4’-三氟甲基-3,2’-吡咯烷基双螺环氧化吲哚化合物的合成与表征
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摘要
对具有高生物活性的4’-三氟甲基-3,2’-吡咯烷基双螺环氧化吲哚及其衍生物进行了探索合成。在有机小分子碱三乙胺催化作用下,由3-异硫氰基氧化吲哚与3-三氟亚乙基羟吲哚在二氯甲烷(DCM)溶剂中于室温下发生3+2环合加成反应,高产率(85%~96%)获得4’-三氟甲基-3,2’-吡咯烷基双螺环氧化吲哚。通过核磁共振氢谱和碳谱、高分辨质谱等手段对已合成的产物进行表征。这一合成方法具有简单,高效,环保的特点。
The synthesis of 4'-trifluoromethyl-substituted 3,3'-pyrrolidinyl-dispirooxindoles and its derivatives with high biological activity was explored. Under the catalysis of organic triethylamine, 3-isothiocyanato oxindoles reacted with 3-trifluoroethylidene oxindoles in dichloromethane(DCM) at room temperature, A 3+2 cyclization addition reaction was carried out to obtain a high yield(85%~96%) of 4'-trifluoromethyl-substituted 3,3'-pyrrolidinyl-dispirooxindoles. The synthesized products were characterized by 1 H-NMR, 19 F-NMR, 13 C-NMR and high-resolution mass spectrometry. This synthetic method is simple, efficient and environmentally friendly.
The synthesis of 4'-trifluoromethyl-substituted 3,3'-pyrrolidinyl-dispirooxindoles and its derivatives with high biological activity was explored. Under the catalysis of organic triethylamine, 3-isothiocyanato oxindoles reacted with 3-trifluoroethylidene oxindoles in dichloromethane(DCM) at room temperature, A 3+2 cyclization addition reaction was carried out to obtain a high yield(85%~96%) of 4'-trifluoromethyl-substituted 3,3'-pyrrolidinyl-dispirooxindoles. The synthesized products were characterized by 1 H-NMR, 19 F-NMR, 13 C-NMR and high-resolution mass spectrometry. This synthetic method is simple, efficient and environmentally friendly.
引文
[1]Klaus M,Christoph F,Fran?ois D.Fluorine in pharmaceuticals:Looking beyond intuition[J].Science,2007,317(5846):1881-1886.
[2]Badillo J J,Hanhan N V,Franz A K.Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery[J].Curr.Opin.Drug.Disc.,2010,13(21):758-776.
[3]Yu B,Yu D Q,Liu H M.Spirooxindoles:Promising scaffolds for anticancer agents[J].Eur.J.Med.Chem.,2015,97(1):673-698.
[4]Rottmann M.Spiroindolones,a potent compound class for the treatment of malaria[J].Science.,2010,329(5996):1175-1180.
[5]朱文润,邓晓怡,魏江存,等.3-二氢吡咯烷基螺环氧化吲哚及其衍生物的合成与表征[J].井冈山大学学报:自然科学版,2018,39(1):32-36..
[6]李术艳,沈淑君.2-烯-1,4-二酮及其衍物的合成及晶体结构[J].井冈山大学学报:自然科学版,2017,38(2):35-39.
[7]Shangary S,Qin D,Mc Eachern D,et al.Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition[J].Proc.Natl.Acad.Sci.USA.,2008,105(10):3933-3938.
[8]Zhao Y,Liu L,Sun W,et al.Diastereomeric spirooxindoles as highly potent and efficacious MDM2inhibitors[J].J.Am.Chem.Soc.,2013,135(19):7223-7234.
[9]Sun Q T,Li X Y,Su J H,et al.The squaramide-catalyzed 1,3-Dipolar cycloaddition of nitroalkenes with N-2,2,2-Trifluoroethylisatin ketimines:An approach for the Synthesis of5’-Trifluoromethyl-spiro[pyrrolidin-3,2’-oxindoles][J].Advanced Synthesis&Catalysis,2015,357(14):3187-3196.
[10]Ma M X,Zhu Y Y,Sun Q T,et al.The asymmetric synthesis of CF3-containing spiro[pyrrolidin-3,2’-oxindole]through the organo-catalytic 1,3-dipolar cycloaddition reaction[J].Chem.Commun.,2015,51(42):8789-8792.
[11]龙先文,黄伟杰,朱文润,等.有机小分子催化构建氧化吲哚C(3)位螺环化合物的研究进展[J].化学试剂,2017,(02):148-156+174.
[12]Huang W J,Chen C,Lin N,et al.Asymmetric synthesis of trifluoromethyl-substituted 3,3’-pyrrolidinyl-dispirooxindoles through organocatalytic1,3-dipolar cycloaddition reactions[J].Org.Chem.Front.,2017,4(3):472-482.
