Synthesis of Double Bonds

Wittig Reaction ! ! !

• Georg Wittig: Nobel Prize 1979

For their development of the use of boron-

and phosphorous-containing compounds
respectively, into important reagents in
organic synthesis.

(shared prize with H. C. Brown)

Ph X Ph Ph
Ph P Ph PhLi Ph P Ph Ph P Ph
H
H H H H H H
ylide

Ph H H
Ph P Ph O
+
Ph Ph Ph Ph
H H 84%

http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1979/wittig-facts.html
Wittig Reaction
General Principles ! ! !

R' R'
R3P CH + O R3P O +
Y R' Y R'

- can get high selectivity for either E or Z olefin depending on:

1. ylide type
2. type of C=O
3. reaction conditions

• Ylide Types & Outcomes

stabilized ylides: have strongly conjugating functionality (CO2R, CN, SO2Ph)

favor formation of trans olefin

moderately stabilized ylides: have less strongly conjugating functionality (allyl, aryl)
show little stereoselectivity

non stabilized ylides: have no conjugating substituents

favor formation of cis olefin
Wittig Reaction
General Principles ! ! !

• early example

O
OAc
PPh3 OH
NaOH, MeOH
Br
98% vitamin A
BASF 1956

• ylide preparation

X
Δ strong
Ph3P + Ph3P R Ph3P R Ph3P R
X R base

- bases include: NaH, KH

nBuLi, PhLi
LDA, LiHMDS, NaHMDS, KHMDS
tBuOK
CH3(S=O)CH2-
Wittig Reaction Ph3P
R
+
O H H

H H R' R R'
Nonstabilized Ylides ! ! !

• original mechanism
- stepwise, ionic process (betaine mechanism)

Ph3P O H R'
R O Ph3P O
Ph3P +
H R' H R' R H
H H R' R H R H
anti (E)

H Ph3P O H H
Ph3P Ph3P O
R'
H H H H H R R'
R O R R' R R'
syn (Z)
betaine oxaphosphatane

80 kcal/mol
130 kcal/mol
Ph3P O H H
+ Ph3P O
H H R R'
R R'
Wittig Reaction
Nonstabilized Ylides ! ! !

• alternate mechanism
- synchronous cycloddition process ([2+2] mechanism)

O R
R O [2+2]
Ph3P + Ph3P
H H R' ? R'

O R O PPh3 H R
Ph3P
H
≡ H H
+ Ph3P O
H R' R' R H R'

consistent with available evidence, but

does not rule out other possibilities!
Wittig Reaction
Nonstabilized Ylides ! ! !

• counterion dependence

- generally consider nonstabilized ylides to give cis olefins

- BUT, reaction is complex!

X
1. base Ph
Ph3P + Ph
2. PhCHO

LiHMDS 50 : 50

KHMDS 98 : 2

- use salt free conditions

- NaX, KX less soluble; ppt out of reaction medium
Wittig Reaction
Nonstabilized Ylides ! ! !

• Schlosser modification

- Li+ catalyzes oxaphosphatane opening (stabilizes betaine)

- excess salt promotes equilibration and formation of E alkene
- Na+, K+ counterions do not have sufficient Lewis acidity to cleave oxaphosphatane
(not recommended for Schlosser).

R O -78°C Ph3P O Ph3P O Ph3P O

PhLi
Ph3P +
H H -78°C H H
H H R' R R' R R' R R'
β-oxido ylide

tBuOH Ph3P O warm

R'
R H to rt R
H R'
oxaphosphatane (E)

X 1. LiHMDS
2. PhCHO Ph
Ph3P + Ph
3. PhLi, -78°C
4. tBuOH --> rt
4 : 96
Wittig Reaction
Nonstabilized Ylides ! ! !

• Trisubstituted Olefins

- reaction with ketones typically not stereoselective

- rare exceptions  large steric difference between ketone R groups

Me O Me
+ Me + Me
Ph3P
Me Et Me

~1:1

Me
Ph3P

O Me
Ph3P

H H
Wittig Reaction
Nonstabilized Ylides ! ! !

• Trisubstituted Olefins

- reaction with α-alkoxy ketones can be stereoselective

Me
O Ph3P
+
OTHP OTHP OTHP

41 : 1

- branching at α position of ketone increases selectivity

Me
O Ph3P
+
OTHP OTHP OTHP

200 : 1

- branching at α' position of ketone not tolerated

Me
O Ph3P
+
OTHP OTHP OTHP

1:1
Wittig Reaction
Nonstabilized Ylides ! ! !

• Trisubstituted Olefins

- reaction with α-alkoxy ketones can be stereoselective

- application to α-santalol

O
PPh3 1. O OMe

2. AcOH (aq)
OH

> 99 : 1
Wittig Reaction
Stabilized Ylides ! ! !

