A method for synthesizing methylene amide-substituted cyclohexane

Abstract

The present invention discloses a method for synthesizing methylene amide-substituted cyclohexane. The method includes: in an organic solvent and under an inert gas atmosphere, reacting an exocyclic olefin represented by Formula 2 and an amidation reagent represented by Formula 3 under the action of a metal nickel catalyst NiA, a ligand L, a hydrogen source, an ionic additive, and a proton additive. After the reaction is completed, through post-treatment, methylene amide-substituted cyclohexane represented by Formula 1 is obtained. The reaction formula is as follows: Wherein, R1 is one or more of unsubstituted or substituted alkyl, aryl, ester group, amino group, substituted amino group, amide group, sulfonyl group, alkoxy group, silyl ether, thioether, alkynyl group, halogen; R2 is one or more of unsubstituted or substituted alkyl, aryl, alkoxy group, silyl ether, thioether, alkynyl group.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing methylene amide-substituted cyclohexanes. Background Art

[0002] Organic amine compounds have extensive applications in the fields of pharmaceuticals, materials, and organic synthesis. C-N bond formation reactions are some of the most widely used reactions in medicinal chemistry. Among them, the intermolecular hydrogenation reaction of olefins is an important method for introducing nitrogen-containing groups into widely available raw chemical materials. However, the existing methods for synthesizing methylene amide-substituted cyclohexanes have disadvantages such as poor substrate practicability and cumbersome operations.

[0003] Therefore, a more feasible idea is to study and find an efficient method for synthesizing thermodynamically unstable methylene amide-substituted cyclohexane compounds. Summary of the Invention

[0004] The object of the present invention is to provide a method for synthesizing methylene amide-substituted cyclohexanes, which method is simple to operate, the raw materials are cheap and easily available, the substrate functional group compatibility is good, and it has good regioselectivity and stereoselectivity.

[0005] To achieve the above object, the present invention adopts the following technical solutions:

[0006] The present invention provides a method for synthesizing methylene amide-substituted cyclohexanes, the method comprising:

[0007] In an organic solvent and under an inert gas atmosphere, the exocyclic olefin shown in formula 2 and the amidation reagent shown in formula 3 are reacted under the action of a metal nickel catalyst NiA, a ligand L, a hydrogen source, an ionic additive, and a proton additive. After the reaction is completed, post-treatment is carried out to obtain the methylene amide-substituted cyclohexane shown in formula 1, and the reaction formula is as follows:

[0008]

[0009] Formula 2 Formula 3 Formula 1;

[0010] Wherein, R1 is one or more of unsubstituted or substituted alkyl, aryl, ester group, amino group, substituted amino group, amide group, sulfonyl group, alkoxy group, silyl ether, thioether, alkynyl group, halogen; R2 is one or more of unsubstituted or substituted alkyl, aryl, alkoxy group, silyl ether, thioether, alkynyl group;

[0011] The ligand L is selected from one of the following:

[0012]

[0013] Further, for the ionic additive, its cation is Li +, Na + , K + , Mg 2+ , Zn 2+ , Cs + Any one of, and the anion is F – , Cl – , Br – , I – , [CH3COO] – , [CF3COO] – Any one of.

[0014] Furthermore, the hydrogen source is any one of polymethylhydrosiloxane, trimethoxyhydrosilane, triethoxyhydrosilane, diethoxymethylhydrosilane, triethylhydrosilane, diphenylhydrosilane, dimethoxymethylhydrosilane, triphenylhydrosilane, borane and its complexes, and pinacolborane.

[0015] Furthermore, the proton additive is one or more of water, methanol, isopropanol, and tert-butanol.

[0016] Furthermore, the organic solvent is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, ethyl acetate, acetone, acetonitrile, phenylacetonitrile, and saturated alkyl nitriles of C3-C 12 .

[0017] Furthermore, in the metal nickel-based catalyst NiA, A is Cl – , Br – , I – , [CH3COO] – , [CF3COO] – , [acac] – , Br – with 1 ethylene glycol dimethyl ether, [NO3] – Any one of with 4 crystal waters.

[0018] Furthermore, the ligand L is any one of the following:

[0019] .

