CN110526848B - 分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法 - Google Patents
分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法 Download PDFInfo
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Abstract
本发明公开了一种由分子间氢迁移引发环胺β‑C(sp3)–H官能化合成β‑取代的吡咯烷类化合物的方法，属于化学合成技术领域。本发明的方法通过分子间氢迁移实现杂原子β‑C(sp3)–H官能化。本方法反应条件温和且底物普适性好；避免传统方法实现胺类化合物β‑C(sp3)–H官能化必须预先安装导向基或者采用过渡金属和外加氧化剂、还原剂等苛刻条件，合成过程绿色、高效、高原子经济性，为氢迁移领域开辟了新的道路。
Description
技术领域
本发明涉及化学合成技术领域，特别涉及一种由分子间氢迁移引发环胺β-C(sp3)–H官能 化合成β-取代的吡咯烷类化合物的方法。
背景技术
含有环胺骨架的杂环化合物在药物和天然产物中广泛存在，它也是二级胺手性催化剂和 含氮配体的重要组成。环胺类化合物的衍生在有机合成和药物开发中意义重大，简单可操作 性高的方法可以为合成工作者节省很多时间，为药物分子的发现提供新的化合物数据库。直 接对环胺进行C(sp3)–H官能化是最为高效的衍生方式，但目前绝大多数工作都投入到其 α-C(sp3)–H官能化，关于环胺β-C(sp3)–H的报道仍然较少。这无疑为β-取代的环胺类衍生物 的开发应用带来了困境。传统的方法，要实现胺类化合物β-C(sp3)–H官能化，必须预先安装 导向基或者采用过渡金属和外加氧化剂、还原剂等苛刻条件，如下所示：
这些方法不仅需要额外的合成步骤、昂贵的过渡金属或者外加当量的氧化剂或还原剂， 不符合当今以绿色、高效、高原子经济性为主题的合成理念。因此开发简单的无金属催化的 合成方法，在这一领域意义重大。
Ma课题组(Chemical Communication,2019,55(9):1217–1220)通过B(C6F5)3催化的中性 氧化还原策略实现了三级胺的β-烷基化。
该反应通过B(C6F5)3对叔胺β-位攫氢后形成B(C6F5)3-H物种与亚胺离子，经过互变异构 后与对亚甲基醌进行共轭加成生成β-取代的亚胺离子，最后由起初形成的B(C6F5)3-H物种还 原得到最后的目标产物。该反应首次实现了中性氧化还原的胺的β-C(sp3)–H官能化，但是在 胺类底物普适性方面尚有不足。
发明内容
针对现有技术中存在的问题，本发明的目的在于提供一种由分子间氢迁移引发环胺 β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法。
一种由分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法， 是由芳胺类化合物Ⅰ与酮酸酯类化合物Ⅱ作为反应底物，经分子间氢迁移引发环胺 β-C(sp3)–H官能化而成，化学反应式如下：
其中，
虚线表示有无；
R是C1-C3烷基、卤素、甲氧基、酯基、硼酸、乙酰基、苯基、4-F-C6H4-、4-Me-C6H4- 或无中的任意一种；
R1是三氟甲基或-CO2Et中任意一种；
R2是C1-C3烷基中任意一种。
在上述方案的基础上，所述催化剂为三氟甲烷磺酸、樟脑磺酸、对甲苯磺酸、联萘酚磷 酸酯、三氟乙酸、三氟甲磺酸钪、三氟甲磺酸铜、三氟甲磺酸锌或三氟甲磺酸铟；
优选地，选用三氟甲烷磺酸做催化剂。
在上述方案的基础上，所述三氟甲烷磺酸的用量为10mol％。
在上述方案的基础上，所述反应温度为60℃。
在上述方案的基础上，所述溶剂为1,2-二氯乙烷、正己烷、氯仿、甲苯、二恶烷、四氢 呋喃或二甲基亚砜。
优选地，选用1,2-二氯乙烷做溶剂。
在上述方案的基础上，所述芳胺类化合物与酮酸酯类化合物的用量比为1:1.5～2:1。
在上述方案的基础上，所述化合物Ⅲ具体包括以下结构：
在上述方案的基础上，所述由分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷 类化合物的方法，具体步骤如下：
反应底物芳胺类化合物与酮酸酯类化合物摩尔比1.2:1，在溶剂中添加10mol％的反应催 化剂，在60℃条件下反应；通过薄层色谱监测反应，反应完成后，旋蒸浓缩、柱层析分离纯 化，得到产物。
上述方法合成的β-取代的吡咯烷类化合物。
反应机理是：在
酸的活化作用下，少量三氟丙酮酸乙酯作为分子间氢受体接受 N-芳基吡咯烷氮原子α-位的负氢，生成亚胺阳离子中间体Ⅰ引发该反应。然后中间体Ⅰ经过 烯亚胺互变转化为中间体Ⅱ，转变为烯胺的中间体Ⅱ对已被
