The Wittig reaction involves phosphorus ylides as the nucleophilic carbon

species.

P+ CH2-

H3C

H3CH3C P CH2

H3C

H3CH3C

YLIDE YLENE>

The Wittig and Related Reactions

of Phosphorus Stabilized Carbon Nucleophiles

•Phosphorus ylides are stable, but usually quite reactive, compounds. They can be

represented by two limiting resonance structures, which are sometimes referred to

as the ylide and ylene forms. The ylene form is pentavalent at phosphorus and

implies involvement of phosphorus 3d orbitals. Using (CH3)3PCH2

(trimethylphosphonium methylide) as an example, the two forms are

YLIDE

a molecule that has a contributing Lewis structure with opposite

charges on adjacent atoms, each of which has an octet of

electrons.

The synthetic potential of phosphorus ylides was initially developed by G.

Wittig and his associates at the University of Heidelberg. The reaction of a

phosphorus ylide with an aldehyde or ketone introduces a carbon-carbon

double bond in place of the carbonyl bond:

P+ CR'2-

R

RR C C

R'

R'+ O

R''

R''P O

R

RR

R''

R''+

The mechanism proposed is an addition of the nucleophilic ylide carbon

to the carbonyl group to yield a dipolar intermediate (a betaine),

followed by elimination of a phosphine oxide. The elimination is

presumed to occur after formation of a four-membered oxaphosphetane

intermediate. An alternative mechanism might involve direct formation

of the oxaphosphetane.

There have been several theoretical studies of these intermediate.

Oxaphosphetane intermediates have been observed by NMR studies at low

temperature. Betaine intermediates have been observed only under special

conditions that retard the cyclization and elimination steps.

P+ CR'2-

R

RR C C

R'

R'+ O

R''

R''P O

R

RR

R''

R''+

R'R'

R''R''

-O

R3P+

betaine

R'R'

R''R''

R3P+

O

oxaphosphetane

Phosphorus ylides are usually prepared by deprotonation of phosphonium

salts. The phosphonium salts most often used are alkyltriphenylphosphonium

halides, which can be prepared by the reaction of triphenylphosphine and an

alkyl halide:

Ph3P + R X P+ CH2RX-

Ph

PhPh

X = I, Br or Cl

P+ CH2RX-

Ph

PhPh base PPh3 CHR

•The alkyl halide must be one that is reactive toward SN2 displacement.

•Alkyltriphenylphosphonium halides are only weakly acidic, and strong bases

must be used for deprotonation. These include organolithium reagents, the

sodium salt of dimethyl sulfoxide, amide ion, or substituted amide anions such

as hexamethyldisilylamide (HMDS).

•The ylides are not normally isolated so the reaction is carried out either with

the carbonyl compound present or it may be added immediately after ylide

formation. Ylides with nonpolar substituents, for example, H, alkyl, or aryl, are

quite reactive toward both ketones and aldehydes.

•Use of sodium amide or sodium hexamethyldisilylamide as bases gives

higher selectivity for Z-alkenes than is obtained when ylides are prepared

with alkyllithium reagents as base.

stereoselectivity of

the Wittig reaction

depends

strongly

on the structure of the ylide

on the reaction conditions

UNSTABILIZED YLIDES

STABILIZED YLIDES

Z-ALKENE

E-ALKENE

•The dependence of the stereoselectivity on the nature of the base is

attributed to complexes involving the lithium halide salt which is present

when alkyllithium reagents are used as bases.

•The stereoselectivity of the Wittig reaction is believed to be the result of

steric effects which develop as the ylide and carbonyl compound

approach one another.

•The three phenyl substituents on phosphorus impose large steric

demands which govern the formation of the diastereomeric adduct.

•Reactions of unstabilized phosphoranes are believed to proceed through

an early transition state, and steric factors usually make such transition

states selective for the Z-alkene.

A usefull extension of this method is one in which the -oxido ylide

intermediate, instead of being protonated, is allowed to react with

formaldehyde. The -oxido ylide and formaldehyde react to give, on

warming, an allylic alcohol.

The reaction is valuable for the stereoselective synthesis of Z-allylic

alcohols from aldehydes.

•The reaction of unstabilized ylides with aldehydes can be induced to yield E-

alkenes with high stereoselectivity by a procedure known as the Schlosser

modification of the Wittig reaction.

•This complex is then treated with an equivalent of strong base such as

phenyllithium to form a -oxido ylide.

•In this procedure, the ylide is generated as a lithium halide complex and

allowed to react with an aldehyde at low temperature, presumably forming a

mixture of diastereomeric betaine-lithium halide complexes. At the

temperature at which the addition is carried out, fragmentation to an alkene

and triphenylphosphine oxide does not occur.

•Addition of t-butyl alcohol protonates the -oxido ylide stereoselectively to

give the more stable syn-betaine as a lithium halide complex.

•Warming the solution causes the syn-betaine-lithium halide complex to give

the E-alkene by a syn elimination.

•The Wittig reaction can be extended to functionalized ylides.

Methoxymethylene and phenoxymethylene ylides lead to vinyl ethers,

which can be hydrolyzed to aldehydes.

