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Wittig Reaction - Phosphorous Ylides
O
R H
+Ph3P CHCH3
H3C R
ylide
•Stereoselectivity increases as the size of R increases•cis-olefin is derived from non-stabilized ylides
Mechanism: Irreversible [2+2] cycloaddition
O
R H
PPh3
H3C H
+
P
H3C H
Ph3
OR
H
R group of aldehyde
far away from ylide
CH3
!" !
2!a + 2!s cycloaddition
Ph3P O
H3C R
HH H3C R+ Ph3PO
PPh3
NaHMDS
O O
OMeH
O
OMe
Chem Ber. 1976, 1694.
E-selective Wittig ReactionsO
R2 H
Ph3P CHR1
ylide
O PPh3
R1R2
PhLiLiO PPh3
R1R2
1 eq. HCl O PPh3
R1R2
equilibrates to the morestable oxaphosphetane
R1
R2
ACIEE, 1966, 126R1 R2 E:Z
CH3 C5H11 99:1
C5H11 CH3 96:4
CH3 Ph 99:1
Stabilized Ylides are much less reactive than alkyl ylides; the react with aldehydes, but only slowly with ketones
Br
O
OR
PPh3
Ph3P
O
OR
Na2CO3
Ph3P
O
OR
A
A + R1CHO
slow
reversible
O PPh3
CO2RR1
minor kinetic
fast
R1
CO2R
+O PPh3
CO2RR1
major kinetic
R1 CO2R
thermodynamicproduct:
slow
Stabilize ylides thus formE alkenes as major products
major minor
"Schlosser" Wittig
Horner-Wadsworth-Emmons Wittig: E-selectivePhosphonate esters are easily deprotonated and are more basic/nucleophilic than stabilized ylides; they react withboth ketones and aldehydes
Br
O
OR
POEt)3
P
O
OR
NaO P(OEt)2
CO2EtR1
fast
R1
CO2R
+
R1 CO2R
thermodynamicproduct:
slow
major minor
O
EtO
EtOArbuzov reaction
P CH3
O
EtO
EtO
1. LDA
2.
R'
O
OEt
P
H3C
O
EtO
EtO
O
R'
Claisen Condensation:Synthesis:
Mechanism of Olefin Formation:
P
O
OEt
O
EtO
EtO
NaH
P
O
OEt
O
EtO
EtO
Reversible
O
NaO P(OEt)2
CO2EtR1
O
O P(OEt)2
CO2EtR1
O-
O P(OEt)2
CO2EtR1
O-
R1CHO
HO P(OEt)2
O
+
water solublephosphate can beremoved in aqueousworkup
RDS
JOC, 1961, 1733
TL, 1976, 2829
Good for:
P W
O
EtO
EtO
W= CN, CO2R,
COR, CHO
SO2Ph, Ph
Modifications to the Horner-Emmons Wittig
Masamune and Roush: for Base-sensitive substrates, use LiCl/tertuary amine (Et3N, DBU, iPr2NEt)
O
H
BzCHN
CH3
P
O
EtO
EtO
O
LiCl, iPr2NEt
CH3CN, 23°C
BzCHN
CH3
O
TL, 1984, 2183
JOC, 1989, 896
P
O
EtO
EtO
Ometal ion coordination lowers pKa further: M
HHNR3
Both hindered phosphonates and hindered aldehydes increase E-selectivity:
BnO
O
H
CH3
BnO
CH3
CO2R
PPh3=CHCO2Et 7 :1 E:Z
(iPrO)2POCH2CO2Et/KOtBu 95:5 E:Z
(MeO)2POCH2CO2Me/KOtBu 1:3 E:Z
+
TL, 1981, 3873.
Modifications to the Horner Emmons Wittig, continued
Z-selective olefin synthesis: Still modified phosphonate: TL, 1983, 4407
R1
O
HP
O
F3CH2CO
F3CH2CO
O
OCH3
R
+ KHMDS,
18-crown-6
R'
CO2Me
R
O
H
P
O
F3CH2CO
F3CH2CO
O
OCH3
KHMDS, 18-c-6 CO2Me
Z:E >10:1
BnO
O
CH3
H
P
O
F3CH2CO
F3CH2CO
CO2Me
KH, THFBnO
CH3CO2Me
BnO
CH3
CO2Me
P
O
EtO
EtO
CO2Me
NaH, THF
83%, 12:1 E:Z
84%, 11:1 Z:ETetrahedron, 1987, 2369
R1
O
HP
O
F3CH2CO
F3CH2CO
O
OCH3
CH3
+KHMDS,
18-crown-6
R1
CO2Me
CH3
Z:E >10:1
R1 Z:E
>50:1
>50:1
>50:1
Trisubstituted Olefins:
Ph
O
H
CH3
P
O
R1O
R1O
O
OR2
tBuOK, THF
Ph
CH3 CH3
CO2R2+
CH3 Ph
CH3 CO2R2
CH3
R1 R2 E:Z
CH3 CH3 5:95
CH3 Et 10:90
Et Et 40:60
iPr Et 90:10
iPr iPr 95:5
TL, 1983, 4403
Peterson Olefination: An alternative to the Wittig Reaction
Me3Si
M
M=Li, Mg
Me3Si
R1
Li
R2CHO
non-diastereoselective
Me3Si OH
R1 R2
+
Me3Si OH
R1 R2
Isolate and separate silanol diastereomers
Elimination Step is Stereospecific:
Me3Si OH
R1 R2
H3O+
Me3Si
OH2R1
R2
H
H
R1 R2
control geometry of olefin with conditions for elimination!
