CN103724264A - 铱催化异喹啉不对称氢化合成手性四氢异喹啉衍生物方法 - Google Patents

铱催化异喹啉不对称氢化合成手性四氢异喹啉衍生物方法 Download PDF

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CN103724264A
CN103724264A CN201210391020.7A CN201210391020A CN103724264A CN 103724264 A CN103724264 A CN 103724264A CN 201210391020 A CN201210391020 A CN 201210391020A CN 103724264 A CN103724264 A CN 103724264A
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isoquinoline
chiral
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iridium
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周永贵
叶智识
时磊
陈木旺
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Dalian Institute of Chemical Physics of CAS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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Abstract

一种铱催化异喹啉的不对称氢化合成手性四氢异喹啉衍生物的方法，其用到的催化体系是金属铱的手性双膦配合物。反应能在下列条件内进行，温度：25-60℃；溶剂：四氢呋喃/二氯甲烷的混合溶剂（V/V=1:1）；压力：13-50个大气压；底物和催化剂的比例是50/1；催化剂为(1,5-环辛二烯)氯化铱二聚体和手性双膦配体的配合物。对异喹啉盐氢化能得到相应的手性1-位或3-位取代四氢异喹啉衍生物，其对映体过量可达到96％。本发明操作简便实用，原料易得，对映选择性高，产率好，且反应具有原子经济性，对环境友好。

Description

铱催化异喹啉不对称氢化合成手性四氢异喹啉衍生物方法
技术领域
本发明涉及一种应用铱的均相体系高度对映选择性催化氢化异喹啉合成手性四氢异喹啉衍生物的方法。 
技术背景
四氢异喹啉及其衍生物是一类具有广泛的生理和药理活性的生物碱，具有很高的研究价值和应用前景。这类化合物具有多种潜在的药物活性，如：抗癌、利尿、镇静、麻醉和抗癫痫病等特性。多年来对这类化合物的结构和生物活性研究引起了药学界和有机合成化学家的高度重视。式1的三个常见的药物都含有四氢异喹啉结构单元： 
Figure BDA00002255270400011
四氢异喹啉及其衍生物除了作为药物吸引人们的注意外，它们还被作为手性辅助剂和手性试剂取得了成功的应用。 
鉴于四氢异喹啉及其衍生物在药物和合成化学领域的重要性，化学家们已经发展了一些合成这类杂环化合物的方法。其中，通过对简单易得且廉价的异喹啉化合物进行不对称氢化是合成手性四氢异喹啉及其衍生物最直接有效的手段之一。但是到目前为止，只有很少的例子成功采用不对称氢化方法来合成手性的四氢异喹啉及其衍生物。主要原因是异喹啉性质稳定，氢化反应活性低，同时具有强配位能力易导致催化剂中毒。2006年，zhou小组等首次采用氯甲酸酯活化底物的策略成功实现了1-取代异喹啉的不对称氢化，但只能取得中等的产率和对映选择性（文献1:Lu,S.-M.;Wang,Y.-Q.；Han,X.-W.;Zhou,Y.-G.Angew.Chem.,Int.Ed.2006,45,2260）。最近，该小组又采用加入溴氯海因作为添加剂活化催化剂铱的方法，成功发展了3,4-二取代异喹啉的直接不对称氢化。虽然该体系对3,4-二取代异喹啉氢化能取得高达97%ee，但是1-取代的异喹啉底物却没有进行报道（文献2:Shi,L.;Ye,Z.-S.;Cao,L.-L.;Guo,R.-N.;Hu,Y.;Zhou,Y.-G.Angew.Chem.,Int.Ed.2012,51,8286）。 
从上述例子中可以看出，虽然目前异喹啉的不对称氢化取得了一定的 结果，但是存在的局限也较为明显，例如，底物适用范围不广，对映选择性不高，3-取代异喹啉的不对称氢化至今还未见报道。为了发展一种高对映选择性且底物适用范围广的异喹啉的不对称氢化方法，我们采用先让异喹啉与苄溴衍生物反应成异喹啉盐，再通过金属催化实现异喹啉盐的均相不对称氢化，反应速度快、产物的分离方便、副反应少。 
发明内容
本发明的目的是提供一种铱催化异喹啉不对称氢化高对映选择性合成手性四氢异喹啉衍生物的方法，本发明操作简便实用，原料易得，对映选择性高，产率好，且反应具有原子经济性，环境友好等优点。 
为实现上述目的，本发明的技术方案如下： 
一种铱催化不对称异喹啉的氢化合成手性四氢异喹啉衍生物的方法，其催化体系为铱的手性双膦配合物，反应式和条件如下： 
Figure BDA00002255270400021
式中： 
温度：25-60℃； 
溶剂：二氯甲烷、甲苯、四氢呋喃中的一种或两种以上的混合； 
氢气压力：13-50个大气压； 
时间：20-24小时； 
催化剂为(1,5-环辛二烯)氯化铱二聚体和双膦配体的配合物； 
所述X为氯、溴、碘、三氟甲磺酸根、高氯酸根、四氟化硼及六氟化磷中的一种离子； 
所述Ar为苯基或含取代基的苯基，苯基上的取代基为CF3、Me、MeO、COOMe、COOEt、COOiPr及COOtBu中的一种取代基或二种取代基； 
所述R1或R3为C1-C20的烷基、1或2-位萘基、苯基或含有取代基的苯基，苯基上的取代基为F、Cl、CF3、Me、MeO、COOMe中的一种取代基或二种取代基或三种取代基或四种取代基。 
所述(1,5-环辛二烯)氯化铱二聚体和双膦配体的配合物是由铱的金属前体(1,5-环辛二烯)氯化铱二聚体([Ir(COD)Cl]2)和手性双膦配体在二氯甲烷与四氢呋喃的混合溶剂(V/V=1:1)中室温搅拌10-15分钟而成；(1,5-环辛二烯)氯化铱二聚体与手性双膦配体的摩尔比为1:2.0-2.2，(1,5-环辛二烯)氯化铱于混合溶剂中的摩尔浓度为0.002-0.01mol/L。 
所述手性双膦配体为(R)-MeO-Biphep,(R)-SynPhos,(R)-SegPhos,(R)-BINAP，(R)-DifluorPhos，(R)-P-Phos和(Rax,S，S)-C3*-TunePhos中的一 种。 
所述配合物摩尔量为氢化底物摩尔量的0.5%到2%。 
所述溶剂用量为每0.125毫摩尔氢化底物用2到4毫升。 
所述反应式为对1-位或3-位取代异喹啉的氢化得到相应的手性手性四氢异喹啉衍生物，配体为(Rax，S，S)-C3*-TunePhos，溶剂为四氢呋喃与二氯甲烷的混合溶剂(V/V=1:1)，温度为室温，氢气压力为600psi所述结果最佳，对映体过量可达到96%。 
对异喹啉盐氢化能得到相应的手性1-位或3-位取代四氢异喹啉衍生物，其对映体过量可达到96％。本发明操作简便实用，原料易得，对映选择性高，产率好，且反应具有原子经济性，对环境友好。 
本发明具有以下优点 
1.反应活性和对映选择性高，反应完全，生成产物专一，核磁氢谱没有检测到副反应，使得产物分离方便，易获得具高对映体纯度的产品。 
2.能得到各种类型的手性四氢异喹啉衍生物，例如1-位或3-位芳基或烷基等取代的化合物。 
3.催化剂制备方便，反应操作简便实用。 
4.氢化反应条件温和，在室温下反应就能进行。 
5、与传统合成方法相比，此方法采用少量的手性催化剂即可得到大量手性四氢异喹啉衍生物，实现手性增值，而且还可以通过改变配体的构型而获得不同构型的手性四氢异喹啉衍生物，同时底物范围更加广泛。 
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。 
实施例1：条件的优化 
在一充满氮气的手套箱中，向装有(1,5-环辛二烯)氯化铱二聚体（0.0025毫摩尔,1.7毫克）和手性配体（0.0055毫摩尔）的反应瓶中加入1mL四氢呋喃/二氯甲烷（v/v=1:1）的混合溶剂，室温搅拌10-30分钟，然后将制备好的催化剂用针管转移到另一装有原料异喹啉盐（0.25毫摩尔）的反应瓶中，补加2mL四氢呋喃/二氯甲烷（v/v=1:1）的混合溶剂，使溶剂总量达到3mL。将反应瓶放入一个不锈钢的高压釜中，通入氢气600psi，室温下反应20-24小时。慢慢释放氢气，向反应体系加入饱和NaHCO3水溶液，搅拌10分钟，而后采用二氯甲烷萃取三次，合并有机相并干燥，用旋转蒸发仪除去溶剂后直接柱层析(淋洗剂石油醚和乙酸乙酯的体积比为20:1-10:1)分离得到纯的产物，反应式及配体如下： 
产率为分离收率，产物的对映体过量用手性液相色谱测定，见表1。 
表1.不对称异喹啉氢化配体筛选 
Figure 2012103910207100002DEST_PATH_IMAGE001
实施例2：铱催化异喹啉不对称氢化合成各种手性四氢异喹啉衍生物 
