CN114181256B - 手性双噁唑啉-炔基膦类配体及其制备和应用 - Google Patents

手性双噁唑啉-炔基膦类配体及其制备和应用 Download PDF

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CN114181256B
CN114181256B CN202010976448.2A CN202010976448A CN114181256B CN 114181256 B CN114181256 B CN 114181256B CN 202010976448 A CN202010976448 A CN 202010976448A CN 114181256 B CN114181256 B CN 114181256B
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bisoxazoline
alkynylphosphine
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李长坤
李冰
徐文斌
孙明河
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Abstract

本发明公开了一种手性双噁唑啉‑炔基膦类配体及其制备和应用。本发明从2‑噁唑啉取代的溴苯、末端炔烃和三苯氧基膦出发，实现配体的高效高产率制备。该类配体可用于但不仅限于铑和钴等金属参与的不对称反应，用于以高对映选择性地制备1，2‑二取代的烯丙基胺和手性吡啶等。

Description

手性双噁唑啉-炔基膦类配体及其制备和应用
技术领域
本发明属于化学化工技术领域，涉及手性化合物的制备方法,具体涉及一种手性双噁唑啉-炔基膦类配体及其制备和应用。
背景技术
过渡金属催化的不对称转化是合成手性化合物的有效方法之一,而手性配体则是实现不对称金属催化的关键,以提高反应活性,改变反应化学选择性和实现产物的高对映选择性。
手性三齿配体可以减少金属中心的自由度,有利于提高钴和铑等金属催化的反应的对映选择性。现有技术中的手性双噁唑啉-苯基膦配体可以高选择性实现过渡金属催化的不对称烯丙基取代反应[(a)Yamaishi,T.；Ohnuki,M.；Kiyooka,T.；Masui,D.；Sato,K.；Yamaguchi,M.Tetrahedron:Asymmetry 2003,14,3275.(b)Ghor ai,S.；Chirke,S.S.；Xu,W.-B.；Chen,J.-F.；Li,C.J.Am.Chem.Soc.2019,141,11430.(c)Ghorai,S.；Rehman,S.U.；Xu,W.-B.；Huang,W.-Y.；Li,C.Org.Lett.2020,22,3519-3523.)和端炔对靛红的不对称加成反应[Chen,J.-F.；Li,C.Org.Lett.2020,22,4686.].然而,此类配体所适用的反应类型有限,由于膦原子上相连的苯环的较大的空间位阻,与多取代烯丙基底物间存在排斥作用,不能有效催化反应并实现高对映选择性.此外,此类配体不能在去对称化等反应中达到所要求的远程控制的目的。因此,本发明优化双噁唑啉膦配体,发现还有炔基取代的噁唑啉膦配体可以解决空间位阻的问题，以实现钴和铑催化的更多类型反应的对映选择性控制,具有重要的现实意义。
发明内容
针对现有技术中的问题和缺陷,本发明的目的是提供一种新的手性双噁唑啉-炔基膦类配体及其制备和应用。本发明基于改变反应的活性和空间效应,实现了基于双噁唑啉和炔基膦的手性三齿配体的制备,以及不仅限于多取代烯丙基底物的不对称烯丙基取代反应和去对称化反应中的对映选择性控制。
本发明的手性双噁唑啉-炔基膦类配体应用于铑催化的1,2-二取代烯丙基胺的不对称合成和钴催化的去不对称化[2+2+2]反应中,得到高产率和优异的对映选择性。其中，
本发明的目的是通过以下技术方案来实现的：
第一方面，本发明涉及一种手性双噁唑啉-炔基膦类配体，所述手性双噁唑啉-炔基膦类配体及其对映异构体结构中，膦原子上所连三个基团中,两个为手性2-噁唑啉苯基,另一个为炔基。
进一步的，所述手性双噁唑啉-炔基膦类配体的结构式如式1所示，其对映异构体的结构式如式2所示；
其中，R1为C1-C20的烷基、C3-C20的环烷基、C1-C20的芳基或含有氮、氧、硫、膦或者卤素的C1-C20的取代芳基；
R2为C1-C20的烷基、C3-C20的环烷基、C1-C20的芳基、C1-C20的三烷基硅基或C1-C20的含有芳基的硅基，或者为含杂原子的C1-C20的烷基、C3-C20的环烷基或C1-C20的三烷基硅基；所述杂原子为硅、硼、磷、硫、氧中的一种或几种。
进一步的，所述C1-C20的烷基包括异丙基、叔丁基、甲基、乙基或异丁基；所述C3-C20的环烷基包括环己基或环丙基；所述C1-C20的芳基包括苯基或2,6-二异丙基苯基。
进一步的，所述含杂原子的基团包括三异丙基硅基、叔丁基二苯基硅基、三甲基硅氧亚甲基、羟亚甲基或2,6-二甲氧基苯基。
第二方面，本发明涉及一种手性双噁唑啉-炔基膦类配体的制备方法,所述方法包括如下步骤：
S1、手性含溴噁唑啉底物3用正丁基锂处理后与P(OPh)3反应得到中间体6
S2、中间体6与炔基锂7反应实现双噁唑啉-炔基膦类配体1或者2的制备。
进一步的，步骤S1中，所述手性含溴噁唑啉底物3、正丁基锂、P(OPh)3的摩尔比为(1.0～3.0):(1.0～3.0):1；反应温度为-110℃～室温。作为本发明的一个实施方案，摩尔比为1:2.4:1；反应温度为-78℃。
进一步的，步骤S2中，所述中间体6与炔基锂7的摩尔比为1:2～2:1；反应温度为-110℃～室温。作为本发明的一个实施方案，摩尔比为1:1；反应温度为-78℃～室温。
