CN109232591B - 2, 3-condensed ring indoline alkaloid and synthetic method and application thereof - Google Patents
2, 3-condensed ring indoline alkaloid and synthetic method and application thereof Download PDFInfo
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Abstract
The invention discloses a series of 2, 3-condensed ring indoline alkaloids and a synthesis method and application thereof. The alkaloid is shown as formula (I), and the preparation method comprises: and (3) putting the compound shown in the formula (II) into an organic solvent to react in the presence of oxygen to obtain a crude product of the target product. The structures shown in formula (I) and formula (II) are as follows:
wherein X is oxygen, n ═ 1, R1、R2、R3And R4The selection of (A) is as follows: r1、R3And R4All represent hydrogen, R2Represents (4-methoxy) phenylvinylene; or R1、R3And R4All represent hydrogen, R2Represents a (2-furyl) vinylene group; or R1And R3All represent hydrogen, R2Represents a phenylvinylene group, R4Represents a phenyl group; or R1And R3All represent 4-bromo, R2Represents a phenylvinylene group, R4Represents hydrogen.
Description
The application is a divisional application of '2, 3-condensed ring indoline derivatives, a synthesis method and application thereof', and the application dates of the original application are as follows: 29/6/2017, with the application numbers: 201710518658.5, title of the invention: 2, 3-condensed ring indoline derivative and synthesis method and application thereof.
Technical Field
The invention relates to the technical field of medicines, in particular to a 2, 3-condensed ring indoline derivative and a synthesis method and application thereof.
Background
Indole alkaloids are important natural products, and are always favored by synthetic and pharmaceutical chemists because of their large number, complex structure and often remarkable physiological activity.
The fused ring indoline skeleton, particularly 2, 3-fused ring indoline, is a core structure widely existing in indoline alkaloids and plays a decisive role in the physiological activity and the pharmacological activity of a compound, and the successful construction of the 2, 3-fused ring indoline core skeleton is the key point and difficulty of the total synthesis of the alkaloids, so that the efficient construction of the 2, 3-fused ring indoline skeleton is one of the hot points and difficulties in the organic synthesis. Strategies for constructing such frameworks can be achieved through palladium-catalyzed tandem reactions (Zhang, g.z.; Catalano, v.j.; Zhang, l.m.j.am.chem.soc.2007,129,11358-11359.), oxidative coupling, intramolecular cyclization reactions (Zuo, z.w.; Xie, w.q.; Ma, d.w.j.am.chem.soc.2010,132,13226-13228), and the like, but these methods all have the disadvantages of limited substrates, poor functional group compatibility, complicated steps, complex raw materials and the like.
Disclosure of Invention
The invention aims to provide a series of 2, 3-condensed ring indoline derivatives with novel structures, and a synthetic method and application thereof.
The invention relates to a compound shown as the following formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R1represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R2represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R3represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R4represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
x represents an oxygen or nitrogen atom;
n is 1, 2 or 3.
Among the above compounds:
R1further preferably hydrogen or C1～4Alkyl, or phenyl which is unsubstituted, mono-or di-substituted;
R2further preferably hydrogen or C1～4Alkyl, or phenyl which is unsubstituted, mono-or di-substituted;
R3further preferably hydrogen or C1～4Alkyl, or phenyl which is unsubstituted, mono-or di-substituted;
R4further preferably hydrogen or C1～4Alkyl, or phenyl which is unsubstituted, mono-or di-substituted.
The synthesis method of the compound shown in the formula (I) mainly comprises the following steps: putting a compound shown as a formula (II) in an organic solvent, and reacting in the presence of oxygen to obtain a target crude product;
wherein:
R1represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R2represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4Alkyl of (2)A group, cyano group or halogen atom;
R3represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R4represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
x represents an oxygen or nitrogen atom;
n is 1, 2 or 3.
In the above synthesis method, R1、R2、R3And R4The preferences of (2) are as previously described.
In the above synthesis method, the compound represented by the formula (II) is an N-aryl α, β -unsaturated nitrone derivative, which can be synthesized by referring to the existing literature (Xiao-Pan Ma, Wei-Min Shi, Xue-Ling Mo, Xiao-Hua Li, Liang-Gui Li, Cheng-Xue Pan, Bo Chen, Gui-Fa Su and Dong-Liang Mo, J.Org.Chem.2015,80, 10098-10107), or can be synthesized by selecting a synthetic route, and will not be described in detail herein.
In the above synthesis method, the organic solvent may be one or a combination of two or more selected from benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, chloroform, n-hexane and dioxane. When the organic solvent is selected from the combination of two or more of the above substances, the ratio of the organic solvent to the organic solvent may be any ratio.
In the above synthesis method, the reaction is preferably carried out at a temperature of less than 100 ℃ and more preferably at a temperature of from room temperature to 80 ℃. The completion of the reaction can be followed by TLC. According to the experience of the applicant, when the reaction is carried out at 80 ℃, the reaction time is preferably controlled to be 5-20 h.
In the synthesis method of the present invention, the amount of the organic solvent is preferably such that the raw material participating in the reaction can be dissolved, and usually 1mmol of the compound represented by formula (II) is dissolved in 1 to 10mL of the organic solvent.
The crude compound of formula (I) is obtained by the above process and can be purified by conventional purification methods to increase the purity of the compound of formula (I). The purification is usually carried out by silica gel thin layer chromatography or silica gel column chromatography, or by recrystallization, and the eluent used in the chromatography and the solvent used in the recrystallization are the same, and may be a mixed solvent composed of petroleum ether and ethyl acetate, or a mixed solvent composed of n-hexane and ethyl acetate. In the mixed solvent, the volume ratio of petroleum ether to ethyl acetate is preferably 50: 1-10: 1, the volume ratio of the n-hexane to the ethyl acetate is preferably 50: 1-10: 1.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Compared with the prior art, the invention provides a series of 2, 3-condensed ring indoline derivatives with novel structures, a synthetic method and application thereof, and the applicant finds that part of the 2, 3-condensed ring indoline derivatives have certain antitumor activity. On the other hand, the synthesis method provided by the invention is simple and easy to control, has short period and higher yield, and does not need anhydrous and anaerobic conditions.
Detailed Description
The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.
The N-aryl alpha, beta-unsaturated nitrone derivatives (i.e., compounds represented by formula (II)) referred to in the following examples were synthesized according to the following synthetic routes:
wherein:
R1represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R2represents hydrogen, C1～4Alkyl of (C)1～4Alkoxy group of (C)1～4Or an unsubstituted, mono-, di-, tri-, tetra-or penta-substituted phenyl group, or an unsubstituted furyl group, or an unsubstituted thienyl group, or an unsubstituted naphthyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～4An alkyl group, a cyano group or a halogen atom;
R3represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
R4represents hydrogen, C1～8Alkyl of (C)1～6Alkoxy or C1～4Or an unsubstituted, mono-or di-substituted phenyl group; wherein the substituent is C1～4Alkoxy group of (C)1～4Perfluoroalkyl group of (1), C1～6Alkyl or halogen atom of (a);
x represents an oxygen or nitrogen atom;
n is 1, 2 or 3.
