Preparation method of imino isobenzofuran compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an imino isobenzofuran compound. The invention aims to overcome the defects of the existing imino isobenzofuran compound synthesis method, and develops the imino isobenzofuran compound synthesis method which has the advantages of cheap and easily available catalyst, mild reaction conditions and high yield.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing an iminoisobenzofuran compound. Background Art

[0002] As an important class of heterocyclic skeletons, imidolactones are commonly found in many natural products and bioactive compounds. They are also an important class of organic synthesis intermediates and are widely used in organic reactions. In particular, imidoisobenzofuran compounds have attracted much attention due to their good biological activity, so studying the synthesis of this molecular skeleton compound has important application value.

[0003] In recent years, the methods for preparing iminoisobenzofurans are mainly the following: first, the three-component coupling reaction of in situ generated aromatic alkynes with isocyanates and aldehydes catalyzed by transition metals; second, the selective cyclization coupling reaction of o-alkynylbenzamides catalyzed by transition metals; and third, the free radical addition / intramolecular oxygen cyclization reaction of olefinic amides with free radical precursors by photocatalysis or electrocatalysis. Although these methods can be used for the synthesis of iminoisobenzofuran compounds, they usually require expensive transition metal catalysts, complex substrate synthesis and harsh reaction conditions.

[0004] Based on the wide application of iminoisobenzofuran compounds in organic synthesis and medicinal chemistry, it is particularly important to develop a green, efficient, simple and easy-to-operate synthetic strategy to construct iminoisobenzofuran compounds. Summary of the invention

[0005] The present invention aims to overcome the shortcomings of existing methods for synthesizing iminoisobenzofuran compounds and to provide a method for synthesizing iminoisobenzofuran compounds with low-cost, readily available catalysts, mild reaction conditions and high yield.

[0006] The synthesis method of the iminoisobenzofuran compound provided by the present invention is a remote carbon-hydrogen bond imino lactone cyclization reaction involving a copper-catalyzed molecular lactam nitrogen free radical. The present invention uses N-halobenzoyl (I) as a raw material, copper salt and 2,2'-bipyridine as catalysts, adds an organic solvent to fully dissolve, reacts for 18 hours at a certain temperature and in a nitrogen atmosphere, and after the reaction is completed, the reaction product is separated and purified by silica gel column chromatography to obtain an iminoisobenzofuran compound as shown in formula (II). The reaction equation is:

[0007] In the present invention, R 1 , R 2 , R 3 is hydrogen, alkyl or phenyl; Ar is phenyl or substituted phenyl; X is fluorine or chlorine atom.

[0008] In the present invention, the copper salt is any one of cuprous iodide, cuprous bromide, cuprous bromide dimethyl sulfide, cuprous chloride, cuprous thiophene-2-carboxylate or cupric acetate. Preferably, N-fluoroamide and N-chloroamide use cuprous iodide and cuprous bromide dimethyl sulfide as copper salts, respectively.

[0009] In the present invention, the catalyst is copper salt and 2,2'-bipyridine; the amount of the catalyst is 1-100 mol% of the raw material N-haloamide. Preferably, the amount of the catalyst is 10 mol%.

[0010] In the present invention, the organic solvent is any one of dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, ether, acetonitrile, toluene, and 1,4-dioxane. Preferably, the reaction solvent is tetrahydrofuran.

[0011] In the present invention, the synthesis reaction is carried out at a temperature of 0-80°C for 18 hours. Preferably, the N-fluoroamide and the N-chloroamide are reacted at 50°C and 30°C, respectively.

[0012] The specific control steps of the method of the present invention are as follows: (1) In a nitrogen environment at room temperature, copper salt (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous organic solvent (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-haloamide (0.40 mmol, 1.0 equivalent) was added to the mixture, and the reaction mixture was stirred in an oil bath reactor until the reaction was complete; (2) After the reaction is completed as monitored by thin layer chromatography, the precipitate is filtered out and washed with dichloromethane. The filtrate is concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as an eluent to obtain the corresponding iminoisobenzofuran compound.

