CN109422682A - 一种通过卤键活化异喹啉不对称氢化的方法 - Google Patents

一种通过卤键活化异喹啉不对称氢化的方法 Download PDF

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CN109422682A
CN109422682A CN201710734493.5A CN201710734493A CN109422682A CN 109422682 A CN109422682 A CN 109422682A CN 201710734493 A CN201710734493 A CN 201710734493A CN 109422682 A CN109422682 A CN 109422682A
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isoquinolin
octadiene
cyclo
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周永贵
陈木旺
姬悦
王杰
高翔
孙蕾
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Dalian Institute of Chemical Physics of CAS
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    • 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
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
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Abstract

一种通过卤键活化异喹啉不对称氢化的方法，其用到的催化体系是铱的手性双膦配合物，活化剂为卤化物。反应能在下列条件下进行，温度：25‑100℃；溶剂：四氢呋喃；压力：13‑100个大气压；底物和催化剂的比例是50/l；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。异喹啉氢化得到相应的手性四氢异喹啉衍生物，其对映体过量可达到99％。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，对环境友好等优点。

Description

一种通过卤键活化异喹啉不对称氢化的方法
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含氟吡啶合成手性含氟哌啶衍生物的方法。
技术背景
手性1,2,3,4-四氢异喹啉是一类极其重要的生物碱中间体，广泛存在于天然产物和医药化学品中，具有广谱的生理活性和药理活性，如：抗病毒、镇静、缓解肌肉紧张、降压和致幻作用等。因此对该类化合物的合成和生物活性研究引起了有机化学家和药学界的广泛重视。下面式1的就有药物活性含有手性四氢异喹啉的结构单元：
鉴于手性四氢异喹啉及其衍生物在药物和合成化学领域中的重要性，化学家们已经发展了一些方法来合成该类化合物。但是高对映选择性和高活性地合成该类化合物的方法仍然比较少。到目前为止，仅有少数几例报道通过不对称氢化用于手性的四氢异喹啉及其衍生物的合成。2006年，zhou小组首次采用氯甲酸酯活化底物的策略实现了1-取代异喹啉衍生物的不对称氢化，但是只能获得中等的对映选择性和产率，并且需要脱除酯基的保护。(文献1:S.-M.Lu,Y.-Q.Wang,X.-W.Han,Y.-G.Zhou,Angew.Chem.Int.Ed.2006,45,2260.)。2012年，zhou小组又报道了3,4-二取代异喹啉的高非对映选择性和高对映选择性的氢化研究，但是底物一般是官能团化的异喹啉(文献2:L.Shi,Z.-S.Ye,L.-L.Cao,R.-N.Guo,Y.Hu,Y.-G.Zhou,Angew.Chem.Int.Ed.2012,51,8286.)zhou小组于2013年又采用苄溴活化的策略实现了异喹啉的不对称氢化(文献3:Z.-S.Ye,R.-N.Guo,X.-F.Cai,M.-W.Chen,L.Shi,Y.-G.Zhou,Angew.Chem.Int.Ed.2013,52,3685.)。2013年，Mishima等报道了采用盐酸盐活化的策略实现了异喹啉的不对称氢化(文献4:a)A.Iimuro,K.Yamaji,S.Kandual,T.Nagano,Y.Kita,K.Mishima,Angew.Chem.Int.Ed.2013,52,2046；b)Y.Kita,K.Yamaji,K.Higashida,K.Sathaiah,A.Limuro,K.Mashima,Chem.Eur.J.2015,21,1915.)。其后，zhang小组也采用盐酸盐的策略实现异喹啉的不对称氢化(文献5:J.Wen,R.Tan,S.Liu,Q.Zhao,X.Zhang,Chem.Sci.2016,7,3047.)。
