CN113563307B - Method for synthesizing alpha-cyclic amine maleimide hybrid - Google Patents

Method for synthesizing alpha-cyclic amine maleimide hybrid Download PDF

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CN113563307B
CN113563307B CN202110847475.4A CN202110847475A CN113563307B CN 113563307 B CN113563307 B CN 113563307B CN 202110847475 A CN202110847475 A CN 202110847475A CN 113563307 B CN113563307 B CN 113563307B
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CN113563307A (en
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范学森
周倩婷
王芳
张新迎
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Henan Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

The invention discloses a method for synthesizing an alpha-cyclic amine maleimide hybrid, belonging to the technical field of organic synthesis. Taking a cyclic amine compound 1 and a maleimide compound 2 as raw materials, and carrying out a heating reaction in an organic solvent in the presence of a catalyst, an oxidant and 2,2,6, 6-tetramethyl piperidine oxynitride (TEMPO) to obtain an alpha-cyclic amine maleimide hybrid 3. Compared with the prior art, the invention has the following advantages: 1) the synthesis process is simple, and the alpha-cyclic amine maleimide hybrid is directly synthesized through the cross dehydrogenation coupling reaction between the cyclic amine compound and the maleimide compound; 2) the raw materials are cheap and easy to obtain, the reaction condition is mild, the operation is simple and convenient, and the application range of the substrate is wide; 3) high atom economy and good selectivity.

Description

Method for synthesizing alpha-cyclic amine maleimide hybrid
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing an alpha-cyclic amine maleimide hybrid.
Background
The alpha-functionalized cyclic amine is the basic structural framework of various natural products and artificially synthesized compounds. Research shows that many compounds containing alpha-functionalized cyclic amine structural units have remarkable antimalarial, anesthetic, antianginal, antipsychotic and other pharmaceutical activities. Based on these pharmaceutical activities, clinical drugs such as mepivacaine, ropivacaine, connine, methylphenidate, thioridazine, etc. have been developed in succession.
In view of the importance of alpha-functionalized cyclic amines, relatively much research has been conducted on the synthesis of such compounds. However, the studies on the synthesis of α -cycloamineimide hybrids are still insufficient. In view of the important use of maleimide compounds in the development of new drugs, optoelectronic materials, organic synthesis, etc., it is necessary to research and develop a new green method for synthesizing α -cyclic maleimide hybrids.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing an alpha-cyclic amine maleimide hybrid, which is realized by cross dehydrogenation coupling reaction between an easily obtained cyclic amine compound and a maleimide compound, and has the advantages of simple and easily obtained raw materials, simple and convenient operation, mild conditions, high atom economy, good selectivity, wide substrate application range and the like.
The invention adopts the following technical scheme for solving the technical problems, and the method for synthesizing the alpha-cyclic amine maleimide hybrid comprises the following operations: taking a cyclic amine compound 1 and a maleimide compound 2 as raw materials, and carrying out a heating reaction in an organic solvent in the presence of a catalyst, an oxidant and 2,2,6, 6-tetramethyl piperidine oxynitride (TEMPO) to obtain an alpha-cyclic amine maleimide hybrid 3. The reaction equation is:
Figure BDA0003181129220000011
wherein: r1Is 2-naphthyl, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is C1-4Alkyl, halogen, C1-4Alkoxy, trifluoromethyl, C1-4One or more (mono-or poly-substituted) of alkoxycarbonyl, R2Is C1-4Alkyl or phenyl, R3Is C1-4Straight or branched alkyl, C3-8Cycloalkyl, benzyl, phenyl or substituted phenyl, the substituent on the phenyl ring of the substituted phenyl being C1-4Alkyl, halogen, C1-4Alkoxy, trifluoromethyl or C1-4An alkoxycarbonyl group; x is O or C, and n is 0 to 3 (integer).
Further, in the above technical scheme, the catalyst is ferric trichloride hexahydrate, anhydrous ferric trichloride, ferric sulfate, ferric nitrate nonahydrate, cupric bromide or cupric chloride dihydrate.
Further, in the above technical solution, the oxidant is di-tert-butyl peroxide (TBP), Cumene Hydroperoxide (CHP), or dicumyl peroxide (DCP). Among them, dicumyl peroxide is preferred as the oxidizing agent.
Further, in the above technical solution, the reaction solvent is used for dissolving the raw material, and preferably acetonitrile, 1, 2-dichloroethane, 1, 4-dioxane, toluene or tetrahydrofuran.
Further, in the above technical scheme, the reaction temperature is 60-100 ℃.
Further, in the technical scheme, the molar ratio of the cyclic amine compound 1, the maleimide compound 2 and the oxidant to the catalyst is 1-1.5:1-1.5:0.5-1.5: 0.01-0.2.
Further, in the above technical scheme, the cyclic amine compound 1 is replaced by
Figure BDA0003181129220000021
Formation of aromatization products
Figure BDA0003181129220000022
For example, N-phenylindoline (1Fa) and N-phenylmaleimide (2a) are used as raw materials, and in the presence of anhydrous ferric trichloride, dicumyl peroxide and 2,2,6, 6-tetramethylpiperidine oxynitride, the temperature is raised in an organic solvent to react to obtain N-phenylindole-2-maleimide 3 Fa: the reaction equation is expressed as:
Figure BDA0003181129220000023
the invention has the beneficial effects that:
compared with the prior art, the invention has the following advantages: 1) the synthesis process is simple, and the alpha-cyclic amine maleimide hybrid is directly synthesized through the cross dehydrogenation coupling reaction between the cyclic amine compound and the maleimide compound; 2) the raw materials are cheap and easy to obtain, the reaction condition is mild, the operation is simple and convenient, and the application range of the substrate is wide; 3) high atom economy and good selectivity.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
Figure BDA0003181129220000031
Adding 1a, an organic solvent, a catalyst, an oxidant, TEMPO and 2a into a 15mL pressure resistant tube in sequence, covering a plug for sealing, and placing the tube in an oil bath for heating and stirring reaction. After the reaction is finished, quenching by saturated saline solution, extracting by ethyl acetate and anhydrous Na2SO4And (5) drying. Spin-dry and silica gel column separation (20/1 petroleum ether/ethyl acetate) afforded product 3 a.
Various reaction results are obtained by changing the catalyst, the oxidant, the organic solvent, the temperature and the dosage ratio of the reaction, and the reaction results are shown in table 1.
TABLE 1 Synthesis of 3a under different reaction conditionsa
Figure BDA0003181129220000032
Figure BDA0003181129220000041
Example 2
Figure BDA0003181129220000042
To a 15mL pressure resistant tube were added 1a (81mg,0.5mmol), toluene (2mL), anhydrous ferric trichloride (8mg,0.05mmol), dicumyl peroxide (135mg,0.5mmol), 2,6, 6-tetramethylpiperidine nitroxide (78mg,0.5mmol) and 2a (86mg,0.5mmol) in this order, and the mixture was sealed with a stopper under an air atmosphere, and then placed in an oil at 80 ℃ under a sealed conditionThe reaction was stirred in the bath for 12 hours. After the reaction, the reaction mixture was cooled to room temperature, quenched with saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and extracted with anhydrous Na2SO4And (5) drying. Spin-dried and silica gel column separated (20/1 petroleum ether/ethyl acetate) to give product 3a as a yellow oil (121mg, 73%).1H NMR(400MHz,CDCl3):δ7.44(t,J＝8.0Hz,2H),7.34(d,J＝7.6Hz,1H),7.31(d,J＝8.0Hz,2H),7.23-7.27(m,2H),6.95(d,J＝8.4Hz,2H),6.89(d,J＝7.2Hz,1H),6.34(d,J＝1.2Hz,1H),4.80(t,J＝4.8Hz,1H),3.30-3.33(m,2H),2.09-2.17(m,1H),1.97-2.05(m,1H),1.83-1.92(m,1H),1.71-1.81(m,1H),1.61-1.69(m,2H).13C{1H}NMR(100MHz,CDCl3):δ170.0,169.2,150.6,149.7,131.4,129.4,129.1,128.5,127.7,125.9,120.9,118.1,53.1,49.3,30.6,25.7,21.3.HRMS(ESI)m/z:[M+H]+Calcd for C21H21N2O2 +333.1598；Found:333.1594.
