A method for preparing an indole ketone compound containing a quaternary carbon center

Abstract

The present invention discloses a method for preparing an indolinone compound containing a quaternary carbon center. The target compound is obtained by subjecting N-arylacrylamide to an intramolecular tandem oxidative cyclization reaction initiated by the addition of an intramolecular alkyl radical with a tertiary alkane in the presence of a copper catalyst. This novel synthetic route for indolinone compounds containing a quaternary carbon center offers advantages such as high efficiency, relatively mild reaction conditions, a wide range of substrate applicability, and high atom and step economies, and has potential applications in pharmaceutical synthesis.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for preparing an indole ketone compound containing a quaternary carbon center. Background Art

[0002] Indole ketoconazole skeletons containing quaternary carbon centers are widely found in the structures of natural products and pharmaceutical molecules, such as the natural products horsfiline, convolutamydine A, and spirotryprostain A. These skeletons possess important physiological activities, including anti-tumor, anti-tuberculosis, and anti-cardiovascular activities. Many drug molecules, such as the laxative diacetaminophen, the antidepressant amine, the anti-cancer drug sunitinib, the non-steroidal anti-inflammatory drug tenidap, the Parkinson's disease drug ropinirole hydrochloride, the atypical antipsychotic ziprasidone, and the autophosphorylation inhibitor semasanib, also contain this core structural fragment. Consequently, methods for constructing these skeletons have attracted considerable attention from synthetic and medicinal chemists.

[0003]

[0004] Indole skeletons containing quaternary carbon centers are generally prepared by free radical-initiated tandem cyclization reactions of N-arylacrylamides. Currently, various carbon radical precursors have been developed, such as halogenated alkanes, dialkyl peroxides, carboxylic acids, aldehydes, α-diketones and other compounds. Among them, most existing synthetic strategies for introducing alkyl groups on the 3-side chain of indole require activated alkyl radical precursors, such as halogenated alkanes (Org. Lett., 2021, 23, 4662-4666) or peroxides (Chem. Commun., 2014, 50, 3865-3867), expensive transition metal catalysts (Angew. Chem. Int. Ed., 2011, 50, 12578-12581), and a large excess of alkylating agents (Org. Lett., 2014, 16, 382-385). In summary, the above methods have disadvantages such as expensive reagents, more by-products, substrate limitations, and harsh reaction conditions.

[0005] Given the application value of this type of indole alkaloid skeleton in organic synthesis (Eur. J. Org. Chem., 2003, 2209-2219), natural products (Angew. Chem. Int. Ed., 2007, 46, 8748-8758), and medicinal chemistry (Science, 2010, 329, 1175-1180), the divergent and structurally diverse preparation of a molecular library of indole derivatives containing quaternary carbon centers will provide inspiration and a material basis for the creation of new drugs and the discovery of lead compounds. In addition, the introduction of a full-carbon quaternary carbon center into the molecule will enhance its three-dimensional conformational restriction, which will have a significant impact on the biological and pharmacological activities of the compound (J. Med. Chem., 2020, 63, 13291-13315). Therefore, it is of great significance in the field of organic synthesis to develop a method for preparing indole ketone compounds containing quaternary carbon centers that is efficient, has high atomic utilization and economy, uses inexpensive metal catalysts, and has a wide range of substrate applicability. Summary of the Invention

[0006] The purpose of this section is to summarize some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of this application to avoid obscuring the purpose of this section, the abstract and the title of the invention, and such simplifications or omissions should not be used to limit the scope of the present invention.

[0007] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0008] One of the objectives of the present invention is to provide a method for preparing an indole ketone compound containing a quaternary carbon center. The new synthetic route has the advantages of high efficiency, mild reaction conditions, a wide range of substrate applicability, and high atom and step economy.

