CN109970795A - 吡啶环上4-位取代手性螺环胺基膦配体制备方法及其应用 - Google Patents
吡啶环上4-位取代手性螺环胺基膦配体制备方法及其应用 Download PDFInfo
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Abstract
本发明涉及一种吡啶环上4‑位取代手性螺环胺基膦配体制备方法和应用。该吡啶环上4‑位取代手性螺环胺基膦配体是具有式1所示的化合物,或其消旋体或旋光异构体,或其催化可接受的盐,主要结构特征是具有手性螺二氢茚骨架和具有吡啶基团。该吡啶环上4‑位取代手性螺环胺基膦配体可以由具有螺环骨架的7‑二芳/烷基膦基‑7′‑氨基‑1,1′‑螺二氢茚类化合物为手性起始原料合成。该吡啶环上4‑位取代手性螺环胺基膦配体与过渡金属(铱)盐形成配合物后,可用于催化α‑芳胺取代内酯化合物的不对称催化氢化反应。表现出很高的催化活性(TON达到5000)和对映选择性(高达98%ee),具有实用价值。
Description
技术领域
本发明涉及一种吡啶环上4-位取代手性螺环胺基膦配体制备方法和应用,特别是一种具有螺环骨架的手性螺环胺基吡啶三齿配体的制备方法及其在α-芳胺取代内酯化合物的动态动力学不对称催化氢化反应方面的应用,属于有机合成技术领域。
背景技术
不对称催化氢化是合成手性化合物最绿色、原子经济的有效方法,在工业生产手性药物、香料等方面已得到了广泛的应用。实现高效、高选择性并具有工业应用价值的不对称催化氢化反应的关键是手性配体及其催化剂。正因如此,学术界和工业界一直关心设计合成新的高效手性配体及催化剂来发展更多具有应用前景的不对称催化新反应。
手性2-位胺基取代的1,4-或1,5-二醇,特别是手性2-芳胺基取代的1,4-丁二醇是合成手性药物如目前临床试验用于治疗小细胞肺癌和血液病恶性肿瘤的口服Bcl-2家族蛋白抑制剂ABT-263(navitoclax)(Elmore,S.W.;et al.,J.Med.Chem.2008,51,6902-6915)和具有较好选择性和血脑屏障透过性的小分子口服Hsp90抑制剂SNX-0723(Mclean,P.J.;et al.,J.Pharmacol.Exp.Ther.2010,332,849-857)等的潜在手性原料。然而,目前不对称合成2-芳胺基取代的1,4-或1,5-二醇的方法主要是通过光学活性的天冬氨酸或谷氨酸经酯基的还原和过渡金属催化的偶联反应来引入N-芳基。目前发展的不对称催化合成的方法非常少,主要是通过α-N-酰基亚胺酯的不对称Mannich加成反应(Kobayashi,S.;et al.,J.Am.Chem.Soc.2003,125,2507)、高烯丙醚的不对称羟胺化反应(Willis,A.C.Tetrahedron 2009,65,831)并经多步转化来获得。正因如此,发展高效、高选择性的不对称催化合成手性2-位胺基取代的1,4-或1,5-二醇的新反应对实现上述潜在的手性新药的合成显得非常重要。
相应的消旋α-芳胺基取代内酯的动态动力学拆分的不对称催化氢化无疑是不对称合成2-芳胺基取代的1,4-或1,5-二醇的最直接、原子经济的方法。然而,该类消旋内酯的不对称催化氢化仍然存在挑战。如我们研究发现手性螺环吡啶胺基膦三齿配体的铱络合物Ir-SpiroPAP(Xie,J.-H.;Zhou,Q.-L.;et al.,Angew.Chem.Int.Ed.2011,50,7329-9332.周其林,谢建华,刘晓艳,谢剑波,王立新CN 102040625A)对于一系列消旋α-芳基和烷基取代的戊内酯可给出86-95%ee的对映选择性(Xie,J.-H.;Zhou,Q.-L.;et al.,Chem.Sci.2017,8,1811-1814)。但用已发展的该类铱络合物直接催化这类消旋α-芳胺取代内酯的不对称氢化仅给出相对较低的对映选择性(不超过84%ee)。据此,我们通过系统的定位改造手性螺环吡啶胺基膦三齿配体SpiroPAP配体,发展出吡啶环4-位取代基立体效应更加显著的新的手性螺环胺基膦配体及其铱络合物的基础上,实现了消旋α-芳胺取代γ-丁内酯和δ-戊内酯的高效、高对映选择性(对映选择性高达98%ee)不对称催化氢化,从而为相应的光学活性手性2-芳胺基取代1,4-或1,5-二醇的不对称合成提供了高效合成新方法。该合成方法具有绿色、原子经济、反应条件温和、操作简单、适于工业化生产的优点,以及具有非常好的应用前景和价值。
发明内容
