The [1,2]-Wittig Rearrangement

2010/06/19

D2 Hidaka Ikemoto
 Overview

Introduction

Scope and Limitation

Mechanism

Stereochemistry

Chirality Transfer

Synthetic Applications

Summary
 Introduction
H base [1,2] R2
R2 R2
R1 R1 O R1 OH
O then H+

Wittig (1942)
1'
H PhLi (5 eq) R [1,2] R
Ph 2 O + Ph OH +
R
Ph O THF, rt, 1-2 days 1 Ph OH
rearrangement elimination

R rearrangement (%) elimination (%)

Et 41 50
i-Pr 66 24
t-Bu 90 0

Wittig, G.; Lohmann, L. Liebigs Ann. Chem. 1942, 550, 260.

H Li Li R2 H+ R2
R2 R2 R2
R1 O R1 O R1 O R1 OH
R1 O Li
 Introduction
H base [1,2] R2
R2 R2
R1 R1 O R1 OH
O then H+

H base
R2
R1 O

SnBu3 R Li
1 R2
R O [1,2]-Wittig Rearrangement
Li R2
(SePh) reductive R2
R1 O R1 OH
SPh lithiation
1 R2
R O

TMS F or
R2
R1 O MeLi

W. C. Still.; A. Mike. J. Am. Chem. Soc. 1978, 100, 1927.

Hoffmann, R.; Buckert, T.; Bruckner, R. Tetrahedron Lett. 1993, 34, 297.
Maleczka, R. E., Jr.; Geng, F. Org. Lett. 1, 1999, 1111.
 Scope and Limitation
R R R
H O PhLi (5 eq) Li O [1,2] H O

THF, rt, 1-2 days

R yield (%)
Bn 86
Et 61
Me 42
Ph 16

migratory aptitude

> Ph > > > > >

Ph
allyl benzyl tert-alkyl sec-alkyl prim-alkyl methyl phenyl

This order is roughly consistent with the stability order of the corresponding
radicals or cations involved. or

Wittg, G. Angew. Chem. 1954, 66, 10.

 Scope and Limitation
H base [1,2] R2
R2 R2
R1 R1 O R1 OH
O then H+

SnBu3 n-BuLi (1.5 eq) Li Ph

Ph O Li
Ph O THF, -78 C HO
sec-
[1,2] LN =
K. Tomooka, T. Igarashi, T. Nakai, Tetrahedron 1994, 50, 5927-5932. (90%) lithium naphthalenide

O Ph O Ph OH
LN
Ph
SePh Li
THF
tBu -78 C, 20 min tBu tBu
tert- [1,2]
R. Hoffmann, T. Riickert, R. Bruckner, Tetrahedron Lett. 1993, 34, 297-300. (56-60%)

SnBu3 Li cyclohexanone Ph
n-BuLi HO
+
Ph O THF, -78 C Ph O
HO
prim- Ph O
[1,2] adduct
W. C. Still, J. Am. Chem. Soc. 1978, 100, 1481-1487. (0%) (98%)
 Scope and Limitation

SnBu3 n-BuLi Li O

O O Ph THF, -78 to rt O O Ph
HO Ph
[1,2] (16%)

SnBu3 n-BuLi Li O
+
O O THF, -78 to rt O O O O
HO
[1,2] (0%) de-Sn product (40%)

SnBu3 n-BuLi Li
+
O C7H15 THF, -78 to rt O C7H15 HO C7H15 O C7H15
[1,2] (0%) de-Sn product (75%)

K. Tomooka, T. Igarashi, T. Nakai, Tetrahedron 1994, 50, 5927-5932.

 Mechanistic Aspects
H base [1,2] R2
R2 R2
R1 R1 O R1 OH
O then H+

(i) 1 step inversion

retention
zy z z z
x y x x z y y x
x SNi z y [1,2]-shift
y x
R1
O C O C O
O R1 R2 OH
C O
R1 R2
R2
(iI) 2 steps Li
C R'
Ph O
(a)
A

Li (b) R' R'

C R' C
Ph O Ph OLi Ph O Li
B
(c) (a) migrates as a cation via an ion pair of the type A
H R' (b) migrates as a radical via a radical pair B
C (c) migrates anionically via the intermediate C
Ph O Li
C
 Mechanistic Aspects
(i) 1 step inversion
retention
z z z
zy x y x x z y y x
x SNi z y [1,2]-shift
y x
R1
O C O C O
O R2 C O
R1 OH
R1 R2
R2

