Ruthenium complex, method for producing said complex, and method for producing optically active secondary alcohol using said complex as a catalyst

Abstract

The present invention addresses the problem of providing a novel ruthenium complex, in which addition of a base during catalyst activation is not necessary, which exhibits excellent crystallinity and stability, for which large scale synthesis and long term storage are easy, and which exhibits excellent catalytic activity and asymmetry-inducing performance in an asymmetric hydrogenation reaction. The present invention relates to a ruthenium complex represented by general formula (1). (Definitions of groups in formula (1) are as mentioned in the description.)

Description

[Technical field]

[0001] The present invention relates to a novel ruthenium complex, a method for producing the complex, and a method for producing an optically active secondary alcohol using the complex as a catalyst. [Background technology]

[0002] Optically active secondary alcohols are extremely important compounds for use in pharmaceuticals, agricultural chemicals, functional materials, fragrances, synthetic intermediates, etc., and research and development into their production methods is still being actively conducted. Among these production methods, the catalytic asymmetric hydrogenation of asymmetric ketones using hydrogen molecules as a reducing agent is one of the most important methods from the perspective of the SDGs and green chemistry, which have been attracting attention recently, due to its excellent atom efficiency and the ability to significantly reduce waste.

[0003] In the industrialization of such catalytic asymmetric hydrogenation reactions, catalysts with excellent catalytic activity, asymmetric induction ability, and stability are essential, and therefore their development has been actively pursued for many years. Among the catalysts developed in this way, the ruthenium complexes RuCl2(dm-binap)(dpen) and RuCl2(dm-binap)(daipen) [Non-Patent Document 1], RuH(η 1 -BH4)(dm-binap)(dpen) [Non-Patent Document 2] and RuH(η 1 -BH4)(t-binap)(daipen) [Non-Patent Document 3] is known to exhibit extremely good catalytic activity and asymmetric induction ability in catalytic asymmetric hydrogenation of asymmetric ketones. Later, ruthena bicyclic complexes [Patent Document 1, Non-Patent Document 4] were developed as an advanced form of these ruthenium complexes, and it has been reported that these complexes have even better catalytic ability than those developed by Noyori et al. For reference, the structural formulas of these ruthenium complexes are shown in Formula 1 below.

[0004] [ka]

[0005] [In the above structural formula, An represents a 4-methoxyphenyl group, Ph represents a phenyl group, Tol represents a 4-methylphenyl group, and Xyl represents a 3,5-dimethylphenyl group.] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2011 / 135753 [Non-patent literature]

[0007] [Non-Patent Document 1] Takeshi Ohkuma, Masatoshi Koizumi, Henri Doucet, Trang Pham, Masami Kozawa, Kunihiko Murata, Eiji Katayama, Tohru Yokozawa, Takao Ikariya, and Ryoji Noyori, J.Am.Chem.Soc., 1998, 120, 13529. [Non-Patent Document 2] Takeshi Ohkuma, Masatoshi Koizumi, Kilian Muniz, Gerhard Hilt, Chizuko Kabuto, and Ryoji Noyori, J.Am.Chem.Soc., 2002, 124, 6508. [Non-Patent Document 3] Christian A. Sandoval, Yoshiki Yamaguchi, Takeshi Ookuma, Koichi Kato and Ryoji Noyori, Magn. Reson. Chem., 2006, 44, 66. [Non-Patent Document 4] Kazuhiko Matsumura, Noriyoshi Arai, Takao Saito, Noboru Sayo, and Takeshi Ohkuma, J.Am.Chem.Soc.,2011,133,10696. Summary of the Invention [Problem to be solved by the invention]

[0008] As mentioned above, although many asymmetric hydrogenation catalysts have been developed, there are still problems to be improved. For example, for all of the ruthenium complexes described in Non-Patent Document 1, the addition of a base is essential to activate the catalyst. Therefore, it is difficult to use as a substrate a compound that is unstable under basic conditions among asymmetric ketones. Even if an asymmetric ketone that is stable under basic conditions is used, potassium tert-butoxide, which is widely used as a base, easily absorbs moisture and decomposes, so that a complicated weighing operation using a special device such as a glove box is required to carry out the reaction. Even in the ruthena bicyclic complexes described in Patent Document 1 and Non-Patent Document 4, which are advanced versions of these complexes, a base is still essential for their activation, so these problems still remain.

[0009] On the other hand, the ruthenium complex described in Non-Patent Document 2, which is obtained by the reaction of the complex described in Non-Patent Document 1 with sodium borohydride, exhibits catalytic activity without the addition of a base, and therefore, compared with the above-mentioned ruthenium complex and ruthena bicyclic complex, it is possible to expand the substrate application range and simplify the reaction operation. However, since this complex has poor crystallinity and stability, it is difficult to isolate and purify it by crystallization, and in order to exert its original performance, it must be prepared immediately before use. In addition, the ruthenium complex described in Non-Patent Document 3, which is obtained by a similar reaction, shows excellent catalytic activity without a base, but is extremely unstable and decomposes within a few hours even in heavy benzene, so it is difficult to industrially synthesize this complex in large quantities and use it in catalytic hydrogenation reactions. Therefore, an asymmetric hydrogenation catalyst that does not require activation by a base and has excellent crystallinity, stability, catalytic activity, and asymmetric induction ability is still strongly desired from the viewpoint of efficient production of optically active secondary alcohols.

[0010] The present invention has been made in view of the above-mentioned current situation. That is, an object of the present invention is to provide a novel ruthenium complex having the following characteristics: 1) no need for the addition of a base for catalyst activation, 2) excellent crystallinity and stability, 3) ease of mass synthesis and long-term storage, and 4) excellent catalytic activity and asymmetric induction ability in asymmetric hydrogenation reactions, and an efficient method for producing optically active secondary alcohols using this complex as a catalyst. [Means for solving the problem]

[0011] In the course of our investigations to solve the above problems, the present inventors were inspired by the synthesis method for ruthenium complexes (formula 2) described in Non-Patent Document 3, and attempted to react the ruthena bicyclic complex described in Patent Document 1 with sodium borohydride (formula 3). As a result, a novel complex with an unknown structure was produced, but curiously, the hydride (H) ligand and η ligand that could be introduced by this reaction were not clearly identified. 1 -Borohydride (η 1 -BH4) ligand, the complex was analyzed by proton nuclear magnetic resonance spectroscopy ( 1H NMR) analysis (Figure 1). 1 In H NMR, the H ligand is around -13.9 ppm, and η 1 The -BH4 ligand is observed around -0.24 ppm.

[0012] [ka]

[0013] Based on this finding, the inventors further conducted intensive research and discovered that this novel ruthenium complex has unexpectedly excellent crystallinity and stability. Taking advantage of these properties, they produced single crystals of this complex and performed X-ray structural analysis. To their surprise, they found that the complex was composed of η ligands rather than H ligands. 1 The -BH4 ligand is trapped in the cavity of the complex and its free movement is restricted. 1 It became clear that this could not be observed by H NMR. For reference, a typical single crystal X-ray structural analysis result (thermal vibration ellipsoid diagram) of this novel ruthenium complex is shown in Figure 2, but the present invention is not limited to this diagram in any way.

[0014] Furthermore, the present inventors have found that, although this novel complex does not have an H ligand capable of functioning as a reducing agent, it exhibits catalytic activity in a hydrogen atmosphere without the addition of a base, and exhibits excellent catalytic activity and asymmetric induction ability in catalytic asymmetric hydrogenation of asymmetric ketones. Based on these fundamental findings, the present inventors have conducted further investigations and have completed the present invention.

[0015] That is, the present invention includes the following [1] to [7]. [1] A ruthenium complex represented by general formula (1).

[0016] [ka]

[0017] [In formula (1), a solid line represents a single bond, a double line represents a double bond, a dashed line represents a coordinate bond, and a wavy line represents a three-center two-electron bond. B represents a boron atom, N represents a nitrogen atom, and P represents a phosphorus atom. H and H B represent hydrogen atoms, and C, C P1 , C P2 , C a , C N1 and C N2 Each represents a carbon atom. Ru represents a divalent ruthenium ion. R P represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent. R P1 , R P2 , R P3 and R P4 each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, an alkenyl group, an alkoxy group, a halogenoalkoxy group, a hydroxy group, and a halogeno group. R P1 and R P2 are combined with each other to form C P1 and C P2 may form a ring together with R N1 and R N3 each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, an aryl group, and an aralkyl group. R N2 , R N4 , R N5 and R N6 each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, a halogenoalkyl group, an alkoxy group, and a halogeno group. [2]R P is an optionally substituted aryl group. [3] R P3 , R P4 , R N3 , R N4 , R N5 and R N6are all hydrogen atoms. [4] The ruthenium complex according to any one of the above [1] to [3], which is an optically active substance. [5] A method for producing a ruthenium complex according to any one of the above [1] to [4], comprising a step of reacting a ruthenium complex represented by the following general formula (2) with a borohydride compound:

[0018] [ka]

[0019] [In formula (2), the solid lines represent single bonds, the double lines represent double bonds, and the dashed lines represent coordinate bonds. Cl represents a chlorine atom, H represents a hydrogen atom, N represents a nitrogen atom, and P represents a phosphorus atom. C, C P1 , C P2 , C a , C N1 and C N2 Each represents a carbon atom. Ru represents a divalent ruthenium ion. R P represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent. R P1 , R P2 , R P3 and R P4 each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, an alkenyl group, an alkoxy group, a halogenoalkoxy group, a hydroxy group, and a halogeno group. R P1 and R P2 are combined with each other to form C P1 and C P2 may form a ring together with R N1 and R N3 each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, an aryl group, and an aralkyl group. R N2 , R N4, R N5 and R N6 each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, a halogenoalkyl group, an alkoxy group, and a halogeno group. [6] The method for producing a ruthenium complex according to [5] above, wherein the borohydride compound is sodium borohydride. [7] A method for producing an optically active secondary alcohol by catalytic asymmetric hydrogenation of an asymmetric ketone using the ruthenium complex according to the above item [4] as a catalyst. Effect of the Invention

