Ortho-adamantyl phenylphosphine heterocyclic compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of adamantane compounds, and provides an ortho-adamantyl phenylphosphine heterocyclic compound as well as a preparation method and application thereof. The structural formula of the ortho-adamantyl phenylphosphine heterocyclic compound is shown in the specification, and n is 1, 2 or 3. The ortho-adamantyl phenylphosphine heterocyclic compound disclosed by the invention is applied to Buchwald-Harwig coupling reaction of a large steric hindrance substrate, and shows excellent catalytic activity, so that the product yield reaches 92% or above; the method provided by the invention has the advantages of simple steps, mild conditions, yield of more than 80%, good repeatability and industrial feasibility.

Description

Technical Field

[0001] This invention relates to the field of adamantane compound technology, and more particularly to an ortho-adamantylphenylphosphine heterocyclic compound, its preparation method, and its application. Background Technology

[0002] The adamantane structure, due to its high symmetry, three-dimensional rigidity, and strong hydrophobicity, holds significant value in medicinal chemistry, materials science, and ligand design. In recent years, adamantane-substituted phosphine ligands have demonstrated excellent stereoregulation and chemical stability in asymmetric catalytic reactions. Compared to conventional aryl or alkylphosphine ligands, adamantane-substituted phosphine ligands, due to their strong steric hindrance and unique electronic effects, can provide higher catalytic efficiency in transition metal-catalyzed cross-coupling reactions, hydrogenation reactions, and CH activation reactions. Furthermore, adamantane-substituted phosphine ligands have potential applications in both homogeneous catalysis and asymmetric synthesis.

[0003] However, most existing adamantyl phosphine ligands are open-chain structures, lacking the combination of a cyclic skeleton and aryl substitution. Introducing an adamantyl group at the ortho-aryl position and combining it with a phosphine heterocycle can provide a new structural unit for constructing novel chiral ligands.

[0004] To address this issue, it is necessary to provide ortho-adamantylarylated phosphine ligands to expand the family of adamantanephosphine ligands and provide an important foundation for the development of novel phosphine ligands and functional molecules. Summary of the Invention

[0005] The purpose of this invention is to address the current situation of limited types of adamantane-based organophosphines by providing an ortho-adamantylphenylphosphine heterocyclic compound, its preparation method, and its applications.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides an ortho-adamantylphenylphosphine heterocyclic compound, the structural formula of which is as follows: , where n is 1, 2 or 3.

[0007] The present invention also provides a method for preparing the aforementioned ortho-adamantylphenylphosphine heterocyclic compound, comprising the following steps: 1) Under the action of a base, 1-phosphine adamantane and a cyclizing agent undergo a nucleophilic substitution reaction to obtain 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocycle; 2) Under the action of a base, 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocycle and benzoyne precursor undergo an ortho-addition reaction to benzoyne to obtain ortho-adamantane phenylphosphine heterocyclic compound.

[0008] Preferably, the cyclizing agent in step 1) comprises dibromoalkane, dichloroalkane, di(methanesulfonyloxy)alkane, or di(toluenesulfonyloxy)alkane.

[0009] Preferably, the nucleophilic substitution reaction in step 1) is carried out at a temperature of 20-30°C for 6-10 hours.

[0010] Preferably, the molar ratio of 1-phosphine, cyclizing agent and base in step 1) is 5:5~8:5~8.

[0011] Preferably, the benzylene precursor in step 2) can generate benzylene in situ under the action of an alkali.

[0012] Preferably, the temperature of the ortho-addition reaction of benzylene in step 2) is 25~40℃, and the time of the ortho-addition reaction of benzylene is 8~12h.

[0013] Preferably, the molar ratio of 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocycle, benzylene precursor and base in step 2) is 3:3~6:5~8.

[0014] Preferably, the nucleophilic substitution reaction in step 1) is carried out in an organic solvent, and the ortho-addition reaction of benzyne in step 2) is carried out in an organic solvent; The bases mentioned in steps 1) and 2) independently include alkali metals, alkali metal fluorides, alkali metal hydroxides, alkali metal carbonates, alkali metal hydrides, or organic alkali metal salts.

[0015] This invention also provides the application of the aforementioned ortho-adamantylphenylphosphine heterocyclic compound in the Buchwald-Hartwig coupling reaction of sterically hindered substrates.

