D. A. Evans
Pericyclic Reactions: Part–4
Chem 206
! Other Reading Material:
http://www.courses.fas.harvard.edu/colgsas/1063
[3,3] Sigmatropic Rearrangements
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5,
Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope)
Chapter 7.2, Claisen
Chemistry 206
Advanced Organic Chemistry
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)
S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope)
Lecture Number 14
T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen)
Pericyclic Reactions–4
! [3,3] Sigmatropic Rearrangements: Introduction
! Cope Rearrangements & Variants
! Claisen Rearrangements & Variants
Paquette, L. A. (1990). “Stereocontrolled construction of complex cyclic
ketones by oxy-Cope rearrangement.” Angew. Chem., Int. Ed. Engl. 29: 609.
! Problems of the Day:
Predict the stereochemical outcome of this Claisen rearrangement
Et
! Reading Assignment for week:
Et
O
O
Carey & Sundberg: Part A; Chapter 11
Concerted Pericyclic Reactions
K. Houk, Transition Structures of Hydrocarbon Pericyclic Rxns
Angew Chem. Int. Ed. Engl. 1992, 31, 682-708
diastereoselection
>87:13
144 °C, 6h
CMe3
CMe3
Ireland, JOC 1983, 48, 1829
K. Houk, Pericyclic Reaction Transition States: Passions & Punctilios, Accts.
Chem. Res. 1995, 28, 81-90
Angew Chem. Int. Ed. Engl. 1992, 31, 682-708
Provide a mechanism for the indicated fransformation
OH
O
Me
D. A. Evans
Friday,
October 20, 2006
H
Me
KH, ! THF
H3O+ quench
Me
H
Me
Schreiber, JACS 1984, 106, 4038
Database Problem number 117: Key words: Rearrangement + Claisen
In a recent article, MacMillan and Yoon (JACS 2001, 123, 2448) reported the complex rearrangement illustrated below.
R2N
O
O
R2N
Cl
Me
Me
several equiv
Me
O
Yb(OTf)3
CH2Cl2, R3N
R2N
A
NR2
Me
Me
diastereoselection >95:5
Part A. Provide a mechanism for this overall transformation. In answering this question, you should illustrate
those transition states where stereocenters are generated and where stereochemcal information is relayed.
Part B. From your answer in Part A, illustrate the stereochemical relationships in the diamide product A.
Database Problem number 195: Key words: Rearrangement + Claisen
Provide a mechanism for the indicated transformation that accounts for the observed stereochemical outcome
(JACS, 1984, 7643).
O
SAr
O
Cl
S
O
C O
Ar
Cl
H Cl Cl
D. A. Evans
Introduction to [3, 3]-Sigmatropic Rearrangements
Chem 206
General Reviews:
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)
S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope)
T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen)
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5,
Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope)
Chapter 7.2, Claisen
The CopeTransition States
‡
X
‡
X
X
X
Z
Z
Z
?
Relative Energy !!G‡:
CHAIR
BOAT
0
+ 5.8 kcal/mol
CHAIR
BOAT
0
+ 5.3 kcal/mol
•
X
X & Z = C, O, N etc
Z
•
X
X
O
O
Relative Energy !G°:
The Boat and Chair geometries for these transition structures are well defined.
Cope Rearrangement, Ea = 33.5 kcal/mol
Claisen Rearrangement Ea = 30.6 kcal/mol
The Reaction Energetics Goldstein, JACS 1972, 94, 7147
The FMO Analysis (Fleming page 101)
Bring two allyl radicals together to access for a possible bonding interaction
between termini.
‡
X
‡
X
‡
•
•
E
!G523‡ = 46.3
!G523‡ = 40.5
The nonbonding
allyl MO
!2
X
X
bonding
bonding
X
It is evident that synchronous bonding is possible in this rearrangement
Chem 206
The Doering–Roth Experiments
D. A. Evans
Doering/Roth Experiments: Tetrahedron 18, 67, (1962):
The Geometry of the transltion state (boat vs chair) can be analyzed via
the rearrangement of substituted 1,5-dienes:
H
The Results
H
favored
Me
Me
Me
Me
Me
Me
Threo isomer
Me
Results:
Threo isomer
Me
H less favored
H
Me
Me
Me
H
H
Me
trans-trans:
90%
Me
Me
H
Me
Me
Me
Me
H disfavored
H
Me
H
Me
cis-cis:
10%
H
H
Me
trans-cis:
< 1%
Me
Meso isomer
Me
! Measure product composition from rearrangement of each diene isomer
H
H
favored
Me
Me
trans-trans
Me
H
Me
Me
Predictions:
Threo isomer
H less favored
H
Me
Me
Predictions:
Meso isomer
H
trans-trans: 0.3%
H
H
trans-cis
X
Relative Energy !!G‡:
H
Me trans-trans
H
CHAIR
BOAT
0
+ 5.8 kcal/mol
CHAIR
BOAT
0
+ 5.3 kcal/mol
trans-cis
Me
H
H
H
Me disfavored
Me
Me
‡
Me
H
disfavored
Me
favored
H
Me
cis-cis
Me
Me
!!G‡
~ 5.7 kcal/mol
H
The CopeTransition States
H
H
Me
H
trans-cis: 99.7%
Me
H
Me
Me
H disfavored
Me
favored
H
Me
H
H
Me
H
Results:
Meso isomer
Me
H
Me
Me
H
Relative Energy !G°:
The Boat and Chair geometries for these transition structures are well defined.
