CN110669006A - Indeno isoquinoline compounds and preparation method thereof - Google Patents
Indeno isoquinoline compounds and preparation method thereof Download PDFInfo
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Abstract
The invention discloses indenoisoquinoline compounds and a preparation method thereof, which are characterized in that a diene molecule with a prefabricated functional group is subjected to intramolecular diarylation reaction under the action of a palladium catalyst, a ligand and alkali metal acetate (such as sodium acetate) to obtain the indenoisoquinoline compounds. The method adopts a one-step method, realizes intramolecular diarylation reaction of allene molecules through palladium catalysis, has a simple system, can obtain the indeno isoquinoline compounds without additional treatment, is simple and easy to operate, is easy to operate, has wide substrate applicability, can tolerate various functional groups, and has a product yield remarkably higher than that of the traditional synthetic method. The invention successfully realizes the synthesis of the indeno isoquinoline compounds, and the indeno isoquinoline compounds with high yield can be easily prepared. The indenoisoquinoline compound can be directly used as an antitumor drug precursor or used as an antitumor drug precursor after being further modified. The invention provides a new synthesis means for developing a novel anti-tumor drug, and has economic practicability and industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of indeno isoquinoline compounds, and particularly relates to an indeno isoquinoline compound and a preparation method thereof.
Background
The indenoisoquinoline and the derivatives thereof, as potential anti-tumor active compounds, have the advantages of more stable activity, lower cytotoxicity and the like compared with camptothecin topoisomerase I inhibitors (topotecan and the like). Some of the indenoisoquinoline derivatives have been subjected to preliminary antitumor activity tests (Song, Y., Shao, z., Dexheimer, t.s., Scher, e.s., Pommier, Y. & Cushman, m.j.med.chem.2010,53, 1979-:
regarding the construction of indenoisoquinoline skeleton, the currently reported synthesis method mainly uses (2, 2-dimethoxyethyl) benzylamine and benzaldehyde or aryl imine to condense in hydrochloric acid. However, the synthesis yield of the reaction is very low, the substrate universality is also narrow, and the research and the application of the indeno isoquinoline compounds are limited. Therefore, a simple and efficient preparation method of the indeno isoquinoline compound is urgently needed to be developed.
Disclosure of Invention
The invention aims to provide an indeno isoquinoline compound and a preparation method thereof, and the preparation of the indeno isoquinoline compound is realized through a allene intramolecular diarylation reaction so as to overcome the defects in the prior art.
The invention relates to an indeno isoquinoline compound, which is characterized in that the indeno [1,2-c ] isoquinoline skeleton structure is shown as a formula II:
substituent R in indenoisoquinoline compounds of formula II1、R2、R3、R4、R6、R7、R8、R9And R12Each independently selected from alkyl, alkoxy, halogen or hydrogen; substituent R10And R11Each independently selected from hydrogen, alkyl, aryl or heteroaryl.
In a particular embodiment, R10And R11One of which is hydrogen and the other is tert-butyl.
In a particular embodiment, R10And R11One of which is hydrogen and the other is phenyl.
In a particular embodimentIn the scheme, R10And R11One of which is hydrogen and the other is heteroaryl.
Specifically, the indenoisoquinoline compounds comprise compounds with the following structures:
specifically, the indenoisoquinoline compounds include the following compounds:
the invention also relates to a preparation method of the indenoisoquinoline compound, which is characterized by comprising the following steps: using allene molecules with prefabricated functional groups, adopting a one-step method to synthesize an indenoisoquinoline skeleton,
wherein the substituent R1、R2、R3、R4、R6、R7、R8、R9And R12Each independently selected from alkyl, alkoxy, halogen or hydrogen;
wherein the substituent R5Selected from acyl, sulfonyl or sulfinyl;
wherein the substituent R10And R11Each independently selected from hydrogen, alkyl, aryl or heteroaryl;
wherein the substituent X is halogen;
as used herein, acyl refers to alkyl-C (═ O) -or aryl-C (═ O) -.
As used herein, sulfonyl means alkyl-S (═ O)2-or aryl-S (═ O)2-。
As used herein, sulfinyl refers to alkyl-S (═ O) -or aryl-S (═ O) -.
As used herein, alkyl includes, but is not limited to, C1-6Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl, n-hexyl, and the like.
As used herein, alkoxy includes, but is not limited to, C1-6Alkoxy, such as methoxy, ethoxy, isopropoxy, and the like.
