CN109251192B - 3位或4位三氟甲基取代异香豆素的制备方法 - Google Patents
3位或4位三氟甲基取代异香豆素的制备方法 Download PDFInfo
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- CN109251192B CN109251192B CN201811488129.6A CN201811488129A CN109251192B CN 109251192 B CN109251192 B CN 109251192B CN 201811488129 A CN201811488129 A CN 201811488129A CN 109251192 B CN109251192 B CN 109251192B
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- trifluoromethyl
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- isocoumarin
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- IQZZFVDIZRWADY-UHFFFAOYSA-N isocumarine Natural products C1=CC=C2C(=O)OC=CC2=C1 IQZZFVDIZRWADY-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title claims abstract description 15
- 125000003151 isocoumarinyl group Chemical class C1(=O)OC(=CC2=CC=CC=C12)* 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 20
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 15
- IOPDYTCCKSYLJG-UHFFFAOYSA-N 3,3,3-trifluoroprop-1-ynylbenzene Chemical class FC(F)(F)C#CC1=CC=CC=C1 IOPDYTCCKSYLJG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 24
- 239000005711 Benzoic acid Substances 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 7
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了3位或4位三氟甲基取代异香豆素的制备方法,该方法采用各种取代的苯甲酸和三氟甲基苯乙炔作为反应底物。其反应收率可达到中等到优秀,反应的化学选择性优秀,反应条件温和,底物的适用范围广(其中R=H或CH3、OCH3等基团,以及噻吩杂环等;Ar=各种取代的苯环);其操作简便、成本较低、副反应少、产品纯度高、便于分离提纯和可适用于较大规模的制备,所以其所得的产物具有非常好的生物医药领域的应用前景。
Description
技术领域
本发明涉及有机化学领域,尤其涉及3位或4位三氟甲基取代异香豆素化合物的制备方法。
背景技术
含氧杂环化合物是众多天然产物和药物分子的核心结构,异香豆素是苯并六元内酯类化合物,是一类重要的含氧杂环化合物(A.Saddiqa,M.Usman,O.Akmak,Turk.J.Chem.,2017,41,153–178.)。异香豆素及其衍生物作为一种代表性含氧杂环化合物,具有广谱的杀菌、消炎、抗癌、抑制蛋白酶和除草等生理和药物活性((a)L.Pochet,R.Frédérick,B.Masereel,Curr.Pharm.Design,2004,10,3781–3796;(b)A.Saeed,Euro.J.Med.Chem.,2016,116,290–317.)。同时,异香豆素及其衍生物可以作为有效的雌激素受体((a)M.DeAngelis,F.Stossi,M.Waibel,B.S.Katzenellenbogen,J.A.Katzenellenbogen,Bioorg.Med.Chem.2005,13,6529–6542;(b)T.Tuccinardi,G.Poli,M.Dell'Agnello,C.Granchi,F.Minutolo,A.Martinelli,J.Enzym.Inhib.Med.Chem.,2015,30,662–670;(c)J.Fang,J.Shen,F.Cheng,Z.Xu,G.Liu,Y.Tang,Mol.Inf.,2011,30,539–549;(d)K.W.Nettles,J.B.Bruning,G.Gil,J.Nowak,S.K.Sharma,J.B.Hahm,K.Kulp,R.B.Hochberg,H.Zhou,J.A.Katzenellenbogen,B.S.Katzenellenbogen,Y.Kim,A.Joachimiak,G.L.Greene,Nat.Chem.Bio.,2008,4,241–247.),以及阿兹海默病探针等(C.Frédéric,A.da C.Cristine,A.Erwan,A.David,D.Cécile,F.Michael,H.J.Martinez,L.Solveig,M.Philippe,P.Andrea,P.Agnès,P.Christopher,R.Philippe,StG.Peter,W.Sherwin,Curr.Alzheimer Research,2005,2,327–334.),在生物医学领域有广泛应用。因此,异香豆素类化合物的快速高效合成及其后期多样性修饰一直是有机化学家和药物化学家的一个研究重点((a)P.Saikia,S.Gogoi,Adv.Synth.Catal.2018,360,2063–2075;(b)M.Bu,G.Lu,C.Cai,Catal.Comm.,2018,114,70–74;(c)Z.Ashraf,Chem.Heterocycl.Compd.2016,52,149–151;(d)A.Saeed,F.A.Larik,Chem.Heterocycl.Compd.2016,52,450–452;(e)S.Pal,V.Chatare,M.Pal,Curr.Org.Chem.,2011,15,782–800;(f)A.Saeed,M.Haroon,F.Muhammad,F.
