CN106008191A - 一种多取代二芳基化合物的合成方法 - Google Patents

一种多取代二芳基化合物的合成方法 Download PDF

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CN106008191A
CN106008191A CN201610331856.6A CN201610331856A CN106008191A CN 106008191 A CN106008191 A CN 106008191A CN 201610331856 A CN201610331856 A CN 201610331856A CN 106008191 A CN106008191 A CN 106008191A
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李文军
石振艳
徐显宏
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Qingdao University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Abstract

本发明公开了一种多取代二芳基化合物的合成方法，是在反应溶剂中，以对亚甲基醌和姜黄素衍生物为反应原料，以路易斯碱为催化剂，反应得到多取代的二芳基化合物。本发明反应条件温和，原料易得价廉，反应操作简单，产率较高，为很多天然产物和药物的合成提供关键的骨架结构，可以广泛适用于工业化规模生产。

Description

一种多取代二芳基化合物的合成方法
技术领域
本发明具体涉及一种制备多取代二芳基化合物的合成方法，属于有机化合物工艺应用技术领域。
背景技术
多取代二芳基化合物是一类非常重要医药化工中间体，具有非常高的应用价值。很多药物和生物活性分子，如cherylline, tolterodine, COP-840, podophyllotoxin等，都具有二芳基的骨架，如下所示：
本发明首次创新地提出了一种绿色环保，简单高效制备多取代二芳基化合物的新方法，通过使用路易斯碱为催化剂，可以高效地实现反应的转化。如以上式(I)所示，本发明利用对亚甲基醌和姜黄素衍生物为反应原料，以路易斯碱为催化剂，在反应溶剂中进行反应，合成多取代二芳基化合物。
本发明中，R1, R2是烷基或芳香基或取代的芳环和杂环、各类侧链，Ar是芳香基或取代的芳环和杂环。
本发明中，所述起始原料对亚甲基醌和姜黄素衍生物的用量比例为1∶1-1∶5。优选地，两者用量比例为1∶2。
本发明中，所述催化剂是二乙胺、哌啶、三乙胺、四甲基胍或1,8-二氮杂双环[5.4.0]十一碳-7-烯；所述催化剂的用量为1-100％。优选地，所述催化剂是1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)。所述催化剂的用量为原料对亚甲基醌的1-100 mol％。优选地，所述催化剂用量为20 mol％。
本发明中，所述反应溶剂是甲苯、氯仿、四氢呋喃、DMA、1，2-二氯乙烷、THF或乙腈。所述反应溶剂包括但不局限于以上，还可以是氯苯、1，4-二氧六环、DMF，DMSO。
本发明中，所述合成反应是在20-80℃温度下进行。优选地，是在25℃温度下进行反应。
具体地，本发明合成反应是在反应瓶A中，将对亚甲基醌(底物1，X mmol)和姜黄素衍生物(底物2，Y mmol)溶解在Z mL反应溶剂中，室温下，加入DBU(W mmol)。反应在20-80℃下反应3个小时。用TLC检测反应进程。反应完毕后，直接加硅胶，旋干柱层析，分离得到目标产物3。
本发明合成反应的优点包括：本发明合成方法所使用的各原料非常简单，简单易得，来源广泛，并且性能非常稳定，不需要特殊保存条件。本发明所用的各种催化剂也都是常用的商品化试剂，非常稳定。本发明以简单易得的对亚甲基醌和姜黄素衍生物为反应原料，在路易斯碱作用下，反应得到多取代的二芳基化合物。反应操作比较简单，反应条件温和，产率较高，适合大规模工业化生产。本发明合成的多取代二芳基化合物是很多天然产物和活性药物分子的核心骨架，本发明创新设计的反应路线为合成这类化合物提供了一个广泛适用的制备方法。
具体实施方式
结合以下具体实施例，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
点都被包括在本发明中，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。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯
度通过核磁共振鉴定。
实施例1
在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.05 mmol，16.2 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3aa (83％)。Yellow oil, 83% yield. 1H NMR (CDCl3, 500 MHz): δ(ppm) 7.53-7.50 (m, 3H), 7.48-7.45 (m, 3H), 7.36-7.34 (m, 6H),7.26-7.25 (m, 2H), 7.07 (s, 2H), 6.94 (d, J = 15.0 Hz, 1H), 6.79-6.76 (m,3H), 5.09 (d, J = 10.0 Hz, 1H), 4.99 (d, J = 10.0 Hz, 2H), 3.71 (s, 3H), 1.32(s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 194.2, 194.0, 158.1, 152.4, 144.1,143.6, 135.8, 134.4, 134.3, 134.3, 132.3, 130.7, 130.6, 128.9, 128.8, 128.6,128.5, 124.9, 124.6, 124.0, 114.0, 71.4, 55.1, 50.5, 34.3, 30.2. HRMS (ESI):exact mass calculated for M+ (C41H45O4) requires m/z 601.3318, found m/z601.3320.
