Transcript Slide 1

“The Use of Ferrocenyl Ligands
in Asymmetric Catalytic
Hydrogenation”
Beth Moscato-Goodpaster
April 12, 2007
1
Utility of Ferrocenyl Ligands
Asymmetric Negishi Couplings:
Pd (II)
R'
Zn
R
R
Ph 2P
Me2 N
H
R'
Br
R'
95% yield
85% ee
Fe
Aza-Claisen Rearrangements:
Ph
N
Ph
MeO
CF3
N
R
O
N
Ts
Pd Cl
R
R
R = H, Me
Fe
MeO
CF3
R
R
R
R
N
*
O
99% yield
99.7% ee
AgTFA; proton sponge
Weiss, M; et al. Angew. Chem. Int. Ed. 2006, 45, 5694. Genov, M.; et al.
Tetrahedron: Asymmetry 2006, 17, 2593
2
Utility of Ferrocenyl Ligands
Cu-Catalyzed Conjugate Additions:
PCy 2
Fe
O
R''
MgBr +
R
PPh 2
R''
R'
O
R
R'
CuBr*SMe2
91% yield
98% ee
>94:6 regio.
Rhodium-Catalyzed Ring Openings:
H
Me2N
N
HNR2
+
Ph2 P
Boc
Fe
PPh 2
R'
R'
NMe2
H
Rh
R'
R 2N
R'
98% yield
>99% ee.
HN
Boc
Lopez, F.; et al. JACS 2004, 126, 12784-12785. Cho, Y.-h.; et al. JACS 2006, 128, 3
6837. Harutyunyan, S. R.; et al. JACS 2006, 128, 9103.
Asymmetric Hydrogenation
R''
M / L*
R'
H2
Y
R
“…hydrogenation is arguably the
most important catalytic method in
synthetic organic chemistry….”
“Of the <20 full-scale chemocatalyzed [asymmetric] reactions
known to be running [in industry]
currently, more than half are used
for reducing various
functionalities….”
H
*Y
R
H
R''
R'
Ph2 P
P
P
N
Boc
(R,R)-Me DuPhos
PPh 2
(2S,4S)-BPPM
PCy 2
PPh2
PPh2
(R)-BINAP
Blaser, H.; et al. Adv. Synth. Catal. 2003, 345, 103-151.
Federsel, H. Nat. Rev. Drug Discovery 2005, 4, 685-697.
Fe
PPh 2
Josiphos
4
General Scope of Hydrogenation
R
R'
COOH
AcHN
R
NHAc
R
R'
OAc
R''
COOH
R'
R
R'
R
R''
R'
R'''
COOH
COOH
O
Olefins
O
R
N
X
R
Ketones and Imines
O
R'
O
O
R
R''
R'
OR''
R'
R
5
Blaser, H.; et al. Adv. Synth. Catal. 2003, 345, 103-151.
Outline
• Features of Ferrocenyl Ligands
– why ferrocenes?
– reactivity and synthesis
– modularity
• Applications of Ferrocenyl Ligands to
Specific Substrates in Asymmetric
Hydrogenation
• Conclusions
6
Why Ferrocenes?
P
R
R
NHAc Ar
NHAc
N
R
R
Rh / (R,R)-binaphane
+
Ar
P
Ar
1.3 atm H 2
Ar
100% yield
NHAc 99% ee
M / (R,R)-binaphane
NR
H2
M = Ru, Ir
Xiao, D.; Zhang, X. Angew. Chem. Int. Ed. 2001, 40, 3425-3428.
Xiao, D; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679-1681.
7
Why Ferrocenes?
P
P
(R,R)-binaphane
P
Fe
P
•low rotation barrier of
ferrocenyl backbone offers
flexibility, facilitating binding
of sterically demanding
imines.
• electron donating ability
and large P-M-P bite angle
increases electron backdonating ability from Ir to
an imine substrate.
(R,R)-f-binaphane
Xiao, D.; Zhang, X. Angew. Chem. Int. Ed. 2001, 40, 3425-3428.