MeLi (5 eq) Li Li
H
Ph O Ph
Ph O Ph
Ph O Ph THF (0.2 M) Ph O Ph Li
rt, 2 days

H H
H
Ph O Ph O Ph O Ph
Ph O
Li Li
Li Ph Li
Ph Ph
MeLi MeLi
Ph Me
solvent X (%) Y (%)
Ph OH Ph OH Et2O-THF (1:1) 87 3
X Y THF-NEt3 (1:1) 82 8
THF 74 16
THF-DME (1:1) 68 23
P. T. Lansbury and V. A. Pattison. J. Am. Chem. Soc. 1966, 88, 78.
 Mechanistic Aspects
(i) 1 step inversion
retention
z z z
zy x x x z y y x
y y [1,2]-shift
x SNi z
y x
R1 C O
O O R2 C O C O
R1 OH
R1 R2
R2
Et Et
R n-BuLi Li R R Me 1. H2O R Me
Et Et *
*
Ph O * Me THF, -60 C Ph O * Me 2. [O] Ph O
Ph OLi
(S)-1 (S)-2

R ee (%) of (S)-2
H 20 80% racemization = 60% with retention and 40% with inversion
Ph 80 20% racemization = 90% with retention and 10% with inversion

If the reaction proceeded in one step, the carbon atom should migrate either with total retention or inversion.

The stereochemical findings opposed a one-step course for the rearrangement and
pointed to a two-step cleavage-recombination mechanism.

P. T. Lansbury and V. A. Pattison. J. Am. Chem. Soc. 1966, 88, 78.

Ulrich Schollkopf. Angew. Chem. Int. Ed. 1968, 7, 588.
(ii) 2 steps Mechanistic Aspects
(a) migrates as a cation via an ion pair of the type A

Li (a) Li R'
C R' C R'
Ph O Ph O Ph O Li
A
Li [1,2]
MeLi (2 eq)
Ph O +
Ph O then sat.NH4Cl
THF, rt, 24 hr Ph OH
Ph OH
94% 6%
(a)

Li
+
Ph O Ph OH
major
Me
MeLi (2 eq) Li [1,2] Me
Me Me
Ph O Ph O then sat.NH4Cl
Me THF, rt, 24 hr Me 30%
Ph OH
(a)
Me
Li Me Me Me
+ Me
Ph O Me Me Me Ph OH
major
P. T. Lansbury and V. A. Pattison. J. Am. Chem. Soc. 1962, 84, 4295.
 Mechanistic Aspects
(ii) 2 steps

Li (b) R' R'

C R' C
Ph O Ph OLi Ph O Li
B
(c) (b) migrates as a radical via a radical pair B
H R' (c) migrates anionically via the intermediate C
C
Ph O Li
C
MeLi (5 eq) Li
Ph + + s.m.
Ph O Ph O HO
THF-Et2O trace
OH -elimination
1-adamantyl ether = 1:1
-70 C to rt [1,2] trace
1-2 days 36%

MeLi (5 eq) Li
Ph + + s.m.
Ph O Ph O HO
THF-Et2O 44%
= 1:1 OH
1-norbornyl ether -70 C to rt [1,2] -elimination
not detected 55%
1-2 days

>

stable
P. T. Lansbury and V. A. Pattison. J. Org. Chem. 1962, 27, 1933.
 Mechanistic Aspects
(ii) 2 steps

Li (b) R' R'

C R' C
Ph O Ph OLi Ph O Li
B
(c) (b) migrates as a radical via a radical pair B
H R' (c) migrates anionically via the intermediate C
C
Ph O Li
C
H t-BuLi Li
R
R R
Ph O THF Ph O Ph OH
-60 C

R' krel
methyl 1
ethyl 39
isopropyl 162
tert-butyl 2080

Linear relation between the dissociation energy D of C-H bonds

and the logarithm of the krel values for the rearrangement of alkyl groups

Tetrahedron Lett. 1968, 24, 2809

 Mechanistic Aspects
(ii) 2 steps (b) migrates as a radical via a radical pair B

Li (b) tBu tBu

C tBu C
Ph O Ph OLi Ph O Li
B

CIDNP:Chemically Induced Dynamic Nuclear Polarization

The phenomenon of enhanced NMR absorption (A) and emission (E)
during radical reactions has been called CIDNP
(low field ESR lines emission, high field lines absorption, immediately after formation of the radicals)

