CN111004164B - Preparation method of polysubstituted 2-aryl indole derivative - Google Patents
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- C07D209/04—Indoles; Hydrogenated indoles
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses a preparation method of a polysubstituted 2-aryl indole derivative, which specifically comprises the following steps: 2-ethynylaniline compounds and ketone compounds are used as raw materials, and the polysubstituted 2-aryl indole derivatives are prepared by the oxidative cyclization reaction of the 2-ethynylaniline compounds and the ketone compounds under the action of a catalyst, a ligand and an oxidant. The method has the characteristics of easily obtained raw materials, simple and convenient operation, high chemical selectivity, high regioselectivity and the like, and has higher implementation value and social and economic benefits.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical and chemical intermediate synthesis, and particularly relates to a preparation method of a polysubstituted 2-aryl indole derivative.
Background
After long-term research and summary, medicinal chemists find that certain small molecular frameworks existing in organisms can be combined on a plurality of receptors with high affinity, and can become new receptor agonists and antagonists after structural modification. In 1988, Evans et al (J.Med. chem.,1988,31(12): 2235. sup. 2246.) defined such structures as "dominant structures". In the initial stage of drug discovery, modification of the dominant structures is a viable strategy for discovery of new drugs. Indole is one of such predominant structures, and compounds having an indole skeleton play an important role in organisms, and thus indole is considered to be one of the most important structures in drug discovery. Among them, 2-aryl indole is the most representative compound in indole compounds, and it is widely present in drug molecules as an active skeleton. Among them, the indoxifene (Zindoxifene) (j.med.chem.,1984,27,1439-1447.) is an estrogen antagonist, which was the earliest developed drug for 2-arylindole derivatives as selective estrogen receptor modulators. The structural formula is as follows:
because of the special biological and pharmacological activity of polysubstituted pyridine derivatives, many researchers have focused on the synthesis methods of these compounds. In 2007, Prim and colleagues (Eur. J.org.chem.2007,72, 5332-containing 5335) reported that under the synergetic catalysis of Fe and Pd, indole is formed by intramolecular hydroamination of alkyne, and then Michael addition is carried out on the indole and methylvinylketone. The method has the defects of using expensive noble metal palladium, having low yield of a virulent reagent methyl vinyl ketone, having a single product structure and the like. The Shanghai organic institute of Chinese academy of sciences, issue group (chem. -Eur.J.2014, 20,3040-3044) reported the iridium-catalyzed allylamine one-pot method for the construction of N-allyl 2-arylindoles. The method uses noble metal iridium, and simultaneously, the method needs to use a special ligand, and the ligand is prepared repeatedly, thereby being not beneficial to further research. The Lvxingyo (J.org.chem.2014,79,9000-9008) first achieved an inexpensive copper-catalyzed coupling/cyclization reaction of 2-alkynylanilines and boronic acids to produce N-alkyl 2-arylindoles in a one-pot process, but with low efficiencies and limited substrate ranges. Therefore, the method for synthesizing the polysubstituted 2-aryl indole derivative has the advantages of simple operation, easily obtained raw materials and high selectivity and is worthy of being researched.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a preparation method of polysubstituted 2-aryl indole derivatives, which has the characteristics of easily obtained raw materials, simple and convenient operation, high chemical selectivity, high regioselectivity and the like.
The preparation method of the polysubstituted 2-aryl indole derivative shown in the formula (I) is characterized by comprising the following steps: dissolving a 2-alkynyl aniline compound shown in a formula (II), a ketone compound shown in a formula (III), a catalyst, a ligand and an oxidant in a solvent, reacting at a proper temperature, and extracting, concentrating and separating a reaction solution by column chromatography after the reaction is finished to obtain a polysubstituted 2-aryl indole derivative shown in a formula (I);
the reaction equation is as follows:
wherein R is1Is substituted aryl or heteroaryl, R2Is alkyl, halogen or hydrogen, R3Is C1-C6Alkyl, substituted aryl or heteroaryl, R1Or R3The substituent in the substituted aryl group includes methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl or nitro.
The preparation method of the polysubstituted 2-aryl indole derivative is characterized in that the catalyst is selected from one or more of copper acetate, cuprous acetate, copper trifluoromethanesulfonate, cupric chloride, cupric bromide, cupric iodide, cuprous chloride, cuprous bromide, cuprous iodide, palladium acetate and ferric chloride; the amount of the catalyst is 5-40 mol%, preferably 8-20 mol% of the 2-alkynyl aniline compound.
