CN107382874B - 一类手性六元氮杂环卡宾前体盐的制备方法及其应用 - Google Patents
一类手性六元氮杂环卡宾前体盐的制备方法及其应用 Download PDFInfo
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Abstract
本发明涉及有机合成领域,具体为具有四氢嘧啶骨架的手性六元氮杂环卡宾前体盐的合成及其应用。本发明所述的手性六元氮杂环卡宾前体化合物为具有式(Ⅲ)所示结构的化合物或者其如式(Ⅲ’)所示的对映异构体:R1选自苯基、1‑萘基、2‑萘基、苄基、异丙基、异丁基、仲丁基、叔丁基或环己基;R2选自氯离子、溴离子、四氟硼酸根离子或六氟磷酸根离子,优选自氯离子和四氟硼酸根离子;R3选自氢、1‑萘甲酰基、2‑萘甲酰基、2,4,6‑三甲基苯甲酰基、对甲氧基苯甲酰基或对叔丁基苯甲酰基。本发明开发一种C2对称的新型手性六元氮杂环卡宾前体化合物的合成方法,扩大其在药物中间体合成及有机不对称合成反应中的应用范畴。
Description
技术领域
本发明涉及有机合成领域,具体为具有四氢嘧啶骨架的手性六元氮杂环卡宾前体盐的合成及其应用。
背景技术
氮杂环卡宾(NHCs)的研究起始于上个世纪70年代,直到1991年,Arduengo等人首次制备得到游离的氮杂环卡宾单体之后,卡宾化学得到了飞跃式的发展。由于氮杂环卡宾具有制备相对简单并且对反应环境要求不苛刻等优点,因此受到越来越多的关注。此外,氮杂环卡宾具有的强σ供电性和弱π接受性使得它能够与多数金属形成稳定的金属络合物,并表现出更好的空气和热力学稳定性,因而此类络合物能催化许多重要的有机化学反应,如烯烃复分解反应、偶联反应、共轭加成反应、氢化还原反应等。其催化性能在部分反应中已经超过传统的膦配体,因此氮杂环卡宾及其金属络合物在有机催化领域正发挥越来越重要的作用。
就目前而言,国内外课题组所发展的无论是单齿还是双齿手性NHC配体,其基本结构单元主要基于五元环的咪唑或者二氢咪唑等结构。
近些年,具有六元嘧啶环结构的氮杂环卡宾配体陆续被国内外一些课题组所报道。与传统的五元氮杂环卡宾配体相比,六元氮杂环卡宾配体在空间布局以及电子特性方面都表现出显著的变化。相关报道表明,六元氮杂环卡宾铑羰基络合物羰基的红外振动频率较五元类似物有明显的降低,表明具有更强的亲核性(碱性),使得其可能与过渡金属形成更加稳定的络合物,成为非常有前景的催化剂;此外,大量的六元环NHC配体的晶体结构均表明其较五元环类似物具有更大的N-CNHC-N夹角,进而导致N原子上的取代基与卡宾碳中心和金属中心距离更近(N-CNHC-N夹角的增大会导致R-N-CNHC夹角减小),最终致使N原子上取代基的改变对配体电子效应和空间效应的影响更显著。另外,六元环NHC配体与五元NHC配体构象不甚相同,多具有半椅式构象。表明六元环NHC配体比近平面型的咪唑类配体更具有一定的柔韧性,使得其在催化循环中的氧化加成和转化金属等步骤不会因为过大的位阻而受到障碍,从而有利于催化剂保持较高的催化活性。因此六元环卡宾配体在现代有机化学中发挥着越来越重要的作用。
1999年,布里斯托大学的Alder课题组在Chemical Communications上首次报道了六元卡宾钾配合物二聚体,其结构如下。
2003年,渥太华大学的Richeson课题组在JACS(Journal ofthe AmericanChemical Society)上报道了一种具有萘嵌间二氮杂苯骨架结构的六元氮杂环卡宾铑配合物,其结构如下。
加州大学的Bertrand课题组于2005年在JACS上报道了一种具有类似环硼氮烷结构的六元氮杂卡宾铑络合物,该类卡宾配体的卡宾碳中心的电性可以通过硼原子取代基的改变而得到调整,其结构如下。
2009年,德克萨斯大学的Bielawski课题组在JACS上报道了一种骨架含有两个羰基的六元氮杂环卡宾配体,该类卡宾配体因羰基官能团的引入显示出独特的电性,既保留了卡宾碳与过渡金属的络合能力,又进一步拓宽卡宾配体在催化反应中的应用。
手性六元卡宾配体的研究起步较晚,2010年,弗罗里达州立大学的McQuade课题组设计合成了一类具有三环骨架的手性六元氮杂卡宾前体盐及其与金属铜的络合物,并将其应用于ɑ,β不饱和酯和烯丙基芳基醚的不对称硼酸酯加成反应,取得了较好的对映选择性。
