CN109721590B - Method for preparing C2 alpha acyloxy indole by cobalt catalysis - Google Patents
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Abstract
Method for preparing C2 alpha acyloxy indole by cobalt catalysis, which synthesizes compound by using Co (II) as catalyst, tert-butyl peroxyester as oxidant and acyloxy source
Indole derivatives selected from the group consisting of1Is hydrogen, methyl, benzyl, tert-butyl, tert-butyloxycarbonyl, pyrimidine, R2Hydrogen, methyl, phenyl, benzyl, ethyl; r3Hydrogen, methyl, methoxy, benzyloxy, tert-butoxy, ethyl, aldehyde group, amino, sulfonamide, fluorine, chlorine, bromine, iodine, cyano, ester group, carboxyl; t-butyl peroxyester is selected from R4Is alkyl, heteroatom substituted alkyl, ester group, phenyl or heterocycle; co (II) catalyst selected from Co (OAc)2·4H2O、CoCl2、CoBr2Or Co (acac)2One of (1); the organic solvent is selected from one or two mixed solvents of 1, 2-dichloroethane, trichloromethane, cyclohexane, N-butyl ether, diethyl ether, isopropanol, 1, 4-dioxane, ethyl acetate, methanol, ethanol, N-butanol, acetonitrile, toluene, dimethyl sulfoxide, N-dimethylformamide, dichloromethane, carbon tetrachloride, petroleum ether, methyl tert-butyl ether, tetrahydrofuran or benzene.
Description
Technical Field
The invention relates to a method for preparing C2 alpha acyloxy indole by cobalt catalysis, belonging to the field of organic synthetic chemistry.
Background
Indoles and their derivatives are widely found in natural products, pharmaceuticals, and functional molecules. Among them, the C2 alpha functionalized indole is a common structural unit in medicines, and the molecules have activities of resisting HIV, HPV, influenza virus and the like. They are also the core structures of some complex natural products such as the natural products kopsiyunnanine H and gibertine. The direct C-H functionalization reaction for synthesizing the C2 alpha functionalized indole is concerned by synthetic chemists and pharmaceutical chemists because the method does not need pre-functionalization and has the advantages of step economy, atom economy, environmental friendliness and the like.
The reported direct C-H functionalization reaction synthesis of C2 alpha-functionalized indoles: method one, in TBAI and PhI (OAc)2The acetylation reaction of C-H at the alpha position of C2 of 2, 3-disubstituted indole is realized under the condition. Method two, in Pd (OAc)2And PhI (OAc)2Under the condition of realizingEtherification of C2 alpha C-H of a 2, 3-disubstituted indole. The currently reported indole C2. alpha.C-H functionalization reaction has the following limitations: 1. substrate limitations. Substrates are only limited to the C-H functional group reaction at the alpha position of 2, 3-disubstituted indole C2; 2. is limited to acetylation and etherification of C-H at the alpha position of C2; 3. The problem of regioselectivity of C-H functionalization at the C2 alpha and C3 alpha positions; 4. the iodobenzene acetate is used, so that an iodobenzene byproduct is generated in the reaction, and the purification of the product is not facilitated and the environment is protected. Therefore, it is desirable to develop an efficient, environmentally friendly, regioselective C-H acyloxidation reaction at the C2 α. [ see: (a) zaimoku, t.hatta, t.taniguchi and h.ishibashi, org.lett.,2012,14, 6088; (b) y.nakano and d.w. Lupton, chem.commun.,2014,50,1757)
