Chiral carbene ligands, processes for their preparation and use in asymmetric synthesis

Abstract

The application provides a chiral carbene ligand, a preparation method thereof and application in asymmetric synthesis, the chiral carbene ligand catalyzes asymmetric hydroarylation reaction of various kinds of olefin substrates such as aryl olefin, alpha-olefin and diene, and aryl bromine or aryl chloride, and synthesizes four kinds of drug molecules or drug molecule intermediates in one step. The chiral carbene ligand has a flexible chain structure, is self-adapting, can effectively adapt to different transition metal centers and substrate configurations, and improves the universality and selectivity of the catalytic system; the raw material used in the preparation method of the chiral carbene ligand is easy to obtain, the synthesis route is short, and post-treatment is simple; various reagents can exist stably at normal temperature and pressure without special treatment; only by regulating the nickel catalyst and the new chiral carbene ligand, high regioselectivity and enantioselectivity of the chiral benzyl-containing compound can be realized; the asymmetric synthesis method can obtain the target product in one step, and greatly reduces the production cost of synthesizing the compound.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a chiral carbene ligand, its preparation method, and its application in asymmetric synthesis. Background Technology

[0002] Chiral benzylmethyl structures, as an important and advantageous backbone, are widely found in natural products, drug molecules, and functional materials. Their efficient and selective construction has always been a research hotspot and core objective in the field of asymmetric synthesis. In recent years, transition metal-catalyzed asymmetric hydrogen aromatization reactions of alkenes and various aromatic hydrocarbons have become an efficient strategy for constructing chiral benzylmethyl structural fragments due to their outstanding advantages such as high atom economy, simple reaction steps, and good functional group compatibility, showing broad application prospects in drug development and fine chemical production.

[0003] However, the catalytic efficiency, stereoselectivity, and substrate applicability of such asymmetric hydrogen aromatization reactions are highly dependent on the structure and properties of the chiral ligands. The design and synthesis of chiral ligands is both a core key to driving breakthroughs in this reaction technology and a current research challenge in the field. Meanwhile, the aryl reagents used in the existing technology still have significant limitations, specifically in the following three aspects:

[0004] A) Simple aryl reagents, activated via CH bond. This strategy has attracted widespread research interest due to its high atom economy, but its substrates are limited to introducing directing groups or specific active sites on aromatic hydrocarbons to trigger the reaction (Grélaud, S.; Cooper, P.; Feron, LJ; Bower, JFJ Am. Chem. Soc. 2018, 140, 9351; Liu, Y.-H.; Xie, P.-P.; Liu, L.; Fan, J.; Zhang, Z.-Z.; Hong, X.; Shi, B.-FJ Am. Chem. Soc. 2021, 143, 19112.).

[0005]

[0006] B) Affinity reagents, mostly arylboronic reagents, have only successfully achieved the conversion of aryl alkenes and aryl dienes as substrates. Expanding the reaction system still faces challenges (Lv, X.-Y.; Fan, C.; Xiao, L.-J.; Xie, J.-H.; Zhou, Q.-L. CCS Chem. 2019, 1, 328; Chen, Y.-G.; Shuai, B.; Xu, X.-T.; Li, Y.-Q.; Yang, Q.-L.; Qiu, H.; Zhang, K.; Fan, P.; Mei, T.-SJ Am. Chem.Soc. 2019, 141, 3395; Marcum, JS Taylor, TR Meek, SJ Angew. Chem.Int. Ed. 2020, 59, 14070.).

[0007]

[0008] C) Electrophilic aryl reagents, including aryl trifluoromethanesulfonates and aryl halides. While aryl trifluoromethanesulfonates exhibit excellent substrate range and selectivity control with aryl and alkyl alkenes, they are not only limited in commercial availability but also extremely expensive (Liu, C.-F.; Wang, Z.-C.; Luo, X.; Lu, J.; Ko, CHM; Shi, S.-L.; Koh, MJ Nat. Catal. 2022, 5, 934; Wang, Z.-C.; Luo, X.; Zhang, J.-W.; Liu, C.-F.; Koh, MJ; Shi, S.-L. Nat. Catal.2023, 6, 1087.). For other electrophilic aryl reagents, namely aryl iodine, only asymmetric hydrogen aromatization reactions of activated alkenes such as aryl alkenes or heteroatom-substituted alkenes can be achieved so far. Reactions for dienes and α-alkenes have not been successful (He, Y.; Liu, C.; Yu, L.; Zhu, S. Angew. Chem. Int. Ed. 2020, 59, 21530; He, Y.; Ma, J.; Song, H.; Zhang, Y.; Liang, Y.; Wang, Y.; Zhu, S. Nat. Commun. 2022, 13, 2471.). Asymmetric hydrogen aromatization reactions of aryl bromides with alkenes utilize noble metal Pd / Cu bimetallic coordinating catalysis, but the substrate scope is relatively limited (Friis, SD; Pirnot, MT; Buchwald, SLJ Am. Chem. Soc. 2016, 138, 8372.).

[0009]

[0010] In summary, aryl bromides and aryl chlorides, with their wide availability and low cost, are electrophilic aryl reagents with great application potential. Their efficient utilization in the asymmetric reduction of Heck's reaction is a key path to overcome existing technological bottlenecks and enhance the industrial value of the reaction. Therefore, there is an urgent need to develop a novel chiral carbene ligand, focusing on enhancing the activation efficiency of the C-Br bond of aryl bromides and the C-Cl bond of aryl chlorides, thereby significantly improving the stereoselectivity and conversion efficiency of the catalytic reaction, effectively expanding the substrate applicability range, and overcoming the technical challenges of the limitations of existing aryl reagent applications and the shortcomings of ligand performance. Summary of the Invention

[0011] To address the problems existing in the prior art, one objective of this invention is to provide a chiral carbene ligand with a flexible chain structure and excellent self-adaptability; another objective is to provide a method for preparing the chiral carbene ligand; and a third objective is to provide an application of the chiral carbene ligand in the nickel-catalyzed asymmetric synthesis of olefins with aryl bromides or aryl chlorides.

[0012] Therefore, the present invention adopts the following technical solution:

[0013] A chiral carbene ligand has the following structural formula:

[0014]

[0015] in:

[0016] R 1 R 2 R 3 R 4 R 5 The alkyl group is hydrogen, alkyl, or aryl, either individually or in combination; preferably, the alkyl group is methyl, ethyl, tert-butyl, or isopropyl; the aryl group is phenyl or a substituted phenyl group, and the substituent of the substituted phenyl group is methyl, ethyl, tert-butyl, or isopropyl.

[0017] R 6 The alkyl group is an alkyl group, preferably methyl, ethyl, tert-butyl or isopropyl.

[0018] Preferably, the chiral carbene ligand is one of the following structural formulas:

[0019] .

[0020] A method for preparing the above-mentioned chiral carbene ligand, the reaction process and steps are as follows:

[0021]

[0022] S1, Preparation of compound C (chiral 1,4-disubstituted butane-2,3-diamine):

[0023] Inside a glove box, compounds A ((1R,2R)-1,2-diaminoethane-1,2-dimethylbisphenol), B (phenylacetaldehyde), and a solvent were added to a reaction tube that had been dried in an oven. The resulting solution was subjected to freezing-vacuuming-thawing and degassing, and then heated to 100–150 °C and stirred for 12–48 h. After the reaction system cooled to room temperature, HCl aqueous solution was added for acidification, and stirring was continued for 1–48 h. Subsequently, NaOH aqueous solution was added dropwise for alkalization, and the mixture was filtered and dried to obtain product C.

[0024] S2, Preparation of compound E (N²,N³-bis(5-adamantyl-2-alkylphenyl)-1,4-disubstituted butane-2,3-diamine):

[0025] Inside the glove box, compound C, compound D (1-(3-bromo-4-alkylphenyl)adamantane), bis(dibenzylacetone)palladium(0), and racemic bis(naphthyl)diphenylphosphine prepared by S1 were added to the oven-dried reaction tube. t BuONa and toluene; the resulting solution was frozen-vacuumed-thawed and degassed, then heated to 100-120 °C and stirred for 24-48 h; after the reaction was completed, the solution was cooled to room temperature, and the volatile solvent was removed by vacuum distillation. The residue was purified by rapid silica gel column chromatography to give product E (N²,N³-bis(5-adamantyl-2-alkylphenyl)-1,4-disubstituted butane-2,3-diamine).

