A method for synthesizing β-indole ketones by nickel-catalyzed ring-opening 1,2-functionalization of arylcyclopropyl ketones.

Abstract

This invention discloses a nickel-catalyzed method for the 1,2-functionalization of arylcyclopropyl ketones to synthesize β-indole ketones. The method uses arylcyclopropyl ketones and indole compounds as reaction substrates, nickel(II) ether halide complexes as pre-catalysts, 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene as ligands, and zinc powder as a reducing agent. This method efficiently and selectively achieves the 1,2-functionalization of mono-activated arylcyclopropyl ketones to prepare β-indole ketones. This invention has the advantages of inexpensive and readily available reaction systems, a wide substrate range, mild reaction conditions, and high yield of the target product, showing broad application prospects.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of single-activated cyclopropyl ring-opening 1,2-functionalization methodology, and specifically relates to a method for realizing 1,2-functionalization of an indole compound and an aryl cyclopropyl ketone to obtain a beta-indole ketone compound by using 4,5-bis(diphenylphosphino)-9,9-dimethyloxyanthracene (a ligand) to regulate in-situ generation of a catalytically active species of an ether halide complex of nickel (II) in combination with zinc powder as a reducing agent. BACKGROUND

[0002] The basic skeleton of an organic compound is composed of carbon-carbon bonds, and the breaking process thereof is widely present in industrial development and life processes. The activation reaction of carbon-carbon sigma bonds can exploit rich and economical raw materials in nature, but compared with the widely studied carbon-carbon bond formation methodology, the research on carbon-carbon bond breaking is still relatively lagging behind.

[0003] The cyclopropane structure is one of the most important skeletons in organic chemistry, which is widely present in drugs and agricultural chemicals. Due to its small ring tension, cyclopropane can be used as an effective substrate for studying carbon-carbon bond breaking. For the subsequent functionalization reaction after the ring-opening of aryl cyclopropyl ketone, the most studied reactions are the alkylation reaction with alkyl bromide, the hydrogen-arylation reaction with arylating reagents, and the reaction with nucleophilic reagents to construct carbon heteroatoms. These reactions can realize various types of 1,3-functionalization reactions after the ring-opening of aryl cyclopropyl ketone, but the functionalization site of the ring-opening is always at the 1,3-position, 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, the current reaction of cyclopropane and indole can be roughly divided into two categories according to the type of the generated product: (1) Lewis acid catalyzed coupling of the 3-position carbon of cyclopropane ring-opening with indole to form a new carbon-carbon bond to obtain a straight-chain target product; (2) Lewis acid catalyzed DA cyclopropane ring-opening and indole expansion reaction to obtain a target product with a tri-ring structure. There is no reported example of coupling of the 2-position carbon after cyclopropane ring-opening with indole to obtain a branched structure target product. Literature research shows that the preparation of beta-indole ketone substances is mainly from the Michael addition reaction of alpha, beta-unsaturated ketone and indole, which is catalyzed by Lewis acid and undergoes 1,4-addition to obtain the product. Due to the high activity of alpha, beta-unsaturated ketone raw materials, the currently used alpha, beta-unsaturated ketone is mainly chalcone substances, that is, a structure with phenyl groups at both ends. For conventional alpha, beta-unsaturated ketone substrates with a methyl group at the end, due to their high activity, purification is difficult, they are almost impossible to be commercially purchased and have high preparation requirements, and there are limited examples of related structures reported. SUMMARY

[0005] The application aims to provide a method for synthesizing beta-indolone compounds by nickel-catalyzed aryl cyclopropyl ketone ring-opening 1,2-functionalization. The method starts from the ring-opening 1,2-functionalization of a single-activated aryl cyclopropyl ketone, the catalytic system for breaking the carbon-carbon σ bond is cheap and easy to obtain, and the reaction condition is mild, safe, efficient and the like.

[0006] To achieve the above object, the application adopts the following scheme: under the protection of inert gas, aryl cyclopropyl ketone shown in formula I, indole compound shown in formula II, ether halide complex of nickel (II), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and zinc powder are added into an organic solvent, and then the mixture is reacted at 70-100 DEG C. After the reaction is completed, the beta-indolone compound shown in formula III is obtained after separation and purification.

[0007]

[0008] In the formula, Ar represents any one of aryl, heterocyclic aryl, substituted aryl, substituted heterocyclic aryl, and specifically any one of phenyl, thienyl, naphthyl, or any one of C1-C4 alkyl, C1-C4 alkoxy, halogen, phenyl, phenoxy, benzyloxy and the like substituted phenyl; 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 and the like.

