CN115160211B - Green synthesis method of isoindolinone compound - Google Patents

Abstract

The invention discloses a green synthesis method of isoindolinone compounds, which includes the following steps: adding N-methoxybenzamide compound, phenoxyacetonitrile, rhodium catalyst and sodium carbonate to the organic solvent trifluoroethanol , heating the oil bath to 80-110°C under air conditions for 12 hours to react. After the reaction is complete, post-processing is performed to obtain the isoindolinone compounds. This method uses phenoxyacetonitrile, which is simple, easy to prepare and stable, as a one-carbon synthon (C1). In the absence of oxidants, ligands and Lewis acid additives, the nucleophilicity of the cyano group is achieved through rhodium-catalyzed inert carbon-hydrogen bonds. The addition and subsequent series cyclization reaction realize the one-step preparation of isoindolinone compounds. The transformation operation is simple, the reaction activity is high, the atom economy is good, the substrate is widely used, and the functional group compatibility is good, providing an efficient synthetic route for the preparation of isoindolinone compounds.

Description

A green synthesis method of isoindolinone compounds

Technical field

The invention belongs to the field of organic synthesis, and specifically relates to a green synthesis method of isoindolinone.

Background technique

Isoindolinone skeletons are core components of many drug molecules, natural products, bioactive molecules and functional molecules, and are widely used in the fields of medicine, functional materials and optoelectronic materials. Traditional synthesis methods of isoindolinone compounds often require multi-step synthesis under harsh reaction conditions. In order to comply with the synthesis concepts of green synthetic chemistry and atom economy, it is of great research value to seek new methods for the synthesis of isoindolinone compounds that are simple and efficient.

In recent years, transition metal-catalyzed functionalization of inert carbon-hydrogen bonds has provided an efficient synthetic route for the construction of nitrogen-containing heterocyclic compounds. Among them, rhodium-catalyzed benzamide-directed carbon-hydrogen bond activation and the conversion of functional groups of one-carbon synthons into isoindolinone skeletons provide new ideas. Up to now, various coupling reagents have been developed, such as allenols, ketene imines, diazo compounds, propargyl alcohol and other substrates. However, in the above-mentioned transformations, the one-carbon synthon used has the challenge of being difficult to synthesize and unstable; in addition, in some of the above-mentioned transformations, an equivalent amount of oxidant is often required to achieve the catalytic cycle of the system. Therefore, it is of certain research value to develop new simple, easy-to-prepare, and stable one-carbon synthons to achieve efficient preparation of isoindolinones.

Nitriles are a type of organic functional synthon that can be converted into other types of organic skeletons. It is particularly worth mentioning that transition metal-catalyzed functional group conversion of nitriles paves the way for the preparation of various ketones, nitriles, and heterocyclic compounds. Therefore, the present invention combines the transition metal-catalyzed functional group conversion of inert carbon-hydrogen bonds with the conversion of nitrile substrates, and realizes for the first time the direct nucleophilicity of cyano groups via inert carbon-hydrogen bonds using nitrile substrates as one-carbon synthons. The addition and subsequent series cyclization reaction realize the preparation of isoindolinone products in one step. The present invention uses N-methoxybenzamide and phenoxyacetonitrile as substrates, dimer of pentamethylcyclopentadiene rhodium dichloride as catalyst, sodium carbonate as base, in trifluoroethanol reaction solvent, Isoindolinone compounds can be successfully synthesized by reacting for 12 hours in an air reaction atmosphere of 80-110°C. This conversion has a wide range of substrates and does not require the use of additional oxidants, ligands and Lewis acids, providing a new green and environmentally friendly synthesis method for the synthesis of isoindolinone compounds substituted with different functional groups.

Contents of the invention

The invention provides a green, simple and easy-to-operate synthesis method for preparing isoindolinone compounds from N-methoxybenzamide and phenoxyacetonitrile compounds through a series cyclization reaction. The substrate application range of the synthesis method is Broad range, good functional group compatibility, good chemical selectivity, and high reactivity.

