Substituted benzoxphosphine ligand, palladium acetate complex of substituted benzoxphosphine ligand and application of substituted benzoxphosphine ligand in coupling reaction

Abstract

The invention belongs to the technical field of catalysts, and provides a substituted benzoxphosphine ligand and a palladium acetate complex and application thereof. The substituted benzoxphosphine ligand disclosed by the invention is applied to a coupling reaction of palladium-catalyzed aryl halide and has a relatively good reaction result.

Description

Technical Field

[0001] The invention relates to the technical field of catalysts, and in particular to a substituted benzoxazine ligand and a palladium acetate complex thereof and applications in coupling reactions. Background Art

[0002] The formation of CC or CN bonds is very important in various fields of chemical synthesis. Among them, the Suzuki coupling reaction is the construction of C (sp2) -C (sp2) Biaryl ring structures are one of the most important strategies for the synthesis of C-C bonds. Biaryl ring structures can be found in many alkaloids, natural products, drugs and pesticide molecules. In addition, chiral biaryl ring compounds with atropisomerism are also important ligands or catalysts in asymmetric catalytic reactions. Therefore, how to develop efficient catalysts to improve the coupling efficiency of C-C bonds (especially the coupling of C-C bonds with large steric hindrance) is the current focus of synthesis. In the past few decades, along with the development of various ligands, palladium-catalyzed C-C bond coupling has made rapid progress (Chem. Rev. 1995, 95, 2457; Angew. Chem. Int. Ed. 2003, 42, 3690; Angew. Chem. Int. Ed. 2006, 45, 3484; Angew. Chem. Int. Ed. 2010, 49, 5879; J. Org. Chem. 2009, 74, 8191; J. Am. Chem. Soc. 2000, 122, 4020; J. Am. Chem. Soc. 2014, 136, 6534; J. Am. Chem. Soc. 2023, 145, 8308; Acc. Chem. Res. 2019, 52, 1101). Many highly efficient and advantageous phosphine ligands have also been born.

[0003]

[0004] Nevertheless, in most palladium-catalyzed CC bond formation reactions, many phosphine ligands are not well suited for large sterically hindered aromatic CC bond couplings, and are prone to dehalogenation or even difficult to react. On the other hand, the CC bond coupling reaction of sterically hindered aromatic chlorides with lower activity and lower price has not been well solved. In order to improve the activity of palladium catalysts, on the one hand, it is necessary to improve the electrical properties of the coordinating atoms in the phosphine ligand, that is, to improve the ability of the central metal to undergo oxidative addition. On the other hand, a more sterically hindered and rigid skeleton can promote the reduction elimination process of high-valent palladium metal complexes. In addition, the synthesis of new efficient ligands should further consider factors such as simple and easy-to-obtain raw materials, low price, and simple steps. Therefore, the development of stable, efficient, and easy-to-prepare ligands for CC bond coupling reactions of inert, cheap, and sterically hindered alkyl chlorides is still of great research significance. Summary of the invention

[0005] In view of the problems that need to be improved in the prior art, the problem to be solved by the present invention is to provide a benzoxophosphine ligand, whose complex with palladium shows excellent activity in the CC bond coupling reaction of sterically hindered aryl halides and arylboronic acids or CN bonds of aromatic amines.

[0006] In order to achieve the above object, the present invention provides:

[0007] In one aspect, the present invention provides a substituted benzoxazine ligand, the structure of which is shown in formula (I):

[0008] in,

[0009] R 4 is hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, alkylOC(═O)-, alkylC(═O)O-, dialkylphosphino, diarylphosphino, di(3,5-dimethyl-4-methoxyphenyl)phosphino, di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino, dicycloalkylphosphino, dialkoxyphosphino, diaryloxyphosphino, dicycloalkyloxyphosphino, dialkylphosphino(═O)-, diarylphosphino(═O)-, dicycloalkylphosphino(═O)-, dialkoxyphosphino(═O)-, diaryloxyphosphino(═O)-, dicycloalkyloxyphosphino(═O)-, ferrocene, aryl, heteroaryl, alkyloxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl; or, R 4 and R 5 connected to form a cycloalkyl or heterocyclic group; or, R 4 and its adjacent R 6 are connected, together with the carbon atoms to which they are connected, to form a cycloalkyl or heterocyclyl group;

[0010] X 1 N or CR X1 ;

[0011] X 2 N or CR X2 ;

[0012] R X1 and R X2 each is independently hydrogen, amino, hydroxy, alkylNH-, (alkyl)2N-, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyloxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy or halogen;

[0013] =O or =S; or does not exist;

[0014] R1 is hydrogen, alkyl, aryl, heteroaryl, alkyloxy or halogen;

[0015] R 2 is hydrogen, alkyl, aryl, heteroaryl, alkyloxy or halogen;

[0016] or R 1 and R 2 connected to form an aryl or heteroaryl group together with the carbon atoms to which they are connected

[0017] R 3 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or alkyloxy;

[0018] R 5 is hydrogen, alkyl, aryl, heteroaryl or alkyloxy;

[0019] R 6 is hydrogen;

[0020] n is 0 or 1;

[0021] or R 4 for in,

[0022] X 1a N or CR X1a ;

[0023] X 2a N or CR X2a ;

[0024] R X1a and R X2a each is independently hydrogen, amino, hydroxy, alkylNH-, (alkyl)2N-, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyloxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, fluorine, chlorine, bromine or iodine;

[0025] =O or =S; or does not exist;

[0026] Z is a bond, cycloalkylene, heterocyclylene, arylene, heteroarylene, alkylene or

[0027] R 1a is hydrogen, alkyl, aryl, heteroaryl, alkyloxy or halogen;

[0028] R 2a is hydrogen, alkyl, aryl, heteroaryl, alkyloxy or halogen;

[0029] or R 1a and R 2aconnected to form an aryl or heteroaryl group together with the carbon atoms to which they are connected

[0030] R 3a is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or alkyloxy;

[0031] R 5a is hydrogen, alkyl, aryl, heteroaryl or alkyloxy;

[0032] m is 0 or 1

[0033] The alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylene, heterocyclylene, arylene, heteroarylene and alkylene mentioned in the above single group or composite group are each independently and optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydroxy, amino, halogen, carboxyl, sulfonyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyloxy, alkylthio, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkylNH-, (alkyl)2N-, alkylOC The alkyl group is substituted with a substituent selected from the group consisting of alkyl (=O)-, alkyl C(=O)O-, dialkyl phosphino, diaryl phosphino, di(3,5-dimethyl-4-methoxyphenyl)phosphino, di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino, dicycloalkyl phosphino, dialkoxy phosphino, diaryloxy phosphino, dicycloalkyloxy phosphino, dialkyl phosphino (=O) group, diaryl phosphino (=O) group, dicycloalkyl phosphino (=O) group, dialkoxy phosphino (=O) group, diaryloxy phosphino (=O) group and dicycloalkyloxy phosphino;

