CN106995377B - 仿生催化不对称氢化合成手性含氟炔丙胺衍生物的方法 - Google Patents

仿生催化不对称氢化合成手性含氟炔丙胺衍生物的方法 Download PDF

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CN106995377B
CN106995377B CN201610050611.6A CN201610050611A CN106995377B CN 106995377 B CN106995377 B CN 106995377B CN 201610050611 A CN201610050611 A CN 201610050611A CN 106995377 B CN106995377 B CN 106995377B
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周永贵
陈木旺
吴波
陈章培
孙蕾
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Dalian Institute of Chemical Physics of CAS
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Abstract

仿生催化不对称氢化合成手性含氟炔丙胺衍生物的方法，其用到的催化体系是钌和手性磷酸。反应能在下列条件内进行，温度：25‑100℃；溶剂：1,2‑二氯乙烷；压力：13‑80个大气压；底物和催化剂的比例是100/l；催化剂为(4‑异丙基甲苯)碘化钌二聚体和手性磷酸。通过含氟的炔基取代的亚胺的选择性氢化能得到相应的手性含氟丙胺衍生物的方法，其对映体过量可达到98％。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

仿生催化不对称氢化合成手性含氟炔丙胺衍生物的方法
技术领域
本发明涉及一种应用仿生催化体系高度化学选择性和对映选择性氢化含氟取代的炔基亚胺合成手性含氟手性炔丙胺衍生物的方法。
背景技术
手性炔丙胺是合成许多天然产物，药物和复杂化学分子的重要合成子，通常具有广谱的生理活性和药理活性。这类化合物具有多种潜在的药物活性，如：抗艾滋、镇静、安眠、消炎和利尿等特性。大量研究表明将氟原子或含氟基团选择性地引入有机分子能显著地改变原有分子的生理活性和增加其亲脂性。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的就具有抗艾滋病的含氟炔丙胺的结构单元：
鉴于含氟炔丙胺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。但是仅有的几例都是通过炔烃对三氟甲基亚胺的加成来合成三氟甲基炔丙胺。然而通过选择性不对称氢化C＝N可以绿色、高效、且原子经济性较好地合成手性炔丙胺化合物炔没有报道。2004年，studer小组和后来的卿小组分别实现通过手性叔丁基亚磺酰基底物诱导，炔基对亚胺的加成来合成含氟手性炔丙胺(文献1:a)M.Crucianelli,F.De Angelis,F.Lazzaro,L.Malpezzi,A.Volonterio,M,Zanda,J.Fluor.Chem.2004,125,573；b)H.Xiao,Y.Huang,F.-L.Qing,Tetrahedron:Asymmetry2010,21,2949.)。之后张和马等科学家又分别实现了以锌或铑催化炔基对含氟亚胺的加成来合成含氟手性炔丙胺(文献6:a)G.Huang,J.Yang,X.Zhang,Chem.Commun.2011,47,5587；b)F.-G,Zhang,H.Ma,J.Nie,Y.Zheng,Q.Gao,J.-A.Ma,Adv.Synth.Catal.2012,354,1422；c)F.-G.Zhang.；H.Ma,Y.Zheng,J.-A.Ma,Tetrahedron2012,68,7663；d)K.Morisaki,M.Sawa,J.Nomaguchi,H.Morimoto,Y.Takeuchi,K.Mashima,T.Ohshima,Chem.Eur.J.2013,19,8417；e)G.Huang,Z.Yin,X.Zhang,Chem.Eur.J.2013,19,11992.)。
从上述例子中，通过加成反应来合成含氟手性炔丙胺取得了一些不错的结果，但是他们一般条件都较苛刻如需要-78℃，或当量的催化剂等等。因此，发展一种高产率、高立体选择性的方法合成含氟手性炔丙胺化合物仍然是目前研究的难点和热点。
发明内容
本发明的目的是提供一种仿生催化不对称选择性氢化合成手性含氟炔丙胺衍生物的方法，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：
