Synthesis method of an α-substituted-β-oxocycloamine compound

Abstract

The present invention discloses a method for synthesizing α-substituted-β-oxocyclic amine compounds, belonging to the technical field of organic synthesis. The key points of the technical solution of the present invention are as follows: The present invention directly synthesizes α-substituted-β-oxocyclic amine compounds through a tandem reaction of an oxoammonium salt to promote the reaction between saturated amine compounds and different nucleophiles. This reaction directly realizes the simultaneous functionalization of the α-position and the β-position of the cyclic amine. The whole process is simple to operate and does not require any metal catalyst; the raw materials are simple and easily available, and the reaction conditions are mild; the scope of application of the substrate is wide, which is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing α-substituted-β-oxocycloamine compounds. Background Art

[0002] α-Substituted-β-oxocycloamine compounds are the main structural units of many natural products and antimalarial drugs, and have important research value in the fields of chemical biology and drug synthesis. At present, the synthesis methods of α-substituted-β-oxocycloamine compounds mainly include: (1) base-promoted further functionalization of the α-position of β-oxocycloamine; (2) reduction of 3-hydroxy-substituted azaaromatic compounds; (3) multi-step condensation reactions of substituted chain amines, etc. Although these methods are relatively reliable, there are still problems such as difficult preparation of reaction raw materials, cumbersome reaction steps, harsh reaction conditions, and narrow substrate scope. Therefore, it is necessary to improve the current synthesis method, that is, to directly complete the one-pot efficient construction of the α-substituted-β-oxocycloamine structural unit starting from easily available simple saturated cycloamines, and there is no literature report yet. In view of this, it is of great significance to further study and develop a simple and efficient new method for directly synthesizing α-substituted-β-oxocycloamine compounds starting from easily available saturated cycloamines. Summary of the Invention

[0003] The technical problem solved by the present invention is to provide a method for synthesizing α-substituted-β-oxocycloamine compounds. This method synthesizes the target product α-substituted-β-oxocycloamine compounds through a one-pot multi-step tandem reaction between easily available saturated amine compounds and nucleophiles promoted by an oxoammonium salt, and has the advantages of simple operation, mild conditions, wide substrate scope, etc., and is suitable for industrial production.

[0004] The present invention adopts the following technical solution to solve the above technical problem. A method for synthesizing α-substituted-β-oxocycloamine compounds is characterized in that the specific synthesis process is as follows: Dissolve saturated amine compound 1 and nucleophile 2 in a solvent, and then add oxoammonium salt T + X - and an additive, and react at 0-50°C under an air atmosphere to obtain the target product α-substituted-β-oxocycloamine compound 3. The reaction equation in the synthesis process is:

[0005]

[0006] wherein R is phenyl, substituted phenyl or naphthyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy or phenyl; Nu -is a malonic ester, allyltrimethylsilane, potassium phenyltrifluoroborate or substituted potassium phenyltrifluoroborate, and the substituent on the benzene ring of the substituted phenyl is C 1-4 alkyl or C 1-4 alkoxy; X - is BF 4 - 、ClO 4 - 、PF 6 - or OTf - ; The additive is calcium chloride, calcium fluoride, ferric chloride or acetic acid.

[0007] Further defined, the solvent is ethyl acetate, tetrahydrofuran or dichloromethane.

[0008] Further defined, the molar ratio of the saturated amine compound 1, the nucleophile 2, the oxammonium salt T + X - to the additive is 1:1 - 3:2 - 4:0.5 - 2.

[0009] Compared with the prior art, the present invention has the following advantages: (1) The present invention directly synthesizes α-substituted-β-oxocyclic amine compounds through the tandem reaction of oxammonium salts to promote the reaction between saturated amine compounds and different nucleophiles. This reaction directly realizes the simultaneous functionalization of the α-position and β-position of the cyclic amine. The whole process is simple to operate and does not require any metal catalyst; (2) The raw materials are simple and easy to obtain, and the reaction conditions are mild; (3) The substrate has a wide range of applicability. Therefore, the present invention provides an economical and practical new method for the synthesis of α-substituted-β-oxocyclic amine compounds. Detailed implementation mode

[0010] The following further elaborates on the above content of the present invention through examples, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0011] Example 1

[0012]

