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Olefination Reactions

Olefination Reactions
- Wittig Reaction (Phosphorous ylides)
- Horner-Wadsworth-Emmons Reaction (Phosphonates)
- McMurry Coupling (Titanium complexes)
- Peterson Olefination (Silanes)
- Petasis / Tebbe Olefination (Carbene complexes)
- J ulia-Lythgoe (Sulphones)
Mechanism
Stereochemistry (Z / E)
Experimental Examples
Wittig Reaction
Olefination Reactions
X: Cl, Br, I, OTs
R
3
, R
4
: alkyl, aryl
Wittig Reaction
Olefination Reactions
R
1
X
H
PR
3
R
1
PR
3
H
Base
R
1
PR
3
H R
1
PR
3
H
H
O
R
2
R
1
PR
3
H
H
O
R
2
O PR
3
H
R
2
H R
1
R
1
PR
3
H
R
2
O
H
O PR
3
H
H
R
2
R
1
R
1
H R
2
H R
1
H H
R
2
Rate limitating step
Zmajor
E minor
betaines
oxaphophetane
(kinetic product) (thermod. product)
Mechanism:
1.Deprotonation
2.Coupling of the ylide to
the carbonyl compound
(RL step) to form the
betaine
3.Cyclation to the
oxaphosphetane
4.Rearrangement to the
olefins
Olefination Reactions
Stereochemistry:
1.the cis product is
favoured due to steric
inderance during the
attack of the carbonyl to
the ylide.
Supra-supra
forbidden
Antara-supra
Constricted
(higher selectivity)
Olefination Reactions
Stereochemistry:
1.the cis product is
favoured due to steric
inderance during the
attack of the carbonyl to
the ylide.
2.Non polar solvents and
salt free conditions induce
Z-olefin formation due to
the destabiliyation of the
betaines.
R
1
X
H
PR
3
R
1
PR
3
H
Base
R
1
PR
3
H R
1
PR
3
H
H
O
R
2
R
1
PR
3
H
H
O
R
2
O PR
3
H
R
2
H R
1
R
1
PR
3
H
H
O
R
2
O PR
3
H
H
R
2
R
1
R
1
H R
2
H R
1
H H
R
2
Rate limitating step
Zmajor
E minor
betaines
oxaphophetane
(kinetic product) (thermod. product)
Olefination Reactions
Preparation
Labile ylide Semistable ylide Stable ylide
Base used
Selectivity
In situ In situ isolated
n
BuLi
NaNH
2
K
t
BuO
NaEtO
Aq. NaOH
NaOH
90% cis
90% trans cis, trans
Stereochemistry:
1.the cis product is
favoured due to steric
inderance during the
attack of the carbonyl to
the ylide.
2.Non polar solvents and
salt free conditions induce
Z-olefin formation due to
the destabiliyation of the
betaines.
3.By increasing the
stability of the ylide, the
proportion of E-olefin
increases.
Wittig Reaction
Olefination Reactions
Examples:
O
PPh
3
CH
2
Wittig, 1950s
Olefination Reactions
X: Cl, Br, I, OTs
Schlosser Modification
Schlosser Modification
Olefination Reactions
R
1
X
H
PR
3
R
1
PR
3
H
Base
R
1
PR
3
H R
1
PR
3
H
H
O
R
2
R
1
PR
3
H
H
O
R
2
H
PR
3
R
1
H
O
R
2
betaines
1 eq. PhLi
1 eq. PhLi
R
1
PR
3
H
O
R
2
PR
3
H
O
R
2
R
1
1 eq. HCl
(proton source)
1 eq. HCl
(proton source)
H
PR
3
R
1
H
O
R
2
R
1
PR
3
H
H
O
R
2
R
1
R
2
Mechanism:
1.Deprotonation
2.Coupling of the ylide to the
carbonyl at low temperature
3.Quick equilibriumbetween
the two betaines by second
deprotonation
4.Formation of the
oxaphosphetane (trans)
5.Rearrangement to the
olefins
Schlosser Modification
Olefination Reactions
Example:
Horner-Wadsworth-Emmons
Reaction
Olefination Reactions
Arbuzov Reaction
Olefination Reactions
1. nucleophilic subs.
2. dealkylation
Mechanism
Olefination Reactions
R
1
P(O)(OEt)
2
R
1
X
X: Cl, Br, I
P(OEt)
3
120-140 C
Arbuzov Reaction
Olefination Reactions
(EtO)
2
P
O
OR
O
(EtO)
2
P
O
OR
1
O
H
(EtO)
2
P
O
OR
1
O
O
H R
2
O
H R
2
(EtO)
2
P
O
OR
1
O
O
R
2
H
(EtO)
2
P
O
OR
1
O
P(OEt)
2
O
COOR
2
H
H
R
2
O
P(OEt)
2
O
COOR
2
R
2
H
H
O
R
2
OOC
H R
2
H R
2
OOC
H H
R
2
O
(EtO)
2
P
O
Na
R
2
NaH
COOR
2
R-L step
P(OEt)
2
NaO
O
ws
E maj or
Z
1. deprotonation.