[0020] The ruthenium complex represented by the general formula (1) [hereinafter referred to as ruthenium complex (1)] can be easily synthesized, has excellent crystallinity and can be isolated and purified by crystallization or recrystallization, and has excellent stability in air and can be stored for a long time, so that it is suitable for mass production in industrialization. In addition, since this ruthenium complex (1) exhibits excellent catalytic activity and asymmetric induction ability in asymmetric hydrogenation reactions of asymmetric ketones without adding a base, substrates that can be decomposed under basic conditions can be used in these reactions, and complicated weighing operations of bases using special equipment are not required. Therefore, by using the ruthenium complex (1) of the present invention as a catalyst, it is possible to more efficiently produce optically active secondary alcohols that are of high industrial value. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 is a spectrum showing the results of proton nuclear magnetic resonance spectroscopy ( 1 H NMR) analysis of a novel complex produced by reacting a ruthena bicyclic complex described in Patent Document 1 with sodium borohydride. [Diagram 2] FIG. 2 shows a typical single crystal X-ray structure analysis result (thermal ellipsoid diagram) of the ruthenium complex of the present invention. [Diagram 3] FIG. 3 shows the results of single crystal X-ray structural analysis of the ruthenium complex produced in Example 1 (thermal ellipsoid diagram; atomic presence probability 50%). [Figure 4]FIG. 4 shows the results of 1H NMR (lower spectrum) measured in deuterated benzene immediately after production of the ruthenium complex produced in Example 1, and 1H NMR (upper spectrum) measured after leaving the complex in air at room temperature for 4 weeks. [Diagram 5] FIG. 5 shows the results of single crystal X-ray structural analysis of the ruthenium complex produced in Example 2 (thermal ellipsoid diagram; atomic presence probability 50%). [Figure 6] FIG. 6 shows the results of single crystal X-ray structural analysis of the ruthenium complex produced in Example 3 (thermal ellipsoid diagram; atomic presence probability 50%). [Figure 7] FIG. 7 shows the results of 1H NMR (lower spectrum) measured in deuterated benzene immediately after production of the ruthenium complex produced in Example 3, and 1H NMR (upper spectrum) measured after leaving the complex in air at room temperature for 4 weeks. [Figure 8] FIG. 8 shows the results of single crystal X-ray structural analysis of the ruthenium complex produced in Example 4 (thermal ellipsoid diagram; atomic presence probability 50%). [Figure 9] FIG. 9 shows the results of 1H NMR (lower spectrum) measured in deuterated benzene immediately after production of the ruthenium complex produced in Example 5, and 1H NMR (upper spectrum) measured after leaving the complex in air at room temperature for 4 weeks. [Figure 10] FIG. 10 shows the results of single crystal X-ray structural analysis of the ruthenium complex produced in Example 6 (thermal ellipsoid diagram; atomic presence probability 50%). [Figure 11] FIG. 11 shows the results of 1H NMR (lower spectrum) measured in deuterated benzene immediately after production of the ruthenium complex produced in Example 6, and 1H NMR (upper spectrum) measured after leaving the complex in air at room temperature for 4 weeks. [Figure 12] FIG. 12 shows the results of single crystal X-ray structural analysis of the ruthenium complex produced in Example 7 (thermal ellipsoid diagram; atomic presence probability 50%). [Figure 13] FIG. 13 shows the results of single crystal X-ray structural analysis of the ruthenium complex produced in Example 8 (thermal ellipsoid diagram; atomic presence probability 50%). [Figure 14]FIG. 14 shows the results of 1H NMR (lower spectrum) measured in deuterated benzene immediately after production of the ruthenium complex produced in Example 8, and 1H NMR (upper spectrum) measured after leaving the complex in air at room temperature for 4 weeks. [Figure 15] FIG. 15 shows the results of single crystal X-ray structural analysis of the ruthenium complex produced in Example 9 (thermal ellipsoid diagram; atomic presence probability 50%). [Figure 16] FIG. 16 shows the results of 1H NMR (lower spectrum) measured in deuterated benzene immediately after production of the ruthenium complex produced in Example 10, and 1H NMR (upper spectrum) measured after leaving the complex in air at room temperature for 4 weeks. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The ruthenium complex (1) of the present invention will now be described in detail. In the general formula (1), a solid line represents a single bond, a double line represents a double bond, a dashed line represents a coordinate bond, and a wavy line represents a three-center two-electron bond. B represents a boron atom, N represents a nitrogen atom, and P represents a phosphorus atom. H and H B represent hydrogen atoms, and C, C P1 , C P2 , C a , C N1 and C N2 Each represents a carbon atom. Ru represents a divalent ruthenium ion. R P represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent, and preferably represents an aryl group which may have a substituent. R P1 , R P2 , R P3 and R P4each independently represents a hydrogen atom, or a group selected from the group consisting of an alkyl group, an alkenyl group, an alkoxy group, a halogenoalkoxy group, a hydroxy group, and a halogeno group, and preferably represents a hydrogen atom, or a group selected from the group consisting of an alkyl group, an alkenyl group, an alkoxy group, and a hydroxy group. R P1 and R P2 are combined with each other to form C P1 and C P2 may form a ring together with R N1 and R N3 each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, an aryl group, and an aralkyl group, and preferably represents a hydrogen atom or an alkyl group. R N2 , R N4 , R N5 and R N6 each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, a halogenoalkyl group, an alkoxy group, and a halogeno group, and preferably represents a hydrogen atom or an alkoxy group.

[0023] Next, the wavy line in the general formula (1) will be described in more detail. B Between and H B The wavy lines between -B represent three-center two-electron bonds, i.e., Ru, H B This represents a state in which the three atoms, Ru and B, share two electrons. B Not only the bond between H B Since the bond between -B can also be cleaved and activated, it is believed that the ruthenium complex (1) of the present invention exhibits catalytic activity even in the absence of a base, unlike general ruthenium complexes having simple anionic ligands.

[0024] Next, R in the general formula (1) P We will explain in more detail about R PThe alkyl group in may be linear or branched and includes, for example, an alkyl group having 1 to 12 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, and more preferably an alkyl group having 1 to 4 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an s-butyl group, an isobutyl group, and a tert-butyl group.

[0025] R P The cycloalkyl group in may be monocyclic or polycyclic and is, for example, a cycloalkyl group having 3 to 20 carbon atoms, preferably a cycloalkyl group having 3 to 15 carbon atoms, more preferably a cycloalkyl group having 3 to 10 carbon atoms. Specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 1-adamantyl group, and a 2-adamantyl group.

[0026] R P The heteroaryl group in the above formula (I) includes heteroaryl groups derived from a 5-membered aromatic heterocycle containing an oxygen atom or a sulfur atom, and specific examples thereof include a 2-furyl group, a 3-furyl group, a 2-thienyl group, and a 3-thienyl group.

[0027] R P The aryl group in the formula (I) is, for example, an aryl group having 6 to 18 carbon atoms, preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms. Specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group, and a preferred specific example is a phenyl group. The aryl group may have a substituent.

[0028] R P The substituents that the aryl group in R may have include an alkyl group, a halogenoalkyl group, an alkoxy group, and a dialkylamino group, and preferably an alkyl group. The alkyl group in these substituents is P Examples of the alkyl group include the same alkyl groups as those described in detail in the explanation of 1., and a preferred specific example is a methyl group.

[0029] The halogenoalkyl group in these substituents includes a halogenoalkyl group formed by replacing at least one hydrogen atom on the above alkyl group with a halogen atom, and a specific example thereof is a trifluoromethyl group.

[0030] The alkoxy group in these substituents may be linear or branched and includes, for example, an alkoxy group having 1 to 12 carbon atoms, preferably an alkoxy group having 1 to 8 carbon atoms, and more preferably an alkoxy group having 1 to 4 carbon atoms. Specific examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an s-butoxy group, an isobutoxy group, and a tert-butoxy group.

[0031] The dialkylamino group in these substituents includes a dialkylamino group formed by substituting two hydrogen atoms on an amino group with the above-mentioned alkyl groups, and specifically includes an N,N-dimethylamino group.

[0032] Next, R in the general formula (1) P1 , R P2 , R P3 and R P4 We will explain in more detail about R P1 ~R P4 Examples of the alkyl group in the formula (I) include alkyl groups having 1 to 9 carbon atoms, preferably alkyl groups having 1 to 6 carbon atoms, and more preferably alkyl groups having 1 to 3 carbon atoms. Specific examples include a methyl group, an ethyl group, and an n-propyl group.

[0033] R P1 ~R P4 The alkenyl group in the formula (I) is, for example, an alkenyl group having 2 to 9 carbon atoms, preferably an alkenyl group having 2 to 6 carbon atoms, more preferably an alkenyl group having 2 to 3 carbon atoms. Specific examples include a vinyl group and a 1-propenyl group, and a preferred specific example is a vinyl group.

[0034] R P1 ~R P4The alkoxy group in may be linear or branched, and examples thereof include alkoxy groups having 1 to 9 carbon atoms, preferably alkoxy groups having 1 to 6 carbon atoms, and more preferably alkoxy groups having 1 to 3 carbon atoms. Specific examples include methoxy groups, ethoxy groups, n-propoxy groups, and isopropoxy groups, and a preferred specific example is methoxy groups.

[0035] R P1 ~R P4 The halogenoalkoxy group in the above formula (I) includes a halogenoalkoxy group formed by substituting at least one hydrogen atom of the above alkoxy group with a halogen atom, and specifically includes a difluoromethoxy group.

[0036] R P1 ~R P4 Specific examples of the halogeno group in include a fluoro group, a chloro group, a bromo group and an iodo group.

[0037] In addition, R P1 and R P2 are combined with each other to form C P1 and C P2 Hereinafter, preferred specific examples of this ring formation mode will be shown in the following general formulae (1-A) to (1-F).

[0038] [ka]

[0039] [ka]

[0040] [ka]

[0041] [ka]

[0042] [ka]

[0043] [ka]

[0044] [In the general formulae (1-A) to (1-F), a solid line, a double line, a dashed line, a wavy line, B, N, P, H, H B , C, C P1 , C P2 , C a , C N1 , C N2 , Ru, R P , R P3 , R P4 , R N1 , R N2 , R N3 , R N4 , R N5 and R N6 are all the same as defined in the explanation of the general formula (1). O represents an oxygen atom, F represents a fluorine atom, and Me represents a methyl group.

[0045] Next, R in the general formula (1) N1 ~R N6 We will explain in more detail about R N1 and R N3 The alkyl group in R P Examples of the alkyl group include the same groups as those described in detail in the description of the alkyl group, and a preferred specific example is an isopropyl group. N1 and R N3 The aryl group in R P Examples of the aryl groups include the same aryl groups as those described in detail in the description of R N1 and R N3 The aralkyl group in the formula (I) includes an aralkyl group formed by substituting at least one hydrogen atom on the alkyl group with the aryl group, and a specific example thereof is a benzyl group.

[0046] R N2 and R N4 ~R N6 The alkyl group in R P Examples of the alkyl group include the alkyl groups described in detail in the description of R. N2 and R N4 ~R N6 The halogenoalkyl group in the formula (I) includes a halogenoalkyl group formed by replacing at least one hydrogen atom on the alkyl group with a halogen atom, and specifically includes a trifluoromethyl group. N2 and R N4 ~R N6 The alkoxy group in R P1 ~R P4 Examples of the alkoxy groups include the same alkoxy groups as those described in detail in the description of R, and a preferred specific example is a methoxy group. N2 and R N4 ~R N6 The halogeno group in P1 ~R P4 Examples of the halogeno groups include those described in detail in the description of the above.

[0047] In the ruthenium complex (1) of the present invention, the structure is C N1 is an asymmetric carbon [hereinafter, the absolute configuration of the central chirality caused by this asymmetric carbon is represented by 1R and 1S], R N1 and R N3 If they are different, C N2 can also be an asymmetric carbon [hereinafter, the absolute configuration of the central chirality thus generated will be represented as 2R and 2S]. a -C a When the free rotation of the intermolecular bond is suppressed, axial asymmetry occurs [hereinafter, the absolute configuration of the axial asymmetry thus generated is represented by aR and aS], and secondary octahedral asymmetry is induced in Ru on the ruthenium complex (1) due to these central and axial asymmetries. Therefore, the ruthenium complex (1) of the present invention may be a mixture of stereoisomers resulting from these various asymmetries or a single stereoisomer, but from the viewpoint of application as a catalyst, it is preferably a single stereoisomer, i.e., an optically active substance.

