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WO2025164594A1 - Complexe de ruthénium-diphosphine-carboxylate et son procédé de production - Google Patents

Complexe de ruthénium-diphosphine-carboxylate et son procédé de production

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Publication number
WO2025164594A1
WO2025164594A1 PCT/JP2025/002530 JP2025002530W WO2025164594A1 WO 2025164594 A1 WO2025164594 A1 WO 2025164594A1 JP 2025002530 W JP2025002530 W JP 2025002530W WO 2025164594 A1 WO2025164594 A1 WO 2025164594A1
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Prior art keywords
group
trap
ruthenium
diphosphine
general formula
Prior art date
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Pending
Application number
PCT/JP2025/002530
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English (en)
Japanese (ja)
Inventor
裕治 中山
瑞希 関
拓海 原部
和彦 坂口
奈和 玉城
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Takasago International Corp
Original Assignee
Takasago International Corp
Takasago Perfumery Industry Co
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Publication of WO2025164594A1 publication Critical patent/WO2025164594A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/08—Acetic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/124—Acids containing four carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C61/12—Saturated polycyclic compounds
    • C07C61/125—Saturated polycyclic compounds having a carboxyl group bound to a condensed ring system
    • C07C61/135—Saturated polycyclic compounds having a carboxyl group bound to a condensed ring system having three rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F17/00—Metallocenes
    • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F19/00—Metal compounds according to more than one of main groups C07F1/00 - C07F17/00
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands

Definitions

  • the present invention relates to a novel ruthenium-diphosphine-carboxylate complex that is useful as a catalyst in various organic synthesis reactions, including aromatic asymmetric hydrogenation, and an efficient method for producing the same.
  • Optically active cyclic compounds are extremely important compounds for use in pharmaceuticals, agrochemicals, functional materials, fragrances, and synthetic intermediates, and research and development into their production methods is still underway.
  • catalytic asymmetric hydrogenation of aromatic and heteroaromatic compounds, or aromatic asymmetric hydrogenation has the advantage of being able to simultaneously introduce multiple asymmetric carbons into target molecules, while also being highly atom-efficient and capable of significantly reducing waste. Therefore, aromatic asymmetric hydrogenation is not only useful as a method for producing optically active cyclic compounds, but is also one of the most important catalytic reactions from the perspectives of the Sustainable Development Goals (SDGs), which have recently attracted attention, and green chemistry, which contributes to reducing environmental impact.
  • SDGs Sustainable Development Goals
  • Non-Patent Document 2 Ryoichi Kuwano et al. of Kyushu University developed a ruthenium complex of Ph-TRAP, [RuCl(p-cymene)(Ph-trap)]Cl. They demonstrated that reaction reproducibility was significantly improved by preparing this complex outside the reaction system, isolating it, and using it as a catalyst (Non-Patent Documents 2 and 8).
  • Patent Document 1 Japanese Patent Application Laid-Open No. 4-283596
  • Non-Patent Document 1 Masaya Sawamura, Hitoshi Hamashima, and Yoshihiko Ito, Tetrahedron: Asymmetry, 1991, 7(2), 593-596.
  • Non-patent document 2 Ryoichi Kuwano, J. Synth. Org. Chem. , Jpn. , 2007, 65(2), 109-118.
  • Non-patent document 3 Ryoichi Kuwano, Nao Kameyama, and Ryuhei Ikeda, J. Am. Chem. Soc., 2011, 133(19), 7312-7315.
  • Non-patent document 4 Ryoichi Kuwano, J. Synth. Org. Chem. , Jpn.
  • Non-Patent Document 5 Masaya Sawamura, Hitoshi Hamashima, Masanobu Sugawara, Ryoichi Kuwano, and Yoshihiko Ito, Organometallics, 1995, 14(10), 4549-4558.
  • Non-Patent Document 6 Ryoichi Kuwano, and Masaya Sawamura, Catalysts for Fine Chemical Synthesis: Vol. 5, Regio- and Stereo-Controlled Oxidations and Reductions, Wiley, Chicago, 2007, 5, 73-86.
  • Non-Patent Document 7 Michael A. Schmidt, Eric M. Simmons, Carolyn S. Wei, Hyunsoo Park, and Martin D. Eastgate, J. Org.
  • Non-Patent Document 8 Ryoichi Kuwano and Manabu Kashiwabara, Org. Lett., 2006, 8(12), 2653-2655.
  • Non-Patent Document 9 Ryoichi Kuwano, Ryuichi Morioka, Manabu Kashiwabara, and Nao Kameyama, Angew. Chem. Int. Ed., 2012, 51(17), 4136-4139.
  • Non-Patent Document 10 Ryoichi Kuwano, Ryuhei Ikeda, and Kazuki Hirasada, Chem. Commun., 2015, 51, 7558-7561.
