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Lecture 8: the aldol reaction and conjugate additions Just what it says in the title.
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E
FUNCTIONAL GROUPINTERCONVERSIONS
CHAPTER 11
123.3
12
functional group interconversions
CHAPTER eleventhe aldol reaction & conjugate additions
enolates as nucleophile...
OLi
R X
O
RLi X
previously, we had looked at enolates...
the carbonyl as electrophile...
R1 R2
O
Cnuc
R1 R2
HO Cnuc
previously, we hadlooked attack on the
carbonyl group
combine the two...
©marvel/sony pictures
“the aldol reaction”
©Anchor Bay Entertainment
THE ALDOL REACTION IS THE KING OF C-C BOND FORMING REACTIONS
The aldol reaction
O O OH ONaOH
Othis is the original/simplest aldol reaction
The aldol reaction
O O OH ONaOH
Oit can go further in a
reaction known as the aldol condensation & generate an
enone
mechanism of the aldol reaction
O
HHO
OHO
H
O
O OOH O HO
H
you should know the mechanism by now!
mechanism of the aldol condensation
HO O
H
HO
OH Oenolisation
elimination
Othis is the base-mediated
elimination. It can also be achieved under acidic conditions
the problem with the aldol
reaction
©caro wallis@flickr
how do we control chemoselectivity?
O
O
OH O
O OH
O OH
OH O
if we have two different carbonylcompounds we can form four different products
(two homo-coupling & two cross coupling products)
& that numberincreases if we consider
enantiomers
©kevin steele@flickr
possible solutions
correct choice of nucleophile
R
O
enolate nucleophilicity
EtO
O
>C
O
>H
O
correct choice of nucleophile
R
O
enolate nucleophilicity
EtO
O
>C
O
>H
O
esters are more reactive enolates, so will preferentially
act as nucleophiles
correct choice of electrophile
carbonyl electrophilicity
R1 R2
O
C1 H
O
> >C1 C2
O
C1 OEt
O
aldehydes are most electrophilic
©fe ilya@flickr
EtO
O O
EtO
O
Et
OH
correct choice allows selective transformations.
alternatively...
correct choice of reagents (no choice of reaction)
H
OO
OH O
NaOH
only one enolisable carbonylaldehyde better
electrophile than bulky ketone
pre-form enolate...
R1R2
O
R1R2
OLi
LDA
another solution is to form the enolate first, performing the reaction at low temperature to
slow/prevent self-condensation
...then add Electrophile
R1R2
OLi
O
R3
R1
O
R2
OH
R3
Synthesise an enolate equivalent
R1R2
O
R1R2
OSiMe3
Me3SiCl
Et3N
simple to previous strategy...make the enolate equivalent first then...
R1R2
OSiMe3
O
R3
R1
O
R2
OH
R3
add Electrophile
often require acid or lewis acid to promote addition
Synthesise an enolate equivalent
R1R2
O
R1
OBCy2Cy2BCl
Et3N
R2
boron enolates are incrediblyuseful in the aldol reaction, I really wish I had more time to go into their use (look it up in a
book, its worth it)
O
R3
R1
O
R2
OH
R3R1
OBCy2
R2
add Electrophile
OB
O
Me
H
H
MeMe
Me
Me
Me
Me
R
Me
allows us to control stereochemistry
“aldol-like chemistry”
a lot of chemistry gets lumped together with the aldol reaction as a
lot of chemistry shares the same principles
the claisen condensation
O
OEt
O
OEt
NaOEtO
OEt
O
this is the reaction of two esters to give a !-ketoester
mechanism involvesenolate formation before addition to a carbonyl with a leaving group
(hence ketone formed)
the dieckman cyclisation
OEtO
O
OEt
NaOEt
O
OEt
O
this is the intramolecular version of the claisen condensation
Darzens reaction
!"##$%&'()"%*$+#
enamine reaction
Mannich reaction
enamine reaction
Darzens reaction
many other examples...
