CN105669503B - 三氟甲硫基试剂及其制备方法与在不对称三氟甲硫基化反应中的应用 - Google Patents
三氟甲硫基试剂及其制备方法与在不对称三氟甲硫基化反应中的应用 Download PDFInfo
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Abstract
本发明公开了三氟甲硫基试剂及其制备方法与在不对称三氟甲硫基化反应中的应用。本发明制备的三氟甲硫基试剂由商业可得的氟化银、二苯磺酰亚胺、次氯酸叔丁酯等基础原料合成得到。反应步骤简短、操作简单,产率高。通过该方法合成的新型三氟甲硫基试剂化学性质稳定,对环境友好,便于储存。并且该试剂在烯烃的不对称三氟甲硫基酯化反应中展现了很高的活性,并在许多有机反应中具有广阔的应用前景。
Description
技术领域:
本发明涉及有机氟化学领域,具体地说,涉及一种三氟甲硫基试剂及其制备方法及其在不对称三氟甲硫基酯化反应中的应用。
背景技术:
氟是卤族中的第一个元素,由于氟原子和氢原子的原子半径相近,大小相似,当分子中的氢原子被氟原子取代后,并不会引起该分子立体构型的显著变化。但是,由于氟原子具有很大的电负性,当氟原子取代氢原子后,往往会使原来分子的电子性质发生很大的改变。从分子学的水平来看,这样的改变通常会引起分子亲脂性的变化,和目标结构静电作用的变化及对一些代谢途径的抑制作用。从生理学的水平来看,含氟药物和一般的药物相比,具有更好的生物穿透性,有更好的与目标器官作用的选择性,通常会使使用的剂量大大降低。因此,含氟药物的应用研究越来越深入。近年来,含氟药物不断问世,如氧氟沙星、诺氟沙星、氟哌酸等。在医药化学领域,向有机分子中引入氟原子是开发新的抗癌药物、抗肿瘤药物、抗病毒药物、消炎药物等的重要方向((a)Jeschke,P.ChemBioChem2004, 5,570.(b)Hagmann,W.K.J.Med.Chem.2008,51,4359.(c)Purser,S.; Moore,P.R.;Swallow,S.;Gouverneur,V.Chem.Soc.Rev.2008,37,320. (d)Manteau,B.;Pazenok,S.;Vors,J.-P.;Leroux,F.R.J.Fluorine Chem. 2010,131,140.(e)Isanbor,C.;D.J.FluorineChem.2006,127, 303.)。在现代农作物保护方面,含氟农用化学品已广泛用作除草剂、杀虫剂以及杀菌剂等。
在有机氟化学的大家族中,三氟甲硫基基团则是众多含氟基团中性质最特殊的一个,因为它的好的稳定性、强的吸电性以及良好的膜渗透性,使得含三氟甲硫基基团的化合物成为好的药物候选。因此,如何快速向有机小分子中引入三氟甲硫基基团成为人们研究的焦点。据目前的文献报道,向有机小分子中引入三氟甲硫基基团有两种方法。其一为直接形成碳-三氟甲硫基键,其二为通过卤素交换等方式的间接法。当然由于直接法反应效率更高、底物适应范围更广而更受到人们的青睐。为了避免使用高毒性的三氟甲硫基试剂,一些低毒、稳定、不同活性的亲电三氟甲硫基试剂被相继开发出来,并成功应用于各类反应中((a) Ferry,A.;Billard,T.;Langlois,B.R.;Bacque,E.J.Org.Chem.2008, 73,9362–9365.(b)Ferry,A.;Billard,T.;Langlois,B.R.;Bac-que,E. Angew.Chem.,Int.Ed.2009,48,8551.(c)Shao,X.;Wang,X.;Yang,T.; Lu,L.;Shen,Q.Angew.Chem.,Int.Ed.2013,52,3457(d)Xu,C.;Ma, B.;Shen,Q.Angew.Chem.,Int.Ed.2014,53,9316.(e)Kang,K.;Xu,C.;Shen,Q.Org.Chem.Front.2014,1,294.(f)Yang,Y.-D.;Azuma,A.; Tokunaga,E.;Yamasaki,M.;Shiro,M.;Shibata,N.J.Am.Chem.Soc.2013, 135,8782.(g)Tran,L.D.;Popov,I.;Daugulis,O.J.Am.Chem.Soc.2012, 134,18237.)。为了满足不同底物以及不同反应条件的需求,开发出新的、稳定的、更高活性的三氟甲硫基试剂成为研究的重点问题。
