CN115850318A - Amide-oriented asymmetric hydrogenation ethynylation method for non-activated olefin - Google Patents
Amide-oriented asymmetric hydrogenation ethynylation method for non-activated olefin Download PDFInfo
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Abstract
The invention relates to an asymmetric hydrogenation ethynylation method of amide-oriented non-activated olefin. Under the argon atmosphere, using metal nickel salt, chiral ligand, alkali, hydrogen source and the like to dissolve olefin and alkynyl bromide compound in an organic solvent for reaction, and obtaining the chiral homopropargylamine product with excellent regioselectivity and enantioselectivity. The method has the advantages of simple and convenient experimental process, easy operation, mild condition and good functional group universality, uses cheap transition metal nickel as a catalyst, uses commercially available alkynyl bromide as a raw material.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a method for obtaining a chiral homopropargylamine compound with excellent regioselectivity and enantioselectivity by asymmetric hydroacetylation of amide-guided inactive olefin.
Background
The fatty amine belongs to an important organic compound and is a constituent unit of various natural products, agricultural chemicals and medicines with biological activity, so that the fatty amine has important practical significance and value for the research of the fatty amine. Many researchers have been working on finding new synthetic approaches to obtain such compounds.
Olefins, which are widely found in natural products and pharmaceuticals, are one of the most abundant organic molecules and are available in large quantities from fossil feedstocks and renewable resources. In recent years, transition metal-catalyzed functionalization reactions of olefins have attracted attention, and the method is an effective strategy for rapidly improving molecular complexity and diversity and has high atom economy and step economy.
The hydrogenation and alkynylation reaction of the olefin can quickly and efficiently obtain the aliphatic amine containing various alkyne modifications. The complex molecules required by people are simply, conveniently and quickly generated by the olefin substrate which is easy to obtain. In 2016, the Libyjie group of subjects reported an iridium-catalyzed asymmetric hydroacetylation reaction of β -selective vinylamines. This is the first time that alkynylation occurs at the β position, which is relatively electron rich, rather than the α position, which is relatively electron deficient. (Bai, X-Y. \8225; wang, Z-X. \8225; li, B. -J.), Angew. Chem. Int. Ed.2016, 559007-9011.) in the same year, he reported the same series of catalystsThe asymmetric alkyne and chemical reaction of the gamma-position of the alkenyl acid derivative has better functional group tolerance and excellent enantioselectivity. (Wang, Z. -X.; bai, X. -Y.; yao, H. -C.; li, B. -J.), J. Am. Chem. Soc.2016, 13814872.) in 2021, the Juolin project group discovered remote hydroalkynylation and asymmetric alkynylation of phenyl-substituted, non-activated olefins. The reaction takes the polymethylhydrosiloxane as a hydrogen source to act with the alkynyl bromide, and the remote hydroacetylation reaction of migrating to the benzyl position is realized. (X, jiang, B, han, Y, xue, M, duan, Z, gui, Y, wang, S, zhu,Nat. Commun. 2021 ,12, 3792.）。
most of the previous catalytic systems are carried out by using expensive noble metals, and the system for catalyzing unactivated olefin by using cheap metal nickel is rare, and particularly asymmetric alkynylation of chiral homopropargylamine is not reported. Therefore, we invented a milder, extensive alkynyl range, high regioselectivity and enantioselectivity method to synthesize the required chiral beta alkynyl branched amine.
Disclosure of Invention
The invention aims to provide a method for synthesizing chiral homopropargylamine, which has the advantages of simple and convenient experimental process, easy operation, mild conditions, good functional group universality, excellent regioselectivity and enantioselectivity, uses cheap transition metal nickel as a catalyst, uses commercially available alkynyl bromide as a raw material, and is suitable for synthesis of chiral homopropargylamine.
In order to solve the problem of asymmetric hydroalkynylation of a non-activated olefin substrate, the synthesis of chiral homopropargylamine is realized at a lower temperature by optimizing the conditions of the type of a catalyst, a ligand, alkali, a solvent, a hydrogen source, temperature, reaction time and the like. The experimental method can be used for converting corresponding chiral alkylamine (such as example 19) and chiral alkenylamine (such as examples 20 and 21) and the like, has potential downstream modification capability, and can also be used for further modifying alkynyl-containing medicaments (such as ethisterone) and pesticides (such as clodinafop-propargyl) to promote new characteristics.
