CN111592444A - 一种(z)-5-氟-2-三氟甲基烯烃衍生物及其制备方法 - Google Patents
一种(z)-5-氟-2-三氟甲基烯烃衍生物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种(Z)‑5‑氟‑2‑三氟甲基烯烃衍生物及其制备方法,将式Ⅱ结构的内炔加入到氟试剂、三氟试剂及硝酸银、氟化铯、双(三氟乙酰氧基)碘苯的溶剂中混合,反应完成后经后处理得到。本发明首次通过炔烃的远程氟‑三氟甲基化,一步实现了(Z)‑5‑氟‑2‑三氟甲基烯烃衍生物的立体选择性合成。该反应条件温和,底物适用范围广,反应收率良好,操作简单,对于含氟的三氟甲基烯烃化合物的合成提供了新途径。
Description
技术领域
本发明属于有机合成领域,具体涉及一种(Z)-5-氟-2-三氟甲基烯烃衍生物及其制备方法。
背景技术
C-H键是有机化合物中最简单、最常见的官能团。它的转化对有机合成、药物化学和新材料等领域研究都具有重要意义。由于碳-氢键较高的键能和稳定性,它的直接转化充满挑战。与传统的官能团转化反应相比,碳-氢键直接官能团化避免了预先官能团化,缩短了步骤,提高了效率,因而备受关注。实现C-H的选择性活化,一般依赖于设计合适的导向基团,选择过渡金属作催化剂获得目标产物。导向基团辅助的过渡金属催化可以实现碳-氢键官能团化,但是导向基团的引入和去除导致反应步骤增加,效率下降,因此,发展新的碳-氢键官能团化策略非常重要。
近年来,自由基迁移反应为惰性碳-氢键官能团化提供了新思路。目前,炔烃自由基加成启动的远程碳-氢键官能团化反应可以构建多根化学键,甚至形成多个碳环或杂环,显示出很高的合成效率和产物结构多样性。尽管取得了进展,这方面的工作还刚起步,更重要的是,还存在一些亟待解决的问题,首先这一反应往往经历自由基加成原子迁移后就会被环化形成环状物而得不到烯烃加成产物。
其次炔烃的氢-自由基加成一般是顺式加成,主要生成热力学稳定的(E)-烯烃,而炔烃反式氢-自由基加成、制备热力学较不稳定的(Z)-烯烃面临更大挑战。如能实现反式加成,对于(Z)-烯烃及含有(Z)-烯烃结构单元的药物分子合成具有重要价值。同时因为内炔活性较低,且加成区域选择性较难控制,所以,以往的研究一般是自由基加到炔烃末端碳原子(α-加成),而非末端炔烃的β-加成很难实现。
将含氟基团引入药物分子中是药物改性的重要策略之一。一方面,由于氟的强吸电子性,将其引入药物分子中能改变它的酸碱性,从而提高药物分子的脂溶性。另一方面,由于氟具有很强的吸电子能力,最大电负性,向药物分子引入氟元素中既能增强药物分子的抗氧化性,又能提高药物分子稳定性。随着氟化学的发展,越来越多的含氟化合物广泛应用于医药、农药和材料等领域。在这些化合物中,三氟甲基类化合物占很大比例。三氟烯烃类化合物作为重要的有机合成中间体,常用于药物、精细化学品及杀虫剂的合成中。因此,合理的催化体系,实现非末端炔烃炔烃自由基加成启动的乙烯基自由基诱导的远程C(sp3)-H氟化反应,选择性的同时引入氟和三氟甲基,合成(Z)式含氟的三氟烯烃衍生物,在理论研究和实际应用中都具有重要意义。
发明内容
本发明提供了一种(Z)-5-氟-2-三氟甲基烯烃衍生物及其制备方法,该制备方法实现了炔烃的远程氟-三氟甲基化反应,通过炔烃三氟甲基、分子内氢迁移和碳自由基氟化的反应历程,一步实现了(Z)-5-氟-2-三氟甲基烯烃衍生物的立体选择性合成。首次实现了炔烃自由基加成启动的乙烯基自由基诱导的远程C(sp3)-H氟化反应,高效的实现了包括C(sp2)-CF3、C(sp2)-H、C(sp3)-F多个化学键的构建。该反应条件温和,底物适用范围广,可以通过取代基的改变实现(Z)-5-氟-2-三氟甲基烯烃衍生物的制备方法的结构多样性合成,反应收率良好,操作简单,对于含氟的三氟甲基烯烃化合物的合成提供了新途径。
一种(Z)-5-氟-2-三氟甲基烯烃衍生物,为式I结构:
其中,式I中,R为苯基、对甲基苯基、邻甲基苯基、对氟苯基、对氯苯基、对溴苯基、对三氟甲基苯基、对乙酰基苯基、对氰基苯基或对甲酰基苯基中的一种。