A.Larik,E.Hesham,P.A.Channar,J.Organomet.Chem.,2017,834,88–103.)。
最近二十年研究发现过渡金属可以有效催化惰性碳氢键直接官能团,由于其具有底物不需要预活化,选择性好,效率高等优点,成为有机化学研究领域的一个新热点((a)J.Q.Yu,Z.J.Shi(Eds.),C–H Activation,Topics in Current Chemistry,Springer,Heidelberg,Germany,2010;(b)P.H.Dixneuf,H.Doucet(Eds.),C–H Bond Activation andCatalytic Functionalization,Topics in Current Chemistry,Springer,Heidelberg,Germany,2016;(c)H.M.L.Davies,D.Morton,J.Org.Chem.2016,81,343–350;(d)T.Gensch,M.N.Hopkinson,F.Glorius,J.Wencel-Delord,Chem.Soc.Rev.2016,45,2900–2936;(e)F.Kakiuchi,N.Chatani,Adv.Synth.Catal.2003,345,1077–1101;(f)V.Ritleng,C.Sirlin,M.Pfeffer,Chem.Rev.2002,102,1731–1769.)。苯甲酸和炔烃的直接碳氢活化氧化偶联环化反应是制备3,4-双取代异香豆素最直接,最高效的合成方法((a)L.Ackermann.,Acc.Chem.Res.,2014,47,281–295;(b)Y.Yang,K.Li,Y.Cheng,D.Wan,M.Li,J.You,Chem.Commun.,2016,52,2872–2884.)。该反应选用苯甲酸和炔烃作为起始原料,底物便宜易得,可以得到结构多样性的产物。文献报道的过渡金属催化剂主要包含金属铑((a)X.Liu,H.Gao,S.Zhang,Q.Li,H.Wang,ACS Catal.,2017,7,5078–5086;(b)E.Kudo,Y.Shibata,M.Yamazaki,K.Masutomi,Y.Miyauchi,M.Fukui,H.Sugiyama,H.Uekusa,T.Satoh,M.Miura,K.Tanaka,Chem.Eur.J.,2016,22,14190–14194;(c)K.Ueura,T.Satoh,M.Miura,J.Org.Chem.,2007,72,5362–5367;(d)M.Shimizu,K.Hirano,T.Satoh,M.Miura,J.Org.Chem.,2009,74,3478–3483;(e)P.B.Dalvi,K.Lin,M.V.Kulkarni,C.Sun,Org.Lett.,2016,18,3706–3709;(f)K.Ueura,T.Satoh,M.Miura,Org.Lett.,2007,9,1407–1409;(g)Q.Li,Y.Yan,X.Wang,B.Gong,X.Tang,J.Shi,H.E.Xu,W.Yi,RSC Adv.,2013,3,23402–23408;(h)Y.Unoh,K.Hirano,T.Satoh,M.Miura,Tetrahedron 2013,69,4454–4458.),钌((a)S.Warratz,C.Kornhaaβ,A.Cajaraville,B.D.Stalke,L.Ackermann,Angew.Chem.Int.Ed.,2015,54,5513–5517;(b)R.K.Chinnagolla,M.Jeganmohan,Chem.Commun.,2012,48,2030–2032;(c)M.Deponti,S.I.Kozhushkov,D.S.Yufit,L.Ackermann,Org.Biomol.Chem.,2013,11,142–148;(d)L.Ackermann,J.Pospech,K.Graczyk,K.Rauch,Org.Lett.,2012,14,930–933.),铱(D.A.Frasco,C.P.Lilly,P.D.Boyle,E.A.Ison,ACS Catal.,2013,3,2421–2429.),钴((a)T.T.Nguyen,L.Grigorjeva,O.Daugulis,Angew.Chem.Int.Ed.,2018,57,1688–1691;(b)R.Mandal,B.Sundararaju,Org.Lett.,2017,19,2544–2547.)等。
三氟甲基是一个特殊的基团,具有许多优异的物理化学性能,普遍存在于各种新药物和新材料当中。由于氟原子的特殊性,往往给这些新药物和新材料带来意想不到的效果和性能((a)W.Zhu,J.Wang,S.Wang,Z.Gu,J.L.K.Izawa,H.Liu,V.A.Soloshonok,J.Fluorine Chem.,2014,167,37–54;(b)O.Reiser,Chem,2016,1,342–350;(c)K.Sato,A.Tarui,M.Omote,A.Ando,I.Kumadaki,Synthesis,2010,11,1865–1882;(d)M.Bassetto,S.Ferla,F.Pertusati,Future Med.Chem.,2015,7,527–546;(e)F.Meyer,Chem.Commun.,2016,52,3077–3094;(f)B.Koksch,N.Sewald,K.Burger,H.D.Jakubke,Amino Acids,1996,11,425–434;(g)M.Shimizu,T.Hiyama,Angew.Chem.Int.Ed.,2005,44,214–231;(h)M.Schlosser,Angew.Chem.Int.Ed.,2006,45,5432–5446;(i)M.Zanda,New J.Chem.,2004,28,1401–1411.)。因此,研究和发展简单有效的方法,将三氟甲基基团引入异香豆素骨架,合成3位或4位三氟甲基取代异香豆素化合物具有十分重要的科学意义和实际应用价值。然而,通过大量文献调研我们发现文献报道的合成此类化合物的方法却十分有限,并且反应都存在着一些局限性,难以大规模生产和应用。目前的已知的方法主要有两种:第一种是对异香豆素骨架的改造,从相应碘代异香豆素出发,和三氟甲基化试剂反应,制备三氟甲基取代异香豆素((a)M.De Angelis,F.Stossi,M.Waibel,B.S.Katzenellenbogen,J.A.Katzenellenbogen,Bioorg.Med.Chem.,2005,13,6529–6542;(b)S.Roy,S.Roy,B.Neuenswander,D.Hill,R.C.Larock,J.Comb.Chem.,2009,11,1128–1135.)。