A method for nickel-catalyzed hydroamination alkylation of aliphatic olefins

Abstract

The invention discloses a method for hydrogenation of aliphatic olefins by nickel catalysis. The reaction process is as follows: in a nitrogen atmosphere, a compound 2, a nickel catalyst, an aromatic boronic acid, a base, a solvent, an additive, a phosphine ligand and a compound 1 are sequentially mixed, stirred at 80-120°C for reaction for 18-36 hours, cooled to room temperature, decompressed to remove the solvent, and separated by column chromatography to obtain a target product. When the phosphine ligand is tri-tert-butyl phosphine, the target product is compound 3, and when the phosphine ligand is diphenylethyl phosphine, the target product is compound 4. The molar ratio of the compound 2, the phosphine ligand, the nickel catalyst, the aromatic boronic acid, the base and the additive is 1:(0.1-0.4):(0.05-0.2):(0.2-1.2):(0.4-1.2):(0.05-0.2), the equivalent ratio of the compound 1 to the compound 2 is 1:(1-3), R 1 is an alkyl group or a silicon group, R 2 is an alkyl, aryl or heteroaryl group, R 3 The present invention can selectively synthesize branched or chain alkylamine compounds only by regulating the ligand in the nickel catalyst.

Description

Technical Field

[0001] The present invention relates to the technical field of material preparation, and particularly relates to a method for nickel-catalyzed hydroamination alkylation of aliphatic olefins. Background Art

[0002] The hydroamination alkylation reaction of olefins refers to the reaction of adding a hydrogen atom and an aminoalkyl group to the double bond of an olefin, which has important value in the synthesis of pharmaceuticals, pesticides and fine chemicals. By regulating the catalyst, branched or linear alkylamine products can be selectively synthesized, and different products can be synthesized from the same starting substrate, which makes it have higher synthesis efficiency and atom economy. However, there has been no reported regioselective hydroamination alkylation reaction that can achieve such catalyst regulation. In the past few decades, early transition metal and late transition metal catalysts have been developed for the hydroamination alkylation reaction of aliphatic olefins:

[0003] A) Early transition metal catalysts (such as titanium, zirconium, tantalum, niobium and scandium, etc.) have attracted extensive research interest due to their high activity. However, they are sensitive to air and moisture, and the functional group tolerance is limited (DiPucchio, R.; S.-C.; Schafer, L. L. Angew. Chem., Int. Ed. 2018, 57, 3469; Bielefeld, J.; Doye, S. Angew. Chem., Int. Ed. 2020, 59, 6138). They are commonly used for methylamine substrates and give branched-chain selective products, but the reactions they catalyze have poor selectivity for other alkylamine substrates. The hydroamination alkylation reaction formula of early transition metal-catalyzed aliphatic olefins is as follows:

[0004]

[0005] B) Late transition metal catalysts (such as noble metal catalysts such as ruthenium and iridium), although they have good functional group tolerance, the reactions are limited to amine substrates with pyridine directing groups and usually give linear products (Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935; Pan, S.; Endo, K.; Shibata, T. Org. Lett. 2011, 13, 4692). The hydroamination alkylation reaction formula of late transition metal-catalyzed aliphatic olefins is as follows:

[0006]

[0007] C) Late transition metal nickel is an abundant and inexpensive metal on Earth. Although there have been reports of nickel-catalyzed aliphatic olefin hydroamine alkylation reactions, using a zero-valent nickel complex coordinated by tricyclohexylphosphine (PCy3) as a catalyst, the selectivity of the product is not controlled, and usually both branched and linear mixed products are obtained at the same time, with a ratio of approximately 1:1 (Yan, X.-B.; Li, L.; Wu, W.-Q.; Xu, L.; Li, K.; Liu, Y.-C.; Shi, H. Nat. Commun. 2021, 12, 5881). The reaction formula is as follows:

[0008]

[0009] Although progress has been made, the efficient and selective hydroamine alkylation of aliphatic olefins usually requires a combination of specific substrates, which is not practical. The catalysts reported so far are mainly early transition metals that are sensitive to water and oxygen and expensive late transition metals. So far, there has been no report on the regioselective hydroamine alkylation of aliphatic olefins catalyzed by nickel. Summary of the invention

[0010] The purpose of the present invention is to provide a method for the hydrogenation of aliphatic olefins by nickel catalysis. The hydrogenation of aliphatic olefins is simple and practical. The method can selectively synthesize branched or chain alkylamine compounds by reacting cheap aliphatic olefins with simple sulfonamide reagents only by regulating the ligands in the nickel catalyst. The selectivity of the nickel-catalyzed hydrogenation of aliphatic olefins is regulated by changing the organic phosphine ligands.

[0011] To this end, the present invention adopts the following technical solutions:

[0012] A nickel-catalyzed hydroamine alkylation method for aliphatic olefins, the reaction formula and reaction process are as follows:

[0013]

[0014] In a nitrogen atmosphere, compound 2, a nickel catalyst, an aromatic boronic acid, a base, a solvent, an additive, a phosphine ligand and compound 1 are sequentially mixed, stirred at 80 to 120° C. for 18 to 36 hours, cooled to room temperature, the solvent is removed under reduced pressure, and the target product is separated by column chromatography. When the phosphine ligand is tri-tert-butylphosphine (P t When the phosphine ligand is diphenylethylphosphine (PPh2Et), the target product is compound 4;

[0015] The molar ratio of the compound 2, phosphine ligand, nickel catalyst, arylboronic acid, base and additive is 1:(0.1 - 0.4):(0.05 - 0.2):(0.2 - 1.2):(0.4 - 1.2):(0.05 - 0.2), and the equivalent ratio of compound 1 and compound 2 is 1:(1 - 3), R 1 is alkyl or silyl, R 2 is alkyl, aryl or heteroaryl, R 3 is aryl.

[0016] In the above technical solution, the dosage ratio of the compound 2 and the solvent is 1 mmol:(2 - 10) ml.

[0017] In the above technical solution, the nickel catalyst is NiBr2·DME.

[0018] In the above technical solution, the additive is one of aryl bromide, aryl imine and alkyl imine.

[0019] In the above technical solution, the base is potassium tert-butoxide.

[0020] In the above technical solution, the solvent is benzene, toluene or mesitylene.

[0021] In the above technical solution, the arylboronic acid is phenylboronic acid, 4-methoxyphenylboronic acid or 4-methylphenylboronic acid.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. By only regulating the organic phosphorus ligand in the nickel catalyst, the selective synthesis of branched or linear alkylamine compounds can be achieved;

[0024] 2. All kinds of reagents used in the present invention are commercially available, the raw materials are widely sourced and inexpensive, and all kinds of reagents can stably exist under normal temperature and pressure, the operation and treatment are convenient, and no special treatment is required;

[0025] 3. The present invention has carried out gram-scale experiments, and the reaction is suitable for large-scale production;

[0026] 4. The operation of the present invention is simple, and the target product can be obtained by one-step reaction, avoiding the use of dangerous reagents such as organometallic reagents that are extremely sensitive to air and water, and there are no special requirements for post-treatment, greatly reducing the production cost of synthesizing such compounds and improving safety;

[0027] 5. The present invention uses an inexpensive and stable divalent nickel catalyst, which meets the requirements of simplifying the process, facilitating post-treatment, convenient solvent recovery and utilization, and reducing environmental pollution while maintaining good catalytic effects and reducing costs. Specific embodiments

[0028] The method of the present invention will be described in detail below in conjunction with embodiments.

[0029] P used in the following embodiments t Bu3 are all PBu3 solutions with a concentration of 50 wt% dissolved in toluene, i.e.: P t Bu3, 50 wt% in toluene, is a commercially available product. t Bu3, 50 wt% in toluene, is a commercially available product.

[0030] Example 1

[0031] Synthesis of N-(1-cyclohexyl-2-methyl-4-phenylbutyl)-4-methylbenzene sulfonamide (3a).

[0032] The synthesis route is as follows:

[0033]

[0034] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1a (30.0 μL, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and silica gel column chromatography separation (the eluent is a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:8) is carried out to obtain 39.5 mg of white solid (3a) with a yield of 99%. 11H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.25–7.14 (m, 5H), 7.01 (d, J = 7.4 Hz, 2H), 4.47 (d, J = 9.7 Hz, 1H), 3.15 (ddd, J = 10.2, 7.4, 3.4 Hz, 1H), 2.47 (dt, J = 9.3, 6.2 Hz, 2H), 2.34 (s, 3H), 1.75–1.65 (m, 4H), 1.61–1.54 (m, 2H), 1.41–1.35 (m, 1H), 1.32–1.26 (m, 1H), 1.18–1.05 (m, 4H), 0.90 (dt, J = 12.4, 8.8 Hz, 2H), 0.78 (d, J = 6.8 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 142.7, 142.2, 139.4, 129.3, 128.3, 128.2, 126.8, 125.6, 62.9, 40.9, 36.4, 33.8, 33.5, 30.7, 29.7, 26.3, 26.2, 21.5, 14.2. HRMS (ESI) calcd. for 24 H 33 NO2S, M+Na] + : 422.2124, found: 422.2128. m.p. = 102–103 °C.