Example 3
Various alpha-cyclic Aminomaleimide hybrids 3 were synthesized by varying reactants 1 and 2 according to the procedure and procedure of example 2a,bThe concrete results are as follows:
Figure BDA0003181129220000051
representative product characterization data are as follows:
1-Phenyl-3-(1-(p-tolyl)piperidin-2-yl)-1H-pyrrole-2,5-dione(3b)
Yellow oil(149mg,86％).1H NMR(400MHz,CDCl3):δ7.43(t,J＝8.0Hz,2H),7.34(d,J＝7.6Hz,1H),7.30(dd,J1＝8.4Hz,J2＝1.2Hz,2H),7.05(d,J＝8.0Hz,2H),6.87(d,J＝8.0Hz,2H),6.32(d,J＝1.2Hz,1H),4.64(t,J＝5.2Hz,1H),3.28-3.34(m,1H),3.10-3.16(m,1H),2.26(s,3H),2.09-2.17(m,1H),1.82-1.93(m,2H),1.70-1.78(m,1H),1.60-1.69(m,2H).13C{1H}NMR(150MHz,CDCl3):δ170.0,169.3,150.1,148.7,131.5,131.0,129.9,129.1,128.3,127.7,125.9,119.2,53.7,51.3,31.3,25.9,21.9,20.6.HRMS(ESI)m/z:[M+H]+Calcd for C22H23N2O2 +347.1754；Found:347.1749.
1-Phenyl-3-(1-(4-(trifluoromethyl)phenyl)piperidin-2-yl)-1H-pyrrole-2,5-dione(3c)
Yellow oil(96mg,48％).1H NMR(400MHz,CDCl3):δ7.46(dd,J1＝16.0Hz,J2＝8.0Hz,4H),7.32-7.38(m,3H),6.93(d,J＝8.8Hz,2H),6.34(d,J＝1.6Hz,1H),5.06(t,J＝3.6Hz,1H),3.60-3.65(m,1H),3.24-3.31(m,1H),3.20-3.26(m,1H),2.06-2.15(m,1H),1.89-1.94(m,1H),1.72-1.80(m,2H),1.52-1.60(m,1H).13C{1H}NMR(150MHz,CDCl3):δ170.0,168.7,150.3(q,1JC-F＝371.9Hz),131.3,129.1,128.4(q,2JC-F＝100.4Hz),126.7(q,4JC-F＝3.6Hz),125.9,114.8,52.0,45.6,29.0,25.1,19.8.19F{1H}NMR(376MHz,CDCl3)δ-61.4Hz.HRMS(ESI)m/z:[M+H]+Calcd for C22H20FN2O2 +401.1471；Found:401.1470.
Ethyl4-(2-(2,5-dioxo-1-phenyl-2,5-dihydro-1H-pyrrol-3-yl)piperidin-1-yl)benzoate(3d)
Yellow oil(75mg,37％).1H NMR(400MHz,CDCl3):δ7.93(d,J＝9.2Hz,2H),7.45(t,J＝7.6Hz,2H),7.32-7.37(m,3H),6.85-6.89(m,2H),6.33(d,J＝1.6Hz,1H),5.14(d,J＝2.4Hz,1H),4.33(q,J＝7.2Hz,2H),3.69-3.75(m,1H),3.24-3.30(m,1H),2.26-2.30(m,1H),2.04-2.14(m,1H),1.89-1.93(m,1H),1.70-1.80(m,2H),1.51-1.57(m,1H),1.36(t,J＝7.2Hz,3H).13C{1H}NMR(150MHz,CDCl3):δ169.7,168.6,166.5,153.0,148.4,134.3,131.4,131.3,129.2,129.1,129.0,127.9,126.1,125.9,120.6,113.8,60.5,51.8,44.8,28.8,25.0,19.6,14.4.HRMS(ESI)m/z:[M+H]+Calcd for C24H25N2O4 +405.1809；Found:405.1801.
3-(1-(3-Bromophenyl)piperidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3e)
Yellow oil(148mg,72％).1H NMR(400MHz,CDCl3):δ7.45(t,J＝8.0Hz,2H),7.36(d,J＝7.6Hz,1H),7.32(dd,J1＝8.4Hz,J2＝1.2Hz,2H),7.10(t,J＝8.0Hz,1H),7.07(t,J＝2.0Hz,1H),6.97-7.00(m,1H),6.83(dd,J1＝8.4Hz,J2＝1.6Hz,1H),6.36(d,J＝1.6Hz,1H),4.85-4.88(m,1H),3.37-3.43(m,1H),3.24-3.30(m,1H),2.08-2.14(m,2H),1.85-1.90(m,1H),1.67-1.78(m,2H),1.56-1.63(m,1H).13C{1H}NMR(150MHz,CDCl3):δ169.8,168.9,151.6,148.9,131.3,130.6,129.1,128.7,127.9,125.9,123.5,123.1,120.0,115.4,52.7,47.5,29.8,25.4,20.5.HRMS(ESI)m/z:[M+H]+Calcd for C21H20BrN2O2 +411.0703；Found:411.0701.
3-(1-(2-Fluorophenyl)piperidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3f)
Yellow oil(135mg,77％).1H NMR(400MHz,CDCl3):δ7.42(t,J＝7.6Hz,2H),7.32(t,J＝7.6Hz,1H),7.28(dd,J1＝8.4Hz,J2＝1.2Hz,2H),7.01-7.02(m,4H),6.37(d,J＝1.6Hz,1H),4.42-4.45(m,1H),3.38-3.43(m,1H),2.83-2.89(m,1H),2.14-2.19(m,1H),1.75-1.87(m,3H),1.67-1.73(m,1H),1.59-1.63(m,1H).13C{1H}NMR(150MHz,CDCl3):δ169.7,169.4,157.4(1J＝246.2Hz),150.5,139.1(2J＝9.9Hz),131.4,129.0,127.7,127.4,125.9,124.8(3J＝7.7Hz),124.5(4J＝3.3Hz),123.4,116.7(2J＝20.7Hz),54.6,53.7,32.8,25.9,23.2.19F{1H}NMR(376MHz,CDCl3):δ-122.4.HRMS(ESI)m/z:[M+H]+Calcd for C21H20FN2O2 +351.1503；Found:351.1506.
3-(1-(2-Chlorophenyl)piperidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3g)
Yellow oil(130mg,71％).1H NMR(400MHz,CDCl3):δ7.42(t,J＝8.0Hz,2H),7.39(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.32(d,J＝7.6Hz,1H),7.27(d,J＝8.0Hz,2H),7.14-7.18(m,1H),6.99-7.06(m,2H),6.29(d,J＝1.2Hz,1H),4.34-4.36(m,1H),3.33-3.38(m,1H),2.54-2.61(m,1H),2.17-2.20(m,1H),1.81-1.93(m,2H),1.75-1.78(m,1H),1.54-1.61(m,2H).13C{1H}NMR(150MHz,CDCl3):δ169.7,169.5,151.1,148.5,131.5,131.4,130.9,129.0,127.70,127.67,127.3,125.9,125.6,123.0,55.0,54.8,33.8,25.9,24.0.HRMS(ESI)m/z:[M+H]+Calcd for C21H20ClN2O2 +367.1208；Found:367.1206.
3-(1-(2-Bromophenyl)piperidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3h)
Yellow oil(148mg,72％).1H NMR(400MHz,CDCl3):δ7.58(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.42(t,J＝8.0Hz,2H),7.32(t,J＝7.6Hz,1H),7.26(dd,J1＝8.4Hz,J2＝1.6Hz,2H),7.19-7.23(m,1H),7.05(dd,J1＝8.0Hz,J2＝1.6Hz,1H),6.93-6.98(m,1H),6.29(d,J＝1.2Hz,1H),4.32-4.34(m,1H),3.31-3.36(m,1H),2.50-2.57(m,1H),2.17-2.20(m,1H),1.82-1.94(m,2H),1.75-1.79(m,1H),1.52-1.59(m,2H).13C{1H}NMR(150MHz,CDCl3):δ169.7,169.5,151.1,149.7,134.0,131.4,129.0,128.4,127.7,127.5,126.2,125.9,123.1,122.9,55.6,55.0,34.0,25.8,24.1.HRMS(ESI)m/z:[M+H]+Calcd for C21H20BrN2O2 +411.0703；Found:411.0703.
