CN113999158A - 3- (1-hydroxyalkylene) indolone and preparation method thereof - Google Patents

3- (1-hydroxyalkylene) indolone and preparation method thereof Download PDF

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CN113999158A
CN113999158A CN202111440933.9A CN202111440933A CN113999158A CN 113999158 A CN113999158 A CN 113999158A CN 202111440933 A CN202111440933 A CN 202111440933A CN 113999158 A CN113999158 A CN 113999158A
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indolone
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cyanobenzyl
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李思琦
黄贺
张露云
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Yanbian University
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Abstract

The invention relates to 3- (1-hydroxyalkylene) indolone and a preparation method thereof, belonging to the technical field of organic synthesis. Solves the technical problem that the existing synthesis method of 3- (1-hydroxyalkylene) indolone is not beneficial to large-scale production and use. The 3- (1-hydroxyalkylene) indolone is represented by the formula [2]The dicarbonyl oxygen sulfur ylide is obtained by intramolecular carbene insertion reaction, and the structural formula is shown as a formula [1]；
Figure DDA0003382826020000011
Wherein R is1、R2And R3Each independently represents an alkyl group having 1 to 15 carbon atoms, a cycloalkyl group having 3 to 15 carbon atoms, a cycloalkylalkyl group having 4 to 15 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aryl group having 7 to 15 carbon atomsAn aralkyl group of (2). The invention adopts dicarbonyl oxygen sulfur ylide compounds as raw materials, the raw materials are simple and easy to obtain, and complicated operation is not needed, thus the method is a simple and convenient method suitable for large-scale preparation. The 3- (1-hydroxy alkylidene) indolone is a very important organic intermediate and drug intermediate.

Description

3- (1-hydroxyalkylene) indolone and preparation method thereof
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to 3- (1-hydroxyalkylene) indolone and a preparation method thereof.
Background
3- (1-hydroxyalkylene) indolones are a very heavy classThe organic intermediate has wide application in the fields of pharmaceutical chemistry and synthetic chemistry. In medicinal chemistry, 3- (1-hydroxyalkylene) indolones exhibit a number of biological activities, such as the antirheumatic drug Tenidap (Tenidap) (M a rtaPorcs-Makkay, gyulaSimig. organic Process Research) developed by Peucedanum&Development,2000,4,10.), a non-steroidal anti-inflammatory analgesic drug containing 3- (1-hydroxy alkylidene) indolone structure, which can inhibit cyclooxygenase and lipoxygenase, regulate the activity of cell factors, effectively reduce the acute phase reaction indexes such as serum amyloid, C-reactive protein, erythrocyte sedimentation rate and interleukin-6, and has small toxic and side effects; furthermore, 3- (1-hydroxyalkylene) indolone structures are also present in GSK3 kinase inhibitor II (Marta Bol os, Silvia Fernandez, Ignacio. journal of Biological Chemistry,2010,285,17693.) and in influenza endonuclease inhibitor III (Kevin E.B. Parkes, Philipp Ermert,
Figure RE-GDA0003426117150000011
journal of Medicinal Chemistry,2003,46, 1153), etc. In the field of synthesis, starting from 3- (1-hydroxyalkylene) indolones, a number of important compounds can be synthesized (Deyun Qian, Junliang Zhang.chemical Communications,2012,48, 7082; Egle M.Beccalli, France sca Clerici, Alessandro Marchesini.tetrahedron,2001,57, 4787-.
