CN105732726B - 一种含樟脑的亚胺膦配体的合成方法及其用途 - Google Patents

一种含樟脑的亚胺膦配体的合成方法及其用途 Download PDF

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CN105732726B
CN105732726B CN201610067668.7A CN201610067668A CN105732726B CN 105732726 B CN105732726 B CN 105732726B CN 201610067668 A CN201610067668 A CN 201610067668A CN 105732726 B CN105732726 B CN 105732726B
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陈巍峰
刘巧灵
李志芳
徐利文
郑战江
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Hangzhou Normal University
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Abstract

本发明涉及膦氮配体领域，公开了一种含樟脑的亚胺膦配体的合成方法及其用途。含樟脑的亚胺膦配体的合成方法，选用手性胺1‑6中的一种和天然樟脑作为原料，在缩合剂存在下进行脱水缩合制备。本发明的含樟脑的亚胺膦配体是以天然樟脑以及含膦手型胺为原料在缩合剂存在下进行脱水缩合合成。本发明的含樟脑的亚胺膦手性配体，原料易得、合成路线简单、操作简便、易于纯化；将本发明的含樟脑的亚胺膦配体应用于不对称烯丙基取代反应中，具有不对称催化效率高、对映选择性高、收率高得的优点。

Description

一种含樟脑的亚胺膦配体的合成方法及其用途
技术领域
本发明涉及膦氮配体领域，尤其涉及一种含樟脑的亚胺膦配体的合成方法及其用途。
背景技术
手性的膦氮配体在合成具有生物活性的天然产物以及药物中间体已经有了广泛的应用(Trost B M.,Crawley M L.Chem.Rev.2003,103,2921～2943)。已报道的能够催化烯丙基烷基化反应的配体类型虽然也有膦配体和氮配体，但手性膦氮配体占绝对优势地位，其钯的配合物在该反应中有突破性的催化效果(Mcmanus H A,GuiryP.J.Chem.Rev.2004,104,4151～4202)。但已有的一些手性的膦氮配体在不对称合成中存在一些缺陷：1、配体合成复杂不容易制备；2、底物普适性差；3、对映选择性和产率差，影响了工业化的应用。因而设计和开发廉价易得、高活性和高选择性的配体是膦氮手型配体在不对称催化应用中的关键。
发明内容
为了解决上述技术问题，本发明提供了一种含樟脑的亚胺膦配体的合成方法及其用途。本发明的含樟脑的亚胺膦手性配体的合成方法，具有原料易得、合成路线简单、操作简便、易于纯化的优点，将本发明的含樟脑的亚胺膦配体应用于不对称烯丙基取代反应中，具有不对称催化效率高、对映选择性高、收率高得的优点。
本发明的具体技术方案为：一种含樟脑的亚胺膦配体，具有L1-L6六种化学结构式：
其中n＝0－1；R为C1－C12烷基、C5－C7的环烷基、苯基、苄基、(1-苯基)乙基、1-萘基或2-萘基；R’为氢、C1－C12烷基、C5－C7的环烷基、苯基、苄基、(1-苯基)乙基、1-萘基、2-萘基、甲氧基或卤素；Ar为苯基、1-萘基、2-萘基、2-烷基苯基、3-烷基苯基、4-烷基苯基、2,6-二烷基苯基、3,4-二烷基苯基、2,4,6-三烷基苯基、2-烷氧基苯基、3-烷氧基苯基、4-烷氧基苯基、2,6-二烷氧基苯基、3,4-二烷氧基苯基、2,4,6-三烷氧基苯基、2-卤素苯基、3-卤素苯基、4-卤素苯基、2,6-二卤素苯基、3,4-二卤素苯基或2,4,6-三卤素苯基。
本发明所述的含樟脑的亚胺膦配体，是以天然樟脑以及含膦手型胺为原料在缩合剂存在下进行脱水缩合合成：
其中，原料1－6和天然樟脑在缩合剂存在下进行脱水缩合制备。
作为优选，上述反应中所用溶剂为氯仿、甲醇、乙醇、丙醇、丁醇、戊醇、四氢呋喃、环戊基甲醚、2-甲基四氢呋喃、乙醚、异丙醚、正丙醚、二甲基亚砜、甲苯、苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、氯仿、二氯甲烷、1,2-二氯乙烷、四氯化碳、正己烷、环己烷、乙酸乙酯、乙酸异丙酯、乙腈中的一种。
作为进一步的优选，上述反应中所用溶剂为甲苯或四氢呋喃。
作为优选，所用缩合剂选自硫酸镁、氧化铝、三氟化硼乙醚、四氯化钛、钛酸四乙酯、钛酸四异丙酯、甲磺酸、对甲基苯磺酸、苯磺酸、樟脑磺酸、三氟甲磺酸、三氟乙酸、三氯乙酸。
作为进一步的优选，缩合剂为三氟乙酸。
含樟脑的亚胺膦配体在不对称烯丙基取代反应中的应用：
其中Ligand为化合物L1－6中的一种。
Pd salt为氯化钯、二(三叔丁基膦)钯、四三苯基膦钯、醋酸钯、烯丙基氯化钯、双(二亚苄基丙酮)钯中的一种。
Base为氢氧化钠、氢氧化钾、氢氧化铯、磷酸钾、磷酸钠、磷酸氢钾、抗坏血酸钠、碳酸铯、碳酸钾、碳酸钠、醋酸钠、醋酸钾和醋酸铯中的一种。
R1和R2为氢、C1－C12烷基、C5－C7的环烷基、苯基、苄基(1-苯基)乙基、1-萘基、2-萘基、2-烷基苯基、3-烷基苯基、4-烷基苯基、2,6-二烷基苯基、3,4-二烷基苯基、2,4,6-三烷基苯基、2-烷氧基苯基、3-烷氧基苯基、4-烷氧基苯基、2,6-二烷氧基苯基、3,4-二烷氧基苯基、2,4,6-三烷氧基苯基、2-卤素苯基、3-卤素苯基、4-卤素苯基、2,6-二卤素苯基、3,4-二卤素苯基或2,4,6-三卤素苯基中的一种。
