CN106995413A - 一种铱催化氢化不对称合成哌嗪衍生物的方法 - Google Patents

一种铱催化氢化不对称合成哌嗪衍生物的方法 Download PDF

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CN106995413A
CN106995413A CN201610048339.8A CN201610048339A CN106995413A CN 106995413 A CN106995413 A CN 106995413A CN 201610048339 A CN201610048339 A CN 201610048339A CN 106995413 A CN106995413 A CN 106995413A
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anion
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周永贵
黄文学
柳莲今
吴波
孙蕾
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Dalian Institute of Chemical Physics of CAS
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Abstract

一种铱催化不对称氢化合成手性哌嗪生物的方法，其用到的催化剂是铱的手性双膦配合物。反应能在下列条件下进行，温度：‑20‑70℃；溶剂：甲苯、四氢呋喃、乙酸乙酯；压力：10‑80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)氯化铱二聚体和手性双膦的配合物。3‑取代、3,5‑二取代和2,3‑二取代的吡嗪盐均能很好地被氢化，得到相应的手性哌嗪衍生物，对映体过量最高可达96％。本发明操作简便，原料易得，对映选择性高，产率好，为3‑取代、3,5‑二取代以及2,3‑二取代的哌嗪衍生物的合成提供了一条原子经济性，环境友好的路线。

Description

一种铱催化氢化不对称合成哌嗪衍生物的方法
技术领域
本发明涉及一种铱催化氢化吡嗪盐，高收率、高对映选择性的合成手性哌嗪衍生物的方法。
背景技术
手性哌嗪结构广泛存在于天然产物和药物活性分子中(式1)。虽然目前已有多种方法构建手性哌嗪结构，但是这些方法大多从手性氨基酸出发，经历关环、羰基还原等步骤，因此存在原料价格昂贵，合成路线长，步骤繁琐等缺点，而且羰基还原时手性中心易消旋化[(a)Dinsmore,C.J.；Beshore,D.C.Org.Prep.Proced.Int.2002,34,367；(b)Crestey,F.；Witt,M.；Jaroszewski,J.W.；Franzyk,H.J.Org.Chem.2009,74,5652；(c)Maity,P.；B.Org.Lett.2008,10,1473；(d)Kwon,S.H.；Lee,S.M.；Byun,S.M.；Chin,J.；Kim,B.M.Org.Lett.2012,14,3664；(e)Manna,S.K.；Panda,G.RSC Adv.2013,3,18332.]。若能从简单易得的吡嗪出发，经由不对称氢化，可以简洁、快速的合成手性哌嗪化合物，极大的缩短合成路线。
由于吡嗪具有稳定的芳香性和较强的配位能力，吡嗪类化合物的不对称氢化报道很少。1997年，Fuchs等人完成了吡嗪化合物的首例不对称氢化。采用铑-双膦催化剂，他们成功实现了吡嗪-2-羧酸衍生物的不对称氢化，最高只取得78％的ee值，底物也仅限于吡嗪-2-羧酸衍生物[Fuchs,R.EuropeanPatent Application EP 803502,1997.]。除了吡嗪的直接不对称氢化，Rossen等人设计了三步反应策略来实现吡嗪的氢化。首先，采用钯碳对底物进行部分氢化，然后上保护基，得到1,4,5,6-四氢吡嗪-2-羧酸衍生物，最后通过均相铑或钌催化剂实现不对称氢化。虽然能得到很好的对映选择性，但是步骤繁琐，底物范围也局限于吡嗪-2-羧酸衍生物[K.Rossen,S.A.Weissman,J.Sager,R.A.Reamer,D.Askin,R.P.Volante,P.J.Reider.TetrahedronLett.1995,36,6419.]。Ito等人也采用类似方法实现了吡嗪-2-羧酸衍生物的不对称氢化。[Kuwano,R.；Ito,Y.J.Org.Chem.1999,64,1232.]。结合以上背景，发展一种对映选择性高、步骤简单、底物适用范围广泛的体系，来实现吡嗪底物的不对称氢化具有重要的研究和应用价值。
最近，我们小组成功的开发了一种烷基盐活化底物策略，该策略成功实现了吡啶和异喹啉衍生物的不对称氢化[(a)Ye,Z.-S.；Chen,M.-W.；Chen,Q.-A.；Shi,L.；Duan,Y.；Zhou,Y.-G.Angew.Chem.,Int.Ed.2012,51,10181；(b)Ye,Z.-S.；Guo,R.-N.；Cai,X.-F.；Chen,M.-W.；Shi,L.；Zhou Y.-G.Angew.Chem.,Int.Ed.2013,52,3685；(c)Huang,W.-X.；Yu,C.-B.；Shi,L.；Zhou,Y.-G.Org.Lett.2014,16,3324.]。我们决定将该策略应用于吡嗪类底物。我们采用均相铱催化剂，通过对溶剂、氢气压力、反应温度以及手性配体的筛选，成功实现了三种不同取代的吡嗪盐的氢化，高收率、高对映选择性得到手性的哌嗪衍生物。该反应速度快、产物分离方便、副反应少，易于放大，为2-取代、3,5-二取代以及2,3-二取代吡嗪衍生物的不对称合成提供了一条简洁的路线。
发明内容
本发明的目的是提供一种铱催化氢化高对映选择性的合成哌嗪衍生物的方法，对于2-取代底物，所用配体为(R,Sp)-tBu-JosiPhos，溶剂为甲苯和1,4-二氧六环混合(体积比1/1)，温度为-20℃，氢气压力为1200psi所得结果最佳，对映体过量最高可达91％。对于3,5-二取代的底物，所用配体为(R)-SegPhos效果最佳，d.r.>20:1，对映体过量最高可达93％。对于2,3-二取代的底物，所用配体为(R)-MP2-SegPhos效果最佳，d.r.>20:1，对映体过量最高可达96％。
为实现上述目的，本发明的技术方案如下：
一种铱催化不对称氢化合成3-羟基哌啶衍生物的方法，其催化体系为铱的双膦配合物，反应式和条件如下：
式中：
温度：-20-70℃；
溶剂：甲苯、四氢呋喃、乙酸乙酯、1,4-二氧六环、1,2-二氯乙烷、二氯甲烷、苯中的一种或两种的混合；
氢气压力：10-90个大气压；
时间：20-36小时；
所述催化剂为(1,5-环辛二烯)氯化铱二聚体和双膦配体的配合物；
所述X为氯负离子、溴负离子、碘负离子、三氟甲磺酸根负离子、高氯酸根负离子、四氟化硼负离子及六氟磷负离子中的一种；
所述R1为C1-C20的烷基，苄基或含取代基的苄基，苄基苯环上取代基为甲基、甲氧基、三氟甲基、甲氧羰基、乙氧羰基、异丙基氧羰基中的一种或二种；
所述R为C1-C20的烷基、萘基、苯基或含有取代基的苯环，苯环上取代基为甲基、甲氧基、苄氧基、氟、氯、溴、三氟甲基、甲氧羰基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)和双膦配体在溶剂中室温搅拌10-15分钟而成；(1,5-环辛二烯)氯化铱二聚体与双膦配体的摩尔比为1:2.0-3.0，铱配合物在溶剂中的摩尔浓度为0.002-0.003mol/L。
所述双膦配体为(R)-MeO-Biphep,(R)-SegPhos,(R)-MP2-SegPhos,(R,Sp)-JosiPhos,(S)-f-Binaphane中的一种。
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0.25％到1％。
所述溶剂用量为每0.2毫摩尔氢化底物2到4毫升。
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，分离方便，能获得高收率。
2.催化剂制备过程简单，操作简便。
3.氢化反应条件温和，反应在-20-70℃下进行。
4、比较传统的合成方法，此方法采用少量的铱催化剂就可以得到大量的手性哌嗪衍生物，合成路线简短，原子经济性高，底物适用范围广泛，具有很高的实用价值。
