M.C. White, Chem 153
Nu attack on Olefins -327-
Week of November 25, 2002
Olefin functionalization via metal promoted Nu attack
C
Recall that the balance of electron flow in olefin-metal
bonding can be shifted predominantly in one direction
depending on the electronic properties of the metal. If
the metal is electron withdrawing, M-L σ-bonding
predominates and withdraws electron density from the
π-bond of the olefin (see Structure and Bonding, pg.
39). This results in the induction of a δ+ charge on the
olefin that activates it towards nucleophilic attack.
M
C
Dewar-ChattDuncanson Model
C-H σ-donation to the electrophilic metal activates the metal alkyl towards
β-hydride elimination.
olefin σ-donation to the electrophilic metal activates it towards Nu attack
R
Nu
δ+
X
Pd
X
L
Nu
X
PdII
X
II
L
Nu
R
R
X
PdII
L
R
Nu
X
H
Pd II
L
H
recall that the equilibrium for late
metals lies towards the olefin form
which is stabilized via π-backbonding.
σ donation>>
π-backbonding
Catalyst regeneration
stoichiometric
oxidants
H H2O2
L
O 2/ 2 HX
Pd II
O
L
X
L
Pd
L
II
RE
Pd II
O
O
L
H
L
Pd
L
II
0
2 Cu X2
L
H
L
O
I
2 Cu X
HX
O
L
H+
O
OH
OH
X
PdII
X
PdIILn
Pd 0Ln
O
HO
2 HX
Pd IILn
O
O
O
H+
OH
M.C. White, Chem 153
Nu attack on Olefins -328-
Week of November 25, 2002
Wacker Oxidation
PdCl2 (cat)
CuCl2 (cat)
O2, H2O, HCl
R
O
2 mechanistic possibilities for hydroxypalladation:
R
OH
The Wacker oxidation is used
industrially to produce ~ 4 million tons
of acetaldehyde/year.
H2O
Cl
PdII
OH
H2O
Cl
Pd
II Cl
Cl
2 CuCl
H 2O
2 CuCl2
Pd
R
Cl
II
H2O
OH 2
PdII
Cl
O
PdII
Cl
H2O
Cl
R
Pd II
Pd
II
H
H2O
Cl
D
R
OH
H
OH 2
LnPdII
H
H
β-hydride elimination
D H
LnPd II
H+
D
OH
H D
CO
OH
HO
Commericial production of acetaldehyde
H
D
H
DH
D
O
· Binding specificity: terminal olefins
· Regioselectivity: 2o carbon
· Remote functionality tolerated
OH
Deuterium labeling study indicates that hydroxypalladation proceeds
via palladium-nucleophile anti-addition.
R
R
Pd
Cl
II
OH 2
R
OH 2+
HCl
H2O
Cl
Pd
anti hydroxypalladation
II Cl
R
LnPd(0)
H
H2O
Cl
HCl
H2O
R
R
Cl
H2O
Pd II
Cl
H 2O
hydroxypalladation
1/2 O2
+ 2 HCl
H2O
R
R
H2O
syn hydroxypalladation
O
Stille JOMC 1979 (169) 239.
Pd 0Ln
O
HD
OH
Pd IILn
M.C. White, Chem 153
Nu attack on Olefins -329-
Week of November 25, 2002
Oxidation of terminal olefins
Standard Wacker conditions:
Selective oxidation
of terminal olefins
O
PdCl2 (cat.)
CuCl2 (cat.)/O2
DMF/H2O
O
O
70%
Chadha J. Chem. Soc. Perkin I 1979 2346.
Cuprous chloride (CuCl)/O2 as the oxidant system leads to faster reactions with no chlorinated biproducts.
H
PdCl2 (30 mol%)
CuCl (1.6 eq)/O2
DMF/H2O (10:1.2)
O
H
H
H
OTHP
H
PdCl2 (20 mol%)
CuCl (10 mol%)/O2
DMF/H2O (9:1)
O
H
77%
O
O
OTHP
O
O
O
91%
OTBS
OTBS
O
Ikegami Tetrahedron 1981 (37) 4411.
Money Tetrahedron 1996 (52) 6307.