R3为C1－C12烷基、C5－C7的环烷基、苯基、苄基(1-苯基)乙基、1-萘基、2-萘基、2-烷基苯基、3-烷基苯基、4-烷基苯基、2,6-二烷基苯基、3,4-二烷基苯基、2,4,6-三烷基苯基、2-烷氧基苯基、3-烷氧基苯基、4-烷氧基苯基、2,6-二烷氧基苯基、3，4-二烷氧基苯基、2,4,6-三烷氧基苯基、2-卤素苯基、3-卤素苯基、4-卤素苯基、2,6-二卤素苯基、3,4-二卤素苯基或2,4,6-三卤素苯基、C4-C7的环(N、O、S)杂环、苯并C4-C7的环(N、O、S)杂环、(2、3、4、5、6)-(C1-C12烷基、C5－C7的环烷基、苯基、1-萘基、2-萘基、2-烷基苯基、3-烷基苯基、4-烷基苯基)取代的C4-C7环(N、O、S)杂环、(2、3、4、5、6、7、8)-(C1-C12烷基、C5－C7的环烷基、苯基、1-萘基、2-萘基、2-烷基苯基、3-烷基苯基、4-烷基苯基)取代的苯并C4-C7环(N、O、S)杂环中的一种。
上述方法中使用含樟脑的亚胺膦手性配体的量为钯盐的0.1～10倍(摩尔比)。所述含樟脑的亚胺膦手性配体的量为底物的0.001％～100％(摩尔百分数)；所述1.3-二取代基团(单取代)-2-烯丙基-1-醇的乙酸酯与base的摩尔比为1：0.02至1：10；所述1,3-二取代基团(单取代)-2-烯丙基-1-醇乙酸酯与亲核试剂R3XH的比为1:1至1:10；N，O-二(三甲基硅)乙酰胺(BSA)与底物的摩尔比为1:0.1至1:10；所述溶剂的用量为每毫摩尔1,3-二取代基团(单取代)-2-烯丙基-1-醇乙酸酯使用0.1～10mL。
一般来说，过渡金属配合物的合成法通常依赖于合理的设计和至少有一个固有手性中心的廉价的手性源合成的手性配体。基于这方面，廉价的天然樟脑极具吸引力，由于其价格低廉，樟脑骨架上有多个手性中心、刚性结构以及活性酮的结构，是有效的磷配体。与此同时，手性的氮膦广泛的应用到过渡金属的不对称催化领域中。值得注意的是，现今令人满意和广泛应用的、高效的、易合成的、结构新颖的氮磷配体在工业上仍能是一个巨大的挑战。因此，这促使研究人员开发新的和实用的方法合成结构简单的可调整的手性氮磷配体。因此，我们认为天然樟脑是个重要的手性结构，发展天然樟脑结构，合成简单的氮膦配体应用在钯催化的不对称反应中，可以填补一个现代配体设计及催化的空白。我们在之前发现的N-P席夫碱的基础上应用天然樟脑模块化合成了此配体。我们提供了高度模块化的合成方法，合成了刚性席夫碱含有磷和氮原子，并进一步修饰了此类配体的立体结构和电子性质。手性中心来源于伯胺和天然樟脑，这两个原料价格低廉，合成方法简单。这种结构具有易得，空气稳定，是一种与亚胺手性匹配的单磷配体。
与现有技术对比，本发明的有益效果是：
天然樟脑化合物具有价廉、易得、稳定、溶解性能好、结构易于修饰、大空间位阻效应的特点，将樟脑应用到氮膦配体中，合成的亚胺型膦配体，能提高配体的手性诱导效果。本发明成功开发了一种基于天然樟脑为骨架的膦氮手型配体，可以有效的应用于金属钯催化的烯丙基取代反应，以高的对映选择性和收率得到取代产物。
因此，本发明的含樟脑的亚胺膦手性配体的合成方法，原料易得、合成路线简单、操作简便、易于纯化；将本发明的含樟脑的亚胺膦配体应用于不对称烯丙基取代反应中，具有不对称催化效率高、对映选择性高、收率高得的优点。
具体实施方式
下面结合实施例对本发明作进一步的描述：其中实施例1-6为樟脑亚胺膦手性配体的合成，实施例7-18为配体在不对称烯丙基取代反应中的应用。
实施例1：
(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺的合成。
在(S)-1-[2-(二苯基膦)苯基]乙胺(2.135g,7.0mmol)和天然樟脑(1.064g,7.0mmol)的甲苯(35mL)溶液中加入对甲基苯磺酸(5mg)，加热回流十二小时，真空蒸出甲苯。剩余物经乙酸乙酯萃取(3×10mL)，合并有机相，有机相经水洗、饱和氯化钠溶液洗涤。无水硫酸钠干燥后，减压蒸去溶剂，得到粗产品进一步经柱层析分离纯化，得到纯品无色油状物产品(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺2.551g，产率83％。 1H NMR(400MHz,CDCl3)δ7.77(dd,J＝7.1,4.2Hz,1H),7.27–7.11(m,11H),6.98(td,J＝7.6,1.0Hz,1H),6.72(ddd,J＝7.6,4.4,0.9Hz,1H),5.15–5.08(m,1H),2.18–2.12(m,1H),1.65(t,J＝4.4Hz,1H),1.57–1.52(m,1H),1.40(td,J＝12.2,3.9Hz,1H),1.33–1.19(m,2H),1.17(d,J＝6.4Hz,3H),1.01–0.95(m,1H),0.89(s,3H),0.77(s,3H),0.64(s,3H)；13C NMR(101MHz,CDCl3)δ179.73,151.73,151.51,137.70,137.59,137.02,136.91,134.43,134.23,133.71,133.52,133.13,129.41,128.76,128.59,128.56,128.52,128.49,128.42,127.73,127.67,126.54,58.07,57.83,53.39,47.01,43.86,35.41,35.38,31.90,27.27,24.74,19.51,19.10,11.64(Some peaksof rotamer are visible due to assumed hindered rotation)；31P NMR(202MHz,CDCl3)δ-16.08.HRMS(FAB,positive)m/z calcd.for C30H35NP[M+H]+,440.2502；found 440.2519[M+H]+。
实施例2
(R)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺的合成。