[0035] Example 2

[0036] Synthesis of N-(1-cyclohexyl-2-methylheptyl)-4-methylbenzenesulfonamide (3b).

[0037] The synthetic route is as follows:

[0038]

[0039] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: sequentially adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), benzene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P tBu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1b (28.0 μL, 0.20 mmol) were stirred and reacted under nitrogen at 80 °C for 18 hours and then cooled to room temperature. After the reaction was completed, the solvent was removed under reduced pressure and separated by silica gel column chromatography (the eluent used for silica gel column chromatography was a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether was 1:8), obtaining 29.9 mg of a white solid (3b) with a yield of 82%. 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 4.59–4.41 (m, 1H), 3.07 (ddd, J = 10.2, 7.4, 3.5 Hz, 1H), 2.41 (s, 3H), 1.78–1.67 (m, 3H), 1.60 (d, J = 10.8 Hz, 3H), 1.34–1.28 (m, 1H), 1.21–1.04 (m, 8H), 1.03–0.97 (m, 2H), 0.91 (ddd, J = 14.3, 8.3, 4.2 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 142.7, 139.5, 129.3, 126.9, 63.0, 40.9, 34.7, 34.1, 32.0, 30.7, 29.7, 26.9, 26.4, 26.3, 22.6, 21.4, 14.2, 14.1. HRMS (ESI) calcd. for 21 H 35 NO2S, M+Na] + : 388.2281, found: 388.2280. m.p. = 114–115 °C.

[0040] Example 3

[0041] Synthesis of N-(1-cyclohexyl-2-methyldecyl)-4-methylbenzenesulfonamide (3c).

[0042]

[0043] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol) into a reaction flask, tBuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (0.8 mg, 0.005 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1c (38.0 μL, 0.20 mmol) were stirred at 100 °C under nitrogen for 18 h and then cooled to room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (the eluent for silica gel column chromatography was a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether was 1:10), to give 39.5 mg of a white solid (3c) in a yield of 97%. 1 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 4.44 (d, J = 9.7 Hz, 1H), 3.08 (ddd, J = 10.3, 7.3, 3.5 Hz, 1H), 2.40 (s, 3H), 1.79–1.66 (m, 4H), 1.63–1.55 (m, 3H), 1.31–1.19 (m, 8H), 1.16–1.02 (m, 8H), 0.94–0.87 (m, 5H), 0.80 (dq, J = 11.4, 3.9, 3.2 Hz, 1H), 0.71 (d, J = 6.8 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 142.7, 139.5, 129.3, 126.9, 63.0, 40.9, 34.8, 34.1, 31.9, 30.7, 29.7, 29.7, 29.5, 29.4, 27.3, 26.4, 26.3, 22.7, 21.4, 14.3, 14.1. HRMS (ESI) calcd. for 24 H 41 NO2S, M-H] - : 406.2785, found: 406.2787. m.p. = 90–91 °C.

[0044] Example 4

[0045] Synthesis of N-(1-cyclohexyl-2,4-dimethylpentyl)-4-methylbenzenesulfonamide (3d).

[0046] The synthetic route is as follows:

[0047]

[0048] The method for nickel-catalyzed hydroamination alkylation of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1d (16.8 mg, 0.20 mmol) into a reaction flask, and stirring and reacting at 100 °C under a nitrogen atmosphere for 18 hours, then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and separation by silica gel column chromatography (the eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:10) gives 21.1 mg of a white solid (3d) with a yield of 60%. 1 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 5.1 Hz, 2H), 4.24 (d, J = 9.7 Hz, 1H), 3.04 (ddd, J = 10.1, 7.4, 3.2 Hz, 1H), 2.40 (s, 3H), 1.80–1.63 (m, 5H), 1.44 (dt, J = 13.5, 6.7 Hz, 1H), 1.32 (dt, J = 11.4, 3.7 Hz, 1H), 1.18–1.07 (m, 3H), 1.02–0.84 (m, 3H), 0.83–0.73 (m, 2H), 0.69 (dd, J = 6.7, 3.4 Hz, 6H), 0.66 (d, J = 6.4 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 142.7, 139.5, 129.4, 126.9, 63.2, 44.0, 41.0, 31.2, 30.8, 29.9, 26.4, 26.3, 26.3, 24.8, 23.0, 22.0, 21.4, 14.2. HRMS (ESI) calcd. for [C 20 H 33 NO2S, M-H] - : 350.2159, found: 350.2158. m.p. = 189–190 °C.

[0049] Example 5

[0050] Synthesis of N-(1,3-dicyclohexyl-2-methylpropyl)-4-methylbenzenesulfonamide (3e).

[0051] The route is as follows:

[0052]

[0053] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: sequentially adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhCH=NTs (5.2 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1e (24.8 mg, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and silica gel column chromatography separation is carried out (the eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether, and the ratio of ethyl acetate to petroleum ether is 1:10 by volume), obtaining 23.0 mg of white solid (3e) with a yield of 59%. 1 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.37 (s, 1H), 2.95 (ddd, J = 10.1, 7.3, 3.1 Hz, 1H), 2.33 (s, 3H), 1.76–1.59 (m, 5H), 1.44 (t, J = 8.7 Hz, 2H), 1.38–1.18 (m, 4H), 1.05 (qd, J = 19.5, 16.2, 10.9 Hz, 8H), 0.87 (qd, J = 12.2, 3.2 Hz, 3H), 0.74–0.68 (m, 1H), 0.64–0.53 (m, 5H). 13 13C NMR (101 MHz, CDCl3) δ 142.7, 139.5, 129.3, 126.9, 63.2, 42.4, 41.0, 34.4, 33.8, 32.8, 30.7, 30.3, 29.8, 26.7, 26.4, 26.3, 26.3, 26.3, 26.2, 21.4, 14.3. HRMS (ESI) calcd. for [C 23 H 37 NO2S, M-H]- : 390.2472, found: 390.2475. m.p. = 115–117 °C.

[0054] Example 6

[0055] Synthesis of N-(1-cyclohexyl-2-methylnon-8-en-1-yl)-4-methylbenzenesulfonamide (3f).

[0056] The route is as follows:

[0057]

[0058] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1f (33.0 mg, 0.30 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and separation by silica gel column chromatography (the eluent used in silica gel column chromatography is a mixture of ethyl acetate and petroleum ether, and the ratio of ethyl acetate to petroleum ether is 1:10 by volume) gives 29.7 mg of a white solid (3f) with a yield of 79%. 1 1H NMR (400 MHz, CDCl3) δ 7.7 (d, J = 7.9 Hz, 2H), 7.2 (d, J = 8.0 Hz, 2H), 5.8–5.1 (m, 2H), 5.0–4.7 (m, 1H), 4.4 (dt, J = 17.5, 8.9 Hz, 1H), 3.0 (ddd, J = 10.1, 7.1, 3.4 Hz, 1H), 2.3 (d, J = 2.6 Hz, 3H), 1.9 (d, J = 6.8 Hz, 1H), 1.7–1.6 (m, 4H), 1.5 (dd, J = 10.4, 5.3 Hz, 3H), 1.2 (dddd, J = 16.2, 12.6, 7.6, 3.8 Hz, 2H), 1.1–1.0 (m, 6H), 0.9–0.8 (m, 4H), 0.6 (d, J = 6.8 Hz, 3H). 1313C NMR (101 MHz, CDCl3) δ 142.7, 139.5, 139.0, 127.0, 126.9, 114.2, 63.0, 40.9, 40.9, 34.6, 34.1, 33.6, 30.7, 29.7, 28.9, 26.7, 26.3, 21.5, 17.9, 14.2. HRMS (ESI) calcd. for 22 H 35 NO2S, M - H] - : 376.2316, found: 376.2318. m.p. = 83–84 °C.

[0059] Example 7

[0060] Synthesis of 5 - cyclohexyl - 4 - methyl - 5 - ((4 - methylphenyl)sulfonamido)pentyl benzoate (3 g).

