reactions of enolate anions: enolates + electrophiles ii
DESCRIPTION
Reactions of Enolate Anions: Enolates + Electrophiles II. Condensations: Many Types, and (Other Reactions). Condensations: Aldol, Claisen, Dieckmann, Acetoacetic / Malonic esters, etc. (Decarboxylation) (Acylation) (Michael Addition) (Lithium cuprates). C. C. O. O. H. C. C. OH. - PowerPoint PPT PresentationTRANSCRIPT
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Reactions of Enolate Anions:Reactions of Enolate Anions: Enolates + Electrophiles II Enolates + Electrophiles II
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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)
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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
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Acylation of Ketones with Esters
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Acylation of Ketones with Esters
Esters that cannot form an enolate can be used to acylate ketone enolates.
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Example
1. NaH1. NaH
2. H2. H33OO++
(60%)(60%)
++CHCH33CHCH22OOCCOCHOCH22CHCH33
OO OO
OO
CCOCHOCH22CHCH33
OO
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Example
1. NaOCH1. NaOCH22CHCH33
2. H2. H33OO++
(62-71%)(62-71%)
CCOCHOCH22CHCH33
OO
++
OO
CCHH33CC
OO
OO
CCCCHH22CC
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Example
1. NaOCH1. NaOCH33
2. H2. H33OO++
(70-71%)(70-71%)
CHCH33CHCH22CCHCCH22CHCH22COCHCOCH22CHCH33
OO OO
OO
OO
CHCH33
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Ketone Synthesis via -Keto Esters
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Ketone Synthesis
-Keto acids decarboxylate readily to give ketones.
++
OO
RCHRCH22CCHCCH22RR
OO OO
RCHRCH22CCHCOHCCHCOH
RR
COCO22
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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
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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
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Example
1. NaOCH1. NaOCH22CHCH33
2. H2. H33OO++
(80%)(80%)
2 CH2 CH33CHCH22CHCH22CHCH22COCHCOCH22CHCH33
OO
CHCH33CHCH22CHCH22CHCH22CCHCOCHCCHCOCH22CHCH33
OO OO
CHCH22CHCH22CHCH33
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Example
1. KOH, H1. KOH, H22O, 70-80°CO, 70-80°C
2. H2. H33OO++
CHCH33CHCH22CHCH22CHCH22CCHCOCHCCHCOCH22CHCH33
OO OO
CHCH22CHCH22CHCH33
CHCH33CHCH22CHCH22CHCH22CCHCOHCCHCOH
OO OO
CHCH22CHCH22CHCH33
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Example
70-80°C70-80°C
(81%)(81%)
OO
CHCH33CHCH22CHCH22CHCH22CCHCCH22CHCH22CHCH22CHCH33
CHCH33CHCH22CHCH22CHCH22CCHCOHCCHCOH
OO OO
CHCH22CHCH22CHCH33
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QuickTime™ and aGraphics decompressor
are needed to see this picture.
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Decarboxylation of 3-Oxocarboxylic Acids
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The Acetoacetic Ester Synthesis
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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
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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.
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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
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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
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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
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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++
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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++
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Example
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CCHCCH22COCHCOCH22CHCH33
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Example
(70%)(70%)
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CCHCCH22COCHCOCH22CHCH33
OO OO
CHCH33CCHCOCHCCHCOCH22CHCH33
CHCH22CHCH22CHCH22CHCH33
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Example
(60%)(60%)
OO
CHCH33CCHCCH22CHCH22CHCH22CHCH22CHCH33
1. NaOH, H1. NaOH, H22OO2. H2. H++
3. heat, -CO3. heat, -CO22
OO OO
CHCH33CCHCOCHCCHCOCH22CHCH33
CHCH22CHCH22CHCH22CHCH33
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Example: Dialkylation OO OO
CHCH33CCCCHHCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
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Example: Dialkylation
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22II
OO OO
CHCH33CCCCHHCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CCCOCHCCCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CHCH22
(75%)(75%)
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1. NaOH, H1. NaOH, H22OO2. H2. H++
3. heat, -CO3. heat, -CO22
OO
CHCH33CCCOCHCCCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CHCH22
Example: Dialkylation CHCH33CCHCCH CHCH22CHCH CHCH22
OO
CHCH33CHCH22
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Another Example OO OO
HH
COCHCOCH22CHCH33
-Keto esters other than ethyl acetoacetate may be used.
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Another Example OO OO
HH
COCHCOCH22CHCH33
1. NaOCH1. NaOCH22CHCH33
2. 2. HH22CC CHCHCHCH22BrBr
OO OO
CHCH22CHCH
COCHCOCH22CHCH33
CHCH22(89%)(89%)
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Another Example
OO OOCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
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Another Example OO
HH
OO OOCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
1. NaOH, H1. NaOH, H22OO2. H2. H++
3. heat, -CO3. heat, -CO22
CHCH22CHCH CHCH22 (66%)(66%)
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The Malonic Ester Synthesis
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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
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An Analogy
OO OO
CHCH33CCHCCH22COCHCOCH22CHCH33
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.