在一充满氮气的手套箱中，向装有(1,5-环辛二烯)氯化铱二聚体（0.0025毫摩尔,1.7毫克）和手性配体(Rax,S，S)-C3*-TunePhos（0.0055毫摩尔）的反应瓶中加入1mL混合溶剂四氢呋喃/二氯甲烷（v/v=1:1），室温搅拌10-30分钟，然后将制备好的催化剂用针管转移到另一装有原料异喹啉盐（0.25毫摩尔）的反应瓶中，共用3mL溶剂混合溶剂四氢呋喃/二氯甲烷（v/v=1:1）。将反应瓶放入一个不锈钢的高压釜中，通入氢气600psi，室温下反应20-24小时。反应结束后，缓慢释放氢气，向体系加入饱和NaHCO3水溶液，搅拌10min，而后采用二氯甲烷萃取三次，合并有机相并干燥，用旋转蒸发仪除去溶剂后直接柱层析(淋洗剂石油醚和乙酸乙酯的体积比为10:1-5:1)分离得到纯的产物，反应式如下： 
Figure BDA00002255270400051
N-苄基-1-苯基-1,2,3,4-四氢异喹啉(2a):99%产率,93%对映选择性,未知化合物，白色固体,熔点:139-140°C,旋光[α]29 D=-94.3(浓度c 1.85,CHCl3),Rf＝0.45(石油醚/乙酸乙酯为40/1).1H NMR(400MHz,CDCl3)δ7.48-7.27(m,10H),7.20-7.15(m,2H),7.10-7.06(m,1H),6.81(d,J=7.8Hz,1H),4.69(s,1H),3.90(d,J=13.6Hz,1H),3.32(d,J=13.6Hz,1H),3.21-3.11(m,2H),2.88-2.81(m,1H),2.63-2.56(m,1H);13C NMR(100MHz,CDCl3)δ144.5,139.7,138.7,134.9,129.8,129.0,128.8,128.6,128.4,128.3,127.3,126.9,126.0,125.7,70.0,59.0,47.4,29.4;高分辨质谱HRMS计算值C22H22N[M+H]+300.1752,实际值300.1761;手性高效液相色谱HPLC:ChirapakAD-H手性柱,荧光吸收为254nm,温度为30°C,正己烷/异丙醇为90/10,流速为1.0mL/min,液相保留时间3.5min(主峰)和3.9min。（N-Benzyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline(2a):99%yield,93%ee,unknown compound,white solid,mp 139-140°C,[α]29 D=-94.3(c 1.85,CHCl3),Rf=0.45(petroleum ether/EtOAc 40/1).1H NMR(400MHz,CDCl3)δ7.48-7.27(m,10H),7.20-7.15(m,2H),7.10-7.06(m,1H),6.81(d,J=7.8Hz,1H),4.69(s,1H),3.90(d,J=13.6Hz,1H),3.32(d,J=13.6Hz,1H),3.21-3.11(m,2H),2.88-2.81(m,1H),2.63-2.56(m,1H);13C NMR(100MHz,CDCl3)δ144.5,139.7,138.7,134.9,129.8,129.0,128.8,128.6,128.4,128.3,127.3,126.9,126.0,125.7,70.0,59.0,47.4,29.4;HRMS Calculated for C22H22N[M+H]+300.1752,found 300.1761;HPLC:ChirapakAD-H column,254nm,30°C,n-hexane/i-propanol=90/10,flow=1.0mL/min,retention time 3.5min(maj)and 3.9min.） 
N-苄基-1-(4-甲氧基苯基)-1,2,3,4-四氢异喹啉(2b):99%产率,94%对映选择性,未知化合物,白色固体,熔点:118-119°C,旋光[α]29 D=-94.6(浓度c 2.05,CHCl3),Rf＝0.30(石油醚/乙酸乙酯为40/1). 1H NMR(400MHz,CDCl3)δ7.31-6.97(m,10H),6.87-6.83(m,2H),6.73(d,J=7.7Hz,1H),4.56(s,1H),3.82(d,J=13.6Hz,1H),3.78(s,3H),3.22(d,J=13.6Hz,1H),3.11-3.00(m,2H),2.78-2.72(m,1H),2.53-2.46(m,1H);13C NMR(100MHz,CDCl3)δ158.9,139.8,139.0,136.6,135.0,130.8,129.0,128.8,128.6,128.3,126.9,126.0,125.7,113.8,68.3,58.9,55.4,47.4,29.4;高分辨质谱HRMS计算值C23H24NO[M+H]+330.1858,实际值330.1849;手性高效液相色谱HPLC:Chiracel OD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为95/5,流速为1.0mL/min,液相保留时间4.6min和5.0min(主峰)。（N-Benzyl-1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline(2b):99% yield,94%ee,unknown compound,white solid,mp 118-119°C,[α]29 D=-94.6(c 2.05,CHCl3),Rf=0.30(petroleum ether/EtOAc 40/1).1H NMR(400MHz,CDCl3)δ7.31-6.97(m,10H),6.87-6.83(m,2H),6.73(d,J=7.7Hz,1H),4.56(s,1H),3.82(d,J=13.6Hz,1H),3.78(s,3H),3.22(d,J=13.6Hz,1H),3.11-3.00(m,2H),2.78-2.72(m,1H),2.53-2.46(m,1H);13C NMR(100MHz,CDCl3)δ158.9,139.8,139.0,136.6,135.0,130.8,129.0,128.8,128.6,128.3,126.9,126.0,125.7,113.8,68.3,58.9,55.4,47.4,29.4;HRMS Calculated for C23 H24NO[M+H]+330.1858,found 330.1849;HPLC:Chiracel OD-H column,230nm,30°C,n-hexane/i-propanol=95/5,flow=1.0mL/min,retention time 4.6min and 5.0min(maj).） 
N-苄基-1-(4-三氟甲基苯基)-1,2,3,4-四氢异喹啉(2c):97%产率,92%对映选择性,未知化合物,白色固体,熔点:126-127°C,旋光[α]29 D=-83.7(浓度c 2.23,CHCl3),Rf=0.45(石油醚/乙酸乙酯为40/1). 1H NMR(400MHz,CDCl3)δ7.57(d,J=8.1Hz,2H),7.50(d,J=8.1Hz,2H),7.31-6.99(m,8H),6.67(d,J=7.8Hz,1H),4.68(s,1H),3.76(d,J=13.5Hz,1H),3.28(d,J=13.5Hz,1H),3.12-3.02(m,2H),2.81-2.75(m,1H),2.56-2.50(m,1H);13C NMR(100MHz,CDCl3)δ148.9,139.2,137.6,135.0,130.1,129.6(q,J=32.1Hz),128.87,128.86,128.78,128.4,127.2,126.4,125.9,125.4(q,J=3.8Hz),68.4,59.0,47.3,29.1;19F NMR(376MHz,CDCl3)δ-62.3;高分辨质谱HRMS计算值C23H21NF3[M+H]+368.1626,实际值368.1640;手性高效液相色谱HPLC:Chiracel OD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为95/5,流速为1.0mL/min,液相保留时间3.9min和5.3min(主峰)。（N-Benzyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline(2c):97%yield,92%ee,unknown compound,white solid,mp 126-127°C,[α]29 D=-83.7(c 2.23,CHCl3),Rf=0.45(petroleum ether/EtOAc 40/1).1H NMR(400MHz,CDCl3)δ7.57(d,J=8.1Hz,2H),7.50(d,J=8.1Hz,2H),7.31-6.99(m,8H),6.67(d,J=7.8Hz,1H),4.68(s,1H),3.76(d,J=13.5Hz,1H),3.28(d,J=13.5Hz,1H),3.12-3.02(m,2H),2.81-2.75(m,1H),2.56-2.50(m,1H);13C NMR(100MHz,CDCl3)δ148.9,139.2,137.6,135.0,130.1,129.6(q,J=32.1Hz),128.87,128.86,128.78,128.4,127.2,126.4,125.9,125.4(q,J=3.8Hz),68.4,59.0,47.3,29.1;19F NMR(376MHz,CDCl3)δ-62.3;HRMS Calculated for C23H21NF3[M+H]+368.1626,found 368.1640;HPLC:Chiracel OD-H column,230nm,30°C,n-hexane/i-propanol=95/5,flow=1.0mL/min,retention time 3.9min and 5.3min(maj).） 
