CN114057694B - Preparation method of 7-maleimide indole compound - Google Patents
Preparation method of 7-maleimide indole compound Download PDFInfo
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Abstract
The invention discloses a preparation method of a 7-maleimide indole compound, which comprises the following steps: in HFIP solvent with [ RhCp Cl ] 2 ] 2 And Cu (OTf) 2 Is used as catalyst, sodium carbonate as additive, and indolesThe compound and maleimide compound are taken as substrates to synthesize the 7-maleimide indole compound under the heating condition. The invention has cheap and easily obtained reaction raw materials, simple preparation method and simple operation. The method can be used for synthesizing a series of 7-maleimide indole compounds, and the synthesized product can be used as an intermediate compound for further constructing complex active compounds; meanwhile, the compounds have great medicinal activity potential.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a 7-maleimide indole compound by rhodium catalysis.
Background
Maleimides have a very important role in pharmaceutical chemistry, biochemistry and synthetic chemistry. Maleimide derivatives are widely found in natural products and clinical drug candidates. Due to the important biological activity of maleimide derivatives, the synthesis of the compounds attracts extensive research of synthetic chemists. Transition metal catalyzed inert carbon-hydrogen bond functionalization is considered to be one of the most effective strategies for directly building new carbon-carbon bonds. Therefore, methods for constructing maleimide derivatives by transition metal-catalyzed hydrocarbon activation have been widely explored. In recent years, several methods of direct coupling of (hetero) aromatic rings and maleimides catalyzed by targeting groups to transition metals have been reported. Because the reaction intermediate does not have beta hydrogen on the syn side, the beta hydrogen can not be eliminated. Therefore, most of such reactions produce succinimide derivatives through the 1, 4-addition pathway. Few reports have been made of the formation of maleimide derivatives via the oxidative Heck-type pathway.
Indole nuclei are widely distributed among natural products, pharmaceutically active molecules and functional materials, and are considered to be one of the best nuclei for designing biologically active molecules and drug molecules. Therefore, the synthesis of substituted indoles is a research hotspot in the field of organic chemistry. Currently, several groups have developed site-directed, transition metal catalyzed direct coupling of indoles and maleimides, respectively. The method synthesizes 2-succinimide indole through indole carbon bi-hydrogen aromatization. Recently, the Liu research group first reported a method for synthesizing 2-maleimide indole by rhodium-catalyzed double-site olefination of indole carbon. Functionalization directly at the indole phenyl ring moiety remains very challenging in modern organic synthesis due to the lower reactivity of the phenyl ring moiety than the pyrrole ring moiety. In 2018, a Prabhu research group reports a coupling reaction of four carbon positions of maleimide and indole, wherein rhodium is used as a catalyst, and trifluoroacetyl is used as a positioning group. The method can realize selective synthesis of 4-maleimide indole and 4-succinimide indole by changing additives. Subsequently, the Ravikumar research group developed a cobalt-catalyzed olefination of the maleimide and indole carbon four-positions. 7-substituted indoles are widely distributed as parent nuclei in natural products and biologically active compounds. Therefore, a method for synthesizing 7-substituted indole compounds by direct regioselective functionalization of seven positions of indole carbon has been studied in a large amount. The greatest challenge of this method is the existence of more reactive carbon two-and three-position competing reactions. In 2010, the Hartwig research group first reported iridium-catalyzed regioselective boronation of the seven-position indole carbon, a method that controlled the regioselectivity of the reaction via a diethyl silicon group. Subsequently, different groups developed methods for direct olefination, aromatization, sulfonylamination, alkylation, acylation and alkynylation of the seven-position indole carbon using different transition metal catalysts (e.g., ruthenium, rhodium, iridium, palladium) and directing groups. However, no method for synthesizing 7-maleimide indole by directly coupling seven positions of maleimide and indole carbon exists at present. Therefore, it is very important and urgent to develop a method for directly coupling the seven-position indole carbon and maleimide with regioselectivity. The establishment of the method has important significance and value in synthetic chemistry; meanwhile, the comprehensive research on the biological activity of the 7-maleimide indole compound is further promoted, and a new medicinal active compound is discovered.
Disclosure of Invention
The invention provides a new compound expressed by [ RhCp Cl 2 ] 2 And Cu (OTf) 2 Is used as a catalyst, sodium carbonate is used as an additive, and indole and maleimide are used as raw materials to regioselectively synthesize 7-maleimide indoleThe raw materials of the method are easy to obtain, and the preparation method is simple.