A simple, green, and efficient synthesis method of isoindolinone compounds, including the following steps: adding N-methoxybenzamide compound, phenoxyacetonitrile compound, rhodium catalyst, and sodium carbonate into an organic solvent, and air The reaction is carried out by heating to 80-110°C under the conditions for 12 hours. After the reaction is complete, post-processing (extraction and column chromatography separation) is performed to obtain the corresponding isoindolinone compounds;

The structure of the N-methoxybenzamide compound is shown in formula (II):

The structure of the phenoxyacetonitrile compound is shown in formula (III):

The structure of the isoindolinone compound is shown in formula (I):

In formulas (I) to (III), R ¹ is selected from H, alkyl, alkoxy, phenyl, halogen, dimethylamino, or naphthyl; R ² is selected from H, alkyl, alkoxy, phenyl group, halogen, nitro, trifluoromethyl, cyano, acetyl, or naphthyl.

In the present invention, phenoxyacetonitrile, which is simple, easy to prepare and stable, is directly used as a one-carbon synthon, and in the absence of oxidants, ligands, and Lewis acids, rhodium catalyzes the activation of inert carbon-hydrogen bonds and the conversion of C-H bonds to cyano groups. Nucleophilic addition and subsequent series cyclization reactions successfully realize the one-step preparation of isoindolinone compounds.

Preferably, the organic solvent is trifluoroethanol.

Preferably, the reaction temperature is 80-110°C and the reaction time is 12 hours.

Compared with the prior art, the beneficial effects of the present invention are reflected in:

(1) For the first time, the present invention utilizes a simple, easy-to-prepare, and stable phenoxyacetonitrile substrate as a one-carbon synthon to achieve the preparation of isoindolinone compounds.

(2) The reaction conditions of the present invention are simple and mild, and the preparation of isoindolinone products can be achieved with excellent yields without the action of oxidants, ligands, Lewis acids and other additives.

(3) The synthesis method of the present invention is simple to operate, has high reactivity, and has a wide substrate adaptability. The generated target product can be subsequently converted into a high-value organic compound skeleton.

Description of drawings

Figure 1 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 1;

Figure 2 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 2;

Figure 3 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 3;

Figure 4 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 4;

Figure 5 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 5;

Figure 6 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 6;

Figure 7 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 7;

Figure 8 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 8;

Figure 9 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 9;

Figure 10 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 10;

Figure 11 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 11;

Figure 12 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 12;

Figure 13 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 13;

Figure 14 is the hydrogen spectrum and carbon spectrum of the compound obtained in Example 14;

Among them, the hydrogen spectrum was tested on a 500MHz nuclear magnetic instrument. Carbon spectra were tested on a 125MHz nuclear magnetic instrument. The test conditions are all at room temperature using tetramethylsilane as the internal standard and the sample dissolved in deuterated chloroform.

Detailed ways

The present invention will be further described below with reference to specific examples. The following specific examples are all optimal implementation modes of the present invention.

Examples 1 to 18

According to the raw material ratio in Table 1, add N-methoxybenzamide compound (II, 0.2mmol), phenoxyacetonitrile substrate (III, 0.4mmol), rhodium catalyst (0.010mmol), and carbonic acid into a 25mL sealed tube. Sodium (0.2 mmol) and organic solvent trifluoroethanol (1 mL) were mixed and stirred evenly, and reacted in an oil bath (80-110°C) for 12 hours in an air atmosphere. After the reaction is completed according to the reaction conditions in Table 2, cool, extract and collect the organic phase and dry it with sodium sulfate. Mix the sample with silica gel and purify it through column chromatography to obtain the corresponding isoindolinone compound (I). The reaction process is as shown in the following formula :

Table 1 Raw material ratios of Examples 1 to 18

Table 2 Reaction conditions and reaction results of Examples 1 to 18

In Table 1 and Table 2, T is the reaction temperature and t is the reaction time.

Structural confirmation data of some compounds prepared in Examples 1 to 18:

4-(2,6-dimethoxyphenyl)-2,5-diphenyloxazole(I-1)

Yellow oil(50.6mg,89%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.86(d,J＝7.0Hz,1H) ,7.63-7.56(m,2H),7.54-7.51(t,J＝7.0Hz,1H),7.26-7.23(m,2H),6.95(t,J＝7.0Hz,1H),6.84(d,J ＝8.0Hz,2H),4.28(d,J＝9.5Hz,1H),4.24(d,J＝9.0Hz,1H),4.07(s,3H),2.25(br,2H). ¹³ C NMR (125MHz , CDCl ₃ )δ164.8,158.1,143.5,132.9,129.8,129.7,129.5,123.6,122.5,121.6,114.8,77.0,70.8,65.5.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₆ H ₁₇ N ₂ O ₃ 285.1234; Found 285.1228.