本发明中,通过三甲基硅(TMSCF3)为三氟试剂,该三氟试剂在硝酸银、氟化铯、双(三氟乙酰氧基)碘苯作用下产生三氟甲基自由基,其与内炔加成形成含三氟甲基的烯基自由基,该自由基诱导远程C(sp3)-H活化,通过1,5-氢迁移产生的新自由基中间体,随后受氟试剂的进攻最终形成了(Z)-氟三氟甲基烯烃的目标产物。
一种(Z)-5-氟-2-三氟甲基烯烃衍生物的制备方法,包括以下步骤:
将式Ⅱ结构的内炔加入到含氟试剂、三氟试剂及硝酸银、氟化铯、双(三氟乙酰氧基)碘苯的溶剂中混合,形成反应体系,反应完成后经后处理得到式Ⅰ结构的(Z)-5-氟-2-三氟甲基烯烃衍生物的制备;
其中,R为苯基、对甲基苯基、邻甲基苯基、对氟苯基、对氯苯基、对溴苯基、对三氟甲基苯基、对乙酰基苯基、对氰基苯基或对甲酰基苯基中的一种。
涉及的反应的具体合成路线如下所示:
首次实现了其式Ⅱ结构的末端炔烃的自由基加成启动的乙烯基自由基诱导的远程C(sp3)-H氟化反应,该制备方法简单、有效地实现了(Z)-5-氟-2-三氟甲基烯烃衍生物衍生物。
所述的氟试剂为1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐,所述的三氟试剂为三氟甲基三甲基硅(TMSCF3)。所述的溶剂为乙腈。
所述的式Ⅱ结构的内炔、氟试剂、三氟试剂、硝酸银、氟化铯、双(三氟乙酰氧基)碘苯的摩尔比为1:1.5~2.5:2~3:1.5~2.5:2~3:0.5~1.5,进一步优选为1:1.8~2.2:2.3~2.7:1.8~2.2:2.3~2.7:0.8~1.2,最优选为1:2:2.5:2:2.5:1。
所述的反应体系的反应温度为15~35℃,进一步优选为20~30℃,最优选为25℃。
所述的反应体系的反应时间为14h~24h,进一步优选为16h~20h,最优选为18h。
所述的后处理包括:淬灭、萃取、洗涤有机相、干燥和柱层析分离。
所述的淬灭采用加水淬灭,所述的萃取采用乙酸乙酯萃取三次,所述的洗涤有机相采用饱和食用水洗涤,所述的干燥采用无水硫酸钠干燥,所述的柱层析分离采用硅胶柱层析分离。
同现有技术相比,本发明具有如下优点:
1、首次实现了非杂原子取代的末端炔烃的远程氟-三氟甲基化反应。。
2、首次实现了炔烃自由基加成启动的乙烯基自由基诱导的远程C(sp3)-H氟化反应,一步高效的实现了包括C(sp2)-CF3、C(sp2)-H、C(sp3)-F多个化学键的构建。
3、首次通过自由基途径区域选择性的合成了直链含氟的三氟甲基烯烃化合物。
4、反应条件温和,操作简单,底物适用范围广,官能团兼容性好,具有良好应用前景;故本发明具有较大的理论创新价值以及实施价值。
具体实施方式
实施例1
取一支干燥的反应管,氮气氛围下将内炔1a(34.4mg,0.2mmol)加入到含硝酸银(68mg,0.4mmol)、氟化铯(76mg,0.5mmol)、双(三氟乙酰氧基)碘苯(86mg,0.2mmol)、氟试剂(1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐,141.7mg,0.4mmol)、三氟甲基三甲基硅(71.1mg,0.5mmol)的乙腈(2mL)混合体系中,形成反应体系。该体系在室温25℃下搅拌18h后,加15mL水淬灭,用乙酸乙酯(10mL)萃取三次,合并后用饱和食用水洗涤有机相,无水硫酸钠干燥。有机相浓缩后用硅胶(300-400目)柱层析分离得到41mg淡黄色液体2a,收率79%。产物波谱分析1H NMR(600MHz,CDCl3)δ7.38–7.35(m,2H),7.31(dd,J=17.8,7.3Hz,3H),6.86(s,1H),2.52–2.48(m,2H),1.97–1.88(m,2H),1.46(s,3H),1.42(s,3H);13CNMR(151MHz,CDCl3)δ135.47(q,J=3.8Hz),135.0,130.3(q,J=28.3Hz),128.4(dd,J=4.4,2.1Hz),128.0,127.9,123.9(q,J=278.2Hz),94.9(d,J=166.6Hz),40.6(d,J=23.1Hz),27.6,26.6(d,J=24.7Hz);19F NMR(565MHz,CDCl3)δ-59.0,-140.2;GCMS(EI)called for C14H16F4 260.1188,found 260.1。
