CN107141279B - 一种3-(噻吩-2-基)环己-2-烯酮衍生物的制备方法 - Google Patents
一种3-(噻吩-2-基)环己-2-烯酮衍生物的制备方法 Download PDFInfo
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- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 title claims abstract description 40
- 229930192474 thiophene Natural products 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 69
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 239000002904 solvent Substances 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 23
- -1 silver hexafluoroantimonate Chemical compound 0.000 claims abstract description 21
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical class C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 13
- 239000012074 organic phase Substances 0.000 claims abstract description 13
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 13
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Chemical class [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims abstract description 13
- 229910001958 silver carbonate Inorganic materials 0.000 claims abstract description 13
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical class Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 3
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- 239000000376 reactant Substances 0.000 claims abstract description 3
- 150000003577 thiophenes Chemical class 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- QENGPZGAWFQWCZ-UHFFFAOYSA-N 3-Methylthiophene Chemical group CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 claims description 15
- WYJOVVXUZNRJQY-UHFFFAOYSA-N 2-Acetylthiophene Chemical group CC(=O)C1=CC=CS1 WYJOVVXUZNRJQY-UHFFFAOYSA-N 0.000 claims description 9
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- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical group BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 claims description 6
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical group ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 claims description 6
- JZGZKRJVTIRPOK-UHFFFAOYSA-N ethyl thiophene-2-carboxylate Chemical group CCOC(=O)C1=CC=CS1 JZGZKRJVTIRPOK-UHFFFAOYSA-N 0.000 claims description 6
- KQFADYXPELMVHE-UHFFFAOYSA-N 2-chloro-3-methylthiophene Chemical group CC=1C=CSC=1Cl KQFADYXPELMVHE-UHFFFAOYSA-N 0.000 claims description 3
- XQQBUAPQHNYYRS-UHFFFAOYSA-N 2-methylthiophene Chemical group CC1=CC=CS1 XQQBUAPQHNYYRS-UHFFFAOYSA-N 0.000 claims description 3
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- UGYRYNXDEOFIQB-UHFFFAOYSA-N benzene thiophene Chemical group S1C=CC=C1.C1=CC=CC=C1.C1=CC=CC=C1 UGYRYNXDEOFIQB-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
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- 229910052708 sodium Inorganic materials 0.000 claims 1
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- 241001597008 Nomeidae Species 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 46
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
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- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 3
- MXPZKSOVGFZLSQ-UHFFFAOYSA-N 2-(2-methylphenyl)thiophene Chemical compound CC1=CC=CC=C1C1=CC=CS1 MXPZKSOVGFZLSQ-UHFFFAOYSA-N 0.000 description 3
- QUYLXJZXWFABNS-UHFFFAOYSA-N 2-chloro-4-methylthiophene Chemical compound CC1=CSC(Cl)=C1 QUYLXJZXWFABNS-UHFFFAOYSA-N 0.000 description 3
- DMSWBBTZANPEDZ-UHFFFAOYSA-N 4-methoxythiophene Chemical compound COC1=[C]SC=C1 DMSWBBTZANPEDZ-UHFFFAOYSA-N 0.000 description 3
- GZXDOXSIKJNUEW-UHFFFAOYSA-N 5-methylthiophene Chemical compound CC1=C=C[CH]S1 GZXDOXSIKJNUEW-UHFFFAOYSA-N 0.000 description 3
- 238000005691 oxidative coupling reaction Methods 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
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- 125000000524 functional group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 238000000034 method Methods 0.000 description 2
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- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