进一步的，步骤S2中，所述炔基锂7由炔烃5与正丁基锂在-110℃～室温反应0.5～12小时制备得到；所述炔烃5与正丁基锂的摩尔比为1:1～2:1。作为本发明的一个实施方案，所述炔基锂7由炔烃5与正丁基锂在-78℃反应1小时制备得到；所述炔烃5与正丁基锂的摩尔比为1:1.3。
第三方面，本发明涉及一种手性双噁唑啉-炔基膦类配体在不对称合成中的应用。
进一步的，所述手性双噁唑啉-炔基膦类配体应用于铑/双噁唑啉-炔基膦催化的1,2-二取代烯丙基胺8的制备。
进一步的，所述手性双噁唑啉-炔基膦类配体应用于钴/双噁唑啉-炔基膦催化的含手性四级碳的吡啶9的合成。
与现有技术相比,本发明具有如下的有益效果:
1)本发明所提供的手性双噁唑啉-炔基膦类配体不仅手性原料简单易得,制备线路短,反应产率高,可以克级规模以上制备,而且结构易于调整,可以用类似方法合成多种取代的手性配体,得到手性化合物库,从而对产率和对映选择性等进行优化。
2)本发明所提供的手性双噁唑啉-炔基膦类配体可以用于如表1所示反应,即1,2-二取代烯丙基胺类化合物8的制备,与之前的配体相比有明显提高,反应的产率和对映选择性可分别达到91％和97％。
3)本发明所提供的手性双噁唑啉-炔基膦类配体可以用于如表2所示反应,即潜手性二炔的去对称化[2+2+2]反应,用于制备含有四级手性碳的吡啶类化合物9,与之前的配体相比有明显提高,反应的对映选择性最高可达到93％ee。
具体实施方式
下面结合实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干调整和改进。这些都属于本发明的保护范围。
本发明中，化合物1,2,3,4,5,6,7，8，9的通式如下:
所述制备方法包括如下步骤:
本发明中使用的2-(2-溴苯基)噁唑啉3是参照文献制备的。具体的,R1为异丙基(实施例1，2，3，4，5，6，7，8，9和10)和叔丁基(实施例11和12)时，参照Jin,Y.；Du,D.-M.Tetrahedron,2012,68,3633。当R1为苯基(实施例18)时，参照Liu,W.；Ali,S.Z.；Ammann,S.E.；White,M.C.J.Am.Chem.Soc.2018,140,10658。当R1为环己基(13，14和15)时，参照Tani，K；Behenna，D.C.；McFadden,R.M.；Stoltz,B.M.Org.Lett.2007,9,2529。当R1为甲基(实施例16)时，参照Kim，K.S.；Moon,C.W.；Hong,J.K.；Kim,J.H.Bull.Korean.Chem.Soc.2001,22,237。当R1为乙基(实施例17)时，参照Tang,X.；Zhang,D.；Jie,S.；Sun,W.-H.；Chen,J.J.Organomet.Chem.2005,690,3918。
本发明中使用的末端炔烃5是市购获得。
本发明的制备方法可进一步用代表化合物的制备过程体现如下：
将2.0当量2-(2-溴苯基)噁唑啉(4mmol)溶解于20毫升四氢呋喃,在-78℃缓慢加入2.4当量正丁基锂(9.6mmol),并在此温度反应1小时；将反应液进一步降低到-100℃；将一个当量P(OPh)3 4(4.0mmol)溶解于2毫升四氢呋喃中,通过注射器加入到上述-100℃的溶液中；将反应体系温度升到室温,并在室温下反应5小时,得到中间体6的溶液；在另一反应瓶中将1当量末端炔烃5(4.0mmol)溶解于20毫升四氢呋喃,并将反应温度降低到-78℃；缓慢加入1.3当量正丁基锂(5.2mmol),在-78℃反应1小时,得到炔基锂中间体7；将中间体6的四氢呋喃溶液在-78℃缓慢加入到炔基锂7的溶液中,将温度升至室温,反应12小时；使用NH4Cl饱和溶液(15mL)将反应后的体系小心淬灭，通过分液漏斗分液后，使用Et2O(20mL)萃取水相三次，合并有机相并用无水Na2SO4干燥。在减压条件下旋干溶剂，得到的粗产物使用柱层析(PE/EA＝15/1)提纯，最终得到的配体。
具体见以下各实施例：
实施例1
手性双噁唑啉-炔基膦类配体1a(R1＝异丙基；R2＝苯基)的制备。
产率，61％；m.p.237.5-239.2℃；1H NMR(400MHz,Chloroform-d)δ7.95–7.89(m,3H),7.59–7.53(m,1H),7.51–7.46(m,2H),7.46–7.41(m,2H),7.39–7.34(m,2H),7.34–7.29(m,3H),4.52–4.26(m,2H),4.16–3.91(m,4H),1.84–1.78(m,1H),1.72–1.59(m,1H),1.04(d,J＝6.7Hz,3H),0.93(d,J＝6.7Hz,3H),0.83(d,J＝6.7Hz,3H),0.73(d,J＝6.7Hz,3H)；13C NMR(101MHz,CDCl3)δ163.1(d,J＝3.0Hz),162.7(d,J＝3.0Hz),138.9(d,J＝19.2Hz),138.3(d,J＝20.2Hz),134.2,133.3,131.72,131.70,131.5(d,J＝24.2Hz),131.1(d,J＝22.2Hz),130.3,130.3,129.6(d,J＝4.0Hz),129.4(d,J＝4.0Hz),128.3,128.2,128.1,128.0,123.7(d,J＝2.0Hz),105.9,90.0(d,J＝24.2Hz),73.1,73.0,70.3,70.2,33.0,32.8,19.0,18.8,18.5,18.3.31P NMR(162MHz,CDCl3)δ-36.6.HRMS(ESI)calcd forC32H33N2O2PH([M+H]):509.2352.Found:509.2355.
