Chapter 21: Ester Enolates 21.1: Ester  Hydrogens and Their

Chapter 21: Ester Enolates 21.1: Ester Hydrogens and Their pKa’s. The -protons of esters are less acidic that ketones and aldehydes. Typical pKa’s of carbonyl compounds ( -protons): aldehydes 17 O O O C C C ketones 19 H C CH H C H H C OCH esters 24 O H C C N amides 30 C H C N(CH ) nitriles 25 Acidity of 1,3-dicarbonyl compounds 3 3 3 3 3 3 3 3 2 O O H3C C H3C OCH3 H3CO O C C C O O OCH3 CH3 ketone pKa 19 ester pKa 24 O C H 3C C C C O O OCH3 H H H H 1,3-diester pKa 13 1,3-keto ester pKa 11 H3C C C C CH3 H H 1,3-diketone pKa 9 1

21.2: The Claisen Condensation Reaction. Base-promoted condensation of two esters to give a -keto-ester product O 2 H3C C OEt Ethyl acetate NaOEt EtOH then H3O O O H3C CH CH2 C OEt Ethyl 3-oxobutanoate (Ethyl acetoacetate) Mechanism (Fig. 21.1, page 884-5) is a nucleophilic acyl substitution of an ester by an ester enolate and is related to the mechanism of the aldol condensation. 2

21.3: Intramolecular Claisen Condensation: The Dieckmann Cyclization. Dieckmann Cyclization works best with 1,6-diesters, to give a 5-membered cyclic -keto ester product, and 1,7-diesters to give 6-membered cyclic -keto ester product. O OEt O OEt O O EtONa, EtOH CO2Et EtONa, EtOH OEt O CO2Et OEt O Mechanism: same as the Claisen Condensation 3

21.4: Mixed Claisen Condensations. Similar restrictions as the mixed aldol condensation. O Four possible products O H3CH2CH2C C C EtONa, EtOH O OEt H3C C C C5 C O C OEt H3C H O then H3O C3 C H3CH2C C C O O C OEt C H3CH2CH2CH2C H3C H OEt H H3CH2CH2C O C O C H3CH2C OEt H H H H C H3CH2CH2CH2C O C H3CH2CH2C C OEt H Esters with no -protons can only act as the electrophile O C OEt H3C C C O EtONa, EtOH O C C OEt C OEt H3C H then H3O H H O Discrete (in situ) generation of an ester enolate with LDA O O H3CH2CH2C C C LDA, THF, -78 C OEt H3C O Li H3 CH2 CH2 C H H C C C C H H OEt then H2O H O OEt H3CH2C C O C H3CH2CH2C C OEt H O O H3C C C H H LDA , TH F, -78 C OEt O H3C C H C Li H3CH2CH2C C C H H OEt then H3O O OEt H3CH2CH2CH2C C O C C H3C H OEt 4

21.5: Acylation of Ketones with Esters. An alternative to the Claisen condensations and Dieckmann cyclization. b) O a) LDA, THF, -78 C O H3CO O C O OCH3 OCH3 H3CO- Na , H3COH Equivalent to a mixed Claisen condensation O O b) a) LDA, THF, -78 C Equivalent to a Dieckmann cyclization H3CO O O O C OCH3 OR O O H3C O C OCH3 OCH3 H3CO- Na , H3COH O H3CO O OCH3 5

21.6: Ketone Synthesis via -Keto Esters. The -keto ester products of a Claisen condensation or Dieckmann cyclization can be hydrolyzed to the -keto acid and decarboxylated to the ketone. O H3CH2CO C O C C NaOH, H2O OCH2CH3 H R or H3O H O O C C C H - CO2 O H OH H R O C C H OH H3CH2CO O C C C H R O NaOH, H2O R' or H3O O C H R C C H R H - CO2 O R' H C C OH H R enol O O tautomerization C carboxylic acid O C R enol O tautomerization R' H C C R' H R ketone 6

21.7: Acetoacetic Ester Synthesis. The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2). The product, a -keto ester, is then hydrolyzed to the -keto acid and decarboxylated to the ketone. O H3C C C CO2Et RH2C-X H H ethyl acetoacetate EtO EtOH alkyl halide O Na C CO2Et HCl, Δ H 3C C RH2C H EtO Na , EtOH O O C CO 2 H H3 C C R H2 C H H3C C C CH2R H H ketone R 'H2 C-X O O O C C H3 C C OEt R 'H2 C CH2 R HCl, Δ O O C C H3 C C OH R 'H2 C CH2 R H3 C C C CH2 R H CH2 R ' An acetoacetic ester can undergo one or two alkylations to give an -substituted or -disubstituted acetoacetic ester The enolates of acetoacetic esters are synthetic equivalents to 7 ketone enolates

-Keto esters other than ethyl acetoacetate may be used. The products of a Claisen condensation or Dieckmann cyclization are acetoacetic esters ( -keto esters) O O EtONa, EtOH OEt O CO2Et then H3O O H3O CO2Et Δ Br acetoacetic ester OEt O EtONa, EtOH Dieckmann cyclization NaOEt O 2 H3CH2C C OEt EtOH then H3O O H3CH2C C Claisen condensation O HC C OEt acetoacetic ester CH3 EtONa, EtOH O Br H3CH2C C O C C OEt CH3 H3 O Δ O H H3 CH2 C C C CH2 CH CH2 CH3 8

21.8: The Malonic Acid Synthesis. overall reaction CO2Et RH2C-X EtOH CO2Et diethyl malonate Et ethyl EtO alkyl halide Na EtO2C C CO2Et HCl, Δ CO 2 H RH2C-CH2-CO2H carboxylic acid R 'H2 C-X HCl, Δ EtO 2 C C R H2 C H RH2C H EtO Na , EtOH HO 2 C C CO 2 Et R H2 C CH2 R ' HO 2 C C CO 2 H R H2 C CH2 R ' CH2 R CH CO 2 H R 'H2 C carboxylic acid 9

O H C C CH3 H3CO O H H H H3C C O C C OCH3 H3CO H 3C H H O C C C C O OEt OCH3 H3COH pKa 16 H O C CH3 O acetoacetic ester pKa 11 H H3COH pKa 16 H acetoacetic ester pKa 19 O C C EtO H H H C C OEt EtOH pKa 16 H ethyl acetate pKa 25 O O EtO C C C OEt H H diethyl malonate pKa 13 EtO EtO O O C C C OEt EtOH pKa 16 H 10

Summary: Malonic ester synthesis: equivalent to the alkylation of a carboxylic (acetic) acid enolate Acetoacetic ester synthesis: equivalent to the alkylation of an ketone (acetone) enolate 21.9: Michael Addition of Stablized Anions. Enolates of malonic and acetoacetic esters undergo Michael (1,4-) addition to , -unsaturated ketones. O H3 C C O C CH2 H electrophile EtO C EtONa, EtOH O C C O H H O C C C H3 C C C CH3 H H H CO2 Et CH3 H H nucleophile This Michael addition product can beO decarboxylated O O H H O H H H3O , Δ C C C H3C C C CH3 - EtOH, -CO 2 H H H CO2Et H3 C C C C C C H H H H CH3 11

21.10: Reactions of LDA-Generated Ester Enolates. Ester enolates can be generated with LDA in THF rapidly and quantitatively. The resulting enolates can undergo carbonyl addition reactions with other esters, aldehydes, ketones or alkylation reactions with alkyl halides or tosylates. O C O OEt LDA, THF C RH2C-X CH2R OEt CO2Et -78 C O O O O LDA, THF O RH2C-X O CH2R -78 C 12