JP4500289B2 - 2,3-bis (dialkylphosphino) pyrazine derivative, method for producing the same, and metal complex having the derivative as a ligand - Google Patents

Description

  The present invention relates to an optically active 2,3-bis (dialkylphosphino) pyrazine derivative and a method for producing the same. This pyrazine derivative is useful as a ligand for an asymmetric catalyst of a metal complex used in an asymmetric synthesis reaction. The present invention also relates to a metal complex for an asymmetric synthesis catalyst having the pyrazine derivative as a ligand.

  An optically active phosphine ligand having an asymmetric center on the P atom plays an important role in a catalytic asymmetric synthesis reaction using a transition metal complex. However, in general, the phosphine ligand often has a large number of reaction stages until the desired product is obtained from the starting material. Therefore, a phosphine ligand that can be synthesized more simply than before has been desired. In addition, the above phosphine ligand may not have sufficient storage stability in the air, and it is necessary to pay attention to its handling.

  The present inventors previously proposed a 1,2-bis (dialkylphosphino) benzene derivative as an optically active phosphine ligand having an asymmetric center on the P atom (see Patent Document 1). Since this ligand adopts a single chelate conformation that is very stable with respect to the transition metal, the asymmetric environment around the central metal is efficiently transferred to the substrate. Therefore, transition metal complexes such as rhodium metal complexes using this ligand are extremely useful as asymmetric catalysts for asymmetric hydrogenation reactions. However, there has been a demand for a ligand that is easier to synthesize than this benzene derivative and has good handleability.

JP 2000-319288 A

  Accordingly, an object of the present invention is to provide an optically active phosphine ligand that is easier to synthesize and has better handleability than conventional phosphine ligands.

  The present invention achieves the above object by providing an optically active 2,3-bis (dialkylphosphino) pyrazine derivative represented by the following general formula (1).

式中、Ｒ¹は、直鎖状若しくは分岐状の非環式アルキル基又は脂環式アルキル基を示し、炭素数は２〜１０である。Ｒ²は、Ｒ¹よりも炭素数の少ない、直鎖状又は分岐状のアルキル基を示す。Ｒ³及びＲ⁴は、ハロゲン原子で置換されていてもよい炭素数１〜６のアルキル基又は水素原子を示し、同一でもよく又は異なっていてもよい。Ｒ³及びＲ⁴は互いに結合して飽和又は不飽和の環を形成していてもよい。

In the formula, R ^1, a linear or branched acyclic alkyl group or an alicyclic alkyl group indicates, is 2 to 10 carbon atoms. R ² is, small number of carbon atoms than R ^1, represents a linear or branched alkyl group. R ³ and R ⁴ represent an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a hydrogen atom, and may be the same or different. R ³ and R ⁴ may be bonded to each other to form a saturated or unsaturated ring.

  Moreover, this invention is a preferable manufacturing method of the pyrazine derivative represented by the above general formula (1), and the 2,3-dihalogenopyrazine derivative represented by the following general formula (3) is substituted with the following general formula ( 4) an optically active 2,3-bis (dialkylphosphino), characterized in that a dialkylphosphine-borane represented by 4) is deprotonated to effect a nucleophilic substitution reaction and then a deboraneation reaction. A method for producing a pyrazine derivative is provided.

  Furthermore, this invention provides the metal complex for asymmetric synthesis catalysts characterized by using the pyrazine derivative represented by the general formula (1) as a ligand.

  Since the pyrazine derivative of the present invention exists stably in the air, handling properties including storage stability are very good. Moreover, according to the manufacturing method of this invention, the pyrazine derivative of this invention can be manufactured easily. Furthermore, when the metal complex having the pyrazine derivative of the present invention as a ligand is used as a catalyst for asymmetric synthesis, it has high enantioselectivity and reaction activity, and can be widely applied to various asymmetric synthesis.

In the pyrazine derivative of the present invention represented by the general formula (1), R ¹ represents an optionally substituted linear or branched 2 to 10 alkyl group. Examples thereof include ethyl group, isopropyl group, n-propyl group, isobutyl group, n-butyl group, sec-butyl group, tert-butyl group, isoheptyl group, n-heptyl group, isohexyl group, n-hexyl group, A cyclopentyl group, a cyclohexyl group, an adamantyl group, etc. are mentioned. These groups may be appropriately substituted with at least one monovalent substituent. In particular, R ¹ is preferably a bulky group having steric hindrance. From this viewpoint, when R ¹ is an acyclic alkyl group, a secondary alkyl group is preferable to a primary alkyl group, and a tertiary alkyl group is preferable to a secondary alkyl group. It is also preferred that R ¹ is an alicyclic alkyl group. Preferred alkyl groups include a tert-butyl group and an adamantyl group.