从上述例子中，目前异喹啉的不对称氢化已取得了一些不错的结果，但是氯甲酸酯、苄溴、盐酸等活化剂活化底物策略合成手性四氢异喹啉衍生物。它需要上保护和去保护，而通过简单异喹啉的直接不对称氢化报道却很少。我们通过卤化物和异喹啉形成卤键，然后通过金属催化剂实现异喹啉的直接不对称氢化，反应速度快、产物的分离方便、副反应少且避免上保护和去保护的操作。
发明内容
本发明的目的是提供一种通过卤键活化异喹啉不对称氢化合成手性四氢异喹啉的方法，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。
为实现上述目的，本发明的技术方案如下：
一种通过卤键活化异喹啉不对称氢化的方法，其催化体系为铱的手性双膦配合物，活化剂为卤化物。反应式和条件如下：
式中：
温度：25-100℃，优选80℃；
溶剂：二氯甲烷、甲苯、乙酸乙酯、二氧六环、四氢呋喃中的一种或两种以上的混合,优选四氢呋喃；
氢气压力：13-100个大气压,优选80个大气压；
时间：20-48小时,优选48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；
所述卤化物为N-碘代丁二酰亚胺、N-溴代丁二酰亚胺、N-氯代丁二酰亚胺、三氯异氰尿酸、二溴海因、二氯海因、溴氯海因等的一种；
所述Ar为苯基及含取代基的苯基，取代基为-CF3、Me、MeO、Ph以及F，取代基可以是其中的一种，或二种取代基或三种取代基或四种，取代基的位置为苯基的2位至6位；Ar为1或2-位萘基；
所述R1,R2,R3可以为苯基及含取代基的苯基，取代基为-CF3、Me、MeO、Ph以及F，取代基可以是其中的一种，或二种取代基或三种取代基或四种，取代基的位置为苯基的2位至6位；也可以为C1-C20的烷基。
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)和手性双膦配体在四氢呋喃中室温搅拌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中的一种。
所述配合物摩尔量为氢化底物摩尔量的0.5％到3％。
所述溶剂用量为每0.125毫摩尔氢化底物用2到4毫升。
所述反应式为对异喹啉的氢化得到相应的手性四氢异喹啉衍生物，配体为(R)-SegPhos，溶剂为四氢呋喃，卤化物为三氯异氰尿酸，温度为80度，氢气压力为1200psi所述结果最佳，对映体过量可达到99％。
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，分离方便，能获得高的对映体过量纯品。
2.能得到各种类型的手性四氢异喹啉衍生物。
3.催化剂制备方便，反应操作简便实用。
4.无需上保护和去保护操作。
5、比较传统合成方法，此方法采用少量的手性催化剂就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，同时底物范围较广泛。
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1毫升四氢呋喃，室温搅拌10-30分钟，然后加入卤化物搅拌10-30分钟，将异喹啉(0.25毫摩尔)和加入到有催化剂的反应瓶中，在加入2毫升四氢呋喃。将反应瓶放入一个不锈钢的高压釜中，通入氢气1200psi，80度下反应20-48小时。慢慢释放氢气，体系加入饱和Na2CO3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10:1-5:1)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.不对称异喹啉氢化溶剂、配体和卤化物的筛选
实施例1：卤键活化铱催化不对称异喹啉不对称氢化
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(R)-SegPhos(0.0055毫摩尔)的反应瓶中加入1毫升四氢呋喃，室温搅拌10-30分钟，然后加入添加物三氯异氰尿酸(TCCA)(0.092毫摩尔)搅拌10-30分钟，在加入异喹啉(0.25毫摩尔)和2毫升四氢呋喃。将反应瓶放入一个不锈钢的高压釜中，通入氢气1200psi，80度下反应20-48小时。慢慢释放氢气，体系加入饱和Na2CO3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10:1-5:1)分离得到纯的产物，反应式如下：
(R)-(-)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline(2a):known compound,pale yellow solid,yield:96％,13.0min,t2＝15.5min(maj).
