Dialkyl substituted alpha chiral primary amine and catalytic asymmetric cross-coupling synthesis method thereof

Abstract

The invention relates to the technical field of asymmetric catalysis, and particularly discloses a method for catalyzing asymmetric cross-coupling synthesis of dialkyl-substituted alpha chiral primary amine.According to the method, tetrazole N, N, P-tridentate chiral anion ligands (Zhang's peak type chiral anion ligands) derived from independently researched and developed cinchona alkaloid are used for catalyzing asymmetric cross-coupling synthesis of dialkyl-substituted alpha chiral primary amines; the asymmetric catalytic cross-coupling reaction of the primary amine equivalent of the sulfoximide and the free radical of the dialkyl-substituted secondary iodo-alkane is successfully realized, and a plurality of chiral alpha amine compounds are constructed. The method not only can effectively realize efficient asymmetric conversion of the chain substrate, but also has good applicability to the annular substrate. The method not only solves the major problem that the chirality of non-activated dialkyl substituted free radicals is difficult to control in the field of asymmetric catalysis of free radicals, but also provides a brand-new method for synthesizing the dialkyl substituted alpha primary amine compound.

Description

Technical Field

[0001] The invention relates to the technical field of asymmetric catalysis, and specifically discloses a dialkyl-substituted α-chiral primary amine and a catalytic asymmetric cross-coupling synthesis method thereof. Background Art

[0002] α-chiral primary amines are widely found in natural products and represent an important class of synthons. For over a century, the construction of carbon-nitrogen bonds through cross-coupling reactions has been a key focus in organic chemistry. In recent years, the use of transition metals and chiral ligands for the coordinated catalysis of chiral compounds has garnered increasing attention. The rapid construction of α-chiral primary amines using this approach remains a significant area of ​​research in this field.

[0003] α-chiral primary amines play an important role in organic synthesis, biology, functional materials, natural products, and pharmaceutical research. However, current asymmetric catalytic methods are mostly limited to constructing primary amine compounds containing functional groups at the ortho position. In contrast, the more general dialkyl-substituted α-chiral primary amine construction methods remain rare. Therefore, the development of novel carbon-nitrogen bond asymmetric cross-coupling reaction systems to construct these important dialkyl α-chiral primary amines is both extremely important and challenging. Summary of the Invention

[0004] In order to solve the problems existing in the prior art, the first aspect of the present invention provides a dialkyl-substituted α-chiral primary amine compound, as shown in Formula C,

[0005]

[0006] Ar is selected from substituted or unsubstituted monocyclic aromatic groups;

[0007] The R 1 and R 2 Each is independently selected from substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched-chain alkyl, hydrogen, substituted or unsubstituted heterocyclic group, substituted or unsubstituted cycloalkyl;

[0008] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0009] In some specific embodiments of the first aspect, the compound of formula C is represented by formula C-1, C-2 or C-3:

[0010]

[0011] The R2 is selected from adamantyl, C4 to C8 cycloalkyl, piperidinyl, tetrahydropyranyl, -(CH2) n CH2R a 、-(CH2) p (CO)Rb or

[0012] The R a Selected from C1 to C6 straight chain alkyl or branched chain alkyl, monocyclic aromatic group, condensed aromatic group, halogen, cyano group, alkoxy group, ester group, amino group, -CF3, C4 to C8 cycloalkyl group, adamantyl group, piperidinyl group, tetrahydropyranyl group, azido group;

[0013] The R b Select from -OR ba , the R ba Selected from methyl, ethyl, monocyclic aromatic group;

[0014] The Ar1 is selected from C4 to C8 cycloalkyl, piperidinyl, tetrahydropyranyl, adamantyl, or

[0015] Ar is selected from a monocyclic aromatic group, and any H on the monocyclic aromatic group is substituted by a methyl group, a halogen group, or a cyano group;

[0016] Said n and p are each independently selected from any positive integer from 1 to 10;

[0017] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0018] In some specific embodiments of the first aspect, said R2 is selected from -(CH2) p (CO)R b , the R b Select from -OR ba , the R ba is selected from monocyclic aryl groups, wherein H on the monocyclic aryl group is optionally substituted by halogen;

[0019] Said R2 is selected from -(CH2) n CH2R a , the R a Selected from amino, wherein any H on the amino is substituted by methyl, monocyclic aromatic group, or amino;

[0020] The R2 is selected from n-butyl, and any H on the n-butyl is substituted by halogen;

[0021] The Ar1 is selected from cyclohexane, and the H on the cyclohexane is replaced by R c Substituted, the R c Selected from C1 to C5 straight chain alkyl, ester group, halogen, monocyclic aromatic group,

[0022] Alternatively, Ar1 is selected from cyclohexane, and the alkylene group on the cyclohexane is optionally substituted by -CO-.

[0023] In some specific embodiments of the first aspect, Ar is selected from a monocyclic aromatic group, and the H at the para position of the monocyclic aromatic group is substituted by a methyl group, a halogen group, a cyano group, or a methoxy group.

[0024] The second aspect of the present invention provides a specific implementation of the dialkyl-substituted α-chiral primary amine compound described in the first aspect:

[0025]

[0026]

[0027] The third aspect of the present invention provides a method for synthesizing a dialkyl-substituted α-chiral primary amine compound represented by formula C, comprising:

[0028] The compound of formula A and the compound of formula B are mixed with an organic solvent, and under the catalytic action of a copper salt, a base and a ligand L, a compound of formula C is obtained;

[0029]

[0030] R1, R2 and Ar are as defined in any embodiment of the first aspect, wherein when one of R1 and R2 is methyl, the other is not cyclohexane;

[0031] The ligand L is any one of L5 to L14;

[0032] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0033] In some specific embodiments of the third aspect, the catalytic reaction is carried out under light of 350-400 nm.

[0034] In some specific embodiments of the third aspect, the copper salt is selected from any one of CuI, CuBr, CuCl, CuOAc, copper trifluoromethanesulfonate, copper acetate, cuprous thiophenecarboxylate, copper hexafluoroacetylacetonate, or other monovalent or divalent copper.

[0035] In some specific embodiments of the third aspect, the organic solvent is selected from one or more of diethyl ether, isopropyl ether, tert-butyl methyl ether, butyl ether, toluene, trifluorotoluene, chlorobenzene, xylene, n-pentane, n-hexane, n-heptane, and cyclohexane.

[0036] In some specific embodiments of the third aspect, the reaction temperature is -78 to 0°C.

[0037] In a fourth aspect, the present invention provides a method for deprotecting a dialkyl-substituted α-chiral primary amine compound represented by formula C to obtain a compound represented by formula D, comprising:

[0038] The compound of formula C is added to an organic solvent, the temperature is controlled, and magnesium is added to obtain a compound of formula D;

[0039]

[0040] Said R1, R2 and Ar are as defined in any embodiment of the first aspect;

[0041] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0042] In some specific embodiments of the fourth aspect, the organic solvent is selected from one or more of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dichloromethane, toluene, tert-butyl ether and methanol, and the temperature of the temperature control is -5 to 0°C.

[0043] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, the carbon ring may contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms. Wherein the partially unsaturated monocyclic or polycyclic hydrocarbon group is a saturated cycloalkyl group or may optionally contain one, two or more double bonds and / or triple bonds in its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl group.

[0044] The term "heterocyclyl" refers to a non-aromatic fully saturated or partially unsaturated cyclic group (e.g., a 3- to 7-membered monocyclic ring) having at least one heteroatom in a ring containing at least one carbon atom. Preferably, the heterocyclyl is a 5- or 6-membered heterocyclyl. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Non-limiting exemplary heterocyclic groups include thienyl, furanyl, pyrrolyl, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, azetidinyl, azocanyl, diazepanyl, diazaoctanyl, morpholin-4-yl, oxazepanyl, pyrrolidinyl, thiomorpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, thiiranyl, 2-imidazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 2H-pyrrolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2 -oxopiperazinyl, homopiperazinyl, 2-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolane, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, tetrahydrothienyl, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, tetrahydro-1,1-dioxathienyl, N-formylpiperazinyl.

[0045] The term "ester group" refers to a structure such as -(CO)OR x , the R x It is a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl group, a monocyclic aromatic group, or a condensed-ring aromatic group.