In view of the importance of 3- (1-hydroxyalkylene) indolones, different preparation processes were developed one after the other. The major methods currently used to synthesize 3- (1-hydroxyalkylene) indolone structures can be broadly divided into two broad categories. One is directly synthesized by indolone, and the structure of 3- (1-hydroxy alkylidene) indolone is synthesized by modifying five-membered ring of indolone constructed in advance. The hydrogen at the 3-position of the indolone is very active and can be easily removed under the action of alkali to form carbanions which can generate nucleophilic addition reaction with carboxylic acid derivatives, such as acyl chloride, ester or ortho methyl ester, and the like to obtain the corresponding 3- (1-hydroxy alkylene) indolone structure (M a)&Development,2000,4, 10.). Such methods have been found to be early and suitable for large scale preparation, but the indole ring substituents in the productThe functional groups must be built up in a previous step. The other is the construction of 3- (1-hydroxy alkylene) indolone structure by intramolecular cyclization reaction of substituted acetanilide. Using acetanilide in the presence of a base and an oxidant Ag2The 3- (1-hydroxyalkylene) indolone structure is generated under the action of O, the operation is simple, the raw material is easy to prepare, but the reaction yield is low, the large-scale production and use are not suitable, and the aryl 3- (1-hydroxyalkylene) indolone cannot be synthesized (Zhengsen Yu, Lijuan Ma, Wei Yu. Synlett,2010,17, 2607.). The preparation of 3- (1-hydroxyalkylene) indolones using acetyl-2-iodoaniline in the presence of a copper catalyst and proline, which must be carried out using a specific iodoaniline, limits the applicability of the reaction (Biao Lu, Dawei Ma. Organic Letters,2006,8, 6115). Propynamide is activated to generate a 3- (1-hydroxyalkylene) indolone structure through intramolecular C-H bond of gold carbene under the catalysis of noble metal gold (II), the reaction condition is mild, the substrate range is wide, the yield can reach 95%, but a complex catalyst system is required to be used in the reaction process, and the reaction process needs to be carried out under strict anhydrous and anaerobic conditions, so that the popularization and application of the method are limited (Deyun Qian, Junliang Zhang, Chemical Communications,2012,48, 7082). Diazoanilide compounds are common raw materials for constructing 3- (1-hydroxyalkylene) indolone structures by intramolecular cyclization reaction generated by C-H bond activation of metal carbene. Diazoacylanilides can effect this conversion under the catalysis of a variety of transition metals (Nola Etkin, Suresh D. Babu, Catherine J. Fooks, et al. the Journal of Organic Chemistry,1990, 55, 1093; Wai-Wing Chan, Tsz-Lung Kwong, Wing-Yiu Yu. Organic Chemistry&Biomolecular Chemistry,2012,10, 3749; Hong-Li Wang, Zhe Li, Gang-Wei Wang, et al chemical Communications,2011,47, 11336; shanyan Mo, Zhanhui Yang, Jianxi xu. European Journal of Organic Chemistry,2014,2014,3923.). However, the use of diazo compounds is often limited due to their unstable specific structural properties, tendency to dimerize, tendency to explode, and high toxicity, and is not suitable for mass reactions. Thus, the search for non-diazocarbene precursors has been an important area of investigation by organic chemists. The dicarbonyl sulfur ylide is taken as a carbene precursor to generate under the action of a photocatalyst containing noble metal Ir3- (1-hydroxy alkylidene) indolone (Xu-Dong Xia, Liang-Qiu Lu, Wen-Qiang Liu, et al.chemistry-A European Journal,2016,22,8432) is obtained with high yield by photoreaction, but the photocatalyst used in the reaction is expensive, and the strict reaction conditions are not favorable for large-scale production.
Disclosure of Invention
The invention provides 3- (1-hydroxyalkylene) indolone and a preparation method thereof, aiming at solving the technical problems that in the prior art, a photocatalyst is expensive, the reaction conditions are strict, and the method is not beneficial to large-scale production and use in the method for synthesizing the 3- (1-hydroxyalkylene) indolone by using dicarbonyl sulfur ylide as a carbene precursor under the action of the photocatalyst containing noble metal Ir. The preparation method of the invention adopts dicarbonyl oxygen sulfur ylide compounds as raw materials, the raw materials are simple and easy to obtain, and complicated operation is not needed, thus the preparation method is a simple and convenient method suitable for large-scale preparation. The 3- (1-hydroxy alkylidene) indolone is a very important organic intermediate and drug intermediate.
In order to solve the technical problems, the technical scheme of the invention is as follows:
the invention provides 3- (1-hydroxyalkylene) indolone, which is 3- (1-hydroxyalkylene) indolone shown in a formula [1] obtained by activating a dicarbonyl oxysulfide ylide intramolecular C-H bond shown in a formula [2 ];
Figure RE-GDA0003426117150000031
Figure RE-GDA0003426117150000041
formula [1]Is of the formula [2]In, R1、R2And R3Each independently represents an alkyl group having 1 to 15 carbon atoms, a cycloalkyl group having 3 to 15 carbon atoms, a cycloalkylalkyl group having 4 to 15 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 15 carbon atoms; wherein the aryl group may have an alkyl group, an alkoxy group, an aryloxy group in the ortho-or para-positionFluorine, chlorine, bromine, cyano, nitro, or the like; cycloalkyl and aryl groups may be fused rings; r1、R2And R3It is also possible to form a carbocycle or heterocycle with the phenyl radical.