A preparation method of a 7-maleimide indole compound comprises the following steps: in a solvent with [ RhCp Cl ] 2 ] 2 And Cu (OTf) 2 The catalyst is sodium carbonate as an additive, indole and maleimide react, and the 7-maleimide indole is obtained by post-treatment after the reaction is finished;
the structure of the 7-maleimide indole compound is shown in any one of formulas (I) to (VI):
in the formula (I), R 1 Is hydrogen, C 1 ～C 4 Alkyl radical, C 1 ～C 4 Alkoxy or halogen, R 2 Is C 1 ～C 6 Alkyl, phenyl or benzyl.
The structure of the indole compound is shown in any one of formulas (VII) to (IX):
in the formula (VII), R 1 Is hydrogen, C 1 ～C 4 Alkyl radical, C 1 ～C 4 Alkoxy or halogen;
the maleimide compound has a structure represented by any one of chemical formulas (X) to (XIII):
in the formula (X), R 2 Is C 1 ～C 6 Alkyl, phenyl or benzyl.
Preferably, one of said catalysts is [ RhCp Cl ] 2 ] 2 Other types of catalysts, including other ruthenium catalysts, rhodium catalysts and iridium catalysts, all produce the reactionReduced rate or no product formation; the other is Cu (OTf) 2 Other types of catalysts, including other copper catalysts and silver catalysts, result in reduced reaction yields or no product formation.
The additive is sodium carbonate, and other additives including acid, oxide and salt can reduce the reaction yield or generate no product.
Preferably, the molar ratio of the indole compound to the maleimide compound is 1. Reducing the amount of maleimide results in a reduction in the reaction yield.
Preferably, said indole is complexed with said catalyst [ RhCp Cl 2 ] 2 ，Cu(OTf) 2 Additive sodium carbonate in a molar ratio of 1.05. Reducing the amount of catalyst and additives reduces the reaction yield.
Preferably, the reaction solvent is HFIP (hexafluoroisopropanol), and other types of solvents, including other polar and non-polar solvents, result in reduced reaction yields or no product formation.
In the invention, the reaction temperature is 115-125 ℃, the reaction temperature is preferably 120 ℃, and the reaction time is 4-24 h.
The reaction equation of the synthesis is as follows:
preferably, R 1 Is hydrogen, methyl, methoxy, fluorine or chlorine; r 2 Is methyl, ethyl, tert-butyl, cyclohexyl, phenyl or benzyl.
The possible principle of the synthesis reaction is as follows: [ RhCp Cl ] 2 ] 2 Reacting with sodium carbonate and copper trifluoromethanesulfonate to generate active cations; the active cation and the indoxyl pivoxyl are coordinated and activated by a carbon-hydrogen bond to generate a six-membered ring intermediate containing rhodium; inserting maleimide into a carbon-rhodium bond of the rhodium-containing six-membered ring intermediate to generate a bicyclic intermediate; deprotonation of the bicyclic intermediate by carbonate to give the final productThe compound 7-maleimidoindole, with the trivalent rhodium being reduced to monovalent rhodium; copper trifluoromethanesulfonate or air oxidized monovalence rhodium is used as a trivalent rhodium reagent for circular catalysis.
Compared with the prior art, the invention has the following advantages:
the method takes indole and maleimide as raw materials, and synthesizes the 7-maleimide indole compound through direct regioselective indole carbon hepta-alkylene. The reaction raw materials are cheap and easy to obtain, and the preparation method is simple; with [ RhCp Cl ] 2 ] 2 And Cu (OTf) 2 Is used as a catalyst, sodium carbonate is used as an additive, and the reagent is easy to obtain. The reaction is carried out in an air atmosphere, so the operation is simple. The method can be applied to synthesizing different 7-maleimide indole compounds.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited thereto.
