CN108409743A - 一种烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法 - Google Patents
一种烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法 Download PDFInfo
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- quinoxaline compounds
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- IEOUSWADWJLLCH-UHFFFAOYSA-N pyrrolo[1,2-a]quinoxaline Chemical class C1=NC2=CC=CC=C2N2C1=CC=C2 IEOUSWADWJLLCH-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 239000001301 oxygen Substances 0.000 claims abstract description 10
- -1 amino N phenylpyrrole Chemical group 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000007800 oxidant agent Substances 0.000 claims abstract description 9
- 230000001590 oxidative effect Effects 0.000 claims abstract description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical class CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000010949 copper Substances 0.000 claims abstract description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052802 copper Inorganic materials 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 150000003254 radicals Chemical class 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000007243 oxidative cyclization reaction Methods 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims description 3
- 229920006395 saturated elastomer Chemical class 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 238000004809 thin layer chromatography Methods 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- YDYCXDWUKJSHMI-UHFFFAOYSA-N n-cyclobutylidenehydroxylamine Chemical compound ON=C1CCC1 YDYCXDWUKJSHMI-UHFFFAOYSA-N 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical group CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims 1
- 239000005751 Copper oxide Substances 0.000 claims 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims 1
- 150000004054 benzoquinones Chemical class 0.000 claims 1
- 230000031709 bromination Effects 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 claims 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims 1
- 229940116318 copper carbonate Drugs 0.000 claims 1
- 229910000431 copper oxide Inorganic materials 0.000 claims 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims 1
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 claims 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 150000002978 peroxides Chemical class 0.000 claims 1
- 239000001119 stannous chloride Substances 0.000 claims 1
- 235000011150 stannous chloride Nutrition 0.000 claims 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 238000009423 ventilation Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 8
- 150000002148 esters Chemical group 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract 2
- 150000002923 oximes 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 96
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 28
- 239000000047 product Substances 0.000 description 25
