Method for synthesizing beta-indolone compound by nickel-catalyzed ring opening 1, 2-functionalization of aryl cyclopropyl ketone

Abstract

The invention discloses a method for synthesizing beta-indolone compounds by nickel-catalyzed ring-opening 1, 2-functionalization of aryl cyclopropyl ketone, which comprises the following steps: by taking aryl cyclopropyl ketone and an indole compound as reaction substrates, an ether halide complex of nickel (II) as a pre-catalyst, 4, 5-bis (diphenylphosphino)-9, 9-dimethyl xanthene as a ligand and zinc powder as a reducing agent, reacting at the temperature of 60-80 DEG C for 1-2 hours, thereby obtaining the beta-indolone compounds. The beta-indolone compound is prepared by efficiently and highly selectively realizing cyclopropyl ring opening 1, 2-functionalization of mono-activated aryl cyclopropyl ketone. The method has the advantages that the reaction system is cheap and easy to obtain, the substrate range is wide, the reaction condition is mild, the yield of the target product is high, and the method has a wide application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of the methodology of mono-activated cyclopropyl ring-opening 1,2-functionalization. Specifically, it is a method for using 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (ligand) to regulate the in-situ generation of catalytically active species of nickel(II) ether halide complexes, combined with zinc powder as a reducing agent, to achieve the ring-opening 1,2-functionalization of the cyclopropyl structure in indole compounds and aryl cyclopropyl ketones to obtain β-indolones. Background Art

[0002] The basic skeleton of organic compounds is composed of carbon-carbon bonds, and the process of their cleavage widely exists in industrial development and life processes. The activation reaction of carbon-carbon σ bonds can explore rich and economical raw materials in nature. However, compared with the widely studied carbon-carbon bond formation methodologies, the research on carbon-carbon bond cleavage is still relatively lagging behind.

[0003] The cyclopropane structure is one of the most important skeletons in organic chemistry and is widely present in drugs and agrochemicals. Due to its small ring strain, cyclopropane can be used as an effective substrate for studying carbon-carbon bond cleavage. For the subsequent functionalization reactions of aryl cyclopropyl ketone ring-opening, currently, more research has been done on alkylation reactions with alkyl bromides, hydroarylation reactions with arylating reagents, and reactions with nucleophiles to construct carbon-hetero bonds, etc. These reactions can achieve various ring-opening 1,3-functionalization reactions of aryl cyclopropyl ketones, but the ring-opening functionalization sites always remain at the 1,3-positions, and there are few reports on 1,2-functionalization. Therefore, it is of great significance to develop a 1,2-functionalization reaction.

[0004] Through literature research on the current reactions of cyclopropane and indole, they can be roughly divided into two categories according to the types of products formed: (1) The reaction of the 3-position carbon of the cyclopropane ring-opening catalyzed by Lewis acid with indole to form a new carbon-carbon bond, obtaining a linear target product; (2) The ring-expansion reaction of the DA cyclopropane ring-opening catalyzed by Lewis acid with indole to obtain a target product with a tricyclic structure. However, there are no reported examples of the coupling of the 2-position carbon of the cyclopropane ring-opening with indole to obtain a branched-chain structure target product. From literature research, it can be known that currently, the preparation of β-indolones is mainly from the Michael addition reaction of α,β-unsaturated ketones and indoles, catalyzed by Lewis acid and undergoing a 1,4-addition manner. Due to the high activity of the α,β-unsaturated ketone raw materials, the currently used α,β-unsaturated ketones are mainly chalcone-like substances, that is, structures with phenyl groups connected at both ends. For conventional α,β-unsaturated ketone substrates with a methyl group connected at the end, due to their high activity and difficult purification, they are almost impossible to commercially purchase and have high preparation requirements, and there are limited examples of related structure reports. Summary of the Invention

[0005] The object of the present invention is to provide a method for synthesizing β - indolones by nickel - catalyzed ring - opening 1,2 - functionalization of aryl cyclopropyl ketones. This method starts from the cyclopropyl group of the mono - activated aryl cyclopropyl ketone, and the catalytic system for carbon - carbon σ - bond cleavage and ring - opening 1,2 - functionalization is inexpensive and readily available, with mild reaction conditions, safe and efficient steps.