N-苄基-1-甲基-1,2,3,4-四氢异喹啉(2d)1a:99%产率,70%对映选择性,已知化合物,无色液体,旋光[α]29 D=+7.6(浓度c 1.43,CHCl3),Rf=0.50(石油醚/乙酸乙酯为20/1).1H NMR(400MHz,CDCl3)δ7.47-7.30(m,5H),7.22-7.11(m,4H),3.96(q,J=6.7Hz,1H),3.89(d,J=13.6Hz,1H),3.77(d,J=13.6Hz,1H),3.14-3.10(m,1H),2.97-2.93(m,1H),2.80-2.76(m,2H),1.46(d,J=6.7Hz,3H);13CNMR(100MHz,CDCl3)δ140.7,139.9,134.6,129.1,129.0,128.5,127.7,127.1,126.0,125.9,58.5,56.5,44.1,27.7,20.0;手性高效液相色谱HPLC:Chiracel OD-H手性柱,荧光吸收为220nm,温度为30°C,正己烷/异丙醇为98/2,流速为1.0mL/min,液相保留时间4.8min(主峰)和5.1min。（N-Benzyl-1-methyl-1,2,3,4-tetrahydroisoquinoline(2d)1a:99%yield,70%ee,known compound,colorless oil,[α]29 D=+7.6(c1.43,CHCl3),Rf=0.50(petroleum ether/EtOAc 20/1).1H NMR(400MHz,CDCl3)δ7.47-7.30(m,5H),7.22-7.11(m,4H),3.96(q,J=6.7Hz,1H),3.89(d,J=13.6Hz,1H),3.77(d,J=13.6Hz,1H),3.14-3.10(m,1H),2.97-2.93(m,1H),2.80-2.76(m,2H),1.46(d,J=6.7Hz,3H); 13C NMR(100MHz,CDCl3)δ140.7,139.9,134.6,129.1,129.0,128.5,127.7,127.1,126.0,125.9,58.5,56.5,44.1,27.7,20.0;HPLC:Chiracel OD-H column,220nm,30°C,n-hexane/i-propanol=98/2,flow=1.0mL/min,retention time 4.8min(maj)and 5.1min.） 
N-苄基-1-异丙基-1,2,3,4-四氢异喹啉(2e):99%产率,74%对映选择性,未知化合物,无色液体,旋光[α]30 D=+14.0(浓度c 0.83,CHCl3),Rf=0.50(石油醚/乙酸乙酯为20/1).1H NMR(400MHz,CDCl3) δ7.36-7.00(m,9H),3.71(d,J=13.6Hz,1H),3.64(d,J=13.6Hz,1H),3.27-3.20(m,2H),2.88-2.80(m,1H),2.72-2.57(m,2H),1.93(dq,J=13.6,6.8Hz,1H),1.05(d,J=6.7Hz,3H),0.87(d,J=6.7Hz,3H);13C NMR(100MHz,CDCl3)δ140.5,137.4,135.6,129.5,128.9,128.8,128.3,126.9,126.1,125.0,67.8,59.4,44.1,34.1,25.0,20.49,20.48;高分辨质谱HRMS计算值C19H24N[M+H]+266.1909,实际值266.1904;手性高效液相色谱HPLC:Chiracel OJ-H手性柱,荧光吸收为220nm,温度为30°C,正己烷/异丙醇为95/5,流速为1.0mL/min,液相保留时间4.8min(主峰)和5.2min。（N-Benzyl-1-isopropyl-1,2,3,4-tetrahydroisoquinoline(2e):99%yield,74%ee,unknown compound,colorless oil,[α]30 D=+14.0(c 0.83,CHCl3),Rf=0.50(petroleum ether/EtOAc 20/1).1H NMR(400MHz,CDCl3)δ7.36-7.00(m,9H),3.71(d,J=13.6Hz,1H),3.64(d,J=13.6Hz,1H),3.27-3.20(m,2H),2.88-2.80(m,1H),2.72-2.57(m,2H),1.93(dq,J=13.6,6.8Hz,1H),1.05(d,J=6.7Hz,3H),0.87(d,J=6.7Hz,3H);13C NMR(100MHz,CDCl3)δ140.5,137.4,135.6,129.5,128.9,128.8,128.3,126.9,126.1,125.0,67.8,59.4,44.1,34.1,25.0,20.49,20.48;HRMS Calculated for C19H24N[M+H]+266.1909,found 266.1904;HPLC:Chiracel OJ-H column,220nm,30°C,n-hexane/i-propanol=95/5,flow=1.0mL/min,retention time 4.8min(maj)and 5.2min.） 
N-(2-异丙氧羰基苄基)-1-苯基-1,2,3,4-四氢异喹啉(2f):99%产率,96%对映选择性,未知化合物,无色液体,旋光[α]28 D=-69.0(浓度c 2.40,CHCl3),Rf=0.35(石油醚/乙酸乙酯为40/1).1H NMR(400MHz,CDCl3)δ7.72-7.65(m,2H),7.42-7.00(m,10H),6.74(d,J=7.5Hz,1H),5.15(brs,1H),4.71(s,1H),3.98(d,J=15.0Hz,1H),3.80(d,J=15.0Hz,1H),3.02-3.00(m,2H),2.87-2.79(m,1H),2.55-2.53(m,1H),1.31-1.24(m,6H).13C NMR(100MHz,CDCl3)δ167.8,144.0,141.0,138.5,134.9,131.7,131.4,129.8,129.7,129.4,129.1,128.6,128.2,127.2,126.5,126.1,125.7,68.4,56.0,46.9,28.9,22.02,22.96;高分辨质谱HRMS计算值C26H27NO2Na[M+Na]+408.1939,实际值408.1930;手性高效液相色谱HPLC:Chirapak AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为90/10,流速为1.0mL/min,液相保留时间4.5min和5.0min(主峰)。（N-(2-Isopropylcarbonyl benzyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline(2f):99%yield,96%ee,unknown compound,colorless oil,[α]28 D=-69.0(c 2.40,CHCl3),Rf=0.35(petroleum ether/EtOAc 40/1).1H NMR(400MHz,CDCl3)δ7.72-7.65(m,2H),7.42-7.00(m,10H),6.74(d,J=7.5Hz,1H),5.15(brs,1H),4.71(s,1H),3.98(d,J=15.0Hz,1H),3.80(d,J=15.0Hz,1H),3.02-3.00(m,2H),2.87-2.79(m,1H),2.55-2.53(m,1H),1.31-1.24(m,6H).13C NMR(100MHz,CDCl3)δ167.8,144.0,141.0,138.5,134.9,131.7,131.4,129.8,129.7,129.4,129.1,128.6,128.2,127.2,126.5,126.1,125.7,68.4,56.0,46.9,28.9,22.02,22.96;HRMS Calculated for C26H27NO2Na[M+Na]+408.1939,found 408.1930;HPLC:Chirapak AD-H column,230nm,30°C,n-hexane/i-propanol=90/10,flow=1.0mL/min,retention time 4.5min and 5.0min(maj).） 
