ENOLS AND ENOLATES

Marino Petrini
Advanced Organic Chemistry
Chemistry and Advanced Chemical
Methodologies

ACIDITY OF CARBON-HYDROGEN BONDS

O
O Li
pKa = 20
N N
H
Li H
O
O Li
pKa = 25 OEt
N OEt N
H
Li H
Na
O O O O
EtOH
pKa = 11 OEt EtONa
OEt
H

O O Na
N THF
NaH N
pKa = 10 O O
H
O
O Li
H
pKa = 17 N N
Li
H
 The nature of the base used affects the equilibrium:

O
K < 1 O Na
R EtONa
EtOH
R
H

O
K> 1 O K
R t -BuOK t-BuOH
R
H

The following basic systems have pKa >30 and are able to completely convert the
carbonyl derivative into the corresponding enolate anion:

Organometallic systems such as BuLi are strong bases and are used to generate
non nucleophilic lithium amides.

N n-BuLi N n-BuH
H Li

REGIOSELECTIVITY IN THE ENOLATE FORMATION

Unsymmetrical ketones may generate regioisomeric mixtures of enolate anions:

 KINETIC CONTROL

The LESS substituted enolate is preferentially formed (deprotonation of less hindered

hydrogen atoms is faster).

Deprotonation should be: RAPID

QUANTITATIVE
IRREVERSIBLE
O

ka + BH

O
+ B

O
ka >> kb kb
+ BH

Experimental conditions for a good KINETIC CONTROL:

BASE STRONG LDA, LTMP, LHMDS,

SOLVENT POLAR APROTIC THF, Et2O

TEMPERATURE LOW -78°C

COUNTERCATIONS SMALL Li+

OTHER NO CARBONYL EXCESS

THERMODYNAMIC CONTROL
The LESS substituted enolate is preferentially formed.
It is mandatory that an equilibrium is established.

O
+ BH

O
+ B

O
+ BH

Experimental conditions for a good THERMODYNAMIC CONTROL:

BASE WEAK Et3N, NaOH

SOLVENT POLAR PROTIC EtOH

TEMPERATURE ROOM TEMPERATURE 0 – 25 °C

COUNTERCATIONS LARGE Na+, K+, R4N+

OTHER CARBONYL EXCESS

 NITROGEN ANALOGUES OF ENOLATES

IMINES (AZAENOLATES)

H H+ Nt-Bu
+ t- BuNH2
O

Li+ Li+ Li+

H
LDA Nt-Bu Nt-Bu Nt-Bu
Nt-Bu
THF
0°C

Unsymmetrical ketones usually give regioisomeric mixtures:

LDA Li+
N N
THF

Li + Li+
N LDA N N
+
THF
Hindered imines are poorly metalated:

LDA Li+
N N
THF <1%

HYDRAZONES

Metalation is FASTER at SYN position to the N-NR2 group

NMe2 Li+ NMe2

N N
LDA
THF
-60°C

A chelate system is responsible for the observed regioselectivity:

Me Me
N
N
Li

NITROCOMPOUNDS

Under acidic conditions the nitronate anion is protonated at oxygen leading to the
corresponding nitronic acid. A fast tautomerism restores the nitro function:
 ENOLATE ALKYLATIONS
Enolate alkylation is a common SN2 reaction which is affected by the nature of the solvent

SOLVENT DIELECTRIC CONSTANT e RELATIVE RATE

BENZENE 2.3 1

THF 7.3 14

DME (MeOCH2CH2OMe) 6.8 80

DMF 37 970

DMSO 47 1420

Effect of polar aprotic solvents……….

Weakly coordinating solvents (THF, ether, hexane, benzene etc.) favor the formation of
hexameric structures:

OLi
THF
6
These aggregates can be disrupted using cosolvents amenable of complexating the cation
(e.g.TMEDA or HMPA):

OLi
+ 6 N N 6
6 O
TMEDA
Li
6 N N
O
HMPA = N P N
N

The enolate reactivity is also affected by the nature of countercation

according to the following scale:

R4N+ > K+ > Na+ > Li+ > Mg++

REGIOSELECTIVITY IN THE ALKYLATION:

CARBON vs OXYGEN

Oxygen has a higher electronic density that makes it more basic (protonation of enolate
anions occurs faster at oxygen leading to the corresponding enol) .

