CN102816109B - 一种合成Hantzsch酯的方法 - Google Patents
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Abstract
一种合成Hantzsch酯的方法:本发明以过渡金属[Ru(II),Rh(I)]为催化剂实现了Hantzsch吡啶的催化加氢来合成Hantzsch酯。而且,本发明还将Hantzsch酯的原位再生应用到亚胺的不对称转移氢化中,将Hantzsch酯的用量由原来的化学当量降为催化量。
Description
技术领域
本发明涉及一种合成Hantzsch酯的方法。
背景技术
Hantzsch酯作为氢源应用在不对称仿生转移氢化中的良好前景已经引起了广泛的关注,该方法的研究在短短数年间就已经成绩斐然。(文献1.(a)You,S.L.Chem.Asian J.2007,2,820.(b)Ouellet,S.G.;Walji,A.M.;Macmillan,D.W.C.Acc.Chem.Res.2007,40,1327.(c)Connon,S.J.Org.Biomol.Chem.2007,5,3407.(d)Wang,C.;Wu,X.F.;Xiao,J.L.Chem.Asian J.2008,3,1750.(e)Rueping,M.;Sugiono,E.;Schoepke,F.R.Synlett 2010,852.)德国马普煤炭研究所的List,美国普林斯顿大学的MacMillan,德国亚琛工业大学的Rueping,上海有机所的游书力,北京大学的杜大明和中国科技大学的龚流柱等研究小组在手性磷酸催化的以Hantzsch酯作为氢源的仿生转移氢化反应方面作出了一些开创性的工作。(文献:2(a)Yang,J.W.;Hechavarria Fonseca,M.T.;List,B.Angew.Chem.,Int.Ed.2004,43,6660.(b)Hoffmann,S.;Seayad,A.M.;List,B.Angew.Chem.,Int.Ed.2005,44,7424.(c)Ouellet,S.G.;Tuttle,J.B.;MacMillan,D.W.C.J.Am.Chem.Soc.2005,127,32.(d)Rueping,M.;Sugiono,E.;Azap,C.;Theissmann,T.;Bolte,M.Org.Lett.2005,7,3781.(e)Yang,J.W.;Hechavarria Fonseca,M.T.;Vignola,N.;List,B.Angew.Chem.,Int.Ed.2005,44,108.(f)Martin,N.J.A.;List,B.J. Am.Chem.Soc.2006,128,13368.(g)Mayer,S.;List,B.Angew.Chem.,Int.Ed.2006,45,4193.(h)Rueping,M.;Antonchick,A.R.;Theissmann,T.Angew.Chem.,Int.Ed.2006,45,3683.(i)Tuttle,J.B.;Ouellet,S.G.;MacMillan,D.W.C.J. Am.Chem.Soc.2006,128,12662.(j)Kang,Q.;Zhao,Z.A.;You,S.L.Adv.Synth.Catal.2007,349,1657.(k)Li,G.L.;Liang,Y.X.;Antilla,J.C.J.Am.Chem.Soc.2007,129,5830.(l)Martin,N.J.A.;Ozores,L.;List,B.J. Am.Chem.Soc.2007,129,8976.(m)Rueping,M.;Antonchick,A.P.Angew.Chem.,Int.Ed.2007,46,4562.(n)Zhou,J.;List,B.J.Am.Chem.Soc.2007,129,7498.(o)Guo,Q.S.;Du,D.M.;Xu,J.Angew.Chem.,Int.Ed.2008,47,759.(p)Kang,Q.;Zhao,Z.A.;You,S.L.Org.Lett.2008,10,2031.(q)Rueping,M.;Theissmann,T.;Raja,S.;Bats,J.W.Adv.Synth.Catal.2008,350,1001.(r)Li,G.L.;Antilla,J.C.Org.Lett.2009,11,1075.(s)Nguyen,T.B.;Bousserouel,H.;Wang,Q.A.;Gueritte,F.Org.Lett.2010,12,4705.(t)Rueping,M.;Brinkmann,C.;Antonchick,A.P.;Atodiresei,I.Org.Lett.2010,12,4604.(u)Rueping,M.;Merino,E.;Koenigs,R.M.Adv.Synth.Catal.2010,352,2629.(v)Rueping,M.;Sugiono,E.;Steck,A.;Theissmann,T.Adv.Synth.Catal.2010,352,281.(w)Rueping,M.;Tato,F.;Schoepke,F.R.Chem.Eur.J.2010,16,2688.(x)Rueping,M.;Theissmann,T.Chem.Sci.2010,1,473.(y)Wakchaure,V.N.;Zhou,J.;Hoffmann,S.;List,B.Angew.Chem.,Int.Ed.2010,49,4612.(z)Nguyen,T.B.;Bousserouel,H.;Wang,Q.;Guéritte,F.Adv.Synth.Catal.2011,353,257.)