[13]Zhao J Q,Wu Z J,Zhou M Q,et al.Zn-catalyzed diastereo-and enantioselective cascade reaction of3-Isothiocyanato oxindoles and 3-Nitroindoles:stereocontrolled syntheses of polycyclic Spirooxindoles[J].Org.Lett.,2015,17(20):5020-5023.
[14]Zhao Y L,Lou Q X,Wang L S,et al.organocatalytic friedel-crafts alkylation/lactonization reaction of naphthols with 3-Trifluoroethylidene oxindoles:The asymmetric Synthesis of Dihydrocoumarins[J].Angew.Chem.Int.Ed.,2017,56(1):338-342.
[15]Xiao M J,Xu D F,Liang W H,et al.Organocatalytic enantioselective friedel-crafts alkylation/lactonization reaction of hydroxyindoles with methylene oxindoles[J].Adv.Synth.Catal.,2018,360(5),917-924.
[16]Atsuko A,Takayoshi A.Catalytic asymmetric exo’-selective[3+2]cycloaddition for constructing stereochemically diversified spiro[pyrrolidin-3,3’-oxindole]s[J].Chem.Eur.J.2012,18(27):8278-8282.
[17]Wang L,Shi X M,Dong W P,et al.Efficient construction of highly function alized spiro[γ-butyrolactone-pyrrolidin-3,3’-oxindole]tricyclic skeletons via an organocatalytic 1,3-dipolar cycloaddition[J].Chem.Commun.,2013,49(33):3458-3460.
[18]Yang W L,Liu Y Z,Luo S,et al.The copper-catalyzed asymmetric construction of a dispiropyrrolidine skeleton via 1,3-dipolar cycloaddition of azomethine ylides to a-alkylidene succinimides[J].Chem.Commun.,2015,51(44):9212-9215.
[19]Wang Y M,Zhang H H,Li C,et al.Catalytic asymmetric chemoselective 1,3-dipolar cycloadditions of an azomethine ylide with isatin-derived imines:diastereo-and enantioselective construction of a spiro[imidazolidine-2,3’-oxindole]framework[J].Chem.Commun.,2016,52(9):1804-1807.
[20]Takayoshi A,Hiroki O,Atsuko A,et al.Py bidineCu(OTf)2-Catalyzed asymmetric[3+2]cycloaddition with imino esters:Harmony of Cu–Lewis acid and imidazolidine-nh hydrogen bonding in concerto catalysis[J].Angew.Chem.Int.Ed.2015,54(5):1595-1599.
[21]Arun Y,Bhaskar G,Balachandran C,et al.Facile one-pot synthesis of novel dispirooxindole-pyrrolidine derivatives and their antimicrobial and anticancer activity against A549 human lung adenocarcinoma cancer cell line[J].Bioorganic&Medicinal Chemistry Letters.,2013,23(6):1839-1845.
[22]Satavisha K,Santanu M.Catalytic enantioselective cascade Michael/cyclization reaction of3-isothiocyanato oxindoles with exocyclicα,β-unsaturated ketones en route to 3,2′-pyrrolidinyl bispirooxindoles[J].Org.Biomol.Chem.,2016,14(43):10175-10179.
[23]Wu C L,Jing L H,Qin D B,et al.Organocatalytic asymmetric synthesis of trans-configured trispirooxindoles through a cascade Michaelcyclization reaction[J].Tetrahedron Lett.,2016,57(26):2857-2860.
[24]Jiang X X,Cao Y M,Wang Y Q,et al.A unique approach to the concise synthesis of highly optically active spirooxazolines and the discovery of a more potent oxindole-type phytoalexin analogue[J].J.Am.Chem.Soc.2010,132(43):15328-15333.
[25]Chen W B,Wu Z J,Hu J,et al.Organocatalytic direct asymmetric aldol reactions of 3-isothiocyanato oxindoles to ketones:stereocontrolled synthesis of spirooxindoles bearing highly congested contiguous tetrasubstituted stereocenters[J].Org.Lett.,2011,13(9):2472-2475.
[26]Han Y Y,Chen W B,Han W Y,et al.Highly efficient and stereoselective construction of dispiro-[oxazolidine-2-thione]bisoxindoles and dispiro[imidazolidine-2-thione]bisoxindoles[J].Org.Lett.,2012,14(2):490-493.
[27]Satavisha K,Santanu M.Catalytic aldol-cyclization cascade of 3-isothiocyanato oxindoles withα-ketophosphonates for the enantioselective synthesis ofβ-Amino-α-hydroxyphosphonates[J].Org.Lett.2015,17(21):5508-5511.
