Quinazolinone-derived chiral monophosphine ligand as well as synthesis method and application thereof

Abstract

The invention discloses a series of chiral monophosphine ligands derived from quinazolinone as well as a synthesis method and application of the chiral monophosphine ligands. Through experiments, the applicant discovers that the chiral monophosphine ligand derived from quinazolinone can catalyze an allyl substitution reaction and an alkyne cyclization reaction when being used as a catalyst ligand and matched with a palladium catalyst or a gold catalyst, enantioselectivity of the reaction is improved, and when the chiral monophosphine ligand derived from quinazolinone is matched with the palladium catalyst to be applied to the allyl substitution reaction, the chiral monophosphine ligand derived from quinazolinone can be used for catalyzing the allyl substitution reaction and the alkyne cyclization reaction. The enantioselectivity of the reaction reaches 90% or above.

Description

Technical Field

[0001] The present invention relates to a catalyst ligand, in particular to a chiral monophosphine ligand derived from quinazolinone, a synthesis method and application thereof. Background Art

[0002] Catalyst ligands are organic molecules that can bind to metal ions to form complexes during catalytic reactions. They play a crucial role in catalytic reactions, primarily by regulating the electronic state of metal ions, adjusting the structure of activating groups, and enhancing reaction efficiency and selectivity through van der Waals interactions.

[0003] Chiral phosphine ligands have gained significant attention due to their versatility as ligands for selective metal catalysis (MM Pereira, MJ F Calvete, RMB Carrilhoa, ARAbreu, Chem. Soc. Rev., 2013, 42, 6990-7027). Among the numerous phosphine ligand examples reported so far, phosphines based on a binaphthyl skeleton appear as a common ligand, which are considered to be highly effective ligands in many enantioselective transition metal-catalyzed reactions. Therefore, the development of chiral phosphine catalysts with novel skeletons for other reactions and the synthesis of optically pure compounds have always been a hot topic of research. However, there are currently no reports on chiral monophosphine ligands derived from quinazolinone and their synthesis methods. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a series of chiral monophosphine ligands derived from quinazolinone with novel structures and high selectivity, as well as synthesis methods and applications thereof.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0006] The chiral monophosphine ligand derived from quinazolinone of the present invention is a compound having the structure shown in the following formula 1:

[0007]

[0008] in,

[0009] R represents a cyclohexyl group or a phenyl group, or a mono- or di-substituted phenyl group;

[0010] R 1 Represents a hydrogen atom or C 1～4 Alkoxy;

[0011] R 2 represents a hydrogen atom or a halogen atom;

[0012] R 3 Represents a hydrogen atom or C 1～4Alkyl;

[0013] R 4 represents a hydrogen atom or a halogen atom;

[0014] R 5 Indicates C 1～4 an alkyl or benzyl group;

[0015] R 6 Represents a hydrogen atom or C 1～4 Alkyl;

[0016] R 7 represents a hydrogen atom or a halogen atom;

[0017] R 8 represents a hydrogen atom or a halogen atom;

[0018] R 9 represents a hydrogen atom or a phenyl group;

[0019] R 10 Represents a hydrogen atom or C 1～4 Alkoxy;

[0020] R 11 Represents a hydrogen atom or C 1～4 Alkyl;

[0021] R 12 Represents a hydrogen atom.

[0022] In the general structure of the above-mentioned chiral monophosphine ligand derived from quinazolinone, each substituent is preferably as follows:

[0023] R represents cyclohexyl, phenyl, 4-methylphenyl or 3,5-dimethylphenyl;

[0024] R 1 represents a hydrogen atom or a methoxy group;

[0025] R 2 represents a hydrogen atom or a bromine atom;

[0026] R 3 represents a hydrogen atom or a methyl group;

[0027] R 4 represents a hydrogen atom or a chlorine atom;

[0028] R 5 represents a methyl or benzyl group;

[0029] R 6 represents a hydrogen atom or a methyl group;

[0030] R 7 represents a hydrogen atom or a bromine atom;

[0031] R 8represents a hydrogen atom or a chlorine atom;

[0032] R 9 represents a hydrogen atom or a phenyl group;

[0033] R 10 represents a hydrogen atom or a methoxy group;

[0034] R 11 represents a hydrogen atom or a methyl group;

[0035] R 12 Represents a hydrogen atom.

[0036] Furthermore, the chiral monophosphine ligand derived from quinazolinone according to the present invention is specifically any one of the following 1a to 1o:

[0037] 1a: R=Ph,R 1 =H, R 2 =H, R 3 =H, R 4 =H, R 5 =Me, R 6 =H, R 7 =H, R 8 =H, R 9 =H, R 10 =H, R 11 =H, R 12 =H;

[0038] 1b: R=Ph,R 1 =H, R 2 =H, R 3 =H, R 4 =Cl, R 5 =Me, R 6 =H, R 7 =H, R 8 =H, R 9 =H, R 10 =H, R 11 =H, R 12 =H;

[0039] 1c: R=Ph,R 1 =H, R 2 =H, R 3 =Me, R 4 =H, R 5 =Me, R 6 =H, R 7 =H, R 8 =H, R 9 =H, R 10 =H, R 11 =H, R 12 =H;

[0040] 1d:R=Ph,R 1 =H,R 2 =Br,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0041] 1e:R=Ph,R 1 =OMe,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0042] 1f:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Bn,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0043] 1g:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =Me,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0044] 1h:R=Ph,R 1 =H,R2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =Br,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0045] 1i:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =Cl,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0046] 1j:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =Ph,R 10 =H,R 11 =H,R 12 =H;

[0047] 1k:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =OMe,R 11 =H,R 12 =H;

[0048] 1l:R=Ph,R 1 =H,R 2 =H,R 3 =H,R4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =Me,R 12 =H;

[0049] 1m:R=Cy,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =Me,R 12 =H;

[0050] 1n:R=p-Tolyl,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =Me,R 12 =H;

[0051] 1o:R=3,5-2MeC6H3,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =Me,R 12 =H。

[0052] The synthesis method of the quinazolinone-derived chiral monophosphine ligand of the present invention mainly comprises the following steps: placing compound S7 in a first organic solvent, adding a first alkaline substance and a reducing agent, and reacting under heating conditions to obtain a crude target compound; the structure of compound S7 is shown below:

[0053]

[0054] in,

[0055] R represents cyclohexyl or phenyl, or a mono-substituted or di-substituted phenyl;

[0056] R 1 represents a hydrogen atom or a methoxy group;

[0057] R 2 Represents a hydrogen atom or C 1～4 Alkoxy;

[0058] R 2 represents a hydrogen atom or a halogen atom;

[0059] R 3 Represents a hydrogen atom or C 1～4 Alkyl;

[0060] R 4 represents a hydrogen atom or a halogen atom;

[0061] R 5 Indicates C 1～4 an alkyl or benzyl group;

[0062] R 6 Represents a hydrogen atom or C 1～4 Alkyl;

[0063] R 7 represents a hydrogen atom or a halogen atom;

[0064] R 8 represents a hydrogen atom or a halogen atom;

[0065] R 9 represents a hydrogen atom or a phenyl group;

[0066] R 10 Represents a hydrogen atom or C 1～4 Alkoxy;

[0067] R 11 Represents a hydrogen atom or C 1～4 Alkyl;

[0068] R 12 Represents a hydrogen atom.

[0069] In the synthesis method of the present invention, R and R in compound S71 ~R 12 The preferred range is the same as that of the compound represented by the structure of Formula 1 above.

[0070] In the synthesis method of the present invention, the reaction is preferably carried out under the protection of an inert gas (such as nitrogen, argon or helium). The reaction temperature is generally greater than or equal to 50°C, more preferably greater than or equal to 80°C, and more preferably carried out under conditions between 100°C and the boiling point of the first organic solvent. The reaction is followed by TLC detection until the reaction is complete. According to the applicant's experience, when the reaction is carried out at 110°C, the reaction time is preferably controlled at 20 to 48 hours.