将苯磺酸(5mg)加入到(R)-1-[2-(二苯基膦)苯基]乙胺(1.525g,5.0mmol)和天然樟脑(0.760g,5.0mmol)的甲苯(25mL)溶液中，加热回流十二小时，减压蒸出甲苯。将剩余物经乙酸乙酯萃取(3×10mL)，合并有机相，有机相经水洗和饱和氯化钠溶液洗涤。无水硫酸钠干燥后，减压蒸出溶剂，得到粗产品进一步经柱层析分离纯化，得到纯品无色油状物产品(R)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺1.823g，产率83％。 1H NMR(400MHz,CDCl3)δ7.74(dd,J＝7.1,4.3Hz,1H),7.26–7.12(m,11H),7.00(td,J＝7.6,1.1Hz,1H),6.76–6.73(m,1H),5.12–5.06(m,1H),1.76–1.63(m,4H),1.55(td,J＝12.3,4.0Hz,1H),1.29–1.26(m,1H),1.20(d,J＝6.5Hz,3H),1.10–1.03(m,1H),0.89(s,3H),0.77(s,3H),0.34(s,3H)；13C NMR(101MHz,CDCl3)δ180.46,151.81,151.58,137.53,137.42,136.94,136.83,134.27,134.07,133.79,133.59,133.47,133.10,129.33,128.69,128.55,128.51,128.48,128.45,127.33,127.27,126.43,57.87,57.63,53.47,46.98,43.99,35.91,35.88,32.21,27.51,25.05,19.55,19.06,11.48(Some peaks of rotamer are visible due to assumed hindered rotation)；31P NMR(202MHz,CDCl3)δ-16.64.HRMS(FAB,positive)m/z calcd.for C30H35NP[M+H]+,440.2502；found 440.2500[M+H]+。
实施例3
(S)-1-(2-(二苯基膦)苯基)丙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺的合成。
在(S)-1-[2-(二苯基膦)苯基]丙胺(1.596g,5.0mmol)和天然樟脑(0.836g,5.5mmol)的THF(15mL)溶液中加入钛酸四乙酯(1.140g,5.0mmol)，加热回流十小时，减压蒸出THF。剩余物经乙酸乙酯萃取(3×10mL)，合并有机相，有机相经水洗、饱和氯化钠溶液洗涤。无水硫酸钠干燥后，减压蒸去溶剂，得到粗产品进一步经柱层析分离纯化，得到纯品无色油状物产品(S)-1-(2-(二苯基膦)苯基)丙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺1.813g，产率80％。 1H NMR(400MHz,CDCl3)δ7.66-7.64(m,1H),7.21–7.11(m,11H),6.97(t,J＝7.56Hz,1H),6.77–6.75(m,1H),4.91–4.85(m,1H),2.13(dd,J＝16.8,2.2Hz,1H),1.62–1.51(m,4H),1.40(t,J＝12.4Hz,1H),1.21–1.17(m,2H),1.00–0.95(m,1H),0.90(s,3H),0.78(s,3H),0.68–0.65(m,6H)；13C NMR(101MHz,CDCl3)δ180.21,150.95,150.71,137.79,137.67,137.19,137.08,134.32,134.12,133.80,133.61,133.28,129.16,128.68,128.53,128.49,128.47,128.43,128.09,127.92,127.98,127.86,126.37,64.19,63.96,53.69,46.66,43.98,36.06,36.03,32.57,32.11,27.17,19.69,19.07,11.66,11.37(Some peaks of rotamer are visible due to assumedhindered rotation)；31P NMR(202MHz,CDCl3)δ-16.57.HRMS(FAB,positive)m/zcalcd.for C31H37NP[M+H]+,454.2658；found 454.2659[M+H]+。
实施例4
(R)-1-(2-(二苯基膦)苯基)丙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺的合成。
在(R)-1-[2-(二苯基膦)苯基]丙胺(1.596g,5.0mmol)和天然樟脑(0.836g,5.5mmol)的THF(15mL)溶液中加入钛酸四异丙酯(1.421g,5.0mmol)，加热回流十小时，减压蒸出THF。剩余物经乙酸乙酯萃取(3×10mL)，合并有机相，有机相经水洗、饱和氯化钠溶液洗涤。无水硫酸钠干燥后，减压蒸去溶剂，得到粗产品进一步经柱层析分离纯化，得到纯品无色油状物产品(R)-1-(2-(二苯基膦)苯基)丙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺1.813g，产率80％。 