A method for synthesizing isoindolinone compounds

Abstract

The present invention relates to the technical field of synthesis of nitrogen-containing heterocyclic compounds, and specifically to a method for synthesizing isoindolinone compounds, comprising the following steps: in a solvent, a compound represented by formula I and a compound represented by formula II undergo a C-H bond activation cyclization reaction in the presence of a catalyst and a base to obtain an isoindolinone compound represented by formula III; wherein R1 and R2 are independently selected from any one of H, C1-C4 alkyl, halogen, aryl, and substituted aryl. The method can synthesize an isoindolinone five-membered ring skeleton under simple reaction conditions using an electron-rich alkenyl cyclic carbonate as a starting material, thereby solving the problem that the existing synthesis method is not applicable to electron-rich olefins. #imgabs0#

Description

Technical Field

[0001] The invention relates to the technical field of synthesis of nitrogen-containing heterocyclic compounds, and in particular to a method for synthesizing isoindolinone compounds. Background Art

[0002] Isoindolone compounds are a common class of nitrogen-containing heterocyclic compounds with significant pharmacological activity, such as 3-hydroxyisoindolone, 3-methyleneisoindolone, 5,6-dihydroisoindolo[1,2-a]isoquinoline-8-(12bH)-one compounds, etc., which are widely found in natural products and marketed drugs.

[0003] In recent years, many methods for synthesizing isoindolinone compounds have been reported in the literature. For example, the literature (Zhang Yaming, Zhang Yanxia, ​​et al. One-pot synthesis of new isoindolinone derivatives [J]. Synthetic Chemistry, 2020, 28 (3), 188-193.) records that 12 new compounds with isoindolinone as the parent nucleus were synthesized by a one-pot method using divalent copper as a catalyst, o-bromobenzoic acid, phenylacetylene and primary amine as raw materials. This method has easy-to-obtain raw materials, simple operation, and good substrate applicability. It can synthesize heterocyclic modified isoindolinone compounds, which lays a foundation for enriching the structural diversity of isoindolinone compounds and the activity screening of cardiovascular system drugs. The chemical formula is as follows:

[0004]

[0005] The patent application with publication number CN112245425A discloses the use of an isoindolinone compound in the preparation of an anti-tumor drug, and the structural formula is as follows:

[0006]

[0007] Traditional synthetic methods such as cyclization of ortho-olefins and alkynylbenzamides ([1] Khan, MW; Reza, AFGMTetrahedron 2005, 61, 11204-11210. [2] Kundu, NG; Khan, MW Tetrahedron Lett. 1997, 38, 6937-6940. [3] Yao, T.; Larock, RCJ Org. Chem. 2005, 70, 1432-1437), o-aminomethylbenzoic acid lactamization ([4] Shi, L.; Hu, L.; Wang, J.; Cao, X.; Gu, H. Org. Lett. 2012, 14, 1876-1879), difunctionalization of olefinic amides, etc., although they can synthesize isoindolinone compounds, these methods require complex substrate preparation processes, and the substrate range is limited, and the atom economy is poor; therefore, the transition metal-catalyzed CH activation cyclization reaction of benzamides has attracted widespread attention.

[0008] Under the action of transition metal catalysts, electron-poor and electron-neutral olefins, propargyl alcohol derivatives, allenes, 1,3-enynes, etc. can all be used as coupling reagents to participate in cyclization reactions. For example, the following prior art: [5] Ishizuka, T.; Xu, Y.; Komiyama, MAJ Am. Chem. Soc. 2013, 135, 14-17. [6] Boobalan, R.; Santhoshkumar, R.; Cheng, C.-H., Adv. Synth. Catal. 2019, 361, 1140-1145. [7] Hu, W.; Yan, L.; Zuo, Y.; Kong, S.; Pu, Y.; Tang, Q.; Wang, X.; He, X.; Shang, Y. Adv. Synth. Catal. 2022, 364, 2589-2595. [8] Wu, X.; Wang, B.; Zhou, S.; Zhou, Y.; Liu, H. ACS Catalysis 2017, 7, 2494-2499. [9] Sun, J.; Bai, D.; Wang, P.; Wang, K.; Zheng, G.; Li, X. Org. Lett. 2019, 21, 1789–1793. All of them are used to synthesize isoindolinone compounds with high atom economy and wide substrate applicability. However, although these methods have shown their superiority, they are not suitable for transition metal-catalyzed CH activation cyclization reactions of benzamides using electron-rich olefins as coupling reagents. Therefore, the present invention provides a method for synthesizing isoindolinone compounds using electron-rich olefins as coupling reagents. Summary of the invention