本发明的目的在于提供一种吡啶环上4-位取代手性螺环胺基膦配体制备方法和应用,该手性螺环三齿配体是基于手性螺环吡啶胺基膦三齿配体的铱络合物Ir-SpiroPAP的基础上设计发展的吡啶环4-位含有立体效应更加显著取代基的新手性螺环膦-氨基-吡啶三齿配体。通过在吡啶环4-位引入立体效应更加显著的取代基从而更好控制催化氢化反应过程中的手性传递,从而显著地提高了催化剂对底物的手性控制,并在消旋α-芳胺取代内酯化合物的不对称催化氢化中获得了优秀的对映选择性(高达98%ee)和高达5000的高转化数(TON),为催化酯类化合物不对称氢化的手性配体及其催化剂提供了一类新产品,也为光学活性手性2-芳胺基取代1,4-或1,5-二醇的不对称合成提供了绿色、高效、实用的合成方法。
本发明提供的一种吡啶环上4-位取代手性螺环胺基膦配体具有式1的化合物或其对映体、消旋体,或其催化可接受的盐。
其中,R1选自C1~C10的烃基、苯基、取代苯基、1-萘基、2-萘基、杂芳基或苄基;所述的苯基上的取代基为C1~C10的烃基、烷氧基,取代基数量为1~5;杂芳基为呋喃基、噻吩基或吡啶基;
R2、R3、R4分别独立选自H、C1~C10烷基、苯基、取代苯基、取代酯基;所述的苯基上的取代基为C1~C10的烃基、烷氧基,取代基数量为1~5;R2~R4并为C3~C7脂肪环、吡咯环、芳香环;R2、R3、R4相同或不同。
本发明提供的所述的吡啶环上4-位取代手性螺环胺基膦配体选自如下化合物的对映体、消旋体或其催化可接受的盐:
本发明提供的所述的吡啶环上4-位取代手性螺环胺基膦配体的制备方法包括:以具有手性螺二氢茚骨架的式2所示的消旋或旋光活性的7-二芳/烷基膦基-7′-氨基-1,1′-螺二氢茚类化合物为起始原料,经过下述反应式:
具有手性螺二氢茚骨架的式2所示的化合物是按文献方法制备(Jian-Bo Xie,Jian-Hua Xie,Xiao-Yan Liu,Wei-Ling Kong,Shen Li,Qi-Lin Zhou,J.Am.Chem.Soc.2010,132,4538;周其林,谢建华,谢剑波,王立新,CN 101671365A)。
具体步骤如下:
在有机溶剂和还原剂存在的条件下,具有式2所示的化合物与醛、酸在反应器中反应2~24小时制备得到式1所示的化合物;
所述的有机溶剂为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、苯、苯甲醚、甲苯、二甲苯、甲基叔丁基醚、乙醚、二氧六环、N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、1,2-二氯乙烷、丙酮、石油醚、正己烷中的一种或其中几种的混合溶剂。
所述的还原试剂可为氢化铝锂、硼氢化钠、三乙酰氧基硼氢化钠、腈基硼氢化钠;述的酸包括有机酸和无机酸,可为盐酸、硫酸、硝酸、甲酸、乙酸、苯甲酸。
所述的碱包括有机碱和无机碱,可为吡啶、三乙胺、三丁胺、N-甲基吗啡啉、N,N-二乙基异丙基胺、二异丙基氨基锂、氢化锂、氢化钾、氢化钠、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾。
本发明提供的所述的吡啶环上4-位取代手性螺环胺基膦配体的应用是:该配体与过渡金属(铱)金属盐原位形成配合物,铱配合物(可直接不脱溶或脱溶后制备成可存放的固体)作为铱催化剂,用于催化α-芳胺取代内酯化合物的不对称催化氢化反应:
所述的铱配合物原位制备包括如下步骤:
在有机溶剂和25~120℃的反应条件下,吡啶环上4-位取代手性螺环胺基膦配体首先与铱催化剂前体反应0.5~4小时,然后再在0.1~50atm的氢气氛围中搅拌反应0.1~3小时,便可得到氢化反应所需的吡啶环上4-位取代手性螺环胺基膦配体铱催化剂;
所述的手性螺环胺基膦配体与铱催化剂前体的摩尔比为1:1~2:1;
作为优先方案,在惰性气体氛围下,将所述的吡啶环上4-位取代手性螺环胺基膦配体与铱催化剂前体加入有机溶剂中,在25℃的反应条件下反应0.5~4小时;随后在0.1~20atm的氢气氛围中搅拌反应1~3小时制备得到吡啶环上4-位取代手性螺环胺基膦配体与铱催化剂前体形成的配合物。
作为更进一步的优先方案,所述的吡啶环上4-位取代手性螺环胺基膦配体与过渡金属盐的摩尔比为1.2:1~1.8:1。
所述的铱催化剂前体为[Ir(COD)Cl]2(COD=环辛二烯)、[Ir(COD)2]BF4、[Ir(COD)2]PF6、[Ir(COD)2]SbF6或[Ir(COD)2]OTf。
本发明提供的所述的用于催化α-芳胺取代内酯化合物的不对称催化氢化反应包括如下步骤:
在氮气保护下,于氢化反应器的有机溶剂中加入吡啶环上4-位取代手性螺环胺基膦配体铱催化剂,并加入α-芳胺取代内酯化合物和碱,并在0.1~100atm的氢气氛围中搅拌反应0.1~80小时,旋转蒸发仪脱除溶剂和催化剂,用薄层层析或者核磁共振分析反应的转化率和收率。
所述的α-芳胺取代内酯底物与催化剂的摩尔比为10:1~5000:1,即催化剂用量为0.1~0.02mol%;底物浓度为0.001~10.0M;
所述的碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、乙醇钠、乙醇钾、叔丁醇钠、叔丁醇钾、叔丁醇锂、三乙胺、三丁胺或N-甲基吗啉;碱浓度为0.005M~1.0M;反应温度为0~80℃。
所述的有机溶剂为甲醇、乙醇、正丙醇、异丙醇、丁醇、四氢呋喃、甲苯、甲基叔丁基醚、二氧六环、N,N-二甲基甲酰胺、二甲亚砜中的一种或其中几种的混合溶剂。
本发明提供了一种吡啶环上4-位取代手性螺环胺基膦配体制备方法和应用,该手性螺环三齿配体是基于手性螺环吡啶胺基膦三齿配体的铱络合物Ir-SpiroPAP的基础上设计发展的吡啶环4-位含有立体效应更加显著取代基的新手性螺环膦-氨基-吡啶三齿配体。通过在吡啶环4-位引入立体效应更加显著的取代基从而更好控制催化氢化反应过程中的手性传递,从而显著地提高了催化剂对底物的手性控制,并在消旋α-芳胺取代内酯化合物的不对称催化氢化中获得了优秀的对映选择性(高达98%ee)和高达5000的高转化数(TON),为催化酯类化合物不对称氢化的手性配体及其催化剂提供了一类新产品,也为光学活性手性2-芳胺基取代1,4-或1,5-二醇的不对称合成提供了绿色、高效、实用的合成方法。
总之,本发明提供的新的吡啶环上4-位取代手性螺环胺基膦配体,合成方法简单,条件温和。其具有手性螺二氢茚骨架,可作为手性配体用于铱催化的α-芳胺取代内酯化合物的不对称催化氢化反应中,具有很高的催化活性和手性诱导效果,对映选择性(高达98%ee),而且具有很强的调节能力。
具体实施方式
下面结合实施例对本发明作进一步详细、完整的说明,列出的实施例将有助于理解本发明,但不能限制本发明的内容。
实施例1:
在氩气氛围中,称取(R)-7′-二-(3,5-二叔丁基苯基)膦基-7'-氨基-1,1′-螺二氢茚SpiroAP(160mg,0.25mmol)于100mL干燥的Schlenk管中,注射器打入30mL无水甲醇,搅拌溶解。滴入4-羧酸乙酯吡啶甲醛(89.5mg0.50mmol)和冰醋酸(45mg,0.75mmol)。室温搅拌反应2小时。打开反口塞,一次性倒入NaBH3CN(31.5mg,0.50mmol),反应在40度下反应12小时。反应结束后冷却至室温,体系旋干,加入乙酸乙酯溶解,饱和碳酸氢钠溶液淬灭。乙酸乙酯萃取,合并有机相,有机相用无水硫酸镁干燥,抽滤除去干燥剂,滤液用旋转蒸发仪脱除溶剂。残余物经硅胶柱层析(石油醚:乙酸乙酯=20:1)得到白色固体201mg,收率为96%。熔点:80-81℃;
1H NMR(400MHz,CDCl3)δ7.64(s,1H),7.60(d,J=5.0Hz,1H),7.35(d,J=7.3Hz,1H),7.28(s,1H),7.24(dd,J=4.5,2.8Hz,2H),7.11(dd,J=10.3,5.2Hz,2H),6.86(dd,J=8.0,1.7Hz,2H),6.76(dd,J=7.6,1.8Hz,2H),6.71(d,J=7.4Hz,1H),4.57–4.24(m,3H),3.98(dt,J=32.6,16.0Hz,1H),3.73(dd,J=16.0,3.8Hz,1H),3.19–3.04(m,2H),2.96(dt,J=40.5,16.1Hz,1H),2.84(ddd,J=19.6,10.8,5.2Hz,1H),2.50(dd,J=21.5,11.4Hz,1H),2.32–2.16(m,3H),1.44–1.32(m,3H),1.18(s,18H),1.11(s,18H).13C NMR(101MHz,CDCl3)δ165.3,160.0,149.8(d),149.5,144.3(d),143.87,138.3(d),137.9,136.0(d),134.8(d),133.8,132.9,128.8–127.8(m),126.9,125.7,122.1,121.4,120.7,120.3,114.0,108.5,61.6,48.3,36.0,34.7(d),31.5–30.5(m),14.2.31P NMR(162MHz,CDCl3)δ-19.034.HRMS(MALDI)Calcd for C54H67N2OP([M+H]+):807.5013,Found:807.5018.