3-amino-2-methoxy-5-methyl-3-(phenoxymethyl)isoindolin-1-one(I-2)

Yellow oil(48.3mg,81%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.64(d,J＝7.5Hz,1H) ,7.32(s,1H),7.22(d,J＝8.0Hz,1H),7.19-7.14(m,2H),6.87-6.84(m,1H),6.78(d,J＝8.0Hz,2H), 4.18-4.14(m,2H),3.96(s,3H),2.35(s,3H),2.15(br,2H). ¹³ C NMR(125MHz, CDCl ₃ )δ165.2,158.1,143.7,143.6,130.6,129.5 ,127.0,123.5,123.0,121.5,114.8,76.9,70.9,65.4,22.0.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₇ H ₁₉ N ₂ O ₃ 299.1390; Found299.1393 .

3-amino-2-methoxy-3-(phenoxymethyl)-5-phenylisoindolin-1-one(I-3)

Yellow oil(54.7mg,76%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.89(d,J＝8.0Hz,1H) ,7.81(s,1H),7.70(d,J＝8.0Hz,1H),7.58(d,J＝7.0Hz,2H),7.44(t,J＝7.0Hz,2H),7.38(t,J＝ 7.0Hz,1H),7.22(t,J＝8.0Hz,2H),6.92(t,J＝7.5Hz,1H),6.83(d,J＝8.0Hz,2H),4.32(d,J＝9.0Hz ,1H),4.27(d,J＝9.0Hz,1H),4.07(s,3H),2.27(br,2H). ¹³ C NMR (125MHz, CDCl ₃ )δ164.8,158.1,146.1,144.2,140.0,129.5 ,129.0,128.8,128.5,128.3,127.4,124.0,121.6,121.2,114.9,77.2,71.0,65.5.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd forC ₂₂ H ₂₁ N ₂ O ₃ 361.1547; Found 361.1542.

3-amino-2,5-dimethoxy-3-(phenoxymethyl)isoindolin-1-one(I-4)

Yellow oil(42.1mg,67%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.68(d,J＝8.5Hz,1H) ,7.16(t,J＝7.0Hz,2H),7.02(s,1H),6.93(d,J＝8.5Hz,1H),6.87(t,J＝6.5Hz,1H),6.76(d,J＝ 7.5Hz,2H),4.18(d,J＝9.0Hz,1H),4.13(d,J＝9.0Hz,1H),3.96(s,3H),3.78(s,3H),2.38(br,2H) . ¹³ C NMR (125MHz, CDCl ₃ ) δ165.4,163.7,158.1,145.9,129.5,125.3,121.8,121.6,116.1,114.8,107.7,76.8,71.1,65.5,55.7.HRMS (ESI-TOF) m/z: [M+H] ⁺ Calcd for C ₁₇ H ₁₉ N ₂ O ₄ 315.1339; Found 315.1340.

3-amino-5-(dimethylamino)-2-methoxy-3-(phenoxymethyl)isoindolin-1-one(I-5)

Yellow oil(52.3mg,80%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.68(d,J＝8.5Hz,1H) ,7.25(t,J＝8.0Hz,2H),6.94(t,J＝7.5Hz,1H),6.87(d,J＝8.0Hz,2H),6.80(s,1H),6.75-6.73(m, 1H),4.24(d,J＝9.5Hz,1H),4.21(d,J＝9.5Hz,1H),4.02(s,3H),3.05(s,6H),2.19(br,2H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 166.9, 158.3, 153.8, 145.8, 129.5, 125.0, 121.4, 116.0, 114.8, 112.9, 104.6, 76.7, 71.7, 65.6, 40.4. HRMS (ESI-TOF) m/z: [M+ H] ⁺ Calcd forC ₁₈ H ₂₂ N ₃ O ₃ 328.1656; Found 328.1661.

3-amino-5-fluoro-2-methoxy-3-(phenoxymethyl)isoindolin-1-one(I-6)

Yellow oil(33.2mg,55%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.85-7.83(m,1H),7.31( d,J＝6.0Hz,1H),7.24(t,J＝8.0Hz,2H),7.20(t,J＝9.0Hz,1H),6.95(t,J＝7.5Hz,1H),6.83(d, J＝8.0Hz, 2H), 4.28 (d, J＝9.0Hz, 1H), 4.20 (d, J＝9.0Hz, 1H), 4.06 (s, 3H), 2.23 (br, 2H). ¹³ C NMR ( 125MHz, CDCl ₃ )δ165.7(CF,J _CF =251.3Hz),164.0,157.9,129.5,125.9(CF,J _CF =8.8Hz),125.7(CF,J _CF =5.1Hz),121.8,117.4( CF,J _CF =23.0Hz),114.8,110.5,110.3,76.8,70.6,65.6.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₆ H ₁₆ FN ₂ O ₃ 303.1139; Found 303.1142.