[0009] In order to solve the problem that the existing synthesis method is not suitable for the transition metal-catalyzed CH activation cyclization reaction of benzamide using electron-rich olefins as coupling reagents, the purpose of the present invention is to provide a synthesis method of isoindolinone compounds suitable for using electron-rich olefins as coupling reagents. The present invention aims to synthesize isoindolinone compounds by using electron-rich alkenyl cyclic carbonates through the CH bond activation cyclization reaction of N-methoxybenzamide compounds.

[0010] To achieve the above objectives, the technical solution of the present invention is as follows.

[0011] The present invention provides a method for synthesizing isoindolinone compounds, comprising the following steps:

[0012] In a solvent, the compound represented by formula I and the compound represented by formula II undergo a CH bond activation cyclization reaction in the presence of a catalyst and a base to obtain an isoindolinone compound represented by formula III;

[0013] The reaction formula is as follows:

[0014]

[0015] In the formula, R1 and R2 are independently selected from any one of H, C1-C4 alkyl, halogen, aryl, and substituted aryl.

[0016] In some embodiments of the present invention, R1 is selected from any one of H, C1-C4 alkyl, and halogen;

[0017] R2 is selected from any one of C1-C4 alkyl, aryl, and substituted aryl;

[0018] The substituent in the substituted aryl group is selected from any one of methyl, methoxy and halogen.

[0019] In some embodiments of the present invention, R1 is selected from any one of H, methyl, ethyl, and Br;

[0020] R2 is selected from any one of methyl, ethyl, phenyl, substituted phenyl and naphthyl.

[0021] In some embodiments of the present invention, the compound represented by formula I is selected from any one of the following compounds:

[0022]

[0023] In some embodiments of the present invention, the compound represented by formula II is selected from any one of the following compounds:

[0024]

[0025] In some embodiments of the present invention, the isoindolinone compound represented by formula III is selected from any one of the following compounds:

[0026]

[0027]

[0028] In some embodiments of the present invention, the molar ratio of the compound represented by formula I to the compound represented by formula II is 1:1.8 to 2.3;

[0029] The molar ratio of the compound represented by formula II, the catalyst and the base is 40:1:36-40.

[0030] In some embodiments of the present invention, the catalyst is any one of [Ru(p-cymene)Cl2]2, [Cp*RhCl2]2, Cp*Co(CO)I2, Pd(OAc)2, Cu(OAc)2;

[0031] The base is any one of KOAc, LiOAc, KH2PO4, and Na2CO3.

[0032] In some embodiments of the present invention, the solvent is any one of DCE, DCM, TFE, THF, and HFIP.

[0033] In some embodiments of the present invention, the reaction temperature of the CH bond activation cyclization reaction is 90-100° C., and the reaction time is 12-24 h.

[0034] In some embodiments of the present invention, the concentration of the compound represented by Formula II in the reaction solution is 0.18-0.23 mol / L.

[0035] Beneficial effects of the present invention:

[0036] 1. The present invention mainly uses N-methoxybenzamide and electron-rich alkenyl cyclic carbonate, which are stable and easily available in the air, as reaction raw materials, adds a catalyst and a base in the presence of a solvent, and efficiently synthesizes isoindolinone products under appropriate reaction conditions. The method of the present invention is simple and efficient, and solves the problem that the existing synthesis method is not suitable for transition metal-catalyzed benzamide CH activation cyclization reaction using electron-rich olefins as coupling reagents.

[0037] 2. The method of the present invention is simple to operate and has a wide range of substrates, and provides a further atom-economical method for the construction of the five-membered ring skeleton of isoindolinone compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The product prepared in Example 1 1 H NMR spectrum.

