CN112062770A - 一种稠环二氢吡啶酮的制备方法 - Google Patents

一种稠环二氢吡啶酮的制备方法 Download PDF

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CN112062770A
CN112062770A CN202010852231.0A CN202010852231A CN112062770A CN 112062770 A CN112062770 A CN 112062770A CN 202010852231 A CN202010852231 A CN 202010852231A CN 112062770 A CN112062770 A CN 112062770A
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dihydropyridone
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孙嫚嫚
王治明
杨健国
王磊
马永敏
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Taizhou University
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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    • 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
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Abstract

本发明公开了一种稠环二氢吡啶酮的制备方法，包括：(1)联烯酯加合物1和芳酰胺2在碱和溶剂的作用下进行消除反应，得到中间反应液；(2)向步骤(1)所述的中间反应液中加入钯催化剂、氨基酸配体和铜盐，在空气或者氧气作用下，进行C‑H官能化和烯丙基胺化反应得到所述的稠环二氢吡啶酮。该方法原子利用率高，成本低，在合成领域具有重要的意义。

Description

一种稠环二氢吡啶酮的制备方法
技术领域
本发明属于有机合成领域，具体涉及一种稠环二氢吡啶酮的制备方法。
背景技术
杂芳环或芳环稠合的二氢吡啶酮化合物普遍存在于具有生物活性的天然产物和药物分子中，同时也是其他重要活性分子的合成前体。与通过多步反应构建该类化合物骨架的传统方法相比，过渡金属催化的包含C-H 活化过程的芳酰胺与烯烃的[4+2]环加成反应更占优势。然而，目前该类方法主要由昂贵的铑催化剂催化实现。用钯作催化剂时，由于竞争性的β-H 消除反应的存在，主要得到烯基化产物，不能得到[4+2]环加成产物。为解决这一问题，化学家们用共轭二烯代替普通烯烃进行反应，通过稳定的烯丙基钯中间体，成功实现了钯催化下芳酰胺与烯烃的[4+2]环加成反应，合成了一些稠环二氢吡啶酮化合物。然而目前报道中用到的共轭二烯结构都比较简单，以链状或单支链取代的共轭二烯为主，多取代尤其是吸电子基团为支链的共轭二烯报道很少。主要原因包括缺电子的支链共轭二烯难合成、二烯的Z/E选择性难控制、产物中碳碳双键的Z/E选择性难控制和共轭二烯副反应较多。鉴于1,3-共轭二烯也广泛存在于天然产物和药物活性分子中，且也是有机合成中非常重要的合成子，因此发展温和、高效的共轭二烯的合成方法并用于稠环二氢吡啶酮化合物制备的方法具有重大应用价值。
有机膦催化的联烯酸酯的反应是有机合成中非常重要的反应，被广泛用于环状和非环状化合物的合成。其中，联烯酸酯的亲核加成反应操作简单、成本较低，是制备取代烯烃的高效方法。尽管各类亲核加成反应已经被广泛研究，对于亲核加成产物的应用却很少报道。2018年，我们课题组发现，由Kwon课题组研发的α-苄基联烯酸酯的β’-加成产物在碱性条件下易发生消除反应得到传统方法中难以得到的1,2-双取代的缺电子共轭二烯化合物，并与邻碘苯酚化合物实现了钯催化的串联反应，合成了一系列二氢苯并呋喃和二氢吲哚化合物。该方法条件温和、转化高效、产物立体选择性高且产物中具有多个活性官能团，是非常具有应用价值的共轭二烯的合成前体。
发明内容