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a method for preparing C2 alpha acyloxy indole by cobalt catalysis. The method has the advantages of easily available raw materials, mild reaction conditions, cheap catalyst, good functional group tolerance, regiospecificity, simple post-treatment, environmental friendliness and the like. The technical scheme adopted by the invention is as follows: a series of C2 alpha-acyloxy indole compounds are synthesized by heating 2-substituted indole derivatives serving as a substrate, Co (II) serving as a catalyst, tert-butyl peroxyester serving as an oxidant and an acyloxy source in a solvent, wherein the reaction formula is as follows:
wherein the indole derivative is selected from the group consisting of R1Is hydrogen, methyl, benzyl, tert-butyl, tert-butyloxycarbonyl, pyrimidine, R2Hydrogen, methyl, phenyl, benzyl, ethyl;
R3hydrogen, methyl, methoxy, benzyloxy, tert-butoxy, ethyl, aldehyde group, amino, sulfonamide, fluorine, chlorine, bromine, iodine, cyano, ester group, carboxyl;
the tert-butyl peroxyester is selected from R4Is alkyl, heteroatom substituted alkyl, ester group, phenylOr a heterocycle;
said Co (II) catalyst is selected from Co (OAc)2·4H2O、CoCl2、CoBr2Or Co (acac)2One of (1);
the organic solvent is one or two mixed solvents selected from 1, 2-dichloroethane, chloroform, cyclohexane, N-butyl ether, diethyl ether, isopropanol, 1, 4-dioxane, ethyl acetate, methanol, ethanol, N-butanol, acetonitrile, toluene, dimethyl sulfoxide, N-dimethylformamide, dichloromethane, carbon tetrachloride, petroleum ether, methyl tert-butyl ether, tetrahydrofuran or benzene.
1. The method for preparing C2 alpha acyloxy indole by cobalt catalysis comprises the following steps:
(a) sequentially adding the 2-substituted indole derivative, a solvent, tert-butyl peroxyester and a Co (II) catalyst into a 25mL Schlenk bottle, then adding a refined organic solvent, placing the mixture into an oil bath for reaction, controlling the reaction temperature to be 50-120 ℃, controlling the reaction reagent to be 5-20 hours, wherein the molar ratio of the 2-substituted indole derivative to the tert-butyl peroxyester is 1:1-4, the molar ratio of the 2-substituted indole derivative to the Co (II) catalyst is 1:0.05-0.2, and the adding amount of the organic solvent is 30-100 times that of the 2-substituted indole derivative;
(b) after the reaction is finished, adding ethyl acetate for dilution, filtering, and removing the organic solvent under reduced pressure;
(c) eluting with petroleum ether/ethyl acetate, and separating with silica gel column to obtain series C2 alpha acyloxy indole compounds.
The invention has the beneficial effects that: a method for preparing C2 alpha acyloxy indole by cobalt catalysis comprises the steps of taking a 2-substituted indole derivative as a substrate, Co (II) as a catalyst, taking tert-butyl peroxyester as an oxidant and an acyloxy source, and heating in a solvent for reaction to synthesize a series of C2 alpha acyloxy indole compounds. At present, the prior art is limited to C2 alpha-C-H acyl oxidation reaction of 2, 3-disubstituted indole, and compared with the prior art, the invention mainly provides a simple and efficient C2 alpha-C-H acyl oxidation reaction of 2-substituted indole, and the method has the advantages of easily obtained raw materials, cheap catalyst, mild reaction conditions, good functional group tolerance, regiospecificity, environmental friendliness and the like. The C2 alpha acyloxy indole compound is an important skeleton structure and a synthetic intermediate, and has wide application in the fields of organic synthesis and pharmaceutical chemistry.