3-(1-(3,5-Dimethylphenyl)piperidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3i)
Yellow oil(112mg,62％).1H NMR(400MHz,CDCl3):δ7.44(t,J＝8.0Hz,2H),7.35(t,J＝7.2Hz,1H),7.31(dd,J1＝8.8Hz,J2＝1.6Hz,2H),6.58(s,2H),6.55(s,1H),6.38(d,J＝1.6Hz,1H),4.77-4.80(m,1H),3.27-3.31(m,2H),2.26(s,6H),2.07-2.15(m,1H),1.98-2.04(m,1H),1.81-1.87(m,1H),1.70-1.77(m,1H),1.59-1.66(m,2H).13C{1H}NMR(150MHz,CDCl3):δ170.1,169.3,150.9,149.9,138.5,131.5,129.1,128.5,127.7,125.9,122.9,116.0,53.3,49.3,30.6,25.7,21.6,21.3.HRMS(ESI)m/z:[M+H]+Calcd for C23H25N2O2 +361.1911；Found:361.1904.
3-(1-(Naphthalen-1-yl)piperidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3j)
Yellow oil(134mg,70％).1H NMR(600MHz,CDCl3):δ8.43(d,J＝8.4Hz,1H),7.82(d,J＝7.8Hz,1H),7.58(d,J＝7.8Hz,1H),7.54(t,J＝7.8Hz,1H),7.49(t,J＝7.2Hz,1H),7.39(t,J＝8.4Hz,2H),7.34(d,J＝7.8Hz,1H),7.30(t,J＝7.8Hz,1H),7.23(d,J＝8.4Hz,2H),7.12(d,J＝7.2Hz,1H),6.10(s,1H),4.46(br s,1H),3.39-3.41(m,1H),2.65(br s,1H),2.27-2.29(m,1H),1.92-2.01(m,2H),1.79-1.81(m,1H),1.61-1.65(m,2H).13C{1H}NMR(150MHz,CDCl3):δ169.8,169.5,148.6,134.9,131.4,130.5,129.0,128.5,127.6,126.27,126.26,125.9,125.7,125.0,122.9,117.6,55.6,34.5,26.4,24.6,24.5.HRMS(ESI)m/z:[M+H]+Calcd for C25H23N2O2 +383.1754；Found:383.1752.
3-(4-Methyl-1-phenylpiperidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3k)
Yellow oil(126mg,73％).1H NMR(400MHz,CDCl3):δ7.44(t,J＝8.0Hz,2H),7.31-7.36(m,3H),7.23-7.27(m,2H),6.91(d,J＝8.4Hz,2H),6.81(t,J＝7.6Hz,1H),6.37(d,J＝1.6Hz,1H),5.20-5.21(m,1H),3.66-3.71(m,1H),3.21-3.27(m,1H),2.28-2.32(m,1H),1.84-1.88(m,1H),1.70-1.78(m,1H),1.59-1.68(m,1H),1.34-1.45(m,1H),1.01(d,J＝6.4Hz,3H).13C{1H}NMR(150MHz,CDCl3):δ170.1,168.9,149.4,148.7,131.4,129.5,129.1,128.9,127.8,125.9,119.1,115.0,52.2,43.9,36.7,33.8,26.0,21.8.HRMS(ESI)m/z:[M+H]+Calcd for C22H23N2O2 +347.1754；Found:347.1750.
3-(1,4-Diphenylpiperidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3l)
Yellow oil(157mg,77％).1H NMR(400MHz,CDCl3):δ7.44(t,J＝8.0Hz,2H),7.21-7.36(m,10H),6.96(d,J1＝8.0Hz,2H),6.85(t,J＝7.2Hz,1H),6.48(d,J＝2.0Hz,1H),5.36-5.37(m,1H),3.82-3.87(m,1H),3.37-3.44(m,1H),2.73-2.81(m,1H),2.58-2.63(m,1H),2.24-2.33(m,1H),2.08-2.13(m,1H),1.88-1.99(m,1H).13C{1H}NMR(150MHz,CDCl3):δ170.0,168.8,149.2,148.1,144.7,131.3,129.6,129.4,129.1,128.7,127.8,126.8,126.7,125.9,119.3,115.0,52.6,44.0,37.2,35.4,33.1.HRMS(ESI)m/z:[M+H]+Calcd for C27H25N2O2 +409.1911；Found:409.1907.
1-Phenyl-3-(4-phenylmorpholin-3-yl)-1H-pyrrole-2,5-dione(3m)
Yellow oil(124mg,74％).1H NMR(600MHz,CDCl3):δ7.43(t,J＝7.8Hz,2H),7.33(t,J＝7.8Hz,1H),7.27-7.28(m,4H),6.93(d,J＝8.4Hz,2H),6.91(d,J＝7.8Hz,1H),6.49(d,J＝1.2Hz,1H),4.82(br s,1H),4.18(dd,J1＝11.4Hz,J2＝3.0Hz,1H),4.05-4.09(m,2H),3.82-3.86(m,1H),3.39-3.43(m,1H),3.31-3.34(m,1H).13C{1H}NMR(100MHz,CDCl3):δ170.0,168.8,148.8,145.6,131.3,130.0,129.6,129.1,127.9,125.9,121.0,116.2,69.6,67.2,51.7,45.6.HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O3 +335.1390；Found:335.1386.
1-Phenyl-3-(4-(p-tolyl)morpholin-3-yl)-1H-pyrrole-2,5-dione(3n)
Yellow oil(136mg,78％).1H NMR(600MHz,CDCl3):δ7.43(t,J＝7.8Hz,2H),7.34(t,J＝7.8Hz,1H),7.28(d,J＝7.8Hz,2H),7.08(d,J＝8.4Hz,2H),6.85(d,J＝8.4Hz,2H),6.49(s,1H),4.74(br s,1H),4.08(d,J＝3.6Hz,2H),4.03-4.06(m,1H),3.84-3.88(m,1H),3.36-3.40(m,1H),3.22-3.26(m,1H),2.27(s,3H).13C{1H}NMR(100MHz,CDCl3):δ169.9,168.9,146.8,145.7,131.3,130.8,130.1,130.0,129.1,127.8,125.9,117.1,69.8,67.3,52.2,46.9,20.5.HRMS(ESI)m/z:[M+H]+Calcd for C21H21N2O3 +349.1547；Found:349.1543.
3-(4-(4-Bromophenyl)morpholin-3-yl)-1-phenyl-1H-pyrrole-2,5-dione(3o)
Yellow oil(142mg,69％).1H NMR(600MHz,CDCl3):δ7.44(t,J＝8.4Hz,2H),7.37(d,J＝9.0Hz,2H),7.35(t,J＝7.8Hz,1H),7.28(d,J＝7.8Hz,2H),6.80(d,J＝9.0Hz,2H),6.49(s,1H),4.77(br s,1H),4.18(dd,J1＝12.0Hz,J2＝2.4Hz,1H),4.04-4.10(m,2H),3.82-3.86(m,1H),3.35-3.39(m,1H),3.27-3.30(m,1H).13C{1H}NMR(100MHz,CDCl3):δ169.9,168.6,147.8,145.1,132.4,131.2,130.0,129.1,127.9,125.9,117.7,113.2,69.5,67.0,51.3,45.2.HRMS(ESI)m/z:[M+Na]+Calcd for C20H17BrN2O3Na+435.0315；Found:435.0316.
1-Methyl-3-(1-phenylpiperidin-2-yl)-1H-pyrrole-2,5-dione(3p)
Yellow solid(104mg,77％),mp 100-101℃.1H NMR(400MHz,CDCl3):δ7.20-7.24(m,2H),6.89(d,J＝8.0Hz,2H),6.86(t,J＝7.2Hz,1H),6.18(d,J＝2.0Hz,1H),4.69-4.73(m,1H),3.26-3.28(m,2H),2.95(s,3H),2.03-2.11(m,1H),1.90-1.98(m,1H),1.79-1.87(m,1H),1.69-1.76(m,1H),1.60-1.68(m,1H),1.53-1.58(m,1H).13C{1H}NMR(100MHz,CDCl3):δ171.3,170.5,150.6,149.7,129.3,128.3,120.7,117.9,52.9,49.2,30.5,25.7,23.7,21.2.HRMS(ESI)m/z:[M+H]+Calcd for C16H19N2O2 +271.1441；Found:271.1444.
