CN103910758B - 一种轴手性联芳基氧膦及轴手性联芳基膦的制备方法 - Google Patents
一种轴手性联芳基氧膦及轴手性联芳基膦的制备方法 Download PDFInfo
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Abstract
本发明公开了一种轴手性联芳基氧膦及轴手性联芳基膦的制备方法,尤其涉及具有如下结构式<b>I</b>的轴手性联芳基氧膦的制备方法。其制备方法是,在碱和溶剂的环境中,以2-双(芳基)氧膦基-1-芳基卤化物或其磺酸酯,2-取代芳基硼酸或对应的硼酸酯或硼酸盐为反应底物,使用金属钯为催化剂,经由催化不对称Suzuki反应,一步直接制备得到轴手性联芳基氧膦,再通过溶剂重结晶,得到光学纯的轴手性联芳基氧膦。进一步采用硅烷还原或其它常用的还原方法,得到相应的轴手性联芳基膦。所述的制备方法操作简单、经济、合成效率高,不需要常见的拆分过程,可以避免已有制备方法步骤繁多、原料浪费的缺点。所述的制备方法为轴手性联芳基氧膦和相应的轴手性联芳基单膦的合成提供了一条更为便捷的途径。
Description
技术领域
本发明涉及一种轴手性联芳基氧膦及轴手性联芳基膦的制备方法。
背景技术
具有联芳结构的单膦配体在有机合成中具有重要的应用价值[(a)Wolfe,J.P.;Singer,R.A.;Yang,B.H.;Buchwald,S.L.J.Am.Chem.Soc.1999,121,9550-9661;(b)Wolfe,J.P.;Buchwald,S.L.Angew.Chem.,Int.Ed.Engl.1999,38,2413-2416;(c)Martin,R.;Buchwald,S.L.Acc.Chem.Res.,2008,41,1461–1473;(d)Yang,Y.;Buchwald,S.L.J.Am.Chem.Soc.2013,135,10642-10645.],可参与众多的碳-碳键形成反应,构建复杂的有机分子。在金属催化的不对称反应中,手性联芳结构的单膦配体的重要性越来越显著,应用越来越广泛(Hayashi,T.Acc.Chem.Res.2000,33,354-362.)。1991年Hayashi课题组通过多步反应,制备了(S)-2-二苯基膦-2’-甲氧基-1,1’-联萘(MOP),此类配体在非官能团烯烃的不对称硅氢化反应中得到很好的应用(Uozumi,Y.;Hayashi,T.J.Am.Chem.Soc.1991,113,9887-9888.)。该课题组将该类配体进行了扩展,合成了一系列MOP类配体(Uozumi,Y.;Suzuki,N.;Ogiwara,A.;Hayashi,T.Tetrahedron1994,50,4293-4302.)。此后,该类配体在多种金属催化的不对称反应中得到了应用,并表现出优秀的反应活性及手性诱导能力[(a)Uozumi,Y.;Hayashi,T.J.Am.Chem.Soc.1994,116,115-176;(b)Hayashi,T.Acc.Chem.Res.2000,33,354-362;(c)Hanzawa,Y.;Taguchi,T.Angew.Chem.Int.Ed.1999,38,2395-2398;(d)Chen,C.;Li,X.-D.;Schreiber,S.J.Am.Chem.Soc.2003,125,10174-10175;(e)Shi,M.;Chen,L.-H.;J.Am.Chem.Soc.2005,127,3790-3800;(f)Shintani,R.;Inoue,M.;Hayashi,T.Angew.Chem.Int.Ed.2006,45,3353–3356;(g)Hoshi,T.;Hagiwara,H.Org.Lett.2011,13,932-935.]。而且,在催化不对称反应合成有生物活性的化合物的研究中,此类配体已得到了重要应用。例如,使用(S)-kenPhos为配体,可实现天然产物(-)-Rhazinilam类似物的不对称催化合成(Herrbach,A.;Marinetti,A.;Baudoin,O.;Guénard,D.;Guéritte,F.J.Org.Chem.2003,68,4897-4905.)。