On the other hand, in the general formula (1), R ² represents an optionally substituted linear or branched alkyl group having a carbon number smaller than that of R ¹ . The difference in carbon number between R ¹ and R ² needs to be at least 1. When the pyrazine derivative of the present invention is used as a ligand of a metal complex for an asymmetric synthesis catalyst, there is a large difference in the steric hindrance between R ¹ and R ² in consideration of the formation of a highly asymmetric space. Preferably there is. That is, R ¹ is preferably a bulky group having steric hindrance, that is, a maximal group, whereas R ² is preferably a minimal group. Therefore, R ¹ and R ² are more preferable as the difference in carbon number is larger. Specifically, the difference in carbon number between R ¹ and R ² is preferably 2 or more, particularly 3 or more, particularly 4 or more. Considering that R ² is a minimal group, the most preferred group as R ² can be said to be a methyl group. In general, however, the groups that can be used as R ² are determined relatively in relation to R ¹ . Particularly preferred combinations of R ¹ and R ² include a combination of R ¹ = tert-butyl group, R ² = methyl group, a combination of R ¹ = adamantyl group, and R ² = methyl group.

In general formula (1), R ³ and R ⁴ represents an alkyl group or a hydrogen atom having 1 to 6 carbon atoms. R ³ and R ⁴ may be the same or different. Examples of R ³ and R ⁴ include ethyl group, isopropyl group, n-propyl group, isobutyl group, n-butyl group, sec-butyl group, tert-butyl group, isoheptyl group, n-heptyl group, isohexyl group, n -A hexyl group, a cyclopentyl group, a cyclohexyl group, etc. are mentioned. These groups may be appropriately substituted with at least one monovalent substituent. R ³ and R ⁴ may be bonded to each other to form a saturated or unsaturated ring. Examples of the ring formed by combining R ³ and R ⁴ include a saturated or unsaturated 5-membered ring or 6-membered ring. For example, a phenyl group, a cyclohexyl group, a cyclopentyl group, etc. are mentioned. These rings may be appropriately substituted with at least one monovalent substituent.

Particularly preferred as R ³ and R ⁴ is the case where both are bonded to form a phenyl group, in which case the compound according to the present invention is a quinoxaline derivative represented by the following general formula (2). is there.

In the general formula (2), the monovalent substituent represented by R ⁵ is not particularly limited. Examples of R ⁵ include a halogen atom.

  Specific examples of the 2,3-bis (dialkylphosphino) pyrazine derivative represented by the general formula (1) include (R, R) -2,3-bis (tert-butylmethylphosphino). ) Quinoxaline, (R, R) -2,3-bis (adamantylmethylphosphino) quinoxaline, (R, R) -2,3-bis (tert-butylmethylphosphino) pyrazine, (R, R) -2 , 3-bis (adamantylmethylphosphino) pyrazine and the like.

  In the pyrazine derivative represented by the general formula (1), the electron density of the P atom in the phosphine moiety is lowered due to the electron withdrawing attributed to the pyrazine skeleton. As a result, the phosphine moiety becomes inactive against oxidation by air, and the storage stability is increased. In particular, when the pyrazine derivative represented by the above general formula (1) is a quinoxaline derivative represented by the above general formula (2), the phosphine moiety becomes more inactive against oxidation by air and is stored. Stability is further increased.

  Further, the pyrazine derivative represented by the general formula (1) has high rigidity due to the pyrazine skeleton, and the included angle formed between the two phosphine moieties and the transition metal becomes large. As a result, when a transition metal complex having the pyrazine derivative as a ligand is used as a catalyst, reductive elimination can easily proceed. In particular, when the pyrazine derivative represented by the general formula (1) is a quinoxaline derivative represented by the general formula (2), the included angle is further increased and reductive elimination is further facilitated. Can proceed to.