Vargas, S.; et al. Tetrahedron Let. 2005, 46, 2049.
8
Why Ferrocenes?
MeO
MeO
N
HN
Ir / (R,R)-f-binaphane
68 atm H 2
Ar
NH 2
CAN
MeOH, H 2O
Ar
Ar
72-75% yield
96-98% ee
(R,R)-f-binaphane
has unprecedented
enantioselectivity!
P
Fe
P
(R,R)-f-binaphane
Xiao, D.; Zhang, X. Angew. Chem. Int. Ed. 2001, 40, 3425-3428.
Vargas, S.; et al. Tetrahedron Let. 2005, 46, 2049.
9
Synthesis of Chiral Ferrocenes:
Lithiation
Fe
NMe2
n-BuLi
Me
Fe
H
Me
NMe2
H
Li
+
(R,R) - 96%
Li
Fe
NMe2
H
Me
(R,S) - 4%
Stereoselective lithiation results in the synthesis of a single
diastereomer.
Me
NMe2
Fe
H
Li
Me
NMe2
n-BuLi
TMBDA
Fe
H
Li
Me
NMe2
ClPPh2
Li
Fe
H
PPh 2
PPh2
NMe2
Me
2
H
1
PPh2
ClPPh2
Me
NMe2
Fe
H
PPh 2
10
Marquarding, D.; et al. JACS 1970, 92, 5389-5393.
SN1 Retention of Stereochemistry
Fe
Me
NMe2
H
PPh2
Ac 2O
Fe
Ac
Me
NMe2
H
PPh2
Me
H
- NMe2 Ac
Fe
PPh2
Subsequent attack
of nucleophile
occurs from exo
side and proceeds
with retention of
stereochemistry.
Iron center donates
electron density to
the carbocation,
stabilizing and
preventing
racemization.
Nu:Fe
Me
Nu
H
PPh2
11
Hayashi, T.; et al. Tetrahedron Let. 1974, 15, 4405.
Synthesis of BPPFA Derivatives
Me
NMe2
Fe
1.) Ac 2O
2.)
MeHN
Fe
PPh2
BPPFA
NR 2
Me
Me N
H
PPh2
useful for asymmetric
hydrogenation of
dehydroamino acids
1.) Ac 2O
2.) n-BuLi
3.) H 2O
NR2
H
PPh2
PPh2
used for rhodium-catalyzed
hydrogenation of
tetrasubstituted acrylic
acids
Fe
Me
OH
H
PPh2
BPPFOH
PPh2
used for rhodium-catalyzed
hydrogenation of prochiral
carbonyl compounds
Hayashi, T.; Kawamura, N.; Ito, Y. JACS 1987 109, 7876. Hayashi, T;
Kawamura, N; Ito, Y. Tetrahedron Let. 1988, 29, 5969-5972 Hayashi, T.; et al.
Tetrahedron Let. 1976, 17, 1133-1134
12
Modular Synthesis: Josiphos
Fe
NMe 21.) n-BuLi
H
2.) Ph2 PCl
PPh2
NMe 2 HPCy
2
H
AcOH
Fe
Fe
PPh 2
PCy2
H
Sequential addition of phosphines allows rapid synthesis of a large ligand
library with varying steric and electronic properties!
Fe
Fe
Fe
P(tBu) 2
PCy 2
H
PPh2
PCy 2
H
PCy2
PCy 2
H
Fe
Fe
Fe
P(tBu)2
PPh2
H
PPh 2
PPh2
H
PCy2
PPh2
H
Fe
Fe
Fe
P(tBu) 2
P(xyl)2
H
PPh 2
P(xyl)2
H
PCy2
P(xyl)2
H
13
Togni, A.; et al. JACS 1994, 116, 4062-4066.
Modular Electronic Effects
OH
O
1.) Rh / L*
BH
+
2.) H2 O2 , NaOH
O
Electronic properties of ligand strongly influence
enantioselectivity!
