New Catalyst for Asymmetric hydrogenation

Stereoselective AsymmetricHydrogenation Catalysts-XylSKEWPHOS Catalysts
CatalystsWe Kanto Chemical launched asymmetric hydrogenation catalysts, which were discovered by NOYORI Molecular Catalysis Project of Exploratory Research for Advanced Technology (ERATO) by
Japan Science and Technology Corporation (JST) and were developed by Exploitation and Application Study supported by JST. These catalysts have both diphosphine and diamine ligands, and thecatalyst performance is tunable by the choice of these chiral ligands. Chiral Ru catalysts with BINAP
ligand have high reactivity and enantioselectivity for the reaction of ketones1, but higher enantioselectivity is desirable for certain ketonic substrates.
We examined the structure of the catalysts, and the chiral Ru catalysts with 1,3-diphosphine, XylSKEWPHOS [(2,4-bis(di-3,5-xylylphosphino)pentane)] were found to have higher enantioselectivity
than the prototype BINAP catalysts. Now we launch these asymmetric hydrogenation catalysts.

List of Products
Product

Product number Package

Dibromo[(R,R)-XylSKEWPHOS][(R,R)-DPEN]ruthenium(Ⅱ)
Dibromo[(R,R)-2,4-bis(di-3’,5’-xylylphosphino)pentane][(R,R)-1,2-diphenylethanediamine]ruthenium(Ⅱ)

【RuBr2[(R,R)-xylskewphos][(R,R)-dpen]】
C51H62Br2N2P2Ru
F.W：1025.88

Ar2 BrP
RuP
Ar2 Br

H2
N

Ph

N
H2

Ph

Ar = 3,5-(CH3)2C6H310535-68

100mg

10535-95

500mg

10537-68

100mg

10537-95

500mg

10536-68

100mg

10536-95

500mg

10538-68

100mg

10538-95

500mg

Dibromo[(R,R)-XylSKEWPHOS][(S)-DAIPEN]ruthenium(Ⅱ)
Dibromo[(R,R)-2,4-bis(di-3’,5’-xylylphosphino)pentane][(S)-1,1-bis(p-methoxyphenyl)-2-isopropyl-1,2-ethanediamine]ruthenium(Ⅱ)
Ar Br【RuBr2[(R,R)-xylskewphos][(S)-daipen]】
C56H72Br2N2O2P2Ru
F.W：1128.01

P

2

OCH3

H2
N

OCH3

Ru

P
Ar2 BrN
H2

Ar = 3,5-(CH3)2C6H3

Dibromo[(S,S)-XylSKEWPHOS][(S,S)-DPEN]ruthenium(Ⅱ)
Dibromo[(S,S)-2,4-bis(di-3’,5’-xylylphosphino)pentane][(S,S)-1,2-diphenylethanediamine]ruthenium(Ⅱ)

【RuBr2[(S,S)-xylskewphos][(S,S)-dpen]】
C51H62Br2N2P2Ru
F.W：1025.88

Ar2 BrP
RuP
Ar2 Br

H2
N

Ph

N
H2

Ph

Ar = 3,5-(CH3)2C6H3

Dibromo[(S,S)-XylSKEWPHOS][(R)-DAIPEN]ruthenium(Ⅱ)
Dibromo[(S,S)-2,4-bis(di-3’,5’-xylylphosphino)pentane][(R)-1,1-bis(p-methoxyphenyl)-2-isopropyl-1,2-ethanediamine]ruthenium(Ⅱ)
Br【RuBr2[(S,S)-xylskewphos][(R)-daipen]】
C56H72Br2N2O2P2Ru
F.W：1128.01

