CN115160211A - Green synthesis method of isoindolinone compounds - Google Patents
Green synthesis method of isoindolinone compounds Download PDFInfo
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- CN115160211A CN115160211A CN202210720638.7A CN202210720638A CN115160211A CN 115160211 A CN115160211 A CN 115160211A CN 202210720638 A CN202210720638 A CN 202210720638A CN 115160211 A CN115160211 A CN 115160211A
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- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical class C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- -1 N-methoxy benzamide compound Chemical class 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 7
- 239000010948 rhodium Substances 0.000 claims abstract description 7
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 239000007800 oxidant agent Substances 0.000 claims abstract description 6
- 230000001590 oxidative effect Effects 0.000 claims abstract description 6
- 239000002841 Lewis acid Substances 0.000 claims abstract description 5
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 5
- 239000003446 ligand Substances 0.000 claims abstract description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 5
- 239000000654 additive Substances 0.000 claims abstract description 4
- 230000000996 additive effect Effects 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 16
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical compound CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 claims description 2
- 239000000539 dimer Substances 0.000 claims description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 abstract description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 18
- 239000000758 substrate Substances 0.000 abstract description 9
- VLLSCJFPVSQXDM-UHFFFAOYSA-N 2-phenoxyacetonitrile Chemical compound N#CCOC1=CC=CC=C1 VLLSCJFPVSQXDM-UHFFFAOYSA-N 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 6
- 125000000524 functional group Chemical group 0.000 abstract description 5
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 3
- 238000005935 nucleophilic addition reaction Methods 0.000 abstract description 3
- 230000009466 transformation Effects 0.000 abstract description 3
- 238000013459 approach Methods 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 239000004215 Carbon black (E152) Substances 0.000 abstract 1
- 229930195733 hydrocarbon Natural products 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 238000001228 spectrum Methods 0.000 description 30
- 238000004440 column chromatography Methods 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 229910052739 hydrogen Inorganic materials 0.000 description 19
- 239000001257 hydrogen Substances 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 239000003480 eluent Substances 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- 150000002825 nitriles Chemical class 0.000 description 5
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- XTBAPWCYTNCZTO-UHFFFAOYSA-N isoindol-1-one Chemical compound C1=CC=C2C(=O)N=CC2=C1 XTBAPWCYTNCZTO-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- PBQZQTQFQFYBNJ-UHFFFAOYSA-N n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1 PBQZQTQFQFYBNJ-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008358 core component Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- NFDFQCUYFHCNBW-SCGPFSFSSA-N dienestrol Chemical compound C=1C=C(O)C=CC=1\C(=C/C)\C(=C\C)\C1=CC=C(O)C=C1 NFDFQCUYFHCNBW-SCGPFSFSSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000013384 organic framework Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/50—Iso-indoles; Hydrogenated iso-indoles with oxygen and nitrogen atoms in positions 1 and 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a green synthesis method of isoindolinone compounds, which comprises the following steps: adding N-methoxy benzamide compound, phenoxyacetonitrile, rhodium catalyst and sodium carbonate into organic solvent trifluoroethanol, heating in oil bath to 80-110 ℃ under the air condition to react for 12 hours, and after the reaction is completed, carrying out post-treatment to obtain the isoindolinone compound. The method uses phenoxy acetonitrile which is simple and easy to prepare and stable as a carbon synthon (C1), and prepares the isoindolinone compound by a one-step method through the nucleophilic addition of an inert hydrocarbon bond catalyzed by rhodium to a cyano group and the subsequent series cyclization reaction in the absence of an oxidant, a ligand and a Lewis acid additive. The transformation operation is simple, the reaction activity is high, the atom economy is good, the substrate application range is wide, the functional group compatibility is good, and an efficient synthetic approach is provided for the preparation of the isoindolinone compounds.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a green synthesis method of isoindolinone.
Background
The isoindolinone skeleton is a core component of a plurality of drug molecules, natural products, bioactive molecules and functional molecules, and has wide application in the fields of medicines, functional materials and photoelectric materials. The traditional synthesis method of the isoindolinone compounds is often realized through multi-step synthesis under more severe reaction conditions. In order to match the synthesis concepts of green synthetic chemistry and atom economy, a new simple and efficient method for synthesizing the isoindolinone compounds is sought, and important research values are provided.
In recent years, functionalization of transition metal catalytic inert carbon-hydrogen bonds provides an efficient synthetic approach for the construction of nitrogen-containing heterocyclic compounds. Wherein, rhodium catalyzes the activation of the benzamide-oriented carbon-hydrogen bond and the preparation of converting the functional group of the one-carbon synthon into the isoindolinone skeleton. Up to now, various classes of coupling reagents have been developed in succession such as: a substrate such as a dienol, a ketene imine, a diazo compound, propargyl alcohol, and the like. However, in these transformations, the one-carbon synthon used presents the challenge of being difficult to synthesize and unstable; furthermore, in some of the above conversions, an equivalent amount of oxidant is often required to achieve catalytic recycle of the system. Therefore, the development of a novel simple and easy-to-prepare stable one-carbon synthon for realizing the efficient preparation of the isoindolinone has certain research value.