为解决上述技术问题，本发明提供了一种稠环二氢吡啶酮的制备方法，该制备方法原子利用率高，成本低。
本发明提供了一种稠环二氢吡啶酮的制备方法，包括：
(1)联烯酯加合物1和芳酰胺2在碱和溶剂的作用下进行消除反应，得到中间反应液；
(2)向步骤(1)所述的中间反应液中加入钯催化剂、氨基酸配体和铜盐，在空气或者氧气作用下，进行C-H官能化和烯丙基胺化反应得到所述的稠环二氢吡啶酮；
反应式如下：
Figure BDA0002645122960000021
其中，R为-COOEt、-COOMe、-COOBn或CN；
Ar1为取代或者未取代的芳基，所述芳基上的取代基为C1～C4烷基或卤素；优选为取代或者未取代的苯基，
Ar2为取代或者未取代的芳基或者杂芳基，所述芳基或者杂芳基上的取代基C1～C4烷基、C1～C4烷氧基或卤素；优选为取代或者未取代的苯基、噻吩基、呋喃基、吲哚基、苯并噻吩基。
作为优选，Ar1为取代或者未取代的苯基。
作为优选，Ar2为取代或者未取代的苯基、噻吩基、呋喃基、吲哚基、苯并噻吩基。
作为优选，步骤(1)中，所述的碱为氮双杂环二氮杂二环。
作为优选，步骤(1)中，所述的有机溶剂为对二甲苯。
作为优选，步骤(1)中，反应温度为80～100℃，反应时间为10～20 小时。
作为优选，步骤(2)中，所述的钯催化剂为三氟乙酸钯；
所述配体为N-乙酰甘氨酸。
作为优选，步骤(2)中，所述的铜盐为醋酸铜。
作为优选，步骤(2)中，反应温度为110～130℃，反应时间为20～30 小时。
作为优选，所述的稠环二氢吡啶酮为化合物4aa～4am、4ba～4ma和 6a～6o中的一种，这些化合物的具体结果见具体实施方式部分。
同现有技术相比，本发明的有益效果体现在：
本发明所采用的催化剂价格较便宜，底物容易获得，转化高效，得到的产物选择性好，方法的原子经济性好，可以或多含有多种官能团的稠环二氢吡啶酮，在合成上具有重要的应用意义。
具体实施方式
实施例1～16
10mL史莱克管中加入联烯酯加合物1a(0.4mmol)、碱(用量见表1) 和对二甲苯2mL，90℃敞口搅拌反应12小时，然后加入杂芳酰胺 2a(0.2mmol)、三氟乙酸钯(6.6mg,0.02mmol)，配体(见表1，0.012mmol)，醋酸铜(7.3mg,0.04mmol)，120℃敞口搅拌反应24小时。将反应体系冷却至室温，砂芯过滤，乙酸乙酯洗涤，浓缩溶剂，用石油醚/乙酸乙酯过柱得到目标产品4aa，条件和收率见表1。反应式如下：
Figure BDA0002645122960000031
表1实施例1～16的反应条件和收率
Figure BDA0002645122960000032
Figure BDA0002645122960000041
a中间产物3不分离；b分离收率。
实施例17～39
10mL史莱克管中加入联烯酯加合物1(0.4mmol)、杂芳酰胺 2(0.2mmol)、DBU(60.9mg,0.04mmol)和对二甲苯2mL，90℃敞口搅拌反应12小时，然后加入三氟乙酸钯(6.6mg,0.02mmol)，N-乙酰甘氨酸(4.7mg, 0.012mmol)，醋酸铜(7.3mg,0.04mmol)，120℃敞口搅拌反应24小时。将反应体系冷却至室温，砂芯过滤，乙酸乙酯洗涤，浓缩溶剂，用石油醚/ 乙酸乙酯＝5/1或3/1过柱得到目标产品4ab～4am和4ba～4ma。
化学反应式如下：
Figure BDA0002645122960000042
目标产品4ab～4am的结构如下：
Figure BDA0002645122960000051
目标产品4ba～4ma的结构和收率如下：
Figure BDA0002645122960000052
实施例40～54
10mL史莱克管中加入联烯酯加合物1a(0.6mmol)，苯甲酰胺5 (0.2mmol)，DBU(91.3mg,0.06mmol)，对二甲苯2mL，90℃敞口搅拌反应 12小时，然后加入三氟乙酸钯(6.6mg,0.02mmol)，N-乙酰甘氨酸(4.7mg, 0.012mmol)，醋酸铜(7.3mg,0.04mmol)，120℃敞口搅拌反应24小时。将反应体系冷却至室温，砂芯过滤，乙酸乙酯洗涤，浓缩溶剂，用石油醚/ 乙酸乙酯＝5/1或3/1过柱得到目标产品6a～6o。
化学反应式如下：
Figure BDA0002645122960000053
