Reactions of Enolate Anions: Enolates Electrophiles II

1
Reactions of Enolate Anions Enolates
Electrophiles II
2
Condensations Many Types, and (Other Reactions)

• Condensations
• Aldol, Claisen, Dieckmann,
• Acetoacetic / Malonic esters, etc.
• (Decarboxylation)
• (Acylation)
• (Michael Addition)
• (Lithium cuprates)

3
Condensation

• A chemical definition Addition with subsequent
  loss of H2O
• (eg. Dehydration of b-hydroxy carbonyl compounds)

4
Acylation of Ketones with Esters
5
Acylation of Ketones with Esters

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

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Example

1. NaH
2. H3O
(60)
7
Example

1. NaOCH2CH3
2. H3O
O
(62-71)
8
Example
1. NaOCH3
2. H3O
(70-71)
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Ketone Synthesis via b-Keto Esters
10
Ketone Synthesis

RCH2CCH2R
CO2

• b-Keto acids decarboxylate readily to give
  ketones.

11
Ketone Synthesis
H2O

R'OH

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

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Ketone Synthesis
1. NaOR'

R'OH
2. H3O

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

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Example
1. NaOCH2CH3
2. H3O
(80)
14
Example
1. KOH, H2O, 70-80C
2. H3O
15
Example
70-80C
(81)
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Decarboxylation of 3-Oxocarboxylic Acids
18
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.

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Deprotonation of Ethyl Acetoacetate


CH3CH2O

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

pKa 11
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Deprotonation of Ethyl Acetoacetate


CH3CH2O

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

pKa 11
K 105
CH3CH2OH

pKa 16
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Alkylation of Ethyl Acetoacetate

• 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).

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Alkylation of Ethyl Acetoacetate

• 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).

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Conversion to Ketone

• Saponification and acidification convert the
  alkylated derivative to the corresponding b-keto
  acid.
• The b-keto acid then undergoes decarboxylation to
  form a ketone.

1. HO, H2O
2. H
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Conversion to Ketone

• Saponification and acidification convert the
  alkylated derivative to the corresponding b-keto
  acid.
• The b-keto acid then undergoes decarboxylation to
  form a ketone.

C
CO2
H3C
CH2R
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Example
1. NaOCH2CH3
2. CH3CH2CH2CH2Br
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Example
1. NaOCH2CH3
2. CH3CH2CH2CH2Br
(70)
28
Example
(60)
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Example Dialkylation
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Example Dialkylation
1. NaOCH2CH3
2. CH3CH2I
(75)
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Example Dialkylation
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Another Example

• b-Keto esters other than ethyl acetoacetate may
  be used.

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Another Example
1. NaOCH2CH3
(89)
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Another Example
O
COCH2CH3
35
Another Example
O
H
(66)
O
COCH2CH3
36
The Malonic Ester Synthesis
37
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.

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An Analogy

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

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Example
1. NaOCH2CH3
2.
(85)
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Example
(75)
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Dialkylation
1. NaOCH2CH3
2. CH3Br
(79-83)
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Dialkylation
CH3CH2OCCCOCH2CH3
CH3(CH2)8CH2
CH3
1. NaOCH2CH3
2. CH3(CH2)8CH2Br
44
Dialkylation
CH3CH2OCCCOCH2CH3
CH3(CH2)8CH2
CH3
1. NaOH, H2O
2. H
3. heat, -CO2
(61-74)
CH3(CH2)8CH2CHCOH
CH3
45
Another Example
1. NaOCH2CH3
2. BrCH2CH2CH2Br
46
Another Example

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

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Another Example
(60-65)
NaOCH2CH3
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Another Example
1. NaOH, H2O
2. H
3. heat, -CO2
(80)
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Barbiturates
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Barbituric acid is made from diethyl malonate and
urea

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Barbituric acid is made from diethyl malonate and
urea

1. NaOCH2CH3
2. H
(72-78)
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Barbituric acid is made from diethyl malonate and
urea

H
O
1. NaOCH2CH3
N
2. H
O
N
O
(72-78)
H
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Substituted derivatives of barbituric acid are
madefrom alkylated derivatives of diethyl
malonate
1. RX, NaOCH2CH3
2. R'X, NaOCH2CH3
54
Substituted derivatives of barbituric acid are
madefrom alkylated derivatives of diethyl
malonate
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Examples
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Examples
O
H
N
O
CH3CH2
N
H
O
5-Ethyl-5-(1-methylbutyl)barbituric
acid(pentobarbital Nembutal)
57
Examples
O
H
N
O
N
H
O
5-Allyl-5-(1-methylbutyl)barbituric
acid(secobarbital Seconal)
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Addition of Carbanions toa,b-Unsaturated
Carbonyl CompoundsThe Michael Reaction
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Michael Addition

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

60
Example


KOH, methanol
(85)
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The Stork Enamine Reaction
Enamines are used in place of enolates in Michael
reactions
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Michael Addition

• 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
  .

63
Example
NaOHheat
not isolateddehydrates under reaction conditions
64
Example
NaOHheat
(85)
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Michael Additions of Stabilized Anions
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Stabilized Anions

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

69
Example

70
Example

KOH, ethanol
(85)
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Example
O
(42)
1. KOH, ethanol-water
2. H
3. heat
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Conjugate Addition of Organocopper Reagents to
a,b-Unsaturated Carbonyl Compounds
74
Addition of Organocopper Reagents
toa,b-Unsaturated Aldehydes and Ketones

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

75
Example

LiCu(CH3)2
(98)