[0034] The condition is that the structure represented by the formula (I) does not contain the following structure:

[0035]

[0036] Or the condition is that, in the structure shown in the formula (I), when R X1a When F, =O or =S;

[0037] Or the condition is that, in the structure shown in the formula (I), when R X1a When F, R 4is hydrogen, alkenyl, cycloalkyl, heterocyclyl, alkylOC(═O)-, alkylC(═O)O-, dialkylphosphino, diarylphosphino, di(3,5-dimethyl-4-methoxyphenyl)phosphino, di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino, dicycloalkylphosphino, dialkoxyphosphino, diaryloxyphosphino, dicycloalkyloxyphosphino, dialkylphosphino(═O)-, diarylphosphino(═O)-, dicycloalkylphosphino(═O)-, dialkoxyphosphino(═O)-, diaryloxyphosphino(═O)-, dicycloalkyloxyphosphino(═O)-, ferrocene, alkyloxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl; or, R 4 and R 5 connected to form a cycloalkyl or heterocyclic group; or, R 4 and its adjacent R 6 connected to form a cycloalkyl or heterocyclic group; or R 4 for

[0038] In some embodiments, Each independently selected from:

[0039]

[0040]

[0041]

[0042] In some embodiments, R 4 Selected from:

[0043]

[0044] In some embodiments, R 3 or R 3a Each independently selected from:

[0045]

[0046] In some embodiments, Z is selected from:

[0047]

[0048] In some embodiments, the compound represented by Formula I is selected from:

[0049]

[0050]

[0051] In another aspect, the present invention provides a palladium bisphosphine acetate complex having the structure described in Formula II:

[0052]

[0053] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , Y and n have the definitions described in the present invention.

[0054] In some embodiments, the palladium bisphosphine acetate complex has The structure of R 4 Has the definition described in the present invention.

[0055] In some embodiments, the palladium bisphosphine acetate complex has The structure of R 4 On the other hand, the present invention also provides a coupling reaction method, wherein the method uses the bisphosphine acetate palladium complex prepared by the substituted benzoxazine ligand of the present invention or the bisphosphine acetate palladium complex of the present invention as a catalyst.

[0056] In some embodiments, the coupling reaction method is a CC coupling reaction, comprising: reacting an aryl halide and an aryl boronic acid structure in the palladium bisphosphine acetate complex in an organic solvent and alkaline conditions; or the coupling reaction method is a CN coupling reaction, comprising: reacting an aryl halide and an aryl amine structure in the palladium bisphosphine acetate complex in an organic solvent and alkaline conditions;

[0057] The solvent is N,N-dimethylformamide, toluene, trifluorotoluene, carbon tetrachloride, dioxane, hexafluoroisopropanol, and ethyl acetate; the base is potassium tert-butoxide, sodium tert-butoxide, lithium methoxide, cesium carbonate, sodium acetate, sodium hydroxide, potassium hydroxide, and sodium hydroxide.

[0058] In some embodiments, the aryl boronic acid structure includes aryl boronic acid or aryl boronic ester; the aryl halide is aryl chloride and aryl bromide; the aryl amine structure includes aryl primary amine or aryl secondary amine.

[0059] In some embodiments, the palladium bisphosphine acetate is used in the CC bond formation reaction of an aryl halide (eg, an aryl bromide) and an aryl boronic acid:

[0060]

[0061] Wherein, X is chlorine or bromine. The ligand used is a compound A more preferred structure is The amount of the catalyst used is 0.1 to 10%.

[0062] In some embodiments, the palladium bisphosphine acetate is used for the CN bond formation reaction between an aryl halide (such as an aryl chloride) and an arylamine structure:

[0063]

[0064] Wherein, X is chlorine or bromine. The ligand used is a compound A more preferred structure is The amount of the catalyst used is 0.05-2.5%.

[0065] Beneficial Effects

[0066] The present invention provides a series of benzoxophosphine ligands and their application in CC and CN bond coupling of aryl halides, which have the following beneficial effects compared with the prior art:

[0067] (1) The preparation steps of this type of ligand are short and can be started from simple and readily available aldehydes. Secondly, this type of ligand is electron-rich, rigid, and air-stable.

[0068] (2) The present invention can provide a phosphine ligand which is applied to the palladium-catalyzed coupling reaction of aryl halides and has a good reaction result.

[0069] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

[0070] Terminology

[0071] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0072] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0073] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0074] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means 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 representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0075] In the following, all numbers disclosed herein are approximate, regardless of whether the words "about" or "approximately" are used. The value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Whenever a number having a value of N is disclosed, any number having a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15% or N+ / -20% is explicitly disclosed, where "+ / -" means plus or minus.

[0076] A single group means that the group is formed by one group, such as an alkyl group, an aryl group, a heteroaryl group, etc.; a composite group means that the group is formed by a combination of two or more groups, such as an arylalkyl group, an alkyloxy group, an alkylthio group, a cycloalkyloxy group, a heterocyclyloxy group, a dicycloalkylphosphine group, etc.; the composite groups involved in this article are uniformly connected to the rest of the molecule by the right-hand group, for example, an arylalkyl group, the aryl group is connected to the alkyl group, and the composite group is connected to the rest of the molecule with the alkyl group as the connecting point.

[0077] In the present application, the alkyl group, whether as a single group or part of a composite group, represents a carbon atom-containing, saturated straight or branched hydrocarbon group. In one embodiment, the alkyl group contains 1-6 carbon atoms, i.e., C1-6 alkyl; in another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C1-4 alkyl; in another embodiment, the alkyl group contains 1-3 carbon atoms, i.e., C1-3 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and the like.

[0078] In the present application, the alkenyl group, whether as a single group or part of a composite group, means a straight or branched monovalent hydrocarbon group containing carbon atoms, wherein there is at least one unsaturated site, i.e., there is a carbon-carbon sp2 double bond, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2-6 carbon atoms, i.e., C2-C6 alkenyl; in another embodiment, the alkenyl group contains 2-4 carbon atoms, i.e., C2-C4 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0079] In the present application, the cycloalkyl group, whether as a single group or part of a composite group, refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including a spirocyclic, fused or bridged system (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which may be fully saturated or contain one or more unsaturations, but may not have an aromatic ring. In one embodiment, In the scheme, the cycloalkyl contains 3-6 carbon atoms, such as C3-6 saturated or partially unsaturated cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and the like. In one embodiment, the saturated or partially unsaturated cycloalkyl is selected from: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, partially unsaturated tricyclic cycloalkyl. C4-7 cycloalkyl represents a cycloalkyl with 4-7 ring atoms. C3-6 cycloalkyl represents a cycloalkyl with 3-6 ring atoms.