[0026] S3, Preparation of chiral carbene ligand F:

[0027] Compound E prepared by S2 was added to a round-bottom flask that had been dried in an oven. Then ammonium tetrafluoroborate and triethyl orthoformate were added. After the flask was fitted with a spherical condenser, it was heated and stirred in an oil bath at 100-120°C for 12-24 h. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by vacuum concentration. The residue was subjected to silica gel column chromatography to obtain chiral carbene ligand F.

[0028] Preferably, in step S1 above, the equivalence ratio of compound B to A is (2-4):1; the solvent is toluene or mesitylene, and the amount used is 2-8 mL per millimole of compound A; the concentration of the HCl aqueous solution is 1-3N, and the amount used is 1-3 mL per millimole of A; the concentration of the NaOH aqueous solution is 1-3N, and the amount used is 1-3 mL per millimole of A; in the structural formula of compound B, R 7 It is phenyl or benzyl, R 8 It can be methyl, ethyl, tert-butyl, or isopropyl.

[0029] Preferably, in step S2 above, compound D, t The equivalent ratio of BuONa to compound C is (2-4):(3-8)1; the molar ratio of bis(dibenzylacetone)palladium(O), racemic biphenylphosphine to compound C is (5-20):(10-40):100; the amount of toluene used is 10-20 mL per millimole of compound C; in the structural formula of compound D, R 8 It can be methyl, ethyl, tert-butyl or isopropyl.

[0030] Preferably, in step S3 above, the amount of triethyl orthoformate used is 10 to 30 mL per millimole of compound E, and the equivalent ratio of ammonium tetrafluoroborate to compound E is (1 to 2): 1.

[0031] The present invention also provides another method for preparing the chiral ben ligand, the reaction process and steps of which are as follows:

[0032] , ;

[0033] (1) Preparation of compound I ((R)-1,1-bis(2,5-dimethylphenyl)-2-phenylethane-1,2-diol):

[0034] Under an argon atmosphere, tetrahydrofuran was added to a reaction apparatus containing magnesium shavings and iodine initiator, and the mixture was heated to reflux. Then, compound G (2-bromo-1,4-dimethylbenzene) was added dropwise, and after the addition was complete, the mixture was refluxed and stirred for 0.5–3 h. A tetrahydrofuran solution of compound H ((R)-2-phenyl-2-((trimethylsilyl)oxy)methyl acetate) was slowly added dropwise, and the mixture was refluxed for 6–24 h after the addition was complete. After the reaction was complete, the mixture was quenched in a saturated ammonium chloride solution, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated NaCl water, and then subjected to anhydrous MgSO4. 4） After drying, the product was concentrated under reduced pressure. The residue was purified by recrystallization from n-hexane to give a white solid product I.

[0035] Preferably, the equivalent ratio of the magnesium shavings, compound H, and compound G is (1-2):(1-2):1; the amount of tetrahydrofuran solution used is 1-3 mL per millimole of compound G; and the amount of iodine used is 1%-2% mol of metallic magnesium.

[0036] (2) Preparation of compound DB ((5R,5'R)-4,4,4',4'-tetrakis(2,5-dimethylphenyl)-5,5'-diphenyl-2,2'-bi(1,3,2-dioxoborane):

[0037] Compound I prepared by S1, tetrahydroxydiboron and tetrahydrofuran were added to a flask that had been dried in an oven and equipped with a magnetic stir bar and a 4 Å molecular sieve. The mixture was heated and stirred under reflux for 1-6 h. After filtration through a diatomaceous earth short column, the filtrate was concentrated under reduced pressure. The residue was crystallized from n-hexane to obtain a white solid product DB.

[0038] Preferably, the amount of the 4 Å molecular sieve is 5–20 mol% of compound I; the equivalent ratio of the tetrahydroxydiboron compound I is (1–1.5):1; and the amount of tetrahydrofuran is 10–30 mL per millimole of compound I.

[0039] (3) Preparation of compound K (chiral 1,4-disubstituted butane-2,3-diammonium hydrochloride):

[0040] Compound J (substituted phenylacetonitrile) was placed in a solvent at -78 °C, and diisobutylaluminum hydride was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 1–3 h, then heated to room temperature and stirred for another 1–3 h. The system was then cooled to -78 °C again, and methanol and compound DB prepared by S2 were added sequentially. The mixture was heated to room temperature and stirred for 6–24 h. The system was acidified with an aqueous HCl solution and stirred for 0.5–2 h, resulting in the precipitation of a pale yellow solid. The obtained solid (using dichloromethane) was washed, filtered, and dried to obtain the pale yellow solid product K.

[0041] Preferably, the equivalence ratio of diisobutylaluminum hydride, methanol, compound DB, and compound J is (1-2):(1-3):(0.5-0.6):1; the solvent is dichloromethane, toluene, or tetrahydrofuran, and the amount used is 3-6 mL per millimole of compound J; the concentration of the HCl aqueous solution is 1-3N, and the amount used is 1-3 mL per millimole of compound J; in the structural formula of compound J, R 9 The substituted phenyl group is methyl, ethyl, tert-butyl, isopropyl, or phenyl.

[0042] (4) Preparation of compound L (N²,N³-bis(5-adamantyl-2-alkylphenyl)-1,4-disubstituted butane-2,3-diamine):

[0043] Inside a glove box, compounds K, D, sodium tert-butoxide, and toluene prepared by S3 were added to a reaction tube pre-dried in an oven. The resulting solution was degassed using a freeze-vacuum-thaw method and then stirred at room temperature for 1–3 h. Bis(dibenzylacetone)palladium(O), racemic bis(naphthyl)phosphine, and... t BuONa: The reaction tube was placed in an oil bath preheated to 100-120 °C and stirred continuously for 24-48 h. After the reaction was completed, the mixture was cooled to room temperature, and the volatile solvent was removed by vacuum distillation. The residue was purified by rapid silica gel column chromatography to obtain a pale yellow solid product.

[0044] Preferably, compound D, t The equivalence ratio of BuONa to compound K is (2–4):(3–8):1; the amounts of bis(dibenzylacetone)palladium(0) and racemic dinaphthalenephosphine are 5–20 mol% and 10–40 mol% of compound K, respectively; the amount of toluene is 10–20 mL per millimole of compound K. In the structural formula of compound D, R 8 It can be methyl, ethyl, tert-butyl or isopropyl.

[0045] (5) Preparation of chiral carbene ligand M:

[0046] Compound L, prepared by S4, was added to a round-bottom flask that had been dried in an oven. Ammonium tetrafluoroborate and triethyl orthoformate were then added. After assembling a spherical condenser, the flask was placed in an oil bath at 100–120 °C and heated and stirred for 12–24 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel column chromatography to give a pale yellow solid product M.

[0047] Preferably, the amount of ammonium tetrafluoroborate used is 1 to 2 equivalents of compound L; the amount of triethyl orthoformate used is 10 to 30 mL per millimole of compound L.

[0048] This invention also provides an application of the above-mentioned chiral carbene ligand in the nickel-catalyzed asymmetric synthesis of olefins with aryl bromides or aryl chlorides, the reaction formula and reaction process of which are as follows:

[0049]

[0050] The nickel catalyst, the chiral carbene ligand, the base, and the solvent were added sequentially to the reaction flask, and pre-complexed for 10–60 minutes. Then, a hydrogen source and the additive isopropanol were added. i PrOH), stir for 0-10 minutes to fully dissolve; then add raw material 1 and raw material 2, stir at 40-80℃ for 6-24 hours in a nitrogen atmosphere, then cool to room temperature, remove solvent under reduced pressure, and obtain target product 3 by column chromatography.

[0051] Preferably, in the structural formula of raw material 1, R is aryl, alkenyl, or alkyl; and in the structural formula of raw material 2, Ar is aryl or heteroaryl.

