A method for preparing chiral geminal diarylmethylene silane compound

Abstract

The invention discloses a method for preparing a chiral geminal diaryl methylene silane compound, using N-aryl sulfonyl hydrazone compounds, aryl bromides and (dimethylphenylsilyl) boric acid pinacol ester as raw materials, and enantioselective three-component coupling is carried out under the co-catalysis of palladium and copper to prepare chiral geminal diaryl methylene silane. The above preparation method has mild reaction conditions, easy to obtain reactants and good functional group tolerance, and the synthetic product has high stereoselectivity and high yield, and can quickly and efficiently prepare the enantiomer of the target compound. In addition, the method has a wide range of substrates, can be used to prepare chiral silanes that cannot be obtained by carbene Si-H insertion method, and provides new ideas for designing and synthesizing novel chiral organosilane compounds.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for preparing a chiral geminal diarylmethylene silane compound. Background Art

[0002] Chiral organosilanes play a unique role in materials science, drug modification and chemical synthesis. Silicon-substituted compounds have low toxicity and favorable metabolism, and have received extensive attention in medicinal chemistry. In addition, chiral silicon-containing organic compounds are very useful blocks in organic chemistry, and chiral catalysts containing silicon atoms are also widely used in asymmetric organic catalysis. Therefore, the catalytic asymmetric synthesis of chiral organosilanes has made significant progress in recent years. However, most methods are only applicable to chiral benzylsilanes with one aromatic group. The main methods include asymmetric hydrosilylation of aromatic olefins, chiral transfer strategies of benzyl halides or quaternary ammonium salts, and asymmetric carbene insertion. Although geminal diarylmethine fragments are widely present in bioactive molecules (J. Med. Chem. 1996, 39, 2411-2421; Curr. Med. Res. Opin. 2004, 20, 1347-1355.), and silicon can be used as a bioisostere of carbon to modify drugs (J. Med. Chem. 2013, 56, 388-405.), there are few reports on the synthesis of chiral geminal diarylmethine silanes.

[0003] Since two sterically similar aromatic substituents are attached to the chiral center, it is extremely challenging to develop asymmetric catalytic reactions to construct geminal diarylmethine silanes. The methods that have been reported so far are: 1) chiral transfer reactions catalyzed by palladium or nickel (Chem. Commun. 2016, 52, 5609-5612; Org. Lett. 2021, 23, 1333-1338.), both of which only report one example and the enantioselectivity of the reaction is poor; 2) iridium-catalyzed chiral transfer reactions of prochiral geminal diarylmethine silanes with B 2 pin 2Desymmetrization reaction (Angew.Chem., Int.Ed.2017,56,7205-7208.), the disadvantage of this strategy is that it cannot flexibly construct target compounds with different aromatic substitutions. 3) Rhodium-catalyzed carbene enantioselective insertion into Si-H bonds. Although the reaction process of this method is simple, the carbene precursor needs to be specially designed. For example, in 2019, Zhu et al. reported a work using conjugated enynone as a carbene precursor to synthesize enantiomer-enriched α-furanyl-substituted geminal diarylmethylsilane (ACS Catal.2019,9,5353-5357.). In 2020, Zhou et al. made a breakthrough in the rhodium-catalyzed enantioselective Si-H insertion of diaryldiazo compounds as carbene precursors, which can quickly synthesize chiral geminal diarylmethylsilane (J.Am.Chem.Soc.2020,142,12394-12399.). However, this method requires that the two aromatic groups must have significant electrical differences in order to obtain excellent enantioselectivity. In the same year, Franz et al. reported similar work to Zhou (Franz, AK et al. J. Am. Chem. Soc. 2020, 142, 11674-11679.), in which they used the steric hindrance difference between the two aromatic groups to improve the enantioselectivity of the product, and it was crucial that one of the aromatic groups had an ortho-substituent.

[0004] Since the current methods for constructing geminal diarylmethylene silanes generally have problems such as poor enantioselectivity and substrate limitations, it is impossible to efficiently synthesize target compounds with different aromatic substitutions. Therefore, there is an urgent need to develop new synthetic methods to efficiently prepare chiral geminal diarylmethylene silane compounds. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing a chiral geminal diarylmethylidene silane compound, wherein N-arylsulfonylhydrazone compounds, aryl bromides and (dimethylphenylsilyl)boronic acid pinacol ester are used as raw materials, and a three-component coupling is performed under the co-catalysis of palladium and copper to prepare the chiral geminal diarylmethylidene silane. The method has a wide substrate range, and the product has high stereoselectivity, and the chiral geminal diarylmethylidene silane compound can be efficiently prepared.

[0006] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0007] The first aspect of the present invention provides a method for preparing a chiral geminal diaryl methylene silane compound, wherein an N-sulfonyl hydrazone compound shown in formula 1, a bromoaromatic compound shown in formula 2 and a silicon boron reagent are subjected to a coupling reaction in the presence of a palladium salt, a chiral phosphine ligand, a copper salt and a solvent to obtain a chiral geminal diaryl methylene silane compound shown in formula 4; the silicon boron reagent is PhMe 2SiBpin;

[0008] The structures of the above formula 1, formula 2, and formula 4 are respectively as follows:

[0009]

[0010] Wherein, R is p-tolyl or mesitylene, R 1 H, F, Cl, C 1 ~C 12 Alkyl, phenyl, naphthyl, C 1 ~C 10 An alkoxy group, ester group, cyano group or thiophene ring;

[0011] R 2 H, F, C 1 ~C 12 Alkyl, phenyl, amino, C 1 ~C 10 An alkoxy group, ester group, benzofuran or indole ring.

[0012] Furthermore, the C 1 ~C 12 In the alkane group of , the alkane group preferably has 2 to 6 carbon atoms.

[0013] Furthermore, the palladium salt is preferably palladium acetate (Pd(OAc) 2 ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), tris(dibenzylideneacetone)dipalladium-chloroform adduct (Pd 2 (dba) 3 ·CHCl 3 ), bis(dibenzylideneacetone)palladium (Pd(dba) 2 ), PdCl 2 , dichloro(dihydroxymethylbutyrate)palladium ([Pd(dmba)Cl] 2 ), more preferably [Pd(dmba)Cl] 2 .