第二种是使用五氟化锑(SbF5)对苯并四元环和五元环进行扩环,制备三氟甲基取代异香豆素((a)Y.V.Zonov,V.M.Karpov,V.E.Platonov,J.Fluorine Chem.,2007,128,1065–1073;(b)Y.V.Zonov,T.V.Mezhenkova,V.M.Karpov,V.E.Platonov,J.Fluorine Chem.,2008,129,1206–1208;(c)Y.V.Zonov,V.M.Karpov,V.E.Platonov,J.Fluorine Chem.,2012,135,159–166;(d)Y.V.Zonov,V.M.Karpov,V.E.Platonov,J.Fluorine Chem.,2014,162,71–77;(e)Y.V.Zonov,V.M.Karpova,T.V.Mezhenkova,T.V.Rybalova,Y.V.Gatilov,V.E.Platonov,J.Fluorine Chem.,2016,188,117–125;(f)Y.V.Zonov,V.M.Karpov,V.E.Platonov,Y.V.Gatilov,Russ.J.Org.Chem.,2008,44,202–217;(g)Y.V.Zonov,T.V.Mezhenkova,V.M.Karpov,V.E.Platonov,Russ.J.Org.Chem.,2008,44,1652–1656;(h)Y.V.Zonov,V.M.Karpova,V.E.Platonov,Russ.J.Org.Chem.,2010,46,1517–1526;(i)Y.V.Zonov,V.M.Karpov,V.E.Platonov,Russ.J.Org.Chem.,2011,47,207–213.)。五氟化锑是具有吸湿性,挥发性的粘稠液体,暴露在空气中会产生剧毒的烟雾,限制了此方法的实际应用。
发明内容
针对上述问题,本发明的目的在于提供3位或4位三氟甲基取代异香豆素的制备方法。
本发明采用以下技术方案。
采用各种取代的苯甲酸作为反应底物,使其与一系列三氟甲基苯乙炔在二氯(五甲基环戊二烯基)合铱(III)二聚体([Cp*IrCl2]2)催化下,通过一个直接碳氢活化的串联氧化环化反应,制得3位或4位三氟甲基取代异香豆素化合物。所述各种取代的苯甲酸的苯环上可以有各种取代基团,所述一系列三氟甲基苯乙炔为三氟甲基苯乙炔的苯环上可以有各种取代基团。
3位或4位三氟甲基取代异香豆素的制备方法,其特征在于,在有机溶剂中,在氧化剂和催化剂参与的条件下,使苯甲酸或其衍生物(化合物1)与三氟甲基苯乙炔或其衍生物(化合物2)反应,得到所述的3位或4位三氟甲基取代异香豆素;其反应式如下:
式中,化合物1为苯甲酸或其衍生物,化合物2为三氟甲基苯乙炔或其衍生物,化合物3为3位三氟甲基取代异香豆素,化合物4为4位三氟甲基取代异香豆素;其中,R为氢、烷基或烷氧基等基团,Ar为苯基或取代苯基。
优选地,R为-H、-CH3或-OCH3,Ar为苯基。
上述方法中,苯甲酸或其衍生物(化合物1)也可以替换为噻吩甲酸或其衍生物,噻吩甲酸或其衍生物优选为噻吩-3-甲酸。
上述方法中,苯甲酸或其衍生物(化合物1)与三氟甲基苯乙炔或其衍生物(化合物2)的摩尔比例可以为1:1.5。
上述方法中,有机溶剂可以为三氟乙醇。
上述方法中,催化剂可以为二氯(五甲基环戊二烯基)合铱(III)二聚体([Cp*IrCl2]2)。
上述方法中,氧化剂可以为醋酸银。
上述方法中,反应温度可以为50℃,反应时间可以为24小时。
根据上述方法制备得到的3位或4位三氟甲基取代异香豆素可以应用于生物医药领域。
本发明的技术效果是:本发明利用过渡金属催化的直接碳氢活化的串联氧化环化反应,从苯甲酸和三氟甲基苯乙炔出发,在比较温和的条件下高效率、高选择性地合成3位或4位三氟甲基取代异香豆素化合物。本发明方法的反应收率可达到中等到优秀,反应的化学选择性高,条件温和,底物适用范围广,操作简便,成本较低,副反应少,产品纯度高,便于分离提纯和可适用于较大规模的制备。本方法所得产物具有潜在的生物和药物活性,因此可应用于生物医药领域,具有非常好的应用前景。
附图说明
图1为3-三氟甲基-4-苯基-异香豆素化合物3a的X-单晶衍射结构图。
图2为3-三氟甲基-4-苯基-异香豆素化合物3a单晶结构对应的化合物分子结构图。
图3为4-三氟甲基-3-苯基-异香豆素化合物4a的X-单晶衍射结构图。
图4为4-三氟甲基-3-苯基-异香豆素化合物4a单晶结构对应的化合物分子结构图。
具体实施方式
下面将结合附图实施例详细说明本发明所具有的有益效果,旨在帮助阅读者更好地理解本发明的实质,但不能对本发明的实施和保护范围构成任何限定。
本发明方法的具体操作为:向反应试管中分别依次加入苯甲酸或其衍生物、催化剂二氯(五甲基环戊二烯基)合铱(III)二聚体、氧化剂醋酸银、溶剂三氟乙醇,最后加入三氟甲基苯乙炔或其衍生物,用橡胶塞密封反应试管;把试管置于50℃油浴中搅拌加热24小时左右,反应过程中用TLC检测至完全反应;后处理时先将溶剂旋干,直接上硅胶柱层析分离得纯净的产物3位三氟甲基取代异香豆素3和4位三氟甲基取代异香豆素4。
实施例1
向反应试管中分别依次加入苯甲酸(0.2mmol)、催化剂二氯(五甲基环戊二烯基)合铱(III)二聚体(3.5mol%)、氧化剂醋酸银(2.0equiv)、溶剂三氟乙醇(4mL),最后加入三氟甲基苯乙炔(1.5equiv),用橡胶塞密封反应试管。把试管置于50℃油浴中搅拌加热24小时左右,反应过程中用TLC检测至完全反应。后处理时先将溶剂旋干,直接上硅胶柱层析分离得纯净的产物3-三氟甲基-4-苯基-异香豆素化合物3a和4-三氟甲基-3-苯基-异香豆素化合物4a。
化合物3a,产率:85%;白色固体;熔点139-140℃;1H NMR(400MHz,CDCl3)δ8.42(dd,J=7.6,1.2Hz,1H),7.73–7.62(m,2H),7.55–7.46(m,3H),7.34–7.27(m,2H),7.07(d,J=8.0Hz,1H);13C NMR(100MHz,CDCl3)δ159.4,138.9(q,JC-F=35.9Hz),137.1,135.2,130.5,130.4,129.9,129.8(q,JC-F=1.3Hz),129.1,128.7,126.9,121.6,121.0(q,JC-F=2.2Hz),119.2(q,JC-F=272.8Hz);19F NMR(376MHz,CDCl3)δ-63.18;HRMS(pos.ESI):m/z[M+H]+for C16H10F3O2calcd:291.0627,found:291.0630。
化合物4a,产率:13%;白色固体;熔点120-123℃;1H NMR(400MHz,CDCl3)δ8.39(d,J=8.0Hz,1H),7.86(d,J=4.0Hz,2H),7.65(p,J=4.0Hz,1H),7.56–7.45(m,5H);19F NMR(376MHz,CDCl3)δ-53.60;HRMS(pos.ESI):m/z[M+H]+for C16H10F3O2calcd:291.0627,found:291.0631.
