CN110283180B - 一种合成吡啶[3,4-c]香豆素的方法 - Google Patents
一种合成吡啶[3,4-c]香豆素的方法 Download PDFInfo
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- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 235000001671 coumarin Nutrition 0.000 title claims abstract description 41
- 229960000956 coumarin Drugs 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title abstract description 33
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title abstract description 16
- 230000002194 synthesizing effect Effects 0.000 title abstract description 4
- 125000001495 ethyl group Chemical class [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 44
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- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 7
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- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 229910052751 metal Inorganic materials 0.000 claims abstract description 5
- 239000002184 metal Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
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- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 239000001632 sodium acetate Substances 0.000 claims description 11
- 235000017281 sodium acetate Nutrition 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
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- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 8
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- 238000006243 chemical reaction Methods 0.000 abstract description 63
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- 238000007796 conventional method Methods 0.000 description 2
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- 239000013076 target substance Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical group CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 102000003962 Dopamine D4 receptors Human genes 0.000 description 1
- 108090000357 Dopamine D4 receptors Proteins 0.000 description 1
- JAGZUIGGHGTFHO-UHFFFAOYSA-N Ethyl 3-phenylpropanoate Chemical compound CCOC(=O)CCC1=CC=CC=C1 JAGZUIGGHGTFHO-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
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- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 1
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- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—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
- 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
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种合成吡啶[3,4‑c]香豆素的方法。该方法是以(E)‑3‑(1‑(乙酰氧基亚胺)‑2‑取代乙基)香豆素类化合物与炔烃于有机溶剂中,在一定温度下,经金属催化体系催化反应数小时,得到目标化合物。该方法克服了现有技术中,底物获取困难,反应条件苛刻(温度高、时间长),需要使用强酸,步骤繁琐、收率低、不能制备吡啶环多碳取代的目标物等缺点。本发明公开的合成方法将在吡啶并香豆素衍生物的研究领域发挥重要作用。
Description
技术领域