[0014] Furthermore, the copper salt is preferably CuCl, CuBr, CuI, CuBr . SMe 2 , cuprous thiophene-2-carboxylate (CuTc), CuCl 2 , CuBr 2 ,CuF 2 、Copper acetylacetonate (Cu(acac) 2 ), copper trifluoromethanesulfonate (Cu(OTf) 2 ), more preferably CuBr.

[0015] Furthermore, the chiral phosphine ligand is preferably one of the compounds represented by formulas L1 to L12, and the structures of formulas L1 to L12 are shown below:

[0016]

[0017] Wherein, Ph is phenyl; Cy is cyclohexyl; t Bu is tert-butyl; i Pr is isopropyl; Ad is adamantyl.

[0018] Furthermore, the chiral phosphine ligand is more preferably a compound represented by formula L11.

[0019] Furthermore, the solvent is one or more of tetrahydrofuran, cyclohexane, methylcyclohexane, 1,4-dioxane, dichloromethane, toluene, p-xylene, and mesitylene, preferably cyclohexane or methylcyclohexane.

[0020] Furthermore, the reaction temperature of the coupling reaction is 40 to 70° C., and the reaction time is 5 to 18 hours.

[0021] Furthermore, the reaction temperature of the coupling reaction is preferably 50-60° C., and the reaction time is preferably 8-12 h.

[0022] Furthermore, the molar ratio of the N-sulfonylhydrazone compound represented by Formula 1, the brominated aromatic compound represented by Formula 2 and the silicon boron reagent is preferably 1:1-5:1-5, more preferably 1:1.5:3.

[0023] Furthermore, the molar ratio of the N-sulfonylhydrazone compound, palladium salt and copper salt shown in Formula 1 is 1:0.05-0.5:0.01-0.3, more preferably 1:0.05:0.1.

[0024] Furthermore, the molar ratio of the palladium salt to the chiral phosphine ligand is preferably 1:1-5, more preferably 1:4.4.

[0025] Furthermore, under an inert atmosphere, a palladium salt and a chiral phosphine ligand are subjected to ligand exchange in the presence of a solvent, and then an N-sulfonylhydrazone compound shown in Formula 1, a bromoaromatic compound shown in Formula 2, a silicon boron reagent and a copper salt are added for a coupling reaction to obtain the chiral geminal diarylmethylsilane compound.

[0026] Furthermore, the reaction temperature of the ligand exchange is 40-60°C, and the reaction time is 30min-1h.

[0027] Furthermore, the coupling reaction is carried out in the presence of a base and an additive; the base is cesium carbonate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium acetate or sodium methoxide, and the additive is pyridine, 4-methylpyridine, 4-trifluoromethylpyridine, 4-methoxypyridine, 4-N,N-dimethylpyridine, quinoline, 2-methylpyridine, tetrahydroquinoline or 1,4-diazabicyclo[2.2.2]octane.

[0028] Furthermore, the molar ratio of the N-sulfonylhydrazone compound, the base and the additive shown in Formula 1 is preferably 1:1.1-5:0.1-1.5, more preferably 1:4.5:1. The present invention has found in the experimental process that the addition of the base and the additive can effectively improve the ee value of the product.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. The present invention uses N-arylsulfonylhydrazone compounds, aryl bromides and (dimethylphenylsilyl)boronic acid pinacol ester as raw materials, and performs three-component coupling under the co-catalysis of palladium and copper to prepare chiral geminal diarylmethylsilane. The preparation method is simple, the reaction conditions are mild, the reactants are easily available, and the reaction has good functional group tolerance. No complicated pre-functionalization is required. The enantiomers of the target compound can be quickly prepared through the aryl substituents of N-arylsulfonylhydrazone and aryl bromide, with high yield and high stereoselectivity, and the ee value is as high as 96%.

[0031] 2. The preparation method provided by the present invention can efficiently prepare chiral geminal diarylmethylene silane compounds, and because the method is applicable to a wide range of substrates, chiral silanes that cannot be obtained by carbene Si-H insertion methods can be prepared, and at the same time, a new idea is provided for the design and synthesis of new chiral organosilane compounds. In addition, the chiral geminal diarylmethylene silane compounds prepared by the present invention have good application prospects in medicinal chemistry, chiral catalysts, organic synthesis, etc. DETAILED DESCRIPTION

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0033] The present invention is further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0034] Example 1

[0035] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1a, the bromoaromatic compound shown in Formula 2a and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4aa. The reaction formula is as follows:

[0036]

[0037] The specific preparation process is as follows:

[0038] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were added and stirred at 60°C for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1a (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50°C for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 71.1mg of product 4aa with a yield of 68%.

[0039] The prepared product 4aa was characterized by H-NMR, C-NMR, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0040] 1 H NMR (400 MHz, CDCl 3 )δ7.41-7.26(m,5H),7.09-6.99(m,6H),6.76(d,J=8.8Hz,2H),3.77(s,3H),3.67(s,1H),2.30(s,3H),0.31(s,3H),0.30(s,3H).

[0041] 13 C NMR (100 MHz, CDCl 3 ,All peak signals have been listed)δ157.21,139.61,137.88,134.70,134.40,129.83,128.97,128.85,128.70,127.48,113.58,55.16,43.90,20.89,-3.12,-3.15.[α] D 20 =5.1(c=0.5,CHCl 3 ).

[0042] HRMS(EI)m / z calculated for C 23 H 26 OSi[M] + :346.1753,found:346.1746.

[0043] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 9.27 min (major), 9.90 min (minor). HPLC measured 94% ee.

[0044] Example 2

[0045] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1a, the bromoaromatic compound shown in Formula 2a and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L6, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4aa. The reaction formula is as follows:

[0046]

[0047] The specific preparation process is as follows:

[0048] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L6 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1a (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 56.4mg product 4aa with a yield of 54%. HPLC measured 86% ee.

[0049] Example 3

[0050] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1b, the bromoaromatic compound shown in Formula 2b and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula ent-4aa. The reaction formula is as follows:

[0051]

[0052] The specific preparation process is as follows:

[0053] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were added and stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1b (0.3mmol), substrate 2b (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 12h. The reaction solution was concentrated and separated by column chromatography to obtain 62.6mg of product ent-4aa with a yield of 60%.

[0054] The prepared product ent-4aa was characterized by nuclear magnetic resonance hydrogen spectrum, carbon spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0055] 1 H NMR (400 MHz, CDCl 3 )δ7.42-7.27(m,5H),7.11-6.97(m,6H),6.76(d,J=8.7Hz,2H),3.76(s,3H),3.66(s,1H),2.29(s,3H),0.30(s,1H),0.29(s,3H).

