# US 6,720,439 B1 · Synthesis of ruthenium-hydride complexes and preparation procedures of chiral alcohols and ketones

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- Number: US 6,720,439 B1
- Document ID: US6720439B1
- Status: Granted
- Kind: B1
- Application number: 10/291,611
- Filed: 2002-11-12
- Granted: 2004-04-13
- Earliest claimed: 2002-11-12
- Assignees: Nagoya Industrial Science Research Institute
- Inventors: Takeshi Ohkuma; Masatoshi Koizumi; Kilian Muñiz; Ryoji Noyori
- Web page: https://patentgrep.com/patent/US6720439B1

## CPC

- C07C 67/31: by introduction of functional groups containing oxygen only in singly bound form
- B01J 31/121: {Metal hydrides}
- B01J 31/1805: {the ligands containing nitrogen}
- B01J 31/2409: {with more than one complexing phosphine-P atom}
- C07B 53/00: Asymmetric syntheses
- C07C 29/145: with hydrogen or hydrogen-containing gases
- C07C 67/56: by solid-liquid treatment; by chemisorption
- C07C 213/00: Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07D 303/22: with monohydroxy compounds
- C07D 317/24: esterified
- C07F 15/0053: {without a metal-carbon linkage}
- B01J 2231/643: of R2C=O or R2C=NR (R= C, H)
- B01J 2531/0266: Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
- B01J 2531/821: Ruthenium
- C07B 2200/07: Optical isomers
- C07C 2601/14: The ring being saturated
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

trans-RuH(η1-BH4)[(S)-xylbinap][(S,S)-dpen] (0.00125 mmol), acetophenone (5.0 mmol), and 2-propanol (2.5 mL) were placed in an autoclave, and the resulting solution was repeatedly subject 5 times to a procedure of performing pressure reduction and argon introduction while stirring the solution for deaeration. A hydrogen tank was then connected to the autoclave, and after replacing the air inside an introduction tube with hydrogen, the pressure inside the autoclave was adjusted to 5 atmospheres and then hydrogen was released until the pressure dropped to 1 atmosphere. After repeating this procedure 10 times, the hydrogen pressure was adjusted to 8 atmospheres and stirring at 25° C. was performed for 12 hours. By concentrating the solution obtained by depressurization and subjecting the crude product to simple distillation, (R)-1-phenylethanol (yield: 95%) in the form of a colorless oily substance was obtained at an ee of 99%.

## Claims

### Claim 1

A ruthenium hydride complex expressed by the following general formula (1):
(wherein for R1R2P—W—PR3R4, W is a binaphthyl group, which is bonded to phosphorus atoms at positions 2 and 2′ and may have one or more substituents at any of the other positions, each of R1 to R4 is the same or different hydrocarbon group that may or may not have one or more substituents, R1 and R2 may together form a carbon chain ring that may have one or more substituents, R3 and R4 may together form a carbon chain ring that may have one or more substituents,
each of R5 to R8 is the same or different hydrocarbon group that may or may not have one or more substituents,
Z is a hydrocarbon group that may or may not have one or more substituents, and
each of the ligands of Ru may be positioned in any manner).

### Claim 2 (depends on 1)

The ruthenium hydride complex as set forth in claim 1, wherein
the amine ligand is an optically active diamine.

### Claim 3 (depends on 1)

The ruthenium hydride complex as set forth in claim 1, wherein
the phosphine ligand is an R form and the amine ligand is an optically active diamine with the chiral center carbon being an R,R form.

### Claim 4 (depends on 1)

The ruthenium hydride complex as set forth in claim 1, wherein
the phosphine ligand is an R form and the amine ligand is an optically active diamine with the chiral center carbon being an S,S form.

### Claim 5 (depends on 1)

The ruthenium hydride complex as set forth in claim 1, wherein
the phosphine ligand is an S form and the amine ligand is an optically active diamine with the chiral center carbon being an S,S form.

### Claim 6 (depends on 1)

The ruthenium hydride complex as set forth in claim 1, wherein
the phosphine ligand is an S form and the amine ligand is an optically active diamine with the chiral center carbon being an R,R form.

