CN105665011B - 手性有机硒硫催化剂及其制备方法与在不对称反应中的应用 - Google Patents
手性有机硒硫催化剂及其制备方法与在不对称反应中的应用 Download PDFInfo
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- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
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Abstract
本发明公开了手性有机硒硫催化剂及其制备方法与在不对称反应中的应用。本发明的手性有机硒硫催化剂从商业可得、价格低廉的手性茚胺醇出发，经过多步合成，能够高效的制得，步骤简短，操作方便。通过本发明技术方案制备获得的基于有机茚骨架的手性硒硫催化剂，用途广泛，在许多有机反应中获得良好的催化效果，并且具备优良的对应异构体选择性。特别是在烯烃的不对称三氟甲基硫酯化反应中展现了优良的光学选择性，而这也成功的开启了烯烃的不对称三氟甲硫基酯化反应的先河，并且催化效率高，对映选择性好。
Description
技术领域：
本发明涉及手性有机硒硫催化领域，具体地说，涉及一种手性有机硒硫催化剂及其制备方法与在不对称三氟甲硫基酯化反应中的应用。
背景技术：
有机硒硫是化学家族中的重要元素，近20年来有机硒硫化学发展较为迅速，新的有机硒硫试剂在有机合成化学中起着重要作用，并广泛用于天然产物及医学药物的合成中。有机硒硫试剂具有多种化学性能，可作为氧化剂、还原剂、亲核试剂和亲电试剂等。值得注意的是，有机硒硫化合物中的硒硫原子具有孤对电子，可以充当Lewis碱催化某些反应。与传统的有机金属配合物催化剂相比，有机硒硫催化剂具有环境友好、价格低廉、在空气中稳定、操作条件简便等优点。所以，近年来，有机硒硫催化剂在反应中的应用受到越来越多的关注。然而，因缺乏高效的手性催化剂，手性有机硒硫分子催化的反应却鲜有报道。从而，寻找合适的有机骨架，发展新型手性有机硒硫催化剂成为硒硫手性催化的关键问题。
有机氟化学是化学领域最为活跃的领域之一。含氟基团能够大大改善母体化合物的物理、化学、、生物特性，受到有机化学家和药学家广泛地关注。而三氟甲硫基基团则是众多含氟基团中性质最特殊的一个，因为它具有高的稳定性、强的吸电子能力以及良好的膜渗透性，使得含三氟甲硫基基团的分子成为好的药物候选。为此，众多三氟甲硫基试剂被相继开发出来并成功向有机小分子中高效引入三氟甲硫基基团。相比之下，不对称三氟甲硫基化反应的成功范例十分稀少，特别是烯烃的不对称三氟甲硫基化反应因为缺乏合适的催化体系高效产生手性曾未获得成功。
发明内容：
本发明的目的是为了提供一种新型手性有机硒硫催化剂及其制备方法，以解决现有技术无法完成的烯烃的不对称三氟甲硫基酯化反应的问题。
一种手性有机硒硫催化剂，其结构式为
上述手性有机硒硫催化剂的制备方法，包括以下步骤：
(1)将(1S,2R)-(+)-1-氨基-2-茚醇、(1R,2S)-(+)-1-氨基-2-茚醇、(1S,2S)-(+)-1-氨基-2-茚醇或(1R,2R)-(-)-1-氨基-2-茚醇置于反应瓶中，先抽真空充氮气，如此反复三次；再把反应瓶置于冰浴中冷却至0℃后将Boc2O和重蒸的乙腈加入反应器中，撤去冰浴搅拌，待溶液澄清透明表明反应已进行完全；直接旋干得到粘稠状液体，直接进行下一步；该步骤合成式为：
(2)将上述中制得的Boc保护的茚胺醇置于反应瓶中，先抽真空充氮气，如此反复三次；加入重蒸的二氯甲烷后再把反应瓶置于冰浴中冷却至0℃后将三乙胺和乙基磺酰氯分别加入其中，让冰浴慢慢回到室温；反应搅拌过夜后，用饱和氯化铵淬灭反应，用二氯甲烷萃取溶液三次，接着用饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤后旋干；用乙酸乙酯溶解有机物，然后加入石油醚置于冰箱中，待大量固体析出后抽滤得到白色固体产物；该步骤合成式为：
(3)将上述(2)中所得的产物和碳酸钾置于反应瓶中，先抽真空充氮气，如此反复三次；加入无水乙醇后于室温下搅拌，接着把芳基硫酚或芳基硒醇溶于四氢呋喃溶液并一起注入反应容器中；油浴加热至80℃回流12小时后，将反应容器冷却至室温；加入水淬灭反应，用二氯甲烷萃取三次并用水洗涤，最后用饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋干；快速柱层析得到白色固体，即为手性催化剂，该步骤合成式为：
在上述制备方法中，步骤(3)中的芳香基团选自苯基、2,6-二甲苯基、2,6-二乙苯基、2,6-二丙苯基、2,6-二甲氧苯基、2,6-二乙氧苯基和2,6-二丙氧苯基。
在上述制备方法中，步骤(3)中的无机碱为碳酸钾、碳酸钠或氢化钠。
与现有技术相比，本发明具有如下有益效果：本发明的手性有机硒硫催化剂从商业可得、价格低廉的手性茚胺醇出发，经过多步合成，能够高效的制得，步骤简短，操作方便。通过本发明技术方案制备获得的基于有机茚骨架的手性硒硫催化剂，用途广泛，在许多有机反应中获得良好的催化效果，并且具备优良的对应异构体选择性。特别是在烯烃的不对称三氟甲硫基酯化反应中展现了优良的光学选择性，而这也成功的开启了烯烃的不对称三氟甲硫基酯化反应的先河，并且催化效率高，对映选择性好。
