钯催化烯烃碳胺化反应构建含氮杂环医药中间体

摘要含氮杂环作为现代有机化学的重要结构单元，因其独特的电子特性和多样的生物活性而备受关注。作为许多药物合成所不可或缺的中间体，含氮杂环以及衍生物的应用越来越广泛。钯催化碳胺化反应因其更加高效且具有更高的原子经济性，现已作为构建含氮杂环骨架的重要方法。基于此，探索可以合成含氮杂环的新型钯催化烯烃的碳胺化反应具有很重要的意义。本论文围绕钯催化烯烃碳胺化反应构建含氮杂环化合物这一策略展开研究。主要包括两方面内容的研究工作：1.钯催化烯烃碳胺化反应合成二氢吡唑类化合物的研究二氢吡唑骨架是许多药物以及天然产物的重要结构之一。本章成功开发了以β,γ-不饱和腙与芳基三氟甲磺酸酯为底物，借助钯催化碳胺化反应合成多种芳基取代的二氢吡唑类化合物。该方法仅用一步反应即可同时构建C-C键和C-N键，为合成多种芳基取代二氢吡唑衍生物提供了更加便捷且高效的方法。2.钯催化烯烃碳胺化反应合成2-咪唑烷酮类化合物的研究2-咪唑烷酮因其低毒、强极性和优异渗透性等特点，其衍生物作为关键合成砌块在药物研发领域具有重要作用。在本章节中，利用N-烯丙基脲和2-(炔丙基氧基)碘苯为起始底物，通过钯催化碳胺化串联环化反应能够合成一系列含咪唑烷酮的的双杂环化合物。该反应具有底物兼容性广，为合成新型的双杂环化合物合成提供新的策略。关键词：钯催化；碳胺化反应；含氮杂环；二氢吡唑；2-咪唑烷酮AbstractNitrogen-containingheterocycles,aspivotalstructuralmotifsinmodernorganicchemistry,haveattractedconsiderableattentionduetotheirdistinctiveelectronicpropertiesanddiversebiologicalactivities.Servingasindispensableintermediatesinpharmaceuticalsynthesis,theseheterocycliccompoundsandtheirderivativesarefindingincreasinglybroadapplications.Palladium-catalyzedcarboaminationreactionshaveemergedasapowerfulstrategyforconstructingnitrogen-containingheterocyclicscaffolds,owingtotheirremarkableefficiencyandsuperioratomeconomy.Inthiscontext,exploringnovelpalladium-catalyzedcarboaminationreactionsofalkenesforsynthesizingnitrogenheterocyclesholdssignificantimportance.Thisdissertationfocusesontheconstructionofnitrogen-containingheterocyclesviapalladium-catalyzedalkenecarboamination,withresearcheffortsprimarilyconcentratedintwoaspects:1.SynthesisofDihydropyrazoleDerivativesviaPalladium-CatalyzedCarboaminationThedihydropyrazolescaffoldrepresentsaprivilegedstructuralmotiffoundinnumerouspharmaceuticalsandnaturalproducts.Inthischapter,wehavesuccessfullydevelopedapalladium-catalyzedcarboaminationreactionbetweenβ,γ-unsaturatedhydrazonesandaryltriflatesfortheefficientsynthesisofdiversearyl-substituteddihydropyrazolederivatives.ThisinnovativemethodologyenablesthesimultaneousformationofbothC-CandC-Nbondsinasingletransformation,providingamoreconvenientandefficientapproachforconstructingvariousaryl-substituteddihydropyrazoleframeworks.2.Synthesisof2-ImidazolidinonesviaPalladium-CatalyzedCarboaminationDuetotheirlowtoxicity,strongpolarity,andexcellentpermeability,2-imidazolidinonederivativesserveaskeysyntheticbuildingblocksindrugdevelopment.Inthischapter,usingN-allylureasand2-(propargyloxy)iodobenzeneasstartingsubstrates,aseriesofimidazolidinone-containingbis-heterocycliccompoundsweresynthesizedviaapalladium-catalyzedcarboaminationtandemcyclizationreaction.Thisreactionexhibitsbroadsubstratecompatibility,offeringanewstrategyforthesynthesisofnovelbis-heterocycliccompounds.Keywords:PalladiumCatalysis,CarboaminationReaction;Nitrogen-containingHeterocycles;Dihydropyrazole;2-Imidazolidone

