CN114539122A - Method and compound for synthesizing beta-carbonyl indoline-3-ketone containing C2 site - Google Patents
Method and compound for synthesizing beta-carbonyl indoline-3-ketone containing C2 site Download PDFInfo
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Abstract
The invention discloses a method and a compound for synthesizing beta-carbonyl indoline-3-ketone containing C2 site, wherein the synthesis method comprises the step of reacting 2- (ethynyl) nitrobenzene compounds, ketone compounds and organic phosphine compounds in an organic solvent under the action of inorganic base to obtain the beta-carbonyl indoline-3-ketone containing C2 site. The method has the advantages of easily obtained raw materials, mild reaction conditions, simple operation, high yield, wide substrate range, no need of a metal catalyst for reaction and the like.
Description
Technical Field
The invention belongs to the technical field of organic compounds, and particularly relates to a method and a compound for synthesizing beta-carbonyl indoline-3-ketone containing C2 site.
Background
Indoline-3-ketone compounds are important structural units constituting a plurality of natural product molecules and drug molecules with biological activity, and have wide application in the fields of medicines, pesticides and the like, for example, austamide can be applied in the fields of antibiosis, insecticide, insect repelling and the like (J.Am.chem.Soc.2002,124,7904), and for example, isatisine A extracted from leaves of isatis roots shows excellent antiviral properties, including virus such as influenza, viral pneumonia and hepatitis (Angew.chem., int.Ed.2010,49,1133). On the other hand, in the fields of dyes and materials, indoline-3-ketone compounds can be applied to the research of fluorescent dyes and solar cells (J.Am.chem.Soc.2009, 131, 4566; chem.Commun.2011,47,7500).
The synthesis methods of indoline-3-ketone derivatives are many, but the synthesis methods of C2 position beta-carbonyl indoline-3-ketone containing carbonyl functional group introduced at C2 position are very few, and the compounds can be conveniently transformed by introducing the carbonyl functional group at C2 position, thereby being beneficial to further synthesizing natural products with complex molecular structures or compounds with biological activity. The existing synthesis methods of C2-position beta-carbonyl indoline-3-ketone are few, such as nitrone and [3+2 ] of olefin]Cycloaddition followed by neutral redox N-O bond cleavage under the action of Ru catalysts (org. Lett.2015,17, 2870-2873); cs2CO3Catalytic 2-indolone and enone oxidation (J.org.chem.2016,81, 12443-12450); mannich addition of ketones to iminoketones (chem. Commun.2018,54, 9151-9154;); and our previous work on a one-pot two-step synthesis method (adv. synth. call.2017, 359,4147-4152) by using 2-alkynyl aryl azide, p-toluenesulfonic acid and ketone as raw materials under the catalysis of palladium, and the like, but the known methods still have many problems, such as the use of expensive metal catalysts, high reaction temperature, difficult raw material synthesis, multi-step reaction requirement and the like. Therefore, how to synthesize the C2-site beta-carbonyl indoline-3-ketone compound by using a simple and efficient synthesis method with easily obtained raw materials has great research value and application prospect.
Disclosure of Invention
This section is for the purpose of summarizing some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. In this section, as well as in the abstract and the title of the invention of this application, simplifications or omissions may be made to avoid obscuring the purpose of the section, the abstract and the title, and such simplifications or omissions are not intended to limit the scope of the invention.
The present invention has been made keeping in mind the above and/or other problems occurring in the prior art.
One of the purposes of the invention is to provide a method for synthesizing beta-carbonyl indoline-3-ketone containing C2 site, which has the advantages of easily obtained raw materials, mild reaction conditions, simple operation, high yield, wide substrate range, no need of metal catalyst in the reaction and the like.
In order to solve the technical problems, the invention provides the following technical scheme: a method for synthesizing beta-carbonyl indoline-3-ketone containing C2 site comprises the following steps,
reacting a 2- (ethynyl) nitrobenzene compound shown in a formula I, a ketone compound shown in a formula II and an organic phosphine compound shown in a formula III in an organic solvent under the action of inorganic base to obtain a compound shown in a formula IV;
wherein R is1、R2、R3、R4Are each independently a group;
R1one selected from hydrogen, alkyl, alkoxy, halogen, carbonyl, ester group, carboxyl, nitro and cyano;
R2one selected from hydrogen, alkyl, carbonyl, ester group, carboxyl, phenyl, halogen substituted phenyl, alkyl substituted phenyl, naphthyl, thienyl, furyl, indolyl and trimethylsilyl;
R3one selected from hydrogen, alkyl, phenyl, halogen substituted phenyl and alkyl substituted phenyl;
R4one selected from hydrogen, alkyl, halogen substituted phenyl, alkyl substituted phenyl, naphthalene ring, indole ring, furan ring, thiophene ring, pyridine ring and alpha-alkyl carbonyl;
R5、R6、R7are each independently of the other R5、R6、R7Is selected from one of alkyl, phenyl, alkyl substituted phenyl, halogen substituted phenyl and cycloalkyl.
