Chapter 21by

21.
7 The Acetoacetic Ester Synthesis
Dr. Wolf's CHM 201 & 202
21-1
Acetoacetic Ester O H3 C C H C O C H OCH2CH3
Acetoacetic ester is another name for ethyl acetoacetate. acetoacetate. The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones.
21-2
Deprotonation of Ethyl Acetoacetate O H3 C C H C O C H Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. OCH2CH3 + CH3CH2O
pKa ~ 11
21-3
Deprotonation of Ethyl Acetoacetate O H3 C C H pKa ~ 11 O H3 C C C H
O C C H K ~ 105 O C + OCH2CH3 CH3CH2O
Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.
OCH2CH3 + CH3CH2OH pKa ~ 16

21-4
Alkylation of Ethyl Acetoacetate O H3 C C C H R X
O C 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).
21-5
Alkylation of Ethyl Acetoacetate O H3 C C C H R O H3 C C H

OCH2CH3
O C C R 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).
21-6
Conversion to Ketone O H3 C C H C O C OH Saponification and acidification convert the alkylated derivative to the corresponding F-keto acid. The F-keto acid then undergoes decarboxylation to form a ketone.
21-7
R 1. HO, H2O 2. H+ O C C R OCH2CH3
O H3 C C H
Conversion to Ketone O H3 C C H C O C R OH Saponification and acidification convert the alkylated derivative to the corresponding F-keto acid. The F-keto acid then undergoes decarboxylation to form a ketone.
21-8
O H3 C C + CH2R CO2
Example O O
CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br
21-9
Example O O
CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br O O
CH3CCHCOCH2CH3 CH2CH2CH2CH3 (70%)

21-10
Example
O CH3CCH2CH2CH2CH2CH3 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O (60%)
CH3CCHCOCH2CH3 CH2CH2CH2CH3
21-11
Example: Dialkylation
CH3CCHCOCH2CH3 CCH CH2CH CH2
21-12
CH3CCHCOCH2CH3 CCH CH2CH CH2
1. NaOCH2CH3 2. CH3CH2I O O CH3CCCOCH2CH3 CH3CH2

CH2CH
CH2
21-13
(75%)
O CH3CCH CH3CH2 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O CH3CCCOCH2CH3 CH3CH2 CH2CH CH2
21-14
CH2CH
CH2
Another Example
O COCH2CH3 H
F-Keto esters other than ethyl acetoacetate may be used.
21-15
Another Example
O COCH2CH3 H 1. NaOCH2CH3 2. H2C CHCH2Br
O COCH2CH3 CH2CH CH2 (89%)

21-16
Another Example
O COCH2CH3 CH2CH CH2

21-17
Another Example
O H CH2CH CH2 (66%)
1. NaOH, H2O 2. H+ 3. heat, -CO2 O COCH2CH3 CH2CH CH2

21-18
21.8 The Malonic Ester Synthesis
21-19
Malonic Ester O CH3CH2O C H C O C H OCH2CH3
Malonic ester is another name for diethyl malonate. malonate. The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids.
21-20
An Analogy O O O O
CH3CCH2COCH2CH3
CH3CH2OCCH2COCH2CH3 OCC
O CH3CCH2R
O HOCC HOCCH2R
The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids.
21-21
Example
CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. H2C O O CHCH2CH2CH2Br
CH3CH2OCCHCOCH2CH3 CH2CH2CH2CH
CH2
21-22
(85%)
Example
O HOCCH2CH2CH2CH2CH CH2 (75%)
1. NaOH, H2O 2. H+ 3. heat, -CO2 O O
CH3CH2OCCHCOCH2CH3 CH2CH2CH2CH
CH2
21-23
Dialkylation
CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. CH3Br O O (79(79-83%)
CH3CH2OCCHCOCH2CH3 CH3
21-24
Dialkylation
O O
CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH3 1. NaOCH2CH3 2. CH3(CH2)8CH2Br O O
CH3CH2OCCHCOCH2CH3 CH3
21-25
Dialkylation
O O
CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH3 1. NaOH, H2O 2. H+ 3. heat, -CO2 O CH3(CH2)8CH2CHCOH CH3

(61(61-74%)
21-26
Another Example
CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. BrCH2CH2CH2Br BrCH O O
CH3CH2OCCHCOCH2CH3 CH2CH2CH2Br
21-27
Another Example
This product is not isolated, but cyclizes in the presence of sodium ethoxide.
21-28
Another Example
O O CH3CH2OCCCOCH2CH3 H2 C C H2 NaOCH2CH3 O O CH2 (60(60-65%)
21-29
Another Example
O O CH3CH2OCCCOCH2CH3 H2 C C H2 CH2 1. NaOH, H2O 2. H+ 3. heat, -CO2 CO2H CH2 C H2 (80%)