[0071] In the synthesis method of the present invention, the first organic solvent is preferably benzene, toluene, chlorobenzene, or xylene, more preferably toluene; the amount of the first organic solvent can be determined as needed to fully dissolve the raw materials involved in the reaction. The first alkaline substance is preferably selected from any one of triethylamine, N,N-diisopropylethylamine (DIEPA), ethylenediamine, and 4-methylethylenediamine, more preferably triethylamine; the first alkaline substance is used in excess relative to compound S7, typically at least 5 times the molar amount of compound S7, preferably 10 to 25 times the molar amount of compound S7. The reducing agent is trichlorosilane or lithium aluminum hydride, more preferably trichlorosilane; the amount of the reducing agent is preferably 1 to 5 times the molar amount of compound S7.

[0072] The crude target compound obtained by the above method is a crude product. Therefore, the synthesis method described in the present invention also includes a step of purifying the crude target compound. Specifically, conventional purification methods can be used to purify the crude product to increase the purity of the target compound. Specifically, the crude product can be purified by silica gel column chromatography. More preferably, the reaction product is extracted before being subjected to silica gel column chromatography to reduce the burden on the silica gel column. The eluent used for elution during silica gel column chromatography is preferably a mixed solvent of petroleum ether (PE) and ethyl acetate (EA), or petroleum ether and dichloromethane. In the mixed solvent, the volume ratio of petroleum ether to ethyl acetate is preferably 20:1 to 6:1; the volume ratio of petroleum ether to dichloromethane is preferably 20:1 to 10:1. If extraction is involved, the extractant is a conventional extractant, such as ethyl acetate.

[0073] The raw material compound S7 involved in the synthesis method of the present invention can be prepared specifically by the following method:

[0074] 1) Compound S1 and Compound S2 are placed in a second organic solvent, an acidic catalyst is added to react, and an oxidant is added to the reaction mixture to continue the reaction to obtain Compound S3;

[0075] 2) Compound S3 is placed in a third organic solvent, and a second alkaline substance is added to react to remove the acetyl group from compound S3 to obtain compound S4;

[0076] 3) Compound S4 is placed in a fourth organic solvent, and a catalyst Cat is added to react to cyclize the alkyne to obtain compound S5;

[0077] 4) Compound S5 is placed in a fifth organic solvent, and a third basic substance and trifluoromethanesulfonic anhydride are added to react to protect the hydroxyl group on compound S5 to obtain compound S6;

[0078] 5) Compound S6 is placed in a sixth organic solvent, and a palladium catalyst, a phosphine ligand coordinated with the palladium catalyst, a fourth basic substance, and a phosphorus-oxy derivative are added to react to obtain compound S7;

[0079] In the above preparation method, the structures of the compounds S1 to S6 and the catalyst Cat are shown below, respectively, and the structure of the phosphorus-oxygen derivative is shown in the following formula (I):

[0080]

[0081] Among them, R and R in compounds S1 to S6 and phosphorus-oxygen derivatives 1 ~R 12 The selection and preferred range are the same as those of the compound with the structure shown in Formula 1 above.

[0082] In step 1) of the above-mentioned method for preparing compound S7, the second organic solvent can specifically be tetrahydrofuran, ethanol, N,N-dimethylformamide or p-xylene; its amount can be determined as needed to fully dissolve the raw materials involved in the reaction. The acidic catalyst is preferably p-toluenesulfonic acid, cuprous oxide or acetic acid, and its amount is generally 0.3 to 0.5 times the molar amount of compound S2. The oxidant is preferably 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), iodine, oxygen, iodobenzene diacetate or potassium permanganate, and its amount is generally 1.0 to 1.5 times the molar amount of compound S2.

[0083] In step 2) of the method for preparing compound S7, the third organic solvent can be tetrahydrofuran, methanol, or acetonitrile; its amount can be determined as needed to fully dissolve the raw materials involved in the reaction. The second alkaline substance is preferably hydrazine hydrate, triethylamine, potassium carbonate, or cesium carbonate, and its amount is generally 1.5 to 3 times the molar amount of compound S3.

[0084] In step 3) of the above-mentioned method for preparing compound S7, the fourth organic solvent can specifically be chloroform, carbon tetrachloride, 1,2-dichloroethane, dichloromethane or acetonitrile, etc.; its amount can be determined as needed to fully dissolve the raw materials participating in the reaction.

[0085] In step 4) of the method for preparing compound S7, the fifth organic solvent can be dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, or acetonitrile; its amount can be determined as needed to fully dissolve the reactants. The third alkaline substance is preferably triethylamine, diisopropylethylamine, or pyridine, and its amount is typically 1.0 to 1.5 times the molar amount of compound S5.

[0086] In step 5) of the method for preparing compound S7, the sixth organic solvent can be dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, or toluene; its amount can be determined as needed to fully dissolve the raw materials involved in the reaction. The palladium catalyst can be palladium acetate or diphenylphosphine palladium dichloride, and its amount is generally 0.1 to 0.5 times the molar amount of compound S5. The palladium catalyst ligand can be 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (XantPhos), 1,2-bis(diphenylphosphine)butane (DPPB) or (1,2-bis(diphenylphosphine)ethane (DPPE), etc., and its usage is usually 0.05 to 0.1 times the molar amount of the palladium catalyst. The fourth alkaline substance can be pyridine, N,N-diisopropylethylamine, triethylamine, ethylenediamine or 4-methylethylenediamine, etc., and its usage is used in excess relative to compound S6, usually more than 2 times the molar amount of compound S6, preferably 3 to 5 times the molar amount of compound S6.

[0087] In step 5) of the above-mentioned method for preparing compound S7, when R represents cyclohexyl, phenyl, 4-methylphenyl or 3,5-dimethylphenyl, the corresponding phosphorus-oxygen derivatives are dicyclohexylphosphine oxide, diphenylphosphine oxide, bis(p-methylphenyl)phosphine oxide, and bis(3,5-dimethylphenyl)phosphine oxide, respectively.

[0088] The reactions in steps 1) to 4) of the method for preparing compound S7 are preferably carried out at room temperature or in an ice bath. The reaction in step 5) is preferably carried out under an inert gas (e.g., nitrogen, argon, or helium) and under heating, with the reaction temperature more preferably being 100-150°C. Completion of the reaction is monitored by thin-layer chromatography in each step.

[0089] The crude product of compound S7 obtained by the above method can be purified by conventional methods such as silica gel column chromatography. The eluent used for elution during silica gel column chromatography is preferably a mixed solvent consisting of dichloromethane and methanol in a volume ratio of 20:1 to 6:1. Prior to silica gel column chromatography, the reaction mixture can be extracted with ethyl acetate, and the organic phase collected, washed with saturated sodium chloride solution, dried, and the solvent removed before silica gel column chromatography.

[0090] In the above-mentioned preparation method of compound S7, in order to improve the yield of compound S7, it is preferred to purify the product obtained in each step before using it in the subsequent step. The purification method is silica gel column chromatography or recrystallization.

[0091] In the preparation method of the above-mentioned compound S7, the raw material S1 involved can be prepared with reference to the existing literature (A. Arumugam, P. Palani, M. Anandan, V. Nutalapati, G. Chandru Senadi, Eur. J. Org. Chem., 2023, 26, e202300100.), the raw material S2 can be prepared with reference to the existing literature (L. Zeng, J. Li, S. Cui, Angew. Chem. Int. Ed., 2022, 61, e202205037), and the catalyst Cat involved can be prepared with reference to the existing literature (SMMaddox, GADawson, NC Rochester, ABA Yonon, CE Moore, ALRheingold, JLGustafson, ACS Catal., 2018, 8, 5443–5447.), or a self-designed synthesis route can be synthesized, which will not be described in detail here.

[0092] In the methods of the present invention, the first organic solvent, second organic solvent, third organic solvent, fourth organic solvent, fifth organic solvent, and sixth organic solvent all refer to organic solvents, and the terms "first," "second," "third," "fourth," "fifth," and "sixth" are merely used to distinguish between different organic solvents used in different methods or steps. Similarly, the first alkaline substance, second alkaline substance, third alkaline substance, and fourth alkaline substance all refer to alkaline substances, and the terms "first," "second," "third," and "fourth" are merely used to distinguish between them.