[0020] Further, the dosage ratio of the nickel-based catalyst NiA: ligand: hydrogen source: ionic additive: proton additive: exocyclic olefin: amidation reagent: organic solvent is in moles: moles: moles: moles: moles: moles: volume mL = 0.05: 0.05: 5: 5: 1: 1.5: 0.75.

[0021] Further, the reaction temperature is -20~40 °C.

[0022] Further, the methylene amide-substituted cyclohexane shown in Formula 1 includes:

[0023] .

[0024] Further, the post-treatment includes removing the organic solvent by reduced pressure concentration and then separating and purifying by column chromatography.

[0025] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0026] The present invention provides a method for synthesizing 1, 3-disubstituted cyclic compounds. By using a specific ligand, an exocyclic olefin, a hydrogen source, and an amidation reagent are subjected to a one-pot reaction under the action of a nickel metal catalyst to prepare an amide organic compound. This reaction method can not only efficiently synthesize the target compound, but also has strong substrate applicability, excellent regioselectivity (rr>99:1) and stereoselectivity (dr>99:1). The raw materials used in this method are cheap and easily available, the operation is simple, the substrate functional group compatibility is good, and amide compounds can be efficiently synthesized. Detailed implementation manners

[0027] The following will explain the solution of the present invention in combination with embodiments. Those skilled in the art will understand that the following embodiments are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the embodiments regarding specific technologies or conditions, they shall be carried out according to the technologies or conditions described in the literature in the field or according to the product specifications. The methods used, unless otherwise specified, are all conventional methods well-known in the art. The consumables and reagents used, unless otherwise specified, are all commercially available. Unless otherwise stated, the professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the described content can also be applied to the present invention.

[0028] In the following embodiments, NiBr2·DME refers to nickel(II) bromide ethylene glycol dimethyl ether, (MeO)3SiH refers to trimethoxyhydrosilane, 1,4-dioxane refers to 1,4-dioxane. THF refers to tetrahydrofuran.

[0029] The following will describe in detail a method for synthesizing methylene amide - substituted cyclohexane of the present application in combination with examples, comparative examples, and experimental data.

[0030] Example 1

[0031]

[0032] In a glove box filled with argon, nickel(II) bromide ethylene glycol dimethyl ether (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), and (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4 - dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1a (60.9 mg, 0.4 mmol) and 2a (97.8 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 87%) was obtained by column chromatography separation and purification. 1 H NMR (600 MHz, Chloroform - d ) δ 7.84 – 7.69 (m, 2H), 7.54 –7.46 (m, 1H), 7.46 – 7.37 (m, 2H), 6.17 (s, 1H), 3.49 (dd, J = 7.8, 5.8 Hz,2H), 1.95 (ddh, J = 7.5, 5.1, 2.4 Hz, 1H), 1.77 – 1.73 (m, 2H), 1.60 – 1.55 (m,2H), 1.51 (tt, J = 13.6, 4.5 Hz, 2H), 1.19 (qd, J = 13.1, 3.4 Hz, 2H), 1.00 (tt, J = 12.1, 3.2 Hz, 1H), 0.85 (s, 9H) ppm; 13 C NMR (151 MHz, Chloroform - d ) δ 167.6,134.9, 131.3, 128.6, 126.9, 48.5, 41.2, 33.0, 32.6, 28.6, 27.5, 21.9 ppm;HRMS (ESI) calculated [M + H] +for C 18 H 28 NO + = 274.2165, found: 274.2159.

[0033] Example 2

[0034]

[0035] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1b (88.2 mg, 0.4 mmol) and 2a (97.8 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 74%) was obtained by column chromatography separation and purification. 1 1H NMR (600 MHz, Chloroform- d ) δ 7.82 – 7.70 (m, 2H), 7.53 –7.45 (m, 1H), 7.42 (dd, J = 8.3, 6.9 Hz, 2H), 6.20 (s, 1H), 3.42 (dd, J = 7.6,5.9 Hz, 2H), 1.86 – 1.79 (m, 1H), 1.79 – 1.72 (m, 4H), 1.55 – 1.40 (m, 8H),1.30 (q, J = 7.4 Hz, 2H), 1.19 – 1.09 (m, 5H), 0.93 – 0.79 (m, 7H) ppm; 13 13C NMR(151 MHz, Chloroform- d ) δ 167.6, 135.0, 131.3, 128.6, 126.9, 43.1, 41.7,40.3, 39.8, 37.5, 35.3, 33.5, 30.4, 27.4, 25.6, 20.1, 14.5 ppm; HRMS (ESI)calculated [M + H] + for C23 H 36 NO + = 342.2791, found: 342.2785.

