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,
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
Pronounced preference for the formation of a trans double bond in the
Claisen-Schmidt condensation of methyl ketones.
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.
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.
2.1.3. Control of Regiochemistry and Stereochemistry of
Mixed Aldol Reactions of Aliphatic Aldehyde and Ketones
2.1.3.1. Lithium Enolates
Kinetic controlled conditions
Directed Aldol Reaction
Cyclic Transition State
E-enolate
Anti-ketol
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 synaldol product is formed. Order: t-butyl>i-propyl>ethyl
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.
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.
Ketones with one tertiary alkyl substituent give mainly the Z-enolate.
However, less highly substituted ketones usually give mixtures of E- and ZEnolates.
Control of stereochemistry of aldol reaction
(1) Control of enolate stereochemistry
(2) enhancement of the stereoselectivity in the addition step.
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.
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
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.
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
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.
Cyclic mechanism
for hydride transfer
E-boron enolate
Z-enolate
Anti-aldol product
Boron enolates parallel lithium enolates in their stereoselectivity but show
enhanced stereoselectivity. (ref. table 2.3)
2.1.3.3. Titanium, Tin, Zirconium Enolates: intermediate between Li+ and covalent
boron enolate.
Z-enolate
Cyclic transition state
N-acyloxazolidinone
Syn-aldol
catalytic
Tin enolates
N-acylthiazolinethiones
E-enolates
Syn-selective
(Cp)2ZrCl2 with lithium enolate
Addition of silyl enol ethers can be catalyzed by (Cp)2Zr2+ species.
The order of stereoselectivity is Bu2B>(Cp)2Zr>Li. These results are consistent
With reactions proceeding through a cyclic transition state.
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.
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.
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.
The oxazolinone substituents R’ direct the approach of the aldehyde.
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.
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.
The s-enantiomer of the product is obtained in high enantiomeric excess with
L-proline,.
L-proline participates in the proton-transfer step.
2.2. Addition reactions of Imines and Iminium Ions.
The reactivity order is C=NR<C=O<[C=NR2]+<[C=OH]+.
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.
The dialkylation reaction can be used in ring closure.
Synthesis of Mannich base
Bis(methylamino)methane
N,N-Dimethylmethyleneammonium idode
“Eschenmoser’s salt”
Thermal elimination of the amines or the derived quaternary salts provides
a-methylene carbonyl compounds.
Vernolepin having antileukemia activity
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.
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.
Decarboxylative condensation is carried out in pyridine, which can not
form an imine intermediate. concerted decarboxylation
Enzyme-Metal Combo Catalysis as a
New Chirotechnology
김만주 교수
포항공대 화학과
2.3. Acylation of Carbanions
Ester self-condensation is Claisen Condensation.
Most acidic species
Final step drives the reaction to completion.
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.
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, and magnesium enolates play an important
role in C-acylation reaction.
Acyl imidazolides are more reactive than esters but not as reactive as acyl halides
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.
Organolithium compounds
Unstabilized ylides give predominantly the Z-alkene whearas stabilized
ylides give mainly the E-alkene. Use of sodium amide or sodium hexamethyldisilylamide as bases gives higher selectivity for Z-alkenes than
with alkyllithium reagent as base.
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.
Z-formation mechansim
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
E . V e d e js , e t a l J . Am . C h e m . S o c ., 1 9 7 3 , 9 5 , 5 7 7 8
R
R
P
R
R'
O
R 3P
O
C
H
C
R
R
H
H
H
R'
The reaction of unstbilized ylide proceeds through early transition state.
That of stabilized ylide proceeds through late transition state.
R'
R
R
C
O
H
H
P
R
R 3P = O
C
H
R'
R'
+
H
R'
S ch lo sser's m o d ificatio n :
ad d itio n o f P h L i
H 3C
H
cis
R'
+ O =PPh3
H
Li
Ph 3 P
+
CH
CH 3
H
CH 3
H
Ph 3 P
R 'C H O
LiO
PhLi
CH 3
Ph 3 P
H
LiO
R'
H 3C
H
O =PPh3 +
H
R'
Ph 3 P
LiO
+
R'
CH 3
t-BuOH
1) HCHO
o
H
H
2) 25 C
R'
tra n s
H 3C
H
CH 2 OH
R'
Phosphonoacetate esters are used to prepare a,b-unsaturated esters:
Wadsworth-Emmons reaction: usually lead to the E-isomer.
b -C a ro te n e
A rb u zo v R e a c tio n
O
(CH 3 O) 3 P
CH 3 I
+
CH 3 O P
CH
OCH
3
3
I
C 2H 5
(CH 3 O) 3 P
+
(CH 3 O) 2
C 2H 5I
C 2H 5
(CH 3 O) 2
P
O
+
CH 3 I
P
O CH
3
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.
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-trimethylsilylsubstituted carbanion to an aldehyde or ketone (Peterson reaction).
The separate elimination step is not necessary because fragmentation of the
intermediate occurs spontaneously.
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.
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
Dimethylsulfonium metylide is less stable than dimethylsulfoxonium methylide,
so it is generated and used at a low temperature.
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.