(R)-(-)-1-(4-(Trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline(2b):known com-pound,pale yellow solid,yield:95％,ee:96％,[α]20 D＝-28.6(c0.66,CHCl3)[lit.:for(+)-isomer[α]20 D＝+17.0(c 1.0,CH2Cl2)for 98％ee],Rf＝0.10(ethyl acetate)；1H NMR(400MHz,CDCl3)δ7.57(d,J＝8.0Hz,2H),7.39
(R)-(-)-1-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline(2c):known compound,pale yellow solid,yield:82％,ee:96％,[α]20 D＝-15.8(c0.44,CHCl3)[lit.:[α]20 D＝-29.6(c 0.5,CH2Cl2)for 88％ee],Rf＝0.21(ethylacetate)；1H NMR(400MHz,CDCl3)δ7.19-7.12(m,4H),7.05-7.01(m,1H),6.86(d,J＝
(R)-(-)-1-p-Tolyl-1,2,3,4-tetrahydroisoquinoline(2d):known compound,pale yellow solid,yield:91％,
(R)-(-)-1-m-Tolyl-1,2,3,4-tetrahydroisoquinoline(2e):known compound,pale yellow solid,yield:
80/20,detector:254nm,flow rate:0.70mL/min,30℃),t1＝14.0min(maj),t2＝15.0min.
(R)-(+)-1-Isopropyl-1,2,3,4-tetrahydroisoquinoline(2f):known compound,pale yellow oil,yield:15.7；Enantiomeric excess was determined by HPLC for the correspondingbenzamide(AD-H column,Hexanes/i-PrOH＝70/30,detector:230nm,flow rate:0.70mL/min,30℃),t1＝8.1min(maj),t2＝11.7min.
(R)-(+)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline(2g):known compound,pale yellowsolid,yield:76％,ee:85％,[α]20 D＝+32.4(c0.51,CHCl3)[lit.:[α]29 D＝+10.4(c 0.50,CHCl3)for 94％ee],Rf＝0.2(dichloromethane/MeOH＝15/1)；1H NMR(400MHz,CDCl3)δ7.34-7.24(m,5H),6.63(s,1H),
(1R,3R)-(-)-1,3-Diphenyl-1,2,3,4-tetrahydroisoquinoline(2h):known compound,pale yellow solid,t2＝16.8min(maj).
(1R,3R)-(-)-1,3-Diphenyl-3-p-tolyl-1,2,3,4-tetrahydroisoquinoline(2i):pale yellow oil,yield:90％,ee:99％,[α]20 D＝-19.9(c 0.67,CHCl3),Rf＝0.72(hexanes/ethyl acetate 30:1)；1H NMR(400MHz,CDCl3)δ7.45-7.25(m,7H),7.23-7.09(m,4H),7.04(dd,J＝6.3,4.2Hz,1H),6.74(t,J＝7.1Hz,1H),5.28(s,1H),HRMS(ESI)m/z Calculated for C22H22N[M+H]+300.1747,found 300.1752.
(1R,3R)-(-)-3-(4-Methoxyphenyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline(2j):pale yellow solid,m.p.＝143-145℃,yield:86％,ee:98％,[α]20 D＝-22.2(c 0.68,CHCl3)Rf＝0.71(hexanes/ethyl acetate30:1)；1H NMR(400MHz,CDCl3)δ7.46-7.29(m,7H),7.19-7.11(m,2H),7.11-7.01(m,1H),6.91(d,J＝Hexanes/i-PrOH＝95/5,detector:230nm,flow rate:0.8mL/min,30℃),t1＝7.6min,t2＝10.3min(maj)；HRMS(ESI)m/z Calculated for C22H22NO[M+H]+316.1696,found 316.1701.
126.7,126.2,125.8,113.8,63.7,59.3,55.3,39.1；Enantiomeric excess wasdetermined by HPLC(OD-H column,Hexanes/i-PrOH＝95/5,detector:230nm,flow rate:0.8mL/min,30℃),t1＝8.3min(maj),t2＝12.0min.