目录TOC\o"1-3"\h\u1. 前言 [22]。（REF_Ref198104711\h图32）图STYLEREF1\s3SEQ图\*ARABIC\s12钯催化碳胺化反应合成对映选择性咪唑啉-2-酮3.2课题的提出基于上述2-咪唑烷酮的重要性，开发一种新型的合成2-咪唑烷酮结构的杂环化合物的方法具有十分重要的意义。我们设想能否通过简单易得的N-烯丙基脲衍生物和2-(炔丙基氧基)碘苯为起始底物，通过钯催化多米诺串联环化反应合成一系列具有重要意义的的2-咪唑烷酮类双杂环化合物。（REF_Ref198104717\h图33）图STYLEREF1\s3SEQ图\*ARABIC\s13课题的设想3.3反应条件的筛选首先选择了N-烯丙基脲衍生物3-1a(0.2mmol,1.0equiv)和2-(炔丙基氧基)碘苯3-2a(0.3mmol,1.5equiv)作为模板底物对反应进行探究。首先，确立了以三(二亚苄基丙酮)二钯(Pd2(dba)3)为催化剂，叔丁醇钠(NaOtBu)作为碱性试剂，甲苯为反应溶剂的基础体系，80oC氩气条件下对不同的配体进行筛选（表3-1,Entry1-3）。实验结果表明，采用Dppm或Xphos作为配体时，反应效率较低，目标产物3-3a的分离收率分别仅为19%和35%（表3-1,Entry1-2）。令人高兴的是，采用三环己基膦(PCy3)作为配体时，该催化体系展现出良好的反应活性，目标产物3-3a的分离收率达到55%（表3-1,Entry3）。接着对其他的钯催化剂进行考察，如Pd(acac)2、Pd(OAc)2、Pd(cod)Cl2，但没有得到理想的结果，分别能够以25-41%的收率得到目标产物3-3a（表3-1,Entry4-6）。随后对溶剂进行了筛选，THF作为溶剂时，目标产物的收率仅为18%（表3-1,Entry7），当采用EA和MeCN时，仅检测到痕量产物生成（表3-1,Entry8-9）。值得注意的是，当反应溶剂更换为氯苯时，产物收率显著提升至72%（表3-1,Entry10）。最后对碱进行了筛选，如Na2CO3、LiOtBu，但几乎都不反应（表3-1,Entry11-12）。当反应规模扩大至0.3mmol时，目标化合物的分离收率进一步提高至76%（表3-1,Entry13）。将反应条件氩气氛围改为在空气条件下反应时，产率有所下降，只有48%（表3-1,Entry14）。之后，还尝试了不加催化剂和不加碱的反应（表3-1,Entry15-16），但都只能以痕量的产率得到目标产物，这表明了催化剂和碱在反应中的必要性。最后，我还尝试不加配体的反应，反应的收率只能达到31%（表3-1,Entry17）。表STYLEREF1\s3SEQ表\*ARABIC\s11条件优化EntryCatalystLigandBaseSolventYield(%)b1Pd2(dba)3DppmNaOtBuToluene192Pd2(dba)3XphosNaOtBuToluene353Pd2(dba)3PCy3NaOtBuToluene554cPd(acac)2PCy3NaOtBuToluene395cPd(OAc)2PCy3NaOtBuToluene416cPd(cod)Cl2PCy3NaOtBuToluene257Pd2(dba)3PCy3NaOtBuTHF188Pd2(dba)3PCy3NaOtBuEANR9Pd2(dba)3PCy3NaOtBuMeCNTrace10Pd2(dba)3PCy3NaOtBuChlorobenzene7211Pd2(dba)3PCy3Na2CO3ChlorobenzeneNR12Pd2(dba)3PCy3LiOtBuChlorobenzeneTrace13dPd2(dba)3PCy3NaOtBuChlorobenzene7614ePd2(dba)3PCy3NaOtBuChlorobenzene4815--PCy3NaOtBuChlorobenzeneTrace16Pd2(dba)3PCy3--ChlorobenzeneTrace17Pd2(dba)3--NaOtBuChlorobenzene31[a]反应条件:3-1a(0.2mmol,1.0equiv)，3-2a(0.3mmol,1.5equiv)，碱(0.4mmol,2.0equiv),钯催化剂(5mol%)，配体(12mol%)，甲苯(2.0mL)，氩气氛围中80oC反应24小时。[b]分离产率。[c]使用钯催化剂(10mol%)。[d]3-1a(0.3mmol,1.0equiv)，3-2a(0.45mmol,1.5equiv),氩气氛围中80oC反应48小时。[e]3-1a(0.3mmol,1.0equiv)，3-2a(0.45mmol,1.5equiv)，在空气80oC下反应48小时。3.4底物的普适性考察在完成了反应条件优化之后，接着对底物的普适性进行了考察。（REF_Ref198318242\h图34）首先，考察底物3-1a和不同取代基的2-(炔丙基氧基)碘苯进行反应。当2-(炔丙基氧基)碘苯芳环的对位上是供电子基时，如甲基，甲氧基，叔丁基时，能够以良好的收率(78-86%)获得目标产物3-3b-3-3d。当取代基为吸电子基团的底物时，如对位为氯，氟取代基时，反应相对较差，只能以53%和70%的收率得到3-3e和3-3f。当R1是甲基时，能够以77%的收率获得目标产物3-3g。当2-(炔丙基氧基)碘苯的5位有氟取代基时，产率有所下降，3-3h是产率只有51%。当用杂环的2-(炔丙基氧基)碘苯时，产率也能很好的兼容，能以59%的产率得到目标产物3-3j。但是当2-(炔丙基氧基)碘苯的取代基是TMS时，产率较低，只能以10%的收率得到3-3j。当底物中的苯环变为环丙烷时，该转化反应仍能高效进行，最终以64%的收率获得目标化合物3-3k。[a]反应条件：3-1a(0.3mmol,1.0equiv)，3-2(0.45mmol,1.5equiv)，NaOtBu(0.6mmol,2.0equiv),Pd2(dba)3(5mol%)，PCy3(12mol%)，2.0mL氯苯，氩气氛围中80oC反应48小时。图STYLEREF1\s3SEQ图\*ARABIC\s142-(炔丙基氧基)碘苯的底物适用范围随后又对N-烯丙基脲进行了考察，我发现苯环对位为供电子基团的底物表现出中等反应活性，分别以67%和64%的收率获得产物3-3l和3-3m。相比之下，当苯环对位引入吸电子取代基时，反应效率显著提升，产物3-3n至3-3r的收率范围达到69%-95%。我们进一步通过X射线单晶衍射确定了产物3-3r的构型。令人遗憾的是，当苯环的邻位被甲基取代时，只有12%的产率得到目标产物3-3t，说明位阻反应的影响较大。当R3为苯环时，能以65%的收率得到目标产物3-3v。当R4取代基用甲基来代替H时，反应也能很好的兼容，能够以89%的产率得到目标产物3-3w。