[0052] More preferably, the aryl group is phenyl, substituted phenyl, or fused-ring aryl, wherein the substituent in the substituted phenyl group is alkyl, trifluoromethyl, phenyl, alkoxy, nitrogen, silicon, ester, or halogen, and wherein the alkyl group is preferably methyl, ethyl, tert-butyl, or isopropyl.

[0053] More preferably, the heteroaryl group is a substituted pyridine, a substituted thiophene, or a substituted furan, and the substituent in the three heteroaryl groups is methyl, ethyl, tert-butyl, isopropyl, trifluoromethyl, phenyl, alkyl, halogen, alkoxy, or nitrogen, wherein the alkyl group is methyl, ethyl, tert-butyl, or isopropyl.

[0054] Preferably, the nickel catalyst is Ni(COD)2, Ni(acac)2, NiBr2·DME, and Ni( tBu One of the three (stb) is used in an amount of 5-10 mol of the raw material 1.

[0055] Preferably, the chiral carbene ligand is one of the following structural formulas:

[0056]

[0057] The amount of chiral carbene ligand used is 6–12 mol of raw material 1.

[0058] Preferably, the alkali is one of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, and sodium isopropoxide, and the amount used is 10-20 mol% of the raw material 1; the solvent is one of toluene, acetone, and tetrahydrofuran, and the amount used is 5-20 mL per millimole of raw material 1.

[0059] Preferably, the hydrogen source is sodium isopropoxide (Sodium isopropoxide) i The amount of PrONa is 1 to 3 equivalents of raw material 1; the amount of the additive isopropanol is 0 to 3 equivalents of raw material 1.

[0060] The chiral carbene ligand of this invention forms a catalytic system with transition metal coordination for asymmetric synthesis reactions. This chiral carbene ligand can catalyze asymmetric hydrogenarylation reactions of various olefin substrates, such as arylolefins, α-olefins, and dienes, with aryl bromides or aryl chlorides, and synthesize four drug molecules or drug intermediates in one step, achieving highly efficient preparation of the target product with high regioselectivity and high enantioselectivity.

[0061] Compared with the prior art, the present invention has the following beneficial effects:

[0062] 1. The chiral carbene ligand of the present invention has a flexible chain structure, strong self-adaptation, and can effectively adapt to different transition metal centers and substrate configurations, thereby improving the universality and selectivity of the catalytic system.

[0063] 2. The chiral carbene ligand preparation method of the present invention uses readily available raw materials, has a short synthetic route, and is simple in post-processing.

[0064] 3. This invention achieves highly regioselective and enantioselective synthesis of compounds containing chiral benzyl structures simply by using a nickel catalyst in combination with a novel chiral carbene ligand.

[0065] 4. The reagents used in this invention are commercially available, the raw materials are widely available and inexpensive, and all reagents are stable at room temperature and pressure without the need for special treatment.

[0066] 5. The asymmetric synthesis method of the present invention is simple to operate, and the target product can be obtained in one step. It avoids the use of dangerous reagents such as alkyl metal reagents that are extremely sensitive to air and water, and there are no special requirements for post-processing, which greatly reduces the production cost of synthesizing this type of compound.

[0067] 6. This invention successfully synthesized four drug molecules or intermediates. Detailed Implementation

[0068] The synthesis method of the present invention will be described in detail below with reference to the embodiments, but the present invention is by no means limited to the contents shown in the following embodiments.

[0069] Example 1

[0070] The preparation of (S,S)-1,3-bis(5-adamantyl-2-methylphenyl)-4,5-dibenzyl-1H-imidazolium-3-onium tetrafluoroborate (abbreviated as L1 / HBF4) is as follows:

[0071]

[0072] Preparation of S1,(2S,3S)-1,4-diphenylbutane-2,3-diamine:

[0073] Inside a glove box, (1R,2R)-1,2-diaminoethane-1,2-dimethylbisphenol (488 mg, 2.0 mmol), 2-phenylacetaldehyde (600 mg, 5.0 mmol), and toluene (12 mL) were added to a reaction tube that had been dried in an oven. The resulting solution was subjected to freezing-vacuuming-thawing and degassing, then heated to 110 °C and stirred for 24 h. After the reaction system cooled to room temperature, 2 mol / L HCl solution was added for acidification, and stirring was continued for another 24 h. Subsequently, NaOH solution was added dropwise for alkalization, followed by filtration and drying to obtain 90 mg of a pale yellow solid, with a yield of 19%.

[0074] Preparation of S2,(2S,3S)-N²,N³-bis(5-adamantyl-2-methylphenyl)-1,4-diphenylbutane-2,3-diamine:

[0075] Inside a glove box, (2S,3S)-1,4-diphenylbutane-2,3-diamine (90 mg, 0.4 mmol), 1-(3-bromo-4-methylphenyl)adamantane (300 mg, 1 mmol), bis(dibenzylacetone)palladium(0) (37 mg, 0.04 mmol), and racemic naphthalenediphenylphosphine (50 mg, 0.08 mmol) prepared by S1 were added to an oven-dried reaction tube. tBuONa (192 mg, 2.0 mmol) and toluene (6 mL) were reacted. The resulting solution was degassed by a freeze-vacuum-thaw reaction, and then heated to 115°C with stirring for 48 h. After the reaction was completed, the mixture was cooled to room temperature, and the volatile solvent was removed by vacuum distillation. The residue was purified by rapid silica gel column chromatography with petroleum ether / dichloromethane as eluent (10:1) to give 91 mg of a pale yellow solid, in 33% yield.

[0076] Preparation of S3, L1 / HBF4:

[0077] Add 91 mg (0.13 mmol) of ammonium tetrafluoroborate (11 mg, 0.1 mmol) and triethyl orthoformate (1 mL) to a round-bottom flask that has been dried in an oven. After assembling a spherical condenser, the flask was heated and stirred in an oil bath at 120 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography with dichloromethane / methanol as the eluent (80:1) to give 77 mg of a pale yellow solid, in 75% yield (diastereomer ratio 70:15:15).

[0078] 1 H NMR (600 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.55 (s, 2H), 7.34 (d,J = 8.2 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.18 – 7.11 (m, 6H), 6.89 – 6.78(m, 4H), 4.86 (d, J = 5.4 Hz, 2H), 3.10 – 2.99 (m, 2H), 2.98 – 2.81 (m, 2H), 2.31 (s, 6H), 2.10 (s, 6H), 1.91 (s, 12H), 1.76 (s, 12H). 13C NMR (151 MHz, Chloroform-d) δ 156.1, 155.7, 155.7, 152.2, 133.6, 133.5, 133.5, 132.9,132.4, 131.5, 131.0, 130.1, 130.0, 129.9, 129.3, 128.9, 128.6, 128.4, 128.2,126.9, 126.7, 124.4, 68.1, 67.0, 42.9, 42.8, 42.8, 37.7, 36.6, 36.6, 36.2,28.8, 18.4, 17.6, 17.6. HRMS (ESI) calcd. for [C 51 H 59 N2, M-BF4] + : 699.4673, found: 699.4667 [α] D 28 = -215.20 (c 0.2, CHCl3).

[0079] Example 2

[0080] The preparation of (S,S)-1,3-bis(5-adamantyl-2-methylphenyl)-4,5-bis(2-methylbenzyl)-1H-imidazolium-3-onium tetrafluoroborate (abbreviated as L2 / HBF4) is as follows:

[0081]

[0082] Preparation of S1, (2S,3S)-1,4-di-o-tolylbutane-2,3-diamine:

[0083] Inside a glove box, (1R,2R)-1,2-diaminoethane-1,2-diylbisphenol (488 mg, 2.0 mmol), 2-o-methylphenylacetaldehyde (675 mg, 5.0 mmol), and toluene (12 mL) were added to a reaction tube that had been pre-dried in an oven. The resulting solution was degassed using a freeze-vacuum-thaw method, then heated to 120 °C and stirred for 72 h. After cooling the reaction system to room temperature, 2 mol / L HCl solution was added for acidification, and stirring continued for 24 h. Subsequently, NaOH solution was added dropwise for alkalization, followed by filtration and drying to obtain 200 mg of a pale yellow solid, with a yield of 37%.

