A method for preparing axially chiral bisphosphine monooxygen ligand

Abstract

The present invention discloses a method for preparing an axially chiral bisphosphine monooxygen ligand. The method of the present invention selectively reduces a compound of formula (I) (bisphosphine oxide substrate) under the action of a catalyst of formula (II), or a combination of a compound of formula (IV) and a compound of formula (V), to produce a product of formula (III) (bisphosphine monooxygen compound) in a single step. The method of the present invention has a wide range of substrate applicability and can efficiently prepare bisphosphine monooxygen compounds under mild conditions.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing an axially chiral bisphosphine monooxygen ligand. Background Art

[0002] Various phosphine ligands play a crucial role in metal-catalyzed catalytic reactions. Axially chiral bisphosphine ligands, due to their unique axial chiral structure, have become the most widely used "advantage ligand" in metal-catalyzed asymmetric synthesis. The oxidation of a trivalent phosphine in a bisphosphine ligand can produce a novel class of bisphosphine monooxide ligands. These ligands contain two types of coordination atoms with significantly different properties: a relatively "soft" phosphine coordination site and a "hard" phosphine oxide coordination site. As mixed ligands, they can form stable complexes with many metals with different properties. The most commonly used in organometallic catalysis are Group VIII, IB, and IB metals. Compared with bisphosphine ligands, bisphosphine monooxide ligands have relatively poor binding ability with these metals, and the phosphine oxide coordination site is easily dissociated, thereby vacating new coordination sites. This makes bisphosphine monooxide ligands exhibit better reactivity than bisphosphine ligands in many reactions. Related art also publicly reports that bisphosphine monooxygen ligands give higher yields and better enantioselectivity than bisphosphine ligands in asymmetric Heck reactions.

[0003] Although bisphosphine monooxygen ligands have good reactivity, their application is not widespread. This is mainly due to the lack of effective synthesis methods. The traditional method for synthesizing axially chiral bisphosphine monooxygen compounds is complicated and often requires 4-6 chemical reactions, resulting in very low yields. Taking the synthesis of (R)-(2′-(Diphenylphosphanyl)-5,5′,6,6′,7,7′,8,8′-octahydro-[1,1′-binaphthalen]-2-yl)diphenylphosphine oxide ((R)-H8-BINAP(O)) as an example, the synthesis method in the literature (Batuecas M, Luo J, Gergelitsova I, et al. Catalytic Asymmetric C-HArylation of (η6-Arene)Chromium Complexes: Facile Access to Planar-ChiralPhosphines[J]. Acs Catalysis, 2019.) requires 4 steps and the total yield is only 34.5%. It can be seen that the use of this type of method has a long reaction time, consumes a large amount of additives, has a low yield, and has low synthesis efficiency.

[0004] A catalytic synthesis method based on the selective monooxidation of bisphosphine compounds is disclosed in the literature (Grushin V V. Catalysis for Catalysis: Synthesis of Mixed Phosphine-Phosphine Oxide Ligands via Highly Selective, Pd-Catalyzed Monooxidation of Bidentate Phosphines [J]. Journal of the American Chemical Society, 1999.). However, the reaction relies on precious metal palladium catalysis, consumes a large amount of additives, and has complicated steps. Summary of the Invention

[0005] The present invention aims to at least partially address one of the technical problems in the related art. To this end, one object of the present invention is to provide a method for preparing an axially chiral bisphosphine monooxygen ligand. Another object of the present invention is to provide a novel axially chiral bisphosphine monooxygen ligand.

[0006] The method for preparing an axially chiral bisphosphine monooxygen ligand provided in an embodiment of the present invention comprises the following steps: reacting a compound of formula (I) and a reducing agent in the presence of a catalyst of formula (II) to generate a product of formula (III);

[0007]

[0008] In formula (I) and formula (III), ring A is a benzene ring, a naphthalene ring or a pyridine ring; R 1 、R 2 Choose from the following three:

[0009] (a)R 1 、R 2 Each is independently one of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl;

[0010] (b) R on the same ring A 1 、R 2 Combined together to form -OR 3 -O- group, where R 3 is C1-C6 alkylene or halogenated alkylene;

[0011] (c)R 1is one of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl; R on the two rings A 2 Combined together to form -OR 3 -O- group, where R 3 is C1-C6 alkylene or halogenated alkylene;

[0012] Ar is substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted phenyl, furyl, thienyl;

[0013] In formula (II), n is 0, 1, 2 or 3, represents a single bond or a double bond;

[0014] R 4 、R 5 、R 6 Each is independently one of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl; Y is one of halogen, trifluoromethanesulfonate anion, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 arylsulfonate anion, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted tetraarylborate anion.

