Preparation method of 3-functionalized indole-2-ketone compound

Abstract

The invention discloses a preparation method of 3-functionalized indole-2-ketone compounds, which is characterized in that a series of 3-trichloromethylated indole-2-ketone compounds are prepared by cascade cyclization of carbon tetrachloride and N-aryl acrylamide under an optimized free radical initiation system (TBAH / K2S2O8) at the yield of 98%. Compared with a method in the prior art, toxic, harmful and expensive reagents are avoided, and the reaction cost is remarkably reduced. The method has the advantages of wide functional group universality, mild and simple reaction conditions, easy operation, and suitableness for industrial production.

Description

Technical Field

[0001] The present application belongs to the technical field of organic synthesis, and specifically relates to a method for preparing a 3-functionalized indole-2-one compound. Background Art

[0002] 3-Functionalized indole-2-ones are important synthetic intermediates in organic synthesis and are widely found in natural products and drug-related molecules. Therefore, the synthesis of 3-functionalized indole-2-ones has attracted extensive attention. Among all the methods developed for the synthesis of 3-functionalized indole-2-ones, free radical-induced cascade cyclization of N-arylacrylamides is one of the most effective methods.

[0003] Among the reported 3-functionalized indole-2-one compounds, 3-trichloroethyl indole-2-one compounds are an important class of compounds. The trichloromethyl group is an important functional group. It is known that the trichloromethyl group can be easily further converted into alkynes, carboxylic acids or their esters, amides, etc. Therefore, 3-trichloroethyl indole-2-one compounds can also be used as important organic synthesis and drug synthesis intermediates. The reported free radical-induced N-aryl acrylamide cascade cyclization methods for preparing 3-trichloroethyl indole-2-one compounds mainly involve the following two categories: one is to use the Csp of trichloromethane to prepare 3-trichloroethyl indole-2-one compounds; the other ... 3-H bond activation to form free radicals (J.Org.Chem.2024,89,4120-4127; ACS Omega 2022,7,48564-48571; Org.Chem.Front.2022,9,1004-1009; Chin.J.Org.Chem.2016,36,325-329; TetrahedronLett.56(2015)20,2559-2563; J.Org.Chem.2021,86,15544-15557), and the other is to use carbon tetrachloride to activate the C-Cl bond to form free radicals, such as Weijun Fu et al. reported the radical tandem cyclization reaction of N-aryl acrylamide and carbon tetrachloride under the conditions of fac-Ir(ppy)3 / K2CO3 and 5W blue light LED. This method requires the use of expensive photocatalyst fac-Ir(ppy)3 (Heterocycl. Commun. 2015, 21, 387-390). Chengming Wang et al. reported the radical tandem cyclization reaction of N-aryl acrylamide and bromotrichloromethane in the presence of N-heterocyclic radical carbene. This method uses a catalyst, the price of bromotrichloromethane is also relatively expensive, and the yield is only about 50%, which is not suitable for industrial production (Org. Lett. 2021, 23, 4662-4666). Shu-Yu Zhang et al. reported the free radical tandem cyclization reaction of N-aryl acrylamide and bromotrichloromethane under electrochemical synthesis conditions, and when carbon tetrachloride was used as the reaction raw material, the yield of the target product was significantly reduced to 19% (Chem. Commun. 2022, 58, 9230-9233). In addition, transition metal (Fe, Cu, Mn, etc.) catalysis and other synthesis strategies under other reaction conditions also have defects such as low yield, harsh reaction conditions, expensive reagents, and long reaction time (Tetrahedron Lett. 2020, 61, 152316; Org. Lett. 2014, 16, 4698-4701; J. Org. Chem. 2023, 88, 15389-15394; J. Org. Chem. 2024, 89, 12753-12761).