Ar2
P

OCH3

H2
N

Ru

P
Ar2 Br

OCH3

N
H2

Ar = 3,5-(CH3)2C6H3

Asymmetric Hydrogenation
1

Hydrogenation of Aromatic Ketones

XylSKEWPHOS catalysts hydrogenate aromatic ketones effectively with high enantioselectivity to yield
optically active alcohols2. For example, acetophenone is hydrogenated with RuCl2(tolbinap)(daipen) toafford 1-phenylethanol in 91% ee and RuBr2(xylskewphos)(daipen) gives 98% ee for the same substrate.
Aromatic ketones with several substituents on aromatic rings are also hydrogenated efficiently to give optically active alcohols in high ee. To obtain high enantioselectivity, proper selection of the catalysts is necessary. The DPEN catalyst usually gives higher enantioselectivity than the DAIPEN catalyst for the reaction of o-substituted aromatic ketones. For example, o-chloroacetophenone is hydrogenated with the
DPEN and the DAIPEN catalyst in 97% ee and 94% ee, respectively. o-Bromoacetophenone is hydrogenated in >99% ee with both of the DPEN and the DAIPEN catalyst. For the reaction of m- and psubstututed aromatic ketones, the DAIPEN catalyst is assumed to have better enantioselectivity than the
DPEN catalyst. For example, m-chloro and m-bromoacetophenone are hydrogenated with the DAIPEN
catalyst in 97% ee and 99% ee, respectively. p-Fluoro, p-chloro and p-bromoacetophenone are also hydrogenated with the DAIPEN catalyst in 97% ee, 97% ee and 99% ee, respectively.

ExampleChiral Ru cat: RuBr2[(S,S)-xylskewphos][(S,S)-dpen] (cat A)
RuBr2[(S,S)-xylskewphos][(R)-daipen] (cat B)
Conditions: ketone/Ru/t-C4H9OK = 10,000:1:40, [ketone]0 = 2.0-2.5 mol/L2

Hydrogenation of Heteroaromatic Ketones

RuCl2(binap)(diamine) catalysts don’t have high enantioselectivity for the asymmetric hydrogenation ofhetero aromatic ketones. RuBr2(xylskewphos)(daipen) has higher enantioselectivity for these ketones.
For example, 2-acetylfuran and 2-acetylthiophene are hydrogenated efficiently to give optically active 1(2-furanyl)ethanol in 97% ee and 1-(2-thienyl)ethanol in 96% ee.

ExampleChiral Ru cat: RuBr2[(S,S)-xylskewphos][(R)-daipen]
Conditions: ketone/Ru/t-C4H9OK = 2,000-10,000:1:40, [ketone]0 = 2.5 mol/L

3

Hydrogenation of Other Ketones

Carbonyl compounds with conjugated or unconjugated carbon-carbon multiple bonds can be converted
effectively to the corresponding unsaturated alcohols. Cyclohexyl ketone, which is a difficult substrate
to obtain with high enantioselectivity, can be hydrogenated in 94% ee with this catalyst. -N,NDimethylaminoacetophenone is also hydrogenated enantioselectively with 97% ee.

ExampleS/C = 2,000-10,000
Chiral Ru cat: RuBr2[(S,S)-xylskewphos][(R)-daipen]
Conditions: ketone/Ru/t-C4H9OK = 2,000-10,000:1:10-40, [ketone]0 = 2.0-2.5 mol/L

4

Hydrogenation of Imines

Catalytic asymmetric hydrogenation of imines is one of the most efficient and convenient method for the
preparation of optically active amines. We found that RuBr2(xylskewphos)(dpen) is an excellent catalyst for the asymmetric hydrogenation of imines3 in the joint research project with Prof. Ohkuma in Hokkaido University . Various imines can be hydrogenated efficiently with this catalyst to afford the amine
products in high ee’s.

Example (reaction solvent)
Reactions can be conducted in a variety of aprotic slovents such as toluene (hydrocarbon solvent) and THF(ether solvent). For example, hydrogenation of N-2-methoxyphenyl (OMP) acetophenone imine is completed within 15 h in various aprotic solvents in the presence of potassium tert-butoxide at a substrate-tocatalyst molar ratio (S/C) of 1,000 under 10 atm of hydrogen pressure, leading to the optically active
phenetylamine in 99% ee.

