Ruthenium complexes, method for producing the complexes, and method for producing optically active secondary alcohol using the complexes as catalysts

Abstract

An object of the present application is to provide a novel ruthenium complex which does not require addition of a base to activate it as a catalyst, has excellent crystallinity and stability, is easy to synthesize in large scale and store for a long period of time, and has excellent catalytic activity and asymmetric induction ability in an asymmetric hydrogenation reaction. The present application relates to a ruthenium complex represented by general formula (1). [The definitions of the groups in formula (1) are as described in the specification.]

Description

TECHNICAL FIELD

[0001] The present application relates to a novel ruthenium complex, a production method of the complex, and a production method of optically active secondary alcohols using the complex as a catalyst. BACKGROUND

[0002] Since optically active secondary alcohols are extremely important compounds used in medicines, agrochemicals, functional materials, perfumes, and synthetic intermediates, production methods thereof have been actively researched and developed. Among these production methods, catalytic asymmetric hydrogenation of unsymmetrical ketones using molecular hydrogen as a reducing agent is one of the most important methods from the viewpoints of SDG and green chemistry, and has recently become a focus of attention due to superior atom efficiency and significant reduction of waste.

[0003] Since a catalyst having excellent catalytic activity, asymmetric induction ability, and stability is essential for industrialization of such catalytic asymmetric hydrogenation, it has been vigorously developed for many years. Among the catalysts thus developed, ruthenium complexes such as RuCl2(dm-binap)(dpen) and RuCl2(dm-binap)(daipen) [Non-patent Literature 1], RuH(η 1 -BH4)(dm-binap)(dpen) [Non-patent Literature 2], and RuH(η 1 -BH4)(t-binap)(daipen) [Non-patent Literature 3] developed by Ryoji Noyori who won the Nobel Prize in Chemistry in 2001 and his colleagues are known to exhibit excellent catalytic activity and asymmetric induction ability in asymmetric hydrogenation of unsymmetrical ketones. Several years later, a ruthenium bicyclo complex as a higher form of the above-mentioned ruthenium complexes was developed [Patent Literature 1 and Non-patent Literature 4], and it was reported that the ruthenium bicyclo complex has even better catalytic activity than the complexes developed by Noyori and his colleagues. For reference, the structural formulas of these ruthenium complexes are shown in the following Formula 1.

[0004] Formula 1

[0005]

[0006] [In the above structural formulas, 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.]

[0007] PRIOR ART DOCUMENTS

[0008] PATENT LITERATURE

[0009] Patent Literature 1: WO2011 / 135753.

[0010] Non-Patent Literature

[0011] Non-Patent Literature 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.

[0012] Non-Patent Literature 2: Takeshi Ohkuma, Masatoshi Koizumi, Kilian Muniz, Gerhard Hilt, Chizuko Kabuto, and Ryoji Noyori, J. Am. Chem. Soc, 2002, 124, 6508.

[0013] Non-Patent Literature 3: Christian A. Sandoval, Yoshiki Yamaguchi, Takeshi Ohkuma, Koichi Kato, and Ryoji Noyori, Magn. Reson. Chem., 2006, 44, 66.

[0014] Non-Patent Literature 4: Kazuhiko Matsumura, Noriyoshi Arai, Takao Saito, Noboru Sayo, and Takeshi Ohkuma, J. Am. Chem. Soc, 2011, 133, 10696. SUMMARY

[0015] PROBLEMS TO BE SOLVED BY THE INVENTION

[0016] Although, as described above, many catalysts for asymmetric hydrogenation have been developed to date, there are still some problems to be improved at present. For example, all of the ruthenium complexes described in Non-Patent Literature 1 require the addition of a base to activate them as catalysts. Therefore, it is difficult to use an unsymmetrical ketone which is not stable under basic conditions as a substrate. Even if an unsymmetrical ketone which is stable under basic conditions is used as a substrate, it is necessary to perform a complicated weighing operation using special equipment such as a glove box because potassium tert-butoxide which is usually used as a base for the reaction is liable to absorb moisture and decompose. The ruthenium bis-cyclometalated complex described in Patent Literature 1 and Non-Patent Literature 4 which is a higher form of the above-mentioned complex also requires a base to activate itself, so these problems still exist.

[0017] On the other hand, the ruthenium complex described in Non-Patent Literature 2 which is obtained by the reaction of the complex in Non-Patent Literature 1 with sodium borohydride exhibits catalytic activity without the addition of a base. Therefore, compared with the above-mentioned ruthenium complex and ruthenium bis-cyclometalated complex, this complex enables us to expand the range of application of substrates and simplify the reaction operation. However, this complex is difficult to isolate and purify by crystallization due to lack of crystallinity and stability, and must be prepared immediately before use to achieve its full performance. In addition, the ruthenium complex described in Non-Patent Literature 3 which is obtained by a reaction similar to the above-mentioned reaction also shows excellent catalytic activity without the addition of a base, but it is extremely unstable and decomposes within several hours even in deuterated benzene, making it difficult to synthesize a large amount of this complex industrially and use it for catalytic asymmetric hydrogenation. Therefore, from the viewpoint of improving the production efficiency of optically active secondary alcohols, there is still a strong demand for a catalyst for asymmetric hydrogenation which does not require activation with a base and which has excellent crystallinity, stability, catalytic activity and asymmetric induction ability.

[0018] The present application has been made in view of the above-mentioned current situation. That is, the object of the present application is to provide a novel ruthenium complex having the following properties: 1) no addition of a base is required to activate itself as a catalyst, 2) excellent crystallinity and stability, 3) easy mass production and long-term storage, 4) excellent catalytic activity and asymmetric induction ability in asymmetric hydrogenation; and to provide an efficient production of an optically active secondary alcohol using the complex as a catalyst.

[0019] Approach to the solution of the problem

[0020] In the course of investigation to solve the above-mentioned problems, the present inventors were inspired by the synthesis of the ruthenium complex described in Non-Patent Literature 3 (Formula 2) and tried the reaction of the ruthenium bis-cyclometalated complex described in Patent Literature 1 with sodium borohydride (Formula 3). As a result, a novel complex of unknown structure was formed, but very curiously, the proton nuclear magnetic resonance spectrum of this complex (1H NMR) was completely different from that of the starting material (Formula 3) and the ruthenium complex (Formula 2) described in Non-Patent Literature 3. The present inventors have found that this complex has the following properties: 1) no addition of a base is required to activate itself as a catalyst, 2) excellent crystallinity and stability, 3) easy mass production and long-term storage, 4) excellent catalytic activity and asymmetric induction ability in asymmetric hydrogenation. Thus, the present inventors have completed the present application. 1H NMR) analysis, no hydrogenated (H) ligand or η 1 -BH4) ligand that should be introduced by the reaction was observed. 1 -BH4) ligand that should be introduced by the reaction was observed. Figure 1 ). [According to Non-Patent Literature 3, in 1 H NMR, the H ligand was observed around -13.9 ppm, and the η 1 -BH4 ligand was observed around -0.24 ppm].

[0021] Formula 2

[0022]

[0023] Formula 3

[0024]

[0025] Based on this finding, the present inventors further investigated the novel ruthenium complex and found that it has unexpectedly excellent crystallinity and stability. Utilizing these properties, the present inventors decided to prepare a single crystal of the complex to perform X-ray crystallography analysis. The analysis results revealed that the η 1 -BH4 ligand, but not the H ligand, was unexpectedly incorporated into the void of the complex, and the free movement of the ligand was inhibited, and thus could not be observed by 1 H NMR. For reference, typical X-ray crystallography analysis results (thermal ellipsoid plot) of the novel ruthenium complex are shown in Figure 2 , but the present invention is not in any way limited to this figure.

[0026] Further, the present inventors found that, despite the lack of the H ligand as a reducing agent on the complex, the novel complex exhibited catalytic activity in a hydrogen atmosphere without the addition of a base, and exhibited excellent catalytic activity and asymmetric induction ability in the asymmetric hydrogenation of an asymmetric ketone. The present inventors completed the present invention based on these fundamental findings, by further investigation.

[0027] Specifically, the present invention includes the following [1] to [7]

[0028] [1] A ruthenium complex represented by the following general formula (1):

[0029]

[0030] [wherein, a solid line represents a single bond, a double line represents a double bond, a dotted 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 each represent a hydrogen 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 can 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 haloalkoxy group, a hydroxyl group, and a halo group; R P1 and R P2 may be combined with each other to form a ring with C P1 and C P2 ; 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 haloalkyl group, an alkoxy group, and a halo group].

[0031] [2] The ruthenium complex according to the above [1], wherein R P is an aryl group which can have a substituent.

[0032] [3] The ruthenium complex according to the above [1] or [2], wherein R P3 , R P4 , R N3 , R N4 , R N5 , and R N6 are all hydrogen atoms.

[0033] [4] The ruthenium complex according to any one of the above [1] to [3], which is an optically active substance.

[0034] [5] A production method of a ruthenium complex according to any one of the above [1] to [4], the method comprising a step of reacting a ruthenium complex represented by the following general formula (2) with a borohydride compound,

[0035]

[0036] (wherein, a solid line represents a single bond, a double line represents a double bond, and a dotted line represents a coordination bond; 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 CN2 Each represents a carbon atom; Ru represents a divalent ruthenium ion; R P R represents a group selected from the group consisting of alkyl, cycloalkyl, heteroaryl, and aryl groups that may have substituents; P1 R P2 R P3 and R P4 Each group independently represents a hydrogen atom, or a group selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkoxy, hydroxyl, and halogroup; R P1 and R P2 They can be combined with each other to form C P1 and C P2 Forming a ring; R N1 and R N3 Each group independently represents a hydrogen atom, or a group selected from the group consisting of alkyl, aryl, and aralkyl groups; R N2 R N4 R N5 and R N6 Each of these groups independently represents a hydrogen atom, or a group selected from the group consisting of alkyl, haloalkyl, alkoxy, and halogen groups.

[0037] [6] The method for producing the ruthenium complex according to [5] above, wherein the borohydride compound is sodium borohydride.

[0038] [7] A method for producing an optically active secondary alcohol, the method comprising the production of an optically active secondary alcohol by catalytic asymmetric hydrogenation of an asymmetric ketone using a ruthenium complex as a catalyst according to [4] above.