2012年,Trapp课题组报道了一种N原子连接手性取代基的手性六元氮杂环卡宾配体,并在羰基的不对称ɑ芳基化反应中显示较好的对映选择性。
国内涉猎手性六元环氮杂卡宾金属化学的有两个课题组,2014年孙智华等人报道了具有二氢喹唑啉母核的手性卡宾前体盐,并在铜催化的ɑ,β酯的不对称硼酸酯加成反应取得了较好的对映选择性。
2015年本课题组以手性纯的(1S,3S)1,3-二苯基丙二胺为原料,设计合成了系列手性中心位于四氢嘧啶环的手性六元氮杂环卡宾前体盐,并在铜催化的不对称共轭加成反应中获得良好的对映选择性,构建系列具有手性季碳中心的化合物。
纵观六元氮杂环卡宾的发展历程,该领域尚处在起步阶段。尽管如此,此类结构独特的配体在催化反应中的应用已表现出一定的优势和显著的特点。然而,现有的手性六元氮杂环卡宾大多合成步骤较多,总收率较低。因此,开发新的简洁的合成手性六元氮杂卡宾配体的方法显得尤为重要,不但能推动该领域的产业化,而且能应用于不对称反应而降低部分手性药物合成中间体的生产成本。
发明内容
本发明的目的是通过一条简洁的有机合成路线,开发一种C2对称的新型手性六元氮杂环卡宾前体化合物的合成方法,从而扩大其在药物中间体合成反应及有机不对称合成反应中的应用范畴。
本发明所述的手性六元氮杂环卡宾前体化合物,为具有式(Ⅲ)所示结构的化合物或者其如式(Ⅲ’)所示的对映异构体:
其中R1分别为苯基、1-萘基、2-萘基、苄基、异丙基、异丁基、仲丁基、叔丁基、环己基;
R2分别为氯离子、溴离子、四氟硼酸根离子、六氟磷酸根离子;
R3分别为氢、1-萘甲酰基、2-萘甲酰基、2,4,6-三甲基苯甲酰基、对甲氧基苯甲酰基、对叔丁基苯甲酰基;
优选地,R2选自氯离子和四氟硼酸根离子。
或者,所述手性六元氮杂环卡宾前体盐化合物选自以下化合物之一:
上述的手性六元氮杂环卡宾前体化合物的合成路线如下:
(ⅰ)1,3-二溴丙烷;(ⅱ)原甲酸三乙酯或原甲酸三甲酯,铵盐(如四氟硼酸铵、氯化铵);(ⅲ)三乙胺,酰氯。
手性六元氮杂环卡宾前体化合物的制备方法该方法包括以下的步骤:
(ⅰ)在无反应溶媒的条件下,将如通式(Ⅰ)所示的手性胺醇和1,3-二溴丙烷加热反应,然后从反应产物中收集式(Ⅱ)化合物,反应通式如下:
(ⅱ)将如通式(Ⅱ)所示的光学纯取代胺醇类化合物、原甲酸三甲酯或原甲酸三乙酯在路易斯酸作用下进行反应,然后从反应产物中收集式(Ⅲ-A)化合物,反应通式如下:
(ⅲ)在非质子溶剂中,将如通式(Ⅲ-A)所示的手性氮杂环卡宾前体盐和酰氯在碱性条件下进行反应,然后从反应产物中收集式(Ⅲ-B)化合物,反应通式如下:
优选地,上述反应步骤(i)中式(Ⅰ)化合物和1,3-二溴丙烷的摩尔比为2:1,反应温度为100℃,反应时间为6~12小时;步骤(ii)中反应温度为80~120℃,反应时间为5~16小时,式(Ⅱ)化合物、原甲酸三甲酯或原甲酸三乙酯、路易斯酸的摩尔比为1:1:1;步骤(iii)中反应温度为0~25℃,反应时间为5~12小时,式(Ⅲ-A)化合物、酰氯、碱的摩尔比为1:4:5;非质子溶剂选自二氯甲烷、四氢呋喃、乙二醇二甲醚或甲苯。
本发明以手性胺醇为起始原料,通过两步反应制备手性卡宾前体盐(Ⅲ-A)的总收率在73~92%。本发明以化合物(Ⅲ-A)为原料,通过反应制备酰化产物(Ⅲ-B)的收率在72~90%。
本发明提供的手性六元氮杂环卡宾前体化合物在催化反应中的应用,所述应用优选为手性六元氮杂环卡宾前体化合物与金属形成络合物催化C-H偶联反应;或手性加成反应。
优选地,所述的C-H偶联反应为钯催化的二芳基甲烷的DCCP反应;所述的手性加成反应为二乙基锌对芳香醛的不对称1,2-加成反应;
所述的钯催化的二芳基甲烷的DCCP反应优选为以下反应:
反应(Ⅰ):
其中,Ar分别为苯基、取代苯基、1-萘基、2-萘基。
在非质子溶液中,将醋酸钯和手性六元氮杂环卡宾前体化合物、4-苄基吡啶、如通式(Ⅳ)所示的化合物在碱作用下反应,然后从反应产物中收集式(Ⅴ)化合物。优选地,上述反应的反应条件优选为:反应温度为60-80℃,反应时间为12-18h,其中4-苄基吡啶、(Ⅳ)化合物、碱、手性六元氮杂环卡宾前体化合物、醋酸钯的摩尔比为1.2:1:3:0.075:0.05。
所述二乙基锌对芳香醛的不对称1,2-加成反应优选为以下反应:
反应(Ⅱ)