N-(2-异丙氧羰基苄基)-1-对甲基苯基-1,2,3,4-四氢异喹啉(2g):99%产率,96%对映选择性,未知化合物,无色液体,旋光[α]29 D=-76.4(浓度c 2.50,CHCl3),Rf＝0.35(石油醚/乙酸乙酯为40/1).1H NMR(400MHz,CDCl3)δ7.71-7.66(m,2H),7.43-7.39(m,1H),7.26-6.98(m,8H),6.75(d,J=7.7Hz,1H),5.17-5.12(m,1H),4.68(s,1H),3.95(d,J=15.1Hz,1H),3.79(d,J=15.1Hz,1H),3.02-2.97(m,2H),2.83-2.78(m,1H),2.54-2.51(m,1H),2.29(s,3H),1.30(d,J=6.3Hz,3H),1.25(d,J=6.2Hz,3H);13CNMR(100MHz,CDCl3)δ167.8,141.1,140.9,138.8,136.7,134.9,131.7,131.4,129.7,129.6,129.4,129.1,129.0,128.6,126.4,126.0,125.7,68.4,68.2,56.0,47.0,29.0,22.03,21.97,21.2;高分辨质谱HRMS计算值C27H29NO2Na[M+Na]+422.2096,实际值422.2104;手性高效液相色谱HPLC:Chirapak AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为90/10,流速为1.0mL/min,液相保留时间4.0min和4.6min(主峰)。（N-(2-Isopropylcarbonyl benzyl)-1-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline(2g):99%yield,96%ee,unknown compound, colorless oil,[α]29 D=-76.4(c 2.50,CHCl3),Rf=0.35(petroleum ether/EtOAc 40/1).1H NMR(400MHz,CDCl3)δ7.71-7.66(m,2H),7.43-7.39(m,1H),7.26-6.98(m,8H),6.75(d,J=7.7Hz,1H),5.17-5.12(m,1H),4.68(s,1H),3.95(d,J=15.1Hz,1H),3.79(d,J=15.1Hz,1H),3.02-2.97(m,2H),2.83-2.78(m,1H),2.54-2.51(m,1H),2.29(s,3H),1.30(d,J=6.3Hz,3H),1.25(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ167.8,141.1,140.9,138.8,136.7,134.9,131.7,131.4,129.7,129.6,129.4,129.1,129.0,128.6,126.4,126.0,125.7,68.4,68.2,56.0,47.0,29.0,22.03,21.97,21.2;HRMS Calculated for C27H29NO2Na[M+Na]+422.2096,found 422.2104;HPLC:Chirapak AD-H column,230nm,30°C,n-hexane/i-propanol=90/10,flow=1.0mL/min,retention time 4.0min and 4.6min(maj).） 
N-(2-异丙氧羰基苄基)-1-间甲基苯基-1,2,3,4-四氢异喹啉(2h):99%产率,95%对映选择性,未知化合物,无色液体,mp 57-58°C,旋光[α]30 D=-18.0(浓度c 1.78,CHCl3),Rf=0.35(石油醚/乙酸乙酯为40/1).1H NMR(400MHz,CDCl3)δ7.72-7.64(m,2H),7.41(t,J=7.6Hz,1H),7.26-6.99(m,8H),6.76(d,J=7.7Hz,1H),5.18-5.12(m,1H),4.66(s,1H),3.95(d,J=15.0Hz,1H),3.80(d,J=15.1Hz,1H),3.03-2.99(m,2H),2.82-2.77(m,1H),2.58-2.51(m,1H),2.29(s,3H),1.31(d,J=6.3Hz,3H),1.25(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ167.8,143.9,141.1,138.7,137.7,134.9,131.7,131.4,130.6,129.6,129.4,129.1,128.6,128.1,128.0,127.0,126.4,126.0,125.7,68.7,68.4,56.1,47.2,29.1,22.04,21.96,21.6;高分辨质谱HRMS计算值C27H29NO2Na[M+Na]+422.2096,实际值422.2102;手性高效液相色谱HPLC:Chirapak AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为98/2,流速为1.0mL/min,液相保留时间5.6min和6.4min(主峰)。 
（N-(2-Isopropylcarbonyl benzyl)-1-(m-tolyl)-1,2,3,4-tetrahydroisoquinoline(2h):99%yield,95%ee,unknown compound,colorless oil,mp 57-58°C,[α]30 D=-18.0(c 1.78,CHCl3),Rf=0.35(petroleum ether/EtOAc 40/1).1H NMR(400MHz,CDCl3)δ7.72-7.64(m,2H),7.41(t,J=7.6Hz,1H),7.26-6.99(m,8H),6.76(d,J=7.7Hz,1H),5.18-5.12(m,1H),4.66(s,1H),3.95(d,J=15.0Hz,1H),3.80(d,J=15.1Hz,1H),3.03-2.99(m,2H),2.82-2.77(m,1H),2.58-2.51(m,1H),2.29(s,3H),1.31(d,J=6.3Hz,3H),1.25(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ167.8,143.9,141.1,138.7,137.7,134.9,131.7,131.4,130.6,129.6,129.4,129.1,128.6,128.1,128.0,127.0,126.4,126.0,125.7,68.7,68.4,56.1,47.2,29.1,22.04,21.96,21.6;HRMS Calculated for C27H29NO2Na[M+Na]+422.2096,found 422.2102;HPLC:Chirapak AD-H column,230nm,30°C,n-hexane/i-propanol=98/2,flow=1.0mL/min,retention time 5.6min  and 6.4min(maj).） 
N-(2-异丙氧羰基苄基)-1-对甲氧基苯基-1,2,3,4-四氢异喹啉(2i):99%产率,94%对映选择性,未知化合物,无色液体,旋光[α]30 D=-77.9(浓度c 2.60,CHCl3),Rf=0.15(石油醚/乙酸乙酯为40/1).1HNMR(400MHz,CDCl3)δ7.72-7.64(m,2H),7.43-7.39(m,1H),7.26-6.99(m,6H),6.82-6.74(m,3H),5.18-5.12(m,1H),4.66(s,1H),3.95(d,J=15.1Hz,1H),3.80(d,J=15.1Hz,1H),3.76(s,3H),3.03-2.97(m,2H),2.83-2.79(m,1H),2.58-2.51(m,1H),1.31(d,J=6.3Hz,3H),1.26(d,J=6.2Hz,3H).13CNMR(100MHz,CDCl3)δ167.8,158.8,141.1,138.8,136.1,134.9,131.7,131.4,130.8,129.7,129.4,129.1,128.6,126.4,126.0,125.7,113.6,68.4,67.8,55.9,55.3,47.0,29.0,22.0,21.9;高分辨质谱HRMS计算值C27H29NO3Na[M+Na]+438.2045,实际值438.2032;手性高效液相色谱HPLC:Chiracel Chirapak AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为98/2,流速为1.0mL/min,液相保留时间8.8min和9.9min(主峰)。（N-(2-Isopropylcarbonyl benzyl)-1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline(2i):99%yield,94%ee,unknown compound,colorless oil,[α]30 D=-77.9(c 2.60,CHCl3),Rf=0.15(petroleum ether/EtOAc 40/1).1H NMR(400MHz,CDCl3)δ7.72-7.64(m,2H),7.43-7.39(m,1H),7.26-6.99(m,6H),6.82-6.74(m,3H),5.18-5.12(m,1H),4.66(s,1H),3.95(d,J=15.1Hz,1H),3.80(d,J=15.1Hz,1H),3.76(s,3H),3.03-2.97(m,2H),2.83-2.79(m,1H),2.58-2.51(m,1H),1.31(d,J=6.3Hz,3H),1.26(d,J=6.2Hz, 3H).13CNMR(100MHz,CDCl3)δ167.8,158.8,141.1,138.8,136.1,134.9,131.7,131.4,130.8,129.7,129.4,129.1,128.6,126.4,126.0,125.7,113.6,68.4,67.8,55.9,55.3,47.0,29.0,22.0,21.9;HRMS Calculated for C27H29NO3Na[M+Na]+438.2045,found 438.2032;HPLC:Chiracel Chirapak AD-H column,230nm,30°C,n-hexane/i-propanol=98/2,flow=1.0mL/min,retention time 8.8min and 9.9min(maj).） 