[0080] In the present application, the heterocyclic group, whether as a single group or part of a composite group, refers to a saturated (i.e., "heterocycloalkyl") or partially unsaturated monovalent monocyclic or bicyclic group, which has 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., one, two, three or four) heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2 and NR', wherein R' represents a hydrogen atom or a C1-6 alkyl or a halo-C1-6 alkyl. The heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present) in the ring. In particular, a 3-10 membered heterocyclyl group is a group having 3-10 (e.g., 3-7, 4-6, or 5-6) carbon atoms and heteroatoms in the ring, such as, but not limited to, an oxirane, an aziridine, an azetidinyl, an oxetanyl, a tetrahydrofuranyl, a dioxolinyl, a pyrrolidinyl, a pyrrolidonyl, an imidazolidinyl, a pyrazolidinyl, a pyrrolinyl, a tetrahydropyranyl, a piperidinyl, a morpholinyl, a dithianyl, a thiomorpholinyl, a piperazinyl, or a trithianyl.

[0081] In the present application, the aryl group, whether as a single group or part of a composite group, refers to an optional functional group or substituent derived from an aromatic carbocyclic ring, and the aryl group can be a monocyclic aryl group (e.g., phenyl) or a polycyclic aryl group. In other words, the aryl group can be a monocyclic aryl group, a condensed ring aryl group, two or more monocyclic aryl groups connected by a carbon-carbon single bond conjugation, a monocyclic aryl group and a condensed ring aryl group connected by a carbon-carbon single bond conjugation, and two or more condensed ring aryl groups connected by a carbon-carbon single bond conjugation, wherein at least one ring is an aromatic ring. That is, unless otherwise specified, two or more aromatic groups connected by a carbon-carbon single bond conjugation can also be regarded as the aryl group of the present application. Among them, the condensed ring aryl group can, for example, include a bicyclic condensed aryl group (e.g., naphthyl), a tricyclic condensed aryl group (e.g., phenanthrenyl, fluorenyl, anthracenyl), etc. The aryl group does not contain heteroatoms such as B, N, O, S, P, Se, and Si. Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, fluorenyl, phenyl-naphthyl, spirobifluorenyl, anthracenyl, phenanthrenyl, biphenyl, terphenyl, triphenylene, peryl, benzo[9,10]phenanthrenyl, pyrenyl, benzofluoranthenyl, Aryl may represent monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic and has one or more points of attachment to the rest of the molecule. Unless otherwise specified, the group “C 6-14 "Aryl" means an aromatic group containing 6 to 14 ring carbon atoms

[0082] In the present application, the heteroaryl group, whether as a single group or part of a composite group, refers to a monovalent aromatic ring or a derivative thereof containing 1, 2, 3, 4, 5 or 6 heteroatoms in the ring, and the heteroatoms may be one or more of B, O, N, P, Si, Se and S. The heteroaryl group may be a monocyclic heteroaryl group or a polycyclic heteroaryl group. In other words, the heteroaryl group may be a single aromatic ring system or a plurality of aromatic ring systems conjugated by carbon-carbon single bonds, and any aromatic ring system may be an aromatic monocyclic ring or an aromatic condensed ring, wherein at least one ring is a heteroaromatic ring. By way of example, the heteroaryl group may include a thienyl group, a furyl group, a pyrrolyl group, an imidazolyl group, a thiazolyl group, an oxazolyl group, an oxadiazolyl group, a triazolyl group, a pyridyl group, a bipyridyl group, a pyrimidyl group, a triazine group, an acridinyl group, a pyridazinyl group, a pyrazinyl group, a quinolyl group, a quinazolinyl group, a quinoxalinyl group, a phenoxazinyl group, a phthalazinyl group, a pyridopyrimidinyl group, a pyridopyrazinyl group, a pyrazinopyrazinyl group, an isoquinolyl group, an indolyl group, a carbazolyl group, a benzoxazolyl group, a benzimidazolyl group, a benzothiazolyl group, a benzocarbazolyl group, a benzothienyl group, a dibenzothienyl group, a thienothiphenyl group, a benzofuranyl group, a phenanthrolinyl group, an isoxazolyl group, a thiadiazolyl group, a phenothiazinyl group, a silyfluorenyl group, a dibenzofuranyl group, and an N-phenylcarbazolyl group, an N-pyridylcarbazolyl group, an N-methylcarbazolyl group, and the like, without being limited thereto. Heteroaryl may represent monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, wherein at least one ring is aromatic and has one or more points of attachment to the rest of the molecule. Unless otherwise specified, the group 5-14 membered heteroaryl represents a heteroaryl group containing 5-14 ring atoms.

[0083] Cycloalkylene, heterocyclylene, arylene, heteroarylene and alkylene are cycloalkyl, heterocyclyl, aryl, heteroaryl and alkylene respectively described in the present invention and used as connecting groups, which are divalent groups, i.e., have two connecting points connected to the rest of the molecule.

[0084] When describing the rest of the molecule of a group, this refers to the rest of the molecule excluding the substituents of the group itself.

[0085] In the present application, "plurality" means more than 2, for example, 2, 3, 4, 5, 6, etc.

[0086] The hydrogen atoms in the structures of the compounds of the present application include various isotope atoms of the hydrogen element, such as hydrogen (H), deuterium (D) or tritium (T).

[0087] Unless explicitly stated otherwise, the descriptions used in the present invention such as "each...is independently" and "...are each independently" and "...are independently" are interchangeable and should be understood in a broad sense, which may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0088] The terms "optional", "optionally" or "arbitrarily", "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted with..." means that the substitution may or may not occur.

[0089] When the term "each independently" is used in combination with "arbitrarily", for example, "each independently arbitrarily replaced by..." means that the specific options are replaced by... or not by... without affecting each other.

[0090] The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0091] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0092] The term "two substituents are linked to form a ring" means that the two substituents are linked by a bond or a long chain of one atom or multiple atoms, forming a ring together with the atoms between the two substituents in the parent molecule.