[0009] In order to solve the above technical problems, the present invention provides the following technical solutions: a method for preparing an indole ketone compound containing a quaternary carbon center, comprising:

[0010] An N-aryl acrylamide represented by formula I and a tertiary alkane represented by formula II undergo an intramolecular tandem oxidative cyclization reaction initiated by intramolecular alkyl radical addition in the presence of a copper catalyst to obtain a compound represented by formula III;

[0011]

[0012]

[0013] Where R 1 is one of hydrogen, methyl, methoxy, halogen, cyano, trifluoromethyl, and phenyl;

[0014] R2 It is one of methyl, phenyl and benzyl;

[0015] R 3 is a substituted or unsubstituted C1-C10 alkyl or benzyl group;

[0016] EWG 1 and EWG 2 is an electron-withdrawing substituent, including one of ester, acyl, cyano, and sulfonyl groups, wherein EWG 1 and EWG 2 Same or different.

[0017] As a preferred embodiment of the method for preparing an indolinone compound containing a quaternary carbon center of the present invention, the copper catalyst is one of copper acetate, cuprous iodide, cuprous bromide, cuprous cyanide, cuprous chloride, cuprous oxide, cupric oxide, copper acetate, copper trifluoromethanesulfonate, copper acetylacetonate and cuprous thiophene-2-carboxylate.

[0018] As a preferred embodiment of the method for preparing the indole ketone compound containing a quaternary carbon center of the present invention, the copper catalyst is cuprous iodide.

[0019] As a preferred embodiment of the method for preparing the indole one compound containing a quaternary carbon center of the present invention, the molar ratio of the N-aryl acrylamide to the copper catalyst is 5 to 10:1.

[0020] As a preferred embodiment of the method for preparing the indole ketone compound containing a quaternary carbon center of the present invention, the oxidative cyclization reaction has a reaction temperature of 70 to 120° C. and a reaction time of 12 hours.

[0021] As a preferred embodiment of the method for preparing the indole ketone compound containing a quaternary carbon center of the present invention, the oxidative cyclization reaction is carried out at a temperature of 90° C. and a reaction time of 12 h.

[0022] As a preferred embodiment of the method for preparing an indole one compound containing a quaternary carbon center of the present invention, the oxidative cyclization reaction is carried out in a solvent, the solvent comprising one of dimethyl sulfoxide, N,N-dimethylformamide, chlorobenzene, N-methylpyrrolidone and 1,4-dioxane; the molar volume ratio of the N-arylacrylamide to the solvent is 0.2 mmol:1 to 3 mL; the preferred solvent is dimethyl sulfoxide, and the preferred molar volume ratio is 0.2 mmol:2 mL.

[0023] As a preferred embodiment of the method for preparing an indole one compound containing a quaternary carbon center of the present invention, the method further comprises adding a reaction accelerator to the reaction system, wherein the reaction accelerator comprises one of di-tert-butyl peroxide, tert-butyl hydroperoxide, lauroyl peroxide, silver carbonate and p-benzoquinone; preferably, the reaction accelerator is di-tert-butyl peroxide.

[0024] As a preferred embodiment of the method for preparing the indole one compound containing a quaternary carbon center of the present invention, the molar ratio of the N-aryl acrylamide to the reaction accelerator is 1:2 to 1:4, preferably 1:3.

[0025] As a preferred embodiment of the method for preparing the indole one compound containing a quaternary carbon center of the present invention, the molar ratio of the N-aryl acrylamide to the tertiary alkane is 1:1 to 1:2.

[0026] In summary, the chemical reaction formula of the present invention is:

[0027]

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The reaction conditions of the present invention are mild. During the preparation, the copper salt catalyst and starting materials used, including N-arylacrylamide and tertiary alkane, are all relatively cheap, easily available, and highly stable. Compared with the traditional polysubstituted indolinone synthesis route, the method is greener and more efficient, has simple steps, and has a wider range of substrate applicability. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. Those skilled in the art can also derive other drawings based on these drawings without inventive effort. Among them:

[0031] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the target product of Example 1 of the present invention;

[0032] Figure 2 This is the carbon NMR spectrum of the target product of Example 1 of the present invention;

[0033] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the target product of Example 5 of the present invention;

[0034] Figure 4 This is the carbon NMR spectrum of the target product of Example 5 of the present invention. DETAILED DESCRIPTION

[0035] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0036] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0037] Secondly, the term "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in various places throughout this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive of other embodiments.

