Method for realizing asymmetric alkylation of saturated heterocyclic ring based on hydrogen atom transfer

Abstract

The invention provides a method for realizing asymmetric alkylation of a saturated heterocyclic ring based on hydrogen atom transfer, and belongs to the technical field of organic synthesis. In an inert gas atmosphere, materials including olefin, a heterocyclic compound, a metal nickel catalyst, a ligand, an oxidizing agent, a silane compound and alkali react at the temperature of 0-20 DEG C to obtain the chiral heterocyclic alkane with the heteroatom substituted by the alkyl at the alpha position. The reaction substrate involved in the method is simple and easy to obtain, the use of a noble metal catalyst and an expensive photosensitizer is avoided, the synthesis cost is greatly reduced, and the method is simple to operate, good in functional group tolerance and wide in applicable substrate range, and is an efficient, green and low-cost method for synthesizing the chiral heterocyclic compound.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for realizing asymmetric alkylation of saturated heterocycles based on hydrogen atom transfer. Background Art

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

[0003] Saturated nitrogen or oxygen heterocycles (pyrrolidine, piperidine, tetrahydrofuran, etc.) are cheap and readily available. 3 The conversion of these compounds into high value-added chiral saturated heterocyclic compounds through )-H alkylation has attracted great interest from academia and industry. Due to the inherent atom economy and step economy 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 There is only one case report of )-H alkylation, and the reaction conditions are relatively harsh, requiring a lithiation-zinc metalation reaction at the α-position of the saturated nitrogen heterocycle, followed by a Negishi asymmetric cross coupling with an alkyl halide. Moreover, when a primary alkyl halide is used as a coupling component, the enantioselectivity of the reaction drops sharply. 3 )-H alkylation reaction has not been reported.

[0005] In order to solve the above chemical problems and difficulties, researchers urgently need to develop a method to achieve asymmetric C(sp 3 The method has the advantages of mild reaction conditions, high yield, good optical purity and simple operation, thereby meeting the needs of scientific research and industrial production. Summary of the invention

[0006] In view of the deficiencies of the above prior art, the present invention provides a method for realizing asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer, wherein cheap and easily prepared olefin A and heterocyclic compound B are used as reaction substrates, and oxygen free radicals generated by a single-electron oxidant are used to capture the hydrogen atom at the α position of the heteroatom on the heterocyclic compound B, thereby generating corresponding free radicals at the α position of the heteroatom; at the same time, an alkyl nickel complex generated after the metal nickel catalyst is inserted into the olefin A combines with the heterocyclic alkane free radical generated in the hydrogen atom transfer (HAT) process, and then undergoes reduction elimination to obtain a chiral heterocyclic alkane C substituted with an alkyl group at the α position of the heteroatom; through subsequent transformations, the chiral heterocyclic alkane C can be further derivatized to realize the synthesis of various natural products or active drug molecules.

[0007] To achieve the above purpose, the specific technical solutions of the present invention are as follows:

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

[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 metal nickel catalyst is selected from one of nickel chloride, nickel bromide, nickel chloride dimethyl ether, nickel bromide dimethyl ether, cyclooctadiene nickel, nickel acetylacetonate, nickel perchlorate, nickel iodide, and nickel acetate tetrahydrate.

[0016] Furthermore, the metal nickel catalyst is nickel bromide 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), (4R,4'R)-2,2'-(1-propylbenzene-2,2-diyl)bis(4,5,5-tri phenyl-4,5-dihydrooxazole) (L3), (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] Further, the oxidant D is selected from one of the following structures:

[0021]

[0022] Furthermore, the oxidant is tert-butyl peroxide (D1) or diisopropylbenzene 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] Further, the base 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 base is potassium bicarbonate, potassium phosphate or cesium carbonate.

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

[0029] Furthermore, the material also includes an additive, and the additive is selected from one of zinc powder, manganese powder, magnesium powder, biboric acid pinacol ester, tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium iodide.

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

[0031] Furthermore, the molar ratio of the olefin A to the 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 mixed solvent composed of one or more of ethyl acetate, trifluorotoluene, and acetone; the concentration of the olefin A in the solvent is 0.05-2 mol / L.