（REF_Ref198236203\h图35）[a]反应条件：3-1(0.3mmol,1.0equiv)，3-2a(0.45mmol,1.5equiv)，NaOtBu(0.6mmol,2.0equiv),Pd2(dba)3(5mol%)，PCy3(12mol%)，2.0mL氯苯，氩气氛围中80oC反应48小时。图STYLEREF1\s3SEQ图\*ARABIC\s15N-烯丙基脲的底物适用范围3.5反应机理基于前期文献报道，我们提出了如REF_Ref198104748\h图36所示的反应机理：首先Pd(0)L与2-(炔丙基氧基)碘苯发生氧化加成，生成中间体I。随后该中间体经历炔烃的迁移插入过程，形成烯基钯中间体II。在NaOtBu作用下，中间体II与底物3-1a发生配体交换，得到复合物III。复合物III进一步发生烯烃插入得到中间体IV，中间体IV通过还原消除得到目标产物3-3a，并再生Pd(0)L催化剂完成催化循环。图STYLEREF1\s3SEQ图\*ARABIC\s16反应可能的机理3.6小结综上所述，我们成功开发了一种高效的钯催化碳胺化反应体系。该体系以N-烯丙基脲和2-(炔丙基氧基)碘苯为起始原料，采用Pd2(dba)3/PCy3催化系统，以叔丁醇钠为碱，氯苯为溶剂，在80℃惰性气氛(氩气)下反应48小时，高效构建了23种不同类型的2-咪唑烷酮双杂环化合物，收率良好至优秀。该反应体系具有温和的反应条件、广泛的底物适用性、良好的官能团耐受性，为含氮杂环化合物的合成提供了一条新的可行途径。3.7实验仪器与实验试剂3.7.1实验仪器第三章实验仪器与第二章一致。3.7.2实验试剂表3-2实验试剂试剂名称生产公司无水乙醇(AR)上海玲峰化学试剂有限公司氯苯(AR)国药集团化学试剂有限公司二氯甲烷(AR)安徽泽升科技有限公司乙酸乙酯(AR)安徽泽升科技有限公司石油醚(60-90，AR)安徽泽升科技有限公司四氢呋喃安徽泽升科技有限公司三氯甲烷(AR)国药集团化学试剂有限公司烯丙基氯化镁安徽泽升科技有限公司钯(AR)安徽泽升科技有限公司甲苯(AR)国药集团化学试剂有限公司二氯乙烷(AR)安徽泽升科技有限公司苯甲醛(AR)国药集团化学试剂有限公司氯化铵(AR)国药集团化学试剂有限公司乙酰肼(AR)国药集团化学试剂有限公司无水吡啶(AR)安徽泽升科技有限公司二氯甲烷(AR)安徽泽升科技有限公司3.8实验部分 3.8.1反应合成的一般步骤标准操作方法：在10mL密封反应管中加入磁子，依次称取：Pd2(dba)3(13.7mg,0.015mmol,0.05equiv)，PCy3(10.1mg,0.036mmol,0.12equiv),N-烯丙基脲(0.3mmol,1.0equiv),2-(炔丙基氧基)碘苯(0.45mmol,1.5equiv)和叔丁醇钠(57.7mg,0.6mmol,2.0equiv)，加入2mL氯苯作为混合溶剂。于-78oC对混合物抽换气。在氩气气氛下，混合物在80℃持续搅拌反应48h。待反应完成后，真空浓缩混合物，残余物经硅胶柱层析，分离得到目标化合物。（REF_Ref198104763\h图37）图STYLEREF1\s3SEQ图\*ARABIC\s17反应合成的一般步骤3.8.2产物的核磁数据4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-1-methyl-3-(p-tolyl)imidazolidin-2-one(3-3a)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到白色固体93.7mg,76%yield,MP:164-166℃。1HNMR(CDCl3,400MHz,)δ7.51(d,J=7.6Hz,1H),7.45-7.42(m,2H),7.36(t,J=7.2Hz,1H),7.23-7.20(m,3H),7.16(d,J=7.2Hz,2H),7.11(d,J=8.0Hz,2H),6.89-6.85(m,2H),5.03(d,J=14.8Hz,1H),4.80(d,J=14.4Hz,1H),4.14-4.08(m,1H),3.37(t,J=8.4Hz,1H),3.29(dd,J1=8.8Hz,J2=3.6Hz,1H),3.20-3.14(m,1H),3.07-3.04(m,1H),2.85(s,3H),2.32(s,3H);13CNMR(CDCl3,100MHz)δ164.5,158.5,141.5,136.0,135.4,133.2,130.1,129.4,129.1,128.3,127.7,127.1,125.0,123.7,121.1,120.6,110.7,75.0,52.9,49.1,35.7,31.1,20.8.4-(2-(benzofuran-2(3H)-ylidene)-2-(p-tolyl)ethyl)-1-methyl-3-(p-tolyl)imidazolidin-2-one(3-3b)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色固体109.1mg,86%yield,MP:161-163℃。1HNMR(CDCl3,400MHz,)δ7.48(d,J=8.0Hz,1H),7.23-7.17(m,5H),7.10(d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),6.86–6.81(m,2H),5.03(d,J=14.4Hz,1H),4.78(d,J=14.4Hz,1H),4.12-4.04(m,1H),3.33(t,J=8.4Hz,1H),3.26(dd,J1=8.8Hz,J2=3.6Hz,1H),3.16-3.10(m,1H),3.04-3.01(m,1H),2.83(s,3H),2.39(s,3H),2.31(s,3H);13CNMR(CDCl3,100MHz)δ164.4,158.5,138.4,137.5,136.0,135.1,133.1,129.9,129.6,129.4,128.4,126.9,125.1,123.6,121.0,120.5,110.6,75.1,52.9,49.0,35.5,31.0,21.1,20.7.4-(2-(benzofuran-2(3H)-ylidene)-2-(4-methoxyphenyl)ethyl)-1-methyl-3-(p-tolyl)imidazolidin-2-one(3-3c)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色油状液体103.0mg,78%yield。