CN110483373B - 一种通过分子间氢迁移合成β-取代的烯胺类哌啶化合物的方法 - Google Patents
一种通过分子间氢迁移合成β-取代的烯胺类哌啶化合物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 21
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- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 230000005012 migration Effects 0.000 title claims abstract description 8
- 238000013508 migration Methods 0.000 title claims abstract description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title claims description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 13
- JKNHZOAONLKYQL-UHFFFAOYSA-K Indium(III) bromide Inorganic materials Br[In](Br)Br JKNHZOAONLKYQL-UHFFFAOYSA-K 0.000 claims abstract description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 238000012546 transfer Methods 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及一种通过分子间氢迁移合成β‑取代的烯胺类哌啶化合物的方法，属于化学合成技术领域。本发明方法通过分子间氢迁移策略/烯亚胺互变/羰基‑ene反应一步构建β‑取代的烯胺类哌啶化合物。该反应以1,2‑二氯乙烷为溶剂，20mol％InBr3为催化剂，在80℃条件下即可实现了上述反应，条件温和且底物普适性好。该方法操作简单，副产物只有水，为今后绿色高效地合成β‑取代的烯胺类哌啶化合物提供了新思路。
Description
技术领域
本发明涉及化学合成技术领域，特别涉及一种通过分子间氢迁移合成β-取代的烯胺类哌啶化合物的方法。
背景技术
自小分子药物被发掘以来，由于具有良好的药理性质，哌啶及其衍生物受到来自工业界和学术界化学家的广泛关注。哌啶杂环是最普遍的六元氮杂环，特别是在小分子药物中，如抗组胺剂Clarinex、氟喹诺酮类药物Moxifloxacin、镇痛和抗癫痫药Tiagabine等。因此，对哌啶类化合物衍生的重要性不言而喻。
传统的合成哌啶衍生物的方法通常需要较多步骤，而且副产物多、操作麻烦。因此，开发一种绿色高效、简单的直接衍生方法一直是有机化学家的研究热点。
Chang课题组(The Journal of American Chemical Society,2018,140(41):13209–13213)报道了一种构建桥联Si-N-杂环的新颖方法。该反应使用B(C6F5)3作为催化剂，通过N-芳基哌啶和含氢硅烷的串联硅烷化，连续构建C(sp3)-Si、C(sp2)-Si键。详细的机理研究表明N-硅烷哌啶硼氢化物的形成是该反应的关键。
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通过分子间氢迁移合成β-取代的烯胺类哌啶化合物的方法。
一种通过分子间氢迁移合成β-取代的烯胺类哌啶化合物方法，
是以芳基哌啶类化合物Ⅰ与三氟丙酮酸乙酯Ⅱ作为反应底物，在添加催化剂的溶剂中，经分子间氢迁移合成β-取代的烯胺类哌啶化合物Ⅲ；
化学反应式如下：
其中，
R是化合物Ⅰ或Ⅲ中苯环上的一个或多个取代基团，所述的取代基团是C1-C3烷基、卤素、甲氧基、与苯环相并的五元环或六元环、与苯环相并的含取代基的五元环或六元环中的一种或多种。
在上述方案的基础上，所述催化剂为溴化铟、三氟甲磺酸铟、三氟甲磺酸钇、三氟甲磺酸锌、三氟甲磺酸钪、三氟甲磺酸铜、三氟甲磺酸镁、三氟甲烷磺酸、甲烷磺酸、三氟乙酸、联萘酚磷酸酯或樟脑磺酸。
在上述方案的基础上，所述催化剂优选的为溴化铟。
在上述方案的基础上，所述溶剂为1,2-二氯乙烷、氯仿、二氯甲烷、二恶烷、四氢呋喃、甲苯、乙腈、N,N-二甲基甲酰胺或乙醇。
在上述方案的基础上，所述溶剂优选的为1,2-二氯乙烷。
在上述方案的基础上，所述反应还包括反应添加剂，所述反应添加剂为
M.S。
在上述方案的基础上，所述通过分子间氢迁移合成β-取代的烯胺类哌啶化合物的方法，具体步骤如下：
芳基哌啶类化合物与三氟丙酮酸乙酯摩尔比1:2，在溶剂中添加20mol％反应催化剂，在
M.S存在下，在80℃条件下反应24h；通过薄层色谱检测反应，待反应完成后，旋蒸浓缩、柱色谱分离纯化，得到产物。
上述方法合成的β-取代的烯胺类哌啶化合物，所述化合物的结构式为以下任意一种：