3-amino-5-iodo-2-methoxy-3-(phenoxymethyl)isoindolin-1-one(I-7)

Yellow oil (50.0mg, 61%), Column chromatography on silica gel (Eluent: petroleum ether/dichloromethane, 2/1). ¹ H NMR (500MHz, CDCl ₃ ) δ7.84 (d, J＝7.5Hz, 1H) ,7.59(s,2H),7.52(s,1H),7.31(d,J＝8.5Hz,2H),6.70(d,J＝8.5Hz,2H),4.24(d,J＝9.0Hz,1H) ,4.21(d,J=9.0Hz,1H),4.05(s,3H),2.23(br,2H). ¹³ C NMR (125MHz, CDCl ₃ )δ164.8,157.2,143.2,132.8,132.3,129.9,129.8, 123.6,122.4,116.7,113.9,76.9,71.1,65.5.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₆ H ₁₆ IN ₂ O ₃ 411.0200; Found 411.0199.

3-amino-2-methoxy-3-(phenoxymethyl)-2,3-dihydro-1H-benzo[f]isoindol-1-one(I-8)

Yellow oil(42.8mg,64%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ8.38(s,1H),8.04(s, 1H),8.01(d,J＝7.5Hz,1H),7.92(d,J＝7.5Hz,1H),7.62-7.56(m,2H),7.24-7.21(m,2H),6.93(t,J ＝7.5Hz,1H),6.84(d,J＝8.0Hz,2H),4.36(d,J＝9.0Hz,1H),4.33(d,J＝9.0Hz,1H),4.11(s,3H), 2.35(br,2H). ¹³ C NMR (125MHz, CDCl ₃ ) δ164.1,158.0,138.6,135.5,133.7,129.6,129.5,128.5,128.0,127.2,127.1,124.2,121.9,121.6,114.8,71 .0,65.5. HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₂₀ H ₁₉ N ₂ O ₃ 335.1390; Found 335.1389.

3-amino-2-methoxy-3-((p-tolyloxy)methyl)isoindolin-1-one(I-9)

Yellow oil(42.9mg,72%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.76(d,J＝7.5Hz,1H) ,7.52-7.48(m,2H),7.43-7.40(m,1H),6.94(d,J＝8.5Hz,2H),6.64(d,J＝8.5Hz,2H),4.16(d,J＝9.0 Hz, 1H), 4.12 (d, J = 9.0Hz, 1H), 3.97 (s, 3H), 2.16 (s, 3H), 2.03 (br, 2H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 164.7, 156.0 ,143.5,132.7,130.9,129.9,129.7,129.7,123.6,122.5,114.7,71.1,65.4,20.4.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₇ H ₁₉ N ₂ O ₃ 299.1390; Found299.1394.

3-amino-2-methoxy-3-((4-methoxyphenoxy)methyl)isoindolin-1-one(I-10)

Yellow oil(53.4mg,85%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.84(d,J＝7.5Hz,1H) ,7.60-7.56(m,2H),7.52-7.49(m,1H),6.78-6.74(m,4H),4.23(d,J＝9.5Hz,1H),4.18(d,J＝9.5Hz,1H ), 4.06 (s, 3H), 3.73 (s, 3H), 2.19 (br, 2H). ¹³ C NMR (125MHz, CDCl ₃ ) δ164.7,154.5,152.3,143.5,132.7,129.7,129.7,123.6,122.4, 116.0,114.7,77.1,71.8,65.4,55.7.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₇ H ₁₉ N ₂ O ₄ 315.1339; Found 315.1331.