The specific synthesis method comprises the following steps: placing alpha, beta-unsaturated oxime substrate S1(0.5mmol) and potassium hydroxide (0.75mmol) in a reaction tube, adding 5mL of carbon tetrachloride, stirring for 5min at room temperature, adding a high-valent iodine reagent S2(0.75mmol), reacting for 1-24h at room temperature, removing the solvent from the obtained reactant under reduced pressure, and separating the residue by silica gel column chromatography (petroleum ether/ethyl acetate is 4: 1-1: 1 in volume ratio) to obtain a target product 1 (namely the compound N-aryl alpha, beta-unsaturated nitrone shown in the formula (II)).
Example 1
The 2, 3-condensed ring indoline derivative provided by the invention is synthesized according to the following synthetic route.
2a:R1＝H,R2＝PhCH＝CH,R3＝H,R4＝H,n＝1；
2b:R1＝H,R2＝PhCH＝CH,R3＝4-OMe,R4＝H,n＝1；
2c:R1＝H,R2＝PhCH＝CH,R3＝4-Me,R4＝H,n＝1；
2d:R1＝H,R2＝PhCH＝CH,R3＝4-tBu,R4＝H,n＝1；
2e:R1＝H,R2＝PhCH＝CH,R3＝4-Cl,R4＝H,n＝1；
2f:R1＝H,R2＝PhCH＝CH,R3＝4-F,R4＝H,n＝1；
2g:R1＝H,R2＝PhCH＝CH,R3＝4-CF3,R4＝H,n＝1；
2h:R1＝H,R2＝PhCH＝CH,R3＝4-CO2Me,R4＝H,n＝1；
2i:R1＝H,R2＝PhCH＝CH,R3＝3-OMe,R4＝H,n＝1；
2j:R1＝H,R2＝PhCH＝CH,R3＝3-NO2,R4＝H,n＝1；
2k:R1＝H,R2＝PhCH＝CH,R3＝3,5-Me,R4＝H,n＝1；
2l:R1＝H,R2＝PhCH＝CH,R3＝2-Me,R4＝H,n＝1；
2ab:R1＝H,R2＝(4-OMe)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ac:R1＝H,R2＝(4-Me)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ad:R1＝H,R2＝(4-F)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ae:R1＝H,R2＝(4-CF3)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2af:R1＝H,R2＝(3-OMe)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ag:R1＝H,R2＝(3-Br)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ah:R1＝H,R2＝(2-Br)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ai:R1＝H,R2＝(2-furyl)CH＝CH,R3＝H,R4＝H,n＝1；
2aj:R1＝H,R2＝Me,R3＝H,R4＝H,n＝1；
2ak:R1＝H,R2＝Me,R3＝H,R4＝Me,n＝1；
2al:R1＝H,R2＝PhCH＝CH,R3＝H,R4＝Ph,n＝1；
2am:R1＝4-F,R2＝PhCH＝CH,R3＝H,R4＝H,n＝1；
2an:R1＝3-Br,R2＝Me,R3＝H,R4＝H,n＝1；
2ao:R1＝3,5-Me,R2＝Me,R3＝H,R4＝H,n＝1；
2ap:R1＝H,R2＝H,R3＝H,R4＝H,n＝1；
2aq:R1＝H,R2＝H,R3＝H,R4＝H,n＝1,X＝NH；
2ar:R1＝H,R2＝H,R3＝H,R4＝H,n＝2；
2as:R1＝H,R2＝H,R3＝H,R4＝H,n＝3。
Putting the N-aryl alpha, beta-unsaturated nitrone substrate 1(0.2mmol) into a reaction tube, adding 2mL of organic solvent (wherein the organic solvent adopted by the target 2a-2l is carbon tetrachloride, the organic solvent adopted by the target 2af-2am is benzene, toluene, cyclohexane, petroleum ether, tetrahydrofuran, ethyl acetate, acetonitrile and diethyl ether respectively, and the organic solvent adopted by the target 2an-2as is a mixed solvent of benzene and tetrahydrofuran in a volume ratio of 1: 1) into the reaction tube, stirring and reacting the mixture at 80 ℃ for 5 to 20 hours, decompressing the obtained reactant to remove the solvent, and separating the residue by silica gel column chromatography (the petroleum ether/ethyl acetate ratio is 50: 1-10: 1, and the volume ratio) to obtain the target product 2. The different target products and their characterization were as follows:
2 a: solid, 50mg, 70% yield; mp 161 and 162 ℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.29(d,J＝7.6Hz,2H),7.24(t,J＝7.2Hz,2H),7.19–7.15(m,1H),7.11(d,J＝7.6Hz,1H),7.07–7.03(m,J＝6.8Hz,3H),6.90–6.86(m,2H),6.76(t,J＝6.8Hz,2H),6.63(d,J＝8.0Hz,1H),6.40(d,J＝15.6Hz,1H),4.66(d,J＝12.8Hz,1H),4.30(brs,1H),4.27(d,J＝12.4Hz,1H)；13C NMR(100MHz,CDCl3):δ197.0,154.2,149.9,135.7,132.7,130.1,129.1,129.0,128.6,128.2,127.4,126.9,126.8,124.6,122.7,122.1,120.3,117.6,110.8,69.9,63.0,61.6.IR(thin film)3367,2925,2848,1709,1602,1482,1214,1059,755cm-1；HRMS(ESI)m/z calcd for C24H20NO2[M+H]+:354.1494,found:354.1495.
2 b: solid, 52mg, 67% yield; mp 51-52 ℃.1H NMR(400MHz,CDCl3):δ9.51(s,1H),7.29(d,J＝7.2Hz,2H),7.24–7.21(m,2H),7.19–7.15(m,1H),7.12(d,J＝7.6Hz,1H),7.08–7.04(m,1H),6.90–6.86(m,2H),6.77(d,J＝8.4Hz,1H),6.64(d,J＝6.4Hz,3H),6.40(d,J＝16.0Hz,1H),4.65(d,J＝16.4Hz,1H),4.28(d,J＝12.4Hz,1H),4.10(brs,1H),3.64(s,3H).13C NMR(100MHz,CDCl3):δ202.2,154.6,144.3,139.6,136.2,131.5,129.8,128.6,128.5,128.4,127.9,127.7,127.5,126.6,122.1,117.5,115.4,111.9,110.4,71.0,66.5,64.9,55.3.IR(thin film)3433,3025,2924,1709,1638,1459,1272,752cm-1；HRMS(ESI)m/z calcd for C25H22NO3[M+H]+:384.1600,found:384.1594.
2 c: solid, 46mg, 63% yield; mp 186-.1H NMR(400MHz,CDCl3):δ9.49(s,1H),7.30(d,J＝7.6Hz,2H),7.25–7.15(m,3H),7.11–7.04(m,2H),6.90–6.86(m,4H),6.77(d,J＝8.4Hz,1H),6.55(d,J＝9.2Hz,1H),6.40(d,J＝15.6Hz,1H),4.66(d,J＝12.4Hz,1H),4.29(d,J＝12.8Hz,1H),4.20(brs,1H),2.17(s,3H).13C NMR(100MHz,CDCl3):δ197.1,154.2,147.6,135.8,132.6,130.7,129.9,129.3,128.9,128.6,128.1,127.5,127.1,126.8,125.1,122.8,122.1,117.6,110.7,70.0,62.7,61.4,20.6.IR(thin film)3360,3028,2923,1709,1614,1493,1263,821,748cm-1；HRMS(ESI)m/z calcd for C25H22NO2[M+H]+:368.1651,found:368.1664.