[0048] Specific examples of the octahedral asymmetry secondarily induced by the above-mentioned central asymmetry and axial asymmetry include OC-6-32-A, OC-6-32-C, OC-6-42-A, OC-6-42-C, OC-6-43-A and OC-6-43-C, based on the structural requirements of ruthenium complex (1). Preferred specific examples include OC-6-32-A and OC-6-32-C.

[0049] A preferred embodiment of the ruthenium complex (1) of the present invention is specifically the following: P is an aryl group which may have a substituent, and R P3 , R P4 , R N3 , R N4 , R N5 and R N6 are hydrogen atoms [hereinafter referred to as ruthenium complex (1')].

[0050] [ka]

[0051] [In formula (1'), solid line, double line, dashed line, wavy line, B, N, P, H, H B , C, C P1 , C P2 , C a , C N1 , C N2 , Ru, R P1 , R P2 , R N1 and R N2 are all the same as those defined and described in detail in the explanation of the above general formula (1). Ar represents an aryl group which may have a substituent.

[0052] Particularly preferred specific examples of the ruthenium complex (1) of the present invention include ruthenium complexes ((OC-6-32-A)-(1S,2R,aR)-1'-A1) to ((OC-6-32-C)-(1R,2S,aS)-1'-G3) shown in the following formulae 4 to 7. In accordance with the convention below, in the drawing of the structural formulae, the carbon atom, the hydrogen atom on the carbon atom, and the subscript on the hydrogen atom are omitted. In addition, in order to make the structural formulae easier to understand, the secondarily induced octahedral chirality is shown separately from the compound number, and possible trivial names are shown together with the compound number.

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [In the above structural formula, O represents an oxygen atom, MeO and OMe each represent a methoxy group, Ph represents a phenyl group, Tol represents a 4-methylphenyl group, and Xyl represents a 3,5-dimethylphenyl group.]

[0058] Next, a method for producing the ruthenium complex (1) of the present invention will be described in detail. The ruthenium complex (1) can be easily produced by reacting a ruthenium complex represented by the above general formula (2) [hereinafter referred to as conventional complex (2)] with a borohydride compound.

[0059] Hereinafter, the conventional complex (2) which is the raw material of the ruthenium complex (1) of the present invention will be described in detail. In the above general formula (2), the solid line, double line, dashed line, H, N, P, C, C P1 , C P2 , C a , C N1 , C N2 , Ru, R P , R P1 , R P2 , R P3 , R P4 , R N1 , R N2 , R N3 , R N4 , R N5 and R N6 are all the same as those defined and described in detail in the explanation of the above general formula (1), and Cl represents a chlorine atom.

[0060] Next, we will explain in detail about the borohydride compound that reacts with the conventional complex (2). A borohydride compound is a negatively charged atomic group (BH4 - ) and a compound formed from a positively charged atom or atomic group. Specific examples of preferred borohydride compounds include alkali metal borohydrides such as lithium borohydride, sodium borohydride, and potassium borohydride, magnesium borohydrides such as magnesium borohydride and magnesium borohydride-dimethylsulfide complex, alkaline earth metal borohydrides such as calcium borohydride and calcium borohydride-tetrahydrofuran complex, and ammonium borohydrides such as tetramethylammonium borohydride, tetraethylammonium borohydride, and methyltrioctylammonium borohydride. From the viewpoints of cost and availability, a particularly preferred example is sodium borohydride. The amount of the borohydride compound used is not particularly limited, but is appropriately selected from the range of usually 0.5 to 50 equivalents, preferably 0.8 to 20 equivalents, and more preferably 1 to 10 equivalents relative to the conventional complex (2).

[0061] The reaction of the conventional complex (2) with the borohydride compound is preferably carried out in the presence of a solvent. Preferred solvents include aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, n-decane, cyclohexane, and decalin, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, p-cymene, and 1,4-diisopropylbenzene, halogenated aromatic hydrocarbons such as chlorobenzene and o-dichlorobenzene, alcohols such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, 2-methyl-2-butanol, and 2-ethoxyethanol, and alcohols such as ethylene glycol, propylene glycol, 1,2-propanediol, and glycerin. Examples of the solvent include polyhydric alcohols, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, and 1,4-dioxane, amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, nitriles such as acetonitrile and benzonitrile, and sulfoxides such as dimethyl sulfoxide. Particularly preferred examples include toluene and ethanol. These solvents may be used alone or in combination of two or more. A preferred example of the solvent used in combination of two or more is a combination of toluene and ethanol. The amount of the solvent used is not particularly limited, but is appropriately selected from the range of usually 1 to 200 times the volume of the conventional complex (2), preferably 2 to 100 times the volume, and more preferably 5 to 50 times the volume of the conventional complex (2).

[0062] The reaction between the conventional complex (2) and the borohydride compound is preferably carried out under an inert gas atmosphere. Specific examples of the inert gas include argon gas and nitrogen gas, and a preferred specific example is nitrogen gas. The reaction temperature is appropriately selected from the range of usually -78°C to 150°C, preferably -20°C to 125°C, and more preferably 0°C to 100°C. The reaction time varies depending on conditions such as the structure of the borohydride compound, the reaction solvent, and the reaction temperature, but is appropriately selected from the range of usually 1 minute to 12 hours, preferably 2 minutes to 6 hours, and more preferably 5 minutes to 3 hours.

[0063] The reaction solution containing the ruthenium complex (1) of the present invention obtained by the reaction of the conventional complex (2) with a borohydride compound may be subjected to post-treatment as required. Furthermore, the ruthenium complex (1) of the present invention may be isolated from this reaction solution as required and further purified. Specific examples of the post-treatment method include concentration, solvent replacement, washing, extraction, filtration and crystallization, and these methods may be used alone or in combination. Specific examples of the isolation and purification method include decolorization using an adsorbent, column chromatography and recrystallization, and these methods may be used alone or in combination.

[0064] In addition, when the ruthenium complex (1) of the present invention is used as a catalyst, the reaction solution of the conventional complex (2) and the borohydride compound may be used as it is, or may be used after the above-mentioned post-treatment as necessary, or may be used after isolation and purification. On the other hand, since the ruthenium complex (1) has excellent crystallinity and stability, it is preferable to use it after isolation and purification in order to utilize these properties. In addition, this ruthenium complex (1) may be used alone as a catalyst, or two or more kinds may be used in combination as a catalyst.

[0065] A preferred embodiment of the conventional complex (2) used in the production of the ruthenium complex (1) is specifically the following: P is an aryl group which may have a substituent, and R P3 , R P4 , R N3 , RN4 , R N5 and R N6 are hydrogen atoms [hereinafter referred to as conventional complex (2')].

[0066] [ka]

[0067] [In formula (2'), solid line, double line, dashed line, H, N, P, C, C P1 , C P2 , C a , C N1 , C N2 , Ru, R P1 , R P2 , R N1 and R N2 are all the same as those defined and described in detail in the explanation of the above general formula (1). Cl represents a chlorine atom, and Ar represents an aryl group which may have a substituent.]

[0068] Furthermore, the ruthenium complex (1'), which is a preferred embodiment of the ruthenium complex (1) of the present invention, can be easily produced by reacting this conventional complex (2') with a borohydride compound.

[0069] For reference, the production method of conventional complex (2) will be briefly described below. Conventional complex (2) can be easily produced by reacting a ruthenium source, dichloro(p-cymene)ruthenium(II) dimer [hereinafter referred to as [RuCl2(p-cymene)]2] with a compound represented by the following general formula (3) [hereinafter referred to as diphosphine ligand (3)] in the presence of a solvent, and then reacting it with a compound represented by the following general formula (4) [hereinafter referred to as diamine ligand (4)] in the presence of a base, following the methods described in Patent Document 1 and Non-Patent Document 4.

[0070] [ka]

[0071] [In formula (3), solid line, double line, P, C, C P1 , C P2 , C a , R P , R P1 , R P2 , R P3 and R P4 are all the same as those defined and described in detail in the explanation of the general formula (1).

[0072] [ka]

[0073] [In formula (4), solid line, double line, N, H, C, C N1 , C N2 , R N1 , R N2 , R N3 , R N4 , R N5 and R N6 are the same as those defined and described in detail in the explanation of the above general formula (1).

[0074] A preferred embodiment of the diphosphine ligand (3) is P is an aryl group which may have a substituent, and R P3 and R P4 are all hydrogen atoms [hereinafter referred to as diphosphine ligand (3')].

[0075] [ka]

[0076] [In formula (3'), solid line, double line, P, H, C, C P1 , C P2 , C a , R P , R P1 and R P2 are all the same as those defined and described in detail in the explanation of the above general formula (1), and Ar represents an aryl group which may have a substituent.]

[0077] Particularly preferred specific examples of the diphosphine ligand (3) include the diphosphine ligand ((aR)-3'-A1) to the diphosphine ligand ((aS)-3'-G3) shown in the following formulae 8 and 9. In order to make the structural formulae easier to understand, the common names of these diphosphine ligands are written together with the compound numbers.

[0078] [ka]

[0079] [ka]

[0080] [In the structural formula, F represents a fluorine atom, O represents an oxygen atom, Me represents a methyl group, MeO represents a methoxy group, Ph represents a phenyl group, Tol represents a 4-methylphenyl group, and Xyl represents a 3,5-dimethylphenyl group.]

[0081] A preferred embodiment of the diamine ligand (4) is represented by the general formula (4) R N3 , R N4 , R N5 and R N6 are all hydrogen atoms [hereinafter referred to as diamine ligand (4')].

[0082] [ka]

[0083] [In formula (4'), solid line, double line, N, H, C, C N1 , C N2 , R N1 and R N2 are the same as those defined and described in detail in the explanation of the above general formula (1).

[0084] Particularly preferred specific examples of the diamine ligand (4) include the diamine ligand ((2R)-4'-1) and the diamine ligand ((2S)-4'-1) shown in the following formula 10. In order to make the structural formula easier to understand, the common names of these diamine ligands are written together with the compound numbers.

[0085] [ka]

[0086] [In the above structural formula, MeO and OMe both represent a methoxy group.]

[0087] Conventional complex (2'), which is a preferred form of conventional complex (2), can be easily prepared by reacting [RuCl2(p-cymene)]2 with a diphosphine ligand (3') in the presence of a solvent, and then reacting it with a diamine ligand (4') in the presence of a base.

[0088] The ruthenium complex (1) of the present invention thus produced is useful as a catalyst in various catalytic organic synthesis reactions. These organic synthesis reactions are not particularly limited, but specifically include oxidation reactions, reduction reactions, hydrogenation reactions, dehydrogenation reactions, hydrogen transfer reactions, addition reactions, conjugate addition reactions, pericyclic reactions, functional group conversion reactions, isomerization reactions, rearrangement reactions, polymerization reactions, bond formation reactions, and bond cleavage reactions, and further, these organic synthesis reactions may all be asymmetric reactions. Among these organic synthesis reactions, preferred specific examples include hydrogenation reactions, dehydrogenation reactions, and hydrogen transfer reactions, and particularly preferred specific examples include asymmetric hydrogenation reactions of asymmetric ketones.