[0046] Unless otherwise noted, chemicals were purchased from commercial products and were not further purified. Most reactions were performed using Schlenk tubes under an argon atmosphere. CuI was purchased from Sigma-Aldrich, and CuTc was purchased from Alfa Aesar and Bide. Anhydrous diethyl ether (Et2O) was purchased from Shanghai Lingfeng Chemical Reagent Co., Ltd. and used directly without further treatment. Thin layer chromatography (TLC) was performed using 60GF254 silica gel plates. Silica gel column chromatography used Qingdao Marine Silica Gel (particle size 0.040-0.063 mm). TLC development was performed using UV light (254 nm), iodine, or acidic KMnO4 solution. 1 H NMR, 13 CNMR and19 F NMR was characterized using a Bruker 400 MHz or 500 MHz NMR instrument, with deuterated chloroform, deuterated methanol, or deuterated DMSO as the solvent, and tetramethylsilane (TMS) as the internal standard. The units of chemical shifts are ppm, and the units of coupling constants are Hz. 1 In H NMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, p represents quintet, m represents multiplet, and br represents broad peak. 13 In CNMR, δ represents chemical shift. Mass spectral data were obtained using a Bruker Apex IV RTMS. Enantiomeric excess was determined using an Agilent chiral HPLC instrument with a Hatachi detector.

[0047] Advantages of the present invention: The present invention successfully realizes the free radical asymmetric catalytic cross-coupling reaction of primary amine equivalents such as sulfenyl imine and dialkyl-substituted secondary iodinated alkanes by using the independently developed cinchona alkaloid-derived tetrazole N,N,P-tridentate chiral anionic ligand (Zhang Yufeng type chiral anionic ligand), thereby constructing a variety of chiral α-amine compounds. This method can not only effectively realize the efficient asymmetric transformation of chain substrates, but also has good applicability to cyclic substrates. This method not only solves the major problem that non-activated dialkyl-substituted free radicals are difficult to control the chirality in the field of free radical asymmetric catalysis, but also provides a new method for synthesizing dialkyl-substituted α-primary amine compounds.

[0048] In the present invention, the structures of L1 to L4 are as follows:

[0049]

[0050] In the present invention, the structures of L5 to L10 are as follows:

[0051]

[0052] In the present invention, the structures of L11 to L14 are as follows:

[0053] DETAILED DESCRIPTION

[0054] The following will be combined with the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the embodiments described are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field based on the present application are within the scope of protection of this application.

[0055] Example 1

[0056] Reaction condition screening: Under argon protection, cuprous thiophene-2-carboxylate (CuTc) (10 mol%), any of ligands L1 to L14 (12 mol%), cesium carbonate (4.0 equivalents) and diisopropyl ether ( i Pr2O, 1.0 mL) was pre-stirred at 50°C for 2 hours. A dialkyl iodide (E1, 0.05 mmol, 1.0 equiv) and a sulfenyl imide (N1, 0.05 mmol, 1.0 equiv) were then added sequentially to the mixture, and pre-stirring at 50°C continued for 1 hour. The system was cooled to room temperature, and Mes2IBF4 (bis(2,4,6-trimethylphenyl)iodonium tetrafluoroborate, CAS: 125125-30-6, 0.075 mmol, 1.5 equiv) and 20 microliters of dichloromethane were added to the system and allowed to react for three days. After completion of the reaction (monitored by TLC), the precipitate was filtered and washed with the solvent. The solution was then evaporated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain product 1. The yield and ee values ​​are shown in Tables 1 and 2.

[0057]

[0058] Product 1 characterization data: colorless oil. HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=6.43min,t R (major) = 7.60 min; 1 H NMR (400MHz, CDCl3) δ7.87(d,J=8.4Hz,2H),7.81(d,J=8.3Hz,2H),7.24(d,J=8.1Hz,4H),3.3 4–3.01(m,1H),2.36(s,6H),1.66–1.29(m,4H),1.22(d,J=6.3Hz,3H),0.88(t,J=7.1Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 142.8, 142.7, 139.0, 138.4, 129.7, 129.6, 128.7, 128.5, 50.5, 43.0, 24.8, 21.5, 19.9, 14.3. HRMS (ESI) m / z accurate mass calculation C 19 H 26 NOS[M+H] + 316.1730, measured value 316.1720.

[0059] Catalysis using L1 to L7 ligands: Table 1

[0060] Ligand type L1 L2 L3 L4 L5 L6 L7 Yield (yield%) <5 <5 21 66 85 69 77 Enantiomeric excess (ee%) 24 28 14 27 47 52 56

[0061] Catalysis using L8-L14 ligands: Table 2

[0062] Ligand type L8 L9 L10 L11 L12 L13 L14 Yield (yield%) 78 74 79 85 85 78 81 Enantiomeric excess (ee%) 60 60 60 50 58 57 56

[0063] Example 2 (cooling the system to -20°C)

[0064] Reaction conditions (Thermal condition A): Under argon protection, cuprous thiophene-2-carboxylate (CuTc, 10 mol%), ligand L9 (12 mol%), cesium carbonate (4.0 equivalents) and diisopropyl ether ( i Pr2O, 1.0 mL) was added and pre-stirred at 50°C for 2 hours. Then, dialkyl iodide (E1, 0.05 mmol, 1.0 equivalent) and sulfenyl imine (N1, 0.05 mmol, 1.0 equivalent) were added to the mixture in sequence, and pre-stirred at 50°C for 1 hour. The system was cooled to -20°C, and Mes2IBF4 (0.075 mmol, 1.5 equivalents) and 20 microliters of dichloromethane were added to the system and reacted for three days. After the reaction was completed (monitored by TLC), the precipitate was filtered off and washed with solvent, and the solution was then evaporated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain product 1 with a yield of 85% and an ee value of 72%.

[0065] The reason for the increase in the enantioselectivity of the reaction is that the ee value of the reaction is increased by cooling the system to -20°C.

[0066] Example 3 (cooling the system to -78°C)

[0067] Reaction conditions (photocatalytic condition B): Under argon, cuprous thiophene-2-carboxylate (CuTc) (10 mol%), ligand L9 (12 mol%), cesium carbonate (4.0 equiv), toluene (tol) (0.5 mL), and 1,3-difluorobenzene (1,3-F2C6H4) (0.5 mL) were added to a Schlenk tube equipped with a magnet and pre-stirred at 50°C for 2 hours. Then, a dialkyl iodide (E1, 0.05 mmol, 1.0 equiv) and a sulfenyl imide (N1, 0.05 mmol, 1.0 equiv) were added sequentially to the mixture, and pre-stirring at 50°C was continued for 1 hour. The system was cooled to -78°C and reacted under 390 nm LED light for three days. After completion of the reaction (monitored by TLC), the precipitate was filtered off and washed with solvent, then the solution was evaporated and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 10) to give product 1 with a yield of 52% and an ee value of 90%.

[0068] The reason for the increase in reaction enantioselectivity is that by cooling the system to -78°C, the ee value of the reaction can be effectively improved.

[0069] Example 4

[0070] General method A: Under argon protection, cuprous thiophene-2-carboxylate (CuTc, 10 mol%), ligand L9 (12 mol%), cesium carbonate (4.0 equivalents) and diisopropyl ether ( i Pr2O, 4.0mL) was added to the mixture and pre-stirred at 50°C for 2 hours. Then, dialkyl iodide (0.10mmol, 1.0 equivalent) and sulfenyl imine (0.10mmol, 1.0 equivalent) were added to the mixture in sequence and pre-stirred at 50°C for 1 hour. The system was cooled to -20°C, and Mes2IBF4 (0.15mmol, 1.5 equivalents) and 80 microliters of dichloromethane were added to the system and reacted for three days. After the reaction was completed (monitored by TLC), the precipitate was filtered off and washed with solvent, and the solution was then evaporated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain the product.

[0071]

[0072] General Method B: Under argon, cuprous thiophene-2-carboxylate (CuTc, 10 mol%), ligand L12 (12 mol%), cesium carbonate (4.0 equiv), toluene (2.0 mL), and 1,3-difluorobenzene (1,3-F2C6H4, 2.0 mL) were added to a Schlenk tube equipped with a magnetic rod and pre-stirred at 50°C for 2 hours. Then, a dialkyl iodide (0.10 mmol, 1.0 equiv) and a sulfenyl imine (0.10 mmol, 1.0 equiv) were added sequentially to the mixture, and pre-stirring at 50°C was continued for 1 hour. The system was cooled to -78°C and reacted under 390 nm LED light for three days. After completion of the reaction (monitored by TLC), the precipitate was filtered and washed with the solvent. The solution was then evaporated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain the product.