1-Ethyl-3-(1-phenylpiperidin-2-yl)-1H-pyrrole-2,5-dione(3q)
Orange oil(108mg,76％).1H NMR(600MHz,CDCl3):δ7.22(t,J＝7.8Hz,2H),6.90(d,J＝8.4Hz,2H),6.86(t,J＝7.2Hz,1H),6.17(s,1H),4.71(t,J＝4.8Hz,1H),3.50(q,J＝7.2Hz,2H),3.26-3.29(m,2H),2.04-2.08(m,1H),1.94-1.99(m,1H),1.81-1.84(m,1H),1.70-1.75(m,1H),1.61-1.65(m,1H),1.55-1.58(m,1H),1.14(t,J＝7.2Hz,3H).13C{1H}NMR(150MHz,CDCl3):δ171.1,170.3,150.6,149.4,129.3,128.3,120.6,117.9,52.9,49.0,32.8,30.5,25.7,21.2,13.9.HRMS(ESI)m/z:[M+H]+Calcd for C17H21N2O2 +285.1598；Found:285.1591.
3-(1-Phenylpiperidin-2-yl)-1-propyl-1H-pyrrole-2,5-dione(3r)
Yellow solid(116mg,78％),mp 56-57℃.1H NMR(600MHz,CDCl3):δ7.21(t,J＝7.8Hz,2H),6.90(d,J＝8.4Hz,2H),6.86(t,J＝7.2Hz,1H),6.17(s,1H),4.69(t,J＝5.4Hz,1H),3.39-3.42(m,2H),3.27(t,J＝6.0Hz,2H),2.03-2.08(m,1H),1.93-1.98(m,1H),1.81-1.85(m,1H),1.70-1.75(m,1H),1.59-1.65(m,1H),1.54-1.58(m,3H),0.85(t,J＝7.2Hz,3H).13C{1H}NMR(150MHz,CDCl3):δ171.3,170.6,150.7,149.4,129.3,128.2,120.7,118.0,52.9,49.2,39.5,30.5,25.7,21.8,21.2,11.2.HRMS(ESI)m/z:[M+H]+Calcd for C18H23N2O2 +299.1754；Found:299.1755.
1-(tert-Butyl)-3-(1-phenylpiperidin-2-yl)-1H-pyrrole-2,5-dione(3s)
Yellow solid(123mg,79％),mp 56-57℃.1H NMR(600MHz,CDCl3):δ7.22(t,J＝7.8Hz,2H),6.89(d,J＝8.4Hz,2H),6.85(t,J＝7.2Hz,1H),6.04(s,1H),4.67(t,J＝4.8Hz,1H),3.22-3.30(m,2H),2.00-2.05(m,1H),1.91-1.94(m,1H),1.81-1.83(m,1H),1.69-1.73(m,1H),1.54-1.63(m,2H),1.53(s,9H).13C{1H}NMR(150MHz,CDCl3):δ172.4,171.7,150.6,148.4,129.2,128.5,120.4,117.7,57.3,52.5,48.7,30.3,28.9,25.7,21.0.HRMS(ESI)m/z:[M+H]+Calcd for C19H25N2O2 +313.1911；Found:313.1912.
1-Benzyl-3-(1-phenylpiperidin-2-yl)-1H-pyrrole-2,5-dione(3t)
Yellow oil(128mg,74％).1H NMR(600MHz,CDCl3):δ7.30(t,J＝7.8Hz,2H),7.26-7.27(m,3H),7.20(t,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),6.85(t,J＝7.2Hz,1H),6.21(s,1H),4.69(t,J＝5.4Hz,1H),4.60(d,J＝3.0Hz,2H),3.26(t,J＝6.6Hz,2H),2.02-2.07(m,1H),1.94-1.98(m,1H),1.80-1.83(m,1H),1.70-1.73(m,1H),1.55-1.63(m,2H).13C{1H}NMR(150MHz,CDCl3):δ170.9,170.0,150.6,149.7,136.3,129.3,128.7,128.5,128.2,127.8,120.8,118.0,53.0,49.2,41.4,30.5,25.6,21.3.HRMS(ESI)m/z:[M+H]+Calcd for C22H23N2O2 +347.1754；Found:347.1750.
1-Cyclohexyl-3-(1-phenylpiperidin-2-yl)-1H-pyrrole-2,5-dione(3u)
Yellow oil(118mg,70％).1H NMR(600MHz,CDCl3):δ7.21(t,J＝7.8Hz,2H),6.89(d,J＝7.8Hz,2H),6.85(t,J＝7.2Hz,1H),6.12(s,1H),4.69(t,J＝5.4Hz,1H),3.80-3.85(m,1H),3.23-3.31(m,2H),1.95-2.07(m,4H),1.79-1.81(m,3H),1.68-1.75(m,1H),1.60-1.65(m,4H),1.53-1.58(m,1H),1.25-1.32(m,2H),1.16-1.22(m,1H).13C{1H}NMR(150MHz,CDCl3):δ171.3,170.6,150.6,148.8,129.3,128.3,120.5,117.7,52.8,50.8,48.7,30.3,30.02,29.98,26.0,25.6,25.1,21.1.HRMS(ESI)m/z:[M+H]+Calcd for C21H27N2O2 +339.2067；Found:339.2064.
1-(4-Fluorophenyl)-3-(1-phenylpiperidin-2-yl)-1H-pyrrole-2,5-dione(3v)
Orange oil(123mg,70％).1H NMR(600MHz,CDCl3):δ7.27-7.30(m,2H),7.24-7.26(m,2H),7.12(t,J＝8.4Hz,2H),6.95(d,J＝8.4Hz,2H),6.90(t,J＝7.2Hz,1H),6.34(d,J＝1.8Hz,1H),4.78(t,J＝4.8Hz,1H),3.29-3.32(m,2H),2.10-2.14(m,1H),1.98-2.02(m,1H),1.85-1.88(m,1H),1.74-1.78(m,1H),1.61-1.68(m,2H).13C{1H}NMR(150MHz,CDCl3):δ169.9,169.0,161.7(1J＝246.2Hz),150.6,149.8,129.4,128.5,127.7(3J＝8.7Hz),127.3(4J＝3.3Hz),121.0,118.1,116.0(2J＝23.1Hz),53.1,49.4,30.6,25.7,21.3.19F{1H}NMR(376MHz,CDCl3):δ-113.5.HRMS(ESI)m/z:[M+H]+Calcd for C21H20FN2O2 +351.1503；Found:351.1505.
1-(4-Bromophenyl)-3-(1-phenylpiperidin-2-yl)-1H-pyrrole-2,5-dione(3w)
Yellow solid(148mg,72％),mp 93-94℃.1H NMR(600MHz,CDCl3):δ7.55(d,J＝8.4Hz,2H),7.21-7.26(m,4H),6.94(d,J＝8.4Hz,2H),6.89(t,J＝7.8Hz,1H),6.34(d,J＝1.8Hz,1H),4.78(t,J＝5.4Hz,1H),3.29-3.31(m,2H),2.10-2.15(m,1H),1.96-2.01(m,1H),1.84-1.88(m,1H),1.73-1.78(m,1H),1.59-1.69(m,2H).13C{1H}NMR(150MHz,CDCl3):δ169.6,168.7,150.6,150.0,132.2,130.5,129.4,128.5,127.2,121.3,121.0,118.2,53.1,49.5,30.6,25.7,21.3.HRMS(ESI)m/z:[M+H]+Calcd for C21H20BrN2O2 +411.0703；Found:411.0702.
1-Phenyl-3-(1-phenylpyrrolidin-2-yl)-1H-pyrrole-2,5-dione(3Ba)
Yellow oil(119mg,75％).1H NMR(600MHz,CDCl3):δ7.45-7.48(m,2H),7.38(dd,J1＝8.4Hz,J2＝1.2Hz,2H),7.36(t,J＝7.2Hz,1H),7.23-7.25(m,2H),6.75(t,J＝7.2Hz,1H),6.54(d,J＝7.8Hz,2H),6.34(d,J＝1.8Hz,1H),4.73-4.75(m,1H),3.63-3.66(m,1H),3.33-3.37(m,1H),2.35-2.42(m,1H),2.10-2.14(m,2H),2.01-2.06(m,1H).13C{1H}NMR(100MHz,CDCl3):δ169.7,169.0,150.7,146.2,131.4,129.4,129.1,127.8,127.7,125.9,117.1,112.4,55.5,48.6,32.0,23.5.HRMS(ESI)m/z:[M+H]+Calcd for C20H19N2O2 +319.1441；Found:319.1440.
