19 stereoselective olefination reactions

Myers

Chem 115

Stereoselective Olefination Reactions: The Wittig Reaction

Reviews:
Vedejs, E.; Peterson, M. J. In Topics in Stereochemistry; Eliel, E. L. and Wilen, S. H. Ed.; John
Wiley & Sons: New York, 1994, Vol. 21, pp. 1–158.

• Phosphonium ylides react with aldehydes to produce oxaphosphetane 1Z or 1E, which
decomposes by a syn-cycloreversion process to the alkene.

Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927.
Wittig Olefination, Background:
• Olefin synthesis employing phosphonium ylides was introduced in 1953 by Wittig and Geissler:

O
Ph

Ph3P CH3

Ph

Br

• The reaction of non-stabilized phosphonium ylides with aldehydes favors (Z)-alkene products.

CH2

PhLi

Ph

Et2O, 84%

• In the formation of Z-alkenes, an early, four-centered transition state is proposed. TSZ is believed to
be kinetically favored over TSE because it minimizes 1,2 interactions between R1 and R2 in the
forming C–C bond.

Ph

Wittig, G.; Geissler G. Liebigs Ann. 1953, 580, 44-57.

Non-stabilized Ylides:

Ar3P

• Terminology introduced by Professor E. J. Corey in Chem 115 to help students conduct
retrosynthetic analysis of trisubstituted olefins:
T-branch
(trans)

RT

O

C-branch
(cis)

O

Ar
Ar3P

+

Ar
P

H
O

H R2

H

H

H
R2

R1
1Z

R1

Ph3P

CCl3

THF, –40 ºC

59%

O

O

N

CCl3

CCl3

R2

(Z)-alkene

Karatholuvhu, M. S.; Sinclair, A.; Newton, A. F.; Alcaraz, M.-L.; Stockman, R. A.; Fuchs, P. L. J. Am.
Chem. Soc. 2006, 128, 12656–12657.

Ar3P O

O

+

Ar3P O

R1
TSZ

R1

NaHMDS

Cl–

N

H

Mechanism:

Ar

R = simple alkyl

H

L-branch
(lone)

RL
Rc

R

H

H
R2

R1

R2

2
Ar
Ar

Ar
P

H
O
H

TSE

R1 R2

R2

Ar3P O
H
R1
1E

H

R2

R1

Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1–157.
Vedejs, E.; Peterson, M. J. Advances in Carbanion Chemistry 1996, 2, 1–85.

(E)-alkene
Fan Liu

1


Myers

Chem 115

Stereoselective Olefination Reactions: The Wittig Reaction

• Stabilized ylides are proposed to have a later and more product-like transition state with 1E
thermodynamically favored over 1Z.

Synthesis of Phosphonium Ylides

Ph3PCH2R

• The reaction of stabilized phosphonium ylides with aldehydes favors (E)-alkene products. These
reactions generally proceed at higher temperatures than reactions of non-stabilized ylides.

Stabilized Ylides: Ar3P

CHO

H3C
CH3

R

• Phosphonium ylides are generally prepared by deprotonation of
phosphonium salts, which come from the reaction of trialkyl or
triarylphosphines with alkyl halides.

R = aryl, alkenyl, -CO2R, or any anion-stabilizing groups.

Ph3P

CO2Et
CH3

CH2Cl2

CO2Et

H3C

23 ºC, 85%
E:Z = 92:8

CH3

R

pKa (DMSO)

H

22.5

Ph

17.4

CN
O
CPh

6.9
6.1

• Alkyl/aryl phosphonium halides are only weakly acidic. A strong base is required for deprotonation.
Precursors to stabilized ylides are more acidic than alkyl phosphonium salts and can be generated
using weaker bases.

CH3
Bordwell, F. G.; Zhang, X.-M. J. Am. Chem. Soc. 1994, 116, 968–972.

Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J. Org. Chem. 1996, 61, 1082–1100.

•

Lithium ions catalyze the reversible formation of betaine 2 (depicted previous page), which

contributes to erosion in stereoselectivity.

O
O
Br

O

1. NaI, NaHCO3
DMF, 100 ºC
2. PPh3, K2CO3
CH3CN, 85 ºC

O
O
Ph3P

O
I–

NaHMDS
THF;

88%

O
H

O
H

+

Ph3P

O

C6H6
Et

23 ºC, 88%
Z : E = 96 : 4

O

OO

Et

OTBS

O
OTBS

O
H

+

Ph3P

C6H6, LiI
Et

Et

23 ºC, 81%
Z : E = 83 : 17
Keinan, E.; Sinha, S. C.; Singh, S. P. Tetrahedron 1991, 47, 4631–4638.
Krüger, J.; Hoffmann, R. W. J. Am. Chem. Soc. 1997, 119, 7499–7504.

Schlosser, M. ; Christmann, K. F. Liebigs Ann. Chem., 1976, 708, 1–35.

Fan Liu

2


Myers

Chem 115

Stereoselective Olefination Reactions: The Wittig Reaction

Examples
• !,"-unsaturated carbonyl compounds can undergo phosphoniosilylation and Wittig olefination to give
substituted enones.

• Industrial synthesis of vitamin A (>1000 tons of vitamin A are produced per year using this
chemistry):

CH3

H3C CH3

CH3
PPh3
Br

CH3

O

+

OAc

NaOCH3
CH3OH
23 ºC, 98%

H

O

OTBS
TBSOTf, PPh3
THF, 23 ºC

CH3

H3C CH3

PPh3+OTf–

CH3

1. n-BuLi, THF, –78 ºC
OH

CH3

O

2.

H3C

vitamin A

H
CH3

Pommer, H. Angew. Chem. 1960, 72, 811–819.
Pommer, H.; Nürrenbach, A. Pure Appl. Chem. 1975, 43, 527–551.
Paust, J. Pure Appl. Chem. 1991, 63, 45–58.

O

OTBS
TBAF

86%, E:Z = 13:1

THF/Hexane
H

H

H3C
O

N

CH3 OTBDPS
Ph3P

N

CH2Cl2, 40 ºC

H
H3C OH

H3C

CH3
O

71%

H3C

H

80%

CH3

H3C

CH3

OTBDPS
H3C

CH3
O

H
H3C OH

Kozikowski, A. P.; Jung, S. H. J. Org. Chem. 1986, 51, 3400–3402.

• Methoxymethylene ylides lead to vinyl ethers, which can be hydrolyzed to aldehydes. An example of
this in synthesis:

Overman, L. E.; Bell, K. L.; Ito, F. J. Am. Chem. Soc. 1984, 106, 4192–4201.
H3C

O

BocHN

NH

OH
(2.00 kg)

O

1. SO3•pyr, DMSO
i-Pr2NEt, CH2Cl2, 23 ºC
2.

Et3P

CO2Et

–5 # 23 ºC, 86%

BocHN

NH

CO2Et

CH3
H
H

H3C H
H3C H
TBSO

O
H
O

I

1.

OCH3
Ph3P
THF, –30 ºC

2. TfOH, i-PrOH
CH2Cl2
77%

H3C
H3C H
H3C H
TBSO

CH3
H
H
O
I

H

O

(2.17 kg)

Chen, L.; Lee, S.; Renner, M.; Tian, Q.; Nayyar, N. Org. Process Res. Dev. 2006, 10, 163–164.

MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117, 10391–10392.

Fan Liu

3


Myers
Schlosser's Modification:

• The ylide intermediate can be trapped with formaldehyde, providing a stereospecific synthesis of Ztrisubstituted alcohols (note the hydroxymethyl group is in the C-branch).

• Reaction of non-stabilized phosphonium ylides with aldehydes can be made to favor formation of
(E)-alkenes using a modified procedure.

H
O

PPh3+I–

CH3

O

1. n-BuLi, THF, 0 ºC
2.

Et

H3C

O

O

Chem 115

Stereoselective Olefination Reactions: The Wittig Reaction

1. PhLi, THF, 0 ºC

2.