仿生催化不对称选择性氢化合成手性含氟炔丙胺衍生物的方法，其催化体系为(4-异丙基甲苯)碘化钌二聚体和手性磷酸，反应式和条件如下：
式中：
温度：25-100℃；
溶剂：二氯甲烷、甲苯、四氢呋喃、乙酸乙酯、1,4-二氧六环、1,2-二氯乙烷中的一种或二种以上；
氢气压力：13-80个大气压；
时间：20-48小时；
催化剂：(4-异丙基甲苯)碘化钌二聚体和手性磷酸；
所述R1为苯基或含取代基的苯基或为萘基，取代基为-CF3、Me、MeO、Ph以及Cl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，取代基个数为1-5个；萘基为1或2-位萘基；
所述R2为C1-C20的烷基、C2-C20烯基、C2-C20炔基以及苯基或含取代基的苯基或萘基，苯基上的取代基为-CF3、Me、MeO、Ph以及F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，取代基个数为1-5个；萘基为1或2-位萘基；
所述Rf为F、CF2H、C1-C6全氟取代的烷基中的一种；
所述磷酸是八氢联萘酚骨架或联萘酚骨架的手性磷酸，Ar为1-位萘基、苯或含有取代基的苯环，苯环上的取代基为F、Cl、CF3、Me、MeO中的一种取代基或二种取代基，取代基的个数为1-5个；
所述菲啶(Phenanthridine)及其衍生物是简单菲啶，8位是甲基、甲氧基或三氟甲基取代的菲啶中的一种或二种以上。
如上所述将(4-异丙基甲苯)碘化钌二聚体和手性磷酸，菲啶和底物1加入溶剂，在室温搅拌2-5分钟；然后充入氢气13-80个大气压，在25-100℃下搅拌反应20-48h后，柱层析得目标产物。
所述催化剂为手性磷酸，是由手性BINOL或H8-BINOL，将3,3’位碘化后和相应的取代苯硼酸ArB(OH)2经过Suzuki偶联制备，反应中手性磷酸催化剂的使用量和含氟的炔基取代的亚胺的摩尔比0.005:1～0.02:1。
所述菲啶及其衍生物反应所需的仿生氢源，反应中使用量和含氟的炔基取代的亚胺的摩尔比为0.1:1。
以(4-异丙基甲苯)碘化钌二聚体计，所述配合物摩尔量为氢化底物摩尔量的0.01％到0.05％。
所述溶剂用量为每0.25毫摩尔氢化底物用2到4毫升。
所述反应式为对含氟的炔基取代亚胺通过仿生催化不对称选择性氢化得到相应的手性含氟炔丙胺衍生物，钌金属前体为(4-异丙基甲苯)碘化钌二聚体，仿生氢源为8-甲基菲啶(10mol％)，手性磷酸为(R)-CPA的Ar为9-蒽基，溶剂为1,2-氯乙烷，温度为室温，氢气压力为1000psi，所述结果最佳，对映体过量可达到98％。
(4-异丙基甲苯)碘化钌二聚体的制备过程或相关制备文献(该金属可以通过商业购买获得)，也可参考文献(M.A.Bennett,A.K.Smith,J.Chem.Soc.,Dalton Trans.,1974,233-241.)。
本发明具有以下优点：
1.反应活性、化学选择性和对映选择性高，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含氟炔丙胺衍生物。
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，反应在室温就能进行。
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含氟炔丙胺衍生物，实现手性增值，而且还可以通过改变手性磷酸的构型而获得不同构型的手性含氟炔丙胺衍生物，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
往安培瓶中加入称量好的(4-异丙基甲苯)碘化钌二聚体(0.001毫摩尔,1.0毫克)和手性磷酸(0.0004毫摩尔)，8-甲基菲啶(0.02毫摩尔,3.8毫克)，氟代炔基亚胺(0.2毫摩尔)，1,2-二氯乙烷2.0毫升，搅拌2-5分钟。然后将安培瓶放入一个不锈钢的高压釜中，通入氢气1000psi，室温下反应20-48小时。慢慢释放氢气，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30:1)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.溶剂和手性磷酸的筛选
[a]反应条件:1a(0.1mmol),CPA 3(2mol％),溶剂(2.0mL),菲啶(10mol％),[Ru(p-cymene)I2]2(0.5mol％),H2(500psi),RT,48h.[b]Reaction conversion determinedby 1H NMR spectroscopy.[c].Ee was determined by chiral HPLC analysis.[d]H2(1000psi).[e]8甲基菲啶.
