21.821.8

BarbituratesBarbiturates

Barbituric acid Barbituric acid is made from is made from diethyl diethyl malonate and malonate and ureaurea

HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

++ CC

HH22NN

OO

HH22NN

HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

++ CC

HH22NN

OO

HH22NN

1. NaOCH1. NaOCH22CHCH33

2. H2. H++

HH22CC

OO

CC

CC

OO

CC

NN

OO

NN

HH

HH

(72-78%)(72-78%)

Barbituric acid Barbituric acid is made from is made from diethyl diethyl malonate and malonate and ureaurea

HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

++ CC

HH22NN

OO

HH22NN

1. NaOCH1. NaOCH22CHCH33

2. H2. H++

OO

OO

NN

OO

NN

HH

HH

(72-78%)(72-78%)

Barbituric acid Barbituric acid is made from is made from diethyl diethyl malonate and malonate and ureaurea

Substituted derivatives of barbituric acid are madeSubstituted derivatives of barbituric acid are madefrom alkylated derivatives of diethyl malonatefrom alkylated derivatives of diethyl malonate

HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

1. 1. RRX,X,NaOCHNaOCH22CHCH33

2. 2. R'R'X,X,NaOCHNaOCH22CHCH33

CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

RR

R'R'

Substituted derivatives of barbituric acid are madeSubstituted derivatives of barbituric acid are madefrom alkylated derivatives of diethyl malonatefrom alkylated derivatives of diethyl malonate

OO

OO

NNOO

NN

HH

HH

RR

R'R'CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

RR

R'R'

(H(H22N)N)22CC OO

ExamplesExamples

OO

OO

NNOO

NN

HH

HH

CHCH33CHCH22

CHCH33CHCH22

5,5-Diethylbarbituric acid5,5-Diethylbarbituric acid(barbital; Veronal)(barbital; Veronal)

ExamplesExamples

OO

OO

NNOO

NN

HH

HH

CHCH33CHCH22

5-Ethyl-5-(1-methylbutyl)barbituric acid5-Ethyl-5-(1-methylbutyl)barbituric acid(pentobarbital; Nembutal)(pentobarbital; Nembutal)

CHCH33CHCH22CHCH22CHCH

HH33CC

ExamplesExamples

OO

OO

NNOO

NN

HH

HH

5-Allyl-5-(1-methylbutyl)barbituric acid5-Allyl-5-(1-methylbutyl)barbituric acid(secobarbital; Seconal)(secobarbital; Seconal)

CHCH33CHCH22CHCH22CHCH

HH33CC

CHCHCHCH22HH22CC

21.921.9

Michael Additions of Stabilized Michael Additions of Stabilized

AnionsAnions

Stabilized AnionsStabilized Anions The anions The anions derived by derived by deprotonation of deprotonation of -keto esters -keto esters and diethyl and diethyl malonate are malonate are weak bases.weak bases.

Weak bases Weak bases react with react with ,,--unsaturated unsaturated carbonyl carbonyl compounds by compounds by conjugate conjugate addition.addition.

CCCC

CCOCHOCH22CHCH33

HH

OO OO

••••––HH33CC

CCCC

CCOCHOCH22CHCH33

HH

OO OO

CHCH33CHCH22OO••••

––

ExampleExample

OO OO

CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33++ HH22CC CHCCHCHCCH33

OO

ExampleExample

KOH, ethanolKOH, ethanol

OO OO

CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33

(85%)(85%)

++ HH22CC CHCCHCHCCH33

OO

CHCH22CHCH22CCHCCH33

OO OO

CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33

OO

ExampleExample

1. KOH, ethanol-water1. KOH, ethanol-water

CHCH22CHCH22CCHCCH33

OO OO

CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33

OO

2. H2. H++

3. heat3. heat

CHCH33CCHCCH22CHCH22CHCH22COHCOH

OOOO

(42%)(42%)

21.1021.10

-Deprotonation of Carbonyl -Deprotonation of Carbonyl

CompoundsCompounds

by Lithium Dialkylamidesby Lithium Dialkylamides

Deprotonation of Simple EstersDeprotonation of Simple Esters

Ethyl acetoacetate (pKa ~11) and diethyl Ethyl acetoacetate (pKa ~11) and diethyl malonate (pKa ~13) are completely malonate (pKa ~13) are completely deprotonated by alkoxide bases.deprotonated by alkoxide bases.

Simple esters (such as ethyl acetate) are not Simple esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts completely deprotonated, the enolate reacts with the original ester, and Claisen with the original ester, and Claisen condensation occurs.condensation occurs.

Are there bases strong enough to completely Are there bases strong enough to completely deprotonate simple esters, giving ester enolates deprotonate simple esters, giving ester enolates quantitatively?quantitatively?

Lithium diisopropylamideLithium diisopropylamide

Lithium dialkylamides are strong bases (just as Lithium dialkylamides are strong bases (just as NaNHNaNH22 is a very strong base). is a very strong base).

Lithium diisopropylamide is a strong base, but Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to because it is sterically hindered, does not add to carbonyl groups.carbonyl groups.

LiLi++

CC NN CC HHHH

CHCH33

CHCH33

CHCH33

CHCH33

••••

••••

––

Lithium diisopropylamide (LDA)Lithium diisopropylamide (LDA)

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

CHCH33CHCH22CHCH22COCHCOCH33

OO

++

ppKKaa ~ 22 ~ 22

LiN[CH(CHLiN[CH(CH33))22]]22

CHCH33CHCH22CHCOCHCHCOCH33

OO

++ HN[CH(CHHN[CH(CH33))22]]22••••

––++ LiLi+

+

ppKKaa ~ 36 ~ 36

Lithium diisopropylamide (LDA)Lithium diisopropylamide (LDA)

Enolates generated from esters and LDA can be Enolates generated from esters and LDA can be alkylated.alkylated.

CHCH33CHCH22CHCOCHCHCOCH33

OO

CHCH33CHCH22CHCOCHCHCOCH33

OO

••••

––

CHCH33CHCH22II

CHCH22CHCH33

(92%)(92%)

Aldol addition of ester enolatesAldol addition of ester enolates

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

CHCH33COCHCOCH22CHCH33

OO1. LiNR1. LiNR22, THF, THF

2. 2. (CH(CH33))22CC OO

3. H3. H33OO++

CCHH33CC

CHCH33

HOHO

CHCH22COCHCOCH22CHCH33

OO

(90%)(90%)

Ketone EnolatesKetone Enolates

Lithium diisopropylamide converts ketones Lithium diisopropylamide converts ketones quantitatively to their enolates.quantitatively to their enolates.

CHCH33CHCH22CC(CHCC(CH33))33

OO1. LDA, THF1. LDA, THF

2. 2. CHCH33CHCH22CHCH OO

3. H3. H33OO++

CHCH33CHCC(CHCHCC(CH33))33

OO

HOCHCHHOCHCH22CHCH33(81%)(81%)