HPLC(AD-H column,Hexanes/i-PrOH＝95/5,detector:230nm,flow rate:0.8mL/min,30℃),t1＝10.5min,t2＝14.6min(maj)；HRMS(ESI)m/z Calculated for C22H22NO[M+H]+316.1696,found 316.1700.
(1R,3R)-(-)-1,3-Bis(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline(2m):pale yellow solid,the known compound,yield:92％,ee:91％,[α]20 D＝-30.3(c 0.72,CHCl3)[lit.:for(1S,3S)-isomer[α]20 D＝+37.3(c 1.0,CHCl3)for 98％ee],Rf＝0.18(hexanes/ethyl acetate 20:1)；1H NMR(400MHz,CDCl3)δAr＝4-MeOC6H4 138.7,137.5,132.1,130.6,129.6,129.5,128.0,127.6,115.8,115.7,65.7,60.6,57.2,57.1,41.0；Enantiomeric excess was determined by HPLC(OD-Hcolumn,Hexanes/i-PrOH＝98/2,detector:230nm,flow rate:1.0mL/min,30℃),t1＝14.2min(maj),t2＝16.3min.
(1R,3S)-(-)-3-Butyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline(2n):paleyellow oil,yield:97％,ee:90％,[α]20 D＝-26.3(c 0.64,CHCl3)Rf＝0.40(hexanes/ethyl acetate 20:1)；1H NMR(400MHz,CDCl3)δ7.36-7.28(m,5H),7.13(d,J＝4.0Hz,2H),7.01(dt,J＝8.4,4.3Hz,1H),6.67(d,J＝7.7Hz,1H),5.11(s,
(1R,3R)-(+)-1-Cyclohexyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline(2o):known compound,pale95/5,detector:230nm,flow rate:0.8mL/min,30℃),t1＝14.3min(maj),t2＝18.7min.
(3R,4R)-(-)-4-Fluoro-6-methyl-3-propyl-1,2,3,4-tetrahydroisoquinoline(2p):colorless oil,the known compound,91％yield,93％ee,[α]20 D＝-57.9(c0.47,CHCl3)[lit.:[α]20 D＝-22.9(c 0.97,CHCl3)for 91％ee],Rf＝0.30(hexanes/EtOAc 5:1)；1H NMR(400MHz,CDCl3)δ7.23-7.07(m,2H),6.99(d,J＝7.7Hz,21.0Hz),47.9(d,J＝1.1Hz),33.8(d,J＝4.4Hz),21.0,19.4,14.2；19F NMR(376MHz,CDCl3)δ-172.5；Enantiomeric excess was determined by HPLC for the correspondingbenzamide(OD-H column,Hexanes/i-PrOH＝95/5,detector:254nm,flow rate:0.8mL/min,30℃)t1＝10.0min,t2＝10.8min(maj).
(3R,4R)-(-)-3-Butyl-4-fluoro-6-methyl-1,2,3,4-tetrahydroisoquinoline(2q):colorless oil,the known compound,83％yield,93％ee,[α]20 D＝-55.0(c 0.46,CHCl3)[lit.:[α]20 D＝-57.0(c 1.0,CHCl3)for 91％ee],Rf 132.2,131.7(d,J＝2.2Hz),130.6(d,J＝4.4Hz),125.9(d,J＝2.8Hz),87.(d,J＝170.1Hz),57.3(d,J＝21.0Hz),48.1(d,J＝1.6Hz),31.6(d,J＝4.7Hz),28.6,23.0,21.1,14.2；19F NMR(376MHz,CDCl3)δ-172.5；Enantiomeric excess was determined by HPLCfor the corresponding benzamide(OD-H column,Hexanes/i-PrOH＝95/5,detector:254nm,flow rate:0.8mL/min,30℃)t1＝8.9min,t2＝9.5min(maj).