实施例2：仿生催化不对称选择性氢化合成手性含氟炔丙胺衍生物
往安培瓶中加入称量好的(4-异丙基甲苯)碘化钌二聚体(0.001毫摩尔,1.0毫克)和手性磷酸((R)-3f,0.0004毫摩尔)，8-甲基菲啶(0.02毫摩尔,3.8毫克)，氟代炔基亚胺(0.2毫摩尔)，1,2-二氯乙烷2.0毫升，搅拌2-5分钟。然后将安培瓶放入一个不锈钢的高压釜中，通入氢气1000psi，室温下反应20-48小时。慢慢释放氢气，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30:1)分离得到纯的产物，反应式如下：
(R)-4-Methoxy-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)aniline(2a):95％yield,pale yellow oil,Rf＝0.60(petroleum ether/ethyl acetate＝30/1),95％ee,[α]20 D＝-231.18(c 1.16,CHCl3)；1H NMR(400MHz,CDCl3)1H NMR(400 MHz,CDCl3)δ7.43-7.41(m,2H),7.33-7.29(m,3H),6.84-6.77(m,4H),4.75(q,J＝5.8 Hz,1H),3.76(s,4H)；13CNMR(100 MHz,CDCl3)δ154.2,138.9,132.0,129.1,128.4,123.8(q,J＝280.0 Hz),121.5,117.0,114.9,86.3,80.9,55.7,52.2(q,J＝34.0Hz)；19F NMR(376 MHz,CDCl3)δ-75.7；Enantiomeric excess was determined by HPLC for the corresponding benzamide(AD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝11.2 min,t2＝12.0 min(maj).
(R)-4-Methoxy-N-(1,1,1-trifluoro-4-p-tolylbut-3-yn-2-yl)anilin e(2b):90％yield,pale yellow solid,mp＝56-58℃,Rf＝0.33(petroleum ether/ethylacetate＝30/1),95％ee,[α]20 D＝-249.00(c 1.02,CHCl3)；1H NMR(400 MHz,CDCl3)δ7.31(d,J＝8.1 Hz,2H),7.10(d,J＝7.9Hz,2H),6.83-6.76(m,4H),4.73(q,J＝6.3 Hz,1H),3.75(s,3H),3.73(brs,1H)；13C NMR(100 MHz,CDCl3)δ154.2,139.4,139.0,131.9,129.1,123.8(q,J＝280 Hz),118.4,116.9,114.9,86.5,80.2(d,J＝2.0 Hz),55.7,52.2(d,J＝34.0 Hz),21.5；19F NMR(376 MHz,CDCl3)δ-75.7；Enantiomeric excess was determinedby HPLC for the corresponding benzamide(As-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝8.8 min,t2＝10.0 min(maj).
(R)-4-Methoxy-N-(1,1,1-trifluoro-4-(4-methoxyphenyl)but-3-yn-2-yl)aniline(2c):96％yield,pale yellow oil,Rf＝0.15(petroleum ether/ethyl acetate＝30/1),95％ee,[α]20 D＝-239.63(c 1.20,CHCl3)；1H NMR(400 MHz,CDCl3)δ7.35(d,J＝8.9 Hz,2H),6.83-6.75(m,6H),4.73(q,J＝6.2 Hz,1H),3.79(s,3H),3.75(s,4H)；13C NMR(100 MHz,CDCl3)δ160.2,154.1,139.0,133.5,123.9(q,J＝280.0 Hz),116.9,114.9,113.5,86.3,79.5(d,J＝2.0 Hz),55.7,52.4,52.2(q,J＝34.0Hz),；19F NMR(376 MHz,CDCl3)δ-75.7；Enantiomeric excess was determined by HPLC for the correspondingbenzamide(AD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝19.6 min,t2＝20.8 min(maj).