Ph3P CO2Me Ph3P CHO

- corresponding phosphonium salt can be deprotonated with weaker base

- trans selective
- will not react with ketones

OBz OBz
Ph3P CHO
CHO CHO
benzene, Δ
CO2Me CO2Me

O O O
Ph3P buffer
O ph 8.4

OHC 60%
Wittig Reaction O
EtO P W
EtO
Phosphonates ! ! !

• Horner-Wadsworth-Emmons Reaction

- Horner described use of phosphine oxides in Wittig type reactions in 1958

- 1961: Wadsworth and Emmons described the increased reactivity of phosphonate
stabilized carbanions with α-electron withdrawing groups.
- no alkene produced if W = alkyl

CO2Et
O
O
EtO P CO2Et
EtO

NaH
Wittig Reaction
Phosphonates ! ! !

• Horner-Wadsworth-Emmons Reaction

preparation: Arbuzov reaction

Br O
(EtO)3P + Br CO2Et (EtO)3P CO2Et
- EtBr EtO P CO2Et
EtO

deprotonation: nBuLi, tBuOK, NaH

Wittig Reaction
Horner-Wadsworth-Emmons Reaction ! ! !

• mechanism

O slow O H H H
RO CO2Me
RO P CO2Me RO P
RO O R' R' CO2Me
R'CHO
R' O H
(Z)
kinetic
O product

RO P CO2Me
RO -
fast O H
O RO H CO2Me
R'CHO CO2Me
RO P CO2Me RO P
RO O H R' H
R' O R'
(E)
RDS
Wittig Reaction
Horner-Wadsworth-Emmons Reaction ! ! !

• application to prostaglandin synthesis

O
HO
O

HO OH
RO OR
prostaglandin F2α

O
CO2H
MeO
O

OMe
CHO RO O
RO
Wittig Reaction
Horner-Wadsworth-Emmons Reaction ! ! !

• application to prostaglandin synthesis

HO
O O
O O
O O
EtO P C5H7
HO OH EtO

prostaglandin F2α NaH

CHO
AcO AcO O

O OH
O O
1. Zn(BH4)2 1. K2CO3 (aq)
2. separate 2. DHP, pTsOH
3. DIBAL
AcO OH THPO OTHP

HO HO
Ph3P
CO2- AcOH

THPO OTHP HO OH
Wittig Reaction
Horner-Wadsworth-Emmons Reaction ! ! !

• Trisubstituted Olefins

- reaction with ketones typically not stereoselective

- rare exceptions  large steric difference between ketone R groups

O
EtO P CO2Et
O
EtO
TBSO TBSO + TBSO
O NaH OEt

4:1 O OEt

O EtO2C CO2Et
O
EtO P CO2Et
EtO
O O + O
NaH

9:1
Wittig Reaction
Horner-Wadsworth-Emmons Reaction ! ! !

• Trisubstituted Olefins

- reaction with ketones typically not stereoselective

- can get useful levels of selectivity with α-substituted phosphonates

O
EtO P CO2Et
EtO
CHO CO2Et
O NaH O 14 : 1
E:Z
Wittig Reaction
Horner-Wadsworth-Emmons Reaction ! ! !

• Trisubstituted Olefins  Still-Gennari modification

- cis selective!
- selectivities from 10 to 50 : 1

O O
CF3CH2O P CO2Me CF3CH2O P CO2Me
CF3CH2O CF3CH2O

O
O
18-cr-6
CF3CH2O P CO2Me + R
CF3CH2O H R KHMDS CO2Me

O
O
18-cr-6 R
CF3CH2O P CO2Me +
CF3CH2O H R KHMDS CO2Me
Wittig Reaction
Horner-Wadsworth-Emmons Reaction ! ! !

• Trisubstituted Olefins  Still-Gennaro modification

- cis selective!
- selectivities from 10 to 50 : 1

O
18-cr-6
CHO + CF3CH2O P CO2Me
CF3CH2O KHMDS
CO2Me
78% >50:1 (Z:E)
Phosphorous Ylides & Phosphonates
Selectivity Summary ! !

• Unstabilized Ylides

RCHO R
Wittig
Ph3P

RCHO

O
OTHP
Schlosser
R

OTHP Still
Phosphorous Ylides & Phosphonates
Selectivity Summary ! !

• Stabilized Ylides

CO2R
Ph3P

R'CHO

O R'
R'CHO with stabilized ylide
R"O P CO2R
R"O or phosphonate
CO2R
X
R'CHO

R'CHO R' CO2R

Still-Gennari (X = H; R" = CF3CH2)

R' CO2R
Still-Gennari (X = Me; R" = CF3CH2)