Alkylations in weak polar or protic polar solvents mainly lead to “C” alkylation:

OK O O OEt O O O
+ EtO S OEt + OEt
OEt OEt
O Et

HMPA 83 15

t BuOH 0 94

THF 0 94
 The leaving group, on the alkylating agent is of paramount importance:

M O O OEt O O O
HMPA
+ Et X +
OEt OEt OEt
Et

X = OTs 88 11

Cl 60 32

Br 39 38

I 13 71

“C” alkylation is thus favored according to the following scale:

R-I > R-Br > R-Cl > R-OSO2O-R > R-OTs > R3O+BF4-

“O” alkylation is favored by large countercations:

R4N+ > K+ > Na+ > Li+

SUMMARIZING

X Halogen (I > Br > Cl)

“C” S THF, DME, dioxane
ALKYLATION
R 1°, allyl, benzyl

X OTs, OMs, OSO2R1

“O” S DMF, DMSO, HMPTA
ALKYLATION
R 2° , 3°
 b-DICARBONYL SYSTEMS
Because of the low pKa value of methylene hydrogens (9-13) these derivatives can be
deprotonated by metal alkoxides and the corresponding stabilized anion promptly alkylated.
O O
O O EtONa OEt
OEt + Br
EtOH

O O
EtONa CO2Et
EtO OEt +
Br Cl EtOH CO2Et

The alkylation products of b-ketoesters may be hydrolysed and upon decarboxylation

converted into monofunctionalized derivatives.

O O O O O
1. OH- D
R
OEt OH
2. H+ -CO2
R R

Dianions of b-diketones and b-ketoesters can be generated using 2 equivalents of base:

O O O O Li+ O O Li+ O O
1 eq. LDA 1 eq. LDA
Li +
+
Li

Li+ O O Li+

O O OLi OLi Br
2 eq. LDA 1.

THF 2. H3O+ O O
 METAL ENOLATES
A drawback often observed during enolate alkylation is formation of polyalkylation products:

OLi O
OMe
MeO A
+ 10 eq MeI A = 68%
r.t., 0.5h, 75%
B + C = 32%
OLi
OLi

C B
O OLi OLi O
MeI MeI

The hexameric aggregate structure of the enolate causes a considerable slowing down of
the alkylation reaction. Therefore the monolakylated product A may react with the ketone
enolate, still present in the reaction mixture, generating a regioisomeric couple of new
enolates which upon alkylation afford bisalkylated compounds B and C.

Polyalkylation can be partially or completely suppressed by using the following trickeries:

1. Utlization of dipolar aprotic cosolvents (HMPA, DMSO, DMF, etc.) which increase the
reaction rate of the enolate:

OLi O O O
3eq HMPA
+ 5eq MeI + +
THF
-78°C, 10 h
97%

97% 3%

2. Disaggregation of the enolate adding dimethylzinc to the reaction:

OLi O O
3eq HMPA Bu
+ BuI Bu +
THF Bu
-60°C
70 30

+ 1eq Me2Zn 99 1
3. Use of enolates with low basicity:

OK O O

THF
+ Br +
r.t. 74%

Et3B 58 42

OBEt3K

THF
+ Br 100 0
r.t. 90%

Concerning the electrophiles reactivity the usual scale can be followed:

L I > Br > Cl

R
R PhCH2 > > RCH2 > CH
R

SILYL ENOL ETHERS ALKYLATION

Silyl enol ethers are less reactive than metal enolates because of the covalent character
of the O-Si bond. These compounds can be prepared by silylation of metal enolates or
directly from the carbonyl derivative. A kinetic or thermodynamic control may be realized.

Silyl enol ethers are stable compounds (they can be isolated and purified) and may be used
to generate metal enolates:

OSiMe3 OLi O
LiNH2 n-BuI
Bun
NH3, THF
-33°C
 Silyl enol ethers are less nucleophilic compared to metal enolates. Therefore in alkylation
processes the elctrophile must be activated (i.e. made more reactive) by interaction with
Lewis acids in a process that closely resembles the Friedel-Crafts alkylation of aromatic
compounds:

OSiMe3 O
TiCl4
But
t-BuI, CH2Cl 2
-40°C

A crucial point in these reaction is the solvent employed since it should not contain basic
lone pairs such as occurs in ethers, esters or similar. For this purpose the most used solvent
is CH2Cl2 or other halogenated compounds.

