CN110372725A - 一种桥环多环多取代四氢喹啉及其制备方法 - Google Patents
一种桥环多环多取代四氢喹啉及其制备方法 Download PDFInfo
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- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 claims abstract 5
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Chemical group 0.000 claims description 12
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
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- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
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- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明公开了一种桥环多环多取代四氢喹啉及其制备方法，属于有机合成技术领域。本发明通过将烯胺酮和N‑烷基喹啉盐加在乙腈溶剂中，以四甲基胍为碱，在60℃的温度下发生1,4‑加成“诱导”的多级环化串联反应来制备桥环多取代四氢喹啉。本发明开辟了N‑烷基喹啉盐新的反应模式，使其反应位点开发到最多（C2、C3和C4）。本发明避免分离中间体，反应完全后，通过简单的过滤即可拿到纯品。本发明具有反应条件温和、反应时间短、操作简便、底物普适性广等优点。
Description
技术领域
本发明属于有机合成领域，具体涉及一种桥环多环多取代四氢喹啉及其制备方法。
背景技术
四氢喹啉及其衍生物是一类重要的生物碱，是很多天然产物和药物分子的活性骨架，具有广泛的生理活性。因此发展更加高效的方法来合成结构多样的这类化合物具有十分重要的研究意义和应用价值。通过文献调研发现，喹啉盐的去芳构化反应是制备四氢喹啉最直接、最有效的方法之一。喹啉盐通过与一系列亲核试剂发生加成反应，得到氢化的喹啉。但是，这些反应通常发生在C2-或(和)C4-位，反应相对简单，且具有较差的区域选择性，通常得到C2-和C4-位官能化的混合产物(图1，Org.Lett.2017,19,3783；Tetrahedron2011,67,2863.)。这些反应仅仅利用了喹啉盐的C2和C4反应位点，而C3反应位点还没有被利用。因此，开发喹啉盐新的更多的反应位点用以合成结构新型的复杂多取代桥环四氢喹啉具有很重要的意义。
发明内容
针对现有技术中存在的问题，本发明提供一种桥环多环多取代四氢喹啉及其制备方法，开辟了喹啉盐新的反应位点，操作简单、反应条件温和、且目标产物容易分离。
为解决上述技术问题，本发明采用以下技术方案：
一种桥环多环多取代四氢喹啉，其结构式如下：
其中，R1为烷基、卤素或氢；R2为甲基或氢，R3为烷基，R4为烷基、卤素或氢。
所述的桥环多环多取代四氢喹啉的制备方法，步骤如下：将烯胺酮和N-烷基喹啉盐，在有机溶剂中，碱的存在下，25-80℃反应5分钟至24小时，薄层色谱跟踪反应至完全，反应结束后，通过用布氏漏斗过滤分离纯化，得目标产物，其反应通式如下：
其中，R1为烷基、卤素或氢；R2为甲基或氢，R3为烷基，R4为烷基、卤素或氢。
进一步，所述的碱为无机碱或有机碱，所述无机碱为碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、醋酸钠；有机碱为三乙胺、吡啶、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、1,4-二叠氮双环[2.2.2]辛烷(DABCO)、四甲基胍(TMG)，所述的碱优选TMG。
进一步，所述的碱的物质的量为烯胺酮的物质的量的2倍。
进一步，所述的有机溶剂为乙腈、甲醇、乙醇、甲苯、氯仿、二氯甲烷、1,2-二氯乙烷、乙醚、四氢呋喃、1,4-二氧六环或乙酸乙酯，优选为乙腈。
进一步，所述反应温度优选为60℃。
进一步，所述烯胺酮与N-烷基喹啉盐的摩尔比为1:1-1:4，优选为1:2.2。
本发明的有益效果：本发明通过将烯胺酮和N-烷基喹啉盐加在乙腈溶剂中，以四甲基胍为碱，在60℃的温度下发生1,4-加成“诱导”的环化串联反应来制备桥环多环多取代四氢喹啉。本发明开辟了N-烷基喹啉盐新的反应模式，通过和烯胺酮反应，使其反应位点开发到最大(3个)，生成了一种结构新颖、具有多环桥环复杂结构的多取代四氢喹啉化合物。本发明中间产物不需分离纯化，且目标产物容易分离；操作简单、反应条件温和、反应时间短，收率高达99％。