The preparation method of the polysubstituted 2-aryl indole derivative is characterized in that the oxidant is selected from 2,2,4, 4-tetramethyl piperidine nitroxide radical (TEMPO) and 4-hydroxy-2, 2,4, 4-tetramethyl piperidine nitroxide radical (4-OH-TEMPO).
The preparation method of the polysubstituted 2-aryl indole derivative is characterized in that the mass ratio of the 2-alkynyl aniline compound to the ketone compound is l: 1-4, and preferably l: 1-2.
The preparation method of the polysubstituted 2-aryl indole derivative is characterized in that a solvent is one of chlorobenzene, toluene, acetonitrile, dimethyl sulfoxide, 1, 2-dichlorobenzene, N-dimethylformamide, isopropylbenzene, dioxane and 1, 2-dichloroethane.
The preparation method of the polysubstituted 2-arylindole derivative is characterized in that the ligand is selected from one of pyridine, 2' -bipyridine, tetramethyl ethylenediamine and 1, 10-phenanthroline.
The preparation method of the polysubstituted 2-aryl indole derivative is characterized in that the reaction temperature is 60-150 ℃, and preferably 80-120 ℃.
The preparation method of the polysubstituted 2-aryl indole derivative is characterized in that the reaction time is 12-48 hours, preferably 24-36 hours.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method has the characteristics of easily obtained reaction raw materials, simple and convenient operation, high chemical selectivity, high regioselectivity and the like, and has higher implementation value and social and economic benefits.
Detailed Description
The invention is further described below with reference to specific examples, but is not limited to the embodiments described by the specific examples listed in the present invention.
Example 1: preparation of 1-phenyl-3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ia)
A10 mL reactor was charged with 2-phenylethynylaniline (96.6mg, 0.5mmol), propiophenone (80.5mg, 0.6mmol), Cu (OAc)2(9.1mg, 0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), 4-hydroxy-2, 2,4, 4-tetramethylpiperidinyloxy free radical (4-OH-TEMPO) (86.1mg, 0.5mmol), and 3mL of 1, 2-dichlorobenzene. After heating at 120 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure and separated by column chromatography (n-hexane/ethyl acetate 50/1, v/v) to give 1-phenyl-3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ia) (133.4mg, 82%) as a white solid, melting point: 134 to 137 ℃.1H NMR(400MHz,CDCl3, ppm)7.76(d,J＝7.2Hz,2H),7.65(d,J＝8.0Hz,1H),7.60-7.38(m, 9H),7.25(d,J＝7.2Hz,1H),7.16(d,J＝7.6Hz,1H),6.61(s,1H), 4.75-4.64(m,2H),3.33-3.23(m,2H).13C NMR(100MHz,CDCl3,ppm) 197.8,141.1,137.2,136.2,133.4,132.7,129.4,128.7,128.6,128.5, 128.2,128.0,121.9,120.7,120.2,109.8,102.9,39.3,38.5.HRMS (ESI-TOF)calcd for C23H19NNaO[M+Na]+:348.1352；found:348.1359.
Example 2: preparation of 1-phenyl-3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ia)
A10 mL reactor was charged with 2-phenylethynylaniline (96.6mg, 0.5mmol), propiophenone (80.5mg, 0.6mmol), Cu (OAc)2(9.1mg, 0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), 2,4, 4-tetramethylpiperidinyloxy free radical (TEMPO) (78.1mg, 0.5mmol), and 3mL1, 2-dichlorobenzene. After heating at 120 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure and separated by column chromatography (n-hexane/ethyl acetate 50/1, v/v) to give Ia (120.4mg, 74%) as a white solid, melting point: 134 to 137 ℃.
Example 3: preparation of 1-phenyl-3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ia)
A10 mL reactor was charged with 2-phenylethynylaniline (96.6mg, 0.5mmol), propiophenone (80.5mg, 1.0mmol), Cu (OAc)2(9.1mg, 0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), TEMPO (78.1mg, 0.5mmol) and 3mL chlorobenzene. After heating at 120 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure and separated by column chromatography (n-hexane/ethyl acetate 50/1, v/v) to give Ia (71.6mg, 44%) as a white solid, melting point: 134 to 137 ℃.
