CN108148046B - 一种吡啶基桥联吡唑基吲哚衍生物及制备和应用 - Google Patents
一种吡啶基桥联吡唑基吲哚衍生物及制备和应用 Download PDFInfo
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- MZASQQDCQLEXBR-UHFFFAOYSA-N chembl2414979 Chemical class N1C=CC(C=2NC3=CC=CC=C3C=2)=N1 MZASQQDCQLEXBR-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 125000004076 pyridyl group Chemical group 0.000 title claims abstract description 11
- BTJVCXWTEQSJND-UHFFFAOYSA-N 2-bromo-6-(1h-pyrazol-5-yl)pyridine Chemical compound BrC1=CC=CC(C=2NN=CC=2)=N1 BTJVCXWTEQSJND-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 238000006356 dehydrogenation reaction Methods 0.000 claims abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 34
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
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- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
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- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- QBPCHTVAENAPSK-UHFFFAOYSA-N [K].CC1=NNC(=C1)C Chemical compound [K].CC1=NNC(=C1)C QBPCHTVAENAPSK-UHFFFAOYSA-N 0.000 description 1
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- 150000004696 coordination complex Chemical class 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
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- 239000003814 drug Substances 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004983 proton decoupled 13C NMR spectroscopy Methods 0.000 description 1
- 238000000607 proton-decoupled 31P nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
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
- C07D401/14—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 three or more hetero rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/70—Oxidation reactions, e.g. epoxidation, (di)hydroxylation, dehydrogenation and analogues
- B01J2231/76—Dehydrogenation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
- B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
- B01J2531/0244—Pincer-type complexes, i.e. consisting of a tridentate skeleton bound to a metal, e.g. by one to three metal-carbon sigma-bonds
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/821—Ruthenium