[0006] For the above object, the solution adopted by the present invention is: under the protection of an inert gas, an aryl cyclopropyl ketone represented by formula I, an indole compound represented by formula II, an ether halide complex of nickel(II), 4,5 - bis(diphenylphosphino) - 9,9 - dimethyloxanthrene, and zinc powder are added to an organic solvent, and the reaction is carried out at 70 - 100 °C. After the reaction is completed, separation and purification are carried out to obtain a β - indolone compound represented by formula III;

[0007]

[0008] In the formula, Ar represents any one of aryl, heteroaryl, substituted aryl, and substituted heteroaryl, specifically, for example, any one of phenyl, thienyl, naphthyl, or phenyl substituted by any one of C1 - C4 alkyl, C1 - C4 alkoxy, halogen, phenyl, phenoxy, benzyloxy, etc.; R represents a substituent at any position on the indole ring, and the substituent is selected from any one of hydrogen, C1 - C4 alkyl, C1 - C4 alkoxy, halogen, benzyloxy, C2 - C4 ester group, benzyl, phenyl, etc.

[0009] In the above - mentioned synthesis method, preferably, the ether halide complex of nickel(II) is any one of nickel(II) dimethoxyethane bromide, nickel(II) dimethoxyethane chloride, and nickel(II) dibutyl ether bromide complex.

[0010] Furthermore, preferably, the addition amount of the ether halide complex of nickel(II) is 10% - 20% of the molar amount of the aryl cyclopropyl ketone.

[0011] In the above - mentioned synthesis method, preferably, the addition amount of 4,5 - bis(diphenylphosphino) - 9,9 - dimethyloxanthrene is 5% - 10% of the molar amount of the aryl cyclopropyl ketone.

[0012] In the above - mentioned synthesis method, preferably, the addition amount of zinc powder is 2 - 3 times the molar amount of the aryl cyclopropyl ketone.

[0013] In the above - mentioned synthesis method, preferably, the addition amount of the indole compound is 1 - 2 times the molar amount of the aryl cyclopropyl ketone.

[0014] In the above - mentioned synthesis method, preferably, the organic solvent is any one of tetrahydrofuran, 2 - methyltetrahydrofuran, ethanol, and 1,4 - dioxane.

[0015] In the above - mentioned synthesis method, preferably, the reaction is carried out at 70 - 100 °C for 6 - 12 hours.

[0016] The beneficial effects of the present invention are as follows:

[0017] The present invention uses an ether halide complex of nickel (II) as a precatalyst, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene as a ligand, and zinc powder as a reducing agent to achieve the 1,2-functionalization reaction of ring-opening of the cyclopropyl group on aryl cyclopropyl ketones to obtain β-indolones. The present invention has the advantages of a cheap and easily available reaction system, a wide substrate range, mild reaction conditions, a relatively high yield of the target product, and broad application prospects. Specific Embodiments

[0018] The present invention will be further described in detail below with reference to the embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0019] Example 1

[0020] Synthesize 3-(1H-indol-3-yl)-1-phenylbutanone with the following structural formula

[0021]

[0022] In a glove box, 0.0093 g (0.03 mmol) of nickel bromide dimethoxyethane, 0.0086 g (0.015 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 0.0392 g (0.6 mmol) of zinc powder, 0.0429 mg (0.4 mmol) of indole, 28 μL (0.2 mmol) of phenylcyclopropyl ketone, and 0.5 mL of 1,4-dioxane were added to a Schlenk tube. The glass stopper of the Schlenk tube was sealed with vacuum grease, and it was removed from the glove box and stirred at 100 °C for 12 hours. After the reaction was completed, the reaction mixture was filtered through a silica gel gasket and purified by flash column chromatography using petroleum ether and ethyl acetate as eluents to obtain 3-(1H-indol-3-yl)-1-phenylbutanone with a yield of 85%. The spectral data of the product are as follows: 11H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.94 (d, J = 6.8 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.11 (t, J = 6.8 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 3.83 (h, J = 6.8 Hz, 1H), 3.46 (dd, J = 16.4, 4.8 Hz, 1H), 3.23 (dd, J = 16.4, 8.8 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, Chloroform-d) δ 200.0, 137.4, 136.6, 133.1, 128.7, 128.2, 126.4, 122.1, 121.5, 120.4, 119.3, 119.3, 111.4, 46.6, 27.2, 21.1.