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- 230000008878 coupling Effects 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000003447 ipsilateral effect Effects 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- 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
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D333/26—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 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 ring carbon atoms
- C07D333/28—Halogen atoms
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D333/26—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 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 ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- 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
- C07D333/26—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 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 ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及噻吩衍生物制备方法技术领域,具体涉及一种3‑(噻吩‑2‑基)环己‑2‑烯酮衍生物的制备方法。本发明一种3‑(噻吩‑2‑基)环己‑2‑烯酮衍生物的制备方法,包括如下步骤:(1)在反应器中,按摩尔比3:1:0.1:2.5:0.1:0.2依次加入环己烯酮、噻吩或取代的噻吩、氯化钯、碳酸银、N‑乙酰甘氨酸和六氟锑酸银,加入溶剂将反应物溶解,在室温下混合均匀,随后在60~120℃条件下反应5~48小时;(2)反应完成后将反应器冷却至室温,用乙酸乙酯溶解,依次用饱和氯化铵和饱和氯化钠水溶液洗涤,有机相经无水硫酸钠干燥后,过滤,在旋转蒸发仪上旋去溶剂;(3)将旋去溶剂后的剩余物用硅胶柱层析分离纯化,收集目标产物,旋蒸出去溶剂,油泵抽干。
Description
技术领域
本发明涉及噻吩衍生物制备方法技术领域,具体涉及一种3-(噻吩-2-基)环己-2-烯酮衍生物的制备方法。
技术背景
噻吩是重要的芳族杂环化合物,其衍生物是各种生物活性分子和功能材料中作为关键组分[参见:(a)Acc.Chem.Res.2001,34,359–369;(b)Angew.Chem.,Int.Ed.2005,44,5452–5456.]。取代的酚类衍生物是一种非常重要的化学中间体被广泛应用于制备各种药物,农药,聚合物及精细化学品领域。然而由于受到苯酚羟基的强邻对位效应,间位取代的酚类化合物通常比较难以合成。近年来发展的利用3-取代的环己-2-烯酮类衍生物经过进一步氧化制备间位取代的酚类化合物(Angew.Chem.Int.Ed.2013,52,3672–3675;GreenChem.,2016,18,6462–6467)。然而,目前3-取代的环己-2-烯酮化合物通常需要预官能团化的底物,经过两步或三步才能制备。钯催化的C-H/C-H氧化偶联反应制备3-取代的环己-2-烯酮类无疑是一种最经济和步骤最简洁的反应路线,然而环己烯酮作为偶联试剂在钯催化的Heck反应中由于生成的钯中间体与β-碳上的氢要在同侧才能发生β-氢消除反应,而环的张力使得碳-钯键自由旋转受限(Angew.Chem.Int.Ed.2013,52,3672–3675),目前过渡金属催化的环己烯酮与杂环的直接C-H/C-H氧化偶联反应构筑3-杂环基环己-2-烯酮衍生物仍没有解决,因此急需开发一种基于直接C-H/C-H氧化偶联反应构筑3-杂环基环己-2-烯酮衍生物的方法,继而在酸性条件下氧化得到3-杂环苯酚衍生物。