[0013] In the present invention, the above reaction yield reaches 54-93%.

[0014] In the present invention, the structure of the compound is 1 H NMR, 13 The product was characterized and confirmed by C NMR and HRMS.

[0015] Compared with the prior art, the present invention has the following advantages: (1) The present invention provides a new synthetic strategy to construct iminoisobenzofuran compounds through a selective carbon-hydrogen bond functionalization reaction involving free radicals, and provides a new idea for the synthesis of drug molecules and functional materials.

[0016] (2) The present invention uses low-cost copper salt and 2,2-bipyridine as catalysts, and the raw materials are easily available, the reaction conditions are mild, and the yield and selectivity are high, and the present invention has potential industrial value; (3) The synthesis method provided by the present invention not only has high atom economy but also has excellent substrate practicality, and can obtain differently substituted iminoisobenzofuran compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 For II-a 1 H NMR spectrum; Figure 2 For II-a 13 C NMR spectrum; Figure 3 For II-b 1 H NMR spectrum; Figure 4 For II-b 13 C NMR spectrum; Figure 5 For II-c 1 H NMR spectrum; Figure 6 For II-c 13 C NMR spectrum; Figure 7 For II-d 1 H NMR spectrum; Figure 8 For II-d 13 C NMR spectrum; Fig. 9 For II-e 1 H NMR spectrum; Fig.10 For II-e 13 C NMR spectrum; Fig.11 For II-f 1 H NMR spectrum; Fig.12 For II-f 13 C NMR spectrum; Fig.13 For II-g 1 H NMR spectrum; Fig.14 For II-g 13 C NMR spectrum; Fig.15 For II-h 1 H NMR spectrum; Fig.16 For II-h13 C NMR spectrum; Fig.17 For II-i 1 H NMR spectrum; Fig.18 For II-i 13 C NMR spectrum; Fig.19 For II-j 1 H NMR spectrum; Fig. 20 For II-j 13 C NMR spectrum; Fig.21 For II-k 1 H NMR spectrum; Fig. 22 For II-k 13 C NMR spectrum; Fig.23 For II-l 1 H NMR spectrum; Fig.24 For II-l 13 C NMR spectrum; Fig.25 For II-m 1 H NMR spectrum; Fig.26 For II-m 13 C NMR spectrum; Fig. 27 For II-n 1 H NMR spectrum; Fig.28 For II-n 13 C NMR spectrum; Fig.29 For II-o 1 H NMR spectrum; Fig.30 For II-o 13 C NMR spectrum; Fig.31 For II-p 1 H NMR spectrum; Fig.32 For II-p 13 C NMR spectrum; Fig.33 For II-q 1 H NMR spectrum; Fig.34 For II-q 13 C NMR spectrum; Fig.35For II-r 1 H NMR spectrum; Fig.36 For II-r 13 C NMR spectrum; Fig.37 For II-s 1 H NMR spectrum; Fig.38 For II-s 13 C NMR spectrum; Implementation

[0018] The present invention is further described below by specific examples. The raw materials and reagents involved in the following examples are all commercially available products, or can be prepared by known methods. Example 1

[0019] The preparation technology route of Ⅱ-a is:

[0020] In a sealable reaction tube equipped with a magnetic stirrer under nitrogen atmosphere at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence. Then, N-fluoroformamide Ia (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a white solid, namely, iminoisobenzofuran compound II-a, with a yield of 79%.