本发明涉及一种吡啶并香豆素稠环化合物的制备方法,具体地说,涉及一种由(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素类化合物与炔烃反应制备吡啶[3,4-c]香豆素类化合物的方法。
背景技术
香豆素和吡啶核是多种天然产物和生物活性药物的两个非常重要的杂环骨架。作为这两个片段的稠环衍生物,吡啶[3,4-c]香豆素类化合物已被发现是存在于多个天然产物及人工生物活性分子中的一种新出现的三环分子杂化体。这些吡啶香豆素衍生物被证实具有多样化的活性,包括抗抑郁、抗病毒、抗精神病药、抗肿瘤、抗菌的功能,同时也显示出光物理性质和多巴胺D4受体标记剂的潜力。迄今为止,已经建立了几种制备这类骨架的合成方法,丰富了吡啶香豆素类似物数据库,有利于进一步药物开发。其中,一种传统策略是在多聚磷酸或三溴化硼存在下,对4-芳基烟酸衍生物进行催化环化(Eur J Org Chem,2008, 2008(9): 1507-1509;Org Lett, 2016,18(20): 5432-5435)。另一种传统的方法是以乙酸铵为催化剂和氮源,将水杨醛、氰基乙酸酯和醛(酮)进行多组分缩合(Bull ChemSocJpn, 1970,43(9): 2925-2933;J Heterocycl Chem, 1988, 25(6): 1767-1768),这种方法一般用来合成4-氨基色烯[3,4-c]吡啶-5-酮。近年来,逆电子D-A反应已成为合成二氢吡啶衍生物结构的有力工具,二氢吡啶衍生物很容易发生进一步的脱氢反应,合成其饱和杂环化合物(Chem Commun, 2010,46(15): 2665-2667;Org Lett, 2012, 14(12): 3226-3229)。后来,Xiao课题组研究了一种串联方法,以4-炔基-3-甲酰基香豆素为原料,获得C-4官能化的吡啶[3,4-c]香豆素类化合物(Adv Synth Catal, 2014, 356(8): 1835-1845)。在2016年,Villemin和他的同事们公开了一种高效实用的方法,通过4-(2-氨基)乙烯基-3-氰酸酯反应合成4-烷氨基吡啶[3,4-c]香豆素(Tetrahedron, 2016, 72(13): 1653-1661)。最近,Chen等人报道了布莱斯反应中间体和3-氰基香豆素的CuCl2催化串联反应,有效地获得了4-氨基-1,2-二取代吡啶[3,4-c]香豆素类化合物(Synlett, 2018,DOI:10.1055/s-0036-1591535)。目前为止,尽管在研究多功能、高效率吡啶[3,4-c]香豆素类化合物的合成方面取得了很多成就,但是在吡啶环部分的三个C位上都实现C-基官能化仍然具有挑战性。
综观文献,现有技术中存在的缺陷是:底物获取困难,反应条件苛刻(温度高、时间长),需要使用强酸,步骤繁琐、收率低、不能制备吡啶环多碳取代的目标物等。
,提出了一种从香豆素O-乙酰基肟和内炔化合物合成高取代吡啶[3,4-c]香豆素类化合物的有效方法。
因此,提供一种步骤简洁、条件温和、成本低廉、对环境友好的吡啶[3,4-c]香豆素类化合物制备方法成为本发明需要解决的技术问题。
发明内容
本发明的目的是提供一种工艺简单、条件温和、环境友好的吡啶[3,4-c]香豆素类化合物的制备方法。
本发明所要制备的吡啶[3,4-c]香豆素类化合物,其结构式如式II所示:
而本发明所提供的制备式II所示化合物的方法,其特征在于,所述方法的主要步骤是:在金属催化体系作用下,由式I所示(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素类化合物与炔烃(结构式如式III所示)在有机溶剂中于一定温度反应数小时,得到目标产物II:
其中,R1为氢,烷基,烷氧基,卤素;R2为烷基,芳基。
所述的金属催化剂体系是指二氯(五甲基环戊二烯基)合铑(III)二聚物([Cp*RhCl2]2),碱,和(或)银盐构成的催化体系。
所述的碱是指乙酸盐,碳酸盐和磷酸盐,优选乙酸钠,乙酸钾和乙酸铯。
所述的银盐是指六氟锑酸银,三氟甲磺酸银,乙酸银,硝酸银。
所述的有机溶剂是指烷基醇,卤代烷基醇,卤代烷,优选甲醇,乙醇,六氟异丙醇,1,2-二氯乙烷。
所述的一定温度是指30~80 oC,优选50 oC。
所述的数小时是指4~12 h,优选8h。
本发明的特点是:以容易制备的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素类化合物(式I所示化合物)和炔烃(式III所示化合物)为原料,经一步反应即可得到目标产物(式II所示化合物),克服了现有技术中底物制备困难、需要用到强酸、多步、反应条件苛刻(温度高、时间长)、收率低、不能制备吡啶环多碳取代的目标物等不足。
下面结合具体实例对本发明做进一步详细说明。
具体实施方式
下述实施中所用方法如无特殊说明均为常规方法。
实施例1、(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素与二苯炔合成吡啶[3,4-c]香豆素类化合物,并检测不同添加剂对反应的影响(以式所示II-1化合物为例);
往反应管中,先后加入(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素(0.1 mmol)、二苯炔(0.12 mmol)、[Cp*RhCl2]2(2.5 mol%)、添加剂(30 mol%)(乙酸钠、乙酸钾、乙酸铯、碳酸铯、磷酸钾)和甲醇(0.5 mL),于60oC下封口反应8h。用乙酸乙酯萃取,有机相蒸干,用硅胶柱层析分离出目标产物,计算分离收率如表1所示,其中,使用乙酸钠时目标产物II-1的收率获得最高值,为80%,将乙酸钠定为最优添加剂。
Mp 243-246oC ;1H NMR (400 MHz, CDCl3) δ 7.37 – 7.28 (m, 5H), 7.19 (s,5H), 7.12 (d, J = 6.4 Hz, 2H), 6.82 (d, J = 8 Hz, 1H), 6.75 (t, J = 7.4 Hz,1H), 3.17 (s, 3H);13C NMR (101 MHz, CDCl3) δ 162.83, 162.26, 160.07, 152.64,141.76, 139.87, 138.30, 131.51, 130.78, 129.58, 129.44, 129.24, 128.79,128.11, 127.90, 127.66, 123.26, 117.48, 117.27, 114.60, 27.51。