1H NMR(400MHz,CDCl3)δ7.68(dd,J＝7.3,4.1Hz,1H),7.23–7.13(m,11H),6.99(t,J＝7.3,1H),6.76(d,J＝6.8,4.1Hz,1H),4.86(d,J＝12.9,6.6Hz,1H),1.69–1.53(m,6H),1.32–1.25(m,2H),1.07(td,J＝12.4,3.8Hz,1H),0.89(s,3H),0.76(s,3H),0.67(t,J＝7.3Hz,3H),0.32(s,3H)；13C NMR(101MHz,CDCl3)δ180.92,150.92,150.69,137.58,134.47,137.04,136.93,134.25,134.05,133.83,133.64,133.18,129.13,128.65,128.54,128.52,128.48,128.47,128.46,127.60,127.55,126.33,63.94,63.71,53.59,46.85,43.98,36.44,36.41,32.62,27.56,19.58,19.00,11.57,11.24(Some peaks of rotamer are visible due to assumed hinderedrotation)；31P NMR(202MHz,CDCl3)δ-16.57.HRMS(FAB,positive)m/z calcd.for C31H37NP[M+H]+,454.2658；found 454.2676[M+H]+。
实施例5
(S)-8-((二苯基膦)-1,2,3,4-四氢萘)-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-1-亚胺的合成。
在(S)-8-(二苯基膦)-1,2,3,4-四氢-1-萘胺(0.993g,3mmol)和天然樟脑(0.912g,6mmol)的甲苯(30mL)溶液中加入三氟乙酸(30μL)，并加热回流18小时，减压蒸出甲苯。剩余物经乙醚萃取(3×10mL)，合并有机相，有机相经水洗、饱和氯化钠洗涤。无水硫酸钠干燥后，减压蒸去溶剂，得到粗产品进一步经柱层析分离纯化，得到无色油状物产品(S)-8-((二苯基膦)-1,2,3,4-四氢萘)-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-1-亚胺1.116g，产率80％。 1H NMR(500MHz,CDCl3)δδ7.31–7.26(m,8H),7.16–7.14(m,3H),7.07(t,J＝6.0Hz,1H),6.78(dd,J＝5.6,3.4Hz,1H),5.10(s,1H),3.06(d,J＝13.1Hz,1H),2.89–2.83(m,1H),2.44–2.34(m,2H),2.27–2.19(m,1H),1.89–1.83(m,2H),1.75–1.68(m,3H),1.28–1.14(m,2H),1.17(td,J＝9.8,3.2Hz,1H),0.86(s,3H),0.78(s,3H),0.77(s,3H)；13C NMR(126MHz,CDCl3)δ179.90,144.97,144.76,138.97,138.87,138.06,137.97,137.73,137.67,136.51,136.40,133.70,133.54,133.47,133.33,132.99,130.93,128.38,128.32,128.28,128.14,128.09,127.79,126.80,56.88,56.72,53.20,47.71,43.87,36.11,36.04,31.03,30.45,30.16,27.57,19.49,19.07,18.23,11.57(Some peaks of rotamer are visible due to assumed hindered rotation)；31P NMR(202MHz,CDCl3)δ-15.56.HRMS(FAB,positive)m/z calcd.for C32H37NP[M+H]+,466.2658；found 466.2681[M+H]+。
实施例6
(R)-8-((二苯基膦)-1,2,3,4-四氢萘)-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-1-亚胺的合成。
在(R)-8-(二苯基膦)-1,2,3,4-四氢-1-萘胺(1.986g,6mmol)和天然樟脑(1.824g,12mmol)的甲苯(30mL)溶液中中加入三氟化硼乙醚(50μL)，加热回流18小时，减压蒸出甲苯。剩余物经乙醚萃取(3×10mL)，合并有机相，有机相经水洗、饱和氯化钠溶液洗涤。无水硫酸钠干燥后，减压蒸去溶剂，得到粗产品进一步经柱层析分离纯化，得到无色油状物产品(R)-8-((二苯基膦)-1,2,3,4-四氢萘)-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-1-亚胺2.232g，产率80％。 1H NMR(500MHz,CDCl3)δ7.32–7.31(m,5H),7.26–7.25(m,3H),7.16–7.11(m,3H),7.08(t,J＝10.8Hz,1H),6.83(dd,J＝5.5,3.0Hz,1H),5.04(s,1H),3.05(d,J＝13.2Hz,1H),2.89–2.81(m,2H),2.22–2.17(m,1H),1.98–1.95(m,2H),1.89–1.80(m,2H),1.73–1.71(m,2H),1.61(td,J＝9.8,3.0Hz,1H),1.25(dd,J＝10.1,3.1Hz,1H),1.17(td,J＝9.8,3.0Hz,1H),0.86(s,3H),0.72(s,3H),0.69(s,3H)；13C NMR(126MHz,CDCl3)δ180.24,145.24,145.03,139.11,139.01,138.25,138.16,137.64,137.58,136.50,136.40,133.60,133.49,133.44,133.35,133.14,133.13,130.89,128.35,128.29,128.23,127.98,127.93,127.59,126.82,56.53,56.36,53.87,46.69,44.38,36.07,36.01,33.05,31.32,30.29,20.20,20.13,19.24,18.36,11.22(Some peaksof rotamer are visible due to assumed hindered rotation)；31P NMR(202MHz,CDCl3)δ-16.64.HRMS(FAB,positive)m/z calcd.for C32H37NP[M+H]+,466.2658；found 466.2668[M+H]+。