(R)-4-Methoxy-N-(1,1,1-trifluoro-4-(4-fluorophenyl)but-3-yn-2-yl)aniline(2d):98％yield,pale yellow oil,Rf＝0.37(petroleum ether/ethyl acetate＝30/1),95％ee,[α]20 D＝-204.91(c 1.26,CHCl3)；1H NMR(400 MHz,CDCl3)δ7.42-7.38(m,2H),7.00(t,J＝8.7 Hz,2H),6.80(dd,J＝24.3,9.0 Hz,4H),4.74(q,J＝6.2 Hz,1H),3.76(s,3H),3.73(brs,1H)；13C NMR(100 MHz,CDCl3)δ1630(d,J＝249.0 Hz),154.2,138.8,134.0(d,J＝8.0 Hz),123.7(q,J＝280.0 Hz),117.5(d,J＝3.0 Hz),116.9,115.8,115.6,114.9,85.2,80.7,55.6,52.2(q,J＝34.0 Hz)；19F NMR(376 MHz,CDCl3)δ-75.7,-109.4；Enantiomeric excess was determined by HPLC for the corresponding benzamide(AS-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝11.5 min,t2＝17.7 min(maj)；HRMS(ESI)m/z Calculated for C17H14F4NO[M+H]+324.1006,found 324.1011.
(R)-4-Methoxy-N-(1,1,1-trifluoro-4-(2-fluorophenyl)but-3-yn-2-yl)aniline(2e):91％yield,pale yellow oil,Rf＝0.56(petroleum ether/ethyl acetate＝30/1),94％ee,[α]20 D＝-230.49(c 1.18,CHCl3)；1H NMR(400 MHz,CDCl3)δ7.40-7.38(m,1H),7.36-7.26(m,1H),7.11-7.01(m,2H),6.87-6.76(m,4H),4.78(q,6.2 Hz,1H),3.79(brs,1H),3.75(s,3H)；13C NMR(100 MHz,CDCl3)δ163.1(d,J＝251.0 Hz),154.3,138.8,133.8(d,J＝1.0 Hz),130.9(d,J＝8.0 Hz),124.5(d,J＝280.0 Hz),124.0(d,J＝4.0Hz),117.1,115.6(d,J＝21.0 Hz),114.9,110.1(d,J＝16.0 Hz),86.0(t,J＝3.0 Hz),79.9,55.6,52.3(q,J＝34.0 Hz)；19F NMR(376 MHz,CDCl3)δ-75.6,-109.4；Enantiomericexcess was determined by HPLC for the corresponding benzamide(As-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝11.1 min,t2＝14.2 min(maj)；HRMS(ESI)m/z Calculated for C17H14F4NO[M+H]+324.1006,found324.1007.
(R)-N-(4-Cyclohexenyl-1,1,1-trifluorobut-3-yn-2-yl)-4-methoxya niline(2f):98％yield,pale yellow oil,Rf＝0.52(petroleum ether/ethyl acetate＝30/1),94％ee,[α]20 D＝-200.40(c 1.22,CHCl3)；1H NMR(400 MHz,CDCl3)δ6.85-6.77(m,2H),6.77-6.67(m,2H),6.22-6.02(m,1H),4.70-4.52(m,1H),3.75(s,3H),3.66(d,J＝9.4 Hz,1H),2.08(dd,J＝6.1,4.3 Hz,4H),1.67-1.48(m,4H)；13C NMR(100 MHz,CDCl3)δ154.0,139.1,137.1,123.8(d,J＝280.0 Hz),119.4,116.7,114.8,88.1,78.1(d,J＝2.2 Hz),55.6,52.0(d,J＝34.0 Hz),28.8,25.6,22.1,21.3；19F NMR(376 MHz,CDCl3)δ-75.9；Enantiomeric excess was determined by HPLC for the corresponding benzamide(OD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝7.0 min(maj),t2＝7.8 min.
(R)-4-Methoxy-N-(1,1,1-trifluorooct-3-yn-2-yl)aniline(2g):98％yield,pale yellow oil,Rf＝0.57(petroleum ether/ethyl acetate＝30/1),95％ee,[α]20 D＝-131.87(c 1.12,CHCl3)；1H NMR(400 MHz,CDCl3)δ6.73(d,J＝9.0 Hz,2H),6.64(d,J＝8.9Hz,2H),4.42(q,J＝6.3 Hz,1H),3.68(s,3H),3.53(d,J＝8.8 Hz,1H),2.14-2.09(m,2H),1.44-1.24(m,4H),0.81(t,J＝7.3 Hz,3H)；13C NMR(100 MHz,CDCl3)δ154.0,139.1,123.9(q,J＝280.0 Hz),116.7,114.8,87.4,72.1(d,J＝2.0Hz),55.6,51.6(q,J＝34.0 Hz),30.3,21.8,18.3,13.5；19F NMR(376MHz,CDCl3)δ-76.2；Enantiomeric excess wasdetermined by HPLC for the corresponding benzamide(AD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝6.7 min(maj),t2＝8.5min.