本发明用到的催化剂是铱的手性双膦配合物。反应能在下列条件下进行，温度：-20-60℃；溶剂：甲苯、四氢呋喃、乙酸乙酯；压力：10-80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)氯化铱二聚体和手性双膦的配合物。3-取代、3,5-二取代和2,3-二取代的吡嗪盐均能很好地被氢化，得到相应的手性哌嗪衍生物，对映体过量最高可达96％。
本发明操作简便，原料易得，对映选择性高，产率好，为3-取代、3,5-二取代以及2,3-二取代的哌嗪衍生物的合成提供了一条原子经济性，环境友好的路线。
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(0.002毫摩尔，1.3毫克)和双膦配体(0.0044毫摩尔)的反应瓶中加入1.0毫升甲苯溶剂，室温搅拌10-15分钟，然后将制备好的催化剂用针管转移到另一装有原料3-苯基吡啶盐1a(0.20毫摩尔，65.4毫克)的反应瓶中，2.0毫升甲苯洗瓶、转移残留的催化剂，共用3毫升溶剂。将反应瓶放入一个不锈钢的高压釜中，通入氢气600psi，30℃下反应36小时。缓慢释放氢气，将反应液过滤，用旋转蒸发仪除去溶剂后直接柱层析(淋洗剂二氯甲烷和甲醇的体积比为20:1)，即可分离得到纯的产物，反应式及配体如下：
转化率由核磁测定，ee值由HPLC测定，结果见表1。
表1. 3-苯基吡嗪盐1a氢化的配体筛选
实施例2：均相铱催化不对称氢化合成3-取代哌嗪衍生物
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(0.002毫摩尔，1.3毫克)和(R,Sp)-tBu-JosiPhos(0.0044毫摩尔，2.4毫克)的反应瓶中加入1.0毫升溶剂甲苯，室温搅拌10-15分钟，然后将制备好的催化剂用针管转移到另一装有原料3-取代吡嗪盐1(0.20毫摩尔)的反应瓶中，0.5毫升甲苯和1.5毫升1,4-二氧六环溶剂洗瓶、转移残留的催化剂，共用3毫升溶剂。将反应瓶放入一个不锈钢的高压釜中，通入氢气1200psi，-20℃下反应36小时。将反应釜从低温反应器中取出，缓慢升至室温，然后释放氢气。向反应液中加入过量碳酸钠粉末，搅拌20分钟，中和氢化产生的氢溴酸。将反应液过滤，用旋转蒸发仪除去溶剂后直接柱层析(淋洗剂二氯为甲烷和甲醇，体积比为30:1-20:1)，即可分离得到哌嗪产物2，苯甲酰氯保护后测定产物的ee值。反应式及配体如下：
(S)-Isopropyl 2-((3-phenylpiperazin-1-yl)methyl)benzoate(2a):yellow oil,90％yield,91％ee,[α]20 D＝+3.0(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.1Hz,1H),7.56–7.17(m,8H),5.35–5.14(m,1H),3.87–3.77(m,3H),3.10–2.93(m,2H),2.84(d,J＝10.8Hz,1H),2.77(d,J＝10.9Hz,1H),2.21(td,J＝11.0,3.5Hz,1H),2.10(t,J＝10.6Hz,1H),1.99(s,1H),1.38(d,J＝6.2Hz,6H)；13C NMR(100MHz,CDCl3)δ168.2,142.6,138.9,132.3,130.8,130.1,129.6,128.4,127.4,127.1,126.9,68.3,61.2,60.6,60.4,53.3,46.3,22.0.HRMS Calculated for C21H26N2O2[M+H]+339.2067,found 339.2070.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 11.0min and 12.8min(maj).
(–)-Isopropyl 2-((3-m-tolylpiperazin-1-yl)methyl)benzoate(2b):yellow oil,93％yield,91％ee,[α]20 D＝–8.0(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.6Hz,1H),7.50–7.35(m,2H),7.28(t,J＝8.5Hz,1H),7.22–7.09(m,3H),7.05(d,J＝7.2Hz,1H),5.24(hept,J＝6.2Hz,1H),3.90–3.72(m,3H),3.10–2.92(m,2H),2.83(d,J＝10.8Hz,1H),2.77(d,J＝11.0Hz,1H),2.32(s,3H),2.21(td,J＝11.0,3.4Hz,1H),2.09(t,J＝10.6Hz,1H),1.98(s,1H),1.39(d,J＝6.2Hz,6H)；13C NMR(100MHz,CDCl3)δ168.2,142.6,139.0,138.0,132.3,130.8,130.1,129.6,128.2,128.2,127.7,126.9,124.2,68.3,61.2,60.6,60.4,53.3,46.3,22.0,21.4.HRMS Calculated forC22H28N2O2[M+H]+353.2222,found 353.2225.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retentiontime 8.8min and 11.5min(maj).
(–)-Isopropyl 2-((3-p-tolylpiperazin-1-yl)methyl)benzoate(2c):yellow oil,92％yield,92％ee,[α]20 D＝–15.0(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.6Hz,1H),7.48–7.35(m,2H),7.32–7.20(m,3H),7.10(d,J＝7.8Hz,2H),5.23(hept,J＝6.3Hz,1H),3.90–3.71(m,3H),3.10–2.90(m,2H),2.81(d,J＝10.8Hz,1H),2.76(d,J＝11.0Hz,1H),2.31(s,3H),2.20(td,J＝10.9,3.5Hz,1H),2.07(t,J＝10.5Hz,1H),1.82(s,1H),1.38(d,J＝6.2Hz,6H)；13C NMR(100MHz,CDCl3)δ168.2,139.7,139.0,137.0,132.3,130.8,130.1,129.6,129.0,127.0,127.0,68.3,61.3,60.6,60.1,53.3,46.3,22.0,21.1.HRMS Calculated for C22H28N2O2[M+H]+353.2222,found 353.2225.HPLC:Chiralpak IC column,220 nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 29.9min(maj)and 32.8min.
(–)-Isopropyl
2-((3-(3,5-dimethylphenyl)piperazin-1-yl)methyl)benzoate(2d):93％yield,yellow oil,90％ee,[α]20 D＝–19.0(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.5Hz,1H),7.49–7.34(m,2H),7.33–7.24(m,1H),6.96(s,2H),6.88(s,1H),5.35–5.17(m,1H),3.93–3.68(m,3H),3.12–2.92(m,2H),2.79(dd,J＝19.3,10.8Hz,2H),2.28(s,6H),2.20(td,J＝11.0,3.5Hz,1H),2.08(t,J＝10.5Hz,1H),1.79(s,1H),1.39(d,J＝6.3Hz,6H)；13C NMR(100 MHz,CDCl3)δ168.2,142.5,139.0,137.9,132.3,130.8,130.1,129.6,129.0,126.9,124.8,68.3,61.2,60.6,60.4,53.4,46.3,22.0,21.3.HRMS Calculated forC23H30N2O2[M+H]+367.2380,found 367.2382.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retentiontime 7.3min and 9.9min(maj).