具有联芳结构的单膦配体的制备方法一般是通过还原相应的联芳基氧膦获得,联芳基氧膦是制备对应的单膦配体的重要前体。而获得联芳基氧膦的常用方法是:使用联芳基卤化物或磺酸酯,与二芳基氯化膦(如二苯基氯化膦)或二芳基氧化膦,经由偶联反应制备获得(Uozumi,Y.;Suzuki,N.;Ogiwara,A.;Hayashi,T.Tetrahedron1994,50,4293-4302.)。然而,这些卤化物或者磺酸酯底物的制备通常需要经过多步反应,尤其是在制备光学纯的对映体时,常常需要使用拆分消旋体的手段,造成整个合成过程原料浪费,成本高,降低了合成效率[(a)Ding,K.;Wang,Y.;Yun,H.;Liu,J.;Wu,Y.;Terada,M.;Okubo,Y.;Mikami,K.Chem.Eur.J.1999,5,1734-1737;(b)Luo,Y.;Wang,F.;Zhu,G.;Zhang,Z.Tetrahedron:Asymmetry2004,15,17-19;(c)Hoshi,T.;Hayakawa,T.;Suzuki,T.;Hagiwara,H.J.Org.Chem.2005,70,9085-9087;(d)Hoshi,T.;Sasaki,K.;Sato,S.;Ishii,Y.;Suzuki,T.;Hagiwara,H.Org.Lett.2011,13,932-935.]。例如,Hayashi课题组制备MOP类配体时,以光学纯的BINOL为原料,需要经过4步反应才能得到相应的轴手性联芳基氧膦,造成了手性原料的浪费(Uozumi,Y.;Suzuki,N.;Ogiwara,A.;Hayashi,T.Tetrahedron1994,50,4293-4302.)。或者,合成过程中采用化学计量的手性试剂进行诱导,如我们课题组在制备桥联轴手性单膦配体时,就采用这种方法(CN102516300A和CN102532196A)。但需要的手性诱导试剂价格昂贵,用量大,合成步骤多,导致制备的成本高。
综上所述,发展有效便利的制备轴手性联芳基氧膦新方法,将为相应的轴手性膦配体制备提供更为高效的途径。
发明内容
本发明的目的是提供一种轴手性联芳基氧膦及相应的轴手性联芳基膦的制备方法。
为实现上述发明目的,本发明采取了以下技术方案:
一种轴手性联芳基氧膦的制备方法,以2-双(芳基)氧膦基-1-芳基卤化物(II)或其磺酸酯(II),2-取代芳基硼酸(III)或对应的2-取代芳基硼酸酯为反应底物或对应的硼酸盐(IV)为反应底物,使用金属钯为催化剂,在碱和溶剂的环境中,在反应温度为0℃~150℃条件下,经由催化不对称Suzuki反应,一步直接制备得到轴手性联芳基氧膦,反应方程式如下eq1所示:
结构式中II芳基卤化物或其磺酸酯;结构式I、II、III、IV中,R1、R2、R4、R5均选自氢、硝基、氟、氯、三氟烷基、C1-20的烃基、C1-20的烷氧基、羧基、酯基、羟基、氰基、NH2或C1-20的N,N-二烷基取代基;R3为氢、氟、氯、溴、羟基、C1-20的烃基或C1-20的烷氧基、芳氧基、芳基或取代芳基;X为氯、溴、碘或三氟甲基磺酸酯、甲基磺酸酯、甲基苯磺酸酯;Ar为苯基、对甲基苯基、3,5-二甲基苯基、3,5-二叔丁基苯基、3,5-二叔丁基-4-甲氧基苯基等芳基或杂环芳基或环己基;联芳骨架是取代的苯基取代的萘基取代的蒽基取代的菲基等稠环结构,联芳骨架也包括取代的杂原子芳环结构,其中的R6、R7是氢、氯、氟、三氟烷基、C1-20的烃基、C1-20的烷氧基或NH2、C1-20的N,N-二烷基取代基;联芳骨架还包括如下结构:
其中,R’为氢或C1-20的烃基,Y为氢、氟、氯、三氟烷基、氰基或硝基等。
