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.

14

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

44

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