Mechanism
3. Evolution to the
oxaphosphetane
4. Rearrangement
2. Coupling with the
aldehyde and formation
of the betaine (stable)
Horner
Olefination Reactions
Example
Horner
I
I
I
I
Br
Br
I
I
(EtO)
2
(O)P
P(O)(OEt)
2
I
I
(EtO)
2
(O)P
P(O)(OEt)
2
I
I
R
1
R
1
R
1
R
1
R
2
R
2
KIO
4
, I
2
H
2
SO
4
/ AcOH
NBS
hv
P(OEt)
3
CHO
R
1
K
t
BuO
CuI, PdCl
2
(PPh)
3
R
2
cruciforms
Olefination Reactions
Horner
-1 11 10 9 8 7 6 5 4 3 2 1 0 ppm
I
I
OMe
OMe
OMe MeO
MeO OMe
B
A
C
C
B
A
D
D
J
trans
=16Hz.
Still-Gennari modification:
R
1
P(O)(OCH
2
CF
3
)
2
R
2
H
O
R
2
Z
R
1
Olefination Reactions
KHMDS:
Olefination Reactions
1. Deprotonation
(with KHMDS).
Mechanism
4. Rearrangement
2. Coupling with the
aldehyde and formation
of the betaine (unstable)
Still-Gennari
3. Evolution to the
oxaphosphetane
Olefination Reactions
Example
Still-Gennari
Peterson Olefination
Olefination Reactions
R
2
, R
3
: alkyl, aryl
R
1
: alkyl, aryl, ester, cyano, amide
Highly versatile
Olefination Reactions
R
1
Si
R
R
R
M+
R
2
R
3
O
Si
MO
R
3
R
1
R
2
H
Si
MO
R
3
H
R
2
R
1
R
R
R
R
R
R
H
2
O
Si
HO
R
3
R
1
R
2
H
Si
HO
R
3
H
R
2
R
1
R
R
R
R
R
R
-hydroxysilanes
R
2
R
3
H
R
1
R
2
R
3
R
1
H
base
base
acid
quick evolution if R
1
is EWG
quick evolution if R
1
is EWG
Mechanism:
1. Adition of the carbonyl
2. Formation of the -hydroxysilanes. Isolable only if R
1
is a donor
3. Elimination to the olefins. Syn or anti depending on the conditions
Z
E
Olefination Reactions
Mechanism:
Olefination Reactions
Example:
This is the only methodology to
intruduce this (Z)alkene moiety
J ulia-Lythgoe Olefination
Olefination Reactions
X: Cl, Br, OCOR
3
R
1
: H, alkyl, aryl
R
2
: H, alkyl, aryl, alkenyl
J ulia-Lythgoe Olefination
Olefination Reactions
S R
1
Base
O O
Ph
S R
1
O O
Ph
M
R
2
O
H
S R
1
O O
Ph
R
2
O
M
R
3
O
X
S R
1
O O
Ph
R
2
O
O
R
3
S R
1
O O
Ph
R
2
O
O
R
3
Na(Hg)
MeOH
(MeONa)
S R
1
O O
Ph
R
2
H
Na(Hg)
S R
1
ONa O
Ph
R
2
H
R
1
R
2
H
NaO
2
SPh
R
1
R
2
H
R
2
H
R
1
Na(Hg)
R
1
R
2
H
MeOH
R
1
R
2
H
H
E product
Modified J ulia-Lythgoe
Olefination Reactions
R
1
: H, alkyl, aryl
R
2
: H, alkyl, aryl, alkenyl
S
N
N
N
N
N
N
Ph
PYR
PT
BT
pyridin-2yl- benzothiazol-2yl-
1-phenyl-1H-tetrazol
Onepot
reaction
Modified J ulia-Lythgoe
Olefination Reactions
Mechanism
Smiles rearrangement
Modified J ulia-Lythgoe
Olefination Reactions
Example
N
N
N
N
O
2
S
Ph
O
MeO
TESO
OHC
NaHMDS
HMPA
DME, -78 C
TESO
O
MeO
(E)
35%
McMurry Coupling
Olefination Reactions
R: H, alkyl, aryl
Uncontrolled reaction. Random stereochemistry
McMurry Coupling
Olefination Reactions
O
K
2
O
K
2
TiCl
3
K Ti
2+
+KCl 2Cl
-
+
2KCl
O O
Ti
TiO
2
1. Re-dox over the
carbonyl group.
2. Coupling of the
radicals (Ti
2+
mediated).
3. Rearrangement
with re-oxidation
of Ti(II) to Ti(IV)
Mechanism
Exmaple
McMurry Coupling
Olefination Reactions
O
O
TiCl
3
Zn-Cu
THF
Takai Olefination
Olefination Reactions
Takai Olefination
Olefination Reactions
R
1
H
O
R
1
R
2
R
2
CHX
2
CrCl
2
R
2
CrCl
2
CrCl
2
H
R
2
CrCl
2
R
1
H
OCrCl
2
E2
Complementary to
WittigStork
Takai Olefination
Olefination Reactions
Example
Tebbe/Petasis reaction
Olefination Reactions
Tebbe/Petasis reaction
Olefination Reactions
Tebbe/Petasis reaction
Olefination Reactions
Example:

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