CN103664704B - 一种合成n,n’-二取代基脲的方法 - Google Patents
一种合成n,n’-二取代基脲的方法 Download PDFInfo
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Abstract
本发明公开了一种合成N,N’-二取代基脲的新方法,在反应容器中,加入N-取代基脲、金属铱、铑或钌络合物催化剂、碱、化合物醇和溶剂(或不加溶剂);反应混合物在90-130oC下反应数小时后,冷却到室温;旋转蒸发除去溶剂,然后通过柱分离,得到目标化合物。同现有技术相比,本发明从商品化或容易合成的N-取代基脲出发,通过和醇发生区域选择性烷基化反应,得到的N,N’-二取代基脲,反应展现出三个显著的优点:1)使用近于无毒的醇为烷基化试剂;2)反应只生成水为副产物,无环境危害;3)反应原子经济性高;因此,该反应符合绿色化学的要求,具有广阔的发展前景。
Description
技术领域
本发明属有机合成化学技术领域,具体涉及一种区域选择性N-烷基化反应合成N,N’-二取代基脲的方法。
背景技术
N,N’-二取代基脲一类非常重要的含氮化合物,有着非常广泛的药物活性。例如,它们作为瞬时受体电位香草酸亚型1(TRPV1)抗体、α7-烟碱乙酰胆碱受体抗体、丝裂原活化蛋白激酶抑制剂和可溶性环氧化物水解酶抑制剂等。((a)R.E.Kouhen,C.S.Surowy,B.R.Bianchi,T.R.Neelands,H.A.McDonald,W.Niforatos,A.Gomtsyan,C.H.Lee,P.Honore,J.P.Sullivan,M.F.Jarvis,C.R.Faltynek,J.Pharmacol.Exp.ther.2005,314,400-409;b)P.Honore,C.T.Wismer,J.Mikusa,C.Z.Zhu,C.Zhong,D.M.Gauvin,A.Gomtsyan,R.E.Kouhen,C.H.Lee,K.Marsh,J.P.Sullivan,C.R.Faltynek,M.F.Jarvis,J.Pharmacol.Exp.Ther.2005,314,410-421;c)P.N.Sidharta,P.L.M.VanGiersbergen,J.Dingemanse,J.Clin.Pharmacol.2009,49,1168-1175;d)D.S.Millan,M.E.Bunnage,J.L.Burrows,K.J.Butcher,P.G.Dodd,T.J.Evans,D.A.Fairman,S.J.Hughes,I.C.Kilty,A.Lemaitre,R.A.Lewthwaite,A.Mahnke,J.P.Mathias,J.Philip,R.T.Smith,M.H.Stefaniak,M.Yeadon,C.Phillips,J.Med.Chem.2011,54,7797-7814;e)I.Kim,H.Tsai,K.Nishi,T.Kasagami,C.Morisseau,B.D.Hammock,J.Med.Chem.2007,50,5217-5226.)
传统的方法合成N,N’-二取代基脲是通过胺和异氰酸酯反应。然而,异氰酸酯是一类剧毒、危险和不稳定的化合物。因此通过一些相对安全的原料在反应过程中通过重排反应生成异氰酸酯的方法已经发展起来,这些原料包括氨基甲酸酯、酰基叠氮化合物、羧酸化合物、酰基羟胺化合物、氨基甲酸化合物和乙酰乙酸苯胺化合物。((a)Y.Matsumura,Y.Satoh,O.Onomura,T.Maki,J.Org.Chem.2000,65,1549-1551;b)H.Lebel,O.Leogane,Org.Lett.2006,8,5717-5720;b)A.C.Donovan,J.F.Valliant,J.Org.Chem.2009,74,8133-8138;c)M.T.Migawa,E.E.Swayze,Org.Lett.2000,2,3309-3311;d)P.Dube,N.F.F.Nathel,M.Vetelino,M.Couturier,C.L.Aboussafy,S.Pichette,M.L.Jorgensen,M.Hardink,Org.Lett.2009,11,5622-5625;e)S.L.Peterson,S.M.Stucka,C.J.Dinsmore,Org.Lett.2010,12,1340-1343;f)Y.Wei,J.Liu,S.Lin,H.Ding,F.Liang,B.Zhao,Org.Lett.2010,12,4220-4223.)