1-Phenyl-3-(1-(p-tolyl)pyrrolidin-2-yl)-1H-pyrrole-2,5-dione(3Bb)
Yellow oil(141mg,85％).1H NMR(600MHz,CDCl3):δ7.45-7.48(m,2H),7.38(dd,J1＝9.0Hz,J2＝1.2Hz,2H),7.35(t,J＝7.8Hz,1H),7.05(d,J＝8.4Hz,2H),6.46(d,J＝9.0Hz,2H),6.33(d,J＝1.8Hz,1H),4.69-4.71(m,1H),3.61-3.64(m,1H),3.29-3.33(m,1H),2.34-2.40(m,1H),2.26(s,3H),2.08-2.12(m,2H),2.01-2.04(m,1H).13C{1H}NMR(100MHz,CDCl3):δ169.7,169.0,151.1,144.2,131.5,129.9,129.1,127.7,127.6,126.2,125.9,112.4,55.6,48.8,32.0,23.5,20.3.HRMS(ESI)m/z:[M+H]+Calcd for C21H21N2O2 +333.1598；Found:333.1595.
1-Phenyl-3-(1-(o-tolyl)pyrrolidin-2-yl)-1H-pyrrole-2,5-dione(3Bc)
Yellow oil(131mg,79％).1H NMR(600MHz,CDCl3):δ7.42-7.45(m,2H),7.33(t,J＝7.8Hz,1H),7.31(dd,J1＝8.4Hz,J2＝1.2Hz,2H),7.17(dd,J1＝7.8Hz,J2＝1.2Hz,1H),7.10(t,J＝7.8Hz,1H),6.92-6.94(m,2H),6.24(d,J＝1.8Hz,1H),4.78-4.81(m,1H),3.74-3.78(m,1H),2.90-2.94(m,1H),2.59-2.64(m,1H),2.36(s,3H),1.99-2.10(m,2H),1.85-1.92(m,1H).13C{1H}NMR(100MHz,CDCl3):δ169.9,169.5,151.5,147.2,131.8,131.7,131.5,129.1,127.7,126.5,126.4,125.9,122.7,118.0,56.1,53.7,33.1,24.6,19.5.HRMS(ESI)m/z:[M+H]+Calcd for C21H21N2O2 +333.1598；Found:333.1594.
3-(1-(2-Fluorophenyl)pyrrolidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Bd)
Yellow oil(128mg,76％).1H NMR(600MHz,CDCl3):δ7.44-7.46(m,2H),7.33-7.36(m,3H),6.96-7.02(m,2H),6.71-6.74(m,1H),6.67-6.70(m,1H),6.31(d,J＝1.8Hz,1H),4.98-5.01(m,1H),3.75-3.78(m,1H),3.39-3.43(m,1H),2.41-2.47(m,1H),1.99-2.07(m,3H).13C{1H}NMR(100MHz,CDCl3):δ169.7,169.3,152.0(1J＝239.8Hz),151.6,135.2,131.5,129.1,127.7,126.3,125.9,124.7(4J＝2.9Hz),118.8(3J＝8.0Hz),116.6(2J＝21.0Hz),116.3(2J＝31.0Hz),56.3,50.7,32.5,23.5.19F{1H}NMR(376MHz,CDCl3):δ-125.8.HRMS(ESI)m/z:[M+H]+Calcd for C20H18FN2O2 +337.1347；Found:337.1344.
3-(1-(2-Chlorophenyl)pyrrolidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Be)
Yellow oil(136mg,77％).1H NMR(600MHz,CDCl3):δ7.42-7.45(m,2H),7.32-7.34(m,2H),7.30(dd,J1＝7.8Hz,J2＝1.2Hz,2H),7.13-7.16(m,1H),6.96(dd,J1＝8.4Hz,J2＝1.8Hz,1H),6.88-6.91(m,1H),6.33(d,J＝1.8Hz,1H),5.01-5.04(m,1H),4.00-4.04(m,1H),3.10-3.14(m,1H),2.58-2.63(m,1H),2.07-2.13(m,1H),2.00-2.04(m,1H),1.90-1.96(m,1H).13C{1H}NMR(100MHz,CDCl3):δ169.8,169.4,151.0,145.1,131.4,131.3,129.1,127.7,127.4,126.7,126.6,125.9,122.7,119.6,56.0,52.9,33.2,24.8.HRMS(ESI)m/z:[M+H]+Calcd for C20H18ClN2O2 +353.1051；Found:353.1046.
3-(1-(3,5-Dimethylphenyl)pyrrolidin-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Bf)
Yellow oil(144mg,83％).1H NMR(600MHz,CDCl3):δ7.45-7.48(m,2H),7.39(dd,J1＝8.4Hz,J2＝1.2Hz,2H),7.35(t,J＝7.8Hz,1H),6.42(s,1H),6.35(d,J＝1.8Hz,1H),6.18(s,2H),4.71-4.73(m,1H),3.60-3.64(m,1H),3.30-3.34(m,1H),2.30-2.35(m,1H),2.27(s,6H),2.07-2.12(m,2H),1.98-2.03(m,1H).13C{1H}NMR(100MHz,CDCl3):δ169.8,169.1,151.1,146.5,139.1,131.5,129.1,127.7,125.9,119.2,110.3,55.5,48.7,31.9,23.4,21.7.HRMS(ESI)m/z:[M+H]+Calcd for C22H23N2O2 +347.1754；Found:347.1750.
1-Cyclohexyl-3-(1-phenylpyrrolidin-2-yl)-1H-pyrrole-2,5-dione(3Bg)
Yellow oil(89mg,55％).1H NMR(600MHz,CDCl3):δ7.20-7.24(m,2H),6.72(t,J＝7.8Hz,1H),6.49(d,J＝8.4Hz,2H),6.11(d,J＝1.2Hz,1H),4.62-4.63(m,1H),3.86-3.92(m,1H),3.57-3.60(m,1H),3.29-3.33(m,1H),2.28-2.34(m,1H),2.02-2.09(m,4H),1.83-1.85(m,2H),1.66-1.70(m,3H),1.20-1.35(m,4H).13C{1H}NMR(100MHz,CDCl3):δ171.0,170.4,150.0,146.3,129.3,127.4,116.9,112.3,55.3,50.9,48.5,31.9,30.1,26.0,25.1,23.4.HRMS(ESI)m/z:[M+H]+,Calcd for C20H25N2O2 +325.1911；Found:325.1912.
1-Phenyl-3-(1-phenylazepan-2-yl)-1H-pyrrole-2,5-dione(3Ca)
Yellow oil(139mg,80％).1H NMR(400MHz,CDCl3):δ7.37-7.41(m,2H),7.26-7.30(m,3H),7.14-7.18(m,2H),6.65(t,J＝7.2Hz,1H),6.58(d,J＝8.4Hz,2H),6.27(d,J＝1.6Hz,1H),4.54-4.58(m,1H),3.68-3.72(m,1H),3.33-3.40(m,1H),2.60-2.67(m,1H),1.60-1.93(m,5H),1.26-1.40(m,2H).13C{1H}NMR(100MHz,CDCl3):δ169.8,169.0,151.0,147.6,131.5,129.5,129.1,127.8,126.6,126.0,116.6,111.2,55.8,44.7,34.4,29.6,28.1,26.2.HRMS(ESI)m/z:[M+H]+Calcd for C22H23N2O2 +347.1754；Found:347.1751.
1-Phenyl-3-(1-(p-tolyl)azepan-2-yl)-1H-pyrrole-2,5-dione(3Cb)
Yellow oil(148mg,82％).1H NMR(400MHz,CDCl3):δ7.44-7.48(m,2H),7.35-7.37(m,3H),7.05(d,J＝8.4Hz,2H),6.57(d,J＝8.8Hz,2H),6.33(d,J＝1.6Hz,1H),4.59-4.63(m,1H),3.73-3.77(m,1H),3.39-3.45(m,1H),2.66-2.73(m,1H),2.25(s,3H),1.87-1.99(m,2H),1.63-1.83(m,3H),1.32-1.47(m,2H).13C{1H}NMR(100MHz,CDCl3):δ169.8,169.1,151.2,145.5,131.5,130.0,129.1,127.8,126.5,126.0,125.7,111.2,55.9,44.8,34.4,29.6,28.2,26.2,20.1.HRMS(ESI)m/z:[M+H]+Calcd for C23H25N2O2 +361.1911；Found:361.1906.