[0036] Example 3

[0037]

[0038] In an argon-filled glove box, nickel(II) bromide ethylene glycol dimethyl ether (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1c (99.4 mg, 0.4 mmol) and 2a (97.8 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 80%) was obtained by column chromatography purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.81 – 7.71 (m, 2H), 7.53 –7.46 (m, 1H), 7.45 – 7.38 (m, 2H), 6.19 (s, 1H), 3.40 (dd, J = 7.4, 5.9 Hz,2H), 1.75 (dt, J = 11.0, 3.6 Hz, 1H), 1.73 – 1.70 (m, 4H), 1.51 (dddd, J = 21.1,12.2, 7.8, 3.9 Hz, 4H), 1.45 – 1.33 (m, 5H), 1.33 – 1.24 (m, 4H), 1.18 – 1.06(m, 6H), 0.90 – 0.81 (m, 7H) ppm; 13 C NMR (151 MHz, Chloroform- d) δ 167.6, 135,131.3, 128.6, 126.9, 43.8, 39.9, 38.2, 37.6, 36.0, 35.5, 35.2, 33.5, 33.4,31.4, 28.7, 26.7, 20.1, 14.5 ppm; HRMS (ESI) calculated [M + H] + for C 25 H 40 NO + =370.3104, found: 370.3108.

[0039] Example 4

[0040]

[0041] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1d (94.5 mg, 0.4 mmol) and 2a (97.8 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 88%) was obtained by column chromatography separation and purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.76 (d, J = 7.6 Hz, 2H), 7.48(t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 6.27 (s, 1H), 3.93 (d, J = 3.0 Hz,4H), 3.42 (t, J = 6.7 Hz, 2H), 1.85 – 1.80 (m, 1H), 1.76 (d, J = 11.0 Hz, 4H),1.54 – 1.41 (m, 10H), 1.23 (d, J = 9.1 Hz, 4H) ppm; 1313C NMR (151 MHz, Chloroform- d ) δ 167.6, 134.9, 131.3, 128.5, 126.9, 109.1, 64.2, 64.2, 43.0, 40.7, 38.9,35.2, 34.7, 27.5, 27.3, 25.7 ppm; HRMS (ESI) calculated [M + H] + for C 22 H 32 NO3 + =358.2377, found: 358.2374.

[0042] Example 5

[0043]

[0044] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1f (116.2 mg, 0.4 mmol) and 2a (97.8 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 67%) was obtained by column chromatography separation and purification. 1 1H NMR (400 MHz, Chloroform- d ) δ 7.79 – 7.74 (m, 2H), 7.51 –7.45 (m, 1H), 7.45 – 7.38 (m, 2H), 7.08 – 7.01 (m, 1H), 6.98 (ddd, J = 11.9,7.8, 2.1 Hz, 1H), 6.88 (ddt, J = 8.1, 3.8, 1.7 Hz, 1H), 6.20 (t, J = 5.8 Hz, 1H),3.43 (dd, J = 7.6, 6.0 Hz, 2H), 2.39 (tt, J= 12.3, 3.2 Hz, 1H), 1.95 – 1.80 (m, 5H), 1.56 – 1.43 (m, 8H), 1.36 (td, J = 13.2, 12.5, 3.6 Hz, 2H), 1.26 – 1.15(m, 2H), 1.10 – 0.98 (m, 2H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 167.7, 144.9, 135.0, 131.4, 128.7, 126.9, 122.7, 122.6, 122.6, 116.9, 116.8, 115.6, 115.4, 43.8, 43.0, 41.6, 39.8, 35.3, 34.5, 30.6, 27.4, 25.6 ppm; 19 F NMR (376MHz, Chloroform- d ) δ -138.6, -142.4.

