a73 Introduction & Overview of E2 Process
a73 Dehydration: Burgess Reagent & Martin Sulfurane
a73 Selenoxide Elimination & Applications
a73 Ramberg-Backland & Related Cheletropic Rxns
a73 Vicinal Debromination and Related Rxns
a73 The Takai Reaction
a73 The McMurry Reaction
a73 The Julia Reaction
Chemistry 206
Advanced Organic Chemistry
Handout 27A
Vicinal Elimination Reactions: An Overview
Matthew D. Shair Wednesday, November, 20, 2002
Chem 115
D. A. Evans
Elimination & Fragmentation Reactions in C=C Bond Constructions
a73
Dehydrohalogenation:
base
a73
Selenoxide Elimination:
Anti
Stereochemistry
Syn
Stereochemistry
?
–HOSeAr
–HX
–HONR
2
?
Syn
Stereochemistry
a73
Cope Elimination:
+
– –
+
Anti
Stereochemistry
a73
Hoffmann Elimination:
+
–
base
–HNR
3
Vicinal Elimination reactions: One Heteroatom
–
+
–HOSAr
?
Syn
Stereochemistry
a73
Sulfoxide Elimination:
?
–HOXCR
Syn
Stereochemistry
a73
Acetate/Xanthate Pyrolysis:
X(–)
H(+)
The following discussion is intended to provide a general overview of useful elimination reactions of value in the construction of olefins
?
?
?
Review: Lowry & Richardson,
Mechanism & Theory in Org. Chem.
, 3rd Ed, p 588-620
X = O, S
a73
Elimination Reactions: The limiting cases
+
X
–
+B
–
E1 family
E1cb family
–X
–
(E1 conjugate base)
:
–
+B
–
–BH
–BH
rds
rds
rds
–BH
E2 family
+B
–
+B
–
δ
–
δ
–
?
δ
–
δ
–
E1-like TS
E2
δ
–
δ
–
δ
–
δ
–
E1cb-like TS
a73
The E2 process encompasses a range of synchronous geometries
a73
Why is the anti elimination geometry preferred?
For
π
Bonds:
Better
than
σ
C–H
HOMO
X
σ
* C–X
LUMO
σ
* C–X
LUMO
σ
C–HY
HOMO
X
H
H
Better
than
Anti Geometry
Syn Geometry
Trost, Ed.,
Comprehensive
Organic Synthesis
1992
, Vol 6, Chapter 5.1
Comprehensive
Organic Synthesis
,
6
, Ch 5.1, p 949
Comprehensive
Organic Synthesis
,
6
, Ch 5.1, p 949
Comprehensive
Organic Synthesis
,
6
, Ch 5.3, p 1011
Comprehensive
Organic Synthesis
,
6
, Ch 5.3, p 1011
Comprehensive
Organic Synthesis
,
6
, Ch 5.3, p 1011
Comprehensive
Organic Synthesis
,
6
, Ch 5.3, p 1011
?
C H
C
R
2
X
C
C
C
C H
CC
CC
C H
CX
C H
C
C
CX
X
CX
C H
B
H B
C
X
CC
H
CX
B
H B
CX
R
2
R
1
R
2
H
Se
R
1
R
1
R
2
O
Ar
N
R
O
H
X
R
1
R
2
R
2
R
1
R
1
H
R
2
R
NR
R
2
R
2
R
1
R
1
H
R
R
S
Ar
O
R
2
R
1
R
1
H
R
2
H
R
R
2
R
1
R
1
X
O
R
2
R
1
R
2
R
1
X
H
C
AB
AB
CC
CC
27A-01-Elimination Rxns
12/7/93
12:00 PM
25
→
75 °C
exothermic
Chem 115
D. A. Evans
Elimination Reactions: The E2 Process
a73
Syn E2 elimination can be promoted by steric or torsional factors
98 : 2
Brown
JACS
1970
,
92
, 200
RONa
+
+
anti
syn
base
base
%
syn
R
1
R
2
base
Ph
Me
2
CH
HO
–
6925
HO
–
Me
PhPh
D
E
tO
–
<5
Saunders
JACS
1983
,
105
, 3183
a73
Direction of E2 elimination can be controlled by leaving group
MeO
–
81:19
X = I
X
Ratio
X =Br
72:2867:33
X =ClX =F
30:6005:95
X =NMe
3
+
+
+
HO
–
HO
–
Nonbonding interactions disfavor
internal elimination (Hoffmann)
Some of the Practical Dehydrating Agents
a73
The Burgess Reagent:
Burgess:
JACS
,
1970
,
92
, 5224-5226.
Burgess:
JOC
,
1973
,
38
, 26-31.
Burgess:
Org. Synth. Coll. Vol. VI.
