JP2988757B2 - Novel asymmetric axially asymmetric bisphosphine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel asymmetrical asymmetric bisphosphine derivative having no twice-rotational axis, which is useful as a ligand of a catalyst for various organic synthesis reactions, particularly an asymmetric hydrogenation reaction. It is.

[0002]

2. Description of the Related Art At present, a large number of optically active bisphosphine derivatives have been developed as ligands for catalysts for asymmetric synthesis.
The present inventors have previously discovered that by changing the electronic and steric environment of each phosphino group of bisphosphine so as to have different functions, it is possible to achieve higher catalytic activity (Japanese Patent Application Laid-Open No. Sho 63). -5094, JP-A-64-1908
No. 5). However, a bisphosphine derivative having an asymmetric axis asymmetry without a double rotation axis has not been known.

[0003]

SUMMARY OF THE INVENTION Conventional bisphosphine derivatives require complex preparation with a transition metal such as rhodium or ruthenium, or require a high hydrogen pressure during reduction. With the shortcomings you need,
Has practical challenges.

[0004] From this point of view, in a series of studies, based on the finding that the functions of two phosphino groups differ from each other in terms of the asymmetric hydrogenation mechanism, the electronic and steric properties of each phosphino group in the molecule are determined. Inspired by an asymmetric bisphosphine derivative [I] that does not have a twice-rotation axis in different environments, the results of research indicate that the compound of the present invention is a practical and useful ligand for a catalyst for asymmetric synthesis. To complete the present invention.

[0005]

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[Wherein R ¹ and R ² are the same or different and each is a phenyl group (the phenyl group is 1 to 5 members selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) R ³ , R ⁴ , R ⁷ , and R ⁸ may be the same or different and a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, R ⁵ and R ⁶ is the same or different and is a lower alkyl group, a lower alkoxy group,
Represents a trifluoromethyl group, or R ⁴ and R ⁵ , R ⁶
And R ⁷ together represent an aromatic ring, wherein R ³ and R ⁸ , R ⁴ and R ⁷ , R ⁵ and R ^6, and R ¹ and R ² are at least one pair of different substituents Represents].

According to the present invention, the asymmetric bissymmetric phosphine derivative having no twice-rotational axis represented by the above-mentioned general formula [I] can be prepared from the compound represented by the general formula [VII] by the following route. Can be manufactured.

(1) The compound represented by the general formula [I] is
The compound of formula [VII] wherein Y ¹ is P (O) _n (R ¹ ) ₂ can be produced by optical resolution and then reducing the phosphinyl group.

[0009]

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Wherein R ² is a phenyl group (the phenyl group may be substituted by 1 to 5 members selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or cyclohexyl Groups represented by R ³ , R
⁴ , R ⁷ and R ⁸ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group; R ⁵ and R ⁶ are the same or different and are a lower alkyl group or a lower alkoxy group; , A trifluoromethyl group, or R ⁴ and R ⁵ , R ⁶ and R ⁷ together represent an aromatic ring, Y ¹ is a halogen atom, P (O) _n (R ¹ ) ₂ (where R ¹ is a phenyl group (the phenyl group may be substituted with 1 to 5 groups selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or a cyclohexyl group, and n is 0 or 1 Wherein R ³ and R ⁸ , R ⁴ and R ⁷ , R ⁵ and R ^6, and R ¹ and R ² represent at least one pair of different substituents].

Here, the optical resolution is preferably fractionation using a chiral column, for example, a chiral pack OT (+) (manufactured by Daicel Corporation).

In the above optical resolution, it is preferable that at least one phosphinyl group is present.

The reduction of the phosphinyl group is carried out by using a reducing agent
For example, it is preferable to use trichlorosilane, for example, in chlorobenzene as a solvent, and to carry out the heating.

(2) The compound represented by the general formula [I] is
After optically resolving the compound in which Y ¹ is a halogen atom in the general formula (VII), if necessary, after reducing the phosphinyl group, the compound is reacted with the compound represented by the general formula (XIII), and then, if necessary, the phosphinyl group is converted. It can be produced by reduction.

[0015]

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Wherein R ² is a phenyl group (the phenyl group may be substituted by 1 to 5 members selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or cyclohexyl group, n represents a represents 0 or the number 1), X ³ represents an halogen atom,
R ³ and R ^8, R ⁴ and R ^7, R ⁵ and R ⁶ and R ¹ and R
² , at least one of the pairs represents a different substituent].

The optical resolution and the reduction of the phosphinyl group are (1)
Method. In the reaction with the compound represented by the general formula (XIII), the compound in which Y ¹ is a halogen atom in the general formula (VII) is lithiated with an organic lithium reagent in an organic solvent such as ether or tetrahydrofuran, After preparing a Grignard reagent with metallic magnesium, the compound represented by the general formula [XIII] can be allowed to act, but an organic lithium reagent such as n-butyllithium or t-butyllithium is used, and the reaction temperature is -50 to -70 ° C
It is preferable to carry out in. In the case of this reaction, it is advantageous that the phosphinyl group of the compound of the general formula [VII] is reduced to a phosphino group.

The compound represented by the general formula [VII] can be synthesized according to the following chemical formula 25.

[0019]

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The reaction in Chemical formula 25 is easily carried out by the method described below. a) Halogenation: The halogenation reaction is performed in an organic solvent such as acetic acid or methylene chloride at a reaction temperature of 10 to 50.
It is preferably carried out at a temperature of ° C. As the halogenating agent, a normal halogenating agent can be used, but bromine is particularly preferable.

B) Sandmeyer reaction: In the Sandmeyer reaction, a diazonium salt is prepared with sodium nitrite in an organic solvent such as acetic acid, nitric acid or hydrogen bromide.
It is preferable to act potassium iodide or cuprous bromide as a halogenating agent. The reaction is preferably performed at a temperature of 0 to 30 ° C.

C) Reduction of nitro group: In the case of reduction of a nitro group, an ordinary reducing agent can be used, but when another substituent contains a halogen atom, an iron-hydrochloric acid system is preferable. In the case of a group, catalytic reduction using a palladium-carbon catalyst is preferred. In the case of catalytic reduction, the solvent is preferably alcohol.

D) Curtius rearrangement: The method of converting a lower alkoxycarbonyl group into an amino group is preferably a method utilizing Curtius rearrangement. After hydrolyzing the lower alkoxycarbonyl group, the resulting carboxylic acid compound is converted with thionyl chloride or the like. Or acid chloride, or with chloroalkyl carbonate, acid anhydride, then with sodium azide,
It can be converted to an acyl azide form, converted to an isocyanate form by refluxing in an organic solvent such as benzene or toluene, and further converted to an amino form by hydrolysis with an alkali.

E) Reaction with X ³ P (O) _n (R ¹ ) ₂ : reaction between the compound represented by the above general formula [VII] wherein Y ¹ is a halogen atom and the compound represented by the general formula [XIII] According to the reaction.

F) Oxidation reaction of phosphino group: Oxidation reaction of phosphino group can be easily carried out using a usual oxidizing agent, for example, aqueous hydrogen peroxide.

G) Reduction reaction of phosphinyl group: According to the method described in (1) above.