[0039] Figure 2 The product prepared in Example 1 13 C NMR spectrum.

[0040] Figure 3 The product prepared in Example 2 1 H NMR spectrum.

[0041] Figure 4 The product prepared in Example 2 13 C NMR spectrum.

[0042] Figure 5 The product prepared in Example 3 1 H NMR spectrum.

[0043] Figure 6 The product prepared in Example 3 13 C NMR spectrum.

[0044] Figure 7 The product prepared in Example 4 1 H NMR spectrum.

[0045] Figure 8 The product prepared in Example 4 13 C NMR spectrum.

[0046] Fig. 9 The product prepared in Example 5 1 H NMR spectrum.

[0047] Fig.10 The product prepared in Example 5 13 C NMR spectrum.

[0048] Fig.11 The product prepared in Example 6 1 H NMR spectrum.

[0049] Fig.12 The product prepared in Example 6 13 C NMR spectrum.

[0050] Fig.13 The product prepared in Example 7 1 H NMR spectrum.

[0051] Fig.14 The product prepared in Example 7 13 C NMR spectrum.

[0052] Fig.15 The product prepared in Example 8 1H NMR spectrum.

[0053] Fig.16 The product prepared in Example 8 13 C NMR spectrum.

[0054] Fig.17 The product prepared in Example 9 1 H NMR spectrum.

[0055] Fig.18 The product prepared in Example 9 13 C NMR spectrum. DETAILED DESCRIPTION

[0056] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0057] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without making any creative work shall fall within the scope of protection of the present invention.

[0058] The present invention provides a method for synthesizing isoindolinone compounds, comprising the following steps:

[0059] In a solvent, the compound represented by formula I and the compound represented by formula II undergo a CH activation cyclization reaction in the presence of a catalyst and a base, and the isoindolinone compound represented by formula III is obtained after separation and purification;

[0060] The reaction formula is as follows:

[0061]

[0062] In the formula, R1 and R2 are independently selected from any one of H, C1-C4 alkyl, halogen, aryl, and substituted aryl.

[0063] The invention uses N-methoxybenzamide (compound shown in formula I) and electron-rich alkenyl cyclic carbonate (compound shown in formula II) as reaction raw materials, adds a catalyst and a base in the presence of a solvent, and efficiently synthesizes isoindolinone compounds under mild reaction conditions. The method is simple to operate and has a wide substrate range. This conversion provides a further atom-economic method for constructing a five-membered ring skeleton of isoindolinone compounds.

[0064] In some embodiments of the present invention, R1 is selected from one of H, C1-C4 alkyl, and halogen;

[0065] R2 is selected from one of C1-C4 alkyl, aryl, and substituted aryl;

[0066] The substituent in the substituted aryl group is selected from any one of methyl, methoxy and halogen.

[0067] In some preferred embodiments of the present invention, R1 is selected from any one of H, methyl, ethyl, and Br; R2 is selected from any one of methyl, ethyl, phenyl, substituted phenyl, and naphthyl.

[0068] In some preferred embodiments of the present invention, the compound represented by formula I is selected from any one of the following compounds:

[0069]

[0070] In some embodiments of the present invention, the compound represented by formula II is selected from any one of the following compounds:

[0071]

[0072] In some embodiments of the present invention, the isoindolinone compound represented by formula III is selected from any one of the following compounds:

[0073]

[0074]

[0075] In some embodiments of the present invention, the catalyst is any one of [Ru(p-cymene)Cl2]2, [Cp*RhCl2]2, Cp*Co(CO)I2, Pd(OAc)2, Cu(OAc)2; the base is any one of KOAc, LiOAc, KH2PO4, Na2CO3; the solvent is any one of DCE, DCM, TFE, THF, HFIP. Wherein, DCE: dichloroethane; DCM: dichloromethane; TFE: trifluoroethanol; THF: tetrahydrofuran; HFIP: hexafluoroisopropanol.

[0076] In some embodiments of the present invention, the molar ratio of the compound represented by Formula I to the compound represented by Formula II is 1:1.8 to 2.3, preferably 1:2. For example, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, etc.