[0093] The term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of each other. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0094] Group Abbreviation:

[0095] Ad is adamantyl, Cy is cyclohexyl, tBu is tert-butyl, Me is methyl, OMe is methoxy, iPr is isopropyl, Ar is aryl, Ph is phenyl, and OAc is acetoxy. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 This is the H NMR image of ligand 4

[0097] Figure 2 This is the carbon NMR image of ligand 4

[0098] Figure 3 This is the phosphorus NMR image of ligand 4

[0099] Figure 4 This is the H NMR spectrum of ligand 21

[0100] Figure 5 This is the carbon NMR spectrum of ligand 21

[0101] Figure 6 This is the fluorine NMR image of ligand 21

[0102] Figure 7 This is the phosphorus NMR image of ligand 21

[0103] Figure 8 This is the H NMR spectrum of ligand 56

[0104] Fig. 9 This is the carbon NMR spectrum of ligand 56

[0105] Fig.10 This is the phosphorus NMR image of ligand 56

[0106] Fig.11 This is the H NMR spectrum of product 57

[0107] Fig.12 This is the carbon NMR spectrum of product 57

[0108] Fig.13 This is the H NMR spectrum of product 58

[0109] Fig.14 This is the carbon NMR spectrum of product 58 DETAILED DESCRIPTION

[0110] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0111] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0112] Example 1: Synthesis process of ligand (taking ligand 4 as an example)

[0113]

[0114] In an argon atmosphere at room temperature, the corresponding substrate phosphine (0.2 mmol) was dissolved in 2 mL of dry tetrahydrofuran, and potassium tert-butoxide solid (0.3 mmol, 1.5 equiv.) and the corresponding 2,6-dimethoxybenzaldehyde (0.3 mmol, 1.5 equiv.) were added in sequence, and the reaction was stirred until the raw material was completely consumed as detected by TLC. Column chromatography was used for purification, and degassed petroleum ether-ethyl acetate (100:0-20:1) was used as the eluent to obtain 4 as a colorless oily liquid with a yield of 88% and a diastereoselectivity greater than 20:1.

[0115] Structural characterization data of product 4:

[0116] 63.4mg, 80% yield, 24h, colorless oil. 1 H NMR (400MHz, Chloroform-d) δ7.23-7.14(m,2H),6.57-6.40(m,5H),3.85(s,3H),3.64(s,6H),1.07(d,J=11.9Hz,9H). 31 P NMR(162MHz,Chloroform-d)δ13.31. 13 C NMR(101MHz,Chloroform-d)δ166.2,161.0(d,J=11.7Hz),158.7,131.3,129.4(d,J=1.8Hz),117.9(d,J=16.0Hz),112.2( d,J=14.5Hz),104.4,103.7,101.8(d,J=2.4Hz),75.7(d,J=23.9Hz),55.8,55.4,31.8(d,J=19.4Hz),27.3(d,J=14.2Hz).

[0117] Example 2: Synthesis process of ligand (taking ligand 1 as an example)

[0118]

[0119] In an argon atmosphere at room temperature, the corresponding substrate phosphine (0.2 mmol) was dissolved in 2 mL of dry tetrahydrofuran, and potassium tert-butoxide solid (0.3 mmol, 1.5 equiv.) and the corresponding 2-triphenylphosphine benzaldehyde (0.3 mmol, 1.5 equiv.) were added in sequence, and the reaction was stirred until the raw material was completely consumed as detected by TLC. Column chromatography was used for purification, and degassed petroleum ether-ethyl acetate (100:0-20:1) was used as the eluent to obtain 1 as a white solid in 83% yield and greater than 20:1 diastereoselectivity.

[0120] Structural characterization data of product 1:

[0121] White solid, 80 mg, 83% yield, >20:1dr. 1 H NMR (600MHz, CDCl3) δ (ppm) 7.35-7.31 (m, 6H), 7.31-7.23 (m, 6H), 7.20-7.13 (m, 2H), 7.10 (t, J = 7.3Hz, 1H), 6.90 (dd, J = 7.5 ,4.8Hz,1H),6.74(d,J=4.5Hz,1H),6.65(d,J=8.1Hz,1H),6.49(dd,J=8.1,3.5Hz,1H),3.81(s,3H),0.96(d,J=12.0Hz,9H). 13 C NMR (101MHz, CDCl3) δ (ppm) 166.1, 162.4 (d, J = 11.7Hz), 146.5 (dd, J = 22.9, 15.4Hz), 136.6 (dd ,J=67.4,10.5Hz),134.7,134.1(d,J=18.9Hz),133.9(d,J=19.4Hz),132.6,129.7,128.8(d,J= 9.8Hz), 128.7 (d, J = 4.8Hz), 128.6 (d, J = 6.6Hz), 127.7 (d, J = 2.1Hz), 125.6 (t, J = 5.7Hz), 104. 1,103.1(d,J=2.0Hz),83.0(t,J=28.5Hz),55.5,33.7(d,J=22.6Hz),27.6(dd,J=13.3,2.8Hz). 31 P NMR (243MHz, CDCl3) δ (ppm) 11.07 (d, J = 17.7Hz), -19.44 (d, J = 17.6Hz).

[0122] Example 3: Synthesis process of ligand (taking ligand 5 as an example)

[0123]

[0124] In an argon atmosphere at room temperature, the corresponding substrate phosphine (4.0 mmol) was dissolved in 40 mL of dry tetrahydrofuran, and potassium tert-butoxide solid (6.0 mmol, 1.5 equiv.) and the corresponding 2,4,6-trimethoxybenzaldehyde (6.0 mmol, 1.5 equiv.) were added in sequence, and the reaction was stirred until the raw material was completely consumed as detected by TLC. Column chromatography was used for purification, and degassed petroleum ether-ethyl acetate (100:0-20:1) was used as the eluent to obtain 5 as a white solid with a yield of 89% and a diastereoselectivity greater than 20:1.

[0125] Structural characterization data of product 5:

[0126] White solid, 1.38 g, 89% yield, >20:1 dr. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.17 (t, J = 8.1Hz, 1H), 6.50-6.39 (m, 3H), 6.08 (s, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 3.63 (s, 6H), 1.05 (d, J = 11.8Hz, 9H). 13 C NMR (101MHz, CDCl3) δ (ppm) 166.1, 161.3 (d, J = 1.5Hz), 161.0 (d, J = 11.5Hz), 159.5, 131.2, 112.9-110.1 (m) ,103.8,101.7(d,J=2.2Hz),91.1,75.6(d,J=23.2Hz),55.8,55.5,31.8(d,J=19.2Hz),27.3(d,J=14.2Hz). 31 PNMR(162MHz,CDCl3)δ(ppm)12.42.