[0016] The beneficial effects of this invention are: The ortho-adamantylphenylphosphine heterocyclic compound of this invention exhibits excellent catalytic activity when applied to the Buchwald-Hartwig coupling reaction with sterically hindered substrates, achieving a product yield of over 92%. Using adamantylphosphine and benzyne precursors as raw materials, this invention fully utilizes the steric hindrance effect of adamantane and alkali metal-induced C–P bond breaking to achieve efficient synthesis of the ortho-adamantylphenylphosphine heterocyclic compound via benzyne addition. The method of this invention is simple, the conditions are mild, the yield reaches over 80%, and the reproducibility is good, demonstrating industrial feasibility. Detailed Implementation

[0017] This invention provides an ortho-adamantylphenylphosphine heterocyclic compound, the structural formula of which is as follows: , where n is 1, 2 or 3.

[0018] In this invention, the ortho-adamantylphenylphosphine heterocyclic compound preferably comprises 1-(2-((3R,5R,7R)-adamant-1-yl)phenyl)phosphine heterobutyl ring, 1-(2-((3R,5R,7R)-adamant-1-yl)phenyl)phosphine heteropentane ring, and 1-(2-((3R,5R,7R)-adamant-1-yl)phenyl)phosphine heterohexane ring.

[0019] The present invention also provides a method for preparing the aforementioned ortho-adamantylphenylphosphine heterocyclic compound, comprising the following steps: 1) Under the action of a base, 1-phosphine adamantane and a cyclizing agent undergo a nucleophilic substitution reaction to obtain 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocycle; 2) Under the action of a base, 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocycle and benzoyne precursor undergo an ortho-addition reaction to benzoyne to obtain ortho-adamantane phenylphosphine heterocyclic compound.

[0020] In this invention, step 1) involves constructing a phosphine heterocyclic precursor with an adamantyl group, and step 2) involves an ortho-addition reaction between the in-situ generated benzoyne and the phosphine heterocyclic precursor with the adamantyl group. Because the phosphine heterocyclic precursor with the adamantyl group contains both adamantyl and phosphine heterocyclic structures, it has significant overall steric hindrance. Under the action of a base, it can readily cleave the CP bond, generating highly reactive carbocation and phosphine anion intermediates. The benzoyne precursor generates highly reactive benzoyne under the action of a base. The highly reactive carbocation and phosphine anion intermediates efficiently add to the benzoyne, forming a new CP bond at the ortho position of the benzene ring, thereby obtaining the ortho-adamantylphenylphosphine heterocyclic compound.

[0021] In this invention, the structural formula of the 1-phosphine is as follows: .

[0022] The synthetic route for the ortho-adamantylphenylphosphine heterocyclic compound in this invention is as follows: .

[0023] In this invention, the cyclizing agent in step 1) preferably includes dibromoalkane, dichloroalkane, di(methanesulfonyloxy)alkane, or di(toluenesulfonyloxy)alkane.

[0024] In this invention, the dibromoalkane preferably comprises 1,3-dibromopropane, 1,4-dibromobutane, or 1,5-dibromopentane; The dichloroalkane preferably comprises 1,3-dichloropropane, 1,4-dichlorobutane, or 1,5-dichloropentane; The di(methanesulfonyloxy) alkyl group preferably comprises 1,4-di(methanesulfonyloxy)butane or 1,5-pentanediol dimethanesulfonate. The di(toluenesulfonyloxy) alkyl group preferably comprises 1,5-pentanediol bis(p-toluenesulfonic acid) ester.

[0025] In this invention, the temperature of the nucleophilic substitution reaction in step 1) is preferably 20~30℃, more preferably 22~28℃, and even more preferably 25℃; the time of the nucleophilic substitution reaction is preferably 6~10h, more preferably 7~9h, and even more preferably 8h.

[0026] In this invention, the molar ratio of 1-phosphine alkylene, cyclizing agent and base in step 1) is preferably 5:5~8:5~8, more preferably 5:5.5~7.5:6~7, and even more preferably 5:6~7:6.5.

[0027] In this invention, the benzylene precursor in step 2) is preferably capable of generating benzylene in situ under the action of an alkali.

[0028] In this invention, the benzylene precursor in step 2) preferably includes one or more of bromobenzene, phenyltrifluoromethane sulfonate, and iodobenzene.

[0029] In this invention, the temperature of the ortho-addition reaction of benzylene in step 2) is preferably 25~40℃, more preferably 28~37℃, and even more preferably 30~35℃; the time of the ortho-addition reaction of benzylene is preferably 8~12h, more preferably 9~11h, and even more preferably 10h.