实施例2
手性双噁唑啉-炔基膦类配体1b(R1＝异丙基；R2＝甲基)的制备。
产率，52％；m.p.222.1-223.8℃；1H NMR(400MHz,Chloroform-d)δ7.89–7.66(m,2H),7.48–7.09(m,6H),4.31–4.21(m,1H),4.20–4.13(m,1H),4.05–3.81(m,4H),1.79–1.61(m,5H),0.98(d,J＝6.7Hz,3H),0.92(d,J＝6.7Hz,3H),0.87(d,J＝6.7Hz,3H),0.81(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ163.2(d,J＝2.0Hz),162.9(d,J＝3.0Hz),139.4(d,J＝19.2Hz),138.9(d,J＝21.2Hz),133.9,133.2,131.4(d,J＝23.2Hz),131.1(d,J＝23.2Hz),130.5,130.3,129.5(d,J＝4.0Hz),129.4(d,J＝3.0Hz),128.1,127.9,103.9,78.2(d,J＝17.2Hz),77.3,73.0,72.9,70.2,70.1,33.0,32.7,19.0,18.8,18.4,18.1,5.7(d,J＝2.0Hz).31P NMR(162MHz,CDCl3)δ-35.8.HRMS(ESI)calcd for C27H31N2O2PH([M+H]):447.2196.Found:447.2189.
实施例3
手性双噁唑啉-炔基膦类配体1c(R1＝异丙基；R2＝环丙基)的制备。
产率，62％；m.p.232.1-233.8℃；1H NMR(400MHz,Chloroform-d)δ7.87–7.81(m,2H),7.78–7.72(m,1H),7.51–7.45(m,1H),7.40–7.34(m,2H),7.33–7.27(m,2H),4.31–4.25(m,2H),4.04–3.98(m,4H),1.79–1.72(m,2H),1.68–1.62(m,1H),1.01(d,J＝6.7Hz,3H),0.90(d,J＝6.7Hz,3H),0.83(d,J＝6.7Hz,3H),0.81–0.74(m,4H),0.72(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ162.1(d,J＝2.0Hz),161.7(d,J＝2.0Hz),138.2(d,J＝19.2Hz),137.7(d,J＝20.2Hz),132.7,132.0,130.3(d,J＝24.2Hz),129.9(d,J＝23.2Hz),129.3,129.1,128.3(d,J＝4.0Hz),128.2(d,J＝4.0Hz),126.9,126.6,110.4,76.1,72.9(d,J＝18.2Hz),71.8,71.7,69.0,68.9,31.8,31.5,17.9,17.6,17.3,17.0,7.8,0.02.31P NMR(162MHz,CDCl3)δ-35.6.HRMS(ESI)calcd for C29H33N2O2PH([M+H]):473.2352.Found:473.2355.
实施例4
手性双噁唑啉-炔基膦类配体1d(R1＝异丙基；R2＝叔丁基)的制备。
产率，71％；m.p.248.1-249.8℃；1H NMR(400MHz,Chloroform-d)δ7.90–7.77(m,3H),7.45–7.33(m,3H),7.31–7.23(m,2H),4.40–4.21(m,2H),4.12–3.94(m,4H),1.82–1.76(m,1H),1.65–1.59(m,1H),1.24(s,9H),1.01(d,J＝6.7Hz,3H),0.91(d,J＝6.7Hz,3H),0.80(d,J＝6.7Hz,3H),0.72(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ163.5(d,J＝3.3Hz),162.8(d,J＝2.0Hz),139.7(d,J＝19.2Hz),139.0(d,J＝22.2Hz),133.9,133.0,131.6(d,J＝24.2Hz),131.1(d,J＝22.2Hz),130.4,130.1,129.5(d,J＝3.0Hz),129.2(d,J＝3.0Hz),128.0,127.6,116.1,77.2,73.1,72.8,70.3,70.2,33.0,32.8,30.9(d,J＝1.0Hz),28.7(d,J＝2.0Hz),19.0,18.7,18.5,18.3.31P NMR(162MHz,CDCl3)δ-36.5.HRMS(ESI)calcdfor C30H37N2O2PH([M+H]):489.2665.Found:489.2655.