[0021] Structural characterization of heterocyclic compound II-a: 1 H NMR (400 MHz, CDCl3) 7.81 (d, J = 7.6 Hz,1H), 7.49-7.44 (m, 1H), 7.42-7.36 (m, 1H), 7.35-7.32 (m, 1H), 5.31 (s, 2H),1.40 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 157.0, 142.5, 132.0, 130.9, 128.2,123.7, 121.1, 72.0, 53.6, 30.1. HRMS (ESI) m / z calcd. for C 12 H 16NO [M+H] + 190.1226, found 190.1226. Example 2

[0022] The preparation technology route of Ⅱ-b is:

[0023] In a sealable reaction tube equipped with a magnetic stirrer under nitrogen atmosphere at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence. Then, N-fluoroformamide Ib (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a white solid, namely, iminoisobenzofuran compound II-b, with a yield of 85%.

[0024] Structural characterization of heterocyclic compound II-a: 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.8 Hz,1H), 7.20 (d, J = 7.6 Hz, 1H), 7. 15-7. 11 (m, 1H), 5.26 (s, 2H), 2.42 (s,3H), 1.40 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 157.3, 142.9, 141.4, 129.3,123.5, 121.5, 71.9, 53.5, 30.1, 21.7. HRMS (ESI) m / z calcd. for C 13 H 18 NO [M+H] + 204.1383, found 204.1380. Example 3

[0025] The preparation technology route of Ⅱ-c is:

[0026] In a sealable reaction tube equipped with a magnetic stirrer under nitrogen atmosphere at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence. Then, N-fluoroformamide Ic (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a white solid, namely, iminoisobenzofuran compound II-c, with a yield of 75%.

[0027] Structural characterization of heterocyclic compound II-c: 1 H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.31-7.25 (m, 1H), 7.23-7.19 (m, 1H), 5.27 (s, 2H), 2.39 (s, 3H), 1.40 (s, 9H); 13 CNMR (101 MHz, CDCl3) δ 157.2, 139.7, 138.3, 132.1, 140.0, 123.8, 120.8, 72.0,53.5, 30.1, 21.1. HRMS (ESI) m / z calcd. for C 13 H 18 NO [M+H] + 204.1383, found 204.1380. Example 4

[0028] The preparation technology route of Ⅱ-d is:

[0029] In a sealable reaction tube equipped with a magnetic stirrer under nitrogen atmosphere at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence. Then, N-fluoroformamide Id (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-d, with a yield of 64%.

[0030] Structural characterization of heterocyclic compound II-d: 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 1.9 Hz,1H), 7.43 (dd, J = 8.1, 1.9 Hz, 1H), 7.30-7.21 (m, 1H), 5.28 (s, 2H), 1.38 (s,9H); 13 C NMR (101 MHz, CDCl3) δ 155.3, 140.6, 134.5, 134.1, 131.1, 123.8,122.4, 71.8, 53.7, 30.0. HRMS (ESI) m / z calcd. for C 12 H 15 ClNO [M+H] + 224.0837, found 224.0840. Example 5

[0031] The preparation technology route of Ⅱ-e is:

[0032] In a sealable reaction tube equipped with a magnetic stirrer under nitrogen atmosphere at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence. Then, N-fluoroformamide Ie (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a white solid, namely, iminoisobenzofuran compound II-e, with a yield of 81%.

[0033] Structural characterization of heterocyclic compound II-e: 1 H NMR (400 MHz, CDCl3) δ 7.28 -7.22 (m, 1H),7.15 (d, J = 8.3 Hz, 1H), 7.02 (dd, J = 8.3, 2.4 Hz, 1H), 5.49 (q, J = 6.5 Hz, 1H), 3.86 (s, 3H), 1.53 (d,J = 6.5 Hz, 3H), 1.40 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ160.2, 156.7, 139.6, 133.3, 121.6, 119.9, 105.7, 79.4, 55.7, 53.5, 30.0,21.5. HRMS (ESI) m / z calcd. for C 14 H 20 NO2[M+H] + 234.1489, found 234.1492. Example 6

[0034] The preparation technology route of Ⅱ-f is:

[0035] In a nitrogen environment at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-fluoroformamide If (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-f, with a yield of 71%.