As a preferable embodiment of the method for synthesizing the C2-containing beta-carbonyl indoline-3-ketone, the method comprises the following steps: the molar weight ratio of the compound shown in the formula I to the compound shown in the formula II is 1: 1-3.
As a preferred embodiment of the method for synthesizing the beta-carbonyl indolin-3-ketone containing C2, the method comprises the following steps: the molar weight ratio of the compound shown in the formula I to the compound shown in the formula II is 1: 3.
As a preferred embodiment of the method for synthesizing the beta-carbonyl indolin-3-ketone containing C2, the method comprises the following steps: the compound of formula III is preferably triphenylphosphine.
As a preferred embodiment of the method for synthesizing the beta-carbonyl indolin-3-ketone containing C2, the method comprises the following steps: the molar ratio of the compound shown in the formula I to the organic phosphine is 1: 1.5-5.
As a preferred embodiment of the method for synthesizing the beta-carbonyl indolin-3-ketone containing C2, the method comprises the following steps: the molar ratio of the compound shown in the formula I to the organic phosphine is 1: 3.
As a preferred embodiment of the method for synthesizing the beta-carbonyl indolin-3-ketone containing C2, the method comprises the following steps: the inorganic base is one or more of sodium hydroxide, potassium carbonate, sodium hydride, cesium carbonate, potassium phosphate and potassium tert-butoxide; preferably, the inorganic base is potassium carbonate.
As a preferred embodiment of the method for synthesizing the beta-carbonyl indolin-3-ketone containing C2, the method comprises the following steps: the molar ratio of the inorganic base to the compound shown in the formula I is 1-5: 1.
As a preferred embodiment of the method for synthesizing the beta-carbonyl indolin-3-ketone containing C2, the method comprises the following steps: the molar ratio of the inorganic base to the compound of formula I is 3: 1.
As a preferred embodiment of the method for synthesizing the beta-carbonyl indolin-3-ketone containing C2, the method comprises the following steps: the organic solvent is one or more of dimethyl sulfoxide, acetonitrile, toluene, N, N-dimethylformamide and 1, 4-dioxane; preferably, the organic solvent is acetonitrile.
As a preferred embodiment of the method for synthesizing the beta-carbonyl indolin-3-ketone containing C2, the method comprises the following steps: the reaction is carried out in an organic solvent, the reaction temperature is 20-90 ℃, and the reaction time is 3-8 h; the reaction temperature is preferably 90 ℃ and the reaction time is preferably 6 h.
In conclusion, the chemical equation of the optimal reaction conditions of the present invention is as follows:
as a preferred embodiment of the method for synthesizing the beta-carbonyl indolin-3-ketone containing C2, the method comprises the following steps: and (3) after the reaction is finished, directly performing gel column chromatography, wherein an eluent is ethyl acetate: the petroleum ether is mixed liquid according to the volume ratio of 1: 20-1: 8.