[0056] 13 C NMR (100 MHz, CDCl 3 ,All peak signals have been listed)δ157.21,139.61,137.88,134.70,134.40,129.83,128.97,128.85,128.70,127.49,113.57,55.17,43.91,20.89,-3.12,-3.15.[α] D 20 =-6.5(c=0.6,CHCl 3 ).

[0057] HRMS(EI)m / z calculated for C 23 H 26 OSi[M] + :346.1753,found:346.1747.

[0058] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 9.25 min (minor), 9.87 min (major). HPLC measured 92% ee.

[0059] Example 4

[0060] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1c, the bromoaromatic compound shown in Formula 2a and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4ca. The reaction formula is as follows:

[0061]

[0062] The specific preparation process is as follows:

[0063] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were added and stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1c (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 57.5mg product 4ca with a yield of 59%.

[0064] The prepared product 4ca was characterized by H-NMR, C-NMR, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0065] 1 H NMR (400 MHz, CDCl 3 )δ7.45-7.28(m,5H),7.26-7.19(m,2H),7.19-7.12(m,3H),7.10(d,J=8.8Hz,2 H),6.80(d,J=8.8Hz,2H),3.79(s,3H),3.73(s,1H),0.34(s,3H),0.33(s,3H).

[0066] 13 C NMR (100 MHz, CDCl 3,All peak signals have been listed)δ157.30,142.70,137.68,134.38,129.94,129.03,128.72,128.11,127.50,125.02,113.61,55.14,44.50,-3.13,-3.21.[α] D 20 =23.3(c=0.5,CHCl 3 ).

[0067] HRMS(EI)m / z calculated for C 22 H 24 OSi[M] + :332.1596,found:332.1592.

[0068] HPLC separation conditions: Daicel Chiralpak IA column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 9.38 min (major), 9.84 min (minor). HPLC measured 93% ee.

[0069] Example 5

[0070] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1d, the bromoaromatic compound shown in Formula 2a and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4da. The reaction formula is as follows:

[0071]

[0072] The specific preparation process is as follows:

[0073] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were added and stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1d (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 70.2mg product 4da with a yield of 60%.

[0074] The prepared product 4da was characterized by H-NMR, C-C spectrum, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0075] 1 H NMR (400 MHz, CDCl 3 )δ7.39-7.29(m,5H),7.23(d,J=6.7Hz,2H),7.07(d,J=8.4Hz,4H),6.77(d,J= 8.7Hz,2H),3.77(s,3H),3.68(s,1H),1.30(s,9H),0.32(s,3H),0.30(s,3H).

[0076] 13 C NMR (100 MHz, CDCl 3 )δ157.21,147.71,139.48,137.91,134.67,134.41,129.88,128.94,128. 34,127.45,124.99,113.55,55.15,43.85,34.21,31.38,-3.11(twopeaks overlap).[α] D 20 =-3.7(c=0.5,CHCl 3 ).

[0077] HRMS(EI)m / z calculated for C 26 H 32 OSi[M] + :388.2222,found:388.2215.

[0078] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 7.83 min (minor), 8.23 ​​min (major). HPLC measured 95% ee.

[0079] Example 6

[0080] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1e, the bromoaromatic compound shown in Formula 2a and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4ea. The reaction formula is as follows:

[0081]

[0082] The specific preparation process is as follows:

[0083] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1e (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 90.2mg product 4ea with a yield of 74%.

[0084] The prepared product 4ea was characterized by H-NMR, C-C spectrum, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0085] 1 H NMR (400 MHz, CDCl 3 )δ7.61(dd,J=8.4,1.3Hz,2H),7.48(d,J=8.4Hz,2H),7.44(t,J=7.6Hz,2H),7.40-7.30(m,6H),7.21(d,J=8 .2Hz,2H),7.14(d,J=8.8Hz,2H),6.83(d,J=8.9Hz,2H),3.80(s,3H),3.78(s,1H),0.37(s,3H),0.36(s,3H).

[0086] 13 C NMR (100 MHz, CDCl 3 )δ157.36,141.93,140.95,137.76,137.61,134.42,134.28,129.99,129.08,129.0 5,128.65,127.54,126.88,126.80,126.76,113.69,55.16,44.20,-3.07,-3.22.[α] D 20 =-9.8(c=0.5,CHCl 3 ).

[0087] HRMS(EI)m / z calculated for C 28 H 28 OSi[M] + :408.1909,found:408.1908.

[0088] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 16.09 min (major), 18.56 min (minor). HPLC measured 95% ee.

[0089] Example 7

[0090] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1f, the bromoaromatic compound shown in Formula 2b and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula ent-4ea. The reaction formula is as follows:

[0091]

[0092] The specific preparation process is as follows:

[0093] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1f (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 12h. The reaction solution was concentrated and separated by column chromatography to obtain 61.3mg of product ent-4ea with a yield of 50%.

[0094] The prepared product ent-4ea was characterized by nuclear magnetic resonance hydrogen spectrum, carbon spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0095] 1 H NMR (400 MHz, CDCl 3 )δ7.60(d,J=7.2Hz,2H),7.52-7.28(m,10H),7.20(d,J=8.3Hz,2H),7.13(d,J=8.8 Hz,2H),6.82(d,J=8.8Hz,2H),3.80(s,3H),3.77(s,1H),0.37(s,3H),0.36(s,3H).

[0096] 13 C NMR (100 MHz, CDCl 3)δ157.37,141.94,140.95,137.76,137.61,134.42,134.28,129.99,129.09,129.0 5,128.66,127.54,126.88,126.81,126.77,113.69,55.17,44.21,-3.06,-3.21.[α] D 20 =7.2(c=0.5,CHCl 3 ).

[0097] HRMS(EI)m / z calculated for C 28 H 28 OSi[M] + :408.1909,found:408.1905.

[0098] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 16.00 min (minor), 18.49 min (major). HPLC measured 96% ee.

[0099] Example 8

[0100] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1g, the bromoaromatic compound shown in Formula 2a and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4ga. The reaction formula is as follows:

[0101]

[0102] The specific preparation process is as follows:

[0103] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1g (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 71.8mg product 4ga with a yield of 65%.