[0036] Structural characterization of heterocyclic compound II-f: 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.6 Hz, 1H), 7.48-7.43 (m, 1H), 7.41-7.35 (m, 1H), 7.29-7.24 (m, 1H), 5.55 (q, J = 6.6 Hz, 1H), 1.56 (d, J = 6.6 Hz, 3H), 1.40 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 156.6, 147.1, 131.8, 130.9,128.3, 123.7, 120.8, 79.6, 53.5, 30.0, 21.3. HRMS (ESI) m / z calcd. forC 13 H 18 NO [M+H] + 204.1383, found 204.1380. Example 7

[0037] The preparation technology route of Ⅱ-g is:

[0038] In a nitrogen environment at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-fluoroformamide Ig (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-g, with a yield of 80%.

[0039] Structural characterization of heterocyclic compound II-g: 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.7 Hz,1H), 7.48-7.42 (m, 1H), 7.40-7.34 (m, 1H), 7.29-7.23 (m, 1H), 5.46 (dd, J =7.7, 3.9 Hz, 1H), 2.00-1.90 (m, 1H), 1.76-1.61 (m, 1H), 1.57-1.38 (m, 11H),0.97 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 156.7, 145.9, 132.2, 130.8,128.2, 123.6, 120.9, 83.2, 53.5, 37.8, 30.0, 18.3, 14.0. HRMS (ESI) m / zcalcd. for C 15 H 22 NO [M+H] + 232.1696, found 232.1695. Example 8

[0040] The preparation technology route of Ⅱ-h is:

[0041] In a sealable reaction tube equipped with a magnetic stirrer under nitrogen atmosphere at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence. Then, N-fluoroformamide Ih (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-h, with a yield of 77%.

[0042] Structural characterization of heterocyclic compound II-h: 1 H NMR (400 MHz, CDCl3) δ 7.81 (dd, J = 7.6,1.2 Hz, 1H), 7.46-7.41 (m, 1H), 7.40-7.35 (m, 1H), 7.32-7.18 (m, 6H), 5.46(dd, J = 8.2, 3.6 Hz, 1H), 2.87-2.69 (m, 2H), 2.33-2.24(m, 1H), 2.05-1.93 (m,1H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 156.5, 145.6, 141.2, 132.2,133.0, 128.6, 128.5, 128.4, 126.1, 123.7, 120.9, 82.3, 53.7, 37.5, 31.4,30.1. HRMS (ESI) m / z calcd. for C 20 H 24 NO [M+H] + 294.1852, found 294.1852. Example 9

[0043] The preparation technology route of Ⅱ-i is:

[0044] In a nitrogen environment at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-fluoroformamide Ii (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-i, with a yield of 87%.

[0045] Structural characterization of heterocyclic compound II-i: 1 H NMR (400 MHz, CDCl3) δ 7.77-7.73 (m, 1H), 7.43-7.32 (m, 2H), 7.31-7.19 (m, 5H), 7.09-7.04 (m, 1H), 5.67 (t, J = 6.3 Hz,1H), 3.21-3.08 (m, 2H), 1.38 (s, 9H); 13 HRMS (ESI) m / z calcd. for C 19 H22 NO [M+H] + 280.1696, found 280.1700. Example 10

[0046] The preparation technology route of Ⅱ-j is:

[0047] In a nitrogen environment at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-fluoroformamide Ij (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-j, with a yield of 82%.

