CN109485667B - 一种2-芳基-四氢喹啉-4-硼酯类化合物的合成方法 - Google Patents
一种2-芳基-四氢喹啉-4-硼酯类化合物的合成方法 Download PDFInfo
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- 229910052796 boron Inorganic materials 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 50
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 16
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims abstract description 15
- BOIWYTYYWPXGAT-UHFFFAOYSA-N ethyl 2-phenylprop-2-enoate Chemical class CCOC(=O)C(=C)C1=CC=CC=C1 BOIWYTYYWPXGAT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003446 ligand Substances 0.000 claims abstract description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 8
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical class [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000035484 reaction time Effects 0.000 claims abstract description 4
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
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- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
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- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
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- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
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- YLOCGHYTXIINAI-XKUOMLDTSA-N (2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 YLOCGHYTXIINAI-XKUOMLDTSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明属于化学制药和精细化工制备技术领域,具体涉及一种2‑芳基‑四氢喹啉‑4‑硼酯类化合物的合成方法,以3‑取代苯基丙烯酸乙酯和联硼酸频哪醇酯为原料,在三氟甲磺酸酮(II)、膦配体、叔丁醇锂和叔丁醇作用下,于四氢呋喃中室温下反应,一步制得2‑芳基‑四氢喹啉‑4‑硼酯类化合物。本发明的有益效果是:反应条件温和,反应操作简单,反应时间短,合成产物为高度官能团化的硼试剂,可用于多种化学转化,具有重要的应用价值。
Description
技术领域
本发明属于化学制药和精细化工制备技术领域,涉及一种2-芳基-四氢喹啉-4-硼酯类化合物的合成方法。
背景技术
喹啉及其衍生物四氢喹啉,是一类重要的结构单元,见于很多人工合成的药物分子和具有生物活性的天然产物。如镇痛消炎药物格拉非宁包含7-氯喹啉结构,见化学式(a)。又如科学家从一种南美洲芸香科植物(Galipea officinalis)提取到了多种1,2,3,4-四氢喹啉生物碱,其中一些具有很好的抗疟活性,见化学式(b)。因此,如何方便快捷地构筑这一类结构单元具有重要意义。
有机硼化合物在有机合成领域具有广泛应用,可通过与卤代物的Suzuki偶联反应快速高效地合成很多重要的药物中间体,本身也可被氧化后转化成羟基。含四氢喹啉结构的硼酯作为一类官能团化的有机硼化合物,可为药物分子中引入四氢喹啉砌块提供有力帮助。