Example 4: preparation of 1-phenyl-3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ia)
A10 mL reactor was charged with 2-phenylethynylaniline (96.6mg, 0.5mmol), propiophenone (80.5mg, 0.6mmol), Cu (OAc)2(9.1mg, 0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), TEMPO (78.1mg, 0.5mmol) and 3mL toluene. After heating at 110 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure and separated by column chromatography (n-hexane/ethyl acetate 50/1, v/v) to give Ia (100.8mg, 62%) as a white solid, melting point: 134 to 137 ℃.
Example 5: preparation of 1-phenyl-3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ia) 2-phenylethynylaniline (96.6mg, 0.5mmol), propiophenone (80.5mg, 0.6mmol), Cu (OAc) were added to a 10mL reactor2(9.1mg, 0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), TEMPO (78.1mg, 0.5mmol) and 3mL dioxane. After heating at 100 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure and separated by column chromatography (n-hexane/ethyl acetate 50/1, v/v) to give Ia (61.8mg, 38%) as a white solid, melting point: 134 to 137 ℃.
Example 6: preparation of 1-phenyl-3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ia)
2-Phenylethynylaniline (96.6mg, 0.5mmol), propiophenone (80.5mg, 0.6mmol), CuCl were added to a 10mL reactor2(6.7mg, 0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), 4-OH-TEMPO (86.1mg, 0.5mmol) and 3mL1, 2-dichlorobenzene. After heating at 120 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure, and separated by column chromatography (n-hexane/ethyl acetate 50/1, v/v) to give Ia (65.1mg, 40%) as a white solid,melting point: 134 to 137 ℃.
Example 7: preparation of 1-phenyl-3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ia)
A10 mL reactor was charged with 2-phenylethynylaniline (96.6mg, 0.5mmol), propiophenone (80.5mg, 0.6mmol), Cu (OAc)2(9.1mg, 0.05mmol), tetramethylethylenediamine (11.6mg, 0.1mmol), 4-OH-TEMPO (86.1mg, 0.5mmol) and 3mL1, 2-dichlorobenzene. After heating at 120 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure and separated by column chromatography (n-hexane/ethyl acetate 50/1, v/v) to give Ia (19.54 mg, 12%) as a white solid, melting point: 134 to 137 ℃.
Example 8: preparation of 1-phenyl-3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ia)
A10 mL reactor was charged with 2-phenylethynylaniline (96.6mg, 0.5mmol), propiophenone (80.5mg, 0.6mmol), Cu (OAc)2(9.1mg, 0.05mmol), 1, 10-phenanthroline (18.2mg, 0.1mmol), 4-OH-TEMPO (86.1mg, 0.5mmol) and 3mL1, 2-dichlorobenzene. After heating at 120 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure and separated by column chromatography (n-hexane/ethyl acetate 50/1, v/v) to give Ia (58.6 mg, 36%) as a white solid, melting point: 134 to 137 ℃.
Example 9: preparation of 1- (2-fluorophenyl) -3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ib)
A10 mL reactor was charged with 2-phenylethynylaniline (96.6mg, 0.5mmol), o-fluorophenylacetone (91.2mg, 0.6mmol), Cu (OAc)2(9.1mg, 0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), 4-OH-TEMPO (86.1mg, 0.5mmol) and 3mL1, 2-dichlorobenzene. After heating at 120 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure and separated (n-hexane/ethyl acetate 50/1, v/v) to give 1- (2-fluorophenyl) -3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ib) (137.7mg, 80%) as a white solid. Melting point: 82 to 83 ℃.1H NMR(400MHz,CDCl3,ppm)7.83(td,J＝7.6,1.6Hz, 1H),7.68(d,J＝7.6Hz,1H),7.57-7.42(m,7H),7.30-7.16(m,4H), 7.13-7.05(m,1H),6.59(s,1H),4.68(d,J＝7.6Hz,2H),3.39-3.28(m, 2H).13C NMR(100MHz,CDCl3,ppm)195.9(JC-F＝3.7Hz),162.1 (JC-F＝253.7Hz),141.2,137.2,135.0(JC-F＝9.0Hz),132.8,135.0(JC-F＝ 9.0Hz),129.4,128.7,128.4,128.2,124.9(JC-F＝12.2Hz),124.5(JC-F＝ 3.3Hz),121.9,120.7,120.1,116.7(JC-F＝23.5Hz),109.8,102.8,43.3 (JC-F＝7.7Hz),38.9(JC-F＝2.1Hz).HRMS(ESI-TOF)calcd for C23H18FNNaO[M+Na]+:366.1260；found:366.1265.