尽管合成N,N’-二取代基脲的上述方法已经取得了进展,但是这些方法在反应过程中必然经过生成异氰酸酯的步骤,从安全的角度,反应还存在着隐患。而且上述方法生成大量的副产物,造成反应的原子经济性低。因此,发展一种更简单、安全、高原子经济性和环境友好的的方法来合成N,N’-二取代基脲有非常重要的意义。
发明内容
本发明的目的在于提供一种N,N’-二取代基脲的新方法。
本发明通过下述技术方案实现:一种合成N,N’-二取代基脲(式I)的新方法
其包含使N-取代基脲(式II)
与化合物醇(式III)反应
反应是在过渡金属催化剂和碱的存在下发生,其反应通式为
其中,R1选自C1-C4烷基、取代苄基、单或多取代芳基或芳基、单或多取代芳基优选甲基苯基、甲氧基苯基、甲巯基苯基、三氟甲氧基苯基或卤代苯基;
R2代表一个取代基,选自氢、C1-C7烷基、芳基、单或多取代芳基,单或多取代芳基优选甲基苯基、甲氧基苯基、三氟甲基、三氟甲氧基苯基或卤代苯基。
本发明合成N,N’-二取代基脲的新方法通过下述具体步骤实现:
在反应容器中,加入N-取代基脲、金属铱、铑或钌络合物催化剂、碱、化合物醇和溶剂(或不加溶剂);反应混合物在90-130℃下反应数小时后,冷却到室温;旋转蒸发除去溶剂,然后通过柱分离,得到目标化合物。
其中,金属铱、铑或钌络合物催化剂选自[Cp*IrCl2]2(Cp*=pentamethylcyclopentadienyl)、[Cp*RhCl2]2或[Ru(p-cymene)Cl2]2;碱选自氢氧化钠、氢氧化钾、碳酸钾、磷酸钾、叔丁醇钠或叔丁醇钾;金属铱、铑或钌络合物催化剂用量相对于N-取代基脲为0.1-0.4mol%;碱的摩尔量为N-取代基脲的摩尔量的0.1-0.4mol%;化合物醇的摩尔量为N-取代基脲摩尔量的1.2-4equiv.;溶剂选自叔戊醇、甲苯或二氧六环;反应温度为90-130℃;反应时间为2~12小时。
同现有技术相比,本发明从商品化或容易合成的N-取代基脲出发,通过和醇发生区域选择性烷基化反应,得到的N,N’-二取代基脲,反应展现出三个显著的优点:1)使用近于无毒的醇为烷基化试剂;2)反应只生成水为副产物,无环境危害;3)反应原子经济性高;因此,该反应符合绿色化学的要求,具有广阔的发展前景。
附图说明
图1是本发明实施例1合成产物的核磁氢谱图。
图2是本发明实施例1合成产物的核磁碳谱图。
图3是本发明实施例2合成产物的核磁氢谱图。
图4是本发明实施例2合成产物的核磁碳谱图。
具体实施方式
展示一下实例来说明本发明的某些实施例,且不应解释为限制本发明的范围。对本发明公开的内容可以同时从材料,方法和反应条件上进行许多改进,变化和改变。所有这些改进,变化和改变均确定地落入本发明的精神和范围之内。
实施例1:1-苄基-3-苯基脲
1-benzyl-3-phenylurea
将1-苯基脲(136mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%,市售)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:92%
1HNMR(500MHz,DMSO-d6)δ8.67(brs,1H,ArNH),7.40(d,J=7.8Hz,2H,ArH),7.33-7.29(m,4H,ArH),7.25-7.20(m,3H,ArH),6.88(t,J=7.1Hz,1H,ArH),6.73(brs,1H,AlkylNH),4.29(t,J=5.3Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.3,140.5,140.4,128.7,128.3,127.1,126.7,121.1,117.7,42.7.
实施例2:1-(4-甲基苄基)-3-苯基脲
1-(4-methylbenzyl)-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、4-甲基苄醇(146mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:82%
1HNMR(500MHz,DMSO-d6)δ8.67(brs,1H,ArNH),7.40(d,J=7.8Hz,2H,ArH),7.33-7.29(m,4H,ArH),7.25-7.20(m,3H,ArH),6.88(t,J=7.1Hz,1H,ArH),6.73(brs,1H,AlkylNH),4.29(t,J=5.3Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.3,140.5,140.4,128.7,128.3,127.1,126.7,121.1,117.7,42.7.
实施例3:1-(4-甲氧基苄基)-3-苯基脲
1-(4-methoxybenzyl)-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、4-甲氧基苄醇(166mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:90%
1HNMR(500MHz,CDCl3)δ7.27-7.23(m,4H,ArH),7.18(d,J=8.7Hz,2H,ArH),7.06-7.03(m,1H,ArH),6.81(d,J=8.6Hz,1H,ArH),6.73(brs,1H,ArNH),5.34(t,J=5.5Hz,1H,AlkylNH),4.29(d,J=5.6Hz,2H,CH2),3.76(s,3H,OCH3);13CNMR(125MHz,CDCl3)δ158.9,155.8,138.4,130.9,129.3,128.8,123.9,121.2,114.1,55.3,43.8.
实施例4:1-(3,4-二甲氧基苄基)-3-苯基脲
1-(3,4-dimethoxybenzyl)-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、3,4-二甲氧基苄醇(202mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:85%
1HNMR(500MHz,DMSO-d6)δ8.49(brs,1H,ArNH),7.39(d,J=7.9Hz,2H,ArH),7.22(t,J=7.7Hz,2H,ArH),6.91-6.87(m,3H,ArH),6.82(d,J=7.9Hz,1H,ArH),6.50(t,J=5.5Hz,1H,AlkylNH),4.21(d,J=5.5Hz,2H,CH2),3.74(s,3H,OCH3),3.72(s,3H,OCH3);13CNMR(125MHz,DMSO-d6)δ155.1,148.7,147.7,140.4,132.6,128.6,112.0,119.3,117.6,111.8,111.3,55.6,55.4,42.6.
