 NaOCH 2 CH 3 , ethanol Acetone diethyl oxalateH11001 1. NaOCH 2 CH 3 2. H H11001 Acetophenone diethyl carbonateH11001 1. NaOCH 2 CH 3 2. H H11001 Problems 855 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.25 Show how you could prepare each of the following compounds. Use the starting material indicated along with ethyl acetoacetate or diethyl malonate and any necessary inorganic reagents. Assume also that the customary organic solvents are freely available. (a) 4-Phenyl-2-butanone from benzyl alcohol (b) 3-Phenylpropanoic acid from benzyl alcohol (c) 2-Allyl-1,3-propanediol from propene (d) 4-Penten-1-ol from propene (e) 5-Hexen-2-ol from propene (f) Cyclopropanecarboxylic acid from 1,2-dibromoethane (g) (h) HO 2 C(CH 2 ) 10 CO 2 H from HO 2 C(CH 2 ) 6 CO 2 H 21.26 Diphenadione inhibits the clotting of blood; that is, it is an anticoagulant. It is used to con- trol vampire bat populations in South America by a “Trojan horse” strategy. A few bats are trapped, smeared with diphenadione, and then released back into their normal environment. Other bats, in the course of grooming these diphenadione-coated bats, ingest the anticoagulant and bleed to death, either internally or through accidental bites and scratches. Suggest a synthesis of diphenadione from 1,1-diphenylacetone and dimethyl 1,2-benzenedicar- boxylate. 21.27 Phenylbutazone is a frequently prescribed antiinflammatory drug. It is prepared by the reac- tion shown. What is the structure of phenylbutazone? 21.28 The use of epoxides as alkylating agents for diethyl malonate provides a useful route to H9253- lactones. Write equations illustrating such a sequence for styrene oxide as the starting epoxide. Is the lactone formed by this reaction 3-phenylbutanolide, or is it 4-phenylbutanolide? O C 6 H 5 O 3-Phenylbutanolide O O C 6 H 5 4-Phenylbutanolide Diethyl butylmalonate CH 3 CH 2 CH 2 CH 2 CH(COOCH 2 CH 3 ) 2 H11001 1,2-Diphenylhydrazine C 6 H 5 NHNHC 6 H 5 Phenylbutazone C 19 H 20 N 2 O 2 CCH O O O Diphenadione CNH 2 O CNH 2 O from 1,2-dibromoethane 856 CHAPTER TWENTY-ONE Ester Enolates Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.29 Diethyl malonate is prepared commercially by hydrolysis and esterification of ethyl cyano- acetate. The preparation of ethyl cyanoacetate proceeds via ethyl chloroacetate and begins with acetic acid. Write a sequence of reactions describing this synthesis. 21.30 The tranquilizing drug meprobamate has the structure shown. Devise a synthesis of meprobamate from diethyl malonate and any necessary organic or inorganic reagents. Hint: Carbamate esters, that is, compounds of the type , are prepared from alcohols by the sequence of reactions 21.31 When the compound shown was heated in refluxing hydrochloric acid for 60 hours, a prod- uct with the molecular formula C 5 H 6 O 3 was isolated in 97% yield. Identify this product. Along with this product, three other carbon-containing substances are formed. What are they? COCH(CH 3 ) 2 O CH 3 O CH 3 O COCH(CH 3 ) 2 O Alcohol ROH H11001 Phosgene ClCCl O Chlorocarbonate ester ROCCl O Carbamate ester ROCNH 2 O NH 3 , H 2 O ROCNH 2 O X C CH 3 CH 2 CH 2 H 3 C CH 2 OCNH 2 CH 2 OCNH 2 O O Meprobamate NPCCH 2 COCH 2 CH 3 O X Ethyl cyanoacetate Problems 857 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website