[0034] Compared with the prior art, the present invention is beneficial in that:

[0035] The present invention provides a strategy for realizing asymmetric alkylation of saturated heterocycles based on hydrogen atom transfer, using a series of simple and easily available olefins A and heterocyclic compounds B as reaction substrates to prepare chiral heterocyclic compounds containing heteroatom ortho-alkyl substitutions. The method avoids the use of noble metal catalysts and expensive photosensitizers, greatly reducing the synthesis cost. In addition, the method of the present invention has mild reaction conditions, good functional group tolerance, and a wide range of substrate applications. It has the advantages of low cost, high atom utilization, and step economy, and is an efficient, green, and inexpensive method for synthesizing chiral heterocyclic compounds. DETAILED DESCRIPTION

[0036] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

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

[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 metal nickel catalyst is selected from one of nickel chloride, nickel bromide, nickel chloride dimethyl ether, nickel bromide dimethyl ether, cyclooctadiene nickel, nickel acetylacetonate, 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 base 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 the olefin A, heterocyclic compound B, metal 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 further includes an additive, and the additive is selected from one of zinc powder, manganese powder, magnesium powder, bipyralidone borate, tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium iodide.

[0054] In some examples, the molar ratio of the olefin A to the 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 mixed solvent consisting of one or more of ethyl acetate, trifluorotoluene, and acetone; the concentration of the olefin A in the solvent is 0.05~2 mol / L.

[0056] In the following specific examples, unless otherwise specified, all materials and reagents used were purchased conventionally.

[0057] Example 1

[0058]

[0059] Preparation of compound 1: Under 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 rod, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A1 (24.9 mg, 0.1 mmol), nitrogen heterocycle B1 (86.8 mg, 0.5 mmol), diisopropylbenzene 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 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 eluent to obtain an 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 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 rod, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A3 (15 mg, 0.1 mmol), nitrogen heterocycle 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 biboric acid pinacol ester (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A3 was 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 eluent to obtain an 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 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 rod, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A6 (13.2 mg, 0.1 mmol), nitrogen heterocycle B1 (86.8 mg, 0.5 mmol), diisopropylbenzene peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol) and biboric acid pinacol ester (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A6 was 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 eluent to obtain an 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 C 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 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 pole, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A7 (21.1 mg, 0.1 mmol), nitrogen heterocycle B1 (86.8 mg, 0.5 mmol), diisopropylbenzene peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol) and biboric acid pinacol ester (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A7 was 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 eluent to obtain an 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 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 pole, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A8 (16.6 mg, 0.1 mmol), nitrogen heterocycle B1 (86.8 mg, 0.5 mmol), diisopropylbenzene peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium phosphate (21.2 mg, 0.1 mmol) and biboric acid pinacol ester (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A8 was 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 eluent to obtain an 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 C 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; found342.1613.

[0077] Example 6

[0078]

[0079] Preparation of compound 6: Under 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 pole, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A10 (28.6 mg, 0.1 mmol), nitrogen heterocycle B1 (86.8 mg, 0.5 mmol), diisopropylbenzene peroxide D2 (162.2 mg, 0.6 mmol), anhydrous potassium bicarbonate (10.0 mg, 0.1 mmol) and biboric acid pinacol ester (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A10 was 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 eluent to obtain an 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 NOS + [M+H] + 462.2248; found 462.2240.

[0081] Example 7

[0082]

[0083] Preparation of compound 7: Under 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 rod, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A11 (22.6 mg, 0.1 mmol), nitrogen heterocycle B1 (86.8 mg, 0.5 mmol), diisopropylbenzene 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 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 eluent to obtain an 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 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 electron, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A14 (24.9 mg, 0.1 mmol), nitrogen heterocycle B1 (86.8 mg, 0.5 mmol), diisopropylbenzene 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 A14 was consumed. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated. A solution of tetrabutylammonium fluoride (100 μL, 0.1 mmol) in tetrahydrofuran (1 mL) was added to the mixture until the silicon protecting group was removed. The mixture was then purified by silica gel column chromatography using ethyl acetate as the eluent to obtain an 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 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 pole, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A17 (11.8 mg, 0.1 mmol), nitrogen heterocycle 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 biboric acid pinacol ester (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A3 was 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 eluent to obtain an 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: Under argon atmosphere, 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 rod, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A19 (21.0 mg, 0.1 mmol), nitrogen heterocycle 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 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 eluent to obtain an anhydrous oily product 10 (15.4 mg, 40% yield, 94% ee).