实施例2
在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.05 mmol，16.2 mg)，底物2b (0.10 mmol，31.2mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ab (77％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.51-7.38 (m, 6H), 7.25-7.23 (m, 2H), 7.06-7.02 (m, 6H), 6.85 (d, J = 15.0 Hz,1H), 6.78-6.77 (m, 2H), 6.68 (d, J = 15.0 Hz, 1H), 5.03 (d, J = 10.0 Hz, 1H),4.98 (br, 1H), 4.95 (d, J = 10.0 Hz, 1H), 3.71 (s, 3H), 1.31 (s, 18H). 13C NMR(CDCl3, 125 MHz): δ(ppm) 194.1, 193.9, 165.1, 163.1, 158.2, 152.4, 142.8,142.2, 135.8, 130.5 (d, J = 35.0 Hz), 130.4, (d, J = 35.0 Hz), 128.9, 124.6,124.5, 123.7, 116.1 (d, J = 10.0 Hz), 160.0 (d, J = 10.0 Hz), 114.0, 110.0,71.6, 55.1, 50.5, 34.3, 30.2. HRMS (ESI): exact mass calculated for M+ (C41H43F2O4) requires m/z 637.3129, found m/z 637.3132。
实施例3
在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.05 mmol，16.2 mg)，底物2c (0.10 mmol，34.4mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ac (67％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.45-7.31 (m, 9H), 7.25-7.22 (m, 3H), 7.04 (s, 2H), 6.88 (d, J = 15.0 Hz, 1H),6.78-6.77 (m, 2H)，6.70 (d, J = 15.0 Hz, 1H), 5.03 (d, J = 10.0 Hz, 1H), 4.99(br, 1H), 4.95 (d, J = 10.0 Hz, 1H), 3.71 (s, 3H), 1.31 (s, 18H). 13C NMR(CDCl3, 125 MHz): δ(ppm) 194.1, 193.9, 158.1, 152.4, 142.7, 142.1, 136.7,136.6, 135.8, 134.2, 132.7, 132.1, 129.8, 129.6, 129.2, 129.1, 129.0, 128.9,125.1, 124.6, 124.3, 114.0, 71.6, 55.1, 50.5, 34.3, 30.2. HRMS (ESI): exactmass calculated for M+(C41H43Cl2O4) requires m/z 669.2538, found m/z 669.2541.