Example 1
At room temperature, N-pivaloyl indole (0.2 mmol), N-ethylmaleimide (0.8 mmol) and [ RhCp. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol), and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (10% ethyl acetate in petroleum ether) to give 45.4mg of the product in 70% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(600MHz,CDCl 3 )δ7.71(d,J＝3.7Hz,1H),7.66(d,J＝7.2Hz,1H),7.30-7.27(m,2H),6.65(d,J＝3.7Hz,1H),6.47(s,1H),3.59(q,J＝7.2Hz,2H),1.48(s,9H),1.23(t,J＝7.2Hz,3H)ppm； 13 C NMR(151MHz,CDCl 3 )δ178.78,171.26,170.53,149.65,133.36,131.45,127.28,126.58,123.47,123.34,120.97,117.76,107.51,41.28,32.73,28.50,14.04ppm.
example 2
At room temperature, N-pivaloyl indole (0.2 mmol), N-ethylmaleimide (0.8 mmol) and [ Ru (cymene) Cl were added to a 4mL reaction flask 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol), and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, substantially no product was formed and the reaction proceeded as shown in the following formula:
example 3
N-pivaloyl indole (0.2 mmol), N-ethylmaleimide (0.8 mmol) and [ RhCp Cl ] were added to a 4mL reaction flask at room temperature 2 ] 2 (0.01mmol)、Cu(OAc) 2 (0.01 mmol), sodium carbonate (0.4 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (10% ethyl acetate in petroleum ether) to give 30.5mg of the product in 47% yield, which was obtained as shown in the following formula:
example 4
At room temperature, N-pivaloyl indole (0.2 mmol), N-ethylmaleimide (0.8 mmol) and [ RhCp. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.01mmol)、AgSbF 6 (0.04 mmol), sodium carbonate (0.4 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped.Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (10% ethyl acetate in petroleum ether) to give 27.9mg of the product in 43% yield, which was reacted as shown in the following formula:
example 5
At room temperature, N-pivaloyl indole (0.2 mmol), N-ethylmaleimide (0.8 mmol) and [ RhCp. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.4 mmol) and TFE (trifluoroethanol) (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, substantially no product was formed and the reaction proceeded as shown in the following formula:
example 6
At room temperature, N-pivaloyl-3-methylindole (0.2 mmol), N-ethylmaleimide (0.8 mmol) and [ RhCp. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (15% ethyl acetate in petroleum ether) to give 55.5mg of the product in 82% yield, which was obtained by the following reaction:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(600MHz,CDCl 3 )δ7.59(d,J＝7.6,1.3Hz,1H),7.47(d,J＝1.0Hz,1H),7.31(t,J＝7.5Hz,1H),7.27(d,J＝1.1Hz,1H),6.45(s,1H),3.58(q,J＝7.2Hz,2H),2.31(d,J＝1.1Hz,3H),1.46(s,9H),1.22(t,J＝7.2Hz,3H)ppm； 13 C NMR(151MHz,CDCl 3 )δ178.35,171.30,170.42,149.76,133.77,132.33,127.27,123.54,123.18,121.20,120.67,117.78,116.40,41.10,32.67,28.44,14.02,9.64ppm.
example 7
N-pivaloyl-4-methoxyindole (0.2 mmol), N-ethylmaleimide (0.8 mmol) and [ RhCp Cl ] were added to a 4mL reaction flask at room temperature 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 4 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (10% ethyl acetate in petroleum ether) to give 56.7mg of the product in 80% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝3.8Hz,1H),7.23(d,J＝8.2Hz,1H),6.76(d,J＝3.8Hz,1H),6.71(d,J＝8.3Hz,1H),6.38(s,1H),3.96(s,3H),3.57(q,J＝7.2Hz,2H),1.47(s,9H),1.22(t,J＝7.2Hz,3H)ppm； 13 C NMR(101MHz,CDCl 3 )δ179.05,171.46,170.72,154.99,149.54,134.56,128.92,124.99,121.62,119.44,111.00,104.33,103.66,55.57,41.30,32.63,28.47,14.06ppm.
example 8
At room temperature, N-pivaloyl-4-chloroindole (0.2 mmol), N-ethylmaleimide (0.8 mmol) and [ RhCp. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.016mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol), and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (10% ethyl acetate in petroleum ether) to give 35.8mg of a product in 50% yield, which was as follows:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(400MHz,CDCl 3 )δ7.75(d,J＝3.8Hz,1H),7.30(d,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H),6.80(d,J＝3.8Hz,1H),6.47(s,1H),3.58(q,J＝7.2Hz,2H),1.48(s,9H),1.22(t,J＝7.2Hz,3H)ppm； 13 C NMR(101MHz,CDCl 3 )δ178.84,170.98,170.37,148.72,133.87,130.11,128.95,127.89,127.10,123.20,121.30,116.40,105.66,41.39,32.79,28.42,14.04ppm.