[0045] Example 6

[0046]

[0047] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, alkene 1g (96.5 mg, 0.4 mmol) and 2a (97.8 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by evaporation under reduced pressure, and the target product (white solid, yield 78%) was obtained by column chromatography purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.88 – 7.74 (m, 4H), 7.74 – 7.64 (m, 2H), 7.54 – 7.46 (m, 1H), 7.43 (td, J = 7.7, 7.3, 1.8 Hz, 2H), 6.37(s, 1H), 4.15 (tt, J= 12.6, 4.4 Hz, 1H), 3.66 (dd, J = 7.9, 6.0 Hz, 2H), 2.44(qd, J = 13.1, 3.7 Hz, 2H), 2.13 (ddt, J = 7.6, 5.0, 2.8 Hz, 1H), 1.90 – 1.85 (m,2H), 1.66 (tt, J = 13.9, 4.4 Hz, 2H), 1.63 – 1.53 (m, 2H) ppm; 13 C NMR (151 MHz,Chloroform- d ) δ 168.4, 167.6, 134.8, 133.9, 132.0, 131.4, 128.6, 126.9,123.1, 50.4, 41.0, 31.8, 27.3, 24.4 ppm; HRMS (ESI) calculated [M + H] + forC 22 H 23 N2O3 + =363.1703, found: 363.1699.

[0048] Example 7

[0049]

[0050] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, alkene 1h (68.9 mg, 0.4 mmol) and 2a (97.8 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 78%) was obtained by column chromatography separation and purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.82 – 7.73 (m, 2H), 7.53 –7.47 (m, 1H), 7.43 (dd, J= 8.3, 6.9 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.25 (s,2H), 7.21 – 7.16 (m, 1H), 6.19 (t, J = 6.1 Hz, 1H), 3.57 (dd, J = 7.7, 5.9 Hz,2H), 2.61 (tt, J = 10.3, 3.8 Hz, 1H), 2.02 (dp, J = 7.9, 4.9, 3.9 Hz, 1H), 1.73(qdd, J = 15.4, 10.7, 8.7 Hz, 8H) ppm; 13 C NMR (151 MHz, Chloroform- d ) δ 167.7,146.9, 134.9, 131.4, 128.6, 128.3, 127.0, 126.9, 125.9, 43.3, 41.9, 33.6,28.9, 28.0 ppm; HRMS (ESI) calculated [M + H] + for C 20 H 24 NO + =294.1852, found:294.1854.

[0051] Example 8

[0052]

[0053] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1i (68.9 mg, 0.4 mmol) and 2a (97.8 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 78%) was obtained by column chromatography purification. 1 H NMR (600 MHz, Chloroform- d) δ 7.82 – 7.73 (m, 2H), 7.53 –7.47 (m, 1H), 7.43 (dd, J J = 8.3, 6.9 Hz, 2H), 7.30 (t, J J = 7.6 Hz, 2H), 7.25 (s,2H), 7.21 – 7.16 (m, 1H), 6.19 (t, J J = 6.1 Hz, 1H), 3.57 (dd, J J = 7.7, 5.9 Hz,2H), 2.61 (tt, J J = 10.3, 3.8 Hz, 1H), 2.02 (dp, J J = 7.9, 4.9, 3.9 Hz, 1H), 1.73(qdd, J J = 15.4, 10.7, 8.7 Hz, 8H) ppm; 13 C NMR (151 MHz, Chloroform- d ) δ 167.7,146.9, 134.9, 131.4, 128.6, 128.3, 127.0, 126.9, 125.9, 43.3, 41.9, 33.6,28.9, 28.0 ppm; HRMS (ESI) calculated [M + H] + for C 20 H 24 NO + =294.1852, found:294.1854.

[0054] Example 9

[0055]

