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8.

Enolatos - Parte 2

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8.4. Reaes Aldlicas


8.4.1. Consideraes Iniciais
8.4.2. Reao Aldlica de Mukaiyama
8.4.3. Reaes Aldlicas Assimtricas Mediadas por Boro
8.4.4. Reao Aldlica Assimtrica catalisada por Prolina: Organocatlise
8.4.5. Reao de Reformatsky
8.4.6. Reao de Mannich
8.4.7. Reao de Perkin
8.4.8. Reao de Knoevenagel
8.4.9. Reao de Baylis-Hillman

Reaes Aldlicas

Bibliografia:
Asymmetric Aldol Reactions using Boron Enolates, Cowden e Paterson, Org.
React. 1997, Vol. 51, p. 1.
Reaes Aldlicas Assimtricas Catalticas, Crrea e Pilli, Quim. Nova 2003, 26,
531.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

8.4.1. Consideraes Iniciais


Reaes Aldlicas: Definio
Reaes de adio nucleoflica de um enol (ou de um on enolato)
carbonila de um aldedo ou de uma cetona so chamadas de reaes aldlicas.
Esquema Geral:

A adio aldlica entre aldedos que contm um hidrognio em leva a hidroxialdedos. Exemplo:

Este mtodo no muito eficiente para a obteno de -hidroxicetonas.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Mecanismo:

-Hidrxi-aldedos e -hidrxi-cetonas podem ser facilmente


desidratados, tanto em condies cidas quanto em condies bsicas.
Equao Geral:

Prof. Luiz F. Silva Jr - IQ-USP - 2012

and the product


is again
a hydroxy8. Enolatos - Parte 2 Each step is the same as the aldol sequence with acetaldehyde,
QFL-5928
- Sntese
Orgnica

carbonyl compound, but this time a hydroxy-ketone. Introduction: the aldol reaction
The acetaldehyde reaction works well when one drop of dilute sodium hydroxide is added to acetaldehyde. The
acetone
reaction
is best
done with
barium
Ba(OH)
2. Both!approaches
Each
step is the
same as the
aldol sequence
withinsoluble
acetaldehyde,
and thehydroxide,
product is again
a hydroxykeep the
basecompound,
concentration
low.
Without
this precaution, the aldol products are not the compounds
isocarbonyl
but this
time
a hydroxy-ketone.
With the acetone
reaction
is required to ensure that
The the
acetaldehyde
reaction
well
whenfurther
one dropreactions
of dilute sodium
hydroxide
is added
to acetaldelated from
reaction.
Withworks
more
base,
occur,
because
the aldol
products
dehydrate
product does not meet the
The acetone reaction is best done with insoluble barium hydroxide, Ba(OH)2. Both approaches apparatus is arranged so
ratherhyde.
easily
under the reaction conditions to give stable conjugated
unsaturated
carbonyl
compounds.
heating, the volatile aceto
Introduction: the aldol reaction

keep the base concentration low. Without this precaution, the aldol products are not the compounds iso- condensed into a vessel c
Reaes
de Eliminao
OH With
Omore base,
O
dehydration
product
lated from the reaction.
further reactions occur, because
the
aldol products
dehydrate insoluble base. The less v
base
aldol product
product is kept away from
but-2-enal,
or
rather
easily
under
the
reaction
conditions
to
give
stable
conjugated
unsaturated
carbonyl
compounds.
from acetaldehyde Each step is the same as the aldol sequence with acetaldehyde, and the product is again a hydroxy- !

Mecanismo em meio cido (E1):


crotonaldehyde
O
O
carbonylOH
compound,
time a hydroxy-ketone.
Hbut this
H product
dehydration
base

aldol product
but-2-enal,
or
dilute sodium
hydroxide is added to acetaldefrom acetaldehydeThe acetaldehyde reaction works well when one drop of
crotonaldehyde
OHacetone
O reaction
H
H barium
hyde. The
is base
best done with insoluble
hydroxide,
Ba(OH)
O
2. Both approaches
dehydration
product

aldol productkeep the base concentration low. Without this precaution, the aldol products
are not the compounds iso4-methylpent-3-en-2-one,
OH
O
from acetonelated from
dehydration
product
base
the reaction. With
more base, furtherOreactions
occur, because
the aldol
products dehydrate
or
mesityl
oxide
aldol product
from acetone
rather

4-methylpent-3-en-2-one,

easily under the reaction conditions to give stable orconjugated


unsaturated carbonyl compounds.
mesityl oxide
OH

With the acetone r


is required to ensu
product does not m
apparatus is arran
heating, the volati
condensed into a v
insoluble base. Th
product is kept aw

dehydration product
aldol product
These are elimination
reactions, and youbase
met them in Chapter
19. You
cannot normally eliminate
but-2-enal,
or
acetaldehyde
These arefrom
elimination
reactions, and you met them in Chapter 19. Youcrotonaldehyde
cannot normally eliminate
H
H
waterwater
fromfrom
an an
alcohol
solution
it iscarbonyl
the carbonyl
group
allowshere.
it toAhappen here. A
alcoholin
in basic
basic solution
andand
it is the
group that
allowsthat
it to happen
!
Mecanismo
em meio bsico
(E1cB):
OH
O
second
enolization
reaction
starts
things
off,
and
these
are
E1cB
reactions.
second enolization reaction starts things off, and
these are E1cB reactions.
O
dehydration product
See p. 000 for a discussio
base
aldol product

OH O O

OH

the elimination
step
the elimination

the
enolization
step
the
enolization
step
from
acetone

OH

step4-methylpent-3-en-2-one,
or mesityl oxide

mechanism.

OH and
O you met them in Chapter 19. YouOcannot normally eliminate
These are elimination reactions,
water
that allows it to happen here. A
H and it is the carbonyl group
H from an alcohol in basic solution
H
second enolization reaction starts things off,
H and these are E1cB reactions.
H

H
HO H

enolate ion

the elimination step

the enolization step

OH

HO

enolate ion

See p. 000 for a di


mechanism.

In the examples that follow in the rest of the


you will see that base-catalysed
aldol reacOH chapter
O
O
tions sometimes give the aldol
and sometimes the elimination product. The choice is partly based on
H
Inconditionsthe
the examples more
that vigorous
follow in
the rest(stronger
of the chapter
youtemperatures,
will see that
base-catalysed aldol reacH
conditions
base,
higher
H longer reaction
H
tions time)
sometimes
give
the
aldol
and
sometimes
the
The
choice
is partly based on
tend to give
the
elimination
productand
partly
on the structureproduct.
of the reagents:
some comenolate
ion elimination
HO
binations
are
easy
to
stop
at
the
aldol
stage,
while
some
almost
always
give
the
elimination
reaction
conditionsthe more vigorous conditions (stronger base, higher temperatures, aslonger reaction
In the
examples
that
in the
rest ofif the
youtowill
You do not,
of course,
need
tofollow
learn the
results:
youchapter
ever need
dosee
an that
aldolbase-catalysed
reaction you aldol
can reactime)well.
tend
to give
the
elimination
productand
partly
on the
structure
of the
reagents:
some comtions
sometimes
give
the
aldol
and
sometimes
the
elimination
product.
The
choice
is
partly
based on
consult the massive review in the 1968 volume of Organic Reactions to find the best conditions for
conditionsthe
morealdol
vigorous
conditions
(stronger
base, higher
temperatures,
longer reactionreaction as
binations
toyou
stop
at the
stage,
while some
almost
always
give the elimination
gettingare
theeasy
result
want.
time)
to give
the elimination
productand
partly
onever
the
structure
of the
reagents:
com- you can
well. You
not,
oftend
course,
need
learn
the and
results:
if you
need
to
do
an aldolsome
reaction
Thedo
elimination
is even
easier
into
acid
solution
acid-catalysed
aldol
reactions
commonly
give
binations are easy to stop at the aldol stage, while some almost always give the elimination reaction as
unsaturated
products
instead ofthe
aldols.
In this
simple example
with Reactions
a symmetrical
ketone,
the conditions for
consult
the massive
review
1968
volume
Organic
tocyclic
best
well. You
do not, in
of course,
need to
learn theof
results:
if you ever
need to do
anfind
aldolthe
reaction
you can
enone is formed in good yield in acid or base. We shall use the acid-catalysed reaction to illustrate the
getting the result
youthe
want.
consult
massive review in the 1968 volume of Organic Reactions to find the best conditions for
mechanism. First the ketone is enolized under acid catalysis as you saw in Chapter 21.

result youaldlica
want. pode ser feita em meio cido. Exemplo:
Aelimination
reao getting
de condensao
The
istheeven
acid-catalysed
enolization
step easier in acid solution and acid-catalysed aldol reactions commonly give
The elimination
is even easier in acid solution and acid-catalysed aldol reactions commonly give
H
unsaturated products
instead
ofinstead
aldols.
In this
example
with
a symmetrical
cyclicthe
ketone, the
unsaturated
products
of aldols.
In simple
thisOH
simple
example with
a symmetrical
cyclic ketone,
O
O
enone is formed
in good
yield
in acid
base.
We We
shall
use
acid-catalysed
reaction
to illustrate
the
enone
is formed
in good
yield or
in acid
or base.
shall
usethe
the acid-catalysed
reaction
to illustrate
the
H
mechanism.
First
the
ketone
is
enolized
under
acid
catalysis
as
you
saw
in
Chapter
21.
H
mechanism. First the ketone is enolized under acid catalysis as you saw in Chapter 21.
acid-catalysed enolization step

Mecanismo:
acid-catalysed enolization step
cyclopentanone

enol

OH

O Then the aldol reactionH O


OH than enolates, and the reaction
takes place. Enols are less nucleophilic
H

occurs because
H the electrophilic carbonyl component is protonated: the addition is acid-catalysed.
An acid-catalysed aldol reaction takesHplace.
cyclopentanone
enol
acid-catalysed
aldol addition
step with aldehydes and ketones: the aldol reaction
27 . Reactions
of enolates

692

Then the aldol reaction takes place. Enols are less nucleophilic than enolates, and the reaction
H
H enol
occurs because the electrophilic
carbonyl component
is protonated:
the addition is acid-catalysed.
O
O
The aldol An
is aacid-catalysed
tertiary alcoholaldol
and would
be takes
likely place.
to eliminate by an E1 mechanism in acid even
reaction

O
cyclopentanone

Then
thethealdol
reaction
takes
place. Enols
less the
nucleophilic
than
enolates,
and the reaction
without
carbonyl
group.
thestep
carbonyl
ensures are
that only
stable conjugated
enone
is
acid-catalysed
aldol But
addition
OH
OHin the very
Notice
thatelectrophilic
the dehydration too
is genuinely
acid-catalysed asisthe
acid reappears
O H the
occursformed.
because
carbonyl
component
protonated:
the
addition
is
acid-catalysed.
H
last step.
H
O
O
O
H aldol reaction takes place.
An acid-catalysed
the aldol product

the acid-catalysed dehydration step (E1 elimination)

acid-catalysed aldol addition step

OH

H
OH2

condensation of cyclopentanone

HO
or H

OH

the aldol product

!Condensation reactions

OH

OH

OH

None
O of these intermediates is detected or isolated in practicesimple treatment of the ketone
with acid gives the enone in good yield. A base-catalysed reaction gives the same product via the
H elimination mechanism.
the aldol product
aldolE1cB

Base-catalysed aldol reactions may give the aldol product, or may give the
+ H 2O

The term condensation is often


used of reactions like this.
Condensations are reactions
where two molecules combine
with the loss of another small
moleculeusually water. In this

dehydrated enone or enal by an E1cB mechanism

Acid-catalysed aldol reactionsmay give the aldol product, but usually give the

dehydrated enone or enal by an E1 mechanism


Prof. Luiz F. Silva Jr - IQ-USP
- 2012
O

OH

O
and/or

8.

compound. These form only a tiny fraction of known aldol reactions. Those that occur between two
Cross-condensations
different carbonyl compounds,
one acting as a nucleophile in its enol or enolate form, and the other
So farcross-condensations.
we have considered only self-condensationsdimerization
reactions
of a single carbonyl
as an electrophile, are called
They are more interesting than
self-condensacompound. These form only a tiny fraction of known aldol reactions. Those
that occur between-two
Enolatostions,
- Parte
2
QFL-5928
Sntese
but working out what happens needs more thought.
different carbonyl compounds, one acting as a nucleophile in its enol or enolate form, and the other
We shall start with an example
that works
well.cross-condensations.
The ketone PhCOMe
reacts
4-nitrobenzaldeas an electrophile,
are called
They are
morewith
interesting
than self-condensations, but
working
out what to
happens
more thought.
hyde in aqueous ethanol under
NaOH
catalysis
give needs
a quantitative
yield of an enone.