[0077] In some embodiments of the present invention, the molar ratio of the compound represented by formula II, the catalyst and the base is 40:1:36-40, preferably 40:1:40, for example, 40:1:36, 40:1:37, 40:1:38, 40:1:39, 40:1:40, etc.

[0078] In some embodiments of the present invention, the reaction temperature of the CH bond activation cyclization reaction is 90-100° C., preferably 100° C. For example, 90° C., 91° C., 92° C., 93° C., 94° C., 95° C., 96° C., 97° C., 98° C., 99° C., 100° C., etc.

[0079] In some embodiments of the present invention, the reaction time of the CH bond activation cyclization reaction is 12 to 24 hours, for example, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, etc.

[0080] In some embodiments of the present invention, the concentration of the compound represented by Formula II in the reaction solution is 0.18 to 0.23 mol / L, for example, 0.18 mol / L, 0.19 mol / L, 0.20 mol / L, 0.21 mol / L, 0.22 mol / L, 0.23 mol / L, etc.

[0081] Taking the catalyst [Cp*RhCl2]2 as an example, the reaction principle of the present invention is explained:

[0082] The invention uses electron-rich alkenyl cyclic carbonate as a coupling reagent and easily available benzamide as a reaction raw material under the action of a metal catalyst. First, an active metal catalyst ([Cp*RhCl2]2) coordinates with benzamide to activate the ortho-CH bond to form a five-membered ring metal compound, and then undergoes olefin insertion and β-H elimination with the alkenyl cyclic carbonate to obtain an alkenylated intermediate compound; RhH in the intermediate compound adds to the double bond to obtain an intermediate containing a five-membered ring isoindolinone, and then reduction elimination, oxidation addition, β-O elimination and the like occur to finally obtain a target product, and simultaneously generates carbon dioxide and water as well as active catalyst species to complete the catalytic cycle.

[0083] The synthesis method of an isoindolinone compound provided by the present invention is further described in detail below with reference to the examples.

[0084] Unless otherwise specified, the methods described in the following examples are all conventional methods; the reagents and materials described are all commercially available unless otherwise specified.

[0085] Example 1

[0086] A method for synthesizing isoindolinone compounds comprises the following steps:

[0087]

[0088] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4,4-dimethyl-5-methylene-1,3-dioxane-2-one (II-1) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of [Cp*RhCl2]2 as a catalyst and 0.2 mmol of Na2CO3 as a base. The mixture was stirred at 100°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid with a yield of 72%.

[0089] NMR characterization of products Figure 1 and Figure 2 As shown:

[0090] 1 H NMR(400MHz,Chloroform-d)δ7.83(d,J=7.5Hz,1H),7.55(td,J=7.5,1.2Hz,1H),7.45(t,J=7.5Hz,1H),7.33–7.19( m,1H),5.41(d,J=9.4Hz,1H),5.06(dq,J=9.6,1.6Hz,1H),3.95(s,3H),1.98(d,J=1.3Hz,3H),1.86(d,J=1.3Hz,3H).

[0091] 13 C NMR (101MHz, Chloroform-d) δ164.3,144.4,141.3,132.0,128.7,126.9,126.3,125.2,119.2,64.6,58.9,26.0,18.5.

[0092] Example 2

[0093] A method for synthesizing isoindolinone compounds comprises the following steps:

[0094]

[0095] 0.1 mmol of 3-methyl-N-methoxybenzamide (I-2) and 0.2 mmol of 4,4-dimethyl-5-methylene-1,3-dioxane-2-one (II-1) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol [Ru(p-cymene)Cl2]2 as catalyst and 0.2 mmol KOAc as base. The mixture was stirred at 120°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white oil with a yield of 65%.

[0096] NMR characterization of products Figure 3 and Figure 4 As shown:

[0097] 1 H NMR(400MHz,Chloroform-d)δ7.70–7.57(m,1H),7.42–7.30(m,1H),7.13(d,J=7.7Hz,1H),5.35(d,J=9.4Hz,1 H),5.03(dp,J=9.4,1.4Hz,1H),3.93(s,3H),2.50–2.33(m,3H),1.95(d,J=1.4Hz,3H),1.84(d,J=1.5Hz,3H).