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 238000001819 mass spectrum Methods 0.000 description 24
- 230000005311 nuclear magnetism Effects 0.000 description 24
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 150000003252 quinoxalines Chemical class 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- NZZIMKJIVMHWJC-UHFFFAOYSA-N dibenzoylmethane Chemical compound C=1C=CC=CC=1C(=O)CC(=O)C1=CC=CC=C1 NZZIMKJIVMHWJC-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000002466 imines Chemical group 0.000 description 2
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 2
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 2
- RRHNGIRRWDWWQQ-UHFFFAOYSA-N n-iodoaniline Chemical group INC1=CC=CC=C1 RRHNGIRRWDWWQQ-UHFFFAOYSA-N 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 1
- 108010063919 Glucagon Receptors Proteins 0.000 description 1
- 102100040890 Glucagon receptor Human genes 0.000 description 1
- ZLQPMUPROAZYTQ-UHFFFAOYSA-N N#CCC(Cc1ccccc1)c1nc2ccccc2[n]2c1ccc2 Chemical compound N#CCC(Cc1ccccc1)c1nc2ccccc2[n]2c1ccc2 ZLQPMUPROAZYTQ-UHFFFAOYSA-N 0.000 description 1
- GDMZHPUPLWQIBD-UHFFFAOYSA-N Nc(cccc1)c1-[n]1cccc1 Chemical compound Nc(cccc1)c1-[n]1cccc1 GDMZHPUPLWQIBD-UHFFFAOYSA-N 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Chemical group 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000007342 radical addition reaction Methods 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供了一种新型的利用邻氨基N‑苯基吡咯为原料在比较温和的反应条件下与苄酯环丁肟合成多取代的烷基腈取代的吡咯并[1,2‑a]喹喔啉化合物的方法。本发明在特戊酸铜为催化剂的反应条件下，以常压的氧气为氧化剂，N‑甲基吡咯烷酮为溶剂，简单直接合成了多取代的烷基腈取代的吡咯并[1,2‑a]喹喔啉化合物。该反应的首次利用邻氨基N‑苯基吡咯为底物合成多取代的烷基腈取代的吡咯并[1,2‑a]喹喔啉化合物，且所用氧化剂为常压氧气，反应需要的步骤少。同时本发明还具有原料制备简单，操作安全，收率高等特点，具有极大的工业化应用价值。
Description
技术领域
本发明属于有机合成技术领域，具体涉及一种多取代吡咯并喹喔啉化合物的制备方法。
背景技术
吡咯并[1,2-a]喹喔啉化合物是一类重要的化合物，该类化合物不仅是许多天然产物的核心结构单元，而且在生物、医药等领域有着广泛的应用。例如，胰高血糖素受体拮抗剂，抗疟疾药物，抗HIV药物，抗癌药物等中都含有吡咯并[1,2-a]喹喔啉骨架。因此吡咯并[1,2-a]喹喔啉化合物合成的方法学研究一直被人们所关注。
近年来吡咯并[1,2-a]喹喔啉化合物的合成方法取得了较好的进展。列举如下：
(1)以2-醛基吡咯和邻碘苯胺为底物：
Reeves小组发现2-醛基吡咯和邻碘苯胺在碱性条件下用碘化亚铜作为催化剂，通过环化生成最终产物吡咯并[1,2-a]喹喔啉。1
(2)以2-吡咯苯胺和苯乙酮为底物：
Chen Ma小组发现在以2-吡咯苯胺和苯乙酮为原料，用I2作为催化剂， DMSO作为氧化剂，2-吡咯苯胺和苯乙酮通过sp3和sp2交叉脱氢偶联，生成吡咯并[1,2-a]喹喔啉化合物。2
(3)以2-吡咯苯胺和二苯甲酰甲烷为底物：
Chen Ma小组用2-吡咯苯胺和二苯甲酰甲烷为原料，用对甲苯磺酸作为催化剂，通过形成亚胺和碳碳键的断裂过程等形成最终产物吡咯并[1,2-a]喹喔啉化合物。3
(4)以2-吡咯苯胺和二甲基亚砜为底物：
Chen Ma小组在以2-吡咯苯胺和二甲基亚砜为原料，在醋酸作用下，二甲基亚砜在高温条件下生产甲基自由基，通过自由基加成形成亚胺中间体，最终通过亲电取代形成吡咯并[1,2-a]喹喔啉。4
(5)以2-吡咯苯胺和醛类化合物为底物：
Hongbin Zhai5a和Ramesh Chandra5b小组发现以化合物2-吡咯苯胺和醛为底物时，首先2-吡咯苯胺和醛通过脱水缩合形成亚胺，之后通过分子内的环化氧化形成吡咯并[1,2-a]喹喔啉化合物。
(6)以2-吡咯苯胺和炔为底物：
Hong Liu小组发现在金催化下，以2-吡咯苯胺和炔为原料通过芳基化形成吡咯并[1,2-a]喹喔啉化合物。6
(7)以2-吡咯硝基苯、2-吡咯苯胺和烷基醇为底物：
Valérie Thiéry7a小组和Gaoxi Jiang7b小组分别以2-吡咯硝基苯、2-吡咯苯胺和烷基醇为底物经过一系列的氧化环化合成吡咯并[1,2-a]喹喔啉化合物。
(8)以2-吡咯异氰基苯和苯基碘(III)二羧酸酯试剂为底物：
Timothy F.Jamison发现了一种用2-吡咯异氰基苯和苯基碘(III)二羧酸酯试剂制备吡咯并[1,2-a]喹喔啉的方法。这种方法用可见光诱导引发自由基反应，通过自由基耦合制备各种各样的喹喔啉杂环。8
以上几种方法的缺点是原料制备方法复杂，反应条件苛刻，原料不稳定，有些需要昂贵的金属催化剂或氧化剂，成本较高，无法实现工业化应用，其次至今没有提供很好的能够简单合成烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法。