[0004] The inventor's research group reported that in the TBAHS / K2S2O8 oxidation system, Csp 3-H bond compounds are first activated to form free radicals, and then undergo a tandem cyclization reaction with N-aryl acrylamide to obtain a series of 3-functionalized indolone compounds. When chloroform is used as a reaction substrate, the reaction is carried out at 100 ° C for 24 hours to obtain the target compound with a high yield of 92% (J.Org.Chem.2021,86,15544-15557). Further studies have shown that when carbon tetrachloride is used as a reaction substrate, under the same reaction conditions, the yield of the target product is significantly reduced to about 40%. In order to further develop novel synthetic routes for 3-functionalized indole-2-one compounds, and considering that the price of chloroform is often about twice as expensive as carbon tetrachloride, in order to reduce the cost of synthesis, the inventors conducted in-depth research and extensive experiments based on this discovery, and finally proposed the scheme of the present invention. Summary of the invention

[0005] The purpose of the present invention is to develop a novel synthesis route for 3-functionalized indole-2-one compounds to overcome the defects of the existing synthesis strategies, such as expensive raw materials and / or reagents, high cost, harsh reaction conditions and low yield. Under the preferred free radical initiation system (TBAH / K2S2O8) of the present invention, carbon tetrachloride and N-aryl acrylamide are cascaded cyclized to prepare a series of 3-trichloromethylated indole-2-one compounds with a yield of up to 98%.

[0006] A method for preparing a 3-functionalized indole-2-one compound provided by the present invention comprises the following steps:

[0007] The N-aryl acrylamide compound shown in Formula 1, the oxidant potassium persulfate, and the quaternary ammonium salt are sequentially added to the reactor, followed by the addition of carbon tetrachloride or bromotrichloromethane, and the reactor is placed in an inert gas atmosphere, heated and stirred for reaction, and after the reaction is complete, the 3-functionalized indole-2-one compound shown in Formula 2 is obtained by post-treatment. The reaction formula is as follows:

[0008]

[0009] Wherein, R1 is selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 6-12 Aryl, C 3-8 Cycloalkyl-C 1-3 Alkyl, C 3-8 Cycloalkyl-C 1-3 Alkoxy, C 6-12 Aryl-C 1-3 Alkyl, C 6-12 Aryl-C1-3 Alkoxy, C 1-6 Acyl, C 1-6 Alkoxycarbonyl.

[0010] Preferably, R1 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, benzyl, benzyloxy, acetyl, acetoxy.

[0011] More preferably, R1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, and cyclopropylmethoxy.

[0012] R2 is selected from C 1-6 Alkyl, C 1-6 Acyl, C 1-6 Alkylsulfonyl, C 6-14 Arylsulfonyl.

[0013] Preferably, R2 is selected from methyl, ethyl, acetyl or p-toluenesulfonyl; further preferably, R2 is selected from methyl or p-toluenesulfonyl.

[0014] According to the aforementioned preparation method of the present invention, wherein the quaternary ammonium salt is selected from TBAH (tetrabutylammonium hydroxide) or TBAF (tetrabutylammonium fluoride), preferably TBAH (tetrabutylammonium hydroxide).

[0015] According to the aforementioned preparation method of the present invention, the molar ratio of the N-aryl acrylamide compound, the oxidant potassium persulfate and the quaternary ammonium salt is 1:2-8:2-6; preferably 1:2-5:2-4; most preferably 1:3:2.5.

[0016] According to the aforementioned preparation method of the present invention, the feeding amount of carbon tetrachloride or bromotrichloromethane is not particularly limited. In the reaction of the present invention, it serves as a reaction raw material and also as a reaction solvent. Generally speaking, the feeding amount of carbon tetrachloride or bromotrichloromethane is such that the reaction materials can be evenly dispersed and facilitate stirring.

[0017] According to the aforementioned preparation method of the present invention, wherein the inert atmosphere is a nitrogen atmosphere or an argon atmosphere.

[0018] According to the aforementioned preparation method of the present invention, the reaction temperature of the heating and stirring reaction is 80-100° C., preferably 90° C.; the reaction time is 12-48 h, preferably 24 h.