Benzoquinone can be used as a stoichiometric oxidant:
Cu(OAc)2/O2 oxidant system:
O
O
H
O
O
PdCl2 (10 mol%)
Cu(OAc)2 (20 mol%)/O2
DMF: H 2O (7:1)
O
Pd(OAc)2 (10 mol%)
HClO4 (0.3M), CH 3CN
H
O
O
H
H
O
O
85%
Smith JACS 1999 (121) 10468.
O
O
Santelli TL 1994 (35) 6481.
O
H
H
H
H
M.C. White,M.S. Taylor Chem 153
Olefin Nu attack -330-
Week of November 25, 2002
Palladium (II)-mediated [3,3]-sigmatropic rearrangements
PdCl2(MeCN)2
(10 mol%)
OAc
BnO
OBn
PdCl2(MeCN)2
(10 mol%)
BnO
OBn
THF, 23°C
OAc
OBn
THF, 23°C
OAc
OAc
OAc
BnO
82%
BnOH2C
Cl2Pd
R
OAc
BnOH2C
O
Cl2Pd
O
BnOH2C
O
R
O
O
Cl2Pd
CH3
CH3
R
CH3
Saito TL 1988 (29) 1157.
The vinyl ether 1 is unreactive to Pd(II) catalysis. However, the similar substrate 2 shows good reactivity:
Et
O
O
PdCl2(MeCN)2
(10 mol%)
THF, 23°C
1
Et
Recovered starting
material
O
PdCl2(MeCN)2
(10 mol%)
THF, 23°C
Me
2
Et
O
Me
71%
Bickelhaupt TL 1986 (27) 6267.
The authors speculate that when reacting with 1, Pd(II) binds preferentially to the electron-rich vinyl ether olefin over the terminal olefin.
Such binding does not lead to a productive reaction. When the steric bulk of the vinyl ether is increased, as in 2, binding to the vinyl ether is
less favourable. Pd(II) coordination to the terminal allylic olefin occurs resulting in catalysis of the Claisen rearrrangement. Note that these
structural requirements limit the scope of this reaction.
M.C. White, Chem 153
Nu attack on Olefins -331-
Week of November 25, 2002
Cyclic ether formation
Pd(OAc)2 (20 mol%)
Cu(OAc)2 (50 mol%)/O2
MeOH/H2O
OH
Pd(OAc)2
O
54%
H
LnPdII
Pd(OAc)2
O
OAc
Cycle A
OAc
2 Cu(OAc)
1/2 O2
+ 2 HOAc
2 Cu(OAc)2
H 2O
Cycle B
Pd II
O
H
PdII
O
OH
5-exo-trig
O
HOAc
O
HOAc
LnPd0
Hosokawa Bull. Chem. Soc. Jpn. 1975 (48) 1533.
Asymmetric version:
5 membered ring formation
Pd(OCOCF3) 2 (10 mol%)
(S,S)-boxax (10 mol%)
MeOH
O
OH
O
O
(4 eq)
5-exo-trig
71 % yield
93 % ee
6 membered ring formation
O
Pd(OCOCF3) 2 (10 mol%)
(S,S)-boxax (10 mol%)
MeOH
R
N
PdII
*
O
6-exo-trig
Hayashi JACS 1997 (119) 5063.
O
OCOCF3
N
O
OH
R
(4 eq)
61 % yield
97 % ee
O
OCOCF3
M.C. White, M.S. Taylor Chem 15
Nu attack on Olefins -332-
Week of November 25, 2002
Application of an intramolecular Wacker oxidation
in the synthesis of Garsubellin A
O
O
O
O
O
O
O
Na2P dCl4 (40 mol%)
t-BuOOH
O
O
HO
O
O
O
O
HO
AcOH / H2O
69%
– HCl
AcOH / H2 O
Pd
0
Garsubellin A
O
O
O
reductive
elimination
of HCl
HClPdII
O
t-BuOOH
HCl
HO
OH
β-hydride
elimination
O
O
O
O
HO
HO
OH
H
O
HO
Shibasaki OL 2002 (4) 859.
O
O
HO
PdIICl2
Cl2PdII
O
Pd IICl2
O
O
O
– HCl
PdIICl
O
O
O
M.C. White, Chem 153
Nu attack on Olefins -333-
Week of November 25, 2002
Tandem oxopalladation/Heck-type cyclization
H
H
i-Pr
i-Pr
i-Pr
i-Pr
N O
Pd II
OCOCF3 20 mol%
F3 COCO
N
O
H
OBz
O
HO
OBz
5%, 45% ee
+
o
O (4 eq) CH 2Cl2, 0 C
O
68%, 95% ee
(single diastereomer)
OBz
O
27%, 60% ee
Sasai JACS 2001 (123) 2907.