[0023] Example 2

[0024] Synthesize 3-(6-methyl-1H-indol-3-yl)-1-phenylbutan-1-one with the following structural formula

[0025]

[0026] In this example, 6-methylindole was used to replace the indole used in Example 1 in an equimolar amount, and the other steps were the same as those in Example 1 to obtain 3-(6-methyl-1H-indol-3-yl)-1-phenylbutan-1-one with a yield of 72%. The spectral data of the product are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 7.2 Hz, 2H), 7.92 (s, 1H), 7.60 - 7.55 (m, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.15 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.49 (dd, J = 16.4, 4.8 Hz, 1H), 3.25 (dd, J = 16.4, 9.2 Hz, 1H), 2.48 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H); 1313C NMR (101 MHz, Chloroform-d) δ 200.0, 137.4, 137.1, 133.1, 131.9, 128.7, 128.2, 124.2, 121.4, 121.1, 119.7, 119.0, 111.4, 46.6, 27.3, 21.8, 21.1.

[0027] Example 3

[0028] Synthesize 3-(5-methyl-1H-indol-3-yl)-1-phenylbutanone with the following structural formula

[0029]

[0030] In this example, 5-methylindole was used to replace the indole used in Example 1 in an equimolar amount, and the other steps were the same as those in Example 1, obtaining 3-(5-methyl-1H-indol-3-yl)-1-phenylbutanone with a yield of 77%. The spectral data of the product are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 8.00–7.98 (m, 2H), 7.96 (s, 1H), 7.59 - 7.56 (m, 1H), 7.49 - 7.45 (m, 3H), 7.26 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 8.4, 1.6 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.49 (dd, J = 16.4, 4.4 Hz, 1H), 3.27 (dd, J = 16.4, 9.2 Hz, 1H), 2.49 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, Chloroform-d) δ 200.1, 137.4, 134.9, 133.1, 128.7, 128.5, 128.2, 126.6, 123.7, 121.0, 120.5, 118.9, 111.1, 46.6, 27.1, 21.7, 21.0.

[0031] Example 4

[0032] Synthesize 3-(6-methoxy-1H-indol-3-yl)-1-phenylbutanone with the following structural formula

[0033]

[0034] In this example, indole used in Example 1 was replaced with equimolar 6-methoxyindole, and other steps were the same as those in Example 1, to obtain 3-(6-methoxy-1H-indol-3-yl)-1-phenylbutanone, with a yield of 70%. The spectral data of the product are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.98–7.95(m,3H),7.58–7.54(m,2H),7.45(t,J=7.6Hz,2H),6.89(d,J=2.4Hz,1H),6.84–6.80(m,2H),3.83(s,3H),3.81-3.76(m,1H),3.47(dd,J=16.4,5.2Hz,1H),3.24(dd,J=16.4,8.8Hz,1H),1.45(d,J=6.8Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ200.0,156.5,137.4,137.3,133.1,128.7,128.2,121.5,120.8,119.9,119.01,109.3,94.9,55.7,46.6,27.3,21.1;HRMS(ESI)m / z C 19 H 19 NNaO2 + [M+Na] + : theoretical value 316.1308, measured value 316.1300.

