CN111793023B - 一锅法仿生合成手性四氢喹啉化合物 - Google Patents

一锅法仿生合成手性四氢喹啉化合物 Download PDF

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CN111793023B
CN111793023B CN202010803554.0A CN202010803554A CN111793023B CN 111793023 B CN111793023 B CN 111793023B CN 202010803554 A CN202010803554 A CN 202010803554A CN 111793023 B CN111793023 B CN 111793023B
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周永贵
赵子彪
孙蕾
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Dalian Institute of Chemical Physics of CAS
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Abstract

本发明提供一种一锅法仿生合成手性四氢喹啉化合物的方法，由简单易得的2‑氨基查尔酮类底物出发，经一锅法仿生合成手性的四氢喹啉化合物，其对映体过量可达到92％。本发明操作简便实用，对映选择性高，产率好，且环境友好绿色，反应条件温和，具有潜在的实际应用价值。

Description

一锅法仿生合成手性四氢喹啉化合物
技术领域
本发明涉及一锅法仿生合成手性四氢喹啉化合物方法，属于不对称催化合成领域。
技术背景
四氢喹啉是一种重要且普遍存在的结构单元，广泛存在于许多生物活性分子、天然产物和药物分子中。这些含四氢喹啉骨架的生物分子具有多种优异的生物活性:如降压、抗糖尿病、抗菌和抗疟疾活性(I-II)。在医药领域，含四氢喹啉骨架的分子也可以用作雄激素受体激动剂和孕激素受体拮抗剂(III-IV)。除此之外，含四氢喹啉骨架的分子也是一类有价值的合成中间体，其可以用作有机化学中含氮配体的合成和作为多功能的染料应用于工业应用。
Figure BDA0002628273260000011
手性四氢喹啉由于其在日常生活和医药领域的重要性，已经引起科研工作者广泛关注。由容易获得的起始原料进行多步的串联反应来合成手性的四氢喹啉化合物的方法已得到开发。在这些开发的方法中，采用了不同的、易得的起始原料来进行串联反应。使用2-氨基查耳酮及其衍生物，Rueping小组合成手性四氢喹啉的串联反应。在该反应中具体经历了连续的光环化反应/不对称转移氢化过程。随后，Yang小组也开发了一种类似的方法，即通过可见光诱导的环化反应/手性磷酸催化的转移氢化反应进行合成手性四氢喹啉。在这两类方法中，光促进了2-苯基喹啉中间体的生成。2018年Cheon小组使用手性磷酸作为唯一的催化剂进行环化/不对称还原反应。然而，以上报道的方法中都需要采用化学计量的汉栖酯进行不对称氢化反应。在反应中，汉栖酯受到再生的限制并易产生脱氢产物吡啶。这就导致了反应的低原子经济性，也造成了产品分离的困难。
发明内容
本发明的目的是提供一种一锅法仿生合成手性四氢喹啉化合物的方法，本发明操作简便实用，原料易得，对映选择性高，产率好，且反应具有绿色原子经济性，环境友好等优点，为合成其他手性化合物提供一种有效的合成方法。
为实现上述目的，本发明以金属钌、菲啶，手性磷酸、分子筛和一定的溶剂形成仿生的催化体系，以简单易得2-氨基查尔酮为底物，发生一锅法仿生不对称串联/还原反应合成手性四氢喹啉。
本发明的技术方案如下：
所述方法以金属钌、菲啶，手性磷酸、分子筛和一定的溶剂形成仿生的催化体系，以简单易得2-氨基查尔酮为底物，所述方法的反应式如下：
Figure BDA0002628273260000021
所述方法以钌的络合物作为氢源再生催化剂，以手性磷酸为转移催化剂，以菲啶为氢源，以分子筛为吸水剂；
