Preparation method of amide-containing indolo [2, 1-a] isoquinoline compound

Abstract

The invention discloses a preparation method of an amide-containing indolo [2, 1-a] isoquinoline compound, which comprises the following steps: reacting a 1-(2-(2-iodophenyl)-1H-indole-1-yl)-2-methylpropane-2-ene-1-one compound, aromatic amine and chloroform in an organic solvent in an argon atmosphere under the action of a catalyst and alkali to obtain the amide-containing indolo [2, 1-a] isoquinoline compound. The invention relates to a 1, 1-a] isoquinoline compound. The reaction operation is simple and convenient, the product specificity is high, the substrate application range is wide, and the reaction substrate is rich in source and low in price. The invention provides a simple and efficient preparation method of the amide-containing indolo [2, 1-a] isoquinoline compound for the first time.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing an amide-containing indole[2,1-a]isoquinoline compound. Technical Background

[0002] Indolo[2,1-a]isoquinoline is a special alkaloid, a cyclic compound containing two units of indole structure and isoquinoline structure. Because of its unique chemical structure, it has special biological activity and is also the core skeleton of many natural compounds. This structure is generally widely found in functional materials, medicines and some natural products. It is an important class of nitrogen-containing fused heterocyclic compounds in organic chemistry. In particular, indolo[2,1-a]isoquinoline containing a tetracyclic system has a wide range of pharmaceutical activities, such as microtubule polymerization inhibitors, melatonin antagonists, estrogen receptor nucleophilic cell inhibitors, etc. In addition, the amide group is a functional group in many organic compounds, and it has very important chemical properties in many aspects. First, the amide group can act as a good reaction intermediate and participate in many organic chemical reactions. It can be affected by chemical reactions such as oxidation, nitration and reduction, so that the properties of the compound are changed. Although achievements have been made in the preparation of indolo[2,1-a]isoquinoline derivatives, there are still few reports on the installation of amide groups, so it is still a challenge to introduce amide groups into the indolo[2,1-a]isoquinoline alkaloid skeleton. The present invention provides a simple and efficient preparation method of amide-containing indolo[2,1-a]isoquinoline compounds. Summary of the invention

[0003] The main purpose of the present invention is to efficiently and conveniently synthesize amide-containing indolo[2,1-a]isoquinoline compounds through a one-pot cascade reaction. The method has the characteristics of high product specificity, a wide range of substrate applicability, abundant reaction substrates and low price. Amide-containing indolo[2,1-a]isoquinoline compounds containing different substituent groups can be obtained through the method.

[0004] The technical solution of the method of the present invention is as follows:

[0005] A method for synthesizing a polycyclic condensed amide-containing indole[2,1-a]isoquinoline compound, wherein a 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one compound (1), an aromatic amine (2) and chloroform are reacted in an organic solvent under an argon atmosphere in the presence of a catalyst and a base, and the reaction is carried out at 100° C. for 24 hours to obtain a plurality of amide-containing indole[2,1-a]isoquinoline compounds (3), wherein the reaction formula is as follows:

[0006]

[0007] In the above reaction equation: R 1 For various halogens and alkyl groups, R 2 is phenyl and benzyl, R 3 The method of the present invention has good adaptability to the type and position of the functional group.

[0008] The above-mentioned halogen refers to fluorine, chlorine and bromine atoms.

[0009] The catalyst used in the method of the present invention is palladium chloride (PdCl2), which can be a commercial reagent and does not require special treatment; the dosage is preferably 10% equivalent based on the 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one.

[0010] The carbonyl source used in the method of the present invention is chloroform (CHCl3), which can be a commercial reagent and does not require special treatment; the amount used is preferably 3.0 equivalents based on the 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one.

[0011] The base used in the method of the present invention is cesium hydroxide monohydrate (CsOH·H2O), which can be a commercial reagent and does not require special treatment; the amount used is preferably 10.0 equivalents based on the 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one.