目前,文献报道了较多含四氢喹啉的芳基硼酯或硼酸,即5-/6-/7-/8-硼化合物,常用的合成方法是采用已包含四氢喹啉结构的芳基卤代物为原料。如方程式(1)所示,以5-溴-四氢喹啉与联硼酸频哪醇酯为原料,在金属钯和醋酸钾作用下反应,可获得四氢喹啉-5-硼酯。该反应采用了贵重金属钯催化剂,且一般要加热。
又如方程式(2)所示,以6-溴-四氢喹啉为原料,首先在强碱下脱卤,然后与三甲氧基硼反应,最后水解得到四氢喹啉-6-硼酸。该反应为多步骤反应,操作繁琐,且丁基锂试剂需要低温反应,本身也价格昂贵,不适用工业化大量生产。
由此可见,含四氢喹啉结构的有机硼化合物的合成方法非常有限,现有方法均以喹啉或其衍生物为原料,喹啉及其衍生物本身需要多步合成。
发明内容
本发明要解决的技术问题是:基于背景技术部分指出的四氢喹啉有机硼化合物的重要性和目前合成方法的有限性,本发明提供一种新的四氢喹啉-4-硼酯的合成方法,一步构筑四氢喹啉骨架的同时引入硼基团。
本发明提供的2-芳基-四氢喹啉-4-硼酯的合成方法如下:
在氮气保护下,向无水四氢呋喃中加入三氟甲磺酸酮(II)、膦配体、叔丁醇锂,室温下搅拌30分钟得到混合物,接着将3-取代苯基丙烯酸乙酯1、联硼酸频哪醇酯、叔丁醇溶于四氢呋喃后注入到之前的混合物中继续搅拌,薄层色谱跟踪反应,待反应结束后减压蒸馏除去有机溶剂,残留物以石油醚和乙酸乙酯为洗脱剂,经硅胶色谱柱分离,得到2-芳基-四氢喹啉-4-硼酯类化合物2。
上述反应过程概括为如下反应方程式(3):
其中R1为氢、甲基、叔丁基、三氟甲基、甲氧基、苯基、氰基、CH3CH2OCO-、氟、氯、溴中任一种;
R2为氢、甲基、叔丁基、三氟甲基、甲氧基、苯基、氰基、CH3CH2OCO-、氟、氯、溴中任一种;
R3为氢、甲基、氟、氯、溴中任一种;芳基Ar具体为苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-碘苯基、2-硝基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-甲基苯基、3-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-三氟甲基苯基、4-氰基苯基、4-叔丁基苯基、4-甲氧基苯基、2-溴-5-氯苯基、2-溴-5-甲氧基苯基、3,4-二氯苯基、萘-2-基、呋喃-2-基、噻吩-2-基中任一种。
3-取代苯基丙烯酸乙酯1可以方便地从相应的2-氨基肉桂酸乙酯S1与芳醛S2缩合反应获得,如反应方程式(4)所示,以硫酸镁为脱水剂,在甲苯中加热反应12小时即可(参考文献Ascic,E.;Buchwald,S.L.J.Am.Chem.Soc.2015,137,4666)。其中,2-氨基肉桂酸乙酯S1可根据具体结构参照文献制备或直接购买;芳醛S2大部分市售。
其中R1为氢、甲基、叔丁基、三氟甲基、甲氧基、苯基、氰基、CH3CH2OCO-、氟、氯、溴中任一种;
R2为氢、甲基、叔丁基、三氟甲基、甲氧基、苯基、氰基、CH3CH2OCO-、氟、氯、溴中任一种;
R3为氢、甲基、氟、氯、溴中任一种;芳基Ar具体为苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-碘苯基、2-硝基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-甲基苯基、3-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-三氟甲基苯基、4-氰基苯基、4-叔丁基苯基、4-甲氧基苯基、2-溴-5-氯苯基、2-溴-5-甲氧基苯基、3,4-二氯苯基、萘-2-基、呋喃-2-基、噻吩-2-基中任一种。
膦配体为1,3-双(二苯膦基)丙烷(dppp)、1,4-双(二苯膦基)丁烷(dppb)、三邻甲基苯基膦中任一种。
3-取代苯基丙烯酸乙酯1、联硼酸频哪醇酯、三氟甲磺酸酮(II)、膦配体、叔丁醇锂和叔丁醇的摩尔比为1:1.1~1.5:0.1~0.2:0.1~0.2:1.1~1.5:1.1~1.5。
反应时间为0.5~1小时。
本发明方法合成了一种全新结构的2-芳基-四氢喹啉-4-硼酯类化合物,可作为Suzuki偶联反应试剂,可被进一步氧化,如使用过氧化氢将硼基氧化后得到4-羟基-四氢喹啉类化合物,又如脱硼脱氢反应后给出取代喹啉化合物,从而获得一系列结构新颖的包含四氢喹啉或喹啉骨架的化合物,为合成四氢喹啉和喹啉类药物中间体提供了一种方便快捷的高效方法。本发明合成的2-芳基-四氢喹啉-4-硼酯类化合物与已知的四氢喹啉硼化合物的区别在于:参与Suzuki偶联反应后四氢喹啉与其他基团链接的位置不同,从而获得不同结构的四氢喹啉偶联产物,而这在药物化学中是非常重要的。