式中：R为H、苯基、萘基、杂环、含有取代基I的苯环或C1-7的烷基，所述取代基I为卤素、C1-C20的烷基中的至少一种；Ar为萘基、芳环或含有取代基II的芳环，所述取代基II为卤素、烷氧基或C1-C20的烷基中的至少一种。
基于上述方案，优选地，所述杂环为五元杂环或六元杂环；所述Ar为苯基或含有取代基II的苯基；所述钌的络合物为[Ru(p-cymene)I2]2；所述手性磷酸为联萘骨架的手性磷酸；所述分子筛为
Figure BDA0002628273260000022
或
Figure BDA0002628273260000023
基于上述方案，优选地，所述底物、钌、手性磷酸、菲啶的摩尔比为1:0.04～1:0.1～1:0.2；反应温度为-40-100℃；反应时间为3-108小时。
基于上述方案，优选地，所述底物、钌、手性磷酸、菲啶的摩尔比为1:0.04～0.1:0.1～0.3:0.2；所述反应温度为35-50℃；所述反应时间为42-72小时。
基于上述方案，优选地，所述方法包括以下步骤：
步骤一、在安培瓶中称取钌的络合物、手性磷酸、菲啶、分子筛和底物，并在手套箱内加入有机溶剂，搅拌，得到混合物；
步骤二、将所述混合物转移至反应器中，充入氢气，进行反应，反应结束后，分离纯化，得到所述产物。
基于上述方案，优选地，所述有机溶剂为甲苯、均三甲苯、对二甲苯、二氯甲烷、二氯乙烷、氯仿、四氢呋喃、三氟甲苯和乙酸乙酯中的一种或两种混合。
基于上述方案，优选地，所述有机溶剂为均三甲苯；所述反应温度为40℃；所述反应时间72小时；所述产物对映体过量92％。
本发明制备的手性四氢喹啉可用于药物或者含氮配体的合成。
有益效果
1.原料简单易得，操作简单。
2.反应活性高，原料转化完全，分离方便，能获得高纯度的产物。
3.立体选择性好，能高对映选择性地得到单一的非对映异构体，对映体过量可达到92％。
4.反应条件温和，环境友好绿色。
5.本发明从简单易得的原料2-氨基查尔酮类底物出发，利用新开发的一锅法仿生催化体系合成手性四氢喹啉化合物，该体系使用了催化量菲啶作为可再生氢源，体系新颖，用于手性四氢喹啉化合物合成时反应的对映选择性好，收率较高，菲啶催化量使用，不会造成副产物的产生，反应的原子经济性高。菲啶商业可得，不用繁琐合成。
具体实施方式
下面通过实施例详述本发明，但本发明并不限于下述的实施例。
2-氨基查尔酮类化合物合成参考文献：Chen,X.；Qiu,S.；Wang,S.；Wang,H.；Zhai,H.Org.Biomol.Chem.,2017,15,6349-6352.手性磷酸的合成参考文献：Tay,J.-H.；Arguelles,A.；Nagorny,P.Org.Lett.,2015,17,3774-3777.其余原料均商业可得。
实施例1-15
条件的优化
改变手性磷酸、有机溶剂的种类、反应温度、分子筛和反应时间。
在安培瓶中称量钌、手性磷酸、菲啶、分子筛和2-氨基查尔酮类底物，在手套箱内加入均三甲苯3毫升，并在手套箱中搅拌5分钟。然后将该混合物转移至高压釜中，装釜，充入氢气(500psi)，在35-50℃条件下反应42-72小时。随后，小心释放氢气，打开高压釜，并将反应混合物通过柱层析直接纯化，使用石油醚/乙酸乙酯作为洗脱剂，石油醚和乙酸乙酯的体积比为25:1，得到所需的目标还原产物。产物的对映选择性使用高效液相色谱仪进行测定。所述2-氨基查尔酮、钌、手性磷酸、菲啶的摩尔比为1:0.04:0.1:0.2。具体结果如表1。
Figure BDA0002628273260000041
表1.一锅法仿生合成手性四氢喹啉条件的优化
Figure BDA0002628273260000042
实施例16-31
一锅法仿生合成手性四氢喹啉化合物。
安培瓶中称量钌、手性磷酸、菲啶、分子筛和2-氨基查尔酮类底物，在手套箱内加入均三甲苯3毫升，并在手套箱中搅拌5分钟。然后将该混合物转移至高压釜中，装釜，充入氢气(500psi)，在40℃条件下反应72小时。随后，小心释放氢气，打开高压釜，并将反应混合物通过柱层析直接纯化，使用石油醚/乙酸乙酯作为洗脱剂，石油醚和乙酸乙酯的体积比为25:1，得到所需的目标还原产物。产物的对映选择性可以使用高效液相色谱仪进行测定。所述2-氨基查尔酮、钌、手性磷酸、菲啶的摩尔比为1:0.04:0.1:0.2。改变反应中原料和底物的种类得到16个不同的实施例，改变的种类具体见表2。