酸活化的三氟丙酮酸乙 酯发生亲核进攻(羰基-ene反应)，生成中间体Ⅲ后被另一分子N-芳基吡咯烷氮原子α-位的 负氢还原，生成目标产物3。与此同时，另一分子N-芳基吡咯烷1又转化为亚胺阳离子中间 体Ⅰ，继续进行下一个催化循环。整个反应机理分为两个部分，第一部分引发只需要少量的 三氟丙酮酸乙酯参与，随后的中性氧化还原过程占据着主导地位。
本发明有益效果：反应条件温和且底物普适性好；合成过程绿色、高效、高原子经济性； 解决了氢迁移反应在C(sp3)–H官能化邻域只能实现杂原子α-C(sp3)–H官能化而无法实现杂原 子β-C(sp3)–H官能化这一科学问题。经过细致的机理研究，一种两次分子间氢迁移的过程得 以证实，这也为氢迁移领域开辟了新的道路。
附图说明
图1为本发明实施例2中化合物3a的1H NMR谱
图2为本发明实施例2中化合物3a的13C NMR谱
图3为本发明实施例2中化合物3a的19F NMR谱
具体实施方式
在本发明中所使用的术语，除非有另外说明，一般具有本领域普通技术人员通常理解的 含义。
下面结合具体实施例，并参照数据进一步详细的描述本发明。以下实施例只是为了举例 说明本发明，而非以任何方式限制本发明的范围。
实施例1
以2-四氢吡咯基萘作为模板底物，在20mol％的三氟甲烷磺酸的催化下，以无水1,2-二 氯乙烷为溶剂，当亲电试剂为三氟丙酮酸乙酯时，在不同温度条件下(25-100℃)反应，发 现温度为60℃时，可以以90％的收率和1.5:1的非对映选择性得到目标产物。同时通过X- 射线晶体分析对产物结构和相对构型进行了进一步确认。
实施例2
以
和
为例制备
反应底物的用量比、催化剂及 其摩尔百分比、溶剂和反应温度如表1所示。
表1
注：反应条件为，在20mol％催化剂作用下，化合物1a(0.2mmol)和化合物无2a(0.1mmol) 在1.0mL溶剂中反应48h，反应温度为60℃；产率为柱层析后的分离产率；dr由核磁共振 氢谱测定；序号13、16-21的催化剂的摩尔百分比为10mol％；序号14的催化剂的摩尔百分 比为5mol％、序号15的催化剂的摩尔百分比为3mol％。
结果显示，最优反应条件为：以10mol％的TfOH为催化剂，1,2-二氯乙烷为溶剂，反应 底物1a与2a配比为1.2:1，温度为60℃。
实施例3
在实施例2所述的最优反应条件下，进行放大化实验。将反应底物1a投料量加大到6 mmol级别，该反应仍能以82％的收率和2.3:1的dr得到目标化合物3a。这一结果显示出了该方法在合成化学的应用可行性，为大量制备β-取代的吡咯烷类化合物提供了可行性。
同时使用更加复杂的底物5在标准条件下予以考察，该反应仍能以81％的收率和较高的 dr(8.9:1)顺利进行。底物5是传统氢迁移/环化反应的经典底物，在最优反应条件下，这一 策略性不仅可以实现氢迁移/环化，而且也完成了β-C(sp3)–H官能化，这一结果更加充分的展 示出了该方法潜在的应用价值。
实施例4
为阐明反应机理，进行反应机理研究。首先，模板反应在氮气环境下的效率不受影响， 因此排除了O2作为氧化剂的可能性，这与三氟代丙酮酸乙酯作为氧化剂将胺氧化成亚胺离子 是一致的。为了进一步确定氢给体的来源，制备氘化底物[D]-1a并进行氘代实验。通过核磁 确认了在产物[D]-3a中吡咯烷α-位仍然是100％的氘，这一发现证明了该反应经历了中性氧 化还原过程。使用N-芳基吡咯烷酮7在LiBHEt3作用下原位生成烯胺中间体并向反应体系中 加入三氟丙酮酸乙酯，结果发现只有β-官能化的烯胺8生成。由此证明，该反应中烯胺是反 应的关键中间体，同时没有3a的生成也说明了在没有氢源的条件下只能经过β-氢消除得到烯 胺8。最终，在标准条件下，烯胺8与氘化底物[D]-1a反应生成产物[H/D]-3a，且[H/D]-3a中 氮原子α-位存在一个完整的氘，这一结果充分证明了另一分子胺会还原亚胺离子完成中性氧 化还原的过程。
为了验证是进一步确认三氟丙酮酸乙酯引发该反应，在CDCl3溶剂中进行了模板反应。 待反应10小时后将反应液直接进行氟谱表征，发现在反应体系中存在着微量的3,3,3-三氟-2- 羟基-丙酸乙酯，这说明在反应初期确实是三氟酮酸酯作为氢受体接受氮邻位负氢，进而生成 3,3,3-三氟-2-羟基-丙酸乙酯，该发现为第一步的引发提供了充分的证据。
[D]-1a的波谱数据如下：
1H NMR(500MHz,CDCl3)δ7.68–7.58(m,3H),7.32(t,J＝7.5Hz,1H),7.13(t,J＝7.4Hz,1H),6.95(dd,J＝8.9,2.3Hz,1H),6.72(d,J＝1.9Hz,1H),1.97(s,4H).13C NMR(126MHz,CDCl3)δ146.08,135.38,128.88,127.70,126.34,126.23,125.84,121.24,115.79,104.71,47.30 (m),25.35.HRMS(ESI)calcd for C14H12D4N[M+H]+:202.1528,found:202.1530.
