Transcript Document 7723757

Wacker Oxidation and Wacker-Type
Reactions
Literature Meeting
Presented by:
Alexandre Côté
September 6th, 2005
University of Montreal
1 /52
The Wacker Process
Wacker Process was developped by Wacker-Chemie: 1957
O
PdCl2 (cat) / CuCl (cat)
O2 / H2O
H
Applied to the industrial synthesis of acetaldehyde and acetone
Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J. Seiber, R.; Ruttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176.
Organic synthesis procedure
O
PdCl2 (10 mol%)
C8H17
CuCl (1 equiv)
DMF/H2O (7:1)
O2 (1 atm)
24h, r.t.
C8H17
65-73% yield
Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth. 1984, 62, 9.
2
Review: Tsuji, J. Synthesis 1984, 369.
Overview on Wacker Oxidation
Metals used in Wacker oxidation and Wacker-type reactions
Pd >> Pt, Rh, Ir, Ru
2 types of reaction conditions
Low Cl- concentration
High Cl- concentration
- Increase the solubility of Pd(0)
(avoid the precipitation of Pd black)
- Facilitate the oxidation of Pd(0) by Cu(II)
Redox potential
Pd(II) oxidation potential
Cu(I) reduction potential
E°/ V
Pd2+
+ 2 e-
Pd(0)
0.951
- Decrease disproportionation of Cu(I) into Cu(0) and Cu(II)
- Lower Pd(II) and Cu(II) loading
- Corrosive conditions
(Increase HCl formation)
-Increased chlorinated by-products
[PdCl4]2- + 2 eCu2+
+ 2 e-
Cu2+
+
e-
Pd(0) + 4 Cl- 0.591
Cu(0)
0.342
Cu+
0.153
Mechanism of the Wacker Oxidation:
High Cl- Concentration
1/2 O2 + 2 HCl
H2O + 2 CuCl2
2 CuCl
R
OH
+
H +
[PdCl4]-2
[Pd(0)Cl2]-2
R
Cl-
Cl
ClPd
H HO
Catalytic cycle
High Cl- concentration


R
Cl
Cl
Pd
Cl
-Hydride
H2O
ClPd
Cl


R
-
R
OH
Cl
ClRate determining step
ClPd
Cl-
R
OH
H+
Hamed, O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1997, 62, 7082.
Hamed, O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1999, 64, 7745.
4
Mechanism of the Wacker Oxidation:
Low Cl- Concentration
1/2 O2 + 2 HCl
H2O + 2 CuCl2
OH
-
+
R
H + 2 Cl +
Pd
R
Cl
2 CuCl
ClPd
H HO
(0)
PdCl2
+ H2O
Catalytic cycle
Low Cl- concentration


R
Cl
Cl
Pd
O
H


R
H
-Hydride
ClPd
Cl
R
OH
Cl
ClPd
O
H


R
H+
Rate determining step
Hamed, O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1997, 62, 7082.
Hamed, O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1999, 64, 7745.
5
By-Products Observed in the Wacker
Oxidation: Isomerization of Alkenes
R
R
...
R
Minor products
Internal alkenes react slower than terminal alkenes (Wacker oxidation)
Mechanism
H
Pd(II)
H
Pd(IV)
Pd(II)
H
6
By-Products in the Wacker Oxidation:
Chlorination Products
Example of the acetaldehyde synthesis:
O
O
PdCl2, CuCl2
+
H2O, LiCl, O2
+
Cl
H
OH
H
Cl
+ ...
up to 5%
Chlorinated products increase with heavier alkenes
Chlorinated products increase at high concentration of ClLow Cl- concentration systems using molybdovanadophosphate( H3PMo6V6O40) as co-oxidant reduce
by-products by 99% giving access to higher olefins: propene, butene, ...
O
O
2 CuCl2
Cl
H
+ 2 CuCl + HCl
H
O2 promotes this side reaction
-
Cl3Pd
OH
2 CuCl2
Cl
+ 2 CuCl + HCl
OH
7
By-Products in the Wacker Oxidation: Allylic
Oxidation Products
OAc
OAc
O
OH
PdCl2/CuCl2/O2
NaOH (pH=6), AcOH
OAc
(R)-Limonene
major
(NaOAc as base)
OH
OH
major
O
major
(LiCl was added)
OH
OH
PdCl2/CuCl2/t-BuOOH
t-BuOH
(R)-Limonene
CHO
OOt-Bu
OOt-Bu
OOt-Bu
OH
major
(with and without LiCl)
Silva, A. D.; Patitucci, M. L.; Bizzo, H. R.; D'Elia, E.; Antunes, O. A. C. Catalysis Communication 2002, 3, 435.