附图说明
图1为实施例1化合物3a的1H NMR图；
图2为实施例1化合物3a的13C NMR图；
图3为实施例1化合物3m的X-射线单晶衍射图；
图4为喹啉盐的反应模式。
具体实施方式
下面结合具体实施例，对本发明做进一步说明。应理解，以下实施例仅用于说明本发明而非用于限制本发明的范围，该领域的技术熟练人员可以根据上述发明的内容作出一些非本质的改进和调整。
实施例1
桥环多环多取代四氢喹啉3a的制备：往10mL硬质玻璃反应试管中，加入烯胺酮1a(0.15mmol，34.4mg)，N-苄基喹啉溴盐2a(0.33mmol，99.1mg)，0.8mL乙腈，然后加入34.6mg四甲基胍(0.30mmol)，混合物在60℃搅拌5min。反应完全后，过滤，滤饼即为目标化合物3a(白色固体，97.7mg，收率98％，>20:1dr，)。
所得化合物3a的核磁共振氢谱、碳谱、红外以及高分辨质谱数据如下:
1H NMR(400MHz,CDCl3),δ7.66(d,J＝8.0Hz,1H),7.29-7.21(m,5H),7.10(d,J＝4.0Hz,5H),7.03-6.96(m,3H),6.92(d,J＝8.0Hz,2H),6.75(t,J＝8.0Hz,1H),6.67(d,J＝8.0Hz,1H),6.61(t,J＝8.0Hz,4H),6.43(d,J＝8.0Hz,1H),5.35(s,2H),5.01(d,J＝16.0Hz,1H),4.78(d,J＝16.0Hz,1H),4.68(d,J＝16.0Hz,1H),4.50(s,1H),4.21(d,J＝16.0Hz,1H),3.73(t,J＝8.0Hz,1H),2.44(d,J＝8.0Hz,1H),2.33(s,3H),2.10-2.03(m,3H),1.83(d,J＝16.0Hz,1H),0.90(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3)δ162.9,158.0,150.1,142.9,141.6,138.8,138.5,131.3,129.8,129.4,128.7,128.2,127.3,127.1,127.1,126.8,126.8,126.6,126.5,125.3,123.0,121.2,119.7,118.3,116.7,114.5,114.0,110.7,82.9,56.6,55.7,53.2,41.5,41.0,40.6,31.2,29.0,28.9,27.7,20.8.IR(KBr)ν3421,3029,2951,1597,1494,1222,747cm-1.HRMS(ESI)calcd for C47H46N3O[M+H]+668.3635,found668.3617.
化合物3b-t的制备方法同化合物3a，投料比与化合物3a相同，可得到化合物3b-t，反应产率见表1，但需要强调的是本发明的化合物并不局限于表1中所示化合物。
表1：含有不同取代基的复杂桥环多环多取代四氢喹啉的制备结果
化合物3b(白色固体，84％收率，2.7:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.67(d,J＝8.0Hz,1H),7.35-6.91(m,15H),6.78-6.54(m,7H),6.44(d,J＝12.0Hz,1H),5.78-5.35(m,2H),5.01(d,J＝16.0Hz,1H),4.80-4.43(m,3H),4.21(d,J＝16.0Hz,1H),3.74(q,J＝8.0Hz,1H),2.45(d,J＝12.0Hz,1H),2.03(t,J＝12.0Hz,3H),1.81(dd,J1＝8.0Hz,J2＝12.0Hz,1H),0.90(s,3H),0.79(s,3H)；13C NMR(100MHz,CDCl3)δ162.9,158.3,152.8,142.9,141.6,138.7,138.5,129.8,128.8,128.6,128.5,128.3,128.2,127.3,127.1,127.1,126.9,126.7,126.5,125.2,122.9,122.1,121.2,119.8,118.3,116.7,114.5,113.9,110.7,82.9,56.6,55.6,53.1,41.5,41.0,40.6,31.2,28.9,27.6.IR(KBr)ν3434,2953,1594,1492,1381,746cm-1.HRMS(ESI)calcd for C46H44N3O[M+H]+654.3479,found654.3461.