[0104] The prepared product 4ga was characterized by nuclear magnetic resonance hydrogen spectrum, carbon spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0105] 1 H NMR (400 MHz, CDCl 3 )δ7.42-7.34(m,1H),7.33-7.29(m,4H),7.17(d,J=8.4Hz,2H),7.05(d,J=8.7Hz,2H),7.01( d,J=8.5Hz,2H),6.79(d,J=8.7Hz,2H),3.78(s,3H),3.67(s,1H),0.31(s,3H),0.31(s,3H).

[0106] 13 C NMR (100 MHz, CDCl 3 )δ157.46,141.34,137.22,134.35,133.84,130.71,129.94,129.88,129.21,128.17,127.61,113.75,55.17,43.92,-3.15,-3.42.[α] D 20 =17.7(c=0.5,CHCl 3 ).

[0107] HRMS(EI)m / z calculated for C 22 H 23 ClOSi[M] + :366.1207,found:366.1205.

[0108] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 10.39 min (major), 10.08 min (minor). HPLC measured 94% ee.

[0109] Example 9

[0110] In this embodiment, the N-sulfonylhydrazone compound shown in formula 1h, the bromoaromatic compound shown in formula 2a and the silicon boron reagent shown in formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in formula 4ha. The reaction formula is as follows:

[0111]

[0112] The specific preparation process is as follows:

[0113] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1h (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 63.9mg product 4ha with a yield of 60%.

[0114] The prepared product 4ha was characterized by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0115] 1 H NMR (400 MHz, CDCl 3 )δ7.41-7.34(m,1H),7.33-7.29(m,4H),7.08-6.99(m,4H),6.90(t,J=8 .7Hz,2H),6.79(d,J=8.8Hz,2H),3.78(s,3H),3.68(s,1H),0.31(s,6H).

[0116] 13 C NMR (100 MHz, CDCl 3 )δ160.78(d,J=243.1Hz),157.39,138.42(d,J=3.0Hz),137.39,134.36,134.23,129.93(d,J =7.7Hz),129.84,129.15,127.58,114.84(d,J=21.1Hz),113.72,55.16,43.61,-3.17,-3.37.

[0117] 19 F NMR (376 MHz, CDCl 3 )δ-118.73.[α] D 20 =17.5(c=0.4,CHCl 3 ).

[0118] HRMS(EI)m / z calculated for C 22 H 23 FOSi[M] +:350.1502,found:350.1497.

[0119] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 10.03 min (major), 10.91 min (minor). HPLC measured 91% ee.

[0120] Example 10

[0121] In this embodiment, the N-sulfonylhydrazone compound shown in formula 1i, the bromoaromatic compound shown in formula 2a and the silicon boron reagent shown in formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in formula 4ia. The reaction formula is as follows:

[0122]

[0123] The specific preparation process is as follows:

[0124] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1i (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 71.5mg product 4ia with a yield of 61%.

[0125] The prepared product 4ia was characterized by H-NMR, C-NMR, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0126] 1 H NMR (400 MHz, CDCl 3 )δ7.87(d,J=8.5Hz,2H),7.40-7.33(m,1H),7.32-7.26(m,4H),7.13(d,J=8.3Hz,2H),7.08( d,J=8.8Hz,2H),6.80(d,J=8.8Hz,2H),3.89(s,3H),3.77(s,4H),0.30(s,3H),0.30(s,3H).

[0127] 13C NMR (100 MHz, CDCl 3 )δ167.17,157.56,148.55,136.99,134.32,133.32,130.13,129.44,129.2 6,128.34,127.62,126.85,113.80,55.16,51.87,45.13,-3.11,-3.51.[α] D 20 =36.1(c=0.4,CHCl 3 ).

[0128] HRMS(EI)m / z calculated for C 24 H 26 O 3 Si[M] + :390.1651,found:390.1646.

[0129] HPLC separation conditions: Daicel Chiralpak ODH column; hexane / 2-propanol=98.5 / 1.5, 0.5 mL / min. Retention times: 15.52 min (minor), 16.45 min (major). HPLC measured 94% ee.

[0130] Embodiment 11

[0131] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1j, the bromoaromatic compound shown in Formula 2a and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4ja. The reaction formula is as follows:

[0132]

[0133] The specific preparation process is as follows:

[0134] Under nitrogen protection, add [Pd(dmba)Cl] 2(0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60°C for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1j (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50°C for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 61.1mg product 4ja with a yield of 57%.

[0135] The prepared product 4ja was characterized by H-NMR, C-NMR, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0136] 1 H NMR (400 MHz, CDCl 3 )δ7.45(d,J=8.4Hz,2H),7.38(t,J=7.2Hz,1H),7.30(t,J=7.4Hz,2H),7.25(d,J=7.4Hz,2H),7.11(d ,J=8.4Hz,2H),7.06(d,J=8.8Hz,2H),6.80(d,J=8.8Hz,2H),3.78(s,3H),3.75(s,1H),0.30(s,6H).

[0137] 13 C NMR (100 MHz, CDCl 3 )δ157.80,148.85,136.53,134.28,132.67,131.86,130.24,129.49,12 8.87,127.75,119.23,113.98,108.56,55.20,45.46,-3.05,-3.73.[α] D 20 =43.9(c=0.35,CHCl 3 ).

[0138] HRMS(EI)m / z calculated for C 23 H 23 NOSi[M] + :357.1549,found:357.1542.

[0139] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=98 / 2, 0.5 mL / min. Retention times: 19.81 min (major), 23.11 min (minor). HPLC measured 87% ee.

[0140] Example 12

[0141] In this embodiment, the N-sulfonylhydrazone compound shown in formula 1k, the bromoaromatic compound shown in formula 2a and the silicon boron reagent shown in formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in formula 4ka. The reaction formula is as follows:

[0142]

[0143] The specific preparation process is as follows:

[0144] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1k (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 72.4mg product 4ka with a yield of 70%.

[0145] The prepared product 4ka was characterized by nuclear magnetic hydrogen spectrum, carbon spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0146] 1 H NMR (400 MHz, CDCl 3 )δ7.42-7.27(m,5H),7.11(t,J=7.5Hz,1H),7.07(d,J=8.5Hz,2H),6.94(d,J=7.8Hz,2H),6.90( s,1H),6.78(d,J=8.6Hz,2H),3.78(s,3H),3.67(s,1H),2.27(s,3H),0.32(s,3H),0.31(s,3H).