发明内容:
本发明的目的是提供一种新型三氟甲硫基试剂。
本发明的另一目的是提供一种三氟甲硫基试剂的制备方法。
本发明的进一步目的是提供三氟甲硫基试剂在不对称三氟甲硫基酯化反应中的应用。
本发明的三氟甲硫基试剂,其表达式为:
三氟甲硫基试剂的制备方法,包括以下步骤:
(1)在手套箱中将氟化银装入烘干的反应瓶中,盖好瓶塞拿出手套箱;在氮气气氛中加入重蒸的乙腈和二硫化碳,快速装好回流冷凝管于80℃回流过夜;然后将二硫化碳蒸出,再把剩下的乙腈用旋转蒸发仪旋干得到黑色固体;接着用乙酸乙酯溶解洗涤黑色固体并用硅藻土过滤,并多次洗涤;在避光条件下将滤液旋干得到粘稠固体,用乙腈溶解粘稠固体后,把乙醚沿着瓶壁缓慢加入瓶中;将此混合液于室温下静止12小时后,置于-20℃静置24小时;倒去乙醚并继续旋干得到有金属光泽的灰白色固体氟化银,该步骤合成式为:
(2)将二苯磺酰亚胺置于反应瓶中,抽真空充氮气,如此反复三次;然后加入 1,2-二氯乙烷于反应瓶中,再将次氯酸叔丁酯快速加入溶剂中并室温下搅拌30 分钟,将此混合液旋干得到白色固体产物,该步骤合成式为:
(3)将(1)中合成的三氟甲硫基化银和(2)中合成的2置于反应瓶中,抽真空充氮气,如此反复三次;然后在避光条件下将溶剂加于反应瓶中并反应,将此浑浊液用硅藻土抽滤并用溶剂多次洗涤;将滤液避光条件下旋干并置于冰箱中得到白色固体产物,即为三氟甲硫基试剂1,该步骤合成式为:
作为优选,在上述三氟甲硫基试剂的制备方法中,步骤(2)或(3)中的溶剂选自于1,2-二氯乙烷、二氯甲烷。
与现有技术相比,本发明具有如下有益效果:本发明制备的三氟甲硫基试剂由商业可得的氟化银、二苯磺酰亚胺、次氯酸叔丁酯等基础原料合成得到。反应步骤简短、操作简单,产率高。通过该方法合成的新型三氟甲硫基试剂化学性质稳定,对环境友好,便于储存。并且该试剂在烯烃的不对称三氟甲硫基酯化反应中展现了很高的活性,并在许多有机反应中具有广阔的应用前景。
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)在手套箱中将7.5g氟化银装入烘干的反应瓶中,盖好瓶塞拿出手套箱。在氮气气氛中加入40mL重蒸的乙腈和12mL的二硫化碳,快速装好回流冷凝管于 80℃回流过夜。然后将二硫化碳蒸出,再把剩下的乙腈用旋转蒸发仪旋干得到黑色固体。接着用乙酸乙酯溶解洗涤黑色固体并用硅藻土过滤,并多次洗涤。在避光条件下将滤液旋干得到粘稠固体,用30滴乙腈溶解粘稠固体后,把90mL 乙醚沿着瓶壁缓慢加入瓶中。将此混合液于室温下静止12小时后,置于-20℃静置24小时。倒去乙醚并继续旋干得到有金属光泽的灰白色固体氟化银4g。该步骤合成式为:
(2)将4.8g二苯磺酰亚胺置于反应瓶中,抽真空充氮气,如此反复三次。然后加入45mL 1,2-二氯乙烷于反应瓶中,再将2.5mL次氯酸叔丁酯快速加入溶剂中并室温下搅拌30分钟。将此混合液旋干得到白色固体产物。该步骤合成式为:
(3)将(1)中合成的三氟甲硫基化银4g和(2)中合成的25.29g置于反应瓶中,抽真空充氮气,如此反复三次。然后在避光条件下将60mL 1,2-二氯乙烷加于反应瓶中并反应1小时,将此浑浊液用硅藻土抽滤并用1,2-二氯乙烷多次洗涤。将滤液避光条件下旋干并置于冰箱中一段时间得到白色固体产物。即为三氟甲硫基试剂1,该步骤合成式为:
1H NMR(400MHz,CDCl3)δ8.04(d,J=8.0Hz,4H),7.70(t,J=7.3Hz, 2H),7.56(t,J=7.7Hz,4H).