[0013] In the reaction tube, add 1a (32 mg, 0.2 mmol), THF (1 mL), 2a (46 μL, 0.4 mmol), T + BF 4 -(97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred and reacted at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3a (37 mg, 60%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.27 (t, J = 8.0 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.87 (t, J = 7.6 Hz, 1H), 4.94 (d, J = 7.2 Hz, 1H), 4.00 (d, J = 7.6 Hz, 1H), 3.73 (s, 3H), 3.63 (s, 3H), 3.60 - 3.54 (m, 1H), 3.47 - 3.40 (m, 1H), 2.68 - 2.62 (m, 1H), 2.56 - 2.48 (m, 1H), 2.27 - 2.22 (m, 1H), 2.17 - 2.12 (m, 1H). 13 C{ 1 H}NMR (150 MHz, CDCl 3 ): δ 207.8, 167.7, 167.5, 148.1, 129.5, 120.0, 115.9, 66.5, 52.8, 52.7, 44.5, 37.1, 22.6. HRMS (ESI) m / z: [M+Na] + Calcd for C 16 H 19 NO 5 Na 328.1155; Found 328.1152.

[0014] Example 2

[0015] 1a (32 mg, 0.2 mmol), THF (1 mL), 2a (46 μL, 0.4 mmol), T + ClO 4 - (102 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were added successively to a reaction tube. The mixture was stirred and reacted at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3a (33 mg, 54%).

[0016] Example 3

[0017] 1a (32 mg, 0.2 mmol), THF (1 mL), 2a (46 μL, 0.4 mmol), T + PF 6 - (120 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were successively added into a reaction tube. The reaction was stirred at 25 °C for 0.5 h under an air atmosphere, and then the reaction was quenched by adding 10 mL of saturated sodium chloride solution. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3a (23 mg, 38%).

[0018] Example 4

[0019] 1a (32 mg, 0.2 mmol), THF (1 mL), 2a (46 μL, 0.4 mmol), T + OTf - (122 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were successively added into a reaction tube. The reaction was stirred at 25 °C for 0.5 h under an air atmosphere, and then the reaction was quenched by adding 10 mL of saturated sodium chloride solution. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3a (27 mg, 44%).

[0020] Example 5

[0021] 1a (32 mg, 0.2 mmol), THF (1 mL), 2a (46 μL, 0.4 mmol), T + BF 4 - (97 mg, 0.4 mmol) and calcium fluoride (8 mg, 0.1 mmol) were successively added into a reaction tube. The reaction was stirred at 25 °C for 0.5 h under an air atmosphere, and then the reaction was quenched by adding 10 mL of saturated sodium chloride solution. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3a (32 mg, 52%).

[0022] Example 6

[0023] 1a (32 mg, 0.2 mmol), THF (1 mL), 2a (46 μL, 0.4 mmol), T + BF 4- (97 mg, 0.4 mmol) and iron(III) chloride (16 mg, 0.1 mmol) were stirred at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give the yellow liquid product 3a (19 mg, 31%).

[0024] Example 7

[0025] 1a (32 mg, 0.2 mmol), THF (1 mL), 2a (46 μL, 0.4 mmol), and T + BF 4 - (97 mg, 0.4 mmol) and acetic acid (6 μL, 0.1 mmol) were stirred at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give the yellow liquid product 3a (20 mg, 33%).

[0026] Example 8

[0027] 1a (32 mg, 0.2 mmol), THF (1 mL), 2a (46 μL, 0.4 mmol), and T + BF 4 - (97 mg, 0.4 mmol) and calcium chloride (44 mg, 0.4 mmol) were stirred at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give the yellow liquid product 3a (32 mg, 52%).

[0028] Example 9

[0029] 1a (32 mg, 0.2 mmol), THF (1 mL), 2a (46 μL, 0.4 mmol), and T + BF 4 -(146 mg, 0.6 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred and reacted at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3a (24 mg, 40%).

[0030] Example 10

[0031] 1a (32 mg, 0.2 mmol), THF (1 mL), 2a (69 μL, 0.6 mmol), and T + BF 4 - (97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred and reacted at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3a (37 mg, 60%).

[0032] Example 11

[0033] 1a (32 mg, 0.2 mmol), ethyl acetate (1 mL), 2a (46 μL, 0.4 mmol), and T + BF 4 - (97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred and reacted at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3a (34 mg, 56%).

[0034] Example 12

[0035] 1a (32 mg, 0.2 mmol), dichloromethane (1 mL), 2a (46 μL, 0.4 mmol), and T + BF 4 -(97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred and reacted at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3a (20 mg, 33%).