[0015] The method of the embodiment of the present invention selectively reduces the compound of formula (I) (bisphosphine oxide substrate) under the action of the catalyst of formula (II) to synthesize the product of formula (III) (bisphosphine monooxygen compound) in one step. The method of the embodiment of the present invention can efficiently prepare bisphosphine monooxygen compounds under mild conditions.

[0016] In some embodiments, in formula (II), n is 0, 1 or 2, R 4 、R 5 、R 6 Each is independently hydrogen, C1-C3 alkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl, and Y is halogen, or substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl sulfonate anion.

[0017] Furthermore, in formula (II), n is 0 or 1, R 4 is one of methyl, ethyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted phenyl, R 5 、R6 Each is independently a hydrogen atom, a methyl group or a phenyl group, and Y is a halogen.

[0018] In some embodiments, the molar ratio of the compound of formula (I), the reducing agent, and the catalyst of formula (II) is: 1: (1-1.5): (0.1-0.2).

[0019] In some embodiments, the catalyst of formula (II) is replaced by a combination of a compound of formula (IV) and a compound of formula (V);

[0020]

[0021] In formula (IV), n is 0, 1, 2 or 3, Represents a single bond or a double bond; R 4 、R 5 、R 6 Each is independently one of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl;

[0022] The compound of formula (V) is one of formula (V-1), formula (V-2), formula (V-3), formula (V-4), formula (V-5), formula (V-6), formula (V-7), and formula (V-8);

[0023]

[0024] In formula (V-1), R 7 is hydrogen or C1-C3 alkyl, R 8 It is one of methyl, ethyl and benzyl.

[0025] In some embodiments, in formula (IV), n is 0, 1 or 2, R 4 、R 5 、R 6 Each is independently one of hydrogen, C1-C3 alkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl.

[0026] Furthermore, in formula (IV), n is 0 or 1, R 4 is one of methyl, ethyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted phenyl, R 5 、R 6 Each is independently a hydrogen atom, a methyl group or a phenyl group.

[0027] In some embodiments, the molar ratio of the compound of formula (IV) to the compound of formula (V) is 1:(0.2-1.5); the preferred molar ratio is 1:(0.5-1).

[0028] In some embodiments, the reducing agent has a structural formula as shown in Formula (VI):

[0029]

[0030] In formula (VI), R 9 、R 10 、R 11 Each is independently one of hydrogen, C1-C6 alkoxy, C1-C6 alkyl or phenyl.

[0031] In some embodiments, the reducing agent is phenylsilane.

[0032] In some embodiments, the molar ratio of the compound of formula (I), the reducing agent, the compound of formula (IV), and the compound of formula (V) is: 1: (1-1.5): (0.05-0.15): (0.05-0.15).

[0033] In some embodiments, the reaction is carried out under nitrogen or argon conditions.

[0034] In some embodiments, the reaction temperature is room temperature, and the reaction time is 8 to 24 hours.

[0035] The embodiments of the present invention also provide a novel axially chiral bisphosphine monooxygen ligand, the structural formula of which is shown in any one of Formula (III-1) to Formula (III-11) or an enantiomer thereof.

[0036]

[0037] The advantages and beneficial effects of the present invention are:

[0038] (1) The embodiment of the present invention provides a one-step catalytic synthesis method for bisphosphine monooxygen compounds, which can be used to synthesize optically pure bisphosphine monooxygen compounds.

[0039] (2) The substrates used in the present invention are all commercially available compounds, which have extremely high step economy.

[0040] (3) The present invention has mild conditions, wide substrate applicability, fast reaction speed, and can achieve efficient preparation at room temperature.

[0041] (4) The catalyst used in the present invention has a simple structure, is stable to air, and is easy to operate. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1This is the synthetic route of (R)-H8-BINAP(O) in relevant literature.

[0043] Figure 2 Schematic diagram of the reaction principle of the present invention. DETAILED DESCRIPTION

[0044] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and intended to be used to explain the present invention, but should not be understood as limiting the present invention.

[0045] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0046] Unless otherwise specified, the materials, reagents, and devices used in the following examples can be obtained from commercial sources or prepared according to methods in the literature.

[0047] The following is a description of terms or words, and unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0048] As used herein, the words "comprise," "include," and "includes" and variations thereof mean that additional elements or integers may be included although permitted but not specifically described.

[0049] Unless otherwise indicated, the term "alkyl" as used herein refers to a straight or branched saturated aliphatic hydrocarbon group. For example, the term "C1-C6 alkyl" refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 6 carbon atoms; in one embodiment, containing 1 to 4 carbon atoms; in another embodiment, containing 1 to 3 carbon atoms; non-limiting examples of "C1-C6 alkyl" include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, etc.