CH3

H

CH2TMS

CH2OTHP
CH3

3. PhLi, Et2O,
–78 ! 0 ºC

O

Et

H3C

O

OH

–78 ºC

PPh3+I–

CH2OTHP

3. sec-BuLi, –25 ºC
4. (CH2O)n, 0 ºC

CH3

50%, single isomer
Corey, E. J.; Yamamoto, H. J. Am. Chem. Soc. 1970, 92, 6636–6637
O

• Haloalkenes can also be prepared:

O

CH3

CH3
O

CH2TMS

O
1. PhLi•LiBr

O

71%
E:Z = 96:4.

Ph3P
Br

CH3

THF, Et2O
–75 ! 25 ºC

H

2. Ph

THF, –75 ºC

3. BrCF2CF2Br

CH3

Ph
–75 ! 25 ºC

Br

3. PhLi•LiBr

47%, E : Z = 1 : 99
Schmidt, R.; Huesmann, P. L.; Johnson, W. S. J. Am. Chem. Soc. 1980, 102, 5122–5123.
• The presence of soluble lithium salts promotes the reversible formation of betaine 2. Addition of the
second equivalent of PhLi deprotonates the "-position. The resulting #-oxido ylide is hypothesized
to possess a cyclic geometry where steric interactions are minimized between the
triphenylphosphonium group and R2.

R1

+

Ar3P O

PPh3+I–

H
PhLi
R2

H
R1

R2
+

Ar3P OLi

Ar3P OLi
H

H
R2

R1

PhLi

Li
R1

H
R2

OCH3

2.

I–Ph3P+

1. PhLi•LiBr

O
H

• Interestingly, bromination is very sensitive to the size of the alkylidene: increasing the size of the ylide
led predominantly to E-alkenes:

n-Hexyl

THF, Et2O
–78 ! 25 ºC

H3CO

H
O , –78 ºC

3. PhLi•LiBr, –78 ! 25 ºC
4. BrCF2CF2Br, –78 ! 25 ºC

2

LiI

OCH3
H3CO
Br Li

R2

Li
R1
(E)-alkene

Br

Ar3P
R1

Corey, E. J.; Ulrich, P.; Venkateswarlu, A. Tetrahedron Lett. 1977, 18, 3231–3234.

O

82%, E : Z > 99 : 1

n-Hexyl

H
R2
Wang, Q.; Deredas, D.; Huynh, C.; Schlosser, M. Chem. Eur. J. 2003, 9, 570–574.
Hodgson, D. M.; Arif, T. J. Am. Chem. Soc. 2008, 130, 16500–16501.

Fan Liu

4


Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination

Myers

Reviews:

Chem 115

Mechanism:

Wadsworth, W. S., Jr. Org. React. 1977, 25, 73–253.
Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
Kelly, S. E. In Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I. Ed.;
Pergamon: Oxford, 1991, Vol. 1, pp. 729–817.

H O M
W

Applications in Natural Product Synthesis: Nicolaou, K. C.; Härter, M. W.; Gunzner, J. L.; Nadin, A.
Liebigs Ann./Recueil 1997, 1283–1301.

R'
H

R'
(RO)2(O)P R''

O P(OR)2
O M
2E

1E

R'CHO

R''
W

R'

R''

H

W

(E)-alkene

+
Asymmetric Wittig-Type Reactions: Rein, T.; Reiser, O. Acta. Chem. Scand. 1996, 50, 369–379.

O
(RO)2P
M

Development and General Aspects:
• Olefin synthesis employing phosphonium ylides was introduced in 1953 by Wittig and Geissler.

W
R''

R'

H O M

W
R''

Wittig, G.; Geissler G. Liebigs Ann. 1953, 580, 44-57.

P(O)(OR)2
1Z

• In 1958, Horner disclosed a modified Wittig reaction employing phosphonate-stabilized

R'
H

W

R'

R''
O P(OR)2
O M
2Z

H

W
R''

(Z)-alkene

carbanions; the scope of the reaction was further defined by Wadsworth and Emmons.

O
(EtO)2P

CO2Et

1. NaH, DME, 23 °C

O
OEt

W = CO2–, CO2R, CN, aryl, vinyl, SO2R, SR, OR, NR2

+

2. Cyclohexanone,
23 °C, 15 min.

(EtO)2PO2Na

70%

• Phosphonate anion addition to the carbonyl or breakdown of the oxaphosphetane intermediate can

• Phosphonate-stabilized carbanions are more nucleophilic (and more basic) than the
corresponding phosphonium ylides.

be rate-determining, depending on the identity of OR.

• The by-product dialkylphosphate salt is readily removed by aqueous extraction.

• Carbanion-stabilizing group (W) at the phosphonate-substituted carbon is necessary for elimination

• In contrast to phosphonium ylides, phosphonate-stabilized carbanions are readily alkylated:

O
(EtO)2P

1. NaH, DME

O
OEt

2. n-BuBr, 50 °C

O
(EtO)2P

1. NaH, DME

O

OEt 2. CH2O

to occur; nonstabilized phosphonates (W = R or H) afford stable !-hydroxyphosphonates.
Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5654-5656.

O
H3C

OEt
CH2

60%, two steps

• The ratio of olefin isomers is dependent upon the stereochemical outcome of the initial addition and

upon the ability of the intermediates to equilibrate.

CH3
Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Chem. Ber. 1958, 91, 61–63.
Horner, L.; Hoffmann, H. M. R.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499–2505.
Wadsworth, W. S.; Emmons, W. D. J. Org. Chem. 1961, 83, 1733–1738.

Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
Kent Barbay, Fan Liu

5


Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination

Myers

Michaelis-Becker Reaction:

Acidity of Stabilized Phosphonates in DMSO:
O
(EtO)2P

W

Chem 115

Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.;

O
EtO P H
EtO

Bordwell, F. G. Unpublished results.

W

pKa

CN

16.4

CO2Et

18.6

corresponding phosphonates:

Cl

26.2

(Ph3P+CH2CN)Cl–: pKa = 6.9

Ph

27.6

(Ph3P+CH2CO2Et)Cl–: pKa = 8.5

SiMe3

28.8

Bordwell, F. G.; Zhang, X.-M. J. Am. Chem. Soc. 1994, 116, 968–972.

( />
1. Na, hexane
2. ClCH2CO2Et

O
EtO P
EtO

O
OEt

58%

• Phosphonium salts are considerably more acidic than the
Kosolapoff, G. M. J. Am. Chem. Soc. 1946, 68, 1103–1105.
Acylation of Alkylphosphonate Anions:

• !-ketophosphonates are prepared by acylation of alkylphosphonate anions:

Preparation of phosphonates:

O
(EtO)2P CH3

Michaelis-Arbusov Reaction:
Review: Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415–430.

1. n-BuLi, THF,
–60 °C
2. CuI
3.

O
(EtO)2P

O
CH3
CH3

O
86%

H3C

Cl
CH3

O
Br

P(OEt)3
OEt

CH3

O
– EtBr

(EtO)3P
Br

reflux

OEt
CH3

O
EtO P
EtO

O
Mathey, F.; Savignac, P. Tetrahedron, 1978, 34, 649–654.

OEt
CH3

Phosphonate Ester Interchange:

59%
O
(EtO)2P

Arbusov, A. E.; Durin, A. A. J. Russ. Phys. Chem. Soc. 1914, 46, 295.

CH2
CH3

O

O
MeO P
MeO

O

PCl5
OMe

0 " 75 °C

O

O

Cl P
Cl

F3CCH2OH
OMe

DIPEA, PhH

O
F3CH2CO P
F3CH2CO

O
OMe

40%, two steps
• The synthesis of !-ketophosphonates from #-haloketones by the Michaelis-Arbusov reaction can

be impractical due to competing formation of dialkyl vinyl phosphates by the Perkow reaction:

Still, W.C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
Bodnarchuk, N. D.; Malovik, V. V.; Derkach, G. I. Zh. Obshch. Khim. 1970, 40, 1210.
Ester Interchange:

O
Br

CH3 100 °C

O P(OEt)3

O

(EtO)3P
(EtO)3P
Br

CH3

H2C

CH3 Br

O
O P(OEt)2

– EtBr
H2C

CH3

major product
(yield not provided)

• The use of isopropyl phosphonates minimizes alkoxy exchange at phosphorus.
CH3
O
(i-PrO)2P

O

(–)-menthol
OMe

cat. DMAP
toluene, reflux
94%

Machleidt, H.; Strehlke, G. U. Angew. Chem. Int. Ed. 1964, 3, 443–444.
Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415–430.