反应机理是：在Lewis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-芳基哌啶氮原子α-位的负氢转化为相应的醇，同时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在Lewis酸的活化下对三氟丙酮酸乙酯发生亲核进攻(羰基-ene反应)，生成中间体Ⅲ。中间体Ⅲ脱质子得到中间体Ⅳ，中间体Ⅳ上羟基质子化后脱水，生成的中间体Ⅴ被另一分子N-芳基哌啶氮原子α-位的负氢还原，生成目标产物3。与此同时，另一分子N-芳基哌啶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：本发明通过分子间氢迁移策略实现了N-芳基哌啶的β-C(sp3)–H官能化，合成了各种氮β-位带有三氟甲基和酯基官能团的N-芳基哌啶。该反应以DCE为溶剂，20mol％InBr3为催化剂，在80℃条件下即可实现了上述反应，条件温和且底物普适性好。该方法操作简单，副产物只有水，为今后绿色高效地合成β-取代的烯胺类哌啶化合物提供了新思路。
附图说明
图1为本发明实施例2产物的1H NMR谱；
图2为本发明实施例2产物的13C NMR谱；
图3为本发明实施例2产物的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
(1)4-哌啶烷基甲苯1a与三氟丙酮酸乙酯2a为模板底物制备化合物3a；催化剂、溶剂、反应温度如表1所示。
表1
注：反应条件为，在80℃条件下，1a(0.1mmol)和2a(0.2mmol)在添加有50mg
M.S的1mL溶剂中经20mol％催化剂作用发生反应；产率为纯化后的分离产率。
由实验结果可知，由分子间氢迁移过程引发的4-哌啶烷基甲苯1a与三氟丙酮酸乙酯2a的反应的最优条件为：在
分子筛的存在下，20mol％InBr3为催化剂，DCE为溶剂，80℃下反应24小时。
实施例2-13所述化合物的制备方法为：取0.10mmol芳基哌啶类化合物1于5mL封管中，加入1mL的无水DCE，向上述混液中加入0.2mmol的三氟丙酮酸乙酯2，最后，称取7.1mg(20mol％)的InBr3和50mg的
M.S加入封管中，于80℃下搅拌进行反应，通过TLC监测反应。反应完成后，旋蒸浓缩、柱色谱分离纯化。
实施例2
产物化学式：C17H21F3NO2
分子量：328.15
结构式：
产率：82％
1H NMR(500MHz,CDCl3)δ7.08(d,J＝8.4Hz,2H),6.81(d,J＝8.5Hz,2H),6.66(s,1H),4.30–4.16(m,2H),3.65(q,J＝8.9Hz,1H),3.54–s 3.41(m,2H),2.28(s,3H),2.19(ddd,J＝16.5,13.2,6.1Hz,2H),2.02–1.90(m,2H),ss1.29(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.88,144.26,132.64,129.91,129.78,124.51(q,J＝281.0Hz),115.78,99.20,61.57,55.12(q,J＝29.0Hz),45.27,23.31,22.11,20.46,14.09.19F NMR(471MHz,CDCl3)δ-67.39.
实施例3
产物化学式：C17H21F3NO3
分子量：344.15
结构式：
产率：62％
1H NMR(500MHz,CDCl3)δ6.85(d,J＝1.8Hz,4H),6.59(s,1H),4.29–4.16(m,2H),3.77(s,3H),3.67–3.58(m,1H),3.53–3.37(m,2H),2.26–2.11(m,2H),2.03–1.88(m,2H),1.30(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.91,154.16,140.85,133.18,124.52(q,J＝282.2Hz),117.61,114.61,98.59,61.54,55.66,55.09(q,J＝29.0Hz),45.86,23.24,22.11,14.10.19F NMR(471MHz,CDCl3)δ-67.43.
实施例4
产物化学式：C16H18F4NO2
分子量：332.13
结构式：
产率：51％
1H NMR(500MHz,CDCl3)δ7.03–6.94(m,2H),6.91–6.79(m,2H),6.61(s,1H),4.29–4.19(m,2H),3.65(q,J＝8.9Hz,1H),3.52–3.41(m,2H),2.20(qd,J＝17.0,8.1Hz,2H),2.04–1.92(m,2H),1.30(td,J＝7.1,1.7Hz,3H).13C NMR(126MHz,CDCl3)δ166.79,157.51(d,J＝239.4Hz),143.03(d,J＝2.5Hz),132.56,124.43(q,J＝281.0Hz),117.17(d,J＝7.6Hz),115.77(d,J＝22.7Hz),99.88,61.63,55.02(q,J＝29.0Hz),45.65,23.24,22.07,14.09.19F NMR(471MHz,CDCl3)δ-67.37,-123.80.