[0050] As used herein, unless otherwise indicated, the term "alkoxy" refers to an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom, i.e., -O-alkyl. The term "C1-C6 alkoxy" refers to a C1-C6 alkyl group attached to the remainder of the molecule through an oxygen atom, wherein "C1-C6 alkyl" has the meaning as defined herein. Non-limiting examples of "C1-C6 alkoxy" include methoxy, ethoxy, 1-propoxy, 2-propoxy, tert-butoxy, and the like.

[0051] As used herein, unless otherwise indicated, the term "cycloalkyl" refers to a cyclic, saturated aliphatic hydrocarbon group. For example, the term "C3-C6 cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic or bicyclic ring system containing 3-6 carbon atoms. Non-limiting examples of "C3-C6 cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0052] Unless otherwise indicated, the term "aryl" as used herein refers to a monocyclic or fused-ring aromatic hydrocarbon group having a conjugated π-electron system. For example, the term "C6-C12 aryl" as used herein refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-12 ring atoms, wherein at least one ring system is aromatic. Non-limiting examples of "C6-C12 aryl" include phenyl, indenyl, naphthyl, and the like.

[0053] As used herein, unless otherwise indicated, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0054] Unless otherwise specified, the term "each independently" as used herein means that at least two groups (or fragments) with the same or similar value ranges in a structure may have the same or different meanings under specific circumstances. For example, R 4 、R 5 , are each independently one of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl; when R 4 When it is hydrogen, R 5 It can be hydrogen, methyl, ethyl, phenyl, etc. Similarly, when R 5 When it is hydrogen, R 4 It may be hydrogen, or may be methyl, ethyl, phenyl, or the like.

[0055] Unless otherwise indicated, the term "substituted" and its variants as used herein refer to the replacement of one or more (such as 1, 2, 3 or 4) atoms or groups of atoms (such as hydrogen atoms) on the designated atom by other specific substituents, provided that the normal valence of the designated atom or group of atoms in the current situation is not exceeded and a stable compound can be formed. Unless otherwise indicated, a substituent group can be substituted at each substitutable position of a given structure. When more than one position in a given structure can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at each position in the same or different manner.

[0056] Unless otherwise specified, the terms "normal temperature" and "room temperature" used herein generally refer to 25±5°C.

[0057] The abbreviations used in this document have the following meanings:

[0058] Ph: phenyl;

[0059] Me: methyl;

[0060] Et: ethyl.

[0061] Tol: 4-methylphenyl;

[0062] xyl: 3,5-dimethylphenyl.

[0063] The method for preparing an axially chiral bisphosphine monooxygen ligand provided in an embodiment of the present invention comprises the following steps: reacting a compound of formula (I) and a reducing agent in the presence of a catalyst of formula (II) to generate a product of formula (III);

[0064]

[0065] In formula (I) and formula (III), ring A is a benzene ring, a naphthalene ring or a pyridine ring; R 1 、R 2 Choose from the following three:

[0066] (a)R 1 、R 2 Each is independently one of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl;

[0067] (b) R on the same ring A 1 、R 2 Combined together to form -OR 3 -O- group, where R 3 is C1-C6 alkylene or halogenated alkylene;

[0068] (c)R 1 is one of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl; R on the two rings A 2 Combined together to form -OR 3 -O- group, where R 3 is C1-C6 alkylene or halogenated alkylene;

[0069] Ar is substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted phenyl, furyl, thienyl;

[0070] In formula (II), n is 0, 1, 2 or 3, represents a single bond or a double bond;

[0071] R 4 、R 5 、R6 Each is independently one of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl; Y is one of halogen, trifluoromethanesulfonate anion, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 arylsulfonate anion, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted tetraarylborate anion.

[0072] The method of the embodiment of the present invention selectively reduces the compound of formula (I) (bisphosphine oxide substrate) under the action of the catalyst of formula (II) to synthesize the product of formula (III) (bisphosphine monooxygen compound) in one step. The method of the embodiment of the present invention can efficiently prepare bisphosphine monooxygen compounds under mild conditions.

[0073] In some embodiments, in formula (II), n is 0, 1 or 2, R 4 、R 5 、R 6 Each is independently hydrogen, C1-C3 alkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl, and Y is halogen, or substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl sulfonate anion.

[0074] Furthermore, in formula (II), n is 0 or 1, R 4 is one of methyl, ethyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted phenyl, R 5 、R 6 Each is independently a hydrogen atom, a methyl group or a phenyl group, and Y is a halogen.