(–)-Isopropyl
2-((3-(3-methoxyphenyl)piperazin-1-yl)methyl)benzoate(2e):yellowoil,86％yield,86％ee,[α]20 D＝–14.2(c 0.5,CHCl3).1H NMR(400 MHz,CDCl3)δ7.69(dd,J＝7.6,0.9Hz,1H),7.51–7.35(m,2H),7.33–7.16(m,2H),7.01–6.89(m,2H),6.78(dd,J＝8.2,1.8Hz,1H),5.31–5.17(m,1H),3.90–3.73(m,6H),3.09–2.93(m,2H),2.84(d,J＝10.8Hz,1H),2.77(d,J＝11.0Hz,1H),2.20(td,J＝11.0,3.5Hz,1H),2.08(t,J＝10.5Hz,1H),1.83(s,1H),1.39(dd,J＝6.3,1.3Hz,6H)；13C NMR(100MHz,CDCl3)δ168.2,159.7,144.3,138.9,132.2,130.9,130.1,129.6,129.3,126.9,119.4,113.0,112.4,68.3,61.2,60.6,60.4,55.3,53.3,46.3,22.0.HRMS Calculated for C22H28N2O3[M+H]+369.2173,found 369.2175.HPLC:Chiralpak IA column,220 nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 13.5min and 17.2min(maj).
(–)-Isopropyl
2-((3-(4-fluorophenyl)piperazin-1-yl)methyl)benzoate(2f):colorless oil,91％yield,90％ee,[α]20 D＝–11.2(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.70(dd,J＝7.6,1.0Hz,1H),7.48–7.36(m,2H),7.36–7.24(m,3H),7.07–6.89(m,2H),5.30–5.16(m,1H),3.91–3.72(m,3H),3.11–2.91(m,2H),2.86–2.71(m,2H),2.20(td,J＝10.9,3.6Hz,1H),2.04(t,J＝10.6Hz,1H),1.78(s,1H),1.38(d,J＝6.3Hz,6H)；13C NMR(100MHz,CDCl3)δ168.1,162.1(d,JC-F＝243.7Hz),138.9,138.4(d,JC-F＝3.1Hz),132.2,130.9,130.1,129.7,128.6(d,JC-F＝7.9Hz),126.9,115.1(d,JC-F＝21.0Hz),68.3,61.3,60.5,59.7,53.2,46.2,22.0；19F NMR(376MHz,CDCl3)δ-115.3.HRMS Calculatedfor C21H25FN2O2[M+H]+357.1973,found 357.1977.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retentiontime 10.8min and 14.7min(maj).
(–)-Isopropyl
2-((3-(4-chlorophenyl)piperazin-1-yl)methyl)benzoate(2g):yellowoil,80％yield,87％ee,[α]20 D＝–22.8(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.70(dd,J＝7.6,0.9Hz,1H),7.46–7.36(m,2H),7.32–7.22(m,5H),5.23(hept,J＝6.3Hz,1H),3.89–3.71(m,3H),3.11–2.92(m,2H),2.86–2.70(dd,J＝13.9,6.1Hz,2H),2.19(td,J＝11.0,3.5Hz,1H),2.03(t,J＝10.6Hz,1H),1.80(s,1H),1.38(d,J＝6.3Hz,6H)；13C NMR(100MHz,CDCl3)δ168.1,141.2,138.8,133.0,132.2,130.9,130.1,129.7,128.4,128.4,127.0,68.3,61.2,60.5,59.7,53.2,46.2,22.0.HRMS Calculated for C21H25ClN2O2[M+H]+373.1677,found373.1677.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time11.9min and18.2min(maj).
(–)-Isopropyl 2-((3-(4-bromophenyl)piperazin-1-yl)methyl)benzoate(2h):yellow oil,85％yield,86％ee,[α]20 D＝–18.5(c 2.0,CHCl3).1HNMR(400MHz,CDCl3)δ7.70(d,J＝7.5Hz,1H),7.52–7.36(m,4H),7.34–7.18(m,3H),5.31–5.16(m,1H),3.90–3.71(m,3H),3.11–2.92(m,2H),2.87–2.69(m,2H),2.20(td,J＝11.0,3.4Hz,1H),2.03(t,J＝10.6Hz,1H),1.83(s,1H),1.38(d,J＝6.3Hz,6H)；13C NMR(100MHz,CDCl3)δ168.1,141.6,138.8,132.2,131.4,130.9,130.1,129.7,128.8,127.0,121.1,68.3,61.1,60.5,59.8,53.2,46.2,22.0.HRMSCalculated for C21H25BrN2O2[M+H]+417.1172,found 417.1175.HPLC:Chiralpak IA column,220 nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8 mL/min,retention time 13.1min and 21.2min(maj).
(–)-1-Benzyl-3-(4-(trifluoromethyl)phenyl)piperazine(2j):whitesolid,mp 62–63℃,91％yield,85％ee,[α]20 D＝–9.0(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.62–7.46(m,4H),7.37–7.21(m,5H),3.95(dd,J＝10.1,2.6Hz,1H),3.54(s,2H),3.14–2.99(m,2H),2.94–2.78(m,2H),2.20(td,J＝10.8,4.2Hz,1H),2.03(t,J＝10.5Hz,1H),1.86(s,1H)；13C NMR(100MHz,CDCl3)δ146.6,137.8,129.7(q,JC-F＝32.1Hz),129.2,128.3,127.4,127.2,125.3(q,JC-F＝3.8Hz),124.2(q,JC-F＝270.3Hz),63.3,61.1,60.0,53.1,46.1；19F NMR(376MHz,CDCl3)δ-62.43.HRMS Calculated for C18H19F3N2[M+H]+321.1573,found 321.1575.HPLC:Chiracel OD-H column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 10.4minand 12.2min(maj).
(–)-1-Benzyl-3-(biphenyl-4-yl)piperazine(2j):yellow oil,82％yield,88％ee,[α]20 D＝–14.4(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.60–7.21(m,15H),3.93(dd,J＝10.1,2.5Hz,1H),3.55(s,2H),3.16–3.01(m,2H),2.93(d,J＝10.9Hz,1H),2.85(d,J＝11.0Hz,1H),2.21(td,J＝10.6,4.4Hz,1H),2.10(t,J＝10.6Hz,1H),1.96(s,1H)；13C NMR(100MHz,CDCl3)δ141.7,140.9,140.4,137.9,129.3,128.8,128.3,127.5,127.3,127.1,127.1,63.4,61.2,60.1,53.2,46.3.HRMS Calculated for C23H24N2[M+H]+329.2012,found 329.2013.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 16.2min(maj)and 17.7min.