[0147] 13 C NMR (100 MHz, CDCl 3)δ157.25,142.53,137.79,137.53,134.48,134.42,129.91,129.69,129.0 0,127.95,127.44,125.79,125.73,113.59,55.15,44.41,21.46,-3.18(two peaks overlap).[α] D 20 =20.3(c=0.4,CHCl 3 ).

[0148] HRMS(EI)m / z calculated for C 23 H 26 OSi[M] + :346.1753,found:346.1750.

[0149] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 9.80 min (major), 10.76 min (minor). HPLC measured 94% ee.

[0150] Embodiment 13

[0151] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 11, the bromoaromatic compound shown in Formula 2a and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 41a. The reaction formula is as follows:

[0152]

[0153] The specific preparation process is as follows:

[0154] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL of anhydrous cyclohexane were added and stirred at 60°C for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1l (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50°C for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 64.1mg of product 4la with a yield of 59%.

[0155] The prepared product 4la was characterized by H-NMR, C-C spectrum, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0156] 1 H NMR (400 MHz, CDCl 3 )δ7.44-7.35(m,1H),7.35-7.29(m,4H),7.16-7.03(m,5H),6.97(d,J=6 .9Hz,1H),6.80(d,J=8.8Hz,2H),3.78(s,3H),3.67(s,1H),0.32(s,6H).

[0157] 13 C NMR (100 MHz, CDCl 3 )δ157.52,144.91,137.07,134.35,133.87,133.51,130.00,129.26,129.2 4,128.60,127.61,126.71,125.16,113.79,55.17,44.42,-3.18,-3.45.[α] D 20 =30.4(c=0.5,CHCl 3 ).

[0158] HRMS(EI)m / z calculated for C 22 H 23 ClOSi[M] + :366.1207,found:366.1201.

[0159] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 10.57 min (major), 11.57 min (minor). HPLC measured 96% ee.

[0160] Embodiment 14

[0161] In this embodiment, the N-sulfonylhydrazone compound shown in formula 1m, the bromoaromatic compound shown in formula 2a and the silicon boron reagent shown in formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in formula 4ma. The reaction formula is as follows:

[0162]

[0163] The specific preparation process is as follows:

[0164] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1m (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 47.1mg product 4ma with a yield of 45%.

[0165] The prepared product 4ma was characterized by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0166] 1 H NMR (400 MHz, CDCl 3 )δ7.41-7.33(m,1H),7.33-7.29(m,4H),7.14(q,J=7.4Hz,1H),7.06(d,J=8.8Hz,2H),6.8 6(d,J=7.8Hz,1H),6.83-6.77(m,4H),3.78(s,3H),3.69(s,1H),0.31(s,3H),0.30(s,3H).

[0167] 13 C NMR (100 MHz, CDCl 3 )δ162.75(d,J=244.9Hz),157.51,145.48(d,J=7.3Hz),137.18,134.34,133.64,130.01,129.34(d,J=8.3Hz),129.23,12 7.61, 124.26 (d, J = 2.7Hz), 115.30 (d, J = 21.6Hz), 113.77, 111.81 (d, J = 21.1Hz), 55.18, 44.51 (d, J = 1.7Hz), -3.12, -3.42.

[0168] 19 F NMR (376 MHz, CDCl 3 )δ-113.67.[α] D 20 =34.9(c=0.5,CHCl 3 ).

[0169] HRMS(EI)m / z calculated for C 22 H 23 FOSi[M] + :350.1502,found:350.1498.

[0170] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 10.63 min (major), 12.04 min (minor). HPLC measured 96% ee.

[0171] Embodiment 15

[0172] In this embodiment, the N-sulfonylhydrazone compound shown in formula 1n, the bromoaromatic compound shown in formula 2a and the silicon boron reagent shown in formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in formula 4na. The reaction formula is as follows:

[0173]

[0174] The specific preparation process is as follows:

[0175] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1n (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 74.4mg product 4na with a yield of 68%.

[0176] The prepared product 4na was characterized by nuclear magnetic hydrogen spectrum, carbon spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0177] 1 H NMR (400 MHz, CDCl 3)δ7.41-7.28(m,5H),7.13(t,J=7.9Hz,1H),7.09(d,J=8.8Hz,2H),6.79(d,J=8.7Hz,2H),6.7 3(d,J=7.7Hz,1H),6.68(d,J=8.1Hz,1H),6.65(s,1H),3.78(s,3H),3.69(s,4H),0.32(s,6H).

[0178] 13 C NMR (100 MHz, CDCl 3 )δ159.33,157.32,144.30,137.73,134.40,134.18,129.95,129.05,128.97,1 27.52,121.21,114.40,113.63,110.54,55.15,54.94,44.60,-3.10,-3.26.[α] D 20 =23.2(c=0.5,CHCl 3 ).

[0179] HRMS(EI)m / z calculated for C 23 H 26 O 2 Si[M] + :362.1702,found:362,1700.

[0180] HPLC separation conditions: Daicel Chiralpak IC column; hexane / 2-propanol=98.5 / 1.5, 0.5 mL / min. Retention times: 10.34 min (major), 11.30 min (minor). HPLC measured 94% ee.

[0181] Example 16

[0182] In this embodiment, the N-sulfonylhydrazone compound shown in formula 1o, the bromoaromatic compound shown in formula 2a and the silicon boron reagent shown in formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in formula 4oa. The reaction formula is as follows:

[0183]

[0184] The specific preparation process is as follows:

[0185] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were added and stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1o (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 75.5mg product 4oa with a yield of 66%.

[0186] The prepared product 4oa was characterized by nuclear magnetic hydrogen spectrum, carbon spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0187] 1 H NMR (400 MHz, CDCl 3 )δ7.79(d,J=9.4Hz,1H),7.71(d,J=8.6Hz,2H),7.57(s,1H),7.49-7.26(m,8H),7.16(d, J=8.7Hz,2H),6.82(d,J=8.7Hz,2H),3.91(s,1H),3.79(s,3H),0.37(s,3H),0.36(s,3H).

[0188] 13 C NMR (100 MHz, CDCl 3, All peak signals have been listed)δ157.37,140.41,137.68,134.44,134.29,133.56,131.51,130.08,129.11,128.10 ,127.56,127.47,127.44,126.52,125.72,124.89,113.68,55.16,44.58,-3.05,-3.11.[α] D 20 =0.7(c=0.5,CHCl 3 ).