  • the objective of the present invention is to provide a new catalyst that can be suitably used in various organic synthesis reactions, as well as an efficient method for producing the same.
  • Ph-TRAP aforementioned ruthenium complex of Ph-TRAP, i.e., [RuCl(p-cymene)(Ph-trap)]Cl
  • this complex exhibits excellent performance as an aromatic asymmetric hydrogenation catalyst
  • various problems remain from the perspective of industrial use, as described below.
  • the synthesis of Ph-TRAP used to produce this complex requires various reagents and solvents that are difficult to use industrially.
  • Ph-TRAP takes the form of an amorphous compound that is unstable in air or a highly toxic benzene solvate, making it extremely difficult to produce industrially using conventional methods (Equation 3; Non-Patent Documents 5-7).
  • the present inventors evaluated the performance of various catalysts using the asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole, a sterically bulky and poorly reactive heteroaromatic compound, as a model reaction.
  • the results showed that the reaction proceeded almost completely without the addition of a base when using the conventional catalyst [RuCl(p-cymene)(Ph-trap)]Cl or the common catalyst Ru(O 2 CMe) 2 (binap).
  • RuCl(p-cymene)(Ph-trap) the conventional catalyst
  • Ru(O 2 CMe) 2 (binap) the common catalyst
  • the newly developed Ru(O 2 CMe) 2 (Ph-trap) as a catalyst, the reaction proceeded rapidly to completion without the addition of a base, and the catalyst amount could be reduced to just 0.05 mol%.
  • the present inventors have further investigated and completed the present invention. That is, the present invention includes the following [1] to [11].
  • a solid line represents a single bond, a double line represents a double bond, and a dashed line represents a coordinate bond;
  • H represents a hydrogen atom, C represents a carbon atom, O represents an oxygen atom, and P represents a phosphorus atom;
  • Me represents a methyl group;
  • Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the bold line represents six electrons donated by the cyclopentadienyl anion to Fe;
  • R P represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent;
  • Ru represents a divalent ruthenium ion;
  • R C represents a group selected from the group consisting of an alkyl group, a halogenoalkyl group, a cycloalkyl group, and an aryl
  • Solid lines represent single bonds; H represents a hydrogen atom, C represents a carbon atom, and P represents a phosphorus atom; Me represents a methyl group; Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the bold line represents six electrons donated by the cyclopentadienyl anion to Fe; R P represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent. and a diphosphine compound represented by the following general formula (3):
  • a solid line represents a single bond, a double line represents a double bond, and a dashed line represents a coordinate bond;
  • C represents a carbon atom and O represents an oxygen atom;
  • Ru represents a divalent ruthenium ion, AB represents alkylbenzenes, and the thick dashed line represents six-electron donation of the alkylbenzenes to Ru;
  • R C represents a group selected from the group consisting of an alkyl group, a halogenoalkyl group, a cycloalkyl group, and an aryl group.
  • the present invention provides a ruthenium-diphosphine-carboxylate complex represented by the general formula (1), i.e., Ru(O 2 CRC ) 2 (R P -trap) (hereinafter referred to as ruthenium complex (1) of the present invention).
  • the ruthenium complex (1) of the present invention can be easily produced by reacting a diphosphine compound represented by the general formula (2) with a ruthenium-alkylbenzene-carboxylate complex represented by the general formula (3) in a non-halogenated solvent that is readily available for industrial use.
  • a preferred form of ruthenium complex (1) of the present invention has excellent crystallinity, facilitating isolation and purification and long-term storage.
  • FIG. 1 shows the results of single crystal X-ray structural analysis of Ru(O 2 CMe) 2 ((S C ,S C ,R P ,R P )-Ph-trap) produced in Example 1 below.
  • FIG. 2 shows the results of single crystal X-ray structural analysis of Ru(O 2 C t Bu) 2 ((S C ,S C ,R P ,R P )-Ph-trap) produced in Example 2 below.
  • FIG. 3 shows the results of single crystal X-ray structural analysis of Ru(O 2 C t Bu) 2 ((R C ,R C ,S P ,S P )-Ph-trap) produced in Example 3 below.
  • FIG. 1 shows the results of single crystal X-ray structural analysis of Ru(O 2 CMe) 2 ((S C ,S C ,R P ,R P )-Ph-trap) produced in Example 1 below.
  • FIG. 2 shows the results of single crystal X-ray structural analysis of Ru(O 2 C t Bu
  • FIG. 4 shows the results of single crystal X-ray structural analysis of Ru(O 2 CAd) 2 (( SC , SC , RP , RP )-Ph-trap) produced in Example 4 below.