NMR signal of the methine proton of lithium phenyl tert-butyl methoxide

(a) immediately after the rearrangement, (b) after decay of the polarization

R. Kaptein and L. J. Oosterhoff. Chem. Phys. Letters 1969, 4, 195,.

 Mechanistic Aspects
(ii) 2 steps

Ph O Ph OLi rotate through 180 Ph OLi

base
C
R3 R1 R3 R2
R2 C R1 C R1
R2 R3

Ph OLi Ph OLi

C C
R3 R1 R2 R1
R 2 R 3

retention inversion

Racemization with partial retention can be explained in a two-step rearrangement.

The alkyl radicals themselves (which are assumed to be planar) are

achiral, since they possess a symmetry plane.
 Solvent Cage Effect
I I*

h I , I 2I
cage pair
I I

quantum yield of I2 dissociation (mPa s) at 25 C

gas phase 1 0.0186
0.66 0.29
0.075 3
NF95 0.048 80
USP335 0.036 380

I , I
= solvent molecule

Y. Tanimoto.; H. Hayashi.; S. Nagakura.; H. Sakuragi.; K. Tokumaru. Chem. Phys. Letters 1977, 41, 267.
 Stereochemical Aspects
R2 Li R2
migrating carbon [1,2]
* G
R1 * O G R1 * *
OH
Li-bearing terminus

R1 R2 yield (%)
retention
Ph H 55
Ph Me 26
O n-BuLi (3 eq) O Ph Et 6
H Ph n-Bu 4
O THF, rt, 3 hr
HO R Ph Ph 41
R2 R1 2 12
R1 2-Pyridyl H
2-MeOPh H 67
Gartner, P. et al. Tetrahedron: Asymmetry 2000, 11, 1003. 3,4,5-(MeO)3Ph H 42

Et Et
R n-BuLi Li R R Me 1. H2O R Me
Et Et *
*
Ph O * Me THF, -60 C Ph O * Me 2. [O] Ph O
Ph OLi
(S)-1 (S)-2
R ee (%) of (S)-2
H 20 60% retention
Ph 80 90% retention

U. Schollkouf, H. Schafer. Justus Liehim Ann. Chem. 1963, 663, 22.

 Stereochemical Aspects
OMe 1. n-BuLi (3 eq) OMe
O THF
MeO MeO O 1 (1, 1'S)
MeO -78 C to -50 C, 1 hr
MeO >98%
MeO TMS MeO
O 2. NaOMe (5,6 eq) dr at C1' = 99:1
MeOH, rt, 30 min HO 1'
H (71%)
1. n-BuLi (3 eq)
OMe OMe OH
THF
MeO O TMS -78 C to -50 C, 1 hr MeO O (1, 1'R)
O
MeO MeO >98%
MeO 2. NaOMe (5,6 eq) MeO dr at C1' = 87:13
H
MeOH, rt, 30 min
(71%)
O Li OH
O Li
Li
O TMS
H

TMS Li
(1, 1'S) (1, 1'R)
radical involved is coupled in a "cage" rapidly enough to avoid epimerization!

retention of configuration at the migrating carbon

J. Am. Chem. Soc. 1996, 118, 3317-3318.

 Stereochemical Aspects
Li R R
SnBu3 etc.
R +
R HO G HO G
O G O G
retention inversion

LDBB inversion

O SPh THF 79% OH

-78 C to 0 C O O
Li Li
E. J. Verner. T. Cohen. J Am. Chem. Soc. 1992, 114. 375-377.