[0075] In some embodiments, the molar ratio of the compound of formula (I), the reducing agent, and the catalyst of formula (II) is 1:(1-1.5):(0.1-0.2). For example, when the compound of formula (I) is 1 mol, the reducing agent can be 1 mol, 1.1 mol, 1.2 mol, 1.3 mol, 1.5 mol, etc., and the catalyst of formula (II) can be 0.1 mol, 0.12 mol, 0.15 mol, 0.18 mol, 0.2 mol, etc.

[0076] For example, the compound of formula (I) may be one of the structures shown in Table 1, and may be used to generate the compound of formula (III) according to the methods of the embodiments of the present invention. It is understood that both isomers (R and S) of the compound of formula (I) may be used in accordance with the methods of the embodiments of the present invention, and their chirality may be maintained during the reaction.

[0077] Table 1

[0078]

[0079]

[0080]

[0081] For example, the catalyst of formula (II) can be one of formula (II-1) to formula (II-6):

[0082]

[0083] In some embodiments, the catalyst of formula (II) is replaced by a combination of a compound of formula (IV) and a compound of formula (V);

[0084]

[0085] In formula (IV), n is 0, 1, 2 or 3, Represents a single bond or a double bond; R 4 、R 5 、R 6 Each is independently one of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl;

[0086] The compound of formula (V) is one of formula (V-1), formula (V-2), formula (V-3), formula (V-4), formula (V-5), formula (V-6), formula (V-7), and formula (V-8);

[0087]

[0088] In formula (V-1), R 7 is hydrogen or C1-C3 alkyl, R 8 It is one of methyl, ethyl and benzyl.

[0089] In some embodiments, in formula (IV), n is 0, 1 or 2, R 4 、R 5 、R 6Each is independently one of hydrogen, C1-C3 alkyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted C6-C12 aryl.

[0090] Furthermore, in formula (IV), n is 0 or 1, R 4 is one of methyl, ethyl, substituted (C1-C6 alkyl, C1-C6 alkoxy, halogen or cyano) or unsubstituted phenyl, R 5 、R 6 Each is independently a hydrogen atom, a methyl group or a phenyl group.

[0091] In some embodiments, the molar ratio of the compound of formula (IV) to the compound of formula (V) is 1:(0.2-1.5); the preferred molar ratio is 1:(0.5-1), and non-limiting examples include: the molar ratio can be 1:0.2, 1:0.5, 1:0.8, 1:1, 1:1.5, etc.

[0092] For example, the compound of formula (IV) may be one of formula (IV-1) to formula (IV-5):

[0093]

[0094] In some embodiments, the reducing agent has a structural formula as shown in Formula (VI):

[0095]

[0096] In formula (VI), R 9 、R 10 、R 11 Each is independently one of hydrogen, C1-C6 alkoxy, C1-C6 alkyl or phenyl.

[0097] Non-limiting examples include: the reducing agent can be: PhSiH3, Ph2SiH2, Ph3SiH, (EtO)3SiH, (EtO)2SiMeH, (Me2SiH)2O. Preferably, the reducing agent is phenylsilane.

[0098] In some embodiments, the molar ratio of the compound of formula (I), the reducing agent, the compound of formula (IV), and the compound of formula (V) is: 1: (1-1.5): (0.05-0.15): (0.05-0.15). For example, when the compound of formula (I) is 1 mol, the reducing agent can be 1 mol, 1.1 mol, 1.2 mol, 1.3 mol, 1.5 mol, etc., the compound of formula (IV) can be 0.05 mol, 0.08 mol, 0.10 mol, 0.12 mol, 0.15 mol, etc., and the compound of formula (V) can be 0.05 mol, 0.08 mol, 0.10 mol, 0.12 mol, 0.15 mol, etc.

[0099] In some embodiments, the reaction is carried out under nitrogen or argon conditions.

[0100] In some embodiments, the reaction temperature is room temperature, and the reaction time is 8 to 24 hours. For example, the reaction time can be 8 hours, 12 hours, 15 hours, 18 hours, 24 hours, etc.

[0101] Taking BINAPO2 ([1,1'-binaphthyl]-2,2'-diylbis[1,1-diphenylphosphine oxide]) as the substrate, phenylsilane as the reducing agent, and the compound of formula (II-1) as the catalyst, Figure 2 The reaction principle of the present invention is illustrated. Catalyst II-1 and a substrate, a bisphosphine oxide (BINAPO2, for example), form an active complex, which is then converted into phosphine oxides IV-1 and VII. IV-1 is reduced to a trivalent phosphine by phenylsilane, which further reacts with VII to regenerate II-1 and produce the bisphosphine monooxide product, BINAP(O).

[0102] The synthesis of the substrate in the embodiment of the present invention can be carried out according to known literature, and the synthesis steps can refer to literature (1) to literature (9) and the like.