本发明所要解决的技术问题在于提供简单高效全新的烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法。
为解决上述技术问题，本发明采用的技术方案是：一种烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法，包括以下步骤：在反应器中加入具有通式I和II的化合物，溶剂NMP(N-甲基吡咯烷酮)，催化剂特戊酸铜，常压氧气作为氧化剂，抽换气3次，放在80℃的油浴锅中，反应8.0h，薄层色谱监测反应进程，直至反应完全；用乙酸乙酯和饱和食盐水萃取，用无水硫酸钠干燥，减压蒸出溶剂，残渣用石油醚/乙酸乙酯＝10/1的流动相经硅胶柱层析分离纯化，得到化合物III，反应方程式如下：
方程式中：R1为氢、烷基、卤素、吡咯基，R2为氢、苄基。
上述的这种烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法，其特征在于，用廉价易得的常压氧气作为氧化剂，在催化氧化条件下对环丁酮肟进行开环，形成自由基，通过自由基耦合，氧化环化得到最终产物。
本发明与现有技术相比具有以下优点：
1、本发明所用原料廉价易得，反应条件温和，操作简便，底物兼容性好，产率高等优点
2、本发明使用氧气做氧化剂，整个反应过程包括了开环、自由基耦合、氧化环化的过程，合成了烷基腈取代的吡咯并[1,2-a]喹喔啉化合物。
3、本发明不需要昂贵的催化剂且操作安全。
下面通过实施例，对本发明技术方案做进一步的详细说明。具体实施方式
实施例1：本实施例的制备方法包括以下步骤：
在反应管中依次加入化合物Ia(0.30mmol)、IIa(0.36mmol)、NMP(2 mL)、Cu(OPiv)2(0.03mmol)、常压氧气抽换气3次，放在80℃的油浴锅中，反应8.0h，薄层色谱监测反应进程，直至反应完全；用乙酸乙酯和饱和食盐水萃取，用无水硫酸钠干燥，减压蒸出溶剂，残渣用石油醚/乙酸乙酯＝10/1的流动相经硅胶柱层析分离纯化，得到化合物IIaa，收率81％。反应方程式如下：
实施例1所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.93-7.90(m,2H),7.84-7.82(m,1H), 7.53-7.48(m,1H),7.46-7.42(m,1H),6.89-6.86(m,2H),3.39-3.35(m,2H),3.08- 3.04(m,2H)；13CNMR(100MHz,CDCl3,ppm):δ＝151.7,135.5,129.8,127.6, 127.3,125.3,125.2,119.7,114.7,113.8,113.7,105.7,29.9,14.1；HRMS calcd for C14H12N3[M+H]+222.1026；found:222.1029.
实施例2所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.84(s,1H),7.69-7.66(m,2H), 7.29-7.25(m,1H),6.81(s,2H),3.34-3.30(m,2H),3.04-3.00(m,2H),2.47(s,3 H)；13C NMR(100MHz,CDCl3,ppm):δ＝151.5,135.3,135.0,129.4,128.6,125.1, 125.0,119.8,114.4,113.4,113.3,105.3,29.8,21.0,14.0；HRMS calcd for C15H14N3 [M+H]+236.1182；found:236.1188.
实施例3所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.89-7.88(m,1H),7.79-7.77(d,J＝8.4Hz,1H),7.62(s,1H),7.24-7.23(d,J＝1.6Hz,1H),6.85-6.84(d,J＝2.0Hz,1 H),3.37-3.33(m,2H),3.06-3.03(m,2H),2.54(s,3H)；13C NMR(100MHz, CDCl3,ppm):δ＝150.7,138.1,133.4,129.3,127.0,126.5,125.3,119.8,114.3,113.7, 113.6,105.3,29.9,21.8,14.1；HRMS calcd for C15H14N3[M+H]+236.1182；found: 236.1176.
实施例4所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.27-8.26(m,1H),7.78-7.75(m,1 H),7.31-7.25(m,2H),6.87-6.85(m,1H),6.83-6.81(m,1H),3.33-3.30(m,2H), 3.04-3.01(m,2H),2.89(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ＝151.2, 137.0,131.0,128.1,127.5,126.4,125.3,124.6,120.2,119.8,112.9,104.9,29.6,23.8, 13.9；HRMS calcd for C15H14N3[M+H]+236.1182；found:236.1188.
实施例5所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.88-7.87(m,1H),7.69(s,1H),7.60 (s,1H),6.85-6.84(d,J＝2.0Hz,2H),3.38-3.35(m,2H),3.06-3.02(m,2H),2.49 (s,3H)；13C NMR(100MHz,CDCl3,ppm):δ＝150.7,137.1,134.2,133.6,129.7, 125.3,125.2,119.9,114.2,114.1,113.4,105.2,29.9,20.3,19.6,14.3；HRMS calcd for C16H16N3[M+H]+250.1339；found:250.1334.
实施例6所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.92-7.88(m,2H),7.77-7.74(d,J＝ 8.8Hz,1H),7.57-7.54(m,1H),6.86-6.83(m,2H),3.38-3.34(m,2H),3.07-3.03 (m,2H),1.41(s,9H)；13C NMR(100MHz,CDCl3,ppm):δ＝151.6,148.5,135.1, 125.9,125.3,125.2,125.0,119.7,114.4,113.5,113.2,105.4,34.6,31.36,30.0,14.3；HRMS calcd for C18H20N3[M+H]+278.1652；found:278.1659.