(3R,4R)-(-)-3-Butyl-6-chloro-4-fluoro-1,2,3,4-tetrahydroisoquinoline(2r):colorless oil,the known compound,94％yield,92％ee,[α]20 D＝-54.9(c 0.57,CHCl3)[lit.:[α]20 D＝-55.0(c 0.90,CHCl3)for 93％ee],Rf＝0.15(hexanes/EtOAc 2:1)；1H NMR(400MHz,CDCl3)δ7.38(s,1H),7.34-7.23(m,1H),7.05(d,J＝8.221.0Hz),47.8(d,J＝1.0Hz),31.3(d,J＝5.0Hz),28.5,23.0,14.2；19F NMR(376MHz,CDCl3)δ-173.6；Enantiomeric excess was determined by HPLC for the correspondingbenzamide(IC column,Hexanes/i-PrOH＝90/10,detector:254nm,flow rate:0.8mL/min,30℃)t1＝13.5min,t2＝17.4min(maj).
(3R,4R)-(-)-3-Butyl-4,7-difluoro-1,2,3,4-tetrahydroisoquinoline(2s):the known compound,colorless oil,94％yield,92％ee,[α]20 D＝-70.9(c 0.53,CHCl3)[lit.:[α]20 D＝-70.2(c 0.86,CHCl3)for91％ee],Rf＝0.35(hexanes/EtOAc2:1)；1H NMR(400MHz,CDCl3)δ7.37(t,J＝6.1Hz,1H),6.96(t,J(dd,J＝22.0Hz,J＝4.0Hz),112.5(dd,J＝21.0Hz,J＝3.0Hz),86.1(d,J＝170.0Hz),57.3(d,J＝21.0Hz),48.4(t,J＝2.0Hz),31.5(d,J＝5.0Hz),28.6,23.0,14.2；19F NMR(376MHz,CDCl3)δ-111.1(d,J＝8.8Hz),-171.5(d,J＝8.2Hz)；Enantiomeric excess wasdetermined by HPLC for the corresponding benzamide(IA column,Hexanes/i-PrOH＝80/20,detector:254nm,flow rate:0.8mL/min,30℃)t1＝7.8min(maj),t2＝9.6min.
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
本发明对异喹啉的不对称氢化得到相应的手性四氢异喹啉衍生物，其对映体过量可达到99％。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、避免上保护和去保护操作等优点。

Claims (7)

1.一种通过卤键活化异喹啉不对称氢化的方法，其催化体系为铱的手性双膦配合物，活化剂为卤化物；反应式和条件如下：
式中：
温度：25-100℃，优选80℃；
溶剂：二氯甲烷、甲苯、乙酸乙酯、二氧六环、四氢呋喃中的一种或两种以上的混合,优选四氢呋喃；
氢气压力：13-100个大气压，优选80个大气压；
时间：20-48小时，优选48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；
所述卤化物为N-碘代丁二酰亚胺、N-溴代丁二酰亚胺、N-氯代丁二酰亚胺、三氯异氰尿酸、二溴海因、二氯海因、溴氯海因等的一种或二种以上；
所述Ar为苯基及含取代基的苯基，取代基为-CF3、Me、MeO、Ph以及F，取代基可以是其中的一种，或二种取代基或三种取代基或四种，取代基的位置为苯基的2位至6位，Ar为1或2-位萘基；
所述R1,R2,R3可以为苯基及含取代基的苯基，取代基为-CF3、Me、MeO、Ph以及F取代基可以是其中的一种，或二种取代基或三种取代基或四种，取代基的位置为苯基的2位至6位，也可以为C1-C20的烷基。
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)和手性双膦配体在四氢呋喃中室温搅拌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。
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中的一种或二种以上。
4.如权利要求1所述的方法，其特征在于：卤化物摩尔量为氢化底物摩尔量的1-3当量。
5.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3％。
6.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。
7.如权利要求1所述的方法，其特征在于：所述反应式为对异喹啉的氢化得到相应的手性含氟哌啶衍生物，配体为(R)-SegPhos，溶剂为四氢呋喃，卤化物为三氯异氰尿酸，温度为80度，氢气压力为1200psi所述结果最佳，对映体过量可达到99％。
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