[0103] (1)Xu, Q.; Zhang, H.; Ge, F.-B.; Wang, X.-M.; Zhang, P.; Lu, C.-J.; Liu, R.-R. Atropismers.Org.Let.2022,24,3138-3143.

[0104] (2)Ma,B.;Miao,T.;Sun,Y.;He,Y.;Liu,J.;Feng,Y.;Chen,H.;Fan,Q.-H.A NewClass of Tunable Dendritic Diphosphine Ligands:Synthesis and Applications inthe Ru-Catalyzed Asymmetric Hydrogenation of FunctionalizedKetones.Chem.Eur.J.2014,20,9969-9978.

[0105] (3)Hu,A.;Ngo,H.L.;Lin,W.Remarkable 4,4′-Substituent Effects on Binap:Highly Enantioselective Ru Catalysts for Asymmetric Hydrogenation ofβ-ArylKetoesters and Their Immobilization in Room-Temperature IonicLiquids.Angew.Chem.Int.Ed.2004,43,2501-2504.

[0106] (4)Alame,M.;Jahjah,M.;Berthod,M.;Lemaire,M.;Meille,V.;de Bellefon,C.New 5,5′-disubstituted BINAP derivatives:Syntheses and pressure andelectronic effects in Rh asymmetric hydrogenation.J.Mol.Catal.A:Chem.2007,268,205-212.

[0107] (5)Zuo,Z.;Kim,R.S.;Watson,D.A.Synthesis of Axially Chiral 2,2′-Bisphosphobiarenes via aNickel-Catalyzed Asymmetric Ullmann Coupling:GeneralAccess to Privileged Chiral Ligands without OpticalResolution.J.Am.Chem.Soc.2021,143,1328-1333.

[0108] (6)Jeulin,S.;Duprat de Paule,S.;Ratovelomanana-Vidal,V.; J.-P.;Champion,N.;Dellis,P.Difluorphos,an Electron-Poor Diphosphane:A Good MatchBetween Electronic and Steric Features.Angew.Chem.Int.Ed.2004,43,320-325.

[0109] (7)Pai,C.-C.;Lin,C.-W.;Lin,C.-C.;Chen,C.-C.;Chan,A.S.C.;Wong,W.T.Highly Effective Chiral Dipyridylphosphine Ligands:Synthesis,StructuralDetermination,and Applications in the Ru-Catalyzed Asymmetric HydrogenationReactions.J.Am.Chem.Soc.2000,122,11513-11514.

[0110] (8)Zhang,P.;Han,Z.;Wang,Z.;Ding,K.Spiro[4,4]-1,6-Nonadiene-BasedDiphosphine Oxides in Lewis Base Catalyzed Asymmetric Double-Aldol Reactions.Angew.Chem.Int.Ed.2013,52,11054-11058.

[0111] (9) Liu, X.; Ma, Y.; Liu, Q.; Wei,

[0112] For example, the substrate is prepared by the following method:

[0113] Bisphosphine (Bidentate phosphines) (0.5mmol, 1.0 equivalent) and 10mL DCM are added in the 50mL flask.After being cooled to 0 ℃, dropwise add H o (30% weight H o, 2.5mmol, 5.0 equivalent).Solvent was stirred 30 minutes at 0 ℃, then heated to room temperature.After stirring for 2 hours, use the 20mL DCM diluting solvent.Use 2x10mL H o and 2x10mL saturated Na sO the aqueous solution washing organic phase.Use MgSO dry organic phase and vaporising under reduced pressure to obtain pure product.

[0114]

[0115] In an embodiment of the present invention, the catalyst of formula (II) can be synthesized with reference to known literature (J.Org.Chem.2022,87,22,15539–15546 or J.Am.Chem.Soc.2019,141,12507).

[0116] Taking formula (II-1) as an example, the preparation method includes the following steps:

[0117] 384 mg of 3-methyl-1-phenyl-2-phosphorus-1-oxide was added to a 100 mL Schlenk flask. An oil bubbler was assembled on the Schlenk flask, and the tail gas was absorbed with an alkaline aqueous solution. This auxiliary device is used to relieve pressure to prevent the system from being over-pressurized and causing danger. The atmosphere in the system was replaced with argon, and 10 mL of dichloroethane solution was added to dissolve. Argon was continued to be introduced into the system to keep the pressure in the system slightly higher than atmospheric pressure. 356 μL of oxalyl bromide was slowly added dropwise through a syringe. After the addition was complete, the reaction was continued for 5 minutes. The solvent was removed by decompression to obtain a yellow oily liquid crude product. The crude product was transferred to a glove box. Washed with a 1:1 mixture of dichloromethane and n-pentane solvent to obtain 603 mg of a light yellow solid with a yield of 90%. 1H NMR (400MHz, CDCl3) δ8.30(ddd,J=16.7,7.1,1.8Hz,2H),7.90-7.67(m,3H),6.45(d,J=33.4Hz,1H),3.89(s,2H),3.63(d,J=16.5Hz,2H),2.48(s,3H). 31 P{1H}NMR (162MHz,CDCl3)δ79.7.