[0036] Example 13

[0037]

[0038] 1b (0.2 mmol, 36 mg), THF (1 mL), 2a (46 μL, 0.4 mmol), and T were successively added to the reaction tube. + BF 4 - (97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred and reacted at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3b (47 mg, 72%). The characterization data of this compound are as follows: 1 1H NMR (400 MHz, CDCl 3 3): δ 6.93 - 6.84 (m, 4H), 4.69 (d, J = 7.6 Hz, 1H), 3.86 (d, J = 7.2 Hz, 1H), 3.66 (s, 3H), 3.56 (s, 3H), 3.37 - 3.33 (m, 2H), 2.62 - 2.57 (m, 1H), 2.48 - 2.40 (m, 1H), 2.14 - 2.06 (m, 2H). 13 13C{ 1 1H} NMR (150 MHz, CDCl 3 3): δ 207.5, 167.55, 167.46, 157.6 (d, 1 J C-F = 238.4 Hz), 144.8 (d, 4 J C-F = 2.1 Hz), 119.1 (d, 3 J C-F = 7.7 Hz), 115.9 (d, 2 J C-F = 21.9 Hz), 67.3, 52.8, 52.74, 52.71, 46.6, 37.4, 23.0. 19 19F{1 H}NMR(CDCl 3 , 376 MHz): δ -123.1. HRMS(ESI) m / z: [M + H] + Calcd for C 16 H 19 FNO 5 324.1242; Found 324.1238。

[0039] Example 14

[0040]

[0041] 1c (0.2 mmol, 57 mg), THF (1 mL), 2a (46 μL, 0.4 mmol), T + BF 4 - (97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were successively added to a reaction tube. The reaction was stirred at 25 °C for 0.5 h under an air atmosphere, then quenched by adding 10 mL of saturated sodium chloride solution, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate. Filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3c (52 mg, 60%). The characterization data of this compound are as follows: 1 1H NMR (400 MHz, CDCl 3 ): δ 7.55 - 7.51 (m, 2H), 6.62 (dd, J 1 = 12.0 Hz, J 2 = 3.2 Hz, 2H), 4.90 (d, J = 7.2 Hz, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 3.57 - 3.51 (m, 1H), 3.43 - 3.37 (m, 1H), 2.68 - 2.61 (m, 1H), 2.55 - 2.47 (m, 1H), 2.27 - 2.22 (m, 1H), 2.17 - 2.12 (m, 1H). 13 13C{ 1 1H} NMR (150 MHz, CDCl 3 ): δ 207.3, 167.5, 167.3, 147.7, 138.1, 117.4, 81.4, 66.0, 52.91, 52.87, 52.7, 44.0, 36.8, 22.4. HRMS(ESI) m / z: [M + H] + Calcd for C 16 H 19 INO5 432.0302; Found 432.0306.

[0042] Example 15

[0043]

[0044] 1d (0.2 mmol, 43 mg), THF (1 mL), 2a (46 μL, 0.4 mmol), and T + BF 4 - (97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were successively added into a reaction tube. The mixture was stirred at 25 °C for 0.5 h under an air atmosphere, and then the reaction was quenched by adding 10 mL of saturated sodium chloride solution. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3d (30 mg, 42%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.29 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.88 (d, J = 7.2 Hz, 1H), 3.99 (d, J = 7.2 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 3.54 - 3.49 (m, 1H), 3.46 - 3.43 (m, 1H), 2.68 - 2.62 (m, 1H), 2.55 - 2.49 (m, 1H), 2.24 - 2.14 (m, 2H), 1.29 (s, 9H). 13 C{ 1 H} NMR (150 MHz, CDCl 3 ): δ 207.9, 167.8, 167.6, 145.7, 143.0, 126.3, 116.0, 66.7, 52.9, 52.74, 52.72, 45.0, 37.3, 34.0, 31.4, 22.7. HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 28 NO 5 362.1962; Found 362.1954.