Another object of the present invention is to provide a compound obtained by the method for synthesizing C2-containing beta-carbonylindolin-3-one as described above, wherein the structural formula of the compound is as follows:
wherein R is1、R2、R3、R4Are each independently a group;
R1one selected from hydrogen, alkyl, alkoxy, halogen, carbonyl, ester group, carboxyl, nitro and cyano;
R2one selected from hydrogen, alkyl, carbonyl, ester group, carboxyl, phenyl, halogen substituted phenyl, alkyl substituted phenyl, naphthyl, thienyl, furyl, indolyl and trimethylsilyl;
R3one selected from hydrogen, alkyl, phenyl, halogen substituted phenyl and alkyl substituted phenyl;
R4one selected from hydrogen, alkyl, halogen substituted phenyl, alkyl substituted phenyl, naphthalene ring, indole ring, furan ring, thiophene ring, pyridine ring and alpha-alkyl carbonyl.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a simple and efficient synthesis method of a C2-site beta-carbonyl indoline-3-ketone compound, the used raw material 2- (ethynyl) nitrobenzene is simple and easy to obtain, a metal catalyst is not needed in the reaction, the reaction condition is mild, the operation is simple, the substrate range is wide, and the yield is high. The beta-carbonyl indoline-3-ketone compound containing C2 site can be used as an organic synthesis intermediate, and has wide application prospect in the fields of medicines, materials, solar cells and the like.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without inventive exercise. Wherein:
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a target product 1 prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the objective product 1 prepared in example 1 of the present invention;
FIG. 3 is a NMR hydrogen spectrum of a target product 2 prepared in example 2 of the present invention;
FIG. 4 is a NMR hydrogen spectrum of a target product 3 prepared in example 3 of the present invention;
FIG. 5 is a NMR hydrogen spectrum of a target product 4 prepared in example 4 of the present invention;
FIG. 6 is a NMR hydrogen spectrum of a target product 5 prepared in example 5 of the present invention;
FIG. 7 is a NMR hydrogen spectrum of a target product 6 produced in example 6 of the present invention;
FIG. 8 is a NMR hydrogen spectrum of a target product 7 produced in example 7 of the present invention;
FIG. 9 shows a NMR spectrum of a target product 8 produced in example 8 of the present invention.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, specific embodiments thereof are described in detail below with reference to examples of the specification.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced otherwise than as specifically described herein, and it will be appreciated by those skilled in the art that the present invention may be practiced without departing from the spirit and scope of the present invention and that the present invention is not limited by the specific embodiments disclosed below.
Furthermore, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
Example 1
To a 10mL test tube were added 2- (ethynylphenyl) nitrobenzene (0.1mmol), acetophenone (0.3mmol), triphenylphosphine (0.3mmol), potassium carbonate (0.3mmol), and acetonitrile (1mL) in that order, and the mixture was stirred at 90 ℃ for 6 hours under nitrogen. And monitoring the reaction by TLC, after the reaction is finished, performing rotary evaporation to remove the solvent, performing 100-200-mesh silica gel column chromatography on the crude product, performing gradient elution by using a mixed solvent of petroleum ether and ethyl acetate (the volume ratio is 20:1-8:1) as an eluent, collecting the eluent, performing rotary evaporation to remove the solvent to obtain 28mg of a target product 1, and calculating the yield to obtain 86%.
The reaction formula for example 1 is:
the target product 1 is characterized, and the result is as follows: a yellow solid;1H NMR(400MHz, CDCl3):δ＝7.91(d,J＝7.4Hz,2H),7.62–7.53(m,5H),7.52–7.38(m,4H), 7.32–7.24(m,3H),7.23–7.18(m,1H),6.96(d,J＝8.2Hz,1H),6.84–6.76(m,1 H),6.32(s,1H),4.44(d,J＝17.8Hz,1H),3.18(d,J＝17.9Hz,1H)；13C NMR(101 MHz,CDCl3) Delta 201.32,198.45,160.91,138.68,138.43,137.20,134.37,129.38,129.34, 128.75,128.21,126.27,125.98,119.50,118.77,112.43,69.91 and 45.36, wherein the nuclear magnetic resonance hydrogen spectrum of the target product 1 is shown in figure 1; the nuclear magnetic resonance carbon spectrum of the target product 1 is shown in figure 2. According to the characterization data, the prepared purpose is knownTitle product 1 was 2- (2-oxo-2-phenylethyl) -2-phenylindol-3-one.
Example 2
To a 10mL test tube were added 4-methyl-2-nitro-1- (phenylethynyl) benzene (0.1mmol), acetophenone (0.3mmol), triphenylphosphine (0.3mmol), potassium carbonate (0.3mmol), and acetonitrile (1mL) in that order, and the mixture was stirred at 90 ℃ for 6 hours under nitrogen. And monitoring the reaction by TLC, after the reaction is finished, rotationally evaporating to remove the solvent, performing 100-200-mesh silica gel column chromatography on the crude product, performing gradient elution by using a mixed solvent of petroleum ether and ethyl acetate (the volume ratio is 20:1-8:1) as an eluent, collecting the eluent, rotationally evaporating to remove the solvent to obtain 20mg of a target product 2, and calculating the yield to obtain 86%.