[0056] In a glove box filled with argon, nickel(II) bromide ethylene glycol dimethyl ether (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), and (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1j (90.5 mg, 0.4 mmol) and 2a (97.8 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product was obtained by column chromatography purification (light yellow oil, yield 55%). 1 H NMR (600 MHz, Chloroform- d )δ 7.85 – 7.78 (m, 2H), 7.51 –7.46 (m, 1H), 7.42 (ddt, J = 8.2, 6.6, 1.2 Hz, 2H), 6.44 (t, J = 6.2 Hz, 1H),3.73 (s, 3H), 3.67 (s, 3H), 3.57 (dt, J = 13.5, 6.8 Hz, 1H), 3.39 (d, J = 10.3Hz, 1H), 3.30 (ddd, J = 13.8, 8.5, 5.5 Hz, 1H), 2.45 (dtd, J = 13.8, 7.9, 3.6 Hz,1H), 2.04 – 1.98 (m, 1H), 1.65 – 1.50 (m, 5H), 1.44 – 1.35 (m, 2H), 1.30(dtd, J = 14.8, 10.7, 9.5, 4.8 Hz, 1H) ppm; 13 C NMR (151 MHz, Chloroform- d ) δ169.3, 169.1, 167.4, 134.7, 131.3, 128.5, 126.9, 55.6, 52.4, 52.4, 42.9,33.0, 32.8, 32.6, 29.6, 28.7, 20.7 ppm; HRMS (ESI) calculated [M + H] + forC19 H 26 NO5 + = 348.1805, found: 348.1808.

[0057] Example 10

[0058]

[0059] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, alkene 1k (60.9 mg, 0.4 mmol) and 2a (97.8 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 48%) was obtained by column chromatography separation and purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.80 – 7.74 (m, 2H), 7.52 –7.46 (m, 1H), 7.46 – 7.39 (m, 2H), 6.11 (s, 1H), 3.47 (dd, J = 8.9, 6.0 Hz,2H), 2.16 (ddq, J = 10.4, 7.1, 3.5 Hz, 1H), 1.83 – 1.69 (m, 4H), 1.64 (tdq, J =12.3, 6.5, 3.2 Hz, 1H), 1.49 (dp, J = 9.6, 6.5 Hz, 1H), 1.15 – 1.08 (m, 1H),1.09 – 1.01 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.92 –0.86 (m, 1H), 0.85 (d, J = 6.4 Hz, 3H) ppm; 13 C NMR (151 MHz, Chloroform- d) δ 167.7, 135.0, 131.3, 128.6, 126.8, 47.2, 37.4, 37.2, 35.6, 35.5, 29.5, 26.2, 25.4, 22.8, 21.8, 20.8 ppm; HRMS (ESI) calculated [M + H] + for C 18 H 28 NO + = 274.2165, found: 274.2162.

[0060] Example 11

[0061]

[0062] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1a (60.9 mg, 0.4 mmol) and 2b (115.9 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 74%) was obtained by column chromatography purification. 1 1H NMR (600 MHz, Chloroform- d ) δ 7.74 (d, J = 8.9 Hz, 2H), 6.96–6.86 (m, 2H), 6.18 (s, 1H), 3.83 (s, 3H), 3.46 (dd, J = 7.8, 5.8 Hz, 2H), 1.94 (ddq, J = 7.8, 5.0, 2.6 Hz, 1H), 1.77 – 1.71 (m, 2H), 1.58 – 1.53 (m, 2H), 1.49 (tt, J = 13.6, 4.5 Hz, 2H), 1.18 (qd, J = 13.0, 3.4 Hz, 2H), 1.00 (dt, J= 12.2, 3.2 Hz, 1H), 0.84 (s, 9H) ppm; 13 C NMR (151 MHz, Chloroform- d ) δ 167.1, 162.0, 128.6, 127.2, 113.7, 55.4, 48.4, 41.1, 33.0, 32.6, 28.6, 27.5, 21.9 ppm; HRMS (ESI) calculated [M + H] + for C 19 H 30 NO2 + = 304.2271, found: 304.2269.

[0063] Example 12

[0064]

[0065] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1a (60.9 mg, 0.4 mmol) and 2c (118.5 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 67%) was obtained by column chromatography separation and purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.75 – 7.67 (m, 2H), 7.44 – 7.35 (m, 2H), 6.13 (d, J = 6.0 Hz, 1H), 3.48 (dd, J = 7.8, 5.8 Hz, 2H), 1.94 (ttt, J = 7.2, 4.5, 2.2 Hz, 1H), 1.76 – 1.71 (m, 2H), 1.59 – 1.55 (m, 2H), 1.51 (tt, J = 13.7, 4.5 Hz, 2H), 1.18 (qd, J= 13.0, 3.4 Hz, 2H), 1.00 (tt, J = 12.2, 3.2 Hz, 1H), 0.85 (s, 9H) ppm; 13 C NMR (151 MHz, Chloroform- d ) δ 166.5, 137.5, 133.3, 128.8, 128.3, 48.4, 41.3, 33.0, 32.6, 28.6, 27.5, 21.9 ppm; HRMS (ESI) calculated [M + H] + for C 18 H 27 ClNO + = 308.1775, found: 308.1774.

