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22.7 Alkylation of Ester Enolate Ions

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22.7 Alkylation of Ester Enolate Ions 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1084 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 car- bonyl 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 car- bon–carbon bond. The anion of malonic ester can be alkylated twice in two successive reactions with differ- ent 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 di- ethyl 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 derived from CH3(CH2)4Br substituted acetic acid 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1086 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 CH3CH2CH2CH2 CH2 C OR I_ (22.67) LLL + 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1087 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 deriva- tive. 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 syn- thesis. 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 mal- onic ester synthesis, the preparation and alkylation of enolate ions with amide bases is partic- ularly 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 fol- lowing 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.
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