2. Reaction of Carbon Nucleophile with Carbonyl Group

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2. Reaction of Carbon Nucleophile with Carbonyl
Group
Introduction aldol and Claisen condensation,
Robinson annulation Wittig reaction, and related
olefination methods
2.1 Aldol Addition and Condensation
Reactions 2.1.1. The General Mechanism
Prototypical aldol addition reaction is the acid-
or base-catalyzed dimerization of ketone and
aldehyde,
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The equilibrium constant for the dehydration
phase is usually favorable, because of the
conjugated a,b-unsaturated carbonyl system that
is formed.
2.1.2 Mixed Aldol condensation with Aromatic
Aldehyde
One of the most general mixed aldol condensation
inovolves the use of aromatic aldehyde with alkyl
ketones or aldehyde.
Non-enolizable
Claisen-Schmidt Condensation
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Pronounced preference for the formation of a
trans double bond in the Claisen-Schmidt
condensation of methyl ketones.
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Base-catalyzed dehydration is slow relative to
the reverse of the addition phase for the
branched-chain isomer.
In base, the straight-chain ketol is the only
intermediate which is dehydrated. The branched
chain ketol reverts to starting material. Under
acid condition, both intermediates are
dehydrated, however, the branched-chain ketol is
formed most rapidly, because of the preference
for acid-catalyzed enolization to give the more
substituted enol.
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Under acid condition, Both intermediates are
dehydrated, however, the branched-chain ketol is
formed most rapidly, because of the preference
for acid-catalyzed enolization to give the more
substituted enol
forms rapidly
major
Base catalysis favors reaction at a methyl
position over a methylene group, whereas acid
catalysis gives the opposite preference.
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2.1.3. Control of Regiochemistry and
Stereochemistry of Mixed Aldol Reactions of
Aliphatic Aldehyde and Ketones
2.1.3.1. Lithium Enolates
Directed Aldol Reaction
Kinetic controlled conditions
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Cyclic Transition State
Anti-ketol
E-enolate
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The enolate formed from 2,2-dimethyl-3-pentanone
under kinetically controlled conditions is the
Z-isomer. Reaction with benzaldehyde gives syn
aldol.
When alkyl substituent of ketone is bulky,
Z-enolate is formed. And syn- aldol product is
formed. Order t-butylgti-propylgtethyl
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The enolate of cyclohexanone reacts with
benzaldehyde are necessarily E-isomers.
Anti-isomer is major.
Because the aldol reaction is reversible, it is
possible to adjust reaction conditions so that
the two stereoisomeric aldol products
equilibriate.
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1) Z-enolate ? syn aldol E-enolate ? anti
aldol 2) When the enolate has no bulky
substituents, stereselectivity is low 3)
Z-enolates are more stereoselctive than
E-enolates. Ref. Table 2.1
For synthetic efficiency, it is useful to add
MgBr2.
The greater stability of the anti-isomer is
attributed to the pseudoequitorial position of
the methyl group in the chair-like chelate. With
larger substituent groups, the thermodynamic
preference for the anti-isomer is still greater.
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Ketones with one tertiary alkyl substituent give
mainly the Z-enolate. However, less highly
substituted ketones usually give mixtures of E-
and Z- Enolates.
Control of stereochemistry of aldol reaction

1. Control of enolate stereochemistry
2. enhancement of the stereoselectivity in the
   addition step.

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For simple ester, the E-enolate is preferred
under kinetic conditions using a strong base
such as LDA in THF. But Inclusion of a
strong cation sovating co-solvent, such as HMPA
favors the Z-enolate.
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With LDA/THF conditions, cyclic transition state,
an open transition state in the presence of an
aprotic dipolar solvent
If R bulky, selectivity is increased
Simple alkyl esters show rather low
stereoselectivity. Highly hindered esters provide
the anti-stereoisomers. See Table 2.2.
HMPA
Z-enolate
Syn-major
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a-alkoxy ester higher stereoselectivity in some
cases it can be explained In terms of a
chelated ester enolate. The aldehyde R group
avoids being between the a-alkoxy and the methyl
group in the ester enolate. When the ester alkyl
group R becomes very bulky, the stereoselectivity
is reversed.