实施例4
在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.05 mmol，16.2 mg)，底物2d (0.10 mmol，43.2mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ad (67％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.49-7.40 (m, 5H), 7.36-7.34 (m, 3H), 7.30-7.22 (m, 4H), 7.04 (s, 2H), 6.90 (d, J= 15.0 Hz, 1H), 6.78-6.70 (m, 3H), 5.03 (d, J = 10.0 Hz, 1H), 4.98 (br, 1H),4.94 (d, J = 10.0 Hz, 1H), 3.71 (s, 3H), 1.31 (s, 18H). 13C NMR (CDCl3, 125MHz): δ(ppm) 194.1, 193.8, 158.2, 152.4, 142.7, 142.1, 135.8, 134.2, 133.2,132.1, 132.1, 132.1, 129.9, 129.7, 128.9, 125.2, 125.1, 125.0, 124.6, 124.3,114.0, 71.6, 55.1, 50.5, 34.3, 30.2. HRMS (ESI): exact mass calculated for M+ (C41H43Br2O4) requires m/z 757.1528, found m/z 757.1533。
实施例5
在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.05 mmol，16.2 mg)，底物2e (0.10 mmol，33.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ae (76％)。1H NMR (CDCl3, 500 MHz): δ(ppm)7.49-7.41 (m, 6H), 7.25-7.23 (m, 2H), 7.05 (s, 2H), 6.87-6.82 (m, 5H), 6.76 (d, J= 10.0 Hz, 2H), 6.68 (d, J = 20.0 Hz, 1H), 5.03 (d, J = 10.0 Hz, 1H), 4.97(d, J = 10.0 Hz, 2H), 3.82 (s, 6H), 3.70 (s, 3H), 1.32 (s, 18H). 13C NMR(CDCl3, 125 MHz): δ(ppm) 194.1, 193.9, 161.7, 161.7, 158.0, 152.3, 143.8,143.4, 135.6, 134.7, 132.5, 130.4, 130.3, 128.9, 127.1, 127.1, 124.6, 122.8,121.8, 114.3, 113.9, 71.4, 55.4, 55.3, 55.1, 50.3, 34.3, 30.2. HRMS (ESI):exact mass calculated for M+ (C43H49O6) requires m/z 661.3529, found m/z661.3533.
实施例6
在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.05 mmol，16.2 mg)，底物2f (0.10 mmol，33.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3af (82％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.43-7.42 (m, 1H), 7.33-7.26 (m, 3H), 7.06-6.97 (m, 4H), 6.93-6.91 (m, 2H), 6.86-6.82 (m, 3H), 6.77-7.76 (m, 2H), 5.14(d, J = 10.0 Hz, 1H), 4.98 (d, J = 10.0 Hz, 1H), 4.94 (br, 1H),3.83 (s, 3H),3.81 (s, 3H), 3.70 (s, 3H), 1.32 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm)194.5, 194.2, 158.7, 158.6, 158.0, 152.2, 139.1, 138.8, 135.6, 134.8, 132.6,131.9, 131.8, 131.2, 129.0, 128.8, 128.7, 125.8, 124.7, 123.4, 120.6, 113.9,111.1, 111.0, 70.6, 55.5, 55.4, 55.1, 50.5, 34.3, 30.2. HRMS (ESI): exactmass calculated for M+(C43H49O6) requires m/z 661.3529, found m/z 661.3532.
实施例7
在25mL的试管反应器中，用氮气交换空气3次。将底物1a (0.05 mmol，16.2 mg)，底物2g (0.10 mmol，28.8mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ag (70％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.61(d, J = 15.0 Hz, 1H), 7.54 (d, J = 15.0 Hz, 1H), 7.39-7.37 (m, 2H), 7.26-7.22(m, 4H), 7.04-7.01 (m, 4H), 6.78-6.76 (m, 2H), 6.69 (d, J = 15.0 Hz, 1H),6.56 (d, J = 15.0 Hz, 1H), 4.97-4.94 (m, 3H), 3.71 (s, 3H), 1.32 (s, 18H). 13CNMR (CDCl3, 125 MHz): δ(ppm) 193.6, 193.4, 158.1, 152.3, 139.8, 139.8, 136.5,136.0, 135.7, 134.5, 132.3, 132.2, 129.3, 129.2, 128.9, 128.4, 128.2, 124.6,123.6, 122.9, 113.9, 101.7, 71.3, 55.1, 50.4, 34.3, 30.2. HRMS (ESI): exactmass calculated for M+(C37H41O4S2) requires m/z 613.2446, found m/z 613.2449.