O
(i-PrO)2P

O
O
H3C

CH3

Hatakeyama, S.; Satoh, K.; Kuniya, S.; Seiichi, T. Tetrahedron Lett. 1987, 28, 2713–2716.
Kent Barbay

6


Myers

Chem 115

Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination

Stereoselectivity of HWE Olefination:

Disubstituted Olefins:

TESO

• Reaction of phosphonates with aldehydes favors formation of (E)-alkenes.

H3C

OTBS
CHO

O

O

NaOEt, EtOH
OEt

RCHO

R

R
OEt

Aldehyde
PhCHO

TESO

OTBS

OEt

68% for R = i-Pr

Ratio of products
(E : Z)

R

4

CH3 CH3

O
OEt

O

H3C

+

E

CO2Et
5

LiTMP, THF, –30 °C

CH3 CH3
O
(EtO)2P

O
(RO)2P

Z
Me

Ratio of products
(E : Z)
98 : 2

n-PrCHO

95 : 5

i-PrCHO

84 : 16

1 : 1.2

Et

1.75 : 1

i-Pr

E only

CH(Et)2

E only

Boschelli, D.; Takemasa, T.; Nishitani, Y.; Masamune, S. Tetrahedron Lett. 1985, 26, 5239–5242.
Trisubstituted Olefins:

Larsen, R. O.; Aksnes, G. Phosphorus Sulfur, 1983, 16, 339–344.

Reaction of !-Branched Phosphonates with Aldehydes:
• In a systematic study of the synthesis of disubstituted olefins by HWE, E : Z ratio increases:
(1) in DME relative to THF,
(2) at higher reaction temperatures,
(3) M+ = Li > Na > K,
(4) with increasing !-substitution of the aldehyde.
In general, conditions which increase the reversibility of the reaction (i.e., increase the rate of
retroaddition relative to the rate of elimination) favor the formation of E-alkenes.

• The size of the phosphonate and ester substituents plays a critical role in determining the
stereochemical outcome in the synthesis of trisubstituted olefins – large substituents favor (E)alkenes.
O
(R1O)2P
CHO
CH3

Thompson, S. K.; Heathcock, C. H. J. Org. Chem. 1990, 55, 3386–3388.

O
OR2

CO2R

CH3
t-BuOK, THF
–78 °C

CH3

+

CH3 CH3

CH3 CO2R

(E)-alkene

(Z)-alkene

• Bulky phosphonate and ester substituents enhance (E)-selectivity in disubstituted olefin synthesis:
CH3
BnO

Reagent

CHO

t-BuOK, THF

–78 °C

O

O
(MeO)2P

O

CH3 CO2R
CO2R

+ BnO

Ratio of products
(E : Z)

Reagent
O
(i-PrO)2P

CH3
BnO

95 : 5
OEt
1:3
OMe

R2

Ratio of products
(E : Z)

Me

Me

5 : 95

Me

Et

10 : 90

Et

Et

40 : 60

i-Pr

Et

90 : 10

i-Pr

i-Pr

95 : 5

Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873–3888.
• (Z)-selective olefination with the trimethyl phosphonate (R1, R2 = CH3) is unsuccessful with aromatic
aldehydes. The Still modification of the HWE olefination (see below) can be applied for (Z)-selective
olefination of aromatic aldehydes.

Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873–3888.

R1

Kent Barbay

7


Myers

Chem 115

Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination

Olefination of Ketones:

O

• (E)-selectivities are typically modest in condensations with ketones. In some cases, use of a bulky
ester increases the selectivity:

O

H3C

O

H H
O
H
O

H

O

O

O
(MeO)2P

O
OR

CH3
CH3

H3C

O

H3C

O
H
R2

t-BuOK, DMF

H3C CH3

Me

H
R1

O
O

O
O

O

CH3
OTIPS

t-Bu

9:1

76%

H3C CH3

O
MeO

MeOH

single olefin isomer

CH3

2.7 : 1

CH3
OTIPS
K2CO3

O

86%

A: R1 = CO2R, R2 = H
B: R1= H, R2 = CO2R

O
O

CH3CN

1 mM

O

CH3

O

LiCl, Et3N

H

Ratio of products
(A : B)

R

H H
O

H3C CH3

O
O

H3C

H

P(OEt)2

O

O

CH3
OTIPS

HO

• The failure of this hindered ketone to react with Ph3P=CHCO2Et (benzene, reflux) provides an
example of the increased reactivity of phosphonates in comparison to phosphonium ylides.

Evans, D. A.; Carreira, E. M. Tetrahedron Lett. 1990, 31, 4703–4706.

Mulzer, J.; Steffin, U.; Zorn, L.; Schneider, C.; Weinhold, E.; Münch, W.; Rudert, R.;
Luger, P.; Hartl, H. J. Am. Chem. Soc. 1988, 110, 4640–4646.

• Tetrasubstitued olefins can be prepared in some cases, but isomeric mixtures are obtained:
O

Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T. J. Org. Chem. 1987, 52, 1201–1210.

O
(MeO)2P

O
O

MeO

O

O

O

EtO2C

O

O
Ot-Bu

CH3

CH3O

O

MeO

NaH, LiBr, THF, 23 °C

O

O
P(OEt)2
CH3

H3CO

CH3
EtO2C

OCH3

83%

E

OCH3

+ EtO2C

CH3 OCH3

NaH, THF, 55 °C

CH3 O

O

CH3

CH3O

CH3
CH3
Z

E : Z = 28 : 72

Ot-Bu

77%, 7:1 E : Z
Bestmann, H. J.; Ermann, P.; Rüppel, H.; Sperling, W. Liebigs. Ann. Chem. 1986, 479–498.
White, J. D.; Theramongkol, P.; Kuroda, C.; Engelbrecht, J. R. J. Org. Chem. 1988, 53, 5909–5921.
Single-step two-carbon homologation of esters:
• Control of double-bond geometry in tri-substituted olefin synthesis has been accomplished by the
use of a tethered HWE reagent:

O
H3C CH3
O
O

CH3
OTIPS

O
(EtO)2P

O

(1:1 mixture of diastereomers)

P(OEt)2

O

O
O(CH2)5CO2H

DCC, DMAP, CH2Cl2
HO

OEt

100%

H3C CH3
O

O
O

O

O
(EtO)2P

O

OEt
n-BuLi, THF, –78 °C;
DIBAL-H, –78 ! 23 °C

OEt
O
81%, 91 : 9 E : Z

CH3
OTIPS

• Ester reduction in the presence of the phosphonate minimizes overreduction of the intermediate
O

aldehyde.
Takacs, J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986, 27, 1257–1260.

Kent Barbay

8


Myers

Chem 115

Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination

Olefination of Base-Sensitive Substrates (Masamune-Roush Conditions):

(Z)-Selective Olefination – Still Modification of HWE Olefination:

• Masamune and Roush reported mild conditions (LiCl, amine base, ambient temperature) for

Disubstituted olefins:

olefinations employing base-sensitive substrates or phosphonates:

NHCbz
CHO

O
(EtO)2P

O
(CF3CH2O)2P

O

NHCbz

OMe

CHO

H3C

CH3

H3C

KHMDS, 18-crown-6,
THF, –78 °C

CH3

LiCl, DIPEA

CH3CN, 23 °C, 17 h

CH3

O

O

CO2Me
90%, 12 : 1 Z : E

CH3
aldehyde

product

Z:E

yield, %

90%
CHO

H3C

• This aldehyde substrate epimerizes under standard HWE conditions (NaH as base).

H3C

CO2Me

ambient temperature.