Figure BDA0002628273260000051
表2.一锅法仿生合成一系列手性四氢喹啉化合物
Figure BDA0002628273260000052
(R)-2-苯基-1,2,3,4-四氢喹啉(2a):38mg,91％yield,colorless oil,knowncompound,Rf＝0.70(hexanes/ethyl acetate 20/1),87％ee,[α]20 D＝38.28(c 0.70,CHCl3).1H NMR(400MHz,CDCl3)δ7.40-7.30(m,4H),7.29-7.24(m,1H),7.05-6.93(m,2H),6.67-6.59(m,1H),6.51(d,J＝7.6Hz,1H),4.41(dd,J＝9.3,3.3Hz,1H),4.00(brs,1H),2.96-2.84(m,1H),2.76-2.65(m,1H),2.16-2.05(m,1H),2.03-1.91(m,1H).13C NMR(100MHz,CDCl3)δ144.9,144.8,129.4,128.7,127.5,127.0,126.6,121.0,117.3,114.1,56.3,31.1,26.5.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 6.1min(major)and 14.4min.
(R)-2-对甲基苯基-1,2,3,4-四氢喹啉(2b):42mg,94％yield,colorless oil,known compound,Rf＝0.65(hexanes/ethyl acetate 20/1),91％ee,[α]20 D＝28.62(c0.80,CHCl3),1H NMR(400MHz,CDCl3)δ7.29-7.21(m,2H),7.19-7.11(m,2H),7.03-6.92(m,2H),6.62(t,J＝7.3Hz,1H),6.49(d,J＝7.8Hz,1H),4.37(dd,J＝9.4,3.2Hz,1H),3.96(brs,1H),2.97-2.83(m,1H),2.76-2.64(m,1H),2.33(s,3H),2.12-2.02(m,1H),2.00-1.90(m,1H).13C NMR(100MHz,CDCl3)δ144.9,141.9,137.2,129.4,129.3,127.0,126.6,121.0,117.2,114.1,56.1,31.1,26.6,21.2.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 6.2min(major)and 9.0min.
(R)-2-间甲基苯基-1,2,3,4-四氢喹啉(2c):43mg,96％yield,colorless oil,known compound,Rf＝0.70(hexanes/ethyl acetate 20/1),87％ee,[α]20 D＝32.79(c0.86,CHCl3).1H NMR(400MHz,CDCl3)δ7.24-7.16(m,3H),7.09(d,J＝7.3Hz,1H),7.04-6.95(m,2H),6.68-6.60(m,1H),6.52(d,J＝7.6Hz,1H),4.38(dd,J＝9.5,3.2Hz,1H),4.00(brs,1H),2.97-2.86(m,1H),2.78-2.68(m,1H),2.35(s,3H),2.15-2.05(m,1H),2.04-1.92(m,1H).13C NMR(100MHz,CDCl3)δ144.8,144.8,138.3,129.3,128.5,128.2,127.3,126.9,123.7,120.9,117.2,114.0,56.3,31.1,26.6,21.5.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 5.4min(major)and8.9min.