实施例8
在25mL的试管反应器中，用氮气交换空气3次。将底物1b (0.05 mmol，14.7 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ba (81％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.52-7.44 (m, 6H), 7.36-7.33 (m, 8H), 7.25-7.22 (m, 3H), 7.07 (s, 2H), 6.92 (d, J= 15.0 Hz, 1H), 6.77 (d, J = 15.0 Hz, 1H), 5.13 (d, J = 10.0 Hz, 1H), 5.02(br, 1H), 4.96 (d, J = 10.0 Hz, 1H), 1.31 (s, 18H). 13C NMR (CDCl3, 125 MHz):δ(ppm) 194.1, 193.9, 152.4, 144.2, 143.7, 142.2, 135.8, 134.3, 131.9, 130.7,130.7, 128.8, 128.6, 128.6, 128.5, 127.9, 126.6, 124.7, 124.7, 124.1, 71.1,51.2, 34.3, 30.2. HRMS (ESI): exact mass calculated for M+(C40H43O3) requiresm/z 571.3212, found m/z 571.3218.
实施例9
在25mL的试管反应器中，用氮气交换空气3次。将底物1c (0.05 mmol，15.6 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ca (85％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.54-7.44 (m, 6H), 7.37-7.35 (m, 5H), 7.30-7.25 (m, 4H), 7.04 (s, 1H), 6.94-6.91(m, 3H), 6.76 (d, J = 15.0 Hz, 1H), 5.07-5.00 (m, 3H), 1.32 (s, 18H). 13C NMR(CDCl3, 125 MHz): δ(ppm) 193.9, 193.7, 152.5, 144.5, 143.9, 138.1, 135.9,134.2 (d, J = 20.0 Hz), 131.7, 130.8 (d, J = 50.0 Hz), 129.4 (d, J = 30.0Hz), 128.9, 128.8, 128.7, 128.5, 128.4, 127.9, 124.7, 124.6, 123.9, 115.4 (d,J = 85.0 Hz), 71.2, 50.3, 34.3, 30.2. HRMS (ESI): exact mass calculated for M+(C40H42FO3) requires m/z 589.3118, found m/z 589.3122.
实施例10
在25mL的试管反应器中，用氮气交换空气3次。将底物1d (0.05 mmol，16.4 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3da (61％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.55-7.51 (m, 3H), 7.48-7.44 (m, 3H), 7.38-7.35 (m, 6H), 7.27-7.20 (m, 4H), 7.03(s, 2H), 6.92 (d, J = 20.0 Hz, 1H), 6.76 (d, J = 20.0 Hz, 1H), 5.07 (d, J =10.0 Hz, 1H), 5.01 (br, 1H), 5.00 (d, J = 10.0 Hz, 1H), 1.32 (s, 18H). 13C NMR(CDCl3, 125 MHz): δ(ppm) 193.7, 193.5, 152.6, 144.6, 143.9, 140.9, 135.9,134.2, 134.1, 132.3, 131.4, 130.9, 130.8, 129.3, 128.9, 128.9, 128.7, 128.7,128.5, 124.6, 124.6, 123.8, 71.0, 50.4, 34.3, 30.2. HRMS (ESI): exact masscalculated for M+(C40H42ClO3) requires m/z 605.2822, found m/z 605.2828.
实施例11
在25mL的试管反应器中，用氮气交换空气3次。将底物1e (0.05 mmol，18.7 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ea (84％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.55-7.51 (m, 3H), 7.47-7.44 (m, 3H), 7.39-7.35 (m, 8H), 7.21-7.20 (m, 2H), 7.03(s, 2H), 6.91 (d, J = 15.0 Hz, 1H), 6.75 (d, J = 15.0 Hz, 1H), 5.07 (d, J =10.0 Hz, 1H), 5.01 (br, 1H), 4.99 (d, J = 10.0 Hz, 1H), 1.32 (s, 18H). 13C NMR(CDCl3, 125 MHz): δ(ppm) 193.7, 193.5, 152.6, 144.6, 143.9, 141.4, 135.9,134.2, 134.1, 131.7, 131.3, 130.9, 130.8, 129.6, 128.9, 128.9, 128.7, 128.5,124.6, 124.5, 123.8, 120.5, 70.9, 50.5, 34.3, 30.2. HRMS (ESI): exact masscalculated for M+ (C40H42BrO3) requires m/z 649.2317, found m/z 649.2321.