实施例2:
操作过程同实施例1a。白色固体164mg,80%收率。熔点:99-100℃。 1H NMR(400MHz,CDCl3)δ:8.23(d,J=4.8Hz,1H),7.32(d,J=7.2Hz,1H),7.24(s,1H),7.22–7.17(m,2H),7.12–7.05(m,2H),7.02(d,J=4.4Hz,1H),6.91(s,1H),6.85(d,J=6.8Hz,2H),6.76–6.65(m,3H),6.11(d,J=8.0Hz,1H),4.19(br,1H),4.00(dd,J=16.0,6.8Hz,1H),3.57(d,J=16.0Hz,1H),3.11–2.82(m,4H),2.55–2.42(m,1H),2.25–2.17(m,2H),2.16–2.07(m,1H),1.73–1.66(m,4H),1.14(s,18H),1.07(s,18H),0.70–0.60(m,6H).13C NMR(101MHz,CDCl3)δ158.5,155.3(2),152.7,150.0(2),149.9(2),148.7,144.5,144.3,144.2,144.1,144.1,138.5,138.4,136.1,136.0,135.0,134.8,134.1(2),133.2,133.1,128.4,128.2,128.1,128.0(2),126.9,125.8,122.3,121.5,119.0,117.6,114.0,108.9,77.1,67.2,61.9,61.8,48.4,39.0,38.9,35.9,34.8(2),34.7,31.4,31.3,31.0,29.9,7.8,7.7.31P NMR(162MHz,CDCl3)δ:–18.41.HRMS(MALDI)Calcd for C56H74N2OP([M+H]+):821.5533;Found:821.5538.
实施例3:
操作过程同实施例1a。白色固体166mg,80%收率。熔点:96-97℃. 1H NMR(400MHz,CDCl3)δ:8.22(d,J=5.2Hz,1H),7.32(d,J=7.2Hz,1H),7.24(s,1H),7.22–7.17(m,2H),7.12–7.04(m,2H),7.04–7.01(m,1H),6.93(s,1H),6.85(dd,J=8.0,1.6Hz,2H),6.72(dd,J=7.6,1.6Hz,2H),6.68(d,J=7.6Hz,1H),6.09(d,J=7.6Hz,1H),4.25(d,J=4.4Hz,1H),4.04–3.93(m,1H),3.56(dd,J=16.0,2.4Hz,1H),3.09–3.03(m,1H),3.01(s,3H),2.98–2.85(m,2H),2.54–2.44(m,1H),2.26–2.17(m,2H),2.15–2.08(m,1H),1.82–1.72(m,2H),1.67–1.60(m,2H),1.14(s,18H),1.07(s,18H),0.65–0.56(m,6H).13C NMR(101MHz,CDCl3)δ158.3,153.9,152.9,152.7,149.9(2),148.6,144.4,144.3,144.2,144.1,144.1,138.6,138.5,136.2,136.1,134.9,134.7,134.1(2),133.2,133.1,129.0,128.4,128.2,128.1,128.0,127.9,126.9,125.8,122.2,121.4,119.8,118.7,113.9,108.9,81.0,61.9,61.8,49.5,48.4,39.0(2),35.9,35.0(2),34.8(2),34.6,31.4,31.0,28.3,7.4(2).31P NMR(162MHz,CDCl3)δ:-19.00.HRMS(MALDI)Calcd for C57H76N2OP([M+H]+):835.5690;Found:835.5695.
实施例4:
操作过程同实施例1a。白色固体209mg,90%收率。熔点:132-133℃。 1H NMR(400MHz,CDCl3)δ:8.24(d,J=5.2Hz,1H),7.32(d,J=7.4Hz,1H),7.29–7.18(m,3H),7.14–7.07(m,1H),7.05–6.95(m,3H),6.90(d,J=8.4Hz,2H),6.74(d,J=7.6Hz,2H),6.65(d,J=7.2Hz,1H),5.98(d,J=8.0Hz,1H),4.13(s,1H),3.91(dd,J=16.4,6.0Hz,1H),3.69(d,J=16.0Hz,1H),3.18–2.84(m,4H),2.51(d,J=10.9Hz,1H),2.30–2.19(m,2H),2.17–2.06(m,1H),1.78–1.55(m,11H),1.34–1.19(m,4H),1.14(d,J=8.2Hz,36H),1.04–0.58(m,7H).13C NMR(101MHz,CDCl3)δ:158.1,153.3,152.9,152.6,149.9,149.8,149.8,149.8,148.2,144.2,144.2,144.0,143.9,143.6,143.5,138.5,138.3,136.1,136.0,134.9,134.7,134.1,134.1,132.9,132.9,128.2,128.1,128.0,127.9,127.8,126.9,125.7,122.1,121.3,119.7,118.5,113.9,109.0,80.3,61.8,61.7,48.3,44.1,43.7,39.0,38.9,35.8,34.8,34.7,31.4,31.3,31.2,30.9,27.2,27.1,26.8,26.7,26.6,26.6,26.5,26.3.31P NMR(162MHz,CDCl3)δ:–18.98.HRMS(ESI)Calcd forC64H86N2OP([M+H]+):929.6472;Found:929.6476.