*
N
Proposed mechanism:
N
OCOCF3
II
Pd OCOCF3
OH
HO
6-endo-trig
O
OH
N
Pd
II
OCOCF3
OCOCF3
H
OBz
2 HOCOCF3 +
N
Pd II
N
N
Pd
O
OCOCF3
H
N
OBz
O
OCOCF3
H
OBz
O
N
Pd
N
N
II
OBz
O
H
OCOCF3
HOCOCF3
H
N
N
Pd 0
O
OBz
N
Pd II
N
O
OBz
O
OBz
H
N
O
OBz
OCOCF3
Pd II
N
N
O
OBz
HOCOCF3
Pd II
N
O
N
H
N
OBz
Pd II
H
OCOCF3
M.C. White, Chem 153
Nu attack on Olefins -334-
Week of November 25, 2002
Tandem sequences
Oxo-palladation/intermolecular Heck
AcO
Pd(OAc)2 (10 mol%)
CuCl (1 eq)/O2, DMF
OH
CO2Me
CO2Me
PdII
O
O
CO2Me
β-hydride elimination is not an
option for this intermediate
(or Ph)
89%
Semmelhack TL 1993 (34) 7205.
Oxo-palladation/carbonylation
L
PdII
Pd(Cl)2 (10 mol%)
CuCl2 (3 eq), MeOH
R
CO
OH
R
O
Cl
O
CO
Pd(Cl)Ln
R
O
O
HOMe
R
Semmelhack JACS 1984 (106) 1496.
OMe O
Pr
OH
Pr
OMe O
O
Pd(Cl) 2 (10 mol%)
CuCl2 (3 eq), MeOH
CO
O
+ 30% of the
furan product
O
70%
note: O2 is not necessary to re-oxidize Pd if
supra-stoichiometric amounts of Cu(II) salts
are used
OMe O
OMe
O
CO
PdII
L
Cl
Pr
OH
O
O
O
70% (trans:cis ,3:1)
Pr
O
CO2Me
O
CO2Me
Semmelhack JACS 1982 (104) 5850.
M.C. White, Chem 153
Nu attack on Olefins -335-
Week of November 25, 2002
Nitrogen nucleophiles
Conversion of o-allylanilines to indoles:
Disubstituted olefins
The excess quinone and the Cl are
thought to alter the regioselectivity
of aminopalladation by coordinating
to the Pd.
PdCl2(CH3CN)2 (10 mol%)
THF
N
H
R
O
N
R
O (1 eq)
N
R
R= H, 86%
R = Me, 89%
R= C(O)CH3, 71%
Both benzoquinone and Cu(II) salts
are effective stoichiometric oxidants
for Pd(0) in the presence of readily
oxidized o-allylanilines and indoles.
NH2
standard cat.
conditions
Hydrogenation of "trapped" Pd-alkyl intermediate leads to formal hydroamination product
PdCl2(CH3CN)2
(10 mol%)
LiCl (10 eq)
O
H2
PdCl2(CH3CN) (1 eq)
NEt3, THF
NH2
N
H
no reaction occurs in
the absence of NEt3
+
N
H
O
(2 eq)
PdClLn
NH2
N
H
79%
N
mj. product
Hegedus JACS 1978 (100) 5800.
Proposed mechanism:
Asymmetric synthesis of 5-membered nitrogen heterocycles
O
NHTs
5 mol% pre-cat*/AgOCOCF3
CH2Cl 2:MeNO 2 (1:1)
rt (10-20 h)
OAc
O
X
pre-catalyst:
SiMe3
O
t-Bu
N
I
Pd II
X
NTs
H
X = O, 96% (91% ee)
NH, 96% (90% ee)
CH2, 95% (90% ee)
C
N
Ts
NH
O
OCOCF3
Pd II O
R
O
or
Fe
N
Pd
C
II
HOCOCF3
O
X
Ts
N
*
X
N
Ts
N C
O
X
Pd O
R
O
Ts
N
*
X
O
C
O
Pd II
N
O
OCOR
Overman JACS 2001 (124) 12.