2 d: solid, 49mg, 60% yield; mp 163-.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.30(d,J＝7.2Hz,2H),7.25–7.21(m,2H),7.19–7.16(m,1H),7.11–7.03(m,4H),6.89–6.85(m,2H),6.77(d,J＝8.0Hz,1H),6.59(d,J＝8.4Hz,1H),6.41(d,J＝16.0Hz,1H),4.67(d,J＝12.4Hz,1H),4.31(d,J＝12.4Hz,1H),4.19(brs,1H),1.18(s,9H).13C NMR(100MHz,CDCl3):δ197.3,154.3,147.5,143.6,135.8,132.5,129.5,128.9,128.6,128.1,127.5,127.2,127.1,126.8,122.4,122.0,121.3,117.7,110.4,70.0,63.1,61.9,34.3,31.5.IR(thin film)3376,3033,2960,1716,1613,1490,1270,824,749cm-1；HRMS(ESI)m/z calcd for C28H28NO2[M+H]+:410.2120,found:410.2115.
2 e: solid, 41mg, 53% yield; mp 167-.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.29–7.17(m,5H),7.10(t,J＝7.2Hz,2H),7.02(d,J＝8.4Hz,2H),6.90–6.84(m,2H),6.79(d,J＝8.0Hz,1H),6.55(d,J＝8.0Hz,1H),6.38(d,J＝15.6Hz,1H),4.62(d,J＝12.4Hz,1H),4.32(brs,1H),4.28(d,J＝15.6Hz,1H).13C NMR(100MHz,CDCl3):δ196.4,154.2,148.4,135.5,133.0,130.1,129.2,128.7,128.6,128.3,127.4,126.8,126.5,125.0,124.9,124.6,122.3,117.7,111.7,70.4,62.8,61.6.IR(thin film)3360,2923,2854,1713,1602,1482,756,690cm-1；HRMS(ESI)m/z calcd for C24H19ClNO2[M+H]+:388.1104,found:388.1087.
2 f: solid, 45mg, 60% yield; mp 169-170 ℃.1H NMR(400MHz,CDCl3):δ9.52(s,1H),7.30(d,J＝7.2Hz,2H),7.26(t,J＝7.2Hz,2H),7.20–7.18(m,1H),7.12–7.06(m,2H),6.91–6.86(m,2H),6.80–6.74(m,3H),6.57(dd,J＝8.4Hz,4.0Hz,1H),6.39(d,J＝16.0Hz,1H),4.63(d,J＝12.4Hz,1H),4.28(d,J＝12.4Hz,1H),4.20(brs,1H).13C NMR(100MHz,CDCl3):δ196.7,158.8(d,J＝237Hz),154.2,145.9,135.6,132.9,129.1,128.8,128.6,128.3,127.4,126.8,126.7,124.4(d,J＝8Hz),122.3,117.7,116.8(d,J＝23.3Hz),112.1(d,J＝24.1Hz),111.4(d,J＝8.1Hz),70.6,62.8,61.8.IR(thin film)3359,2925,2853,1708,1608,1487,1221,757cm-1；HRMS(ESI)m/z calcd for C24H19FNO2[M+H]+:372.1400,found:372.1385.
2 g: solid, 34mg, 40% yield; mp 122-.1H NMR(400MHz,CDCl3):δ9.53(s,1H),7.33–7.18(m,7H),7.12–7.08(m,2H),6.93–6.89(m,1H),6.87–6.79(m,2H),6.68(d,J＝8.0Hz,1H),6.40(d,J＝16.0Hz,1H),4.64(d,J＝12.4Hz,1H),4.59(brs,1H),4.33(d,J＝12.8Hz,1H).13C NMR(100MHz,CDCl3):δ196.2,154.2,152.5,135.4,133.1,129.3,128.7,128.5,128.3,128.1,128.0,127.4,126.8,126.1,123.2,122.4,122.2,122.1,117.9,110.0,70.2,62.7,61.2.IR(thin film)3339,2923,2853,1710,1623,1274,1104,758cm-1；HRMS(ESI)m/z calcd for C25H19F3NO2[M+H]+:422.1368,found:422.1368.
2 h: solid, 40mg, 49% yield; mp 73-74 ℃.1H NMR(400MHz,CDCl3):δ9.51(s,1H),7.82(d,J＝8.0Hz,1H),7.75(s,1H),7.30–7.18(m,5H),7.11–7.07(m,2H),6.91–6.83(m,2H),6.79(d,J＝8.4Hz,1H),6.63(d,J＝8.0Hz,1H),6.39(d,J＝16.0Hz,1H),4.71(brs,1H),4.67(d,J＝12.4Hz,1H),4.33(d,J＝12.8Hz,1H),3.77(s,3H).13C NMR(100MHz,CDCl3):δ196.2,166.5,154.2,153.7,135.4,133.0,132.9,129.3,128.7,128.4,128.0,127.4,126.8,126.6,126.2,122.8,122.3,122.0,117.9,109.6,70.4,63.1,61.2,51.7.IR(thin film)3345,3025,2924,1708,1518,1285,753cm-1；HRMS(ESI)m/z calcd for C26H22NO4[M+H]+:412.1549,found:412.1552.
2 i: solid, 48mg, 63% yield; mp 43-44 ℃.1H NMR(400MHz,CDCl3):δ9.48(s,1H),9.46(s,1H),7.30(d,J＝7.2Hz,4H),7.24(t,J＝7.2Hz,4H),7.19–7.16(m,2H),7.11–7.03(m,4H),6.95–6.83(m,6H),6.77(d,J＝8.0Hz,2H),6.58(d,J＝7.6Hz,1H),6.51(d,J＝7.6Hz,1H),6.47–6.36(m,4H),4.97(d,J＝12.4Hz,1H),4.65(d,J＝12.0Hz,1H),4.28–4.19(m,4H),2.20(s,3H),2.16(s,3H).13C NMR(100MHz,CDCl3):δ197.0,196.3,155.0,154.2,150.2,150.0,140.4,137.0,135.8,133.0,132.6,130.1,129.2,129.0,128.9,128.8,128.6,128.5,128.2,128.1,127.4,127.3,127.2,127.0,126.9,126.8,126.7,124.3,122.8,122.1,122.0,121.2,119.8,119.5,117.7,117.5,111.6,108.6,70.4,70.0,63.0,62.9,62.6,61.4,21.3,18.5.IR(thin film)3368,3025,2924,1708,1614,1459,1272,752cm-1；HRMS(ESI)m/z calcd for C25H22NO3[M+H]+:384.1600,found:384.1583.
2 j: solid, 38mg, 48% yield; mp 187-.1H NMR(400MHz,CDCl3):δ9.60(s,1H),7.43(d,J＝8.0Hz,1H),7.28–7.18(m,6H),7.11(d,J＝7.6Hz,2H),6.92–6.89(m,2H),6.83(d,J＝8.0Hz,1H),6.72(d,J＝16.0Hz,1H),6.72(d,J＝16.0Hz,1H),4.61(brs,1H),4.60(d,J＝12.6Hz,1H),4.54(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ195.7,154.1,150.5,150.0,135.3,133.5,130.0,129.5,128.7,128.6,127.8,127.4,126.8,125.9,125.1,122.6,117.8,115.7,105.1,70.8,62.9,61.5.IR(thin film)3349,2923,2852,1716,1529,1351,802,759cm-1；HRMS(ESI)m/z calcd for C24H19N2O2[M+H]+:399.1345,found:399.1339.
