CN106957207A - 2‑芳基（烯基）‑乙烯基磺酰氟化合物的制备方法 - Google Patents

2‑芳基（烯基）‑乙烯基磺酰氟化合物的制备方法 Download PDF

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CN106957207A
CN106957207A CN201710240070.8A CN201710240070A CN106957207A CN 106957207 A CN106957207 A CN 106957207A CN 201710240070 A CN201710240070 A CN 201710240070A CN 106957207 A CN106957207 A CN 106957207A
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aryl
alkenyl
vinvlsulfonamido
fluorine compounds
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秦华利
查高峰
冷静
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Wuhan University of Technology WUT
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Abstract

本发明公开了一种2‑芳基(烯基)‑乙烯基磺酰氟化合物的制备方法。以有机碘化合物为原料，与乙烯基磺酰氟、钯催化剂、银盐和溶剂混合，20℃至120℃反应2h以上，分离纯化，得乙烯基磺酰氟化产物。有机碘化合物为芳基碘化合物时，产物为2‑芳基‑乙烯基磺酰氟。有机碘化合物为烯基碘化合物时，产物为2‑烯基‑乙烯基磺酰氟。本发明所提供的制备方法不需要无水无氧，在空气条件下即可进行，钯催化剂负载低(正常为2％)，不需要外加膦配体，且反应产率高。对绝大部分的官能团均能耐受，反应选择性好，具备实验室大量制备和工业放大生产的技术潜力。