Orgnica

We shall start with an example that works well. The ketone PhCOMe reacts with 4-nitrobenzalde-

O hyde in aqueous ethanol under NaOH catalysis toOgive a quantitative yield of an enone.
O

O
NaOH

99% yield

NaOH

H O/EtOH
H
2

99% yield

H O/EtOH

2
NO2
NO2
NO2
2
A reao aldlica cruzada entreNO
dois
aldedos pode ser feita quando
um dos

first step must


be the
formation
of an
enolate
anion using
as a base. Though
both carThe first step must be theThe
formation
of an
enolate
anion
using
NaOH
as a NaOH
base. Though
both caraldedos no possui
um H. Alm
esta
reao
pode
serenolization
entre
aldedos
bonyl compounds
are unsymmetrical,
there
is only
one
site for
there
is only
bonyl compounds
are unsymmetrical,
there
is disto,
only one
site
for
enolization
asrealizada
there isasonly
one
setoneofset of
protons, on the methyl group of the ketone. The aldehyde has no protons at all.
protons,aromticos
on the methyl
group ofExemplo:
the ketone. The aldehyde has no protons at all.
e cetonas.
no protons

no protons

no protons

no protons

OH

NO2

NO2

O
H

OH

only protons
in either molecule

only possible enolate

To get the observed


the enolate obviously attacks the aldehyde to give an aldol, which
onlyproduct,
protons
only possible enolate
then dehydrates byinthe
E1cBmolecule
mechanism.
either

To get the observed


product, the enolate obviously attacks the
aldehyde to give an aldol, which
H OR
O
O
O
O
OH
O
then dehydrates by the E1cB
mechanism.
aldol

O
aldol
O

OH

HORH

OH

NO2

E1cB

H
NO2

H
NO2

NO2

NO2
OR

OH
O

NO2

OH

OH

NO2

Now, in this step there was a choice. The enolate could have attacked another molecule of unenolized ketone. It didnt, because ketonesE1cB
are less reactive than aldehydes (Chapter 6). In this case the
aldehyde has an electron-withdrawing nitro substituent too, making it even more reactive. The enolate selects the better electrophile, that is, the aldehyde.
In other cases the balance mayNO
shift
a crossed
2 towards self-condensation. You might think thatNO
2
aldol reaction between acetaldehyde and benzophenone (diphenylketone Ph2C=O) should work
well.

enolization

enolization
H H

NO2
O

NO2

H
NO2
OR

O
Now, in this step there wasOa choice. TheO enolate ?could have Ph
attacked
another molecule of uneno+
lized ketone. It didnt, because
ketones
are
less
reactive
than
aldehydes
(Chapter
6). In this case the
Ph
Ph
Me
H
Ph
H
aldehyde has an electron-withdrawing
nitro substituent
too, making
it even more
reactive. The
A condensao aldlica
intramolecular
importante
na formao
de enolate selects anis
the better
electrophile,
that
is,
the
aldehyde.
de cinco e de seis membros. Exemplo:
In other cases the balance may shift towards self-condensation. You might think that a crossed
aldol reaction between acetaldehyde and benzophenone (diphenylketone Ph2C=O) should work
well.

Ph

Ph

Me

Ph

+
H

Prof. Luiz F. Silva Jr - IQ-USP - 2012

Ph

O
H

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

27 . Reactions of enolates with aldehydes and ketones: the aldol reaction

98

Specific enol equivalents are intermediates that still have the reactivity of enols or
enolates
but are stable enough to be prepared in good yield from the carbonyl
compound without any aldol reaction.
Sensible choice of an appropriate specific enol equivalent will allow almost any aldol reaction
to be performed successfully. The first two compounds in our list, the silyl enol ethers and the
lithium enolates, have a specially wide application and we should look first at the way these work. As the
table suggests, silyl enol ethers are more like enols: they are nonbasic and not very reactive. Lithium
enolates are more like enolate anions: they are basic and reactive. Each is appropriate in different
circumstances.
27 . Reactions of enolates with aldehydes and ketones: the aldol reaction

98
O

carbonyl
ompound

LDA
[i -Pr2NLi]
78 C,
THF

Li

R
lithium
enolate

e formation of lithium enolates was


cussed in Chapter 26.

dehydes are an exception. You


an make lithium enolates from
ome aldehydesLDA
such as i-PrCHO, Li
O
Ois
ut generally
self-condensation
[i -Pr2NLi]
o fast, so unwanted aldol selfondensation
products
78 C, areR
R
THFformation of
oduced during the
carbonylenolate. To makelithium
e lithium
compound
enolate
pecific enolates of aldehydes we
eed to use another type of
!
erivative: see later.

he formation of lithium enolates was


iscussed in Chapter 26.

here are four coordination sites


n!
the lithium atomthose we do
Aldehydes
an exception.
ot
show areare
occupied
by THF You
can
make Before
lithiumthe
enolates
olecules.
aldol from
some
such as
actionaldehydes
can take place,
onei-PrCHO,
of
but
generally
self-condensation
e THFs
must be
displaced by is
too
fast, so unwanted
selfe electrophilic
carbonylaldol
partner.
condensation products are
produced during the formation of
O To make
O
the lithium enolate.
Li
specific enolates
of aldehydes we
O
O
need to use
another
type of
derivative: see later.

Lithium enolates in aldol reactions

LithiumSpecific
enolatesenol
are usually
made at
temperature in
THF
a hindered
lithium
base
equivalents
arelow
intermediates
that
stillwith
have
the reactivity
of amide
enols or
(often LDA)
and
are
stable
under
those
conditions
because
of
the
strong
OLi
bond.
The
formation
enolates but are stable enough to be prepared in good yield from the carbonyl
of the enolate begins with LiO bond formation before the removal of the proton from the posicompound without any aldol reaction.
tion by the basic nitrogen atom.
Sensible choice of an appropriate
specific enol equivalent
will allow almost any
Li aldol reaction
LiNR2
Li
O
O
NRin2 our list, the silylOenol ethers and the
toO be performed
successfully.
The
first
two
compounds
LDA
lithium enolates, have a speciallyHwide application and we should
look first at the way these work. As the
H
R
R table suggests, silyl enol
R ethers are more like enols:
R
they are nonbasic and not
very reactive. Lithium
lithium
enolate
enolates are more like enolate anions: they are basic and reactive. Each is appropriate
in different
circumstances.
This reaction happens very quicklyso quickly that the partly formed enolate does not have a
chance to react with unenolized carbonyl compound before proton removal is complete.
Reao
Aldlica Dirigida
Lithium enolates in aldol
reactions

OLimade at low temperature in THF with a hindered lithium amide base


Lithium enolates are usually
Li
Oforte no because
(often
LDA)
and
are
stable
under
those
of the
OLietc);
bond. The formation
Ostrong
O Formao
O
do enolato
com
baseconditions
nucleoflica
(LDA,
LICA,
LDA the removal of the proton from the posiR LiO bond formation before
of the enolate begins with
the
Reao
com aldedo
ou cetona.
mecanismo:
R Exemplo efast
R
tion
basic
atom.
R by
R nitrogen
slow
lithium enolate
Li
LiNR2
Li
O
O
O
O
NR
2
Now, if a second
LDA carbonyl compound is added, it too complexes with the same lithium atom. This
allows the aldol reaction to take place
H by a cyclic mechanism in
H the coordination sphere of the lithiR
R atom.
R
R
um

lithium enolate

aldol reaction with a lithium enolate

This reaction happens very quicklyso quickly that the partly formed enolate does not have a
2. cyclic mechanism
1. electrophilic
3. aqueous work-up
chance to react
withcompound
unenolized carbonyl
gives thecompound
aldol productbefore proton removal is complete.
carbonyl
O

Li

forms a complex with


the lithium atom

O
PhCHO

R enolate
lithium

OLi Li
O

R
R
slow

O
Ph
R

Li
LDA

fast

H2O
O
Ph

Li

OH
Ph

lithium enolate

The aldol step itself is now a very favourable intramolecular reaction with a six-membered cyclic
Now, if a second carbonyl compound is added, it too complexes with the same lithium atom. This
transition state. The product is initially the lithium alkoxide of the aldol, which gives the aldol on
allows the aldol reaction to take place by a cyclic mechanism in the coordination sphere of the lithiR
work-up.
the tetrahedral structure of a
um atom.
lithium
enolate
in
THF
This reaction works well even if the electrophilic partner is an enolizable aldehyde. In this exam!
aldol
with a lithium
enolate
ple,
an reaction
unsymmetrical
ketone
(blocked on one side by an aromatic ring) as the enol partner reacts in
There are four coordination sites
on the lithium atomthose we do excellent yield with a very enolizable aldehyde.
This is the first complete
aldol reaction we have
2. cyclic mechanism
1. electrophilic
3. aqueous work-up
not show are occupied by THF
gives notice
the aldolthe
product
compound
shown you usingcarbonyl
a specific
enol equivalent:
important point that it is done in two steps
molecules. Before the aldol
forms a complex with
first, form the
specific
enol equivalent (here, the lithium enolate); then add the electrophile. Contrast
the lithium atom
Li
reaction can take place, one of
Li
Li
the
crossed
aldols
earlier
in the chapter,
where
enolizable
base,
O
O
the THFs must be displaced by
O
O component,
O
O
OH were all
H2O and electrophile
Prof.carbonyl
Luiz partner.
F. Silva
Jr -together
IQ-USP
2012
mixed
in one- step.
the electrophilic
R

PhCHO

Ph

Ph

Ph

circumstances.

Lithium
enolates in aldol reactions
8. Enolatos - Parte
2
Li
LDA
[i -Pr2NLi]

78 C,
THF

arbonyl
mpound

R
lithium
enolate

QFL-5928 - Sntese Orgnica

Lithium enolates are usually made at low temperature in THF with a hindered lithium amide base
(often LDA) and are stable under those conditions because of the strong OLi bond. The formation
of the enolate begins with LiO bond formation before the removal of the proton from the position by the basic nitrogen atom.
O

LiNR2

LDA

Li

NR2

ReaoHAldlica Dirigida
R

Li

ormation of lithium enolates was


ussed in Chapter 26.

ehydes are an exception. You


make lithium enolates from
me aldehydes such as i-PrCHO,
generally self-condensation is
fast, so unwanted aldol selfdensation products are
duced during the formation of
lithium enolate. To make
cific enolates of aldehydes we
d to use another type of
vative: see later.

auto-condensao
comunenolized
cetonas: carbonyl compound before proton removal is complete.
chance to react with

lithium enolate
Na reao aldlica dirigida a formao do enolato mais rpida do que a

This reaction happens very quicklyso quickly that the partly formed enolate does not have a

re are four coordination sites


he lithium atomthose we do
show are occupied by THF
ecules. Before the aldol
ction can take place, one of
THFs must be displaced by
electrophilic carbonyl partner.