O
(EtO2)P

O
OEt

M

solvent

pKa

K

DMSO

19.2

Li

diglyme

12.2

87

4:1

74

>50 : 1

>95

22 : 1

81

CHO

• Addition of LiCl enhances acidity of phosphonate, allows use of weak bases (DBU, i-Pr2NEt) and

M

>50 : 1
CO2Me

CHO
CH3O

CH3O
CH3

• Application of the Masamune-Roush conditions does not alter the inherent (E)-selectivity of the

CO2Me

CHO

H3C

CH3

CH3

CH3
H3C

CO2Me

HWE reaction.
Trisubstituted olefins:
Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T.
Tetrahedron Lett. 1984, 25, 2183–2186.

O
(CF3CH2O)2P

• Application of mild HWE conditions to (Z)-selective olefin synthesis (see adjacent column):

O

O
CHO
H
H3C

O
H

CH3

O

aldehyde

O

O

H3C
MeO2C

CH3
LiCl, DBU, CH3CN

O

H
H3C

H

CHO

H3C

O

CHO

Hammond, G.S.; Cox Blagg, M.; Weimer, D. F. J. Org. Chem. 1990, 55, 128.

>50 : 1

79

CH3

>50 : 1

80

CH3

30 : 1

>95

CO2Me

A
crown-6) yielded only the internal aldol product A.

CH3

H3C

yield, %

CO2Me

80%, 3 : 1 Z : E

• Application of the normal conditions for (Z)-selective HWE (KHMDS, 18-

Z:E

CO2Me

CO2Me

CH3

CH3

88%, 46 : 1 Z : E

product
CHO

CH3

H3C

KHMDS, 18-crown-6,
THF, –78 °C

O
P(OCH2CF3)2

MeO

OMe
CH3

CHO

H3C

O

H

H

H3C CH3

From: Still, W.C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
• The electrophilic phosphonate and the use of strongly dissociating conditions favor rapid breakdown
of the oxaphosphetane, resulting in excellent (Z)-selectivity.
Kent Barbay

9


Myers

Chem 115

Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination
Trisubstituted olefins:

(Z)-Selective Olefination – (Diarylphosphono)acetates:
Disubstituted olefins:
O
(PhO)2P

O
(ArO)2P

O

OEt

OEt

CHO

CH3

O

NaH, THF
–78 ! –10 °C

R'

RCHO

CH3

R
base, THF

CO2Et

R'
CO2Et

100%, Z : E = 90 : 10
aldehyde
aldehyde

product
CHO

CH3

base

CH3
CO2Et

Me3NBuOH

Z:E

Ar

product

R'

89 : 11

97

n-Pr

CHO o-MePh

Me

CO2Et

CO2Et

91 : 9

Me

Ph

n-Bu

Ph

n-Bu

CO2Et

98
CHO

CHO

CH3

CH3
CO2Et

CH3

TBSO

TBSO

CO2Et

NaH

CHO

97

t-BuOK

97 : 3

100

NaH

96 : 4

91

NaH

95 : 5

85

NaH–LiBr

91 : 9

75

NaH

98 : 2

65

CO2Et

94 : 6

97 : 3

n-Bu

n-Bu

CO2Et

CH3

100

CH3

78

CH3

Ph

i-Pr

Ph

i-Pr

CH3
CO2Et

n-C7H15

CH3

CHO
OCH2Ph

CH3

CH3
CO2Et

PhCH2O

• (Z)-Selectivity was further enhanced using ortho-alkyl substituted (diarylphosphono)acetates:
O
(ArO)2P

89 : 11

98

n-C7H15CHO

CH3

CHO

93 : 7

n-Bu

NaH

Me3NBuOH

n-Bu

CH3

CH3
CH3

Me3NBuOH

yield, %

CH3
o-i-PrPh

CHO
CO2Et

Z:E

CH3

n-Pr

CHO
CHO
NaH

base

yield, %

Ando, K. J. Org. Chem. 1998, 63, 8411–8416.

O

• 93 : 7 – 99 : 1 (Z)-selectivity, 92–100% yield.
OEt

• Aryl, ",#-unsaturated, alkyl, branched alkyl, and
"-oxygenated aldehydes are suitable substrates.

• Masamune and Roush's mild conditions have been adapted for (Z)-selective olefin synthesis using
(diarylphosphono)acetates:

Ar = o-MePh, o-EtPh, o-i-PrPh
• In analogy to Still's (Z)-selective HWE reaction employing [bis(trifluoroethyl)phosphono]acetates, (Z)-

selectivity is attributed to the electron-withdrawing nature of the aryloxy substituent, which
accelerates elimination relative to equilibration of oxaphosphatane intermediates.
Ando, K. J. Org. Chem. 1997, 62, 1934–1939.
• For (diphenylphosphono)acetate esters, (Z)-selectivity increases with increasing steric bulk of the
ester moiety.

Ando, K. J. Org. Chem. 1999, 64, 8406–8408.

O
(PhO)2P

1. NaI, DBU, THF, 0 °C

O
OEt

2.

CH3
CH3

CHO
NHSO2Ar

–78 ! 0 °C

CH3
CH3
ArSO2N

H

CO2Et

89%, 87 : 13 Z : E
• no racemization

Ar = 2,4,6-trimethylphenyl

Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem. 2000, 65, 4745–4749. Kent Barbay

10


Myers
HWE Reaction in Macrolide Synthesis:

Amphotericin B:

(–)-Vermiculine:

H3C
O

O

CH3

O
NaH

O

P(OMe)2
THF, 23 °C
O
5.6 mM

49%

O

S
S CHO

O

O

CH3

O

Chem 115

Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination

O

S

S

S

S

TBSO

CH3

O

O

O
O

O

O
2

H3C

CHO

OEt

LDA, THF, –78 ! 0 °C
60%

O
O

O

OTHP

TBSO

H3C
O
(–)-Vermiculine

O

O
(EtO)2P

CH3

H3C

O

H3C

OTHP

CH3
OEt

H3C
O

• High-dilution or syringe-pump additions are frequently required to achieve high-yielding

OTBS

macrocyclizations.
Burri, K. F.; Cardone, R. A.; Chen, W. Y.; Rosen, P. J. Am. Chem. Soc. 1978, 100, 7069–7071.

H3C
TBSO

(–)-Asperdiol:

O
P(O)(OEt)2

H

O

O

O

H3C CH3

O

H3C CH3

Me
EEO

CH3

CH3

OMe

DBU, CH3CN, 10 mM
LiCl, 25 °C, 4 h

O

O

70%

OEt

O

O

Me
EEO

CH3CN, 23 °C
3 mM

CH3

OTBS

H3C

CH3
(E) only

61%

TBSO

OCH3

O
O
CH3

O

O

H3C CH3

O

O

O

OH

O

CHO

OEt

HO

O
O HO
CH3

OH

HO

OH

OH

OH O

OH
O

H
H3C

LiCl, DBU
Me
EEO

CH3CN, 23 °C
CH3
4 mM

CH3

O

O

Amphotericin B
HO

CH3
OH
NH2

CH3

30 %
CH3

O
O

H3C

Me
EEO

OMe

H3C

based on ring size and substitution. For example, compare to above:

P(O)(OEt)2

OTBS

O

H3C CH3

• Intramolecular HWE olefinations are usually selective for (E)-alkenes, but the selectivity can vary

H

P(OMe)2

O

Tius, M.A.; Fauq, A. J. Am. Chem. Soc. 1986, 108, 6389–6391.

EtO

O

H

LiCl, DBU

CHO

O

O
CH3

OTBS

H3C

O

EtO

OCH3

O

2:1E:Z

Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 1035–1039.

Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y. J. Am. Chem. Soc. 1988, 110,
4685–4696.
Nicolaou, K.C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110,
4696–4705.
Kent Barbay

11


Myers

Chem 115

Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination

Asymmetric HWE:

Asymmetric Olefin Synthesis – Chiral Ester:

Chiral Phosphonamidates:

O
Li
H
H3C

H

O
Ph
O P
N
i-Pr

t-BuLi, THF

H3C

–70 °C;

Li

H

O
(MeO)2P

R' = i-Pr

R

O

R

O
O PR'
N

O
(MeO)2P

CH3

O

Ph
O

Ph
O

n-BuLi, THF;

CH3

CH3
CH3

O

O

CH3

CH3

O

H

H

H
H

O
O

H
H3C

O
O P
N

OTf
OH
R

Ph3COTf, 2,6-lutidine
CH3CN, 60 °C

i-Pr Ph

H
H3C

O
O P
N

R

R

yield, %

CPh3
OH

O

THF, –60 °C

Attack by "-face of phosphonate on
convex face of ketone

R

i-Pr Ph

94-98%, 88-100% de

Ph

O

ee, %

t-Bu

65

>99

Me

72

86

Ph

71

>99

CO2t-Bu

75

95

O
(MeO)2P

O

LiO

H

CH3
Ph
O

CH3
H

Ph
O
syn-elimination

O

CH3
CH3

H

H
93%, 90% de

H

O

CH3

O

CH3

O

O

• Electrophilic attack occurs from the less hindered !-face of the phosphonamidate-stabilized
carbanion. Bulky nucleophiles display high selectivity for equatorial attack on cyclohexanones.

• Stable "-hydroxy phosphonamidates are isolated and transformed to alkenes by electrophilic
activation with trityl salts. This procedure results in stereospecific syn-cycloelimination.
(Attempted base-catalyzed olefin formation led to retroaddition.)

Gais, H.-J.; Schmeidl, G.; Ball, W. A.; Bund, J.; Hellmann, G.; Erdelmeier, I. Tetrahedron Lett.
1988, 29, 1773–1774.
8-phenylmenthol: Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908–6909.

Denmark, S. E.; Chen, C.-T. J. Am. Chem. Soc. 1992, 114, 10674–10676.
Denmark, S. E.; Chen, C.-T. J. Org. Chem. 1994, 59, 2922–2924.
Kent Barbay

12


Myers

Chem 115

Stereoselective Olefination Reactions: Horner-Wadsworth-Emmons Olefination
Discrimination of enantiotopic or diastereotopic carbonyls:

Kinetic Resolution:
H

O
O
(F3CCH2O)2P

Ph
O

3 eq

CH3
CH3

1.1 eq

Ph
O

H3C

H

CH3

O

CH3

O

O

H
+

O

H

CO2R

81%, 98% de

14%, 92% de

OHC

OTBS
CHO

OTBS

H3C

O

O
(F3CCH2O)2P

major product
synelimination

O

H

Ph
O

CO2R

(RL = OR)

CH3

O

H

O
Nu

H

Tullis, J. S.; Vares, L.; Kann, N.; Norrby, P.-O.; Rein, T. J. Org. Chem. 1998, 63, 8284-8294.
1.
CH3

CO2R
P(O)(OR)2

O

53%, 90% de

preferentially bis-olefinated.

O

Attack from !-face of (Z)-enolate
H2C O

CH3 CH3

• Diastereoselectivity is dependent on conversion, because the minor diastereomeric products are

P(O)(OR)2

Felkin-Anh addition

CH3

O
P(OMe)2

Exercise: Based on the previous example, rationalize the stereochemical outcome of these
olefinations. (Note that the phosphonate used in this example is enantiomeric to that used in
the previous example).

O

CH3

O

O

See: Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987, 109, 1525-1529.
H

Nu
H H
fast-reacting
enantiomer

K • 18-crown-6

Ph
O

H3C

H
CO2R

O

CO2R

OHC
CH3

O

CH3 CH3

83%, 96% de

CH3 CH3

• Mechanistic hypothesis:

O

CHO

KHMDS, 18-crown-6
THF, –100 °C

• E and Z products are formed from different enantiomers of the starting aldehyde.

H

TBSO

RO2C

Crude Z : E = 85 : 15

O CH2

O
P(OCH2CF3)2

H3C

CO2R

1 eq KHMDS,
18-crown-6
THF, –100 °C

O

O
H

H H
slow-reacting
enantiomer

H3C

Ph
O

O

O
P(OMe)2

H

CO2R

(Slow step may be addition or elimination)
minor product

H3C

Ph
O

O

K

O
P(OMe)2

O

Ph
O

H3C

O

O
P(OMe)2

t-BuOK, THF

O

–50 °C, 30 min
CH3
O

• Incapable of syn-elimination,
therefore reverts
O CH3

O
CH3

• For consideration of the stereochemical outcome of addition to "-alkyloxy aldehydes, see:

H3C

(MeO)2(O)P
CO2R
LiO

CH3
H3C

O

CH3

NaH, DMF, 23 °C
2. Acetone,
Amberlyst-15

H3C

synelimination

O

(CH2)2I
CH3
O
O

(MeO)2(O)P
CO2R
LiO

CO2R

O
O CH3

Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353–3361.

O

CH3

• Auxiliary shields "-face of (Z)-enolate

Rein, T.; Kann, N.; Kreuder, R.; Benoit, G.; Reiser, O. Angew. Chem., Int. Ed. Engl. 1994, 33, 556–558.
Rein, T.; Reiser, O. Acta. Chem. Scand. 1996, 50, 369–379.

80%, 98% de
• Attack occurs at either diastereomeric carbonyl from the face opposite the methyl group.
Mandai, T.; Kaihara, Y.; Tsuji, J. J. Org. Chem. 1994, 59, 5847–5849.
Kent Barbay

13


Myers

Advantages over the Wittig Reaction

Reviews
Kelly, S. E. Alkene Synthesis in Comprehensive Organic Synthesis; Trost, S. M.; Fleming, I., Ed.;
Pergamon, Oxford, 1991, 1, 729–818.
Weber, W. P. Peterson Reaction in Silicon Reagents for Organic Synthesis. Springer-Verlag, Berlin,
1983, 14, 58–78.
Magnus, P. Aldrichimica Acta 1980, 13, 43.
Overview

• The Peterson reagents are more basic and nucleophilic and less sterically hindered. As a result, they
are more reactive than phosphorus ylides.
• The byproduct siloxanes tend to be easier to remove than phosphorus byproducts.

Synthesis of Peterson Reagents, Applications

• via halogen-metal exchange

• The Peterson olefination reaction was first reported in 1968. It is considered to be the silicon variant
of the Wittig reaction.

O
n-BuLi

Ph3Si
Br

O
Ph

Chem 115

Stereoselective Olefination Reactions: Peterson Olefination

(H3C)3Si
Ph

MgCl

OH

(H3C)3Si

THF

Ph Ph

KH, THF

Li

Et2O

Ph

Ph

• via Deprotonation

O
(H3C)3Si

Mechanism
R1

OLi

Cy2NLi
OEt

(H3C)3Si

THF, –78 ºC

R2

H3C CH3

R3

CH3

Nu
TBSO

O
R2

Base R3Si

OH

R1

R2

R3Si
Acid
R1

R3

R3
R2
OH2

R2

R2

O

R1

+

H3C CH3

–78 " –25 ºC
82%
Z:E = 93:7

CH3
CO2Et

TBSO

Galano, J.-M.; Audran, G.; Monti, H. Tetrahedron Lett. 2001, 42, 6125–6128.
sec-BuLi

R3
R1

OEt

O

R3Si

R3

Ph
HO

Substituted silanes can be metalated if an anion-stabilizing group is present.

• Magnesium and lithium alkoxides are not prone to elimination while sodium and potassium
alkoxides readily form the product alkene.

R1

Ph3Si

81%

Brook, A. G.; Duff, J. M.; Anderson, D. G. Can. J. Chem. 1970, 48, 561–569.

23 ºC, 86%

Peterson, D. J. J. Org. Chem. 1968, 33, 780–784.

R3Si

H

Ph

Ph3Si

H3CO

Si(CH3)3

THF
–78 " –25 ºC

R3

Li
H3CO

H3C O

Si(CH3)3

O
O

H
H3C CH3

Nu
R3Si
R3Si
R1

R2
R3
OH2

Acid

R1

OH
R3

R2

R3Si

O

Base
R1

R3

R2

• The silicon-substituted carbanion adds irreversibly to the carbonyl substrate, producing a mixture
of diastereomeric !-silylcarbinols. Each diastereomer undergoes stereospecific decomposition to
give either E or Z alkenes depending on the elimination conditions, as shown above.
• when R1 = EWG, the intermediate !-silyl alkoxide undergoes spontaneous fragmentation as it is
formed to give the olefinic products.