[0093] The applicants have experimentally discovered that the chiral monophosphine ligands derived from quinazolinones described herein can bind to metal ions to form organic molecules as complexes, and can enhance enantioselectivity in catalytic reactions. Therefore, the present invention also encompasses the use of these chiral monophosphine ligands derived from quinazolinones as catalyst ligands in catalytic reactions. Furthermore, the present invention encompasses the use of these chiral monophosphine ligands derived from quinazolinones as catalyst ligands in combination with palladium or gold catalysts in catalytic allylic substitution reactions and alkyne cyclization reactions.

[0094] Compared to the prior art, the present invention provides a series of novel quinazolinone-derived chiral monophosphine ligands and their synthesis methods. The applicants have experimentally discovered that the quinazolinone-derived chiral monophosphine ligands described herein, when used as catalyst ligands in conjunction with palladium or gold catalysts, can catalyze allylic substitution reactions and alkyne cyclization reactions, improving the selectivity of the reactions. Specifically, when used in conjunction with a palladium catalyst in the allylic substitution reaction, the enantioselectivity of the product reaches over 90%. DETAILED DESCRIPTION

[0095] In order to better explain the technical solution of the present invention, the present invention is further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0096] The catalyst Cat involved in the following examples was prepared according to the following synthetic route:

[0097]

[0098] The raw materials compound S8 (methyl 3,5-dibromobenzoate) and compound S9 (3,5-di-tert-butylphenylboronic acid) in the synthesis route can be purchased directly from the market, and the raw material S12 is prepared with reference to existing literature (B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett. 2005, 7, 1967-1969).

[0099] The specific preparation method is:

[0100] ① Under argon protection, compound S8 (5 mmol), compound S9 (15 mmol), Pd(PPh3)4 (0.2 mmol), THF / H2O (3:1, V / V, 120 mL), and Cs2CO3 (6 mmol) were added to a 250 mL round-bottom flask in sequence with electromagnetic stirring, and the mixture was stirred in an oil bath at 80°C (the reaction was monitored by TLC, the developing solvent was V PE After the reaction was completed, the mixture was returned to room temperature, extracted with EA (40 mL × 3), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (eluent: V PE :VEA =50:1) to obtain compound S10 as a white solid.

[0101] ② Under electromagnetic stirring, compound S10 (3 mmol), THF / H2O (5:1, V / V, 24 mL), and KOH (15 mmol) were added to a 100 mL round-bottom flask in sequence and stirred in an oil bath at 60°C (the reaction was monitored by TLC, developing solvent: V PE :V EA =10:1). After the reaction was completed, the temperature was restored to room temperature, 1 M HCl solution was added to adjust the pH to 3, extracted with EA (30 mL × 3), dried over anhydrous Na2SO4, the solvent was removed under reduced pressure, and purified by column chromatography (eluent: V PE :V EA =10:1) to obtain compound S11 as a white solid.

[0102] ③ Under electromagnetic stirring, compound S11 (1 mmol), DCM (20 mL), oxalyl chloride (1.1 mmol), and 3 drops of DMF were added to a 100 mL round-bottom flask in sequence, stirred at 0°C for 15 min, transferred to room temperature and reacted for 1 h, and then added to compound S12 treated with NaH and reacted at room temperature for 12 h (the reaction was monitored by TLC, developing solvent: V PE :V EA =1:1). After the reaction was completed, the mixture was extracted with DCM (30 mL×3), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (eluent: V PE :V EA =1:2) to obtain a white solid compound Cat.

[0103] Example 1

[0104] The chiral monophosphine ligand derived from quinazolinone of the present invention is synthesized according to the following synthetic route.

[0105]

[0106] 1a: R=Ph,R 1 =H, R 2 =H, R 3 =H, R 4 =H, R 5 =Me, R 6 =H, R 7 =H, R 8 =H, R 9 =H, R 10 =H, R 11 =H, R 12 =H;

[0107] 1b: R=Ph,R1 =H,R 2 =H,R 3 =H,R 4 =Cl,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0108] 1c:R=Ph,R 1 =H,R 2 =H,R 3 =Me,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0109] 1d:R=Ph,R 1 =H,R 2 =Br,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0110] 1e:R=Ph,R 1 =OMe,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0111] 1f:R=Ph,R 1 =H,R 2 =H,R3 =H,R 4 =H,R 5 =Bn,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0112] 1g:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =Me,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0113] 1h:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =Br,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0114] 1i:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =Cl,R 9 =H,R 10 =H,R 11 =H,R 12 =H;

[0115] 1j:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =Ph,R 10 =H,R 11 =H,R 12 =H;

[0116] 1k:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =OMe,R 11 =H,R 12 =H;

[0117] 1l:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =Me,R 12 =H;

[0118] 1m:R=Cy,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =Me,R 12 =H;

[0119] 1n:R=p-Tolyl,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R7 =H, R 8 =H, R 9 =H, R 10 =H, R 11 =Me, R 12 =H;

[0120] 1o: R=3,5-2MeC6H3,R 1 =H, R 2 =H, R 3 =H, R 4 =H, R 5 =Me, R 6 =H, R 7 =H, R 8 =H, R 9 =H, R 10 =H, R 11 =Me, R 12 =H.

[0121] The specific synthesis method is:

[0122] 1) Under electromagnetic stirring, compound S2 (3 mmol), anhydrous MgSO4 (540 mg), THF (60 mL), TsOH (p-toluenesulfonic acid, 0.9 mmol) were added to a 100 mL round-bottom flask in sequence, and the mixture was stirred at room temperature for 30 min. Compound S1 (3 mmol) was added and the mixture was stirred at room temperature for 1 h (the reaction was monitored by TLC: V PE :V EA =2:1). After the reaction was completed, the mixture was transferred to an ice-water bath and stirred for 5 min. DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone, 3.3 mmol) was added and stirred for 10 min in an ice-water bath (the reaction was monitored by TLC, the developing solvent was V PE :V EA =1:4). After the reaction was completed, the product was filtered and washed with EA (20 mL). The solvent was removed from the filtrate under reduced pressure and purified by silica gel column chromatography (eluent: V PE :V EA =20:1, 10:1, 6:1, V DCM , V PE :V EA =2:1) ​​to obtain yellow solid compound S3.

[0123] 2) Under electromagnetic stirring, compound S3 (3 mmol) and THF (30 mL) were added to a 100 mL round-bottom flask in sequence, and the mixture was stirred and cooled in an ice-water bath for 5 min. Hydrazine hydrate (6 mmol) was added and the mixture was stirred and reacted in an ice-water bath for 10 min (the reaction was monitored by TLC, developing solvent: V PE :V EAAfter the reaction was completed, the mixture was extracted with EA (30 mL × 3), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The resulting crude product was recrystallized (DCM:PE=1:5), filtered, and washed with EA to obtain a yellow solid compound S4.

[0124] 3) Compound S4 (2 mmol), CHCl3 (100 mL), and catalyst Cat (5 mol%) were added to a 100 mL round-bottom flask in sequence under electromagnetic stirring and reacted at room temperature for 20 h (the reaction was monitored by TLC, developing solvent: V PE :V EA =4:1). The solvent was removed under reduced pressure and the mixture was purified by silica gel column chromatography (eluent: V PE :V EA =20:1, 10:1, 1:6, DCM) to give yellow solid compound S5.