CF3
MeO
Best results are obtained
with:
N
N
P
P
N
N
F
C
P
N
σ-donating,
electron-rich
pyrazole
nitrogen
3
2
2
2
and strongly π-accepting phosphorous.
N
Fe
Fe
Fe
The resulting “electronic asymmetry” at the metal center
90% ee enhances enantioselectivity.
95% ee
98.5% ee
F3C
MeO
F3C
N
2P
F3 C
N
N
N
CF3
2P
N
CF3
2P
N
Fe
Fe
Fe
5% ee
33% ee
40% ee
Schnyder, A.; Hintermann, L.; Togni, A. Angew. Chem. Int. Ed. 1995, 34, 931-933
14
Outline
• Features of Ferrocenyl Ligands
• Applications of Ferrocenyl Ligands to
Specific Substrates in Asymmetric
Hydrogenation
– hydrogenation of unprotected enamines
– hydrogenation of 2- and 3-substituted indoles
– hydrogenation of vinyl boronates
– hydrogenation of (S)-Metolachlor
• Conclusions
15
Synthesis of Unprotected β-Amino
Acids: Catalyst Screening
M/L
NH 2 O
Ph
OMe
NH2 O
6 atm H2 , 50 C, 18 hrs
2,2,2-trifluoroethanol
Ph
OMe
Ligand
Yield
ee
(S,S)-Me-DuPHOS / Rh
71%
9% (S)
(S)-BINAPHANE / Rh
11%
11% (R)
(S)-f-BINAPHANE / Rh
77%
10% (S)
(R,R)-EtFerroTANE / Rh
77%
88% (R)
(R)-(S)-1 / Rh
94%
96% (S)
P(tBu) 2
Fe
Hsiao, Y.; et al. JACS 2004, 126, 9918-9919.
1
P
CF3 2
16
Synthesis of Unprotected β-Amino
Acids
P(tBu) 2
Rh /
Fe
P
CF3 2
NH 2 O
Ar
OMe
7.5 atm H 2, 50 C, 6-24 hrs
2,2,2-trifluoroethanol
OMe
85-98% yield
93-96% ee
NHPh
74-94.0% yield
96-97% ee
NH2 O
Ar
P(tBu) 2
Rh /
Fe
PPh2
NH 2 O
NH2 O
Ar
NHPh
7.5 atm H2 , 50 C, 8 hrs
MeOH
Ar
17
Hsiao, Y.; et al. JACS 2004, 126, 9918-9919.
Product Inhibition
NH 2 O
Me
NH2 O
1:1 Rh : L
NHPh
32 atm H2
Me
NHPh
NH 2 O
Results are consistent
with
either
NH2 aO first1:1
Rh
:
L
Me
NHPh
order dependence
[substrate]
OR
NH 2 O
32on
atm H
Me
NHPh
2
+ 32 mol %
Me product
NHPh inhibition.
Results are consistent with product inhibition!
P(tBu) 2
Fe
P
18
Hansen, K. B.; et al. Org. Lett. 2005, 7, 4935.
CF3 2
Product Inhibition
2 eq Boc2O
1:1 Rh / L
NH 2 O
+
Me
NHPh
32 atm H2
Boc
NH
O
Me
NHPh
P(tBu) 2
Fe
P
CF3 2
Addition of Boc2O selectively protects the free
amine, preventing product inhibition and accelerating
the overall reaction.
Hansen, K. B.; et al. Org. Lett. 2005, 7, 4935.
19
Synthesis of β-Amino Acid
Pharmacophore
F
F
COOH
1.) 1,1'-carbonyldiimidazole,
CH 3CN
2.) methyl potassium malonate,
Et3 N, MgCl2
F
F
O
F
F
F
F
Boc2 O
COOMe
+
NH 2
F
F
NH 4OAc
MeOH, reflux
COOMe
0.6 mol % Rh / L*
7 atm H 2, MeOH
COOMe
HN
F
Boc
F
75% yield
>97% ee
Me
Fe
Kubryk, M.; Hansen, K. Tetrahedron: Asymmetry 2006, 17, 205-209.