Among the compounds represented by Chemical Formula 25, the compound represented by the general formula [XIX] is a compound represented by the general formula [XX] and the compound represented by the general formula [XXI] Can be produced by acting in the presence of

[0028]

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Wherein R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group; R ⁵ represents a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group; Represents a group or R ⁴
And R ⁵ together represent an aromatic ring, Y ³ represents a hydrogen atom, a nitro group or a lower alkoxycarbonyl group, and X ⁴ represents a halogen atom or a boric acid group.

[0030]

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Wherein R ⁷ and R ⁸ are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, and R ⁶ represents a lower alkyl group, a lower alkoxy group or a trifluoromethyl group; Represents a group or R ⁶
And R ⁷ together represent an aromatic ring, Y ⁴ represents a hydrogen atom, a nitro group, a lower alkoxycarbonyl group, X ⁵ represents a halogen atom or a boric acid group, but X ⁴ and X ⁵ are simultaneously a boric acid group. Absent〕.

In the reaction of the compound represented by the general formula [XX] with the compound represented by the general formula [XXI], X ⁴ and X ⁵
When both are halogen atoms, for example, using copper powder as a metal catalyst, sulfolane, in an organic solvent such as quinoline,
The reaction is preferably performed at a reaction temperature of 170 to 250 ° C. Here, when Y ³ and Y ⁴ are a nitro group or a lower alkoxycarbonyl group, X ⁴ and X ⁵ are preferably a bromine atom, and when Y ³ and / or Y ⁴ are a hydrogen atom,
It is preferably an iodine atom.

In the reaction of the compound represented by the general formula [XX] with the compound represented by the general formula [XXI], X ⁴ or X ⁵
Is a boric acid group, using a palladium catalyst, particularly a tetrakistriphenylphosphine palladium zero-valent complex,
It is preferable to carry out the reaction in an organic solvent such as benzene, toluene and methylene chloride at the reflux temperature of the solvent.

Further, the general formula as a raw material [XX] and the compound represented by the general formula [XXI] is known literature (e.g. Tetrahedron, 37, 747 (1981), etc.) or can be synthesized according to, or even nitrated Alternatively, a necessary raw material can be produced by reacting with an organolithium reagent or the like and then reacting with a trialkyl borate.

[0035]

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

Embodiment 13-methoxy-2,4-dimethyl-2'-nitro-
4 ', 6'-bis (trifluoromethyl) -1,1'-
Synthesis of biphenyl 3-Iodo-2,6-dimethyl in sulfolane (70 ml)
Luanisole (26.21 g), 1-bromo-2-nitto
B-4,6-bis (trifluoromethyl) benzene (3
3.80 g) was completely dissolved, and copper powder (13.98 g) was added.
The mixture was stirred at 170 ° C. for 5 hours. Brown reaction slurry liquid
After cooling to room temperature, ether (100 ml) was added.
Then, suction filtration was performed to remove a brown solid. Ate in the filtrate
(400 ml), water (200 ml x 3), saturated
After successive washing with brine (200 ml), anhydrous magnesium sulfate
Dried with um. After distilling off the ether under reduced pressure, brown syrup
Of the residue (40.00 g) was separated by silica gel chromatography.
Separation and purification (n-hexane: ethyl acetate = 200: 1)
The target product (31.46 g) was obtained as a slightly yellow solid (yield: 80).
%).

Melting point 80-81 ° C. Elemental analysis (%): as C ₁₇ H ₁₃ F ₆ NO ₃ H-NMR (δ, CDCl ₃ ): 1.97 (3H,
s), 2.34 (3H, s), 3.73 (3H, s),
6.75 (1H, d, J = 7.9 Hz), 7.06 (1
H, d, J = 7.9 Hz), 8.21 (1H, s),
8.22 (1H, s) IR (νmax, cm ⁻¹ ): 15
40, 1340 (KBr).

Embodiment 22'-amino-3-methoxy-2,4-dimethyl-
4 ', 6'-bis (trifluoromethyl) -1,1'-
Synthesis of biphenyl In ethanol (200 ml), the compound of Example 1 (39.
33 g) was completely dissolved and 5% palladium on carbon (50%
Water-containing, 8.00 g), and added for 40 hours at room temperature in a hydrogen stream.
While stirring. Filter the black suspension reaction solution, 5% palladium
The carbon was removed. After removing ethanol by filtration under reduced pressure, vacuum drying
The desired product (35.97 g) was obtained as a white powder (yield 9).
9%).

Melting point 121-122 ° C. Elemental analysis (%): as C ₁₇ H ₁₅ F ₆ NO H-NMR (δ, CDCl ₃ ): 1.97 (3H,
s), 2.35 (3H, s), 3.74 (3H, s),
6.79 (1H, d, J = 7.7 Hz), 7.12 (1
H, d, J = 7.7 Hz), 7.12 (1H, s),
7.36 (1H, s) IR (νmax, cm ⁻¹ ): 34
60, 3350, 1625, 1265 (KBr).

Embodiment 32'-iodo-3-methoxy-2,4-dimethyl-
4 ', 6'-bis (trifluoromethyl) -1,1'-
Synthesis of biphenyl Acetic acid (200 ml) was added to the compound of Example 2 (36.33).
g) was completely dissolved and cooled. With vigorous stirring,
Sodium nitrite to keep the reaction solution at 15-20 ° C
(7.59g) and sulfuric acid aqueous solution prepared from sulfuric acid (80ml)
After dropping the nitrosyl solution over 1 hour, 30 minutes at room temperature
While stirring, a diazonium salt solution was prepared. Water (200
ml) completely dissolve potassium iodide (36.52 g)
And while cooling, keep the temperature of the reaction solution at 20-30 ° C.
After dropping a color-transparent diazonium salt solution over 1 hour,
Stir at warm for 17 hours. Add cold water (100
0 ml) and extracted with ether (500 ml).
The separated organic layer was subjected to 2N aqueous sodium hydroxide solution (20
0 ml x 2), water (200 ml x 3), saturated saline (2
00ml) and dried over anhydrous magnesium sulfate
did. After the ether was distilled off under reduced pressure, the residue of yellow crystals (50.
00g) was separated and purified by silica gel chromatography (n-f
Xan) to give the desired product as a yellow solid (37.91 g).
(80% yield). This was further reconstituted from n-hexane.
When crystallized, it becomes a colorless transparent needle-like crystal.

Melting point 91-92 ° C. Elemental analysis (%): as C ₁₇ H ₁₃ F ₆ IO H-NMR (δ, CDCl ₃ ): 1.89 (3H,
s), 2.37 (3H, s), 3.75 (3H, s),
6.66 (1H, d, J = 7.9 Hz), 7.11 (1
H, d, J = 7.9 Hz), 8.01 (1H, s),
8.37 (1H, s).