实施例5:
操作过程同实施例1a。白色固体202mg,86%收率。熔点:119-120℃。 1H NMR(400MHz,CDCl3)δ:8.24(d,J=5.2Hz,1H),7.33–7.29(m,1H),7.29–7.26(m,1H),7.24–7.17(m,2H),7.22–7.19(m,1H),7.04–6.97(m,2H),6.97–6.94(m,1H),6.91(dd,J=8.0,1.6Hz,2H),6.75(dd,J=7.6,1.6Hz,2H),6.62(d,J=7.6Hz,1H),5.95(d,J=8.0Hz,1H),4.19–4.11(m,1H),3.94–3.82(m,1H),3.82–3.71(m,1H),3.39(s,3H),3.17–2.88(m,4H),2.51(q,J=11.2Hz,1H),2.26–2.19(m,2H),2.17–2.10(m,1H),1.92(q,J=11.2Hz,2H),1.78–1.52(m,10H),1.17–1.14(m,36H),1.07–0.79(m,10H).13C NMR(101MHz,CDCl3)δ157.9,152.9,152.7,152.3,149.7,149.9,149.9(2),148.1,144.3,144.2,144.0,143.9,143.6(2),138.6,138.5,136.3,136.2,135.0,134.8,134.2,134.2,132.8,132.8,131.0,128.8,128.2,128.2,128.1,128.0,127.9,127.0,125.8,122.1,121.4,121.1,119.9,113.8,109.0,84.7,61.8,61.8,53.1,48.4,42.3,41.9,39.1,39.0,35.9,34.9,34.8,31.6,31.4,31.3,31.0,28.4,28.1,27.8,27.4(2),27.3,27.2,26.8,26.7.31P NMR(162MHz,CDCl3)δ:-19.03.HRMS(MALDI)Calcd for C65H88N2OP([M+H]+):943.6629;Found:943.6631.
实施例6:
操作过程同实施例1a。白色固体211mg,87%收率。熔点:119-120℃。 1H NMR(400MHz,CDCl3)δ:8.17(d,J=5.2Hz,1H),7.25–7.17(m,3H),7.13(t,J=7.4Hz,1H),7.09–7.02(m,2H),6.98(s,1H),6.95(d,J=5.2Hz,1H),6.91(d,J=7.2Hz,2H),6.84(dd,J=8.0,2.0Hz,2H),6.79–6.70(m,6H),6.66(d,J=7.6Hz,1H),6.06(d,J=7.6Hz,1H),4.35–4.28(m,1H),3.91(dd,J=16.0,6.4Hz,1H),3.68–3.55(m,1H),3.12–2.76(m,4H),2.62(s,1H),2.35–2.28(m,1H),2.23(d,J=11.2Hz,12H),2.18–2.15(m,1H),2.06–1.99(m,1H),1.15(s,18H),1.07(s,18H).13C NMR(101MHz,CDCl3)δ:158.3,155.6,152.7,152.4,149.8,149.7,148.3,145.7,145.5,144.1(2),144.0,143.9(2),138.4,138.2,137.5(2),136.0(2),134.9,134.6,133.8(2),132.9,132.8,129.3,129.2,128.2,128.0(2),127.8(d),126.7,125.5(2),122.0,121.3,120.8,119.4,113.7,108.5,81.1,61.6(2),48.3,38.8(2),35.8,34.7,34.6,31.3,21.5,21.4.31P NMR(162MHz,CDCl3)δ:–18.67.HRMS(ESI)Calcd for C68H82N2OP([M+H]+):973.6159;Found:973.6176.
实施例7:
操作过程同实施例1a。白色固体222mg,90%收率。熔点:110-111℃。 1H NMR(400MHz,CDCl3)δ8.10(d,J=5.2Hz,1H),7.29–7.26(m,1H),7.23–7.16(m,4H),7.10–7.03(m,3H),6.93–6.86(m,6H),6.80(dd,J=8.0,1.8Hz,2H),6.76(dd,J=7.6,1.8Hz,2H),6.64(d,J=7.4Hz,1H),6.08(d,J=8.0Hz,1H),4.57–4.50(m,1H),3.94(dd,J=16.0,6.4Hz,1H),3.66(dd,J=16.0,3.6Hz,1H),3.10–2.92(m,3H),2.91(s,3H),2.86–2.76(m,1H),2.42–2.31(m,1H),2.24(d,J=8.8Hz,12H),2.18–2.11(m,2H),2.07–2.00(m,1H),1.15(s,18H),1.01(s,18H).13C NMR(101MHz,CDCl3)δ157.9,153.9,152.5,152.3,149.8,149.7(2),149.6,148.3,144.1(3),144.0(2),142.3,138.3,138.2,137.2,136.3,136.2,134.8,134.5,133.8,133.7,132.7,132.6,129.0,128.2,128.1,128.0,127.9,127.8,126.6(2),125.5,121.7,121.3,121.0,119.9,113.5,108.3,86.3,61.6(2),52.0,48.1,38.7(2),35.8,34.7,34.5,31.3,31.2,30.8,21.5(2).31P NMR(162MHz,CDCl3)δ–18.3.HRMS(ESI)Calcd for C69H84N2OP([M+H]+):987.6316;Found:987.6318.