[0019] According to the aforementioned preparation method of the present invention, the post-processing operation is as follows:

[0020] After the reaction is complete, water is added to quench the reaction, and the organic phase is extracted and dried and concentrated to obtain a residue. The residue is separated by silica gel column chromatography to obtain the 3-functionalized indole-2-one compound shown in formula 2.

[0021] Compared with the prior art, the method of the present invention has the following significant advantages:

[0022] 1) The present invention provides a novel synthetic route for 3-functionalized indole-2-one compounds. Under the preferred free radical initiation system (TBAH / K2S2O8) of the present invention, a series of 3-trichloromethylated indole-2-one compounds are prepared with a yield of up to 98%, which has a significantly higher yield of the target product than the prior art.

[0023] 2) The reaction system of the present invention is cheap, wherein the price of carbon tetrachloride is only half of that of chloroform, and TBAH / K2S2O8 is an environmentally friendly and low-cost reagent. Compared with the prior art method, it avoids the use of toxic, harmful, and expensive reagents, thereby significantly reducing the reaction cost.

[0024] 3) Compared with the prior art methods, the synthetic route of the present invention is applicable to both chloroform and bromotrichloromethane substrates, has broad functional group universality, mild and simple reaction conditions, easy operation, and is suitable for industrial production. DETAILED DESCRIPTION

[0025] The present invention is further described in detail below in conjunction with specific examples. In the following, unless otherwise specified, the methods used are all conventional methods in the art, and the reagents and raw materials used are prepared by methods known in the art and / or purchased through conventional commercial channels without further purification.

[0026] Example 1-14 Reaction Condition Optimization Test

[0027] Using N-methyl-N-phenyl-methacrylamide as a template substrate, the effects of different conditions on the yield of the target product of the free radical reaction of the present invention were investigated, and the results are shown in Table 1. The reaction formula is as follows:

[0028]

[0029] Table 1:

[0030] Example Oxidant (equiv) Quaternary ammonium salt (equiv) Temperature(℃) Time (h) Yield (%) 1 <![CDATA[K2S2O8(2.0)]]> — 90 24 0 2 — TBAI (2.0) 90 24 0 3 <![CDATA[K2S2O8(2.0)]]> TBAI (2.0) 90 24 45 4 <![CDATA[K2S2O8(2.0)]]> TBAHS(2.0) 90 24 47 5 <![CDATA[K2S2O8(2.0)]]> TBAB(2.0) 90 24 10 6 <![CDATA[K2S2O8(2.0)]]> TBAH(2.0) 90 24 73 7 <![CDATA[K2S2O8(2.0)]]> TBAF(2.0) 90 24 65 8 <![CDATA[K2S2O8(2.0)]]> BTBAB(2.0) 90 24 13 9 <![CDATA[K2S2O8(2.0)]]> TBAH(1.5) 90 24 80 10 <![CDATA[K2S2O8(2.0)]]> TBAH(2.5) 90 24 85 11 <![CDATA[K2S2O8(2.5)]]> TBAH(2.5) 90 24 92 12 <![CDATA[K2S2O8(3.0)]]> TBAH(2.5) 90 24 95 13 <![CDATA[K2S2O8(3.0)]]> TBAH(2.5) 100 24 83

[0031] Conditions: 1a (0.2 mmol), CCl4 (1.5 mL). Isolated yield. TBAI: tetrabutylammonium iodide; TBAHS: tetrabutylammonium hydrogen sulfate; TBAB: tetrabutylammonium bromide; TBAH: tetrabutylammonium hydroxide; BTBAB: benzyltributylammonium bromide.