The allylic stabilization of the c-deprotonation
product can lead to kinetic selectivity in the
deprotomation.
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2.1.3.2. Boron Enolates
The stereoselctivity is higher than for lithium
enolates, since the O-B bond distances are
shorter than the O-Li bond in the lithium
enolates, and this leads to a more compact
transition state.
Trifluoromethanesulfonate triflate
Z-isomer
Syn-isomer
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E-boron enolate
Anti-isomer
Use of boron triflates with a more hindered amine
favors the Z-enolate. The E-boron enolates of
some ketone can be preferentially obtained with
the use of dialkylboron chlorides.
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Cyclic mechanism for hydride transfer
Z-enolate
E-boron enolate
Anti-aldol product
Boron enolates parallel lithium enolates in their
stereoselectivity but show enhanced
stereoselectivity. (ref. table 2.3)
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2.1.3.3. Titanium, Tin, Zirconium Enolates
intermediate between Li and covalent boron
enolate.
Z-enolate
Syn-aldol
Cyclic transition state
N-acyloxazolidinone
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catalytic
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Tin enolates
Syn-selective
N-acylthiazolinethiones
E-enolates
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(Cp)2ZrCl2 with lithium enolate
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Addition of silyl enol ethers can be catalyzed by
(Cp)2Zr2 species.
The order of stereoselectivity is
Bu2Bgt(Cp)2ZrgtLi. These results are
consistent With reactions proceeding through a
cyclic transition state.
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2.1.3.4 The Mukaiyama Reaction
Lewis-acid-catalyzed aldol addition reactions of
enol derivatives.
Not a strong enough nucleophile, but with Lewis
acid the reaction proceeds through an acyclic
transition state.
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For a-substituted aldehyde show a preference for
a syn relationship between the a-substituent and
hydroxy group. This is consistence with a
Felkin-Ahn Transition state.
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2.1.3.5. Control of Enantioselectivity
The combined interactions of chiral centers in
both the aldehyde and the enolate determine the
stereoselectivity. The result is called
double stereodifferentiation.
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The oxazolinone substituents R direct the
approach of the aldehyde.
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2.1.4. Intramolecular Aldol Reaction and the
Robinson Annulation
Robinson Annulation is a procedure which
construct a new 6-membered ring from a ketone.
Originally thermodynamic controlled reaction is
required.
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The role of the trimethylsilyl group is to
stabilize the enol formed in the conjugate
addition. The silyl group is then removed during
the dehydration step. It can be used under
aprotic conditions.
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The s-enantiomer of the product is obtained in
high enantiomeric excess with L-proline,.
L-proline participates in the proton-transfer
step.
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2.2. Addition reactions of Imines and Iminium
Ions.
The reactivity order is CNRltCOltCNR2ltCOH.
2.2.1. the Mannich Reaction the condensation of
an enolizable carbonyl compound with an
iminium ion.
The reaction is usually limited to secondary
amines, because dialkylation can occur with
primary amines.
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The dialkylation reaction can be used in ring
closure.
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Synthesis of Mannich base
Bis(methylamino)methane
N,N-Dimethylmethyleneammonium idode Eschenmosers
salt
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Thermal elimination of the amines or the derived
quaternary salts provides a-methylene carbonyl
compounds.
Vernolepin having antileukemia activity
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Tropinone, alkaloid tropine by Sir Rober Robinson
in 1917
2.2.2. Amine-Catalyzed Condensation Reactions
Amine and acid are required mixed aldol followed
by dehydration catalyzed by amine and buffer
system Knoevenagel condensation.
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Malonic ester, cyanoacetic ester, cyanoamide are
examples of compounds which undergo condensation
reactions under Knoevenagel conditions.
Nitroalkanes are also good nucleophilic reagent
in which a hydrogens are deprotonated
under weakly basic conditions.
Secondary amine is used as catalysts, iminium ion
is involved in addition step.