[0009] In the above synthesis method, preferably, the ether halide complex of nickel (II) is any one of ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, and nickel (II) diethylene glycol dimethyl ether complex.

[0010] Further, 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 synthesis method, preferably, the addition amount of the 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene is 5%-10% of the molar amount of the aryl cyclopropyl ketone.

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

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

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

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

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

[0017] The present application uses ether halide complex of nickel(II) as pre-catalyst, 4,5-bis(diphenylphosphino)-9,9-dimethyloxyanthracene as ligand, and zinc powder as reducing agent to make 1,2-functionalization reaction of ring opening of aryl cyclopropyl ketone to obtain β-indole ketone compounds. The present application has the advantages of cheap and easy-to-obtain reaction system, wide substrate range, mild reaction conditions, high yield of target product, and wide application prospect. DETAILED DESCRIPTION

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

[0019] Example 1

[0020] Synthesis of 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 ethylene glycol dimethyl ether nickel bromide, 0.0086 g (0.015 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethyloxyanthracene, 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 Schlenk tube was sealed with a vacuum grease, the glass plug was removed from the glove box, and the Schlenk tube was stirred at 100℃ for 12 hours. After the reaction was completed, the reaction mixture was filtered through a silica gel pad, 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 product spectral data are as follows: 1H 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 C 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] Synthesis of 3-(6-methyl-lH-indol-3-yl)-l-phenylbutanone

[0025]

[0026] In this example, 6-methylindole was used instead of indole in Example 1, and other procedures were the same as in Example 1, to give 3-(6-methyl-lH-indol-3-yl)-l-phenylbutanone in 72% yield. The spectral data of the product are as follows: 1 H 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); 13C 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] 3-(5-Methyl-lH-indol-3-yl)-l-phenylbutan-l-one was synthesized according to the following structural formula

[0029]

[0030] In this example, 5-methylindole was used instead of indole in Example 1, and other procedures were the same as those in Example 1, to obtain 3-(5-methyl-lH-indol-3-yl)-l-phenylbutan-l-one with a yield of 77%. The spectral data of the product were as follows: 1 HNMR (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 C 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] 3-(6-Methoxy-lH-indol-3-yl)-l-phenylbutan-l-one was synthesized according to the following structural formula

[0033]

[0034] In this example, 6-methoxyindole was used instead of indole in Example 1, and other procedures were the same as Example 1 to obtain 3-(6-methoxy-lH-indol-3-yl)-l- phenylbutanone in a yield of 70%. The spectral data of the product were as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.98 - 7.95 (m, 3H), 7.58 - 7.54 (m, 2H), 7.45 (t, J = 7.6 Hz, 2H), 6.89 (d, J = 2.4 Hz, 1H), 6.84 - 6.80 (m, 2H), 3.83 (s, 3H), 3.81 - 3.76 (m, 1H), 3.47 (dd, J = 16.4, 5.2 Hz, 1H), 3.24 (dd, J = 16.4, 8.8 Hz, 1H), 1.45 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 200.0, 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, found 316.1300.

[0035] Example 5

[0036] 3-(5-benzyloxy-lH-indol-3-yl)-l-phenylbutanone was synthesized according to the following structural formula

[0037]

[0038] In this example, 6-methoxyindole was used instead of indole in Example 1, and other procedures were the same as Example 1 to obtain 3-(6-methoxy-lH-indol-3-yl)-l- phenylbutanone in a yield of 70%. The spectral data of the product were as follows: 1H 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 C 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] Synthesis of 3-(6-fluoro-lH-indol-3-yl)-l-phenylbutanone

[0041]

[0042] In this example, 6-fluoroindole was used instead of indole in Example 1, and other procedures were the same as in Example 1 to give 3-(6-fluoro-lH-indol-3-yl)-l-phenylbutanone in 77% yield. The spectral data of the product are as follows: 1 H 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); 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] + : Theoretical 304.1108, Found 304.1102.

[0043] Example 7

[0044] 3-(5-Carboxymethyl-lH-indol-3-yl)-l-phenylbutanone was synthesized according to the following structure

[0045]

[0046] In this example, 5-carboxymethylindole was used instead of indole in Example 1 in an equimolar amount, and other procedures were the same as in Example 1 to give 3-(5-carboxymethyl-lH-indol-3-yl)-l-phenylbutanone in a yield of 72%. The spectral data of the product were 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 CNMR (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] + : Calcd. 344.1257, Found 344.1255.