[0012] The organic solvent used in the method of the present invention is preferably toluene. The amount of the organic solvent used is measured at 10 ml of organic solvent per mmol of 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one (1).

[0013] The preferred molar ratio of the two reactants in the method of the present invention is 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one compound: aromatic amine=1:2.

[0014] The reaction temperature of the above reaction is 100° C. and the reaction time is 24 hours. The heating process can be carried out by using an oil bath (such as silicone oil, paraffin oil, etc.) or other heating methods.

[0015] The method of the present invention realizes, for the first time, the one-pot synthesis of amide-containing indole [2,1-a] isoquinoline compounds using chloroform (CHCl3) as a carbonyl source and aromatic amines as a nitrogen source catalyzed by transition metal palladium. The method has the advantages of high reaction efficiency, good economy, and a wide range of substrate applications, and can be widely used in the preparation of various amide-containing indole [2,1-a] isoquinoline compounds. Specifically, the present invention has the following advantages:

[0016] 1. The various amide-containing indole[2,1-a]isoquinoline compounds prepared by the present invention have potential application value in the fields of organic synthesis, new drug and new material research and development;

[0017] 2. The synthesis process of the present invention has fewer by-products and high atom economy;

[0018] 3. The present invention has the characteristics of simple operation and good specificity;

[0019] 4. The raw materials involved in the method of the present invention are simple and easy to obtain;

[0020] 5. The carbonyl source used in the present invention is abundant and inexpensive.

[0021] 6. The present invention can directly obtain a polycyclic condensed amide-containing indole[2,1-a]isoquinoline compound. DETAILED DESCRIPTION

[0022] The present invention is further described below in conjunction with embodiments, but the scope of implementation of the present invention is not limited in any way.

[0023] Example 1

[0024] Synthesis of N-(4-chlorophenyl)-2-(5-methyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)acetamide

[0025] 38.7 mg (ie 0.1 mmol) of 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one, 25.5 mg (ie 0.2 mmol) of 4-chloroaniline, 35.8 mg (ie 0.3 mmol) of chloroform, 1.8 mg (ie 0.01 mmol) of palladium chloride, and 168 mg (ie 1 mmol) of cesium hydroxide monohydrate were added to a 10 mL glass reaction tube in sequence, and 1.0 mL of toluene was added, and argon was replaced three times. The mixture was stirred at 100 ° C. for 24 hours, concentrated after the reaction, and purified by silica gel column chromatography using petroleum ether: ethyl acetate in a volume ratio of 3:1 as the eluent to obtain N-(4-chlorophenyl)-2-(5-methyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)acetamide, whose structure is shown in the following formula:

[0026]

[0027] The compound is a yellow solid with a yield of 48%. Its NMR data are as follows:

[0028] 1H NMR(600MHz,Chloroform-d)δ8.59(d,J=8.1Hz,1H),7.83(d,J=7.7Hz,1H),7.61(s,1H),7.58(d,J=7.7Hz,1H),7.36(t,J=7.7Hz,1H),7.31(t,J=7.4Hz, 2H),7.28-7.24(m,1H),7.17(d,J=7.9Hz,1H),7.02(d,J=8.5Hz,3H),6.96(d ,J=8.5Hz,2H),3.60(d,J=16.1Hz,1H),2.95(d,J=16.1Hz,1H),1.50(s,3H). 13 C NMR(151MHz,Chloroform-d)δ173.1,167.9,137.8,135.9,135.5,130.8,129.0,128.9,128.7,12 7.4,125.2,125.0,124.6,124.2,120.9,120.6,116.6,103.4,77.3,77.1,76.8,46.6,46.2,30.4.