实施例5:1-(4-三氟甲基苄基)-3-苯基脲
1-(4-(trifluoromethyl)benzyl)-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、4-三氟甲基苄醇(211mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:81%
mp169-170℃;1HNMR(500MHz,DMSO-d6)δ8.64(brs,1H,ArNH),7.70(s,2H,ArH),7.52-7.40(m,4H,ArH),7.22(s,2H,ArH),6.90(s,1H,ArH),6.73(brs,1H,AlkylNH),4.39(s,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.2,145.5,140.3,128.6,127.6,127.3(q,JC-F=31.4Hz),125.1(d,JC-F=3.5Hz),124.3(q,JC-F=264.8Hz),121.2,117.8,42.3;HRMS-EI(70eV)m/zcalcdforC15H13N2OF3Na[M+Na]+317.0878,found317.0876.
实施例6:1-(4-三氟甲基苄基)-3-苯基脲
1-(4-(trifluoromethoxy)benzyl)-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、4-三氟甲氧基苄醇(230mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:76%
1HNMR(500MHz,DMSO-d6)δ8.59(brs,1H,ArNH),7.43-7.39(m,4H,ArH),7.33(d,J=7.4Hz,2H,ArH),7.22(t,J=7.0Hz,2H,ArH),6.89(t,J=6.8Hz,1H,ArH),6.67(brs,1H,AkylNH),4.32(d,J=4.4Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.2,147.1,140.3,140.0,128.8,128.6,121.1,120.9,120.1(q,JC-F=254.4Hz),117.7,42.0;HRMS-EI(70eV)m/zcalcdforC15H13N2O2F3Na[M+Na]+333.0827,found333.0822.
实施例7:1-(2-氯苄基)-3-苯基脲
1-(2-chlorobenzyl)-3-phenylurea
将1-苯基脲(136mg,lmmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、2-氯苄醇(171mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:86%
1HNMR(500MHz,DMSO-d6)δ8.68(brs,1H,ArNH),7.45(d,J=7.4Hz,1H,ArH),7.40(d,J=7.6Hz,3H,ArH),7.34(t,J=7.3Hz,1H,ArH),7.29(t,J=7.5Hz,1H,ArH),7.22(t,J=7.9Hz,2H,ArH),6.90(t,J=7.3Hz,1H,ArH),6.67(t,J=6.0Hz,1H,AkylNH),4.37(d,J=5.8Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.1,140.3,137.3,132.0,129.0,128.8,128.6,128.5,127.1,121.1,117.7,40.7.
实施例8:1-(4-氯苄基)-3-苯基脲
1-(4-chlorobenzyl)-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、4-氯苄醇(171mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:82%
1HNMR(500MHz,DMSO-d6)δ8.60(brs,1H,ArNH),7.39(dd,J=8.3HzandJ=2.1Hz,4H,ArH),7.32(d,J=8.4Hz,2H,ArH),7.22(t,J=7.8Hz,2H,ArH),6.89(t,J=7.4Hz,1H,ArH),6.67(t,J=5.9Hz,lH,AkylNH),4.28(d,J=6.0Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.2,140.4,139.5,131.2,128.9,128.6,128.2,121.1,117.7,42.0.
实施例9:1-(4-溴苄基)-3-苯基脲
1-(4-bromobenzyl)-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、4-溴苄醇(224mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:84%
1HNMR(500MHz,DMSO-d6)δ8.86(brs,1H,ArNH),7.52-7.40(m,4H,ArH),7.27-7.21(m,4H,ArH),6.95(s,1H,ArH),6.88(brs,1H,AlkylNH),4.26(s,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.3,140.5,140.1,131.0,129.3,128.5,121.0,119.5,117.7,42.0;HRMS-EI(70eV)m/zcalcdforC14H14N2OBr[M+H]+305.0289,found305.0288.
实施例10:1-(2-萘甲基)-3-苯基脲
1-(naphthalen-2-ylmethyl)-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、2-萘甲醇(190mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:73%
1HNMR(500MHz,DMSO-d6)δ8.60(brs,1H,ArNH),7.89(d,J=7.4Hz,2H,ArH),7.79(s,1H,ArH),7.52-7.47(m,3H,ArH),7.42(d,J=7.5Hz,2H,ArH),7.22(t,J=7.5Hz,2H,ArH),6.90(t,J=7.3Hz,1H,ArH),6.72(t,J=5.5Hz,1H,AlkylNH),4.47(d,J=5.0Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.3,140.4,138.0,132.9,132.1,128.6,127.9,127.5,126.1,125.9,125.5,125.1,121.1,117.7,42.9.
实施例11:1-乙基-3-苯基脲
1-hexyl-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、(16mg,0.4mmol,0.4equiv.)和乙醇(184mg,4mmol)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:42%
1HNMR(500MHz,DMSO-d6);δ8.38(brs,1H,ArNH),7.37(d,J=7.9Hz,2H,ArH),7.20(t,J=8.0Hz,2H,ArH),6.87(t,J=7.4Hz,1H,ArH),6.07(brs,1H,CH2NH),3.10(quint,J=6.7Hz,5H,CH2),1.05(t,J=7.2Hz,3H,CH3);13CNMR(125MHz,DMSO-d6)δ155.1,140.6,128.6,120.9,117.6,33.9,15.4.
