ENOLATES IN ORGANIC

SYNTHESIS

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 ENOLATES IN ORGANIC SYNTHESIS
Recall

Enolate alkylation, Aldol addition and condensation can provide access to a

wide variety of multi-functional compounds, which can lend themselves to
further functionalization in multi-step organic synthesis

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 Enolates in Organic Synthesis
Bases for Generation of Enolates
Inorganic bases: NaOH and KOH in aqueous solution can be employed
(Caution: Ester substrates may be hydrolysed)
Hydride bases: NaH and KH are also common
Alkoxide bases:NaOMe, NaOEt and KO-t-Bu are also effective
Nitrogenous bases:NaNH2, LiNH2, KNH2 can also be employed.
The most effective nitrogenous base, however, is lithium diisopropylamide
(LDA). LDA is a secondary amine-derived base that is soluble in organic
solvents.

+ n-BuLi Li + n-BuH
N H N

Butane
Diisopropylamine LDA
pKa = 40 pKa = 48
LDA is a strong, relatively hindered band therefore non-nucleophilic base.
LDA is readily commercially available.
Its amine by-product (Diisopropylamine) is low-molecular weight, volatile
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 Enolates in Organic Synthesis
Bases for Generation of Enolates
Alternative nitrogenous bases that have attracted wide use include sodium
hexamethyldisilazide (NaHMDS) or lithium hexamethyldisilazide (LiHMDS).
These bases can be generated from the reaction of hexamethyldisilazane
with an appropriate base.

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 Generation of Enolates in Acyclic Systems:
The Challenges
The generation of enolates in unsymmetrical acyclic enolizable carbonyl
compounds has to address two issues of concern:
(i) The site of deprotonation (Regiochemical problem): Thermodynamic vs
Kinetic enolate
(ii) Geometry of enolate formed (Stereochemical problem):E- vs Z-Enolate

Regiochemical Problem
The reaction of unsymmetrical ketones with bases provides regioisomeric
enolates..

With judicious choice of a base and reaction conditions, one regioisomer can predominate. Whereas a
strong base at low temperature favours the kinetic enolate, a weak base at high temperature allows
3:51 PM for equilibriation to occur to favour the thermodynamic enolate 5
 Regioselective Generation of Enolates in Cyclic
Systems
Kinetic vs Thermodynamic Enolate: Depends on the base and the reaction
conditions

Regiospecific Generation of E-Enolates in Cyclic Systems: Dissolving metal

conditions

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 Enolate Alkylation
Malonic Ester Synthesis

Example

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 Enolate Alkylation
Malonic Ester Synthesis

Example
Dialkylation of the malonic ester platform is possible leading to complex
derivatives of synthetic relevance.

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 Aldol Condensation
Aldol condensations involve the nucleophilic addition of an enolate of an
aldehyde or ketone to another aldehyde or ketone with initial formation of a
b-hydroxyaldehyde or ketone, which undergoes dehydration under the
reaction conditions with eventual formation of an a,b-unsaturated aldehyde
or a,b-unsaturated ketone. The product is commonly referred to as an
“Aldol’ condensation product.

The extra stabilization achieved from the conjugation in the a,b-unsaturated

product favours the dehydration step and particularly when the conjugation
is further extended by an aromatic substituent. The a,b-unsaturated
aldehydes or ketones obtained in Aldol condensation reactions are very
important in conjugate addition reactions (Michael addition reactions)

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 Mechanism of the Aldol Condensation
Base-Catalysed Aldol Condensation

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 Stereochemistry of Aldol Condensation
In acyclic systems

Mechanism: E1Cb: Unimolecular Elimination via Conjugate Base

E-Alkenes are the predominant products in Aldol condensation

reactions. 11
 Aldol Condensation
The dehydration step in Aldol condensation reactions become even more
facile when further conjugation can be achieved especially with the use of
aromatic system, wherein additional conjugation to the aromatic nucleus
serves to stabilize the a,b-unsaturated condensation product further.
Consider the industrial synthesis of cinnamaldehyde, wherein only the Aldol
condensation product is isolated since the conjugation in the product is
further extended by the Ph substituent. No Aldol addition product is
isolated.

Cinnamaldehyde occurs naturally In the

cinnamon plant
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 Conjugate Addition of Enolates
Enolates, by virtue of being resonance stabilized, are soft nucleophiles;
consequently they undergo conjugate addition (1,4-addition or Michael
addition) reactions to a,b-unsaturated enones.

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 Conjugate Addition of Enolates

Conjugate additions of enolates generate 1,5-dicarbonyl products like those

employed in intramolecular Aldol condensation reactions.

This conjugate addition is the first step in the Robinson annulation towards
the synthesis of the Wieland Miescher ketone. This is followed by an
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 Robinson Annulation
The Robinson annulation generates a cyclohexenone ring on top of a pre-
existing ring thereby providing a 5-6 or 6-6 ring system.
Robinson annulation involves the following basic steps:
(1) Michael addition \ conjugate addition \ 1,4-addition
(2) Aldol addition
(3) Dehydration (base-catalysed)

O O O
O
NaOCH2CH3 Methyl vinyl ketone (MVK)

Conjugate addition

NaOCH2CH3

O O
Dehydration
HO

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 Robinson Annulation
Preparation of the Wieland-Miescher Ketone
The Wieland Miescher ketone has been employed in the total synthesis of
more than 50 natural products, predominantly steroids possessing possible
biological properties including anticancer, antibacterial and immunodulatory
activities.
O
O
O O
CH3 KOH KOH O
CH3
CH3 or
CH3
O O
H
O Isolable N O
Michael addition product
(MVK) from thermodynamic enolate
(1) H2, Raney Ni

(2) CH3I

OH O
O CH3
CH3 Dehydration O
O
OH
OH - H2O
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Wieland Miescher ketone
 Mannich Reaction
The Mannich reaction is the condensation of an enolizable carbonyl
compound with an iminium ion leading to an a-alkylation through
introduction of a diakylaminomethyl substituent.

The electrophilic (iminum) species is often generated in situ from the reaction
of the parent dialkylamine and formaldehyde in a presence of an acid
catalyst.

Mechanism

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 Mannich Reaction
Thermal elimination of the dialkylaminomethyl ketones formed in the
Mannich reaction provides a-methylene carbonyl compounds.

Alternatively, the elimination to an a-methylene can be accomplished

through a two-step sequence involving the derived quarternary salts

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 Synthetic Applications of the Mannich Reaction
Example

a-Methylene lactones are present in a number of natural products. The

reaction of ester enolates with the Eschenmoser salt was used to introduce
the a-methylene group in the synthesis of vernolepin, a compound with anti-
leukemic activity.

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