CN111808072B - 一种3-甲酰基吲哚衍生物的合成方法 - Google Patents
一种3-甲酰基吲哚衍生物的合成方法 Download PDFInfo
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Classifications
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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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种3‑甲酰基吲哚衍生物的合成方法，包括：在钯催化剂和氧化剂的作用下，3‑(二甲氨基)‑1‑(2‑吡啶基)‑2‑丙烯酮与N‑取代苯胺在溶剂中进行反应，反应结束后经过后处理得到所述的3‑甲酰基吲哚衍生物。该方法基于C‑H/C‑H交叉脱氢偶联的策略作为关键步骤，简便地合成7种具有潜在活性的3‑甲酰基吲哚衍生物，该方法所用的原料廉价并且简单易得。
Description
技术领域
本发明属于有机合成领域，具体涉及一种3-甲酰基吲哚衍生物的合成方法。
背景技术
吲哚环是一类非常有应用价值的结构单元，广泛存在于香料、农药、煤焦油、精油和染料中。除此之外，从神经递质血清素等简单衍生物到临床上使用的抗癌药物长春碱和丝裂霉素C等复合生物碱，再到抗高血压生物碱利血平，吲哚衍生物在医药领域的作用不容忽视。其中，3-甲酰基吲哚衍生物呈现出了广泛的药理活性，被应用于治疗止吐、降压、抗肿瘤、抗炎、抗抑郁等诸多病症中。
随着人们对吲哚化合物用途认识的深入，对吲哚环化合物合成方法的研究也越来越多，现在每年都有不少关于这方面的报道。与此同时，过渡金属催化的C-H/C-H交叉脱氢偶联反应在有机合成中发挥着越来越重要的作用。2008年Frank Glorius教授报道了一种直接氧化偶联合成吲哚环结构的方式，实现了由(Z)-3-(苯胺基)丁-2-烯酸甲酯发生分子内环化反应合成吲哚的过程。该方法需要预先合成(Z)-3-(苯胺基)丁-2-烯酸甲酯底物，并且，对某些含有杂环(例如吡啶环)的底物反应活性不高。
发明内容
本发明提供了一种3-甲酰基吲哚衍生物的合成方法，该合成方法能够以价廉易得的原料一步合成3-甲酰基吲哚衍生物，并且底物上可以含有吡啶环。
一种3-甲酰基吲哚衍生物的合成方法，包括：
在钯催化剂和氧化剂的作用下，3-(二甲氨基)-1-(2-吡啶基)-2-丙烯酮与N-取代苯胺在溶剂中进行反应，反应结束后经过后处理得到所述的3-甲酰基吲哚衍生物；
所述的3-(二甲氨基)-1-(2-吡啶基)-2-丙烯酮的结构如式(II)所示：
所述的N-取代苯胺的结构如式所示：
所述的3-甲酰基吲哚衍生物的结构如式(I)所示：
式(I)和(III)中，R1选自H、卤素、C1～C4烷基或C1～C4烷氧基；
R2选自C1～C4烷基。
本发明中，钯催化剂、氧化剂和溶剂会对反应产生较大的影响，作为优选，所述的钯催化剂为醋酸钯。
作为优选，所述的氧化剂为醋酸铜或者醋酸银。
作为优选，所述的溶剂为三氟甲苯。
本发明中，R1优选为H、F、甲基或甲氧基。
R2优选为甲基或者乙基。
作为优选，反应温度为80～100℃，反应时间为12～24小时。
本发明的所述的3-甲酰基吲哚衍生物的合成方法，还包括3-(二甲氨基)-1-(2-吡啶基)-2-丙烯酮的合成：
2-乙酰基吡啶与N,N-二甲基甲酰胺二甲缩醛在甲苯中进行反应，得到所述的3-(二甲氨基)-1-(2-吡啶基)-2-丙烯酮。
同现有技术相比，本发明的有益效果体现在：
(1)本发明的起始原料简单易得，能够经过一步反应，方便地获得3-甲酰基吲哚衍生物；
(2)本发明的方法获得的产物具有多样性，可以含有杂环基团。
具体实施方式
以下结合具体实施例对本发明做进一步的描述。
本发明所用的主要仪器如下：
AvanceⅢ500MHz核磁共振仪(瑞士Bruker公司)；AvanceⅢ400MHz核磁共振仪(瑞士Bruker公司)；ESI-Q-TOF高分辨质谱仪(美国Waters公司)；