2 k: solid, 46mg, 60% yield; mp 96-97 ℃.1H NMR(400MHz,CDCl3):δ9.58(s,1H),7.42(d,J＝8.0Hz,1H),7.26–7.17(m,4H),7.10(d,J＝7.6Hz,3H),6.92–6.85(m,2H),6.80(d,J＝8.0Hz,1H),6.72(d,J＝16.0Hz,1H),6.70(d,J＝16.0Hz,1H),4.65(brs,1H),4.60(d,J＝12.6Hz,1H),4.52(d,J＝12.4Hz,1H),2.06(s,3H),2.03(s,3H).13C NMR(100MHz,CDCl3):δ195.7,154.1,150.5,150.0,135.3,133.5,130.0,129.5,128.7,128.6,127.8,127.4,126.8,125.9,125.1,122.6,117.8,115.7,105.1,70.8,62.9,61.5,16.8,16.1.IR(thin film)3451,3032,2924,2850,1733,1606,1510,968,635cm-1；HRMS(ESI)m/z calcd for C26H24NO2[M+H]+:382.1807,found:382.1829.
2 l: solid, 50mg, 68% yield; mp 220 and 221 ℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.30(d,J＝7.6Hz,2H),7.25–7.21(m,2H),7.19–7.13(m,2H),7.08–7.04(m,1H),6.89–6.86(m,4H),6.77(d,J＝8.0Hz,1H),6.72(t,J＝7.6Hz,1H),6.43(d,J＝16.0Hz,1H),4.64(d,J＝12.4Hz,1H),4.31(d,J＝12.4Hz,1H),4.09(brs,1H),2.07(s,3H).13C NMR(100MHz,CDCl3):δ197.1,154.3,148.5,135.8,132.6,131.1,129.4,128.9,128.6,128.5,128.2,127.4,127.2,126.8,122.2,122.0,120.5,120.2,117.7,69.7,63.2,62.0,16.7.IR(thin film)3352,3023,2926,1705,1582,1485,1058,762,688cm-1；HRMS(ESI)m/z calcd for C25H22NO2[M+H]+:368.1651,found:368.1640.
2 ab: solid, 58mg, 75% yield; mp 59-60 ℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.23(d,J＝8.4Hz,2H),7.12(d,J＝7.6Hz,1H),7.07–7.03(m,3H),6.89(d,J＝7.6Hz,1H),6.82–6.73(m,5H),6.63(d,J＝8.0Hz,1H),6.27(d,J＝15.6Hz,1H),4.66(d,J＝12.4Hz,1H),4.29(brs,1H),4.26(d,J＝12.8Hz,1H),3.72(s,3H).13C NMR(100MHz,CDCl3):δ197.0,159.7,154.3,149.9,132.2,130.1,128.9,128.5,128.0,127.5,127.1,126.9,124.6,122.7,122.1,120.3,117.6,114.0,110.7,70.0,63.0,61.6,55.3.IR(thin film)3360,3032,2924,1709,1606,1257,809,753cm-1；HRMS(ESI)m/z calcd for C25H22NO3[M+H]+:384.1600,found:384.1586.
2 ac: solid, 32mg, 43% yield; mp 38-39 ℃.1H NMR(400MHz,CDCl3):δ9.51(s,1H),7.20(d,J＝7.2Hz,2H),7.12–7.04(m,6H),6.90(t,J＝7.2Hz,2H),6.77–6.75(m,2H),6.65(d,J＝8.0Hz,1H),6.36(d,J＝16.0Hz,1H),4.74(brs,1H),4.67(d,J＝12.0Hz,1H),4.30(d,J＝12.4Hz,1H),2.26(s,3H).13C NMR(100MHz,CDCl3):δ197.0,154.2,149.7,138.2,133.0,132.6,130.1,129.3,128.9,128.1,127.5,127.0,126.7,124.7,122.7,122.1,120.3,117.6,110.8,70.0,63.0,61.6,21.1.IR(thin film)3371,3001,2924,1708,1607,1483,1261,1100,803cm-1；HRMS(ESI)m/z calcd for C25H22NO2[M+H]+:368.1651,found:368.1636.
2 ad: solid, 35mg, 47% yield; mp 132-.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.23(d,J＝7.2Hz,2H),7.12–7.04(m,6H),6.90(t,J＝7.2Hz,2H),6.75–6.70(m,2H),6.65(d,J＝8.0Hz,1H),6.36(d,J＝16.0Hz,1H),4.73(brs,1H),4.65(d,J＝12.0Hz,1H),4.33(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ197.1,153.2,149.1,138.2,133.0,132.4,130.1,129.1,128.8,128.0,127.4,127.0,125.7,124.5,122.4,122.0,120.3,117.3,110.8,70.3,63.1,61.6.IR(thin film)3369,3004,2925,1706,1605,1481,1260,1106,801cm-1；HRMS(ESI)m/z calcd for C24H19NO2[M+H]+:372.1400,found:372.1387.
2 ae: solid, 48mg, 57% yield; mp 128-129 ℃.1H NMR(400MHz,CDCl3):δ9.65(s,1H),7.25(d,J＝7.6Hz,2H),7.12–7.07(m,2H),7.00(t,J＝8.0Hz,3H),6.85–6.80(m,3H),6.71–6.66(m,2H),6.53(d,J＝8.0Hz,1H),6.46(d,J＝15.8Hz,1H),4.59(d,J＝12.0Hz,1H),4.49(d,J＝12.0Hz,1H),4.45(brs,1H).13C NMR(100MHz,CDCl3):δ196.1,155.2,153.5,134.4,133.2,128.9,128.7,128.4,128.2,128.1,128.0,127.9,126.7,126.0,123.1,122.3,122.1,122.0,117.8,110.0,70.1,62.5,61.1.IR(thin film)3365,2924,2846,1705,1603,1480,1262,1105,794cm-1；HRMS(ESI)m/z calcd for C25H19F3NO2[M+H]+:422.1368,found:422.1347.
2 af: solid, 48mg, 62% yield; mp 67-68 ℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.17(d,J＝9.2Hz,1H),7.10–7.04(m,3H),6.90–6.81(m,3H),6.84(d,J＝9.2Hz,2H),6.77–6.75(m,3H),6.64(d,J＝8.0Hz,1H),6.40(d,J＝15.6Hz,1H),4.67(d,J＝12.4Hz,1H),4.30(brs,1H),4.27(d,J＝12.4Hz,1H),3.71(s,1H).13C NMR(100MHz,CDCl3):δ196.9,159.8,154.2,149.8,143.3,137.1,132.6,130.1,129.6,129.4,129.0,127.4,124.6,122.6,122.2,120.4,119.4,117.7,113.9,112.0,110.8,69.9,63.0,61.6,55.2.IR(thin film)3364,3002,2931,1705,1600,1481,1263,1105,796cm-1；HRMS(ESI)m/z calcd for C25H22NO3[M+H]+:384.1600,found:384.1605.
