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CN114085251B - 一类手性二茂铁-螺环骨架双膦配体及其制备方法 - Google Patents

一类手性二茂铁-螺环骨架双膦配体及其制备方法 Download PDF

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CN114085251B
CN114085251B CN202111287691.4A CN202111287691A CN114085251B CN 114085251 B CN114085251 B CN 114085251B CN 202111287691 A CN202111287691 A CN 202111287691A CN 114085251 B CN114085251 B CN 114085251B
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biphosphine ligand
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CN114085251A (zh
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聂慧芳
张生勇
李斌
姜茹
张东旭
魏朝
姚琳
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Fourth Military Medical University FMMU
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Abstract

一类手性二茂铁‑螺环骨架双膦配体及其制备方法，配体是以手性二茂铁胺为原料，邻位锂化后与三氯化膦反应得到二氯膦中间体，再经四氢锂铝还原得到伯膦中间体，该中间体与螺环二苄反应生成手性二茂铁‑螺环骨架单膦代物，最后和不同仲膦反应，得到具有不同手性中心的二茂铁‑螺环骨架双膦配体。本发明的双膦配体不仅兼具优势二茂铁和螺环骨架，而且合成简便，具有模块化优点，与金属形成的络合物催化剂在前手性烯烃、前手性酮和前手性亚胺等的不对称还原反应中表现出很高的催化活性和立体选择性。

Description

一类手性二茂铁-螺环骨架双膦配体及其制备方法
技术领域
本发明涉及一类手性二茂铁-螺环骨架双膦配体及其制备方法。
背景技术
手性精细化工产品在医药、农药和香料等领域应用十分广泛，因此，它们的制备具有十分重要的意义。合成手性化合物的方法主要有手性源合成、外消旋体拆分和催化不对称合成等，而在催化不对称合成中的不对称催化氢化由于其原子经济性、优秀的催化效率和绿色洁净的生产工艺等优点成为最理想的合成手性化合物的方法，不对称催化氢化也是目前工业生产中发展最成熟的手性催化技术。不对称催化氢化反应的关键是金属络合物催化剂，而配体则是金属络合物催化剂的核心和关键。因此，设计合成结构新颖的配体一直是不对称催化氢化反应研究的热点，也是不对称合成研究中最活跃的领域。
二茂铁骨架和螺环骨架是手性配体设计中的优势骨架，基于这两类骨架开发的优秀配体不计其数，如Josiphos和SDP等，而将两类骨架连接到同一配体结构中的f-spiroPhos也是其中的优秀代表。虽然人们已经报道了数以万计的手性配体，其中许多也表现出很高的立体选择性，然而由于催化活性低、制备繁琐、修饰苦难，价格昂贵等原因真正应用于工业生产的例子并不多。因此开发活性高、合成简便且易于修饰的新型配体具有重要意义。
上段提到的配体结构如下：
发明内容
为了克服上述现有技术的不足，本发明的目的是提供一类手性二茂铁-螺环骨架双膦配体及其制备方法，本配体不仅兼具优势二茂铁和螺环骨架，而且合成简便，具有模块化优点，与金属形成的络合物催化剂在前手性烯烃、前手性酮和前手性亚胺等的不对称还原反应中表现出很高的催化活性和立体选择性。
为了实现上述目的，本发明采用的技术方案是：
一类手性二茂铁-螺环骨架双膦配体，其分子结构式如式1所示：