  • FIG. 5 shows the results of single crystal X-ray structural analysis of Ru(O 2 CAd) 2 ((R C ,R C ,S P ,S P )-Ph-trap) produced in Example 5 below.
  • FIG. 6 shows the results of single crystal X-ray structural analysis of Ru(O 2 CAd) 2 ((R C ,R C ,S P ,S P )-Ph-trap) ⁇ H 2 O produced in Example 5 below.
  • FIG. 7 shows the results of single crystal X-ray structural analysis of (S)-N-Boc-2-phenylindoline prepared in Example 9 below.
  • FIG. 8 shows the results of single crystal X-ray structural analysis of (R)-N-Boc-2-phenylindoline prepared in Example 14 below.
  • FIG. 9 shows the results of single crystal X-ray structural analysis of (S)-N-Boc-3-phenylindoline prepared in Example 17 below.
  • ruthenium complex (1) of the present invention will be described in detail below.
  • a solid line represents a single bond
  • a double line represents a double bond
  • a dashed line represents a coordinate bond
  • H represents a hydrogen atom
  • C represents a carbon atom
  • O represents an oxygen atom
  • P represents a phosphorus atom
  • Me represents a methyl group
  • Fe represents a divalent iron ion
  • the pentagon containing a circle represents a cyclopentadienyl anion
  • the thick line represents six electrons donated by the cyclopentadienyl anion to Fe.
  • R 1 P represents a group selected from the group consisting of an alkyl group, a cycloalkyl group, a heteroaryl group, and an aryl group which may have a substituent, preferably an aryl group which may have a substituent.
  • Ru represents a divalent ruthenium ion.
  • R 1 C represents a group selected from the group consisting of an alkyl group, a halogenoalkyl group, a cycloalkyl group, and an aryl group, preferably an alkyl group or a cycloalkyl group.
  • all four R 1 Ps present on the molecule represent the same group
  • all two R 1 Cs present on the molecule represent the same group.
  • the alkyl group in R P may be linear or branched, and examples thereof include alkyl groups having 1 to 12 carbon atoms, preferably alkyl groups having 1 to 8 carbon atoms, and more preferably alkyl groups having 1 to 4 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group.
  • the cycloalkyl group for R P may be monocyclic or polycyclic, and examples thereof include 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 thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 1-adamantyl group, and a 2-adamantyl group.
  • the heteroaryl group in R 1 P includes heteroaryl groups derived from a 5-membered heteroaromatic ring containing an oxygen atom or a sulfur atom, and specific examples thereof include a 2-furyl group, a 3-furyl group, a 2-thienyl group, and a 3-thienyl group.
  • Examples of the aryl group in R P 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, and specific examples include phenyl groups, 1-naphthyl groups, and 2-naphthyl groups, and a preferred specific example is phenyl groups.
  • the aryl groups may have a substituent.
  • Substituents that the aryl group in R 1 P may have include an alkyl group, a halogenoalkyl group, an aryl group, an alkoxy group, a dialkylamino group, and a halogeno group.
  • alkyl group examples include the same alkyl groups as those detailed in the description of R 1 P , specifically methyl and tert-butyl groups, and a preferred specific example is methyl.
  • the halogenoalkyl group includes a halogenoalkyl group formed by replacing at least one hydrogen atom on the alkyl group with a halogen atom, and a specific example is a trifluoromethyl group.
  • aryl group examples include the same aryl groups as those described in detail in the description of R 1 P , and specific examples include a phenyl group.
  • the alkoxy group may be linear or branched, and examples include 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 groups.
  • the dialkylamino group includes a dialkylamino group formed by substituting two hydrogen atoms on an amino group with the alkyl group, and specifically includes an N,N-dimethylamino group.
  • halogeno groups include fluoro, chloro, bromo, and iodo groups.
  • the alkyl group in R C may be linear or branched, and examples thereof include alkyl groups having 1 to 12 carbon atoms, preferably alkyl groups having 1 to 8 carbon atoms, and more preferably alkyl groups having 1 to 4 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group, and preferred specific examples thereof include a methyl group and a tert-butyl group.
  • the halogenoalkyl group for R 3 C includes a halogenoalkyl group formed by substituting at least one hydrogen atom on the alkyl group described above with a halogen atom, and a specific example thereof is a trifluoromethyl group.
  • the cycloalkyl group for R C may be monocyclic or polycyclic, and examples thereof include 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 a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 1-adamantyl group, and a 2-adamantyl group, and a preferred specific example is a 1-adamantyl group.
