A method for asymmetric alkylation of saturated heterocycles based on hydrogen atom transfer

Abstract

The application provides a method for realizing asymmetric alkylation of saturated heterocycle based on hydrogen atom transfer, and belongs to the technical field of organic synthesis. The method comprises the following steps: under the condition of inert gas atmosphere, reacting materials including olefin, heterocyclic compound, metal nickel catalyst, ligand, oxidant, silane compound and alkali at 0-20 DEG C to obtain chiral heterocyclic alkane with heteroatom alpha position alkyl substitution. The method is simple in operation, good in functional group tolerance, and wide in applicable substrate range, and is a high-efficiency, green and low-cost method for synthesizing chiral heterocyclic compounds.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for achieving asymmetric alkylation of saturated heterocycles based on hydrogen atom transfer. Background Technology

[0002] Chiral saturated heterocycles (including nitrogen heterocycles and oxygen heterocycles) are ubiquitous in natural products and active pharmaceutical molecules. They are commonly used and important molecular skeletons in medicinal chemistry. A considerable number of FDA (Food and Drug Administration) approved drugs contain nitrogen heterocycles and oxygen heterocycles. Developing a simple and direct method to synthesize chiral saturated heterocycles has always been one of the major challenges in organic synthesis.

[0003] Saturated nitrogen or oxygen heterocycles (pyrrolidine, piperidine, tetrahydrofuran, etc.) are inexpensive and readily available, and can be obtained through C(sp... 3 The conversion of these compounds into high-value chiral saturated heterocyclic compounds via alkylation (H-H) has attracted significant interest from both academia and industry. Due to the inherent atom and step economies of this strategy, as well as the abundance of starting materials, this chemical transformation is undoubtedly a revolutionary method.

[0004] Currently, enantioselective saturated nitrogen heterocyclic C(sp) 3 Only one case of α-H alkylation has been reported. This reaction is subject to stringent conditions, requiring prior lithiation-zinc metallization at the α-position of the saturated nitrogen heterocycle, followed by Negishi asymmetric cross-coupling with an alkyl halide. Furthermore, the enantioselectivity of the reaction decreases sharply when the primary alkyl halide is used as the coupling component. Meanwhile, the α-H alkylation of the oxygen heterocycle without a directing group... 3 The )-H alkylation reaction has not been reported.

[0005] To solve the aforementioned chemical problems and challenges, researchers urgently need to develop a method to achieve asymmetric C(sp)2O3 from inexpensive saturated heterocyclic hydrocarbons. 3 The method of alkylation with H-H has the advantages of mild reaction conditions, high yield, good optical purity and simple operation, thus meeting the needs of scientific research and industrial production. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer (HAT). Using inexpensive and readily prepared olefin A and heterocyclic compound B as reaction substrates, an oxygen free radical generated by a single-electron oxidant is used to capture a hydrogen atom at the α-position of the heteroatom in heterocyclic compound B, thereby generating a corresponding free radical at the α-position of the heteroatom. Simultaneously, the alkyl-nickel complex formed after the insertion of olefin A into the nickel catalyst combines with the heterocyclic alkane free radical generated during HAT, followed by reductive elimination to obtain a chiral heterocyclic alkane C with alkyl substitution at the α-position of the heteroatom. Through subsequent transformations, this chiral heterocyclic alkane C can be further derivatized to achieve the synthesis of various natural products or active pharmaceutical molecules.

[0007] To achieve the above objectives, the specific technical solution of the present invention is as follows:

[0008] A method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer includes the following steps: under an inert gas atmosphere, materials including olefin A, heterocyclic compound B, nickel catalyst, ligand L, oxidant D, silane compound E, and base are reacted at 0~20 °C to obtain chiral heterocyclic alkane C with heteroatom α-alkyl substitution.

[0009] Furthermore, the olefin A is selected from one of the following structures:

[0010]

[0011]

[0012]

[0013] Furthermore, the heterocyclic compound B is selected from one of the following structures:

[0014]

[0015] Furthermore, the nickel catalyst is selected from one of nickel chloride, nickel bromide, nickel chloride ethylene glycol dimethyl ether, nickel bromide ethylene glycol dimethyl ether, cyclooctadiene nickel, nickel acetylacetone, nickel perchlorate, nickel iodide, and nickel acetate tetrahydrate.

[0016] Furthermore, the nickel catalyst is nickel bromide ethylene glycol dimethyl ether.

[0017] Furthermore, the ligand L is selected from one of the following structures:

[0018]

[0019] Furthermore, the ligand is (4S,4'S)-4,4',5,5'-tetrahydro-4,4'-diphenyl-2,2'-bisoxazole (L1), (4R,4'R)-4,4'-bis(3,5-di-tert-butylphenyl)-4,4',5,5'-tetrahydro-2,2'-bisoxazole (L2), or (4R,4'R)-2,2'-(1-propenyl-2,2-diyl)bis(4,5,5-triphenyl-2,2'-bisoxazole. (4R,4'R)-2,2'-(1-(4-(tert-butyl)phenyl)propyl-2,2-diyl)bis(4,5,5-triphenyl-4,5-dihydrooxazole) (L4) or (4S,4'S)-2,2'-(1-(4-(tert-butyl)phenyl)propyl-2,2-diyl)bis(4,5,5-triphenyl-4,5-dihydrooxazole) (L5).

[0020] Furthermore, the oxidant D is selected from one of the following structures:

[0021]

[0022] Furthermore, the oxidant is tert-butyl peroxide (D1) or dicumyl peroxide (D2).