Description

2-芳基(烯基)-乙烯基磺酰氟化合物的制备方法
技术领域
本发明涉及药物化学技术领域，具体涉及一种2-芳基(烯基)-乙烯基磺酰氟化合物及其制备方法。
背景技术
六价硫氟交换化学(Sulfur(VI)Fluoride Exchange,SuFEx,Angew.Chem.Int.Ed.,2014,9430)是诺贝尔化学奖得主夏普莱斯(K.B.Sharpless)于2014年提出的新一代点击化学(Click Chemistry)。而磺酰氟(SO2F)、乙烯基磺酰氟(ESF)是研究较为深入的含氟六价硫砌块，目前在聚合物合成(Angew.Chem.Int.Ed.,2014,9466)、化学生物学(J.Am.Chem.Soc.,2016,7353)、共价键药物研究(Chem.Sci.,2015,2650)等领域显示出巨大的应用价值。
目前已知的2-芳基-乙烯基磺酰氟主要有两种合成方法，一种是使用2-芳基-乙烯基磺酰氯为原料，通过卤素交换法制备。而2-芳基-乙烯基磺酰氯的合成方法较为有限，制备方法使用芳基乙烯或芳基甲醛为原料，经过多步合成制备2-芳基-乙烯基磺酰氯为原料，再通过卤素交换法制备。需要使用正丁基锂、氯化砜，反应条件苛刻，对反应原料的预处理和设备的要求高，且产率较低，官能团耐受性差，仅能制备出少量的、官能团单一的2-取代苯基-乙烯基磺酰氟(J.Am.Chem.Soc.,1954,3230；Bioorg.Med.Chem.Lett.,2001,313)。
另一种是使用芳基重氮盐(Angew.Chem.Int.Ed.,2016,14155)、芳基硼酸(org.Lett.,2017,480)乙烯基磺酰氟为起始原料，通过Heck偶联反应实现2-芳基-乙烯基磺酰氟的合成。使用芳基硼酸为原料的制备方法需要外加氧化剂，原子利用率低，且产率较低，反应需要在氮气保护下进行，无法用于大量制备此类化合物。而使用芳基重氮盐为原料的制备方法，所需原料芳基重氮盐不稳定、易爆炸，无法用于大规模制备。这些制备方法仅能制备出少量、且官能团较为单一的2-芳基-乙烯基磺酰氟。
并且，目前2-烯基-乙烯基磺酰氟则无合成方法报道。良好合成方法的缺乏大大限制了这一系列化合物在相关领域的应用。
发明内容
本发明旨在提供一种具有官能团多样性的2-芳基(烯基)-乙烯基磺酰氟化合物，该系列化合物具有官能团多样性强、数量多(多达88个)的特点。同时提供了一种原料易得、反应条件温和、反应选择性好、产率高、仪器设备要求低和操作简单的乙烯基磺酰氟化方法，有望用于大规模合成多种2-芳基(烯基)-乙烯基磺酰氟化合物，应用于有机合成、聚合物合成、化学生物学等领域。
为达到上述目的，采用技术方案如下：
2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，包括以下步骤：
以有机碘化合物为原料，与乙烯基磺酰氟(ESF)、钯催化剂、银盐和溶剂混合，20℃至120℃反应2h以上，分离纯化，得乙烯基磺酰氟化产物。
按上述方案，所述有机碘化合物为芳基碘化合物，得产物为2-芳基-乙烯基磺酰氟化合物。
按上述方案，所述芳基碘化合物具有以下结构式：
(hetero)aryl-I 式1；
其中，(hetero)ar为苯基、取代苯基、稠环芳基、取代稠环芳基、芳杂环或者芳杂环衍生基团。
按上述方案，所述有机碘化合物为烯基碘化合物，得产物为2-烯基-乙烯基磺酰氟化合物。
按上述方案，所述烯基碘化合物具有以下结构式：
其中，R1、R1、R3分别为烷基、不饱和烃基、芳基、芳杂环或者芳杂环衍生基团。
按上述方案，所述钯催化剂，为Pd(OAc)2,PdCl2,Pd(TFA)2,Pd(PPh3)4、Pd(dppf)2Cl2,Pd(PPh3)2Cl2等，优选催化剂为Pd(OAc)2。
按上述方案，所述银盐为AgTFA,AgOTf、AgSbF6、AgPF6、AgBF4、AgNO3、Ag2O、Ag2CO3等，优选银盐为AgTFA。
按上述方案，所述有机碘化合物、乙烯基磺酰氟、钯催化剂与银盐的摩尔比为1:(1～10):(0.000001～0.2):(0.5～5)。
按上述方案，所述有机碘化合物、乙烯基磺酰氟、钯催化剂与银盐的摩尔比为1:2:0.02:1.2。
按上述方案，所述溶剂为丙酮、二氯甲烷、三氯甲烷、四氢呋喃、甲基叔丁基醚、甲苯或者砜类溶剂。
按上述方案，所述溶剂为丙酮。
按上述方案，反应温度为60℃。
本发明反应式描述如下：
当反应中的原料有机碘化合物为芳基碘化合物时，结构式中的(Hetero)Ar为苯基、取代苯基、稠环芳基、取代稠环芳基、各种芳杂环及其衍生基团等；当起始物有机碘化合物为烯基碘化合物时，结构式中的R1～R3为烷基、不饱和烃基、芳基、各种芳杂环及其衍生基团等；
2-芳基(烯基)-乙烯基磺酰氟是乙烯基磺酰氟的衍生物，同时具有两个亲核反应位点，在芳环区又可引入诸多的取代基，将在有机合成方法学、化学生物学等领域取得更广泛的应用。
相对于现有技术，本发明有有益效果如下：