Mechanism:

O
Si O
Cl
+ Me3SiCl
Cl Ti Cl Ph
Cl Cl
Ph

ALKYLATION OF AZA ANALOGUES OF ENOLATES

ENAMINES
Good results using very reactive electrophiles:

a-Substituted cyclic ketones lead to less substitued enamines:

This is NOT the result of a kinetic control that usually favors the less substituted
regioisomer. As a matter of fact the less substituted enamine A is MORE STABLE than
the other one B because of the lack of repulsve interactions between the methyl and
the pyrrolidine a-hydrogens
 METALATED IMINES
The poor electrophilicity of the azomethine carbon (C=N) allows the azaenolate formation
with Grignard reagents besides classical strong bases (LDA):

C6H11 BrMg C6H11

N N O
EtMgBr 1. n-BuI Bun

THF, D 2. H3O+

Br
CHO
EtMgBr MgBr
1.
N C6H11 N C6H11
THF, D 2. H3O+

C6H11 BrMg C6H11

N N O
EtMgBr 1. CH3I
THF, D 2. H3O+

Advantages over metal enolates and enamines:

C-alkylation even with secondary or poorly reactive halides;

Regioselective formation of the less substituted azaenolate

Protonic transfer reaction are suppressed especially at low temperature (-78°C)

Lithiation of unsymmetrical imines at low temperature (-78°C) is under kinetic control.

Metalation is not affected by the stereochemistry (E or Z) of the imine.

But
Li But But
N N N
LDA MeI
THF THF
-78°C -78°C

At higher temperature (0°C) equilibration privileges formation of the thermodynamic

azaenolate.

Li But Li But But But

N N N N
0°C MeI
+
THF
-78°C
82% 18%
Chiral imines obtained by reaction of a carbonyl compound with an optically active amine
may be metalated and alkylated in a distereoselective fashion.
The chiral amine thus employed acts as a CHIRAL AUXILIARY

METALATED N,N-DIALKYLHYDRAZONES
Lithiated hydrazones are more nucleophilic than the corresponding lithiated imines.
 Enantiopure hydrazines react with carbonyl derivatives generating chiral hydrazones.
These can be diastereoselectively lithiated and alkylated leading to substituted hydrazones.
The latter compounds upon cleavage of the C=N bond restore the carbonyl function leaving an
enantioenriched alkylated carbonyl compound.
The most popular hydrazine used for synthetic purposes are those obtained from (S) or (R)
proline, their acronym are SAMP and RAMP respectively.

Although is formally possible to cleave the C=N bond by acidic hydrolysis, in order to avoid a partial
racemisation of the newly formed stereocenter it is advisable a milder oxidative cleavage using
ozone at low temperature under almost neutral conditions.

Utilization of RAMP leads to enantiomers having an opposite configuration.

N 1. LDA,
O OMe N Et2O, -78°C
+ N
OMe I
NH2 2.
- 110°C
RAMP

N O
N O3
OMe
-78°C 99% ee

The high nucleophilicity of hydrazones allows low polar solvents to be used (THF, Et2O) at
low temperature (-78 to -100°C)
 NITRONATE ANIONS
Nitronate anions are seldom used in alkylation reactions because of their reduced
C-nucleophilicity. Similarly to enolate anions, metal nitronates can be alkylated at
the carbon or at the oxygen.

In order to increase the nucleophilicity at the a-carbon, lithium dianions can be generated
by reaction of the nitroalkane with 2 equivalents of base. These dianions are strong nucleophiles
but being quite unstable must be generated and used at very low temperature ( -90°C)

H Li
LDA OLi LDA OLi
R NO2 R N R N
THF THF
O O

1
R1 R1
RX AcOH
OLi 53-80%
R N R NO2
THF-HMPA
-90°C r.t. O

Nitronate anions can be easily silylated at the oxygen atom leading to silylnitronates.
These compounds are effective 1,3-dipoles in the corresponding cycloaddition reactions.
 IMIDES OF CHIRAL OXAZOLIDINONES

Amino alcohols obtained by direct reduction of a-amino acids (chiral pool) can be converted into
1,3-oxazolidin-2-ones. These work as CHIRAL AUXILIARIES since can be converted into acyl
derivatives. Deprotonation by strong bases (LDA) generates a rigid lithium enolate (complexation
of Li with the carbonyl oxygen) which is diastereoselctively alkylated and then hydrolysed
to produce the optically active a-substituted acid.