The alkyl refers to a straight chain or branched chain alkyl with 1-15 carbon atoms, such as: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, nonyl, decyl, undecyl, or dodecyl and the like. The linear or branched alkyl group having 1 to 12 carbon atoms is preferable, the linear or branched alkyl group having 3 to 10 carbon atoms is particularly preferable, and the linear or branched alkyl group having 3 to 8 carbon atoms is most preferable.
The cycloalkyl group means a cyclic alkyl group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
The cycloalkylalkyl group means a cyclic alkyl group substituted alkyl group having 4 to 15 carbon atoms, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptylmethyl group, a cyclooctylmethyl group, a cyclopropylethyl group, a cyclobutylethyl group, a cyclopentylethyl group, a cyclohexylethyl group, a cycloheptylethyl group, a cyclooctylethyl group, a cyclopropylpropyl group, a cyclobutylpropyl group, a cyclopentylpropyl group, a cyclohexylpropyl group, a cycloheptylpropyl group, or a cyclooctylpropyl group, etc., preferably a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptylmethyl group, a cyclopropylethyl group, a cyclopentylethyl group, a cyclohexylethyl group, a cycloheptylethyl group, a cyclopropylpropyl group, a cyclopentylpropyl group, a cyclohexylpropyl group, or a cycloheptylpropyl group.
The aryl group is an aryl group having 6 to 15 carbon atoms or an aryl group substituted with a substituent, for example, a phenyl group, an o-methylphenyl group, an m-methylphenyl group, a p-methylphenyl group, an o-methoxyphenyl group, an m-methoxyphenyl group, a p-methoxyphenyl group, an o-fluorophenyl group, an m-fluorophenyl group, a p-fluorophenyl group, an o-chlorophenyl group, a m-chlorophenyl group, a p-chlorophenyl group, an o-nitrophenyl group, a p-nitrophenyl group, an o-cyanophenyl group, a m-cyanophenyl group, a p-cyanophenyl group, a biphenyl group, a 1-naphthyl group, a 2-naphthyl group, a substituted naphthyl group or the like.
The aralkyl group refers to an aryl-substituted alkyl group having 7 to 15 carbon atoms. For example, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, o-cyanobenzyl, m-cyanobenzyl, p-cyanobenzyl, biphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, substituted naphthylmethyl, phenylethyl, phenylpropyl, phenylbutyl or phenylpentyl groups, etc.
Preferred R1Represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, p-tolyl, p-chlorophenyl, p-fluorophenyl, p-nitrophenyl, p-methoxyphenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, o-cyanobenzyl, m-cyanobenzyl, p-cyanobenzyl, o-n-nitrobenzyl, p-chlorobenzyl, p-nitrobenzyl, o-cyanobenzyl, m-cyanobenzyl, p-n, p-cyanobenzyl, p-b, b-b, p-b-cyanobenzyl, p-b, Biphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl; more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, o-methylbenzyl, o-pentyl, sec-pentyl, neopentyl, and neopentyl,M-methoxybenzyl, p-methoxybenzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, o-cyanobenzyl, m-cyanobenzyl, biphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl, phenylpropyl or phenylbutyl; most preferred is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl, phenethyl or phenylpropyl.
Preferred R2Represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, p-tolyl, p-chlorophenyl, p-fluorophenyl, p-nitrophenyl, p-methoxyphenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, o-cyanobenzyl, m-cyanobenzyl, p-cyanobenzyl, o-n-nitrobenzyl, p-chlorobenzyl, p-nitrobenzyl, o-cyanobenzyl, m-cyanobenzyl, p-n, p-cyanobenzyl, p-b, b-b, p-b-cyanobenzyl, p-b, Biphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl; more preferred is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, o-fluorobenzylMethyl, m-fluorophenylmethyl, p-fluorophenylmethyl, o-chlorophenylmethyl, m-chlorophenylmethyl, p-chlorophenylmethyl, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, o-cyanophenylmethyl, m-cyanophenylmethyl, p-cyanophenylmethyl, biphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl, phenylpropyl or phenylbutyl; most preferred is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl, phenethyl or phenylpropyl.