本发明所提供的制备方法不需要无水无氧，在空气条件下即可进行，钯催化剂负载低(正常为2％)，不需要外加膦配体，且反应产率高(大部分产率能达到85％以上)，操作简单，仪器设备要求低；原料简单易得，绝大部分芳基碘化合物均有大规模商品供应，对绝大部分的官能团均能耐受(特别是羟基，醛基)，反应选择性好(相同的反应条件下，芳基上的溴和氯取代基均不参与此反应)，具备实验室大量制备和工业放大生产的技术潜力。
具体实施方式
以下实施例进一步阐释本发明的技术方案，但不作为对本发明保护范围的限制。
实施例1
100mL反应瓶中，加入碘苯(4.08g,20mmol)、乙烯基磺酰氟(4.40g,40mmol)、Pd(OAc)2(0.09g,0.4mmol,2mol％)、AgTFA(4.92g,24mmol),丙酮(50mL),搅拌下加热升温反应12h，TLC检测基本无碘苯残留后，反应液使用旋干后用硅胶柱层析纯化(洗脱剂为石油醚:乙酸乙酯＝20:1(v/v))，即得2-苯基-乙烯基磺酰氟(3.54g,95％yield)。也可将反应液使用硅藻土过滤，滤液浓缩至干后加入乙醚结晶得到本品。Mp 99–100℃.1H NMR(400MHz,CDCl3)δ7.81(d,J＝15.6Hz,1H),7.58–7.44(m,5H,),6.87(dd,J＝15.2,1.6Hz,1H,).13CNMR(101MHz,CDCl3)δ149.0，132.8，131.0，129.5，129.2，118.0(d，J＝30.3Hz).19F NMR(376MHz，CDCl3)δ62.1.EI-quadrupole MS calculated for C8H7FO2S[M]+186,found186.Rf＝0.55(EtOAc/Hexanes＝1/8)
实施例2：
100mL反应瓶中，加入2-芳基烯基碘(4.6g,20mmol)、乙烯基磺酰氟(17.60g,160mmol)、Pd(OAc)2(0.22g,1.0mmol,5mol％)、AgTFA(4.92g,24mmol),丙酮(50mL),搅拌下加热升温反应6h，TLC检测基本无烯基碘残留后，反应液使用旋干后用硅胶柱层析纯化(洗脱剂为石油醚:乙酸乙酯＝20:1(v/v))，即得2-苯乙烯基-乙烯基磺酰氟(2.8g,66％yield)。Mp74–76℃.1H NMR(400MHz,CDCl3)δ7.55(dd,J＝14.5Hz,J＝11.2Hz,1H),7.52-7.49(m,2H),7.41-7.40(m,3H),7.11(d,J＝15.5Hz,1H),6.86(dd,J＝15.6Hz,J＝11.2Hz,1H).6.44(dd,J＝14.8Hz,J＝1.8Hz,1H).19F NMR(376MHz,CDCl3)δ63.0(s,1F).13C NMR(126MHz,CDCl3)δ147.7(d,J＝2.7Hz),139.5,133.5,131.0,130.1,129.9,127.4,118.4(d,J＝28.1Hz).ESI-MS HRMS calculated for C10H10FO2S[M+1]+213.0380,found213.0375.Rf＝0.5(PE/EA＝10/1)
实施例3
100mL反应瓶中，加入间二碘苯(6.6g,20mmol)、乙烯基磺酰氟(8.80g,80mmol)、Pd(OAc)2(0.45g,2.0mmol,10mol％)、AgTFA(9.84g,48mmol),丙酮(100mL),搅拌下加热升温反应12h，补加Pd(OAc)2(0.22g,1.0mmol,5mol％)、AgTFA(2.26g,12mmol)，继续反应6h后再补加(0.09g,0.4mmol,2mol％)反应6h后，反应液使用旋干后用硅胶柱层析纯化(洗脱剂为石油醚:乙酸乙酯＝2:1(v/v))，即得1，3-双乙烯基磺酰氟(5.59g,95％yield)。也yield.Mp234–235℃.1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.07-8.02(m,4H),7.97(dd,J＝15.5Hz,J＝1.9Hz,2H),7.67(t,J＝7.8Hz,1H).19F NMR(376MHz,DMSO-d6)δ62.8(s,2F).13C NMR(126MHz,DMSO-d6)δ148.7(d,J＝2.7Hz),134.1,132.6,130.6,130.2,120.3(d,J＝26.4Hz).ESI-MS HRMS calculated for C10H9F2O4S2[M+1]+294.9905,found 294.9901.Rf＝0.3(PE/EA＝5/1).
采用本发明的方法合成2-芳基-乙烯基磺酰氟，其典型结构及反应产率如下所示，所公开的2-芳基-乙烯基磺酰氟分子结构式不作为对本发明保护范围的限制。
采用本发明的方法合成2-烯基-乙烯基磺酰氟，其典型结构及反应产率如下所示，所公开的2-烯基-乙烯基磺酰氟分子结构式不作为对本发明保护的限制。
本发明的公开的具有官能团多样性的2-芳基(烯基)-乙烯基磺酰氟化合物及其制备方法。该系列化合物具有官能团多样性强、数量多(多达88个)，且提供一种具有原料易得、反应条件温和、反应选择性好、产率高、仪器设备要求低和操作简单的乙烯基磺酰氟化方法。