仅改变相应的反应物,用同样的方法得到实施例2-20。
实施例2
3-三氟甲基-6-甲基-4-苯基-异香豆素化合物3b,产率:82%;白色固体;熔点117-119℃;1H NMR(400MHz,CDCl3)δ8.29(d,J=8.4Hz,1H),7.57–7.48(m,3H),7.46(d,J=8.0Hz,1H),7.32–7.27(m,2H),6.81(s,1H),2.38(s,3H);13C NMR(100MHz,CDCl3)δ159.5,146.7,139.0(q,JC-F=35.7Hz),137.1,131.6,130.6,129.9,129.8(q,JC-F=1.3Hz),129.0,128.7,126.8,120.9(q,JC-F=2.2Hz),119.3(q,JC-F=272.9Hz),119.1,22.1;19F NMR(376MHz,CDCl3)δ-63.11;HRMS(pos.ESI):m/z[M+H]+for C17H12F3O2calcd:305.0784,found:305.0788。
4-三氟甲基-6-甲基-3-苯基-异香豆素化合物4b,产率:13%;白色固体;熔点124-125℃;1H NMR(400MHz,CDCl3)δ8.27(d,J=8.0Hz,1H),7.62(s,1H),7.55–7.45(m,6H),2.56(s,3H);19F NMR(376MHz,CDCl3)δ-53.48;HRMS(pos.ESI):m/z[M+H]+for C17H12F3O2calcd:305.0784,found:305.0788。
实施例3
3-三氟甲基-6-甲氧基-4-苯基-异香豆素化合物3c,产率:51%;白色固体;熔点143-144℃;1H NMR(400MHz,CDCl3)δ8.34(d,J=8.8Hz,1H),7.51–7.49(m,3H),7.30–7.28(m,2H),7.15(dd,J=8.8,2.4Hz,1H),6.41(d,J=2.4Hz,1H),3.74(s,3H);13C NMR(100MHz,CDCl3)δ165.0,159.2,139.5,139.4(q,JC-F=35.7Hz),132.3,130.6,129.8(q,JC-F=1.4Hz)129.1,128.7,120.7(q,JC-F=2.3Hz),119.2(q,JC-F=272.9Hz),117.4,114.5,110.4,55.6;19F NMR(376MHz,CDCl3)δ-63.22;HRMS(pos.ESI):m/z[M+H]+for C17H12F3O3calcd:321.0733,found:321.0735。
4-三氟甲基-6-甲氧基-3-苯基-异香豆素化合物4c,产率:13%;白色固体;熔点120-121℃;1H NMR(400MHz,CDCl3)δ8.31(d,J=9.2Hz,1H),7.55–7.45(m,5H),7.24–7.21(m,1H),7.17(dd,J=8.8,2.0Hz,1H),3.97(s,3H);19F NMR(376MHz,CDCl3)δ-53.73;HRMS(pos.ESI):m/z[M+H]+for C17H12F3O3calcd:321.0733,found:321.0735。
实施例4
3-三氟甲基-7-甲基-4-苯基-异香豆素化合物3d,产率:75%;白色固体;熔点154-155℃;1H NMR(400MHz,CDCl3)δ8.22(s,1H),7.51–7.49(m,4H),7.30–7.27(m,2H),6.95(d,J=8.0Hz,1H),2.50(s,3H);13C NMR(100MHz,CDCl3)δ159.6,141.1,138.1(q,JC-F=35.9Hz),136.4,134.6,130.7,129.8,129.7,128.9,128.7,126.8,121.5,121.0(q,JC-F=2.3Hz),119.3(q,JC-F=272.6Hz),21.4;19F NMR(376MHz,CDCl3)δ-63.05;HRMS(pos.ESI):m/z[M+H]+for C17H12F3O2calcd:305.0784,found:305.0789。
4-三氟甲基-7-甲基-3-苯基-异香豆素化合物4d,产率:13%;白色固体;熔点135-136℃;1H NMR(400MHz,CDCl3)δ8.20(q,J=0.4Hz,1H),7.75(dd,J=8.4,2.0Hz,1H),7.66(dd,J=8.4,1.6Hz,1H),7.55–7.46(m,5H),2.52(s,3H);19F NMR(376MHz,CDCl3)δ-53.66.HRMS(pos.ESI):m/z[M+H]+for C17H12F3O2calcd:305.0784,found:305.0788。
实施例5
3-三氟甲基-7-甲氧基-4-苯基-异香豆素化合物3e,产率:38%;白色固体;熔点97-98℃;1H NMR(400MHz,CDCl3)δ7.81(d,J=2.8Hz,1H),7.51–7.49(m,3H),7.30–7.27(m,2H),7.24(dd,J=9.2,2.8Hz,1H),6.98(d,J=8.8Hz,1H),3.94(s,3H);13C NMR(100MHz,CDCl3)δ161.1,159.7,130.8,130.4,129.7(q,JC-F=1.3Hz),129.0,128.7,128.5,124.3,123.1,121.0(q,JC-F=2.3Hz),119.4(q,JC-F=272.2Hz),110.7,56.0(one carbonmissing);19F NMR(376MHz,CDCl3)δ-62.80;HRMS(pos.ESI):m/z[M+H]+forC17H12F3O3calcd:321.0733,found:321.0738。
4-三氟甲基-7-甲氧基-3-苯基-异香豆素化合物4e,产率:8%;白色固体;熔点128-129℃;1H NMR(400MHz,CDCl3)δ7.79–7.76(m,2H),7.55–7.47(m,5H),7.42(dd,J=9.2,2.8Hz,1H),3.96(s,3H);19F NMR(376MHz,CDCl3)δ-53.62;HRMS(pos.ESI):m/z[M+H]+forC17H12F3O3calcd:321.0733,found:321.0738。