[0189] HRMS(EI)m / z calculated for C 26 H 26 OSi[M] + :382.1753,found:382.1750.

[0190] HPLC separation conditions: Daicel Chiralpak IA column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 14.80 min (minor), 15.69 min (major). HPLC measured 95% ee.

[0191] Embodiment 17

[0192] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1p, the bromoaromatic compound shown in Formula 2a and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4pa. The reaction formula is as follows:

[0193]

[0194] The specific preparation process is as follows:

[0195] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were added and stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1p (0.3mmol), substrate 2a (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 31.2mg product 4pa with a yield of 31%.

[0196] The prepared product 4pa was characterized by H NMR spectrum, C NMR spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0197] 1 H NMR (400 MHz, CDCl 3 )δ7.40-7.33(m,1H),7.33-7.28(m,4H),7.18(dd,J=4.9,3.0Hz,1H),7.01(d,J=8 .7Hz,2H),6.83-6.75(m,4H),3.80(s,1H),3.78(s,3H),0.29(s,3H),0.27(s,3H).

[0198] 13 C NMR (100 MHz, CDCl 3)δ157.25,142.49,137.53,134.33,134.15,129.46,129.11,128.97,127.55,124.64,119.69,113.63,55.21,39.44,-3.21,-3.70.[α] D 20 =-3.9(c=0.3,CHCl 3 ).

[0199] HRMS(EI)m / z calculated for C 20 H 22 OSSi[M] + :338.1161,found:338.1160.

[0200] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 10.78 min (major), 11.61 min (minor). HPLC measured 89% ee.

[0201] Embodiment 18

[0202] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1a, the bromoaromatic compound shown in Formula 2b and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4ab. The reaction formula is as follows:

[0203]

[0204] The specific preparation process is as follows:

[0205] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL of anhydrous cyclohexane were added and stirred at 60°C for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1a (0.3mmol), substrate 2b (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50°C for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 76.8mg of product 4ab with a yield of 67%.

[0206] The prepared product 4ab was characterized by H-NMR, C-C spectrum, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0207] 1 H NMR (400 MHz, CDCl 3 )δ7.59(d,J=7.1Hz,2H),7.51-7.40(m,4H),7.40-7.29(m,6H),7.20(d, J=8.3Hz,2H),7.13-7.03(m,4H),3.78(s,1H),2.32(s,3H),0.35(s,6H).

[0208] 13 C NMR (100 MHz, CDCl 3 )δ141.79,140.98,139.08,137.77,137.65,134.66,134.43,129.13,129.07,128.9 7,128.94,128.66,127.53,126.87,126.81,126.76,44.83,20.92,-3.04,-3.22.[α] D 20 =5.9(c=0.5,CHCl 3 ).

[0209] HRMS(EI)m / z calculated for C 28 H 28 Si[M] + :392.1960, found:392.1954. Separation conditions: Daicel Chiralpak OZH column; hexane / 2-propanol=99.8 / 0.2, 0.5mL / min. Retention times: 10.48min(minor), 10.96min(major). HPLC measured 95%ee.

[0210] Embodiment 19

[0211] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1e, the bromoaromatic compound shown in Formula 2c and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula ent-4ab. The reaction formula is as follows:

[0212]

[0213] The specific preparation process is as follows:

[0214] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1e (0.3mmol), substrate 2c (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 77.6mg of product ent-4ab with a yield of 66%.

[0215] The prepared product ent-4ab was characterized by nuclear magnetic resonance hydrogen spectrum, carbon spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0216] 1 H NMR (400 MHz, CDCl 3 )δ7.60(d,J=7.1Hz,2H),7.50-7.41(m,4H),7.41-7.30(m,6H),7.21(d, J=8.2Hz,2H),7.14-7.04(m,4H),3.79(s,1H),2.33(s,3H),0.36(s,6H).

[0217] 13 C NMR (100 MHz, CDCl 3 )δ141.80,140.99,139.08,137.77,137.65,134.67,134.44,129.14,129.08,128.9 7,128.95,128.66,127.53,126.87,126.82,126.76,44.84,20.92,-3.04,-3.22.[α] D 20 =-9.8(c=0.8,CHCl 3 ).

[0218] HRMS(EI)m / z calculated for C 28 H 28 Si[M] + :392.1960,found:392.1956.

[0219] HPLC separation conditions: Daicel Chiralpak OZH column; hexane / 2-propanol=99.8 / 0.2, 0.5 mL / min. Retention times: 10.85 min (major), 11.37 min (minor). HPLC measured 89% ee.

[0220] Embodiment 20

[0221] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1a, the bromoaromatic compound shown in Formula 2d and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4ad. The reaction formula is as follows:

[0222]

[0223] The specific preparation process is as follows:

[0224] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were added and stirred at 60°C for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1a (0.3mmol), substrate 2d (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50°C for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 75.2mg of product 4ad with a yield of 70%.

[0225] The prepared product 4ad was characterized by H-NMR, C-NMR, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0226] 1 H NMR (400 MHz, CDCl 3 )δ7.38-7.28(m,5H),7.06-7.00(m,6H),6.65(d,J=8.8Hz,2H),3.64(s,1H),2.90(s,6H),2.29(s,3H),0.31(s,3H),0.30(s,3H).

[0227] 13 C NMR (100 MHz, CDCl 3)δ148.40,140.07,138.27,134.43,134.11,130.83,129.68,128.84,1 28.73,128.66,127.43,112.89,43.57,40.82,20.89,-2.97,-3.10.[α] D 20 =16.9(c=0.5,CHCl 3 ).

[0228] HRMS(EI)m / z calculated for C 24 H 29 NSi[M] + :359.2069,found:359.2063.

[0229] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 9.60 min (major), 10.10 min (minor). HPLC measured 91% ee.

[0230] Embodiment 21

[0231] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1a, the bromoaromatic compound shown in Formula 2e and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4ae. The reaction formula is as follows:

[0232]

[0233] The specific preparation process is as follows:

[0234] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL of anhydrous cyclohexane were added and stirred at 60°C for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1a (0.3mmol), substrate 2e (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50°C for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 65.8mg of product 4ae with a yield of 54%.

