CN110066231B - 一种氮杂β-取代Morita-Baylis-Hillman型化合物及其合成方法 - Google Patents

一种氮杂β-取代Morita-Baylis-Hillman型化合物及其合成方法 Download PDF

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CN110066231B
CN110066231B CN201910436982.1A CN201910436982A CN110066231B CN 110066231 B CN110066231 B CN 110066231B CN 201910436982 A CN201910436982 A CN 201910436982A CN 110066231 B CN110066231 B CN 110066231B
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赵立明
刘坤
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Abstract

一种氮杂β‑取代Morita‑Baylis‑Hillman型化合物的合成方法，包括，向取代N‑亚苄基‑4‑甲基苯磺酰胺和4‑溴巴豆酸酯的无水THF混合物中加入Zn，回流搅拌反应1小时，然后将反应温度降至室温，将DBU加入反应混合物中，3小时后，将混合物用乙酸乙酯萃取，干燥，减压蒸除溶剂，并通过硅胶柱色谱法纯化残余物，得氮杂β‑取代Morita‑Baylis‑Hillman型化合物。本发明的合成方法与传统合成方法相比具有反应时间短，底物范围广，操作简单等优点，且具有广泛的适用性，能够用于多种氮杂β‑取代Morita‑Baylis‑Hillman型化合物的合成。

Description

一种氮杂β-取代Morita-Baylis-Hillman型化合物及其合成 方法
技术领域
本发明涉及化合物的合成，具体涉及一种氮杂β-取代Morita-Baylis-Hillman型化合物及其合成方法。
背景技术
氮杂Morita-Baylis-Hillman(MBH)型化合物是一种高官能团化的β-氨基羰基化合物，能够进行水解、烷基化、氢化、双羟化、偶联、环加成、环氧化等多种类型的反应，在有机合成、药物合成及天然产物合成中应用广泛。
目前，氮杂MBH型化合物一般是通过氮杂MBH反应来获得，即采用α,β-不饱和化合物与亚胺在催化剂作用下合成。但是，经典的MBH反应存在两个局限：一是反应速率很慢，一般需要数天甚至数周才能完成反应；二是这类反应只适用于β位无取代的α,β-不饱和化合物，无法合成β-取代的氮杂MBH型化合物。因此，有必要发明一种反应时间短、底物适用范围广，可以合成氮杂β-取代的MBH型化合物的新方法。
溴代巴豆酸酯类化合物在金属的作用下是一类良好的亲核试剂，例如在镁的作用下可以与亚胺发生Grignard反应；在锌的作用下可以与亚胺发生Reformatsky反应等。但现有文献并未记载使用溴代巴豆酸酯类化合物与亚胺反应得到氮杂β-取代的MBH型化合物的方法。
发明内容
针对现有技术中存在的不足，本发明提供了一种使用溴代巴豆酸酯类化合物与亚胺快速反应得到氮杂β-取代MBH型化合物的新方法。
一种氮杂β-取代Morita-Baylis-Hillman型化合物及其合成方法，包括：
S1：于有机溶剂中，在回流搅拌和金属试剂存在的条件下使下式1所示化合物与下式2所示化合物反应一段时间；
Figure BDA0002070813260000011
其中，R1为苯基，2-甲基苯基，3-甲基苯基，4-甲基苯基，2-溴苯基，3-溴苯基，4-溴苯基，4-氟苯基，4-三氟甲基苯基，4-甲氧基苯基，3，4-二甲氧基苯基，3，4-二氧亚甲基苯基，4-苯基苯基，呋喃基，噻吩基，萘基，蒽基，苯乙基，苯乙烯基，环己基或丙基；
R2为乙基或甲基；
S2：将反应温度降至室温，将DBU加入反应混合物中，一段时间后，萃取，干燥，减压蒸除溶剂，通过硅胶柱色谱法纯化残余物，得氮杂β-取代MBH型化合物。
进一步的，所述金属试剂为锌。
进一步的，所述化合物1与化合物2的摩尔比为1:1.1。
进一步的，所述有机溶剂为四氢呋喃。
进一步的，所述反应温度为有机溶剂回流温度。
本发明还提供了由上述合成方法制备的氮杂β-取代Morita-Baylis-Hillman型化合物，其结构式如下式3所示：
Figure BDA0002070813260000021
其中，R1为苯基，2-甲基苯基，3-甲基苯基，4-甲基苯基，2-溴苯基，3-溴苯基，4-溴苯基，4-氟苯基，4-三氟甲基苯基，4-甲氧基苯基，3，4-二甲氧基苯基，3，4-二氧亚甲基苯基，4-苯基苯基，呋喃基，噻吩基，萘基，蒽基，苯乙基，苯乙烯基，环己基或丙基；
R2为乙基或甲基。
与现有技术相比，本发明的有益效果：
本发明的合成方法提供了一种通过使用溴代巴豆酸酯类化合物与亚胺快速反应得到氮杂β-取代MBH型化合物的新方法，与传统合成方法相比具有反应时间短，底物范围广，操作简单等优点，且具有广泛的适用性，能够用于多种氮杂β-取代Morita-Baylis-Hillman型化合物的合成。
具体实施方式：
实施例1
Figure BDA0002070813260000022
向取代N-亚苄基-4-甲基苯磺酰胺1(0.50mmol)和4-溴巴豆酸酯2(0.55mmol)的无水THF(2mL)混合物中加入锌粉(0.75mmol)。回流搅拌反应1小时，然后将反应温度降至室温，将DBU(150μL，1.00mmol)加入反应混合物中，3小时后，将混合物用乙酸乙酯(3×10mL)萃取，干燥，减压蒸除溶剂，并通过硅胶柱色谱法(石油醚:乙酸乙酯＝4:1-2:1)纯化残余物，得氮杂β-取代MBH型化合物3，所得各氮杂β-取代MBH型化合物的化学式及表征如下：
2-(((4-甲基苯基)磺酰氨基)(苯基)甲基)丁-2-烯酸乙酯(3aa).