[0030] In this invention, the molar ratio of 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocycle, benzylene precursor and base in step 2) is preferably 3:3~6:5~8, more preferably 3:3.5~5.5:5.5~7.5, and even more preferably 3:4~5:6~7.

[0031] In this invention, the nucleophilic substitution reaction in step 1) is preferably carried out in an organic solvent, and the ortho-addition reaction of benzyne in step 2) is preferably carried out in an organic solvent; The base mentioned in steps 1) and 2) preferably comprises an alkali metal, an alkali metal fluoride, an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydride, or an organoalkali metal salt. The base effectively promotes the breaking and reforming of CP bonds.

[0032] In this invention, the organic solvent preferably comprises one or more of tetrahydrofuran, acetonitrile, and 1,4-dioxane.

[0033] In this invention, the nucleophilic substitution reaction in step 1) is preferably carried out in a nitrogen atmosphere, and the ortho-addition reaction of benzyne in step 2) is preferably carried out in a nitrogen atmosphere.

[0034] This invention also provides the application of the aforementioned ortho-adamantylphenylphosphine heterocyclic compound in the Buchwald-Hartwig coupling reaction of sterically hindered substrates.

[0035] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0036] Example 1

[0037] Under a nitrogen atmosphere, 5 mmol of 1-phosphine-1-yl)phosphonobutane and 50 mL of tetrahydrofuran were placed in a 250 mL three-necked flask. 5 mmol of cesium carbonate was added and the mixture was stirred until homogeneous. 6 mmol of 1,3-dibromopropane was added dropwise at 0 °C over 3 min. After the addition was complete, the mixture was stirred at 25 °C and 600 rpm for 6 h. After the reaction was complete, the inorganic salts were removed by filtration, and the filtrate was obtained. The filtrate was extracted successively with 100 mL of dichloromethane and 100 mL of water. The organic phases obtained from the extraction were combined and evaporated to dryness to obtain the crude product. The crude product was recrystallized from anhydrous ethanol and n-hexane in a 1:3 volume ratio to obtain 1-((3S,5S,7S)-adamantane-1-yl)phosphonobutane. 1-((3S,5S,7S)-adamantane-1-yl)phosphonobutane was a pale yellow solid with a mass of 0.96 g, and a yield of 92%.

[0038] Under a nitrogen atmosphere, 3 mmol of 1-((3S,5S,7S)-adamantane-1-yl)phosphine cyclobutane and 30 mL of anhydrous acetonitrile were placed in a 100 mL three-necked flask, along with 4.5 mmol of bromobenzene and 6 mmol of anhydrous cesium fluoride. The mixture was stirred at 600 rpm for 8 h at 25 °C to carry out an ortho-addition reaction of benzyne. After the reaction was completed, the inorganic salt was removed by filtration, and the filtrate was obtained. The filtrate was extracted three times with 20 mL of dichloromethane each time. The organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was recrystallized from a 1:5 (v / v) mixture of dichloromethane and anhydrous ethanol to obtain a white crystalline powder, which is 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane. The mass of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane was 0.81 g, with a single-step yield of 95%.

[0039] The structure of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine heterobutane was characterized, and the results are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.49 – 7.12 (m, 3H), 6.91 (dd, J= 6.9, 1.4Hz, 1H), 2.68 (t, J = 9.0 Hz, 4H), 2.38 – 2.08 (m, 3H), 1.99 (d, J = 4.7 Hz, 6H), 1.91 – 1.57 (m, 8H). 13 C NMR (125 MHz, CDCl3) δ 146.44, 137.06, 132.84, 129.67, 129.23, 129.07, 41.67, 39.48, 38.08, 30.09, 28.75, 19.94. Example 2 Under a nitrogen atmosphere, 5 mmol of 1-phosphine-1-yl)phosphapentane and 50 mL of tetrahydrofuran were placed in a 250 mL three-necked flask. 5 mmol of cesium carbonate was added and the mixture was stirred until homogeneous. 6 mmol of 1,4-dibromobutane was added dropwise at 0 °C over 3 min. After the addition was complete, the mixture was stirred at 600 rpm for 8 h at 25 °C. After the reaction was complete, the inorganic salts were removed by filtration, and the filtrate was obtained. The filtrate was extracted successively with 100 mL of dichloromethane and 100 mL of water. The organic phases obtained from the extraction were combined and evaporated to dryness to obtain the crude product. The crude product was recrystallized from a 1:4 volume ratio of toluene to n-hexane to give 1-((3S,5S,7S)-adamantane-1-yl)phosphapentane. 1-((3S,5S,7S)-adamantane-1-yl)phosphapentane was a pale yellow solid with a mass of 0.98 g, yielding 88%.