[0029] Example 2

[0030] Synthesis of N-(4-ethylphenyl)-2-(5-methyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)acetamide

[0031] 38.7 mg (ie 0.1 mmol) of 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one, 24.2 mg (ie 0.2 mmol) of 4-ethylaniline, 35.8 mg (ie 0.3 mmol) of chloroform, 1.8 mg (ie 0.01 mmol) of palladium chloride, and 168 mg (ie 1 mmol) of cesium hydroxide monohydrate were added to a 10 mL glass reaction tube in sequence, and 1.0 mL of toluene was added, and argon was replaced three times. The mixture was stirred at 100 ° C. for 24 hours, concentrated after the reaction, and purified by silica gel column chromatography using petroleum ether: ethyl acetate in a volume ratio of 3:1 as the eluent to obtain N-(4-ethylphenyl)-2-(5-methyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)acetamide, whose structure is shown in the following formula:

[0032]

[0033] The compound is a brown solid with a yield of 73%. Its NMR data are as follows:

[0034] 1H NMR(600MHz,Chloroform-d)δ8.59(d,J=8.1Hz,1H),7.81(d,J=7.5Hz,1H),7.5 6(d,J=7.7Hz,1H),7.50(s,1H),7.34(t,J=7.7Hz,1H),7.30-7.24(m,4H),7.04( d,J=8.1Hz,2H),6.99(s,1H),6.87(d,J=8.0Hz,2H),3.64(d,J=15.9Hz,1H),3. 00(d,J=15.9Hz,1H),2.46(q,J=7.7Hz,2H),1.52(s,3H),1.09(t,J=7.7Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ173.1,167.5,140.1,138.0,135.6,135.1,130.8,128.8,128.0,127.3,125. 2,125.1,124.6,124.4,124.2,120.5,120.0,116.7,103.2,77.3,77.1,76.8,46.7,46.4,30.4,28.2,15.6.

[0035] Example 3

[0036] Synthesis of N-(4-(tert-butyl)phenyl)-2-(5-methyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)acetamide

[0037] 38.7 mg (ie 0.1 mmol) of 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one, 29.8 mg (ie 0.2 mmol) of 4-(tert-butyl)aniline, 35.8 mg (ie 0.3 mmol) of chloroform, 1.8 mg (ie 0.01 mmol) of palladium chloride, and 168 mg (ie 1 mmol) of cesium hydroxide monohydrate were added to a 10 mL glass reaction tube in sequence, and 1.0 mL of toluene was added, and argon was replaced three times. The mixture was stirred at 100° C. for 24 hours, concentrated after the reaction, and purified by silica gel column chromatography using petroleum ether: ethyl acetate in a volume ratio of 3:1 as the eluent to obtain N-(4-(tert-butyl)phenyl)-2-(5-methyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)acetamide, the structure of which is shown in the following formula:

[0038]

[0039] The compound is a yellow solid with a yield of 65%. Its NMR data are as follows:

[0040] 1 H NMR (600MHz, DMSO-d6) δ9.94(s,1H),8.47(d,J=7.8Hz,1H),8.04(d,J=7.9Hz,1H),7.68(d,J=7.8Hz,1H),7.56(d,J=7.8Hz,1H),7.38(d,J=6.3Hz,2H) ,7.34(m,J=17.0,7.3Hz,3H),7.22(d,J=8.9Hz,2H),7.15(d,J=9.0Hz,2H) ,3.62(d,J=16.5Hz,1H),3.42(d,J=16.5Hz,1H),1.55(s,3H),1.16(s,9H). 13 C NMR(151MHz,DMSO-d6)δ173.4,168.4,145.9,139.0,136.5,136.2,135.3,130.9,129.3,127.5,126.1,125.6,125.1,12 4.7,124.5,124.5,121.1,119.2,116.5,103.1,46.5,46.2,40.4,40.3,40.1,40.0,39.9,39.7,39.6,34.3,31.6,30.4.