  Next, a method for producing a 2,3-bis (dialkylphosphino) pyrazine derivative according to the present invention will be described. First, a 2,3-dihalogenopyrazine derivative represented by the following general formula (3), such as 2,3-dichloroquinoxaline, is prepared. 2,3-dichloroquinoxaline is a commercially available compound.

  Separately, a dialkylphosphine-borane represented by the following general formula (4) is prepared and deprotonated in an inert solvent such as tetrahydrofuran. For deprotonation, for example, butyl lithium is used.

  A dialkylphosphine-borane in a deprotonated state is allowed to act on the 2,3-dihalogenopyrazine derivative. The electrons of the carbon atom to which the halogen in the 2,3-dihalogenopyrazine derivative is bonded are attracted by the adjacent nitrogen atom. Therefore, the deprotonated dialkylphosphine-borane, that is, the nucleophile, attacks the carbon atom to cause a nucleophilic substitution reaction. This reaction proceeds rapidly in a liquid nitrogen environment or at room temperature. By this reaction, an intermediate diphosphine-borane body is generated in the reaction system.

  Subsequently, a deboraneation reaction of the diphosphine-borane body as the intermediate is performed. For the deboration reaction, for example, N, N, N ′, N′-tetramethylethylenediamine (TMEDA) may be added to the reaction system. Deboraneation is completed in tens of minutes to several hours at room temperature. As a result, the desired 2,3-bis (dialkylphosphino) pyrazine derivative is obtained. The overall reaction scheme is as follows, showing that it is an addition / elimination reaction.

  According to the above method, there is an advantage that the target substance can be obtained from the starting material in a substantially one-step reaction. Also noteworthy is that the stericity of the P atom is not impaired during the reaction.

  In addition, the dialkyl phosphine-borane which is a nucleophile used for the said reaction can be prepared by a well-known method. Examples of such a method include the method described in JP-A-2001-253889. Specifically, the following method is mentioned.

  A dialkyl (hydroxymethyl) phosphine-borane represented by the following general formula (5) is dissolved in pyridine at 0 ° C. to room temperature. To this solution is added benzoyl chloride dropwise.

  This reaction produces a dialkyl (benzoyloxymethyl) phosphine-borane represented by the following general formula (6). The reaction is diluted with water and extracted with ether. The organic layer is washed with hydrochloric acid, and the solvent is removed to obtain dialkyl (benzoyloxymethyl) phosphine-borane crystals.

  The dialkyl (benzoyloxymethyl) phosphine-borane crystal represented by the general formula (6) is dissolved in ethanol, and an aqueous potassium hydroxide solution is added dropwise thereto to perform a hydrolysis reaction. Next, an aqueous solution containing potassium hydroxide, potassium persulfate and ruthenium trichloride is added dropwise to carry out the reaction. The reaction mixture is neutralized with hydrochloric acid and extracted with ether. The solvent is removed to obtain a dialkylphosphine-borane crystal represented by the general formula (4).

  The 2,3-bis (dialkylphosphino) pyrazine derivative of the present invention represented by the general formula (1) can form a complex with a transition metal as a ligand. This complex is useful as an asymmetric synthesis catalyst. Examples of the asymmetric synthesis include an asymmetric hydrogenation reaction, an asymmetric 1,4-addition reaction to an electron-deficient olefin using an organic boronic acid, an asymmetric hydrosilyl reaction, an asymmetric Michael reaction, and the like.

  Examples of the transition metal that can form a complex include rhodium, ruthenium, iridium, palladium, nickel, and iron. A preferred metal is rhodium. As a method of forming a complex with rhodium using a 2,3-bis (dialkylphosphino) pyrazine derivative represented by the general formula (1) as a ligand, for example, Experimental Chemistry Course 4th Edition (Edited by Chemical Society of Japan) , Published by Maruzen Co., Ltd., Vol. 18, pp. 327-353). Specifically, by reacting the 2,3-bis (dialkylphosphino) pyrazine derivative represented by the general formula (1) with bis (cycloocta-1,5-diene) rhodium tetrafluoroborate, Rhodium complexes can be produced.