上述的C1-20的烃基为甲基、乙基、异丙基、叔丁基、环戊基、环己基、苯基、对甲基苯基、3,5-二甲基苯基、3,5-二叔丁基苯基、4-甲氧基-3,5-二叔丁基苯基或萘基、苄基、1-萘甲基或2-萘甲基等。C1-20的烷氧基和芳氧基是甲氧基、乙氧基、异丙氧基、叔丁氧基、环戊氧基、环己氧基、苯氧基、苄氧基、1-萘甲氧基、2-萘甲氧基等。C1-20的N,N-二烷基取代基是N,N-二甲基、N,N-二乙基、N,N-二异丙基、1-N-杂环丙烷基或其它1-N-杂环烷基等。
反应式eq1中,以具有结构式V~X的化合物为膦配体。
结构式V~X的R8、R9、R10选自氢、C1-20的烃基。C1-20的烃基如甲基、乙基、异丙基、叔丁基、环戊基、环己基、苯基、对甲基苯基、3,5-二甲基苯基、3,5-二叔丁基苯基、4-甲氧基-3,5-二叔丁基苯基、萘基、苄基、1-萘甲基、2-萘甲基等。
V~X所示的单膦配体的绝对构型为R构型或者S构型。结构式X的桥侧链为手性链或非手性链,具体范围与CN102516300A和CN102532196A界定的手性链以及非手性链范围相同,为手性链时,其手性碳原子绝对构型为R构型或者S构型。手性配体也包括基于螺环结构的单膦配体或基于H8-BINOL衍生的八氢联萘基单膦配体或具有中心手性结构的单膦配体。
本发明上述制备联芳基氧膦的方法中,反应物II和反应物III(或III对应的硼酸酯或IV)的摩尔比为1:1~5之间,推荐使用1:2。金属钯与膦配体的摩尔比是Pd:膦配体配体=1:1~3,推荐使用1:1.2。合成方法中使用的有机溶剂为四氢呋喃、乙二醇二甲醚、乙二醇、聚乙二醇、乙醚、甲基叔丁基醚、甲苯、二甲苯、苯、三甲苯、甲醇、乙醇、异丙醇、叔丁醇、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、吡咯烷酮、N-甲基吡咯烷酮以及它们的混合物或者和水的混合物等。使用的钯是零价钯如Pd2(dba)3,或者是二价钯化合物如氯化钯、醋酸钯、三氟乙酸钯、Pd(CH3CN)Cl2等。所使用的碱是氢氧化钠、氢氧化钾、氢氧化钡、碳酸钾、碳酸钠、碳酸铯、碳酸氢钾、碳酸氢钠、氟化钾、氟化铯、磷酸钾、磷酸钠、磷酸二氢钾、磷酸二氢钠、磷酸一氢钾、磷酸一氢钠、叔丁醇钾、叔丁醇钠、氟氢化钾等,碱的用量是反应物I的1~10当量。反应温度为0℃~150℃。
与现有技术相比,本发明具有如下有益效果:本发明在碱和溶剂的环境中,以2-双(芳基)氧膦基-1-芳基卤化物或磺酸酯,2-取代芳基硼酸或对应的硼酸酯或硼酸盐为反应底物,使用金属钯为催化剂,经由催化不对称Suzuki反应,一步直接制备得到高ee值的轴手性联芳基氧膦,再经过重结晶,可以得到光学纯轴手性联芳基氧膦。进一步采用硅烷还原或其它常用的还原方法,得到相应的轴手性联芳基膦。所述的制备方法操作简单、经济,尤其是制备轴手性联芳基氧膦对映体时,所述制备方法的合成效率高,可以避免已有制备方法步骤繁多、原料浪费的缺点。所述的制备方法为轴手性联芳基氧膦及相应的轴手性联芳基膦提供了一种更为便捷的途径。
具体实施方式
通过下述实施例有助于进一步理解本发明,但并不限制本发明的内容。
实施例1:化合物的制备
在氮气保护下,将103mg(0.25mmol)(1-溴-2-萘基)-二苯基氧膦、68mg(0.5mmol)2-甲基苯硼酸、159mg(0.75mmol)K3PO4、5.77mg(0.012mmol)配体L1、4.58mg(0.005mmol)Pd2(dab)3加入反应管中。3mL无水无氧甲苯为溶剂,100℃反应72小时。反应体系过滤除去不溶物,浓缩,粗品过硅胶柱分离纯化得浅黄色固体(消旋体)。产率:80%。对映选择性67%ee(高效液相色谱,ChiralcelOD-H柱,25℃,正己烷:异丙醇=90:10,0.5mL/min,230nm,tR=13.71min,15.62min)。[α]25 D-0.8(c=5.0,CHCl3),ESI-MS:419.3[M+H]+。
