CN111675654A - 一种以惰性环丙烷为原料合成四氢喹啉类化合物的方法 - Google Patents
一种以惰性环丙烷为原料合成四氢喹啉类化合物的方法 Download PDFInfo
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Abstract
本发明提供了一类惰性环丙烷在硼路易斯酸催化下高效合成四氢喹啉类化合物的方法,属于应用技术领域。本发明解决问题的要点在于实现惰性环丙烷的分子内扩环反应,环丙烷与亚胺正离子先形成七元环中间体,后经BTMG(2‑叔丁基‑1,1,3,3‑四甲基胍)进攻β位质子生成含氮杂环化合物。
Description
技术领域
本发明提供了一类惰性环丙烷在硼路易斯酸催化下高效合成四氢喹啉类化合物的方法,属于应用技术领域。
背景技术
环丙烷作为有机化学中一种重要的C3合成子,其开环反应一直是研究的热点。但由于C-C键极化程度低,实现其断裂所需要的能垒较高,为降低反应的活化能,多种反应策略相继被发展。
a)在环丙烷结构中引入吸电子基团和给电子基团构建Donor-Acceptor环丙烷,通过“拉推作用”增大C-C键极化程度,利用路易斯酸实现其开环反应。
b)在环丙烷上引入弱活化基团,如烯基、羰基、酰胺基等,通过这些导向基团与过渡金属螯合,实现环丙烷对过渡金属的氧化加成作用,促进环丙烷C-C键断裂。
c)对于简单、惰性环丙烷,如何实现其直接开环反应是该领域的研究难点。相对于前两节介绍的活化类环丙烷可以发生不同类型的环加成反应,惰性环丙烷的反应类型局限,研究报道较少,涉及的反应类型单一,反应底物局限,官能团耐受性较差。
Nagahara课题组利用AlCl3催化简单环丙烷开环硅氢化反应,但反应底物范围局限(Nagahara,S.,Yamakawa,T.,Yamamoto,H.Tetrahedron Letters,2001,42,5057);Stephan课题组利用“受阻的路易斯酸碱对”实现惰性环丙烷开环生成1,3-偶极子化合物(Morton,J.G.,Dureen,M.A.,Stephan,D.W.Chem.Commun.,2010,46,8947);Lectka课题组利用光照条件实现惰性环丙烷的双官能化反应,该反应局限于芳基取代的环丙烷(Pitts,C.R.,Ling,B.,Snyder,J.A.,Bragg,A.E.,Lectka,T.J.Am.Chem.Soc.2016,138,6598);Szabó课题组使用高价碘化合物实现惰性环丙烷的1,3-二氟化反应,该反应需要使用当量的高价碘化合物(Ilchenko,N.O.,Hedberg,M.,Szabó,K.J.Chem.Sci.,2017,8,1056)。
综上所述,拓展惰性环丙烷的反应类型和开发新的反应体系对后续环丙烷领域的发展具有非常重要的理论研究价值和实际意义。本专利希望借助于高效、绿色的新型催化剂,实现惰性环丙烷的开环,以及开环后与其他试剂的反应,拓展惰性环丙烷的反应类型。
发明内容
本发明提供了一类惰性环丙烷在硼路易斯酸催化下高效合成四氢喹啉类化合物的方法,属于应用技术领域。本发明解决问题的要点在于实现惰性环丙烷的分子内扩环反应,环丙烷与亚胺正离子先形成七元环中间体,后经BTMG(2-叔丁基-1,1,3,3-四甲基胍)进攻β位质子生成含氮杂环化合物。
1.一种以惰性环丙烷为原料合成四氢喹啉类化合物的方法,其特征在于该方法的具体步骤为:
在反应瓶中依次加入原料1和B(C6F5)3催化剂以及溶剂,随后依次加入BTMG(2-叔丁基-1,1,3,3-四甲基胍)和TMSOTf(三氟甲磺酸三甲基硅酯)在氮气氛围中150℃下搅拌24小时,冷却至室温,减压除去溶剂,硅胶柱层析分离得到目标产物。
2.本发明所涉及到的路易斯酸催化剂是B(C6F5)3,催化剂的用量一般为20mol%。
3.本发明所涉及到的添加剂是BTMG和TMSOTf,其用量一般为20mol%。