O
OH O O
O
Me
HOH
HH
Me
O
(–)-laulimalide(fijianolide B)
look at the synthesis of this carcinogen
aldol reaction in total synthesis
O
CO2MeHH
Me
(+)-Ipc2BO
H O
O
HOTBS
OPMB
Me
O
OHCO2MeOPMB
O
Me
HOTBS
HH
Me
O
86%62%de
here the aldol reaction is usedto join the two halves together by C-C
bond formation
aldol reaction in total synthesis
O
CO2MeHH
Me
(+)-Ipc2BO
H O
O
HOTBS
OPMB
Me
O
OHCO2MeOPMB
O
Me
HOTBS
HH
Me
O
86%62%de
even better it controls the stereochemistry of the
new alcohol
ipc=pinene derived chiral borane (see 7 slides ago)
de=diastereomeric excessmeans we have only 19% of the
wrong diastereoisomer
“michael Additions”(conjugate additions
1,4-additions)
conjugate addition also known as Michael Addition or 1,4-addition
R2
O
R1
Nuc
R2
O
R1
Nuc
H
R2
O
R1
Nuc
this is the generalreaction - addition of a nucleophile to an activated alkene (numbering starts with o=1 for the name)
R2
O
R1 R2R1
OHNucNuc
potential problem: 1,2-addition
nucleophile can adddirectly to the carbonyl group
(numbering starts with o=1 for the name)
all about the interplay of two factors depending on the nucleo-phile & the conditions: kinetic vs thermodynamic & Hard vs softpage 230 onwards
the details about why we can get both additions etc
can be found...
Solution: change nucleophile
H3C Li2 x CuIH3C
CuCH3
Li
there are a number ofmethods to avoid 1,2-addition. The
most common is the use of organocuprates
these are readily prepared from other organometallic reagents
Solution: change nucleophile
O
H3CCu
CH3
Li
CH3
OH
O
CH3
organocuprates alwaysundergo 1,4-addition (in fact they only react with highly activated
carbonyl compounds such as acyl chlorides)
cuprates can be made from grignard reagents
O
H3C MgBr
CuClcat
O
CH3
only need a sub-stoichiometric quantity of a copper(I) salt to
achieve this
organocoprates are soft nucleophiles
C Mg!– !+
C Li!– !+
C Cu!+!–
two possible reasons for theexclusive 1,4-attack. Cuprates are soft
nucleophiles so attack soft electrophile (the alkene not the hard carbonyl)
cuprates are softbecause copper is less
electropositive than lithium or magnesium, thus C-Cu bond is
less polarised
C•personally, i think the
reaction is probably radical & radicals add reversibly to c=O bonds so we observe 1,4
addition instead
Text
©kathybragg@flickr
as an aside, why shouldtwo negatively charged electrons ever travel as a pair? doesn’t really make
sense
Addition of 1,3-dicarbonyl compounds
O
OEt
O
OEt
O
NaOEt
O
EtO O
OEt
O
another solution is touse a 1,3-dicarbonyl-based enolate. these invariably
undergo 1,4-addition
1,3-dicarbonyls are soft nucleophiles
O
OEt
O
O
OEt
OO
OEt
O O
OEt
O
!
soft nucleophiles because chargeis spread over 5 atoms so add to the soft
electrophile (the alkene)
Text
if we combine conjugate addition & aldol condensation we
get...
the robinson annulation
O
O
ONaOH
O
O
combining these two reactions gives us a ‘one-pot’ route to 6-membered rings
Mechanism of the robinson annulation
O
O
HO
O
O
O
O O
O
O O
OH
H2O
HO
the robinson annulation starts with a conjugate
addition
O
O O OO
O
OOH
O
O
O
H2O
OH
Mechanism of the robinson annulation
and ends with an aldol condensation
the next one is a bit of a tongue twister...
the next reaction has a wonderful name. you don’t
need to know it but...
the Hajos-Parrish-Eder-Sauer-Wiechert reaction
O O
O
NH
CO2H
O
OHO
99%
93% ee
proline catalysed intramolecular aldol reaction with exquisite control
of stereochemistry
synthesis is about finding the hidden
patterns©moominsean@flickr
synthesis is about finding the hidden
patterns©moominsean@flickr
retrosynthesis, the next partof this course is all about recognising
these patterns
C-C at !position
R1
O
R2
R1
O
R2 X
if we want to make a bond adjacent to a carbonyl group think
enolate
1,3-di-O relationship
R1
O
R2
OH
R1
O
R2
O
if there are twooxygens in a 1,3-relationship (regardless of oxidation
state), think aldol
R1
O
R2
O
R1
O
R2
O
EtO
1,3-di-O relationship
or at least aldol-like chemistry
R1
O
R2
R1
O
R2
O
enone relationship
even an enone can be made from an aldol
reactioni told you the
aldol was good!
1,4-di-O relationship
R1
O
R1
O
R2
OH
R2
O
changing the electrophile allows different patterns to
be accessed
1,5-di-O relationship
R1
O
R1
O
R2
O
R2
O
and repeat...
Text
learn to recognise patterns