H3C
H

OCH3
O
O

H3CO
H3C
KH, THF

TMS
OH O

H

O

0 ºC, 85%
H3C CH3

Z:E = 3:1

H3C CH3 73%
inseparable mixture of diastereomers

Analogous reactions with the corresponding phosphonium and phosphonate reagents were not as
successful.
Magnus, P.; Roy, G. J. Chem. Soc., Chem. Commun. 1979, 822–823.
Kende, A. S. Blacklock, T. J. Tetrahedron Lett. 1980, 21, 3119–3122.

Fan Liu

14


Myers

• Methylenation using commercially available (trimethylsilyl)methyllithium or
(trimethylsilyl)methylmagnesium chloride:

• via addition of organometallics to vinylsilanes
O
Li

EtLi

Si(CH3)3

THF, –78 ºC

Et

H

H3C
Si(CH3)3

Et

91%

Si(CH3)3
OH

O

Et

SPh

23 ºC

Hudrlik, P. F. Peterson, D. Tetrahedron Lett. 1974, 15, 1133–1136.

OTBS

H3C

SPh

H3C CH3

(4.5 equiv)

OTBS

MgCl

O

PivO
CbzHN N
Cbz
Ot-Bu

90%

2. SOCl2, C5H5N
86%

Li

Li

Si(CH3)3

• Reaction with Ph3P CH2 at room temperature was not successful and more forcing conditions
resulted in decomposition.

Si(CH3)3
THF, –78 ºC

CH3

SPh

H

1. (H3C)3Si

O
PivO
CbzHN N
Cbz OOt-Bu

• via reductive lithiation
N(CH3)2

H CH3

Lebsack, A. D.; Overman, L. E.; Valentekovich, R. J. J. Am. Chem. Soc. 2001, 123, 4851–4852.

Z:E = 28:72

H3C

Li

pentane, THF, –78 ºC
2. HF•pyr, CH3CN
23 ºC, 84%

H3C CH3

NaH, HMPA
Et

1. (H3C)3Si

H CH3

H

Et

H3C

Chem 115

Stereoselective Olefination Reactions: Peterson Olefination

H3C

Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 2103–2112.

CH3

Stereoselective Synthesis of !-silylcarbinols
O
H3C

O–K+
Ar
Si(CH3)3

anti

H3C

H3C

Ar
Si(CH3)3

+

CH3

O–K+

H3C

CH3

H
KOAc

OBn
OBn

• Because "-silylcarbanion additions to carbonyl compounds are irreversible, the diastereomeric ratio in
the addition step defines the cis/trans-alkene product ratio unless diastereomeric adducts can be
separated and processed individually.

• Other approaches rely on the stereoselective generation of !-silylcarbinols.

96%, Z:E = 5:95

fast elimination
–78 ºC

(H3C)3Si

n-Pr

DIBAL-H

(H3C)3Si

pentane, –120 ºC

n-Pr

n-Pr
n-Pr
BF3•OEt2

97%

H3C
OBn

CH2Cl2, 0 ºC

CH3

n-Pr

n-Pr

99%, Z:E = 94:6

OBn
H3C

n-Pr

OH

O
slow elimination
AcOH, 60 ºC

n-Pr

KH, THF, 23 ºC

syn

Hudrlik, P. F. Peterson, D. Tetrahedron Lett. 1974, 15, 1133–1136.
68%
E:Z = 77:1

• The syn-hydroxysilane in the example above underwent facile (base-mediated) elimination at –
78 ºC while the anti-hydroxysilane did not react until acetic acid was added to give (after
heating) the E-alkene.

Tamao, K.; Kawachi, A. Organometallics 1995, 14, 3108–3111.
Perales, J. B.; Makino, N. F.; Van Vranken, D. L. J. Org. Chem. 2002, 67, 6711–6717.

O
C5H11

Ph
Si(CH3)3

MeLi, Et2O
–78 # 23 ºC

Ph

LiO CH3
C5H11

Ph
Si(CH3)3

C5H11

TFA
–78 # 23 ºC

H3C
57%
E:Z = 9:91

Barrett, A. G. M.; Flygare, J. A. J. Org. Chem. 1991, 56, 638–642.
Fan Liu

15

Myers

Chem 115

Stereoselective Olefination Reactions: Tebbe, Petasis Olefinations
Petasis Modification (1990):

Reviews:
Oleg G. Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789–2834.
Petasis, N. A.;Hu, Y.-H. Curr. Org. Chem. 1997, 1, 249–286.
Brown-Wensley, K. A.; Buchwald, S. L.; Cannizzo, L.; Clawson, L.; Ho, S.; Meinhardt, D.;
Stille, J. R.; Straus, D.; Grubbs, R. H. Pure Appl. Chem. 1983, 55, 1733–1744.

Ti

Cl

MeLi or

Cl

MeMgBr

Generalized Reaction:
• The Tebbe and Petasis olefinations are useful methods for the methenylation of a wide variety of
carbonyl compounds. The active complex is a titanocene methylidene complex, which can be
generated from either the Tebbe reagent or the Petasis reagent.

CH3

Ti

"-elimination

CH3

Ti CH2

#
titanocene methylidene

Petasis reagent

• This is a milder version of the Tebbe reagent, which avoids generation of the Lewis acidic aluminum
intermediate.
• This reagent is also effective for olefination of silyl esters and acylsilanes.

Ti
O
R1

R2

CH3

Al

CH3

Cl

Ti

or

(Tebbe Reagent)

Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392-6394.

CH3

Order of Reactivity:

CH3

O
R1

(Petasis Reagent)

R2

O

>

O

>

O

>

R

H

R1

R2

R1

OR

R1

NR2

R

H

R1

R2

R1

OR

R1

NR2

Tebbe reagent (1978):
O

Cp2TiCH2AlCl(CH3)2
!15 ºC, 65%

Acid halides and anhydrides:

Ti

Cl

2 Al(CH3)3

Cl
Al(CH3)2Cl,
CH4

Ti

Al
Cl

CH3

Lewis base

Ti CH2

CH3
Al(CH3)2Cl

• Acid halides provide ketones rather than olefins under Tebbe or Petasis conditions. Anhydrides give
ketones under Tebbe conditions and olefins under Petasis conditions.

O

titanocene methylidene

Tebbe reagent

R

O

or
Cl

R

Cp2TiCH2AlCl(CH3)2

O

Cp2Ti

R

O

H+

O

O
R

R

Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611–3613.

CH3

Cl– or AcO–

Mechanism:
• The Tebbe olefination reaction follows a mechanism similar to the Wittig olefination, but the
titanocene methylidene is generally more nucleophilic and less basic than Wittig reagents.

O

LB

R
O

Ti

Al
Cl

CH3
CH3

Ti CH2

Ti CH2

R1

R1
O

R2

R2

Cp Ti CH2
Cp
Cp2TiO

Cp2Ti(CH3)2

O
O

R

O
R

O

R

Chou, T.-S.; Huang, S.-B. Tetrahedron Lett. 1983, 24, 2169 - 2170.
Advantages:
• Reagents are relatively simple to prepare.
• Relatively bulky carbonyl groups can be olefinated.
• An alternative to the Wittig reaction, and works well on hindered carbonyls.
Disdvantages:

R1

R2

• A full equivalent of the reagent is required.
• Limited to methylenation: substituted olefinations are difficult.

Alpay Dermenci

16

Myers

Chem 115

Stereoselective Olefination Reactions: Tebbe, Petasis Olefinations

R1

• Selective mono- or bis-methylenation of dicarbonyls can be achieved by varying the equivalents of
reagent.