2 ag: solid, 56mg, 65% yield; mp 56-57 ℃.1H NMR(400MHz,CDCl3):δ9.49(s,1H),7.44(s,1H),7.31(d,J＝7.6Hz,1H),7.21–7.18(m,2H),7.12–7.05(m,4H),6.91(t,J＝7.2Hz,1H),6.85(d,J＝16.0Hz,1H),6.79–6.75(m,2H),6.65(d,J＝7.6Hz,1H),6.41(d,J＝15.6Hz,1H),4.67(d,J＝12.4Hz,1H),4.35(brs,1H),4.30(d,J＝12.8Hz,1H).13C NMR(100MHz,CDCl3):δ196.9,154.2,149.7,137.9,131.2,131.0,130.8,130.2,130.1,129.6,129.1,127.3,126.5,125.4,124.7 122.8,122.6,122.2,120.5,117.8,110.9,69.8,63.0,61.7.IR(thin film)3368,2925,2854,1709,1606,1483,1261,1022,752cm-1；HRMS(ESI)m/z calcd for C24H19BrNO2[M+H]+:432.0599,found:432.0583.
2 ah: solid, 52mg, 60% yield; mp 54-55 ℃.1H NMR(400MHz,CDCl3):δ9.46(s,1H),7.49(d,J＝7.6Hz,1H),7.34(d,J＝7.6Hz,1H),7.28(d,J＝15.6Hz,1H),7.18–7.13(m,2H),7.09–7.02(m,4H),6.92–6.89(m,1H),6.79(t,J＝7.6Hz,2H),6.67(d,J＝8.0Hz,1H),6.29(d,J＝16.0Hz,1H),4.69(d,J＝12.4Hz,1H),4.35(brs,1H),4.31(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ197.1,154.2,149.9,136.2,132.8,132.2,131.8,130.2,129.4,129.1,127.5,127.4,127.3,126.6,124.6,123.9,122.6,122.2,120.4,117.7,110.9,69.9,63.0,61.5.IR(thin film)3360,2923,2852,1703,1609,1465,1259,741cm-1；HRMS(ESI)m/z calcd for C24H19BrNO2[M+H]+:432.0599,found:432.0583.
2 ai: solid, 38mg, 55% yield; mp 59-60 ℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.27–7.24(m,1H),7.11–7.04(m,4H),6.90–6.86(m,1H),6.78–6.74(m,2H),6.69–6.61(m,2H),6.37(d,J＝15.6Hz,1H),6.31–6.28(m,1H),6.21(m,1H),4.65(d,J＝12.4Hz,1H),4.28(brs,1H),4.25(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ196.8,154.3,151.5,149.8,142.5,130.1,129.0,127.6,127.4,126.7,124.7,122.7,122.1,121.0,120.4,117.6,111.4,110.8,109.5,69.8,63.0,61.7.IR(thin film)3364,2924,2853,1714,1604,1261,1016,752cm-1；HRMS(ESI)m/z calcd for C22H18NO3[M+H]+:344.1287,found:344.1275.
2 aj: solid, 24mg, 46% yield; mp 123-.1H NMR(400MHz,CDCl3):δ9.65(s,1H),7.26(d,J＝7.2Hz,1H),7.08–7.02(m,3H),6.93(d,J＝7.2Hz,1H),6.76(dd,J＝13.6Hz,7.6Hz,2H),6.58(d,J＝7.6Hz,1H),4.49(d,J＝12.4Hz,1H),4.30(brs,1H),4.26(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ198.7,153.5,149.8,129.9,129.4,128.7,125.6,124.8,123.4,121.9,120.0,117.5,110.7,65.5,62.7,60.9,24.5.IR(thin film)3365,3072,2952,1707,1606,1251,1094,804cm-1；HRMS(ESI)m/z calcd for C17H16NO2[M+H]+:266.1181,found:266.1208.
2 ak: solid, 25mg, 44% yield; mp 138-139℃.1H NMR(400MHz,CDCl3):δ7.25(d,J＝7.6Hz,1H),7.05–6.98(m,3H),6.89(t,J＝7.2Hz,1H),6.76–6.72(m,1H),6.65(d,J＝8.0Hz,1H),6.53(d,J＝7.6Hz,1H),4.53(d,J＝12.4Hz,1H),4.26(d,J＝12.8Hz,1H),4.23(brs,1H),2.00(s,3H),1.60(s,3H).13C NMR(100MHz,CDCl3):δ209.1,153.7,150.1,130.0,129.3,128.3,127.2,125.7,123.9,121.7,120.1,117.3,110.9,66.1,64.1,62.7,28.7,24.3.IR(thin film)3434,3013,2925,1697,1607,1464,1093,755,630cm-1；HRMS(ESI)m/z calcd for C18H18NO2[M+H]+:280.1338,found:280.1325.
2 al: solid, 57mg, 66% yield; mp 208-.1H NMR(400MHz,CDCl3):δ7.24–7.08(m,9H),7.06(dd,J＝17.6Hz,8.0Hz,5H),6.87–6.83(m,1H),6.77–6.72(m,2H),6.60–6.56(m,2H),6.31(d,J＝16.0Hz,1H),4.72(d,J＝12.0Hz,1H),4.60(d,J＝12.0Hz,1H),4.07(brs,1H).13C NMR(100MHz,CDCl3):δ201.9,154.7,150.5,139.7,136.1,131.5,131.4,129.7,129.0,128.6,128.5,128.4,127.9,127.8,127.5,127.4,126.8,126.6,124.6,122.1,120.4,117.7,111.1,70.9,67.1,64.6.IR(thin film)3329,2924,2852,1651,1484,1238,744cm-1；HRMS(ESI)m/z calcd for C30H24NO2[M+H]+:430.1807,found:430.1803.
2 am: solid, 39mg, 52% yield; mp 110-.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.31–7.18(m,5H),7.10(dd,J＝18.4Hz,7.6Hz,2H),6.91(d,J＝16.0Hz,1H),6.81–6.71(m,4H),6.67(d,J＝7.6Hz,1H),6.37(d,J＝15.6Hz,1H),4.66(d,J＝12.4Hz,1H),4.28(brs,1H),4.25(d,J＝12.0Hz,1H).13C NMR(100MHz,CDCl3):δ196.7,158.9(d,J＝239.1Hz),150.4,149.6,135.5,133.1,130.2,128.8,128.7,128.4,128.1(d,J＝5.8Hz),126.8,124.6,122.4,120.5,119.1(d,J＝8Hz),116.4(d,J＝23.3Hz),113.2(d,J＝23.3Hz),110.8,70.0,63.3,61.4.IR(thin film)3363,2936,2867,1704,1602,1481,1267,1083,797cm-1；HRMS(ESI)m/z calcd for C24H19FNO2[M+H]+:372.1400,found:372.1395.
2 an: solid, 26mg, 38% yield; mp 59-60 ℃.1H NMR(400MHz,CDCl3):δ9.61(s,1H),7.11–7.01(m,4H),6.77–6.73(m,1H),6.58(d,J＝8.0Hz,1H),4.50(d,J＝12.4Hz,1H),4.25(brs,1H),4.21(d,J＝12.4,1H),1.67(s,3H).13C NMR(100MHz,CDCl3):δ198.2,154.4,149.6,130.1,127.9,127.0,125.1,124.8,123.1,121.6,120.6,120.3,110.7,65.4,62.8,60.7,24.3.IR(thin film)3350,2925,1709,1597,1261,1034,832cm-1；HRMS(ESI)m/z calcd for C17H15BrNO2[M+H]+:344.0286,found:344.0274.