(–)-Isopropyl
2-((3-(naphthalen-2-yl)piperazin-1-yl)methyl)benzoate(2k):yellowoil,87％yield,86％ee,[α]20 D＝–29.80(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.86–7.66(m,5H),7.52–7.35(m,5H),7.33–7.23(m,1H),5.32–5.18(m,1H),3.98(dd,J＝10.1,2.5Hz,1H),,3.91–3.77(m,2H),3.16–2.98(m,2H),2.92(d,J＝10.8Hz,1H),2.80(d,J＝11.0Hz,1H),2.26(td,J＝10.9,3.6Hz,1H),2.17(t,J＝10.5Hz,1H),1.96(s,1H),1.39(dd,J＝6.2,2.0Hz,6H)；13C NMR(100MHz,CDCl3)δ168.2,140.1,138.9,133.4,132.9,132.3,130.9,130.2,129.7,127.9,127.9,127.6,126.9,126.0,125.7,125.6,125.5,68.4,61.2,60.6,60.4,53.3,46.3,22.1.HRMS Calculated for C25H28N2O2[M+H]+389.2224,found389.2225.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.8mL/min,retention time 9.6min and 25.8min(maj).
(+)-1-Benzyl-3-(4-fluoro-2-methylphenyl)piperazine(2l):yellow oil,95％yield,68％ee,[α]20 D＝+8.8(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.48(dd,J＝8.5,6.2Hz,1H),7.41–7.19(m,5H),6.91–6.76(m,2H),4.04(dd,J＝9.9,2.3Hz,1H),3.63–3.47(m,2H),3.15–3.01(m,2H),2.91–2.77(m,2H),2.30(s,3H),2.26–2.14(m,1H),1.94(t,J＝10.6Hz,1H),1.80(s,1H)；13C NMR(100MHz,CDCl3)δ161.6(d,JC-F＝243.2Hz),137.9,137.7(d,JC-F＝7.5Hz),136.3(d,JC-F＝2.9Hz),129.2,128.3,127.9(d,JC-F＝8.2Hz),127.1,116.8(d,JC-F＝20.7Hz),112.7(d,JC-F＝20.4Hz),63.2,60.1,55.8,53.3,46.4,19.3；19FNMR(376MHz,CDCl3)δ-116.45.HRMS Calculated for C18H21FN2[M+H]+285.1762,found 285.1763.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 7.9minand 9.4min(maj).
实施例3：均相铱催化不对称氢化合成3,5-二取代哌嗪衍生物
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(0.002毫摩尔，1.3毫克)和(R)-SegPhos(0.0044毫摩尔，2.7毫克)的反应瓶中加入1.0毫升溶剂甲苯，室温搅拌10-15分钟，然后将制备好的催化剂用针管转移到另一装有原料3,5-二取代吡嗪盐3(0.20毫摩尔)的反应瓶中，0.5毫升甲苯和1.5毫升1,2-二氯乙烷溶剂洗瓶、转移残留的催化剂，共用3毫升溶剂。将反应瓶放入一个不锈钢的高压釜中，通入氢气600psi，-20℃下反应24小时。将反应釜从低温反应器中取出，缓慢升至室温，然后释放氢气。向反应液中加入过量碳酸钠粉末，搅拌20分钟，中和氢化产生的氢溴酸。将反应液过滤，用旋转蒸发仪除去溶剂后直接柱层析(淋洗剂为二氯甲烷和甲醇，体积比为30:1-20:1)，即可分离得到哌嗪产物4，苯甲酰氯保护后测定产物的ee值。反应式及配体如下：
反应式及结果如下：
(3R,5S)-1-Benzyl-3-methyl-5-phenylpiperazine(4a):light yellowsolid,mp 84–85℃,94％yield,91％ee,>20:1d.r.,[α]20 D＝+0.8(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.42–7.17(m,10H),3.95(dd,J＝10.3,2.7Hz,1H),3.59–3.46(m,2H),3.12–3.00(m,1H),2.88(dd,J＝10.8,1.7Hz,1H),2.80(d,J＝10.7Hz,1H),2.00(t,J＝10.6Hz,1H),1.76(t,J＝10.4Hz,1H),1.68(s,1H),1.06(d,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ142.7,138.0,129.3,128.4,128.3,127.4,127.2,127.1,63.2,60.8,60.5,60.4,51.0,20.1.HRMS Calculated forC18H23N2[M+H]+267.1856,found 267.1855.HPLC:Chiralpak AD-H column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retentiontime 10.9min(maj)and 14.4min.
(–)-1-Benzyl-3-methyl-5-m-tolylpiperazine(4b):yellow oil,93％yield,90％ee,>20:1 d.r.,[α]20 D＝–3.9(c 1.0,CHCl3).1H NMR(400MHz,DMSO-d6)δ7.35–7.27(m,4H),7.26–7.21(m,1H),7.21–7.10(m,3H),7.03(d,J＝6.8Hz,1H),3.77(dd,J＝10.2,2.3Hz,1H),3.45(s,2H),2.96–2.84(m,1H),2.77–2.66(m,2H),2.27(s,3H),1.79(t,J＝10.5Hz,1H),1.65(t,J＝10.4Hz,1H),0.98(d,J＝6.3Hz,3H)；13C NMR(100MHz,DMSO-d6)δ143.6,138.6,137.5,129.4,128.6,128.4,128.1,128.0,127.3,124.6,62.7,61.2,60.5,60.1,50.8,21.5,20.1.HRMS Calculated for C19H25N2[M+H]+281.2012,found 281.2013.HPLC:Chiralpak AD-H column,230nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 8.5min and 9.1min(maj).
(–)-1-Benzyl-3-methyl-5-p-tolylpiperazine(4c):yellow oil,95％yield,88％ee,>20:1 d.r.,[α]20 D＝–3.0(c 0.5,CHCl3).1H NMR(400MHz,DMSO-d6)δ7.33–7.17(m,7H),7.06(d,J＝7.3Hz,2H),3.74(d,J＝10.1Hz,1H),3.43(s,2H),2.86(s,1H),2.67(d,J＝10.3Hz,2H),2.49(s,1H),2.24(s,3H),1.75(t,J＝10.3Hz,1H),1.62(t,J＝10.2Hz,1H),0.95(d,J＝5.5Hz,3H)；13C NMR(100MHz,DMSO-d6)δ140.8,138.7,136.6,129.6,129.2,128.8,127.5,127.5,62.8,61.4,60.6,60.0,50.9,21.3,20.3.HRMS Calculated for C19H25N2[M+H]+281.2012,found 281.2015.HPLC:Chiralcel OD-H column,230nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 8.8min and 10.4min(maj).
(–)-1-Benzyl-3-(3,5-dimethylphenyl)-5-methylpiperazine(4d):colorless oil,81％yield,90％ee,>20:1 d.r.,[α]20 D＝–5.6(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.36–7.21(m,5H),6.99(s,2H),6.88(s,1H),3.88(dd,J＝10.3,2.7Hz,1H),3.61–3.48(m,2H),3.13–3.00(m,1H),2.88(dd,J＝10.8,2.3Hz,1H),2.81(dd,J＝10.7,1.9Hz,1H),2.28(s,6H),2.01(t,J＝10.6Hz,1H),1.87–1.71(m,3H),1.08(d,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ142.4,137.9,129.3,129.1,128.3,127.1,124.9,63.1,60.5,60.5,60.4,51.0,21.3,20.0.HRMS Calculated for C20H27N2[M+H]+295.2169,found 295.2172.HPLC:Chiralpak AD-H column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 6.1minand 7.3min(maj).