Preferred R3Represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, p-tolyl, p-chlorophenyl, p-fluorophenyl, p-nitrophenyl, p-methoxyphenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, o-cyanobenzyl, m-cyanobenzyl, p-cyanobenzyl, o-n-nitrobenzyl, p-chlorobenzyl, p-nitrobenzyl, o-cyanobenzyl, m-cyanobenzyl, p-n, p-cyanobenzyl, p-b, b-b, p-b-cyanobenzyl, p-b, Biphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl, phenylpropyl, phenylbutyl or phenylpentyl; more preferred is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-chlorobenzylA phenyl group, a m-chlorobenzyl group, a p-chlorobenzyl group, an o-nitrobenzyl group, a m-nitrobenzyl group, a p-nitrobenzyl group, an o-cyanobenzyl group, a m-cyanobenzyl group, a p-cyanobenzyl group, a biphenylmethyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group, a phenethyl group, a phenylpropyl group or a phenylbutyl group; most preferred are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl, phenylethyl, phenylpropyl.
The invention also provides a preparation method of the 3- (1-hydroxyalkylene) indolone, which comprises the following steps:
the dicarbonyl oxygen sulfur ylide shown in the formula [2] is subjected to intramolecular carbene insertion reaction to obtain 3- (1-hydroxy alkylidene) indolone shown in the formula [1 ];
Figure RE-GDA0003426117150000071
wherein R is1、R2And R3Each independently represents an alkyl group having 1 to 15 carbon atoms, a cycloalkyl group having 3 to 15 carbon atoms, a cycloalkylalkyl group having 4 to 15 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 15 carbon atoms.
Further, the solvent used in the above reaction is one or more of acetonitrile, propionitrile, butyronitrile, valeronitrile, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane, tetrachloroethylene and dichlorobenzene.
More preferably, the preparation method is that the 3- (1-hydroxyalkylene) indolone shown in the formula [1] is prepared by direct intramolecular cyclization reaction catalyzed by dichloro (pentamethylcyclopentadienyl) rhodium in a mixed solution of 1, 2-dichloroethane and acetonitrile through dicarbonyl thioxoylide.
Further, the reaction is carried out for 10-24 hours at the temperature of 80-150 ℃ by stirring.
The invention has the beneficial effects that:
the 3- (1-hydroxy alkylidene) indolone compounds prepared by the invention are very important organic intermediates, have wide application in the fields of pharmaceutical chemistry and synthetic chemistry, and show various biological activities, such as anti-inflammation, sterilization and the like.
The preparation method of the 3- (1-hydroxyalkylene) indolone provided by the invention takes the simple and easily available dicarbonyl oxysulfide as a raw material, and the raw material can be purchased from public commercial channels or prepared according to a known method. The method is simple to operate, has a short synthetic route, can be used for synthesizing 3- (1-hydroxyalkylene) indolone compounds containing structural diversity, is suitable for large-scale preparation, and has very important significance for the synthesis and application of the compounds.
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example one
5-chloro-3- (1-hydroxyvinyl) -1-methylindol-2-one
N- (4-chlorophenyl) -2- (dimethyl (oxo) -l 6-thioylide) -N-methyl-3-oxopropanamide (60mg) was placed in a 10mL reaction tube, 2mL of dried 1, 2-dichloroethane was added, dichloro (pentamethylcyclopentadienyl) rhodium (5mg) was added, and the reaction was stirred at 100 ℃ for 20 hours. Filtering, removing solvent from the filtrate by spinning, and separating by silica gel column to obtain light yellow solid. 31mg, yield 69%, Rf＝0.42(PE/EA＝2:1,v/v). 1H NMR(300MHz,Chloroform-d)δ12.09(br.s,1H),7.34–7.24(m,1H),7.17(dd, J＝8.3,2.0Hz,1H),6.84(d,J＝8.4Hz,1H),3.32(s,3H),2.44(s,3H).13C NMR (75MHz,Chloroform-d)δ174.3,170.8,137.2,127.6,124.8,123.6,119.7,109.1, 101.2,25.8,20.4,
Example two
1-benzyl-3- (1-hydroxyvinyl) -1-methylindol-2-one
By the method described in example one, using N-phenyl-2- (dimethyl (oxo) -l 6-Thiobesite) -N-benzyl-3-oxopropanamide (66mg) as starting material gave 1-phenyl-3- (1-hydroxyvinyl) -1-methylindol-2-one as a yellow solid, 35mg, yield 69%, Rf＝0.58(PE/EA＝2:1,v/v).1H NMR(300 MHz,Chloroform-d)δ13.59(br.s,1H),7.42–7.36(m,1H),7.33–7.26(m,5H), 7.15–7.05(m,2H),6.86(dd,J＝7.0,1.9Hz,1H),5.06(s,2H),2.49(s,3H)；13C NMR(75MHz,Chloroform-d)δ173.3,171.1,138.1,136.1,128.8,127.6,127.2, 125.2,122.4,122.2,119.8,109.4,101.7,43.3,20.4.