8
Mostly observed for internal alkenes using conditions where AcOH is the solvent
By-Products in the Wacker Oxidation:
Oxidative Cleavage Products
PdCl2 (0.2 mol%)
Aliquat 336
O
O
H
+
H2O2 30% (6 equiv)
ClCH2CH2Cl, 80 °C
79%
O
12%
OH
+
14%
Normally observed with styrene derivatives
Cl
+
Aliquat 336 =
N
9
Barak, G.; Sasson, Y. J. Chem. Soc., Chem. Commun. 1987, 1266.
Variation to the Classical Wacker Oxidation:
Co-Oxidant
Co-oxidants
Stoichiometric oxidants
Cu(OAc)2
N
OH
N
OH
O
H2O2
Cu(NO3)2
pyr Co(TPP) NO2
OOH
pyr Co(saloph) NO2
H3+xPMo12-xVxO40 (HPA)
O
saloph
TTP = Tetraphenylporphyrin
Decrease chlorinated by-products
HPA reduction:
+
+
6
6
Mo O Mo
H2
5+
5+
Mo O Mo
+ 2H
+
H2
4+
4+
Mo O Mo
Irreversible step
O2
-H2O
Nowinska, K.; Dodko, D. Applied Catalysis A: General 1997, 159, 75.
Transition metal salts as
additive disfavours the
second reduction:
Increase TON
Variation to the Classical Wacker Oxidation:
Co-Oxidant
Pd(OAc)2 (5 mol%)
H3PMo6V6O40 (1 mol%) /O2
C8H17
NaCl (5 mol%)
EtOH/H2O, 60 °C, 6h
O
C8H17
82% yield
Yokota, T.; Sakakura, A.; Tani, M.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2002, 43, 8887.
O
Pd(NO3)3 / CuSO4 / H3PMo12O40
(0.16/1.3/ 1.3 mol%)
TOF = 400 h-1
MeCN, 80 °C, 50 bar of air
80% conv. after 1h
H2O2 70% in water as oxidant
PdCl2 / CuCl2
65% conv. after 15 min
TOF = 836 h-1
Large quantities of chlorinated products
Classic Wacker conditions
Melgo, M. S.; Lindner, A.; Schuchardt, U. Applied Catalysis A: General 2004, 273, 217.
11
Variation to the Classical Wacker Oxidation:
Solid Phase Supported Catalyst
Cl
N
O C
HO2C
H
N
Cl
Pd
N
H
CO2H
N
C
n
O
R
Ethanol/H2O, 60 °C
CuCl2, O2, 30 min
O
(2 mol%)
Can be recycled
R
62% yield
Ahn, J.-H.; Sherrington, D. C. Macromolecules 1996, 29, 4164.
Pd(II)/ V2O5/ Alumina
Scholten, J. J. F. et al. J. Catal. 1995, 152, 130.
Pd(II)/ V2O5/ Titania
Scholten, J. J. F. et al. Applied Catalysis A: General 1997, 156, 219.
Pd(II)/ H3PMo6V6O40/ C
Kishi, A.; Higashino, T.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2000, 41, 99.
Can be recycled
Low TON
12
Variation to the Classical Wacker
Oxidation: Phase Transfert Catalyst
-cyclodextrin-CN (1 mol%)
O
PdCl2 (1 mol%), CuCl2 (10 mol%)
H2O, 60 °C, O2, 5 atm
95% yield
Pd(II)
CN
-cyclodextrin-CN
Karakhanov, E.; Maximov, A.; Kirillov, A. J. Mol. Cat. A: Chem. 2000, 157, 25.
OR
4-6
Calixarene-based catalyst
Maksimov, A. L.; Buchneva, T. S.; Karakhanov, E. A. J. Mol. Cat. A: Chem. 2004, 217, 59.
