1 “the use of ferrocenyl ligands in asymmetric catalytic hydrogenation” beth moscato-goodpaster...
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1
“The Use of Ferrocenyl Ligands in Asymmetric Catalytic
Hydrogenation”Beth Moscato-Goodpaster
April 12, 2007
2
Utility of Ferrocenyl Ligands
Weiss, M; et al. Angew. Chem. Int. Ed. 2006, 45, 5694. Genov, M.; et al. Tetrahedron: Asymmetry 2006, 17, 2593
Fe
Me2NH
Ph2PR
R'
Br
RZn
R'95% yield85% ee
MeO
N
CF3
O
R
MeO
N
CF3
O
R*
AgTFA; proton sponge
99% yield99.7% ee
Fe
Pd
R
R
RR
R
Cl
R = H, Me
R'
Pd (II)
N
NPh
Ph
Ts
Asymmetr ic Negishi Couplings:
Aza-Claisen Rearrangements:
3
Utility of Ferrocenyl Ligands
Lopez, F.; et al. JACS 2004, 126, 12784-12785. Cho, Y.-h.; et al. JACS 2006, 128, 6837. Harutyunyan, S. R.; et al. JACS 2006, 128, 9103.
FePPh2
PCy2
R
O
R' R
R'' O
R'CuBr*SMe2
91% yield98% ee
>94:6 regio.
N
R'
R'
Boc
R2N
HNBoc
R'
R'
98% yield>99% ee.
R''MgBr
Fe
PPh2
NMe2H
Ph2P
Me2NH
Rh
HNR2+
+
Cu-Catalyzed Conjugate Additions:
Rhodium-Catalyzed Ring Openings:
4
Asymmetric Hydrogenation
“…hydrogenation is arguably the most important catalytic method in synthetic organic chemistry….”
“Of the <20 full-scale chemo-catalyzed [asymmetric] reactions known to be running [in industry] currently, more than half are used for reducing various functionalities….”
Blaser, H.; et al. Adv. Synth. Catal. 2003, 345, 103-151.Federsel, H. Nat. Rev. Drug Discovery 2005, 4, 685-697.
PPh2
PPh2
(R)-BINAP
(R,R)-Me DuPhos
FePPh2
PCy2
Josiphos
PP
N
Ph2P
Boc PPh2
(2S,4S)-BPPM
YR
R''
R'
M / L*
H2
YH H
R'R''*
R
5
General Scope of Hydrogenation
R'
COOH
NHAc
R
R
COOHAcHN
R' R'
R
COOH
COOH
OAc
R'
R
R'' R'
R R''
R'''
Olefins
Blaser, H.; et al. Adv. Synth. Catal. 2003, 345, 103-151.
R R'
O O
R X
OO
R'
O
OR''
R
R
N
R'
R''
Ketones and Imines
6
Outline
• Features of Ferrocenyl Ligands– why ferrocenes?– reactivity and synthesis– modularity
• Applications of Ferrocenyl Ligands to Specific Substrates in Asymmetric Hydrogenation
• Conclusions
7
Why Ferrocenes?
Xiao, D.; Zhang, X. Angew. Chem. Int. Ed. 2001, 40, 3425-3428.Xiao, D; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679-1681.
P P
Ar NHAc
R
Ar NHAc
R+
Rh / (R,R)-binaphane
1.3 atm H2 Ar NHAc
R 100% yield99% ee
M / (R,R)-binaphane
H2R
NAr
NRM = Ru, Ir
8
Why Ferrocenes?
Xiao, D.; Zhang, X. Angew. Chem. Int. Ed. 2001, 40, 3425-3428.Vargas, S.; et al. Tetrahedron Let. 2005, 46, 2049.
P P
FeP
P
(R,R)-f-binaphane
(R,R)-binaphane
•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 back-donating ability from Ir to an imine substrate.
9
Why Ferrocenes?
Xiao, D.; Zhang, X. Angew. Chem. Int. Ed. 2001, 40, 3425-3428.Vargas, S.; et al. Tetrahedron Let. 2005, 46, 2049.
FeP
P
(R,R)-f-binaphane
Ir / (R,R)-f-binaphane
68 atm H2Ar
N
Ar
HN
MeO MeO
CAN
MeOH, H2O Ar
NH2 72-75% yield96-98% ee
(R,R)-f-binaphane has unprecedented enantioselectivity!