本发明的有益效果是:以包含亚胺结构的3-取代苯基丙烯酸乙酯类化合物和联硼酸频哪醇酯为原料,以三氟甲磺酸铜为催化剂,使用膦配体,以叔丁醇锂为碱,叔丁醇为质子源,在室温范围内,利用分子内碳硼化反应,一步法高区域选择性且高立体选择性地制得含官能团化四氢喹啉的烷基硼酯。该反应原料制备简单,反应条件温和,反应操作简单,反应时间短,合成的产物进一步丰富了硼试剂的种类,可用于多种化学转化,具有重要的应用价值。
具体实施方式
现在结合具体实施例对本发明作进一步说明,以下实施例旨在说明本发明而不是对本发明的进一步限定。
本发明使用的3-取代苯基丙烯酸乙酯1是参考相关文献制备(参考文献Ascic,E.;Buchwald,S.L.J.Am.Chem.Soc.2015,137,4666-4669)。所用试剂联硼酸频哪醇酯为市场购得后直接使用。溶剂四氢呋喃经过纯化和精制。
实施例1
取干燥过的10mL封管,称取三氟甲磺酸铜7.2mg(0.02mmol,10mol%),1,4-双(二苯膦基)丁烷(dppb)10.3mg(0.024mmol,12mol%)和叔丁醇锂17.6mg(0.22mmol,1.1eq),抽空换氮后,加入干燥过的四氢呋喃1mL,置于室温下搅拌30min,然后将1a(55.9mg,0.2mmol)、联硼酸频哪醇酯(55.6mg,0.22mmol)和叔丁醇(16.3mg,0.22mmol)混合到四氢呋喃(1mL)里,再将其注射到之前的混合物里,放置室温搅拌1小时。然后将其减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到64.5mg黄色油状物2a,产率为79%。1H NMR(400MHz,CDCl3)δ7.50(d,J=7.7Hz,1H),7.41(d,J=7.3Hz,2H),7.36(t,J=7.4Hz,2H),7.30(dd,J=8.1,5.8Hz,1H),7.01(t,J=7.6Hz,1H),6.77(t,J=7.5Hz,1H),6.61(d,J=7.9Hz,1H),4.68(d,J=3.1Hz,1H),3.91–3.79(m,2H),3.38(dd,J=5.7,3.3Hz,1H),3.02(d,J=5.6Hz,1H),1.25(s,6H),1.23(s,6H),0.92(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3)δ172.0,144.5,141.8,129.8,128.3,127.6,126.7,126.1,121.4,118.5,114.9,83.7,59.9,58.3,48.1,25.0,24.6,13.9.
实施例2
取干燥过的10mL封管,称取三氟甲磺酸铜14.4mg(0.04mmol,20mol%),1,4-双(二苯膦基)丙烷(dppb)16.5mg(0.04mmol,20mol%)和叔丁醇锂17.6mg(0.22mmol,1.1eq),抽空换氮后,加入干燥过的四氢呋喃1mL,置于室温下搅拌30min,然后将1b(61.9mg,0.2mmol)、联硼酸频哪醇酯(55.6mg,0.22mmol)和叔丁醇(16.3mg,0.22mmol)混合到四氢呋喃(1mL)里,再将其注射到之前的混合物里,放置室温搅拌0.5小时。然后将其减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到68.2mg黄色油状物2b,产率为78%。1H NMR(400MHz,CDCl3)δ7.47(d,J=7.7Hz,1H),7.30(d,J=8.6Hz,2H),7.02-7.00(m,1H),6.89(d,J=8.7Hz,2H),6.74(m,1H),6.57(d,J=7.9Hz,1H),4.62(d,J=3.1Hz,1H),3.92–3.84(m,2H),3.81(s,3H),3.31(dd,J=5.7,3.2Hz,1H),2.99(d,J=5.6Hz,1H),1.24(s,6H),1.22(s,6H),0.96(t,J=7.1Hz,3H).13C NMR(75MHz,CDCl3)δ172.1,159.1,144.6,133.9,129.8,127.8,126.1,121.4,118.4,114.8,113.7,83.7,59.9,57.8,55.4,48.1,25.0,24.7,14.0.HRMS(ESI)m/z理论值C25H32BNNaO5 +[M+Na]+460.2266,实测值460.2260.