Ar1为1-萘基、2-萘基、苯基、2-甲基苯基、3-甲基苯基、3,4-二甲基苯基、2,4,6-三甲基苯基、4-乙基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-氟苯基、4-氟苯基、4-溴苯基基、4-三氟甲基苯基、3,5-二氟苯基、3-吡啶基、2-噻吩基、2-喹啉基。
在非质子溶剂中加入手性六元氮杂环卡宾化合物,在碱性条件下加入二乙基锌和通式(Ⅵ)所示的化合物,然后从反应产物中收集式(Ⅶ)化合物。上述反应的反应条件优选为:在非质子溶剂中加入手性六元氮杂环卡宾化合物,在碱性条件下搅拌10分钟,加入二乙基锌,再搅拌5分钟后,加入如通式(Ⅵ)所示的化合物,在室温下反应24小时,然后从反应产物中收集式(Ⅶ)化合物,反应温度为25℃,反应时间为24h,其中通式为(Ⅵ)化合物、碱、手性六元氮杂环卡宾前体化合物、二乙基锌的摩尔比为1:0.3:0.1:2。
上述反应中,非质子溶剂优选为苯、甲苯、二甲苯、四氢呋喃、乙二醇二甲醚、1,4-二氧六环,所用的碱优选为叔丁醇钠、叔丁醇钾、叔丁醇锂、二(三甲基硅基)氨基钾、二(三甲基硅基)氨基钠、二(三甲基硅基)氨基锂。
上述手性六元氮杂环卡宾前体化合物可作为手性有机催化剂催化手性加成反应,如二乙基锌对芳香醛的不对称1,2-加成反应;还可以作为配体与金属形成络合物用于催化C-H偶联反应,如钯催化的二芳基甲烷的DCCP反应。
具体实施方式
化合物Ⅲ-A的代表性合成方法(通法1):
将4mmol化合物I(2eq)、2mmol 1,3-二溴丙烷(1eq)加入反应管中,在100℃搅拌8~12小时,反应结束后,将反应物用50%NaOH溶液(40mL)溶解,用二氯甲烷萃取(15mL)三次,合并有机相,有机相用饱和食盐水洗涤,加入无水Na2SO4干燥,滤过,滤液旋干,得到黄色油状物Ⅱ。将Ⅱ(2mmol)、原甲酸三乙酯(2mmol)、四氟硼酸铵(2mmol)加入反应管,在120℃搅拌5~8小时,反应结束后,将混合物柱层析分离(CH2Cl2:CH3OH=80:1~40:1)得到产物Ⅲ-A。
原甲酸三乙酯可用原甲酸三甲酯代替;四氟硼酸铵可以用氯化铵、六氟磷酸铵代替。
化合物Ⅲ-B的代表性合成方法(通法2):
将2mmol化合物Ⅲ-A加入装有20mL二氯甲烷溶剂的反应管中,依次滴加8mmol酰氯、10mmol三乙胺,25℃搅拌12小时,反应结束后,将反应物用饱和碳酸氢钠溶液(30mL)溶解,用二氯甲烷萃取(15mL)三次,合并有机相,用1mol/L氢氧化钠溶液(20mL)洗涤,加入无水Na2SO4干燥,滤过,滤液蒸干,将剩余物柱层析分离(CH2Cl2:CH3OH=100:1~50:1)得到产物Ⅲ-B。
二氯甲烷可用三氯甲烷代替。
实施例1
化合物Ⅲ-1的制备与表征:
将548.7mg(4mmol)化合物Ⅰ-1与204μL的1,3-二溴丙烷加入到反应管中,采用通法1进行反应,在100℃反应12小时,反应结束后,将反应物用50%NaOH溶液(40mL)溶解,用二氯甲烷萃取(15mL)三次,合并有机相,有机相用饱和食盐水洗涤,加入无水Na2SO4干燥,滤过,滤液旋干,得到黄色油状物Ⅱ-1。将Ⅱ-1(2mmol)、333μL原甲酸三乙酯、210mg四氟硼酸铵加入反应管,在120℃搅拌4小时,反应结束后,将混合物柱层析分离(CH2Cl2:CH3OH=80:1~40:1)得到产物Ⅲ-1共689mg,为浅黄色油状化合物,产率为84%;1HNMR(500MHz,CDCl3):δ8.58(s,1H),7.39–7.34(m,5H),7.30(m,5H),4.93(dd,J=9.8,3.4Hz,2H),4.24–4.17(m,2H),4.09(d,J=11.0Hz,2H),3.28–3.23(m,2H),3.15–3.11(m,2H),1.91(m,2H);13C NMR(125MHz,CDCl3):δ153.53,133.41,129.35,129.32,127.68,69.19,60.21,40.51,18.85;HR-ESIMS:m/z 325.2209[M-BF4]+(calcd for C20H25N2O2 +,325.1911)。
实施例2
化合物Ⅲ-2的制备与表征:
制备条件同实施例1,黄色油状化合物,产率为86%;1H NMR(500MHz,CDCl3):δ7.97(s,1H),3.96(dd,J=12.5,3.7Hz,2H),3.68(dd,J=12.4,9.4Hz,2H),3.48–3.37(m,4H),3.30(m,2H),2.19–2.15(m,2H),1.96–1.89(m,2H),1.02(d,J=6.6Hz,6H),0.97(d,J=6.6Hz,6H);13C NMR(125MHz,CDCl3):δ154.05,59.75,40.72,29.72,27.29,19.75,19.37;HR-ESIMS:m/z 257.2229[M-BF4]+(calcd for C14H29N2O2 +,257.2224)。
实施例3
化合物Ⅲ-3的制备与表征:
制备条件同实施例1,黄色油状化合物,产率为92%;1HNMR(500MHz,CDCl3):δ7.94(s,1H),3.95(dd,J=12.4,3.7Hz,2H),3.68(dd,J=12.2,9.4Hz,2H),3.46–3.35(m,6H),2.21–2.13(m,2H),1.73(m,2H),1.41(m,2H),1.14(m,2H),0.97(d,J=6.6Hz,6H),0.91(t,J=7.4Hz,6H);13C NMR(125MHz,CDCl3):δ154.00,71.78,59.74,41.04,33.20,25.54,18.79,15.22,10.38;HR-ESIMS:m/z 285.2796[M-BF4]+(calcd for C16H33N2O2 +,285.2537)。
实施例4
化合物Ⅲ-4的制备与表征:
制备条件同实施例1,黄色油状化合物,产率为82%;1H NMR(500MHz,CDCl3):δ8.02(s,1H),3.74(m,4H),3.58(m,2H),3.40(m,4H),2.16(m,2H),1.52(m,4H),1.32(m,2H),0.96(d,J=6.7,6H),0.94(d,J=6.7,6H);13C NMR(125MHz,CDCl3):δ153.78,65.51,61.80,40.09,36.43,24.78,22.99,21.64;HR-ESIMS:m/z 285.2815[M-BF4]+(calcd for C16H33N2O2 +,285.2537)。
实施例5
化合物Ⅲ-5的制备与表征:
制备条件同实施例1,黄色油状化合物,产率为73%;1H NMR(500MHz,CDCl3):δ7.92(s,1H),3.99–3.85(m,4H),3.56(m,2H),2.16(m,2H),1.70(m,4H),1.02(m,18H);13C NMR(125MHz,CDCl3):δ169.05,100.00,58.51,34.34,27.52,26.80,18.97;HR-ESIMS:m/z285.2721[M-BF4]+(calcd for C16H33N2O2 +,285.2537)。
实施例6
化合物Ⅲ-6的制备与表征:
制备条件同实施例1,黄色油状化合物,产率为73%;1H NMR(500MHz,CDCl3):δ7.94(s,1H),7.30(t,J=7.2Hz,4H),7.26(d,J=7.0Hz,2H),7.06(d,J=7.1Hz,4H),3.91(m,2H),3.85–3.75(m,4H),3.31–3.24(m,2H),3.04–2.97(m,2H),2.92(dd,J=14.5,5.2Hz,2H),2.66(dd,J=14.4,10.4Hz,2H),1.69(m,2H);13C NMR(125MHz,CDCl3):δ152.83,136.02,129.07,128.81,127.22,68.62,61.57,41.99,35.15,18.44;HR-ESIMS:m/z353.2513[M-BF4]+(calcd for C22H29N2O2 +,353.2224)。
实施例7
化合物Ⅲ-7的制备与表征:
将824mg(2mmol)化合物Ⅲ-1、1562μL对叔丁基苯甲酰氯、1386μL三乙胺加入反应管中,采用通法2进行反应,25℃搅拌12小时,反应结束后,将反应物用饱和碳酸氢钠溶液(30mL)溶解,用二氯甲烷萃取(15mL)三次,合并有机相,用1mol/L氢氧化钠溶液(25mL)洗涤,加入无水Na2SO4干燥,滤过,滤液蒸干,将剩余物柱层析分离(CH2Cl2:CH3OH=100:1~80:1)得到产物Ⅲ-7共1208mg,为白色固体化合物,产率为84%;1HNMR(500MHz,CDCl3):δ9.22(s,1H),8.19(d,J=8.6Hz,4H),7.60(d,J=8.6Hz,4H),7.29(d,J=7.5Hz,2H),7.13(t,J=7.8Hz,4H),6.99(d,J=7.5Hz,4H),5.61(dd,J=10.7,3.5Hz,2H),5.46–5.35(m,2H),4.47(m,2H),3.35–3.21(m,2H),2.89–2.76(m,2H),1.80–1.73(m,2H),1.38(s,18H);13C NMR(125MHz,CDCl3):δ166.44,157.70,131.59,131.58,130.14,129.48,129.32,127.57,125.95,125.85,65.75,60.10,38.75,35.27,31.16,18.65;HR-ESIMS:m/z 645.3891[M-BF4]+(calcd for C42H49N2O4 +,645.3687)。
实施例8
化合物Ⅲ-8的制备与表征:
制备条件同实施例7,浅黄色油状化合物,产率为78%;1H NMR(500MHz,CDCl3):δ8.53(s,1H),7.99(d,J=8.6Hz,4H),7.46(d,J=8.6Hz,4H),4.78(dd,J=12.4,10.4Hz,2H),4.27(dd,J=12.4,3.4Hz,2H),3.95(m,2H),3.47–3.37(m,2H),3.20–3.09(m,2H),2.03–1.94(m,2H),1.82(dd,J=6.5,4.0Hz,2H),1.33(s,18H),1.02(d,J=6.6Hz,6H),0.52(d,J=6.6Hz,6H);13C NMR(125MHz,CDCl3):δ166.35,157.56,155.43,129.90,125.88,125.71,70.31,60.73,38.82,35.17,31.06,26.80,19.10,18.98;HR-ESIMS:m/z 577.4247[M-BF4]+(calcd for C36H53N2O4 +,577.4000)。
实施例9
化合物Ⅲ-9的制备与表征:
制备条件同实施例7,白色固体化合物,产率为88%;1H NMR(500MHz,CDCl3):δ8.53(s,1H),8.02(d,J=8.6Hz,4H),7.49(d,J=8.7Hz,4H),4.80(dd,J=12.3,10.5Hz,2H),4.25(dd,J=12.4,3.4Hz,2H),4.03(m,2H),3.43(dd,J=12.7,6.2Hz,2H),3.16–3.07(m,2H),2.02–1.98(m,2H),1.57–1.52(m,2H),1.33(s,18H),0.97(d,J=6.6Hz,6H),0.87–0.81(m,2H),0.75(m,2H),0.50(t,J=7.4Hz,6H)。13C NMR(125MHz,CDCl3):δ166.37,157.42,155.34,129.82,126.01,125.72,69.17,61.05,39.06,35.14,32.99,31.05,25.10,18.74,14.98,10.69;HR-ESIMS:m/z605.4575[M-BF4]+(calcd for C38H57N2O4 +,605.4313)。
实施例10
化合物Ⅲ-10的制备与表征:
制备条件同实施例7,浅黄色油状化合物,产率为72%;1H NMR(500MHz,CDCl3):δ8.53(s,1H),8.02(d,J=8.6Hz,4H),7.49(d,J=8.6Hz,4H),4.75(dd,J=12.3,10.1Hz,2H),4.35(dd,J=9.3,4.6Hz,2H),4.02(dd,J=12.4,3.4Hz,2H),3.53–3.42(m,2H),3.27–3.16(m,2H),2.05(dd,J=7.3,4.2Hz,2H),1.43(m,2H),1.33(s,18H),1.31–1.27(m,2H),1.17–1.10(m,2H),0.72(d,J=6.6Hz,6H),0.63(d,J=6.5Hz,6H);13C NMR(125MHz,CDCl3):δ166.46,157.52,154.79,129.92,125.89,125.77,62.60,62.31,38.47,36.24,35.18,31.08,29.70,24.61,22.82,21.46;HR-ESIMS:m/z 605.4595[M-BF4]+(calcd for C38H57N2O4 +,605.4313)。