化合物6a～6o的结构和收率如下：
Figure BDA0002645122960000061
其中，6i与6i’、6j和6j’、6k和6k’为顺反异构的混合物。
实施例1～54部分产物的表征数据如下:
化合物4aa
Figure BDA0002645122960000062
1H NMR(400MHz,CDCl3)δ8.36(d,J＝8.6Hz,2H),8.23(d,J＝8.6 Hz,2H),7.61(d,J＝7.9Hz,1H),7.54(d,J＝8.3Hz,1H),7.49(t,J＝7.7Hz, 1H),7.34(t,J＝7.5Hz,1H),7.31–7.25(m,3H),7.09–7.06(m,2H),6.73(s, 1H),5.99(d,J＝7.1Hz,1H),3.76(dd,J＝17.4,7.2Hz,1H),3.66–3.58(m, 1H),3.57–3.49(m,1H),3.46(d,J＝17.5Hz,1H),0.69(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ167.7,156.8,155.9,150.5,143.9,141.4,134.9,133.5,131.3,130.9,129.3,128.7,128.1,126.0,125.2,124.4,123.5,121.7, 112.9,61.6,60.9,26.2,13.1；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C28H22N2O8SNa)569.0995,found 569.0998.
化合物4ab
Figure BDA0002645122960000071
1H NMR(400MHz,CDCl3)δ8.36(d,J＝8.9Hz,2H),8.23(d,J＝8.9 Hz,2H),7.43(d,J＝9.1Hz,1H),7.31–7.28(m,3H),7.12–7.04(m,3H), 6.96(d,J＝2.6Hz,1H),6.72(s,1H),5.97(d,J＝7.2Hz,1H),3.84(s,3H), 3.73(dd,J＝17.3,7.3Hz,1H),3.69–3.54(m,2H),3.43(d,J＝17.4Hz,1H), 0.73(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ167.7,157.0,155.8, 152.0,150.5,144.0,142.0,134.9,133.5,131.2,131.0,129.3,128.6,128.1,125.9,125.6,123.5,119.3,113.6,102.3,61.6,60.8,55.9,26.2,13.2；HRMS (ESI-TOF)m/z calcd for[M+Na]+(C29H24N2O9SNa)599.1100,found 599.1098.
化合物4ae
Figure BDA0002645122960000072
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.9Hz,2H),8.25(d,J＝8.9 Hz,2H),7.86(d,J＝7.9Hz,1H),7.78(d,J＝7.3Hz,1H),7.50(t,J＝7.6Hz, 1H),7.45(t,J＝7.2Hz,1H),7.31–7.27(m,3H),7.12–7.09(m,2H),6.76(s, 1H),6.00(d,J＝6.9Hz,1H),3.74(dd,J＝17.3,7.0Hz,1H),3.67–3.52(m, 2H),3.46–3.38(m,1H),0.62(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3) δ167.7,159.5,150.5,144.0,143.1,139.9,136.8,134.7,133.5,131.3,131.1, 129.3,129.2,128.7,128.4,128.1,125.4,123.7,123.5,123.4,61.6,60.6,28.9,13.0；HRMS(ESI-TOF)m/z calcd for[M+Na]+(C28H22N2O7S2Na)585.0766, found 585.0770.