[0038] N-aryl acrylamide was prepared according to the method described in the literature (Chem. Commun., 2020, 56, 7969-7972); tertiary alkanes were prepared according to the method described in the literature (Angew. Chem. Int. Ed. 2021, 60, 9706-9711). Unless otherwise specified, other raw materials used in the examples, including copper catalysts, reaction accelerators, and solvents, were purchased commercially.

[0039] Example 1

[0040] To a 10 mL Schlenk tube, N-methyl-N-phenylmethylacrylamide (0.2 mmol, 35.0 mg) and cuprous iodide (0.04 mmol, 7.6 mg) were added. The reaction tube was purged with nitrogen three times. Under a nitrogen atmosphere, diethyl methylmalonate (0.3 mmol, 52.3 mg), di-tert-butyl peroxide (0.6 mmol, 87.7 mg), and dimethyl sulfoxide (2 mL) were added sequentially via syringe. The mixture was heated to 90°C and stirred for 12 h. After completion of the reaction, the reaction solution was cooled to room temperature, quenched with saturated NH4Cl solution, and extracted three times with EtOAc. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was isolated by silica gel column chromatography (gradient elution with petroleum ether:ethyl acetate = 10:1 → 6:1) to obtain a white solid (65.3 mg). The yield was 94%.

[0041] The structural formula of the compound is:

[0042]

[0043] The H NMR spectrum of the target product is shown in Figure 1 As shown, the carbon NMR spectrum is as follows Figure 2 As shown; the characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.28-7.24(m,1H),7.10(d,J=7.3Hz,1H),7.00(t,J=7.5Hz,1H),6.85(d,J=7.8Hz,1H),4.15-4.09(m,2H),3 .78(q,J=7.1Hz,2H),3.22(s,3H),2.76(d,J=4.0Hz,2H),1.36(s,3H),1.20(t,J=7.1Hz,3H),1.09(t,J=7.1Hz,3H),1.02(s,3H). 13 C NMR (101MHz, CDCl3) δ180.0,172.1,171.3,143.3,131.8,128.2,124.0,122.0,108.3,61. 5,61.1,52.9,46.3,41.1,28.0,26.4,18.9,14.0,13.7.HRMS(ESI):m / zcalcd.for:[M+H] + :C 19 H 26 NO5 348.1805; found:348.1810.

[0044] According to the characterization data, the obtained reaction product is diethyl 2-((1,3-dimethyl-2-oxo-3-indolyl)methyl-2-methylmalonate.

[0045] Example 2

[0046] To a 10 mL Schlenk tube, N-methyl-N-(p-bromo)methylacrylamide (0.2 mmol, 50.8 mg) and cuprous iodide (0.04 mmol, 7.6 mg) were added. The reaction tube was purged with nitrogen three times. Under a nitrogen atmosphere, diethyl methylmalonate (0.3 mmol, 52.3 mg), di-tert-butyl peroxide (0.6 mmol, 87.7 mg), and dimethyl sulfoxide (2 mL) were added sequentially via syringe. The mixture was heated to 90°C and stirred for 12 h. After completion of the reaction, the reaction solution was cooled to room temperature, quenched with saturated NH4Cl solution, and extracted three times with EtOAc. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was separated by silica gel column chromatography (gradient elution with petroleum ether:ethyl acetate = 10:1 → 6:1) to obtain a colorless oily liquid (76.7 mg). The yield was 90%.