Specific examples of the resulting rhodium complex include Rh ((S, S)-(1)) Cl, Rh ((S, S)-(1)) Br, Rh ((S, S)-(1) ) I, [Rh ((S, S)-(1)) (cod)] BF ₄ , [Rh ((S, S)-(1)) (cod)] ClO ₄ , [Rh ((S, S )-(1)) (cod)] PF ₆ , [Rh ((S, S)-(1)) (cod)] BPh ₄ , [Rh ((S, S)-(1)) (nbd)] BF ₄ , [Rh ((S, S)-(1)) (ndb)] ClO ₄ , [Rh ((S, S)-(1)) (ndb)] PF ₄ , [Rh ((S, S )-(1)) (ndb)] BPh ₄ , Rh ((R, R)-(1)) Cl, Rh ((R, R)-(1)) Br, Rh ((R, R)-( 1)) I, [Rh ((R, R)-(1)) (cod)] BF ₄ , [Rh ((R, R)-(1)) (cod)] ClO ₄ , [Rh ((R, R)-(1)) (cod)] PF ₆ , [Rh ((R, R) - (1)) (cod) ] BPh 4, [Rh ((R, R) - (1)) (nbd)] BF 4, [Rh ((R, R) - (1)) (ndb)] ClO ₄ , [Rh ((R, R)-(1)) (ndb)] PF ₆ , [Rh ((R, R)-(1)) (ndb)] BPh _{4 and the} like. [Rh ((S, S)-(1)) (cod)] BF ₄ is particularly preferable. In addition, (1) in the rhodium complex represents a 2,3-bis (dialkylphosphino) pyrazine derivative represented by the general formula (1). cod represents 1,5-cyclooctadiene, nbd represents norbornadiene, and Ph represents phenyl.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, this is merely an example and does not limit the invention.

[Example 1]
(1) Synthesis of Compound Represented by General Formula (4) According to the following procedure, (R) -tert-butylmethylphosphine-borane which is a kind of the compound represented by General Formula (4) ( 9) was synthesized.

  (R) -tert-butyl (hydroxymethyl) methylphosphine-borane (7) (92% ee, 2.22 g, 15.0 mmol) was dissolved in 10 ml of pyridine at 0 ° C. with stirring, benzoyl chloride. (2.1 mL, 18 mmol) was added dropwise. The reaction mixture was then heated to room temperature. After 1 hour, the reaction mixture was diluted with water and extracted three times with ether. The obtained organic layer was washed with 1M hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, and dehydrated with sodium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 3/1). A colorless solid was obtained, and this solid was recrystallized twice with a mixed solvent of hexane / ethyl acetate. In this way optically pure benzoyloxymethyl (tert-butyl) methylphosphine-borane (8) was obtained. The yield was 2.34 g, and the yield was 62%.

  A solution of benzoyloxymethyl (tert-butyl) methylphosphine-borane (8) (99% ee, 6.05 g, 24.0 mmol) in 25 mL of ethanol in potassium hydroxide (4. 0 g, 72 mmol) was added dropwise. Hydrolysis was complete in about 1 hour. The reaction mixture was diluted with water and extracted three times with ether. The extract was washed with saturated brine and dehydrated with sodium sulfate. The solvent was removed by a rotary evaporator, and the residue was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 3/1), and (R) -tert-butyl (hydroxymethyl) methylphosphine-borane (7). Got. This compound was dissolved in 72 mL of acetone. Aqueous solution (0 ° C.) of potassium hydroxide (13.5 g, 240 mmol), potassium persulfate (19.4 g, 72.0 mmol) and ruthenium trichloride trihydrate (624 mg, 2.4 mmol) dissolved in 150 mL of water In addition, the acetone solution was gradually added while vigorously stirring the aqueous solution. After 2 hours, the reaction mixture was neutralized with 3M hydrochloric acid and extracted three times with ether. The extract was washed with saturated brine and dehydrated with sodium sulfate. The solvent was removed at room temperature with a rotary evaporator, and the residue was purified by silica gel column chromatography (mobile phase: pentane / ether = 8/1). Thus, (R) -tert-butylmethylphosphine-borane (9) was obtained. The yield was 2.27 g, and the yield was 80%.

(2) Synthesis of Compound Represented by General Formula (1) According to the following procedure, (R, R) -2,3-bis ( tert-Butylmethylphosphino) quinoxaline (12) was synthesized.