实施例7所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.70-8.69(m,1H),7.51-7.49(d,J＝8.0Hz,1H),7.00-6.98(d,J＝8.0Hz,1H),6.86-6.85(m,1H),6.79-6.77(m,1H), 4.03(s,3H),3.33-3.30(m,2H),3.03-3.00(m,2H)k；13C NMR(100MHz,CDCl3, ppm):δ＝151.8,149.6,137.5,125.6,124.3,122.3,121.5,119.8,118.5,112.5,108.9, 104.8,56.1,29.7,14.0；HRMScalcd for C15H14N3O[M+H]+252.1132；found: 252.1138.
实施例8所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.87(s,1H),7.86-7.74(m,1H), 7.58-7.55(m,1H),7.24-7.19(m,1H),6.89-6.85(m,2H),3.37-3.33(m,2H),3.06- 3.03(m,2H)；13C NMR(100MHz,CDCl3,ppm):δ＝161.0-158.6(d,J＝243Hz,1 C),153.0,136.6-136.5(d,J＝11Hz,1C),125.1-119.8(d,J＝528Hz,1C),123.9, 115.4,115.2,115.0,114.9,114.8,113.9,106.1,29.9,14.0；HRMS calcd for C14H11FN3[M+H]+240.0932；found:240.0937.
实施例9所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.88-7.87(m,1H),7.78-7.75(m,1H), 7.59-7.56(m,1H),7.24-7.19(m,1H),6.89-6.85(m,2H),3.37-3.34(m,2H),3.06- 3.03(m,2H)；13CNMR(100MHz,CDCl3,ppm):δ＝160.9,158.5,152.9,136.6- 136.5(d,J＝11Hz,1C),125.0-119.7(d,J＝534Hz,1C),123.9,115.3,115.1, 114.9,114.8-114.7(d,J＝10Hz,1C),113.9,106.0,29.8,13.9；HRMS calcd for C14H11FN3[M+H]+240.0932；found:240.0938.
实施例10所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.42-8.37(m,1H),8.35-8.34(d,J＝ 0.4Hz,1H),7.79-7.74(m,1H),7.10-7.09(m,1H),6.91-6.90(m,1H),3.32-3.29 (m,2H),3.03-3.00(m,2H)；13C NMR(100MHz,CDCl3,ppm):δ＝153.5,149.8- 148.2(dd,J＝154Hz,15Hz,1C),147.4-145.7(dd,J＝150Hz,14Hz,1C),131.7- 123.7(dd,J＝801Hz,10Hz,1C),124.3,120.6,117.1,116.4-116.2(d,J＝18Hz,1 C),114.3,107.3,104.0,103.7,29.2,13.5；HRMScalcd for C14H10F2N3[M+H]+ 258.0838；found:258.0830.
实施例11所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.91-7.90(d,J＝2.4Hz,1H),7.90- 7.89(m,1H),7.77-7.74(d,J＝8.8Hz,1H),7.47-7.44(m,1H),6.91-6.87(m,1H), 3.39-3.35(m,2H),3.07-3.03(m,1H)；13C NMR(100MHz,CDCl3,ppm):δ＝152.9, 136.3,130.3,129.2,127.6,125.9,125.2,119.7,115.0,114.8,114.2,106.3,29.8,13.9； HRMS calcd for C14H11ClN3[M+H]+256.0636；found:256.0630.
实施例12所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.82-7.78(m,3H),7.37-7.34(m,1 H),6.88(s,2H),3.37-3.33(m,2H),3.06-3.02(m,1H)；13C NMR(100MHz, CDCl3,ppm):δ＝151.8,133.9,132.9,130.8,127.8,125.6,125.1,119.7,114.9,114.3, 113.8,106.1,29.8,13.9；HRMScalcd for C14H11ClN3[M+H]+256.0636；found: 256.0643.
实施例13所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.89-7.88(m,1H),7.71-7.69(m,1 H),7.50-7.48(m,1H),7.38-7.34(m,1H),6.90-6.86(m,2H),3.40-3.64(m,2H), 3.13-3.10(m,1H)；13CNMR(100MHz,CDCl3,ppm):δ＝152.1,134.2,132.3, 128.3,127.2,125.9,125.2,119.8,115.3,114.4,112.4,106.2,29.9,13.8；HRMS calcd for C14H11ClN3[M+H]+256.0636；found:256.0642.