实施例12
在25mL的试管反应器中，用氮气交换空气3次。将底物1f (0.05 mmol，15.5 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3fa (95％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.52-7.43 (m, 5H), 7.36-7.35 (m, 5H), 7.25-7.21 (m, 4H), 7.07-7.03 (m, 4H), 6.92(d, J = 15.0 Hz, 1H), 6.77 (d, J = 15.0 Hz, 1H), 5.11 (d, J = 10.0 Hz, 1H),4.98 (d, J = 10.0 Hz, 1H), 4.96 (br, 1H), 2.23 (s, 3H), 1.31 (s, 18H). 13C NMR(CDCl3, 125 MHz): δ(ppm) 194.2, 194.0, 152.4, 144.1, 143.6, 139.2, 136.1,135.7, 134.4, 134.3, 132.1, 130.7, 130.6, 129.3, 128.8, 128.6, 128.5, 127.7,124.8, 124.6, 124.1, 71.2, 50.9, 34.3, 30.2, 21.0. HRMS (ESI): exact masscalculated for M+(C41H45O3) requires m/z 585.3369, found m/z 585.3374.
实施例13
在25mL的试管反应器中，用氮气交换空气3次。将底物1g (0.05 mmol，18.7 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ga (79％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.56-7.43 (m, 7H), 7.37-7.35 (m, 6H), 7.28-7.25 (m, 2H), 7.13-7.11 (m, 1H), 7.04(s, 2H), 6.90 (d, J = 15.0 Hz, 1H), 6.75 (d, J = 15.0 Hz, 1H), 5.07 (d, J =10.0 Hz, 1H), 5.02 (br, 1H), 4.98 (d, J = 10.0 Hz, 1H), 1.32 (s, 18H). 13C NMR(CDCl3, 125 MHz): δ(ppm) 193.6, 193.4, 152.6, 144.7, 143.9, 136.0, 131.3,130.9, 130.8, 130.1, 129.7, 128.9, 128.9, 128.7, 128.5, 126.4, 124.8, 124.4,124.0, 110.0, 70.8, 50.7, 34.3, 30.2. HRMS (ESI): exact mass calculated for M+(C40H42BrO3) requires m/z 649.2317, found m/z 649.2320.
实施例14
在25mL的试管反应器中，用氮气交换空气3次。将底物1h (0.05 mmol，16.2 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ha (74％)。1H NMR (CDCl3, 500 MHz): δ(ppm)7.52-7.42 (m, 5H), 7.36-7.25 (m, 7H), 7.15-7.13 (m, 3H), 7.08 (s, 2H), 6.94-6.90(m, 2H), 6.77 (d, J = 15.0 Hz, 1H), 5.11 (d, J = 10.0 Hz, 1H), 4.97 (br, 1H),4.96 (d, J = 10.0 Hz, 1H), 2.26 (s, 3H), 1.32 (s, 18H). 13C NMR (CDCl3, 125MHz): δ(ppm) 194.2, 193.9, 152.4, 144.1, 143.5, 142.1, 138.1, 135.7, 134.4,134.3, 132.0, 130.7, 130.6, 129.0, 128.8, 128.6, 128.4, 128.4, 127.4, 124.7,124.6, 124.2, 71.2, 51.2, 34.3, 30.2, 21.5. HRMS (ESI): exact mass calculatedfor M+(C41H45O4) requires m/z 601.3368, found m/z 601.3372.
实施例15
在25mL的试管反应器中，用氮气交换空气3次。将底物1i (0.05 mmol，18.7 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ia (78％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.56-7.53 (m, 3H), 7.48-7.45 (m, 5H), 7.36-7.35 (m, 5H), 7.27-7.25 (m, 2H), 7.19(s, 2H), 7.05 (d, J = 15.0 Hz, 1H), 6.99-6.96 (m, 1H), 6.73 (d, J = 15.0 Hz,1H), 5.67 (d, J = 10.0 Hz, 1H), 5.16 (d, J = 10.0 Hz, 1H), 5.00 (br, 1H),1.33 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 193.8, 193.6, 152.6, 144.3,144.2, 141.0, 135.7, 133.4, 130.8, 130.7, 128.9, 128.8, 128.8, 128.5, 128.0,127.7, 125.3, 124.8, 122.8, 110.0, 71.1, 48.7, 34.3, 30.2. HRMS (ESI): exactmass calculated for M+ (C40H42BrO3) requires m/z 649.2317, found m/z 649.2319.