(–)-1-Benzyl-3-(3-methoxyphenyl)-5-methylpiperazine(4e):yellowoil,92％yield,92％ee,>20:1 d.r.,[α]20 D＝–4.1(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.40–7.15(m,6H),7.02–6.91(m,2H),6.78(dd,J＝7.5,2.0Hz,1H),3.99–3.89(m,1H),3.78(s,3H),3.60–3.45(m,2H),3.12–2.99(m,1H),2.89(d,J＝10.7Hz,1H),2.79(d,J＝10.6Hz,1H),1.99(t,J＝10.6Hz,1H),1.75(t,J＝10.4Hz,2H),1.06(d,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ159.7,144.4,138.0,129.3,129.3,128.3,127.1,119.5,112.8,112.8,63.2,60.7,60.5,60.4,55.3,51.0,20.1.HRMS Calculated for C19H25N2O[M+H]+297.1961,found297.1965.HPLC:Chiralpak AD-H column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 11.7min(maj)and 15.6min.
(–)-1-Benzyl-3-(4-methoxyphenyl)-5-methylpiperazine(4f):colorless oil,95％yield,84％ee,>20:1 d.r.,[α]20 D＝–2.2(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.38–7.19(m,7H),6.82(d,J＝8.5Hz,2H),3.89(dd,J＝10.3,2.5Hz,1H),3.75(s,3H),3.58–3.47(m,2H),3.12–2.99(m,1H),2.85(d,J＝10.7Hz,1H),2.79(d,J＝10.6Hz,1H),1.97(t,J＝10.6Hz,1H),1.75(t,J＝10.4Hz,2H),1.05(d,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ158.9,138.0,134.9,129.3,128.3,128.2,127.1,113.7,63.2,60.8,60.4,59.9,55.3,51.0,20.1.HRMS Calculated for C19H25N2O[M+H]+297.1961,found 297.1965.HPLC:Chiralpak AD-H column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 19.4min(maj)and 20.9min.
(–)-1-Benzyl-3-(4-(benzyloxy)phenyl)-5-methylpiperazine(4g):yellow oil,93％yield,92％ee,>20:1 d.r.,[α]20 D＝–1.3(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.43–7.18(m,12H),6.89(d,J＝8.6Hz,2H),4.99(s,2H),3.88(dd,J＝10.3,2.5Hz,1H),3.59–3.43(m,2H),3.09–2.98(m,1H),,2.84(d,J＝10.7Hz,1H),2.78(d,J＝10.5Hz,1H),1.97(t,J＝10.6Hz,1H),1.74(t,J＝10.4Hz,2H),1.04(d,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ158.2,138.1,137.1,135.2,129.3,128.6,128.3,128.3,128.0,127.5,127.1,114.7,70.0,63.2,60.8,60.4,59.9,51.1,20.1.HRMS Calculated for C25H29N2O[M+H]+373.2274,found 373.2276.HPLC:Chiralpak AD-H column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 23.8min(maj)and 30.3min.
(+)-1-Benzyl-3-(4-fluorophenyl)-5-methylpiperazine(4h):yellow oil,95％yield,88％ee,>20:1 d.r.,[α]20 D＝+0.6(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.40–7.20(m,7H),7.01–6.92(m,2H),3.92(dd,J＝10.3,2.7Hz,1H),3.58–3.46(m,2H),3.11–3.00(m,1H),2.82(ddd,J＝16.8,10.6,2.0Hz,2H),1.94(t,J＝10.6Hz,1H),1.75(t,J＝10.4Hz,1H),1.65(s,1H),1.06(d,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ161.1(d,JC-F＝243.6Hz),138.5(d,JC-F＝3.1Hz),138.0,129.3,128.7(d,JC-F＝7.9Hz),128.3,127.1,115.1(d,JC-F＝20.1Hz),63.1,60.9,60.3,59.8,51.0,20.1；19F NMR(376MHz,CDCl3)δ-115.3.HRMSCalculated for C18H22FN2[M+H]+285.1762,found 285.1766.HPLC:ChiralpakAD-H column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 9.4min and 10.0min(maj).
(–)-1-Benzyl-3-(3-chloro-4-fluorophenyl)-5-methylpiperazine(4i):white solid,87％yield,93％ee,12:1 d.r.,[α]20 D＝–10.4(c 1.0,CHCl3)；mp 94–95℃.1H NMR(400MHz,CDCl3)δ7.45–7.15(m,9H),3.92(dd,J＝10.3,2.6Hz,1H),3.61–3.44(m,2H),3.14–2.98(m,1H),2.85(d,J＝10.6Hz,1H),2.79(d,J＝10.6Hz,1H),1.94(t,J＝10.6Hz,1H),1.75(t,J＝10.4Hz,1H),1.65(s,1H),1.06(d,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ144.8,137.9,134.2,129.6,129.2,128.3,127.6,127.3,127.1,125.4,63.1,60.6,60.3,60.0,50.9,20.0.HRMSCalculated for C18H22ClN2[M+H]+301.1466,found 301.1469.HPLC:Chiralpak AD-H column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 13.2min and 14.8min(maj).
(–)-1-Benzyl-3-methyl-5-(4-(trifluoromethyl)phenyl)piperazine(4j):colorless oil,94％yield,93％ee,>20:1 d.r.,[α]20 D＝–6.50(c1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.59–7.46(m,4H),7.37–7.21(m,5H),4.01(dd,J＝10.3,2.6Hz,1H),3.61–3.46(m,2H),3.14–3.01(m,1H),2.87(d,J＝10.7Hz,1H),2.81(d,J＝10.6Hz,1H),1.95(t,J＝10.6Hz,1H),1.77(t,J＝10.4Hz,1H),1.70(s,1H),1.08(d,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ146.7,137.9,129.6(q,JC-F＝32.1Hz),129.2,128.3,127.5,127.1,125.3(q,JC-F＝3.7Hz),124.2(q,JC-F＝270.4Hz),63.1,60.6,60.3,60.1,50.9,20.0；19F NMR(376MHz,CDCl3)δ-62.4.HRMS Calculated for C19H22F3N2[M+H]+335.1730,found 335.1730.HPLC:Chiracel AD-H column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 19.2min(maj)and 23.3min.
(–)-1-Benzyl-3-(biphenyl-4-yl)-5-methylpiperazine(4k):yellow oil,96％yield,90％ee,>20:1 d.r.,[α]20 D＝–13.6(c 0.5,CHCl3).1H NMR(400MHz,DMSO-d6)δ7.69–7.52(m,4H),7.50–7.40(m,4H),7.40–7.21(m,6H),3.85(dd,J＝10.2,2.3Hz,1H),3.48(s,2H),2.99–2.85(m,1H),2.74(t,J＝12.3Hz,2H),2.53–2.48(m,1H),1.82(t,J＝10.4Hz,1H),1.67(t,J＝10.3Hz,1H),0.99(d,J＝6.2Hz,3H)；13C NMR(100MHz,DMSO-d6)δ143.0,140.7,139.6,138.7,129.6,129.5,128.8,128.2,127.9,127.5,127.2,127.0,62.9,61.2,60.6,59.9,50.9,20.3.HRMSCalculated for C24H27N2[M+H]+343.2169,found 343.2172.HPLC:ChiralpakAD-H column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 11.4min(maj)and 13.8min.