Example (scope of substrates)
The reaction of N-substituted imines, where the N-substituent is the phenyl group, electron-donating methoxyphenyl group, or electron-withdrawing halogenated phenyl group, also proceed efficiently. For example, N-OMP acetophenone imine is hydrogenated at a S/C of 5,000 under 10 atm of H2 to afford the optically active amine in 99% ee quantitatively. The methoxyphenyl group is readily deprotected to give theoptically active primary amines4. Although the reactivity of N-alkyl imines is relatively low, the enantioselectivity is maintained high. For example, N-n-Bu imine is reduced at a S/C of 2,000 to afford theamine product in 97% ee with 85% yield. The ee value of product from N-Benzyl imines is low.

This catalyst system is applicable to a variety of N-aryl imines. N-OMP imines derived from acetophenones with an electron-donating or an electron-withdrawing group on the phenyl ring are hydrogenated at
a S/C of 1,500-3,000 under 10 atm of H2 to afford the optically active amines in up to 99% ee quantitatively. The reaction of imine with naphthalene ring, propiophenone imine and butyrophenone imine proceed efficiently. Heteroaromatic imines, such as pyridyl imines, ferrocenyl imine and ,-unsaturated
imine, are also hydrogenated in high ee’s. The hydrogenation of diimine derived from 1,3diacetylbenzene affords the diamine product with a high diastereo (dl:meso = 96:4) and high enantioselectivity (>99% ee) in 99% yield.

The N-substituted imine with 3-bromophenyl group or 4-Boc-aminopheny group is converted to the corresponding chiral amine in 96% ee or 93% ee, respectively. These chiral amines are enable to the synthetic
intermediates of biologically active compounds5, 6.

NBoc
HN

Cl
S/C = 3,000
99% yield
93% ee5

Procedure for Hydrogenation of Ketones

A representative procedure for the asymmetric hydrogenation of ketones using RuBr2(xylskewphos)(dpen) at a S/C of
2,000 is described below.
Reaction vessel (internal volume : 100 mL)*1
The ready-to-use Ruthenium(II) complex : ca. 10 mg (0.01 mmol)*2(A solid substrate of ketone should be added with the Ruthenium(II) complex at this point.
Ketone substrate : 20 mmol)
Purging away the inside gas of the vessel and displacing with inert gas (1 time)
Ketone substrate : 20 mmol*30.01 mol/L Solution of potassium alkoxide in 2-propanol: 10 mL (0.1 mmol)*4*5*6
Purging away the inside gas of the vessel and displacing with inert gas*7
Replacing the inside gas of the vessel with hydrogen under stirring(H2 is introduced into the vessel, before being reduced to 1 atm. This procedure isrepeated 3~5 times)*8*9
Pressurizing with H2 (10 atm)
Hydrogenation (stirring, 30~60 °C)*10*11
Isolating the alcohol product*12*1: Pressure resistant glass vessel with guard jacket can be used as well as stainlesssteel autoclave. In case of the poor reactivity, pretreatment of vessel may be effective.
*2: Ruthenium complexes can be handled in the air. It should be kept under inert gas in a long term preservation.
*3: Because this hydrogenation is sensitive even small amount of acid, acidic impurities should be carefully removed.
By the following step, washing the substrate dissolved in appropriate solvent with an aqueous KOH solution thendrying over Na2SO4 anhydride, the substrate can be purified with an appropriate purity.
*4: Please use commercial 0.01 mol/L potassium tert-butoxide/2-propanol solution by our company, or prepare it fromcommercially available potassium tert-butoxide and dry 2-propanol.
*5: The strong base more than 2 equivalent of Ruthenium complex is required for the hydrogenation. Some enones
might be unstable against a base may polymerize in this conditions. In that case, the concentration of the strong
base should be optimized, or using a weak base such as K2CO3 instead of the strong base is effective.