[0047] Example 8

[0048] 3-(2,5-Dimethyl-1H-indol-3-yl)-1-phenylbutan-1-one was synthesized according to the following structural formula

[0049]

[0050] In this example, 2,5-dimethylindole was used instead of indole in Example 1, and other procedures were the same as Example 1 to obtain 3-(2,5-dimethyl-1H-indol-3-yl)-1-phenylbutan-1-one with a yield of 71%. The spectral data of the product were as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.93 - 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 = 8.0 Hz, 1H), 6.93 (d, J = 6.4 Hz, 1H), 3.78-3.69 (m, 1H), 3.52 (dd, J = 16.4, 6.4 Hz, 1H), 3.40 (dd, J = 16.0, 7.6 Hz, 1H), 2.48 (s, 3H), 2.37 (s, 3H), 1.51 (d, J = 7.2 Hz, 3H); 13 CNMR (101 MHz, Chloroform-d) δ 200.3, 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] 3-(1H-Indol-3-yl)-1-(4-methoxyphenyl)butan-1-one was synthesized according to the following structural formula

[0053]

[0054] In this example, 4-methoxycyclopropyl phenone was used instead of phenylcyclopropyl ketone in Example 1, and other procedures were the same as Example 1 to obtain 3-(1H-indol-3-yl)-1-(4-methoxyphenyl)butan-1-one with a yield of 83%. The spectral data of the product were as follows: 1H 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 C 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] Synthesis of 3-(lH-indol-3-yl)-l-(2-methoxyphenyl)butanone

[0057]

[0058] In this example, equimolar 2-methoxyphenylcyclopropyl ketone was used to replace phenylcyclopropyl ketone in Example 1, and other steps were the same as those in Example 1 to give 3-(lH-indol-3-yl)-l-(2-methoxyphenyl)butanone with a yield of 86%. The spectral data of the product were as follows: 1 H 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); 13C 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] + : Theoretical value 316.1308, found 316.1299.

[0059] Example 11

[0060] 1 -(4-Phenoxyphenyl)-3-(1 H-indol-3-yl)butan-1 -one was synthesized according to the procedure described in Example 1, except that 4-phenoxyphenyl- butanone was used instead of phenylcyclopropyl ketone. The yield of the product was 75%. The spectral data of the product are as follows:

[0061]

[0062] In this example, 4-phenoxyphenylcyclopropyl ketone was used instead of phenylcyclopropyl ketone in Example 1, and other procedures were the same as those in Example 1 to give 1 -(4-phenoxyphenyl)-3-(1 H-indol-3-yl)butan-1 -one in 75% yield. The spectral data of the product are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.08 (s, 1 H), 7.98 - 7.94 (m, 2H), 7.71 (d, J = 8.0 Hz, 1 H), 7.45 - 7.39 (m, 2H), 7.36 (d, J = 8.0 Hz, 1 H), 7.25 - 7.20 (m, 2H), 7.14 (t, J = 6.8 Hz, 1 H), 7.10 - 7.07 (m, 2H), 7.02 - 6.98 (m, 3H), 3.90 - 3.81 (m, 1 H), 3.46 (dd, J = 16.0, 4.8 Hz, 1 H), 3.22 (dd, J = 16.4, 8.8 Hz, 1 H), 1.48 (d, J = 7.2 Hz, 3H); 13 C 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] +Calcd 392.1621, Found 392.1618.

[0063] Example 12

[0064] 1-(4-Fluoro)-3-(1H-indol-3-yl)butan-1-one was synthesized according to the following structural formula

[0065]

[0066] In this example, 4-benzyloxy cyclopropyl phenyl ketone was used instead of phenyl cyclopropyl ketone in Example 1, and other procedures were the same as Example 1 to give 1-(4-benzyloxyphenyl)-3-(1H-indol-3-yl)butan-1-one in 71% yield. The spectral data of the product were as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.46 - 7.40 (m, 4H), 7.47-7.40 (m, 2H), 7.40-7.35 (m, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.00 (d, J = 8.8 Hz, 3H), 5.13 (s, 2H), 3.89 - 3.80 (m, 1H), 3.44 (dd, J = 16.0, 4.8 Hz, 1H), 3.21 (dd, J = 16.4, 9.2 Hz, 1H), 1.47 (d, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 198.5, 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] + : Calcd 392.1621, Found 392.1618.