[0125] 4) Under electromagnetic stirring, compound S5 (2 mmol) and DCM (30 mL) were added to a 100 mL round-bottom flask in sequence, and the mixture was stirred and cooled in an ice-water bath for 5 min. Et3N (2.4 mmol) was added and the reaction was continued for 10 min. Tf2O (trifluoromethanesulfonic anhydride, 3 mmol) was added and the mixture was stirred and reacted in an ice-water bath for 5 min (the reaction was monitored by TLC, developing solvent: V PE :V EA =10:1). After the reaction was completed, the mixture was extracted with DCM (20 mL×3), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (eluent: V PE :V EA =1:20, 1:10) to give yellow solid compound S6. Here, only the substituents are selected as R=Ph, R 1 =H, R 2 =H, R 3 =H, R 4 =H, R 5 =Me, R 6 =H, R 7 =H, R 8 =H, R 9 =H, R 10 =H, R 11 =H, R 12 Characterization data of compound S6 with =H:

[0126] Pale yellow solid, 0.986 g, 85% yield, Mp: 177-178 ° C; 1H NMR (400MHz, CDCl3): δ8.84(d,J=2.4Hz,1H),8.47(dd,J=8.2,1.5Hz,1H),7.99–7.91(m,2H),7.86–7.77(m,1H),7.72(dd ,J=8.3,1.1Hz,1H),7.68–7.59(m,1H),7.57–7.40(m,4H),7.01(s,1H),6.39(d,J=2.3Hz,1H),3.97(s,3H),3.10(s,3H). 13 C NMR (100MHz, CDCl3): δ163.3,161.2,157.3,147.4,147.0,142.6,138.1,136.7,134.8,132.5,132.0,131.8,129 .5,128.1,127.6,127.5,126.9,126.5,126.2,125.9,125.1,120.1,119.1,118.3,109.0,98.9,98.0,55.8,55.7. 19 F NMR(376MHz,CDCl3):δ-74.47.HRMS(ESI)m / z calcd for C 29 H 20 F3N2O6S[M+H] + 581.0989,found 581.0967.

[0127] 5) Under argon protection, compound S6 (2 mmol), Pd(OAc)2 (0.2 mmol), DPPE (1,2-bis(diphenylphosphino)ethane, 0.1 mmol), DMSO (20 mL), and DIEPA (N,N-diisopropylethylamine, 10 mmol) were added to a 100 mL round-bottom flask in sequence with electromagnetic stirring. The mixture was stirred at room temperature for 10 min, and diphenylphosphine oxide (4 mmol) was added. The mixture was transferred to a 120 °C oil bath and stirred for 20 h (the reaction was monitored by TLC, developing solvent: V PE :V EA =1:2). After the reaction was completed, the product was extracted with EA (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (eluent: V DCM , V DCM :V MeOH =20:1) to give yellow solid compound S7. Here, only the substituents selected as R=Ph, R 1 =H, R 2 =H, R 3 =H, R4 =H, R 5 =Me, R 6 =H, R 7 =H, R 8 =H, R 9 =H, R 10 =H, R 11 =H, R 12 Characterization data of compound S7 with =H:

[0128] Yellow solid, 1.137 g, 98% yield, Mp: 125-126 ° C; 1 H NMR (400MHz, DMSO-d6): δ8.54(d,J=2.3Hz,1H),8.33(d,J=8.0Hz,1H),8.06–7.95(m,2H),7.87(t,J=7.7Hz,1H),7.70– 7.35(m,15H),7.29(t,J=7.4Hz,1H),7.22–7.13(m,2H),6.68(s,1H),6.47(d,J=2.4Hz,1H),3.88(s,3H),2.96(s,3H). 13 C NMR (100MHz, DMSO-d6): δ162.7,160.8,157.6,147.2,146.8,145.6,145.5,141.6,13 7.0,135.4,134.5,134.2,133.9,133.5,133.1,132.1,132.0,131.9,131.9,131.6,13 1.5,131.5,128.9,128.8,128.5,128.4,128.3,128.2,128.1,127.9,127.7,127.5,127.4,127.3,127.0,126.4,126.2,126.0,124.4,119.7,110.2,99.8,97.8,56.2,56.1. 31 P NMR(160MHz,DMSO-d6):δ26.26.HRMS(ESI)m / z calcdfor C 40 H 30 N2O4P[M+H] + 633.1938, found 633.1912.

[0129] 6) Under argon protection, compound S7 (0.1 mmol), toluene (5 mL), Et3N (2.4 mmol), and HSiCl3 (0.5 mmol) were added sequentially to a 25 mL reaction tube with electromagnetic stirring. The mixture was stirred at room temperature for 10 min, and then transferred to a 110°C oil bath and stirred for 24 h (the reaction was monitored by TLC, developing solvent: V PE :V EA =10:1). After the reaction was completed, the product was extracted with EA (20 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (eluent: V PE :V EA =10:1) to obtain the target product 1 (i.e., a chiral monophosphine ligand derived from quinazolinone with the structure shown in Formula 1).

[0130] The different target products and their characterizations are as follows: 1a: yellow solid, 0.053 g, 86% yield; mp 139-140°C; 1 H NMR (400MHz, CDCl3): δ8.84(d,J=2.2Hz,1H),8.44(d,J=8.1Hz,1H),7.82(d,J=8.2Hz,1H),7.76–7.71(m,2H),7.65–7.59(m,2H), 7.47–7.41(m,2H),7.37–7.30(m,2H),7.24–7.20(m,10H),6.82(d,J=1.8Hz,1H),6.23(d,J=2.3Hz,1H),3.94(s,3H),2.82(s,3H). 13 C NMR (100MHz, CDCl3): δ163.5,160.9,157.4,147.7,147.3,147.1,146.9,143.8,137.9,137.8,137.7,137.6,134.6,133.9,133.3,133.1, 131.7,131.1,129.7,128.3,128.4,128.2,127.8,127.6,127.3,126. 7,126.5,126.3,125.5,124.4,119.9,110.6,98.8,97.9,55.7,55.3. 31 P NMR(160MHz,CDCl3):δ-13.8.HRMS(ESI)m / z calcd for C 40 H 30 N2O3P[M+H] + :617.1989, found617.1962. Its structural formula is as follows:

[0131]

[0132] 1b: yellow solid, 0.055 g, 85% yield; mp 185-186°C; 1 H NMR (400MHz, CDCl3): δ8.87(d,J=2.2Hz,1H),8.11–8.07(m,2H),8.01–7.96(m,2H),7.91–7.84(m,2H),7.78–7.73(m, 9H),7.59–7.53(m,4H),7.01(d,J=2.7Hz,1H),6.91(d,J=2.3Hz,1H),6.25(d,J=2.5Hz,1H),3.97(s,3H),2.85(s,3H). 13 C NMR (100MHz, CDCl3): δ161.3,160.9,158.2,151.5,149.7,148.5,141.9,137.8,137.6,137.3,137.1,133.9,133.8,133.1,132.7,132.4, 128.8,128.7,128.4,127.8,127.7,127.6,126.8,126.4,125.9,125. 4,124.8,123.7,123.6,116.9,114.9,110.7,98.4,98.2,55.8,55.7. 31 P NMR(160MHz,CDCl3):δ-13.1.HRMS(ESI)m / z calcd for C 40 H 29 ClN2O3P[M+H] + :651.1604, found 651.1598. Its structural formula is as follows:

[0133]

[0134] 1c: yellow solid, 0.056 g, 89% yield; mp 151-152°C; 1H NMR (400MHz, CDCl3): δ8.87(d,J=2.2Hz,1H),8.25(d,J=8.2Hz,1H),7.85–7.77(m,2H),7.62(d,J=1.4Hz,2H),7.52–7.45(m,9H),7.40–7. 36(m,2H),7.34–7.29(m,2H),6.95(d,J=2.5Hz,1H),6.89(d,J=2.1Hz,1H),6.21(d,J=2.3Hz,1H),3.91(s,3H),2.78(s,3H).2.56(s,3H). 13 C NMR (100MHz, CDCl3): δ163.6,160.3,157.8,151.7,149.5,148.4,141.7,137.9,137.4,137.2,137.0,133.7,133.7,133.4,132.8,132.5,128 .9,128.6,128.5,127.7,127.6,127.6,126.6,126.4,125.7,125.3,12 4.5,123.5,123.6,116.7,114.8,110.8,99.1,98.5,55.9,55.7,21.5. 31 P NMR(160MHz,CDCl3):δ-14.1.HRMS(ESI)m / z calcd for C 41 H 32 N2O3P[M+H] + :631.2151, found 631.2138. Its structural formula is as follows:

[0135]