[0118] Example 1:

[0119] Prepared according to the following formula:

[0120]

[0121] Under argon, 0.2 mmol of (R)-[1,1'-binaphthyl]-2,2'-diylbis(diphenylphosphine oxide), 0.03 mmol of 3-methyl-1-phenyl-2-phosphine-1-oxide (Formula IV-1), and 0.02 mmol of carbon tetrabromide were dissolved in 2.0 mL of dichloroethane. 0.24 mmol of phenylsilane was then added, and the mixture was stirred at room temperature for 12 hours. The reaction was stopped, and the pure product with a single configuration was isolated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1). The yield was 95%. 1 H NMR (400MHz, CDCl3) δ7.92(dd,J=8.6,2.4Hz,1H),7.82(d,J=8.1Hz,1H),7.74(d,J=8.5Hz,1 H),7.70(d,J=8.2Hz,1H),7.64–7.55(m,3H),7.41(dd,J=8.5,2.9Hz,1H),7.39–7.29(m,6H), 7.28–7.19(m,7H),7.14(t,J=7.3Hz,1H),7.09(td,J=7.7,2.9Hz,2H),7.06–7.00(m,2H),6.9 5(t,J=7.9Hz,2H),6.91–6.85(m,1H),6.83(s,1H),6.77–6.69(m,1H),6.64(d,J=8.6Hz,1H). 31 P NMR(162MHz, CDCl3)δ27.21,-15.26.[α] D 25 :+108.1(c=1.0,CHCl3).

[0122] Example 2:

[0123] Prepared according to the following formula:

[0124]

[0125] Under argon, 0.2 mmol of (R)-[1,1'-binaphthyl]-2,2'-diylbis(diphenylphosphine oxide), 0.03 mmol of 3-methyl-1-phenyl-2-phosphine-1-oxide (Formula IV-1), and 0.02 mmol of N-bromosuccinimide were dissolved in 2.0 mL of dichloroethane. 0.24 mmol of phenylsilane was then added, and the mixture was stirred at room temperature for 12 hours. The reaction was stopped, and the pure product with a single configuration was isolated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1). The yield was 57%.

[0126] Example 3:

[0127]

[0128] Under argon, 0.2 mmol of (R)-[1,1'-binaphthyl]-2,2'-diylbis(diphenylphosphine oxide) and 0.03 mmol of 1-bromo-4-methyl-1-phenyl-2,3-dihydro-1H-phosphinium bromide (Formula II-1) were dissolved in 2.0 mL of dichloroethane. 0.24 mmol of phenylsilane was then added, and the mixture was stirred at room temperature for 12 hours. The reaction was stopped, and the pure product was isolated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain the product. The yield was 99%.

[0129] Example 4:

[0130]

[0131] Under argon, 0.2 mmol of (R)-[1,1'-binaphthyl]-2,2'-diylbis(di-p-methylphenylphosphine oxide) and 0.03 mmol of catalyst II-1 were dissolved in 2.0 mL of dichloroethane. 0.24 mmol of phenylsilane was added and stirred at room temperature for 12 hours. The reaction was stopped and the pure product was isolated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1). The yield was 99%. 1H NMR (400MHz, CDCl3) δ7.95 (dd, J=8.6, 2.3Hz, 1H), 7.85 (d, J=8.2Hz, 1H), 7.71 ( ddd,J=11.2,8.6,2.8Hz,3H),7.49–7.40(m,3H),7.38–7.26(m,4H),7.19(t,J=7 .3Hz,2H),7.07–6.95(m,5H),6.95–6.81(m,7H),6.77(ddd,J=8.3,6.8,1.3Hz, 1H),6.65(d,J=8.5Hz,1H),2.32(s,3H),2.30(s,3H),2.27(s,3H),2.26(s,3H).

[0132] 31 P NMR (162MHz, CDCl3) δ27.56,-16.99.

[0133] Example 5

[0134] The products in Table 2 were prepared using the same method as in Example 4 and the corresponding substrates.

[0135] Table 2

[0136]

[0137]

[0138] Example 6

[0139] The products in Table 3 were prepared using the same method as in Example 4 and the corresponding substrates.