[0066] Example 13

[0067]

[0068] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, alkene 1a (60.9 mg, 0.4 mmol) and 2d (101.5 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 63%) was obtained by column chromatography separation and purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.51 (dt, J = 3.7, 1.3 Hz, 1H), 7.45 (dd, J = 5.0, 1.1 Hz, 1H), 7.06 (ddd, J = 4.8, 3.7, 0.9 Hz, 1H), 6.11(s, 1H), 3.46 (dd, J = 7.8, 5.9 Hz, 2H), 1.93 (dqd, J= 7.6, 5.0, 2.4 Hz, 1H), 1.76 – 1.71 (m, 2H), 1.56 (dd, J = 13.2, 3.5 Hz, 2H), 1.49 (tt, J = 13.6, 4.5 Hz, 2H), 1.17 (qd, J = 13.0, 3.4 Hz, 2H), 0.99 (tt, J = 12.0, 3.1 Hz, 1H), 0.84 (s, 9H) ppm; 13 C NMR (151 MHz, Chloroform- d ) δ 161.9, 139.2, 129.6, 127.8, 127.6, 48.4, 41.2, 33.1, 32.6, 28.6, 27.5, 21.9 ppm; HRMS (ESI) calculated [M + H] + for C 16 H 26 NOS + = 280.1729, found: 280.1724.

[0069] Example 14

[0070]

[0071] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1a (60.9 mg, 0.4 mmol) and 2e (198.2 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 69%) was obtained by column chromatography separation and purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.84 (dd, J = 5.4, 3.0 Hz, 2H), 7.73 (dd, J= 5.4, 3.0 Hz, 2H), 6.21 (t, J = 5.7 Hz, 1H), 3.70 (dd, J = 13.9, 4.3Hz, 1H), 3.63 (dd, J = 13.9, 8.3 Hz, 1H), 3.23 (ddd, J = 13.5, 7.8, 5.7 Hz, 1H),3.16 (ddd, J = 13.4, 7.7, 5.7 Hz, 1H), 2.48 – 2.38 (m, 1H), 2.16 (qd, J = 14.3,6.4 Hz, 2H), 1.80 (dt, J = 13.3, 6.6 Hz, 2H), 1.67 (ddt, J = 16.4, 13.7, 2.9 Hz,2H), 1.51 (td, J = 9.4, 8.2, 4.0 Hz, 2H), 1.44 (tq, J = 13.1, 4.1 Hz, 2H), 1.22(t, J = 7.1 Hz, 2H), 1.14 – 1.04 (m, 2H), 0.97 (t, J = 3.2 Hz, 1H), 0.95 (d, J =6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.82 (s, 9H) ppm; 13 C NMR (151 MHz,Chloroform- d ) δ 171.4, 169.0, 134.0, 131.9, 123.3, 48.4, 41.9, 41.5, 40.7,39.9, 33.5, 32.8, 32.5, 28.6, 27.5, 25.2, 22.7, 22.6, 21.8, 21.8 ppm;HRMS(ESI) calculated [M + H] + for C 27 H 41 N2O3 + =441.3111, found: 441.3118.

[0072] Example 15

[0073]