式中：R1为C1～C6的烷基和环烷基的脂肪基团；C6～C20的芳香基团；R2为C1～C6的烷基和环烷基的脂肪基团；苄基的C7～C20在内的芳香基团与脂肪基团的组合基团；芳基的C6～C20内的芳香基团；上述通式包含其立体异构体。
所述的一类手性二茂铁-螺环骨架双膦配体合成路线如下：
一类手性二茂铁-螺环骨架双膦配体的制备方法，其特征在于，包括以下步骤：
在-10～30℃下，向(S)-1或(R)-1为原料的甲基叔丁基醚溶液缓慢滴加叔丁基锂戊烷溶液，反应物与叔丁基锂的摩尔比为1：1～1.2，滴加完毕后升至室温反应；再次将反应液置于-40～-80℃以下，用注射器缓慢加入PCl3，缓慢升至室温反应1～6h，过滤除去不溶物，旋干溶剂得红棕色油状物；
-10～30℃下，四氢呋喃溶解后滴加至LiAlH4的甲基叔丁基醚溶液中，反应物与LiAlH4的摩尔比为1：2～6，室温反应12～24h，加入氢氧化钠溶液搅拌，分层后干燥蒸干溶剂得粗产物，减压蒸馏得伯膦中间体(S,Rp)-2，直接用于下步反应；
称取NaH加入Schlenk反应管中，抽真空/充Ar加入四氢呋喃搅拌，用注射器加入溶于四氢呋喃的螺环二苄(R)-3，将温度降至-40～-80℃，缓慢加入溶于四氢呋喃的伯膦中间体(S,Rp)-2，加毕后，自然升温反应12～24h，再回流反应12～24h，向反应液中加入饱和碳酸氢钠溶液淬灭反应，溶液分层后有机相依次用蒸馏水和饱和食盐水洗涤，然后用无水硫酸钠干燥，过滤，旋干，柱层析(乙酸乙酯:石油醚:三乙胺＝1:20:0.5)分离纯化得橘黄色泡状产物4。
所述的手性双膦配体的过渡金属络合物催化剂，金属是钌(Ru)、铑(Rh)、铱(Ir)、钯(Pd)、铂(Pt)、铁(Fe)、钴(Co)、镍(Ni)和锰(Mn)。
所述的过渡金属络合物催化剂用于催化不对称氢化反应，氢甲酰化反应、氢氰基化反应、氢硅化反应，氢硼化反应，烯烃复分解反应，异构化反应，Diels-Alder反应，Heck反应，Aldol反应，Michael加成反应，不对称环氧化反应。
本发明的有益效果是：
本发明的双膦配体不仅兼具优势二茂铁和螺环骨架，而且合成简便，具有模块化优点，与金属形成的络合物催化剂在前手性烯烃、前手性酮和前手性亚胺等的不对称还原反应中表现出很高的催化活性和立体选择性。
本发明中的手性配体连接了优势二茂铁骨架和螺环骨架，且引入了易于修饰的侧链膦基团，相对于f-spiroPhos不仅少使用了昂贵的手性螺环砌块，且增加了一个易于修饰的位点，同时合成路线非常简洁高效。
具体实施方式
以下结合实施例对本发明进一步叙述。
一类手性二茂铁-螺环骨架双膦配体，其分子结构式如式1所示：
式中：R1为C1～C6的烷基和环烷基的脂肪基团；C6～C20的芳香基团；R2为C1～C6的烷基和环烷基的脂肪基团；苄基的C7～C20在内的芳香基团与脂肪基团的组合基团；芳基的C6～C20内的芳香基团；上述通式包含其立体异构体，以下给出了本发明手性配体的具体实例(L1-L5)
A、配体的合成
实施例1
在0℃下，向(S)-1(2.57g,10mmol)的甲基叔丁基醚溶液缓慢滴加1.3M叔丁基锂(8.1mL,10.5mmol)戊烷溶液，滴加完毕后升至室温反应1.5h；再次将反应液置于-78℃以下，用注射器缓慢加入PCl3(1.5g,10.9mmol)，缓慢升至室温反应6h，过滤除去不溶物，旋干溶剂得红棕色油状物。0℃下，四氢呋喃溶解后滴加至LiAlH4(0.95g,25mmol)的甲基叔丁基醚溶液中，室温反应过夜，加入15％氢氧化钠溶液搅拌2h，分层后干燥蒸干溶剂得粗产物，减压蒸馏得伯膦中间体(S,Rp)-2，直接用于下步反应。
称取NaH(320mg,8mmol)加入Schlenk反应管中，抽真空/充Ar加入10mL四氢呋喃搅拌，用注射器加入溶于5mL四氢呋喃的螺环二苄(R)-3(632mg,2mmol)，将温度降至-78℃，缓慢加入溶于5mL四氢呋喃的伯膦中间体(S,Rp)-2(578mg,2mmol)，加毕后，自然升温反应20h，再回流反应10h，向反应液中加入饱和碳酸氢钠溶液淬灭反应，溶液分层后有机相依次用蒸馏水和饱和食盐水洗涤，然后用无水硫酸钠干燥，过滤，旋干，柱层析(乙酸乙酯:石油醚:三乙胺＝1:20:0.5)分离纯化得橘黄色泡状产物(S,Rp,Rspiro)-4810mg，产率76％。