Li tBu tBu

LDBB = lithium 4,4'-di-tert-butylbiphenylide

SePh LiNaphth Li inversion OH

t-Bu OR OR R
THF, -78 C t-Bu t-Bu
R = CD2CH CH2: (48%)
R = CH2Bn: (56-60%)
R. Hoffmann, R. Briickner. Chem. Ber. 1992, 125, 1957.
 Stereochemical Aspects
Li R R
SnBu3 etc.
R +
R HO G HO G
O G O G
retention inversion

SnBu3 n-BuLi
1 3 Ph Ph Ph Ph
Ph S O R THF OH OH OH OH
-78 C to rt
1 (79%) 3 4 ent-3 ent-4
7 : 67 : 23 : 3
SnBu3
1
n-BuLi
3
0 : 10 : 88 : 2
Ph S O S
THF
2 -78 C to rt (87%) 90% retention
74% inversion
H
1 Ph
Ph S
LiO S
OH
solvent cage 98% retention
90% inversion
H
2 Ph
Ph S
LiO R
OH
solvent cage
K. Tomooka, T. Igarashi, T. Nakai.
invesion of configuration at the lithium center
Tetrahedron Lett. 1993, 34, 8139.
 Stereochemical Aspects
SnBu3 Ph H
n-BuLi (3 eq) Li 74% inversion
Ph O HO
THF, -78 C Ph O 90%
(R)-1 88% ee (R)-2 42% ee

H H
Ph
Ph O O
Li Li

K. Tomooka, T. Igarashi, Nakai. Tetrahedron Lett. 1994, 35, 1913.

n-BuLi
Me H TMEDA 61% inversion Me
Me Li
Ph O THF Ph O 87% Ph OH
100% ee -78 C to -25 C 22% ee

Li H R H
H
G O R
R G OLi G OLi
inversion

H
Li H H R R
R G OLi
G O G OLi retention
K. Tomooka, T. Inoue, T. Nakai. Chem. Lett. 2000, 418.
 Stereochemical Aspects-exceptional case-

O n-BuLi (3 eq) O HO H O HO H O
O O O O O+ O
solvent
Bu3Sn H Ph -78 C Li H Ph retention Ph inversion Ph

solvent retntion / inversion yield (%) Ph

10% THF/Hexane 70:30 43 O O
30% THF/Hexane 47:53 59 Li
H H
THF 28:72 93 H O
LiCl saturated THF 19:81 81

chelation [1,2]-Wittig with

HO H O controlled O "normal" inversion HO H O
O O O O
[1,2]-Wittig of lithium
Ph rearrangement Bu3Sn H Ph bearing terminus Ph
retention inversion

Robert E. Maleczka, Jr.,* and Feng Geng. J. Am. Chem. Soc. 1998, 120, 8551.
 Chirality Transfer
O
O Ph OH O OH O
Ph t-BuLi (3 eq) NLiPh
NHPh + Ph NHPh
Ph O Ph NHPh
Ph O THF
-78 C, 1 hr Ph Ph
Li anti 94% ee syn
>98% ee
(69%, anti / syn = 9.9)
O
O Me OH O OH O
t-BuLi (3 eq) NLiPh
Me
NHPh Ph O Me NHPh + Me NHPh
THF
Ph O Me Me
-78 C, 1 hr
Li anti 95% ee syn
>98% ee
(77%, anti / syn = 2.2)
O
O OH O OH O
t-BuLi (3 eq) Me
Me NLiPh +
NHPh NHPh NHPh
THF O
O Me Me
-78 C, 1 hr
Li anti 80% ee syn 80% ee
>98% ee
(55%, anti / syn = 1.2)
O solvent cage Despite its radical character,
H + the integrity of the two radical stereocenter
Ph OLi NLiPh fast recombination is retained to an appreciate extent.
H
Ph = solvent molecule

O. Kitagawa et al. Tetrahedron Letters 2001, 42, 4865.

 Side Reaction-elimination and [1,4]-shift-
, '-elmination

R1 base R1 H R1
H ' +
O R2
O R2 O R2

TBSO(CH2)8 H n-BuLi TBSO(CH2)8

THF, -78 to 0 C
O Ph (90%)
M. Matsushita, Y. Nagaoka. H. Hioki, Y. Fukuyama, M. Kodama. Chem. Lett. 1996, 1039.

