Asymmetric Transfer
Hydrogenation Catalysts

OH

OH

O
99% yield, 96% ee(S/C = 1000)

OH
89% yield, 99% ee(S/C = 300)

>99% yield, 97% ee(S/C = 200)

OH
OH
X
OH
R

78% yield, 95% ee(S/C = 200)

(S,S)-Ru cat

X = CN, N3, NO2 R = H, CH3, F
67-100% yield, 92-98% ee(S/C = 100-1000)

OH
OH
N
OH
100% yield
dl:meso = 98.6:1.4, >99% ee(S/C = 1000)

OH

O

OH
O

( )n ORR = CH(CH3)2, n = 0, 94% yield, 75% ee
R = C2H5, n = 1, 94% yield, 93% ee
R = C2H5, n = 3, 99% yield, 95% ee>99% yield, 98% ee(S/C = 200)

97% yield, 95% ee(S/C = 200)

Asymmetric Transfer Hydrogenation Catalysts

Contents
Introduction ⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 2
Asymmetric transfer hydrogenation of ketones ⋯⋯⋯⋯⋯⋯ 2
Asymmetric transfer hydrogenation of benzyls⋯⋯⋯⋯⋯⋯ 5

Kinetic resolution of secondary alcohols ⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 5

Asymmetric transfer hydrogenation of imines ⋯⋯⋯⋯⋯⋯⋯6
Standard operating procedures for the asymmetric transferhydrogenation of ketones ⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 7
Reference ⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 8
Products
1⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯⋯ 9

Introduction
Optically active alcohols and amines are usefulintermediates of pharmaceuticals or pesticides. Chiralruthenium complexes with chiral diamine ligands, whichwere discovered by NOYORI Molecular Catalysis Projectof Exploratory Research for Advanced Technology(ERATO) by Japan Science and Technology Corporation(JST), are extremely effective catalysts for theasymmetric transfer hydrogenation of ketones 1)-11) andimines 9), 12), 13) leading to optically active alcohols andamines with high optical purities in high yields.

As organic compounds such as 2-propanol and formic
acid are used as hydrogen donors in this asymmetric
reaction, this reaction can be easily implemented using
laboratory equipments such as flasks and is therefore
highly versatile.
KANTO CHEMICAL CO.,INC. launches of pre-formedchiral ruthenium complexes, which are easily handled
and can be used for this asymmetric transferhydrogenation.

Asymmetric Transfer Hydrogenation Catalysts
Chloro complexes

Amide complexes

RuCl[(S,S)-Tsdpen](η6-arene)

Ru[(S,S)-Tsdpen](η6-arene)

Ts

Ts
Rn

N

Ru

Ru
N
H2

Rn

N
N
H

Cl

Ts = SO2C6H4-p -CH3
1a ; Rn = 1-CH3-4-CH(CH3)2
1b ; Rn = 1,3,5-(CH3)3
1c ; Rn = 1,2,3,4,5,6-(CH3)6

Ts = SO2C6H4-p -CH3
3a ; Rn = 1-CH3-4-CH(CH3)23b ; Rn = 1,3,5-(CH3)3

RuCl[(S,S)-Msdpen](η6-arene)
Ms
Rn

N
Ru
N
H2

Cl

Ms = SO2CH3
2a ; Rn = 1-CH3-4-CH(CH3)2

1. Asymmetric transfer hydrogenation of ketones 1)-10) (Synthesis of optically active secondary alcohols)《Selection of hydrogen donors》
Organic compounds such as 2-propanol and formic acidcan be used as the hydrogen donors for this reaction.
As the reaction in 2-propanol is reversible, the reaction isproceeded after adjusting the substrate concentrationand S/C (the substrate/catalyst molar ratio). Conversely,

the reaction which uses formic acid as a hydrogen donor
is not reversible, and therefore even if the reaction is
implemented with a high substrate concentration or high
S/C, a high yield of optically active alcohols with highoptical purities can be obtained.