13
Variation to the Classical Wacker
Oxidation: Biphasic System
O
C7F15
Pd
O
(5 mol%)
C7F15
2
O
t-BuOOH (1.5 equiv)
benzene / C8F17Br, 56 °C
Catalyst can be recycled
O
Ph
Ph
Ph
Ph
73% yield
O
Ph
CO2Et
Ph
CO2Et
59% yield
Betzemeier, B.; Lhermitte, F.; Knochel, P. Tetrahedron Lett. 1998, 39, 6667.
14
Chemoselectivity of Wacker Oxidation:
Steric Hindrance
Pd(OAc)2 (5 mol%)
H3PMo6V6O40 (1 mol%)/O2
No isomerization
NaCl (5 mol%)
EtOH/H2O, 60 °C, 6h
No over oxidation
O
97% yield
Internal alkenes:
Harsh conditions are required
Lower regioselectivities
More side reactions are observed (isomerization and allylic oxidation)
15
Yokota, T.; Sakakura, A.; Tani, M.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2002, 43, 8887.
Chemoselectivity of Wacker Oxidation:
External vs Internal Alkenes
Br
n-Bu
(1equiv)
n-Bu
n-Bu
PdBrL2
H
PdBr2 (PhCN)2 (3 mol%)
DME, 0 °C to r.t., 6h
Br
Br
PdBrL2
Br
1 step
n-Bu
PdBr2 (PhCN)2 (3 mol%)
CuCl (1 equiv), H2O
O2, r.t., 24h
Br
83% yield
n-Bu
O
Br
No isomerization
No over oxidation
70% yield
Thadani, A.N.; Rawal, V. H. Org. Lett. 2002, 4, 4317.
Thadani, A.N.; Rawal, V. H. Org. Lett. 2002, 4, 4321.
16
Chemoselectivity of Wacker Oxidation:
Steric Hindrance
MeO2C
OMe
PdCl2 (40 mol%)
CuCl (1 equiv)
MeO2C
MeO2C
OMe O
OMe O
O2, 3h
33h
O
No over oxidation
OMe
Wacker Oxidation
OMe
71% yield
OMe
O
r.t.
O
50 °C
O
No over oxidation
51% yield
17
Tsuji, J. Synthesis 1984, 369.
Chemoselectivity of Wacker Oxidation:
Compatibility with Functional Groups
CHO
PdCl2 (10 mol %)
Cu(OAc)2 (20 mol%)
O
CHO
isomeric carbonyl
compounds
+
AcNMe2/H2O (7:1)
O2, r.t., 30h
62% yield
3-10% yield
Smith III, A. B.; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998, 39, 8765.
OH
O
Tol
OH
OH
PdCl2 (20 mol%)
F
CuCl2 (1 equiv)
O2, DME, r.t., overnight
S
O
Tol
O
OH
Tol
S
O
S
F
F
O
O
80% yield
18
Bravo, P. et al. J. Org. Chem. 2001, 66, 8336.
Chemoselectivity of Wacker Oxidation:
Compatibility with Functional Groups
O
Ph
PdCl2 (10 mol %)
CuCl2 (1 equiv)
O
O
O
OMe
O
Ph
O
O
DMF/H2O (1:1)
O2, r.t., 5h
O
O
OMe
45% yield
Wood, A. J.; Holt, D. J.; Dominguez, M.-C.; Jenkins, P. R. J. Org. Chem. 1998, 63, 8522.
O
O
PdCl2 (10 mol %)
CuCl2 (1 equiv)
PhFN
CO2Bn
DMF/H2O (6:1)
O2, r.t., 24h
PhF =
PhFN
O
CO2Bn
80% yield
Jeannote, G.; Lubell, W. D. J. Org. Chem. 2004, 69, 4656.
19
Wacker-Type External Oxo-Nucleophiles
Addition
O
O
PdCl2/CuCl2
MeOH and EtOH
can also be used
Ethylene glycol
90% yield
Loyd, W. G.; Luberoff, B. J. J. Org. Chem. 1969, 34, 3949.
OAc
Pd(OAc)2
+
AcOH, r.t.
OAc
85% yield
10% yield
Kitching, W.; Rappoport, Z.; Winstein, S.; Young, W. G. J. Am. Chem. Soc. 1966, 88, 2054.
20
Wacker-Type Amino Cyclisation
(Oxidative Amination)
PdCl
PdCl2 (10 mol%)
H
N
H
N
CuCl2 (3 equiv), CO
MeOH, r.t., 24h
O
H
N
N
O
CO
79% yield
N
O
N
O
CO2Me
Bn
H
N
N
Bn
O
N
97% yield
N
O
CO2Me
H
N
88% yield
O
O
N
O
O
21
Harayama, H.; Abe, A.; Sakado, T.; Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1997, 62, 2113.