CONJUGATE ADDITIONS
Conjugate additions of enolate anions to electronpoor olefins result in the formation of
a second stabilized anion which can be trapped by an electrophilic specie E+ (usually H+).
An important aspect of this process is formation of various stereocenters which are often
needed to be controlled.

X R R
1 E 1
W + R W R * W
R
R1 * *
X X E

These additions involve frontier orbital interactions of type HOMOENOLATE – LUMOENONE

in a cyclic transition state
1,3-DICARBONYL SYSTEMS

The original Michael addition has been studied on these derivatives.

They are successfully employed in Robinson annulation, a tandem conjugate addition-
intrmolecular aldol reaction to produce bicyclic systems used as building blocks in the
preparation of steroids.

The Michael addition-hydrolysis-decarboxylation process overall results in the formation

of 1,5-dicarbonyl derivatives

Nitroolefins are good Michael acceptors and can be used for the preparation of
1,4-dicarbonyl derivatives:
 METAL ENOLATES
The enolate configuration (E or Z) affects the stereochemical outcome of the product

OLi O O Ph O
THF
+ Ph R
R -78°C

Z Anti
O
Li
Ph
O
R

Z enolates can be easily generated from ketones having a non enolisable hindered side:

O OLi
LDA
Z>99%
THF, -78°C

Formation of the E enolate (less stable) is usually favored under kinetic control

O OLi OLi
LDA
+
-78°C

Z E

THF 25 75

THF / HMPA 95 5
 HMPA and other aprotic polar solvents favor the Z enolate by equilibration :

SILYL ENOL ETHERS

As usual the reaction is catalysed by Lewis acids (interaction of LA with basic

carbonyl oxygen):

OSiMe3 O O
O
1. TiCl4, CH2Cl2, -78°C
+
2. K2CO3, H2O

With open-chain systems the process is ANTI-stereoconvergent

this is probably due to an equilibration via retro-Michael reaction which privileges

the more stable isomer through a thermodynamic control.
 Silyl derivatives of esters are named silyl ketene acetals.
These enol ethers give a SYN stereoconvergent reaction under kinetic control

Mechanism:

ENAMINES

Using optically active secondary amines it is possible a stereoinduction in the

conjugate addition

MeO S O
N 1. Et 2O CO2Me
+ CO2Me
2. HCl, CH2Cl 2

ee > 90%
A SYN simple distereoselection is observed especialy with reactive acceptors such as
nitroolefins:

O O CO2Et

N + EtO C NO2
2 NO2

NaBH4
MeOH, 0°C

O O
O N O
H
- HNO2 NO2

NITROCOMPOUNDS
Nitronate anions add 1,4-regioselectively to a,b-unsaturated carbonyls

A wide array of basic systems can be used to catalyse/promote the addition:

Heterogeneous Amberlyst A-21 silica gel/Et3N

basic Al2O3 KF/Al2O3
(macroreticular resin, (powder, solid
catalyst/promoter (white powder)
1-2 mm spheres)
(white powder)
supported base)

Homogeneous
Ph3P t-BuOK
catalyst/promoter
 O O
O
CO2Et t-BuOK MeOH
+
NO2 THF r.t.
NO2
EtO2C
CO2Et

At the end of the process the nitrogroup can be removed by radical denitration:

NO2 O NO2 Bu3SnH

DBU OMe AIBN OMe
+
OMe MeCN C6H6
O D O

CHIRAL HYDRAZONES
 ENANTIOSELECTIVE CATALYTIC
CONJUGATE ADDITIONS

ORGANOMETALLIC CATALYSIS
Organometallic catalysts are formed by transition metals linked to organic molecules
of synthetic origin or derived from the chiral pool.

