CN114957097B - Preparation method of indoline compound - Google Patents
Preparation method of indoline compound Download PDFInfo
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- CN114957097B CN114957097B CN202210615743.4A CN202210615743A CN114957097B CN 114957097 B CN114957097 B CN 114957097B CN 202210615743 A CN202210615743 A CN 202210615743A CN 114957097 B CN114957097 B CN 114957097B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/96—Spiro-condensed ring systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Abstract
The invention discloses a preparation method of indoline compounds, and belongs to the technical field of organic synthesis. The preparation method of the invention comprises the following steps: the indoline compound is prepared by cyclizing an indole compound and an alkyne compound under the action of a metal catalyst and acid. The preparation raw materials of the invention are subjected to the combined action of the metal catalyst and the acid; intramolecular and intermolecular [2+2] cycloaddition occurs; the indoline compound is prepared. The preparation method of the invention has high atom economy and high selectivity, and realizes the large-scale preparation of indoline compounds; the preparation raw materials, the metal catalyst and the acid are cheap and easy to obtain; thereby greatly reducing the production cost.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of indoline compounds.
Background
Cyclobutene is widely found in natural products or drug molecules. Meanwhile, due to ring tension and reactivity, the modified polyethylene can be used as an important synthesis precursor of a core skeleton in various natural products or drug molecules, and is present in various active molecules. On the other hand, indoline compounds are also widely present as core skeletons in indole alkaloids and drug molecules.
The preparation of the cyclobutenoindoline compounds in the related art mainly comprises the following strategies: (1) Photocatalytic intermolecular [2+2] cycloaddition, and the N-Me substituted indole derivative and electron-deficient alkyne are used for constructing a cyclobutene indoline compound; (2) Acid-catalyzed intermolecular [2+2] cycloaddition, wherein N-1-alkyl substituted indole derivatives and conjugated alkyne are used as substrates to construct a cyclobutene indoline compound; (3) Photocatalytic intramolecular [2+2] cycloaddition is carried out by introducing long-chain alkyne from N-1 position of indole for cyclization, thus constructing the multi-condensed ring cyclobutenoindoline compound. It is noted that the above method is limited by the electronic nature of the alkene and alkyne, often applicable to specific substrates, and has poor selectivity.
In summary, there is a need to develop a method for preparing indolines, which has a good selectivity.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides a preparation method of indoline compounds, which has good selectivity.
The invention provides a preparation method of indoline compounds, which comprises the following steps:
the indole compound and the alkyne compound are subjected to cyclization reaction under the action of a metal catalyst and acid to prepare the indoline compound;
the indole compound is a compound shown in a formula I or a formula II;
the alkyne compound is a compound shown in a formula I or a compound shown in a formula III;
the indoline compound is one of a compound shown in a formula IV, a compound shown in a formula V or a compound shown in a formula VI;
the compound shown in the formula I and the compound shown in the formula IV are respectively and independently selected from one of methylene, oxygen atoms, NTs and 2, 2-dimethyl malonate groups;
compounds of formula I, formula II, formula IV, formula V and formula VI R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 Each independently selected from one of hydrogen, halogen atom, nitro, alkyl, haloalkyl, alkoxy, aryl, substituted aryl, heteroaryl, acyloxy, amido and hydroxyalkyl;
compounds of formula III, formula V and formula VI, R in the compounds 8 、R 9 And are independently selected from one of hydrogen, halogen atom, alkyl, alkoxy, amido, aryl and substituted aryl.
According to one of the technical schemes of the preparation method, the preparation method at least has the following beneficial effects:
the preparation raw material of the invention is under the combined action of the metal catalyst and the acid (the metal catalyst can activate alkynyl and then is attacked and cyclized by enamine of indole to generate indoline), the acid can enhance the activation capability of the metal on one hand and avoid being poisoned due to complexation of indole nitrogen atom and the metal catalyst on the other hand; intramolecular and intermolecular [2+2] cycloaddition occurs; the indoline compound is prepared. The preparation method of the invention has high atom economy and high selectivity, and realizes the large-scale preparation of indoline compounds; meanwhile, the preparation raw materials, the metal catalyst and the acid are cheap and easy to obtain; thereby greatly reducing the production cost.
According to some embodiments of the invention, the indoline is a cyclobutenoindoline.
According to some embodiments of the invention, the NTs have the formula:
wherein the dashed line represents the position where the dehydrogen atom forms a radical.
According to some embodiments of the invention, the NTs are groups formed by the loss of two hydrogen atoms from the nitrogen atom in the tosylamide.
According to some embodiments of the invention, the dimethyl 2, 2-malonate group has a structural formula as follows:
according to some embodiments of the invention, the alkyl is C 1～5 Is a hydrocarbon group.
According to some embodiments of the invention, the alkyl group is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
According to some embodiments of the invention, the alkoxy group is C 1～5 Alkoxy groups of (a).
According to some embodiments of the invention, the alkyl group is one of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.
According to the inventionSome embodiments, the haloalkyl is C 1～5 Is a haloalkyl group of (2).
According to some embodiments of the invention, the haloalkyl is one of fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl.
According to some embodiments of the invention, the fluoroalkyl is C 1～5 Is a fluorinated alkyl group of (2).
According to some embodiments of the invention, the fluoroalkyl is trifluoromethyl.
According to some embodiments of the invention, the chloroalkyl is C 1～5 Is a chlorinated alkyl group.
According to some embodiments of the invention, the bromoalkyl group is C 1～5 Is a bromoalkyl group of (2).
According to some embodiments of the invention, the iodo-alkyl group is C 1～5 Is an iodinated alkyl group.
According to some embodiments of the invention, the aryl is C 1～20 Aryl groups of (a).
According to some embodiments of the invention, the aryl is one of phenyl, naphthyl.
According to some embodiments of the invention, the heteroaryl is C 1～20 Heteroaryl of (a).
According to some embodiments of the invention, the heteroaryl is at least one of thienyl, furyl, pyridyl, imidazolyl, thiazolyl, piperazinyl.
According to some embodiments of the invention, at least one H in the substituted aryl is substituted with a corresponding group as defined herein.
According to some embodiments of the invention, the substituted aryl is substituted phenyl.
According to some embodiments of the invention, the substitution positions in the substituted phenyl groups may be ortho, meta and para.
According to some embodiments of the invention, the substituted phenyl is one of o-methoxyphenyl, phenol, nitrophenyl, benzyl, cyanophenyl, fluorophenyl, trifluoromethylphenyl, tolyl.
Any substituent of the present invention may be attached to the parent nucleus structure at any position that can be substituted without particular definition.
According to some embodiments of the invention, the halogen atom is one of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
According to some embodiments of the invention, the hydroxyalkyl group is C 1 ～C 5 Hydroxyalkyl groups of (a).
According to some embodiments of the invention, the hydroxyalkyl group is one of hydroxymethyl, hydroxyethyl, hydroxypropyl.
According to some embodiments of the invention, the acyloxy group is C 1 ～C 10 Is an acyloxy group.
According to some embodiments of the invention, the acyloxy group is-CH 2 COOEt。
According to some embodiments of the invention, the amide group is one of a sulfonamide group, a carboxamide group, an acetamido group, a benzamide group.
According to some embodiments of the invention, the sulfonamide group is a sulfonamide ethyl group.
According to some embodiments of the invention, the sulfonylaminoethyl group is-CH 2 CH 2 NHTs。
The substituent is selected, so that the yield of the preparation method is improved.
According to some embodiments of the invention, the metal catalyst is at least one of an iron catalyst or a copper catalyst.
The price of the iron catalyst and the copper catalyst is low, and the catalysts are selected, so that the production cost is greatly reduced; meanwhile, the iron catalyst and the copper catalyst have good catalytic effect on the reaction, thereby greatly improving the yield of the reaction.
According to some embodiments of the invention, the iron catalyst is at least one of ferric trichloride, ferric nitrate, ferric triflate, ferric p-toluenesulfonate, ferric sulfate, ferric oxide, ferrous acetate.
According to some embodiments of the invention, the copper catalyst is one of copper nitrate, copper bromide, and cuprous bromide.
The metal salt has high catalytic efficiency (only 10% equivalent is needed to catalyze the reaction smoothly), low price and low production cost.
According to some embodiments of the invention, the acid is a strong mineral acid or a sulfonic acid compound.
According to some embodiments of the invention, the strong inorganic acid is at least one of nitric acid and hydrogen chloride.
According to some embodiments of the invention, the sulfonic acid compound is at least one of p-toluene sulfonic acid and trifluoro methane sulfonic acid.
The acid can obviously activate alkynyl, and the price of the acid is low; thereby reducing the production cost.
According to some embodiments of the invention, the solvent for the cyclization reaction is at least one of chloroform, dichloromethane, dichloroethane, 1, 2-dichloroethane, toluene, 1, 4-dioxane, methanol, ethanol, acetonitrile, trifluoroethanol, and hexafluoroisopropanol.
According to some embodiments of the invention, the temperature of the cyclization reaction is-10 ℃ to 100 ℃.
By controlling the reaction temperature, the reaction yield and the regioselectivity are improved.
According to some embodiments of the invention, the cyclisation reaction temperature is 25 ℃ to 70 ℃.
According to some embodiments of the invention, the cyclization reaction time is from 0.5h to 10h.
According to some embodiments of the present invention, a method for preparing a compound of formula iv comprises the steps of:
the compound shown in the formula I, a metal catalyst, acid and a solvent are mixed to carry out intramolecular cyclization reaction.
According to some embodiments of the invention, the ratio of the amounts of the compound of formula I and the metal catalyst in the intramolecular cyclization reaction is 1:0.01-0.5.
According to some embodiments of the invention, the ratio of the amounts of the compound of formula I and the acid in the intramolecular cyclization reaction is 1:0.1-5.
According to some embodiments of the invention, the compound of formula I, the acid, the metal catalyst and the solvent comprise a mixture prior to intramolecular cyclization; the molar concentration of the compound shown in the formula I in the mixture is 0.01mol/L to 5.0mol/L.