[0235] The prepared product 4ae was characterized by H-NMR, C-NMR, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0236] 1 H NMR (400 MHz, CDCl 3 )δ7.40-7.27(m,7H),7.12-7.02(m,7H),6.97(d,J=7.6Hz,2H),6.87(d,J=8.7Hz,2H),3.71(s,1H),2.31(s,3H),0.33(s,3H),0.32(s,3H).

[0237] 13 C NMR (100 MHz, CDCl 3 )δ157.73,154.40,139.21,137.72,137.58,134.65,134.39,129.95,129.58,129.0 7,128.96,128.79,127.51,122.74,118.95,118.32,44.38,20.91,-3.09,-3.32.[α] D 20 =-5.7(c=0.5,CHCl 3 ).

[0238] HRMS(EI)m / z calculated for C 28 H 28 OSi[M] + :408.1909,found:408.1905.

[0239] HPLC separation conditions: Daicel Chiralpak OZH column; hexane / 2-propanol=99.8 / 0.2, 0.5 mL / min. Retention times: 12.54 min (major), 13.51 min (minor). HPLC measured 93% ee.

[0240] Embodiment 22

[0241] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1a, the bromoaromatic compound shown in Formula 2f and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4af. The reaction formula is as follows:

[0242]

[0243] The specific preparation process is as follows:

[0244] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were added and stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1a (0.3mmol), substrate 2f (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 50.6mg product 4af with a yield of 45%.

[0245] The prepared product 4af was characterized by H-NMR, C-NMR, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0246] 1 H NMR (400 MHz, CDCl 3 )δ7.86(d,J=8.6Hz,2H),7.40-7.33(m,1H),7.32-7.27(m,4H),7.14(d,J=8 .4Hz,2H),7.05(s,4H),3.88(s,3H),3.78(s,1H),2.30(s,3H),0.30(s,6H).

[0247] 13 C NMR (100 MHz, CDCl 3 )δ167.19,148.39,138.15,137.02,135.04,134.34,129.44,129.26,129.1 0,129.04,128.43,127.61,126.87,51.88,45.77,20.90,-3.10,-3.51.[α] D 20 =-23.7(c=0.5,CHCl 3 ).

[0248] HRMS(EI)m / z calculated for C 24 H 26 O 2 Si[M] + :374.1702,found:374.1696.

[0249] HPLC separation conditions: Daicel Chiralpak IG column; hexane / 2-propanol=98 / 2, 0.5 mL / min. Retention times: 15.50 min (minor), 17.08 min (major). HPLC measured 89% ee.

[0250] Embodiment 23

[0251] In this embodiment, the N-sulfonylhydrazone compound shown in Formula 1a, the bromoaromatic compound shown in Formula 2g and the silicon boron reagent shown in Formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in Formula 4ag. The reaction formula is as follows:

[0252]

[0253] The specific preparation process is as follows:

[0254] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1a (0.3mmol), substrate 2g (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 69.0mg product 4ag with a yield of 64%.

[0255] The prepared product 4ag was characterized by H-NMR, C-NMR, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0256] 1 H NMR (400 MHz, CDCl 3 )δ7.42-7.27(m,5H),7.08-6.98(m,4H),6.67(d,J=7.9Hz,1H),6.64(d,J=1.9Hz,1H),6.59(dd ,J=8.0,1.9Hz,1H),5.89(d,J=3.1Hz,2H),3.65(s,1H),2.31(s,3H),0.33(s,3H),0.32(s,3H).

[0257] 13 C NMR (100 MHz, CDCl 3)δ147.36,145.05,139.34,137.68,136.53,134.59,134.36,129.05,128.92,12 8.71,127.53,121.73,109.50,107.93,100.65,44.62,20.89,-3.10,-3.14.[α] D 20 =1.3(c=0.5,CHCl 3 ).

[0258] HRMS(EI)m / z calculated for C 23 H 24 O 2 Si[M] + :360.1546,found:360.1540.

[0259] HPLC separation conditions: Daicel Chiralpak ODH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 11.01 min (minor), 12.46 min (major). HPLC measured 90% ee.

[0260] Embodiment 24

[0261] In this embodiment, the N-sulfonylhydrazone compound shown in formula 1n, the bromoaromatic compound shown in formula 2h and the silicon boron reagent shown in formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in formula 4nh. The reaction formula is as follows:

[0262]

[0263] The specific preparation process is as follows:

[0264] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1n (0.3mmol), substrate 2h (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 83.3mg product 4nh with a yield of 59%.

[0265] The prepared product 4nh was characterized by H NMR spectrum, C NMR spectrum, high-resolution mass spectrum and HPLC. The characterization results are as follows:

[0266] 1 H NMR (400 MHz, CDCl 3 )δ7.57(d,J=2.2Hz,1H),7.41-7.27(m,7H),7.19-7.07(m,2H),6.78(d,J=7.8H z,1H),6.73-6.65(m,3H),3.85(s,1H),3.70(s,3H),0.35(s,3H),0.34(s,3H).

[0267] 13 C NMR (100 MHz, CDCl 3 )δ159.38,153.24,144.93,144.37,137.71,136.62,134.42,129.09,129.02,127.53,127.4 4,125.79,121.36,121.02,114.63,110.83,110.55,106.53,54.97,45.37,-3.00,-3.19.[α] D 20 =30.4(c=0.5,CHCl 3 ).

[0268] HRMS(EI)m / z calculated for C 24 H 24 O 2 Si[M] + :372.1546,found:372.1543.

[0269] HPLC separation conditions: Daicel Chiralpak IG column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 11.02 min (major), 13.34 min (minor). HPLC measured 89% ee.

[0270] Embodiment 25

[0271] In this embodiment, the N-sulfonylhydrazone compound shown in formula 1n, the bromoaromatic compound shown in formula 2i and the silicon boron reagent shown in formula 3 are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand L11, copper salt and solvent to obtain the chiral geminal diarylmethylsilane compound shown in formula 4ni. The reaction formula is as follows:

[0272]

[0273] The specific preparation process is as follows:

[0274] Under nitrogen protection, add [Pd(dmba)Cl] 2 (0.0075mmol), organic phosphine ligand L11 (0.033mmol) and 3mL anhydrous cyclohexane were added and stirred at 60℃ for 0.5h. CuBr (0.03mmol), lithium tert-butoxide (1.35mmol), 4-methoxypyridine (0.3mmol), substrate 1n (0.3mmol), substrate 2i (0.45mmol) and substrate 3 (0.9mmol) were added in sequence and stirred at 50℃ for 8h. The reaction solution was concentrated and separated by column chromatography to obtain 62.2mg product 4ni with a yield of 56%.