1HNMR(CDCl3,400MHz)δ7.48(d,J=7.2Hz,1H),7.24-7.17(m,3H),7.13-7.08(m,4H),6.95(d,J=8.4Hz,2H),6.87-6.84(m,2H),5.05(d,J=16.4Hz,1H),4.82(d,J=14.4Hz,1H),4.14-4.07(m,1H),3.86(s,3H),3.35(t,J=8.8Hz,1H),3.28(dd,J1=9.2Hz,J2=4.0Hz,1H),3.16-3.10(m,1H),3.04-3.01(m,1H),2.85(s,3H),2.33(s,3H);13CNMR(CDCl3,100MHz)δ164.3,158.9,158.5,136.0,135.0,133.6,133.2,129.9,129.4,128.3,128.1,125.1,123.5,121.1,120.5,114.3,110.6,75.1,55.2,53.0,49.0,35.6,31.1,20.7.4-(2-(benzofuran-2(3H)-ylidene)-2-(4-(tert-butyl)phenyl)ethyl)-1-methyl-3-(p-tolyl)imidazolidin-2-one(3-3d)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色油状液体109.1mg,78%yield。1HNMR(CDCl3,400MHz)δ7.52(d,J=7.6Hz,1H),7.43(d,J=8.0Hz,2H),7.23-7.18(m,3H),7.12-7.08(m,4H),6.89-6.84(m,2H),5.08(d,J=14.8Hz,1H),4.84(d,J=14.4Hz,1H),4.16-4.09(m,1H),3.36(t,J=8.8Hz,1H),3.30(dd,J1=9.2Hz,J2=4.0Hz,1H),3.20-3.14(m,1H),3.08-3.05(m1H),2.85(s,3H),2.33(s,3H),1.39(s,9H);13CNMR(CDCl3,100MHz)δ164.4,158.5,150.6,138.3,136.0,135.1,133.1,129.9,129.4,128.4,126.8,125.8,125.2,123.6,121.0,120.5,110.7,75.2,52.9,49.0,35.4,34.6,31.2,31.1,20.7.4-(2-(benzofuran-2(3H)-ylidene)-2-(4-chlorophenyl)ethyl)-1-methyl-3-(p-tolyl)imidazolidin-2-one(3-3e)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色固体70.6mg,53%yield,MP:180-182℃。1HNMR(CDCl3,400MHz)δ7.48(d,J=7.6Hz,1H),7.39(d,J=8.0Hz,2H),7.24-7.17(m,3H),7.13-7.07(m,4H),6.89-6.85(m,2H),4.98(d,J=14.8Hz,1H),4.78(d,J=14.8Hz,1H),4.13-4.08(m,1H),3.37(t,J=8.8Hz,1H),3.27(dd,J1=8.8Hz,J2=3.6Hz,1H),3.17-3.11(m,1H),3.03-3.00(m,1H),2.84(s,3H),2.32(s,3H);13CNMR(CDCl3,100MHz)δ164.5,158.5,139.9,136.2,135.9,133.5(2C),130.4,129.5,129.3,128.6,126.9,124.7,123.7,121.3,120.7,110.8,74.9,53.0,49.1,35.6,31.1,20.8.4-(2-(benzofuran-2(3H)-ylidene)-2-(4-fluorophenyl)ethyl)-1-methyl-3-(p-tolyl)imidazolidin-2-one(3-3f)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色固体89.5mg,70%yield,MP:159-161℃。1HNMR(CDCl3,400MHz)δ7.48(d,J=7.6Hz,1H),7.22-7.16(m,3H),7.11-7.10(m,6H),6.88-6.84(m,2H),4.97(d,J=14.8Hz,1H),4.77(d,J=14.8Hz,1H),4.13-4.07(m,1H),3.36(t,J=8.8Hz,1H),3.26(dd,J1=9.2Hz,J2=3.6Hz,1H),3.16-3.10(m,1H),3.01-2.98(m,1H),2.83(s,3H),2.31(s,3H);13CNMR(CDCl3,100MHz)δ164.5,161.9(d,J=246.3Hz),158.4,137.4(d,J=3.5Hz),136.0,135.9,133.4,130.3,129.5,128.9(d,J=7.9Hz),127.1,124.8,123.7,121.2,120.7,116.1(d,J=21.3Hz),110.8,74.9,52.9,49.1,35.8,31.1,20.7.1-methyl-4-(2-(5-methylbenzofuran-2(3H)-ylidene)-2-phenylethyl)-3-(p-tolyl)imidazolidin-2-one(3-3g)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色固体98.6mg,77%yield,MP:61-63℃。1HNMR(CDCl3,400MHz)δ7.45-7.42(m,2H),7.37-7.31(m,2H),7.23(d,J=8.8Hz,2H),7.17(d,J=6.8Hz,2H),7.12(d,J=8.0Hz,2H),7.02(d,J=8.0Hz,1H),6.75(d,J=8.4Hz,1H),5.00(d,J=14.4Hz,1H),4.79(d,J=14.4Hz,1H),4.14-4.08(m,1H),3.35(t,J=8.8Hz,1H),3.26(dd,J1=8.8Hz,J2=3.6Hz,1H),3.19-3.13(m,1H),3.09-3.06(m,1H),2.86(s,3H),2.32(s,3H),2.29(s,3H);13CNMR(CDCl3,100MHz)δ162.6,158.5,141.6,136.1,135.6,133.2,130.8,129.8,129.5,129.0,127.9,127.7,127.2,124.9,124.0,121.0,110.2,75.2,53.1,49.2,35.6,31.0,21.0,20.7.4-(2-(5-fluorobenzofuran-2(3H)-ylidene)-2-phenylethyl)-1-methyl-3-(p-tolyl)imidazolidin-2-one(3-3h)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色固体65.2mg,51%yield,MP:168-169℃。