21-30
H C H2 C
Barbiturates
21-31
Barbituric acid is made from diethyl malonate and urea
O COCH2CH3 H2 C COCH2CH3 O + H2 N H2 N C O
21-32
Barbituric acid is made from diethyl malonate and urea O C H2 C C O

O COCH2CH3 H2 C COCH2CH3 H O 1. NaOCH2CH3 2. H+ + H2 N H2 N C O
N C N H (72(72-78%) O
21-33
Barbituric acid is made from diethyl malonate and urea
O COCH2CH3 H2 C COCH2CH3 H O 1. NaOCH2CH3 2. H+ + H2 N H2 N C O
O N
O N O
(72(72-78%)
21-34
Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate
O COCH2CH3 H2 C COCH2CH3 O
1. RX, R NaOCH2CH3 R'X, 2. R'X, R' NaOCH2CH3
O COCH2CH3 C COCH2CH3 O
21-35
Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate
O O R R' O H N O N H R' (H2N)2C O R C COCH2CH3 O COCH2CH3
21-36
Examples
O CH3CH2 CH3CH2 O
H N O N H
5,55,5-Diethylbarbituric acid (barbital; Veronal)
21-37
Examples H3 C CH3CH2CH2CH CH3CH2 O
H N O N H
5-Ethyl-5-(1-methylbutyl)barbituric acid Ethyl- (1(pentobarbital; Nembutal)
21-38
Examples H3 C CH3CH2CH2CH H2 C CHCH2 O
H N O N H
5-Allyl-5-(1-methylbutyl)barbituric acid Allyl- (1(secobarbital; Seconal)
21-39
21.9 Michael Additions of Stabilized Anions
21-40
Stabilized Anions O H3 C C C H O CH3CH2O C C H

OCH2CH3
OCH2CH3
The anions derived by deprotonation of F-keto esters and diethyl malonate are weak bases. Weak bases react with E,Funsaturated carbonyl compounds by conjugate addition.
21-41
Example O O H2 C O CHCCH3
CH3CH2OCCH2COCH2CH3 +
21-42
Example O O H2 C O CHCCH3
CH3CH2OCCH2COCH2CH3 +
KOH, ethanol O O (85%)
CH3CH2OCCHCOCH2CH3 CH2CH2CCH3 O
21-43
Example
O (42%)
CH3CCH2CH2CH2COH
1. KOH, ethanol-water ethanol2. H+ 3. heat O O
CH3CH2OCCHCOCH2CH3 CH2CH2CCH3 O
21-44
21.10 Reactions of LDA-Generated Ester Enolates Lithium diisopropylamide (LDA)
21-45
Deprotonation of Simple Esters Ethyl acetoacetate (pKa ~11) and diethyl malonate (pKa ~13) are completely deprotonated by alkoxide bases. Simple esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts with the original ester, and Claisen condensation occurs. Are there bases strong enough to completely deprotonate simple esters, giving ester enolates quantitatively?
21-46
Lithium diisopropylamide
CH3 Li + H C CH3
CH3 C CH3 H
Lithium dialkylamides are strong bases (just as NaNH2 is a very strong base). Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to carbonyl groups.
21-47
Lithium diisopropylamide (LDA) Lithium diisopropylamide converts simple esters to the corresponding enolate. O CH3CH2CH2COCH3 + pKa ~ 22 O CH3CH2CHCOCH3 +
LiN[CH(CH3)2]2
HN[CH(CH3)2]2 pKa ~ 36
Li
+
21-48
Lithium diisopropylamide (LDA)

Enolates generated from esters and LDA can be alkylated. O CH3CH2CHCOCH3 CH2CH3 O CH3CH2CHCOCH3
CH3CH2I
(92%)
21-49
Aldol addition of ester enolates Ester enolates undergo aldol addition to aldehydes and ketones. O 1. LiNR2, THF CH3COCH2CH3 2. (CH3)2C 3. H3O+ O HO H3 C
C CH2COCH2CH3 CH3 (90%)

21-50
Ketone Enolates Lithium diisopropylamide converts ketones quantitatively to their enolates. O 1. LDA, THF CH3CH2CC(CH3)3 2. CH3CH2CH O 3. H3O+ O CH3CHCC(CH3)3
HOCHCH2CH3
(81%)
21-51
End of Chapter 21
21-52

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21.