OLi
O
R

706

Li

R
R

Li

LDA

slow

fast

lithium enolate

Now, if a second carbonyl compound is added, it too complexes with the same lithium atom. This
allows the aldol reaction to take place by a cyclic mechanism in the coordination sphere of the lithium atom.
aldol reaction with a lithium enolate
1. electrophilic
carbonyl compound
forms a complex with
the lithium atom

Li

PhCHO

R
O

2. cyclic mechanism
gives the aldol product

Li

O
Ph

3. aqueous work-up

Li

H2O
Ph

OH

Ph

lithium enolate

. Reactions
aldol stepofitself
is nowwith
a very
favourable
reaction
with a six-membered cyclic
27 The
enolates
aldehydes
andintramolecular
ketones: the aldol
reaction

Li

the tetrahedral structure of a O


O
lithium enolate in THF

OEt
cyclic mechanism for ester
aldol reaction

transition state. The product is initially the lithium alkoxide of the aldol, which gives the aldol on
work-up.
reao
aldlica
tambm
ser himalchene
feita com by
cidos
A good Aexample
is the
first stepdirigida
in a synthesis
of the costuma
natural product
Oppolzer and
Snowden.
Even though
the ester
theifaldehyde
are both crowded
with
the aldol
reac- In this examThis reaction
works
welland
even
the electrophilic
partner
issubstituents,
an enolizable
aldehyde.
carboxlicos e com seus derivados, como steres e amidas. Pode ser feita tambm
tion
works
well
with
the
lithium
enolate
of
the
ester.
The
cyclic
mechanism
ensures
that
the
enolate
ple, an unsymmetrical ketone (blocked on one side by an aromatic ring) as the enol partner reacts in
adds nitrilas.
directly
to
thewith
carbonyl
group
of the aldehyde
and notThis
in a conjugate
(Michael)
fashion.
com
Exemplos:
excellent
yield
a very
enolizable
aldehyde.
is the first
complete
aldol reaction we have
shown you using a specific enol equivalent:
notice the important point that it is done in two steps
OLi
CHO
OH
CO2Et the specific enol equivalent (here, the lithium
first, form
enolate); then
add the electrophile. Contrast
LDA, 78 C
CO2and
Et electrophile were all
OEt
the crossed aldolsTHF
earlier in the chapter, where enolizable component, base,
mixed together in one step.
72% yield
706 lithium enolate
27 . Reactions
of enolates with aldehydes and ke
A etapa de adio ocorre via um estado de transio cclico:

Zinc enolates, made from the bromoesters, are a good alternative to lithium enolates of esters.
Li
A good
is the
step in a synthesis of the natura
The mechanism for zinc enolate formation should
remind you
of theexample
formation
of first
a Grignard
O
O
Snowden. Even though the ester and the aldehyde are both cr
reagent.
Zn

!
Zinc, like magnesium, is a twoelectron donor and likes to be
oxidized from Zn(0) to Zn(II). This
enolate is often called the
Reformatsky reagent after its
inventor, which is fine, and often
drawn as a CZn compound,
which is not fine because it isnt
one.
O

BrZn

zinc enolate

OLi

CO2Et

LDA, 78 C

Reviso: Boron-Mediated Aldol Reaction of Carboxylic Esters,

OEt

There is no danger of self-condensation with zinc enolates as they do not reactTHF


with esters. But
they do react cleanly with
aldehydes
and
ketones
to
give
aldols
on
work-up.
You
will
appreciate that
A. Abiko, Acc. Chem. Res. 2004, 37, 387.
the use of zinc enolates is therefore special to esters: you cannot make a zinc enolate from a 2-brolithium enolate
moaldehyde or an -bromoketone as then you would get self-condensation.
ZnBr

RCHO
OEt

!
The dehydration product from this
aldol product is best made
directly by one of the Wittig
variants we discussed earlier. The

cyclic mechanism for ester


OEt aldol reaction
OEt

OEt

OEt

bad structure

Br

Br

tion works well with the lithium enolate of the ester. The cyc
adds directly to the carbonyl group of the aldehyde and not in

OEtZnBr

Zn

Br
Zn

Prof. Luiz F. Silva Jr - IQ-USP - 2012

O
OEt

Br
Zn

Zinc, like magnesium, is a twoelectron donor and likes to be


Ester enolate equivalents
oxidized from Zn(0) to Zn(II). This

Zinc enolates, made from the bromoesters, are a good a


The mechanism for zinc enolate formation should remind
OH
O
H2O
reagent.
OEt

Br

Zn

OEt

Br
OEt

Zn

OEt

Zn

OE

essary Lewis acid, here TiCl4. The mechanism described on p. 000 gives the aldol after work-up in an
excellent 95% yield. No more than 5% of other reactions can have occurred.

08

27 . Reactions of enolates withCHO


aldehydes and ketones: the aldol reaction

8. Enolatos - Parte 2
CHO

QFL-5928 - Sntese Orgnica

OH

CHO

Me3SiCl

need the silyl enol ether from isobutyraldehyde. The other aldehyde is now added along with the necOSiMe3
TiCl4mechanism described on p. 000 gives the aldol after work-up in an
Et3N essary Lewis acid, here TiCl4. The
excellent 95% yield. No more than 5% of other reactions can have occurred.
95% aldol isolated

stable silyl enol ether

CHO

Other useful specific enol equivalents of aldehydes and ketones are enamines and aza-enolates, OH
which you saw in use in alkylation
in Chapter 26. Aza-enolatesthe lithium enolates of
CHO
CHO Mereactions
3SiCl
OSiMe
iminesderived from aldehydes are useful too in aldol reactions.
Azaenolatos
3
TiCl4and this can be isolated
Et3Nstable imine even with acetaldehyde
Cyclohexylamine gives a reasonably
de aldedos
pode ser realizada de maneira lithium
eficiente com
and lithiated with LDA to give Athecondensao
aza-enolate.stable
The
mechanism
95% aldol isolated
silyl enol etheris similar to the formation of
enolates and the lithium atom binds the nitrogen atom of the aza-enolate, just as it binds the oxygen
azaenolatos. Exemplo:
Other useful specific enol equivalents of aldehydes and ketones are enamines and aza-enolates,
atom of an enolate.
which you saw in use in alkylation reactions in Chapter 26. Aza-enolatesthe lithium enolates of
i -Pr from aldehydes are useful too in aldol
i -Pr reactions.
iminesderived
i -Pr
Li
i -Pr
O
Li
acid or
N
Cyclohexylamine
gives
a reasonably stable imineNeven with acetaldehyde
and this can be isolated
N
N
Lewis acid
LDA
+
and
lithiated
with
LDA
to
give
the
aza-enolate.
The
mechanism
is
similar
to
the
formation of lithium
H + H
H
H
enolates
and
the
lithium
atom
binds
the
nitrogen
atom
of
the
aza-enolate,
just
as
it binds the oxygen
H
H2N
H
H
atom of an enolate.
H H
H

dehyde

o
est not
To
actions
e
sms of
!olysis

primary amine

imine

aza-enolate

i -Pr

i -Pr

i -Pr
Li
i -PrEven the
The aza-enolate
reacts cleanly with other
ketones
to give aldol products.
O
acid oraldehydes or
N
N
N
Lewis acidon another similar enolizable aldehydeoccurs
mostH challenging of cross-couplingsattack
in
LDA
H +
good yield. H +
H
H

H2N

aldehyde

Li

primary amine

H
O

Li
H

H
H

Li imine
N

aza-enolate

The aza-enolate reacts cleanly with other aldehydes or ketones to give aldol products. Even the
H
H
H most challenging of cross-couplingsattack on another
similar enolizable aldehydeoccurs in
mines are susceptible
to
electrophilic and
first
formed
product
contains
good
yield.
ydrolysis and they
are best
not
enolizable
aldehyde
imine and lithium alkoxide

tored but used at once. To


nderstand fully these
The reactions
initial product is a new imine, which
The
Li is easily hydrolysed during acidic aqueous work-up.
Li
ou should ensure you are
N and finally the aldol is dehydrated toOgive the
N
alkoxide is protonated, the imine hydrolysed,
enal
O
amiliar with the mechanisms of
yield in this case.
mine formation65%
and overall
hydrolysis
H
H
H
om Chapter 14.

H+, H2O
imine hydrolysis

Li

electrophilic and
enolizable aldehyde

first formed product contains


imine and lithium alkoxide

H+, H2O

OH

Azaenolatos
The initial product is a new imine,
which is easily hydrolysed during acidic aqueous work-up. The
alkoxide
is protonated, the imine hydrolysed, and finally
H
H the aldol is dehydrated to give the enal
65% overall yield in this case.
imine alcohol
OH

aldol product

Li H
N

H+
dehydration

H+, H2O

final enal product, 65% yield

OH

H
The key to the success of the aza-enolates isH that the imine is first formed from the aldehyde with
imine is
alcohol
the primary amine, a relatively weak base, and under these conditions imine formation
faster than
+, H Othe imine is formed OH
self-condensation. OnlyHafter
is LDAOadded whenH+self-condensation cannot
2
occur simply because no aldehyde is left.
H

imine hydrolysis

aldol product

dehydration

final enal product, 65% yield

The key to the success of the aza-enolates is that the imine is first formed from the aldehyde with
the primary amine, a relatively weak base, and under these conditions imine formation is faster than
self-condensation. Only after the imine is formed is LDA added when self-condensation cannot
occur simply because no aldehyde is left.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

8.4.2. Reao Aldlica de Mukaiyama (Mukaiyama Aldol Reaction)

Mukaiyama, 1973;
Reao entre teres enlicos de silcio e compostos carbonlicos na presena de
um cido de Lewis.
O enol ter pode ser oriundo de aldedos, cetonas, steres e tiosteres.
Exemplo:

Reao de Mukaiyama: Mecanismo

Prof. Luiz F. Silva Jr - IQ-USP - 2012

Me Si OMe SiMe

OMe

3
3
Me3Si
SiMe3
Lithium hexamethyldisilazide

8. Enolatos - Parte 2

H
OSiMe
3
QFL-5928
Sntese
BuLi-OSiMe
3

OSiMe
3 hexamethyldisilazide (LiHMDS) is a little more
Lithium
OSiMe3

lithium
hindered than LDA and a little less basic. Itkinetic
is made
by enolate N
lithium
Me3Si kineticSiMe
3 enolate
deprotonating hexamethyldisilazane with BuLi.

Li
Orgnica
N

Me3Si

SiMe3

Specific enol equivalents for ketones


711
hexamethyldisilazane
lithium hexamethyldisilazide
(LiHMDS)
Lithium hexamethyldisilazide
Lithium hexamethyldisilazide
H
Li
Li
BuLi Hon pentanal was successful and
Lithium hexamethyldisilazide
(LiHMDS)
is a little
more with this lithium enolate
Li the protecting group
AnOLi
aldol
reaction
BuLi
Lithium
hexamethyldisilazide
(LiHMDS)
is
a
little
more
N
N
less basic. It is made by
N and a little(the
OMe
OMehindered than LDA
silyl
ether)
conveniently
fell
off
during
work-up
to
give
gingerol
itself.
However,
the yield was
Me
Me
Si
SiMe
Si
SiMe
N
N
hindered than LDA
a little less basic.
3 It is made by3
3
deprotonating
withand
BuLi.
Me3Si hexamethyldisilazane
SiMe
enol
equivalents3 for
3
Me3ketones
Me3Specific
Si
SiMe
Si
SiMe3
3
deprotonating
hexamethyldisilazane
with
BuLi.
only 57%. When
the silyl
enolum
ether
was used
withlithium
TiClhexamethyldisilazide
hexamethyldisilazane
4 as the Lewis acid catalyst, the yield jumped
Mukaiyama
via
Enolato
Cintico
(LiHMDS)
hexamethyldisilazane
lithium hexamethyldisilazide
to 92%. This is one of the
many
successful
uses
of
this
style of aldol
reaction
OSiMe
OSiMe3
3
(LiHMDS)by Mukaiyama, the
Li
OLi
O
inventor
of the
method.
kinetic
lithium
enolate
An aldol reaction with this lithium enolate
group !
N was successful and the protecting
OMe
OMe on pentanal
! Science
An aldolOLi
reaction
with
this
lithium
on
pentanal
wasOSiMe
successful
and the protecting
group of the
Me3Sito enolate
Teruaki Mukaiyama,
3
(the silyl ether) conveniently
fell
off during
work-up
giveSiMe
gingerol
itself. However,
3the yield was
University
of Tokyo
(and Teruaki
formerlyMuka
of th
(the
silyl
ether)
conveniently
fell
off
during
work-up
to
give
gingerol
itself.
However,
the
yield
was
hexamethyldisilazide
only 57%. When the silyl enol ether was used with TiCl
Lewis
University
of
Tokyo Institute of Technology
and the
4 as theMe
3SiClacid catalyst, the yield jumped OMe
OMe
OSiMe
OSiMe
only
57%.
When
the
silyl
enol
ether
was
used
with
TiCl
as
the
Lewis
acid
catalyst,
the
yield
jumped
3
3
Tokyo
Institu
University of Tokyo) is one
of the
4
H many successful uses
Li style of aldol reaction
to
92%.
This
is
one
of
the
of
this
by
Mukaiyama,
the
amethyldisilazide (LiHMDS) is a little more to 92%. This is one BuLi
foremost Japanese
whose
University
of
enolate
of the many successful
uses of thiskinetic
style lithium
of aldol
reaction by Mukaiyama,
the chemists,
N
inventor
ofmade
the by
method. N
an LDA and a little less
basic. It is
work has had a significant
impact on
foremost
Jap
Me
Me
Si
SiMe
Si
SiMe
3
3
3
inventor
of the 3method.
ng hexamethyldisilazane with BuLi.
the development of the aldol
work reaction
has had
OSiMe
OSiMe