N-(2-异丙氧羰基苄基)-1-间甲氧基苯基-1,2,3,4-四氢异喹啉(2j):97%产率,94%对映选择性,未知化合物,无色液体,旋光[α]20 D=-69.5(浓度c 2.55,CHCl3),Rf＝0.15(石油醚/乙酸乙酯为40/1).1H NMR(400MHz,CDCl3)δ7.72-7.67(m,2H),7.43-7.40(m,1H),7.27-7.01(m,5H),6.90-6.74(m,4H),5.18-5.12(m,1H),4.67(s,1H),3.98(d,J=15.1Hz,1H),3.81(d,J=15.1Hz,1H),3.74(s,3H),3.05-2.98(m,2H),2.84-2.78(m,1H),2.59-2.52(m,1H),1.31(d,J=6.3Hz,3H),1.25(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ167.8,159.6,145.6,141.1,138.3,134.8,131.7,131.4,129.7,129.4,129.1,129.0,128.6,126.5,126.1,125.7,122.4,115.4,112.6,68.5,68.4,56.1,55.2,47.1,28.9,22.0,21.9;高分辨质谱HRMS计算值C27H29NO3Na[M+Na]+438.2045,实际值438.2042;手性高效液相色谱HPLC:Chirapak AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为95/5,流速为1.0mL/min,液相保留时间5.7min(主峰)和6.3min。（N-(2-Isopropylcarbonyl benzyl)-1-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline(2j):97%yield,94%ee,unknown compound,colorless oil,[α]20 D=-69.5(c 2.55,CHCl3),Rf=0.15(petroleum ether/EtOAc 40/1).1H NMR(400MHz,CDCl3)δ7.72-7.67(m,2H),7.43-7.40(m,1H),7.27-7.01(m,5H),6.90-6.74(m,4H),5.18-5.12(m,1H),4.67(s,1H),3.98(d,J=15.1Hz,1H),3.81(d,J=15.1Hz,1H),3.74(s,3H),3.05-2.98(m,2H),2.84-2.78(m,1H),2.59-2.52(m,1H),1.31(d,J=6.3Hz,3H),1.25(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ167.8,159.6,145.6,141.1,138.3,134.8,131.7,131.4,129.7,129.4,129.1,129.0,128.6,126.5,126.1,125.7,122.4,115.4,112.6,68.5,68.4,56.1,55.2,47.1,28.9,22.0,21.9;HRMS Calculated for C27H29NO3Na[M+Na]+438.2045,found 438.2042;HPLC:Chirapak AD-H column,230nm,30°C,n-hexane/i-propanol=95/5,flow=1.0mL/min,retention time 5.7min(maj)and 6.3min.） 
N-(2-异丙氧羰基苄基)-1-对氯苯基-1,2,3,4-四氢异喹啉(2k):99%产率,94%对映选择性,未知化合物,无色液体,旋光[α]28 D=-77.7(浓度c 2.60,CHCl3),Rf＝0.35(石油醚/乙酸乙酯为40/1);1H NMR(400MHz,CDCl3)δ7.72(d,J=7.7Hz,1H),7.61(d,J=7.8Hz,1H),7.44-7.40(m,1H),7.28-7.00(m,8H),6.71(d,J=7.7Hz,1H),5.19-5.12(m,1H),4.68(s,1H),3.98(d,J=15.0Hz,1H),3.78(d,J=15.0Hz,1H),3.00-2.96(m,2H),2.84-2.79(m,1H),2.56-2.53(m,1H),1.31(d,J=6.3Hz,3H),1.26(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ167.7,142.7,140.8,137.9,134.9,133.0,131.6,131.5,131.1,129.8,129.3,129.0,128.8,128.4,126.6,126.3,125.8,68.4,67.7,56.0,47.0,28.7,22.0,21.9;高分辨质谱HRMS计算值C26H26NO2ClNa[M+Na]+442.1550,实际值442.1558;手性高效液相色谱HPLC:Chiracel AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为95/5,流速为1.0mL/min,液相保留时间5.1min和6.0min(主峰)。（N-(2-Isopropylcarbonyl benzyl)-1-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline(2k):99%yield,94%ee,colorless oil,unknown compound,[α]28 D=-77.7(c 2.60,CHCl3),Rf=0.35(petroleum ether/EtOAc 40/1);1H NMR(400MHz,CDCl3)δ7.72(d,J=7.7Hz,1H),7.61(d,J=7.8Hz,1H),7.44-7.40(m,1H),7.28-7.00(m,8H),6.71(d,J=7.7Hz,1H),5.19-5.12(m,1H),4.68(s,1H),3.98(d,J=15.0Hz,1H),3.78(d,J=15.0Hz,1H),3.00-2.96(m,2H),2.84-2.79(m,1H),2.56-2.53(m,1H),1.31(d,J=6.3Hz,3H),1.26(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ167.7,142.7,140.8,137.9,134.9,133.0,131.6,131.5,131.1,129.8,129.3,129.0,128.8,128.4,126.6,126.3,125.8,68.4,67.7,56.0,47.0,28.7,22.0,21.9;HRMSCalculated for C26H26NO2ClNa[M+Na]+442.1550,found 442.1558;Chiracel AD-H column,230nm,30 °C,n-hexane/i-propanol=95/5,flow=1.0mL/min,retention time 5.1min and 6.0min(maj).） 
N-(2-异丙氧羰基苄基)-1-对三氟甲基苯基-1,2,3,4-四氢异喹啉(2l):96%产率,93%对映选择性,未知化合物,无色液体,旋光[α]28 D=-58.5(浓度c 2.73,CHCl3),Rf＝0.35(石油醚/乙酸乙酯为10/1).1H NMR(400MHz,CDCl3)δ7.74-7.01(m,11H),6.70(d,J=7.8Hz,1H),5.18-5.12(m,1H),4.77(s,1H),4.03(d,J=14.9Hz,1H),3.77(d,J=15.0Hz,1H),3.03-2.98(m,2H),2.86-2.82(m,1H),2.62-2.60(m,1H),1.31(d,J=6.3Hz,3H),1.25(d,J=6.2Hz,3H).13C NMR(100MHz,CDCl3)δ167.7,148.3,140.6,137.3,135.0,131.7,131.5,130.0,129.9,129.5(q,JC-F=32.3Hz),129.4,129.0,128.9,126.7,126.5,125.9,125.2(q,JC-F=3.8Hz),68.5,67.9,56.2,46.9,28.6,22.0,21.9;19F NMR(376MHz,CDCl3)δ-62.4;高分辨质谱HRMS计算值C27H26NO2NaF3[M+Na]+476.1813,实际值476.1816;手性高效液相色谱HPLC:Chiracel OD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为95/5,流速为1.0mL/min,液相保留时间3.7min和4.4min(主峰)。 