According to some embodiments of the invention, the temperature of the intramolecular cyclization reaction is-10 ℃ to 100 ℃.
According to some embodiments of the invention, the temperature of the intramolecular cyclization reaction is 25 ℃ to 70 ℃.
According to some embodiments of the invention, the intramolecular cyclization reaction time is from 0.5h to 10h.
According to some embodiments of the invention, after the intramolecular cyclization reaction is finished, adding triethylamine for quenching and solid-liquid separation; the liquid phase was collected, concentrated under reduced pressure and then subjected to column chromatography.
According to some embodiments of the invention, the chromatographic liquid of the column chromatography consists of petroleum ether and ethyl acetate.
According to some embodiments of the invention, the volume ratio of petroleum ether to ethyl acetate is 7-9:1.
According to some embodiments of the present invention, a process for preparing a compound of formula i comprises the steps of:
s1, mixing a compound shown in a formula VII, carbonate, halopropyne and a ketone solvent for reaction to prepare an intermediate;
s2, mixing the intermediate, a compound shown in a formula VIII, a palladium catalyst, cuprous halide, an amine compound and an amide solvent for reaction;
wherein Y in the formula IX is one of chlorine atom, bromine atom and iodine atom.
According to one embodiment of the invention, the temperature of the reaction in step S1 is 50 to 70 ℃.
According to some embodiments of the invention, the carbonate is at least one of potassium carbonate, sodium carbonate, and cesium carbonate.
According to some embodiments of the invention, the halopropyne is at least one of propargyl chloride, propargyl bromide, and propargyl iodide.
According to some embodiments of the invention, the ketone solvent is acetone or butanone.
According to some embodiments of the invention, the molar ratio of the compound of formula VII, the carbonate and the halopropyne is from 1:1 to 1.1:1 to 1.1.
According to one embodiment of the invention, the temperature of the reaction in step S2 is 20 ℃ to 30 ℃.
According to some embodiments of the invention, the palladium catalyst is Pd (PPh 3 ) 4 。
According to some embodiments of the invention, the cuprous halide is at least one of cuprous chloride, cuprous bromide, and cuprous iodide.
According to some embodiments of the invention, the amine compound is triethylamine (Et) 3 N)。
According to some embodiments of the invention, the amide solvent is DMF (N, N-dimethylformamide).
According to some embodiments of the invention, the molar ratio of the compound of formula viii, the palladium catalyst, the cuprous halide and the amine compound is 1: 1-1.5:0.01-0.1:0.1-0.2: 1.5 to 2.5. According to some embodiments of the present invention, a method for preparing a compound represented by formula V or a compound represented by VI comprises the steps of:
the compound shown in the formula II, the compound shown in the formula III, the metal catalyst, the acid and the solvent are mixed to carry out intermolecular cyclization reaction.
According to some embodiments of the invention, the intermolecular cyclization reaction is carried out such that the ratio of the amounts of the compound of formula II to the compound of formula III is 1:0.9 to 2.0.
According to some embodiments of the invention, the intermolecular cyclization reaction is carried out in an amount of 1:1 to 1.5 of the compound of formula II to the compound of formula III.
According to some embodiments of the invention, the intermolecular cyclization reaction is such that the ratio of the amounts of the compound of formula II and the metal catalyst is from 1:0.01 to 0.5.
According to some embodiments of the invention, the intermolecular cyclization reaction is such that the ratio of the amounts of the compound of formula II and the acid is 1:0.1-5.
According to some embodiments of the present invention, prior to the intermolecular cyclization reaction, a mixture of a compound of formula II, a compound of formula III, an acid, a metal catalyst, and a solvent; the molar concentration of the compound shown in the formula II in the mixture is 0.01 mol/L-5.0 mol/L.
According to some embodiments of the invention, the intermolecular cyclization reaction has a concentration ranging from 0.01mol/L to 5.0mol/L.
According to some embodiments of the invention, the intermolecular cyclization reaction is at a temperature of-10 ℃ to 100 ℃.
According to some embodiments of the invention, the temperature of the intermolecular cyclization reaction is 25 ℃ to 70 ℃.
According to some embodiments of the invention, the intermolecular cyclization reaction time is 0.5h to 10h.
According to some embodiments of the invention, after the intermolecular cyclization reaction is finished, adding triethylamine for quenching and solid-liquid separation; the liquid phase was collected, concentrated under reduced pressure and then subjected to column chromatography.
According to some embodiments of the invention, the chromatographic liquid of the column chromatography consists of petroleum ether and ethyl acetate.
According to some embodiments of the invention, the volume ratio of petroleum ether to ethyl acetate is 7-9:1.
According to some embodiments of the invention, the indolines are used for the preparation of benzazepines.
According to some embodiments of the invention, the compound of formula iv, the compound of formula v or the compound of formula vi is used for preparing a benzazepine compound.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
In the description of the present invention, the descriptions of the terms "one embodiment," "some embodiments," "illustrative embodiments," "examples," "specific examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The chemical reagents used in the following reactions are all commercially available starting materials and no further treatment is required. The yield of each reaction was calculated by column chromatography separation yield or HPLC, and each reaction was detected by a Qingdao silica gel thin layer analysis plate under UV, developed by iodine and developed by heating after infiltration with ethanol solutions of sulfuric acid and phosphomolybdic acid.
Nuclear magnetic spectra were obtained by Bruker Advance 500 (1 h:500mhz,13c:125 mhz) analysis. The abbreviations below are used to explain the split case, s stands for single, d stands for doublet, t stands for triplet, q stands for quateset, m stands for multiplet, and b stands for broad.
Specific embodiments of the present invention are described in detail below.
The preparation method of the compound 1 with the general formula as a raw material in the embodiment comprises the following steps:
the first step: to a solution of the compound of formula S1 (1.0 mmol,1.0 eq.) in acetone (3 mL) at room temperature (25 ℃ C.) was added potassium carbonate (1.1 mmol,1.1 eq.) and propargyl bromide (1.1 mmol,1.1 eq.) in this order, and after the addition was completed, the reaction system was heated to 60 ℃ C., until the reaction was completed. After cooling to room temperature, adding saturated ammonium chloride aqueous solution to quench the reaction, extracting the aqueous phase with ethyl acetate three times (15 ml x 3), merging the organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing silica gel column chromatography to obtain the intermediate S2.
And a second step of: pd (PPh) was added sequentially to a solution of S2 (2.0 mmol,1.0 eq.) in DMF (2 mL) at room temperature (25 ℃ C.) under nitrogen atmosphere 3 ) 4 (0.1 mmol,0.05 eq.) and CuI (0.2 mmol,0.1 eq.) Et 3 N (4.0 mmol,2.0 eq.) was added and stirred at room temperature (25 ℃) for 10 minutes, then aryl iodide (3.0 mmol,1.5 eq.) was added thereto, after completion of TLC detection, saturated aqueous ammonium chloride solution was added to quench the reaction, the aqueous phase was extracted three times with ethyl acetate (15 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then chromatographed on silica gel column to give Compound 1 of general formula (I).
The compounds 1a to 1t are prepared by referring to the preparation method of the compound 1 in the general formula.
Nb-p-Toluenesulfonyl tryptamine (CAS number: 86658-78-8) is selected as the general formula compound S1 in the preparation process of the compound 1 a; the aryl iodide is iodobenzene; white solid was prepared; from 1.45g of starting material, 1.58g of product 1a are obtained in 90% yield.
1 H NMR(400MHz,Chloroform-d)δ H 8.11(s,1H),7.84–7.76(m,2H),7.67(dd,J＝8.1,1.2Hz,1H),7.39(dt,J＝8.1,1.0Hz,1H),7.35–7.17(m,6H),7.14(d,J＝2.4Hz,1H),7.13–7.10(m,2H),7.08(ddd,J＝8.0,7.0,1.0Hz,1H),4.44(s,2H),3.78–3.43(m,2H),3.17(dd,J＝9.1,6.5Hz,2H),2.35(s,3H).
The preparation of compound 1b differs from that of compound 1a in that: the aryl iodide is 2-iodoanisole (CAS number is 529-28-2); yellow solid was prepared; 550mg of product 1b was obtained in 60% yield from 705mg of starting material.
1 H NMR(400MHz,Chloroform-d)δ H 8.12(s,1H),7.82–7.76(m,2H),7.70–7.64(m,1H),7.37(dt,J＝8.2,0.9Hz,1H),7.33–7.25(m,1H),7.23–7.16(m,3H),7.13(d,J＝2.3Hz,1H),7.05(ddd,J＝8.0,7.0,1.0Hz,1H),6.96(dd,J＝7.9,1.8Hz,1H),6.88–6.81(m,2H),4.50(s,2H),3.79(s,3H),3.66–3.58(m,2H),3.21–3.13(m,2H),2.32(s,3H).
The preparation of compound 1c differs from that of compound 1a in that: the aryl iodide is 2-iodophenol (CAS number: 533-58-4); yellow solid was prepared; 302mg of product 1c was obtained in 64% yield from 373mg of starting material.
1 H NMR(500MHz,Chloroform-d)δ H 8.09(s,1H),7.79–7.73(m,2H),7.60(dd,J＝8.0,1.3Hz,1H),7.41–7.35(m,1H),7.28–7.18(m,4H),7.11(d,J＝2.3Hz,1H),7.11–7.07(m,1H),7.06(dd,J＝7.8,1.7Hz,1H),6.90(dd,J＝8.4,1.1Hz,1H),6.83(td,J＝7.5,1.1Hz,1H),5.53–5.45(m,1H),4.39(s,2H),3.62(dd,J＝8.7,6.5Hz,2H),3.14(dd,J＝8.7,6.5Hz,2H),2.36(s,3H).
The preparation of compound 1d differs from that of compound 1a in that: the aryl iodide is 2-iodonitrobenzene (CAS number: 609-73-4); yellow solid was prepared; 343mg of product 1d were obtained in 83% yield from 381mg of starting material.