M.C. White, Chem 153
Nu attack on Olefins -336-
Week of November 25, 2002
Nitrogen nucleophiles/O2 as a stoichiometric oxidant
Pd(OAc)2 (10 mol%)
Ts
N
pyridine (10 mol%)
O2, toluene, 80oC
NHR
Ts
N
R = Ts, 87%
Ns, 87%
Cbz, 76%
Ts
N
91%
60%
Proposed mechanism:
2 AcOH
N
N
PdII
O
H2O2
N
O
PdII
OAc
Pd II
OAc
N
O
N
NHR
O
N
O2
OAc
N
N
Pd0
N
PdII
Ph
Ph
OAc
N
NHR
AcOH
N
Pd
N
II
OAc
statistically and
sterically prefered
site of elimination
H
N
H
AcOH
OAc
N
Pd II
N
PdII
OAc
N
Ts
N
NTs
Stahl ACIEE 2002 (41) 164.
NTs
Stahl JACS 2001 (129) 7188.
M.C. White, Chem 153
Nu attack on Olefins -337-
Week of November 25, 2002
Hydroamination
Ph
Ph
P
OTf
Pd II
OTf
P
PhPh
2 mol%
Fe
NH 2
Original mechanism proposed:
Ar
NHAr
NHPh
P
H
H
OTf
Pd II
P
OTf
toluene, 100oC
97%
Ph 2
P
P
Pd II
P
Ph 2
NH 2
OTf
NHPh
OTf
PdII
OTf
P
OTf
P
P
OTf
OTf
PdII
NH2Ar
ArH2N
10 mol%
Ar
Ar
toluene, 45oC, 36 h
>99% yield, 64% ee
NH2Ar
Hartwig JACS 2000 (122) 9546.
Revised mechanism based on "isolation of a catalytic intermediate"
P
Pd
P
NAr
OTf
Ph 2
P
Pd II
P
Ph 2
OTf
II
OTf
NH2
Ar
based on crystal
P
ArNH2 -H
+
P
Pd
P
0
H
Pd II
P
OTf
Ar
P
Pd
inversion
OTf
P
H
Pd II
II
P
P
Ar
OTf
Me
(S)
Pd H
P
P
H2NAr
major diastereomer isolated
P
Pd II
NHPh
Ar
H
Hartwig claims the η3-arylethyl complex is chemically
and kinetically competent to be a reactive
intermediate. When heated in the presence of excess
aniline at 75oC for 2h, hydroaminated products were
formed in 61-83% yields (note, no direct comparison
with the catalytic system under identical conditions is
made).
(S)
H
Me
observed in
catalytic reaction
OTf
P
Ar
retention
NHAr
(R)
Me
H
observed
NHAr
NH 2Ar
Hartwig claims that minor diastereomer (not isolated) reacts faster (3.5 x) based on a comparison
of rates of the mj. vs. the mixture of η3-aryl complexes. Note that he never makes a reaction rate
comparison with the catalytic reaction.
Hartwig JACS 2002 (124) 1166.
M.C. White, Chem 153
Nu attack on Olefins -338-
Week of November 25, 2002
C nucleophiles
Enol ether nucleophilic attack/ β-hydride elimination
CO2Et
O
Pd(OAc)2 (1 eq)
CH3CN
SiMe3
O
Ln(OAc)Pd
CO2Et
PdIILn
SiMe3
H
CO2Et
O
O
O
(OAc)HPd II
A catalytic process for the addition of C
nucleophiles to Pd(II) activated olefins is
precluded in this case (as in most) by the
competative oxidation of the carbon
nucleophile by the stoichiometric oxidant.
CO2Et
O
O
58%
Quadrone
Kende JACS 1982 (104) 5808.
Hydroalkylation
H
O
O
O
OH
O
O
O
R
R
R
PdCl2(CH3CN) 2 5-10 mol%
dioxane, rt
Cl
Pd
Cl
R
PdCl2(CH3CN)2
II
NCCH3
protonolysis
O
Cl
PdII Cl
NCCH3
H
It's unclear why protonolysis rather than
β-hydride elimination occurs in this system.
Widenhoefer JACS 2001 (123) 11290.
