CN113636972B - 一种多取代苯类化合物及其合成方法 - Google Patents
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- -1 Polysubstituted benzene compound Chemical class 0.000 title claims abstract description 37
- 238000001308 synthesis method Methods 0.000 title claims abstract description 5
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical class CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 239000003446 ligand Substances 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 3
- 238000010189 synthetic method Methods 0.000 claims 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 9
- 238000006352 cycloaddition reaction Methods 0.000 abstract description 8
- 229910017052 cobalt Inorganic materials 0.000 abstract description 5
- 239000010941 cobalt Substances 0.000 abstract description 5
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 229910001873 dinitrogen Inorganic materials 0.000 abstract 1
- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical compound Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 9
- 238000004896 high resolution mass spectrometry Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- 150000001345 alkine derivatives Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- DZOOXMGZVWHNAS-UHFFFAOYSA-N pent-3-yn-2-one Chemical compound CC#CC(C)=O DZOOXMGZVWHNAS-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000010276 construction Methods 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- YECVQOULKHBGEN-UHFFFAOYSA-N 1,3-diphenylprop-2-yn-1-one Chemical compound C=1C=CC=CC=1C(=O)C#CC1=CC=CC=C1 YECVQOULKHBGEN-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 150000001491 aromatic compounds Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- BKFAZDGHFACXKY-UHFFFAOYSA-N cobalt(II) bis(acetylacetonate) Chemical compound [Co+2].CC(=O)[CH-]C(C)=O.CC(=O)[CH-]C(C)=O BKFAZDGHFACXKY-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000006142 intramolecular cycloaddition reaction Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- 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
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一类多取代苯类化合物及其合成方法,以炔酮类化合物和2‑乙酰基吡啶/嘧啶化合物为原料,在催化剂作用下,合成得到如式(I)所示的多取代苯类化合物。该类化合物是通过钴与双氮配体催化体系促进的具有优秀区域选择的环加成反应制备得到的。本发明制备方法具有催化剂低毒廉价,选择性专一,原料简单易得、普适性好、后处理简便、收率良好、对环境友好且原子利用率高等优点。
Description
技术领域
本发明属于有机化合物合成及过渡金属催化的技术领域,涉及钴催化的区域选择性的环加成反应合成多取代苯类化合物的方法。
背景技术
多取代苯及其衍生物由于作为天然产物,活性药物和农用化学品中非常重要的结构单元而得到了很多关注。同时,它们还被广泛用作光学和功能材料构建的重要支架和砌块。因此,很多科研工作者投入了大量的精力来研究构建多取代苯的合成方法。通常,传统方法主要通过亲电子和亲核芳基取代过程来制备多取代芳基化合物。文献(1)Kirkham.J.D.;Butlin,R.J.;Harrity,J.P A.Angew.Chem.Int.Ed.2012,51,6402-6405.然而由于电子性质和取代基效应,某些基团可能难以通过这些方法引入苯环的合成中。文献(2)Joshi,P.R.;Undeela,S.;Reddy,D.D.;Singarapu,K.K.;Menon,R.S.Org.Lett.2015,17,1449-1452.相比之下,通过环加成反应制备苯类化合物,在取代基的控制方面则具有更大的优势。文献(3)Teo,W.T.;Rao,W.;Ng,C.J.H.;Koh,S.W.Y.;Chan,P.W.H.Org.Lett.2014,16,1248-1251.这种通过无环结构单元构建芳烃化合物,是多取代芳烃重要的合成反应之一。文献(4)Hoye,T.R.;Baire,B.;Niu,D.;Willoughby,P.H.;Woods,B.P.Nature 2012,490,208-212.文献(5)Raji Reddy,C.;Dilipkumar,U.;DamoderReddy,M.Org.Lett.2014,16,3792-3795.文献(6)Karmakar,R.;Yun,S.Y.;Chen,J.;Xia,Y.;Lee,D.Angew.Chem.,Int.Ed.2015,54,6582-6586.
