Nano product preview march 2009 the applause “ this is a fantastic effort”

Alkylation of Ethyl AcetoacetateAlkylation of Ethyl Acetoacetate C C C OCH2CH3H primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination... Alkylation of

21.7 The Acetoacetic Ester Synthesis

Acetoacetic Ester

Acetoacetic Ester

The "acetoacetic ester synthesis" uses

acetoacetic ester as a reactant for the

Deprotonation of Ethyl Acetoacetate

Deprotonation of Ethyl Acetoacetate

pKa ~ 11 Ethyl acetoacetate can be converted

readily to its anion with bases such as sodium ethoxide

Deprotonation of Ethyl Acetoacetate

Deprotonation of Ethyl Acetoacetate

CH3CH2OC

K ~ 105

Alkylation of Ethyl Acetoacetate

Alkylation of Ethyl Acetoacetate

C

C C OCH2CH3H

primary and secondary alkyl halides work best;

tertiary alkyl halides undergo elimination)

Alkylation of Ethyl Acetoacetate

Alkylation of Ethyl Acetoacetate

C

C C OCH2CH3H

primary and secondary alkyl halides work best;

tertiary alkyl halides undergo elimination)

C

C C OCH2CH3H

H3C

R

Conversion to Ketone

Conversion to Ketone

Saponification and acidification convert the alkylated

derivative to the corresponding -keto acid

The -keto acid then undergoes

decarboxylation to form a ketone

C

C C OCH2CH3H

Conversion to Ketone

Conversion to Ketone

Saponification and acidification convert the alkylated

derivative to the corresponding -keto acid

The -keto acid then undergoes

decarboxylation to form a ketone

1 NaOH, H2O

2 H+

3 heat, -CO2O

Another Example

Another

HCOCH2CH3

-Keto esters other than ethyl acetoacetate

may be used

Another Example

Another

HCOCH2CH3

1 NaOCH2CH3

2 H2C CHCH2Br

OO

CH2CHCOCH2CH3

CH2 (89%)

Another Example

Another Example

OO

COCH2CH3

CH2CH CH2

Another Example

Another

H

OO

21.8 The Malonic Ester Synthesis

Malonic Ester

Malonic Ester

The "malonic ester synthesis" uses diethyl

malonate as a reactant for the preparation of

The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids

CH2CH2CH2CH

CH3CH2OCCHCOCH2CH3

Another Example

Another Example

Another Example

Another Example

This product is not isolated, but cyclizes in the presence of sodium ethoxide

CH2CH2CH2Br

CH3CH2OCCHCOCH2CH3

Another Example

Another Example

Another Example

Another Example

Barbiturates

H2N

O

H2N

OCOCH2CH3

COCH2CH3O

CO

CN

ON

OCOCH2CH3

COCH2CH3O

O

N

ON

Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate

Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate

H2C

OCOCH2CH3

COCH2CH3O

COCH2CH3O

RR'

Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate

Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate

O

O

N

ON

H

HR

OCOCH2CH3

COCH2CH3O

RR'(H2N)2C O

HH

21.9 Michael Additions of Stabilized

Anions

Stabilized Anions

derived by deprotonation of

-keto esters and diethyl malonate are weak bases

Weak bases react with ,-unsaturated carbonyl

compounds by conjugate

addition

C

C C OCH2CH3H

CH3CH2O – ••

(42%)

21.10 Reactions of LDA-Generated Ester Enolates

Lithium diisopropylamide (LDA)

Deprotonation of Simple Esters

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

Lithium diisopropylamide

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

Lithium diisopropylamide (LDA)

Lithium diisopropylamide (LDA)

Lithium diisopropylamide converts simple esters

to the corresponding enolate

Lithium diisopropylamide (LDA)

Lithium diisopropylamide (LDA)

Enolates generated from esters and LDA can be

Aldol addition of ester enolates

Aldol addition of ester enolates

Ester enolates undergo aldol addition to

aldehydes and ketones

Ketone Enolates

Ketone Enolates

Lithium diisopropylamide converts ketones

quantitatively to their enolates

End of Chapter 21