实施例3
取干燥过的10mL封管,称取三氟甲磺酸铜7.2mg(0.02mmol,10mol%),三邻甲基苯基膦6.1mg(0.02mmol,10mol%)和叔丁醇锂24.0mg(0.3mmol,1.1eq),抽空换氮后,加入干燥过的四氢呋喃1mL,置于室温下搅拌30min,然后将1c(71.6mg,0.2mmol)、联硼酸频哪醇酯(76.2mg,0.3mmol)和叔丁醇(22.2mg,0.3mmol)混合到四氢呋喃(1mL)里,再将其注射到之前的混合物里,放置室温搅拌1小时。然后将其减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到70.0mg黄色固体2c,产率为72%。Mp:147.5℃.1H NMR(400MHz,CDCl3)δ7.47(t,J=8.0Hz,3H),7.27(d,J=8.4Hz,2H),7.00(t,J=7.6Hz,1H),6.76(t,J=7.5Hz,1H),6.58(d,J=7.8Hz,1H),4.64(d,J=3.1Hz,1H),3.94-3.81(m,2H),3.35(dd,J=5.7,3.3Hz,1H),2.98(d,J=5.6Hz,1H),1.26(s,6H),1.24(s,6H),0.96(t,J=7.1Hz,3H).13C NMR(75MHz,CDCl3)δ171.8,144.1,141.0,131.3,129.8,128.6,126.2,121.4,121.3,118.7,115.0,83.7,60.1,57.6,47.9,25.0,24.7,14.0.HRMS(ESI)m/z理论值C24H30BBrNNaO4 +[M+Na]+508.1265,实测值508.1270.
实施例4
取干燥过的10mL封管,称取三氟甲磺酸铜7.2mg(0.02mmol,10mol%),1,4-双(二苯膦基)丁烷(dppb)10.3mg(0.024mmol,12mol%)和叔丁醇锂17.6mg(0.22mmol,1.1eq),抽空换氮后,加入干燥过的四氢呋喃1mL,置于室温下搅拌30min,然后将1d(58.7mg,0.2mmol)、联硼酸频哪醇酯(55.6mg,0.22mmol)和叔丁醇(16.3mg,0.22mmol)混合到四氢呋喃(1mL)里,再将其注射到之前的混合物里,放置室温搅拌1小时。然后将其减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到67.4mg黄色油状物2d,产率为80%。1H NMR(300MHz,CDCl3)δ7.51(dd,J=6.5,1.2Hz,1H),7.26-7.13(m,3H),7.12(d,J=7.3Hz,1H),7.02-6.98(m,1H),6.76(td,J=7.5,1.1Hz,1H),6.60(dd,J=7.9,1.1Hz,1H),4.64(d,J=3.1Hz,1H),3.86(q,J=7.1Hz,2H),3.36(dd,J=5.7,3.2Hz,1H),3.01(d,J=5.6Hz,1H),2.38(s,3H),1.26(s,6H),1.24(s,6H),0.93(t,J=7.1Hz,3H).13CNMR(75MHz,CDCl3)δ172.0,144.5,141.7,137.8,129.8,128.3,128.2,127.3,126.1,123.8,121.4,118.4,114.9,83.7,59.8,58.4,48.1,25.0,24.6,21.6,13.9.HRMS(ESI)m/z理论值C25H33BNNaO4 +[M+Na]+444.2317,实测值444.2317.