金属钴作为绿色环保,具有长远发展潜力的催化剂吸引了很多科研工作者的关注,并在环加成反应中得以研究和应用。涉及的环化的底物通常为不饱和烯烃,炔烃等,在这些分子间或分子内的环加成方式通常存在着化学和区域选择性控制方面的问题。基于现有合成的不足之处,例如反应原料过度官能团化不易获得、催化剂价格昂贵以及官能团兼容性较窄等。因此,仍需要发展更加经济、简便和反应条件温和的环加成反应,还可以通过该种策略合成多种结构特别的环状化合物。
发明内容
本发明的目的是提供一类多取代苯类化合物及其合成方法,发展了一种钴催化的低成本、对环境友好的,区域选择性优秀的环加成反应。本发明提出的多取代苯类化合物,是许多天然产物和药物中主要结构单元,大多具有较强的生物活性,在药物合成以及功能性材料研究方面具有重大价值。
本发明提出了一种多取代苯类化合物,其结构如式(I)所示:
其中,
R1为氢、吸电子或给电子取代苯基、卤素、烷氧基等;其中,吸电子基为三氟甲基、硝基;给电子基为烷基、烷氧基;
R2为氢、吸电子或给电子取代基苯基、烷基、卤素;其中,吸电子基为三氟甲基、氰基;给电子基为烷基、烷氧基;
R3为氢、嘧啶基,给电子取代吡啶基;其中,给电子基为烷基。
优选地,
R1为氢、三氟甲基取代苯基、硝基取代苯基、C1-C10烷基取代苯基、C1-C10烷氧基取代苯基、卤素、C1-C10烷氧基等;
R2为氢、三氟甲基取代苯基、氰基取代苯基、C1-C10烷基取代苯基、C1-C10烷氧基取代苯基、C1-C10烷基、卤素;
R3为氢、嘧啶基,C1-C10烷基取代吡啶基。
进一步优选地,
R1为氢、甲基取代苯基、甲氧基取代苯基、三氟甲基取代苯基、卤素、硝基取代苯基、甲氧基;
R2为氢、甲基取代苯基、甲氧基取代苯基、三氟甲基取代苯基、卤素、氰基取代苯基、甲基;
R3为氢、甲基取代吡啶基。
本发明还提供了一种多取代苯类化合物的制备方法,在溶剂中,以炔酮类化合物和2-乙酰基吡啶/嘧啶化合物为原料,在催化剂、配体和还原剂的作用下,合成得到如式(I)所示的多取代苯类化合物,其反应过程如式(II)所示:
其中,
R1为氢、吸电子或给电子取代苯基、卤素、烷氧基等;其中,吸电子基为三氟甲基、硝基;给电子基为烷基、烷氧基;
R2为氢、吸电子或给电子取代基苯基、烷基、卤素;其中,吸电子基为三氟甲基、氰基;给电子基为烷基、烷氧基;
R3为氢、嘧啶基,给电子取代吡啶基;其中,给电子基为烷基。
优选地,
R1为氢、三氟甲基取代苯基、硝基取代苯基、C1-C10烷基取代苯基、C1-C10烷氧基取代苯基、卤素、C1-C10烷氧基等;
R2为氢、三氟甲基取代苯基、氰基取代苯基、C1-C10烷基取代苯基、C1-C10烷氧基取代苯基、C1-C10烷基、卤素;
R3为氢、嘧啶基,C1-C10烷基取代吡啶基。
进一步优选地,
R1为氢、甲基取代苯基、甲氧基取代苯基、三氟甲基取代苯基、卤素、硝基取代苯基、甲氧基;
R2为氢、甲基取代苯基、甲氧基取代苯基、三氟甲基取代苯基、卤素、氰基取代苯基、甲基;
R3为氢、甲基取代吡啶基。
本发明所述反应原理为:第一步,在催化剂作用下,一分子炔酮化合物与2-乙酰基吡啶/嘧啶发生氧化加成反应生成五元环钴中间体;第二步,另一分子2-乙酰基吡啶/嘧啶插入五元环钴中间体生成七元环钴中间体;第三步,还原消除后合成得到二醇化合物,随后脱掉两分子水得到如式(I)所示的多取代苯类化合物。