Drawings
FIG. 1 is a drawing of Compound 1a1H-NMR。
FIG. 2 is a drawing of Compound 1a13C-NMR。
FIG. 3 is a drawing of Compound 1b1H-NMR。
FIG. 4 is a drawing of Compound 1b13C-NMR。
FIG. 5 is a drawing of Compound 1c1H-NMR。
FIG. 6 is a drawing of Compound 1c13C-NMR。
FIG. 7 is a drawing of Compound 1d1H-NMR。
FIG. 8 is a drawing of Compound 1d13C-NMR。
FIG. 9 is a drawing of Compound 1e1H-NMR。
FIG. 10 is a drawing of Compound 1e13C-NMR。
FIG. 11 is a drawing of Compound 1f1H-NMR。
FIG. 12 is a drawing of Compound 1f13C-NMR。
Detailed Description
The invention is further illustrated by the following examples:
example 1: synthesis of methyl (1- (pyrimidin-2-yl) -1H-indol-2-yl) benzoate (1a)
2-substituted indole (0.5mmol,164mg), tert-butyl peroxybenzoate (1.5 mmol), toluene (3mL), and Co (acac)2(0.05mmol,10 mol%) were added to a 25mL schlenk flask in sequence. Then placed in an oil bath at 80 ℃ and stirred for 8 hours. Cooling the reaction solution to room temperature, diluting with ethyl acetate (5mL), filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography (petroleum ether/ethyl acetate) to obtain (1- (pyrimidin-2-yl) -1H-indol-2-yl) benzylMethyl ester (1a), white solid, 125mg, 76% yield, mp 132-.1H NMR(400MHz,CDCl3)δ8.72 (d,J＝4.8,2H),8.57(d,J＝8.4Hz,1H),7.98(d,J＝8.3Hz,2H), 7.62(d,J＝8.0Hz,1H),7.56–7.52(m,1H),7.41(t,J＝8.0Hz, 2H),7.36–7.32(m,1H),7.27–7.23(m,1H),7.06(t,J＝4.8, 1H),6.86(s,1H),5.97(s,2H)；13C NMR(101MHz,CDCl3)δ166.2, 158.1,158.0,137.1,135.1,132.9,130.1,129.5,128.9,128.3,123.8, 122.2,120.5,116.8,115.1,108.7,62.0；HRMS(ESI/[M+Na]+)calcd for C20H15O2N3Na+:352.1056,found 352.1059.
Example 2: synthesis of methyl (1- (5-fluoropyrimidin-2-yl) -1H-indol-2-yl) benzoate (1b)
2-substituted indole (0.5mmol,173mg), tert-butyl peroxybenzoate (1.5 mmol), toluene (3mL), and Co (acac)2(0.05mmol,10 mol%) were added to a 25mL schlenk flask in sequence. Then placed in an oil bath at 80 ℃ and stirred for 8 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (5mL), filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate) to give methyl (1- (5-fluoropyrimidin-2-yl) -1H-indol-2-yl) benzoate (1b) as a white solid in 107mg, 62% yield, mp 112-;1H NMR(400MHz,CDCl3)δ 8.57(s,2H),8.44(d,J＝8.4Hz,1H),7.97(d,J＝8.3Hz,2H), 7.62(d,J＝7.7Hz,1H),7.55(t,J＝7.6Hz，1H),7.41(t,J＝7.6 Hz,2H),7.34(t,J＝7.8Hz,1H),7.27–7.23(m,1H),6.86(s, 1H),5.91(s,2H)；13C NMR(101MHz,CDCl3)δ166.1,154.7(d,J＝260.4Hz),154.2(d,J＝2.9Hz),145.8(d,J＝21.9Hz),137.1, 135.1,133.1,130.0,129.6,128.7,128.4,124.0,122.4,120.7,114.6, 109.0,61.6；HRMS(ESI/[M+Na]+)calcd for C20H14O2N3FNa+:370.0962, found 370.0965.
example 3: synthesis of methyl (5-methyl-1- (pyrimidin-2-yl) -1H-indol-2-yl) benzoate (1c)
Under air conditions, indole (0.5mmol,171mg), tert-butyl peroxybenzoate (2.0mmol), toluene (3mL), and Co (acac)2(0.05mmol,10 mol%) were added to a 25mL schlenk flask in sequence. Then placed in an oil bath at 80 ℃ and stirred for 12 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (5mL), filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate) to give methyl (5-methyl-1- (pyrimidin-2-yl) -1H-indol-2-yl) benzoate (1c) as a colorless oily liquid, 95mg, 55% yield,1H NMR(400MHz,CDCl3)δ8.70 (d,J＝4.8,2H),8.46(d,J＝8.6,Hz,1H),7.98(d,J＝8.0Hz, 2H),7.54(t,J＝8.0Hz,1H),7.42–7.38(m,3H),7.15(d,8.6 Hz,1H),7.04(d,J＝4.8,1H),6.78(s,1H),5.95(s,2H),2.45(s, 3H)；13C NMR(101MHz,CDCl3)δ166.2,158.2,157.9,135.4,135.3, 132.9,131.6,130.2,129.6,129.1,128.3,125.3,120.4,116.5,114.9, 108.5,62.1,21.3；HRMS(ESI/[M+Na]+)calcd for C21H17O2N3Na+:366.1213, found 366.1216.