实施例12:1-己基-3-苯基脲
1-hexyl-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、(16mg,0.4mmol,0.4equiv.)和己醇(408mg,4mmol)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:75%
1HNMR(500MHz,DMSO-d6)δ8.36(brs,1H,ArNH),7.37(d,J=8.0Hz,2H,ArH),7.20(t,J=7.8Hz,2H,ArH),6.87(t,J=7.3Hz,1H,ArH),6.10(t,J=5.6Hz,1H,AlkylNH),3.06(quarter,J=6.6Hz,2H,CH2N),1.41(quint,J=6.9Hz,2H,CH2),1.30-1.27(m,6H,3xCH2),0.87(t,J=6.7Hz,3H,CH3);13CNMR(125MHz,DMSO-d6)δ155.2,140.6,128.6,120.8,117.5,39.0,31.0,29.7,26.0,22.1,13.9.
实施例13:1-辛基-3-苯基脲
1-octyl-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)和辛醇(520mg,4mmol)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去未反应的辛醇,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:83%
1HNMR(500MHz,DMSO-d6)δ8.43(brs,1H,ArNH),7.37(d,J=7.8Hz,2H,ArH),7.20(t,J=7.8Hz,2H,ArH),6.87(t,J=7.4Hz,1H,ArH),6.16(t,J=5.6Hz,1H,AlkylNH),3.05(quarter,J=6.5Hz,2H,CH2N),1.43-1.40(m,2H,CH2),1.27-1.24(m,10H,5xCH2),0.86(t,J=6.3Hz,3H,CH3);13CNMR(125MHz,DMSO-d6)δ155.2,140.6,128.6,120.8,117.5,39.0,31.3,29.8,28.8,28.7,26.4,22.1,13.9.
实施例14:1-异戊基-3-苯基脲
1-isopentyl-3-phenylurea
将1-苯基脲(136mg,1mmol、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)和异戊醇(352mg,4mmol)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去未反应的异戊醇,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:70%
1HNMR(500MHz,DMSO-d6)δ8.36(brs,1H,ArNH),7.37(d,J=7.9Hz,2H,ArH),7.20(t,J=7.8Hz,2H,ArH),6.87(t,J=7.4Hz,1H,ArH),6.07(t,J=5.5Hz,1H,AlkylNH),3.09(quarter,J=6.7Hz,2H,CH2N),1.60(heptet,J=6.7Hz,1H,CH),1.32(quarter,J=7.1Hz,2H,CH2),0.89(d,J=6.8Hz,6H,2xCH3);13CNMR(125MHz,DMSO-d6)δ155.2,140.6,128.6,120.8,117.5,38.8,37.2,25.1,22.4;HRMS-EI(70eV)m/zcalcdforC12H18N2ONa[M+Na]+229.1317,found229.1313.
实施例15:1-苄基-3-邻甲基苯基脲
1-benzyl-3-o-tolylurea
将1-(2-甲基苯基)脲(150mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:83%
1HNMR(500MHz,DMSO-d6)δ7.84(d,J=8.2Hz,1H,ArH),7.71(brs,1H,ArNH),7.36-7.31(m,4H,ArH),7.26(t,J=6.7Hz,1H,ArH),7.10(m,2H,ArH),6.99(t,J=6.0Hz,1H,AlkylNH),6.87(t,J=7.5Hz,1H,ArH),4.30(d,J=5.5Hz,2H,CH2),2.18(s,3H,CH3);13CNMR(125MHz,DMSO-d6)δ155.4,140.2,138.1,130.0,128.3,127.2,126.8,126.7,126.1,121.9,120.4,42.9,17.9.
实施例16:1-苄基-3-对甲基苯基脲
1-benzyl-3-p-tolylurea
将1-(4-甲基苯基)脲(150mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:87%
mp185-187℃(lit.mp184℃);1HNMR(500MHz,DMSO-d6)δ8.43(brs,1H,ArNH),7.34-7.37(m,6H,ArH),7.23(t,J=7.0Hz,1H,ArH),7.02(d,J=8.1Hz,2H,ArH),6.54(t,J=6.0Hz,1H,AlkylNH),4.28(d,J=5.9Hz,2H,CH2),2.21(s,3H,CH3);13CNMR(125MHz,DMSO-d6)δ155.3,140.4,137.9,129.8,129.1,128.3,127.1,126.7,117.8,42.8,20.3.
实施例17:1-苄基-3-(2-甲氧基苯基)脲
1-benzyl-3-(2-methoxyphenyl)urea
将1-(2-甲氧基苯基)脲(166mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:85%
1HNMR(500MHz,DMSO-d6)δ8.10(d,J=7.9Hz,1H,ArH),8.02(brs,1H,ArNH),7.35-7.29(m,5H,ArH),7.25(t,J=7.0Hz,1H,AlkylNH),6.96(d,J=7.8Hz,1H,ArH),6.89-6.82(m,2H,ArH),4.29(d,J=5.7Hz,2H,CH2),3.82(s,3H,OCH3);13CNMR(125MHz,DMSO-d6)δ155.2,147.3,140.2,129.4,128.3,127.2,126.7,121.0,120.4,118.0,110.6,55.6,42.7.