EXAMPLE 10 preparation of 1- (4-methoxyphenyl) -3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ic)
A10 mL reactor was charged with 2-phenylethynylaniline (96.6mg, 0.5mmol), p-methoxypropiophenone (98.5mg, 0.6mmol), Cu (OAc)2(9.1mg, 0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), 4-OH-TEMPO (86.1mg, 0.5mmol) and 3mL1, 2-dichlorobenzene. After heating at 120 ℃ for 24H, the solvent was recovered by concentration under reduced pressure and separated (n-hexane/ethyl acetate 50/1, v/v) to give 1- (4-methoxyphenyl) -3- (2-phenyl-1H-indol-1-yl) propan-1-one (Ic) (125.7mg, 75%) as a white solid. Melting point: 121 ℃ and 122 ℃.1H NMR(600MHz,CDCl3,ppm)8.19(d,J＝7.8Hz,1H), 8.02(d,J＝9.0Hz,2H),7.75(d,J＝8.4Hz,1H),7.53(dd,J＝7.8,1.8Hz, 2H)7.63(d,J＝9.0Hz,2H),7.51-7.46(m,3H),1.35(s,9H).13C NMR (150MHz,CDCl3,ppm)167.3,158.7,156.8,140.8,139.0,137.3,131.9, 129.0,128.8,128.6,128.0,127.3,124.2,117.6,82.2,27.6.HRMS (ESI-TOF)calcd for C22H20BrNNaO2[M+Na]+:432.0549；Found: 432.0570.
Example 11: preparation of 3- (2- (4-methoxyphenyl) -1H-indol-1-yl) -1-phenylpropan-1-one (Id)
A10 mL reactor was charged with 2- ((4-methoxyphenyl) ethynyl) aniline (111.6mg, 0.5mmol), propiophenone (80.5mg, 0.6mmol), Cu (OAc)2(9.1mg, 0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), 4-OH-TEMPO (86.1mg, 0.5mmol) and 3mL1, 2-dichlorobenzene. After heating at 120 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure and separated (n-hexane/ethyl acetate 50/1, v/v) to give 3- (2- (4-methoxyphenyl) -1H-indol-1-yl) -1-phenylpropan-1-one (Id) (142) as a white solid.1mg, 80%), melting point: 134 ℃ and 135 ℃.1H NMR(400MHz,CDCl3,ppm)7.78-7.72(m,2H),7.63 (d,J＝7.6Hz,1H),7.56-7.48(m,1H),7.44-7.35(m,5H),7.26-7.19(m, 1H),7.14(td,J＝7.6,0.8Hz,1H),6.98(td,J＝8.8,2.4Hz,2H),6.51(s, 1H),4.68-4.57(m,2H),3.85(s,3H),3.28-3.17(m,2H).13C NMR(100 MHz,CDCl3,ppm)197.9,159.6,140.9,137.0,136.2,133.4,130.6, 128.6,128.5,128.0,125.1,121.7,120.6,120.1,114.2,109.7,102.4,55.4, 39.2,38.5.HRMS(ESI-TOF)calcd for C24H21NNaO2[M+Na]+: 378.1457；found:378.1465.
Example 12: preparation of 3- (5-fluoro-2-phenyl-1H-indol-1-yl) -1-phenylpropan-1-one (Ie)
A10 mL reactor was charged with 4-fluoro-2- (phenylethynyl) aniline (105.6mg, 0.5mmol), propiophenone (80.5mg, 0.6mmol), Cu (OAc)2(9.1mg, 0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), 4-OH-TEMPO (86.1mg, 0.5mmol) and 3mL of 1, 2-dichlorobenzene. After heating at 120 ℃ for 24 hours, the solvent was recovered by concentration under reduced pressure and separated (n-hexane/ethyl acetate 50/1, v/v) to give 3- (5-fluoro-2-phenyl-1H-indol-1-yl) -1-phenylpropan-1-one (Ie) (133.9mg, 78%) as a white solid, melting point: 122 ℃ and 123 ℃.1H NMR(400MHz,CDCl3,ppm)7.79-7.71(m,2H), 7.57-7.41(m,6H),7.39(t,J＝8.0Hz,2H),7.35-7.25(m,2H),6.98(td,J ＝9.2,2.4Hz,1H),6.52(s,1H),4.68-4.57(m,2H),3.26-3.16(m,2H). 13C NMR(100MHz,CDCl3,ppm)197.6,158.2(JC-F＝233.5Hz), 142.7,136.1,133.8,133.5,132.4,129.3,128.8,128.7(JC-F＝10.0Hz), 128.7,128.5,127.9,110.4(JC-F＝9.7Hz),110.2(JC-F＝26.1Hz),105.0 (JC-F＝23.3Hz),102.8(JC-F＝4.6Hz),39.5,38.4.HRMS(ESI-TOF) calcd for C23H18FNNaO[M+Na]+:366.1262；found:366.1265.
