H 3 C OCH 3 3 C N(CH 3 ) 2 H 3 C H H 3 C CH 3. ketone. pk a = 9 H H. 1,3-keto ester pk a = 11

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1 hapter 21: Ester Enolates 21.1: Ester α ydrogens and Their pk a s. The α-protons of s are less acidic that ketones and aldehydes. Typical pk a s of carbonyl compounds (α-protons): aldehydes 17 ketones s 24 amides 30 nitriles 25 3 N( 3 ) 2 Acidity of 1,3-dicarbonyl compounds 3 3 1,3-di pk a = pk a = ,3-keto pk a = ketone pk a = 19 3 N ,3-diketone pk a = : The laisen ondensation Reaction. Base-promoted condensation of two s to give a β-keto- product 2 3 Et Ethyl acetate NaEt Et 3 2 Et then 3 + Ethyl 3-oxobutanoate (Ethyl acetoacetate) Mechanism (Fig. 21.1, page 884-5) is a nucleophilic acyl substitution of an by an enolate and is related to the mechanism of the aldol condensation

2 21.3: Intramolecular laisen ondensation: The Dieckmann yclization. Dieckmann yclization works best with 1,6-dis, to give a 5-membered cyclic β-keto product, and 1,7-dis to give 6-membered cyclic β-keto product. Et EtNa, Et Et EtNa, Et 2 Et Et Et Mechanism: same as the laisen ondensation 2 Et : Mixed laisen ondensations. Similar restrictions as the mixed aldol condensation. Four possible products Et 3 Et 5 3 EtNa, Et then Et Et 3 Esters with no α-protons can only act as the electrophile 3 2 Et Et Et + 3 Et EtNa, Et then 3 + Et 3 Discrete (in situ) generation of an enolate with LDA 3 Li + Et LDA, TF, Et Et Et then Li + LDA, TF, Et 3 Et Et then Et

3 21.5: Acylation of Ketones with Esters. An alternative to the laisen condensations and Dieckmann cyclization. a) LDA, TF, -78 b) Equivalent to a mixed laisen condensation R 3 - Na +, a) LDA, TF, -78 b) Equivalent to a Dieckmann cyclization Na +, : Ketone Synthesis via β-keto Esters. The β-keto products of a laisen condensation or Dieckmann cyclization can be hydrolyzed to the β-keto acid and decarboxylated to the ketone R Na, 2 or 3 + R - 2 R enol tautomerization R carboxylic acid 3 2 R' R Na, 2 or 3 + R' R - 2 R' R enol tautomerization R' R ketone

4 21.7: Acetoacetic Ester Synthesis. The anion of ethyl acetoacetate can be alkylated using an alkyl halide (S N 2). The product, a β-keto, is then hydrolyzed to the β-keto acid and decarboxylated to the ketone. 3 2 Et + R 2 -X alkyl ethyl acetoacetate halide Et Na + Et 2 Et 3 R 2 Et Na +, Et R' 2 -X 3 Et R' 2 2 R l,! l,! 2 3 R 2 3 R' 2 2 R 3 2 R ketone 3 2 R 2 R' An acetoacetic can undergo one or two alkylations to give an α-substituted or α-disubstituted acetoacetic The enolates of acetoacetic s are synthetic equivalents to 197 ketone enolates β-keto s other than ethyl acetoacetate may be used. The products of a laisen condensation or Dieckmann cyclization are acetoacetic s (β-keto s) Et Et EtNa, Et then Et acetoacetic EtNa, Et Br 2 Et 3 +! Dieckmann cyclization Et NaEt Et then acetoacetic laisen condensation Et 3 EtNa, Et 3 + Br 3 2 Et! =

5 21.8: The Malonic Acid Synthesis. overall reaction 2 Et 2 Et diethyl malonate Et= ethyl + R 2 -X alkyl halide Et Na + Et Et 2 2 Et R 2 Et Na +, Et R' 2 -X Et 2 2 Et l,! l,! 2 2 R R carboxylic acid 2 R 2 R 2 2 R' R' 2 R 2 2 R' carboxylic acid acetoacetic pk a = acetoacetic pk a = Et ethyl acetate pk a = 25 + Et Et + Et Et Et diethyl malonate pk a = 13 + Et Et Et + Et

6 Summary: Malonic synthesis: equivalent to the alkylation of a carboxylic (acetic) acid enolate Acetoacetic synthesis: equivalent to the alkylation of an ketone (acetone) enolate 21.9: Michael Addition of Stablized Anions. Enolates of malonic and acetoacetic s undergo Michael (1,4-) addition to α,β-unsaturated ketones. 3 2 electrophile + Et 3 nucleophile EtNa, Et Et This Michael addition product can be decarboxylated 3 +,! Et, Et : Reactions of LDA-Generated Ester Enolates. Ester enolates can be generated with LDA in TF rapidly and quantitatively. The resulting enolates can undergo carbonyl addition reactions with other s, aldehydes, ketones or alkylation reactions with alkyl halides or tosylates. Et LDA, TF -78 Et R 2 -X 2 R 2 Et LDA, TF -78 R 2 -X 2 R