reactions of enolate anions: enolates + electrophiles ii

Reactions of Enolate Anions:Reactions of Enolate Anions: Enolates + Electrophiles II Enolates + Electrophiles II

Condensations: Many Types, and (Other Reactions)Condensations: Many Types, and (Other Reactions)

Condensations:Condensations:

Aldol, Claisen, Dieckmann, Aldol, Claisen, Dieckmann,

Acetoacetic / Malonic esters, etc.Acetoacetic / Malonic esters, etc.

(Decarboxylation)(Decarboxylation)

(Acylation)(Acylation)

(Michael Addition)(Michael Addition)

(Lithium cuprates)(Lithium cuprates)

A chemical definition: Addition with subsequent loss of HA chemical definition: Addition with subsequent loss of H22OO

(eg. Dehydration of (eg. Dehydration of -hydroxy carbonyl compounds)-hydroxy carbonyl compounds)

CondensationCondensation

CC OO

CC

CCOHOH

HHCC OO

CC

CC

Acylation of Ketones with Esters

Acylation of Ketones with Esters

Esters that cannot form an enolate can be used to acylate ketone enolates.

Example

1. NaH1. NaH

2. H2. H33OO++

(60%)(60%)

++CHCH33CHCH22OOCCOCHOCH22CHCH33

OO OO

OO

CCOCHOCH22CHCH33

OO

Example

1. NaOCH1. NaOCH22CHCH33

2. H2. H33OO++

(62-71%)(62-71%)

CCOCHOCH22CHCH33

OO

++

OO

CCHH33CC

OO

OO

CCCCHH22CC

Example

1. NaOCH1. NaOCH33

2. H2. H33OO++

(70-71%)(70-71%)

CHCH33CHCH22CCHCCH22CHCH22COCHCOCH22CHCH33

OO OO

OO

OO

CHCH33

Ketone Synthesis via -Keto Esters

Ketone Synthesis

-Keto acids decarboxylate readily to give ketones.

++

OO

RCHRCH22CCHCCH22RR

OO OO

RCHRCH22CCHCOHCCHCOH

RR

COCO22

Ketone Synthesis

-Keto acids decarboxylate readily to give ketones .-Keto acids are available by hydrolysis of -keto esters.

OO OO

RCHRCH22CCHCOR'CCHCOR'

RR

OO OO

RCHRCH22CCHCOHCCHCOH

RR

HH22OO++ R'OHR'OH

Ketone Synthesis

-Keto acids decarboxylate readily to give ketones .-Keto acids are available by hydrolysis of -keto esters.-Keto esters can be prepared by the Claisen condensation.

2RCH2RCH22COR'COR'

OO1. NaOR'1. NaOR'

2. H2. H33OO++++ R'OHR'OH

OO OO

RCHRCH22CCHCOR'CCHCOR'

RR

Example


2. H2. H33OO++

(80%)(80%)

2 CH2 CH33CHCH22CHCH22CHCH22COCHCOCH22CHCH33

OO

CHCH33CHCH22CHCH22CHCH22CCHCOCHCCHCOCH22CHCH33

OO OO

CHCH22CHCH22CHCH33

Example

1. KOH, H1. KOH, H22O, 70-80°CO, 70-80°C

2. H2. H33OO++

CHCH33CHCH22CHCH22CHCH22CCHCOCHCCHCOCH22CHCH33

OO OO

CHCH22CHCH22CHCH33

CHCH33CHCH22CHCH22CHCH22CCHCOHCCHCOH

OO OO

CHCH22CHCH22CHCH33

Example

70-80°C70-80°C

(81%)(81%)

OO

CHCH33CHCH22CHCH22CHCH22CCHCCH22CHCH22CHCH22CHCH33

CHCH33CHCH22CHCH22CHCH22CCHCOHCCHCOH

OO OO

CHCH22CHCH22CHCH33

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Decarboxylation of 3-Oxocarboxylic Acids

The Acetoacetic Ester Synthesis

Acetoacetic Ester

Acetoacetic ester is another name for ethyl acetoacetate.The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones.

CCCC

CCOCHOCH22CHCH33

HH HH

OO OO

HH33CC

Deprotonation of Ethyl Acetoacetate

CHCH33CHCH22OOCCCC

CCOCHOCH22CHCH33

HH HH

OO OO

HH33CC++ ––

ppKKaa ~ 11 ~ 11Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.