Embodiment 46-bromo-2'-iodo-3-methoxy-2,4-di
Methyl-4 ', 6'-bis (trifluoromethyl)-
Synthesis of 1,1'-biphenyl Acetic acid (100 ml) was added to the compound of Example 3 (47.42).
g) was completely dissolved, and bromine (24.00 g) was removed under ice-cooling.
After slowly adding, the mixture was stirred at room temperature for 3 hours. Red transparent anti
Add the reaction solution to cold water (1000 ml) and add dichloromethane
(500 ml). The separated organic layer was washed with water (20
0 ml), 2N aqueous sodium hydroxide solution (200 ml
× 2), water (200ml × 3), saturated saline (200m
After sequentially washing in 1), the resultant was dried with anhydrous magnesium sulfate.
After distilling off dichloromethane under reduced pressure, the residue of red syrup (5
8.33 g) was separated and purified by silica gel chromatography (n
-Hexane: ethyl acetate = 100: 1) to give a yellow solid
The desired product (53.33 g) was obtained (96% yield). This one
Was further recrystallized from n-hexane to give slightly yellow needles.
It becomes a crystal.

Melting point: 76-77 ° C. Elemental analysis (%): as C ₁₇ H ₁₂ BrF ₆ IO H-NMR (δ, CDCl ₃ ): 1.88 (3H,
s), 2.35 (3H, s), 3.73 (3H, s),
7.37 (1Hs), 8.03 (1H, s), 8.40
(1H, s).

Example 5 3-Methoxy-2,4-dimethyl-6,2'-bis (di-
Phenylphosphinyl) -4 ′, 6′-bis (trifur
Synthesis of ( olomethyl) -1,1′-biphenyl The compound of Example 4 (5.53 g) was completely dissolved in dry tetrahydrofuran (90 ml) and cooled to −70 ° C. After adding t-butyllithium (1.5 mol / L pentane solution: 28 ml) and stirring at the same temperature for 30 minutes, chlorodiphenylphosphine oxide (10.4 ml) dissolved in dry tetrahydrofuran (10 ml) was added to the reaction solution.
1 g), and the mixture was stirred at the same temperature for 1 hour, and further stirred for 15 hours while gradually returning to room temperature. Tetrahydrofuran was distilled off under reduced pressure, and the brown syrup residue was dissolved in dichloromethane (100 ml) and water (100 ml). A 1N aqueous sodium hydroxide solution (50 ml) and water (30 ml ×
3) After washing with a saturated saline solution (30 ml) in that order, the extract was dried over anhydrous magnesium sulfate. After dichloromethane was distilled off under reduced pressure, a yellow solid residue (12.50 g) was separated and purified by silica gel chromatography (n-hexane: ethyl acetate = 7:
3) to obtain the target product (5.54 g) as a white powder (yield 74%). When this is further recrystallized from ethyl acetate, it becomes colorless needle-like crystals.

Melting point: 274-275 ° C. Elemental analysis (%): C ₄₁ H ₃₂ F ₆ O ₃ P ₂ H-NMR (δ, CDCl ₃ ): 1.37 (3H,
s), 2.28 (3H, s), 3.66 (3H, s),
7.08 (1H, d, J = 14.2 Hz), 7.23 to
7.76 (21H, m), 8.02 (1H, s).

Example 6 3-Methoxy-2,4-dimethyl-6,2'-bis (di
Phenylphosphinyl) -4 ′, 6′-bis (trifur
Optical Resolution of (Oromethyl) -1,1′-biphenyl The compound (500 mg) obtained in Example 5 was dissolved in n-hexane-isopropyl alcohol (4: 1, 50 ml), and the mixture was dissolved in an optically active column (Chiralpak OT (+ ) (Manufactured by Daicel)), and optically resolved with a developing solvent n-hexane-isopropyl alcohol (4: 1). The above fractions were collected and concentrated to give white crystals (219 mg) (88% yield). HPLC analysis indicated about 100% ee.

Melting point 251 to 252 ° C. [α] _D ²⁰ : -20.0 ° (c, 1.00, CHC
l ₃ ) Elemental analysis (%): as C ₄₁ H ₃₂ F ₆ O ₃ P ₂ H-NMR (δ, CDCl ₃ ): 1.37 (3H,
s), 2.28 (3H, s), 3.66 (3H, s),
7.08 (1H, d, J = 14.2 Hz), 7.22 to
7.77 (21H, m), 8.02 (1H, brs) IR (νmax, cm ⁻¹ ): 3460, 3350, 16
25, 1265 (KBr).

Example 7 (-)-3-methoxy-2,4-dimethyl-6,2'-
Bis (diphenylphosphino) -4 ′, 6′-bis (G
Synthesis of ( fluoromethyl) -1,1′-biphenyl In a pressure tube, the compound of Example 6 (75 mg) was dissolved in dried and degassed chlorobenzene (4 ml), triethylamine (486 mg), an argon stream, and ice-cooled. Underneath, trichlorosilane (542 mg) was added in order, and after purging with argon, the tube was sealed and stirred at 140 ° C. for 5 hours. A degassed 20% aqueous sodium hydroxide solution was added to the reaction solution under ice cooling until the white suspension was dissolved, and the atmosphere was replaced with argon.
Stirred at 70 ° C. for 30 minutes. Subsequently, the mixture was cooled to room temperature, chlorobenzene (4 ml) was added, the organic layer was separated, washed sequentially with water (5 ml × 3) and saturated saline (3 ml), and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (toluene) to obtain the desired product (65 mg) as a white solid (yield 90%).

Melting point: 146 to 147 ° C. [α] _D ²² : -74.7 ° (c, 0.506, benzene) CD [θ] (λ nm) (EtOH): -80,600
(288), +198,000 (239), -115,
000 (206) Elemental analysis (%): as C ₄₁ H ₃₂ F ₆ OP ₂ H-NMR (δ, CDCl ₃ ): 1.09 (3H,
s), 2.25 (3H, s), 3.51 (3H, s),
6.84 to 6.91 (2H, m), 7.02 (1H,
d, J = 2.9 Hz), 7.15 to 7.42 (18H,
m), 7.58 (1H, brs), 7.81 (1H,
brs).

Example 8 3-methoxy-2,4-dimethyl-2'-diphenylphospho
Sphinyl-4 ', 6'-bis (trifluoromethyl)
Synthesis of -1,1′-biphenyl The desired product was obtained by reacting the compound of Example 3 with diphenylphosphinyl chloride in the same manner as in Example 5.

Melting point 85-86 ° C. Elemental analysis (%): as C ₂₉ H ₂₃ F ₆ O ₂ P H-NMR (δ, CDCl ₃ ): 1.67 (3H,
s), 2.20 (3H, s), 3.63 (3H, s),
6.22 (1H, d, J = 7.7 Hz), 6.48 (1
H, d, J = 7.7 Hz), 7.29 to 7.63 (10
H, m), 8.10 (1H, d, J = 12.8 Hz),
8.17 (1H, s).

Example 9 3-methoxy-2,4-dimethyl-2'-bis (3,5
-Dimethylphenyl) phosphinyl-4 ', 6'-bis
Synthesis of (trifluoromethyl) -1,1′-biphenyl In the same manner as in Example 5, di (3,5-
The desired product was obtained by the action of (dimethylphenyl) phosphinyl chloride.

Melting point: 153 to 154 ° C. Elemental analysis (%): as C ₃₃ H ₃₁ F ₆ O ₂ P

Example 10 6-Bromo-3-methoxy-2,4-dimethyl-2'-
Diphenylphosphinyl-4 ', 6'-bis (trifur
Synthesis of (olomethyl) -1,1′-biphenyl The compound of Example 8 was brominated in the same manner as in Example 4 to obtain the desired product.