[0039] The effects of the invention

[0040] Ruthenium complexes represented by general formula (1) [hereinafter referred to as ruthenium complex (1)] can be readily synthesized, exhibit excellent crystallinity, can be isolated and purified by crystallization or recrystallization, and can be stored for a long time due to their excellent stability in air, making them suitable for large-scale production during industrialization. Furthermore, even without the addition of a base, ruthenium complex (1) exhibits excellent catalytic activity and asymmetric induction in the asymmetric hydrogenation of asymmetric ketones, thus allowing the use of substrates that tend to decompose under alkaline conditions in the reaction without the need for complex weighing operations of bases using specialized equipment. Therefore, by using ruthenium complex (1) as a catalyst, optically active secondary alcohols with high industrial value can be produced more efficiently. Attached Figure Description

[0041] [ Figure 1 ] Figure 1 This is a proton nuclear magnetic resonance spectroscopy method for displaying novel complexes formed by the reaction of ruthenium bicyclic complexes described in Patent Document 1 with sodium borohydride. 1Spectrogram showing the results of H NMR.

[0042] [ Figure 2 ] Figure 2 Typical X-ray crystallographic analysis results (thermal ellipsoid plot) of the ruthenium complex of the present application are shown.

[0043] [ Figure 3 ] Figure 3 X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex produced in Example 1 are shown.

[0044] [ Figure 4 ] Figure 4 Spectrogram of the ruthenium complex produced in Example 1 showing the results of H NMR measured in deuterated benzene immediately after production 1 H NMR (lower graph) and H NMR measured after 4 weeks at room temperature in air (upper graph) of the ruthenium complex produced in Example 1. 1 H NMR (lower graph) and H NMR measured after 4 weeks at room temperature in air (upper graph) of the ruthenium complex produced in Example 1.

[0045] [ Figure 5 ] Figure 5 X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex produced in Example 2 are shown.

[0046] [ Figure 6 ] Figure 6 X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex produced in Example 3 are shown.

[0047] [ Figure 7 ] Figure 7 Spectrogram of the ruthenium complex produced in Example 3 showing the results of H NMR measured in deuterated benzene immediately after production 1 H NMR (lower graph) and H NMR measured after 4 weeks at room temperature in air (upper graph) of the ruthenium complex produced in Example 3. 1 H NMR (lower graph) and H NMR measured after 4 weeks at room temperature in air (upper graph) of the ruthenium complex produced in Example 3.

[0048] [ Figure 8 ] Figure 8 X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex produced in Example 4 are shown.

[0049] [ Figure 9 ] Figure 9 Spectrogram of the ruthenium complex produced in Example 5 showing the results of H NMR measured in deuterated benzene immediately after production 1 H NMR (lower graph) and H NMR measured after 4 weeks at room temperature in air (upper graph) of the ruthenium complex produced in Example 5. 1 H NMR (lower graph) and H NMR measured after 4 weeks at room temperature in air (upper graph) of the ruthenium complex produced in Example 5.

[0050] [ Figure 10 ] Figure 10X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex produced in Example 6.

[0051] [ Figure 11 ] Figure 11 is a spectrum of the ruthenium complex produced in Example 8, showing the results of H NMR measured in deuterated benzene immediately after production 1 H NMR (lower graph) and the results of H NMR measured after 4 weeks at room temperature in air (upper graph). 1 H NMR (lower graph) and the results of H NMR measured after 4 weeks at room temperature in air (upper graph).

[0052] [ Figure 12 ] Figure 12 X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex produced in Example 7.

[0053] [ Figure 13 ] Figure 13 X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex produced in Example 8.

[0054] [ Figure 14 ] Figure 14 is a spectrum of the ruthenium complex produced in Example 8, showing the results of H NMR measured in deuterated benzene immediately after production 1 H NMR (lower graph) and the results of H NMR measured after 4 weeks at room temperature in air (upper graph). 1 H NMR (lower graph) and the results of H NMR measured after 4 weeks at room temperature in air (upper graph).

[0055] [ Figure 15 ] Figure 15 X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex produced in Example 9.

[0056] [ Figure 16 ] Figure 16 is a spectrum of the ruthenium complex produced in Example 10, showing the results of H NMR measured in deuterated benzene immediately after production 1 H NMR (lower graph) and the results of H NMR measured after 4 weeks at room temperature in air (upper graph). 1 H NMR (lower graph) and the results of H NMR measured after 4 weeks at room temperature in air (upper graph). DETAILED DESCRIPTION

[0057] Hereinafter, the ruthenium complex (1) of the present application is described in detail. In General Formula (1), a solid line represents a single bond, a double line represents a double bond, a dotted 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 both represent a hydrogen atom. C, C P1 , C P2 , C a , C N1and C N2 All represent carbon atoms. Ru represents a divalent ruthenium ion. R P The group represents a group selected from the group consisting of alkyl, cycloalkyl, heteroaryl, and aryl groups that may have substituents, and preferably, aryl groups that may have substituents. R P1 R P2 R P3 and R P4 Each of these groups independently represents a hydrogen atom, or a group selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkoxy, hydroxyl, and halogroup, and preferably a hydrogen atom, or a group selected from the group consisting of alkyl, alkenyl, alkoxy, and hydroxyl. R P1 and R P2 They can be combined with each other to form C P1 and C P2 Forming a ring. R N1 and R N3 Each of the following groups independently represents a hydrogen atom, or a group selected from the group consisting of alkyl, aryl, and aralkyl groups, and preferably, a hydrogen atom or an alkyl group. N2 R N4 R N5 and R N6 Each of the groups independently represents a hydrogen atom, or a group selected from the group consisting of alkyl, haloalkyl, alkoxy, and halogroup, and preferably a hydrogen atom or an alkoxy group.

[0058] Next, the wavy line in general formula (1) will be described in more detail. Ru-H B and H B The wavy lines between -B represent three-center two-electron bonds, namely Ru and H. B The three atoms of Ru and H share a state where two electrons are bonded. Due to the nature of this three-center, two-electron bond, not only Ru and H... B The key between, and H B The bond between B and ruthenium can also be broken to activate it. Therefore, unlike ordinary ruthenium complexes with simple anionic ligands, the ruthenium complex (1) of the present invention is believed to exhibit catalytic activity even in the absence of a base.

[0059] Then, the R in general formula (1) is described in more detail. P R P The alkyl group can be straight-chain or branched, 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 include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0060] R PThe cycloalkyl group can be monocyclic or polycyclic, for example, a cycloalkyl group having 3 to 20 carbon atoms, preferably a cycloalkyl group having 3 to 15 carbon atoms, and more preferably a cycloalkyl group having 3 to 10 carbon atoms; specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-adamantyl, and 2-adamantyl.

[0061] R P Examples of heteroaryl groups include heteroaryl groups derived from five-membered aromatic heterocycles containing oxygen or sulfur atoms; specific examples include 2-furanyl, 3-furanyl, 2-thienyl, and 3-thienyl.

[0062] R P Examples of aryl groups include aryl groups having 6 to 18 carbon atoms, preferably aryl groups having 6 to 14 carbon atoms, and more preferably aryl groups having 6 to 10 carbon atoms; specific examples include phenyl, 1-naphthyl, and 2-naphthyl; preferred specific examples include phenyl. Furthermore, the aryl group may have substituents.

[0063] R P Examples of substituents that the aryl group can have include alkyl, haloalkyl, alkoxy, and dialkylamino groups, and preferably alkyl. Examples of alkyl substituents include those with R P The group detailed in the description is an alkyl group similar to that described in the text; preferred specific examples include methyl.

[0064] Examples of these substituents that are alkyl halides include those formed by replacing at least one hydrogen atom on the alkyl group with a halogen atom; specific examples include trifluoromethyl.

[0065] The alkoxy groups in these substituents can be straight-chain or branched, for example, alkoxy groups having 1 to 12 carbon atoms, preferably alkoxy groups having 1 to 8 carbon atoms, and more preferably alkoxy groups having 1 to 4 carbon atoms; specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy.

[0066] Examples of dialkylamino groups among these substituents include dialkylamino groups formed by replacing two hydrogen atoms on an amino group with the aforementioned alkyl group; specific examples include N,N-dimethylamino.

[0067] Then, the R in general formula (1) is described in more detail. P1 R P2 R P3 and R P4 R P1 To R P4 Examples of alkyl groups 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 methyl, ethyl, and n-propyl.

[0068] R P1 Examples of the alkenyl group in R P4 include an alkenyl group having a carbon number of 2 to 9, preferably an alkenyl group having a carbon number of 2 to 6, more preferably an alkenyl group having a carbon number of 2 to 3; specific examples thereof include ethenyl and 1-propenyl; preferred specific examples thereof include ethenyl.

[0069] R P1 Examples of the alkoxy group in R P4 include a linear or branched alkoxy group having a carbon number of 1 to 9, preferably an alkoxy group having a carbon number of 1 to 6, more preferably an alkoxy group having a carbon number of 1 to 3; specific examples thereof include methoxy, ethoxy, n-propoxy, and isopropoxy; preferred specific examples thereof include methoxy.

[0070] R P1 Examples of the haloalkoxy group in R P4 include a haloalkoxy group formed by substituting at least one hydrogen atom in the above-described alkoxy group with a halogen atom; a specific example thereof includes difluoromethoxy.

[0071] R P1 Specific examples of the halo group in R P4 include a fluoro group, a chloro group, a bromo group, and an iodo group.

[0072] Further, R P1 and R P2 may be combined with each other to form a ring with C P1 and C P2 . Hereinafter, preferred specific examples of this ring formation mode are shown by the following general formulae (1-A) to (1-F):

[0073]

[0074]

[0075]

[0076]

[0077] [In general formulae (1-A) to (1-F), a solid line, a double line, a dotted 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 , RN4 , R N5 , and R N6 are all the same as those defined in the description of the general formula (1). O represents an oxygen atom, F represents a fluorine atom; and Me represents a methyl group.

[0078] Next, R N1 to R N6 in the general formula (1) are described in more detail. N1 Examples of the alkyl group in R N3 include similar groups to the alkyl group described in the description of R P ; preferred specific examples thereof include an isopropyl group. N1 Examples of the aryl group in R N3 include similar groups to the aryl group described in the description of R P . N1 Examples of the aryl group in R N3 include aryl groups formed by substituting at least one hydrogen atom on the above-described alkyl group with the above-described aryl group; specific examples thereof include a benzyl group.

[0079] Examples of the alkyl group in R N2 , and R N4 to R N6 include similar groups to the alkyl group described in the description of R P . N2 Examples of the haloalkyl group in R N4 , and R N6 to R N2 include haloalkyl groups formed by substituting at least one hydrogen atom on the above-described alkyl group with a halogen atom; specific examples thereof include a trifluoromethyl group. N4 Examples of the alkoxy group in R N6 , and R P1 to R P4 include similar groups to the alkoxy group described in the description of R N2 , and R N4 to R N6 include similar groups to the halo group described in the description of R P1 to R P4 .