1HNMR(300MHz,CDCl3)δ7.88(dd,J=8.6,2.9Hz,2H),7.72(dd,J=11.5,8.5Hz,1H),7.58-7.20(m,13H),7.14-7.09(m,1H),6.92(d,J=7.4Hz,1H),6.89(d,J=7.1Hz,1H),6.83(d,J=7.7Hz,1H),1.66(s,3H)ppm;
13CNMR(75MHz,CDCl3)δ145.96,145.84,137.90,136.44,136.37,134.84,134.81,134.11,133.89,132.90,132.73,132.51,131.97,131.85,131.78,131.65,131.38,131.34,131.23,131.19,131.12,129.41,129.03,128.69,128.53,128.31,128.20,128.15,128.09,128.07,128.04,128.01,127.67,127.34,127.17,126.96,124.69,20.49ppm;
31PNMR(121MHz,CDCl3)δ28.31ppm。
实施列2:化合物的制备
方法步骤同实施例1,产率90%。对映选择性68%ee(高效液相色谱,ChiralcelOD-H柱,25℃,正己烷:异丙醇=75:25,1.0mL/min,230nm,tR=6.23min,8.13min)。[α]25 D-28.8(c=0.9,CHCl3),ESI-MS:457.2[M+Na]+。
1HNMR(300MHz,CDCl3)δ7.80-7.85(m,2H),7.57-7.71(m,3H),7.28-7.52(m,9H),7.10-7.23(m,4H),6.81-6.86(m,1H),6.36(d,J=8.4Hz,1H),3.29(s,3H)ppm;
13CNMR(75MHz,CDCl3)δ156.69,143.87,143.76,134.78,134.43,134.08,133.44,133.29,133.14,133.06,132.70,132.34,132.22,131.33,131.28,131.21,130.81,130.78,130.03,129.89,128.89,128.73,128.66,128.37,128.21,128.09,127.87,127.70,127.47,127.29,126.70,125.90,125.83,119.80,109.41,54.71ppm;
31PNMR(121MHz,CDCl3)δ28.65ppm.
实施列3:化合物的制备
方法步骤同实施例1,产率89%。对映选择性66%ee(高效液相色谱,ChiralcelOD-H柱,25℃,正己烷:异丙醇=95:5,0.8mL/min,230nm,tR=44.00min,48.40min)。[α]25 D-3.9(c=1.0,CHCl3),ESI-MS:477.2[M+Na]+。
1HNMR(300MHz,CDCl3)δ7.87-7.96(m,2H),7.77-7.84(m,1H),7.43-7.62(m,6H),7.08-7.34(m,9H),7.00-7.05(m,2H),6.85-6.94(m,3H)ppm;
13CNMR(75MHz,CDCl3)δ144.52,134.86,134.83,134.79,133.55,132.97,132.88,132.41,132.27,131.97,131.85,131.19,131.15,131.02,130.88,130.64,130.60,130.31,129.16,129.00,128.97,128.89,128.86,128.69,128.15,128.06,127.99,127.93,127.70,127.56,127.02,126.92,125.83,125.53,124.90ppm;
31PNMR(121MHz,CDCl3)δ29.29ppm.