[0136] 1d: yellow solid, 0.059 g, 85% yield; mp 175-176 °C; 1 H NMR (400MHz, CDCl3): δ8.83(d,J=2.4Hz,1H),8.31(d,J=8.6Hz,1H),7.93–7.82(m,3H),7.63–7.54(m,2H),7.47–7.40 (m,2H),7.31–7.25(m,3H),7.27–7.21(m,9H),6.87(d,J=2.5Hz,1H),6.25(d,J=2.4Hz,1H),3.94(s,3H),2.82(s,3H). 13C NMR (100MHz, CDCl3): δ163.1,160.6,158.7,151.8,151.6,148.9,148.3,146.1,145.6,140.7,137.5,137.1,134.8,133.7,133.5,132.7, 132.3,131.0,130.6,128.8,128.7,128.6,128.3,127.4,126.3,126. 0,125.6,124.8,124.0,116.5,110.7,109.0,99.8,96.9,56.7,55.8. 31 P NMR(160MHz,CDCl3):δ-12.8.HRMS(ESI)m / z calcd for C 40 H 29 BrN2O3P[M+H] + :695.1099, found 695.1105. Its structural formula is as follows:

[0137]

[0138] 1e: yellow solid, 0.059 g, 91% yield; mp 175-176 °C; 1 H NMR (400MHz, CDCl3): δ8.80(d,J=2.4Hz,1H),8.55(d,J=8.4Hz,1H),7.84–7.80(m,1H),7.78–7.71(m,2H),7.60–7.51(m,9H) ,7.41–7.36(m,4H),7.30–7.24(m,3H),6.75(d,J=2.0Hz,1H),6.15(d,J=2.5Hz,1H),3.91(s,3H),3.52(s,3H),2.82(s,3H). 13 C NMR (100MHz, CDCl3): δ163.3,160.6,157.9,153.8,151.6,147.7,140.6,138.3,138.9,137.5,137.1,133.6,132.8,132.4,128.9,128.5,128 .3,127.7,127.5,127.4,126.6,126.2,126.0,125.6,125.1,124.9,12 3.6,120.8,118.8,114.8,113.5,110.9,98.9,98.6,56.3,55.9,55.7. 31P NMR(160MHz,CDCl3):δ-11.5.HRMS(ESI)m / z calcd for C 41 H 32 N2O4P[M+H] + :647.2100, found 647.2112. Its structural formula is as follows:

[0139]

[0140] 1f: yellow solid, 0.063 g, 82% yield; mp 140-141 °C; 1 H NMR (400MHz, CDCl3): δ8.25 (dd, J=7.9, 1.3Hz, 1H), 8.13–8.06 (m, 1H), 7.96–7.92 ( m,1H),7.94–7.88(m,1H),7.84(dd,J=8.5,1.2Hz,1H),7.75–7.71(m,1H),7.66–7. 60(m,1H),7.54–7.46(m,3H),7.45–7.39(m,4H),7.39–7.25(m,13H),7.18(d,J=2. 2Hz,1H),7.16–7.11(m,4H),6.49(d,J=2.2Hz,1H),5.61(s,1H),5.01–4.95(m,4H). 13 C NMR (100MHz, CDCl3): δ162.3,160.6,158.9,158.8,145.6,145.5,140.7,139.1,138 .6,137.7,137.1,136.7,135.4,133.7,133.6,133.4,132.7,132.3,131.0,130.6,1 30.1,129.1,128.9,128.8,128.7,128.3,128.0,127.6,127.3,127.1,126.7,126.6,126.3,126.0,124.0,120.8,118.1,113.5,110.4,104.7,102.0,96.9,71.2,70.8. 31 P NMR(162MHz,CDCl3):δ-12.4.HRMS(ESI)m / z calcd forC 52 H 38 N2O4P[M+H] + :769.2620, found 769.2612. Its structural formula is as follows:

[0141]

[0142] 1g: yellow solid, 0.056g, 88% yield; mp 150-151°C; 1 H NMR (400MHz, CDCl3): δ8.27(dd,J=7.9,1.3Hz,1H),8.11(dd,J=7.2,1.6Hz,1H),7.93–7.88(m,1H),7.84(dd,J=8.5,1.2Hz,1H),7.74 –7.71(m,1H),7.55–7.43(m,5H),7.39–7.35(m,2H),7.35–7.25(m,8H),6.53(d,J=2.2Hz,1H),5.64(s,1H),3.90(s,3H),3.81(s,3H). 13 C NMR (100MHz, CDCl3): δ165.5,162.1,161.8,151.9,148.4,147.3,147.1,140.0,138.7,137.2,136.1,134.9,132.9,132.8,132.5,132.2,131.8, 128.9,128.7,128.6,128.1,128.0,127.8,127.5,127.2,126.8,126.7, 126.6,126.5,124.1,120.8,119.7,116.3,96.1,94.6,56.2,55.1,22.9. 31 P NMR(160MHz,CDCl3):δ-14.9.HRMS(ESI)m / z calcd for C 41 H 32 N2O3P[M+H] + :631.2151, found 631.2142. Its structural formula is as follows:

[0143]

[0144] 1h: yellow solid, 0.063 g, 90% yield; mp 172-173 °C; 1H NMR (400MHz, CDCl3): δ8.28–8.19(m,3H),7.84(dd,J=8.5,1.2Hz,1H),7.80(d,J=1.3Hz,1H),7.76–7.72(m,1H),7.60–7.46(m,3H), 7.44(d,J=2.2Hz,1H),7.39–7.26(m,6H),7.13(dt,J=7.7,1.3Hz,4H),6.53(d,J=2.2Hz,1H),5.61(s,1H),3.90(s,2H),3.81(s,2H). 13 C NMR (100MHz, CDCl3): δ165.5,162.1,161.8,152.0,148.4,147.3,147.1,138.7,136.6,136.5,136.1,134.0,133.7,133.3,132.3,132.0,131 .2,128.7,128.6,128.6,128.1,128.1,127.3,126.9,126.7,126.5,12 6.4,124.7,124.1,123.2,120.3,119.7,116.0,96.1,94.6,56.2,55.1. 31 P NMR(160MHz,CDCl3):δ-11.3.HRMS(ESI)m / z calcd for C 40 H 29 BrN2O3P[M+H] + :695.1099, found695.1089. Its structural formula is as follows:

[0145]

[0146] 1i: yellow solid, 0.057 g, 87% yield; mp 167-168 ° C; 1 H NMR (400MHz, CDCl3): δ8.25(dd,J=7.9,1.3Hz,1H),8.11–8.04(m,2H),7.84(dd,J=8.5,1.2Hz,1H),7.74–7.71(m,1H),7.60(dd,J=8.5,1.2Hz, 1H),7.52–7.42(m,4H),7.39–7.32(m,2H),7.35–7.26(m,4H),7.21–7.1 0(m,4H),6.53(d,J=2.2Hz,1H),5.61(s,1H),3.90(s,2H),3.79(s,2H). 13C NMR(100MHz, CDCl3):165.5,162.1,161.8,152.0,148.4,147.7,147.3,138.7,137.2,136.8,136.1,134.0,133.7,132.1,132.0,131.5,1 31.4,128.7,128.6,128.4,128.1,127.1,126.7,126.5,126.1,125.8,125.5,124.1,122.7,120.3,119.7,116.0,96.1,94.6,56.2,55.1. 31 P NMR(160MHz,CDCl3):δ-11.9.HRMS(ESI)m / z calcd for C 40 H 29 ClN2O3P[M+H] + :651.1604, found 651.1601. Its structural formula is as follows:

[0147]