The reaction formula for example 2 is:
the target product 2 is characterized, and the result is as follows: a yellow solid;1H NMR(400MHz, CDCl3):δ7.92(d,J＝7.7Hz,2H),7.61–7.51(m,3H),7.51–7.40(m,3H), 7.31–7.24(m,2H),7.23–7.18(m,1H),6.77(s,1H),6.64(d,J＝7.9Hz,1H),6.24 (s,1H),4.44(d,J＝17.9Hz,1H),3.17(d,J＝17.9Hz,1H),2.38(s,3H)；13C NMR (101MHz,CDCl3) Delta 200.57,198.57,161.42,150.18,138.93,137.25,134.35,129.38, 129.31,128.75,128.13,125.99,125.94,121.38,116.51,112.42,70.13,45.37 and 23.18, and the nuclear magnetic resonance hydrogen spectrum of the target product 2 is shown in figure 3. According to the characterization data, the prepared target product 2 is 6-methyl-2- (2-oxo-2-phenylethyl) -2-phenylindol-3-one.
Example 3
To a 10mL test tube were added 4-fluoro-1-nitro-2- (phenylethynyl) benzene (0.1mmol), acetophenone (0.3mmol), triphenylphosphine (0.3mmol), potassium carbonate (0.3mmol), and acetonitrile (1mL) in that order, and the mixture was stirred at 90 ℃ for 6 hours under nitrogen. And monitoring the reaction by TLC, after the reaction is finished, performing rotary evaporation to remove the solvent, performing 100-200-mesh silica gel column chromatography on the crude product, performing gradient elution by using a mixed solvent of petroleum ether and ethyl acetate (the volume ratio is 20:1-8:1) as an eluent, collecting the eluent, and performing rotary evaporation to remove the solvent to obtain 31mg of a target product 3, wherein the yield is 89%.
The reaction formula for example 3 is:
the target product 3 is characterized, and the result is as follows: a yellow solid;1H NMR(400MHz, CDCl3):δ7.92(d,J＝7.2Hz,2H),7.63–7.55(m,3H),7.53–7.36(m,2H), 7.35–7.21(m,5H),6.97–6.90(m,1H),6.25(s,1H),4.43(d,J＝17.9Hz,1H), 3.25(d,J＝17.8Hz,1H)；13C NMR(101MHz,CDCl3) δ 201.12,198.21,158.23(d, J240.4 Hz),157.59,138.44,137.10,134.43,129.41,129.40,128.76,128.37,126.57(d, J25.3 Hz),125.95,119.27(d, J8 Hz),113.59(d, J7.07 Hz),110.95(d, J22.2 Hz),71.02,45.53, the nmr spectrogram of the target product 3 is shown in fig. 4. According to the characterization data, the prepared target product 3 is 5-fluoro-2- (2-oxo-2-phenylethyl) -2-phenylindol-3-one.
Example 4
To a 10mL test tube were added 1- ((4-ethylphenyl) ethynyl) -2-nitrobenzene (0.1mmol), acetophenone (0.3mmol), triphenylphosphine (0.3mmol), potassium carbonate (0.3mmol), and acetonitrile (1mL) in that order, and the mixture was stirred at 90 ℃ under nitrogen for 6 hours. And monitoring the reaction by TLC, after the reaction is finished, performing rotary evaporation to remove the solvent, performing 100-200-mesh silica gel column chromatography on the crude product, performing gradient elution by using a mixed solvent of petroleum ether and ethyl acetate (the volume ratio is 20:1-8:1) as an eluent, collecting the eluent, and performing rotary evaporation to remove the solvent to obtain 27mg of a target product 4, wherein the yield is 77%.
The reaction formula for example 4 is:
the target product 4 is characterized, and the result is as follows: a yellow solid;1H NMR(400MHz, CDCl3):δ7.92(d,J＝7.8Hz,2H),7.62–7.52(m,2H),7.53–7.40(m,5H),7.11(d, J＝8.1Hz,2H),6.95(d,J＝8.3Hz,1H),6.84–6.76(m,1H),6.31(s,1H),4.43(d,J ＝18.0Hz,1H),3.18(d,J＝17.9Hz,1H),2.57(q,J＝7.6Hz,2H),1.16(t,J＝7.6 Hz,3H)；13C NMR(101MHz,CDCl3) Delta 201.52,198.51,160.92,144.15,138.34, 137.26,135.84,134.32,129.37,128.91,128.77,126.28,125.86,119.42,118.87,112.38, 69.83,45.26,28.96 and 15.93, the nuclear magnetic resonance hydrogen spectrum of the target product 4 is shown in figure 5. According to the characterization data, the prepared target product 4 is 2- (4-ethylphenyl) -2- (2-oxo-2-phenylethyl) indol-3-one.