但是目前的研究中仍然存在着一些不足之处没有解决,并严重制约着该方法的进一步应用。最为突出的一点就是反应的原子利用效率低(<1%),Hantzsch酯中仅有两个氢原子得以利用,而且反应通常需要加入超过一个当量的Hantzsch酯才能得到较好的收率。一方面,Hantzsch酯不易合成,成本较高;另一方面,Hantzsch酯氧化生成的吡啶副产物带来的分离问题使得仿生转移氢化无法应用到工业级产品的生产。
因此,将Hantzsch吡啶加氢还原Hantzsch酯仍是目前研究的难点和热点。我们以过渡金属[Ru(II),Rh(I)]作为催化剂实现了Hantzsch吡啶的催化加氢。而且,本发明还将Hantzsch酯的原位再生应用到亚胺的不对称转移氢化中,将Hantzsch酯的用量由原来的化学当量降为催化量。
发明内容
本发明的目的是提供一种由吡啶为原料合成Hantzsch酯的方法。
为实现上述目的,本发明以过渡金属[Ru(II),Rh(I)]为催化剂实现了Hantzsch吡啶的催化加氢。而且,本发明还将Hantzsch酯的原位再生应用到亚胺的不对称转移氢化中,将Hantzsch酯的用量由原来的化学当量降为催化量。
本发明的技术方案如下:
本发明提供的是一种由吡啶为原料合成Hantzsch酯的方法,其合成路线如下:
其中:
R1、R2、R3、R4、R5分别为氢,C1-C6烷基、芳基或C1-C6的烷基取代芳基;MLn为Ru(II)或Rh(I)的金属络合物;
反应步骤为:
a)将吡啶1溶于有机溶剂中,向该体系按摩尔比1∶0.001~1∶0.1加入金属催化剂。室温下搅拌10min后,将反应体系转移至高压反应釜中并充入氢气(1~100atm);0~100℃搅拌反应6-48h后,小心释放掉剩余的氢气,柱层析或重结晶得到Hantzsch酯2。
所述的有机溶剂为四氢呋喃、乙醚、二氯甲烷、氯仿、甲苯、1,4-二氧六环、乙酸乙酯、甲醇、乙醇或异丙醇。
所述的金属催化剂为Ru(II),Rh(I)的金属络合物。
所述的氢气压力为20~70atm。
所述的反应温度为25~100℃。
本发明具有以下优点
1.原料易得。
2.反应步骤少,收率高。
3.将本发明Hantzsch酯的原位再生方法应用到亚胺的不对称转移氢化中,可将Hantzsch酯的用量由原来的化学当量降为催化量。
具体实施方式
本发明采用Ru(II),Rh(I)的金属络合物为催化剂,实现其合成路线如下:
其中:
R1、R2、R3、R4、R5分别为氢,C1-C6烷基、芳基或C1-C6的烷基取代芳基;MLn为Ru(II)或Rh(I)的金属络合物;
下面通过实施例详述本发明;但本发明并不限于下述的实施例。
实施例1:化合物(2a)的合成
将吡啶1a(50mg,0.20mmol)和[Ru(p-cymene)I2]2(2.0mg,0.002mmol)溶于乙醇中。室温下搅拌10min后,将反应体系转移至高压反应釜中并充入氢气(40atm)。50℃搅拌反应24h后,小心释放掉剩余的氢气,柱层析得到Hantzsch酯2a,黄色固体49mg,产率96%,mp 160-162℃,1H NMR(400MHz,CDCl3)δ5.25(s,1H),4.16(q,J=7.1Hz,4H),3.25(s,2H),2.18(s,6H),1.27(t,J=7.1Hz,6H).13C NMR(100MHz,CDCl3)δ168.1,144.8,99.5,59.7,24.8,19.2,14.5.
实施例2:化合物(2b)的合成
将吡啶1b(60mg,0.20mmol)和[Rh(COD)Cl2]2(0.9mg,0.002mmol)溶于乙醇中。室温下搅拌10min后,将反应体系转移至高压反应釜中并充入氢气(40atm)。50℃搅拌反应24h后,小心释放掉剩余的氢气,柱层析得到Hantzsch酯2b,黄色固体58mg,产率97%,mp 196-198℃,1H NMR(400MHz,DMSO-d6)8.87(s,1H),7.09-7.45(m,5H),4.89(s,1H),3.54(s,6H),2.28(s,6H),13C NMR(100MHz,DMSO-d6):168.6,148.3,146.1,129.7,128.4,127.3,127.3,101.2,51.10,37.3,18.5.