（N-(2-Isopropylcarbonyl benzyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline(2l):96%yield,93%ee,unknown compound,colorless oil,[α]28 D=-58.5(c 2.73,CHCl3),Rf=0.35(petroleum ether/EtOAc 10/1).1H NMR(400MHz,CDCl3)δ7.74-7.01(m,11H),6.70(d,J=7.8Hz,1H),5.18-5.12(m,1H),4.77(s,1H),4.03(d,J=14.9Hz,1H),3.77(d,J=15.0Hz,1H),3.03-2.98(m,2H),2.86-2.82(m,1H),2.62-2.60(m,1H),1.31(d,J=6.3Hz,3H),1.25(d,J=6.2Hz,3H).13C NMR(100MHz,CDCl3)δ167.7,148.3,140.6,137.3,135.0,131.7,131.5,130.0,129.9,129.5(q,JC-F=32.3Hz),129.4,129.0,128.9,126.7,126.5,125.9,125.2(q,JC-F=3.8Hz),68.5,67.9,56.2,46.9,28.6,22.0,21.9;19F NMR(376MHz,CDCl3)δ-62.4;HRMS Calculated for C27H26NO2NaF3[M+Na]+476.1813,found 476.1816;HPLC:Chiracel OD-H column,230nm,30°C,n-hexane/i-propanol=95/5,flow=1.0mL/min,retention time 3.7min and 4.4min(maj).） 
N-(2-异丙氧羰基苄基)-1-对氟苯基-1,2,3,4-四氢异喹啉(2m):99%产率,94%对映选择性,未知化合物,无色液体,旋光[α]28 D=-60.3(浓度c 2.58,CHCl3),Rf＝0.35(石油醚/乙酸乙酯为40/1).1H NMR(400MHz,CDCl3)δ7.72(d,J=7.7Hz,1H),7.62(d,J=7.7Hz,1H),7.44-6.93(m,9H),6.72(d,J=7.8Hz,1H),5.19-5.12(m,1H),4.69(s,1H),3.97(d,J=15.0Hz,1H),3.79(d,J=15.0Hz,1H),3.03-2.97(m,2H),2.84-2.80(m,1H),2.60-2.54(m,1H),1.31(d,J=6.3Hz,3H),1.26(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ167.8,161.7(d,JC-F=243.6Hz),140.9,139.8(d,JC-F=3.3Hz),138.2,134.9,131.7,131.4,131.2(d,JC-F=7.9Hz),129.8,129.4,129.0,128.7,126.6,126.2,125.8,115.15(d,JC-F=21.1Hz),68.4,67.6,56.0,47.0,28.7,22.0,21.97;19F NMR(376MHz,CDCl3)δ-115.7;高分辨质谱HRMS计算值C26H26NO2NaF[M+Na]+426.1845,实际值426.1840;手性高效液相色谱HPLC:Chirapak AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为95/5,流速为1.0mL/min,液相保留时间5.0min和6.0min(主峰)。（N-(2-Isopropylcarbonyl benzyl)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline(2m):99%yield,94%ee,unknown compound,colorless oil,[α]28 D=-60.3(c 2.58,CHCl3),Rf=0.35(petroleum ether/EtOAc 40/1).1H NMR(400MHz,CDCl3)δ7.72(d,J=7.7Hz,1H),7.62(d,J=7.7Hz,1H),7.44-6.93(m,9H),6.72(d,J=7.8Hz,1H),5.19-5.12(m,1H),4.69(s,1H),3.97(d,J=15.0Hz,1H),3.79(d,J=15.0Hz,1H),3.03-2.97(m,2H),2.84-2.80(m,1H),2.60-2.54(m,1H),1.31(d,J=6.3Hz,3H),1.26(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ167.8,161.7(d,JC-F=243.6Hz),140.9,139.8(d,JC-F=3.3Hz),138.2,134.9,131.7,131.4,131.2(d,JC-F=7.9Hz),129.8,129.4,129.0,128.7,126.6,126.2,125.8,115.15(d,JC-F=21.1Hz),68.4,67.6,56.0,47.0,28.7,22.0,21.97;19F NMR(376MHz,CDCl3)δ-115.7;HRMS Calculated for C26H26NO2NaF[M+Na]+426.1845,found 426.1840;HPLC:Chirapak AD-H column,230nm,30°C,n-hexane/i-propanol=95/5,flow=1.0mL/min,retention time 5.0min and 6.0min(ma).） 
N-(2-异丙氧羰基苄基)-1-(3,5-二氟苯基)-1,2,3,4-四氢异喹啉(2n):99%产率,90%对映选择性,未知化合物,无色液体,旋光[α]29 D=-53.2(浓度c 2.58,CHCl3),Rf=0.35(石油醚/乙酸乙酯为40/1).1HNMR(400MHz,CDCl3)δ7.77(d,J=7.7Hz,1H),7.61(d,J=7.7Hz,1H),7.48-7.07(m,5H),6.87-6.67(m,4H),5.23-5.17(m,1H),4.70(s,1H),4.07(d,J=14.7Hz,1H),3.84(d,J=14.7Hz,1H),3.03-2.95(m,2H),2.89-2.82(m,1H),2.65-2.59(m,1H),1.35(d,J=6.3Hz,3H),1.30(d,J=6.3Hz,3H);13C NMR(100MHz,CDCl3)δ167.7,163.0(d,JC-F=246.7Hz),162.9(d,JC-F=246.6Hz),148.5(d,JC-F=7.9Hz),148.4(d,JC-F=8.1Hz),140.4,136.6,134.9,131.8,131.5,129.9,129.5,129.0,128.9,126.8,126.7,126.0,112.5(d,JC-F=6.6Hz),112.3(d,JC-F=6.6Hz),102.9(d,JC-F=25.3Hz),102.6(d,JC-F=25.4Hz),68.5,67.4,56.1,46.6,28.2,22.0,21.9;19F NMR(376MHz,CDCl3)δ-110.3;高分辨质谱HRMS计算值C26H25NO2NaF2[M+Na]+444.1751,实际值444.1759;手性高效液相色谱HPLC:Chirapak AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为95/5,流速为1.0mL/min,液相保留时间3.9min和4.2min(主峰)。（N-(2-Isopropylcarbonyl benzyl)-1-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline(2n):99%yield,90%ee,unknown compound,colorless oil,[α]29 D=-53.2(c 2.58,CHCl3),Rf=0.35(petroleum ether/EtOAc 40/1).1HNMR(400MHz,CDCl3)δ7.77(d,J=7.7Hz,1H),7.61(d,J=7.7Hz,1H),7.48-7.07(m,5H),6.87-6.67(m,4H),5.23-5.17(m,1H),4.70(s,1H),4.07(d,J=14.7Hz,1H),3.84(d,J=14.7Hz,1H),3.03-2.95(m,2H),2.89-2.82(m,1H),2.65-2.59(m,1H),1.35(d,J=6.3Hz,3H),1.30(d,J=6.3Hz,3H);13C NMR(100MHz,CDCl3)δ167.7,163.0(d,JC-F=246.7Hz),162.9(d,JC-F=246.6Hz),148.5(d,JC-F=7.9Hz),148.4(d,JC-F=8.1Hz),140.4,136.6,134.9,131.8,131.5,129.9,129.5,129.0,128.9,126.8,126.7,126.0,112.5(d,JC-F=6.6Hz),112.3(d,JC-F=6.6Hz),102.9(d,JC-F=25.3Hz),102.6(d,JC-F=25.4Hz),68.5,67.4,56.1,46.6,28.2,22.0,21.9;19F NMR(376MHz,CDCl3)δ-110.3;HRMSCalculated for C26H25NO2NaF2[M+Na]+444.1751,found 444.1759;HPLC:Chirapak AD-H column,230nm,30°C,n-hexane/i-propanol=95/5,flow=1.0mL/min,retention time 3.9min and 4.2min(maj).） 