Example 5
To a 10mL test tube were added 1- ((4-chlorophenyl) ethynyl) -2-nitrobenzene (0.1mmol), acetophenone (0.3mmol), triphenylphosphine (0.3mmol), potassium carbonate (0.3mmol), and acetonitrile (1mL) in that order, and the mixture was stirred at 90 ℃ for 6 hours under nitrogen. And (3) monitoring the reaction by TLC, after the reaction is finished, performing rotary evaporation to remove the solvent, performing silica gel column chromatography on the crude product through 100-200 meshes, performing gradient elution by using a mixed solvent of petroleum ether and ethyl acetate (the volume ratio is 20:1-8:1) as an eluent, collecting the eluent, and performing rotary evaporation to remove the solvent to obtain 33mg of a target product 5, wherein the yield is calculated to be 93%.
The reaction formula for example 5 is:
the target product 5 is characterized, and the result is as follows: a yellow solid;1H NMR(400MHz, CDCl3):δ7.90(d,J＝7.7Hz,2H),7.62–7.55(m,2H),7.55–7.48(m,3H), 7.47–7.42(m,2H),7.25(d,J＝8.3Hz,2H),6.97(d,J＝8.2Hz,1H),6.87–6.79(m, 1H),6.35(s,1H),4.39(d,J＝18.0Hz,1H),3.16(d,J＝18.0Hz,1H)；13C NMR(101 MHz,CDCl3) Delta 200.90,198.35,160.77,138.63,137.38,137.01,134.55,134.19,129.44, 129.41,128.73,127.57,126.29,119.73,118.54,112.56,69.45 and 45.44, and the nuclear magnetic resonance hydrogen spectrum of the target product 5 is shown in figure 6. According to the characterization data, the prepared target is knownTitle product 5 was 2- (4-chlorophenyl) -2- (2-oxo-2-phenylethyl) indol-3-one.
Example 6
To a 10mL test tube were added 2- ((2-nitrophenyl) ethynyl) thiophene (0.1mmol), acetophenone (0.3mmol), triphenylphosphine (0.3mmol), potassium carbonate (0.3mmol), and acetonitrile (1mL) in that order, and the mixture was stirred at 90 ℃ under nitrogen for 6 hours. And monitoring the reaction by TLC, after the reaction is finished, performing rotary evaporation to remove the solvent, performing 100-200-mesh silica gel column chromatography on the crude product, performing gradient elution by using a mixed solvent of petroleum ether and ethyl acetate (the volume ratio is 20:1-8:1) as an eluent, collecting the eluent, performing rotary evaporation to remove the solvent to obtain 28mg of a target product 6, and calculating the yield to obtain 84%.
The reaction formula for example 6 is:
the target product 6 is characterized, and the result is as follows: a red solid;1H NMR(400MHz, CDCl3):δ7.92(d,2H),7.62(d,J＝7.8Hz,1H),7.60–7.55(m,1H),7.53–7.42(m,3 H),7.14–7.09(m,2H),6.95(d,J＝8.3Hz,1H),6.93–6.88(m,1H),6.88–6.80(m, 1H),6.43(s,1H),4.31(d,J＝17.6Hz,1H),3.19(d,J＝17.7Hz,1H)；13C NMR(101 MHz,CDCl3) Delta 199.96,198.13,160.60,143.39,138.51,137.14,134.41,129.37,128.79, 128.15,126.37,125.35,124.35,119.98,118.51,112.78,68.56 and 46.02, and the nuclear magnetic resonance hydrogen spectrum of the target product 6 is shown in figure 7. According to the characterization data, the prepared target product 6 is 2- (2-oxo-2-phenethyl) -2- (2-thienyl) indol-3-one.
Example 7
To a 10mL test tube were added 2- (ethynylphenyl) nitrobenzene (0.1mmol), 4-nitroacetophenone (0.3mmol), triphenylphosphine (0.3mmol), potassium carbonate (0.3mmol) and acetonitrile (1mL) in that order, and the mixture was stirred at 90 ℃ under nitrogen for 6 hours. And monitoring the reaction by TLC, after the reaction is finished, performing rotary evaporation to remove the solvent, performing 100-200-mesh silica gel column chromatography on the crude product, performing gradient elution by using a mixed solvent of petroleum ether and ethyl acetate (the volume ratio is 20:1-8:1) as an eluent, collecting the eluent, performing rotary evaporation to remove the solvent to obtain 29mg of a target product 7, and calculating the yield to obtain 78%.