As used herein, halogen includes fluorine, chlorine, bromine and iodine.
As used herein, aryl groups may be selected from phenyl, naphthyl, and substituted aryl (e.g., substituted phenyl); the substituted aryl group includes, but is not limited to, alkyl groups, alkoxy groups, halogen groups, and the like substituted aryl groups (e.g., phenyl groups), such as methyl groups, methoxy groups, fluorine atoms, or chlorine atoms substituted aryl groups (e.g., phenyl groups).
The term "heteroaryl" denotes a monovalent aromatic heterocyclic mono-or polycyclic ring system of 5 to 12 ring atoms comprising 1,2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, and the like,
Oxazolyl, thiazolyl, triazolyl,
Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, aza
Radical diaza
Basic group, hetero
Azolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl
Azolyl, benzisoyl
Azolyl, benzothiazolyl, benzisothiazolyl, benzo
Oxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzothienyl, benzoquinolinyl, and benzoisoquinolinyl groups. Heteroaryl groups may be substituted, for example, with alkyl, alkoxy, halo, and the like.
In a particular embodiment, R5Selected from acetyl or p-toluenesulfonyl. In a particular embodiment, R10And R11One of which is hydrogen and the other is phenyl.
The specific operation steps are as follows:
under the protective atmosphere, a divinyl compound and a derivative thereof, namely a compound of a formula 1 are used as reaction substrates, the compound of the formula 1, a palladium catalyst, a ligand and alkali metal acetate are added into an organic solvent, wherein the molar ratio of the compound of the formula 1 to the palladium catalyst is 100: 1-10: 1, the molar ratio of the palladium catalyst to the ligand is 1: 1-1: 2, the molar ratio of the compound of the formula 1 to the acetate is 2: 1-1: 5, an arylation reaction is carried out for 8-36 hours at 80-140 ℃, a reaction end point is determined by a thin-layer chromatography dot plate, and then column chromatography is carried out to obtain a corresponding indeno-isoquinoline compound II or a corresponding product marked by an enantiomer, a racemate, a diastereoisomer or an isotope thereof.
In some embodiments, the palladium catalyst is tetrakistriphenylphosphine palladium, bis (dibenzylideneacetone) palladium, or tris (dibenzylideneacetone) dipalladium.
In some embodiments, the ligand is triphenylphosphine, tris (m-methoxyphenyl) phosphine, tris (p-dimethylaminophenyl) phosphine, or 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene.
In some embodiments, the protective atmosphere is nitrogen, argon, or helium.
In some embodiments, the molar ratio of the compound of formula 1 to the palladium catalyst is from 100:1 to 10:1, preferably 10: 1.
In some embodiments, the molar ratio of palladium catalyst to ligand is from 1:1 to 1:2, preferably 1: 1.
In some embodiments, the molar ratio of the compound of formula 1 to alkali metal acetate is from 2:1 to 1:5, preferably 1: 3.
In some embodiments, the alkali metal acetate is selected from sodium acetate, potassium acetate, and the like, preferably sodium acetate.
In some embodiments, the organic solvent is selected from polar organic solvents such as N, N-dimethylformamide, N-dimethylacetamide or dimethylsulfoxide, preferably N, N-dimethylformamide.
In some embodiments, the reaction temperature is 80-140 ℃, preferably 100 ℃.
In some embodiments, the reaction time is 8 to 36 hours, preferably 8 hours.
According to the synthesis method of the indenoisoquinoline compound, a one-step method is adopted, allene molecules with prefabricated functional groups are subjected to intramolecular diarylation reaction under the action of a palladium catalyst, a ligand and alkali metal acetate (such as sodium acetate), and the indenoisoquinoline compound is obtained; the existing synthesis method of the indenoisoquinoline compound is realized by using (2, 2-dimethoxyethyl) benzylamine and benzaldehyde or aryl imine through condensation reaction, so that the reaction yield of the final step is low, and the waste of valuable raw materials is serious. Because the invention adopts a one-step method, realizes intramolecular diarylation reaction of allene molecules by palladium catalysis, has simple system, can obtain indeno isoquinoline compounds without additional treatment, is simple and easy to operate, wide in substrate applicability, capable of tolerating various functional groups, and has the product yield remarkably higher than that of the traditional synthetic method (the total synthetic yield is generally lower than 10%). The invention not only successfully realizes the synthesis of the indeno isoquinoline compounds, but also simplifies the traditional synthesis method, and the indeno isoquinoline compounds with high yield can be easily prepared. The indenoisoquinoline compound can be directly used as an antitumor drug precursor or used as an antitumor drug precursor after being further modified. The invention provides a new synthesis means for developing a novel anti-tumor drug, and has economic practicability and industrial application prospect.