化合物4ag
Figure BDA0002645122960000081
1H NMR(400MHz,CDCl3)δ8.34(d,J＝9.0Hz,2H),8.27(d,J＝9.0 Hz,2H),7.56(d,J＝1.9Hz,1H),7.33(dd,J＝8.9,2.0Hz,1H),7.32–7.24(m, 4H),7.12–7.06(m,2H),6.76(s,1H),5.95(d,J＝6.8Hz,1H),3.95(s,3H), 3.71(dd,J＝16.8,6.9Hz,1H),3.59–3.51(m,1H),3.44(d,J＝16.9Hz,1H), 3.36–3.28(m,1H),0.65(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3) δ168.0,158.5,150.4,144.5,138.6,134.5,133.8,131.5,130.9,129.1,128.6,128.0,127.2,126.8,125.0,124.5,123.6,120.2,118.9,111.6,61.2,61.0,31.7, 26.5,13.1；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C29H24ClN3O7SNa)616.0921,found616.0928.
化合物4ah
Figure BDA0002645122960000082
1H NMR(400MHz,CDCl3)δ8.36(d,J＝9.0Hz,2H),8.22(d,J＝8.9 Hz,2H),8.00(d,J＝7.5Hz,1H),7.35–7.18(m,6H),7.13–7.04(m,2H),6.74 (s,1H),5.95(d,J＝7.0Hz,1H),3.69(s,3H),3.67(dd,J＝15.6,7.2Hz,1H), 3.61–3.53(m,1H),3.43(d,J＝17.2Hz,1H),3.39–3.32(m 1H),0.73(t,J＝ 7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ167.9,160.6,150.2,145.3,144.1, 138.0,134.4,133.6,131.4,130.9,129.2,128.6,128.1,124.9,123.5,123.4, 122.9,120.7,109.8,104.1,61.6,59.3,30.1,27.2,13.2；HRMS(ESI-TOF)m/zcalcd for[M+Na]+(C29H25N3O7SNa)582.1311,found 582.1310.
化合物4aj
Figure BDA0002645122960000091
1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.9Hz,2H),8.22(d,J＝8.9 Hz,2H),7.59(d,J＝1.7Hz,1H),7.32–7.28(m,3H),7.08–7.06(m,2H),6.62 (s,1H),6.42(d,J＝1.7Hz,1H),5.86(d,J＝7.1Hz,1H),3.90–3.71(m,2H), 3.58(dd,J＝17.3,7.2Hz,1H),3.20(d,J＝17.3Hz,1H),0.90(t,J＝7.1Hz, 3H)；13C NMR(100MHz,CDCl3)δ167.6,154.7,150.5,149.1,144.1,140.9, 134.9,133.6,131.2,131.2,131.0,129.2,128.6,128.1,123.4,111.3,61.6,60.7, 27.4,13.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C24H20N2O8SNa)519.0838,found 519.0844.
化合物4ak
Figure BDA0002645122960000092
1H NMR(400MHz,CDCl3)δ8.32(d,J＝8.7Hz,2H),8.23(d,J＝9.0 Hz,2H),7.62(d,J＝4.9Hz,1H),7.31–7.29(m,3H),7.09–7.07(m,2H), 6.93(d,J＝4.9Hz,1H),6.66(s,1H),5.89(d,J＝7.0Hz,1H),3.76–3.68(m, 2H),3.62(dd,J＝17.1,7.1Hz,1H),3.38(d,J＝17.1Hz,1H),0.88(t,J＝7.2 Hz,3H)；13C NMR(100MHz,CDCl3)δ167.6,158.8,150.5,144.5,144.2, 135.4,134.8,133.7,131.2,131.2,129.2,129.2,128.6,128.1,127.5,123.4,61.5,60.4,30.5,13.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C24H20N2O7S2Na)535.0610,found 535.0616.
化合物4al
Figure BDA0002645122960000101
1H NMR(400MHz,CDCl3)δ8.31(d,J＝9.0Hz,2H),8.24(d,J＝8.9 Hz,2H),7.32–7.26(m,3H),7.13–7.04(m,2H),6.74(d,J＝2.4Hz,1H),6.62 (s,1H),5.94(d,J＝2.4Hz,1H),5.84(d,J＝6.8Hz,1H),3.82–3.77(m,5H), 3.52(dd,J＝16.8,6.9Hz,1H),3.15(d,J＝16.7Hz,1H),0.94(t,J＝7.2Hz, 3H)；13C NMR(100MHz,CDCl3)δ167.9,157.4,150.2,145.2,134.2,134.1, 132.0,131.7,130.7,128.8,128.8,128.5,128.1,123.5,119.4,106.8,61.2,60.9, 36.3,28.3,13.5；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C25H23N3O7SNa)532.1154,found 532.1158.