1 H NMR(500MHz,Chloroform-d)δ H 8.13(s,1H),8.01(dd,J＝8.2,1.4Hz,1H),7.76(d,J＝8.2Hz,2H),7.65(d,J＝7.9Hz,1H),7.51(td,J＝7.6,1.4Hz,1H),7.48–7.42(m,1H),7.37(d,J＝8.1Hz,1H),7.25(dd,J＝7.7,1.5Hz,1H),7.20–7.15(m,4H),7.09(t,J＝7.4Hz,1H),4.46(s,2H),3.71–3.64(m,2H),3.17(t,J＝7.6Hz,2H),2.27(s,3H).
The preparation of compound 1e differs from that of compound 1a in that: the aryl iodide is 3-iodoanisole (CAS number: 766-85-8); yellow solid was prepared; 703mg of product 1e were obtained in 76% yield from 709mg of starting material.
1 H NMR(400MHz,Chloroform-d)δ H 8.14(s,1H),7.83–7.76(m,2H),7.66(dq,J＝8.0,0.9Hz,1H),7.38(dt,J＝8.1,0.9Hz,1H),7.27–7.24(m,2H),7.23–7.16(m,2H),7.13(d,J＝2.4Hz,1H),7.08(ddd,J＝8.0,7.0,1.0Hz,1H),6.87(ddd,J＝8.3,2.7,1.0Hz,1H),6.72(dt,J＝7.6,1.2Hz,1H),6.66(dd,J＝2.7,1.4Hz,1H),4.43(s,2H),3.79(s,3H),3.65–3.57(m,2H),3.20–3.12(m,2H),2.35(s,3H).
The preparation of compound 1f differs from that of compound 1a in that: 3-methyl iodobenzene (CAS number: 625-95-6) is selected as aryl iodide; yellow solid was prepared; 751mg of product 1f was obtained in 85% yield from 704mg of starting material.
1 H NMR(500MHz,Chloroform-d)δ H 8.11(s,1H),7.80(d,J＝7.9Hz,2H),7.67(d,J＝7.9Hz,1H),7.38(d,J＝8.2Hz,1H),7.26(d,J＝8.1Hz,2H),7.21(t,J＝7.7Hz,1H),7.17–7.11(m,3H),7.08(t,J＝7.5Hz,1H),6.94(d,J＝6.0Hz,2H),4.44(s,2H),3.62(t,J＝7.9Hz,2H),3.16(t,J＝7.9Hz,2H),2.36(s,3H),2.32(s,3H).
Compound 1g was prepared by a procedure different from that of compound 1a in that: the aryl iodide is 4-iodoanisole (CAS number: 696-62-8); yellow solid was prepared; 640mg of product 1g was obtained in 68% yield from 718mg of starting material.
1 H NMR(400MHz,Chloroform-d)δ H 8.13(s,1H),7.83–7.75(m,2H),7.66(dq,J＝7.9,0.9Hz,1H),7.38(dt,J＝8.1,0.9Hz,1H),7.26–7.23(m,2H),7.21(ddd,J＝8.2,7.0,1.2Hz,1H),7.13(d,J＝2.4Hz,1H),7.11–7.04(m,3H),6.83–6.76(m,2H),4.42(s,2H),3.82(s,3H),3.65–3.56(m,2H),3.20–3.11(m,2H),2.36(s,3H).
The preparation of compound 1h differs from that of compound 1a in that: the aryl iodide is 4-methyl iodobenzene (CAS number: 624-31-7); yellow solid was prepared; 313mg of product was obtained 1h,73% yield from 352mg of starting material.
1 H NMR(500MHz,DMSO-d 6 )δ H 10.90–10.87(m,1H),7.76–7.71(m,2H),7.52(d,J＝7.9Hz,1H),7.35(d,J＝8.0Hz,3H),7.24(d,J＝2.3Hz,1H),7.13(d,J＝7.9Hz,2H),7.06(ddd,J＝8.1,6.9,1.2Hz,1H),7.01–6.96(m,2H),6.91(td,J＝7.4,6.8,1.0Hz,1H),4.45(s,2H),3.48–3.42(m,2H),3.06–3.00(m,2H),2.31(s,3H),2.28(s,3H).
The procedure for the preparation of compound 1i differs from that of compound 1a in that: the aryl iodide is 4-iodophenol (CAS number: 540-38-5); yellow solid was prepared; 378mg of product 1i was obtained in 80% yield from 373mg of starting material.
1 H NMR(500MHz,DMSO-d 6 )δ H 10.89–10.86(m,1H),9.85(s,1H),7.76–7.70(m,2H),7.52(d,J＝7.9Hz,1H),7.38–7.32(m,3H),7.23(d,J＝2.4Hz,1H),7.06(ddd,J＝8.2,6.9,1.2Hz,1H),6.95–6.88(m,3H),6.72–6.67(m,2H),4.42(s,2H),3.46–3.40(m,2H),3.05–2.98(m,2H),2.32(s,3H).
The preparation of compound 1j differs from that of compound 1a in that: the aryl iodide is 4-iodobenzonitrile (CAS number: 3058-39-7); yellow solid was prepared; from 529mg of starting material 501mg of product 1j were obtained in 74% yield.
1 H NMR(600MHz,Chloroform-d)δ H 8.18(s,1H),7.77(d,J＝7.9Hz,2H),7.61(d,J＝8.0Hz,1H),7.54(d,J＝7.9Hz,2H),7.39(d,J＝8.3Hz,1H),7.24(d,J＝8.0Hz,2H),7.21(t,J＝7.8Hz,1H),7.16(d,J＝8.0Hz,2H),7.13(s,1H),7.07(t,J＝7.8Hz,1H),4.42(s,2H),3.60(t,J＝7.8Hz,2H),3.15(t,J＝7.9Hz,2H),2.35(s,3H).
The process for the preparation of compound 1k differs from that of compound 1a in that: the aryl iodide is 4-fluoroiodobenzene (CAS number: 352-34-1); yellow solid was prepared; 266mg of product 1k was obtained in 57% yield from 352mg of starting material.
1 H NMR(400MHz,DMSO-d 6 )δ H 10.91–10.86(m,1H),7.77–7.70(m,2H),7.54–7.48(m,1H),7.38–7.31(m,3H),7.24(d,J＝2.4Hz,1H),7.22–7.11(m,4H),7.06(ddd,J＝8.2,7.0,1.2Hz,1H),6.91(ddd,J＝8.0,7.0,1.0Hz,1H),4.45(s,2H),3.49–3.40(m,2H),3.07–2.98(m,2H),2.30(s,3H).
The preparation of compound 1l differs from that of compound 1a in that: the aryl iodide is 4-trifluoromethyl iodobenzene (CAS number: 455-13-0); yellow solid was prepared; 350mg of product 1l were obtained from 352mg of starting material in 70% yield.
1 H NMR(400MHz,DMSO-d 6 )δ H 10.90(s,1H),7.77–7.72(m,2H),7.72–7.67(m,2H),7.52(dd,J＝7.9,1.1Hz,1H),7.38–7.31(m,3H),7.31–7.26(m,2H),7.25(d,J＝2.4Hz,1H),7.06(ddd,J＝8.2,7.0,1.2Hz,1H),6.92(ddd,J＝7.9,7.0,1.0Hz,1H),4.51(s,2H),3.53–3.44(m,2H),3.10–3.00(m,2H),2.26(s,3H).
The preparation of compound 1m differs from that of compound 1a in that: the compound S1 of the general formula is Nb-p-tolutesulfenyl-2-methyl tryptamine; yellow solid was prepared; from 743mg of starting material 807mg of product 1m was obtained in 90% yield.
1 H NMR(400MHz,Chloroform-d)δ H 7.89(s,1H),7.80–7.75(m,2H),7.56(d,J＝7.9Hz,1H),7.34–7.20(m,6H),7.15–7.10(m,3H),7.05–6.98(m,1H),4.45(s,2H),3.56–3.39(m,2H),3.14–3.05(m,2H),2.41(s,3H),2.34(s,3H).
The preparation of compound 1n differs from that of compound 1a in that: the aryl iodide is 1-iodonaphthalene (CAS number: 90-14-2); yellow solid was prepared; 752mg of product 1b were obtained from 705mg of starting material S2 in 79% yield.
1 H NMR(400MHz,Chloroform-d)δ H 8.07(s,1H),7.87–7.80(m,5H),7.67(dd,J＝8.0,1.2Hz,1H),7.52(ddd,J＝8.3,6.8,1.3Hz,1H),7.44(ddd,J＝8.2,6.8,1.3Hz,1H),7.41–7.34(m,3H),7.21–7.17(m,1H),7.16(s,1H),7.15(d,J＝1.6Hz,2H),7.02(ddd,J＝8.0,7.0,1.0Hz,1H),4.60(s,2H),3.78–3.64(m,2H),3.22(dd,J＝9.0,6.5Hz,2H),2.17(s,3H).
The procedure for the preparation of compound 1o differs from that of compound 1a in that: the aryl iodide is 2-iodothiophene (CAS number: 3437-95-4); yellow solid was prepared; from 705mg starting material 580mg of product 1o was obtained in 67% yield.
1 H NMR(400MHz,Chloroform-d)δ H 8.17(s,1H),7.82–7.76(m,2H),7.68(d,J＝7.9Hz,1H),7.39(d,J＝8.1Hz,1H),7.30–7.26(m,2H),7.26–7.22(m,2H),7.15–7.09(m,2H),6.99(dd,J＝3.7,1.2Hz,1H),6.95(dd,J＝5.1,3.6Hz,1H),4.45(s,2H),3.64–3.56(m,2H),3.16(dd,J＝9.2,6.4Hz,2H),2.39(s,3H).
The process for the preparation of compound 1p differs from that of compound 1a in that: nb-p-tolutesulfenyl-5-methyl tryptamine (CAS number: 881766-02-5) is selected as the compound S1; yellow solid was prepared; 668mg of product 1p is obtained from 733mg of starting material S2 in 75% yield.