[0089] Hereinafter, a method for producing an optically active secondary alcohol by catalytic asymmetric hydrogenation of an asymmetric ketone using the ruthenium complex (1) of the present invention as a catalyst will be described in detail. First, the asymmetric ketone may be an asymmetric ketone represented by the following general formula (5) [hereinafter referred to as asymmetric ketone (5)].

[0090] [ka]

[0091] [In formula (5), the solid line represents a single bond, and the double line represents a double bond. O represents an oxygen atom, C C R represents a carbon atom. L and R S Each of the groups represents a hydrocarbon group which may have a substituent, and the Cahn-Ingold-Prelog ranking of these groups is R L >R S Also, R L and R S are combined with each other to form C C may form a ring together with

[0092] By subjecting this asymmetric ketone (5) to a catalytic asymmetric hydrogenation reaction, it is possible to produce optically active secondary alcohols represented by the following general formulas ((R)-6) and ((S)-6) [hereinafter, these are referred to as optically active secondary alcohol ((R)-6) and optically active secondary alcohol ((S)-6), respectively, and further collectively referred to as optically active secondary alcohol (6)].

[0093] [ka]

[0094] [In formula ((R)-6) and formula ((S)-6), solid lines, O, C C , R L and R S is the same as defined in the explanation of the above general formula (5). The solid wedge line represents a single bond toward the front side of the paper, the broken wedge line represents a single bond toward the back side of the paper, and H represents a hydrogen atom.

[0095] In addition, by using a ruthenium complex (1) with an appropriate stereochemical configuration as a catalyst, it is possible to stereoselectively produce optically active secondary alcohols ((R)-6) and ((S)-6).

[0096] The catalytic asymmetric hydrogenation reaction of the asymmetric ketone (5) using the ruthenium complex (1) of the present invention as a catalyst can be carried out without a solvent, but from the viewpoint of reaction control, it is preferable to carry out the reaction in the presence of a solvent. Specific examples of the preferable solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, n-decane, cyclohexane, and decalin, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, p-cymene, and 1,4-diisopropylbenzene, alcohols such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, 2-methyl-2-butanol, and 2-ethoxyethanol, polyhydric alcohols such as ethylene glycol, propylene glycol, 1,2-propanediol, and glycerin, diethyl ether, diisopropyl alcohol, and the like. Examples of the solvent include isopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, and 1,4-dioxane, and other ethers; formamide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, and other nitriles; acetonitrile, benzonitrile, and other nitriles; dimethyl sulfoxide, and other sulfoxides; and water. Particularly preferred examples include ethanol and isopropanol. These solvents may be used alone or in combination of two or more kinds. A preferred example of the solvent used in combination of two or more kinds is a combination of ethanol and isopropanol. The amount of the solvent used is not particularly limited, but is appropriately selected from the range of usually 0.5 to 100 times the volume of the asymmetric ketone (5), preferably 1 to 75 times the volume, and more preferably 2 to 50 times the volume of the asymmetric ketone (5).

[0097] In this reaction, the catalytic activity of the ruthenium complex (1) can be improved by the coexistence of not only a solvent but also a base, but the range of application of the substrate asymmetric ketone (5) is narrowed and a complicated weighing operation of the base is required, so that this reaction is preferably carried out in the absence of a base. The amount of the ruthenium complex (1) used in this reaction is not particularly limited, but in the absence of a base, it is appropriately selected from the range of usually 0.00002 to 2 mol% [substrate / catalyst ratio (S / C) = 50 to 50,000], preferably 0.00004 to 1 mol% [S / C = 100 to 25,000], more preferably 0.0001 to 0.5 mol% [S / C = 200 to 10,000] relative to the asymmetric ketone (5).

[0098] The catalytic asymmetric hydrogenation reaction of the asymmetric ketone (5) using the ruthenium complex (1) of the present invention as a catalyst can be carried out under a hydrogen gas atmosphere, a hydrogen / argon mixed gas atmosphere, or a hydrogen / nitrogen mixed gas atmosphere, but from the viewpoint of operation, it is preferably carried out under a hydrogen gas atmosphere. The hydrogen gas pressure is not particularly limited, but is usually appropriately selected from the range of 0.1 to 10 MPa, preferably 0.2 to 8 MPa, more preferably 0.5 to 6 MPa. The reaction temperature is usually appropriately selected from the range of -78°C to 200°C, preferably -20°C to 150°C, more preferably 0°C to 125°C. The reaction time naturally varies depending on conditions such as the reaction solvent, the amount of the ruthenium complex (1) used, the hydrogen gas pressure, and the reaction temperature, but is usually appropriately selected from the range of 15 minutes to 48 hours, preferably 30 minutes to 24 hours, more preferably 1 hour to 12 hours.

[0099] The reaction solution containing the optically active secondary alcohol (6) obtained by this reaction may be post-treated as necessary. Furthermore, the optically active secondary alcohol (6) may be isolated from the reaction solution and further purified as necessary. Specific examples of the post-treatment method include concentration, solvent replacement, washing, filtration, and crystallization, and these methods may be used alone or in combination. Specific examples of the isolation and purification method include decolorization using an adsorbent, column chromatography, distillation, recrystallization, and sublimation, and these methods may be used alone or in combination.

[0100] Particularly preferred specific examples of the asymmetric ketone (5) and the optically active secondary alcohol (6) include the asymmetric ketones (5-1) to (5-3) and the optically active secondary alcohols ((R)-6-1) to ((S)-6-3) shown in the following formula 11.

[0101] [ka]

[0102] This production method, i.e., the catalytic asymmetric hydrogenation of an asymmetric ketone (5) using the ruthenium complex (1) of the present invention as a catalyst, makes it possible to efficiently produce an optically active secondary alcohol (6), which is a useful compound. EXAMPLES

[0103] The production of the ruthenium complex (1) of the present invention and the production of the optically active secondary alcohol (6) using the ruthenium complex (1) as a catalyst will be described in detail below with reference to specific examples, but the present invention is not limited to these examples. In the examples, the apparatuses, measurement conditions, and analysis conditions used for measuring physical properties are as follows.

[0104] 1) Proton nuclear magnetic resonance spectroscopy ( 1 H NMR): 400MR DD2 type instrument (resonance frequency 400 MHz; Agilent Technologies)

[0105] 2) Phosphorus-31 Nuclear Magnetic Resonance Spectroscopy ( 31 P NMR): 400MR DD2 type instrument (resonance frequency 161MHz; Agilent Technologies)

[0106] 3) Single crystal X-ray structure analysis: XtaLAB Synergy-S type instrument (manufactured by Rigaku Oxford Diffraction) [Measurement and analysis conditions] X-ray source: MoKα or CuKα, device control program: CrysAlis PRO,Structural analysis software: Olex 2 1.3-ac4,Structural analysis program: SHELXS·SHELXL-2018 / 3,Drawing software: Mercury4.3.0.

[0107] 4) Gas chromatography (GC): Nexis GC-2030 (Shimadzu Corporation) [Measurement conditions] Column: CP-Chirasil-Dex-CB (Agilent Technologies), Sample introduction temperature: 220°C, Sample detection temperature: 250°C, Measurement temperature: 120°C, Measurement time: 20 minutes.

[0108] Examples 1 to 10 relate to the preparation of the ruthenium complex (1) of the present invention, Examples 11 to 17 relate to the preparation of an optically active secondary alcohol (6) using the ruthenium complex (1) as a catalyst, and Comparative Examples 1 to 5 relate to an attempt at catalytic asymmetric hydrogenation of an asymmetric ketone (5) using a conventional complex (2).

[0109] Unless otherwise noted, the substrate and solvent were charged under a nitrogen stream, the reaction and post-treatment were carried out under a nitrogen atmosphere, and the product was isolated and purified under a nitrogen stream. In order to make the examples easier to understand, the compound numbers of the conventional complex (2), diphosphine ligand (3), and diamine ligand (4) were omitted and their common names were written, and the compound names and compound numbers of the asymmetric ketone (5) and optically active secondary alcohol (6) were both written. In addition, the description of the ruthenium complex (1) of the present invention regarding the secondarily induced octahedral chirality was omitted, and the possible common names and compound numbers were both written.

[0110] [Example 1] Ru(η 1 Preparation of -BH4)[(1S,2R)-daipena][(R)-binap]((1S,2R,aR)-1'-A1) (Equation 12)

[0111] [ka]

[0112] Step 1: A 100 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. [RuCl2(p-cymene)]2 (1.50 g, 2.45 mmol, 1.0 equivalent), (R)-BINAP (3.08 g, 4.95 mmol, 2.02 equivalent), and dehydrated methanol (30 mL) were sequentially charged into this flask. The resulting red slurry was heated in an oil bath while stirring with a magnetic stirrer, and stirred at 50 °C for 2 hours. The resulting red-orange solution was cooled to room temperature, and then (R)-DAIPEN (1.62 g, 5.15 mmol, 2.1 equivalent) and diethylamine (558 μL, 5.39 mmol, 2.2 equivalent) were sequentially charged, and the mixture was heated in an oil bath and stirred at 50 °C for 2 hours. The resulting yellow slurry was cooled to -20°C in a dry ice-acetone bath and then filtered under suction under a nitrogen stream. The filtered crystals were washed with dehydrated methanol (20mL) cooled to -20°C, and then dried by heating under reduced pressure (1Torr, 40°C, 1 hour) to obtain 4.50g of the conventional complex RuCl[(1S,2R)-daipena][(R)-binap] as a yellow powder. Purity: 99.7% by weight (the main impurity was p-cymene), isolated yield: 85.4%. 31 P NMR(161MHz,C6D6):δ=61.88(d,J=39.0Hz,1P),54.54(d,J=39.0Hz,1P).

[0113] Step 2: A 100 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. The RuCl[(1S,2R)-daipena][(R)-binap] (purity: 99.7% by weight, 1.0 g, 0.929 mmol, 1.0 equivalent) produced in Step 1, dehydrated toluene (20 mL), dehydrated ethanol (10 mL), and sodium borohydride (176 mg, 4.64 mmol, 5.0 equivalent) were sequentially charged into this flask. The resulting yellow-orange suspension was heated in an oil bath while stirring with a magnetic stirrer, and stirred for 15 minutes under reflux conditions. Next, about 20 mL of the solvent was recovered under reduced pressure while stirring the reaction solution, and the resulting concentrated solution was allowed to cool to room temperature, and then dehydrated n-hexane (20 mL) was slowly added. The resulting yellow-orange slurry was cooled to 5° C. in an ice-water bath and then filtered under suction under a nitrogen stream. The filtered crystals were washed successively with n-hexane (5 mL), tap water (20 mL) and n-hexane (5 mL), and then dried by heating under reduced pressure (1 Torr, 40° C., 1 hour) to obtain the ruthenium complex of the present invention, Ru(η 1 1.01 g of (1S,2R)-daipena][(R)-binap]((1S,2R,aR)-1'-A1) was obtained as a yellow-orange powder. Purity: 86.6% by weight (the main impurities were toluene and n-hexane), isolated yield: 89.5%. 31 P NMR(161MHz,C6D6):δ=64.56(d,J=37.5Hz,1P),61.75(d,J=37.5Hz,1P).

