21.

8
Barbiturates

Barbituric acid
is made from
diethyl
malonate and
urea

O
COCH2CH3

H2N
+

H2C
COCH2CH3
O

C
H2N

Barbituric acid
is made from
diethyl
malonate and
urea
O

COCH2CH3
COCH2CH3

C
C

N
H

H2N

H2C

H2N
+

H2C

H
C

(72-78%)

1. NaOCH2CH3
2. H+

Barbituric acid
is made from
diethyl
malonate and
urea

O
COCH2CH3

H2C
COCH2CH3

O
N
H

H2N

1. NaOCH2CH3
2. H+

H2N

(72-78%)

Substituted derivatives of barbituric acid are made

from alkylated derivatives of diethyl malonate
O
COCH2CH3
H2C
COCH2CH3
O

O
1. RX,
NaOCH2CH3 R
2. R'X,
R'
NaOCH2CH3

COCH2CH3
C
COCH2CH3
O

Substituted derivatives of barbituric acid are made

from alkylated derivatives of diethyl malonate
O

H
N
O

R'
O

N
H

(H2N)2C

R
R'

COCH2CH3
C
COCH2CH3
O

Examples

CH3CH2

H
N
O

CH3CH2
O

N
H

5,5-Diethylbarbituric acid
(barbital; Veronal)

Examples
H3C

CH3CH2CH2CH

H
N
O

CH3CH2
O

N
H

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

Examples
H3C

CH3CH2CH2CH
H2C

H
N
O

CHCH2
O

N
H

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

21.9
Michael Additions of Stabilized
Anions

Stabilized Anions
O
H3C

OCH2CH3

H
O
CH3CH2O

C
H

OCH2CH3

The anions
derived by
deprotonation of
-keto esters
and diethyl
malonate are
weak bases.
Weak bases
react with ,unsaturated
carbonyl
compounds by
conjugate
addition.

Example
O

CH3CH2OCCH2COCH2CH3

H2C

CHCCH3

Example
O

CH3CH2OCCH2COCH2CH3

H2C

CHCCH3

KOH, ethanol
O

CH3CH2OCCHCOCH2CH3
CH2CH2CCH3
O

(85%)

Example

CH3CCH2CH2CH2COH

(42%)

1. KOH, ethanol-water
2. H+
3. heat
O

CH3CH2OCCHCOCH2CH3
CH2CH2CCH3
O

21.10
-Deprotonation of Carbonyl
Compounds
by Lithium Dialkylamides

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?

Lithium diisopropylamide

Li

CH3
H

C
CH3

CH3
C

CH3

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.

Lithium diisopropylamide (LDA)

Lithium diisopropylamide converts simple esters
to the corresponding enolate.
O
CH3CH2CH2COCH3

+ LiN[CH(CH3)2]2

pKa ~ 22
O

CH3CH2CHCOCH3

+ HN[CH(CH3)2]2
pKa ~ 36

Li

Lithium diisopropylamide (LDA)

Enolates generated from esters and LDA can be
alkylated.
O
CH3CH2CHCOCH3
CH2CH3
O

CH3CH2CHCOCH3

CH3CH2I

(92%)

Aldol addition of ester enolates

Ester enolates undergo aldol addition to
aldehydes and ketones.
O
CH3COCH2CH3

1. LiNR2, THF
2. (CH3)2C
3. H3O+

O
HO
H3C

C CH2COCH2CH3
CH3

(90%)

Ketone Enolates
Lithium diisopropylamide converts ketones
quantitatively to their enolates.
O
CH3CH2CC(CH3)3

1. LDA, THF
O
2. CH3CH2CH
3. H3O+
O
CH3CHCC(CH3)3
HOCHCH2CH3

(81%)