(R)-4-Methoxy-N-(1,1,1-trifluoro-6-phenylhexa-3,5-diyn-2-yl)a niline(2h):95％yield,pale yellow oil,Rf＝0.59(petroleum ether/ethyl acetate＝30/1),94％ee,[α]20 D＝-334.82(c 1.24,CHCl3)；1H NMR(400 MHz,CDCl3)1H NMR(400 MHz,CDCl3)δ7.52-7.44(m,2H),7.41-7.27(m,3H),6.87-6.81(m,2H),6.75(d,J＝8.9 Hz,2H),4.67(q,J＝6.1 Hz,1H),3.76(s,3H),3.71(d,J＝10.0 Hz,1H)；13C NMR(100 MHz,CDCl3)δ154.5,138.3,132.7,129.8,128.5,123.3(q,J＝280.0 Hz),120.8,117.1,114.9,79.1,74.0(d,J＝1.8 Hz),72.7,71.0,55.6,52.4(q,J＝34.0 Hz)；19F NMR(376 MHz,CDCl3)δ-75.2；Enantiomeric excess was determined by HPLC for the corresponding benzamide(AD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝14.2 min(maj),t2＝17.4 min；HRMS(ESI)m/z Calculated for C19H15F3NO[M+H]+330.1100,found 330.1106.
(R)-4-Methyl-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)aniline(2i):90％yield,pale yellow oil,Rf＝0.15(petroleum ether/ethyl acetate＝30/1),93％ee,[α]20 D＝-210.11(c 0.82,CHCl3)；1H NMR(400MHz,CDCl3)δ7.35(dd,J＝7.9,1.6 Hz,2H),7.30-7.18(m,3H),6.98(d,J＝8.1 Hz,2H),6.63(d,J＝8.3 Hz,2H),4.77(q,J＝6.1Hz,1H),3.81(s,1H),2.19(s,3H)；13C NMR(100 MHz,CDCl3)δ142.7,132.0,123.0,129.7,129.1,128.4,123.8(q,J＝280.0 Hz),121.5,114.9,86.1,80.8(d,J＝2.6 Hz),51.2(q,J＝34.0 Hz),20.5；19F NMR(376 MHz,CDCl3)δ-75.7；Enantiomeric excess wasdetermined by HPLC for the corresponding benzamide(AD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝7.6 min,t2＝8.5 min(maj).
(R)-4-Chloro-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)aniline(2j):93％yield,pale yellow oil,Rf＝0.65(petroleum ether/ethyl acetate＝30/1),93％ee,[α]20 D＝-233.58(c 1.14,CHCl3)；1H NMR(400MHz,CDCl3)δ7.46-7.40(m,2H),7.38-7.27(m,3H),7.22-7.16(m,2H),6.77-6.64(m,2H),4.87-4.81(m,1H),4.03(d,J＝8.9 Hz,1H)；13C NMR(100 MHz,CDCl3)δ143.6,132.0,129.4,128.4,127.8,125.1,123.6(q,J＝280.0Hz),121.2,115.8,86.5,80.0(t,J＝3.0 Hz),50.7(q,J＝34.0 Hz)；19F NMR(376 MHz,CDCl3)δ-75.6；Enantiomeric excess was determined by HPLC for the correspondingbenzamide(AD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝10.1 min,t2＝11.6 min(maj)；HRMS(ESI)m/z Calculated forC16H12F3NCl[M+H]+310.0605,found 310.0604.
(R)-N-(1,1,1-Trifluoro-4-phenylbut-3-yn-2-yl)-4-(trifluoromet hyl)aniline(2k):95％yield,pale yellow oil,Rf＝0.61(petroleum ether/ethyl acetate＝30/1),95％ee,[α]20 D＝-174.60(c 1.30,CHCl3)；1H NMR(400 MHz,CDCl3)δ7.58-7.41(m,4H),7.41-7.27(m,3H),6.80(d,J＝8.6 Hz,2H),5.01-4.94(m,1H),4.36(d,J＝9.2 Hz,1H)；13C NMR(100 MHz,CDCl3)δ147.5,132.0,129.4,128.5,126.9(q,J＝5.0 Hz),123.5(q,J＝280.0 Hz),123.2(t,J＝269.0 Hz),122.5(q,J＝33.0Hz),121.0,113.5,86.7,79.5(d,J＝3.0 Hz),49.8(q,J＝34.0 Hz)；19F NMR(376 MHz,CDCl3)δ–61.5,-75.6；Enantiomericexcess was determined by HPLC for the corresponding benzamide(AD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝10.1 min,t2＝11.1 min(maj)；HRMS(ESI)m/z Calculated for C17H12F6N[M+H]+344.0868,found344.0879.