In order to achieve the purpose, the invention discloses the following technical scheme
An amide-oriented asymmetric hydroalkynylation method of non-activated olefin is characterized by comprising the following steps:
(1) Weighing a metal nickel salt catalyst in a dry reaction tube in a glove box filled with argon, adding a ligand, an olefin substrate with a guide group, alkali, a corresponding alkynyl bromide, a solvent and a hydrogen source, and stirring and reacting a reaction system at 40 ℃ for 24 hours;
(2) After the reaction is finished, concentrating the obtained solution in vacuum, purifying the crude product by silica gel column chromatography, and calculating the separation yield by using a mixture of ethyl acetate and n-hexane as an eluent;
wherein R1 means:
r2 refers to: me;
r3 refers to: n-Pr;
r4 refers to:
the nickel salt is nickel ethylene glycol dimethyl ether bromide, and the chiral ligand L * See below for Na as base 2 CO 3 The hydrogen source is trimethoxy silane, and the solvent is N, N-dimethyl formamide. The dosage ratio of the metal nickel catalyst, chiral ligand, alkali, hydrogen source, olefin substrate, alkynyl bromine compound and organic solvent is as follows: the mol: the mol: the mol: the mol: mole: volume mL = 0.02; the reaction temperature is 30-40 ℃, and the volume ratio of ethyl acetate to n-hexane as an eluent is 1:10; l is *
The invention further discloses the application of the method in the aspect of realizing products with high regioselectivity, high enantioselectivity and high separation rate under mild conditions. The use of non-activated olefins as substrates yields high value-added chiral high propargylamine products (see examples 1-18 for details). Especially in applications with further modifications, the experimental results show that: the invention can maintain excellent enantioselectivity, and other optically active substances such as chiral alkylamine (4 a), chiral alkenylamine (4 b-4 c) and the like can be obtained by converting chiral high alkynylamine. The alkynyl-containing medicaments (such as ethisterone) and pesticides (such as clodinafop-propargyl) can be further modified to generate new characteristics;
the invention has the advantages and positive effects that:
1. when the non-activated olefin is used as a substrate, the chiral high-propargylamine product with high additional value can be obtained with high regioselectivity and high enantioselectivity.
2. The method has the advantages of simple and convenient experimental process, easy operation, mild condition and good functional group universality, uses cheap transition metal nickel as a catalyst, uses commercially available alkynyl bromide as a raw material.
3. The method has wide substrate application range, is suitable for primary alkyl alkynyl bromide, secondary alkyl alkynyl bromide, tertiary alkyl alkynyl bromide and aryl alkynyl bromide, and has higher separation yield.
4. A variety of simple and versatile amides can be used as targeting groups, providing β -branched alkynylamines that are widespread in the chemical and pharmaceutical industries, and are of great research value in both novelty and utility.
Detailed Description
Further features and advantages of the present invention will be understood by the following detailed description. The examples provided are merely illustrative of the method of the present invention and do not limit the remainder of the disclosure in any way;
in the following examples, TIPS refers to a ligand
L1 * Finger/device>
NiBr 2 DME refers to nickel bromide ethylene glycol dimethyl ether complex, (MeO) 3 SiH means trimethoxysilane and DMF means N, N-dimethylformamide. The hydrogen source, the solvent, the moiety L as described above and in the invention * All are commercially available, the remainder L * Ligand synthesis see literature: 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, 261742-1747 Synthesis of non-activated alkenes is described in Triandafillidi, I., kokotou, M.G., kokotos. C.G.Org. Lett.2018, 2036-39, and Alhalib, A., kamouka, S., moran. W. J.Org. Lett.2015, 171453-1456 synthesis of alkynyl bromides is described in the literature: 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. Thomson 1 , Edward A. Anderson 1 ，Chem. Eur. J.2015, 21, 12627 - 12639.
Example 1
In a glove box filled with argon, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2a (0.4 mmol, 2 equiv), DMF (1 mL)，(MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to obtain the objective product (white solid, 89% yield, 92% ee).
1 H NMR (400 MHz, CDCl 3 ) 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 (101 MHz, CDCl 3 ) 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, CHCl 3 ). HPLC condition: 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 for minor isomer.
Example 2
In a glove box filled with argon, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2b (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 30 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (colorless oil, 85% yield, 92% ee).