实施例18:1-苄基-3-(4-甲氧基苯基)脲
1-benzyl-3-(4-methoxyphenyl)urea
将1-(4-甲氧基苯基)脲(166mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:82%
1HNMR(500MHz,DMSO-d6)δ8.34(brs,1H,ArNH),7.33-7.22(m,7H,ArH),6.81(d,J=8.5Hz,2H,ArH),6.50(t,J=5.5Hz,1H,AlkylNH),4.28(d,J=5.2Hz,2H,CH2),2.50(s,3H,OCH3);13CNMR(125MHz,DMSO-d6)δ155.5,154.0,140.5,135.6,128.3,127.1,126.7,119.5,113.9,55.1,42.8.
实施例19:1-苄基-3-(4-甲巯基苯基)脲
1-benzyl-3-(4-(methylthio)phenyl)urea
将1-(2-甲氧基苯基)脲(182mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,l.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:83%
1HNMR(500MHz,DMSO-d6)δ8.65(brs,1H,ArNH),7.38(d,J=8.5Hz,2H,ArH),7.35-7.29(m,4H,ArH),7.24(t,J=7.2Hz,1H,ArH),7.17(d,J=8.6Hz,2H,ArH),6.68(t,J=5.9Hz,1H,AlkylNH),4.29(d,J=5.9Hz,2H,CH2),2.41(s,3H,SCH3);13CNMR(125MHz,DMSO-d6)δ155.2,140.3,138.4,128.9,128.3,128.0,127.1,126.7,118.5,42.7,16.2.
实施例20:1-苄基-3-(4-(三氟甲氧基)苯基)脲
1-benzyl-3-(4-(trifluoromethoxy)phenyl)urea
将1-(2-甲氧基苯基)脲(220mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:80%
1HNMR(500MHz,DMSO-d6)δ8.79(brs,1H,ArNH),7.51(s,2H,ArH),7.31-7.23(m,7H,ArH),6.69(s,1H,AlkylNH),4.30(s,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.0,142.0,140.1,139.7,128.2,127.1,126.7,121.5,120.1(q,JC-F=253.6Hz),118.7,42.7;HRMS-EI(70eV)m/zcalcdforC15H13N2O2F3Na[M+Na]+333.0827,found333.0834.
实施例21:1-苄基-3-(4-氟苯基)脲
1-benzyl-3-(4-fluorophenyl)urea
将1-(4-氟苯基)脲(154mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:92%
1HNMR(500MHz,DMSO-d6)δ8.59(brs,1H,ArNH),7.42-7.39(m,2H,ArH),7.35-7.29(m,4H,ArH),7.24(t,J=7.3Hz,1H,ArH),7.06(t,J=8.9Hz,1H,ArH),6.60(t,J=5.7Hz,1H,AlkylNH),4.29(d,J=5.9Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ156.9(d,JC-F=235.7Hz),155.3,140.3,136.8,128.3,127.1,126.7,119.3(d,JC-F=7.4Hz),115.1(d,JC-F=22.2Hz),42.7.
实施例22:1-苄基-3-(2-氯苯基)脲
1-benzyl-3-(2-chlorophenyl)urea
将1-(2-氯苯基)脲(170mg,1mmol)[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:76%
1HNMR(500MHz,DMSO-d6)δ8.16(d,J=8.4Hz,1H,ArH),8.12(brs,1H,ArNH),7.49(t,J=5.4Hz,1H,AlkylNH),7.40(d,J=8.2Hz,1H,ArH),7.36-7.31(m,4H,ArH),7.25(m,2H,ArH),6.95(t,J=7.7Hz,1H,ArH),4.31(d,J=5.2Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ154.8,139.8,136.7,129.1,128.4,127.4,127.3,126.9,122.5,121.2,120.8,42.9.
实施例23:1-苄基-3-(4-氯苯基)脲
1-benzyl-3-(4-chlorophenyl)urea
将1-(4-氯苯基)脲(170mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:84%
1HNMR(500MHz,DMSO-d6)δ8.71(brs,1H,ArNH),7.43(d,J=8.9Hz,2H,ArH),7.35-7.29(m,4H,ArH),7.27-7.23(m,3H,ArH),6.66(t,J=6.0Hz,1H,AlkylNH),4.29(d,J=6.0Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.1,140.2,139.4,128.4,128.3,127.1,126.7,124.5,119.2,42.7.
实施例24:1-苄基-3-(2-溴苯基)脲
1-benzyl-3-(2-bromophenyl)urea
将1-(2-溴苯基)脲(215mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:78%
1HNMR(500MHz,DMSO-d6)δ8.08(dd,J=8.3HzandJ=1.1Hz,1H,ArH),7.95(brs,1H,ArNH),7.56(dd,J=8.0HzandJ=1.3Hz,2H,ArH),7.37-7.25(m,6H,ArH,AlkylNH),6.90(td,J=7.6HzandJ=1.3Hz,1H,ArH),4.31(d,J=5.8Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ154.8,140.0,137.8,132.3,128.4,127.9,127.3,126.8,123.3,121.6,112.3,42.9;HRMS-EI(70eV)m/zcalcdforC14H13N2ONaBr[M+Na]+327.0109,found327.0105.