D. A. Evans
Chem 206
Strain–Accelerated Cope Rearrangements
Ring Strain can be employed to drive the Cope process:
! Ring extension via divinylcyclopropane rearrangement
O
O
H
Me
"quantitative"
5-20 °C
I
H
90%
Me
1.5 equiv
+
Li
–
(PhS)Cu
H
120 °C
Me
Me
Brown Chem. Commun. 1973, 319
O Me Me
heat
xylene
Me
Me
LDA
Me
Vogel Annalen 1958, 615, 1
MeI
O
H
(EtO)2P
Me Me
H
Me
Li
60 °C
Reese Chem. Commun. 1970, 1519
H
equilibrium stongly favors this isomer
O Me Me
Me
LDA
Me
OMe Me
Me
O
(EtO)2PCl
Me
Me
Piers, Can J. Chem. 1983, 61, 1226, 1239
! Position of Equilibrium dictated by ring strain issues:
‡
20 °C
(Ph3)3RhCl
EtNH2/THF
!-himachalene
Ring Strain can be employed to drive the Cope process:
H2
H
Vogel Angew. Chem. Int. Ed.
1963, 2, 739
favored
W. von E. Doering's Bullvalene
!
!
H
H
Wharton J. Org. Chem.
1973, 38, 4117
H
!
! However, tautomerism can shift the equilibrium:
H
keq ~ 10+5
220 °C
Bullvalene: Ea = 13.9 kcal/mol
3h
OH
At 100 °C one carbon is observed in nmr spectrum
Carey, Vol 1, page 630–631
OH
90%
O
Marvell, Tet. Lett. 1970, 509
Energetically, how much does
tautomerization give you?
D. A. Evans
Documentation of Alkoxy Substituent Effect
Accelerated Cope Rearrangements
HO
Chem 206
The Anionic Oxy-Cope Rearrangement
‡
HO
k1
O
HO
–OX
OX
OX
–O
k2
= 10 + 10
k1
–O
k2
10 + 17
66 °C
THF
10 +12 rate acceleration
A priori Estimate of the Acceleration (DAE)
pka (SM)
–O
‡
HO
Origin of the Rate Effect
pka (TS)
–O
OH
1.2 hrs
–OK
1.4 min
–OK
11 hrs
–O- +K
4.4 min
66 °C
10 °C
No Rxn
!!G‡estimate = 15 kca mol -1
!!G‡experiment = 13 kca mol -1
‡
–O
HO
‡
Effect probably comes from both
reactant destabilization
&
transition state stabilization
!G‡O – = !G‡OH + 2.3RT [ pka TS – pka SM]
O –=
–ONa
!GO –
–O
!G‡
no rxn
–O
??
!G‡
(HMPT)
!
‡
–OLi
MeO
!GOH
!G‡O –
(66 yrs)
XO
66 °C
THF
HO
–OH
OMe
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5,
Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope)
"Recent applications of anionic oxy-Cope rearrangements."
Paquette, L. A. Tetrahedron 1997, 53, 13971-14020
!G‡OH
H
MeO
Evans, Golob, JACS 1975, 97, 4765.
HO
H
Half-life
+
!G‡O – = !G‡OH +
2.3RT [18 – 29] (in DMSO)
HO
"
" –!
~ 15 kcal/mol
1.4 [– 11]
!G‡O – = !G‡OH – 15 kcal/mol at 298 K (in DMSO)
Maximal rates are observed under conditions where reactant is maximally destabilized
D. A. Evans
Chem 206
Anionic Substituent Effects: Bond Homolysis
Substituent Effects in Bond Homolysis
HO C CR3
DI
HO C•
DI!I
–
+ •CR3
–
X
–O C•
–
+ •CR3
X
X
H
(H2O) pKa = 10.7
–
X
R
–
R
–
–
Ph
X
R
[1,3]
X Y
X Y
R
DI – DII = 2.3 RT [pka (A) – pka (B)]
HO C•
Y
[2,3]
R
H
–
Y
ketyl
Acidities of these radicals are
HO C• known in H2O, Hayon, Accts.