788-791
(preparation of the reagent).
-
+
1
a73
The Basic Process:
1
-
+ HNEt
3
a73
Dehydration usually proceeds via a
cis
-elimination:
-
11
-
Burgess:
JACS
,
1970
,
92
, 5224-5226.
a73
Dehydration of 2° and 3° alcohols:
Crabbé,
JOC
,
1970
,
35
, 2594-2596.
1
, PhH, 25 °C
75%
1
, MeCN
66%
Duncan,
JACS
,
1990
,
112
, 8433-8442
Ph
Ph
H
H
OH
H
O
S
O
O
Ph
Ph
N
CO
2
Me
Ph
D
Ph
R
R
H
OH
H
O
S
O
O
R
R
MeO
N
S
NEt
3
O
O
O
H
Ph
Ph
D
OH
D
O
S
O
O
Ph
Ph
N
CO
2
Me
Ph
H
Ph
H
DH
DH
D
H
OTs
H
D
H
H
CC
H
NMe
3
D
H
R
1
R
2
C
R
1
R
2
C
H
D
NMe
3
H
C
H
R
2
C
D
R
1
C
R
2
C
D
R
1
H
X
Me
Me
Me
Me
Me
C
H
H
9
C
4
C
H
Me
N
H
Me
Me
CC
H
NMe
3
C
4
H
9
H
H
H
Me
Me
Me
Me
Me
MeH
HO
N
CO
2
Me
RH
R
H
Me
MeH
OO
OH
Me
Me
27A-02-E2 elimination
12/6/93
10:26 AM
70 °C, 2 h
P. Wipf
ring closure occurs with inversion
a73
Cyclodehydrations to form oxazolines:
Westellamide
JACS
,
1992
,
114
, 10975-10978
JOC
,
1993
,
58
, 1575-1578
Tet. Let
,
1992
,
33
, 907
a73
Dehydration of primary amides to form nitriles:
Other uses of the Burgess Reagent:
-
+
1
3 equiv
1
82%
no dehydration of 2° alcohols observedClaremon,
TL
,
1988
,
29
, 2155-2158.
This allylic rearrangement has not been exploited
McCague,
JCS PT1
,
1987
, 1011-1015
2.8 : 1
1
or
a73
Cationic behavior noted in some instances
Burgess:
JOC
,
1973
,
38
, 26-31.
1)
1
, THF then
2) NaH, RT
94%
1
, triglyme, 75 °C
73%
a73
Allylic alcohols can undergo a [3,3] sigmatropic rearrangement:
Burgess:
Org. Synth. Coll. Vol. VI.
788-791.
1
, 95°
80%
a73
Primary alcohols are displaced to form the urethane:
Chem 115
D. A. Evans & D. Barnes
Elimination Reactions: The Burgess Reagent
Me
OH
Me
NH
OMe
O
Me
Me
OH
Me
Me
Me
Ph
Me
NHCO
2
Me
Ph
H
HO
Et
OMe
Ph
Ph
OH
H
Et
MeO
Ph
Ph
OMe
Et
Ph
Et
OMe
Ph
Me
O
Me
S
N
MeO
OO
O
M
Me
O
Me
H
OH CONH
2
HO
Me
Me
O
Me
O
Me
H
OH CN
HO
Me
Me
O
MeO
N
S
NEt
3
O
O
O
R
HN
OMe
O
O
Me
HO
O
N
R
O
OMe
Me
ON
O
NH
Me
Me
N
O
HN
Me
Me
N
O
NH
O
Me
Me
Me
Me
Me
O
27A-03-Burgess reagent-2
12/6/93
10:33 AM
25°C
98%
1
a73
Rxns with amides result in transesterification:
Martin,
JACS
,
1974
,
97
, 6137
Elimination Reactions: The Martin Sulfurane
1
a73
Rxns with diols generate cyclic ethers:
Martin,
JACS
,
1974
,
96
, 4604-4611
1
Evans,
JACS
,
1978
,
100
, 1548-1557
1
(±)-Cherylline
a73
Applications:
1
Martin Sulfurane: Only product (92%)Burgess Reagent:
1 : 4
Snieckus,
TL
,
1982
,
23
, 1343-1346
–
OC(CF
3
)
2
Ph
+
+ HOC(CF
3
)
2
Ph
a73
Mechanism: Reagent provides both good leavilng group and moderate base
82%
0 °C 45 min
Martin,
JACS
,
1971
,
93
, 4327-4329
JACS
,
1972
,
94
, 5003-5010
However, 1° alcohols react to give the ether:
1
1
a73
Dehydrations to form alkenes:
Martin:
Org. Synth. Coll. Vol. VI.
