C549 R.M. Williams The Wittig Olefination Reaction Non-Stabilized Ylids. The Wittig reaction is one of the most useful methods for the synthesis of olefins from aldehydes and ketones. The general reaction is shown below: + phosphorus ylid C O R' R' C R' C P Ph Ph Ph R 1 R 2 R' C R 1 R 2 O P Ph Ph Ph aldehyde or ketone + triphenylphosphine oxide new olefin The Wittig reagent (the phosphorous ylid) is prepared from triphenylphosphine and an alkyl halide (saturated 1 o or 2 o ) to initially form the triphenylphosphonium salt. These salts are typically stable and can be bottled and stored. When the Wittig reaction is about to be run, the phosphonium salt (pKa ~ 22 in DMSO) is deprotonated with a strong base, such as NaH or n-BuLi. Acidification of carbon by the adjacent (Ph) 3 P + species is through a combination of inductive and resonance effects. It is generally accepted that the principal p-bonding stabilization is via overlap of the lone pair on carbon with an antibonding P-Ph orbital. This type of phosphorous ylid is called a “non-stabilized” ylid. This mode of carbanion stabilization is strictly analogous to that for sulfur-stabilized carbanions. + Br – triphenylphosphonium salt S N 2 C P Ph Ph Ph R 2 R 1 H C H R 1 R 2 Br P Ph Ph Ph strong base (NaH or n-BuLi) + phosphorus ylid C P Ph Ph Ph R 1 R 2 C P Ph Ph Ph R 1 R 2 With simple aldehydes, the reaction with primary phosphorous ylids leads stereoselectively to Z- disubstituted olefins (cis-olefins). + C P Ph Ph Ph H R 2 C O R 1 H + R 2 R 1 O=P(Ph) 3 + Z-olefins The stereoselective formation of the cis-olefin can be rationalized as shown below. At low temperature, the only species observed is the oxaphosphetane. Vedejs has proposed that the oxaphosphetane is formed by an asynchronous cycloaddition through a puckered, early transition state that minimizes steric interactions between the R 1 and R 2 substituents (1,2-interactions) in the forming oxaphosphetane intermediate. In the disfavored transition state, the R 1 group of the aldehyde substrate experiences steric compression with the axial phenyl group of the triphenyl phosphonium moiety (1,3-interactions). + C P Ph Ph Ph H R 2 CO R 1 H P O R 2 R 1 H H early, puckered transition state: favored P O R 2 H H R 1 disfavored P O R 2 R 1 Ph Ph Ph cis-oxaphosphatene P O R 2 R 1 Ph Ph Ph betaine P O R 2 R 1 Ph Ph Ph R 1 R 2 R 2 R 1 cis-olefin It has long been assumed that the salt-free betaine is an intermediate on the path to the formation of the oxaphosphetane and the ultimate olefination. Vedejs has shown by 31 P nmr, that salt-free betaines are not observable in solution.
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C549R.M. Williams
The Wittig Olefination Reaction
Non-Stabilized Ylids. The Wittig reaction is one of the most useful methods for the synthesis of olefins fromaldehydes and ketones. The general reaction is shown below:
+
phosphorus ylid
COR'
R'C
R'C P
PhPh
Ph
R1
R2
R'C
R1
R2O P
PhPh
Phaldehyde or ketone
+
triphenylphosphine oxidenew olefin
The Wittig reagent (the phosphorous ylid) is prepared from triphenylphosphine and an alkyl halide(saturated 1o or 2o) to initially form the triphenylphosphonium salt. These salts are typically stable and can bebottled and stored. When the Wittig reaction is about to be run, the phosphonium salt (pKa ~ 22 in DMSO) isdeprotonated with a strong base, such as NaH or n-BuLi. Acidification of carbon by the adjacent (Ph)3P+
species is through a combination of inductive and resonance effects. It is generally accepted that the principalp-bonding stabilization is via overlap of the lone pair on carbon with an antibonding P-Ph orbital. This type ofphosphorous ylid is called a “non-stabilized” ylid. This mode of carbanion stabilization is strictly analogousto that for sulfur-stabilized carbanions.
+ Br–
triphenylphosphonium salt
SN2C P
PhPh
Ph
R2
R1H
CH
R1
R2Br P
PhPh
Ph
strong base
(NaH or n-BuLi)+
phosphorus ylid
C PPh
PhPh
R1
R2C P
PhPh
Ph
R1
R2
With simple aldehydes, the reaction with primary phosphorous ylids leads stereoselectively to Z-disubstituted olefins (cis-olefins).
+C PPh
PhPh
H
R2CO
R1
H+
R2 R1 O=P(Ph)3+
Z-olefins
The stereoselective formation of the cis-olefin can be rationalized as shown below. At low temperature,the only species observed is the oxaphosphetane. Vedejs has proposed that the oxaphosphetane is formed byan asynchronous cycloaddition through a puckered, early transition state that minimizes steric interactionsbetween the R1 and R2 substituents (1,2-interactions) in the forming oxaphosphetane intermediate. In thedisfavored transition state, the R1 group of the aldehyde substrate experiences steric compression with theaxial phenyl group of the triphenyl phosphonium moiety (1,3-interactions).