3-(([1,1'-biphenyl]-4-yloxy)methyl)-3-amino-2-methoxyisoindolin-1-one(I-11)

Yellow solid(59.8mg,83%).mp:152-153℃.Column chromatography onsilica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.86(d,J ＝7.5Hz,1H),7.62-7.58(m,2H),7.53-7.49(m,3H),7.46(d,J＝8.5Hz,2H),7.39(t,J＝8.0Hz,2H),7.28 (t,J＝7.5Hz,1H),6.89(d,J＝8.5Hz,2H),4.31(d,J＝9.0Hz,1H),4.27(d,J＝9.0Hz,1H),4.08(s ,3H),2.25(br,2H). ¹³ C NMR (125MHz, CDCl ₃ )δ164.8,157.6,143.4,140.6,134.8,132.7,129.8,129.8,128.7,128.2,126.8,126.7,123.7,122.5,115 .1, 115.0,71.0,65.5.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₂₂ H ₂₁ N ₂ O ₃ 361.1547; Found 361.1540.

3-amino-3-((4-fluorophenoxy)methyl)-2-methoxyisoindolin-1-one(I-12)

Yellow oil(50.1mg,83%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.76(d,J＝7.5Hz,1H) ,7.51(d,J＝3.5Hz,2H),7.47-7.40(m,1H),7.06(t,J＝8.0Hz,1H),6.83(d,J＝8.0Hz,1H),6.74(s, 1H),6.63-6.61(m,1H),4.17(d,J＝9.5Hz,1H),4.15(d,J＝9.0Hz,1H),3.97(s,3H),2.15(br,2H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 164.8, 158.7, 143.2, 133.8 (CF, J _CF = 274.6Hz), 130.2, 129.8 (CF, J _CF = 11.1Hz), 123.6 (CF, J _CF = 1.8Hz), 122.4,121.8,115.4,113.2,76.9,71.0,65.5.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₆ H ₁₆ FN ₂ O ₃ 303.1139; Found 303.1145.

amino-2-methoxy-3-((4-nitrophenoxy)methyl)isoindolin-1-one(I-13)

Yellow oil(36.8mg,56%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,1/2). ¹ H NMR(500MHz, CDCl ₃ )δ8.14(d,J＝9.5Hz,2H) ,7.86(d,J＝7.5Hz,1H),7.62(d,J＝6.0Hz,2H),7.56-7.53(m,1H),6.91-6.86(m,2H),4.37(s,2H), 4.07(s,3H),2.22(br,2H). ¹³ C NMR (125MHz, CDCl ₃ ) δ165.1,162.7,142.8,142.2,133.0,130.1,129.8,125.8,123.8,122.3,114.8,70.9,65.7.HRMS (ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₆ H ₁₆ N ₃ O ₅ 330.1084; Found 330.1093.

3-((4-acetylphenoxy)methyl)-3-amino-2-methoxyisoindolin-1-one(I-14)

colourless oil(26.1mg,40%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,1/2). ¹ H NMR(500MHz, CDCl ₃ )δ7.86(t,J＝8.0Hz,3H) ,7.60(s,2H),7.52(s,1H),6.85(d,J＝8.5Hz,2H),4.34(d,J＝9.0Hz,1H),4.31(d,J＝9.0Hz,1H) ,4.06(s,3H),2.51(s,3H),2.24(br,2H). ¹³ C NMR (125MHz, CDCl ₃ )δ196.4,164.8,161.8,143.1,132.8,131.2,130.2,129.8,123.7,122.4 ,114.5,76.9,70.8,65.5,29.6,26.2.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₈ H ₁₉ IN ₂ O ₄ 327.1339; Found 327.1338.

3-amino-2-methoxy-3-((4-(trifluoromethyl)phenoxy)methyl)isoindolin-1-one(I-15)

Yellow oil(52.8mg,75%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,1/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.86(d,J＝7.5Hz,1H) ,7.61(d,J＝4.0Hz,2H),7.55-7.51(m,1H),7.50(t,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),4.32(d, J＝9.0Hz, 1H), 4.30 (d, J＝9.0Hz, 1H), 4.06 (s, 3H), 2.26 (br, 2H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 164.9, 160.4, 143.0, 132.8 ,130.0,129.7,126.9(CF,J _CF =3.8Hz),124.2(CF,J _CF =270.0Hz),123.5(CF,J _CF =32.8Hz),123.1,122.4,114.8,76.8,70.8,65.6. HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₇ H ₁₆ F ₃ N ₂ O ₃ 353.1108; Found 353.1100.