[0023] Furthermore, the silane E is selected from one of the following structures:

[0024]

[0025] Furthermore, the silane is trimethoxysilane (E1), triethoxysilane (E2), methyldiethoxysilane (E4), polymethylsiloxane (E7), or methyldimethoxysilane (E8).

[0026] Furthermore, the alkali includes, but is not limited to, one of sodium carbonate, potassium carbonate, potassium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium bicarbonate, sodium bicarbonate, lithium carbonate, cesium carbonate, sodium phosphate, and sodium acetate.

[0027] Furthermore, the alkali is potassium bicarbonate, potassium phosphate, or cesium carbonate.

[0028] Furthermore, the molar ratio of the olefin A, heterocyclic compound B, nickel catalyst, ligand L, oxidant D, silane compound E, and base is 1:(5~150):(0.15~0.2):0.2:(3~10):(3~10):1.

[0029] Furthermore, the material also includes additives selected from one of zinc powder, manganese powder, magnesium powder, pinacol diboronate, tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium iodide.

[0030] Furthermore, the additive is zinc powder, pinacol diboronate, or tetrabutylammonium iodide.

[0031] Furthermore, the molar ratio of olefin A to additive is 1:(1~2).

[0032] Furthermore, the reaction is carried out in a solvent, or the reaction does not require the addition of a solvent.

[0033] Furthermore, when the reaction is carried out in a solvent, the solvent includes, but is not limited to, a mixture of one or more of ethyl acetate, trifluorotoluene, and acetone; the concentration of olefin A in the solvent is 0.05~2 mol / L.

[0034] Compared with the prior art, the advantages of the present invention are:

[0035] This invention provides a strategy for the asymmetric alkylation of saturated heterocycles based on hydrogen atom transfer. It uses a series of readily available olefins A and heterocyclic compounds B as reaction substrates to prepare chiral heterocyclic compounds with ortho-alkyl substitutions of heteroatoms. This method avoids the use of precious metal catalysts and expensive photosensitizers, significantly reducing synthesis costs. Furthermore, the method of this invention features mild reaction conditions, good functional group tolerance, and a wide range of applicable substrates. It offers advantages such as low cost, high atom utilization, and economical steps, making it an efficient, green, and inexpensive method for synthesizing chiral heterocyclic compounds. Detailed Implementation

[0036] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0037] This invention provides a method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer, comprising the following steps: under an inert gas atmosphere, reacting materials including olefin A, heterocyclic compound B, nickel catalyst, ligand L, oxidant D, silane compound E, and base at 0~20 °C to obtain chiral heterocyclic alkane C with heteroatom α-alkyl substitution.

[0038] In some examples, the olefin A is selected from one of the following structures:

[0039]

[0040]

[0041]

[0042] In some examples, the heterocyclic compound B is selected from one of the following structures:

[0043]

[0044] In some examples, the metallic nickel catalyst is selected from one of nickel chloride, nickel bromide, nickel chloride ethylene glycol dimethyl ether, nickel bromide ethylene glycol dimethyl ether, cyclooctadiene nickel, nickel acetylacetone, nickel perchlorate, nickel iodide, and nickel acetate tetrahydrate.

[0045] In some examples, the ligand L is selected from one of the following structures:

[0046]

[0047] In some examples, the oxidant D is selected from one of the following structures:

[0048]

[0049] In some examples, the silane E is selected from one of the following structures:

[0050]

[0051] In some examples, the alkali includes, but is not limited to, one of sodium carbonate, potassium carbonate, potassium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium bicarbonate, sodium bicarbonate, lithium carbonate, cesium carbonate, sodium phosphate, and sodium acetate.

[0052] In some examples, the molar ratio of olefin A, heterocyclic compound B, nickel catalyst, ligand L, oxidant D, silane compound E, and base is 1:(5~150):(0.15~0.2):0.2:(3~10):(3~10):1.

[0053] In some examples, the material also includes additives selected from one of zinc powder, manganese powder, magnesium powder, pinacol diboronate, tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium iodide.

[0054] In some examples, the molar ratio of olefin A to additive is 1:(1~2).

[0055] In some examples, the reaction is carried out in a solvent, or the reaction does not require the addition of a solvent; when the reaction is carried out in a solvent, the solvent includes, but is not limited to, a mixture of one or more of ethyl acetate, trifluorotoluene, and acetone; the concentration of olefin A in the solvent is 0.05~2 mol / L.

[0056] In the following specific embodiments, unless otherwise specified, all materials and reagents used are obtained through conventional purchase.

[0057] Example 1

[0058]

[0059] Preparation of Compound 1: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (38 μL, 0.3 mmol), and anhydrous ethyl acetate (0.05 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A1 (24.9 mg, 0.1 mmol), nitrogen-containing heterocyclic compound B1 (86.8 mg, 0.5 mmol), dicumyl peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium bicarbonate (10.0 mg, 0.1 mmol), and zinc powder (13.3 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A1 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (2 / 1) as the eluent to give anhydrous oily product 1 (25.9 mg, 61% yield, 97% ee).