[0073]

[0074]

[0075] General Method C: Under argon protection, copper(II) thiophene-2-carboxylate (CuTc) (10 mol%), ligand L9 (12 mol%), cesium carbonate (4.0 equivalents) and diisopropyl ether ( iPr2O) (4.0mL), pre-stirred at 50°C for 2 hours. Then, dialkyl iodide (0.10mmol, 1.0 equivalent) and sulfenyl imine (0.10mmol, 1.0 equivalent) were added to the mixture in sequence, and pre-stirred at 50°C for 1 hour. The system was cooled to -40°C, Mes2IBF4 (0.15mmol, 1.5 equivalents) and 80 microliters of dichloromethane were added to the system, and the reaction was continued for three days. After the reaction was completed (monitored by TLC), the precipitate was filtered off and washed with solvent, and the solution was then evaporated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain the product.

[0076]

[0077] General Procedure D: Under argon, cuprous thiophene-2-carboxylate (CuTc, 10 mol%), ligand L12 (12 mol%), cesium carbonate (4.0 equiv), toluene (2.0 mL), and 1,3-difluorobenzene (1,3-F2C6H4, 2.0 mL) were added to a Schlenk tube equipped with a magnetic rod and pre-stirred at 50°C for 2 hours. Then, a dialkyl iodide (0.10 mmol, 1.0 equiv) and a sulfenyl imine (0.10 mmol, 1.0 equiv) were added sequentially to the mixture, and pre-stirring at 50°C was continued for 1 hour. The system was cooled to -50°C and reacted under 390 nm LED light for three days. After completion of the reaction (monitored by TLC), the precipitate was filtered and washed with the solvent. The solution was then evaporated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain the product.

[0078]

[0079] Example 5

[0080]

[0081] According to the general method B, bisalkyl iodide E1 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 1 as a colorless oil (52% yield, 90% ee).

[0082] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=6.43min,t R (major) = 7.60 min; 1H NMR (400MHz, CDCl3) δ7.87(d,J=8.4Hz,2H),7.81(d,J=8.3Hz,2H),7.24(d,J=8.1Hz,4H),3.3 4–3.01(m,1H),2.36(s,6H),1.66–1.29(m,4H),1.22(d,J=6.3Hz,3H),0.88(t,J=7.1Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 142.8, 142.7, 139.0, 138.4, 129.7, 129.6, 128.7, 128.5, 50.5, 43.0, 24.8, 21.5, 19.9, 14.3. HRMS (ESI) m / z accurate mass calculation C 19 H 26 NOS[M+H] + 316.1730, measured value 316.1720.

[0083] Example 6:

[0084]

[0085] According to the general method B, bisalkyl iodide E2 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 2 as a colorless oil (53% yield, 86% ee).

[0086] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=6.11min,t R (major) = 7.40 min; 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.3Hz,2H),7.83(d,J=8.3Hz,2H),7.26(d,J=8.0Hz,4H),3.22–3.12(m ,1H),2.38(s,6H),1.68–1.57(m,1H),1.56–1.26(m,5H),1.23(d,J=6.3Hz,3H),0.91(t,J=7.1Hz,3H). 13C NMR (100 MHz, CDCl3) δ 142.73, 142.65, 139.1, 138.5, 129.62, 129.60, 128.7, 128.5, 50.7, 40.4, 28.9, 24.8, 22.8, 21.4, 14.2. HRMS (ESI) m / z accurate mass calculation C 20 H 28 NOS[M+H] + 330.1886, measured value 330.1874.

[0087] Example 7:

[0088]

[0089] According to the general method B, bisalkyl iodide E3 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used to purify the reaction by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the product 3 as a colorless oil (70% yield, 95% ee).

[0090] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=7.27min,t R (major) = 8.69 min; 1 H NMR (400MHz, CDCl3) δ7.87(d,J=8.3Hz,2H),7.82(d,J=8.3Hz,2H),7.27(d,J=8.5Hz,4H),3.64–3.49(m,2H),3 .26–3.16(m,1H),2.39(s,6H),2.16–1.98(m,1H),1.97–1.83(m,1H),1.73–1.63(m,2H),1.25(d,J=6.4Hz,3H). 13 CNMR (100 MHz, CDCl3) δ 142.92, 142.85, 138.8, 138.3, 129.71, 129.67, 128.52, 128.49, 49.9, 45.5, 37.5, 29.8, 24.8, 21.4. HRMS (ESI) m / z accurate mass calculation C 19 H 24 NOS[M-Cl] - 314.1584, measured value 314.1573.

[0091] Example 8:

[0092]

[0093] According to the general method B, bisalkyl iodide E4 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used to purify the reaction by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the product 4 as a colorless oil (50% yield, 91% ee).

[0094] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 85 / 15, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=9.66min,t R (major) = 10.94 min; 1 H NMR (400MHz, CDCl3) δ7.83(t,J=8.3Hz,4H),7.41–7.08(m,4H),3.28–3.16(m,1H),2.49–2.23(m,8H),2.00–1.58(m,4H),1.23(d,J=6.3Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 143.04, 142.99, 138.6, 138.3, 129.8, 129.7, 128.5, 128.4, 120.1, 49.4, 38.9, 24.7, 22.4, 21.4, 17.1. HRMS (ESI) m / z accurate mass calculation C 20 H 25 N2OS[M+H] + 341.1682, measured value 341.1671.

[0095] Example 9:

[0096]

[0097] According to the general method B, bisalkyl iodide E5 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used to purify the reaction by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the product 5 as a colorless oil (52% yield, 88% ee).

[0098] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 95 / 5, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=17.63min,t R (major) = 19.58 min;1 H NMR (400MHz, CDCl3) δ7.86(d,J=8.3Hz,2H),7.82(d,J=8.3Hz,2H),7.25(d,J=8.1Hz,4H),4.07(t,J=6.6Hz,2H ),3.25–3.11(m,1H),2.37(s,6H),2.04(s,3H),1.95–1.80(m,1H),1.80–1.48(m,3H),1.23(d,J=6.3Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 171.2, 142.9, 142.8, 138.8, 138.3, 129.7, 129.6, 128.54, 128.49, 64.9, 50.2, 36.6, 25.8, 24.8, 21.4, 21.0. HRMS (ESI) m / z accurate mass calculation C 21 H 28 NO3S[M+H] + 374.1784, measured value 374.1773.

[0099] Example 10:

[0100]

[0101] According to the general method B, bisalkyl iodide E6 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 6 as a colorless oil (66% yield, 91% ee).

[0102] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 95 / 5, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=10.47min,t R (major) = 11.84 min; 1 H NMR (400MHz, CDCl3) δ7.85(d,J=8.3Hz,2H),7.79(d,J=8.3Hz,2H),7.31–7.13(m,9H),3.24–3.12(m,1H),2.58(q ,J=8.3,7.3Hz,2H),2.36(s,6H),1.89–1.77(m,1H),1.78–1.60(m,2H),1.58–1.46(m,1H),1.21(d,J=6.3Hz,3H). 13C NMR (100 MHz, CDCl3) δ 143.0, 142.8, 142.7, 138.9, 138.4, 129.7, 129.6, 128.6, 128.51, 128.49, 128.2, 125.5, 50.5, 40.2, 36.0, 28.4, 24.8, 21.5. HRMS (ESI) m / z accurate mass calculation C 25 H 30 NOS[M+H] + 392.2043, measured value 392.2029.

[0103] Example 11:

[0104]

[0105] According to the general method B, bisalkyl iodide E7 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used to purify the reaction by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the product 7 as a colorless oil (50% yield, 88% ee).

[0106] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=9.05min,t R (major) = 11.17 min; 1 H NMR (400MHz, CDCl3) δ7.86(d,J=8.3Hz,2H),7.80(d,J=8.3Hz,2H),7.24(d,J=8.4Hz,4H),4.12(q,J=7.1Hz,2H),3.21–3.12(m,1 H), 2.36 (s, 6H), 2.28 (td, J = 7.9, 2.3Hz, 2H), 1.89–1.70 (m, 2H), 1.67–1.44 (m, 2H), 1.25 (t, J = 7.1Hz, 3H), 1.22 (d, J = 6.3Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 174.0, 142.8, 142.7, 138.9, 138.3, 129.7, 129.6, 128.6, 128.5, 60.1, 50.3, 39.9, 34.4, 24.7, 22.1, 21.4, 14.3. HRMS (ESI) m / z accurate mass calculation C 22 H 30 NO3S[M+H] +388.1941, measured value 388.1927.