+C PPh
PhPh
H
R2
C OR1
HP O
R2
R1H
H
early, puckered transition state:favored
P O
R2
HH
R1
disfavored
PO
R2
R1
PhPhPh
cis-oxaphosphatene
PO
R2
R1
PhPhPh
betaine
PO
R2
R1
PhPhPh
R1
R2
R2 R1cis-olefin
It has long been assumed that the salt-free betaine is an intermediate on the path to the formation ofthe oxaphosphetane and the ultimate olefination. Vedejs has shown by 31P nmr, that salt-free betaines are notobservable in solution.
When alkyltriphenylphosphonium bromides are treated with n-BuLi in either ether or THF, the LiBr saltremains in solution. Vedejs has shown that the presence of the soluble salt, LiBr, decreases the stereoselectivityof the olefination reaction. While the reasons for this are not completely clear, it is thought that dissolved saltfacilitates oxaphosphetane reversal and eventual partial equilibration to a mixture of cis- and trans-oxaphosphetanes. In this situation, LiBr adds stoichiometrically with the oxaphosphetane to generate abetaine-lithium bromide adduct; these are often insoluble and precipitate from solution.
PO
R2
R1
PhPhPh LiBr P
LiO
R2
R1
PhPhPh
Br
For the best stereoselectivity in Wittig olefination reactions with non-stabilized ylids, a salt-free reagentis prepared by treating the phosphonium bromide with NaNH2 in liquid ammonia, evaporating the ammoniaand filtering the salt-free ylid off as a solution in ether, toluene or THF.
Vedejs has also found that the P-ethyldibenzophosphole ylid shown below displays excellent E-selectivity. This has been rationalized by the planar (and E-selective) transition state structure that is possibledue to the presence of the smaller axial ethyl ligand on the phosphorous atom.
PMe
Et
Me Me
PhCHO
+ P
H
Me
OMe
H
Me MePh
planar transition state:E-selective
Me Me
PhMe
1:9, Z : E
It is important to point out that, the mechanism of the Wittig and related reactions is complex withmany subtleties that are affected by the solvent used, the structure of the substrate and the ligands aroundphosphorous. For a review on the Wittig reaction, see: (a) Maryanoff, B.E.; Reitz, A.B., Chem.Rev., 1989, 89,863~927. The mechanism of the Wittig and related reactions has been studied by Vedejs, see: (b) Vedejs, E.;Marth, C.F.; Ruggeri, R., J.Am.Chem.Soc., 1988, 110, 3940~3948; (c) Vedejs, E.; Marth, C.F.; J.Am.Chem.Soc.,1988, 110, 3948~3958; (d) Vedejs, E.; Meier, G.P.; Snoble, K.A.J., J.Am.Chem.Soc., 1981, 103, 2823~2831; (e)Vedejs, E.; Fleck, T.J., J.Am.Chem.Soc., 1989, 111, 5861~5871.
Stabilized ylids. Another commonly used Wittig-type reagent are the so-called “stabilized ylids” that bear anelectron-stabilizing group on the carbon. These in general, show a marked preference for E-selective olefinationreactions. Vedejs has proposed a model to account for the observed E-selectivity that involves a relativelyplanar oxaphosphetane with a late transition state
PPhO
CO2RH
H
RPh
Ph
late transition state:oxaphosphetane-like interaction
R H
OPh3PCO2R
+ R
CO2R
Phosphoryl-stabilized Carbanions: The Horner Wadsworth Emmons (HWE) Modification of the WittigReaction. The phosphonates used in the HWE reaction are most typically prepared by an Arbuzov reaction asshown below.
PMeOMeO OMe Br
R+
Arbuzov reactionPMeO
MeO
ORSN2
+ CH3Br
Like the other stabilized ylids discussed above, the HWE reaction gives rise to E-olefins preferentially.The mechanism is thought to proceed via a stepwise addition to give initially the alkoxy (aldol-like)intermediate which equilibrates to the more stable trans- four-centered intermediate that then decomposes tothe E-olefin.
PMeOMeO
OR + R'CHO P
O
R
R'
OMeOMeO
H
O
R'R
HPO
MeOMeO
R
R'
base
A few examples of the Wittig and related reactions used in synthetic applications are shown below.
Me Me
Me
P(Ph)3
Me1. NaOMe, MeOH
2.
OHC OAc
Me
Me Me
Me
Me
OAcMe
I2
70:30 trans : cis
Me Me
Me
Me OAcMe
from: Pommer, H., Angew Chem. Int.Ed.Engl, 1977, 16, 423.
Me P(Ph)3Br1. NaN(TMS)2
2. remove salt3.OHC CO2Me
CO2MeMe
80%, >98% Z-from: Bestmann, et al., Chem.Ber., 1976, 109, 1694.
