A method for amide-directed asymmetric hydroamidation of unactivated olefins

Abstract

The application relates to an amide-oriented asymmetric hydroamidation method of non-activated olefins. In an argon atmosphere, a metal nickel salt, a chiral ligand, an alkali, a hydrogen source and the like are used to react an olefin with an alkynyl bromide compound in an organic solvent, so that a chiral homoallylamine product is obtained with excellent regioselectivity and enantioselectivity. The method is simple and convenient in the experimental process, easy to operate, uses cheap transition metal nickel as a catalyst, uses commercially available alkynyl bromide as a raw material, has mild conditions and good functional group universality.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry technology, and in particular relates to a method for the amide-directed asymmetric hydroacetylation of non-activated olefins to obtain chiral high propargylamine compounds with excellent regioselectivity and enantioselectivity. Background Technology

[0002] Aliphatic amines belong to an important class of organic compounds and are constituent units of many bioactive natural products, agrochemicals, and pharmaceuticals. Therefore, the study of fatty amines has significant practical implications and value. Many researchers are dedicated to finding new synthetic methods to obtain these compounds.

[0003] Alkenes, widely found in natural products and pharmaceuticals, are among the most abundant organic molecules, readily available from fossil fuels and renewable resources. In recent years, transition metal-catalyzed functionalization reactions of alkenes have attracted increasing attention, representing an effective strategy for rapidly increasing molecular complexity and diversity, exhibiting high atom and step economy.

[0004] Hydroynylation of alkenes can rapidly and efficiently yield aliphatic amines modified with various alkynes. Using readily available alkene substrates, we can easily and quickly generate the complex molecules we need. In 2016, Li Bijie's research group reported an iridium-catalyzed, β-selective asymmetric hydroynylation of vinylamines. This was the first time that ynylation occurred at the relatively electron-rich β-position, rather than the relatively electron-deficient α-position. (Bai, X. -Y.‡; Wang, Z. -X.‡; Li, B. -J.*, Angew. Chem. Int. Ed. 2016, 55 In the same year, he also reported the asymmetric hydrogenation and alkylation reactions at the γ-position of alkenyl acid derivatives in the same catalytic system, exhibiting good functional group tolerance and excellent enantioselectivity. (Wang, Z.-X.; Bai, X.-Y.; Yao, H.-C.; Li, B.-J.*) J. Am. Chem. Soc. 2016, 138 In 2021, Professor Shaolin Zhu's research group discovered long-range hydroynkylation and asymmetric ynkylation reactions of phenyl-substituted non-activated alkenes. This reaction, using polymethylhydrosiloxane as a hydrogen source, reacts with ynkyne bromides to achieve long-range hydroynkylation reactions migrating to the benzylic position. (X. Jiang, B. Han, Y. Xue, M. Duan, Z. Gui, Y. Wang*, S. Zhu*, 14872.) Nat. Commun. 2021 12 , 3792.).

[0005] Previous catalytic systems have mostly used expensive precious metals, and systems using inexpensive nickel as a catalyst for the activation of unactivated alkenes are relatively rare, especially the asymmetric alkynelation of chiral β-alkynylamines, which has never been reported. Therefore, we have invented a milder method with a broad alkyne range and high regioselectivity and enantioselectivity to synthesize the desired chiral β-alkynyl branched amines. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing chiral high propargylamines. This method is simple, convenient, and easy to operate. It uses inexpensive transition metal nickel as a catalyst, commercially available alkynyl bromides as raw materials, and operates under mild conditions with good functional group universality. It also exhibits excellent regioselectivity and enantioselectivity.

[0007] To address the asymmetric hydrogenation and alkyneation of unactivated olefin substrates, this invention optimizes conditions such as catalyst type, ligand, base, solvent, hydrogen source, temperature, and reaction time to achieve the synthesis of chiral high-propyne amines at relatively low temperatures. This experimental method can be used to convert these compounds into corresponding chiral alkylamines (e.g., Example 19) and chiral alkenylamines (e.g., Examples 20 and 21), demonstrating potential downstream modification capabilities. It can also further modify alkyne-containing drugs (e.g., ethinyleneprogesterone) and pesticides (e.g., clodinafop-propargyl) to induce new properties.

[0008] To achieve the above objectives, the present invention discloses the following technical solution.

[0009] An amide-directed asymmetric hydroynkylation method for non-activated olefins, characterized by the following steps:

[0010] (1) In a glove box filled with argon, weigh the nickel salt catalyst into a dry reaction tube, add the ligand, the olefin substrate with the directing group, the base, the corresponding alkynyl bromide, the solvent, and the hydrogen source, and stir the reaction system at 40°C for 24 h.

[0011] (2) After the reaction is complete, the resulting solution is concentrated under vacuum, and the crude product is purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane as the eluent. The separation yield is calculated.