(R)-3-Methoxy-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-yl)anilin e(2l):92％yield,pale yellow oil,Rf＝0.56(petroleum ether/ethyl acetate＝30/1),92％ee,[α]20 D＝-188.83(c 1.12,CHCl3)；1H NMR(400MHz,CDCl3)δ7.43(dd,J＝7.6,1.3 Hz,2H),7.38-7.24(m,3H),7.15(t,J＝8.1 Hz,1H),6.44-6.32(m,3H),4.89(q,J＝6.1 Hz,1H),4.06(d,J＝9.2 Hz,1H),3.77(s,3H)；13C NMR(100 MHz,CDCl3)δ160.9,146.4,132.0,130.3,129.2,128.4,123.8(q,J＝280.0 Hz),121.4,107.1,105.3,100.8,86.2,80.5(d,J＝2.2 Hz),55.2,50.5(d,J＝34.0 Hz)；19F NMR(376 MHz,CDCl3)δ-75.7；Enantiomericexcess was determined by HPLC for the corresponding benzamide(AD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝12.1 min,t2＝16.6 min(maj).
(R)-N-(1,1,1-Trifluoro-4-phenylbut-3-yn-2-yl)aniline(2m):96％yield,pale yellow oil,Rf＝0.43(petroleum ether/ethyl acetate＝30/1),94％ee,[α]20 D＝-188.85(c 1.06,CHCl3)；1H NMR(400 MHz,CDCl3)δ7.49-7.40(m,2H),7.39-7.21(m,5H),6.95-6.84(m,1H),6.82-6.72(m,2H),4.91(s,1H),4.02(s,1H)；13C NMR(100 MHz,CDCl3)δ145.0,132.0,129.5,129.2,128.4,124.3(d,J＝280.0 Hz),121.4,120.2,114.5,86.2,80.5(d,J＝3.0 Hz),50.6(q,J＝34.0 Hz)；19F NMR(376 MHz,CDCl3)δ-75.7；Enantiomericexcess was determined by HPLC for the corresponding benzamide(AD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝8.0 min,t2＝9.5 min(maj).
(R)-4-Methoxy-N-(2,2,3,3,3-pentafluoro-4-phenylbut-3-yn-2-yl)aniline(2n):99％yield,pale yellow oil,Rf＝0.38(petroleum ether/ethyl acetate＝30/1),98％ee,[α]20 D＝-227.45(c 1.42,CHCl3)；1H NMR(400 MHz,CDCl3)δ7.49-7.26(m,5H),6.91-6.72(m,4H),4.84(dd,J＝12.2,10.9 Hz,1H),3.76(s,3H),3.64(s,1H)；13C NMR(100MHz,CDCl3)δ154.4,138.7,131.9,129.1,128.4,121.5,117.3,116.2(q,J＝285.0 Hz),114.9,113.1,87.1,80.4(d,J＝4.0 Hz),55.6,50.9(t,J＝26.0 Hz)；19F NMR(376 MHz,CDCl3)δ-80.7(s,3F)；-120.2(d,1F),-123.4(d,1F)；Enantiomeric excess wasdetermined by HPLC for the corresponding benzamide(OD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝7.3 min,t2＝9.8min(maj)；HRMS(ESI)m/z Calculated for C18H15F5NO[M+H]+356.1068,found356.1069.