[0084] Preparation of S2,(2S,3S)-N²,N³-bis(5-adamantyl-2-methylphenyl)-1,4-di-o-tolylbutane-2,3-diamine:

[0085] Inside a glove box, (2S,3S)-1,4-di-o-tolylbutane-2,3-diamine (200 mg, 0.7 mmol), 1-(3-bromo-4-methylphenyl)adamantane (549 mg, 1.8 mmol), bis(dibenzylacetone)palladium(0) (64 mg, 0.07 mmol), and racemic naphthalenediphenylphosphine (87 mg, 0.14 mmol) were added to a reaction tube that had been pre-dried in an oven. t BuONa (192 mg, 2.0 mmol) and toluene (6 mL) were reacted. The resulting solution was degassed by a freeze-vacuum-thaw reaction, and then heated to 110 °C with stirring for 48 h. After the reaction was completed, the mixture was cooled to room temperature, and the volatile solvent was removed by vacuum distillation. The residue was purified by rapid silica gel column chromatography with petroleum ether / dichloromethane as eluent (10:1) to give 300 mg of a pale yellow solid, in 60% yield.

[0086] Preparation of S3, L2 / HBF4:

[0087] (2S,3S)-N²,N³-bis(5-adamantyl-2-methylphenyl)-1,4-di-o-tolylbutane-2,3-diamine (300 mg, 0.4 mmol) was added to a round-bottom flask that had been dried in an oven. Ammonium tetrafluoroborate (42 mg, 0.4 mmol) and triethyl orthoformate (4 mL) were then added. The flask was fitted with a spherical condenser and heated and stirred in an oil bath at 120 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was purified by rapid silica gel column chromatography using dichloromethane / methanol (80:1) as the eluent, yielding 180 mg of a pale yellow solid (55% yield).

[0088] 1 H NMR (600 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.59 (s, 2H), 7.39 (d,J = 8.2 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.10 – 6.89 (m, 6H), 6.80 (d, J =7.5 Hz, 2H), 4.88 – 4.63 (m, 2H), 3.15 – 2.80 (m, 4H), 2.51 (s, 6H), 2.11 (s,6H), 1.93 (s, 12H), 1.81 – 1.70 (m, 18H). 13C NMR (151 MHz, Chloroform-d)156.0, 152.2, 136.1, 132.3, 131.6, 131.0, 130.4, 130.0, 127.6, 126., 126.2,124.4, 65.7, 42.8, 36.5, 36.2, 35.9, 28.8, 18.6, 17.8. HRMS (ESI) calcd. for[C 53 H 63 N2, M-BF4] + : 727.4986, found: 727.4989 [α] D 28 = -162.13 (c 0.3, CHCl3)

[0089] Example 3

[0090] The preparation of (S,S)-4,5-bis([1,1'-biphenyl]-4-ylmethyl)-1,3-bis(5-adamantyl-2-methylphenyl)-1H-imidazolium-3-onium tetrafluoroborate (abbreviated as L3 / HBF4) is as follows:

[0091]

[0092]

[0093] Preparation of S1,(R)-1,1-bis(2,5-dimethylphenyl)-2-phenylethane-1,2-diol:

[0094] Under an argon atmosphere, tetrahydrofuran (120 mL) was added to a reaction apparatus containing magnesium shavings (4.2 g, 174 mmol) and iodine, and the mixture was heated to reflux. Then, 2-bromo-1,4-dimethylbenzene (32.9 g, 174 mmol) was added dropwise, and the mixture was refluxed and stirred for 2 h after the addition was complete. A tetrahydrofuran solution (120 mL) of (R)-2-phenyl-2-((trimethylsilyl)oxy)acetic acid methyl ester (13.7 g, 58 mmol) was slowly added dropwise, and the mixture was refluxed for 18 h after the addition was complete. After the reaction was complete, the mixture was quenched in a saturated ammonium chloride solution, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed with saturated NaCl water, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by recrystallization from n-hexane to give 13.5 g of a white solid, with a yield of 67%.

[0095] Preparation of S2, (5R,5'R)-4,4,4',4'-tetrakis(2,5-dimethylphenyl)-5,5'-diphenyl-2,2'-bi(1,3,2-dioxoborane) (DB):

[0096] To a flask dried in an oven and equipped with a magnetic stirrer and a 4 Å molecular sieve, (R)-1,1-bis(2,5-dimethylphenyl)-2-phenylethane-1,2-diol (13.5 g, 39 mmol, 2.0 equivalent), tetrahydroxydiboron (1.8 g, 19.5 mmol, 1.0 equivalent), and tetrahydrofuran (300 mL) were added sequentially. The mixture was heated under reflux and stirred for 3 h, filtered through a diatomaceous earth short column, and the filtrate was concentrated under reduced pressure. The residue was crystallized from n-hexane to give 11.1 g of a white solid, yield 80%.

[0097] 1 H NMR (600 MHz, Chloroform-d) δ 7.68 (s, 2H), 7.24 (d, J = 17.8 Hz,2H), 7.13 – 6.87 (m, 14H), 6.70 (d, J = 7.5 Hz, 2H), 6.55 (d, J = 8.8 Hz,4H), 2.43 (s, 6H), 2.12 (s, 6H), 1.89 (s, 6H), 1.50 (s, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 138.6, 137.4, 135.7, 134.7, 134.2, 132.7, 131.1, 131.0,128.6, 128.5, 127.7, 127.6, 127.4, 127.3, 126.1, 91.8, 84.3, 21.7, 21.4,21.4, 21.0.

[0098] Preparation of S3,(2S,3S)-1,4-bis([1,1'-biphenyl]-4-yl)butane-2,3-diammonium hydrochloride:

[0099] At -78 °C, diisobutylaluminum hydride (10 mL, 10 mmol, 1.0 mol / L toluene solution) was added dropwise to a solution of 1.9 g (10 mmol) of 2-([1,1'-biphenyl]-4-yl)acetonitrile (1.9 g, 10 mmol) in dichloromethane (10 mL). After the addition was complete, the mixture was stirred at -78 °C for 3 h, then heated to room temperature and stirred for another 2 h. The system was then cooled to -78 °C again, and methanol (352 mg, 11 mmol) and DB (3.6 g, 5 mmol) were added sequentially. The mixture was then heated to room temperature and stirred for an additional 12 h. HCl solution was added to the system, and after stirring for 2 h, a pale yellow solid precipitated. The obtained solid was washed several times with dichloromethane, filtered, and dried to give 980 mg of a pale yellow solid, with a yield of 40%.

[0100] Preparation of S4,(2S,3S)-1,4-bis([1,1'-biphenyl]-4-yl)-N²,N³-bis(5-adamantyl-2-methylphenyl)butane-2,3-diamine:

[0101] Inside a glove box, (2S,3S)-1,4-bis([1,1'-biphenyl]-4-yl)butane-2,3-diammonium hydrochloride (470 mg, 1.0 mmol), 1-(3-bromo-4-methylphenyl)adamantane (763 mg, 2.5 mmol), sodium tert-butoxide (480 mg, 5.0 mmol), and toluene (12 mL) were added to a reaction tube that had been pre-dried in an oven. The resulting solution was degassed using a freeze-vacuum-thaw method and then stirred at room temperature for 2 h. Bis(dibenzylacetone)palladium(0) (91 mg, 0.1 mmol, 0.1 equivalent), racemic binaphthalenediphenylphosphine (125 mg, 0.2 mmol), and... t BuONa (288 mg, 3.0 mmol) was reacted in an oil bath preheated to 110 °C with stirring for 48 h. After the reaction, the mixture was cooled to room temperature, and the volatile solvent was removed by vacuum distillation. The residue was purified by rapid silica gel column chromatography with petroleum ether / dichloromethane as eluent (10:1) to give 731 mg of a pale yellow solid, in 87% yield.