  • the aryl group for R C includes, for example, an aryl group having 6 to 18 carbon atoms, preferably an aryl group having 6 to 14 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms, and specific examples thereof include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • the ruthenium complex (1) of the present invention has two carbon-centered asymmetries (hereinafter, the absolute configurations of these carbon-centered asymmetries will be represented by R C and S C ), two planar asymmetries (hereinafter, the absolute configurations of these planar asymmetries will be represented by R P and S P ), and one secondarily induced ruthenium-centered asymmetry (hereinafter, the absolute configurations of this ruthenium-centered asymmetry will be represented by ⁇ and ⁇ ). Therefore, it may be a mixture of stereoisomers resulting from these various asymmetries, or a single stereoisomer. However, particularly from the viewpoint of application to aromatic asymmetric hydrogenation, a single stereoisomer, i.e., an optically active substance, is preferred.
  • Preferred forms of the optically active ruthenium complex (1) of the present invention due to structural requirements, include Ru(O 2 CR C ) 2 ((S C ,S C ,R P ,R P )-R P -trap) ((S C ,S C ,R P ,R P )-1) and Ru(O 2 CR C ) 2 ((R C ,R C ,S P ,S P ) -R P -trap ) ((R C ,R C ,S P , S P )-1), which have the stereostructural formula shown in Formula 10 below (according to convention, in drawing the stereostructural formulas in this specification, secondarily induced ruthenium-centered asymmetry and the carbon atom C and hydrogen atom H are omitted).
  • the solid wedge line represents a carbon-carbon bond toward the front side of the paper
  • the dashed wedge line represents a carbon-carbon bond toward the back side of the paper.
  • Particularly preferred examples of the ruthenium complex (1) of the present invention include Ru(O 2 CMe) 2 ((S C ,S C ,R P ,R P )-Ph-trap), Ru(O 2 CMe) 2 ((R C ,R C ,S P ,S P )-Ph-trap), Ru(O 2 C t Bu) 2 ((S C , S C ,R P ,R P )-Ph-trap), Ru(O 2 C t Bu ) 2 ((R C ,R C ,S P ,S P )-Ph-trap), and Ru ( O 2 CAd) 2 ((S C ,S C ,R P ,R P )-Ph-trap) , which have the stereostructural formula shown in the following formula 11 .
  • Ph represents a phenyl group
  • Me represents a methyl group
  • the ruthenium complex (1) of the present invention can be easily produced by reacting a diphosphine compound represented by the general formula (2) (hereinafter referred to as R P -TRAP (2)) with a ruthenium-alkylbenzene-carboxylate complex represented by the general formula (3), i.e., Ru(O 2 CR C ) 2 (AB) (3) (hereinafter referred to as the ruthenium source (3)), while dissociating the alkylbenzene, i.e., AB, as shown in formula 13 below.
  • R P -TRAP (2) diphosphine compound represented by the general formula (2)
  • a ruthenium-alkylbenzene-carboxylate complex represented by the general formula (3) i.e., Ru(O 2 CR C ) 2 (AB) (3)
  • the ruthenium source (3) hereinafter referred to as the ruthenium source (3)
  • R P -TRAP (2) in the production method of the present invention will be described in detail below.
  • the solid line, H, C, P, Me, Fe, the pentagon containing a circle, the thick line, and R P are all the same as those defined and described in detail in the explanation of the general formula (1).
  • R P -TRAP (2) all four R Ps present on the molecule represent the same group.
  • R P -TRAP (2) Since R P -TRAP (2) has two carbon-center chiralities and two planar chiralities, it may be a mixture of stereoisomers resulting from these chiralities or a single stereoisomer. However, similar to the ruthenium complex (1) of the present invention, a single stereoisomer, i.e., an optically active form, is preferred, particularly from the viewpoint of application to aromatic asymmetric hydrogenation.
  • optically active R P -TRAP (2) based on structural requirements, include (S C ,S C ,R P ,R P )-R P -TRAP((S C ,S C ,R P ,R P )-2) and (R C ,R C ,S P ,S P )-R P -TRAP(( R C ,R C , S P , S P ) -2), whose stereostructural formulas are shown in Formula 14 below.
  • R P -TRAP (2) in the production method of the present invention include (S C ,S C ,R P ,R P )-Ph-TRAP, (R C ,R C ,S P ,S P )-Ph-TRAP, (S C ,S C ,R P ,R P )-Tol-TRAP, and ( R C , R C ,S P ,S P )-Tol-TRAP, which have the stereostructural formula shown in the following formula 15 .
  • Ph represents a phenyl group
  • Tol represents a 4-methylphenyl group.
  • R P -TRAP (2) can be easily synthesized with good reproducibility from commercially available N,N-dimethyl-1-ferrocenylethylamine (commonly known as Ugi's Amine) through a multi-step reaction including lithiation and halogenation (Step 1), phosphination (Step 2), reaction with a borane source (Step 3), reaction with a magnesium source (Step 4), reaction with an oxidizing agent (Step 5), and deprotection reaction (Step 6).