Detailed Description
The reagents used in the examples were purchased from Annaige corporation.
First substrate synthetic route:
under the protection of nitrogen atmosphere, a rotor is put into a 100mL round-bottom flask, 4mmol of cuprous bromide, 20mmol of aldehyde, 30mmol of o-bromobenzylamine and 30mmol of alkyne are weighed and placed in a bottle, 40mL of toluene is added as a solvent, and the reaction is refluxed for 12 hours. The reaction was then cooled to room temperature, filtered through celite, and the filtrate washed with saturated ammonium chloride solution until the aqueous phase was no longer visibly blue. The aqueous phases are combined and extracted once with 20mL of ethyl acetate. The organic phases were combined, washed once with 20mL of saturated sodium chloride solution, then dried over anhydrous sodium sulfate and the solvent was removed using a rotary evaporator. The residue was purified by column chromatography to give the product (petroleum ether/ethyl acetate in a ratio of 99:1 as eluent).
Under the protection of nitrogen atmosphere, a rotor is put into a 100mL round-bottom flask, 10mmol of amine, 2mmol of p-Dimethylaminopyridine (DMAP), 20mmol of p-toluenesulfonyl chloride and 25mmol of triethylamine are weighed and dissolved in 20mL of dichloromethane, and the mixture is refluxed for two days. The reaction mother liquor was then washed three times with 20mL of saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed using a rotary evaporator. The residue was purified by column chromatography to give the product (petroleum ether/ethyl acetate in a ratio of 40:1 as eluent).
Under the protection of nitrogen, a rotor was put into a 50mL round-bottom flask, and 5mmol of propargylamide, 0.5mmol of DBU and 10mL of methylene chloride were weighed as solvents and stirred at room temperature for 12 hours. The solvent was then removed directly using a rotary evaporator. The residue was purified by column chromatography to give product I (petroleum ether/ethyl acetate in a ratio of 40:1 as eluent).
Second substrate synthetic route:
under the protection of nitrogen atmosphere, a rotor is put into a 25mL round-bottom flask, 20mmol of aldehyde, 20mmol of p-toluenesulfonamide and 5mL of tetraethoxysilane are weighed as solvents, and the reaction is stirred for 5 hours at 160 ℃. Then directly pouring the reaction into 100mL of anhydrous ether while the reaction is hot, stirring vigorously, standing for half an hour after the solid is completely separated out, and then carrying out suction filtration to obtain a white or light yellow solid product.
Under the protection of nitrogen atmosphere, a rotor is put into a 100mL round-bottom flask, 40mmol of alkyne is weighed and dissolved in 40mL of toluene, and 20mL of 1M dimethyl zinc toluene solution is added while stirring. Stirring for 2 hours at room temperature, directly adding 10mmol of imine into a reaction system under the protection of nitrogen atmosphere, heating to 50 ℃, and stirring for 12 hours. The reaction was then cooled to room temperature and washed three times with 20mL of saturated ammonium chloride. The aqueous phases are combined and extracted once with 20mL of ethyl acetate. The organic phases were combined, washed once with 20mL of saturated sodium chloride solution, then dried over anhydrous sodium sulfate and the solvent was removed using a rotary evaporator. The residue was purified by column chromatography to give the product (petroleum ether/ethyl acetate at 20:1 ratio as eluent).
Under the protection of nitrogen atmosphere, a rotor is put into a 100mL round bottom flask, 10mmol of propargylamide and 15mmol of sodium hydride are weighed, 20mL of dry DMF is added as a solvent, and the mixture is stirred at room temperature until the reaction solution is an orange solution and no bubbles are generated. 20mmol of o-bromobenzyl bromide were then added directly to the reaction and the resulting mixture was stirred further at room temperature. After confirming the completion of the reaction using thin layer chromatography, 5mL of water was added dropwise to quench the reaction. The quenched reaction solution was directly poured into a large beaker containing 100mL of water, 50mL of petroleum ether and 10mL of ethyl acetate, and the mixture was stirred vigorously until the solid was completely precipitated. And (3) carrying out suction filtration to obtain a white or light pink solid, and recrystallizing by using a mixed solvent with the ratio of petroleum ether to ethyl acetate being 10:1 to obtain a target product.
