CN113816843A - 一种2-羟基-9-芴酮衍生物及其合成方法和应用 - Google Patents
一种2-羟基-9-芴酮衍生物及其合成方法和应用 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
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- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
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- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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Abstract
本发明公开了一种2‑羟基‑9‑芴酮衍生物及其合成方法和应用，以邻呋喃芳基炔酮类化合物为原料，在催化剂作用下，利用其分子内D‑A反应、环氧开环、芳构化等反应过程，“一锅法”完成了式(I)2‑羟基‑9芴酮衍生物的合成。本发明制备方法具有原料简单易得、无金属催化剂、反应条件相对温和、反应对空气不敏感、底物普适性好、后处理简单、收率优秀、对环境友好等优点。制得的2‑羟基‑9‑芴酮类衍生物能够应用于制备抗病毒、抗肿瘤、解热、消炎等药物，荧光探针、敏化染料等功能材料中。
Description
技术领域
本发明属有机化合物及合成技术领域，涉及2-羟基-9-芴酮类化合物及其合成方法。
背景技术
9-芴酮类化合物是许多药物和天然产物分子重要的结构单元，在医药及材料领域中应用广泛。在医药应用上，早在1970年Tiorone就已发现在老鼠体内具有抗病毒药理作用，后来陆续发现该化合物还具有增强自然杀伤细胞的吞噬活性、解热、抗纤维化、消炎、抗肿瘤以及干扰素诱生等。这些药效作用部分归因于芴酮骨架的平面结构修饰。9-芴酮类化合物由于其独特的光电性能，也常作为可调控的合成子，应用于有机半导体光电聚合材料领域，譬如聚合物PF可以作为电子注射材料；HIQF1可以作为太阳能电池敏化染料等。
关于9-芴酮类化合物的合成已有文献报道，大概分为两类方法：1)分子内环化反应构建9-芴酮衍生物，包括不同催化条件下2-羧酸(烷基、醛基、羟甲基等)联苯类化合物氧化环化，二芳基甲酮(醇)分子内氧化环化，芴氧化成芴酮等，代表性文献如下：[1]Ruzi,R.；Zhang,M.L.；Ablajan,K.*；Zhu.C.J.*J.Org.Chem.2017,82,12834-12839；[2]Fukuyama,T.*；Maetani,S.；Miyagawa,K.；Ryu,I.*Org.Lett.2014,16,3216-3219；[3]Laha,J.K.*Patel,K.V.；Dubey,G.；Jethava,K.P.Org.Biomol.Chem.,2017,15,2199-2210[4]Laha,J.K.；*Jethava,K.P.；Patel,S.；Patel,K.V.J.Org.Chem.2017,82,76-85；[5]Li,H.；Zhu,R.Y.；Shi,W.；He,K.H.；Shi,Z.J.*Org.Lett.,2012,14,4850-4853；[6]Seo,S.；Slater,M.；Greaney*,M.F.Org.Lett.,2012,14,2650-2653；[7]Gao,Q.；Xu,S.M*.Org.Biomol.Chem.,2018,16,208-212；[8]Zhang,J.R.；Yao,Q.Z.；Liu,Z.L.*Molecules.2015,20,21458-21463；2)分子间环化反应构建9-芴酮衍生物，包括2-卤联苯插羰环化，邻卤芳香醛与各种硼酸偶联环化，二卤代烃、CO、苯硼酸三组分串联环化，导向基团诱导C-H键活化环化反应等，具体参考文献：[1]Campo，M.A.；Larock，R.C.*Org.Lett.,2000,2,3675-3677；[2]Paul,S.；Samanta,S.；Ray,J.K.Tetrahedron Letters.,2010,51,5604-5608；[3]Liu,T.P.；Liao,Y.X.；Xing,C.H.；Hu,Q.S.Org.Lett.,2011,13,2452-2455；[4]Song,J.；Wei,F.L.；Sun,W.；Li,K.；Tian,Y.N.；Liu,C.；Li,Y.L.；Xie,L.H.Org.Lett.2015,17,2106-2109；[5]Sun,D.；Li,B.；Lan,J.B.*；Huang,Q.；You,J.S*.Chem.Commun.,2016,52,3635-3638；[6]Vignesh,A.；Kaminsky,W.；Dharmaraj,N.*ChemCatChem.,2016,8,3207-3212；[7]Chen,X.Y.；Ozturk,S.；Sorensen,E.J.*Org.Lett.2017,19,1140-1143；[8]Wang,Y.F.；Xu,W.G.；Sun,B.；Yu,Q.Q.；Li,T.J.；Zhang,F.L.*J.Org.Chem.,2019,84,13104-13111.