Petasis reagent

O
R2

R1

toluene or THF

R2
Ti

O

Substrate

Temp. (oC)

Product

Yield (%)
O

O
H

H3C

H

H3C

O
Ph

Ph

Ph

60–65

60–65

Ph

CH3
O

(n equiv)

O

43

CH3
O

O

THF, 65 oC
70%
1.0 equiv

10

:

1

2.0 equiv

2

:

1

4.0 equiv

0

:

1

90

O
60–65

60
Ti
O

O

O

O

OCH3

OCH3

60–65

O

O

60–65

CH3
OSi(CH3)2t-Bu

Ph

OSi(CH3)2t-Bu

70

70

Ph

OCH3

OMe

65

67

65

65

O
OEt

OEt
Ph

Ph

N(CH3)2

Ph

N(CH3)2

70

54

O
H3C

SPh
CH3

1.5 equiv

1

:

0

4.0 equiv

1

:

20

CH3
O

CH3
HO
CH3

O

CH3

THF, –78 oC

CH3
76%

Ireland, R. E.; Thaisrivongs, S.; Dussault, P. H. J. Am. Chem. Soc. 1988, 110, 5768 - 5779.
• Site-Selective Olefination:

O

Ph

O

Tebbe reagent
(1.5 equiv)

HO
O

O
Ph

N CH3

• Hindered carbonyls:

O
Ph

41

Ph

Ph

N CH3

toluene, 75 oC
75%

O
O

CH3

(n equiv)

N CH3

60

CH3

H3C

SPh
CH3

Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392-6394.
Petasis, N. A.; Lu, S.-P. Tetrahedron Lett. 1995, 36, 2393 - 2396.

75

70

H3CO
O
O

N

O

H3C H
Ph

O

Cp2TiMe2 (2.5 equiv)
65 oC, 8 h
THF

O

N

52%
Colson, P.-J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918 - 5924.

O

H3CO
O

CH3
Ph

Alpay Dermenci

17


Myers

Chem 115

Stereoselective Olefination Reactions: Tebbe, Petasis Olefinations

• A strained enecarbamate was prepared using Petasis' olefination conditions:

• Acyl chlorides can be converted into the corresponding methyl ketones without epimerization.

CH3
CH3

Cl
Cp2Ti

(1.2 equiv)
Cl

BnO

toluene, 0

CH3

O
OEt

H3C

Ti
O

OH

BocO

oC

HN
NH4Cl

O

HN
77%

CH3

CH3

(90.4% ee)

14 steps

(90.4% ee)

Tandem Olefination/Aldol:
Gelsemoxonine

OH

HO
O

N OMe

H3C

O
Ph

CH3

Cl

Diethelm, S.; Carreira, E. M. J. Am. Chem. Soc. 2013, 135, 8500–8503.

Cl
Cp2Ti

(1.2 equiv)

O

PhCHO

O

Ph

toluene, 0 oC

OH

Ph

Ph

69%

Industrial-Scale Petasis Reaction:
• Dimethyltitanocene was used to produce Aprepitant, a recently approved substance P antagonist
used to prevent chemotherapy-induced nausea and vomiting:

CF3
O

Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1983, 105, 1664–1665.
Tandem Olefination/Metathesis:

O

• Cyclic enol ethers can be prepared through an olefination, ring-closing metathesis cascade
sequence:

N

H
BnO
BnO

H

O

H

H

H
O

O
O

H

CH3

H
BnO
BnO

THF, 25 oC (20 min)
then reflux (5 h), 71%

H

O

H

H

H
O

O

H
BnO
BnO

H

O

H

H

H
O

O

CH3
CH2

H

CF3

H3C

CF3
O

Cp2Ti(CH3)2
(2.9 equiv)
THF, 91%

F

CF3

O

O

steps

N

(250 kg)

N

H
N

F

Ph

HN

(227 kg)

CF3
O

F
N

Aprepitant
(Emend!)

O

H

65%

Tebbe reagent
(1.3 equiv)

THF, 20 min 25 oC

CH3

CF3

O

Ph

Tebbe reagent
(4 equiv)

CH3

H O

N
H

CH3
Ti

OEt

CH3

BnO

76%

BnO

O

H3C

C5H5N, toluene
70 oC, 8 h, 77%

O

O

OH

BocO

Cp2Ti(CH3)2

Tebbe reagent
(2.0 equiv)
THF, 3 h, reflux

CH3

77%
Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem. Soc. 1996, 118, 1565–1566.

CF3

Relative reactivity:

O
H3C
H3C

OCH3
CH3

<

O H3C CH3
H3C

O

R

R: alkyl, CH2Ph

O
<

H3C

O

CH3
O

CH3

O

<

CH3

CF3
O

N
Ph

F

Payack, J. F.; Huffman, M. A.; Cai, D.; Hughes, D. L.; Collins, P. C.; Johnson, B. K.; Cottrell, I. F.;
Tuma, L. D. Org. Proc. Res. Dev. 2004, 8, 256–259.
Alpay Dermenci

18


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Stereoselective Olefination Reactions: The Takai Reaction

Chem 115

Haloforms

Reviews:

O

Furstner, A. Chem. Rev. 1999, 99, 991–1045.
H3C

Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1–36.

H

Reaction Overview:

R2

Xa

CrCl2-DMF
THF

R1
E-isomer
(major)

H

R1

THF

Temp (ºC)

time (h)

65
0
50

Cl
I
Brb

X

CHX3, CrCl2

O

R2 CHI2

CHX3, CrCl2, THF

X
H3C

yield (%)

2

2
1

76
82
76

R1
E-isomer
(major)

R2=alkyl, aryl, B(OR)2, SiR3, SnR3

aReaction
bCrBr

conditions: aldehyde (1 equiv), CHX3 (2 equiv), CrCl2 (6 equiv), THF.
LiAlH4 (1:0.5) was employed in lieu of CrCl2.

3 and

• Aldehydes are more reactive than ketones:

Mechanism:

O
O

CHX3

E/Z
95/5
83/17
95/5

2 CrCl2

X

CrIIIX2
CrIIIX2

X2CrIIIO

O

+

H

R1

R1

H

H X

CHI3, CrCl2
CHO

H3 C

I

H3C
75% (E/Z = 81:19)

THF, 0 oC

I

CrIIIX2

I

H3C
5%
X

R1

(E)-alkenyl halide
(major)

+

R1
X
(Z)-alkenyl halide

(minor)

Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410.
1,1-Geminal Dihalides
CH3

O
H
General Trends:
• Reactivity is dependent on the haloform: I > Br > Cl.
• E/Z ratios are greatest in the order Cl > Br > I.
• Aldehydes react faster than ketones.
• The E-isomer is the predominant product for both haloforms and 1,1-geminal dihalides.

H3C

THF, 97%
E:Z = 94:6

CH3

Disadvantages
• Stoichiometric amounts of by-products are generated.
• Excess reagent is typically required.

H3C

H3C
CH3

t-Bu

t-BuCHI2
CrCl2-DMF

O
Advantages
• Reagents are readily available.
• Reaction is selective for the E-isomer.
• High functional group tolerance.

CH3CHI2, CrCl2

H

THF, 90%
E:Z = 94:6

H3C

Okazoe, T.; Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109, 951–953.

Alpay Dermenci

19


Myers

Chem 115

Stereoselective Olefination Reactions: The Takai Reaction

• Olefination of ketones:

H3C
O

I

CHI3, CrCl2

OH

CH3

O

NBoc

O

t-Bu

THF

t-Bu

H

CH3 CH3 CH3

H3C
OH

CrCl2, CHI3

O

NBoc

I

THF-dioxane

CH3

CH3 CH3 CH3
96%

Lin, Y.-Y.; Wang, Y.-J.; Lin, C.-H.; Cheng, J.-H.; Lee, C.-F. J. Org. Chem. 2012, 77, 6100–6106

O
H2N

O

Takai Olefination in Natural Product Synthesis

H

CH3

CH3
H3CO

CH3
OH

H

NHAc

O
TBSO

CH3

HO

2. PPTS, EtOH
H

64% (2 steps)

O
I

O

CH3 CH3

Superstolide A

O

1. CrCl2, CHI3, THF
O

H3C

OH

CH3

CH3

Tortosa, M.; Yakelis, N. A.; Roush, W. R. J. Org. Chem. 2008, 73, 9657 - 9667.

O
Sch-642305
CH3

CH3

SEMO
Dermenci, A; Selig, P. S.; Domaoal, R. A.; SpasovK. A.; Anderson, K. A.; Miller, S. J. Chem.
Sci. 2011, 2, 1568–1572.