4.本发明所用溶剂是甲苯,其用量是为每毫摩尔原料1对应使用范围5mL至10mL。
5.本发明所涉及到的反应可以在150℃下进行。
6.本发明所用原料1中的环丙烷上取代基R可以为氢、烷基、芳基等取代基团,R1可以为甲氧基、苄氧基、杂环等取代基团。
本发明的优点是:
1.本发明利用B(C6F5)3催化惰性环丙烷开环,生成七元环中间体,再利用强碱BTMG进攻进攻β位质子生成含氮杂环化合物。反应适用性好,底物范围广泛。
2.本发明操作简便,一步反应即可得到目标产物,后处理也无特别要求。
3.本发明所使用的是非金属催化剂,有良好的催化效果,减少环境污染。
具体实施方法
下面的实施示例将更好的说明本发明,但需将强调的是本发明决不仅限于这几个实施示例所表示内容。以下实例显示了本发明的不同侧面。所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。
实施例1:7b-(4-methoxyphenyl)-3-methyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]Quinoline的合成
氮气气氛下,在15mL的反应瓶中将原料1a(26.7mg,0.1mmol),B(C6F5)3(10.24mg,0.02mmol),溶于干燥的甲苯(1mL)中,再加入BTMG(3.42mg,0.02mmol),TMSOTf(4.44mg,0.02mmol)在150℃下反应24小时。反应结束,硅胶柱层析分离,淋洗剂为(石油醚/乙酸乙酯=100/1),得产物2a为17.2mg(白色固体),收率65%。1H NMR(400MHz,CDCl3)δ7.32-7.3(m,2H),7.29-7.26(m,1H),7.07-7.03(m,1H),6.90-6.88(m,2H),6.67-6.56(m,3H),3.83(s,3H),3.35(d,J=10.4Hz,1H),3.25(d,J=10.4Hz,1H),2.85(s,3H),1.81-1.80(m,1H),1.72-1.69(m,1H),1.32-1.29(m,1H);13C NMR(101MHz,CDCl3)δ158.4,144.5,136.9,131.9,130.3,128.5,126.1,117.7,113.8,111.3,77.48,55.4,48.5,39.2,27.9,27.1,13.8.HRMS(ESI)m/z calcd for C18H20NO+(M+H)+266.1539,found 266.1542.
实施例2:2-(1-(4-methoxyphenyl)cyclopropyl)-N,N,5-trimethylaniline的合成
氮气气氛下,在15mL的反应瓶中将原料1b(28.1mg,0.1mmol),B(C6F5)3(10.24mg,0.02mmol),溶于干燥的甲苯(1mL)中,再加入BTMG(3.42mg,0.02mmol),TMSOTf(4.44mg,0.02mmol)在150℃下反应24小时。反应结束,硅胶柱层析分离,淋洗剂为(石油醚/乙酸乙酯=100/1),得产物2b为15.6mg(白色固体),收率56%。1H NMR(400MHz,CDCl3)δ7.29(d,J=8.2Hz,1H),6.98(d,J=8.6Hz,2H),6.82-6.81(m,2H),6.74(d,J=8.6Hz,2H),3.75(s,3H),2.60(s,6H),2.33(s,3H),1.41-1.38(m,2H),1.28-1.25(m,2H);13C NMR(101MHz,CDCl3)δ157.1,153.4,139.8,137.2,134.3,133.4,126.8,122.7,120.1,113.4,55.4,44.4,26.36,21.5,19.3.HRMS(ESI)m/z calcd for C19H24NO+(M+H)+282.1852,found 282.1859.