Me3Si ONa
R1 R2
NaH Me3Si O
R1 R2R1
R2
syn elimination trans
anti elimination
cis
(base)
irreversible
2-step procedure: Addition to aldehyde (non-stereoselective) and silanol elimination (stereospecific)
JOC, 1968, 781
Elimination Step is Stereospecific:
tBuPh2Si OH
Ph R
anti elimination
Stereoselective Additions in the Peterson Olefination:
threo product favored by small SiR3 (Me3Si)
erythro product favored by large SiR3 (t-BuPh2Si)
O
R
H
H
R3Si
Ph
R3Si O-
H
HR
Ph
threo
O
R
H
H
Ph
R3Si
R3Si O-
R
HH
Ph
erythro
maintain an anti relationship between aldehyde R and largest substitutent on the silicon reagent
small SiR3
large SiR3
3.0 KH
Ph R
R Z:EMe 92:8Ph 85:15vinyl 95:5
tBuPh2Si OH
Ph Bu
BF3•OEt2
Ph
Bu
E:Z = 99:1
Synthesis, 2000, 1223
Julia Olefination: E-selective synthesis
R1
O
H
+
R2
SO2R
Non stereoselective
R1
R2
SO2R
OH
mixture of diastereomers:
Ac2OR1
R2
SO2R
OAc
R1
R2
Na/Hg
reductivefragmentation
R1
R2
OAc
H
radical intermediate
prefers R1 and R2 trans
major
TL 1973, 4833.
O
TBSO
PhO2S
OMe
BuLi
C5H11CHO
O
TBSO
PhO2S
OMe
OH
C5H11
1. MsCl, Et3N
2. Na/Hg
O
TBSO
OMe
C5H11
76%
N
NO2S
R2BuLi
R1CHO
N
NO2S
R2
OH
R1SmI2
THF
R1
R2
TL, 1990, 7105see also:JOC, 1995, 3194Org. Lett. 2005, 2373.
Tebbe Reagent: Cp2Ti AlMe2
Cl
Reacts with aldehydes, ketones, esteres, lactones, amides to give methylene compounds:
O
X
Tebbe CH2
X
JACS, 1978, 3611
Ph
O
OEt
Ph
CH2
OEt
Ph
O
NPh
CH2
N
O
O
O
CH2
see also: Petasis reagent: Cp2TiMe2 JACS, 1990, 6392.
O CH2
Tebbe
Tebbe
Tebbe
Tebbe
Corey-Winter Reaction: Vicinal Diol Elimination
HO OH
R
H H
R'
S
Cl Cl
O O
R
H H
R'
S
P(OEt)3
heat
O O
R
H H
R'
+ (EtO)3PS
R R'
-CO2
synelimination
JACS, 1963, 2677JACS,1965, 934
Shapiro Reaction:
H
O TsNHNH2
H
N
NH
Ts 2 MeLiN
N
Ts N
N
vinyl anion
R-I
R
H3O+HTL, 1975, 1811.
Carbene:
O
TsNHNH2
NNHTs
2 BuLi
Li
BuBr
H3O+
H
Shapiro Reaction:
Acc. Chem. Res. 1983, 55.
Dehydration of alcohols to form alkenes
Burgess Reagent:
O
O N
S
O O
NEt3
R
OH
R'
Burgess
Exothermic R
O
R'
S
OO
N
S
O O
NEt3
H
H
H
cis elimination
for 2° and 3° alcohols only
R
R'
JACS, 1970, 5224JOC, 1973, 26
Ph
OH
Ph
HD
Ph
OH
Ph
DH
Burgess
Burgess
Ph
Ph
Ph
Ph
D
H
CH3
HO
Burgess
CH3
JACS, 1990, 8433
Martin Sulfurane:
R
OH
R'
Martin Sulfurane
R
O
R'
S
Ph OR
Ph
for 2° and 3° alcohols only
R
R'
JACS, 1971, 4327JOC, 1973, 26S
Ph
Ph
OC(CF3)2Ph
OC(CF3)2Ph
H
R
O
R'
S
Ph
Ph
H
OR
Eliminations for 1° alcohols: Grieco method
OHMsCl
Et3N
OMs
NO2
SeCN
NaBH4
Se
NO2
H2O2
Se
NO2O-H
retro-hetero-enereaction
JOC, 1975, 1450.
Other selenide eliminations:
see JACS, 1973, 5813JOC, 1975, 542.