表1不同添加剂对反应的影响
反应溶剂 | 乙酸钠 | 乙酸钾 | 乙酸铯 | 碳酸铯 | 磷酸钾 |
分离收率(%) | 80 | 78 | 76 | Trace | Trace |
实施例2、(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素与二苯炔合成吡啶[3,4-c]香豆素类化合物,并检测不同溶剂对反应的影响(以式所示II-1化合物为例)。
往反应管中,先后加入(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素(0.1 mmol)、二苯炔(0.12 mmol)、[Cp*RhCl2]2(2.5 mol%)、乙酸钠(30 mol%)和溶剂(0.5 mL)(甲醇、乙醇、乙腈、1,2-二氯乙烷、六氟异丙醇、N,N-二甲基甲酰胺、二甲基亚砜),于60oC下封口反应8h。用乙酸乙酯萃取,有机相蒸干,用硅胶柱层析分离出目标产物,计算分离收率如表2所示,其中,在甲醇中目标产物II-1的收率获得最高值,为80%,将最佳溶剂定为甲醇。
表2不同溶剂对反应的影响
反应溶剂 | 甲醇 | 乙醇 | 乙腈 | 1,2-二氯乙烷 | 六氟异丙醇 | N,N-二甲基甲酰胺 | 二甲基亚砜 |
分离收率(%) | 80 | 70 | trace | 20 | 30 | N.D. | N. D. |
实施例3、(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素与二苯炔合成吡啶[3,4-c]香豆素类化合物,并检测银盐对反应的影响(以式所示II-1化合物为例)。
往反应管中,先后加入(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素(0.1 mmol)、二苯炔(0.12 mmol)、[Cp*RhCl2]2(2.5 mol%)、乙酸钠(30 mol%)、银盐(20 mol%)(无、六氟锑酸银、三氟甲磺酸银、乙酸银、硝酸银)和甲醇(0.5 mL),于60oC下封口反应8h。用乙酸乙酯萃取,有机相蒸干,用硅胶柱层析分离出目标产物,计算分离收率如表3所示,其中,不添加银盐和加入硝酸银时目标产物II-1的收率均为80%,因此催化体系不添加银盐。
表3不同银盐对反应的影响
反应溶剂 | 无 | 六氟锑酸银 | 三氟甲磺酸银 | 乙酸银 | 硝酸银 |
分离收率(%) | 80 | 77 | 79 | 75 | 80 |
实施例4、(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素与二苯炔合成吡啶[3,4-c]香豆素类化合物,并检测不同温度对反应的影响(以式所示II-1化合物为例)。
往反应管中,先后加入(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素(0.1 mmol)、二苯炔(0.12 mmol)、[Cp*RhCl2]2(2.5 mol%)、乙酸钠(30 mol%)和甲醇(0.5 mL),于不同温度(30 oC, 50 oC, 60 oC, 80 oC)下封口反应8h。用乙酸乙酯萃取,有机相蒸干,用硅胶柱层析分离出目标产物,计算分离收率如表4所示,其中,在50oC时目标产物II-1的收率获得最高值,为81%,将最佳温度定为50 oC。
表4不同温度对反应的影响
温度(<sup>o</sup>C) | 30 | 50 | 60 | 80 |
分离收率(%) | 73 | 81 | 80 | 65 |
实施例5、(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素与二苯炔合成吡啶[3,4-c]香豆素类化合物,并检测不同反应时间对反应的影响(以式所示II-1化合物为例)。
往反应管中,先后加入(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素(0.1 mmol)、二苯炔(0.12 mmol)、[Cp*RhCl2]2(2.5 mol%)、乙酸钠(30 mol%)和甲醇(0.5 mL),于50oC下封口分别反应4 h, 6 h, 8h, 12 h。用乙酸乙酯萃取,有机相蒸干,用硅胶柱层析分离出目标产物,计算分离收率如表5所示,其中,反应8 h后目标产物II-1的收率获得最高值,为81%,将反应时间定为8h。
表5不同反应时间对反应的影响
反应时间(h) | 4 | 6 | 8 | 12 |
分离收率(%) | 70 | 76 | 81 | 78 |
实施例6、式所示II-2化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)丙基)香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率63%。
Mp 236-238oC;1H NMR (400 MHz, CDCl3) δ 7.33 (quint, J = 7.8 Hz, 5H),7.20 (s, 5H), 7.13 (d, J = 7.2 Hz, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.75 (t, J= 7.6 Hz, 1H), 3.59 (q, J = 7.3 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H);13C NMR (101MHz, CDCl3) δ 167.43, 162.16, 159.66, 152.57, 141.95, 139.99, 138.47, 131.39,130.82, 129.73, 129.23, 129.16, 128.82, 128.07, 127.86, 127.80, 127.60,123.16, 117.41, 113.99, 32.25, 13.53。
实施例7、式所示II-3化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)丁基)-香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率69%。