  236 mg (2.0 mmol) of (R) -tert-butylmethylphosphine-borane (9) was dissolved in 4 mL of tetrahydrofuran to obtain a solution. This solution was cooled to −78 ° C. with liquid nitrogen, and 1.25 mL of a hexane solution (1.6 M) of n-butyllithium was added dropwise thereto. After 15 minutes, a solution obtained by dissolving 133 mg (0.67 mmol) of 2,3-dichloroquinoxaline (10) in 4 mL of tetrahydrofuran was added dropwise under vigorous stirring. As a result, an intermediate diphosphine-borane (11) is obtained. The liquid temperature was brought to room temperature over 1 hour, followed by stirring for 3 hours. Next, 1 mL of TMEDA was added, and stirring was continued for another 2 hours to perform a deboranation reaction. 1M hydrochloric acid was added to terminate the reaction, and the reaction solution was extracted with hexane. The extract was washed with 1M hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was removed by vacuum suction, and the residue was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 30/1). This gave an orange solid of (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline (12). This solid was recrystallized with hot methanol (1.7 mL). This gave orange crystals (> 99% ee, 80% yield). The physical property values of this compound were as follows.

Melting point 102-103 ° C .; [β] ²² _D- 54.3 (c1.00, CHCl ₃ ); ¹ H NMR (395.75 MHz, CDCl ₃ ): β 1.00-1.03 (m, 18H), 1.42-1.44 (m, 6H), 7.70-7.74 (m, 2H), 8.08-8.12 (m, 2H); ¹³ C NMR (99.45 MHz, CDCl ₃ ) : Β 4.77 (t, J = 4.1 Hz), 27.59 (t, J = 7.4 Hz), 31.90 (t, J = 7.4 Hz), 129.50, 129.60, 141 .63, 165.12 (dd, J = 5.7, 2.4 Hz); ³¹ P NMR (202.35 MHz, CDCl ₃ ): β-17.7 (s); IR (KBR) 2950, 1470, 780 cm ^-1 ; HRMS (FAB) calculated value (C ₁₈ H ₂₉ N ₂ P ₂ (M ⁺ + H)) 335.1 809, actual value 335.1826

[Example 2]
Asymmetric hydrogenation reaction using rhodium complex A 50 mL reaction tube was charged with 0.5 mmol of the substrate shown in Table 1 below. The reaction tube was connected to a hydrogen gas tank with a stainless steel tube. The reaction tube was filled with 1 atmosphere of hydrogen gas (Nippon Oxygen, 99.9999%). 1.9 mg (5.0 μmol) [Rh (nbd) ₂ ] BF ₄ and 2.0 mg (6.0 μmol) (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline (12 ) Was added to 1 mL of degassed methanol using a syringe. Next, the pressure of hydrogen gas in the reaction tube was set to 3 atm. The reaction mixture was evaporated and the residue was purified by flash chromatography on silica gel. Ethyl acetate was used as the eluent. The absolute configuration and ee value of the product was determined from a comparison of retention time and reported values.

Example 3
1,4-addition reaction of organoboronic acid to β, β-unsaturated carbonyl compound using rhodium complex 1.8 mg (9.0 μmol) of [RhCl (C ₂ H ₄ ) ₂ ] ₂ and 3.3 mg ( (9.9 μmol) of (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline (12) was added to 1 mL of dioxane and stirred for 15 minutes at room temperature under nitrogen atmosphere. Thereto was added 0.1 ml of a 1.5 M aqueous potassium hydroxide solution, and the mixture was stirred for 15 minutes. Further, organoboronic acid (0.60 mmol) and β, β-unsaturated carbonyl compound (0.30 mmol) shown in Table 2 were added. After stirring at 40 ° C. for 1 hour, the reaction was terminated with a saturated aqueous sodium hydrogen carbonate solution and extracted five times with ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Finally, the residue was purified by TLC (silica gel, hexane / ethyl acetate = 3/1). The absolute configuration and ee value of the product was determined from a comparison of retention time and reported values.

Example 4
Asymmetric ring-opening reaction using palladium catalyst 7.1 mg (0.025 mmol) PdCl ₂ (cod) and 8.3 mg (0.025 mmol) (R, R) -2,3-bis (tert-butylmethyl) Phosphino) quinoxaline (12) was added to 1 mL of CH ₂ Cl ₂ and stirred at room temperature under nitrogen atmosphere for 2 hours. A solution prepared by dissolving 0.5 mmol of oxabenzonorbornadiene shown in Table 3 in 15 mL of CH ₂ Cl ₂ was added thereto. Subsequently, 1.0 M hexane solution of dimethylzinc (0.75 mL) or 1.0 M hexane solution of diethylzinc (0.75 mL) was added. The solution was stirred until the reaction was complete. A few drops of water were added to terminate the reaction. The reaction mixture was passed through Celite (trade name) and then concentrated. Finally, the residue was purified by TLC (silica gel, hexane / ethyl acetate = 3/1). The absolute configuration and ee value of the product was determined from a comparison of retention time and reported values.