Melting point: 164 to 165 ° C. Elemental analysis (%): as C ₂₉ H ₂₂ BrF ₆ O ₂ P H-NMR (δ, CDCl ₃ ): 1.82 (3H,
s), 2.19 (3H, s), 3.68 (3H, s),
6.87 (1H, s), 7.29 to 7.71 (10H,
m), 7.95 (1H, d, J = 12.8 Hz), 8.
18 (1H, s).

Embodiment 116-bromo-3-methoxy-2,4-dimethyl-2'-
Bis (3,5-dimethylphenyl) phosphinyl-
4 ', 6'-bis (trifluoromethyl) -1,1'-
Synthesis of biphenyl The compound of Example 8 was brominated in the same manner as in Example 4.
More objective was obtained.

Melting point: 168-170 ° C. Elemental analysis (%): as C ₃₃ H ₃₀ BrF ₆ O ₂ P

Example 12 6-Bromo-3-methoxy-2,4-dimethyl-2'-
Diphenylphosphino-4 ', 6'-bis (trifluoro
Synthesis of (methyl) -1,1′-biphenyl The compound of Example 10 was treated in the same manner as in Example 7 to obtain the desired product.

Melting point: 144-145 ° C. Elemental analysis (%): as C ₂₉ H ₂₂ BrF ₆ OP H-NMR (δ, CDCl ₃ ): 1.29 (3H,
s), 2.33 (3H, s), 3.54 (3H, s),
7.13 to 7.44 (11H, m), 7.65 (1H,
s), 8.00 (1H, s).

Example 13 6-Bromo-3-methoxy-2,4-dimethyl-2'-
Bis (3,5-dimethylphenyl) phosphino-4 ′,
6'-bis (trifluoromethyl) -1,1'-biphe
Synthesis of Nyl The compound of Example 11 was treated in the same manner as in Example 7 to obtain the desired product.

Melting point: 141 to 142 ° C. Elemental analysis (%): as C ₃₃ H ₃₀ BrF ₆ OP

Example 14 3-methoxy-2,4-dimethyl-6-bis (3,5-
Dimethylphenyl) phosphinyl-2'-diphenylpho
Sphinyl-4 ', 6'-bis (trifluoromethyl)
Synthesis of -1,1′-biphenyl The compound of Example 12 was reacted with chlorobis (3,5-dimethylphenyl) phosphine in the same manner as in Example 5,
Then, the obtained residue was dissolved in dichloromethane (30 ml) and water (5 ml), and the mixture was dissolved in ice-cooled 31% aqueous hydrogen peroxide (5 ml).
ml) and stirred at room temperature for 3 hours. The organic layer was separated, washed sequentially with a 1N aqueous sodium hydroxide solution (10 ml), water (20 ml × 3), and saturated saline (20 ml), and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (ethyl acetate) to obtain the desired product.

Melting point: 290-292 ° C. Elemental analysis (%): as C ₄₅ H ₄₀ F ₆ O ₃ P ₂ H-NMR (δ, CDCl ₃ ): 1.50 (3H,
s), 2.10 (6H, s), 2.27 (3H, s),
2.29 (6H, s), 3.69 (3H, s), 6.9
4 (1H, s), 7.09 (2H, d, J = 12.8H)
z), 7.08-7.22 (6H, m), 7.27-
7.30 (1H, m), 7.38 to 7.47 (3H,
m), 7.57 to 7.71 (3H, m), 7.78 (1
H, d, J = 13.2 Hz), 8.05 (1H, s).

Example 15 6-Dicyclohexylphosphinyl-3,3'-dimethoate
Xy-2,2 ', 4,4'-tetramethyl-6'-dif
Synthesis of phenylphosphinyl- 1,1'-biphenyl 6,6'-dibromo-3,3'-dimethoxy-2,
2 ′, 4,4′-Tetramethyl-1,1′-biphenyl (1.0 g) was dissolved in dry tetrahydrofuran (30 ml), and after substituting with argon, 1.5M t-butyl was cooled to −70 ° C. A lithium / n-pentane solution (2.0 ml) was added, and the mixture was stirred at the same temperature for 30 minutes. Subsequently, chlorodiphenylphosphine (0.51 g) dissolved in dry tetrahydrofuran (5 ml) was added at the same temperature, and the mixture was stirred at the same temperature for 30 minutes and gradually returning to room temperature over 12 hours. After cooling to −70 ° C. again,
Mt-butyllithium / n-pentane solution (2.0 m
l) was added and the mixture was stirred at the same temperature for 30 minutes. Subsequently, chlorodicyclohexylphosphine (0.55 g) dissolved in dry tetrahydrofuran (5 ml) was added at the same temperature.
The mixture was stirred while gradually returning to room temperature over 0 minutes and further 12 hours. Tetrahydrofuran was distilled off under reduced pressure, the residue was dissolved in dichloromethane (30 ml) and water (5 ml), and 31% aqueous hydrogen peroxide (5 ml) was added under ice-cooling, followed by stirring at room temperature for 3 hours. The organic layer was separated, and 1N sodium hydroxide (10 ml), water (20 ml × 3), and saturated saline (20 ml) were used.
ml), and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (ethyl acetate) to obtain the desired product (220 mg) as a white solid (yield: 14%).

Melting point: 225-227 ° C. Elemental analysis (%): as C ₄₂ H ₅₂ O ₄ P ₂ .H ₂ O H-NMR (δ, CDCl ₃ ): 1.36 (3H,
s), 1.51 to 2.07 (22H, m), 1.85
(3H, s), 2.23 (3H, s), 2.35 (3
H, s), 3.68 (3H, s), 3.75 (3H,
s), 6.98 (1H, d), 7.03 (1H, d),
7.26 to 7.47 (6H, m), 7.58 to 7.71
(4H, m).

Example 16 6-Dicyclohexylphosphinyl-3,3'-dimethoate
Xy-2,2 ', 4,4'-tetramethyl-6'-dif
Optical resolution of phenylphosphinyl-1,1′-biphenyl The compound (250 mg) obtained in Example 15 was subjected to optical resolution using an optically active substance preparative column (Chiralpak OT (+) (manufactured by Daicel)). , White solid (110m
g) was obtained.

Example 17 6-Dicyclohexylphosphino-3,3'-dimethoxy
C-2,2 ', 4,4'-tetramethyl-6'-dife
Synthesis of Nylphosphino-1,1′-biphenyl In a pressure tube, the compound of Example 16 (110 mg) was dissolved in dried and degassed chlorobenzene (15 ml), and triethylamine (0.81 g), an argon stream, and ice-cooling were used. Then, trichlorosilane (0.8 g) was added in order, and the atmosphere was replaced with argon, and the tube was sealed and stirred at 140 ° C. for 5 hours. A degassed aqueous 30% sodium hydroxide solution was added to the reaction mixture under ice cooling until the white suspension was dissolved, and the mixture was purged with argon and stirred at 70 ° C. for 30 minutes. Subsequently, the mixture was cooled to room temperature, chlorobenzene (30 ml) was added, the organic layer was separated, and water (20 ml × 3) and saturated saline (20 ml) were added.
And then dried over anhydrous magnesium sulfate.
The organic layer was concentrated under reduced pressure, the residue was separated and purified by silica gel chromatography (toluene), and the target substance as a white solid (72 m
g) (68% yield).