X-4B显微熔点仪(上海仪电物理光学仪器有限公司)。
主要试剂如下：
2-乙酰基吡啶、N,N-二甲基甲酰胺二甲缩醛、N-烷基芳香胺(萨恩化学技术(上海)有限公司)；醋酸钯(阿法埃莎化学有限公司)；所用其他试剂均为国产分析纯，未经处理直接使用；柱层析硅胶从青岛海洋化工公司购买。
本发明合成3-甲酰基吲哚衍生物(3a-3g)的一般反应式如下：
3a.R1＝H,R2＝CH3；3b.R1＝p-CH3,R2＝CH3；3c.R1＝p-OCH3,R2＝CH3；3d.R1＝p-F,R2＝CH3；3e.R1＝m-CH3,R2＝CH3；3f.R1＝H,R2＝CH2CH3
实施例1
(1)3-(二甲氨基)-1-(2-吡啶基)-2-丙烯酮(2)的合成
在100mL圆底烧瓶中加入5.02g(41.5mmol)2-乙酰基吡啶，10.36g(87mmol)N,N-二甲基甲酰胺二甲缩醛，用25mL甲苯溶解完全，在120℃下回流12h，跟踪点板以确定反应是否完全。停止反应后，减压抽滤得粗产品，向粗产品中加入60mL正己烷搅拌15min，抽滤。滤渣转移至60mL无水乙醚中搅拌15min。抽滤，用10mL无水乙醚洗涤滤渣，干燥得6.45g暗绿色固体(2,CAS no.75415-00-8)，产率88.3％,m.p.106-107℃。1H NMR(500MHz,CDCl3)δ8.63(d,1H,J＝4.5Hz),8.14(d,1H,J＝8.0Hz),7.92(d,1H,J＝12.5Hz),7.80(t,1H,J＝7.75Hz),7.36(t,1H,J＝6Hz),6.45(d,1H,J＝12.5Hz),3.18(s,3H),3.00(s,3H)；13C NMR(100MHz,CDCl3)δ186.8,156.2,154.7,148.2,136.7,125.4,122.0,91.1,45.1,37.4；HRMS(ESI)[M+H]+,C10H12N2O,实测值(计算值),m/z:177.1022(177.1022)。
(2)3-甲酰基吲哚衍生物(3)的合成
在35mL Schlenk管中加入0.044g(0.25mmol)3-(二甲氨基)-1-(2-吡啶基)-2-丙烯酮(2)，0.107g(1.0mmol)N-甲基苯胺(1)，0.006g(0.025mmol)醋酸钯，0.0545g(0.3mmol)醋酸铜，2.5mL三氟甲苯，90℃下反应24h。反应结束后，将体系冷却至室温，浓缩后经柱色谱分离(V(乙酸乙酯):V(石油醚)＝1:3)得化合物3a(Reaxys ID:9483414)。
结构表征数据如下：
3-(1-甲基-1H-吲哚基)-2-吡啶基-甲酮3a黄褐色固体，产率29％,m.p.102-103℃。1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.75(d,1H,J＝4.8Hz),8.64(d,1H,J＝6.8Hz),8.21(d,1H,J＝8Hz),7.92(t,1H,J＝7.8Hz),7.49(t,1H,J＝5.6Hz),7.39(m,3H),3.92(s,3H)；13C NMR(100MHz,CDCl3)δ186.3,156.8,148.0,140.6,137.1,137.0,128.2,125.7,123.6,123.4,123.0,122.9,113.8,109.5,33.6；HRMS(ESI)[M+H]+,C15H12N2O,实测值(计算值),m/z:237.1029(237.1022)。
实施例2～7化合物3b-3g的合成
合成方法的条件与化合物3a相同，不同之处在于反应底物不同，反应底物可以参考一般反应式，分别得到化合物3b-3g。
得到的产物表征数据和收率如下