[0061] The route is as follows:

[0062]

[0063] The nickel - catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1g (38.0 mg, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and separation by silica gel column chromatography (the eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether, and the ratio of ethyl acetate to petroleum ether is 1:10 by volume) gives 28.8 mg of a white solid with a yield of 63%. 11H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.3 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 4.41 (d, J = 9.6 Hz, 1H), 4.07 (t, J = 6.7 Hz, 2H), 3.12 (ddd, J = 10.4, 7.5, 3.4 Hz, 1H), 2.37 (s, 3H), 1.75–1.64 (m, 7H), 1.63–1.60 (m, 2H), 1.35–1.29 (m, 1H), 1.17–1.06 (m, 4H), 0.93–0.85 (m, 2H), 0.77 (d, J = 6.8 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 166.6, 143.0, 139.4, 132.9, 129.5, 129.4, 128.3, 126.9, 65.0, 62.8, 40.9, 33.8, 31.0, 30.7, 29.7, 26.4, 26.3, 26.2, 26.2, 21.4, 14.1. HRMS (ESI) calcd. for 26 H 35 [C - HNO4S, M - H]

[0064] Example 8

[0065] Synthesis of N-(5-((tert-butyldimethylsilyl)oxy)-1-cyclohexyl-2-methylpentyl)-4-methylbenzenesulfonamide (3h).

[0066] The route is as follows:

[0067]

[0068] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P tBu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1h (40.0 mg, 0.20 mmol) were stirred and reacted under nitrogen at 100 °C for 18 hours and then cooled to room temperature. After the reaction was completed, the solvent was removed under reduced pressure, and column chromatography separation (silica gel column chromatography) was carried out. The eluent used for silica gel column chromatography was a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether was 1:10, and 36.0 mg of a white solid was obtained with a yield of 77%. 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 5.3 Hz, 2H), 4.13 (d, J = 9.7 Hz, 1H), 3.44–3.30 (m, 2H), 3.05 (ddd, J = 10.0, 6.9, 3.9 Hz, 1H), 2.38 (s, 3H), 1.63 (t, J = 17.2 Hz, 5H), 1.42–1.24 (m, 4H), 1.14–0.98 (m, 5H), 0.96–0.89 (m, 2H), 0.86 (s, 9H), 0.70 (d, J = 6.8 Hz, 3H), 0.00 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 142.7, 139.5, 129.3, 126.9, 63.2, 62.9, 40.8, 34.0, 30.8, 30.5, 30.5, 29.4, 26.3, 26.2, 26.0, 21.4, 18.3, 14.5, -5.3, -5.3. HRMS (ESI) calcd. for [C 25 H 45 NO3SSi, M-H] - : 466.2817, found: 466.2820. m.p. = 98–99 °C.

[0069] Example 9

[0070] Synthesis of N-(1-cyclohexyl-2-methyl-6-phenoxyhexyl)-4-methylbenzenesulfonamide (3i).

[0071] The route is as follows:

[0072]

[0073] The method for nickel-catalyzed hydroamination alkylation of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1i (32.4 mg, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used in silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:10, obtaining 35.8 mg of a white solid with a yield of 81%. 1 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 2H), 7.25 (dd, J = 10.2, 7.9 Hz, 4H), 6.93 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 8.1 Hz, 2H), 4.36 (d, J = 9.5 Hz, 1H), 3.85 (t, J = 6.6 Hz, 2H), 3.10 (ddd, J = 10.2, 7.5, 3.3 Hz, 1H), 2.38 (s, 3H), 1.71–1.54 (m, 8H), 1.30 (dp, J = 11.0, 3.7 Hz, 3H), 1.09 (td, J = 12.6, 5.8 Hz, 4H), 0.91 (ddt, J = 16.1, 12.5, 6.2 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 159.1, 142.8, 139.5, 129.4, 129.4, 126.9, 120.5, 114.5, 67.6, 62.9, 40.9, 34.5, 34.1, 30.7, 29.8, 29.3, 26.3, 26.2, 23.7, 21.4, 14.2. HRMS (ESI) calcd. for [C 26 H 37 NO3S, M-H] - : 442.2421, found: 442.2426. m.p. = 120–121 °C.

[0074] Example 10

[0075] Synthesis of methyl 4-((5-cyclohexyl-4-methyl-5-((4-methylphenyl)sulfonamido)pentyl)-carbamoyl)bicyclo[2.2.2]octane-1-carboxylate (3j).

[0076] The route is as follows:

[0077]

[0078] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: sequentially adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1j (55.8 mg, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:4, obtaining 43.7 mg of a colorless liquid with a yield of 80%. 1 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.29 (s, 2H), 5.82 (t, J = 5.2 Hz, 1H), 4.53 (d, J = 9.6 Hz, 1H), 3.63 (s, 3H), 3.09 (p, J = 5.5, 5.1 Hz, 3H), 2.43 (s, 3H), 1.80 (s, 12H), 1.71–1.46 (m, 8H), 1.37 (ddd, J = 23.9, 12.7, 6.0 Hz, 2H), 1.05 (dt, J = 24.1, 10.9 Hz, 4H), 0.88–0.81 (m, 1H), 0.76 (d, J = 6.7 Hz, 3H), 0.69–0.58 (m, 1H). 1313C NMR (101 MHz, CDCl3) δ 178.0, 177.4, 143.0, 139.2, 129.4, 126.9, 61.9, 51.7, 40.5, 39.6, 38.7, 38.7, 33.8, 31.6, 30.6, 29.9, 28.1, 28.0, 26.8, 26.2, 26.1, 21.5, 14.4. HRMS (ESI) calcd. for [C 30 H 46 N2O5S, M - H] - : 545.3055, found: 545.3055.

[0079] Example 11

[0080] Synthesis of methyl 3 - ((5 - cyclohexyl - 4 - methyl - 5 - ((4 - methylphenyl)sulfonamido)pentyl)carbamoyl)-bicyclo[1.1.1]pentane - 1 - carboxylate (3k).

[0081] The route is as follows:

[0082]

[0083] The nickel - catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1k (47.2 mg, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:4, and 35.8 mg of white solid is obtained, with a yield of 71%. 11H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.09 (d, J = 5.8 Hz, 1H), 4.41 (d, J = 9.6 Hz, 1H), 3.62 (s, 3H), 3.11 (ddt, J = 32.7, 18.5, 8.0 Hz, 3H), 2.39 (s, 3H), 2.24 (s, 6H), 1.57 (dd, J = 50.7, 10.4 Hz, 6H), 1.44–1.34 (m, 3H), 1.16 (d, J = 9.7 Hz, 2H), 1.00 (dq, J = 31.5, 11.2, 10.2 Hz, 4H), 0.91–0.82 (m, 1H), 0.74 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 170.1, 169.5, 143.1, 139.0, 129.5, 126.9, 61.4, 52.3, 51.7, 40.5, 39.6, 33.7, 31.6, 30.6, 30.1, 29.3, 27.1, 26.4, 26.1, 26.1, 21.5, 14.4. HRMS (ESI) calcd. for 27 H 40 N2O5S, M+Na] + : 527.2550, found: 527.2554. m.p. = 66–67 °C.

[0084] Example 12

[0085] Synthesis of N-(6-chloro-1-cyclohexyl-2-methylhexyl)-4-methylbenzenesulfonamide (3l).

[0086] The route is as follows:

[0087]

[0088] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P tBu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1l (23.6 mg, 0.20 mmol) were stirred and reacted at 100 °C under nitrogen for 18 hours and then cooled to room temperature. After the reaction was completed, the solvent was removed under reduced pressure and separated by column chromatography (silica gel column chromatography). The eluent used for silica gel column chromatography was a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether was 1:10, and 30.5 mg of white solid was obtained with a yield of 79%. 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 4.47 (d, J = 9.7 Hz, 1H), 3.38 (t, J = 6.9 Hz, 2H), 3.09–3.01 (m, 1H), 2.39 (s, 3H), 1.67 (d, J = 11.0 Hz, 4H), 1.49 (q, J = 7.2 Hz, 2H), 1.34–1.20 (m, 4H), 1.07 (p, J = 12.5 Hz, 4H), 0.93–0.79 (m, 4H), 0.71 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 142.9, 139.5, 129.4, 126.9, 62.9, 44.9, 40.8, 34.0, 32.7, 30.7, 29.9, 26.3, 26.2, 24.6, 21.5, 14.0. HRMS (ESI) calcd. for [C 20 H 32 ClNO2S, M-H] - : 384.1770, found: 384.1775. m.p. = 114–115 °C.

[0089] Example 13

[0090] Synthesis of N-(1-cyclohexyl-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-methylpropyl)-4-methylbenz enesulfonamide (3m).