[0047] The structural formula of the compound is:

[0048]

[0049] The characterization data of the target product are as follows: 1 H NMR (400MHz, CDCl3) δ7.36(dd,J=8.0Hz,1H),7.16(d,J=1.9Hz,1H),6.71(d,J=8.2Hz,1H),4.16-4.02(m,2H),3.9 2-3.77(m,2H),3.17(s,3H),2.70(q,J=7.9Hz,2H),1.32(s,3H),1.15(ddd,J=16.0,7.7,6.7Hz,6H),1.01(s,3H). 13 C NMR (101MHz, CDCl3) δ179.4,171.9,170.9,142.3,133.8,131.1,127.2,114.8,1 09.8,61.6,61.4,52.7,46.5,41.0,27.8,26.5,18.9,14.0,13.8.HRMS(ESI):m / z calcd.for:[M+H] + :C 19 H 25 BrNO5 426.0911; found:426.0915.

[0050] According to the characterization data, the obtained reaction product is diethyl 2-((5-bromo-1,3-dimethyl-2-oxo-3-indolyl)methyl)-2-methylmalonate.

[0051] Example 3

[0052] N-benzyl-N-phenylmethylacrylamide (0.2 mmol, 50.3 mg) and cuprous iodide (0.04 mmol, 7.6 mg) were added to a 10 mL Schlenk tube. The reaction tube was purged with nitrogen three times. Under a nitrogen atmosphere, diethyl methylmalonate (0.3 mmol, 52.3 mg), di-tert-butyl peroxide (0.6 mmol, 87.7 mg), and dimethyl sulfoxide (2 mL) were added sequentially to the reaction tube using a syringe. The mixture was heated to 90°C and stirred for 12 h. After completion of the reaction, the reaction solution was cooled to room temperature, quenched with saturated NH4Cl solution, and extracted three times with EtOAc. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was isolated by silica gel column chromatography (gradient elution with petroleum ether:ethyl acetate = 10:1 → 6:1) to obtain a white solid (70.0 mg). The yield was 83%.

[0053] The structural formula of the compound is:

[0054]

[0055] The characterization data of the target product are as follows: 1 H NMR (400MHz, CDCl3) δ7.32-7.28(m,4H),7.25-7.22(m,1H),7.16-7.09(m,2H),6.9 6(td,J=7.5,1.0Hz,1H),6.75(d,J=7.6Hz,1H),5.07(d,J=15.6Hz,1H),4.75(d,J= 15.6Hz, 1H), 4.13 (dd, J=7.1, 1.7Hz, 2H), 3.78 (dd, J=7.1, 2.0Hz, 2H), 2.80 (d, J=2 .4Hz,2H),1.41(s,3H),1.20(t,J=7.1Hz,3H),1.08(t,J=7.1Hz,3H),1.04(s,3H). 13 C NMR (101MHz, CDCl3) δ180.0,172.1,171.3,142.4,135.9,131.9,128.8×2,128.0,127.6(d,J=9.4Hz) ×2,124.0,122.0,109.3,61.5,61.1,53.0,46.3,44.0,40.8,28.6,19.1,14.0,13.7.HRMS(ESI):m / z calcd.for:[M+H] + :C 25 H 30 NO5 424.2118; found:424.2113.

[0056] According to the characterization data, the obtained reaction product is diethyl 2-((1-benzyl-3-methyl-2-oxo-3-indolyl)methyl)-2-methylmalonate.

[0057] Example 4

[0058] To a 10 mL Schlenk tube, N-methyl-N-phenylmethylacrylamide (0.2 mmol, 35.0 mg) and cuprous iodide (0.04 mmol, 7.6 mg) were added. The reaction tube was purged with nitrogen three times. Under a nitrogen atmosphere, diethyl 2-(cyclopropylmethyl)malonate (0.3 mmol, 64.3 mg), di-tert-butyl peroxide (0.6 mmol, 87.7 mg), and dimethyl sulfoxide (2 mL) were added sequentially via syringe. The mixture was heated to 90°C and stirred for 12 h. After completion of the reaction, the reaction solution was cooled to room temperature, quenched with saturated NH4Cl solution, and extracted three times with EtOAc. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was separated by silica gel column chromatography (gradient elution with petroleum ether:ethyl acetate = 10:1 → 6:1) to obtain a yellow oily liquid (71.9 mg); the yield was 93%.