example 4: synthesis of ethyl 1- (1- (5-bromopyrimidin-2-yl) -1H-indol-2-yl) benzoate (1d)
2-substituted indole (0.5mmol,210mg), tert-butyl peroxybenzoate (1.5 mmol), toluene (3mL), and Co (acac)2(0.05mmol,10 mol%) were added to a 25mL schlenk flask in sequence. Then placed in an oil bath at 80 ℃ and stirred for 8 hours. Cooling the reaction solution to room temperature, diluting with ethyl acetate (5mL), filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography (petroleum ether/ethyl acetate) to obtain 1- (1- (5-bromopyrimidin-2-yl) -1H-indol-2-yl) ethyl benzoate (1d) as a white solid, 115mg, 55% yield, mp 107-;1H NMR(400MHz，CDCl3)δ 8.67(s，2H)，8.31(d，J＝8.3Hz，1H)，7.90(d，J＝7.8Hz，2H)， 7.62(d，J＝7.7Hz，1H)，7.52(t，J＝7.3Hz，1H)，7.37(t，J＝7.6 Hz，2H)，7.32(t，J＝7.7Hz，1H)，7.25(t，J＝7.6Hz，1H)，7.02 (q，J＝6.4Hz，1H)，6.92(s，1H)，1.86(d，J＝6.4Hz，4H)；13C NMR (101MHz，CDCl3)δ165.7，158.5，156.2，140.4，136.9，132.9，130.2， 129.4，128.6，128.2，124.0，122.4，120.7，114.7，114.4，107.1，67.3， 19.8；HRMS(ESI/[M+H]+)calcd for C21H17BrN3O2 +422.0499，found 422.0496.
example 5: synthesis of (1- (5-bromopyrimidin-2-yl) -1H-indol-2-yl) methyl 1-naphthoate (1e)
2-substituted indole (0.5mmol, 228mg), tert-butyl peroxybenzoate (1.5 mmol), toluene (3mL), and Co (acac)2(0.05mmol,10 mol%) were added to a 25mL schlenk flask in sequence. Then placed in an oil bath at 80 ℃ and stirred for 8 hours. Cooling the reaction solution to room temperature, diluting with ethyl acetate (5mL), filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography (petroleum ether/ethyl acetate) to obtain (1- (5-bromopyrimidin-2-yl) -1H-indol-2-yl) methyl 1-naphthoate (1e) as a white solid, 143mg, 62% yield, mp 114-;1H NMR(400MHz, CDCl3)δ8.92(d,J＝8.6Hz,1H),8.75(s,2H),8.53(d,J＝8.4 Hz,1H),8.08(d,J＝7.2Hz,1H),8.01(d,J＝8.2Hz,1H),7.88 (d,J＝8.1Hz,1H),7.60(t,J＝7.9Hz,2H),7.55–7.52(m,1H), 7.45(t,J＝7.7Hz,1H),7.35(t,J＝7.7Hz,1H),7.28–7.25(m, 1H),6.91(s,1H),5.99(s,2H)；13C NMR(101MHz,CDCl3)δ167.0, 158.5,156.3,137.0,135.2,133.8,133.5,131.4,130.3,129.0,128.5, 127.8,126.8,126.2,125.7,124.5,124.2,122.6,120.7,115.3,114.2, 109.9,61.8；HRMS(ESI/[M+Na]+)calcd for C24H16O2N3BrNa+:480.0318, found 480.0320.
