四氢异喹啉酮-4-羧酸类化合物的合成及抑菌活性_李敏.pdf

研究论文doi:10.16801/j.issn.1008-7303.2022.0102四氢异喹啉酮-4-羧酸类化合物的合成及抑菌活性李敏,员春霞,房雅丽,张治家,王德龙*(山西农业大学植物保护学院，山西太谷030801)摘 要：具有异喹啉-1(2H)-酮骨架的天然产物分布广泛且有丰富多样的生物活性，为进一步明确该类化合物的农用抑菌活性，本文利用 Castagnoli-Cushman 反应及酯化反应合成了 22 个具有该骨架的四氢异喹啉酮-4-羧酸(酯)类化合物。离体抑菌活性测定结果表明，在 100g/mL下，5a5k 和和 6a6f 对油菜菌核病菌菌丝生长抑制率高于 80%，其中 5k 活性最高，EC50值为5.8g/mL，但低于对照药剂啶酰菌胺(EC50=0.094g/mL)。初步构效关系分析表明，在 N 上引入苯基要优于烷基，苯基上引入不同取代基后抑菌活性均有所提高且表现出位置和数目的选择性；C3 位苯基和 C4 位羧基引入取代基对活性不利。室内离体叶片法结果表明，在 500g/mL下，5k 的保护作用防治效果为 94.6%，与啶酰菌胺在 10g/mL 下的防治效果(95.8%)相当。本研究可为该类化合物的进一步结构优化提供借鉴。关键词:异喹啉-1(2H)-酮骨架；Castagnoli-Cushman 反应；抑菌活性；油菜菌核病菌中图分类号：TQ450.11文献标志码：ASynthesis and antifungal activity of tetrahydroisoquinolone-4-carboxylicacid derivativesLIMin,YUNChunxia,FANGYali,ZHANGZhijia,WANGDelong*(College of Plant Protection,Shanxi Agricultural University,Taigu 030801,Shanxi Province,China)Abstract:Compoundsbearingstructurallyuniqueisoquinolin-1(2H)-onescaffoldwerefoundtobewidelydistributedinvariousorganismsandtheyexhibitedabroadspectrumofbiologicalactivities.Inthepresentstudy,22derivativesoftheisoquinolin-1(2H)-onescaffoldweresynthesizedbyCastagnoli-Cushmanreactionandesterificationreactionandtheirantifungalactivitywasevaluatedagainst7phytopathogens.Thein vitrobioassayresultsindicatedthatthemycelialgrowthinhibitionratesofcompounds5a-5kand6a-6fwerehigherthan80%againstSclerotinia sclerotiorumattheconcentrationof100g/mL.Compound5kwasthemostpotentactivitywiththeEC50valueof5.8g/mL,whichwaslowerthanthecommercialboscalid(EC50=0.094g/mL).Thestructure-activityrelationshipanalysisrevealedthatthephenylonNatomsiteissuperiortothealkyl,andtheintroductionofdifferentsubstituentstothephenylgroupcouldimprovetheantifungalactivity,whichwassubjecttothe收稿日期：2022-05-31；录用日期：2022-08-10；网络首发日期：2022-09-13.Received:May31,2022;Accepted:August10,2022;Published online:September13,2022.URL:https:/doi.org/10.16801/j.issn.1008-7303.2022.0102http:/ Journal of Pesticide