3
and on3other areas of organic
OSiMe
the developm
lithium hexamethyldisilazide
3
Lithium
hexamethyldisilazide
synthesis.
and on other
(LiHMDS)
OLi
OSiMe3
O
OH
O
Me3SiCl
synthesis.
OMe
OMe
H
Li
Me
BuLi
Lithium hexamethyldisilazide (LiHMDS)
more
3SiCl
OMe is a little
OMe
l reaction with this lithium enolate onhindered
pentanal
successful
and
theIt protecting
OMe
N
thanwas
LDA and
a little less
basic.
is made by group N !
H BuLi. the yield
Me3Si
Me3was
Si
SiMe3 Mukaiyama, of the Science
SiMe3
Teruaki
deprotonating
with
her) conveniently fell off during work-up
to givehexamethyldisilazane
gingerol itself. However,
University of Tokyo (and formerly of the
hexamethyldisilazaneOSiMe3
lithium hexamethyldisilazide
3
When the silyl enol ether was used with TiClOSiMe
catalyst, the yield jumped
Tokyo Institute of Technology and the
4 as the Lewis acidOSiMe
(LiHMDS)
OSiMe
gingerol,
92% is
yield
3
3
University
of
Tokyo)
one
of the
TiCl
OH
his is one of the many successful uses
by Mukaiyama,
the
O of this style of aldol 4reaction OH
O
foremost Japanese chemists, whose
O
OH work
O successful
the method.
has
had a significant
impact
on
!
An aldol reaction with this lithium enolate on pentanal
was
and
the
protecting
group
OMe of the aldol reaction
the development
Teruaki Mukaiyama, of the Sc
(the Hsilyl
ether)
conveniently
fell
off
during
work-up
to
give
gingerol
itself.
However,
the
yield
was
OMe
and
on other areas of organic
OSiMe
3
Making
thesilyl
more
substituted
enolate
equivalent:
thermodynamic
enolates
University of Tokyo (and forme
Henol ether
synthesis.
only
57%.
When
the
was
used
with
TiCl
as
the
Lewis
acid
catalyst,
the
yield
jumped
Tokyo Institute of Technology
4
Me3SiCl
OMe
OMe
University
Tokyo)
is one of t
gingerol,
92%
yield
Being
anone
alkene,
enol
or enolate
stable
if it reaction
has more
substituents.theSo the
wayofto
make
This is
of thean
many
successful
uses isofmore
this style
of OH
aldol
by Mukaiyama,
TiCl4 to 92%.
foremost Japanese chemists
gingerol, 92% yield
TiCl
inventor
the 4method.
theof more
substituted enolate equivalent is to make it under conditions
where the
OH
work two
has hadenolates
a significant imp

OLi

hexamethyldisilazane

the development of the aldol r

can interconvert: OSiMe


equilibration will give the more stable. You have seen in Chapter 26 (p. 000)

OSiMe3

3
and on other areas of organic
OLi
OSiMe3
Making the more substituted
enolate equivalent:
thermodynamic
enolates
synthesis.
how
the
silyl
enol
ether
on
the
more
substituted
side
of
a
ketone
can
be
made
by treating
OH
O
Me
SiCl
3
Making the more substituted
enolate equivalent: thermodynamic
enolates
OMe
OMe
Being an alkene, an enol or enolate is more stable if it has more substituents. So the way to make

the ketone with Me3OMe


SiCl and a weak base, but these thermodynamic silyl enol ethers have been
Beingenolate
an alkene,
an enolisortoenolate
is more
stable
if it has
morethe
substituents.
So the way to make
the more substituted
equivalent
make it
under
conditions
where
little used in enolate
aldol reactions.
One
successful
example
istwo
theenolates
thermodynamic
silyl enol ether
more substituted
is to have
makeseen
it under
conditions
OSiMe
3 equivalent
can interconvert:the
equilibration
will give OSiMe
the more
stable. You
in Chapter
26 3(p.where
000) the two enolates
of
1-phenylpropan-2-one:
enolization
on
the
conjugated
side
is
overwhelmingly
favoured
gingerol,
92%
yield
TiCl4
canether
interconvert:
equilibration
give of
theOH
have by
seentreating
in Chapter 26 (p. 000) thermoOH will side
O
how the silyl enol
on the more
substituted
amore
ketone
can You
be made
O stable.
dynamically.
The
aldol
reaction
with
a
2-keto-aldehyde
goes
exclusively
more reactive
how
the silyl enol ether on the more substituted side of a ketonehave
can been
be madefor
by the
treating
the ketone with Me
3SiCl and a weak base, but these thermodynamic silyl enol ethersOMe
aldehyde
group.
H
the reactions.
ketone
with
Mesuccessful
andenolates
aexample
weak base,
butthermodynamic
these thermodynamic
silyl ether
enol ethers have been
3SiCl
little used
in aldol
One
is the
silyl enol
he more substituted
enolate
equivalent:
thermodynamic
little
used
in
aldol
reactions.
One
successful
example
is
the
thermodynamic
silyl enol ether
of
1-phenylpropan-2-one:
enolization
on
the
conjugated
side
is
overwhelmingly
favoured
thermokene, an enol or enolate is more stable if it hasTiCl
more
substituents. So the way gingerol,
to make92% yield
4
OH
O favoured thermoMukaiyama
via um Enolato
Termodinmico
of
1-phenylpropan-2-one:
enolization
on
the
conjugated
side
is
overwhelmingly
dynamically.
with a 2-keto-aldehyde
goes exclusively for the more reactive
ubstituted enolate
equivalent The
is to aldol
make reaction
it under conditions
where the two enolates
O
OH
Thehave
aldol
reaction
with26a (p.
2-keto-aldehyde
goes exclusively for the more reactive
onvert: equilibration
will group.
give the dynamically.
more stable. You
seen
in Chapter
000)
aldehyde
Making
theofmore
substituted
enolate
thermodynamic enolates
H
aldehyde
group.
ilyl enol ether on the more substituted
side
a ketone
can be made
by equivalent:
treating
H

Me3Si
Being
alkene,
an enol silyl
or enolate
is more
stable
if it has
with Me3SiCl and a weak base, but
theseanthermodynamic
enol ethers
have
been
O
O more
O make
O substituents. So the way to
Me
3SiCl
the
more
substituted
enolate
equivalent
is
to
make
it
under
conditions
where
the
two
enolates
in aldol reactions. One successful example is the thermodynamic silyl enol ether
O
OH
O
can
interconvert:
equilibration
will
give
the
more
stable.
You
have
seen
in
Chapter
26
(p.
000) O
lpropan-2-one: enolization on the conjugated side is overwhelmingly favoured
Et3N thermo-H
TiCl4
how
the
silyl
enol
ether
on
the
more
substituted
side
of
a
ketone
can
be
made
by
treating
Me3Si for the more reactive
y. The aldol reaction with a 2-keto-aldehyde goes exclusively
H
1-phenylpropan-2-one
silylsilyl
enolenol
etherethers have been
O
O
Me
SiCl Me3SiCl and a O
the ketone
weak base,Me
but
thesethermodynamic
thermodynamic
3with
roup.
3Si
O
O
O silyl enol ether
O
Me3SiCl
little used in aldol reactions.
One successful example
is the thermodynamic
Et
N
3
of 1-phenylpropan-2-one:
is overwhelmingly
favoured thermo4
O enolization on the conjugated sideTiCl
Et3N with a 2-keto-aldehyde
reaction
reactive
TiClmore
4
1-phenylpropan-2-onedynamically. The aldol thermodynamic
silyl enolOether OH goes exclusively for the
83% yield
aldehyde group. H
1-phenylpropan-2-one
thermodynamic silyl enol ether
Me3SiCl

Me3Si

pan-2-one

TiCl4
thermodynamic silyl enol ether

Me3SiCl

Me3Si

83% yie

Et3N

OH

OH

83% yield

A reao de Mukaiyama
pode ser realizada de maneiraTiCl
assimtrica.
Et3N
4
Reviso:
Diastereoselection in Lewis-Acid-Mediated
Aldol
Reactions, Mahrwald,
1-phenylpropan-2-one
thermodynamic silyl enol
ether

O
83% yield

Chem. Rev. 1999, 99, 1095.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

10

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao Aldlica de Mukaiyama:


Diastereosseletividade
A diastereosseletividade da reao aldlica de Mukaiyama a seguinte:
Quando R2 pequeno e R3 volumoso, a reao leva ao produto anti
independente da configurao da ligao dupla. Estado de transio A o mais
favorecido;
Quando R2 grande e R3 pequeno, o produto sin predomina independente
da geometria do enol ter. Estado de transio D o mais favorecido;
Quando o aldedo capaz de quelao, a formao do diastereoismero sin
favorecida.

Reao Aldlica de Mukaiyama:


Diastereosseletividade

Prof. Luiz F. Silva Jr - IQ-USP - 2012

11

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao Aldlica de Mukaiyama:


Sntese Total

An Approach to the Acetate Aldol Problem


H3C

CH3
O

Use of terminal trimethylsilyl enol ethers p


H3C

SCH3

CH3
O

1. n-Bu2BOTf, i-Pr2NEt
CH2Cl2, 0 C
2. PhCHO
78 23 C

O
O

OH
R
SCH3

O
O

3. Ra-Ni, 60 C
acetone
4. 2N KOH
CH3OH, 0 C

86-99% de

H
R
HN

OH

HO

A temporary substituent is used to afford acetate


aldol products selectively. Simple N-acetyl imides
do not react selectively.

Nu

A transition state is proposed in which the


R = Ph, CH3,
n-C3H7, i-C3H7

Corey, E. J.; Cywin, C. L; Roper, T. D. Tetr

80-90% (4 steps)
86-99% ee

Catalytic, Enantioselective Mukaiyama A

Evans, D. A.;Reao
Bartroli, J.;Aldlica
Shih, T. L. J.de
Am.Mukaiyama
Chem. Soc. 1981,Assimtrica
103, 2127-2129.
An Enantioselective Mukaiyama Aldol Reaction Catalyzed by a Tryptophan-Derived
Oxazaborolidine

O
H

N
H

O
R1

OSi(CH3)3
H

R1

O
N B
n-Bu
Ts

St-Bu

2
3

3
aldehyde

3 (20 mol%), 14 h
C2H5CN, 78 C;

R2

1N HCl/THF
R2

yield (%)

OH O
R1

PhCHO

R2

PhCH2CH2CH
ee (%)

Ph

C6H5

82

89

c-C6H11

C6H5

67

93

2-furyl

C6H5

100

92

n-C4H9

56

86

c-C6H11

OSi(CH3)3
H

furylCHO

c-C6H11CH

PhCH2OCH2C

This reaction is highly sensitive to the sol


The Lewis-acid catalyzed addition of silyl enol ethers to aldehydes is known as
the Mukaiyama Aldol reaction: Kobayashi, S.; Uchiro, H.; Shina, I.; Mukaiyama, T.
Tetrahedron 1993, 49, 1761-1772.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

Keck, G. E.; Krishnamurthy, D. J. Am. Chem

12

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao Aldlica de Mukaiyama Assimtrica

Use of terminal trimethylsilyl enol ethers provide the highest level of enantioselectivities.

H3
O

CH3

OH
R

CH3

Nu

SCH3
3. Ra-Ni, 60 C
acetone
4. 2N KOH
CH3OH, 0 C

O B
O N

H
R

HN

OH
R
A transition state is proposed in which the si face of the aldehyde is blocked by the indole ring.

m CH ,
h,
3
-C3H7, i-C3H7

Use of terminal trimethylsilyl enol ethers provide the highest level of enantioselectivities.

H3C

CH3
O

, i-Pr NEt

% (42 steps)
C
-99% ee

CH3

Corey, E. J.; Cywin, C. L; Roper, T. D. Tetrahedron Lett. CH


1992,
33, 6907-6910.
3

OH

Nu

SCH3

3. Ra-Ni, 60 C
acetone
de
4. 2N KOH
a Tryptophan-Derived CH3OH, 0 C

, 2127-2129.

R = Ph, CH3,
n-C3H7, i-C3H7
80-90% (4 steps)
86-99% ee

OSi(CH3)3

1) (S)-BINOL, Ti(Oi-Pr)4
(20 mol%), 4-MS
Et2O, 20 C

Catalytic, Enantioselective Mukaiyama Aldol Condensation of Silyl Thioketene Acetals

aldehyde

O
e (%)
N B
n-Bu
Ts

yield (%)

89 3
93

OSi(CH
3)3
PhCH
2CH2CHO

80

100

92

56

86

97 OH O

c-C6H11CHO

70

89

PhCH2OCH2CHO

82

>98

R2

82
des is known
as 89
93
67
a, I.; Mukaiyama, T.