[0048] Structural characterization of heterocyclic compound II-j: 1 H NMR (400 MHz, CDCl3) δ 7.83-7.77 (m, 1H),7.48-7.42 (m, 1H), 7.41-7.36 (m, 1H), 7.32-7.28 (m, 1H), 5.82-5.70 (m, 1H),5.51 (dd, J = 6.7, 4.8 Hz, 1H), 5.20-5.07 (m, 2H), 2.77-2.67 (m, 1H), 2.61-2.47(m, 1H), 1.40 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 156.4, 145.2, 132.4, 132.3,130.8, 128.4, 123.7, 121.1, 118.8, 82.4, 53.6, 39.9, 30.0. HRMS (ESI) m / zcalcd. for C 15 H 20 NO [M+H] + 230.1539, found 230.1540. Embodiment 11

[0049] The preparation technology route of Ⅱ-k is:

[0050] In a sealable reaction tube equipped with a magnetic stirrer under nitrogen atmosphere at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence. Then, N-fluoroformamide Ik (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a white solid, namely, iminoisobenzofuran compound II-k, with a yield of 93%.

[0051] Structural characterization of heterocyclic compound II-k: 1 H NMR (400 MHz, CDCl3) δ 7.83-7.77 (m, 1H),7.48-7.42 (m, 1H), 7.41-7.36 (m, 1H), 7.32-7.28 (m, 1H), 5.82-5.70 (m, 1H),5.51 (dd, J = 6.7, 4.8 Hz, 1H), 5.20-5.07 (m, 2H), 2.77-2.67 (m, 1H), 2.61-2.47(m, 1H), 1.40 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 156.4, 145.2, 132.4, 132.3, 130.8, 128.4,123.7, 121.1, 118.8, 82.4, 53.6, 39.9, 30.0. HRMS (ESI) m / z calcd. forC 15 H 20 NO [M+H] + 230.1539, found 230.1540. Example 12

[0052] The preparation technology route of Ⅱ-1 is:

[0053] In a nitrogen environment at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-fluoroformamide Il (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-1, with a yield of 58%.

[0054] Structural characterization of heterocyclic compound II-1: 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz,1H), 7.49-7.43 (m, 1H), 7.42-7.36 (m, 2H), 4.98 (d, J = 7.3 Hz, 1H), 1.40 (s,9H), 1.17-1.07 (m, 1H), 0.73-0.43 (m, 4H); 13 C NMR (101 MHz, CDCl3) δ 157.1,144.1, 130.6, 129.3, 126.9, 122.0, 119.8, 84.5, 52.0, 28.4, 13.8, 0.3. HRMS(ESI) m / z calcd. for C 15 H 20 NO [M+H] + 230.1539, found 230.1540. Example 13

[0055] The preparation technology route of Ⅱ-m is:

[0056] In a nitrogen environment at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-fluoroformamide Im (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-m, with a yield of 67%.

[0057] Structural characterization of heterocyclic compound II-m: 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.7 Hz,1H), 7.47-7.42 (m, 1H), 7.38-7.33 (m, 1H), 7.19 (dd, J = 7.5, 1.0 Hz, 1H),2.05-1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.56 (s, 3H), 1.41 (s, 9H), 0.71 (t, J =7.3 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 156.5, 149.2, 132.2, 130.9, 128.2,123.6, 120.2, 89.3, 53.4, 33.7, 29.9, 26.5, 8.0. HRMS (ESI) m / z calcd. forC 15 H 22 NO [M+H] + 232.1696, found 232.1695. Embodiment 14

[0058] The preparation technology route of Ⅱ-n is:

[0059] In a nitrogen environment at room temperature, cuprous iodide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-fluoroformamide In (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 50 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-n, with a yield of 68%.

[0060] Structural characterization of heterocyclic compound II-n: 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.41-7.35 (m, 1H), 7.34-7.30 (m, 1H), 5.29 (s, 2H), 1.75 (s, 2H), 1.44 (s, 6H), 1.02 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 155.1,142.3, 132.5, 130.6, 128.2, 123.7, 121.1, 71.8, 57.3, 55.2, 32.1, 31.9, 30.4.HRMS (ESI) m / z calcd. for C 16 H 24 NO [M+H] + 246.1852, found 246.1853. Embodiment 15

[0061] The preparation technology route of Ⅱ-o is:

[0062] Under nitrogen atmosphere at room temperature, cuprous bromide dimethyl sulfide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-chloroformamide Io (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 30 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-o, with a yield of 65%.