[0012]

[0013] Where R1 refers to:

[0014]

[0015] R2 refers to: Me;

[0016] R3 refers to: n-Pr;

[0017] R4 refers to:

[0018]

[0019] The nickel salt is nickel bromide ethylene glycol dimethyl ether, and the chiral ligand L... * The base described below is Na₂CO₃, the hydrogen source is trimethoxysilane, and the solvent is N,N-dimethylformamide. The molar ratio of nickel catalyst: chiral ligand: base: hydrogen source: olefin substrate: alkynyl bromide compound: organic solvent is 0.02:0.024:0.4:0.6:0.2:0.4:1.0 (mol:mol:mol:mol:mol:volume / mL). The reaction temperature is 30℃~40℃, and the volume ratio of ethyl acetate to n-hexane as eluent is 1:10. *

[0020]

[0021] This invention further discloses the application of the method in achieving high regioselectivity, high enantioselectivity, and high separation rates of products under mild conditions. High-value chiral high-alkyne amine products are obtained when inactivated olefins are used as substrates (see Examples 1-18). Particularly in applications with further modifications, experimental results show that this invention can maintain excellent enantioselectivity, converting chiral high-alkyne amines to chiral alkylamines (4a), chiral alkenylamines (4b-4c), and other optically active substances. Similarly, alkyne-containing drugs (e.g., ethinyleneprogesterone) and pesticides (e.g., clodinafop-propargyl) can be further modified to produce new properties.

[0022]

[0023] The advantages and positive effects of this invention are as follows:

[0024] 1. When non-activated olefins are used as substrates, chiral high-value-added propargylamine products can be obtained with high regioselectivity and high enantioselectivity.

[0025] 2. The experimental process of the present invention is simple and convenient, easy to operate, uses inexpensive transition metal nickel as a catalyst, uses commercially available alkynyl bromide as raw material, has mild conditions, and has good functional group universality.

[0026] 3. The method of the present invention has a wide range of applicable substrates, and is suitable for primary alkyl alkynyl bromide, secondary alkyl alkynyl bromide, tertiary alkyl alkynyl bromide and aryl alkynyl bromide, with a high separation yield.

[0027] 4. Many simple and widely used amides can be used as directing groups, providing β-branched alkyne amines that are widely available in the chemical and pharmaceutical industries, which have great research value in terms of novelty and practicality. Detailed Implementation

[0028] The features and advantages of the present invention can be further understood through the following detailed description. The provided embodiments are merely illustrative of the method of the present invention and do not limit the remaining contents disclosed in the present invention in any way;

[0029] In the following embodiments, TIPS ligands L1 * refer to NiBr2·DME refers to nickel bromide ethylene glycol dimethyl ether complex, (MeO)3SiH refers to trimethoxysilane, and DMF refers to N,N-dimethylformamide. The hydrogen source, solvent, and L24 mentioned above and in the invention are also mentioned. * All of these are commercially available, the rest L * For ligand synthesis, see: D. Qian, S. Bera, X. Hu, J. Am. Chem. Soc. 2021, 143, 1959–1967. and Guan, Yong; Attard, Jonathan W.; Mattson, Anita E. Chem. Eur. J , 2020, 26 , 1742-1747. For the synthesis of non-activated alkenes, see: Triandafillidi, I., Kokotou, MG, Kokotos. CG Org. Lett. 2018, 20 , 36−39. and Alhalib, A., Kamouka, S., Moran. WJ Org. Lett. 2015, 17 , 1453−1456. For the synthesis of alkynyl bromides, see: Craig D. Campbell 1 Rebecca L. Greenaway 1 Oliver T. Holton 1 P. Ross Walker 1 Helen A. Chapman 2 C. Adam Russell 2 Greg Carr 3 Amber L. Thomson1 Edward A. Anderson 1 , Chem. Eur. J. 2015, 21 , 12627 - 12639.

[0030] Example 1

[0031]

[0032] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2a (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (white solid, 89% yield, 92% ee).

[0033] 1 H NMR (400 MHz, CDCl3) δ 7.81–7.73 (m, 2H), 7.52–7.46 (m, 1H), 7.44–7.39 (m, 2H), 6.54 (s, 1H), 3.76–3.67 (m, 1H), 3.32–3.23 (m, 1H), 2.89–2.77(m, 1H), 1.25 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 2.9 Hz, 21H); 13 C NMR (101MHz, CDCl3) δ 167.4, 134.6, 131.5, 128.5, 126.9, 110.7, 82.2, 44.8, 27.8,18.6, 18.6, 11.2. HRMS (ESI) m / z calculated for C 21 H 34 NOSi + [M+H] +344.2404, found: 344.2394. Optical rotation: [α] 20 D = -44.90 (c = 1.0 g / L, CHCl3). HPLCcondition: Chiral column OD-H, n-hexane / i-PrOH = 95:5, flow rate = 1.0 mL / min, wavelength =254 nm, tR = 7.5 min for majorr isomer, tR = 8.8 min forminor isomer.