[28]Chen W B,Han W Y,Han Y Y,et al.Highly efficient synthesis of spiro[oxazolidine-2-thione-oxindoles]with 3-isothiocyanato oxindoles and aldehydes via an organocatalytic cascade aldol-cyclization reaction[J].Tetrahedron.,2013,69(26):5281-5286.
[29]Shota K,Motomu K,Shigeki M.Catalytic asymmetric synthesis of spirooxindoles via addition of isothiocyanato oxindoles to aldehydes under dinuclear nickel schiff base catalysis[J].Chem.Asian J.,2013,8(8):1768-1771.
[30]Shota K,Tatsuhiko Y,Masakatsu S,et al.Catalytic asymmetric synthesis of spirooxindoles by a mannich-type reaction of isothiocyanato oxindoles[J].Angew.Chem.Int.Ed.,2012,51(28):7007-7010.
[31]Yuan X,Zhag S J,Du W,et al.Asymmetric diels–alder cycloadditions of trifluoromethylated dienophiles under trienamine catalysis[J].Chem.-Eur.J.,2016,22(31):11048-11052.
[2]Badillo J J,Hanhan N V,Franz A K.Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery[J].Curr.Opin.Drug.Disc.,2010,13(21):758-776.
[3]Yu B,Yu D Q,Liu H M.Spirooxindoles:Promising scaffolds for anticancer agents[J].Eur.J.Med.Chem.,2015,97(1):673-698.
[4]Rottmann M.Spiroindolones,a potent compound class for the treatment of malaria[J].Science.,2010,329(5996):1175-1180.
[5]朱文润,邓晓怡,魏江存,等.3-二氢吡咯烷基螺环氧化吲哚及其衍生物的合成与表征[J].井冈山大学学报:自然科学版,2018,39(1):32-36..
[6]李术艳,沈淑君.2-烯-1,4-二酮及其衍物的合成及晶体结构[J].井冈山大学学报:自然科学版,2017,38(2):35-39.
[7]Shangary S,Qin D,Mc Eachern D,et al.Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition[J].Proc.Natl.Acad.Sci.USA.,2008,105(10):3933-3938.
[8]Zhao Y,Liu L,Sun W,et al.Diastereomeric spirooxindoles as highly potent and efficacious MDM2inhibitors[J].J.Am.Chem.Soc.,2013,135(19):7223-7234.
[9]Sun Q T,Li X Y,Su J H,et al.The squaramide-catalyzed 1,3-Dipolar cycloaddition of nitroalkenes with N-2,2,2-Trifluoroethylisatin ketimines:An approach for the Synthesis of5’-Trifluoromethyl-spiro[pyrrolidin-3,2’-oxindoles][J].Advanced Synthesis&Catalysis,2015,357(14):3187-3196.
[10]Ma M X,Zhu Y Y,Sun Q T,et al.The asymmetric synthesis of CF3-containing spiro[pyrrolidin-3,2’-oxindole]through the organo-catalytic 1,3-dipolar cycloaddition reaction[J].Chem.Commun.,2015,51(42):8789-8792.
[11]龙先文,黄伟杰,朱文润,等.有机小分子催化构建氧化吲哚C(3)位螺环化合物的研究进展[J].化学试剂,2017,(02):148-156+174.
[12]Huang W J,Chen C,Lin N,et al.Asymmetric synthesis of trifluoromethyl-substituted 3,3’-pyrrolidinyl-dispirooxindoles through organocatalytic1,3-dipolar cycloaddition reactions[J].Org.Chem.Front.,2017,4(3):472-482.
[13]Zhao J Q,Wu Z J,Zhou M Q,et al.Zn-catalyzed diastereo-and enantioselective cascade reaction of3-Isothiocyanato oxindoles and 3-Nitroindoles:stereocontrolled syntheses of polycyclic Spirooxindoles[J].Org.Lett.,2015,17(20):5020-5023.
[14]Zhao Y L,Lou Q X,Wang L S,et al.organocatalytic friedel-crafts alkylation/lactonization reaction of naphthols with 3-Trifluoroethylidene oxindoles:The asymmetric Synthesis of Dihydrocoumarins[J].Angew.Chem.Int.Ed.,2017,56(1):338-342.
[15]Xiao M J,Xu D F,Liang W H,et al.Organocatalytic enantioselective friedel-crafts alkylation/lactonization reaction of hydroxyindoles with methylene oxindoles[J].Adv.Synth.Catal.,2018,360(5),917-924.