实施例5-27所述化合物是在实施例2所述的最优反应条件下，按下列反应式进行反应所 得产物。
实施例5
产物化学式：C19H21F3NO3
分子量：368.15
结构式：
产率：94％
1H NMR(500MHz,CDCl3)δ7.68(t,J＝8.3Hz,2H),7.63(d,J＝8.3Hz,1H),7.35(t,J＝ 7.5Hz,1H),7.17(t,J＝7.4Hz,1H),6.98(d,J＝8.9Hz,1H),6.76(s,1H),4.49–4.37(m,2H), 3.98(s,1H),3.57(t,J＝8.7Hz,1H),3.53(d,J＝9.7Hz,1H),3.49(d,J＝9.3Hz,1H),3.41(dd,J ＝16.7,8.8Hz,1H),3.13–3.04(m,1H),2.09–1.99(m,1H),1.92–1.80(m,1H),1.38(t,J＝7.1 Hz,3H).13C NMR(126MHz,CDCl3)δ169.57,145.43,135.10,128.91,127.62,126.61,126.28, 125.92,123.49(q,J＝287.3Hz),121.64,120.07,115.49,105.19,77.00(q,J＝30.2Hz),64.30, 47.38,46.88,40.35,25.38,14.03.19F NMR(471MHz,CDCl3)δ-76.16.
实施例6
产物化学式：C20H23F3NO3
分子量：382.16
结构式：
产率：88％
1H NMR(500MHz,CDCl3)δ7.62(d,J＝3.1Hz,0.5H),7.60(d,J＝3.1Hz,0.5H),7.54(dd, J＝8.3,5.5Hz,1H),7.45(s,1H),7.21(d,J＝1.5Hz,0.5H),7.19(d,J＝1.5Hz,0.5H),6.95(dd,J ＝8.9,2.4Hz,0.5H),6.90(dd,J＝8.9,2.4Hz,0.5H),6.74(d,J＝1.9Hz,0.5H),6.69(d,J＝2.1Hz, 0.5H),4.49–4.37(m,2H),3.98(s,0.5H),3.94(s,0.5H),3.58–3.46(m,2H),3.41(qd,J＝9.2,6.9 Hz,1H),3.32–3.23(m,1H),3.14–3.04(m,1H),2.44(s,3H),2.28(m,1H),2.19(m,0.5H),2.08 –1.99(m,0.5H),1.87(m,,0.5H),1.38(td,J＝7.1,4.2Hz,3H).13C NMR(126MHz,CDCl3)δ 169.86,169.59,144.93,144.82,133.21,133.18,131.03,130.96,128.59,128.53,128.26,128.21, 126.82,126.58,126.57,125.84,125.79,123.49(q,J＝287.3Hz),123.46(q,J＝287.3Hz),115.55, 115.44,105.26,105.20,77.04(q,J＝29.0Hz),64.34,64.27,47.96,47.76,47.45,46.94,40.55, 40.34,25.37,25.31,21.42,14.02,14.01.19F NMR(471MHz,CDCl3)δ-75.68,-76.16.
实施例7
产物化学式：C20H23F3NO4
分子量：398.16
结构式：
产率：82％
1H NMR(500MHz,CDCl3)δ7.60(dd,J＝8.8,3.0Hz,1H),7.55(dd,J＝8.8,5.3Hz,1H), 7.06(dd,J＝8.9,2.3Hz,1H),7.03(s,1H),6.97(dd,J＝8.8,2.1Hz,0.67H),6.92(dd,J＝8.9,2.1 Hz,0.33H),6.75(s,0.66H),6.70(s,0.33H),4.49–4.36(m,2H),4.00(s,0.33H),3.95(s,0.33H), 3.87(s,3H),3.57–3.36(m,3.40H),3.30–3.21(m,0.66H),3.09(m,1H),2.32–2.23(m,0.34H), 2.23–2.15(m,0.34H),2.02(m,0.70H),1.93–1.82(m,0.70H),1.45–1.32(m,3H).13C NMR (126MHz,CDCl3)δ169.88,169.60,154.90,154.87,144.20,144.09,130.47,130.43,127.71, 127.67,127.52,127.47,127.21,123.51(q,J＝287.3Hz),123.47(q,J＝287.3sHz),119.01,118.95, 116.00,115.88,105.94,105.80,105.72,77.07(q,J＝29.0Hz),64.33,64.26,55.31,48.07,47.88, 47.56,47.05,40.55,40.33,25.38,25.30,14.02.19F NMR(471MHz,CDCl3)δ-74.81,-75.71.