  • Step 1 lithiation and halogenation
  • Step 2 reaction with a borane source
  • Step 4 reaction with a magnesium source
  • Step 5 reaction with an oxidizing agent
  • deprotection reaction Step 6
  • R P -TRAP (2) obtained by this synthesis method may form a stable solvate together with the solvent used in the deprotection reaction (Step 6), and preferred examples of such a solvent include n-propyl alcohol and n-butanol.
  • B represents a boron atom
  • Mg represents a magnesium atom
  • N represents a nitrogen atom
  • X represents a halogen atom
  • the ruthenium source (3) in the production method of the present invention will be described in detail below.
  • the solid line, double line, dashed line, C, O, Ru, and R C are all the same as those defined and described in detail in the explanation of the general formula (1).
  • AB represents an alkylbenzene
  • the thick dashed line represents six-electron donation of the alkylbenzene to Ru.
  • both of the two R Cs present on the molecule represent the same group.
  • alkylbenzenes in AB examples include benzene (C 6 H 6 ) and compounds in which at least one hydrogen atom on the benzene is substituted with an alkyl group, such as alkylbenzenes having 6 to 24 carbon atoms, preferably alkylbenzenes having 6 to 18 carbon atoms, and more preferably alkylbenzenes having 6 to 12 carbon atoms.
  • benzene 1,3,5-trimethylbenzene (mesitylene), 1-methyl-4-isopropylbenzene (p-cymene), and hexamethylbenzene, and a preferred specific example is 1-methyl-4-isopropylbenzene (p-cymene).
  • Particularly preferred specific examples of the ruthenium source (3) in the production method of the present invention include Ru(O 2 CMe) 2 (p-cymene), Ru(O 2 C t Bu) 2 (p-cymene), and Ru(O 2 CAd) 2 (p-cymene), whose structural formulas are shown in the following formula 17. Note that all of these ruthenium sources (3) can be easily synthesized following known methods.
  • Me represents a methyl group
  • t Bu represents a tert-butyl group
  • Ad represents a 1-adamantyl group.
  • R P -TRAP (2) used in this reaction is not particularly limited, but from the viewpoint of atom efficiency, it is appropriately selected from the range of usually 0.5 to 1.5 equivalents, preferably 0.8 to 1.2 equivalents, and more preferably 0.9 to 1.1 equivalents relative to the ruthenium source (3).
  • R P -TRAP (2) with the ruthenium source (3) can in principle be carried out in the absence of a solvent. However, this requires special equipment such as a ball mill or a kneader. Therefore, in practice, it is preferable to carry out the reaction in the presence of a solvent.
  • a solvent is preferably one that is not involved in the decomposition reaction of the ruthenium complex (1) of the present invention.
  • such a solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, n-decane, cyclohexane, and decalin; aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, p-cymene, and 1,4-diisopropylbenzene; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, and 1,4-dioxane; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; and
  • aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, p-cymene, and 1,4-diisopropylbenzene.
  • Toluene is particularly preferred because it is inexpensive, easy to handle, and has excellent substrate solubility.
  • These solvents may be used alone or in combination of two or more.
  • the amount of the solvent used is not particularly limited, but is usually selected from the range of 1 to 200 times by volume, preferably 1.5 to 100 times by volume, and more preferably 2 to 50 times by volume relative to the weight of R P -TRAP (2) used.
  • the reaction between R P -TRAP (2) and the ruthenium source (3) is preferably carried out under an inert gas atmosphere to prevent decomposition of the substrate and reaction intermediates.
  • inert gases include argon gas and nitrogen gas, with nitrogen gas being a preferred example.
  • the reaction temperature is typically selected from the range of -20°C to 160°C, preferably 0°C to 140°C, and more preferably 20°C to 120°C.
  • the reaction time depends on the structures of R P -TRAP (2) and the ruthenium source (3), the amount of R P -TRAP (2) used, the reaction solvent, and the reaction temperature, but is typically selected from the range of 5 minutes to 24 hours, preferably 10 minutes to 12 hours, and more preferably 20 minutes to 6 hours.
  • the reaction solution obtained from R P -TRAP (2), the ruthenium source (3), and the solvent may be post-treated as necessary, and the ruthenium complex (1) of the present invention may be isolated from the reaction solution and further purified.
  • Specific post-treatment techniques include filtration of the reaction solution, concentration, and solvent substitution.
  • Specific isolation techniques include drying and crystallization of the reaction solution, and filtration, washing, and drying of the crude crystals.
  • Specific purification techniques include dissolution of the crude crystals, decolorization with an adsorbent, recrystallization, and filtration, washing, and drying of the purified crystals. These techniques may be used alone or in combination.