(–)-1-Benzyl-3-methyl-5-(naphthalen-2-yl)piperazine(4l):yellowoil,94％yield,78％ee,>20:1 d.r.,[α]20 D＝–10.0(c 1.0,CHCl3).1HNMR(400MHz,CDCl3)δ7.88–7.70(m,4H),7.52–7.17(m,8H),4.09(dd,J＝10.3,2.5Hz,1H),3.61–3.45(m,2H),3.17–3.04(m,1H),2.95(d,J＝10.7Hz,1H),2.82(d,J＝10.6Hz,1H),2.06(t,J＝10.6Hz,1H),1.80(t,J＝10.4Hz,2H),1.08(d,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ140.2,138.0,133.5,133.0,129.3,128.3,128.0,127.9,127.7,127.1,126.0,125.7,125.7,125.5,63.2,60.8,60.6,60.4,51.1,20.1.HRMS Calculated for C22H25N2[M+H]+317.2012,found 317.2016.HPLC:Chiralpak AD-H column,254 nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 7.8min and 10.5min(maj).
(+)-1-Benzyl-3-methyl-5-(naphthalen-1-yl)piperazine(4m):yellowoil,91％yield,86％ee,>20:1 d.r.,[α]20 D＝+57.7(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ8.18(d,J＝8.3Hz,1H),7.85–7.79(m,1H),7.77–7.69(m,2H),7.52–7.38(m,3H),7.37–7.26(m,4H),7.25–7.18(m,1H),4.76(dd,J＝10.1,2.3Hz,1H),3.55(q,J＝13.2Hz,2H),3.27–3.16(m,1H),3.12(d,J＝10.9Hz,1H),2.86(d,J＝10.6Hz,1H),2.11(t,J＝10.6Hz,1H),1.84(t,J＝10.5Hz,2H),1.11(d,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ138.3,138.0,133.8,131.1,129.3,129.0,128.3,127.7,127.1,126.0,125.6,125.5,123.7,123.0,63.0,60.5,60.1,56.0,51.4,20.2.HRMS Calculated for C22H25N2[M+H]+317.2012,found 317.2016.HPLC:Chiralpak AD-H column,220 nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 10.2min(maj)and 13.6min.
(+)-1-Benzyl-3-ethyl-5-phenylpiperazine(4n):colorless oil,96％yield,80％ee,>20:1 d.r.,[α]20 D＝+5.7(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.43–7.16(m,10H),3.92(dd,J＝10.3,2.5Hz,1H),3.53(q,J＝13.1Hz,2H),2.94–2.78(m,3H),2.00(t,J＝10.7Hz,1H),1.79(t,J＝10.9Hz,2H),1.52–1.32(m,2H),0.91(t,J＝7.5Hz,3H)；13C NMR(100MHz,CDCl3)δ142.8,138.1,129.3,128.4,128.3,127.4,127.2,127.1,63.2,61.1,60.5,59.0,57.1,27.4,10.5.HRMS Calculatedfor C19H25N2[M+H]+281.2012,found 281.2015.HPLC:Chiralpak AD-H column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retentiontime 8.9min(maj)and 12.2min.
(+)-1-Benzyl-3-phenyl-5-propylpiperazine(4o):colorless oil,90％yield,70％ee,>20:1 d.r.,[α]20 D＝+6.4(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.43–7.15(m,10H),3.92(dd,J＝10.3,2.6Hz,1H),3.63–3.44(m,2H),3.00–2.90(m,1H),2.90–2.78(m,2H),2.00(t,J＝10.6Hz,1H),1.88–1.63(m,2H),1.46–1.19(m,4H),0.98–0.83(m,3H)；13C NMR(100MHz,CDCl3)δ142.8,138.0,129.3,128.4,128.3,127.4,127.2,127.1,63.2,61.1,60.5,59.3,55.3,36.8,19.1,14.3.HRMS Calculated for C20H27N2[M+H]+295.2169,found 295.2163.HPLC:Chiralpak AD-H column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 7.8min(maj)and 11.6min.
(+)-1-Benzyl-3-butyl-5-phenylpiperazine(4p):yellow oil,92％yield,86％ee,>20:1 d.r.,[α]20 D＝+7.5(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.47–7.16(m,10H),3.92(dd,J＝10.3,2.5Hz,1H),3.53(q,J＝13.1Hz,2H),3.00–2.78(m,3H),2.00(t,J＝10.7Hz,1H),1.81(t,J＝10.4Hz,2H),1.47–1.19(m,6H),0.87(t,J＝6.9Hz,3H)；13C NMR(100MHz,CDCl3)δ142.8,138.0,129.3,128.4,128.3,127.5,127.2,127.1,63.2,61.1,60.5,59.3,55.6,34.3,28.1,22.9,14.1.HRMS Calculated for C21H29N2[M+H]+309.2325,found 309.2329.HPLC:Chiralpak AD-H column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 7.5min(maj)and 11.5min.
(+)-1-Benzyl-3-isobutyl-5-phenylpiperazine(4q):yellow oil,86％yield,76％ee,>20:1 d.r.,[α]20 D＝+5.0(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.43–7.17(m,10H),3.93(dd,J＝10.3,2.6Hz,1H),3.53(q,J＝13.1Hz,2H),3.08–2.96(m,1H),2.88(d,J＝10.7Hz,1H),2.82(d,J＝10.6Hz,1H),2.00(t,J＝10.6Hz,1H),1.80(t,J＝10.4Hz,2H),1.72–1.57(m,1H),1.39–1.14(m,2H),0.89(dd,J＝10.1,6.6Hz,6H)；13C NMR(100MHz,CDCl3)δ142.7,137.9,129.3,128.4,128.3,127.5,127.2,127.1,63.3,61.0,60.5,59.6,53.3,43.6,24.3,23.4,22.4.HRMS Calculated for C21H29N2[M+H]+309.2325,found 309.2330.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 10.5min(maj)and 14.4min.
(+)-1-Benzyl-3-cyclopropyl-5-phenylpiperazine(4r):light yellow oil,90％yield,83％ee,>20:1 d.r.,[α]20 D＝+18.6(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.47–7.15(m,10H),3.85(dd,J＝10.3,2.6Hz,1H),3.60(d,J＝13.1Hz,1H),3.51(d,J＝13.1Hz,1H),2.98(d,J＝9.7Hz,1H),2.84(dd,J＝10.7,1.9Hz,1H),2.16–1.96(m,4H),0.92–0.76(m,1H),0.49–0.36(m,2H),0.26–0.07(m,2H)；13C NMR(100MHz,CDCl3)δ142.8,138.0,129.4,128.5,128.4,127.6,127.4,127.2,63.2,61.7,60.9,60.7,58.8,15.0,2.8,2.3.HRMS Calculated for C20H24N2[M+H]+293.2012,found 293.2013.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝80/20,flow＝0.8mL/min,retention time 10.5min(maj)and 14.4min.