[0091] The route is as follows:

[0092]

[0093] The method for nickel-catalyzed hydroamination alkylation of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1m (47.0 mg, 0.20 mmol) into a reaction flask, stirring and reacting under nitrogen at 100 °C for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:10, obtaining 45.7 mg of a white solid with a yield of 91%. 1 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 2H), 7.09–7.00 (m, 6H), 6.92–6.87 (m, 2H), 6.77–6.67 (m, 2H), 4.56 (d, J = 12.1 Hz, 1H), 3.36 (td, J = 7.8, 3.9 Hz, 1H), 3.24–3.10 (m, 6H), 2.35 (s, 3H), 2.01 (qd, J = 7.2, 2.1 Hz, 1H), 1.71–1.64 (m, 2H), 1.38 (d, J = 12.3 Hz, 2H), 1.33–1.25 (m, 2H), 1.18 (dt, J = 11.2, 3.7 Hz, 1H), 1.02 (td, J = 12.7, 11.8, 9.0 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H), 0.69 (td, J = 12.8, 12.3, 3.2 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 148.3, 142.6, 139.1, 134.2, 129.9, 129.5, 126.6, 126.2, 122.6, 119.6, 60.3, 55.0, 41.7, 32.0, 31.5, 30.1, 29.9, 29.1, 26.2, 26.2, 21.6, 12.8. HRMS (ESI) calcd. for [C 31 H 38 N2O2S, M+Na] + : 525.2546, found: 525.2550. m.p. = 162–163 °C.

[0094] Example 14

[0095] Synthesis of N-(6-(9H-carbazol-9-yl)-1-cyclohexyl-2-methylhexyl)-4-methylbenzenesulfon-amide (3n).

[0096] The route is as follows:

[0097]

[0098] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1n (49.8 mg, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used in silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:10, and 43.4 mg of white solid is obtained with a yield of 84%. 1 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.7 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.49–7.43 (m, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.22 (t, J = 6.4 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 4.43 (t, J = 6.6 Hz, 1H), 4.18 (t, J = 7.2 Hz, 2H), 3.02 (ddd, J = 10.2, 7.6, 3.2 Hz, 1H), 2.23 (s, 3H), 1.69–1.62 (m, 4H), 1.60–1.49 (m, 4H), 1.25–1.16 (m, 3H), 1.03 (dt, J = 22.6, 6.4 Hz, 4H), 0.90–0.79 (m, 3H), 0.65 (d, J = 6.8 Hz, 3H). 1313C NMR (101 MHz, CDCl3) δ 142.8, 140.4, 139.5, 129.4, 126.9, 125.6, 122.9, 120.4, 118.8, 108.7, 62.8, 42.8, 40.8, 34.4, 33.9, 30.6, 29.9, 29.0, 26.3, 26.3, 25.0, 21.3, 14.1. HRMS (ESI) calcd. for [C 32 H 40 N2O2S, M - H] - : 515.2738, found: 515.2736. m.p. = 80–82 °C.

[0099] Example 15

[0100] Synthesis of N-(1-cyclohexyl-2-methyl-6-(pyridin-2-yloxy)hexyl)-4-methylbenzenesulfonamide (3o).

[0101] The route is as follows:

[0102]

[0103] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (6.2 mg, 0.02 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1o (32.6 mg, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:10, and 22.7 mg of white solid is obtained, with a yield of 53%. 11H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 5.2, 1.9 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.60–7.53 (m, 1H), 7.20 (d, J = 7.9 Hz, 2H), 6.85 (dd, J = 7.1, 5.1 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 4.44 (t, J = 7.6 Hz, 1H), 4.01 (td, J = 6.6, 4.3 Hz, 2H), 3.12 (ddd, J = 10.3, 7.4, 3.4 Hz, 1H), 2.33 (s, 3H), 1.80–1.57 (m, 8H), 1.32 (dq, J = 11.9, 4.3 Hz, 1H), 1.13 (dt, J = 18.5, 7.1 Hz, 4H), 0.94 (tdd, J = 12.4, 9.5, 4.9 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 163.9, 146.9, 142.9, 139.4, 138.5, 129.4, 126.9, 116.5, 111.0, 65.8, 62.9, 40.8, 33.9, 31.0, 30.7, 29.7, 26.7, 26.3, 26.2, 21.4, 14.2. HRMS (ESI) calcd. for 24 C 34 19H24N2O3S, M - H] - : 429.2217, found: 429.2215. m.p. = 93–95 °C.

[0104] Example 16

[0105] Synthesis of N-(1-cyclohexyl-6-(5-fluoro-1H-indol-1-yl)-2-methylhexyl)-4-methylbenzenesulfonamide (3p).

[0106] The route is as follows:

[0107]

[0108] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol) into the reaction flask, tBuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1p (43.4 mg, 0.20 mmol) were stirred and reacted at 100 °C under nitrogen for 18 hours and then cooled to room temperature. After the reaction was completed, the solvent was removed under reduced pressure, and column chromatography separation (silica gel column chromatography) was carried out. The eluent used for silica gel column chromatography was a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether was 1:10, and 40.7 mg of a white solid was obtained with a yield of 84%. 1 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.30–7.23 (m, 2H), 7.21–7.18 (m, 2H), 7.09 (d, J = 3.2 Hz, 1H), 6.97–6.92 (m, 1H), 6.43 (d, J = 3.2 Hz, 1H), 4.34 (d, J = 9.7 Hz, 1H), 3.99 (t, J = 7.2 Hz, 2H), 3.04 (ddd, J = 10.3, 7.6, 3.2 Hz, 1H), 2.32 (s, 3H), 1.61–1.47 (m, 6H), 1.17 (td, J = 14.3, 6.7 Hz, 4H), 1.05 (td, J = 13.0, 11.4, 7.6 Hz, 4H), 0.86 (ddt, J = 25.5, 14.0, 7.8 Hz, 4H), 0.69 (d, J = 6.8 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 157.7 (d, J = 234.0 Hz), 142.9, 139.4, 132.6, 129.4, 129.3, 128.7 (d, J = 10.2 Hz), 126.9, 109.9 (d, J = 9.7 Hz), 109.7 (d, J = 26.5 Hz), 105.6 (d, J = 23.2 Hz), 100.8 (d, J = 4.8 Hz). 62.7, 46.5, 40.8, 34.1 (d, J = 28.2 Hz), 30.6, 30.2, 29.8, 26.3, 26.2, 24.6, 21.4, 14.1. 19 19F NMR (376 MHz, CDCl3) δ -125.8. HRMS (ESI) calcd. for 28 H 37 FN2O2S M-H] - : 483.2487, found: 483.2485. m.p. = 81–83 °C.

[0109] Example 17

[0110] Synthesis of N-(2-cyclohexyloctan-3-yl)-4-methylbenzenesulfonamide (3q).

[0111] The route is as follows:

[0112]

[0113] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2ab (25.5 mg, 0.1 mmol), NiBr2·DME (6.2 mg, 0.02 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1q (22.0 mg, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:10, and 15.8 mg of a colorless liquid is obtained with a yield of 43%. 1 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.29 (d, J = 9.1 Hz, 1H), 3.40–3.33 (m, 1H), 2.41 (s, 3H), 1.69–1.58 (m, 4H), 1.39–1.31 (m, 2H), 1.23–1.14 (m, 4H), 1.10 (dq, J = 7.1, 2.9 Hz, 4H), 1.06–0.96 (m, 4H), 0.82 (t, J = 7.0 Hz, 5H), 0.73 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 143.0, 138.8, 129.5, 127.1, 55.4, 40.6, 38.7, 33.8, 31.7, 31.5, 29.6, 26.5, 26.5, 26.4, 25.5, 22.4, 21.5, 13.9, 10.8. HRMS (ESI) calcd. for [C 21 H 35 NO2S, M+Cl]- : 400.2083, found: 400.2080.

[0114] Example 18

[0115] Synthesis of N-(bicyclo[2.2.1]heptan-2-yl(cyclohexyl)methyl)-4-methylbenzenesulfonamide (3r).

[0116] The route is as follows:

[0117]

[0118] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1s (18.8 mg, 0.20 mmol) into a reaction flask, stirring and reacting under nitrogen at 120 °C for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:10, and 35.1 mg of white solid is obtained with a yield of 97%. 1 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 4.41 (d, J = 9.4 Hz, 1H), 2.96 (td, J = 9.3, 3.3 Hz, 1H), 2.38 (s, 3H), 2.07 (d, J = 3.7 Hz, 1H), 1.96 (d, J = 3.6 Hz, 1H), 1.72–1.60 (m, 2H), 1.56–1.50 (m, 2H), 1.46–1.36 (m, 5H), 1.20 (t, J = 1.9 Hz, 1H), 1.13–0.86 (m, 10H). 1313C NMR (101 MHz, CDCl3) δ 142.7, 139.5, 129.3, 126.9, 63.8, 44.8, 41.5, 39.7, 36.5, 35.7, 35.3, 31.0, 30.4, 28.6, 27.1, 26.5, 26.4, 26.3, 21.5. HRMS (ESI) calcd. for [C 21 H 31 NO2S, M - H] - : 360.2003, found: 360.2001. m.p. = 126–128 °C.