Under the protection of nitrogen, a rotor was put into a 50mL round-bottom flask, and 5mmol of benzylpropargylamide, 0.5mmol of DBU and 10mL of methylene chloride were weighed and stirred at room temperature for 12 hours. The solvent was then removed directly using a rotary evaporator. The residue was purified by column chromatography to give product I (petroleum ether/ethyl acetate in a ratio of 40:1 as eluent).
Example 1: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under an argon atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which was previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a thin-layer chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid with the yield of 92%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277 and found 294.1275. It was confirmed that the white solid product obtained by the above reaction was 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 2: preparation of 6-phenyl-4-methoxy-6H-indeno [1,2-c ] isoquinoline (2b)
1b as the starting substrate for the reaction to produce the desired product 2b, in a manner essentially identical to the procedure of example 1.
The product yield is 83%; a white solid;1H NMR(400MHz,CDCl3)δ9.28(s,1H),8.02(t,J＝8.7Hz,2H),7.56(d,J＝8.0Hz,1H),7.53–7.42(m,2H),7.30–7.21(m,3H),7.15–7.11(m,2H),7.01(dd,J＝8.3,2.3Hz,1H),6.89(d,J＝2.2Hz,1H),5.26(s,1H),3.81(s,3H).13C NMR(101MHz,CDCl3)δ160.45,154.31,153.34,150.68,140.62,133.54,133.40,133.29,130.67,129.04,128.92,128.15,127.60,127.12,125.74,123.12,121.13,113.48,110.87,55.52,51.86.HRMS(ESI):m/z Calcd.for C23H18NO[M+H]+:324.1383,found:324.1410.
example 3: preparation of 2-methyl-6-phenyl-6H-indeno [1,2-c ] isoquinoline (2c)
1c as the starting substrate for the reaction to produce the desired product 2c, for a reaction time of 20 hours, in a manner substantially identical to the procedure of example 1.
The product yield is 80%; a white solid;1H NMR(400MHz,CDCl3)δ9.34(s,1H),8.04–7.99(m,1H),7.62–7.57(m,1H),7.52–7.45(m,2H),7.28–7.22(m,3H),7.21–7.15(m,3H),7.13–7.09(m,2H),5.24(s,1H),3.05(s,3H).13C NMR(101MHz,CDCl3)δ156.2,152.8,149.1,141.0,137.9,134.5,134.2,133.0,130.4,129.8,129.0,128.7,128.1,127.6,127.3,127.0,126.1,123.4,122.2,51.6,19.5.HRMS(ESI):m/z Calcd.for C23H18N[M+H]+:308.1434,found:308.1438.
example 4: preparation of 8-phenyl-8H-benzo [6,7] indeno [1,2-c ] isoquinoline (2d)
1d as the starting substrate for the reaction to produce the desired product 2d, for a reaction time of 24 hours, in a manner substantially identical to the procedure of example 1.
The product yield is as follows: 60 percent; a light yellow solid;1H NMR(400MHz,CDCl3)δ9.91(d,J＝8.4Hz,1H),9.39(s,1H),8.05–7.98(m,1H),7.92–7.86(m,1H),7.78–7.68(m,2H),7.64–7.59(m,1H),7.57–7.52(m,1H),7.51–7.44(m,2H),7.42(d,J＝8.3Hz,1H),7.27–7.18(m,3H),7.13–7.07(m,2H),5.24(s,1H).13C NMR(101MHz,CDCl3)δ156.5,152.8,147.3,140.0,135.3,134.7,133.4,132.8,130.5,129.2,129.0,128.7,128.6,128.3,128.2,127.2,127.1,126.8,126.0,125.8,125.6,123.2,122.5,52.1.HRMS(ESI):m/z Calcd.for C26H18N[M+H]+:344.1434,found:344.1438.
example 5: preparation of 6-phenyl-2, 3-dimethoxy-6H-indeno [1,2-c ] isoquinoline (2e)
1e as the starting substrate for the reaction to produce the desired product 2e for 24 hours in substantially the same manner as in example 1.