[0035] Example 5

[0036] Synthesize 3-(5-benzyloxy-1H-indol-3-yl)-1-phenylbutanone with the following structural formula

[0037]

[0038] In this example, indole used in Example 1 was replaced with equimolar 5-benzyloxyindole, and other steps were the same as those in Example 1, to obtain 3-(5-benzyloxy-1H-indol-3-yl)-1-phenylbutanone, with a yield of 68%. The spectral data of the product are as follows: 11H NMR (400 MHz, Chloroform-d) δ 7.94–7.92 (m, 3H), 7.55 - 7.51 (m, 1H), 7.48 - 7.45 (m, 2H), 7.44 - 7.40 (m, 2H), 7.36 - 7.33 (m, 2H), 7.29 - 7.25 (m, 1H), 7.21 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.96–6.91 (m, 2H), 5.08 (s, 2H), 3.81–3.72 (m, 1H), 3.39 (dd, J = 16.4, 4.8 Hz, 1H), 3.19 (dd, J = 16.4, 8.8 Hz, 1H), 1.41 (d, J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, Chloroform-d) δ 200.0, 153.0, 137.7, 137.4, 133.1, 131.9, 128.7, 128.6, 128.2, 127.9, 127.8, 126.7, 112.9, 112.1, 102.9, 71.1, 46.4, 27.1, 21.0.

[0039] Example 6

[0040] Synthesize 3-(6-fluoro-1H-indol-3-yl)-1-phenylbutan-1-one with the following structural formula

[0041]

[0042] In this example, 6-fluoroindole with an equimolar amount was used to replace the indole used in Example 1, and other steps were the same as those in Example 1 to obtain 3-(6-fluoro-1H-indol-3-yl)-1-phenylbutan-1-one, and its yield was 77%. The spectral data of the product are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.96 (d, J = 7.6 Hz, 2H), 7.59–7.54 (m, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.04–7.00 (m, 1H), 6.98 (s, 1H), 6.92–6.87 (m, 1H), 3.86 - 3.77 (m, 1H), 3.45 (dd, J = 16.4, 5.2 Hz, 1H), 3.25 (dd, J = 16.4, 8.4 Hz, 1H), 1.45 (d, J = 6.8 Hz, 3H); 13CNMR (101 MHz, Chloroform-d) δ 199.9, 161.2, 158.8, 137.3, 136.6, 136.4, 133.2, 128.7, 128.2, 123.1, 121.6, 120.5, 120.0, 119.9, 108.1, 107.9, 97.8, 97.5, 46.5, 27.1, 21.2; 19 FNMR (376 MHz, Chloroform-d) δ -121.18 (t, J = 8.9 Hz); HRMS (ESI) m / z C 18 H 16 FNNaO + [M + Na] + : Calculated value 304.1108, measured value 304.1102.

[0043] Example 7

[0044] Synthesize 3-(5-(methoxycarbonyl)-1H-indol-3-yl)-1-phenylbutan-1-one with the following structural formula

[0045]

[0046] In this example, indole-5-carboxylic acid methyl ester in equimolar amount was used to replace the indole used in Example 1, and other steps were the same as those in Example 1 to obtain 3-(5-(methoxycarbonyl)-1H-indol-3-yl)-1-phenylbutan-1-one with a yield of 72%. The spectral data of the product are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 8.45 (s, 1H), 7.96 - 7.94 (m, 2H), 7.89 (dd, J = 8.4, 1.6 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.33 (d, J = 8.8 Hz, 1H), 7.06 (s, 1H), 3.93 (s, 3H), 3.90 - 3.82 (m, 1H), 3.47 (dd, J = 16.4, 5.6 Hz, 1H), 3.27 (dd, J = 16.4, 8.4 Hz, 1H), 1.46 (d, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 199.8, 168.5, 139.3, 137.2, 133.2, 128.7, 128.2, 126.0, 123.4, 122.7, 122.2, 121.8, 121.2, 111.2, 52.0, 46.4, 27.1, 21.3; HRMS (ESI) m / z C 20 H19 NNaO3 + [M+Na] + : Theoretical value 344.1257, measured value 344.1255.

[0047] Example 8

[0048] Synthesize 3-(2,5-dimethyl-1H-indol-3-yl)-1-phenylbutanone with the following structural formula

[0049]

[0050] In this example, equimolar 2,5-dimethylindole was used to replace the indole used in Example 1, and other steps were the same as those in Example 1 to obtain 3-(2,5-dimethyl-1H-indol-3-yl)-1-phenylbutanone, with a yield of 71%. The spectral data of the product are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.93–7.90(m,2H),7.63(s,1H),7.55–7.50(m,1H),7.47(s,1H),7.44-7.39(m,2H),7.14(d,J=8.0Hz,1H),6.93(d,J=6.4Hz,1H),3.78-3.69(m,1H),3.52(dd,J=16.4,6.4Hz,1H),3.40(dd,J=16.0,7.6Hz,1H),2.48(s,3H),2.37(s,3H),1.51(d,J=7.2Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ200.3,137.4,133.9,132.9,130.6,128.6,128.2,128.1,127.5,122.2,119.0,115.12,110.3,45.9,27.4,21.8,21.1,12.2.