C Kanto Kagaku
2

●Reaction with the 2-propanol as a hydrogen donor 1), 4)-6), 8)
OH

O
Ar

OH

+

R

O

(S,S )-cat
Ar s(CH3)2CHOH

R+

93〜98% yield(S,S )-cat = [RuCl2(mesitylene)]2−(S,S )-TsDPEN−KOH(mole ratio 1:2:5)

OH

OH
R

OH

OH

R

R = CH3 97% ee
R = C2H5 97% ee

R = m -Cl 98% ee
R = p -Cl 93% ee
R = m -OCH3 96% ee

93% ee98% ee●Reaction with the formic acid as a hydrogen donor 2), 4)O

OH(S,S )-1b

Ar

R

Ar s

HCOOH/N(C2H5)3
28 ℃

R93〜99% yield

OH

OH

OH
S/C = 200
R = m -Cl 97% ee
R = p -Cl 95% ee
R = m -OCH3 98% ee
R = p -OCH3 97% ee

R
S/C = 1000
96% eeOH

OH

S/C = 200
97% eeOH
OH
R

S/C = 200
83% eeS/C = 200
96% eeS/C = 200
R = CH2 99% ee
R = (CH2)2 99% ee

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3

S/C = 200
70% yield, 83% ee《Selection of substrates》
In addition to the simple ketones referred to above, thereaction can also proceed efficiently and without loss ofthe functional group in the case of ketones that have afunctional group such as a carbon-carbon multiple bondor a heteroatom, producing optically active alcohols withhigh optical purities. For example, acetylenic alcoholwith 97% ee can be obtained in a high yield by anreaction of acetylene-ketone. The reaction of ketones
that have a furan ring or thiophene ring also proceed
properly, resulting in alcohols with high optical purities.
Moreover ketone having a pyridyl group also react well,resulting in optically active pyridyl alcohol with 95% ee.
This reaction can also be applied to the reaction of
ketones that have a multiple number of functional groups

such as a pyridyl group, carbon-carbon multiple bond oran ester group, allowing the successful synthesis of the
key intermediate of a carbonic anhydrase inhibitor, MK0417. Furthermore, the reaction of unsymmetrically
substituted 1, 2- diketones leads to optically active
α-hydroxyketones or optically active 1, 2- diols
separately depending on the reaction conditions.
Further, the reaction of acetophenone derivatives with acyano group, azido group or nitro group in the second
position also proceeds efficiently, producing optically
active alcohols. These compounds can be easily
reduced by usual reducing agents, leading to optically
active amino alcohols, which are useful synthetic
intermediates for pharmaceutical products.

OH
OH

OH

s

s

R

OH

O

cat : (S,S )-1b
S/C = 200>99%, 98% ee2), 4)

cat : (S,S )-1b
S/C = 200
47%, 98% ee2), 4)sO
cat : (S,S )-3b
S/C = 200>99%, 97% ee4)

OH

OH

S

X

cat : (R,R )-1b
S/C = 200
X = S 95%, 99% ee
X = SO2 95%, 98% ee2), 4)OH

O

OC2H5 Cl（）nN

CO2CH3RN
cat : (S,S )-1acat : (S,S )-1a
S/C = 200n = 1 94%, 93% ee4)5)>97%, 95% ee
n = 3 99%, 95% ee2)

cat : (R,R )-1b
S/C = 200
68%, 92% ee2),4)

OH

O

OH
X

OH
cat : (S,S )-1a
S/C = 300 (10 ℃)
89%, 99% ee6)OH

R = H ; X = CN 100%, 98%ee
R = H ; X = N3 65%, 92%ee
7)
R = H ; X = NO2 90%, 98%ee
X : CN, N3, NO2
R = F ; X = NO2 95%, 96%ee
cat : (S,S )-1a
S/C = 100−1000 (30 ℃) R = CH3 ; X = NO2 67%, 95%ee
R

cat : (S,S )-1a
S/C = 200 (40 ℃)
78%, 95% ee6)

C Kanto Kagaku
42. Asymmetric transfer hydrogenation of benzyls 11) (Synthesis of optically active hydrobenzoins)
Benzyls can be rapidly reduced at room temperature
with a chiral ruthenium catalyst in a mixture of formic
acid/triethylamine, producing optically activeOhydrobenzoins with high optical purities almost
quantitatively.

OH(S,S )-1a

Ar

Ar
O

Ar

R

Ar

HCOOH/N(C2H5)3
DMF, 30−60 ℃

ROH
Ar = C6H5 100%, dl :meso = 98.6:1.4, >99% ee
Ar = p -CH3-C6H4 67%, dl :meso = 96.7:3.3, >99% ee
Ar = p -CH3O-C6H4 75%, dl :meso = 94.4:5.6, >99% ee
Ar = p -F-C6H4 100%, dl :meso = 94.2:5.8, >99% ee

S/C = 1000−2000

3. Kinetic resolution of secondary alcohols 4), 12)As asymmetric transfer hydrogenation in 2-propanol is areversible reaction, it has previously been difficult toimplement the high enantioselectivities in the reductionof high-reduction-potential ketones with an electron
donating group on the aromatic ring. However, throughOH
Ar

the kinetic resolution of racemic alcohols using a chiralruthenium catalyst, optically active alcohols with highoptical purities are now obtainable. This method canalso be applied to the synthesis of natural products
such as (-)-chokol G14) and (-) -pentenomycin15) .