[0127] Example 4: Synthesis process of ligand (taking ligand 51 as an example)

[0128]

[0129] In an argon atmosphere at room temperature, the corresponding substrate phosphine (0.2 mmol) was dissolved in 2 mL of dry tetrahydrofuran, and potassium tert-butoxide solid (0.3 mmol, 1.5 equiv.) and the corresponding 2-methylbenzaldehyde (0.3 mmol, 1.5 equiv.) were added in sequence, and the reaction was stirred until the raw material was completely consumed as detected by TLC. Column chromatography was used for purification, and degassed petroleum ether-ethyl acetate (100:0-20:1) was used as the eluent to obtain 51 in a colorless oily liquid with a yield of 88% and a diastereoselectivity greater than 20:1.

[0130] Structural characterization data of product 51:

[0131] Colorless oil, 63mg, 88% yield, >20:1dr. 1 H NMR (600MHz, CDCl3) δ (ppm) 7.40-7.33 (m, 2H), 7.23-7.18 (dd, J=7.2, 2.1Hz, 3H), 7.17-7.12 (t, J=7.0Hz, 1H),6.95(d,J=8.2Hz,1H),6.90(t,J=8.1Hz,2H),6.68(td,J=8.0,3.8Hz,1H),6.58(s,1H),2.38(s,3H). 13 C NMR (151MHz, CDCl3) δ (ppm) 167.0 (d, J = 7.6Hz), 164.8 (dt, J = 249.6, 8.7Hz), 164.5 (dd, J = 24 9.4, 13.6Hz), 138.0 (d, J = 21.0Hz), 134.3 (d, J = 4.8Hz), 133.8 (d, J = 9.2Hz), 132.9 (t, J = 10.7 Hz), 131.0 (d, J = 2.2Hz), 127.9 (d, J = 3.3Hz), 126.4 (d, J = 2.5Hz), 124.4 (d, J = 6.2Hz), 112.7 -111.5(m),108.2(d,J=21.8Hz),107.1(d,J=3.4Hz),85.7(d,J=22.3Hz),20.0(d,J=6.3Hz). 19 F NMR(565MHz, CDCl3)δ(ppm)-101.44(m),-103.10(m). 31 P NMR (243MHz, CDCl3) δ (ppm)-37.48 (td, J = 33.0, 32.4, 6.9Hz).

[0132] Example 5: Synthesis process of ligand (taking ligand 52 as an example)

[0133]

[0134] In an argon atmosphere at room temperature, the corresponding substrate phosphine (0.2 mmol) was dissolved in 2 mL of dry tetrahydrofuran, and potassium tert-butoxide solid (0.3 mmol, 1.5 equiv.) and the corresponding pyridine-2-carboxaldehyde (0.3 mmol, 1.5 equiv.) were added in sequence, and the reaction was stirred until the raw material was completely consumed as detected by TLC. Column chromatography was used for purification, and degassed petroleum ether-ethyl acetate (100:0-20:1) was used as the eluent to obtain 52 as a white solid in 88% yield and greater than 20:1 diastereoselectivity.

[0135] Structural characterization data of product 52:

[0136] Colorless oil, 51 mg, 88% yield, >20:1dr. 1 H NMR (400MHz, CDCl3) δ (ppm) 8.59 (d, J = 4.9 Hz, 1H), 7.58 (td, J = 7.7, 1.8 Hz, 1H), 7.32 (td, J = 8.1, 6.1 Hz, 1H), 7.20- 7.09(m,2H),6.91(dd,J=8.2,0.8Hz,1H),6.70(tdd,J=8.0,3.2,0.8Hz,1H),6.09(s,1H),1.14(d,J=12.7Hz,9H). 13 C NMR (101MHz, CDCl3) δ (ppm) 166.0-165.7 (m), 163.4 (d, J = 12.6Hz), 160.6 (d, J = 14.3Hz), 149.7, 136.9, 132.9 (d, J = 9.2Hz), 122.2 (d, J = 2.5Hz) ,119.3(d,J=3.6Hz), 109.7(d,J=27.7Hz), 108.8-108.2(m), 107.1(d,J=3.3Hz), 86.3(d,J=28.6Hz), 32.3(d,J=21.4Hz), 27.0(d,J=14.5Hz). 19 F NMR(376MHz, CDCl3)δ(ppm)-102.71. 31 P NMR (162MHz, CDCl3) δ (ppm) 11.69.

[0137] Example 6: Synthesis process of ligand (taking ligand 53 as an example)

[0138]

[0139] In an argon atmosphere at room temperature, the corresponding substrate phosphine (0.5 mmol) was dissolved in 2 mL of dry tetrahydrofuran, and potassium tert-butoxide solid (0.6 mmol, 3.0 equiv.) and the corresponding 1,3-isophthalaldehyde (0.2 mmol, 1.0 equiv.) were added in sequence, and the reaction was stirred until the raw material was completely consumed as detected by TLC. Column chromatography was used for purification, and degassed petroleum ether-ethyl acetate (100:0-20:1) was used as the eluent to obtain 53 as a white solid in a yield of 49% and a diastereoselectivity of 6:1.

[0140] Structural characterization data of product 53:

[0141] White solid, 49 mg, 49% yield, 6:1 dr. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.31-7.19 (m, 3H), 7.10 (d, J = 6.7Hz, 3H), 6.79 (ddd, J = 13.7, 8. 1,0.8Hz,2H),6.67(dt,J=8.0,4.1Hz,2H),5.94(d,J=3.4Hz,2H),1.08(d,J=12.6Hz,18H). 13 C NMR (101MHz, CDCl3) δ (ppm) 165.8 (d, J = 8.5Hz), 163.4 (d, J = 12.4Hz), 141.7 (d, J = 16.6Hz), 132.9 (d, J = 9.2Hz), 129.0, 124.0 (dt, J = 7.8, 2.1Hz), 12 1.5(t,J=7.0Hz), 109.4(dd,J=27.6,20.8Hz), 108.2(d,J=22.7Hz), 107. 1-106.6(m),84.9(d,J=28.1Hz),32.1(d,J=20.8Hz),27.0(d,J=14.6Hz). 19 F NMR(376MHz,CDCl3)δ(ppm)-102.99. 31 P NMR (162MHz, CDCl3) δ (ppm) 12.36, 12.30.HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 28 H 31 F2O2P2 + =499.1762;Found 499.1761.

[0142] Example 7: Synthesis of ligand (taking ligand 54 as an example)

[0143]

[0144] In an argon atmosphere at room temperature, the corresponding substrate phosphine (0.5 mmol) was dissolved in 2 mL of dry tetrahydrofuran, and potassium tert-butoxide solid (0.6 mmol, 3.0 equiv.) and the corresponding ferrocene dialdehyde (0.2 mmol, 1.0 equiv.) were added in sequence, and the reaction was stirred until the raw material was completely consumed as detected by TLC. Column chromatography was used for purification, and degassed petroleum ether-ethyl acetate (100:0-20:1) was used as the eluent to obtain 54 as a yellow liquid in a yield of 49% and a diastereoselectivity greater than 20:1.