1 H NMR(400MHz,Chloroform-d)δ H 8.07(s,1H),7.83–7.78(m,2H),7.44–7.40(m,1H),7.33–7.24(m,6H),7.15–7.08(m,3H),7.04(dd,J＝8.3,1.6Hz,1H),4.47(s,2H),3.66–3.58(m,2H),3.18–3.10(m,2H),2.36(s,3H),2.35(s,3H).
The procedure for the preparation of compound 1q differs from that of compound 1a in that: the compound S1 is Nb-p-tolutesulfenyl-5-methoxy tryptamine (CAS number 102016-76-2); yellow solid was prepared; 545mg of product 1q was obtained in 79% yield from 574mg of starting material.
1 H NMR(500MHz,Chloroform-d)δ H 8.16–8.12(m,1H),7.86–7.78(m,2H),7.33–7.29(m,1H),7.28–7.23(m,5H),7.14–7.09(m,4H),6.88(dd,J＝8.8,2.4Hz,1H),4.43(s,2H),3.78(s,3H),3.65–3.59(m,2H),3.15(dd,J＝9.1,6.4Hz,2H),2.35(s,3H).
The preparation of compound 1r differs from that of compound 1a in that: the compound S1 is N1-methyl-Nb-p-tolutesulfenyl-tryptamine (CAS number: 1318072-81-9); is prepared by the method; a yellow solid was obtained.
1 H NMR(500MHz,Chloroform-d)δ H 7.81–7.75(m,2H),7.64(d,J＝7.9Hz,1H),7.33–7.29(m,2H),7.28–7.22(m,5H),7.11(dt,J＝7.0,1.5Hz,2H),7.06(ddd,J＝8.0,7.0,1.0Hz,1H),6.99(s,1H),4.43(s,2H),3.77(s,3H),3.62–3.55(m,2H),3.17–3.11(m,2H),2.34(s,3H).
The procedure for the preparation of compound 1i differs from that of compound 1a in that: the compound S1 of the general formula is Propanedioic acid 2- [2- (1H-indol-3-yl) ethyl ] -1,3-dimethyl ester (CAS number: 1394825-55-8); yellow solid was prepared; 266mg of product 1s were obtained in 84% yield from 255mg of starting material.
1 H NMR(400MHz,Chloroform-d)δ H 8.03(s,1H),7.68(dd,J＝7.9,1.1Hz,1H),7.43–7.40(m,2H),7.37(dt,J＝8.1,0.9Hz,1H),7.31(dd,J＝5.1,1.9Hz,3H),7.20(ddd,J＝8.2,7.0,1.2Hz,1H),7.08(ddd,J＝8.0,7.1,1.0Hz,1H),7.03(d,J＝2.3Hz,1H),3.77(s,6H),3.25(s,2H),2.84–2.75(m,2H),2.66–2.57(m,2H).
The procedure for the preparation of compound 1i differs from that of compound 1a in that: the compound S1 of the general formula adopts color alcohol (CAS number: 526-55-6); yellow solid was prepared; 83mg of product 1t are obtained from 77mg of starting material in 77% yield.
1 H NMR(500MHz,Chloroform-d)δ H 8.02(s,1H),7.68(d,J＝7.9Hz,1H),7.51–7.44(m,2H),7.38(d,J＝8.1Hz,1H),7.34(qd,J＝4.7,1.6Hz,3H),7.26–7.21(m,1H),7.16(t,J＝7.5Hz,1H),7.11(d,J＝2.3Hz,1H),4.46(s,2H),3.95(t,J＝7.2Hz,2H),3.16(t,J＝7.2Hz,2H).
Example 1
The purpose of this embodiment is: optimizing the preparation condition of indoline compounds.
The preparation method of the indoline compound in the embodiment comprises the following steps:
under specific temperature conditions, tryptamine derivative 1a (0.1 mmol,1 eq.) metal catalyst (0.01 mmol,10 mol%), acid additive (0.1 mmol,1.0 eq.) and solvent (1.0 ml,1 m) were added sequentially to a reaction flask containing the magneton, and the reaction was continued with stirring at this temperature after the addition. After TLC monitoring reaction is finished, the reaction solution is quenched by adding triethylamine, filtered by diatomite, and the mixture is concentrated under reduced pressure and then subjected to column chromatography (the volume ratio of petroleum ether to ethyl acetate is 8:1) to obtain the cyclobutenoindoline compound 2a.
The conversion and yield of compound 2a produced in this example at various temperatures, metal catalysts, acid additives, solvents and reaction times are shown in table 1.
TABLE 1 conversion and yield of Compound 2a produced in this example at various temperatures, metal catalysts, acid additives, solvents and reaction times
In Table 1 a Represents the reaction with 0.5 equivalent of nitric acid solution (66% -68% by mass); in Table 1 b Representative conversion was determined by HPLC; in Table 1 c Representative yields were determined by HPLC; in Table 1 d Representative yield calculations were calculated by column chromatography separation.
From table 1, it is known that: this example improves the yield of compound 2a by selecting temperature, metal catalyst, solvent, acid additive.
Example 2
This example illustrates the preparation of indolines by intramolecular cyclization under different preparation starting materials.
To a reaction flask containing a magneton, compound of general formula 1 (0.02 mmol,1 equiv.) and Fe (NO 3 ) 3 ·9H 2 O(0.01mmol,5mol％)、HNO 3 (0.2 mmol,1.0 equiv.) and TFE (2.0 mL, 0.1M), the reaction was continued with 25 degrees stirring after addition. After TLC monitoring reaction is finished, the reaction solution is quenched by adding triethylamine, filtered by diatomite, and the mixture is concentrated under reduced pressure and then subjected to column chromatography (the volume ratio of petroleum ether to ethyl acetate is 8:1) to obtain the general formula compound 2 (cyclobutenoindoline products).
Referring to the above experimental procedure, reference is made to Ar groups, X, R in the product of Table 2 1 、R 2 、R 3 A structure of (a); changing the reaction substrate (namely selecting the compounds 1 a-1 t) to prepare the compounds 2 a-2 t.
Ar groups in tables 1 to 13 and 16 to 20 are substituents in phenyl; for example hydrogen, then phenyl; p-OMe, p-methoxyphenyl.
In Table 2, the Ar group in 14 is a 2-naphthyl group; in Table 2, 15 Ar is 2-thienyl.
Ar group and X, R in Compounds 2a to 2t prepared in this example 1 、R 2 、R 3 The structure, reaction time and yield of (c) are shown in table 2.
TABLE 2 Ar group X, R in the compounds 2a to 2t prepared in this example 1 、R 2 、R 3 Structure, reaction time and yield of (2)
In Table 2 a Representing that the reaction is carried out at 50 ℃;
1 H NMR(500MHz,Chloroform-d)δ H 7.66(d,J＝8.3Hz,2H),7.36(td,J＝7.0,1.5Hz,2H),7.30–7.24(m,3H),7.22(d,J＝8.0Hz,2H),7.06(dd,J＝7.5,1.2Hz,1H),7.00(td,J＝7.7,1.3Hz,1H),6.66(td,J＝7.5,1.1Hz,1H),6.60–6.54(m,1H),4.58(d,J＝13.9Hz,1H),4.53(d,J＝1.1Hz,1H),3.85(dt,J＝13.6,4.5Hz,1H),3.71(dd,J＝13.8,1.3Hz,1H),3.24(ddd,J＝13.1,11.2,3.6Hz,1H),2.41(s,3H),2.25(dt,J＝13.6,3.8Hz,1H),2.16(ddd,J＝13.6,11.2,4.7Hz,1H).
64.0mg of the product was obtained from 71.1mg of the starting material in 89% yield.
1 H NMR(500MHz,Chloroform-d)δ H 7.71–7.66(m,2H),7.29(td,J＝7.8,1.7Hz,1H),7.25(dd,J＝7.6,1.7Hz,1H),7.21(d,J＝8.0Hz,2H),7.11(dd,J＝7.5,1.3Hz,1H),7.02(td,J＝7.7,1.3Hz,1H),6.97(td,J＝7.5,1.1Hz,1H),6.92(d,J＝8.3Hz,1H),6.68(td,J＝7.5,1.0Hz,1H),6.58(d,J＝7.8Hz,1H),4.70(d,J＝14.1Hz,1H),4.52–4.48(m,1H),3.96–3.85(m,4H),3.77(dd,J＝14.1,1.3Hz,1H),3.31(ddd,J＝13.2,11.3,3.7Hz,1H),2.42(s,3H),2.25(dt,J＝13.6,3.8Hz,1H),2.15(ddd,J＝13.6,11.2,4.9Hz,1H).
59.8mg of product was obtained from 61.1mg of starting material in 98% yield.
1 H NMR(600MHz,Chloroform-d)δ H 7.78–7.73(m,2H),7.37(d,J＝8.0Hz,2H),7.27(dd,J＝7.6,1.7Hz,1H),7.20(ddd,J＝8.7,7.3,1.7Hz,1H),7.16(t,J＝7.6Hz,2H),6.98–6.95(m,1H),6.94–6.89(m,2H),6.87(td,J＝7.4,1.2Hz,1H),4.68(dd,J＝13.5,1.2Hz,1H),4.46(d,J＝1.4Hz,1H),3.97(dtd,J＝12.8,4.4,1.2Hz,1H),3.39(dd,J＝13.4,1.5Hz,1H),3.17(ddd,J＝12.8,8.8,6.3Hz,1H),2.49(s,3H),2.36–2.33(m,2H).
47.5mg of product was obtained from 87.0mg of starting material in 54% yield.
1 H NMR(400MHz,Chloroform-d)δ H 7.83(dd,J＝8.1,1.3Hz,1H),7.71–7.64(m,2H),7.56(td,J＝7.6,1.3Hz,1H),7.45(td,J＝7.8,1.4Hz,1H),7.30(dd,J＝8.6,7.0Hz,3H),7.10(dd,J＝7.5,1.2Hz,1H),7.06(td,J＝7.7,1.3Hz,1H),6.71(td,J＝7.5,1.0Hz,1H),6.61(dd,J＝7.8,0.9Hz,1H),4.62(d,J＝1.0Hz,1H),4.42(d,J＝14.0Hz,1H),3.91–3.84(m,1H),3.76(dd,J＝14.0,1.2Hz,1H),3.31(ddd,J＝13.4,10.5,4.2Hz,1H),2.47(s,3H),2.34–2.14(m,2H).