[0080] In the ruthenium complex (1) of the present application, C N1 becomes a chiral carbon [hereinafter, the absolute configuration of the central chirality induced by this chiral carbon is represented by 1R and 1S] due to the structural requirement, and if R N1 and R N3 are different, C N2 may also become a chiral carbon [hereinafter, the absolute configuration of the central chirality induced thereby is represented by 2R and 2S]. Furthermore, if Ca -C a The free rotation of the single bond between the two carbon atoms is inhibited, the axial chirality is induced [hereinafter, the absolute configuration of the axial chirality thus induced is represented by aRand aS], and these central chirality and axial chirality secondarily induce the octahedral chirality at Ruin the ruthenium complex (1). Therefore, the ruthenium complex (1) of the present application can be a mixture of stereoisomers, or a single stereoisomer derived from these chiralities, and from the viewpoint of its use as a catalyst, a single stereoisomer is preferred.

[0081] Specific examples of the absolute configuration of the octahedral chirality secondarily induced by the above-mentioned central chirality and axial chirality due to the structural requirement of the ruthenium complex (1) 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; and preferred specific examples thereof include OC-6-32-A and OC-6-32-C.

[0082] Specific examples of the preferred form of the ruthenium complex (1) of the present application include a ruthenium complex represented by the following general formula (1') [hereinafter referred to as a ruthenium complex (1')], i.e., R P is an aryl group which can have a substituent, and R P3 , R P4 , R N3 , R N4 , R N5 , and R N6 are all hydrogen atoms:

[0083]

[0084] [In the general formula (1'), the solid line, double line, dotted 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 in the description of the general formula (1); and Ar represents an aryl group which can have a substituent.]

[0085] Particularly preferred specific examples of the ruthenium complex (1) of the present application include the 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 formulas 4 to 7. According to convention, in the drawing of structural formulas, carbon atoms, hydrogen atoms on carbon atoms, and subscripts on hydrogen atoms are omitted. For the sake of clarity of structural formulas, the absolute configuration of the secondary induced octahedral chirality is shown separately from the compound number, and the possible conventional name is listed together with the compound number.

[0086] Formula 4

[0087]

[0088] Formula 5

[0089]

[0090] Formula 6

[0091]

[0092] Formula 7

[0093]

[0094] [In the above structural formulas, O represents an oxygen atom; MeO and OMe both represent a methoxy group, Ph represents a phenyl group, Tol represents a 4-methylphenyl group, and Xyl represents a 3,5-dimethylphenyl group.]

[0095] Next, the production method of the ruthenium complex (1) of the present application will be described in detail. The ruthenium complex (1) can be easily produced by reacting a ruthenium complex represented by general formula (2) [hereinafter referred to as a conventional complex (2)] with a borohydride compound.

[0096] Hereinafter, the conventional complex (2) as a raw material of the ruthenium complex (1) of the present application will be described in detail. In general formula (2), the solid line, the double line, the dotted line, H, N, P, C, C P1 P2 a N1 N2 P P1 P2 P3 P4 N1 N2 N3 N4 N5 N6 ​​​​​​​​​​​​​​​All are the same as those defined and detailed in the description of the general formula (1); and Cl is a chlorine atom.

[0097] Then, the borohydride compound to be reacted with the conventional complex (2) is described in detail. The borohydride compound is defined as a compound formed from a negatively charged atom group (BH4 - ) consisting of one boron atom (B) and four hydrogen atoms (H) and a positively charged atom or atom group. Specific examples of the preferred borohydride compound include alkali metal borohydride classes such as lithium borohydride, sodium borohydride, and potassium borohydride; magnesium borohydride classes such as magnesium borohydride and magnesium borohydride-dimethylsulfide complex; alkaline earth metal borohydride classes such as calcium borohydride and calcium borohydride-tetrahydrofuran complex; ammonium borohydride classes such as tetramethylammonium borohydride, tetraethylammonium borohydride, and methyltrioctylammonium borohydride; and particularly preferred specific examples thereof include sodium borohydride from the viewpoint of cost and availability. 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, more preferably 1 to 10 equivalents, relative to the conventional complex (2).

[0098] The reaction between the conventional complex (2) and the borohydride compound is preferably performed in the presence of a solvent. Specific examples of the preferred solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, n-decane, cyclohexane, and naphthane; 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, t-butanol, 2-methyl-2-butanol, and 2-ethoxyethanol; polyhydric alcohols such as ethylene glycol, propylene glycol, 1,2-propanediol, and glycerol; ethers such as diethyl ether, diisopropyl ether, t-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; and particularly preferred specific examples thereof include toluene and ethanol. Each of these solvents can be used alone, or two or more thereof can be used in combination; and preferred specific examples of the combination of two or more solvents include the 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, preferably 2 to 100 times, more preferably 5 to 50 times, the volume relative to the conventional complex (2).

[0099] The reaction between the conventional complex (2) and the borohydride compound is preferably carried out in an inert gas atmosphere. Specific examples of the inert gas include argon and nitrogen; preferred specific examples thereof include nitrogen. The reaction temperature is suitably selected from the range of usually -78°C to 150°C, preferably -20°C to 125°C, more preferably 0°C to 100°C. The reaction time is dependent on the structure of the borohydride compound, the reaction solvent, and the reaction temperature, but is suitably selected from the range of usually 1 minute to 12 hours, preferably 2 minutes to 6 hours, more preferably 5 minutes to 3 hours.

[0100] The reaction solution containing the ruthenium complex (1) of the present application obtained by the reaction between the conventional complex (2) and the borohydride compound can be subjected to a post-treatment as needed. The ruthenium complex (1) can be separated from the reaction solution and further purified as needed. Specific examples of the post-treatment method include concentration, solvent replacement, washing, extraction, filtration, and crystallization, which can be carried out individually or in combination. Specific examples of the separation and purification method include decolorization by an adsorbent, column chromatography, and recrystallization, which can be carried out individually or in combination.

[0101] When the ruthenium complex (1) of the present application is used as a catalyst, the reaction solution of the conventional complex (2) and the borohydride compound can be used as it is, or can be used after the above-mentioned post-treatment as needed, or after the above-mentioned separation and purification. On the other hand, since the ruthenium complex (1) has excellent crystallinity and stability, in order to utilize these properties, it is preferred to use after the separation and purification. The ruthenium complex (1) can be used as a catalyst individually, or can be used as a catalyst in combination of two or more.

[0102] Specific examples of the preferred form of the conventional complex (2) used for the production of the ruthenium complex (1) include a ruthenium complex represented by the following general formula (2') [hereinafter referred to as a conventional complex (2')], i.e., R P is an aryl group which can have a substituent, and R P3 , R P4 , R N3 , R N4 , R N5 , and R N6 are all hydrogen atoms:

[0103]

[0104] [in the general formula (2'), the solid line, the double line, the dotted 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 all of which are the same as those defined in the description of general formula (1); Cl represents a chlorine atom; and Ar represents an aryl group which can have a substituent.

[0105] Further, the above-described ruthenium complex (1') which is a preferred form of the ruthenium complex (1) of the present application can be easily produced by reacting the conventional complex (2') with the above-described borohydride compound.

[0106] For reference, a production method of the conventional complex (2) is outlined below. The conventional complex (2) can be easily produced by reacting (p-methylisopropylbenzene) dichlororuthenium (II) dimer [hereinafter referred to as [RuCl2(p-cymene)]2] as a ruthenium source 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 with a compound represented by general formula (4) [hereinafter referred to as diamine ligand (4)] in the presence of a base, according to the method described in Patent Literature 1 and Non-Patent Literature 4.

[0107]

[0108] [in general formula (3), the solid line, the double line, P, C, C P1 , C P2 , C a , R P , R P1 , R P2 , R P3 , and R P4 all of which are the same as those defined in the description of general formula (1).]

[0109]

[0110] [in general formula (4), the solid line, the double line, N, H, C, C N1 , C N2 , R N1 , R N2 , R N3 , R N4 , R N5 , and R N6 all of which are the same as those defined in the description of general formula (1).]

[0111] Specific examples of the preferred form of the diphosphine ligand (3) include a diphosphine ligand represented by the following general formula (3') [hereinafter referred to as diphosphine ligand (3')], i.e., R P is an aryl group which can have a substituent, and both of R P3 and R P4 are hydrogen atoms:

[0112]

[0113] [In General Formula (3'), the solid line, the double line, P, H, C, C P1 P2 a P P1 P2 all are the same as those defined in the description of General Formula (1); Ar represents an aryl group which can have a substituent group.]

[0114] Particularly preferred specific examples of the diphosphine ligand (3) include the diphosphine ligands ((aR)-3'-Al) to ((aS)-3'-G3) shown in the following Formulas 8 and 9. For the sake of clarity of the structural formulas, the conventional names of these diphosphine ligands are listed together with the compound numbers.

[0115] Formula 8

[0116]

[0117] Formula 9

[0118]

[0119] [In the above structural formulas, 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.]

[0120] Specific examples of the preferred form of the diamine ligand (4) include the diamine ligand represented by the following General Formula (4') [hereinafter referred to as diamine ligand (4')], i.e., the case where R N3 N4 N5 N6 all are hydrogen atoms in General Formula (4) described above:

[0121]

[0122] [In General Formula (4'), the solid line, the double line, N, H, C, C N1 N2 N1 N2 all are the same as those defined in the description of General Formula (1).]

[0123] ​​​​​​​​​​​Particularly preferred specific examples of the diamine ligand (4) include the diamine ligands ((2R)-4'-1) and ((2S)-4'-1) shown in the following formula 10. For the sake of clarity of the structural formula, the conventional names of these diamine ligands are listed together with the compound numbers.

[0124] Formula 10

[0125]

[0126] [In the above structural formula, both MeO and OMe represent methoxy group.]

[0127] The conventional complex (2') which is a preferred form of the conventional complex (2) can be easily produced by reacting [RuCl2(p-cymene)]2with the diphosphine ligand (3') in the presence of a solvent, and then with the diamine ligand (4') in the presence of a base.

[0128] The ruthenium complex (1) thus produced is useful as a catalyst in various catalytic organic synthesis reactions. There is no particular limitation on these organic synthesis reactions, but specifically include oxidation reactions, reduction reactions, hydrogenation reactions, dehydrogenation reactions, hydrogen transfer reactions, addition reactions, conjugate addition reactions, pericyclic reactions, functional group transformation reactions, isomerization reactions, rearrangement reactions, polymerization reactions, bond formation reactions, and bond cleavage reactions; all of these organic synthesis reactions can be asymmetric reactions. Preferred specific examples of these organic synthesis reactions include hydrogenation reactions, dehydrogenation reactions, and hydrogen transfer reactions; particularly preferred specific examples thereof include asymmetric hydrogenation of an asymmetric ketone.