13C NMR(101MHz,CDCl3)δ137.94,135.07,132.30(q,J=317.8Hz),129.31,129.20,129.11,125.99,122.83.
19F NMR(377MHz,CDCl3)δ-48.17.
HR-EI-MS m/z calcd.for C13H10F3NO4S3[M]+:396.9724,found:396.9715.
实施例2:
(1)在手套箱中将15g氟化银装入烘干的反应瓶中,盖好瓶塞拿出手套箱。在氮气气氛中加入80mL重蒸的乙腈和25mL的二硫化碳,快速装好回流冷凝管于 80℃回流过夜。然后将二硫化碳蒸出,再把剩下的乙腈用旋转蒸发仪旋干得到黑色固体。接着用乙酸乙酯溶解洗涤黑色固体并用硅藻土过滤,并多次洗涤。在避光条件下将滤液旋干得到粘稠固体,用60滴乙腈溶解粘稠固体后,把180mL 乙醚沿着瓶壁缓慢加入瓶中。将此混合液于室温下静止12小时后,置于-20℃静置24小时。倒去乙醚并继续旋干得到有金属光泽的灰白色固体氟化银8g。该步骤合成式为:
(2)将9.6g二苯磺酰亚胺置于反应瓶中,抽真空充氮气,如此反复三次。然后加入100mL 1,2-二氯乙烷于反应瓶中,再将5mL次氯酸叔丁酯快速加入溶剂中并室温下搅拌30分钟。将此混合液旋干得到白色固体产物。该步骤合成式为:
(3)将(1)中合成的三氟甲硫基化银8g和(2)中合成的210.5g置于反应瓶中,抽真空充氮气,如此反复三次。然后在避光条件下将100mL 1,2-二氯乙烷加于反应瓶中并反应1小时,将此浑浊液用硅藻土抽滤并用1,2-二氯乙烷多次洗涤。将滤液避光条件下旋干并置于冰箱中一段时间得到白色固体产物。即为三氟甲硫基试剂1,该步骤合成式为:
1H NMR(400MHz,CDCl3)δ8.04(d,J=8.0Hz,4H),7.70(t,J=7.3Hz, 2H),7.56(t,J=7.7Hz,4H).
13C NMR(101MHz,CDCl3)δ137.94,135.07,132.30(q,J=317.8Hz),129.31,129.20,129.11,125.99,122.83.
19F NMR(377MHz,CDCl3)δ-48.17.
HR-EI-MS m/z calcd.for C13H10F3NO4S3[M]+:396.9724,found:396.9715.
实施例3:催化反应实例1
将16.22mg(0.1mmol)4-苯基-3-丁烯酸、60mg三氟甲硫基试剂1和8 mg催化剂置于反应瓶中,于0℃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,84%产率,90%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.
实施例4:催化反应实例2
将17.6mg(0.1mmol)丁烯酸、60mg三氟甲硫基试剂1和8mg催化剂置于反应瓶中,于0℃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,90%产率,90%ee值。
1H NMR(400MHz,CDCl3)δ7.25(m,J=8.7Hz,4H),5.34(d,J=6.5Hz, 1H),3.96–3.84(m,1H),3.21(dd,J=18.2,8.4Hz,1H),2.80(dd,J =18.1,7.5Hz,1H),2.38(s,3H).
13C NMR(101MHz,CDCl3)δ172.65,139.43,134.18(q,J=307.5Hz),134.16,132.77,131.11,129.57,128.05,125.33,125.00,124.97,84.35,45.53, 36.30,21.05.
19F NMR(377MHz,CDCl3)δ-39.62.
HR-ESI-MS m/z calcd.for C12H11F3NaO2S[M+Na]+:299.0324,found:299.0327.
实施例5:催化反应实例3
将19.2mg(0.1mmol)丁烯酸、60mg三氟甲硫基试剂1和8mg催化剂置于反应瓶中,于0℃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,89%产率,81%ee值。
1H NMR(400MHz,CDCl3)δ7.38(t,J=7.8Hz,1H),7.25(d,J=7.0Hz, 1H),7.05–6.89(m,2H),5.65(d,J=3.7Hz,1H),4.11(dt,J=8.5, 4.3Hz,1H),3.88(s,3H),3.15(dd,J=18.3,8.6Hz,1H),2.71(dd,J =18.3,4.5Hz,1H).