### Claim 7

A method of preparing an alcohol compound wherein
a ruthenium hydride complex expressed by the following general formula (1) is used to prepare an alcohol compound by reduction of a carbonyl compound under the non-presence of a strong base, under the presence of at least one compound selected from the group consisting of hydrogen and hydrogen donating compounds, and either in a reaction solvent or under solvent-free conditions,
General formula (1):
(wherein for R1R2P—W—PR3R4, W is a binaphthyl group, which is bonded to phosphorus atoms at positions 2 and 2′ and may have one or more substituents at any of the other positions, each of R1 to R4 is the same or different hydrocarbon group that may or may not have one or more substituents, R1 and R2 may together form a carbon chain ring that may have one or more substituents, R3 and R4 may together form a carbon chain ring that may have one or more substituents,
each of R5 to R8 is the same or different hydrocarbon group that may or may not have one or more substituents,
Z is a hydrocarbon group that may or may not have one or more substituents, and
each of the ligands of Ru may be positioned in any manner).

### Claim 8 (depends on 7)

The method as set forth in claim 7 wherein
an optically active alcohol compound is prepared by chiral reduction of an asymmetric carbonyl compound.

### Claim 9 (depends on 7)

The method as set forth in claim 7 wherein
said reaction solvent is a secondary alcohol.

### Claim 10 (depends on 7)

The method as set forth in claim 7 wherein
said carbonyl compound is an asymmetric carbonyl compound that is sensitive to base.

### Claim 11 (depends on 10)

The method as set forth in claim 10 wherein
said asymmetric carbonyl compound that is sensitive to base is an asymmetric carbonyl compound having at least one group selected from the group consisting of ester groups, epoxy groups, β-amino groups, and groups with an α, β-unsaturated bond.

### Claim 12

A method of preparing an alcohol compound wherein
a ruthenium hydride complex expressed by the following general formula (1) is prepared and used without being isolated to prepare an alcohol compound by reduction of a carbonyl compound under the non-presence of a strong base and under the presence of at least one compound selected from the group consisting of hydrogen and hydrogen donating compounds,
General formula (1):
(wherein for R1R2P—W—PR3R4, W is a binaphthyl group, which is bonded to phosphorus atoms at positions 2 and 2′ and may have one or more substituents at any of the other positions, each of R1 to R4 is the same or different hydrocarbon group that may or may not have one or more substituents, R1 and R2 may together form a carbon chain ring that may have one or more substituents, R3 and R4 may together form a carbon chain ring that may have one or more substituents,
each of R5 to R8 is the same or different hydrocarbon group that may or may not have one or more substituents,
Z is a hydrocarbon group that may or may not have one or more substituents, and
each of the ligands of Ru may be positioned in any manner).

### Claim 13 (depends on 12)

The method as set forth in claim 12 wherein
an optically active alcohol compound is prepared by chiral reduction of an asymmetric carbonyl compound.

### Claim 14 (depends on 12)

The method as set forth in claim 12 wherein
said reaction solvent is a secondary alcohol.

### Claim 15 (depends on 12)

The method as set forth in claim 12 wherein
said carbonyl compound is an asymmetric carbonyl compound that is sensitive to base.

### Claim 16 (depends on 15)

The method as set forth in claim 15 wherein
said asymmetric carbonyl compound that is sensitive to base is an asymmetric carbonyl compound having at least one group selected from the group consisting of ester groups, epoxy groups, β-amino groups, and groups with an α, β-unsaturated bond.

### Claim 17

A method of separating racemic carbonyl compounds wherein
a ruthenium hydride complex expressed by the following general formula (1) is used to selectively reduce one enantiomer among carbonyl compounds which are a mixture of different enantiomers to thereby obtain the other enantiomer, under the non-presence of a strong base, under the presence of at least one selected from the group consisting of hydrogen and hydrogen donating compounds, and either in a reaction solvent or under solvent-free conditions,
General formula (1):
(wherein for R1R2P—W—PR3R4, W is a binaphthyl group, which is bonded to phosphorus atoms at positions 2 and 2′ and may have one or more substituents at any of the other positions, each of R1 to R4 is the same or different hydrocarbon group that may or may not have one or more substituents, R1 and R2 may together form a carbon chain ring that may have one or more substituents, R3 and R4 may together form a carbon chain ring that may have one or more substituents,
each of R5 to R8 is the same or different hydrocarbon group that may or may not have one or more substituents,
Z is a hydrocarbon group that may or may not have one or more substituents, and
each of the ligands of Ru may be positioned in any manner).

### Claim 18 (depends on 17)

The method as set forth in claim 17, wherein
said carbonyl compounds are selected from the group consisting of α-alkyl ketones, α-alkoxy ketones, and α-amino ketones.

### Claim 19 (depends on 17)

The method as set forth in claim 17 wherein
said reaction solvent is a secondary alcohol.