1HNMR(CDCl3,400MHz)δ7.45-7.41(m,2H),7.38-7.34(m,1H),7.20-7.10(m,7H),6.92-6.87(m,1H),6.75(dd,J1=8.8Hz,J2=4.4Hz,1H),5.03(d,J=14.8Hz,1H),4.82(d,J=14.8Hz,1H),4.13-4.07(m,1H),3.35(t,J=8.8Hz1H),3.20(dd,J1=8.8Hz,J2=3.6Hz,1H),3.09-3.01(m,2H),2.84(s,3H),2.31(s,3H);13CNMR(CDCl3,100MHz)δ160.5,158.5,157.1(d,J=236.0Hz),141.2,135.9,135.1(d,J=2.8Hz),133.5,129.7,129.6,129.1,128.0,127.1,125.8(d,J=8.9Hz),121.2,116.5(d,J=24.5Hz),110.8(d,J=8.6Hz),110.4(d,J=26.1Hz),75.8,53.1,49.3,35.6,31.1,20.7.4-(2-(benzofuran-2(3H)-ylidene)-2-(thiophen-2-yl)ethyl)-1-methyl-3-(p-tolyl)imidazolidin-2-one(3-3i)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到棕色油状液体74mg,59%yield。1HNMR(CDCl3,400MHz)δ7.48(d,J=8.0Hz,1H),7.41-7.39(m,1H),7.28-7.25(m,2H),7.19(t,J=8.0Hz,1H),7.14(d,J=8.4Hz,2H),7.07-7.06(m,1H),6.99-6.97(m,1H),6.86-6.83(m,2H),5.14(d,J=14.4Hz,1H),4.96(d,J=14.8Hz,1H),4.17-4.11(m,1H),3.32(t,J=8.8Hz,1H),3.25(dd,J1=9.2Hz,J2=3.6Hz,1H),3.15-3.09(m,1H),3.05-3.02(m,1H),2.83(s,3H),2.33(s,3H);13CNMR(CDCl3,100MHz)δ164.3,158.5,141.8,136.0,135.7,133.5,130.1,129.5,126.5,126.3,125.1,123.7,123.0,122.4,121.5,120.7,110.7,75.4,53.4,49.0,35.3,31.1,20.8.4-(2-(benzofuran-2(3H)-ylidene)-2-(trimethylsilyl)ethyl)-1-methyl-3-(p-tolyl)imidazolidin-2-one(3-3j)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到白色固体12.5mg,10%yield,MP:79-81℃。1HNMR(CDCl3,400MHz)δ7.55(d,J=8.0Hz,1H),7.31(d,J=8.4Hz,2H),7.23-7.18(m,3H),6.88(d,J=8.4Hz,1H),6.83(t,J=8.0Hz,1H),5.05(s,2H),4.29-4.22(m,1H),3.33(t,J=8.8Hz,1H),3.21(dd,J1=8.8Hz,J2=3.2Hz,1H),2.98-2.92(m,1H),2.79(s,3H),2.73-2.70(m,1H),2.35(s,3H),0.17(s,9H);13CNMR(CDCl3,100MHz)δ164.8,158.9,147.8,135.8,134.6,130.6,129.5,126.3,126.2,125.4,124.0,120.6,110.9,75.0,54.4,48.7,33.8,31.0,20.9,-0.5.4-(2-(benzofuran-2(3H)-ylidene)-2-cyclopropylethyl)-1-methyl-3-(p-tolyl)imidazolidin-2-one(3-3k)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色固体72.1mg,64%yield,MP:114-116℃。1HNMR(CDCl3,400MHz)δ7.42-7.39(m,3H),7.19-7.13(m,3H),6.87-6.81(m,2H),5.15(s,2H),4.47-4.41(m,1H),3.38(t,J=8.8Hz,1H),3.26(dd,J1=9.2Hz,J2=3.2Hz,1H),2.83(s,3H),2.72-2.66(m,1H),2.43-2.40(m,1H),2.34(s,3H),1.23-1.19(m,1H),0.84-0.77(m,2H),0.55-0.50(m,1H),0.41-0.35(m,1H);13CNMR(CDCl3,100MHz)δ164.3,158.5,136.1(2C),133.6,129.4,129.2,125.7,125.2,123.4,121.9,120.5,110.4,74.3,53.2,48.9,31.8,31.0,20.8,15.1,5.8,5.0.4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-1-methyl-3-phenylimidazolidin-2-one(3-3l)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到白色固体79.8mg,67%yield,MP:123-125℃。