22.7 Alkylation of Ester Enolate Ions

Home , Dicarbonyl, Diethyl malonate, Enolate, Ethyl acetoacetate

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1084 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS

O S O S OH C N NH _O acetyl-CoA carboxylase H2CCA" SCoA H H enol form of Lacetyl-CoA+ R S H carboxybiotin O S O O S S HN NH

_OCC CH2 SCoA H H LLmalonyl-CoALL + R S H biotin

Provide a curved-arrow mechanism for this reaction, using B as a base (which is part of the 3 enzyme) and |BH as its conjugate acid.

22.7 ALKYLATION OF ESTER ENOLATE IONS

Sections 22.4–22.6 described reactions in which enolate ions react as nucleophiles at the carbonyl carbon atom. This section considers two reactions in which enolate ions are used as nu-

cleophiles in SN2 reactions.

A. Malonic Ester Synthesis Diethyl malonate (malonic ester), like many other b-dicarbonyl compounds, has unusually acidic a-hydrogens. (Why?) Consequently, its conjugate-base enolate ion can be formed nearly completely with alkoxide bases such as sodium ethoxide.

O O O O S S S S _ (22.64a) EtO_ EtOC CH2 C OEt EtO H EtOC CH C OEt 2 3 ++LL LL 2 L enolateLL ion of 2diethylLL malonate 2 diethyl malonate 2 pKa 12.9 = The conjugate-base anion of diethyl malonate is nucleophilic, and it reacts with alkyl halides

and sulfonate esters in typical SN2 reactions. Such reactions can be used to introduce alkyl groups at the a-position of malonic ester.

CH2CH3 CH2CH3

Na CH(CO Et) CH "CH Br CH "CHCH(CO Et) Na Br (22.64b) | _ 2 2 3 EtOH 3 2 2 | _ 3 ++L (83% yield)

As this example shows, even secondary halides can be used in this reaction. (See Further Ex- ploration 22.2.) The importance of this reaction is that it can be extended to the preparation of carboxylic acids. Saponification (Sec. 21.7A) of the diester and acidification of the resulting solution Further Exploration 22.2 Malonic Ester gives a substituted malonic acid derivative. Recall that heating any malonic acid derivative Alkylation causes it to decarboxylate (Sec. 20.11). The result of the alkylation, saponification, and decar- 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1085

22.7 ALKYLATION OF ESTER ENOLATE IONS 1085

boxylation sequence is a carboxylic acid that conceptually is a substituted acetic acid—an acetic acid molecule with an alkyl group on its a-carbon.

decarboxylation protonation (Sec. 20.11) CH2CH3 CH2CH3 CH2CH3

NaOH H3O| heat CH3"CHCH(CO2Et)2 CH3"CHCH(CO2 Na )2 CH3"CHCH(CO2H)2 H2O _ |

CH2CH3 ester saponification (Sec. 21.7A) CH3"CHCH2CO2H CO2 + a “substituted acetic acid” (22.64c)

The overall sequence of ionization, alkylation, saponiﬁcation and decarboxylation starting from diethyl malonate (Eqs. 22.64a–c) is called the malonic ester synthesis. Notice that the alkylation step of the malonic ester synthesis (Eq. 22.64b) results in the formation of a new carbon–carbon bond. The anion of malonic ester can be alkylated twice in two successive reactions with different alkyl halides (if desired) to give, after hydrolysis and decarboxylation, a disubstituted acetic acid. This possibility allows us to think of any disubstituted acetic acid in terms of diethyl malonate and two alkyl halides, as follows (X halogen): = acetic acid unit

R CH CO2H RC(CO2Et)2 CH2(CO2Et)2, R X, RЈ X (22.65) L L LLL "RЈ "RЈ

If the alkyl halides R X and R9 X are among those that will undergo the SN2 reaction, then the target carboxylicL acid can inL principle be prepared by the malonic ester synthesis. This analysis is illustrated in Study Problem 22.4.

Study Problem 22.4 Outline a malonic ester synthesis of the following carboxylic acid:

CH3

CH3(CH2)4"CH CO2H L 2-methylheptanoic acid

Solution Using the analysis in the text, identify the “acetic acid” unit in the carboxylic acid. The two alkyl groups—in this case, a methyl group and a pentyl group—are derived from alkyl halides.