实施例8:
操作过程同实施例1a。白色固体248mg,87%收率。熔点:130-131℃。 1H NMR(400MHz,CDCl3)δ:8.19(d,J=5.2Hz,1H),7.35–7.30(m,2H),7.23(s,1H),7.21–7.17(m,2H),7.14(t,J=7.4Hz,1H),7.11–6.99(m,4H),6.98(s,3H),6.91–6.83(m,3H),6.72(dd,J=7.6,1.6Hz,2H),6.64(d,J=7.2Hz,1H),6.06(d,J=7.6Hz,1H),4.19–4.12(m,1H),3.88(dd,J=15.6,6.4Hz,1H),3.58(dd,J=15.6,3.6Hz,1H),3.06–2.81(m,4H),2.57(s,1H),2.39–2.14(m,3H),2.07–1.95(m,1H),1.21(d,J=3.2Hz,36H),1.14(s,18H),1.08(s,18H).13C NMR(101MHz,CDCl3)δ:158.6,156.6,152.8(2),152.6,150.2,150.1(2),149.8,149.7(2),148.1,144.8,144.7,144.1,144.0,143.9,138.5,138.4,136.0,135.9,134.8,134.6,134.0,133.9,132.9(2),128.3,128.1,127.9(2),127.7,126.7,125.6,122.3,122.2,122.1,121.2(2),121.1,121.0,119.2,113.7,108.4,82.1,61.6(d),48.4,39.0(2),35.8,34.9,34.7,31.4,31.3,31.2,30.8.31P NMR(162MHz,CDCl3)δ:-18.94.HRMS(ESI)Calcd for C80H106N2OP([M+H]+):1141.8037;Found:1141.8042.
实施例9:
操作过程同实施例1a。白色固体231mg,80%收率。熔点:114-115℃。
1H NMR(400MHz,CDCl3)δ8.10(d,J=5.2Hz,1H),7.30–7.26(m,4H),7.21–7.16(m,3H),7.14–7.00(m,7H),6.83(d,J=7.6Hz,2H),6.76(d,J=7.6Hz,1H),6.62(d,J=7.6Hz,1H),6.06(d,J=7.6Hz,1H),4.45–4.41(m,1H),3.89(dd,J=15.6,6.0Hz,1H),3.67–3.61(m,1H),3.04–2.93(m,2H),2.91(s,3H),2.89–2.78(m,2H),2.43–2.34(m,1H),2.19–2.13(m,2H),2.07–2.00(m,1H),1.23(s,36H),1.15(s,18H),1.04(s,18H).13C NMR(101MHz,CDCl3)δ158.1,155.1,152.8,152.5,149.8(3),149.7,148.1,144.2(2),144.1(2),144.0,141.2,141.1,138.4,138.3,136.4,136.3,134.8,134.6,133.9(2),132.8,132.7,128.3,128.2,128.1,128.0,127.9,126.7,125.6,123.6,123.4,121.8,121.3,121.2,120.8,119.9,113.5,108.3,87.3,61.7(2),51.8,48.3,39.0,38.9,35.9,34.9,34.7,34.7,31.5,31.4,31.3,30.9.31P NMR(162MHz,CDCl3)δ:-18.51.HRMS(ESI)Calcd for C81H108N2OP([M+H]+):1155.8194;Found:1155.8199.
实施例10:
操作过程同实施例1a。白色固体137mg,60%收率。熔点:108-109℃。 1H NMR(400MHz,CDCl3)δ:8.21(d,J=5.2Hz,1H),7.32–7.28(m,3H),7.28–7.26(m,1H),7.25–7.22(m,3H),7.21–7.14(m,4H),7.14–7.09(m,3H),7.08–7.02(m,2H),6.99–6.94(m,2H),6.85(d,J=1.6Hz,1H),6.83(d,J=1.6Hz,1H),6.72(d,J=2.0Hz,1H),6.70(d,J=2.0Hz,1H),6.67(d,J=7.2Hz,1H),6.02(d,J=8.0Hz,1H),4.24–4.18(m,1H),3.91(dd,J=16.0,6.4Hz,1H),3.60(dd,J=16.0,3.6Hz,1H),3.04–2.82(m,4H),2.61(s,1H),2.31–2.13(m,3H),2.01–1.93(m,1H),1.14(s,18H),1.07(s,18H).13C NMR(101MHz,CDCl3)δ:158.5,155.4,152.8,152.5,149.9(2),149.8(2),148.6,145.7,145.4,144.2(2),144.1(2),143.7(2),138.4,138.3,136.1,136.0,135.0,134.7,134.0,133.9,133.0(2),128.3,128.1(2),128.0,127.9,127.8(2),127.7,127.6,126.8,125.6,122.1,121.3,120.6,119.5,113.9,108.8,81.2,77.4,77.1,76.8,61.7,61.6,48.2,38.9,38.8,35.8,34.7,31.4,31.2,30.8.31P NMR(162MHz,CDCl3)δ:-18.84.HRMS(MALDI)Calcd forC64H74N2OP([M+H]+):917.5533Found:917.5537.