163-166.
a73
Preparation of the Martin Sulfurane:
D. A. Evans, D. M. Barnes
Chem 115
1
MsCl, SOCl
2
,
p
-chlorobenzoyl chloride, CSA, Burgess Reagent, TFAA / base,
Tf
2
O / pyridine all ineffective in the dehydration.
Evans, Black,
JACS
,
1993
,
115
, 4497
fast
100%
1
25 °C
seconds
90:10
R
R
S
OC(CF
3
)
2
Ph
OH
OC(CF
3
)
2
Ph
PhPh
R
R
Me
OH
Me
Me
Me
Me
OH
CH
2
Me
OH
R
R
S
Ph Ph
OC(CF
3
)
2
Ph
OC(CF
3
)
2
Ph
R
R
O
S
Ph OR
S
Ph
H
Ph
O
Ph
R
R
R
R
HOMe
Me
Me
Me
CONMe
2
Me
Me
Me
Me
CONMe
2
Me
CONMe
2
Me
Me
NMe
OH
OMe
MeO
O
MeO
BnO
OH
NMe
OMe
MeO
O
MeO
BnO
NMe
MeO
HO
Ph
NH
Me
O
O
O
Ph
CF
3
CF
3
Ph
Me
Me
HO
Cl
R
OH
MeO
Cl
Me
Me
OH
O
Et
HO
H
OH
H
H
OTBS
OTIPS
Me
O
OH
H
H
O
Et
O
OH
H
H
OTBS
OTIPS
Me
O
H
H
Me
Me
OC
F
3
CF
3
Ph
27A-04-MartinSulfurane
12/6/93
10:20 AM
Tomoda,
Chem. Commun
1982
, 871;
Tet. Lett
1982
,
23
, 1361
PhSeCN
?
[Ox]
a73
Functionalization of Olefins:
Sharpless,
J. Org. Chem.
1974
,
39
, 429.
3
<1
2
49
97999851
OAcOHOMeCl
Chapter 5,
Selenium Reagents and Intermediates in Organic Synthesis
,
C. Paulmier,1986 Pergamon Press.
Chapter 4,
Organoselenium Chemistry
, D. Liotta, 1987 Wiley-Interscience.
RSeCN or RSeSeR and NaBH
4
, RSe
-
M
+
, RSeH (with Lewis Acid)
Chapter 1,
Organoselenium Chemistry
, D. Liotta, 1987 Wiley-Interscience.
RSeCl, RSeBr, RSe(O)Cl, RSeSeR, alkyl selenium succinimide, RSeSO
2
Ar, ...
H
2
O
2
, MCPBA, RCOOOH, NaIO
4,
, O
3
, (
t
-BuO)
2
, Th
III
Nitrate, NCS or NBS/H
2
O
a73
Some useful oxidizing agents:
a73
Electrophilic Selenium Reagents:
a73
Nucleophilic Selenium Reagents:
The selenoxide elimination is usually two steps: A. Selinide formationB. Oxidation & elimination.
Selenium in Natural Products Synthesis
, K. C. Nicolaou, N. A. Petasis
Organoselenium Chemistry
, D. Liotta, 1987 Wiley-Interscience.
Selenium Reagents and Intermediates in Organic Synthesis
, C. Paulmier,
? 1986 Pergamon Press.
General Selenium References:
-20?C
→
40?C
Elimination Reactions of Selenoxides
D. H. Ripin & D. A. Evans
Chem 115
+
The Selenoxide Elimination Reaction
+
?
By comparison:
?
+
+
80 ?C
→
130?C
-PhSeOH-PhSOH
20?C
The first example:
Jones,
Chem. Commun
1970
, 86.
O
3
+
PhSe–
X
[Ox]
?
X
Ratio
X = OAc, OH, CN, Cl, Br,
+X
–
a73
Epoxide Ring Opening-Refunctionalization:
PhSe–
SePh
NaBH
4
[Ox]
Both of the above reactions have been heavily exploited in synthesis
SePhCN
Me
Se
H
H
Se
Me
Se–Ph
MeH
Ph–Se
H
R
R
H
H
O–
R HH
R
XX
Ph
H
H
Ph
O
-
X SePh
O
SePhOH
OH
Se
O
H
H
R
R
H
Ph
S
Ph
H
O
RR
H
H
R H
HR
Ph–S
O–
H
H
R
R
H
CN
27A-05-Selenoxide elim-1
12/6/93
11:00 AM
free radical addn
Rollin
Synthesis
1984
, 134.
?
NaIO
4
NaHCO
3
83%
85%
BF
3
OEt
2
55%
[Ox]
Raucher
Tet. Lett.
1979
, 3057.
H
+
steps
25 °C
DBU, xylene,
↑↓
Holmes
J. Am. Chem. Soc.
1993
,
115
, 10400.