Mp 168-170oC;1H NMR (400 MHz, CDCl3) δ 7.36 – 7.28 (m, 5H), 7.19 (s,5H), 7.12 (d, J = 6.4 Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H), 6.74 (t, J = 7.6 Hz,1H), 3.54 (t,J=9.6 Hz, 2H), 1.90 (sext, J = 7.4 Hz, 2H), 1.11 (t, J = 7.2 Hz,3H);13C NMR (101 MHz, CDCl3) δ 166.42, 162.08, 159.69, 152.56, 141.93, 140.00,138.46, 131.39, 130.82, 129.70, 129.24, 129.16, 128.82, 128.07, 127.85,127.62, 123.15, 117.40, 117.37, 114.14, 40.80, 22.82, 14.46。
实施例8、式所示II-4化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)(苯基)乙基)香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率49%。
Mp 292-294oC;1H NMR (400 MHz, CDCl3) δ 7.68 – 7.67 (m, 2H), 7.47 (d, J= 1.6 Hz, 3H), 7.40 – 7.31 (m, 5H), 7.27 (d, J = 6.8 Hz, 2H), 7.21-7.16 (m,5H), 6.86 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H);13C NMR (101 MHz,CDCl3) δ 162.39, 161.95, 159.33, 152.69, 142.47, 141.12, 139.59, 138.20,131.55, 130.86, 130.04, 129.74, 129.35, 129.23, 128.94, 128.75, 128.26,128.06, 128.02, 127.58, 123.33, 117.64, 117.38, 113.39。
实施例9、式所示II-5化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)乙基)-7-甲氧基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率73%。
Mp 222-224oC;1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 5.2 Hz, 3H), 7.18(s, 5H), 7.12 (d, J = 4.8 Hz, 2H), 6.78 (s, 1H), 6.68 (d, J = 9.2 Hz, 1H),6.33 (d, J = 9.2 Hz, 1H), 3.80 (s, 3H), 3.15 (s, 3H);13C NMR (101 MHz, CDCl3)δ 162.83, 161.98, 160.31, 154.40, 142.13, 140.02, 138.48, 130.82, 129.87,129.53, 129.21, 128.62, 128.00, 127.78, 127.62, 113.49, 111.08, 110.22,101.22, 55.61, 27.48。
实施例10、式所示II-6化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)丙基)-7-甲氧基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率70%。
Mp 246-249oC;1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 5.2 Hz, 3H), 7.19(s, 5H), 7.12 (d, J = 6.8 Hz, 2H), 6.77 (s, 1H), 6.67 (d, J = 9.6 Hz, 1H),6.31 (d, J = 9.2 Hz, 3H), 3.79 (s, 1H), 3.56 (q, J = 7.3 Hz, 2H), 1.43 (t, J= 9.4 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 167.42, 161.90, 161.87, 159.86,154.30, 142.30, 140.16, 138.65, 130.87, 129.89, 129.69, 129.22, 128.37,127.98, 127.75, 127.57, 112.86, 110.99, 110.30, 101.12, 55.61, 32.28, 13.57。
实施例11、式所示II-7化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)丁基)-7-甲氧基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率67%。
Mp196-198oC;1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 5.6 Hz, 3H), 7.18(s, 5H), 7.11 (d, J = 6.8 Hz, 2H), 6.76 (s, 1H), 6.67 (d, J = 9.2 Hz, 1H),6.31 (d, J = 9.3 Hz, 1H), 3.78 (s, 3H), 3.51 (t, J= 7.6 Hz, 2H), 1.99 (sext,J= 7.3 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 166.41,161.87, 161.82, 159.88, 154.29, 142.29, 140.14, 138.63, 130.86(2C), 129.90,129.65(2C), 129.22(2C), 128.39, 127.98, 127.75, 127.58(2C), 113.01, 110.99,110.29, 101.10, 55.62, 40.84, 22.85, 14.49。