Wacker-Type Amino Cyclisation
(Oxidative Amination)
NHR
NR
Pd(OAc)2 (5 mol%)
Pyridine (10 mol%)
O2, toluene, 80 °C
time (h)
Substrate
PG
N
NHPG
PG = Ts
yield (%)
Product
Ns
2
8
Cbz
48
NHTs
1.5
87
87
Ts
N
NHTs
2
81 (7:3)
Ts
N
94 (1:1)
2
NHTs
76
Ts
N
Ts
N
Ts
N
91
Ts
N
NHTs
16
60
22
Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chen. Int. Ed. 2002, 41, 164.
Proposed Catalytic Cycle for Copper Free
Wacker-Type Reaction
H2O2
[(pyr)2Pd(II)(OAc)2]
2 AcOH
(pyr)2Pd(II)
O
Catalytic cycle
Wacker oxidation
O
[(pyr)2Pd(0)]
Pyridine favours the reoxidation
O2
[(pyr)m(Pd(0))n]
Catalyst inactivation
Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chen. Int. Ed. 2002, 41, 164.
23
Wacker-Type External Amino-Nucleophile
Addition
Alkene
(6 equiv)
+
Alkene
Pd(OAc)2 (10 mol%)
Amide
PhCn, 60 °C, O2, 24h
Amide
Product
Enamine or imine
yield*
NPhth
90
(6:1)
PhthNH
PhthNH
NPhth
80
(16:1)
O
PhthNH =
NPhth
NH
O
92
PhthNH
NTs
63
TsNH2
NPhth
PhthNH
* Isomeric ratio in parentheses
56
24
Brice, J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi, N. R. Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868.
Asymmetric Wacker-Type Cyclization
OAc
Pd
2
(10 mol%)
Cu(OAc)2/ O2
MeOH
OH
O
O
major
Cu(OAc)2/ O2
77% yield, 13:87 ratio, 18% ee
t-BuOOH
52% yield, 18:82 ratio, 17% ee
Product
HO
yield (%)
ratio
ee (%)
44
17:83
26
Me-
76
17:83
21
H-
77
13:87
18
Cl-
72
10:90
6
-CO2Me
74
4:96
1
MeO
Me
H
+
H
H
H
O
Pd
Hosokawa,T.;Okuda, C.; Murahashi, S.-I. J. Org. Chem. 1985, 50, 1282.
Hosokawa,T.;Uno, T.; Inui,S.; Murahashi, S.-I. J. Am. Chem. Soc. 1981, 103, 2318.
25
Asymmetric Wacker-Type Cyclization
O
N
N
(10 mol%)
O
X
X
Pd(OCOCF3)2 (10 mol%)
Benzoquinone (4 equiv)
MeOH, 60 °C, 24h
OH
Substrate
O
Up to 96% ee
Pd source
yield (%)
ee (%)
H
Pd(OAc)2
44
54
H
Pd(Cl)2(MeCN)2
0
0
H
Pd(OCOCF3)2
75
96
4-Me
Pd(OCOCF3)2
86
94
4-F
Pd(OCOCF3)2
82
92
4-Ph
Pd(OCOCF3)2
62
90
6-Me
Pd(OCOCF3)2
71
94
Uozumi,Y.; Kato, K.; Hayashi, T. J. Am. Chem Soc. 1997, 119, 5063.
Uozumi,Y.; Kyota, H.; Kato, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 1999, 64, 1620.
Uozumi,Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071.
26
Catalytic Asymmetric Wacker-Type Cyclization:
Limited to Tetrasubstituted Alkenes
O
N
O
OH
N
(4 mol%)
Pd(MeCN)2(BF4)2 (2 mol%)
Benzoquinone (4 equiv)
MeOH, 60 °C, 5h
O
85% yield, 95% ee
OH
O
90% yield, 9% ee
Uozumi,Y.; Kato, K.; Hayashi, T. J. Am. Chem Soc. 1997, 119, 5063.
Uozumi,Y.; Kyota, H.; Kato, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 1999, 64, 1620.
Uozumi,Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071.