收率88％；mp 110-112℃.E:Z＝77:23；1H NMR(400MHz,CDCl3)major isomerδ7.68(d,J＝8.0Hz,2H),7.26-7.20(m,7H),6.86(q,J＝7.2Hz,1H),6.34(d,J＝10.4Hz,1H),5.60(d,J＝10.4Hz,1H),4.08-3.94(m,2H),2.40(s,3H),1.83(d,J＝7.2Hz,3H),1.13(t,J＝7.2Hz,3H)；minor isomerδ7.68(d,J＝8.0Hz,2H),7.26-7.20(m,7H),6.09(q,J＝7.2Hz,1H),5.78(d,J＝9.6Hz,1H),5.15(d,J＝9.6Hz,1H),4.08-3.94(m,2H),2.40(s,3H),1.83(d,J＝7.2Hz,3H),1.08(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ165.9,143.1,140.6,139.1,138.3,131.2,129.3,128.4,127.3,127.0,125.8,60.8,53.2,21.5,14.3,14.0.HRMS(ESI)m/z calcd for C20H23NNaO4S[M+Na]+396.1245；found 396.1251.
2-((2-溴苯基)((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸乙酯(3ba).
收率78％；mp 161-163℃.E:Z＝90:10；1H NMR(400MHz,CDCl3)major isomerδ7.63(d,J＝8.0Hz,2H),7.44(t,J＝8.0Hz,2H),7.15(d,J＝8.4Hz,2H),7.11(t,J＝8.0Hz,1H),7.02(t,J＝8.0Hz,1H),6.81(q,J＝7.2Hz,1H),6.36(d,J＝10.0Hz,1H),5.82(d,J＝10.0Hz,1H),4.09-4.00(m,2H),2.35(s,3H),1.92(d,J＝7.2Hz,3H),1.18(t,J＝7.2Hz,3H)；minor isomerδ7.63(d,J＝8.0Hz,2H),7.44(t,J＝8.0Hz,1H),7.29(d,J＝8.0Hz,1H),7.19-7.00(m,4H),6.16(q,J＝7.2Hz,1H),5.75(d,J＝8.8Hz,1H),5.59(d,J＝8.8Hz,1H),4.09-3.96(m,2H),2.36(s,3H),1.86(d,J＝7.2Hz,3H),1.17(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.8,143.1,137.9,137.6,132.8,130.3,129.8,129.2,128.8,127.1,127.0,122.9,60.9,53.7,21.4,15.4,14.0.HRMS(ESI)m/z calcd forC20H22BrNNaO4S[M+Na]+474.0351；found 474.0378.
2-((3-溴苯基)((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸乙酯(3ca).
收率79％；mp 91-93℃.E:Z>95:5；1H NMR(400MHz,CDCl3)major isomerδ7.66(d,J＝8.0Hz,2H),7.33(s,1H),7.32(s,1H),7.22(d,J＝8.0Hz,2H),7.19(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),6.88(q,J＝7.2Hz,1H),6.34(d,J＝10.4Hz,1H),5.55(d,J＝10.4Hz,1H),4.10-3.96(m,2H),2.40(s,3H),1.83(d,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ165.7,143.4,141.5,141.2,138.0,130.7,130.4,129.9,129.4,129.0,126.9,124.6,122.6,60.9,52.8,21.5,14.4,14.0.HRMS(ESI)m/z calcd for C20H22BrNNaO4S[M+Na]+474.0351；found 474.0380.
2-((4-溴苯基)((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸乙酯(3da)
收率75％；mp 85-87℃.E:Z＝65:35；1H NMR(400MHz,CDCl3)major isomerδ7.66(d,J＝8.0Hz,2H),7.37(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,2H),7.13(d,J＝8.4Hz,2H),6.86(q,J＝7.2Hz,1H),6.33(d,J＝10.4Hz,1H),5.52(d,J＝10.0Hz),4.10-3.95(m,2H),2.41(s,3H),1.82(d,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H)；minor isomer 1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.0Hz,2H),7.36(d,J＝7.6Hz,2H),7.24(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,2H),6.07(q,J＝7.2Hz,1H),5.86(d,J＝9.6Hz,1H),5.08(d,J＝9.6Hz,1H),4.10-3.95(m,2H),2.41(s,3H),1.82(d,J＝7.6Hz,3H),1.11(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ165.8,143.3,140.9,138.3,138.1,131.5,130.9,129.4,127.7,126.9,121.3,60.9,52.9,21.5,14.3,14.0.HRMS(ESI)m/z calcd forC20H22BrNNaO4S[M+Na]+474.0351；found 474.0377.