化合物3c(白色固体，83％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.48(d,J＝8.0Hz,1H),7.21(d,J＝4.0Hz,1H),7.24-7.14(m,5H),7.03-6.95(m,8H),6.72-6.55(m,8H),5.76(t,J＝8.0Hz,1H),5.44(s,1H),4.80(d,J＝16.0Hz,1H),4.58(t,J＝16.0Hz,2H),4.38(s,1H),4.03(d,J＝16.0Hz,1H),3.60(t,J＝8.0Hz,1H),2.37(d,J＝8.0Hz,1H),2.07-2.00(m,3H),1.78(d,J＝16.0Hz,1H),0.89(s,3H),0.81(s,3H)；13C NMR(100MHz,CDCl3)δ160.4,158.2,148.5,142.8,141.1,138.4,138.3,129.3,128.5,128.5,128.4,127.3,127.2,127.1,126.9,126.9,126.8,126.6,124.5(d,J＝73.0Hz,1C),122.5,121.0,120.9,117.9(d,J＝33.0Hz,1C),115.5,115.4,115.3,114.0,110.8,85.2,57.9,56.8,54.0,41.5,41.1,40.0,31.2,29.2,27.8,27.4.IR(KBr)ν3437,3033,2954,1599,1494,1215,750cm-1.HRMS(ESI)calcd for C46H43FN3O[M+H]+672.3385,found 672.3361.
化合物3d(白色固体，99％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.67(d,J＝4.0Hz,1H),7.32-7.27(m,3H),7.15(t,J＝8.0Hz,7H),6.99-6.93(m,5H),6.61(d,J＝8.0Hz,3H),6.51(d,J＝12.0Hz,1H),6.40(d,J＝12.0Hz,1H),5.42(t,J＝8.0Hz,1H),5.31(s,1H),4.94(d,J＝16.0Hz,1H),4.76(d,J＝16.0Hz,1H),4.64(d,J＝16.0Hz,1H),4.40(s,1H),4.19(d,J＝20.0Hz,1H),3.69(t,J＝8.0Hz,1H),2.39(t,J＝4.0Hz,1H),2.35(s,3H),2.13-2.03(m,3H),1.85(d,J＝16.0Hz,1H),0.92(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3)δ162.7,158.2,149.8,141.4,140.1,138.0(2C),131.6,129.5,129.4,128.8,128.4(2C),127.3,127.0,126.8,126.7,126.6,126.5,126.4,124.4,123.0,122.5,121.9,119.7,115.9,113.4,111.9,82.8,56.5,56.2,53.4,41.4,40.9,40.3,31.2,28.9,28.6,27.9,20.8.IR(KBr)ν3419,2955,1603,1493,1218,878cm-1.HRMS(ESI)calcdforC47H44Cl2N3O[M+H]+736.2856,found 736.2847.
化合物3e(白色固体，93％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.74(d,J＝4.0Hz,1H),7.31(d,J＝8.0Hz,3H),7.19(d,J＝4.0Hz,7H),7.00(s,5H),6.66(dd,J1＝J2＝8.0Hz,3H),6.55(d,J＝8.0Hz,1H),6.44(d,J＝8.0Hz,1H),5.47(t,J＝8.0Hz,1H),5.36(s,1H),4.98(d,J＝20.0Hz,1H),4.80(d,J＝20.0Hz,1H),4.68(d,J＝16.0Hz,1H),4.45(s,1H),4.24(d,J＝16.0Hz,1H),3.73(t,J＝8.0Hz,1H),2.70(t,J＝8.0Hz,2H),2.42(d,J＝12.0Hz,1H),2.11(dd,J1＝J2＝16.0Hz,3H),1.90(d,J＝16.0Hz,1H),1.31(t,J＝8.0Hz,3H),0.97(s,3H),0.82(s,3H)；13C NMR(100MHz,CDCl3)δ162.7,158.2,150.0,141.3,140.1,138.1,138.0(2C),129.4,128.8,128.4(2C),128.3,127.3,127.0,126.8,126.7,126.6,126.4(2C),124.3,123.0,122.5,121.9,119.7,115.9,113.4,111.9,82.8,56.5,56.1,53.4,41.4,40.9,40.3,31.2,28.9,28.6,28.3,27.9,15.8.IR(KBr)ν3442,2958,1603,1492,1220,860cm-1.HRMS(ESI)calcd for C48H46Cl2N3O[M+H]+750.3012,found 750.3000.