[0114] In addition, this ruthenium complex 1 H NMR measurements revealed that the H ligands or η 1 Neither the -BH4 ligand (which is observed as a peak at around -13.9 ppm and -0.24 ppm in the complex described in Non-Patent Document 3) was observed. Therefore, when single crystals of this ruthenium complex were prepared in a toluene / n-hexane system and subjected to X-ray structural analysis, it was found that neither the H ligand nor the η 1It was revealed that the -BH4 ligand was introduced, and the absolute configuration of the complex was also determined.

[0115] The results of single crystal X-ray structural analysis (thermal ellipsoid diagram; atomic presence probability 50%) of the ruthenium complex ((1S,2R,aR)-1'-A1) of the present invention produced in Example 1 are shown in Figure 3. In order to make the structure of the complex easier to understand, the crystallization solvents (toluene and n-hexane) are omitted in Figure 3.

[0116] In addition, the main parameters that ensure the accuracy of the analysis results were as follows: Crystal system: monoclinic, space group: P21(#4), lattice constants: a = 11.2546(2) Å, b = 46.7626(6) Å, c = 12.0648(2) Å, β = 92.2230(10)°, reliability factor (R1): 0.0390, weighted reliability factor (wR2): 0.0715, goodness of fit (GOF): 1.013, Flack parameter: -0.026(8).

[0117] In addition, the ruthenium complex ((1S,2R,aR)-1'-A1) of the present invention produced in Example 1 was measured in heavy benzene immediately after production. 1 H NMR (lower part of Figure 4) and after standing in air at room temperature for 4 weeks 1 The results of H NMR (upper part of Figure 4) are shown in Figure 4. These analytical results demonstrated that this complex is extremely stable even in air.

[0118] [Example 2] Ru(η 1 Preparation of -BH4)[(1R,2S)-daipena][(S)-binap]((1R,2S,aS)-1'-A1) (Equation 13)

[0119] [ka]

[0120] In the same manner as in Example 1, (S)-BINAP was used instead of (R)-BINAP, and (S)-DAIPEN was used instead of (R)-DAIPEN, to obtain the ruthenium complex of the present invention, Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-binap]((1R,2S,aS)-1'-A1) was obtained as a stable yellow-orange powder in air at room temperature in 1.01 g. Purity: 88.0% by weight (the main impurities were toluene and n-hexane), isolation yield in Step 2: 90.3%. Single crystals of this complex could be prepared in a toluene / n-hexane system. 31 P NMR(161MHz,C6D6):δ=64.60(d,J=38.0Hz,1P),61.79(d,J=38.0Hz,1P).

[0121] The results of single crystal X-ray structural analysis (thermal vibration ellipsoid diagram; atomic presence probability 50%) of the ruthenium complex of the present invention ((1R,2S,aS)-1'-A1) produced in Example 2 are shown in FIG. 5. From these results, it is clear that this complex has 1 η that cannot be observed by H NMR 1 It was found that the -BH4 ligand was introduced. In order to make the structure of the complex easier to understand, the crystallization solvents (toluene and n-hexane) are omitted in Figure 5.

[0122] In addition, the main parameters that ensure the accuracy of the analysis results are as follows: Crystal system: monoclinic, space group: P21(#4), lattice constant: a=11.25710(10)Å,b=46.8281(7)Å,c=12.0353(2)Å ,β=92.2350(10)°,R1:0.0417,wR2:0.0859,GOF:1.058,Flack parameter:-0.018(8).

[0123] [Example 3] Ru(η 1 Preparation of -BH4)[(1S,2R)-daipena][(R)-t-binap]((1S,2R,aR)-1'-A2) (Equation 14)

[0124] [ka]

[0125] Step 1: A 50 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. [RuCl2(p-cymene)]2 (1.00 g, 1.63 mmol, 1.0 equivalent), (R)-T-BINAP (2.24 g, 3.29 mmol, 2.02 equivalent), and dehydrated methanol (20 mL) were sequentially charged into this flask. The resulting red slurry was heated in an oil bath while stirring with a magnetic stirrer, and stirred at 50 °C for 2 hours. The resulting red solution was cooled to room temperature, and then (R)-DAIPEN (1.08 g, 3.42 mmol, 2.1 equivalent) and diethylamine (371 μL, 5.39 mmol, 2.2 equivalent) were sequentially charged, and the mixture was heated in an oil bath and stirred at 50 °C for 2 hours. The resulting orange slurry was cooled to 5°C in an ice-water bath and then filtered under suction under a nitrogen stream. The filtered crystals were washed with dehydrated methanol (15 mL) cooled to 5°C, and then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour) to obtain 2.85 g of the conventional complex RuCl[(1S,2R)-daipena][(R)-t-binap] as an orange powder. Purity: 99.9% by weight (the main impurity was p-cymene), isolated yield: 77.5%. 31 P NMR(161MHz,C6D6):δ=60.75(d,J=39.4Hz,1P),52.98(d,J=39.4Hz,1P).

[0126] Step 2: A 100 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. The flask was charged with RuCl[(1S,2R)-daipena][(R)-t-binap] (purity: 99.9 wt%, 1.0 g, 0.886 mmol, 1.0 equivalent) produced in Step 1, dehydrated toluene (20 mL), dehydrated ethanol (10 mL), and sodium borohydride (168 mg, 4.43 mmol, 5.0 equivalent) in sequence. The resulting orange suspension was stirred at room temperature for 1 hour while stirring with a magnetic stirrer. Next, about 20 mL of the solvent was recovered under reduced pressure while stirring the reaction solution, and the resulting concentrated solution was allowed to cool to room temperature, and then dehydrated n-hexane (20 mL) was slowly added. The resulting yellow slurry was cooled to 5°C in an ice-water bath and then suction filtered under a nitrogen stream. The filtered crystals were washed successively with n-hexane (5 mL), tap water (20 mL) and n-hexane (5 mL), and then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour) to obtain the ruthenium complex of the present invention, Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-t-binap]((1S,2R,aR)-1'-A2) was obtained as a yellow powder in an amount of 1.03 g. Purity: 92.3% by weight (the main impurity was toluene), isolated yield: 96.9%. Single crystals of this complex could be prepared in a toluene / n-hexane system. 31 P NMR(161MHz,C6D6):δ=63.26(d,J=38.0Hz,1P),59.93(d,J=38.0Hz,1P).

[0127] The results of single crystal X-ray structural analysis (thermal vibration ellipsoid diagram; atomic presence probability 50%) of the ruthenium complex ((1S,2R,aR)-1'-A2) of the present invention produced in Example 3 are shown in FIG. 6. From these results, it is clear that this complex has 1 η that cannot be observed by H NMR 1 It was found that the -BH4 ligand was introduced. In order to make the structure of the complex easier to understand, the crystallization solvent (toluene) is omitted in Figure 6.

[0128] In addition, the main parameters that ensure the accuracy of the analysis results are as follows: Crystal system: Rectangular, Space group: P212121(#19), Lattice constant: a=12.79926(15)Å,b=19.9189(3)Å,c=23.2821(3)Å,R1:0.0380,wR2:0.0854,GOF:1.038,Flack parameter:-0.036(4).

[0129] In addition, the ruthenium complex ((1S,2R,aR)-1'-A2) of the present invention produced in Example 3 was measured in heavy benzene immediately after production. 1 H NMR (lower part of Figure 7) and after standing in air at room temperature for 4 weeks 1 The results of H NMR (upper part of Figure 7) are shown in Figure 7. These analytical results demonstrated that this complex is extremely stable even in air.

[0130] [Example 4] Ru(η 1 Preparation of -BH4)[(1R,2S)-daipena][(S)-t-binap]((1R,2S,aS)-1'-A2) (Equation 15)

[0131] [ka]

[0132] In the same manner as in Example 3, (S)-T-BINAP was used instead of (R)-T-BINAP, and (S)-DAIPEN was used instead of (R)-DAIPEN, to obtain the ruthenium complex of the present invention, Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-t-binap]((1R,2S,aS)-1'-A2) was obtained as a stable yellow powder in air at room temperature in 1.02 g. Purity: 92.6% by weight (the main impurity was toluene), isolation yield in Step 2: 97.1%. Single crystals of this complex could be prepared in a toluene / n-hexane system. 31P NMR(161MHz,C6D6):δ=63.29(d,J=37.0Hz,1P),59.96(d,J=37.0Hz,1P).

[0133] The results of single crystal X-ray structural analysis (thermal vibration ellipsoid diagram; atomic presence probability 50%) of the ruthenium complex ((1R,2S,aS)-1'-A2) of the present invention produced in Example 4 are shown in FIG. 8. From these results, it is clear that this complex has 1 η that cannot be observed by H NMR 1 It was found that the -BH4 ligand was introduced. In order to make the structure of the complex easier to understand, the crystallization solvent (toluene) is omitted in Figure 8.

[0134] In addition, the main parameters that ensure the accuracy of the analysis results are as follows: Crystal system: Orthogonal system, Space group: P212121(#19), Lattice constant: a=12.79151(10)Å,b=19.92170(15)Å,c= 23.2697(2)Å,R1:0.0324,wR2:0.0745,GOF:1.043,Flack parameter:-0.018(4).

[0135] [Example 5] Ru(η 1 Synthesis of -BH4)[(1R,2S)-daipena][(R)-t-binap]((1R,2S,aR)-1'-A2) (Equation 16)

[0136] [ka]

[0137] Step 1: A 100 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. [RuCl2(p-cymene)]2 (1.50 g, 2.45 mmol, 1.0 equivalent), (R)-T-BINAP (3.36 g, 4.95 mmol, 2.02 equivalent), and dehydrated methanol (30 mL) were sequentially charged into this flask. The resulting red slurry was heated in an oil bath while stirring with a magnetic stirrer, and stirred at 50 °C for 2 hours. The resulting red solution was cooled to room temperature, and then (S)-DAIPEN (1.62 g, 5.15 mmol, 2.1 equivalent) and diethylamine (634 μL, 6.13 mmol, 2.5 equivalent) were sequentially charged, and the mixture was heated in an oil bath and stirred at 55 °C for 2 hours. The resulting orange slurry was cooled to -20°C in a dry ice-acetone bath and then filtered under suction under a nitrogen stream. The filtered crystals were washed twice with dehydrated methanol (7.5 mL) cooled to -20°C, and then dried under reduced pressure (1 Torr, 40°C, 1 hour) to obtain 5.14 g of the conventional complex RuCl[(1R,2S)-daipena][(R)-t-binap] as an orange powder. Purity: 99.7% by weight (the main impurity was methanol), isolated yield: 92.6%. 31 P NMR(161MHz,C6D6):δ=57.96(d,J=39.0Hz,1P),56.27(d,J=39.0Hz,1P).