实施例6
3-三氟甲基-6,7-二甲氧基-4-苯基-异香豆素化合物3f,产率:60%;白色固体;熔点126-127℃;1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.52–7.50(m,3H),7.32–7.29(m,2H),6.38(s,1H),4.02(s,3H),3.70(s,3H);13C NMR(100MHz,CDCl3)δ159.4,155.2,151.2,137.9(q,JC-F=35.8Hz),132.5,130.9,129.7(q,JC-F=1.3Hz),129.1,128.7,120.7(q,JC-F=2.4Hz),119.3(q,JC-F=272.6Hz),115.1,109.8,107.4,56.5,56.0;19F NMR(376MHz,CDCl3)δ-62.86;HRMS(pos.ESI):m/z[M+H]+for C18H14F3O4calcd:351.0839,found:351.0840。
4-三氟甲基-6,7-二甲氧基-3-苯基-异香豆素化合物4f,产率:7%;白色固体;熔点134-135℃;1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.55–7.47(m,4H),7.19(d,J=1.2Hz,1H),4.04(s,3H),4.03(s,3H);19F NMR(376MHz,CDCl3)δ-53.58;HRMS(pos.ESI):m/z[M+H]+for C18H14F3O4calcd:351.0839,found:351.0840。
实施例7
3-三氟甲基-5,7-二甲基-4-苯基-异香豆素化合物3g,产率:79%;白色固体;熔点121-122℃;1H NMR(400MHz,CDCl3)δ8.17(s,1H),7.47–7.41(m,3H),7.32–7.31(m,3H),2.44(s,3H),1.66(s,3H);13C NMR(100MHz,CDCl3)δ160.2,141.1,140.7,138.4(q,JC-F=34.6Hz),137.5,133.3,131.2,130.5(q,JC-F=1.5Hz),129.0,128.8,128.3,122.6,121.4(q,JC-F=2.2Hz),119.6(q,JC-F=273.0Hz),22.5,21.0;19F NMR(376MHz,CDCl3)δ-61.27;HRMS(pos.ESI):m/z[M+H]+for C18H14F3O2calcd:319.0940,found:319.0944。
4-三氟甲基-5,7-二甲基-3-苯基-异香豆素化合物4g,产率:trace。
实施例8
3-三氟甲基-8-甲氧基-4-苯基-异香豆素化合物3h,产率:24%;白色固体;熔点147-149℃;1H NMR(400MHz,CDCl3)δ7.59(t,J=8.2Hz,1H),7.49(s,3H),7.26(s,2H),7.10(d,J=8.4Hz,1H),6.56(d,J=8.0Hz,1H),4.05(s,3H);13C NMR(100MHz,CDCl3)δ161.9,155.9,140.0,136.0,131.1,129.9(q,JC-F=1.0Hz),128.9,128.6,120.2(q,JC-F=1.8Hz),119.1(q,JC-F=272.6Hz),118.8,112.2,110.2,56.6(one carbon missing);19F NMR(376MHz,CDCl3)δ-63.38;HRMS(pos.ESI):m/z[M+H]+for C17H12F3O3calcd:321.0733,found:321.0738。
4-三氟甲基-8-甲氧基-3-苯基-异香豆素化合物4h,产率:10%;白色固体;熔点130-131℃;1H NMR(400MHz,CDCl3)δ7.76(t,J=8.4Hz,1H),7.57–7.38(m,6H),7.10(d,J=8.4Hz,1H),4.05(s,3H);19F NMR(376MHz,CDCl3)δ-53.57;HRMS(pos.ESI):m/z[M+H]+forC17H12F3O3calcd:321.0733,found:321.0738。
实施例9
6-三氟甲基-7-苯基-噻吩并吡喃酮化合物3i,产率:35%;白色固体;熔点110-111℃;1H NMR(400MHz,CDCl3)δ7.72(d,J=5.2Hz,1H),7.55–7.51(m,4H),7.42–7.39(m,2H);13C NMR(100MHz,CDCl3)δ155.4,152.5,131.1,129.9,129.8,129.0,128.8(q,JC-F=1.3Hz),126.6,125.7,119.2(q,JC-F=272.8Hz),119.0(q,JC-F=2.3Hz)(one carbon missing);19FNMR(376MHz,CDCl3)δ-62.64;HRMS(pos.ESI):m/z[M+H]+for C14H8F3O2S calcd:297.0192,found:297.0195。
7-三氟甲基-6-苯基-噻吩并吡喃酮化合物4i,产率:5%;白色固体;熔点102-103℃;1H NMR(400MHz,CDCl3)δ7.68(d,J=5.6Hz,1H),7.58(d,J=7.2Hz,2H),7.53–7.47(m,4H);19F NMR(376MHz,CDCl3)δ-55.06;HRMS(pos.ESI):m/z[M+H]+for C14H8F3O2S calcd:297.0192,found:297.0195。
实施例10