(R)-2-邻甲基苯基-1,2,3,4-四氢喹啉(2d):41mg,92％yield,colorless oil,known compound,Rf＝0.65(hexanes/ethyl acetate 20/1),78％ee,[α]20 D＝46.44(c0.76,CHCl3).1H NMR(400MHz,CDCl3)δ7.53-7.45(m,1H),7.21-7.14(m,3H),7.04-6.95(m,2H),6.69-6.60(m,1H),6.56-6.50(m,1H),4.66(dd,J＝9.2,3.2Hz,1H),3.92(brs,1H),2.98-2.86(m,1H),2.80-2.70(m,1H),2.37(s,3H),2.14-2.05(m,1H),1.97-1.84(m,1H).13CNMR(100MHz,CDCl3)δ145.1,142.6,134.8,130.6,129.4,127.1,127.0,126.5,126.1,120.9,117.1,114.1,52.2,29.2,26.6,19.1.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝0.7mL/min,retention time 7.3min(major)and7.9min.
(R)-2-(4-环己基苯基)-1,2,3,4-四氢喹啉(2e):52mg,89％yield,colorlessoil,new compound,Rf＝0.75(hexanes/ethyl acetate 20/1),86％ee,[α]20 D＝12.31(c1.04,CHCl3).1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.1Hz,2H),7.23(d,J＝8.1Hz,2H),7.07-7.00(m,2H),6.71-6.64(m,1H),6.57-6.52(m,1H),4.43(dd,J＝9.5,3.2Hz,1H),4.04(brs,1H),3.02-2.89(m,1H),2.83-2.72(m,1H),2.61-2.46(m,1H),2.19-2.10(m,1H),2.08-1.98(m,1H),1.96-1.85(m,4H),1.83-1.74(m,1H),1.51-1.39(m,4H),1.35-1.25(m,1H).13C NMR(100MHz,CDCl3)δ147.4,144.9,142.2,129.3,127.0,126.9,126.6,120.9,117.1,114.0,56.1,44.3,34.6,31.0,27.0,26.6,26.2.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 5.4min(major)and7.4min.HRMS Calculated for C21H26N[M+H]+292.2060,found:292.2054.
(R)-2-(4-(叔丁基苯基)-1,2,3,4-四氢喹啉(2f):51mg,96％yield,colorlessoil,known compound,Rf＝0.70(hexanes/ethyl acetate 20/1),80％ee,[α]20 D＝15.88(c1.02,CHCl3).1H NMR(400MHz,CDCl3)δ7.44-7.32(m,4H),7.07-6.97(m,2H),6.67(t,J＝7.3Hz,1H),6.54(d,J＝8.1Hz,1H),4.43(dd,J＝9.5,3.1Hz,1H),4.05(brs,1H),3.02-2.88(m,1H),2.82-2.73(m,1H),2.17-2.08(m,1H),2.07-1.96(m,1H),1.35(s,9H).13C NMR(100MHz,CDCl3)δ150.4,144.8,141.8,129.3,126.9,126.3,125.5,120.9,117.1,114.0,56.0,34.6,31.4,30.9,26.6.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 5.0min(major)and 7.0min.
(R)-2-(4-甲氧基苯基)-1,2,3,4-四氢喹啉(2g):44mg,92％yield,white solid,known compound,Rf＝0.60(hexanes/ethyl acetate 20/1),90％ee,[α]20 D＝29.39(c0.82,CHCl3).1H NMR(400MHz,CDCl3)δ7.39-7.32(m,2H),7.08-7.01(m,2H),6.98-6.89(m,2H),6.69(t,J＝7.3Hz,1H),6.56(d,J＝8.2Hz,1H),4.41(dd,J＝9.5,3.1Hz,1H),4.02(brs,1H),3.84(s,3H),3.04-2.91(m,1H),2.86-2.73(m,1H),2.18-2.08(m,1H),2.07-1.94(m,1H).13C NMR(100MHz,CDCl3)δ159.0,144.9,137.0,129.4,127.7,127.0,121.0,117.2,114.1,114.0,55.8,55.4,31.2,26.6.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 10.9min(major)and50.3min.