[0045] Example 16

[0046]

[0047] 1e (0.2 mmol, 35 mg), THF (1 mL), 2a (46 μL, 0.4 mmol), T + BF 4 - (97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were successively added to a reaction tube. The mixture was stirred at 25 °C for 0.5 h under an air atmosphere, and then the reaction was quenched by adding 10 mL of saturated sodium chloride solution. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3e (26 mg, 40%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.21 - 7.13 (m, 3H), 7.08 - 7.04 (m, 1H), 4.54 (d, J = 6.4 Hz, 1H), 3.69 - 3.65 (m, 7H), 3.19 - 3.15 (m, 1H), 3.05 - 2.99 (m, 1H), 2.81 - 2.75 (m, 1H), 2.56 - 2.47 (m, 1H), 2.19 - 2.14 (m, 4H), 2.00 - 1.95 (m, 1H). 13 C{ 1 H}NMR (150 MHz, CDCl 3 ): δ 207.4, 167.9, 167.8, 147.6, 135.4, 131.5, 126.8, 125.3, 122.4, 68.3, 52.8, 52.6, 52.5, 51.7, 38.7, 23.3, 17.3. HRMS (ESI) m / z: [M + H] + Calcd for C 17 H 22 NO 5 320.1492; Found 320.1497.

[0048] Example 17

[0049]

[0050] 1f (0.2 mmol, 47 mg), THF (1 mL), 2a (46 μL, 0.4 mmol), T + BF 4 -(97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred and reacted at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3f (48 mg, 63%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.56 - 7.52 (m, 4H), 7.41 (t, J = 8.0 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.03 - 7.00 (m, 2H), 5.00 (d, J = 7.2 Hz, 1H), 4.05 (d, J = 7.6 Hz, 1H), 3.74 (s, 3H), 3.65 - 3.60 (m, 4H), 3.50 - 3.44 (m, 1H), 2.69 - 2.64 (m, 1H), 2.58 - 2.51 (m, 1H), 2.31 - 2.25 (m, 1H), 2.20 - 1.15 (m, 1H). 13 C{ 1 H}NMR (150 MHz, CDCl 3 ): δ 207.7, 167.7, 167.5, 147.3, 140.6, 132.5, 128.8, 128.1, 126.6, 126.5, 115.7, 66.3, 52.88, 52.86, 52.83, 44.3, 37.0, 22.6. HRMS (ESI) m / z: [M + H] + Calcd for C 22 H 24 NO 5 382.1649; Found 382.1644.

[0051] Example 18

[0052]

[0053] 1 g (0.2 mmol, 42 mg), THF (1 mL), 2a (46 μL, 0.4 mmol), and T + BF 4 -(97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred and reacted at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain 3 g (40 mg, 56%) of a yellow liquid product. The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.76 - 7.68 (m, 3H), 7.43 - 7.39 (m, 1H), 7.32 - 7.20 (m, 2H), 7.19 (s, 1H), 5.08 (d, J = 7.6 Hz, 1H), 4.08 (d, J = 7.6 Hz, 1H), 3.75 - 3.67 (m, 4H), 3.59 - 3.55 (m, 4H), 2.71 - 2.65 (m, 1H), 2.60 - 2.54 (m, 1H), 2.31 - 2.29 (m, 1H), 2.20 - 1.18 (m, 1H). 13 C{ 1 H}NMR (150 MHz, CDCl 3 ): δ 207.8, 167.6, 167.4, 145.8, 134.5, 129.3, 128.5, 127.5, 126.7, 126.6, 123.7, 118.4, 110.9, 66.6, 52.85, 52.80, 52.77, 44.9, 37.1, 22.8. HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 22 NO 5 356.1492; Found 356.1498.

[0054] Example 19

[0055]

[0056] 1h (0.2 mmol, 35 mg), THF (1 mL), 2b (μL, 0.4 mmol) were successively added to a reaction tube, and T + BF 4 -(97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred and reacted at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to obtain the yellow liquid product 3h (44 mg, 54%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.06 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.78 (d, J = 8.0 Hz, 1H), 3.80 (d, J = 8.0 Hz, 1H), 3.55 - 3.50 (m, 1H), 3.45 - 3.42 (m, 1H), 2.66 - 2.61 (m, 1H), 2.51 - 2.45 (m, 1H), 2.26 - 2.20 (m, 4H), 2.12 - 2.11 (m, 1H), 1.45 (s, 9H), 1.35 (s, 9H). 13 C{ 1 H}NMR (150 MHz, CDCl 3 ): δ 208.4, 166.6, 166.3, 146.4, 129.8, 129.1, 116.4, 82.1, 66.8, 55.3, 44.9, 37.4, 27.9, 27.7, 23.5, 20.4. HRMS (ESI) m / z: [M + H] + Calcd for C 23 H 34 NO 5 404.2431; Found 404.2436.