其中,所述溶剂为四氢呋喃,甲苯,1,4-二氧六环等中的一种或几种;优选地,为1,4-二氧六环。
其中,所述催化剂为CoBr2、CoI2、CoCl2、Co(OAc)2、Co(acac)2等中的一种或几种;优选地,为CoBr2。
其中,所述配体为邻菲罗啉、2-联吡啶、对叔丁基取代2-联吡啶、乙二胺、N,N’-二甲基乙二胺、N,N’-二甲基-1,2-环己二胺、四甲基乙二胺等中的一种或几种;优选地,为2-联吡啶。
其中,所述还原剂为锌粉,锰粉等中的一种或几种;优选地,为锌粉。
其中,所述反应的温度为80-140℃;优选地,为80、100、120、130、140℃(T1)。
其中,所述反应的时间为12-24小时;优选地,为12小时。
其中,所述炔酮类化合物:2-乙酰基吡啶/嘧啶化合物:催化剂:配体:还原剂的摩尔比为1.0:4.0:10mol%:10mol%:3.0。
现有技术中使用非过渡金属和过渡金属体系构建多取代芳烃化合物时,存在合成需要多步组分底物参与、底物需要高度官能团化、选择性仍待完善、反应不适应于简单普通的底物等缺点。
相比于现有技术,本发明的有益效果在于:本发明制备方法具有催化剂低毒廉价,选择性专一,原料简单易得、普适性好、后处理简便、收率良好(56-86%)、对环境友好且原子利用率高等优点。本发明制备的多取代苯类化合物是许多天然产物和药物中主要结构单元,大多具有较强的生物活性,在药物合成以及功能性材料研究方面具有重大价值。
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。实施本发明的过程、条件、实施方法等,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尝试,本发明没有特别限制内容。
实施例1:IA的合成
炔酮化合物、2-乙酰基吡啶化合物、溶剂、催化剂、还原剂,配体分别选用对1,3-二苯丙-2-炔-1-酮、2-乙酰基吡啶、1,4-二氧六环、溴化钴、锌粉、2-联吡啶,原料的用量分别为1,3-二苯丙-2-炔-1-酮0.1mmol、2-乙酰基吡啶0.4mmol、溶剂1ml,溴化钴10mol%、锌粉0.3mmol、2-联吡啶10mol%,在140℃反应12小时,然后冷却至室温,过滤,柱层析得目标产物式(IA),白色固体,分离收率85%。mp 178-180℃。
核磁数据:
1H NMR(400MHz,CDCl3)δ8.75(d,J=4.8Hz,1H),8.40-8.35(m,2H),8.11(s,1H),7.88(d,J=8.0Hz,1H),7.80(t,J=7.6Hz,1H),7.63-7.57(m,4H),7.33-7.28(m,4H),7.20-7.15(m,5H),7.07(t,J=6.4Hz,1H);13C NMR(100MHz,CDCl3):δ199.0,157.5,156.6,150.2,149.2,142.3,140.6,140.3,139.2,138.9,137.2,136.5,132.4,129.6,129.4,129.2,128.1,128.1,127.5,127.0,123.4,122.9,122.2,121.1;HRMS(ESI)calcd for C29H21N2O[M+H]+:413.1648,found 413.1679.
高分辨率质谱数据:HRMS(ESI)calcd for C29H21N2O[M+H]+:413.1648,found413.1679.