实施列4:化合物的制备
方法步骤同实施例1,产率91%。对映选择性45%ee(高效液相色谱,ChiralcelOD-H柱,25℃,正己烷:异丙醇=95:5,0.5mL/min,230nm,tR=17.29min,18.98min)。[α]25 D-71.8(c=0.9,CHCl3),ESI-MS:513.3[M+Na]+。
1HNMR(300MHz,CDCl3)δ7.82(d,J=8.7Hz,2H),7.63-7.70(m,1H),7.45-7.50(m,1H),7.29-7.33(m,4H),7.21-7.24(m,1H),7.12-7.18(m,1H),7.04(m,3H),6.84-6.91(m,2H),6.38(d,J=8.1Hz,1H),3.30(s,3),2.27(s,6H),2.18(s,6H)ppm;
13CNMR(75MHz,CDCl3)δ156.85,143.59,143.45,138.44,138.27,137.82,137.64,137.25,137.08,134.74,134.72,134.19,133.89,133.50,133.24,133.08,133.05,132.83,132.61,132.58,132.52,130.76,130.09,130.03,130.02,129.93,129.81,129.48,129.40,129.17,129.06,129.04,128.95,128.88,128.26,128.05,128.00,127.70,127.44,127.32,127.30,127.17,126.52,126.07,126.00,119.72,119.67,109.40,54.87,21.68,21.57ppm;
31PNMR(121MHz,CDCl3)δ28.96ppm.
实施例5:化合物的制备
在氮气保护下,将47.6mg(0.1mmol)(1-三氟甲基磺酸酯基-2-萘基)-二苯基氧膦、40.0mg(0.2mmol)2-联苯硼酸、64mg(0.3mmol)K3PO4、3.6mg(0.0048mmol)配体L2、1.8mg(0.002mmol)Pd(OAc)2加入反应管中。2mL无水无氧四氢呋喃为溶剂,70℃反应24-120小时。反应体系过滤除去不溶物,浓缩,粗品过硅胶柱分离纯化得浅黄色固体物。产率:46%。对映选择性65%ee(高效液相色谱,ChiralcelOD-H柱,25℃,正己烷:异丙醇=75:25,1.0mL/min,230nm,tR=7.35min,10.42min)。[α]25 D-14.8(c=1.0,CHCl3),ESI-MS:503.3[M+Na]+。
1HNMR(300MHz,CDCl3)δ7.76(d,J=8.4Hz,1H),7.71(d,J=8.17Hz,1H),7.32-7.50(m,15H),7.12-7.19(m,4H),686-6.97(m,4H)ppm;
13CNMR(75MHz,CDCl3)δ146.46,146.36,142.49,141.55,136.33,136.27,135.09,134.98,134.33,133.78,133.72,133.62,132.24,132.20,132.11,132.07,131.49,131.01,130.02,129.63,129.23,128.70,128.56,128.47,128.41,128.31,127.97,127.92,127.83,127.36,127.10,126.93,126.84,126.46,126.34,125.51ppm;
31PNMR(121MHz,CDCl3)δ29.82ppm.
实施例6:化合物的制备
方法步骤同实施例5,产率:50%,对映选择性25%ee(高效液相色谱,ChiralcelOD-H柱,25℃,正己烷:异丙醇=75:25,1.0mL/min,230nm,tR=17.35min,20.46min)。[α]25 D-8.8(c=1.0,CHCl3),ESI-MS:503.3[M+Na]+。
1HNMR(300MHz,CDCl3)δ6.73-6.80(m,2H),6.84-6.87(m,4H),6.95-6.99(m,4H),7.04-7.10(m,1H),7.18-7.39(m,8H),7.49-7.55(m,1H),7.60-7.69(m,5H)ppm;
31PNMR(121MHz,CDCl3)δ28.83ppm。
实施例7:化合物的制备
方法步骤同实施例5,产率:81%,对映选择性70%ee(高效液相色谱,ChiralcelAD-H柱,25℃,正己烷:异丙醇=80:20,1.0mL/min,230nm,tR=9.91min,15.57min)。[α]25 D-34.2(c=1.0,CHCl3),ESI-MS:491.3[M+H]+。
1HNMR(300MHz,CDCl3)δ7.83-7.95(m,3H),7.68(d,J=8.7Hz,1H),7.42-7.50(m,4H),7.34(d,J=6.9Hz,1H),7.27(d,J=6.9Hz,1H),7.21-7.25(m,2H),7.00-7.19(m,7H),6.85-6.91(m,3H),2.57(s,3H)ppm;
13CNMR(75MHz,CDCl3)δ144.62,144.50,135.11,134.85,134.81,133.81,133.71,133.67,133.37,133.29,133.03,132.97,132.39,132.33,132.27,132.16,132.06,131.92,131.80,131.65,131.45,131.03,130.95,130.91,130.83,130.79,130.31,130.29,130.08,129.95,129.12,128.97,128.81,128.65,128.08,127.97,127.92,127.89,127.81,127.72,127.70,127.48,127.44,127.28,126.90,125.68,125.64,125.47,125.41,125.34,124.09,19.77ppm;
31PNMR(121MHz,CDCl3)δ29.32ppm.