ScienceE-mail:positionalselectivityandthenumberofsubstituentsonthephenylgroup.However,introducingdifferentsubstituentsatC3phenylandC4carboxylgroupwereunfavorablefortheactivity.Thepreventivecontrolefficacyof5kwas94.6%at500g/mL,whichwascomparabletothatofboscalidat10g/mL(95.8%).Takentogether,theseresultscouldprovidesomeimportantcuesforfurtheroptimizationoftetrahydroisoquinolone-4-carboxylicacidderivatives.Keywords:isoquinolin-1(2H)-onescaffold;Castagnoli-Cushmanreaction;antifungalactivity;Sclerotinia sclerotiorum天然产物因其结构的多样性和新颖性表现出丰富多样的生物活性，其中一些不仅可以直接作为农药使用，而且为许多商品化农药提供了重要的结构上的借鉴1-2。人们常以具有农用活性的天然产物或其活性结构片段为先导物，通过进一步结构改造优化，得到具有商品化潜力的农药分子。例如，近些年来登记的新烟碱类杀虫剂氟吡呋喃酮就是以百部叶碱中的丁烯羟酸内酯结构片段为先导经结构优化而来3；而杀虫剂 afidopyropen则是在原有天然产物结构上经过衍生修饰而来的4-5；对天然产物 UK-2A 进行衍生修饰得到吡啶酰胺类杀菌剂 fenpicoxamid，进一步提取其活性结构片段进行类似物合成得到杀菌剂 florylpicoxamid6-7。具有异喹啉-1(2H)-酮骨架的天然生物碱在自然界中分布广泛。Cava 早在 1966 年就从莲叶桐Hernandia ovigeraL.中分离出有此骨架结构的生物碱 N-methylcorydaldine8。后来，人们又相继从其他植物、动物和微生物中分离得到了该类化合物9-14，其主要以 3,4 位饱和的(1)或者以其不饱和的(2)形式存在9(图式 1)。异喹啉-1(2H)-酮类生物碱及其衍生物具有广泛的生物活性。在医药方面，该类化合物表现出抗肿瘤15-19、抗病毒20、抗菌消炎21-22、抗胃溃疡10、保肝11、治疗中枢神经系统疾病23和心血管疾病24等生物活性；在农业方面，异喹啉-1(2H)-酮类化合物不仅可以防治植物病害25，还能增强植物对非生物胁迫的抗逆能力26，同时具有出一定的除草活性27。目前国内外对异喹啉-1(2H)-酮类化合物的农用活性研究报道较少，有文献报道具该骨架的N 和 C3 位取代的四氢异喹啉酮类化合物对小麦白粉病、小麦叶锈病、番茄灰霉病和葡萄霜霉病有一定的室内防效25。由于 Castagnoli-Cushman 反应具有操作简单、反应条件温和与后处理较简便等优点，在基于多样性导向合成构建化合物库中有重要的应用28-29，因此本研究通过该反应合成了一系列具有异喹啉-1(2H)-酮骨架的衍生物四氢异喹啉酮-4-羧酸类化合物(合成路线见图式 2)，并测定其抑菌活性，以期能发现有较高活性的化合物，同时对所合成化合物进行构效关系分析，旨在为进一步结构优化提供参考。1 实验部分 1.1 仪器、试剂与药剂BrukerAvanceIII400MHz 核磁共振仪，以DMSO-d6和 CDCl3为溶剂；用 WatersXevoG2-XSQTof 高分辨质谱仪(ESI 离子源)。SZCL-3B 数显智能控温磁力搅拌器(巩义市英峪博研仪器设备厂)；DF-101S 集热式恒温加热磁力搅拌器(巩义市予华仪器有限责任公司)；RE-52AA 旋转蒸发器(上海亚荣生化仪器厂)；ZF-6 型三用紫外线分析仪(上海嘉鹏科技有限公司)；北京恒奥德X-5 数字显微熔点仪。试剂均为分析纯(AR)，均购于麦克林试剂网(上海麦克林生化科技有限公司)。二氯甲烷(DCM)和甲苯(toluene)在氮气保护下分别经氢化钙和钠丝干燥后蒸馏除水使用，其他试剂除特别注明外，均未经进一步处理。对照药剂为 98%啶酰菌胺(boscalid)原药，购自上海阿拉丁生化科技股份有限公司。1.2 供试菌株及材料供试菌株：油菜菌核病菌 Sclerotinia sclerotio-rum、番茄灰霉病菌 Botrytis cinerea、西瓜枯萎病N2OR1345678NOR12图式 1 3,4 位饱和(1)和不饱和(2)的天然异喹啉-1(2H)-酮骨架Scheme 1 The skeleton of saturated(1)and unsaturated(2)natural isoquinoline-1(2H)-one at C3 and C4 positionsNo.1李敏等:四氢异喹啉酮-4-羧酸类化合物的合成及抑菌活性63菌 Fusarium oxysporumf.sp.niveum、胶孢炭疽菌Colletotrichum gloeosporioides、粉红聚端孢菌Trichothecium roseum、苹果斑点落叶病菌Alternaria mali 和立枯丝核菌 Rhizoctonia solani，均由山西农业大学植物保护学院植物病害研究室粮食作物病害课题组提供并保存。