化合物3f(白色固体，86％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.73(s,1H),7.33(d,J＝8.0Hz,3H),7.19(d,J＝8.0Hz,5H),7.02-6.93(m,7H),6.70-6.64(m,3H),6.54(d,J＝8.0Hz,1H),6.44(d,J＝8.0Hz,1H),5.46(t,J＝8.0Hz,1H),5.35(s,1H),4.99(d,J＝16.0Hz,1H),4.80(d,J＝20.0Hz,1H),4.68(d,J＝20.0Hz,1H),4.45(s,1H),4.24(d,J＝16.0Hz,1H),3.85(s,3H),3.73(t,J＝8.0Hz,1H),2.41(d,J＝8.0Hz,1H),2.24-2.00(m,3H),1.90(d,J＝16.0Hz,1H),0.96(s,3H),0.81(s,3H)；13C NMR(100MHz,CDCl3)δ163.2,158.2,155.3,145.7,141.4,140.1,138.0,137.9,129.4,128.8,128.4(2C),127.3,127.0,126.8,126.7,126.6,126.4(2C),124.3,123.0,122.5,121.9,120.8,115.9,114.3,113.5,111.9,82.8,56.4,56.2,55.5,53.4,41.4,40.9,40.3,31.2,28.9,28.6,28.0.IR(KBr)ν3424,2953,1602,1494,1228,879cm-1.HRMS(ESI)calcdforC47H44Cl2N3O2[M+H]+752.2805,found 752.2807.
化合物3g(白色固体，71％收率，3.5:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.70(s,1H),7.32-6.94(m,16H),6.71(d,J＝8.0Hz,2H),6.60(d,J＝8.0Hz,1H),6.51(d,J＝8.0Hz,1H),6.39(d,J＝8.0Hz,1H),5.43(d,J＝8.0Hz,1H),5.33(s,1H),4.94(d,J＝20.0Hz,1H),4.78-4.59(m,2H),4.55-4.36(m,1H),4.20(d,J＝16.0Hz,1H),3.69(t,J＝8.0Hz,1H),2.39(d,J＝8.0Hz,1H),2.11-2.01(m,3H),1.83(d,J＝16.0Hz,1H),0.91(s,3H),0.77(s,3H)；13C NMR(100MHz,CDCl3)δ162.7,158.5,152.4,141.3,140.1,137.9,137.9,129.2,128.9,128.7,128.4,128.3,127.3,127.1,127.0,126.8,126.7,126.6,126.4,124.3,123.0,122.4,122.3,121.8,119.7,115.9,113.3,111.9,82.7,56.4,56.1,53.3,41.4,40.9,40.2,31.1,28.9,28.6,27.8.IR(KBr)ν3426,2955,1596,1489,1377,1220,703cm-1.HRMS(ESI)calcd for C46H42Cl2N3O[M+H]+722.2699,found 722.2705.
化合物3h(黄色固体，83％收率，5.0:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.66(s,1H),7.28-6.95(m,14H),6.62(d,J＝8.0Hz,3H),6.51(d,J＝8.0Hz,2H),6.39(d,J＝8.0Hz,1H),5.42(d,J＝8.0Hz,1H),5.33(s,1H),4.94(d,J＝16.0Hz,1H),4.78-4.48(m,2H),4.39(s,1H),4.20(d,J＝16.0Hz,1H),3.69(t,J＝8.0Hz,1H),2.38(d,J＝8.0Hz,1H),2.08-2.01(m,3H),1.82(d,J＝16.0Hz,1H),0.91(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3)δ163.7,158.8,148.4,140.7(d,J＝127.0Hz,1C),137.9,137.8,129.2,128.8,128.6,128.5,128.4,128.3,127.3,127.0,126.9,126.7,126.6,126.4,124.3,122.7(d,J＝53.0Hz,1C),121.9,120.9,120.8,115.9,115.6,115.4,113.3,111.9,82.8,56.3,56.2,53.3,41.4,40.9,40.2,31.2,28.9,28.6,27.9.IR(KBr)ν3440,2955,1600,1493,1213,725cm-1.HRMS(ESI)calcd for C46H41Cl2FN3O[M+H]+740.2605,found 740.2609.