实施例16
在25mL的试管反应器中，用氮气交换空气3次。将底物1j (0.05 mmol，15.0 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ja (83％)。1H NMR (CDCl3, 500 MHz): δ(ppm)7.61 (d,J = 15.0 Hz, 1H), 7.55-7.53 (m, 2H), 7.45-7.34 (m, 8H), 7.25 (s, 2H), 7.13(s, 2H), 6.95 (d, J = 15.0 Hz, 1H), 6.89-6.83 (m, 2H), 6.74 (d, J = 15.0 Hz,1H), 5.30 (d, J = 10.0 Hz, 1H), 5.02 (d, J = 10.0 Hz, 1H), 5.01 (br, 1H),1.32 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm) 193.5, 193.1, 152.7, 146.3,144.5, 143.6, 140.6, 135.8, 134.3, 130.8, 130.7, 130.1, 128.9, 128.8, 128.7,128.6, 128.1, 126.6, 124.8, 124.2, 124.1, 101.8, 72.6, 46.5, 34.3, 30.2. HRMS(ESI): exact mass calculated for M+(C38H41O3S) requires m/z 577.2776, found m/z577.2779.
实施例17
在25mL的试管反应器中，用氮气交换空气3次。将底物1k (0.05 mmol，14.7 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ka (82％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 8.62(s, 1H), 8.39-8.38 (m, 1H), 7.66-7.65 (m, 1H), 7.57-7.46 (m, 5H), 7.37-7.35(m, 5H), 7.25-7.18 (m, 3H), 7.05 (s, 2H), 6.91 (d, J = 15.0 Hz, 1H), 6.78 (d,J = 15.0 Hz, 1H), 5.11 (d, J = 10.0 Hz, 1H), 5.05 (d, J = 10.0 Hz, 1H), 5.04(br, 1H), 1.32 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ(ppm)193.3, 193.1, 152.7,149.2, 147.7, 145.1, 144.1, 138.1, 136.1, 135.6, 134.1, 134.0, 131.0, 130.9,130.7, 128.9, 128.7, 128.5, 125.0, 124.7, 124.3, 123.7, 123.5, 70.6, 48.6,34.3, 30.2. HRMS (ESI): exact mass calculated for M+(C39H42NO3) requires m/z572.3165, found m/z 572.3169.
实施例18
在25mL的试管反应器中，用氮气交换空气3次。将底物1l (0.05 mmol，17.2 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入四氢呋喃 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3la (63％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 8.44(d, J = 10.0 Hz, 1H), 7.76 (d, J = 5.0 Hz, 1H), 7.66 (d, J = 5.0 Hz, 1H),7.58-7.50 (m, 2H), 7.47-7.40 (m, 5H), 7.38-7.30 (m, 6H), 7.28-7.25 (m, 3H),7.17 (s, 2H), 6.85 (d, J = 15.0 Hz, 1H), 6.72 (d, J = 15.0 Hz, 1H), 5.90 (d,J = 10.0 Hz, 1H), 5.30 (d, J = 10.0 Hz, 1H), 4.94 (br, 1H), 1.28 (s, 18H). 13CNMR (CDCl3, 125 MHz): δ(ppm) 194.7, 193.8, 152.4, 143.8, 143.7, 137.9, 135.7,134.3, 131.8, 131.4, 130.7, 130.5, 128.8, 128.7, 128.6, 128.5, 127.4, 126.1,125.5, 125.3, 125.1, 124.9, 124.1, 123.9, 123.7, 71.2, 45.9, 34.2, 30.2. HRMS(ESI): exact mass calculated for M+(C44H45O3) requires m/z 621.3369, found m/z621.3375.