Claims (10)

1.2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，其特征在于包括以下步骤：
以有机碘化合物为原料，与乙烯基磺酰氟、钯催化剂、银盐和溶剂混合，20℃至120℃反应2h以上，分离纯化，得乙烯基磺酰氟化产物。
2.如权利要求1所述2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，其特征在于所述有机碘化合物为芳基碘化合物，得产物为2-芳基-乙烯基磺酰氟化合物；所述芳基碘化合物具有以下结构式：
(hetero)ary-l 式1；
其中，(hetero)ar为苯基、取代苯基、稠环芳基、取代稠环芳基、芳杂环或者芳杂环衍生基团。
3.如权利要求1所述2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，其特征在于所述有机碘化合物为烯基碘化合物，得产物为2-烯基-乙烯基磺酰氟化合物；所述烯基碘化合物具有以下结构式：
其中，R1、R1、R3分别为烷基、不饱和烃基、芳基、芳杂环或者芳杂环衍生基团。
4.如权利要求1所述2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，其特征在于所述钯催化剂，为Pd(OAc)2,PdCl2,Pd(TFA)2,Pd(PPh3)4、Pd(dppf)2Cl2,Pd(PPh3)2Cl2等，优选催化剂为Pd(OAc)2。
5.如权利要求1所述2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，其特征在于所述银盐为AgTFA,AgOTf、AgSbF6、AgPF6、AgBF4、AgNO3、Ag2O、Ag2CO3等，优选银盐为AgTFA。
6.如权利要求1所述2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，其特征在于所述有机碘化合物、乙烯基磺酰氟、钯催化剂与银盐的摩尔比为1:(1～10):(0.000001～0.2):(0.5～5)。
7.如权利要求1所述2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，其特征在于所述有机碘化合物、乙烯基磺酰氟、钯催化剂与银盐的摩尔比为1:2:0.02:1.2。
8.如权利要求1所述2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，其特征在于所述溶剂为丙酮、二氯甲烷、三氯甲烷、四氢呋喃、甲基叔丁基醚、甲苯或者砜类溶剂。
9.如权利要求1所述2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，其特征在于所述溶剂为丙酮。
10.如权利要求1所述2-芳基(烯基)-乙烯基磺酰氟化合物的合成方法，其特征在于反应温度为60℃。
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CN108516945A (zh) * 2018-05-08 2018-09-11 武汉理工大学 一种邻位酯基取代的2-芳基-乙烯基磺酰氟化合物的制备方法
CN108516945B (zh) * 2018-05-08 2020-11-06 武汉理工大学 一种邻位酯基取代的2-芳基-乙烯基磺酰氟化合物的制备方法
CN114105837A (zh) * 2020-08-25 2022-03-01 中国科学院上海有机化学研究所 一类含烯基磺酰基分子的合成与应用
CN114105837B (zh) * 2020-08-25 2023-05-12 中国科学院上海有机化学研究所 一类含烯基磺酰基分子的合成与应用
WO2022214054A1 (en) * 2021-04-09 2022-10-13 Nanjing University Conjugate and the preparing method and use thereof
CN113943252A (zh) * 2021-10-15 2022-01-18 武汉理工大学 吡唑烷基磺酰氟化合物及其制备方法
CN113979897A (zh) * 2021-10-15 2022-01-28 武汉理工大学 一种γ-芳基烯丙基磺酰氟化合物及其制备方法与应用
CN113816878A (zh) * 2021-11-02 2021-12-21 扬州工业职业技术学院 一种3-丁烯-1-磺酰氟类化合物的制备方法

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