[Α] _D ²² : -2.1353 ° (c, 0.
002, ethanol / methylene chloride = 100/3) CD [θ] (λ nm) (EtOH / CH ₂ Cl ₂ = 10)
0/3): -123,630 (λ 274 nm (po
s. max), 237 nm (neg. max) 1 H-NMR (δ, CDCl ₃ ): 1.56 (3H,
s), 1.81 (3H, s), 1.51 to 2.07 (2
2H, m), 2.23 (3H, s), 2.35 (3H,
s), 3.52 (3H, s), 3.71 (3H, s),
6.86 (3H, s), 6.88 (3H, s), 7.1
8-7.29 (10H, m).

Example 18 (1- (2-nitro-4,6-ditrifluoromethylphenyl)
Phenyl) naphthalen-2-yl) carboxylate
Forming (1-bromonaphthalene-2-yl) carboxylate and 1-bromo - nitro-4,6-ditrifluoromethylbenzene in the same manner as in Example 1, the reaction temperature from 200 to 2
The mixture was treated at 20 ° C. for 3 hours to obtain a light yellow prism crystal as a target product (yield: 43%).

Melting point: 154 to 155 ° C. Elemental analysis (%): as C ₂₀ H ₁₁ NF ₆ O ₄

Example 19 2-amino-1- (2-nitro-4,6-ditrifluoro)
Synthesis of romethylphenyl) naphthalene The compound of Example 18 (1.45 g) was added to a solution of a 1% aqueous sodium hydroxide solution (20 ml) and ethanol (5 ml), and the mixture was heated and stirred at 50 to 60 ° C. for 1 hour, and then cooled. And
Acidified with concentrated hydrochloric acid. The precipitate was collected by filtration and dried to give 1.3 g.
A carboxylic acid compound was obtained. This is thionyl chloride (20m
After refluxing for 1 hour in addition to l), excess thionyl chloride was distilled off. Benzene was added to the residue and concentrated under reduced pressure. After performing this operation twice, acetone (20 ml) was added, and -5 ° C.
Then, a solution prepared by dissolving sodium azide in water (8 ml) was added dropwise. After stirring at 0 ° C. for another 30 minutes, water (20 m
l) and extracted with benzene (10 ml × 2). The organic layer was dried over anhydrous magnesium sulfate and refluxed for 2 hours.
A 50% aqueous sodium hydroxide solution (20 ml) was added, and the mixture was further refluxed for 1 hour. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (dichloromethane: n-hexane = 1: 2) to obtain the desired product (0.85 g) as an orange prism crystal.

Melting point: 144-146 ° C. Elemental analysis (%): as C ₁₈ H ₁₂ N ₂ F ₆ O ₂

Example 20 2-amino-1- (2-amino-4,6-ditrifluoro)
Synthesis of romethylphenyl) naphthalene The compound of Example 19 was treated in the same manner as in Example 2 to obtain the desired product as white prism crystals (quantitative yield).

Melting point: 166-168 ° C. Elemental analysis (%): as C ₁₈ H ₁₂ N ₂ F ₆

Example 21 2-Iodo-1- (2-iodo-4,6-ditrifluoro)
Synthesis of romethylphenyl) naphthalene The compound of Example 20 was treated in the same manner as in Example 3 to obtain the desired product as white prism crystals (yield 53.8).
%).

Melting point: 126 to 128 ° C. Elemental analysis (%): as C ₁₈ H ₈ F ₆ I ₂

Example 22 2-Diphenylphosphinyl-1- (2-diphenylpho
Sphinyl-4,6-ditrifluoromethylphenyl)
Synthesis of naphthalene The target compound was obtained by treating the compound of Example 21 in the same manner as in Example 5 (yield: 46.8%). 232-233 ° C FAB MS: 741 (M ⁺⁺ 1).

Example 23 2-Diphenylphosphinyl-1- (2-diphenylphosphine)
Sphinyl-4,6-ditrifluoromethylphenyl)
Optical Resolution of Naphthalene The compound of Example 22 was applied to an optically active column (Chiralpak O
Optical resolution was performed using T (+) (manufactured by Daicel Corporation) and developing solvent n-hexane-isopropyl alcohol (9: 1). The above fractions were collected and concentrated to obtain the desired product as prism crystals. Melting point: 232 to 233 ° C. [α] _D ²⁴ : −71.0 ° (c, 1.00, chloroform) Elemental analysis (%): As C ₄₂ H ₂₈ F ₆ O ₂ P ₂ H-NMR (δ, CDCl ₃ ): 6.66 (1H, br)
d), 6.87 (1H, m), 7.08-7.17.
(2H, m), 7.20 to 7.56 (16H, m),
7.66 to 7.91 (7H, m), 8.12 (1H, b
rs) IR (νmax, cm ^-1 ): 1200,116
0,1135,1110 (KBr).

Example 24 ( -)-2-diphenylphosphino-1- (2-diphene)
Nylphosphino-4,6-ditrifluoromethylphenyi
Lu) Synthesis of naphthalene The compound of Example 23 (74 mg) was dried in a pressure tube,
After dissolving in degassed chlorobenzene (4 ml), triethylamine (486 mg), trichlorosilane (542 mg) were added in that order under an argon stream and ice-cooling, and after purging with argon, the tube was sealed and stirred at 140 ° C. for 5 hours. A degassed 20% aqueous sodium hydroxide solution was added to the reaction mixture under ice cooling until the white suspension was dissolved, and the mixture was purged with argon and stirred at 70 ° C. for 30 minutes. Subsequently, the mixture was cooled to room temperature, chlorobenzene (4 ml) was added, the organic layer was separated, washed sequentially with water (5 ml × 3) and saturated saline (3 ml), and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (toluene) to obtain the target product (61 mg) as a white solid (yield 86%).

Melting point 90-92 ° C. [α] _D ²³ : −148.3 ° (c, 0.76, benzene) CD [θ] (λ nm) (EtOH): −53,000
(290.8), +126,000 (246), -11
4,000 (218) H-NMR (δ, CDCl ₃ ): 6.44 (1H, d,
J = 8.8 Hz), 6.68 to 6.80 (4H, m),
7.04 (2H, t, J = 6.8 Hz), 7.11 to
7.31 (14H, m), 7.34 to 7.42 (2H,
m), 7.46 (1H, dd, J = 2.5, 8.6H
z), 7.68-7.76 (2H, m), 7.86 (1
H, d, J = 8.3 Hz), 8.01 (1H, br)
s).

Example 25 1- (3-methoxy-2,4-dimethylphenyl) naph
Synthesis of methyl taren-2-ylcarboxylate Methyl 1-bromonaphthalen-2-ylcarboxylate (3.17 g), tetrakistriphenylphosphinepalladium (0) (0.32 g), sodium carbonate (2.
1 g), 3-methoxy-2,4-dimethylphenylboric acid (1.9 g), water (10 ml), ethanol (2 m
A mixture of 1) and toluene (20 ml) was refluxed for 10 hours and extracted with benzene. The organic layer was washed with water, a 10% aqueous sodium hydroxide solution and water in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue crystals were washed with n-hexane and collected by filtration, and the target substance (3.0 g) as white prism crystals was obtained.
Was obtained (yield: 78.9%).