3-三氟甲基-4-(4-氟苯基)-异香豆素化合物3j,产率:77%;白色固体;熔点130-131℃;1H NMR(400MHz,CDCl3)δ8.32(dd,J=8.0,1.2Hz,1H),7.65(td,J=7.6,1.2Hz,1H),7.58(td,J=7.2,0.8Hz,1H),7.23–7.19(m,2H),7.15–7.10(m,2H),6.98(d,J=7.6Hz,1H);13C NMR(100MHz,CDCl3)δ163.1(d,JC-F=247.6Hz),159.2,139.2(q,JC-F=36.0Hz),136.9,135.3,131.7(dd,JC-F=8.2,1.2Hz),130.5,130.0,126.6,126.3(q,JC-F=3.5Hz),121.6,120.0(q,JC-F=2.2Hz),119.2(q,JC-F=272.9Hz)116.0(d,JC-F=21.7Hz);19F NMR(376MHz,CDCl3)δ-63.13,-111.94;HRMS(pos.ESI):m/z[M+H]+for C16H9F4O2calcd:309.0533,found:309.0536。
4-三氟甲基-3-(4-氟苯基)-异香豆素化合物4j,产率:11%;白色固体;熔点140-142℃;1H NMR(400MHz,CDCl3)δ8.39(d,J=8.0Hz,1H),7.86–7.85(m,2H),7.68–7.64(m,1H),7.57(dd,J=8.4,5.2Hz,2H),7.17(t,J=8.6Hz,2H);19F NMR(376MHz,CDCl3)δ-53.61,-108.55;HRMS(pos.ESI):m/z[M+H]+for C16H9F4O2calcd:309.0533,found:309.0537。
实施例11
3-三氟甲基-4-(4-氯苯基)-异香豆素化合物3k,产率:63%;白色固体;熔点125-127℃;1H NMR(400MHz,CDCl3)δ8.41(dd,J=7.8,1.0Hz,1H),7.75–7.65(m,2H),7.50(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,2H),7.06(d,J=8.0Hz,1H);13C NMR(100MHz,CDCl3)δ159.2,139.2(q,JC-F=36.0Hz),136.7,135.4,135.3,131.2(q,JC-F=1.4Hz),130.6,130.1,129.1,129.0,126.6,121.6,119.8(q,JC-F=2.1Hz),119.1(q,JC-F=273.0Hz);19F NMR(376MHz,CDCl3)δ-63.11;HRMS(pos.ESI):m/z[M+H]+for C16H9F3O2Cl calcd:325.0238,found:325.0248。
4-三氟甲基-3-(4-氯苯基)-异香豆素化合物4k,产率:16%;白色固体;熔点112-114℃;1H NMR(400MHz,CDCl3)δ8.39(d,J=8.0Hz,1H),7.89–7.85(m,2H),7.68–7.65(m,1H),7.47(dt,J=6.6,5.2Hz,1H);19F NMR(376MHz,CDCl3)δ-53.59;HRMS(pos.ESI):m/z[M+H]+for C16H9F3O2Cl calcd:325.0238,found:325.0247。
实施例12
3-三氟甲基-4-(4-溴苯基)-异香豆素化合物3l,产率:76%;白色固体;熔点127-128℃;1H NMR(400MHz,CDCl3)δ8.41(dd,J=8.0,1.2Hz,1H),7.74–7.67(m,2H),7.66(d,J=8.4Hz,2H),7.19(d,J=8.4Hz,2H),7.06(d,J=8.0Hz,1H);13C NMR(100MHz,CDCl3)δ159.2,139.1(q,JC-F=36.0Hz),136.6,135.3,132.1,131.5(q,JC-F=1.3Hz),130.6,130.1,129.5,126.6,123.6,121.6,119.8(q,JC-F=2.3Hz),119.1(q,JC-F=272.9Hz);19F NMR(376MHz,CDCl3)δ-63.09;HRMS(pos.ESI):m/z[M+H]+for C16H9F3BrO2calcd:368.9733,found:368.9745。
4-三氟甲基-3-(4-溴苯基)-异香豆素化合物4l,产率:15%;白色固体;熔点106-107℃;1H NMR(400MHz,CDCl3)δ8.39(d,J=8.0Hz,1H),7.89–7.83(m,2H),7.68–7.66(m,1H),7.62(d,J=8.4Hz,2H),7.43(d,J=8.4Hz,2H);19F NMR(376MHz,CDCl3)δ-53.58;HRMS(pos.ESI):m/z[M+H]+for C16H9F3BrO2calcd:368.9733,found:368.9743。
实施例13
3-三氟甲基-4-(4-碘苯基)-异香豆素化合物3m,产率:71%;白色固体;熔点148-149℃;1H NMR(400MHz,CDCl3)δ8.41(dd,J=7.6,0.8Hz,1H),7.86(d,J=8.0Hz,2H),7.76–7.65(m,2H),7.06(d,J=8.4Hz,3H);13C NMR(100MHz,CDCl3)δ159.1,139.0(q,JC-F=36.0Hz),138.0,136.6,135.3,131.6(q,JC-F=1.3Hz),130.6,130.1,130.0,126.6,121.6,119.9(q,JC-F=2.1Hz),119.1(q,JC-F=273.0Hz),95.2;19F NMR(376MHz,CDCl3)δ-63.07;HRMS(pos.ESI):m/z[M+H]+for C16H9F3O2I calcd:416.9594,found:416.9596。
4-三氟甲基-3-(4-碘苯基)-异香豆素化合物4m,产率:20%;白色固体;熔点125-126℃;1H NMR(400MHz,CDCl3)δ8.39(d,J=7.6Hz,1H),7.89–7.82(m,4H),7.68–7.64(m,1H),7.29(d,J=8.4Hz,2H);19F NMR(376MHz,CDCl3)δ-53.56;HRMS(pos.ESI):m/z[M+H]+for C16H9F3O2I calcd:416.9594,found:416.9597。
实施例14