实施例5
手性双噁唑啉-炔基膦类配体1e(R1＝异丙基；R2＝三异丙基硅基)的制备。
产率，65％；m.p.257.2-258.8℃；1H NMR(400MHz,Chloroform-d)δ7.94–7.86(m,2H),7.85–7.78(m,1H),7.69–7.62(m,1H),7.42–7.31(m,4H),4.37–4.25(m,2H),4.14–3.90(m,4H),1.82–1.76(m,1H),1.71–1.65(m,1H),1.06(s,21H),1.01(d,J＝6.8Hz,3H),0.91(d,J＝6.7Hz,3H),0.85(d,J＝6.7Hz,3H),0.73(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ163.2(d,J＝3.0Hz),162.7(d,J＝3.0Hz),138.9(d,J＝19.2Hz),138.7(d,J＝20.2Hz),133.8,133.5,131.2(d,J＝14.1Hz),131.0(d,J＝22.2Hz),130.4,130.3,129.5(d,J＝4.0Hz),129.3(d,J＝4.0Hz),128.0,127.9,111.0(d,J＝6.1Hz),109.3,109.0,73.0,72.9,70.2,70.0,32.9,32.7,19.1,18.8,18.6,18.4,18.1,11.3.31P NMR(162MHz,CDCl3)δ-36.0.HRMS(ESI)calcd forC30H37N2O2PH([M+H]):489.2665.Found:489.2655.
实施例6
手性双噁唑啉-炔基膦类配体1f(R1＝异丙基；R2＝叔丁基二苯基硅基)的制备。
产率，66％；m.p.263.2-264.8℃；1H NMR(500MHz,CDCl3)δ7.91(dd,J＝11.9,5.7Hz,2H),7.77–7.75(m,5H),7.39–7.29(m,10H),4.27(dd,J＝15.8,7.5Hz,2H),4.04–3.98(m,3H),3.88(dd,J＝16.5,7.8Hz,1H),1.73–1.63(m,2H),1.03(s,9H),0.95(d,J＝6.6Hz,3H),0.83(dd,J＝6.7,2.4Hz,6H),0.70(d,J＝6.7Hz,3H)；13C NMR(126MHz,CDCl3)δ162.9(d,J＝3.8Hz),162.5(d,J＝3.8Hz),138.5(d,J＝2.5Hz),138.4,135.7,133.7(d,J＝8.8Hz),133.5,131.3(d,J＝23.9Hz),130.5(d,J＝5.5Hz),129.5(d,J＝5.0Hz),129.6,129.4,128.2(d,J＝15.1Hz),127.6,112.6(d,J＝31.5Hz),109.1(d,J＝6.3Hz),73.1(d,J＝15.1Hz),70.2(d,J＝18.9Hz),33.0,32.8,27.1,18.8,18.8,18.4,18.2.31P NMR(202MHz,CDCl3)δ-36.0.
实施例7
手性双噁唑啉-炔基膦类配体1g(R1＝异丙基；R2＝2,6-二异丙基苯基)的制备。
产率，66％；m.p.223.5-224.9℃；1H NMR(400MHz,CDCl3)δ7.91(dd,J＝11.9,5.7Hz,2H),7.77–7.75(m,5H),7.39–7.29(m,10H),4.27(dd,J＝δ7.99–7.96(m,3H),7.49–7.40(m,5H),4.46–4.39(m,2H),4.18–4.10(m,4H),1.91–1.85(m,2H),1.05(d,J＝6.8Hz,6H),0.95(d,J＝6.8Hz,6H).13C NMR(126MHz,CDCl3)δ163.2,162.8,136.0(d,J＝12.0Hz),133.9,130.8(d,J＝10.9Hz),129.7(d,J＝11.5Hz),128.5,128.5,127.9,113.2,112.9,109.0,109.0,97.6,76.8,69.0,68.9,34.2,34.0,27.5,27.3,26.3,26.2,19.1.31P NMR(202MHz,CDCl3)δ-29.0.
实施例8
手性双噁唑啉-炔基膦类配体1h(R1＝异丙基；R2＝2,6-二甲氧基苯基)的制备。
产率，72％；m.p.244.1-245.8℃；1H NMR(500MHz,CDCl3)δ8.02–7.78(m,4H),7.40–7.31(m,4H),7.15(t,J＝8.4Hz,1H),6.47(d,J＝8.4Hz,2H),4.34(dt,J＝11.1,8.0Hz,2H),4.09–3.97(m,4H),3.82(s,6H),1.81–1.76(m,1H),1.69–1.67(m,1H),1.00(d,J＝6.7Hz,3H),0.87(dd,J＝16.4,6.7Hz,6H),0.74(d,J＝6.7Hz,3H).13C NMR(126MHz,CDCl3)δ163.5(d,J＝3.8Hz),161.8(s),139.1(d,J＝20.4Hz),138.7(d,J＝21.4Hz),134.2(d,J＝81.3Hz),131.4(t,J＝23.6Hz),130.4(d,J＝22.6Hz),129.6,129.4(d,J＝3.8Hz),129.2(d,J＝3.8Hz),103.7(s),102.5,98.4,97.7(d,J＝20.7Hz),73.0(d,J＝18.4Hz),70.2(d,J＝3.9Hz),56.0(s),32.8,32.7,19.1,18.4,18.3,18.2.31P NMR(202MHz,CDCl3)δ-35.7.