Catalyst should also provide an

activation of one or both
reactants in order to suppress
background reactions.

Transition metals are able to establish strong

interactions with reactants using low energy
d-empty orbitals.
These interactions involve highly ordered
transition states in which hydrogen bonding
between polar groups may be operative.
 ORGANOCATALYSIS
Organocatalysts are purely organic molecules mostly of natural origin (amono acids, alkaloids)

O CF3
H
N Ph N
N N S
HO H H
O N
N N CF3
MeO N CO 2H H H
H HO OH

N
OMe

These organic molecules work establishing weak interactions (hydrophobic, electrostatic

or hydrogen bonding).
Activation of reactants is realized through a Brønsted or a Lewis acid-base catalysis.

N
HO
O O O R1
HO
NO2 NO2
OR + R1
N CO2R
10 mol %, THF, -60°C
75-94% dr = 91: 9 a > 98:2
ee = 92-99%
ENAMINE AND IMINIUM ION ORGANOCATALYSIS

ENAMINE ORGANOCATALYSIS
Chial cyclic secondary amines are able to temporarily form enamines with carbonyls.
These nucleophilic azaenolates may react with Michael acceptors (a,b-unsaturated systems)
IMINIUM ION ORGANOCATALYSIS
Activation occurs by iminium ion formation with the a,b-unsaturated system.
This determines an increase of the electrophilicy of the Michael acceptor.

ALDOL CONDENSATIONS
METAL ENOLATES OF CARBONYLS

The aldol condensation is a reversible process which equlibrium constant depends from:
1. Nature of the carbonyl involved in the process.
2. Nature of the metal M which can stabilize or not the intermediate chelated structure.
Stereochemistry: Z enolates are easier to obtain with simple carbonyls leading to the
preferential formation of the SYN stereoisomer
A chair-like transition state is involved

E enolates give an ANTI diastereoselectivity which is less pronounced compared to that

observed with Z enolates

Good ANTI diastereomeric excess can be obtained through a thermodynamic control.

The process reversibility increases with temperature and with enolate basicity.
 The enolate stereochemistry may be addressed with a suitable choice of the base.

O OLi OLi
Base
+
i-Pr THF i-Pr i-Pr
-78°C
Z E
LDA 56 44
LMTP 32 68
LHMDS 97 3
The presence of large groups on one side of the carbonyl function favors the Z enolate.
Therefore when aldehydes or methyl ketones must be used as enolates, the efficient formation
of the Z eolate is not ensured.
The solution of this drawback is to use ketones bearing large dummy groups which:
1. ensures a perfect Z stereocontrol in the enolate formation.
2. can be replaced by H upon oxidative demolition.

BORON ENOLATES (VINYLOXY BORANES)

Direct preparation:

O Et3N OBBu2
+ Bu2BOTf Z
R Et2O R
Boron enolates allow a more efficient control on the enolate stereochemistry.
This goal is achieved by a suitable choice of the boron ligands which affect the rotameric
conformation of the transition state.
The selective deprotonation of the a-carbonyl hydrogen atoms leads to the formation of
the enolate couple with high stereoselection.

Boron enolates give the same trend of lithium enolates for what concerns the
stereopreference ( Z → SYN and E → ANTI).
The reduced distance of the O-B bond allows a superior distereoselectivity in aldol
condensation because of more tight transition state enhances the stereoelectronic
effects which are responsible of the distereoselection.
 TITANIUM ENOLATES
Titanium enolates are less basic compared to those of lithium and boron
The more covalent character of the Ti-O bond makes less easy retraldol processes.
The reaction is SYN-stereoconvergent.

This is an advantage when cyclic ketones which are not amenable to give Z enolates
are involved in the formation of SYN aldols.

The origin for this stereoconvergence is probably due to two different transition states
involving stereoisomeric Ti enolates:
 ENANTIOSELECTIVE CATALYTIC
ALDOL CONDENSATIONS
As an example, enantioselective reactions catalysed by L-proline are able to provide
the corresponding aldols with high ee via enamine:

N CO2H
O H O OH
O
20 mol %
H DMSO

97%, ee =96%

mechanism
O H
O N
R H H
N CO2H N CO2H
H R O O
O
H
H

O OH O2C N OH
R R