example 9
At room temperature, N-pivaloyl-5-fluoroindole (0.2 mmol), N-ethylmaleimide (0.8 mmol) and [ RhCp. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.016mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (10% ethyl acetate in petroleum ether) to give 41.1mg of the product in 60% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(400MHz,CDCl 3 )δ7.75(d,J＝3.8Hz,1H),7.32(dd,J＝8.0,2.5Hz,1H),7.02(dd,J＝9.4,2.5Hz,1H),6.62(d,J＝3.8Hz,1H),6.48(s,1H),3.58(q,J＝7.2Hz,2H),1.47(s,9H),1.23(t,J＝7.2Hz,3H)ppm； 13 C NMR(101MHz,CDCl 3 )δ178.51,170.81,170.11,158.90(d,J＝241.5Hz),148.48,132.65(d,J＝10.0Hz),129.91,128.11,121.83,118.70(d,J＝9.0Hz),114.72(d,J＝26.3Hz),108.55(d,J＝23.0Hz),107.36(d,J＝4.0Hz),41.24,32.83,28.48,14.00ppm； 19 F NMR(376MHz,CDCl3)δ-120.09ppm.
example 10
At room temperature, N-pivaloyl-6-methoxyindole (0.2 mmol), N-ethylmaleimide (0.8 mmol) and [ RhCp Cl ] were added to a 4mL reaction flask 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol), and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (15% ethyl acetate in petroleum ether) to give 44.6mg of the product in 63% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(600MHz,CDCl 3 )δ7.57-7.55(m,2H),6.98(d,J＝8.6Hz,1H),6.55(d,J＝3.7Hz,1H),6.52(s,1H),3.85(s,3H),3.61(q,J＝18.9,7.2Hz,2H),1.43(s,9H),1.24(t,J＝7.2Hz,3H)ppm； 13 C NMR(151MHz,CDCl 3 )δ178.23,171.79,170.94,155.91,142.88,135.03,125.69,125.66,125.25,123.07,108.43,107.16,106.15,56.79,41.21,32.71,28.49,13.98ppm.
example 11
At room temperature, N-pivaloyl indole (0.2 mmol), N-tert-butylmaleimide (0.8 mmol) and [ RhCp. Multidot. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.016mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (5% ethyl acetate in petroleum ether) to give 45.8mg of the product in 65% yield, which was reacted as follows:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(600MHz,CDCl 3 )δ7.73(d,J＝3.8Hz,1H),7.64(d,J＝7.7Hz,1H),7.28(t,J＝7.6Hz,1H),7.23(d,J＝6.8Hz,1H),6.65(d,J＝3.8Hz,1H),6.34(s,1H),1.61(s,9H),1.50(s,9H)ppm； 13 C NMR(101MHz,CDCl 3 )δ178.00,172.82,171.64,149.05,133.54,131.37,127.45,126.57,123.47,123.01,120.96,118.18,107.65,57.14,41.16,29.05,28.54ppm.
example 12
At room temperature, N-pivaloyl indole (0.2 mmol), N-cyclohexylmaleimide (0.8 mmol) and [ RhCp. Multidot. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.016mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (10% ethyl acetate in petroleum ether) to give 46.1mg of the product in 61% yield, which was obtained by the following reaction:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 )δ7.73(d,J＝3.6Hz,1H),7.67(d,J＝7.3Hz,1H),7.32-7.28(m,2H),6.67(d,J＝3.7Hz,1H),6.43(s,1H),3.96–3.90(m,1H),2.14–2.05(m,2H),1.85(d,J＝12.6Hz,2H),1.74–1.60(m,3H),1.49(s,9H),1.35–1.22(m,3H)ppm； 13 C NMR(101MHz,CDCl 3 )δ178.69,171.66,170.76,149.36,133.57,131.57,127.50,126.73,123.61,123.36,121.05,118.10,107.67,50.82,41.40,30.27,28.66,26.18,25.28ppm.