3-三氟甲基-4-(4-硝基苯基)-异香豆素化合物3n,产率:66%;白色固体;熔点133-134℃;1H NMR(400MHz,CDCl3)δ8.45(dd,J=7.2,1.2Hz,1H),8.40(d,J=8.4Hz,2H),7.77–7.70(m,2H),7.55(d,J=8.4Hz,2H),6.96(d,J=7.6Hz,1H);13C NMR(100MHz,CDCl3)δ158.8,148.5,139.3(q,JC-F=36.4Hz),137.5,135.8,135.6,131.1(q,JC-F=1.4Hz),131.0,130.4,126.2,124.0,121.5,119.0(q,JC-F=2.2Hz),118.9(q,JC-F=273.1Hz);19F NMR(376MHz,CDCl3)δ-63.16;HRMS(pos.ESI):m/z[M+H]+for C16H9F3NO4calcd:336.0478,found:336.0485。
4-三氟甲基-3-(4-硝基苯基)-异香豆素化合物4n,产率:24%;白色固体;熔点131-132℃;1H NMR(400MHz,CDCl3)δ8.42(d,J=8.0Hz,1H),8.35(d,J=8.8Hz,2H),7.93–7.86(m,2H),7.75(d,J=8.8Hz,2H),7.71–7.69(m,1H);19F NMR(376MHz,CDCl3)δ-53.59;HRMS(pos.ESI):m/z[M+H]+for C16H9F3NO4calcd:336.0478,found:336.0485。
实施例15
3-三氟甲基-4-(4-三氟甲基苯基)-异香豆素化合物3o,产率:73%;白色固体;熔点136-137℃;1H NMR(400MHz,CDCl3)δ8.43(dd,J=7.8,1.0Hz,1H),7.80(d,J=8.0Hz,2H),7.76–7.68(m,2H),7.47(d,J=8.0Hz,2H),6.99(d,J=7.6Hz,1H);13C NMR(100MHz,CDCl3)δ159.0,139.2(q,JC-F=36.3Hz),136.3,135.4,134.5,131.5(q,JC-F=32.7Hz),130.7,130.4(q,JC-F=1.4Hz),130.2,126.5,125.8(q,JC-F=3.7Hz),123.8(q,JC-F=270.7Hz),121.6,119.6(q,JC-F=2.0Hz),119.0(q,JC-F=272.9Hz);19F NMR(376MHz,CDCl3)δ-62.83,-63.21;HRMS(pos.ESI):m/z[M+H]+for C17H9F6O2calcd:359.0501,found:359.0501。
4-三氟甲基-3-(4-三氟甲基苯基)-异香豆素化合物4o,产率:19%;白色固体;熔点89-90℃;1H NMR(400MHz,CDCl3)δ8.41(d,J=8.0Hz,1H),7.89–7.87(m,2H),7.75(d,J=8.4Hz,2H),7.71–7.67(m,3H);19F NMR(376MHz,CDCl3)δ-53.63,-62.98;HRMS(pos.ESI):m/z[M+H]+for C17H9F6O2calcd:359.0501,found:359.0501。
实施例16
3-三氟甲基-4-(4-羧酸甲酯苯基)-异香豆素化合物3p,产率:74%;白色固体;熔点157-158℃;1H NMR(400MHz,CDCl3)δ8.43(d,J=7.2Hz,1H),8.19(d,J=8.0Hz,2H),7.74–7.67(m,2H),7.41(d,J=8.4Hz,2H),7.00(d,J=7.6Hz,1H),3.98(s,3H);13C NMR(100MHz,CDCl3)δ166.4,159.2,138.9(q,JC-F=36.2Hz),136.4,135.4,135.3,131.0,130.7,130.1,130.0(q,JC-F=1.3Hz),129.9,126.6,121.5,120.1(q,JC-F=2.2Hz),119.2(q,JC-F=272.9Hz)52.4;19F NMR(376MHz,CDCl3)δ-63.21;HRMS(pos.ESI):m/z[M+H]+forC18H12F3O4calcd:349.0682,found:349.0684。
4-三氟甲基-3-(4-羧酸甲酯苯基)-异香豆素化合物4p,产率:15%;白色固体;熔点122-123℃;1H NMR(400MHz,CDCl3)δ8.41(d,J=8.0Hz,1H),8.15(d,J=8.4Hz,2H),7.88–7.87(m,2H),7.70–7.60(m,1H),7.64(d,J=8.4Hz,2H),3.97(s,3H);19F NMR(376MHz,CDCl3)δ-53.63;HRMS(pos.ESI):m/z[M+H]+for C18H12F3O4calcd:349.0682,found:349.0685。
实施例17
3-三氟甲基-4-(4-羧酸乙酯苯基)-异香豆素化合物3q,产率:64%;白色固体;熔点148-149℃;1H NMR(400MHz,CDCl3)δ8.43(d,J=7.2Hz,1H),8.20(d,J=8.4Hz,2H),7.73-7.66(m,2H),7.41(d,J=8.0Hz,2H),7.00(d,J=7.6Hz,1H),4.44(q,J=7.2Hz,2H),1.44(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ165.9,159.1,139.0(q,JC-F=36.3Hz),136.5,135.3,135.2,131.4,130.6,130.1,130.0(q,JC-F=1.1Hz),129.9,126.5,121.6,120.1(q,JC-F=2.2Hz),119.1(q,JC-F=272.9Hz),61.3,14.3;19F NMR(376MHz,CDCl3)δ-63.23;HRMS(pos.ESI):m/z[M+H]+for C19H14F3O4calcd:363.0839,found:363.0840。