NaIO
4
NaHCO
3
73%
(+)-Laurencin
Metz,
Tet. Lett
1982
,
23
, 4067
[Ox]
?
CH
2
=CHOEt
PhSeBr
h
ν
PhSe-SO
2
Ph
?
[Ox]
Kice,
Tet. Lett
1980
,
21
, 4155
Raucher,
Tet. Lett
1977
, 3909
[Ox]
?
PhSeBr
MeCN
This is kinetic product at
lower temperatures
Beau,
JACS
,
1983
,
105
, 621
pyr
H
2
O
2
Cl
–
0 °C
PhSeCl
a73
Functionalization of Olefins:
+
Synthetic Applications
Chem 115
D. H. Ripin & D. A. Evans
Elimination Reactions of Selenoxides
These rxns are quite valuable in setting up Claisen rearrangements
OO
OTBDPS
SePh
O
OTBDPS
O
H
OAc
O
Et
Br
H
OTBDPS
OO
OH
Me
CO
2
Me
Me
PhSe
C(OMe)
3
SePh
Me
Me
Me
OTBS
OTBS
Me
CO
2
Me
OOAc
AcO
AcO
Ph
Se
OH
AcO
AcO
OO
SePh
O
O
AcO
AcO
AcO
AcO
O
Me
SePh
Cl
SePh
Me
OTBS
Me
Me
OTBS
Me
Br
Cl
SePh
C
6
H
13
C
6
H
13
C
6
H
13
SePh
Br
SO
2
Ph
Ph
Ph
Ph
SO
2
Ph
OH H
MeOCH
2
Br
OEt
PhSe
MeOCH
2
HO
OEt
SePh
EtO
2
C
CHO
H
MeOCH
2
27A-06-Selenoxide elim-2
12/7/93
12:02 PM
Clive
JOC
1982
,
47
, 1632.
Kowakski
JACS
1980
,
102
, 7950.
Note the different mechanism for eliminationin this case
MsCl/Et
3
N
ZnCl
2
b) H
2
O
2
, THF, 0?C
o
-O
2
NC
6
H
4
SeCN
NaBH
4
, 20?C
59%
Grieco
J. Org. Chem.
1975
,
40
, 1450.
H
2
O
2
3 : 1
Sharpless,
Tet. Lett.
1973
, 1979.
H
2
O
2
69% H
2
O
2
4 : 1
Reich
J. Am. Chem. Soc.
1973
,
95
, 5813.
9 : 1
Grieco
J. Org. Chem.
1975
,
40
, 542.
Elimination Reactions of Selenoxides
D. H. Ripin & D. A. Evans
Chem 115
a73
Epoxide Cleavage/Refunctionalization:
Ph
2
Se
2
NaBH
4
H
2
O
2
63%
steps
lycoricidine
Ohta,
Tet. Lett
1975
, 2279
NaBH
4
Ph
2
Se
2
NaIO
4
70%
Ac
2
O
MCPBA
Ph
2
Se
2
NaBH
4
NaIO
4
steps
lycorine
Tsuda,
Chem. Commun
1975
, 933
NH
OO
O
THPO
THPO
OH
SePh
O O
NH
NH
OO
OH
THPO
OH
O O
Me
O
Me
SePh
Me
O
Me
NH
OH
OO
OH
O O
N H
H
H
HN
Me
O
O
Me
SePh
HH
O
O
H
OO
HH
O
Me
Me
PhSe
H
Me
Ph
Me
H
Ph
MePh
Me
Me
OMe
MeOOC MsO
MeOOC
OMe
OTMS
Me
SePh
O
H
O
OO
O
HO
SePh
H
HO
O
O O
N H
H
HN
OO
O
AcO
O
OH
H
AcO
O
O O
N H
N
OO
HO
OH
Me
SePh
OH
Me
O
27A-07-Selenoxide elim-3
12/6/93
1:10
PM
Effects the transformation of alkenes to 1,3-dienes.
(
E
):(
Z
) = 94:6
tBuOK
tBuOH,
?
1,3-diene
alkene
(
E
):(
Z
) = 17:83
tBuOH,
?
tBuOK
DBU
CH
2
Cl
2
, h
ν
BrCH
2
SO
2
Br
(
E
):(
Z
) = 10:1
a73
Vinylogous Ramberg-Backlünd Reaction
a73
Reviews
Modified procedure allows one-pot conversion of sulfone to olefin.Reaction of resulting olefin with dichlorocarbene generated in stronglybasic chlorinating medium can sometimes complicate reaction:
tBuOH,
?