27
Catalytic Asymmetric Wacker-Type Cyclization:
Limited to Trisubstituted Alkenes
CO2Me
O
N
O
MeO2C
OH
OH
N
(15 mol%)
Pd(MeCN)2(BF4)2 (5 mol%)
Benzoquinone (4 equiv)
MeOH, 20 °C, 12h
O
80% yield, 96% ee
O
30% yield, 4% ee
Uozumi,Y.; Kato, K.; Hayashi, T. J. Am. Chem Soc. 1997, 119, 5063.
Uozumi,Y.; Kyota, H.; Kato, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 1999, 64, 1620.
Uozumi,Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071.
28
Catalytic Asymmetric Wacker-Type Cyclization:
6-Membereds Rings
O
N
Bn
OH
O
N
Bn
(25 mol%)
Pd(OCOCF3)2 (25 mol%)
Benzoquinone (4 equiv)
MeOH, 60 °C, 24h
O
61% yield, 97% ee
Uozumi,Y.; Kato, K.; Hayashi, T. J. Am. Chem Soc. 1997, 119, 5063.
Uozumi,Y.; Kyota, H.; Kato, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 1999, 64, 1620.
Uozumi,Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071.
29
Stereochemistry of the Oxypalladation Step
HO
Pd(II)
Pd(II)
anti-addition
H
syn-addition
D
O
H
D
H
D
Wacker type-cyclization
+
Pd
Pd
OH
O
O
syn-addition intermediate
anti-addition intermediate
-hydride
(syn-process)
D
H
O
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.
O
30
Stereochemistry of the Oxypalladation Step
D
OH
Pd(MeCN)2(BF4)2 (5 mol%)
O
(S,S)-ip-boxax (10 mol%)
A+B+C+D
Benzoquinone (4 equiv)
MeOH, 40 °C, 4h
16 : 46 : 29 : 9
H
D
-D elimination
Pd
Pd-D addition
D
Pd H
O
D
A (16%)
cis-intermediate
H
Pd
H
Pd D
O
O
O
78% yield
H
N
N
-H elimination
H
isomerization
D
Pd-H addition
O
O
O
Pd H
H
D
O
B (46%)
Pd
Pd H
D
-H elimination
D
O
O
D
Pd-H addition
O
D (9%)
D
O
Thermodynamic product
C (29%)
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.
31
Stereochemistry of the Oxypalladation Step
D
Pd(MeCN)2(BF4)2 (5 mol%)
OH
(S,S)-ip-boxax (10 mol%)
A+B+C+D
Benzoquinone (4 equiv)
MeOH, 40 °C, 4h
16 : 46 : 29 : 9
78% yield
Syn-oxypalladdation
Syn-oxypalladdation products
H
H
O
B (46%)
A (16%)
O
O
O
D
D
D
C (29%)
D (9%)
Anti-oxypalladdation products
D
O
O
D
D
D
O
O
32
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.
Stereochemistry of the Oxypalladation Step
D
Pd(Cl)2(MeCN)2 (10 mol%)
Na2CO3 (2 equiv), LiCl (2 equiv)
A+B+C+D
Benzoquinone (1 equiv)
THF, reflux, 24h
6 : 5 : 7 : 82
OH
59% yield
Anti-oxypalladdation favorized
Syn-oxypalladdation products
H
H
O
B (5%)
A (6%)
O
O
O
D
D
D
C (7%)
Anti-oxypalladdation products
D
O
O
D
D
D
O
O
D
O
D (82%)
Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036.
Desymmetrization by Wacker-Type Cyclization
H
H
i-Pr
i-Pr
O
N
N
O
i-Pr
i-Pr
i-Pr-SPRIX
Bis(isoxazoline)
R
Pd(OCOCF3)2 (15 mol%)
R
i-Pr-SPRIX (18 mol%)
R
Benzoquinone (4 equiv)
CH2Cl2, r.t., 15-21h
OH
*
*
O
OH
OH
Markovnikov product
R
Me
yield (%)
ee (%)
70
70
Et
86
70
Bn
81
63
*
OH
O
not observed
6-endo specific reaction
tertiary carbocation more stable
34
Arai, M., A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907.