  • the ruthenium complex (1) of the present invention may contain a solvent used in the reaction, post-treatment, isolation, or purification, or an alkylbenzene dissociated during the reaction.
  • a solvent used in the reaction post-treatment, isolation, or purification
  • alkylbenzene dissociated during the reaction Preferred examples of such solvents and alkylbenzenes include toluene, n-heptane, acetone, water, and p-cymene.
  • the reaction liquid when using the ruthenium complex (1) of the present invention as a catalyst, the reaction liquid may be used as is, or may be used after carrying out the above-mentioned post-treatment, isolation, and purification as necessary.
  • the preferred form of the ruthenium complex (1) of the present invention is one that has excellent crystallinity and stability and can be stored for a long period of time, and therefore, from the perspective of utilizing these properties, it is preferable to use it as a catalyst after isolation.
  • the ruthenium complex (1) of the present invention may be used as a catalyst either alone or in combination with two or more types, but from a practical perspective, it is preferable to use it as a catalyst alone.
  • the ruthenium complex (1) of the present invention produced in this manner can be suitably used as a catalyst in various organic synthesis reactions.
  • organic synthesis reactions are not particularly limited, but specific examples 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 may be asymmetric, and a preferred example is the asymmetric hydrogenation of aromatic compounds and heteroaromatic compounds, i.e., aromatic asymmetric hydrogenation.
  • aromatic asymmetric hydrogenation include the asymmetric hydrogenation of indoles, oxazoles, imidazoles, and naphthalenes under neutral conditions, and these reactions enable the efficient production of industrially useful optically active cyclic compounds.
  • the method for producing the ruthenium complex (1) of the present invention and the asymmetric aromatic hydrogenation using this complex as a catalyst are described in detail below with specific examples and comparative examples, but the present invention is in no way limited by these descriptions.
  • the substrate, reagents, and solvent were charged and added under a nitrogen stream, the reaction was carried out under a nitrogen atmosphere, and post-treatment, isolation, and purification were carried out in air.
  • the instruments, measurement conditions, and analysis conditions used to measure physical properties in the examples are as follows:
  • Step 2 Preparation of Ru(O 2 CMe) 2 ((S C ,S C ,R P ,R P )-Ph-trap)
  • Step 1 After recovering approximately 30 mL of solvent, the inside of the apparatus was filled with nitrogen gas. Next, a toluene solution (approximately 30 mL) of Ru(O 2 CMe) 2 (p-cymene) ( ⁇ 2.34 mmol, 1.0 equivalent) prepared in Step 1 was placed in the dropping funnel and added dropwise to the reaction solution at room temperature, followed by stirring for 2 hours while heating in an oil bath at 70°C.
  • Step 1 Synthesis of Ru(O 2 C t Bu) 2 (p-cymene)
  • Toluene (80 mL) was added to the reaction mixture, and the pressure was gradually reduced to 60 Torr while stirring at 60°C. After approximately 80 mL of solvent had been recovered, the apparatus was filled with nitrogen gas. Toluene (120 mL) was added to the resulting reddish-brown slurry, which was then filtered using diatomaceous earth under a nitrogen stream. The filtered residue was then washed with toluene (40 mL). The combined filtrate was transferred to a 500 mL four-neck round-bottom flask and equipped with a magnetic stir bar, thermometer, Claisen distillation apparatus, and a three-way stopcock.
  • the filtrate was then gradually reduced to 50 Torr while stirring at 60°C. After approximately 130 mL of solvent had been recovered, the apparatus was filled with nitrogen gas. n-Heptane (90 mL) was added to the concentrated filtrate, and the pressure was gradually reduced to 70 Torr while stirring at 60°C. After approximately 90 mL of solvent had been recovered, the apparatus was filled with nitrogen gas. To the resulting orange slurry, n-heptane (90 mL) was added with stirring, and the mixture was cooled to 0°C in an ice-water bath and then suction filtered using a Kiriyama funnel.
  • Step 2 Preparation of Ru(O 2 C t Bu) 2 ((S C ,S C ,R P ,R P )-Ph-trap) [Charge and reaction]
  • a 50 mL four-neck round-bottom flask was charged with (S C ,S C ,R P ,R P )-Ph-TRAP ⁇ n-BuOH (purity: 92.9 wt%, 1.0 g, 1.17 mmol, 1.0 equivalent), and equipped with a magnetic stir bar, thermometer, Claisen distillation apparatus, Dimroth condenser, and three-way stopcock. The inside of the flask was purged with nitrogen.
  • the filtered crystals were washed with a mixed solvent of anhydrous n-heptane (10 mL) and anhydrous toluene (1 mL) cooled to 0°C and then heated to 60°C under a reduced pressure of 1 Torr and dried for 1 hour. This yielded 1.21 g of the desired Ru(O 2 C t Bu) 2 ((R C ,R C ,S P ,S P )-Ph-trap) as an air-stable orange powder. Purity: 96.8 wt% (the main impurity was 3.4 wt% toluene), isolated yield: 95.2%.