3-(1,5-二甲基-1H-吲哚基)-2-吡啶基-甲酮3b:棕黄色液体，产率29％。1H NMR(500MHz,CDCl3)δ8.67(d,1H,J＝4.5Hz),8.66(s,1H),8.43(s,1H),8.15(d,1H,J＝8Hz),7.86(t,1H,J＝7.5Hz),7.43(t,1H,J＝6.5Hz),7.24(d,1H,J＝8Hz),7.15(d,1H,J＝8.5Hz),3.82(s,3H),2.52(s,3H)；13C NMR(125MHz,CDCl3)δ186.3,157.0,148.0,140.6,137.0,135.4,132.5,128.4,125.6,124.9,123.5,122.8,113.5,109.2,33.6,21.6；HRMS(ESI)[M+H]+,C16H14N2O,实测值(计算值),m/z:251.1177(251.1179)。
3-(1-甲基-5-甲氧基-1H-吲哚基)-2-吡啶基-甲酮3c(CAS no.59908-55-3):棕褐色固体，产率33％,m.p.101-102℃。1H NMR(400MHz,CDCl3)δ8.74(d,1H,J＝8Hz),8.72(s,1H),8.20(d,1H,J＝7.6Hz),8.17(d,1H,J＝2.4Hz),7.92(t,1H,J＝7.8Hz),7.48(t,1H,J＝6.2Hz),7.29(s,1H),7.01(d,1H,J＝8.8Hz),3.98(s,3H),3.89(s,3H)；13C NMR(125MHz,CDCl3)δ186.2,156.9,156.8,148.0,140.6,137.0,132.0,129.1,125.6,123.5,121.4,113.8,110.3,104.4,55.8,33.7；HRMS(ESI)[M+H]+,C16H14N2O2,实测值(计算值),m/z:267.1144(267.1128)。
3-(1-甲基-5-氟-1H-吲哚基)-2-吡啶基-甲酮3d:黄褐色针状结晶，产率20％,m.p.92-93℃。1H NMR(500MHz,CDCl3)δ8.82(s,1H),8.75(d,1H,J＝6Hz),8.33(d,1H,J＝12Hz),8.21(d,1H,J＝9.5Hz),7.94(t,1H,J＝9.5Hz),7.51(t,1H,J＝4.75Hz),7.32(t,1H,J＝7.5Hz),7.12(t,1H,J＝11Hz),3.92(s,3H)；13C NMR(125MHz,CDCl3)δ185.0,159.1(d,J＝243.9Hz),155.5,147.1,140.5,136.1,132.5,128.0(d,J＝10.9Hz),124.8,122.5,112.8(d,J＝4.5Hz),110.6(d,J＝27Hz),109.3(d,J＝10Hz),107.5(d,J＝25.9Hz),32.8；HRMS(ESI)[M+H]+,C15H11FN2O,实测值(计算值),m/z:255.0929(255.0928)。
3-(1,6-二甲基-1H-吲哚基)-2-吡啶基-甲酮3e:棕褐色固体，产率16％,m.p.96-97℃。1H NMR(500MHz,CDCl3)δ8.75(d,1H,J＝6Hz),8.69(s,1H),8.51(d,1H,J＝10Hz),8.21(d,1H,J＝10Hz),7.93(t,1H,J＝9.75Hz),7.49(t,1H,J＝7.5Hz),7.24(d,1H,J＝10Hz),7.21(s,1H),3.89(s,3H),2.57(s,3H)；13C NMR(125MHz,CDCl3)δ186.2,156.9,148.0,140.2,137.4,137.0,133.4,125.9,125.6,124.5,123.5,122.7,113.9,109.6,33.5,21.9；HRMS(ESI)[M+H]+,C16H14N2O,实测值(计算值),m/z:251.1178(251.1179)。