97

St-Bu
R
2) Silyl thioketene
acetal>98
furylCHO
88

OH O

ee (%)

ee (%)

1) (S)-BINOL, Ti(Oi-Pr)4
90 4-MS
(20 mol%),
Et2O, 20 C

3) 10% HCl, CH3OH

R1

St-Bu

R
2) Silyl thioketene acetal
3)
10%
HCl,
CH
OH
3 33, 6907-6910.
Corey, E. J.; Cywin, C. L; Roper, T. D. Tetrahedron Lett. 1992,

PhCHO

3 (20 mol%), 14 h
C92
2H5CN, 78 C;

OH O

St-Bu

R2

yield (%)

A transition state
+ is proposed in which the si face of the aldehyde is blocked by the indole ring.

OH
O by a Tryptophan-Derived
action
Catalyzed

861N HCl/THF

Reao Aldlica de Mukaiyama Assimtrica

hem. Soc. 1981, 103, 2127-2129.

R1O

O
O

HN

OH

HO

cetate
l imides

Catalytic, Enantioselective Mukaiyama Aldol Condensation


of Silyl Thioketene Acetals
O B

aldehyde

yield (%)

ee (%)

PhCHO

90

97

PhCH2CH2CHO

80

97

St-Bu

furylCHO
This reaction is highly sensitive to the
solvent and to88reactant>98
concentrations.

c-C6H11CHO

Keck, G. E.; Krishnamurthy, D. J.

PhCHChem.
2OCH2CHO
Am.
Soc.

70
82
1995,

89

117,

>98
2363-2364.

M. Movassaghi
This reaction is highly sensitive to the solvent and to reactant concentrations.

enol ethers to aldehydes is known as


, S.; Uchiro, H.; Shina, I.; Mukaiyama, T.

Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363-2364.

M. Movassaghi

Prof. Luiz F. Silva Jr - IQ-USP - 2012

13

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

8.4.3. Reaes Aldlicas Assimtricas Mediadas por Boro


Caractersticas dos Enolatos de Boro

Homogneos e descomplicados em termos de estados de agregao (o que no


verdade para o enolatos de ltio, por exemplo);
Estados de transio organizados;
Ligaes B-O so relativamente curtas e menos nucleoflicas do que as
correspondentes com metais.

As caractersticas acima so importantes nas reaes estereosseletivas.

Preparao de Enolatos de Boro (Z) e (E)


Para alcanar algum nvel de estereosseletividade preciso primeiro ser
capaz de converter uma cetona no correspondente enolato Z ou E.

Preparation of (Z)- and (E)-Boron Enolates

O tratamento de um cetona com um reagente de dialquilboro e uma amina

(Z)-Selective Prep

terciria leva ao enolato de boro cintico.

O
CH3

Et

(n-Bu)2BOTf

i-Pr2NEt, Et2O
78 C, 30 min

Et

Et

(c-Hex)2BCl
Et3N, Et2O
78 C, 10 min

>97% (Z)

Et

77%

syn

O
PhCHO

CH3
>99% (E)

Ph
CH3

OB(c-Hex)2
Et

OH

PhCHO
78 C

O
CH3

OB(n-Bu)2
CH3

78 C
75%

>99%

OH

Et

Ph

n-Bu
O
H3C

CH3
anti

>97%

Dialkylboron triflates typically afford (Z)-boron enolates, with little sensitivity toward the
amine used or the steric requirements of the alkyl groups on the boron reagent.
InJr
the-case
of dialkylboron
chlorides the geometry of the the product enolates is much more
Prof. Luiz F. Silva
IQ-USP
- 2012
sensitive to variations in the amine and the alkyl groups on boron.

14

n-

Et
Et

CH3
CH3

8. Enolatos - Parte 2

(n-Bu)2BOTf
i-Pr2NEt, Et2O
78
i-Pr2C,
NEt,30Etmin
2O
78 C, 30 min

O
Et O

Et

CH3

(c-Hex)2BCl

CH3

(c-Hex)2BCl
Et3N, Et2O
78 C, 10 min
Et3N, Et2O
78 C, 10 min

Et
Et

OB(nCH
-Bu)
32
CH3

PhCHO
78 C

>97% (Z)

78
77%C

>97% (Z)

77%

OH
Ph
Et CH3 Ph
3
syn CH
>99%
QFL-5928
syn

OB(c-Hex)2
PhCHO
Et OB(c-Hex)2
PhCHO
78
C
CH3
Et
78
75%C
>99%CH
(E3)

Et

Et

- Sntese Orgnica

OO

>99%
OH

Et

B
N

OH
Ph

CH3

Ph
CH
3
anti >97%

>99% (de
E) Boro75%
Preparao de Enolatos
(Z) e (E) anti

>97%

n-B

+ H
n-Bu B
+
nO
-Bu
H3C O
H3C
FAV

F
Dialkylboron triflates typically afford (Z)-boron enolates, with little sensitivity toward the
amine used or the steric requirements of the alkyl groups on the boron reagent.
Dialkylboron triflates typically afford (Z)-boron enolates, with little sensitivity toward the
amine used or the steric requirements of the alkyl groups on the boron reagent.
In the case of dialkylboron chlorides the geometry of the the product enolates is much more
sensitive to variations in the amine and the alkyl groups on boron.
In the case of dialkylboron chlorides the geometry of the the product enolates is much more
sensitive to variations in the amine and the alkyl groups on boron.
The combination of (c-Hex)2BCl and Et3N provides the (E)-boron enolate preferentially.

n-Bu

n-BB
O
O

The combination of (c-Hex)2BCl and Et3N provides the (E)-boron enolate preferentially.

N
O

O
Evans, D. A.; Vogel, E.; Nelson, J. V.; J. Am. Chem. Soc. 1979, 101, 6120-6123.

Observed selectivity:

Evans,
J. V.;L.J.R.;
Am.
Chem.
Soc.
1979, D.
101J., 6120-6123.
Evans, D.
D. A.;
A.; Vogel,
Takacs,E.;
J.Nelson,
M.; McGee,
Ennis,
M. D.;
Mathre,
Bartroli, J. Pure & Appl.
Chem. 1981, 53, 1109-1127.
Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J. Bartroli, J. Pure & Appl.
Chem.
, 1109-1127.
Brown,1981,
H. C.;53
Dhar,
R. K. Bakshi, R. K. Pandiarajan, P. K.; Singaram, B. J. Am. Chem. Soc.
1989, 111, 3441-3442.
Brown, H. C.; Dhar, R. K. Bakshi, R. K. Pandiarajan, P. K.; Singaram, B. J. Am. Chem. Soc.
1989, 111, 3441-3442.

Observed selectiv

Evans, D. A.; Takacs, J


Chem. 1981, 53, 1109Evans, D. A.; Takac
Chem. 1981, 53, 11

Diastereosseletividade Simples em Reaes Aldlicas: Regra Geral

Exceo: no h correlao enolato E/produto anti no caso de enolatos de


ltio de cetonas! Maior seletividade observada com enolatos de boro. Alguns
artigos interessantes: JACS 1981, 103, 3099; JACS 1979, 101, 6120.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

15

H
H3C

8. Enolatos - Parte 2

OML2

R1

din in 1872 where he first


ehyde under the influence of

O
L

R2

QFL-5928 - Sntese Orgnica


CH3

anti
L

R1
R2

R2CHO

H3C
H

O
L

OH
R2

R1
CH3

syn

OH
R2

R1

DISFAVORED
Estado de Transio
de Zimmerman-Traxler

R2

R1

FAVORED

CH3
+

OH

CH3

syn

Zimmerman and Traxler proposed that the aldol reaction with metal enolates proceeds via a
chair-like, pericyclic process. In practice, the stereochemistry can be highly metal dependent.
Only a few metals, such as boron, reliably follow the indicated pathways.
(Z)- and (E)-enolates afford syn- and anti-aldol adducts, respectively, by minimizing
1,3-diaxial interactions between R1 and R2 in each chair-like TS.

OH
R2

R1
CH3

Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920-1923.


Dubois, J. E.; Fellman, P. Tetrahedron Lett. 1975, 1225-1228.

anti
Heathcock, C. H.; Buse, C. T.; Kleschnick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J. Org.
Chem. 1980, 45, 1066-1081.

M. Movassaghi

Estado de Transio de Zimmerman-Traxler

Enolato Z 1,2-sin:

Tipicamente: (n-Bu)2BOTf, i-Pr2NEt


Artigo interessante: JOC 1993, 58, 147.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

16

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Estado de Transio de Zimmerman-Traxler

Enolato E 1,2-anti:

Tipicamente: (c-C6H11)2BCl, Et3N

Exemplos de Reaes Aldlicas com Enolatos de Boro

Seria melhor i-Pr2NEt

Prof. Luiz F. Silva Jr - IQ-USP - 2012

17

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reaes Aldlicas com Enolatos de Boro:


Verso Assimtrica
A maneira mais comum para alcanar induo assimtrica em qualquer tipo
de reao utilizar um elemento quiral dentro de um dos reagentes/substratos para
direcionar sua interao com outro. No contexto das reaes aldlicas, isso est
relacionado com a utilizao de aldedos quirais no racmicos com um
estereocentro no carbono alfa.

Estado de Transio de Zimmerman-Traxler e o Modelo de Felkin-Ahn para


Reao de Enolatos de Boro com Aldedos Contendo um Centro
Estereognico no Carbono

Prof. Luiz F. Silva Jr - IQ-USP - 2012

18

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao Aldlica Assimtrica de Enolatos de Boro:


Aldedo Quiral

Pequena estereosseletividade observada, se o grupo em alfa no aldedo


no for muito volumoso.

Reao Aldlica Assimtrica de Enolatos de Boro:


Enolato e Aldedo Quirais (Double Asymmetric Induction)

Excelente
diastereosseletividade foi
obtida: Matched.
1,2-sin

Prof. Luiz F. Silva Jr - IQ-USP - 2012

19

Bn

a
Enolatos
yield of 8.
B (%)

CH3

CH3 CH2

78 0 C

CH3 CH2

90%

- Parte 2

QFL-5928 - Sntese Orgnica

Esterification:

16

H3C

100

H3C
O

H3C
H
O

O
CH3

CH3

CH3

N
O
Mtodos
para a Remoo do Auxiliar Quiral
Other Methods for Removal
CH3 of the Chiral Auxiliary
Ph
BnOLi
THF, 0 C
Reductive cleavage:

<1
30

N
R
H
OH
clic carbonyl group.
B

O
Bn

mides.

yield of B (%)a
dinone-derived
.

77%

O
H
N3C

Br

CH3 CH2
H3C
CH3 O
H
H
BnO
O

H3C
CH3
LiAlH4, THF
Br
O
HO
OBOM OBn
O
78 0 C
CH3 CH2
CH3
CH3
CH3 90%

Esterification:
Transamination (as before):

16

H3C

CH3
O
H3C
OH
O
Al(CH
)
OBn
OBOM
3 3
CH3
O
CH
O
3
O
N
H3C
N
CH3
OBn
CH3 OCH3ONHCH3HCl
O
H
H
CH3 OBn
CH
Cl
,
0
C
Bn
2 2 CH
CH3
CH
3
3
N
O
O
92%
CH3
Ph
BnOLi
THF, 0 C
A free -hydroxyl group is required.
O

100
O
OH
N3

<1
30

NHBoc
OBn
O

ocyclic carbonyl group.

O
, 6141-6144.
yl
imides.
N
R
+
H
OH
zolidinone-derived
ary.
B

O of B (%)a
A (%)a yield
OH
N3 16
100
NHBoc
OBn

O
<1

e presence of 30
unactivated

oduct.
28, 6141-6144.

he exocyclic carbonyl group.

ed acyl imides.

f oxazolidinone-derived
auxiliary.

CH3
CH3

Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc.


1988, 110, 2506-2526.
77%
H3C
CH3
O
H3C
OBOM OBn
O
H3C
O
CH3
H
H
CH3
CH3
BnO
O

M. Movassaghi

Transamination (as before):


O

O
O

OH

OH
CH3

N
OBn

N3
OProf.