实施例7
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(4.8mg,0.013mmol)和(R)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(6mg,0.013mmol)的甲苯(1mL)反应液在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(163mg,0.648mmol)的甲苯(5mL)溶液、苄胺(70mg,0.648mmol,70μL)、K2CO3(164mg，1.189mmol)。氩气保护下反应六小时后，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：98％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak OJ-H，正己烷：异丙醇＝87:13，1.0ml/min)，ee值为96％。1H NMR(400MHz,CDCl3)δ7.34(d,J＝7.4Hz,2H),7.27(d,J＝7.6Hz,4H),7.25–7.22(m,4H),7.18(dd,J＝10.7,4.3Hz,4H),7.10(t,J＝6.5Hz,1H),6.49(d,J＝15.8Hz,1H),6.23(dd,J＝15.8,7.5Hz,1H),4.31(d,J＝7.4Hz,1H),3.74–3.65(m,2H),2.01(s,1H).13C NMR(101MHz,CDCl3)δ142.79,140.27,137.01,132.51,130.57,128.69,128.56,128.48,128.28,127.52,127.47,127.38,127.04,126.50,64.61,51.39。
实施例8
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(4mg,0.0079mmol)的甲苯(1mL)溶液在氩气保护下室温反。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的甲苯(3mL)溶液、环已胺(118mg,1.189mmol,136μL)、N，O-二(三甲基硅)乙酰胺(BSA)(242mg,1.189mmol,291μL)。氩气下反应六小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：98％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak AD-H，正己烷：异丙醇＝99:1，0.5ml/min)，ee值为97％.1H NMR(400MHz,CDCl3)δ7.38(d,J＝7.4Hz,2H),7.33(dt,J＝12.5,6.4Hz,4H),7.26(dd,J＝12.5,4.8Hz,2H),7.21(dd,J＝15.1,6.4Hz,2H),6.51(d,J＝15.8Hz,1H),6.30(dd,J＝15.8,7.3Hz,1H),4.55(d,J＝7.3Hz,1H),2.54–2.39(m,1H),1.97(d,J＝11.5Hz,1H),1.88(d,J＝12.5Hz,1H),1.68(d,J＝3.4Hz,2H),1.57(s,2H),1.14(dd,J＝20.2,9.3Hz,4H).13C NMR(101MHz,CDCl3)δ143.58,137.16,133.42,129.83,128.58,128.50,127.34,127.10,126.44,61.93,53.61,34.00,33.83,26.23,25.14,25.10。
实施例9
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(4mg,0.0079mmol)的甲苯(1mL)溶液在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的甲苯(5mL)溶液、吗啉(104mg,1.189mmol,104μL)、碳酸铯(387mg,1.189mmol,)。氩气保护下反应六小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：96％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak OD-H，正己烷：异丙醇＝90:10，1.0ml/min)，ee值为86％。1H NMR(400MHz,CDCl3)δ7.39(d,J＝7.4Hz,2H),7.33(dt,J＝10.4,5.3Hz,4H),7.29–7.24(m,2H),7.24–7.16(m,2H),6.56(d,J＝15.8Hz,1H),6.27(dd,J＝15.8,8.9Hz,1H),3.78(d,J＝8.9Hz,1H),3.70(t,J＝4.7Hz,4H),2.54(d,J＝10.7Hz,2H),2.44–2.33(m,2H).13C NMR(101MHz,CDCl3)δ141.59,136.81,131.63,131.41,128.70,128.55,128.08,127.60,127.34,126.43,74.82,67.20,52.22。
实施例10