实施例8
产物化学式：C20H23F3NO4
分子量：398.16
结构式：
产率：82％
1H NMR(500MHz,CDCl3)δ7.61(d,J＝8.9Hz,1H),7.56(d,J＝8.8Hz,1H),6.97(d,J＝ 2.3Hz,1H),6.87–6.76(m,2H),6.69(s,1H),4.43(qq,J＝10.7,7.1Hz,2H),3.99(s,1H),3.89(s, 3H),3.57(t,J＝8.7Hz,1H),3.54–3.47(m,2H),3.41(dt,J＝16.2,8.1Hz,1H),3.13–3.03(m, 1H),2.04(m,1H),1.91–1.82(m,1H),1.39(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ 169.56,169.56,158.20,145.87,136.29,129.14,128.71,123.48(q,J＝287.3Hz),122.08,114.30, 113.03,104.58,104.17,76.94(q,J＝29.0Hz),64.30,55.19,47.40,46.87,40.32,25.37,14.03.19F NMR(471MHz,CDCl3)δ76.17.
实施例9
产物化学式：C19H20BrF3NO3
分子量：446.06
结构式：
产率：84％
1H NMR(500MHz,CDCl3)δ7.80(s,1H),7.57(d,J＝8.8Hz,1H),7.51–7.44(m,1H),7.39 (d,J＝8.7Hz,1H),6.97(d,J＝8.9Hz,0.54H),6.92(d,J＝8.9Hz,0.46H),6.70(s,0.54H),6.64(s, 0.46H),4.49–4.37(m,2H),4.00(s,0.54H),3.95(s,0.46H),3.56–3.44(m,2H),3.44–3.35(m, 1H),3.27(p,J＝8.5Hz,1H),3.15–3.04(m,1H),2.29(dd,J＝21.3,10.6Hz,0.46H),2.21(t,J＝ 10.0Hz,0.46H),2.07–1.99(m,0.54H),1.90–1.83(m,0.54H),1.38(dd,J＝12.1,5.9Hz,3H). 13C NMR(126MHz,CDCl3)δ169.49,145.45,133.53,129.54,129.47,128.06,127.63,127.59, 123.46(q,J＝287.3Hz),123.43(q,J＝287.3Hz),116.24,114.69,105.00,76.65(q,J＝29.0Hz), 64.42,64.36,47.89,47.65,47.40,46.90,40.56,40.30,25.36,25.31,14.03.19F NMR(471MHz, CDCl3)δ-75.66,-76.17.
实施例10
产物化学式：C19H20BrF3NO3
分子量：446.06
结构式：
产率：79％
1H NMR(500MHz,CDCl3)δ7.78(d,J＝1.6Hz,1H),7.64(d,J＝9.0Hz,1H),7.52(d,J＝8.6 Hz,1H),7.22(dd,J＝8.6,1.9Hz,1H),6.96(dd,J＝9.0,2.4Hz,1H),6.62(d,J＝2.2Hz,1H), 4.44(qq,J＝10.7,7.1Hz,2H),3.98(s,1H),3.58–3.47(m,3H),3.40(td,J＝9.6,6.8Hz,1H), 3.08(ddd,J＝17.8,11.5,8.6Hz,1H),2.10–2.00(m,1H),1.91–1.83(m,1H),1.39(t,J＝7.1Hz, 3H).13C NMR(126MHz,CDCl3)δ169.49,145.93,136.34,129.28,128.89,127.74,124.83, 124.74,123.44(q,J＝287.3Hz),120.47,115.70,103.98,64.35,47.25,46.75,40.32,25.34,14.03. 19F NMR(471MHz,CDCl3)δ-76.21.
实施例11
产物化学式：C22H25F3NO5
分子量：440.17
结构式：
产率：82％
1H NMR(500MHz,CDCl3)δ8.44(s,1H),7.94(d,J＝8.6Hz,1H),7.78(d,J＝8.8Hz,1H), 7.61(d,J＝8.5Hz,1H),6.99(d,J＝8.9Hz,1H),6.73(s,1H),4.50–4.36(m,4H),4.01(s,1H), 3.57(dt,J＝20.9,9.4Hz,3H),3.42(dd,J＝17.0,8.3Hz,1H),3.14–3.04(m,1H),2.05(p,J＝ 10.4Hz,1H),1.92–1.81(m,1H),1.47–1.34(m,6H).13C NMR(126MHz,CDCl3)δ169.44, 167.25,146.98,137.56,131.08,130.64,125.92,125.67,125.23,123.44(q,J＝287.3Hz),123.15, 115.90,104.63,76.85(q,J＝30.2Hz),64.37,60.65,47.19,46.69,40.32,25.34,14.49,14.03.19F NMR(471MHz,CDCl3)δ-76.22.