The reaction formula for example 7 is:
the target product 7 is characterized, and the result is as follows: a yellow solid;1H NMR(400MHz, CDCl3):δ8.28(d,J＝8.5Hz,2H),8.05(d,J＝8.5Hz,2H),7.62–7.49(m,4H), 7.35–7.29(m,2H),7.28–7.23(m,1H),7.01(d,J＝8.3Hz,1H),6.89–6.81(m,1H), 6.18(s,1H),4.43(d,J＝17.9Hz,1H),3.31(d,J＝17.9Hz,1H)；13C NMR(101MHz, CDCl3) Delta 200.75,196.98,160.84,151.20,141.40,138.57,138.31,129.78,129.48,128.47, 126.26,125.82,124.57,119.87,118.84,112.50,69.62 and 46.23, and the nuclear magnetic resonance hydrogen spectrum of the target product 7 is shown in figure 8. According to the characterization data, the prepared target product 7 is 2- (2- (4-nitrophenyl) -2-oxyethyl) -2-phenylindol-3-one.
Example 8:
to a 10mL test tube were added 2- (ethynylphenyl) nitrobenzene (0.1mmol), 4-bromoacetophenone (0.3mmol), triphenylphosphine (0.3mmol), potassium carbonate (0.3mmol), and acetonitrile (1mL) in that order, and the mixture was stirred at 90 ℃ under nitrogen for 6 hours. And monitoring the reaction by TLC, after the reaction is finished, performing rotary evaporation to remove the solvent, performing 100-200-mesh silica gel column chromatography on the crude product, performing gradient elution by using a mixed solvent of petroleum ether and ethyl acetate (the volume ratio is 20:1-8:1) as an eluent, collecting the eluent, performing rotary evaporation to remove the solvent to obtain 37mg of a target product 8, and calculating the yield to obtain 91%.
The reaction formula for example 8 is:
the target product 8 is characterized, and the result is as follows: a yellow solid;1H NMR(400MHz, CDCl3):δ7.75(d,J＝8.6Hz,2H),7.62–7.52(m,5H),7.52–7.46(m,1H), 7.32–7.25(m,2H),7.24–7.19(m,1H),6.96(d,J＝8.3Hz,1H),6.85–6.77(m,1 H),6.27(s,1H),4.37(d,J＝17.8Hz,1H),3.15(d,J＝17.9Hz,1H)；13C NMR(101 MHz,CDCl3) Delta 201.12,197.43,160.87,138.53,138.48,135.88,132.70,130.22,129.69, 129.39,128.30,126.27,125.90,119.62,118.78,112.46,69.79 and 45.40, the nuclear magnetic resonance hydrogen spectrum of the target product 8 is shown in figure 9. According to characterization data, the target product 8 is 2- (2- (4-bromophenyl) -2-oxyethyl) -2-phenylindol-3-one.
Example 9:
to a 10mL test tube were added 2- (ethynylphenyl) nitrobenzene (0.1mmol), acetophenone (0.3mmol), triphenylphosphine (0.3mmol), potassium carbonate (0.3mmol), and acetonitrile (1mL) in that order, and the mixture was stirred at 90 ℃ for 6 hours under nitrogen. And monitoring the reaction by TLC, after the reaction is finished, performing rotary evaporation to remove the solvent, performing 100-200-mesh silica gel column chromatography on the crude product, performing gradient elution by using a mixed solvent of petroleum ether and ethyl acetate (the volume ratio is 20:1-8:1) as an eluent, collecting the eluent, performing rotary evaporation to remove the solvent to obtain a target product 9 of 32mg, and calculating the yield to obtain 85%.
The reaction formula for example 9 is:
the target product 9 is characterized, and the result is as follows: a yellow solid;1H NMR(400MHz, DMSO-d6):δ8.77(s,1H),8.13(d,J＝8.0Hz,1H),7.98(d,J＝8.1Hz,3H),7.90(d, J＝8.3Hz,1H),7.70–7.56(m,4H),7.51–7.45(m,1H),7.42(d,J＝7.8Hz,1H), 7.38–7.30(m,2H),7.30–7.22(m,1H),7.03(d,J＝8.2Hz,1H),6.77–6.69(m,1 H),4.39(d,J＝18.0Hz,1H),3.86(d,J＝17.9Hz,1H)；13C NMR(101MHz, DMSO-d6) Delta 201.16,196.72,161.67,139.81,137.49,135.59,134.11,132.69,131.01, 130.17,129.26,128.90,128.76,128.12,127.74,127.44,126.04,124.84,123.77,118.78, 117.91,112.41,69.38 and 46.19, according to the characterization data, the prepared target product 9 is 2-, (B)2- (naphthalen-2-yl) -2-oxoethyl) -2-phenylindol-3-one.