[0059] The structural formula of the compound is:

[0060]

[0061] The characterization data of the target product are as follows: 1 H NMR (400MHz, CDCl3) δ7.23 (td, J=7.7, 1.2Hz, 1H), 7.10-7.06 (dd, J=7.4, 0.7Hz, 1H), 6.97 (td, J=7. 5,0.9Hz,1H),6.81(d,J=7.8Hz,1H),4.16-3.99(m,2H),3.75-3.64(m,2H),3.19(s,3H),2.88(d,J=1 5.0Hz,1H),2.68(d,J=15.0Hz,1H),1.47-1.42(m,1H),1.35(s,3H),1.29(dd,J=14.5,7.4Hz,1H),1 .19-1.16(m,3H),1.07(t,J=7.1Hz,3H),0.86-0.72(m,1H),0.36-0.26(m,2H),-0.06--0.23(m,2H). 13 CNMR (101MHz, CDCl3) δ179.6,171.5,170.9,143.4,131.8,128.1,123.9,121.8,108.2,61.2,60. 8,56.8,46.1,38.9,36.5,28.1,26.3,13.9,13.7,6.2,4.3,4.3.HRMS(ESI):m / zcalcd.for:[M+H] + :C 22 H 30NO5 388.2118; found:388.2120.

[0062] According to the characterization data, the obtained reaction product is diethyl 2-(cyclopropylmethyl)-2-((1,3-dimethyl-2-oxo-3-indolyl)methyl)malonate.

[0063] Example 5

[0064] To a 10 mL Schlenk tube, add N-methyl-N-phenylmethylacrylamide (0.2 mmol, 35.0 mg) and cuprous iodide (0.04 mmol, 7.6 mg). The reaction tube was purged with nitrogen three times. Under a nitrogen atmosphere, ethyl 2-(phenylsulfonyl)propionate (0.3 mmol, 72.7 mg), di-tert-butyl peroxide (0.6 mmol, 87.7 mg), and dimethyl sulfoxide (2 mL) were added sequentially to the reaction tube using a syringe. The mixture was heated to 90°C and stirred for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with saturated NH4Cl solution, and extracted three times with EtOAc. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and separated by silica gel column chromatography (gradient elution with petroleum ether:ethyl acetate = 10:1→6:1) to obtain a white solid (78.5 mg); the yield was 95% (dr = 1.2:1).

[0065] The structural formula of the compound is:

[0066]

[0067] The H NMR spectrum of the target product is shown in Figure 3 As shown, the carbon NMR spectrum is as follows Figure 4 As shown; the characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.81 (d, J = 1.1 Hz, 2H), 7.79 (t, J = 1.5 Hz, 2H), 7.63 (dd, J = 7.4, 5. 2Hz,2H),7.55-7.47(m,4H),7.23-7.17(m,3H),7.05-6.91(m,3H),6.79(dd,J=7.7,4.4 Hz,2H),4.12-4.02(m,2H),3.78-3.70(m,1H),3.64-3.58(m,1H),3.16(s,3H),3.09(s ,2H),2.89-2.55(m,3H),1.31(d,J=12.9Hz,5H),1.21-1.17(m,6H),0.95-0.89(m,5H). 13CNMR (101MHz, CDCl3) δ179.6,177.8,168.0,167.6,143.1,142.7,135.3,134.3,134 .2,133.4,130.9,130.2,128.7(d,J=6.9Hz)×2,128.5(d,J=2.4Hz)×2,125.2,122.9 ,122.8,122.1,108.5,108.4,72.9,72.2,62.6,62.2,46.5,46.4,39.2,39.0,27.6( d,J=2.8Hz)×2,26.5,26.1,15.9,14.3,13.7,13.5.HRMS(ESI):m / zcalcd.for:[M+H] + :C 22 H 26 NO5S 416.1526; found:416.1523.