[0041] Example 4

[0042] Synthesis of N-(4-fluoro-3-methylphenyl)-2-(5-methyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)acetamide

[0043] 38.7 mg (ie 0.1 mmol) of 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one, 34.4 mg (ie 0.2 mmol) of 4-fluoro-3-methylaniline, 35.8 mg (ie 0.3 mmol) of chloroform, 1.8 mg (ie 0.01 mmol) of palladium chloride, and 168 mg (ie 1 mmol) of cesium hydroxide monohydrate were added to a 10 mL glass reaction tube in sequence, and 1.0 mL of toluene was added, and argon was replaced three times. The mixture was stirred at 100 ° C. for 24 hours, concentrated after the reaction, and purified by silica gel column chromatography using petroleum ether: ethyl acetate in a volume ratio of 3:1 as the eluent to obtain N-(4-fluoro-3-methylphenyl)-2-(5-methyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)acetamide, whose structure is shown in the following formula:

[0044]

[0045] The compound is a brown solid with a yield of 51%. Its NMR data are as follows:

[0046] 1 H NMR(600MHz,DMSO-d6)δ10.00(s,1H),8.47(d,J=7.7Hz,1H),8.04(d,J=8.7Hz ,1H),7.68(d,J=6.8Hz,1H),7.56(d,J=7.7Hz,1H),7.38(m,J=8.1Hz,3H),7.34 (m,J=6.6Hz,2H),7.28(d,J=4.4Hz,1H),7.09-7.06(m,1H),6.92(t,J=9.2Hz, 1H),3.62(d,J=16.7Hz,1H),3.42(d,J=16.7Hz,1H),2.07(s,3H),1.55(s,3H). 13 C NMR(151MHz,DMSO-d6)δ173.4,168.4,156.9(d,J C-F =234.0Hz),139.0,136.2,135.3,135.1,130.9,129.3,127.5,126.1,125.2,124.7,124.6,124.5(d,J C-F =3.6Hz),122.2,121.1,118.5(d,J C-F =7.6Hz),116.5,115.2(d,J C-F =23.0Hz),103.1,46.2,40.4,40.3,40.2,40.0,39.9,39.7,39.6,30.4,14.6. 19 F NMR(565MHz,DMSO-d6)δ-123.86.

[0047] Example 5

[0048] Synthesis of 2-(10-fluoro-5-methyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)-N-phenylacetamide

[0049] 38.7 mg (ie 0.1 mmol) of 1-(5-fluoro-2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one, 18.6 mg (ie 0.2 mmol) of aniline, 35.8 mg (ie 0.3 mmol) of chloroform, 1.8 mg (ie 0.01 mmol) of palladium chloride, and 168 mg (ie 1 mmol) of cesium hydroxide monohydrate were added to a 10 mL glass reaction tube in sequence, and 1.0 mL of toluene was added, and argon was replaced three times. The mixture was stirred at 100 ° C. for 24 hours, concentrated after the reaction, and purified by silica gel column chromatography using petroleum ether: ethyl acetate in a volume ratio of 3:1 as the eluent to obtain 2-(10-fluoro-5-methyl-6-oxo-5,6-dihydroindole [2,1-a] isoquinolin-5-yl)-N-phenylacetamide, whose structure is shown in the following formula:

[0050]

[0051] The compound is a yellow solid with a yield of 50%. Its NMR data are as follows:

[0052] 1 H NMR (600MHz, DMSO-d6) δ10.00(s,1H),8.45(q,J=9.0,4.8Hz,1H),8.05(d,J=7.8Hz ,1H),7.58(d,J=7.9Hz,1H),7.49(d,J=9.1Hz,1H),7.41(t,J=7.5Hz,1H),7.37(t, J=6.0Hz,2H),7.30(d,J=8.1Hz,2H),7.19(t,J=9.2Hz,1H),7.14(t,J=7.8Hz,2H), 6.93(t,J=7.4Hz,1H),3.62(d,J=16.6Hz,1H),3.45(d,J=16.6Hz,1H),1.56(s,3H). 13 C NMR(151MHz,DMSO-d6)δ173.3,168.6,159.9(d,J C-F =238.4Hz),139.3,139.0,138.0,132.2,132.1,131.8,129.7,129.0,12 7.6,126.2,124.7,124.2,123.6,119.4,119.3,117.7,117.6,112.5(d,J C-F =25.0Hz),106.6(d,J C-F =23.9Hz),102.8(d,J C-F=3.8Hz),46.6,46.1,40.5,40.3,40.2,40.0,39.9,39.8,39.6,30.2. 19 F NMR(565MHz,DMSO-d6)δ-118.30.