(R)-2-(3-甲氧基苯基)-1,2,3,4-四氢喹啉(2h):44mg,92％yield,colorlessoil,known compound,Rf＝0.50(hexanes/ethyl acetate 20/1),85％ee,[α]20 D＝39.43(c0.88,CHCl3).1H NMR(400MHz,CDCl3)δ7.29(t,J＝7.9Hz,1H),7.06-6.97(m,4H),6.88-6.83(m,1H),6.71-6.65(m,1H),6.56(d,J＝7.7Hz,1H),4.43(dd,J＝9.4,3.2Hz,1H),4.06(brs,1H),3.83(s,3H),3.01-2.89(m,1H),2.81-2.71(m,1H),2.18-2.09(m,1H),2.07-1.95(m,1H).13C NMR(100MHz,CDCl3)δ159.9,146.6,144.7,129.6,129.3,126.9,120.9,118.9,117.2,114.0,112.8,112.1,56.3,55.3,31.0,26.5.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 7.4min(major)and16.2min.
(R)-2-(3,4-二甲基苯基)-1,2,3,4-四氢喹啉(2i):45mg,95％yield,colorlessoil,new compound,Rf＝0.85(hexanes/ethyl acetate 20/1),87％ee,[α]20 D＝25.93(c0.86,CHCl3).1H NMR(400MHz,CDCl3)δ7.23-7.13(m,3H),7.08-6.99(m,2H),6.72-6.64(m,1H),6.55(dd,J＝8.3,0.8Hz,1H),4.39(dd,J＝9.6,3.2Hz,1H),4.01(brs,1H),3.03-2.90(m,1H),2.83-2.73(m,1H),2.31(s,3H),2.30(s,3H),2.17-2.09(m,1H),2.07-1.94(m,1H).13C NMR(100MHz,CDCl3)δ144.9,142.3,136.8,135.8,129.8,129.3,127.9,126.9,124.0,121.0,117.1,114.0,56.1,31.2,26.7,19.9,19.5.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 5.2min(major)and6.1min.HRMS Calculated for C17H20N[M+H]+238.1590,found:238.1593.
(R)-2-(3,5-二甲氧基苯基)-1,2,3,4-四氢喹啉(2j):44mg,82％yield,colorless oil,new compound,Rf＝0.50(hexanes/ethyl acetate 20/1),84％ee,[α]20 D＝41.06(c 0.66,CHCl3).1H NMR(400MHz,CDCl3)δ7.07-6.98(m,2H),6.70-6.64(m,1H),6.61-6.53(m,3H),6.41(t,J＝2.3Hz,1H),4.38(dd,J＝9.5,3.2Hz,1H),4.05(brs,1H),3.80(s,6H),3.01-2.88(m,1H),2.83-2.71(m,1H),2.20-2.08(m,1H),2.06-1.93(m,1H).13CNMR(100MHz,CDCl3)δ161.0,147.5,144.6,129.3,126.9,120.9,117.3,114.1,104.5,99.3,56.5,55.4,31.1,26.5.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 9.3min and 10.0min(major).HRMSCalculated for C17H20NO2[M+H]+270.1489,found:270.1489.