[16]Atsuko A,Takayoshi A.Catalytic asymmetric exo’-selective[3+2]cycloaddition for constructing stereochemically diversified spiro[pyrrolidin-3,3’-oxindole]s[J].Chem.Eur.J.2012,18(27):8278-8282.
[17]Wang L,Shi X M,Dong W P,et al.Efficient construction of highly function alized spiro[γ-butyrolactone-pyrrolidin-3,3’-oxindole]tricyclic skeletons via an organocatalytic 1,3-dipolar cycloaddition[J].Chem.Commun.,2013,49(33):3458-3460.
[18]Yang W L,Liu Y Z,Luo S,et al.The copper-catalyzed asymmetric construction of a dispiropyrrolidine skeleton via 1,3-dipolar cycloaddition of azomethine ylides to a-alkylidene succinimides[J].Chem.Commun.,2015,51(44):9212-9215.
[19]Wang Y M,Zhang H H,Li C,et al.Catalytic asymmetric chemoselective 1,3-dipolar cycloadditions of an azomethine ylide with isatin-derived imines:diastereo-and enantioselective construction of a spiro[imidazolidine-2,3’-oxindole]framework[J].Chem.Commun.,2016,52(9):1804-1807.
[20]Takayoshi A,Hiroki O,Atsuko A,et al.Py bidineCu(OTf)2-Catalyzed asymmetric[3+2]cycloaddition with imino esters:Harmony of Cu–Lewis acid and imidazolidine-nh hydrogen bonding in concerto catalysis[J].Angew.Chem.Int.Ed.2015,54(5):1595-1599.
[21]Arun Y,Bhaskar G,Balachandran C,et al.Facile one-pot synthesis of novel dispirooxindole-pyrrolidine derivatives and their antimicrobial and anticancer activity against A549 human lung adenocarcinoma cancer cell line[J].Bioorganic&Medicinal Chemistry Letters.,2013,23(6):1839-1845.
[22]Satavisha K,Santanu M.Catalytic enantioselective cascade Michael/cyclization reaction of3-isothiocyanato oxindoles with exocyclicα,β-unsaturated ketones en route to 3,2′-pyrrolidinyl bispirooxindoles[J].Org.Biomol.Chem.,2016,14(43):10175-10179.
[23]Wu C L,Jing L H,Qin D B,et al.Organocatalytic asymmetric synthesis of trans-configured trispirooxindoles through a cascade Michaelcyclization reaction[J].Tetrahedron Lett.,2016,57(26):2857-2860.
[24]Jiang X X,Cao Y M,Wang Y Q,et al.A unique approach to the concise synthesis of highly optically active spirooxazolines and the discovery of a more potent oxindole-type phytoalexin analogue[J].J.Am.Chem.Soc.2010,132(43):15328-15333.
[25]Chen W B,Wu Z J,Hu J,et al.Organocatalytic direct asymmetric aldol reactions of 3-isothiocyanato oxindoles to ketones:stereocontrolled synthesis of spirooxindoles bearing highly congested contiguous tetrasubstituted stereocenters[J].Org.Lett.,2011,13(9):2472-2475.
[26]Han Y Y,Chen W B,Han W Y,et al.Highly efficient and stereoselective construction of dispiro-[oxazolidine-2-thione]bisoxindoles and dispiro[imidazolidine-2-thione]bisoxindoles[J].Org.Lett.,2012,14(2):490-493.
[27]Satavisha K,Santanu M.Catalytic aldol-cyclization cascade of 3-isothiocyanato oxindoles withα-ketophosphonates for the enantioselective synthesis ofβ-Amino-α-hydroxyphosphonates[J].Org.Lett.2015,17(21):5508-5511.
[28]Chen W B,Han W Y,Han Y Y,et al.Highly efficient synthesis of spiro[oxazolidine-2-thione-oxindoles]with 3-isothiocyanato oxindoles and aldehydes via an organocatalytic cascade aldol-cyclization reaction[J].Tetrahedron.,2013,69(26):5281-5286.
[29]Shota K,Motomu K,Shigeki M.Catalytic asymmetric synthesis of spirooxindoles via addition of isothiocyanato oxindoles to aldehydes under dinuclear nickel schiff base catalysis[J].Chem.Asian J.,2013,8(8):1768-1771.
[30]Shota K,Tatsuhiko Y,Masakatsu S,et al.Catalytic asymmetric synthesis of spirooxindoles by a mannich-type reaction of isothiocyanato oxindoles[J].Angew.Chem.Int.Ed.,2012,51(28):7007-7010.
[31]Yuan X,Zhag S J,Du W,et al.Asymmetric diels–alder cycloadditions of trifluoromethylated dienophiles under trienamine catalysis[J].Chem.-Eur.J.,2016,22(31):11048-11052.