21.8
Barbiturates
Barbituric acid
is made from
diethyl
malonate and
urea
O
COCH2CH3
H2N
+
H2C
COCH2CH3
O
C
H2 N
O
Barbituric acid
is made from
diethyl
malonate and
urea
O
COCH2CH3
COCH2CH3
C
C
O
N
H
C
O
H2 N
O
N
H2C
H2N
+
H2C
H
C
O
O
(72-78%)
1. NaOCH2CH3
2. H+
Barbituric acid
is made from
diethyl
malonate and
urea
O
COCH2CH3
+
H2C
COCH2CH3
O
N
H
O
H2 N
1. NaOCH2CH3
2. H+
N
O
C
O
H
O
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
O
R
H
N
(H2N)2C
O
R
C
O
R'
O
N
H
COCH2CH3
R'
COCH2CH3
O
Examples
O
CH3CH2
H
N
O
CH3CH2
O
N
H
5,5-Diethylbarbituric acid
(barbital; Veronal)
Examples
H3C
O
CH3CH2CH2CH
H
N
O
CH3CH2
O
N
H
5-Ethyl-5-(1-methylbutyl)barbituric acid
(pentobarbital; Nembutal)
Examples
H3C
O
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
C
O
••
–C
C
OCH2CH3
H
O
C
CH3CH2O
O
••
–C
H
C
OCH2CH3
The anions
derived by
deprotonation of
b-keto esters
and diethyl
malonate are
weak bases.
Weak bases
react with a,bunsaturated
carbonyl
compounds by
conjugate
addition.
Example
O
O
O
CH3CH2OCCH2COCH2CH3 +
H2C
CHCCH3
Example
O
O
O
CH3CH2OCCH2COCH2CH3 +
H2C
CHCCH3
KOH, ethanol
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CCH3
O
(85%)
Example
O
O
CH3CCH2CH2CH2COH
(42%)
1. KOH, ethanol-water
2. H+
3. heat
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CCH3
O
21.10
a-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
CH3
Li
+
H
C
CH3
–
••
N
••
CH3
C
H
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
1. LiNR2, THF
CH3COCH2CH3
2. (CH3)2C
3. H3O+
O
HO
H3C
O
C CH2COCH2CH3
CH3
(90%)
Ketone Enolates
Lithium diisopropylamide converts ketones
quantitatively to their enolates.
O
1. LDA, THF
CH3CH2CC(CH3)3
O
2. CH3CH2CH
3. H3O+
O
CH3CHCC(CH3)3
HOCHCH2CH3
(81%)