KOH, CCl
4
Chem 115
D. A. Evans
Cheletropic Elimination Reactions
Block,
JACS
1983
,
105
, 6164, 6165.
a73
Acyclic Olefin Synthesis
t-BuOK
DMSO
(
E
):(
Z
) > 97:3
(
E
):(
Z
) = 21:79
aq NaOH
?
?
Olefin geometry dependent upon reaction conditions.
The Ramburg-Backlünd Reaction
Base
a73
General Reaction Protocol
NaH
NCS orC
2
Cl
6
NaOMe
MeOH,
?
Meyers' Modification:
X = halogen, tosylate, triflate
Paquette,
Organic
Reactions
1977
,
25
, 1.
Magnus,
Tetrahedron
1977
,
33
, 2019.
Vedejs,
Tetrahedron
1982
,
38
, 2857.
Trost, Ed., Comprehensive
Organic
Synthesis
1992
, Vol 3, Ch 3.8.
Meyers,
JACS
1969
,
91
, 7510
KOH, CCl
4
tBuOH,
?
+
35%
65%
97%
66%
Scholz,
Liebigs Ann. Chem.
1984
, 264.
?
Strong base (tBuOK) equilibrates episulfone intermediate to
thermodynamically favored trans configuration giving (
E
)-olefins.
(Z)-vinylogous sulfones yield opposite olefin geometry (
trans
):
59%
61%
base
X
Ph
S
R
O
O
O
S
O
O
O
R
Ph
Cl
Ph
O
R
1
SR
2
R
OO
Ph
Ph
S
P
h
O
O
Ph
nC
5
H
11
nC
4
H
9
SB
r
O
O
Br
S
R
1
R
2
O
O
R
1
R
2
Cl
HO
2
CS
E
t
O
O
Et
S
O
O
Br
HO
2
C
HO
2
C
Et
nC
4
H
9
nC
4
H
9
nC
4
H
9
SB
r
O
O
nC
4
H
9
S
O
O
Cl
Cl
S
O
O
R
2
R
1
R
1
R
2
27A-08-Ramberg-Backlund Rxn
12/6/93
1:11 PM
A wide variety of annulation procedures for direct 9-member ring formationwere unsuccessful.
Boeckman,
JACS
1991
,
113
, 9682.
85%
82%
Eremantholide A
a73
Eremantholide A
9-15%
Wender,
Tet. Lett.
1988
,
29
, 909.
Cheletropic elimination occurs with
σ
rather than
π
-bond formation.
PhH/CH
3
CN
Ph
2
CO, h
ν
a73
Neocarzinostatin Chromophore: A Related Reaction
Nicolaou,
JACS
1992
,
114
, 7360.
32-52%
Neidlein,
Leibigs Ann. Chim.
1980
,1540.
If cheletropic elimination is sufficiently slow, dehydrohalogenation can compete.
Base
Paquette,
JACS
1974
,
96
, 5801.
81%
a73
Deuterated Olefins
18%
Gassman,
JACS
1983
,
105
, 667.
35-49%
Intraannular Ramberg-Backlünd reactions succeed where many annulation procedures fail in producing highly strained ring systems.
Chem 115
D. A. Evans, S. Nelson
Cheletropic Elimination Reactions
Becker,
Helv. Chim. Acta
1983
,
66
, 1090.
a73
Enediyne Synthesis:
Calicheamicin/Esperamicin Models
Applications to Synthesis
a73
Strained Ring Systems
tBuOK, THF
-75 °C to rt
NaOD
D
2
O
?
tBuOK, THF
Acidity of
α
-methylene groups provides ready access to deuterated olefins via the
Ramberg-Backlünd reaction.
Na
2
S
1) NCS, CCl
4
2) mCPBA
tBuOK
Et
2
O, 0 °C
n
tBuOK
THF, -78 °C
n
n = 3-8
Et
3
COK
HMPA, DME
?
H
3
O
+
SO
O
Br
SO
2
O
2
S
(CH
2
)
Cl
Cl
(CH
2
)
O
O
O
O
2
S
MeH
O
Me
Me
O
Me
Cl
O
Me
Me
O
H
Me
D
D
Cl
SO
2
D
DD
H
H
S
OTs
TsO
H
H
H
H
O
2
S
Cl
HH
O Me
O
O
O
O
MeO
MeH
O
Me
Me
O
OH
SO
2
SO
2
HH
Cl
HO
SO
2
Me
HO
Me
27A-09-Ramberg Applications
12/7/93
12:04 PM
Gaoni,
Tet. Let
1977
, 947 (the LAH cleavage procedure)
LiAlH
4
/Et
2
O
Chou,
JOC
1987
,
52
, 5082.