[0060] 1 H NMR (600 MHz, CDCl3) (75:25 mixture of rotamers) δ 8.11 (d, J = 7.7Hz, 2.00H), 7.55 - 7.44 (m, 4.00H), 7.44 - 7.29 (m, 5.00H), 7.23 (t, J = 7.3Hz, 2.00H), 4.31 (t, J= 7.2 Hz, 1.50H), 4.27 - 4.14 (m, 1.25H), 3.84 - 3.77(m, 0.25H), 3.77 - 3.71 (m, 0.25H), 3.61 - 3.52 (m, 0.25H), 3.46 - 3.34 (m,1.50H), 2.11 - 2.02 (m, 1.00H), 2.02 - 1.95 (m, 1.00H), 1.94 - 1.86 (m,2.00H), 1.84 - 1.76 (m, 1.00H), 1.75 - 1.64 (m, 2.00H), 1.64 - 1.55 (m,1.00H), 1.47 - 1.32 (m, 4.00H), 1.23 - 1.10 (m, 1.00H), 1.04 - 0.79 (m,1.00H). 13 C NMR (151 MHz, CDCl3) δ 169.8, 140.4, 137.5, 129.8, 128.1, 127.3,126.4, 125.5, 122.7, 120.2, 118.6, 108.6, 60.4, 57.2, 50.1, 43.0, 33.6, 31.7,30.2, 29.3, 28.8, 27.2, 25.7, 25.0. HRMS: (ESI) calcd for C 29 H 33 N2O + [M+H] + 425.2587; found 425.2584.

[0061] Example 2

[0062]

[0063] Preparation of Compound 2: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (77 μL, 0.6 mmol), and anhydrous ethyl acetate (0.2 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A3 (15 mg, 0.1 mmol), nitrogen heterocyclic B1 (86.8 mg, 0.5 mmol), di-tert-butyl peroxide D1 (111 μL, 0.6 mmol), anhydrous potassium phosphate (10.0 mg, 0.1 mmol), and pinacol diboronate (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A3 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (2 / 1) as the eluent to give anhydrous oily product 2 (15.3 mg, 47% yield, 99% ee).

[0064] 1 H NMR (600 MHz, CDCl3) (70:30 mixture of rotamers) δ 7.54 - 7.47 (m,1.50H), 7.44 - 7.34 (m, 3.50H), 7.29 (s, 1.00H), 6.27 (s, 1.00H), 6.01 - 5.89(m, 1.00H), 4.32 - 4.19 (m, 0.70H), 3.89 - 3.80 (m, 0.30H), 3.80 - 3.71 (m, 0.30H), 3.63 - 3.58 (m, 0.30H), 3.48 - 3.35 (m, 1.40H), 2.61 (t, J = 7.5 Hz, 1.40H), 2.52 (t, J = 7.8 Hz, 0.60H), 2.15 - 2.04 (m, 1.25H), 2.04 - 1.91 (m,1.75H), 1.92 - 1.80 (m, 1.00H), 1.76 - 1.58 (m, 3.00H), 1.50 - 1.29 (m,5.00H), 1.22 - 1.07 (m, 1.00H), 1.05 - 0.80 (m, 1.00H). 13C NMR (151 MHz, CDCl3) δ 169.8, 156.5, 140.6, 137.5, 129.7, 128.3, 128.1, 127.3, 110.0,104.5, 57.4, 50.1, 33.7, 31.2, 30.3, 29.4, 29.1, 28.0, 27.9, 25.8, 25.1.HRMS: (ESI) calcd for C 21 H 28 NO2 + [M+H] + 326.2115; found 326.2109.

[0065] Example 3

[0066]

[0067] Preparation of Compound 3: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (38 μL, 0.3 mmol), and anhydrous ethyl acetate (0.05 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A6 (13.2 mg, 0.1 mmol), nitrogen-containing heterocyclic B1 (86.8 mg, 0.5 mmol), dicumyl peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol), and pinacol diboronate (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A6 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (4 / 1) as the eluent to give anhydrous oily product 3 (18.4 mg, 60% yield, 95% ee).

[0068] 1 H NMR (600 MHz, CDCl3) (75:25 mixture of rotamers) δ 7.56 - 7.45 (m,1.50H), 7.43 - 7.29 (m, 5.5H), 7.06 (d, J= 7.9 Hz, 1.50H), 6.95 - 6.85 (m, 0.50H), 4.34 - 4.20 (m, 0.75H), 4.08 - 3.80 (m, 0.25H), 3.80 - 3.66 (m, 0.25H), 3.65 - 3.57 (m, 0.25H), 3.48 - 3.28 (m, 1.50H), 2.60 (t, J = 8.1 Hz, 1.50H), 2.43 - 2.20 (m, 0.50H), 2.15 - 1.92 (m, 2.00H), 1.90 - 1.81 (m, 1.00H), 1.78 - 1.54 (m, 4.00H), 1.50 - 1.33 (m, 2.00H), 1.31 - 1.17 (m, 1.00H). 13 13C NMR (151 MHz, CDCl3) δ 169.9, 141.5, 137.4, 131.2, 130.2, 129.8, 128.2, 127.3, 124.3, 119.3, 57.2, 50.1, 35.1, 33.3, 31.1, 30.2, 25.2, 25.1. HRMS: (ESI) calcd for C 21 H 25 BrNO + [M+H] + 386.1114; found 386.111.

[0069] Example 4

[0070]

[0071] Preparation of Compound 4: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (38 μL, 0.3 mmol), and anhydrous ethyl acetate (0.05 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A7 (21.1 mg, 0.1 mmol), nitrogen-containing heterocyclic B1 (86.8 mg, 0.5 mmol), dicumyl peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol), and pinacol diboronate (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A7 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (4 / 1) as the eluent to give anhydrous oily product 4 (22.0 mg, 57% yield, 98% ee).