1HNMR(400Hz,CDCl3)δ7.24–7.18(m,1H),7.18–7.07(m,2H),6.97(d,J＝7.4Hz,1H),6.77(t,J＝7.5Hz,1H),5.87(d,J＝7.5Hz,1H),4.27(s,1H),4.11(dd,J＝6.8,3.0Hz,1H),4.04(s,5H),3.99(s,1H),3.13(s,1H),3.07–2.95(m,2H),2.92–2.78(m,4H),2.76–2.63(m,2H),2.32–2.19(m,2H),2.15(s,6H),2.04–1.92(m,1H),1.92–1.80(m,1H),1.24(d,J＝6.8Hz,3H)；13C NMR(101Hz,CDCl3)δ148.0(d,J＝4.4Hz),146.5,143.0,142.0,133.6(d,J＝6.5Hz),130.8(d,J＝6.0Hz),129.3,128.3(d,J＝5.4Hz),127.4,125.9,122.5(d,J＝3.0Hz),121.5,96.9(d,J＝22.0Hz),77.3,74.5(d,J＝18.3Hz),71.2(d,J＝5.1Hz),69.4,69.1(d,J＝3.2Hz),66.9,61.3,56.9(d,J＝8.4Hz),39.3,38.6,37.5,30.5(d,J＝17.7Hz),28.4(d,J＝24.4Hz),26.5(d,J＝14.0Hz),7.5；31P NMR(162Hz,CDCl3)δ-31.99；HRMS(ESI)calcd for C33H37FeNP[M+H]+:534.2013,Found:534.2103。
实施例2
以(R)-1为原料按实施实例1相同步骤得伯膦中间体(R,Sp)-2。以螺环二苄(R)-3为原料按实施实例1相同步骤得橘黄色泡状产物(R,Sp,Rspiro)-4，产率73％。(乙酸乙酯:石油醚:三乙胺＝1:20:0.5)。1H NMR(400Hz,CDCl3)δ7.25–7.09(m,4H),7.04(d,J＝7.5Hz,1H),6.98(d,J＝7.6Hz,1H),4.27–4.21(m,2H),4.19(s,5H),4.11(s,1H),4.01(s,1H),3.21–3.12(m,1H),3.12–2.92(m,4H),2.90–2.75(m,3H),2.19(s,6H),2.14–2.02(m,2H),2.02–1.92(m,1H),1.86–1.74(m,1H),1.26(d,J＝2.2Hz,3H)；13C NMR(101Hz,CDCl3)δ148.3,147.1(d,J＝4.5Hz),143.0,142.9(d,J＝2.7Hz),134.7(d,J＝6.8Hz),132.1(d,J＝5.1Hz),129.4,127.9(d,J＝6.0Hz),127.6(d,J＝3.0Hz),126.6,122.8,122.06(d,J＝3.6Hz),98.0(d,J＝25.0Hz),77.3,76.3(d,J＝27.8Hz),70.5(d,J＝5.9Hz),69.3,68.2,68.0(d,J＝4.2Hz),65.9,61.7,56.6(d,J＝11.0Hz),39.3,37.9,31.5(d,J＝14.3Hz),30.2(d,J＝13.9Hz),27.7(d,J＝25.7Hz),7.7；31P NMR(162Hz,CDCl3)δ-26.86；HRMS(ESI)calcdfor C33H37FeNP[M+H]+:534.2013,Found:534.2051。
实施实3
向单膦中间体(S,Rp,Rspiro)-4(533mg，1mmol)的冰醋酸(5mL)溶液加入二叔丁基膦(146mg，1mmol)，反应温度升至82～107℃，31PNMR监测至反应结束。降至室温后，二氯甲烷稀释反应液，依次用水、饱和NaHCO3溶液和饱和NaCl洗涤，干燥，旋干，柱层析(乙酸乙酯:石油醚＝1:30)得橘黄色双膦配体L1412 mg，产率65％。