[0138] Step 2: A 100 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. The RuCl[(1R,2S)-daipena][(R)-t-binap] (purity: 99.7% by weight, 1.50 g, 1.32 mmol, 1.0 equivalent) produced in Step 1, dehydrated toluene (30 mL), dehydrated ethanol (7.5 mL), and sodium borohydride (150 mg, 3.96 mmol, 3.0 equivalent) were sequentially charged into this flask. The resulting orange suspension was heated in an oil bath while stirring with a magnetic stirrer, and stirred at 35°C for 1 hour. Next, about 22.5 mL of the solvent was recovered under reduced pressure while stirring the reaction solution, and the resulting concentrated solution was allowed to cool to room temperature, and then dehydrated n-hexane (30 mL) was added. The resulting reddish-orange suspension was filtered using diatomaceous earth (1.5 g) under a nitrogen stream, and the filtered residue was washed with a mixed solvent of dehydrated n-hexane (15 mL) and dehydrated toluene (3 mL). The filtrates were combined and concentrated to dryness under reduced pressure, and the resulting residue was dissolved by adding dehydrated toluene (3 mL), and then dehydrated n-hexane (30 mL) was slowly added. The resulting yellow-orange slurry was cooled to -20°C in a dry ice-acetone bath and then suction filtered under a nitrogen stream. The filtered crystals were washed twice with dehydrated n-hexane (7.5 mL) cooled to -20°C and then dried by heating under reduced pressure (1 Torr, 40°C, 3 hours) to obtain the complex of the present invention, Ru(η 1 1.32 g of (1R,2S)-daipena][(R)-t-binap]((1R,2S,aR)-1'-A2) was obtained as a yellow powder. Purity: 98.9 wt% (the main impurity was n-hexane), isolated yield: 89.2%. 31 P NMR(161MHz,C6D6):δ=64.36(d,J=38.0Hz,1P),60.21(d,J=38.0Hz,1P).

[0139] The ruthenium complex ((1R,2S,aR)-1'-A2) of the present invention produced in Example 5 was measured in deuterated benzene immediately after production. 1 H NMR (lower part of Figure 9) and after standing in air at room temperature for 4 weeks 1The results of H NMR (upper part of Figure 9) are shown in Figure 9. These analytical results demonstrated that this complex is extremely stable even in air.

[0140] [Example 6] Ru(η 1 Preparation of -BH4)[(1S,2R)-daipena][(R)-dm-binap]((1S,2R,aR)-1'-A3) (Equation 17)

[0141] [ka]

[0142] Step 1: A 100 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. [RuCl2(p-cymene)]2 (1.50 g, 2.45 mmol, 1.0 equivalent), (R)-DM-BINAP (3.64 g, 4.95 mmol, 2.02 equivalent), and dehydrated methanol (30 mL) were sequentially charged into this flask. The resulting red slurry was heated in an oil bath while stirring with a magnetic stirrer, and stirred at 50 °C for 1 hour. The resulting dark red solution was cooled to room temperature, and then (R)-DAIPEN (1.62 g, 5.15 mmol, 2.1 equivalent) and diethylamine (558 μL, 5.39 mmol, 2.2 equivalent) were sequentially charged, and the mixture was heated in an oil bath and stirred at 60 °C for 2 hours. After the reaction mixture was cooled to room temperature, the orange solid was crushed with a spoon, and the resulting orange slurry was heated in an oil bath and stirred at 40°C for 1 hour. The slurry was cooled to -20°C in a dry ice-acetone bath, and then suction filtered under a nitrogen stream. The filtered crystals were washed with dehydrated methanol (10 mL) cooled to -20°C, and then dried under reduced pressure (1 Torr, 40°C, 1 hour), yielding 4.56 g of the conventional complex RuCl[(1S,2R)-daipena][(R)-dm-binap] as an orange powder. Purity: 97.7% by weight (the main impurity was p-cymene), isolated yield: 76.7%. 31P NMR(161MHz,C6D6):δ=61.02(d,J=39.0Hz,1P),53.24(d,J=39.0Hz,1P).

[0143] Step 2: A 100 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. The RuCl[(1S,2R)-daipena][(R)-dm-binap] (purity: 97.7 wt%, 1.0 g, 0.825 mmol, 1.0 equivalent) produced in Step 1, dehydrated toluene (10 mL), dehydrated ethanol (5 mL), and sodium borohydride (94 mg, 2.48 mmol, 3.0 equivalent) were sequentially charged into this flask. The resulting red-orange suspension was heated in an oil bath while stirring with a magnetic stirrer, and stirred under reflux for 15 minutes. Next, about 7.5 mL of the solvent was recovered under reduced pressure while stirring the reaction solution, and the resulting concentrated solution was allowed to cool to room temperature, and then dehydrated n-hexane (20 mL) was added. The resulting suspension was filtered using diatomaceous earth (1 g) under a nitrogen stream, and the filtered residue was washed with a mixed solvent of dehydrated n-hexane (8 mL) and dehydrated toluene (2 mL). The filtrates were combined and concentrated to dryness under reduced pressure, and the resulting residue was dissolved by adding dehydrated toluene (2 mL), and then dehydrated n-hexane (10 mL) was slowly added. The resulting yellow-orange slurry was cooled to 5°C in an ice-water bath and then suction filtered under a nitrogen stream. The filtered crystals were washed with dehydrated n-hexane (5 mL) cooled to 5°C and then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour) to obtain the complex of the present invention, Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-dm-binap]((1S,2R,aR)-1'-A3) was obtained as a yellow powder in an amount of 777 mg. Purity: 98.8% by weight (the main impurity was n-hexane), isolated yield: 80.0%. Single crystals of this complex could be prepared in a toluene / n-hexane system. 31 P NMR(161MHz,C6D6):δ=63.20(d,J=37.0Hz,1P),60.72(d,J=37.0Hz,1P).

[0144] The results of single crystal X-ray structural analysis (thermal vibration ellipsoid diagram; atomic presence probability 50%) of the ruthenium complex of the present invention ((1S,2R,aR)-1'-A3) produced in Example 6 are shown in FIG. 10. From these results, it is clear that this complex has 1 η that cannot be observed by H NMR 1 It was found that the -BH4 ligand was introduced. In order to make the structure of the complex easier to understand, the crystallization solvents (n-hexane, toluene, and n-hexane) are omitted in Figure 10.

[0145] In addition, the main parameters that ensure the accuracy of the analysis results are as follows: Crystal system: Rectangular system, Space group: P212121(#19), Lattice constant: a=13.1636(2)Å,b=15.0632(2)Å,c=33.5513(4)Å,R1:0.0253,wR2:0.0613,GOF:1.080,Flack parameter:-0.017(4).

[0146] The ruthenium complex ((1S,2R,aR)-1'-A3) of the present invention produced in Example 6 was measured in heavy benzene immediately after production. 1 H NMR (lower part of Figure 11) and after standing in air at room temperature for 4 weeks 1 The results of 1 H NMR (upper part of Figure 11) are shown together in Figure 11. These analytical results revealed that this complex is extremely stable even in air.

[0147] [Example 7] Ru(η 1 Preparation of -BH4)[(1R,2S)-daipena][(S)-dm-binap]((1R,2S,aS)-1'-A3) (Equation 18)

[0148] [ka]

[0149] In the same manner as in Example 6, (S)-DM-BINAP was used instead of (R)-DM-BINAP, and (S)-DAIPEN was used instead of (R)-DAIPEN, to obtain the ruthenium complex of the present invention, Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-dm-binap]((1R,2S,aS)-1'-A3) was obtained as a stable yellow powder in air at room temperature in an amount of 766 mg. Purity: 98.0% by weight (the main impurity was n-hexane), isolation yield in Step 2: 78.2%. Single crystals of this complex could be prepared in a toluene / n-hexane system. 31 P NMR(161MHz,C6D6):δ=63.16(d,J=37.0Hz,1P),60.68(d,J=37.0Hz,1P).

[0150] The results of single crystal X-ray structural analysis (thermal vibration ellipsoid diagram; atomic presence probability 50%) of the ruthenium complex of the present invention ((1R,2S,aS)-1'-A3) produced in Example 7 are shown in FIG. 12. From these results, it is clear that this complex has 1 η that cannot be observed by H NMR 1 It was found that the -BH4 ligand was introduced. In order to make the structure of the complex easier to understand, the crystallization solvents (toluene and n-hexane) are omitted in Figure 12.

[0151] In addition, the main parameters that ensure the accuracy of the analysis results are as follows: Crystal system: Orthogonal system, Space group: P212121(#19), Lattice constant: a=13.18064(10)Å,b=15.03165(9)Å,c= 33.5094(2)Å,R1:0.0305,wR2:0.0792,GOF:1.034,Flack parameter:-0.021(2).

[0152] [Example 8] Ru(η 1 Preparation of -BH4)[(1S,2R)-daipena][(R)-dm-segphos]((1S,2R,aR)-1'-B3) (Formula 19)

[0153] [ka]

[0154] Step 1: A 100 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. [RuCl2(p-cymene)]2 (1.50 g, 2.45 mmol, 1.0 equivalent), (R)-DM-SEGPHOS (3.58 g, 4.95 mmol, 2.02 equivalent), and dehydrated methanol (30 mL) were sequentially charged into this flask. The resulting red slurry was heated in an oil bath while stirring with a magnetic stirrer, and stirred at 50 °C for 1 hour. The resulting red-orange suspension was cooled to room temperature, and then (R)-DAIPEN (1.62 g, 5.15 mmol, 2.1 equivalent) and diethylamine (558 μL, 5.39 mmol, 2.2 equivalent) were sequentially charged, and the mixture was heated in an oil bath and stirred at 60 °C for 3 hours. Anhydrous methanol (7.5 mL) was added to the resulting yellow slurry, cooled to -20°C in a dry ice-acetone bath, and then suction filtered under a nitrogen stream. The filtered crystals were washed with anhydrous methanol (20 mL) cooled to -20°C, and then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour), yielding 3.96 g of the conventional complex RuCl[(1S,2R)-daipena][(R)-dm-segphos] as a yellow powder. Purity: 97.7% by weight (the main impurity was p-cymene), isolated yield: 68.5%. 31 P NMR(161MHz,C6D6):δ=57.40(d,J=39.0Hz,1P),52.60(d,J=39.0Hz,1P).

[0155] Step 2: A 100 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. The RuCl[(1S,2R)-daipena][(R)-dm-segphos] (purity: 97.7% by weight, 1.50 g, 1.25 mmol, 1.0 equivalent) produced in Step 1, dehydrated toluene (30 mL), dehydrated ethanol (7.5 mL), and sodium borohydride (236 mg, 6.25 mmol, 5.0 equivalent) were sequentially charged into this flask. The resulting yellow-orange suspension was heated in an oil bath while stirring with a magnetic stirrer, and stirred under reflux conditions for 1 hour. Next, about 30 mL of the solvent was recovered under reduced pressure while stirring the reaction solution, and the resulting concentrate was allowed to cool to room temperature, and then dehydrated n-hexane (30 mL) was slowly added. The resulting light brown slurry was cooled to 5°C in an ice-water bath, tap water (15 mL) was added, and the mixture was filtered by suction under a nitrogen stream. The filtered crystals were washed with tap water (15 mL) and n-hexane (15 mL) in that order, and then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour) to obtain the ruthenium complex of the present invention, Ru(η 1 The product was obtained as a cream-colored powder in an amount of 1.41 g. Purity: 99.2% by weight (the main impurity was n-hexane), isolated yield: 96.8%. 31 P NMR (161 MHz, CD): δ = 60.48 (d, J = 37.5 Hz, 1P), 60.13 (d, J = 37.5 Hz, 1P). Single crystals of this complex could be prepared in a toluene / n-hexane system.