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- Chemical Kinetics & Catalysis (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种吡啶基桥联吡唑基吲哚衍生物的制备方法。以2‑溴‑6‑吡唑基吡啶为原料，通过简单取代反应合成了目标吡啶基桥联吡唑基吲哚衍生物。此类化合物可作为三齿配体用于合成高效的饱和氮杂环脱氢催化剂。本发明具有原料价廉易得、合成效率高和产物易于衍生化等优点。
Description
技术领域
本发明涉及一种吡啶基桥联吡唑基吲哚衍生物的制备方法。以2-溴-6-吡唑基吡啶为原料与吲哚化合物发生取代反应，制备富电子型的吡啶基桥联吡唑基吲哚衍生物。本发明具有原料价廉易得、合成效率高和产物易于衍生化等优点。该吡啶基桥联吡唑基吲哚衍生物可用于钌金属配合物催化剂的制备，并应用于催化饱和氮杂环的脱氢反应。
技术背景
含氮杂环化合物是一类非常重要的有机化合物，在医药、有机发光材料、染料等领域有着广泛应用。传统的氮杂环化合物合成方法往往需要当量的氧化剂以及繁琐的实验步骤。金属配合物催化饱和氮杂环无氧化剂条件下的催化脱氢反应受到广泛关注。该方法易操作，原子利用率高，氢气为唯一的反应副产物,符合绿色化学发展的概念。Yamaguchi小组(R.Yamaguchi,et al.J.Am.Chem.Soc.2009131,8410；J.Am.Chem.Soc.2014,136,4829.)设计合成了一系列2,2’-吡啶二酮配体及其铱金属配合物，此类催化剂高效的实现了饱和氮杂环的脱氢反应。研究指出催化剂的高活性与配体存在可互变的吡啶酮官能团结构有关。Xiao小组(J.Xiao,etal.Angew.Chem.Int.Ed.2013,52,6983；Angew.Chem.Int.Ed.2015,54,5223.)报道了一系列亚胺类配体及铱配合物催化剂，此类配合物高效的实现了饱和氮杂环的脱氢反应。
近几年来，一系列非对称和手性的吡啶基桥联三齿配体被成功制备(Z.K.Yu,etal.Organometalltics 2008,27,2898；Chem.Eur.J.2012,18,10843；Organometallics2016,35,1251.)，并且其钌配合物可应用于催化酮的转移氢化反应、仲醇脱氢反应以及基于借氢策略的碳碳键构筑反应，并取得了非常优异的结果，而钌金属配合物催化的氮杂环脱氢反应鲜有报道。
本发明公开了一种吡啶基桥联吡唑基吲哚衍生物及其合成方法。以2-溴-6-吡唑基吡啶为原料，通过简单取代反应合成了吡啶基桥联吡唑基吲哚衍生物。此类化合物可作为三齿配体用于合成高效的饱和氮杂环脱氢钌催化剂。本发明具有原料价廉易得、合成效率高和产物易于衍生化等优点。
发明内容
本发明的目的在于提供一种原料易得、反应条件温和、适应性广、能高效地合成含吡啶基桥联吡唑基吲哚化合物的方法。
为了实现上述目的，本发明的技术方案如下：
2-溴-6-吡唑基吡啶2与吲哚化合物3在铜催化下发生取代反应，反应结束后按常规分离纯化方法进行产物分离和表征，得到吡啶基桥联吡唑基吲哚衍生物1。
技术方案的特征在于：
1、2-溴-6-吡唑基吡啶2为合成子，可以通过简单制备得到；
2、吲哚化合物3为商品化产品，可以直接购买使用；
3、2-溴-6-吡唑基吡啶2与吲哚化合物3反应的催化剂为CuOAc、CuBr、CuCl、或CuI,催化剂与2-溴-6-吡唑基吡啶2的摩尔比为0.01:1-0.2:1；
3、反应所用碱为碳酸钠、碳酸铯、叔丁醇钾或叔丁醇钠，碱与2-溴-6-吡唑基吡啶2的摩尔比为0.5:1-4:1；
4、2-溴-6-吡唑基吡啶2与吲哚化合物3的反应溶剂为1,4-二氧六环、邻二甲苯、甲苯中的一种或者两种；
5、2-溴-6-吡唑基吡啶2与吲哚化合物3的摩尔比为1:1-1:3；反应温度为70-150℃；反应时间为5-15小时。
总之，本发明以2-溴-6-吡唑基吡啶为原料，通过简单取代反应合成了目标吡啶基桥联吡唑基吲哚衍生物。此类化合物可用于合成高效的饱和氮杂环脱氢钌金属催化剂。本发明具有原料价廉易得、合成效率高和产物易于衍生化等优点。
具体实施方式
通过下述实施例有助于进一步理解本发明，但本发明的内容并不仅限于此。
2-溴-6-吡唑基吡啶2参照文献方法合成，由2,6-二溴吡啶与吡唑钾盐发生取代反应制备得到(Z.K.Yu,et al.Organometallics 2005,24,2959.)。
以化合物2a的合成为例。N2氛围下，将2,6-二溴吡啶(2.37g,10.0mmol)、3,5-二甲基吡唑钾盐(2.01g,15.0mmol)、四氢呋喃(50mL)加入到反应瓶中，回流搅拌反应10小时。反应结束后，将混合物冷至室温，硅藻土过滤，减压下除去挥发组份，然后用硅胶柱层析分离(洗脱液为石油醚(60-90℃)/乙酸乙酯，v/v＝50:1)，得到白色固体产物2a(2.04g,收率81％)。目标产物通过核磁共振谱得到确认。
实施例1
在25mL Schlenk反应瓶中，依次加入2-溴-6-(3,5-二甲基吡唑)吡啶2a(252mg，1.0mmol)、吲哚3a(117mg，1.0mmol)、溴化亚铜(14mg，0.01mmol)、1,10-邻二菲啰啉(36mg，0.02mmol)、碳酸钠(159mg，1.5mmol)和1,4-二氧六环(5mL)，100℃搅拌反应10小时。反应结束后，将混合物冷至室温，减压下除去挥发组份，然后用硅胶柱层析分离(洗脱液为石油醚(60-90℃)/乙酸乙酯，v/v＝30:1)，得到白色固体目标产物1a(228mg,收率79％)。目标产物通过核磁共振谱和高分辨质谱测定得到确认。