Me
HO OTs
MeMe
Al2O3, (Ph)3P=CH2
O
Me
H
MeMe
CH2
Me
H
Me Me
from Buchi, G.H., et al., J.Am.Chem.Soc., 1966, 88, 4113
BnO CHO
Me
MePPh3
EtO2C BnOMe Me
CO2Et
MeO PO
MeO
CO2Me
Me
NaH, THF
BnOMe CO2Me
Me
from Johnson, M.R.; Kishi, Y., Tetrahedron Lett., 1979, 4347~4350
HO2C MeCH2OBz
OTBS
COCl2, DMF MeCH2OBz
OTBSCl
OPh3P Me
Br
n-BuLiMe
CH2OBz
OTBSO
Me
Ph3P
stabilized ylid
Me
BOCO
O
O
HBOCO
MeCH2OBz
OTBSO
MeMe
BOCO
OBOCO
from: Ireland, R.E.; Smith, M.G., J.Am.Chem.Soc., 1988, 110, 854
BnO O
H PO
CO2Eti-PrOi-PrO
KOt-Bu, THFBnO
HCO2Et
Hfrom Finan, J.M.; Kishi, Y., Tetrahedron Lett., 1982, 23, 2719~2722
BnO OHDMSO, (COCl)2
Et3N(Swern oxidation)
The HWE reaction has become an important tool for the synthesis of cyclic olefins, particularly for theformation of macrolides. A few examples are shown below.
OHCO
Me
TBSO
Me
Me O O O
Me Me
TBSO
O O OMe Me
OMe
CH2OSiPh2tBu
OTBS
O
P OOMeMeO
O
O O OMe Me
TBSO
O O OMe Me
OMe
CH2OSiPh2tBu
OTBS
Me
Me
Me
TBSO
Ofrom: Nicolaou, K.C., et al., J.Chem.Soc. Chem.Comm., 1986, 413
amphoteronolide B
O
O
Me
OO
O
Me
Me
OTBSMe
OO
OMeOMe
MeTBSO
CHO
O
O
Me
OO
O
Me
Me
OTBSMe
OO
OMeOMe
MeTBSO
PO
MeOMeO
K2CO3, 18-Cr-6
80%
from: Nicolaou, K.C., J.Am.Chem.Soc., 1982, 104, 2030~2031
O
O
O
O
MePhOCHN
Me NHCOPh
SS
O
O
O
O
MeO
Me O
O OSS
vermiculine
O
CHO
O
MePhOCHN
SS
POOEtEtO
NaH, THF
~45%
Burri, K.F., et al., J.Am.Chem.Soc., 1978, 100, 7069~7071
The Peterson Olefination. An alternative procedure to the Wittig reaction, particularly for ketone substratesthat are often unreactive in the Wittig reaction, is the Peterson olefination as shown below. The initiallygenerated trimethylsilanol, formed upon workup is unstable to spontaneous dehydration forming the volatiletrimethylsiloxane. This attractive feature of the Peterson olefination renders separation of the final productvery convenient relative to the Wittig and related reactions where, often polar phosphorous by-products mustbe removed by chromatography.
Me3Si
Cl
Mgo
THF
Me3Si
MgCl
R R'
O
Me3Si
R'R
OMgCl HOAc, rt
R R'
CH2 + (Me3Si)2O
OH
Me
MeMe3Si MgCl
THFH
Me
Me1.
2. HOAc, rt
b-gorgonene15%
no reaction(Ph)3P=CH2
Me
MeLi
SiPh3Me
MeSiPh3
Li
C10H21CHO+ Me
MeMe
50%, 1: 1 Z:E
The Tebbe Reagent. Lactones, esters and amides in general, do not react with any of the Wittig and relatedreagents in olefinations. Nucleophilic transition metal carbene complexes, on the other hand, have been foundto react with esters and lactones to form enol ethers as shown below. The most widely used system is theTebbe reagent. The Tebbe reagent, is prepared by the reaction of trimethyl aluminum and titanocene dichloride.In the presence of pyridine, this complex reacts as the synthetic equivalent of “Cp2Ti=CH2” and has beenfound to be very useful for the olefination of carbonyl derivatives, including esters and lactones.
Ti ClCl + AlMe3 Ti Cl
AlMe
Mepyridine
Ti
"Tebbe reagent"The reaction proceeds through a mechanism involving formation of an oxometallacycle which cyclo-reverts togive the olefination product and a very stable titanium (IV) oxo species.
TiO
X
R Ti O
X
R
X= H, R, OR, NR2
Ti OH2CX
R+
Some synthetic applications of this reaction are shown below.
Ti
O
Me MeMe
OCHO
H+
O
Me MeMe
OH92%
from: Paquette, et al., J.Am.Chem.Soc., 1991, 113, 2762
Ti
from: Holmes, A.B., Tetrahedron Lett., 1992, 33, 671
OOTMS
MeO
RO+O
OTMS
MeH2C
RO94%
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