[0102] Preparation of S5, L3 / HBF4:

[0103] (2S,3S)-1,4-bis([1,1'-biphenyl]-4-yl)-N²,N³-bis(5-adamantyl-2-methylphenyl)butane-2,3-diamine (731 mg, 0.9 mmol), followed by the addition of ammonium tetrafluoroborate (105 mg, 1.0 mmol) and triethyl orthoformate (6 mL). The flask was fitted with a spherical condenser and heated and stirred in an oil bath at 120 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel column chromatography using dichloromethane / methanol (80:1) as the eluent, yielding 710 mg of a pale yellow solid in 84% yield.

[0104] 1 H NMR (600 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.59 (s, 2H), 7.39 –7.25 (m, 18H), 6.89 (d, J = 7.6 Hz, 4H), 5.33 – 4.47 (m, 2H), 3.13 – 2.94 (m,4H), 2.44 (s, 6H), 2.09 (s, 6H), 1.92 (s, 12H), 1.76 (s, 12H). 13 C NMR (151MHz, Chloroform-d) δ 156.1, 152.3, 140.1, 140.0, 132.3, 132.2, 131.6, 130.2,129.5, 128.8, 127.4, 127.4, 127.0, 126.8, 124.5, 68.0, 42.7, 37.3, 36.5,36.2, 28.8, 17.7. HRMS (ESI) calcd. for [C 63 H 67 N2, M-BF4] + : 851.5299, found:851.5302 [α] D 28 = +132.87 (c 0.6, CHCl3)

[0105] Example 4

[0106] The synthesis method of (S)-1-methoxy-4-(1-phenylethyl)benzene (P1) is as follows:

[0107]

[0108] Add Ni(COD)₂ (1.4 mg, 0.005 mmol) and L₃ / HBF₄ (5.7 mg, 0.006 mmol) to the reaction flask. t BuONa (1.0 mg, 0.01 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes. Then, [the following was added] i PrONa (16.4 mg, 0.2 mmol) and i PrOH (6.0 mg, 0.1 mmol) was added and stirred for 5 minutes. Starting materials 1a (10 mg, 0.1 mmol) and 2a (37 mg, 0.2 mmol) were added, and the reaction was carried out at 60 °C under nitrogen for 12 hours. After the reaction was completed, silica gel column chromatography was performed, using ethyl acetate / petroleum ether as eluent to give 20 mg of a colorless liquid, with a yield of 94%. 1 H NMR (600 MHz, Chloroform-d) δ 7.31 – 7.23 (m, 2H), 7.22 – 7.18 (m, 2H), 7.19 – 7.16 (m,1H), 7.13 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H), 4.10 (q, J = 7.4 Hz, 1H), 3.78 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ157.8, 146.7, 138.5, 128.5, 128.3, 127.5, 125.9, 113.7, 55.2, 43.9, 22.0.HRMS (EI) calcd. for [C 15 H 16 O, M] + : 212.1201, found: 212.1193. [α] D 27 = -0.6 (c0.2, CHCl3). HPLC analysis: the ee (97%) was determined using a Chiralpak ® OJ-3 column, hexane / 2-propanol = 95:5, flow rate = 1.0 mL / min, 230 nm UVdetector, t R(minor) = 15.78 min, t R (major) = 16.60 min.

[0109] Example 5

[0110] The synthesis method of (S)-1-methoxy-4-(1-phenylethyl)benzene (P1) differs from that of Example 4 mainly in that isopropanol, an additive, is not used. The steps are as follows:

[0111]

[0112] Add Ni(COD)₂ (1.4 mg, 0.005 mmol) and L₃ / HBF₄ (5.7 mg, 0.006 mmol) to the reaction flask. t BuONa (1.0 mg, 0.01 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes. Then, [the following was added] i PrONa (16.4 mg, 0.2 mmol) was stirred for 5 minutes. Starting materials 1a (10 mg, 0.1 mmol) and 2a (37 mg, 0.2 mmol) were reacted at 60 °C under nitrogen for 12 hours. After the reaction was complete, silica gel column chromatography was performed, using ethyl acetate / petroleum ether as eluent, to give 15 mg of colorless liquid in 70% yield. 1 H NMR (600 MHz, Chloroform-d) δ 7.31 – 7.23 (m,2H), 7.22 – 7.18 (m, 2H), 7.19 – 7.16 (m, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.82(d, J = 8.0 Hz, 2H), 4.10 (q, J = 7.4 Hz, 1H), 3.78 (s, 3H), 1.61 (d, J = 7.2Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 157.8, 146.7, 138.5, 128.5, 128.3,127.5, 125.9, 113.7, 55.2, 43.9, 22.0. HRMS (EI) calcd. for [C 15 H 16 O, M] + :212.1201, found: 212.1193. [α] D27 = -1.2 (c 0.3, CHCl3). HPLC analysis: the ee(97%) was determined using a Chiralpak ® OJ-3 column, hexane / 2-propanol = 95:5, flow rate = 1.0 mL / min, 230 nm UV detector, t R (minor) = 16.64 min, t R (major) = 17.16 min.

[0113] Example 6

[0114] The synthesis of (S)-4-(3,3-dimethylbutan-2-yl)-N,N-dimethylaniline (P2) follows these steps:

[0115]

[0116] Add Ni(COD)₂ (1.4 mg, 0.005 mmol) and L₃ / HBF₄ (5.7 mg, 0.006 mmol) to the reaction flask. t BuONa (1.0 mg, 0.01 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes. Then, [the following was added] i PrONa (16.4 mg, 0.2 mmol), and i PrOH (6.0 mg, 0.1 mmol) was added and stirred for 5 minutes. Starting materials 1b (8 mg, 0.1 mmol) and 2b (40 mg, 0.2 mmol) were added, and the mixture was reacted at 60 °C under nitrogen for 12 hours. After the reaction was complete, silica gel column chromatography was performed, using ethyl acetate / petroleum ether as eluent, to give 9 mg of colorless liquid, with a yield of 44%. 1 H NMR (600 MHz, Chloroform-d) δ 7.03 (d, J = 8.1 Hz, 2H), 6.67 (d, J = 8.2 Hz, 2H), 2.91 (s,6H), 2.46 (q, J = 7.4 Hz, 1H), 1.22 (d, J = 7.3 Hz, 3H), 0.85 (s, 9H). 13C NMR (151 MHz, Chloroform-d) δ 129.6, 129.6, 112.0, 112.0, 48.9, 40.8, 33.8, 27.8,15.9. HRMS (EI) calcd. for [C 14 H 23 N, M] + : 205.1830, found: 205.1827. [α] D 25 = +5.6 (c 0.15, CHCl3). HPLC analysis: the ee (93%) was determined using aChiralpak ® OJ-3 column, hexane / 2-propanol = 98:2, flow rate = 1.0 mL / min, 250nm UV detector, t R (minor) = 10.34 min, t R (major) = 23.48 min.

[0117] Example 7

[0118] The synthesis of (S,E)-4,4'-(but-1-ene-1,3-diyl)bis(methoxybenzene) (P3) follows these steps:

[0119]

[0120] Add Ni(COD)₂ (1.4 mg, 0.005 mmol) and L₃ / HBF₄ (5.7 mg, 0.006 mmol) to the reaction flask. t BuONa (1.0 mg, 0.01 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes. Then, [the following was added] i PrONa (16.4 mg, 0.2 mmol), and i PrOH (6.0 mg, 0.1 mmol) was added and stirred for 5 minutes. Starting materials 1c (16 mg, 0.1 mmol) and 2a (37 mg, 0.2 mmol) were added, and the mixture was reacted at 60 °C under nitrogen for 12 hours. After the reaction was complete, silica gel column chromatography was performed, using ethyl acetate / petroleum ether as eluent, to give 17 mg of a colorless liquid, in 63% yield. 1H NMR (600 MHz, Chloroform-d) δ 7.21 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.85 –6.69 (m, 4H), 6.26 (d, J = 15.8 Hz, 1H), 6.15 (dd, J = 15.9, 6.7 Hz, 1H), 3.72 (s, 6H), 3.55 – 3.44 (m, 1H), 1.35 (d, J = 6.9 Hz, 3H). 13 HRMS (EI) calcd. for [C 18 H 20 O2, M] + : 268.1463, found: 268.1459. [α] D 28 = -22.8 (c 0.10, CHCl3). HPLC analysis: the ee (91%) was determined using a Chiralpak ® OJ-3 column, hexane / 2-propanol = 95: 5, flowrate = 1.0 mL / min, 230 nm UV detector, t R (minor) = 20.69 min, t R (major) = 25.29 min.