[0057] Example 20

[0058]

[0059] 1a (0.2 mmol, 32 mg), THF (1 mL), 2c (74 mg, 0.4 mmol), and T + BF 4 -(97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give the yellow liquid product 3i (21 mg, 42%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.34 - 7.31 (m, 4H), 7.29 - 7.20 (m, 3H), 6.79 - 6.76 (m, 3H), 5.33 (s, 1H), 3.73 - 3.66 (m, 2H), 2.60 - 2.54 (m, 1H), 2.48 - 2.44 (m, 1H), 2.14 - 2.06 (m, 2H). 13 C{ 1 H}NMR (150 MHz, CDCl 3 ): δ 206.3, 148.5, 136.9, 129.4, 128.9, 127.7, 126.2, 118.1, 113.0, 69.2, 44.3, 36.9, 21.2. HRMS (ESI) m / z: [M + H] + Calcd for C 17 H 18 NO2 52.1383; Found 252.1393.

[0060] Example 21

[0061]

[0062] 1a (0.2 mmol, 32 mg), THF (1 mL), 2d (86 mg, 0.4 mmol), T + BF 4 - (97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were stirred at 25 °C for 0.5 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give the yellow liquid product 3j (34 mg, 60%). The characterization data of this compound are as follows: 1 H NMR (400 MHz, CDCl 3 ): δ 7.25 - 7.20 (m, 4H), 6.85 (dd, J 1= 8.8 Hz, J 2 = 3.2 Hz, 2H), 6.79 - 6.75 (m, 3H), 5.26 (s, 1H), 3.78 (s, 3H), 3.71 - 3.63 (m, 2H), 2.61 - 2.54 (m, 1H), 2.45 - 2.37 (m, 1H), 2.13 - 2.06 (m, 2H). 13 C{ 1 H}NMR(150 MHz, CDCl 3 ): δ 206.6, 159.2, 148.6, 129.4, 128.6, 127.4, 118.0, 114.4, 113.1, 68.7, 55.3, 44.2, 36.8, 21.2. HRMS(ESI) m / z: [M + H] + Calcd for C 18 H 20 NO 2 282.1489; Found 282.1491。

[0063] Example 22

[0064]

[0065] 1i (0.2 mmol, 39 mg), THF (1 mL), 2e (64 μL, 0.4 mmol), T + BF 4 - (97 mg, 0.4 mmol) and calcium chloride (11 mg, 0.1 mmol) were successively added to a reaction tube. The mixture was stirred at 25 °C for 0.5 h under an air atmosphere, then quenched with 10 mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, evaporation, and separation by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v), the yellow liquid product 3k (21 mg, 43%) was obtained. The characterization data of this compound are as follows: 1 H NMR(400 MHz, CDCl 3 ): δ 7.21 - 7.17 (m, 2H), 6.78 - 6.75 (m, 2H), 5.75 - 5.65 (m, 1H), 5.07 - 5.02 (m, 2H), 4.20 (t, J = 7.2 Hz, 1H), 3.53 - 3.37 (m, 2H), 2.56 - 2.45 (m, 4H), 2.16 - 2.08 (m, 2H). 13 C{ 1 H}NMR(150 MHz, CDCl 3): δ 208.4, 147.5, 133.4, 129.2, 123.7, 118.1, 116.3, 67.1, 42.9, 36.9, 34.0, 22.8. HRMS(ESI) m / z: [M+H] + Calcd for C 14 H 17 ClNO 250.0993; Found 250.0997.

[0066] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing α-substituted-β-oxocycloamine compounds, characterized in that The specific synthesis process is as follows: Dissolve the saturated amine compound 1 and the nucleophile 2 in a solvent, and then add the oxammonium salt T to the reaction system. + X - and an additive, and react at 0 - 50 °C under an air atmosphere to obtain the target product α-substituted-β-oxocyclic amine compound 3. The reaction equation in the synthesis process is as follows: wherein R is phenyl, substituted phenyl or naphthyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 1-4 alkoxy or phenyl; X - is BF 4 - , ClO 4 - , PF 6 - or OTf - ; The additive is calcium chloride, calcium fluoride, ferric chloride or acetic acid.

2. The method for synthesizing α-substituted-β-oxocycloamine compounds according to claim 1, characterized in that: The solvent is ethyl acetate, tetrahydrofuran or dichloromethane.

3. The method for synthesizing α-substituted-β-oxocycloamine compounds according to claim 1, characterized in that: The saturated amine compound 1, nucleophile 2, and oxammonium salt T + X - The molar ratio of the feed of the additive is 1:1 - 3:2 - 4:0.5 - 2.

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