[0096] 1 1H NMR (600 MHz, CDCl3) (75:25 mixture of rotamers) δ 7.50 (d, J J = 6.6 Hz, 1.50H), 7.45 - 7.33 (m, 3.50H), 4.34 - 4.14 (m, 0.75H), 3.88 - 3.80 (m, 0.25H), 3.78 - 3.71 (m, 0.25H), 3.52 - 3.45 (m, 0.25H), 3.45 - 3.32 (m, 1.50H), 2.26 - 2.04 (m, 1.25H), 2.04 - 1.92 (m, 1.75H), 1.90 - 1.83 (m, 0.75H), 1.82 - 1.62 (m, 2.25H), 1.49 - 1.37 (m, 2.0.H), 1.37 - 1.28 (m, 5.00H), 1.24 (s, 12.00H), 1.04 (d, J J = 28.1 Hz, 1.00H), 0.97 - 0.85 (m, 1.00H), 0.82 - 0.66 (m, 1.00H). 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 H 31 BNO3 + [M + H] + 386.2861; found 386.2848.

[0097] Example 11

[0098]

[0099] Preparation of compound 11: Under 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 rod, and 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-butyl peroxide 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 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 eluent to obtain an 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 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 rod, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A1 (24.9 mg, 0.1 mmol), oxygen heterocycle B11 (260.3 mg, 2.0 mmol), di-tert-butyl peroxide 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 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 eluent to obtain an 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] Embodiment 13

[0106]

[0107] Preparation of compound 13: Under argon atmosphere, 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 rod, and the reaction mixture was stirred at room temperature for 1 h. Then olefin A1 (24.9 mg, 0.1 mmol), oxygen heterocycle B15 (0.5 mL), di-tert-butyl peroxide D1 (186 μL, 1 mmol), anhydrous potassium bicarbonate (10 mg, 0.1 mmol) and biboric acid pinacol ester (50.9 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0 °C until the raw material A1 was 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 eluent to obtain an 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] Embodiment 14

[0110]

[0111] Preparation of compound 14: Under 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 pole, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A1 (24.9 mg, 0.1 mmol), nitrogen heterocycle B1 (86.8 mg, 0.5 mmol), diisopropylbenzene 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 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 eluent to obtain an 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] Embodiment 15

[0114]

[0115] Preparation of compound 15: Under 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 electron, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A48 (32.4 mg, 0.1 mmol), nitrogen heterocycle 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 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 eluent to obtain an 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 C 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 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 magnet, and the reaction mixture was stirred at room temperature for 1 h. Then, olefin A44 (25.8 mg, 0.1 mmol), nitrogen heterocycle 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 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 eluent to obtain an 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] Embodiment 17

[0122]

[0123] Preparation of compound 17: Under 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 pole, and 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 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 eluent to obtain an 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 specific embodiments describe the implementation of the present invention in detail, but the present invention is not limited to the specific details in the above embodiments. Within the scope of the claims and technical concept of the present invention, the technical solution of the present invention can be modified and changed in many simple ways, and these simple modifications all belong to 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, metal nickel catalysts, ligands, oxidants, silane compounds, and bases are reacted at 0-20° C. to obtain chiral heterocycloalkane substituted with an alkyl group at the α-position of the heteroatom.

2. The method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer according to claim 1, characterized in that: The olefin is selected from one of the following structures: ； ； 。 3. The method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer according to claim 1, characterized in that: The heterocyclic compound is selected from one of the following structures: 。 4. The method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer according to claim 1, characterized in that: The metal nickel catalyst is selected from one of nickel chloride, nickel bromide, nickel chloride glycol dimethyl ether, nickel bromide glycol dimethyl ether, cyclooctadiene nickel, nickel acetylacetonate, nickel perchlorate, nickel iodide, and nickel acetate tetrahydrate.

5. The method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer according to claim 1, characterized in that: The ligand is selected from one of the following structures: 。 6. The method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer according to claim 1, characterized in that: The oxidant is selected from one of the following structures: 。 7. The method for asymmetric alkylation of saturated heterocyclic hydrocarbons based on hydrogen atom transfer according to claim 1, characterized in that: The silane is selected from one of the following structures: 。 8. 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, the heterocyclic compound, the metal nickel catalyst, the ligand, the oxidant, the silane compound and the base is 1:(5-150):(0.15-0.2):0.2:(3-10):(3-10):

1.

9. 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 an additive, and the additive is selected from one of zinc powder, manganese powder, magnesium powder, biboric acid pinacol ester, tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium iodide.

10. A chiral heterocycloalkane substituted with an alkyl group at the alpha position of the heteroatom prepared by the method according to any one of claims 1 to 9.

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