[0119] Example 19

[0120] Synthesis of N-(cyclohexyl(1 - methylcyclobutyl)methyl)-4 - methylbenzenesulfonamide (3s).

[0121] The route is as follows:

[0122]

[0123] The nickel - catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1t (13.6 mg, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:10, obtaining 30.1 mg of a white solid with a yield of 90%. 11H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 4.61 (d, J = 9.4 Hz, 1H), 3.10 (dd, J = 9.6, 5.6 Hz, 1H), 2.41 (s, 3H), 1.95–1.70 (m, 4H), 1.56 (dt, J = 14.5, 4.1 Hz, 4H), 1.46–1.41 (m, 1H), 1.26 (td, J = 7.3, 3.6 Hz, 2H), 1.18–1.08 (m, 2H), 1.06 (s, 3H), 1.03–0.82 (m, 4H). 13 13C NMR (101 MHz, CDCl3) δ 142.7, 139.5, 129.3, 126.9, 67.6, 42.7, 39.9, 33.0, 32.7, 31.9, 29.6, 26.5, 26.3, 26.1, 21.5, 20.7, 14.9. HRMS (ESI) calcd. for 19 C 29 H - NO2S, M - H]

[0124] Example 20

[0125] Synthesis of tert - butyl 6 - (cyclohexyl((4 - methylphenyl)sulfonamido)methyl)-6 - methyl - 2 - azaspiro[3.3]heptane - 2 - carboxylate (3u).

[0126] The route is as follows:

[0127]

[0128] The nickel - catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (4.5 mg, 0.04 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P tBu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1u (41.8 mg, 0.20 mmol) were stirred and reacted at 100 °C under nitrogen for 18 h, and then cooled to room temperature. After the reaction was completed, the solvent was removed under reduced pressure, and column chromatography separation (silica gel column chromatography) was carried out. The eluent used for silica gel column chromatography was a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether was 1:4, and 27.1 mg of white solid was obtained with a yield of 57%. 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 4.92 (d, J = 9.5 Hz, 1H), 3.92–3.85 (m, 2H), 3.67 (s, 2H), 3.00 (dd, J = 9.5, 6.0 Hz, 1H), 2.43 (s, 3H), 2.03 (d, J = 12.1 Hz, 2H), 1.93 (d, J = 12.1 Hz, 1H), 1.84 (dd, J = 12.1, 4.0 Hz, 1H), 1.65–1.54 (m, 5H), 1.41 (s, 9H), 1.39 (s, 1H), 1.26 (s, 1H), 1.08 (tt, J = 12.2, 3.2 Hz, 2H), 0.97 (s, 3H), 0.85 (ddd, J = 15.3, 11.9, 3.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 156.0, 143.0, 139.4, 129.4, 126.8, 79.2, 67.2, 44.5, 43.9, 39.9, 37.9, 31.7, 31.5, 29.5, 29.3, 28.4, 26.4, 26.2, 26.0, 21.5, 21.1. HRMS (ESI) calcd. for 26 H 40 N2O4S, M-H] - : 475.2636, found: 475.2633. m.p. = 116–118 °C.

[0129] Example 21

[0130] (2S)-N-(5-cyclohexyl-4-methyl-5-((4-methylphenyl)sulfonamido)pentyl)-2-(6-methoxynaphthalen-2-yl)propanamide (3v) was synthesized.

[0131] The route is as follows:

[0132]

[0133] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: sequentially adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1v (59.4 mg, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used in silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:4, obtaining 47.5 mg of a colorless liquid with a yield of 88%. 1 1H NMR (400 MHz, CDCl3) δ 7.74–7.60 (m, 5H), 7.40 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 9.2 Hz, 2H), 5.78 (d, J = 30.4 Hz, 1H), 4.58 (dd, J = 23.5, 9.5 Hz, 1H), 3.88 (s, 3H), 3.67 (q, J = 7.3 Hz, 1H), 2.98 (ddt, J = 26.9, 14.1, 6.7 Hz, 3H), 2.36 (d, J = 6.5 Hz, 3H), 1.63–1.54 (m, 6H), 1.30 (t, J = 7.7 Hz, 2H), 1.22 (d, J = 14.3 Hz, 5H), 1.03 (td, J = 15.4, 14.8, 6.9 Hz, 3H), 0.80 (ddd, J = 22.0, 12.6, 7.5 Hz, 2H), 0.66 (dd, J = 16.2, 6.8 Hz, 4H). 1313C NMR (101 MHz, CDCl3) δ 174.4, 157.7, 157.6, 142.9, 139.3, 139.2, 137.0, 136.8, 133.7, 133.7, 129.3, 129.3, 129.0, 127.4, 127.3, 126.9, 126.4, 126.4, 126.2, 126.1, 119.0, 118.9, 105.7, 62.3, 62.1, 55.3, 47.0, 46.9, 40.6, 40.5, 39.6, 39.6, 36.5, 35.7, 33.8, 33.7, 31.5, 31.5, 31.5, 31.4, 30.7, 30.6, 29.9, 29.8, 29.3, 27.1, 26.9, 26.8, 26.2, 26.2, 26.1, 21.4, 18.6, 18.4, 14.3, 14.3. HRMS (ESI) calcd. for [C 33 H 44 N2O4S, M+Na] + : 563.2949, found: 563.2947.

[0134] Example 22

[0135] Synthesis of N-(5-cyclohexyl-4-methyl-5-((4-methylphenyl)sulfonamido)pentyl)-3-(4,5-diphenyloxazol-2-yl)propanamide (3w).

[0136] The route is as follows:

[0137]

[0138] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: sequentially adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P tBu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1w (72.1 mg, 0.20 mmol) were stirred and reacted under nitrogen at 100 °C for 18 hours, and then cooled to room temperature. After the reaction was completed, the solvent was removed under reduced pressure, and column chromatography separation (silica gel column chromatography) was carried out. The eluent used for silica gel column chromatography was a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether was 1:4, and 51.4 mg of a colorless liquid was obtained with a yield of 82%. 1 H NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 8.4, 2.5 Hz, 2H), 7.63–7.59 (m, 2H), 7.56 (d, J = 6.7 Hz, 2H), 7.39–7.30 (m, 6H), 7.24 (dd, J = 8.8, 2.9 Hz, 2H), 6.24 (d, J = 6.1 Hz, 1H), 4.29 (dd, J = 9.9, 2.5 Hz, 1H), 3.20 (td, J = 7.4, 2.6 Hz, 2H), 3.15–3.03 (m, 3H), 2.74 (td, J = 7.4, 2.5 Hz, 2H), 2.39 (d, J = 2.6 Hz, 3H), 1.85 (s, 1H), 1.64 (t, J = 9.0 Hz, 4H), 1.43 (ddt, J = 10.0, 6.8, 3.6 Hz, 2H), 1.20 (qd, J = 8.6, 7.5, 4.1 Hz, 2H), 1.13–0.92 (m, 5H), 0.82 (d, J = 12.0 Hz, 1H), 0.70 (dd, J = 7.0, 2.6 Hz, 4H). 13 C NMR (101 MHz, CDCl3) δ 171.3, 171.3, 162.5, 145.4, 143.1, 139.1, 134.9, 132.5, 129.5, 129.4, 128.9, 128.7, 128.6, 128.6, 128.5, 128.4, 128.1, 127.9, 127.9, 126.9, 126.9, 126.5, 126.4, 62.0, 40.7, 39.6, 33.7, 33.0, 31.6, 30.6, 29.9, 26.9, 26.2, 26.1, 24.1, 21.5, 14.3. HRMS (ESI) calcd. for [C 37 H 45 N3O4S, M+Na] + : 650.3023, found: 650.3029.

[0139] Example 23

[0140] Synthesis of 4-methyl-N-(3-methyl-1-phenylheptan-4-yl)benzenesulfonamide (3aa).

[0141] The route is as follows:

[0142]

[0143] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2aa (22.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), CyCH=NTs (5.3 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1a (30.0 μL, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used in silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:10, and 29.8 mg of colorless liquid is obtained, with a yield of 83% (including diastereomers dr = 75:25). 1 1H NMR (400 MHz, CDCl3) δ 7.7 (t, J = 8.1 Hz, 2H), 7.3–7.2 (m, 4H), 7.2–7.1 (m, 1H), 7.1–7.1 (m, 2H), 4.7–4.6 (m, 1H), 3.3–3.2 (m, 1H), 2.6–2.4 (m, 2H), 2.4 (d, J = 8.3 Hz, 3H), 1.6 (tq, J = 10.4, 5.1 Hz, 2H), 1.3–1.3 (m, 2H), 1.2–1.1 (m, 3H), 0.8 (dd, J = 6.7, 3.4 Hz, 3H), 0.7 (t, J = 7.2 Hz, 3H). 1313C NMR (101 MHz, CDCl3) δ 143.1, 142.4, 142.2, 138.6, 129.5, 128.4, 128.3, 128.3, 128.3, 128.3, 127.0, 127.0, 127.0, 125.8, 125.7, 58.0, 57.5, 53.8, 36.3, 35.5, 34.7, 34.5, 33.6, 33.5, 32.6, 31.2, 21.5, 19.2, 18.9, 14.7, 14.3, 13.8. HRMS (ESI) calcd. for [C 21 H 29 NO2S, M - H] - : 358.1846, found: 358.1846.