46.9mg of product was obtained from 54.7mg of starting material in 86% yield.
1 H NMR(500MHz,Chloroform-d)δ H 7.69(d,J＝8.0Hz,2H),7.31(t,J＝7.9Hz,1H),7.26(d,J＝8.0Hz,2H),7.10(d,J＝7.4Hz,1H),7.04(td,J＝7.6,1.2Hz,1H),6.90(d,J＝7.6Hz,1H),6.87(dd,J＝8.3,2.6Hz,1H),6.81(t,J＝2.0Hz,1H),6.70(t,J＝7.5Hz,1H),6.60(d,J＝7.8Hz,1H),4.60(d,J＝13.8Hz,1H),4.54(s,1H),3.85(s,4H),3.75(d,J＝13.9Hz,1H),3.28(ddd,J＝13.8,11.1,3.6Hz,1H),2.45(s,3H),2.28(dt,J＝13.7,3.9Hz,1H),2.19(ddd,J＝13.7,11.1,4.7Hz,1H).
42.8mg of product was obtained from 54.3mg of starting material in 79% yield.
1 H NMR(500MHz,Chloroform-d)δ H 7.70(d,J＝8.2Hz,2H),7.29–7.24(m,3H),7.15–7.07(m,4H),7.03(td,J＝7.7,1.3Hz,1H),6.69(td,J＝7.4,1.1Hz,1H),6.60(d,J＝7.9Hz,1H),4.61(d,J＝13.9Hz,1H),4.55(d,J＝1.1Hz,1H),3.88(dt,J＝13.2,4.5Hz,1H),3.74(dd,J＝13.8,1.2Hz,1H),3.27(ddd,J＝13.1,11.2,3.6Hz,1H),2.45(s,3H),2.39(s,3H),2.28(dt,J＝13.6,3.8Hz,1H),2.19(ddd,J＝13.7,11.2,4.8Hz,1H).
63.2mg of product were obtained from 68.5mg of starting material in 92% yield.
1 H NMR(500MHz,Chloroform-d)δ H 7.72–7.67(m,2H),7.28–7.24(m,4H),7.08(dd,J＝7.5,1.3Hz,1H),7.03(td,J＝7.6,1.3Hz,1H),6.95–6.91(m,2H),6.69(td,J＝7.4,1.1Hz,1H),6.60(dd,J＝7.9,1.0Hz,1H),4.58(d,J＝13.7Hz,1H),4.52(d,J＝1.1Hz,1H),3.85(s,4H),3.71(dd,J＝13.7,1.2Hz,1H),3.26(ddd,J＝13.1,11.3,3.5Hz,1H),2.45(s,3H),2.27(dt,J＝13.7,3.7Hz,1H),2.17(ddd,J＝13.6,11.2,4.7Hz,1H).
50.2mg of product was obtained from 53.7mg of starting material in 94% yield.
1H NMR(600MHz,Chloroform-d)δ H 7.71–7.67(m,2H),7.25(d,J＝8.0Hz,2H),7.20(s,4H),7.08(dd,J＝7.5,1.3Hz,1H),7.03(td,J＝7.6,1.3Hz,1H),6.68(td,J＝7.4,1.0Hz,1H),6.59(d,J＝7.8Hz,1H),4.59(d,J＝13.8Hz,1H),4.53(d,J＝1.2Hz,1H),3.87(dt,J＝13.2,4.5Hz,1H),3.73(d,J＝13.8Hz,1H),3.27(ddd,J＝12.9,11.2,3.5Hz,1H),2.44(s,3H),2.38(s,3H),2.27(dt,J＝13.6,3.8Hz,1H),2.17(ddd,J＝13.6,11.2,4.7Hz,1H).
48.6mg of product was obtained from 51.6mg of starting material in 94% yield.
1 H NMR(500MHz,DMSO-d 6 )δ H 9.68(s,1H),7.66(d,J＝8.1Hz,2H),7.34(d,J＝8.0Hz,2H),7.25–7.20(m,2H),6.96(d,J＝7.3Hz,1H),6.88(td,J＝7.7,1.3Hz,1H),6.83–6.79(m,2H),6.44(td,J＝7.4,1.1Hz,1H),6.39(d,J＝7.7Hz,1H),6.11(d,J＝3.1Hz,1H),4.45(d,J＝14.1Hz,1H),4.43(d,J＝3.2Hz,1H),3.76(dt,J＝13.4,4.2Hz,1H),3.53(d,J＝13.9Hz,1H),3.16(ddd,J＝13.1,10.9,4.2Hz,1H),2.40(s,3H),2.10–1.95(m,2H).
38.6mg of product was obtained from 64.1mg of starting material in 60% yield.
1 H NMR(500MHz,Chloroform-d)δ H 7.70(d,J＝8.0Hz,2H),7.65(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,2H),7.30(d,J＝8.1Hz,2H),7.10–7.04(m,2H),6.72(t,J＝7.5Hz,1H),6.64(d,J＝7.9Hz,1H),4.64(s,1H),4.59(d,J＝13.7Hz,1H),3.89(dt,J＝13.4,4.4Hz,1H),3.69(d,J＝13.8Hz,1H),3.27–3.16(m,1H),2.46(s,3H),2.33(dt,J＝13.7,3.7Hz,1H),2.25(ddd,J＝13.6,11.1,4.8Hz,1H).
40.1mg of product was obtained from 49.3mg of starting material in 81% yield.
1 H NMR(400MHz,Chloroform-d)δ H 7.70(d,J＝8.3Hz,2H),7.29(ddd,J＝8.4,5.0,1.9Hz,5H),7.09(d,J＝8.6Hz,3H),7.07–7.02(m,1H),6.71(td,J＝7.5,1.1Hz,1H),6.62(dd,J＝7.9,0.9Hz,1H),4.63–4.52(m,2H),3.95–3.85(m,1H),3.68(dd,J＝13.9,1.2Hz,1H),3.24(ddd,J＝13.1,11.2,3.7Hz,1H),2.46(s,3H),2.29(dt,J＝13.6,3.8Hz,1H),2.20(ddd,J＝13.7,11.2,4.8Hz,1H).
From 47.7mg of starting material, 32.2mg of product was obtained in 68% yield.
1 H NMR(500MHz,Chloroform-d)δ H 7.73–7.67(m,2H),7.63(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),7.28(d,J＝8.1Hz,2H),7.11(dd,J＝7.5,1.2Hz,1H),7.06(td,J＝7.7,1.3Hz,1H),6.72(td,J＝7.5,1.1Hz,1H),6.67–6.58(m,1H),4.63–4.62(m,1H),4.60(d,J＝13.8Hz,1H),3.91(dq,J＝13.2,4.6Hz,1H),3.73(d,J＝13.8Hz,1H),3.26(ddd,J＝13.1,11.2,3.6Hz,1H),2.45(s,3H),2.32(dt,J＝13.8,3.7Hz,1H),2.24(ddd,J＝13.7,11.2,4.8Hz,1H).
17.9mg of product was obtained from 55.3mg of starting material in 32% yield (after introduction of a substituent at the C2 position of the starting material for indole preparation, steric hindrance of the reaction increased, resulting in a decrease in the reaction yield).
1 H NMR(600MHz,Chloroform-d)δ H 7.73–7.69(m,2H),7.37(td,J＝7.5,1.4Hz,2H),7.34–7.31(m,2H),7.32–7.26(m,1H),7.27–7.24(m,2H),7.13(dd,J＝7.6,1.3Hz,1H),7.04(td,J＝7.7,1.3Hz,1H),6.69(td,J＝7.5,1.1Hz,1H),6.61(dd,J＝7.9,1.0Hz,1H),4.61(dd,J＝14.1,1.1Hz,1H),3.87(dtd,J＝13.3,4.7,1.1Hz,1H),3.81(d,J＝14.1Hz,1H),3.41(ddd,J＝13.2,10.8,3.7Hz,1H),2.43(s,3H),2.15(ddd,J＝13.7,10.8,4.9Hz,1H),2.02(dt,J＝13.8,4.0Hz,1H),1.46(s,3H).
39.0mg of product was obtained from 62.1mg of starting material in 62% yield.
1 H NMR(600MHz,Chloroform-d)δ H 7.99–7.94(m,1H),7.92–7.88(m,1H),7.85(d,J＝8.1Hz,1H),7.61(d,J＝7.9Hz,2H),7.52(ddd,J＝7.2,4.4,1.7Hz,2H),7.49(t,J＝7.6Hz,1H),7.42(d,J＝7.1Hz,1H),7.21(d,J＝7.9Hz,2H),7.17(d,J＝7.4Hz,1H),7.06(t,J＝7.6Hz,1H),6.74(t,J＝7.5Hz,1H),6.59(d,J＝7.8Hz,1H),4.83(s,1H),4.40(d,J＝13.7Hz,1H),3.98(dt,J＝13.2,4.3Hz,1H),3.76(d,J＝13.7Hz,1H),3.34–3.26(m,1H),2.43(s,3H),2.36(dt,J＝13.7,3.7Hz,1H),2.30(ddd,J＝13.6,11.3,4.6Hz,1H).
34.3mg of product was obtained from 42.8mg of starting material in 80% yield.
1 H NMR(500MHz,Chloroform-d)δ H 7.73–7.68(m,2H),7.32(dd,J＝4.7,1.5Hz,1H),7.29–7.25(m,2H),7.10–7.03(m,4H),6.72(td,J＝7.5,1.1Hz,1H),6.67(d,J＝7.8Hz,1H),4.55–4.51(m,2H),3.95–3.86(m,1H),3.62(dd,J＝14.0,1.2Hz,1H),3.24(ddd,J＝13.2,11.3,3.5Hz,1H),2.45(s,3H),2.27(dt,J＝13.7,3.7Hz,1H),2.19(ddd,J＝13.7,11.3,4.7Hz,1H).