Example 5
(1) Synthesis of compound represented by general formula (4) According to the following procedure, (R) -adamantylmethylphosphine-borane (15), which is a kind of compound represented by general formula (4) Was synthesized.

  (R) -adamantyl (hydroxymethyl) methylphosphine-borane (13) (88% ee, 1.57 g, 6.94 mmol) and 4-dimethylaminopyridine (43 mg, 0.35 mmol) were dissolved in 20 mL of tetrahydrofuran. To the solution, benzoyl chloride (1.22 mL, 10.5 mmol) and triethylamine (1.95 mL, 14 mmol) were added with stirring. After the mixture was stirred overnight, the reaction mixture was treated with 1M hydrochloric acid and extracted three times with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. After the solvent was distilled off with a rotary evaporator, the residue was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 1/1). A colorless solid was obtained, which was recrystallized twice with methanol. In this way optically pure adamantyl (benzoyloxymethyl) methylphosphine-borane (14) was obtained. The yield was 1.09 g, and the yield was 47%. The NMR spectrum data was as follows.

¹ H NMR (396 MHz, CDCl ₃ ): δ 0.46 (br q, 3H), 1.32-1.35 (d, 3H), 1.68-2.04 (m, 15H), 4.66 -4.77 (m, 2H), 7.26-7.49 (t, 2H), 7.58-7.62 (t, 1H) 8.03-8.05 (d, 2H)

  To a solution of adamantyl (benzoyloxymethyl) methylphosphine-borane (14) (99% ee, 1.09 g, 3.3 mmol) dissolved in 10 mL of acetone, 10 mL of 1 M aqueous potassium hydroxide solution was added dropwise. After 1 hour, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off using a rotary evaporator, and the residue was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate = 1/1), and (R) -adamantyl (hydroxymethyl) methylphosphine-borane (13) was purified. Obtained. This compound was dissolved in 6 mL of acetone. This acetone solution was added to a solution of potassium hydroxide (1.85 g, 33 mmol) and potassium persulfate (2.67 g, 9.9 mmol) in 9 mL of water. The reaction vessel was immersed in an ice bath and ruthenium trichloride trihydrate (87 mg, 0.33 mmol) was added with vigorous stirring. After 15 minutes, the ice bath was removed, and the mixture was further stirred at room temperature for 2 hours, and then neutralized with 1M hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off with a rotary evaporator, and the residue was purified by silica gel column chromatography (mobile layer: hexane / ethyl acetate = 5/1). In this way (R) -adamantylmethylphosphine-borane (15) was obtained. The yield was 506 mg and the yield was 78%. The NMR spectrum data was as follows.

¹ H NMR (396 MHz, CDCl ₃ ): δ 0.45 (br q, 3H), 1.26 (dd, 3H), 1.71-2.05 (m, 15H), 3.73-3.80 4.63-4.70 (m, 1H)

(2) Synthesis of the compound represented by the general formula (1) According to the following procedure, 2,3-bis (adamantylmethylphosphino) quinoxaline which is a kind of the compound represented by the general formula (1) (17) was synthesized.

８６ｍｇ（０．４４ｍｍｏｌ）の（Ｒ）−アダマンチルメチルホスフィン−ボラン（１５）を２ｍＬのジエチレングリコールジメチルエーテルに溶解して溶液を得た。この溶液に窒素雰囲気下でｎ−ブチルリチウムのヘキサン溶液（２．５５Ｍ、０．１７ｍＬ）を０℃でゆっくり滴下した。１５分経過後、２，３−ジクロロキノキサリン（１０）（４０ｍｇ、０．２ｍｍｏｌ）を加え、室温で３時間撹拌した。これによって中間体であるジホスフィン−ボラン体（１６）を得る。次いで０．２９ｍＬ（２ｍｍｏｌ）のＴＭＥＤＡを添加して、更に３時間攪拌を継続し、脱ボラン化反応を行った。反応混合物を１Ｍの塩酸で処理し、次いでヘキサンで抽出した。抽出液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、溶媒をロータリーエバポレータで留去した。残渣をシリカゲルカラムクロマトグラフィー（移動層：ヘキサン／酢酸エチル＝２００／１）で精製することにより，２，３−ビス（アダマンチルメチルホスフィノ）キノキサリン（１７）を橙色無定形質固体として得た（収率７５％）。この化合物の物性値は次の通りであった。