The product yield is as follows: 79 percent; a white solid;1H NMR(400MHz,CDCl3)δ9.40(s,1H),8.07–7.95(m,1H),7.63–7.53(m,1H),7.53–7.42(m,2H),7.31–7.17(m,3H),7.15–7.06(m,2H),7.00(d,J＝8.1Hz,1H),6.87(d,J＝8.1Hz,1H),5.24(s,1H),4.18(s,3H),3.90(s,3H).13C NMR(101MHz,CDCl3)δ153.64,153.60,152.6,144.9,142.3,141.0,134.9,133.5,132.9,130.5,129.0,128.7,128.0,127.5,127.0,126.3,123.4,120.2,112.8,61.6,56.6,51.3.HRMS(ESI):m/z Calcd.for C24H20NO2[M+H]+:354.1489,found:354.1492.
example 6: preparation of 6-phenyl-4-chloro-6H-indeno [1,2-c ] isoquinoline (2f)
1f as the starting substrate for the reaction to produce the objective product 2f in a reaction time of 14 hours in substantially the same manner as in example 1.
The product yield is as follows: 93 percent; a white solid;1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.06–8.01(m,2H),7.59–7.47(m,3H),7.42(dd,J＝8.1,1.9Hz,1H),7.31–7.25(m,4H),7.13–7.08(m,2H),5.26(s,1H).13C NMR(101MHz,CDCl3)δ153.7,153.2,150.1,139.6,139.2,134.3,133.9,133.1,130.9,129.2,129.0,128.13,128.10,128.0,127.4,126.5,125.3,123.3,121.3,51.8.HRMS(ESI):m/z Calcd.for C22H15ClN[M+H]+:328.0888,found:328.0893.
example 7: preparation of 6-phenyl-6H-benzo [ f ] indeno [1,2-c ] isoquinoline (2g)
1g of the objective product was prepared as the starting substrate for the reaction in an amount of 2g for 14 hours in substantially the same manner as in example 1.
The product yield is as follows: 70 percent; a light yellow solid;1H NMR(400MHz,CDCl3)δ9.34(s,1H),8.75(d,J＝8.4Hz,1H),8.19(dt,J＝7.7,0.9Hz,1H),7.91(d,J＝8.8Hz,1H),7.84(dd,J＝7.9,1.4Hz,1H),7.78(d,J＝8.8Hz,1H),7.56(ddd,J＝8.0,7.0,1.1Hz,1H),7.50–7.39(m,3H),7.35(td,J＝7.4,1.2Hz,1H),7.18–7.07(m,5H),5.85(s,1H).13C NMR(101MHz,CDCl3)δ158.2,152.7,148.5,139.9,139.1,134.6,133.5,133.4,129.1,128.7,128.54,128.47,128.19,128.17,127.9,127.7,127.1,127.01,126.98,126.2,126.1,124.5,120.8,54.8.HRMS(ESI):m/z Calcd.for C26H18N[M+H]+:344.1434,found:344.1436.
example 8: preparation of 6-phenyl-9-fluoro-6H-indeno [1,2-c ] isoquinoline (2H)
1h as the initial substrate of the reaction, and the reaction time is 22 hours, and the preparation method is basically the same as the operation steps in the example 1.
The product yield is as follows: 96 percent; a white solid;1H NMR(400MHz,CDCl3)δ9.25(s,1H),8.12(d,J＝7.6Hz,1H),7.66–7.55(m,2H),7.49–7.42(m,1H),7.35–7.21(m,6H),7.09(d,J＝6.3Hz,2H),5.24(s,1H).13C NMR(101MHz,CDCl3)δ160.2(d,J＝249.7Hz),153.9(d,J＝2.1Hz),152.5(d,J＝5.5Hz),148.3,140.3,140.2,134.5,130.4,129.1,128.7(d,J＝8.9Hz),128.2,128.0,127.7,127.2,126.0(d,J＝8.4Hz),124.8,121.3(d,J＝25.5Hz),120.3,111.8(d,J＝20.7Hz),51.9.HRMS(ESI):m/z Calcd.for C22H15FN[M+H]+:312.1183,found:312.1188.
example 9: preparation of 6H-indeno [1,2-c ] isoquinoline (2i)
1i as the starting substrate for the reaction to produce the objective product 2i, for a reaction time of 21 hours, in substantially the same manner as in example 1.