74%
LHMDS
97%
+
El(+)
Retro [4+2] preceeds cheletropic elimination of SO
2
.
a73
1,3-Diene Synthesis
Related Cheletropic Eliminations
a73
Dihydrothiepin-1,1-dioxide: 1, 3, 5-Trienyl Anion Equivalent
Cheletropic Elimination Reactions
D. A. Evans
Chem 115
LHMDSacetone
?
X = H, Me, Ph
100%
E
53-95%
Yamada,
JCS Chem Comm
1987
, 332.
1) Base, R
1
X
2) Base, R
2
X
76-93%
?
>91% stereoselectivity for (
E, E
)-diene
Bloch,
Tet. Lett.
1983
,
24
, 1247.
a73
α
-Sinensal
LHMDS
+
?
α
-Sinensal
60%
Desai,
Syn. Comm.
1990
,
24
, 523.
56-83%
1) nBuLi
2) RX or RCHO
175 °C68-77%
a73
The Reactions:
Rigby,
Synlett
1993
, 829.
(-)
+
El(+)
-SO
2
(-)
equivalency
Equivalent Synthons
1)TBHP, SeO
2
2) PDC
S
X
O
O
S
O
O
X
Me
Me
OH
Me
Me
OH
X
S
O
O
S
O
O
SO
2
SO
2
R
R
S
O
O
S
O
O
S
O
O
ElEl
R
1
R
2
H
R
1
R
2
Me
S
O
O
Me
Me
Me
Br
Me
Me
Me
SO
2
Me
Me
SO
2
Me
CHO
Me
Me
CHO
Me
Me
S
SO
2
O
O
Me
Me
Me
Me
Me
Br
Br
Me
Me
Me
Me
S
O
O
27A-10-Related Eliminations
12/6/93
1:35 PM
NaI
NBS, HCl
X(+)
Y(–)
–HOSiR
3
Syn
Stereochemistry
base
a73
X = HO; Y = SiR
3
:
acid
–HOSiR
3
Anti
Stereochemistry
base
Syn
Stereochemistry
–HOPR
3
+
–HOPR
2
Anti
Stereochemistry
PCl
3
Lawrence,
Chem. Commun.
1993
, 1187
Krief,
Tet. Lett.
1976
, 3743
PCl
3
Anti
Stereochemistry
–HOSePh
(Peterson elimination)
a73
X = HO; Y = PR
3
:
(Wittig Reaction)
a73
X = HO; Y = PR
2
:
a73
X = HO; Y = SePh
:
a73
X = HO; Y = SPh
:
–HOSPh
Anti
Stereochemistry
Pl
3
Krief,
Tet. Lett.
1979
, 4111
D. A. Evans
Chem 115
Vicinal Elimination reactions: Two Heteroatoms
Y(–)
X(–)
+ 2e
-
Reductive Fragmentation Reactions
a73
Representative Substrates:
Comprehensive
Organic Synthesis
,
6
, Ch 5.1, p 949
a73
Vicinal Dihalides:
These reactions are nearly stereospecific
Sonnett,
Tet
1980
,
36
, 577
Sonnett,
JOC
1980
,
41
, 3284
93% (Z), 95% overall yield
85 °C
-78 °C
NaI, DMF
a73
Vicinal Dihalides:
Inversion of olefin geometry is possible
Fe/Gr
Savoia,
JOC
1982
,
47
, 376
Fe/Gr
96.4% (Z)
is also an effective reducing agent: Engmann,
Tet. Let.
1982
,
23
, 3601
X
Y
R
2
R
1
R
2
R
1
R
2
R
1
R
2
R
1
HO
PR
3
R
1
R
2
R
2
R
1
PR
2
HO
R
1
R
2
R
2
R
1
HO
SePh
R
1
R
2
R
2
R
1
SPh
HO
R
1
R
2
R
2
R
1
SiR
3
HO
R
1
R
2
HO
OH
R
1
R
2
Br
Br(OR)
R
1
R
2
R
2
R
1
SO
2
R
AcO
Ph
Ph
Br
Br
C
4
H
9
Ph
Ph
Br
Br
C
4
H
9
C
4
H
9
R
2
R
1
R
2
R
1
Y
X
C
4
H
9
S
TeNa
Me
OAc
I
Cl
Me
RR
Me
Cl
Br
OAc
Me
27A-11-HO-X eliminations
12/7/93
12:06 PM
2 CrCl
2
mechanism ?