[0140] Table 3

[0141]

[0142] Example 7

[0143] The products in Table 4 were prepared using the same method as in Example 4 and the corresponding substrates.

[0144] Table 4

[0145]

[0146] Example 8

[0147] The products in Table 5 were prepared using the same method as in Example 4 and the corresponding substrates.

[0148] Table 5

[0149]

[0150] Example 9

[0151] The products in Table 6 were prepared using the same method as in Example 4 and the corresponding substrates.

[0152] Table 6

[0153]

[0154] Example 10

[0155] The products in Table 7 were prepared using the same method as in Example 4 and the corresponding substrates.

[0156] Table 7

[0157]

[0158]

[0159] Example 11

[0160] The products in Table 8 were prepared using the same method as in Example 4 and the corresponding substrates.

[0161] Table 8

[0162]

[0163] Example 12

[0164] The products in Table 9 were prepared using the same method as in Example 4 and the corresponding substrates.

[0165] Table 9

[0166]

[0167]

[0168] Example 13

[0169] The products in Table 10 were prepared using the same method as in Example 4 and the corresponding substrates.

[0170] Table 10

[0171]

[0172] Example 14

[0173] The products in Table 11 were prepared using the same method as in Example 4 and the corresponding substrates.

[0174] Table 11

[0175]

[0176]

[0177] Example 15

[0178] The products in Table 12 were prepared using the same method as in Example 4 and the corresponding substrates.

[0179] Table 12

[0180]

[0181] Example 16

[0182] The products in Table 13 were prepared using the same method as in Example 4 and the corresponding substrates.

[0183] Table 13

[0184]

[0185]

[0186] Example 17

[0187] The products in Table 14 were prepared using the same method as in Example 4 and the corresponding substrates.

[0188] Table 14

[0189]

[0190] Example 18

[0191] The products in Table 15 were prepared using the same method as in Example 4 and the corresponding substrates.

[0192] Table 15

[0193]

[0194]

[0195] Example 19

[0196] The products in Table 16 were prepared using the same method as in Example 4 and the corresponding substrates.

[0197] Table 16

[0198]

[0199] Example 20

[0200]

[0201] 0.2 mmol (R)-SYNPHOS was dissolved in 10 mL of dichloromethane, and 0.5 mmol of aqueous hydrogen peroxide was slowly added. The reaction was allowed to react for 30 min. The reaction was stopped and washed once with 5 mL of water and once with 5 mL of saturated sodium sulfite solution. Drying and removal of the solvent under vacuum gave a white solid with a crude yield of 100%. The crude product was directly used in the next reaction without further purification. Under Ar conditions, the above-obtained product and 0.02 mmol of catalyst II-1 were dissolved in 2 mL of dichloroethane, 0.24 mmol of phenylsilane was added, and the reaction was allowed to react for 12 h. The product was isolated by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) with a yield of 83%.

[0202] Comparative Example 1

[0203] References: J.Am.Chem.Soc.2020,142,2161

[0204]

[0205] Under Ar protection, 0.2mmol (R)-SYNPHOS, 0.02mmol PdI2, 1.0mmol 1,2-dibromoethane and dissolved in 1.5mL degassed dichloromethane. Then add 2mL 10M NaOH aqueous solution, stir vigorously, and react for 48h. Dilute with water and extract with 10mL DCM three times. Dry and concentrate under vacuum. Add 0.04mmol 1,2-bis(diphenylphosphine)ethane to the crude product and stir for 15 minutes to remove the Pd catalyst. The crude product is purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) with a yield of 21%.

[0206] 1 H NMR (400MHz, CDCl3) δ7.66(dd,J=11.9,7.5Hz,2H),7.61–7.15(m,18H),6.91–6.73(m,3H),6.63(dd,J=8.4,3.5Hz,1H),4.05( ddd,J=11.1,7.6,3.9Hz,2H),3.78(tdd,J=23.4,10.0,4.3Hz,4H),3.46(dd,J=11.3,6.5Hz,1H),3.13(dd,J=11.3,7.0Hz,1H).

[0207] 31 P NMR (162MHz, CDCl3) δ28.3,-16.0.

[0208] [α] D 20 :+51.5(c=1.0,CHCl3)

[0209] By comparing Example 20 with Comparative Example 1, it can be seen that, under the same substrate, the method of the present application avoids the use of expensive palladium catalysts and a large amount of additives, and has a short reaction time and high yield.

[0210] In the present invention, the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples without contradiction.

