辜玲慧, 田 雯, 何 菱
(四川大学 华西药学院,四川 成都 610041)
·快递论文·
铜盐催化β-双羰基化合物α-位氮宾转移反应
辜玲慧, 田雯, 何菱*
(四川大学 华西药学院,四川 成都610041)
摘要:以对氯苯磺酰胺为氮源,PhI(OAc)2为氧化剂,Cu(CF3SO3)2为催化剂,β-双羰基衍生物为底物,于35 ℃用“一锅法”合成了6个α-氨基-β-双羰基化合物(3a~3f, 3b~3f为新化合物),其结构经1H NMR,13C NMR和HR-ESI-MS表征。
关键词:对氯苯磺酰胺; α-氨基-β-双羰基化合物; 铜盐催化; 氮宾转移反应
α-氨基-β-双羰基化合物是一种常用的结构模块,可用于合成杂环化合物[1],模拟肽[2],α-氨基酸[3]和β-羟基α-氨基酯[4]化合物。此外,该结构模块在某些天然产物[5]和药物分子[6]的合成中也有较关键的作用。氨基酸和生物活性肽均具有良好的生物活性,如免疫调节、抗血栓、抗高血压、降胆固醇、抑制细菌、病毒和抗癌作用,抗氧化作用等[7]。
目前,合成α-氨基-β-双羰基化合物的方法主要有:强碱介导的酮亚胺衍生物酰化反应[8],特定底物的N—C酰基迁移反应[9],α-肟[10]和苯偶氮β-双羰基化合物[11]还原反应,噁唑-4-羧酸衍生物水解反应[12],金属碳烯N-H插入反应[13]及高氯酸锌催化β-双羰基化合物反应[14]。以上方法的缺点主要在于:需使用强碱,底物局限性大和反应步骤繁杂等。
本文以对氯苯磺酰胺(2)为氮源,PhI(OAc)2为氧化剂,Cu(CF3SO3)2为催化剂,β-双羰基衍生物(1a~1f)为底物,于35 ℃用“一锅法”合成了6个α-氨基-β-双羰基化合物(3a~3f, 3b~3f为新化合物),其结构经1H NMR,13C NMR和HR-ESI-MS表征。该方法具有反应条件温和,不需使用强碱,操作简单等优点。
Scheme 1
1实验部分
1.1仪器与试剂
Varian Mercury 400 MHz型核磁共振仪(CDCl3为溶剂,TMS为内标);Bio ToF-Q型高分辨质谱仪。
所用试剂均为分析纯。
1.23a~3f的合成通法
氮气保护下,在干燥的反应瓶中依次加入1a~1f 1 mmol, 2 1.5 mmol, PhI(OAc)21.5 mmol, Cu(CF3SO3)20.2 mmol, 分子筛0.2 mmol和干燥CH2Cl230 mL,搅拌下于35 ℃反应完全(TLC监测)。浓缩,残余物经硅胶柱层析[洗脱剂:V(石油醚) ∶V(乙酸乙酯)=10 ∶1]纯化得白色固体3a和淡黄色油状液体3b~3f。
3a: m.p.348~350 ℃;1H NMRδ: 7.81(d,J=8.8 Hz, 2H, ArH), 7.49(d,J=8.8 Hz, 2H, ArH), 5.67(d,J=8.4 Hz, 1H, NH), 4.67(d,J=8.4 Hz, 1H, CH), 4.18~4.11(m, 4H, OCH2), 1.25~1.19(m, 6H, CH3);13C NMRδ: 165.4, 139.5, 138.1, 129.3, 128.7, 62.9, 58.7, 13.8; HR-ESI-MSm/z: Calcd for C13H16NO6SClNa{[M+Na]+}372.028 5, found 372.029 7。
3b:1H NMRδ: 7.77(d,J=8.4 Hz, 2H, ArH), 7.41(d,J=8.4 Hz, 2H, ArH), 7.36~7.34 (m, 3H, ArH), 7.26~7.24(m, 2H, ArH), 5.99(s, 1H, NH), 5.10(s, 2H, OCH2), 4.77(s, 1H, CH), 3.65(s, 3H, CH3);13C NMRδ: 165.8, 165.3, 139.5, 137.9, 134.3, 129.3, 128.7, 128.6, 128.2, 68.4, 58.6, 53.6; HR-ESI-MSm/z: Calcd for C17H16NO6SClNa{[M+Na]+}420.028 5, found 420.029 8。
3c:1H NMRδ: 7.76(d,J=8.4 Hz, 2H, ArH), 7.46(d,J=8.4 Hz, 2H, ArH), 7.33~7.23(m, 3H, ArH), 7.17~7.15(m, 2H, ArH), 5.67(d,J=8.4 Hz, 1H, NH), 4.68(d,J=8.4 Hz, 1H, CH), 4.33~4.26(m, 2H, OCH2), 3.63(s, 3H, CH3), 2.91~2.88(m, 2H, a-H);13C NMRδ: 165.7, 165.2, 139.7, 137.8, 136.8, 129.4, 128.8, 128.7, 128.6, 126.8, 67.2, 58.4, 53.5, 34.6; HR-ESI-MSm/z: Calcd for C18H18NO6SClNa{[M+Na]+}434.044 1, found 434.044 2。
3d:1H NMRδ: 7.76(d,J=8.4 Hz, 2H, ArH), 7.42(d,J=8.4 Hz, 2H, ArH), 7.37~7.35(m, 2H, ArH), 7.31~7.27(m, 2H, ArH), 7.21~7.20(m, 3H, ArH), 6.96~6.94(d,J=6.4 Hz, 3H, ArH), 6.20(s, 1H, NH), 5.19~5.06(m, 2H, OCH2), 4.80~4.75(m, 1H, a-H), 4.63(d,J=5.2 Hz, 1H, CH), 3.56(s, 3H, CH3), 3.14~3.01(m, 2H, b-H);13C NMRδ: 170.4, 166.8, 162.9, 139.6, 137.6, 134.9, 134.7, 129.4, 129.2, 128.7, 128.6, 128.5, 127.3, 127.2, 67.6, 67.5, 58.9, 53.6, 37.3; HR-ESI-MSm/z: Calcd for C26H25N2O7SClNa{[M+Na]+}567.096 9 , found 567.098 6。