实施例12、式所示II-8化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)乙基)-8-甲氧基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率61%。
Mp252-254oC;1H NMR (400 MHz, CDCl3) δ 7.35-7.28 (m, 3H), 7.18 (s, 5H),7.11 (d, J = 6.8 Hz, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.69 (t, J = 8.2 Hz, 1H),6.40 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.18 (s, 3H);13C NMR (101 MHz, CDCl3)δ 162.82, 162.28, 159.51, 147.64, 142.69, 142.00, 139.94, 138.39, 130.88,129.62, 129.57, 129.06, 128.00, 127.84, 127.64, 122.59, 120.18, 118.06,114.60, 113.12, 56.30, 27.45。
实施例13、式所示II-9化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)丙基)-8-甲氧基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率53%。
Mp263-265oC;1H NMR (400 MHz, CDCl3) δ 7.35 – 7.28 (m, 3H), 7.19 (s,5H), 7.11 (d, J = 7.2 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.68 (t, J = 8.2 Hz,1H), 6.39 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.59 (q, J = 7.3 Hz, 2H), 1.44(t, J = 9.4 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 167.39, 162.17, 159.09, 147.56,142.57, 142.19, 140.04, 138.53, 130.92, 129.73, 129.38, 129.08, 127.99,127.83, 127.59, 122.52, 120.20, 118.13, 113.96, 112.96, 56.29, 32.20, 13.52。
实施例14、式所示II-10化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)丁基)-8-甲氧基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率59%。
Mp208-210oC;1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 6.8 Hz, 3H), 7.19(s, 5H), 7.11 (d, J = 6.8 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.68 (t, J = 8.2Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.55 (t, J=7.4, 2H), 1.95 –1.85 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 166.40,162.08, 159.13, 147.58, 142.60, 142.17, 140.05, 138.54, 130.92(2C), 129.69(2C), 129.34, 129.06(2C), 127.97, 127.81, 127.60(2C), 122.49, 120.21, 118.16,114.12, 112.98, 56.30, 40.67, 22.78, 14.41。
实施例15、式所示II-11化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)乙基)-6-甲基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率92%。
Mp 233-236oC;1H NMR (400 MHz, CDCl3) δ 7.38 – 7.31 (m, 3H), 7.21 –7.17 (m, 7H), 7.12 (d, J = 7.2 Hz, 2H), 6.48 (s, 1H), 3.17 (s, 3H), 1.90 (s,3H);13C NMR (101 MHz, CDCl3) δ 162.83, 161.96, 160.25, 150.66, 141.92, 139.90,138.53, 132.46, 132.30, 130.77, 129.65, 129.39, 129.23, 129.13, 127.94,127.88, 127.65, 117.00, 116.75, 114.67, 27.52, 20.91。
实施例16、式所示II-12化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)丙基)-6-甲基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率69%。
Mp 218-220oC;1H NMR (400 MHz, CDCl3) δ 7.35 (quint, J = 7.3 Hz, 3H),7.26-7.12 (m, 9H), 6.48 (s, 1H), 3.58 (q, J = 7.3 Hz, 2H), 1.89 (s, 3H), 1.44(t, J = 7.4 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 167.40, 161.85, 159.83, 150.58,142.10, 140.04, 138.71, 132.36, 132.19, 130.82, 129.81, 129.26, 129.13,127.91, 127.84, 127.59, 116.91, 116.84, 114.05, 32.28, 20.92, 13.53。