example 13
At room temperature, N-pivaloyl indole (0.2 mmol), N-phenylmaleimide (0.8 mmol) and [ RhCp. Multidot. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.016mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol), and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (10% ethyl acetate in petroleum ether) to give 37.2mg of the product in 50% yield, which was obtained by the following reaction:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(400MHz,CDCl 3 )δ7.72–7.69(m,2H),7.49–7.45(t,J＝7.5Hz,2H),7.38–7.34(m,5H),6.67(d,J＝3.8Hz,1H),6.63(s,1H),1.42(s,9H)ppm； 13 C NMR(101MHz,CDCl 3 )δ178.92,170.26,169.35,149.78,133.40,131.79,131.48,129.04,127.81,127.36,126.63,123.57,123.55,120.96,117.51,107.59,41.26,28.48ppm.
example 14
At room temperature, N-pivaloyl indole (0.2 mmol), N-benzyl maleimide (0.8 mmol) and [ RhCp. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (10% ethyl acetate in petroleum ether) to give the product 48.7mg in 63% yield, which was obtained by the following reaction:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(600MHz,CDCl 3 )δ7.70(d,J＝3.8Hz,1H),7.66(dd,J＝7.5,1.4Hz,1H),7.38(d,J＝7.4Hz,2H),7.31–7.23(m,5H),6.65(d,J＝3.8Hz,1H),6.51(s,1H),4.69(s,2H),1.36(s,9H)ppm； 13 C NMR(151MHz,CDCl 3 )δ178.65,171.01,170.35,149.78,136.42,133.38,131.45,128.55,128.21,127.56,127.34,126.64,123.49,123.40,120.87,117.70,107.56,41.37,41.16,28.41ppm.
example 15
At room temperature, N-pivaloyl tryptol (0.2 mmol), N-benzyl maleimide (0.8 mmol) and [ RhCp. Multidot. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (15% ethyl acetate in petroleum ether) to give 62.4mg of product in 69% yield, which was obtained by the following reaction:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(600MHz,CDCl 3 )δ7.67(d,J＝7.6Hz,1H),7.55(s,1H),7.33–7.27(m,2H),6.46(s,1H),4.39(t,J＝6.8Hz,2H),3.58(q,J＝7.2Hz,2H),3.07(t,J＝6.8Hz,2H),1.46(s,9H),1.22(t,J＝7.2Hz,3H),1.19(s,9H)ppm； 13 C NMR(151MHz,CDCl 3 )δ178.53,178.47,171.20,170.44,149.58,133.74,131.36,127.53,123.92,123.33,121.19,120.91,117.91,116.87,63.20,41.17,38.70,32.71,28.44,27.16,24.50,14.02ppm
example 16
At room temperature, N-pivaloyl tryptamine (0.2 mmol), N-benzyl maleimide (0.8 mmol) and [ RhCp. Multidot. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol), and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (15% ethyl acetate in petroleum ether) to give 55.1mg of the product in 61% yield, which was reacted as shown in the following formula:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(600MHz,CDCl 3 )δ7.66(d,J＝7.6Hz,1H),7.54(s,1H),7.31–7.27(m,2H),6.44(s,1H),5.84(brs,1H),3.61–3.55(m,4H),2.94(t,J＝6.9Hz,2H),1.45(s,9H),1.21(t,J＝7.2Hz,3H),1.16(s,9H)ppm； 13 C NMR(151MHz,CDCl 3 )δ178.60,178.52,171.17,170.43,149.54,133.87,131.32,127.53,123.81,123.34,121.23,120.89,117.93,117.80,41.15,39.00,38.62,32.69,28.40,27.52,25.22,14.00ppm.
example 17
At room temperature, N-pivaloyl indole (0.2 mmol), N-carbomethoxymaleimide (0.8 mmol) and [ RhCp. Multidot. Cl ] were added to a 4mL reaction flask 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (30% ethyl acetate in petroleum ether) to give 49.7mg of the product in 65% yield, which was reacted as follows:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(400MHz,CDCl 3 )δ7.65(d,J＝3.8Hz,1H),7.61(dd,J＝7.3,1.6Hz,1H),7.24-7.20(m,2H),6.60(d,J＝3.8Hz,1H),6.42(s,1H),3.80-3.77(t,7.5Hz,2H),3.63(s,3H),2.63-2.59(t,7.7Hz,2H),1.41(s,9H)ppm； 13 C NMR(101MHz,CDCl 3 )δ171.83,164.21,163.84,163.21,142.76,126.22,124.42,120.27,119.59,116.50,116.47,113.90,110.45,100.57,44.84,34.25,26.43,25.81,21.47ppm.