Melting point: 120 to 121 ° C. Elemental analysis (%): As C ₂₁ H ₂₀ O ₃

Example 26 2-amino-1- (3-methoxy-2,4-dimethylphenol)
Synthesis of phenyl) naphthalene The compound of Example 25 was treated in the same manner as in Example 19 to obtain the desired product as pale yellow needles (yield 70.1).
%). H-NMR (δ, CDCl ₃ ): 1.87 (3H,
s), 2.33 (3H, s), 3.23 (2H, br)
s), 3.37 (3H, s), 6.70 to 7.30 (6
H, m), 7.43-7.80 (2H, m) MS: 277 (M ^<+> ).

Example 27 2-Iodo-1- (3-methoxy-2,4-dimethylphenyl)
Synthesis of phenyl) naphthalene The compound of Example 26 was treated in the same manner as in Example 3 to obtain the desired product (yield: 58.0%). H-NMR (δ, CDCl ₃ ): 1.87 (3H,
s), 2.37 (3H, s), 3.73 (3H, s),
6.63 (1H, d, J = 8.0 Hz), 6.83-
7.90 (7H, m) MS: 388 (M ^<+> ).

Example 28 1- (6-Bromo-3-methoxy-2,4-dimethylphenyl)
Synthesis of enyl) -2-iodonaphthalene The compound of Example 27 was treated in the same manner as in Example 4 to obtain the desired product as white prism crystals (yield 96.3).
%). H-NMR (δ, CDCl ₃ ): 1.73 (3H,
s), 2.30 (3H, s), 3.63 (3H, s),
6.97-7.96 (7H, m) MS: 467 (M ^<+> ).

Embodiment 292-diphenylphosphinyl-1- (6-diphenylpho
Sphinyl-3-methoxy-2,4-dimethylphenyi
Le) Synthesis of naphthalene Using the compound of Example 28 as in Example 5
The target product was obtained as whiter plate crystals (yield 62.0).
%). H-NMR (δ, CDCl_Three): 1.33 (3
H, s), 2.17 (3H, s), 3.60 (3H,
s), 6.50-7.87 (7H, m) Melting point 148-151 ° C Elemental analysis (%): C₄₃H₃₈O_ThreeP_Two・ As EtOH

Example 30 1- (3-Methoxy-2,4-dimethyl-6-nitrophenyl
Synthesis of methyl (enyl) naphthalen-2-ylcarboxylate A light yellow prism was obtained by treating methyl 1-bromonaphthalen-2-ylcarboxylate and 2,6-dimethyl-4-nitro-3-bromoanisole in the same manner as in Example 1. The desired product was obtained as crystals (yield 35.6%). MP 100-102 ^<0> C MS: 365 (M ^<+> ).

Example 31 2-amino-1- (3-methoxy-2,4-dimethyl-
Synthesis of 6-nitrophenyl) naphthalene The compound of Example 30 was treated in the same manner as in Example 19 to obtain the desired product (68.4% yield). MS: 322 (M ^<+> ).

Example 32 2-amino-1- (6-amino-3-methoxy-2,4
Synthesis of -Dimethylphenyl) naphthalene The compound of Example 31 was treated in the same manner as in Example 2 to obtain the desired product as pale yellow prism crystals (yield: 85.50).
8%). Mp 145-147 [deg.] C MS: 292 (M ^<+> ).

Example 33 2-Iodo-1- (6-iodo-3-methoxy-2,4
Synthesis of -dimethylphenyl) naphthalene The compound of Example 32 was treated in the same manner as in Example 3 to obtain the desired product as white prism crystals (yield 29.0).
%). 140-141 [deg.] C MS: 514 (M ^<+> ).

Embodiment 342-diphenylphosphinyl-1- (6-diphenylpho
Sphinyl-3-methoxy-2,4-dimethylphenyi
Le) Synthesis of naphthalene Using the compound of Example 33 as in Example 5
The desired product was obtained as whiter plate crystals. 148-151 ° C FAB MS: 663 (M⁺) The spectrum data of this compound is the same as that of Example 29.
Matched.

Example 35 1- (3-methoxy-2,4-dimethylphenyl) -2
Synthesis of -diphenylphosphinylnaphthalene The compound of Example 27 was treated in the same manner as in Example 5 to obtain the desired product as a pale yellow oil (yield: 84.0).
%). FAB MS: 463 (M ⁺ ).

Example 36 1- (6-Bromo-3-methoxy-2,4-dimethylphenyl)
Enyl) -2-diphenylphosphinylnaphthalene
The compound of Synthesis Example 35 was treated in the same manner as in Example 4 to obtain the desired product (yield: 71.2%). FAB MS: 542 (M
⁺ ).

Example 37 ( +)-2-diphenylphosphino-1- (6-dife
Nylphosphino-3-methoxy-2,4-dimethylphen
Synthesis of nyl) naphthalene The compound of Example 36 (1.0 g) was charged into an optically active column (Chiralpak OT (+) (manufactured by Daicel Corporation) using a developing solvent n-
Optical resolution was performed using hexane-isopropyl alcohol (4: 1). Collect the above fraction, 0.29
g was obtained. This was reduced according to the method of Example 24 to give 2
-Diphenylphosphino-1- (6-bromo-3-methoxy-2,4-dimethylphenyl) naphthalene (0.26 g). [Α] _D ²³ : −43.8 ° (c, 0.2, chloroform) H-NMR (δ, CDCl ₃ ): 1.40 (3H,
s), 2.38 (3H, s), 3.60 (3H, s),
7.26-7.87 (17H, m).

This is performed in the same manner as in Example 5 to
(6-Bromo-3-methoxy-2,4-dimethylphenyl) -2-diphenylphosphinonaphthalene 0.10 g
Thus, 2-diphenylphosphino-1- (6-diphenylphosphinyl-3-methoxy-2,4-dimethylphenyl) naphthalene (78 mg) was obtained. H-NMR (δ,
CDCl ₃ ): 1.80 (3H, s), 2.23 (3
H, s), 3.73 (3H, s), 6.83-8.03.
(27H, m).

This was reduced again according to the method of Example 24 to obtain the desired product (49 mg). Melting point 241-221
° C. [α] _D ²³ : -38.2 ° (c, 0.12, chloroform) H-NMR (δ, CDCl ₃ ): 1.37 (3H,
s), 2.30 (3H, s), 3.50 (3H, s),
6.83-7.70 (27H, m).

The asymmetric bissymmetric phosphine derivative having no optically active double-rotational axis represented by the general formula [I] thus obtained is asymmetric as a ligand of a rhodium or ruthenium metal complex catalyst. It can be used for various asymmetric organic syntheses such as hydrogenation.

As a method for preparing a catalyst used for asymmetric organic synthesis, an asymmetric bisphosphine derivative having no optically active biaxial axis represented by the general formula [I], a rhodium-cyclooctadiene- It can be adjusted by allowing a rhodium complex such as a chloro complex or a ruthenium complex such as a ruthenium-p-cymene-iodine complex to act under heating in an organic solvent such as methanol or methylene chloride or a mixed solvent thereof.

These may be those prepared and adjusted in the reaction system or may be prepared and isolated in advance. Next, an example of asymmetric reduction using the compound of the present invention will be described.