反应式如下:
实施例2
除用结构式1b所示的内炔衍生物代替实施例1中结构式1a所示的内炔外,其余操作步骤同实施例1,产率:78%,淡黄色液体2b。
产物波谱分析1H NMR(600MHz,CDCl3)δ7.19(dd,J=23.3,8.1Hz,4H),6.81(s,1H),2.57–2.44(m,2H),2.38(s,3H),2.00–1.82(m,2H),1.46(s,3H),1.42(s,3H);13C NMR(151MHz,CDCl3)δ137.9,135.6(q,J=3.8Hz),132.0,129.5(q,J=28.4Hz),128.8,128.4(dd,J=4.7,2.3Hz),124.0(q,J=275.8Hz),94.9(d,J=166.4Hz),40.7(d,J=23.1Hz),27.7(dd,J=5.3,2.5Hz),26.6(d,J=24.7Hz),21.2;19F NMR(565MHz,CDCl3)δ-58.9,-140.2;GCMS(EI)called for C15H18F4 274.1345,found 274.1。
反应式如下:
实施例3
除用结构式1c所示的内炔衍生物代替实施例1中结构式1a所示的内炔外,其余操作步骤同实施例1,产率:50%,淡黄色液体2c。
产物波谱分析1H NMR(600MHz,CDCl3)δ7.28–7.11(m,4H),6.83(s,1H),2.51(dd,J=12.5,4.5Hz,2H),2.26(s,3H),2.03–1.86(m,2H),1.47(s,3H),1.43(s,2H);13C NMR(151MHz,CDCl3)δ137.6,135.6(q,J=3.9Hz),135.0,130.0(dd,J=57.1,28.4Hz),129.0(d,J=2.2Hz),128.7,127.9,125.4(q,J=2.6Hz),123.9(q,J=277.1Hz),94.9(d,J=166.2Hz),40.6(d,J=23.0Hz),27.6(dd,J=5.4,2.3Hz),26.6(d,J=24.7Hz),21.3;19FNMR(565MHz,CDCl3)δ-59.8,-140.2;GCMS(EI)called for C15H18F4 274.1345,found274.1。
反应式如下:
实施例4
除用结构式1d所示的内炔衍生物代替实施例1中结构式1a所示的内炔外,其余操作步骤同实施例1,产率:79%,淡黄色液体2d。
产物波谱分析:1H NMR(600MHz,CDCl3)δ7.62(d,J=8.2Hz,2H),7.39(d,J=8.1Hz,2H),6.86(s,1H),2.61–2.50(m,2H),1.96(s,2H),1.46(s,3H),1.43(s,3H);13C NMR(151MHz,CDCl3)δ162.4(d,J=247.8Hz),134.4(q,J=3.8Hz),130.9(d,J=3.4Hz),130.3–130.1(m),123.8(q,J=275.9Hz),115.1,115.0,94.8(d,J=166.3Hz),40.5(d,J=23.1Hz),27.6,26.7,26.5;19FNMR(565MHz,CDCl3)δ-59.0,-113.5,-140.4;GCMS(EI)calledfor C14H15F5 278.1094,found 278.1。
反应式如下:
实施例5
除用结构式1e所示的内炔衍生物代替实施例1中结构式1a所示的内炔外,其余操作步骤同实施例1,产率:72%,淡黄色液体2e。