Desymmetrization by Wacker-Type Cyclization
Isomerisation
Pd(OCOCF3)2 (10-20 mol%)
i-Pr-SPRIX (12-24 mol%)
H
Benzoquinone (4 equiv)
0 °C, 24-85h
OH
+
*
O
OBn
OBn
A
+
*
O
OBn
B
-hydride
elimination
product ratio (ee (%))
Solvent
yield (%)
A
B
C
CH2Cl2
96
5 (45)
27 (60)
68 (95)
MeOH
95
6 (26)
12 (31)
83 (68)
THF
22
77 (11)
3 (22)
20 (88)
Toluene
16
74 (31)
9 (45)
17 (85)
CH2Cl2/MeOH (10/1)
92
2 (29)
15 (52)
83 (89)
CH2Cl2/MeOH (1/1)
99
3 (36)
8 (57)
89 (82)
O
C BnO
Pd
O
intermediate
Arai, M., A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907.
35
Anti-Markovnikov Wacker Oxidation
O
Normal
Abnormal
R
R
H
R
O
Markovnikov
Anti-Markovnikov
Anticipated product
Few examples
Nu
H2O
X

R
Pd(II)


R
(II)
Pd

Nu
Steric strain
Pd(II)
R 

Nu
Reversed polarity
Stability of carbocation
>
>
36
Anti-Markovnikov Products: Steric Effect
NHTs
R1
Ts
N
Pd(OAc)2 (5 mol%)
NaOAc (2 equiv)
R2
DMSO, O2
40-100 °C, 18-72h
n
R3
Substrate
Ts
N
R1
Product
R1
yield (%)
regioselectivity
44
Anti-Markovnikov
40
Anti-Markovnikov
86
Anti-Markovnikov
62
Markovnikov
62
Anti-Markovnikov
R2
R3
Ts
N
NHTs
Ts
N
NHTs
Ts
N
NHTs
Ts
N
NHTs
Ph
NHTs
R2
R3 +
Ph
Ts
N
37
Larock, R. C.; Hightower, T. R.; Hasvold, L., A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584.
Anti-Markovnikov Products:
Proximal Complexing Function
Pd(II)
R
GP
R

GP
O
R
Markovnikov product favoured

R
O
Pd(II)

Mixture of Markovnikov and anti-Markovnikov
(most of the time)

Typical example:
OBn
OBn
O
H
PdCl2, CuCl, O2
DMF/H2O (7:1), r.t.
+
OBn
O
75% yield, 1:1 ratio
38
Kang, S.-K.; Jung, K.-Y.; Chung, J.-U.; Namkoong, E.-Y.; Kim, T.-H. J. Org. Chem, 1995, 60, 4678.
Anti-Markonikov Products: Proximal
Complexing Function
PdCl2 (10 mol%)
CuCl (1 equiv)
Substrate
Substratre
Product
OH
OH
yield (%)
regioselectivity
O
MPMO
MPMO
Product
DMF/H2O (7:1), r.t., O2
90
Markovnikov
H
93
Anti- Markovnikov
H
83
Anti- Markovnikov
H
95
Anti- Markovnikov
OH
OH
O
O
MPMO
MPMO
O
O
O
O
O
MPMO
MPMO
O
O
O
OH
O
MPMO
MPMO
O
O
O
Kang, S.-K.; Jung, K.-Y.; Chung, J.-U.; Namkoong, E.-Y.; Kim, T.-H. J. Org. Chem, 1995, 60, 4678.
39
Anti-Markovnikov Products:
Proximal Complexing Function
EtO
OEt
EtO
OEt
PdCl2 (10 mol%)
CuCl (50 mol%)
Cbz
N
H
Cbz
N
Cbz
DMF/H2O (4:1)
O2, r.t., 6h
N
O
N
H
Cbz
H
76% yield
Anti-Markovnikov
40
Stragies, R.; Blechert, S. J. Am. Chem. Soc. 2000, 122, 9584.
Anti-Markovnikov Products:
Proximal Double Bond
PdCl2 (50 mol%)
CuCl (1 equiv)
Me
Me
DMF/H2O, O2, 24h, r.t.
O
H
anti-Markovnivov
99% yield
Proposed mechanism:
Me
Me
Me
O
O
HO
Pd(II)
H2O
Pd(II)
Pd(II)
Non classical carbocation
41
Ho, T.-L.; Chang, M.H.; Chen, C. Tetrahedron Lett. 2003, 44, 6955.
