Synthesis method of 3-chloro-substituted indole compounds

Abstract

The present invention relates to a method for synthesizing a 3-chloro-substituted indole compound, comprising: dissolving an N,N-substituted o-alkynylaniline derivative (structural formula II) in dimethyl sulfoxide, adding thionyl chloride dropwise under ice bath conditions, and reacting at 30-45° C. to obtain a 3-chloro-substituted indole compound (I); the reaction formula is as follows: 1 、R 2 、R 3 、R 4 are independent of each other, and R 1 is a hydrogen atom, a chlorine atom or a bromine atom; R 2 is phenyl, substituted phenyl or thiophene; R 3 is p-toluenesulfonyl or methylsulfonyl; R 4 The present invention generates 3-chloroindole derivatives through an internal cyclization reaction of the molecule, which has the advantages of simple operation, cheap and readily available raw materials, mild reaction conditions, short reaction time, high yield, and easy purification.

Description

Technical Field

[0001] The present invention relates to the technical field of compound synthesis, and in particular to a method for synthesizing 3-chloro-substituted indole compounds. Background Art

[0002] Over the past few decades, the synthesis of indoles and their derivatives has been a field of intense interest. The indole skeleton is one of the most abundant and important building blocks in nature, occurring extensively in natural products such as Tripterygium wilfordii and Catharanthus roseus. Furthermore, many best-selling small-molecule drugs, including fluvastatin, tadalafil, and pamoate, possess the indole skeleton within their structures. While numerous methods for synthesizing indoles have been developed, further research and development are needed to develop more efficient and economical strategies for the synthesis of functionalized indoles with unique substituents. 3-Chloroindole, as an intermediate in organic synthesis and the core structure of many biologically active indole derivatives, holds broad synthetic value. While studies on the chlorination of the C-3 position of indoles have been reported, most have been limited to specific substrates and substitution patterns containing only a few substituents. New methods for synthesizing 3-chloroindoles via intramolecular cyclization have yet to be explored. Summary of the Invention

[0003] (1) Technical issues to be solved

[0004] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a method for synthesizing 3-chloro-substituted indole compounds, which generates 3-chloroindole derivatives through an internal cyclization reaction of the molecule.

[0005] (2) Technical solution

[0006] The technical solution of the present invention is summarized as follows:

[0007] A method for synthesizing a 3-chloro-substituted indole compound, comprising:

[0008] The N,N-substituted o-alkynylaniline derivative (structural formula II) is dissolved in dimethyl sulfoxide, and dichlorothionyl is added dropwise in an ice bath. The reaction is carried out at 30-45° C. to obtain a 3-chloro-substituted indole compound (I). The reaction formula is as follows:

[0009]

[0010] R 1 、R 2 、R 3 、R 4 are independent of each other, and in which:

[0011] R 1 is a hydrogen atom, a chlorine atom or a bromine atom;

[0012] R 2 is phenyl, substituted phenyl or thiophene;

[0013] R 3 is p-toluenesulfonyl or methylsulfonyl;

[0014] R 4 It is methyl or ethyl.

[0015] According to a preferred embodiment of the present invention, in the N,N-substituted o-alkynylaniline derivative, when R 1 When it is a chlorine atom or a bromine atom, R 1 In the meta or para position of the amine group.

[0016] According to a preferred embodiment of the present invention, R 2 is methoxyphenyl, halogenated phenyl or methylphenyl.

[0017] According to a preferred embodiment of the present invention, the molar ratio of the N,N-substituted o-ethynylaniline derivative to thionyl chloride is preferably 1:2-4; preferably 1:3.

[0018] According to a preferred embodiment of the present invention, 1 mmol of the N,N-substituted o-ethynylaniline derivative is dissolved in 1.5-2.5 mL of dimethyl sulfoxide.

[0019] According to a preferred embodiment of the present invention, the reaction temperature is 40°C.

[0020] According to a preferred embodiment of the present invention, after the reaction is completed, the reaction solution is extracted with water and dichloromethane in a volume ratio of 1:3, the organic phases are combined, the organic phase is washed with saturated sodium bicarbonate, and then with saturated brine, and anhydrous sodium sulfate is added to dry the organic phase. The organic phase is added to a column of silica gel and evaporated to dryness, and separated by column chromatography (ethyl acetate: petroleum ether = 5:95) to obtain a white solid.

[0021] According to a preferred embodiment of the present invention, the reaction is terminated when TLC shows that the substrate has completely reacted.