化合物3i(白色固体，91％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.63(d,J＝4.0Hz,1H),7.31-7.28(m,5H),7.16(s,5H),7.01-6.95(m,5H),6.64(d,J＝8.0Hz,3H),6.53(d,J＝8.0Hz,1H),6.41(d,J＝8.0Hz,1H),5.42(t,J＝8.0Hz,1H),5.33(s,1H),4.95(d,J＝16.0Hz,1H),4.77(d,J＝16.0Hz,1H),4.65(d,J＝16.0Hz,1H),4.36(s,1H),4.20(d,J＝16.0Hz,1H),3.69(t,J＝8.0Hz,1H),2.37(d,J＝12.0Hz,1H),2.11-2.05(m,3H),1.84(d,J＝16.0Hz,1H),0.93(s,3H),0.80(s,3H)；13C NMR(100MHz,CDCl3)δ163.6,159.1,151.0,141.4,140.1,137.9,137.8,129.2,128.9,128.8,128.4(2C),127.5,127.3,127.0,126.8,126.7(2C),126.6,126.4,124.4,123.0,122.4,122.0,121.2,116.0,113.3,112.0,82.9,56.3(2C),53.4,41.4,41.0,40.2,31.2,28.9,28.6,27.9.IR(KBr)ν3442,1634,1487,725cm-1.HRMS(ESI)calcd for C46H41Cl3N3O[M+H]+756.2310,found756.2314.
化合物3j(白色固体，76％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.61(s,1H),7.42(d,J＝8.0Hz,2H),7.28(s,4H),7.15(s,5H),6.96(s,5H),6.64-6.50(m,5H),6.40(d,J＝8.0Hz,1H),5.41(t,J＝8.0Hz,1H),5.32(s,1H),4.93(d,J＝16.0Hz,1H),4.75(d,J＝16.0Hz,1H),4.64(d,J＝16.0Hz,1H),4.35(s,1H),4.19(d,J＝16.0Hz,1H),3.67(t,J＝8.0Hz,1H),2.36(d,J＝8.0Hz,1H),2.05(s,2H),1.82(d,J＝16.0Hz,1H),0.92(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3)δ163.5,159.1,151.4,141.4,140.1,138.0,137.9,131.8,129.2,128.8,128.6,128.5,128.4,127.4,127.0,126.9,126.7,126.6,126.4,124.4,123.0,122.4,122.0,121.7,116.0,115.1,113.3,112.0,82.9,56.3,53.4,41.4,41.1,41.0,40.2,31.3,28.9,28.6,27.9.IR(KBr)ν3420,2955,1601,1487,1382,1219,725cm-1.HRMS(ESI)calcd for C46H41BrCl2N3O[M+H]+800.1657,found 800.1659.
化合物3k(白色固体，96％收率，6.6:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.70(s,1H),7.29-6.84(m,15H),6.61-6.49(s,4H),6.39(d,J＝12.0Hz,1H),5.42(t,J＝8.0Hz,1H),5.32(s,1H),4.94(d,J＝16.0Hz,1H),4.78-4.61(m,2H),4.41(s,1H),4.20(d,J＝16.0Hz,1H),3.69(t,J＝8.0Hz,1H),2.35(t,J＝20.0Hz,4H),2.06(q,J＝20.0Hz,3H),1.83(d,J＝16.0Hz,1H),0.92(s,3H),0.77(s,3H)；13C NMR(100MHz,CDCl3)δ162.5,158.3,152.4,141.3,140.1,138.6,137.9,137.9,129.3,128.7,128.5,128.5,128.4,128.3,127.3,127.0,126.8,126.7,126.6,126.6,126.4,124.3,123.1,123.0,122.5,121.9,120.4,116.7,115.9,113.3,111.9,82.8,56.4,56.1,53.4,41.4,40.9,40.2,31.2,28.6,27.8,21.5.IR(KBr)ν3439,2953,1596,1490,1376,879cm-1.HRMS(ESI)calcdfor C47H44Cl2N3O[M+H]+736.2856,found 736.2861.
