Sigmatropic Rearrangements

Neil Stevenson
12/01/05
 Pericyclic Reactions
• Continuous concerted reorganisation of electrons

• 5 major categories:
– Electrocyclic ring opening/closure
– Cycloaddition/cycloreversion reactions
– Cheletropic reactions (e.g. carbene addition)
– Group transfer reactions (e.g. H2 transfer)
– Sigmatropic rearrangements
 Sigmatropic Rearrangements
• Migration of a -bond across a conjugated -system
• [m,n] shift when the -bond migrates across m atoms of
one system and n of another
2 2
3 1 [1,3]-shift 3 1

1'
R 1' R

2 2
1 3
1 3 [3,3]-shift
3'
3'
R 1' R 1'
2'
2'
Conjugated π Systems
Antibonding
4
3


3

2 nonbonding

2


1
1
Bonding

2 p-orbitals 3 p-orbitals 4 p-orbitals

 Suprafacial/Antarafacial
• Suprafacial migration: Group moves across same face

R R' R' R R R'

R R'
R R' R R'

• Antarafacial migration: Group moves from one face to the

other
R R'
R' R'
R R' R R' R R'
R
R
 FMO Analysis
• [1,3] Sigmatropic Rearrangements: H migration
+
H H H

R R' R R' R R'

1s proton LUMO H

2 allyl anion HOMO R R' R R'

H

Suprafacial migration Antarafacial migration

FORBIDDEN ORBITALLY ALLOWED BUT

H CANNOT BRIDGE DISTANCE
 FMO Analysis
• [1,3] Sigmatropic Rearrangements: C migration
+
CH3 H3C CH3

R R' R R' R R'

2p Carbon LUMO H
C H H H
H
C
H
2 allyl anion HOMO R R' R R'

Suprafacial migration Suprafacial migration

Retention at carbon Inversion at carbon
FORBIDDEN ALLOWED
 FMO Analysis
• [1,5] Sigmatropic Rearrangements

X + X
X
R R' R R' R R'

1s proton LUMO
H
Suprafacial migration Antarafacial migration
3 pentadienyl anion HOMO
ALLOWED FORBIDDEN

C 2p carbon LUMO

3 pentadienyl anion HOMO C

Suprafacial migration Antarafacial migration

Retention at Carbon Inversion at Carbon
ALLOWED ALLOWED
 Dewar-Zimmerman
• Dewar-Zimmerman model:
– Choose a set of 2p atomic orbitals and arbitrarily assign phase
– Connect the orbitals in the starting material
– Allow reaction to proceed according to postulated geometry and
connect reacting lobes.
– Count number of phase inversions: Odd = Möbius, Even = Hückel
– Assign transition state as aromatic or antiaromatic based on
number of electrons:
System Aromatic Antiaromatic
Hückel 4n + 2 4n
Möbius 4n 4n + 2
– Aromatic = Thermally allowed (Photochemically forbidden)
– Antiaromatic = Thermally forbidden (Photochemically allowed)
 Dewar-Zimmerman
• [1,3]-H shift H H

R R' R R'

Suprafacial: Antarafacial:
Two Phase Inversions Three Phase Inversions
Hückel Topology Möbius Topology
Four electrons Four electrons
H H FORBIDDEN ALLOWED

• [1,5]-H shift H H

R R' R R'

Suprafacial:
Zero Phase Inversions
Hückel Topology
Six electrons
THERMALLY ALLOWED
H H
 Woodward-Hoffman
• A ground-state pericyclic change is symmetry-allowed
when the total number of (4q+2)s and (4r)a components is
odd.

• [1,5]-H shift – suprafacial

4s No. (4q+2)s = 1
H
H H 2s
No. (4r)a =0
Total =1
ALLOWED

• [1,5]-H shift – antarafacial H 4a

H
2s
No. (4q+2)s = 1
No. (4r)a =1
Total =2
H FORBIDDEN
 Woodward-Hoffman
• [1,7]-H shift – antarafacial 6a
No. (4q+2)s = 1
No. (4r)a =0
Total =1
H ALLOWED
H H
2s

R R
• [3,3] rearrangement

Chair Boat
2s
No. (4q+2)s = 3 No. (4q+2)s = 3
2s
No. (4r)a =0 2s No. (4r)a =0
R Total =3 Total =3
2s R
ALLOWED ALLOWED