[0121] Example 8

[0122] The synthesis of (S)-1-fluoro-4-(1-(4-methoxyphenyl)ethyl)benzene (P4) follows these steps:

[0123]

[0124] Add Ni(COD)₂ (1.4 mg, 0.005 mmol) and L₃ / HBF₄ (5.7 mg, 0.006 mmol) to the reaction flask. tBuONa (1.0 mg, 0.01 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes. Then, [the following was added] i PrONa (16.4 mg, 0.2 mmol), and i PrOH (6.0 mg, 0.1 mmol) was added and stirred for 5 minutes. Starting materials 1d (13 mg, 0.1 mmol) and 2c (26 mg, 0.2 mmol) were added, and the reaction was carried out at 80°C under nitrogen for 12 hours. After the reaction was complete, silica gel column chromatography was performed, using ethyl acetate / petroleum ether as eluent to give 10 mg of colorless liquid P4, in 43% yield. 1 H NMR (600MHz, Chloroform-d) δ 7.18 – 7.06 (m, 4H), 6.95 (d, J = 8.5 Hz, 2H), 6.83 (d,J = 8.3 Hz, 2H), 4.09 (q, J = 7.3 Hz, 1H), 3.78 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 161.2 (d, J = 244.3 Hz), 142.5 (d, J =2.7 Hz), 128.9 (d, J = 7.6 Hz), 128.4, 115.0 (d, J = 21.5 Hz), 113.8, 55.2,43.2, 22.2. 19 F NMR (376 MHz, Chloroform-d) δ -117.7. HRMS (EI) calcd. for[C 15 H 15 FO, M] + : 230.1107, found: 230.1102. [α] D 28 = -6.0 (c 0. 2, CHCl3). HPLC analysis: the ee (95%) was determined using a Chiralpak ® OJ-3 column, hexane / 2-propanol = 95:5, flow rate = 1.0 mL / min, 230 nm UV detector, t R (major) = 9.80 min, tR (minor) = 13.23 min.

[0125] Example 9

[0126] The synthesis of Isopropyl (S)-4-(1-cyclohexylethyl)benzoate (P5) follows these steps:

[0127]

[0128] Ni(COD)₂ (2.8 mg, 0.01 mmol) and L₃ / HBF₄ (11.4 mg, 0.012 mmol) were added to the reaction flask. t BuONa (2.0 mg, 0.02 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes; then added... i PrONa (16.4 mg, 0.2 mmol) and i PrOH (6.0 mg, 0.1 mmol) was added and stirred for 5 minutes. Starting materials 1e (11 mg, 0.1 mmol) and 2d (40 mg, 0.2 mmol) were added, and the reaction was carried out at 60 °C under nitrogen for 24 hours. After the reaction was complete, silica gel column chromatography was performed, using dichloromethane / petroleum ether as eluent, to give 20 mg of a white solid, in 73% yield. 1 H NMR (600 MHz, Chloroform-d) 7.95 (d, J = 7.9 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 5.34 – 5.05(m, 1H), 2.61 – 2.23 (m, 1H), 1.87 (d, J = 12.9 Hz, 1H), 1.78 – 1.69 (m, 1H), 1.62 – 1.60 (m, 2H), 1.44 – 1.31 (m, 9H), 1.24 – 1.19 (m, 4H), 1.14 – 1.04(m, 2H), 0.98 – 0.87 (m, 1H), 0.84 – 0.73 (m, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 165.2, 151.5, 128.3, 127.4, 126.6, 67.00, 45.0, 43.0, 30.4,29.5, 25.4, 25.4, 20.9, 17.6. HRMS (EI) calcd. for [C18 H 26 O2, M] + : 274.1933, found: 274.1928. [α] D 28 = +15.44 (c 0.5, CHCl3). HPLC analysis: the ee (93%) was determined using a Chiralpak ® AD-H column, hexane / 2-propanol = 100:0, flowrate = 0.5 mL / min, 250 nm UV detector, t R (minor) = 36.28 min, t R (major) = 41.50 min.

[0129] Example 10

[0130] The synthesis of Isopropyl (S,E)-4-(4-(4-methoxyphenyl)but-3-en-2-yl)benzoate (P6) follows these steps:

[0131]

[0132] Ni(COD)₂ (2.8 mg, 0.01 mmol) and L₃ / HBF₄ (11.4 mg, 0.012 mmol) were added to the reaction flask. t BuONa (2.0 mg, 0.02 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes. Then, [the following was added] i PrONa (16.4 mg, 0.2 mmol), and i PrOH (6.0 mg, 0.1 mmol) was added and stirred for 5 minutes. Starting materials 1f (16 mg, 0.1 mmol) and 2d (40 mg, 0.2 mmol) were added, and the reaction was carried out at 60 °C under nitrogen for 24 hours. After the reaction was completed, silica gel column chromatography was performed, using ethyl acetate / petroleum ether as eluent, to give 17 mg of colorless liquid, yield 51%. 11H NMR (600 MHz, Chloroform-d) δ 7.98 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.30 – 7.19 (m, 2H), 6.83 (d, J = 8.3 Hz, 2H), 6.35 (d, J = 15.8 Hz, 1H), 6.21 (dd, J = 15.9, 6.8 Hz, 1H), 5.33 – 5.13 (m, 1H), 3.79 (s, 3H), 3.70 – 3.62 (m, 1H), 1.46 (d, J = 7.0 Hz, 3H), 1.36 (d, J = 6.3 Hz, 6H). 13 13C NMR (151 MHz, Chloroform-d) δ 166.1, 158.9, 151.1, 132.1, 130.1, 129.8, 128.9, 128.5, 127.3, 127.3, 113.9, 68.1, 55.3, 42.6, 21.9, 21.2. HRMS (EI) calcd. for [C 21 18 24 H + 15O3, M] D 28 : 324.1725, found: 324.1720. [α] ® = -14.5 (c 0.8, CHCl3). HPLC analysis: the ee (93%) was determined using a Chiralpak R AD-H column, hexane / 2-propanol = 95:5, flow rate = 1.0 mL / min, 250 nm UV detector, t R (minor) = 15.32 min, t

[0133] Example 11

[0134] (R)-3-(1-(4-fluorophenyl)ethyl)benzo[b]thiophene (P7) was synthesized as follows:

[0135]

[0136] Add Ni(COD)₂ (1.4 mg, 0.005 mmol) and L₃ / HBF₄ (5.7 mg, 0.006 mmol) to the reaction flask. t BuONa (1.0 mg, 0.01 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes. Then, [the following was added] i PrONa (16.4 mg, 0.2 mmol), and i PrOH (6.0 mg, 0.1 mmol) was added and stirred for 5 minutes. 1 g of starting material (16 mg, 0.1 mmol) and 2e (35 mg, 0.2 mmol) were added. The reaction was carried out at 60 °C under nitrogen for 12 hours. After the reaction was completed, silica gel column chromatography was performed, using ethyl acetate / petroleum ether as eluent, to give 19 mg of a white solid, yield 74%. 1 H NMR (600 MHz, Chloroform-d) δ 7.84 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.28 (d,J = 7.7 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.21 (s, 1H), 7.18 (d, J = 8.2,2H), 6.95 (d, J = 8.4 Hz, 2H), 4.43 (q, J = 7.2 Hz, 1H), 1.71 (d, J = 7.1 Hz,3H). 13 C NMR (151 MHz, Chloroform-d) δ 161.4 (d, J = 244.4 Hz), 141.1 (d, J =2.2 Hz), 140.7, 140.2, 138.3, 128.8 (d, J = 7.6 Hz), 124.2, 123.8, 122.8,122.4, 121.5, 115.3 (d, J = 21.5 Hz), 38.8, 22.5. 19 F NMR (376 MHz,Chloroform-d) δ -117.0. HRMS (EI) calcd. for [C 16 H 13 FS, M] + : 256.0722, found:256.0717. [α] D 28= -27.5 (c 0.38, CHCl3). HPLC analysis: the ee (94%) was determined using a Chiralpak ® OD-H column, hexane / 2-propanol = 98:2, flow rate= 3.0 mL / min, 230 nm UV detector, t R (minor) = 2.09 min, t R (major) = 2.52min. mp: 68–70 ℃