[0107] Example 12:

[0108]

[0109] According to the general method B, bisalkyl iodide E8 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used to purify the reaction by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 8 as a dark yellow oil (46% yield, 90% ee).

[0110] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 95 / 5, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=8.52min,t R (major)=10.65min;1H NMR (400MHz, CDCl3) δ7.89–7.82(m,2H),7.82–7.77(m,2H),7.25(d,J=8.1Hz,4H),3.26(td,J=6.8,3. 3Hz,2H),3.21–3.12(m,1H),2.37(s,6H),1.90–1.77(m,1H),1.73–1.48(m,3H),1.22(d,J=6.3Hz,3H). 13C NMR (100 MHz, CDCl3) δ 142.94, 142.87, 138.7, 138.3, 129.71, 129.68, 128.5, 51.6, 50.0, 37.3, 25.9, 24.8, 21.4. HRMS (ESI) m / z accurate mass calculation C 19 H 25 N4OS[M+H] + 357.1744, measured value 357.1731.

[0111] Example 13:

[0112]

[0113] According to the general method B, bisalkyl iodide E9 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the product 9 as a dark yellow oil (52% yield, 92% ee).

[0114] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 85 / 15, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=13.00min,t R (major)=16.12min;1H NMR (400MHz, CDCl3) δ7.84(d,J=8.3Hz,2H),7.78(d,J=8.2Hz,2H),7.42–7.35(m,2H),7.35–7.28(t,J=7.3Hz,1H),7.22(d,J=8.0Hz,4H),7.15( d,J=7.4Hz,2H),3.26(s,3H),3.13–3.01(m,1H),2.35(s,6H),2.15–1.9 7(m,2H),1.91–1.57(m,2H),1.55–1.29(m,2H),1.17(d,J=6.3Hz,3H). 13C NMR (100 MHz, CDCl3) δ 173.3, 144.3, 142.8, 142.6, 138.9, 138.2, 129.7, 129.6, 128.7, 128.4, 127.6, 127.3, 50.5, 40.2, 37.3, 34.2, 24.8, 22.7, 21.4. HRMS (ESI) m / z accurate mass calculated C 27 H 33 N2O2S[M+H] + 449.2257, measured value 449.2243.

[0115] Example 14:

[0116]

[0117] According to the general method B, bisalkyl iodide E10 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 10 as a colorless oil (55% yield, 83% ee).

[0118] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 95 / 5, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=8.96min,t R (major) = 9.90 min; 1H NMR (400MHz, CDCl3) δ7.87(d,J=8.3Hz,2H),7.82(d,J=8.3Hz,2H),7.27(dd,J=8.3,2.7Hz,4H) ,3.26–3.12(m,1H),2.39(s,6H),2.16–1.98(m,2H),1.86–1.49(m,4H),1.24(d,J=6.3Hz,3H). 13 C NMR (100MHz, CDCl3) δ143.0,142.9,138.7,138.3,129.70,129.69,128.48,128.47,127. 4(q,J=275.0Hz),50.0,39.3,33.7(q,J=28.2Hz),24.7,21.40,21.38,18.9(d,J=2.9Hz). 19 F NMR (376 MHz, CDCl3) δ–66.27. HRMS (ESI) m / z accurate mass calculation C 20 H 25 F3NOS[M+H] + 384.1603, measured value 384.1591.

[0119] Example 15:

[0120]

[0121] According to the general method C, bisalkyl iodide E11 (0.10 mmol, 1.0 equiv) and sulfinyl imine N2 (0.10 mmol, 1.0 equiv) were used to purify the reaction by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the product 11 as a colorless oil (62% yield, 90% ee).

[0122] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 95 / 5, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=16.71min,t R (major) = 21.49 min; 1 H NMR(400MHz, CDCl3)8.42–7.95(m,4H),7.91–7.69(m,4H),7.61–7.39(m,2H),7.10–6.86(m,2H),3. 30–3.19(m,1H),2.57(t,J=7.4Hz,2H),1.79–1.65(m,2H),1.68–1.42(m,4H),1.21(d,J=6.3Hz,3H). 13C NMR (100 MHz, CDCl3) δ 171.9, 149.7, 145.4, 144.8, 133.1, 133.0, 132.5, 129.4, 129.3, 123.4, 118.9, 117.2, 116.68, 116.66, 50.7, 39.7, 34.2, 25.7, 24.8, 24.4. HRMS (ESI) m / z accurate mass calculation C 27 H 25 BrN3O3S[M+H] + 550.0795, measured value 550.0788.

[0123] Example 16:

[0124]

[0125] According to the general method C, bisalkyl iodide E12 (0.10 mmol, 1.0 equiv) and sulfinyl imine N3 (0.10 mmol, 1.0 equiv) were reacted with L14 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 12 as a colorless oil (51% yield, 92% ee).

[0126] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 95 / 5, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=9.68min,t R (major) = 10.32 min; 1 H NMR (400MHz, CDCl3) δ8.15–8.00(m,1H),7.93–7.76(m,3H),7.77–7.65(m,3H),7.65–7.56(m,2H), 7.56–7.42(m,4H),7.41–7.29(m,2H),3.64–2.99(m,3H),2.20–1.82(m,2H),1.32(d,J=6.3Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 140.5, 139.9, 138.6, 133.9, 132.4, 131.9, 130.2, 130.1, 128.8, 127.8, 127.6, 126.5, 125.8, 125.7, 125.6, 125.4, 123.9, 50.7, 41.0, 29.9, 24.6. HRMS (ESI) m / z accurate mass calculation C 26 H 24 Br2NOS[M+H] +557.9919, measured value 557.9915.

[0127] Example 17:

[0128]

[0129] According to the general method C, bisalkyl iodide E13 (0.10 mmol, 1.0 equiv) and sulfinyl imine N3 (0.10 mmol, 1.0 equiv) were reacted with L8 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 13 as a colorless oil (84% yield, 90% ee).

[0130] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 98 / 2, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=11.67min,t R (major) = 12.84 min; 1 H NMR (400MHz, CDCl3) δ7.82–7.71(m,2H),7.73–7.65(m,2H),7.59–7.43(m,4H),3.21–3.09(m,1H),1.80–1.67(m ,1H),1.51–1.42(m,1H),1.25–1.16(m,1H),1.12(d,J=6.3Hz,3H),0.78(d,J=6.7Hz,3H),0.74(d,J=6.5Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 140.7, 140.2, 132.4, 130.2, 130.1, 127.7, 127.6, 49.9, 48.8, 24.97, 24.95, 23.1, 22.5. HRMS (ESI) m / z accurate mass calculation C 18 H 22 Br2NOS[M+H] + 457.9783, measured value 457.9783.

[0131] Example 18:

[0132]

[0133] According to general method A, bisalkyl iodide E14 (0.10 mmol, 1.0 equiv) and sulfenyl imine N3 (0.10 mmol, 1.0 equiv) were reacted with L8 at -30 ° C. and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 14 as a colorless oil (82% yield, 89% ee).

[0134] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 98 / 2, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=5.95min,t R (major) = 7.01 min; 1 H NMR (400MHz, CDCl3) δ7.86–7.79(m,2H),7.79–7.72(m,2H),7.66–7.43(m,4H) ,3.31–3.20(m,1H),1.94–1.39(m,7H),1.38–1.04(m,7H),0.94–0.64(m,2H). 13 C NMR (100 MHz, CDCl3) δ 140.6, 140.2, 132.4, 132.3, 130.3, 130.1, 127.7, 127.5, 48.4, 48.1, 34.6, 33.8, 33.2, 26.7, 26.4, 26.3, 25.1. HRMS (ESI) m / z accurate mass calculation C 21 H 26 Br2NOS[M+H] + 500.0076, measured value 500.0062.

[0135] Example 19:

[0136]

[0137] According to the general method A, bisalkyl iodide E15 (0.10 mmol, 1.0 equiv) and sulfinyl imine N3 (0.10 mmol, 1.0 equiv) were reacted with L8 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 15 as a colorless oil (69% yield, 92% ee).