[0098] 13 C NMR (101MHz, Chloroform-d) δ165.3,140.1,139.9,138.5,133.2,129.7,123.9,122.6,120.3,64.4,59.1,26.0,21.4,18.4.

[0099] Example 3

[0100] A method for synthesizing isoindolinone compounds comprises the following steps:

[0101]

[0102] 0.1 mmol of 3-methoxy-N-methoxybenzamide (I-4) and 0.2 mmol of 4,4-dimethyl-5-methylene-1,3-dioxane-2-one (II-1) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of Cp*Co(CO)I2 as a catalyst and 0.2 mmol of KH2PO4 as a base. The mixture was stirred at 80°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid with a yield of 44%.

[0103] like Figure 5 and Figure 6 As shown, the product NMR characterization:

[0104] 1 H NMR(400MHz,Chloroform-d)δ7.67(d,J=8.1Hz,1H),7.58(dd,J=8.1,1.6Hz,1H),7.40(t,1H),5.37(d ,J=9.4Hz,1H),5.03(dt,J=9.5,1.5Hz,1H),3.92(s,3H),1.95(d,J=1.4Hz,3H),1.86(d,J=1.3Hz,3H).

[0105] 13 C NMR (101MHz, Chloroform-d) δ164.3,144.4,141.3,132.0,128.7,126.9,126.3,125.2,119.2,64.6,58.9,26.0,18.5.

[0106] Example 4

[0107] A method for synthesizing isoindolinone compounds comprises the following steps:

[0108]

[0109] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4-methyl-5-methylene-4-phenyl-1,3-dioxane-2-one (II-2) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of Pd(OAc)2 as a catalyst and 0.2 mmol of Na2CO3 as a base. The mixture was stirred at 100°C for 24 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid with a yield of 63%.

[0110] NMR characterization of products Figure 7 and Figure 8 As shown:

[0111] 1 H NMR(400MHz,Chloroform-d)δ7.87(d,J=7.5Hz,1H),7.57(td,J=7.5,1.2Hz,1H),7.48(t,J=7.5Hz,1H),7.46–7.41 (m,2H),7.39–7.27(m,4H),5.66(dd,J=9.5,1.4Hz,1H),5.60(d,J=9.5Hz,1H),3.99(s,3H),2.41(d,J=1.2Hz,3H).

[0112] 13 C NMR (101MHz, CDCl3) δ165.5,142.1,141.1,141.0,132.6,131.6,129.8,128.9,127.6,124.0,123.4,123.0,122.0,64.8,59.6,29.8,16.6.

[0113] Example 5

[0114] A method for synthesizing isoindolinone compounds comprises the following steps:

[0115]

[0116] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4-methyl-5-methylene-4-(p-toluene)-1,3-dioxolane-2-one (II-3) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of Cu(OAc)2 as a catalyst and 0.2 mmol of LiOAc as a base. The mixture was stirred at 120°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid with a yield of 45%.

[0117] NMR characterization of products Fig. 9 and Fig.10 As shown:

[0118] 1 H NMR (400MHz, DMSO-d6) δ7.75(dd,J=7.5,1.1Hz,1H),7.67(td,J=7.5,1.3Hz,1H),7.56(t,J=7.5Hz,1H),7.48–7.36(m,3H), 7.17(d,J=8.0Hz,2H),5.95(d,J=9.3Hz,1H),5.61(dd,J=9.4,1.5Hz,1H),3.88(s,3H),2.37(d,J=1.3Hz,3H),2.30(s,3H).

[0119] 13 C NMR(101MHz,DMSO)δ163.9,143.1,141.7,139.2,137.6,133.1,129.8,129.5, 129.2,126.1,123.9,123.5,122.3,64.2,60.3,59.0,21.30,21.2,16.7,14.6.