110.1mg of product was obtained from 144.9mg of starting material in 80% yield.
1 H NMR(400MHz,Chloroform-d)δ H 7.70(d,J＝8.3Hz,2H),7.42–7.37(m,2H),7.34–7.29(m,3H),7.24(d,J＝8.0Hz,2H),6.93(d,J＝1.7Hz,1H),6.87(ddd,J＝8.0,1.8,0.8Hz,1H),6.55(d,J＝7.9Hz,1H),4.61(d,J＝14.0Hz,1H),4.54(d,J＝1.2Hz,1H),3.90–3.79(m,2H),3.36(ddd,J＝13.3,10.9,3.7Hz,1H),2.44(s,3H),2.30–2.23(m,4H),2.17(ddd,J＝13.7,10.9,4.7Hz,1H).
From 115.0mg of starting material, 75.4mg of product was obtained in 66% yield.
1 H NMR(600MHz,Chloroform-d)δ H 7.69(d,J＝7.9Hz,2H),7.39(t,J＝7.6Hz,2H),7.32(d,J＝7.3Hz,3H),7.26(d,J＝7.9Hz,2H),6.73(d,J＝2.4Hz,1H),6.64–6.58(m,2H),4.62(d,J＝13.8Hz,1H),4.58(s,1H),3.86(dt,J＝13.3,4.5Hz,1H),3.72(d,J＝16.4Hz,4H),3.27–3.20(m,1H),2.44(s,3H),2.28(dt,J＝13.7,3.8Hz,1H),2.19(td,J＝13.9,12.6,4.8Hz,1H).
77.6mg of product was obtained from 85.5mg of starting material in 91% yield.
1 H NMR(500MHz,Chloroform-d)δ H 7.68(d,J＝8.2Hz,2H),7.40(t,J＝7.4Hz,2H),7.35–7.29(m,3H),7.25(d,J＝8.0Hz,2H),7.10(td,J＝7.7,1.3Hz,1H),7.05(dd,J＝7.5,1.3Hz,1H),6.59(td,J＝7.5,1.0Hz,1H),6.39(d,J＝7.9Hz,1H),4.60(d,J＝13.8Hz,1H),4.46(s,1H),3.90(dt,J＝13.2,4.4Hz,1H),3.76(d,J＝13.7Hz,1H),3.27(ddd,J＝13.1,11.3,3.5Hz,1H),2.94(s,3H),2.45(s,3H),2.27(dt,J＝13.6,3.8Hz,1H),2.18(ddd,J＝13.6,11.3,4.7Hz,1H).
43.2mg of product was obtained from 43.3mg of starting material in 91% yield.
1 H NMR(400MHz,Chloroform-d)δ H 7.46–7.41(m,2H),7.36–7.30(m,3H),7.25–7.19(m,1H),7.04(td,J＝7.7,1.3Hz,1H),6.75(td,J＝7.4,1.1Hz,1H),6.62(dd,J＝7.9,1.0Hz,1H),4.58(s,1H),3.79(s,3H),3.56(s,3H),3.52(dd,J＝13.8,1.7Hz,1H),2.76(dd,J＝13.8,1.5Hz,1H),2.66–2.57(m,1H),2.44–2.31(m,2H),2.08(td,J＝14.2,4.3Hz,1H).
59.2mg of product was obtained from 63.4mg of starting material in 93% yield.
1 H NMR(400MHz,Chloroform-d)δ H 7.42(dd,J＝7.5,1.2Hz,1H),7.40–7.32(m,4H),7.34–7.24(m,1H),7.10(td,J＝7.7,1.3Hz,1H),6.82(td,J＝7.5,1.1Hz,1H),6.70–6.66(m,1H),4.82(d,J＝0.9Hz,1H),4.66(dd,J＝13.3,0.8Hz,1H),4.39(dd,J＝13.3,1.0Hz,1H),4.09(d,J＝3.3Hz,1H),4.07(t,J＝3.3Hz,1H),2.42(ddd,J＝13.6,9.4,6.6Hz,1H),2.32(dtd,J＝13.6,3.2,0.9Hz,1H).
Example 3
This example illustrates the preparation of indolines by intermolecular cyclization under different starting materials.
The general reaction scheme in this example is as follows:
sequentially adding electron-rich indole compound 3 (0.2 mmol,1 eq.) and Fe (NO 3 ) 3 ·9H 2 O(0.01mmol,5mol％)、HNO 3 (0.2 mmol,1.0 eq.) and TFE (2.0 mL, 0.1M) were added quickly, and the reaction was continued at 25℃with stirring after the addition of unactivated alkyne compound 4 (0.3 mmol,1.5 eq.). After TLC monitoring reaction is finished, adding triethylamine into the reaction solution to quench, filtering the reaction solution by using diatomite, concentrating the mixture under reduced pressure, and performing column chromatography to obtain the cyclobutenoindoline compounds of the general formula 5 and the general formula 6.
Referring to the above experimental procedure, reference is made to substituents, R in the phenyl groups in the products of Table 3 1 、R 2 、R 3 、R 4 Is of a structure of (2); the reaction substrates (i.e., compound 3 of formula and compound 4 of formula) were changed to produce compounds 5a to 5p and 6a to 6p.
The substituents R in the phenyl groups in the compounds 5a to 5p and compounds 6a to 6p obtained in this example 1 、R 2 、R 3 、R 4 The structure, reaction time and yield (calculated as the ratio of the sum of compound 5 and compound 6 to the theoretical yield: 100%) are shown in table 3.
TABLE 3 substituents R in phenyl groups in Compounds 5a to 5p and Compounds 6a to 6p prepared in this example 1 、R 2 、R 3 、R 4 Structure, reaction time and yield of (2)
Wherein the mass ratio of the compound of the formula 5 to the compound of the formula 6 is as a crude product 1 H-NMR spectrum determination.
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In the preparation process of the compounds 5a and 6a, 3-methylindole (CAS number: 83-34-1) is selected as the general formula compound 3, and phenylacetylene (CAS number: 536-74-3) is selected as the general formula compound 4.
7b-methyl-2-phenyl-2a,7 b-dihydro-3H-cyclob-b-in-ole (5 a): yellow oily; 71.5mg of products 5a and 6a are obtained from 130.2mg of starting material in 31% yield (sum of product 5a and product 6 a/theoretical yield 100%).
Nuclear magnetic resonance hydrogen spectrum data for compound 5 a: 1 H NMR(500MHz,DMSO-d 6 )δ7.47(d,J＝7.6Hz,2H),7.36(dd,J＝7.5Hz,2H),7.28(dd,J＝7.4Hz,1H),7.07(d,J＝7.3Hz,1H),6.91(dd,J＝7.6Hz,1H),6.61(d,J＝2.1Hz,1H),6.53(dd,J＝7.4Hz,1H),6.42(d,J＝7.8Hz,1H),6.27(s,1H),4.56(d,J＝2.2Hz,1H),1.51(s,3H).
the difference between the preparation of compounds 5b and 6b and the preparation of compounds 5a and 6a is that: the compound 3 of the general formula adopts 1,3-dimethyl indole (CAS number: 875-30-9).
3,7b-dimethyl-2-phenyl-2a,7b-dihydro-3H-cyclob ] input (5 b): yellow solid; 40.8mg of products 5b and 6b were obtained from 140.9mg of starting material in 17% yield (cf. Calculation at compound 5 a); melting point: 44-46 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 5 b: 1 H NMR(500MHz,Chloroform-d)δ7.45(d,J＝8.3Hz,2H),7.35(dd,J＝7.5Hz,2H),7.28(dd,J＝5.0,3.0Hz,1H),7.12(dd,J＝7.9Hz,2H),6.67(dd,J＝7.4Hz,1H),6.58(d,J＝1.7Hz,1H),6.41(d,J＝7.8Hz,1H),4.54(d,J＝2.0Hz,1H),3.03(s,2H),1.62(s,3H).
the difference between the preparation of compounds 5c and 6c and the preparation of compounds 5a and 6a is that: the compound 3 of the general formula is 1H-Indole,3-methyl-1-phenyl (CAS number: 112817-88-6).
3-benzyl-7b-methyl-2-phenyl-2a,7 b-dihydro-3H-cyclob-a [ b ] input (5 c): yellow solid; 94.7mg of products 5c and 6c were obtained from 225.5mg of starting material in 29% yield (cf. Calculation at compound 5 a); melting point: 64-66 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 5 c: 1 H NMR(500MHz,Chloroform-d)δ7.33–7.22(m,10H),7.20(dd,J＝7.3,1.3Hz,1H),7.10(td,J＝7.7,1.4Hz,1H),6.74(td,J＝7.4,1.0Hz,1H),6.62(d,J＝2.1Hz,1H),6.46(d,J＝7.9Hz,1H),4.66–4.52(m,3H),1.64(s,3H).
the difference between the preparation of compounds 5d and 6d and the preparation of compounds 5a and 6a is that: 3-ethylindole (CAS number: 1484-19-1) is selected as compound 3 of the general formula.
7b-methyl-2-phenyl-2a,7 b-dihydro-3H-cyclob-b-in-ole (5 d): yellow solid; 42.5mg of product 5d and 6d were obtained from 189.4mg of starting material in 13% yield (cf. Calculation at compound 5 a); melting point: 60-61 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 5 d: 1 H NMR(500MHz,Chloroform-d)δ7.49–7.43(m,2H),7.37(t,J＝7.5Hz,2H),7.33–7.25(m,1H),7.17(dd,J＝7.4,1.3Hz,1H),7.08(td,J＝7.6,1.4Hz,1H),6.82–6.75(m,1H),6.65(d,J＝7.8Hz,1H),6.61(d,J＝1.9Hz,1H),4.77(d,J＝2.0Hz,1H),2.01(ddt,J＝23.4,14.2,7.2Hz,2H),1.04(t,J＝7.4Hz,3H).
the difference between the preparation of compounds 5e and 6e and the preparation of compounds 5a and 6a is that: the general formula compound 3 is selected from tryptophane.