The product yield is as follows: 37 percent; a white solid;1H NMR(400MHz,CDCl3)δ9.28(s,1H),8.14(d,J＝7.5Hz,1H),8.05(d,J＝8.2Hz,1H),7.98(dd,J＝8.3,1.0Hz,1H),7.75(ddd,J＝8.2,6.9,1.2Hz,1H),7.64(d,J＝7.4Hz,1H),7.57(ddd,J＝8.1,6.9,1.1Hz,1H),7.49(t,J＝7.4Hz,1H),7.41(td,J＝7.4,1.2Hz,1H),4.14(s,2H).13C NMR(101MHz,CDCl3)δ154.1,152.5,142.8,142.1,133.6,131.2,130.8,128.9,127.5,127.3,126.3,125.0,123.1,120.3,100.0,33.3.HRMS(ESI):m/z Calcd.for C16H12N[M+H]+:218.0964,found:218.0972.
example 10: preparation of 6-tert-butyl-6H-indeno [1,2-c ] isoquinoline (2j)
1j as the starting substrate for the reaction to produce the objective product 2j for a reaction time of 36 hours in substantially the same manner as in example 1.
The product yield is as follows: 46 percent; a white solid;1H NMR(400MHz,CDCl3)δ9.12(s,1H),7.96(d,J＝8.3Hz,2H),7.90(d,J＝8.2Hz,1H),7.59–7.49(m,2H),7.43–7.31(m,2H),7.21(td,J＝7.5,1.2Hz,1H),4.16(s,1H),0.88(s,9H).13C NMR(101MHz,CDCl3)δ155.27,152.61,147.28,142.17,135.06,134.33,129.58,128.61,127.50,127.41,126.45,125.98,125.84,125.52,120.06,55.87,36.72,29.15.HRMS(ESI):m/z Calcd.for C20H20N[M+H]+:274.1590,found:274.1598.
example 11: preparation of 6- (4-methylphenyl) -6H-indeno [1,2-c ] isoquinoline (2k)
1k as the starting substrate for the reaction to produce the desired product 2k, for a reaction time of 12 hours, in a manner substantially identical to the procedure of example 1.
The product yield is as follows: 99 percent; a white solid;1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.13(d,J＝7.5Hz,1H),7.99(dd,J＝7.2,1.5Hz,1H),7.60(d,J＝8.4Hz,1H),7.52–7.40(m,3H),7.34–7.26(m,2H),7.05(d,J＝7.8Hz,2H),6.98(d,J＝8.1Hz,2H),5.21(s,1H),2.28(s,3H).13CNMR(101MHz,CDCl3)δ154.15,153.41,148.91,140.56,137.34,136.68,134.55,133.32,130.72,129.72,128.91,128.20,128.12,127.98,127.62,126.21,124.81,123.46,120.30,51.58,21.14.HRMS(ESI):m/z Calcd.for C23H18N[M+H]+:308.1434,found:308.1439.
example 12: preparation of 6- (4-methoxyphenyl) -6H-indeno [1,2-c ] isoquinoline (2l)
1l of the reaction starting substrate was used to prepare 2l of the objective product by a reaction time of 12 hours in substantially the same manner as in example 1.
The product yield is as follows: 98 percent; a white solid;1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.15(d,J＝7.6Hz,1H),8.07–7.97(m,1H),7.62(d,J＝8.3Hz,1H),7.55–7.42(m,3H),7.36–7.29(m,2H),7.04(d,J＝8.7Hz,2H),6.80(d,J＝8.7Hz,2H),5.22(s,1H),3.75(s,3H).13C NMR(101MHz,CDCl3)δ158.63,154.06,153.43,149.02,140.52,134.58,133.30,132.33,130.70,129.11,128.91,128.18,128.13,127.62,126.21,124.79,123.44,120.29,114.41,55.19,51.17.HRMS(ESI):m/z Calcd.for C23H18NO[M+H]+:324.1383,found:324.1385.
example 13: preparation of 6- (2-methoxyphenyl) -6H-indeno [1,2-c ] isoquinoline (2m)
1m as the starting substrate for the reaction to produce the desired product 2m for 12 hours, in substantially the same manner as in example 1.
The product yield is as follows: 54 percent; a white solid;1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.13(d,J＝7.4Hz,1H),8.03(dd,J＝7.0,1.4Hz,1H),7.61–7.39(m,5H),7.30(td,J＝7.5,1.2Hz,1H),7.20(t,J＝7.0Hz,1H),7.08(br,1H),6.62(br,1H),6.29(br,1H),6.01(br,1H),4.14(br,3H).13C NMR(101MHz,CDCl3)δ157.30,154.44,153.13,149.26,140.85,134.97,133.21,130.63,128.84,128.06,127.39,126.12,124.84,123.74,121.13,120.21,111.02,55.80,43.84.HRMS(ESI):m/z Calcd.for C23H18NO[M+H]+:324.1388,found:324.1396.
example 14: preparation of 6- (4-chlorophenyl) -6H-indeno [1,2-c ] isoquinoline (2n)
1n as the starting substrate for the reaction to produce the desired product 2n, for a reaction time of 14 hours, in substantially the same manner as in example 1.