3-(1-乙基-1H-吲哚基)-2-吡啶基-甲酮3f:黄色液体，产率17％。1H NMR(500MHz,CDCl3)δ8.71(s,1H),8.63(d,1H,J＝4Hz),8.54(d,1H,J＝7Hz),8.09(d,1H,J＝8Hz),7.79(t,1H,J＝7.75Hz),7.36(t,1H,J＝6Hz),7.27(m,3H),4.17(q,2H,J＝7.5Hz),1.46(t,3H,J＝7Hz)；13C NMR(125MHz,CDCl3)δ185.3,155.9,147.1,138.0,136.0,135.1,127.4,124.6,122.5,122.2,122.1,121.8,113.0,108.6,40.9,14.2；HRMS(ESI)[M+H]+,C16H14N2O,实测值(计算值),m/z:251.1178(251.1179)。
1-(5,6-二氢-4H-吡咯并[3,2,1-IJ]喹啉基)-2-吡啶基-甲酮3g:棕黄色液体，产率40％。1H NMR(400MHz,CDCl3)δ8.74(m,2H),8.33(d,1H,J＝7.6Hz),8.21(d,1H,J＝8.0Hz),7.91(t,1H,J＝7.8Hz),7.47(t,1H,J＝6.0Hz),7.29(t,1H,J＝7.6Hz),7.07(d,1H,J＝6.8Hz),4.27(t,2H,J＝5.8Hz),3.05(t,2H,J＝6.0Hz),2.30(m,2H)；13C NMR(125MHz,CDCl3)δ186.4,156.9,148.0,137.5,137.0,134.2,126.2,125.5,123.5,123.2,122.0,120.7,120.5,114.3,44.9,24.4,22.8；HRMS(ESI)[M+H]+,C17H14N2O,实测值(计算值),m/z:263.1176(263.1179)。
实施例8～23
合成产物与实施例1相同，不同之处在于步骤(2)的反应条件改变，反应条件和反应结果见下表1。
表1步骤(2)反应条件的影响
N.D表示未检测到产物。
由表1可知，当反应不添加醋酸银时，反应均无法进行；当分别加入醋酸锰，氧化银或氯化铜时，反应效率明显下降，可见氧化剂对该反应效率有着较大的影响。
当使用氯化钯或三氟乙酸钯(II)代替醋酸钯为催化剂时，反应活性都不如醋酸钯，当不加入醋酸钯时，反应完全不能发生，可见催化剂对该反应的效率也有着较大的影响。
当分别使用甲苯、二甲苯代替三氟甲苯为溶剂时，反应效率略有降低；当使用极性相对较大的N,N-二甲基甲酰胺、1,2-二氯乙烷时，反应效率明显降低，甚至表现为完全抑制，可见溶剂对该反应的效率也有着较大的影响。
当反应温度升高，反应效率反而略微降低，当将反应温度降低，反应效率随之明显降低，因此，反应温度对该反应的效率也有着较大的影响。
Claims (5)
1.一种3-甲酰基吲哚衍生物的合成方法，其特征在于，包括：
在钯催化剂和氧化剂的作用下，3-(二甲氨基)-1-(2-吡啶基)-2-丙烯酮与N-取代苯胺在溶剂中进行反应，反应结束后经过后处理得到所述的3-甲酰基吲哚衍生物；
所述的3-(二甲氨基)-1-(2-吡啶基)-2-丙烯酮的结构如式（II）所示：
所述的N-取代苯胺的结构如式所示：
所述的3-甲酰基吲哚衍生物的结构如式（I）所示：
式（I）和（III）中，R1选自H、卤素、C1~C4烷基或C1~C4烷氧基；
R2选自C1~C4烷基；
所述的钯催化剂为醋酸钯；
所述的氧化剂为醋酸铜或者醋酸银；
所述的溶剂为三氟甲苯；
反应温度为80~100℃。
2.根据权利要求1所述的3-甲酰基吲哚衍生物的合成方法，其特征在于，R1选自H、F、甲基或甲氧基。
3.根据权利要求1所述的3-甲酰基吲哚衍生物的合成方法，其特征在于，R2选自甲基或者乙基。
4.根据权利要求1所述的3-甲酰基吲哚衍生物的合成方法，其特征在于，反应时间为12~24小时。
5.根据权利要求1所述的3-甲酰基吲哚衍生物的合成方法，其特征在于，还包括3-(二甲氨基)-1-(2-吡啶基)-2-丙烯酮的合成：
2-乙酰基吡啶与N,N-二甲基甲酰胺二甲缩醛在甲苯中进行反应，得到所述的3-(二甲氨基)-1-(2-吡啶基)-2-丙烯酮。
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