[0034] Example 2

[0035]

[0036] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2b (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 30 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (colorless oil, 85% yield, 92% ee).

[0037] 1 H NMR (400 MHz, CDCl3) δ 7.83–7.77 (m, 2H), 7.53–7.48 (m, 1H), 7.47–7.42 (m, 2H), 7.42–7.39 (m, 2H), 7.32–7.28 (m, 3H), 6.54 (s, 1H), 3.81–3.74(m, 1H), 3.43–3.36 (m, 1H), 3.08–3.00 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H); 13CNMR (101 MHz, CDCl3) δ 167.6, 134.6, 131.7, 131.5, 128.7, 128.3, 128.1,126.9, 123.2, 91.5, 82.3, 45.0, 27.5, 18.5. HRMS (ESI) m / z calculated forC 18 H 18 NO + [M+H] + 264.1383, found: 264.1390. Optical rotation: [α] 20 D = -117.80(c = 1.0 g / L, CHCl3). HPLC condition: Chiral column IC, n-hexane / i-PrOH = 99:1, flow rate = 2.0 mL / min, wavelength =254 nm, tR = 81.2 min for majorrisomer, tR = 77.4 min for minor isomer.

[0038] Example 3

[0039]

[0040] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1b (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2a (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (colorless oil, 95% yield, 91% ee).

[0041] 11H NMR (400 MHz, CDCl3) δ 7.78–7.71 (m, 2H), 6.94–6.88 (m, 2H), 6.43(s, 1H), 3.85 (s, 3H), 3.74–3.67 (m, 1H), 3.29–3.21 (m, 1H), 2.88–2.78 (m,1H), 1.24 (d, J J = 6.9 Hz, 3H), 1.06 (d, J J = 3.1 Hz, 21H).; 13 13C NMR (101 MHz,CDCl3) δ 167.0, 162.3, 128.8, 127.0, 113.9, 110.9, 82.3, 55.6, 44.9, 28.0,18.8, 18.7, 11.3. HRMS (ESI) m / z calculated for C 22 18 36 11 + NO2Si + [M+H]+ 20 D 374.2510,found: 374.2518. Optical rotation: [α]

[0042] Example 4

[0043]

[0044] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1c (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2a (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (white solid, 89% yield, 92% ee).

[0045] 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.9 Hz, 1H), 7.42–7.33 (m, 2H), 7.13–7.06 (m, 1H), 6.10 (s, 1H), 3.73–3.66 (m, 1H), 3.32–3.25 (m, 1H), 2.92–2.84 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H), 1.00 (s, 21H); 13 C NMR (101 MHz, CDCl3) δ 169.5, 142.3, 140.1, 131.3, 128.2, 128.2, 110.5, 92.5, 82.6, 45.0,27.8, 18.8, 18.7, 11.3. HRMS (ESI) m / z calculated for C 21 H 33 INOSi + [M+H] + 470.1371, found: 470.1374. Optical rotation: [α] 20 D= -4.19 (c = 1.0 g / L, CHCl3). HPLC condition: Chiral column OD-H, n-hexane / i-PrOH = 95:5, flowrate = 1.0 mL / min, wavelength =254 nm, tR = 7.2 min for majorr isomer, tR =7.8 min for minor isomer.

[0046] Example 5

[0047]

[0048] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1d (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2a (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (colorless oil, 74% yield, 90% ee).

[0049] 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.2Hz, 2H), 6.53 (s, 1H), 3.77–3.70 (m, 1H), 3.31–3.24 (m, 1H), 2.90–2.82 (m,1H), 1.26 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 2.4 Hz, 21H); 13 C NMR (101 MHz, CDCl3) δ 166.2, 133.5 (q, J = 32.8 Hz), 127.5, 125.8 (q, J = 3.7 Hz), 123.8(q,J = 272.5 Hz), 110.5, 82.7, 45.0, 27.9, 21.5, 18.8, 18.7, 11.3; 19 F NMR(376 MHz, CDCl3) δ -62.94. HRMS (ESI) m / z calculated for C 22 H 33 F3NOSi + [M+H] + 412.2278, found: 412.2284. Optical rotation: [α] 20 D = -6.59 (c = 1.0 g / L, CHCl3).HPLC condition: Chiral column AD-H, n-hexane / i-PrOH = 98:2, flow rate= 1.0 mL / min, wavelength =254 nm, tR = 8.9 min for majorr isomer, tR = 8.0min for minor isomer.

[0050] Example 6

[0051]

[0052] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1e (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2b (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 30 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (white solid, 92% yield, 90% ee).