实施例9
手性双噁唑啉-炔基膦类配体1i(R1＝异丙基；R2＝三甲基硅氧亚甲基)的制备。
产率，62％；m.p.203.5-205.1℃；1H NMR(500MHz,CDCl3)δ7.88–7.78(m,3H),7.55–7.53(m,1H),7.39–7.30(m,4H),4.45(d,J＝2.0Hz,2H),4.30–4.27(m,2H),4.06–3.98(m,4H),1.78–1.74(m,2H),1.00(d,J＝6.7Hz,3H),0.90(d,J＝6.7Hz,3H),0.86(s,9H),0.82(d,J＝6.8Hz,3H),0.69(d,J＝6.7Hz,3H).13C NMR(126MHz,CDCl3)δ163.1(d,J＝2.5Hz),162.8(d,J＝3.8Hz),138.7(d,J＝17.6Hz),138.2(d,J＝20.2Hz),133.6(d,J＝87.2Hz),131.3(d,J＝22.7Hz),130.4(d,J＝25.0Hz),129.5(d,J＝3.8Hz),129.4(d,J＝3.8Hz),128.1(d,J＝29.5Hz),105.7,84.8(d,J＝24.6Hz),72.9(d,J＝3.8Hz),70.1(d,J＝20.2Hz),52.8(s),33.0,32.6,25.8(s),19.0,18.8,18.4,18.2,18.0.31P NMR(202MHz,CDCl3)δ-37.8.
实施例10
手性双噁唑啉-炔基膦类配体1j(R1＝异丙基；R2＝羟亚甲基)的制备。
产率，95％；m.p.213.6-215.2℃；1H NMR(500MHz,CDCl3)δ7.86–7.75(m,3H),7.49(dd,J＝8.8,4.1Hz,1H),7.41–7.38(m,2H),7.33–7.31(m,2H),4.33(d,J＝1.7Hz,2H),4.32–4.25(m,2H),4.07–3.96(m,4H),1.77(dq,J＝13.4,6.7Hz,1H),1.64(dq,J＝13.2,6.7Hz,1H),0.99(d,J＝6.7Hz,3H),0.90(d,J＝6.7Hz,3H),0.81(d,J＝6.7Hz,3H),0.71(d,J＝6.7Hz,3H).13C NMR(126MHz,CDCl3)δ163.4,163.2,138.5(d,J＝18.9Hz),137.8(d,J＝18.9Hz),134.0,133.2,131.4(d,J＝23.9Hz),130.9(d,J＝23.9Hz),130.5(d,J＝34.0Hz),129.6(d,J＝3.8Hz),129.3(d,J＝3.8Hz),128.2(d,J＝46.6Hz),105.5,73.9(d,J＝37.8Hz),70.3(d,J＝6.3Hz),51.9,32.9,32.3,19.0,18.7,18.4,18.2.31P NMR(202MHz,CDCl3)δ-38.0.CHCl3).
实施例11
手性双噁唑啉-炔基膦类配体1k(R1＝叔丁基；R2＝叔丁基)的制备。
产率，77％；m.p.242.2-243.8℃；1H NMR(400MHz,Chloroform-d)δ7.91–7.85(m,3H),7.42–7.36(m,2H),7.37–7.32(m,1H),7.30–7.24(m,2H),4.27(t,J＝9.4Hz,1H),4.22–4.14(m,2H),4.06(t,J＝8.5Hz,1H),4.00–3.94(m,2H),1.23(s,9H),0.93(s,9H),0.71(s,9H).13C NMR(101MHz,CDCl3)δ163.4(d,J＝3.0Hz),162.4(d,J＝3.0Hz),140.0(d,J＝20.2Hz),139.1(d,J＝23.2Hz),134.1,133.0,131.4(d,J＝23.2Hz),130.8(d,J＝22.2Hz),130.4,130.1,129.6(d,J＝4.0Hz),129.2(d,J＝3.0Hz),128.0,127.6,115.7,77.3,76.3,34.1,33.6,31.0(d,J＝2.0Hz),28.7(d,J＝2.0Hz),26.0,25.8.31P NMR(162MHz,CDCl3)δ-36.2.HRMS(ESI)calcd forC32H41N2O2PH([M+H]):517.2978.Found:517.2979.