[0145] Structural characterization data of product 54:

[0146] Yellow oil, 53mg, 44% yield, >20:1dr. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.24 (td, J = 8.1, 6.2Hz, 2H), 6.74 (t, J = 7.8Hz, 2H), 6.65 (tdd, J = 7 .9,3.4,1.5Hz,2H),5.75(d,J=7.5Hz,2H),4.24-3.97(m,8H),1.07(dd,J=12.6,4.3Hz,18H). 13 C NMR (101MHz, CDCl3) δ (ppm) 165.4 (dd, J = 8.8, 5.3Hz), 164.4 (ddd, J = 246.7, 12.4, 3.8Hz), 13 2.8(d,J=9.1Hz),110.3(ddd,J=27.4,19.0,4.7Hz),107.7(d,J=22.9Hz),107.3(dd,J=5.2,3 .2Hz),89.1(dd,J=21.9,15.5Hz),82.2(dd,J=26.6,6.1Hz),69.4,69.4(d,J=30.5Hz),68.4( dd,J=46.1,8.2Hz), 67.5(dd,J=14.7,8.0Hz), 32.0(d,J=19.3Hz), 27.1(dd,J=14.5,2.6Hz). 19 F NMR(376MHz, CDCl3)δ(ppm)-103.46. 31 PNMR (162MHz, CDCl3) δ (ppm) 1.63, 1.08.

[0147] Example 8: Synthesis process of ligand (taking ligand 55 as an example)

[0148]

[0149] In an argon atmosphere at room temperature, the corresponding substrate phosphine (0.2 mmol) was dissolved in 2 mL of dry tetrahydrofuran, and potassium tert-butoxide solid (0.3 mmol, 1.5 equiv.) and the corresponding benzaldehyde (0.3 mmol, 1.5 equiv.) were added in sequence, and the reaction was stirred until the raw material was completely consumed by TLC. Then sulfur powder (0.6 mmol, 3.0 equiv.) was added under an argon atmosphere and stirred at room temperature for 0.5 hours. Column chromatography was used for purification, and degassed petroleum ether-ethyl acetate (100:0-20:1) was used as the eluent to obtain 55 as a white solid in a yield of 91% and a diastereoselectivity greater than 20:1.

[0150] Structural characterization data of product 55:

[0151] White solid, 55 mg, 91% yield, >20:1dr. 1 H NMR (400MHz, CDCl3) δ (ppm) 8.49 (dd, J = 3.9, 1.8Hz, 1H), 7.41-7.32 (m, 5H), 7.25-7.22 (m, 2H), 5.93 (d, J = 1.4Hz, 1H), 1.36 (d, J = 17.6Hz, 9H). 13 C NMR (101MHz, CDCl3) δ (ppm) 158.0 (d, J = 28.7Hz), 146.2 (d, J = 14.9Hz), 140.4 (d, J = 101.5Hz), 133.8 (d, J = 2.2Hz), 128.6 (d, J = 2.6H z), 128.1 (d, J = 1.8Hz), 127.1 (d, J = 2.8Hz), 126.9 (d, J = 4.3Hz), 120.0 (d, J = 5.0Hz), 79.2 (d, J = 40.4Hz), 36.2 (d, J = 47.9Hz), 24.4. 31 PNMR(162MHz,CDCl3)δ(ppm)65.47.

[0152] Example 9: Synthesis process of ligand (taking ligand 21 as an example)

[0153]

[0154] In an argon atmosphere at room temperature, the corresponding substrate phosphine (0.2 mmol) was dissolved in 1 mL of dry tetrahydrofuran, and potassium tert-butoxide solid (0.3 mmol, 1.5 equiv.) and the corresponding ethylene oxide solution (1.0 mL, 1.0 mmol, 5.0 equiv.) were added in sequence, and the reaction was stirred until the raw material was completely consumed by TLC detection, and then sulfur powder (0.6 mmol, 3.0 equiv.) was added under an argon atmosphere, and stirred at room temperature for 0.5 hours. Column chromatography was used for purification, and degassed petroleum ether-ethyl acetate (100:0-20:1) was used as the eluent to obtain 21 in an 80% yield as a colorless oily liquid.

[0155] Structural characterization data of product 21:

[0156] 82.0mg, 80% yield, 24h, colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.33 (q, J = 7.9Hz, 1H), 6.79-6.70 (m, 2H), 4.66-4.52 (m, 1 H),4.51-4.41(m,1H),2.85-2.75(m,1H),2.22-2.08(m,1H),1.27(d,J=18.1Hz,9H). 13 C NMR (100MHz, CDCl3) δ (ppm) 164.1 (d, J = 250.1Hz), 160.5 (dd, J = 7.3, 1.4Hz), 133.5 (d, J = 10.7Hz), 114.8 (dd, J = 4.4, 3.6Hz), 109.1 (dd, J = 23. 2, 4.4Hz), 105.4 (dd, J = 63.9, 22.8Hz), 77.3, 77.0, 76.7, 63.4 (d, J = 6.6Hz), 35.8 (d, J = 52.1Hz), 30.1 (d, J = 51.7Hz), 25.3 (dd, J = 4.3, 2.8Hz). 19 FNMR(376MHz, CDCl3)δ(ppm)-96.10. 31 PNMR(162MHz,CDCl3)δ(ppm)39.40.

[0157] Example 10: Synthesis of ligand (taking ligand 23 as an example)

[0158]

[0159] In an argon atmosphere at room temperature, the corresponding substrate phosphine (0.4 mmol) was dissolved in 1 mL of dry tetrahydrofuran, and potassium tert-butoxide solid (0.6 mmol, 1.5 equiv.) and the corresponding epoxide (0.6 mmol, 1.5 equiv.) were added in sequence. The reaction was stirred until the raw material was completely consumed by TLC detection, and then sulfur powder (4.0 mmol, 10.0 equiv.) was added under an argon atmosphere and stirred at room temperature for 2 hours. Column chromatography was used for purification with degassed petroleum ether-ethyl acetate (100:0-5:1) as the eluent to obtain 23 as a white solid in 89% yield.