[0144] Example 24

[0145] Synthesis of 4 - methyl - N-(3 - methyl - 1 - phenylnonan - 4 - yl)benzenesulfonamide (3ab).

[0146] The route is as follows:

[0147]

[0148] The nickel - catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2ab (25.5 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1a (30.0 μL, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:10, obtaining 31.0 mg of a colorless liquid with a yield of 80% (including diastereomers dr = 80:20). 11H NMR (400 MHz, CDCl3) δ 7.7 (d, J = 8.0 Hz, 2H), 7.2 (d, J = 7.6 Hz, 4H), 7.2 (dd, J = 6.8, 3.0 Hz, 1H), 7.1–7.1 (m, 2H), 4.6 (q, J = 10.5, 8.2 Hz, 1H), 3.3–3.1 (m, 1H), 2.6–2.4 (m, 2H), 2.4 (d, J = 7.0 Hz, 3H), 1.6 (ddd, J = 14.0, 7.6, 3.2 Hz, 2H), 1.4–1.3 (m, 2H), 1.2–1.0 (m, 7H), 0.8 (dt, J = 19.6, 6.8 Hz, 6H). 13 13C NMR (101 MHz, CDCl3) δ 143.1, 142.4, 142.3, 138.6, 138.5, 129.5, 129.1, 128.3, 128.3, 128.3, 127.2, 127.0, 125.8, 125.7, 58.3, 57.7, 36.4, 35.6, 34.7, 34.5, 33.7, 33.6, 32.5, 31.5, 31.4, 30.5, 29.7, 25.7, 25.5, 25.4, 22.5, 22.4, 21.5, 14.7, 14.4, 13.9. HRMS (ESI) calcd. for 23 H 33 NO2S, M - H] - : 386.2159, found: 386.1713.

[0149] Example 25

[0150] Synthesis of N-(2,4 - dimethyl - 6 - phenylhexan - 3 - yl)-4 - methylbenzenesulfonamide (3ac).

[0151] The route is as follows:

[0152]

[0153] The nickel - catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2ac (22.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P tBu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol) and compound 1a (30.0 μL, 0.20 mmol) were stirred and reacted under nitrogen at 100 °C for 18 hours, and then cooled to room temperature. After the reaction was completed, the solvent was removed under reduced pressure, and column chromatography separation (silica gel column chromatography) was carried out. The eluent used for silica gel column chromatography was a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether was 1:10, and 32.1 mg of a colorless liquid was obtained with a yield of 89%. 1 1H NMR (400 MHz, CDCl3) δ 7.7 (dt, J = 8.2, 1.8 Hz, 2H), 7.2–7.1 (m, 5H), 7.1–7.0 (m, 2H), 4.8–4.5 (m, 1H), 3.1 (ddd, J = 9.6, 7.2, 3.8 Hz, 1H), 2.6–2.4 (m, 2H), 2.3 (s, 3H), 1.7–1.6 (m, 2H), 1.5–1.4 (m, 1H), 1.2 (ddt, J = 13.6, 7.8, 2.7 Hz, 1H), 0.9–0.7 (m, 9H). 13 13C NMR (101 MHz, CDCl3) δ 142.8, 142.3, 139.4, 129.4, 128.3, 128.2, 126.8, 125.6, 63.6, 36.4, 34.3, 33.4, 31.2, 31.1, 21.5, 20.4, 19.3, 14.4. HRMS (ESI) calcd. for 21 C 29 H - NO2S, M-H]

[0154] Example 26

[0155] Synthesis of 4-methyl-N-(2-methyl-4-phenyl-1-(tetrahydro-2H-pyran-4-yl)butyl)benzene-sulfonamide (3ag).

[0156] The route is as follows:

[0157]

[0158] In this example, the nickel-catalyzed hydroamination alkylation method of aliphatic olefins includes: successively adding compound 2ad (26.9 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (4.9 mg, 0.04 mmol) into a reaction flask, tBuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1a (30.0 μL, 0.20 mmol) were stirred at 100 °C under nitrogen for 18 h and then cooled to room temperature. After completion of the reaction, the solvent was removed under reduced pressure and the residue was separated by column chromatography (silica gel column chromatography). The eluent for silica gel column chromatography was a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether was 1:10. A white solid (36.9 mg) was obtained with a yield of 72%. 1 1H NMR (400 MHz, CDCl3) δ 7.7 (d, J = 8.3 Hz, 2H), 7.2 (dd, J = 8.1, 6.6 Hz, 2H), 7.2–7.1 (m, 3H), 7.1–7.0 (m, 2H), 4.5 (d, J = 9.6 Hz, 1H), 3.9–3.9 (m, 2H), 3.3–3.2 (m, 3H), 2.5 (dt, J = 9.2, 5.9 Hz, 2H), 2.3 (s, 3H), 1.7–1.6 (m, 2H), 1.6–1.5 (m, 2H), 1.4–1.3 (m, 2H), 1.3–1.2 (m, 2H), 0.8 (d, J = 6.8 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 143.0, 142.0, 139.1, 129.5, 128.3, 128.2, 126.8, 125.7, 68.0, 67.6, 62.4, 38.5, 36.2, 33.4, 33.0, 30.6, 30.2, 21.5, 13.7. HRMS (ESI) calcd. for 23 H 31 [C - HNO3S, M-H]

[0159] Example 27

[0160] Synthesis of 4-methyl-N-(2-methyl-4-phenyl-1-(tetrahydro-2H-pyran-4-yl)butyl)benzene-sulfonamide (3ag).

[0161] The route is as follows:

[0162]

[0163] The method for nickel-catalyzed hydroamination alkylation of aliphatic olefins in this example includes: sequentially adding compound 2ae (34.0 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1a (30.0 μL, 0.20 mmol) into a reaction flask, stirring and reacting under nitrogen at 100 °C for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used in silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:5, obtaining 39.7 mg of a white solid with a yield of 84%. 1H NMR (400 MHz, CDCl3) δ 7.76–7.69 (m, 2H), 7.26–7.14 (m, 5H), 7.07–6.98 (m, 2H), 4.96 (s, 1H), 3.79 (t, J = 8.6 Hz, 1H), 3.71 (t, J = 8.6 Hz, 1H), 3.61 (dd, J = 8.9, 6.3 Hz, 1H), 3.52 (td, J = 9.0, 2.3 Hz, 2H), 2.69–2.60 (m, 1H), 2.50–2.40 (m, 2H), 2.36 (s, 3H), 1.42 (s, 12H), 0.77 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 156.2, 143.4, 141.7, 138.6, 129.7, 128.3, 128.3, 128.2, 126.8, 125.8, 79.5, 60.0, 35.1, 34.7, 33.3, 32.0, 28.4, 27.0, 21.5, 14.2. HRMS (ESI) calcd. for [C26H36N2O4S, M-H]-: 471.2323, found: 471.2326. m.p. = 135–137 °C.

[0164] Example 28

[0165] Synthesis of N-(1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2-methyl-4-phenylbutyl)-4-methylbenzenesulfonami de (3af).

[0166] The route is as follows:

[0167]

[0168] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: sequentially adding compound 2af (26.9 mg, 0.1 mmol), NiBr2·DME (6.2 mg, 0.02 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1a (30.0 μL, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under a nitrogen atmosphere for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography separation (silica gel column chromatography) is carried out. The eluent used for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether. By volume, the ratio of ethyl acetate to petroleum ether is 1:5, obtaining 16.1 mg of a white solid with a yield of 40%. 1 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 2H), 7.30–7.24 (m, 4H), 7.20 (t, J = 7.3 Hz, 1H), 7.14–7.06 (m, 2H), 4.61 (d, J = 9.5 Hz, 1H), 3.64 (d, J = 9.6 Hz, 1H), 2.54 (t, J = 7.8 Hz, 2H), 2.41 (s, 3H), 1.81 (t, J = 2.7 Hz, 6H), 1.61–1.51 (m, 2H), 1.36–1.31 (m, 1H), 0.86 (d, J = 6.5 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 143.5, 141.9, 138.4, 129.7, 128.4, 128.3, 127.0, 125.8, 73.8, 54.5 (d, J = 24.3 Hz), 53.1 (d, J = 21.1 Hz), 35.8 (d, J = 4.4 Hz), 33.4, 31.5 (d, J = 41.6 Hz), 29.7, 21.5, 14.5. 19 19F NMR (376 MHz, CDCl3) δ -148.1. HRMS (ESI) calcd. for [C 23 H 28 FNO2S, M-H] - : 400.1752, found: 400.1752. m.p. = 137–138 °C.