[0156] The results of single crystal X-ray structural analysis (thermal ellipsoid diagram) of the ruthenium complex ((1S,2R,aR)-1'-B3) of the present invention produced in Example 8 are shown in FIG. 13. From these results, it is clear that the present complex has 1 η that cannot be observed by H NMR 1 It was found that the -BH4 ligand was introduced. In order to make the structure of the complex easier to understand, the crystallization solvent (toluene) is omitted in Figure 13.

[0157] In addition, the main parameters that ensure the accuracy of the analysis results are as follows: Crystal system: monoclinic, space group: C2(#5), lattice parameters: a=23.4930(3)Å, b=12.54820(10)Å, c=22.9459(2)Å, β=99.7850(10)°, R1:0.0270, wR2:0.0639, GOF:1.028, Flack parameter:-0.026(6).

[0158] The ruthenium complex ((1S,2R,aR)-1'-B3) of the present invention produced in Example 8 was measured in heavy benzene immediately after production. 1 H NMR (lower part of Figure 14) and after standing in air at room temperature for 4 weeks 1 The results of H NMR (upper part of Figure 14) are shown together in Figure 14. These analytical results revealed that this complex is extremely stable even in air.

[0159] [Example 9] Ru(η 1 Preparation of -BH4)[(1R,2S)-daipena][(S)-dm-segphos]((1R,2S,aS)-1'-B3) (Formula 20)

[0160] [ka]

[0161] In the same manner as in Example 8, (S)-DM-SEGPHOS was used instead of (R)-DM-SEGPHOS, and (S)-DAIPEN was used instead of (R)-DAIPEN, to obtain the ruthenium complex of the present invention, Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-dm-segphos]((1R,2S,aS)-1'-B3) was obtained as a cream-colored powder, stable even in air at room temperature, in an amount of 1.40 g. Purity: 99.0% by weight (the main impurity was n-hexane), isolation yield in Step 2: 96.2%. Single crystals of this complex could be prepared in a toluene / n-hexane system. 31P NMR(161MHz,C6D6):δ=60.49(d,J=37.5Hz,1P),60.14(d,J=37.5Hz,1P).

[0162] The results of single crystal X-ray structural analysis (thermal vibration ellipsoid diagram; atomic presence probability 50%) of the ruthenium complex ((1R,2S,aS)-1'-B3) of the present invention produced in Example 9 are shown in FIG. 15. From these results, it is clear that this complex has 1 η that cannot be observed by H NMR 1 It was found that the -BH4 ligand was introduced. In order to make the structure of the complex easier to understand, the crystallization solvent (toluene) is omitted in Figure 15.

[0163] In addition, the main parameters that ensure the accuracy of the analysis results are as follows: Crystal system: monoclinic, space group: C2(#5), lattice parameters: a=23.5053(2)Å, b=12.54830(10)Å, c=22.9340(3)Å, β=99.7550(10)°, R1:0.0270, wR2:0.0639, GOF:1.028, Flack parameter:-0.026(6).

[0164] [Example 10] Ru(η 1 Preparation of -BH4)[(1S,2R)-daipena][(R)-h8-binap]((1S,2R,aR)-1'-C1) (Equation 21)

[0165] [ka]

[0166] Step 1: A 50 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. [RuCl2(p-cymene)]2 (1.0 g, 1.63 mmol, 1.0 equivalent), (R)-H8-BINAP (2.08 g, 3.29 mmol, 2.02 equivalent), and dehydrated methanol (20 mL) were sequentially charged into this flask. The resulting red slurry was heated in an oil bath while stirring with a magnetic stirrer, and stirred at 50 °C for 2 hours. After cooling the resulting red-orange slurry to room temperature, (R)-DAIPEN (1.08 g, 3.42 mmol, 2.1 equivalent), diethylamine (422 μL, 4.08 mmol, 2.5 equivalent), and dehydrated methanol (5 mL) were sequentially charged, and the mixture was heated in an oil bath and stirred at 55 °C for 2 hours. The resulting yellow-orange slurry was cooled to -20°C in a dry ice-acetone bath and then filtered under suction under a nitrogen stream. The filtered crystals were washed twice with dehydrated methanol (5 mL) cooled to -20°C, and then dried under reduced pressure (1 Torr, 40°C, 2 hours) to obtain 2.93 g of the conventional complex RuCl[(1S,2R)-daipena][(R)-h8-binap] as a yellow powder. Purity: 99.1% by weight (the main impurity was methanol), isolated yield: 82.4%. 31 P NMR(161MHz,C6D6):δ=59.25(d,J=39.9Hz,1P),54.20(d,J=39.9Hz,1P).

[0167] Step 2: A 100 mL four-neck round-bottom flask was equipped with a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way cock, and the inside was replaced with nitrogen. The RuCl[(1S,2R)-daipena][(R)-h8-binap] (purity: 99.1% by weight, 1.50 g, 1.38 mmol, 1.0 equivalent) produced in Step 1, dehydrated toluene (30 mL), dehydrated ethanol (7.5 mL), and sodium borohydride (156 mg, 4.14 mmol, 3.0 equivalent) were sequentially charged into this flask. The resulting yellow suspension was heated in an oil bath while stirring with a magnetic stirrer, and stirred at 35°C for 1 hour. Next, about 22.5 mL of the solvent was recovered under reduced pressure while stirring the reaction solution, and the resulting concentrated solution was allowed to cool to room temperature and washed four times with degassed water (7.5 mL), and the organic layer was concentrated to dryness under reduced pressure. The residue was dissolved in dehydrated toluene (4.5 mL), and dehydrated n-hexane (90 mL) was slowly added. The resulting cream-colored slurry was filtered under suction in a nitrogen stream. The filtered crystals were washed with dehydrated n-hexane (30 mL) and then dried by heating under reduced pressure (1 Torr, 40° C., 3 hours) to obtain the complex of the present invention, Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-h8-binap]((1S,2R,aR)-1'-C1) was obtained as a cream-colored powder in 1.30 g. Purity: >99.9 wt. %, isolated yield: 88.9%. 31 P NMR(161MHz,C6D6):δ=60.62(d,J=38.0Hz,1P),60.18(d,J=38.0Hz,1P).

[0168] The ruthenium complex ((1S,2R,aR)-1'-C1) of the present invention produced in Example 10 was measured in deuterated benzene immediately after production. 1 H NMR (lower part of Figure 16) and in deuterated benzene after standing in air at room temperature for 4 weeks. 1 The results of H NMR (upper part of Figure 16) are summarized in Figure 16. These analytical results revealed that this complex is extremely stable even in air.

[0169] [Example 11 and Comparative Example 1] Ru(η 1 Asymmetric hydrogenation of acetophenone (5-1) using acetophenone-BH4)[(1S,2R)-daipena][(R)-binap] ((1S,2R,aR)-1'-A1) and RuCl[(1S,2R)-daipena][(R)-binap] as catalysts to produce (S)-1-phenylethanol ((S)-6-1) (Equation 22).

[0170] [ka]

[0171] A magnetic stir bar was attached to a stainless steel 50 mL autoclave apparatus, and the ruthenium complex of the present invention, Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-binap]((1S,2R,aR)-1'-A1) (purity: 86.6 wt%, 3.0 mg, 0.05 mol%) was charged and the inside was replaced with nitrogen. Next, dehydrated ethanol (2.5 mL) and acetophenone (5-1) (600 mg, 583 μL, 5.00 mmol, 1.0 equivalent) were charged in sequence. Furthermore, the inside of the apparatus was replaced with hydrogen gas to set the internal pressure to 5 MPa, and the reaction solution was stirred at 30 °C for 2 hours to obtain the desired (S)-1-phenylethanol ((S)-6-1). Conversion rate: >99%, selectivity: >99%, optical purity: 97.6% ee (all by GC analysis). The GC retention times of each compound were as follows. Acetophenone: 3.8 min, (R)-1-phenylethyl alcohol: 7.1 min, (S)-1-phenylethyl alcohol: 7.3 min.

[0172] On the other hand, in Comparative Example 1, an asymmetric hydrogenation reaction of acetophenone (5-1) was attempted under the same conditions as in Example 11 using the conventional complex RuCl[(1S,2R)-daipena][(R)-binap] (purity: 99.7 wt%, 2.7 mg, 0.05 mol%) as a catalyst, but the conversion rate was only 0.3%.

[0173] [Example 12 and Comparative Example 2] Ru(η 1 Asymmetric hydrogenation of acetophenone (5-1) using acetophenone-BH4)[(1S,2R)-daipena][(R)-t-binap] ((1S,2R,aR)-1'-A2) and RuCl[(1S,2R)-daipena][(R)-t-binap] as catalysts to produce (S)-1-phenylethanol ((S)-6-1) (Equation 23).

[0174] [ka]

[0175] Ru(η 1 The reaction was carried out for 2 hours at 30°C in the same manner as in Example 11 using acetophenone (5-1) with 1S,2R)-daipena][(R)-t-binap]((1S,2R,aR)-1'-A2) (purity: 92.3 wt%, 3.0 mg, 0.05 mol%) as a catalyst, to obtain the desired (S)-1-phenylethanol ((S)-6-1) from acetophenone (5-1). Conversion: >99%, selectivity: >99%, optical purity: 95.7%ee (all by GC analysis).

[0176] On the other hand, in Comparative Example 2, an asymmetric hydrogenation reaction of acetophenone (5-1) was attempted under the same conditions as in Example 12 using the conventional complex RuCl[(1S,2R)-daipena][(R)-t-binap] (purity: 99.9 wt%, 2.8 mg, 0.05 mol%) as a catalyst, but the conversion rate was only 1.2%.

[0177] [Example 13 and Comparative Example 3] Ru(η 1 Asymmetric hydrogenation of acetophenone (5-1) using (1S,2R)-daipena][(R)-dm-binap] ((1S,2R,aR)-1'-A3) and RuCl[(1S,2R)-daipena][(R)-dm-binap] as catalysts to produce (S)-1-phenylethanol ((S)-6-1) (Equation 24).

[0178] [ka]

[0179] Ru(η 1 The reaction was carried out for 7 hours at 20°C in the same manner as in Example 11 using acetophenone (5-1) with 1S,2R)-daipena][(R)-dm-binap]((1S,2R,aR)-1'-A3) (purity: 98.8 wt%, 2.9 mg, 0.05 mol%) as a catalyst, to obtain the desired (S)-1-phenylethanol ((S)-6-1) from acetophenone (5-1). Conversion: >99%, selectivity: >99%, optical purity: 99.3% ee (all by GC analysis).

[0180] On the other hand, in Comparative Example 3, an asymmetric hydrogenation reaction of acetophenone (5-1) was attempted under the same conditions as in Example 13 using a conventional complex RuCl[(1S,2R)-daipena][(R)-dm-binap] (purity: 97.7 wt %, 3.0 mg, 0.05 mol %) as a catalyst, but the conversion rate was only 4.2%.

[0181] [Example 14 and Comparative Example 4] Ru(η 1 Asymmetric hydrogenation of acetophenone (5-1) using (1S,2R)-daipena][(R)-dm-segphos] ((1S,2R,aR)-1'-BH4) and RuCl[(1S,2R)-daipena][(R)-dm-segphos] as catalysts to produce (S)-1-phenylethanol ((S)-6-1) (Equation 25).