实施例2:IB的合成
炔酮化合物、2-乙酰基吡啶化合物、溶剂、催化剂、还原剂,配体分别选用对1,3-二甲苯丙-2-炔-1-酮、2-乙酰基吡啶、1,4-二氧六环、溴化钴、锌粉、2-联吡啶,原料的用量分别为1,3-二甲苯丙-2-炔-1-酮0.1mmol、2-乙酰基吡啶0.4mmol、溶剂1ml,溴化钴10mol%、锌粉0.3mmol、2-联吡啶10mol%,在140℃反应12小时,然后冷却至室温,过滤,柱层析得目标产物式(IB),白色固体,分离收率81%。mp 222-224℃。
核磁数据:
1H NMR(400MHz,CDCl3)δ8.74(d,J=4.8Hz,1H),8.40(d,J=4.8Hz,1H),8.35(s,1H),8.09(s,1H),7.87(d,J=8.4Hz,1H),7.79(t,J=7.6Hz,1H),7.57(d,J=4.4Hz,2H),7.51(d,J=8.4Hz,2H),7.31-7.27(m,1H),7.20(d,J=8.0Hz,2H),7.07-6.96(m,5H),2.26(s,6H);13C NMR(100MHz,CDCl3):δ198.7,157.6,156.7,150.1,149.3,143.2,142.2,140.3,140.2,139.1,137.5,137.1,136.4,129.5,129.3,129.2,128.9,128.9,126.9,123.6,122.8,122.2,121.0,21.3,20.8;
高分辨率质谱数据:HRMS(ESI)calcd for C31H25N2O[M+H]+:441.1961,found441.1954.
实施例3:IC的合成
炔酮化合物、2-乙酰基吡啶化合物、溶剂、催化剂、还原剂,配体分别选用对3-(4-甲氧基苯基)-2-苯基丙-2-炔-1-酮、2-乙酰基吡啶、1,4-二氧六环、溴化钴、锌粉、2-联吡啶,原料的用量分别为3-(4-甲氧基苯基)-2-苯基丙-2-炔-1-酮0.1mmol、2-乙酰基吡啶0.4mmol、溶剂1ml,溴化钴10mol%、锌粉0.3mmol、2-联吡啶10mol%,在140℃反应12小时,然后冷却至室温,过滤,柱层析得目标产物式(IC),白色固体,分离收率63%。mp 178-180℃。
核磁数据:
1H NMR(400MHz,CDCl3)δ8.74(d,J=4.8Hz,1H),8.41-8.33(m,2H),8.08(s,1H),7.87(d,J=8.0Hz,1H),7.80(t,J=7.6Hz,1H),7.63-7.56(m,4H),7.34-7.28(m,2H),7.24-7.16(m,4H),7.09-7.02(m,1H),6.74(d,J=8.4Hz,2H),3.73(s,3H);13C NMR(100MHz,CDCl3):δ199.2,159.2,157.5,156.6,150.2,149.2,141.9,140.5,140.3,139.1,138.9,137.2,136.5,132.7,132.4,130.7,129.3,129.2,128.1,126.7,123.4,122.9,122.2,121.1,113.6,55.0;
高分辨率质谱数据:HRMS(ESI)calcd for C30H23N2O2[M+H]+:443.1754,found443.1756.
实施例4:ID的合成
炔酮化合物、2-乙酰基吡啶化合物、溶剂、催化剂、还原剂,配体分别选用对1-(4-甲氧基苯基)-3-苯基丙-2-炔-1-酮、2-乙酰基吡啶、1,4-二氧六环、溴化钴、锌粉、2-联吡啶,原料的用量分别为1-(4-甲氧基苯基)-3-苯基丙-2-炔-1-酮0.1mmol、2-乙酰基吡啶0.4mmol、溶剂1ml,溴化钴10mol%、锌粉0.3mmol、2-联吡啶10mol%,在140℃反应12小时,然后冷却至室温,过滤,柱层析得目标产物式(ID),白色固体,分离收率60%。mp 212-214℃。
核磁数据:
1H NMR(400MHz,CDCl3)δ8.74(d,J=4.8Hz,1H),8.43(d,J=4.8Hz,1H),8.36(s,1H),8.12(s,1H),7.88(d,J=8.0Hz,1H),7.80(t,J=7.6Hz,1H),7.60-7.54(m,4H),7.32-7.26(m,3H),7.23-7.17(m,3H),7.11-7.05(m,1H),6.74(d,J=8.4Hz,2H),3.75(s,3H);13CNMR(100MHz,CDCl3):δ197.6,163.2,157.7,156.6,150.1,149.4,142.0,140.4,140.4,140.2,139.2,137.2,136.4,132.0,131.8,129.5,129.1,128.2,127.5,127.2,123.7,122.9,122.2,121.1,113.3,55.1;
高分辨率质谱数据:HRMS(ESI)calcd for C30H23N2O2[M+H]+:443.1754,found443.1755.