实施例4：均相铱催化不对称氢化合成2,3-二取代哌嗪衍生物
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(0.002毫摩尔，1.3毫克)和(R)-MP2-SegPhos(0.0044毫摩尔，2.0毫克)的反应瓶中加入1.0毫升溶剂四氢呋喃，室温搅拌10-15分钟，然后将制备好的催化剂用针管转移到另一装有原料3,5-二取代吡嗪盐5(0.20毫摩尔)的反应瓶中，0.5毫升四氢呋喃和1.5毫升乙酸乙酯溶剂洗瓶、转移残留的催化剂，共用3毫升溶剂。将反应瓶放入一个不锈钢的高压釜中，通入氢气400psi，50℃下反应24小时。将反应釜降至室温，然后小心释放氢气。向反应液中加入过量碳酸钠粉末，搅拌20分钟，中和氢化产生的酸。将反应液过滤，用旋转蒸发仪除去溶剂后直接柱层析(淋洗剂为二氯甲烷和甲醇，体积比为30:1-20:1)，即可分离得到哌嗪产物6，苯甲酰氯保护后测定产物的ee值。反应式及配体如下：
反应式及结果如下：
(2S,3R)-1-Methyl-2,3-diphenylpiperazine(6a):yellow oil,knowncompound,96％yield,94％ee,>20:1d.r.,[α]20 D＝+92.4(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.48–7.37(m,2H),7.23(d,J＝7.2Hz,2H),7.18–7.00(m,6H),4.43(d,J＝3.7Hz,1H),3.85(d,J＝3.7Hz,1H),3.39(dt,J＝11.3,3.6Hz,1H),3.27–3.15(m,1H),3.12–3.01(m,1H),2.74(s,1H),2.60(dt,J＝11.6,3.6Hz,1H),2.15(s,3H)；13CNMR(100MHz,CDCl3)δ141.0,136.0,131.1,127.8,127.3,127.1,126.9,70.3,64.2,49.8,45.3,43.6.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.8mL/min,retention time 6.9min(maj)and 10.8min.
(+)-1-Methyl-2,3-dim-tolylpiperazine(6b):yellow oil,98％yield,92％ee,>20:1d.r.,[α]20 D＝+84.3(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.30(d,J＝7.5Hz,1H),7.21(s,1H),7.12–6.92(m,5H),6.88(d,J＝7.4Hz,1H),4.45(d,J＝3.6Hz,1H),3.86(d,J＝3.7Hz,1H),3.40(dt,J＝11.4,3.6Hz,1H),3.35–3.17(m,2H),3.15–3.06(m,1H),2.66(dt,J＝11.6,3.5Hz,1H),2.23(s,3H),2.19(s,6H)；13C NMR(100MHz,CDCl3)δ140.5,137.3,136.8,135.1,132.0,128.7,128.3,128.1,127.7,127.6,127.2,124.9,70.1,63.9,49.9,45.0,43.4,21.5,21.4.HRMS Calculated for C19H24N2[M+H]+281.2012,found 281.2014.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.8mL/min,retention time 5.4min(maj)and 6.2min.
(+)-1-Methyl-2,3-dip-tolylpiperazine(6c):yellow oil,93％yield,93％ee,>20:1 d.r.,[α]20 D＝+74.0(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.32(d,J＝7.9Hz,2H),7.13(d,J＝7.9Hz,2H),6.92(t,J＝7.9Hz,4H),4.31(d,J＝3.6Hz,1H),3.74(d,J＝3.7Hz,1H),3.35(dt,J＝11.1,3.6Hz,1H),3.14(td,J＝10.6,3.5Hz,1H),3.04–2.91(m,1H),2.49(dt,J＝11.5,3.7Hz,1H),2.23(s,3H),2.19(s,3H),2.11(s,3H)；13C NMR(100MHz,CDCl3)δ138.7,136.1,136.0,133.5,131.1,128.4,127.9,127.7,70.2,64.5,49.9,45.7,43.7,21.1,21.0.HRMS Calculated for C19H24N2[M+H]+281.2012,found 281.2015.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.8mL/min,retention time 6.3min(maj)and 8.5min.
(+)-2,3-Bis(3-methoxyphenyl)-1-methylpiperazine(6d):yellow oil,94％yield,95％ee,>20:1 d.r.,[α]20 D＝+68.6(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.20(s,1H),7.17–7.10(m,2H),7.06(t,J＝7.9Hz,1H),6.92(d,J＝7.6Hz,1H),6.85(s,1H),6.82–6.75(m,1H),6.65(dd,J＝8.1,2.0Hz,1H),4.81(d,J＝3.4Hz,1H),4.24(d,J＝3.6Hz,1H),3.71(s,3H),3.64(s,3H),3.61–3.52(m,1H),3.48(dt,J＝12.1,3.4Hz,1H),3.37–3.26(m,1H),3.13–3.02(m,1H),2.34(s,3H)；13CNMR(100MHz,CDCl3)δ159.2,159.1,139.6,133.4,129.1,129.0,124.0120.3,117.4,114.0,113.6,113.2,69.0,62.3,55.3,55.2,49.4,43.6,42.6.HRMS Calculated for C19H24N2O2[M+H]+313.1911,found 313.1908.HPLC:Chiralpak AD-H column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 9.9min and 11.8min(maj).
(+)-2,3-Bis(4-fluorophenyl)-1-methylpiperazine(6e):yellow oil,95％yield,93％ee,>20:1 d.r.,[α]20 D＝+103.9(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.47–7.33(m,2H),7.22–7.11(m,2H),6.87–6.72(m,4H),4.32(d,J＝3.8Hz,1H),3.74(d,J＝3.8Hz,1H),3.35(dt,J＝11.1,3.5Hz,1H),3.15(td,J＝10.7,3.6Hz,1H),3.00–2.89(m,1H),2.51(dt,J＝11.7,3.6Hz,1H),2.11(s,3H),1.75(s,1H)；13CNMR(100MHz,CDCl3)δ163.0(d,JC-F＝31.6Hz),160.5(d,JC-F＝31.3Hz),137.2(d,JC-F＝3.2Hz),132.5(d,JC-F＝7.5Hz),132.2(d,JC-F＝3.3Hz),129.1(d,JC-F＝7.8Hz),114.6(d,JC-F＝20.1Hz),114.0(d,JC-F＝20.5Hz),69.6,63.8,49.4,45.8,43.5；19F NMR(376MHz,CDCl3)δ-115.9,-116.0.HRMS Calculated for C17H18F2N2[M+H]+289.1511,found285.1512.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.8mL/min,retention time 7.9min(maj)and 11.2min.
(+)-2,3-Bis(3-chlorophenyl)-1-methylpiperazine(6f):yellow oil,94％yield,82％ee,>20:1 d.r.,[α]20 D＝+71.0(c 2.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.62(s,1H),7.34(d,J＝7.5Hz,1H),7.29(s,1H),7.24–7.03(m,5H),4.59(d,J＝3.6Hz,1H),4.00(d,J＝3.7Hz,1H),3.49–3.29(m,2H),3.16–3.02(m,1H),2.81(dt,J＝11.9,3.4Hz,1H),2.24(s,3H)；13C NMR(100MHz,CDCl3)δ141.4,136.0,133.9,133.6,131.0,129.5,129.4,129.0,128.1,127.8,127.6,125.9,68.9,62.6,49.3,44.4,43.2.HRMS Calculated for C17H18Cl2N2[M+H]+321.0920,found 321.0922.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.8mL/min,retention time 6.7min(maj)and 7.7min.
(+)-1-Methyl-2,3-bis(3-(trifluoromethyl)phenyl)piperazine(6g):yellow oil,92％yield,81％ee,>20:1 d.r.,[α]20 D＝+69.90(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.0Hz,2H),7.46–7.32(m,6H),4.49(d,J＝3.7Hz,1H),3.91(d,J＝3.8Hz,1H),3.40(dt,J＝11.3,3.5Hz,1H),3.22(td,J＝10.8,3.6Hz,1H),3.07–2.92(m,1H),2.60(dt,J＝11.8,3.6Hz,1H),2.43–2.25(s,1H),2.14(s,3H)；13C NMR(100MHz,CDCl3)δ144.8,139.9,131.2,129.3(q,JC-F＝32.1Hz),129.2(q,JC-F＝32.1Hz),127.8,125.5,124.9(q,JC-F＝2.8Hz),124.2(q,JC-F＝2.8Hz),124.1(q,JC-F＝270.3Hz),124.0(q,JC-F＝270.4Hz),69.5,63.7,49.3,45.3,43.5；19F NMR(376MHz,CDCl3)δ-62.5.HRMS Calculatedfor C19H18F6N2[M+H]+389.1447,found 389.1448 HPLC:Chiracel IA column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.8mL/min,retentiontime 6.5min(maj)and 9.5min.
