钯催化C-H键活化实现偶氮苯与醇的氧化交叉偶联反应-硕士答辩.

复旦大学钯催化C-H键活化实现偶氮苯与醇的氧化交叉偶联反应作者姓名唐*学科专业应用化学指导教师林*副教授答辩日期2015年6月1日2主要内容1研究背景2偶氮苯与醇的反应研究3结论3C-H键活化（杂）芳环的直接C-H酰基化反应N,O,S第一章研究背景4DGR+ArCHOPd(OAc)2(10mol%)xylene,air,120or130℃DGROArDG=2-Py,-C(O)(2-Py),-O(2-Py)+Pd(PhCN)2Cl2Ag2O,K2S2O8Dioxane/AcOH/DMSO120℃NROOHOHNORGe,H.,etal.Org.Lett.,2010,12(15):3464-3467.Cheng,etal.J.,Org.Lett.,2009,11(14):3120-3123.1.1过渡金属催化N原子导向的酰基化反应5+PdCl2(5mol%)TBHP(3equiv)PhCl,140℃NR1R2OHNR1R2OLi,C.-J.,etal.Org.Lett.,2011,13(7):1614-1617.DGHR1+HHHR210%Pd(OAc)2tBuOOH(2equiv)120℃DGR1OR2R1=H,OMe,BrR2=H,Me,OMe,ClDG=NNONOMe2-Py-O(2-Py)-C=N-OMePatel,B.K.,etal.Org.Lett.,2012,14(20):5294-5297.6NR2R1+HOR3OPd(OAc)2,TFAA100℃,16hNR2R1R3OFu,H.,etal.Adv.Synth.Catal.2013,355:529-536HNOMe+HR2O[Cp*RhCl2]2(0.05equiv)AgSbF6(0.2equiv)Ag2CO3(2.5equiv)CH2Cl2(0.2M)85℃,24hR1NOMeR1R2OLi,Y.C.,etal.Adv.Synth.Catal.2012,354:2916-2920.7Tan,Z.,etal.Chem.Commun.,2013,49(15):1560-1562.HXNOMeR+OHPd(OAc)2(5mol%)TBHP(3equiv)XNOMeROAcOH(3equiv)DCE(0.3M),80℃Kim,I.S.,etal.Eur.J.Org.Chem.2013,6656–6665.NHOR2R1+OOHO10%Pd(OAc)2(NH4)2S2O8diglyme,N2NHOR2R1O8HNMeOMe+Pd(OAc)2(0.05equiv)TBHP(6equiv)AcOH(3equiv)DCE,80℃,6hNMeOMeArOClArOArClKim,I.S.,etal.J.Org.Chem.2014,79:275–284.NNR1R2+OHOOPd(OAc)2(10mol%)K2S2O8(2.0equiv)dioxane/AcOH/DMSO=7:2:180℃，10hNNR1R2OWang,G.-W.,etal.J.Org.Chem.2013,78:10414-10420.9NNRHR+OR1HPd(OAc)2TBHPNNRROR1Zn-NH4ClNNRR1RWang,L.,etal.Org.Lett.2013,15(3):620-623.NN+CH3Pd(OAc)2(10mol%)TBHP(12equiv)PhCF3,80℃,30hNNOZeng,W.,etal.Org.Lett.,2013,15(21):5444–5447.10HNOH+ROOHO10mol%Pd(TFA)22equiv(NH4)2S2O8diglyme,rtNHOROGe,H.,etal.J.Am.Chem.Soc.2010,132(34):11898-11899.NHR1OR2+OHPd(OAc)2(10mol%)TBHP(4equiv）TfOH(0.5equiv)AcOH/DMA90℃,5hNHR1OR2OWang,X.,etal.Adv.Synth.Catal.,2011,353(18):3373-3379.1.2过渡金属催化O原子导向的酰基化反应11NHR2OR1+H5mol%Pd(TFA)2TBHP,toluene90℃,24hNHR2OR1OOR3R3Kwong,F.Y.,etal.Org.Lett.,2011,13(12):3258-3261.HNO+R1R2Pd(OAc)2(5mol%)TBHP(4equiv)DMSO,100℃,20hNHR1OOR2Sun,P.P.,etal.J.Org.Chem.2012,77:11339-11344.12COOHHR1+R2OOHOPd(TFA)2(10%)Ag2CO3(3.0equiv)DME,150℃COOHR1OR2OHOHR1+R2OOR2O[{Rh(cod)Cl}2](1.5mol%)Cs2CO3,mesitylene16h,145℃OHOR1OR2Ge,H.B.,etal.Org.Lett..2013,15(12):2930–2933.J.Gooßen,L.,etal.Angew.Chem.Int.Ed.2013,52:6704-6708.13OCONMe2HClR1+OHOOR2Pd(OAc)2,(NH4)2S2O8TfOH,DCE,r.t.,20hOClR1OR2OMe2NKim,I.S.,etal.Adv.Synth.Catal.2013,355:667-672.141.3过渡金属催化S原子导向的酰基化反应SRHR2+OHOOPd(OAc)2(5mol%)Ag2CO3(2.0equiv)DMA,120℃SRR2OR1R1Kuang,C.X.,etal.Eur.J.Org.Chem.2014,2576-2583.15本课题的设计与提出CH2OHNNOxidantPdNNOH16第二章偶氮苯与醇的反应研究表2-1催化剂对反应的影响NNHCH2OHPdcatalyst(10mol%)TBHP(4.0equiv),DCEAr,110℃,30hNNO1a2a3-1aEntryCatalystYield(%)[b]1PdCl2372Pd(TFA)2343PdCl2(MeCN)2354PdCl2(PPh3)2trace5Pd(OAc)2406--02.1反应条件优化17表2-2氧化剂对反应的影响NNHCH2OHPd(OAc)2(10mol%)Oxidant(4.0equiv),DCEAr,110℃,30hNNO1a2a3-1aEntryOxidantYield(%)b1TBHP402DDQtrace3MnO2trace4Na2S2O8trace5O2trace6PhI(OAc)2trace18表2-3溶剂对反应的影响EntrySovlentTempretureYield(%)b1CH2ClCH2Cl110℃402DMSO110℃trace3DMF110℃NR4CHCl2CHCl2110℃475CH3NO2110℃286chlorobenzene110℃687trifluorotoluene110℃5881,4-dioxane110℃NR19EntrySovlentTempretureYield(%)b9CH3CN80℃2310CH3COOC2H580℃3511CH2Cl270℃42续上表20表2-4温度对反应的影响NNHCH2OHPd(OAc)2(10mol%)Ar,Chlorobenzene,TBHP(4.0equiv),temp30hNNO1a2a3-1aEntryTemperatureTimeYield(%)b1125℃30h492110℃30h68380℃30h81460℃30h6821表2-5时间对反应的影响NNHCH2OHPd(OAc)2(10mol%)Ar,Chlorobenzene,TBHP(4.0equiv),80℃timeNNO1a2a3-1aEntryTemperatureTimeYield(%)b180℃30h81280℃48h63380℃24h5822表2-6物料比对反应的影响NNHCH2OHPd(OAc)2(10mol%)Ar,Chlorobenzene,TBHP(xequiv),80℃30hNNO1a2a3-1aEntry1a2aTBHPYield111663%211481%311363%411233%512463%611.5468%23表2-7醇类底物的拓展NNPd(OAc)2(10mol%)TBHP(4.0equiv)NNRO1a23HRCH2OHPhCl,80oC,30h+NNO3-1a:81%NNO3-1b:56%MeNNO3-1c:48%NNO3-1d:43%HOMeMeOOMeNNO3-1h:59%BrNNO3-1e:0%NNO3-1g:67%ClNNO3-1f:71%OHF2.2底物的拓展24NNO3-1j:83%NNO3-1k:80%NNO3-1i:80%NO2CF3NN3-1l:27%O2NOSNNO3-1n:28%NNO3-1o:26%NNO3-1m:33%25表2-8偶氮苯类底物的拓展NNPd(OAc)2(10mol%)TBHP(4.0equiv)NNPhO12a3HCH2OHPhCl,80oC,30hR1+R1R2R2NNO3-2a:60%NNO3-2b:66%NNO3-2c:27%MeMeMeMeMeMeNNO3-2d:68%NNO3-2e:42%NNO3-2f:51%MeOOMeFFClCl26NNO3-2g:48%NNO3-2h:80%NNO3-2i:37%BrBrEtO2CCO2EtHMeONNO3-2j:27%NNO3-2k:32%NNO3-2l:25%MeMeOMeOMeMeONNNNO3-2o:0%NNO3-2m:37%NNO3-2n:20%CO2EtEtO2C272.3机理的研究CH2OHPd(OAc)2(10mol%)TBHP(4.0equiv)PhCl(2mL),80oC,12hCHO2a2abNNCH2OHNNO1a2a3a-1HPd(OAc)2(10mol%)TBHP(4equiv)TEMPO(1.0equiv)PhCl(2mL),80oC,30hnotobserved(58%GCyield)a)c)NNNNO1a2ab3a-1HPd(OAc)2(10mol%)TBHP(4equiv)PhCl(2mL),80oC,30hb)HO75%yield28Pd(OAc)2NNNNPdOAcR-CH2OHORNNPd(IV)RONNOR1aABCDETBHPRCHOtBuOtBuOH.F图2-1钯催化偶氮苯与苯甲醇的酰基化反应机理292.4应用-偶氮基芴酮类化合物4的合成反应NNNNONN+Pd(OAc)2(10mol%)TBHP(4.0equiv)PhCl,80oC,30h60%yieldPd(PPh3)4(10mol%)DavePhos(10mol%)KOAc(2.0equiv)1a2p3-2p4HOBrBrOK2CO3(2.0equiv)DMA,110oC,24h35%yield301.利用偶氮化合物中N=N双键作为导向基团，以偶氮苯和苯甲醇做为反应底物，研究了在Pd(OAc)2/PhCl体系下实现偶氮苯邻位酰基化反应的可能性，从而构建C-C键。通过一系列的条件筛选后，得到了最优反应条件，即在氩气保护下，偶氮苯(1a)(0.15mmol)，苯甲醇(2a)(0.15mmol)，醋酸钯(10mol%)，TBHP(4equiv)溶于溶剂PhCl中(2.0mL)中，在80℃反应30h，能以25%-83%的收率得到酰基化产物，并合成了30种酰基化产物。2.通过机理研究控制实验，我们提出了一个可能的机理：首先Pd(OAc)2与偶氮苯通过sp2C-H活化得到五元环钯中间体，苯甲醇在TBHP的作用下，自由基引发得到苯甲酰基自由基与五元环钯中间体进行自由基氧化加成，得到新环钯中间体。最后，新环钯中间体发生还原消除反应，得到邻位酰基化产物，释放出二价