2-((4-氟苯基)((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸乙酯(3ea)
收率72％；mp 123-125℃.E:Z>95:5；1H NMR(400MHz,CDCl3)major isomerδ7.66(d,J＝8.0Hz,2H),7.24-7.21(m,4H),6.94(t,J＝8.8Hz,2H),6.85(q,J＝7.2Hz,1H),6.34(d,J＝10.0Hz,1H),5.55(d,J＝10.4Hz,1H),4.09-3.96(m,2H),2.41(s,3H),1.81(d,J＝7.2Hz,2H),1.15(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ165.9,162.0(J＝244.3Hz),143.3,140.8,138.1,134.8(J＝3.0Hz),131.0,129.4,127.6(J＝8.0Hz),126.9,115.3(J＝21.2Hz),60.8,52.8,21.5,14.3,14.0.HRMS(ESI)m/z calcd for C20H22FNNaO4S[M+Na]+414.1151；found 414.1151.
2-(((4-甲基苯基)磺酰氨基)(4-(三氟甲基)苯基)甲基)丁-2-烯酸乙酯(3fa).
收率86％；E:Z＝86:14；1H NMR(400MHz,CDCl3)major isomerδ7.66(d,J＝8.0Hz,2H),7.50(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),6.91(q,J＝7.2Hz,1H),6.42(d,J＝10.4Hz,1H),5.62(d,J＝10.4Hz,1H),4.09-3.95(m,2H),2.40(s,3H),1.84(d,J＝7.2Hz,3H),1.14(t,J＝7.2Hz,3H)；minor isomerδ7.66(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),6.11(q,J＝7.2Hz,1H),6.02(d,J＝9.6Hz,1H),5.18(d,J＝9.6Hz,1H),4.10-3.95(m,2H),2.40(s,3H),1.84(d,J＝7.2Hz,3H),1.10(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ165.8,143,5 141.3,138.0,130.7,129.4,126.9,125.4(q,J＝3.8Hz),61.0,53.1,21.5,14.4,14.0.HRMS(ESI)m/z calcd for C21H22F3NNaO4S[M+Na]+464.1119；found 464.1110.
2-(((4-甲基苯基)磺酰氨基)(邻甲苯基)甲基)丁-2-烯酸乙酯(3ga)
收率81％；mp 120-122℃.E:Z＝91:9；1H NMR(400MHz,CDCl3)major isomerδ7.62(d,J＝8.4Hz,2H),7.20(d,J＝8.8Hz,2H),7.17-7.01(m,4H),6.75(q,J＝7.2Hz,1H),6.25(d,J＝10.0Hz,1H),5.70(d,J＝10.0Hz,1H),4.05-3.91(m,2H),2.39(s,3H),2.38(s,3H),1.78(d,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H)；minor isomerδ7.62(d,J＝8.4Hz,2H),7.19(d,J＝8.8Hz,2H),7.17-7.01(m,4H),6.05(q,J＝7.2Hz,1H),5.51(d,J＝8.4Hz,1H),5.28(d,J＝8.0Hz,1H),4.05-3.91(m,2H),2.39(s,3H),2.20(s,3H),1.83(d,J＝7.2Hz,3H),1.13(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.7,143.0,140.4,138.1,136.5,136.4,130.7,129.2,127.6,127.2,127.1,125.8,60.8,51.7,21.5,19.8,14.4,14.0.HRMS(ESI)m/z calcd for C21H25NNaO4S[M+Na]+410.1402；found 410.1396.
2-(((4-甲基苯基)磺酰氨基)(间甲苯基)甲基)丁-2-烯酸乙酯(3ha).
收率87％；mp 91-93℃.E:Z>95:5；1H NMR(400MHz,CDCl3)major isomerδ7.67(d,J＝8.0Hz,2H),7.21(d,J＝8.0Hz,2H),7.13(t,J＝7.6Hz,1H),7.09(s,1H),7.01(d,J＝7.6Hz,2H),6.84(q,J＝7.2Hz,1H),6.35(d,J＝10.4Hz,1H),5.56(d,J＝10.4Hz,1H),4.08-3.94(m,2H),2.39(s,3H),2.27(s,3H),1.82(d,J＝7.2Hz,3H),1.13(t,J＝7.2Hz,3H)；minor isomerδ7.67(d,J＝8.0Hz,2H),7.21(d,J＝8.0Hz,2H),7.13(t,J＝7.6Hz,1H),7.09(s,1H),7.01(d,J＝7.6Hz,2H),6.09(q,J＝7.2Hz,1H),5.79(d,J＝9.6Hz,1H),5.12(d,J＝9.6Hz,1H),4.08-3.94(m,2H),2.39(s,3H),2.24(s,3H),1.82(d,J＝7.2Hz,3H),1.08(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.0,143.1,140.5,139.0,138.3,138.0,131.2,129.3,128.3,128.0,127.0,126.6,122.8,60.7,53.2,21.5,21.5,14.3,14.0.HRMS(ESI)m/z calcd for C21H25NNaO4S[M+Na]+410.1402；found 410.1404.