Nitriles are a class of organic functional synthons that can be converted to other classes of organic frameworks. Particularly, the transition metal catalyzes the functional group of the nitrile to be converted into various ketones, nitriles and heterocyclic compounds, thereby paving the way. Therefore, the invention combines the functional group conversion of the inert carbon-hydrogen bond catalyzed by the transition metal with the conversion of the nitrile substrate, realizes the one-step preparation of the isoindolinone product by taking the nitrile substrate as a carbon synthon, and through the direct nucleophilic addition of the inert carbon-hydrogen bond to the cyano group and the subsequent tandem cyclization reaction for the first time. According to the method, N-methoxybenzamide and phenoxyacetonitrile are used as substrates, a dimer of pentamethylcyclopentadienyl rhodium dichloride is used as a catalyst, sodium carbonate is used as alkali, and the isoindolinone compounds can be smoothly synthesized by reacting in a trifluoroethanol reaction solvent for 12 hours in a reaction atmosphere of air at the temperature of 80-110 ℃. The transformation substrate has a wide range, does not need additional oxidant, ligand and Lewis acid, and provides a new green and environment-friendly synthesis method for synthesizing isoindolinone compounds substituted by different functional groups.
Disclosure of 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.
A simple, green and efficient synthesis method of isoindolinone compounds comprises the following steps: adding an N-methoxybenzamide compound, a phenoxyacetonitrile compound, a rhodium catalyst and sodium carbonate into an organic solvent, heating to 80-110 ℃ under the air condition for reaction for 12 hours, and performing post-treatment (extraction and column chromatography separation) after the reaction is completed to obtain a corresponding isoindolinone compound;
the structure of the N-methoxybenzamide compound is shown as a formula (II):
the structure of the phenoxyacetonitrile compound is shown as a formula (III):
the structure of the isoindolinone compound is shown as the formula (I):
in the formulae (I) to (III), R 1 Selected from H, alkyl, alkoxy, phenyl, halo, dimethylamino, or naphthyl; r is 2 Selected from H,Alkyl, alkoxy, phenyl, halo, nitro, trifluoromethyl, cyano, acetyl, or naphthyl.
In the invention, the isoindolinone compound is prepared by a one-step method smoothly by directly using the phenoxy acetonitrile which is simple, easy to prepare and stable as a one-carbon synthon through rhodium-catalyzed inert carbon-hydrogen bond activation, nucleophilic addition of a C-H bond to a cyano group and subsequent series cyclization reaction in the absence of an oxidant, a ligand and Lewis acid.
Preferably, the organic solvent is trifluoroethanol.
Preferably, the reaction temperature is 80 to 110 ℃ and the reaction time is 12 hours.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention realizes the preparation of the isoindolinone compound by using a simple, easily prepared and stable phenoxyacetonitrile substrate as a carbon synthon for the first time.
(2) The method has simple and mild reaction conditions, and can realize the preparation of isoindolinone products with excellent yield under the action of additives such as oxidant, ligand, lewis acid and the like.
(3) The synthetic method of the invention has simple operation, high reaction activity and wide substrate application range, and the generated target product can be converted into an organic compound framework with high value through subsequent conversion.
Drawings
FIG. 1 is a hydrogen spectrum and a carbon spectrum of the compound obtained in example 1;
FIG. 2 is a hydrogen spectrum and a carbon spectrum of the compound obtained in example 2;
FIG. 3 shows a hydrogen spectrum and a carbon spectrum of the compound obtained in example 3;
FIG. 4 shows a hydrogen spectrum and a carbon spectrum of the compound obtained in example 4;
FIG. 5 shows a hydrogen spectrum and a carbon spectrum of the compound obtained in example 5;
FIG. 6 shows a hydrogen spectrum and a carbon spectrum of the compound obtained in example 6;
FIG. 7 shows a hydrogen spectrum and a carbon spectrum of the compound obtained in example 7;
FIG. 8 is a hydrogen spectrum and a carbon spectrum of the compound obtained in example 8;
FIG. 9 shows a hydrogen spectrum and a carbon spectrum of the compound obtained in example 9;
FIG. 10 shows a hydrogen spectrum and a carbon spectrum of the compound obtained in example 10;
FIG. 11 is a hydrogen spectrum and a carbon spectrum of the compound obtained in example 11;
FIG. 12 shows a hydrogen spectrum and a carbon spectrum of the compound obtained in example 12;
FIG. 13 is a hydrogen spectrum and a carbon spectrum of the compound obtained in example 13;
FIG. 14 shows a hydrogen spectrum and a carbon spectrum of the compound obtained in example 14;
wherein the hydrogen spectra were tested on a 500MHz nuclear magnetic instrument. Carbon spectra were tested on a 125MHz nuclear magnetic instrument. The test conditions are that tetramethylsilane is used as an internal standard at room temperature, and a sample is dissolved by deuterated chloroform.