[0068] According to the characterization data, the obtained reaction product is ethyl 3-(1,3-dimethyl-2-oxo-3-indole)-2-methyl-2-(phenylsulfonyl)propionate.

[0069] Example 6

[0070] Example 6 is basically the same as Example 1, except that the catalyst and reaction temperature are different, as shown in Table 1 below.

[0071] Table 1

[0072] catalyst Temperature (℃) Yield (%) Copper acetate 120 54 Copper trifluoromethanesulfonate 120 35 Cuprous bromide 120 73 Cuprous cyanide 120 75 Cuprous chloride 120 <5 Cuprous iodide 120 90 Cuprous oxide 120 84 Copper oxide 120 <5 Copper acetylacetonate 120 <5 Cuprous 2-thiophenecarboxylate 120 <5 Cuprous iodide 110 91 Cuprous iodide 90 94 Cuprous iodide 70 85 Ferrous chloride 90 0 Manganese acetate dihydrate 90 0

[0073] The data in Table 1 show that under the same temperature conditions, the reaction efficiency of various metal salts varies, with cuprous iodide providing the best catalytic effect. Using cuprous iodide as the catalyst and lowering the reaction temperature to 90°C slightly increases the yield to 94%. Further lowering the temperature to 70°C significantly decreases the yield.

[0074] Example 7

[0075] Example 7 is substantially the same as Example 1, except that the amount of cuprous iodide used is different, as shown in Table 2 below.

[0076] Table 2

[0077] Amount of cuprous iodide (mol%) Yield (%) 15 92 10 82 0 0

[0078] It can be seen from the data in Table 2 that reducing the amount of copper catalyst still results in a higher yield, but no product is obtained without adding the catalyst.

[0079] Example 8

[0080] Example 8 is basically the same as Example 1, except that the N-aryl acrylamide and the tertiary alkane are different, as shown in Table 3 below.

[0081] Table 3

[0082]

[0083]

[0084]

[0085] Example 9

[0086] Example 9 is basically the same as Example 1, except that the type or amount of solvent added is different, as shown in Table 4 below.

[0087] Table 4

[0088] solvent Amount of solvent added (mL) Yield (%) dimethyl sulfoxide 1 82 dimethyl sulfoxide 2 94 dimethyl sulfoxide 3 78 N,N-Dimethylformamide 2 68 chlorobenzene 2 20 N-Methylpyrrolidone 2 <5 1,4-Dioxane 2 <5

[0089] It can be seen from the data in Table 4 that under the same reaction conditions, the type of solvent has a significant effect on the reaction efficiency. Among them, the yield of the target product in N-methylpyrrolidone and 1,4-dioxane is extremely low, and the yield in dimethyl sulfoxide is higher. Among them, the yield is the highest when the amount of dimethyl sulfoxide added is 2 mL. Continuing to increase the amount of dimethyl sulfoxide added will lead to a decrease in the yield.

[0090] Example 10

[0091] Example 10 is basically the same as Example 1, except that the type or addition amount of the reaction accelerator is different, as shown in Table 5 below.

[0092] Table 5

[0093] Accelerator Amount of accelerator added (mmol) Yield (%) Di-tert-butyl peroxide 0.4 77 Di-tert-butyl peroxide 0.6 94 Di-tert-butyl peroxide 0.8 82 tert-Butyl hydroperoxide 0.6 <5 Lauroyl peroxide 0.6 <5 Silver carbonate 0.6 73 p-Benzoquinone 0.6 <5

[0094] It can be seen from the data in Table 5 that under the same reaction conditions, the type of reaction promoter has a significant effect on the reaction efficiency. Among them, the yield of the target product under tert-butyl hydroperoxide, lauroyl peroxide, and p-benzoquinone is extremely low, and the yield under di-tert-butyl peroxide is higher. Among them, the yield is the highest when the addition amount of di-tert-butyl peroxide is 0.6 mmol. Continuing to increase the addition amount of di-tert-butyl peroxide will lead to a decrease in the yield.

