21.6 The Acetoacetic Ester Synthesis

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21.6The Acetoacetic Ester Synthesis
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Acetoacetic Ester

• Acetoacetic ester is another name for ethyl
  acetoacetate.
• The "acetoacetic ester synthesis" uses
  acetoacetic ester as a reactant for the
  preparation of ketones.

3
Deprotonation of Ethyl Acetoacetate


CH3CH2O

• Ethyl acetoacetate can be converted readily to
  its anion with bases such as sodium ethoxide.

pKa 11
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Deprotonation of Ethyl Acetoacetate


CH3CH2O

• Ethyl acetoacetate can be converted readily to
  its anion with bases such as sodium ethoxide.

pKa 11
K 105
CH3CH2OH

pKa 16
5
Alkylation of Ethyl Acetoacetate

• The anion of ethyl acetoacetate can be alkylated
  using an alkyl halide (SN2 primary and
  secondary alkyl halides work best tertiary
  alkyl halides undergo elimination).

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Alkylation of Ethyl Acetoacetate

• The anion of ethyl acetoacetate can be alkylated
  using an alkyl halide (SN2 primary and
  secondary alkyl halides work best tertiary
  alkyl halides undergo elimination).

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Conversion to Ketone

• Saponification and acidification convert the
  alkylated derivative to the corresponding b-keto
  acid.
• The b-keto acid then undergoes decarboxylation to
  form a ketone.

1. HO, H2O
2. H
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Conversion to Ketone

• Saponification and acidification convert the
  alkylated derivative to the corresponding b-keto
  acid.
• The b-keto acid then undergoes decarboxylation to
  form a ketone.

C
CO2
H3C
CH2R
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Example
1. NaOCH2CH3
2. CH3CH2CH2CH2Br
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Example
1. NaOCH2CH3
2. CH3CH2CH2CH2Br
(70)
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Example
(60)
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Example Dialkylation
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Example Dialkylation
1. NaOCH2CH3
2. CH3CH2I
(75)
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Example Dialkylation
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Another Example

• b-Keto esters other than ethyl acetoacetate may
  be used.

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Another Example
1. NaOCH2CH3
(89)
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Another Example
O
COCH2CH3
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Another Example
O
H
(66)
O
COCH2CH3
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21.7The Malonic Ester Synthesis
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Malonic Ester

• Malonic ester is another name for diethyl
  malonate.
• The "malonic ester synthesis" uses diethyl
  malonate as a reactant for the preparation of
  carboxylic acids.

21
An Analogy

• The same procedure by which ethyl acetoacetate
  is used to prepare ketones converts diethyl
  malonate to carboxylic acids.

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Example
1. NaOCH2CH3
2.
(85)
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Example
(75)
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Dialkylation
1. NaOCH2CH3
2. CH3Br
(79-83)
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Dialkylation
CH3CH2OCCCOCH2CH3
CH3(CH2)8CH2
CH3
1. NaOCH2CH3
2. CH3(CH2)8CH2Br
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Dialkylation
CH3CH2OCCCOCH2CH3
CH3(CH2)8CH2
CH3
1. NaOH, H2O
2. H
3. heat, -CO2
(61-74)
CH3(CH2)8CH2CHCOH
CH3
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Another Example
1. NaOCH2CH3
2. BrCH2CH2CH2Br
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Another Example

• This product is not isolated, but cyclizes in
  the presence of sodium ethoxide.

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Another Example
(60-65)
NaOCH2CH3
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Another Example
1. NaOH, H2O
2. H
3. heat, -CO2
(80)