*6: When a ketone substrate is hard to dissolve in 2-propanol, toluene or THF can be used as a cosolvent.
*7: Repeated operation as follows (remove the internal gas by vacuum line and replace with inert gas) is enable.
*8: For safety, replacing the internal gas of the vessel with H2 should be operated in a draft-chamber (refer to theprocedure in the literature: M. Kitamura, M. Tokunaga, T. Ohkuma and R. Noyori, Org. Synth. 1993, 71, 113).
*9: Please keep hydrogen pressure of vessel at more than 1 atm to prevent contamination by air.
*10: High speed reaction is enable with a high speed stirring.
*11: After the completion of hydrogenation, the hydrogen pressure will be decreased to the range of 4-5 atm.
*12: The residual catalyst can be removed from the product by filtration through a silica-gel pad.
Hydrogenation with more than S/C = 3,000 can be operated by the same procedure. Quantitative conversion ispossible with S/C>100,000 at optimized conditions. For a detail, please consult us.

Hydrogenation under atmospheric pressure of hydrogen is possible with these Noyori type asymmetrichydrogenation catalysts. In case of the atmospheric pressure reaction, reaction at a S/C of 500-1,000 is
the first recommended trial, as the reaction rate is largely decreased than the reaction under the pressureof hydrogen.

6

Procedure for Hydrogenation of Imines

A representative procedure for the asymmetric hydrogenation of N-OMP acetophenone imine at a S/C of 3,000 is described below using RuBr2(xylskewphos)(dpen) as a catalyst.
Reaction vessel (internal volume: 100 mL)*1
Imine substrate: 6.8 g (30 mmol)*2(a liquid substrate of imine should not be added at this point)
The ready-to-use Ruthenium complex: ca. 10 mg (0.01 mol)*3
Potassium tert-butoxide: 110 mg (1.0 mmol)
Purging away the internal gas of the vessel and displacing with inert gas
Toluene: 7.5 mL*4
(A liquid substrate of imine should be added at this poiont. imine substrate: 30 mmol)
Purging away the internal gas of the vessel and displacing with inert gas*5
Replacing the internal gas of the vessel with hydrogen under stirring(H2 is introduced into the vessel, before being reduced to 1 atm. This procedure is repeated 3~5 times)*6*7
Pressurizing with H2 (10~50 atm)*8
Hydrogenation (stirring, 30~60 °C)*9
Isolating the amine product*1: Stainless steel autoclave (~50 atm) and pressure resistant glass vessel(~10 atm) can be used dependent on the pressure of hydrogen.
*2: The hydrogenation of imines doesn't proceed with alcohols. Coexistence of ketones in imine substrates causes producing alcohols from the hydrogenation of ketones. Please carefully remove ketones from imine substrates.
*3: Ruthenium complexes can be handled in the air. It should be kept under inert gas in a long term preservation.
*4: A variety of aprotic solvents such as benzene, THF and MTBE can be used as a solvent.
*5: Repeated operation as follows (remove the internal gas by vacuum line and replace with inert gas) is enable.

*6: For safety, replacing the internal gas of the vessel with H2 should be operated in a draft-chamber (refer to theprocedure in the literature: M. Kitamura, M. Tokunaga, T. Ohkuma and R. Noyori, Org. Synth. 1993, 71, 113).
*7: Please keep hydrogen pressure of vessel at more than 1 atm to prevent contamination by air.
*8: Higher pressure of hydrogen leads to increase reaction rate as keeping enatioselectiviy high.
*9: Higher temperature leads to increase reaction rate, but enantioselectivity is slightly decreased.

[References]