example 18
N-pivaloyl indole (0.2 mmol), N-glycolylmaleimide (0.8 mmol) and [ RhCp. Cl ] were added to a 4mL reaction flask at room temperature 2 ] 2 (0.01mmol)、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (50% ethyl acetate in petroleum ether) to give product40.8mg of substance, yield 60%, the reaction was as follows:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(400MHz,CDCl 3 ) 1 H NMR(400MHz,DMSO)δ8.07(d,J＝3.8Hz,1H),7.79–7.75(m,1H),7.36–7.35(m,2H),6.87(s,1H),6.81(d,J＝3.8Hz,1H),4.84(t,J＝5.8Hz,1H),3.48(m,4H),1.40(s,9H)ppm； 13 C NMR(101MHz,CDCl 3 )178.85,171.75,171.18,149.94,133.26,131.46,127.34,126.68,123.62,123.55,120.85,117.41,107.78,61.22,41.29,41.00,28.49ppm.
example 19
N-pivaloyl indole (0.2 mmol), glycine derivative (0.8 mmol) and [ RhCp Cl ] were added to a 4mL reaction flask at room temperature 2 ] 2 (0.01mmol、Cu(OTf) 2 (0.01 mmol), sodium carbonate (0.2 mmol) and HFIP (2.0 mL). Heating to 120 ℃ and stirring. The reaction was monitored by TLC. After 24 hours, the reaction was stopped. Water and methylene chloride were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three to five times with methylene chloride. All organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (50% ethyl acetate in petroleum ether) to give 51.5mg of the product in 50% yield, which was obtained by the following reaction:
the product prepared in this example was subjected to nmr analysis:
1 H NMR(400MHz,CDCl 3 )δ7.71(d,J＝3.8Hz,1H),7.67(dd,J＝7.2,1.7Hz,1H),7.36–7.33(m,5H),7.30–7.26(m,2H),6.67(d,J＝3.8Hz,1H),6.47(s,1H),6.29(m,1H),5.16(s,2H),4.07(d,J＝5.2Hz,2H),3.89-3.85(t,J＝7.2Hz,2H),2.61(t,J＝7.4Hz,2H),1.47(s,9H)ppm； 13 C NMR(101MHz,CDCl 3 )δ178.92,171.03,170.29,170.02,169.64,149.82,135.09,133.26,131.45,128.61,128.51,128.34,127.37,126.64,123.53,123.47,121.03,117.50,107.66,67.18,41.38,41.32,34.90,34.06,28.54ppm。
Claims (5)
1. a preparation method of 7-maleimide indole compounds is characterized in that [ RhCp Cl ] is added into a solvent 2 ] 2 And Cu (OTf) 2 The catalyst is sodium carbonate as an additive, the indole compound and the maleimide compound react, and the 7-maleimide indole compound is obtained after the reaction is finished and post-treatment is carried out;
the structure of the 7-maleimide indole compound is shown as any one of the formulas (I) - (VI):
in the formula (I), R 1 Is hydrogen, C 1 ~C 4 Alkyl radical, C 1 ~C 4 Alkoxy or halogen, R 2 Is C 1 ~C 6 Alkyl, phenyl or benzyl;
the structure of the indole compound is shown in any one of formulas (VII) - (IX):
in the formula (VII), R 1 Is hydrogen, C 1 ~C 4 Alkyl radical, C 1 ~C 4 Alkoxy or halogen;
the maleimide compound has a structure shown in any one of chemical formulas (X) - (XIII):
in the formula (X), R 2 Is C 1 ~C 6 Alkyl, phenyl or benzyl;
the solvent is hexafluoroisopropanol.
2. The process for preparing 7-maleimidoindoles according to claim 1, wherein R is 1 Is hydrogen, methyl, methoxy, fluorine or chlorine.
3. The process for preparing 7-maleimidoindoles according to claim 1, wherein R is 2 Is methyl, ethyl, tert-butyl, cyclohexyl, phenyl or benzyl.
4. The process for producing a 7-maleimidoindole compound according to claim 1, wherein the reaction temperature is 115 to 125 ℃ and the reaction time is 4 to 24 hours.
5. The method for preparing a 7-maleimide indole compound according to claim 1, wherein the molar ratio of the indole compound to the maleimide compound is 1:3.5 to 4.5; the indole compound and the catalyst [ RhCp Cl 2 ] 2 、Cu(OTf) 2 The molar ratio of the additive sodium carbonate is 1: 0.04-0.06.
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