上述报道的合成方法，存在的问题是：有的需要使用昂贵的贵金属催化剂，有的涉及较为复杂的配体，有的在高温下反应，有的原料合成不易获得，有的产物收率较低，有的反应原子经济性较低，有的官能团容忍性较差等，这些方法从成本和环保的角度考虑都具有一定的局限性。更重要的是，这些方法难以直接在9-芴酮类化合物2-位引入羟基，9-芴酮骨架2-位引入羟基便于进一步衍生物，譬如两分子2-羟基-9-芴酮类化合物与1,3-苯二磺酰胺偶联，产物可作为胶原结合蛋白荧光探针。
发明内容
针对现有技术存在的问题，本发明提供了一种2-羟基-9-芴酮衍生物合成方法，提供了一种非金属催化的、反应条件温和的、低成本、对环境友好的2-羟基-9-芴酮衍生物及其合成方法。
本发明提供了一种2-羟基-9-芴酮类衍生物，其结构如式(I)所示：
式(I)中，R1为氢、6-氯、6-氟、6,7-二甲氧基、7-羟基；R2为芳基、烷基。
本发明还提出了一种2-羟基-9-芴酮类衍生物的合成方法，具体为：以邻呋喃芳基炔酮类化合物为原料，在空气条件下，加入有机溶剂和催化剂，在温和的反应温度(50℃-120℃；优选100℃)下反应一段时间(3h-48h；优选8h-17h)，一步催化合成得到式(I)2-羟基-9-芴酮类衍生物，其反应过程如式(II)所示：
式(II)中，R1为氢、卤素、烷氧基；R2为芳基、烷基；
优选地，R1为氢、6-氯、6-氟、6,7-二甲氧基、7-羟基；R2为苯基、4-甲基苯基、4-氯苯基、正丁基、环丙基的一种或多种；
其中，所述式(II)邻呋喃芳基炔酮类化合物为母环上连有吸电子基取代或供电子基取代的邻呋喃芳基炔酮、炔基取代的苯环上连有吸电子基或供电子基团。
其中，所述催化剂为TsOH·H2O、FeCl3、ZnCl2、AlCl3、BF3·Et2O的一种；优选为一水合对甲苯磺酸TsOH·H2O。
其中，所述有机溶剂选自二氯甲烷、DMF、1,4-二氧六环、甲苯的一种；优选为甲苯。
其中，式(II)邻呋喃芳基炔酮类化合物、催化剂的摩尔比为10:1～1:1；优选为10.0:1.0。
其中，当式(II)邻呋喃芳基炔酮类化合物为0.3mmol时，有机溶剂的用量为3mL。
其中，所述制备方法的收率为88％-96％。
在一个具体的实施方式中，在空气中，依次加入邻呋喃芳基炔酮类化合物、一水合对甲苯磺酸、甲苯，然后在100℃下反应8-17小时，TLC检测原料反应完全，冷却、浓缩、柱层析后，得到红色固体式(I)。
本发明还提出了所述式(I)2-羟基-9-芴酮类衍生物在制备抗病毒、抗肿瘤、解热、消炎等药物，荧光探针、敏化染料等功能材料中的潜在应用价值。
本发明的有益效果在于：无需使用贵金属催化剂，所用非金属催化剂一水合对甲苯磺酸(TsOH·H2O)廉价易得，原料邻呋喃芳基炔酮类化合物合成简便，反应对空气不敏感，反应条件较为温和，底物普适性好，后处理简单，反应收率大于88％，对环境友好。该方法一步实现了在9-芴酮衍生物2-位引入羟基，便于进一步衍生化，对于药物Tiorone低成本合成及以9-芴酮为关键骨架的荧光探针的制备提供了重要的参考。
具体实施方式
结合一下具体实施例，对本发明作进一步的详细说明，本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都包括在本发明中，并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。
本发明提供了一种2-羟基-9-芴酮类化合物的合成方法，直接在9-芴酮化合物2-位引入羟基，便于进一步衍生化，对于相关药物分子、功能材料的开发与修饰等具有重要的现实意义。
本发明方法中，邻呋喃芳基炔酮类化合物，在一水合对甲苯磺酸催化下的多步串联环化反应，如式(II)所示，在空气下，在催化剂一水合对甲苯磺酸存在下，将邻呋喃芳基炔酮化合物溶于甲苯中，在100℃下，反应8-17小时，经分离提纯后，得到式(I)2-羟基-9-芴酮类衍生物。