SEMO
OH

OTHP
Cl
H3C
CH3

OTES
CH3
CHO

CrCl2, CHCl3
THF, 65 ºC

Cl
H3C

OTES
CH3

CH3

1. DMP

I

2. CrCl2, CHI3, THF

CH3
69%

Cl

OTHP

23 ºC, 77%
E:Z = 19:1

CH3

CH3
HO
OH

CH3
H
O
Br
CH3
Cl
H3C
Cl
aplysiapyranoid C
Jung, M. E.; Fahr, B. T.; D'Amico, D. C. J. Org. Chem. 1998, 63, 2982–2987.

CH3

O
H3C

O

CH3

Amphidinolide J

Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198–11199.

Alpay Dermenci

20


Myers

Chem 115

Stereoselective Olefination Reactions: The Julia Olefination

Reviews

• The reductive elimination step can follow two different pathways depending on the reducing agent,
however each pathway shows a preference for forming the E-olefin isomer.

Dumeunier, R.; Marko, I. E. Modern Carbonyl Olefination 2004, 104–150.
Julia, M. Pure Appl. Chem. 1985, 57, 763–768.

Na(Hg)/MeOH Reduction:

Reaction
• The Julia olefination and modified Julia olefination reactions involve the coupling of aryl sulfones

with aldehydes or ketones to provide olefins.
• Initial Report:

SO2Ar
Ph

1. n-BuLi (2 equiv)
2. MgI2 (2 equiv)
3.

Ph
PhO2S

O

Al/Hg
Ph

90%

Ph
H

Ph

O

Ar

S

Ph

NaOCH3

MeO

SO2Ar
H
R4
O
R1
H R2 O

R2

–ArSO2Na

• Typically, strong bases and stoichiometric quantities of reagents are required.

SO2Ar

R2

O
R3

R1

R1

ArO2S

R4

O

R1
R3

O
R2

H

Reductant

E-isomer

H

X

R4

R3
R1

(E)-alkene

Ar

SO2Ar
H
R4
O
R1
H R2 O

R2
H

R2

R1

SmI2 Reduction:

O
Base

1 e"

H
Z
(disfavored)

MeOH

• Often Julia olefination requires trapping of the initially formed !-oxido sulfone, which is then

reduced to give the E-alkene.

SO2Ar
O
R1
R2
R3

1 e"

Na(Hg)

R2

H

• The reaction predominantly forms (E)-olefins

Na(Hg)

R2

R1

E
(favored)

R1

S O

H

H

R2

O

R1

R2

R1

H

Pascali, V.; Umani-Ronchi, A. J. Chem. Soc., Chem. Comm. 1973, 351.
Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 49, 4833–4836.

SO2Ar

Ar

O–Na+

R1

Ph

Ph

Ph

SO2Ar
H
R4
O
R1
H R2 O

H
R1

R2

SmI2
R1

1 e"

H

OCOR4

O
OSmI2
S
R4
O

H
H R2 O

H R2 O

SmI2

H

1 e"

R1

R2

H

OCOR4

R4

O

R1

R1
H

R2

H

OCOR4

• A variety of different trapping and reducing agents can be used.

H
Trapping agents: Ac2O, BzCl, MsCl, TsCl
Reducing agents: SmI2 (most common), RMgX, Bu3SnH, Li or Na in ammonia, Na2S2O4,
Raney/Ni, Al(Hg) amalgam, LiAlH4, SmI2/HMPA

R2

R1

E-isomer

H
Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194–3204.

Alpay Dermenci

21


Stereoselective Olefination Reactions: The Julia Olefination

Myers

• Second-generation Julia olefination reactions employ an one-pot procedure: use of specially

designed heterocycles allows for in situ reductive elimination to occur, via a Smiles
rearrangement-like mechanism.

Julia-Silvestre

• In general, the E/Z ratio is dependent on reaction conditions, with PT-sulfones giving higher Eselectivities.

Julia-Kocienski
Ph
N N
N N

S
Ar:

Ar:

N

SO2Het

1-phenyl-1H-tetrazole

"BT-sulfone"

"PT-sulfone"

Mechanism:

N

Base

R1

O O
S

N

S

O
R1

R1

H

1. (Me3Si)2NM
CH3

benzothiazole

O O
S

Chem 115

O O

S

N

S

S

O

BT-sulfone
Yield (%)

E/Z

PT-sulfone
Yield (%)

Li

2

70 : 30

94

72 : 28

Na

32

75 : 25

95

89 : 11

4

76 : 24

81

99 : 1

Solvent

M

DME

K

R1

CH3

2. c-C6H11CHO

E/Z

R2
Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett. 1998, 26–28.

R1
R1

O

N

R2

S

R2

S
O

N

O

O O
S

S O

R1
• Origin of Selectivity:
R2
closed transition state

N

+

O
S

N N
N
N
Ph
O S HO
R1

SO2

H R2

Sulfone Preparation

Ph
N
N
SH
N N

commercially
available

1. DIAD, PPh3, THF
0 ! 23 ºC, 89%

OH
CH3

CH3

N N
N
N
SO2
Ph

2. m-CPBA, NaHCO3
CH2Cl2, 23 ºC, 68%

Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett. 1998, 26–28.

CH3

R1
CH3

R1

Li

H

R2

O

SO2PT
R2
O
Li

open transition state

SO2PT
O

H

Smiles
rearrangement

O
PT S H O K
R1
R2
O
H

R1

R2

R1

SO2PT
R2
O

R1

H

SO2PT
R2

O
H

Smiles
rearrangement

R1

R2

PT-sulfone

Alpay Dermenci

22

Stereoselective Olefination Reactions: The Julia Olefination

Myers
Examples

• Application to the synthesis of BMS-644950, a next-generation statin candidate:

OTBS
OTBS
TBDPSO

CH3
+

H

O

PTO2S

H

F

CH3 CH3

CH3

CH3

N
N
N N

E:Z

NaHMDS, THF, –78 oC

1:8

LiHMDS
DMF, DMPU, –35 oC

O
TBDPSO

N
N

O

+

O

CH3

CH3

H
CH3

O NH4

HO

•H2O
N
N
N N

O

N

+

t-Bu

OCH3
O

H3C CH3
(168.5 g)

(27.6 kg)

N N

N
N

CH3

CH3

(33.6 kg)

74%, E : Z = 91 : 1

O

H
O

N
N

BMS-644950

O

O

CH3

O

i-Pr

90%

CH3

Ot-Bu

F
1. HCl
2. NH3

N
N

H3C
O
H3C
O

O

i-Pr

S

2. EtOH, H2O
(crystallization)

CH3

• The Julia olefination reaction was applied to the synthesis of LAF389, an anti-cancer agent. The
addition of TMSCl was found to be crucial: the authors propose that TMSCl stabilizes the anionic
intermediate and the sensitive aldehyde substrate by attenuating the basicity of the reaction.

S

S

O
CH3 CH3

F

t-Bu

1. LHMDS, THF

CH3

Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772 - 10773.

O

O

(38.4 kg)

HO

O

Ot-Bu

N
N Ph
N N

(27.5 kg)

OTBS
OTBS

>30:1

H3C
O
H3C
O

i-Pr

Conditions

Conditions

O

O

O

O

Chem 115

(120.0 g)

1. n-BuLi, TMSCl
THF, CH3CN
2. MTBE
(crystallization)

OCH3
O

O

H3C CH3
(65.9 g)

45%, single isomer

Xu, D. D.; Waykole, L.; Calienni, J. V.; Ciszewski, L.; Lee, G. T.; Liu, W.; Szewczyk, J.; Vargas, K.;
Prasad, K.; Repic, O.; Blacklock, T. J. Org. Process Res. Dev. 2003, 7, 856–865.

Hobson, L. A.; Akiti, O.; Deshmukh, S. S.; Harper, S.; Katipally, K.; Lai, C. J.; Livingston, R. C.; Lo,
E.; Miller, M. M.; Ramakrishnan, S.; Shen, L.; Spink, J.; Tummala, S.; Wei, C.; Yamamoto, K.;
Young, J.; Parsons, R. L. Org. Process Res. Dev. 2010, 14, 441–458.
Alpay Dermenci, Fan Liu

23