实施例5
取干燥过的10mL封管,称取三氟甲磺酸铜7.2mg(0.02mmol,10mol%),1,4-双(二苯膦基)丁烷(dppb)10.3mg(0.024mmol,12mol%)和叔丁醇锂17.6mg(0.22mmol,1.1eq),抽空换氮后,加入干燥过的四氢呋喃1mL,置于室温下搅拌30min,然后将1e(71.6mg,0.2mmol)、联硼酸频哪醇酯(55.6mg,0.22mmol)和叔丁醇(16.3mg,0.22mmol)混合到四氢呋喃(1mL)里,再将其注射到之前的混合物里,放置室温搅拌1小时。然后将其减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到83.6mg黄色固体2e,产率为86%。Mp:154.8℃.1H NMR(400MHz,CDCl3)δ7.57(s,1H),7.52(d,J=7.7Hz,1H),7.43(d,J=7.9Hz,1H),7.32(d,J=7.7Hz,1H),7.22(t,J=7.8Hz,1H),7.01(t,J=7.6Hz,1H),6.77(t,J=7.4Hz,1H),6.60(d,J=7.8Hz,1H),4.65(d,J=2.8Hz,1H),3.96(s,1H),3.89(q,J=6.9Hz,2H),3.37(dd,J=5.6,3.2Hz,1H),2.97(d,J=5.5Hz,1H),1.24(s,6H),1.22(s,6H),0.97(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3)δ171.8,144.4,144.1,130.6,129.9,129.8,126.2,125.6,122.5,121.5,118.9,115.1,83.7,60.1,57.7,48.2,25.0,24.7,14.0.HRMS(ESI)m/z理论值C24H31BBrNO4 +[M+H]+486.1446,实测值486.1430.
实施例6
取干燥过的10mL封管,称取三氟甲磺酸铜7.2mg(0.02mmol,10mol%),1,4-双(二苯膦基)丁烷(dppb)10.3mg(0.024mmol,12mol%)和叔丁醇锂17.6mg(0.22mmol,1.1eq),抽空换氮后,加入干燥过的四氢呋喃1mL,置于室温下搅拌30min,然后将1f(53.8mg,0.2mmol)、联硼酸频哪醇酯(55.6mg,0.22mmol)和叔丁醇(16.3mg,0.22mmol)混合到四氢呋喃(1mL)里,再将其注射到之前的混合物里,放置室温搅拌1小时。然后将其减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到69.1mg黄色油状物2f,产率为87%。1H NMR(300MHz,CDCl3)δ7.44(dt,J=7.7,1.2Hz,1H),7.37(d,J=1.2Hz,1H),7.03–6.96(m,1H),6.75(td,J=7.5,1.2Hz,1H),6.60(dd,J=7.9,1.2Hz,1H),6.32(dd,J=3.2,1.8Hz,1H),6.21(dt,J=3.2,0.9Hz,1H),4.76(d,J=2.9Hz,1H),4.03–3.92(m,2H),3.54(dd,J=6.0,3.3Hz,1H),2.91(d,J=5.9Hz,1H),1.22(s,6H),1.20(s,6H),1.07(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3)δ172.1,154.7,143.5,141.5,129.9,126.2,121.6,118.8,115.3,110.3,105.8,83.6,60.3,52.5,45.4,24.9,24.7,14.1.HRMS(ESI)m/z理论值C22H28BNNaO5 +[M+Na]+420.1953,实测值420.1951.
实施例7
取干燥过的10mL封管,称取三氟甲磺酸铜7.2mg(0.02mmol,10mol%),1,4-双(二苯膦基)丁烷(dppb)10.3mg(0.024mmol,12mol%)和叔丁醇锂17.6mg(0.22mmol,1.1eq),抽空换氮后,加入干燥过的四氢呋喃1mL,置于室温下搅拌30min,然后将1g(57.1mg,0.2mmol)、联硼酸频哪醇酯(55.6mg,0.22mmol)和叔丁醇(16.3mg,0.22mmol)混合到四氢呋喃(1mL)里,再将其注射到之前的混合物里,放置室温搅拌1小时。然后将其减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到74.4mg黄色油状物2g,产率为90%。1H NMR(400MHz,CDCl3)δ7.42(d,J=7.7Hz,1H),7.21(dd,J=5.0,1.1Hz,1H),7.04(d,J=3.5Hz,1H),7.00(t,J=7.6Hz,1H),6.96(dd,J=5.0,3.6Hz,1H),6.79–6.72(m,1H),6.60(dd,J=7.9,0.8Hz,1H),5.00(d,J=3.1Hz,1H),4.18(b,1H),3.97(q,J=7.1Hz,2H),3.43(dd,J=5.9,3.3Hz,1H),2.99(d,J=5.8Hz,1H),1.20(s,6H),1.18(s,6H),1.05(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3)δ171.9,145.6,143.7,129.9,126.6,126.2,124.3,124.2,121.5,118.8,115.1,83.6,60.3,54.1,48.0,25.0,24.7,14.0.HRMS(ESI)m/z理论值C22H29BNO4S+[M+H]+414.1905,实测值414.1904.