[0095] The present invention provides a method for preparing an indole one compound containing a quaternary carbon center. The indole one compound is obtained by copper-catalyzed intramolecular cyclization reaction initiated by intramolecular alkyl radical addition of N-aryl acrylamide and tertiary alkane. The present invention uses tertiary alkane as an alkyl radical precursor, avoids the use of activated alkanes such as halogenated hydrocarbons, carboxylic acids and derivatives thereof, diazonium salts, etc., directly oxidizes the sp3 carbon-hydrogen bond of the tertiary alkane to form a tertiary alkyl radical. The raw materials are cheap and readily available. The synthetic method has the advantages of being green and efficient, simple steps, a wider range of substrate applications, and less waste generation. The present invention provides a method for synthesizing an indole one compound containing multiple quaternary carbon centers, and the quaternary carbon outside the ring can be further derivatized. The structural diversity and complexity of the products provide a reasonable approach for the synthesis of potential drugs.

[0096] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for preparing an indole ketone compound containing a quaternary carbon center, characterized in that: include, An N-aryl acrylamide represented by formula I and a tertiary alkane represented by formula II undergo an intramolecular tandem oxidative cyclization reaction initiated by intramolecular alkyl radical addition in the presence of a copper catalyst to obtain a compound represented by formula III; (Formula I); (Formula II); (Formula III); Where R 1 is one of hydrogen, methyl, methoxy, halogen, cyano, trifluoromethyl, and phenyl; R 2 It is one of methyl, phenyl and benzyl; R 3 is a substituted or unsubstituted C1~C10 alkyl or benzyl group; EWG 1 and EWG 2 is an electron-withdrawing substituent selected from one of ester, acyl, cyano, and sulfonyl groups, wherein EWG 1 and EWG 2 Same or different; Wherein, the copper catalyst is one of copper acetate, cuprous bromide, cuprous cyanide, cuprous iodide, and cuprous oxide; The oxidative cyclization reaction is carried out in a solvent, and the solvent is one of dimethyl sulfoxide and N,N-dimethylformamide; The method further comprises adding a reaction accelerator into the reaction system, wherein the reaction accelerator is one of di-tert-butyl peroxide and silver carbonate.

2. The method for preparing the indole ketone compound containing a quaternary carbon center according to claim 1, wherein: The copper catalyst is cuprous iodide.

3. The method for preparing an indole ketone compound containing a quaternary carbon center according to claim 1 or 2, wherein: The molar ratio of the N-aryl acrylamide to the copper catalyst is 5 to 10:

1.

4. The method for preparing an indole ketone compound containing a quaternary carbon center according to claim 3, wherein: The oxidative cyclization reaction has a reaction temperature of 70-120° C. and a reaction time of 12 h.

5. The method for preparing an indole ketone compound containing a quaternary carbon center according to claim 4, wherein: The oxidative cyclization reaction has a reaction temperature of 90° C. and a reaction time of 12 h.

6. The method for preparing an indole one compound containing a quaternary carbon center according to any one of claims 1, 2, 4, and 5, wherein: The molar volume ratio of the N-arylacrylamide to the solvent is 0.2 mmol:1-3 mL.

7. The method for preparing an indole ketone compound containing a quaternary carbon center according to claim 6, wherein: The molar ratio of the N-arylacrylamide to the reaction accelerator is 1:2 to 1:

4.

8. The method for preparing an indole one compound containing a quaternary carbon center according to any one of claims 1, 2, 4, 5, and 7, wherein: The molar ratio of the N-arylacrylamide to the tertiary alkane is 1:1 to 1:2.

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