2-(((4-甲基苯基)磺酰氨基)(对甲苯基)甲基)丁-2-烯酸乙酯(3ia)
收率83％；mp 92-94℃.E:Z＝78:22；1H NMR(400MHz,CDCl3)major isomerδ7.67(d,J＝8.0Hz,2H),7.21(d,J＝8.0Hz,2H),7.14(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),6.83(q,J＝7.2Hz,1H),6.33(d,J＝10.4Hz,1H),5.56(d,J＝10.4Hz,1H),4.07-3.94(m,2H),2.40(s,3H),2.29(s,3H),1.81(d,J＝7.2Hz,3H),1.14(t,J＝7.2Hz,3H)；minorisomerδ7.67(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),7.08-7.02(m,4H),6.09(q,J＝7.2Hz,1H),5.76(d,J＝9.2Hz,1H),5.12(d,J＝9.6Hz,1H),4.07-3.94(m,2H),2.40(s,3H),2.29(s,3H),1.81(d,J＝7.2Hz,3H),1.09(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)majorisomerδ166.0,143.1,140.4,138.3,136.9,136.1,131.3,129.3,129.1,127.0,125.8,60.7,53.1,21.5,21.0,14.3,14.0.HRMS(ESI)m/z calcd for C21H25NNaO4S[M+Na]+410.1402；found 410.1395.
2-((4-甲氧基苯基)((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸乙酯(3ja).
收率85％；mp 105-107℃.E:Z>95:5；1H NMR(400MHz,CDCl3)major isomerδ7.66(d,J＝8.4Hz,2H),7.21(d,J＝8.0Hz,2H),7.17(d,J＝8.8Hz,2H),6.82(q,J＝7.2Hz,1H),6.78(d,J＝8.8Hz,2H),6.34(d,J＝10.4Hz,1H),5.54(d,J＝10.4Hz,1H),4.07-4.00(m,2H),3.76(s,3H),2.40(s,3H),1.80(d,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.0,158.8,143.1,140.4,138.2,131.2,131.1,129.3,127.1,127.0,113.8,60.7,55.2,52.8,21.5,14.2,14.0.HRMS(ESI)m/z calcd forC21H25NNaO5S[M+Na]+426.1351；found 426.1352.
2-((3,4-二甲氧基苯基)((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸乙酯(3ka).
收率87％；mp 80-82℃.E:Z＝80:20；1H NMR(400MHz,CDCl3)major isomerδ7.67(d,J＝8.4Hz,2H),7.22(d,J＝8.0Hz,2H),6.86(s,1H),6.85(q,J＝7.2Hz,1H),6.73-6.66(m,2H),6.36(d,J＝10.4Hz,1H),5.54(d,J＝10.0Hz,1H),4.10-3.97(m,2H),3.83(s,3H),3.79(s,3H),2.40(s,3H),1.82(d,J＝7.2Hz,3H),1.16(t,J＝7.2Hz,3H)；minor isomerδ7.67(d,J＝8.4Hz,2H),7.22(d,J＝8.0Hz,2H),6.86(s,1H),6.73-6.66(m,2H),6.08(q,J＝7.2Hz,1H),5.73(d,J＝9.2Hz,1H),5.11(d,J＝9.2Hz,1H),4.11-3.97(m,2H),3.83(s,3H),3.76(s,3H),2.40(s,3H),1.82(d,J＝7.2Hz,3H),1.12(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.1,149.0,148.3,143.1,140.5,138.3,131.6,129.3,127.0,117.9,110.8,109.4,60.8,55.9,55.8,53.1,21.5,14.2,14.1.HRMS(ESI)m/z calcd forC22H27NNaO6S[M+Na]+456.1457；found 456.1444.
2-(苯并[d][1,3]二氧杂环戊烯-5-基((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸乙酯(3la).
收率79％；mp 130-132℃.E:Z＝78:22；1H NMR(400MHz,CDCl3)major isomerδ7.66(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),6.83(q,J＝7.2Hz,1H),6.77(s,1H),6.73-6.66(m,2H),6.34(d,J＝10.4Hz,1H),5.91(s,2H),5.49(d,J＝10.4Hz,1H),4.10-3.97(m,2H),2.40(s,3H),1.80(d,J＝7.2Hz,3H),1.17(t,J＝7.2Hz,3H)；minor isomerδ7.66(d,J＝8.0Hz,2H),7.25(d,J＝8.4Hz,2H),6.72(s,1H),6.66(d,J＝7.6Hz,2H),6.06(q,J＝7.2Hz,1H),5.91(s,2H),5.74(d,J＝9.6Hz,1H),5.05(d,J＝9.2Hz,1H),4.10-3.97(m,2H),2.41(s,3H),1.81(d,J＝7.2Hz,3H),1.13(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)majorisomerδ166.0,147.9,146.8,143.2,140.5 138.2,133.0,131.2,129.3,127.0,119.2,108.0,106.8,101.1,60.8,53.1,21.5,14.2,14.0.HRMS(ESI)m/z calcd for C21H23NNaO6S[M+Na]+440.1144；found 440.1155.