其中，R1为氢、6-氯、6-氟、6,7-二甲氧基、7-羟基；R2为芳基、烷基；
实施例1：1-苯基-2-羟基-9-芴酮(IA)的合成
空气下(无需惰性气体保护)，向10毫升封管中，加入邻呋喃苯基炔酮0.3mmol、甲苯3mL、一水对甲苯磺酸0.03mmol。在100℃反应17小时，然后冷却至室温，浓缩，柱层析，得到目标产物式(IA)，红色固体，分离收率95％。MP 194-196℃。
产物核磁数据：1H NMR(CDCl3,400MHz):δ5.32(s,1H),7.07(d,J＝8.0Hz,1H),7.17(d,J＝3.2Hz,1H),7.37-7.43(m,5H),7.47-7.54(m,5H)；13C NMR(CDCl3,100MHz):δ119.526,120.34,120.84,124.06,127.61,127.92,128.98,129.15,129.62,131.21,131.60,134.14,134.63,137.45,144.05,154.15,192.91.高分辨率质谱数据：HRMS(ESI,m/z)calcd.for C19H12O2[M+H]+calc.:273.0916；found:273.0920.
实施例2：1-苯基-2-羟基-6-氯-9-芴酮(IB)的合成
空气下(无需惰性气体保护)，向10毫升封管中，加入氯取代邻呋喃芳基炔酮0.3mmol、甲苯3mL、一水对甲苯磺酸0.03mmol。在100℃反应18小时，然后冷却至室温，浓缩，柱层析，得到目标产物式(IB)，深红色固体，分离收率90％。MP 206-207℃。
产物核磁数据：1H NMR[(CD3)2SO,400MHz]:δ7.09(d,J＝8.0Hz,1H),7.27-7.31(m,3H),7.36-7.39(m,4H),7.66(d,J＝8.0Hz,1H),7.80(d,J＝1.6Hz,1H),10.03(s,1H)；13CNMR[(CD3)2SO,100MHz]:δ120.11,120.44,121.77,124.92,127.28,127.43,128.92,130.03,131.56,132.02,133.09,133.97,139.80,145.87,156.86,190.99.
高分辨率质谱数据：HRMS(ESI,m/z)calcd.for C19H11ClO2[M+H]+calc.:307.0520；found:307.0512.
实施例3：1-苯基-2-羟基-6-氟-9-芴酮(IC)的合成
空气下(无需惰性气体保护)，向10毫升封管中，加入氟取代邻呋喃芳基炔酮0.3mmol、甲苯3mL、一水对甲苯磺酸0.03mmol。在100℃反应18小时，然后冷却至室温，浓缩，柱层析，得到目标产物式(IC)，红色固体，分离收率100％。MP 210-213℃。
产物核磁数据：1H NMR[(CD3)2SO,400MHz]:δ6.97-7.02(m,1H),7.09(d,J＝8.0Hz,1H),7.30-7.34(m,2H),7.35-7.41(m,3H),7.43(dd,J1＝8.2Hz,J2＝5.6Hz,1H),7.56(dd,J1＝9.0Hz,J2＝2.0Hz,1H),7.62(d,J＝8.0Hz,1H),10.02(s,1H)；13C[(CD3)2SO,100MHz]:δ107.73(d,J＝24.6Hz),114.01(d,J＝23.4Hz),120.27,121.66,125.84(d,J＝10.4Hz),127.22,127.27,128.78,129.82,130.06,131.85,133.12,133.76,147.12(J＝10.6Hz),156.84,166.85(d,J＝250Hz),190.65.
高分辨率质谱数据：HRMS(ESI,m/z)calcd.for C19H11FO2[M+H]+calc.:291.0816；found:291.0808.