实施例3:7b-(4-(benzyloxy)phenyl)-3-methyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]Quinolone的合成
氮气气氛下,在15mL的反应瓶中将原料1c(34.3mg,0.1mmol),B(C6F5)3(10.24mg,0.02mmol),溶于干燥的甲苯(1mL)中,再加入BTMG(3.42mg,0.02mmol),TMSOTf(4.44mg,0.02mmol)在150℃下反应24小时。反应结束,硅胶柱层析分离,淋洗剂为(石油醚/乙酸乙酯=100/1),得产物2c为21mg(白色固体),收率62%。1H NMR(400MHz,CDCl3)δ7.51-7.49(m,2H),7.43-7.40(m,2H),7.40-7.36(m,3H),7.12-7.08(m,1H),7.02-7.0(m,2H),6.74-6.72(m,1H),6.68-6.62(m,3H),5.12(s,2H),3.39(d,J=11.5Hz,1H),3.29(d,J=11.5Hz,1H),2.89(s,3H),1.88-1.84(m,1H),1.77-1.75(m,1H),1.37-1.34(m,1H);13C NMR(101MHz,CDCl3)157.6,144.5,137.2,131.9,130.2,128.8,128.5,128.1,127.7,126.1,117.8,114.7,111.3,70.2,48.5,39.2,27.9,27.2,13.8.HRMS(ESI)m/z calcd for C24H24NO+(M+H)+342.1852,found 342.1856.
实施例4:5-fluoro-3-methyl-7b-phenyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolone的合成
氮气气氛下,在15mL的反应瓶中将原料1d(28.5mg,0.1mmol),B(C6F5)3(10.24mg,0.02mmol),溶于干燥的甲苯(1mL)中,再加入BTMG(3.42mg,0.02mmol),TMSOTf(4.44mg,0.02mmol)在150℃下反应24小时。反应结束,硅胶柱层析分离,淋洗剂为(石油醚/乙酸乙酯=100/1),得产物2d为12.5mg(白色固体),收率44%。1H NMR(400MHz,CDCl3)δ7.30(d,J=8.5Hz,2H),6.89(d,J=8.5Hz,2H),6.59-6.55(m,1H),6.35-6.31(m,1H),6.28-6.23(m,1H),3.83(s,3H),3.37(d,J=10.5Hz,1H),3.29(d,J=10.5Hz,1H),2.83(s,3H),1.79-1.76(m,1H),1.60-1.57(m,1H),1.33-1.30(m,1H);13C NMR(101MHz,CDCl3)δ162.0(d,J=247Hz),158.4,145.7(d,J=9.9Hz),136.8,131.8,129.2(d,J=9.5Hz),125.7(d,J=4.9Hz),113.9,103.5(d,J=21.1Hz),98.8(d,J=26.2Hz),55.5,48.5,39.3,27.2,26.6,13.9.HRMS(ESI)m/z calcd for C18H19FNO+(M+H)+284.1445,found 284.1448.
实施例5:6-chloro-7b-(4-methoxyphenyl)-3-methyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]Quinoline的合成
氮气气氛下,在15mL的反应瓶中将原料1e(30.1mg,0.1mmol),B(C6F5)3(10.24mg,0.02mmol),溶于干燥的甲苯(1mL)中,再加入BTMG(3.42mg,0.02mmol),TMSOTf(4.44mg,0.02mmol)在150℃下反应24小时。反应结束,硅胶柱层析分离,淋洗剂为(石油醚/乙酸乙酯=100/1),得产物2e为13.4mg(白色固体),收率45%。1H NMR(400MHz,CDCl3)δ7.28(d,J=8.7Hz,2H),6.99-6.97(m,1H),6.89(d,J=8.5Hz,2H),6.61-6.60(m,1H),6.52(d,J=8.7Hz,1H),3.84(s,3H),3.34(d,J=10.4Hz,1H),3.23(d,J=10.5Hz,1H),2.83(s,3H),1.84-1.79(m,1H),1.69-1.66(m,1H),1.34-1.31(m,1H);13C NMR(101MHz,CDCl3)δ158.6,143.1,136.0,132.2,131.9,128.2,125.7,122.7,114.1,112.5,55.5,48.4,39.3,28.0,27.2,14.0.HRMS(ESI)m/z calcd for C18H19ClNO+(M+H)+300.1150,found 300.1157.