Example 10
Example 10 is essentially the same as example 1, except that the inorganic base is different, as shown in table 1 below.
TABLE 1
| Inorganic base | Addition amount (mmol) | Yield (%) |
| |
0 | 0 |
| Potassium carbonate | 0.1 | 82 |
| Potassium carbonate | 0.3 | 86 |
| Potassium carbonate | 0.6 | 86 |
| Sodium hydroxide | 0.6 | ＜5 |
| Potassium tert-butoxide | 0.6 | ＜5 |
| Cesium carbonate | 0.6 | 79 |
As can be seen from table 1, the target product cannot be obtained without adding the inorganic base, because the inorganic base acts to pull out the α hydrogen of the ketone compound, so that the ketone compound can undergo a nucleophilic addition reaction, thereby obtaining the target product. While under the same reaction conditions, the yield was reduced to 82% when the amount of potassium carbonate was reduced to 0.1 mmol. The amount of potassium carbonate was increased to 0.6mmol, and the reaction yield was not improved. By changing different inorganic bases, such as sodium hydroxide, potassium tert-butoxide, the yield decreased significantly and only trace amounts of product were observed by monitoring the reaction by TLC. When the base was replaced with cesium carbonate, the reaction yield decreased to 79%.
Example 11
Example 11 is essentially the same as example 1, except that the solvents are different, as shown in table 2 below.
TABLE 2
| Solvent(s) | Yield (%) |
| Acetonitrile (ACN) | 86 |
| 1, 4-dioxane | 46 |
| N, N-dimethylformamide | 58 |
| Dimethyl sulfoxide | 61 |
| Toluene | 18 |
As can be seen from table 2, when the solvents were changed to 1, 4-dioxane, N-dimethylformamide, dimethylsulfoxide, and toluene, respectively, there were significant decreases in the reaction yields, 46%, 58%, 61%, and 18%, respectively.
Example 12
Example 12 is substantially the same as example 1 except that the reaction temperature and reaction time are different, as shown in Table 3 below.
TABLE 3
| Reaction temperature (. degree.C.) | Reaction time (h) | Yield (%) |
| 20 | 6 | ＜5 |
| 60 | 6 | 38 |
| 90 | 3 | 72 |
| 90 | 6 | 86 |
| 90 | 8 | 86 |
As can be seen from Table 3, only trace amounts of product could be detected by TLC when the reaction temperature was lowered to 20 ℃ and the reaction yield was reduced to 38% when the reaction temperature was lowered to 60 ℃. After the reaction time is shortened to 3h, the reaction yield is reduced to 72; prolonging the reaction time to 8h had no effect on the reaction yield.
Example 13
Example 13 is substantially the same as example 1 except that the amount of the organic phosphine or ketone compound added is different, as shown in Table 4 below.
TABLE 4
The organic phosphorus compound reacts with the 2- (ethynyl) nitrobenzene compound to obtain a reaction intermediate imine ketone, and the reaction intermediate can perform nucleophilic addition with a ketone compound to obtain a target product. As can be seen from Table 3, the reaction yield decreased to 68% when the amount of triphenylphosphine used was reduced to 0.2mmol under the same reaction conditions. Under the same reaction conditions, when the amount of the ketone compound is reduced to 0.12mmol and 0.2mmol respectively, the reaction yield is reduced to 76% and 78% respectively.
The invention provides a simple and efficient synthesis method of a beta-carbonyl indoline-3-ketone compound containing C2 bit, which comprises the steps of reacting an organic phosphorus compound with a 2- (ethynyl) nitrobenzene compound to obtain a reaction intermediate imine ketone, removing alpha hydrogen of the ketone compound by using an inorganic base to enable the reaction intermediate imine ketone to generate a nucleophilic addition reaction, and performing nucleophilic addition on the reaction intermediate and the ketone compound to obtain a target product containing the beta-carbonyl indoline-3-ketone containing C2 bit.
In the preparation of the target product, a series of beta-carbonyl indoline-3-ketone compounds containing C2 site can be efficiently synthesized by regulating a series of conditions such as the type of the selected inorganic base, the addition amount of the inorganic base, the solvent for reaction, the reaction temperature and the like. Among these, for different inorganic bases, such as: potassium carbonate, sodium hydroxide, potassium tert-butoxide, cesium carbonate and the like, wherein the potassium carbonate has the optimal effect and the highest yield; for different solvents, such as: acetonitrile, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, toluene and the like, wherein the acetonitrile effect is optimal, and the yield is highest; the target product can be obtained at different temperatures within the range of 20-90 ℃, the temperature is optimal at 90 ℃, and the yield is highest; the corresponding product can be obtained after 3-8 hours of reaction, the reaction time is optimal in 6 hours, and the yield is highest.