[0072] 1 H NMR (600 MHz, CDCl3) (75:25 mixture of rotamers) δ 7.56 – 7.45 (m,1.50H), 7.43 – 7.29 (m, 5.5H), 7.06 (d, J = 7.9 Hz, 1.50H), 6.95 – 6.85 (m,0.50H), 4.34 – 4.20 (m, 0.75H), 4.08 – 3.80 (m, 0.25H), 3.80 – 3.66 (m,0.25H), 3.65 – 3.57 (m, 0.25H), 3.48 – 3.28 (m, 1.50H), 2.60 (t, J = 8.1 Hz,1.50H), 2.43 – 2.20 (m, 0.50H), 2.15 – 1.92 (m, 2.00H), 1.90 – 1.81 (m,1.00H), 1.78 – 1.54 (m, 4.00H), 1.50 – 1.33 (m, 2.00H), 1.31 – 1.17 (m,1.00H). 13C NMR (151 MHz, CDCl3) δ 169.9, 141.5, 137.4, 131.2, 130.2, 129.8,128.2, 127.3, 124.3, 119.3, 57.2, 50.1, 35.1, 33.3, 31.1, 30.2, 25.2, 25.1.HRMS: (ESI) calcd for C 21 H 25 BrNO + [M+H] + 386.1114; found 386.1111.

[0073] Example 5

[0074]

[0075] Preparation of Compound 5: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (38 μL, 0.3 mmol), and anhydrous ethyl acetate (0.05 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A8 (16.6 mg, 0.1 mmol), nitrogen-containing heterocyclic compound B1 (86.8 mg, 0.5 mmol), dicumyl peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol), and pinacol diboronate (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A8 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (4 / 1) as the eluent to give anhydrous oily product 5 (20.1 mg, 59% yield, 98% ee).

[0076] 1 H NMR (600 MHz, CDCl3) (75:25 mixture of rotamers) δ 7.48 (d, J = 7.1Hz, 1.50H), 7.42 – 7.33 (m, 3.50H), 7.25 – 7.17 (m, 2.00H), 7.11 (d, J= 7.9Hz, 1.50H), 7.00 – 6.88 (m, 0.50H), 4.34 – 4.16 (m, 0.75H), 4.07 – 3.81 (m,0.25H), 3.80 – 3.69 (m, 0.25H), 3.63 – 3.48 (m, 0.25H), 3.48 – 3.27 (m,1.50H), 2.60 (q, J = 7.7 Hz, 1.50H), 2.42 – 2.25 (m, 0.50H), 2.18 – 1.98 (m,2.00H), 1.95 – 1.79 (m, 1.00H), 1.77 – 1.54 (m, 4.00H), 1.53 – 1.31 (m,2.00H), 1.30 – 1.20 (m, 1.00H). 13 13C NMR (151 MHz, CDCl3) δ 169.9, 141.0, 137.5,131.2, 129.80, 129.77, 128.4, 128.3, 128.2, 127.3, 57.2, 50.2, 35.1, 33.4,31.2, 30.3, 25.2, 25.1. HRMS: (ESI) calcd for C 21 H 25 ClNO + [M+H] + 342.1619; found 342.1613.

[0077] Example 6

[0078]

[0079] Preparation of Compound 6: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (38 μL, 0.3 mmol), and anhydrous ethyl acetate (0.05 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A10 (28.6 mg, 0.1 mmol), nitrogen-containing heterocyclic compound B1 (86.8 mg, 0.5 mmol), dicumyl peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium bicarbonate (10.0 mg, 0.1 mmol), and pinacol diboronate (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A10 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (4 / 1) as the eluent to give anhydrous oily product 6 (21.7 mg, 47% yield, 94% ee).

[0080] 1 H NMR (600 MHz, CDCl3) (70:30 mixture of rotamers) δ 7.54 (d, J = 7.1Hz, 4.00H), 7.49 (d, J = 6.9 Hz, 1.50H), 7.43 – 7.32 (m, 13.00H), 7.31 – 7.27(m, 1.50H), 4.42 – 4.29 (m, 0.70H), 3.91 – 3.80 (m, 0.30H), 3.79 – 3.69 (m,0.30H), 3.62 – 3.46 (m, 0.30H), 3.43 – 3.30 (m, 1.40H), 2.25 – 2.08 (m,1.40H), 2.07 – 1.97 (m, 0.60H), 1.96 – 1.75 (m, 2.00H), 1.74 – 1.59 (m,2.00H), 1.55 – 1.44 (m, 1.00H), 1.44 – 1.28 (m, 1.00H). 13C NMR (151 MHz, CDCl3) δ 170.0, 137.4, 135.6, 135.4, 134.9, 134.4, 129.8, 129.5, 129.4,128.3, 128.1, 127.9, 127.4, 126.3, 59.6, 50.4, 29.8, 27.8, 25.0, 9.1. HRMS:(ESI) calcd for C 31 H 32 NOSi + [M+H] + 462.2248; found 462.2240.

[0081] Example 7

[0082]

[0083] Preparation of Compound 7: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L3 (14.3 mg, 0.02 mmol), trimethoxysilane E1 (38 μL, 0.3 mmol), and anhydrous ethyl acetate (0.05 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A11 (22.6 mg, 0.1 mmol), nitrogen heterocyclic B1 (86.8 mg, 0.5 mmol), dicumyl peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol), and zinc powder (13.3 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A11 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (4 / 1) as the eluent to give anhydrous oily product 7 (24.1 mg, 60% yield, 96% ee).