2s 2s
[1,2] Sigmatropic Rearrangements
• [1,2]-C shift to cation: Wagner-Meerwein Rearrangement
R R
2p Carbon radical C

+
1 olefin
H radical cation
OH
Suprafacial migration: ALLOWED

• [1,2]-C shift to anion: Wittig Rearrangement

R R
2p Carbon radical C

2 olefin
R
radical anion
R BuLi Li
O O
Suprafacial migration: FORBIDDEN
Must be stepwise
[2,3] Sigmatropic Rearrangements
R R' R R'
* R R' *
X X Y Y
Y X

X, Y = C, N, O, S, Se, P

• FMO Analysis

2 vinyl radical X Y
Suprafacial migration
ALLOWED
2 allyl radical
[2,3] Sigmatropic Rearrangements
• X=O, Y=C Wittig Rearrangement1

BuLi [2,3]
O O +
Li LiO Ph
Ph Ph

• X=S, Y=C Sulfonium Ylide Rearrangement2

BuLi [2,3]
+ +
S S
+
Li S S
S S

1. Baldwin, JACS 1971, 93, 3556

2. Lythgoe, Chem. Comm. 1972, 757
[2,3] Sigmatropic Rearrangements
• X=N, Y=C Ammonium Ylide Rearrangement3 (Stevens)
R R R
BuLi [2,3]
+ +
N N +
Me2N
Li
CN CN CN

• X=C, Y=C All-carbon Rearrangement4

Cu(I) [2,3] ROH

-N2 O
O O
N2 O OR
H

3. Buchi, J. Am. Chem. Soc. 1974, 96, 7573

4. Smith, J. Org. Chem. 1977, 42, 3165
[2,3] Sigmatropic Rearrangements
• X=N, Y=O Meisenheimer Rearrangement5
R
R R
[2,3] Zn/HOAc
Et N
+ Et O
O N OH
Et
Et

• X=S, Y=O Sulfoxide Rearrangement6

(MeO)3P
MeOH
+ O
S [2,3] S OH
Ph O
Ph BuLi
PhSCl

5. Tanabe, Tet. Lett. 1975, 3005

6. Evans, Accts. Chem. Res. 1974, 7, 147
[2,3] Sigmatropic Rearrangements
• X=Se, Y=N Related Rearrangement7

Ph Ph
[2,3] MeOH Ph
Se
+ N
Ph N Se Ts NHTs
Ph
Ts

• X=S, Y=N Related Rearrangement8

TsO
TsO TsO
NaN(Cl)Ts [2,3]
+
(MeO)3P S N
SPh Ph N N
MeOH PhS Ts Ts
Ts

7. Hopkins, Tet. Lett. 1984, 25, 15

8. Dolle, Tet. Lett. 1989, 30, 4723
[2,3] Sigmatropic Rearrangements
• Olefin Selectivity from starting olefin
– 1,2-Disubstitution(E)
R R R'
X
Y R'
H Y
R R' X
H
X R
Y H R'
X H
Y R Y
R' X

– R and R’ prefer to sit in pseudo-equatorial positions9

2 LDA (E) selectivity: 75%
O
HO CO2H
CO2H
9. Nakai, Tet. Lett. 1981, 22, 69
[2,3] Sigmatropic Rearrangements
• Olefin Selectivity from starting olefin
– 1,2-Disubstitution(Z)
R R R'
X
Y H
H Y
R R' X

X R' R
Y R' R'
X H
Y R Y
H X

– Generally, higher levels of 1,3 induction seen with Z olefins10

R R
BuLi OH Only E isomer
Bu3Sn O obtained

10. Still, J. Am. Chem. Soc. 1978, 100, 1927

[2,3] Sigmatropic Rearrangements
• Olefin Selectivity from starting olefin
– (E)-Trisubstituted
R R R'
X
Y R'
H Y
R R' H X

X R
Y H R'
X H
Y R Y
R' X

– E transition state still generally preferred but R-Me interaction

may cause significant destabilisation10

n-Bu BuLi
>96% Z isomer
Bu3Sn O n-Bu
OH
[2,3] Sigmatropic Rearrangements
• Olefin Selectivity from starting olefin
– (Z)-Trisubstituted
R R R'
X
Y H
H Y
R R' X

X R' R
Y R' R'
X H
Y R Y
H X

– Again, generally higher levels of 1,3 induction seen with Z

olefins due to highly destabilising R-R’ interaction
[2,3] Sigmatropic Rearrangements
• Olefin Selectivity from allylic position