1) R. Noyori, T. Ohkuma, Asymmetric Catalysis by Architectural and Functional Molecular Engineerig: Practical
Chemo- and Stereoselective Hydrogenation of Ketones, Angew. Chem. Int. Ed. 2001, 40, 40.
2) Novel Ruthenium complexes and preparation of alcohols with these Ruthenium catalysts. Patent 3566955(Japan).
3) N. Arai, N. Utsumi, Y. Matsumoto, K. Murata, K. Tsutsumi, T. Ohkuma, Adv. Synth. Catal. 2012, 354, 2089.
4) a) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg, P. L. Alsters, F. L. van Delft, F. P. J. T. Rutjes, Tetrahedron Lett. 2006, 47, 8109. b) N. Mršić, A. J. Minnaard, B. L. Feringa, J. G. de Vries, J. Am. Chem.
Soc. 2009, 131, 8358. c) D. Xiao, X. Zhang, Angew. Chem. Int. Ed. 2001, 40, 3425. d) J. M. M. Verkade, F. vander Pijl, M. M. J. H. P. Willems, P. J. L. M. Quaedflieg, F. L. van Delft, F. P. J. T. Rutjes, J. Org. Chem. 2009,
74, 3207. e) J. R. Porter, J. F. Traverse, A. H. Hoveyda, M. L. Snapper, J. Am. Chem. Soc. 2001, 123, 984. f)
M. Ohara, S. Nakamura, N. Shibata, Adv. Synth. Catal. 2011, 353, 3285.
5) D. Angst, B. Bollbuck, P. Janser, J. Quancard, (Novartis AG.), PCT Int. WO2010/072712 A1, 2010.
6) K. Schnatbaum, D. Scharn, E. Locardi, T. Polaakowski, U. Richter, U. Reineke, G. Hummel, (Jerini AG.), PCT
Int. WO2006/128670 A1, 2006.
[Conformation of Complexes]
RuBr2(xylskewphos)(diamine) complexes present as two diastereomeric mixtures by 31P-NMR analysis.
●RuBr2[(S,S)-xylskewphos][(S,S)-dpen] and RuBr2[(R,R)-xylskewphos][(R,R)-dpen]
31

P-NMR(CDCl3, -25 oC) ppm, major: 65.0 (d, J = 42.6 Hz), 41.6 (d, J = 43.6 Hz),minor: 59.8 (d, J = 43.6 Hz), 49.0 (d, J = 48.0 Hz). major/minor = 10:9
●RuBr2[(S,S)-xylskewphos][(R)-daipen] and RuBr2[(R,R)-xylskewphos][(S)-daipen]
31

P-NMR(CDCl3, -25 oC) ppm, major: 60.0 (d, J = 48.0 Hz), 46.8 (d, J = 43.6 Hz),minor: 60.6 (d, J = 48.0 Hz), 48.2 (d, J = 48.0 Hz). major/minor = 10:3

Related Products, Asymmetric Hydrogenation Catalysts
Product

Product number

Package

Dichloro[(
Dichloro[(RR)-2,22,2´´-bis(diphenylphosphino)bis(diphenylphosphino)--1,1
1,1´´-binaphthyl]binaphthyl]-[([(R
R,R)-1,2
1,2--diphenylethanediamine]ruthenium(II)
RuCl2[(R)-binap][(R,R)-dpen]

11404-65

1g11404-95

200mg

Dichloro[(
Dichloro[(RR)-2,22,2´´-bis(diphenylphosphino)bis(diphenylphosphino)--1,1
1,1´´-binaphthyl]binaphthyl]-[([(SS,S)-1,2
1,2--diphenylethanediamine]ruthenium(II)
RuCl2[(R)-binap][(S,S)-dpen]

11405-65

1g11405-95

200mg

Dichloro[(
Dichloro[(SS)-2,22,2´´-bis(diphenylphosphino)bis(diphenylphosphino)--1,1
1,1´´-binaphthyl]binaphthyl]--

11402-65

1g

[(
[(R
R,R)-1,2
1,2--diphenylethanediamine]ruthenium(II)
RuCl2[(S)-binap][(R,R)-dpen]

11402-95

200mg

Dichloro[(
Dichloro[(SS)-2,22,2´´-bis(diphenylphosphino)bis(diphenylphosphino)--1,1
1,1´´-binaphthyl]binaphthyl]--

11403-65

1g[(
1,2--diphenylethanediamine]ruthenium(II)S,S)-1,2[(S
RuCl2[(S)-binap][(S,S)-dpen]