实施例5:IE的合成
炔酮化合物、2-乙酰基吡啶化合物、溶剂、催化剂、还原剂,配体分别选用对1-苯基-3-(3,4,5-三甲氧基苯基)-3-苯基丙-2-炔-1-酮、2-乙酰基吡啶、1,4-二氧六环、溴化钴、锌粉、2-联吡啶,原料的用量分别为1-苯基-3-(3,4,5-三甲氧基苯基)-3-苯基丙-2-炔-1-酮0.1mmol、2-乙酰基吡啶0.4mmol、溶剂1ml,溴化钴10mol%、锌粉0.3mmol、2-联吡啶10mol%,在140℃反应12小时,然后冷却至室温,过滤,柱层析得目标产物式(IE),白色固体,分离收率68%。mp 202-204℃。
核磁数据:
1H NMR(400MHz,CDCl3)8.75(d,J=4.8Hz,1H),8.44(d,J=4.8Hz,1H),8.38(s,1H),8.13(s,1H),7.88(d,J=8.0Hz,1H),7.81(t,J=8.0Hz,1H),7.64-7.57(m,2H),7.34-7.57(m,3H),7.25-7.19(m,3H),7.11(t,J=5.6Hz,1H),6.89(s,2H),3.82(s,3H),3.72(s,6H);13C NMR(100MHz,CDCl3):δ197.8,157.7,156.5,152.7,150.2,149.4,142.3,141.9,140.7,140.4,140.4,138.8,137.2,136.5,134.1,129.4,129.2,128.3,127.6,127.1,123.5,123.0,122.3,121.1106,9,60,7,56.0;
高分辨率质谱数据:HRMS(ESI)calcd for C32H27N2O4[M+H]+:503.1965,found503.1971.
实施例6:IF的合成
炔酮化合物、2-乙酰基吡啶化合物、溶剂、催化剂、还原剂,配体分别选用对1-苯基-3-(4-(三氟甲氧基)苯基)-3-苯基丙-2-炔-1-酮、2-乙酰基吡啶、1,4-二氧六环、溴化钴、锌粉、2-联吡啶,原料的用量分别为1-苯基-3-(4-(三氟甲氧基)苯基)-3-苯基丙-2-炔-1-酮0.1mmol、2-乙酰基吡啶0.4mmol、溶剂1ml,溴化钴10mol%、锌粉0.3mmol、2-联吡啶10mol%,在140℃反应12小时,然后冷却至室温,过滤,柱层析得目标产物式(IF),白色固体,分离收率67%。mp 152-154℃。
核磁数据:
1H NMR(400MHz,CDCl3)δ8.75(d,J=5.2Hz,1H),8.43(s,1H),8.37(d,J=5.2Hz,1H),8.10(s,1H),7.89(d,J=8.0Hz,1H),7.82(t,J=7.6Hz,1H),7.66-7.62(m,2H),7.58(d,J=8.0Hz,2H),7.47(d,J=8.8Hz,2H),7.41(d,J=8.4Hz,2H),7.35-7.31(m,2H),7.19(t,J=7.6Hz,2H),7.09-7.06(m,1H);13C NMR(100MHz,CDCl3):δ198.6,157.1,156.2,150.3,149.3,144.0,141.0,140.6,140.6,139.1,138.8,137.3,136.7,136.1,132.7,129.9,129.4,129.3,129.0,128.9,128.2,128.2,127.4,127.2,125.6,125.1,125.1,123.3,123.1,122.4,121.1;
高分辨率质谱数据:HRMS(ESI)calcd for C30H20F3N2O[M+H]+:481.1522,found481.1523.