[0138] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 98 / 2, flow rate 1.0 ml / min, λ = 254 nm), t R (major)=42.95min,t R (minor) = 47.72min; 1H NMR (400MHz, CDCl3) δ7.90–7.71(m,4H),7.66–7.53(m,4H),4.03(brs,2H),3.34–3.21(m,1H),2.69(b rs,2H),1.90–1.50(m,4H),1.45(s,9H),1.37–1.28(m,1H),1.18(d,J=6.2Hz,3H),1.17–0.81(m,2H). 13 C NMR (100 MHz, CDCl3) δ 154.9, 140.4, 140.2, 132.5, 132.4, 130.08, 130.05, 127.74, 127.72, 79.2, 47.7, 47.2, 44.0, 32.8, 32.6, 31.9, 28.5, 24.9. HRMS (ESI) m / z accurate mass calculated for C 25 H 33 Br2N2O3S[M+H] + 601.055, measured value 601.0535.

[0139] Example 20:

[0140]

[0141] According to the general method A, bisalkyl iodide E16 (0.10 mmol, 1.0 equiv) and sulfinyl imine N3 (0.10 mmol, 1.0 equiv) were reacted with L8 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the product 15 as a colorless oil (66% yield, 90% ee).

[0142] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 95 / 5, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=13.33min,t R (major) = 14.70 min; 1 H NMR (400MHz, CDCl3) δ7.84–7.75(m,4H),7.69–7.48(m,4H),3.96–3.86(m,2H) ,3.56–3.08(m,3H),1.83–1.70(m,1H),1.63–1.47(m,3H),1.44–0.95(m,6H). 13C NMR (100 MHz, CDCl3) δ 140.5, 140.2, 132.5, 132.4, 130.09, 130.07, 127.73, 127.69, 68.1, 68.0, 47.6, 47.4, 33.5, 33.0, 31.8, 24.9. HRMS (ESI) m / z accurate mass calculation C 20 H 24 Br2NO2S[M+H] + 501.9869, measured value 501.9851.

[0143] Example 21:

[0144]

[0145] According to the general method A, bisalkyl iodide E17 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 17 as a colorless oil (80% yield, 92% ee).

[0146] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=6.66min,t R (major) = 8.11 min; 1 H NMR (400MHz, CDCl3) δ7.93–7.85(m,2H),7.85–7.76(m,2H),7.29–7.21(m,4H),3.40–3.27(m,1H),2.38 (s, 6H), 1.77 (dd, J = 14.0, 5.2 Hz, 1H), 1.45 ( dd, J = 14.0, 6.1 Hz, 1H), 1.27 ( d, J = 6.2 Hz, 3H), 0.91 ( s, 9H). 13 C NMR (100 MHz, CDCl3) δ 142.7, 142.6, 139.3, 138.6, 129.58, 129.57, 128.6, 128.4, 54.8, 48.1, 30.6, 30.3, 27.2, 21.4. HRMS (ESI) m / z accurate mass calculation C 21 H 30 NOS[M+H] + 344.2043, measured value 344.2027.

[0147] Example 22:

[0148]

[0149] According to the general method A, bisalkyl iodide E18 (0.10 mmol, 1.0 equiv) and sulfinyl imine N3 (0.10 mmol, 1.0 equiv) were reacted with L8 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 18 as a colorless oil (82% yield, 93% ee).

[0150] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=6.71min,t R (major) = 8.69 min; 1 H NMR (400MHz, CDCl3) δ7.89–7.79(m,2H),7.78–7.73(m,2H),7.65–7.55(m,4H),3.44–3.33(m,1H),1.94–1.86 (m,3H),1.71–1.63(m,3H),1.62–1.54(m,4H),1.55–1.41(m,6H),1.34–1.27(m,1H),1.21(d,J=6.3Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 140.9, 140.3, 132.4, 130.13, 130.07, 127.6, 127.5, 55.8, 46.6, 43.1, 37.1, 32.7, 28.7, 27.4. HRMS (ESI) m / z accurate mass calculation C 25 H 30 Br2NOS[M+H] + 552.0389, measured value 552.0371.

[0151] Example 23:

[0152]

[0153] According to the general method A, the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) with dialkyl iodide E19 (0.10 mmol, 1.0 equivalent) and sulfinyl imine N1 (0.10 mmol, 1.0 equivalent) to give product 19 as a colorless oil (82% yield, 95% ee). HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=17.90min,tR (major) = 21.08 min; 1 H NMR (400MHz, CDCl3) δ7.84(d,J=7.8Hz,2H),7.77(d,J=7.8Hz,2H),7.55–7.01(m,9H),5.13(s,2H),4.24(brs,2H),3.02–2.91(m,1H) ,2.85–2.64(m,2H),2.36(s,6H),2.03–1.90(m,1H),1.75–1.65(m,1H),1.60–1.48(m,1H),1.45–1.22(m,2H),1.18(d,J=6.3Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 155.3, 142.9, 142.8, 139.1, 138.2, 137.1, 129.64, 129.59, 128.6, 128.5, 128.4, 127.82, 127.77, 66.9, 54.5, 44.5, 44.44, 44.36, 28.81, 28.76, 21.5, 21.4. HRMS (ESI) m / z accurate mass calculation C 29 H 35 N2O3S[M+H] + 491.2363, measured value 491.2348.

[0154] Example 24:

[0155]

[0156] According to the general method A, the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) with bisalkyl iodide E20 (0.10 mmol, 1.0 equivalent) and sulfinyl imine N1 (0.10 mmol, 1.0 equivalent) to give the product 20 as a colorless oil (98% yield, 96% ee). HPLC analysis: Chiralcel IA3 (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=48.12min,t R (major) = 50.58 min; 1H NMR (400MHz, CDCl3) δ7.89(d,J=8.3Hz,2H),7.80(d,J=8.3Hz,2H),7.27(d,J=8.2Hz,4H),4.10–3.96(m,2H),3.48–3.34 (m,2H),3.02–2.91(m,1H),2.39(s,6H),1.97–1.89(m,1H),1.66–1.56(m,2H),1.53–1.34(m,2H),1.22(d,J=6.4Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 143.0, 142.8, 139.0, 138.0, 129.7, 129.6, 128.7, 128.5, 68.5, 68.2, 54.9, 43.4, 30.0, 29.9, 21.52, 21.46, 21.4. HRMS (ESI) m / z accurate mass calculation C 21 H 28 NO2S[M+H] + 358.1835, measured value 358.1822.

[0157] Example 25:

[0158]

[0159] According to the general method D, bisalkyl iodide E21 (0.10 mmol, 1.0 equiv) was reacted with sulfinyl imine N1 (0.10 mmol, 1.0 equiv), L14, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 10 / 1) to give the product 21 as a colorless oil (60% yield, 92% ee).

[0160] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 85 / 15, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=36.48min,t R (major) = 42.50 min; 1 H NMR (400MHz, CDCl3) δ7.87–7.73(m,4H),7.32–7.17(m,4H),3.37–2.78(m,5H),2.38(s ,6H),2.36–2.18(m,2H),2.06–1.94(m,2H),1.71–1.58(m,1H),1.19(d,J=6.4Hz,3H). 13CNMR (100 MHz, CDCl3) δ 143.3, 143.2, 138.4, 137.9, 129.8, 128.5, 128.3, 53.3, 51.4, 51.3, 43.7, 26.8, 26.3, 21.4, 21.1. HRMS (ESI) m / z accurate mass calculation C 21 H 28 NO3S2[M+H] + 406.1505, measured value 406.1493.

[0161] Example 26:

[0162]

[0163] According to the general method D, bisalkyl iodide E22 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 22 as a colorless oil (71% yield, 95% ee).

[0164] HPLC analysis: Chiralcel IA3 (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=6.56min,t R (major) = 12.83 min; 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.4Hz,2H),7.79(d,J=8.3Hz,2H),7.23(d,J=8.1Hz,4H),2.98–2.89(m,1H), 2.36(s,6H),2.03–1.96(m,1H),1.80–1.73(m,3H),1.69–1.61(m,1H),1.41–1.32(m,1H),1.30–0.92(m,8H). 13 CNMR (100 MHz, CDCl3) δ 142.6, 142.5, 139.4, 138.4, 129.6, 129.5, 128.8, 128.5, 55.4, 46.1, 29.8, 29.6, 26.8, 26.6, 21.8, 21.4. HRMS (ESI) m / z accurate mass calculation C 20 H 30 NOS[M+H] + 356.2043, measured value 356.2031.