[0084] 1H NMR (600 MHz, CDCl3) (70:30 mixture of rotamers) δ 7.55 - 7.46 (m,1.50H), 7.44 - 7.29 (m, 3.50H), 7.02 - 6.67 (m, 3.00H), 4.34 - 4.20 (m,0.70H), 4.17 - 4.08 (m, 1.40H), 4.08 - 3.93 (m, 0.60H), 3.93 - 3.77 (m,0.30H), 3.80 - 3.68 (m, 0.30H), 3.63 - 3.53 (m, 0.30H), 3.52 - 3.36 (m,1.40H), 2.13 - 2.06 (m, 1.00H), 2.05 - 1.98 (m, 1.00H), 1.98 - 1.91 (m,1.00H), 1.90 - 1.82 (m, 1.00H), 1.81 - 1.57 (m, 4.00H), 1.54 - 1.35 (m,4.00H), 1.29 - 1.16 (m, 1.00H), 1.12 - 0.91 (m, 1.00H). 13 C NMR (151 MHz,CDCl3) δ 169.8, 156.31 (d, J = 247.6 Hz), 156.28 (d, J = 249.2 Hz), 137.5, 129.7,129.2, 128.3, 128.1, 127.3, 126.5, 122.5, 112.1 (d, J = 4.5 Hz), 112.0 (d, J =6.0 Hz), 74.7, 57.3, 50.1, 33.7, 30.3, 29.9, 29.3, 25.8, 25.6, 25.1. 19 F NMR(565 MHz, CDCl3) δ -128.29 (t, J = 6.3 Hz), -128.39 (t, J = 7.0 Hz). HRMS: (ESI)calcd for C 23 H 28 F2NO2 + [M+H] + 388.2083; found 388.2072.

[0085] Example 8

[0086]

[0087] Preparation of Compound 8: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (38 μL, 0.3 mmol), and anhydrous ethyl acetate (0.05 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A14 (24.9 mg, 0.1 mmol), nitrogen-containing heterocyclic B1 (86.8 mg, 0.5 mmol), dicumyl peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium bicarbonate (10.0 mg, 0.1 mmol), and zinc powder (13.3 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the starting material A14 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated, and a tetrahydrofuran (1 mL) solution of tetrabutylammonium fluoride (100 μL, 0.1 mmol) was added to the mixture until the silanyl protecting group was removed. The mixture was then purified by silica gel column chromatography with ethyl acetate as the eluent to give anhydrous oily product 8 (16.4 mg, 63% yield, 89% ee).

[0088] 1 H NMR (600 MHz, CDCl3) (75:25 mixture of rotamers) δ 7.54 – 7.43 (m,1.67H), 7.42 – 7.31 (m, 3.33H), 4.34 – 4.22 (m, 0.75H), 3.85 (s, 0.25H), 3.79– 3.69 (m, 0.27H), 3.67 – 3.56 (m, 1.73H), 3.49 – 3.34 (m, 2.00H), 2.14 – 2.05 (m, 1.00H), 2.04 – 1.96 (m, 1.00H), 1.96 – 1.90 (m, 1.00H), 1.89 – 1.83(m, 1.00H), 1.75 – 1.62 (m, 2.00H), 1.61 – 1.54 (m, 1.00H), 1.50 – 1.27 (m, 5.00H), 1.12 – 0.90 (m, 1.00H). 13C NMR (151 MHz, CDCl3) δ 170.0, 137.4, 129.8,128.1, 127.3, 62.7, 57.1, 50.1, 33.7, 32.6, 30.3, 25.55, 25.47, 25.1. HRMS: (ESI) calcd for C 16 H 24 NO2 + [M+H] + 262.1802; found 262.1800.

[0089] Example 9

[0090]

[0091] Preparation of Compound 9: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (77 μL, 0.6 mmol), and anhydrous ethyl acetate (0.2 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A17 (11.8 mg, 0.1 mmol), nitrogen heterocyclic B1 (86.8 mg, 0.5 mmol), di-tert-butyl peroxide D1 (111 μL, 0.6 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol), and pinacol diboronate (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A3 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (4 / 1) as the eluent to give anhydrous oily product 9 (15.5 mg, 53% yield, 99% ee).

[0092] 1 H NMR (600 MHz, CDCl3) (75:25 mixture of rotamers) δ 7.54 – 7.48 (m,1.50H), 7.46 – 7.33 (m, 3.50H), 4.30 – 4.22 (m, 0.75H), 3.91 – 3.81 (m,0.25H), 3.81 – 3.72 (m, 0.25H), 3.67 – 3.57 (m, 0.25H), 3.54 (t, J= 6.8 Hz,1.50H), 3.48 – 3.36 (m, 2.00H), 2.14 – 2.06 (m, 0.75H), 2.06 – 1.93 (m,1.50H), 1.92 – 1.84 (m, 0.75H), 1.78 (p, J = 7.0 Hz, 11.75H), 1.75 – 1.66 (m,1.75H), 1.52 – 1.43 (m, 2.00H), 1.43 – 1.34 (m, 3.00H), 1.25 – 1.12 (m,1.00H), 1.12 – 0.92 (m, 1.00H). 13 C NMR (151 MHz, CDCl3) δ 169.9, 137.5,129.8, 128.2, 127.3, 57.3, 50.1, 45.2, 33.7, 32.6, 30.3, 28.9, 26.9, 25.7,25.1. HRMS: (ESI) calcd for C 17 H 25 ClNO + [M+H] + 294.1619; found 294.1614.

[0093] Example 10

[0094]

[0095] Preparation of Compound 10: Nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L3 (14.3 mg, 0.02 mmol), and trimethoxysilane E1 (128 μL, 1 mmol) were added to a transparent reaction tube equipped with a magnetic stir bar under an argon atmosphere. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A19 (21.0 mg, 0.1 mmol), nitrogen heterocyclic B1 (86.8 mg, 0.5 mmol), di-tert-butyl peroxide D1 (186 μL, 1 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol), and zinc powder (13.3 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A19 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (2 / 1) as the eluent to give anhydrous oily product 10 (15.4 mg, 40% yield, 94% ee).