P(t-Bu) 2
PPh2
20
Hydrogenation of Indoles
Bu
N
Ac
Ph2 P
N
Boc
PPh 2
(2S,4S)-BPPM
PPh2
PPh2
(R)-BINAP
PPh2
1 mol % Rh(acac)(cod) / L*
Bu
N
Ac
50 atm H2 , iPrOH, 60 C, 2 hrs
Ligand
Yield
ee
(R)-BINAP
100%
1% (S)
(2S,3S)-Chiraphos
100%
1% (S)
(R)-(S) BPPFA
100%
0%
(-)-(2R,3R)-DIOP
100%
0%
(R,R)-Me-DuPhos
100%
0%
(2S,4S)-BPPM
100%
0%
(S,S)-(R,R)-PhTRAP
77%
85% (R)
PPh2
PPh2
O
O
H
(2R,3R)-DIOP
Me2 N
Me
Fe
PPh 2
PPh2
(R)-(S)-BPPFA
PPh 2
PPh 2
H
PPh 2
(2S,3S)-Chiraphos
(S,S)-(R,R)-PhTRAP
21
Kuwano, R.; et al. Tetrahedron: Asymmetry. 2006, 17, 521-535.
Hydrogenation of 2-Substituted
Indoles
Hydrogenation of 2-substituted indoles proceeds smoothly ...
R
N
Ac
1:1 Rh : L
10 mol % Cs2 CO3
50 atm H2 , 60 C, 1-2 hrs
R
N
Ac
83-98% yield
87-95% ee
... but hydrogenation of 3-substituted indoles mostly results in
hydrolysis of the protected carbamide.
Me
Me
Me
1:1 Rh : L
10 mol % Cs 2 CO3
PPh2
N
Ac
100 atm H 2, 60 C, 2 hrs
H
N
Ac
37% yield
86% ee
N
H
55% yield
H
PPh 2
(S,S)-(R,R)-PhTRAP
Kuwano, R.; et al. JACS 2000, 122, 7614-7615.
22
Hydrogenation of 3-Substituted
Indoles
R
R
1:1 Rh : L*
10 mol % Cs2CO3
N
Ts
50 atm H2, 80 C, 24 hrs
71-94% yield
95-98% ee
N
Ts
R
Yield
ee
i-Pr
94%
97%
Ph
93%
96%
CH2CH2OTBS
94%
98%
CH2CH2CO2(t-Bu)
93%
97%
CH2CH2NHBoc
71%
95%
PPh2
H
H
PPh 2
(S,S)-(R,R)-PhTRAP
Kuwano, R.; et al. Org. Lett. 2004, 6, 2213..
23
Hydrogenation of N-Boc Protected
Indoles
(R')
R
N
Boc
1:1 Ru / PhTRAP
10 mol % Cs 2CO3
(R')
R
N
Boc
50 atm H 2, 60 C, 2-48 hrs
R
R
1:1 Ru / PhTRAP
10 mol % Cs2 CO 3
N
Boc
N
Boc
50 atm H 2, 40 C, 24 hrs
85-92% yield
87-94% ee
Me
Me
Me
N
Boc
91-99% yield
87-95% ee
1:1 Ru / PhTRAP
10 mol % NEt3
50 atm H 2, 80 C, 72 hrs
59% yield
72% ee
Me
N
Boc
PPh2
H
H
PPh 2
Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653-2655.
(S,S)-(R,R)-PhTRAP
24
Hydrogenation of Vinyl
Bis(boronates)
Ar
Alk
B(pin)
B(pin)
B(pin)
B(pin)
1:2 Rh : Walphos #1
H 2 O2, NaOH
20 atm H2 , 23 C, 24 hrs,
toluene
THF, 23 C, 3 hrs
1:2 Rh : Walphos #2
H2 O2 , NaOH
20-30 atm H 2, 23 C, 24 hrs, THF, 23 C, 3 hrs
dichloroethane
OH
Ar
OH
60-92% yield
77-93% ee
OH
72-89% yield
85-93% ee
OH
Alk
CF3
F3C
P
2
Fe
PR'2
Walphos #1: R = Ph
#2: R = Cy
25
Morgan, J. B.; Morken, J. P. JACS 2004, 126, 15338-15339.