[0053] Example 6

[0054] Synthesis of N-phenyl-2-(5,9,11-trimethyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)acetamide

[0055] To a 10 mL glass reaction tube, 41.5 mg (ie, 0.1 mmol) of 1-(2-(2-iodophenyl)-5,6-dimethyl-1H-indol-1-yl)-2-methylprop-2-en-1-one, 18.6 mg (ie, 0.2 mmol) of aniline, 35.8 mg (ie, 0.3 mmol) of chloroform, 1.8 mg (ie, 0.01 mmol) of palladium chloride, and 168 mg (ie, 1 mmol) of cesium hydroxide monohydrate were added in sequence, and 1.0 mL of toluene was added. The argon gas was replaced three times, and the mixture was stirred at 100° C. for 24 hours. After the reaction, the mixture was concentrated, and the mixture was eluted with petroleum ether:ethyl acetate in a volume ratio of 3:1. The mixture was purified by silica gel column chromatography to obtain N-phenyl-2-(5,9,11-trimethyl-6-oxo-5,6-dihydroindole[2,1-a]isoquinolin-5-yl)acetamide, the structure of which is shown in the following formula:

[0056]

[0057] The compound is a white solid with a yield of 60%. Its NMR data are as follows:

[0058] 1 H NMR (600MHz, DMSO-d6) δ10.01(s,1H),8.14(s,1H),8.04(d,J=7.1Hz,1H),7.54(d,J=7.2Hz,1H),7.41(s,1H),7.37-7.29(m,4H) ,7.14(s,2H),6.98(s,1H),6.93(s,1H),3.61(d,J=16.5Hz,1H),3.42(d,J=16.4Hz,1H),2.52(s,3H),2.41(s,3H),1.53(s,3H). 13CNMR(151MHz,DMSO-d6)δ173.4,168.6,139.1,138.7,135.4,135.0,134.7,129.7,129.0,128.9,128.2,127.5,126.4,126.0,124.9,124.2,123.5,119.3,114.3,101.9,46.5,46.1,40.4,40.3,40.1,40.0,39.8,39.7,39.6,30.4,22.1,18.6。

Claims

1. A method for synthesizing a polycyclic condensed amide-containing indole [2,1-a] isoquinoline compound, comprising reacting a 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-ene-1-one compound shown in Formula 1 and an aminoaromatic hydrocarbon shown in Formula 2 in toluene in an argon atmosphere in the presence of a catalyst and a base to obtain an amide-containing indole [2,1-a] isoquinoline compound shown in Formula 3: in, R 1 For various halogens and alkyl groups, R 2 is phenyl and benzyl, R 3 It is various halogens and alkyls.

2. The preparation method according to claim 1, characterized in that The catalyst is palladium chloride.

3. The preparation method according to claim 1, characterized in that: The amount of palladium chloride used is preferably 10% equivalent to 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one.

4. The preparation method according to claim 1, characterized in that: The amount of chloroform used is preferably 3.0 equivalents based on 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one.

5. The preparation method according to claim 1, characterized in that: The base is cesium hydroxide monohydrate.

6. The preparation method according to claim 1, characterized in that: The amount of cesium hydroxide monohydrate used is preferably 10 equivalents of 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one.

7. The preparation method according to claim 1, characterized in that: The molar ratio of the reactants is 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one compound: aromatic amine=1:

2.

8. The preparation method according to claim 1, characterized in that: The organic solvent is toluene, and the amount used is 10 ml per mmol of 1-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one.

9. The preparation method according to claim 1, characterized in that: The reaction temperature was 100°C and the reaction time was 24 hours.

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