[0096] 1 H NMR (600 MHz, CDCl3) (75:25 mixture of rotamers) δ 7.50 (d, J J = 6.6 Hz, 1.50 H), 7.45 - 7.33 (m, 3.50 H), 4.34 - 4.14 (m, 0.75 H), 3.88 - 3.80 (m, 0.25 H), 3.78 - 3.71 (m, 0.25 H), 3.52 - 3.45 (m, 0.25 H), 3.45 - 3.32 (m, 1.50 H), 2.26 - 2.04 (m, 1.25 H), 2.04 - 1.92 (m, 1.75 H), 1.90 - 1.83 (m, 0.75 H), 1.82 - 1.62 (m, 2.25 H), 1.49 - 1.37 (m, 2.0 H), 1.37 - 1.28 (m, 5.00 H), 1.24 (s, 12.00 H), 1.04 (d, J J = 28.1 Hz, 1.00 H), 0.97 - 0.85 (m, 1.00 H), 0.82 - 0.66 (m, 1.00 H). 13 13C NMR (151 MHz, CDCl3) δ 169.8, 129.7, 128.1, 127.3, 126.5, 82.8, 57.5, 50.1, 33.8, 32.5, 30.3, 29.5, 25.9, 25.1, 24.8, 24.0. HRMS: (ESI) calcd for C 27 22 H 31 37 BNO3 + [M+H]+ + 386.2861; found 386.2848.

[0097] Example 11

[0098]

[0099] Preparation of Compound 11: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (38 μL, 0.3 mmol), and ethyl acetate (1 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A1 (24.9 mg, 0.1 mmol), tetrahydrofuran B9 (1 mL), di-tert-butylperoxide D1 (186 μL, 1 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol), and tetrabutylammonium iodide (36.9 mg, 0.1 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A1 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (20 / 1) as the eluent to give anhydrous oily product 11 (19.6 mg, 61% yield, 97% ee).

[0100] 1 H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 7.7 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.23 (t, J = 7.4 Hz, 2H), 4.30 (t, J = 7.3 Hz, 2H), 3.84 (q, J = 7.3 Hz, 1H), 3.77 - 3.65 (m, 2H), 1.97 - 1.91 (m, 1H), 1.91 - 1.78(m, 4H), 1.57 - 1.49 (m, 1H), 1.45 - 1.33 (m, 7H), 1.33 - 1.27 (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 140.4, 125.5, 122.8, 120.3, 118.6, 108.6, 79.3, 67.6, 43.0, 35.6, 31.3, 29.5, 28.9, 27.3, 26.2, 25.7. HRMS: (ESI) calcd for C 22 H 28 NO + [M+H] +322.2165; found 322.2164.

[0101] Example 12

[0102]

[0103] Preparation of Compound 12: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (38 μL, 0.3 mmol), and ethyl acetate (1 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A1 (24.9 mg, 0.1 mmol), oxonium B11 (260.3 mg, 2.0 mmol), di-tert-butylperoxide D1 (186 μL, 1 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol), and tetrabutylammonium iodide (36.9 mg, 0.1 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A1 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (20 / 1) as the eluent to give anhydrous oily product 12 (15.5 mg, 41% yield, >20 / 1 dr).

[0104] 1 H NMR (600 MHz, CDCl3) δ 8.13 - 8.04 (m, 2H), 7.50 - 7.43 (m, 2H), 7.43 - 7.38 (m, 2H), 7.26 - 7.18 (m, 2H), 4.50 (t, J = 6.7 Hz, 1H), 4.30 (dq, J =7.3, 4.0 Hz, 2H), 4.10 (q, J = 6.5 Hz, 1H), 3.73 (s, 3H), 2.32 - 2.19 (m, 1H), 2.05 - 1.94 (m, 2H), 1.87 (q, J = 7.0 Hz, 2H), 1.51 - 1.44 (m, 1H), 1.44 - 1.25 (m, 8H). 13C NMR (151 MHz, CDCl3) δ 174.1, 140.4, 125.5, 122.8, 120.3, 118.7,108.6, 80.6, 76.5, 52.0, 43.0, 35.3, 30.9, 30.1, 29.4, 28.9, 27.2, 25.8.HRMS: (ESI) calcd for C 24 H 30 NO3 + [M+H] + 380.2220; found 380.2213.

[0105] Example 13

[0106]

[0107] Preparation of Compound 13: Nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L5 (15.5 mg, 0.02 mmol), silane E8 (123 μL, 1 mmol), and ethyl acetate (1 mL) were added to a transparent reaction tube equipped with a magnetic stir bar under an argon atmosphere. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A1 (24.9 mg, 0.1 mmol), oxonium B15 (0.5 mL), di-tert-butyl peroxide D1 (186 μL, 1 mmol), anhydrous potassium bicarbonate (10 mg, 0.1 mmol), and pinacol diboronate (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A1 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (20 / 1) as the eluent to give anhydrous oily product 13 (22.6 mg, 62% yield, 97% ee).

[0108] 1 H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 7.7 Hz, 2H), 7.46 (td, J = 7.6,7.0, 1.2 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.23 (t, J = 7.4 Hz, 2H), 4.30 (t, J =7.2 Hz, 2H), 3.93 (td, J= 12.1, 2.9 Hz, 1H), 3.84 - 3.74 (m, 2H), 1.88 (p, J =7.3 Hz, 2H), 1.56 - 1.44 (m, 2H), 1.42 (s, 3H), 1.41 - 1.38 (m, 2H), 1.37 (s,3H), 1.36 - 1.29 (m, 5H), 1.29 - 1.25 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ140.4, 125.5, 122.8, 120.3, 118.7, 108.6, 98.1, 68.8, 60.0, 43.0, 36.4, 31.2,30.0, 29.4, 28.9, 27.2, 24.7, 19.2. HRMS: (ESI) calcd for C 24 H 32 NO2 + [M+H] + 366.2428; found 366.2431.