Hydrogenation of Vinyl
Bis(boronates)
Single Pot Diboronation / Hydrogenation /
Oxidation of Phenylacetylene
Ph
5% (Ph 3P) 2Pt(=)
B2pin2
5:7 Rh : Walphos #1
toluene, 100 C,
48 hrs
20 atm H 2 , 23 C, 24 hrs
toluene
H 2O 2,
NaOH
OH
OH
66% yield
91% ee
Single Pot Hydrogenation / Homologation /
Oxidation of Vinyl Bis(boronate)
Ph
B(pin)
B(pin)
1:2 Rh : Walphos #1
1.) ClCH2 Li, THF
CF3
20 atm H 2 , 23 C, 24 hrs 2.) H 2O 2, NaOH
toluene
F3C
HO
OH
76% yield
92% ee
P
2
PR'2
Fe
26
Morgan, J. B.; Morken, J. P. JACS 2004, 126, 15338-15339.
Walphos #1: R = Ph
#2: R = Cy
Hydrogenation of Vinyl
Bis(boronates)
B(pin)
B(pin)
OH
H 2O 2, NaOH
Rh / Walphos #1
OH
15 atm H2 , 23 C, 24 hrs, THF, 23 C, 3 hrs
toluene
entry
Ligand : Rh
ratio
% yield
% ee
configuration
1
0.8
90
52
R
2
1
83
37
R
3
2
84
93
S
CF3
F3C
P
2
Fe
PR'2
27
Morgan, J. B.; Morken, J. P. JACS 2004, 126, 15338-15339.
Walphos #1: R = Ph
#2: R = Cy
Hydrogenation of Vinyl Boronates
NHBn
81% yield
>95% ee
B(pin)
1
Rh / L* / H2
OH
2
86% yield
95% ee
CF3
1: BCl3, then BnN3; 22 C
2: (i) ClCH2Li, THF, -78 C
(ii) NaOH, H2O2
Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415.
F 3C
P
2
Fe
28 PPh2
Hydrogenation of Vinyl Boronates
B(pin)
R
5:8 Rh : Walphos
35 atm H 2, -35 C
12 hrs
B(pin)
R
Me
>95% conv.
R=
ee (toluene)
ee (DCE)
cyclohex
97
95
n-hex
81
84
TBSOCH2CH2
90
85
PivOCH2CH2
90
86
PivOCH2CH2CH2
92
89
tBuO2CCH2CH2
94
59
PhCH2
88
79
>20:1 dr
>20:1 dr
>20:1 dr
>20:1 dr
CF3
TBSO
TBSO
F 3C
P
2
Fe
Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415.
PPh2
29
Hydrogenation of Vinyl Boronates
5 mol % Rh
8 mol % (R,R)-Walphos
35 atm H2 , -35 C
10 min
O
O
B
OMe
O
TBSO
TBSO
84% conv
<10% conv
32% conv
70% conv
Boronate is activating: sterics alone are not
responsible for high reactivity.
30
Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415.
Hydrogenation of Vinyl Boronates
5 mol % Rh
8 mol % (R,R)-Walphos
35 atm H2 , -35 C
10 min
O
O
B
OMe
O
TBSO
84% conv
TBSO
<10% conv
32% conv
70% conv
Reactivity not due solely to the π-acceptor properties
of boronate: methyl methacrylate exhibits much less
reactivity.
Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415.
31
Hydrogenation of Vinyl Boronates
5 mol % Rh
8 mol % (R,R)-Walphos
35 atm H2 , -35 C
10 min
O
O
B
OMe
O
TBSO
84% conv
TBSO
<10% conv
32% conv
70% conv
Enhanced reactivity not due to inductive donation
from boron to carbon: inductively withdrawing phenyl
ring provides similar levels of reactivity, but no
enantioselectivity.
Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415.
32
(S)-Metolachlor: Dual Magnum
MeO
MeO
O
O
N
CH 2Cl
N
MeO
CH 2Cl
MeO
O
N
CH 2Cl
O
N
MeO
CH 2Cl
O
N
CH 2Cl
• Important grass herbicide used in
corn and other crops.
• Over 10,000 tons / year produced
by Syngenta AG (trademark: Dual
Magnum)
• Hydrogenation is largest
enantioselective catalytic process
used in industry; one of fastest
homogeneous systems known.
Arrayas, R.; Andreo, J.; Carretaro, J. Angew. Chem. Int. Ed. 2006, 45, 7674-7715.
Blaser, H.; et al. Top. Catal. 2002, 19, 3-16.
33
Dorta, R.; et al. Chem. Eur. J. 2004, 10, 4546-4555.
Syngenta website: www.syngenta.com
(S)-Metolachlor: Dual Magnum
MeO
MeO
O
N
CH 2Cl
MeO
O
N
CH 2Cl
MeO
O
N
O
N
CH 2Cl
ACTIVE!
MeO
CH 2Cl
N
CH 2Cl
INACTIVE!
Pt / C
H 2 SO 4
NH 2
1970: Metolachlor discovered
1978: rac-Metolachlor
production started, >10,000
tons/yr produced
O
+
O
OMe
MeO
1982: Metolachlor
stereoisomers synthesized;
(S)-isomer found to be active.
O
NH
Cl
5 atm H 2, 50 C
MeO
CH 2 Cl
O
N
CH 2Cl
34
Blaser, H.; et al. Chimia 1999, 53, 275-280.
(S)-Metolachlor: Requirements for
Industrially Feasible Process
• Enantioselectivity
• Catalyst
productivity
• Catalyst activity
• Catalyst stability
• Availability and
quality of starting
material
• ee > 80%
• S/C > 50,000
• TOF > 10,000 h-1
Spindler, F.; et al. In Catalysis of Organic Reactions; Maltz, R., Jr., Ed. pp153166.
35
(S)-Metolachlor: Enantioselective
Synthesis
MeO
N
MeO
OMe
O
O
N
CH 2 Cl
O
N
CH 2 Cl
R
1.) H2 , chiral cat.
OMe
2.) TsX
product
(1)
product
(2)
or
or
O
CH 2 Cl Rh / L*
OTs
OMe
NH
+
(ClCOCH 2Cl)
R = H or COCH2 Cl
MeO
MeO
Only
possible
approach!
N
M / L*
H2
NH
ClCOCH2 Cl
product
(3)
36
Blaser, H.; et al. Chimia 1999, 53, 275-280.
(S)-Metolachlor: Imine
Hydrogenation
MeO
MeO
[Ir(cod)Cl]2 / L*
TBAI
N
NH
O
25 atm H 2 , 24 hrs
PPh 2
PPh2
O
PPh2 PPh2
(2R,4R)-bdpp
H
H
Ligand
Temp
% conv
TOFavg
ee
diop
25 C
95.5
32 h-1
61% (S)
bdpp
25 C
10.6
4 h-1
31% (S)
-5 C
79
26 h-1
78% (S)
(4S,5S)-diop
Conclusions from Initial Screening:
• Addition of halogen anions increases rate, esp.
with both Cl- and I- in sol’n.
• Catalyst deactivation major problem: rates
dependant on ligand structure, solvent and
temperature.
Spindler, F.; et al. In Catalysis of Organic Reactions; Maltz, R., Jr., Ed. pp153166.
37
(S)-Metolachlor: Imine
Hydrogenation
MeO
MeO
0.1 mol % Ir / L*
TBAI, AcOH
N
NH
25 atm H 2 , 24 hrs
R
R’
% Conv
TOF
ee
Ph
tBu
6
3 h-1
n/a
4-CF3Ph
Cy
80
18 h-1
21%
4-CF2Ph
Ph
100
44 h-1
21%
Ph
3,5-Xyl
100 (2 hrs!)