[0182] [ka]

[0183] Ru(η 1Using acetophenone (5-1) at 20°C for 7 hours using acetophenone (5-1) as a catalyst (Purity: 99.2 wt%, 2.9 mg, 0.05 mol%), the reaction was carried out in the same manner as in the Examples, to obtain the desired (S)-1-phenylethanol ((S)-6-1). Conversion: >99%, selectivity: >99%, optical purity: 98.4% ee (all by GC analysis).

[0184] On the other hand, in Comparative Example 4, an asymmetric hydrogenation reaction of acetophenone (5-1) was attempted under the same conditions as in Example 14 using a conventional complex, RuCl[(1S,2R)-daipena][(R)-dm-segphos] (purity: 97.7 wt%, 2.9 mg, 0.05 mol%), as a catalyst, but the conversion rate was only 0.5%.

[0185] [Example 15 and Comparative Example 5] Ru(η 1 Asymmetric hydrogenation of acetophenone (5-1) using acetophenone-BH4)[(1S,2R)-daipena][(R)-h8-binap] ((1S,2R,aR)-1'-C1) and RuCl[(1S,2R)-daipena][(R)-h8-binap] as catalysts to produce (S)-1-phenylethanol ((S)-6-1) (Equation 26).

[0186] [ka]

[0187] Ru(η 1The reaction was carried out for 2 hours at 30°C in the same manner as in Example 11 using acetophenone (5-1) with 1S,2R)-daipena][(R)-h8-binap]((1S,2R,aR)-1'-C1) (purity: >99.9 wt%, 2.7 mg, 0.05 mol%) as a catalyst to obtain the desired (S)-1-phenylethanol ((S)-6-1) from acetophenone (5-1). Conversion: >99%, selectivity: >99%, optical purity: 96.5% ee (all by GC analysis).

[0188] On the other hand, in Comparative Example 5, an asymmetric hydrogenation reaction of acetophenone (5-1) was attempted under the same conditions as in Example 15 using the conventional complex RuCl[(1S,2R)-daipena][(R)-h8-binap] (purity: 99.1 wt%, 2.7 mg, 0.05 mol%) as a catalyst, but the conversion rate was only 1.5%.

[0189] The results of Examples 11 to 15 and Comparative Examples 1 to 5 are summarized in Table 1 below. Note that the combination of central chirality and axial chirality in the ruthenium complex of the present invention and the conventional complexes used as catalysts in these Examples and Comparative Examples is (1S,2R,aR), and therefore in order to make the results easier to understand, only the compound numbers corresponding to these complexes are shown in Table 1.

[0190] [Table 1]

[0191] As can be seen from Table 1, in the asymmetric hydrogenation reaction of acetophenone (5-1) using the ruthenium complexes of the present invention ((1S,2R,aR)-1'-A1 to (1S,2R,aR)-1'-C1) that do not require a base for activation as catalysts (Examples 11 to 15), the conversion and selectivity were both >99%, and the optical purity of the product (S)-1-phenylethyl alcohol ((S)-6-1) was also extremely excellent, at 95.7 to 99.3% ee. On the other hand, when conventional complexes ((1S,2R,aR)-2'-A1 to (1S,2R,aR)-2'-C1) that require a base for activation were used as catalysts (Comparative Examples 1 to 5), the conversion of this reaction was only 0.3 to 4.2%. These results clearly demonstrate that the ruthenium complex (1) of the present invention exhibits excellent performance as an asymmetric hydrogenation catalyst even in the absence of a base, and is superior to the conventional complex (2).

[0192] [Example 16] Ru(η 1 Asymmetric hydrogenation of 4-acetylbenzonitrile (5-2) using (1S,2R)-BH4)[(1S,2R)-daipena][(R)-dm-binap] ((1S,2R,aR)-1'-A3) as a catalyst to produce (S)-4-(1-hydroxyethyl)benzonitrile ((S)-6-2) (Equation 27).

[0193] [ka]

[0194] A magnetic stir bar was attached to a stainless steel 50 mL autoclave apparatus, and the ruthenium complex of the present invention, Ru(η 1-BH4)[(1S,2R)-daipena][(R)-dm-binap]((1S,2R,aR)-1'-A3) (purity: 98.8 wt%, 2.9 mg, 0.1 mol%) and 4-acetylbenzonitrile (5-2) (363 mg, 2.50 mmol, 1.0 equivalent) were sequentially charged and the inside was replaced with nitrogen. Then, dehydrated ethanol (2.5 mL) was sequentially charged, the inside of the apparatus was replaced with hydrogen gas to set the internal pressure to 1 MPa, and the reaction solution was stirred at 50 °C for 5 hours to obtain the desired (S)-4-(1-hydroxyethyl)benzonitrile ((S)-6-2). Conversion rate: >99%, selectivity: >99%, optical purity: 99.2% ee (all by GC analysis). The GC retention times of each compound were as follows. 4-Acetylbenzonitrile: 6.8 min, (R)-4-(1-hydroxyethyl)benzonitrile: 19.6 min, (S)-4-(1-hydroxyethyl)benzonitrile: 21.2 min.

[0195] [Example 17] Ru(η 1 Asymmetric hydrogenation of methyl 4-acetylbenzoate (5-3) using (1S,2R)-BH4)[(1S,2R)-daipena][(R)-dm-binap] ((1S,2R,aR)-1'-A3) as a catalyst to produce methyl (S)-4-(1-hydroxyethyl)benzoate ((S)-6-3) (Equation 28).

[0196] [ka]

[0197] A magnetic stir bar was attached to a stainless steel 50 mL autoclave apparatus, and the ruthenium complex of the present invention, Ru(η 1-BH4)[(1S,2R)-daipena][(R)-dm-binap]((1S,2R,aR)-1'-A3) (purity: 98.8 wt%, 1.2 mg, 0.1 mol%) and methyl 4-acetylbenzoate (5-3) (178 mg, 1.00 mmol, 1.0 equivalent) were charged in sequence, and the inside was replaced with nitrogen. Next, dehydrated ethanol (2.0 mL) and dehydrated isopropanol (2.0 mL) were charged in sequence, and the inside of the apparatus was replaced with hydrogen gas to set the internal pressure to 5 MPa. The reaction solution was stirred at 50 °C for 7 hours to obtain the desired (S)-4-(1-hydroxyethyl)methyl benzoate ((S)-6-3). Conversion rate: >99%, selectivity: >99%, optical purity: 96.0% ee (all by GC analysis). The GC retention times of each compound were as follows: Methyl 4-acetylbenzoate: 8.6 min, (R)-methyl 4-(1-hydroxyethyl)benzoate: 18.2 min, (S)-methyl 4-(1-hydroxyethyl)benzoate: 19.0 min.

[0198] As can be seen from Examples 16 and 17, by using the ruthenium complex (1) of the present invention, which does not require a base for activation, as a catalyst, even when an asymmetric ketone having a cyano group or a methoxycarbonyl group that is easily decomposed under basic conditions is used as a substrate, the asymmetric hydrogenation reaction proceeds with high stereoselectivity without damaging these functional groups, and the target optically active secondary alcohol can be produced in good yield. These results clearly demonstrate the usefulness of the ruthenium complex (1) of the present invention, which exhibits catalytic activity without the addition of a base.

[0199] Although the present invention has been described in detail and with reference to specific embodiments, it is apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention. This application is based on a Japanese patent application (Patent Application No. 2020-175074) filed on October 19, 2020, the contents of which are incorporated herein by reference. [Industrial Applicability]

[0200] The ruthenium complex (1) of the present invention can be easily synthesized by reacting a conventional complex (2) with a borohydride compound, and has various advantages, such as excellent crystallinity and stability, and exhibiting catalytic activity without the addition of a base. Furthermore, by catalytic asymmetric hydrogenation of an asymmetric ketone (5) using this ruthenium complex (1) as a catalyst, it is possible to efficiently produce an industrially useful optically active secondary alcohol (6) without damaging the functional group that can be decomposed under basic conditions.

Claims

1. A ruthenium complex represented by the following general formula (1): 【Chemistry 1】 [In formula (1), a solid line represents a single bond, a double line represents a double bond, a dashed line represents a coordinate bond, and a wavy line represents a three-center two-electron bond. B represents a boron atom, N represents a nitrogen atom, and P represents a phosphorus atom. H and H Ｂ represent hydrogen atoms, and C, C Ｐ１ , C Ｐ２ , C ａ , C Ｎ１ and C Ｎ２ Each represents a carbon atom. Ru represents a divalent ruthenium ion. R Ｐ represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent. R Ｐ１ , R Ｐ２ , R Ｐ３ and R Ｐ４ each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, an alkenyl group, an alkoxy group, a halogenoalkoxy group, a hydroxy group, and a halogeno group. R Ｐ１ and R Ｐ２ are bonded to each other to form C Ｐ１ and C Ｐ２ may form a ring together with R Ｎ１ and R Ｎ３ each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, an aryl group, and an aralkyl group. R Ｎ２ , R Ｎ４ , R Ｎ５ and R Ｎ６ each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, a halogenoalkyl group, an alkoxy group, and a halogeno group.

2. R Ｐ The ruthenium complex according to claim 1 , wherein is an aryl group which may have a substituent.

3. R Ｐ３ , R Ｐ４ , R Ｎ３ , R Ｎ４ , R Ｎ５ and R Ｎ６ The ruthenium complex according to claim 1 or 2, wherein each of the is a hydrogen atom.

4. The ruthenium complex according to any one of claims 1 to 3, which is an optically active substance.

5. A method for producing the ruthenium complex according to any one of claims 1 to 4, comprising a step of reacting a ruthenium complex represented by the following general formula (2) with a borohydride compound: 【Chemistry 2】 In formula (2), the solid lines represent single bonds, the double lines represent double bonds, and the dashed lines represent coordinate bonds. Cl represents a chlorine atom, H represents a hydrogen atom, N represents a nitrogen atom, and P represents a phosphorus atom. C, C Ｐ１ , C Ｐ２ , C ａ , C Ｎ１ and C Ｎ２ Each represents a carbon atom. Ru represents a divalent ruthenium ion. R Ｐ represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent. R Ｐ１ , R Ｐ２ , R Ｐ３ and R Ｐ４ each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, an alkenyl group, an alkoxy group, a halogenoalkoxy group, a hydroxy group, and a halogeno group. R Ｐ１ and R Ｐ２ are bonded to each other to form C Ｐ１ and C Ｐ２ may form a ring together with R Ｎ１ and R Ｎ３ each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, an aryl group, and an aralkyl group. R Ｎ２ , R Ｎ４ , R Ｎ５ and R Ｎ６ each independently represents a hydrogen atom or a group selected from the group consisting of an alkyl group, a halogenoalkyl group, an alkoxy group, and a halogeno group.

6. The method for producing a ruthenium complex according to claim 5, wherein the borohydride compound is sodium borohydride.

7. A method for producing an optically active secondary alcohol by catalytic asymmetric hydrogenation of an asymmetric ketone using the ruthenium complex according to claim 4 as a catalyst.

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