[0160] Structural characterization data of product 23:

[0161] White solid, 152 mg, 89% yield. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.38 (q, J = 8.1Hz, 1H), 6.84-6.77 (m, 2H), 4.04-3.84 (m, 1H), 3.80-3.66 (m, 1H), 3.40 (t, J = 10.5Hz, 1H), 2.95-2.82 (m,1H),2.70(dd,J=14.5,6.0Hz,1H),2.44(d,J=15.0Hz,1H),2.22(t,J=14.9Hz,1H),1.91-1.76(m,3H),1.45(s,9H),1.22(d,J=18.0Hz,9H). 13 C NMR (101MHz, CDCl3) δ (ppm) 164.2 (d, J = 253.0Hz), 157.0 (d, J = 6.3Hz), 154.7, 133.9 (d, J = 11.2Hz), 115.6 (dd, J = 4.5, 3.2Hz), 110.0 (dd, J=23.5,4.6Hz),105.4(dd,J=64.3,20.4Hz),79.8,75.7(d,J=5.8Hz),39.8,39.3,39.1,39.0,36.9,36.4,31.8,28.4,24.7(t,J=2.9Hz). 19 FNMR(376MHz, CDCl3)δ(ppm)-95.21. 31 PNMR(162MHz,CDCl3)δ(ppm)32.17.

[0162] Example 11: Palladium-catalyzed Suzuki coupling reaction

[0163]

[0164] In an argon atmosphere at room temperature, the corresponding aryl chloride (0.5 mmol), phenylboronic acid (0.75 mmol) and potassium trimethylsilanol (1.0 mmol) were added to a 10 mL pressure-resistant sealed tube in sequence, dissolved in 1 mL of toluene, and finally the pre-complexed palladium / ligand complex solution (0.1% mol) was added, and the reaction was carried out at 100° C. for 24 hours. The final product 49 or 50 was purified by column chromatography.

[0165] Structural characterization data of product 49:

[0166] 82.0mg, 90% yield, 24h, colorless oil. 1 H NMR (400MHz, CDCl3): δ (ppm) 7.16-7.24 (m, 5H), 7.39 (dt, J = 7.0, 1.2Hz, 1H,), 7.48 (dt, J = 7.0, 1.1Hz, 2H), 2.10 (s, 6H). 13 CNMR (100MHz, CDCl3): δ (ppm) 141.8, 141.0, 136.0, 129.0, 128.4, 127.2, 127.0, 126.6, 20.8.

[0167] Structural characterization data of product 50:

[0168] 86.5mg, 95% yield, 24h, colorless oil. 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),8.05-7.94(m,2H),7.93-7.85(m,2H),7.83-7.71(m,2H),7.54-7.39(m,3H). 13 C NMR (101MHz, DMSO-d6) δ (ppm) 193.2, 146.3, 139.3, 135.6, 130.6, 129.6, 129.1, 127.8, 127.6.

[0169] Example 12: Palladium-catalyzed CN coupling reaction

[0170] Ligand 56 was synthesized using the method described in Example 3.

[0171]

[0172] Structural characterization data of ligand 56:

[0173] White solid. 1H NMR (400MHz, CDCl3): δ (ppm) 8.10 (dd, J=7.7, 3.8Hz, 2H), 7.56 (dd, J=8.2, 2.9Hz,

[0174] 1H),7.40(ddd,J=12.3,8.7,4.9Hz,4H),7.30-7.21(m,2H),7.00(dd,J=7.7,2.9Hz,1H),6.95(d,J =8.1Hz,1H),6.53(d,J=3.8Hz,1H),6.17(s,2H),3.82(s,3H),3.74(s,6H),0.59(d,J=12.1Hz,9H). 13 C NMR (100MHz, CDCl3): δ (ppm) 166.7, 161.3, 159.1, 141.4, 139.1, 139.0, 138.9, 131.2, 125.8, 125.3, 124.2, 123.9, 123.6, 123.2, 120.2, 119.9, 119.8,119.7,119.5,119.4,112.1,112.0,110.4,110.3,110.1,109.4, 91.0,77.3,77.0,76.7,75.5,75.2,55.7,55.4,31.4,31.2,26.5,26.3. 31 P NMR (162MHz,CDCl3)δ15.52.

[0175] Synthesis of compound 57:

[0176]

[0177] In an argon atmosphere at room temperature, the corresponding Pd2dba3 and ligand 56 are prepared into a toluene solution with a molar concentration of [Pd] of 0.002 mmol / mL according to a molar ratio of 0.5:2.2 (e.g., Pd2dba3 (0.05 mol%), 56 (0.22 mol%), and the solution of the complex is stirred for 30 minutes under an argon atmosphere. Subsequently, the corresponding carbazole (1.1 mmol) and sodium hydride (1.1 mmol) are added to a dry 10 mL pressure-resistant sealed tube, and 1 mL of toluene is added. Stirring at room temperature for 10 minutes, chlorobenzene (1.0 mmol), the corresponding [Pd] catalyst, and toluene are added again to make the reaction solvent volume 3.0 mL. After the addition is completed, the reaction tube is placed at 110° C. for 24 hours. The solvent is then removed by distillation under reduced pressure, and the final target product 57 is obtained by column chromatography (pure petroleum ether as eluent). The corresponding separation yield is as described in the above equation.

[0178] When Pd2dba3 is 0.025 mol% and 56 is 0.11 mol%, the reaction can also proceed smoothly.

[0179] Structural characterization data of product 57:

[0180] White solid. 1 H NMR (400MHz, CDCl3): δ (ppm) 8.09 (d, J = 7.8Hz, 2H), 7.53-7.46 (m, 4H), 7.41-7.31 (m, 5H), 7.23 (ddd, J = 8.0, 5.8, 2.3Hz, 2H). 13 C NMR (400MHz, CDCl3) δ140.8,137.6,129.8,127.3,127.0,125.9,123.3,120.2,119.9,109.7,77.3,77.0,76.7.

[0181] Synthesis 58:

[0182]

[0183] In an argon atmosphere at room temperature, the corresponding Pd2dba3 (4.6 mg, 0.005 mmol) and ligand 56 (11.55 mg, 0.022 mmol) were dissolved in 1 mL of toluene, and the complex solution was stirred for 30 minutes under an argon atmosphere. Subsequently, the corresponding 2,6-dimethylchlorobenzene (0.2 mmol), 2,6-dimethylaniline (0.4 mmol) and sodium methoxide (0.4 mmol) were added to a dry 10 mL pressure-resistant sealed tube, and 1 mL of toluene was added. After the addition was completed, the reaction tube was placed at 110 ° C for 24 hours. The solvent was then distilled off under reduced pressure, and the final target product 58 was obtained by column chromatography (pure petroleum ether as eluent). The corresponding separation yield is described in the above equation.

[0184] Structural characterization data of product 58:

[0185] White solid, 45.1 mg, >99% yield. 1 H NMR (400MHz, CDCl3): δ (ppm) 6.97 (d, J = 7.5Hz, 4H), 6.83 (t, J = 7.5Hz, 2H), 4.79 (s, 1H), 2.00 (s, 12H). 13 C NMR (400MHz, CDCl3) δ13C NMR (101MHz, CDCl3) δ141.7,129.5,128.7,121.7,77.3,77.0,76.7,19.1.