实施例8
取干燥过的10mL封管,称取三氟甲磺酸铜7.2mg(0.02mmol,10mol%),1,4-双(二苯膦基)丁烷(dppb)10.3mg(0.024mmol,12mol%)和叔丁醇锂17.6mg(0.22mmol,1.1eq),抽空换氮后,加入干燥过的四氢呋喃1mL,置于室温下搅拌30min,然后将1h(74.4mg,0.2mmol)、联硼酸频哪醇酯(55.6mg,0.22mmol)和叔丁醇(16.3mg,0.22mmol)混合到四氢呋喃(1mL)里,再将其注射到之前的混合物里,放置室温搅拌1小时。然后将其减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到82.0mg黄色固体2h,产率为82%。Mp:38.5℃.1H NMR(400MHz,CDCl3)δ7.59(d,J=8.0Hz,1H),7.52(d,J=7.8Hz,1H),7.43(d,J=7.8Hz,1H),7.31(t,J=7.5Hz,1H),7.17(t,J=7.6Hz,1H),6.61(d,J=7.8Hz,1H),6.43(s,1H),4.91(d,J=2.1Hz,1H),3.93–3.72(m,3H),3.57(dd,J=5.5,2.8Hz,1H),2.97(d,J=5.5Hz,1H),2.24(s,3H),1.25(s,6H),1.22(s,6H),0.89(t,J=7.1Hz,3H).13C NMR(75MHz,CDCl3)δ172.1,144.4,140.5,135.5,132.9,129.9,129.0,128.3,127.2,123.5,120.0,119.1,116.0,83.7,59.9,57.7,45.3,25.1,24.7,21.2,14.0.HRMS(ESI)m/z理论值C25H31BBrNNaO4 +[M+Na]+522.1422,实测值522.1411.
实施例9
取干燥过的10mL封管,称取三氟甲磺酸铜7.2mg(0.02mmol,10mol%),1,4-双(二苯膦基)丁烷(dppb)10.3mg(0.024mmol,12mol%)和叔丁醇锂17.6mg(0.22mmol,1.1eq),抽空换氮后,加入干燥过的四氢呋喃1mL,置于室温下搅拌30min,然后将1i(59.9mg,0.2mmol)、联硼酸频哪醇酯(55.6mg,0.22mmol)和叔丁醇(16.3mg,0.22mmol)混合到四氢呋喃(1mL)里,再将其注射到之前的混合物里,放置室温搅拌1小时。然后将其减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到70.1mg黄色油状物2i,产率为82%。1H NMR(400MHz,CDCl3)δ8.46(s,1H),7.47–7.43(m,2H),7.12-7.03(m,3H),6.86(d,J=8.0Hz,1H),4.17–4.04(m,2H),2.88(dd,J=15.5,9.4Hz,1H),2.73-2.62(m,2H),2.32(s,3H),1.23(t,J=7.0Hz,3H).1.22(s,6H),1.18(s,6H).13C NMR(100MHz,CDCl3)δ173.6,151.6,148.1,143.6,139.0,132.5,131.5,130.3,130.0,127.7,126.4,117.8,83.63,60.5,37.4,24.724.6,18.0,14.4.HRMS(ESI)m/z理论值for C23H30BNNaO4S+[M+Na]+450.1881,实测值450.1883.