实施例3:化合物(2a)的原位再生应用于不对称转移氢化
将吡啶化合物3a(40mg,0.20mmol),1a(5mg,0.02mmol),[Ru(p-cymene)I2]2(2.4mg,0.0025mmol)和手性磷酸(S)-5(1.4mg,0.002mmol)溶于混合溶剂THF/CH2Cl2(v/v,1/3,2mL)中。室温下搅拌10min后,将反应体系转移至高压反应釜中并充入氢气(70atm)。50℃搅拌反应48h后,小心释放掉剩余的氢气,柱层析得到化合物4a,白色固体42mg,产率93%,mp 115-116℃,93% yield,98%ee,[α]20 D=+98.6(c 0.84,CHCl3),Rf=0.30(petroleum ether/EtOAc 10/1).1H NMR(400MHz,CDCl3):δ7.36-7.43(m,5H),7.01-7.07(m,2H),6.81-6.90(m,2H),5.08(d,J=1.7Hz,1H),4.23(s,1H).;13C NMR(100MHz,CDCl3):δ165.4,141.1,136.5,132.6,129.2,127.7,125.4,120.5,117.1,115.1,59.4.HPLC:Chiracel OD-H column,230nm,30℃,n-hexane/i-propanol=70/30,flow=0.7mL/min,retention time 10.0min and13.0min(maj).
Claims (4)
1.一种合成Hantzsch酯的方法,其特征在于它是经过下述步骤实现:
其中:
R1、R2、R3、R4、R5分别为氢,C1-C6烷基、芳基或C1-C6的烷基取代芳基;MLn为Ru(II)或Rh(I)的金属络合物;
反应步骤为:
a)将吡啶化合物1溶于有机溶剂中,向该体系按摩尔比1:0.001~1:0.1加入金属催化剂;室温下搅拌后,将反应体系转移至高压反应釜中并充入氢气至釜内压力为1~100atm;0~100℃搅拌反应6-48h后,小心释放掉剩余的氢气,柱层析或重结晶得到Hantzsch酯2;
步骤a所用的金属催化剂为Ru(II)或Rh(I)的金属络合物,其为[Ru(p-cymene)I2]2,或[Rh(COD)Cl2]2。
2.如权利要求1所述的合成方法,其特征在于:步骤a所用的有机溶剂为四氢呋喃、乙醚、二氯甲烷、氯仿、甲苯、1,4-二氧六环、乙酸乙酯、甲醇、乙醇或异丙醇。
3.如权利要求1所述的合成方法,其特征在于步骤a所用的氢气压力为20~70atm。
4.如权利要求1所述的合成方法,其特征在于步骤a所用反应温度为25~100℃。
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US4338322A (en) * | 1975-07-02 | 1982-07-06 | Fujisawa Pharmaceutical Co., Ltd. | 1,4-Dihydropyridine derivatives, pharmaceutical compositions containing same and methods of effecting vasodilation using same |
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US4284634A (en) * | 1975-07-02 | 1981-08-18 | Fujisawa Pharmaceutical Co., Ltd. | 1,4-Dihydropyridine derivatives, and pharmaceutical method of the same |
US4338322A (en) * | 1975-07-02 | 1982-07-06 | Fujisawa Pharmaceutical Co., Ltd. | 1,4-Dihydropyridine derivatives, pharmaceutical compositions containing same and methods of effecting vasodilation using same |
US4579859A (en) * | 1983-05-27 | 1986-04-01 | Fujisawa Pharmaceutical Co., Ltd. | Vasodilating trinitratoalkyl esters of 2-cyano-1,4-dihydropyridines |
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"A New Synthesis of 1.4-Dihydropyridines";Tomy Chennat et al.;《Journal of the chemical society,Pekin Transactions 1》;19751231(第10期);第926-929页 * |
"Reduction of 3,5-Disubstituted Pyridines to Dihydropyridines";Evans Booker et al.;《Journal of the chemical society,Pekin transactions 1》;19751231(第10期);第929-931页 * |
"芳香杂环化合物不对称催化氢化反应的研究进展";卢胜梅 等;《有机化学》;20051231;第25卷(第6期);第634-640页 * |
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