实施例5
产物化学式：C16H18ClF3NO2
分子量：348.10
结构式：
产率：64％
1H NMR(500MHz,CDCl3)δ7.22(d,J＝9.0Hz,2H),6.84–6.80(m,2H),6.65(s,1H),4.30–4.18(m,2H),3.66(q,J＝8.9Hz,1H),3.52–3.42(m,2H),2.27–2.14(m,2H),2.04–1.91(m,2H),1.30(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.66,144.89,131.73,129.15,125.36,124.37(q,J＝282.2Hz),116.64,100.94,61.69,55.01(q,J＝29.0Hz),45.13,23.28,22.03,14.08.19F NMR(471MHz,CDCl3)δ-67.30.
实施例6
产物化学式：C16H18BrF3NO2
分子量：392.05
结构式：
产率：77％
1H NMR(500MHz,CDCl3)δ7.36(d,J＝8.9Hz,2H),6.77(d,J＝8.9Hz,2H),6.65(s,1H),4.30–4.16(m,2H),3.66(q,J＝8.9Hz,1H),3.53–3.39(m,2H),2.28–2.15(m,2H),2.04–1.92(m,2H),1.30(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.64,145.30,132.05,131.59,124.35(q,J＝281.0Hz),117.03,112.66,101.12,61.70,55.01(q,J＝27.7Hz),45.05,23.28,22.01,14.08.19F NMR(471MHz,CDCl3)δ-67.29.
实施例7
产物化学式：C22H23F3NO2
分子量：390.17
结构式：
产率：55％
1H NMR(500MHz,CDCl3)δ7.54(dd,J＝13.7,8.0Hz,4H),7.41(t,J＝7.7Hz,2H),7.29(t,J＝7.4Hz,1H),6.98(d,J＝8.7Hz,2H),6.76(s,1H),4.33–4.17(m,2H),3.69(q,J＝8.9Hz,1H),3.55(qdd,J＝11.5,7.1,4.1Hz,2H),2.31–2.17(m,2H),2.07–1.93(m,2H),1.30(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.77,145.55,140.65,133.18,131.96,128.78,127.88,126.66,126.55,124.46(q,J＝282.2Hz),115.67,100.51,61.66,55.11(q,J＝29.0Hz),45.05,23.39,22.13,14.11.19F NMR(471MHz,CDCl3)δ-67.28.
实施例8
产物化学式：C18H23F3NO2
分子量：342.17
结构式：
产率：40％
1H NMR(500MHz,CDCl3)δ7.02(d,J＝8.2Hz,1H),6.71(d,J＝2.4Hz,1H),6.69–6.62(m,2H),4.29–4.18(m,2H),3.65(q,J＝9.0Hz,1H),3.53–3.43(m,2H),2.27–2.14(m,8H),2.02–1.89(m,2H),1.29(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.90,166.89,144.65,137.42,132.80,130.28,128.73,124.54(q,J＝282.2Hz),117.34,113.30,98.99,61.55,55.16(q,J＝27.7Hz),45.30,23.31,22.14,20.16,18.81,14.10.19F NMR(471MHz,CDCl3)δ-67.37.
实施例9
产物化学式：C17H19F3NO4
分子量：357.13
结构式：
产率：59％
1H NMR(500MHz,CDCl3)δ6.72(d,J＝8.4Hz,1H),6.55(s,1H),6.50(d,J＝2.1Hz,1H),6.33(dd,J＝8.4,2.1Hz,1H),5.91(s,2H),4.30–4.18(m,2H),3.63(q,J＝8.9Hz,1H),3.49–3.40(m,2H),2.26–2.13(m,2H),1.95(pt,J＝13.1,6.4Hz,2H),1.30(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.81,148.33,142.38,141.93,133.18,124.47(q,J＝281.0Hz),108.86,108.33,101.07,99.16,99.12,61.57,55.05(q,J＝27.7Hz),46.18,23.25,22.08,14.09.19F NMR(471MHz,CDCl3)δ-67.40.
实施例10
产物化学式：C19H25F3NO5
分子量：404.17
结构式：
产率：47％
1H NMR(500MHz,CDCl3)δ6.62(s,1H),6.11(s,2H),4.30–4.19(m,2H),3.86(s,6H),3.79(s,3H),3.68(q,J＝8.9Hz,1H),3.55–3.46(m,2H),2.29–2.15(m,2H),2.05–1.91(m,2H),1.31(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.77,153.71,143.33,132.72,132.57,124.44(q,J＝281.0Hz),100.00,94.08,61.63,61.05,56.14,55.07(q,J＝29.0Hz),45.78,23.35,22.13,14.09.19F NMR(471MHz,CDCl3)δ-67.30.