1HNMR(CDCl3,400MHz)δ7.52(d,J=7.6Hz,1H),7.44-7.40(m,2H),7.36-7.24(m,5H),7.21-7.14(m,3H),7.07-7.03(m,1H),6.89-6.83(m,2H),5.02(d,J=14.8Hz,1H),4.77(d,J=14.4Hz,1H),4.16-4.11(m,1H),3.39-3.30(m,2H),3.21-3.15(m,1H),3.06-3.03(m,1H),2.84(s,3H);13CNMR(CDCl3,100MHz)δ164.5,158.2,141.4,138.6,135.6,130.2,129.1,128.8,128.2,127.8,127.1,125.0,123.6,123.4,120.6,120.5,110.8,75.0,52.6,48.9,35.5,31.0.4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-3-(4-methoxyphenyl)-1-methylimidazolidin-2-one(3-3m)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到白色固体69.0mg,54%yield,MP:150-151℃。1HNMR(CDCl3,400MHz)δ7.43-7.39(m,3H),7.36-7.32(m,1H),7.21-7.18(m,3H),7.13(d,J=7.6Hz,2H),6.88-6.82(m,4H),4.98(d,J=14.8Hz,1H),4.82(d,J=14.4Hz,1H),4.10-4.03(m,1H),3.80(s,3H),3.36(t,J=8.8Hz,1H),3.22(dd,J1=9.2Hz,J2=4.4Hz,1H),3.14-3.04(m,2H),2.82(s,3H);13CNMR(CDCl3,100MHz)δ164.4,158.9,156.5,141.6,135.4,131.5,130.1,129.0,128.3,127.7,127.1,125.0,124.0,123.7,120.6,114.2,110.7,75.0,55.4,53.8,49.4,36.1,31.1.4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-3-(4-fluorophenyl)-1-methylimidazolidin-2-one(3-3n)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到白色固体86.1mg,69%yield,MP:123-125℃。1HNMR(CDCl3,400MHz)δ7.49(d,J=8.0Hz,1H),7.43-7.40(m,2H),7.36-7.32(m,1H),7.25-7.18(m,3H),7.13-7.11(m,2H),6.97(t,J=8.8Hz,2H),6.89-6.84(m,2H),5.00(d,J=14.8Hz,1H),4.79(d,J=14.4Hz,1H),4.13-4.06(m,1H),3.38(t,J=8.8Hz,1H),3.29(dd,J1=8.8Hz,J2=3.6Hz,1H),3.18-3.13(m,1H),3.03-3.00(m,1H),2.84(s,3H);13CNMR(CDCl3,100MHz)δ164.5,159.1(d,J=242.1Hz),158.3,141.4,135.6,134.6(d,J=2.8Hz),130.2,129.1,128.0,127.8,127.1,124.9,123.5,122.8(d,J=7.9Hz),120.6,115.(d,J=22.3Hz),110.8,75.0,53.1,49.0,35.7,31.0;4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-3-(4-chlorophenyl)-1-methylimidazolidin-2-one(3-3o)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到白色固体89.6mg,69%yield,MP:135-137℃。1HNMR(CDCl3,400MHz)δ7.54(d,J=8.0Hz,1H),7.43(t,J=7.2Hz,2H),7.37-7.33(m,1H),7.25-7.19(m,5H),7.14(d,J=7.6Hz,2H),6.91-6.84(m,2H),5.04(d,J=14.8Hz,1H),4.76(d,J=14.8Hz,1H),4.12-4.05(m,1H),3.40-3.33(m,2H),3.23-3.17(m,1H),3.00-2.97(m,1H),2.85(s,3H);13CNMR(CDCl3,100MHz)δ164.6,157.8,141.2,137.2,135.8,130.3,129.1,128.8,128.1,127.9,127.8,127.1,124.9,123.5,121.1,120.6,110.9,75.0,52.3,48.7,35.2,31.0.4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-3-(4-bromophenyl)-1-methylimidazolidin-2-one(3-3p)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到白色固体101.9mg,71%yield,MP:153-154℃。1HNMR(CDCl3,400MHz)δ7.55(d,J=7.6Hz,1H),7.46-7.42(m,2H),7.38-7.35(m,3H),7.24-7.14(m,5H),6.92-6.85(m,2H),5.06(d,J=14.4Hz,1H),4.77(d,J=14.8Hz,1H),4.13-4.07(m,1H),3.41-3.35(m,2H),3.25-3.19(m,1H),3.01-2.97(m,1H),2.86(s,3H);13CNMR(CDCl3,100MHz)δ164.6,157.7,141.2,137.7,135.8,131.7,130.3,129.1,127.9,127.8,127.1,124.9,123.4,121.2,120.6,115.7,110.9,75.0,52.2,48.6,35.2,31.0.4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-1-methyl-3-(4-(trifluoromethyl)phenyl)imidazolidin-2-one(3-3q)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色固体98.3mg,71%yield,MP:135-137℃1HNMR(CDCl3,400MHz)δ7.60(d,J=7.6Hz,1H),7.50-7.37(m,7H),7.25-7.17(m,3H),6.92(t,J=7.6Hz,1H),6.87(d,J=8.0Hz,1H),5.09(d,J=14.8Hz,1H),4.77(d,J=14.8Hz,1H),4.20-4.12(m,1H),3.43(d,J=5.6Hz,2H),3.32-3.26(m,1H),3.03-2.99(m,1H),2.90(s,3H);13CNMR(CDCl3,100MHz)δ164.7,157.4,141.8,141.1,136.0,130.4,129.2,128.0,127.6,127.1,126.0(q,J=3.7Hz),124.8,124.2(q,J=269.9Hz),124.1(q,J=32.6Hz),123.4,120.7,118.1,111.0,75.0,51.8,48.4,34.9,30.9.4-(5-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-3-methyl-2-oxoimidazolidin-1-yl)benzonitrile(3-3r)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到白色固体120.5mg,95%yield,MP:171-173℃1HNMR(CDCl3,400MHz)δ7.58(d,J=7.6Hz,1H),7.49-7.38(m,7H),7.22(t,J=7.6Hz,1H),7.17(d,J=7.6Hz,2H),6.92(t,J=7.6Hz,1H),6.86(d,J=8.0Hz,1H),5.07(d,J=14.8Hz,1H),4.75(d,J=14.8Hz,1H),4.18-4.10(m,1H),3.44(d,J=5.2Hz,2H),3.33-3.26(m,1H),2.98-2.95(m,1H),2.89(s,3H);13CNMR(CDCl3,100MHz)δ164.7,156.9,142.7,140.9,136.2,132.9,130.4,129.3,128.0,127.2,127.0,124.7,123.2,120.6,119.0,117.8,111.0,104.7,74.9,51.5,48.1,34.8,30.8.4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-1-methyl-3-(m-tolyl)imidazolidin-2-one(3-3s)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到白色固体87.4mg,71%yield,MP:125-127℃1HNMR(CDCl3,400MHz)δ7.55(d,J=7.2Hz,1H),7.46-7.42(m,2H),7.39-7.35(m,1H),7.23-7.15(m,5H),7.08-7.06(m,1H),6.91-6.85(m,3H),5.05(d,J=14.4Hz,1H),4.80(d,J=14.4Hz,1H),4.15-4.11(m,1H),3.39-3.30(m,2H),3.22-3.15(m,1H),3.08-3.04(m,1H),2.86(s,3H),2.29(s,3H);13CNMR(CDCl3,400MHz)δ164.5,158.3,141.4,138.6,138.5,135.4,130.1,129.0,128.7,128.3,127.7,127.2,125.0,124.1,123.6,121.1,120.6,117.5,110.7,75.0,52.6,48.9,35.4,31.0,21.4.4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-1-methyl-3-(o-tolyl)imidazolidin-2-one(3-3t)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色固体14.9mg,12%yield,MP:122-124℃1HNMR(CDCl3,400MHz)δ7.40-7.36(m,2H),7.32-7.28(m,3H),7.20-7.01(m,5H),6.93(d,J=7.2Hz,1H),6.81(d,J=8.0Hz,1H),6.69-6.65(m,1H),4.94(d,J=14.8Hz,1H),4.82(d,J=14.8Hz,1H),4.07-3.97(m,1H),3.37(t,J=9.2Hz,1H),3.10(d,J=13.2Hz,1H),3.01-2.90(m,2H),2.77(s,3H),2.25(s,3H);13CNMR(CDCl3,100MHz)δ164.3,159.6,142.2,135.1,131.3,130.0,129.0,128.3,127.8,127.7,127.2,126.9,126.7,124.9,123.7,120.6,118.6,110.6,75.0,51.1,37.6,31.3,18.1.4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-3-(3,5-dimethoxyphenyl)-1-methylimidazolidin-2-one(3-3u)根据标准操作petroleumether:ethylacetate=3:1，柱层析得到黄色固体112.7mg,82%yield,MP:149-151℃1HNMR(CDCl3,400MHz)δ7.60(d,J=7.6Hz,1H),7.44-7.40(m,2H),7.36-7.32(m,1H),7.22-7.17(m,3H),6.92-6.84(m,2H),6.61-6.60(m,2H),6.18(s,1H),5.04(d,J=14.8Hz,1H),4.76(d,J=14.4Hz,1H),4.12-4.08(m,1H),3.68(s,6H),3.38-3.34(m,2H),3.26-3.20(m,1H),3.10-3.07(m,1H),2.86(s,3H);13CNMR(CDCl3,100MHz)δ164.5,160.9,157.9,141.3,140.8,136