[0137] Example 12

[0138] The synthesis of (R)-2,4-dimethoxy-1-(1-phenylethyl)benzene (P8) follows these steps:

[0139]

[0140] Add Ni(COD)₂ (1.4 mg, 0.005 mmol) and L₃ / HBF₄ (5.7 mg, 0.006 mmol) to the reaction flask. t BuONa (1.0 mg, 0.01 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes. Then, [the following was added] i PrONa (16.4 mg, 0.2 mmol), and i PrOH (6.0 mg, 0.1 mmol) was added and stirred for 5 minutes. The starting material was added 1 h (16 mg, 0.1 mmol) and 2 f (32 mg, 0.2 mmol). The reaction was carried out at 60 °C under nitrogen for 12 hours. After the reaction was completed, silica gel column chromatography was performed, eluent being petroleum ether, to give 12 mg of colorless liquid, yield 50%. 1 H NMR (600 MHz, Chloroform-d) δ7.27 – 7.23 (m, 4H), 7.15 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.43(d, J = 6.3 Hz, 2H), 4.47 (q, J = 7.3 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 1.55 (d, J = 7.4 Hz, 3H). 13HRMS (EI) calcd. for [C 16 H 18 O2, M] + : 242.1307, found: 242.1302. [α] D 28 = +0.8 (c 0.1, CHCl3). HPLC analysis: the ee (93%) was determined using aChiralpak ® OJ-3 column, hexane / 2-propanol = 95: 5, flow rate = 1.0 mL / min, 230nm UV detector, t R (minor) = 19.16 min, t R (major) = 22.47 min.

[0141] Example 13

[0142] The synthesis of Isopropyl(S)-6-(1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)-2-naphthoate (P9) follows these steps:

[0143]

[0144] Add Ni(COD)₂ (1.4 mg, 0.005 mmol) and L₃ / HBF₄ (5.7 mg, 0.006 mmol) to the reaction flask. t BuONa (1.0 mg, 0.01 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes. Then, [the following was added] i PrONa (16.4 mg, 0.2 mmol), and iPrOH (6.0 mg, 0.1 mmol) was added and stirred for 5 minutes. Starting material 1i (48 mg, 0.2 mmol) and 2 g (27 mg, 0.1 mmol) were added. The reaction was carried out at 60 °C under nitrogen for 12 hours. After the reaction was completed, silica gel column chromatography was performed, using ethyl acetate / petroleum ether as eluent to give 28 mg of colorless liquid, with a yield of 65%. 1 H NMR (600 MHz, Chloroform-d) δ 8.53 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.88 – 7.78 (m, 2H), 7.72 (s, 1H), 7.44 – 7.35 (m, 1H), 7.23 – 7.14 (m, 2H), 6.97 (d, J = 8.2 Hz, 1H), 5.39 – 5.20 (m, 1H), 4.26 (q, J = 7.3 Hz, 1H), 1.72 (d, J = 7.3 Hz, 3H), 1.66 (s, 4H), 1.46 – 1.37 (m, 6H), 1.32 – 1.19 (m, 12H). 13 C NMR (151 MHz, Chloroform-d) δ 166.4, 146.7, 144.7, 142.6, 142.4, 135.6, 131.1, 130.5,129.2, 127.8, 127.6, 126.5, 125.6, 125.3, 125.2, 124.8, 68.4, 44.8, 35.1,35.0, 34.2, 31.9, 31.8, 22.0, 21.8. HRMS (ESI) calcd. for [C 30 H 36 O2, M+Na] + :451.2608, found: 451.2611. [α] D 25 = +1.5 (c 0.37, CHCl3). HPLC analysis: theee (91%) was determined using a Chiralpak ® IN column, hexane / 2-propanol = 99:1, flow rate = 0.5 mL / min, 250 nm UV detector, t R(major) = 15.15 min, t R (minor) = 19.58 min.

[0145] Example 14

[0146] The synthesis of (R)-1,2,3-trimethoxy-5-(1-(4-methoxyphenyl)ethyl)benzene (P10) follows these steps:

[0147]

[0148] Ni(COD)₂ (2.8 mg, 0.01 mmol) and L₃ / HBF₄ (11.4 mg, 0.012 mmol) were added to the reaction flask. t BuONa (2.0 mg, 0.02 mmol) and toluene (1.0 mL) were pre-complexed for 40 minutes. Then, [the following was added] i PrONa (16.4 mg, 0.2 mmol), and i PrOH (6.0 mg, 0.1 mmol) was added and stirred for 5 minutes. Starting materials 1j (19 mg, 0.1 mmol) and 2a (37 mg, 0.2 mmol) were added, and the mixture was reacted at 60 °C under nitrogen for 24 hours. After the reaction was complete, silica gel column chromatography was performed, using ethyl acetate / petroleum ether as eluent, to give 21 mg of a colorless liquid, in 70% yield. 1 H NMR (600 MHz, CDCl3) δ 7.07 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.1 Hz, 2H), 6.35 (s, 2H), 3.97 (q, J = 7.4 Hz, 1H), 3.79 – 3.66 (m, 12H), 1.52 (d, J = 7.2 Hz, 3H). 13 CNMR (151 MHz, CDCl3) δ 157.8, 153.0, 142.5, 138.3, 128.3, 113.7, 113.7,104.5, 60.8, 56.0, 55.2, 44.2, 22.2. HRMS (EI) calcd. for [C 18 H 22 O4, M] + :302.1518, found: 302.1511. [α] D28 = -10.7 (c 0.36, CHCl3). HPLC analysis: theee (92%) was determined using a Chiralpak ® IC-3 column, hexane / 2-propanol =95:5, flow rate = 1.0 mL / min, 230 nm UV detector, t R (major) = 24.31 min, t R (minor) = 26.51 min。

Claims

1. A chiral carbene ligand, characterized in that, The structure is as follows: ； in: R 1 R 2 R 3 R 4 R 5 The alkyl group is hydrogen, alkyl, or aryl, either individually or in combination; preferably, the alkyl group is methyl, ethyl, tert-butyl, or isopropyl; the aryl group is phenyl or a substituted phenyl group, and the substituent of the substituted phenyl group is methyl, ethyl, tert-butyl, or isopropyl. R 6 The alkyl group is an alkyl group, preferably methyl, ethyl, tert-butyl or isopropyl.

2. The chiral carbene ligand according to claim 1, characterized in that, It is one of the following structures: 。 3. A method for preparing the chiral carbene ligand according to claim 1, characterized in that, The reaction process and steps are as follows: ； S1, Preparation of compound C: Inside a glove box, compound A, compound B, and solvent are added to a reaction tube that has been dried in an oven. The resulting solution is then subjected to freezing-vacuuming-thawing degassing, followed by heating to 100–150°C and stirring for 12–48 hours. After the reaction system cools to room temperature, HCl aqueous solution is added for acidification, and stirring continues for 1–48 hours. Subsequently, NaOH aqueous solution is added dropwise for alkalization, followed by filtration and drying to obtain product C. Preferably: The solvent is toluene or mesitylene, and the amount used is 2 to 8 mL per millimole of compound A; The concentration of the HCl aqueous solution is 1-3N, and the amount used is 1-3 mL per millimole of compound A; The concentration of the NaOH aqueous solution is 1-3N, and the amount used is 1-3 mL per millimole of compound A; In the structural formula of compound B, R 7 It is phenyl or benzyl; The equivalent ratio of compound B to A is (2-4):1; S2, Preparation of compound E: Inside the glove box, compounds C and D prepared by S1, bis(dibenzylacetone)palladium(0), and racemic binaphthalenediphenylphosphine were added to the oven-dried reaction tube. t BuONa and toluene; the resulting solution was frozen, vacuumed, thawed and degassed, then heated to 100–120 °C and stirred for 24–48 h; after the reaction was completed, it was cooled to room temperature, and the volatile solvent was removed by vacuum distillation. The residue was purified by rapid silica gel column chromatography to obtain product E. Preferably, the compound D, t The equivalent ratio of BuONa to compound C is (2-4):(3-8)1; the molar ratio of bis(dibenzylacetone)palladium(O), racemic biphenylphosphine to compound C is (5-20):(10-40):100; the amount of toluene used is 10-20 mL per millimole of compound C; in the structural formula of compound D, R 8 It is methyl, ethyl, tert-butyl or isopropyl; S3, Preparation of chiral carbene ligand F: Compound E, prepared by S2, was added to a round-bottom flask dried in an oven. Ammonium tetrafluoroborate and triethyl orthoformate were then added. The flask was fitted with a spherical condenser and placed in an oil bath at 100–120°C with stirring for 12–24 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was then subjected to silica gel column chromatography to obtain the chiral carbene ligand F. Preferably: The amount of triethyl orthoformate used is 10 to 30 mL per millimole of compound E; the equivalent ratio of ammonium tetrafluoroborate to compound E is (1 to 2):