发明内容
本发明的目的是提供一种3-(噻吩-2-基)环己-2-烯酮衍生物的制备方法,原料廉价易得、方法简单、一步合成。
本发明为实现上述目的而采取的技术方案为:
一种3-(噻吩-2-基)环己-2-烯酮衍生物的制备方法,包括如下步骤:
(1)在反应器中,按摩尔比为3:1:0.1:2.5:0.1:0.2依次加入环己烯酮、噻吩或取代的噻吩、氯化钯、碳酸银、N-乙酰甘氨酸和六氟锑酸银,加入溶剂将反应物溶解,在室温下混合均匀,随后在60~120℃条件下反应5~48小时;
(2)反应完成后将反应器冷却至室温,用乙酸乙酯溶解,依次用饱和氯化铵和饱和氯化钠水溶液洗涤,有机相经无水硫酸钠干燥后,过滤,在旋转蒸发仪上旋去溶剂;
(3)将旋去溶剂后的剩余物用硅胶柱层析分离纯化,收集目标产物,旋蒸出去溶剂,油泵抽干。
进一步地,本发明所述的取代的噻吩为3-甲基噻吩、邻苯噻吩、3-甲氧基噻吩、2-氯噻吩、2-溴噻吩、2-氯-3-甲基噻吩、2-甲基噻吩、2-乙酰基噻吩或者2-噻吩羧酸乙酯。
进一步地,本发明所述的溶剂为二甲亚砜、1,1,1,3,3,3-六氟-2-丙醇或者1,4-二氧六环中的一种或者两种以上的混合物。
本发明的技术路线是环己烯酮的C-H键与噻吩的C-H键直接一步交叉偶联,其化学方程式为:
其中,R为甲基、甲氧基、苯基、卤素、酰基、酯基等。
本发明采用核磁共振氢谱(1H NMR)、碳谱(13C NMR)以及高分辨质谱证实了3-(噻吩-2-基)环己-2-烯酮衍生物的结构(如附图)检测所用仪器为:AVANCE III HD 600MHz型核磁共振仪,其中氘代氯仿为内标(氢谱,氘代氯仿:δ7.26ppm).(碳谱,氘代氯仿:δ77ppm)。Thermo Scientific Q Exactive型高分辨质谱仪。
与现有合成方法相比,本发明的优点具体体现为:
(1)本发明采用的交叉偶联反应官能团适用范围较广,包括:含卤素、烷基、苯基、烷氧基、酯基、羰基等官能团底物;
(2)本发明所用合成路线为C-H/C-H直接交叉偶联反应,与传统合成反应,C-X/C-M,C-X/C-H等制备技术相比较,反应步骤简单,提高了合成总产率,降低了总成本;
(3)本发明所用合成路线为C-H/C-H直接交叉偶联反应,未使用任何导向基团,无需额外步骤引入或脱除导向基团;
(4)本发明所用合成路线为C-H/C-H直接交叉偶联反应,为快速高效合成含有环状碳-碳双键的复杂天然产物提供了新的途径。
附图说明
图1为3-(3-甲基噻吩-2-基)环己-2-烯酮的氢谱;
图2为3-(3-甲基噻吩-2-基)环己-2-烯酮的碳谱;
图3为3-(5-苯基噻吩-2-基)环己-2-烯酮的氢谱;
图4为3-(5-苯基噻吩-2-基)环己-2-烯酮的碳谱;
图5为3-(4-甲氧基噻吩-2-基)环己-2-烯酮的氢谱;
图6为3-(4-甲氧基噻吩-2-基)环己-2-烯酮的碳谱;
图7为3-(噻吩-2-基)环己-2-烯酮的氢谱;
图8为3-(噻吩-2-基)环己-2-烯酮的碳谱;
图9为3-(5-氯噻吩-2-基)环己-2-烯酮的氢谱;
图10为3-(5-氯噻吩-2-基)环己-2-烯酮的碳谱;
图11为3-(5-溴噻吩-2-基)环己-2-烯酮的氢谱;
图12为3-(5-溴噻吩-2-基)环己-2-烯酮的碳谱;
图13为3-(5-氯-4-甲基噻吩-2-基)环己-2-烯酮的氢谱;
图14为3-(5-氯-4-甲基噻吩-2-基)环己-2-烯酮的碳谱;
图15为3-(5-甲基噻吩-2-基)环己-2-烯酮的氢谱;
图16为3-(5-甲基噻吩-2-基)环己-2-烯酮的碳谱;
图17为3-(5-乙酰基噻吩-2-基)环己-2-烯酮的氢谱;
图18为3-(5-乙酰基噻吩-2-基)环己-2-烯酮的碳谱;
图19为5-(3-氧代环己-1-烯-1-基)噻吩-2-甲酸乙酯的氢谱;
图20为5-(3-氧代环己-1-烯-1-基)噻吩-2-甲酸乙酯的碳谱。
具体实施方式
下面结合具体实施方式对本发明作进一步详细描述,将有助于对本发明的理解,但并不是以此来限制本发明的权利范围。
实施例1:3-(3-甲基噻吩-5-基)环己-2-烯酮的合成
(1)将3-甲基噻吩(0.024ml,0.25mmol),环己烯酮(0.072ml,0.75mmol),氯化钯(0.0044g,0.0025mmol),N-乙酰甘氨酸(0.0029g,0.0025mmol),碳酸银(0.1723g,0.625mmol),六氟锑酸银(0.0172g,0.05mmol),二甲亚砜(0.05ml),1,1,1,3,3,3-六氟-2-丙醇(0.05ml),1,4-二氧六环(1ml),在干净干燥的密闭反应管中搅拌均匀后加热到60℃,反应24小时。