化合物3l(白色固体，77％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.70(s,1H),7.28-7.14(m,9H),6.94(d,J＝4.0Hz,5H),6.61(d,J＝8.0Hz,2H),6.51(d,J＝8.0Hz,1H),6.39(d,J＝8.0Hz,1H),6.30(d,J＝8.0Hz,2H),5.41(d,J＝8.0Hz,1H),5.32(s,1H),4.95(d,J＝16.0Hz,1H),4.78-4.59(m,2H),4.39(s,1H),4.20(d,J＝16.0Hz,1H),3.80(s,3H),3.69(d,J＝8.0Hz,1H),2.38(d,J＝12.0Hz,1H),2.10(t,J＝16.0Hz,3H),1.84(d,J＝16.0Hz,1H),0.93(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3)δ162.7,160.3,158.6,153.8,141.3,140.1,138.0,137.9,129.7,129.3,128.8,128.4,128.3,127.3,127.3,127.0,126.8,126.7,126.7,126.6,126.4,124.3,123.0,122.4,121.9,115.9,113.3,112.0,111.9,108.3,105.0,82.8,56.4,56.2,55.2,53.4,41.4,40.9,40.2,31.2,28.7,27.8.IR(KBr)ν3433,2953,1593,1488,1149,876cm-1.HRMS(ESI)calcdfor C47H44Cl2N3O2[M+H]+752.2805,found 752.2805.
化合物3m(白色固体，86％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.72(s,1H),7.28-7.14(m,10H),6.95(s,5H),6.64(d,J＝8.0Hz,3H),6.53(d,J＝8.0Hz,1H),6.40(d,J＝8.0Hz,1H),5.42(t,J＝8.0Hz,1H),5.30(s,1H),4.95(d,J＝24.0Hz,1H),4.79-4.62(m,2H),4.43(s,1H),4.20(d,J＝20.0Hz,1H),3.66(t,J＝8.0Hz,1H),2.33(s,5H),2.18(s,2H),1.96(s,3H)；13CNMR(100MHz,CDCl3)δ163.3,159.9,149.7,141.3,140.2,137.9,131.6,129.5,129.4,128.8,128.4,128.3,127.3,127.0,126.8,126.7,126.6,126.4,126.3,124.4,123.0,122.7,121.9,119.8,115.9,114.5,111.8,twocarbons missing in the aromaticregion,82.5,56.2,56.1,53.2,40.1,28.8,27.5,27.3,20.8,20.8.IR(KBr)ν3432,2947,1601,1493,1383,803cm-1.HRMS(ESI)calcd forC45H40Cl2N3O[M+H]+708.2543,found 708.2533.
化合物3n(白色固体，73％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.52(s,1H),7.06(d,J＝8.0Hz,4H),6.79-6.50(m,5H),6.19(d,J＝4.0Hz,1H),5.47(s,1H),4.61(s,1H),4.02(s,1H),3.77(d,J＝8.0Hz,1H),3.52-3.46(m,3H),2.94(s,1H),2.30(s,3H),2.06-1.95(m,4H),1.74(d,J＝16.0Hz,1H),1.24(d,J＝24.0Hz,6H),0.87(s,3H),0.74(s,3H)；13C NMR(100MHz,CDCl3)δ162.5,158.2,149.9,139.7,138.8,132.5,131.2,129.7,129.3,129.2,127.1,126.6,126.2,125.1,123.8,122.0,119.7,113.5,112.3,110.4,97.4,84.3,44.4,44.3,41.7,40.8,40.5,35.8,31.1,29.0,27.2,20.8,13.3,12.7.IR(KBr)ν3437,2961,1604,1492,1380,1219,806cm-1.HRMS(ESI)calcd forC37H40Cl2N3O[M+H]+612.2543,found 612.2529.
化合物3o(白色固体，68％收率，16:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.58(s,1H),7.12-7.08(m,4H),6.84(d,J＝4.0Hz,1H),6.69(d,J＝8.0Hz,1H),6.58(dd,J1＝12.0Hz,J2＝8.0Hz,3H),6.25(d,J＝8.0Hz,1H),5.98-5.84(m,2H),5.52(s,1H),5.31-5.13(m,4H),4.71(t,J＝8.0Hz,1H),4.29(dd,J1＝4.0Hz,J2＝8.0Hz,1H),4.12(d,J＝8.0Hz,4H),3.05(dd,J1＝8.0Hz,J2＝4.0Hz,1H),2.35(s,3H),2.13-1.99(m,4H),1.78(d,J＝16.0Hz,1H),0.93(s,3H),0.81(s,3H)；13C NMR(100MHz,CDCl3)δ162.4,158.0,149.8,140.2,139.1,133.8,133.0,132.7,131.2,129.5,129.2,126.8,126.6,126.2,125.5,123.6,122.5,119.7,117.2,116.6,113.5,113.0,111.2,97.6,83.8,52.2,52.1,41.6,40.7,40.6,35.7,31.1,29.2,28.9,27.1,20.7.IR(KBr)ν3420,2955,1608,1491,1376,1218,929,805cm-1.HRMS(ESI)calcd for C39H40Cl2N3O[M+H]+636.2543,found636.2518.