2- (2-phenyl-2 a,3-dihydro-7 bH-cyclob-7 b-yl) ethane-1-ol (5 e): yellow solid; 46.2mg of products 5e and 6e were obtained from 79.3mg of starting material in 36% yield (cf. Calculation at compound 5 a); melting point: 150-152 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 5 e: 1 H NMR(400MHz,Chloroform-d)δ7.45–7.41(m,2H),7.39–7.34(m,2H),7.32–7.27(m,1H),7.16(dd,J＝7.3,1.3Hz,1H),7.07(td,J＝7.6,1.3Hz,1H),6.78(td,J＝7.4,1.0Hz,1H),6.64(dt,J＝7.9,0.7Hz,1H),6.62(d,J＝1.8Hz,1H),4.90(d,J＝1.8Hz,1H),3.81(ddd,J＝7.1,5.9,1.1Hz,2H),2.33–2.19(m,2H).
the difference between the preparation of compounds 5f and 6f and the preparation of compounds 5a and 6a is that: indole-3-ethyl acetate (CAS number: 778-82-5) is selected as the compound 3.
ethylene 2- (2-phenyl-2 a,3-dihydro-7 bH-cyclic [ b ] indol-7 b-yl) acetate (5 f): yellow oily; 93.6mg of products 5f and 6f were obtained from 162.7mg of starting material in 38% yield (cf. Calculation at compound 5 a).
Nuclear magnetic resonance hydrogen spectrum data for compound 5 f: 1 H NMR(500MHz,Chloroform-d)δ7.48–7.43(m,2H),7.39–7.34(m,2H),7.33–7.27(m,1H),7.22(dd,J＝7.4,1.3Hz,1H),7.09(td,J＝7.6,1.3Hz,1H),6.79(td,J＝7.4,1.0Hz,1H),6.68(d,J＝1.8Hz,1H),6.67–6.65(m,1H),5.01(d,J＝1.8Hz,1H),4.15(q,J＝7.1Hz,2H),3.12–2.83(m,2H),1.21(t,J＝7.1Hz,3H).
the difference between the preparation of compounds 5g and 6g and the preparation of compounds 5a and 6a is that: nb-p-tolutesulfenyl-5-methyl tryptamine (CAS number: 881766-02-5) is selected as compound 3.
4-methyl-N- (2- (6-methyl-2-phenyl-2 a,3-dihydro-7 bH-cyclob-a [ b ] indo-7 b-yl) ethyl) benzene sulfonamide (5 g): yellow solid; 86.1mg of product 5g and 6g,54% yield (cf. Calculation at compound 5 a) were obtained from 125.1mg of starting material; melting point: 55-61 ℃.
Nuclear magnetic resonance hydrogen spectrum data of compound 5 g: 1 H NMR(500MHz,Chloroform-d)δ7.66(d,J＝8.2Hz,2H),7.40–7.32(m,4H),7.31–7.22(m,3H),6.87(dd,J＝8.0,1.8Hz,1H),6.83(d,J＝1.8Hz,1H),6.55(d,J＝7.9Hz,1H),6.52(d,J＝1.8Hz,1H),4.83(t,J＝6.2Hz,1H),4.77(d,J＝1.8Hz,1H),3.10(dtd,J＝12.5,7.3,5.2Hz,1H),2.95(dtd,J＝12.8,7.7,5.3Hz,1H),2.42(s,3H),2.25(s,3H),2.21–2.11(m,2H).
the difference between the preparation of compounds 5h and 6h and the preparation of compounds 5a and 6a is that: the compound 3 is N1-methyl-Nb-p-tolenesulfonyl-tryptamine (CAS number: 1318072-81-9).
2-methyl-N- (2- (3-methyl-2-phenyl-2 a,3-dihydro-7 bH-cyclob-a [ b ] indol-7 b-yl) ethyl) benzene sulfonamide (5 h): yellow solid; 41.2mg of product are obtained 5h and 6h,32% yield (cf. Calculation at compound 5 a) from 98.1mg of starting material; melting point: 56-58 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 5 h: 1 H NMR(400MHz,DMSO-d 6 )δ7.64(t,J＝8.4Hz,3H),7.46(d,J＝7.1Hz,2H),7.36(dd,J＝8.0,6.2Hz,4H),7.28(t,J＝7.3Hz,1H),7.02–6.93(m,2H),6.59(d,J＝1.9Hz,1H),6.54(t,J＝7.3Hz,1H),6.36(d,J＝7.8Hz,1H),4.62(d,J＝1.9Hz,1H),2.89(s,3H),2.84–2.62(m,2H),2.36(s,3H),1.97(dddd,J＝23.7,13.9,9.8,5.9Hz,2H).
the difference between the preparation of compounds 5i and 6i and the preparation of compounds 5a and 6a is that: nb-p-tolutesulfenyl-tryptamine (CAS number: 86658-78-8) is selected as the general formula compound 3; the compound 4 of the general formula adopts 2-chloro-2-phenylacetylene (CAS number: 1483-82-5).
N- (2- (1-chloro-2-phenyl-2 a,3-dihydro-7bH-cyclob [ b ] indol-7 b-yl) ethyl) -4-methyl benzene sulfonamide (5 i): yellow solid; 33.6mg of products 5i and 6i were obtained from 110.8mg of starting material in 21% yield (cf. Calculation at compound 5 a); melting point: 57-62 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 5 i: 1 H NMR(600MHz,Chloroform-d)δ7.68–7.63(m,2H),7.61–7.57(m,2H),7.41–7.37(m,2H),7.35–7.31(m,1H),7.25(d,J＝8.0Hz,2H),7.10(td,J＝7.7,1.3Hz,1H),7.07(dd,J＝7.5,1.3Hz,1H),6.77(td,J＝7.4,1.0Hz,1H),6.64(d,J＝7.8Hz,1H),4.86(s,1H),4.66–4.60(m,1H),3.12(dtd,J＝12.5,7.4,5.0Hz,1H),3.01–2.93(m,1H),2.41(s,3H),2.28(ddd,J＝14.5,7.2,5.0Hz,1H),2.19(dt,J＝14.5,7.8Hz,1H).
the difference between the preparation of compounds 5j and 6j and the preparation of compounds 5i and 6i is that: the compound 4 shown in the general formula adopts phenylacetylene.
4-methyl-N- (2- (2-phenyl-2 a,3-dihydro-7 bH-cyclob-a [ b ] indol-7 b-yl) ethyl) benzene sulfonamide (5 j): yellow solid; 123.2mg of products 5j and 6j were obtained from 138.9mg of starting material in 67% yield (cf. Calculation at compound 5 a); melting point: 60-63 ℃.
Nuclear magnetic resonance hydrogen spectrum data of compound 5 j: 1 H NMR(600MHz,Chloroform-d)δ7.67–7.63(m,2H),7.40–7.33(m,4H),7.31–7.27(m,1H),7.25(d,J＝8.0Hz,2H),7.06(td,J＝7.7,1.3Hz,1H),7.02(dd,J＝7.4,1.3Hz,1H),6.73(td,J＝7.4,1.0Hz,1H),6.62(d,J＝7.8Hz,1H),6.53(d,J＝1.7Hz,1H),4.79(d,J＝1.7Hz,1H),4.65(t,J＝6.3Hz,1H),3.11(dtd,J＝12.7,7.3,5.3Hz,1H),2.98(dtd,J＝13.0,7.6,5.5Hz,1H),2.42(s,3H),2.25–2.11(m,2H).
the difference between the preparation of compounds 5k and 6k and the preparation of compounds 5i and 6i is: the compound 4 of the general formula adopts 2-methyl phenylacetylene (CAS number: 766-47-2).
4-methyl-N- (2- (2- (o-tolyl) -2a,3-dihydro-7 bH-cyclob-a [ b ] indol-7 b-yl) ethyl) benzene sulfonamide (5 k): yellow solid; 53.6mg of product 5k and 6k were obtained from 84.9mg of starting material in 46% yield (cf. Calculation at compound 5 a); melting point: 44-49 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 5 k: 1 H NMR(500MHz,Chloroform-d)δ7.65(d,J＝8.2Hz,2H),7.40–7.34(m,1H),7.26–7.16(m,5H),7.05(td,J＝7.7,1.3Hz,1H),7.01(dd,J＝7.5,1.3Hz,1H),6.75–6.69(m,1H),6.59(d,J＝7.8Hz,1H),6.41(d,J＝1.8Hz,1H),4.83(d,J＝1.8Hz,1H),4.65(t,J＝6.2Hz,1H),3.11(dtd,J＝12.7,7.3,5.4Hz,1H),2.99(dtd,J＝12.8,7.5,5.2Hz,1H),2.41(s,3H),2.33(s,3H),2.26–2.12(m,2H).
the preparation of compounds 5l and 6l differs from the preparation of compounds 5i and 6i in that: the compound 4 of the general formula adopts 2-ethynyl anisole (CAS number: 767-91-9).
N- (2- (2- (2-methoxyphenyl) -2a,3-dihydro-7 bH-cyclob-a [ b ] indol-7 b-yl) ethyl) -4-methylben zenesulfonamide (5 l): yellow solid; from 147.5mg starting material, 64.7mg of product 5l and 6l,31% yield (cf. Calculation method at compound 5 a); melting point: 63-66 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 5 l: 1 H NMR(500MHz,Chloroform-d)δ7.63(d,J＝8.2Hz,2H),7.33(dd,J＝7.6,1.8Hz,1H),7.28–7.22(m,3H),7.04(td,J＝7.6,1.3Hz,1H),6.99(dd,J＝7.5,1.2Hz,1H),6.94(t,J＝7.5Hz,1H),6.90(d,J＝8.3Hz,1H),6.69(t,J＝7.4Hz,1H),6.59(d,J＝8.0Hz,1H),6.58(d,J＝1.7Hz,1H),4.72(d,J＝1.7Hz,1H),4.68(dd,J＝7.4,5.2Hz,1H),3.88(s,3H),3.11(ddd,J＝13.2,7.2,5.7Hz,1H),2.97(dtd,J＝12.8,7.6,5.1Hz,1H),2.41(s,3H),2.17(dd,J＝7.5,5.3Hz,2H).
the difference between the preparation of compounds 5m and 6m and the preparation of compounds 5i and 6i is that: 2-fluorophenylacetylene (CAS number: 766-49-4) is selected as the compound 4 of the general formula.