实施例14所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.60(s,1H),8.48-8.47(d,J＝2.0Hz, 1H),7.94(s,1H),7.15-7.14(d,J＝3.6Hz,1H),6.94-6.92(m,1H),3.35-3.31(m, 2H),3.05-3.01(m,2H)；13C NMR(100MHz,CDCl3,ppm):δ＝154.7,134.6,129.7, 129.6,127.3,126.6,124.6,120.6,117.6,116.8,114.6,108.0,29.2,13.5；HRMS calcd for C14H10Cl2N3[M+H]+290.0247；found:290.0240.
实施例15所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.04-8.03(d,J＝1.6Hz,1H),7.86(s, 1H),7.66-7.64(d,J＝8.8Hz,1H),7.56-7.53(m,1H),6.89-6.86(m,2H),3.37- 3.33(m,2H),3.05-3.02(m,2H)；13C NMR(100MHz,CDCl3,ppm):δ＝152.8, 136.5,132.1,130.2,126.2,125.1,119.7,117.7,114.9,114.2,106.3,29.7,13.8； HRMS calcd for C14H11BrN3[M+H]+300.0131；found:300.0138.
实施例16所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.80-7.79(m,1H),7.79(s,1H),7.74 (s,1H),6.86-6.83(m,2H),3.36-3.32(m,2H),3.05-3.01(m,2H),2.47(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ＝151.8,134.0,133.3,133.2,131.1,125.9,125.0, 119.7,114.7,114.0,113.9,105.9,29.8,19.8,13.9；HRMS calcd for C15H13ClN3 [M+H]+270.0793；found:270.0798.
实施例17所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.26-8.25(m,1H),7.95-7.94(d,J＝ 2.4Hz,1H),7.41-7.40(d,J＝2.0Hz,1H),6.93-6.92(m,1H),6.88-6.86(m,1H), 3.37-3.34(m,2H),3.06-3.02(m,2H),2.88(s,3H)；13C NMR(100MHz,CDCl3, ppm):δ＝152.3,138.2,133.3,130.5,127.3,126.7,126.5,120.5,119.8,117.1,113.6, 105.7,29.6,23.7,13.9；HRMScalcd for C15H13BrN3[M+H]+314.0288；found: 314.0284.
实施例18所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.03-8.02(d,J＝1.2Hz,1H),7.97- 7.96(m,1H),7.92-7.90(d,J＝8.4Hz,1H),7.73-7.71(m,1H),7.00-6.92(m,2H), 3.41-3.37(m,2H),3.10-3.06(m,2H)；13C NMR(100MHz,CDCl3,ppm):δ＝153.2, 135.1,129.4,127.5-127.2(q,J＝18Hz,1C),125.4,125.2-122.5(d,J＝270Hz,1 H),124.0-123.9(d,J＝3.0Hz,1H),119.6,115.4,114.7,114.4,106.8,29.8,13.8； HRMS calcd for C15H11F3N3[M+H]+290.0900；found:290.0908.
实施例19所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.52-8.50(m,1H),8.37-8.36(m,1 H),8.19-8.17(m,1H),7.43-7.40(m,1H),6.94-6.93(m,1H),6.92-6.88(m,1H), 3.39-3.35(m,2H),3.07-3.03(m,1H)；13C NMR(100MHz,CDCl3,ppm):δ＝151.2, 139.7,133.2,131.1,128.0,125.4,119.8,119.6,117.8,114.8,114.3,111.3,106.1, 105.1,29.9,14.1；HRMS calcd forC18H15N4[M+H]+287.1291；found:287.1298.
实施例20所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.52-8.50(m,1H),8.37-8.36(m,1 H),8.19-8.17(m,1H),7.43-7.40(m,1H),6.94-6.93(m,1H),6.89-6.88(m,1H), 3.39-3.35(m,2H),3.07-3.03(m,2H)；13C NMR(100MHz,CDCl3,ppm):δ＝152.7, 146.7,139.3,137.0,130.2,126.6,121.5,119.6,115.9,114.2,107.2,29.7,14.0； HRMS calcd for C13H11N4[M+H]+223.0978；found:223.0982.
实施例21所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.34-8.33(m,2H),8.00-7.99(d,J＝ 1.2Hz,1H),6.92-6.91(m,1H),6.87-6.86(m,1H),3.38-3.35(m,2H),3.06-3.02 (m,2H),2.49(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ＝152.6,147.2,137.4, 137.0,131.3,129.9,126.6,119.6,115.7,113.9,106.9,29.7,18.1,14.0；HRMS calcd for C14H13N4[M+H]+237.1135；found:237.1140.