1 H NMR (400 MHz, CDCl 3 ) 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); 13 C NMR (101 MHz, CDCl 3 ) 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 for C 18 H 18 NO + [M+H] + 264.1383, found: 264.1390. Optical rotation: [α] 20 D = -117.80 (c = 1.0 g/L, CHCl 3 ). 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 majorr isomer, tR = 77.4 min for minor isomer.
Example 3
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1b (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2a (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (colorless oil, 95% yield, 91% ee).
1 H NMR (400 MHz, CDCl 3 ) 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 = 6.9 Hz, 3H), 1.06 (d, J = 3.1 Hz, 21H).; 13 C NMR (101 MHz, CDCl 3 ) 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 H 36 NO 2 Si + [M+H] + 374.2510, found: 374.2518. Optical rotation: [α] 20 D = -6.29 (c = 1.0 g/L, CHCl 3 ). HPLC condition: Chiral column OD-H, n-hexane/i-PrOH = 95:5 , flow rate = 1.0 mL/min, wavelength =254 nm, tR = 10.7 min for majorr isomer, tR = 13.4 min for minor isomer.
Example 4
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1c (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2a (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to obtain the objective product (white solid, 89% yield, 92% ee).
1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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, CHCl 3 ). HPLC condition: Chiral column OD-H, n-hexane/i-PrOH = 95:5 , flow rate = 1.0 mL/min, wavelength =254 nm, tR = 7.2 min for majorr isomer, tR = 7.8 min for minor isomer.
Example 5
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1d (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2a (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to give the desired product (colorless oil, 74% yield, 90% ee).
1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.2 Hz, 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, CDCl 3 ) 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, CDCl 3 ) δ -62.94. HRMS (ESI) m/z calculated for C 22 H 33 F 3 NOSi + [M+H] + 412.2278, found: 412.2284. Optical rotation: [α] 20 D = -6.59 (c = 1.0 g/L, CHCl 3 ).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 = 8.0 min for minor isomer.
Example 6
In an argon-filled glove box, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1e (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2b (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 30 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (white solid, 92% yield, 90% ee).
1 H NMR (400 MHz, CDCl 3 ) 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 C NMR (101 MHz, CDCl 3 ) 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 for C 17 H 22 NO 2 + [M+H] + 272.1645, found: 272.1649. Optical rotation: [α] 20 D = -7.99 (c = 1.0 g/L, CHCl 3 ). 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 majorr isomer, tR = 50.8 min for minor isomer.
Example 7
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1f (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2b (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 30 ℃ for 24 hours. After the reaction is finishedAfter completion, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (brown solid, 94% yield, 88% ee).
1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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/z calculated 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, CHCl 3 ). HPLC condition: Chiral column OD-H, n-hexane/i-PrOH = 95:5 , flow rate = 1.0 mL/min, wavelength =254 nm, tR = 9.8 min for majorr isomer, tR = 10.5 min for minor isomer.
Example 8
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1g (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2b (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (colorless oil, 54% yield, 90% ee).
1 H NMR (400 MHz, CDCl 3 ) 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, 1H), 3.85–3.78 (m, 1H), 3.44–3.36 (m, 1H), 2.96–2.88 (m, 1H), 1.63–1.58 (m, 2H), 1.57–1.41 (m, 2H), 1.41–1.32 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) 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, CHCl 3 ). HPLC condition: Chiral column AD-H, n-hexane/i-PrOH = 97:3 , flow rate = 1.0 mL/min, wavelength =254 nm, tR = 31.9 min for majorr isomer, tR = 27.5 min for minor isomer.
Example 9
In a glove box filled with argon, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1h (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2b (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (colorless oil, 83% yield, 77% ee).
1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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 for C 19 H 16 NO 2 + [M+H] + 290.1176, found: 290.1168. Optical rotation: [α] 20 D = -29.90 (c = 1.0 g/L, CHCl 3 ). 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 majorr isomer, tR = 15.2 min for minor isomer.
Example 10
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2c (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 30 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (pale yellow solid, 95% yield, 95% ee).
1 H NMR (400 MHz, CDCl 3 ) 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 = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) 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 H 20 NO + [M+H] + 278.1539, found: 278.1541. Optical rotation: [α] 20 D = -11.98 (c = 1.0 g/L, CHCl 3 ). HPLC condition: 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 for minor isomer.
Example 11
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2d (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (yellow solid, 96% yield, 92% ee).