OH

77%
Weinreb amides can be readily converted into ketones or aldehydesH(see:
Nahm, S.; Weinreb.,
3C
Other Methods for Removal of the Chiral Auxiliary
CH3
S. M. Tetrahedron Lett. 1981, H
22C
, 3815-3818).
O
3
OBOM OBn
O
Reductive cleavage:
H
C
3
Evans, D. A.; Bender, S. L.; Morris, J. J.OAm. Chem. Soc. 1988, 110, 2506-2526.
CH3
H
H
O
O
CH3
CH
3
BnO
O
Br
LiAlH4, THF
Br
M. Movassaghi
O
N
HO
CH3 CH2
78 0 C
Transamination (as before):
CH3 CH2
Mtodos
Bn para
CH3a Remoo do Auxiliar Quiral
90%
OH
O
O
OH
O
Al(CH3)3
CH3
Esterification:
CH3O
CH3
O
N
N
OBn
CH3 CH3ONHCH3HCl
OBn
CH3
CH
H
CH2Cl2, 0 C
Bn
3C3
CH3
CH3
O
H3C
92%OBOM OBn
O
H3C
O
CH3
O
H
A free -hydroxyl group is required. H
CH3
CH
3
N
O
O
Weinreb amides can be readily converted into ketones or aldehydes (see: Nahm, S.; Weinreb.,
CH3
S. M. Tetrahedron Lett. 1981,
Ph 22, 3815-3818).
BnOLi
THF, 0 C

esence of unactivated

CH3

OBOM OBn

Bn

CH3

Luiz
F. Silva Jr - IQ-USP - 2012
NHBoc
OBn

CH3

Al(CH3)3
CH3ONHCH3HCl
CH2Cl2, 0 C
92%

O
CH3O

OH

N
CH3 OBn

CH3
CH3

20

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao Aldlica Assimtrica de Enolatos de Boro: Sntese Total


Reao Aldlica Assimtrica de Enolatos de Boro:


Enolato e Aldedo Quirais (Double Asymmetric Induction)

Sempre formado o enolato boro Z com as oxazolidinonas quirais de Evans.


Ento como fazer para obter o produto 1,2-anti?

Prof. Luiz F. Silva Jr - IQ-USP - 2012

21

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao Aldlica Assimtrica de Enolatos de Boro:


Formao do Produto de Aldol 1,2-Anti

Reao Aldlica Assimtrica de Enolatos de Boro:


Formao do Produto de Aldol 1,2-Anti

O centro estereognico no enolato na verdade um auxiliar quiral:

Prof. Luiz F. Silva Jr - IQ-USP - 2012

22

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao Aldlica Assimtrica de Enolatos de Boro:

Paterson Aldol

Concluso das Reaes Controladas pelo Substrato


CH3
Reviews:

Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.

Enolatos quirais fornecem o produto com excelente estereocontrole;

Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317.

Utilizando apenas aldedos quirais modesta diastereosseletividade


Syn-Aldol Adducts via Enol Diisopinocamphenylborinates

obtida.
O
H3C

R1

OBIpc2

()-Ipc2BOTf
i-Pr2NEt

H3C

R1

OH O
R2CHO, 15 C;

ketone

aldehyde

CH3
CH3
O

H3CO OCH3
CH3
CH3

CH3 CH3

ereomer)

H3C

H3C
O

CH3
O

H3C

ee (%)

yield (%)

98:2

91

78

96:4

66

45

96:4

80

84

CHO
CH3

O
H3C

R1
CH3

syn:anti

CH3

O
H3C

R2

H2O2

CH2Cl2,78 C

CHO
CHO

CH3

CH3

95:5
88
99
CHO
CH3
O
CH3 Assimtrica
Reao Aldlica
de Enolatos de Boro:
CH3
97:3
86
79
H3C
Reaes Controladas
Mtodo de Paterson

CH3 pelo Reagente
CHO

H3CO OCH3
CH3
CH3 CH3

Enolization occurs selectively on the less hindered side of the ketone and with (Z)-selectivity.
The (E)-Enolate, generated in low yield using ()-Ipc2BCl, does not lead to a selective
anti-aldol reaction.

F, 0 C;
Cl, 25 C

Highest enantioselectivities are obtained with unhindered aldehydes.

H3

CH3 CH3

Aldol additions of methyl ketones are not highly enantioselective (53-73%).


CH3

Premonensin

Paterson Aldol

8.

Paterson, I.; Goodman, J. M.; Lister, M. A.; Scumann, R. C.; McClure, C. K.; Norcross, R. D.
Tetrahedron 1990, 46, 4663-4684.
M. Movassaghi

CH3

+ H

CH3 CH3

Sn(OTf)2
ethylpiperidine
H2Cl2, 78 C

Reviews:
Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317.

94%, 94% de

Syn-Aldol Adducts via Enol Diisopinocamphenylborinates

OH

CH3
O

CH3 CH3
H3C

aBH(OAc)3
AcOH

R1

()-Ipc2BOTf
i-Pr2NEt

OBIpc2
H3C

R1

OH O
R2CHO, 15 C;
H2O2

CH2Cl2,78 C

R2

R1
CH3

Prof. Luiz F. Silva Jr - IQ-USP - 2012

23

1%, >94 de

OH
CH

ketone

aldehyde

syn:anti

ee (%)

yield (%)

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica


Paterson Aldol

O
CH3

Reviews:

CH3 CH3

OTf)2
piperidine
, 78 C

Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.

Reao Aldlica Assimtrica de Enolatos de Boro:

Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317.

Reaes Controladas pelo Reagente Mtodo de Paterson


94% de

Syn-Aldol Adducts via Enol Diisopinocamphenylborinates


CH3

CH3
H3C

OAc)3
H

OBIpc2

()-Ipc2BOTf
i-Pr2NEt

R1

H3C

OH O
R2CHO, 15 C;

R1

R2

R1

H2O2

CH2Cl2,78 C

CH3

94 de
ketone

CH3

aldehyde

H3C

CH3
CH3

H3C
O

O
H3C

CH3

H3C

CH3
O

CH3
CH3

H3C

CH3 CH3

91

78

96:4

66

45

96:4

80

84

95:5

88

99

H3C

97:3

86

79

CHO
CHO

CHO

CH3
O
CH3

undesired diastereomer)

98:2

CH3

CH3

yield (%)

CHO
CH3

O
H3C
H3CO OCH3

ee (%)

CH3

CH3

syn:anti

CH3

CH3

CHO

H3CO OCH3
CH3

H3C

CH3

CH3 CH3

The (E)-Enolate, generated in low yield using ()-Ipc2BCl, does not lead to a selective
anti-aldol reaction.

h, THF, 0 C;
H2O, HCl, 25 C
58%

Enolization occurs selectively on the less hindered side of the ketone and with (Z)-selectivity.

Highest enantioselectivities are obtained with unhindered aldehydes.


Anti-Aldol Reactions of Lactate-Derived Ketones

Aldol additions of methyl ketones are not highly enantioselective (53-73%).

Proposed Origin of Selectivity:

Reao Aldlica Assimtrica de Paterson

CH3
H3C

CH3

CH3 CH3
Premonensin

Paterson, I.; Goodman, J. M.; Lister, M. A.; Scumann, R. C.; McClure, C. K.; Norcross, R. D.
OB()-Ipc2
Tetrahedron 1990, 46, 4663-4684.H3C
R1

CH3

BzO

1. (c-Hex)2BCl
(CH3)2NEt BzO

OB(c-Hex)2 1. RCHO, 1
78 2

Et2O, 0 C
2 h.

CH3

2. H2O2, pH
CH3OH, 0

CH3 CH3

R2CHO

08, 2476-2478.

aldehyde

M. Movassaghi

H3C

CHO

H3C

CHO

H3C
H3C

de (%)

CH3

94

CHO
CH3

H3C

yield (%
95

99

82

90

97

96

97

99

85

CHO
H3C
H

CH3 H

R1
H

CH3

CH3

R1
H
CH3

O
O H3C

R2

PhCHO

H3C
H

H
CH3 H
B

R2
CH3

DISFAVORED

CH3
CH3

O
O H3C

Diastereofacial selectivity is very high; -chiral aldehydes afford a


diastereoselectivity regardless of their stereochemistry.

BzO

OH

FAVORED

CH3

R2

R1
CH3

MATCHED

OB(c-Hex)2
+

MISMATCHED

Other examples:
O

Paterson, I.; Goodman, J. M.; Lister, M. A.; Scumann, R. C.; McClure, C. K.; Norcross, R. D.
Tetrahedron 1990, 46, 4663-4684.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

OBn
CH3

BzO
Diastereofacial selectivity is believed to be due to a favored transition state wherein
steric interactions between the ()-Ipc ligand on boron and the R1 substituent on the ketone
are minimized.

OBn
CH3

CH3 CH3

OH O
R1

OB(c-Hex)2
+
CH3 CH3

BzO

R2

Isolated yield for 3 steps.

CH3
CH3

(c-Hex)2BCl
(CH3)2NEt

O
BzO
CH3

i-PrCHO

95%, 86
O
OBn

BzO
CH3

(c-Hex)2BCl
(CH3)2NEt

i-PrCHO

O
BzO

24

CH3 O

77%, 98

R2

8. Enolatos - Parte 2

B
O
H
O 3C

CH3

CH3

B
O
H
O 3C

R2
CH3

DISFAVORED

CH3

diastereoselectivity regar

OB(c-Hex)2
QFL-5928 - Sntese Orgnica
+
BzO

CH3 CH3

FAVORED

BzO

CH3 CH3

OH O
OH O
Reao
Aldlica Assimtrica de Paterson
R2

R1

R2

CH3

OB(c-Hex)2
+

R1
CH3

Other examples:
O
BzO

Diastereofacial selectivity is believed to be due to a favored transition state wherein


steric interactions between the ()-Ipc ligand on boron and the R1 substituent on the ketone
are minimized.

Paterson, I.; Goodman, J. M.; Lister, M. A.; Scumann, R. C.; McClure, C. K.; Norcross, R. D.
Tetrahedron 1990, 46, 4663-4684.

CH3

O
BzO
CH3

Reao Aldlica Assimtrica de Enolatos de Boro:


Reaes Controladas pelo Reagente

Prof. Luiz F. Silva Jr - IQ-USP - 2012

25

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

8.4.4. Reao Aldlica Assimtrica catalisada por Prolina:


Proline-Catalyzed Asymmetric Aldol Reaction of Acetone

Proline-Catalyzed Asymm

Organocatlise
H

O
H3C

CH3

OH
NH (30 mol%)

+
H

DMSO

+
H3C

H3C

OH

aldehdye

yield

%ee

aldehdye

p-NO2C6H4CHO

68 (60)

76 (86)

c-C6H11CHO

C6H5CHO

62 (60)

60 (89)

i-PrCHO

p-BrC H CHO

74 (85)

65 (67)

o-ClC6H4CHO

94 (71)

69 (74)

6 4
Proline-Catalyzed Asymmetric
Aldol Reaction of Acetone

O 54 (60)
H
OH(65)
97
NH (30 mol%)

-napthaldehyde

i-PrCHO

O
H3C

OH

c-C6H+11CHO
CH3

t-BuCHOH

81

yield85

aldehdye
CHO

t-BuCH2CHO

77 (88)
O

OH

84 (83)
H3C

>99

H3C CH3 O

%ee >99

H32C6HCH
p-NO
3
4CHO

68 (60)

76 (86)

C6H5CHO

62 (60)

60 (89)

NH

94 (71)

63 (45)

OH

Ph

DMTC

CHO
yield (%)

c-C6H11CHO

CH3

o-ClC6H4CHO

60
95

t-BuCH
CHO
38 regio
The 2reaction
is highly
CHO ratio (dr) and e
the anti:syn
O
andOaromatic aldehydes,
t
40
H3C eclipsing interaction betwe
CH3

H3C CH3 O

List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395-2396.

The anti-diol product forme


i-PrCHO
62
reaction complementary to

5,5-Dimethyl thiazolidinium-4-carboxylate
(DMTC)
has also
t-BuCHO
81
>99 been found to be an efficient
S
OH
amino acid catalyst for the acetone aldol reaction. Results with this catalyst
are
H
85
>99
CHO
NH
shown above in parentheses.
DMTC
H3C CH3 Assimtrica catalisada por Prolina
Reao Aldlica

CHH3

aldehdye

69 (74)

84 (83)

OO

OH

Tertiary and -branched


aldehydes result54in(60)
the highest77yields
-napthaldehyde
(88) and enantioselectivities, while
unbranched aliphatic
aldehdes give poor97
yields
i-PrCHO
(65) and enantioselectivities.
96 (96)
c-C6H11CHO

H3+C

H3C

p-BrC
74 (85) is used65
Typically a 20-30
equivalent
in (67)
relation to the aldehyde.
6H4CHO excess of acetone
o-ClC6H4CHO

CHO

96 (96)

63 (45)

DMSO

o-ClC6H4CHO

Proline-Catalyzed Asymmetric Aldol Re

shown below.