[0053] 11H NMR (400 MHz, CDCl3) δ 7.41–7.36 (m, 2H), 7.32–7.27 (m, 3H), 5.93(s, 1H), 4.03–3.97 (m, 2H), 3.58–3.51 (m, 1H), 3.44–3.37 (m, 2H), 3.23 – 3.15(m, 1H), 2.93–2.87 (m, 1H), 2.41–2.32 (m, 1H), 1.86–1.77 (m, 3H), 1.25 (d, J = 6.9 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 174.4, 131.6, 128.3, 128.1, 123.2,91.5, 82.1, 67.3, 44.4, 42.3, 29.3, 27.4, 18.4. HRMS (ESI) m / z calculated forC 17 H 22 NO2 + [M+H] + 272.1645, found: 272.1649. Optical rotation: [α] 20 D = -7.99 (c = 1.0 g / L, CHCl3). HPLC condition: Chiral column OD-H, n-hexane / i-PrOH = 95:5, flow rate = 0.8 mL / min, wavelength =254 nm, tR = 44.6 min for majorrisomer, tR = 50.8 min for minor isomer.

[0054] Example 7

[0055]

[0056] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1f (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2b (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 30 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (brown solid, 94% yield, 88% ee).

[0057] 1 H NMR (400 MHz, CDCl3) δ 7.41–7.36 (m, 2H), 7.31–7.27 (m, 3H), 6.08(s, 1H), 3.57–3.51 (m, 1H), 3.19–3.12 (m, 1H), 2.96–2.87 (m, 1H), 1.25 (d, J = 6.9 Hz, 3H), 1.22 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 178.5, 131.6, 128.3,128.0, 123.3, 91.6, 82.2, 44.3, 38.8, 27.6, 27.4, 18.3. HRMS (ESI) m / zcalculated for C 16 H 22 NO + [M+H] + 244.1696, found: 244.1697. Optical rotation:[α] 20 D = -9.09 (c = 1.0 g / L, CHCl3). HPLC condition: Chiral column OD-H, n-hexane / i-PrOH = 95:5, flow rate = 1.0 mL / min, wavelength =254 nm, tR = 9.8min for majorr isomer, tR = 10.5 min for minor isomer.

[0058] Example 8

[0059]

[0060] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), 1 g of olefin substrate (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2b (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (colorless oil, 54% yield, 90% ee).

[0061] 1 H NMR (400 MHz, CDCl3) δ 7.82–7.77 (m, 2H), 7.52–7.48 (m, 1H), 7.46–7.43 (m, 2H), 7.42–7.39 (m, 2H), 7.33–7.28 (m, 3H), 6.55 (s, 0.93 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDCl3)δ 167.5, 134.7, 131.7, 131.5, 128.6, 128.3, 128.0, 126.9, 123.3, 90.7, 83.2,43.6, 33.2, 32.4, 29.5, 22.5, 14.0. HRMS (ESI) m / z calculated for C 21 H 24 NO + [M+H] +306.1852, found: 306.1855. Optical rotation: [α] 20 D = -39.90 (c = 1.0 g / L, CHCl3). HPLC condition: Chiral column AD-H, n-hexane / i-PrOH = 97:3, flowrate = 1.0 mL / min, wavelength =254 nm, tR = 31.9 min for majorr isomer, tR =27.5 min for minor isomer.

[0062] Example 9

[0063]

[0064] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1h (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2b (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (colorless oil, 83% yield, 77% ee).

[0065] 1 H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 5.4, 3.1 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 7.33–7.30 (m, 2H), 7.26–7.21 (m, 3H), 3.94 (dd, J = 13.3, 8.3 Hz, 1H), 3.74 (dd, J = 13.3, 7.1 Hz, 1H), 3.30–3.21 (m, 1H), 1.31 (d, J =6.9 Hz, 3H);13 C NMR (101 MHz, CDCl3) δ 168.3, 134.0, 132.0, 131.6, 128.1,127.8, 123.3, 90.7, 82.1, 43.1, 26.4, 18.4. HRMS (ESI) m / z calculated forC 19 H 16 NO2 + [M+H] + 290.1176, found: 290.1168. Optical rotation: [α] 20 D = -29.90(c = 1.0 g / L, CHCl3). HPLC condition: Chiral column OD-H, n-hexane / i-PrOH =97:3, flow rate = 0.6 mL / min, wavelength =254 nm, tR = 15.9 min for majorrisomer, tR = 15.2 min for minor isomer.

[0066] Example 10

[0067] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2c (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 30 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (pale yellow solid, 95% yield, 95% ee).

