Highly Selective Hydrogenation Catalysts

CKANTO Reagents

Organics
Three-component catalyst effective for hydrogenation of simple ketones, composed of Ruthenium(II) complexes
with phosphine ligands (or diphosphine), 1,2-diamine and strong base, was discoverd by NOYORI MolecularCatalysis Project of Exploratory Research for Advanced Technology (ERATO) organized by Japan Science andTechnology Corporation (JST).
This catalyst catalyzes highly efficient hydrogenation of simple ketones. In addition to high activity, carbonylselective hydrogenation of aldehydes and ketones with conjugated or unconjugated carbon-carbon multiplebonds 1), and diastereoselective hydrogenation of various ketones 2), 3) are performed smoothly under mildconditions, such as at room temperature and/or under low hydrogen-pressure(1-10atm), to give thecorresponding alcohols in a nearly quantitative yields. The use of chiral Ruthenium(II)-diphosphine complex, incombination with appropriate chiral diamine, catalyzes enantioselective hydrogenation of prochiral ketones togive chiral alcohols with a very high enantiomeric purity 1), 3), 4). Furthermore this catalyst is environmentallyconscientious because of extremely high acitivity minimizing metal disposal after the reaction, compared with thestoichiometric reduction with metal hydride reagents, and the use of 2-propanol as a solvent 5).
Exploitation and Application Study(participants : Nagoya University, Aich Institute of Technology, Tokyo Instituteof Technology, Sumitomo Chemical Co., Ltd., Takasago International Corporation, Nissan Chemical Ind., Ltd.,
Nippon Soda Co., Ltd., and Kanto Chemical Co., Inc.) supported by JST has improved this catalyst into twocomponent catalyst : one of them is the shelf-stable and easy to handle Ruthenium(II) complexes, which haveboth of phosphine(or diphosphine) and 1,2-diamine ligands, and the other is strong base. We are now able tooffer the ready-to-use Ruthenium(II) complexes for easy-handling and simpler preparation of catalyst in alaboratory. Two-component catalyst, which is composed of this improved Ruthenium(II) complexes and strong
base, 6) has realized an exceedingly efficient hydrogenation of simple ketones, which rates and productivities
from one to two orders of magnitude higher than those obtained with three-component catalyst 1)-4), keeping thehigh selectivity. We recommend this catalyst for the laboratory-use, as well as the improvement and development
in your production process.

EXAMPLE OF HYDROGENATION
1. HYDROGENATION OF UNSATURATED ALDEHYDES AND KETONES 1)
Carbonyl compounds with conjugated or unconjugated carbon-carbon multiple bonds can be converted rapidly
and quantitatively to the corresponding unsaturated alcohols.

O+R

UnOH

cat.
H2
1–8 atm

Un(CH3)2CHOH

R

R = H, alkyl, aryl
Un = olefin-, or acetylene-containing groupcat. = RuCl2[P(C6H5)3]3-NH2(CH2)2NH2-KOH (1 : 1 : 2 molar ratio)

ExampleOH
isolated yield 92%
carbonyl-selectivity 100%

OHOH

yield 99.7%
carbonyl-selectivity 99.8%

OHOHn-C3H7
yield 99.8%
carbonyl-selectivity > 99.9%

2

yield 100%carbonyl-selectivity > 99.9%

yield 99.5%
carbonyl-selectivity 100%

Highly Selective Hydrogenation Catalysts

2. DIASTEREOSELECTIVE HYDROGENATION OF KETONES 2)
Example 1.
OOH

OH

cat.
H2
4 atm++(CH3)2CHOH

R
cat. = RuCl2[P(C6H5)3]3-NH2(CH2)2NH2-KOH (1 : 1 : 2 molar ratio)

RR

cistrans

R% yieldcis : transt-C4H9>99

98 : 2

C6H5>99

96 : 4

CH39792 : 8Example 2.
OH

OHOHOH

cis : trans = 4 : 96

98 : 2>99.8 : 0.2

99 : 1OH
endo : exo = 99.1

3. ENANTIOSELECTIVE HYDROGENATION OF KETONES 1), 3), 4)
O+UnOHcat.
R

H2
1–8 atm

Un(CH3)2CHOH* R

R = alkyl
Un = aromatic, olefin-, or acetylene-containing groupcat. = RuCl2(binap)(dmf)n-chiral diamine-KOH (1 : 1 : 2 molar ratio)