.1,130.1,129.1,128.1,127.7,127.1,124.9,123.6,120.6,110.7,97.6,96.0,75.0,55.1,52.5,48.5,35.2,30.9.4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-1-phenyl-3-(p-tolyl)imidazolidin-2-one(3-3v)根据标准操作petroleumether:ethylacetate=10:1，柱层析得到黄色固体91.9mg,65%yield,MP:138-140℃1HNMR(CDCl3,400MHz)δ7.48(d,J=8.0Hz,2H),7.43-7.34(m,4H),7.28(t,J=8.0Hz,2H),7.20(d,J=8.8Hz,2H),7.15-7.10(m,5H),7.02(t,J=7.2Hz,1H),6.80(d,J=8.0Hz,1H),6.65(t,J=7.6Hz,1H),4.97(d,J=14.8Hz,1H),4.80(d,J=14.4Hz,1H),4.29-4.22(m,1H),3.85(t,J=8.8Hz,1H),3.68(dd,J1=9.2Hz,J2=4.4Hz,1H),3.17(d,J=6.8Hz,2H),2.33(s,3H);13CNMR(CDCl3,100MHz)δ164.4,155.1,141.4,139.9,135.7,135.2,134.3,130.2,129.5,129.1,128.7,127.8,127.7,127.2,124.7,123.6,122.8,122.3,120.6,118.0,110.7,75.0,52.5,47.1,36.4,20.8.4-(2-(benzofuran-2(3H)-ylidene)-2-phenylethyl)-4-methyl-1-phenyl-3-(p-tolyl)imidazolidin-2-one(3-3w)根据标准操作petroleumether:ethylacetate=10:1，柱层析得到黄色固体129.3mg,89%yield,MP:177-179℃1HNMR(CDCl3,400MHz)δ7.44-7.42(m,4H),7.38(d,J=7.2Hz,1H),7.33-7.27(m,4H),7.23-7.20(m,4H),7.13(t,J=7.6Hz,1H),7.03(t,J=7.2Hz,1H),6.91(d,J=7.6Hz,1H),6.83(d,J=8.0Hz,1H),6.53(t,J=7.6Hz,1H),5.01(d,J=14.8Hz,1H),4.84(d,J=14.4Hz,1H),3.59(d,J=9.2Hz,1H),3.33(dd,J1=20.4Hz,J2=13.6Hz,1H),3.14(d,J=14.0Hz,1H),2.48(s,3H),1.43(s,3H);13CNMR(CDCl3,100MHz)δ164.4,156.2,142.6,140.1,137.6,136.4,132.9,130.1,130.0,129.7,129.0,128.6,128.2,127.7,127.3,124.6,123.5,122.3,120.3,117.4,110.5,75.0,60.3,54.5,41.7,25.1,21.1.

全文总结本论文主要围绕氮杂环化合物的合成展开研究，通过钯催化碳胺的途径成功实现二氢吡唑和2-咪唑烷酮类杂环化合物的构建。具体内容如下：1）钯催化烯烃碳胺化反应合成二氢吡唑类化合物的合成；2）钯催化烯烃碳胺化反应合成2-咪唑烷酮类化合物的合成1）钯催化烯烃碳胺化反应合成二氢吡唑类化合物的研究本章成功开发了以β,γ-不饱和腙与芳基三氟甲磺酸酯为底物，通过钯催化烯烃碳胺化策略，能够以中等至良好的收率合成30个结构多样的芳基取代二氢吡唑类化合物，为合成多种芳基取代的二氢吡唑衍生物提供了实用且高效的途径。2.钯催化烯烃碳胺化反应合成2-咪唑烷酮类化合物的研究在本章节中，利用N-烯丙基脲和2-(炔丙基氧基)碘苯为起始底物，通过钯催化碳胺化串联环化反应能够合成一系列含咪唑烷酮的的双杂环化合物。该反应具有底物兼容性广，为合成新型的双杂环化合物合成提供新的方法。

参考文献ADDINNE.BibLiuJ,NarvaS,ZhouK,etal.AReviewontheAntitumorActivityofVariousNitrogenous-basedHeterocyclicCompoundsasNSCLCInhibitors.[J].MINI-REVIEWSINMEDICINALCHEMISTRY.2019,19:1517-1530.KumariS,MaddeboinaK,BachuRD,etal.PivotalRoleofNitrogenHeterocyclesinAlzheimer'sDiseaseDrugDiscovery[J].DRUGDISCOVERYTODAY.2022,27.PuranikN,SongM.TherapeuticRoleofHeterocyclicCompoundsinNeurodegenerativeDiseases:InsightsfromAlzheimer'sandParkinson'sDiseases.[J].Neurologyinternational.2025,17.WangY,ZhangW,XiZ.Carbodiimide-basedSynthesisofN-heterocycles:MovingfromTwoClassicalReactiveSitestoChemicalBondBreaking/formingReaction.[J].ChemicalSocietyreviews.2020.YuH,XuF.AdvancesintheSynthesisofNitrogen-ContainingHeterocyclicCompoundsbyinSituBenzyneCycloaddition.[J].RSCadvances.2023,13:8238-8253.Z.J.Garlets,D.R.White,J.P.Wolfe.[J].AsianJ.Org.Chem.2017,6,636.RLira,JPWolfe,Palladium-CatalyzedSynthesisofN-Aryl-2-benzylindolinesviaTandemArylationof2-Allylaniline: ControlofSelectivitythroughinSituCatalystModification[J].J.Am.Chem.Soc.20