实施例17、式所示II-13化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)丁基)-6-甲基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率85%。
Mp 189-192oC;1H NMR (400 MHz, CDCl3) δ 7.34 (quint, J = 7.2 Hz, 3H),7.24 – 7.20 (m, 5H), 7.15 – 7.11 (m, 4H), 6.47 (s, 1H), 3.53 (t, J=9.8 Hz,2H), 1.96 – 1.87 (m, 5H), 1.10 (t, J = 7.4 Hz, 3H)。
13C NMR (101 MHz, CDCl3) δ 166.39, 161.77, 159.85, 150.56, 142.08,140.03, 138.69, 132.35, 132.20, 130.82, 129.79, 129.28, 129.15, 127.93,127.85, 127.62, 116.91, 116.84, 114.19, 40.87, 22.83, 20.96, 14.49。
实施例18、式所示II-14化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)乙基)-6-溴香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率70%。
Mp 239-241oC;1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.8 Hz, 1H), 7.42– 7.36 (m, 3H), 7.26 – 7.17 (m, 6H), 7.12 (d, J = 6.8 Hz, 2H), 6.81 (s, 1H),3.18 (s, 3H);13C NMR (101 MHz, CDCl3) δ 163.04, 162.39, 159.48, 151.52,140.58, 139.54, 137.57, 134.24, 131.78, 130.47, 129.64, 129.50, 128.50,128.11, 127.72, 118.98, 118.84, 116.05, 114.38, 113.96, 27.48。
实施例19、式所示II-15化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)丙基)-6-溴香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,反应8h, 其他反应条件均与实施例5相同,收率74%。
Mp 248-250oC;1H NMR (400 MHz, CDCl3) δ 7.45 -7.37 (m, 4H), 7.26 – 7.16(m, 6H), 7.12 (d, J = 7.2 Hz, 2H), 6.80 (s, 1H), 3.58 (q, J = 7.5 Hz, 2H),1.44 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 167.58, 162.26, 159.05,151.44, 140.73, 139.69, 137.76, 134.10, 131.80, 130.52, 129.79, 129.49,129.24, 128.47, 128.07, 127.65, 118.93, 118.89, 115.94, 113.76, 32.24, 13.43。
实施例20、式所示II-16化合物的合成
以1-苯基-1-丁炔代替实施例5中的二苯基炔,反应8h,其他反应条件均与实施例5相同,收率64%。
Mp 182-184oC;1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 5.2 Hz, 3H), 7.33(t, J = 7.0 Hz, 1H), 7.26 (d, J = 5.2 Hz, 3H), 6.78 – 6.73 (m, 2H), 3.12 (s,3H), 2.62 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz,CDCl3) δ 166.42, 163.00, 160.15, 152.63, 140.76, 138.85, 131.26, 129.75,129.53, 129.19, 128.57, 128.39, 123.31, 117.47, 117.34, 113.60, 29.87, 27.54,13.77。
实施例21、式所示II-16化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)乙基)-6-甲基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,以1-苯基-1-丁炔代替实施例5中的二苯基炔,反应8 h,其他反应条件均与实施例5相同,收率67%。
Mp 153-156oC;1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.26 (d, J = 4.4Hz, 2H), 7.14 (s, 2H), 6.43 (s, 1H), 3.12 (s, 3H), 2.66 (q, J = 7.5 Hz, 2H),1.91 (s, 3H), 1.17 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 166.12,162.99, 160.35, 150.61, 140.93, 139.04, 132.50, 132.06, 129.66, 129.56,129.15, 129.05, 128.26, 116.99, 116.80, 113.65, 29.90, 27.62, 20.98, 13.84。
实施例22、式所示II-18化合物的合成
以3-苯基丙炔酸乙酯代替实施例5中的二苯基炔,反应8 h,其他反应条件均与实施例5相同,收率65%。