[0051] Example 9

[0052] Synthesize 3-(1H-indol-3-yl)-1-(4-methoxyphenyl)butanone with the following structural formula

[0053]

[0054] In this example, equimolar 4-methoxycyclopropyl phenyl ketone was used to replace the phenylcyclopropyl ketone used in Example 1, and other steps were the same as those in Example 1 to obtain 3-(1H-indol-3-yl)-1-(4-methoxyphenyl)butanone, with a yield of 83%. The spectral data of the product are as follows: 11H NMR (400 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.16–7.12 (m, 1H), 7.00 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.85–3.80 (m, 1H), 3.45 (dd, J = 16.4, 4.8 Hz, 1H), 3.21 (dd, J = 16.4, 9.2 Hz, 1H), 1.47 (d, J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, Chloroform-d) δ 198.6, 163.4, 136.6, 130.5, 130.4, 126.4, 122.0, 121.6, 120.3, 119.3, 119.3, 113.8, 111.4, 55.6, 46.2, 27.4, 21.1.

[0055] Example 10

[0056] Synthesize 3-(1H-indol-3-yl)-1-(2-methoxyphenyl)butanone with the following structural formula

[0057]

[0058] In this example, equimolar 2-methoxyphenyl cyclopropyl ketone was used to replace the phenyl cyclopropyl ketone used in Example 1, and the other steps were the same as those in Example 1 to obtain 3-(1H-indol-3-yl)-1-(2-methoxyphenyl)butanone with a yield of 86%. The spectral data of the product are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.61 (dd, J = 7.8, 2.0 Hz, 1H), 7.47–7.43 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 6.8 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.00–6.93 (m, 3H), 3.84 (s, 3H), 3.82 - 3.73 (m, 1H), 3.54 (dd, J = 16.4, 5.2 Hz, 1H), 3.27 (dd, J = 16.4, 8.8 Hz, 1H), 1.42 (d, J = 6.8 Hz, 3H); 1313C NMR (101 MHz, Chloroform-d) δ 203.0, 158.3, 136.6, 133.2, 130.2, 129.1, 126.6, 121.9, 121.8, 120.7, 120.3, 119.4, 119.1, 111.5, 111.3, 55.6, 51.6, 27.3, 21.2; HRMS (ESI) m / z C 19 H 19 NNaO2 + [M + Na] + : Calcd for 316.1308, found 316.1299.

[0059] Example 11

[0060] Synthesis of 1-(4-Phenoxyphenyl)-3-(1H-indol-3-yl)butanone with the following structural formula

[0061]

[0062] In this example, equimolar 4-phenoxycyclopropyl phenyl ketone was used to replace the phenylcyclopropyl ketone used in Example 1, and other steps were the same as in Example 1 to obtain 1-(4-phenoxyphenyl)-3-(1H-indol-3-yl)butanone with a yield of 75%. The spectral data of the product are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.98–7.94 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.45–7.39 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.14 (t, J = 6.8 Hz, 1H), 7.10–7.07 (m, 2H), 7.02 - 6.98 (m, 3H), 3.90–3.81 (m, 1H), 3.46 (dd, J = 16.0, 4.8 Hz, 1H), 3.22 (dd, J = 16.4, 8.8 Hz, 1H), 1.48 (d, J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, Chloroform-d) δ 198.6, 161.9, 155.6, 136.6, 132.0, 130.5, 130.2, 126.4, 124.7, 122.1, 121.5, 120.4, 120.2, 119.3, 117.4, 111.4, 46.3, 27.4, 21.1; HRMS (ESI) m / z C 24 H 21 NNaO2 + [M + Na] +: Theoretical value: 378.1465, measured value: 378.1461.