N-(2-异丙氧羰基苄基)-3-苯基-1,2,3,4-四氢异喹啉(4a):94%产率,85%对映选择性,未知化合物,无色液体,旋光[α]29 D=-12.0(浓度c 2.25,CHCl3),Rf=0.35(石油醚/乙酸乙酯为20/1).1H NMR(400MHz,CDCl3)δ7.75-7.70(m,2H),7.43-7.08(m,10H),6.94(d,J=7.3Hz,1H),5.16-5.10(m,1H),3.95-3.76(m,4H),3.56(d,J=15.7Hz,1H),3.16(d,J=6.3Hz,2H),1.26-1.24(m,6H);13C NMR(100MHz,CDCl3)δ167.8,142.4,140.7,134.9,134.5,131.6,131.4,129.7,129.4,128.6,128.3,128.0,127.4,126.5,126.4,126.3,125.8,68.4,63.7,56.1,53.9,36.9,22.0,21.9.高分辨质谱HRMS计算值C26H28NO2[M+H]+386.2120,实际值386.2126;手性高效液相色谱HPLC:Chirapak AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为90/10,流速为1.0mL/min,液相保留时间5.1min(主峰)和8.8min。（N-(2-Isopropylcarbonyl benzyl)-3-phenyl-1,2,3,4-tetrahydroisoquinoline(4a):94%yield,85%ee,unknown compound,colorless oil,[α]29 D=-12.0(c 2.25,CHCl3),Rf=0.35(petroleum ether/EtOAc 20/1).1H NMR(400MHz,CDCl3)δ7.75-7.70(m,2H),7.43-7.08(m,10H),6.94(d,J=7.3Hz,1H),5.16-5.10(m,1H),3.95-3.76(m,4H),3.56(d,J=15.7Hz,1H),3.16(d,J=6.3Hz,2H),1.26-1.24(m,6H);13C NMR(100MHz,CDCl3)δ167.8,142.4,140.7,134.9,134.5,131.6,131.4,129.7,129.4,128.6,128.3,128.0,127.4,126.5,126.4,126.3,125.8,68.4,63.7,56.1,53.9,36.9,22.0,21.9.HRMS Calculated for C26H28NO2[M+H]+386.2120,found 386.2126;HPLC:Chirapak AD-H column,230nm,30°C,n-hexane/i-propanol=90/10,flow=1.0mL/min,retention time 5.1min(maj)and 8.8min.） 
N-(2-异丙氧羰基苄基)-3-对甲氧基苯基-1,2,3,4-四氢异喹啉(4b):99%产率,80%对映选择性,未知化 合物,无色液体,旋光[α]29 D=-14.1(浓度c 2.60,CHCl3),Rf=0.25(石油醚/乙酸乙酯为20/1).1H NMR(400MHz,CDCl3)δ7.76-7.73(m,2H),7.45(t,J=7.6Hz,1H),7.30-6.85(m,9H),5.20-5.14(m,1H),3.98-3.77(m,7H),3.59(d,J=15.8Hz,1H),3.18(d,J=6.0Hz,2H),1.31-1.28(m,6H);13C NMR(100MHz,CDCl3)δ167.9,158.9,140.8,135.0,134.6,134.4,131.7,131.4,129.6,129.4,129.1,128.3,126.4,126.37,126.3,125.8,113.9,68.4,62.8,56.0,55.3,53.9,36.8,22.0,21.9.高分辨质谱HRMS计算值C27H29NO3Na[M+Na]+438.2045,实际值438.2047;手性高效液相色谱HPLC:Chirapak AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为90/10,流速为1.0mL/min,液相保留时间5.9(主峰)min和8.7min。（N-(2-Isopropylcarbonyl benzyl)-3-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline(4b):99%yield,80%ee,unknown compound,colorless oil,[α]29 D=-14.1(c 2.60,CHCl3),Rf=0.25(petroleum ether/EtOAc 20/1).1H NMR(400MHz,CDCl3)δ7.76-7.73(m,2H),7.45(t,J=7.6Hz,1H),7.30-6.85(m,9H),5.20-5.14(m,1H),3.98-3.77(m,7H),3.59(d,J=15.8Hz,1H),3.18(d,J=6.0Hz,2H),1.31-1.28(m,6H);13C NMR(100MHz,CDCl3)δ167.9,158.9,140.8,135.0,134.6,134.4,131.7,131.4,129.6,129.4,129.1,128.3,126.4,126.37,126.3,125.8,113.9,68.4,62.8,56.0,55.3,53.9,36.8,22.0,21.9.HRMS Calculated forC27H29NO3Na[M+Na]+438.2045,found 438.2047;HPLC:Chirapak AD-H column,230nm,30°C,n-hexane/i-propanol=90/10,flow=1.0mL/min,retention time 5.9(m aj)min and 8.7min.） 
N-(2-异丙氧羰基苄基)-3-异丙基基-1,2,3,4-四氢异喹啉(4c):99%产率,43%对映选择性,未知化合物,无色液体,旋光[α]29 D=-5.5(浓度c 2.60,CHCl3),Rf=0.05(石油醚/乙酸乙酯为20/1).1H NMR(400MHz,CDCl3)δ7.77-7.74(m,2H),7.46(t,J=7.5Hz,1H),7.29-7.07(m,4H),6.91(d,J=7.0Hz,1H),5.16-5.10(m,1H),4.04-3.95(m,2H),3.77(d,J=16.7Hz,1H),3.65(d,J=16.7Hz,1H),2.97-2.92(m,1H),2.73-2.60(m,2H),1.84-1.75(m,1H),1.27-1.25(m,6H),1.04(d,J=6.6Hz,3H),0.93(d,J=6.6Hz,3H);13CNMR(100MHz,CDCl3)δ167.7,141.7,135.0,134.9,131.5,131.4,130.1,129.5,129.1,127.0,126.4,126.1,125.8,68.3,64.2,52.7,51.4,29.9,27.0,22.0,20.7,20.0;高分辨质谱HRMS计算值C23H29NO2Na[M+Na]+374.2096,实际值374.2108;手性高效液相色谱HPLC:Chirapak AD-H手性柱,荧光吸收为230nm,温度为30°C,正己烷/异丙醇为97/3,流速为1.0mL/min,液相保留时间4.0min和4.6min(主峰)。