2 ao: solid, 28mg, 48% yield; mp 187-.1H NMR(400MHz,CDCl3):δ9.64(s,1H),7.08–7.01(m,2H),6.96(s,1H),6.75–6.71(m,1H),6.58(d,J＝8.0Hz,1H),6.50(s,1H),4.46(d,J＝12.4Hz,1H),4.26(brs,1H),4.21(d,J＝12.0,1H),2.12(s,3H),2.07(s,3H),1.67(s,3H).13C NMR(100MHz,CDCl3):δ198.9,151.4,149.9,137.5,130.1,129.8,126.1,125.7,124.8,123.7,120.0,118.1,110.7,65.4,62.8,61.1,24.6,19.4,19.1.IR(thin film)3368,3021,2924,1717,1604,1463,1261,1094,803cm-1；HRMS(ESI)m/z calcd for C19H20NO2[M+H]+:294.1494,found:294.1475.
2 ap: solid, 26mg, 51% yield; mp 100-.1H NMR(400MHz,CDCl3):δ9.62(s,1H),7.25(d,J＝7.2Hz,1H),7.09–7.03(m,3H),6.95(d,J＝7.2Hz,1H),6.78(dd,J＝13.2Hz,7.2Hz,2H),6.50(d,J＝7.6Hz,1H),4.49(d,J＝12.4Hz,1H),4.30(brs,1H),4.26(d,J＝12.4Hz,1H),4.01(s,1H).13C NMR(100MHz,CDCl3):δ198.5,152.3,148.8,129.3,129.4,128.5,125.4,124.7,123.1,121.2,120.1,117.5,110.4,65.2,62.7,60.5.IR(thin film)3363,2951,2829,1708,1605,1250,1084,802cm-1；HRMS(ESI)m/z calcd for C16H14NO2[M+H]+:252.1025,found:252.1006.
2 aq: solid, 25mg, 50% yield; mp 103 and 104 ℃.1H NMR(400MHz,CDCl3):δ9.62(s,1H),7.24(d,J＝7.2Hz,1H),7.08–7.02(m,2H),6.92(d,J＝7.2Hz,2H),6.75(dd,J＝13.6Hz,7.6Hz,2H),6.53(d,J＝7.6Hz,1H),4.45(d,J＝12.4Hz,1H),4.33(brs,2H),4.26(d,J＝12.4Hz,1H),4.10(s,1H).13C NMR(100MHz,CDCl3):δ198.3,153.4,149.8,129.3,129.2,128.5,125.6,124.6,123.1,121.7,121.0,117.0,110.7,65.4,62.7,60.6.IR(thin film)3360,2959,2826,1706,1604,1240,1054,801cm-1；HRMS(ESI)m/z calcd for C16H15NO2[M+H]+:251.1184,found:251.1172.
2 ar: solid, 23mg, 43% yield; mp 123-.1H NMR(400MHz,CDCl3):δ9.61(s,1H),7.27(d,J＝7.4Hz,1H),7.07–7.03(m,3H),6.92(d,J＝7.2Hz,1H),6.74(dd,J＝13.6Hz,7.6Hz,2H),6.50(d,J＝7.6Hz,1H),4.32(brs,1H),4.17(s,1H),3.91–3.84(m,2H),2.46–2.37(m,2H).13C NMR(100MHz,CDCl3):δ197.9,153.2,149.7,129.7,129.4,128.0,125.8,124.7,123.4,121.9,120.6,117.1,110.0,65.4,62.7,60.8,30.6.IR(thin film)3360,3014,2950,2822,1705,1603,1254,1074,793cm-1；HRMS(ESI)m/z calcd for C17H16NO2[M+H]+:266.1181,found:266.1172.
2 as: solid, 22mg, 39% yield; mp 133-.1H NMR(400MHz,CDCl3):δ9.65(s,1H),7.27(d,J＝7.2Hz,1H),7.04–7.01(m,2H),6.91(d,J＝7.2Hz,2H),6.73(dd,J＝13.6Hz,7.6Hz,2H),6.54(d,J＝7.6Hz,1H),4.31(brs,1H),4.16(s,1H),3.90–3.81(m,2H),2.43–2.35(m,2H),2.00–1.89(m,2H).13C NMR(100MHz,CDCl3):δ197.8,153.2,149.2,129.8,129.4,128.7,125.7,124.0,123.4,121.8,120.6,117.0,110.2,65.6,62.4,60.1,30.6,28.5.IR(thin film)3361,3021,2941,2824,1706,1602,1250,1074,797cm-1；HRMS(ESI)m/z calcd for C18H18NO2[M+H]+:280.1338,found:280.1324.
Example 2
The 2, 3-condensed ring indoline derivative provided by the invention is synthesized according to the following synthetic route.
2ba:R1＝4-Br,R2＝PhCH＝CH,R3＝4-Br,R4＝H,n＝1；
2bb:R1＝4-Br,R2＝PhCH＝CH,R3＝3-Br,R4＝H,n＝1；
2bc:R1＝4-Br,R2＝(3-Br)C6H4CH＝CH,R3＝4-Cl,R4＝H,n＝1；
2bd:R1＝4-Br,R2＝(4-Me)C6H4CH＝CH,R3＝4-Cl,R4＝Me,n＝1；
2be:R1＝3-Cl,R2＝Me,R3＝4-Me,R4＝H,n＝1；
2bf:R1＝4-Br,R2＝Me,R3＝4-Me,R4＝4-ClC6H4,n＝1；
2bg:R1＝3-Cl,R2＝Me,R3＝4-Me,R4＝Me,n＝1；
2bh:R1＝4-Br,R2＝H,R3＝4-Br,R4＝H,n＝1；
2bi:R1＝4-Br,R2＝H,R3＝3-Cl,R4＝Me,n＝2；
2bj:R1＝4-Br,R2＝Me,R3＝4-Br,R4＝Me,n＝1,X＝N。
Putting the N-aryl alpha, beta-unsaturated nitrone substrate 1(0.2mmol) into a reaction tube, adding 2mL of organic solvent (wherein the organic solvents adopted by the target 2ba-2bd are acetone, chloroform, N-hexane and dioxane respectively, and the organic solvents adopted by the target 2be-2bj are carbon tetrachloride), stirring and reacting for 10-36h at 25 ℃, removing the solvent from the obtained reactant under reduced pressure, and separating the residue by silica gel column chromatography (the petroleum ether/ethyl acetate ratio is 50: 1-10: 1, volume ratio) to obtain the target product 2. The different target products and their characterization were as follows:
2ba solid, 64mg, 63% yield; mp 89-90 ℃.1H NMR(400MHz,CDCl3):δ9.45(s,1H),7.49(d,J＝7.6Hz,1H),7.34(d,J＝7.6Hz,1H),7.28(d,J＝15.6Hz,1H),7.18–7.13(m,2H),7.09–7.02(m,3H),6.92(s,1H),6.79(t,J＝7.6Hz,2H),6.67(d,J＝8.0Hz,1H),6.29(d,J＝16.0Hz,1H),4.69(d,J＝12.4Hz,1H),4.35(brs,1H),4.31(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ197.0,153.2,149.8,136.1,132.7,132.1,131.7,130.0,129.2,129.1,127.6,127.3,126.4,124.5,122.4,122.2,120.3,117.6,110.8,69.8,63.1,61.4.IR(thin film)3361,2920,2851,1703,1600,1461,1259,740cm-1；HRMS(ESI)m/z calcd for C24H18Br2NO2[M+H]+:509.9704,found:509.9702.