OCH3

P(C6H5)2NH2

P(C6H5)2

NH2

CH3O
NH2(CH3)2CH(S )-BINAP(S, S )-DPEN

NH2(S )-DAIPEN
chiral diamine3Organics
Examples of chiral cat : RuCl2[(S )-binap](dmf)n-(S,S )-DPEN(or(S )-DAIPEN)-KOH

R

carbonyl-selectivity > 98%% ee

OHOH

Ro-, m-, p-CH3

86 – 94

p-(CH3)3C

96o-, m-, p-Cl

90 – 94m-, p-CH3O

88, 92

ROHOH

R% ee

CH291(CH2)298(CH2)3

81

OCH3

OH

OCH3
carbonyl-selectivity 99%
99% eecarbonyl-selectivity 99%
92% eecarbonyl-selectivity 99%
94% eeSELECTION OF THE CATALYSTEnantioselectivity is influenced by the structure and the combination (matched or mismatched) of chiraldiphosphine and diamine ligands5). Appropriate diphosphine and diamine ligands should be selected, dependingon the structure of ketones, to obtain chiral alcohols in high optical yields.
Examples above mentioned show the results using the combination of S-configurated diphosphine and Sconfigurated diamine ligand. However, some cases prefer to employ the other combination of diphosphine anddiamine ligands as follows. Regarding the selection of the best combination, please refer to the references orcontact with our Technical Department of Reagent Division.

Example 1. The preferable combination of (S)-BINAP and (R,R)-DPEN 3)
OOHOH

1cat.
+

H2
4–8 atm+(CH3)2CHOH

5(R)-Carvone(1R,5R)-Carveol
cis(1S,5R)-Carveol
transcat. = RuCl2(binap)(dmf)n-DPEN-KOH

4diphosphine

1,2-diamine

S/C

H2, atm

time, h% yield of alcohol

cis : trans(S )-BINAP(R, R)-DPEN

500

43.5100

100 : 0(S )-BINAP(S, S )-DPEN

500

41694

87 : 13(R)-BINAP(R, R)-DPEN

500

81799

88 : 12(R)-BINAP(S, S )-DPEN

500

81799

34 : 66

Highly Selective Hydrogenation Catalysts

Example 2. The preferable combination of (S)-BINAP and (S,S)-DPEN3)
substrate : (R)-Pulegone
diphosphine : (S )-BINAP
diamine : (S,S )-DPEN
cis : trans = 98 : 2OH

Example 3. DAIPEN complex is preferable than DPEN complex
OH1) diphosphine : (S )-BINAP
1,2-diamine : (S )-DAIPEN
94% ee*2) diphosphine : (S )-BINAP
1,2-diamine : (S,S )-DPEN
82% ee*Example 4. DPEN complex is preferable than DAIPEN complex
OH1) diphosphine : (S )-BINAP
1,2-diamine : (S )-DAIPEN
89% ee*2) diphosphine : (S )-BINAP
1,2-diamine : (S,S )-DPEN
94% ee** obtained by the two-component catalyst composed of the ready-to-use Ruthenium(II) complex and strong base

HYDROGENATION UNDER THE ATMOSPHERIC PRESSURE OF HYDROGEN
Hydrogenation of simple ketones by two-component catalyst, composed of the ready-to-use Ruthenium(II)complex and strong base, takes place even under the atmospheric pressure of hydrogen, so that hydrogenation
can be achieved without a pressure vessel such as an autoclave. In these cases, the enantioselectivities are almost
the same as those under higher pressures of hydrogen. When the rate of the reaction is insufficient, increasing
the molar ratio of the catalyst to the substrate provides the product in the higher yield in shorter reaction time.
(cat. = Ru complex-(CH3)3COK (molar ratio 1 : 10)).

substrate

Ru-complex

S/Ctime, h% yield of alcohol % ee*∫-Ionone

RuCl2[P(p-CH3C6H4)3]2[NH2(CH2)2NH2]

500

24100

—

1'-Acetonaphthone

RuCl2[(R)-binap][(R, R)-dpen]

500

12100

97

1'-Acetonaphthone

RuCl2[(R)-binap][(R, R)-dpen]

2000

2410097

1'-AcetonaphthoneRuCl2[(R)-binap][(R, R)-dpen]

10000

24

5297

1'-Acetonaphthone

RuCl2[(R)-binap][(R, R)-dpen]