The product yield is as follows: 91%; a white solid;1H NMR(400MHz,CDCl3)δ9.33(s,1H),8.14(d,J＝7.6Hz,1H),8.06–8.02(m,1H),7.63–7.59(m,1H),7.55–7.44(m,3H),7.37–7.31(m,2H),7.27–7.22(m,3H),7.15–7.10(m,2H),5.31(s,1H),0.00(s,1H).13C NMR(101MHz,CDCl3)δ154.25,153.53,148.69,140.61,140.49,134.40,133.30,130.76,129.01,128.93,128.19,128.13,127.70,127.11,126.24,124.85,123.41,120.32,51.95.HRMS(ESI):m/zCalcd.for C22H15ClN[M+H]+:328.0893,found:328.0892.
example 15: preparation of 6- (2-thienyl) -6H-indeno [1,2-c ] isoquinoline (2o)
1o as the starting substrate for the reaction to produce the desired product 2o for 16 hours, in substantially the same manner as in example 1.
The product yield is as follows: 57 percent; a white solid;1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.13(dt,J＝7.6,1.0Hz,1H),8.04(d,J＝7.7Hz,1H),7.70(dq,J＝8.4,0.9Hz,1H),7.59–7.39(m,4H),7.34(td,J＝7.4,1.2Hz,1H),7.28(ddd,J＝2.9,1.3,0.5Hz,1H),7.18(dd,J＝5.0,3.0Hz,1H),6.55(dd,J＝5.0,1.3Hz,1H),5.46(s,1H).13C NMR(101MHz,CDCl3)δ153.82,153.51,147.54,140.50,140.19,133.74,133.38,130.81,128.92,128.18,128.09,127.79,126.77,126.51,126.28,124.76,123.23,122.08,120.35,46.99.HRMS(ESI):m/z Calcd.forC20H14NS[M+H]+:300.0847,found:300.0852.
example 16: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under an argon atmosphere, 1 a' (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which had been previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid, wherein the yield of the product is 36%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 17: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under an argon atmosphere, 1a (0.2mmol), tetrakistriphenylphosphine palladium (0.02mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube using N, N-dimethylformamide (3mL) as a reaction solvent, the reaction tube was put into an oil bath which had been previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a thin-layer chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid with the yield of 55%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 18: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under an argon atmosphere, 1a (0.2mmol), bis (dibenzylideneacetone) palladium (0.02mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which was previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid with the yield of 64%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 19: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under an argon atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), triphenylphosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which was previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid with the yield of 34%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 20: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under argon atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (p-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which had been previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid with the yield of 81%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 21: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under argon atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (p-dimethylaminophenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, the reaction tube was put into an oil bath which had been previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a thin-layer chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid, wherein the yield of the product is 85%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 22: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under argon atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (0.01mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and N, N-dimethylformamide (3mL) was added to the reaction tube as a reaction solvent, followed by placing the reaction tube into an oil bath which had been previously heated to 100 ℃ and stirring for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid with the yield of 74%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 23: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under argon atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.002mmol), tris (m-methoxyphenyl) phosphine (0.004mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was added thereto, the reaction tube was put into an oil bath which had been previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid, wherein the yield of the product is 67%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 24: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under an argon atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.1mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which was previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid, wherein the yield of the product is 36%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 25: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under an argon atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (1.0mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which was previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid, wherein the yield of the product is 94%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 26: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under argon atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, the reaction tube was put into an oil bath which had been previously heated to 80 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a thin-layer chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid with the yield of 78%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and NMR carbon Spectroscopy: (MR)13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 27: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under an argon atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which was previously heated to 140 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid with the yield of 83%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 28: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under an argon atmosphere, 1a "(0.2 mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which was previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid, wherein the yield of the product is 11%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 29: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under argon atmosphere, 1 a' (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, the reaction tube was put into an oil bath which had been previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a Thin Layer Chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid, wherein the yield of the product is 67%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 30: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under a nitrogen atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which was previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a thin-layer chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid with the yield of 92%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Example 31: preparation of 6-phenyl-6H-indeno [1,2-c ] isoquinoline (2a)
Under a helium atmosphere, 1a (0.2mmol), tris (dibenzylideneacetone) dipalladium (0.01mmol), tris (m-methoxyphenyl) phosphine (0.02mmol) and sodium acetate (0.6mmol) were added to a reaction tube, and after a rubber stopper was added to the reaction tube, N-dimethylformamide (3mL) was used as a reaction solvent, the reaction tube was put into an oil bath which was previously heated to 100 ℃ and stirred for reaction for 8 hours. And (3) determining the reaction end point by using a thin-layer chromatography (TLC) spot plate, lifting the reaction tube from the oil bath pot when the TLC plate shows that the reaction raw material 1a completely disappears, cooling to room temperature, adding 20mL of water to quench the reaction, extracting by using ethyl acetate, spin-drying the solvent, and performing column chromatography to obtain the target product 2a as a white solid with the yield of 92%.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR and nuclear magnetic resonance carbon Spectroscopy: (13C NMR), analyzing the white solid product, and performing molecular weight determination by High Resolution Mass Spectrometry (HRMS);1H NMR(400MHz,CDCl3)δ9.32(s,1H),8.14(d,J＝7.6Hz,1H),8.07–8.01(m,1H),7.62–7.58(m,1H),7.54–7.43(m,3H),7.37–7.31(m,2H),7.28–7.22(m,3H),7.14–7.10(m,2H),5.30(s,1H).13C NMR(101MHz,CDCl3)δ154.2,153.5,148.7,140.6,140.5,134.4,133.3,130.7,129.0,128.9,128.2,128.1,127.7,127.1,126.2,124.8,123.4,120.3,51.9.HRMS(ESI):m/z Calcd.for C22H16N[M+H]+294.1277, found 294.1275. the white solid product obtained by the above reaction was confirmed to be 6-phenyl-6H-indeno [1,2-c ]]Isoquinoline (2 a).
Claims (10)
1. An indeno isoquinoline compound, which is characterized by having an indeno [1,2-c ] isoquinoline skeleton structure shown in a formula II:
wherein R is1、R2、R3、R4、R6、R7、R8、R9And R12Each independently selected from alkyl, alkoxy, halogen or hydrogen, and
R10、R11each independently selected from hydrogen, alkyl, aryl or heteroaryl.
2. The compound of claim 1, wherein the compound is selected from the group consisting of:
3. a compound selected from
4. A method for preparing indenoisoquinoline compounds,
the method is characterized in that:
adding the compound shown in the formula 1, a palladium catalyst, a ligand and alkali metal acetate into an organic solvent, and synthesizing the indenoisoquinoline compound shown in the formula II or a corresponding product marked by an enantiomer, a racemate, a diastereoisomer or an isotope thereof by adopting a one-step method:
wherein R is1、R2、R3、R4、R6、R7、R8、R9And R12Each independently selected from alkyl, alkoxy, halogen or hydrogen;
R5selected from acyl, sulfonyl or sulfinyl;
R10and R11Each independently selected from hydrogen, alkyl, aryl or heteroaryl;
x is halogen.
5. The method of claim 4, wherein the molar ratio of the compound of formula 1 to the palladium catalyst is from 100:1 to 10:1, the molar ratio of the palladium catalyst to the ligand is from 1:1 to 1:2, and the molar ratio of the compound of formula 1 to the alkali metal acetate is from 2:1 to 1: 5.
6. The process of claim 4, wherein the palladium catalyst is tetrakistriphenylphosphine palladium, bis (dibenzylideneacetone) palladium, or tris (dibenzylideneacetone) dipalladium, or
Wherein the ligand is triphenylphosphine, tri (m-methoxyphenyl) phosphine, tri (p-dimethylaminophenyl) phosphine or 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene.
7. The process according to claim 4, wherein the alkali metal acetate is sodium acetate or the organic solvent is selected from polar organic solvents such as N, N-dimethylformamide, N-dimethylacetamide or dimethylsulfoxide, preferably N, N-dimethylformamide.
8. The method according to claim 4, wherein the method is performed under a protective atmosphere, preferably the protective atmosphere is nitrogen, argon or helium.
9. The process of claim 4, wherein the reaction temperature is 80-140 ℃, or the reaction time is 8-36 hours.
10. The method of claim 4, wherein the indenoisoquinoline-based compound is a compound according to any one of claims 1 to 3.
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