Ph

CHO

51 Che
Notz, W.; List, B. J. Am.
CH3

The anti-diol
product formed
notSelecti
readily
Proposed
Originisof
reaction complementary to the Sharpless

Typically a 20-30 equivalent excess of acetone is used in relation to the aldehyde.

Kandasamy S.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260-5267. The reaction is highly regioselective, and
O
Tertiary and -branched aldehydes result in the highest yields and enantioselectivities, while

aliphatic
aldehdes
give
poor
yields
and enantioselectivities.
Theunbranched
transition state
shown
below
has
been
proposed
to account for the stereoselectivity of
proline-catalyzed aldol reactions.
5,5-Dimethyl thiazolidinium-4-carboxylate (DMTC) has also been found to be an efficient
O aldol reaction. Results with this catalyst are
amino acid catalyst for the acetone
H
shown above in parentheses.

OH

the anti:syn ratio (dr) and enantioselectivi


and aromatic
O
H3Caldehydes, the poor anti:syn
H
eclipsing interaction between the alcohol
OH
OH
shown below.

NH

Notz, W.; List, B. J.


+ Am. Chem. Soc. 2000, 1

OH Proposed Origin of Selectivity:


O
O
O
O
H
CH3 H
R
H3C
H3C
R
H3CChem. Soc.
Kandasamy S.; Notz, W.; Bui, T.; Barbas, C. F., III.HJ. Am.
O2001, 123, 5260-5267.
O
H
R
O

NH
List, B.; Lerner,
R. A.; Barbas,
C. F., III. J. Am. R
Chem. Soc. 2000,
N 122H, 2395-2396.
+

The transition state shown below has been proposed to account for the stereoselectivity of
proline-catalyzed aldol reactions.

H3C

OH

Rankin,K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A. 2002, 106, 5155-5159.
H

Bahmanyar, S.; Houk, K. N.; Martin,


H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475-2479.
OH
O

NH

H3C

CH3 H

N
O
H O
H H3C

H3C

OH
NH

+
O

Rankin,K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A. 2002, 106, 5155-5159.
Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475-2479.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

OH

H
O

eclipsing
interaction

26

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao Aldlica Assimtrica catalisada por Prolina

ne

Proline-Catalyzed Asymmetric Aldol Reaction of Hydroxyacetone


O

H
O

OH

H3C

H3C

NH

OH
(30 mol%)

OH

H3C

DMSO

OH

OH

%ee

aldehdye

yield (%)

anti:syn

%ee (of anti product)

76 (86)

c-C6H11CHO

60

>20:1

>99

60 (89)

i-PrCHO

62

>20:1

>99

65 (67)

o-ClC6H4CHO

95

1.5:1

67

t-BuCH CHO

38

1.7:1

>97

69 (74)

2
Proline-Catalyzed Asymmetric
Aldol Reaction of Hydroxyacetone

Acetone

77 (88)

96 (96)

H 84 (83)
mol%)

>99

H3C

>99

O CH3

OH

S
R

NH

76 (86)

65 (67)

antioselectivities.
0)
77 (88)
96 (96)

also been84found
to be an efficient
(83)
H3C CH3 O
ults with this catalyst are

5)

>99

>99

NH

. 2000, 122, 2395-2396.

DMTC

C) has also been found to be an efficient


n. Results with this catalyst are

OH

sed to account for the stereoselectivity of

2002, 106, 5155-5159.

OH

>20:1

51

>95

yield (%)

>95
>20:1
Reao Aldlica 51
Assimtrica
catalisada
por Prolina

The anti-diol product formed is not readily accessible via asymmetric dihydroxylation, making this
H
reaction complementary to the Sharpless asymmetric dihydroxylation.

OH

HO
H
R

R
O

R HO

H3C

eclipsingH
interaction

OH
NH

HO
R

eclipsing
interaction

Prof. Luiz F. Silva Jr - IQ-USP - 2012

O
HN3C

N
H O

OH

O
H3C

R
OH

H3C

OH

Chris Coletta

O
N
H O

OH

H3C

FAVORED

H
DISFAVORED
H3C
O

OH

. Am. Chem. Soc. 2003, 125, 2475-2479.

OH

Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-7387.

em. A. 2002, 106, 5155-5159.

HO substrates (-branched
N
The reaction is highly regioselective, and with R
suitable
Haliphatic aldehydes)
O
H3C
O
O
Hthe
3C anti:syn ratio (dr)Hand enantioselectivity are excellent. In the
H case of -unbranched aldehydes
H
C
and aromatic
aldehydes,
the
poor
anti:syn
selectivity
is
thought
to
result
from
a
decrease
in
an
3
OH
O
H
OH
eclipsing interaction between the alcohol and the aldehyde in the disfavored boat transition state
FAVORED
NH
shown below.

H3C

DMSO

Notz, W.; List,


J. Am. Chem. Soc. 2000, 122, 7386-7387.
Ph B.CHO

Chem. Soc. 2003, 125, 2475-2479.

H3C

>97
OH

%ee (of anti product)


anti:syn
The anti-diol product formed is not readily accessible via asymmetric dihydroxylation, making this
c-C6H11CHO
60
>99
>20:1
reaction complementary
to the Sharpless
asymmetric dihydroxylation.
i-PrCHO
62
>99
>20:1
o-ClC
H
CHO
95
67
1.5:1
6
4
The reaction is highly regioselective, and with suitable substrates
(-branched aliphatic aldehydes)
t-BuCH
38
the anti:syn
ratio
(dr) and enantioselectivity
In the case of -unbranched aldehydes
1.7:1are excellent.>97
2CHO
and aromatic aldehydes,
the poor anti:syn selectivity is thought to result from a decrease in an
CHO
O
eclipsing interaction
between40the alcohol2:1
and the aldehyde
in the disfavored boat transition state
>97
O
C
shownH3below.

OH

OH

O Origin of Selectivity:
Proposed

J. Am. Chem. Soc. 2001, 123, 5260-5267.

N
O
H O
H3C

NH
R

2:1

OH
(30 mol%)

CH3 of Selectivity:
Proposed Origin

account
for the
ofwhile
highest
yields
andstereoselectivity
enantioselectivities,
and enantioselectivities.

N
H
O
H3C
m. Soc. 2000, 122, 2395-2396.
O

CH3

OH

Chem. Soc. 2001, 123, 5260-5267.


s used in relation to the aldehyde.

CHO

CH

while
1)yields and
69 enantioselectivities,
(74)

5)

Ph

aldehdye3

DMTC

0)
in relation60to(89)
the aldehyde.

5)

H3C

OH

40

H3C

H3C CH3 O

%ee

0)

CHO

H
O

OH
R

H3C
OH

DISFAVORED
Chris Coletta

27

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao Aldlica Assimtrica catalisada por Prolina


The aldol products from -oxyaldehydes can be
of carbohydrates.

Proline-Catalyzed Enantioselective Cross-Aldol Reaction of Aldehydes


O

O
+ H

10 mol% LProline
R2

OH

DMF, 4 C

R2

R1

R1
R1

R2

yield (%)

anti:syn

%ee

Me

Et

80

4:1

99

Me

i-Bu

88

3:1

97

Me

c-C6H11

87

14:1

99

Me

Ph

81

3:1

99

Me

i-Pr

82

24:1

>99

n-Bu

i-Pr

80

24:1

98

Bn

i-Pr

75

19:1

91

Slow addition via syringe pump of the donor aldehyde to a solution of the acceptor
aldehyde and proline is required in order to avoid dimerization of the donor aldehyde.

TIPSO

OH

OR

10 mol% L-Proline
solvent, rt, 24-48h

OAc
OH
Glucose

Solvent

yield (%)

anti:syn

H
OBn

Bn

DMF

73

4:1

98

DMF

64

4:1

97

Reformatsky, 1887;

DMF/dioxane

61

9:1

96

TIPS

DMSO

92

4:1

95

2002, 124, 6798-6799.

OR MgBr2OEt2
65%, 10:1 dr
98% ee

OH
O

OBn
OBn

BnO

H3

BnO

O
O

H
O
O
O
H
O
H O

OBn
OBn
OBn

Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. So

Reviso: Tetrahedron 2004, 60, 9325.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

TMSOTf
74%

Reao de -halosteres,
principalmente
aldedos ou com cetonasH3C
dioxane
TBS
62 bromo,
3:1 com 88
Northrup, de
A. B.;
Mangion,
I. K.; Hettche, F.; MacMillan, D. W. C. J. Am. Chem. Soc.
na presena
Zn
metlico.

OBn
OBn

TMSO

8.4.5.
Reao
de
MOM
DMF
42 Reformatsky
4:1
96
TBDPS

OH

98%ee
78%

HO

PMB

87% yie
>19:1 dr, 9

D-proline

OR

%ee

OH
Manno

Northrup, A. B.; MacMillan, D. W. C. Science 2004,

OR
R

TIPSO

Application in Total Synthesis: Brasoside

OH

TIPSO

79% yield
10:1 dr, 95% ee

Proline-Catalyzed Direct and Enatioselective Aldol Reaction of -Oxyaldehydes


O

OTIPS

MgBr2Et2O
CH2Cl2
20 4 C

Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798-6799.

TIPSO

MgBr2Et2O
Et2O
20 4 C
TIPSO

OH

DMSO
92%, 4:1 (anti:syn)
95% ee

O
The acceptor aldehyde must not be amenable to enamine formation upon extended exposure
to proline in order to avoid self condesation. Either non-enolizable aldehydes or aldehydes
containg - or -branching are suitable acceptor aldehydes for this reaction.

10 mol% L-Proline
H
TIPSO

28

OEt

tion works well with the lithium enolate of the ester. The cyclic mechanism ensures that the enolate
CO2Et
OEt
adds directly
THF to the carbonyl group of the aldehyde and not in a conjugate (Michael) fashion.

cyclic mechanism
for 2
ester
8. Enolatos
- Parte
aldol reaction

CO2Et

lithium enolate

QFL-5928
72% yield - Sntese Orgnica

OLi

CHO

LDA, 78 C

OH

CO2Et
Zinc enolates, made from the bromoesters, are a good
OEt alternative to lithium enolates of esters.
THF
The mechanism for zinc enolate formation should remind you of the formation of a Grignard
reagent.
lithium enolate
72% yield
Zn

Zn

ZnBr

Zinc enolates, made from the bromoesters, are a good alternative to lithium enolates of esters.