10000

488497* enantiomeric excess, % of (S )-1-(1'-Naphthyl)ethanol5

Organics
PROCEDURE(wuitha pressurea pressurevessel) vessel)
PROCEDUREFORFORHYDROGENATIONHYDROGENATION OF
OF KETONESKETONES (withcat. = RuCl2(binap)(dpen), S/C = 2000 (molar ratio)
Reaction vesssel (internal volume : 100 ml)*1
the ready-to-use Ruthenium(II) complex*2 : ca. 10 mg (0.01 mmol)(a solid substrate of ketone should be added with the ready-to-use Ruthenium(II) complex at this point.
Ketone substrate*3 : 20 mmol)

Purging away the inside gas of the vessel and displacing with argon or nitrogen gas (1 time)
Ketone substrate*3 : 20 mmol
0.01 M solution of potassium alkoxide in 2-propanol*4,*5 : 10ml (0.1mmol)

Purging away the inside gas of the vessel and displacing with argon gas*6

Purging away the inside gas of the vessel and displacing with hydrogen gas (3-5 times)*7

Pressurizing with hydrogen gas (9 atm)

Hydrogenation*8

Isolating the alcohol product*1 : In case of hydrogenation at the lower hydrogen pressure than 9 atm, a pressure resistant glass vessel withguard jacket can be used, as well as a stainless steel autoclave.
*2 : Ruthenium(II) complex can be handled in the air, however, it should be kept in inert gas for a long termpreservation.
*3 : Because this hydrogenation is sensitive even to a small amount of acid, acidic impurities should be
carefully removed. By the following step, washing the substrate dissolved in appropriate solvent with anaqueous KOH solution, then drying the solution with Na2SO4 anhydride, the substrate can be purified with
an appropriate purity.
*4 : The strong base more than 2 times of Ruthenium(II) complex in molar ratio is required for hydrogenationof a ketone substrate. Unstable enones against the base may polymerize this conditions. In that case, theconcentration of the strong base should be optimized, or K2CO3, a weak base cocatalyst in place of thestrong base, is effective.
*5 : When a ketone substrate is hard to dissolve in 2-propanol, toluene or tetrahydrofuran can be used as a cosolvent (for example, 2-propanol : toluene = 1 : 1 or 2-propanol : tetrahydrofuran = 1 : 1).
*6 : Depending on a substrate, even a small amount of air should be more strictly eliminated. Freeze-pumpthaw and purifing technique can be recommended (refer to the procedure in the literature : Purification ofLaboratory Chemicals, 3rd Edition, p 19, Pergamon Press (1998).

6

Highly Selective Hydrogenation Catalysts*7 : For keeping safety, purifing with hydrogen in a pressure vessel and hydrogenation procedure should beoperated in a draft-chamber (refer to the procedure in the literature : M. Kitamura, M. Tokunaga, T.
Ohkuma, and R. Noyori, Org. Synth., 71, 1-13, (1993))*8 : After the completion of hydrogenation, the hydrogen pressure will be decreased up to the range of 4-5atom.
Hydrogenation with more than 2000 substrate/catalyst molar ratio can be operated by the same procedure asmentioned above. 100% yield was achieved with 2,400,000 substrate/catalyst molar ratio by the optimization of
the conditions, such as concentration of the strong base and hydrogen pressure (strong base/Ruthenium(II)complex = 24000/1, hydrogen pressure = 45 atm) 6). Regarding details of the operating condition, please refer tothe references or contact us.