Test Example 1 [Catalyst Preparation] Di-μ-iodo-bis [(p-cymene) iodolthenium (II)] complex ([RuI ₂ (p-cy
mene)] ₂ , 2.4 mg, 2.5 × 10 ⁻³ mmo
l) and the compound of the present invention (6.0 × 10 ⁻³ mmol) are dissolved in a mixed solvent (4 ml) of dry and degassed methanol / methylene chloride (1/1), and the mixture is purged with argon and then cooled to 50 ° C.
For 30 minutes.

[Reduction Procedure] Methyl acetoacetate (381)
mg, 5 mmol), a methanol / methylene chloride (1/1) solution of the prepared catalyst, and a mixed solvent (6 ml) of dried / degassed methanol / methylene chloride (1/1) were placed in an autoclave, and hydrogen initial pressure was 10 atm, 30 atm. Stirred at ４０40 ° C. for 20 hours. After completion of the reaction, the reaction addition rate was measured by gas chromatography (column: PEG-20M). Next, the reaction solution was concentrated under reduced pressure, and the residue was distilled under reduced pressure. The optical rotation of the product was measured, and the absolute configuration was determined from the sign. A part of the product was dissolved in dry pyridine, an equivalent amount of benzoyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After treating the reaction solution according to a conventional method, HPLC analysis of the obtained methyl 3-benzoyloxybutyrate (optically active column: CHIRALCEL OB, column solvent: n-hexane / isopropanol (9/1), flow rate: 0.5 ml, UV wavelength 254 nm) to determine the optical purity.

Table 1 shows the experimental results.

[0103]

[Table 1]

Test Example 2 [Catalyst Preparation] Bis (norbornadiene) rhodium (I)
Perchlorate complex ([Rh (NBD) ₂ ] ClO ₄ ,
1.9 mg, 5 × 10 ⁻³ mmol) and the compound of the present invention (5.5 × 10 ⁻³ mmol) were dissolved in a dry and degassed methylene chloride solution (2 ml), and the solution was replaced with argon, followed by 30 minutes.
Stirred at C for 3 hours. After stirring, the solvent was distilled off under reduced pressure, and the pressure was returned to normal pressure under an argon stream. The residue was dissolved by adding dry and degassed methanol (4 ml), and the mixture was purged with argon and stirred at 30 ° C. for 10 minutes.

[Reduction Procedure] 2-aminoacetophenone hydrochloride (858 mg, 5 mmol), dried and degassed triethylamine (2.5 mg, 2.5 × 10 ^-2 mmol)
l) The prepared methanol solution of the catalyst and dried and degassed methanol (10 ml) were placed in an autoclave, and stirred at 50 atm and an initial hydrogen pressure of 90 atm for 7 days. After the reaction was completed, activated carbon (50 mg) was added, and the mixture was stirred for 1 hour to adsorb the catalyst and filtered off. The filtrate was concentrated under reduced pressure to obtain a yellow solid.
The reaction addition rate was determined by measuring ¹ H-NMR (CD ₃ OD) of the residue. Next, the optical rotation of the product was measured, and the absolute configuration was determined from the sign. Further, after dissolving a part of the product in methylene chloride, a 0.5N aqueous sodium hydroxide solution was added thereto under ice cooling and the mixture was stirred, and the organic layer was concentrated under reduced pressure to obtain a free product. The free form was dissolved in dimethylformamide, and triethylamine and benzoyl chloride were added thereto under ice cooling, followed by stirring at room temperature for 3 hours. After treating the reaction solution according to a conventional method, HPLC analysis of the obtained N-benzoyl compound (optically active column: CHIRALCEL OD, column solvent: n-hexane / isopropanol (9/1), flow rate: 0.5 ml, UV wavelength) 254 nm) to determine the optical purity. Table 2 shows the experimental results.

[0106]

[Table 2]

As described above, the compounds of the present invention are practical and useful ligands for catalysts for asymmetric synthesis.

Continuation of the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07F 9/50 C07F 9/53 CA (STN) REGISTRY (STN)

Claims (14)