[0186] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A substituted benzoxazine ligand, characterized in that: Its structure is shown in formula (I), in, R 4 is hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, alkylOC(═O)-, alkylC(═O)O-, dialkylphosphino, diarylphosphino, di(3,5-dimethyl-4-methoxyphenyl)phosphino, di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino, dicycloalkylphosphino, dialkoxyphosphino, diaryloxyphosphino, dicycloalkyloxyphosphino, dialkylphosphino(═O)-, diarylphosphino(═O)-, dicycloalkylphosphino(═O)-, dialkoxyphosphino(═O)-, diaryloxyphosphino(═O)-, dicycloalkyloxyphosphino(═O)-, ferrocene, aryl, heteroaryl, alkyloxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl; or, R 4 and R 5 connected to form a cycloalkyl or heterocyclic group; or, R 4 and its adjacent R 6 are connected, together with the carbon atoms to which they are connected, to form a cycloalkyl or heterocyclyl group; X 1 N or CR X1 ; X 2 N or CR X2 ; R X1 and R X2 each is independently hydrogen, amino, hydroxy, alkylNH-, (alkyl)2N-, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyloxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy or halogen; =O or =S; or does not exist; R 1 is hydrogen, alkyl, aryl, heteroaryl, alkyloxy or halogen; R 2 is hydrogen, alkyl, aryl, heteroaryl, alkyloxy or halogen; or R 1 and R 2 connected to form an aryl or heteroaryl group together with the carbon atoms to which they are connected R 3 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or alkyloxy; R 5 is hydrogen, alkyl, aryl, heteroaryl or alkyloxy; R 6 is hydrogen; n is 0 or 1; or R 4 for in, X 1a N or CR X1a ; X 2a N or CR X2a ; R X1a and R X2a each is independently hydrogen, amino, hydroxy, alkylNH-, (alkyl)2N-, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyloxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, fluorine, chlorine, bromine or iodine; =O or =S; or does not exist; Z is a bond, cycloalkylene, heterocyclylene, arylene, heteroarylene, alkylene or R 1a is hydrogen, alkyl, aryl, heteroaryl, alkyloxy or halogen; R 2a is hydrogen, alkyl, aryl, heteroaryl, alkyloxy or halogen; or R 1a and R 2a connected to form an aryl or heteroaryl group together with the carbon atoms to which they are connected R 3a is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or alkyloxy; R 5a is hydrogen, alkyl, aryl, heteroaryl or alkyloxy; m is 0 or 1 The alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylene, heterocyclylene, arylene, heteroarylene and alkylene mentioned in the above single group or composite group are each independently and optionally substituted by 1, 2, 3, 4 or 5 groups selected from hydroxy, amino, halogen, carboxyl, sulfonyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyloxy, alkylthio, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkylNH-, (alkyl)2N-, alkylOC The alkyl group is substituted with a substituent selected from the group consisting of alkyl (=O)-, alkyl C(=O)O-, dialkyl phosphino, diaryl phosphino, di(3,5-dimethyl-4-methoxyphenyl)phosphino, di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino, dicycloalkyl phosphino, dialkoxy phosphino, diaryloxy phosphino, dicycloalkyloxy phosphino, dialkyl phosphino (=O) group, diaryl phosphino (=O) group, dicycloalkyl phosphino (=O) group, dialkoxy phosphino (=O) group, diaryloxy phosphino (=O) group and dicycloalkyloxy phosphino; The condition is that the structure represented by the formula (I) does not contain the following structure: Or the condition is that, in the structure shown in the formula (I), when R X1a When F, =O or =S; Or the condition is that, in the structure shown in the formula (I), when R X1a When F, R 4 is hydrogen, alkenyl, cycloalkyl, heterocyclyl, alkylOC(═O)-, alkylC(═O)O-, dialkylphosphino, diarylphosphino, di(3,5-dimethyl-4-methoxyphenyl)phosphino, di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino, dicycloalkylphosphino, dialkoxyphosphino, diaryloxyphosphino, dicycloalkyloxyphosphino, dialkylphosphino(═O)-, diarylphosphino(═O)-, dicycloalkylphosphino(═O)-, dialkoxyphosphino(═O)-, diaryloxyphosphino(═O)-, dicycloalkyloxyphosphino(═O)-, ferrocene, alkyloxy, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl; or, R 4 and R 5 connected to form a cycloalkyl or heterocyclic group; or, R 4 and its adjacent R 6 connected to form a cycloalkyl or heterocyclic group; or R 4 for 2. The substituted benzoxophosphine ligand according to claim 1, characterized in that Each independently selected from:

3. The substituted benzoxophosphine ligand according to claim 1, characterized in that R 4 Selected from:

4. The substituted benzoxophosphine ligand according to claim 1, characterized in that R 3 or R 3a Each independently selected from:

5. The substituted benzoxophosphine ligand according to claim 1, characterized in that Z is selected from:

6. The substituted benzoxophosphine ligand according to claim 1, characterized in that The compound represented by formula I is selected from:

7. A palladium bisphosphine acetate complex, characterized in that Having the structure described in formula II: Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , Y and n have the definitions as described in any one of claims 1-6.

8. A coupling reaction method, characterized in that: The method uses the palladium bisphosphine acetate complex prepared from the substituted benzoxazine ligand described in any one of claims 1 to 6 or the palladium bisphosphine acetate complex described in claim 7 as a catalyst.

9. The method according to claim 8, characterized in that The coupling reaction method is a CC coupling reaction, comprising: reacting an aryl halide and an aryl boronic acid structure in the bisphosphine acetate palladium complex in an organic solvent and alkaline conditions; Or the coupling reaction method is a CN coupling reaction, comprising: reacting an aryl halide and an aromatic amine structure in the palladium bisphosphine acetate complex in an organic solvent and alkaline conditions; The solvent is N,N-dimethylformamide, toluene, trifluorotoluene, carbon tetrachloride, dioxane, hexafluoroisopropanol, and ethyl acetate; the base is potassium tert-butoxide, sodium tert-butoxide, lithium methoxide, cesium carbonate, sodium acetate, sodium hydroxide, potassium hydroxide, and sodium hydroxide.

10. The method according to claim 9, characterized in that The aryl boronic acid structure includes aryl boronic acid or aryl boronic ester; the aryl halide is aryl chloride and aryl bromide; the aryl amine structure includes primary aromatic amine or secondary aromatic amine.

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