13C NMR(101MHz,CDCl3)δ174.05,156.61,134.67(q,J=307.4Hz),131.62,130.82,128.56,126.91,125.51,124.68,120.98,111.13,82.80,55.54, 44.27,35.98.
19F NMR(377MHz,CDCl3)δ-37.99.
HR-ESI-MS m/z calcd.for C12H11F3NaO3S[M+Na]+:315.0273,found:315.0277.
实施例6:催化反应实例4
将24.1mg(0.1mmol)丁烯酸、60mg三氟甲硫基试剂1和8mg催化剂置于反应瓶中,于0℃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,65%产率,90%ee值。
1H NMR(400MHz,CDCl3)δ7.58(d,J=8.3Hz,2H),7.25(d,J=8.5Hz, 2H),5.32(d,J=6.9Hz,1H),3.85(q,J=7.8Hz,1H),3.21(dd,J= 18.2,8.5Hz,1H),2.82(dd,J=18.2,7.9Hz,1H).
13C NMR(101MHz,CDCl3)δ172.30,134.95,134.18(q,J=308.0Hz),132.30,131.13,128.07,127.20,125.07,123.73,83.72,45.54,36.38.
19F NMR(377MHz,CDCl3)
δ-39.56.HR-ESI-MS m/z calcd.for C11H8BrF3NaO2S[M+Na]+:362.9273,found:362.9278.
实施例7:催化反应实例5
将21.2mg(0.1mmol)丁烯酸、60mg三氟甲硫基试剂1和8mg催化剂置于反应瓶中,于0℃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,88%产率,90%ee值。
1H NMR(400MHz,CDCl3)δ8.03–7.76(m,4H),7.55(dd,J=6.2,3.2 Hz,2H),7.43(d,J=8.5Hz,1H),5.55(d,J=6.3Hz,1H),4.02(q,J =14.8,7.2Hz,1H),3.25(dd,J=18.2,8.4Hz,1H),2.85(dd,J=18.2, 7.2Hz,1H).
13C NMR(101MHz,CDCl3)δ172.98,134.48(q,J=307.9Hz),133.74,133.35,133.06,131.42,129.52,128.39,128.35,127.98,127.20,127.12,125.34, 124.36,122.44,84.76,45.74,36.46.
19F NMR(377MHz,CDCl3)δ-39.55.
HR-ESI-MS m/z calcd.for C15H11F3NaO2S[M+Na]+:335.0324,found:335.0331.
Claims (1)
1.一种三氟甲硫基试剂制备方法,其特征在于包括以下步骤:
(1)在手套箱中将氟化银装入烘干的反应瓶中,盖好瓶塞拿出手套箱;在氮气气氛中加入重蒸的乙腈和二硫化碳,快速装好回流冷凝管于80℃回流过夜;然后将二硫化碳蒸出,再把剩下的乙腈用旋转蒸发仪旋干得到黑色固体;接着用乙酸乙酯溶解洗涤黑色固体并用硅藻土过滤,并多次洗涤;在避光条件下将滤液旋干得到粘稠固体,用乙腈溶解粘稠固体后,把乙醚沿着瓶壁缓慢加入瓶中;将此混合液于室温下静止12小时后,置于-20℃静置24小时;倒去乙醚并继续旋干得到有金属光泽的灰白色固体氟化银,该步骤合成式为:
(2)将二苯磺酰亚胺置于反应瓶中,抽真空充氮气,如此反复三次;然后加入1,2-二氯乙烷于反应瓶中,再将次氯酸叔丁酯快速加入溶剂中并室温下搅拌30分钟,将此混合液旋干得到白色固体产物,该步骤合成式为:
(3)将(1)中合成的三氟甲硫基化银和(2)中合成的2置于反应瓶中,抽真空充氮气,如此反复三次;然后在避光条件下将溶剂加于反应瓶中并反应,将此浑浊液用硅藻土抽滤并用溶剂多次洗涤;将滤液避光条件下旋干并置于冰箱中得到白色固体产物,即为三氟甲硫基试剂1,该步骤合成式为:
步骤(2)或(3)中的溶剂选自于1,2-二氯乙烷、二氯甲烷。
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