供试材料：将品氏基质(PINDSTRUP)和蛭石按照体积比 8:2 的比例混合作为培养基质，在64cm2盆中种植油菜种子(品种为早熟 938，每盆留苗 35 棵)，并在温室中(25、12h/12h 的光周期)培养。取 68 叶期的离体叶片为供试材料。1.3 目标化合物的合成1.3.1中间体亚胺 3 的合成参考文献方法30制备。将无水硫酸钠(15mmol)加入到 25mL 圆底烧瓶中，再依次加入醛(5.5mmol)、胺(5mmol)和无水二氯甲烷(10mL)，室温下搅拌 24h，用薄层层析(TLC，展开剂为 V(石油醚):V(乙酸乙酯)=9:1)监测至反应完成。过滤得滤液，减压蒸出溶剂，加少量乙醇，充分溶解后减压除去溶剂，得中间体亚胺 3，无需纯化，直接用于下一步反应。1.3.2四氢异喹啉酮-4-羧酸类化合物(5a6f)的合成参考文献方法31制备。向 25mL 的圆底烧瓶中依次加入相应的亚胺 3(3mmol)、高酞酸酐(3mmol)和无水甲苯(20mL)，升温至 120 回流搅拌 6h。待反应完成后，若生成固体，则抽滤并用 5mL 乙腈洗涤后得固体粉末；若未生成固体，则减压除去溶剂，将析出的固体用 10mL 乙腈搅拌悬浮，抽滤并用 5mL 乙腈洗涤，得固体粉末。上述固体粉末在乙腈中重结晶得目标化合物5a6f。1-氧代-2-丙基-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸(5a)：白色粉末，产率 86%；熔点 171175。1HNMR(400MHz,DMSO-d6),:13.10(s,1H),8.007.98(m,1H),7.387.37(m,2H),7.247.17(m,4H),7.117.09(m,2H),5.36(s,1H),4.10(s,1H),3.993.93(m,1H),2.832.78(m,1H),1.671.53(m,2H),0.86(t,J=5.6Hz,3H).13CNMR(100MHz,DMSO-d6),:172.2,163.3,139.6,133.6,131.9,129.7,129.3,128.7,128.0,127.6,126.9,126.1,60.9,50.8,47.8,20.8,11.4.ESI-HRMS:m/zM+H+C19H20NO3计算值：310.1443；测量值：310.1440.1-氧代-2-异丙基-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸(5b)：白色粉末，产率 81%；熔点 179181。1HNMR(400MHz,DMSO-d6),:13.10(s,1H),7.967.94(m,1H),7.387.36(m,2H),7.207.08(m,6H),5.38(s,1H),4.864.80(m,1H),4.04(s,1H),1.20(d,J=6.8Hz,3H),0.85(d,J=7.2Hz,3H).13CNMR(100MHz,DMSO-d6),:172.1,162.6,141.3,133.1,131.5,130.3,129.3,128.3,127.8,127.2,126.9,126.1,56.3,51.6,45.3,20.2,19.6.ESI-HRMS:m/zM+H+C19H20NO3计算值：310.1443；测量值：310.1440.1-氧代-2-戊基-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸(5c)：白色粉末，产率 83%；熔点 157160。1HNMR(400MHz,DMSO-d6),:13.00(s,1H),8.048.02(m,1H),7.557.50(m,2H),7.457.19(m,4H),7.027.00(m,2H),5.11(d,J=4.8Hz,1H),4.73(d,J=4.8Hz,1H),3.853.79(m,1H),2.882.82(m,1H),1.581.52(m,1H),1.471.43(m,1H),1.231.22(m,4H),0.82(t,J=5.2Hz,3H).13CNMR(100MHz,DMSO-d6),:170.4,162.6,137.4,133.5,131.7,129.1,128.1,128.1,127.9,127.7,127.3,127.2,61.2,48.2,45.6,28.5,27.0,21.8,13.8.ESI-HRMS:m/zM+H+C21H24NO3计算值：338.1756；测量值：338.1752.1-氧代-2-正十二烷基-3-苯基-1,2,3,4-四氢异喹啉-4-羧R1NH2R2CHONR2R1OOONOR1Na2SO4,DCMtoluene,reflux,6 hR3OHDCM5,6743DCC,DMAPNOR15a:R1=CH3(CH2)25b:R1=(CH3)2CH5c:R1=CH3(CH2)45d:R1=CH3(CH2)115e:R1=C6H55f:R1=4-FC6H45g:R1=4-ClC6H4 