[0068] 11H NMR (400 MHz, CDCl3) δ 7.82–7.76 (m, 2H), 7.53–7.47 (m, 1H), 7.46–7.40 (m, 2H), 7.39–7.36 (m, 1H), 7.23–7.17 (m, 2H), 7.15–7.09 (m, 1H), 6.56(s, 1H), 3.82–3.75 (m, 1H), 3.45–3.38 (m, 1H), 3.12–3.04 (m, 1H), 2.40 (s,3H), 1.35 (d, J J = 7.0 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 167.7, 140.1, 134.7,132.0, 131.7, 129.5, 128.8, 128.2, 127.0, 125.7, 123.1, 95.7, 81.3, 45.2,27.8, 20.9, 18.8. HRMS (ESI) m / z calculated for C 19 17 20 11 + O2 [M+H]+ + 278.1539,found: 278.1541. Optical rotation: [α]D 20 D = -11.98 (c = 1.0 g / L, CHCl3). HPLCcondition: Chiral column OD-H, n-hexane / i-PrOH = 95:5 , flow rate = 1.0 mL / min, wavelength =254 nm, tR = 18.9 min for majorr isomer, tR = 24.2 min forminor isomer.<​​​​​​​In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2d (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (yellow solid, 96% yield, 92% ee).

[0072] 1 H NMR (400 MHz, CDCl3) δ 7.82–7.77 (m, 2H), 7.57–7.53 (m, 2H), 7.53–7.47 (m, 3H), 7.46–7.41 (m, 2H), 6.53 (s, 1H), 3.79–3.70 (m, 1H), 3.49–3.40(m, 1H), 3.12–3.02 (m, 1H), 1.34 (d, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl3)δ 167.8, 134.7, 132.0, 131.7, 129.9 (q, J = 32.8 Hz), 128.8, 127.2–127.1 (m), 127.0, 125.4 (q, J = 3.7 Hz), 122.7, 94.4, 90.7 (d, J = 1904.7 Hz), 45.0,27.7, 18.4; 19 F NMR (376 MHz, CDCl3) δ -62.79. HRMS (ESI) m / z calculated forC 19 H 17 F3NO + [M+H] + 332.1257, found: 332.1260. Optical rotation: [α] 20 D= -79.90(c = 1.0 g / L, CHCl3). HPLC condition: Chiral column OD-H, n-hexane / i-PrOH =96:4, flow rate = 1.0 mL / min, wavelength =254 nm, tR = 23.7 min for majorrisomer, tR = 29.8 min for minor isomer.

[0073] Example 12

[0074]

[0075] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2e (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (yellow oil, 57% yield, 92% ee).

[0076] 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.3 Hz, 2H), 7.56 (d, J = 8.3Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.44 (dd, J = 14.6, 7.5 Hz, 4H), 6.55 (s,1H), 3.76–3.67 (m, 1H), 3.50–3.43 (m, 1H), 3.13–3.03 (m, 1H), 1.33 (d, J =7.0 Hz, 3H); 13HRMS (ESI)m / z calculated for C 19 H 17 N2O + [M+H] + 289.1335, found: 289.1324. Opticalrotation: [α] 20 D = -47.90 (c = 1.0 g / L, CHCl3). HPLC condition: Chiral columnOD-H, n-hexane / i-PrOH = 90:10, flow rate = 1.0 mL / min, wavelength =254 nm, tR = 24.9 min for majorr isomer, tR = 30.4 min for minor isomer.

[0077] Example 13

[0078]

[0079] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2f (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (yellow solid, 93% yield, 82% ee).

[0080] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J= 8.4 Hz, 2H), 7.82–7.75 (m, 2H),7.57–7.49 (m, 1H), 7.48–7.39 (m, 4H), 6.49 (s, 1H), 3.91 (s, 3H), 3.80–3.73(m, 1H), 3.47–3.40 (m, 1H), 3.11–3.03 (m, 1H), 1.34 (d, J = 6.9 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 167.6, 166.6, 134.6, 131.6, 129.5, 129.4, 128.7,128.0, 126.9, 111.2, 94.9, 81.7, 52.2, 44.9, 27.6, 18.3. HRMS (ESI) m / zcalculated for C 20 H 20 NO3 + [M+H] + 322.1438, found: 322.1429. Optical rotation:[α] 20 D = -8.89 (c = 1.0 g / L, CHCl3). HPLC condition: Chiral column OD-H, n-hexane / i-PrOH = 96:4, flow rate = 1.0 mL / min, wavelength =254 nm, tR = 44.3min for majorr isomer, tR = 55.7 min for minor isomer.

[0081] Example 14

[0082]

[0083] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2 g (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (yellow oil, 95% yield, 93% ee).