[0148] 1j: yellow solid, 0.059 g, 85% yield; mp 142-143 °C; 1 H NMR (400MHz, CDCl3): δ8.36 (d, J=8.6Hz, 1H), 8.25 (dd, J=7.9, 1.3Hz, 1H), 8.01–7.97 (m, 1H ),7.94–7.91(m,1H),7.84(dd,J=8.5,1.2Hz,1H),7.75–7.71(m,1H),7.69–7.64(m,1H),7.6 4–7.58(m,2H),7.58(dd,J=8.2,2.2Hz,1H),7.52–7.47(m,1H),7.49–7.41(m,3H),7.41–7. 26(m,7H),7.16–7.11(m,4H),6.53(d,J=2.2Hz,1H),5.61(s,1H),3.90(s,2H),3.81(s,2H). 13C NMR (100MHz, CDCl3): δ165.5,162.1,161.8,152.0,148.4,147.6,147.2,140. 9,139.6,138.7,138.2,137.5,136.8,136.7,136.1,134.0,134.0,133.8,133 .6,132.1,131.2,129.1,128.7,128.6,128.1,127.9,127.8,127.6,127.4,126.8,126.5,126.3,124.1,123.3,120.5,119.7,116.0,96.1,94.6,56.2,55.1. 31 P NMR(160MHz,CDCl3):δ-12.4.HRMS(ESI)m / zcalcdfor C 46 H 34 N2O3P[M+H] + :693.2307, found 693.2315. Its structural formula is as follows:

[0149] 1k: yellow solid, 0.059 g, 91% yield; mp 151-152 °C; 1 H NMR (400MHz, CDCl3): δ8.25 (dd, J=7.9, 1.3Hz, 1H), 7.87–7.82 (m, 2H), 7.76 (dd, J=8 .7,0.7Hz,1H),7.74–7.71(m,1H),7.60–7.55(m,1H),7.52–7.46(m,2H),7.44(d,J=2 .2Hz,1H),7.39–7.31(m,2H),7.35–7.26(m,4H),7.17–7.11(m,4H),7.07(dd,J=8.8, 1.9Hz,1H),6.53(d,J=2.2Hz,1H),5.61(s,1H),3.90(s,2H),3.82(d,J=10.1Hz,6H). 13C NMR (100MHz, CDCl3): δ165.5,162.1,161.8,159.8,152.0,148.4,147.5,138.7,137.8,136.8,136.3,136.1,134.0,133.4,133.1,132.0,131.5, 130.8,128.7,128.6,128.4,128.4,128.1,126.8,126.6,126.5,126.1, 124.2,120.2,119.6,115.9,113.4,106.9,96.1,94.6,56.2,55.6,55.0. 31 P NMR(160MHz,CDCl3):δ-12.4.HRMS(ESI)m / z calcd for C 41 H 32 N2O4P[M+H] + :647.2100, found647.2104. Its structural formula is as follows:

[0150]

[0151] 1l: yellow solid, 0.057 g, 90% yield; mp 161-162 ° C; 1 H NMR (400MHz, CDCl3): δ8.25 (dd, J=7.9, 1.3Hz, 1H), 7.84 (dd, J=8.5, 1.2Hz, 2H), 7.83 –7.78(m,1H),7.74–7.70(m,1H),7.61(dd,J=8.0,1.5Hz,1H),7.52–7.48(m,1H),7.4 5(d,J=2.2Hz,1H),7.44–7.35(m,1H),7.38–7.26(m,5H),7.16–7.11(m,4H),7.05–7. 02(m,1H),6.53(d,J=2.2Hz,1H),5.64(s,1H),3.90(s,2H),3.81(s,2H),2.78(s,3H). 13C NMR (100MHz, CDCl3): δ165.5,162.1,161.7,151.8,148.5,147.2,138.7,138.0,137.4,136.8,136.1,135.4,134.5,134.0,133.7,133.3,132 .6,131.2,131.0,128.6,128.6,128.3,128.09,126.9,126.7,126.6,1 26.4,125.3,124.1,120.7,119.7,116.3,96.1,94.5,56.2,55.1,20.3. 31 P NMR(160MHz,CDCl3):δ-13.9.HRMS(ESI)m / z calcd for C 41 H 32 N2O3P[M+H] + :631.2151, found631.2142. Its structural formula is as follows:

[0152]

[0153] 1m: yellow solid, 0.051 g, 82% yield; mp 152-153 ° C; 1 H NMR (400MHz, CDCl3) δ8.25 (dd, J=7.9, 1.3Hz, 1H), 8.14–8.06 (m, 1H), 7.93–7.86 (m,2H),7.84(dd,J=8.5,1.2Hz,1H),7.75–7.68(m,2H),7.53–7.49(m,1H),7.52 –7.46(m,2H),7.44(d,J=2.2Hz,1H),6.53(d,J=2.2Hz,1H),5.62(s,1H),3.90(s ,2H),3.81(s,2H),2.51(p,J=7.4Hz,2H),1.79–1.69(m,4H),1.66–1.31(m,16H). 13C NMR (100MHz, CDCl3) δ165.48,162.12,161.76,151.95,148.42,139.58,138.70,136.10,133.86,132.27,132.01,128.66,127.85,127.27,1 27.20,127.17,127.15,126.75,126.48,125.72,124.08,120.54,119 .73,115.91,96.07,94.57,56.22,55.05,36.69,30.08,27.01,26.50. 31 P NMR(160MHz,CDCl3):δ-10.4.HRMS(ESI)m / zcalcd for C 40 H 42 N2O3P[M+H] + :629.2928, found629.2907. Its structural formula is as follows:

[0154]

[0155] 1n: yellow solid, 0.061 g, 94% yield; mp 171-172 °C; 1 H NMR (400MHz, CDCl3): δ8.25 (dd, J=7.9, 1.3Hz, 1H), 8.14–8.06 (m, 1H), 7.96–7.93 ( m,1H),7.94–7.88(m,1H),7.84(dd,J=8.5,1.2Hz,1H),7.72(ddd,J=8.4,7.0,1.3Hz ,1H),7.66–7.60(m,1H),7.54–7.46(m,3H),7.44(d,J=2.2Hz,1H),7.27–7.24(m,4H ),7.12–7.04(m,5H),6.53(d,J=2.2Hz,1H),5.61(s,1H),3.90(s,2H),3.81(s,2H). 13 C NMR (100MHz, CDCl3) δ165.5,162.1,161.8,152.0,148.4,138.8,138.7,136.7,136.1,134.9,133.9,133.7,132.7,131.7,131 .5,129.8,128.7,128.2,127.3,127.2,127.2,126.8,126.5,125.7,124.1,120.5,119.7,116.0,96.1,94.6,56.2,55.1,21.3.31 P NMR(160MHz,CDCl3):δ-14.8.HRMS(ESI)m / zcalcdfor C 42 H 34 N2O3P[M+H] + :645.2302, found 645.2298. Its structural formula is as follows:

[0156]

[0157] 1o: yellow solid, 0.056 g, 84% yield; mp 167-168 ° C; 1 H NMR (400MHz, CDCl3): δ8.25 (dd, J=7.9, 1.3Hz, 1H), 8.14–8.06 (m, 1H), 7.94 (t, J=8.3Hz ,1H),7.94–7.88(m,1H),7.84(dd,J=8.5,1.2Hz,1H),7.72(ddd,J=8.4,7.0,1.3Hz,1H) ,7.66–7.60(m,1H),7.54–7.46(m,3H),7.44(d,J=2.2Hz,1H),6.97(dd,J=2.2,1.2Hz,4 H), 6.93 (t, J = 2.3Hz, 2H), 6.53 (d, J = 2.2Hz, 1H), 5.61 (s, 1H), 3.90 (s, 2H), 3.81 (s, 2H). 13 C NMR (100MHz, CDCl3): δ165.5,162.1,161.8,152.0,148.4,140.4,138.7,136.6,136.1,135.9,133.9,133.7,131.7,131.5,130.0,128.7, 128.6,128.5,128.5,128.5,128.2,127.3,127.2,127.2,126.8,126.5,125.7,124.1,120.5,119.7,116.0,96.1,94.6,56.2,55.1,21.1. 31 P NMR(160MHz,CDCl3):δ28.5.HRMS(ESI)m / z calcd for C 44 H 37 N2O3P[M+H] + :672.2542, found 672.2538. Its structural formula is as follows:

[0158]

[0159] Example 2

[0160] Example 1. Preparation of compound S7 corresponding to compound 1a:

[0161] Compound S7 was prepared by the following method using compound S6 corresponding to compound 1a prepared according to the method described in Example 1 as a raw material:

[0162] Under argon protection, compound S6 (2 mmol), diphenylphosphine palladium dichloride (0.2 mmol), DPPB (1,2-bis(diphenylphosphino)butane, 0.1 mmol), DMF (20 mL), and triethylamine (6 mmol) were added to a 100 mL round-bottom flask in sequence with electromagnetic stirring. The mixture was stirred at room temperature for 10 min, and a phosphorus oxide derivative (R is a phenyl group in the structural formula of the phosphorus oxide derivative, 4 mmol) was added. The mixture was transferred to an oil bath at 150 ° C and stirred for 20 h (the reaction was monitored by TLC, the developing solvent was V PE :V EA =1:2). After the reaction was completed, the product was extracted with EA (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (eluent: V DCM , V DCM :V MeOH =20:1) to give 0.657 g of a yellow solid with a yield of 52%.