86 mg (0.44 mmol) of (R) -adamantylmethylphosphine-borane (15) was dissolved in 2 mL of diethylene glycol dimethyl ether to obtain a solution. To this solution, a hexane solution of n-butyllithium (2.55 M, 0.17 mL) was slowly added dropwise at 0 ° C. under a nitrogen atmosphere. After 15 minutes, 2,3-dichloroquinoxaline (10) (40 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 3 hours. As a result, an intermediate diphosphine-borane (16) is obtained. Next, 0.29 mL (2 mmol) of TMEDA was added, and stirring was continued for another 3 hours to perform a deboranation reaction. The reaction mixture was treated with 1M hydrochloric acid and then extracted with hexane. The extract was washed with saturated brine and dried over sodium sulfate, and then the solvent was distilled off with a rotary evaporator. The residue was purified by silica gel column chromatography (mobile bed: hexane / ethyl acetate = 200/1) to obtain 2,3-bis (adamantylmethylphosphino) quinoxaline (17) as an orange atypical solid ( Yield 75%). The physical property values of this compound were as follows.

[Α] ²⁴ _D = −248; ¹ H NMR (396 MHz, CDCl ₃ ): δ 1.53-1.85 (m, 30H), 1.39-1.42 (m, 6H), 7.72- 7.75 (m, 2H), 8.09-8.13 (m, 2H); ³¹ P NMR (202 MHz, CDCl ₃ ): δ-17.9 (s)

Example 6
A substrate (0.5 mmol) shown in Table 4 below was charged into a pressure resistant reaction tube made of asymmetric hydrogenation reaction glass using a rhodium complex, and the inside of the system was purged with nitrogen. Meanwhile, in a 5 mL round bottom flask, 1.87 mg (5.0 μmol) [Rh (nbd) ₂ ] BF ₄ and 2.94 mg (6.0 μmol) 2,3-bis (adamantylmethylphosphino) quinoxaline ( 17) was added. After substituting the system with nitrogen, 1 mL of degassed methanol was added and stirred for 30 minutes. This solution was transferred into a pressure-resistant reaction tube, and the inside of the system was replaced with 3 atmospheres of hydrogen gas. After 2 hours, the solvent was removed by a rotary evaporator, and the residue was purified by silica gel chromatography (mobile layer: ethyl acetate). The absolute configuration and ee value of the product were determined by comparison with previously reported values using high performance liquid chromatography.

Claims (5)

An optically active 2,3-bis (dialkylphosphino) pyrazine derivative represented by the following general formula (1):

In the formula, R ^1, a linear or branched acyclic alkyl group or an alicyclic alkyl group indicates, is 2 to 10 carbon atoms. R ² is, small number of carbon atoms than R ^1, represents a linear or branched alkyl group. R ³ and R ⁴ represent an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a hydrogen atom, and may be the same or different. R ³ and R ⁴ may be bonded to each other to form a saturated or unsaturated ring. The pyrazine derivative according to claim 1, which is represented by the following general formula (2).

In the formula, R ¹ and R ² are the same as defined above, and R ⁵ represents a halogen atom or a hydrogen atom . The pyrazine derivative according to claim 1 or 2, wherein R ¹ is a t-butyl group or an adamantyl group, and R ² is a methyl group. A method for producing a pyrazine derivative according to claim 1,
The 2,3-dihalogenopyrazine derivative represented by the following general formula (3) is allowed to act by deprotonating the dialkylphosphine-borane represented by the following general formula (4), followed by a nucleophilic substitution reaction. A process for producing an optically active 2,3-bis (dialkylphosphino) pyrazine derivative, characterized by carrying out a deboraneation reaction.

  A metal complex for an asymmetric synthesis catalyst comprising the pyrazine derivative according to claim 1 as a ligand.