CN115160211B - Green synthesis method of isoindolinone compound - Google Patents
Green synthesis method of isoindolinone compound Download PDFInfo
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- CN115160211B CN115160211B CN202210720638.7A CN202210720638A CN115160211B CN 115160211 B CN115160211 B CN 115160211B CN 202210720638 A CN202210720638 A CN 202210720638A CN 115160211 B CN115160211 B CN 115160211B
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- -1 isoindolinone compound Chemical class 0.000 title claims abstract description 33
- 238000001308 synthesis method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 10
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 16
- 230000035484 reaction time Effects 0.000 claims description 3
- WUJLLKJTIKSMEJ-UHFFFAOYSA-L [Cl-].[Cl-].[Rh+2].CC1C(C)=C(C)C(C)=C1C Chemical class [Cl-].[Cl-].[Rh+2].CC1C(C)=C(C)C(C)=C1C WUJLLKJTIKSMEJ-UHFFFAOYSA-L 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 abstract description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 19
- 239000001257 hydrogen Substances 0.000 abstract description 19
- 239000000758 substrate Substances 0.000 abstract description 10
- 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
- 125000000524 functional group Chemical group 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 6
- 239000007800 oxidant agent Substances 0.000 abstract description 5
- 230000001590 oxidative effect Effects 0.000 abstract description 5
- 239000002841 Lewis acid Substances 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 150000007517 lewis acids Chemical class 0.000 abstract description 4
- 239000003446 ligand Substances 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 229910052703 rhodium Inorganic materials 0.000 abstract description 4
- 239000010948 rhodium Substances 0.000 abstract description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 abstract description 4
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- 238000005935 nucleophilic addition reaction Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000000654 additive Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 230000000996 additive effect Effects 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
- 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
- 239000012074 organic phase Substances 0.000 description 4
- 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
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 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
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 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
- PBQZQTQFQFYBNJ-UHFFFAOYSA-N n-methoxybenzamide Chemical compound CONC(=O)C1=CC=CC=C1 PBQZQTQFQFYBNJ-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 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
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 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
- 230000001351 cycling effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 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
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002894 organic compounds Chemical group 0.000 description 1
- 239000013384 organic framework Substances 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
- 239000000126 substance Substances 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
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a green synthesis method of an isoindolinone compound, which comprises the following steps: adding an N-methoxy benzamide compound, phenoxyacetonitrile, a rhodium catalyst and sodium carbonate into an organic solvent trifluoroethanol, heating an oil bath to 80-110 ℃ under the air condition, reacting for 12 hours, and after the reaction is completed, carrying out post-treatment to obtain the isoindolinone compound. The method utilizes simple and easy-to-prepare and stable phenoxyacetonitrile as a carbon synthon (C1), and realizes the one-step preparation of the isoindolinone compound through nucleophilic addition of rhodium catalyzed inert carbon hydrogen bond to cyano and subsequent serial cyclization reaction under the condition of no existence of oxidant, ligand and Lewis acid additive. The method has the advantages of simple conversion operation, high reaction activity, good atom economy, wide substrate application range and good functional group compatibility, and provides a high-efficiency synthesis way for preparing the isoindolinone compound.
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. Traditional synthetic methods of isoindolinone compounds often require multiple steps of synthesis under relatively severe reaction conditions. In order to meet the synthetic concept of green synthetic chemistry and atomic economy, a novel simple and efficient method for synthesizing the isoindolinone compound is sought, and the method has important research value.
In recent years, the transition metal catalyzed functional group of the inert carbon-hydrogen bond provides a high-efficiency synthetic approach for the construction of nitrogen-containing heterocyclic compounds. The rhodium-catalyzed benzamide-oriented hydrocarbon bond activation and the preparation of the isoindolinone skeleton by converting the functional group of the one-carbon synthon are provided with new ideas. To date, various types of coupling reagents have been developed successively as: substrates such as dienols, enoimines, diazo compounds, propargyl alcohols, and the like. However, in these conversions, the one-carbon synthons used present challenges that are difficult to synthesize and unstable; in addition, in some of the conversions described above, an equivalent amount of oxidant is often required to effect catalytic cycling of the system. Therefore, the development of novel simple and easy-to-prepare and stable one-carbon synthetic entities for realizing the efficient preparation of isoindolinone has a certain research value.
Nitriles are one class of organic functional synthons that can be converted into other classes of organic frameworks. In particular, the transition metal catalyzes the conversion of nitrile functional groups into various ketones, nitriles and the preparation of heterocyclic compounds opens the way. Therefore, the invention combines the conversion of the functional group of the transition metal catalytic inert carbon-hydrogen bond with the conversion of the nitrile substrate, takes the nitrile substrate as a carbon synthon for the first time, and realizes the one-step preparation of the isoindolinone product through the direct nucleophilic addition of the inert carbon-hydrogen bond to the cyano group and the subsequent serial cyclization reaction. According to the invention, N-methoxybenzamide and phenoxyacetonitrile are used as substrates, a dimer of pentamethyl cyclopentadiene rhodium dichloride is used as a catalyst, sodium carbonate is used as alkali, and an isoindolinone compound can be smoothly synthesized through a reaction in a trifluoroethanol reaction solvent under the reaction atmosphere of air at 80-110 ℃ for 12 hours. The conversion 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, and the synthesis method has the advantages of wide substrate application range, good functional group compatibility, good chemical selectivity and high reaction activity.