实施例12
产物化学式：C25H32BF3NO5
分子量：494.23
结构式：
产率：59％
1H NMR(500MHz,CDCl3)δ8.21(s,1H),7.72(t,J＝9.1Hz,2H),7.60(d,J＝8.1Hz,1H), 6.95(d,J＝8.9Hz,1H),6.73(s,1H),4.50–4.35(m,2H),3.99(s,1H),3.56(dt,J＝20.1,9.2Hz, 3H),3.42(dd,J＝17.0,8.1Hz,1H),3.13–3.01(m,1H),2.08–1.96(m,1H),1.91–1.79(m,1H), 1.44–1.28(m,15H).13C NMR(126MHz,CDCl3)δ169.52,146.19,136.92,136.22,131.01, 129.91,125.98,125.00,123.45(q,J＝288.5Hz),115.26,104.87,83.59,64.31,47.27,46.76,40.34, 25.36,24.93,14.02.19F NMR(471MHz,CDCl3)δ-76.21.
实施例13
产物化学式：C25H25F3NO3
分子量：444.18
结构式：
产率：71％
1H NMR(500MHz,CDCl3)δ7.90(d,J＝1.3Hz,1H),7.75(d,J＝8.9Hz,1H),7.73–7.67(m,3H),7.64(dd,J＝8.5,1.8Hz,1H),7.45(dd,J＝10.6,4.8Hz,2H),7.32(t,J＝7.4Hz,1H), 7.00(dd,J＝8.9,2.4Hz,1H),6.78(d,J＝2.1Hz,1H),4.43(qq,J＝10.7,7.1Hz,2H),4.01(s,1H), 3.62–3.50(m,3H),3.43(td,J＝9.5,6.8Hz,1H),3.14–3.05(m,1H),2.10–2.01(m,1H),1.88 (dt,J＝17.2,6.1Hz,1H),1.39(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ169.50,145.54, 141.55,134.34,129.30,128.75,127.02,126.66,126.42,125.92,125.58,123.49(q,J＝287.3Hz), 115.87,104.90,76.98(q,J＝29.0Hz),64.32,47.37,46.87,40.35,25.38,14.04,0.02.19F NMR (471MHz,CDCl3)δ-76.20.
实施例14
产物化学式：C25H24F4NO3
分子量：462.17
结构式：
产率：68％
1H NMR(500MHz,CDCl3)δ7.84(s,1H),7.74(d,J＝8.8Hz,1H),7.70(d,J＝8.5Hz,1H), 7.64(d,J＝6.0Hz,2H),7.58(d,J＝8.4Hz,1H),7.13(t,J＝8.3Hz,2H),7.01(d,J＝8.8Hz,1H), 6.78(s,1H),4.50–4.38(m,2H),3.99(s,1H),3.56(ddd,J＝25.5,16.9,8.5Hz,3H),3.44(dd,J＝ 16.9,8.3Hz,1H),3.15–3.05(m,1H),2.11–2.01(m,1H),1.94–1.85(m,1H),1.39(t,J＝7.0 Hz,3H).13C NMR(126MHz,CDCl3)δ169.55,162.14(d,J＝245.7Hz),145.56,137.69(d,J＝ 3.8Hz),134.26,133.28,129.23,128.47(d,J＝7.6Hz),126.69,126.51,125.75,125.42,123.48(q, J＝287.3Hz),115.81(d,J＝21.4Hz),115.48,104.87,76.95(q,J＝29.0Hz),64.33,47.37,46.86, 40.34,25.38,14.03.19F NMR(471MHz,CDCl3)δ-75.75,-129.77.
实施例15
产物化学式：C26H27F3NO3
分子量：458.19
结构式：
产率：72％
1H NMR(500MHz,CDCl3)δ7.87(s,1H),7.74(d,J＝8.8Hz,1H),7.68(d,J＝8.5Hz,1H), 7.63(d,J＝8.5Hz,1H),7.59(d,J＝7.5Hz,2H),7.25(s,2H),6.95(d,J＝8.8Hz,1H),6.73(s, 1H),4.51–4.39(m,2H),3.95(s,1H),3.59(t,J＝8.7Hz,1H),3.46(dd,J＝16.9,8.2Hz,1H),3.36 –3.27(m,2H),3.13(dd,J＝17.5,8.6Hz,1H),2.40(s,3H),2.31(dd,J＝21.3,10.7Hz,1H),2.22 (d,J＝5.7Hz,1H),1.39(t,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ169.84,145.33,138.61, 136.41,134.30,134.15,129.50,129.27,126.84,126.81,126.32,125.95,125.72(q,J＝287.3Hz), 125.22,115.75,104.92,64.39,47.94,47.71,40.57,25.33,21.12,14.02.19F NMR(471MHz, CDCl3)δ-75.68.
实施例16
产物化学式：C27H27F3NO4
分子量：468.19
结构式：
产率：53％
1H NMR(500MHz,CDCl3)δ8.04(d,J＝7.9Hz,2H),7.96(s,1H),7.78(t,J＝9.4Hz,3H), 7.72(d,J＝8.1Hz,1H),7.66(d,J＝8.5Hz,1H),7.02(d,J＝8.8Hz,0.64H),6.97(d,J＝9.0Hz, 0.36H),6.78(s,0.64H),6.73(s,0.36H),4.46(m,2H),4.00(s,0.64H),3.95(s,0.36H),3.58(dt,J＝ 20.9,9.6Hz,2H),3.51–3.27(m,2H),3.18–3.06(m,1H),2.66(s,3H),2.35–2.28(m,0.36H), 2.26–2.20(m,0.36H),2.08(dd,J＝20.7,10.6Hz,0.64H),1.93–1.86(m,0.64H),1.40(t,J＝7.0 Hz,3H).13C NMR(126MHz,CDCl3)δ197.83,169.80,169.50,146.17,146.11,145.90,145.79, 135.22,134.88,132.70,132.62,129.58,129.55,128.99,126.86,126.66,126.62,126.56,126.22, 125.54,125.48,124.61,116.06,115.99,104.78,64.42,64.35,47.87,47.33,46.81,40.58,40.34, 26.67,25.38,14.04.19FNMR(471MHz,CDCl3)δ-75.68,-76.18.