[0120] Example 6

[0121] A method for synthesizing isoindolinone compounds comprises the following steps:

[0122]

[0123] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4-(3-methoxyphenyl)-4-methyl-5-methylene-1,3-dioxane-2-one (II-4) were dissolved in a reactor containing 1 mL of DCM, 0.05 mmol of [Cp*RhCl2]2 was used as a catalyst, 0.2 mmol of KH2PO4 was used as a base, and the mixture was stirred at 120°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white oil.

[0124] NMR characterization of products Fig.11 and Fig.12 As shown:

[0125] 1 H NMR(400MHz,Chloroform-d)δ7.97–7.75(m,1H),7.57(td,J=7.5,1.2Hz,1H),7. 48(t,J=7.5Hz,1H),7.35–7.30(m,1H),7.27(s,1H),7.25(s,0H),7.06–7.01(m,1 H), 6.96 (t, J = 2.1Hz, 1H), 6.85 (ddd, J = 8.3, 2.6, 0.9Hz, 1H), 5.66 (dq, J = 9.5, 1. 3Hz, 1H), 5.60 (d, J = 9.5Hz, 1H), 3.98 (s, 3H), 3.82 (s, 3H), 2.39 (d, J = 1.3Hz, 3H).

[0126] 13 C NMR(101MHz,Chloroform-d)δ165.5,159.7,142.3,142.1,132.5,129.8,129 .5,128.8,124.0,123.0,123.0,118.5,113.0,112.1,64.8,59.7,55.4,16.7.

[0127] Example 7

[0128] A method for synthesizing isoindolinone compounds comprises the following steps:

[0129]

[0130] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4-methyl-5-methylene-4-(naphthalen-1-yl)-1,3-dioxolane-2-one (II-5) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of [Cp*RhCl2]2 as catalyst and 0.2 mmol of Na2CO3 as base. The mixture was stirred at 100°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid with a yield of 38%.

[0131] NMR characterization of products Fig.13 and Fig.14 As shown:

[0132] 1H NMR(400MHz,Chloroform-d)δ7.92–7.86(m,2H),7.86–7.78(m,3H),7.62–7.55(m,2H),7.54–7.43(m,3H),7.37 (dd,J=7.5,1.1Hz,1H),5.81(dd,J=9.4,1.5Hz,1H),5.68(d,J=9.5Hz,1H),4.01(s,3H),2.52(d,J=1.3Hz,3H).

[0133] 13 C NMR(101MHz,Chloroform-d)δ165.5,142.3,142.0,139.3,133.3,133.0,132.6,129.8,128. 8,128.3,128.1,127.6,126.5,126.3,124.9,124.0,124.0,123.3,123.1,64.8,59.8,16.7.

[0134] Example 8

[0135] A method for synthesizing isoindolinone compounds comprises the following steps:

[0136]

[0137] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4-methyl-5-methylene-4-(m-tolyl)-1,3-dioxolane-2-one (II-6) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of Pd(OAc)2 as a catalyst and 0.2 mmol of KH2PO4 as a base. The mixture was stirred at 100°C for 24 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid with a yield of 43%.

[0138] like Fig.15 and Fig.16 As shown, the product NMR characterization:

[0139] 1H NMR(400MHz,Chloroform-d)δ7.91–7.83(m,1H),7.57(td,J=7.6,1.3Hz,1H),7.48(t,J=7.5Hz,1H),7.36–7.29(m,1H),7.24(d,J=3.9H z,3H),7.12(dd,J=6.5,3.5Hz,1H),5.64(dq,J=9.5,1.3Hz,1H),5.60(d,J=9.5Hz,1H),3.99(s,3H),2.39(d,J=1.2Hz,3H),2.36(s,3H).

[0140] 13 C NMR (101 MHz, CDCl3) δ 165.5, 142.4, 142.3, 142.2, 138.1, 132.5, 129.8, 128.8, 128.7, 128.4, 126.7, 123.9, 123.1, 122.6, 64.8, 59.8, 21.5, 16.7. Example 9

[0141] A method for synthesizing isoindolinone compounds comprises the following steps:

[0142]

[0143] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4-(4-chlorophenyl)-4-methyl-5-methylene-1,3-dioxolane-2-one (II-7) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of Cp*Co(CO)I2 as a catalyst and 0.2 mmol of KOAc as a base. The mixture was stirred at 120°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid with a yield of 51%.