R R
X
Y H
R' R' R' Y
R H X

X R
Y H R'
X R'
R > R'
Y R Y
H X

– May expect selectivity dependent on size difference of R vs. R’11

SLi
BuLi (E):(Z) = 3:2
R
S R
[2,3] Sigmatropic Rearrangements
• Chiral Auxiliaries12

O O HO
CH2OR Li CH2OR CH2OR
BuLi
O N O N O N

ROCH2 ROCH2 ROCH2

96% de
– Via:
O M
O

ROCH2 N CH2OR

12. Katsuki, Tet. Lett. 1986, 27, 4577

[2,3] Sigmatropic Rearrangements
• Internal Relay of Stereochemistry13

O
O O O
BuLi O O
O
HO HO
SnBu3
ratio 79:6

– Via: (Felkin-Ahn)
C
O H
H
O
O
[2,3] Sigmatropic Rearrangements
• Steric Effects

X
Y
X
t-Bu X Y
t-Bu Y t-Bu

– Pseudo-equatorial attack generally favoured14

+
t-Bu N2 S Cu(I)
Ph SPh
t-Bu
CO2Et CO2Et
selectivity 91:9

14. Evans, J. Am. Chem. Soc. 1972, 94, 3672

[2,3] Sigmatropic Rearrangements
• Ring Expansion15
Cu(I) CO2Et
[2,3]
+
S N2CHCO2Et S S
CO2Et

• Ring Contraction16
O
Br O MeO
Ph + O
N MeOH
Ph N
Ph

N
O
" +
" O
N
Ph N
Ph
15. Vedejs, Accts. Chem. Res. 1984, 17, 358
[3,3] Sigmatropic Rearrangements
• FMO Analysis X X X
Y Y Y

2 allyl radical

Chair geometry Boat geometry

ALLOWED ALLOWED

• Dewar-Zimmerman

Zero Phase Inversions

Hückel Topology
Six electrons
THERMALLY ALLOWED
[3,3] Sigmatropic Rearrangements
X X X
Y Y Y

X, Y = C, O, N, etc

X X
Cope O Claisen O

• Cope Rearrangement: Boat vs. Chair Transition State17

trans-trans trans-cis cis-cis

17. Doering, Roth, Tetrahedron 1962, 18, 67

[3,3] Sigmatropic Rearrangements
• Cope Rearrangement: Boat vs. Chair Transition State
H H
Me trans-trans 90%
Me Me
H Me
H
Me Me
H cis-cis 10%
H H
H Me
Me
Me H
Me H H trans-cis <1%
H Me Me

Me Me

Me trans-cis 99.7%
H Me
H
H H
Me Me
Me H Me trans-trans 0.3%
H H H
[3,3] Sigmatropic Rearrangements
• Cope Rearrangement: Use of ring strain18
H
5-20°C

H
– Relief of ring strain upon rearrangement

• Oxy-Cope Rearrangement19
H
220°C keq ~ 105

OH OH O

– Tautomerism shifts equilibrium to right

18. Brown, Chem. Comm. 1973, 319

19. Marvell, Tet. Lett. 1970, 509
[3,3] Sigmatropic Rearrangements
• Oxy-Cope Rearrangement
HO HO O
k1

O O 1010 < k2 < 1017

k2
k1

– Significant rate acceleration for anionic Oxy-Cope.20

– Counter-ion also important OX
OX Half-life T/°C
OH (66 yrs)
OX 66°C H OLi No rxn
66
ONa 1.2 hrs
THF H OK 1.4 min
MeO
OK 11 hrs
10
OMe O- K+ 4.4 min
20. Golob, J. Am. Chem. Soc. 1975, 97, 4765
[3,3] Sigmatropic Rearrangements
X X
• Claisen Rearrangement
O O

X = C, H, O, N
– Thermodynamic driving force: (C-O) -bond and (C-C) -bond
formation
– X=Heteroatom leads to higher exothermicity and reaction rate

H OR
~30
O O ~20
H
OR
~20 kcal/mol O
~30 kcal/mol
O
[3,3] Sigmatropic Rearrangements
• Synthesis of allyl vinyl ethers21,22