实施例17
产物化学式：C18H19F3NO3
分子量：354.13
结构式：
产率：76％
1H NMR(500MHz,CDCl3)δ7.68(t,J＝7.7Hz,2H),7.63(d,J＝8.3Hz,1H),7.36(t,J＝7.5Hz, 1H),7.18(t,J＝7.4Hz,1H),6.94(d,J＝8.9Hz,1H),6.73(s,1H),3.98(s,3H),3.91(s,1H),3.57 (t,J＝8.7Hz,1H),3.45(dd,J＝16.7,8.8Hz,1H),3.34–3.25(m,2H),3.15–3.07(m,1H),2.30 (dd,J＝21.2,10.6Hz,1H),2.22(td,J＝12.3,6.3Hz,1H).13C NMR(126MHz,CDCl3)δ170.40, 145.21,135.02,128.97,127.63,126.69,126.36,125.89,123.38(q,J＝287.3Hz),121.79,115.43, 105.33,76.80(q,J＝30.2Hz),54.69,47.99,47.84,40.63,25.29.19F NMR(471MHz,CDCl3)δ -75.70.
实施例18
产物化学式：C21H26NO5
分子量：372.18
结构式：
产率：67％
1H NMR(500MHz,CDCl3)δ7.66(dd,J＝8.4,2.8Hz,2H),7.61(d,J＝8.3Hz,1H),7.36– 7.29(m,1H),7.18–7.11(m,1H),6.95(dd,J＝8.9,2.4Hz,1H),6.73(d,J＝1.9Hz,1H),4.29(qd, J＝7.0,4.1Hz,4H),3.92(s,1H),3.54(t,J＝8.6Hz,1H),3.48(td,J＝8.4,3.7Hz,1H),3.38(ddd, J＝12.2,8.5,3.7Hz,2H),3.32–3.24(m,1H),2.12–2.02(m,2H),1.29(td,J＝7.1,5.6Hz,6H). 13C NMR(126MHz,CDCl3)δ170.09,170.05,145.75,135.16,128.82,127.63,126.56,126.22, 125.92,121.51,115.74,105.28,79.04,62.87,62.83,48.30,47.69,42.51,25.58,14.13,14.10.
实施例19
产物化学式：C15H18F4NO3
分子量：336.12
结构式：
产率：76％
1H NMR(500MHz,CDCl3)δ6.93(t,J＝8.1Hz,2H),6.43(dd,J＝5.4,3.5Hz,2H),4.48– 4.35(m,2H),3.90(s,1H),3.39(t,J＝8.6Hz,1H),3.29(dd,J＝16.6,8.2Hz,1H),3.18–3.02(m, 3H),2.29–2.20(m,1H),2.16(d,J＝5.8Hz,1H),1.36(t,J＝7.0Hz,3H).13CNMR(126MHz, CDCl3)δ169.78,155.15(d,J＝234.4Hz),144.22(d,J＝1.28Hz),123.40(q,J＝287.3Hz), 115.58(d,J＝22.7Hz),112.30(d,J＝7.6Hz),64.31,48.20,48.04,40.54,25.31,13.99.19F NMR (471MHz,CDCl3)δ-75.73,-129.76.
实施例20
产物化学式：C15H18ClF3NO3
分子量：352.09
结构式：
产率：62％
1H NMR(500MHz,CDCl3)δ7.15(d,J＝7.7Hz,2H),6.47(d,J＝8.0Hz,2H),6.42(d,J＝ 8.0Hz,1H),4.48–4.36(m,2H),3.96(s,1H),3.91(s,1H),3.40(t,J＝9.5Hz,2H),3.34(t,J＝9.0 Hz,1H),3.27(dd,J＝17.0,8.6Hz,1H),3.15–3.11(m,1H),3.09–2.99(m,1H),2.28–2.19(m, 1H),2.16(d,J＝5.9Hz,1H),2.04–1.94(m,1H),1.8 7–1.77(m,1H),1.37(q,J＝6.7Hz,3H). 13C NMR(126MHz,CDCl3)δ169.72,169.48,146.07,145.97,128.94,128.92,123.41(q,J＝ 287.3Hz),123.38(q,J＝287.3Hz),121.03,120.95,112.78,112.75,64.36,64.32,47.81,47.60, 47.28,47.26,46.76,40.52,40.30,25.34,25.29,14.01.19F NMR(471MHz,CDCl3)δ-75.74, -76.25.