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Example
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
HH22CC CHCHCHCH22CHCH22CHCH22BrBr2.2.
CHCH22CHCH22CHCH22CHCH22CHCH
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
(85%)(85%)
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Example
(75%)(75%)
1. NaOH, H1. NaOH, H22OO2. H2. H++
3. heat, -CO3. heat, -CO22
CHCH22CHCH22CHCH22CHCH CHCH22
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
HOCCHHOCCH22CHCH22CHCH22CHCH22CHCH CHCH22
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QuickTime™ and aGraphics decompressor
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Dialkylation
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
2. 2. CHCH33BrBr
CHCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33 (79-83%)(79-83%)
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Dialkylation
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
2. 2. CHCH33(CH(CH22))88CHCH22BrBr
CHCH33CHCH33(CH(CH22))88CHCH22
CHCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
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Dialkylation OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
CHCH33
OO
CHCH33(CH(CH22))88CHCH22CHCOHCHCOH
CHCH33CHCH33(CH(CH22))88CHCH22
1. NaOH, H1. NaOH, H22OO2. H2. H++
3. heat, -CO3. heat, -CO22
(61-74%)(61-74%)
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Another Example
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
2. Br2. BrCHCH22CHCH22CHCH22BrBr
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
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Another Example
This product is not isolated, but cyclizes in the presence of sodium ethoxide.
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
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Another Example
NaOCHNaOCH22CHCH33
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
HH22CC CHCH22
CCHH22
(60-65%)(60-65%)
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Another Example
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
HH22CC CHCH22
CCHH22 1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
HH22CC CHCH22
CCHH22
CC
HH COCO22HH
(80%)(80%)
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Barbiturates
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Barbituric acid is made from diethyl malonate and urea
HH22CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
++ CC
HH22NN
OO
HH22NN
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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 is made from diethyl malonate and urea
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HH22CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
++ CC
HH22NN
OO
HH22NN
1. NaOCH1. NaOCH22CHCH33
2. H2. H++
OO
OONN
OO
NN
HH
HH
(72-78%)(72-78%)
Barbituric acid is made from diethyl malonate and urea
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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'
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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
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Examples
OO
OONN
OONN
HH
HHCHCH33CHCH22
CHCH33CHCH22
5,5-Diethylbarbituric acid5,5-Diethylbarbituric acid(barbital; Veronal)(barbital; Veronal)
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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
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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
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Addition of Carbanions toAddition of Carbanions to-Unsaturated Carbonyl Compounds:-Unsaturated Carbonyl Compounds:
The Michael ReactionThe Michael Reaction
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Stabilized carbanions, such as those derived from -diketones undergo conjugateaddition to ,-unsaturated ketones.
Michael AdditionMichael Addition
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ExampleExample
(85%)(85%)
OO
HH22CC CHCCHCHCCH33
CHCH33
OO
OO
OO
CHCH33
OO
OO
CHCH22CHCH22CCHCCH33
KOH, methanolKOH, methanol
++
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The Stork Enamine Reaction
Enamines are used in place of enolates in Michael reactions
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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
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ExampleExample
OO
CHCH33
OO
OO
CHCH22CHCH22CCHCCH33
NaOHNaOHheatheat
OHOH
OO CHCH33
OO
not isolated;not isolated;dehydrates under dehydrates under reaction conditionsreaction conditions
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ExampleExample
(85%)(85%)
OO
CHCH33
OO
OO
CHCH22CHCH22CCHCCH33
NaOHNaOHheatheat
OO
OO
CHCH33
OHOH
OO CHCH33
OO
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Michael Additions of Stabilized Anions
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QuickTime™ and aGraphics decompressor
are needed to see this picture.
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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••••
––
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Example
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33 ++ HH22CC CHCCHCHCCH33
OO
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Example
KOH, ethanolKOH, ethanol
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
(85%)(85%)
++ HH22CC CHCCHCHCCH33
OO
CHCH22CHCH22CCHCCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
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Example
1. KOH, ethanol-water1. KOH, ethanol-water
CHCH22CHCH22CCHCCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
2. H2. H++
3. heat3. heat
CHCH33CCHCCH22CHCH22CHCH22COHCOH
OOOO
(42%)(42%)
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Conjugate Addition of Organocopper Conjugate Addition of Organocopper Reagents to Reagents to
-Unsaturated Carbonyl Compounds-Unsaturated Carbonyl Compounds
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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
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ExampleExampleOO
CHCH33
(98%)(98%)
++ LiCu(LiCu(CHCH33))22
OO
CHCH33
CHCH33
1. diethyl ether1. diethyl ether2. H2. H22OO