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(9mg,0.0198mmol)的甲苯(1mL)溶液在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的甲苯(5mL)溶液、丙烯胺(68mg,1.189mmol,89μL)、抗坏血酸钠(236mg,1.189mmol,)。氩气保护下反应六小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：99％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak OD-H，正己烷：异丙醇＝99:1，1.0ml/min)，ee值为98％.1H NMR(400MHz,CDCl3)δ7.40(d,J＝7.2Hz,2H),7.34(dt,J＝10.9,5.5Hz,4H),7.28(d,J＝7.3Hz,2H),7.26–7.16(m,2H),6.57(d,J＝15.8Hz,1H),6.29(dd,J＝15.8,7.5Hz,1H),5.14(ddd,J＝13.7,11.5,1.4Hz,2H),4.39(d,J＝7.5Hz,1H),3.36–3.13(m,2H),1.56(s,1H).13C NMR(101MHz,CDCl3)δ142.93,137.02,136.83,132.61,130.38,128.64,128.53,127.47,127.37,127.31,126.46,115.98,64.75,50.05。
实施例11：
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(7.1mg,0.0158mmol)的甲苯(1mL)溶剂在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的甲苯(5mL)溶液、对硝基苯胺(164mg,1.189mmol)、磷酸钾(252mg,1.189mmol,)。氩气保护下反应五小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：98％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak AD-H，正己烷：异丙醇＝80:20，1.0ml/min)，ee值为98％.1H NMR(400MHz,CDCl3)δ8.11–7.95(m,2H),7.38(dd,J＝6.8,5.9Hz,5H),7.33(d,J＝10.1Hz,2H),7.29(t,J＝7.3Hz,2H),7.24(t,J＝7.1Hz,1H),6.57(dd,J＝15.6,8.3Hz,3H),6.37(dd,J＝15.9,6.1Hz,1H),5.19(t,J＝5.5Hz,1H),4.96(d,J＝5.3Hz,1H).13C NMR(101MHz,CDCl3)δ152.20,140.37,138.53,136.09,132.32,129.18,128.70,128.68,128.19,128.16,127.15,126.63,126.25,112.16,60.08。
实施例12
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(7.1mg,0.0158mmol)的甲苯(1mL)溶剂在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的甲苯(5mL)溶液、吲哚啉(142mg,1.189mmol,133μL)、磷酸钠(126mg,1.189mmol,)。氩气保护下反应五小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：98％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak OD-H，正己烷：异丙醇＝98:2，0.5ml/min)，ee值为90％.1H NMR(400MHz,CDCl3)δ7.45(d,J＝8.1Hz,2H),7.39–7.30(m,4H),7.27(t,J＝7.5Hz,3H),7.23–7.17(m,1H),7.05(d,J＝7.1Hz,1H),6.93(t,J＝7.6Hz,1H),6.62(dd,J＝14.9,7.2Hz,2H),6.47(dd,J＝15.8,7.7Hz,1H),6.35(d,J＝7.9Hz,1H),5.10(d,J＝7.6Hz,1H),3.39(td,J＝8.6,4.8Hz,2H),2.94(t,J＝8.1Hz,2H).13C NMR(101MHz,CDCl3)δ150.32,139.74,135.68,131.72,129.41,127.52,126.84,126.77,126.63,126.25,126.03,125.50,123.37,116.51,107.35,63.01,49.56,27.35。
实施例13
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(R)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(4mg,0.0079mmol)的四氢呋喃(1mL)溶剂在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的四氢呋喃(5mL)溶液、苯甲醇(129mg,1.189mmol,123μL)、碳酸钠(126mg,1.189mmol)。氩气保护下反应六小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：99％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak OJ-H，正己烷：异丙醇＝98:2，1.0ml/min)，ee值为99％.1H NMR(400MHz,CDCl3)δ7.43(d,J＝7.3Hz,2H),7.35(dd,J＝16.9,7.6Hz,8H),7.28(dd,J＝9.3,6.0Hz,4H),7.20(t,J＝9.1Hz,1H),6.62(d,J＝15.9Hz,1H),6.33(dd,J＝15.9,7.0Hz,1H),5.00(d,J＝7.0Hz,1H),4.56(s,2H).13C NMR(101MHz,CDCl3)δ139.40,136.69,134.85,129.80,128.55,126.80,126.79,126.64,125.97,125.79,125.25,124.87,79.86,68.37。