(R)-4-Methoxy-N-(2,2,3,3,4,4,4-heptafluoro-4-phenylbut-3-yn-2-yl)aniline(2o):97％yield,pale yellow oil,Rf＝0.32(petroleum ether/ethyl acetate＝30/1),97％ee,[α]20 D＝-190.32(c 1.50,CHCl3)；1H NMR(400 MHz,CDCl3)δ7.50–7.25(m,5H),6.91–6.68(m,4H),4.91(s,1H),3.76(s,3H),3.66(s,1H)；13C NMR(100 MHz,CDCl3)δ154.4,138.7,131.9,129.1,128.4,123.9(q,J＝269.0 Hz)121.5,117.3,114.9,114.5,111.9,87.1,80.4(d,J＝4.0 Hz),55.6,51.1(t,J＝26.0 Hz)；19F NMR(376 MHz,CDCl3)δ-80.8(t,3F)；-116.9-117.7.(m,1F),-119.3-120.1(m,1F),-123.8-125.5(m,2F)；Enantiomeric excess was determined by HPLC for the corresponding benzamide(OD-H,elute:Hexanes/i-PrOH＝95/5,detector:254 nm,flow rate:0.8 mL/min),30℃,t1＝6.7 min,t2＝9.0 min(maj)；HRMS(ESI)m/z Calculated for C19H15F7NO[M+H]+406.1036,found 406.1038.
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.仿生催化不对称选择性氢化合成手性含氟炔丙胺衍生物2
本发明对氟代炔基亚胺的不对称氢化得到相应的手性含氟炔丙胺衍生物，其对映体过量可达到98％。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，对环境友好等优点。

Claims (7)

1.仿生催化不对称氢化合成手性含氟炔丙胺衍生物的方法，其催化体系为(4-异丙基甲苯)碘化钌二聚体和手性磷酸，反应式和条件如下：
式中：
温度：25-100℃；
溶剂：二氯甲烷、甲苯、四氢呋喃、1,2-二氯乙烷中的一种或二种以上；
氢气压力：13-80个大气压；
时间：20-48小时；
催化剂：(4-异丙基甲苯)碘化钌二聚体和手性磷酸；
所述R1为苯基或含取代基的苯基或为萘基，苯基上的取代基为-CF3、Me、MeO、Ph以及Cl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；或R1为1或2-位萘基；所述R2为C1-C20的烷基、C2-C20烯基、C2-C20炔基以及苯基或含取代基的苯基或萘基，苯基上的取代基为-CF3、Me、MeO、Ph以及F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；萘基为1或2-位萘基；
所述Rf为F、CF2H、C1-C6全氟取代的烷基中的一种；
所述磷酸是八氢联萘酚骨架或联萘酚骨架的手性磷酸，Ar为苯基、9-蒽基或9-菲基；
所述菲啶(Phenanthridine)及其衍生物是简单菲啶，8位的R基团是甲基、甲氧基或三氟甲基取代的菲啶中的一种或二种以上。
2.如权利要求1所述的方法，其特征在于：将(4-异丙基甲苯)碘化钌二聚体和手性磷酸，菲啶和底物1加入溶剂中在室温搅拌2-5分钟；然后充入氢气13-80个大气压，在25-100℃下搅拌反应20-48h后，柱层析得目标产物。
3.如权利要求1或2所述的方法，其特征在于：所述手性磷酸，是由手性BINOL或H8-BINOL，将3,3’位碘化后和相应的取代苯硼酸ArB(OH)2经过Suzuki偶联制备，反应中手性磷酸催化剂的使用量和含氟的炔基取代的亚胺的摩尔比0.005:1～0.02:1。
4.如权利要求1或2所述的方法，其特征在于：所述菲啶及其衍生物是反应所需的仿生氢源，反应中使用量和含氟的炔基取代的亚胺的摩尔比为0.1:1。
5.如权利要求1或2所述的方法，其特征在于：以(4-异丙基甲苯)碘化钌二聚体计，所述(4-异丙基甲苯)碘化钌二聚体摩尔量为氢化底物摩尔量的0.01％到0.05％。
6.如权利要求1或2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1用2到4毫升。
7.如权利要求1所述的方法，其特征在于：所述反应式为对含氟的炔基取代亚胺通过仿生催化不对称选择性氢化得到相应的手性含氟炔丙胺衍生物，钌金属前体为(4-异丙基甲苯)碘化钌二聚体，仿生氢源为8-甲基菲啶10mol％，手性磷酸为(R)-CPA的Ar为9-蒽基，溶剂为1,2-氯乙烷，温度为室温，氢气压力为1000psi，所述结果最佳，对映体过量达到98％。
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