实施例11:
操作过程同实施例1a。白色固体186mg,80%收率。熔点:113-114℃。 1H NMR(400MHz,CDCl3)δ:8.19(d,J=5.2Hz,1H),7.25–7.22(m,2H),7.21–7.12(m,8H),7.11–6.83(m,13H),6.76–6.63(m,5H),5.91(d,J=8.0Hz,1H),4.16–4.10(m,1H),3.78(s,3H),3.74(d,J=5.2Hz,1H),3.67–3.62(m,1H),3.08–2.77(m,4H),2.24–2.03(m,3H),1.92–1.81(m,1H),1.13(d,J=10.3Hz,36H).13C NMR(101MHz,CDCl3)δ:158.4,157.6,156.0,152.8,152.5,149.8(d),148.4,145.7,144.2(2),144.0(2),143.5(2),138.5,138.4,137.6,136.2,136.0(2),134.8(2),134.6(2),134.0(2),132.8(2),131.9,130.8,128.2,128.1,128.0,127.9,127.8,127.7,126.8,126.1,125.7,123.8,123.3,122.1,121.3,113.7,113.0,108.7,64.0,61.6,61.6,55.2,48.2,39.0,38.9,35.6,34.7,31.5,31.4,31.3,30.8.31P NMR(162MHz,CDCl3)δ:–18.92.HRMS(ESI)Calcd forC71H80N2OP([M+H]+):1007.6003;Found:1007.6008.
实施例12:
操作过程同实施例1a。白色固体143mg,67%收率。熔点:68-69℃。 1H NMR(400MHz,CDCl3)δ:8.13(d,J=5.2Hz,1H),7.29(s,1H),7.28–7.16(m,6H),7.16–7.05(m,4H),6.91(s,1H),6.88–6.80(m,3H),6.75(dd,J=7.6,2.0Hz,2H),6.70(d,J=7.4Hz,1H),6.10(d,J=7.6Hz,1H),4.42–4.35(m,1H),3.97(dd,J=16.0,6.8Hz,1H),3.59(dd,J=15.8,3.2Hz,1H),3.15–2.83(m,4H),2.47–2.35(m,1H),2.24–2.14(m,2H),2.13–2.04(m,1H),1.56(s,6H),1.17(s,18H),1.09(s,18H).13C NMR(101MHz,CDCl3)δ159.6,158.2,152.8,152.6,149.9(3),149.8,148.9,148.7,144.3(2),144.2,144.1,138.5,138.4,136.3,136.2,136.1(2),134.9,134.7,134.6,134.0,133.0(2),128.3(2),128.2,128.1,128.0,127.9,126.9,126.8,126.2,125.8,122.1,121.4,120.4,119.0,113.8,108.7,61.8(2),48.3,42.9,38.9,38.8,35.9(2),34.8(2),31.4,31.0,30.1,30.0,29.8.31P NMR(162MHz,CDCl3)δ:–18.53.HRMS(ESI)Calcd for C60H74N2P([M+H]+):853.5584;Found:853.5594.
实施例13:
吡啶环上4-位取代手性螺环胺基膦配体用于铱催化的α-芳胺取代内酯化合物的不对称催化氢化反应中的应用。
在手套箱中称取配体(R)-1(3.2μmol)和[Ir(COD)Cl]2(1.0mg,1.5μmol)于装有磁力搅拌子的干燥洁净的10mL Schlenk管中,密封备用。取出后加入6mL无水正丙醇,室温下搅拌0.5小时。在氮气保护下,用注射器将该溶液加入到装有玻璃内管和磁力搅拌子的氢化反应釜中,用氢气快速置换反应釜中的气体三次,调节氢气压力为10atm,室温下搅拌反应0.5小时后,缓慢释放出反应釜中的氢气。在氮气保护下,用注射器取出4mL加入装有1.0~10mmol底物和0.05~25mmol叔丁醇钾的正丙醇溶液(0.5mL(0.1mmol/mL)~25mL(1mmol/mL))的应釜中中。用氢气快速置换反应釜中的气体三次,最后调节氢气压力为8~30atm,室温下搅拌反应至氢气压力不再降低为止。缓慢释放出反应釜中的氢气,旋转蒸发仪脱除溶剂后得粗产物。经短硅胶柱过滤除去催化剂后,用薄层层析或者核磁共振分析反应的转化率和收率,高效液相色谱分析产物的光学纯度,所得氢化实验结果见表1。
表1.羰基化合物的不对称催化氢化(n=1,2)。