EXAMPLE III
3- (1-hydroxyvinyl) -1, 5-dimethylindol-2-one
Following the procedure described in example one, starting from N- (4-methylphenyl) -2- (dimethyl (oxo) -l 6-thioylide) -N-methyl-3-oxopropanamide (56mg), 3- (1-hydroxyvinyl) -1, 5-dimethylindol-2-one was obtained as a yellow solid, 30mg, yield 74%, Rf＝0.37(PE/EA＝2:1,v/v).1H NMR(300MHz,Chloroform-d)δδ13.44(br.s,1H),7.17(s,1H),7.03(d,J＝8.0 Hz,1H),6.83(d,J＝8.0Hz,1H),3.32(s,3H),2.44(s,3H),2.40(s,3H).；.13C NMR (75MHz,Chloroform-d)δ172.5,171.0,136.7,131.4,125.6,122.2,120.4,108.0, 101.6,50.7,21.4,20.2.
Example four
3- (1-hydroxyvinyl) -1-methylindol-2-one
Following the procedure described in example one, starting from N-phenyl-2- (dimethyl (oxo) -l 6-thioylide) -N-methyl-3-oxopropanamide (53mg), 3- (1-hydroxyvinyl) -1-methylindol-2-one was obtained as a yellow solid, 33mg, yield 87%, Rf＝0.39(PE/EA＝2:1,v/v).1H NMR(300MHz, Chloroform-d)δ13.42(br.s,1H),7.36(d,J＝7.5Hz,1H),7.22(dd,J＝7.7,7.5Hz, 1H),7.11(dd,J＝7.5,7.5Hz,1H),6.94(d,J＝7.8Hz,1H),3.34(s,3H),2.45(s, 3H).13C NMR(75MHz,Chloroform-d)δ172.8,170.9,138.8,125.2,122.2,122.0, 119.6,108.3,101.7,29.7,25.6,20.2.
EXAMPLE five
1-phenyl-3- (1-hydroxyvinyl) -1-methylindol-2-one
Following the procedure described in example one, starting from N, N-diphenyl-2- (dimethyl (oxo) -l 6-thioylide) -3-oxopropanamide (82mg), 1-phenyl-3- (1-hydroxyvinyl) -1-methylindol-2-one was obtained as a yellow solid, 47mg, yield 75%, Rf＝0.42(PE/EA＝2:1,v/v).1H NMR(300 MHz,Chloroform-d)δ13.75(br.s,1H),7.56(t,J＝7.3Hz,2H),7.48–7.40(m,4H), 7.21–7.14(m,2H),6.97–6.95(m,1H),2.50(s,3H).13C NMR(75MHz, Chloroform-d)δ174.0,170.8,138.6,134.5,130.0,128.7,126.9,125.2,122.6,122.2, 119.5,109.8,101.6,20.3.
Example six antimicrobial activity test:
the antibacterial activity of the target compound was measured by the serial dilution method as follows.
Examples one to four experiments for the in vitro antibacterial activity of the prepared compounds were performed by a continuous dilution method, and the primary evaluation of the antibacterial activity was performed by measuring the Minimum Inhibitory Concentration (MIC). Four gram-positive bacteria were selected in this experiment, including: bacillus subtilis 1021(Bacillus subtilis 1021), Staphylococcus epidermidis 1917(Staphylococcus epidermidis 1917), Staphylococcus aureus 3519and4220 (Staphylococcus aureus 3519and4220), a gram-negative bacterium, Escherichia coli 1924(Escherichia coli 1924). Norfloxacin (Norfloxacin) was chosen as a positive control.
The specific operation steps are as follows:
5mg of the test sample was dissolved in 782. mu.L of DMSO, 20. mu.L of the test strain was inoculated in 2mL of MHB (Mueller-Hinton broth) medium and cultured to log phase, after which the bacteria were diluted to 10% with the medium in a petri dish5CFU/mL. First, 100 mu L of culture medium is taken to be based on a 96-well plate to be detected, and a series of samples with different concentrations are obtained according to the principle of a double dilution method. Then, 100. mu.L of the diluted solution of the bacteria to be detected is added into each micropore, and then the 96-well plate is placed into an enzyme-labeling instrument (650nm), and the absorbance is observed and recorded. After culturing at 37 ℃ in an incubator for 24 hours, the 96-well plate was placed in a microplate reader, and the absorbance at this time was recorded. The MIC value of each compound was obtained from the change in absorbance before and after the change. The experiments were performed 3 times in parallel. Data ofThe results are shown in Table 1.