  • Step 2 Preparation of Ru(O 2 CAd) 2 (( SC , SC , RP , RP )-Ph-trap)
  • Ru(O 2 C t Bu) 2 (p-cymene) (251 mg, 0.573 mmol, 1.0 equivalent) synthesized in Step 1 of Example 2 was reacted with (S C ,S C ,R P ,R P )-Tol-TRAP (purity: 98.5 wt%, 500 mg, 0.579 mmol, 1.01 equivalent) according to the procedure described in Example 6. After further workup, 739 mg of the desired Ru(O 2 C t Bu) 2 ((S C ,S C ,R P ,R P )-Tol-trap) was obtained as a dark brown powder. Purity: 91.7 wt% (major impurities were 3.0 wt% toluene and 5.3 wt% p-cymene), and the isolated yield was quantitative.
  • Ru(O 2 CAd) 2 (p-cymene) (purity: 98.5 wt %, 346 mg, 0.573 mmol, 1.0 equivalent) synthesized in Step 1 of Example 4 was reacted with (S C ,S C ,R P ,R P )-Tol-TRAP (purity: 98.5 wt %, 500 mg, 0.579 mmol, 1.01 equivalent) according to the procedure described in Example 6.
  • 842 mg of the target Ru(O 2 CAd) 2 ((S C ,S C ,R P ,R P )-Tol-trap) was obtained as a dark brown powder. Purity: 91.4 wt % (the main impurities were 3.9 wt % toluene and 4.7 wt % p-cymene), and the isolated yield was quantitative.
  • Example 9 Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole using Ru(O 2 CMe) 2 ((S C ,S C ,R P ,R P )-Ph-trap) as a catalyst (Formula 26)
  • This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated isopropyl alcohol (i PrOH; 12 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60°C for 6 hours.
  • dehydrated isopropyl alcohol i PrOH; 12 mL
  • Example 10 Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole catalyzed by Ru(O 2 C t Bu) 2 (( SC , SC , RP , RP )-Ph-trap)
  • Example 11 Asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole catalyzed by Ru(O 2 CAd) 2 (( SC , SC , RP , RP )-Ph-trap)
  • Example 12 Low-pressure asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole catalyzed by Ru(O 2 C t Bu) 2 (( SC , SC , RP , RP )-Ph-trap)
  • Example 13 Low-pressure asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole catalyzed by Ru(O 2 CAd) 2 (( SC , SC , RP , RP )-Ph-trap)
  • Table 1 summarizes the results of Comparative Examples 1 and 2 and Examples 9 to 13.
  • Formula 27 shows the three-dimensional structural formulas of the various catalysts used in these Comparative Examples and Examples.
  • Example 14 Low-pressure asymmetric hydrogenation of N-Boc-2-phenyl-1H-indole catalyzed by Ru(O 2 CAd) 2 ((R C ,R C ,S P ,S P )-Ph-trap) (Scheme 28)
  • Example 15 Asymmetric hydrogenation of methyl N-Boc-1H-indole-2-carboxylate using Ru(O 2 CMe) 2 ((S C ,S C ,R P ,R P )-Ph-trap) as a catalyst (Formula 29)
  • This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated iPrOH (14 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60°C for 2 hours.
  • Example 15 and Comparative Example 3 by using a preferred form of the ruthenium complex (1) of the present invention in place of conventional catalysts, highly stereoselective asymmetric hydrogenation proceeded even for indoles containing functional groups that are easily decomposed under strongly basic conditions, resulting in quantitative production of industrially useful optically active cyclic amino acids.
  • Example 16 Asymmetric hydrogenation of N-Boc-3-methyl-1H-indole using Ru(O 2 CAd) 2 (( SC , SC , RP , RP )-Ph-trap) as a catalyst (Equation 30)
  • N-Boc-3-methyl-1H-indole (purity: 99.6 wt%, 500 mg, 2.15 mmol, 1.0 equivalent), synthesized according to the method described in Non-Patent Document 8, and Ru(O 2 CAd) 2 (( SC , SC, RP , RP )-Ph-trap) (purity: 98.1 wt%, 5.5 mg, 0.2 mol%), prepared in Example 4, were sequentially charged into a borosilicate glass test tube ( ⁇ 20 mm ⁇ 130 mm) , and a magnetic stirrer bar was attached.
  • This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated iPrOH (5 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60°C for 6 hours.