化合物4am
Figure BDA0002645122960000102
1H NMR(400MHz,CDCl3)δ8.33–8.26(m,4H),7.35–7.29(m,4H), 7.12–7.04(m,2H),6.67(s,1H),5.86(d,J＝6.9Hz,1H),4.06(s,3H), 3.77–3.64(m,2H),3.53(dd,J＝16.5,6.9Hz,1H),3.21(dd,J＝16.6,1.3Hz, 1H),0.90(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ167.9,156.6, 150.6,144.1,135.4,134.8,133.7,131.2,131.0,129.2,129.2,128.6,128.0,123.6,121.4,61.7,61.5,39.1,26.2,13.4；HRMS(ESI-TOF)m/z calcd for[M +Na]+(C24H22N4O7SNa)533.1107,found 533.1109.
化合物4ba
Figure BDA0002645122960000111
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.9Hz,2H),8.22(d,J＝8.9 Hz,2H),7.61(d,J＝7.7Hz,1H),7.54(d,J＝8.4Hz,1H),7.49(t,J＝7.7Hz, 1H),7.34(t,J＝7.4Hz,1H),7.09(d,J＝8.0Hz,2H),6.97(d,J＝8.1Hz,2H), 6.68(s,1H),5.96(d,J＝7.1Hz,1H),3.76(dd,J＝17.4,7.3Hz,1H), 3.67–3.56(m,1H),3.56–3.48(m,1H),3.45(d,J＝17.0Hz,1H),2.32(s,3H), 0.70(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ167.9,156.8,155.9, 150.5,143.9,141.4,139.6,134.8,131.3,130.5,129.7,129.4,129.2,128.1, 126.0,125.2,124.4,123.5,121.7,112.9,61.5,61.1,26.2,21.3,13.1；HRMS (ESI-TOF)m/z calcd for[M+Na]+(C29H24N2O8SNa)583.1151,found 583.1152.
化合物4ca
Figure BDA0002645122960000112
1H NMR(400MHz,CDCl3)δ8.40–8.32(m,2H),8.28–8.20(m,2H), 7.60(d,J＝7.9Hz,1H),7.55(d,J＝8.4Hz,1H),7.5(t,J＝7.2Hz,1H),7.34 (t,J＝7.5Hz,1H),7.32–7.27(m,2H),7.05–6.95(m,2H),6.65(s,1H),5.96(d, J＝7.1Hz,1H),3.76(dd,J＝17.3,7.2Hz,1H),3.68–3.52(m,2H),3.45(dd,J ＝17.4,1.0Hz,1H),1.28(s,9H),0.72(t,J＝7.1Hz,3H)；13C NMR(100 MHz,CDCl3)δ167.9,156.8,155.9,152.8,150.5,143.9,141.4,134.8,131.3, 130.4,129.7,129.2,128.0,126.0,125.6,125.2,124.4,123.5,121.6,112.9,61.5,61.0,34.8,31.1,26.3,13.1；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C32H30N2O8SNa)625.1621,found 625.1620.