2-([1,1'-联苯基]-4-基((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸乙酯(3ma)
收率85％；mp 124-126℃.E:Z＝75:25；1H NMR(400MHz,CDCl3)major isomerδ7.69(d,J＝8.0Hz,2H),7.53(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,2H),7.41(t,J＝7.6Hz,2H),7.34-7.31(m,2H),7.25(s,1H),7.20(d,J＝8.4Hz,2H),6.89(q,J＝7.2Hz,1H),6.39(d,J＝10.4Hz,1H),5.64(d,J＝10.4Hz,1H),4.08-4.00(m,2H),2.39(s,3H),1.85(d,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H)；minor isomerδ7.69(d,J＝8.0Hz,2H),7.53(d,J＝8.0Hz,2H),7.46(d,J＝8.0Hz,2H),7.41(t,J＝7.6Hz,2H),7.34-7.31(m,2H),7.24(d,J＝8.4Hz,2H),6.13(q,J＝7.2Hz,1H),5.85(d,J＝9.6Hz,1H),5.20(d,J＝9.2Hz,1H),4.08-4.00(m,2H),2.39(s,3H),1.85(d,J＝7.2Hz,3H),1.11(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)majorisomerδ166.0,143.2,140.7,140.6,140.2,138.2,138.1,131.1,129.3,128.7,127.3,127.1,127.0,127.0,126.3,60.8,53.1,21.5,14.4,14.0.HRMS(ESI)m/z calcd forC26H27NNaO4S[M+Na]+472.1558；found 472.1546.
2-(((4-甲基苯基)磺酰氨基)(萘-2-基)甲基)丁-2-烯酸乙酯(3na).
收率86％；mp 76-78℃.E:Z＝67:33；1H NMR(400MHz,CDCl3)major isomerδ7.78-7.67(m,5H),7.65(s,1H),7.45-7.41(m,2H),7.37(d,J＝7.6Hz,1H),7.18(d,J＝8.0Hz,2H),6.91(q,J＝7.2Hz,1H),6.49(d,J＝10.0Hz,1H),5.75(d,J＝9.6Hz,1H),4.07-3.94(m,2H),2.35(s,3H),1.88(d,J＝7.6Hz,3H),1.12(t,J＝7.2Hz,3H)；minor isomerδ7.78-7.67(m,5H),7.61(s,1H),7.45-7.41(m,2H),7.29(d,J＝8.4Hz,1H),7.18(d,J＝8.0Hz,2H),6.91(q,J＝7.2Hz,1H),5.92(d,J＝9.2Hz,1H),5.32(d,J＝9.6Hz,1H),4.07-3.94(m,2H),2.35(s,3H),1.86(d,J＝7.6Hz,3H),1.06(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)majorisomerδ166.0,143.2,140.8,138.2,136.4,133.1,132.6,131.1,129.3,128.2,128.0,127.5,127.0,126.1,125.9,124.7,124.1,60.8,53.5,21.5,14.4,14.0.HRMS(ESI)m/zcalcd for C24H25NNaO4S[M+Na]+446.1402；found 446.1391.
2-(蒽-9-基((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸乙酯(3oa).
收率42％；mp 80-82℃.E:Z＝87:13；1H NMR(400MHz,CDCl3)major isomerδ8.23(s,1H),8.06(d,J＝8.0Hz,2H),7.87(d,J＝8.0Hz,2H),7.44-7.38(m,4H),6.89(d,J＝8.0Hz,2H),6.73(d,J＝8.8Hz,1H),6.47(d,J＝8.0Hz,2H),6.21(q,J＝7.2Hz,1H),5.58(d,J＝8.0Hz,1H),4.11-3.92(m,2H),2.11(s,3H),1.91(d,J＝7.2Hz,3H),0.98(t,J＝7.2Hz,3H)；minor isomerδ8.32(d,J＝8.4Hz,2H),8.26(d,J＝8.4Hz,2H),7.88-7.85(m,2H),7.44-7.38(m,4H),7.08(d,J＝8.0Hz,2H),6.93(d,J＝8.8Hz,1H),6.86-6.79(m,1H),6.63-6.60(m,3H),4.11-3.92(m,2H)2.16(s,3H),1.56(d,J＝7.6Hz,3H),1.05(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.9,142.3,136.2,134.7,133.9,131.3,129.3,128.6,128.5,128.4,126.5,126.2,124.8,123.8,60.7,54.2,21.2,15.2,13.8.HRMS(ESI)m/z calcd for C28H27NNaO4S[M+Na]+496.1558；found 496.1556.
2-(呋喃-2-基((4-甲基苯基)磺酰氨基)乙基)丁-2-烯酸甲酯(3pa).
收率67％；mp 75-77℃.E:Z＝63:37；1H NMR(400MHz,CDCl3)major isomerδ7.68(d,J＝8.0Hz,2H),7.25-7.21(m,3H),6.86(q,J＝7.2Hz,1H),6.35(d,J＝10.4Hz,1H),6.23-6.20(m,1H),6.10(dd,J＝12.4,Hz,J＝3.2Hz,1H),5.61(d,J＝10.0Hz,1H),4.17-4.01(m,2H),2.40(s,3H),1.86(d,J＝7.2Hz,3H),1.19(t,J＝7.2Hz,3H)；minor isomerδ7.68(d,J＝8.0Hz,2H),7.25-7.21(m,3H),6.23-6.21(m,1H),6.17(q,J＝7.2Hz,1H),6.07(dd,J＝12.4,Hz,J＝3.2Hz,1H),5.80(d,J＝9.6Hz,1H),5.20(d,J＝9.6Hz,1H),4.17-4.10(m,2H),2.40(s,3H),1.86(d,J＝7.2Hz,3H),1.18(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ165.8,152.0,143.2,141.8,141.3,138.1,129.4,129.3,127.0,110.5,106.6,60.8,48.9,21.5,14.2,14.0.HRMS(ESI)m/z calcd for C18H21NNaO5S[M+Na]+386.1038；found 386.1013.
2-(((4-甲基苯基)磺酰氨基)(噻吩-2-基)甲基)丁-2-烯酸甲酯(3qa).