  • Example 17 Asymmetric hydrogenation of N-Boc-3-phenyl-1H-indole using Ru(O 2 CAd) 2 (( SC , SC , RP , RP )-Ph-trap) as a catalyst (Formula 31)
  • Example 18 Asymmetric hydrogenation of 2,4-diphenyloxazole using Ru(O 2 CAd) 2 (( SC , SC , RP , RP )-Ph-trap) as a catalyst (Equation 32)
  • Example 20 Asymmetric hydrogenation of 1-Boc-4-methyl-2-phenylimidazole using Ru(O 2 CAd) 2 (( SC , SC , RP , RP )-Ph-trap) as a catalyst (Formula 34)
  • Example 21 Asymmetric hydrogenation of diisobutyl naphthalene-2,6-dicarboxylate using Ru(O 2 CAd) 2 (( SC , SC , RP , RP )-Ph-trap) as a catalyst (Equation 35)
  • This test tube was attached to a 50 mL autoclave, and the inside atmosphere was replaced with nitrogen, after which dehydrated iPrOH (4.5 mL) was added. Next, the inside of the autoclave was pressurized to 5 MPa with hydrogen gas, and the contents of the test tube were stirred at 60°C for 6 hours.
  • Table 2 summarizes the results for Examples 16-21 and Comparative Examples 4-9 for each substrate.
  • Formula 36 shows the three-dimensional structural formula of the catalyst used in these Examples and Comparative Examples.
  • the ruthenium complex (1) of the present invention can be easily produced by reacting R P -TRAP (2) with a ruthenium source (3).
  • the preferred form of the ruthenium complex (1) has excellent crystallinity, allowing for easy isolation and purification and long-term storage. Furthermore, it exhibits excellent catalytic activity, asymmetric induction ability, and substrate generality without the addition of a base, and therefore can contribute to the improvement of efficiency and practical application of various organic synthesis reactions, including aromatic asymmetric hydrogenation, which is useful for producing optically active cyclic compounds.

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Abstract

La présente invention concerne un nouveau complexe de ruthénium utile en tant que catalyseur dans diverses réactions de synthèse organique, comprenant une hydrogénation asymétrique aromatique, et son procédé efficace de production. À savoir, la présente invention concerne un complexe de ruthénium-diphosphine-carboxylate représenté par la formule générale (1). La présente invention concerne en outre un procédé de production d'un complexe de ruthénium-diphosphine-carboxylate représenté par la formule générale (1), le procédé comprenant la réaction d'un composé diphosphine représenté par la formule générale (2) avec un complexe de ruthénium-alkylbenzène-carboxylate représenté par la formule générale (3).
PCT/JP2025/002530 2024-01-29 2025-01-28 Complexe de ruthénium-diphosphine-carboxylate et son procédé de production Pending WO2025164594A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04283596A (ja) * 1991-03-12 1992-10-08 Sumitomo Chem Co Ltd 光学活性ビフェロセン誘導体、その中間体及びそれらの製造方法
JP2011510097A (ja) * 2008-01-17 2011-03-31 ノバルティス アーゲー 新規な方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04283596A (ja) * 1991-03-12 1992-10-08 Sumitomo Chem Co Ltd 光学活性ビフェロセン誘導体、その中間体及びそれらの製造方法
JP2011510097A (ja) * 2008-01-17 2011-03-31 ノバルティス アーゲー 新規な方法

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JIN YUSHU, MAKIDA YUSUKE, UCHIDA TATSUYA, KUWANO RYOICHI: "Ruthenium-Catalyzed Chemo- and Enantioselective Hydrogenation of Isoquinoline Carbocycles", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, UNITED STATES, vol. 83, no. 7, 6 April 2018 (2018-04-06), United States, pages 3829 - 3839, XP093341843, ISSN: 0022-3263, DOI: 10.1021/acs.joc.8b00190 *
KUWANO RYOICHI, KAMEYAMA NAO, IKEDA RYUHEI: "Catalytic Asymmetric Hydrogenation of N-Boc-Imidazoles and Oxazoles", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, ACS PUBLICATIONS, vol. 133, no. 19, 18 May 2011 (2011-05-18), pages 7312 - 7315, XP093341844, ISSN: 0002-7863, DOI: 10.1021/ja201543h *
SAWAMURA MASAYA, ITOSHI HAMASHIMA , SUGAWARA MASANOBU, KUWANO RYOICHI, ITO YOSHIHIKO: "Synthesis and Structures of Trans-Chelating Chiral Diphosphine Ligands Bearing Aromatic P-Substituents, (S,S)-(RJl)-and (RtR)-(S,S)-2,2"-Bis [ 1 -(diarylphosphino) ethyl] -1,1 "-biferrocenes (ArylTRAPs), and Their Transition Metal Complexes", ORGANOMETALLICS, vol. 14, 1 January 1995 (1995-01-01), pages 4549 - 4558, XP093216900 *
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