Chem. Res. 1974, 7, 114
X
[3,3]
•
B
A
–O C CR3
Substituent Effects in Molecular Rearrangements
R
[1,2]
–X
X
ene
H
H
HO C•
Ph
pKa = 9.2
Y X
C
–
–
Y X
C
In DMSO, ΔD = 2.3 RT [ 29 – 18] ~15 kcal/mol
Y X
C
–
C
! Substituent Effect based on ab initio calculations
(Evans, Goddard, JACS 1979, 101, 1994)
H
HO C H
H
BDE = 90.7
(BDE = 91.8 expt)
H
NaO C H
H
BDE = 80.6
H
C
H
KO C H
–O C H
H
BDE = 79.0
H
BDE = 74.2
!D
+16.5 kcal/mol
X –
C
C
–
Y X
C
C
C
X–
–
X C
R•
H
–
X C •
R–H
–
X C •
– •
X C
–
D. A. Evans
MeO
Chem 206
Anionic Oxy-Cope Rearrangement: Applications
OMe
MeO
OMe
O
NaH
OH
O
OMe
H
OMe
O
O
Me
H2C
H
H
Me
OH
OR
Jung, JACS 1978, 100, 4309
Jung, JACS 1980, 102, 2463
KH, THF
O Levine, JOC 1981, 46, 2199
KH
Me
ROH2C
OH
200 µg from 75,000
virgin female cockroaches
Me
Me
H
H
Periplanone-B Synthesis
O
H
75%
MgX
O
O
O
H
Me
! THF
Me
ROH2C
Me
Still, JACS 1979, 101, 2493
OH
OR
KH
Me
O
OH
H
Me
KH, THF
Me
Me
Gadwood, JOC, 1982, 47, 2268
Me
O
Me
! THF
Me
Me
2 steps
Schreiber, JACS 1984, 106, 4038
Me
H
Synthesis of (+)-CP-263,114: Shair, JACS 2000, 122, 7424-7425.
O
HC CLi
50 °C
OH
Me
H
Me
H
Me
H
O
CO2H
MeO2C
XMgO CH OR
2
H
Me
poitediol
Me
Me
H
Me
dactylol
Me
R
H
Me
H
O
Gadwood, JACS, 1986, 108, 6343
OMe
O
R
H
Me
Me
OH
OH
OH
Me
H
O
50 % yield
Me
OH
O
O
O
O
H
O
C
R
[3,3]
–78!23 °C
H
R
O
R
H
XMgO CH OR
2
H
O
R
H
53%
Dieckmann
CH2OR
Me
D. A. Evans
The Claisen Rearrangement
! General Reviews:
Chem 206
Recognition Pattern for Organic Synthesis: An Enforced SN2'
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Ch 7.2
Ziegler, Accts. Chem. Res. 1977, 10, 227 (Claisen)
Bennett, Synthesis 1977, 589 (Claisen)
Blechert, Synthesis 1989, 71 (HeteroCope)
R. K. Hill, Asymmetric Synthesis vol 3, Ch 8, p503 (chirality transfer)
Ziegler, Chem Rev. 1989, 89, 1423 (Claisen)
R
R
Claisen
O
R
SN2'
O
–
O
R
R
X
! The Reaction:
#
O
O
R
#H ~ –20 kcal mol-1
R
Stereochemical outcome is syn and controlled by hydroxyl stereocenter
R
1 O
There is good thermodynamic driving force for this reaction.