396 h-1
79%
Conclusions so far:
• Only ferrocenyl diphosphine ligands gave medium to good
ees and catalyst stability.
• Matched chirality necessary.
• Aryl groups at two phosphines necessary for good
performance.
Blaser, H.; et al. J Organomet Chem 2001, 621, 34-38.
PR' 2
PR 2
Fe
38
(S)-Metolachlor: Imine
Hydrogenation
MeO
MeO
N
0.1 mol % Ir / L*
NH
25 atm H 2 , 30 C
TBAI
AcOH
time to 100% conversion
initial rate (mmol / min)
% ee
-
-
10 hr
0.3
71.2
150 mg
-
12 hr
0.3
71.6
-
2 mL
16 hr
0.1
56.2
150 mg
2 mL
0.5 hr
1.5
78.5
In the presence of AcOH and I-, the rate of reaction is
accelerated by a factor of 5, and the time for 100%
conversion is twenty times shorter than without additives!
P(3,5-xyl)2
Fe
PPh2
Blaser, H.; et al. Chimia 1999, 53, 275-280.
Blaser, H.; et al. J Organomet Chem 2001, 621, 34-38.
39
Spindler, F.; et al. In Catalysis of Organic Reactions; Maltz, R., Jr., Ed. pp153-166.
(S)-Metolachlor: Imine
Hydrogenation
MeO
MeO
N
0.001 mol % Ir / L*
TBAI, 10% AcOH
NH
80 atm H2
R’
Time (h)
Conv (%)
TOF (h-1)
ee (%)
4-n-Pr2N-3,5-Xyl
3.5
100
28,000
83
4-Me2N-3,5-Xyl
1
100
100,000
80
3,5-Xyl
0.6
100
167,000
76
4-(N-Pyr)-3,5-Xyl
3
100
33,000
69
While other ligands have slightly higher ees,
Xyliphos’ high activity makes it ideal for industrial
use.
Blaser, H.; Spindler, F. Chimia 1997, 51, 297-299.
Blaser, H.; et al. J. Organomet Chem 2001, 621, 34-38.
Fe
PR' 2
PPh 2
40
(S)-Metolachlor: Imine
Hydrogenation
MeO
MeO
N
Ir / Xyliphos
TBAI, 10% AcOH
NH
80 atm H 2, 50 C
Original Requirements:
• ee > 80%
• S/C > 50,000
• TOF > 10,000 h-1
Final Results:
• ee = 79%
• S/C > 1,000,000
• TOF > 1,800,000 h-1
P(3,5-MePh)2
Blaser, H.; Spindler, F. Chimia 1997, 51, 297-299.
Blaser, H.; et al. J. Organomet Chem 2001, 621, 34-38.
Fe
PPh2
41
(S)-Metolachlor: Production Scale
MeO
MeO
P(3,5-MePh) 2
N
NH
80 atm
H2
Fe
PPh 2
/ Ir
AcOH, TBAI
extraction,
flash distillation,
distillation
S/C = 2,000,000
50 C, 4 hrs
Ir is recycled
Blaser, H.; Spindler, F. Chimia 1997, 51, 297-299.
Blaser, H.; et al. Chimia 1999, 53, 275-280.
42
Conclusions
• Ferrocenes possess unusual properties:
– planar chirality
– stereoretentive SN1 substitution
• Ferrocenyl ligands have been used to
hydrogenate a number of uncommon substrates:
–
–
–
–
N-aryl imines
indoles
unprotected enamines
vinyl boronates
43
Acknowledgements
• Clark Landis and Landis Group Members
• Practice Talk Attendees:
– Brian Hashiguchi
– Avery Watkins
– Katherine Traynor
– Hairong Guan
– Ram Neupane
• Family
• Dow Chemical, for funding
44