7 The Acetoacetic Ester Synthesis

Dr. Wolf's CHM 201 & 202

Acetoacetic Ester O H3 C C H C O C H OCH2CH3

Dr. Wolf's CHM 201 & 202

Deprotonation of Ethyl Acetoacetate O H3 C C H pKa ~ 11 O H3 C C C H

O C C H K ~ 105 O C + OCH2CH3 CH3CH2O

OCH2CH3 + CH3CH2OH pKa ~ 16

Dr. Wolf's CHM 201 & 202

Alkylation of Ethyl Acetoacetate O H3 C C C H R X

Dr. Wolf's CHM 201 & 202

Alkylation of Ethyl Acetoacetate O H3 C C C H R O H3 C C H

R 1. HO, H2O 2. H+ O C C R OCH2CH3

Dr. Wolf's CHM 201 & 202

CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br

Dr. Wolf's CHM 201 & 202

CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br O O

CH3CCHCOCH2CH3 CH2CH2CH2CH3 (70%)

O CH3CCH2CH2CH2CH2CH3 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O (60%)

CH3CCHCOCH2CH3 CCH CH2CH CH2

Dr. Wolf's CHM 201 & 202

CH3CCHCOCH2CH3 CCH CH2CH CH2

1. NaOCH2CH3 2. CH3CH2I O O CH3CCCOCH2CH3 CH3CH2

Dr. Wolf's CHM 201 & 202

F-Keto esters other than ethyl acetoacetate may be used.

Dr. Wolf's CHM 201 & 202

O COCH2CH3 H 1. NaOCH2CH3 2. H2C CHCH2Br

O COCH2CH3 CH2CH CH2 (89%)

Dr. Wolf's CHM 201 & 202

O COCH2CH3 CH2CH CH2

Dr. Wolf's CHM 201 & 202

O H CH2CH CH2 (66%)

1. NaOH, H2O 2. H+ 3. heat, -CO2 O COCH2CH3 CH2CH CH2

Dr. Wolf's CHM 201 & 202

21.8 The Malonic Ester Synthesis

Dr. Wolf's CHM 201 & 202

Malonic Ester O CH3CH2O C H C O C H OCH2CH3

CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. H2C O O CHCH2CH2CH2Br

O HOCCH2CH2CH2CH2CH CH2 (75%)

1. NaOH, H2O 2. H+ 3. heat, -CO2 O O

CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. CH3Br O O (79(79-83%)

CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH3 1. NaOCH2CH3 2. CH3(CH2)8CH2Br O O

CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH3 1. NaOH, H2O 2. H+ 3. heat, -CO2 O CH3(CH2)8CH2CHCOH CH3

CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. BrCH2CH2CH2Br BrCH O O

O O CH3CH2OCCCOCH2CH3 H2 C C H2 NaOCH2CH3 O O CH2 (60(60-65%)

O O CH3CH2OCCCOCH2CH3 H2 C C H2 CH2 1. NaOH, H2O 2. H+ 3. heat, -CO2 CO2H CH2 C H2 (80%)

Dr. Wolf's CHM 201 & 202

Barbituric acid is made from diethyl malonate and urea

Dr. Wolf's CHM 201 & 202

Barbituric acid is made from diethyl malonate and urea O C H2 C C O

O COCH2CH3 H2 C COCH2CH3 H O 1. NaOCH2CH3 2. H+ + H2 N H2 N C O

Barbituric acid is made from diethyl malonate and urea

O COCH2CH3 H2 C COCH2CH3 H O 1. NaOCH2CH3 2. H+ + H2 N H2 N C O

Dr. Wolf's CHM 201 & 202

O O R R' O H N O N H R' (H2N)2C O R C COCH2CH3 O COCH2CH3

Dr. Wolf's CHM 201 & 202

5,55,5-Diethylbarbituric acid (barbital; Veronal)

Dr. Wolf's CHM 201 & 202

Examples H3 C CH3CH2CH2CH CH3CH2 O

5-Ethyl-5-(1-methylbutyl)barbituric acid Ethyl- (1(pentobarbital; Nembutal)

Dr. Wolf's CHM 201 & 202

Examples H3 C CH3CH2CH2CH H2 C CHCH2 O

5-Allyl-5-(1-methylbutyl)barbituric acid Allyl- (1(secobarbital; Seconal)