[0040] Under a nitrogen atmosphere, 3 mmol of 1-((3S,5S,7S)-adamantane-1-yl)phosphapentane and 30 mL of anhydrous acetonitrile were placed in a 100 mL three-necked flask, and 4.5 mmol of bromobenzene and 6 mmol of anhydrous cesium fluoride were added. The mixture was stirred at 600 rpm for 10 h at 25 °C to carry out an ortho-addition reaction of benzyne. After the reaction was completed, the inorganic salt was removed by filtration, and the filtrate was obtained. The filtrate was extracted three times with 20 mL of dichloromethane each time. The organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was recrystallized from a 1:6 (v / v) mixture of dichloromethane and anhydrous ethanol to obtain a white crystalline powder, which is 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphapentane. The mass of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine-pentane was 0.81 g, with a single-step yield of 90%.

[0041] The structure of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine heteropentane was characterized, and the results are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.49 – 7.08 (m, 3H), 6.91 (dd, J = 6.9, 1.3Hz, 1H), 2.89 – 2.33 (m, 4H), 2.35 – 2.04 (m, 3H), 1.99 (d, J = 4.8 Hz, 6H),1.91 – 1.59 (m, 10H). 13 C NMR (125 MHz, CDCl3) δ 146.75, 140.41, 132.67, 129.67, 129.23, 129.05, 41.67, 39.50, 38.08, 30.46, 30.09, 27.94. Example 3 Under a nitrogen atmosphere, 5 mmol of 1-phosphine-1-yl)phosphonium-1-hexane and 50 mL of tetrahydrofuran were placed in a 250 mL three-necked flask. 5 mmol of cesium carbonate was added and the mixture was stirred until homogeneous. 6 mmol of 1,5-dibromopentane was added dropwise at 0 °C over 3 min. After the addition was complete, the mixture was stirred at 600 rpm for 10 h at 25 °C. After the reaction was complete, the inorganic salts were removed by filtration, and the filtrate was obtained. The filtrate was extracted successively with 100 mL of dichloromethane and 100 mL of water. The organic phases obtained from the extraction were combined and evaporated to dryness to obtain the crude product. The crude product was recrystallized from the crude product using a 1:4 volume ratio of ethyl acetate to n-hexane to give 1-((3S,5S,7S)-adamantane-1-yl)phosphonium-1-hexane. 1-((3S,5S,7S)-adamantane-1-yl)phosphonium-1-hexane was a pale yellow solid with a mass of 1.0 g and a yield of 85%.

[0042] Under a nitrogen atmosphere, 3 mmol of 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocyclic ring and 30 mL of anhydrous acetonitrile were placed in a 100 mL three-necked flask, and 4.5 mmol of bromobenzene and 6 mmol of anhydrous cesium fluoride were added. The mixture was stirred at 600 rpm for 12 h at 25 °C to carry out an ortho-addition reaction of benzyne. After the reaction was completed, the inorganic salt was removed by filtration, and the filtrate was obtained. The filtrate was extracted three times with 20 mL of dichloromethane each time. The organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was recrystallized from a 1:5 (v / v) dichloromethane-methanol mixture to obtain a white crystalline powder, which is 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine heterocyclic ring. The mass of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine heterocyclic ring was 0.82 g, with a single-step yield of 87%.

[0043] The structure of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine heterocyclic ring was characterized, and the results are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.51 – 7.12 (m, 3H), 6.91 (m, 1H), 2.66 –2.32 (m, 4H), 2.30 – 2.02 (m, 3H), 1.99 (d, J = 4.7 Hz, 6H), 1.78 (t, J = 5.5Hz, 6H), 1.60 (m, 4H), 1.56 – 1.29 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ 147.25, 139.68, 132.81, 129.67, 129.23,129.05, 41.67, 39.50, 38.08, 30.09, 29.74, 28.58, 25.90. Example 4 In Example 1, cesium carbonate was replaced with potassium tert-butoxide, and everything else was the same as in Example 1.