化合物3p(白色固体，61％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.48(s,1H),7.34-7.20(m,5H),7.12(d,J＝4.0Hz,5H),6.94(d,J＝8.0Hz,2H),6.84(d,J＝8.0Hz,1H),6.80(s,2H),6.58(d,J＝8.0Hz,3H),6.49(d,J＝8.0Hz,1H),6.41(d,J＝8.0Hz,1H),5.40(t,J＝8.0Hz,1H),5.34(s,1H),4.98(d,J＝16.0Hz,1H),4.77(d,J＝16.0Hz,1H),4.64(d,J＝16.0Hz,1H),4.45(s,1H),4.21(d,J＝16.0Hz,1H),3.72(t,J＝8.0Hz,1H),2.43(d,J＝12.0Hz,1H),2.35(s,3H),2.25(s,3H),2.20(s,3H),2.10-2.01(m,3H),1.82(d,J＝16.0Hz,1H),0.91(s,3H),0.79(s,3H)；13C NMR(100MHz,CDCl3)δ163.0,158.1,150.3,140.7,139.3,139.1,138.8,131.3,130.5,129.4,129.3,128.6,128.2,127.7,127.2(2C),127.0(2C),126.8,126.6,125.7,125.4,123.0,121.6,119.6,114.5,114.0,110.6,83.3,56.8,55.8,53.3,41.6,41.0,40.5,31.2,29.1,28.9,27.7,20.8,20.5,20.3.IR(KBr)ν3434,2954,1603,1500,1380,1220,804cm-1.HRMS(ESI)calcd forC49H50N3O[M+H]+696.3948,found 696.3925.
化合物3q(白色固体，81％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.83(s,1H),7.28-7.07(m,13H),6.95(d,J＝8.0Hz,2H),6.61(d,J＝12.0Hz,2H),6.57(d,J＝12.0Hz,1H),6.47(d,J＝12.0Hz,1H),6.39(d,J＝12.0Hz,1H),5.40(t,J＝8.0Hz,1H),5.30(s,1H),4.95(d,J＝20.0Hz,1H),4.78-4.60(m,2H),4.39(s,1H),4.20(d,J＝20.0Hz,1H),3.68(t,J＝12.0Hz,1H),2.39(s,1H),2.35(s,3H),2.09(t,J＝20.0Hz,3H),1.84(d,J＝20.0Hz,1H),0.93(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3)δ162.6,158.2,149.7,141.7,140.5,137.8,137.8,132.1,131.5,131.2,129.5,129.5,128.7,128.5,128.3,127.3,127.1,127.0,126.8,126.4,126.3,124.8,122.4,119.6,116.3,113.3,112.3,110.2,109.0,82.6,56.3,56.0,53.3,41.3,40.7,40.2,31.1,28.7,27.8,20.8.IR(KBr)ν3426,2954,1601,1490,1221,800cm-1.HRMS(ESI)calcd for C47H44Br2N3O[M+H]+824.1846,found 824.1824.
化合物3r(白色固体，77％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ8.68(s,1H),7.95(d,J＝8.0Hz,1H),7.89(s,2H),7.33(s,3H),7.16(s,7H),6.91(s,2H),6.70(d,J＝8.0Hz,1H),6.64(d,J＝8.0Hz,3H),6.54(d,J＝8.0Hz,1H),5.39(t,J＝8.0Hz,2H),5.09(d,J＝16.0Hz,1H),4.84(s,2H),4.55(s,1H),4.30(d,J＝16.0Hz,1H),3.77(t,J＝12.0Hz,1H),2.45(d,J＝8.0Hz,1H),2.33(s,3H),2.21-2.02(m,3H),1.87(d,J＝16.0Hz,1H),0.94(s,3H),0.76(s,3H)；13C NMR(100MHz,CDCl3)δ162.2,157.8,149.0,147.9,147.0,139.2,138.2,136.4,136.1,132.0,129.5,129.4,129.0,128.7,127.9,127.6,126.8,126.5,125.3,125.2,124.7,123.9,123.4,122.2,121.7,119.8,113.4,112.9,110.2,81.7,57.1,56.1,53.6,41.1,40.8,40.6,31.2,29.0,27.9,20.8.IR(KBr)ν3430,2954,1601,1501,1322,1099,738cm-1.HRMS(ESI)calcd for C47H44N5O5[M+H]+758.3337,found758.3315.