实施例6:6-bromo-7b-(4-methoxyphenyl)-3-methyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]Quinoline的合成
氮气气氛下,在15mL的反应瓶中将原料1e(34.5mg,0.1mmol),B(C6F5)3(10.24mg,0.02mmol),溶于干燥的甲苯(1mL)中,再加入BTMG(3.42mg,0.02mmol),TMSOTf(4.44mg,0.02mmol)在150℃下反应24小时。反应结束,硅胶柱层析分离,淋洗剂为(石油醚/乙酸乙酯=100/1),得产物2e为13.7mg(白色固体),收率40%。1H NMR(400MHz,CDCl3)δ7.28(d,J=8.5Hz,2H),7.13-7.10(m,1H),6.89(d,J=8.3Hz,2H),6.72(s,1H),6.46(d,J=8.5Hz,1H),3.84(s,3H),3.34(d,J=10.6Hz,1H),3.23(d,J=10.6Hz,1H),2.82(s,3H),1.83-1.79(m,1H),1.68-1.65(m,1H),1.34-1.31(m,1H);13C NMR(101MHz,CDCl3)δ158.5,136.0,132.6,131.8,130.9,128.7,114.1,113.0,110.1,55.5,48.3,39.3,28.1,27.1,14.1.HRMS(ESI)m/z calcd for C18H19BrNO+(M+H)+344.0645,found 344.0642.
Claims (6)
2.本发明所涉及到的路易斯酸催化剂是B(C6F5)3,催化剂的用量一般为20mol%。
3.本发明所涉及到的添加剂是BTMG和TMSOTf,其用量一般为20mol%。
4.本发明所用溶剂是甲苯,其用量是为每毫摩尔原料1对应使用范围5mL至10mL。
5.本发明所涉及到的反应可以在150℃下进行。
6.本发明所用原料1中的环丙烷上取代基R可以为氢、烷基、芳基等取代基团,R1可以为甲氧基、苄氧基、杂环等取代基团。
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KR101617121B1 (ko) * | 2015-02-05 | 2016-04-29 | 경기대학교 산학협력단 | 신규한 키랄 삼각고리 접합 테트라히드로퀴놀린 유도체와 이의 제조방법 |
WO2018056854A1 (en) * | 2016-09-23 | 2018-03-29 | BIAL - PORTELA & Cª, S.A. | Blood-brain barrier-penetrant dopamine-b-hydroxylase inhibitors |
CN110003081A (zh) * | 2019-04-23 | 2019-07-12 | 许昌学院 | 一种多氟烷基取代的吲哚啉和四氢异喹啉的合成方法 |
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KR101617121B1 (ko) * | 2015-02-05 | 2016-04-29 | 경기대학교 산학협력단 | 신규한 키랄 삼각고리 접합 테트라히드로퀴놀린 유도체와 이의 제조방법 |
WO2018056854A1 (en) * | 2016-09-23 | 2018-03-29 | BIAL - PORTELA & Cª, S.A. | Blood-brain barrier-penetrant dopamine-b-hydroxylase inhibitors |
CN110003081A (zh) * | 2019-04-23 | 2019-07-12 | 许昌学院 | 一种多氟烷基取代的吲哚啉和四氢异喹啉的合成方法 |
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CN112898202A (zh) * | 2021-01-27 | 2021-06-04 | 中国科学院上海有机化学研究所 | 一种杂环基并环丙烷化合物、合成方法 |
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