[0109] Example 14

[0110]

[0111] Preparation of Compound 14: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (4.7 mg, 0.015 mmol), ligand L4 (15.5 mg, 0.02 mmol), trimethoxysilane E1 (38 μL, 0.3 mmol), and anhydrous ethyl acetate (0.05 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A1 (24.9 mg, 0.1 mmol), nitrogen-containing heterocyclic compound B1 (86.8 mg, 0.5 mmol), dicumyl peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium bicarbonate (10.0 mg, 0.1 mmol), and zinc powder (13.3 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A34 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (5 / 1) as the eluent to give anhydrous oily product 14 (28.9 mg, 55% yield, dr>20 / 1).

[0112] 1H NMR (600 MHz, CDCl3) (70:30 mixture of rotamers) δ 7.53 – 7.49 (m,1.50H), 7.44 – 7.36 (m, 3.50H), 7.23 – 7.15 (m, 1.00H), 6.74 – 6.68 (m,1.00H), 6.67 – 6.60 (m, 1.00H), 4.29 – 4.24 (m, 0.70H), 3.95 – 3.90 (m,1.50H), 3.87 – 3.83 (m, 0.50H), 3.79 – 3.74 (m, 0.30H), 3.62 – 3.53 (m,0.40H), 3.47 – 3.37 (m, 1.60H), 2.94 – 2.85 (m, 2.00H), 2.52 – 2.47 (m,1.00H), 2.41 – 2.36 (m, 1.00H), 2.27 – 2.23 (m, 1.00H), 2.17 – 1.94 (m,7.00H), 1.90 – 1.85 (m, 1.00H), 1.80 – 1.70 (m, 3.00H), 1.66 – 1.57 (m,3.00H), 1.53 – 1.47 (m, 4.00H), 1.46 – 1.39 (m, 4.00H), 1.27 – 1.19 (m,1.24H), 1.13 – 1.03 (m, 0.76H), 0.93 (s, 0.45H), 0.91 (s, 2.55H). 13 C NMR (151MHz, CDCl3) δ 221.0, 169.9, 157.2, 137.7, 137.6, 131.8, 129.8, 128.2, 127.3,126.5, 126.3, 114.6, 112.2, 67.9, 57.4, 50.4, 50.2, 48.0, 44.0, 38.4, 35.9,33.7, 31.6, 30.3, 29.7, 29.4, 29.3, 26.6, 26.1, 26.0, 25.9, 25.7, 25.2, 21.6,13.9. HRMS: (ESI) calcd for C 35 H 46 NO3 + [M+H] +528.3472; found 528.3470.

[0113] Example 15

[0114]

[0115] Preparation of Compound 15: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (6.1 mg, 0.02 mmol), ligand L1 (5.8 mg, 0.02 mmol), silane E7 (40 μL, 0.5 mmol), and ethyl acetate (2 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A48 (32.4 mg, 0.1 mmol), nitrogen heterocyclic B1 (87.6 mg, 0.5 mmol), di-tert-butyl peroxide D1 (54 μL, 0.3 mmol), and anhydrous cesium carbonate (32.6 mg, 0.1 mmol) were added. The reaction mixture was stirred at 20 °C until the raw material A48 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as the eluent to give anhydrous oily product 15 (28.0 mg, 56% yield, 93% ee, 92 / 8 d.r.).

[0116] 1 H NMR (600 MHz, CDCl3) (85:15 mixture of rotamers) δ 7.78 - 7.66 (m,3.00H), 7.58 - 7.50 (m, 2.00H), 7.44 - 7.34 (m, 4.00H), 7.32 - 7.29 (m,1.00H), 7.19 - 7.08 (m, 2.00H), 4.42 (q, J= 7.3 Hz, 0.85H), 4.15 - 4.07 (m, 1.70H), 4.06 - 3.99 (m, 0.30H), 3.96 (s, 0.15H), 3.78 - 3.76 (m, 0.15H), 3.56- 3.49 (m, 0.85H), 3.44 - 3.39 (m, 1.00H), 2.23 - 2.20 (m, 0.15H), 2.17 -2.12 (m, 0.85H), 2.09 - 2.00 (m, 2.00H), 1.97 - 1.91 (m, 1.00H), 1.88 - 1.84 (m, 1.00H), 1.80 - 1.70 (m, 2.00H), 1.69 - 1.62 (m, 2.00H), 1.27 (s, 10.20H), 1.21 (s, 1.80H). 13 13C NMR (151 MHz, CDCl3) δ 168.8, 156.1, 136.6, 133.6, 128.8, 128.2, 127.8, 127.2, 127.0, 126.55, 126.53, 126.1, 125.7, 125.1, 122.3, 118.1, 105.6, 81.9, 67.2, 57.8, 49.7, 29.0, 27.8, 24.3, 24.04, 24.00, 23.7. HRMS: (ESI) calcd for C 31 H 39 BNO4 + [M+H] + 500.2967; found 500.2961.

[0117] Example 16

[0118]

[0119] Preparation of Compound 16: Under an argon atmosphere, nickel bromide ethylene glycol dimethyl ether (6.1 mg, 0.02 mmol), ligand L2 (10.3 mg, 0.02 mmol), silane E7 (40 μL, 0.5 mmol), and ethyl acetate (2 mL) were added to a transparent reaction tube equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A44 (25.8 mg, 0.1 mmol), nitrogen heterocyclic B1 (87.6 mg, 0.5 mmol), di-tert-butyl peroxide D1 (54 μL, 0.3 mmol), and anhydrous cesium carbonate (32.6 mg, 0.1 mmol) were added. The reaction mixture was stirred at 20 °C until the raw material A44 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as the eluent to give anhydrous oily product 16 (19.5 mg, 45% yield, 95% ee, 90 / 10 d.r.).