1.

4. A method for preparing the chiral ben ligand according to claim 1, characterized in that, The reaction process and steps are as follows: ， ； (1) Preparation of compound I: Under an argon atmosphere, tetrahydrofuran was added to a reaction apparatus containing magnesium shavings and iodine initiator, and the mixture was heated to reflux. Compound G was then added dropwise, and after the addition was complete, the mixture was refluxed and stirred for 0.5–3 h. A tetrahydrofuran solution of compound H was slowly added dropwise, and after the addition was complete, the mixture was refluxed for 6–24 h. After the reaction was completed, the mixture was quenched in a saturated ammonium chloride solution, and the liquid was separated. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed, dried, and concentrated under reduced pressure. The residue was purified by recrystallization from n-hexane to give a white solid product I. Preferably, the equivalent ratio of the magnesium shavings, compound H, and compound G is (1-2):(1-2):1; the amount of tetrahydrofuran solution used is 1-3 mL per millimole of compound G; and the amount of iodine used is 1%-2% mol of metallic magnesium. (2) Preparation of compound DB: Compound I prepared by S1, tetrahydroxydiboron and tetrahydrofuran were added to a flask that had been dried in an oven and equipped with a magnetic stir bar and a 4 Å molecular sieve. The mixture was heated and stirred under reflux for 1-6 h. After filtration through a diatomaceous earth short column, the filtrate was concentrated under reduced pressure. The residue was crystallized from n-hexane to obtain a white solid product DB. Preferably, the amount of the 4 Å molecular sieve is 5-20 mol% of compound I; the equivalent ratio of the tetrahydroxydiboron compound I is (1-1.5):1; and the amount of tetrahydrofuran is 10-30 mL per millimole of compound I. (3) Preparation of compound K: Compound J was placed in a solvent at -78℃, and diisobutylaluminum hydride was added dropwise. After the addition was complete, the mixture was stirred at -78℃ for 1–3 h, then heated to room temperature and stirred for another 1–3 h. The system was then cooled to -78℃ again, and methanol and compound DB prepared from S2 were added sequentially. The mixture was heated to room temperature and stirred for 6–24 h. The system was acidified with an aqueous HCl solution and stirred for 0.5–2 h, resulting in the precipitation of a pale yellow solid. The obtained solid was washed, filtered, and dried to obtain the pale yellow solid product K. Preferably, the equivalence ratio of diisobutylaluminum hydride, methanol, compound DB to compound J is (1-2):(1-3):(0.5-0.6):1; the solvent is dichloromethane, toluene, or tetrahydrofuran, and the amount used is 3-6 mL per millimole of compound J; the concentration of the HCl aqueous solution is 1-3N, and the amount used is 1-3 mL per millimole of compound J. In the structural formula of compound J, R 9 The substituted phenyl group is methyl, ethyl, tert-butyl, isopropyl, or phenyl. (4) Preparation of compound L: Inside a glove box, compounds K, D, sodium tert-butoxide, and toluene prepared by S3 were added to a reaction tube pre-dried in an oven. The resulting solution was degassed using a freeze-vacuum-thaw method and then stirred at room temperature for 1–3 h. Bis(dibenzylacetone)palladium(O), racemic bis(naphthyl)phosphine, and... t BuONa: The reaction tube was placed in an oil bath preheated to 100-120 °C and stirred continuously for 24-48 h. After the reaction was completed, the mixture was cooled to room temperature, and the volatile solvent was removed by vacuum distillation. The residue was purified by rapid silica gel column chromatography to obtain a pale yellow solid product. Preferably, the amounts of bis(dibenzylacetone)palladium(O) and racemic dinaphthalenebisphenylphosphine are 5–20 mol% and 10–40 mol% of compound K, respectively; the amount of toluene is 10–20 mL per millimole of compound K; and the amounts of compound D, t The equivalence ratio of BuONa to compound K is (2-4):(3-8):1; in the structural formula of compound D, R 8 It is methyl, ethyl, tert-butyl or isopropyl; (5) Preparation of chiral carbene ligand M: Compound L, prepared by S4, was added to a round-bottom flask that had been dried in an oven. Ammonium tetrafluoroborate and triethyl orthoformate were then added. After assembling a spherical condenser, the flask was placed in an oil bath at 100–120 °C and heated and stirred for 12–24 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by rapid silica gel column chromatography to give a pale yellow solid product M. Preferably, the amount of ammonium tetrafluoroborate used is 1 to 2 equivalents of compound L; The dosage of triethyl orthoformate is 10–30 mL per millimole of compound L.

5. The application of the chiral carbene ligand of claim 1 in the nickel-catalyzed asymmetric synthesis of olefins with aryl bromides or aryl chlorides, characterized in that, The reaction formula and reaction process are as follows: ； Nickel catalyst, chiral carbene ligand, base and solvent were added sequentially to the reaction flask and pre-complexed for 10-60 minutes. Then, hydrogen source and additive isopropanol were added and stirred for 0-10 minutes to dissolve completely. Then, raw material 1 and raw material 2 were added and stirred at 40-80°C for 6-24 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature, the solvent was removed under reduced pressure, and the target product 3 was obtained by column chromatography.

6. The application according to claim 5, characterized in that: In the structural formula of raw material 1, R is aryl, alkenyl, or alkyl; in the structural formula of raw material 2, Ar is aryl or heteroaryl. Preferably, the aryl group is phenyl, substituted phenyl, or fused-ring aryl, wherein the substituent in the substituted phenyl group is alkyl, trifluoromethyl, phenyl, alkoxy, nitrogen, silicon, ester, or halogen, wherein the alkyl group is preferably methyl, ethyl, tert-butyl, or isopropyl; the heteroaryl group is substituted pyridine, substituted thiophene, or substituted furan, wherein the substituent in the three heteroaryl groups is trifluoromethyl, phenyl, alkyl, halogen, alkoxy, or nitrogen, wherein the alkyl group is methyl, ethyl, tert-butyl, or isopropyl.

7. The application according to claim 5, characterized in that: The nickel catalyst is Ni(COD)₂, Ni(acac)₂, NiBr₂·DME, and Ni( tBu One of the three (stb) is used in an amount of 5-10 mol of the raw material 1.

8. The application according to claim 5, characterized in that, The chiral carbene ligand is one of the following structural formulas: ； The amount of chiral carbene ligand used is 6–12 mol of raw material 1.

9. The application according to claim 5, characterized in that: The alkali is one of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, and sodium isopropoxide, and the amount used is 10-20 mol% of raw material 1; the solvent is one of toluene, acetone, and tetrahydrofuran, and the amount used is 5-20 mL per millimole of raw material 1.

10. The application according to claim 5, characterized in that: The hydrogen source is sodium isopropoxide, and the amount used is 1 to 3 equivalents of raw material 1; the amount of the additive isopropanol is 0 to 3 equivalents of raw material 1.

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