CH3 derived from CH3I

CH3(CH2)4 "CH CO2H L L

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1086 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS

This analysis leads to the following synthesis:

formation of formation of introduction of the enolate ion the enolate ion the second alkyl group

NaOEt CH3(CH2)3CH2Br NaOEt H3C I CH2(CO2Et)2 EtOH CH3(CH2)3CH2CH(CO2Et)2 EtOH L diethyl malonate introduction of CH3 the first alkyl group CH3(CH2)3CH2"C(CO2Et)2 NaI (22.66) (80% yield) +

Ester saponiﬁcation, acidiﬁcation, and decarboxylation, as in Eq. 22.64c, give the desired product. The two enolate-forming and alkylation reactions must be performed as separate steps. Adding two different alkyl halides and two equivalents of NaOEt to malonic ester at the same time would not give the desired product. (Why?)

PROBLEMS 22.33 Indicate whether each of the following compounds could be prepared by a malonic ester synthesis. If so, outline a preparation from diethyl malonate and any other reagents. If not, explain why. (a) 3-phenylpropanoic acid (b) 2-ethylbutanoic acid (c) 3,3-dimethylbutanoic acid 22.34 Give the product of the following reaction sequence and explain your answer. 2 NaOEt NaOH HCl CH2(CO2Et)2 BrCH2CH2CH2ClEtOH heat (C5H8O2) + 22.35 (a) When the conjugate-base enolate of diethyl malonate is treated with bromobenzene, no

diethyl phenylmalonate is formed. Explain why bromobenzene is inert. .. CH(CO2Et)2 + BrCH(CO2Et)2 + Br

diethyl phenylmalonate (b) When the same enolate ion is treated with bromobenzene and a catalytic amount of

Pd[P(t-Bu)3]4, diethyl phenylmalonate is formed in excellent yield. Explain the role of the catalyst with a mechanism.

B. Direct Alkylation of Enolate Ions Derived from Monoesters

In the synthesis of carboxylic acids by malonic ester alkylation, a CO2Et group is “wasted” because it is later removed. Why not avoid this altogether and alkylateL directly the enolate ion of an acetic acid ester? O O S S CH CH CH CH I _ 3 2 2 2 B _ H3C C OR H2CCOR L (a base)3 + LL 2 LL BH + L O S

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22.7 ALKYLATION OF ESTER ENOLATE IONS 1087

At one time this idea could not be used in practice because enolate ions derived from esters, once formed, undergo another, faster reaction: Claisen condensation with the parent ester (Sec. 22.5A). The direct alkylation shown in Eq. 22.67 is so attractive, however, that chemists continued efforts to ﬁnd conditions under which it would work. It was discovered in the early 1970s that a family of very strong, highly branched nitrogen bases, such as the following two examples, can be used to form stable enolate ions rapidly at 78 C from esters. - °

Li|_N Li|_N 3 2 3 2

lithium lithium diisopropylamide cyclohexylisopropylamide (LDA) (LCHIA) pKa of conjugate acids: ≈35

(Do not confuse the term amide in the names of these bases with the carboxylic acid derivative. This term has a double usage. As used here, an amide is the conjugate-base anion of an

amine.) The conjugate acids of these bases are amines, which have pKa values near 35. Be- cause esters have pKa values near 25, these amide bases are strong enough to convert esters completely into their conjugate-base enolate ions. The ester enolate anions formed with these bases can be alkylated directly with alkyl halides. Notice that esters with quaternary a-carbon atoms can be prepared by this method. (These compounds cannot be prepared by the malonic ester synthesis. Why?)

a quaternary a-carbon

CH3 O CH3 O Li CH3 O

SS78 °C S

-LCHIA H3C I H C CC OEt H C C.. C OEt H C CC OEt LiI 3 " THF 3 " DMSOL 3 " LL 15 min LL L LL L + "H < "CH3 + ethyl 2-methylpropanoate ethyl 2,2-dimethylpropanoate NH (ethyl pivalate) (87% yield) (22.68)

The nitrogen bases themselves are generated from the corresponding amines and butyllithium (a commercially available organolithium reagent) at 78 C in tetrahydrofuran (THF) solvent. - °

78 °C N H CH CH CH CH Li N Li CH CH CH CH (22.69) 3 2 2 2 -THF _ | 3 2 2 3 2 LL+ 2 3 +

This method of ester alkylation is considerably more expensive than the malonic ester synthesis. It also requires special inert-atmosphere techniques because the strong bases that are used react vigorously with both oxygen and water. For these reasons, the malonic ester syn- 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1088