实施例7:IG的合成
炔酮化合物、2-乙酰基吡啶化合物、溶剂、催化剂、还原剂,配体分别选用对3-(对甲苯基)苯基)-1-(4-(三氟甲基)苯基)丙-2-炔-1-酮、2-乙酰基吡啶、1,4-二氧六环、溴化钴、锌粉、2-联吡啶,原料的用量分别为3-(对甲苯基)苯基)-1-(4-(三氟甲基)苯基)丙-2-炔-1-酮0.1mmol、2-乙酰基吡啶0.4mmol、溶剂1ml,溴化钴10mol%、锌粉0.3mmol、2-联吡啶10mol%,在140℃反应12小时,然后冷却至室温,过滤,柱层析得目标产物式(IG),白色固体,分离收率71%。mp 151-153℃。
核磁数据:
1H NMR(400MHz,CDCl3)8.75(d,J=4.8Hz,1H),8.42(s,1H),8.27(d,J=4.8Hz,1H),8.07(s,1H),7.87(d,J=8.0Hz,1H),7.81(t,J=7.6Hz,1H),7.76-7.67(m,4H),7.47-7.42(m,2H),7.35-7.32(m,1H),7.13(d,J=7.6Hz,2H),7.10-7.06(m,1H),7.00(d,J=7.6Hz,2H),2.26(s,3H);13C NMR(100MHz,CDCl3):δ198.1,156.9,156.4,150.2,148.9,142.4,141.9,140.6,140.5,138.6,137.5,137.2,137.0,136.9,133.3,133.0,129.5,129.4,129.4,129.3,129.1,129.0,127.2,126.5,125.1,125.0,125.0,123.0,122.9,122.4,121.1,20.8;
高分辨率质谱数据:HRMS(ESI)calcd for C31H22F3N2O[M+H]+:495.1679,found495.1673.
实施例8:IH的合成
炔酮化合物、2-乙酰基吡啶化合物、溶剂、催化剂、还原剂,配体分别选用对1-苯基庚-2-炔-1-酮、2-乙酰基吡啶、1,4-二氧六环、溴化钴、锌粉、2-联吡啶,原料的用量分别为1-苯基庚-2-炔-1-酮0.1mmol、2-乙酰基吡啶0.4mmol、溶剂1ml,溴化钴10mol%、锌粉0.3mmol、2-联吡啶10mol%,在140℃反应12小时,然后冷却至室温,过滤,柱层析得目标产物式(IH),白色固体,分离收率63%。mp 106-108℃。
核磁数据:
1H NMR(400MHz,CDCl3)δ8.75(d,J=4.8Hz,1H),8.34(d,J=4.8Hz,1H),8.21(s,1H),8.03(s,1H),7.88-7.85(m,1H),7.81(t,J=7.2Hz,1H),7.69(d,J=8.0Hz,2H),7.62-7.54(m,2H),7.39(t,J=7.2Hz,1H),7.32-7.27(m,3H),7.01(t,J=5.6Hz,1H),2.70-2.60(m,2H),1.62-1.53(m,2H),1.28(q,J=7.6,15.2Hz,2H),0.81(t,J=8.8Hz,3H);13C NMR(100MHz,CDCl3):δ188.8,157.3,157.0,150.1,149.0,142.3,140.2,139.6,139.2,138.9,137.1,136.5,132.7,129.2,128.7,128.3,125.1,123.1,122.8,122.1,121.1,33.5,33.1,22.4,13.5;
高分辨率质谱数据:HRMS(ESI)calcd for C27H25N2O[M+H]+:393.1961,found393.1953.
实施例9:II的合成
炔酮化合物、2-乙酰基吡啶化合物、溶剂、催化剂、还原剂,配体分别选用对1,3-二甲苯丙-2-炔-1-酮、2-乙酰基吡啶、1,4-二氧六环、溴化钴、锌粉、2-联吡啶,原料的用量分别为1,3-二甲苯丙-2-炔-1-酮0.1mmol、2-乙酰基吡啶0.4mmol、溶剂1ml,溴化钴10mol%、锌粉0.3mmol、2-联吡啶10mol%,在140℃反应12小时,然后冷却至室温,过滤,柱层析得目标产物式(II),白色固体,分离收率72%。mp 198-200℃。
核磁数据:
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.31(s,1H),8.23(s,1H),8.04(s,1H),7.75(d,J=8.4Hz,1H),7.58(d,J=8.0Hz,1H),7.53-7.46(m,3H),7.37(d,J=8.0Hz,1H),7.18(d,J=7.6Hz,2H),7.03-6.96(m,4H),2.39(s,3H),2.25(s,6H),2.23(s,3H);13C NMR(100MHz,CDCl3):δ198.8,154.8,154.1,150.5,149.7,143.1,142.0,140.2,140.1,138.7,137.0,137.0,136.5,132.4,131.6,129.5,129.4,128.9,128.8,126.5,123.0,120.5,21.3,20.8,17.9,17.8;
高分辨率质谱数据:HRMS(ESI)calcd for C33H29N2O[M+H]+:469.2274,found469.2278.
该合成策略通过羰基化合物以烯醇互变异构体的形式发生,用于合成多取代的苯类衍生物。也是第一例钴催化的酮类化合物与炔烃参与环加成反应,该反应实现了出色的区域选择性,并通过单分子炔酮化合物与两分子单羰基化合物合成的多取代苯衍生物,不同于普通的烯炔环加成体系中,两分子炔烃与单分子烯烃参与环化。
Claims (5)
1.一种多取代苯类化合物的合成方法,其特征在于,在溶剂中,以炔酮类化合物和2-乙酰基吡啶类化合物为原料,在催化剂、配体和还原剂的作用下,合成得到如式(I)所示的多取代苯类化合物,其反应过程如式(II)所示:
其中,
R1为氢、吸电子基或给电子基取代的苯基、卤素、C1-C10烷氧基;其中,吸电子基为三氟甲基、硝基;给电子基为C1-C10烷基、C1-C10烷氧基;
R2为氢、吸电子基或给电子基取代的苯基、C1-C10烷基、卤素;其中,吸电子基为三氟甲基、氰基;给电子基为C1-C10烷基、C1-C10烷氧基;
R3为氢、嘧啶基、给电子基取代的吡啶基;其中,给电子基为C1-C10烷基;
所述催化剂为CoBr2、CoI2、CoCl2、Co(OAc)2中的一种或几种;
所述配体为邻菲罗啉、2-联吡啶、对叔丁基取代2-联吡啶、乙二胺、N,N’-二甲基乙二胺、N,N’-二甲基-1,2-环己二胺、四甲基乙二胺中的一种或几种;
所述还原剂为锌粉,锰粉中的一种或两种。
2.如权利要求1所述的合成方法,其特征在于,所述反应的温度为80-140℃。
3.如权利要求1所述的合成方法,其特征在于,所述反应的时间为12-24小时。
4.如权利要求1所述的合成方法,其特征在于,所述溶剂为四氢呋喃,甲苯,1,4-二氧六环中的一种或几种。
5.如权利要求1所述的合成方法,其特征在于,所述炔酮类化合物:2-乙酰基吡啶类化合物:催化剂:配体:还原剂的摩尔比为1.0:4.0:10mol%:10mol%:3.0。
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