[0129] Hereinafter, a production method of an optically active secondary alcohol by catalytic asymmetric hydrogenation of an asymmetric ketone using the ruthenium complex (1) of the present application as a catalyst will be described in detail. First, examples of the asymmetric ketone include an asymmetric ketone represented by the following general formula (5) [hereinafter referred to as asymmetric ketone (5)].

[0130]

[0131] [In the general formula (5), a solid line represents a single bond, and a double line represents a double bond; O represents an oxygen atom, C C represents a carbon atom; R L and R S each independently represent a hydrocarbon group which can have a substituent, and their priority order is R L > R S ; R L and R S may be combined with each other to form a ring with C C .]

[0132] By carrying out catalytic asymmetric hydrogenation of the unsymmetrical ketone (5), optically active secondary alcohols represented by the following general formulae ((R)-6) and ((S)-6) [hereinafter referred to as optically active secondary alcohol ((R)-6) and optically active secondary alcohol ((S)-6), respectively, collectively as optically active secondary alcohols (6)] can be produced.

[0133]

[0134] [In the general formulae ((R)-6) and ((S)-6), the solid line, O, C C , R L , and R S are all the same as those defined in the description of the general formula (5); the wedge-shaped solid line represents a single bond toward the front, and the wedge-shaped dotted line represents a single bond toward the back; H represents a hydrogen atom.]

[0135] By using the ruthenium complex (1) having an appropriate stereo configuration as a catalyst, the optically active secondary alcohol ((R)-6) and the optically active secondary alcohol ((S)-6) can be produced stereoselectively, respectively.

[0136] The catalytic asymmetric hydrogenation of the unsymmetrical ketone (5) using the ruthenium complex (1) of the present application as a catalyst can be carried out in the absence of a solvent; however, from the viewpoint of reaction control, it is preferable to carry out the reaction in the presence of a solvent. Preferred specific examples of the solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, n-decane, cyclohexane, and naphthane; aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, p-cymene, and 1,4-diisopropylbenzene; alcohols such as methanol, ethanol, isopropanol, n-butanol, t-butanol, 2-methyl-2-butanol, and 2-ethoxyethanol; polyhydric alcohols such as ethylene glycol, propylene glycol, 1,2-propanediol, and glycerol; ethers such as diethyl ether, diisopropyl ether, t-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; sulfoxides such as dimethyl sulfoxide; water; and particularly preferred specific examples thereof include ethanol and isopropanol. Each of these solvents can be used alone, or two or more thereof can be used in combination; preferred specific examples of the combination of two or more solvents include 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, preferably 1 to 75 times, and more preferably 2 to 50 times, by volume relative to the unsymmetrical ketone (5).

[0137] While the catalytic activity of the ruthenium complex (1) can be further improved by coexisting not only a solvent but also a base in the reaction, it is preferred that the reaction be carried out in the absence of a base because the range of use of the asymmetric ketone (5) as a substrate is limited in the presence of a base, and a complicated weighing operation of the base is required. The amount of the ruthenium complex (1) used in the reaction is not particularly limited, but in the absence of a base, it is appropriately selected from the range of usually 0.002 to 2 mol% [substrate / catalyst ratio (S / C) = 50 to 50,000], preferably 0.004 to 1 mol% [S / C = 100 to 25,000], more preferably 0.01 to 0.5 mol% [S / C = 200 to 10,000] relative to the asymmetric ketone (5).

[0138] The catalytic asymmetric hydrogenation of the asymmetric ketone (5) using the ruthenium complex (1) of the present application 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; however, from the viewpoint of the reaction operation, it is preferred that the reaction be carried out under a hydrogen gas atmosphere. The pressure of hydrogen gas is not particularly limited, but is appropriately selected from the range of usually 0.1 to 10 MPa, preferably 0.2 to 8 MPa, more preferably 0.5 to 6 MPa. The reaction temperature is appropriately selected from the range of usually -78°C to 200°C, preferably -20°C to 150°C, more preferably 0°C to 125°C. The reaction time depends on the reaction solvent, the amount of the ruthenium complex (1) used, the pressure of hydrogen gas, and the reaction temperature, but is appropriately selected from the range of usually 15 minutes to 48 hours, preferably 30 minutes to 24 hours, more preferably 1 hour to 12 hours.

[0139] The reaction solution containing the optically active secondary alcohol (6) of the present application obtained by the above reaction can be subjected to a post-treatment as needed. The optically active secondary alcohol (6) can be separated from the reaction solution and further purified as needed. Specific examples of the post-treatment method include concentration, solvent replacement, washing, filtration, and crystallization, which can be carried out individually or in combination. Specific examples of the separation and purification method include decolorization by an adsorbent, column chromatography, distillation, recrystallization, and sublimation, which can be carried out individually or in combination.

[0140] Specific examples of the asymmetric ketone (5) and the optically active secondary alcohol (6) particularly preferably 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.

[0141] Formula 11

[0142]

[0143] The above-described production method, namely, the catalytic asymmetric hydrogenation of an asymmetric ketone (5) using the ruthenium complex (1) of the present invention as a catalyst, can effectively produce optically active secondary alcohols (6) as useful compounds.

[0144] Example

[0145] The production of the ruthenium complex (1) of the present invention and the production of optically active secondary alcohols (6) using the ruthenium complex (1) as a catalyst are described in detail below with reference to specific embodiments, but the present invention is by no means limited to these embodiments. In the embodiments, the equipment, measurement conditions and analytical conditions for measuring physical properties are as follows:

[0146] 1) Proton nuclear magnetic resonance spectroscopy ( 1 H NMR): 400MR DD2 type device (resonance frequency: 400MHz; manufactured by Agilent Technologies, Inc.)

[0147] 2) Phosphorus 31 nuclear magnetic resonance spectroscopy ( 31 P NMR): 400MR DD2 type device (resonance frequency: 161MHz; manufactured by Agilent Technologies, Inc.)

[0148] 3) X-ray crystallography analysis: XtaLAB Synergy-S system (manufactured by Rigaku Oxford Diffraction)

[0149] [Measurement and Analysis Conditions] X-ray source: MoKα rays or CuKα rays; Device control program: CrysAlis PRO Structural analysis software: Olex 2 1.3-ac4; Structural analysis programs: SHELXS and SHELXL-2018 / 3; Graphing software: Mercury 4.3.0.

[0150] 4) Gas Chromatography (GC): Nexis GC-2030 instrument (manufactured by Shimadzu Corporation) [Measurement Conditions] Column: CP-Chirasil-Dex-CB (manufactured by Agilent Technologies, Inc.); Injector temperature: 220°C; Detector temperature: 250°C; Measurement temperature: 120°C; Measurement time: 30 minutes.

[0151] Examples 1-10 relate to the production of the ruthenium complex (1) of the present application; Examples 11-17 relate to the production of optically active secondary alcohols (6) using the ruthenium complex (1) as catalyst; Comparative Examples 1-5 relate to attempts of catalytic asymmetric hydrogenation of unsymmetrical ketones (5) using conventional complexes (2).

[0152] Unless otherwise stated, substrates and solvents are added under a stream of nitrogen; reactions and work-up are carried out under a nitrogen atmosphere; isolation and purification of products are carried out under a stream of nitrogen. In order to make the examples clear, for conventional complexes (2), diphosphine ligands (3) and diamine ligands (4), the compound numbers are omitted, as an alternative, their conventional names are given in the description; in the description, the compound names of unsymmetrical ketones (5) and optically active secondary alcohols (6) are given together with the compound numbers; for the ruthenium complex (1) of the present application, the absolute configuration of the second induced octahedral chirality is omitted, in the description the possible conventional names are given together with the compound numbers.

[0153] [Example 1] Production of Ru(η 1 Production of RuCl[(1S,2R)-daipena][(R)-binap] [(1S,2R,aR)-1'-A1] (Formula 12)

[0154]

[0155] Step 1 : After attaching a magnetic stir bar, a thermometer, a Dimroth condenser and a three-way stopcock to a 100 mL four-necked round-bottomed flask, the interior of the flask was replaced with nitrogen. [RuCl2(p-cymene)]2(1.50 g, 2.45 mmol, 1.0 equiv), (R)-BINAP (3.08 g, 4.95 mmol, 2.02 equiv), and anhydrous methanol (30 mL) were added to the flask in this order. The resulting red slurry was warmed by using an oil bath while stirring with a magnetic stirrer, then stirred at 50 °C for 2 hours. After cooling the resulting red-orange solution to room temperature, (R)-DAIPEN (1.62 g, 5.15 mmol, 2.1 equiv) and diethylamine (558 μL, 5.39 mmol, 2.2 equiv) were added in this order, and the mixture was stirred at 50 °C for 2 hours while heating by using an oil bath. The resulting yellow slurry was cooled to -20 °C by using a dry ice-acetone bath, then filtered by suction under a stream of nitrogen. The filtered crystals were washed with anhydrous methanol (20 mL) cooled to -20 °C, then dried by heating under reduced pressure (1 Torr, 40 °C, 1 hour), thus producing conventional complex RuCl[(1S,2R)-daipena][(R)-binap] in an amount of 4.50 g as a yellow powder. Purity: 99.7% by weight (the main impurity is p-cymene); isolation yield: 85.4%.

[0156] 31 P NMR (161 MHz, C6D6): δ = 61.88 (d, J = 39.0 Hz, 1P), 54.54 (d, J = 39.0 Hz, 1P).

[0157] Step 2: After attaching a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way stopcock to a 100 mL four-necked round-bottom flask, the inside of the flask was replaced with nitrogen. RuCl[(1S,2R)-daipena][(R)-binap] (purity: 99.7 wt%, 1.0 g, 0.929 mmol, 1.0 equiv), produced in Step 1, dehydrated toluene (20 mL), dehydrated ethanol (10 mL), and sodium borohydride (176 mg, 4.64 mmol, 5.0 equiv) were sequentially added to the flask. The resulting yellow-orange suspension was warmed by using an oil bath while stirring with a magnetic stirrer, and then stirred under reflux conditions for 15 minutes. Then, while stirring, the solvent (about 20 mL) was recovered from the reaction solution under reduced pressure to obtain a concentrate, which 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 by using an ice-water bath, and then filtered by suction under a stream of nitrogen. The filtered crystals were washed with n-hexane (5 mL), tap water (20 mL), and n-hexane (5 mL) in this order, and then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour), thereby producing the ruthenium complex of the present application, Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-binap] ((1S,2R,aR)-1'-A1). Purity: 86.6 wt% (main impurities: toluene and n-hexane); separation yield: 89.5%.