[0084] 1 H NMR (400 MHz, CDCl3) δ 7.81–7.77 (m, 2H), 7.52–7.48 (m, 1H), 7.46–7.41 (m, 2H), 7.40–7.36 (m, 1H), 7.26–7.24 (m, 1H), 7.09–7.06 (m, 1H), 6.55(s, 1H), 3.78–3.71 (m, 1H), 3.42–3.35 (m, 1H), 3.04–2.98 (m, 1H), 1.31 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 167.6, 134.6, 131.5, 130.0, 128.6,128.3, 126.9, 125.3, 122.2, 91.1, 44.9, 27.5, 18.5. HRMS (ESI) m / z calculated for C 16 H 16 NOS + [M+H] + 270.0947, found: 270.0940. Optical rotation: [α] 20 D= -77.90 (c = 1.0 g / L, CHCl3). HPLC condition: Chiral column AD-H, n-hexane / i-PrOH = 95:5, flow rate = 0.8 mL / min, wavelength =254 nm, tR = 40.1 min formajor isomer, tR = 34.7 min for minor isomer.

[0085] Example 15

[0086]

[0087] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2h (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (colorless oil, 93% yield, 95% ee).

[0088] 1 H NMR (400 MHz, CDCl3) δ 7.70–7.64 (m, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.27–7.20 (m, 4H), 7.18–7.12 (m, 1H), 6.28 (s, 1H), 3.66–3.59 (m, 1H), 3.21–3.14 (m, 1H), 2.85–2.77 (m, 2H), 2.75–2.68 (m, 1H),2.53–2.46 (m, 2H), 1.18 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.5,140.7, 134.7, 131.4, 128.6, 128.5, 128.3, 126.9, 126.4, 83.1, 81.4, 45.1,35.3, 26.9, 20.9, 18.7. HRMS (ESI) m / z calculated for C 20 H 22 NO + [M+H] + 292.1696, found: 292.1690. Optical rotation: [α] 20 D = -6.89 (c = 1.0 g / L, CHCl3). HPLC condition: Chiral column OD-H, n-hexane / i-PrOH = 96:4, flowrate = 1.0 mL / min, wavelength =254 nm, tR = 32.4 min for majorr isomer, tR =56.5 min for minor isomer.

[0089] Example 16

[0090]

[0091] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2i (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (yellow oil, 88% yield, 93% ee).

[0092] 1 H NMR (400 MHz, CDCl3) δ 7.83–7.76 (m, 2H), 7.53–7.47 (m, 1H), 7.44(t,J = 7.3 Hz, 2H), 6.62 (s, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.69–3.62 (m,1H), 3.28–3.20 (m, 1H), 2.81–2.72 (m, 1H), 2.30–2.24 (m, 2H), 2.04 (s, 3H),1.84–1.77 (m, 2H), 1.20 (d, J = 6.9 Hz, 3H).; 13 C NMR (101 MHz, CDCl3) δ171.1, 167.5, 134.7, 131.4, 128.5, 127.0, 83.1, 80.4, 62.9, 45.2, 28.0, 26.8,20.9, 18.8, 15.4. HRMS (ESI) m / z calculated for C 17 H 22 NO3 + [M+H] + 288.1594,found: 288.1580. Optical rotation: [α] 20 D = -54.90 (c = 1.0 g / L, CHCl3). HPLCcondition: Chiral column AD-H, n-hexane / i-PrOH = 95:5, flow rate = 0.8 mL / min, wavelength =254 nm, tR = 40.6 min for majorr isomer, tR = 37.5 min forminor isomer.

[0093] Example 17

[0094]

[0095] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2j (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (yellow oil, 95% yield, 94% ee).

[0096] 1 H NMR (400 MHz, CDCl3) δ 7.75–7.67 (m, 2H), 7.46–7.41 (m, 1H), 7.37–7.32 (m, 2H), 7.27–7.17 (m, 5H), 6.47 (s, 1H), 4.70 (d, J = 11.8 Hz, 1H), 4.45 (d, J = 11.8 Hz, 1H), 4.04–3.96 (m, 1H), 3.68–3.58 (m, 1H), 3.33–3.20(m, 1H), 2.89–2.77 (m, 1H), 1.76–1.67 (m, 2H), 1.21 (d, J = 6.9 Hz, 3H), 0.98– 0.93 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ 167.6, 138.2, 134.6, 131.6, 128.7,128.5, 127.9, 127.9, 127.7, 127.0, 88.2, 81.1, 70.6, 70.3, 45.0, 29.2, 27.0,18.7, 9.9. HRMS (ESI) m / z calculated for C 22 H 26 NO2 + [M+H] + 336.1958, found:336.1944. Optical rotation: [α] 20D = -38.90 (c = 1.0 g / L, CHCl3). HPLCcondition: Chiral column OD-H, n-hexane / i-PrOH = 97:3, flow rate = 1.0 mL / min, wavelength =254 nm, tR = 28.0, 34.6 min for majorr isomer, tR = 32.9,39.3 min for minor isomer.