实施例21
产物化学式：C21H23F3NO3
分子量：394.16
结构式：
产率：51％
1H NMR(500MHz,CDCl3)δ7.54(d,J＝6.9Hz,2H),7.49(d,J＝7.5Hz,2H),7.38(t,J＝ 6.8Hz,2H),7.25(d,J＝6.3Hz,1H),6.64(d,J＝7.6Hz,2H),4.50–4.35(m,2H),3.97(s,1H), 3.55–3.39(m,3H),3.34(dd,J＝16.3,7.9Hz,1H),3.10–2.97(m,1H),2.06–1.95(m,1H),1.84 (m,1H),1.38(t,J＝6.4Hz,3H).13C NMR(126MHz,CDCl3)δ169.55,146.92,141.33,128.67, 127.84,126.27,125.95,123.47(q,J＝287.3Hz),112.13,77.08(q,J＝29.0Hz),64.30,47.26, 46.74,40.34,25.37,14.02.19F NMR(471MHz,CDCl3)δ-76.18.
实施例22
产物化学式：C17H23F3NO5
分子量：378.15
结构式：
产率：57％
1H NMR(500MHz,CDCl3)δ6.79(d,J＝8.4Hz,1H),6.48(s,1H),6.40(d,J＝8.4Hz,1H), 4.64(s,1H),4.37(ddd,J＝17.5,10.6,6.9Hz,2H),3.83(s,3H),3.77(s,3H),3.39(t,J＝8.2Hz, 1H),3.32(dd,J＝15.2,7.3Hz,1H),3.19(t,J＝8.1Hz,1H),3.07(dd,J＝13.9,6.4Hz,1H),3.03– 2.96(m,1H),1.96(ddd,J＝12.4,8.1,4.5Hz,1H),1.85–1.76(m,1H),1.35(t,J＝6.8Hz,3H). 13C NMR(126MHz,CDCl3)δ169.57,155.60,152.89,132.22,123.74(q,J＝288.5Hz),117.22, 103.30,99.82,78.63(q,J＝29.3Hz),63.60,55.55,55.37,51.23,49.72,39.28,25.03,14.00.19F NMR(471MHz,CDCl3)δ-75.42.
实施例23
产物化学式：C16H19F3NO5
分子量：362.12
结构式：
产率：50％
1H NMR(500MHz,CDCl3)δ6.71(d,J＝8.4Hz,1H),6.17(d,J＝2.4Hz,1H),5.92(dd,J＝ 8.4,2.4Hz,1H),5.87–5.83(m,2H),4.45–4.35(m,2H),3.93(s,1H),3.35(td,J＝8.7,2.1Hz, 1H),3.27(td,J＝9.2,6.7Hz,1H),3.14–3.01(m,3H),2.23(dt,J＝28.5,9.6Hz,1H),2.16–2.09 (m,1H),1.36(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ169.78,148.38,143.88,138.73, 123.42(q,J＝287.3Hz),108.66,103.28,100.54,94.66,76.73(q,J＝29.0Hz),64.27,48.46,48.34, 40.45,25.23,13.99.19F NMR(471MHz,CDCl3)δ-75.74.
实施例24
产物化学式：C18H25F3NO3
分子量：360.18
结构式：
产率：55％
1H NMR(500MHz,CDCl3)δ6.84(s,2H),4.47–4.34(m,2H),4.19(s,1H),3.40(t,J＝8.5 Hz,1H),3.30–3.13(m,3H),3.05(p,J＝8.2Hz,1H),2.24(s,9H),1.96(dd,J＝19.5,9.4Hz,1H), 1.87–1.76(m,1H),1.38(t,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ169.89,141.58, 137.96,135.14,129.47,123.60(q,J＝288.5Hz),77.74(q,J＝29.0Hz),63.90,49.84,49.19,26.44, 20.76,18.69,14.03.19F NMR(471MHz,CDCl3)δ-76.17.
实施例25
产物化学式：C18H25F3NO6
分子量：408.16
结构式：
产率：51％
1H NMR(500MHz,CDCl3)δ5.74(d,J＝25.0Hz,2H),4.43(m,2H),4.00(s,0.8H),3.92(s, 0.2H),3.86(s,6H),3.77(s,3H),3.44–3.26(m,3.6H),3.16(d,J＝8.1Hz,0.4H),3.08–2.98(m, 1H),2.29–2.18(m,0.2H),2.18-2.08(m,0.2H),2.04–1.94(m,0.8H),1.87-1.74(m,0.8H),1.38(t, J＝6.7Hz,3H).13C NMR(126MHz,CDCl3)δ169.84,169.52,153.94,144.61,129.55,123.48(q, J＝288.5Hz),123.43(q,J＝288.5Hz),89.53,64.34,61.17,56.09,48.09,47.78,47.49,47.07, 40.65,40.37,25.41,14.04.19F NMR(471MHz,CDCl3)δ-75.67,-76.20.