(R)-2-(4-氟苯基)-1,2,3,4-四氢喹啉(2k):39mg,86％yield,white solid,known compound,Rf＝0.60(hexanes/ethyl acetate 20/1),89％ee,[α]20 D＝44.36(c0.78,CHCl3).1H NMR(400MHz,CDCl3)δ7.42-7.32(m,2H),7.10-6.98(m,4H),6.73-6.65(m,1H),6.56(d,J＝7.8Hz,1H),4.44(dd,J＝9.3,3.2Hz,1H),4.02(brs,1H),3.01-2.87(m,1H),2.80-2.68(m,1H),2.17-2.06(m,1H),2.04-1.91(m,1H).13C NMR(100MHz,CDCl3)δ162.1(d,1JF-C＝243.5Hz),144.6,140.5(d,4JF-C＝3.0Hz),129.4,128.1(d,3JF-C＝7.9Hz),127.0,120.9,117.4,115.4(d,2JF-C＝21.1Hz)114.1,55.6,31.2,26.3.19F NMR(376MHz,CDCl3)δ-115.3.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 7.3min(major)and 20.0min.
(R)-2-(4-氯苯基)-1,2,3,4-四氢喹啉(2l):42mg,86％yield,white solid,known compound,Rf＝0.60(hexanes/ethyl acetate 20/1),92％ee,[α]20 D＝42.26(c0.84,CHCl3).1H NMR(400MHz,CDCl3)δ7.36-7.31(m,4H),7.07-6.99(m,2H),6.72-6.64(m,1H),6.56(d,J＝7.9Hz,1H),4.44(dd,J＝9.2,3.3Hz,1H),4.03(brs,1H),2.98-2.87(m,1H),2.79-2.68(m,1H),2.15-2.07(m,1H),2.02-1.91(m,1H).13C NMR(100MHz,CDCl3)δ144.4,143.4,133.0,129.4,128.7,128.0,127.0,120.8,117.4,114.1,55.6,31.0,26.2.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 8.3min(major)and 17.5min.
(R)-2-(4-溴苯基)-1,2,3,4-四氢喹啉(2m):48mg,83％yield,white solid,known compound,Rf＝0.75(hexanes/ethyl acetate 20/1),91％ee,[α]20 D＝33.25(c0.40,CHCl3).1H NMR(400MHz,CDCl3)δ7.55-7.47(m,2H),7.32-7.28(m,2H),7.10-7.00(m,2H),6.75-6.66(m,1H),6.58(d,J＝7.9Hz,1H),4.44(dd,J＝9.1,3.3Hz,1H),4.05(brs,1H),3.01-2.87(m,1H),2.81-2.67(m,1H),2.19-2.07(m,1H),2.04-1.93(m,1H).13C NMR(100MHz,CDCl3)δ144.4,143.9,131.7,129.4,128.3,127.0,121.1,120.8,117.5,114.1,55.6,31.0,26.1.HPLC:Chiralpak AS-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 8.6min(major)and 15.4min.
(R)-2-(3-氯苯基)-1,2,3,4-四氢喹啉(2n):43mg,88％yield,colorless oil,known compound,Rf＝0.65(hexanes/ethyl acetate 20/1),86％ee,[α]20 D＝78.42(c0.76,CHCl3).1H NMR(400MHz,CDCl3)δ7.61-7.52(m,2H),7.35-7.28(m,1H),7.18-7.11(m,1H),7.09-7.00(m,2H),6.72-6.66(m,1H),6.59(d,J＝7.9Hz,1H),4.88(dd,J＝8.0,3.6Hz,1H),4.06(brs,1H),2.99-2.84(m,1H),2.77-2.65(m,1H),2.29-2.15(m,1H),2.03-1.90(m,1H).13C NMR(100MHz,CDCl3)δ144.6,143.4,132.9,129.4,128.7,128.1,127.8,127.0,122.5,121.0,117.4,114.1,54.7,28.3,25.6.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 6.7min(major)and7.5min.