[0097] Example 18

[0098]

[0099] In an argon-filled glove box, NiBr2•DME (0.02 mmol, 10 mol%), ligand L1* (0.024 mmol, 12 mol%), olefin substrate 1a (0.2 mmol, 1.0 equiv), Na2CO3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromide electrophilic reagent 2k (0.4 mmol, 2 equiv), DMF (1 mL), and (MeO)3SiH (0.60 mmol, 3 equiv) were added to a 4 mL reaction tube. The reaction mixture was stirred at 40 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (yellow oil, 59% yield, 90% ee).

[0100] 1 H NMR (400 MHz, CDCl3) δ 7.78–7.75 (m, 2H), 7.53–7.50 (m, 1H), 7.47–7.43 (m, 2H), 6.24 (d, J = 7.6 Hz, 1H), 5.03–4.96 (m, 1H), 3.35 (s, 3H), 1.94–1.67 (m, 6H), 1.60–1.45 (m, 6H), 1.36–1.26 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.3, 133.3, 130.6, 127.6, 125.9, 83.9, 83.5,49.7, 42.4, 35.7, 35.7, 28.4, 24.4, 21.8, 9.1. HRMS (ESI) m / z calculated forC 19 H 26 NO2 + [M+H] + 300.1958, found: 300.1948. Optical rotation: [α] 20 D = -21.50(c = 1.0 g / L, CHCl3). HPLC condition: Chiral column OD-H, n-hexane / i-PrOH =95:5, flow rate = 1.0 mL / min, wavelength =254 nm, tR = 13.1 min for majorrisomer, tR = 15.7 min for minor isomer.

[0101] Example 19

[0102] The series of chiral alkyne amines synthesized in this invention have practical synthetic application potential: typical compounds are used in the synthesis of chiral alkylamines (such as 4a) and chiral alkenylamines (4b, 4c) through reduction reactions.

[0103]

[0104] Under a hydrogen atmosphere, alkynylamine 3b (0.2 mmol, 1 equiv), Pd / C (0.02 mmol, 10 mol%), and methanol (4.0 mL) were added sequentially to a 10 mL Shrek tube. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (white solid, 88% yield, 92% ee).

[0105] 1 H NMR (400 MHz, CDCl3) δ 7.76–7.71 (m, 2H), 7.50–7.45 (m, 1H), 7.40(t, J= 7.4 Hz, 2H), 7.29–7.24 (m, 2H), 7.21–7.14 (m, 3H), 6.26 (s, 1H), 3.45–3.38 (m, 1H), 3.34–3.27 (m, 1H), 2.77–2.69 (m, 1H), 2.65–2.57 (m, 1H), 1.82–1.69 (m, 2H), 1.57–1.46 (m, 1H), 1.03 (d, J = 6.6 Hz, 3H); 13 C NMR (101MHz, CDCl3) δ 167.8, 142.5, 134.9, 131.4, 128.6, 128.5, 128.5, 127.0, 125.9, 45.9, 36.4, 33.3, 33.2, 17.8. HRMS (ESI) m / z calculated for C 18 H 22 NO + [M+H] + 268.1696, found: 268.1682. Optical rotation: [α] 20 D = -17.90 (c = 1.0 g / L, CHCl3). HPLC condition: Chiral column OD-H, n-hexane / i-PrOH = 95:5, flow rate = 1.0 mL / min, wavelength = 254 nm, tR = 36.0 min for major isomer, tR = 41.3 min for minor isomer.

[0106] Example 20

[0107]

[0108] Under a hydrogen atmosphere, alkynylamine 3b (0.2 mmol, 1 equiv), zinc powder (0.4 mmol, 2 equiv), cuprous iodide (0.02 mmol, 10 mol%), RuCl2(PPh3)3 (0.01 mmol, 5 mol%), dioxane (1.0 mL), and water (1.6 mmol, 8 equiv) were added sequentially to a 10 mL Shrek tube. The reaction mixture was stirred at 60 °C for 36 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (yellow oil, 85% yield, 92% ee).

[0109] 1 H NMR (400 MHz, CDCl3) δ 7.75–7.68 (m, 2H), 7.50–7.44 (m, 1H), 7.43–7.35 (m, 4H), 7.35–7.28 (m, 2H), 7.25–7.20 (m, 1H), 6.49 (d, J = 15.9 Hz,1H), 6.20 (s, 0.93H), 6.16–6.06 (m, 1H), 3.71–3.61 (m, 1H), 3.34–3.25 (m,1H), 2.73–2.59 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H); 13 HRMS (ESI) m / z calculated for C 18 H 20 NO + [M+H] + 266.1539, found: 266.1527. Optical rotation: [α] 20 D= -69.90 (c = 1.0 g / L, CHCl3). HPLCcondition: Chiral column OD-H, n-hexane / i-PrOH = 95:5, flow rate = 1.0 mL / min, wavelength =254 nm, tR = 28.1 min for major isomer, tR = 33.5 min forminor isomer.