1H NMR(400Hz,CDCl3)δ7.23–7.06(m,3H),6.99(d,J＝7.4Hz,1H),6.79(t,J＝7.4Hz,1H),6.27(d,J＝7.5Hz,1H),4.24(s,1H),4.14(s,1H),4.19–4.09(m,1H),4.06(s,5H),3.95(s,1H),3.66–3.56(m,1H),,3.39(dd,J＝7.5,2.7Hz,1H),3.09–2.98(m,2H),2.93–2.75(m,3H),2.62(dd,J＝13.5,8.7Hz,1H),2.41–2.15(m,3H),2.05–1.93(m,1H),1.89–1.80(m,3H),1.28(d,J＝10.6Hz,9H),1.17(d,J＝10.7Hz,9H)；13C NMR(101Hz,CDCl3)δ148.1(d,J＝4.3Hz),146.8(d,J＝31.5Hz),144.0,142.9,141.9,133.9(d,J＝6.8Hz),133.6,131.5(d,J＝5.9Hz),129.7,129.5,128.5(d,J＝5.4Hz),128.2,127.2(d,J＝2.7Hz),125.5(d,J＝64.5Hz),122.4(d,J＝3.1Hz),121.4,102.2(t,J＝24.2Hz),77.3,72.5(dd,J＝21.2,4.3Hz),71.2(d,J＝4.4Hz),69.9(d,J＝3.4Hz),69.4,66.6,61.3,42.6,38.5,38.2(d,J＝126.8Hz),34.6–33.5(m),31.9(d,J＝13.9Hz),31.6(dd,J＝13.2,3.0Hz),30.9–30.3(m),30.1(d,J＝6.7Hz),28.2(dd,J＝24.7,15.0Hz),27.4(d,J＝15.0Hz),17.2(d,J＝2.7Hz)；31P NMR(162Hz,CDCl3)δ50.61(d,J＝18.5Hz),-35.84(d,J＝17.6Hz)；HRMS(ESI)calcd for C39H49FeP2[M+H]+:635.2659,Found:635.2724。
实施例4
向单膦中间体(S,Rp,Rspiro)-4(533mg，1mmol)的冰醋酸(5mL)溶液加入二环己基膦(198mg，1mmol)，反应温度升至82～107℃，31P NMR监测至反应结束。降至室温后，二氯甲烷稀释反应液，依次用水、饱和NaHCO3溶液和饱和NaCl洗涤，干燥，旋干，柱层析(乙酸乙酯:石油醚＝1:30)得橘黄色双膦配体L2466 mg，产率68％。1H NMR(400Hz,CDCl3)δ7.28–7.08(m,3H),6.99(d,J＝7.3Hz,3H),6.79(t,J＝7.3Hz,1H),6.16(d,J＝7.6Hz,1H),4.21(s,1H),4.15(s,1H),4.07(s,5H),4.00(s,1H),3.50–3.35(m,1H),3.31–3.26(m,1H),3.14–2.61(m,9H),2.40–2.10(m,3H),2.04–1.49(m,21H),1.18(d,J＝8.8Hz,3H)；13C NMR(101Hz,CDCl3)δ148.1(d,J＝4.1Hz),147.0,146.6,144.0,143.0,141.9,133.6(d,J＝7.2Hz),131.2(d,J＝5.9Hz),129.7,129.5,128.5(d,J＝5.4Hz),128.2,127.3(d,J＝2.7Hz),125.9,125.2,122.5(d,J＝3.0Hz),121.5,100.2(dd,J＝24.2,18.4Hz),77.3,72.3(dd,J＝19.7,3.1Hz),71.1(d,J＝4.7Hz),69.3,68.6(d,J＝3.5Hz),67.0,61.3,42.6,38.8,38.5,37.6,34.1(d,J＝24.1Hz),32.5(d,J＝19.9Hz),31.7(d,J＝18.6Hz),31.1,30.8(d,J＝13.1Hz),30.5(d,J＝15.8Hz),30.2(d,J＝3.0Hz),29.7(d,J＝9.4Hz),28.6(dd,J＝23.8,13.7Hz),28.0(d,J＝14.3Hz),27.8(d,J＝4.5Hz),27.6–26.8(m),26.5(d,J＝2.8Hz),15.3(d,J＝2.6Hz)；31PNMR(162Hz,CDCl3)δ14.77(d,J＝17.5Hz),-36.08(d,J＝17.5Hz)；HRMS(ESI)calcd forC43H53FeP2[M+H]+:687.2972,Found:687.3026。