[0063] Structural characterization of heterocyclic compound II-o: 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.6 Hz,1H), 7.52-7.46 (m, 1H), 7.41 (dd, J = 7.4, 7.4 Hz, 1H), 7.32-7.28 (m, 1H), 5.56(q, J = 6.6 Hz, 1H), 3.54 (q, J = 7.3 Hz, 2H), 1.58 (d, J = 6.6 Hz, 3H), 1.28 (t, J =7.3 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 159.4, 147.7, 131.2, 130.3, 128.5,123.3, 121.0, 79.8, 41.7, 21.2, 16.0. HRMS (ESI) m / z calcd. for C 11 H 14 NO [M+H] + 176.1070, found 176.1070. Example 16

[0064] The preparation technology route of Ⅱ-p is:

[0065] Under nitrogen atmosphere at room temperature, cuprous bromide dimethyl sulfide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-chloroformamide Ip (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 30 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-p, with a yield of 58%.

[0066] Structural characterization of heterocyclic compound II-p: 1 H NMR (400 MHz, CDCl3δ 7.83 (d, J = 7.6 Hz,1H), 7.50-7.46 (m, 1H), 7.41 (dd, J = 7.6, 7.6 Hz, 1H), 7.32-7.28 (m, 1H), 5.55(q, J = 6.6 Hz, 1H), 3.50 (t, J = 7.4 Hz, 2H), 1.71-1.63 (m, 2H), 1.58 (d, J = 6.6Hz, 3H), 1.44-1.36 (m, 2H), 1.36-1.30 (m, 4H), 0.92-0.86 (m, 3H); 13 C NMR (101MHz, CDCl3) δ 162.6, 147.7, 131.1, 128.5, 123.3, 120.9, 79.6, 47.4, 31.8,30.9, 27.3, 22.7, 21.3, 14.1. HRMS (ESI) m / z calcd. for C 15 H 22 NO [M+H] + 232.1696, found 232.1695. Embodiment 17

[0067] The preparation technology route of Ⅱ-q is:

[0068] Under nitrogen atmosphere at room temperature, cuprous bromide dimethyl sulfide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-chloroformamide Iq (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 30 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-q, with a yield of 62%.

[0069] Structural characterization of heterocyclic compound II-q: 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.6 Hz,1H), 7.53-7.47 (m, 1H), 7.46-7.40 (m, 3H), 7.35-7.29 (m, 3H), 7.25-7.20 (m,1H), 5.61 (q, J = 6.6 Hz, 1H), 4.74 (s, 2H), 1.60 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.2, 147.9, 140.8, 131.4, 130.2, 128.6, 128.3, 127.9,126.5, 123.6, 121.0, 80.1, 51.0, 21.2. HRMS (ESI) m / z calcd. for C 16 H 16 NO [M+H] + 238.1226, found 238.1227. Embodiment 18

[0070] The preparation technology route of Ⅱ-r is:

[0071] Under nitrogen atmosphere at room temperature, cuprous bromide dimethyl sulfide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-chloroformamide Ir (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 30 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-r, with a yield of 71%.

[0072] Structural characterization of heterocyclic compound II-r: 1 H NMR (400 MHz, CDCl3) δ 7.87 -7.82 (m, 1H),7.49-7.42 (m, 1H), 7.42-7.36 (m, 1H), 7.30-7.25 (m, 1H), 5.54 (q, J = 6.6 Hz,1H), 4.27-4.20 (m, 1H), 2.05-1.93 (m, 2H), 1.83-1.74 (m, 2H), 1.64-1.53 ​​(m,7H); 13 C NMR (101 MHz, CDCl3) δ 158.7, 147.7, 131.0, 130.5, 128.4, 123.4,120.9, 79.5, 57.7, 34.2, 34.1, 24.4, 21.3. HRMS (ESI) m / z calcd. for C 14 H 18 NO[M+H] + 216.1383, found 216.1384. Embodiment 19