1,4-Wittig rearrangement
R1
H base H
R1 O R1
O O O R1

4 H Bu
PrLi
Bu +
1' O
1 THF-pentene O Bu HO
[1,4] [1,2]
(29%) (23%)
H. Felkin, A. Tambute. Tetrahedron Lett. 1969, 821.
 Tandem Wittig Rearrangement / Aldol Reactions

Bu2BOTf O OH
O O Et3N
O + MeO
MeO H CH2Cl2 OH
Ph
Ph

Bu2BOTf (4 eq) [1,2]-Wittig O BBu2 Bu2BOTf

O OBBu3
Et3N (3.2 eq) Rearragemnet Et3N
O O O
MeO MeO MeO
CH2Cl2 0 C to rt, 15 min
Ph Ph Ph

OBBu2 O aldol O OH
aldehyde (1.5 eq) Bu2BO reaction
OBBu2 Ph
MeO H MeO
warm to rt, 1-6 hr OH
Ph Bu2BO OMe Ph
syn-diol

Myra Beaudoin Bertrand and John P. Wolfe.* Org. Lett. 2006, 8, 4661.
Tandem Wittig Rearrangement / Aldol Reactions
Bu2BOTf (4 eq) O OH
O
O Et3N (3.2 eq)
O + MeO R
MeO
H R CH2Cl2 OH
1 Ph 0 C to rt, 15 min Ph
ester aldehyde product dr yield (%)
O OH
O
1 MeO >20:1 67
H OH
Ph
O OH
O
1 MeO Ph >20:1 72
H Ph OH
Ph
O O OH

1 H MeO >20:1 75
OH
Ph
O OH
O
1 MeO C9H19 >20:1 78
H C9H19 OH
Ph

Myra Beaudoin Bertrand and John P. Wolfe.* Org. Lett. 2006, 8, 4661.
 Tandem Wittig Rearrangement / Aldol Reactions
Bu2BOTf (4 eq)
O O OH
O Et3N (3.2 eq)
*R +
OBn H Ph *R Ph
O CH2Cl2
(1.5 eq) Bn OH
0 C to rt

Ph 2-naphth
Ph
SO2
R* Bn
Me N
SO2Mes
Ph
yield (%) 0 62 27 82 0 83

dr 5:1 3:1 3:1 20:1

Bu2BOTf (4 eq) Ph
Ph O Et3N or iPr2NEt (3.2 eq) O OH
O (S)
+ (R)
OR H R1 CH2Cl2 O R1
O
(1.5 eq) 0 C to rt R OH
59-88% yield
dr >20:1-8:1
75-95% ee
John P. Wolfe et al. J.Am. Chem. Soc. 2009, 131, 12556.
 Tandem Wittig Rearrangement / Aldol Reactions
OH O
OH O
3 14 Alder ene 3
OH reaction
7 10
O 11 O 1 O H OH
14
O 1
+
HO2C OH 21 10
20 11

Alternaric Acid [1,2]-Wittig RO2C OH 21

20
rearrangement
/aldol
14
Ph Bu2BOTf (4 eq) O OH
O O 20
iPr2NEt (3.2 eq) 10
O + RO 11
O H HO
CH2Cl2 21
0 C to rt
(1.5 eq)
14 81%, >20:1 dr
3 steps 20
11
HO RO2C 10
3 steps
Br 21

14 (DHQD)2PHAL, OsO4 OH 14
20 K3Fe(CN)6, K2CO3
9-BBN-H dppf, PdCl2 11 HO 11
RO2C 10
RO2C
OTBS 10
THF CH3SO2NH2, H2O 20
K3PO4
21 21
toluene reflux TBSO tBuOH, 0 C TBSO
Suzuki cross-coupling Sharpless asymmetric dihydroxylation

John P. Wolfe et al. J.Am. Chem. Soc. 2009, 131, 12556. Barry M. Trost et al. J.Am. Chem. Soc. 1998, 120, 9228.
 Summary
Li-bearing terminus
migrating carbon R2 Li R2 Li R2
[1,2]-Wittig
* * G
R1 * O G rearrangement R1 * LiO G R1 * *
solvent cage OH

The [1,2]-Wittig rearrangement proceeds via a radical-pair mechanism within a solvent cage.

Regioselectivity and ease of reaction depend on the substituenets of the substrate.

Radical recombination with retention of configuration at the migrating carbon.

Radical recombination with invesion of configuration at the lithium center.

The [1,2]-Wittig rearrangement competes -elimination, [2,3]-Wittig rearrangement and

[1,4]-shift, giving poor to modest yields of produt.

Despite its radical character, chirality transfer has been demonstrated

within the [1,2]-Wittig rearrangement.