Reference
1. T. Ohkuma, H.Ooka, T. Ikariya, and R. Noyori, Preferential Hydrogenation of Aldehydes and Ketone, J. Am.
Chem. Soc., 117, 10417-10418 (1995).
2. T.Ohkuma, H. Ooka, M. Yamakawa, T. Ikariya, and R. Noyori, Stereoselective Hydrogenation of Simple
Ketones Catalyzed by Ruthenium(II) Complexes, J. Org. Chem., 61, 4872-4873 (1996).
3. T. Ohkuma, H. Ikehira, T. Ikariya, and R. Noyori, Asymmetric Hydrogenation of Cyclic å,∫-Unsaturated
Ketones to Chiral Allylic Alcohols, Synlett, 467-468 (1997).
4. T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, and R. Noyori, Practical Enantioselective Hydrogenation ofAromatic Ketones, J. Am. Chem. Soc., 117, 2675-2676 (1995).
5. T. Ohkuma, R. Noyori, Enantioselective Hydrogenation of Simple Ketones, J. Syn. Org. Chem., Japan, 57, 553563 (1996).
6. H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M. Kozawa, E. Katayama, A. F. England, T. Ikariya, and R.
Noyori, trans-[RuCl2(phosphane)2(1,2-diamine)] and Chiral trans-[RuCl2(diphosphane)(1,2-diamine)] : ShelfStable Precatalysts for Rapid, Productive, and Stereoselective Hydrogenation of Ketones, Angew. Chem., Int.
Ed. Engl., 37, 1703-1707 (1998).
7. T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K. Murata, E. Katayama, T. Yokozawa, T. Ikariya,
and R. Noyori, Asymmetric Hydrogenation of Alkenyl, Cyclopropyl, and Aryl Ketones. RuCl2 (xylbinap)(1,2diamine) as a Precatalyst Exhibiting a Wide Scope, J. Am. Chem. Soc., 120, 13529-13530 (1998).

newHydrogenation Catalysts Trial Kit
7Ruthenium Complexes
Cat.No.
11400-65
11400-95
11401-65
11401-95
11403-6511403-95
11409-6511409-95
11402-6511402-95
11405-6511405-95
11404-6511404-95
11408-6511408-95

Package Size

Product Name

1g

Dichlorobis(triphenylphosphine)(1,2-ethanediamine)ruthenium(II)
RuCl2[P(C6H5)3]2[NH2(CH2)2NH2]

200mg
1g

Dichlorobis(tri-p-tolylphosphine)(1,2-ethanediamine)ruthenium(II)
RuCl2[P(p-CH3C6H4)3]2[NH2(CH2)2NH2]

200mg
1g

Dichloro[(S )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl][(S,S )-1,2-diphenylethanediamine]ruthenium(II)
RuCl2[(S )-binap][(S,S )-dpen]

200mg
1g

Dichloro[(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl][(S)-1,1'-bis(p-methoxyphenyl)-2-isopropylethane-1,2-diamine]ruthenium(II)
RuCl2[(S )-binap][(S )-daipen]

200mg
1g

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

200mg
1g

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

200mg

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

200mg

Dichloro[(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl][(R)-1,1'-bis(p-methoxyphenyl)-2-isopropylethane-1,2-diamine]ruthenium(II)
RuCl2[(R)-binap][(R)-daipen]

200mg

1g
1g

Hydrogenation Catalysts Trial Kits
Cat.No.

Product Name

Content

18707-96

Hydrogenation Catalysts Trial Kit 1RuCl2[P(C6H5)3]2[NH2(CH2)2NH2]
RuCl2[P(p-CH3C6H4)3]2[NH2(CH2)2NH2]

20mg
20mg

18708-96

Hydrogenation Catalysts Trial Kit 2

RuCl2[(S )-binap][(S,S )-dpen]
RuCl2[(S )-binap][(S )-daipen]

20mg
20mg

18709-96

Hydrogenation Catalysts Trial Kit 3

RuCl2[(S )-binap][(S,S )-dpen]
RuCl2[(S )-binap][(S )-daipen]
RuCl2[(S )-binap][(R,R)-dpen]
RuCl2[(R)-binap][(S,S )-dpen]

20mg
20mg
20mg
20mg

34062-95

Potassium tert-butoxide, in 2-propanol

0.01mol/l tert-C4H9OK in 2-propanol

100ml

Auxiliary Chiral Ligands
Cat.No.
04970-55
04970-6504969-5504969-6511406-6511406-95
11407-6511407-95

Package Size

Product Name(S )-(–)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl(S )-(–)-BINAP(R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl(R)-(+)-BINAP(S )-1,1'-Bis(p-methoxyphenyl)-2-isopropylethane-1,2-diamine(S )-DAIPEN(R)-1,1'-Bis(p-methoxyphenyl)-2-isopropylethane-1,2-diamine(R)-DAIPEN

5g
1g
5g
1g
1g
200mg
1g200mg

C KANTO CHEMICAL CO., INC.
REAGENT DIVISION
MARUSAN Bldg-2F 11-5, Nihonbashi-Honcho 3-chome, Chuo-ku, Tokyo 103-0023
Telephone+813-3639-8301
Telefax+813-3639-9435
http://www.kanto.co.jp

reag-info@gms.kanto.co.jp