实施例10
取一10mL封管,依次加入四氢喹啉-4-硼酯2i(50mg,0.12mmol),1-溴-3-甲基-苯(28.5mg,0.168mmol),K2CO3(50mg,0.36mmol),Pd2(dba)3(5.5mg,0.006mmol),Xphos(5.7mg,0.012mmol),加入甲苯(2mL)和水(0.2mL),抽空换氮三次,然后加热至80℃反应24小时。然后将反应液减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到19.2mg无色透明油状物3,产率为42%。1H NMR(300MHz,CDCl3)δ7.20(t,J=7.7Hz,1H),7.13(dt,J=9.2,4.6Hz,2H),7.05(d,J=4.7Hz,1H),7.04–6.98(m,2H),6.94(d,J=7.5Hz,1H),6.90–6.87(m,1H),6.84(dd,J=9.2,1.7Hz,1H),6.79(ddd,J=11.5,5.5,1.2Hz,2H),5.54(d,J=3.9Hz,1H),4.29–4.13(m,2H),3.31(td,J=9.4,3.9Hz,1H),3.04(d,J=9.2Hz,2H),2.30(s,3H),1.30(t,J=7.2Hz,3H).13C NMR(75MHz,CDCl3)δ171.9,147.8,143.11,142.3,139.5,129.9,129.4,127.0,126.8,125.6,125.5,125.4,124.8,121.9,119.1,116.7,61.2,60.9,43.0,25.2,21.6,14.3.HRMS(ESI)m/z理论值C23H24NO2S+[M+H]+378.1522,实测值378.1517.
实施例11
取一10mL封管,依次加入四氢喹啉-4-硼酯2i(85.9mg,0.2mmol),30%H2O2(272mg,2.4mmol),3M NaOH(0.53mL,1.6mmol)和四氢呋喃(1mL),室温下搅拌反应,薄层色谱监测,1小时后反应完全,然后将反应液减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到54.6mg白色固体4,产率为90%。Mp:87.2℃.1H NMR(400MHz,CDCl3)δ7.40(d,J=7.6Hz,1H),7.20(d,J=5.0Hz,1H),7.14(t,J=7.6Hz,1H),7.04(d,J=3.1Hz,1H),6.95–6.91(m,1H),6.82(t,J=7.4Hz,1H),6.65(d,J=8.0Hz,1H),5.25(s,1H),5.17(s,1H),4.40(s,1H),4.22–4.12(m,2H),3.39(t,J=4.2Hz,1H),2.65(d,J=7.5Hz,1H),1.20(t,J=7.1Hz,3H).13C NMR(100MHz,CDCl3)δ170.8,144.7,143.0,129.2,129.2,126.7,125.0,124.7,122.8,119.1,114.7,66.8,61.1,51.9,51.4,14.1.HRMS(ESI)m/z理论值C16H17NNaO3S+[M+Na]+326.0821,实测值326.0823.
实施例12
取一10mL封管,依次加入四氢喹啉-4-硼酯2i(171.8mg,0.4mmol),AgNO3(13.6mg,0.08mmol),TFA(182mg,1.6mmol),Selectfluor(425.1mg,1.2mmol),加入二氯甲烷(2mL)和水(2mL),抽空换氮三次,然后加热至50℃反应,薄层色谱监测,12小时后反应完全,然后将反应液减压蒸馏除去溶剂,残留物以石油醚和乙酸乙酯为洗脱液,经硅胶柱色谱分离纯化,得到98.6mg棕色油状物5,产率为87%。1H NMR(400MHz,CDCl3)δ8.60(s,1H),8.21(d,J=8.5Hz,1H),7.90(d,J=8.1Hz,1H),7.87–7.80(m,1H),7.61(t,J=7.5Hz,1H),7.55(dd,J=5.1,0.8Hz,1H),7.51(dd,J=3.6,0.8Hz,1H),7.14(dd,J=5.0,3.8Hz,1H),4.35(q,J=7.1Hz,2H),1.28(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ167.2,149.9,145.9,140.5,139.6,133.0,129.9,129.8,128.4,128.2,127.9,127.2,126.0,125.7,62.3,14.0.