实施例14：
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(7mg,0.0158mmol)的四氢呋喃(1mL)溶剂在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的四氢呋喃(5mL)溶液、2-苯乙醇(145mg,1.189mmol,142μL)、磷酸氢钾(207mg,1.189mmol)。氩气保护下反应五小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：99％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak OJ-H，正己烷：异丙醇＝99:1，1.0ml/min)，ee值为99％.1H NMR(400MHz,CDCl3)δ7.29–7.22(m,6H),7.19(t,J＝7.7Hz,5H),7.15–7.09(m,4H),6.48(d,J＝15.9Hz,1H),6.17(dd,J＝15.9,7.0Hz,1H),4.82(d,J＝7.0Hz,1H),3.70–3.61(m,1H),3.56(dd,J＝11.8,4.5Hz,1H),2.87(t,J＝7.0Hz,2H).13CNMR(101MHz,CDCl3)δ141.37,139.13,136.66,131.30,130.48,129.12,128.58,128.55,128.37,127.76,127.69,126.88,126.68,126.24,82.82,69.69,36.63。
实施例15
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(7mg,0.0158mmol)的四氢呋喃(1mL)溶剂在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的四氢呋喃(5mL)溶液、甲醇(38mg,1.189mmol,48μL)、碳酸钾(164mg,1.189mmol)。氩气保护下反应五小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：99％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak OJ-H，正己烷：异丙醇＝96:4，0.5ml/min)，ee值为98.6％.1H NMR(400MHz,CDCl3)δ7.30(dd,J＝6.5,2.8Hz,6H),7.24–7.18(m,3H),7.15(d,J＝7.9Hz,1H),6.53(s,1H),6.21(dd,J＝15.9,7.0Hz,1H),4.72(d,J＝7.0Hz,1H),3.30(s,3H).13C NMR(101MHz,CDCl3)δ141.07,136.62,131.50,130.18,128.55,127.75,126.88,126.62,84.35,56.47。
实施例16
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(7mg,0.0158mmol)的四氢呋喃(1mL)溶剂在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的四氢呋喃(5mL)溶液、糠醇(117mg,1.189mmol,103μL)、碳酸铯(387mg,1.189mmol)。氩气保护下反应五小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：99％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak OJ-H，正己烷：异丙醇＝90:10，1.0ml/min)，ee值为99％.1H NMR(400MHz,CDCl3)δ7.36–7.31(m,3H),7.28(t,J＝7.8Hz,4H),7.20(t,J＝7.4Hz,3H),7.14(dd,J＝9.5,5.0Hz,1H),6.53(d,J＝15.9Hz,1H),6.25(dd,J＝8.6,6.3Hz,2H),6.22(d,J＝5.1Hz,1H),4.94(d,J＝7.1Hz,1H),4.42(s,2H).13C NMR(101MHz,CDCl3)δ150.80,141.75,139.74,135.49,130.84,128.86,127.52,127.48,126.75,126.72,126.02,125.59,109.21,108.31,80.39,61.12。
实施例17