[0165] Example 27:

[0166]

[0167] According to the general method A, bisalkyl iodide E23 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 22 as a colorless oil (98% yield, 95% ee).

[0168] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=7.39min,t R (major) = 13.98 min; 1 H NMR (400MHz, CDCl3) δ7.90–7.84(m,2H),7.83–7.76(m,2H),7.35–7.11(m,4H),3.27–2.92(m,1H) ), 2.40 (s, 6H), 2.19–2.02 (m, 3H), 1.88–1.62 (m, 3H), 1.53–1.36 (m, 3H), 1.22 (d, J = 6.4Hz, 3H). 13 C NMR (100MHz, CDCl3) δ43.0,142.9,138.8,138.0,129.70,129.66,128.6,128.5,124.1(dd,J=241.8,239. 4Hz), 54.1 (d, J=2.5Hz), 33.7 (dd, J=25.5, 22.1Hz), 25.6 (dd, J=32.3, 9.8Hz), 44.2, 21.7, 21.44, 21.43. 19 F NMR (376 MHz, CDCl3) δ–91.11 (d, J = 233.4 Hz),–102.32 (d, J = 233.5 Hz). HRMS (ESI) m / z accurate mass calculation C 22 H 28 F2NOS[M+H] + 392.1854, measured value 392.1842.

[0169] Example 28:

[0170]

[0171] According to the general method A, bisalkyl iodide E24 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the product 24 as a colorless oil (78% yield, 94% ee).

[0172] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=15.86min,t R (major) = 18.47 min; 1 H NMR(400MHz, CDCl3) δ7.86(d,J=8.3Hz,2H),7.79(d,J=8.3Hz,2H),7.37–6.77(m,4H),3.21–3.07(m,1H ),2.73–2.21(m,11H),2.14–2.05(m,1H),1.93–1.81(m,1H),1.71–1.55(m,2H),1.24(d,J=6.4Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 212.9, 142.9, 142.8, 139.0, 138.2, 129.7, 129.6, 128.51, 128.47, 53.8, 44.3, 40.98, 40.96, 29.4, 28.9, 22.0, 21.43, 21.42. HRMS (ESI) m / z accurate mass calculation C 22 H 28 NO2S[M+H] + 370.1835, measured value 370.1823.

[0173] Example 29:

[0174]

[0175] According to the general method D, bisalkyl iodide E25 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the product 25 as a colorless oil (65% yield, 95% ee).

[0176] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=12.41min,tR (major) = 17.67 min; 1 H NMR (400MHz, CDCl3) δ7.87(d,J=8.3Hz,2H),7.80(d,J=8.3Hz,2H),7.26(d,J=8.2Hz,4H),3.68(s,3H),3.05–2.91(m ,1H),2.39(s,6H),2.31–2.21(m,1H),2.13–2.00(m,3H),1.90–1.82(m,1H),1.55–1.32(m,3H),1.24–1.01(m,5H). 13 C NMR (100 MHz, CDCl3) δ 176.8, 142.8, 142.7, 139.2, 138.2, 129.62, 129.57, 128.7, 128.5, 54.9, 51.5, 45.1, 43.5, 29.1, 28.7, 28.4, 21.8, 21.4. HRMS (ESI) m / z accurate mass calculation C 24 H 32 NO3S[M+H] + 414.2097, measured value 414.2083.

[0177] Example 30:

[0178]

[0179] According to the general method D, bisalkyl iodide E26 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 26 as a colorless oil (65% yield, 95% ee).

[0180] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=5.97min,t R (major) = 7.64 min; 1H NMR (400MHz, CDCl3) δ7.84(d,J=8.3Hz,2H),7.78(d,J=8.2Hz,2H),7.24(d,J=8.2Hz,4H),3.05–2.94(m,1H), 2.37(s,6H),2.14–2.05(m,1H),2.04–1.92(m,3H),1.92–1.83(m,1H),1.45–1.23(m,3H),1.23–1.04(m,5H). 13 C NMR (100MHz, CDCl3) δ142.8,142.7,139.2,138.3,129.61,129.58,128.6,128.5,1 28.0(q,J=278.6Hz),54.7,45.1,42.1(q,J=26.2Hz),28.0,27.6,25.0,21.7,21.4. 19 F NMR (376 MHz, CDCl3) δ–73.72,–73.70. HRMS (ESI) m / z accurate mass calculation C 23 H 29 F3NOS[M+H] + 424.1916, measured value 424.1904.

[0181] Example 31:

[0182]

[0183] According to the general method D, bisalkyl iodide E27 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 27 as a colorless oil (74% yield, 90% ee).

[0184] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=5.70min,t R (major) = 8.11 min; 1H NMR (400MHz, CDCl3) δ7.90(d,J=8.3Hz,2H),7.81(d,J=8.3Hz,2H),7.26(d,J=8.0Hz,4H),3.03–2.9 0(m,1H),2.39(s,6H),2.09–1.98(m,1H),1.87–1.74(m,3H),1.40–0.99(m,15H),0.98–0.82(m,5H). 13 C NMR (100 MHz, CDCl3) δ 142.7, 142.6, 139.3, 138.2, 129.59, 129.55, 128.8, 128.5, 55.4, 46.2, 37.9, 37.5, 33.38, 33.36, 32.3, 29.7, 29.5, 26.7, 22.7, 21.8, 21.4, 14.1. HRMS (ESI) m / z accurate mass calculation C 27 H 40 NOS[M+H] + 426.2825, measured value 426.2810.

[0185] Example 32:

[0186]

[0187] According to the general method D, bisalkyl iodide E28 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv), L14, were purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the product 28 as a colorless oil (58% yield, 96% ee).

[0188] HPLC analysis: Chiralcel IA3 (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=7.45min,t R (major) = 9.92 min; 1 H NMR(400MHz, CDCl3)δ7.88(d,J=8.1Hz,2H),7.81(d,J=8.0Hz,2H),7.43–7.03(m,9H),3.07–2.96(m,1H),2 .54–2.43(m,1H),2.37(s,6H),2.19–2.11(m,1H),2.01–1.87(m,3H),1.58–1.38(m,3H),1.37–1.13(m,5H). 13C NMR (100 MHz, CDCl3) δ 148.0, 142.7, 142.6, 139.4, 138.4, 129.62, 129.57, 128.8, 128.5, 128.3, 126.9, 125.8, 55.2, 45.6, 44.6, 34.34, 34.31, 29.82, 29.80, 21.9, 21.4. HRMS (ESI) m / z accurate mass calculation C 28 H 34 NOS[M+H] + 432.2356, measured value 432.2343.

[0189] Example 33:

[0190]

[0191] According to the general method B, bisalkyl iodide E29 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were reacted with L14 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the product 29 as a colorless oil (51% yield, 87% ee).

[0192] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=7.10min,t R (major) = 9.75 min; 1 H NMR(400MHz, CDCl3) δ7.90(d,J=8.3Hz,2H),7.81(d,J=8.3Hz,2H),7.25(d,J=8.1Hz,4H), 3.05–2.95(m,1H),2.38(s,6H),2.02–1.92(m,2H),1.75–1.36(m,6H),1.28–1.17(m,4H). 13 CNMR (100 MHz, CDCl3) δ 142.7, 142.5, 139.4, 138.4, 129.6, 129.5, 128.8, 128.5, 55.2, 49.3, 30.5, 29.7, 25.6, 25.4, 23.8, 21.42, 21.41. HRMS (ESI) m / z accurate mass calculation C 21 H 28 NOS[M+H] + 342.1886, measured value 342.1875.

[0193] Example 34:

[0194]

[0195] According to the general method B, bisalkyl iodide E30 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were reacted with L14 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the product 30 as a colorless oil (56% yield, 88% ee).

[0196] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=7.24min,t R (major) = 14.02 min.; 1 H NMR (400MHz, CDCl3) δ7.86(d,J=8.3Hz,2H),7.78(d,J=8.3Hz,2H),7.23(d,J=8.0Hz,4H),3. 13–3.03(m,1H),2.36(s,6H),1.93–1.83(m,1H),1.75–1.22(m,12H),1.14(d,J=6.5Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 142.6, 142.5, 139.4, 138.6, 129.6, 129.5, 128.7, 128.5, 55.9, 47.4, 30.8, 30.4, 28.6, 28.4, 27.3, 27.1, 21.4, 21.0. HRMS (ESI) m / z accurate mass calculation C 23 H 32 NOS[M+H] + 370.2199, measured value 370.2187.