Detailed Description
The present invention will be further described with reference to specific examples, which are intended to be illustrative of the best modes for carrying out the invention.
Examples 1 to 18
According to the raw material ratio of table 1, adding N-methoxybenzamide compound (II, 0.2 mmol), phenoxyacetonitrile substrate (III, 0.4 mmol), rhodium catalyst (0.010 mmol), sodium carbonate (0.2 mmol) and organic solvent trifluoroethanol (1 mL) into a 25mL sealed tube, mixing and stirring uniformly, and reacting for 12h under an oil bath (80-110 ℃) in an air atmosphere. After the reaction is completed according to the reaction conditions shown in table 2, cooling, extracting, collecting the organic phase, drying with sodium sulfate, mixing with silica gel, and purifying by column chromatography to obtain the corresponding isoindolinone compound (I), wherein the reaction process is shown as the following formula:
TABLE 1 raw material compounding ratios of examples 1 to 18
Table 2 reaction conditions and reaction results of examples 1 to 18
In tables 1 and 2, T is the reaction temperature and T is the reaction time.
Examples 1 to 18 preparation Structure confirmation data of partial compounds:
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；Found 299.1393.
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 for C 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 )δ166.9,158.3,153.8,145.8,129.5,125.0,121.4,116.0,114.8,112.9,104.6,76.7,71.7,65.6,40.4.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 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(C-F,J C-F ＝251.3Hz),164.0,157.9,129.5,125.9(C-F,J C-F ＝8.8Hz),125.7(C-F,J C-F ＝5.1Hz),121.8,117.4(C-F,J C-F ＝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＝9.0Hz,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 )δ164.7,156.0,143.5,132.7,130.9,129.9,129.7,129.7,123.6,122.5,114.7,71.1,65.4,20.4.HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 17 H 19 N 2 O 3 299.1390；Found 299.1394.
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 on silica 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 )δ164.8,158.7,143.2,133.8(C-F,J C-F ＝274.6Hz),130.2,129.8(C-F,J C-F ＝11.1Hz),123.6(C-F,J C-F ＝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 )δ164.9,160.4,143.0,132.8,130.0,129.7,126.9(C-F,J C-F ＝3.8Hz),124.2(C-F,J C-F ＝270.0Hz),123.5(C-F,J C-F ＝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＝9.0Hz,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 for C 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 (8)
1. a green synthesis method of isoindolinone compounds is characterized by comprising the following steps: adding an N-methoxy substituted benzamide compound, a phenoxyacetonitrile compound, a rhodium catalyst and an additive into an organic solvent, controlling the temperature to be 80-110 ℃ under the air condition, reacting for 6-18 h, and after the reaction is completed, carrying out post-treatment to obtain the isoindolinone compound;
the structure of the N-methoxyl substituted benzamide compound is shown as the formula (II):
the structure of the phenoxyacetonitrile compound is shown as the formula (III):
the structure of the isoindolinone compound is shown as the formula (I):
in the formulae (I) to (III), R 1 Selected from H, alkyl, alkoxy, phenyl, halogen, dimethylamino or naphthyl;
R 2 selected from H, alkyl, alkoxy, phenyl, halogen, nitro, trifluoromethyl, cyano, acetyl or naphthyl.
2. A green synthesis method of isoindolinone compounds according to claim 1, wherein R is 1 Selected from H, methyl, methoxy, phenyl, F, I, dimethylamino or naphthyl; r is 2 Selected from H, methyl, methoxy, F, nitro, trifluoromethyl, cyano, acetyl or naphthyl.
3. The green synthesis method of isoindolinone compounds according to claim 1, wherein the organic solvent is trifluoroethanol.
4. A green synthesis method of isoindolinone compounds according to claim 1, wherein the rhodium catalyst is a dimer of pentamethylcyclopentadienylrhodium dichloride.
5. The green synthesis method of isoindolinone compounds according to claim 1, wherein the additive is sodium carbonate.
6. A green synthesis method of isoindolinone compounds according to claim 1, wherein the reaction condition does not require the introduction of metal oxidant, ligand or Lewis acid.
7. The green synthesis method of isoindolinone compounds according to claim 1, wherein the reaction temperature is 95-105 ℃, and the reaction time is 12 hours under the air reaction condition.
8. The green synthesis method of isoindolinone compounds according to claim 1, wherein the isoindolinone is one of the following compounds:
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