[0063] Example 12

[0064] Synthesize 1-(4-benzyloxyphenyl)-3-(1H-indol-3-yl)butanone with the following structural formula

[0065]

[0066] In this example, equimolar 4-benzyloxycyclopropyl phenyl ketone was used to replace the phenylcyclopropyl ketone used in Example 1, and other steps were the same as those in Example 1. 1-(4-benzyloxyphenyl)-3-(1H-indol-3-yl)butanone was obtained, with a yield of 71%. The spectral data of the product are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.05(s,1H),7.96(d,J=8.8Hz,2H),7.71(d,J=7.6Hz,1H),7.46–7.40(m,4H),7.47-7.40(m,2H),7.40-7.35(m,1H),7.22(t,J=7.6Hz,1H),7.14(t,J=7.2Hz,1H),7.00(d,J=8.8Hz,3H),5.13(s,2H),3.89-3.80(m,1H),3.44(dd,J=16.0,4.8Hz,1H),3.21(dd,J=16.4,9.2Hz,1H),1.47(d,J=7.2Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ198.5,162.6,136.6,136.2,130.6,130.5,128.8,128.4,127.6,126.4,122.1,121.6,120.3,119.3,119.3,114.6,111.4,70.2,46.2,27.4,21.1;HRMS(ESI)m / z C 25 H 23 NNaO2 + [M+Na] + : Theoretical value: 392.1621, measured value: 392.1618.

[0067] Example 13

[0068] Synthesize 1-(4-fluoro)-3-(1H-indol-3-yl)butanone with the following structural formula

[0069]

[0070] In this example, equimolar 4-fluorocyclopropyl phenyl ketone was used to replace the phenylcyclopropyl ketone used in Example 1, and the other steps were the same as those in Example 1 to obtain 1-(4-fluoro)-3-(1H-indol-3-yl) butanone, with a yield of 78%. The spectral data of the product are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.08(s,1H),8.00–7.95(m,2H),7.69(d,J=7.6Hz,1H),7.36(d,J=8.0Hz,1H),7.24–7.20(m,1H),7.17–7.07(m,3H),7.01(d,J=2.4Hz,1H),3.89–3.80(m,1H),3.46(dd,J=16.4,5.2Hz,1H),3.23(dd,J=16.4,5.2Hz,1H),1.48(d,J=7.2Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ198.4,167.0,164.5,136.6,133.8,133.7,130.9,130.8,126.3,122.1,121.3,120.4,119.4,119.2,115.8,115.6,111.5,46.5,27.3,21.1; 19 F NMR(376MHz,Chloroform-d)δ-105.30(p,J=7.5Hz).

[0071] Example 14

[0072] Synthesize 1-(2-naphthyl)-3-(1H-indol-3-yl) butanone with the following structural formula

[0073]

[0074] In this example, equimolar 2-naphthylcyclopropyl ketone was used to replace the phenylcyclopropyl ketone used in Example 1, and the other steps were the same as those in Example 1 to obtain 1-(2-naphthyl)-3-(1H-indol-3-yl) butanone, with a yield of 76%. The spectral data of the product are as follows: 11H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.86–7.82 (m, 3H), 7.72 (d, J = 8.0 Hz, 1H), 7.58–7.48 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.00 (s, 1H), 3.92 - 3.84 (m, 1H), 3.60 (dd, J = 16.0, 4.8 Hz, 1H), 3.35 (dd, J = 16.0, 8.8 Hz, 1H), 1.49 (d, J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, Chloroform-d) δ 200.0, 136.6, 135.6, 134.6, 132.6, 130.0 129.6, 128.5, 127.8, 126.8, 126.4, 124.0, 122.1, 121.5, 120.4, 119.4, 119.3, 111.5, 46.6, 27.5, 21.1.