收率76％；mp 76-78℃.E:Z＝71:29；1H NMR(400MHz,CDCl3)major isomerδ7.69(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.14(d,J＝4.8Hz,1H),6.88-6.82(m,2H),6.76(s,1H),6.49(d,J＝10.4Hz,1H),5.73(d,J＝10.4Hz,1H),4.15-4.00(m,2H),2.40(s,3H),1.86(d,J＝7.2Hz,3H),1.17(t,J＝7.2Hz,3H)；minor isomerδ7.70(d,J＝8.0Hz,2H),7.25(d,J＝8.0Hz,2H),7.14(d,J＝4.8Hz,1H),6.88-6.82(m,1H),6.77(s,1H),6.17(q,J＝7.2Hz,1H),6.02(d,J＝9.6Hz,1H),5.29(d,J＝10.0Hz,1H),4.15-4.00(m,2H),2.40(s,3H),1.86(d,J＝7.2Hz,3H),1.14(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ165.8,143.8,143.3,140.7,138.0,131.0,129.4,127.1,126.9,125.0,124.1,60.9,50.7,21.5,14.1,14.0.HRMS(ESI)m/z calcd for C18H21NNaO4S2[M+Na]+402.0810；found402.0797.
(4E)-2-亚乙基-3-((4-甲基苯基)磺酰氨基)-5-苯基戊-4-烯酸乙酯(3ra).
收率83％；mp 77-79℃.E:Z>95:5；1H NMR(400MHz,CDCl3)major isomerδ7.68(d,J＝8.0Hz,2H),7.27-7.18(m,7H),6.79(q,J＝7.2Hz,1H),6.31(d,J＝16.0Hz,1H),6.09-6.00(m,2H),5.10(dd,J＝10.0Hz,J＝6.4Hz,1H),4.14-4.04(m,2H),2.33(s,3H),1.85(d,J＝7.2Hz,3H),1.23(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.0,143.2,140.0,138.3,136.2,131.3,130.8,129.4,128.4,127.8,127.1,127.1,126.5,60.8,52.9,21.4,14.1.HRMS(ESI)m/z calcd for C22H25NNaO4S[M+Na]+422.1402；found 422.1389.
2-亚乙基-3-((4-甲基苯基)磺酰氨基)-5-苯基戊酸乙酯(3sa).
收率42％；mp 61-63℃.E:Z>95:5；1H NMR(400MHz,CDCl3)major isomerδ7.62(d,J＝8.0Hz,2H),7.28-7.24(m,2H),7.21-7.17(m,3H),7.13(d,J＝7.2Hz,2H),6.57(q,J＝7.2Hz,1H),5.90(d,J＝10.4Hz,1H),4.34-4.28(m,1H),4.05(q,J＝7.2Hz,1H),2.73-2.66(m,1H),2.62-2.55(m,1H),2.40(s,3H),2.18-2.09(m,1H),1.83-1.72(m,1H),1.53(d,J＝7.2Hz,3H),1.20(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.0,143.0,141.0,139.9,138.3,131.2,129.2,128.5,128.4,127.0,126.0,60.5,50.5,36.6,32.2,21.5,14.1,13.8.HRMS(ESI)m/z calcd for C22H27NNaO4S[M+Na]+424.1558；found424.1550.
2-(环己基((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸乙酯(3ta).
收率43％；mp 94-96℃.E:Z>95:5；1H NMR(400MHz,CDCl3)major isomerδ7.60(d,J＝8.0Hz,2H),7.19(d,J＝8.0Hz,2H),6.64(q,J＝7.2Hz,1H),5.84(d,J＝10.0Hz,1H),4.10-4.02(m,2H),3.96(t,J＝10.0Hz,1H),2.39(s,3H),2.17(d,J＝9.2Hz,1H),1.77-1.73(m,1H),1.67(d,J＝7.2Hz,3H),1.63-1.59(m,2H),1.44-1.41(m,1H),1.24(t,J＝7.2Hz,3H),0.96-0.86(m,1H),0.79-0.69(m,1H).13C NMR(100MHz,CDCl3)major isomerδ166.4,142.8,140.7,138.6,130.2,129.1,126.9,60.5,56.3,41.0,30.5,29.9,26.2,26.0,25.8,21.5,14.5,14.1.HRMS(ESI)m/z calcd for C20H29NNaO4S[M+Na]+402.1715；found402.1717.
2-亚乙基-4-甲基-3-((4-甲基苯基)磺酰氨基)戊酸乙酯(3ua).
收率39％；mp 79-81℃.E:Z>95:5；1H NMR(400MHz,CDCl3)major isomerδ7.61(d,J＝8.0Hz,2H),7.19(d,J＝8.0Hz,2H),6.64(q,J＝7.2Hz,1H),5.84(d,J＝10.0Hz,1H),4.06(q,J＝7.2Hz,1H),3.88(t,J＝10.0Hz,1H),2.39(s,3H),2.00-1.90(m,1H),1.69(d,J＝7.2Hz,3H),1.21(t,J＝7.2Hz,3H),1.05(d,J＝6.8Hz,3H),0.73(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.3,142.8,140.6,138.5,130.5,129.1,126.9,60.5,57.5,32.1,21.5,20.1,19.5,14.4,14.1.HRMS(ESI)m/z calcd for C17H25NNaO4S[M+Na]+362.1402；found 362.1401.