[0144] NMR characterization of products Fig.17 and Fig.18 As shown:

[0145] 1 H NMR(400MHz,Chloroform-d)δ7.86(d,J=7.5Hz,1H),7.57(td,J=7.5,1.2Hz,1H),7.52–7.43(m,3H),7.30(d d,J=8.3,6.6Hz,3H),5.64(dd,J=9.4,1.5Hz,1H),5.58(d,J=9.4Hz,1H),3.97(s,3H),2.38(d,J=1.3Hz,3H). 13C NMR (101MHz, CDCl3) δ165.5,142.1,141.1,141.0,132.6,131.6,129.8,128.9,127.6,124.0,123.4,123.0,122.0,64.8,59.6,29.8,16.6.

[0146] Example 10

[0147] A method for synthesizing isoindolinone compounds is basically the same as the method in Example 1, except that the feed ratio of the reaction raw materials is different. The specific method comprises the following steps:

[0148] 0.1 mmol of N-methoxybenzamide (I-1) and 0.18 mmol of 4,4-dimethyl-5-methylene-1,3-dioxane-2-one (II-1) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of Cu(OAc)2 as a catalyst and 0.2 mmol of Na2CO3 as a base. The mixture was stirred at 80°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid.

[0149] Embodiment 11

[0150] A method for synthesizing isoindolinone compounds is basically the same as the method in Example 1, except that the feed ratio of the reaction raw materials is different. The specific method comprises the following steps:

[0151] 0.1 mmol of N-methoxybenzamide (I-1) and 0.23 mmol of 4,4-dimethyl-5-methylene-1,3-dioxane-2-one (II-1) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol [Ru(p-cymene)Cl2]2 as catalyst and 0.2 mmol Na2CO3 as base. The mixture was stirred at 100°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid.

[0152] Example 12

[0153] A method for synthesizing isoindolinone compounds is basically the same as the method in Example 1, except that the feed ratio of the reaction raw materials is different. The specific method comprises the following steps:

[0154] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4,4-dimethyl-5-methylene-1,3-dioxane-2-one (II-1) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of [Cp*RhCl2]2 as a catalyst and 0.18 mmol of LiOAc as a base. The mixture was stirred at 100°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid.

[0155] Example 13

[0156] A method for synthesizing isoindolinone compounds is basically the same as the method in Example 1, except that the reaction temperature is different. The specific method comprises the following steps:

[0157] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4,4-dimethyl-5-methylene-1,3-dioxane-2-one (II-1) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of Pd(OAc)2 as a catalyst and 0.2 mmol of KH2PO4 as a base. The mixture was stirred at 90°C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid.

[0158] Embodiment 14

[0159] A method for synthesizing isoindolinone compounds is basically the same as the method in Example 1, except that the reaction temperature is different. The specific method comprises the following steps:

[0160] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4,4-dimethyl-5-methylene-1,3-dioxane-2-one (II-1) were dissolved in a reactor containing 1 mL of DCM, with 0.05 mmol of Cu(OAc)2 as a catalyst and 0.2 mmol of Na2CO3 as a base. The mixture was stirred at 90°C for 24 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid.

[0161] Embodiment 15

[0162] A method for synthesizing isoindolinone compounds is substantially the same as the method of Example 1, except that the base and the solvent are different. The specific method comprises the following steps:

[0163] 0.1 mmol of N-methoxybenzamide (I-1) and 0.2 mmol of 4,4-dimethyl-5-methylene-1,3-dioxane-2-one (II-1) were dissolved in a reactor containing 1 mL of THF, with 0.05 mmol [Cp*RhCl2]2 as catalyst and 0.2 mmol LiOAc as base. The mixture was stirred at 100 °C for 12 h. The reaction was monitored by TLC and separated by column chromatography to obtain a white solid.

[0164] The yields under different conditions in the above examples are compared as follows.

[0165] 1. Different isoindolinone compounds were synthesized using different reaction raw materials, see Table 1.