产物波谱分析:1H NMR(600MHz,CDCl3)δ7.35–7.30(m,2H),7.22(d,J=8.4Hz,2H),6.78(s,1H),2.54–2.46(m,2H),1.96–1.85(m,2H),1.45(s,3H),1.42(s,3H);13C NMR(151MHz,CDCl3)δ134.1(q,J=3.8Hz),134.0,133.4,129.7(d,J=2.4Hz),128.3,123.7(q,J=276.0Hz),122.2,94.8(d,J=166.7Hz),40.5(d,J=23.1Hz),27.7–27.4(m),26.7,26.5;19F NMR(565MHz,CDCl3)δ-59.0,-140.4;GCMS(EI)called for C14H15F4Cl 294.0798,found 294.1。
反应式如下:
实施例6
除用结构式1f所示的内炔衍生物代替实施例1中结构式1a所示的内炔外,其余操作步骤同实施例1,产率:70%,淡黄色液体2f。
产物波谱分析:1H NMR(600MHz,CDCl3)δ7.55–7.42(m,2H),7.16(d,J=8.4Hz,2H),6.76(s,1H),2.57–2.44(m,2H),1.98–1.84(m,2H),1.45(s,3H),1.42(s,3H);13C NMR(151MHz,CDCl3)δ134.1(q,J=3.8Hz),133.9,131.2,131.0(q,J=14.2Hz),130.0(dd,J=4.6,2.2Hz),123.7(q,J=284.8Hz),122.2,94.8(d,J=166.8Hz),40.4(d,J=23.0Hz),27.5(dd,J=5.2,2.4Hz),26.7,26.5;19F NMR(565MHz,CDCl3)δ-59.0,-140.4;HRMS(ESI)called for C14H15F4BrNa(M+Na)+361.0185,found 361.0183。
反应式如下:
实施例7
除用结构式1g所示的内炔衍生物代替实施例1中结构式1a所示的内炔外,其余操作步骤同实施例1,产率:76%,淡黄色液体2g。
产物波谱分析:1H NMR(600MHz,CDCl3)δ7.62(d,J=8.2Hz,2H),7.39(d,J=8.1Hz,2H),6.86(s,1H),2.60–2.44(m,2H),2.11–1.90(m,2H),1.46(s,3H),1.43(s,3H);13C NMR(151MHz,CDCl3)δ138.7,133.7(q,J=3.7Hz),132.5(q,J=28.5Hz),130.0(q,J=32.6Hz),128.6(dd,J=4.6,2.2Hz),125.0(d,J=3.8Hz),123.7(q,J=276.1Hz),123.8(q,J=272.0Hz),94.7(d,J=166.7Hz),40.4(d,J=23.1Hz),27.4(d,J=2.9Hz),26.7,26.5;19FNMR(565MHz,CDCl3)δ-59.1,-62.7,-140.6;GCMS(EI)called for C15H15F7 328.1062,found328.1。
反应式如下:
实施例8
除用结构式1h所示的内炔衍生物代替实施例1中结构式1a所示的内炔外,其余操作步骤同实施例1,产率:70%,淡黄色液体2h。
产物波谱分析:1H NMR(600MHz,CDCl3)δ7.95(d,J=8.3Hz,2H),7.37(d,J=8.2Hz,2H),6.86(s,1H),2.64(d,J=8.4Hz,3H),2.57–2.48(m,2H),1.98–1.86(m,2H),1.46(s,3H),1.42(s,3H);13C NMR(151MHz,CDCl3)δ134.1(q,J=3.7Hz),132.2(q,J=28.6Hz),128.5(d,J=2.3Hz),128.1,123.6(q,J=279.4Hz),94.7(d,J=166.8Hz),40.4(d,J=23.1Hz),27.4(dd,J=5.2,2.3Hz),26.7,26.6,26.5;19F NMR(565MHz,CDCl3)δ-59.1,-140.5;HRMS(ESI)called for C16H18F4ONa(M+Na)+325.1186,found 325.1170。
反应式如下:
实施例9
除用结构式1i所示的内炔衍生物代替实施例1中结构式1a所示的内炔外,其余操作步骤同实施例1,产率:72%,淡黄色液体2i。