具体实施方式
以下结合实施例对本发明作进一步说明。
实施例1：
(1)将1.34g(1S,2R)-(+)-1-氨基-2-茚醇置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。再把反应瓶置于冰浴中冷却至0℃后将2.55g Boc2O和36mL重蒸的乙腈加入反应器中，撤去冰浴搅拌5小时，待溶液澄清透明表明反应已进行完全。直接旋干得到粘稠状液体，直接进行下一步。该步骤合成式为：
(2)将上述中制得的Boc保护的茚胺醇置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。加入30mL重蒸的二氯甲烷后再把反应瓶置于冰浴中冷却至0℃后将2mL三乙胺和1mL乙基磺酰氯分别加入其中。让冰浴慢慢回到室温。反应搅拌过夜后，用饱和氯化铵淬灭反应，用二氯甲烷萃取溶液三次，接着用饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤后旋干。用10mL乙酸乙酯溶解有机物，然后加入150mL石油醚置于冰箱中，待大量固体析出后抽滤得到白色固体产物。该步骤合成式为：
(3)将上述(2)中所得的产物1.5g和1.82g碳酸钾置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。加入30mL的无水乙醇后于室温下搅拌20分钟，接着把0.80g 2,6-二乙基苯硫酚溶于5mL的四氢呋喃溶液并一起注入反应容器中。油浴加热至80℃回流12小时后，将反应容器冷却至室温。加入水淬灭反应，用二氯甲烷萃取三次并用水洗涤，最后用饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋干。快速柱层析得到白色固体，即为手性催化剂，该步骤合成式为：
1H NMR(400MHz,CDCl3)δ7.39–7.08(m,7H),5.12(s,1H),4.69(d,J＝7.0Hz,1H),3.55–3.34(m,1H),3.15(dt,J＝16.1,8.1Hz,1H),3.04(d,J＝7.1Hz,4H),2.97–2.80(m,1H),1.51(s,9H),1.26(t,J＝7.5Hz,6H).
13C NMR(101MHz,CDCl3)δ155.53,149.44,142.60,140.65,129.08,128.15,127.20,126.60,124.52,124.06,79.67,61.85,55.78,38.03,28.50,28.29,16.01.
HR-ESI-MS m/z calcd.for C24H32NO2S[M+H]+:398.2148,found:398.2148.
实施例2：
(1)将1.34g(1S,2R)-(+)-1-氨基-2-茚醇置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。再把反应瓶置于冰浴中冷却至0℃后将2.55g Boc2O和36mL重蒸的乙腈加入反应器中，撤去冰浴搅拌5小时，待溶液澄清透明表明反应已进行完全。直接旋干得到粘稠状液体，直接进行下一步。该步骤合成式为：
(2)将上述中制得的Boc保护的茚胺醇置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。加入30mL重蒸的二氯甲烷后再把反应瓶置于冰浴中冷却至0℃后将2mL三乙胺和1mL乙基磺酰氯分别加入其中。让冰浴慢慢回到室温。反应搅拌过夜后，用饱和氯化铵淬灭反应，用二氯甲烷萃取溶液三次，接着用饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤后旋干。用10mL乙酸乙酯溶解有机物，然后加入150mL石油醚置于冰箱中，待大量固体析出后抽滤得到白色固体产物。该步骤合成式为：
(3)将上述(2)中所得的产物1.5g和1.82g碳酸钾置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。加入30mL的无水乙醇后于室温下搅拌20分钟，接着把0.82g 2，6-二甲氧苯硫酚溶于5mL的四氢呋喃溶液并一起注入反应容器中。油浴加热至80℃回流12小时后，将反应容器冷却至室温。加入水淬灭反应，用二氯甲烷萃取三次并用水洗涤，最后用饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋干。快速柱层析得到白色固体，即为手性催化剂，该步骤合成式为：
1H NMR(400MHz,CDCl3)δ7.34–7.10(m,5H),6.61(d,J＝8.4Hz,2H),5.03(s,1H),4.80(s,1H),3.91(s,6H),3.79(d,J＝6.8Hz,1H),3.21(dd,J＝16.0,7.9Hz,1H),2.98–2.71(m,1H),1.46(s,2H).