实施例2
反应步骤与操作同实施例1，与实施例1不同之处在于反应催化剂为CuOAc,停止反应，经同样方法后处理得到目标产物1a(167mg,收率58％)。说明使用CuOAc为催化剂，反应收率降低。
实施例3
反应步骤与操作同实施例1，与实施例1不同之处在于反应溶剂为邻二甲苯,停止反应，经同样方法后处理得到目标产物1a(150mg,收率52％)。说明使用邻二甲苯为溶剂，反应收率降低。
实施例4
反应步骤与操作同实施例1，与实施例1不同之处在于碱为叔丁醇钾,停止反应，经同样方法后处理得到目标产物1a(176mg,收率61％)。说明使用叔丁醇钾为碱，反应收率降低。
实施例5
反应步骤与操作同实施例1，与实施例1不同之处在于反应温度为80℃,停止反应，经同样方法后处理得到目标产物1a(118mg,收率41％)。说明降低反应温度，反应收率降低。
实施例6
反应步骤与操作同实施例1，与实施例1不同之处在于反应时间为5h,停止反应，经同样方法后处理得到目标产物1a(101mg,收率35％)。说明缩短反应时间，反应收率降低。
应用例1
25mL Schlenk反应瓶中依次加入配体1a(144mg,0.5mmol)，RuCl2(PPh3)3(480mg,0.5mmol)和甲苯(10mL)，回流2h。冷至室温后，过滤出所得棕红沉淀，并用乙醚洗涤(3×20mL)。真空干燥后得棕红色固体产品4a(389mg，收率82％)。目标产物通过核磁共振谱和单晶结构测定得到确认。
在氮气保护下，将底物四氢喹啉(66.5mg,0.5mmol)，催化剂4a(4.7mg,0.005mmol)，叔丁醇钾(5.6mg,0.05mmol)以及甲苯(0.5mL)加入到Schlenk反应瓶中，回流搅拌反应24小时。反应结束后，反应液做气相色谱分析，四氢喹啉转化率可达到90％，说明该配合物可作为潜在的饱和氮杂环脱氢催化剂使用。
典型化合物表征数据
1-(6-(3’,5’-二甲基吡唑基)-吡啶基)吲哚1a,白色固体,熔点55-56°C。1H NMR(CDCl3,400MHz)δ8.29(d,J＝4.2Hz,1H),7.70(t,J＝8.0Hz,1H),7.59(m,1H),7.49(br,1H),7.42(m,2H),7.30(d,J＝8.0Hz,1H),6.87(m,1H),6.05(s,1H),2.71(s,3H),2.35(s,3H)；13C{1H}NMR(CDCl3,100MHz)δ152.7,150.1,150.0,141.6,140.5,134.8,130.5,126.4,123.1,121.3,121.2,112.5,111.4,110.8,109.5,105.5,15.0,13.7；HRMS calcd forC18H16N4[M]+:288.1375；found:288.1370.
钌配合物4a，棕红色固体，熔点>300℃。1H NMR(CDCl3,400MHz)δ10.09(d,J＝5.4Hz,1H),7.94(d,J＝7.2Hz,1H),7.82(d,J＝8.2Hz,1H),7.66(d,J＝8.2Hz,1H),7.25(m,5H),7.09(m,12H),6.80(d,J＝8.2Hz,1H),6.39(s,1H),2.88(s,3H),2.87(s,3H),2.21(s,3H)；31P{1H}NMR(CDCl3,162MHz)δ29.0.Anal.Calcd for C33H30Cl2N5PRu:C,68.38；H,4.78；N,5.91.Found:C,68.32；H,4.65；N,6.09。
Claims (8)
1.一种吡啶基桥联吡唑基吲哚衍生物，其结构式如下式1所示：
取代基R1与 R2分别为氢、甲基或苯基；R3与 R4分别为氢、甲氧基或硝基。
2.一种权利要求1所述吡啶基桥联吡唑基吲哚衍生物的制备方法，其特征在于：以2-溴-6-吡唑基吡啶2为起始原料，在铜催化碱性条件下与吲哚化合物3反应，生成吡啶基桥联吡唑基吲哚衍生物1；
合成路线如下述反应式所示：
取代基R1与 R2分别为氢、甲基或苯基；R3与 R4分别为氢、甲氧基或硝基。
3.如权利要求2所述的制备方法，其特征在于：2-溴-6-吡唑基吡啶2与吲哚化合物3反应的催化剂为CuOAc、CuBr、CuCl、或CuI中的一种或者两种以上, 催化剂与2-溴-6-吡唑基吡啶2的摩尔比为0.01:1-0.2:1。
4.如权利要求2所述的制备方法，其特征在于：2-溴-6-吡唑基吡啶2与吲哚化合物3的反应所用碱为碳酸钠、碳酸铯、叔丁醇钾或叔丁醇钠中的一种或者两种以上，碱与2-溴-6-吡唑基吡啶2的摩尔比为0.5:1-4:1。
5.如权利要求2所述的制备方法，其特征在于：2-溴-6-吡唑基吡啶2与吲哚化合物3反应的溶剂为1,4-二氧六环、邻二甲苯、甲苯中的一种或者两种以上。
6.如权利要求2所述的制备方法，其特征在于：2-溴-6-吡唑基吡啶2与吲哚化合物3的摩尔比为1:1-1:3。
7.如权利要求2所述的制备方法，其特征在于：反应温度为70-150 oC；反应时间为5-15小时。
8.一种权利要求1所述吡啶基桥联吡唑基吲哚衍生物在饱和氮杂环脱氢反应中的应用，其特征在于：所述吡啶基桥联吡唑基吲哚衍生物为合成饱和氮杂环脱氢催化剂的配体。
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