[0166] Table 1 Raw materials and products of Examples 1 to 9 above

[0167]

[0168]

[0169] It can be seen from the results in Table 1 that when the substituent R1 of the compound shown in Formula I is selected from H and methyl, the product yield is 65-72%, which is relatively high. When the substituent R2 of the compound shown in Formula II is selected from methyl, phenyl, and chlorine substituted benzyl, the product yield is 51-72%, which is relatively high.

[0170] 2. The reaction conditions with different feed ratios under the same reaction raw materials are shown in Table 2.

[0171] Table 2 Reaction of different feed ratios

[0172]

[0173] From the results in Table 2, it can be seen that when the feed amount of compound II-1 is 0.18-0.23 mmol, the product yield reaches 56-72%, especially when the feed amount of compound II-1 is 0.2-0.23 mmol, the product yield reaches 67-72%, and the product yield is relatively high.

[0174] 3. The reaction conditions at different reaction temperatures are shown in Table 3.

[0175] Table 3 Reaction conditions at different reaction temperatures

[0176]

[0177] From the results in Table 3, it can be seen that when the reaction temperature is 90-100° C. and the reaction time is 12-24 h, the product yield can reach 66-72%, which is relatively high.

[0178] From the above analysis, it can be seen that the present invention uses electron-rich alkenyl cyclic carbonate as a coupling reagent and easily available benzamide as a reaction raw material under the action of a metal catalyst. First, the active metal catalyst coordinates with benzamide to activate the ortho-CH bond to form a five-membered ring metal compound, and then undergoes olefin insertion and β-H elimination with the alkenyl cyclic carbonate to obtain an alkenylated intermediate compound; the active metal-H in the intermediate compound adds to the double bond to obtain an intermediate containing a five-membered ring isoindolinone, and then reduction elimination, oxidation addition, β-O elimination and the like occur, and finally the target product is obtained, and carbon dioxide and water as well as active catalyst species are generated to complete the catalytic cycle.

[0179] When the substituent R1 of the compound represented by formula I is selected from H and methyl, and the substituent R2 of the compound represented by formula II is selected from methyl, phenyl, and chlorine-substituted benzyl, the feed amount of compound II-1 is 0.2 to 0.23 mmol, the reaction temperature is 90 to 100°C, and the reaction time is 12 to 24 h, the product yield is relatively high.

[0180] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing isoindolinone compounds, characterized in that: The following steps are involved: In a solvent, the compound represented by formula I and the compound represented by formula II undergo a CH bond activation cyclization reaction in the presence of a catalyst and a base to obtain an isoindolinone compound represented by formula III; The reaction formula is as follows: In the formula, R1 is selected from any one of H, C1-C4 alkyl, and halogen; R2 is selected from any one of C1-C4 alkyl, aryl, and substituted aryl; the substituent in the substituted aryl is selected from any one of methyl, methoxy, and halogen; The catalyst is [Cp*RhCl2]2; The base is any one of KOAc, LiOAc, KH2PO4, and Na2CO3; The solvent is any one of DCE, DCM, TFE, THF, and HFIP.

2. The method for synthesizing isoindolinone compounds according to claim 1, characterized in that: R1 is selected from any one of H, methyl, ethyl, and Br; R2 is selected from any one of methyl, ethyl, phenyl, substituted phenyl and naphthyl.

3. The method for synthesizing isoindolinone compounds according to claim 2, characterized in that: The compound represented by formula I is selected from any one of the following compounds:

4. The method for synthesizing isoindolinone compounds according to claim 2, characterized in that: The compound represented by formula II is selected from any one of the following compounds:

5. The method for synthesizing isoindolinone compounds according to claim 2, characterized in that: The isoindolinone compound represented by formula III is selected from any one of the following compounds:

6. The method for synthesizing isoindolinone compounds according to claim 1, characterized in that: The molar ratio of the compound represented by formula I to the compound represented by formula II is 1:1.8-2.3; The molar ratio of the compound represented by formula II, the catalyst and the base is 40:1:36-40.

7. The method for synthesizing isoindolinone compounds according to claim 1, characterized in that: The reaction temperature of the CH bond activation cyclization reaction is 90-100°C, and the reaction time is 12-24h.

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