实施例11
产物化学式：C20H21F3NO2
分子量：364.15
结构式：
产率：84％
1H NMR(500MHz,CDCl3)δ7.70–7.64(m,2H),7.62(d,J＝8.2Hz,1H),7.34(dd,J＝11.1,4.0Hz,1H),7.23(dd,J＝11.0,3.9Hz,1H),7.15(dd,J＝8.9,2.4Hz,1H),7.09(d,J＝2.3Hz,1H),6.77(s,1H),4.24–4.12(m,2H),3.64(q,J＝8.9Hz,1H),3.57(qdd,J＝11.6,7.3,4.2Hz,2H),2.25–2.12(m,2H),2.01–1.90(m,2H),1.24(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.76,143.96,134.42,132.29,129.11,128.72,127.55,126.72,126.60,124.46(q,J＝281.0Hz),123.60,117.39,110.69,100.72,77.28,77.02,76.77,61.64,55.15(q,J＝29.0Hz),45.35,23.42,22.15,14.10,1.03.19F NMR(471MHz,CDCl3)δ-67.22.
实施例12
产物化学式：C20H20BrF3NO2
分子量：442.06
结构式：
产率：67％
1H NMR(500MHz,CDCl3)δ7.84(d,J＝12.2Hz,1H),7.61(dd,J＝16.1,6.4Hz,1H),7.52(dd,J＝16.0,6.2Hz,1H),7.48–7.38(m,1H),7.20(dd,J＝14.9,5.9Hz,1H),7.07(d,J＝12.0Hz,1H),6.81(d,J＝12.0Hz,1H),4.24(dd,J＝17.2,10.2Hz,2H),3.75–3.65(m,1H),3.58(dd,J＝14.7,7.0Hz,2H),2.25(dd,J＝16.0,10.8Hz,2H),2.02(d,J＝3.9Hz,2H),1.30(dt,J＝7.2,5.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.72,144.21,132.94,131.90,129.90,129.67,129.58,128.42,128.26,124.48(q,J＝281.0Hz),118.23,116.93,110.35,101.45,61.76,55.13(q,J＝29.0Hz),45.26,23.48,22.15,14.16.19F NMR(471MHz,CDCl3)δ-67.20.
实施例13
产物化学式：C23H25F3NO4
分子量：436.17
结构式：
产率：65％
1H NMR(500MHz,CDCl3)δ8.48(d,J＝0.7Hz,1H),8.00(dd,J＝8.6,1.7Hz,1H),7.85(d,J＝9.0Hz,1H),7.69(d,J＝8.7Hz,1H),7.27(dd,J＝8.6,2.0Hz,1H),7.15(d,J＝2.3Hz,1H),6.89(s,1H),4.45–4.40(m,2H),4.31–4.21(m,2H),3.73(q,J＝8.9Hz,1H),3.69–3.59(m,2H),2.35–2.20(m,2H),2.10–1.96(m,2H),1.43(t,J＝7.1Hz,3H),1.32(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ166.94,166.60,145.54,136.85,131.49,130.74,130.70,127.41,126.66,126.17,125.23,124.37(q,J＝281.0Hz),117.60,109.75,102.28,61.76,60.90,55.07(q,J＝29.0Hz),45.11,23.46,22.11,14.44,14.10.19F NMR(471MHz,CDCl3)δ-67.18.
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 (4)
1.一种通过分子间氢迁移合成β-取代的烯胺类哌啶化合物方法，其特征在于，
芳基哌啶类化合物Ⅰ与三氟丙酮酸乙酯Ⅱ作为反应底物，在添加催化剂的溶剂中，经分子间氢迁移合成β-取代的烯胺类哌啶化合物Ⅲ；
化学反应式如下：
其中，
R是化合物Ⅰ或Ⅲ中苯环上的一个或多个取代基团，所述的取代基团是C1-C3烷基、卤素、甲氧基、与苯环相并的五元环或六元环、与苯环相并的含取代基的五元环或六元环中的一种或多种；
所述催化剂为溴化铟、三氟甲磺酸铟、三氟甲磺酸钇、三氟甲磺酸锌、三氟甲磺酸钪或三氟甲磺酸镁；
所述溶剂为氯仿、二氯甲烷或二噁 烷；
所述反应还包括反应添加剂，所述反应添加剂为
M.S。
2.根据权利要求1所述通过分子间氢迁移合成β-取代的烯胺类哌啶化合物方法，其特征在于，所述催化剂为溴化铟。
3.根据权利要求1所述通过分子间氢迁移合成β-取代的烯胺类哌啶化合物方法，其特征在于，所述溶剂为1,2-二氯乙烷。
4.根据权利要求1～3任一项所述通过分子间氢迁移合成β-取代的烯胺类哌啶化合物的方法，其特征在于，具体步骤如下：
芳基哌啶类化合物与三氟丙酮酸乙酯摩尔比1:2，在溶剂中添加20mol％反应催化剂，在
M.S存在下，在80℃条件下反应24h；通过薄层色谱检测反应，待反应完成后，旋蒸浓缩、柱色谱分离纯化，得到产物。
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