A simple, green and efficient synthesis method of isoindolinone compounds comprises the following steps: adding an N-methoxy benzamide 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 after the reaction is completed, carrying out post-treatment (extraction and column chromatography separation) to obtain a corresponding isoindolinone compound;
the structure of the N-methoxy benzamide 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 a formula (I):
in the formulae (I) to (III), R 1 Selected from H, alkyl, alkoxy, phenyl, halogen, dimethylamino, or naphthyl; r is R 2 Selected from H, alkyl, alkoxy, phenyl, halogen, nitro, trifluoromethyl, cyano, acetyl, or naphthyl.
According to the invention, the isoindolinone compound is prepared by directly utilizing simple and easy-to-prepare and stable phenoxyacetonitrile as a carbon synthon and smoothly realizing one-step method through rhodium-catalyzed inert carbon hydrogen bond activation, C-H bond nucleophilic addition to cyano and subsequent serial cyclization reaction under the condition of no existence of oxidant, ligand and Lewis acid.
Preferably, the organic solvent is trifluoroethanol.
Preferably, the reaction temperature is 80-110℃and the reaction time is 12 hours.
Compared with the prior art, the invention has the beneficial effects that:
(1) The preparation method of the isoindolinone compound is realized by taking a simple and easy-to-prepare stable phenoxyacetonitrile substrate as a carbon synthesizer for the first time.
(2) The method has simple and mild reaction conditions, and can realize the preparation of the isoindolinone products with excellent yield under the action of additives such as an oxidant, a ligand, lewis acid and the like.
(3) The synthesis method of the invention has simple operation, high reaction activity and wide substrate application range, and the generated target product can be converted into a high-value organic compound skeleton through subsequent conversion.
Drawings
FIG. 1 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 1;
FIG. 2 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 2;
FIG. 3 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 3;
FIG. 4 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 4;
FIG. 5 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 5;
FIG. 6 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 6;
FIG. 7 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 7;
FIG. 8 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 8;
FIG. 9 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 9;
FIG. 10 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 10;
FIG. 11 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 11;
FIG. 12 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 12;
FIG. 13 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 13;
FIG. 14 is a graph showing the hydrogen spectrum and the carbon spectrum of the compound obtained in example 14;
wherein the hydrogen spectrum was tested on a 500MHz nuclear magnetic instrument. The carbon spectrum was tested on a 125MHz nuclear magnetic instrument. The test conditions were all room temperature using tetramethylsilane as an internal standard and the samples were dissolved in deuterated chloroform.
Detailed Description
The invention is further described with reference to the following specific examples, which are all the best modes for carrying out the invention.
Examples 1 to 18
N-methoxy benzamide 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) are added into a 25mL sealed tube according to the raw material ratio of Table 1, and the mixture is uniformly mixed and stirred to react for 12h in an oil bath (80-110 ℃) under an air atmosphere. After the reaction is completed according to the reaction conditions of Table 2, cooling, extracting and collecting an organic phase, drying the organic phase by using sodium sulfate, mixing the organic phase with silica gel, and purifying the organic phase by column chromatography to obtain the corresponding isoindolinone compound (I), wherein the reaction process is shown as the following formula:
table 1 raw material ratios of examples 1 to 18
TABLE 2 reaction conditions and reaction results for examples 1-18
In tables 1 and 2, T is the reaction temperature and T is the reaction time.
Examples 1 to 18 were prepared to give structure confirmation data for part of the 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 (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:
。
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| US20040235826A1 (en) * | 2001-08-30 | 2004-11-25 | Peckham Jennifer P. | Tyrosine kinase ihnibitors |
| CN102084465A (en) * | 2008-02-01 | 2011-06-01 | 福吉米株式会社 | Polishing composition and polishing method using the same |
| CN102822165A (en) * | 2010-02-11 | 2012-12-12 | 细胞基因公司 | Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same |
| CN104586842A (en) * | 2014-04-25 | 2015-05-06 | 温州大学 | Anti-cancer activity indole derivative, synthesis method and uses thereof |
| CN106536513A (en) * | 2014-07-22 | 2017-03-22 | Viiv保健英国有限公司 | Isoindolinone derivatives useful as antiviral agents |
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| US20040235826A1 (en) * | 2001-08-30 | 2004-11-25 | Peckham Jennifer P. | Tyrosine kinase ihnibitors |
| CN102084465A (en) * | 2008-02-01 | 2011-06-01 | 福吉米株式会社 | Polishing composition and polishing method using the same |
| CN102822165A (en) * | 2010-02-11 | 2012-12-12 | 细胞基因公司 | Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same |
| CN104586842A (en) * | 2014-04-25 | 2015-05-06 | 温州大学 | Anti-cancer activity indole derivative, synthesis method and uses thereof |
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