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(7mg,0.0158mmol)的四氢呋喃(1mL)溶剂在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的四氢呋喃(5mL)溶液、2-吡啶甲醇(130mg,1.189mmol)、醋酸铯(228mg,1.189mmol)。氩气保护下反应五小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：98％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak OJ-H，正己烷：异丙醇＝95:5，1.0ml/min)，ee值为98％.1H NMR(400MHz,CDCl3)δ8.44(d,J＝4.5Hz,1H),7.59(td,J＝7.7,1.6Hz,1H),7.46(d,J＝7.8Hz,1H),7.37(d,J＝7.3Hz,2H),7.28(t,J＝7.3Hz,4H),7.24–7.17(m,3H),7.16–7.10(m,1H),7.07(dd,J＝6.9,5.3Hz,1H),6.59(d,J＝15.9Hz,1H),6.27(dd,J＝15.9,7.1Hz,1H),5.00(d,J＝7.1Hz,1H),4.62(q,J＝13.4Hz,2H).13C NMR(101MHz,CDCl3)δ158.83,149.06,140.93,136.66,136.54,131.92,129.95,128.63,128.57,127.87,127.84,126.98,126.69,122.30,121.42,82.67,71.27。
实施例18
将烯丙基氯化钯二聚体[Pd(η-C3H5)Cl]2(2.9mg,0.0079mmol)和(S)-1-(2-(二苯基膦)苯基)乙基-N-(1,7,7-三甲基-双环[2,2,1]庚烷)-2-亚胺手性配体(7mg,0.0158mmol)的四氢呋喃(1mL)溶剂在氩气保护下室温反应。15min后，往该反应液中依次加入1,3-二苯基-2-烯丙基-1-醇的乙酸酯(100mg,0.396mmol)的四氢呋喃(5mL)溶液、三氟乙醇(119mg,1.189mmol,86μL)、醋酸钾(116mg,1.189mmol)。氩气保护下反应五小时，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(3×10ml)，有机相经水洗、饱和氯化钠溶液洗涤，无水硫酸钠干燥后，减压蒸去溶剂，粗产品经柱层析分离纯化得到无色油状产品。收率：98％，HPLC分析产品对映异构体过量值(ee值)(Chiralpak OJ-H，正己烷：异丙醇＝96:4,0.5ml/min)，ee值为72％.1H NMR(400MHz,CDCl3)δ7.34–7.26(m,6H),7.26–7.19(m,3H),7.19–7.12(m,1H),6.56(d,J＝15.9Hz,1H),6.19(dd,J＝15.9,7.2Hz,1H),4.99(d,J＝7.2Hz,1H),3.94–3.58(m,2H).13C NMR(101MHz,CDCl3)δ137.50,134.01,130.81,126.70,126.57,126.42,126.23,126.10,124.82,124.69,81.72,63.92,63.58,63.24,62.90。
本发明中所用原料、设备，若无特别说明，均为本领域的常用原料、设备；本发明中所用方法，若无特别说明，均为本领域的常规方法。
以上所述，仅是本发明的较佳实施例，并非对本发明作任何限制，凡是根据本发明技术实质对以上实施例所作的任何简单修改、变更以及等效变换，均仍属于本发明技术方案的保护范围。

Claims (8)

1.一种含樟脑的亚胺膦配体的合成方法，其特征在于：选用手性胺3或4中的一种和天然樟脑作为原料，在缩合剂存在下进行脱水缩合制备：
其中L3和L4为两种含樟脑的亚胺膦配体；
n＝0-1；
Ar为苯基、1-萘基、2-萘基、2-烷基苯基、3-烷基苯基、4-烷基苯基、2，6-二烷基苯基、3，4-二烷基苯基、2，4，6-三烷基苯基、2-烷氧基苯基、3-烷氧基苯基、4-烷氧基苯基、2，6-二烷氧基苯基、3，4-二烷氧基苯基、2，4，6-三烷氧基苯基、2-卤素苯基、3-卤素苯基、4-卤素苯基、2，6-二卤素苯基、3，4-二卤素苯基或2，4，6-三卤素苯基。
2.如权利要求1所述的一种含樟脑的亚胺膦配体的合成方法，其特征在于：合成过程中所用溶剂为氯仿、甲醇、乙醇、丙醇、丁醇、戊醇、四氢呋喃、环戊基甲醚、2-甲基四氢呋喃、乙醚、异丙醚、正丙醚、二甲基亚砜、甲苯、苯、二甲苯、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二氯甲烷、1，2-二氯乙烷、四氯化碳、正己烷、环己烷、乙酸乙酯、乙酸异丙酯、乙腈中的一种。
3.如权利要求2所述的一种含樟脑的亚胺膦配体的合成方法，其特征在于：合成过程中所用溶剂为甲苯或四氢呋喃。
4.如权利要求1所述的一种含樟脑的亚胺膦配体的合成方法，其特征在于：合成过程中所用缩合剂为硫酸镁、氧化铝、三氟化硼乙醚、四氯化钛、钛酸四乙酯、钛酸四异丙酯、甲磺酸、对甲基苯磺酸、苯磺酸、樟脑磺酸、三氟甲磺酸、三氟乙酸、三氯乙酸。
5.如权利要求4所述的一种含樟脑的亚胺膦配体的合成方法，其特征在于：合成过程中所用缩合剂为三氟乙酸。
6.一种如权利要求1-5之一所述的合成方法所合成的含樟脑的亚胺膦配体在不对称烯丙基取代反应中的应用，其特征在于反应过程为：
其中Ligand表示配体，为含樟脑的亚胺膦配体L3和L4中的一种；
Pd salt表示钯盐；base表示碱性物质。
7.一种如权利要求6所述的含樟脑的亚胺膦配体在不对称烯丙基取代反应中的应用，其特征在于：Pd salt为氯化钯、二(三叔丁基膦)钯、四三苯基膦钯、醋酸钯、烯丙基氯化钯、双(二亚苄基丙酮)钯中的一种。
8.一种如权利要求6所述的含樟脑的亚胺膦配体在不对称烯丙基取代反应中的应用，其特征在于：base为氢氧化钠、氢氧化钾、氢氧化铯、磷酸钾、磷酸钠、磷酸氢钾、抗坏血酸钠、碳酸铯、碳酸钾、碳酸钠、醋酸钠、醋酸钾和醋酸铯中的一种。
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