[0158] 31 P NMR (161 MHz, C6D6): δ = 64.56 (d, J = 37.5 Hz, 1P), 61.75 (d, J = 37.5 Hz, 1P).

[0159] Although the ruthenium complex was subjected to 1 H NMR analysis, no H ligand and η 1 -BH4ligand (peaks around -13.9 ppm and -0.24 ppm were observed for the complexes described in Non-Patent Literature 3, respectively) that should be introduced in Step 2 could be observed. Therefore, a single crystal of the ruthenium complex was prepared from toluene / n-hexane to perform X-ray crystallography, which revealed that the η 1 -BH4ligand, but not the H ligand, was incorporated into the complex, and the absolute configuration of the complex could also be determined.

[0160] Figure 3 Results of the X-ray crystallographic analysis of the ruthenium complex of the application produced in Example 1 ((1S,2R,aR)-1'-A1) (thermal ellipsoid plot; 50% atomic probability). It should be noted that, in order to make the structure of the complex in Figure 3 clear, the solvents contained in the crystal (toluene and n-hexane) are not described.

[0161] The main parameters ensuring the accuracy of the results of the analysis are as follows. Crystal system: monoclinic; space group: P21 (#4); lattice constants: 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).

[0162] Figure 4 The results of the1H NMR analysis carried out in deuterated benzene immediately after production of the ruthenium complex of the application produced in Example 1 ((1S,2R,aR)-1'-A1), the 1 H NMR analysis carried out in deuterated benzene immediately after production of the ruthenium complex of the application produced in Example 1 ((1S,2R,aR)-1'-A1), the 1 H NMR analysis carried out in deuterated benzene immediately after production of the ruthenium complex of the application produced in Example 1 ((1S,2R,aR)-1'-A1), the

[0163] [Example 2] Production of Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-binap] ((1R,2S,aS)-1'-A1) (Formula 13)

[0164]

[0165] In the same way as in Example 1, by using (S)-BINAP instead of (R)-BINAP and (S)-DAIPEN instead of (R)-DAIPEN, the ruthenium complex of the application Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-binap] ((1R,2S,aS)-1'-A1) was produced in an amount of 1.01 g as a yellow-orange powder stable at room temperature in air. Purity: 88.0% by weight (main impurities: toluene and n-hexane); isolation yield in Step 2: 90.3%. It should be noted that single crystals of the complex can be prepared from toluene / n-hexane. 31 P NMR (161 MHz, C6D6): δ = 64.60 (d, J = 38.0 Hz, 1P), 61.79 (d, J = 38.0 Hz, 1P).

[0166] Figure 5 X-ray crystallography analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex of the application produced in Example 2 ((1R,2S,aS)-1'-A1). The results reveal that the 1 η 1 -BH4ligand is incorporated in the complex. It is noted that in order to make the structure of the complex in Figure 5 The description of the solvents contained in the crystal (toluene and n-hexane) is omitted for clarity of the structure of the complex in

[0167] The main parameters ensuring the accuracy of the analysis results are as follows. Crystal system: monoclinic; space group: P21 (#4); lattice constants: β = 92.2350(10)°; R1 : 0.0417; wR2: 0.0859; GOF: 1.058; Flack parameter: -0.018(8).

[0168] [Example 3] Production of Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-t-binap] ((1S,2R,aR)-1'-A2) (Formula 14)

[0169]

[0170] Step 1 : After attaching a magnetic stirring bar, a thermometer, a Dimroth condenser and a three-way stopcock to a 50 mL four-necked round-bottomed flask, the interior of the flask was replaced with nitrogen. [RuCl2(p-cymene)]2(1.00 g, 1.63 mmol, 1.0 equiv), (R)-T-BINAP (2.24 g, 3.29 mmol, 2.02 equiv), and anhydrous methanol (20 mL) were added to the flask in this order. The resulting red slurry was warmed by using an oil bath while stirring with a magnetic stirrer, then stirred at 50°C for 2 hours. After cooling the resulting red solution to room temperature, (R)-DAIPEN (1.08 g, 3.42 mmol, 2.1 equiv) and diethylamine (371 μL, 3.59 mmol, 2.2 equiv) were added in this order, and the mixture was stirred at 50°C for 2 hours while heating by using an oil bath. The resulting orange slurry was cooled to 5°C by using a dry ice-acetone bath, then filtered by suction under a stream of nitrogen. The filtered crystals were washed with anhydrous methanol (15 mL) cooled to 5°C, then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour), thereby producing 2.85 g of the conventional complex RuCl[(1S,2R)-daipena][(R)-t-binap] in an amount of an orange powder. Purity: 99.9 wt% (the main impurity is p-cymene); separation yield: 77.5%.

[0171] 31 P NMR (161 MHz, C6D6): δ = 60.75 (d, J = 39.4 Hz, 1P), 52.98 (d, J = 39.4 Hz, 1P).

[0172] Step 2: After attaching a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way stopcock to a 100 mL four-necked round-bottom flask, the interior of the flask was replaced with nitrogen. RuCl[(1S,2R)-daipena][(R)-t-binap] produced in Step 1 (purity: 99.9 wt%, 1.0 g, 0.886 mmol, 1.0 equiv), dehydrated toluene (20 mL), dehydrated ethanol (10 mL), and sodium borohydride (168 mg, 4.43 mmol, 5.0 equiv) were sequentially added to the flask. The resulting orange suspension was stirred at room temperature for 1 hour using a magnetic stirrer. Then, while stirring, the solvent (about 20 mL) was recovered from the reaction solution under reduced pressure to give a concentrate, followed by slow addition of dehydrated n-hexane (20 mL). The resulting yellow slurry was cooled to 5°C using an ice-water bath, and then filtered by suction under a stream of nitrogen. The filtered crystals were washed with n-hexane (5 mL), tap water (20 mL), and n-hexane (5 mL) in this order, and then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour) to give the ruthenium complex of the present application, Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-t-binap] ((1S,2R,aR)-1’-A2). Purity: 92.3 wt% (main impurity: toluene); isolation yield: 96.9%. Note that a single crystal of the complex can be prepared from toluene / n-hexane.

[0173] 31 P NMR (161 MHz, C6D6): δ = 63.26 (d, J = 38.0 Hz, 1P), 59.93 (d, J = 38.0 Hz, 1P).

[0174] Figure 6 X-ray crystallography analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex of the present application ((1S,2R,aR)-1’-A2) produced in Example 3 are shown. This result reveals that the η 1 HNMR observable η 1 -BH4 ligand is incorporated into the complex. Note that, in order to make the structure of the complex in Figure 6 The description of the solvent (toluene) contained in the crystal is omitted for the sake of clarity of the structure of the complex in

[0175] The main parameters ensuring the accuracy of the results of the analyses are as follows. Crystal system: orthorhombic; space group: P212121 (#19); lattice constants: R1: 0.0380, wR2: 0.0854; GOF: 1.038; Flack parameter: -0.036(4).

[0176] Figure 7 The results of the analyses of the ruthenium complex of the application ((1S,2R,aR)-1'-A2) produced in Example 3, determined in deuterated benzene immediately after production, are summarized in Table 1 below. 1 The results of the analyses of the H NMR (lower diagram) and of the H NMR (upper diagram) determined after 4 weeks at room temperature in air. These analysis results show that the complex is extremely stable in air. 1 The results of the analyses of the H NMR (lower diagram) and of the H NMR (upper diagram) determined after 4 weeks at room temperature in air. These analysis results show that the complex is extremely stable in air.

[0177] [Example 4] Production of Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-t-binap] ((1R,2S,aS)-1'-A2) (Formula 15)

[0178]

[0179] In the same manner as in Example 3, by using (S)-T-BINAP instead of (R)-T-BINAP and (S)-DAIPEN instead of (R)-DAIPEN, the ruthenium complex of the application Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-t-binap] ((1R,2S,aS)-1'-A2) was produced in an amount of 1.02 g as a yellow powder stable in air at room temperature. Purity: 92.6% by weight (main impurity: toluene); isolation yield in Step 2: 97.1%. It should be noted that single crystals of the complex can be prepared from toluene / n-hexane.

[0180] 31 P NMR (161 MHz, C6D6): δ = 63.29 (d, J = 37.0 Hz, 1P), 59.96 (d, J = 37.0 Hz, 1P).

[0181] Figure 8 The results of the X-ray crystallographic analysis of the ruthenium complex of the application ((1R,2S,aS)-1'-A2) produced in Example 4 (thermal ellipsoid plot; 50% atomic probability) are shown. This result reveals that the η 1 H NMR observable η 1 -BH4 ligand is incorporated into the complex. It should be noted that in order to make Figure 8The structure of the complex in the crystal is clear, the description of the solvent (toluene) contained in the crystal is omitted.

[0182] The main parameters ensuring the accuracy of the analysis results are as follows. Crystal system: orthorhombic; space group: P212121 (#19); lattice constants: R1: 0.0324; wR2: 0.0745; GOF: 1.043; Flack parameter: -0.018(4).

[0183] [Example 5] Production of Ru(η 1 Production of RuCl[(1R,2S)-daipena][(R)-t-binap] (Formula 16)

[0184]

[0185] Step 1: After attaching a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way stopcock to a 100 mL four-necked round-bottom flask, the interior of the flask 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 equivalents), and anhydrous methanol (30 mL) were sequentially added to the flask. The resulting red slurry was warmed by using an oil bath while being stirred with a magnetic stirrer, and then stirred at 50°C for 2 hours. After the resulting red solution was cooled to room temperature, (S)-DAIPEN (1.62 g, 5.15 mmol, 2.1 equivalents) and diethylamine (634 μL, 6.13 mmol, 2.5 equivalents) were sequentially added, and the mixture was stirred at 55°C for 2 hours while being heated by using an oil bath. The resulting orange slurry was cooled to -20°C by using a dry ice-acetone bath, and then filtered by suction under a stream of nitrogen. The filtered crystals were washed twice with anhydrous methanol cooled to -20°C (7.5 mL x 2), and then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour), thereby producing 5.14 g of the regular complex RuCl[(1R,2S)-daipena][(R)-t-binap] as an orange powder. Purity: 99.7 wt% (the main impurity is methanol); isolated yield: 92.6%.

[0186] 31 P NMR (161 MHz, C6D6): δ = 57.96 (d, J = 39.0 Hz, 1P), 56.27 (d, J = 39.0 Hz, 1P).