[0044] In this embodiment, the yield of 1-((3S,5S,7S)-adamantane-1-yl)phosphine cyclobutane was 89%, and the single-step yield of the final product 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane was 87%.

[0045] Example 5

[0046] The tetrahydrofuran in Example 1 was replaced with 1,2-dioxane, and everything else was the same as in Example 1.

[0047] In this embodiment, the yield of 1-((3S,5S,7S)-adamantane-1-yl)phosphine cyclobutane was 90%, and the single-step yield of the final product 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane was 90%.

[0048] Example 6

[0049] In Example 1, bromobenzene was replaced with phenyltrifluoromethane sulfonate, and everything else was the same as in Example 1.

[0050] In this embodiment, the single-step yield of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane was 93%.

[0051] Example 7

[0052] The anhydrous cesium fluoride in Example 1 was replaced with sodium hydride, and everything else was the same as in Example 1.

[0053] In this embodiment, the single-step yield of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine heterobutyl ring was 91%.

[0054] Example 8

[0055] The anhydrous acetonitrile in Example 1 was replaced with tetrahydrofuran, and everything else was the same as in Example 1.

[0056] In this embodiment, the single-step yield of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane was 90%.

[0057] Example 9

[0058] In Example 2, 1,4-dibromobutane was replaced with 1,4-dichlorobutane, and everything else was the same as in Example 2.

[0059] In this embodiment, the yield of 1-((3S,5S,7S)-adamantane-1-yl)phosphine heteropentane was 85%, and the single-step yield of the final product 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine heteropentane was 92%.

[0060] Example 10

[0061] In Example 3, 1,5-dibromopentane was replaced with 1,5-pentanediol dimethane sulfonate, and the rest was the same as in Example 3.

[0062] In this embodiment, the yield of 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocyclic ring was 82%, and the single-step yield of the final product 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine heterocyclic ring was 76%.

[0063] Example 11

[0064] The phrase "the ortho-addition reaction of benzylene was carried out by stirring at 600 rpm for 8 h at 25 °C" in Example 1 was modified to "the ortho-addition reaction of benzylene was carried out by stirring at 600 rpm for 8 h at 40 °C", with the rest remaining the same as in Example 1.

[0065] In this embodiment, the single-step yield of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane was 90%.

[0066] Example 12

[0067] The phrase "the ortho-addition reaction of benzylene was carried out by stirring at 600 rpm for 8 h at 25 °C" in Example 1 was modified to "the ortho-addition reaction of benzylene was carried out by stirring at 600 rpm for 12 h at 25 °C", with the rest remaining the same as in Example 1.

[0068] In this embodiment, the single-step yield of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine butyl ring was 94%.

[0069] Taking the synthesis of 2-isopropyl-N-(o-tolyl)aniline from 1-bromo-2-isopropylbenzene as an example, the application of the ortho-adamantylphenylphosphine heterocyclic compound of the present invention in the Buchwald-Hartwig coupling reaction of sterically hindered substrates is verified.

[0070] Application Example 1

[0071] Under a nitrogen atmosphere, 0.5 mmol of 1-bromo-2-isopropylbenzene, 0.005 mmol of Pd(OAc)₂, 0.01 mmol of 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutoxide prepared in Example 1, and 1 mmol of potassium tert-butoxide were added sequentially to a Schlenk flask. Then, 1 mL of toluene and 1.2 mmol of o-toluidine were added. The Schlenk flask was sealed and placed in an oil bath at 120 °C with stirring at 500 rpm for 10 h. After the reaction was complete, the reaction system was cooled to room temperature and diluted with 5 mL of ethyl acetate. The solution was filtered through a diatomaceous earth mat, and the filtrate was washed sequentially with 10 mL of water and 10 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate volume ratio from 20:1 to 10:1) to obtain 2-isopropyl-N-(o-tolyl)aniline.

[0072] The 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane prepared in Example 1 was placed in an atmospheric environment at 25 °C for 90 days, and the above steps were repeated.

[0073] Application Example 2

[0074] Replace the 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine-hexabutyl ring in Application Example 1 with the 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine-hexapentane ring prepared in Example 2, and otherwise remain the same as in Application Example 1.

[0075] Application Example 3

[0076] The 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine-hexane ring in Application Example 1 was replaced with the 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine-hexane ring prepared in Example 3, and the rest were the same as in Application Example 1.