实施例12
手性双噁唑啉-炔基膦类配体1l(R1＝叔丁基；R2＝叔丁基二苯基硅基)的制备。
产率，73％；m.p.263.1-265.2℃；1H NMR(500MHz,CDCl3)δ7.96–7.93(m,2H),7.80–7.73(m,5H),7.70-7.67(m 1H),7.37–7.28(m,10H),4.18(ddd,J＝19.0,10.0,8.7Hz,2H),4.09(td,J＝8.2,5.9Hz,2H),3.98(dd,J＝10.0,8.5Hz,1H),3.81(dd,J＝10.0,7.9Hz,1H),1.04(s,9H),0.84(s,9H),0.76(s,9H).13C NMR(126MHz,CDCl3)δ162.8(d,J＝3.8Hz),162.5(d,J＝3.8Hz),138.6(d,J＝20.2Hz),138.3(d,J＝21.4Hz),135.7,135.6,133.9(d,J＝22.7Hz),133.5,131.2(d,J＝22.7Hz),130.9(d,J＝22.7Hz),130.5(d,J＝5.0Hz),129.7(d,J＝3.8Hz),129.3,129.3,128.1(d,J＝5.0Hz),127.8,127.6,112.7(d,J＝31.5Hz),108.6(d,J＝6.3Hz),97.3,76.6(d,J＝42.8Hz),68.6(d,J＝18.9Hz),33.9,33.7,27.1,27.0,26.0,25.9,18.8.31P NMR(202MHz,CDCl3)δ-35.1；
实施例13
手性双噁唑啉-炔基膦类配体1m(R1＝环己基；R2＝三异丙基硅基)的制备。
产率，74％；m.p.246.23-248.8℃；1H NMR(500MHz,CDCl3)δ7.94–7.88(m,1H),7.60(dd,J＝9.2,3.8Hz,1H),7.38(dd,J＝8.8,3.4Hz,2H),7.32(dd,J＝5.8,3.4Hz,2H),7.20–7.13(m,1H),6.80(d,J＝7.6Hz,1H),4.40–4.23(m,2H),4.15–3.90(m,4H),1.77–0.93(m,43H).13C NMR(126MHz,CDCl3)δ163.7(d,J＝2.5Hz),163.0(d,J＝2.5Hz)，138.7(d,J＝17.6Hz),138.3(d,J＝20.0Hz),133.9,133.3,131.4,131.8(d,J＝7.6Hz),130.9(d,J＝7.6Hz),130.5(d,J＝18.9Hz),129.7(d,J＝3.8Hz),129.5(d,J＝3.8Hz),129.4,128.3(d,J＝2.5Hz),128.2,127.9,119.6,115.6,111.4(d,J＝35.6Hz),108.9(d,J＝27.9Hz),71.8(d,J＝10.3Hz),70.3(d,J＝35.6Hz),42.6(d,J＝43.3Hz),29.5,29.1,28.8,28.7,26.6,26.5,26.2,26.1,26.1,26.0.31P NMR(202MHz,CDCl3)δ-35.6.
实施例14
手性双噁唑啉-炔基膦类配体1n(R1＝环己基；R2＝叔丁基二苯基硅基)的制备。
产率，81％；m.p.254.3-255.9℃；1H NMR(500MHz,CDCl3)δ7.94–7.92(m,2H),7.84–7.83(m,1H),7.78-7.76(m,4H),7.69(dd,J＝6.4,3.2Hz,1H),7.42–7.28(m,10H),4.29–4.26(m,2H),4.04(dt,J＝10.8,7.2Hz,3H),3.87(dd,J＝16.9,7.9Hz,1H),1.96–1.28(m,18H),1.04(s,9H),0.99–0.79(m,4H).13C NMR(126MHz,CDCl3)δ162.9(d,J＝3.8Hz),162.4(d,J＝3.8Hz),138.6(d,J＝18.9Hz),138.4(d,J＝21.4Hz),135.7,133.9,133.6,131.2(d,J＝23.9Hz),131.0(d,J＝23.9Hz),130.5,130.4,129.4,129.4,129.4,128.2(d,J＝17.6Hz),127.6,127.6,115.7,112.9,112.7,109.2,109.1,77.3,72.2,72.2(d,J＝34.0Hz),43.0,42.6,29.7,29.3,29.1,28.9,27.2,26.6,26.5,26.2,26.1,26.1,26.1,18.8.31P NMR(202MHz,CDCl3)δ-35.9.
实施例15
手性双噁唑啉-炔基膦类配体1o(R1＝环己基；R2＝叔丁基)的制备。
产率，75％；m.p.229.8.2-231.5℃；1H NMR(500MHz,CDCl3)δ7.95–7.84(m,3H),7.42–7.23(m,5H),4.36–4.23(m,2H),4.12(dd,J＝15.3,7.5Hz,1H),4.02–3.97(m,3H),1.75–1.32(m,12H),1.22(s,9H),1.06–0.80(m,10H).13C NMR(126MHz,CDCl3)δ163.3(d,J＝2.5Hz),162.5(d,J＝2.5Hz),139.8(d,J＝18.9Hz),138.9(d,J＝22.7Hz),131.5(d,J＝22.7Hz),131.1(d,J＝22.7Hz),130.4,130.1,129.5(d,J＝3.8Hz),129.2(d,J＝3.8Hz),128.2(d,J＝2.5Hz),128.0,127.5,72.1(d,J＝16.4Hz),70.3(d,J＝32.8Hz),43.0,42.6,29.6,29.2,29.0,28.9,26.6,26.4,26.2,26.2,26.1,26.0.31P NMR(202MHz,CDCl3)δ-36.5.