10
Synthesis of Chiral Ferrocenes: Lithiation
Marquarding, D.; et al. JACS 1970, 92, 5389-5393.
Fe
NMe2
HMe n-BuLi
FeLiH
MeNMe2
+ Fe
NMe2
MeH
Li
(R,R) - 96% (R,S) - 4%
FeLiH
MeNMe2
n-BuLi
TMBDA FeLiH
MeNMe2
Li
ClPPh2
FePPh2
H
MeNMe2
PPh2
Stereoselective lithiation results in the synthesis of a singlediastereomer.
ClPPh2
FePPh2
H
MeNMe2
PPh2
2 1H
Me
NMe2
11
SN1 Retention of Stereochemistry
FePPh2
H
MeNMe2
Ac2O
FePPh2
H
MeNMe2
Ac
FePPh2
HMe
Iron center donateselectron density tothe carbocation,stabilizing and
preventingracemization.
- NMe2Ac
Nu:-
FePPh2
H
MeNuSubsequent attack
of nucleophileoccurs from exoside and proceedswith retention ofstereochemistry.
Hayashi, T.; et al. Tetrahedron Let. 1974, 15, 4405.
12
Synthesis of BPPFA Derivatives
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
FePPh2
H
MeNMe2
PPh2
BPPFA
useful for asymmetrichydrogenation of
dehydroamino acids
FePPh2
H
MeMeN
PPh2
1.) Ac2O2.)
MeHNNR2
used for rhodium-catalyzedhydrogenation of
tetrasubstituted acrylicacids
BPPFOH
used for rhodium-catalyzedhydrogenation of prochiral
carbonyl compounds
FePPh2
H
MeOH
PPh2
NR2
1.) Ac2O2.) n-BuLi3.) H2O
13
Modular Synthesis: Josiphos
Fe
PCy2H
PPh2
Fe
PPh2H
PPh2
Fe
P(xyl)2H
PPh2
Fe
PCy2H
P(tBu)2
Fe
PPh2H
P(tBu)2
Fe
P(xyl)2H
P(tBu)2
Fe
PCy2H
PCy2
Fe
PPh2H
PCy2
Fe
P(xyl)2H
PCy2
Fe
NMe2H
1.) n-BuLi
2.) Ph2PClFe
NMe2H
PPh2
AcOH
HPCy2
Fe
PCy2H
PPh2
Sequential addition of phosphines allows rapid synthesis of a large ligandlibrary with varying steric and electronic properties!
Togni, A.; et al. JACS 1994, 116, 4062-4066.
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Modular Electronic Effects
Fe
P NN
MeO
2
Fe
P NN
2
Fe
P NN
F3C
CF3
2
Fe
P NN
MeO
2
F3C
CF3
Fe
P NN
2
F3C
CF3
Fe
P NN
F3C
2
5% ee 33% ee 40% ee
90% ee 95% ee 98.5% ee
OBH
O+
OH
1.) Rh / L*
2.) H2O2, NaOH
Electronic properties of ligand strongly influenceenantioselectivity!
Schnyder, A.; Hintermann, L.; Togni, A. Angew. Chem. Int. Ed. 1995, 34, 931-933
Best results are obtained with:σ-donating, electron-rich pyrazole nitrogen
and strongly π-accepting phosphorous.
The resulting “electronic asymmetry” at the metal centerenhances enantioselectivity.
15
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
16
Synthesis of Unprotected β-Amino Acids: Catalyst Screening
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)
Ph
NH2
OMe
O
Ph
NH2
OMe
O
6 atm H2, 50 C, 18 hrs2,2,2-trifluoroethanol
M / L
Hsiao, Y.; et al. JACS 2004, 126, 9918-9919.
FeP
P(tBu)2
CF3 21
17
Synthesis of Unprotected β-Amino Acids
Hsiao, Y.; et al. JACS 2004, 126, 9918-9919.
FeP
P(tBu)2
CF3 2
Ar
NH2
OMe
O
Ar
NH2
NHPh
O
Ar
NH2
OMe
O
Ar
NH2
NHPh
O
7.5 atm H2, 50 C, 6-24 hrs2,2,2-trifluoroethanol
7.5 atm H2, 50 C, 8 hrsMeOH
85-98% yield93-96% ee
74-94.0% yield96-97% ee
FePPh2
P(tBu)2
Rh /
Rh /
18
Product Inhibition
Hansen, K. B.; et al. Org. Lett. 2005, 7, 4935.