OH Hg(OAc)2
O
OEt AcOHg O
OEt

Ph O Ph O
Cp2Ti AlMe2
Cl

21. Watanabe, Conlon, J. Am. Chem. Soc. 1957, 79, 2828

22. Evans, Grubbs, J. Am. Chem. Soc. 1980, 102, 3272
[3,3] Sigmatropic Rearrangements
• Endocyclic Olefins23
Et
O
Via Chair intermediate:
O
144°C Et
O

t-Bu t-Bu

t-Bu diastereoselection >87:13

• Exocyclic Olefins24 O
EtO
O OEt
O
OEt
t-Bu t-Bu
t-Bu
ratio 52:48
– Overlap equally good from either face
23. Ireland, J. Org. Chem. 1983, 48, 1829
24. House, J. Org. Chem. 1975, 40, 86
[3,3] Sigmatropic Rearrangements
• Olefin Selectivity
Me CHO
O

O H
Me CHO

H O

– R group prefers to sit in pseudo-equatorial position25

CHO CHO R R’ (E):(Z)

O R'
110°C Me Et 90:10
R' R' Me i-Pr 93:7
R R (E) R (Z) Et Et 90:10

25. Faulkner, J. Am. Chem. Soc. 1973, 95, 553

[3,3] Sigmatropic Rearrangements
• Olefin Selectivity O

Me Et X
O
X
H X Et
O Me
O
Et Et
X
Me Et X
H O

Me
Me

X (E):(Z)
– Extra substituents lead to
H 90:10
enhanced diastereoselection25 Me >99:1
Larger X => better MeO >99:1
selectivity Me2N >98:2
[3,3] Sigmatropic Rearrangements
• Claisen Variants: Johnson Orthoester Claisen26

EtO OEt OEt OEt

OH MeC(OEt)3
O O O
+
H

• Claisen Variants: Eschenmoser Claisen27

MeO NEt2 MeO NEt2 NEt2 NEt2

OH
MeO O O O
Xylene
150°C

26. Johnson, Faulkner, Peterson, J. Am. Chem. Soc. 1970, 92, 741
27. Eschenmoser, Helv. Chim. Acta 1964, 47, 2425
[3,3] Sigmatropic Rearrangements
• Claisen Variants: Ireland Enolate Claisen28
O OTMS OH
LDA
O O O
TMSCl

– Substituted enolates afford an additional stereocentre29

R' R R R' R
O
O R' O
H H
OTBS
OTBS OTBS
R' R H R R' R
O
R' O
O
H
OTBS
OTBS OTBS
28. Ireland, J. Am. Chem. Soc. 1976, 98, 2868
29. Ireland, J. Org. Chem. 1991, 56, 650
[3,3] Sigmatropic Rearrangements
• Lewis Acid catalysed Claisen rearrangement

LA + LA +
O LA O O O
LA

– Presence of Lewis Acid can influence rearrangement30

R O R O
LA
X Lewis X
R Acid R
X R O X X

O LA O

30. Yamamoto, J. Am. Chem. Soc. 1990, 112, 316

[3,3] Sigmatropic Rearrangements
• Chiral Lewis Acid promoted Claisen rearrangement31
Si(t-Bu)Ph2
Ph Ph
(R)-1 O
1.1 - 2 eq 88% ee Al Me
O
DCM, -20°C
O SiMe3 O SiMe3 Si(t-Bu)Ph2

(R)-1
• Enantioselective Claisen Rearrangements32
OBL2 OH
L2BBr -20°C
>97% ee Ph Ph
i-Pr2NEt O O
O DCM N N
ArO2S B SO2Ar
O OH Br
OBL2
L2BBr -20°C L2BBr
O O 96% ee
Et3N
PhMe

31. Yamamoto, J. Am. Chem. Soc. 1990, 112, 7791 32. Corey, J. Am. Chem. Soc. 1991, 113, 4026
[m,n] Sigmatropic Rearrangements
• [4,5] shift
Ph NMe2
Ph NMe2 Ph NMe2
MeONa [4,5]

– [2,3] possible but [4,5] favoured. [2,5] and [3,4] forbidden

• [3,4] shift
OMe
MeO MeO OH
OH
O
 Key Retrons
R
• C=C + X: 1-6 Cope rearrangement
X R'
XH
R R H
R' X
Retro-ene reaction
R'
• C=C + X: 1-5 R
R R'
X Claisen rearrangement
X
R'
R
• C=C + X: 1-4 [2,3] rearrangement
H X Wittig X=O
X
R R'
R' R'
Ene reaction
H
X R'