实施例11
化合物Ⅲ-11的制备与表征:
制备条件同实施例7,白色固体化合物,产率为86%;1HNMR(500MHz,CDCl3):δ8.58(s,1H),7.99(d,J=7.3Hz,4H),7.45(d,J=8.1Hz,4H),4.98(t,J=11.5Hz,2H),4.23(m,4H),3.50(dd,J=12.8,6.1Hz,2H),3.35–3.26(m,2H),2.01–1.93(m,2H),1.33(s,18H),1.26(s,18H);13C NMR(125MHz,CDCl3):δ166.32,157.36,129.81,126.03,125.56,72.41,58.69,40.65,35.11,33.98,31.05,29.67,27.37,18.81;HR-ESIMS:m/z 605.4592[M-BF4]+(calcd for C38H57N2O4 +,605.4313)。
实施例12
化合物Ⅲ-12的制备与表征:
制备条件同实施例7,棕色油状化合物,产率为90%;1H NMR(500MHz,CDCl3):δ8.60(s,1H),7.96–7.89(m,4H),7.46–7.41(m,4H),7.25–7.13(m,10H),4.68(dd,J=12.4,8.9Hz,2H),4.54(d,J=9.8Hz,2H),4.24(dd,J=12.4,3.5Hz,2H),3.14(m,4H),2.99(dd,J=14.4,6.8Hz,2H),2.79(dd,J=14.4,9.2Hz,2H),1.74–1.66(m,2H),1.25(s,18H);13C NMR(125MHz,CDCl3):δ166.04,157.52,154.32,134.83,129.71,129.11,128.88,127.42,125.99,125.72,65.24,62.84,41.03,35.11,34.99,30.98,18.66;HR-ESIMS:m/z 673.4213[M-BF4]+(calcd for C44H53N2O4 +,673.4000)。
实施例13
化合物Ⅲ-13的制备与表征:
制备条件同实施例7,黄色油状化合物,产率为86%;1H NMR(500MHz,CDCl3):δ8.40(s,1H),6.83(s,4H),4.52(m,4H),3.89–3.80(m,2H),3.38(dd,J=12.8,6.5Hz,2H),3.28(dd,J=12.7,6.6Hz,2H),2.28(s,6H),2.26(s,12H)2.04–1.98(m,2H),1.96–1.88(m,2H),1.04(d,J=6.6Hz,6H),0.70(d,J=6.7Hz,6H);13C NMR(125MHz,CDCl3):δ169.16,154.83,139.75,135.27,129.79,128.52,69.83,62.17,39.85,29.68,27.04,21.07,19.93,18.96,18.88;HR-ESIMS:m/z 549.3940[M-BF4]+(calcd for C34H49N2O4 +,549.3687)。
实施例14
化合物Ⅲ-14的制备与表征:
制备条件同实施例7,黄色油状化合物,产率为79%;1H NMR(500MHz,CDCl3):δ8.92(d,J=8.7Hz,2H),8.62(s,1H),8.38(dd,J=7.3,1.1Hz,2H),8.03(d,J=8.2Hz,2H),7.88(d,J=8.1Hz,2H),7.64(m,2H),7.58–7.51(m,4H),4.75(dd,J=12.5,10.4Hz,2H),4.39(dd,J=12.5,3.4Hz,2H),4.00(m,2H),3.49–3.40(m,2H),3.16–3.09(m,2H),2.02–1.95(m,2H),1.83–1.74(m,2H),1.00(d,J=6.6Hz,6H),0.40(d,J=6.6Hz,6H);13C NMR(125MHz,CDCl3):δ166.64,155.07,134.12,133.77,131.43,128.68,128.11,126.27,125.39,125.11,124.97,124.54,70.28,61.16,39.07,29.68,19.03,18.88;HR-ESIMS:m/z565.3234[M-BF4]+(calcd for C36H41N2O4 +,565.3061)。