化合物4ja
Figure BDA0002645122960000121
1H NMR(400MHz,CDCl3)δ8.39(d,J＝8.9Hz,2H),8.23(d,J＝8.8 Hz,2H),7.83–7.69(m,3H),7.62(d,J＝7.9Hz,1H),7.59–7.43(m,5H),7.34 (t,J＝7.5Hz,1H),7.16(d,J＝8.5Hz,1H),6.88(s,1H),6.03(d,J＝7.0Hz, 1H),3.78(dd,J＝17.4,7.3Hz,1H),3.70–3.61(m,1H),3.61–3.54(m,1H), 3.51(d,J＝17.5Hz,1H),0.69(t,J＝7.2Hz,3H)；13C NMR(100MHz, CDCl3)δ167.9,156.9,155.9,150.6,143.9,141.4,135.0,133.3,133.0,131.3,131.0,131.0,129.3,128.5,128.4,128.2,127.7,127.2,126.8,126.0,125.2, 124.8,124.4,123.5,121.7,112.9,61.6,61.0,26.3,13.2；HRMS(ESI-TOF)m/zcalcd for[M+Na]+(C32H24N2O8SNa)619.1151,found 619.1155.
化合物4la
Figure BDA0002645122960000122
1H NMR(400MHz,CDCl3)δ8.27(d,J＝8.9Hz,2H),8.05(d,J＝9.0 Hz,2H),7.59–7.56(m,2H),7.52(t,J＝7.7Hz,1H),7.35(t,J＝7.6Hz,1H), 7.29–7.16(m,6H),7.01(d,J＝7.3Hz,2H),6.81(d,J＝7.0Hz,2H),6.75(s, 1H),5.97(d,J＝7.1Hz,1H),4.52–4.44(m,2H),3.76(dd,J＝17.4,7.3Hz, 1H),3.45(d,J＝17.2Hz,1H)；13C NMR(100MHz,CDCl3)δ167.4,156.9, 155.8,150.3,143.7,141.4,135.2,133.6,133.3,131.1,130.7,129.3,129.0, 128.7,128.4,128.1,126.1,125.2,124.4,123.3,121.7,112.9,67.5,61.0,26.1；HRMS(ESI-TOF)m/z calcd for[M+Na]+(C33H24N2O8SNa)631.1151,found 631.1151.
化合物4ma
Figure BDA0002645122960000131
1H NMR(400MHz,CDCl3)δ8.36–8.29(m,4H),7.64(d,J＝7.9Hz, 1H),7.60–7.56(m,3H),7.53(t,J＝7.8Hz,1H),7.46–7.35(m,4H),7.09(s, 1H),5.97(d,J＝6.9Hz,1H),3.77(dd,J＝17.7,6.9Hz,1H),3.58(d,J＝16.8 Hz,1H)；13C NMR(100MHz,CDCl3)δ157.2,155.3,150.8,146.1,143.7, 141.2,131.8,131.5,130.9,129.7,129.3,129.2,125.6,124.9,124.6,124.0, 121.6,116.3,113.1,108.6,59.3,26.4；HRMS(ESI-TOF)m/z calcd for[M+Na]+(C26H17N3O6SNa)522.0736,found 522.0742.
化合物6a
Figure BDA0002645122960000132
1H NMR(400MHz,CDCl3)δ8.34(d,J＝9.1Hz,2H),8.28(d,J＝9.0 Hz,2H),7.96(d,J＝7.9Hz,1H),7.50(t,J＝7.6Hz,1H),7.33(t,J＝7.6Hz, 1H),7.29–7.24(m,3H),7.21(d,J＝7.6Hz,1H),7.10–7.01(m,2H),6.64(s, 1H),5.86(d,J＝6.3Hz,1H),3.75(dd,J＝16.6,6.7Hz,1H),3.65(q,J＝7.1 Hz,2H),3.32(dd,J＝16.6,1.7Hz,1H),0.87(t,J＝7.2Hz,3H)；13C NMR (100MHz,CDCl3)δ167.6,163.0,150.5,144.2,136.0,135.3,134.3,133.9,131.14,131.13,129.0,128.6,128.5,128.4,128.1,127.9,127.2,123.5,61.3, 58.4,33.7,13.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C26H22N2O7SNa)529.1045,found529.1047.