[0075] Example 15

[0076] Synthesize 1-(thiophen-2-yl)-3-(1H-indol-3-yl)butanone with the following structural formula

[0077]

[0078] In this example, equimolar 2-thiophene cyclopropyl ketone was used to replace the phenyl cyclopropyl ketone used in Example 1, and the other steps were the same as those in Example 1 to obtain 1-(thiophen-2-yl)-3-(1H-indol-3-yl)butanone, with a yield of 74%. The spectral data of the product are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 4.4 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 3.90–3.80 (m, 1H), 3.42 (dd, J = 15.6, 5.2 Hz, 1H), 3.18 (dd, J = 16.0, 9.2 Hz, 1H), 1.48 (d, J = 7.2 Hz, 3H); 1313C NMR (101 MHz, Chloroform-d) δ 192.9, 144.9, 136.6, 133.8, 132.1, 128.2, 126.3, 122.1, 121.2, 120.4, 119.3, 119.3, 111.5, 47.3, 27.8, 21.0。

[0079] In the above Example 1, without adding any one of the precatalyst nickel bromide ethylene glycol dimethyl ether, the ligand 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and the reducing agent zinc powder, and the other steps are the same as those in Example 1, and no target product 3-(1H-indol-3-yl)-1-phenylbutanone is produced, indicating that the above conditions are necessary conditions for the ring-opening 1,2-functionalization of indole compounds and arylcyclopropyl ketones.

Claims

1. A method for synthesizing β - indolones by nickel - catalyzed ring - opening 1,2 - functionalization of aryl cyclopropyl ketones, which is characterized in that: Under an inert gas protection, an arylcyclopropyl ketone represented by Formula I, an indole compound represented by Formula II, an ether halide complex of nickel(II), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and zinc powder are added to an organic solvent, and the reaction is carried out at 70-100 °C. After the reaction is completed, separation and purification are carried out to obtain a β-indolone compound represented by Formula III; In the formula, Ar represents any one of aryl, heteroaryl, substituted aryl, and substituted heteroaryl, and R represents a substituent at any position on the indole ring, and the substituent is selected from any one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, benzyloxy, C2-C4 ester group, benzyl, and phenyl; The ether halide complex of nickel(II) is any one of nickel(II) dimethoxyethane bromide, nickel(II) dimethoxyethane chloride, and nickel(II) dibromide bis(dimethoxyethane) complex.

2. The method for synthesizing β-indolones by nickel-catalyzed ring-opening 1,2-functionalization of aryl cyclopropyl ketones according to claim 1, characterized in that: The Ar represents any one of phenyl, thienyl, and naphthyl, or phenyl substituted by any one of C1-C4 alkyl, C1-C4 alkoxy, halogen, phenyl, phenoxy, and benzyloxy.

3. The method for synthesizing β - indolinone compounds by nickel - catalyzed ring - opening 1,2 - functionalization of aryl cyclopropyl ketones according to claim 1 or 2, characterized in that: The addition amount of the ether halide complex of nickel(II) is 10%-20% of the molar amount of the arylcyclopropyl ketone.

4. The method for synthesizing β-indolones by nickel-catalyzed ring-opening 1,2-functionalization of aryl cyclopropyl ketones according to claim 1 or 2, characterized in that: The addition amount of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene is 5%-10% of the molar amount of the arylcyclopropyl ketone.

5. The method for synthesizing β-indolones by nickel-catalyzed ring-opening 1,2-functionalization of aryl cyclopropyl ketones according to claim 1 or 2, characterized in that: The addition amount of the zinc powder is 2-3 times the molar amount of the arylcyclopropyl ketone.

6. The method for synthesizing β-indolones by nickel-catalyzed ring-opening 1,2-functionalization of aryl cyclopropyl ketones according to claim 1 or 2, characterized in that: The addition amount of the indole compound is 1-2 times the molar amount of the arylcyclopropyl ketone.

7. The method for synthesizing β-indolones by nickel-catalyzed ring-opening 1,2-functionalization of aryl cyclopropyl ketones according to claim 1 or 2, characterized in that: The organic solvent is selected from any one of tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, and 1,4-dioxane.

8. The method for synthesizing β - indolones by nickel - catalyzed ring - opening 1,2 - functionalization of aryl cyclopropyl ketones according to claim 1 or 2, characterized in that: The reaction is carried out at 70-100 °C for 6-12 hours.

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