实施例4：1-苯基-2-羟基-6,7-二甲氧基-9-芴酮(ID)的合成
空气下(无需惰性气体保护)，向10毫升封管中，加入双甲氧基取代邻呋喃芳基炔酮0.3mmol、甲苯3mL、一水对甲苯磺酸0.03mmol。在100℃反应15小时，然后冷却至室温，浓缩，柱层析，得到目标产物式(ID)，红色固体，分离收率85％。MP 264-265℃。
产物核磁数据：1H NMR[(CD3)2SO,400MHz]:δ3.77(s,3H),3.92(s,3H),6.92(s,1H),6.95(d,J＝8.0Hz,1H),7.24(s,1H),7.28-7.40(m,6H),9.61(s,1H)；13C NMR[(CD3)2SO,100MHz]:δ55.67,55.96,103.43,106.75,119.11,119.63,125.66,126.86,126.98,128.57,130.01,131.78,133.41,134.90,139.02,148.28,154.58,155.36,191.32.
高分辨率质谱数据：HRMS(ESI,m/z)calcd.for C21H16O4[M+H]+calc.:333.1121；found:333.1117.
实施例5：2,7-二羟基-9-芴酮(IE)的合成
空气下(无需惰性气体保护)，向10毫升封管中，加入羟基取代邻呋喃芳基炔酮0.3mmol、甲苯3mL、一水对甲苯磺酸0.03mmol。在100℃反应17小时，然后冷却至室温，浓缩，柱层析，得到目标产物式(IE)，红色固体，分离收率90％。
产物核磁数据：1HNMR(500MHz,acetone-d6):δ8.77(s,2H),7.40(d,J＝8.0Hz,2H),7.01(d,J＝2.4Hz,2H),6.95(dd,J＝8.0,2.4Hz,2H).13C NMR(126MHz,acetone d6):δ193.96,158.62,137.50,136.83,121.76,121.73,111.97.高分辨率质谱数据：HRMS(ESI,m/z)calcd.for C13H8O3[M+H]+calc.:213.0552；found:213.0556.
上述实施例只是为了说明本发明的技术构思及特点，其目的在于让本领域内的普通技术人员能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡是根据本发明内容的实质所作出的等效的变化或修饰，都应涵盖在本发明的保护范围内。
Claims (7)
1.一种2-羟基-9-芴酮类衍生物，其特征在于，其结构如式(I)所示，
其中，R1为氢、6-氯、6-氟、6,7-二甲氧基、7-羟基；R2为芳基、烷基。
2.一种如权利要求1所述的2-羟基-9-芴酮类衍生物的合成方法，其特征在于：以邻呋喃芳基炔酮类化合物为原料，在空气氛围下，加入有机溶剂和催化剂，在较温和的50℃-120℃反应温度下，反应3h-48h，一步催化合成得到式(I)所示的2-羟基-9-芴酮类化合物；其反应过程如式(II)所示：
式(II)中，R1为氢、6-氯、6-氟、6,7-二甲氧基、7-羟基；R2为芳基、烷基；所述的芳基为苯基或带有不同电性取代基的苯基。
3.根据权利要求2所述的一种2-羟基-9-芴酮类衍生物的合成方法，其特征在于：所述邻呋喃芳基炔酮类化合物为芳基上连有吸电子基的邻呋喃取代的芳基炔酮；芳基上连有供电子基的邻呋喃芳基取代的芳基炔酮；芳基或烷基取代的邻呋喃苯基炔酮。
4.根据权利要求2所述的2-羟基-9-芴酮类衍生物的合成方法，其特征在于：式(II)邻呋喃芳基炔酮类化合物、催化剂的摩尔比为10:1～1:1。
5.根据权利要求2所述的2-羟基-9-芴酮类衍生物的合成方法，其特征在于：所述的催化剂为FeCl3、ZnCl2、AlCl3、TsOH·H2O、BF3·Et2O的一种。
6.根据权利要求2所述的2-羟基-9-芴酮类衍生物的合成方法，其特征在于，所述的有机溶剂为甲苯、1,4-二氧六环、DMF、二氯甲烷的一种。
7.一种如权利要求1所述的2-羟基-9-芴酮类化合物的应用，其特征在于：所述2-羟基-9-芴酮类化合物应用于制备抗病毒、抗肿瘤、解热、消炎药物以及荧光探针、敏化材料。
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