[0032] Taking Example 12 as an example, the typical experimental operation of the preparation method of the present invention is as follows:

[0033] N-methyl-N-phenyl-methyl acrylamide (0.2 mmol), K2S2O8 (3.0 eq, 0.6 mmol), tetrabutylammonium hydroxide (2.5 eq, 0.5 mmol), and carbon tetrachloride (1.5 mL) were added to a 50 mL Schlenk bottle in sequence. The Schlenk bottle was then evacuated and argon was introduced, and the operation was repeated three times. Finally, the mixture was heated to 90 ° C under an argon atmosphere for 24 h. After the reaction was completed, 10 mL of water was added to the reaction solution, and then extracted with dichloromethane three times (50 mL each time), the organic phases were combined and dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was filtered through a column with petroleum ether / ethyl acetate 15:1 to 12:1 to obtain the target product shown in formula 2a, with a yield of 95%. 1 H NMR (400MHz, CDCl3) δ7.36–7.29(m,2H),7.06(t,J=8.1Hz,1H),6.88(d,J=7.7Hz ,1H),3.70(d,J=15.3Hz,1H),3.34(d,J=16.3Hz,1H),3.24(s,3H),1.40(s,3H); 13 C NMR (100MHz, CDCl3) δ178.6,143.2,129.5,128.5,125.6,122.0,108.4,96.1,59.8,48.0,26.8,26.6.

[0034] In Table 1, in addition to the reaction condition variables shown in Examples 1-11 and 13-14 being different from Example 12, the remaining reaction operations and operations are the same as in Example 12. As can be seen from Table 1, the reaction of the present invention is not carried out without the addition of K2S2O8 or quaternary ammonium salt (Examples 1-2). Under the reaction conditions reported by the inventors before (J.Org.Chem.2021,86,15544-15557), the target product yield is low (Examples 3-5, 8), and when the quaternary ammonium salt is replaced by TBAF or TBAH, the yield is significantly improved (Examples 6-7). Further experiments show that the amount of K2S2O8 and tetrabutylammonium hydroxide in the oxidation reaction system, and temperature are also important factors affecting the target product yield (Examples 9-13), and the optimal K2S2O8 and tetrabutylammonium hydroxide feed ratio is 3.0:2.5, and the optimal reaction temperature is 90 ° C.

[0035] When the optimal reaction conditions (Example 12) were obtained, the inventors further explored the universality of the optimal reaction conditions for the reaction substrates, and the results are as follows:

[0036]

[0037] Structural characterization of the product:

[0038] Compound 2b:

[0039] 1 H NMR (500MHz, CDCl3) δ7.13(dd,J=7.2,1.3Hz,1H),7.04–6.96(m,2H),3.68(d,J=15.3Hz,1H),3.44(d,J=2.7Hz,3H),3.32(d,J=15.3Hz,1H),1.39(s,3H); 13 C NMR (125MHz, CDCl3) δ178.2, 148.0 (d, J = 242.5Hz), 132.4 (d, J = 3.75Hz), 130.0 (d, J = 8.75Hz), 122.4 (d, J = 6. 25Hz), 121.4 (d, J = 3.75Hz), 116.3 (d, J = 18.75Hz), 95.9, 60.0, 48.2 (d, J = 2.5Hz), 29.1 (d, J = 6.25Hz), 27.0.

[0040] Compound 2c:

[0041] 1 H NMR(400MHz, CDCl3) δ7.47(d,J=1.9Hz,1H),7.43(dd,J=8.3,2.0Hz,1H),6.76(d,J=8 .3Hz,1H),3.68(d,J=15.3Hz,1H),3.31(d,J=15.3Hz,1H),3.21(s,3H),1.39(s,3H); 13 C NMR (100MHz, CDCl3) δ177.9,142.3,131.6,131.3,128.8,114.7,109.8,95.8,59.7,48.0,26.7,26.7.

[0042] Compound 2d:

[0043] 11H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 3.68 (d, J = 15.2 Hz, 1H), 3.31 (d, J = 15.3 Hz, 1H), 3.21 (s, 3H), 2.34 (s, 3H), 1.38 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 178.5, 140.8, 131.4, 129.5, 128.7, 126.4, 108.1, 96.2, 59.8, 48.0, 26.8, 26.6, 21.1.