实施例25:1-苄基-3-(4-溴苯基)脲
1-benzyl-3-(4-bromophenyl)urea
将1-(4-溴苯基)脲(170mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:82%
1HNMR(500MHz,DMSO-d6)δ8.78(brs,1H,ArNH),7.38(s,4H,ArH),7.35-7.29(m,4H,ArH),7.24(t,J=7.2Hz,1H,ArH),6.73(t,J=5.4Hz,1H,AlkylNH),4.29(d,J=5.6Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.1,140.2,140.0,131.3,128.3,127.1,126.7,119.6,112.3,42.7.
实施例26:1-苄基-3-(2,4-二甲基苯基)脲
1-benzyl-3-(2,4-dimethylphenyl)urea
将1-(2,4-二甲基苯基)脲(164mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:80%
1HNMR(500MHz,DMSO-d6)δ7.65(s,1H,ArH),7.63(brs,1H,ArNH),7.36-7.30(m,4H,ArH),7.25(t,J=6.7Hz,1H,ArH),6.93(s,1H,ArH),6.90-6.86(m,2H,ArH,AlkylNH),4.29(d,J=5.6Hz,2H,CH2),2.20(s,3H,CH3),2.14(s,3H,CH3);13CNMR(125MHz,DMSO-d6)δ155.5,140.3,135.5,130.8,130.6,128.3,127.2,126.9,126.7,126.4,121.0,42.8,20.2,17.7.
实施例27:1-苄基-3-(4-氯-2-甲基苯基)脲
1-benzyl-3-(4-chloro-2-methylphenyl)urea
将1-(2-甲基-4-氯苯基)脲(170mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:81%
1HNMR(500MHz,DMSO-d6)δ7.91(s,1H,ArH),7.80(brs,1H,ArNH),7.33-7.06(m,7H,ArHandAlkylNH),4.30(s,2H,CH2),2.18(s,3H,CH3);13CNMR(125MHz,DMSO-d6)δ155.2,140.0,137.2,129.5,128.8,128.3,127.2,126.8,125.8,125.2,121.5,42.9,17.6;HRMS-EI(70eV)m/zcalcdforC15H15N2ONaCl[M+Na]+297.0771,found297.0767.
实施例28:1-苄基-3-(2-萘甲基)脲
1-benzyl-3-(naphthalen-1-yl)urea
将1-(1-萘基)脲(186mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:75%
1HNMR(500MHz,DMSO-d6)δ8.62(brs,1H,ArNH),8.85(d,J=8.9Hz,2H,ArH),8.02(d,J=8.0Hz,2H,ArH),7.90(d,J=8.0Hz,2H,ArH),7.57-7.50(m,3H,ArH),7.43(t,J=7.7Hz,1H,ArH),7.36-7.35(m,4H,ArH),7.28-7.25(m,1H,ArH),7.04(t,J=5.4Hz,1H,AlkylNH),4.37(d,J=5.5Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ155.7,140.2,135.1,133.7,128.4,127.2,127.0,126.8,125.9,125.7,125.6,125.4,122.1,121.4,116.5,43.0.
实施例29:1-苄基-3-甲基脲
1-benzyl-3-methylurea
将1-甲基脲(74mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:87%
1HNMR(500MHz,CDCl3)δ7.33-7.24(m,5H,ArH),4.87(brs,1H,AlkylNH),4.52(brs,1H,AlkylNH),4.35(d,J=5.8Hz,2H,CH2),2.74(d,J=4.8Hz,3H,CH3);13CNMR(125MHz,CDCl3)δ160.0,139.5,128.4,127.1,127.0,44.1,26.8.
实施例30:1-苄基-3-乙基脲
1-benzyl-3-ethylurea
将1-乙基脲(88mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:81%
1HNMR(500MHz,CDCl3)δ7.33-7.25(m,5H,ArH),4.79(brs,1H,AlkylNH),4.46(brs,1H,AlkylNH),4.34(d,J=5.5Hz,2H,CH2),3.18(quint,J=6.7Hz,2H,CH2),1.10(t,J=6.9Hz,3H,CH3);13CNMR(125MHz,CDCl3)δ158.8,139.5,128.4,127.2,127.0,44.1,35.0,15.4.
实施例31:1-苄基-3-丁基脲
1-benzyl-3-butylurea
将1-丁基脲(116mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:75%
1HNMR(500MHz,CDCl3)δ7.34-7.24(m,5H,ArH),4.76(s,1H,NH),4.44(s,1H,NH),4.35(d,J=5.7Hz,2H,CH2),3.15(q,J=6.5Hz,2H,CH2),1.47-1.42(m,2H,CH2),1.35-1.29(m,2H,CH2),0.9(t,J=7.4Hz,3H,CH3);13CNMR(125MHz,CDCl3)δ158.7,139.5,128.5,127.2,127.1,44.3,40.1,32.3,20.0,13.7.