3e:1H NMRδ: 7.78(dd,J=8.8 Hz,J=3.2 Hz, 2H, ArH), 7.48(dd,J=8.4 Hz,J=2.0 Hz, 2H, ArH), 7.30~7.26(m, 3H, ArH), 7.10~7.02(m, 2H, ArH), 5.92(s, 1H, NH), 4.77~4.70(m, 1H, a-H), 4.57(s, 1H, CH), 3.75(s, 6H, CH3,CH3), 3.19~3.10(m, 2H, b-H);13C NMRδ: 170.9, 166.8, 162.8, 139.7, 137.6, 135.0, 129.4, 129.3, 129.2, 129.1, 128.7, 128.6, 127.3, 72.6, 72.4, 58.8, 53.6, 37.5; HR-ESI-MSm/z: Calcd for C20H21N2O7SClNa{[M+Na]+}491.065 6, found 491.063 7。
3f:1H NMRδ: 7.82(d,J=8.8 Hz, 2H, ArH), 7.50(d,J=8.4 Hz, 2H, ArH), 7.11(s, 1H, NH), 6.24(s, 1H, NH), 4.68(s, 1H, CH), 4.04~4.01(m, 2H, CH2), 3.76(s, 3H,CH3), 3.67(s, 3H, CH3);13C NMRδ: 169.4, 167.0, 164.0, 139.7, 137.5, 129.4, 128.6, 58.9, 53.5, 52.6, 41.5; HR-ESI-MSm/z: Calcd for C13H16N2O7SCl{[M+H]+}379.036 7, found 379.035 7。
2结果与讨论
2.1合成
以1a为底物,研究了催化剂,氧化剂和氮源对反应的影响。
(1) 催化剂
1a 1 mmol, PhI(OAc)21.5 mmol, 2 1.5 mmol, 分子筛0.2 mmol, 其余反应条件同1.2,研究催化剂对反应的影响,结果见表1。
表1 催化剂对3a收率的影响*
*1a 1 mmol, PhI(OAc)21.5 mmol, 2 1.5 mmol,分子筛0.2 mmol, 其余反应条件同1.2。
由表1可见,Rh2(O2CC7H15)4, Rh2(OAc)4和[Cu(MeCN)4]ClO4(Cat2~Cat4)对反应无催化作用,不能合成相应的胺化产物。Cu(CF3SO3)2(Cat1)催化性能最好,3a收率68%。
(2) 氧化剂
1a 1 mmol, Cu(CF3SO3)20.2 mmol, 2 1.5 mmol, 分子筛0.2 mmol, 其余反应条件同2.1(1),研究氧化剂对反应的影响,结果见表2。由表2可见,以 PhIO,4-methyl-PhIO,4-chloro-PhI(OAc)2, 4-methoxy- PhI(OAc)2(Oxi2~Oxi5)为氧化剂,3a收率均低于PhI(OAc)2(Oxi1, 68%)。
表2 氧化剂对3a收率的影响*
*1a 1 mmol, Cu(CF3SO3)20.2 mmol, 2 1.5 mmol,分子筛0.2 mmol, 其余反应条件同表1。
(3) 氮源
1a 1 mmol, PhI(OAc)21.5 mmol, Cu(CF3SO3)20.2 mmol, 分子筛0.2 mmol,其余反应条件同2.1(1),研究氮源对反应的影响,结果见表3。由表3可见,2为氮源,3a收率最高(68%)。
表3 氮源对3a收率的影响*
*1a 1 mmol, Cu(CF3SO3)20.2 mmol, PhI(OAc)21.5 mmol,分子筛0.2 mmol,其余反应条件同表1。
2.2底物拓展
以1b~1f替代1a,考察了反应条件的普适性。结果表明:反应条件具有较好的普适性,3b~3f收率26%~71%。
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Nitrene Transfer Reaction onα-H ofβ-dicarbonyl Compounds Catalyzed by Copper Salt
GU Ling-hui,TIAN Wen,HE Ling*
(West China School of Pharmacy, Sichuan University, Chengdu 610041, China)
Abstract:Six α-amino-β-dicarbonyl compounds(3a~3f, 3b~3f were novel compounds) were synthesized by “one-pot method” at 35 ℃, using chlorobenzene sulfonamide as nitrogen source, PhI(OAc)2 as oxidizing agent, Cu(CF3SO3)2 as catalyst and β-dicarbonyl compounds as substrate. The structures were characterized by1H NMR,13C NMR and HR-ESI-MS.
Keywords:p-chlorobenzene sulfonamide; α-amino-β-dicarbonyl compound; copper salt catalysis; nitrene transfer reaction
收稿日期:2015-04-22;
修订日期:2016-03-20
基金项目:国家自然科学基金资助项目(21072131)
作者简介:辜玲慧(1989-),女,汉族,四川仁寿人,博士研究生,主要从事药物化学的研究。 E-mail: 790369649@qq.com通信联系人: 何菱,教授,博士生导师, E-mail: lhe2001@sina.com
中图分类号:O625.75; O625.6
文献标志码:A
DOI:10.15952/j.cnki.cjsc.1005-1511.2016.05.15175