实施例5
向单膦中间体(S,Rp,Rspiro)-4(533mg，1mmol)的冰醋酸(5mL)溶液加入二苯基膦(186mg，1mmol)，反应温度升至82～107℃，31P NMR监测至反应结束。降至室温后，二氯甲烷稀释反应液，依次用水、饱和NaHCO3溶液和饱和NaCl洗涤，干燥，旋干，柱层析(乙酸乙酯:石油醚＝1:30)得橘黄色双膦配体L3505 mg，产率75％。1H NMR(400Hz,CDCl3)δ7.45–7.29(m,10H),7.21(d,J＝7.3Hz,1H),7.18–7.14(m,1H),7.13–7.07(m,1H),7.06–7.02(m,1H),6.91(t,J＝7.4Hz,1H),6.35(d,J＝7.5Hz,1H),4.08(s,5H),3.99(s,1H),3.91–3.83(m,1H),3.69(s,1H),3.17–3.12(m,1H),3.10(s,1H),3.06–2.87(m,4H),2.86–2.78(m,2H),2.72(dd,J＝13.8,7.9Hz,1H),2.28(dd,J＝12.1,6.5Hz,1H),2.19(dd,J＝12.3,6.6Hz,1H),2.06–1.95(m,1H),1.91–1.79(m,1H),1.39–1.32(m,3H)；13C NMR(101Hz,CDCl3)δ148.1(d,J＝4.1Hz),146.8,143.1(d,J＝2.4Hz),142.1,137.7,135.6(d,J＝20.0Hz),134.6(d,J＝21.6Hz),133.8(d,J＝19.3Hz),133.3(d,J＝6.5Hz),131.8,131.7,130.8(d,J＝5.8Hz),129.6(d,J＝2.9Hz),129.1,128.6–30.0(m),127.7(d,J＝6.9Hz),127.6,126.0,122.7(d,J＝3.2Hz),121.7,98.3(dd,J＝24.8,21.6Hz),77.3,72.3(dd,J＝18.4,3.4Hz),71.0(d,J＝4.6Hz),69.3,69.0,67.4,61.3,38.6,37.6,30.6(d,J＝11.8Hz),29.6(dd,J＝18.7,11.9Hz),28.5(dd,J＝23.2,9.8Hz),27.0(d,J＝13.7Hz),16.0；31P NMR(162Hz,CDCl3)δ9.12(d,J＝11.0Hz),-36.00(d,J＝10.2Hz)；HRMS(ESI)calcd for C43H41FeP2[M+H]+:675.2033,Found:675.2094。
实施例6
向单膦中间体(S,Rp,Rspiro)-4(533mg，1mmol)的冰醋酸(5mL)溶液加入双(3,5-二甲基苯基膦(242mg，1mmol)，反应温度升至82～107℃，31P NMR监测至反应结束。降至室温后，二氯甲烷稀释反应液，依次用水、饱和NaHCO3溶液和饱和NaCl洗涤，干燥，旋干，柱层析(乙酸乙酯:石油醚＝1:30)得橘黄色双膦配体L4438 mg，产率60％。1H NMR(400Hz,CDCl3)δ7.25–7.14(m,2H),7.10(d,J＝7.3Hz,1H),7.06–6.98(m,4H),6.95–6.84(m,4H),6.36(d,J＝7.5Hz,1H),4.09(s,5H),3.95(s,1H),3.85–3.76(m,1H),3.63(s,1H),3.17–2.97(m,5H),2.96–2.77(m,3H),2.70(dd,J＝13.8,7.9Hz,1H),2.28(d,J＝2.5Hz,13H),2.19(dd,J＝12.4,6.6Hz,1H),2.06–1.95(m,1H),1.91–1.76(m,1H),1.36(t,J＝6.4Hz,3H)；13C