2bb solid, 63mg, 61% yield; mp 93-94 ℃ C.1H NMR (400MHz, CDCl)3):δ9.46(s,1H),7.48(d,J＝7.6Hz,1H),7.35(d,J＝7.6Hz,1H),7.29(d,J＝15.6Hz,1H),7.18–7.15(m,2H),7.08–7.01(m,3H),6.90(s,1H),6.80(t,J＝7.6Hz,2H),6.65(d,J＝8.0Hz,1H),6.30(d,J＝16.0Hz,1H),4.68(d,J＝12.4Hz,1H),4.34(brs,1H),4.30(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ197.1,154.2,149.7,136.3,132.6,132.2,131.7,129.4,129.0,127.5,127.4,126.3,124.4,123.3,122.5,122.3,120.3,117.6,110.7,69.6,63.0,61.3.IR(thin film)3359,2922,2854,1702,1604,1460,1258,741cm-1；HRMS(ESI)m/z calcd for C24H18Br2NO2[M+H]+:509.9704,found:509.9711.
2bc, solid, 50mg, 46% yield; mp 95-96 ℃.1H NMR(400MHz,CDCl3):δ9.46(s,1H),7.49(d,J＝7.6Hz,1H),7.36(d,J＝7.6Hz,1H),7.29(d,J＝15.6Hz,1H),7.18–7.16(m,2H),7.08–7.03(m,2H),6.93(s,1H),6.82(t,J＝7.6Hz,2H),6.64(d,J＝8.0Hz,1H),6.31(d,J＝16.0Hz,1H),4.67(d,J＝12.4Hz,1H),4.33(brs,1H),4.31(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ197.2,154.2,149.4,136.3,132.5,132.4,131.6,130.0,129.4,129.1,127.3,127.2,127.0,126.3,125.4,122.9,122.6,122.2,120.1,117.5,110.7,69.5,63.1,61.3.IR(thin film)3359,2923,2853,1700,1603,1462,1257,742cm-1；HRMS(ESI)m/z calcd for C24H17Br2ClNO2[M+H]+:543.9315,found:543.9327.
2bd, solid, 45mg, 45% yield; mp 80-81 ℃.1H NMR(400MHz,CDCl3):δ7.49(d,J＝7.6Hz,1H),7.35(d,J＝7.6Hz,1H),7.28(d,J＝15.6Hz,1H),7.19–7.16(m,2H),7.07–7.03(m,2H),6.95(s,1H),6.84(t,J＝7.6Hz,2H),6.67(d,J＝8.0Hz,1H),6.30(d,J＝16.0Hz,1H),4.66(d,J＝12.4Hz,1H),4.35(brs,1H),4.30(d,J＝12.4Hz,1H),2.32(s,3H),2.14(s,3H).13C NMR(100MHz,CDCl3):δ197.1,153.2,148.4,137.3,132.6,132.3,131.5,130.1,129.2,129.0,128.1,127.5,127.0,126.2,125.4,123.1,122.8,122.5,121.4,117.4,110.3,69.4,63.0,61.2,27.5,21.3.IR(thin film)3362,2922,2851,1705,1601,1460,1256,743cm-1；HRMS(ESI)m/z calcd for C26H22BrClNO2[M+H]+:494.0522,found:494.0534.
2be solid, 40mg, 56% yield; mp 85-86 ℃.1H NMR(400MHz,CDCl3):δ9.64(s,1H),7.08–7.01(m,2H),6.96(s,1H),6.75–6.71(m,1H),6.58(d,J＝8.0Hz,1H),6.50(s,1H),4.46(d,J＝12.4Hz,1H),4.26(brs,1H),4.21(d,J＝12.0,1H),2.07(s,3H),1.67(s,3H).13C NMR(100MHz,CDCl3):δ198.9,151.4,149.9,137.5,130.1,129.8,126.1,125.7,124.8,123.7,120.0,118.1,110.7,65.4,62.8,61.1,24.6,19.1.IR(thin film)3368,3021,2924,1717,1604,1463,1261,1094,803cm-1；HRMS(ESI)m/z calcd for C18H17NO2[M+H]+:358.0443,found:358.0421.
2bf solid, 47mg, 51% yield; mp 110-111℃.1H NMR(400MHz,CDCl3):δ7.07–7.02(m,3H),6.95(s,1H),6.74–6.71(m,3H),6.78(d,J＝8.0Hz,1H),6.57(d,J＝8.0Hz,1H),6.51(s,1H),4.44(d,J＝12.4Hz,1H),4.25(brs,1H),4.20(d,J＝12.0,1H),2.02(s,3H),1.65(s,3H).13C NMR(100MHz,CDCl3):δ200.1,151.4,149.9,137.5,136.2,134.2,132.6,130.1,129.8,126.1,125.7,124.8,123.7,122.6,120.0,118.1,110.7,65.4,62.8,61.1,24.6,19.1.IR(thin film)3363,3020,2922,1715,1600,1461,1262,1093,801cm-1；HRMS(ESI)m/z calcd for C24H20BrClNO2[M+H]+:468.0366,found:468.0352.
2bg solid, 39mg, 60% yield; mp 117-.1H NMR(400MHz,CDCl3):δ7.09–7.00(m,2H),6.97(s,1H),6.75–6.71(m,1H),6.59(d,J＝8.0Hz,1H),6.52(s,1H),4.45(d,J＝12.4Hz,1H),4.27(brs,1H),4.20(d,J＝12.0,1H),2.13(s,3H),2.07(s,3H),1.66(s,3H).13C NMR(100MHz,CDCl3):δ206.1,151.3,149.8,137.4,132.1,129.7,128.1,125.3,124.2,123.5,120.1,118.0,110.2,65.1,62.6,61.0,24.6,24.4,19.1.IR(thin film)3366,3020,2923,1714,1600,1461,1260,1092,802cm-1；HRMS(ESI)m/z calcd for C19H19ClNO2[M+H]+:328.1104,found:328.1123.
2bh is solid, 50mg, 62% yield; mp 120-.1H NMR(400MHz,CDCl3):δ9.62(s,1H),7.23(d,J＝7.2Hz,1H),7.07–7.02(m,2H),6.96(d,J＝7.2Hz,1H),6.76(d,J＝7.2Hz,1H),6.52(d,J＝7.6Hz,1H),4.49(d,J＝12.4Hz,1H),4.31(brs,1H),4.25(d,J＝12.4Hz,1H),4.00(s,1H).13C NMR(100MHz,CDCl3):δ198.9,152.1,148.7,129.7,129.2,128.7,125.5,124.6,123.0,121.3,120.0,117.4,110.3,65.1,62.8,60.4.IR(thin film)3360,2952,2828,1706,1604,1251,1083,800cm-1；HRMS(ESI)m/z calcd for C16H12BrNO2[M+H]+:407.9235,found:407.9221.