Mp 120-122oC;1H NMR (400 MHz, DMSO) δ 7.77 (d, J = 8.4 Hz, 1H), 7.70(t, J = 7.8 Hz, 1H), 7.54 (s, 5H), 7.48 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.6Hz, 1H), 4.24 (q, J = 7.07 Hz, 2H), 3.00 (s, 3H), 1.03 (t, J = 7.0 Hz, 3H);13CNMR (101 MHz, DMSO) δ 168.73, 163.72, 159.37, 158.86, 152.47, 140.04, 138.82,133.70, 129.84, 128.81, 128.75, 125.88, 125.13, 121.84, 118.20, 115.33,114.53, 62.77, 27.57, 13.64。
实施例23、式所示II-19化合物的合成
以3-己炔代替实施例5中的二苯基炔,反应8h, 其他反应条件均与实施例5相同,收率34%;
Mp 138-140oC;1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H), 7.45(t, J = 7.6 Hz, 1H), 7.30 – 7.23 (m, 2H), 3.07 (q, J = 7.3 Hz, 2H), 2.98 –2.92 (m, 5H), 1.43 (t, J = 7.4 Hz, 3H), 1.29 (t, J = 7.6 Hz, 3H);13C NMR (101MHz, CDCl3) δ 167.18, 160.91, 160.36, 152.22, 141.72, 131.27, 129.12, 127.79,123.88, 117.86, 114.27, 28.90, 27.15, 23.06, 14.38, 14.05。
实施例24、式所示II-20化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)乙基)-6-甲基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,以3-己炔代替实施例5中的二苯基炔,反应8h,其他反应条件均与实施例5相同,收率36%。
Mp 104-107 oC;1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.32 (d, J = 8.4Hz, 1H), 7.25 (t, J = 7.2 Hz, 1H), 3.14 (q, J = 7.2 Hz, 2H), 3.04 – 2.99 (m,5H), 2.46 (s, 3H), 1.51 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.4 Hz, 3H);13C NMR(101 MHz, CDCl3) δ 167.04, 160.87, 160.56, 150.22, 141.84, 133.17, 132.08,129.01, 127.89, 117.49, 114.30, 28.89, 27.21, 23.10, 21.45, 14.39, 14.09。
实施例25、式所示II-21化合物的合成
以(E)-3-(1-(乙酰氧基亚胺)乙基)-7-甲氧基香豆素代替实施例5中的(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素,以3-己炔代替实施例5中的二苯基炔,反应8 h,其他反应条件均与实施例5相同,收率33%。
m.p. 155-157 oC,HRMS (ESI): Calcd for C18H20NO3[M+H]+: 298.1443; Found:298.1445.
实施例26、式所示II-22化合物的合成
以2-丁炔酸乙酯代替实施例5中的二苯基炔,反应8 h,其他反应条件均与实施例5相同,收率29%。
Mp 128-131oC;1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 1H), 7.57(t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 5.6 Hz, 1H), 4.52(q, J = 6.9 Hz, 2H), 3.07 (s, 3H), 2.67 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H);13CNMR (101 MHz, CDCl3) δ 169.40, 164.57, 159.42, 159.19, 152.45, 139.84,132.69, 125.71, 124.28, 121.87, 117.97, 115.49, 113.21, 62.56, 27.29, 23.27,13.86。
Claims (7)
2.如权利要求1所述的方法,其特征在于,所述碱为乙酸钠。
3.如权利要求1所述的制备式II所示化合物的方法,其特征在于,所述有机溶剂为甲醇。
4.如权利要求1所述的方法,其特征在于,所述温度为50℃。
5.如权利要求1~4任一项所述的方法,其特征在于,所述催化体系还包括银盐。
6.如权利要求5所述的方法,其特征在于,所述银盐选自六氟锑酸银、三氟甲磺酸银、乙酸银和硝酸银中的一种。
7.如权利要求1~4任一项所述的方法,其特征在于,所述式I化合物是:(E)-3-(1-(乙酰氧基亚胺)乙基)香豆素、(E)-3-(1-(乙酰氧基亚胺)乙基)-6-甲基香豆素、(E)-3-(1-(乙酰氧基亚胺)乙基)-7-甲氧基香豆素、(E)-3-(1-(乙酰氧基亚胺)乙基)-8-甲氧基香豆素、(E)-3-(1-(乙酰氧基亚胺)乙基)-6-溴香豆素、(E)-3-(1-(乙酰氧基亚胺)丙基)香豆素、(E)-3-(1-(乙酰氧基亚胺)丙基)-6-甲基香豆素、(E)-3-(1-(乙酰氧基亚胺)丙基)-7-甲氧基香豆素、(E)-3-(1-(乙酰氧基亚胺)丙基)-8-甲氧基香豆素、(E)-3-(1-(乙酰氧基亚胺)丙基)-6-溴香豆素、(E)-3-(1-(乙酰氧基亚胺)丁基)香豆素、(E)-3-(1-(乙酰氧基亚胺)丁基)-6-甲基香豆素、(E)-3-(1-(乙酰氧基亚胺)丁基)-7-甲氧基香豆素、(E)-3-(1-(乙酰氧基亚胺)丁基)-8-甲氧基香豆素、(E)-3-(1-(乙酰氧基亚胺)(苯基)甲基)香豆素。
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