1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 )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, CDCl 3 ) δ -62.79. HRMS (ESI) m/z calculated for C 19 H 17 F 3 NO + [M+H] + 332.1257, found: 332.1260. Optical rotation: [α] 20 D = -79.90 (c = 1.0 g/L, CHCl 3 ). 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 majorr isomer, tR = 29.8 min for minor isomer.
Example 12
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2e (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (yellow oil, 57% yield, 92% ee).
1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 7.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 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); 13 C NMR (101 MHz, CDCl 3 ) δ 167.7, 134.5, 132.2, 132.0, 131.7, 128.7, 128.3, 126.9, 118.5, 111.3, 96.6, 80.9, 44.8, 27.6, 18.2. HRMS (ESI) m/z calculated for C 19 H 17 N 2 O + [M+H] + 289.1335, found: 289.1324. Optical rotation: [α] 20 D = -47.90 (c = 1.0 g/L, CHCl 3 ). HPLC condition: Chiral column OD-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.
Example 13
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2f (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After the reaction is completed, the crude product is purified by silica gel column chromatography using ethyl acetateA mixture of ethyl acetate and petroleum ether was used as eluent to give the desired product (yellow solid, 93% yield, 82% ee).
1 H NMR (400 MHz, CDCl 3 ) 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 C NMR (101 MHz, CDCl 3 ) 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/z calculated for C 20 H 20 NO 3 + [M+H] + 322.1438, found: 322.1429. Optical rotation: [α] 20 D = -8.89 (c = 1.0 g/L, CHCl 3 ). HPLC condition: Chiral column OD-H, n-hexane/i-PrOH = 96:4 , flow rate = 1.0 mL/min, wavelength =254 nm, tR = 44.3 min for majorr isomer, tR = 55.7 min for minor isomer.
Example 14
In a glove box filled with argon, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2g (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (yellow oil, 95% yield, 93% ee).
1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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, CHCl 3 ). 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 for majorr isomer, tR = 34.7 min for minor isomer.
Example 15
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2h (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (colorless oil, 93% yield, 95% ee).
1 H NMR (400 MHz, CDCl 3 ) 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); 13 C NMR (101 MHz, CDCl 3 ) 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, CHCl 3 ). HPLC condition: Chiral column OD-H, n-hexane/i-PrOH = 96:4 , flow rate = 1.0 mL/min, wavelength =254 nm, tR = 32.4 min for majorr isomer, tR = 56.5 min for minor isomer.
Example 16
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2i (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (yellow oil, 88% yield, 93% ee).
1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) δ 171.1, 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 NO 3 + [M+H] + 288.1594, found: 288.1580. Optical rotation: [α] 20 D = -54.90 (c = 1.0 g/L, CHCl 3 ). HPLC condition: 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 for minor isomer.
Example 17
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2j (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (yellow oil, 95% yield, 94% ee).
1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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 NO 2 + [M+H] + 336.1958, found: 336.1944. Optical rotation: [α] 20 D = -38.90 (c = 1.0 g/L, CHCl 3 ). HPLC condition: 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.
Example 18
In argon-filled glove boxes, niBr 2 DME (0.02 mmol, 10 mol%), ligand L1 (0.024 mmol, 12 mol%), olefinic substrate 1a (0.2 mmol, 1.0 equiv), na 2 CO 3 (0.40 mmol, 2 equiv), the corresponding alkynyl bromoelectrophile 2k (0.4 mmol, 2 equiv), DMF (1 mL), (MeO) 3 SiH (0.60 mmol, 3 equiv) was added to a 4 mL reaction tube. The reaction mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (yellow oil, 59% yield, 90% ee).
1 H NMR (400 MHz, CDCl 3 ) 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); 13 C NMR (101 MHz, CDCl 3 ) 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 for C 19 H 26 NO 2 + [M+H] + 300.1958, found: 300.1948. Optical rotation: [α] 20 D = -21.50 (c = 1.0 g/L, CHCl 3 ). 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 majorr isomer, tR = 15.7 min for minor isomer.
Example 19
The series chiral alkynylamines synthesized by the method have practical synthesis and application potentials: wherein typical compounds are used for the synthesis of chiral alkylamines (e.g. 4 a) and chiral alkenylamines (4 b, 4 c) by reduction.
To a 10mL Schlenk tube under a hydrogen atmosphere were added alkynylamine 3b (0.2 mmol, 1 equiv), pd/C (0.02 mmol, 10 mol%) and methanol (4.0 mL) in that order, and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (white solid, 88% yield, 92% ee).