[0077] Application Comparative Example 1

[0078] Replace the 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane ring in Application Example 1 with triphenylphosphine, otherwise the same as in Application Example 1.

[0079] The structural formula of triphenylphosphine is: .

[0080] Application Comparative Example 2

[0081] Replace the 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine zobutyl ring in Application Example 1 with tricyclohexylphosphine, otherwise the same as in Application Example 1.

[0082] The structural formula of tricyclohexylphosphine is: .

[0083] Application Comparative Example 3

[0084] Replace the 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane ring in Application Example 1 with tris(1-adamantyl)phosphine, otherwise remain the same as in Application Example 1.

[0085] The structural formula of tri(1-adamantyl)phosphine is: .

[0086] Application Comparative Example 4

[0087] Replace the 1-(2-((3R,5R,7R)-adamantane-1-yl)phenyl)phosphine cyclobutane ring in Application Example 1 with ferrocene tert-butylphosphine ligand, otherwise remain the same as in Application Example 1.

[0088] The structural formula of the tert-butylphosphine ligand of ferrocene is as follows: .

[0089] The product yields of Application Examples 1-3 and Comparative Examples 1-4 were calculated respectively, and the results are shown in Table 1.

[0090] Table 1. Yield of 2-isopropyl-N-(o-tolyl)aniline

[0091] As can be seen from Table 1, the ortho-adamantylphenylphosphine heterocyclic compound of the present invention exhibits excellent catalytic activity in the Buchwald-Hartwig coupling reaction of sterically hindered substrates, with a product yield of over 92%, and the catalytic activity does not decrease significantly after 90 days of storage.

[0092] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A heterocyclic compound of ortho-adamantylphenylphosphine, characterized in that, The structural formula of the ortho-adamantylphenylphosphine heterocyclic compound is as follows: , where n is 1, 2 or 3.

2. The method for preparing the ortho-adamantylphenylphosphine heterocyclic compound according to claim 1, characterized in that, It includes the following steps: 1) Under the action of a base, 1-phosphine adamantane and a cyclizing agent undergo a nucleophilic substitution reaction to obtain 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocycle; 2) Under the action of a base, 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocycle and benzoyne precursor undergo an ortho-addition reaction to benzoyne to obtain ortho-adamantane phenylphosphine heterocyclic compound.

3. The method for preparing the ortho-adamantylphenylphosphine heterocyclic compound according to claim 2, characterized in that, Step 1) The cyclizing agent includes dibromoalkane, dichloroalkane, di(methanesulfonyloxy)alkane, or di(toluenesulfonyloxy)alkane.

4. The method for preparing the ortho-adamantylphenylphosphine heterocyclic compound according to claim 2 or 3, characterized in that, The nucleophilic substitution reaction in step 1) is carried out at a temperature of 20-30°C for 6-10 hours.

5. The method for preparing the ortho-adamantylphenylphosphine heterocyclic compound according to claim 4, characterized in that, In step 1), the molar ratio of 1-phosphine, cyclizing agent, and base is 5:5~8:5~8.

6. The method for preparing the ortho-adamantylphenylphosphine heterocyclic compound according to claim 5, characterized in that, Step 2) The benzyne precursor can be converted into benzyne in situ under the action of alkali.

7. The method for preparing the ortho-adamantylphenylphosphine heterocyclic compound according to claim 5 or 6, characterized in that, Step 2) The temperature of the ortho-addition reaction of benzylene is 25~40℃, and the time of the ortho-addition reaction of benzylene is 8~12h.

8. The method for preparing the ortho-adamantylphenylphosphine heterocyclic compound according to claim 7, characterized in that, Step 2) The molar ratio of 1-((3S,5S,7S)-adamantane-1-yl)phosphine heterocycle, benzylene precursor and base is 3:3~6:5~8.

9. The method for preparing the ortho-adamantylphenylphosphine heterocyclic compound according to claim 8, characterized in that, The nucleophilic substitution reaction in step 1) is carried out in an organic solvent, and the ortho-addition reaction of benzyne in step 2) is carried out in an organic solvent; The bases mentioned in steps 1) and 2) independently include alkali metals, alkali metal fluorides, alkali metal hydroxides, alkali metal carbonates, alkali metal hydrides, or organic alkali metal salts.

10. The use of the ortho-adamantylphenylphosphine heterocyclic compound of claim 1 in the Buchwald-Hartwig coupling reaction of a sterically hindered substrate.

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