CCl
4
Bu
3
P
D. A. Evans
Chem 115
Vicinal Elimination reactions: Two Heteroatoms
a73
halohydrins:
These substrates behave much like vicinal dihalides
NBS
NaBH
4
Zn/i-PrOH
75%
Sinay,
JACS
1983
,
105
, 621
CHI
3
, CrCl
2
Li/NH
3
Ireland,
JACS
1983
,
105
, 1988
a73
Takai Reaction:
These rxns are not stereospecific: Takai,
JACS
1986
,
108
, 7408
(E) selectivity 80:20
CrCl
2
Hodgson,
Tet Let
1992
,
33
, 5603
(
E
):(
Z
)
Yield
Time
Solvent
8h
22:1
40%
4d
4:1
73%
4h
13:1
69%
6:1 Dioxane:THF
Dioxane
THF
CHI
3
CrCl
2
Reaction stereoselectivity can be influenced by solvent (JACS
1993
, 115,
4497
)
71%
diastereoselection
10:1
(
E
):(
Z
) = 9:1
80%
CHI
3
, CrCl
2
,
dioxane/THF
25 °C
Me
2
AlCl,
CH
2
Cl
2
, 0 °C
2 CrCl
2
Bolandi,
SynLett
1993
, 837
(E) selective
[H]
Zn,
CrCl
3
See lecture 13 (Fragment Coupling) for related uses of Cr(II)
RCHO
RCHO
2 CrCl
2
Mechanistic options
O
O
O
TBS
OMe
Me
O
Ph
Ph
O
O
Br
Me
OMeOTBS
O
HO
Ph
O
O
TBS
OMe
Me
O
O
Ph
O
Me
HOTBS
O
(
β)
Npˇ
OHC
Me
OTBS O
O
(
β)
Npˇ
Me
OTBS O
I
HC
II
I
C
Cr(III)
I
Ph
H
O
TBSO
Ph
O
Ph
O
O
Me
OHOTBS
I
TBSO
I
H
HC
I
Cr(III)
Cr(III)
O
H
R
R
O
OTIPS
OTES
O
Me
Et
O
O
O
RO
Me
OH
Me
Me
Me
Me
Cl
Me
RO
O
O
O
O
HO
I
Me
RO
Me
H
O
O
O
Me
Et
R
OM
OAc
Et
Et
OAc
Br
OCr(III)
R
I
RH
O
HC
BrBr
SnBu
3
SnBu
3
R
OX
P
OTBS
I
H
O
OTES
OTIPS
O
O
Me
Et
OTBS
H
H
H
H
H
X
P
Cr(III)
I
R
OCr(III)
R
I
27A-12-HO-X eliminations-2
12/7/93
12:08 PM
See this paper for the optimized procedure: McMurry,
JOC
1989
,
54
, 3748
a73
Recent Review:
J. McMurry,
Chem. Rev
.
1989
,
89
, 1513
Vicinal Elimination reactions: The McMurry Reaction
Chem 115
D. A. Evans
+
"low-valent Ti"
This rxn accomplishes the reverse of olefin ozonolysis
Mechanism:
+
TiCl
3
Zn-Cu
a73
Pinacol Step:
Ti(0) surface
+
Ti(0) surface
+
?
?
Ti(0) surface
Ti(0) surface
Ti(0) surface
?
Ti(0) surface
a73
Elimination Step:
Ti(0)Ti(0)
ratio: 91 : 9ratio: 60 : 40
a73
The elimination step is not stereospecific:
McMurry,
JOC
1978
,
43
, 3255
Zn-Cu
TiCl
3
94% yield
a73
Hindered double bonds may be readily prepared:
McMurry,
JOC
1989
,
54
, 3748
a73
Extended conjugation can be tolerated:
McMurry,
JACS
1974
,
96
, 4708
a73
Intramolecular Rxns are possible:
TiCl
3
Zn-Cu
retinal
β
-Carotene
94% yield
TiCl
3
Zn-Cu
75% yield
Burnell,
Tet. Let
1988
,
29
, 4369
Zn-Cu
TiCl
3
McMurry,
Tet. Let
1982
,
23
, 1777
78% yield
(E):(Z) = 2 : 1
For a general review of vicinal deoxygenation see:
Kocienski in
Comprehensive
Organic Synthesis
,
6
, Ch 5.2, p 949
Me
Me
Me
Me
Me
Me
Me
Me
Me
O
MeMe
O
R
RR
O
O
R
R
R
RR
O
R
R
O
R R
RR
R R
OTi
TiO
RR
R R
O
R
R
RR
O
O
R
R
RR
O
O
O
R
R
R
R
O
R
RR
R
O
O
O
R
R
R
R
RR
R R
O
O
Bu
Bu
OH
OHOH
Bu
Bu
Bu
OH
Bu
Bu
Bu
Me
Me
MeMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
O
H
OO
Me
O
Me
Me
O
Me
Me
Me
Me
Me
MeMe
Me
Me
Me
Me
OHC
O
27A-13-McMurry Rxn
12/7/93
1:27 PM
D. A. Evans, P. Carter
Chem 206
Sulfur-Based Functional Groups-5: Julia Olefin Synthesis
Problem: Work out the
mechanism of reduction step.