[0044] Compound 2e:

[0045] 1 1H NMR (400 MHz, CDCl3) δ 6.94 (dd, J = 4.7, 0.8 Hz, 2H), 6.80 (p, J = 3.7 Hz, 1H), 3.92–3.82 (m, 2H), 3.67 (d, J = 15.2 Hz, 1H), 3.55 (s, 3H), 3.29 (d, J = 15.2 Hz, 1H), 1.37 (s, 3H), 1.27 (dddd, J = 13.2, 6.9, 3.2, 2.1 Hz, 1H), 0.67–0.62 (m, 2H), 0.37–0.34 (m, 2H); 13 13C NMR (100 MHz, CDCl3) δ 178.8, 145.0, 131.5, 131.3, 122.4, 118.2, 113.3, 96.1, 73.8, 60.0, 48.0, 30.0, 27.1, 10.2, 3.1.

[0046] Compound 2f:

[0047] 1 1H NMR (400 MHz, CDCl3) δ 7.38–7.35 (m, 4H), 7.29 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.11–7.07 (m, 1H), 4.14 (d, J = 15.7 Hz, 1H), 3.48 (d, J = 15.6 Hz, 1H), 2.37 (s, 3H), 2.04 (s, 3H); 13C NMR (100MHz, CDCl3) δ173.3,147.7,138.3,137.9,137.5,129.7,129.0,127.2,124.6,119.9,109.8,97.5,60.2,52.1,22.4,21.0.

[0048] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a 3-functionalized indole-2-one compound, comprising the following steps: The N-aryl acrylamide compound shown in Formula 1, the oxidant potassium persulfate and the quaternary ammonium salt are sequentially added to the reactor, and then carbon tetrachloride or bromotrichloromethane is added, and the reactor is placed in an inert gas atmosphere, heated and stirred for reaction, and after the reaction is complete, the 3-functionalized indole-2-one compound shown in Formula 2 is obtained by post-treatment; the reaction formula is as follows: in, R1 is selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 6-12 Aryl, C 3-8 Cycloalkyl-C 1-3 Alkyl, C 3-8 Cycloalkyl-C 1-3 Alkoxy, C 6-12 Aryl-C 1-3 Alkyl, C 6-12 Aryl-C 1-3 Alkoxy, C 1-6 Acyl, C 1-6 Alkoxycarbonyl; R2 is selected from C 1-6 Alkyl, C 1-6 Acyl, C 1-6 Alkylsulfonyl, C 6-14 Arylsulfonyl; The quaternary ammonium salt is selected from TBAH or TBAF.

2. The preparation method according to claim 1, characterized in that: R1 is selected from hydrogen, fluorine, chlorine, bromine, -CN, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, benzyl, benzyloxy, acetyl, acetoxy; R2 is selected from methyl, ethyl, acetyl or p-toluenesulfonyl.

3. The preparation method according to claim 2, characterized in that: R1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, cyclopropylmethoxy; R2 is selected from methyl or p-toluenesulfonyl.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The quaternary ammonium salt is selected from TBAH.

5. The preparation method according to any one of claims 1 to 3, characterized in that: The feeding molar ratio of the N-aryl acrylamide compound, the oxidant potassium persulfate and the quaternary ammonium salt is 1:2-8:2-6.

6. The preparation method according to claim 5, characterized in that: The feeding molar ratio of N-aryl acrylamide compound, oxidant potassium persulfate and quaternary ammonium salt is 1:3:2.

5.

7. The preparation method according to any one of claims 1 to 3, characterized in that: The inert atmosphere is a nitrogen atmosphere or an argon atmosphere.

8. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction temperature of the heating and stirring reaction is 80-100° C., and the reaction time is 12-48 hours.

9. The preparation method according to claim 8, characterized in that: The reaction temperature of the heating and stirring reaction is 90° C. and the reaction time is 24 h.

10. The preparation method according to any one of claims 1 to 3, characterized in that: The post-treatment operation is as follows: after the reaction is complete, water is added to quench, extraction is performed, the organic phase is dried and concentrated to obtain a residue, and the residue is separated by silica gel column chromatography to obtain the 3-functionalized indole-2-one compound shown in formula 2.

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