2-(((4-甲基苯基)磺酰氨基)(苯基)甲基)丁-2-烯酸甲酯(3bb).
收率85％；mp 99-101℃.E:Z＝92:8；1H NMR(400MHz,CDCl3)major isomerδ7.67(d,J＝8.0Hz,2H),7.28-7.21(m,7H),6.86(q,J＝7.2Hz,1H),6.32(d,J＝10.4Hz,1H),5.60(d,J＝10.4Hz,1H),3.57(s,3H),2.40(s,3H),1.83(d,J＝7.2Hz,3H)；minor isomerδ7.67(d,J＝8.0Hz,2H),7.28-7.21(m,7H),6.12(q,J＝7.2Hz,1H),5.76(d,J＝9.6Hz,1H),5.16(d,J＝9.6Hz,1H),3.55(s,3H),2.40(s,3H),1.83(d,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.4,143.2,140.9,139.0,138.2,131.1,129.3,128.4,127.3,127.0,125.8,53.2,51.8,21.5,14.3.HRMS(ESI)m/z calcd for C19H21NNaO4S[M+Na]+382.1089；found 382.1117.
2-((4-溴苯基)((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸甲酯(3cb).
收率85％；mp 114-116℃.E:Z＝86:14；1H NMR(400MHz,CDCl3)major isomerδ7.66(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,2H),7.22(d,J＝8.0Hz,2H),7.12(d,J＝8.0Hz,2H),6.87(q,J＝7.2Hz,1H),6.31(d,J＝10.4Hz,1H),5.53(d,J＝10.4Hz,1H),3.58(s,3H),2.41(s,3H),1.82(d,3H)；minor isomerδ7.66(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,2H),7.25(d,J＝8.0Hz,2H),7.08(d,J＝8.4Hz,2H),6.10(q,J＝7.2Hz,1H),5.84(d,J＝9.6Hz,1H),5.09(d,J＝9.6Hz,1H),3.57(s,3H),2.41(s,3H),1.82(d,3H).13C NMR(100MHz,CDCl3)major isomerδ166.2,143.4,141.3,138.1,138.0,131.5,130.7,129.4,127.7,126.9,121.4,52.8,51.9,21.5,14.4.HRMS(ESI)m/z calcd for C19H20BrNNaO4S[M+Na]+460.0194；found 460.0186.
2-((4-氟苯基)((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸甲酯(3db)
收率82％；mp 106-108℃.E:Z＝85:15；1H NMR(400MHz,CDCl3)major isomerδ7.66(d,J＝8.0Hz,2H),7.23-7.20(m,4H),5.96-5.91(m,2H),6.87(q,J＝7.2Hz,1H),6.32(d,J＝10.0Hz,1H),5.56(d,J＝10.0Hz,1H),3.58(s,3H),2.41(s,3H),1.82(d,J＝7.2Hz,3H)；minor isomerδ7.66(d,J＝8.0Hz,2H),7.37(d,J＝8.4Hz,1H),7.20-7.16(m,2H),7.12(d,J＝8.0Hz,1H),6.96-6.91(m,2H),6.09(q,J＝7.2Hz,1H),5.80(d,J＝9.2Hz,1H),5.12(d,J＝9.6Hz,1H),3.57(s,3H),2.41(s,3H),1.82(d,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.4,162.3(J＝244.3Hz),143.3,141.0,138.1,134.8(J＝3.6Hz),130.9,129.4,127.7(J＝8.0Hz),127.0,115.2(J＝21.9Hz),52.7,51.9,21.5,14.3.HRMS(ESI)m/zcalcd for C19H20FNNaO4S[M+Na]+400.0995；found 400.0973.
2-(((4-甲基苯基)磺酰氨基)(对甲苯基)甲基)丁-2-烯酸甲酯(3eb).
收率81％；mp 133-135℃.E:Z＝85:15；1H NMR(400MHz,CDCl3)major isomerδ7.67(d,J＝8.4Hz,2H),7.21(d,J＝8.0Hz,2H),7.13(d,J＝8.0Hz,2H),7.06(d,J＝8.4Hz,2H),6.84(q,J＝7.2Hz,1H),6.29(d,J＝10.4Hz,1H),5.56(d,J＝10.4Hz,1H),3.57(s,3H),2.40(s,3H),2.29(s,3H),1.82(d,J＝7.2Hz,3H)；minor isomerδ7.67(d,J＝8.4Hz,2H),7.24(d,J＝8.0Hz,2H),7.13(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),6.12(q,J＝7.2Hz,1H),5.70(d,J＝9.2Hz,1H),5.16(d,J＝9.2Hz,1H),3.57(s,3H),2.40(s,3H),2.29(s,3H),1.82(d,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.4,143.1,140.7,138.3,137.0,136.0,131.2,129.3,129.2,127.0,125.8,53.0,51.8,21.5,21.0,14.3.HRMS(ESI)m/z calcd for C20H23NNaO4S[M+Na]+396.1245；found 396.1228.