5h:R1=4-BrC6H4 5i:R1=4-lC6H4 5j:R1=3-BrC6H4 5k:R1=3,4-diClC6H35:R2=C6H56:R1=3,4-diClC6H36a:R2=4-CH3OC6H46b:R2=4-CH3(CH2)4OC6H46c:R2=3,4-diCH3OC6H46d:R2=4-FC6H46e:R2=4-ClC6H46f:R2=4-BrC6H47a:R3=CH37b:R3=C6H57c:R3=C6H5CH27e:R3=cyclohexyl7:R1=3,4-diClC6H3,R2=C6H5R2R2OHOOR3O347d:R3=C6H5(CH2)2图式 2 目标化合物的合成路线Scheme 2 Synthetic route of target compounds64农药学学报Vol.25酸(5d)：白色粉末，产率 75%；熔点 166168。1HNMR(400MHz,DMSO-d6),:13.01(s,1H),8.038.02(m,1H),7.557.48(m,2H),7.447.00(m,6H),5.10(d,J=4.8Hz,1H),4.71(d,J=4.8Hz,1H),3.843.78(m,1H),2.872.82(m,1H),1.541.43(m,2H),1.271.19(m,18H),0.86(t,J=4.4Hz,3H).13CNMR(100MHz,DMSO-d6),:170.4,162.6,137.4,133.5,131.7,129.1,128.5,128.1,127.9,127.7,127.3,126.0,61.2,48.2,45.7,31.3,29.0,29.0,28.9,28.7,27.3,26.3,22.1,13.9.ESI-HRMS:m/zM+H+C28H38NO3计算值：436.2852；测量值：436.2841.1-氧代-2,3-二苯基-1,2,3,4-四氢异喹啉-4-羧酸(5e)：白色粉末，产率 89%；熔点 203205。1HNMR(400MHz,DMSO-d6),:13.03(s,1H),8.098.07(m,1H),7.627.57(m,2H),7.527.48(m,1H),7.337.29(m,2H),7.207.16(m,6H),7.057.03(m,2H),5.50(d,J=5.6Hz,1H),4.96(d,J=5.6Hz,1H).13CNMR(100MHz,DMSO-d6),:170.5,162.9,141.7,137.3,134.3,132.3,129.2,128.6,128.2,128.0,127.9,127.8,127.6,127.4,126.6,64.4,49.0.ESI-HRMS:m/zM+H+C22H18NO3计算值：344.1287；测量值：344.1277.1-氧代-2-(4-氟苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸(5f)：白色粉末，产率 88%；熔点 191193。1HNMR(400MHz,DMSO-d6),:12.97(s,1H),8.108.09(m,1H),7.627.57(m,2H),7.527.49(m,1H),7.247.21(m,2H),7.197.18(m,3H),7.157.11(m,2H),7.077.05(m,2H),5.51(d,J=4.8Hz,1H),4.93(d,J=4.8Hz,1H).13CNMR(100MHz,DMSO-d6),:170.4,163.0,160.2(d,1JC-F=244.9Hz),137.8(d,4JC-F=2.9Hz),137.1,134.4,132.3,129.5(d,3JC-F=8.6Hz),129.0,128.1,128.0,128.0,127.8,127.7,127.6,115.3(d,2JC-F=22.7Hz),64.4,49.0.ESI-HRMS:m/zM+H+C22H17FNO3计算值：362.1192；测量值：362.1189.1-氧代-2-(4-氯苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸(5g)：白色粉末，产率 79%；熔点 201203。1HNMR(400MHz,DMSO-d6),:13.03(s,1H),8.088.06(m,1H),7.607.59(m,2H),7.527.48(m,2H),7.387.35(m,2H),7.237.17(m,4H),7.067.04(m,2H),5.54(d,J=5.6Hz,1H),4.88(d,J=5.6Hz,1H).13CNMR(100MHz,DMSO-d6),:170.5,163.1,140.4,137.1,134.5,132.5,130.8,129.3,128.9,128.6,128.2,128.1,128.0,127.9,127.8,127.7,64.1,49.1.ESI-HRMS:m/zM+H+C22H17ClNO3计算值：378.0897；测量值：378.0888.1-氧代-2-(4-溴苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸(5h)：白色粉末，产率 82%；熔点 223225。