1 H NMR (400 MHz, CDCl 3 ) 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 (101 MHz, CDCl 3 ) 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, CHCl 3 ). 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.
Example 20
To a 10mL Schlenk tube were added, 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%) and RuCl in that order 2 (PPh 3 ) 3 (0.01 mmol, 5 mol%), dioxane (1.0 mL) and water (1.6 mmol, 8 equiv), and the reaction mixture was stirred at 60 ℃ for 36 h. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (yellow oil, 85% yield, 92% ee).
1 H NMR (400 MHz, CDCl 3 ) 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 C NMR (101 MHz, CDCl 3 ) δ 166.5, 136.0, 133.7, 132.0, 130.4, 129.7, 127.6, 127.6, 126.4, 125.8, 125.1, 44.2, 36.8, 17.2. 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, CHCl 3 ). HPLC condition: 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 for minor isomer.
Example 21
To a 10mL Schlenk tube under a hydrogen atmosphere were added alkynylamine 3b (0.2 mmol, 1 equiv), ruCl 2 (PPh 3 ) 3 (0.04 mmol, 2 equiv) and ethanol (2.0 mL), and the reaction mixture was stirred at 35 ℃ for 24 h. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (yellow oil, 65% yield, 92% ee).
1 H NMR (400 MHz, CDCl 3 ) 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 = 11.7 Hz, 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, CDCl 3 ) 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, CHCl 3 ). HPLC condition: 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 for minor isomer.
Example 22
To a 10mL Schlenk tube were added the alkynylamine 3b (0.2 mmol, 1 equiv), CF in that order 3 CH 2 OH (1.0 mL), water (0.4 mmol, 2 equiv) and CF 3 SO 3 H (0.24 mmol, 1.2 equiv), the reaction mixture was stirred at 70 ℃ for 6H. After completion of the reaction, silica gel column chromatography was performed, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to give the objective product (yellow solid, 85% yield, 92% ee).
1 H NMR (400 MHz, CDCl 3 ) 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); 13 C NMR (101 MHz, CDCl 3 ) 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 NO 2 + [M+H] + 282.1489, found: 282.1480. Optical rotation: [α] 20 D = -14.90 (c = 1.0 g/L, CHCl 3 ). HPLC condition: Chiral column OD-H, n-hexane/i-PrOH = 95:5 , flow rate = 1.0 mL/min, wavelength =254 nm, tR = 29.1 min for majorr isomer, tR = 36.3 min for minor isomer。
Claims (5)
1. An amide-directed, non-activated olefin enantioselective hydrochlorination process characterised by the steps of:
(1) Weighing a metal nickel salt catalyst in a dry reaction tube in a glove box filled with argon, adding a ligand, an olefin substrate with a guide group, alkali, a corresponding alkynyl bromide, a solvent and a hydrogen source, and stirring and reacting a reaction system at 40 ℃ for 24 hours;
(2) After the reaction is finished, concentrating the obtained solution in vacuum, purifying the crude product by silica gel column chromatography, and calculating the separation yield by using a mixture of ethyl acetate and n-hexane as an eluent;
wherein R1 means:
r2 refers to: me;
r3 refers to: n-Pr;
r4 means:
2. an amide-directed asymmetric hydroacetylation process as claimed in claim 1, wherein: the metal
L * Is composed of
The nickel salt is nickel ethylene glycol dimethyl bromide, and the chiral ligand L * See above; the alkali is Na 2 CO 3 The hydrogen source is trimethoxy silane, and the solvent is N, N-dimethyl formamide.
3. The metal nickel catalyst comprises chiral ligand, alkali, hydrogen source, olefin substrate, alkynyl bromine compound and organic solvent, and the dosage ratio of the metal nickel catalyst to the chiral ligand to the alkali to the hydrogen source to the olefin substrate to the alkynyl bromine compound to the organic solvent is as follows: the mol: mole: mole: mole: mole: volume mL = 0.02; the reaction temperature is 30-40 ℃, and the volume ratio of ethyl acetate to n-hexane as the eluent is 1:10.
4. an amide-directed asymmetric hydroacetylation process as claimed in claim 1, wherein: when the non-activated olefin is used as an olefin substrate, a chiral high propargylamine product with high added value is obtained.
5. Use of the process according to claim 1 for achieving products with high regioselectivity, high enantioselectivity and high separation rate under mild conditions.
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