Me
NH2
NHPh
O
Me
NH2
NHPh
O1:1 Rh : L
32 atm H2
Me
NH2
NHPh
O
Me
NH2
NHPh
O1:1 Rh : L
32 atm H2
Me
NH2
NHPh
O+ 32 mol %
Results are consistent with either a first-order dependence on [substrate] OR
product inhibition.
Results are consistent with product inhibition!
FeP
P(tBu)2
CF3 2
19
Product Inhibition
Hansen, K. B.; et al. Org. Lett. 2005, 7, 4935.
Addition of Boc2O selectively protects the free amine, preventing product inhibition and accelerating
the overall reaction.
Me
NH2
NHPh
OMe
NH
NHPh
O1:1 Rh / L
32 atm H2+
2 eq Boc2O Boc
FeP
P(tBu)2
CF3 2
20
Synthesis of β-Amino Acid Pharmacophore
FePPh2
Me
P(t-Bu)2
Kubryk, M.; Hansen, K. Tetrahedron: Asymmetry 2006, 17, 205-209.
F
F
F
COOH
F
F
F
O
COOMe
F
F
F
NH2
COOMe
F
F
F
HN
COOMe
Boc
0.6 mol % Rh / L*
7 atm H2, MeOH
1.) 1,1'-carbonyldiimidazole,CH3CN
2.) methyl potassium malonate,Et3N, MgCl2
NH4OAc
MeOH, reflux
+Boc2O
75% yield>97% ee
21
Hydrogenation of Indoles
NBu
Ac
1 mol % Rh(acac)(cod) / L*
50 atm H2, iPrOH, 60 C, 2 hrsN
Bu
Ac
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
(R)-BINAP
PPh2
PPh2
(2S,3S)-Chiraphos
O
O
PPh2
PPh2
(2R,3R)-DIOP
FePPh2
PPh2
MeMe2N
(R)-(S)-BPPFA
N
Ph2P
PPh2Boc
(2S,4S)-BPPM
PPh2
PPh2
H
H
(S,S)-(R,R)-PhTRAP
Kuwano, R.; et al. Tetrahedron: Asymmetry. 2006, 17, 521-535.
22
Hydrogenation of 2-Substituted Indoles
PPh2
PPh2
H
H
(S,S)-(R,R)-PhTRAP
Kuwano, R.; et al. JACS 2000, 122, 7614-7615.
NR
Ac
1:1 Rh : L10 mol % Cs2CO3
50 atm H2, 60 C, 1-2 hrsN
R
Ac
N
Ac
1:1 Rh : L10 mol % Cs2CO3
100 atm H2, 60 C, 2 hrsNAc
Me Me
NH
Me
37% yield86% ee
55% yield
83-98% yield87-95% ee
Hydrogenation of 2-substituted indoles proceeds smoothly ...
... but hydrogenation of 3-substituted indoles mostly results inhydrolysis of the protected carbamide.
23
Hydrogenation of 3-Substituted Indoles
NTs
1:1 Rh : L*10 mol % Cs2CO3
50 atm H2, 80 C, 24 hrsNTs
R R
71-94% yield95-98% ee
Kuwano, R.; et al. Org. Lett. 2004, 6, 2213..
R Yield ee
i-Pr 94% 97%
Ph 93% 96%
CH2CH2OTBS 94% 98%
CH2 CH2CO2(t-Bu) 93% 97%
CH2CH2NHBoc 71% 95%PPh2
PPh2
H
H
(S,S)-(R,R)-PhTRAP
24
Hydrogenation of N-Boc Protected Indoles
Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653-2655.