O

O
+

R

CH3COCH3
28 ℃

racemic

substrate

OH(S,S )-cat
Ar

R

+

Ar

OH
R

+

unreacted alchol
recovery, %ee, %config.

catalyst

time, h

kf/ks

3a
3a
3b

36
22
30

50
47
44

92
92
98

R
R
R

>80
>30
>30

3a
3a

6
6

47
49

97
99

R
R

>40
>50

OH
R

R=H
R = p-OCH3
R = p-N(CH3)2OH

R

R = CH2
R = (CH2)2
S/C = 500

C Kanto Kagaku
54. Asymmetric transfer hydrogenation of imines 4), 15)
Up until now, it has been difficult to achieve the efficientsynthesis of optically active amines through the catalytic
asymmetric hydrogenation of imines. However, thereduction of imines using this catalyst is efficient, andoptically active amines with a high optical purities can beobtained in high yields.

R2

R2(S,S )- or (R,R )-cat

R1

NR3

R1

HCOOH/N(C2H5)3
solvent, 28 ℃

N
H

R3

HN

CH3O
NH

CH3O

cat : (S,S )-1a
S/C = 1000
97%, 94% ee (R )

N
H

NH
R

cat : (S,S )-1a
S/C = 200
R = CH3 86%, 97% ee (R )R = C6H5 83%, 96% ee (R )cat : RuCl[(S,S )-ArSO2dpen](η6-benzene)
Ar = 1-naphthyl
S/C = 10090%, 89% ee (S )

HN

HN

S
6

cat : RuCl[(S,S )-ArSO2dpen](η -benzene)
Ar = 1-naphthyl
S/C = 20072%, 77% ee (S )X

cat : RuCl[(S,S )-ArSO2dpen](η6-benzene)
Ar = 1-naphthyl
S/C = 200
X = S 82%, 85% ee (S )X = SO2 84%, 88% ee (S )C Kanto Kagaku
6

Standard operating procedures for the asymmetric transfer hydrogenation of ketones
Example procedures are shown below for the 1) production of optically active alcohols by the reduction of the ketonic
substrates 2) and 2) production of optically active hydrobenzoin from benzyl 11) , both using a chiral ruthenium catalyst in a
mixture of formic acid and triethylamine.

1）Synthesis of optically active alcohols
Under an inert gas atmosphere, add the ketononic substrate (5.0 mmol) and RuCl [(S,S)-Tsdpen] (mesitylene) (15.5mg,
0.025 mmol) into a Shrenk flask.

Add 2.5 ml of a mixture of formic acid/triethylamine note 1. note 2｡
Mix for 48-hours at 28 C. note 3

Dilute the reaction mixture with water, and extract with ethyl acetate or similar solvents. Wash the organic layer with asodium hydrogen carbonate solution and then with a saturated sodium chloride solution.

The optically active alcohols can be obtained through the prescribed refining operations. note 42）Synthesis of optically active hydrobenzoin
In an inert gas atmosphere, mix triethylamine (19.0 ml, 136 mmol) and formic
acid (8.7 ml, 230 mmol) in a Shrenk flask while keeping the mixture cool. note 1
Add benzyl (11.0g, 52.3 mol)note5 and RuCl [(S,S)-Tsdpen](p-cymene) (33.3 mg, 0.523 mmol)note2｡
Mix for 24-hours at 40 C. note 3

Add water to the reaction mixture, and filter out the deposited crystals.
(R,R)- Hydrobenzoin can be obtained from the recrystallization withethanol. note 4Note 1: The original research paper uses an azeotropic mixture but amixture of formic acid and triethylamine in the optimum ratio canalso be used without distillation. We recommends investigating
the optimum mixture ratio of formic acid and triethylamine for thesubstrate, since the optimum ratio varies depending on thesubstrate.

C Kanto Kagaku
7Note 2: Do not induce the reaction in a closed system, since carbon dioxide will be released. For example, as shown in
the photograph on the previous page, insert an inert gas line or attach a highly airtight gas balloon.
Note 3: Even if the reaction temperature is raised, the lowering of the optical yield is minimal. Therefore please optimize
the reaction temperature and time according to the reactivity of the substrate.
Note 4: The residual catalyst can be removed by filtering the organic layer through a short column of silica gel.
Note 5: An optically active hydrobenzoin can also be obtained from the racemic benzoin as a high yield. See thereferences for details.