[0073] The preparation technology route of II-s is:

[0074] Under nitrogen atmosphere at room temperature, cuprous bromide dimethyl sulfide (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous tetrahydrofuran (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-chloroformamide Is (0.40 mmol, 1.0 equivalent) was added to the mixture and the reaction mixture was stirred at 30 °C for 18 hours. After the reaction was completed (monitored by TLC), the precipitate was filtered out and washed with dichloromethane, the filtrate was concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to obtain a colorless oily liquid, namely, iminoisobenzofuran compound II-s, with a yield of 70%.

[0075] Structural characterization of heterocyclic compound II-s: 1 H NMR (400 MHz, CDCl3) δ 7.96-7.76 (m, 1H),7.50-7.44 (m, 1H), 7.39 (dd, J = 7.4, 7.4 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 5.56(q, J = 6.5 Hz, 1H), 2.16-2.01 (m, 9H), 1.77-1.66 (m, 6H), 1.58 (d, J = 6.6 Hz,3H); 13 C NMR (101 MHz, CDCl3) δ 156.9, 147.1, 131.7, 131.1, 128.4, 124.0,120.8, 79.9, 42.4, 36.8, 29.9, 21.3. HRMS (ESI) m / z calcd. for C 19 H 24 NO [M+H] + 282.1852, found 282.1852.

Claims

1. A method for preparing an iminoisobenzofuran compound, characterized in that: N-halogenated benzoyl (I) is used as a raw material, copper salt and 2,2'-bipyridine are used as catalysts, an organic solvent is added to fully dissolve, and the mixture is reacted for 18 hours under a nitrogen atmosphere at a certain temperature. After the reaction is completed, the reaction product is separated and purified by silica gel column chromatography to obtain an iminoisobenzofuran compound as shown in formula (II). The reaction equation is:

2. Among them: R 1 , R 2 , R 3 is hydrogen, alkyl or phenyl; Ar is phenyl or substituted phenyl; X is fluorine or chlorine atom.

3. The preparation method according to claim 1, characterized in that: The preparation method specifically comprises the following steps: (1) In a nitrogen environment at room temperature, copper salt (0.04 mmol, 10 mol%), 2,2'-bipyridine (0.04 mmol, 10 mol%) and anhydrous organic solvent (2.0 mL) were added in sequence to a sealable reaction tube equipped with a magnetic stirrer. Then, N-haloamide (0.40 mmol, 1.0 equivalent) was added to the mixture, and the reaction mixture was stirred in an oil bath reactor until the reaction was complete. (2) After the reaction is completed as monitored by thin layer chromatography, the precipitate is filtered out and washed with dichloromethane. The filtrate is concentrated under reduced pressure and separated by column chromatography using a mixture of petroleum ether and ethyl acetate as an eluent to obtain the corresponding iminoisobenzofuran compound.

4. The preparation method according to claim 1, characterized in that: The copper salt is cuprous iodide, cuprous bromide, cuprous bromide dimethyl sulfide, cuprous chloride, cuprous thiophene-2-carboxylate or cupric acetate.

5. The preparation method according to claim 1, characterized in that: The organic solvent is dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, ether, acetonitrile, toluene or 1,4-dioxane.

6. The preparation method according to claim 1, characterized in that: The catalyst is copper salt and 2,2'-bipyridine; the amount of the catalyst used is 1-100 mol% of the raw material N-haloamide.

7. The preparation method according to claim 1, characterized in that: The synthesis reaction is carried out at a temperature of 0-80°C and the reaction time is 18 hours.

8. The preparation method according to claim 2, characterized in that: In the step 2), the reaction system is subjected to column chromatography, and the eluent used may be petroleum ether / ethyl acetate (volume ratio is 3:1-10:1); after column chromatography, a pure compound of formula II can be obtained.

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