实施例8:化合物的制备
方法步骤同实施例5,产率:56%,对映选择性79%ee(高效液相色谱,ChiralcelAD-H柱,25℃,正己烷:异丙醇=75:25,1.0mL/min,230nm,tR=8.60min,10.57min)。[α]25 D-24.2(c=1.0,CHCl3),ESI-MS:439.4[M+H]+。
1HNMR(300MHz,CDCl3)δ7.72-7.90(m,3H),7.67-7.70(m,4H),7.28-7.66(m,11H),7.25-7.29(m,2H),7.13-7.7.16(m,1H)ppm;
13CNMR(75MHz,CDCl3)δ141.32,141.22,138.05,138.00,136.77,135.21,134.67,134.64,134.42,133.79,133.64,133.25,132.41,132.20,131.95,131.92,131.84,131.80,131.75,131.68,131.63,131.34,130.00,128.79,128.68,128.62,128.54,128.52,128.44,128.41,128.12,127.95,127.87,126.68,126.64ppm;
31PNMR(121MHz,CDCl3)δ28.75ppm
实施例9:化合物的制备
在氮气保护下,将91mg(0.25mmol)(1-氯-2-萘基)-二苯基氧膦、114mg(0.5mmol)芳基硼酸盐、159mg(0.75mmol)Na3PO4、5.92mg(0.012mmol)配体L3、4.58mg(0.005mmol)Pd(OAc)2加入反应管中。3mL无氧的THF-H2O(10:1)为溶剂,40-100℃反应100小时。反应体系过滤除去不溶物,浓缩,粗品过硅胶柱分离纯化得浅黄色固体产物。产率:63%,对映选择性87%ee(高效液相色谱,ChiralcelOD-H柱,25℃,正己烷:异丙醇=80:20,1.0mL/min,230nm,tR=6.20min,6.98min)。[α]25 D-30.8(c=1.0,CHCl3),ESI-MS:471.2[M+Na]+。
1HNMR(300MHz,CDCl3)δ7.81-7.85(m,2H),7.58-7.71(m,3H),7.28-7.52(m,9H),7.15-7.20(m,3H),7.09(t,J=7.8Hz,1H),6.81(t,J=7.5Hz,1H),6.29(d,J=8.1Hz,1H),3.58-3.68(m,1H),3.42-3.52(m,1H),0.95(t,J=6.9Hz,3H)ppm;
13CNMR(75MHz,CDCl3)δ156.08,140.02,134.68,133.46,133.27,133.11,132.37,132.25,131.28,131.23,131.14,131.11,130.81,130.78,129.85,129.77,128.86,128.70,128.67,128.47,128.35,128.32,128.16,128.12,127.96,127.86,127.83,127.76,127.59,127.58,127.33,127.16,126.44,126.05,125.97,119.57,110.09,62.67,14.80ppm;
31PNMR(121MHz,CDCl3)δ28.87ppm.
实施例10:化合物的制备
方法步骤同实施例9,产率:96%,对映选择性65%ee(高效液相色谱,ChiralcelOD-H柱,25℃,正己烷:异丙醇=80:20,1.0mL/min,230nm,tR=7.65min,16.06min)。[α]25 D-32.7(c=0.9,CHCl3),ESI-MS:487.4[M+Na]+。
1HNMR(300MHz,CDCl3)δ7.79-7.84(m,2H),7.67-7.73(dd,J=7.8Hz,3.3Hz,2H),7.29-7.61(m,10H),7.14-7.21(m,3H),6.39(d,J=8.4Hz,1H),5.89(s,1H),3.77(s,3H),3.27(s,3H)ppm;
13CNMR(75MHz,CDCl3)δ161.29,157.64,143.86,143.77,134.84,134.81,134.41,134.07,133.99,133.68,133.53,133.03,132.68,132.34,132.22,131.30,131.28,131.15,131.02,130.76,130.71,130.55,129.15,128.89,128.72,128.36,128.21,128.18,128.07,127.89,127.81,127.79,127.61,127.40,127.24,126.63,118.69,118.61,103.47,97.65,55.67,54.68ppm;
31PNMR(121MHz,CDCl3)δ28.83ppm.