实施例16
手性双噁唑啉-炔基膦类配体1p(R1＝甲基；R2＝叔丁基二苯基硅基)的制备。
产率，79％；m.p.250.9-252.4℃；1H NMR(500MHz,CDCl3)δ7.92–7.85(m,3H),7.77–7.76(m,4H),7.67–7.65(m,1H),7.40–7.29(m,10H),4.40–4.35(m,2H),4.31–4.22(m,2H),3.83(td,J＝7.7,2.5Hz,2H),1.25(d,J＝6.6Hz,3H),1.07(d,J＝6.5Hz,3H),1.04(s,9H).13C NMR(126MHz,CDCl3)δ163.2(d,J＝2.6Hz),162.8(d,J＝2.6Hz),138.6(d,J＝18.2Hz),138.0(d,J＝18.2Hz),135.5,133.8,133.1(d,J＝17.8Hz),130.3(d,J＝23.7Hz),129.3,129.2,129.2,128.1(d,J＝23.7Hz),127.4,111.8(d,J＝18.1Hz),110.1(d,J＝18.1Hz),73.7(d,J＝7.3Hz),62.0(d,J＝3.8Hz),26.8,21.2,20.8,18.6.31P NMR(202MHz,CDCl3)δ-36.0.
实施例17
手性双噁唑啉-炔基膦类配体1q(R1＝乙基；R2＝叔丁基二苯基硅基)的制备。
产率，72％；m.p.246.3-248.1℃；1H NMR(500MHz,CDCl3)δ7.92–7.85(m,3H),7.77–7.76(m,4H),7.72–7.70(m,1H),7.33(ddd,J＝24.6,11.7,6.6Hz,10H),4.32(dd,J＝12.9,4.6Hz,2H),4.18–4.06(m,2H),3.91(td,J＝7.8,2.7Hz,2H),1.64–1.63(m,1H),1.49(dt,J＝19.9,6.7Hz,2H),1.39(dd,J＝13.9,7.0Hz,1H),1.04(s,9H),0.91(t,J＝7.4Hz,3H),0.76(t,J＝7.4Hz,3H).13C NMR(126MHz,CDCl3)δ163.1(d,J＝2.9Hz),162.7(d,J＝2.9Hz),138.4(d,J＝19.0Hz),135.7,133.4,131.2(d,J＝7.4Hz),129.9(d,J＝16.7Hz),128.2(d,J＝16.7Hz),127.6,112.4(d,J＝31.2Hz),109.6(d,J＝6.0Hz),72.0(d,J＝16.7Hz),68.3,28.7,28.4,27.0,18.8,10.2,9.8.31P NMR(202MHz,CDCl3)δ-36.2.
实施例18
手性双噁唑啉-炔基膦类配体1r(R1＝苯基；R2＝苯基)的制备。
产率，52％；m.p.95.1-96.8℃；1H NMR(400MHz,CDCl3)δ8.03–7.94(m,3H),7.86–7.80(m,1H),7.54–7.41(m,6H),7.38–7.22(m,11H),7.12–7.08(m,2H),5.43–5.35(m,1H),5.07–4.99(m,1H),4.65(ddd,J＝28.2,10.1,8.3Hz,2H),4.12(dt,J＝13.9,8.2Hz,2H).13CNMR(101MHz,CDCl3)δ164.9(d,J＝1Hz),164.1(d,J＝4.0Hz),142.86,142.45,139.59,139.38,138.87,138.69,134.39,134.37,133.58,132.05,131.83,131.80,130.82,130.32,130.10,130.01,129.98,129.81,129.76,128.50,128.46,128.43,128.26,128.20,127.20,127.14,126.80,126.79,126.59,123.47,123.45,107.10,89.67,89.42,74.81,74.60,70.10,69.90.31P NMR(162MHz,CDCl3)δ-37.7. HRMS(ESI):C38H29N2O2P[M+H]+calcd:577.2039,found:577.2038.
实施例19
化合物8的制备:
表1
表中i-Pr为异丙基,Me为甲基,t-Bu为叔丁基，Ph为苯基。
表中序号7为反应40小时。
从表1中看，膦上取代基位阻减小，产物8的对映选择性升高。取代基为空间位阻较大的苯基时(序号1)，47％ee；取代基为空间位阻较小的甲基时(序号2)，80％ee；取代基为空间位阻更小的炔基时(序号3-7)，82％-97％ee，其中当R2是叔丁基时，可以得到的最高97％ee。
以序号7为例：
在10mL耐压Schlenk管中加入[Rh(cod)2]BF4(2.5mol％)和1d(2.5mol％)，将反应管换气三次，在通入氩气的情况下，缓慢打开盖子，使用微量注射器向管内依次加入烯丙基磷酸酯(0.4mmol,1.0equiv)，对甲氧基苯胺(0.8mmol,2.0equiv)和CH3CN(2mL)，最后将反应管密封。将其置于80℃油浴中加热反应40h。待反应完毕后将反应管从油浴中取出，冷却至室温后打开盖子，在减压条件下将溶剂旋干，得到的粗产物使用柱层析提纯(PE/EA＝50/1)，最后得到脱羧烯丙基胺基化反应产物8。
产率，91％；黄色液体；91.3mg.1H NMR(400MHz,Chloroform-d)δ6.76(d,J＝8.9Hz,2H),6.55(d,J＝8.9Hz,2H),5.02(s,1H),4.89(d,J＝1.5Hz,1H),3.75(s,3H),3.72(t,J＝6.8Hz,1H),2.10–1.94(m,2H),1.61–1.55(m,2H),1.49–1.30(m,2H),1.07(t,J＝7.4Hz,3H),0.96(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ152.1,142.6,138.2,126.5,114.8,114.3,55.8,50.5,29.5,23.0,22.0,13.9,13.3.HRMS(ESI)calcd for C15H23NOH([M+H]+):234.1852.Found:234.1852.HPLC Daicel Chiralcel OJ-H柱,正己烷/异丙醇＝99:1,流速:1.0毫升/分,254nm,保留时间＝10.351min(大峰)and 12.358min(小峰),97％ee.