[0187] Step 2: After attaching a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way stopcock to a 100 mL four-necked round-bottom flask, the interior of the flask was replaced with nitrogen. The RuCl[(1R,2S)-daipena][(R)-t-binap] produced in Step 1 (purity: 99.7 wt%, 1.50 g, 1.32 mmol, 1.0 equiv), deuterated toluene (30 mL), deuterated ethanol (7.5 mL), and sodium borohydride (150 mg, 3.96 mmol, 3.0 equiv) were sequentially added to the flask. The resulting orange suspension was warmed by using an oil bath while stirring with a magnetic stirrer, and then stirred at 35°C for 1 hour. Then, while stirring, the solvent (about 22.5 mL) was recovered from the reaction solution under reduced pressure to obtain a concentrate, which was allowed to cool to room temperature, and then deuterated n-hexane (30 mL) was added. The resulting red-orange suspension was filtered through celite (1.5 g) under a stream of nitrogen, and the filtrand was washed with a mixture of deuterated n-hexane (15 mL) and deuterated toluene (3 mL). The filtrate was co-concentrated to dryness under reduced pressure, the resulting residue was dissolved with deuterated toluene (3 mL), and then deuterated n-hexane (30 mL) was slowly added. The resulting yellow-orange slurry was cooled to -20°C by using a dry ice-acetone bath, and then filtered by suction under a stream of nitrogen. The filtered crystals were washed twice with n-hexane cooled to -20°C (7.5 mL x 2), and then dried under reduced pressure with heating (1 Torr, 40°C, 3 hours), thereby producing the ruthenium complex of the present application, Ru(η 1 -BH4)[(1R,2S)-daipena][(R)-t-binap] ((1R,2S,aR)-1’-A2) in an amount of 1.32 g as a yellow powder. Purity: 98.9 wt% (the main impurity is n-hexane); separation yield: 89.2%.

[0188] 31 P NMR (161 MHz, C6D6): δ = 64.36 (d, J = 38.0 Hz, 1P), 60.21 (d, J = 38.0 Hz, 1P).

[0189] Figure 9 The results of the P NMR (lower graph) and the H NMR (upper graph) measured in deuterated benzene immediately after production of the ruthenium complex of the present application ((1R,2S,aR)-1’-A2) produced in Example 5 are summarized in Table 1. These analysis results indicate that the complex is extremely stable in air. 1 H NMR (lower graph) and the H NMR (upper graph) measured after being left in air at room temperature for 4 weeks. These analysis results indicate that the complex is extremely stable in air. 1 H NMR (lower graph) and the H NMR (upper graph) measured after being left in air at room temperature for 4 weeks. These analysis results indicate that the complex is extremely stable in air.

[0190] [Example 6] Ru(η 1Production of RuCl[(1S,2R)-daipena][(R)-dm-binap] (Formula 17)

[0191]

[0192] Step 1 : After attaching a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way stopcock to a 100 mL four-necked round-bottom flask, the interior of the flask was replaced with nitrogen. [RuCl2(p-cymene)]2(1.50 g, 2.45 mmol, 1.0 equiv), (R)-DM-BINAP (3.64 g, 4.95 mmol, 2.02 equiv), and anhydrous methanol (30 mL) were added sequentially to the flask. The resulting red slurry was warmed using an oil bath while stirring with a magnetic stirrer, then stirred at 50 °C for 1 h. After the resulting dark red solution was cooled to room temperature, (R)-DAIPEN (1.62 g, 5.15 mmol, 2.1 equiv) and diethylamine (558 μL, 5.39 mmol, 2.2 equiv) were added sequentially, and the mixture was stirred at 60 °C for 2 h while heating using an oil bath. After the reaction solution was cooled to room temperature, the resulting orange solid was ground using a spatula under a stream of nitrogen, and the resulting orange slurry was stirred at 40 °C for 1 h while heating using an oil bath. The resulting slurry was cooled to -20 °C using a dry ice-acetone bath, then filtered by suction under a stream of nitrogen. The filtered crystals were washed with anhydrous methanol (10 mL) cooled to -20 °C, then dried by heating under reduced pressure (1 Torr, 40 °C, 1 h) to yield 4.56 g of the conventional complex RuCl[(1S,2R)-daipena][(R)-dm-binap] as an orange powder in a quantity of 4.56 g. Purity: 97.7 wt% (the main impurity is p-methylisopropylbenzene); isolated yield: 76.7%.

[0193] 31 P NMR (161 MHz, C6D6): δ = 61.02 (d, J = 39.0 Hz, 1P), 53.24 (d, J = 39.0 Hz, 1P).

[0194] Step 2: After attaching a magnetic stir bar, a thermometer, a Dimroth condenser and a three-way stopcock to a 100 mL four-necked round-bottomed flask, the interior of the flask was replaced with nitrogen. The RuCl[(1S,2R)-daipena][(R)-dm-binap] produced in Step 1 (purity: 97.7 wt%, 1.0 g, 0.825 mmol, 1.0 equiv), dehydrated toluene (10 mL), dehydrated ethanol (5 mL), and sodium borohydride (94 mg, 2.48 mmol, 3.0 equiv) were sequentially added to the flask. The resulting red-orange suspension was warmed by using an oil bath while stirring with a magnetic stirrer, then stirred under reflux conditions for 15 minutes. Then, while stirring, the solvent (about 7.5 mL) was recovered from the reaction solution under reduced pressure to give a concentrate, which was allowed to cool to room temperature, then dehydrated n-hexane (20 mL) was added. The resulting suspension was filtered through celite (1 g) under a stream of nitrogen, and the filter residue was washed with a mixture of dehydrated n-hexane (8 mL) and dehydrated toluene (2 mL). The filtrate was co-concentrated to dryness under reduced pressure, the resulting residue was dissolved with dehydrated toluene (2 mL), then dehydrated n-hexane (10 mL) was slowly added. The resulting yellow-orange slurry was cooled to 5 °C by using a dry ice-acetone bath, then filtered by suction under a stream of nitrogen. The filtered crystals were washed with n-hexane (5 mL) cooled to 5 °C, then dried under reduced pressure with heating (1 Torr, 40 °C, 1 hour), thereby producing 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% (the main impurity is n-hexane); isolated yield: 80.0%. It should be noted that single crystals of the complex can be prepared from toluene / n-hexane.

[0195] 31 P NMR (161 MHz, C6D6): δ = 63.20 (d, J = 37.0 Hz, 1P), 60.72 (d, J = 37.0 Hz, 1P).

[0196] Figure 10 X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex of the present invention ((1S,2R,aR)-1’-A3) produced in Example 6. This result reveals that the η 1 H NMR observed η 1 -BH4 ligand is incorporated into the complex. It should be noted that, in order to make the structure of the complex in Figure 10 The description of the solvents (toluene and n-hexane) contained in the crystal is omitted for the sake of clarity of the structure of the complex in

[0197] The main parameters ensuring the accuracy of the results of the analyses are as follows. Crystal system: orthorhombic; space group: P212121 (#19), lattice constants: R1: 0.0253; wR2: 0.0613; GOF: 1.080; Flack parameter: -0.017(4).

[0198] Figure 11 The results of the analyses of the ruthenium complex of the application ((1S,2R,aR)-1'-A3) produced in Example 6, determined in deuterated benzene immediately after production, are summarized in Table 1 below. 1 H NMR (lower diagram) and after 4 weeks at room temperature in air. 1 H NMR (upper diagram). These analysis results show that the complex is extremely stable in air.

[0199] [Example 7] Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-dm-binap] ((1R,2S,aS)-1'-A3) production (formula 18)

[0200]

[0201] In the same way as in Example 6, by using (S)-DM-BINAP instead of (R)-DM-BINAP and (S)-DAIPEN instead of (R)-DAIPEN, the ruthenium complex of the application Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-dm-binap] ((1R,2S,aS)-1'-A3) was produced in an amount of 766 mg as a yellow powder stable in air at room temperature. Purity: 98.0% by weight (main impurity: n-hexane); isolation yield in step 2: 78.2%. It should be noted that single crystals of the complex can be prepared from toluene / n-hexane.

[0202] 31 P NMR (161 MHz, C6D6): δ = 63.16 (d, J = 37.0 Hz, 1P), 60.68 (d, J = 37.0 Hz, 1P).

[0203] Figure 12 X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability of presence) of the ruthenium complex of the application ((1R,2S,aS)-1'-A3) produced in Example 7 are shown. This result reveals that the η 1 H NMR observable η 1 -BH4 ligand is incorporated into the complex. It should be noted that in order to enable Figure 12The structure of the complex in the crystal is clear, and the description of the solvent (toluene and n-hexane) contained in the crystal is omitted.

[0204] The main parameters ensuring the accuracy of the analysis results are as follows. Crystal system: orthorhombic; space group: P212121 (#19); lattice constants: R1: 0.0305; wR2: 0.0792; GOF: 1.034; Flack parameter: -0.021(2).

[0205] [Example 8] Production of Ru(η 1 Production of Ru(η

[0206]

[0207] Step 1: After attaching a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way stopcock to a 100 mL four-necked round-bottom flask, the inside of the flask 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 equivalents), and dehydrated methanol (30 mL) were sequentially added to the flask. The resulting red slurry was warmed by using an oil bath while being stirred with a magnetic stirrer, and then stirred at 50°C for 1 hour. After the resulting red-orange suspension was cooled to room temperature, (R)-DAIPEN (1.62 g, 5.15 mmol, 2.1 equivalents) and diethylamine (558 μL, 5.39 mmol, 2.2 equivalents) were sequentially added, and the mixture was stirred at 60°C for 3 hours while being heated by using an oil bath. Dehydrated methanol (7.5 mL) was added to the resulting yellow slurry, which was then cooled to -20°C by using a dry ice-acetone bath and filtered by suction under a stream of nitrogen. The filtered crystals were washed with dehydrated methanol (20 mL) cooled to -20°C, and then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour), thereby producing 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-methylisopropylbenzene); separation yield: 68.5%.

[0208] 31 P NMR (161 MHz, C6D6): δ = 57.40 (d, J = 39.0 Hz, 1P), 52.60 (d, J = 39.0 Hz, 1P).

[0209] Step 2: After attaching a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way stopcock to a 100 mL four-necked round-bottom flask, the interior of the flask was replaced with nitrogen. The RuCl[(1S,2R)-daipena][(R)-dm-segphos] produced in Step 1 (purity: 97.7 wt%, 1.50 g, 1.25 mmol, 1.0 equiv), dehydrated toluene (30 mL), dehydrated ethanol (7.5 mL), and sodium borohydride (236 mg, 6.25 mmol, 5.0 equiv) were sequentially added to the flask. The resulting yellow-orange suspension was warmed by using an oil bath while stirring with a magnetic stirrer, and then stirred under reflux conditions for 1 hour. Then, the solvent (about 30 mL) was recovered from the reaction solution under reduced pressure while stirring to obtain a concentrate, which 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 by using an ice-water bath, and then tap water (15 mL) was added, followed by filtration by suction under a stream of nitrogen. The filtered crystals were washed with tap water (15 mL) and n-hexane (15 mL) in this order, and then dried by heating under reduced pressure (1 Torr, 40°C, 1 hour), thereby producing the ruthenium complex of the present application, Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-dm-segphos]((1S,2R,aR)-1’-B3). Purity: 99.2 wt% (main impurity is n-hexane); isolated yield: 96.8%. It should be noted that single crystals of the complex can be prepared from toluene / n-hexane.