(2)反应完成后将反应管冷却至室温,加入40ml乙酸乙酯将反应体系稀释并移入100ml的分液漏斗中,加入20ml饱和氯化铵水溶液,摇晃,静置,移除下面的水相后,再加入20ml饱和食盐水,摇晃,静置,移除下面水相,将有机相用无水硫酸钠干燥,减压移去溶剂,剩余物用硅胶柱层析(石油醚/乙酸乙酯=15:1,v/v)分离纯化,旋蒸除去溶剂,油泵抽干,得到淡黄色油状物,目标产物33.4mg,产率70%。产物中噻吩5位和2位取代的异构体比例为83:17,核磁数据为噻吩5位取代的偶联产物,如图1和图2所示,1H NMR(600MHz,CDCl3)δ7.30(d,J=5.1Hz,1H),6.89(d,J=5.1Hz,1H),6.24(s,1H),2.72(t,J=11.2,5.4Hz,2H),2.45–2.40(m,2H),2.36(s,3H),2.10(dt,J=12.8,6.2Hz,2H).13C NMR(151MHz,CDCl3)δ199.19,153.74,137.64,136.45,132.58,126.16,125.24,36.86,30.76,22.62,16.93.HRMS(ESI+):计算值C11H13OS[M+H]+193.0682,实测值193.0683。
实施例2:3-(5-苯基噻吩-2-基)环己-2-烯酮的合成
(1)将邻苯噻吩(0.0401g,0.25mmol),环己烯酮(0.072ml,0.75mmol),氯化钯(0.0044g,0.0025mmol),N-乙酰甘氨酸(0.0029g,0.0025mmol),碳酸银(0.1723g,0.625mmol),六氟锑酸银(0.0172g,0.05mmol),二甲亚砜(0.05ml),1,1,1,3,3,3-六氟-2-丙醇(0.05ml),1,4-二氧六环(1ml),在干净干燥的密闭反应管中搅拌均匀后加热到60℃,反应24小时。
(2)反应完成后将反应管冷却至室温,加入40ml乙酸乙酯将反应体系稀释并移入100ml的分液漏斗中,加入20ml饱和氯化铵水溶液,摇晃,静置,移除下面的水相后,再加入20ml饱和食盐水,摇晃,静置,移除下面水相,将有机相用无水硫酸钠干燥,减压移去溶剂,剩余物用硅胶柱层析(石油醚/乙酸乙酯=15:1,v/v)分离纯化,旋蒸除去溶剂,油泵抽干,得到黄色固体目标产物47.7mg,产率75%。熔点:129-131℃;如图3和图4所示,1H NMR(600MHz,CDCl3)δ7.61(d,J=7.8Hz,2H),7.40(t,J=7.5Hz,2H),7.36–7.30(m,2H),7.29(d,J=3.7Hz,1H),6.43(s,1H),2.78(t,J=6.0Hz,2H),2.47(t,J=6.6Hz,2H),2.17–2.12(m,2H).13C NMR(151MHz,CDCl3)δ199.26,152.22,147.66,141.51,133.42,129.02,128.54,128.44,125.91,124.08,122.32,37.22,27.61,22.40.HRMS(ESI+):计算值C16H15OS[M+H]+255.0838,实测值255.0836。
实施例3:3-(4-甲氧基噻吩-2-基)环己-2-烯酮的合成
(1)将3-甲氧基噻吩(0.025ml,0.25mmol),环己烯酮(0.072ml,0.75mmol),氯化钯(0.0044g,0.0025mmol),N-乙酰甘氨酸(0.0029g,0.0025mmol),碳酸银(0.1723g,0.625mmol),六氟锑酸银(0.0172g,0.05mmol),二甲亚砜(0.05ml),1,4-二氧六环(1ml),在干净干燥的密闭反应管中搅拌均匀后加热到60℃,反应24小时。
(2)反应完成后将反应管冷却至室温,加入40ml乙酸乙酯将反应体系稀释并移入100ml的分液漏斗中,加入20ml饱和氯化铵水溶液,摇晃,静置,移除下面的水相后,再加入20ml饱和食盐水,摇晃,静置,移除下面水相,将有机相用无水硫酸钠干燥,减压移去溶剂,剩余物用硅胶柱层析(石油醚/乙酸乙酯=15:1,v/v)分离纯化,旋蒸除去溶剂,油泵抽干,得到黄色固体目标产物32.6mg,产率63%。熔点:68-70℃;如图5和图6所示,1H NMR(600MHz,CDCl3)δ7.34(d,J=5.6Hz,1H),6.90(d,J=5.6Hz,1H),6.78(s,1H),3.92(s,3H),2.74(t,J=5.9Hz,2H),2.44–2.40(m,2H),2.11–2.05(m,2H).13C NMR(151MHz,CDCl3)δ199.96,158.43,152.10,126.81,122.51,118.54,116.82,58.54,37.11,29.29,22.62.HRMS(ESI+):计算值C11H13O2S[M+H]+209.0631,实测值209.0631。
实施例4:3-(噻吩-2-基)环己-2-烯酮的合成
(1)将噻吩(0.020ml,0.25mmol),环己烯酮(0.072ml,0.75mmol),氯化钯(0.0044g,0.0025mmol),N-乙酰甘氨酸(0.0029g,0.0025mmol),碳酸银(0.1723g,0.625mmol),六氟锑酸银(0.0172g,0.05mmol),二甲亚砜(0.05ml),1,1,1,3,3,3-六氟-2-丙醇(0.05ml),1,4-二氧六环(1ml),在干净干燥的密闭反应管中搅拌均匀后加热到60℃,反应24小时。
(2)反应完成后将反应管冷却至室温,加入40ml乙酸乙酯将反应体系稀释并移入100ml的分液漏斗中,加入20ml饱和氯化铵水溶液,摇晃,静置,移除下面的水相后,再加入20ml饱和食盐水,摇晃,静置,移除下面水相,将有机相用无水硫酸钠干燥,减压移去溶剂,剩余物用硅胶柱层析(石油醚/乙酸乙酯=15:1,v/v)分离纯化,旋蒸除去溶剂,油泵抽干,得到淡黄色油状物,目标产物19mg,产率43%。如图7和图8所示,1H NMR(600MHz,CDCl3)δ7.42(d,J=5.1Hz,1H),7.37(d,J=3.7Hz,1H),7.10–7.05(m,1H),6.41(s,1H),2.77(t,J=6.0Hz,2H),2.48–2.42(m,2H),2.15–2.09(m,2H).13C NMR(151MHz,CDCl3)δ199.39,152.38,142.70,128.71,128.22,127.28,122.68,37.19,27.96,22.39.HRMS(ESI+):计算值C11H11OS[M+H]+179.0525,实测值179.0525。
实施例5:3-(5-氯噻吩-2-基)环己-2-烯酮的合成
(1)将2-氯噻吩(0.023ml,0.25mmol),环己烯酮(0.072ml,0.75mmol),氯化钯(0.0044g,0.0025mmol),N-乙酰甘氨酸(0.0029g,0.0025mmol),碳酸银(0.1723g,0.625mmol),六氟锑酸银(0.0172g,0.05mmol),二甲亚砜(0.05ml),1,1,1,3,3,3-六氟-2-丙醇(0.05ml),1,4-二氧六环(1ml),在干净干燥的密闭反应管中搅拌均匀后加热到60℃,反应24小时。
(2)反应完成后将反应管冷却至室温,加入40ml乙酸乙酯将反应体系稀释并移入100ml的分液漏斗中,加入20ml饱和氯化铵水溶液,摇晃,静置,移除下面的水相后,再加入20ml饱和食盐水,摇晃,静置,移除下面水相,将有机相用无水硫酸钠干燥,减压移去溶剂,剩余物用硅胶柱层析(石油醚/乙酸乙酯=15:1,v/v)分离纯化,旋蒸除去溶剂,油泵抽干,得到淡黄色固体物质,目标产物25.1mg,产率47%。熔点:66-68℃;如图9和图10所示,1HNMR(600MHz,CDCl3)δ7.15(d,J=4.0Hz,1H),6.90(d,J=4.0Hz,1H),6.26(s,1H),2.71–2.68(m,2H),2.46–2.44(m,2H),2.14–2.10(m,2H).13C NMR(151MHz,CDCl3)δ199.00,151.32,141.08,133.67,127.49,126.84,122.63,37.17,27.24,22.26.HRMS(ESI+):计算值C10H10ClOS[M+H]+213.0135,实测值213.0134。
实施例6:3-(5-溴噻吩-2-基)环己-2-烯酮的合成
(1)将2-溴噻吩(0.024ml,0.25mmol),环己烯酮(0.072ml,0.75mmol),氯化钯(0.0044g,0.0025mmol),N-乙酰甘氨酸(0.0029g,0.0025mmol),碳酸银(0.1723g,0.625mmol),六氟锑酸银(0.0172g,0.05mmol),二甲亚砜(0.05ml),1,1,1,3,3,3-六氟-2-丙醇(0.05ml),1,4-二氧六环(1ml),在干净干燥的密闭反应管中搅拌均匀后加热到60℃,反应24小时。
(2)反应完成后将反应管冷却至室温,加入40ml乙酸乙酯将反应体系稀释并移入100ml的分液漏斗中,加入20ml饱和氯化铵水溶液,摇晃,静置,移除下面的水相后,再加入20ml饱和食盐水,摇晃,静置,移除下面水相,将有机相用无水硫酸钠干燥,减压移去溶剂,剩余物用硅胶柱层析(石油醚/乙酸乙酯=15:1,v/v)分离纯化,旋蒸除去溶剂,油泵抽干,得到淡黄色固体物质,目标产物32.2mg,产率50%。熔点:90-93℃;如图11和图12所示,1HNMR(600MHz,CDCl3)δ7.12(d,J=4.0Hz,1H),7.05(d,J=4.0Hz,1H),6.29(s,1H),2.71–2.69(m,2H),2.46–2.44(m,2H),2.16–2.10(m,2H).13C NMR(151MHz,CDCl3)δ199.04,151.17,143.99,131.20,127.56,122.81,116.37,37.17,27.36,22.29.HRMS(ESI+):计算值C10H10BrOS[M+H]+256.9630,实测值256.9625。
实施例7:3-(5-氯-4-甲基噻吩-2-基)环己-2-烯酮的合成
(1)将2-氯-3-甲基噻吩(0.027ml,0.25mmol),环己烯酮(0.072ml,0.75mmol),氯化钯(0.0044g,0.0025mmol),N-乙酰甘氨酸(0.0029g,0.0025mmol),碳酸银(0.1723g,0.625mmol),六氟锑酸银(0.0172g,0.05mmol),二甲亚砜(0.05ml),1,1,1,3,3,3-六氟-2-丙醇(0.05ml),1,4-二氧六环(1ml),在干净干燥的密闭反应管中搅拌均匀后加热到60℃,反应24小时。
(2)反应完成后将反应管冷却至室温,加入40ml乙酸乙酯将反应体系稀释并移入100ml的分液漏斗中,加入20ml饱和氯化铵水溶液,摇晃,静置,移除下面的水相后,再加入20ml饱和食盐水,摇晃,静置,移除下面水相,将有机相用无水硫酸钠干燥,减压移去溶剂,剩余物用硅胶柱层析(石油醚/乙酸乙酯=15:1,v/v)分离纯化,旋蒸除去溶剂,油泵抽干,得到淡黄色固体物质,目标产物37.9mg,产率67%。熔点:82-84℃;如图13和图14所示,1HNMR(600MHz,CDCl3)δ7.06(s,1H),6.24(s,1H),2.69–2.65(m,2H),2.45–2.41(m,2H),2.17(s,3H),2.13–2.07(m,2H).13C NMR(151MHz,CDCl3)δ199.02,151.44,135.85,129.04,128.82,122.23,37.16,27.14,22.27,13.59.HRMS(ESI+):计算值C11H12ClOS[M+H]+227.0292,实测值227.0290。
实施例8:3-(5-甲基噻吩-2-基)环己-2-烯酮的合成
(1)将2-甲基噻吩(0.024ml,0.25mmol),环己烯酮(0.072ml,0.75mmol),氯化钯(0.0044g,0.0025mmol),N-乙酰甘氨酸(0.0029g,0.0025mmol),碳酸银(0.1723g,0.625mmol),六氟锑酸银(0.0172g,0.05mmol),二甲亚砜(0.05ml),1,1,1,3,3,3-六氟-2-丙醇(0.05ml),1,4-二氧六环(1ml),在干净干燥的密闭反应管中搅拌均匀后加热到60℃,反应24小时。
(2)反应完成后将反应管冷却至室温,加入40ml乙酸乙酯将反应体系稀释并移入100ml的分液漏斗中,加入20ml饱和氯化铵水溶液,摇晃,静置,移除下面的水相后,再加入20ml饱和食盐水,摇晃,静置,移除下面水相,将有机相用无水硫酸钠干燥,减压移去溶剂,剩余物用硅胶柱层析(石油醚/乙酸乙酯=5:1,v/v)分离纯化,旋蒸除去溶剂,油泵抽干,得到淡黄色固体物质,目标产物32.6mg,产率68%。熔点:80-82℃;如图15和图16所示,1H NMR(600MHz,CDCl3)δ7.15(s,1H),6.71(d,J=0.9Hz,1H),6.26(s,1H),2.70(t,J=6.0Hz,2H),2.45(s,3H),2.39(dd,J=9.4,3.8Hz,2H),2.08–2.04(m,2H).13C NMR(151MHz,CDCl3)δ199.19,152.56,144.19,140.13,127.80,126.61,121.51,37.07,27.38,22.27,15.59.HRMS(ESI+):计算值C11H13OS[M+H]+193.0682,实测值193.0682。
实施例9:3-(5-乙酰基噻吩-2-基)环己-2-烯酮的合成
(1)将2-乙酰基噻吩(0.027ml,0.25mmol),环己烯酮(0.072ml,0.75mmol),氯化钯(0.0044g,0.0025mmol),N-乙酰甘氨酸(0.0145g,0.125mmol),碳酸银(0.1379g,0.5mmol),二甲亚砜(0.05ml),1,1,1,3,3,3-六氟-2-丙醇(0.5ml),1,4-二氧六环(0.5ml),在干净干燥的密闭反应管中搅拌均匀后加热到110℃,反应24小时。
(2)反应完成后将反应管冷却至室温,加入40ml乙酸乙酯将反应体系稀释并移入100ml的分液漏斗中,加入20ml饱和氯化铵水溶液,摇晃,静置,移除下面的水相后,再加入20ml饱和食盐水,摇晃,静置,移除下面水相,将有机相用无水硫酸钠干燥,减压移去溶剂,剩余物用硅胶柱层析(石油醚/乙酸乙酯=5:1,v/v)分离纯化,旋蒸除去溶剂,油泵抽干,得到黄色固体物质,目标产物26.6mg,产率48%。熔点:140-141℃;如图17和图18所示,1H NMR(600MHz,CDCl3)δ7.63(d,J=3.7Hz,1H),7.36(d,J=3.7Hz,1H),6.48(s,1H),2.76(t,J=5.9Hz,2H),2.56(s,3H),2.48(t,J=6.6Hz,2H),2.18–2.13(m,2H).13C NMR(151MHz,CDCl3)δ199.04,190.48,151.13,149.83,145.52,132.67,127.20,124.74,37.14,27.89,26.74,22.29.HRMS(ESI+):计算值C12H13O2S[M+H]+221.0631,实测值221.0629。
实施例10:5-(3-氧代环己-1-烯-1-基)噻吩-2-甲酸乙酯的合成
(1)将2-噻吩羧酸乙酯(0.033ml,0.25mmol),环己烯酮(0.072ml,0.75mmol),氯化钯(0.0044g,0.0025mmol),N-乙酰甘氨酸(0.0145g,0.125mmol),碳酸银(0.1379g,0.5mmol),二甲亚砜(0.05ml),1,1,1,3,3,3-六氟-2-丙醇(0.5ml),1,4-二氧六环(0.5ml),在干净干燥的密闭反应管中搅拌均匀后加热到110℃,反应24小时。
(2)反应完成后将反应管冷却至室温,加入乙酸乙酯将反应体系稀释并移入100ml的分液漏斗中,加入饱和氯化铵水溶液,摇晃,静置,移除下面的水相后,再加入饱和食盐水,摇晃,静置,后,再加入饱和食盐水,摇晃,静置,移除下面水相,将有机相用无水硫酸钠干燥,减压移去溶剂,剩余物用硅胶柱层析(石油醚/乙酸乙酯=5:1,v/v)分离纯化,干燥后得到黄色固体物质,目标产物37.4mg,产率60%。熔点:94-95℃;如图19和图20所示,1H NMR(600MHz,CDCl3)δ7.72(d,J=4.0Hz,1H),7.33(d,J=4.0Hz,1H),6.46(s,1H),4.35(q,J=7.1Hz,2H),2.76(t,J=6.0Hz,2H),2.49–2.46(m,2H),2.17–2.13(m,2H),1.37(t,J=7.1Hz,3H).13C NMR(151MHz,CDCl3)δ199.00,161.65,151.23,148.43,135.64,133.65,126.91,124.32,61.52,37.14,27.83,22.28,14.23.HRMS(ESI+):计算值C13H15O3S[M+H]+251.0736,实测值251.0735。
Claims (2)
1.一种3-(噻吩-2-基)环己-2-烯酮衍生物的制备方法,其特征在于包括如下步骤:
(1)在反应器中,按摩尔比为3:1:0.1:2.5:0.1:0.2依次加入环己烯酮、噻吩或取代的噻吩、氯化钯、碳酸银、N-乙酰甘氨酸和六氟锑酸银,加入溶剂将反应物溶解,在室温下混合均匀,随后在60~120℃条件下反应5~48小时;
(2)反应完成后将反应器冷却至室温,用乙酸乙酯溶解,依次用饱和氯化铵和饱和氯化钠水溶液洗涤,有机相经无水硫酸钠干燥后,过滤,在旋转蒸发仪上旋去溶剂;
(3)将旋去溶剂后的剩余物用硅胶柱层析分离纯化,收集目标产物,旋蒸出去溶剂,油泵抽干;
其中所述的溶剂为二甲亚砜、1,1,1,3,3,3-六氟-2-丙醇或者1,4-二氧六环中的一种或者两种以上的混合物。
2.根据权利要求1所述的一种3-(噻吩-2-基)环己-2-烯酮衍生物的制备方法,其特征在于所述的取代的噻吩为3-甲基噻吩、邻苯噻吩、3-甲氧基噻吩、2-氯噻吩、2-溴噻吩、2-氯-3-甲基噻吩、2-甲基噻吩、2-乙酰基噻吩或者2-噻吩羧酸乙酯。
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