Examples 13 to 28: preparation of polysubstituted 2-arylindole derivatives (If-Iu)
A10 mL reactor was charged with 2- (substituted phenylethynyl) anilines (0.5 mmol), ketones (0.6mmol), Cu (OAc)2(91mg,0.05mmol), 2' -bipyridine (15.6mg, 0.1mmol), 4-OH-TEMPO (86.1mg, 0.5mmol) and 3mL1, 2-dichlorobenzene. Heating at 120 ℃ for 24 hours, concentrating under reduced pressure to recover the solvent, and separating (n-hexane/ethyl acetate 50/1, v/v) to obtain polysubstituted 2-arylindole derivatives (If to Iu);
the statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (9)
1. A preparation method of polysubstituted 2-aryl indole derivatives shown in formula (I) is characterized by comprising the following steps: dissolving a 2-alkynyl aniline compound shown in a formula (II), a ketone compound shown in a formula (III), a catalyst, a ligand and an oxidant in a solvent, reacting at a proper temperature, and extracting, concentrating and separating a reaction solution by column chromatography after the reaction is finished to obtain a polysubstituted 2-aryl indole derivative shown in a formula (I);
the reaction equation is as follows:
wherein R is1Is a substituted aryl groupOr heteroaryl, R2Is alkyl, halogen or hydrogen, R3Is C1-C6Alkyl, substituted aryl or heteroaryl, R1Or R3Wherein the substituent in the substituted aryl is selected from methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl or nitro;
the catalyst is selected from one or more of cupric acetate, cuprous acetate, copper trifluoromethanesulfonate, cupric chloride, cupric bromide, cupric iodide, cuprous chloride, cuprous bromide, cuprous iodide, palladium acetate and ferric chloride;
the oxidant is selected from 2,2,4, 4-tetramethyl piperidine nitroxide radical or 4-hydroxy-2, 2,4, 4-tetramethyl piperidine nitroxide radical;
the solvent is chlorobenzene, toluene, acetonitrile, dimethyl sulfoxide, 1, 2-dichlorobenzene,N,N-one of dimethylformamide, cumene, dioxane, 1, 2-dichloroethane;
the ligand is selected from one of pyridine, 2' -bipyridine, tetramethyl ethylenediamine and 1, 10-phenanthroline.
2. The method for producing polysubstituted 2-arylindole derivatives according to claim 1, wherein the amount of the catalyst is 5 to 40 mol% based on the amount of the 2-alkynylaniline compound.
3. The method for producing polysubstituted 2-arylindole derivatives according to claim 1, wherein the mass ratio of the 2-alkynylanilines to the ketones is 1: 1 to 4.
4. The method for preparing polysubstituted 2-arylindole derivatives according to claim 1, wherein the reaction temperature is 60 to 150 ℃.
5. The method for preparing polysubstituted 2-arylindole derivatives according to claim 1, wherein the reaction time is 12 to 48 hours.
6. The method for producing polysubstituted 2-arylindole derivatives according to claim 1, wherein the amount of the catalyst is 8 to 20 mol% based on the amount of the 2-alkynylaniline compound.
7. The method for producing a polysubstituted 2-arylindole derivative according to claim 1, wherein the mass ratio of the 2-alkynylanilines to the ketones is l:1 to 2.
8. The method for preparing polysubstituted 2-arylindole derivatives according to claim 1, wherein the reaction temperature is 80-120 ℃.
9. The method for preparing polysubstituted 2-arylindole derivatives according to claim 1, wherein the reaction time is 24 to 36 hours.
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