2-((4-甲氧基苯基)((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸甲酯(3fb)
收率89％；mp 124-126℃.E:Z>95:5；1H NMR(400MHz,CDCl3)major isomerδ7.66(d,J＝8.0Hz,2H),7.21(d,J＝8.0Hz,2H),7.16(d,J＝8.4Hz,2H),6.83(q,J＝7.2Hz,1H),6.78(d,J＝8.8Hz,2H),6.30(d,J＝10.4Hz,1H),5.54(d,J＝10.4Hz,1H),3.76(s,3H),3.57(s,3H),2.40(s,3H),1.81(d,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.5,158.8,143.1,140.6,138.2,131.1,131.0,129.3,127.1,127.0,113.8,55.3,52.8,51.8,21.5,14.3.HRMS(ESI)m/z calcd for C20H23NNaO5S[M+Na]+412.1195；found 412.1203.
2-((3,4-二甲氧基苯基)((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸甲酯(3gb).
收率93％；mp 103-105℃.E:Z＝86:14；1H NMR(400MHz,CDCl3)major isomerδ7.67(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),6.85(q,J＝7.2Hz,1H),6.85(s,1H),6.72(d,J＝8.4Hz,1H),6.67(d,J＝8.4Hz,1H),6.34(d,J＝10.0Hz,1H),5.55(d,J＝10.4Hz,1H),3.83(s,3H),3.79(s,3H),3.59(s,3H),2.40(s,3H),1.82(d,J＝7.2Hz,3H)；minor isomerδ7.67(d,J＝8.0Hz,2H),7.24(d,J＝8.0Hz,2H),6.73-6.65(m,3H),6.11(q,J＝7.2Hz,1H),5.72(d,J＝9.2Hz,1H),5.12(d,J＝9.2Hz,1H),3.83(s,3H),3.76(s,3H),3.59(s,3H),2.40(s,3H),1.82(d,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ166.6,149.0,148.3,143.2,140.8,138.2,131.5,131.0,129.3,127.0,117.8,110.8,109.4,55.9,55.8,53.0,51.8,21.5,14.3.HRMS(ESI)m/z calcd for C21H25NNaO6S[M+Na]+442.1300；found 442.1300.
2-([1,1'-联苯基]-4-基((4-甲基苯基)磺酰氨基)甲基)丁-2-烯酸甲酯(3hb).
收率88％；mp 152-154℃.E:Z＝87:13；1H NMR(400MHz,CDCl3)major isomerδ7.69(d,J＝8.0Hz,2H),7.53(d,J＝7.6Hz,2H),7.48(d,J＝8.4Hz,2H),7.42(t,J＝7.6Hz,2H),7.35-7.26(m,3H),7.22(d,J＝8.0Hz,2H),6.89(q,J＝7.2Hz,1H),6.37(d,J＝9.6Hz,1H),5.64(d,J＝10.0Hz,1H),3.59(s,3H),2.40(s,3H),1.86(d,J＝7.2Hz,3H)；minor isomerδ7.69(d,J＝8.0Hz,2H),7.53(d,J＝7.6Hz,2H),7.46(d,J＝8.4Hz,2H),7.42(t,J＝7.6Hz,2H),7.35-7.26(m,3H),7.23(d,J＝8.0Hz,2H),6.16(q,J＝7.2Hz,1H),5.82(d,J＝9.2Hz,1H),5.20(d,J＝9.6Hz,1H),3.60(s,3H),2.40(s,3H),1.85(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)major isomerδ166.4,143.2,141.0,140.6,140.3,138.2,138.0,131.0,129.3,128.7,127.3,127.3,127.0,127.0,126.3,53.1,51.9,21.5,14.4.HRMS(ESI)m/zcalcd for C25H25NNaO4S[M+Na]+458.1402；found 458.1393.

Claims (4)

1.一种氮杂β-取代Morita-Baylis-Hillman型化合物的合成方法，其特征在于，包括：
S1：于有机溶剂中，在回流搅拌和锌存在的条件下使下式1所示化合物与下式2所示化合物反应一段时间；
Figure FDA0003051030920000011
其中，R1为苯基，2-甲基苯基，3-甲基苯基，4-甲基苯基，2-溴苯基，3-溴苯基，4-溴苯基，4-氟苯基，4-三氟甲基苯基，4-甲氧基苯基，3，4-二甲氧基苯基，3，4-二氧亚甲基苯基，4-苯基苯基，呋喃基，噻吩基，萘基，蒽基，苯乙基，苯乙烯基，环己基或丙基；
R2为乙基或甲基；
S2：将反应温度降至室温，将DBU加入反应混合物中，一段时间后，萃取，干燥，减压蒸除溶剂，通过硅胶柱色谱法纯化残余物，得下式3所示氮杂β-取代MBH型化合物
Figure FDA0003051030920000012
2.根据权利要求1所述的合成方法，其特征在于：所述化合物1与化合物2的摩尔比为1:1.1。
3.根据权利要求1所述的合成方法，其特征在于：所述有机溶剂为四氢呋喃。
4.根据权利要求1所述的合成方法，其特征在于：所述反应温度为有机溶剂回流温度。
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Publication number Priority date Publication date Assignee Title
CN105541582A (zh) * 2016-01-07 2016-05-04 浙江大学 α,β-不饱和酮与烯丙基醋酸酯的MBH反应

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CN105541582A (zh) * 2016-01-07 2016-05-04 浙江大学 α,β-不饱和酮与烯丙基醋酸酯的MBH反应

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Aza-Baylis-Hillman reaction of N-tosylated imines with β-substituted α,β-unsaturated esters;Yong-Ling Shi和Min Shi;《Tetrahedron》;20051005;第62卷(第2-3期);461-475页 *
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