1HNMR(400MHz,DMSO-d6),:12.99(s,1H),8.098.08(m,1H),7.607.49(m,4H),7.197.15(m,6H),7.077.05(m,2H),5.55(d,J=4.4Hz,1H),4.89(d,J=4.4Hz,1H).13CNMR(100MHz,DMSO-d6),:170.4,163.0,140.8,137.0,134.5,132.5,131.5,129.6,128.9,128.2,128.0,127.9,127.9,127.7,127.7,119.2,64.0,49.1.ESI-HRMS:m/zM+H+C22H17BrNO3计算值：422.0392；测量值：422.0387.1-氧代-2-(4-碘苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸(5i)：白色粉末，产率 80%；熔点 231234。1HNMR(400MHz,DMSO-d6),:12.99(s,1H),8.088.07(m,1H),7.667.59(m,4H),7.517.48(m,1H),7.187.17(m,3H),7.057.01(m,4H),5.53(d,J=4.4Hz,1H),4.89(d,J=4.4Hz,1H).13CNMR(100MHz,DMSO-d6),:170.9,163.4,141.8,137.9,137.5,134.9,133.0,130.3,129.4,128.7,128.6,128.4,128.3,128.2,125.8,92.6,64.5,49.6.ESI-HRMS:m/zM+H+C22H17INO3计算值：470.0253；测量值：470.0246.1-氧代-2-(3-溴苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸(5j)：白色粉末，产率 78%；熔点 217219。1HNMR(400MHz,DMSO-d6),:13.04(s,1H),8.118.10(m,1H),7.627.58(m,2H),7.527.49(m,2H),7.407.17(m,6H),7.107.08(m,2H),5.58(d,J=4.8Hz,1H),4.93(d,J=4.8Hz,1H).13CNMR(100MHz,DMSO-d6),:170.5,163.1,143.0,137.0,134.5,132.6,130.5,130.4,129.5,128.9,128.2,128.1,128.0,127.8,127.7,126.5,120.9,64.1,49.1.ESI-HRMS:m/zM+H+C22H17BrNO3计算值：422.0392；测量值：422.0387.1-氧代-2-(3,4-二氯苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸(5k)：白色粉末，产率 91%；熔点 230232。1HNMR(400MHz,DMSO-d6),:13.01(s,1H),8.098.08(m,1H),7.617.58(m,2H),7.577.54(m,2H),7.527.49(m,1H),7.207.10(m,6H),5.62(d,J=4.4Hz,1H),4.86(d,J=4.4Hz,1H).13CNMR(100MHz,DMSO-d6),:170.5,163.2,141.3,136.8,134.6,132.7,130.7,130.3,129.6,129.0,128.7,128.3,128.2,128.0,127.9,127.8,127.8,63.8,49.2.ESI-HRMS:m/zM+H+C22H16Cl2NO3计算值：412.0507；测量值：412.0500.1-氧代-2-(3,4-二氯苯基)-3-(4-甲氧基苯基)-1,2,3,4-四氢异喹啉-4-羧酸(6a)：白色粉末，产率 76%；熔点 221224。1HNMR(400MHz,DMSO-d6),:12.97(s,1H),8.078.06(m,1H),7.617.49(m,5H),7.167.14(m,1H),6.996.74(m,4H),5.54(d,J=4.4Hz,1H),4.81(d,J=4.4Hz,1H),3.66(s,3H).13CNMR(100MHz,DMSO-d6),:170.5,163.1,158.9,141.4,134.7,132.6,130.7,130.3,129.6,129.2,128.9,128.6,127.9,127.9,127.8,127.7,113.6,63.3,54.9,49.2.ESI-HRMS:m/zM+H+C23H18Cl2NO4计算值：442.0613；测量值：442.0618.1-氧代-2-(3,4-二氯苯基)-3-(4-(戊氧基)苯基)-1,2,3,4-四氢异喹啉-4-羧酸(6b)：白色粉末，产率 80%；熔点208210。