产物波谱分析:1H NMR(600MHz,CDCl3)δ7.65(d,J=8.3Hz,2H),7.38(d,J=8.2Hz,2H),6.83(s,1H),2.58–2.45(m,2H),1.98–1.84(m,2H),1.46(s,3H),1.42(s,3H);13C NMR(151MHz,CDCl3)δ139.8,133.5–133.0(m),133.2–133.1(m),129.0(dd,J=4.7,2.3Hz),123.4(q,J=276.2Hz),118.5,111.7,94.7(d,J=167.1Hz),40.2(d,J=23.1Hz),27.4(dd,J=5.1,2.3Hz),26.7,26.5;19F NMR(565MHz,CDCl3)δ-59.1,-140.6;HRMS(ESI)called forC15H15F4NNa(M+Na)+308.1033,found 308.1033。
反应式如下:
实施例10
除用结构式1j所示的内炔衍生物代替实施例1中结构式1a所示的内炔外,其余操作步骤同实施例1,产率:79%,淡黄色液体2j。
产物波谱分析:1H NMR(600MHz,CDCl3)δ10.04(s,1H),7.88(d,J=8.2Hz,2H),7.44(d,J=8.1Hz,2H),6.87(s,1H),2.60–2.46(m,2H),2.00–1.88(m,2H),1.46(s,3H),1.43(s,2H);13C NMR(151MHz,CDCl3)δ191.7,141.3,135.6,133.9(q,J=3.8Hz),132.7(q,J=28.8Hz),129.4,128.9(d,J=2.4Hz),123.5(q,J=276.2Hz),94.7(d,J=166.9Hz),40.3(d,J=23.1Hz),27.4(dd,J=5.1,2.3Hz),26.6(d,J=24.7Hz);19F NMR(565MHz,CDCl3)δ-59.1,-140.5;HRMS(ESI)called for C15H10F4ONa(M+Na)+311.1029,found 311.1034。
反应式如下:
Claims (10)
3.根据权利要求2所述的(Z)-5-氟-2-三氟甲基烯烃衍生物的制备方法,其特征在于,所述的氟试剂为1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐,所述的三氟试剂为三氟甲基三甲基硅。
4.根据权利要求2所述的(Z)-5-氟-2-三氟甲基烯烃衍生物的制备方法,其特征在于,所述的溶剂为乙腈。
5.根据权利要求2所述的(Z)-5-氟-2-三氟甲基烯烃衍生物的制备方法,其特征在于,所述的式Ⅱ结构的内炔、氟试剂、三氟试剂、硝酸银、氟化铯、双(三氟乙酰氧基)碘苯的摩尔比为1:1.5~2.5:2~3:1.5~2.5:2~3:0.5~1.5。
6.根据权利要求5所述的(Z)-5-氟-2-三氟甲基烯烃衍生物的制备方法,其特征在于,所述的式Ⅱ结构的内炔、氟试剂、三氟试剂、硝酸银、氟化铯、双(三氟乙酰氧基)碘苯的摩尔比为1:1.8~2.2:2.3~2.7:1.8~2.2:2.3~2.7:0.8~1.2。
7.根据权利要求2所述的(Z)-5-氟-2-三氟甲基烯烃衍生物的制备方法,其特征在于,所述的反应体系的反应温度为15~35℃。
8.根据权利要求2所述的(Z)-5-氟-2-三氟甲基烯烃衍生物的制备方法,其特征在于,所述的反应体系的反应时间为14h~24h。
9.根据权利要求2所述的(Z)-5-氟-2-三氟甲基烯烃衍生物的制备方法,其特征在于,所述的后处理包括:淬灭、萃取、洗涤有机相、干燥和柱层析分离。
10.根据权利要求9所述的(Z)-5-氟-2-三氟甲基烯烃衍生物的制备方法,其特征在于,所述的淬灭采用加水淬灭,所述的萃取采用乙酸乙酯萃取三次,所述的洗涤有机相采用饱和食用水洗涤,所述的干燥采用无水硫酸钠干燥,所述的柱层析分离采用硅胶柱层析分离。
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