[0169] Example 29

[0170] Synthesis of N-(1-(benzo[d][1,3]dioxol-5-yl)-2-methyl-4-phenylbutyl)-4-methylbenzenesulfon-amide (3ag).

[0171] The route is as follows:

[0172]

[0173] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: sequentially adding compound 2ag (31.4 mg, 0.1 mmol), NiBr2·DME (6.2 mg, 0.02 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), P t Bu3 (50 wt% in toluene, 16.2 mg, 0.04 mmol), and compound 1a (30.0 μL, 0.20 mmol) into a reaction flask, stirring and reacting at 100 °C under nitrogen for 18 hours, and then cooling to room temperature. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography (silica gel column chromatography) is carried out. The eluent used for silica gel column chromatography is acetone and petroleum ether 1:5, obtaining 20.5 mg of a white solid with a yield of 46%. 1 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 7.3 Hz, 2H), 7.16–7.11 (m, 3H), 7.03 (d, J = 7.2 Hz, 2H), 6.98 (td, J = 5.9, 2.9 Hz, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.48 (d, J = 1.3 Hz, 1H), 5.15 (t, J = 9.3 Hz, 1H), 4.57–4.51 (m, 1H), 3.52 (s, 3H), 2.65 (dt, J = 13.8, 5.1 Hz, 1H), 2.49 (ddd, J = 13.7, 10.0, 6.4 Hz, 1H), 2.25 (s, 3H), 2.07 (ddt, J = 9.0, 7.1, 3.6 Hz, 1H), 1.70 (dt, J = 11.5, 4.1 Hz, 1H), 1.38 (td, J = 9.1, 4.3 Hz, 1H), 1.01 (d, J = 6.7 Hz, 3H). 1313C NMR (101 MHz, CDCl3) δ 142.4, 142.2, 137.7, 136.9, 128.7, 128.4, 128.3, 127.2, 127.0, 125.9, 125.7, 121.6, 119.1, 113.5, 109.1, 56.3, 37.7, 34.9, 33.2, 32.4, 21.4, 15.8. HRMS (ESI) calcd. for 27 H 30 N2O2S, M - H] - : 445.1955, found: 445.1953. m.p. = 149–151 °C.

[0174] Example 30

[0175] Synthesis of N-(1-cyclohexyl-5-phenylpentyl)-4-methylbenzenesulfonamide (4a):

[0176]

[0177] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), PPh2Et (4.3 mg, 0.02 mmol) and compound 1a (30.0 μL, 0.20 mmol) into a reaction flask, and reacting under nitrogen at 100 °C for 18 hours. After the reaction is completed, silica gel column chromatography is carried out, and the eluent is ethyl acetate - petroleum ether at 1:8, to obtain 27.2 mg of a white solid with a yield of 68%. 1 1H NMR (400 MHz, CDCl3) δ 7.8 (d, J = 8.3 Hz, 2H), 7.3–7.2 (m, 4H), 7.2–7.1 (m, 1H), 7.1 (d, J = 8.1 Hz, 2H), 4.6 (td, J = 8.4, 3.5 Hz, 1H), 3.1 (tt, J = 9.0, 5.1 Hz, 1H), 2.4 (d, J = 9.0 Hz, 5H), 1.8–1.6 (m, 5H), 1.5 (d, J = 12.6 Hz, 1H), 1.4–1.3 (m, 4H), 1.2–1.0 (m, 6H), 0.9–0.8 (m, 1H). 1313C NMR (101 MHz, CDCl3) δ 143.0, 142.4, 138.7, 129.5, 128.3, 128.3, 127.1, 125.7, 58.8, 41.4, 35.7, 31.5, 31.2, 28.8, 28.3, 26.4, 26.3, 26.2, 25.2, 21.5. HRMS (ESI) calcd. for 24 H 33 NO2S, M - H] - : 398.2159, found: 398.2161. m.p. = 64–65 °C.

[0178] Example 31

[0179] Synthesis of N-(1,4 - dicyclohexylbutyl)-4 - methylbenzenesulfonamide (4b):

[0180]

[0181] The nickel - catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: sequentially adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (1.0 mL), PhBr (3.1 mg, 0.02 mmol), PPh2Et (4.3 mg, 0.02 mmol) and compound 1e (30.0 μL, 0.20 mmol) into a reaction flask, and reacting at 100 °C under nitrogen for 18 hours. After the reaction, silica gel column chromatography was carried out, and the eluent was ethyl acetate - petroleum ether at 1:10, to obtain 29.3 mg of a colorless liquid with a yield of 75%. 1 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.5 Hz, 2H), 4.58 (d, J = 8.7 Hz, 1H), 3.04 (tt, J = 9.0, 4.9 Hz, 1H), 2.42 (s, 3H), 1.71–1.59 (m, 7H), 1.50 (d, J = 11.9 Hz, 3H), 1.33 (ddd, J = 16.0, 8.8, 4.3 Hz, 2H), 1.20–1.06 (m, 8H), 0.99–0.86 (m, 6H), 0.72 (dd, J = 13.1, 3.6 Hz, 2H). 13CNMR(101MHz,CDCl3)δ142.9,138.7,129.5,129.3,127.0,126.9,59.1,41.7,37.5,37.3,33.2,32.1,28.8,28.3,26.7,26.4,26.3,26.3,26.3,23.0,21.5.HRMS(ESI)calcd.for[C 23 H 37 NO2S,M+Na] + :414.2437,found:414.2443.

[0182] Example 32

[0183] Synthesis of N-(6-((tert-butyldimethylsilyl)oxy)-1-cyclohexylhexyl)-4-methylbenzenesulfonamide (4c):

[0184]

[0185] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), PPh2Et (4.3 mg, 0.02 mmol) and compound 1h (40 mg, 0.20 mmol) into the reaction flask, and reacting at 100 °C under nitrogen for 18 hours. After the reaction is completed, silica gel column chromatography is carried out, and the eluent is ethyl acetate - petroleum ether 1:10, to obtain 29.0 mg of a colorless liquid with a yield of 62%. 1 H NMR(400MHz,CDCl3)δ7.72(d,J=8.3Hz,2H),7.24(d,J=6.9Hz,2H),4.45(d,J=9.2Hz,1H),3.47(t,J=6.5Hz,2H),3.07–2.97(m,1H),2.38(s,3H),1.69–1.56(m,4H),1.47(d,J=12.6Hz,1H),1.37–1.27(m,4H),1.18–1.02(m,7H),0.95(dd,J=12.1,3.4Hz,2H),0.85(s,10H). 1313C NMR (101 MHz, CDCl3) δ 143.0, 138.7, 129.4, 127.0, 63.0, 58.9, 41.4, 32.6, 31.8, 28.9, 28.2, 26.4, 26.3, 26.2, 26.0, 25.6, 25.4, 21.5, 18.4, -5.3. HRMS (ESI) calcd. for 25 H 45 NO3SSi, M - H] - : 466.2817, found: 466.2819.

[0186] Example 33

[0187] Synthesis of N-(3-(9H-carbazol-9-yl)-1-cyclohexylpropyl)-4-methylbenzenesulfonamide (4d):

[0188]

[0189] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol), t BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), PPh2Et (4.3 mg, 0.02 mmol) and compound 1x (38.6 mg, 0.20 mmol) into a reaction flask, and reacting at 100 °C under nitrogen for 18 hours. After the reaction is completed, silica gel column chromatography is carried out, and the eluent is acetone - petroleum ether 1:5, to obtain 28.6 mg of white solid, with a yield of 62%. 11H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.8 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.44–7.39 (m, 2H), 7.22 (dt, J = 12.4, 4.5 Hz, 6H), 4.94 (t, J = 8.3 Hz, 1H), 4.26 (ddd, J = 15.9, 10.7, 5.3 Hz, 1H), 4.16–4.08 (m, 1H), 3.28 (tt, J = 9.0, 4.7 Hz, 1H), 2.36 (s, 3H), 1.99–1.92 (m, 1H), 1.66 (ddd, J = 15.6, 7.2, 3.2 Hz, 4H), 1.48 (d, J = 12.6 Hz, 1H), 1.36–1.30 (m, 1H), 1.10–0.99 (m, 3H), 0.87 (dddd, J = 34.0, 21.0, 13.3, 6.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 143.5, 140.0, 138.3, 129.8, 127.0, 125.7, 122.9, 120.4, 118.9, 108.5, 57.2, 41.9, 40.1, 30.9, 28.7, 28.5, 26.2, 26.1, 26.1, 21.6. HRMS (ESI) calcd. for 28 H 32 N2O2S, M - H] - : 459.2112, found: 459.2115. m.p. = 62–63 °C.