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Decarboxylative condensation is carried out in
pyridine, which can not form an imine
intermediate.? concerted decarboxylation
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2.3. Acylation of Carbanions
Ester self-condensation is Claisen Condensation.
Most acidic species
Final step drives the reaction to completion.
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When a-substituted ester are used, it do not
condense under the normal reaction conditions.
Very strong base converts the ester completely
to its enolate. sodium hydride
Intramolecular version of ester condensation is
called the Dieckmann condensation
Because ester condensation is reversible, product
structure is governed by thermodynamic control
The product is derived from the most stable
enolate.
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Acylation of ester enolates can be carried out
with more reactive acylating agents such as acid
anhydrides and acyl chlorides the reaction must
be done in inert solvents to avoid solvolysis of
the acylating reagent.
N-methoxy-N-methylamides is also useful for
acylation of ester enolates.
Sometimes O-alkylation is problem, magnesium
enolates play an important role in C-acylation
reaction.
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Acyl imidazolides are more reactive than esters
but not as reactive as acyl halides
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2.4 The Wittig and Related Reactions
An ylide is a molecule that has a contributing
Lewis structure with opposite charges on adjacent
atoms, each of which has an octet of electrons.
Phosporus ylides are stable, but usually quite
reactive.
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Organolithium compounds
Unstabilized ylides give predominantly the
Z-alkene whearas stabilized ylides give mainly
the E-alkene. Use of sodium amide or sodium
hexa- methyldisilylamide as bases gives higher
selectivity for Z-alkenes than with alkyllithium
reagent as base.
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The three phenyl substituents on phosphorus
impose large steric demands which govern the
formation of the diastereomeric adducts.
Reactions of unstabilized phosphoranes are
believed to proceed through an early transition
state, and steric factors usually make such
transition states selective for the Z-alkene.
Schlosser modification of the Wittig reaction
the reaction of unstabilized ylide with aldehyde
can be induced to yield E-alkenes with high
stereoselectivity.
b-oxido ylide
Syn-elimination
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Phosphonoacetate esters are used to prepare
a,b-unsaturated esters Wadsworth-Emmons
reaction usually lead to the E-isomer.
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Three modified phosphonoacetate esters have been
found to show selectivity for the Z-enoate
product. Trifluoroethyl, phenyl,
2,6-difluorophenyl esters give good
Z-stereoselectivity.
Carbanions derived form phosphine oxide add to
carbonyl compounds. The adducts are stable but
undergo elimination to form alkenes on heating
with a base such as sodium hydride.
Horner-Wittig reaction.
Usually anti-adduct is the major product, so it
is the Z-alkene which is favored. The syn adduct
is most easily obtained by reduction of b-keto
phosphine oxide.
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2.5 Reactions of Carbonyl Compounds with
a-trimethylsilylcarbanions
b-Hydroxyalkyltrimethylsilanes are converted to
alkenes in either acidic or basic solution. It
begins with nucleophilic addition of an
a-trimethylsilyl- substituted carbanion to an
aldehyde or ketone (Peterson reaction).
The separate elimination step is not necessary
because fragmentation of the intermediate occurs
spontaneously.
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The elimination reactions are anti under acidic
conditions and syn under basic conditions the
result of a cyclic elimination mechanism under
basic conditions, whereas an acyclic
b-elimination under acidic conditions.
The anti-elimination can also be achieved by
converting the b-silyl alcohol to
trifluoroacetate esters.
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2.6 Sulfur Ylide and related Nucleophiles
Sulfur ylides are prepared by deprotonation of
the corresponding sulfonium salts.
Phosphorus ylides Ketone ? alkene
Sulfonium or sulfoxonium ylides ketone ?
epoxide
Intramolecular displacement
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Dimethylsulfonium metylide is less stable than
dimethylsulfoxonium methylide, so it is
generated and used at a low temperature.
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2.7 Nucleophilic Addition-Cyclization
Darzens Reaction The first step is addition of
the enolate of the a-halo ester to the carbonyl
compound followed by intramolecular SN2 reaction.
Trimethylsilyl epoxide can be also preapred by an
addition-cyclization process.
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