[0210] 31 P NMR (161 MHz, C6D6): δ = 60.48 (d, J = 37.5 Hz, 1P), 60.13 (d, J = 37.5 Hz, 1P).

[0211] Figure 13 Results of the X-ray crystallographic analysis of the ruthenium complex of the present application ((1S,2R,aR)-1’-B3) produced in Example 8 (thermal ellipsoid plot; 50% atomic probability). This result reveals that the η 1 H NMR observed η 1 -BH4 ligand is incorporated into the complex. It should be noted that, in order to make the structure of the complex in Figure 12 The description of the solvent (toluene) contained in the crystal is omitted in order to make the structure of the complex in

[0212] The main parameters ensuring the accuracy of the analysis results are as follows. Crystal system: monoclinic; space group: C2 (#5); lattice constants: β = 99.7850(10)°; R1: 0.0270; wR2: 0.0639; GOF: 1.028; Flack parameter: -0.026(6).

[0213] Figure 14 The results of the H NMR (lower trace) and the H NMR determined after 4 weeks of storage at room temperature in air of the ruthenium complex of the application ((1S,2R,aR)-1'-B3) produced in Example 8, which was determined in deuterated benzene immediately after production 1 H NMR (lower trace) and the H NMR determined after 4 weeks of storage at room temperature in air of the ruthenium complex of the application ((1S,2R,aR)-1'-B3) produced in Example 8, which was determined in deuterated benzene immediately after production 1 H NMR (lower trace) and the H NMR determined after 4 weeks of storage at room temperature in air of the ruthenium complex of the application ((1S,2R,aR)-1'-B3) produced in Example 8, which was determined in deuterated benzene immediately after production

[0214] [Example 9] Production of Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-dm-segphos] ((1R,2S,aS)-1'-B3) (Formula 20)

[0215]

[0216] In the same manner as in Example 8, by using (S)-DM-SEGPHOS instead of (R)-DM-SEGPHOS and (S)-DAIPEN instead of (R)-DAIPEN, the ruthenium complex of the application ((1R,2S,aS)-1'-B3), Ru(η 1 -BH4)[(1R,2S)-daipena][(S)-dm-segphos] was produced as a cream-colored powder stable at room temperature in air in an amount of 1.40 g. Purity: 99.0% by weight (main impurity: n-hexane); isolation yield in Step 2: 96.2%. It should be noted that single crystals of the complex can be prepared from toluene / n-hexane.

[0217] 31 P NMR (161 MHz, C6D6): δ = 60.49 (d, J = 37.5 Hz, 1P), 60.14 (d, J = 37.5 Hz, 1P).

[0218] Figure 15 X-ray crystallographic analysis results (thermal ellipsoid plot; 50% atomic probability) of the ruthenium complex of the application ((1R,2S,aS)-1'-B3) produced in Example 9 are shown. This result reveals that the η 1 H NMR observable η 1 -BH4 ligand is incorporated into the complex. It should be noted that the description of the solvent (toluene) contained in the crystal is omitted in order to make the structure of the complex clear. Figure 15 ​

[0219] The main parameters ensuring the accuracy of the results of the analysis are as follows. Crystal system: monoclinic; space group: C2 (#5); lattice constants: β = 99.7550(10)°; R1: 0.0270; wR2: 0.0639; GOF: 1.028; Flack parameter: -0.026(6).

[0220] [Example 10] Production of Ru(η 1 RuCl[(1S,2R)-daipena][(R)-h8-binap] (Example 10) (Formula 21)

[0221]

[0222] Step 1 : After attaching a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way stopcock to a 50 mL four-necked round-bottom flask, the interior of the flask was replaced with nitrogen. [RuCl2(p-cymene)]2(1.00 g, 1.63 mmol, 1.0 equiv), (R)-H8-BINAP (2.08 g, 3.29 mmol, 2.02 equiv), and anhydrous methanol (20 mL) were sequentially added to the flask. The resulting red slurry was warmed by using an oil bath while stirring with a magnetic stirrer, and then 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 equiv), diethylamine (422 μL, 4.08 mmol, 2.5 equiv), and anhydrous methanol (5 mL) were sequentially added, and the mixture was stirred at 55°C for 2 hours while heating by using an oil bath. The resulting yellow-orange slurry was cooled to -20°C by using a dry ice-acetone bath, and then filtered by suction under a stream of nitrogen. The filtered crystals were washed twice with anhydrous methanol (5 mL x 2) cooled to -20°C, and then dried by heating under reduced pressure (1 Torr, 40°C, 2 hours), thereby producing 2.93 g of the conventional complex RuCl[(1S,2R)-daipena][(R)-h8-binap] as a yellow powder. Purity: 99.1 wt% (the main impurity is methanol); isolated yield: 82.4%.

[0223] 31 P NMR (161 MHz, C6D6): δ = 59.25 (d, J = 39.9 Hz, 1P), 54.20 (d, J = 39.9 Hz, 1P).

[0224] Step 2: After attaching a magnetic stir bar, a thermometer, a Dimroth condenser, and a three-way stopcock to a 100 mL four-necked round-bottom flask, the interior of the flask was replaced with nitrogen. The RuCl[(1R,2S)-daipena][(R)-h8-binap] produced in Step 1 (purity: 99.1 wt%, 1.50 g, 1.38 mmol, 1.0 equiv), deuterated toluene (30 mL), deuterated ethanol (7.5 mL), and sodium borohydride (156 mg, 4.14 mmol, 3.0 equiv) were sequentially added to the flask. The resulting yellow suspension was warmed using an oil bath while stirring with a magnetic stirrer, then stirred at 35 °C for 1 hour. Then, while stirring, the solvent (about 22.5 mL) was recovered from the reaction solution under reduced pressure to give a concentrate, which was allowed to cool to room temperature and washed with degassed water four times (7.5 mL x 4), then the resulting organic layer was concentrated to dryness under reduced pressure. The resulting residue was dissolved with deuterated toluene (4.5 mL), then deuterated n-hexane (90 mL) was slowly added, which resulted in a cream-colored slurry, which was then filtered by suction under a stream of nitrogen. The filtered crystals were washed with n-hexane (30 mL), then dried by heating under reduced pressure (1 Torr, 40 °C, 3 hours), which resulted in 1.30 g of the ruthenium complex of the present invention, Ru(η 1 Ru(η

[0225] 31 P NMR (161 MHz, C6D6): δ = 60.62 (d, J = 38.0 Hz, 1P), 60.18 (d, J = 38.0 Hz, 1P).

[0226] Figure 16 The results of the P NMR (bottom) and the H NMR (top) measured in deuterated benzene immediately after production of the ruthenium complex of the present invention ((1S,2R,aR)-1’-C1) produced in Example 10 are summarized in Table 1 below. 1 The results of the P NMR (bottom) and the H NMR (top) measured in deuterated benzene immediately after production of the ruthenium complex of the present invention ((1S,2R,aR)-1’-C1) produced in Example 10 are summarized in Table 1 below. 1 The results of the P NMR (bottom) and the H NMR (top) measured in deuterated benzene immediately after production of the ruthenium complex of the present invention ((1S,2R,aR)-1’-C1) produced in Example 10 are summarized in Table 1 below.

[0227] [Example 11 / Comparative Example 1] The ruthenium complex of the present invention, Ru(η 1Production of (S)-1-phenylethanol ((S)-6-1) from asymmetric hydrogenation of acetophenone (5-1) using Ru(η6

[0228] Formula 22

[0229]

[0230] After attaching a magnetic stir bar to a 50 mL stainless steel autoclave apparatus, the Ru complex of the present application, Ru(η6 1 -BH4)[(1S,2R)-daipena][(R)-t-binap] ((1S,2R,aR)-1'-A2) (purity: 86.6 wt%, 3.0 mg, 0.05 mol%) was added to the apparatus, and the inside of the apparatus was replaced with nitrogen. Then, dehydrated ethanol (2.5 mL) and acetophenone (5-1) (600 mg, 583 μL, 5.00 mmol, 1.0 equivalent) were sequentially added to the apparatus. The inside of the apparatus was replaced with hydrogen gas to set the internal pressure to 5 MPa, and then the reaction solution was stirred at 30°C for 2 hours, thereby producing the desired (S)-1-phenylethanol ((S)-6-1). Conversion: >99%; selectivity: >99%; optical purity: 97.6% ee (according to GC analysis). It should be noted that the GC retention times of each compound were as follows: acetophenone: 3.8 minutes; (R)-1-phenylethanol: 7.1 minutes; (S)-1-phenylethanol: 7.3 minutes.

[0231] On the other hand, as Comparative Example 1, asymmetric hydrogenation of acetophenone (5-1) was attempted under the same conditions as in Example 11 by 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%.

[0232] [Example 12 / Comparative Example 2] Production of (S)-1-phenylethanol ((S)-6-1) from asymmetric hydrogenation of acetophenone (5-1) using Ru(η6 1 Production of (S)-1-phenylethanol ((S)-6-1) from asymmetric hydrogenation of acetophenone (5-1) using Ru(η6

[0233] Formula 23

[0234] The desired (S)-1-phenylethanol ((S)-6-1) was produced from acetophenone (5-1) by using the ruthenium complex Ru(η 1 The desired (S)-1-phenylethanol ((S)-6-1) was produced from acetophenone (5-1) by using the ruthenium complex Ru(η

[0235] On the other hand, as Comparative Example 2, the asymmetric hydrogenation of acetophenone (5-1) was attempted by using the conventional complex RuCl[(1S,2R)-daipena][(R)-t-binap] (purity: 99.9 wt%, 2.8 mg, 0.05 mol%) as a catalyst under the same conditions as in Example 12, but the conversion rate was only 1.2%.