实施例32:1-苄基-3-苯乙基脲
1-benzyl-3-phenethylurea
将1-苯乙基脲(164mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:90%
1HNMR(500MHz,CDCl3)δ7.32-7.20(m,8H,ArH),7.15(d,J=7.2Hz,2H,ArH),4.67(s,1H,ArCH2CH2NH),4.42(s,1H,AlkylNH),4.30(d,J=5.6Hz,2H,CH2),3.43(quarter,J=6.5Hz,2H,CH2N),2.78(t,J=6.9Hz,2H,CH2);13CNMR(125MHz,CDCl3)δ158.2,139.2,139.1,128.7,128.5,128.5,127.3,127.2,126.3,44.3.
实施例33:1-(4-氟苄基)-3-苄基脲
1-(4-fluorobenzyl)-3-benzylurea
将1-(4-氟苯基)脲(168mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:75%
1HNMR(500MHz,CDCl3)δ7.33-7.30(m,2H,ArH),7.26-7.25(m,3H,ArH),7.22-7.20(m,2H,ArH),6.98(t,J=8.6Hz,2H,ArH),4.73(s,2H,AlkylNH),4.35(d,J=5.7Hz,2H,CH2),4.32(d,J=5.8Hz,2H,CH2);13CNMR(125MHz,CDCl3)δ162.1(d,JC-F=244.7Hz),157.9,139.0,134.9,129.1(d,JC-F=7.8Hz),128.7,127.4,115.4(d,JC-F=21.2Hz),44.6,43.8;HRMS-EI(70eV)m/zcalcdforC15H15N2OFNa[M+Na]+281.1066,found281.1070.
实施例34:1-(2-氯苄基)-3-苄基脲
1-(2-chlorobenzyl)-3-benzylurea
将1-(2-氯苯基)脲(184mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:72%
1HNMR(500MHz,DMSO-d6)δ7.42(d,J=6.8Hz,1H,ArH),7.33-7.22(m,8H,ArH),6.59(brs,1H,AlkylNH),6.51(brs,1H,AlkylNH),4.30(d,J=5.0Hz,2H,CH2),4.23(d,J=4.6Hz,2H,CH2);13CNMR(125MHz,DMSO-d6)δ157.9,140.7,137.8,131.8,129.0,128.6,128.3,128.2,127.0,126.9,126.5,43.0,40.9.
实施例35:1-(2-氯苄基)-3-苄基脲
1-benzyl-3-(1-phenylethyl)urea
将1-(1-苯基乙基)脲(164mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:83%
1HNMR(500MHz,CDCl3)δ7.34-7.21(m,8H,ArH),7.16(d,J=7.3Hz,2H,ArH),4.79(quint,J=6.7Hz,1H,CH),4.68(d,J=6.1Hz,1H,AlkylNH),4.59(brs,1H,AlkylNH),4.36-4.27(m,2H,CH2),1.44(d,J=6.9Hz,3H,CH3);13CNMR(125MHz,CDCl3)δ157.7,144.2,139.2,128.6,128.5,127.2,127.1,127.0,125.8,50.1,44.2,23.2.
实施例36:1,3-二苄基脲
1,3-dibenzylurea
将1-苄基脲(150mg,1mmol)、[Cp*IrCl2]2(3.2mg,0.004mmol,0.4mol%)、氢氧化钠(16mg,0.4mmol,0.4equiv.)、苄醇(130mg,1.2mmol)和叔戊醇(1ml)依次加到20mlSchlenk反应瓶中。反应混合物在110℃下反应12小时后,冷却到室温。旋转蒸发除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:85%
1HNMR(500MHz,CDCl3)δ7.30-7.28(m,4H,ArH),7.26-7.22(m,6H,ArH),4.91(s,2H,AlkylNH),4.31(d,J=5.7Hz,4H,2xCH2);13CNMR(125MHz,CDCl3)δ158.4,139.2,128.5,127.3,127.2,44.4.