M.C. White, Chem 153
Q&A -339-
Week of November 25, 2002
Question 1: Intermolecular [5+2]
Propose a mechanism for the following transformation:
O
O
O
CH3
O
H
[Rh(CO) 2Cl]2 (2.5 mol%)
C(O)CH3
CO (1-2 atm), dioxane, 60oC;
H3O+
+
OH
Et
Et
O
transannular
closure
O
O
C(O)CH 3
H
O
(CO) nClRh
Et
H
OH
O
C(O)CH3
O
O
reductive elimination
O
O
Et
O
O
(CO)nClRh
O
O
C(O)CH3
Et
O
H
(CO) nClRh
CO insertion
C(O)CH 3
CO
oxidative
cyclization
O
O
OH
Et
(CO)nClRh
H3O+ work up
Et
(CO) nClRh
O
O
C(O)CH3
O
H
(CO) nClRh
C(O)CH 3
OH
alkyne
insertion
O
Et
Et
Et
Wender JACS 2002 (124) 2876
O
O
CH3
CH3
O
M.C. White, Q. Chen Chem 153
Q&A -340-
Week of November 25, 2002
Question 2: Hydrozirconation
1) Et2Zn (1.1 eq.)
-60 °C
Cp 2Zr(H)Cl (1.1 eq.)
TBDPSO
CH2Cl2, 0 °C
TBDPSO
TBDPSO
Zr(Cl)Cp 2
2)
OH
94% over 3 steps
H
o
O 0 C, 6 h
The authors noted no loss of diene geometry
upon hydrozirconation of this triene.
Cp 2Zr(H)Cl (1.0 eq.)
TBDPSO
Zr(Cl)Cp 2
TBDPSO
CH2Cl2, rt
1) n-BuNC, 0 °C to rt, 4h
2) 3M HCl, -78 °C to 0 °C
OMe
H
TBDPSO
O
N
S
54% over 3 steps
(+)-curacin A
Wipf JOC 1996 6556.
M.C. White,M.S. Taylor Chem 153
Q&A -341-
Week of November 25, 2002
Question 3: oxidative cyclization/hydrosilylation
Provide a mechanism for the following transformation
SiPh3
Ph3SiD
MeO2C
Pd 2(dba)3 (5 mol%)
THF, 25°C, 2 hours
MeO2C
MeO2C
MeO2C
CH2D
MeO2C
+
MeO2C
Ph3Si
DH2C
A
B
6:1 A:B
SiPh3
CH2D
MeO2C
MeO2C
MeO2C
MeO2C
Pd(0)L n
DH2C
SiPh3
B
A
MeO2C
MeO2C
D
PdLn
SiPh3
PdLn
MeO2C
MeO2C
PdLn
MeO2C
MeO2C
MeO2C
MeO2C
Ph 3Si
DH2C
MeO2C
PdLn
MeO2C
Ph3SiD
σ-bond
metathesis
σ-bond
metathesis
D
MeO2C
Takacs OM 1990 (9) 2877.
MeO2C
PdLn
SiPh3
M.C. White,Q. Chen Chem 153
Question -341-
Week of November 25, 2002
Question 1
An interesting synthesis of cyclopropanes has been recently reported by Grigg.
Propose a mechanism for this transformation.
I
Pd 2(dba)3, TFP
NHMe
+
NMe
K2CO 3, DMF
O
O
68%
O
P
TFP =
3
M.C. White,Q. Chen Chem 153
Question -342-
Week of November 25, 2002
Question 2
Murai has described the synthesis of butanolides from a three component coupling shown below.
Propose a mechanism for this process.
O
ethylene (3 atm)
CO (5 atm)
O
S
Me
N
Ru 3CO12 (2.5 mol%)
tol., 140 °C, 20h
O
S
N
Me
M.W. Kanan/M.C. White, Chem 15
Questions -section-
Week of November 25, 2002
Section question 1: Cycloaddition Disconnections
Provide a substrate or pair of substrates for the indicated cycloaddition reactions
O
H
Rh(I)
TsN
H
Rh(I)
MeO2C
MeO2C
+
Rh(I)
O
H
Rh(I)
O
H
Q. Chen /M.C. White,Chem 153
Question -section-
Week of November 25, 2002
Section Question 2
Provide a mechanism for the following transformation:
PdCl2 (10 mol%)
CuCl2 (3.0 equiv.)
NH
NHCH3
O
CO (1 atm)
NaOAc (3.0 equiv.)
HOAc, 23°C
O
N
NMe
O
95%