4-三氟甲基-3-(4-羧酸乙酯苯基)-异香豆素化合物4q,产率:18%;白色固体;熔点108-110℃;1H NMR(400MHz,CDCl3)δ8.40(d,J=7.6Hz,1H),8.15(d,J=8.4Hz,2H),7.88–7.86(m,2H),7.69–7.65(m,1H),7.63(d,J=8.4Hz,2H),4.42(q,J=7.2Hz,2H),1.43(t,J=7.2Hz,3H);19F NMR(376MHz,CDCl3)δ-53.62;HRMS(pos.ESI):m/z[M+H]+forC19H14F3O4calcd:363.0839,found:363.0841。
实施例18
3-三氟甲基-4-(4-叔丁基苯基)-异香豆素化合物3r,产率:83%;白色固体;熔点126-127℃;1H NMR(400MHz,CDCl3)δ8.40(d,J=7.2Hz,1H),7.67(dt,J=24.4,6.8Hz,2H),7.51(d,J=8.4Hz,2H),7.21(d,J=8.4Hz,2H),7.11(d,J=7.6Hz,1H),1.39(s,9H);13C NMR(100MHz,CDCl3)δ159.5,152.1,138.8(q,JC-F=35.7Hz),137.3,135.1,130.3,129.8,129.5(q,JC-F=1.1Hz),127.3,127.0,125.6,121.6,121.1(q,JC-F=2.2Hz),119.3(q,JC-F=272.8Hz),34.8,31.3;19F NMR(376MHz,CDCl3)δ-63.12;HRMS(pos.ESI):m/z[M+H]+forC20H18F3O2calcd:347.1253,found:347.1265。
4-三氟甲基-3-(4-叔丁基苯基)-异香豆素化合物4r,产率:16%;白色固体;熔点106-107℃;1H NMR(400MHz,CDCl3)δ8.38(d,J=8.0Hz,1H),7.84(d,J=2.8Hz,2H),7.67–7.62(m,1H),7.49(s,4H),1.36(s,9H);19F NMR(376MHz,CDCl3)δ-53.57;HRMS(pos.ESI):m/z[M+H]+for C20H18F3O2calcd:347.1253,found:347.1264。
实施例19
3-三氟甲基-4-(2-甲氧基苯基)-异香豆素化合物3s,产率:74%;白色固体;熔点123-124℃;1H NMR(400MHz,CDCl3)δ8.39(d,J=8.0Hz,1H),7.65(dt,J=21.2,7.4Hz,2H),7.49(t,J=7.8Hz,1H),7.18(d,J=7.2Hz,1H),7.08(t,J=7.4Hz,1H),7.05(d,J=8.4Hz,2H),3.73(s,3H);13C NMR(100MHz,CDCl3)δ158.7,156.4,138.1(q,JC-F=35.8Hz),135.8,134.0,130.2(q,JC-F=1.4Hz),129.8,129.1,128.8,125.3,120.7,119.9,118.3,18.2(q,JC-F=272.5Hz),116.7(q,JC-F=2.1Hz),110.0,54.5;19F NMR(376MHz,CDCl3)δ-64.97;HRMS(pos.ESI):m/z[M+H]+for C17H12F3O3calcd:321.0733,found:321.0740。
4-三氟甲基-3-(2-甲氧基苯基)-异香豆素化合物4s,产率:3%;白色固体;熔点104-106℃;1H NMR(400MHz,CDCl3)δ8.40(d,J=8.4Hz,1H),7.84(d,J=8.0Hz,2H),7.66–7.63(m,1H),7.46(t,J=7.4Hz,1H),7.37(d,J=7.2Hz,1H),7.04(t,J=7.6Hz,1H),6.97(d,J=8.4Hz,1H),3.82(s,3H);19F NMR(376MHz,CDCl3)δ-56.86;HRMS(pos.ESI):m/z[M+H]+for C17H12F3O3calcd:321.0733,found:321.0741。
实施例20
3-三氟甲基-4-(3-溴苯基)-异香豆素化合物3t,产率:50%;白色固体;熔点116-117℃;1H NMR(400MHz,CDCl3)δ8.42(dd,J=8.0,0.8Hz,1H),7.74(td,J=7.6,1.2Hz,2H),7.70–7.65(m,2H),7.48(s,1H),7.40(t,J=8.0Hz,1H),7.25(d,J=7.2Hz,1H),7.05(d,J=8.0Hz,1H);13C NMR(100MHz,CDCl3)δ159.1,139.2(q,JC-F=36.2Hz),136.5,135.4,132.7(q,JC-F=1.3Hz),132.6,132.3,130.6,130.3,130.1,128.6(q,JC-F=1.4Hz),126.6,122.8,121.5,119.5(q,JC-F=2.2Hz),119.1(q,JC-F=273.0Hz)。
4-三氟甲基-3-(3-溴苯基)-异香豆素化合物4t,产率:15%;白色固体;熔点118-119℃;1H NMR(400MHz,CDCl3)δ8.40(d,J=8.0Hz,1H),7.88–7.86(m,2H),7.69–7.65(m,1H),7.56(s,1H),7.52–7.49(m,1H),7.43–7.41(m,2H);19F NMR(376MHz,CDCl3)δ-53.68;HRMS(pos.ESI):m/z[M+H]+for C16H9F3BrO2calcd:368.9733,found:368.9743。
以上所述的实施例仅仅是对本发明的优选实施方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案作出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (3)
2.根据权利要求1所述的方法,其特征在于,苯甲酸或其衍生物(化合物1)与三氟甲基苯乙炔或其衍生物(化合物2)的摩尔比例为1: 1.5。
3.根据权利要求1所述的方法,其特征在于,反应温度为50℃,反应时间为24小时。
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