[0067] Example 13

[0068] 1-(4-Fluoro)-3-(1H-indol-3-yl)butan-1-one was synthesized according to the following structural formula

[0069]

[0070] In this example, equal molar of 4-fluorocyclopropyl phenyl ketone was used to replace the phenylcyclopropyl ketone used in Example 1, and other steps were the same as Example 1 to obtain 1-(4-fluoro)-3-(1H-indol-3-yl)butanone with a yield of 78%. The spectral data of the product were: 1 H NMR (400 MHz, Chloroform-d) δ 8.08 (s, 1H), 8.00 - 7.95 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.17 - 7.07 (m, 3H), 7.01 (d, J = 2.4 Hz, 1H), 3.89 - 3.80 (m, 1H), 3.46 (dd, J = 16.4, 5.2 Hz, 1H), 3.23 (dd, J = 16.4, 5.2 Hz, 1H), 1.48 (d, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 198.4, 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 (376 MHz, Chloroform-d) δ -105.30 (p, J = 7.5 Hz).

[0071] Example 14

[0072] 1-(2-naphthyl)-3-(1H-indol-3-yl)butanone was synthesized according to the following structural formula

[0073]

[0074] In this example, equal molar of 4-fluorocyclopropyl phenyl ketone was used to replace the phenylcyclopropyl ketone used in Example 1, and other steps were the same as Example 1 to obtain 1-(4-fluoro)-3-(1H-indol-3-yl)butanone with a yield of 78%. The spectral data of the product were: 1H 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 C 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] Synthesis of l-(thiophen-2-yl)-3-(lH-indol-3-yl)butanone

[0077]

[0078] In this example, equimolar 2-thiophene cyclopropyl ketone was used to replace the phenyl cyclopropyl ketone used in Example 1, and other steps were the same as Example 1, to obtain l-(thiophen-2-yl)-3-(lH-indol-3-yl)butanone with a yield of 74%. The spectral data of the product were as follows: 1 H 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); 13C 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, none of the pre-catalyst, ethylene glycol dimethyl ether nickel bromide, the ligand, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, the reducing agent, zinc powder, was added, and the other steps were the same as Example 1, and no target product, 3-(1H-indol-3-yl)-1-phenylbutanone, was produced, which indicates that the above conditions are necessary conditions for the ring-opening 1,2-functionalization of indole compounds and aryl cyclopropyl ketones.

Claims

1. A method for the synthesis of β-indolones by nickel-catalyzed aryl cyclopropyl ketone ring opening 1,2-functionalization, characterized in that: The arylcyclopropyl ketone of formula I, the indole compound of formula II, the ether halide complex of nickel (II), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and zinc powder are added into an organic solvent under inert gas protection, and then the reaction is carried out at 70-100 ℃, after the reaction is completed, the β-indole ketone compound of formula III is obtained after separation and purification. In the formula, Ar represents any one of phenyl, thienyl, naphthyl, or C1-C4 alkyl, C1-C4 alkoxy, halogen, phenyl, phenoxy, benzyloxy; R represents any substituent on the indole ring, and the substituent is selected from any one of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, benzyloxy, benzyl, phenyl; The ether halide complex of nickel (II) is any one of ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, and bromide nickel (II) diethylene glycol dimethyl ether complex.

2. The process for the synthesis of β-indolones by nickel catalyzed aryl cyclopropyl ketone ring opening 1,2-functionalization as claimed in claim 1, wherein: The amount of the ether halide complex of nickel (II) added is 10-20% of the molar amount of the arylcyclopropyl ketone.

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

4. The process for the synthesis of β-indolones by nickel catalyzed aryl cyclopropyl ketone ring opening 1,2-functionalization as claimed in claim 1, wherein: The amount of the zinc powder added is 2-3 times of the molar amount of the arylcyclopropyl ketone.

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

6. The method for synthesizing β-indole ketones by nickel-catalyzed ring-opening 1,2-functionalization of arylcyclopropyl ketones according to claim 1, characterized in that: The organic solvent is any one of tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, and 1,4-dioxane.

7. The method for synthesizing β-indole ketones by nickel-catalyzed ring-opening 1,2-functionalization of arylcyclopropyl ketones according to claim 1, characterized in that: The reaction is carried out at 70-100 ℃ for 6-12 hours. The arylcyclopropyl ketone of formula I, the indole compound of formula II, the ether halide complex of nickel (II), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and zinc powder are added into an organic solvent under inert gas protection, and then the reaction is carried out at 70-100 ℃, after the reaction is completed, the β-indole ketone compound of formula III is obtained after separation and purification.

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