The raw material 2- (ethynyl) nitrobenzene used in the invention is simple and easy to obtain, the reaction does not need a metal catalyst, the reaction condition is mild, the operation is simple, the substrate range is wide, and the yield is high. The beta-carbonyl indoline-3-ketone compound containing C2 site can be used as an organic synthesis intermediate, and has wide application prospect in the fields of medicines, materials, solar cells and the like.
It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.
Claims (10)
1. A method for synthesizing beta-carbonyl indoline-3-ketone containing C2 site is characterized in that: comprises the steps of (a) preparing a substrate,
reacting a compound shown in a formula I, a compound shown in a formula II and a compound shown in a formula III in an organic solvent under the action of inorganic base to obtain a compound shown in a formula IV;
wherein R is1、R2、R3、R4Are each independently a group;
R1one selected from hydrogen, alkyl, alkoxy, halogen, carbonyl, ester group, carboxyl, nitro and cyano;
R2one selected from hydrogen, alkyl, carbonyl, ester group, carboxyl, phenyl, halogen substituted phenyl, alkyl substituted phenyl, naphthyl, thienyl, furyl, indolyl and trimethylsilyl;
R3one selected from hydrogen, alkyl, phenyl, halogen substituted phenyl and alkyl substituted phenyl;
R4one selected from hydrogen, alkyl, halogen substituted phenyl, alkyl substituted phenyl, naphthalene ring, indole ring, furan ring, thiophene ring, pyridine ring and alpha-alkyl carbonyl;
R5、R6、R7are each independently of the other R5、R6、R7Is selected from one of alkyl, phenyl, alkyl substituted phenyl, halogen substituted phenyl and cycloalkyl.
2. The method of claim 1, wherein the synthesis of the C2 β -carbonylindolin-3-one comprises: the molar weight ratio of the compound shown in the formula I to the compound shown in the formula II is 1: 1-3.
3. The process for the synthesis of β -carbonylindolin-3-one containing C2 according to claim 1 or 2, wherein: the molar ratio of the compound shown in the formula I to the compound shown in the formula III is 1: 1.5-5.
4. The method of claim 3, wherein the synthesis of the C2 β -carbonylindolin-3-one comprises: the molar ratio of the compound of formula I to the compound of formula III is 1: 3.
5. The method of synthesizing a C2-containing β -carbonylindolin-3-one of any one of claims 1, 2,4, wherein: the inorganic base is one or more of sodium hydroxide, potassium carbonate, sodium hydride, cesium carbonate, potassium phosphate and potassium tert-butoxide.
6. The method of claim 5, wherein the synthesis of the C2 β -carbonylindolin-3-one comprises: the molar ratio of the inorganic base to the compound shown in the formula I is 1-5: 1.
7. The method of claim 6, wherein the synthesis of the C2 β -carbonylindolin-3-one comprises: the molar ratio of the inorganic base to the compound of formula I is 3: 1.
8. The method of synthesizing a β -carbonylindolin-3-one containing C2 according to any one of claims 1, 2,4, 6, 7, wherein: the organic solvent is one or more of dimethyl sulfoxide, acetonitrile, toluene, N, N-dimethylformamide and 1, 4-dioxane.
9. The method of claim 8, wherein the synthesis of the C2 β -carbonylindolin-3-one comprises: the reaction is carried out in an organic solvent, the reaction temperature is 20-90 ℃, and the reaction time is 3-8 h.
10. A compound obtained by the method for synthesizing a C2-position β -carbonylindolin-3-one according to any one of claims 1 to 9, wherein: the structural formula of the compound is:
wherein R is1、R2、R3、R4Are each independently a group;
R1one selected from hydrogen, alkyl, alkoxy, halogen, carbonyl, ester group, carboxyl, nitro and cyano;
R2one selected from hydrogen, alkyl, carbonyl, ester group, carboxyl, phenyl, halogen substituted phenyl, alkyl substituted phenyl, naphthyl, thienyl, furyl, indolyl and trimethylsilyl;
R3one selected from hydrogen, alkyl, phenyl, halogen substituted phenyl and alkyl substituted phenyl;
R4one selected from hydrogen, alkyl, halogen substituted phenyl, alkyl substituted phenyl, naphthalene ring, indole ring, furan ring, thiophene ring, pyridine ring and alpha-alkyl carbonyl.
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