化合物6b
Figure BDA0002645122960000141
1H NMR(400MHz,CDCl3)δ8.34(d,J＝9.0Hz,2H),8.27(d,J＝8.9 Hz,2H),7.84(d,J＝8.0Hz,1H),7.31–7.23(m,3H),7.12(d,J＝8.0Hz,1H), 7.09–7.02(m,2H),7.00(s,1H),6.60(s,1H),5.85(d,J＝6.4Hz,1H),3.73- 3.66(m,3H),3.26(d,J＝16.6Hz,1H),2.35(s,3H),0.90(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ157.6,163.0,150.5,145.5,144.3,136.1,135.1, 134.0,131.2,131.1,128.9,128.9,128.8,128.7,128.5,128.1,124.6,123.5, 61.4,58.3,33.7,21.7,13.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C27H24N2O7SNa)543.1202,found 543.1209.
化合物6e
Figure BDA0002645122960000142
1H NMR(400MHz,CDCl3)δ8.34(d,J＝9.0Hz,2H),8.27(d,J＝8.9 Hz,2H),7.91(d,J＝8.8Hz,1H),7.31–7.23(m,3H),7.06–7.03(m,2H),6.82 (dd,J＝8.8,2.4Hz,1H),6.65(d,J＝1.9Hz,1H),6.59(s,1H),5.85(d,J＝6.4 Hz,1H),3.82(s,3H),3.80–3.66(m,3H),3.26(d,J＝16.6Hz,1H),0.91(t,J ＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ167.6,164.4,162.7,150.5, 144.4,138.5,135.2,134.0,131.2,131.1,131.0,128.9,128.5,128.1,123.5,119.7,113.9,112.9,61.4,58.2,55.6,34.0,13.4；HRMS(ESI-TOF)m/z calcd for[M+Na]+(C27H24N2O8SNa)559.1151,found 559.1159.
化合物6i
Figure BDA0002645122960000151
1H NMR(400MHz,CDCl3)δ8.34–8.27(m,4H),7.90(d,J＝8.4Hz, 1H),7.34–7.27(m,4H),7.22(s,1H),7.07–7.04(m,2H),6.61(s,1H),5.86(d, J＝6.3Hz,1H),3.78–3.65(m,3H),3.30(d,J＝16.8Hz,1H),0.91(t,J＝7.1 Hz,3H)；13C NMR(100MHz,CDCl3)δ167.6,162.2,150.6,143.9,140.7, 137.8,135.5,133.8,131.2,130.8,130.2,129.1,128.5,128.4,128.3,128.1, 125.7,123.6,61.5,58.2,33.6,13.4；HRMS(ESI-TOF)m/z calcd for[M+ Na]+(C26H21ClN2O7SNa)563.0656,found 563.0662.
化合物6i'
Figure BDA0002645122960000152
1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.9Hz,2H),8.24(d,J＝8.9 Hz,2H),7.92(d,J＝8.4Hz,1H),7.79(s,1H),7.55–7.51(m,2H),7.48–7.45 (m,3H),7.29(d,J＝8.4Hz,1H),7.16(s,1H),6.21(d,J＝7.7Hz,1H),3.76 (dd,J＝16.5,8.0Hz,1H),3.72–3.65(m,1H),3.63–3.55(m,1H),3.05(d,J＝ 16.7Hz,1H),0.86(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ165.9, 162.8,150.5,144.2,143.3,139.7,137.3,133.9,131.2,130.9,129.7,129.4, 129.1,128.4,128.0,127.5,127.2,123.5,61.2,51.9,34.7,13.7；HRMS (ESI-TOF)m/z calcd for[M+Na]+(C26H21ClN2O7SNa)563.0656,found 563.0658.
