Transcript 21.6 The Acetoacetic Ester Synthesis

21.6
The Acetoacetic Ester Synthesis
Acetoacetic Ester
H3C
O
O
C
C
H
C
OCH2CH3
H
Acetoacetic ester is another name for ethyl
acetoacetate.
The "acetoacetic ester synthesis" uses
acetoacetic ester as a reactant for the
preparation of ketones.
Deprotonation of Ethyl Acetoacetate
O
H3C
C
O
C
C
H
H
pKa ~ 11
+
OCH2CH3
CH3CH2O
–
Ethyl acetoacetate
can be converted
readily to its anion
with bases such as
sodium ethoxide.
Deprotonation of Ethyl Acetoacetate
O
H3C
C
O
+
C
C
OCH2CH3
H
H
pKa ~ 11
K ~ 105
O
H3C
C
O
••
–C
H
C
CH3CH2O
–
Ethyl acetoacetate
can be converted
readily to its anion
with bases such as
sodium ethoxide.
OCH2CH3 + CH3CH2OH
pKa ~ 16
Alkylation of Ethyl Acetoacetate
O
H3C
C
O
••
–C
C
OCH2CH3
H
R
X
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).
Alkylation of Ethyl Acetoacetate
O
H3C
O
••
C
–C
C
OCH2CH3
H
R
H3C
O
O
C
C
C
H
R
X
OCH2CH3
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).
Conversion to Ketone
O
H3C
C
O
C
H
H3C
C
R
1. HO–, H2O
2. H+
O
O
C
C
C
H
OH
R
OCH2CH3
Saponification and
acidification convert
the alkylated
derivative to the
corresponding b-keto
acid.
The b-keto acid then
undergoes
decarboxylation to
form a ketone.
Conversion to Ketone
O
H3C
C
O
C
H
C
OH
R
O
H3C
C
+
CH2R
CO2
Saponification and
acidification convert
the alkylated
derivative to the
corresponding b-keto
acid.
The b-keto acid then
undergoes
decarboxylation to
form a ketone.
Example
O
O
CH3CCH2COCH2CH3
1. NaOCH2CH3
2. CH3CH2CH2CH2Br
Example
O
O
CH3CCH2COCH2CH3
1. NaOCH2CH3
2. CH3CH2CH2CH2Br
O
O
CH3CCHCOCH2CH3
CH2CH2CH2CH3
(70%)
Example
O
CH3CCH2CH2CH2CH2CH3
1. NaOH, H2O
2. H+
3. heat, -CO2
O
O
CH3CCHCOCH2CH3
CH2CH2CH2CH3
(60%)
Example:
Dialkylation
O
O
CH3CCHCOCH2CH3
CH2CH
CH2
Example:
Dialkylation
O
O
CH3CCHCOCH2CH3
CH2CH
CH2
1. NaOCH2CH3
2. CH3CH2I
O O
CH3CCCOCH2CH3
CH3CH2
CH2CH
(75%)
CH2
Example:
Dialkylation
O
CH3CCH
CH2CH
CH2
CH3CH2
1. NaOH, H2O
2. H+
3. heat, -CO2
O O
CH3CCCOCH2CH3
CH3CH2
CH2CH
CH2
Another
Example
O
O
COCH2CH3
H
b-Keto esters other than ethyl acetoacetate
may be used.
Another
Example
O
O
COCH2CH3
H
1. NaOCH2CH3
2. H2C CHCH2Br
O
O
COCH2CH3
CH2CH
CH2
(89%)
Another
Example
O
O
COCH2CH3
CH2CH
CH2
Another
Example
O
H
CH2CH
O
CH2 (66%)
1. NaOH, H2O
2. H+
3. heat, -CO2
O
COCH2CH3
CH2CH
CH2
21.7
The Malonic Ester Synthesis
Malonic Ester
O
O
C
C
CH3CH2O
H
C
OCH2CH3
H
Malonic ester is another name for diethyl
malonate.
The "malonic ester synthesis" uses diethyl
malonate as a reactant for the preparation of
carboxylic acids.
An Analogy
O
O
O
O
CH3CCH2COCH2CH3
CH3CH2OCCH2COCH2CH3
O
O
CH3CCH2R
HOCCH2R
The same procedure by which ethyl
acetoacetate is used to prepare ketones
converts diethyl malonate to carboxylic acids.
Example
O
O
CH3CH2OCCH2COCH2CH3
1. NaOCH2CH3
2. H2C
O
CHCH2CH2CH2Br
O
CH3CH2OCCHCOCH2CH3
CH2CH2CH2CH
(85%)
CH2
Example
O
HOCCH2CH2CH2CH2CH
CH2 (75%)
1. NaOH, H2O
2. H+
3. heat, -CO2
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CH2CH
CH2
Dialkylation
O
O
CH3CH2OCCH2COCH2CH3
1. NaOCH2CH3
2. CH3Br
O
O
CH3CH2OCCHCOCH2CH3
CH3
(79-83%)
Dialkylation
O O
CH3CH2OCCCOCH2CH3
CH3
CH3(CH2)8CH2
1. NaOCH2CH3
2. CH3(CH2)8CH2Br
O
O
CH3CH2OCCHCOCH2CH3
CH3
Dialkylation
O O
CH3CH2OCCCOCH2CH3
CH3(CH2)8CH2
CH3
1. NaOH, H2O
2. H+
3. heat, -CO2
O
CH3(CH2)8CH2CHCOH
CH3
(61-74%)
Another
Example
O
O
CH3CH2OCCH2COCH2CH3
1. NaOCH2CH3
2. BrCH2CH2CH2Br
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CH2Br
Another
Example
This product is not isolated, but cyclizes in the
presence of sodium ethoxide.
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CH2Br
Another
Example
O O
CH3CH2OCCCOCH2CH3
H2C
CH2
(60-65%)
C
H2
NaOCH2CH3
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CH2Br
Another
Example
O O
CH3CH2OCCCOCH2CH3
H2C
CH2
C
H2
H
1. NaOH, H2O
2. H+
3. heat, -CO2
CO2H
C
H2C
CH2
C
H2
(80%)