[0163] The obtained yellow solid was characterized by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry and confirmed to be compound S7 corresponding to compound 1a.

[0164] Example 2. Preparation of compound S7 corresponding to compound 1m:

[0165] Compound S7 was prepared by the following method using compound S6 corresponding to compound 1m prepared according to the method described in Example 1 as a raw material:

[0166] Under argon protection, compound S6 (2 mmol), palladium acetate (0.2 mmol), DPPB (4,5-bis(diphenylphosphino-9,9-dimethylxanthene, 0.1 mmol), 1,4-dioxane (20 mL), and ethylenediamine (6 mmol) were added to a 100 mL round-bottom flask in sequence with electromagnetic stirring. The mixture was stirred at room temperature for 10 min, and a phosphorus oxide derivative (R in the structural formula of the phosphorus oxide derivative is cyclohexyl, 4 mmol) was added. The mixture was transferred to an oil bath at 100 ° C and stirred for reaction until completion (the reaction was monitored by TLC, developing solvent: V PE :V EA=1:2). After the reaction was completed, the product was extracted with EA (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (eluent: V DCM , V DCM :V MeOH =20:1) to give 0.555 g of a yellow solid with a yield of 43%.

[0167] The obtained yellow solid was characterized by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry and confirmed to be compound S7 corresponding to compound 1m.

[0168] Example 3. Preparation of compound 1a:

[0169] Compound S7 prepared in Example 1 of this embodiment was used as a raw material to prepare compound 1a according to the following method:

[0170] Under argon protection, compound S7 (0.1 mmol), xylene (5 mL), ethylenediamine (2.0 mmol), and HSiCl3 (0.3 mmol) were added to a 25 mL reaction tube in sequence with electromagnetic stirring. The mixture was stirred at room temperature for 10 min and then transferred to an oil bath at 115 °C and stirred for 24 h (the reaction was monitored by TLC, developing solvent: V PE :V EA =10:1). After the reaction was completed, the product was extracted with EA (20 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (eluent: V PE :V EA =10:1) to give 0.046 g of a yellow solid with a yield of 75%.

[0171] The obtained yellow solid was characterized by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry and confirmed to be compound 1a.

[0172] Example 4. Preparation of Compound 1a:

[0173] Repeat Example 3 above, except that N,N-diisopropylethylamine was used instead of ethylenediamine. The reaction was stirred in an oil bath at 130°C until completion. Finally, 0.043 g of a yellow solid was obtained, with a yield of 71%.

[0174] The obtained yellow solid was characterized by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrometry and confirmed to be compound 1a.

[0175] Example 5. Preparation of Compound 1m:

[0176] Compound S7 prepared in Example 2 of this embodiment was used as a raw material to prepare compound 1m according to the following method:

[0177] Under argon protection, compound S7 (0.1 mmol), benzene (mL), 4-methylethylenediamine (1.5 mmol), and HSiCl3 (0.3 mmol) were added to a 25 mL reaction tube in sequence with electromagnetic stirring. After mixing evenly, the mixture was transferred to an 80 °C oil bath and stirred until the reaction was complete (the reaction was monitored by TLC, developing solvent: V PE :V EA =10:1). After the reaction was completed, the product was extracted with EA (20 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (eluent: V PE :V EA =10:1) to give 0.039 g of a yellow solid with a yield of 62%.

[0178] The obtained yellow solid was characterized by H NMR, C NMR and high-resolution mass spectrometry and confirmed to be compound 1m.

[0179] Experimental Example 1: Asymmetric reaction of allyl substitution catalyzed by coordination of compound 1a with palladium.

[0180]

[0181] Under argon protection, diallylpalladium dichloride (2.5 mol%), compound 1a (5 mol%), acetonitrile (1 mL) were added to a 25 mL reaction tube with electromagnetic stirring, and the mixture was stirred at room temperature for 30 min. Compound 2 (1,3-bis(4-bromophenyl)allyl acetate, 0.2 mmol), K2CO3 (3 mmol), compound 3 (indole, 0.1 mmol), acetonitrile (1 mL) were added, and the reaction was stirred at -5 ° C for 24 h (the reaction was monitored by TLC: V PE :V EA =10:1). After the reaction was completed, the solvent was removed under reduced pressure and the mixture was purified by silica gel column chromatography (eluent: V PE :V EA =10:1) to give compound 4 as a white solid (known compound, B. Feng, Y.-F. Zhang, S. Li, G.-Y. You, J. Xuan, Eur. J. Org. Chem., 2024, 27, e202300861). 1H NMR (400 MHz, CDCl3): δ 8.03 (s, 1H), 7.45–7.30 (m, 6H), 7.27–7.14 (m, 5H), 7.05–7.01 (m, 1H), 6.89 (d, J = 2.5 Hz, 1H), 6.68–6.63 (m, 1H), 6.32 (dd, J = 15.9, 3.5 Hz, 1H), 5.06 (d, J = 7.1 Hz, 1H). Enantiomeric excess: 91%, determined by HPLC (FLM chiral AD column, n-hexane / isopropanol = 30 / 60, flow rate 0.5 mL / min, T = 25°C, 280 nm): t 1 =12.176min(minor),t 2 =15.715min(major).

[0182] Experimental Example 2: Asymmetric cyclization of alkynes catalyzed by gold coordination with compound 1a.

[0183]

[0184] Under argon protection, under electromagnetic stirring, 1a (5 mol%), dimethyl sulfide gold chloride (5 mol%), and DCM (1 mL) were added to a 25 mL reaction tube in sequence, and the reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and AgNTf2 (5 mol%) and DCE (1 mL) were added. The reaction was stirred at room temperature for 15 min. Compound 5 was added and the reaction was stirred at 30 ° C for 60 h (the reaction was monitored by TLC: V PE :V EA =6:1). After the reaction was completed, the solvent was removed under reduced pressure and purified by column chromatography (eluent: V PE :V EA =6:1) to obtain yellow solid compound 6.

[0185] Yellow solid, 0.039 g, 72% yield; mp 169-170 ° C; 1 H NMR (400MHz, CDCl3): δ8.84(d,J=2.4Hz,1H),8.46(dd,J=8.1,1.5Hz,1H),7.88–7.78(m,3H),7.70(d,J=8.1,1H),7.59–7.51(m,1H), 7.52–7.45(m,1H),7.40–7.31(m,3H),7.23–7.05(m,5H),6.97(s,1H),6.39(d,J=2.3Hz,1H),5.13(s,1H),3.97(s,2H),3.04(s,2H). 13C NMR (100MHz, CDCl3): δ163.6,160.5,157.9,151.7,148.3,147.3,140.8,138.3,137.4,134.5,132.6,128.9,128.6,128.3,127 .9,127.6,126.9,126.4,126.1,125.3,124.9,124.4,123.7,119.7,115.1,110.8,98.8,98.5,71.2,55.9,55.7.HRMS(ESI)m / z calcd for C 35 H 26 N2NaO4[M+Na] + :561.1785, found 561.1760. Enantiomeric excess: 72%, determined by HPLC (FLM chiral AD column, n-hexane / isopropanol = 60 / 40, flow rate 0.5 mL / min, T = 25 ° C, 280 nm): t 1 =10.649min(major),t 2 =14.244min(minor).