[0074] In an argon-filled glove box, nickel(II) bromide ethylene glycol dimethyl ether (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1a (60.9 mg, 0.4 mmol) and 2f (207.1 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 73%) was obtained by column chromatography separation and purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.08 – 7.04 (m, 2H), 6.63 –6.60 (m, 2H), 5.42 (d, J = 6.1 Hz, 1H), 3.70 (t, J = 6.8 Hz, 4H), 3.62 (t, J = 7.1Hz, 4H), 3.28 (dd, J = 7.8, 5.8 Hz, 2H), 2.56 (t, J = 7.5 Hz, 2H), 2.17 (t, J = 7.5Hz, 2H), 1.92 (p, J = 7.5 Hz, 2H), 1.79 (ddt, J = 8.0, 5.7, 2.5 Hz, 1H), 1.66(dq, J = 13.7, 2.1 Hz, 2H), 1.53 (dd, J = 13.1, 3.2 Hz, 2H), 1.45 (tt, J = 13.6,4.4 Hz, 2H), 1.12 (qd, J = 13.2, 3.5 Hz, 2H), 0.97 (tt, J = 12.1, 3.2 Hz, 1H),0.83 (s, 9H) ppm; 1313C NMR (151 MHz, Chloroform- d ) δ 172.8, 144.3, 130.8, 129.7,112.2, 53.6, 48.4, 40.6, 40.6, 36.1, 34.1, 33.0, 32.6, 28.6, 27.5, 21.8 ppm;HRMS (ESI) calculated [M + H] + for C 25 H 41 Cl2N2O + =455.2590, found: 455.2579.

[0075] Example 16

[0076]

[0077] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1a (60.9 mg, 0.4 mmol) and 2g (200.6 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 60%) was obtained by column chromatography separation and purification. 1 1H NMR (600 MHz, Chloroform- d ) δ 7.63 – 7.59 (m, 2H), 7.57 –7.54 (m, 2H), 7.37 – 7.30 (m, 6H), 6.20 (t, J = 5.9 Hz, 1H), 3.28 (dd, J = 7.9,5.8 Hz, 2H), 3.20 (t, J = 7.1 Hz, 2H), 2.76 (t, J = 7.1 Hz, 2H), 1.78 (dqd, J=7.6, 5.1, 2.4 Hz, 1H), 1.65 – 1.60 (m, 2H), 1.48 – 1.43 (m, 2H), 1.38 (tt, J =13.5, 4.4 Hz, 2H), 1.07 (qd, J = 13.4, 3.4 Hz, 2H), 0.95 – 0.91 (m, 1H), 0.80(s, 9H) ppm; 13 C NMR (151 MHz, Chloroform- d ) δ 171.3, 162.5, 145.5, 134.9,132.4, 128.9, 128.7, 128.6, 128.5, 128.1, 127.9, 126.5, 48.4, 40.8, 33.2,32.8, 32.5, 28.5, 27.5, 24.2, 21.8 ppm;HRMS (ESI) calculated [M + H] + forC 29 H 37 N2O2 + =445.2849, found: 445.2837.

[0078] Example 17

[0079]

[0080] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, olefin 1h (68.9 mg, 0.4 mmol) and 2h (111.1 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 68%) was obtained by column chromatography purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.28 (t, J = 7.6 Hz, 2H), 7.25– 7.20 (m, 2H), 7.17 (td,J = 7.2, 1.4 Hz, 1H), 5.68 (t, J = 5.8 Hz, 1H), 3.35(dd, J = 7.7, 5.9 Hz, 2H), 2.58 (tt, J = 9.9, 4.4 Hz, 1H), 2.17 (t, J = 7.6 Hz,2H), 1.87 (tt, J = 7.9, 3.9 Hz, 1H), 1.76 – 1.59 (m, 10H), 1.34 – 1.22 (m, 8H),0.87 (t, J = 6.9 Hz, 3H) ppm; 13 C NMR (151 MHz, Chloroform- d ) δ 173.3, 147.0,128.3, 126.9, 125.9, 43.3, 41.3, 36.9, 33.5, 31.7, 29.3, 29.1, 28.8, 27.9,25.9, 22.6, 14.1 ppm.

[0081] Example 18

[0082]

[0083] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, alkene 1h (68.9 mg, 0.4 mmol) and 2i (101.5 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (white solid, yield 84%) was obtained by column chromatography separation and purification. 1 H NMR (600 MHz, Chloroform- d ) δ 7.28 (t, J = 7.6 Hz, 2H), 7.25– 7.21 (m, 2H), 7.20 – 7.14 (m, 1H), 5.47 (s, 1H), 3.35 (dd,J = 7.7, 5.9 Hz, 2H), 2.58 (tt, J = 9.8, 4.3 Hz, 1H), 2.08 (tt, J = 11.8, 3.5 Hz, 1H), 1.90 – 1.83 (m, 3H), 1.79 (dt, J = 12.2, 3.2 Hz, 2H), 1.75 – 1.62 (m, 9H), 1.44 (qd, J = 12.2, 3.4 Hz, 2H), 1.31 – 1.18 (m, 3H) ppm; 13 C NMR (151 MHz, Chloroform- d ) δ176.2, 146.9, 128.3, 127.0, 125.8, 45.7, 43.3, 41.0, 33.6, 29.9, 28.8, 27.9, 25.8, 25.8 ppm; HRMS (ESI) calculated [M + H] + for C 20 H 30 NO + = 300.2321, found: 300.2313.