以上述依据本发明的理想实施例为启示,通过上述的说明内容,相关工作人员完全可以在不偏离本项发明技术思想的范围内,进行多样的变更以及修改。本项发明的技术性范围并不局限于说明书上的内容,必须要根据权利要求范围来确定其技术性范围。
Claims (4)
1.一种2-芳基-四氢喹啉-4-硼酯类化合物的合成方法,其特征在于,所述的合成方法为:在氮气保护下,向无水四氢呋喃中加入三氟甲磺酸酮(II)、膦配体和叔丁醇锂,室温下搅拌30分钟得到混合物,接着将3-取代苯基丙烯酸乙酯、联硼酸频哪醇酯和叔丁醇溶于四氢呋喃后注入到之前的混合物中继续搅拌,薄层色谱跟踪反应,待反应结束后减压蒸馏除去有机溶剂,残留物以石油醚和乙酸乙酯为洗脱剂,经硅胶色谱柱分离,得到2-芳基-四氢喹啉-4-硼酯类化合物;
所述的3-取代苯基丙烯酸乙酯的结构通式为:
其中,R1为氢、甲基、叔丁基、三氟甲基、甲氧基、苯基、氰基、氟、氯、溴中的任一种;
R2为氢、甲基、叔丁基、三氟甲基、甲氧基、苯基、氰基、氟、氯、溴中的任一种;
R3为氢、甲基、氟、氯、溴中的任一种;芳基Ar具体为苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-碘苯基、2-硝基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-甲基苯基、3-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-三氟甲基苯基、4-氰基苯基、4-叔丁基苯基、4-甲氧基苯基、2-溴-5-氯苯基、2-溴-5-甲氧基苯基、3,4-二氯苯基、萘-2-基、呋喃-2-基、噻吩-2-基中任一种;
所述的2-芳基-四氢喹啉-4-硼酯类化合物的结构通式为:
其中R1为氢、甲基、叔丁基、三氟甲基、甲氧基、苯基、氰基、氟、氯、溴中任一种;
R2为氢、甲基、叔丁基、三氟甲基、甲氧基、苯基、氰基、氟、氯、溴中任一种;
R3为氢、甲基、氟、氯、溴中任一种;
芳基Ar具体为苯基、2-氟苯基、2-氯苯基、2-溴苯基、2-碘苯基、2-硝基苯基、3-氟苯基、3-氯苯基、3-溴苯基、3-甲基苯基、3-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-三氟甲基苯基、4-氰基苯基、4-叔丁基苯基、4-甲氧基苯基、2-溴-5-氯苯基、2-溴-5-甲氧基苯基、3,4-二氯苯基、萘-2-基、呋喃-2-基、噻吩-2-基中任一种。
2.根据权利要求1所述的2-芳基-四氢喹啉-4-硼酯类化合物的合成方法,其特征在于,所述的膦配体为1,3-双(二苯膦基)丙烷(dppp)、1,4-双(二苯膦基)丁烷(dppb)、三邻甲基苯基膦中任一种。
3.根据权利要求1所述的2-芳基-四氢喹啉-4-硼酯类化合物的合成方法,其特征在于,所述的3-取代苯基丙烯酸乙酯、联硼酸频哪醇酯、三氟甲磺酸酮(II)、膦配体、叔丁醇锂和叔丁醇的摩尔比为1:1.1~1.5:0.1~0.2:0.1~0.2:1.1~1.5:1.1~1.5。
4.根据权利要求1所述的2-芳基-四氢喹啉-4-硼酯类化合物的合成方法,其特征在于,所述的反应时间为0.5~1小时。
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