2bi, solid, 40mg, 51% yield; mp 120-.1H NMR(400MHz,CDCl3):δ7.25(d,J＝7.4Hz,1H),7.07–7.02(m,1H),6.91(d,J＝7.2Hz,1H),6.72(d,J＝7.6Hz,2H),6.53(d,J＝7.6Hz,1H),4.33(brs,1H),4.15(s,1H),3.92–3.81(m,2H),2.45–2.39(m,2H).13C NMR(100MHz,CDCl3):δ197.8,153.0,149.5,129.6,129.3,128.1,125.3,124.8,123.2,121.0,120.7,117.3,110.1,65.3,63.7,60.2,30.5.IR(thin film)3359,3015,2952,2821,1704,1602,1250,1071,792cm-1；HRMS(ESI)m/z calcd for C18H16BrClNO2[M+H]+:392.0053,found:392.0042.
2bj solid, 51mg, 57% yield; mp 121-.1H NMR(400MHz,CDCl3):δ7.09–7.03(m,2H),6.95(s,1H),6.74–6.71(m,1H),6.57(d,J＝8.0Hz,1H),6.52(s,1H),4.43(d,J＝12.4Hz,1H),4.26(brs,1H),4.21(d,J＝12.0,1H),2.12(s,3H),2.04(s,3H),1.65(s,3H).13C NMR(100MHz,CDCl3):δ206.2,151.1,149.5,137.3,132.0,129.4,128.9,125.2,124.1,123.2,120.0,118.2,110.1,65.0,62.7,61.9,24.3,24.1,19.9.IR(thin film)3368,3021,2920,1716,1605,1462,1263,1094,801cm-1；HRMS(ESI)m/z calcd for C19H19Br2N2O[M+H]+:448.9864,found:448.9862.
Experimental example 1: the 2, 3-condensed ring indoline derivative of the invention is used for carrying out in vitro inhibitory activity experiments on various human tumor strains:
(1) cell culture: MGC-803, HepG-2, NCI-H460 and SKOV3, T24, 7702 cells were cultured in DMEM medium containing 10% (by volume) fetal calf serum and 1% (by volume) diabesin (containing penicillin and streptomycin) at 37 deg.C with 5% CO2And culturing in 95% air incubator, and changing culture medium every other day. And (5) carrying out passage after the cells grow full, and freezing and storing.
(2) Plate preparation: taking the cells in logarithmic growth phase, removing the old culture medium, washing twice by PBS, digesting the cells by trypsin, adding a new culture medium after the cells become round to stop cell digestion and blowing suspension cells to prepare single cell suspension. Taking a proper amount of cell suspension, adding a certain amount of culture medium for dilution, and inoculating the cell suspension into a 96-well plate, wherein each well contains 180 mu L of cells, and the number of the cells in each well is 20000-40000.
(3) Adding medicine: the sample to be tested was added to a 96-well plate seeded with tumor cells at 20. mu.L per well to give a final concentration of 10. mu.M, and primary screening was performed. And (4) setting different concentration gradients for the compounds according to the result of primary screening, and setting 5 compound holes in each group. Adding compound and then releasing CO2Culturing in incubator for 48 hr, adding 10 μ L of prepared MTT solution into each well, and discharging CO2And continuously culturing for 4-6 h in the incubator.
(4) And (3) testing: and (3) absorbing the culture medium in a 96-well plate, adding 100 mu L of DMSO, and shaking on a shaking table for 5-10 min to completely dissolve the crystallized formazan. The absorbance (OD) was measured at an absorption wavelength of 570nm and a reference wavelength of 630nm using a microplate reader, and the inhibition ratio was calculated. Inhibition rate (1-sample group OD value/blank group OD value) × 100%, and IC of each compound for different tumor cell lines was calculated by SPSS software50The value is obtained. The test results are shown in table 1 below:
table 1:
Claims (6)
1. a method for synthesizing a compound represented by the following formula (I): the method mainly comprises the following steps: putting a compound shown as a formula (II) in an organic solvent, and reacting in the presence of oxygen to obtain a target crude product;
x represents an oxygen atom, n is 1, R1、R2、R3And R4Is defined as one of the following options:
R1、R3and R4All represent hydrogen, R2Represents (4-methoxy) phenylvinylene; or is
R1、R3And R4All represent hydrogen, R2Represents a (2-furyl) vinylene group; or is
R1And R3All represent hydrogen, R2Represents a phenylvinylene group, R4Represents a phenyl group; or is
R1And R3All represent 4-bromo, R2Represents a phenylvinylene group, R4Represents hydrogen.
2. The method of synthesis according to claim 1, characterized in that: the organic solvent is one or more of benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, trichloromethane, n-hexane and dioxane.
3. The method of synthesis according to claim 1, characterized in that: the reaction is carried out at a temperature below 100 ℃.
4. The method of synthesis according to claim 1, characterized in that: the reaction is carried out at a temperature below 80 ℃.
5. The synthesis method according to any one of claims 1 to 4, wherein: further comprises a purification step: specifically, the prepared crude target product is subjected to silica gel thin-layer chromatography, silica gel column chromatography or recrystallization to obtain the purified target product.
6. The method of synthesis according to claim 5, characterized in that: the eluent for silica gel thin layer chromatography or silica gel column chromatography is the same as the solvent for recrystallization, and is a mixed solvent composed of petroleum ether or n-hexane and ethyl acetate.
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| WO1994014777A1 (en) * | 1992-12-28 | 1994-07-07 | Eisai Co., Ltd. | Heterocyclic carbonic acid derivatives which bind to retinoid receptors (rar) |
| CN106432043A (en) * | 2016-09-26 | 2017-02-22 | 广西师范大学 | 2,3-indolinone-3-N-alkenylnitrone cycloaddition derivative and synthesis method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994014777A1 (en) * | 1992-12-28 | 1994-07-07 | Eisai Co., Ltd. | Heterocyclic carbonic acid derivatives which bind to retinoid receptors (rar) |
| CN106432043A (en) * | 2016-09-26 | 2017-02-22 | 广西师范大学 | 2,3-indolinone-3-N-alkenylnitrone cycloaddition derivative and synthesis method and application thereof |
Non-Patent Citations (4)
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| "Catalytic Enantioselective Synthesis of β-Lactams: Intramolecular Kinugasa Reactions and Interception of an Intermediate in the Reaction Cascade";Ryo Shintani et al.;《Angew. Chem. Int. Ed.》;20031231;第42卷;第4082-4085页 * |
| "Complex Bioactive Alkaloid-Type Polycycles through Efficient Catalytic Asymmetric Multicomponent Aza-Diels–Alder Reaction of Indoles with Oxetane as Directing Group";Zhilong Chen et al.;《Angew. Chem. Int. Ed.》;20130109;第52卷;第2027-2031页 * |
| "Construction of 2,3-quaternary fused indolines from alkynyl tethered oximes and diaryliodonium salts through a cascade strategy of N-arylation/cycloaddition/[3,3]-rearrangement";Xiao-Pan Ma et al.;《Green Chemistry》;20171031;第19卷(第24期);第5761-5766页 * |
| "Synthesis of chromenoindole derivatives from Robinia pseudoacacia";Lisa Dejon et al.;《MedChemComm》;20131008;第4卷(第12期);第1580-1583页 * |
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| CN109232591A (en) | 2019-01-18 |
| CN107266458B (en) | 2019-05-10 |
| CN109485651A (en) | 2019-03-19 |
| CN109485651B (en) | 2021-02-02 |
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