21.1: Ester α Hydrogens and Their pKa’s. The α-protons of esters are less acidic that ketones and aldehydes.
Typical pKa’s of carbonyl compounds (α-protons): aldehydes 17 O O O ketones 19 C C C H C H H C CH H C OCH esters 24 3 3 3 3 3 amides 30 O C H3C C N nitriles 25 H3C N(CH3)2 Acidity of 1,3-dicarbonyl compounds O O C C H3C OCH3 H3C CH3 ester ketone pKa= 24 pKa= 19 O O O O O O C C C C C C H3C C OCH3 H C C CH H3CO C OCH3 3 3 H H H H H H 1,3-diester 1,3-keto ester 1,3-diketone 191 pKa= 13 pKa= 11 pKa= 9
21.2: The Claisen Condensation Reaction. Base-promoted condensation of two esters to give a β-keto-ester product NaOEt O O O
2 H3C C OEt EtOH H3C CH CH2 C OEt + then H3O Ethyl acetate 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.
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98 21.3: Intramolecular Claisen Condensation: The Dieckmann Cyclization. Dieckmann Cyclization works best with 1,6-diesters, to give a 5-membered cyclic β-keto ester product, and 1,7-diesters to give 6-membered cyclic β-keto ester product.
O OEt O O EtONa, EtOH OEt EtONa, EtOH O CO Et CO2Et 2 O OEt OEt O Mechanism: same as the Claisen Condensation
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21.4: Mixed Claisen Condensations. Similar restrictions as the mixed aldol condensation. Four possible products O O O O C C C C O O EtONa, H3CH2CH2CH2C C OEt H3CH2C C OEt EtOH H3C H H H3CH2CH2C C + H3C C H3CH2CH2C C OEt C OEt + H H H H then H3O O O O O C C C C C 5 C3 H3CH2C C OEt H3CH2CH2CH2C C OEt H3C H H H3CH2CH2C Esters with no α-protons can only act as the electrophile
O O O EtONa, O EtOH C C C + H3C C OEt C OEt C OEt + H C H H H then H3O 3
Discrete (in situ) generation of an ester enolate with LDA O
H3C C O O O O Li+ C OEt LDA, THF, -78°C H H C C H3CH2CH2C C H3CH2CH2C C H3CH2C C OEt C OEt C OEt + H then H2O H CH CH C H H H 3 2 2 O
H3CH2CH2C C O O Li+ C OEt O O LDA, THF, -78°C H H C C H3C C H3C C C OEt C OEt H3CH2CH2CH2C C OEt 194 + H C H H H H then H3O 3
99 21.5: Acylation of Ketones with Esters. An alternative to the Claisen condensations and Dieckmann cyclization.
b) O O O O a) LDA, THF, -78° C O C H3CO OCH3 OCH3
- + H3CO Na , H3COH Equivalent to a mixed O O Claisen condensation OR + C H3C OCH3
O O b) O O O a) LDA, THF, -78° C C H CO OCH 3 3 OCH3
- + H3CO Na , Equivalent to a H3COH Dieckmann cyclization O O H3CO OCH3
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21.6: Ketone Synthesis via β-Keto Esters. The β-keto ester products of a Claisen condensation or Dieckmann cyclization can be hydrolyzed to the β-keto acid and decarboxylated to the ketone.
H H O O O O - CO2 O tautomerization O NaOH, H O C C 2 C C H C H C H3CH2CO C OCH2CH3 O C OH C OH C OH or H O+ H R 3 H R R H R enol carboxylic acid
H H O O O NaOH, H O O O - CO2 O tautomerization C C 2 H CH CO C R' C C H C H C 3 2 + O C R' C R' C R' H R or H3O H R R H R enol ketone
196
100 21.7: Acetoacetic Ester Synthesis. The anion of ethyl
acetoacetate can be alkylated using an alkyl halide (SN2). The product, a β-keto ester, is then hydrolyzed to the β-keto acid and decarboxylated to the ketone.
O O + O O EtO Na HCl, ! C CO Et C CH R C CO2Et + RH2C-X 2 C CO2H 2 H C C H C C H C C H3C C 3 EtOH 3 3 H H RH C H RH C H H H alkyl 2 2 ethyl acetoacetate halide ketone EtO Na+, R'H2C-X EtOH O O O O O HCl, C C ! C CH R H3C C OH 2 C C H3C C H3C C OEt R'H2C CH2R H CH2R' R'H2C CH2R
An acetoacetic ester can undergo one or two alkylations to give an α-substituted or α-disubstituted acetoacetic ester The enolates of acetoacetic esters are synthetic equivalents to ketone enolates 197
β-Keto esters other than ethyl acetoacetate may be used. The products of a Claisen condensation or Dieckmann cyclization are acetoacetic esters (β-keto esters)
O O O O EtONa, + EtONa, EtOH H3O OEt EtOH CO2Et CO2Et O Br ! then H O+ 3 acetoacetic OEt ester Dieckmann cyclization
EtONa, NaOEt O O O EtOH O O + O H H3O H3CH2C C HC C OEt H CH C C C OEt H3CH2C C C CH2CH=CH2 2 H3CH2C C OEt EtOH Br 3 2 C ! + CH3 CH then H3O acetoacetic CH3 3 ester Claisen condensation
198
101 21.8: The Malonic Acid Synthesis. overall reaction
CO2Et EtO Na+ HCl, ! + RH2C-X EtO C CO Et HO2C CO2H 2 2 C RH2C-CH2-CO2H CO Et EtOH C 2 RH C H RH2C H 2 diethyl alkyl carboxylic malonate halide acid Et= ethyl EtO Na+, R'H2C-X EtOH CH2R HCl, ! HO C CO H 2 2 CH CO H EtO2C CO2Et C 2 C RH2C CH2R' R'H2C RH2C CH2R' carboxylic acid
199
O O + H CO + H COH H C 3 H C 3 C CH3 C CH3 pKa= 16 H H H acetoacetic ester pKa= 19
O O O O + H CO + H COH C C 3 C C 3 H3C C OCH3 H3C C OCH3 pKa= 16 H H H acetoacetic ester pKa= 11
O O H C + EtO H C + EtOH C OEt C OEt pKa= 16 H H H ethyl acetate pKa= 25
O O O O C C + EtO + EtOH EtO C OEt C C EtO C OEt pKa= 16 H H H diethyl malonate 200 pKa= 13
102 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 α,β-unsaturated ketones. EtONa, O O O O H H O EtOH C CH2 + C C C C C H C C 3 EtO C CH3 H3C C C CH3 H H H H H H CO2Et electrophile nucleophile
This Michael addition product can be decarboxylated
O H H O + O H H O H3O , ! C C C C C C H3C C C CH3 - EtOH, H3C C C CH3 -CO2 H H H CO2Et H H H H 201
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 O C RH2C-X CH R OEt LDA, THF C 2 OEt -78° C CO2Et
O O O RH C-X LDA, THF 2 CH R O O O 2 -78° C
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103