13C NMR(101MHz,CDCl3)δ161.51,155.47,143.24,140.60,130.33,127.88,127.03,124.38,124.12,104.27,79.34,62.11,56.34,52.07,37.82,28.49.HR-ESI-MS m/zcalcd.for C22H28NO4S[M+H]+:402.1734,found:402.1730.
实施例3：
(1)将1.34g(1R,2S)-(+)-1-氨基-2-茚醇置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。再把反应瓶置于冰浴中冷却至0℃后将2.55g Boc2O和36mL重蒸的乙腈加入反应器中，撤去冰浴搅拌5小时，待溶液澄清透明表明反应已进行完全。直接旋干得到粘稠状液体，直接进行下一步。该步骤合成式为：
(2)将上述中制得的Boc保护的茚胺醇置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。加入30mL重蒸的二氯甲烷后再把反应瓶置于冰浴中冷却至0℃后将2mL三乙胺和1mL乙基磺酰氯分别加入其中。让冰浴慢慢回到室温。反应搅拌过夜后，用饱和氯化铵淬灭反应，用二氯甲烷萃取溶液三次，接着用饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤后旋干。用10mL乙酸乙酯溶解有机物，然后加入150mL石油醚置于冰箱中，待大量固体析出后抽滤得到白色固体产物。该步骤合成式为：
(3)将上述(2)中所得的产物1.5g和1.82g碳酸钾置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。加入30mL的无水乙醇后于室温下搅拌20分钟，接着把0.99g 2,6-二乙氧苯硫酚溶于5mL的四氢呋喃溶液并一起注入反应容器中。油浴加热至80℃回流12小时后，将反应容器冷却至室温。加入水淬灭反应，用二氯甲烷萃取三次并用水洗涤，最后用饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋干。快速柱层析得到白色固体，即为手性催化剂，该步骤合成式为：
1H NMR(400MHz,CDCl3)δ7.38–6.93(m,5H),6.55(d,J＝8.3Hz,2H),4.96(s,1H),4.79(s,1H),4.10(q,J＝6.9Hz,4H),3.91–3.77(m,1H),3.18(dd,J＝16.0,7.8Hz,1H),2.90(dd,J＝15.9,8.5Hz,1H),1.50–1.36(m,15H).
13C NMR(101MHz,CDCl3)δ160.88,155.48,143.48,140.84,129.96,127.87,126.99,124.43,124.21,110.20,105.43,79.35,64.78,62.29,52.03,38.09,28.47,15.04.
HR-ESI-MS m/z calcd.for C24H32NO4S[M+H]+:430.2047,found:430.2046
实施例4：
(1)将1.34g(1S,2R)-(+)-1-氨基-2-茚醇置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。再把反应瓶置于冰浴中冷却至0℃后将2.55g Boc2O和36mL重蒸的乙腈加入反应器中，撤去冰浴搅拌5小时，待溶液澄清透明表明反应已进行完全。直接旋干得到粘稠状液体，直接进行下一步。该步骤合成式为：
(2)将上述中制得的Boc保护的茚胺醇置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。加入30mL重蒸的二氯甲烷后再把反应瓶置于冰浴中冷却至0℃后将2mL三乙胺和1mL乙基磺酰氯分别加入其中。让冰浴慢慢回到室温。反应搅拌过夜后，用饱和氯化铵淬灭反应，用二氯甲烷萃取溶液三次，接着用饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤后旋干。用10mL乙酸乙酯溶解有机物，然后加入150mL石油醚置于冰箱中，待大量固体析出后抽滤得到白色固体产物。该步骤合成式为：
(3)将0.5g二苯基联二硒与80mg硼氢化钠置于100mL的反应瓶中，先抽真空充氮气，如此反复三次。加入30mL的无水乙醇后于室温下搅拌20分钟。将上述(2)中所得的产物1.5g溶于5mL的四氢呋喃溶液并一起注入反应容器中。油浴加热至80℃回流12小时后，将反应容器冷却至室温。加入水淬灭反应，用二氯甲烷萃取三次并用水洗涤，最后用饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋干。快速柱层析得到白色固体，即为手性催化剂，该步骤合成式为：
1H NMR(400MHz,CDCl3)δ7.65(s,2H),7.33–7.08(m,7H),5.18(s,1H),4.75(d,J＝7.4Hz,1H),3.62(q,J＝8.1Hz,1H),3.30(dd,J＝16.0,7.7Hz,1H),2.97(dd,J＝16.0,8.8Hz,1H),1.49(s,9H).