•2-(1,3-Dioxolanyl)methyl ylides can be used for the introduction of -

unsaturated aldehydes. Methyl ketones have been prepared by an

analogous reaction.

An important complement to the Wittig reaction is the reaction of

phosphonate carbanions with carbonyl compounds.

•The alkylphosphonate esters are made by the reaction of an alkyl halide,

preferably primary, with a phosphite ester.

•Phosphonate carbanions are generated by treating alkylphosphonate

esters with bases such as sodium hydride, n-butyllithium, or sodium

ethoxide. Alumina coated with KF or KOH has also found use as the base.

R X P(OEt)3 P

O

OEtROEt

+ + EtX

P

O

OEtROEt

base P

O

OEtROEt-

•Phosphonate carbanions are more nucleophilic than an analogous ylide,

and even when R is a carbanion-stabilizing substituent, they react readily

with aldehydes and ketones to give alkenes.

Reactions with phosphonoacetate esters are used frequently to prepare -

unsaturated esters. This is known as the Wadsworth-Emmons reaction.

These reactions usually lead to the E-isomer.

P

O

OEtOEt

- +O

R'R'

P

O

OEtR'

O-

R'MeOOC

OEt R'

R'

H

+ P

O

OEt-OOEt

MeO

O O

OMe

Three modified phosphonoacetate esters have been found to show

selectivity for the Z-enoate product. Trifluoroethyl, phenyl and 2,6-

difluorophenyl esters give good Z-stereoselectivity.

P

O

R'R'

+O

HR R

H H

COOMe

O

MeO

R' = CH2CF3, phenyl, 2,6-difluorophenyl

An alternative procedure for effecting the condensation of phophonates is to

carry out the reaction in the presence of lithium chloride and an amine such

as N,N-diisopropyl-N-ethylamine or diazabicycloundecene (DBU). The

lithium chelate of the substituted phosphonate is sufficiently acidic to be

deprotonated by the amine.

Intramolecular reactions have been used to prepare cyclocloalkenes.

Intramolecular condensation of phosphonate carbanions with carbonyl

groups carried out under conditions of high dilution has been utilized in

macrocycle synthesis.

Carbanions derived from phosphine oxides also add to carbonyl

compounds. The adducts are stable but undergo elimination to form alkenes

on heating with a base such as sodium hydride. This reaction is known as

the Horner-Wittig reaction.

P

O

PhR

Ph

-P

O

PhR

Ph

RLi R'CHO P

O

PhPhR

O-

R' R'R

•The unique feature of the Horner-Wittig reaction is that the addition

intermediate can be isolated and purified. This provides a means to

control the stereochemistry of the reaction. It is possible to separate the

two diastereomeric adducts in order to prepare the pure alkenes.

•The elimination process is syn so that the stereochemistry of the alkene

depends on the stereochemistry of the adduct. Usually, the anti adduct is

the major product, so it is the Z-alkene which is favored. The syn adduct

is most easily obtained by reduction of -keto phosphine oxides.

SUMMARY

P+ CR'2R

RR C C

R'

R'+ O

R''

R''P O

R

RR

R''

R''+

-•Wittig reaction

•Schlosser

modification

•synthesys of Z

allylic alcohols

•Wadsworth-Emmons

reactionP

O

OEtOEt

+O

R'R'

P

O

OEtR'

O-

R'OEt

+ P

O

OEt-OOEt

O

MeO

OMeO

O

OMeR'

R'

-

•Horner-Wittig

reactionP

O

PhR

Ph

-P

O

PhR

Ph

RLi R'CHO P

O

PhPhR

O-

R' R'R

Reactions of Carbonyl Compounds with -Trimethylsilylcarbanions

-Hydroxyalkyltrimethylsilanes are converted to alkenes in either acidic or

basic solution. These eliminations provide a synthesis of alkenes that

begins with the nucleophilic addition of an -trimethylsilyl-substituted

carbanion to an aldehyde or ketone. The reaction is sometimes called the

Peterson reaction.

•For example, the organometallic reagents derived from

chloromethyltrimethylsilane adds to an aldehyde or ketone, and the

intermediate can be converted to a terminal alkene by base.

BunLi R2CO(H3C)3Si X(H3C)3Si X

Li

H

XR

R

•Similarly, organolithium reagents of the type (CH3)3SiCH(Li)X, where X is a

carbanion stabilizing substituent, can be prepared by deprotonation of

(CH3)3SiCH2X with n-butyllithium.

•These reagents usually react with aldehydes and ketones to give

substituted alkenes directly. No separate elimination step is necessary

because fragmentation of the intermediate occurs spontaneously under the

reaction conditions.

•In general, the elimination

reactions are anti under acidic

conditions and syn under basic

conditions.

•This stereoselectivity is the result

of a cyclic elimination mechanism

under basic conditions, whereas

under acidic conditions an acyclic

-elimination occurs.

The anti elimination can also be achieved by converting the -silyl alcohols to

trifluoroacetate esters. Because the overall stereoselectivity of the Peterson

olefination depends on the generation of pure syn or anti -silyl alcohols,

several strategies have been developed for their stereoselective preparation.

Li

Me3Si S

OO

H Ph+ S

O

Ph

S S

Li SiMe3

+O

H

S

S

70%

75%