Deprotonation of Ethyl Acetoacetate

ppKKaa ~ 16 ~ 16

CHCH33CHCH22OOCCCC

CCOCHOCH22CHCH33

HH HH

OO OO

HH33CC++

CCCC

CCOCHOCH22CHCH33

HH

OO OO

••••––HH33CC ++ CHCH33CHCH22OHOH

––

ppKKaa ~ 11 ~ 11Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.

KK ~ 10 ~ 1055

Alkylation of Ethyl Acetoacetate

CCCC

CCOCHOCH22CHCH33

HH

OO OO

••••––HH33CC

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).

RR XX

Alkylation of Ethyl Acetoacetate

CCCC

CCOCHOCH22CHCH33

HH

OO OO

••••––HH33CC

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).

RR XX

CCCC

CCOCHOCH22CHCH33

HH

OO OO

HH33CC

RR

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.

CCCC

CCOCHOCH22CHCH33

HH

OO OO

HH33CC

RR

CCCC

CCOHOH

HH

OO OO

HH33CC

RR1. HO1. HO––, H, H22OO2. H2. H++

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.

CCCC

CCOHOH

HH

OO OO

HH33CC

RR

CCCHCH22RR

COCO22

OO

HH33CC++

Example


2. 2. CHCH33CHCH22CHCH22CHCH22BrBr

OO OO

CHCH33CCHCCH22COCHCOCH22CHCH33

Example

(70%)(70%)


2. 2. CHCH33CHCH22CHCH22CHCH22BrBr

OO OO


OO OO

CHCH33CCHCOCHCCHCOCH22CHCH33

CHCH22CHCH22CHCH22CHCH33

Example

(60%)(60%)

OO

CHCH33CCHCCH22CHCH22CHCH22CHCH22CHCH33

1. NaOH, H1. NaOH, H22OO2. H2. H++

3. heat, -CO3. heat, -CO22

OO OO

CHCH33CCHCOCHCCHCOCH22CHCH33

CHCH22CHCH22CHCH22CHCH33

Example: Dialkylation OO OO

CHCH33CCCCHHCOCHCOCH22CHCH33

CHCH22CHCH CHCH22

Example: Dialkylation


2. 2. CHCH33CHCH22II

OO OO

CHCH33CCCCHHCOCHCOCH22CHCH33

CHCH22CHCH CHCH22

OO

CHCH33CCCOCHCCCOCH22CHCH33

CHCH22CHCH CHCH22

OO

CHCH33CHCH22

(75%)(75%)



OO

CHCH33CCCOCHCCCOCH22CHCH33

CHCH22CHCH CHCH22

OO

CHCH33CHCH22

Example: Dialkylation CHCH33CCHCCH CHCH22CHCH CHCH22

OO

CHCH33CHCH22

Another Example OO OO

HH

COCHCOCH22CHCH33

-Keto esters other than ethyl acetoacetate may be used.

Another Example OO OO

HH

COCHCOCH22CHCH33


2. 2. HH22CC CHCHCHCH22BrBr

OO OO

CHCH22CHCH

COCHCOCH22CHCH33

CHCH22(89%)(89%)

Another Example

OO OOCOCHCOCH22CHCH33

CHCH22CHCH CHCH22

Another Example OO

HH

OO OOCOCHCOCH22CHCH33

CHCH22CHCH CHCH22



CHCH22CHCH CHCH22 (66%)(66%)

The Malonic Ester Synthesis

Malonic Ester

Malonic ester is another name for diethyl malonate.The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids.

CCCC

CCOCHOCH22CHCH33

HH HH

OO OO

CHCH33CHCH22OO

An Analogy

OO OO


OO OO

CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33

OO

CHCH33CCHCCH22RR

OO

HOCCHHOCCH22RR

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

Example


OO OO


HH22CC CHCHCHCH22CHCH22CHCH22BrBr2.2.

CHCH22CHCH22CHCH22CHCH22CHCH

OO OO

CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33

(85%)(85%)

Example

(75%)(75%)



CHCH22CHCH22CHCH22CHCH CHCH22

OO OO


OO

HOCCHHOCCH22CHCH22CHCH22CHCH22CHCH CHCH22

Dialkylation


OO OO


2. 2. CHCH33BrBr

CHCH33

OO OO

CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33 (79-83%)(79-83%)

Dialkylation


OO OO

CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33

2. 2. CHCH33(CH(CH22))88CHCH22BrBr

CHCH33CHCH33(CH(CH22))88CHCH22

CHCH33

OO OO


Dialkylation OO OO


CHCH33

OO

CHCH33(CH(CH22))88CHCH22CHCOHCHCOH

CHCH33CHCH33(CH(CH22))88CHCH22



(61-74%)(61-74%)