1088 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS

thesis remains very useful, particularly for large-scale syntheses. However, for the preparation of laboratory samples, or for the preparation of compounds that are unavailable from the malonic ester synthesis, the preparation and alkylation of enolate ions with amide bases is particularly valuable. The possibility of the Claisen condensation as a side reaction was noted in the discussion of Eq. 22.67. The use of a very strong amide base avoids the Claisen condensation for the following reason. The reaction is run by adding the ester to the base. When a molecule of ester enters the solution, it can react either with the strong base to form an enolate ion or with a molecule of already formed enolate ion in the Claisen condensation. The reaction of esters with strong amide bases is so much faster at 78 C than the Claisen condensation that the enolate ion is formed instantly and never has -a chance° to undergo the Claisen condensation. In other words, the Claisen condensation is avoided because the ester and its enolate ion are never present simultaneously (except for an instant) in the reaction ﬂask. Another potential side reaction is the nucleophilic reaction of the amide base (or even its conjugate acid amine, which is, after all, still a base) at the ester carbonyl group. Because amines react with esters to give products of aminolysis (Sec. 21.8C), it might be reasonable to expect the conjugate bases of amines—very strong bases indeed—to react even more rapidly with esters. That this does not happen is once again the result of a competition. When an amide base reacts with the ester, it can either remove a proton or react at the carbonyl carbon. A reaction at the carbonyl carbon is retarded by van der Waals repulsions between groups on the carbonyl compound and the large branched groups on the bases. (These van der Waals repulsions have been aptly termed F-strain, or “front strain.”) For such a branched amide base to react at the carbonyl carbon is somewhat like trying to put a dinner plate into the coin slot of a vending machine. If the amide base could be in contact with the ester long enough, it would eventually react at the carbonyl carbon; but the base instead reacts more rapidly a different way: It abstracts an a-proton. Reaction with a tiny hydrogen does not involve the van der Waals repulsions that would occur if the base were to react at the carbonyl carbon. Hence, the amide base takes the path of least resistance: It forms the enolate ion. Notice that van der Waals repulsions are used productively in this example—to avoid an undesired reaction.

PROBLEMS 22.36 Outline a synthesis of each of the following compounds from either diethyl malonate or ethyl acetate. Because the branched amide bases are relatively expensive, you may use them in only one reaction. (a) (b)CH3CH2CH2 (c) C2H5 CH CO H % 2 L $CH CO2H C2H5 "C CO2Et L "CH3 L % L CH3CH2CH)2 valproic acid (used in treatment of epilepsy)

22.37 The reactions of ester enolate ions are not restricted to simple alkylations. With this in mind, suggest the structure of the product formed when the enolate ion formed by the reaction of tert-butyl acetate with LCHIA reacts with each of the following compounds at 78 C followed by dilute HCl. - ° (a) acetone (b) benzaldehyde 22.38 Predict the product formed when the conjugate-base enolate ion of ethyl 2-methylpropanoate (shown in Eq. 22.68) is treated with bromobenzene and a catalytic amount of

Pd[P(t-Bu)3]4, and explain the role of the catalyst. 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1089

22.7 ALKYLATION OF ESTER ENOLATE IONS 1089

C. Acetoacetic Ester Synthesis Recall that b-keto esters, like malonic esters, are substantially more acidic than ordinary esters (Eq. 22.52c, p. 1074) and are completely ionized by alkoxide bases.

O O O O S S S S _ (22.70) EtO _ H3C C CH2 C OEt EtO H H3C C CH C OEt 2 3 ++LLLL 22 L LL LL 2 ethyl acetoacetate ethanol2 pKa 10.7 pKa 16 = = The enolate ions derived from b-keto esters, like those from malonate ester derivatives, can be alkylated by primary or unbranched secondary alkyl halides or sulfonate esters.

O O O O S S S S _ H3C C CH C OEt Br CH2CH2CH2CH3 H3C C CH C OEt Na| Br _ LL2 LL++3 2 L LL LL 332 Na 1-bromobutane | 2 "CH2CH2CH2CH3 2 ethyl 2-acetylhexanoate (70% yield) (22.71)

Dialkylation of b-keto esters is also possible.

O O O S NaOEt S S (1 equiv.) CH (CH ) I _ 3 2 3 2H3C C OEt H3C C CH C OEt LL LL2 LL Claisen condensation first alkylation

O O O CH3 O S S S S NaOEt H3CI H3C C CH C OEt L H3C C "C C OEt LL LL LLL L (CH" 2)3CH3 second alkylation (CH" 2)3CH3 (22.72)

Alkylation of a Dieckmann condensation product is the same type of reaction:

OO S H S CH2CH2CH3 NaOEt Br CH2CH2CH3 L L (22.73) L CO2Et L CO2Et (from a Dieckmann condensation) ethyl 2-oxo-1-propyl- cyclopentanecarboxylate (85% yield)

Like esters of substituted malonic acids, the alkylated derivatives of ethyl acetoacetate can be hydrolyzed and decarboxylated to give ketones. Ester saponiﬁcation and protonation gives a substituted b-keto acid; and b-keto acids spontaneously decarboxylate at room temperature (Sec. 20.11). This series of reactions is illustrated as carried out on the product of Eq. 22.71: 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1090