3-(1-(4-Fluorophenyl)azepan-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Cc)
Yellow oil(129mg,71％).1H NMR(400MHz,CDCl3):δ7.45-7.49(m,2H),7.36-7.38(m,3H),6.93(d,J＝7.2Hz,2H),6.55(dd,J1＝9.2Hz,J2＝4.0Hz,2H),6.33(d,J＝1.6Hz,1H),4.56(dd,J1＝11.2Hz,J2＝5.6Hz,1H),3.68-3.73(m,1H),3.40-3.47(m,1H),2.66-2.73(m,1H),1.80-2.01(m,3H),1.63-1.73(m,2H),1.34-1.47(m,2H).13C{1H}NMR(100MHz,CDCl3):δ169.7,169.0,155.2(1J＝234.1Hz),150.9,144.3(4J＝1.5Hz),131.4,129.1,127.8,126.5,125.9,115.8(2J＝21.7Hz),111.8(3J＝6.5Hz),56.2,45.1,34.4,29.6,28.1,26.1.19F{1H}NMR(376MHz,CDCl3):δ-129.6.HRMS(ESI)m/z:[M+H]+Calcd for C22H22FN2O2 +365.1660；Found:365.1666.
3-(1-(4-Chlorophenyl)azepan-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Cd)
Yellow oil(137mg,72％).1H NMR(400MHz,CDCl3):δ7.45-7.49(m,2H),7.35-7.37(m,3H),7.17(d,J＝8.8Hz,2H),6.57(d,J＝9.2Hz,2H),6.32(d,J＝1.6Hz,1H),4.56-4.60(m,1H),3.69-3.74(m,1H),3.40-3.47(m,1H),2.68-2.75(m,1H),1.81-2.00(m,3H),1.64-1.73(m,2H),1.34-1.45(m,2H).13C{1H}NMR(100MHz,CDCl3):δ169.6,168.9,150.6,146.2,131.4,129.3,129.1,127.9,126.6,125.96,121.5,112.3,56.0,44.9,34.3,29.5,27.9,26.1.HRMS(ESI)m/z:[M+H]+Calcd for C22H22ClN2O2 +381.1364；Found:381.1363.
3-(1-(4-Bromophenyl)azepan-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Ce)
Yellow oil(155mg,73％).1H NMR(400MHz,CDCl3):δ7.45-7.49(m,2H),7.35-7.37(m,3H),7.30(d,J＝9.2Hz,2H),6.52(d,J＝9.2Hz,2H),6.32(d,J＝1.6Hz,1H),4.55-4.59(m,1H),3.68-3.73(m,1H),3.39-3.46(m,1H),2.67-2.75(m,1H),1.81-2.02(m,3H),1.64-1.74(m,2H),1.32-1.44(m,2H).13C{1H}NMR(100MHz,CDCl3):δ169.6,168.9,150.5,146.7,132.1,131.4,129.1,127.9,126.6,125.9,112.9,108.5,56.0,44.8,34.3,29.5,27.9,26.1.HRMS(ESI)m/z:[M+H]+Calcd for C22H22BrN2O2 +425.0859；Found:425.0853.
3-(1-(4-Methoxyphenyl)azepan-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Cf)
Yellow oil(143mg,76％).1H NMR(400MHz,CDCl3):δ7.44-7.48(m,2H),7.36-7.37(m,3H),6.84(d,J＝8.8Hz,2H),6.60(d,J＝9.2Hz,2H),6.34(d,J＝1.6Hz,1H),4.55-4.59(m,1H),3.75(s,3H),3.70-3.75(m,1H),3.39-3.46(m,1H),2.64-2.71(m,1H),1.87-1.98(m,2H),1.63-1.79(m,3H),1.34-1.45(m,2H).13C{1H}NMR(100MHz,CDCl3):δ169.8,169.1,151.4,151.3,142.3,131.5,129.1,127.8,126.5,125.9,115.1,112.2,56.2,55.9,45.2,34.4,29.7,28.4,26.2.HRMS(ESI)m/z:[M+H]+Calcd for C23H25N2O3 +377.1860；Found:377.1857.
1-Phenyl-3-(1-(m-tolyl)azepan-2-yl)-1H-pyrrole-2,5-dione(3Cg)
Yellow oil(137mg,76％).1H NMR(400MHz,CDCl3):δ7.45-7.49(m,2H),7.36-7.38(m,3H),7.12(t,J＝7.6Hz,1H),6.56(d,J＝7.6Hz,1H),6.45-6.47(m,2H),6.34(d,J＝1.6Hz,1H),4.62-4.66(m,1H),3.75-3.79(m,1H),3.38-3.45(m,1H),2.65-2.74(m,1H),2.31(s,3H),1.64-2.00(m,5H),1.33-1.47(m,2H).13C{1H}NMR(100MHz,CDCl3):δ169.8,169.1,151.1,147.7,139.2,131.5,129.4,129.1,127.8,126.5,125.9,117.6,111.8,108.4,55.8,44.7,34.4,29.6,28.1,26.1,22.1.HRMS(ESI)m/z:[M+H]+Calcd for C23H25N2O2 +361.1911；Found:361.1909.
3-(1-(3-Fluorophenyl)azepan-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Ch)
Yellow oil(131mg,72％).1H NMR(400MHz,CDCl3):δ7.45-7.49(m,2H),7.35-7.38(m,3H),7.12-7.18(m,1H),6.38-6.44(m,2H),6.33-6.37(m,2H),4.57-4.61(m,1H),3.69-3.74(m,1H),3.40-3.47(m,1H),2.68-2.76(m,1H),1.82-2.02(m,3H),1.64-1.73(m,2H),1.34-1.46(m,2H).13C{1H}NMR(100MHz,CDCl3):δ169.6,168.9,164.3(1J＝241.2Hz),150.4,149.5(3J＝10.9Hz),131.4,130.5(3J＝10.1Hz),129.1,127.9,126.6,126.0,106.9(4J＝2.1Hz),103.2(2J＝21.7Hz),98.5(2J＝26.8Hz),56.1,44.9,34.2,29.5,27.9,26.1.19F{1H}NMR(376MHz,CDCl3):δ-111.7.HRMS(ESI)m/z:[M+H]+Calcd for C22H22FN2O2 +365.1660；Found:365.1660.
3-(1-(3-Bromophenyl)azepan-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Ci)
Orange solid(155mg,73％),mp 143-144℃.1H NMR(400MHz,CDCl3):δ7.45-7.49(m,2H),7.36-7.38(m,3H),7.07(t,J＝8.4Hz,1H),6.84(dd,J1＝8.0Hz,J2＝1.2Hz,1H),6.79-6.80(m,1H),6.54(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.33(d,J＝1.6Hz,1H),4.57-4.61(m,1H),3.69-3.74(m,1H),3.39-3.46(m,1H),2.69-2.76(m,1H),1.82-2.02(m,3H),1.64-1.76(m,2H),1.32-1.45(m,2H).13C{1H}NMR(100MHz,CDCl3):δ169.5,168.8,150.3,148.9,131.4,130.7,129.1,127.9,126.6,126.0,123.8,119.5,114.0,109.9,55.9,44.7,34.2,29.5,27.8,26.0.HRMS(ESI)m/z:[M+H]+Calcd for C22H22BrN2O2 +425.0859；Found:425.0856.
1-Phenyl-3-(1-(o-tolyl)azepan-2-yl)-1H-pyrrole-2,5-dione(3Cj)
Orange oil(126mg,70％).1H NMR(400MHz,CDCl3):δ7.45-7.48(m,2H),7.36-7.37(m,3H),7.15(t,J＝8.4Hz,1H),6.34(d,J＝1.6Hz,1H),6.29(t,J＝8.4Hz,2H),6.21-6.22(m,1H),4.61-4.65(m,1H),3.79(s,3H),3.73-3.79(m,1H),3.38-3.45(m,1H),2.67-2.75(m,1H),1.88-2.00(m,2H),1.63-1.84(m,3H),1.33-1.47(m,2H).13C{1H}NMR(100MHz,CDCl3):δ169.7,169.0,161.0,150.9,149.1,131.4,130.2,129.1,127.8,126.6,126.0,104.6,100.8,98.4,55.9,55.2,44.8,34.3,29.6,28.1,26.1.HRMS(ESI)m/z:[M+H]+Calcd for C23H25N2O2 +361.1911；Found:361.1909.