1HNMR(400MHz,DMSO-d6),:12.96(s,1H),8.078.06(m,1H),7.617.55(m,4H),7.517.14(m,2H),6.976.72(m,4H),5.53(d,J=4.4Hz,1H),4.80(d,J=4.4Hz,1H),3.84(t,J=4.8Hz,2H),1.651.61(m,2H),No.1李敏等:四氢异喹啉酮-4-羧酸类化合物的合成及抑菌活性651.341.28(m,4H),0.86(t,J=5.6Hz,3H).13CNMR(100MHz,DMSO-d6),:170.5,163.1,158.3,141.4,134.7,132.6,130.7,130.3,129.6,129.2,128.9,128.7,128.5,128.0,127.9,127.8,127.8,114.1,67.3,63.4,49.3,28.3,27.7,21.9,13.9.ESI-HRMS:m/zM+H+C27H26Cl2NO4计算值：498.1239；测量值：498.1243.1-氧代-2-(3,4-二氯苯基)-3-(3,4-二甲氧基苯基)-1,2,3,4-四氢异喹啉-4-羧酸(6c)：白色粉末，产率 85%；熔点233235。1HNMR(400MHz,DMSO-d6),:13.02(s,1H),8.098.07(m,1H),7.617.49(m,4H),7.217.14(m,2H),6.776.65(m,3H),5.56(d,J=4.0Hz,1H),4.75(d,J=4.0Hz,1H),3.65(s,3H),3.53(s,3H).13CNMR(100MHz,DMSO-d6),:170.7,163.3,148.5,148.0,141.4,134.9,132.6,130.6,130.2,129.8,128.9,128.8,128.2,128.0,127.8,127.7,125.3,120.6,111.7,111.2,63.5,55.3,55.1,49.6.ESI-HRMS:m/zM+H+C24H20Cl2NO5计算值：472.0719；测量值：472.0732.1-氧代-2-(3,4-二氯苯基)-3-(4-氟苯基)-1,2,3,4-四氢异喹啉-4-羧酸(6d)：白色粉末，产率 77%；熔点 233235。1HNMR(400MHz,DMSO-d6),:13.04(s,1H),8.088.07(m,1H),7.637.51(m,5H),7.177.02(m,5H),5.65(d,J=4.4Hz,1H),4.83(d,J=4.4Hz,1H).13CNMR(100MHz,DMSO-d6),:170.5,163.1,161.7(d,1JC-F=245.4Hz),141.1,134.6,133.1(d,4JC-F=2.7Hz),132.7,130.8,130.3,130.1(d,3JC-F=8.2Hz),129.8,129.1,128.5,127.9,127.8,115.1(d,2JC-F=21.5Hz),63.0,49.2.ESI-HRMS:m/zM+H+C22H15Cl2FNO3计算值：430.0413；测量值：430.0416.1-氧代-2-(3,4-二氯苯基)-3-(4-氯苯基)-1,2,3,4-四氢异喹啉-4-羧酸(6e)：白色粉末，产率 82%；熔点 235237。1HNMR(400MHz,DMSO-d6),:13.09(s,1H),8.118.10(m,1H),7.667.53(m,5H),7.327.30(m,2H),7.207.18(m,1H),7.147.12(m,2H),5.68(d,J=4.4Hz,1H),4.89(d,J=4.4Hz,1H).13CNMR(100MHz,DMSO-d6),:170.4,163.1,141.1,135.9,134.4,132.8,132.8,130.8,130.4,129.9,129.7,128.5,128.3,128.0,128.0,127.9,127.7,63.0,49.1.ESI-HRMS:m/zM+H+C22H15Cl3NO3计算值：446.0118；测量值：446.0123.1-氧代-2-(3,4-二氯苯基)-3-(4-溴苯基)-1,2,3,4-四氢异喹啉-4-羧酸(6f)：白色粉末，产率 79%；熔点 245247。1HNMR(400MHz,DMSO-d6),:13.09(s,1H),8.118.09(m,1H),7.717.61(m,5H),7.587.53(m,2H),7.237.18(m,1H),7.077.05(m,2H),5.66(d,J=4.4Hz,1H),4.89(d,J=4.4Hz,1H).13CNMR(100MHz,DMSO-d6),:170.4,163.0,141.1,136.3,134.4,132.7,131.6,130.8,130.3,130.2,129.7,129.1,128.5,128.0,127.9,127.7,126.5,121.4,63.1,49.0.ESI-HRMS:m/zM+H+C22H15BrCl2NO3计算值：489.9612；测量值：489.9607.1.3.3四氢异喹啉酮-4-羧酸酯类衍生物(7a7e)的合成参考文献方法32制备。