实施例22所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.36-8.35(d,J＝1.2Hz,1H),8.16- 8.14(d,J＝8.4Hz,1H),7.43-7.41(d,J＝8.4Hz,1H),6.98-6.92(m,2H),3.42- 3.38(m,2H),3.09-3.05(m,2H)；13C NMR(100MHz,CDCl3,ppm):δ＝152.9, 147.7,140.0,138.7,129.1,126.7,122.0,119.6,116.4,114.8,107.6,29.8,13.9； HRMS calcd for C13H10ClN4[M+H]+257.0589；found:257.0594.
实施例23所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝8.18-8.15,(m,1H),7.84-7.82(m,1 H),7.40-7.34(m,2H),6.38(s,1H),3.47-3.43(m,2H),3.06-3.02(m,2H),2.88(s, 3H),2.57(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ＝152.0,136.4,129.9,129.3, 127.8,126.2,124.4,123.2,120.2,118.4,116.3,115.0,31.1,17.7,14.7,14.0；HRMS calcd for C16H16N3[M+H]+250.1339；found:250.1331.
实施例24所得产品的结构、核磁、高分辨质谱数据如下：
1H NMR(400MHz,CDCl3,ppm):δ＝7.96-7.92,(m,2H),7.84-7.82(m,1 H),7.52-7.48(m,1H),7.46-7.42(m,1H),7.28-7.22(m,2H),7.21-7.18(m,1H), 6.85-6.82(m,2H),3.86-3.79(m,1H),3.40-3.35(m,1H),3.11-3.02(m,2H),2.78- 2.72(m,1H)；13C NMR(100MHz,CDCl3,ppm):δ＝155.0,138.2,135.6,130.0, 129.1,128.7,127.7,127.3,126.9,125.4,125.3,119.2,114.8,113.8,113.7,105.7, 42.4,40.2,20.0；HRMS calcd forC21H18N3[M+H]+312.1495；found:312.1490.
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Claims (6)
1.一种烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法，包括以下步骤：在反应器中加入具有通式I和II的化合物，溶剂NMP(N-甲基吡咯烷酮)，催化剂特戊酸铜，常压氧气换气3次，放在80℃的油浴锅中，反应8.0h，薄层色谱监测反应进程，直至反应完全；用乙酸乙酯和饱和食盐水萃取，用无水硫酸钠干燥，减压蒸出溶剂，残渣用石油醚/乙酸乙酯＝10/1的流动相经硅胶柱层析分离纯化，得到化合物III，反应方程式如下：
方程式中：R1选自氢、烷基、卤素、芳基、吡咯基，R2选自氢、酯基、烷基、芳基、苄基。上述的一种烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法，其特征在于，用廉价易得的氧气作为氧化剂，在催化氧化条件下对环丁酮肟进行开环，形成自由基，通过自由基耦合，氧化环化得到最终产物。
2.根据权利要求1所述的一种多取代烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法，其特征在于，所述氧化剂为常压氧气，常压空气，过氧叔丁醇，过氧叔丁醚，臭氧，双氧水，苯醌。
3.根据权利要求1所述的一种多取代烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法，其特征在于，所述催化剂A为特戊酸铜，氯化亚铜，氯化铜，碘化亚铜，碘化铜，溴化亚铜，溴化铜，氧化铜，碱式碳酸铜，三氟甲磺酸铜。
4.根据权利要求1所述的一种多取代烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法，其特征在于，所述溶剂A为N-甲基吡咯烷酮，1,4-二氧六环，四氢呋喃，乙腈，二氯甲烷，氯仿，二氯乙烷，二甲亚砜，N,N-二甲基乙酰胺，乙醇，甲醇，甲苯。
5.根据权利要求1所述的一种多取代烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法，其特征在于，所述通式化合物I和II、催化剂的用量的摩尔比为1:1.0-3.0:0.1-0.5。
6.根据权利要求1所述的一种多取代烷基腈取代的吡咯并[1,2-a]喹喔啉化合物的制备方法，其特征在于，所述反应温度为60-120℃。
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| CN109400611B (zh) * | 2018-09-27 | 2021-08-24 | 南京林业大学 | 一种1-乙烯基-4,5-二氢吡咯[1,2-a]喹喔啉化合物的合成方法 |
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