实施例37:
除用[Cp*RhCl2]2(2.4mg,0.0042mmol,0.4mol%)代替[Cp*IrCl2]2,,氢氧化钠(40mg,1mmol,1equiv.),其它反应原料,条件和产物同实施例1,产率:41%
实施例38:
除用[Ru(p-cymene)Cl2]2(2.4mg,0.004mmol,0.4mol%)代替[Cp*IrCl2]2,,氢氧化钠(40mg,1mmol,1equiv.),其它反应原料,条件和产物同实施例1,产率:35%
实施例39:
除用碳酸钾(138mg,1mmol,1.0equiv.)代替氢氧化钠,其它反应原料,条件和产物同实施例1,产率:7%
实施例40:
除用磷酸钾(212mg,1mmol,1.0equiv.)代替氢氧化钠,其它反应原料,条件和产物同实施例1,产率:36%
实施例41:
除用氢氧化钾(56mg,1mmol,1.0equiv.)代替氢氧化钠,其它反应原料,条件和产物同实施例1,产率:92%
实施例42:
除用叔丁醇钠(96mg,1mmol,1.0equiv.)代替氢氧化钠,其它反应原料,条件和产物同实施例1,产率:88%
实施例43:
除用叔丁醇钾(112mg,1mmol,1.0equiv.)代替氢氧化钠,其它反应原料,条件和产物同实施例1,产率:90%
实施例44:
除[Cp*IrCl2]2的用量为1.6mg,0.002mmol,0.2mol%,其它反应原料,条件和产物同实施例1,产率:71%
实施例45:
除[Cp*IrCl2]2的用量为0.8mg,0.001mmol,0.1mol%,其它反应原料,条件和产物同实施例1,产率:45%
实施例46:
除NaOH的用量为8mg,0.2mmol,0.2equiv.,其它反应原料,条件和产物同实施例1,产率:76%
实施例47:
除NaOH的用量为4mg,0.1mmol,0.1equiv.,其它反应原料,条件和产物同实施例1,产率:43%
实施例48:
除苄醇的用量为432mg,4.0mmol,4.0equiv.,无溶剂,其它反应原料,条件和产物同实施例1,产率:92%
实施例49:
除苄醇的用量为216mg,2.0mmol,2.0equiv.,其它反应原料,条件和产物同实施例1,产率:95%
实施例50:
除反应溶剂为二氧六环,其它反应原料,条件和产物同实施例1,产率:87%
实施例51:
除反应溶剂为甲苯,其它反应原料,条件和产物同实施例1,产率:85%
实施例52:
除反应温度为130℃,其它反应原料,条件和产物同实施例1,产率:83%.
实施例53:
除反应温度为90℃,其它反应原料,条件和产物同实施例1,产率:40%.
实施例54:
除反应时间为6小时,其它反应原料,条件和产物同实施例1,产率:53%.
实施例55:
除反应时间为2小时,其它反应原料,条件和产物同实施例1,产率:28%.
Claims (6)
1.一种合成N,N’-二取代基脲的方法,其特征在于所述化合物I
是通过N-取代基脲II
与化合物醇III的化合物
在过渡金属催化剂和碱的存在下发生反应,
其中,所述的过渡金属催化剂选自金属铱、铑或钌络合物催化剂,所述的碱选自氢氧化钠、氢氧化钾、碳酸钾、磷酸钾、叔丁醇钠或叔丁醇钾,其中,所述的金属铱、铑或钌络合物催化剂选自[Cp*IrCl2]2、[Cp*RhCl2]2或[Ru(p-cymene)Cl2]2,
R1选自C1-C4烷基、单或多取代芳基或芳基,所述的R1中单或多取代芳基选自甲基苯基、甲氧基苯基、甲巯基苯基、三氟甲氧基苯基或卤代苯基,
R2代表一个取代基,选自氢、C1-C7烷基、芳基、单或多取代芳基,所述的R2中单或多取代芳基选自甲基苯基、甲氧基苯基、三氟甲基、三氟甲氧基苯基或卤代苯基。
2.根据权利要求1所述的合成N,N’-二取代基脲的方法,其特征在于所述合成方法通过下述具体步骤实现:在反应容器中,加入N-取代基脲、金属铱、铑或钌络合物催化剂、碱和化合物醇;反应混合物在90-130℃下反应,反应结束后冷却到室温;旋转蒸发除去溶剂,然后通过柱分离,得到目标化合物。
3.根据权利要求1所述的合成N,N’-二取代基脲的方法,其特征在于反应在溶剂存在下进行,所述的溶剂选自叔戊醇、甲苯或二氧六环。
4.根据权利要求1所述的合成N,N’-二取代基脲的方法,其特征在于所述的催化剂用量相对于N-取代基脲为0.1-0.4mol%;所述的碱的摩尔量为N-取代基脲的摩尔量的0.1-0.4mol%;所述的化合物醇的摩尔量为N-取代基脲摩尔量的1.2-4equiv.。
5.根据权利要求1所述的合成N,N’-二取代基脲的方法,其特征在于所述的反应温度为90~130℃。
6.根据权利要求1所述的合成N,N’-二取代基脲的方法,其特征在于所述的反应时间为2~12小时。
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CN102120734A (zh) * | 2011-01-30 | 2011-07-13 | 南京理工大学 | 激活醇作为烷基化试剂制备2-(n-烷基)氨基苯并噻唑衍生物的方法 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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CN102120734A (zh) * | 2011-01-30 | 2011-07-13 | 南京理工大学 | 激活醇作为烷基化试剂制备2-(n-烷基)氨基苯并噻唑衍生物的方法 |
Non-Patent Citations (2)
Title |
---|
Cp*Ir-catalyzed N-alkylation of amines with alcohols. A versatile and atom economical method for the synthesis of amines;Ken-ichi Fujita等;《Tetrahedron》;20080218;第64卷(第8期);1943-1954 * |
Reaction of tert-butyl urea with some 1,2-chlorohydrins in the presence of acids;Kurbanova, M. M. 等;《 Izvestiya Vysshikh Uchebnykh Zavedenii, Khimiya i Khimicheskaya Tekhnologiya》;20041231;第47卷(第7期);95-96页 * |
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