[0236] [Example 13 / Comparative Example 3] Production of (S)-1-phenylethanol ((S)-6-1) from acetophenone (5-1) by using Ru(η 1 The desired (S)-1-phenylethanol ((S)-6-1) was produced from acetophenone (5-1) by using the ruthenium complex Ru(η

[0237] Formula 24

[0238] The desired (S)-1-phenylethanol ((S)-6-1) was produced from acetophenone (5-1) by using the ruthenium complex Ru(η 1 The desired (S)-1-phenylethanol ((S)-6-1) was produced from acetophenone (5-1) by using the ruthenium complex Ru(η

[0239] On the other hand, as Comparative Example 3, the asymmetric hydrogenation of acetophenone (5-1) was attempted under the same conditions as in Example 13 by using the conventional complex RuCl[(1S,2R)-daipena][(R)-dm-binap] (purity: 97.7 wt%, 3.0 mg, 0.05 mol%) as the catalyst, but the conversion rate was only 4.2%.

[0240] [Example 14 / Comparative Example 4] Production of (S)-1-phenylethanol ((S)-6-1) from the asymmetric hydrogenation of acetophenone (5-1) by using Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-dm-segphos] ((1S,2R,aR)-1'-B3) and RuCl[(1S,2R)-daipena][(R)-dm-segphos] as the catalyst (Formula 25)

[0241] Formula 25

[0242] By using the ruthenium complex Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-dm-segphos] ((1S,2R,aR)-1'-B3) (purity: 99.2 wt%, 2.9 mg, 0.05 mol%) as the catalyst, the desired (S)-1-phenylethanol ((S)-6-1) was produced from acetophenone in the same manner as in Example 11 by reacting for 7 hours at 20°C. Conversion rate: >99%; selectivity: >99%; optical purity: 98.4% ee (according to GC analysis).

[0243] On the other hand, as Comparative Example 4, the asymmetric hydrogenation of acetophenone (5-1) was attempted under the same conditions as in Example 14 by using the conventional complex RuCl[(1S,2R)-daipena][(R)-dm-segphos] (purity: 97.7 wt%, 2.9 mg, 0.05 mol%) as the catalyst, but the conversion rate was only 0.5%.

[0244] [Example 15 / Comparative Example 5] Production of (S)-1-phenylethanol ((S)-6-1) from the asymmetric hydrogenation of acetophenone (5-1) by using Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-h8-binap] ((1S,2R,aR)-1'-C1) and RuCl[(1S,2R)-daipena][(R)-h8-binap] as the catalyst (Formula 26)

[0245] Example 26

[0246] The desired (S)-1-phenylethanol ((S)-6-1) was produced from acetophenone (5-1) in the same manner as in Example 11 by using the ruthenium complex of the present application Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-h8-binap]((1S,2R,aR)-1’-C1)(purity: >99.9 wt%, 2.7 mg, 0.05 mol%) as a catalyst. The conversion rate was >99%, the selectivity was >99%, and the optical purity was 96.5% ee (according to GC analysis).

[0247] On the other hand, as Comparative Example 5, the asymmetric hydrogenation of acetophenone (5-1) was attempted in the same manner as in Example 15 by 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%.

[0248] The results of Examples 11 to 15 and Comparative Examples 1 to 5 are summarized in Table 1 below. Note that since the combination of the absolute configuration of the central chirality and the axial chirality in these complexes in these examples and comparative examples is all (1S,2R,aR), for the sake of clarity, only the compound numbers corresponding to the ruthenium complexes of the present application and the conventional complex used as a catalyst are shown in Table 1.

[0249] [Table 1]

[0250]

[0251] As shown in Table 1, in the asymmetric hydrogenation of acetophenone (5-1) using the ruthenium complexes of the present application ((1S,2R,aR)-1'-A1) to ((1S,2R,aR)-1'-C1) which do not require a base for their activation as catalysts, both the conversion and the selectivity were >99%, and the optical purity of the produced (S)-1-phenylethanol ((S)-6-1) was also excellent, ranging from 95.7 to 99.3% ee (Examples 11 to 15). On the other hand, when the conventional complexes ((1S,2R,aR)-2'-A1) to ((1S,2R,aR)-2'-C1) which require a base for their activation were used as catalysts, the conversion of the reaction was only 0.3 to 4.2% (Comparative Examples 1 to 5). From these results, it was clear that the ruthenium complexes (1) of the present application exhibit excellent performance as catalysts for asymmetric hydrogenation even in the absence of a base, and are superior to the conventional complexes (2).

[0252] [Example 16] Production of (S)-4-(1-hydroxyethyl)benzonitrile ((S)-6-2) by asymmetric hydrogenation of 4-acetylbenzonitrile (5-2) using Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-dm-binap]((1S,2R,aR)-1'-A3) as catalyst (Formula 27)

[0253]

[0254] After attaching a magnetic stirrer bar to a 50 mL stainless steel autoclave apparatus, the ruthenium complex of the present application Ru(η 1 -BH4)[(1S,2R)-daipena][(R)-dm-binap]((1S,2R,aR)-1'-A3) (purity: 98.8% by weight, 2.9 mg, 0.1 mol%) and 4-acetylbenzonitrile (363 mg, 2.50 mmol, 1.0 equivalent) were sequentially added to the apparatus, and the inside of the apparatus was replaced with nitrogen. Then, dehydrated ethanol (2.5 mL) was added to the apparatus. The inside of the apparatus was replaced with hydrogen gas to set the internal pressure to 1 MPa, and then the reaction solution was stirred at 50°C for 5 hours, thereby producing the desired (S)-4-(1-hydroxyethyl)benzonitrile ((S)-6-2). Conversion: >99%; selectivity: >99%; optical purity: 97.6% ee (according to GC analysis). It should be noted that the GC retention times of each compound were as follows: 4-acetylbenzonitrile: 6.8 minutes; (R)-4-(1-hydroxyethyl)benzonitrile: 19.6 minutes; (S)-4-(1-hydroxyethyl)benzonitrile: 21.2 minutes.

[0255] [Example 17] Production of (S)-4-(1-hydroxyethyl)benzonitrile ((S)-6-2) by asymmetric hydrogenation of 4-acetylbenzonitrile (5-2) using Ru(η 1Production of (S)-4-(1-hydroxyethyl)benzoic acid methyl ester ((S)-6-3) by asymmetric hydrogenation of 4-acetylbenzoic acid methyl ester (5-3) with [(1S,2R)-daipena][(R)-dm-binap] ((1S,2R,aR)-1'-A3) as catalyst (Formula 28)

[0256]

[0257] After attaching a magnetic stirring bar to a 50 mL stainless steel autoclave apparatus, the ruthenium complex of the present application 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 4-acetylbenzoic acid methyl ester (178 mg, 1.00 mmol, 1.0 equivalent) were sequentially added to the apparatus, and the inside of the apparatus was replaced with nitrogen. Then, dehydrated ethanol (2.0 mL) and dehydrated isopropanol (2.0 mL) were sequentially added to the apparatus. The inside of the apparatus was replaced with hydrogen gas to set the internal pressure to 5 MPa, and then the reaction solution was stirred at 50°C for 7 hours, thereby producing the desired (S)-4-(1-hydroxyethyl)benzoic acid methyl ester ((S)-6-3). Conversion: >99%; selectivity: >99%; optical purity: 96.0% ee (according to GC analysis). It should be noted that the GC retention times of each compound were as follows: 4-acetylbenzoic acid methyl ester: 8.6 minutes; (R)-4-(1-hydroxyethyl)benzoic acid methyl ester: 18.2 minutes; (S)-4-(1-hydroxyethyl)benzoic acid methyl ester: 19.0 minutes.

[0258] As shown in Examples 16 and 17, asymmetric hydrogenation of asymmetric ketones having a cyano group or a methoxycarbonyl group that tends to decompose under basic conditions was carried out in a highly stereoselective manner by using the ruthenium complex (1) of the present application, which does not require a base for its activation, as a catalyst, without losing any such functional groups, to produce the desired optically active secondary alcohol in a high yield. These results clearly demonstrate the usefulness of the ruthenium complex (1) of the present application, which exhibits catalytic activity without the addition of a base.

[0259] While the present application has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. This application is based on Japanese Patent Application (Japanese Patent Application No. 2020-175074) filed on October 19, 2020, the contents of which are incorporated herein by reference.

[0260] Industrial Applicability

[0261] The ruthenium complex (1) can be easily synthesized by the reaction of the conventional complex (2) with a borohydride compound, and has various advantages such as excellent crystallinity and stability, and exhibits catalytic activity without the addition of a base. Furthermore, the asymmetric hydrogenation of an asymmetric ketone (5) catalyzed by the ruthenium complex (1) can efficiently produce an industrially useful optically active secondary alcohol (6) without losing any functional group which tends to be decomposed under basic conditions.

Claims

1. A ruthenium complex represented by the following general formula (1) : ###0001### (1) wherein a solid line represents a single bond, a double line represents a double bond, a dotted 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; and Ru represents a divalent ruthenium ion. wherein 2. A production method of the ruthenium complex according to claim 1, the method comprising a step of reacting a ruthenium complex represented by the following general formula (2) with sodium borohydride, ###0002### (2) wherein a solid line represents a single bond, a double line represents a double bond, and a dotted line represents a coordinate bond; CI represents a chlorine atom, H represents a hydrogen atom, N represents a nitrogen atom, and P represents a phosphorus atom; and Ru represents a divalent ruthenium ion.

3. A production method of an optically active secondary alcohol, the method producing the optically active secondary alcohol by catalytic asymmetric hydrogenation of an asymmetric ketone using the ruthenium complex according to claim 1 as a catalyst. H and H B each represents a hydrogen atom; C, C P1 , C P2 , C a , C N1 , and C N2 each represents a carbon atom; ​ R P represents a group selected from the group consisting of phenyl, 4-methylphenyl and 3,5-dimethylphenyl; R P1 and the combination of R P2 is a combination selected from the group consisting of R P1 is ethyl and R P2 is ethyl, R P1 is vinyl and R P2 is vinyl, and R P1 or R P2 is methoxy and the other is hydroxy; R P1 and R P2 are bound to each other to form a ring with C P1 and C P2 ; R N1 represents isopropyl, and R N2 represents methoxy; and R P3 , R P4 , R N3 , R N4 , R N5 and R N6 each represent a hydrogen atom. ​ wherein ​ ​ C, C P1 , C P2 , C a , C N1 , and C N2 each represents a carbon atom; ​ R P represents a group selected from the group consisting of phenyl, 4-methylphenyl and 3,5-dimethylphenyl; R P1 and the combination of R P2 is a combination selected from the group consisting of R P1 is ethyl and R P2 is ethyl, R P1 is vinyl and R P2 is vinyl, and R P1 or R P2 is methoxy and the other is hydroxy; R P1 and R P2 are bound to each other to form a ring with C P1 and C P2 ; R N1 represents isopropyl, and R N2 represents methoxy; and R P3 , R P4 , R N3 , R N4 , R N5 and R N6 each represent a hydrogen atom. ​

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