4-((1-amino-2-methoxy-3-oxoisoindolin-1-yl)methoxy)benzonitrile(I-16)

Yellow oil (40.2mg, 65%).Column chromatography on silica gel (Eluent:petroleum ether/dichloromethane,1/1). ¹ H NMR (500MHz, CDCl ₃ ) δ7.85 (d, J＝7.5Hz, 1H) ,7.64-7.58(m,2H),7.55-7.52(m,3H),6.87(d,J＝8.5Hz,2H),4.34(d,J＝9.0Hz,1H),4.31(d,J＝9.0 Hz, 1H), 4.06 (s, 3H), 2.25 (br, 2H). ¹³ C NMR (125MHz, CDCl ₃ ) δ165.0,161.1,142.9,134.0,132.9,130.0,129.8,123.7,122.3,118.7,115.5, 105.1,77.0,70.7,65.6.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd for C ₁₇ H ₁₆ N ₃ O ₃ 310.1186; Found 310.1187.

3-amino-2-methoxy-3-((naphthalen-1-yloxy)methyl)isoindolin-1-one(I-17)

Yellow oil(40.1mg,60%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.90(d,J＝7.5Hz,2H) ,7.73(d,J＝8.0Hz,1H),7.62(d,J＝7.5Hz,1H),7.57(t,J＝7.5Hz,1H),7.51(t,J＝7.5Hz,1H),7.45 -7.36(m,3H),7.30(t,J＝8.0Hz,1H),6.75(d,J＝7.5Hz,1H),4.45(d,J＝9.0Hz,1H),4.42(d,J＝ 9.0Hz, 1H), 4.05 (s, 3H), 2.27 (br, 2H). ¹³ C NMR (125MHz, CDCl ₃ ) δ164.7,153.7,143.4,134.5,132.8,130.0,129.8,127.4,126.5,125.6,125.5 ,125.4,123.6,122.3,121.6,121.2,105.0,77.2,70.5,65.5.HRMS(ESI-TOF)m/z:[M+H] ⁺ Calcd forC ₂₀ H ₁₉ N ₂ O ₃ 335.1390; Found 335.1391.

3-amino-2-methoxy-3-((naphthalen-2-yloxy)methyl)isoindolin-1-one(I-18)

Yellow oil(47.4mg,71%).Column chromatography on silica gel(Eluent:petroleum ether/dichloromethane,2/1). ¹ H NMR(500MHz, CDCl ₃ )δ7.86(d,J＝7.5Hz,1H) ,7.72(d,J＝8.0Hz,1H),7.67(d,J＝8.5Hz,2H),7.63(d,J＝7.5Hz,1H),7.58(t,J＝7.5Hz,1H),7.50 (t,J＝7.5Hz,1H),7.41(t,J＝7.5Hz,1H),7.31(t,J＝7.5Hz,1H),7.08(s,1H),7.04-7.03(m,1H) ,4.39(d,J＝9.0Hz,1H),4.35(d,J＝9.0Hz,1H),4.06(s,3H),2.25(br,2H). ¹³ C NMR (125MHz, CDCl ₃ )δ164. 8,156.0,143.4,134.3,132.8,129.8,129.8,129.6,129.3,127.6,126.8,126.5,124.0,123.6,122.5,118.5,107.4,77.0,70.9,65.5.HRMS (ESI-TOF )m/z:[M +H] ⁺ Calcd for C ₂₀ H ₁₉ N ₂ O ₃ 335.1390; Found 335.1395.

Claims (3)

1. the green synthesis method of the isoindolinone compound is characterized by comprising the following steps of: adding N-methoxy substituted benzamide compound, phenoxyacetonitrile compound, pentamethyl cyclopentadiene rhodium dichloride dimer and sodium carbonate into trifluoroethanol, controlling the temperature to be 80-110 ℃ under the air condition, reacting for 6-18 h, and after the reaction is completed, performing post-treatment to obtain the isoindolinone compound;

the structure of the N-methoxy substituted benzamide compound is shown as a formula (II):

（II）；

the structure of the phenoxyacetonitrile compound is shown as a formula (III):

（III）

the structure of the isoindolinone compound is shown as a formula (I):

（I）

in the formulas (I) - (III), R is ¹ Selected from H, methyl, methoxy, phenyl, F, I or dimethylamino; r is R ² Selected from H, methyl, methoxyF, nitro, trifluoromethyl, cyano or acetyl.

2. The green synthesis method of the isoindolinone compound according to claim 1, wherein the reaction temperature is 95-105 ℃, and the reaction time is 12 hours under the air reaction condition.

3. The green synthesis method of the isoindolinone compound according to claim 1, wherein the isoindolinone is one of the following compounds:

。