化合物6l
Figure BDA0002645122960000161
1H NMR(400MHz,CDCl3)δ8.56(s,1H),8.38(d,J＝9.0Hz,2H),8.30 (d,J＝9.0Hz,2H),7.88(d,J＝8.2Hz,1H),7.77(d,J＝8.2Hz,1H),7.63(s, 1H),7.57(t,J＝7.5Hz,1H),7.48(t,J＝7.2Hz,1H),7.27–7.16(m,3H), 7.02–6.94(m,2H),6.59(s,1H),5.95(d,J＝5.8Hz,1H),3.85(dd,J＝16.2, 6.3Hz,1H),3.72–3.59(m,2H),3.51(d,J＝16.2Hz,1H),0.84(t,J＝7.1Hz, 3H)；13C NMR(100MHz,CDCl3)δ167.6,163.4,150.6,144.2,136.0,135.4, 134.0,132.0,131.2,131.2,130.8,130.8,129.6,129.3,128.9,128.4,128.1,127.3,127.1,126.8,125.1,123.6,61.3,58.3,34.1,13.3；HRMS(ESI-TOF) m/z calcd for[M+Na]+(C30H24N2O7SNa)579.1202,found 579.1199.
化合物6n
Figure BDA0002645122960000162
1H NMR(400MHz,CDCl3)δ8.14(d,J＝7.9Hz,1H),7.53(t,J＝7.5Hz, 1H),7.39(t,J＝7.6Hz,1H),7.31–7.21(m,4H),7.17-7.14(m,2H),6.74(s, 1H),5.63(d,J＝6.5Hz,1H),3.77–3.55(m,3H),3.50(s,3H),3.27(d,J＝ 16.6Hz,1H),0.96(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ168.1, 163.9,136.3,134.8,134.2,134.0,131.3,128.7,128.7,128.4,128.2,128.2, 127.8,127.5,61.4,58.1,42.3,33.5,13.4；HRMS(ESI-TOF)m/z calcd for[M +Na]+(C21H21NO5SNa)422.1038,found 422.1046。

Claims (10)

1.一种稠环二氢吡啶酮的制备方法，其特征在于，包括：
(1)联烯酯加合物1和芳酰胺2在碱和溶剂的作用下进行消除反应，得到中间反应液；
(2)向步骤(1)所述的中间反应液中加入钯催化剂、氨基酸配体和铜盐，在空气或者氧气作用下，进行C-H官能化和烯丙基胺化反应得到所述的稠环二氢吡啶酮；
反应式如下：
Figure FDA0002645122950000011
其中，R为-COOEt、-COOMe、-COOBn或CN；
Ar1为取代或者未取代的芳基，所述芳基上的取代基为C1～C4烷基或卤素；
Ar2为取代或者未取代的芳基或者杂芳基，所述芳基或者杂芳基上的取代基C1～C4烷基、C1～C4烷氧基或卤素。
2.根据权利要求1所述的稠环二氢吡啶酮的制备方法，其特征在于，其特征在于，Ar1为取代或者未取代的苯基。
3.根据权利要求1所述的稠环二氢吡啶酮的制备方法，其特征在于，其特征在于，Ar2为取代或者未取代的苯基、噻吩基、呋喃基、吲哚基、苯并噻吩基。
4.根据权利要求1所述的稠环二氢吡啶酮的制备方法，其特征在于，步骤(1)中，所述的碱为氮双杂环二氮杂二环。
5.根据权利要求1所述的稠环二氢吡啶酮的制备方法，其特征在于，步骤(1)中，所述的有机溶剂为对二甲苯。
6.根据权利要求1所述的稠环二氢吡啶酮的制备方法，其特征在于，步骤(1)中，反应温度为80～100℃，反应时间为10～20小时。
7.根据权利要求1所述的稠环二氢吡啶酮的制备方法，其特征在于，步骤(2)中，所述的钯催化剂为三氟乙酸钯；
所述配体为N-乙酰甘氨酸。
8.根据权利要求1所述的稠环二氢吡啶酮的制备方法，其特征在于，步骤(2)中，所述的铜盐为醋酸铜。
9.根据权利要求1所述的稠环二氢吡啶酮的制备方法，其特征在于，步骤(2)中，反应温度为110～130℃，反应时间为20～30小时。
10.根据权利要求1所述的稠环二氢吡啶酮的制备方法，其特征在于，所述的稠环二氢吡啶酮为化合物4aa～4am、4ba～4ma和6a～6o中的一种。
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Application publication date: 20201211