Bonds Broken: C-C! (65 kcal mol-1) & C-O" (85 kcal mol-1)
Bonds Made: C-O! (85 kcal mol-1) and C-C" (85 kcal mol-1)
X
2
R
R
O
X
O
R
! Themodynamics of Claisen Variants:
X
X
O
X=H
X = OH
X = NH2
O
1 O
!H (kcal mol-1)
Substituent
–16
–31
–30
O
O
77%
~ 20
O
~ 20 kcal/mol
OH
H
180-200 oC
H
O
Rearrangements of Aryl Allyl Ethers: Traditional Applications
OR
O
X
Control of stereocenter 2 evolves into a decision how to
establish the hydroxyl-bearing stereocenter
O
~ 30
2
R
R
(Benson estimates)
H
X
Me
Me
Me 180-200 oC Me
O
Me
Me
OH
O
Cope Me
Me
Me
Me
H
O
~ 30 kcal/mol
OR
91%
O
Me
O
Heteroatom substitution at the indicated position increases
exothermicity as well as reaction rate
N
Me
65%
OH
N
Me
Me
E:Z = 6.7:1
The Claisen Rearrangement-2
D. A. Evans
Synthesis of Allyl Vinyl Ethers
! Endocyclic Olefins: Ireland, JOC 1983, 48, 1829
Et
Hg(OAc)2
O
OH
O
Et
144 °C, 6h
OEt (solvent)
Watanabe, Conlon, JACS 1957, 79, 2828
Bronsted acids can also serve as catalysts
CMe3
R
B
Me3C
H
H2C
H2C
•
Cp2Ti
AlMe2
A
C
H
H
H2C
The Ireland approach to the bicyclic acid A:
R
X
Me
O
O
O
Me3C
Me
Me
HO
HO
A
Me
ratio 52:48
H
H
H
Me
H
OH
Me
Me
Me OH
O
Me
EtOCH=CH2
O
O
Me3C
Me3C
Me
Me
Me
OEt Me3C
H
OH
Me
X=H
HO
OEt
O
Me
Claisen
O
JOC 1962, 27, 1118
H
OEt
heat
96%
(review) S. H. Pines, Organic Reactions 1993, 43, 1
Me3C
! Exocyclic Olefins: House, JOC 1975, 40, 86
CMe3
O
O
Cl
R•
heat
Ph
O
Use of Tebbe's Reagent: Evans, Grubbs, J. Am. Chem. Soc. 1980, 102, 3272.
H
Me3C
C
Ph
CH2
R•
H
CMe3
CH2
O
For endocyclic olefins, overlap between developing sigma and pi bonds required. Best
overlap for forming chair geometry. As shown below, bring a radical up to either face
of the allylic radical. As the bond is formed, overlap must be maintained. Path A
evolves into a chair conformation while Path B evolved into a boat conformation.
H
O
75%
OEt
CH2
H
-EtOH
O
AcOHg
diastereoselection
>87:13
H
Me3C
Chem 206
ratio 75:25
H
H
for exoocyclic olefins, overlap between developing sigma and pi bonds is equally good
from either olefin diastereoface. In this instance, steric effects dominate & this system
shows a modest preference for "equatorial attack." A related case is provided below.
HH
Hg(OAc)2
HO
Me
Me
53% overall
HO
Me
Me
H !
O
H
The new stereocenter (!) introduced via the rearrangement had
the wrong configuration!
D. A. Evans
Claisen Rearrangement as vehicle for stereoselective olefin synthesis
Consider the following rearrangement:
Faulkner suggests that the installation of other substituents on Claisen
transition states will lead to enhanced reaction diastereoselection:
ke
ke
CHO
Me
O
Me
ka
H
Me
O
Me
O
!G‡a - !G‡e = 1.5 kcal/mol
Me
Me
CHO
Me
ka
H
#Note:
O
!!G‡ = +1.5 kcal/mol
For R2 = Et
Me
Me
H
!G° = +1.75 kcal/mol
They then suggest that there is a good correlation between cyclohexane "A-values" &
!!G‡ for the rearrangement process. Their case is fortified by the following expamples:
CHO
110 °C
R2
R1 (E)
R1
R2
Me–
Me–
Et–
Et–
iPr–
Et–
(E):(Z) found
90:10
93:07
90:10
O
X
R2
O
X
(Z)
a‡
Me
(E):(Z) found
H–
Me–
MeO–
90:10
>99:1
>99:1
Me2N–
>98:2
Faulkner, Tet Let 1969, 3243
Faulkner, JACS 1973, 95, 553
Johnson, JACS 1970, 92, 741
X
OY
Et
‡
O
OPMB
R
Me
Et
CHO
R2
R1
X
(Z)
(E):(Z) predicted
91:9
94:6
91:9
Faulkner, JACS 1973, 95, 553
Me
O
R2
R1
Me
! Another comparison: (DAE) M. DiMare, Ph. D. Harvard University, 1988
The A-value of 2-methyl-tetrahydropyran is +2.86 kcal/mol (Lecture No. 6)
O
Me
(E)
R2
e‡
H
X
Me
H
X
O
The R2!X interaction should destabilize a‡ as X gets progressively larger.
Faulkner & Perrin (Tet. Lett. 2783 (1969) have made the correlation between
!!G‡ for rearrangement & !G° for the corrresponding cyclohexane# equilibria:
O
X
R2
R2
110 °C
a‡
H
R2
110 °C
X
e‡
O
O
H
H
Me
Chem 206
The Claisen Rearrangement: Stereoselective Olefin Synthesis
OPMB
Et
procedure
Y = Ac, Ireland
Y = H, Johnson
Y = H, Eschenmoser
conditions
Me
X
LDA, TMSCl
HC(OMe)3, H+
TMSO–
MeO–
MeC(OMe)2NMe2
Me2N–
T, °C
(E):(Z) ratio
-78!+55
130
80
97:3
94:6
97.5:2.5