(57) [Claims] 1. A compound of the general formula [I] [Wherein R ¹ and R ² are the same or different and each is a phenyl group (the phenyl group is substituted by 1 to 5 members selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) Or a cyclohexyl group, R ³ , R ⁴ , R ⁷ , and R ⁸ may be the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, and R ⁵ and R ⁶ The same or different, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or R ⁴ and R ⁵ , R ⁶ and R ⁷ together represent an aromatic ring, but R ³ and R ⁸ , R ⁴ and R ⁷ , R ⁵
And R ⁶ and R ¹ and R ² represent at least one pair of different substituents.] An asymmetric bisphosphine derivative having no optically active twice-rotational axis. 2. The compound of the formula [I], wherein R ³ and R ⁵
Is a trifluoromethyl group, R ⁴ is a hydrogen atom, R ⁶ and R
General formula [II] wherein ⁸ is a methyl group and R ⁷ is a methoxy group [Wherein R ¹ and R ² are the same or different and each is a phenyl group (the phenyl group is substituted by 1 to 5 members selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) Or an asymmetric bissymmetric phosphine derivative having no optically active twice-rotational axis. 3. The compound of the formula [I], wherein R ³ and R ⁵
Is a trifluoromethyl group, R ⁴ and R ⁸ are hydrogen atoms, R
General formula [III] in which ⁶ and R ⁷ together represent an aromatic ring [Wherein R ¹ and R ² are the same or different and each is a phenyl group (the phenyl group is substituted by 1 to 5 members selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) Or an asymmetric bissymmetric phosphine derivative having no optically active twice-rotational axis. 4. A compound represented by the formula (I) wherein R ³ and R ⁵
Is a methyl group, R ⁴ is a methoxy group, R ⁶ and R ⁷ are an aromatic ring together, and R ⁸ is a hydrogen atom. [Wherein R ¹ and R ² are the same or different and each is a phenyl group (the phenyl group is substituted by 1 to 5 members selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) Or an asymmetric bissymmetric phosphine derivative having no optically active twice-rotational axis. 5. In the general formula [I], R ³ , R ⁵ ,
A general formula [V] in which R ⁶ and R ⁸ represent a methyl group, and R ⁴ and R ⁷ represent a methoxy group. [In the formula, R ¹ and R ² are different from each other, and a phenyl group (the phenyl group is 1 to 5 selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom)
An asymmetric bisphosphine derivative having no optically active twice-rotational axis. 6. The compound of the formula (I) wherein R ³ and R ⁸
Is a hydrogen atom, and R ⁴ and R ⁵ and R ⁶ and R ⁷ together represent an aromatic ring. [In the formula, R ¹ and R ² are different from each other, and a phenyl group (the phenyl group is 1 to 5 selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom)
An asymmetric bisphosphine derivative having no optically active twice-rotational axis. 7. A compound of the general formula [VII] [Wherein, R ² represents a phenyl group (the phenyl group may be substituted with 1 to 5 selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or a cyclohexyl group; R ³ , R ⁴ , R ⁷ , R
⁸ is the same or different, a hydrogen atom, a lower alkyl group,
R ⁵ and R ⁶ are the same or different and represent a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, or R ⁴ and R ⁵ , R ⁶ and R ⁷ Represents an aromatic ring in combination, Y ¹ is a halogen atom, P (O) _n (R ¹ ) ₂ (where R ¹ is a phenyl group (the phenyl group is a lower alkyl group, a lower alkoxy group, a trifluoromethyl Or a cyclohexyl group, n represents a number of 0 or 1), and R ³
And R ⁸ , R ⁴ and R ⁷ , R ⁵ and R ^6, and R ¹ and R ² , at least one pair of which represents a different substituent.]
A phosphinyl derivative represented by the formula: 8. A compound of the general formula [VII] [Wherein, R ² represents a phenyl group (the phenyl group may be substituted with 1 to 5 selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or a cyclohexyl group; R ³ , R ⁴ , R ⁷ , R
⁸ is the same or different, a hydrogen atom, a lower alkyl group,
R ⁵ and R ⁶ are the same or different and represent a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, or R ⁴ and R ⁵ , R ⁶ and R ⁷ Represents an aromatic ring, R ³ and R ⁸ , R ⁴ and R ⁷ , R ⁵ and R ^6, and R ¹ and R ² simultaneously represent the same substituent, except that Y ¹ is a halogen atom, P
(O) _n (R ¹ ) ₂ (where R ¹ is a phenyl group, wherein the phenyl group is substituted with 1 to 5 members selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom. Or a cyclohexyl group, n
Represents 0 or 1), but R ³ and R ⁸ , R ⁴
And R ⁷ , R ⁵ and R ^6, and R ¹ and R ² at least one pair represents a different substituent.] An asymmetric symmetric phosphinyl derivative having no rotational axis. 9. A compound of the general formula [VIII] [Wherein, R ² represents a phenyl group (the phenyl group may be substituted with 1 to 5 selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or a cyclohexyl group; R ³ , R ⁴ , R ⁷ , R
⁸ is the same or different, a hydrogen atom, a lower alkyl group,
R ⁵ and R ⁶ are the same or different and represent a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, or R ⁴ and R ⁵ , R ⁶ and R ⁷ Represents an aromatic ring, Y ¹ is a halogen atom, P (O) _m (R ¹ ) ₂ (where R ¹ is a phenyl group (the phenyl group is a lower alkyl group, a lower alkoxy group, a trifluoromethyl Or a cyclohexyl group, m represents 0 or 1), and n represents 0
Or R ¹ and R ⁸ , R ⁴ and R ⁷ , R ⁵
And R ⁶ and R ¹ and R ² , at least one of which represents a different substituent, and n represents 0 when Y ¹ represents a halogen atom or m represents 1. Wherein the mono- or bisphosphine derivative to be used is oxidized. [Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are as described above, Y ¹ ′ is a halogen atom, and P (O) (R ¹ )
₂ (where R ¹ represents a phenyl group (the phenyl group may be substituted with 1 to 5 members selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom)) or a cyclohexyl group )]]. 10. The general formula [X] [Wherein, R ² represents a phenyl group (the phenyl group may be substituted with 1 to 5 selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or a cyclohexyl group; R ³ , R ⁴ , R ⁷ , R
⁸ is the same or different, a hydrogen atom, a lower alkyl group,
R ⁵ and R ⁶ are the same or different and represent a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, or R ⁴ and R ⁵ , R ⁶ and R ⁷ Represents an aromatic ring, Y ¹ is a halogen atom, P (O) _m (R ¹ ) ₂ (where R ¹ is a phenyl group (the phenyl group is a lower alkyl group, a lower alkoxy group, a trifluoromethyl Or a cyclohexyl group, m represents 0 or 1), and n represents 0
Or R ¹ and R ⁸ , R ⁴ and R ⁷ , R ⁵
And R ⁶ and R ¹ and R ² , at least one pair of which represents a different substituent, and n represents 1 when Y ¹ represents a halogen atom or m represents 0. Reducing the mono- or bisphosphinyl derivative to be obtained by the general formula [XI] [Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as described above, Y ¹ ″ is a halogen atom, P (R ¹ ) ₂ (where R ¹ is a phenyl group (The phenyl group may be substituted with 1 to 5 groups selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or a cyclohexyl group.) Manufacturing method. 11. A compound of the general formula [XII] [In the formula, R ³ , R ⁴ , R ⁷ , and R ⁸ are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, and R ⁵ and R ⁶ are the same or different. Represents a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or R ⁴ and R ⁵ , R ⁶ and R ⁷ together represent an aromatic ring, X represents a halogen atom, Y ² represents a hydrogen atom, Halogen atom, P (O) _n (R ¹ ) ₂ (where R
¹ is a phenyl group (the phenyl group may be substituted with 1 to 5 groups selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or a cyclohexyl group, and n is 0 or 1 The compound represented by the general formula [XIII]: [Wherein, R ² represents a phenyl group (the phenyl group may be substituted with 1 to 5 selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or a cyclohexyl group; n represents a number of 0 or 1), and X ³ represents a halogen atom], and a compound represented by the following general formula [XIV]: Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
Y ² and n are as described above, but R ³ and R ⁸ , R ⁴ and R
⁷ , at least one pair of R ⁵ and R ⁶ and R ¹ and R ² represent different substituents]. 12. A compound of the general formula [XV] [In the formula, R ³ , R ⁴ , R ⁷ , and R ⁸ are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, and R ⁵ and R ⁶ are the same or different. , A lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or R ⁴ and R ⁵ , R ⁶ and R ⁷ together represent an aromatic ring, but R ³ and R ⁸ , R ⁴ and R ⁷ And R
⁵ and R ⁶ each represent a substituent in which at least one of the pairs is different, and X ¹ and X ² are the same or different and each represent a halogen atom]. ] [Wherein, R ² represents a phenyl group (the phenyl group may be substituted with 1 to 5 selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or a cyclohexyl group; n represents a number of 0 or 1), and X ³ represents a halogen atom.] [XVI] Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
n is as described above]. 13. A compound of the general formula [XVII] [Wherein, R ² represents a phenyl group (the phenyl group may be substituted with 1 to 5 selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) or a cyclohexyl group; n a represents 0 or the number ^{1), R 3, R 4,} R 7, R 8 are the same or different, a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, R ⁵ and R ⁶ is the same or different and represents a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or R ⁴ and R ⁵ , and R ⁶ and R ⁷ together represent an aromatic ring] General formula [XVIII] characterized in that the compound is halogenated. [Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are as described above, and X ¹ represents a halogen atom]. 14. A compound of the general formula [I] [Wherein R ¹ and R ² are the same or different and each is a phenyl group (the phenyl group is substituted by 1 to 5 members selected from a lower alkyl group, a lower alkoxy group, a trifluoromethyl group and a halogen atom) Or a cyclohexyl group, R ³ , R ⁴ , R ⁷ , and R ⁸ may be the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, and R ⁵ and R ⁶ The same or different, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or R ⁴ and R ⁵ , R ⁶ and R ⁷ together represent an aromatic ring, but R ³ and R ⁸ , R ⁴ and R ⁷ , R ⁵
And a R ⁶ and R ¹ and R ² is at least one of a pair without a Dyad optically active represented by the representative] different substituents asymmetric axis asymmetric bisphosphine derivative
A ligand for an asymmetric reduction catalyst, comprising: