CN105622493A - 一种烯胺酮和醛串联反应合成全取代吡啶类化合物的方法 - Google Patents
一种烯胺酮和醛串联反应合成全取代吡啶类化合物的方法 Download PDFInfo
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 23
- -1 pyridine compound Chemical class 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000010523 cascade reaction Methods 0.000 title claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title description 11
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 title 1
- 150000003222 pyridines Chemical class 0.000 claims abstract description 11
- 150000001299 aldehydes Chemical class 0.000 claims abstract description 10
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 238000000605 extraction Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000010992 reflux Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- XARVANDLQOZMMJ-CHHVJCJISA-N 2-[(z)-[1-(2-amino-1,3-thiazol-4-yl)-2-oxo-2-(2-oxoethylamino)ethylidene]amino]oxy-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)O\N=C(/C(=O)NCC=O)C1=CSC(N)=N1 XARVANDLQOZMMJ-CHHVJCJISA-N 0.000 description 1
- 238000005653 Chichibabin synthesis reaction Methods 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000003445 Hantzsch reaction Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052755 nonmetal Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000007704 transition Effects 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
一种烯胺酮和醛串联反应合成全取代吡啶类化合物的方法，产物的特征是吡啶环为全取代以及平面不对称结构。本发明的优点是：1、反应无需任何金属催化，仅需要加入三氟甲磺酸即可实现，经济实用；2、适用范围好，芳醛、烷基脂肪醛以及烯基烯基脂肪醛均能参加反应；3、操作简单、总产率良好，适合放大。
Description
技术领域
本发明涉及一种串联反应合成全取代吡啶类化合物的方法
背景技术
吡啶是有机杂环化合物的基本类型之一，吡啶衍生物本身以及许多其它的含吡啶片段的有机分子在有机合成、材料化合物以及生物药物等领域均具有重要功能(Chem.Rev.2014,114,10829-10868)。因此，吡啶类化合物的合成在有机化学研究以及相关产业方面一直是重要的研究课题。传统的吡啶合成方法主要有基于Hantzsch反应的1,4-二氢吡啶氧化、Chichibabin反应以及[2+2+2]反应等。最近，通过采用酮肟以及相应的酯相关的串联反应合成吡啶的方法也得到的快速的发展。然而，目前的绝大的合成方法或是需要采用铜、钯等过渡金属催化，或是需要经过一步以上的反应操作以及仅适用于合成平面对称结构的吡啶类产物。因此，发展更加经济高效的合成方法如非金属催化、一步串联反应合成吡啶，特别是具有平面非对称结构的吡啶对于吡啶的合成研究及相关应用具有重要意义。本专利报道了一种采用NH2和常见的醛为底物，无需金属催化，采用TfOH一步串联反应合成具有平面非对称和全取代结构吡啶类化合物的方法。
发明内容
本发明的目的在于提供一种原料经济、操作简便的串联反应全取代吡啶类化合物的方法。
本发明是这样实现的，一种烯胺酮和醛串联反应合成全取代吡啶类化合物的方法，采用含NH2氨基结构的烯胺酮和醛胺2:1摩尔当量投料，在等摩尔当量三氟甲磺酸(TfOH)的促进下，以DMF为溶剂，90℃加热8小时，通过乙酸乙酯萃取，蒸干溶剂后，残余物以石油醚和乙酸乙脂(V/V＝15:1)混合溶剂作为流动相通过硅胶柱色谱进行提纯得到目标产物。
具体方法过程为：将烯胺酮0.6mmol，醛0.3mmol，三氟甲磺酸0.3mmol和2mLDMF置于25mL圆底烧瓶，链接回流冷凝管，在空气氛围下，油浴加热至90℃，搅拌回流8小时。反应结束后冷却至室温，加入10mL水，并以乙酸乙酯萃取(3×10mL)。萃取所得有机相以Na2SO4干燥、过滤。滤液通过减压蒸馏出去溶剂，残余物以石油醚和乙酸乙脂(V/V＝15:1)混合溶剂作为流动相通过硅胶柱色谱进行提纯得到目标产物。产物结构经过核磁共振、高分辨质谱以及代表性产物的单晶衍射测试等确证无误。
吡啶产物的结构特征是环上全部有取代基，且分子为平面非对称结构。
本发明的技术效果是：本发明所用的原料均简单易得、常态下较稳定，无需任何金属催化以及无水无氧等保护操作。过程简便，兼容于不同性质的醛包括方向醛、烷基脂肪醛和烯基脂肪醛等进行反应合成不同类型的全取代吡啶产物，而且易于工业放大，是一类高效实用的合成全取代吡啶的方法。
附图说明
图1为本发明合成反应图。
图2为本发明化合物3a的单晶结构图
图3为本发明化合物3a的核磁共振氢谱图。
图4为本发明化合物3a的核磁共振碳谱图。
图5为本发明化合物3b的核磁共振氢谱图。
图6为本发明化合物3b的核磁共振碳谱图。
图7为本发明化合物3c的核磁共振氢谱图。
图8为本发明化合物3c的核磁共振碳谱图。
具体实施方式
结合图1、2、3、4、5、6、7、8，本发明是这样来实现的：将烯胺酮1(0.6mmol)，醛2(0.3mmol)，三氟甲磺酸(0.3mmol)和DMF(2mL)置于25mL圆底烧瓶，链接回流冷凝管，在空气氛围下，油浴加热至90℃，搅拌回流8小时。反应结束后冷却至室温，加入10mL水，并以乙酸乙酯萃取(3×10mL)。萃取所得有机相以Na2SO4干燥、过滤。滤液通过减压蒸馏出去溶剂，残余物以石油醚和乙酸乙脂(V/V＝15:1)混合溶剂作为流动相通过硅胶柱色谱进行提纯得到目标产物吡啶3。产物结构经过核磁共振、高分辨质谱以及代表性产物的单晶衍射测试等确证无误。
产物表征数据分别为：
(3a)Whitesolid,m.p154-155℃；1HNMR(400MHz,CDCl3):δ7.91(d,J＝8.0Hz,2H),7.64(d,J＝7.2Hz,3H),7.52(t,J＝7.6Hz,4H),7.42(t,J＝7.6Hz,1H),7.29(t,J＝7.6Hz,2H),7.22(d,J＝7.2Hz,3H),2.50(s,3H),2.05(s,3H)；13CNMR(100MHz,CDCl3):δ198.1,197.9,155.7,154.6,142.6,139.2,136.9,136.4,134.6,133.9,133.8,132.3,129.5,129.4,129.3,129.2,128.8,128.6,128.3,23.2,17.0；ESI-HRMSCalcdforC27H22NO2[M+H]+392.1645,found392.1650.
(3b)Yellowliquid；1HNMR(400MHz,CDCl3):δ7.86(d,J＝8.0Hz,4H),7.66-7.62(m,2H),7.53-7.49(m,4H),2.65(q,J＝7.6Hz,2H),2.42(s,3H),1.92(s,3H)1.22(t,J＝7.6Hz,3H)；13CNMR(100MHz,CDCl3):δ198.1,198.0,158.9,154.1,141.3,136.8,136.5,134.4,132.9,132.4,130.0,129.5,129.2,129.1,128.3,29.6,22.8,16.8,14.1；ESI-HRMSCalcdforC23H22NO2[M+H]+344.1645,found344.1655.
(3c)Yellowliquid；1HNMR(400MHz,CDCl3):δ8.16(d,J＝15.6Hz,1H),7.88(t,J＝7.6Hz,4H),7.63(q,J＝7.6Hz,2H),7.50(q,J＝7.6Hz,4H),7.31(d,J＝7.2Hz,1H),7.21(t,J＝7.2Hz,1H),6.95(d,J＝15.2Hz,1H),6.84(q,J＝8.0Hz,2H),3.75(s,3H),2.46(s,3H),1.94(s,3H)；13CNMR(100MHz,CDCl3):δ198.3,198.1,160.1,154.4,151.4,141.7,137.1,136.6,135.2,134.4,133.3,131.7,130.4,129.7,129.5,129.2,128.9,126.5,121.8,114.6,114.1,55.3,23.3,16.8；ESI-HRMSCalcdforC30H26NO3[M+H]+448.1907,found448.1915。
Claims (2)
1.一种烯胺酮和醛串联反应合成全取代吡啶类化合物的方法，其特征在于：采用含NH2氨基结构的烯胺酮和醛胺2:1摩尔当量投料，在等摩尔当量三氟甲磺酸(TfOH)的促进下，以DMF为溶剂，90℃加热8小时，通过乙酸乙酯萃取，蒸干溶剂后，残余物以石油醚和乙酸乙脂(V/V＝15:1)混合溶剂作为流动相通过硅胶柱色谱进行提纯得到目标产物。
2.根据权利要求1所述的一种烯胺酮和醛串联反应合成全取代吡啶类化合物的方法，其特征在于，通过含NH2结构的烯胺酮和醛串联反应一步实现产物构建，产物吡啶环上为全取代，且分子为平面非对称结构。
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|---|---|---|---|---|
| CN113045394A (zh) * | 2021-03-22 | 2021-06-29 | 江西师范大学 | 一种合成α-碘代-β酮基缩醛类化合物的方法 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4175087A (en) * | 1978-01-12 | 1979-11-20 | Eli Lilly And Company | α,β-Unsaturated ketones and aldehydes and method of preparation |
| US4845113A (en) * | 1985-08-19 | 1989-07-04 | Boehringer Biochemia Robin S.P.A. | 2-substituted -1,4-dihydropyridines and pharmaceutical compositions containing them |
| WO2008144268A1 (en) * | 2007-05-15 | 2008-11-27 | Boehringer Ingelheim International Gmbh | Urotensin ii receptor antagonists |
| CN103819400A (zh) * | 2013-09-16 | 2014-05-28 | 江西师范大学 | 一种多组分反应合成具有不对称结构1.4-二氢吡啶及其衍生物的方法 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4175087A (en) * | 1978-01-12 | 1979-11-20 | Eli Lilly And Company | α,β-Unsaturated ketones and aldehydes and method of preparation |
| US4845113A (en) * | 1985-08-19 | 1989-07-04 | Boehringer Biochemia Robin S.P.A. | 2-substituted -1,4-dihydropyridines and pharmaceutical compositions containing them |
| WO2008144268A1 (en) * | 2007-05-15 | 2008-11-27 | Boehringer Ingelheim International Gmbh | Urotensin ii receptor antagonists |
| CN103819400A (zh) * | 2013-09-16 | 2014-05-28 | 江西师范大学 | 一种多组分反应合成具有不对称结构1.4-二氢吡啶及其衍生物的方法 |
Non-Patent Citations (2)
| Title |
|---|
| JIE-PING WAN等: ""Novel Regioselectivity: Three-Component Cascade Synthesis of Unsymmetrical 1,4- and 1,2-Dihydropyridines"", 《J. ORG. CHEM.》 * |
| NARENDAR REDDY GADE等: ""IBX mediated reaction of β-enamino esters with allylicalcohols: a one pot metal free domino approach tofunctionalized pyridines"", 《CHEM. COMMUN.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113045394A (zh) * | 2021-03-22 | 2021-06-29 | 江西师范大学 | 一种合成α-碘代-β酮基缩醛类化合物的方法 |
| CN113045394B (zh) * | 2021-03-22 | 2023-03-10 | 江西师范大学 | 一种合成α-碘代-β酮基缩醛类化合物的方法 |
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