Claims

1. A chiral monophosphine ligand derived from quinazolinone having the structure shown in the following formula 1: in, R represents a cyclohexyl group or a phenyl group, or a mono- or di-substituted phenyl group; R 1 Represents a hydrogen atom or C 1～4 Alkoxy; R 2 represents a hydrogen atom or a halogen atom; R 3 Represents a hydrogen atom or C 1～4 Alkyl; R 4 represents a hydrogen atom or a halogen atom; R 5 Indicates C 1～4 an alkyl or benzyl group; R 6 Represents a hydrogen atom or C 1～4 Alkyl; R 7 represents a hydrogen atom or a halogen atom; R 8 represents a hydrogen atom or a halogen atom; R 9 represents a hydrogen atom or a phenyl group; R 10 Represents a hydrogen atom or C 1～4 Alkoxy; R 11 Represents a hydrogen atom or C 1～4 Alkyl; R 12 Represents a hydrogen atom.

2. The chiral monophosphine ligand derived from quinazolinone according to claim 1, characterized in that: R represents cyclohexyl, phenyl, 4-methylphenyl or 3,5-dimethylphenyl; R 1 represents a hydrogen atom or a methoxy group; R 2 represents a hydrogen atom or a bromine atom; R 3 represents a hydrogen atom or a methyl group; R 4 represents a hydrogen atom or a chlorine atom; R 5 represents a methyl or benzyl group; R 6 represents a hydrogen atom or a methyl group; R 7 represents a hydrogen atom or a bromine atom; R 8 represents a hydrogen atom or a chlorine atom; R 9 represents a hydrogen atom or a phenyl group; R 10 represents a hydrogen atom or a methoxy group; R 11 represents a hydrogen atom or a methyl group; R 12 Represents a hydrogen atom.

3. The chiral monophosphine ligand derived from quinazolinone according to claim 1, characterized in that: Specifically, any one of the following 1a to 1o: 1a:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H; 1b:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =Cl,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H; 1c:R=Ph,R 1 =H,R 2 =H,R 3 =Me,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H; 1d:R=Ph,R 1 =H,R 2 =Br,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H; 1e:R=Ph,R 1 =OMe,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H; 1f:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Bn,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H; 1g:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =Me,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H; 1h:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =Br,R 8 =H,R 9 =H,R 10 =H,R 11 =H,R 12 =H; 1i:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =Cl,R 9 =H,R 10 =H,R 11 =H,R 12 =H; 1j:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =Ph,R 10 =H,R 11 =H,R 12 =H; 1k:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =OMe,R 11 =H,R 12 =H; 1l:R=Ph,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =Me,R 12 =H; 1m:R=Cy,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =Me,R 12 =H; 1n:R=p-Tolyl,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =Me,R 12 =H; 1o:R=3,5-2MeC6H3,R 1 =H,R 2 =H,R 3 =H,R 4 =H,R 5 =Me,R 6 =H,R 7 =H,R 8 =H,R 9 =H,R 10 =H,R 11 =Me,R 12 =H。 4. The method for synthesizing the chiral monophosphine ligand derived from quinazolinone according to claim 1, characterized in that: Compound S7 is placed in a first organic solvent, a first alkaline substance and a reducing agent are added, and the mixture is reacted under heating conditions to obtain a crude target compound. The structure of compound S7 is shown below: in, R represents a cyclohexyl group or a phenyl group, or a mono- or di-substituted phenyl group; R 1 Represents a hydrogen atom or C 1～4 Alkoxy; R 2 represents a hydrogen atom or a halogen atom; R 3 Represents a hydrogen atom or C 1～4 Alkyl; R 4 represents a hydrogen atom or a halogen atom; R 5 Indicates C 1～4 an alkyl or benzyl group; R 6 Represents a hydrogen atom or C 1～4 Alkyl; R 7 represents a hydrogen atom or a halogen atom; R 8 represents a hydrogen atom or a halogen atom; R 9 represents a hydrogen atom or a phenyl group; R 10 Represents a hydrogen atom or C 1～4 Alkoxy; R 11 Represents a hydrogen atom or C 1～4 Alkyl; R 12 Represents a hydrogen atom.

5. The synthesis method according to claim 4, wherein The reaction was carried out under inert gas protection.

6. The synthesis method according to claim 4 or 5, characterized in that: The first organic solvent is benzene, toluene, chlorobenzene or xylene; the first alkaline substance is any one selected from triethylamine, N,N-diisopropylethylamine, ethylenediamine and 4-methylethylenediamine; The reducing agent is trichlorosilane, hydrogen or lithium aluminum hydride.

7. The synthesis method according to claim 4 or 5, characterized in that: The method also includes a step of purifying the obtained target compound.

8. The synthesis method according to claim 4 or 5, characterized in that: Compound S7 was prepared according to the following method: 1) Compound S1 and Compound S2 are placed in a second organic solvent, an acidic catalyst is added to react, and an oxidant is added to the reaction mixture to continue the reaction to obtain Compound S3; 2) Compound S3 is placed in a third organic solvent, and a second alkaline substance is added to react to remove the acetyl group from compound S3 to obtain compound S4; 3) Compound S4 is placed in a fourth organic solvent, and a catalyst Cat is added to react to cyclize the alkyne to obtain compound S5; 4) Compound S5 is placed in a fifth organic solvent, and a third basic substance and trifluoromethanesulfonic anhydride are added to react to protect the hydroxyl group on compound S5 to obtain compound S6; 5) Compound S6 is placed in a sixth organic solvent, and a palladium catalyst, a palladium catalyst ligand coordinated with the palladium catalyst, a fourth basic substance, and a phosphorus-oxy derivative are added to react to obtain compound S7; In the above preparation method, the structures of the compounds S1 to S6 and the catalyst Cat are shown below, respectively, and the structure of the phosphorus-oxygen derivative is shown in the following formula (I): in, R represents a cyclohexyl group or a phenyl group, or a mono- or di-substituted phenyl group; R 1 Represents a hydrogen atom or C 1～4 Alkoxy; R 2 represents a hydrogen atom or a halogen atom; R 3 Represents a hydrogen atom or C 1～4 Alkyl; R 4 represents a hydrogen atom or a halogen atom; R 5 Indicates C 1～4 an alkyl or benzyl group; R 6 Represents a hydrogen atom or C 1～4 Alkyl; R 7 represents a hydrogen atom or a halogen atom; R 8 represents a hydrogen atom or a halogen atom; R 9 represents a hydrogen atom or a phenyl group; R 10 Represents a hydrogen atom or C 1～4 Alkoxy; R 11 Represents a hydrogen atom or C 1～4 Alkyl; R 12 Represents a hydrogen atom.

9. The synthesis method according to claim 8, characterized in that: In step 1), the second organic solvent is tetrahydrofuran, ethanol, N,N-dimethylformamide or p-xylene; the acidic catalyst is p-toluenesulfonic acid, cuprous oxide or acetic acid; the oxidant is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), iodine, oxygen, iodobenzene diacetate or potassium permanganate; In step 2), the third organic solvent is tetrahydrofuran, methanol or acetonitrile; the second alkaline substance is hydrazine hydrate, triethylamine, potassium carbonate or cesium carbonate; In step 3), the fourth organic solvent is chloroform, carbon tetrachloride, 1,2-dichloroethane, dichloromethane or acetonitrile; In step 4), the fifth organic solvent is dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran or acetonitrile; the third alkaline substance is triethylamine, diisopropylethylamine or pyridine; In step 5), the sixth organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane or toluene; the palladium catalyst is palladium acetate or diphenylphosphine palladium dichloride; the palladium catalyst ligand is 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 1,2-bis(diphenylphosphino)butane or 1,2-bis(diphenylphosphino)ethane; the fourth alkaline substance is pyridine, N,N-diisopropylethylamine, triethylamine, ethylenediamine or 4-methylethylenediamine.

10. Use of the chiral monophosphine ligand derived from quinazolinone according to claim 1 as a catalyst ligand in a catalytic reaction.

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