实施例26
产物化学式：C34H41F3NO4
分子量：584.30
结构式：
产率：81％
1H NMR(500MHz,CDCl3)δ7.70(ddd,J＝19.1,14.2,7.9Hz,3H),7.43(dd,J＝15.4,7.9 Hz,1H),7.28–7.22(m,1H),6.97(d,J＝8.9Hz,1H),6.54(d,J＝2.2Hz,0.89H),6.49(d,J＝2.2 Hz,0.11H),6.44(d,J＝2.7Hz,0.89H),6.40(d,J＝2.7Hz,0.11H),4.39–4.29(m,2H),4.07(s, 1H),4.04(s,0.11iH),3.96(s,0.89H),3.80(dd,J＝17.7,8.3Hz,0.89H),3.68(dd,J＝17.7,9.1Hz, 0.11H),3.50(t,J＝8.9Hz,1H),3.34(d,J＝16.6Hz,1H),3.03(d,J＝15.0Hz,1H),2.45(d,J＝ 10.0Hz,1H),2.31(dd,J＝14.0,7.2Hz,0.11H),1.97(tt,J＝19.8,9.9Hz,1H),1.75(dd,J＝13.5, 7.1Hz,0.89H),1.32(s,9H),1.29(t,J＝7.1Hz,3H),1.12(d,J＝6.0Hz,9H).13C NMR(126MHz, CDCl3)δ186.03,185.92,169.58,169.29,148.74,148.58,148.45,148.38,144.58,144.01,140.88, 140.72,139.10,138.78,133.03,128.68,128.65,128.06,127.95,127.63,127.38,126.69,126.60, 123.22(q,J＝287.3Hz),122.10,121.96,121.47,121.39,116.83,116.58,109.73,109.25,79.88(q, J＝27.7Hz),64.62,64.45,64.29,63.59,50.09,50.00,44.80,42.80,39.30,36.45,36.04,35.11, 34.99,34.97,29.38,29.30,29.17,27.29,25.39,13.84,13.81.19F NMR(471MHz,CDCl3)δ-73.46, -73.97.
实施例27
产物化学式：C19H18F3NO3
分子量：365.12
结构式：
1H NMR(500MHz,CDCl3)δ7.70(dd,J＝8.5,5.0Hz,2H),7.65(d,J＝8.2Hz,1H),7.41– 7.37(m,1H),7.27–7.22(m,1H),7.16(t,J＝1.5Hz,1H),7.11(dd,J＝9.0,2.4Hz,1H),6.89(d,J ＝2.3Hz,1H),4.47–4.39(m,2H),4.12(s,1H),3.92(t,J＝9.8Hz,2H),2.92(ddd,J＝9.2,5.1,2.6 Hz,2H),1.39(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ169.01,140.80,134.78,133.23, 129.28,127.91,127.67,126.67,126.32,123.21(q,J＝288.5Hz),122.84,115.14,108.54,106.71, 76.53(q,J＝31.5Hz),64.11,48.94,29.04,14.06.19F NMR(471MHz,CDCl3)δ-68.12.
实施例28
实施例2和5中所述的化合物3a的晶体数据和精细结构如下：
以上所述，仅是本发明的较佳实施例而已，并非是对本发明作其它形式的限制，任何熟 悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施 例。但是凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何 简单修改、等同变化与改型，仍属于本发明技术方案的保护范围。
Claims (7)
1.一种由分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法，其特征在于，是由芳胺类化合物Ⅰ与酮酸酯类化合物Ⅱ作为反应底物，在3-10mol％催化剂、溶剂、25-100℃的条件下，经分子间氢迁移引发环胺β-C(sp3)–H官能化而成，化学反应式如下：
其中，
虚线表示有无；
R是C1-C3烷基、卤素、甲氧基、酯基、硼酸、乙酰基、苯基、4-F-C6H4-、4-Me-C6H4-或氢中的任意一种；
R1是三氟甲基或-CO2Et中任意一种；
R2是C1-C3烷基中任意一种；
所述催化剂为三氟甲烷磺酸、樟脑磺酸、对甲苯磺酸、联萘酚磷酸酯、三氟乙酸、三氟甲磺酸钪、三氟甲磺酸铜、三氟甲磺酸锌或三氟甲磺酸铟中的一种；
所述溶剂为1,2-二氯乙烷、正己烷、氯仿或甲苯。
2.根据权利要求1所述由分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法，其特征在于，所述催化剂为三氟甲烷磺酸。
3.根据权利要求1所述由分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法，其特征在于，所述反应温度为60℃。
4.根据权利要求1所述由分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法，其特征在于，所述溶剂为1,2-二氯乙烷。
5.根据权利要求1所述由分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法，其特征在于，所述芳胺类化合物与酮酸酯类化合物的用量比为1:1.5～2:1。
6.根据权利要求1所述由分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法，其特征在于，所述化合物Ⅲ为以下结构中的任意一种：
7.根据权利要求1～6任一项所述由分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法，其特征在于，步骤如下：
反应底物芳胺类化合物与酮酸酯类化合物摩尔比1.2:1，在溶剂中添加10mol％的反应催化剂，在60℃条件下反应；通过薄层色谱监测反应，反应完成后，旋蒸浓缩、柱层析分离纯化，得到产物。
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