TABLE 1
Figure RE-GDA0003426117150000111
It can be seen that the first, second, third and fourth examples have certain antibacterial activity against different gram-positive or gram-negative bacteria, respectively.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims (10)

1. A3- (1-hydroxyalkylene) indolone represented by the following formula [1 ]:
Figure FDA0003382821000000011
wherein R is1、R2And R3Each independently represents an alkyl group having 1 to 15 carbon atoms, a cycloalkyl group having 3 to 15 carbon atoms, a cycloalkylalkyl group having 4 to 15 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 15 carbon atoms.
2. 3- (1-hydroxyalkylene) indolone according to claim 1, which is obtained by activating a dicarbonyloxythioylide bond represented by the formula [2 ];
Figure FDA0003382821000000012
3. 3- (1-hydroxyalkylene) indolone according to claim 1 wherein said aryl group contains an alkyl group, an alkoxy group, an aryloxy group, fluorine, chlorine, bromine, a cyano group or a nitro group.
4. 3- (1-hydroxyalkylene) indolone of claim 1 wherein said cycloalkyl or aryl group is a fused ring.
5. 3- (1-hydroxyalkylene) indolone of claim 1 wherein R is1、R2And R3It is also possible to form a carbocycle or heterocycle with the phenyl radical.
6. 3- (1-hydroxyalkylene) indolone of claim 1 wherein R is1、R2And R3Each independently represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, p-tolyl, p-chlorophenyl, p-bromophenyl, p-fluorophenyl, p-nitrophenyl, p-methoxyphenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-nitrobenzyl, o-cyanobenzyl, m-cyanobenzyl, o-fluorobenzyl, p-nitrobenzyl, p-chlorobenzyl, m-chlorobenzyl, p-nitrobenzyl, o-cyanobenzyl, m-cyanobenzyl, n-b-nitrobenzyl, p-cyanobenzyl, p-b, P-cyanobenzyl, biphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, phenylethyl, phenylpropyl, phenylbutyl or phenylpentyl.
7. A process for the preparation of a 3- (1-hydroxyalkylene) indolone of claim 1 comprising the steps of:
the dicarbonyl oxygen sulfur ylide shown in the formula [2] is subjected to intramolecular carbene insertion reaction to obtain 3- (1-hydroxy alkylidene) indolone shown in the formula [1 ];
Figure FDA0003382821000000021
wherein R is1、R2And R3Each independently represents an alkyl group having 1 to 15 carbon atoms, a cycloalkyl group having 3 to 15 carbon atoms, a cycloalkylalkyl group having 4 to 15 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 15 carbon atoms.
8. The method for preparing 3- (1-hydroxyalkylene) indolone according to claim 7, wherein the solvent used in the reaction is one or more selected from acetonitrile, propionitrile, butyronitrile, valeronitrile, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane, tetrachloroethylene and dichlorobenzene.
9. The process for producing 3- (1-hydroxyalkylene) indolone according to claim 7, wherein the 3- (1-hydroxyalkylene) indolone represented by the formula [1] is produced by direct intramolecular cyclization reaction catalyzed by dichloro (pentamethylcyclopentadienyl) rhodium in a mixed solution of 1, 2-dichloroethane and acetonitrile by using dicarbonyloxythioylide.
10. The method for preparing 3- (1-hydroxyalkylene) indolone according to claim 7, wherein the reaction is carried out at 80-150 ℃ for 10-24 hours under stirring.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1440589A (en) * 1964-07-21 1966-05-27 Basf Ag Process for the production of novel sulfur-containing compounds
US3442901A (en) * 1965-07-19 1969-05-06 Basf Ag Dimethyl-oxo-surfurylene derivatives
CN1944406A (en) * 2006-10-24 2007-04-11 中国科学院上海有机化学研究所 Indole heterocyclic compounds and intermediate, and synthetic method

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1440589A (en) * 1964-07-21 1966-05-27 Basf Ag Process for the production of novel sulfur-containing compounds
US3442901A (en) * 1965-07-19 1969-05-06 Basf Ag Dimethyl-oxo-surfurylene derivatives
CN1944406A (en) * 2006-10-24 2007-04-11 中国科学院上海有机化学研究所 Indole heterocyclic compounds and intermediate, and synthetic method

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