（N-(2-Isopropylcarbonyl benzyl)-3-isopropyl-1,2,3,4-tetrahydroisoquinoline(4c):99%yield,43%ee,unknown compound,colorless oil,[α]29 D=-5.5(c 2.60,CHCl3),Rf=0.05(petroleum ether/EtOAc 20/1).1H NMR(400MHz,CDCl3)δ7.77-7.74(m,2H),7.46(t,J=7.5Hz,1H),7.29-7.07(m,4H),6.91(d,J=7.0Hz,1H),5.16-5.10(m,1H),4.04-3.95(m,2H),3.77(d,J=16.7Hz,1H),3.65(d,J=16.7Hz,1H),2.97-2.92(m,1H),2.73-2.60(m,2H),1.84-1.75(m,1H),1.27-1.25(m,6H),1.04(d,J=6.6Hz,3H),0.93(d,J=6.6Hz,3H);13C NMR(100MHz,CDCl3)δ167.7,141.7,135.0,134.9,131.5,131.4,130.1,129.5,129.1,127.0,126.4,126.1,125.8,68.3,64.2,52.7,51.4,29.9,27.0,22.0,20.7,20.0;HRMS Calculated forC23H29NO2Na[M+Na]+374.2096,found 374.2108;HPLC:Chirapak AD-H column,230nm,30°C,n-hexane/i-propanol=97/3,flow=1.0mL/min,retention time 4.0min and 4.6min(maj).）产率为分离收率，产物的对映体过量用手性液相色谱测定，见表2。 
表2.铱催化不对称异喹啉氢化合成各种手性四氢异喹啉衍生物2 
Figure DEST_PATH_IMAGE002
Figure BDA00002255270400111
本发明对异喹啉的进行催化不对称氢化得到相应的手性四氢异喹啉衍生物，其对映体过量值可达到96%。本发明操作简便实用，对映选择性高，产率好，且反应具有原子经济性，对环境友好。 

Claims (8)

1.铱催化异喹啉不对称氢化合成手性四氢异喹啉衍生物方法，其催化体系为金属铱的手性双膦配合物，反应通式和反应条件如下：
Figure FDA00002255270300011
式中：
温度：25-60℃；
溶剂：二氯甲烷、甲苯、四氢呋喃中的一种或两种以上的混合体系；
氢气压力：13-50个大气压；
时间：20-24小时；
催化剂为(1,5-环辛二烯)氯化铱二聚体和双膦配体的配合物；
所述X为氯、溴、碘、三氟甲磺酸根、高氯酸根、四氟化硼及六氟化磷中的一种离子；
所述Ar为苯基或含取代基的苯基，苯基上的取代基为CF3、Me、MeO、COOMe、COOEt、COOiPr及COOtBu中的一种取代基或二种取代基；
所述R1或R3为C1-C20的烷基、1或2-位萘基、苯基或含有取代基的苯基，苯基上的取代基为F、Cl、CF3、Me、MeO、COOMe中的一种取代基或二种取代基或三种取代基或四种取代基。
2.如权利要求1所述的方法，其特征在于：所述(1,5-环辛二烯)氯化铱二聚体和双膦配体的配合物是由铱的金属前体(1,5-环辛二烯)氯化铱二聚体([Ir(COD)Cl]2)和手性双膦配体在二氯甲烷与四氢呋喃的混合溶剂(二氯甲烷与四氢呋喃体积比为1:1)中于室温搅拌10-15分钟制备而成；(1,5-环辛二烯)氯化铱二聚体与手性双膦配体的摩尔比为1:2.0-2.2，(1,5-环辛二烯)氯化铱在混合溶剂中的摩尔浓度为0.002-0.01mol/L。
3.如权利要求1或2所述的方法，其特征在于：所述手性双膦配体为(R)-MeO-Biphep,(R)-SynPhos,(R)-SegPhos,(R)-BINAP，(R)-DifluorPhos，(R)-P-Phos和(Rax，S，S)-C3*-TunePhos中的一种。
4.如权利要求1所述的方法，其特征在于：所述X为异喹啉盐的阴离子，阴离子为氯、溴、碘、三氟甲磺酸根、高氯酸根、四氟化硼及六氟化磷中的一种离子。
5.如权利要求1所述的方法，其特征在于：Ar为苯基或含取代基的苯基，取代基为CF3、Me、MeO、CO2Me、CO2Et、CO2 iPr及CO2 tBu中的一种取代基或二种取代基或三种取代基或四种取代基。
6.如权利要求1所述的方法，其特征在于：以(1,5-环辛二烯)氯化铱二聚体计，所述配合物摩尔量为氢化底物摩尔量的0.5%到2%。
7.如权利要求1所述的方法，其特征在于：所述溶剂用量为每0.25毫摩尔氢化底物用2到4毫升。
8.如权利要求1所述的方法，其特征在于：所述反应式为对1-位或3-位取代异喹啉盐的氢化得到相应的手性手性异喹啉衍生物，配体为(Rax,S，S)-C3*-TunePhos，溶剂为四氢呋喃与二氯甲烷的混合溶剂(二氯甲烷与四氢呋喃体积比为1:1)，温度为室温，氢气压力为600psi所述结果最佳，对映体过量可达到96%。
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CN110551285A (zh) * 2018-06-01 2019-12-10 中国科学院大连化学物理研究所 一种铱催化脱氢偶联合成聚硅醚

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101558043A (zh) * 2006-12-12 2009-10-14 马林克罗特公司 由二氢异喹啉制备六氢异喹啉

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101558043A (zh) * 2006-12-12 2009-10-14 马林克罗特公司 由二氢异喹啉制备六氢异喹啉

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
LEI SHI ET AL.: "Enantioselective Iridium-Catalyzed Hydrogenation of 3,4-disubstituted Isoquinolines", 《ANGEW.CHEM.INT.ED.》 *
RYO NAITO ET AL.: "Synthesis and Antimuscarinic Properties of Quinuclidin-3-yl1,2,3,4-Tetrahydroisoquinoline-2-carboxylate Derivatives as Novel Muscarinic Receptor Antagonists", 《J.MED.CHEM.》 *
SHENG-MEI LU ET AL.: "Asymmetric Hydrogenation of Quinolines and Isoquinolines Activated by Chloroformates", 《ANGEW.CHEM.INT.ED.》 *
冯志强等: "四氢异喹啉衍生物的合成研究", 《有机化学》 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108026047A (zh) * 2015-09-01 2018-05-11 默克专利股份公司 吡喹酮及其前体的生产方法
CN106883173A (zh) * 2015-12-15 2017-06-23 中国科学院大连化学物理研究所 一种合成手性三氟甲硫基环状胺的方法
CN106883173B (zh) * 2015-12-15 2019-11-08 中国科学院大连化学物理研究所 一种合成手性三氟甲硫基环状胺的方法
CN106995413A (zh) * 2016-01-25 2017-08-01 中国科学院大连化学物理研究所 一种铱催化氢化不对称合成哌嗪衍生物的方法
CN107540606A (zh) * 2016-06-29 2018-01-05 中国科学院大连化学物理研究所 一种铱催化的双向对映选择性合成手性四氢异喹啉的方法
CN107540606B (zh) * 2016-06-29 2020-09-01 中国科学院大连化学物理研究所 一种铱催化的双向对映选择性合成手性四氢异喹啉的方法
CN108101909A (zh) * 2016-11-24 2018-06-01 中国科学院大连化学物理研究所 铱催化吡咯[1,2-a]并吡嗪不对称氢化合成手性胺的方法
CN108101909B (zh) * 2016-11-24 2021-01-12 中国科学院大连化学物理研究所 铱催化吡咯[1,2-a]并吡嗪不对称氢化合成手性胺的方法
CN109422682A (zh) * 2017-08-24 2019-03-05 中国科学院大连化学物理研究所 一种通过卤键活化异喹啉不对称氢化的方法
CN110551285A (zh) * 2018-06-01 2019-12-10 中国科学院大连化学物理研究所 一种铱催化脱氢偶联合成聚硅醚
CN110041255A (zh) * 2019-04-28 2019-07-23 中国人民解放军第四军医大学 索利那新中间体的不对称合成方法
CN110396405A (zh) * 2019-07-14 2019-11-01 湖南科技大学 一种基于异喹啉的比率型氟离子检测探针及其制备方法和应用
CN110396405B (zh) * 2019-07-14 2024-03-29 湖南科技大学 一种基于异喹啉的比率型氟离子检测探针及其制备方法和应用

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