[0190] Example 34

[0191] Synthesis of N-(1-cyclohexyl-3-(trimethylsilyl)propyl)-4-methylbenzenesulfonamide (4e):

[0192]

[0193] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2a (26.7 mg, 0.1 mmol), NiBr2·DME (3.1 mg, 0.01 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol) into a reaction flask, tBuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), PPh2Et (4.3 mg, 0.02 mmol), and compound 1y (20.0 mg, 0.20 mmol) were stirred at 100 °C under nitrogen for 18 h and then cooled to room temperature. After completion of the reaction, the solvent was removed under reduced pressure and the residue was separated by column chromatography (silica gel column chromatography). The eluent for silica gel column chromatography was a mixture of acetone and petroleum ether, and the volume ratio of acetone to petroleum ether was 1:10. A white solid (30.1 mg) was obtained in 82% yield. 1 HNMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 4.86–4.60 (m, 1H), 3.15 (tt, J = 6.1, 3.0 Hz, 1H), 2.56 (s, 3H), 1.89–1.75 (m, 4H), 1.64 (d, J = 12.8 Hz, 1H), 1.45–1.40 (m, 1H), 1.35–1.15 (m, 5H), 1.04–0.99 (m, 1H), 0.40–0.24 (m, 2H), 0.13 (dd, J = 20.8, 2.9 Hz, 10H). 13 C NMR (101 MHz, CDCl3) δ 145.0, 140.8, 131.5, 129.1, 129.1, 63.2, 42.3, 31.3, 30.0, 28.4, 28.3, 27.7, 23.5, 13.8, 0.2, 0.0. HRMS (ESI) calcd. for [C 19 H 33 NO2SSi, M-H] - : 366.1929, found: 366.1930. m.p. = 82–83 °C.

[0194] Example 35

[0195] Synthesis of 4-methyl-N-(tridecan-6-yl)benzenesulfonamide (4f) and N-(tridecan-6-yl)acetamide (5):

[0196]

[0197] The nickel-catalyzed hydroamination alkylation method of aliphatic olefins in this example includes: successively adding compound 2ab (25.5 mg, 0.1 mmol), NiBr2·DME (1.6 mg, 0.005 mmol), PhB(OH)2 (14.6 mg, 0.12 mmol) into a reaction flaskt BuOK (13.4 mg, 0.12 mmol), toluene (0.2 mL), PhBr (3.1 mg, 0.02 mmol), PPh2Et (2.2 mg, 0.01 mmol), and compound 1b (28.0 μL, 0.20 mmol) were stirred and reacted at 100 °C under nitrogen for 18 h and then cooled to room temperature. After the reaction was completed, the solvent was removed under reduced pressure and separated by column chromatography (silica gel column chromatography). The eluent used for silica gel column chromatography was a mixture of acetone and petroleum ether, and the volume ratio of acetone to petroleum ether was 1:10. 22.9 mg of colorless liquid 4f was obtained with a yield of 65%. 1 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 5.06 (t, J = 6.6 Hz, 1H), 3.28–3.05 (m, 1H), 2.41 (s, 3H), 1.32 (dddd, J = 34.4, 15.2, 7.8, 3.8 Hz, 6H), 1.22–1.04 (m, 14H), 0.86 (t, J = 7.1 Hz, 3H), 0.81 (td, J = 7.2, 6.1, 3.3 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 142.9, 138.7, 129.4, 127.0, 54.1, 35.0, 34.9, 31.7, 31.6, 29.3, 29.1, 25.2, 24.9, 22.6, 22.5, 21.4, 14.1, 13.9. HRMS (ESI) calcd. for 20 C 35 H - NO2S, M−H

[0198] A THF solution (7.5 mL) of compound 4f (0.3 mmol) was cooled under argon at -78 °C, and then 3.3 mL of a 0.9 M solution of lithium naphthalenide (prepared from naphthalene and lithium) in THF was added until the starting material was completely consumed (monitored by TLC). The mixture was heated to -10 °C for 30 minutes. The reaction was quenched with aqueous HCl (1 M), and the pH of the mixture was adjusted to 1. The organic phase was separated, and the aqueous layer was washed with CH2Cl2 (3 times). The pH of the aqueous layer was adjusted to 13 by adding aqueous NaOH (1 M), and then the aqueous layer was extracted with CH2Cl2 (3 times). The combined organic phases were dried over Na2SO4, filtered, and the solvent was carefully removed using a vacuum pump to obtain the intermediate product. The intermediate product was dissolved in CH2Cl2 (9.0 mL), and acetic anhydride (392 μL, 4.2 mmol, 14 eq.) and pyridine (408 μL, 4.8 mmol, 16 eq.) were added. The reaction mixture was stirred at room temperature for 4 hours, and 10 mL of saturated aqueous sodium bicarbonate was added. The aqueous phase was extracted with 20 mL of dichloromethane, and the combined organic phases were dried over anhydrous MgSO4. After removing the solvent under a vacuum pump, purification by column chromatography (eluent: a mixture of petroleum ether and acetone, volume ratio of petroleum ether to acetone was 3:1) gave the white solid 5, namely N-(tridecan-6-yl)acetamide, in a yield of 79% (57.1 mg).

[0199] It should be noted that in the prior art, N-(tridecan-6-yl)acetamide is a natural product isolated from Microcoleus lyngbyaceus and is difficult to synthesize artificially. Using our method, it can be efficiently synthesized in two steps from inexpensive and readily available starting materials. 1 H NMR (400 MHz, CDCl3) δ 5.35 (d, J = 9.2 Hz, 1H), 3.86 (tt, J = 13.1, 5.8 Hz, 1H), 1.95 (s, 3H), 1.48–1.40 (m, 2H), 1.26 (dd, J = 14.0, 6.9 Hz, 18H), 0.85 (t, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 169.6, 49.4, 35.2, 35.2, 31.8, 29.6, 29.2, 25.9, 25.5, 23.5, 22.6, 22.6, 14.1, 14.0. HRMS (ESI) calcd. for 15 H 31 NO,M+Na] + : 264.2298, found: 264.2301. m.p. = 60–61 °C.

[0200] When the phosphine ligand is tricyclohexylphosphine, diadamantylcyclohexylphosphine, triadamantylphosphine or tri-tert-butylphosphine, the ratio of the branched product (b) to the chain product (l) is b / l=63:37, b / l=73:27, b / l=81:19 and b / l>95:5, respectively, so tri-tert-butylphosphine is the optimal ligand for obtaining the branched product; when the phosphine ligand is triethylphosphine, tri-n-butylphosphine or diphenylethylphosphine, the ratio of the chain product (l) to the branched product (b) is l / b=79:21, l / b=79:21 and l / b>95:5, respectively, so diphenylethylphosphine is the optimal ligand for obtaining the chain product.

Claims

1. A method for the alkylation of aliphatic olefins by hydrogenation with amines catalyzed by nickel, characterized in that: The reaction formula and reaction process are as follows: In a nitrogen atmosphere, compound 2, nickel catalyst, arylboronic acid, base, solvent, additive, phosphine ligand and compound 1 are mixed in sequence, stirred at 80-120° C. for 18-36 hours, cooled to room temperature, the solvent is removed under reduced pressure, and the target product is separated by column chromatography. When the phosphine ligand is tri-tert-butylphosphine, the target product is compound 3, and when the phosphine ligand is diphenylethylphosphine, the target product is compound 4; wherein: The molar ratio of the compound 2, the phosphine ligand, the nickel catalyst, the arylboronic acid, the base and the additive is 1: (0.1-0.4): (0.05-0.2): (0.2-1.2): (0.4-1.2): (0.05-0.2); The equivalent ratio of compound 1 to compound 2 is 1:(1-3); R 1 is an alkyl group or a silicon group, R 2 is an alkyl, aryl or heteroaryl group, R 3 is 4-methylphenyl; The nickel catalyst is NiBr2·DME; The additive is PhBr, PhCH=NTs or CyCH=NTs; The base is potassium tert-butoxide; The aryl boronic acid is one of phenylboronic acid, 4-methoxyphenylboronic acid and 4-methylphenylboronic acid.

2. The method for hydrogen amine alkylation according to claim 1, characterized in that: The usage ratio of the compound 2 and the solvent is 1 mmol: (2-10) ml.

3. The method for hydrogen amine alkylation according to claim 1, characterized in that: The solvent is benzene, toluene or mesitylene.

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