化合物3s(白色固体，93％收率，>20:1dr，通过过滤分离纯化)：1H NMR(400MHz,CDCl3),δ7.53(d,J＝4.0Hz,1H),7.10(s,9H),6.89(d,J＝24.0Hz,3H),6.59-6.38(m,8H),5.29(d,J＝16.0Hz,2H),5.00(d,J＝16.0Hz,1H),4.71(q,J＝16.0Hz,2H),4.46(s,1H),4.20(d,J＝16.0Hz,1H),3.69(s,1H),2.40-2.01(m,13H),1.83(d,J＝16.0Hz,1H),0.91(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3)δ163.1,157.9,150.2,143.0,141.6,139.0,138.7,138.5,136.4,131.3,129.6,129.4,128.6,128.1,127.1,127.0,126.9,126.8,126.6,126.5,122.6,120.4,120.1,119.7,119.1,117.6,115.0,114.1,111.3,82.8,56.5,55.5,52.9,41.5,41.0,40.7,31.2,29.1,28.5,27.7,21.9,20.8.IR(KBr)ν3417,2655,1607,1500,1220,708cm-1.HRMS(ESI)calcd for C49H50N3O[M+H]+696.3948,found696.3932.
以上显示和描述了本发明的基本原理和主要特征以及本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (10)
1.一种桥环多环多取代四氢喹啉，其特征在于结构式如下：
其中，R1为烷基、卤素或氢；R2为甲基或氢，R3为烷基，R4为烷基、卤素或氢。
2.根据权利要求1所述的桥环多环多取代四氢喹啉的制备方法，其特征在于步骤如下：将烯胺酮和N-烷基喹啉盐，在有机溶剂中，碱的存在下，25-80℃反应5分钟至24小时，薄层色谱跟踪反应至完全，反应结束后，通过用布氏漏斗过滤分离纯化，得目标产物，其反应通式如下：
其中，R1为烷基、卤素或氢；R2为甲基或氢，R3为烷基，R4为烷基、卤素或氢。
3.根据权利要求2所述的桥环多环多取代四氢喹啉的制备方法，其特征在于：所述的碱为无机碱或有机碱，所述无机碱为碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、醋酸钠；有机碱为三乙胺、吡啶、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、1,4-二叠氮双环[2.2.2]辛烷(DABCO)、四甲基胍(TMG)。
4.根据权利要求3所述的复杂桥环多环多取代四氢喹啉的制备方法，其特征在于：所述的碱为TMG。
5.根据权利要求3或4所述的桥环多环多取代四氢喹啉的制备方法，其特征在于：所述的碱的物质的量为烯胺酮物质的量的2倍。
6.根据权利要求2所述的桥环多环多取代四氢喹啉的制备方法，其特征在于：所述的有机溶剂为乙腈、甲醇、乙醇、甲苯、氯仿、二氯甲烷、1,2-二氯乙烷、乙醚、四氢呋喃、1,4-二氧六环或乙酸乙酯。
7.根据权利要求6所述的桥环多环多取代四氢喹啉的制备方法，其特征在于：所述的有机溶剂为乙腈。
8.根据权利要求2所述的桥环多环多取代四氢喹啉的制备方法，其特征在于：所述反应温度为60℃。
9.根据权利要求2所述的桥环多环多取代四氢喹啉的制备方法，其特征在于：所述烯胺酮与N-烷基喹啉盐的摩尔比为1:1-1:4。
10.根据权利要求9所述的桥环多环多取代四氢喹啉的制备方法，其特征在于：所述烯胺酮与N-烷基喹啉盐的摩尔比为1:2.2。
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| HONG-JIE MIAO ET AL.: "Regio- and diastereoselective dearomatizations of N-alkyl activated azaarenes: the maximization of the reactive sites", 《CHEM. SCI.》 * |
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