N- (2- (2- (2-fluorophenyl) -2a,3-dihydro-7 bH-cyclob-a [ b ] indol-7 b-yl) ethyl) -4-methylbenze nesulfonamide (5 m): yellow solid; from 129.2mg starting material, 69.8mg of product 5m and 6m were obtained in 40% yield (cf. Calculation method at compound 5 a); melting point: 59-61 DEG C
Nuclear magnetic resonance hydrogen spectrum data for compound 5 m: 1 H NMR(500MHz,Chloroform-d)δ7.69–7.61(m,2H),7.37(td,J＝7.5,1.8Hz,1H),7.25(d,J＝8.1Hz,3H),7.11(td,J＝7.5,1.1Hz,1H),7.08–7.03(m,2H),7.01(dd,J＝7.4,1.3Hz,1H),6.71(t,J＝7.3Hz,1H),6.65–6.58(m,2H),4.80–4.73(m,2H),3.10(dtd,J＝12.8,7.3,5.5Hz,1H),2.98(dtd,J＝13.0,7.6,5.4Hz,1H),2.41(s,3H),2.23–2.11(m,2H).
the difference between the preparation of compounds 5n and 6n and the preparation of compounds 5i and 6i is that: 3-methyl phenylacetylene (CAS number: 766-82-5) is selected as the compound 4.
4-methyl-N- (2- (2- (m-tolyl) -2a,3-dihydro-7 bH-cyclob-a [ b ] indol-7 b-yl) ethyl) benzene sulfonamide (5N): yellow solid; from 91.8mg starting material 63.7mg of product 5n and 6n,51% yield (cf. Calculation method at compound 5 a); melting point: 51-57 ℃.
Nuclear magnetic resonance hydrogen spectrum data of compound 5 n: 1 H NMR(400MHz,Chloroform-d)δ7.66(d,J＝8.0Hz,2H),7.27–7.18(m,5H),7.11(d,J＝7.4Hz,1H),7.07(ddd,J＝7.7,1.3Hz,1H),7.03(dd,J＝7.5,1.2Hz,1H),6.75(dd,J＝7.4Hz,1H),6.65(d,J＝7.8Hz,1H),6.52(d,J＝1.7Hz,1H),4.84–4.74(m,2H),3.18–3.04(m,1H),2.96(dtd,J＝12.8,7.5,5.3Hz,1H),2.41(s,3H),2.36(s,3H),2.26–2.11(m,2H).
the difference between the preparation of compounds 5o and 6o and the preparation of compounds 5i and 6i is that: the compound 4 of the general formula adopts 3-ethynyl anisole (CAS number: 768-70-7).
N- (2- (2- (3-methoxyphenyl) -2a,3-dihydro-7 bH-cyclob-a [ b ] indol-7 b-yl) ethyl) -4-methylben zenesulfonamide (5 o): yellow solid; 82.4mg of the products 5o and 6o were obtained from 97.0mg of starting material in 60% yield (cf. Calculation at compound 5 a); melting point: 44-48 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 5 o: 1 H NMR(500MHz,Chloroform-d)δ7.66(d,J＝8.0Hz,2H),7.25(dd,J＝8.1,3.4Hz,3H),7.05(t,J＝7.8Hz,1H),7.01(d,J＝7.4Hz,1H),6.97(d,J＝7.5Hz,1H),6.90(t,J＝2.0Hz,1H),6.84(dd,J＝8.3,2.6Hz,1H),6.72(t,J＝7.4Hz,1H),6.59(d,J＝7.9Hz,1H),6.51(d,J＝1.7Hz,1H),4.82(t,J＝6.2Hz,1H),4.74(d,J＝1.7Hz,1H),3.82(s,3H),3.13–3.02(m,1H),2.97(tdd,J＝13.0,8.5,4.6Hz,1H),2.41(s,3H),2.27–2.10(m,2H).
the difference between the preparation of compounds 5p and 6p and the preparation of compounds 5i and 6i is that: the compound 4 of the general formula adopts 4-methyl phenylacetylene (CAS number: 766-97-2).
4-methyl-N- (2- (2- (p-tolyl) -2a,3-dihydro-7 bH-cyclob-a [ b ] indol-7 b-yl) ethyl) benzene sulfonamide (5 p): yellow solid; 65mg of product 5p and 6p were obtained from 89.1mg of starting material in 53% yield (cf. Calculation at compound 5 a); melting point: 50-53 deg.c.
Nuclear magnetic resonance hydrogen spectrum data of compound 5 p: 1 H NMR(400MHz,Chloroform-d)δ7.66–7.60(m,2H),7.31–7.22(m,4H),7.16(d,J＝7.9Hz,2H),7.05(ddd,J＝7.7,1.3Hz,1H),7.01(dd,J＝7.4,1.3Hz,1H),6.71(ddd,J＝7.4,1.0Hz,1H),6.60(d,J＝7.8Hz,1H),6.46(d,J＝1.7Hz,1H),4.75(d,J＝1.7Hz,1H),4.52(s,1H),3.11(dtd,J＝12.8,6.6Hz,1H),2.97(dtd,J＝12.8,7.4Hz,1H),2.42(s,3H),2.36(s,3H),2.22–2.12(m,2H).
7b-methyl-1-phenyl-2a,7 b-dihydro-3H-cyclob-b-indole (6 a) is white solid with melting point of 82-87 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 6 a: 1 H NMR(400MHz,DMSO-d 6 )δ7.85–7.79(m,1H),7.62–7.54(m,3H),7.42(td,J＝7.6,1.5Hz,1H),7.39–7.30(m,4H),6.97(d,J＝1.4Hz,1H),5.61(d,J＝1.4Hz,1H),1.64(s,3H).
4-methyl-N- (2- (1- (o-tolyl) -2a,3-dihydro-7 bH-cyclob-7 b-yl) ethyl) benzene sulfonamide (6 k) as a yellow solid with a melting point of 55℃to 57 ℃.
Nuclear magnetic resonance hydrogen spectrum data for compound 6 k: 1 H NMR(400MHz,Chloroform-d)δ7.82(dd,J＝7.9,1.2Hz,1H),7.68(t,J＝7.5Hz,3H),7.44–7.19(m,6H),7.14(dd,J＝7.4,1.7Hz,1H),6.55(d,J＝1.3Hz,1H),5.77(d,J＝1.3Hz,1H),4.48(t,J＝6.2Hz,1H),3.05–2.95(m,2H),2.42(s,3H),2.34–2.18(m,5H).
4-methyl-N- (2- (1- (p-tolyl) -2a,3-dihydro-7 bH-cyclob-7 b-yl) ethyl) benzene sulfonamide (6 p) as a yellow solid with a melting point of 61-68 ℃.
Nuclear magnetic resonance hydrogen spectrum data of compound 6 p: 1 H NMR(400MHz,Chloroform-d)δ7.83–7.78(m,1H),7.70–7.65(m,2H),7.43–7.39(m,2H),7.41–7.23(m,5H),7.13(d,J＝7.9Hz,2H),6.59(d,J＝1.3Hz,1H),5.63(d,J＝1.3Hz,1H),4.89(t,J＝6.1Hz,1H),2.98(q,J＝7.0Hz,2H),2.41(s,3H),2.34(s,3H),2.30–2.19(m,2H).
the method has the advantages of high efficiency and selectivity in constructing the cyclobutene indoline skeleton through a cheap and easily available catalyst and simple operation, and has great practical and application values.
In summary, the invention provides a preparation method of indoline compounds, which utilizes a metal catalyst to synthesize the cyclobutene indoline compounds from a simple and easily available preparation raw material (indole-alkyne derivative) in one step in the presence of an acid additive. The preparation method provided by the invention has the characteristics of high selectivity, large-scale preparation, cheap and easily available raw materials and catalysts and convenient operation, and is suitable for intramolecular and intermolecular [2+2] cycloaddition reactions to prepare the cyclobutene indoline compounds.
The present invention is not limited to the above-described embodiments, and various changes may be made within the knowledge of one of ordinary skill in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (1)
1. A preparation method of indoline compounds is characterized in that: the method comprises the following steps:
the indole compound and the alkyne compound are subjected to cyclization reaction under the action of a metal catalyst and acid to prepare the indoline compound; the metal catalyst is ferric nitrate; the acid is at least one of nitric acid, p-toluenesulfonic acid, hydrochloric acid or trifluoromethanesulfonic acid; the solvent of the cyclization reaction is trifluoroethanol;
the temperature of the cyclization reaction is-10-100 ℃;
the indole compound is shown in a formula II;
the alkyne compound is a compound shown in a formula III;
the indoline compound is one of a compound shown in a formula V or a compound shown in a formula VI;
compounds of formula II, formula V and VI, R in the compounds of formula VI 1 、R 2 、R 3 、R 4 Independently selected from one of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl;
R 6 is hydrogen;
R 5 the phenyl is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl, phenyl or substituted phenyl, wherein the substituted phenyl is one of o-methoxyphenyl, phenol, nitrophenyl, cyanophenyl, fluorophenyl, trifluoromethyl phenyl and tolyl;
R 7 selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, -CH 2 CH 2 OH、-CH 2 COOEt、-CH 2 CH 2 NHTs；
Compounds of formula III, formula V and formula VI, R in the compounds 8 、R 9 Independently selected from one of hydrogen, halogen atom, phenyl, nitrophenyl, o-methoxyphenyl, cyanophenyl, fluoro-substituted phenyl or methyl-substituted phenyl, R 8 And R is 9 Are not identical.
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