13C NMR(101MHz,CDCl3)13C NMR(101MHz,CDCl3)δ155.66,142.52,141.25,135.47,129.18,128.21,127.92,127.24,124.49,123.98,79.80,61.49,48.15,38.47,28.54.
HR-ESI-MS m/z calcd.for C20H24NO2Se[M+H]+:390.0967,found:390.0967.
实施例5：催化反应
将16.22mg(0.1mmol)4-苯基-3-丁烯酸、34mg N-trifluoromethylthiosaccharin和8mg实施例3中所得的催化剂置于反应瓶中，于室温加入4mL二氯甲烷和4.4mL TfOH后搅拌12小时，旋干后快速柱层析得到目标产物，92％产率，84％ee值。
1H NMR(400MHz,CDCl3)δ7.51–7.31(m,5H),5.39(d,J＝6.4Hz,1H),3.93(q,J＝7.4Hz,1H),3.21(dd,J＝18.2,8.4Hz,1H),2.81(dd,J＝18.2,7.4Hz,1H).
13C NMR(101MHz,CDCl3)δ172.89,136.14,134.45(q,J＝307.5Hz),131.39,129.67,129.24,128.34,125.66,125.62,84.61,45.83,36.46.
19F NMR(377MHz,CDCl3)δ-39.63.
HR-ESI-MS m/z calcd.for C11H9F3NaO2S[M+Na]+:285.0168,found:285.0173.
Claims (3)
1.一种手性有机硒硫催化剂，其特征在于：其结构式为
2.权利要求1所述手性有机硒硫催化剂的制备方法，其特征在于：包括以下步骤：
(1)将(1S,2R)-(+)-1-氨基-2-茚醇、(1R,2S)-(+)-1-氨基-2-茚醇、(1S,2S)-(+)-1-氨基-2-茚醇或(1R,2R)-(-)-1-氨基-2-茚醇置于反应瓶中，先抽真空充氮气，如此反复三次；再把反应瓶置于冰浴中冷却至0℃后将Boc2O和重蒸的乙腈加入反应器中，撤去冰浴搅拌，待溶液澄清透明表明反应已进行完全；直接旋干得到粘稠状液体，直接进行下一步；该步骤合成式为：
(2)将上述制得的Boc保护的茚胺醇置于反应瓶中，先抽真空充氮气，如此反复三次；加入重蒸的二氯甲烷后再把反应瓶置于冰浴中冷却至0℃后将三乙胺和乙基磺酰氯分别加入其中，让冰浴慢慢回到室温；反应搅拌过夜后，用饱和氯化铵淬灭反应，用二氯甲烷萃取溶液三次，接着用饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤后旋干；用乙酸乙酯溶解有机物，然后加入石油醚置于冰箱中，待大量固体析出后抽滤得到白色固体产物；该步骤合成式为：
(3)将上述(2)中所得的产物和碳酸钾置于反应瓶中，先抽真空充氮气，如此反复三次；加入无水乙醇后于室温下搅拌，接着把芳基硫酚溶于四氢呋喃溶液并一起注入反应容器中；油浴加热至80℃回流12小时后，将反应容器冷却至室温；加入水淬灭反应，用二氯甲烷萃取三次并用水洗涤，最后用饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋干；快速柱层析得到白色固体，即为手性催化剂，该步骤合成式为：
3.权利要求1所述手性有机硒硫催化剂在不对称三氟甲硫基酯化反应中的应用。
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| CN103804348A (zh) * | 2012-11-15 | 2014-05-21 | 中国科学院上海有机化学研究所 | 一种亲电三氟甲硫基试剂、合成方法及其应用 |
| CN104557358A (zh) * | 2015-02-02 | 2015-04-29 | 中国科学院上海有机化学研究所 | 一种烷基三氟甲基硫醚化合物及其制备方法 |
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| CN103804348A (zh) * | 2012-11-15 | 2014-05-21 | 中国科学院上海有机化学研究所 | 一种亲电三氟甲硫基试剂、合成方法及其应用 |
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