[0120] 1 H NMR (600 MHz, CDCl3) (85:15 mixture of rotamers) δ 7.57 - 7.47 (m,1.70H), 7.47 - 7.29 (m, 3.30H), 7.28 - 7.26 (m, 1.30H), 7.25 - 7.23 (m,1.00H), 7.22 - 7.12 (m, 2.70H), 4.37 (q, J = 7.3 Hz, 0.85H), 4.01 (s, 0.15H), 3.94 (s, 0.15H), 3.53 - 3.45 (m, 1.00H), 3.43 (s, 0.15H), 3.39 - 3.35 (m, 0.85H), 2.71 - 2.57 (m, 1.70H), 2.24 - 2.20 (m, 0.30H), 2.12 - 2.04 (m,1.00H), 2.01 - 1.98 (m, 1.00H), 1.88 - 1.77 (m, 2.00H), 1.76 - 1.66 (m,2.00H), 1.66 - 1.61 (m, 2.00H), 1.46 - 1.38 (m, 1.00H), 1.26 (s, 10.20H), 1.20 (s, 1.80H). 13C NMR (151 MHz, CDCl3) δ 169.8, 142.9, 137.7, 129.8, 128.5,128.2, 128.0, 127.5, 125.5, 82.9, 58.8, 50.6, 36.1, 30.9, 29.9, 27.9, 25.3,25.05, 25.02. HRMS: (ESI) calcd for C 27 H 37 BNO3 + [M+H] + 434.2861; found 434.2853.

[0121] Example 17

[0122]

[0123] Preparation of Compound 17: Nickel bromide ethylene glycol dimethyl ether (6.1 mg, 0.02 mmol), ligand L2 (10.3 mg, 0.02 mmol), silane E7 (40 μL, 0.5 mmol), and ethyl acetate (2 mL) were added to a transparent reaction tube equipped with a magnetic stir bar under an argon atmosphere. The reaction mixture was stirred at room temperature for 1 h. Then, olefin A48 (32.4 mg, 0.1 mmol), tetrahydrofuran B9 (72.1 mg, 1.0 mmol), di-tert-butyl peroxide D1 (54 μL, 0.3 mmol), and anhydrous cesium carbonate (32.6 mg, 0.1 mmol) were added. The reaction mixture was stirred at 20 °C until the raw material A48 was completely consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as the eluent to give anhydrous oily product 17 (19.8 mg, 50% yield, 92% ee, 75 / 25 d.r.).

[0124] 1H NMR (600 MHz, CDCl3) δ 7.78 - 7.68 (m, 3H), 7.45 - 7.37 (m, 1H), 7.35 - 7.28 (m, 1H), 7.17 - 7.08 (m, 2H), 4.11 - 4.04 (m, 2H), 3.93 - 3.82(m, 2H), 3.73 - 3.66 (m, 1H), 2.01 - 1.95 (m, 1H), 1.92 - 1.82 (m, 4H), 1.71- 1.65 (m, 1H), 1.63 - 1.59 (m, 1H), 1.57 - 1.43 (m, 1H), 1.32 - 1.31 (m,1H), 1.26 - 1.22 (m, 12H). 13 C NMR (151 MHz, CDCl3) δ 157.1, 134.6, 129.9,129.3, 129.25, 129.21, 128.87, 128.85, 127.61, 127.60, 126.7, 126.3, 126.24,126.20, 123.41, 123.37, 119.15, 119.10, 106.6, 83.21, 83.17, 81.4, 80.6,68.2, 68.1, 67.8, 67.3, 67.2, 62.5, 31.1, 30.9, 28.92, 28.89, 25.9, 25.4,24.9, 24.8, 24.73, 24.67. HRMS: (ESI) calcd for C 24 H 34 BO4 + [M+H] + 397.2545; found 397.2544.

[0125] The above detailed embodiments describe the implementation of the present invention; however, the present invention is not limited to the specific details described in the above embodiments. Within the scope of the claims and technical concept of the present invention, various simple modifications and changes can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. A method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer, characterized in that, In an inert gas atmosphere, materials including olefins, heterocyclic compounds, nickel catalysts, ligands, oxidants, silane compounds, and bases are reacted at 0–20 °C to obtain chiral heterocyclic alkanes with heteroatoms α-alkyl substitution. The olefin is selected from one of the following structures: ； ； ； The heterocyclic compound is selected from one of the following structures: ； The metallic nickel catalyst is selected from one of nickel chloride, nickel bromide, nickel chloride ethylene glycol dimethyl ether, nickel bromide ethylene glycol dimethyl ether, nickel acetylacetone, nickel perchlorate, nickel iodide, and nickel acetate tetrahydrate. The ligand is selected from one of the following structures: ； The oxidant is selected from one of the following structures: ； The silane compound is selected from one of the following structures: ； The alkali includes one of sodium carbonate, potassium carbonate, potassium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium bicarbonate, sodium bicarbonate, lithium carbonate, cesium carbonate, sodium phosphate, and sodium acetate.

2. The method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer according to claim 1, characterized in that, The molar ratio of the olefin, heterocyclic compound, nickel catalyst, ligand, oxidant, silane compound, and base is 1:(5~150):(0.15~0.2):0.2:(3~10):(3~10):

1.

3. The method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer according to claim 1, characterized in that, The material also includes additives, which are selected from one of zinc powder, manganese powder, magnesium powder, pinacol diboronate, tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium iodide.

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