Claims (10)
1.一种吡啶环上4-位取代手性螺环胺基膦配体,其特征在于它是具有式1的化合物或其对映体、消旋体,或其催化可接受的盐。
其中,R1选自C1~C10的烃基、苯基、取代苯基、1-萘基、2-萘基、杂芳基或苄基;所述的苯基上的取代基为C1~C10的烃基、烷氧基,取代基数量为1~5;杂芳基为呋喃基、噻吩基或吡啶基;
R2、R3、R4分别独立选自H、C1~C10烷基、苯基、取代苯基、取代酯基;所述的苯基上的取代基为C1~C10的烃基、烷氧基,取代基数量为1~5;R2~R4并为C3~C7脂肪环、吡咯环、芳香环;R2、R3、R4相同或不同。
2.根据权利要求1所述的吡啶环上4-位取代手性螺环胺基膦配体,其特征在于它选自如下化合物的对映体、消旋体或其催化可接受的盐:
3.权利要求1所述的吡啶环上4-位取代手性螺环胺基膦配体的制备方法,其特征在于:以具有手性螺二氢茚骨架的式2所示的消旋或旋光活性的7-二芳/烷基膦基-7′-氨基-1,1′-螺二氢茚类化合物为起始原料,经过下述反应式:
具体步骤如下:
在有机溶剂和还原剂存在的条件下,具有式2所示的化合物与醛、酸在反应器中反应2~24小时制备得到式1所示的化合物;
所述的有机溶剂为甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃、苯、苯甲醚、甲苯、二甲苯、甲基叔丁基醚、乙醚、二氧六环、N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、1,2-二氯乙烷、丙酮、石油醚、正己烷中的一种或其中几种的混合溶剂;
所述的还原试剂可为氢化铝锂、硼氢化钠、三乙酰氧基硼氢化钠、腈基硼氢化钠;述的酸包括有机酸和无机酸,可为盐酸、硫酸、硝酸、甲酸、乙酸、苯甲酸;
所述的碱包括有机碱和无机碱,可为吡啶、三乙胺、三丁胺、N-甲基吗啡啉、N,N-二乙基异丙基胺、二异丙基氨基锂、氢化锂、氢化钾、氢化钠、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾。
4.根据权利要求1或2中所述的吡啶环上4-位取代手性螺环胺基膦配体的应用,其特征在于该配体与铱金属盐原位形成铱配合物作为铱催化剂,用于催化α-芳胺取代内酯化合物的不对称催化氢化反应。
5.根据权利要求4所述的应用,其特征在于铱配合物原位制备方法包括如下步骤:
在有机溶剂和25~120℃的反应条件下,吡啶环上4-位取代手性螺环胺基膦配体首先与铱催化剂前体反应0.5~4小时,然后再在0.1~50atm的氢气氛围中搅拌反应0.1~3小时,便可得到氢化反应所需的吡啶环上4-位取代手性螺环胺基膦配体铱催化剂;
所述的手性螺环胺基膦配体与铱催化剂前体的摩尔比为1:1~2:1;
所述的铱催化剂前体为[Ir(COD)Cl]2(COD=环辛二烯)、[Ir(COD)2]BF4、[Ir(COD)2]PF6、[Ir(COD)2]SbF6或[Ir(COD)2]OTf。
6.根据权利要求4中所述的应用,其特征在于铱配合物原位制备是在惰性气体氛围下,将所述的吡啶环上4-位取代手性螺环胺基膦配体与铱催化剂前体加入有机溶剂中,在25℃的反应条件下反应0.5~4小时;随后在0.1~20atm的氢气氛围中搅拌反应1~3小时制备得到吡啶环上4-位取代手性螺环胺基膦配体与铱催化剂前体形成的配合物;
所述的吡啶环上4-位取代手性螺环胺基膦配体与过渡金属盐的摩尔比为1.2:1~1.8:1。
7.根据权利要求4中所述的应用,其特征在于所述的用于催化α-芳胺取代内酯化合物的不对称催化氢化反应包括如下步骤:
在氮气保护下,于氢化反应器的有机溶剂中加入吡啶环上4-位取代手性螺环胺基膦配体铱催化剂,并加入α-芳胺取代内酯化合物和碱,并在0.1~100atm的氢气氛围中搅拌反应0.1~80小时,旋转蒸发仪脱除溶剂和催化剂,用薄层层析或者核磁共振分析反应的转化率和收率。
8.根据权利要求7中所述的应用,其特征在于所述的α-芳胺取代内酯底物与催化剂的摩尔比为10:1~5000:1,即催化剂用量为0.1~0.02mol%;底物浓度为0.001~10.0M。
9.根据权利要求7中所述的应用,其特征在于所述的碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、乙醇钠、乙醇钾、叔丁醇钠、叔丁醇钾、叔丁醇锂、三乙胺、三丁胺或N-甲基吗啉;碱浓度为0.005M~1.0M;反应温度为0~80℃。
10.根据权利要求7中所述的应用,其特征在于所述的有机溶剂为甲醇、乙醇、正丙醇、异丙醇、丁醇、四氢呋喃、甲苯、甲基叔丁基醚、二氧六环、N,N-二甲基甲酰胺、二甲亚砜中的一种或其中几种的混合溶剂。
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