Another Example


OO OO


2. Br2. BrCHCH22CHCH22CHCH22BrBr

CHCH22CHCH22CHCH22BrBr

OO OO


Another Example

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


OO OO


Another Example

NaOCHNaOCH22CHCH33


OO OO


OO OO


HH22CC CHCH22

CCHH22

(60-65%)(60-65%)

Another Example

OO OO


HH22CC CHCH22

CCHH22 1. NaOH, H1. NaOH, H22OO

2. H2. H++


HH22CC CHCH22

CCHH22

CC

HH COCO22HH

(80%)(80%)

Barbiturates

Barbituric acid is made from diethyl malonate and urea

HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

++ CC

HH22NN

OO

HH22NN

HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

++ CC

HH22NN

OO

HH22NN


2. H2. H++HH22CC

OO

CC

CC

OO

CC

NN

OO

NN

HH

HH

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


HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

++ CC

HH22NN

OO

HH22NN


2. H2. H++

OO

OONN

OO

NN

HH

HH

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


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

OO

OONN

OONN

HH

HHRR

R'R'CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

RR

R'R'

(H(H22N)N)22CC OO

Examples

OO

OONN

OONN

HH

HHCHCH33CHCH22

CHCH33CHCH22

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

Examples

OO

OONN

OONN

HH

HH

CHCH33CHCH22

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

CHCH33CHCH22CHCH22CHCH

HH33CC

Examples

OO

OONN

OONN

HH

HH

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

CHCH33CHCH22CHCH22CHCH

HH33CC

CHCHCHCH22HH22CC

Addition of Carbanions toAddition of Carbanions to-Unsaturated Carbonyl Compounds:-Unsaturated Carbonyl Compounds:

The Michael ReactionThe Michael Reaction

Stabilized carbanions, such as those derived from -diketones undergo conjugateaddition to ,-unsaturated ketones.

Michael AdditionMichael Addition

ExampleExample

(85%)(85%)

OO

HH22CC CHCCHCHCCH33

CHCH33

OO

OO

OO

CHCH33

OO

OO

CHCH22CHCH22CCHCCH33

KOH, methanolKOH, methanol

++

The Stork Enamine Reaction

Enamines are used in place of enolates in Michael reactions

The Michael reaction is a useful method forforming carbon-carbon bonds.

It is also useful in that the product of the reaction can undergo an intramolecularaldol condensation to form a six-membered ring. One such application is called the Robinsonannulation.

Michael AdditionMichael Addition

ExampleExample

OO

CHCH33

OO

OO


NaOHNaOHheatheat

OHOH

OO CHCH33

OO

not isolated;not isolated;dehydrates under dehydrates under reaction conditionsreaction conditions

ExampleExample

(85%)(85%)

OO

CHCH33

OO

OO


NaOHNaOHheatheat

OO

OO

CHCH33

OHOH

OO CHCH33

OO

Michael Additions of Stabilized Anions

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

CCCC

CCOCHOCH22CHCH33

HH

OO OO

••••––HH33CC

CCCC

CCOCHOCH22CHCH33

HH

OO OO

CHCH33CHCH22OO••••

––

Example

OO OO

CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33 ++ HH22CC CHCCHCHCCH33

OO

Example

KOH, ethanolKOH, ethanol

OO OO


(85%)(85%)

++ HH22CC CHCCHCHCCH33

OO


OO OO


OO

Example

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


OO OO


OO

2. H2. H++

3. heat3. heat

CHCH33CCHCCH22CHCH22CHCH22COHCOH

OOOO

(42%)(42%)

Conjugate Addition of Organocopper Conjugate Addition of Organocopper Reagents to Reagents to

-Unsaturated Carbonyl Compounds-Unsaturated Carbonyl Compounds

The main use of organocopper reagents is toform carbon-carbon bonds by conjugate addition to ,-unsaturated ketones.

Addition of Organocopper Reagents toAddition of Organocopper Reagents to-Unsaturated Aldehydes and Ketones-Unsaturated Aldehydes and Ketones

ExampleExampleOO

CHCH33

(98%)(98%)

++ LiCu(LiCu(CHCH33))22

OO

CHCH33

CHCH33

1. diethyl ether1. diethyl ether2. H2. H22OO

reactions of enolate anions: enolates + electrophiles ii

Documents

corresponding bketo

hydrolysis of b

dehydration of b

preparation of ketones

secondary alkyl halides

tertiary alkyl halides

estersacylation of ketones

acetoacetic malonic