[0022] (3) Beneficial effects

[0023] The invention has many advantages, such as simple operation, cheap and readily available raw materials, mild reaction conditions, short reaction time, high yield, easy purification, etc. The minimum yield is ≥60%, and the maximum yield can exceed 90%.

[0024] This method uses N,N-substituted o-alkynylaniline derivatives and thionyl chloride (SOCl2) as raw materials. Thionyl chloride is a liquid at room temperature and serves as both the reaction raw material and the reaction solvent, being highly dispersible in the reaction solvent. At 30-45°C, the N,N-substituted o-alkynylaniline derivative undergoes intramolecular cyclization and chlorine substitution to produce 3-chloroindole compounds. Thionyl chloride and dimethyl sulfoxide are similar liquids, are well miscible, and can promote the chlorine substitution process of the product by thionyl chloride.

[0025] The synthesis method of the present invention has mild conditions (the optimal reaction temperature is about 40° C.), low energy consumption, fast reaction speed and high product conversion rate. DETAILED DESCRIPTION

[0026] In order to better explain the present invention and facilitate understanding, the present invention is described in detail below in conjunction with specific embodiments.

[0027] The sources of the raw materials used in the following examples are as follows:

[0028] (1) Sulfonyl chloride (SOCl2) was purchased from a commercial company of analytical grade.

[0029] (2) Dimethyl sulfoxide (DMSO) is commercially available absolutely anhydrous dimethyl sulfoxide.

[0030] (3) The reaction raw materials required in each example, namely N,N-substituted o-ethynylaniline, were prepared according to the literature method: see Yin, Y.; Ma, W.Y.; Chai, Z.; Zhao, G.J.; Org. Chem. 2007, 72, 5731. [2] Zhang, Z.Q.; Xu, Y.H.; Dai, J.C.; Li, Y.; Sheng, J.; Wang, X.S. Org. Lett. 2021, 23, 2194.

[0031] Example 1

[0032] The reaction formula for preparing 3-chloro-1-methyl-2-phenyl-1H-indole 1a in the present embodiment is as follows:

[0033]

[0034] N,4-dimethyl-N-(2-(phenylethynyl)phenyl)benzenesulfonamide ll-a (0.5 mmol, 181 mg) was dissolved in dimethyl sulfoxide (1 mL), and thionyl chloride (1.5 mmol, 179 mg) was added dropwise at 0°C, and the reaction was continued at 40°C until TLC showed that the substrate was completely reacted.

[0035] The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL × 3). The organic phases were combined and washed with saturated sodium bicarbonate and then with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The organic phase was added to a silica gel column and evaporated to dryness. The product was separated by column chromatography (ethyl acetate: petroleum ether = 5:95) to give 72 mg of a white solid with a yield of 60% and a melting point of 70-72°C.

[0036] The product characterization data are as follows:

[0037] 1 HNMR(600MHz, CDCl3)δ:7.68(d,J=7.9Hz,1H),7.55-7.51(m,4H),7.50-7.45(m,1H) ),7.37(d,J=8.2Hz,1H),7.32(t,J=7.6Hz,1H),7.24(t,J=7.4Hz,1H),3.68(s,3H); 13 CNMR (151MHz, CDCl3) δ: 136.23, 136.19, 130.6, 129.8, 128.6, 128.5, 125.7, 122.8, 120.4, 118.3, 109.7, 103.6, 31.5.

[0038] Example 2

[0039] This embodiment provides another synthetic method for preparing 3-chloro-1-methyl-2-phenyl-1H-indole, and the reaction formula is as follows:

[0040]

[0041] This reaction essentially replaces the starting material N,4-dimethyl-N-(2-(phenylethynyl)phenyl)benzenesulfonamide in Example 1 with N-methyl-N-(2-(phenylethynyl)phenyl)methanesulfonamide. The product is 3-chloro-1-methyl-2-phenyl-1H-indole in 68% yield and a melting point of 70-72°C. Product characterization data is shown in Example 1.

[0042] Example 3

[0043] The present embodiment prepares the reaction formula of 3,5-dichloro-1-methyl-2-phenyl-1H-indole 1b as follows:

[0044]

[0045] N-(4-chloro-2-(phenylethynyl)phenyl)-N,4-dimethylbenzenesulfonamide ll-b (0.5 mmol, 198 mg) was dissolved in dimethyl sulfoxide (1 mL). Dichlorothionyl (1.5 mmol, 179 mg) was added dropwise at 0°C. The reaction was allowed to proceed at 35°C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined and washed first with saturated sodium bicarbonate and then with saturated brine. The organic phases were dried over anhydrous sodium sulfate and passed through a silica gel column, evaporated to dryness, and separated by column chromatography (ethyl acetate:petroleum ether = 5:95) to afford 102 mg of a yellow oil in a 74% yield.