实施例20
化合物9的制备:
表2
表中Cy为环己基，t-Bu为叔丁基，Ph为苯基。
从表2中看，膦上取代基为空间位阻较大的苯基时(序号1)，84％ee；取代基为空间位阻较小的甲基时(序号2)，88％ee；取代基为空间位阻更小的炔基时(序号3-4)，92％到93％ee，其中当R2是叔丁基二苯基时，可以得到的最高93％ee。膦上有硅基取代炔基时，该反应的对映选择性更好。
在10mL耐压Schlenk管中加入Co(BF4)2(2.5mol％)和1n(3mol％)，将反应管换气三次，在通入氩气的情况下，缓慢打开盖子，使用微量注射器向管内依次加入1毫升CH3CN,HBPin(3mol％),二炔(0.2mmol,1.0equiv)，CH3CN(0.4mmol,2.0equiv),最后将反应管密封。在室温反应40小时后,在减压条件下将溶剂旋干，得到的粗产物使用柱层析提纯(PE/EA＝1/1)，最后得到手性吡啶化合物9(50.4mg)。
收率:95％,50.4mg；1H NMR(500MHz,CDCl3)δ8.40(s,1H),7.28(dd,J＝7.7,1.2Hz,1H),7.11(s,1H),6.98–6.77(m,3H),3.56(dd,J＝16.4,2.8Hz,2H),3.27(s,3H),3.05(dd,J＝23.4,16.2Hz,2H),2.57(s,3H).13C NMR(126MHz,CDCl3)δ179.8,157.2,152.0,145.1,142.8,135.7,134.8,128.7,123.2,121.8,119.9,108.4,54.3,43.9,41.8,26.8,24.6.；HPLC:Daicel Chiralpak OJH柱,正己烷/异丙醇＝95:5,流速:1毫升/分,柱温40℃,254nm；保留时间＝15.2min(小峰),and 16.7min(大峰),94％ee；HRMS(ESI-TOF)m/z:[M+H]+CalcdforC17H16N2O 264.1258；found 264.1260；
以上对本发明的具体实施实例进行了描述。需要理解的是本发明并不局限于上述特定实施方式,本领域技术人员可以在权利要求范围内做出各种变形或修改,这并不影响本发明的实质内容。

Claims (7)

1.一种手性双噁唑啉-炔基膦类配体，其特征在于，所述手性双噁唑啉-炔基膦类配体中膦原子上所连三个基团中, 两个为手性2-噁唑啉苯基, 另一个为炔基；所述手性双噁唑啉-炔基膦类配体的结构式如式1所示；
，
其中，R1为C1-C20的烷基、C3-C20的环烷基、苯基、卤素取代苯基或2,6-二异丙基苯基；
R2为C1-C20的烷基、C3-C20的环烷基、苯基、2,6-二异丙基苯基、三异丙基硅基、叔丁基二苯基硅基、三甲基硅氧亚甲基、羟亚甲基或2,6-二甲氧基苯基。
2.如权利要求1所述的手性双噁唑啉-炔基膦类配体，其特征在于，所述C1-C20的烷基为异丙基、叔丁基、甲基、乙基或异丁基；所述C3-C20的环烷基为环己基或环丙基。
3.一种如权利要求1或2所述的手性双噁唑啉-炔基膦类配体的制备方法, 其特征在于，所述方法包括如下步骤：
S1、手性含溴噁唑啉底物3用正丁基锂处理后与P(OPh)3反应得到中间体6；
S2、中间体6与炔基锂7反应实现双噁唑啉-炔基膦类配体1的制备。
4.如权利要求3所述的制备方法，其特征在于，步骤S1中，所述手性含溴噁唑啉底物3、正丁基锂、P(OPh)3的摩尔比为（1.0～3.0）:（1.0～3.0）:1；反应温度为-110℃～室温。
5.如权利要求3所述的制备方法，其特征在于，步骤S2中，所述中间体6与炔基锂7的摩尔比为1:2～2:1；反应温度为-110℃～室温。
6.一种如权利要求1或2所述的手性双噁唑啉-炔基膦类配体在不对称合成中的应用，其特征在于，所述手性双噁唑啉-炔基膦类配体应用于以和为原料的铑/双噁唑啉-炔基膦催化的1,2-二取代烯丙基胺8的制备。
7.一种如权利要求1所述的手性双噁唑啉-炔基膦类配体在不对称合成中的应用，其特征在于，所述手性双噁唑啉-炔基膦类配体应用于以、MeCN为原料的钴/双噁唑啉-炔基膦催化的含手性四级碳的吡啶9的合成。
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