实施例15
化合物Ⅲ-15的制备与表征:
制备条件同实施例7,黄色油状化合物,产率为83%;1H NMR(500MHz,CDCl3)δ8.73(s,2H),8.67(s,1H),8.08(d,J=8.0Hz,2H),8.02(dd,J=8.6,1.6Hz,2H),7.86(dd,J=8.3,3.1Hz,4H),7.64–7.54(m,4H),4.84(dd,J=12.3,10.6Hz,2H),4.30(dd,J=12.4,3.4Hz,2H),4.03(m,2H),3.50–3.39(m,2H),3.21–3.09(m,2H),2.05–1.97(m,2H),1.86–1.72(m,2H),0.96(d,J=6.6Hz,6H),0.42(d,J=6.6Hz,6H);13C NMR(125MHz,CDCl3)δ166.33,155.02,135.70,132.48,131.77,129.73,128.60,128.37,127.58,126.79,125.98,124.96,70.38,61.26,39.21,26.79,19.03,18.98;HR-ESIMS:m/z 565.3191[M-BF4]+(calcdfor C36H41N2O4 +,565.3061)。
实施例16~17为六元氮杂环卡宾前体Ⅲ-1~Ⅲ-15的催化实验,催化效果及对映选择性(ee)如表1所示。
实施例16
化合物A-2的制备与表征:
在氮气保护条件下,将0.015mmol六元氮杂环卡宾前体溶于2mL无水甲苯,加入0.01mmol醋酸钯,搅拌15分钟后,加入0.6mmol二(三甲基硅基)氨基钠,搅拌20分钟后,将0.4mmol化合物A-1,0.2mmol4-叔丁基溴苯加入反应液中,60℃反应12小时。反应完成后,加入5滴水萃灭反应,取一抽滤漏斗垫入硅藻土,抽滤,用乙酸乙酯淋洗三次,合并有机相后减压旋去溶剂,柱层析分离(石油醚:乙酸乙酯=3:1)得到产物A-2,产率:95%;1H NMR(500MHz,CDCl3):δ8.50(d,J=6.0Hz,2H),7.34–7.21(m,5H),7.10(d,J=7.5Hz,2H),7.07–6.98(m,4H),5.46(s,1H),1.30(s,9H);13C NMR(125MHz,CDCl3):δ153.2,150.0,149.9,142.6,139.1,129.5,129.1,128.7,127.0,125.7,124.8,56.0,34.6,31.5。
实施例17
化合物B-2的制备与表征:
在氮气保护条件下,将0.01mmol六元氮杂环卡宾前体、0.03mmol六甲基二硅基胺基钾和溶于1mL无水二甲苯溶液,搅拌10分钟后,加入0.2mL二乙基锌正己烷溶液(1mol/Linhexane),搅拌5分钟后,加入1-萘醛,室温下反应24小时后,加入1mL稀盐酸溶液(1mol/Lin water)淬灭反应,然后用乙醚萃取3次(5mL),合并有机相后减压旋去溶剂,柱层析分离(石油醚:乙酸乙酯=20:1)得到产物B-2,产率:95%,然后经手性OD-H柱,流动相为正己烷:异丙醇=90:10(体积比),测得ee:58%;1H NMR(500MHz,CDCl3)δ8.14(d,J=8.3Hz,1H),7.91–7.87(m,1H),7.80(d,J=8.2Hz,1H),7.66(d,J=7.1Hz,1H),7.56–7.47(m,3H),5.43(s,1H),2.05(m,1H),1.95(m,2H),1.05(t,J=7.4Hz,3H);13C NMR(125MHz,CDCl3):δ180.06,143.83,141.39,135.42,129.16,128.73,127.85,127.26,124.81,123.41,108.93,52.76,27.11,24.37。
表1:
Claims (10)
1.一类手性六元氮杂环卡宾前体化合物,为具有式(Ⅲ)所示结构的化合物或者其如式(Ⅲ’)所示的对映异构体:
其中,R1选自苯基、1-萘基、2-萘基、苄基、异丙基、异丁基、仲丁基、叔丁基或环己基;
R2选自氯离子、溴离子、四氟硼酸根离子或六氟磷酸根离子;
R3选自氢、1-萘甲酰基、2-萘甲酰基、2,4,6-三甲基苯甲酰基、对甲氧基苯甲酰基或对叔丁基苯甲酰基。
2.根据权利要求1所述的手性六元氮杂环卡宾前体化合物,其特征在于:R2选自氯离子和四氟硼酸根离子。
3.根据权利要求1所述的手性六元氮杂环卡宾前体化合物,其特征在于:手性六元氮杂环卡宾前体化合物选自以下化合物之一:
4.一种根据权利要求1所述的手性六元氮杂环卡宾前体化合物的制备方法,包括以下步骤:
在本方法中,R3选自1-萘甲酰基、2-萘甲酰基、2,4,6-三甲基苯甲酰基、对甲氧基苯甲酰基或对叔丁基苯甲酰基;
(i)在无反应溶媒的条件下,将如式(Ⅰ)所示的手性胺醇和1,3-二溴丙烷加热反应,然后从反应产物中收集式(Ⅱ)化合物,反应通式如下:
(ⅱ)将如通式(Ⅱ)所示的光学纯取代胺醇类化合物、原甲酸三甲酯或原甲酸三乙酯在路易斯酸作用下进行反应,然后从反应产物中收集式(Ⅲ-A)化合物,反应通式如下:
(ⅲ)在非质子溶剂中,将如通式(Ⅲ-A)所示的手性氮杂环卡宾前体盐和酰氯在碱性条件下进行反应,然后从反应产物中收集式(Ⅲ)化合物。
5.根据权利要求4所述的制备方法,其特征在于:步骤(i)中式(Ⅰ)化合物和1,3-二溴丙烷的摩尔比为2:1,反应温度为100℃,反应时间为6~12小时;步骤(ii)中反应温度为80~120℃,反应时间为5~16小时,式(Ⅱ)化合物、原甲酸三甲酯或原甲酸三乙酯、路易斯酸的摩尔比为1:1:1;步骤(iii)中反应温度为0~25℃,反应时间为5~12小时,式(Ⅲ-A)化合物、酰氯、碱的摩尔比为1:4:5;非质子溶剂选自二氯甲烷、四氢呋喃、乙二醇二甲醚或甲苯。
6.一种根据权利要求1所述的手性六元氮杂环卡宾前体化合物在催化反应中的应用,其特征在于:所述催化反应为钯催化的二芳基甲烷的DCCP反应或为二乙基锌对芳香醛的不对称1,2-加成反应。
7.根据权利要求6所述的应用,其特征在于:所述钯催化的二芳基甲烷的DCCP反应为:
其中,Ar选自苯基、1-萘基或2-萘基。
8.根据权利要求7所述的应用,其中所述钯催化的二芳基甲烷的DCCP反应的反应条件为:
在非质子溶液中,将醋酸钯和手性六元氮杂环卡宾前体化合物、4-苄基吡啶、如式(Ⅳ)所示的化合物在碱作用下反应,然后从反应产物中收集式(Ⅴ)化合物,其中反应温度为60-80℃,反应时间为12-18h,其中4-苄基吡啶、式(Ⅳ)化合物、碱、手性六元氮杂环卡宾前体化合物、醋酸钯的摩尔比为1.2:1:3:0.075:0.05;
其中,非质子溶剂为苯、甲苯、二甲苯、四氢呋喃、乙二醇二甲醚或1,4-二氧六环;
碱为叔丁醇钠、叔丁醇钾、叔丁醇锂、二(三甲基硅基)氨基钾、二(三甲基硅基)氨基钠或二(三甲基硅基)氨基锂。
9.根据权利要求6所述的应用,其特征在于:所述的二乙基锌对芳香醛的不对称1,2-加成反应为:
其中,Ar1选自1-萘基、2-萘基、苯基、2-甲基苯基、3-甲基苯基、3,4-二甲基苯基、2,4,6-三甲基苯基、4-乙基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-氟苯基、4-氟苯基、4-溴苯基、4-三氟甲基苯基、3,5-二氟苯基、3-吡啶基、2-噻吩基或2-喹啉基。
10.根据权利要求9所述的应用,其特征在于:所述反应的反应条件为:
在非质子溶剂中加入手性六元氮杂环卡宾化合物,在碱性条件下搅拌10分钟,加入二乙基锌,再搅拌5分钟后,加入如式(Ⅵ)所示的化合物,在室温下反应24小时,然后从反应产物中收集式(Ⅶ)化合物,反应温度为25℃,反应时间为24h,式(Ⅵ)化合物、碱、手性六元氮杂环卡宾前体化合物、二乙基锌的摩尔比为1:0.3:0.1:2;
其中,非质子溶剂为苯、甲苯、二甲苯、四氢呋喃、乙二醇二甲醚或1,4-二氧六环;
碱为叔丁醇钠、叔丁醇钾、叔丁醇锂、二(三甲基硅基)氨基钾、二(三甲基硅基)氨基钠或二(三甲基硅基)氨基锂。
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