1090 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS

O O S S NaOH, H2O H2O, H3O|, heat H3C C CH C OEt LL LL "CH2CH2CH2CH3 ester protonation and saponification decarboxylation

O S H3CC CH2CH2CH2CH2CH3 CO2 EtOH (22.74) LL ++ The alkylation of ethyl acetoacetate followed by saponiﬁcation, protonation, and decarboxylation to give a ketone is called the acetoacetic ester synthesis. The alkylation part of this sequence, like the alkylation of diethyl malonate, involves the construction of new carbon–carbon bonds. Whether a target ketone can be prepared by the acetoacetic ester synthesis can be deter- mined by mentally reversing the synthesis.

O S R C CH2 CO2Et, RЈ Br, RЉ Br O RЈ O RЈ LLL L L S S O RЈ R C "C H R C "C CO2Et S (22.75) LLL LLL R C "CH CO2Et, RЉ Br "RЉ "RЉ LL L L O RЉ replace with CO2Et S L R C "CH CO2Et, RЈ Br LL L L

This analysis involves replacing an a-hydrogen of the target ketone with a CO2Et group. This process unveils the b-keto ester required for the synthesis. The b-keto ester,L in turn, can STUDY GUIDE LINK 22.6 either be prepared directly by a Claisen condensation or can be prepared from other b-keto es- Further Analysis of the Claisen ters by alkylation or dialkylation with appropriate alkyl halides, as indicated by the possibili- Condensation ties in Eq. 22.75.

Study Problem 22.5 Outline a preparation of 2-methyl-3-pentanone by a reaction sequence that involves at least one Claisen condensation.

Solution The discussion in the text leads to the following analysis:

O H O CO2Et S S CH3CH2C "C CH3 CH3CH2C "C CH3 L L L L "CH3 "CH3 2-methyl-3-pentanone A

where the symbol , as usual, means “implies as a starting material.” The b-keto ester A cannot be prepared directly by a Claisen condensation because it would require a crossed Claisen condensation (see Eq. 22.61, p. 1079), and because the reaction could not be made irreversible by de- protonation. A second option is to provide one of the methyl groups by alkylation of the enolate ion derived from b-keto ester B: 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1091

22.7 ALKYLATION OF ESTER ENOLATE IONS 1091

O CO2Et O CO2Et S S CH3CH2C "C CH3 CH3CH2C "CHCH3,H3C I L L LB LL "CH3 A

The enolate ion of compound B, in turn, can be prepared directly by the Claisen condensation of ethyl propionate. (This follows from the analysis shown in Eq. 22.61, p. 1079.)

O CO2Et NaOEt S (1 equiv.) H3CI 2CH3CH2CO2Et EtOH CH3CH2C "C CH3 L A L _ L ethyl propionate enolate ion2 of B Saponifying A and acidifying the solution will give the b-keto acid, which will decarboxylate spontaneously under the acidic reaction conditions to give the desired ketone.

O CO2Et O CO2 O H S S _ S NaOH H3O| CH3CH2C "C CH3 CH3CH2C "C CH3 CH3CH2C "C CH3 CO2 L L L L - L L "CH3 "CH3 "CH3 target molecule A

Do not let the large number of reactions in this chapter obscure a very important central theme: Enolate ions are nucleophiles, and they do many of the things that other nucleophiles

do, such as addition to carbonyl groups, nucleophilic acyl substitution, SN2reactionswithalkyl halides, and so on. The reactions of enolate ions presented here are only a small fraction of Further Exploration 22.3 those that are known. Yet if you grasp the central idea that enolate ions are nucleophiles, and Alkylation of Enolate Ions Derived if you understand the other reactions of nucleophiles, you should have little difﬁculty under- from Ketones standing (and perhaps even predicting) other reactions of enolate ions.

PROBLEMS 22.39 Outline a synthesis of each of the following compounds from ethyl acetoacetate and any other reagents. (a) 5-methyl-2-hexanone (b) 4-phenyl-2-butanone 22.40 Outline a synthesis of each of the following compounds from a b-keto ester; then show how the b-keto ester itself can be prepared. (a) O (b) O S S PhCH2CH C CH2CH3 PhCH C CH2Ph L L L L "CH3 "CH3 22.41 Predict the outcome of the following reaction by identifying A, then B, then the ﬁnal product. (Hint: How do nucleophiles react with epoxides under basic conditions?)

diethyl malonate NaOEt A EtOH

H3C O ABC CH (C H O ) $ $ 2 EtOH 9 14 4 + L H3C $