[0046] The product characterization data are as follows:

[0047] 1 HNMR (400MHz, CDCl3) δ: 7.54 (dd, J = 1.8, 0.8Hz, 1H), 7.45-7.37 (m, 5H), 7.17-7.14 (m, 2H), 3.55 (s, 3H); 13 CNMR (101MHz, CDCl3) δ: 137.5, 134.6, 130.5, 129.3, 128.9, 128.6, 126.6, 126.2, 123.1, 118.9, 117.8, 110.8, 31.6.

[0048] Example 4

[0049] The reaction formula for preparing 6-bromo-3-chloro-1-methyl-2-phenyl-1H-indole 1C in this embodiment is as follows:

[0050]

[0051] N-(5-Bromo-2-(phenylethynyl)phenyl)-N,4-dimethylbenzenesulfonamide ll-c (0.5 mmol, 220 mg) was dissolved in dimethyl sulfoxide (1 mL). Thionyl chloride (1.5 mmol, 179 mg) was added dropwise at 0°C. The reaction was continued at 40°C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined and washed first with saturated sodium bicarbonate and then with saturated brine. The organic phases were dried over anhydrous sodium sulfate and passed through a silica gel column, evaporated to dryness, and separated by column chromatography (ethyl acetate:petroleum ether = 5:95) to afford 112 mg of a yellow oil in a 70% yield.

[0052] The product characterization data are as follows:

[0053] 1HNMR (400MHz, CDCl3) δ: 7.52-7.48 (m, 1H), 7.39-7.33 (m, 5H), 7.09 (d, J = 1.6Hz, 2H), 3.48 (s, 3H); 13 CNMR (101MHz, CDCl3) δ: 136.4, 133.4, 129.3, 128.1, 127.7, 127.5, 127.5, 125.4, 125.0, 122.0, 116.6, 109.8, 30.5.

[0054] Example 5

[0055] The reaction formula for preparing 3-chloro-1-methyl-2-(p-tolyl)-1H-indole 1d in the present embodiment is as follows:

[0056]

[0057] N,4-Dimethyl-N-(2-(p-Toluethynyl)phenyl)benzenesulfonamide ll-d (0.5 mmol, 188 mg) was dissolved in dimethyl sulfoxide (1 mL). Thionyl chloride (1.5 mmol, 179 mg) was added dropwise at 0°C. The reaction was continued at 40°C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined and washed first with saturated sodium bicarbonate and then with saturated brine. The organic phases were dried over anhydrous sodium sulfate and passed through a silica gel column, evaporated to dryness, and separated by column chromatography (ethyl acetate:petroleum ether = 5:95) to afford 99 mg of a white solid with a yield of 78% and a melting point of 88-90°C.

[0058] The product characterization data are as follows:

[0059] 1 HNMR (400MHz, CDCl3) δ: 7.65 (d, J = 7.8Hz, 1H), 7.38 (d, J = 7.8Hz, 2H), 7.30 (q, J = 7.7Hz, 4H), 7.20 (t, J = 7.3Hz, 1H), 3.62 (s, 3H), 2.42 (s, 3H); 13 CNMR (101MHz, CDCl3) δ: 138.7, 136.4, 136.2, 130.5, 129.3, 126.8, 125.7, 122.7, 120.4, 118.3, 109.7, 103.3, 31.5, 21.5.

[0060] Example 6

[0061] The reaction formula for preparing 3-chloro-2-(3-chlorophenyl)-1-methyl-1H-indole in this embodiment is as follows:

[0062]

[0063] N-(2-((3-chlorophenyl)ethynyl)phenyl)-N,4-dimethylbenzenesulfonamide ll-e (0.5 mmol, 198 mg) was dissolved in dimethyl sulfoxide (1 mL). Thionyl chloride (1.5 mmol, 179 mg) was added dropwise at 0°C. The reaction was continued at 40°C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined and washed first with saturated sodium bicarbonate and then with saturated brine. The organic phases were dried over anhydrous sodium sulfate and passed through a silica gel column, evaporated to dryness, and separated by column chromatography (ethyl acetate:petroleum ether = 5:95) to afford 105 mg of a yellow oil in a yield of 76%.