(R)-2-(2-萘基)-1,2,3,4-四氢喹啉(2o):50mg,96％yield,white solid,knowncompound,Rf＝0.75(hexanes/ethyl acetate 20/1),90％ee,[α]20 D＝29.18(c 0.98,CHCl3).1H NMR(400MHz,CDCl3)δ7.90-7.81(m,4H),7.57-7.46(m,3H),7.10-7.02(m,2H),6.70(t,J＝7.4Hz,1H),6.61(d,J＝7.8Hz,1H),4.62(dd,J＝9.2,3.3Hz,1H),4.16(brs,1H),3.05-2.92(m,1H),2.84-2.73(m,1H),2.25-2.17(m,1H),2.16-2.04(m,1H).13C NMR(100MHz,CDCl3)δ144.7,142.2,133.5,133.0,129.4,128.4,127.9,127.7,127.0,126.2,125.8,125.1,124.9,121.0,117.3,114.1,56.4,31.0,26.5.HPLC:Chiralpak AS-Hcolumn,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time7.4min(major)and26.9min.
(R)-2-(2-呋喃基)-1,2,3,4-四氢喹啉(2p):37mg,93％yield,colorless oil,known compound,Rf＝0.75(hexanes/ethyl acetate 20/1),83％ee,[α]20 D＝-40.25(c0.80,CHCl3).1H NMR(400MHz,CDCl3)δ7.39(d,J＝1.1Hz,1H),7.11-6.98(m,2H),6.71-6.65(m,1H),6.56(d,J＝7.9Hz,1H),6.35(dd,J＝3.2,1.9Hz,1H),6.23(d,J＝3.2Hz,1H),4.55(dd,J＝8.2,3.6Hz,1H),4.13(brs,1H),2.94-2.73(m,2H),2.29-2.09(m,2H).13C NMR(100MHz,CDCl3)δ157.0,143.8,141.6,129.3,126.9,121.0,117.6,114.4,110.2,105.3,49.7,26.9,25.6.HPLC:Chiralpak AD-H column,254nm,30℃,n-Hexane/i-PrOH＝85/15,flow＝0.8mL/min,retention time 6.9min(major)and 7.9min.

Claims (5)

1.一种合成手性四氢喹啉的方法，其特征在于，所述方法反应式如下：
Figure FDA0003173126690000011
所述方法以钌的络合物作为氢源再生催化剂，以手性磷酸为转移催化剂，以菲啶为氢源，以分子筛为吸水剂，以甲苯、均三甲苯、二氯甲烷、对二甲苯或乙酸乙酯为反应溶剂；
式中：
R为苯基、4-甲基苯基、3-甲基苯基、2-甲基苯基、4-环己基苯基、4-叔丁基苯基、4-甲氧基苯基、3-甲氧基苯基、3,4-二甲基苯基、3,5-二甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、3-氯苯基、2-萘基、2-呋喃基中的一种；
所述钌的络合物为[Ru(p-cymene)I2]2；所述分子筛为
Figure FDA0003173126690000012
或
Figure FDA0003173126690000013
分子筛；所述手性磷酸结构如下：
Figure FDA0003173126690000014
2.根据权利要求1所述的方法，其特征在于，式I所示底物、钌、手性磷酸、菲啶的摩尔比为1:0.04～1:0.1～1:0.2；反应温度为-40-100℃；反应时间为3-108小时。
3.根据权利要求2所述的方法，其特征在于，所述底物、钌、手性磷酸、菲啶的摩尔比为1:0.04～0.1:0.1～0.3:0.2；所述反应温度为35-50℃；所述反应时间为42-72小时。
4.根据权利要求1所述的方法，其特征在于，所述方法包括以下步骤：
步骤一、在安培瓶中称量钌的络合物、手性磷酸、菲啶、分子筛和底物，并在手套箱内加入反应溶剂，搅拌，得到混合物；
步骤二、将所述混合物转移至反应器中，充入氢气，进行反应，反应结束后，分离纯化，得到式II所示产物。
5.根据权利要求3所述的方法，其特征在于：反应溶剂为均三甲苯；所述反应温度为40℃；所述反应时间为72小时；产物对映体过量92％。
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