NR
Boc
1:1 Ru / PhTRAP10 mol % Cs2CO3
50 atm H2, 60 C, 2-48 hrsN
R
Boc
(R') (R')
NBoc
1:1 Ru / PhTRAP10 mol % Cs2CO3
50 atm H2, 40 C, 24 hrsNBoc
R R
NMe
Boc
1:1 Ru / PhTRAP10 mol % NEt3
50 atm H2, 80 C, 72 hrsN
Me
Boc
Me Me
91-99% yield87-95% ee
85-92% yield87-94% ee
59% yield72% eePPh2
PPh2
H
H
(S,S)-(R,R)-PhTRAP
25
Hydrogenation of Vinyl Bis(boronates)
FePR'2
P
CF3
F3C2
Walphos #1: R = Ph#2: R = Cy
Morgan, J. B.; Morken, J. P. JACS 2004, 126, 15338-15339.
Ar
B(pin)
B(pin)1:2 Rh : Walphos #1
20 atm H2, 23 C, 24 hrs,toluene
H2O2, NaOH
THF, 23 C, 3 hrs Ar
OH
OH60-92% yield77-93% ee
Alk
B(pin)
B(pin)
1:2 Rh : Walphos #2
20-30 atm H2, 23 C, 24 hrs,dichloroethane
H2O2, NaOH
THF, 23 C, 3 hrs Alk
OH
OH72-89% yield85-93% ee
26
Hydrogenation of Vinyl Bis(boronates)
FePR'2
P
CF3
F3C2
Walphos #1: R = Ph#2: R = Cy
Ph
5% (Ph3P)2Pt(=)B2pin2
toluene, 100 C,48 hrs
5:7 Rh : Walphos #1
20 atm H2, 23 C, 24 hrstoluene
H2O2,NaOH
OH
OH66% yield91% ee
Ph
B(pin)
B(pin)
1:2 Rh : Walphos #1
20 atm H2, 23 C, 24 hrstoluene
1.) ClCH2Li, THF
2.) H2O2, NaOH
76% yield92% ee
HO
OH
Single Pot Diboronation / Hydrogenation / Oxidation of Phenylacetylene
Single Pot Hydrogenation / Homologation / Oxidation of Vinyl Bis(boronate)
Morgan, J. B.; Morken, J. P. JACS 2004, 126, 15338-15339.
27
Hydrogenation of Vinyl Bis(boronates)
FePR'2
P
CF3
F3C2
Walphos #1: R = Ph#2: R = CyMorgan, J. B.; Morken, J. P. JACS 2004, 126, 15338-15339.
entry Ligand : Rh ratio
% yield % ee configuration
1 0.8 90 52 R
2 1 83 37 R
3 2 84 93 S
B(pin)
B(pin) Rh / Walphos #1
15 atm H2, 23 C, 24 hrs,toluene
H2O2, NaOH
THF, 23 C, 3 hrs
OH
OH
28
Hydrogenation of Vinyl Boronates
FePPh2
P
CF3
F3C2
Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415.
B(pin)
NHBn
OH
Rh / L* / H2
1
286% yield95% ee
81% yield>95% ee
1: BCl3, then BnN3; 22 C2: (i) ClCH2Li, THF, -78 C (ii) NaOH, H2O2
29
Hydrogenation of Vinyl Boronates
FePPh2
P
CF3
F3C2
Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415.
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
R
B(pin)
R
B(pin)
Me
5:8 Rh : Walphos
35 atm H2, -35 C12 hrs >95% conv.
TBSO
TBSO
30
Hydrogenation of Vinyl Boronates
TBSO
BOO
TBSO
O OMe
5 mol % Rh8 mol % (R,R)-Walphos
35 atm H2, -35 C10 min
84% conv <10% conv 70% conv32% conv
Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415.
Boronate is activating: sterics alone are not responsible for high reactivity.
31
Hydrogenation of Vinyl Boronates
TBSO
BOO
TBSO
O OMe
5 mol % Rh8 mol % (R,R)-Walphos
35 atm H2, -35 C10 min
84% conv <10% conv 70% conv32% conv
Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415.
Reactivity not due solely to the π-acceptor properties of boronate: methyl methacrylate exhibits much less
reactivity.
32
Hydrogenation of Vinyl Boronates
TBSO
BOO
TBSO
O OMe
5 mol % Rh8 mol % (R,R)-Walphos
35 atm H2, -35 C10 min
84% conv <10% conv 70% conv32% conv
Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413-2415.
Enhanced reactivity not due to inductive donation from boron to carbon: inductively withdrawing phenyl
ring provides similar levels of reactivity, but no enantioselectivity.