[0064] The product characterization data are as follows:

[0065] 1 H NMR (400MHz, CDCl3) δ: 7.65 (dt, J = 7.9, 1.0 Hz, 1H), 7.49 (dt, J = 2.5, 1.1 Hz, 1H), 7. 44-7.36(m,3H),7.34-7.27(m,2H),7.22(ddd,J=8.0,6.4,1.5Hz,1H),3.63(s,3H); 13 C NMR (101MHz, CDCl3) δ: 136.3, 134.6, 134.4, 131.5, 130.4, 129.8, 128.7, 128.7, 125.5, 123.3, 120.6, 118.5, 109.85, 104.1, 31.5.

[0066] Example 7

[0067] The reaction formula for preparing 2-(2-bromophenyl)-3-chloro-1-methyl-1H-indole lf in this embodiment is as follows:

[0068]

[0069] N-(2-((2-bromophenyl)ethynyl)phenyl)-N,4-dimethylbenzenesulfonamide ll-f (0.5 mmol, 220 mg) was dissolved in dimethyl sulfoxide (1 mL). Thionyl chloride (1.5 mmol, 179 mg) was added dropwise at 0°C. The reaction was continued at 40°C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined and washed first with saturated sodium bicarbonate and then with saturated brine. The organic phases were dried over anhydrous sodium sulfate and passed through a silica gel column, evaporated to dryness, and separated by column chromatography (ethyl acetate:petroleum ether = 5:95) to afford 95.8 mg of a yellow oil in a 60% yield.

[0070] The product characterization data are as follows:

[0071] 1 HNMR(400MHz, CDCl3)δ:7.91-7.61(m,2H),7.51-7.29(m,5H),7.27-7.22(m,1H),3.54(s,3H); 13 CNMR (101MHz, CDCl3) δ: 141.9, 136.9, 135.6, 133.3, 132.7, 130.7, 127.3, 125.4, 122.9, 122.6, 120.4, 119.5, 118.5, 109.8, 30.9.

[0072] Example 8

[0073] The reaction formula for preparing 3-chloro-2-(3-methoxyphenyl)-1-methyl-1H-indole 1 g in this embodiment is as follows:

[0074]

[0075] N-(2-((3-methoxyphenyl)ethynyl)phenyl)-N,4-dimethylbenzenesulfonamide 11-g (0.5 mmol, 196 mg) was dissolved in dimethyl sulfoxide (1 mL). Dichlorothionyl (1.5 mmol, 179 mg) was added dropwise at 0°C. The mixture was reacted at 40°C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined and washed first with saturated sodium bicarbonate and then with saturated brine. The organic phases were dried over anhydrous sodium sulfate and passed through a silica gel column, evaporated to dryness, and separated by column chromatography (ethyl acetate:petroleum ether = 5:95) to obtain 121 mg of a yellow oil in a yield of 89.5%.

[0076] The product characterization data are as follows:

[0077] 1HNMR(400MHz, CDCl3)δ:7.65(t,J=7.0Hz,1H),7.44-7.34(m,1H),7.28(tddd,J=8.2,6.9,3.6, 2.0Hz,2H),7.25-7.15(m,1H),7.08-7.01(m,2H),6.99-6.93(m,1H),3.81(s,3H),3.61(s,3H); 13 CNMR (101MHz, CDCl3) δ: 161.2, 136.2, 131.0, 129.6, 123.0, 122.9, 120.5, 118.3, 116.32, 116.3, 114.2, 109.9, 109.8, 103.5, 55.4, 31.5.

[0078] Example 9

[0079] The reaction formula for preparing 3-chloro-1-methyl-2-(thiophen-2-yl)-1H-indole 1h in this embodiment is as follows:

[0080]

[0081] N,4-Dimethyl-N-(2-(thiophen-2-ylethynyl)phenyl)benzenesulfonamide ll-h (0.5 mmol, 184 mg) was dissolved in dimethyl sulfoxide (1 mL). Thionyl chloride (1.5 mmol, 179 mg) was added dropwise at 0°C. The reaction was continued at 40°C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined and washed first with saturated sodium bicarbonate and then with saturated brine. The organic phases were dried over anhydrous sodium sulfate and passed through a silica gel column, evaporated to dryness, and separated by column chromatography (ethyl acetate:petroleum ether = 5:95) to afford 103 mg of a yellow oil in an 83% yield.