NMR(101Hz,CDCl3)δ148.0(d,J＝4.3Hz),146.7,143.1,142.0,137.7(d,J＝4.7Hz),137.1(d,J＝16.8Hz),136.8(d,J＝7.8Hz),133.9(d,J＝19.8Hz),133.3(d,J＝19.8Hz),130.7,129.8,129.6–129.0(m),128.3(d,J＝5.6Hz),127.5,125.8,122.7(d,J＝3.0Hz),121.7,98.9–97.3(m),77.2,71.9(d,J＝20.5Hz),70.8(d,J＝4.3Hz),69.4,69.2,67.1,61.2,38.5,37.6,30.5(d,J＝11.7Hz),29.3(dd,J＝18.5,11.2Hz),28.4(dd,J＝22.4,9.4Hz),27.0(d,J＝12.4Hz),21.4(d,J＝11.9Hz),16.2；31P NMR(162Hz,CDCl3)δ9.17(d,J＝7.9Hz),-35.86(d,J＝9.6Hz)；HRMS(ESI)calcd for C47H49FeP2[M+H]+:731.2659,Found:731.2703。
实施例7
向单膦中间体(S,Rp,Rspiro)-4(533mg，1mmol)的冰醋酸(5mL)溶液加入二苯基膦(186mg，1mmol)，反应温度升至82～107℃，31P NMR监测至反应结束。降至室温后，二氯甲烷稀释反应液，依次用水、饱和NaHCO3溶液和饱和NaCl洗涤，干燥，旋干，柱层析(乙酸乙酯:石油醚＝1:30)得橘黄色双膦配体L5492 mg，产率73％。1H NMR(400Hz,CDCl3)δ7.46–7.26(m,12H),7.16(d,J＝7.3Hz,1H),7.08–6.97(m,2H),6.88(d,J＝7.1Hz,1H),4.24(s,5H),4.09(s,1H),4.01(t,J＝6.4Hz,1H),3.76(s,1H),3.74(s,1H),3.28–3.11(m,2H),3.06–2.74(m,6H),2.25–2.05(m,2H),2.00–1.85(m,1H),1.85–1.75(m,1H),1.34(t,J＝6.9Hz,3H)；13CNMR(101Hz,CDCl3)δ148.4,147.0(d,J＝4.7Hz),143.1,142.7(d,J＝2.7Hz),137.9(d,J＝20.1Hz),135.4(d,J＝20.4Hz),134.9–134.4(m),133.8(d,J＝19.6Hz),131.8(d,J＝14.8Hz),129.2(d,J＝29.7Hz),128.4(d,J＝4.4Hz),128.0(d,J＝6.0Hz),127.8(d,J＝7.3Hz),127.6,127.5,126.6,123.0,122.1(d,J＝3.4Hz),98.9(dd,J＝27.9,20.5Hz),77.3,74.7(d,J＝27.1Hz),70.6(d,J＝5.5Hz),69.3,68.9,67.9,38.1,37.8,31.7(t,J＝10.6Hz),30.3(d,J＝9.8Hz),30.6–30.0(m),27.7(d,J＝25.5Hz),16.3；31P NMR(162Hz,CDCl3)δ9.14(d,J＝24.2Hz),-32.15；HRMS(ESI)calcd for C43H41FeP2[M+H]+:675.2033,Found:675.2090。
B、催化不对称氢化反应
实施例8
在氮气保护下，[Ir(COD)Cl]2(1.68mg,0.0025mmol)和二茂铁配体L3(3.7mg，0.0055mmol)和1mL四氢呋喃置于安瓿瓶中，搅拌反应30min，依次加入124mg亚胺底物7、40％HBr(0.1eqiv.)，氮气置换三次后再用氢气置换三次，在50℃和50atm H2下反应20h，用短硅胶柱过滤，将过滤所得滤液浓缩后得产物8，GC测反应转化率97％，对映体过量90％ee。

Claims (3)

1.一类手性二茂铁-螺环骨架双膦配体，其特征在于，其分子结构式如式L1-L5所示：
2.根据权利要求1所述的手性二茂铁-螺环骨架双膦配体过渡金属络合物催化剂，其特征在于，过渡金属是铱(Ir)。
3.根据权利要求2所述的手性二茂铁-螺环骨架双膦配体过渡金属络合物催化剂用于催化前手性亚胺的不对称还原反应。
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