Good sulfone review: Trost,
Bull Chem. Soc. Japan,
1988
,
61
, 107-124.
Elimination is stepwise;
therefore, not stereospecific
Ac
2
O
major
MeOH Na(Hg)
BuLi
R'CHO
Julia Trans Olefin Synthesis:
SO
2
Ph
R
SO
2
Ph
R
R'
OH
R'
R
OAc
R'
R
SO
2
Ph
R'
R
Julia Olefination - Ionomycin
1. add RCHO, -78
o
C;
add Ac
2
O, -78
o
C to R.T.
2. Na/Hg, EtOAc/MeOH, -30
o
C
70% yield
86:14 olefin mixture
Evans,
et al.
JACS
1990
,
112
, 5290.
PhO
2
SL
i
OTBDPS
Me
Me
Me
Me
O
O
Me
Me
HM
e
H
M
e
OTBS
Me
O
O
OTBDPS
Me
Me
Me
Me
O
O
Me
Me
CHO
HM
e
H
M
e
OTBS
Me
O
O
Review:
Kocienski etal.
Phosphorus & Sulfur
1985
,
24
, 97-127
Kochenski,
J. Chem. Soc Perkin Trans I,
1978
, 834
Na(Hg)
? or –
?
+
+ e-
?
+ e-
The reduction step is not stereosecific
R
2
R
1
SO
2
R
X
X
R
2
R
1
R
2
R
1
R
1
R
2
SO
2
Ar
OAc
OAc
SO
2
Ar
OAc
Cytovaricin Synthesis:
JACS
1990
,
112
, 7001
Free acid must be used to prevent
loss of C
4
OH in 2nd step
C
21
OH deprotection
21
C=C construction
Reactions accomplished:
overall yield, 66%
Ac
2
O, pyr
6% Na(Hg)
-40 °C
2 LiNEt
2
, THF
21
3
1
+
TESO
Me
SiO
O
OTES
H
O
Me
OTES
H
MeO
H
H
O
t-Bu
t-Bu
Me
PhSO
2
Me
TESO
O
H
Me OCH
2
OCH
2
CCl
3
O
H
MeH
O
H
H
DEIPSO
Me
CHO
Me
TBSO
OPMB
HO
OPMB
OTES
H
H
H
O
OTES
Me
MeO
O
HO
H
Me
DEIPSO
H
O
O
H Me
H
H
OHMe
H
TBSO
Me
H
O
OTES
Me
O
O
Me
TESO
Si
t-Bu
Me
t-Bu
27A-14 Julia-1
11/13/01
12:27 PM
D. A. Evans, P. Carter
Chem 206
Sulfur-Based Functional Groups-5: Julia Olefin Synthesis-2
Me Br
MeO
O
H
H
O
O
N
O
Me
H
H
H
HO
H
CH
2
Me
O
MeO
OH
H
N
O
H
H
O
O
H
H
Me
HO
46
38
33
19
1
4
9
13
C
39
–C
46
Synthon
Phorboxazole B Synthesis
Br
OMe
NaHMDS
THF, -78?C - rt
CH
3
I
CH
3
I
75%
O
H
E/Z = >95:5
Br
OMe
S
S
N
O
O
Evans, Smith, Fitch, Cee
JACS
2000
,
122
, 10033-10046.
disconnection
Br
OMe
CH
3
I
Julia Construction
Br
OMe
CH
3
I
O–Na
S
O
O
S
N
NaHMDS
RCHO
Br
OMe
CH
3
I
S
N
NaO
Mechanism??
The Mechanism:
CH
3
I
O–Na
S
O
O
S
N
R
CH
3
I
O
S
O
O
S
N
R
SO
2
CH
3
I
O
S
O
O
S
N
R
R
CH
3
I
SO
2
S
N
NaO
Olefin stereochemistry could be
established in the formation of
A
.
A
Recent Modifications of the Julia Process:
Kocienski,
SynLett
2000
,
3
, 365-366.
N
O
2
S
C
4
H
9
N
N
NN
Ph
C
9
H
19
OHC
KHMDS
–60 °C
→
rt
C
4
H
9
E/Z: 99:1 (75%)
N
O
2
S
Ph
N
N
NN
R
OHC
KHMDS
–60 °C
→
rt
C
9
H
19
Ph
R = Ph
: E/Z: 29:71 (70%)
R = tBu
: E/Z: <1:99 (95%)
N
O
2
S
N
N
NN
Ph
R
KHMDS
–60 °C
→
rt
H
R'
O
Me
RO
R'
Me
RO
R
E/Z: >10:1 (64%)
Metternich,
JOC
1999
,
54
, 9632
27A-15 Julia-2
11/13/01
5:31 PM