实施例19
在25mL的试管反应器中，用氮气交换空气3次。将底物1m (0.05 mmol，14.8 mg)，底物2a (0.10 mmol，27.6mg)，DBU (0.01 mmol，1.52 mg)依次称入反应管，抽空换氮气，并在氮气氛围下加入甲苯 (0.15 mL)，在室温下反应3小时。TCL检测反应结束后，直接加硅胶，旋干柱层析，得到黄色油状物3ma (55％)。1H NMR (CDCl3, 500 MHz): δ(ppm) 7.54-7.46(m, 5H), 7.37-7.34 (m, 5H), 7.28-7.23 (m, 4H), 6.95-6.92 (m, 3H), 6.84-6.81(m, 1H), 6.77-6.76 (m, 2H), 5.10 (d, J = 10.0 Hz, 1H), 5.01 (d, J = 10.0 Hz,1H), 4.59 (br, 1H), 3.70 (s, 3H), 3.05-2.99 (m, 2H), 1.17-1.14 (m, 12H). 13CNMR (CDCl3, 125 MHz): δ(ppm) 194.0, 194.0, 158.1, 148.6, 148.2, 144.3, 143.9,134.4, 134.3, 133.6, 130.7, 130.7, 128.9, 128.8, 128.8, 128.7, 128.5, 124.6,124.0, 123.1, 114.0, 71.4, 55.1, 50.2, 27.2, 22.7. HRMS (ESI): exact masscalculated for M+(C39H41O4) requires m/z 573.3005, found m/z 573.3008。

Claims (5)

1.一种多取代二芳基化合物的合成方法，其特征在于，以化合物1和2为反应原料，以路易斯碱为催化剂，一定温度下在反应溶剂中反应得到多取代二芳基化合物；其中，所述路易斯碱为二乙胺、哌啶、三乙胺、四甲基胍或1,8-二氮杂双环[5.4.0]十一碳-7-烯，所述温度为20-80℃；反应过程如式(I)所示；
其中 R1, R2是烷基或芳香基，Ar是芳香基。
2.如权利要求1所述的多取代二芳基化合物的合成方法，其特征在于，所述催化剂是二乙胺、哌啶、三乙胺、四甲基胍或1,8-二氮杂双环[5.4.0]十一碳-7-烯；所述催化剂的用量1-100％。
3.如权利要求1所述的多取代二芳基化合物的合成方法，其特征在于，所述反应溶剂是甲苯、氯仿、四氢呋喃、DMA、1，2-二氯乙烷、THF或乙腈。
4.如权利要求1所述的多取代二芳基化合物的合成方法，其特征在于，所述化合物1和化合物2的比例为1∶1-1∶5。
5.一种多取代二芳基化合物的合成方法，反应过程如以下反应式所示；
在25mL的试管反应器中，用氮气交换空气3次；将0.05 mmol底物1a、0.10 mmol底物2a和0.01 mmol DBU依次称入反应管，抽空换氮气，并在氮气氛围下加入0.15 mL四氢呋喃；将反应体系在室温下反应3小时；TCL检测反应结束后，直接加硅胶，旋干柱层析，得到3aa。
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CN115925527A (zh) * 2023-01-06 2023-04-07 湖南理工学院 一种制备α-二芳基甲基取代酮类化合物的方法

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Title
LORENZO CARUANA ET AL: "A New Organocatalytic Concept for Asymmetric α-Alkylation of Aldehydes", 《JAURNAL OF THE AMERICAN CHEMICAL SOCIETY》 *
褚文道: "亚甲基苯醌的不对称有机催化反应研究", 《中国博士学位论文全文数据库(电子期刊)工程科技I辑》 *

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CN114436793A (zh) * 2022-01-25 2022-05-06 赣南医学院 一种温和的α,α′-二芳基酮的合成方法
CN114436793B (zh) * 2022-01-25 2023-12-26 赣南医学院 一种温和的α,α′-二芳基酮的合成方法
CN115925527A (zh) * 2023-01-06 2023-04-07 湖南理工学院 一种制备α-二芳基甲基取代酮类化合物的方法
CN115925527B (zh) * 2023-01-06 2024-02-09 湖南理工学院 一种制备α-二芳基甲基取代酮类化合物的方法

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