[0197] Example 35:

[0198]

[0199] According to the general method C, bisalkyl iodide E31 (0.10 mmol, 1.0 equiv) and sulfinyl imine N2 (0.10 mmol, 1.0 equiv) were reacted with L8 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the product 31 as a colorless oil (79% yield, 85% ee).

[0200] HPLC analysis: Chiralcel ADH (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (major)=14.02min,t R (minor) = 20.00min; 1 H NMR (400MHz, CDCl3) δ8.13–8.07(m,2H),8.07–8.01(m,2H),7.87–7.75(m,4H),3.35(qd,J=6.5,4.0Hz,1H),1.63 –1.54(m,1H),1.50–1.36(m,2H),1.34–1.26(m,1H),1.25–1.18(m,1H),1.14(d,J=6.5Hz,3H),0.94–0.79(m,6H). 13 C NMR (100 MHz, CDCl3) δ 145.8, 145.2, 133.0, 129.4, 129.3, 117.3, 116.5, 116.4, 52.1, 49.4, 22.5, 22.3, 20.7, 12.2, 12.2.. HRMS (ESI) m / z accurate mass calculation C 21 H 24 N3OS[M+H] + 366.1635, measured value 366.1636.

[0201] Example 36:

[0202]

[0203] According to the general method A, bisalkyl iodide E32 (0.10 mmol, 1.0 equiv) and sulfinyl imine N4 (0.10 mmol, 1.0 equiv) were reacted with L8 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the product 32 as a colorless oil (57% yield, 88% ee).

[0204] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=8.70min,t R (major) = 17.32 min; 1H NMR (400MHz, CDCl3) δ7.96–7.90(m,2H),7.83–7.75(m,2H),6.95–6.88(m,4H),3.82(d,J=2.2 Hz, 6H), 2.67 (q, J = 6.5Hz, 1H), 2.04–1.93 (m, 3H), 1.77–1.49 (m, 12H), 1.10 (d, J = 6.5Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 162.4, 162.2, 134.8, 133.0, 130.8, 130.4, 114.02, 113.96, 59.5, 55.5, 39.1, 37.5, 37.2, 28.8, 17.9. HRMS (ESI) m / z accurate mass calculation C 26 H 34 NO3S[M+H] + 440.2254, measured value 440.2240.

[0205] Example 37:

[0206]

[0207] According to the general method B, bisalkyl iodide E33 (0.10 mmol, 1.0 equiv) and sulfinyl imine N1 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 33 as a colorless oil (58% yield, 70% ee).

[0208] HPLC analysis: Chiralcel ID (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (major)=9.33min,t R (minor) = 10.61min; 1 H NMR (400MHz, CDCl3) δ7.99–7.57(m,4H),7.30–7.21(m,4H),3.04–2.94(m,1H), 2.38(s,6H),1.76–1.30(m,6H),0.96(t,J=7.4Hz,3H),0.89(t,J=7.1Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 142.6, 138.9, 138.8, 129.5, 128.7, 128.6, 56.3, 39.7, 30.7, 21.4, 19.5, 14.4, 10.5. HRMS (ESI) m / z accurate mass calculation C 20H 28 NOS[M+H] + 330.1886, measured value 330.1874.

[0209] Example 38:

[0210]

[0211] According to the general method C, bisalkyl iodide E34 (0.10 mmol, 1.0 equiv) and sulfinyl imine N3 (0.10 mmol, 1.0 equiv) were used and the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 34 as a colorless oil (42% yield, 78% ee).

[0212] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=5.23min,t R (major) = 5.58 min; 1 H NMR (400MHz, CDCl3) δ7.81–7.76(m,4H),7.62–7.56(m,4H),3.17–3.09(m,1H),1.69–1.45(m,4H),0.95(t,J=7.3Hz,3H),0.85(s,9H). 13 CNMR (100 MHz, CDCl3) δ 140.9, 140.7, 132.3, 130.2, 130.0, 127.44, 127.40, 53.6, 51.3, 32.6, 30.6, 30.3, 10.4.. HRMS (ESI) m / z accurate mass calculation C 20 H 26 Br2NOS[M+H] + 488.0076, measured value 488.0074.

[0213] Example 39:

[0214]

[0215] According to the general method C, the reaction was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) with bisalkyl iodide E35 (0.10 mmol, 1.0 equiv) and sulfinyl imine N3 (0.10 mmol, 1.0 equiv) to give the product 35 as a colorless oil (33% yield, 89% ee).

[0216] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (major)=9.82min,t R (minor) = 10.54min.; 1 H NMR (400MHz, CDCl3) δ7.84–7.78(m,2H),7.78–7.72(m,2H),7.65–7.57(m,4H),4.24–3.86(m,2H), 3.51–3.24(m,2H),2.88–2.77(m,1H),1.93–1.67(m,2H),1.61–1.43(m,5H),0.91(t,J=7.4Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 140.7, 140.0, 132.4, 132.3, 130.2, 130.1, 127.61, 127.55, 68.4, 68.2, 60.5, 39.7, 30.1, 29.1, 26.9, 10.0. HRMS (ESI) m / z accurate mass calculation C 20 H 24 Br2NO2S[M+H] + 501.9869, measured value 501.9865.

[0217] Example 40:

[0218]

[0219] According to the general method B, bisalkyl iodide E36 (0.10 mmol, 1.0 equiv) and sulfinyl imine N3 (0.10 mmol, 1.0 equiv) were reacted with L6 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the product 36 as a colorless oil (56% yield, 90% ee).

[0220] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (major)=11.51min,t R (minor) = 28.18min; 1H NMR (400MHz, CDCl3) δ8.00–7.68(m,4H),7.69–7.52(m,4H),3.18(tt,J=11.0,4.4Hz,1H),1.94–1.82(m,1H),1.68–1 .58(m,1H),1.58–1.50(m,1H),1.45–1.31(m,3H),1.29–1.19(m,1H),1.17–1.02(m,1H),0.92(s,3H),0.77(s,3H). 13 C NMR (100 MHz, CDCl3) δ 140.6, 140.4, 132.4, 130.10, 130.07, 127.6, 51.0, 49.9, 38.3, 36.9, 33.2, 31.7, 25.1, 21.5. HRMS (ESI) m / z accurate mass calculation C 20 H 24 Br2NOS[M+H] + 485.9919, measured value 485.9903.

[0221] Example 41:

[0222]

[0223] According to the general method B, bisalkyl iodide E37 (0.10 mmol, 1.0 equiv) and sulfinyl imine N3 (0.10 mmol, 1.0 equiv) were reacted with L6 and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the product 37 as a colorless oil (48% yield, 88% ee).

[0224] HPLC analysis: Chiralcel IA (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min, λ = 254 nm), t R (minor)=9.05min,t R (major) = 10.70 min; 1 H NMR (400MHz, CDCl3) δ7.99–7.71(m,4H),7.71–7.49(m,4H),3.80(ddd,J=13.8,6.1,4.4Hz,1H),3.38–3.26(m,1H) ,3.12(ddd,J=13.8,9.9,3.7Hz,1H),1.98–1.79(m,2H),1.75–1.56(m,2H),1.52(s,3H),1.45(s,9H),1.20(s,3H). 13C NMR (100 MHz, CDCl3) δ 156.2, 140.2, 140.1, 132.6, 132.5, 130.1, 129.9, 127.9, 79.4, 54.95, 50.3, 48.2, 41.0, 35.2, 30.8, 28.6, 24.0 HRMS (ESI) m / z accurate mass calculation C 24 H 31 Br2N2O3S[M+H] + 587.0396, measured value 587.0377.

[0225] Example 42:

[0226] The sulfinyl protection was removed to prepare a dialkyl α-chiral primary amine. Take compound 19 as an example. Compound I (0.1mmol, 1 equivalent) shown in Table 3 was dissolved in 10ml of anhydrous methanol as a feed, and magnesium chips (1mmol, 10 equivalents) were added after cooling to 0°C. Stir until the magnesium chips were completely dissolved and warmed to room temperature, and TLC was used to detect the end of the reaction. Afterwards, the temperature was lowered to 0°C, and 2.5ml of 4.0M hydrochloric acid in 1,4-dioxane was added to the system. After 2 hours, the reaction was directly dried to obtain the compound hydrochloride, and after alkalization, the product compound II was obtained with a test yield and ee%.