Anti-Markovnikov Oxidative Amination
O
O
N
PdCl2(MeCN)2 (5 mol%)
+ HN
O
R
(6 equiv)
CuCl2 (5 mol%), O2
DME, 60 °C, 24h
O
R
(1 equiv)
Anti-Markovnikov
R
yield (%)
H
77
CF3
40
Cl
36
F
89
(8% Markovnikov hydroamination)
Me
56
(11%Markovnikov hydroamination)
OMe
81
No explanation for the regioselectivity
Addition of base reverses the selectivity
O
N
PdCl2(MeCN)2 (5 mol%)
CuCl2 (5 mol%), O2
DME, 60 °C, 24h
Et3N or [Bu4N]OAc (10 mol%)
O
Many examples
(6 olefins and 5 amides)
R
Markovnikov
Vitaliy I. Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 12996.
42
Anti-Markovnikov Products:
Cationic Rhodium Complex
R1
R1
H
N
[Rh(cod)2]BF4/2 PPh3 (2.5 mol%)
R2
+
N
R2
20h, reflux in THF
(1 equiv)
+
(4 equiv)
Ar
Ar
Amine
Et
n-Bu
H
N
H
N
yield (%)
[Rh]
Et
n-Bu
40
48
Ar
Catalytic cycle
H
N
55
[Rh]
[Rh]H2
Ar
H
N
45
Ph
H
N
Ar
HNR2
Ar
9
NR2
H[Rh]
NR2
Beller, M.; Eichberger, M.; Trauthwein, H. Angew. Chem. Int. Ed. Engl. 1997, 36, 2225.
43
Formation of Allylic Acetates under
Wacker Oxidation Conditions
Formation of vinylic acetates
(Side reaction of the Wacker Process)
Pd(II), [O]
R
AcOH, 
OAC
R
Formation of allylic acetates
linear (E)-allylic acetate
R
OAc
Not favoured with
terminal alkenes
R
branched allylic acetate
R
OAc
44
Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346.
Formation of Allylic Acetates in Wacker
Conditions: Effect of Solvent
C-H oxidation products:
Heptyl
Pd(OAc)2 (10 mol%)
OAc Heptyl
Heptyl
Benzoquinone (2 equiv)
40 °C
OAc
A
Classical Wacker oxidation products:
Solvent
A
yield (%)*
B
C
AcOH
3
5
17
14
AcOH:DMSO (1:1)
40
2
3
6
AcOH:CH2Cl2 (1:1)
+
bis-sulfoxide ligand (10 mol%)
8
66
<1
<1
* yield are determined by GC.
B
D
OAc
O
Heptyl
Heptyl
D
C
O
Ph
O
S
S
Ph
Pd
AcO
OAc
bis-sulfoxide palladium
acetate complex
45
Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346 (see supporting info).
Formation of Branched Allylic Acetates
O
O
Ph
O
S
S
Ph
S
Ph
active ligand
OAc
(10 mol%)
Oct
Pd(OAc)2 (10 mol%)
AcOH (52 equiv)
+
Oct
Oct
OAc
major
Benzoquinone (2 equiv)
73% yield, ratio 11:1
dioxane, 43 °C
R
DHQ
SulfoxidePd(OAc)2
AcOH + Sulfoxide
2 AcOH + Sulfoxide
Sulfoxide
Favour -allylic formation
R
Pd(0)Benzoquinone
Pd(OAc)
Benzoquinone
Favour internal addition
Benzoquinone
R
OAc
R
Pd(OAc)Benzoquinone
Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970.
46
Formation of Branched Allylic Acetates
O
O
Ph
R
O
S
R'
(10 mol%)
Pd(OAc)2 (10 mol%)
R'CO2H (1.5-4 equiv)
Benzoquinone (2 equiv)
dioxane, air, 72h, 43 °C
Product
R
major
yield (%)
branched:linear
72
16:1
56
>20:1
64
32:1
OAc
TBDPSO
OAc
TBDPSO
OBz
hept
47
Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970.
Formation of Linear Allylic Acetates
OAc
Pd(OAc)2 (10 mol%)
R
+
R
Benzoquinone (2 equiv)
DMSO / AcOH (1:1)
40 °C, MS 4A, air
Major product
O
OAc
R
major
linear:branched*
E:Z*
yield (%)
>99:1
>20:1
50
>20:1
13:1
54
23:1
12:1
62
>99:1
13:1
65
13:1
12:1
64
O
OAc
O
EtO
OAc
O
(Et)2N
OAc
OAc
H
N
O
OAc
O
* ratios can be increased by chromatography.
Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346 (see supporting info).
48
Application to the Total Synthesis of
Garsubellin A
O
O
O
O
18 steps
O
O
Na2PdCl4 (40 mol%)
t-BuOOH, AcOH-H2O
O
O
O
O
O
2 steps
O
O
O
HO
HO
69% yield
Usuda, H.; Kanai, M.; Shibasaki, M. Org. Lett. 2002, 4, 859.
49
Application to the Total Synthesis of
Calyculin A and B
H2PO4
O
OH
O
Br
OH
OH
OMe
N
OH
O
O
MeO
N
O
OH
O
N
H
NC
PdCl2 (10 mol %)
Cu(OAc)2 (20 mol%)
O
O
AcNMe2/H2O (7:1)
O2, r.t.,30h
O
O
Classical conditions:
lead to acetonide hydrolysis
Smith III, A. B.; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998, 39, 8765.
O
86% yield
No epimerization
Application to Total Synthesis
H
14 steps
H3C
N
CH3
H
H
OTIPS
N
Na2PdCl4 (40 mol%)
t-BuOOH (1.5 equiv)
NaOAc (1 equiv)
H
H3C
AcOH / dioxane / H2O
80 °C
H
N
CH3
H
O
N
H
H
O
O
(-)-alstonerine
60% yield
Liao, X.; Zhou, H.; Wearing, X. Z.; Ma, J.; Cook, J. M. Org. Lett. 2005, 7, 3501.
Tandem Wacker / Heck
OH
Ph
O
O
O
Ph
PdCl2 (15 mol%)
Benzoquinone
MeOH, HC(OMe)3
MeO
O
OH
O
O
25 steps
MeO
O
OH
O
H
N
OMe
O
THF / DMF (20:1)
O
O
O
mycalamide A
5.7 : 1 dr
78% yield
Sohn, J.-H.; Waizumi, N.; Zhong, H. M.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 7290.
51
Conclusion
2 types of conditions:
- High Cl- concentration
- Low Cl- concentration
Wacker Oxidation is well studied:
- Many kinetic studies
- Many sets of conditions available
- Much data on chemo- and regioselectivity
Asymmetric Wacker-type cyclizations are limited
52
53
Anti-Markovnikov Products:
Cationic Rhodium Complex
H
N
+
(1 equiv)
R1
[Rh(cod)2]BF4/2 PPh3 (2.5 mol%)
Ar
20h, reflux in THF
Ar
N
R2
+
Ar
(4 equiv)
Ar
yield (%)
Ph
55
4-Me-Ph
75
4-MeO-Ph
55
2-naphtyl
99
4-F-Ph
18
4-CF3-Ph
O
14
No good explanation for the anti-Markovnikov specificity
Hydroamination is the major side reaction:
- increases with time (non cationic species)
- increases with the polarity of solvent
- is ligand and counter ion dependent
18
NH2
54
Beller, M.; Eichberger, M.; Trauthwein, H. Angew. Chem. Int. Ed. Engl. 1997, 36, 2225.
Beller, M.; Trauthwein, H.; Eichberger, M.; Breindl, C.; Müller, T. E. Eur. J. Inorg. Chem. 1999, 1121.
Anti-Markonikov Products:
Proximal Complexing Function
55
Kang, S.-K.; Jung, K.-Y.; Chung, J.-U.; Namkoong, E.-Y.; Kim, T.-H. J. Org. Chem, 1995, 60, 4678.
To the Frontier of Wacker-Type Reactions:
Wacker-Type Heteroannulation Process
CO2Me
CO2Me
OBn
+
N
O
Me
I
O
PdCl2(PPh3)2 (4 mol%)
(reduce with BuLi)
CO2Me
MeCN, 60 °C
N
CO2Me
O
67% yield
OBn
Ar
Ar
I- N +
Me
OBn
Ar
- Pd(0)
I
N
Ar-I
O
OBn Pd
Pd
Oxidative
addition
I
Pd
Reductive elimination
Ar
OBn
Ar
Pd
Ar
Wacker-Type
Me
(0)
O
Ar
Ar
Process
N
Me
O
I- N +
Me
O
Bossharth, E.; Desbordes, P.; Monteiro, N.; Balm, G. Org. Lett. 2003, 5, 2441.
56