[0211] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A method for preparing an axially chiral bisphosphine monooxygen ligand, characterized in that: The method comprises the following steps: reacting a compound of formula (I) and a reducing agent in the presence of a catalyst of formula (II) to generate a product of formula (III); In formula (I) and formula (III), ring A is a benzene ring, a naphthalene ring or a pyridine ring; R 1 、R 2 Choose from the following three: (a)R 1 、R 2 Each is independently one of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, and substituted or unsubstituted C6-C12 aryl; (b) R on the same ring A 1 、R 2 Combined together to form -OR 3 -O- group, where R 3 is C1-C6 alkylene or halogenated alkylene; (c)R 1 is one of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted C6-C12 aryl; R on the two rings A 2 Combined together to form -OR 3 -O- group, where R 3 is C1-C6 alkylene or halogenated alkylene; Ar is one of substituted or unsubstituted phenyl, furyl, and thienyl; In formula (II), n is 0, 1, 2 or 3, represents a single bond or a double bond; R 4 、R 5 、R 6 Each is independently one of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted C6-C12 aryl; Y is one of halogen, trifluoromethanesulfonate anion, substituted or unsubstituted C6-C12 arylsulfonate anion, substituted or unsubstituted tetraarylborate anion; The structural formula of the reducing agent is shown in formula (VI): In formula (VI), R 9 、R 10 、R 11 Each is independently one of hydrogen, C1-C6 alkoxy, C1-C6 alkyl or phenyl.

2. The method for preparing the axially chiral bisphosphine monooxygen ligand according to claim 1, wherein: In formula (II), n is 0, 1 or 2, R 4 、R 5 、R 6 Each is independently one of hydrogen, C1-C3 alkyl, substituted or unsubstituted C6-C12 aryl, and Y is halogen, or one of substituted or unsubstituted C6-C12 aryl sulfonate anions.

3. The method for preparing the axially chiral bisphosphine monooxygen ligand according to claim 2, wherein: In formula (II), n is 0 or 1, R 4 is one of methyl, ethyl, substituted or unsubstituted phenyl, R 5 、R 6 Each is independently a hydrogen atom, a methyl group or a phenyl group, and Y is a halogen.

4. The method for preparing the axially chiral bisphosphine monooxygen ligand according to claim 1, wherein: The molar ratio of the compound of formula (I), the reducing agent and the catalyst of formula (II) is 1: (1-1.5): (0.1-0.2).

5. The method for preparing the axially chiral bisphosphine monooxygen ligand according to claim 1, wherein: The catalyst of formula (II) is replaced by a combination of a compound of formula (IV) and a compound of formula (V); In formula (IV), n is 0, 1, 2 or 3, Represents a single bond or a double bond; R 4 、R 5 、R 6 Each is independently one of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and substituted or unsubstituted C6-C12 aryl; The compound of formula (V) is one of formula (V-1), formula (V-2), formula (V-3), formula (V-4), formula (V-5), formula (V-6), formula (V-7), and formula (V-8); In formula (V-1), R 7 is hydrogen or C1-C3 alkyl, R 8 It is one of methyl, ethyl and benzyl.

6. The method for preparing the axially chiral bisphosphine monooxygen ligand according to claim 5, characterized in that: In formula (IV), n is 0, 1 or 2, R 4 、R 5 、R 6 Each is independently one of hydrogen, C1-C3 alkyl, and substituted or unsubstituted C6-C12 aryl.

7. The method for preparing the axially chiral bisphosphine monooxygen ligand according to claim 6, characterized in that: In formula (IV), n is 0 or 1, R 4 is one of methyl, ethyl, substituted or unsubstituted phenyl, R 5 、R 6 Each is independently a hydrogen atom, a methyl group or a phenyl group.

8. The method for preparing the axially chiral bisphosphine monooxygen ligand according to claim 5, characterized in that: The molar ratio of the compound of formula (IV) to the compound of formula (V) is 1:(0.2-1.5).

9. The method for preparing the axially chiral bisphosphine monooxygen ligand according to claim 8, characterized in that: The molar ratio of the compound of formula (IV) to the compound of formula (V) is 1:(0.5-1).

10. The method for preparing the axially chiral bisphosphine monooxygen ligand according to claim 5, characterized in that: The molar ratio of the compound of formula (I), the reducing agent, the compound of formula (IV), and the compound of formula (V) is: 1: (1-1.5): (0.05-0.15): (0.05-0.15).

11. The method for preparing the axially chiral bisphosphine monooxygen ligand according to claim 1, characterized in that: The reducing agent is phenylsilane.

12. The method for preparing the axially chiral bisphosphine monooxygen ligand according to any one of claims 1 to 10, characterized in that: The reaction was carried out under nitrogen or argon conditions.

13. The method for preparing the axially chiral bisphosphine monooxygen ligand according to any one of claims 1 to 10, characterized in that: The reaction temperature is room temperature, and the reaction time is 8 to 24 hours.

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