[0227] Table 3

[0228] Type of feed compound I Type of product compound II Yield % ee% Group 1 6 6-1 85.4 90.8 Group 2 13 13-1 89.7 89.2 Group 3 14 14-1 90.0 90.3 Group 4 15 15-1 88.3 90.5 Group 5 17 17-1 87.9 92.3 Group 6 19 19-1 90.7 90.2 Group 7 20 20-1 90.3 88.2 Group 8 22 22-1 92.5 93.6 Group 9 29 29-1 90.5 91.9 Group 10 33 33-1 87.5 90.6

[0229]

[0230] Example 43:

[0231]

[0232] Step 1: Magnesium chips are weighed in a 500ml double-necked flask containing a magnetic rod, and a reflux condenser and a constant pressure dropping funnel are placed on the flask respectively, and argon protection is replaced. Compound S1 (200mmol) is dissolved in 200mL of tetrahydrofuran (THF), added to the constant pressure dropping funnel, and slowly added to the flask, followed by incubation at 60°C for 2 hours to prepare Grignard reagent S2. No post-treatment is required, cool to 0°C, add diethyl phosphite dropwise, slowly warm to room temperature, and react for 2 hours. Post-treatment: Add 200mL of 3.0M hydrochloric acid, stir until the solid is completely dissolved, then extract with ethyl acetate, separate the organic layer, dry over anhydrous sodium sulfate, filter and concentrate in vacuo, and the residue obtained is chromatographed on a silica gel column to obtain intermediate S3.

[0233] Step 2: Intermediate S3 (100 mmol), methyl o-iodobenzoate (150 mmol), alpha-methylbenzylamine (20 mmol), cuprous iodide (20 mmol) and potassium carbonate (300 mmol) are placed in a 500 mL round-bottom flask, argon is replaced three times, and toluene (250 mL) is added. Subsequently, after refluxing for 24 hours, water is added to quench the reaction, and the organic layer is separated. The reaction mixture is extracted three times with ethyl acetate, and the organic phases are combined and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue thus obtained is purified by silica gel column to obtain the product.

[0234] Step 3: Intermediate S4 (100 mmol), arylboronic acid (450 mmol), tetrakistriphenylphosphine palladium (5 mmol) and sodium carbonate (600 mmol) are placed in a 2000 mL round-bottom flask, the argon atmosphere is replaced three times, and toluene (600 mL) and water (600 mL) are added. After refluxing for 24 hours, the mixture is extracted three times with ethyl acetate, and the combined organic phases are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue thus obtained is purified by silica gel column to obtain product S5.

[0235] Step 4: Intermediate S5 (100 mmol), triphenylphosphine (150 mmol) and trichlorosilane (1 mol) were placed in a 500 mL round-bottom flask, and toluene (100 mL) and tetrahydrofuran (100 mL) were added. After refluxing for 24 hours, the mixture was quenched with ice water and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column to obtain product S6.

[0236] Step 5: Intermediate S6 (100 mmol) and lithium hydroxide (2 mol) were placed in a 500 mL round-bottom flask, and water (150 mL) and tetrahydrofuran (150 mL) were added. After refluxing for 24 hours, 3.0 M hydrochloric acid was added to dissolve the solid, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue thus obtained was purified by silica gel column to obtain product S7.

[0237] Step 6: Intermediate S7 (100 mmol), intermediate S8 (100 mmol), EDCI (150 mmol), and DMAP (10 mmol) were placed in a 500 mL round-bottom flask and added with dichloromethane (250 mL). After reacting at room temperature for 16 hours, the reaction was quenched with saturated ammonium chloride solution and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified on a silica gel column to provide the final product, ligands L5 to L14.

[0238] The structure of L5 to L10 is as follows:

[0239]

[0240] In the present invention, the structures of L11 to L14 are as follows:

[0241]

[0242] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A dialkyl-substituted α-chiral primary amine compound, as shown in formula C, Ar is selected from substituted or unsubstituted monocyclic aromatic groups; The R 1 and R 2 Each is independently selected from substituted or unsubstituted straight chain alkyl, substituted or unsubstituted branched chain alkyl, hydrogen, substituted or unsubstituted heterocyclic group, substituted or unsubstituted cycloalkyl; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

2. The dialkyl-substituted α-chiral primary amine compound according to claim 1, characterized in that: The compound of formula C is shown in formula C-1, C-2 or C-3: R2 is selected from adamantyl, C4 to C8 cycloalkyl, piperidinyl, tetrahydropyranyl, -(CH2) n CH2R a 、-(CH2) p (CO)R b or The R a A linear or branched alkyl group selected from C1 to C6, a monocyclic aromatic group, a condensed aromatic group, a halogen, a cyano group, an alkoxy group, an ester group, an amino group, -CF3, a C4 to C8 cycloalkyl group, an adamantyl group, a piperidinyl group, a tetrahydropyranyl group, and an azido group; The R b Select from -OR ba , the R ba Selected from methyl, ethyl, monocyclic aromatic groups; The Ar1 is selected from C4 to C8 cycloalkyl, piperidinyl, tetrahydropyranyl, adamantyl, or Ar is selected from a monocyclic aromatic group, and any H on the monocyclic aromatic group is substituted by a methyl group, a halogen group, or a cyano group; Said n and p are each independently selected from any positive integer from 1 to 10; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

3. The dialkyl-substituted α-chiral primary amine compound according to claim 2, characterized in that: The R2 is selected from -(CH2) p (CO)R b , the R b Select from -OR ba , the R ba is selected from monocyclic aromatic groups, wherein H on the monocyclic aromatic group is optionally substituted by halogen; The R2 is selected from -(CH2) n CH2R a , the R a Selected from amino, any H on the amino is substituted by methyl, monocyclic aromatic group, amino; The R2 is selected from n-butyl, and any H on the n-butyl is substituted by halogen; Ar1 is selected from cyclohexane, and the H on the cyclohexane is replaced by R c Substitute, the R c is selected from C1 to C5 straight chain alkyl, ester group, halogen, monocyclic aromatic group, Or, Ar1 is selected from cyclohexane, and the alkylene group on the cyclohexane is optionally substituted by -CO-.

4. The dialkyl-substituted α-chiral primary amine compound according to any one of claims 1 to 3, characterized in that: The Ar is selected from a monocyclic aromatic group, and the H at the para position of the monocyclic aromatic group is substituted by a methyl group, a halogen group, a cyano group, or a methoxy group.

5. A dialkyl-substituted α-chiral primary amine compound, specifically:

6. A method for synthesizing a dialkyl-substituted α-chiral primary amine compound represented by formula C, comprising: The compound of formula A and the compound of formula B are mixed with an organic solvent, and under the catalytic action of a copper salt, a base and a ligand L, a compound of formula C is obtained; Said R1, R2 and Ar are as defined in any one of claims 1 to 4, wherein when one of said R1 and R2 is methyl, the other is not cyclohexane; The ligand L is any one of L5 to L14; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

7. The method for synthesizing the dialkyl-substituted α-chiral primary amine compound represented by formula C according to claim 6, characterized in that: The catalytic reaction is carried out under light irradiation of 350-400nm.

8. A method for synthesizing a dialkyl-substituted α-chiral primary amine compound represented by formula C according to any one of claims 6 or 7, characterized in that ,, the copper salt is selected from any one of CuI, CuBr, CuCl, CuOAc, copper trifluoromethanesulfonate, copper acetate, cuprous thiophenecarboxylate, copper hexafluoroacetylacetonate or other monovalent or divalent copper, and / or, the organic solvent is selected from one or more of ether, isopropyl ether, tert-butyl methyl ether, butyl ether, toluene, trifluorotoluene, chlorobenzene, xylene, n-pentane, n-hexane, n-heptane, and cyclohexane, and / or, the reaction temperature is -78 to 0°C.

9. A method for deprotecting a dialkyl-substituted α-chiral primary amine compound of formula C to obtain a compound of formula D, comprising: The compound of formula C is placed in an organic solvent, the temperature is controlled, and magnesium is added to obtain a compound of formula D; Said R1, R2 and Ar are as defined in any one of claims 1 to 4; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

10. The method according to claim 9, characterized in that: The organic solvent is selected from one or more of tetrahydrofuran, ether, methyl tert-butyl ether, dichloromethane, toluene, tert-butyl ether and methanol, and the temperature of the temperature control is -5 to 0°C.

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