Reference
1) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori,10) M. Yamamoto, H. Ito, and R. Noyori, “The Metal-Ligand“Asymmetric Transfer Hydrogenation of Aromatic Ketones

Bifunctional Catalysis. A Theoretical Study on the Ruthe-

Catalyzed by Chiral Ruthenium(II) Complexes”, J. Am.

nium(II)-Catalyzed Hydrogen Transfer Between Alcohols

Chem. Soc., 117, 7562-7563 (1995)

and Carbonyl Compounds”, J. Am. Chem. Soc., 122, 1466-

2) A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori,

1478 (2000)“Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogen-11) K. Murata, K. Okano, M. Miyagi, H. Iwane, R. Noyori, T.

ation of Ketones Using a Formic Acid-Triethylamine Mix-

Ikariya, “A Practical Stereoselective Synthesis of Chiralture”, J. Am. Chem. Soc., 118, 2521-2522 (1996)

Hydrobenzoins via Asymmetric Transfer Hydrogenation of3) K. Matsumura, S. Hashiguchi, T. Ikariya, R. Noyori,“Asymmetric Transfer Hydrogenation of α,β-Acetylenic
Ketones”, J. Am. Chem. Soc., 119, 8738-8739 (1997)
4) R. Noyori, S. Hashiguchi, “Asymmetric Transfer Hydrogenation Catalyzed by Chiral Ruthenium Complexes”, Acc.

Benzils”, Org.Lett., 1, 1119-1121 (1999)
12) S. Hashiguchi, A. Fujii, K.-J. Haack, K. Matsumura,T. Ikariya, R. Noyori, “Kinetic Resolution of Racemic Secondary Alcohols by RuII-Catalyzed Hydrogen Transfer”,
Angew. Chem. Int. Ed. Engl., 36, 288-290 (1997)
13) R.M. Kanada, T. Taniguchi, K. Ogasawara, “AsymmetricChem. Res., 30, 97-102 (1997)
5) K. OKano, K. Murata, T. Ikariya, “Stereoselective Synthesisof Optically active Pyridyl Alcohols via Asymmetric Transfer
Hydrogenation of Pyridyl Ketons”, Tetrahedron Lett., 41,

Hydrogenation Transfer Protocol for Enantiocontrolled
Synthesis of (-)-Chokol G”, Chem. Commun., 1998, 1755.
14) Y. Iura, T. Sugahara, K. Ogasawara, “Oxidative Resolution of
2-Cyclopentenols By the Asymmetric Hydrogen Transfer

9277-9280 (2000)
6) T. Koike, K. Murata, T. Ikariya, “Stereoselective Synthesis of
Optically Active α-Hydroxy Ketones and anti-1,2-Diols via

Protocol”, Tetrahedron Lett., 40, 5735-5738 (1999)
15) N.Uematsu, A.Fujii, S.Hashiguchi, T.Ikariya, R.Noyori,

Asymmetric Transfer Hydrogenation of Unsymmetrically“Asymmetric Transfer Hydrogenation of Imines”, J. Am.

Substituted 1,2-Diketones”, Org. Lett., 2, 3833-3836 (2000)

Chem. Soc., 118, 4916-4917 (1996)

7) M. Watanabe, K. Murata, T. Ikariya, J. Org. Chem., in press.
8) M.J. Palmer, M. Wills, “Asymmetric Transfer Hydrogenationof C=O and C=N Bonds”, Tetrahedron Asymmetry, 10,2045-2061 (1999)
9) K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori,“The Catalyst Precursor, Catalyst, and Intermediate in the
RuII-Promoted Asymmetric HydrogenTransfer between
Alcohols and Ketones”, Angew. Chem. Int. Ed. Engl., 36,
285-288 (1997)

C Kanto Kagaku
8Products■Asymmetric Transfer Hydrogenation Catalysts
Product Name
Chloro［（1S, 2S）-N-（p-toluenesulfonyl）-1,2-diphenylethanediamine］（p-cymene）ruthenium（Ⅱ）（p-cymene）（S,S）-1a
RuCl［（S,S）-Tsdpen］
Chloro complex；

Cat.No.