3-(1-(2-Fluorophenyl)azepan-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Ck)
Orange oil(120mg,66％).1H NMR(400MHz,CDCl3):δ7.42-7.46(m,2H),7.31-7.34(m,3H),7.01-7.03(m,1H),6.99(d,J＝7.6Hz,1H),6.91-6.95(m,1H),6.79-6.85(m,1H),6.45(d,J＝1.6Hz,1H),4.78-4.81(m,1H),3.63-3.67(m,1H),3.37-3.40(m,1H),2.48-2.55(m,1H),1.83-1.92(m,1H),1.73-1.81(m,4H),1.62-1.71(m,1H),1.43-1.50(m,1H).13C{1H}NMR(100MHz,CDCl3):δ169.9,169.4,154.9(1J＝242.7Hz),152.2,138.2(3J＝7.9Hz),131.5,129.1,127.7,126.2,125.9,124.5(4J＝3.6Hz),121.0(2J＝28.1Hz),120.8,117.0(2J＝21.7Hz),57.4,49.4,33.6,30.0,29.6,25.3.19F{1H}NMR(376MHz,CDCl3):δ-121.6.HRMS(ESI)m/z:[M+H]+Calcd for C22H22FN2O2 +365.1660；Found:365.1663.
3-(1-(2-Chlorophenyl)azepan-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Cl)
Yellow oil(118mg,62％).1H NMR(400MHz,CDCl3):δ7.42(t,J＝8.0Hz,2H),7.37(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.32(t,J＝7.6Hz,1H),7.24-7.29(m,4H),7.16-7.20(m,1H),6.96-7.00(m,1H),6.62(d,J＝1.6Hz,1H),4.83-4.86(m,1H),3.45-3.51(m,1H),3.30-3.36(m,1H),2.29-2.36(m,1H),1.91-2.02(m,2H),1.70-1.82(m,3H),1.63-1.68(m,1H).13C{1H}NMR(100MHz,CDCl3):δ170.0,169.6,152.1,148.5,131.5,131.4,131.1,129.0,127.7,127.6,126.9,126.3,126.0,124.8,58.1,51.5,32.7,29.9,29.6,25.8 HRMS(ESI)m/z:[M+H]+Calcd for C22H22ClN2O2 +381.1364；Found:381.1357.
1-Cyclohexyl-3-(1-phenylazepan-2-yl)-1H-pyrrole-2,5-dione(3Cm)
Orange yellow oil(107mg,61％).1H NMR(600MHz,CDCl3):δ7.21(t,J＝8.4Hz,2H),6.69(t,J＝7.2Hz,1H),6.60(d,J＝8.4Hz,2H),6.11(d,J＝1.2Hz,1H),4.50-4.53(m,1H),3.86-3.91(m,1H),3.71-3.73(m,1H),3.36-3.40(m,1H),2.61-2.66(m,1H),2.00-2.09(m,1H),1.92-1.95(m,2H),1.78-1.88(m,4H),1.57-1.74(m,4H),1.18-1.43(m,6H).13C{1H}NMR(100MHz,CDCl3):δ171.0,170.5,150.3,147.7,129.4,126.2,116.4,111.1,55.6,50.9,44.6,34.4,30.1,29.6,28.1,26.1,26.0,25.1.HRMS(ESI)m/z:[M+H]+Calcd for C22H29N2O2 +353.2224；Found:353.2216.
1-Phenyl-3-(1-phenylazocan-2-yl)-1H-pyrrole-2,5-dione(3Da)
Yellow oil(139mg,77％).1H NMR(600MHz,CDCl3):δ7.44(t,J＝7.8Hz,2H),7.32-7.35(m,3H),7.23(t,J＝7.8Hz,2H),6.74-6.76(m,2H),6.72(t,J＝7.8Hz,1H),6.23(s,1H),4.81-4.83(m,1H),3.62-3.64(m,2H),2.30-2.34(m,1H),2.00-2.06(m,2H),1.80-1.84(m,1H),1.43-1.72(m,6H).13C{1H}NMR(150MHz,CDCl3):δ169.9,169.0,150.4,147.3,131.4,129.5,129.1,127.8,126.9,125.9,116.9,112.1,54.8,44.5,30.1,28.3,27.5,26.3,25.0.HRMS(ESI)m/z:[M+H]+Calcd for C23H25N2O2 +361.1911；Found:361.1909.
1-Phenyl-3-(1-(p-tolyl)azocan-2-yl)-1H-pyrrole-2,5-dione(3Db)
Yellow oil(152mg,81％).1H NMR(600MHz,CDCl3):δ7.44(t,J＝7.8Hz,2H),7.32-7.35(m,3H),7.05(d,J＝9.0Hz,2H),6.67(d,J＝8.4Hz,2H),6.22(d,J＝1.2Hz,1H),4.78-4.80(m,1H),3.59-3.62(m,2H),2.28-2.33(m,1H),2.24(s,3H),1.98-2.05(m,2H),1.80-1.83(m,1H),1.67-1.73(m,1H),1.46-1.64(m,5H).13C{1H}NMR(150MHz,CDCl3):δ170.0,169.0,150.6,145.1,131.5,130.0,129.1,127.8,126.8,126.0,125.9,112.2,54.9,44.5,30.2,28.3,27.6,26.3,25.1,20.1.HRMS(ESI)m/z:[M+H]+Calcd for C24H27N2O2 +375.2067；Found:375.2068.
3-(1-(4-Bromophenyl)azocan-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3Dc)
Yellow oil(160mg,73％).1H NMR(600MHz,CDCl3):δ7.45(t,J＝7.8Hz,2H),7.35(t,J＝7.8Hz,1H),7.33(d,J＝7.2Hz,2H),7.30(d,J＝9.0Hz,2H),6.62(d,J＝9.0Hz,2H),6.22(d,J＝1.2Hz,1H),4.74-4.77(m,1H),3.59-3.61(m,2H),2.29-2.34(m,1H),1.97-2.06(m,2H),1.80-1.85(m,1H),1.56-1.68(m,4H),1.48-1.53(m,2H).13C{1H}NMR(150MHz,CDCl3):δ169.7,168.8,149.8,146.2,132.2,131.3,129.1,127.9,126.8,125.9,113.8,108.9,54.9,44.5,29.9,28.2,27.1,26.1,24.9.HRMS(ESI)m/z:[M+H]+Calcd for C23H24BrN2O2 +439.1016；Found:439.1002.
1-Phenyl-3-(1-(m-tolyl)azocan-2-yl)-1H-pyrrole-2,5-dione(3Dd)
Yellow oil(140mg,75％).1H NMR(600MHz,CDCl3):δ7.45(t,J＝7.8Hz,2H),7.36-7.35(m,3H),7.12(t,J＝7.8Hz,1H),6.55-6.57(m,3H),6.24(d,J＝1.8Hz,1H),4.82-4.84(m,1H),3.58-3.67(m,2H),2.31(s,3H),2.00-2.06(m,2H),1.80-1.84(m,1H),1.55-1.72(m,4H),1.43-1.53(m,3H).13C{1H}NMR(150MHz,CDCl3):δ170.0,169.0,150.5,147.3,139.2,131.5,129.3,129.1,127.8,126.9,125.9,117.9,112.8,109.4,54.8,44.4,30.1,28.3,27.5,26.3,25.1,22.1.HRMS(ESI)m/z:[M+H]+Calcd for C24H27N2O2 +375.2067；Found:375.2065.