[0082] The product characterization data are as follows:

[0083] 1 H NMR (400MHz, CDCl3) δ: 7.63 (ddt, J=7.8, 2.0, 1.1Hz, 1H), 7.47 (dd, J=2.9, 1.3Hz, 1H), 7.41 (dd, J=5.0 ,3.0Hz,1H),7.27(dddd,J=5.9,4.5,2.2,1.0Hz,3H),7.18(ddt,J=9.3,5.9,1.9Hz,1H),3.63(s,3H); 13CNMR (101MHz, CDCl3) δ: 136.2, 131.6, 129.8, 128.7, 126.2, 125.8, 125.6, 122.9, 120.4, 118.3, 109.7, 103.7, 31.5.

[0084] Example 10

[0085] The reaction formula for preparing 3-chloro-1-ethyl-2-phenyl-1H-indole 11 in the present embodiment is as follows:

[0086]

[0087] N-Ethyl-4-methyl-N-(2-(phenylethynyl)phenyl)benzenesulfonamide ll-i (0.5 mmol, 188 mg) was dissolved in dimethyl sulfoxide (1 mL). Thionyl chloride (1.5 mmol, 179 mg) was added dropwise at 0°C. The reaction was continued at 40°C until TLC indicated complete reaction of the substrate. The reaction solution was extracted with water (20 mL) and dichloromethane (20 mL x 3). The organic phases were combined and washed first with saturated sodium bicarbonate and then with saturated brine. The organic phases were dried over anhydrous sodium sulfate and passed through a silica gel column, evaporated to dryness, and separated by column chromatography (ethyl acetate:petroleum ether = 5:95) to afford 108 mg of a yellow oil in an 85% yield.

[0088] The product characterization data are as follows:

[0089] 1 HNMR(400MHz, CDCl3)δ:7.56(dt,J=7.8,1.0Hz,1H),7.39-7.30(m,5H),7.25(dt,J=8.3,1.0Hz,1H),7.16(d dd,J=8.2,7.0,1.3Hz,1H),7.10(ddd,J=8.0,7.0,1.1Hz,1H),3.97(q,J=7.2Hz,2H),1.09(t,J=7.2Hz,3H); 13 C NMR (101MHz, CDCl3) δ: 134.7, 133.9, 129.3, 128.9, 127.5, 127.4, 124.8, 121.6, 119.2, 117.3, 108.9, 102.7, 38.1, 14.2.

[0090] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing a 3-chloro-substituted indole compound, characterized in that: include: The N,N-substituted o-alkynylaniline derivative (structural formula II) is dissolved in dimethyl sulfoxide, and dichlorothionyl is added dropwise in an ice bath. The reaction is carried out at 30-45° C. to obtain a 3-chloro-substituted indole compound (I). The reaction formula is as follows: R 1 、R 2 、R 3 、R 4 are independent of each other, and in which: R 1 is a hydrogen atom, a chlorine atom or a bromine atom; R 2 is phenyl or thiophene; R 3 is p-toluenesulfonyl or methylsulfonyl; R 4 It is methyl or ethyl.

2. The synthesis method according to claim 1, wherein In N,N-substituted o-alkynylaniline derivatives, when R 1 When it is a chlorine atom or a bromine atom, R 1 In the meta or para position of the amine group.

3. The synthesis method according to claim 1, wherein R 2 is methoxyphenyl, halogenated phenyl or methylphenyl.

4. The synthesis method according to claim 1, characterized in that The molar ratio of the N,N-substituted o-ethynylaniline derivative to thionyl chloride is 1:2-4.

5. The synthesis method according to claim 4, characterized in that The molar ratio of the N,N-substituted o-ethynylaniline derivative to thionyl chloride is 1:

3.

6. The synthesis method according to claim 1, characterized in that 1 mmol of N,N-substituted o-ethynylaniline derivative is dissolved in 1.5-2.5 mL of dimethyl sulfoxide.

7. The synthesis method according to claim 1, characterized in that The reaction temperature was 40°C.

8. The synthesis method according to claim 1, characterized in that After the reaction, the reaction solution was extracted with water and dichloromethane in a volume ratio of 1:3, the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate, and then with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was added to a column of silica gel and evaporated to dryness. The white solid was separated by column chromatography, and the chromatography fluid was prepared by a mixture of ethyl acetate and petroleum ether in a volume ratio of 5:

95.

9. The synthesis method according to claim 1, characterized in that The reaction was terminated when TLC showed that the substrate had reacted completely.

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