example 6: synthesis of methyl (1- (5-bromopyrimidin-2-yl) -1H-indol-2-yl) acetate (1f)
2-substituted indole (0.5mmol,172mg), tert-butyl peroxybenzoate (1.5 mmol), toluene (3mL), and Co (acac)2(0.05mmol,10 mol%) were added to a 25mL schlenk flask in sequence. Then placed in an oil bath at 80 ℃ and stirred for 8 hours. Cooling the reaction solution to room temperature, diluting with ethyl acetate (5mL), filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography (petroleum ether/ethyl acetate) to obtain methyl (1- (5-bromopyrimidin-2-yl) -1H-indol-2-yl) acetate (1f) as a white solid, 56mg, 32%, mp 93-95 ℃;1H NMR(400MHz,CDCl3)δ8.75(s, 2H),8.50(d,J＝8.4Hz,1H),7.58(d,J＝7.6Hz,1H),7.32(t, J＝7.5Hz,1H),7.26–7.22(m,1H),6.78(s,1H)，5.66(s，2H)， 2.08(s，3H)；13C NMR(101MHz，CDC3)δ170.6，158.4，156.2，136.9， 135.2，128.9，124.1，122.6，120.6，115.3，114.1，109.5，61.3,21.0； HRMS(ESI/[M+Na]+)calcd for C15H12O2N3BrNa+:368.0005,found 368.0009。
Claims (2)
1. a method for preparing C2 alpha acyloxy indole by cobalt catalysis is characterized in that: a series of C2 alpha acyloxy indole compounds are synthesized by heating 2-substituted indole derivatives as a substrate, Co (II) as a catalyst, tert-butyl peroxyester as an oxidant and an acyloxy source in an organic solvent, wherein the reaction formula is as follows:
wherein R in said indole derivative1Is hydrogen, methyl, benzyl, tert-butyl, tert-butyloxycarbonyl, pyrimidine, R2Is hydrogen, methyl, phenyl,Benzyl, ethyl, R3Hydrogen, methyl, methoxy, benzyloxy, tert-butoxy, ethyl, aldehyde group, amino, sulfonamide, fluorine, chlorine, bromine, iodine, cyano, ester group, carboxyl;
r in the tert-butyl peroxyester4Is alkyl, heteroatom-substituted alkyl, phenyl or heterocycle;
said Co (II) catalyst is selected from Co (acac)2；
The organic solvent is one or two mixed solvents selected from 1, 2-dichloroethane, chloroform, cyclohexane, N-butyl ether, diethyl ether, isopropanol, 1, 4-dioxane, ethyl acetate, methanol, ethanol, N-butanol, acetonitrile, toluene, dimethyl sulfoxide, N-dimethylformamide, dichloromethane, carbon tetrachloride, petroleum ether, methyl tert-butyl ether, tetrahydrofuran or benzene.
2. The cobalt-catalyzed process for the preparation of C2 α acyloxyindoles according to claim 1 wherein: cobalt-catalyzed C2 α C-H acyl oxidation of 2-substituted indoles comprising the steps of:
(a) sequentially adding the 2-substituted indole derivative, a solvent, tert-butyl peroxyester and a Co (II) catalyst into a 25mL Schlenk bottle, then adding a refined organic solvent, placing the mixture into an oil bath for reaction, controlling the reaction temperature to be 50-120 ℃, controlling the reaction reagent to be 5-20 hours, wherein the molar ratio of the 2-substituted indole derivative to the tert-butyl peroxyester is 1:1-4, the molar ratio of the 2-substituted indole derivative to the Co (II) catalyst is 1:0.05-0.2, and the adding amount of the organic solvent is 30-100 times that of the 2-substituted indole derivative;
(b) after the reaction is finished, adding ethyl acetate for dilution, filtering, and removing the organic solvent under reduced pressure;
(c) eluting with petroleum ether/ethyl acetate, and separating with silica gel column to obtain C2 alpha-acyloxyindole compounds.
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