O
Br O
nc, like magnesium, is a twoThe mechanism
for
zinc
enolate
formation
should remind you of the formation of a Grignard
Br
ectron donor and likes to be
Reao de Reformatsky: Mecanismo
OEt
idized from Zn(0) to Zn(II). This
OEt
OEt
reagent.
olate is often called the
zinc enolate
Zn
eformatsky !
reagent after its
Zn
ZnBr
O of self-condensation O
There is no danger
with zinc enolates as they
ventor, which is fine, and often
O do not react with esters. But
Br
Zinc, like magnesium, is a twoawn as a CZn compound,
they do reactBrcleanly with aldehydes and ketones to give aldols on work-up. You will appreciate that
electron donor and likes to be
hich is not fine because it isnt
OEt
theThis
use of zinc enolates is
therefore special to esters:
a zinc enolate from a 2-brooxidized from Zn(0) to Zn(II).
OEt you cannot makeOEt
e.
enolate
is
often
called
the
moaldehyde
or
an
-bromoketone
as
then
you
would
get
self-condensation.
zinc enolate
O
Reformatsky reagent after its
BrZn
Br
Br
There is no danger of self-condensation with zinc enolates as they do not react with esters. But
inventor,OEt
which is fine, and often
ZnBr
Zn with aldehydes andZn
drawn
as a CZn compound, O
they do reactOcleanly
ketones
to give aldolsOH
on work-up.
You will appreciate that
bad
structure
O
O
O
O
H2O
RCHO
which is not fine because it isnt
the use of zinc enolates is therefore special to esters: you
cannot make a zinc enolate from a 2-broone.
OEt moaldehyde
R or an -bromoketone
OEt
R as then you would
OEt get self-condensation.
R
OEt

e dehydration product
from this
BrZn
Br
Br
OEt
dol product is best made
ZnBr
Zn
Zn
O
ectly by one of the Wittigbad structure
O
O
O
O
OH
Ester
enolate
equivalents
H2O
RCHO
riants we discussed earlier. The
me bromoester is of course the
!
OEt
For aldol reactions
with an
equivalent,
use
R ester enolate
OEt
R
OEt
R
arting material for the ylid
The
dehydration
product
from
this
nthesis.
OLi
lithium enolates or
aldol product is best made
R
CO2Et
directly by one of the Wittig
R
Ester enolate equivalents
OEt
variants we discussed earlier. The
same bromoester is of course the
lithium
enolate
For aldol reactions with an ester enolate equivalent, use
starting material for the ylid
synthesis.
OLi
lithium
OSiMe
silyl enol ethers
or enolates or

O
OEt

CO2EtR

CO2Et
R

R
OEt

OEt

silyl enol etherlithium enolate

silyl enol ethers or


zinc enolates

CO2Et
R

Br Mecanismo
Reao de Reformatsky:

OEt

Enols
and enolates from free carboxylic acids
relacionada tanto com relao a

OEt

silyl enol ether

zinc enolate

A reao zinc
de Reformatsky
enolates est

OSiMe3

OZnBr

CO2Et
R

CO2Et

OZnBr
R

Br
OEtinsuperYou might think that the presence of the acidic proton in a carboxylic
acid would present an
organometlicos quanto com reaes
able barrier to the formation and use of any enol derivatives. In fact, this is zinc
not enolate
a problem with
either
the lithium
enolates
or the silyl enol
aldlicas.
O reagente
de Reformatsky
do ethers. Addition of BuLi or LDA to a carboxylic acid

Enols andcristaliza
enolatescomo
fromum
free carboxylic acids
t-butil bromoacetato
You might think that the presence of the acidic proton in a carboxylic acid would present an insuperable barrier to the formation and use of any enol derivatives. In fact, this is not a problem with
either
enolates
(enolato
) q the
u a nlithium
to um
a C - or
Z nthe silyl enol ethers. Addition of BuLi or LDA to a carboxylic acid
dmero tendo tanto uma ligao O-Zn

(organometlico).

Prof. Luiz F. Silva Jr - IQ-USP - 2012

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8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao de Reformatsky: Sntese Total

Reao de Reformatsky: Exemplos

Com 2-alquil-ciclo-hexanonas, a reao mostra uma preferncia para


ataque equatorial.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

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8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

8.4.6. Reao de Mannich


Tollens e von Marle, 1903;
Mannich, 1917, comprovaram a generalidade da reao;

Reao de Mannich
Reao entre uma cetona (ou aldedo) enolizvel, um aldedo (tipicamente
formaldedo) e uma amina primria ou secundria;
til na obteno de compostos -aminocarbonlicos.
Equao Geral:

Reviso: The Direct Catalytic Asymmetric Mannich Reaction Crdova, Acc.


Chem. Res. 2004, 37, 102.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

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Reao de Mannich: Mecanismo

Reao de Mannich: Exemplos

Prof. Luiz F. Silva Jr - IQ-USP - 2012

32

tion, this is just an intermediate but it is quite stable and the corresponding iodide is sold as
Eschenmosers salt for use in Mannich reactions.
H

O
8. Enolatos - Parte
2N
H

Me
O

Me

Me

Me

HO

Me

HCl

Me

H2O

QFL-5928 -MeSntese Orgnica

Me

Me

nucleophilic attack on more


electrophilic C=O group

H2C

Me

imine salt

The electrophilic salt can now add to the enol (we are in acid solution) of the ketone to give the
product of the reaction, an amine sometimes called a Mannich base.
O

OH

27 . Reactions of enolates with aldehydes and ketones:


Me the aldol reaction
HCl

H2C

NMe2

Me
Reao de Mannich seguida
de Eliminao:
But a more general solution is to use the Mannich
reaction.
A
typical
example is shown here:
Preparao de Enonas
By using
this reaction,
you can(here
add one
of formaldehydeone
onlyto carbonyl comthe reaction involves an enolizable
aldehyde
or ketone
we molecule
use cyclohexanone),
a secondary
pounds. You
might, of
course, reasonably object that the product is not actually an aldol product at
amine (here dimethylamine),
the Mannich
reaction
allindeed, O
if you wanted the aldol product, theOMannich reaction would be of little use to you. It
formaldehyde as its aqueous
remains a very important reaction. First of all, it is a simple way to make amino-ketones
solution, and catalytic HCl.nevertheless
The
Me2NH, CH2=O
and many drug molecules belong
to this class. Secondly, the Mannich products can be converted to
product is an amino-ketone
NMe2
85% yield
enones. We will discuss this reaction next.
from the addition of one molecatalytic
HCl
The most reliable method
for making
the enone is to alkylate the Mannich base with MeI and
cule each of formaldehydethen
andtreat the ammonium salt with base. Enolate ion formation leads to an E1cB reaction rather like
the amine to the ketone. the dehydration of aldols, but with a better leaving group.
The mechanism involves the preliminary formation of an imine salt from the amine and
O
O
O
formaldehyde. The amine is nucleophilic
and attacks
the more electrophilic ofOthe two carbonyl
Me
I
S
2
compounds available. That is,
of course, formaldehyde.
No acid is needed for this addition step, butE1cB
N
NMe
2
NMe3
NMe3
acid-catalysed dehydration of the addition product gives the
H imine salt. In the normal Mannich reacOH corresponding iodide is sold as
tion, this is just an intermediate but it is quite stable and the
1. alkylate
amine
give ammonium
salt 2. treat with base: E1cB elimination gives enone
Eschenmosers salt
for use
intoMannich
reactions.

Enones like this, with two hydrogen atoms at the end of the double bond, are called exo-methylene
Me be made or stored. They
H
Me certainly cannot be
HCl
compounds;
they are Me
very reactive,
and cannot easily
N
H2O
O
N
HO
N
H2C The
N solution is to make the
Me
made
by
aldol
reactions
with
formaldehyde
alone
as we have seen.
Me
H
H
Me
Me
Me
Mannich base, store that, and then to alkylate and eliminate only when the enone is needed. We shall
nucleophilic attack on more
imine salt
see how useful this is in the Michael reaction in Chapter 29.
electrophilic C=O group
If the enone is wanted, the secondary amine does not end up in the molecule so the more conveN
N
The
now(less
addvolatile
to theand
enolless
(we
are incyclic
acidamines,
solution)
of the ketone
to give the
nient
smelly)
pyrrolidine
and piperidine,
are often used. Enones
H electrophilicHsalt can
product
of the reaction,
amine
sometimes called
a Mannich
monosubstituted
double
bonds canbase.
be made in this way.
pyrrolidine
piperidinean with

ne

Me

Me

OH
HCl

H2C

Me

NMe2

Me

By using this reaction, you can add one molecule of formaldehydeone onlyto carbonyl compounds. You might, of course, reasonably object that the product is not actually an aldol product at
allindeed, if you wanted the aldol product, the Mannich reaction would be of little use to you. It
nevertheless remains a very important reaction. First of all, it is a simple way to make amino-ketones
Reao de Mannich seguida de Eliminao:
and many drug molecules belong to this class. Secondly, the Mannich products can be converted to
Preparao de Enonas
enones. We will discuss this reaction next.
The most reliable method for making the enone is to alkylate the Mannich base with MeI and
then treat the ammonium salt with base. Enolate ion formation leads to an E1cB reaction rather like
the dehydration of aldols, but with a better leaving group.
O

Me
NMe2

SN2

NMe3

NMe3

E1cB

OH
1. alkylate amine to give ammonium salt

N
H
piperidine

2. treat with base: E1cB elimination gives enone

Enones like this, with two hydrogen atoms at the end of the double bond, are called exo-methylene
compounds; they are very reactive, and cannot easily be made or stored. They certainly cannot be
made by aldol reactions
alone as we have seen. The solution is to make the
Reaowith
comformaldehyde
o sal de Eschenmoser:
Mannich base, store that, and then to alkylate and eliminate only when the enone is needed. We shall
see how useful this is in the Michael reaction in Chapter 29.
If the enone is wanted, the secondary amine does not end up in the molecule so the more convenient (less volatile and less smelly) cyclic amines, pyrrolidine and piperidine, are often used. Enones
with monosubstituted double bonds can be made in this way.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

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8. Enolatos - Parte 2

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8.4.7. Reao de Perkin (Perkin Reaction, Perkin Condensation)


Perkin, 1868;

Condensao de aldedos aromticos com anidridos de cidos carboxlicos


alifticos na presena de uma base fraca;
Envolve a preparao de cidos carboxlicos ,-insaturados;

Reao de Perkin: Exemplos

Prof. Luiz F. Silva Jr - IQ-USP - 2012

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8. Enolatos - Parte 2

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Reao de Perkin:
Mecanismo

8.4.8. Reao de Knoevenagel (ou Knoevenagel Condensation)


Knoevenagel, 1894;

Reao de aldedos e cetonas com compostos contendo um metileno ativo na


presena de uma base fraca;

Prof. Luiz F. Silva Jr - IQ-USP - 2012

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8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao de Knoevenagel: Mecanismo

Reao de Knoevenagel: Mecanismo

Prof. Luiz F. Silva Jr - IQ-USP - 2012

36

8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Reao de Knoevenagel: Exemplos

8.4.9. Reao de Baylis-Hillman


Morita, 1968: fosfinas tercirias;
Baylis e Hillman, 1972: aminas tercirias;
Formao de ligao C-C entre a posio alfa de compostos carbonlicos
conjugados e carbono eletroflicos de aldedos e cetonas ativadas.
Catalisadores mais utilizados: DABCO, quinuclidina, alcalides derivados da
cinchona.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

37

8. Enolatos - Parte 2

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Reao de Baylis-Hillman: Mecanismo

Reao de Baylis-Hillman: Sntese Total

Prof. Luiz F. Silva Jr - IQ-USP - 2012

38

8. Enolatos - Parte 2

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8.5. Reaes de Acilao


Condensao de Claisen
Exemplo 1 Preparao de -Cetosteres:

Condensao de Claisen

Exemplo 2 Acilao de Cetonas:

Informaes adicionais: Claisen Condensation or Claisen Reaction, p. 86-87


Strategic Applications of Named Reactions in Organic Synthesis,
Laszlo Kurti, Barbara Czako, Academic Press, 1 ed., 2005.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

39

8. Enolatos - Parte 2

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Comparao
entre
Condensao de
Claisen e
Hidrlise de
steres em
condies
bsicas:

Condensao de Dieckmann
A ciclizao de Dieckmann uma condensao de Claisen intramolecular.
Exemplo:

Informaes adicionais: Dieckmann Condensation, p. 138-139


Strategic Applications of Named Reactions in Organic Synthesis,
Laszlo Kurti, Barbara Czako, Academic Press, 1 ed., 2005.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

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8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Segunda possibilidade:

Terceira possibilidade:

8.6. Adies Conjugadas de Enolatos


Reao de enolatos com compostos carbonlicos ,-insaturados.
Exemplos:

nions de nitrocompostos tambm reagem com enonas. Exemplo:

Informaes adicionais: Michael Addition or Michael Reaction, p. 286-287


Strategic Applications of Named Reactions in Organic Synthesis,
Laszlo Kurti, Barbara Czako, Academic Press, 1 ed., 2005.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

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8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

A adio conjugada tambm pode ser feita com steres e amidas ,insaturadas, embora estes compostos sejam menos reativos do que as
correspondentes cetonas. Exemplos:

Reao de Mukaiyama-Michael. Exemplo:

A adio de Michael tambm ocorre com alcino conjugados. Exemplo:

Notar que o alceno formado trans.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

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8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Oxazolidinonas Quirais de Evans: Adio Conjugada


Exemplo:

Anelao de Robinson
Uma adio de Michael seguida de condensao aldlica. A anelao de
Robinson pode ser feita de maneira assimtrica Exemplos:

Informaes adicionais: Robinson Annulation, p. 384-385


Strategic Applications of Named Reactions in Organic Synthesis,
Laszlo Kurti, Barbara Czako, Academic Press, 1 ed., 2005.
Reviso: Synthesis, 1976, (12), 777-794.

Prof. Luiz F. Silva Jr - IQ-USP - 2012

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8. Enolatos - Parte 2

QFL-5928 - Sntese Orgnica

Mecanismo:

Anelao de Robinson utilizando Enaminas


Exemplo:

Prof. Luiz F. Silva Jr - IQ-USP - 2012

44