实施例11:化合物的制备
方法步骤同实施例9,产率:90%,对映选择性86%ee(高效液相色谱,ChiralcelOD-H柱,25℃,正己烷:异丙醇=90:10,1.0mL/min,230nm,tR=6.96min,10.27min)。[α]25 D-83.2(c=0.8,CHCl3),ESI-MS:485.2[M+Na]+。
1HNMR(300MHz,CDCl3)δ7.80-7.84(m,2H),7.64-7.70(m,3H),7.29-7.51(m,9H),7.15-7.20(m,3H),7.05(t,J=7.5Hz,1H),6.76(t,J=7.5Hz,1H),6.34(d,J=8.4Hz,1H),4.07-4.15(m,1H),0.91-0.98(m,6H)ppm;
13CNMR(75MHz,CDCl3)δ155.22,144.17,144.04,134.69,134.67,134.52,134.24,133.37,133.17,133.02,132.85,132.39,132.30,132.27,131.38,131.23,131.20,130.84,130.79,129.67,128.90,128.74,128.29,128.14,127.89,127.87,127.77,127.71,127.28,127.10,126.75,126.69,126.26,119.34,111.31,69.07,22.94,21.31ppm;
31PNMR(121MHz,CDCl3)δ29.21ppm.
实施例12:化合物的制备
在氮气保护下,将103mg(0.25mmol)(1-溴-2-萘基)-二苯基氧膦、62mg(0.5mmol)芳基硼酸酯、159mg(0.75mmol)Na3PO4、5.65mg(0.012mmol)配体L4、4.58mg(0.005mmol)Pd(OAc)2加入反应管中。3mL无氧的二氧六环dioxane为溶剂,40-100℃反应100小时。反应体系过滤除去不溶物,浓缩,粗品过硅胶柱分离纯化得浅黄色固体产物。产率:80%,对映选择性86%ee(高效液相色谱,ChiralcelAD-H柱,25℃,正己烷:异丙醇=75:25,1.0mL/min,230nm,tR=7.69min,12.20min)。[α]25 D-28.3(c=1.1,CHCl3),ESI-MS:533.2[M+Na]+。
1HNMR(300MHz,CDCl3)δ7.83-7.90(m,2H),7.66-7.72(m,2H),7.52-7.63(m,2H),7.31-7.46(m,9H),7.10-7.17(m,6H),6.90(t,J=7.5Hz,1H),6.80-6.83(m,2H),6.44(d,J=8.1Hz,1H),4.68(d,J=12.0Hz,1H),4.55(d,J=8.4Hz,1H)ppm;
13CNMR(75MHz,CDCl3)δ155.81,143.90,137.31,134.76,134.31,134.04,133.55,133.38,133.22,132.93,132.66,132.38,132.26,131.33,131.21,130.79,130.11,129.85,128.86,128.70,128.31,128.21,128.06,127.91,127.82,127.65,127.42,127.24,126.67,126.47,120.12,110.65,68.88ppm;
31PNMR(121MHz,CDCl3)δ28.69ppm.
实施例13:化合物的制备
方法步骤同实施例12,产率:79%,对映选择性64%ee(高效液相色谱,ChiralcelAD-H柱,25℃,正己烷:异丙醇=80:20,1.0mL/min,230nm,tR=11.75min,15.49min)。[α]25 D-23.3(c=0.8,CHCl3),ESI-MS:485.2[M+Na]+。
1HNMR(300MHz,CDCl3)δ7.78-7.83(m,2H),7.44-7.66(m,5H),7.23-7.35(m,4H),7.12-7.19(m,3H),6.98(d,J=7.8Hz,2H),6.83(t,J=7.5Hz,1H),6.38(d,J=8.4Hz,1H),3.25(s,3),2.35(s,3H),2.30(s,3H)ppm;
13CNMR(75MHz,CDCl3)δ156.77,143.64,143.54,141.51,141.48,140.97,140.94,134.74,134.72,133.38,133.34,133.18,132.42,132.33,132.29,132.21,131.43,131.40,131.29,131.13,130.49,130.00,129.71,129.68,129.53,129.36,129.11,129.09,129.02,128.97,128.91,128.82,128.61,128.44,128.29,128.04,127.98,127.75,127.44,127.33,127.16,126.60,126.14,126.06,119.77,109.36,54.71,21.97,21.88ppm;
31PNMR(121MHz,CDCl3)δ29.21ppm.