[0084] Example 19

[0085]

[0086] In an argon-filled glove box, nickel(II) bromide dimethoxyethane (6.2 mg, 0.02 mmol), ligand L1 (5.0 mg, 0.02 mmol), sodium iodide (18.0 mg, 0.12 mmol), (MeO)3SiH (254 μL, 2 mmol) were dissolved in a mixed solvent of 1.2 mL of dry 1,4-dioxane and 0.3 mL of dry tetrahydrofuran. Then, alkene 1h (68.9 mg, 0.4 mmol) and 2j (162.6 mg, 0.6 mmol) were added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 20 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (orange solid, yield 45%) was obtained by column chromatography purification. 1 H NMR (600 MHz, Chloroform- d) δ 7.33 – 7.27 (m, 2H), 7.27– 7.24 (m, 2H), 7.18 (ddt, J J = 7.5, 6.7, 1.5 Hz, 1H), 5.76 (t, J J = 6.1 Hz, 1H),4.67 (t, J J = 1.9 Hz, 2H), 4.36 – 4.31 (m, 2H), 4.19 (s, 5H), 3.50 (dd, J J = 7.7,6.1 Hz, 2H), 2.66 – 2.57 (m, 1H), 1.98 (dt, J J = 7.8, 3.9 Hz, 1H), 1.82 – 1.67(m, 8H) ppm; 13 C NMR (151 MHz, Chloroform- d ) δ 170.2, 147.0, 128.3, 127.0,125.9, 76.5, 70.3, 69.7, 69.7, 68.1, 43.4, 41.3, 33.8, 28.9, 28.0 ppm;HRMS(ESI) calculated [M + H] + for C 24 H 28 FeNO + =402.1514, found: 402.1505.

[0087] Finally, it should also be noted that the term "comprise", "include" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements but also includes other elements not expressly listed, or elements inherent to such process, method, article or device.

[0088] Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications once they learn the basic creative concept. Therefore, the appended claims are intended to be construed to include the preferred embodiments as well as all changes and modifications falling within the scope of the present invention.

[0089] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A method for synthesizing methylene amide-substituted cyclohexane, characterized in that, The method includes: In an organic solvent and under an inert gas atmosphere, the exocyclic olefin shown in Formula 2 and the amidating reagent shown in Formula 3 are reacted under the action of a metal nickel catalyst NiA, a ligand L, a hydrogen source, an ionic additive, and a proton additive. After the reaction is completed, through post-treatment, the methylene amide-substituted cyclohexane shown in Formula 1 is obtained. The reaction formula is as follows: Among them, R1 is one or more of unsubstituted or substituted alkyl groups and aryl groups; the R2 is one or more of unsubstituted or substituted alkyl groups and aryl groups; The ligand L is as follows: ； The ionic additive described above has a cation of Li + , Na + , K + , Cs + , and an anion of F – , Cl – , Br – , I – , any one of them; The hydrogen source is any one of trimethoxysilane, triethoxysilane, diethoxymethylsilane, and dimethoxymethylsilane; The proton additive is one or several of methanol, isopropanol, and tert-butanol; The metal nickel catalyst NiA is NiBr2·DME.

2. The method according to claim 1, wherein The organic solvent is one or several of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, ethyl acetate, acetone, acetonitrile, phenylacetonitrile, and saturated alkyl nitriles with C3-C12.

3. The method according to claim 1, wherein The inert gas is selected from argon or nitrogen.

4. The method according to claim 1, wherein The reaction temperature is -20 - 40 °C.

5. The method according to claim 1, wherein The methylene amide-substituted cyclohexane shown in Formula 1 includes: 。

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