11403-95

200mg

Dichloro[(
Dichloro[(RR)-2,22,2´´-bis(diphenylphosphino)bis(diphenylphosphino)--1,1
1,1´´-binaphthyl]binaphthyl]-[(ethanediamine]-1,2--ethanediamine]
isopropyl--1,2
methoxyphenyl)--2-isopropyl
p-methoxyphenyl)bis(p1,1--bis(R)-1,1[(R
ruthenium(II)
RuCl2[(R)-binap][(R)-daipen]

11408-65

1g11408-95

200mg

Dichloro[(binaphthyl]-1,1´´-binaphthyl]bis(diphenylphosphino)--1,1
2,2´´-bis(diphenylphosphino)S)-2,2
Dichloro[(S[(ethanediamine]-1,2--ethanediamine]
isopropyl--1,2
methoxyphenyl)--2-isopropyl
p-methoxyphenyl)bis(p1,1--bis(S)-1,1[(S
ruthenium(II)
RuCl2[(S)-binap][(S)-daipen]

11409-65

1g11409-95

200mg

10532-68

100mg

10532-95

500mg

10533-68

100mg

10533-95

500mg

10534-68

100mg

10534-95

500mg

Dichloro[(R)-iphan]Ruthenium(II)binap][(RS)-binap][(
Dichloro[(SRuCl2[(S)-binap][(R)-iphan]

H
Cl N2
Ru
P Cl NHPOO2※NIPPON SODA CO., INC.

Dichloro[(S)-dmapen]Ruthenium(II)tolbinap][(SR)-tolbinap][(
Dichloro[(RRuCl2[(R)-tolbinap][(S)-dmapen]

H
Cl N2
Ru
P Cl NP※NIPPON SODA CO., INC.

Dichloro[(R)-dmapen]Ruthenium(II)tolbinap][(RS)-tolbinap][(
Dichloro[(SRuCl2[(S)-tolbinap][(R)-dmapen]
P Cl NRu
P Cl NH

2※NIPPON SODA CO., INC.

Related Products, Chiral Ligands
Product Name
（R)-(+)(+)--2,2
2,2´´-Bis(diphenylphosphino)Bis(diphenylphosphino)--1,1
1,1´´-binaphthyl(R)-(+)-BINAP

Product number Package
04969-3525g

04969-55

5g04969-651g04970-3525g

04970-555g

04970-651g05069-3525g05069-555g05069-65

1g（R)-(+)(+)--2,2
2,2´´-Bis(diBis(di--p-tolylphosphino)
tolylphosphino)--1,1
1,1´´-binaphthyl(R)-(+)-Tol-BINAP

41105-55

5g

41105-65

1g（S)-(-)-2,2
2,2´´-Bis(diBis(di--p-tolylphosphino)
tolylphosphino)--1,1
1,1´´-binaphthyl(S)-(-)-Tol-BINAP

41106-55

5g

41106-65

1g（R)-1,1
1,1--Bis(p-methoxyphenyl)
methoxyphenyl)--2-isopropyl
isopropyl--1,2
1,2--ethanediamine(R)-DAIPEN

11407-65

1g

11407-95

200mg（S)-1,1
1,1--Bis(p-methoxyphenyl)
methoxyphenyl)--2-isopropyl
isopropyl--1,2
1,2--ethanediamine(S)-DAIPEN

11406-651g11406-95

200mg（1R,2R)-(+)(+)--1,2
1,2--Diphenyl
Diphenyl--1,2
1,2--ethanediamine(R,R)-DPEN

11444-35

25g

11444-55

5g

11444-65

1g11445-35

25g

11445-55

5g

11445-65

1g（S)-(-)-2,2
2,2´´-Bis(diphenylphosphino)Bis(diphenylphosphino)--1,1
1,1´´-binaphthyl(S)-(-)-BINAP

rac-2,2
1,1´´-binaphthylBis(diphenylphosphino)--1,1
2,2´´-Bis(diphenylphosphino)
rac-BINAP（1S,2S)-(-)-1,2
1,2--Diphenyl
Diphenyl--1,2
1,2--ethanediamine(S,S)-DPEN

Performance Chemicals Dept.

2013.11