3-(1-(3-Fluorophenyl)azocan-2-yl)-1-phenyl-1H-pyrrole-2,5-dione(3De)
Yellow oil(132mg,70％).1H NMR(600MHz,CDCl3):δ7.45(t,J＝7.8Hz,2H),7.33-7.36(m,3H),7.13-7.17(m,1H),6.49(dd,J1＝9.0Hz,J2＝2.4Hz,1H),6.39-6.46(m,2H),6.22(d,J＝1.2Hz,1H),4.74-4.76(m,1H),3.59-3.61(m,2H),2.30-2.35(m,1H),1.99-2.06(m,2H),1.79-1.85(m,1H),1.57-1.68(m,3H),1.48-1.55(m,3H).13C{1H}NMR(150MHz,CDCl3):δ169.7,168.8,164.3(1J＝240.6Hz),149.9,149.1(3J＝9.9Hz),131.4,130.5(3J＝9.9Hz),129.1,127.8,126.9,125.9,107.7(4J＝2.3Hz),103.5(2J＝20.9Hz),99.4(2J＝26.3Hz),55.2,44.7,29.8,28.2,27.1,26.1,24.9.19F{1H}NMR(376MHz,CDCl3):δ-111.7.HRMS(ESI)m/z:[M+H]+Calcd for C23H24FN2O2 +379.1816；Found:379.1817.
1-Cyclohexyl-3-(1-phenylazocan-2-yl)-1H-pyrrole-2,5-dione(3Df)
Yellow oil(119mg,65％).1H NMR(600MHz,CDCl3):δ7.20-7.22(m,2H),6.68-6.71(m,3H),6.00(d,J＝1.8Hz,1H),4.69-4.71(m,1H),3.82-3.88(m,1H),3.53-3.61(m,1H),2.22-2.27(m,1H),1.91-2.06(m,4H),1.75-1.83(m,2H),1.63-1.65(m,6H),1.44-1.56(m,4H),1.20-1.33(m,4H).13C{1H}NMR(100MHz,CDCl3):δ171.2,170.4,149.7,147.4,129.4,126.6,116.7,112.0,54.6,50.8,44.5,30.1,30.0,28.2,27.5,26.3,26.0,25.1,25.0.HRMS(ESI)m/z:[M+H]+Calcd for C23H31N2O2 +367.2380；Found:367.2363.
example 4
To a 15mL pressure resistant tube were added 1Ea (67mg,0.5mmol), toluene (2mL), anhydrous ferric trichloride (8mg,0.05mmol), dicumyl peroxide (135mg,0.5mmol) and 2,2,6, 6-tetramethylpiperidine nitroxide (78mg,0.5mmol) and 2a (86mg,0.5mmol) in this order, and the mixture was sealed with a stopper under an air atmosphere, and the mixture was placed in an oil bath at 100 ℃ and stirred for reaction for 12 hours. After the reaction, the reaction mixture was cooled to room temperature, quenched with saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and extracted with anhydrous Na2SO4And (5) drying. Spin-dried and separated on silica gel column (20/1 petroleum ether/ethyl acetate) to give the product 3Ea (84mg, 55%) as a yellow oil.
Figure BDA0003181129220000201
3Ea:1H NMR(600MHz,CDCl3):δ7.47(t,J＝8.4Hz,2H),7.35-7.38(m,3H),7.23-7.25(m,2H),6.83(t,J＝7.8Hz,1H),6.69(d,J＝1.8Hz,1H),6.50(d,J＝7.8Hz,2H),4.97(t,J＝9.0Hz,1H),4.08-4.11(m,1H),3.81-3.85(m,1H),2.74-2.80(m,1H),2.45-2.51(m,1H).13C{1H}NMR(150MHz,CDCl3):δ169.2,169.1,150.8,150.6,131.4,129.2,129.1,127.9,126.9,125.9,119.0,112.0,59.1,50.5,25.4.HRMS(ESI)m/z:[M+H]+Calcd for C19H17N2O2 +305.1285；Found:305.1282.
Example 5
To a 15mL pressure resistant tube were added 1Fa (98mg,0.5mmol), toluene (2mL), anhydrous ferric trichloride (8mg,0.05mmol), dicumyl peroxide (135mg,0.5mmol), 2,6, 6-tetramethylpiperidine nitroxide (78mg,0.5mmol) and 2a (86mg,0.5mmol) in this order, and the mixture was sealed with a stopper under an air atmosphere, and the mixture was placed in an oil bath at 100 ℃ and stirred for reaction for 12 hours. After the reaction, the reaction mixture was cooled to room temperature, quenched with saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and extracted with anhydrous Na2SO4And (5) drying. Spin drying, silica gel column separation(petroleum ether/ethyl acetate 20/1) gave 3Fa (40mg, 21%) as a yellow solid.
Figure BDA0003181129220000202
3Fa:1H NMR(600MHz,CDCl3):δ7.97(s,1H),7.76(t,J＝7.8Hz,1H),7.55-7.61(m,3H),7.46(t,J＝8.4Hz,2H),7.34-7.37(m,5H),7.27(t,J＝7.8Hz,1H),7.18(t,J＝7.8Hz,1H),7.04(d,J＝8.4Hz,1H),5.43(s,1H).13C{1H}NMR(150MHz,CDCl3):δ169.8,169.2,141.9,137.7,134.5,131.6,130.4,129.5 129.1,128.6,128.2,127.9,127.6,126.3,126.2,122.8,121.5,118.9,113.6,110.8.HRMS(ESI)m/z:[M+H]+Calcd for C24H17N2O2 +387.1104；Found:387.1101.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.

Claims (8)

1. A method for synthesizing an alpha-cyclic amine maleimide hybrid, comprising the following operations: taking a cyclic amine compound 1 and a maleimide compound 2 as raw materials, and carrying out a heating reaction in an organic solvent in the presence of a catalyst, an oxidant and 2,2,6, 6-tetramethyl piperidine oxynitride to obtain an alpha-cyclic amine maleimide hybrid 3, wherein the reaction equation is as follows:
Figure FDA0003181129210000011
wherein: r1Is 2-naphthyl, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is C1-4Alkyl, halogen, C1-4Alkoxy radical, triFluoromethyl group, C1-4One or more of alkoxycarbonyl; r2Is C1-4Alkyl or phenyl, R3Is C1-4Straight or branched alkyl, C3-8Cycloalkyl, benzyl, phenyl or substituted phenyl, the substituent on the phenyl ring of the substituted phenyl being C1-4Alkyl, halogen, C1-4Alkoxy, trifluoromethyl or C1-4An alkoxycarbonyl group; x is C or O, and n is 0-3.
2. The method for synthesizing an α -cycloamineimide hybrid according to claim 1, wherein: the catalyst is ferric trichloride hexahydrate, anhydrous ferric trichloride, ferric sulfate, ferric nitrate nonahydrate, copper bromide or copper chloride dihydrate.
3. The method for synthesizing an α -cycloamineimide hybrid according to claim 1, wherein: the oxidant is di-tert-butyl peroxide, cumene hydroperoxide or dicumyl peroxide.
4. The method for synthesizing an α -cycloamineimide hybrid according to claim 3, wherein: the oxidant is dicumyl peroxide.
5. The method for synthesizing an α -cycloamineimide hybrid according to claim 1, wherein: the reaction solvent is acetonitrile, 1, 2-dichloroethane, 1, 4-dioxane, toluene or tetrahydrofuran.
6. The method for synthesizing an α -cycloamineimide hybrid according to claim 1, wherein: the reaction temperature is 60-100 ℃.
7. The method for synthesizing an α -cycloamineimide hybrid according to claim 1, wherein: the molar ratio of the cyclic amine compound 1, the maleimide compound 2, the oxidant and the catalyst is 1-1.5:1-1.5:0.5-1.5: 0.01-0.2.
8. A method for synthesizing N-phenylindole-2-maleimide is characterized by adopting a reaction equation as follows:
Figure FDA0003181129210000021
taking N-phenylindoline 1Fa and N-phenylmaleimide 2a as raw materials, and carrying out heating reaction in an organic solvent in the presence of anhydrous ferric trichloride, dicumyl peroxide and 2,2,6, 6-tetramethylpiperidine oxynitride to obtain the N-phenylindoline-2-maleimide 3 Fa.
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Copper catalyzed oxidative alkylation of sp(3) C-H bond adjacent to a nitrogen atom using molecular oxygen in water;Olivier Baslé et al.;《Green Chemistry》;20070709;第9卷(第10期);第1047-1050页 *
FeCl3-Catalyzed Cascade Reactions of Cyclic Amines with 2-Oxo-2-arylacetic Acids toward Furan-2(5H)-one Fused N,O-Bicyclic Compounds;Xiaonan Shi et al.;《Advanced Synthesis & Catalysis》;20171106;第360卷(第2期);第261-266页 *
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