[0275] The prepared product 4ni was characterized by H NMR, C NMR, high-resolution mass spectrometry and HPLC. The characterization results are as follows:

[0276] 1 H NMR (400 MHz, CDCl 3 )δ8.00(d,J=8.6Hz,1H),7.56(d,J=3.7Hz,1H),7.45-7.27(m,6H),7.19-7.09(m,2H),6.78(d,J=7.7Hz,1H) ,6.73-6.65(m,2H),6.47(d,J=3.7Hz,1H),3.85(s,1H),3.69(s,3H),1.68(s,9H),0.35(s,3H),0.34(s,3H).

[0277] 13 C NMR (100 MHz, CDCl 3 )δ159.33,149.78,144.38,137.82,136.50,134.42,133.24,130.73,129.05,128.96,127.52,125. 84,121.35,120.99,114.73,114.55,110.53,107.27,83.41,54.95,45.35,28.17,-2.93,-3.21.[α] D 20 =33.4(c=0.5,CHCl 3 ).

[0278] HRMS(ESI)m / z calculated for C 29 H33 NNaO 3 Si[(M+Na + )]:494.2122,found:494.2134.

[0279] HPLC separation conditions: Daicel Chiralpak ADH column; hexane / 2-propanol=99 / 1, 0.5 mL / min. Retention times: 17.30 min (major), 19.92 min (minor). HPLC measured 91% ee.

[0280] Comparative Example 1

[0281] In this comparative example, the N-sulfonylhydrazone compound represented by formula 1a in Example 1, the bromoaromatic compound represented by formula 2a and the silicon boron reagent represented by formula 3 were used for coupling reaction in the presence of palladium salt, chiral phosphine ligand, copper salt and solvent to pre-prepare the chiral geminal diarylmethylsilane compound represented by formula 4aa. The preparation method is the same as that in Example 1, except that the chiral phosphine ligand is different. In this comparative example, the chiral phosphine ligand M1 is used. The reaction product is identified by nuclear magnetic resonance, and the target product 4aa is not obtained.

[0282] The structure of the chiral phosphine ligand M1 is as follows:

[0283]

[0284] Comparative Example 2

[0285] In this comparative example, the N-sulfonylhydrazone compound represented by formula 1a in Example 1, the bromoaromatic compound represented by formula 2a and the silicon boron reagent represented by formula 3 were used for coupling reaction in the presence of palladium salt, chiral phosphine ligand, copper salt and solvent to pre-prepare the chiral geminal diarylmethylsilane compound represented by formula 4aa. The preparation method is the same as that in Example 1, except that the chiral phosphine ligand is different. In this comparative example, the chiral phosphine ligand M2 is used. The reaction product is identified by nuclear magnetic resonance, and the target product 4aa is not obtained.

[0286] The structure of the chiral phosphine ligand M2 is as follows:

[0287]

[0288] It can be seen from the above embodiments that the present invention uses N-arylsulfonylhydrazone compounds, aryl bromides and (dimethylphenylsilyl)boronic acid pinacol ester as raw materials, and performs three-component coupling under the co-catalysis of palladium and copper in an enantioselective manner to produce different chiral geminal diaryl methylene silane compounds, which has high stereoselectivity, and the ee values ​​of the above products are all above 86%, and even as high as 96%; in addition, it can be seen from the comparative examples that the above preparation method needs to be carried out under the action of a specific chiral palladium complex formed by a specific chiral phosphine ligand and a palladium salt, such as the chiral phosphine ligands L1 to L12, while the chiral phosphine ligands M1 and M2 cannot obtain the target product.

[0289] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A method for preparing a chiral geminal diarylmethylene silane compound, characterized in that: The N-sulfonylhydrazone compound shown in Formula 1, the bromoaromatic compound shown in Formula 2 and the boron silane reagent are subjected to coupling reaction in the presence of palladium salt, chiral phosphine ligand, copper salt and solvent to obtain the chiral geminal diaryl methylene silane compound shown in Formula 4; the boron silane reagent is PhMe2SiBpin; the palladium salt is [Pd(dmba)Cl]2; the copper salt is CuCl, CuBr or CuI; the chiral phosphine ligand is one of the compounds shown in the following structures: ， ； The structures of the above formula 1, formula 2, and formula 4 are respectively as follows: ； Wherein, R is p-tolyl or mesitylene, R 1 H, F, Cl, C1~ C 12 Alkyl, phenyl, naphthyl, C1~C 10 an alkoxy, cyano or thienyl group; R 2 H, F, C1~C 12 Alkyl, phenyl, amino or C1~C 10 of alkoxy.

2. The preparation method according to claim 1, characterized in that: The reaction temperature of the coupling reaction is 40-70° C., and the reaction time is 5-18 h.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the N-sulfonylhydrazone compound, palladium salt and copper salt shown in Formula 1 is 1:0.05-0.5:0.01-0.

3.

4. The preparation method according to claim 1, characterized in that: Under an inert atmosphere, a palladium salt and a chiral phosphine ligand are subjected to ligand exchange in the presence of a solvent, and then an N-sulfonylhydrazone compound shown in Formula 1, a bromoaromatic compound shown in Formula 2, a silicon boron reagent and a copper salt are added to carry out a coupling reaction to obtain the chiral geminal diarylmethylenesilane compound.

5. The preparation method according to claim 4, characterized in that: The reaction temperature of the ligand exchange is 40-60°C, and the reaction time is 30 min-1 h.

6. The preparation method according to claim 1, characterized in that: The coupling reaction is carried out in the presence of a base and an additive; the base is cesium carbonate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium acetate or sodium methoxide, and the additive is pyridine, 4-methylpyridine, 4-trifluoromethylpyridine, 4-methoxypyridine, 4- N , N - lutidine, quinoline, 2-methylpyridine, tetrahydroquinoline or 1,4-diazabicyclo[2.2.2]octane.

7. The preparation method according to claim 6, characterized in that: The molar ratio of the N-sulfonylhydrazone compound, the base and the additive shown in Formula 1 is 1:1.1~5:0.1~1.5.

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