[0110] Example 21

[0111]

[0112] Under a hydrogen atmosphere, alkynylamine 3b (0.2 mmol, 1 equiv), RuCl2(PPh3)3 (0.04 mmol, 2 equiv), and ethanol (2.0 mL) were added sequentially to a 10 mL Shrek tube. The reaction mixture was stirred at 35 °C for 24 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (yellow oil, 65% yield, 92% ee).

[0113] 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.2 Hz, 2H), 7.49–7.42 (m, 1H), 7.41–7.35 (m, 2H), 7.34–7.29 (m, 2H), 7.28–7.18 (m, 3H), 6.58 (d, J = 11.7Hz, 1H), 6.04 (s, 0.95H), 5.55–5.43 (m, 1H), 3.67–3.55 (m, 1H), 3.26–3.07 (m,2H), 1.16 (d, J = 6.4 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 167.4, 137.0, 135.6,134.7, 131.3, 130.6, 128.6, 128.5, 128.5, 127.0, 126.8, 45.7, 32.8, 18.6;HRMS (ESI) m / z calculated for C 18 H 20 NO+ [M+H] + 266.1539, found:266.1534.Optical rotation: [α] 20 D = 23.00 (c = 1.0 g / L, CHCl3). HPLCcondition: Chiral column OD-H, n-hexane / i-PrOH = 95:5, flow rate = 1.0 mL / min, wavelength =254 nm, tR = 19.0 min for major isomer, tR = 21.7 min forminor isomer.

[0114] Example 22

[0115]

[0116] In a 10 mL Shrek tube, 0.2 mmol of alkynylamine 3b (1 equiv), 1.0 mL of CF3CH2OH, 0.4 mmol of water (2 equiv), and 0.24 mmol of CF3SO3H (1.2 equiv) were added sequentially. The reaction mixture was stirred at 70 °C for 6 hours. After the reaction was complete, silica gel column chromatography was performed. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to obtain the target product (yellow solid, 85% yield, 92% ee).

[0117] 1 H NMR (400 MHz, CDCl3) δ 7.99–7.87 (m, 2H), 7.81–7.70 (m, 2H), 7.54(t, J = 7.4 Hz, 1H), 7.48–7.36 (m, 5H), 6.83 (s, 1H), 3.52–3.37 (m, 2H), 3.13–2.92 (m, 2H), 2.65–2.47 (m, 1H), 1.09 (d, J = 6.8 Hz, 3H); 13C NMR (101MHz, CDCl3) δ 199.6, 166.5, 135.9, 133.5, 132.3, 130.3, 127.6, 127.5, 127.1,125.8, 45.2, 43.0, 28.9, 17.9. HRMS (ESI) m / z calculated for C 18 H 20 NO2 + [M+H] + 282.1489, found: 282.1480. Optical rotation: [α] 20 D = -14.90 (c = 1.0 g / L,CHCl3). HPLC condition: Chiral column OD-H, n-hexane / i-PrOH = 95:5 , flowrate = 1.0 mL / min, wavelength =254 nm, tR = 29.1 min for majorr isomer, tR =36.3 min for minor isomer。

Claims

1. An amide-directed enantioselective hydroyynylation method for non-activated olefins, characterized in that... Follow these steps: (1) In a glove box filled with argon, weigh the nickel salt catalyst into a dry reaction tube, add the chiral ligand L*, the olefin substrate with the directing group, the base, the corresponding alkynyl bromide, the solvent, and the hydrogen source, and stir the reaction system at 40°C for 24 h. (2) After the reaction is complete, the resulting solution is concentrated under vacuum, and the crude product is purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane as the eluent. The separation yield is calculated. ; Where R1 refers to: ； R2 refers to either H or Me; R3 refers to H or n-Pr; R4 refers to: ； The nickel salt mentioned refers to nickel bromide ethylene glycol dimethyl ether, and the chiral ligand L... * for , The alkali is Na2CO3, and the hydrogen source is trimethoxysilane. The solvent is N,N-dimethylformamide; Among them, the nickel catalyst: chiral ligand L * The molar ratio of base: hydrogen source: olefin substrate: alkynyl bromide compound: organic solvent is 0.02:0.024:0.4:0.6:0.2:0.4:1.0 (mol: molar: molar: molar: volume mL). The reaction temperature is 30℃~40℃, and the volume ratio of ethyl acetate to n-hexane used as eluent is 1:

10.

2. The amide-directed enantioselective hydroyynylation method for non-activated olefins according to claim 1, characterized in that: When an unactivated olefin is used as an olefin substrate, a highly chiral propyne amide product is obtained.

3. The application of the amide-directed enantioselective hydroacetylation method of claim 1 in achieving products with high regioselectivity, high enantioselectivity and high separation rate under mild conditions.

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