33
(S)-Metolachlor: Dual Magnum
• 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.
N
MeO
CH2Cl
ONNN N
MeO
CH2Cl
OMeO
CH2Cl
OMeO
CH2Cl
OMeO
CH2Cl
O
Arrayas, R.; Andreo, J.; Carretaro, J. Angew. Chem. Int. Ed. 2006, 45, 7674-7715.Blaser, H.; et al. Top. Catal. 2002, 19, 3-16.Dorta, R.; et al. Chem. Eur. J. 2004, 10, 4546-4555.Syngenta website: www.syngenta.com
34
N
MeO
CH2Cl
ONNN N
MeO
CH2Cl
OMeO
CH2Cl
OMeO
CH2Cl
OMeO
CH2Cl
O
(S)-Metolachlor: Dual Magnum
O
OMe
NH
MeO
N
MeO
CH2Cl
O
NH2
Cl CH2Cl
O
Pt / CH2SO4
5 atm H2, 50 C+1970: Metolachlor discovered
1978: rac-Metolachlor production started, >10,000 tons/yr produced
1982: Metolachlor stereoisomers synthesized; (S)-isomer found to be active.
ACTIVE! INACTIVE!
Blaser, H.; et al. Chimia 1999, 53, 275-280.
35
(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. pp153-166.
36
N
MeO
CH2Cl
O
N NCH2Cl
OMeO
CH2Cl
O
NHR
O
OMeOTs
OMe
N
MeO
NH
MeO
Rh / L*product
product
R = H or COCH2Cl
1.) H2, chiral cat.
2.) TsX
H2
M / L* ClCOCH2Cl
(ClCOCH2Cl)
product
or or
OMe
+
(1)
(2)
(3)
(S)-Metolachlor: Enantioselective Synthesis
Blaser, H.; et al. Chimia 1999, 53, 275-280.
Onlypossible
approach!
37
(S)-Metolachlor: Imine Hydrogenation
N
MeO
NH
MeO
25 atm H2, 24 hrs
[Ir(cod)Cl]2 / L*TBAI
O
OH
PPh2
HPPh2PPh2 PPh2
(4S,5S)-diop(2R,4R)-bdpp 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)
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. pp153-166.
38
(S)-Metolachlor: Imine Hydrogenation
N
MeO
NH
MeO
25 atm H2, 24 hrs
0.1 mol % Ir / L*TBAI, AcOH
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%
FePR2
PR'2
Blaser, H.; et al. J Organomet Chem 2001, 621, 34-38.
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.
39
(S)-Metolachlor: Imine Hydrogenation
FePPh2
P(3,5-xyl)2
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
N
MeO
NH
MeO
25 atm H2, 30 C
0.1 mol % Ir / L*
Blaser, H.; et al. Chimia 1999, 53, 275-280.Blaser, H.; et al. J Organomet Chem 2001, 621, 34-38.Spindler, F.; et al. In Catalysis of Organic Reactions; Maltz, R., Jr., Ed. pp153-166.
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!
40
(S)-Metolachlor: Imine Hydrogenation
N
MeO
NH
MeO
80 atm H2
0.001 mol % Ir / L*TBAI, 10% AcOH
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
FePPh2
PR'2
Blaser, H.; Spindler, F. Chimia 1997, 51, 297-299.Blaser, H.; et al. J. Organomet Chem 2001, 621, 34-38.
While other ligands have slightly higher ees, Xyliphos’ high activity makes it ideal for industrial
use.
41
(S)-Metolachlor: Imine Hydrogenation
FePPh2
P(3,5-MePh)2
N
MeO
NH
MeO
80 atm H2, 50 C
Ir / XyliphosTBAI, 10% AcOH
Blaser, H.; Spindler, F. Chimia 1997, 51, 297-299.Blaser, H.; et al. J. Organomet Chem 2001, 621, 34-38.
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
42
(S)-Metolachlor: Production Scale
S/C = 2,000,00050 C, 4 hrs
80 atmH2
extraction,flash distillation,
distillation
Ir is recycled
N
MeO
FePPh2
P(3,5-MePh)2
/ IrAcOH, TBAI
NH
MeO
Blaser, H.; Spindler, F. Chimia 1997, 51, 297-299.Blaser, H.; et al. Chimia 1999, 53, 275-280.
43
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