实施例14:光学纯化合物(>99%ee)的制备
化合物12(86%ee,1.02g,2mmol)在二氯甲烷-正己烷的混合溶液中重结晶,获得光学纯产物12(0.82g,产率:80%,>99%ee);(高效液相色谱,ChiralcelAD-H柱,25℃,正己烷:异丙醇=75:25,1.0mL/min,230nm,tR=7.70min,12.23min);[α]25 D-33.3(c=1.0,CHCl3)。
Claims (6)
1.一种轴手性联芳基氧膦的制备方法,其特征在于,以2-双(芳基)氧膦基-1-芳基卤化物(II)或其磺酸酯,2-取代芳基硼酸(III)或对应的2-取代芳基硼酸酯为反应底物或对应的硼酸盐(IV)为反应底物,使用金属钯为催化剂,在碱和溶剂的环境中,经由催化不对称Suzuki反应,一步直接制备得到轴手性联芳基氧膦,反应方程式如eq1所示:
结构式I、II、III、IV中,R1、R2、R4、R5均选自氢、C1-20的烃基、C1-20的烷氧基;R3选自氢、氟、氯、溴、羟基、C1-20的烃基或C1-20的烷氧基;X选自氯、溴、碘或三氟甲基磺酸酯、甲基磺酸酯、甲基苯磺酸酯;Ar选自苯基、对甲基苯基、3,5-二甲基苯基、3,5-二叔丁基苯基;联芳骨架选自 其中,Y为氢;上述的C1-20的烃基选自甲基、乙基、异丙基、叔丁基、环戊基、环己基、苯基、对甲基苯基、3,5-二甲基苯基、3,5-二叔丁基苯基;C1-20的烷氧基选自甲氧基、乙氧基、异丙氧基、叔丁氧基、环戊氧基、环己氧基、苄氧基;所述膦配体的结构式选自:
结构式V~X的R8、R9、R10选自氢、C1-20的烃基;
V~X所示的单膦配体的绝对构型为R构型或者S构型;结构式X的桥侧链为手性链或非手性链,为手性链时,其手性碳原子绝对构型为R构型或者S构型。
2.如权利要求1所述轴手性联芳基氧膦的制备方法,其特征在于:反应温度为0℃~150℃,反应12~100小时后,再通过溶剂重结晶,得到光学纯的轴手性联芳基氧膦;其中,反应物II和反应物III或III对应的2-取代芳基硼酸酯或对应的硼酸盐(IV)的摩尔比为1:1~5,金属钯与配体的摩尔比为1:1~3,配体的用量是反应物II的1~20mol%,碱的用量是反应物II的1~10当量。
3.如权利要求1所述的轴手性联芳基氧膦的制备方法,其特征是金属钯为零价钯或二价钯化合物。
4.如权利要求1所述的轴手性联芳基氧膦的制备方法,其特征是所述的碱是碳酸钾、碳酸钠、碳酸铯、碳酸氢钾、碳酸氢钠、氟化钾、氟化铯、磷酸钾、磷酸钠、磷酸二氢钾、磷酸二氢钠、磷酸一氢钾、磷酸一氢钠。
5.如权利要求1所述的轴手性联芳基氧膦的制备方法,其特征是所述的溶剂选自四氢呋喃、甲苯以及它们的混合物或者和水的混合物。
6.如权利要求3所述的轴手性联芳基氧膦的制备方法,其特征是所述零价钯化合物为Pd2(dba)3,所述二价钯化合物为氯化钯、醋酸钯、三氟乙酸钯或Pd(CH3CN)Cl2。
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