Package Size

08153-651g08153-95

200mg

Chloro［（1R, 2R）-N-（p-toluenesulfonyl）-1,2-diphenylethanediamine］（p-cymene）ruthenium（Ⅱ）（p-cymene）（R,R）-1a
RuCl［（R,R）-Tsdpen］
Chloro complex；

08154-651g08154-95

200mg

Chloro［（1S, 2S）-N-（p-toluenesulfonyl）-1,2-diphenylethanediamine］（mesitylene）ruthenium（Ⅱ）（mesitylene）（S,S）-1b
RuCl［（S,S）-Tsdpen］
Chloro complex；

08174-651g08174-95

200mg

Chloro［（1S, 2S）-N-（p-toluenesulfonyl）-1,2-diphenylethanediamine］（mesitylene）ruthenium（Ⅱ）（mesitylene）（R,R）-1b
RuCl［（R,R）-Tsdpen］
Chloro complex；

08173-651g08173-95

200mg

Chloro［（1S, 2S）-N-methanesulfonyl-1,2-diphenylethanediamine］（p-cymene）ruthenium（Ⅱ）（p-cymene）（S,S）-2a
RuCl［（S,S）-Msdpen］
Chloro complex；

08176-651g08176-95

200mg

Chloro［（1R, 2R）-N-methanesulfonyl-1,2-diphenylethanediamine］（p-cymene）ruthenium（Ⅱ）（p-cymene）（R,R）-2a
RuCl［（R,R）-Msdpen］
Chloro complex；

08175-651g08175-95

200mg［（1S, 2S）-N-（p-toluenesulfonyl）-1,2-diphenylethanediamine］（p-cymene）ruthenium（Ⅱ）（p-cymene）（S,S）-3aRu［（S,S）-Tsdpen］
Amide complex；

41067-651g41067-95

200mg［（1R, 2R）-N-（p-toluenesulfonyl）-1,2-diphenylethanediamine］（p-cymene）ruthenium（Ⅱ）（p-cymene）（R,R）-3a
Ru［（R,R）-Tsdpen］
Amide complex；

41066-65

1g

41066-95

200mg＜Quality certification＞
Every lot of above products is certified the quality by the performance test.
Ex. RuCl[(S,S)-Tsdpen](p-cymene)

Lot No.＊＊＊＊＊＊＊＊
substrateyieldhydrobenzoin
dl : meso
optical purity

benzil100 %97.8 : 2.2

100% ee（R,R）

Conditions: S/C = 1000, HCO2H/(C2H5)3N = 4.4/2.6, 40 ˚C, 24h

C Kanto Kagaku
9■Auxiliary Chliral Ligands
Product Name

Optical Purity

Cat.No.

Package Size

（1S, 2S）-N-（p-Toluenesulfonyl）-1,2-diphenylethanediamine＞99% ee41051-55

5ｇ（S,S）-TsDPEN（HPLC）

41051-65

1g（1R, 2R）-N-（p-Toluenesulfonyl）-1,2-diphenylethanediamine＞99% ee41052-55

5g（R,R）-TsDPEN（HPLC）

41052-65

1g（1S, 2S）-N--（Methanesulfonyl）-1,2-diphenylethanediamine＞99% ee25954-55

5g（S,S）-MsDPEN（HPLC）

25954-65

1g（1R, 2R）-N（Methanesulfonyl）-1,2-diphenylethanediamine＞99% ee25953-55

5g（R,R）-MsDPEN（HPLC）

25956-65

1g

PurityCat.No.

Package Size

11443-35

25g

11443-55

5g

11443-65

1g

Cat.No.

Package Size

11445-35

25g

11445-55

5g

11445-65

1g11444-35

25g

11444-55

5g

11444-65

1g

18618-35

25g

18618-55

5g

18617-35

25g

18617-55

5g

Cat.No.

Package Size

36502-3525g

36502-55

5g

36502-65

1g■Ruthenium Complex
Product Name
Dichloro（p-cymene）ruthenim（Ⅱ）, dimer［RuCl2（p-cymene）］2＞99 %■Chiral Compounds
Product Name

Optical Purity
NH2＞99% ee

NH2（HPLC）（1S, 2S）-（−）-1,2-Diphenyl-1,2-ethanediamine

NH2＞99% ee

NH2（HPLC）（1R, 2R）-（＋）-1,2-Diphenyl-1,2-ethanediamine

OH＞99% eeOH（HPLC）

OH＞99% eeOH（HPLC）（S,S）-（−）-Hydrobenzoin（R,R）-（＋）-Hydrobenzoin■Ruthenium Salt
Product Name

Assay

Ruthenium（Ⅲ）chloride n-hydrate＞37%

RuCl3・nH2O（as Ru）

C Kanto Kagaku
10Kanto ReagentsC KANTO CHEMICAL CO., INC.
REAGENT DIVISION
11-5, Nihonbashi-Honcho 3-chome, Chuo-ku, Tokyo 103-0023
Telephone+813-3667-6991
Telefax+813-3639-9435
http://www.kanto.co.jp

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