(+)-1-Methyl-2,3-di(naphthalen-2-yl)piperazine(6h):yellow oil,96％yield,93％ee,>20:1 d.r.,[α]20 D＝+83.7(c 2.0,CHCl3).1H NMR(400MHz,CDCl3)δ8.26–7.16(m,14H),5.27(s,1H),4.73(d,J＝3.3Hz,1H),3.81(t,J＝10.5Hz,1H),3.67–3.55(m,1H),3.47(td,J＝11.8,3.5Hz,1H),3.30(d,J＝12.3Hz,1H),2.38(s,3H)；13C NMR(100MHz,CDCl3)δ136.2,133.0,132.9,132.7,132.7,131.2,130.3,128.7,128.0,128.2,127.8,127.5,127.5,126.9,126.4,126.1,126.0,125.9,125.8,69.5,62.9,49.7,44.0,42.9.HRMS Calculated for C25H24N2[M+H]+353.2012,found 353.2015.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝70/30,flow＝0.8mL/min,retention time 8.2min(maj)and 11.5min.
(+)-1-Benzyl-2,3-dimethylpiperazine(6i):white solid,knowncompound,mp 55–56℃,95％yield,91％ee,>20:1d.r.,[α]20 D＝+8.2(c0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.41–7.20(m,5H),5.24(s,2H),3.67(d,J＝13.4Hz,1H),3.53(d,J＝13.4Hz,1H),3.28(qd,J＝6.7,3.3Hz,1H),3.06(dt,J＝12.1,3.5Hz,1H),3.02–2.91(m,1H),2.85(qd,J＝6.7,3.4Hz,1H),2.71–2.60(m,1H),2.43(dt,J＝12.2,3.6Hz,1H),1.19(d,J＝6.8Hz,3H),1.04(d,J＝6.7Hz,3H)；13CNMR(100MHz,CDCl3)δ138.8,128.7,128.3,127.1,58.6,56.0,54.5,44.9,44.3,16.7,5.9.HPLC:Chiralpak IA column,220nm,30℃,n-hexane/i-propanol＝93/7,flow＝0.8mL/min,retention time 14.5min(maj)and 15.6min.
(+)-1-Benzyldecahydroquinoxaline(6j):white solid,known compound,mp 51–52℃,93％yield,96％ee,>20:1d.r.,[α]20 D＝+7.8(c 0.5,CHCl3).1H NMR(400MHz,DMSO-d6,60℃)δ7.36–7.24(m,4H),7.24–7.14(m,1H),3.65–3.47(m,2H),2.91–2.78(m,2H),2.68(td,J＝11.0,3.3Hz,1H),2.61–2.41(m,3H),2.29–2.13(m,1H),1.93(qd,J＝12.1,3.4Hz,1H),1.80–1.60(m,2H),1.58–1.32(m,3H),1.32–1.20(m,1H),1.15–0.98(m,1H)；13C NMR(100MHz,DMSO-d6,60℃)δ140.3,129.0,128.7,127.2,59.6,58.4,55.0,47.4,45.9,31.7,24.8,21.7,19.0.HPLC:Chiralpak OG column,220nm,30℃,n-hexane/i-propanol＝93/7,flow＝0.8mL/min,retention time 14.5min(maj)and 15.6min.
产物的产率为分离收率，见表2,3,4。
表2.铱催化不对称氢化3-取代吡嗪盐
表3.铱催化不对称氢化3,5-二取代吡嗪盐
表4.铱催化不对称氢化2,3-二取代吡嗪盐
本发明通过均相铱催化的不对称氢化，采用烷基盐活化策略，成功实现了铱催化哌嗪盐的不对称氢化，该反应收率高、立体选择性好、底物适用范围广，为一系列3-取代，3,5-二取代以及2,3-二取代吡嗪衍生物的合成提供了一条简洁、高效的合成路线。部分氢化产物是非常有用的中间体，可以用来合成药物分子。

Claims (7)

1.一种铱催化不对称氢化合成哌嗪衍生物的方法，其催化体系为铱的双膦配合物，反应式和条件如下：
式中：
温度：-20-70℃；
溶剂：甲苯、四氢呋喃、乙酸乙酯、1,4-二氧六环、1,2-二氯乙烷、二氯甲烷、苯中的一种或两种以上的混合；
氢气压力：10-80个大气压；
时间：20-36小时；
所述催化剂为(1,5-环辛二烯)氯化铱二聚体和双膦配体的配合物；
所述X为氯负离子、溴负离子、碘负离子、三氟甲磺酸根负离子、高氯酸根负离子、四氟化硼负离子及六氟磷负离子中的一种或两种以上；
所述R1为C1-C20的烷基，苄基或含取代基的苄基，苄基苯环上取代基为甲基、甲氧基、三氟甲基、甲氧羰基、乙氧羰基、异丙基氧羰基中的一种或二种以上，取代基的个数为1-5个；
所述R为C1-C20的烷基、萘基、苯基或含有取代基的苯环，苯环上取代基为甲基、甲氧基、苄氧基、氟、氯、溴、三氟甲基、甲氧羰基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；取代基的个数为1-5个。
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)和双膦配体在溶剂中室温搅拌10-15分钟而成；(1,5-环辛二烯)氯化铱二聚体与双膦配体的摩尔比为1:2.0-3.0，铱配合物在溶剂中的摩尔浓度为0.002-0.003mol/L。
3.如权利要求1或2所述的方法，其特征在于：所述双膦配体为(R)-MeO-BiPhep,(R)-SegPhos,(R)-MP2-SegPhos,(R,Sp)-JosiPhos,(S,S)-f-Binaphane中的一种或二种以上。
4.如权利要求1或2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0.25％到1％。
5.如权利要求1所述的方法，其特征在于：所述溶剂用量为每0.2毫摩尔氢化底物2到4毫升。
6.如权利要求1所述的方法，其特征在于：所述反应式为2-取代、3,5-二取代或2,3-二取代吡嗪的不对称氢化中的一种或二种以上，得到相应的手性哌嗪衍生物。
7.如权利要求6所述的方法，其特征在于：
对于2-取代底物，所用配体为(R,Sp)-tBu-JosiPhos，溶剂为甲苯和1,4-二氧六环混合(体积比为1/1)，温度为-20℃，氢气压力为1200psi所得结果最佳，对映体过量最高可达91％；
对于3,5-二取代的底物，所用配体为(R)-SegPhos效果最佳，d.r.>20:1，对映体过量最高可达93％；
对于2,3-二取代的底物，所用配体为(R)-MP2-SegPhos效果最佳，d.r.>20:1，对映体过量最高可达96％。
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CN110776470B (zh) * 2018-07-31 2021-04-02 中国科学院大连化学物理研究所 一种铱催化喹唑啉酮化合物不对称氢化合成手性3,4-二氢喹唑啉酮的方法
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