化合物 5k(1mmol)加入到 25mL 的圆底烧瓶中，再依次加入无水二氯甲烷(5mL)、二环己基碳二亚胺(DCC)(1.1mmol)、4-二甲氨基吡啶(DMAP)(0.1mmol)和羟基化合物(1.1mmol)，室温下搅拌 8h，TLC 监测(展开剂:V(石油醚):V(乙酸乙酯)=8:2)至反应完成。产物经 1%碳酸氢钠溶液洗涤，合并有机相，用无水硫酸钠干燥，减压除去溶剂，经硅胶柱层析分离(洗脱剂：V(石油醚):V(乙酸乙酯)=15:1)得到粗品，用 V(石油醚):V(乙酸乙酯)=1:1 的混合溶剂重结晶，得化合物 7a7e。1-氧代-2-(3,4-二氯苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸甲酯(7a)：无色透明油状物，产率 83%。1HNMR(400MHz,CDCl3),:8.238.22(m,1H),7.527.51(m,1H),7.497.47(m,2H),7.417.21(m,6H),7.137.12(m,2H),5.60(s,1H),4.03(d,J=0.8Hz,1H),3.76(s,3H).13CNMR(100MHz,CDCl3),:171.3,163.6,142.0,138.8,133.2,133.1,132.5,131.3,130.9,130.0,129.4,129.2,129.2,129.1,128.9,128.6,126.6,126.5,65.0,53.4,51.8.ESI-HRMS:m/zM+H+C23H18Cl2NO3计算值：426.0664；测量值：426.0656.1-氧代-2-(3,4-二氯苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸苯酯(7b)：白色固体，产率 81%；熔点 131134。1HNMR(400MHz,CDCl3)，:8.308.28(m,1H),7.547.52(m,3H),7.407.39(m,4H),7.307.28(m,3H),7.267.23(m,2H),7.207.18(m,2H),7.006.98(m,2H),5.67(s,1H),4.30(d,J=0.8Hz,1H).13CNMR(100MHz,CDCl3)，:169.6,163.5,150.7,141.9,138.6,133.4,133.1,132.0,131.5,131.0,130.0,130.0,129.4,129.4,129.3,129.3,129.1,128.8,126.8,126.7,126.7,121.5,64.9,51.9.ESI-HRMS:m/zM+H+C28H20Cl2NO3计算值：488.0820；测量值：488.0825.1-氧代-2-(3,4-二氯苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸苄酯(7c)：白色固体，产率 84%；熔点 161163。1HNMR(400MHz,CDCl3),:8.258.23(m,1H),7.497.47(m,2H),7.417.40(m,1H),7.347.32(m,4H),7.257.20(m,6H),7.137.12(m,2H),7.067.05(m,1H),5.57(s,1H),5.245.12(m,2H),4.07(d,J=0.8Hz,1H).13CNMR(100MHz,CDCl3),:170.6,163.6,141.9,138.8,135.4,133.2,132.9,132.5,131.2,130.9,129.9,129.3,129.3,129.1,129.0,129.0,128.9,128.6,128.4,126.6,126.3,68.0,65.0,52.1.ESI-HRMS:m/zM+H+C29H22Cl2NO3计算值：502.0977；测量值：502.0981.1-氧代-2-(3,4-二氯苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸苯乙酯(7d)：白色固体，产率 87%；熔点 161164。1HNMR(400MHz,CDCl3),:8.238.22(m,1H),7.487.4566农药学学报Vol.25(m,3H),7.387.37(m,1H),7.257.23(m,6H),7.167.14(m,2H),7.117.10(m,2H),7.037.02(m,2H),5.53(s,1H),4.424.33(m,2H),3.97(d,J=0.4Hz,1H),2.86(t,J=4.4Hz,2H).13CNMR(100MHz,CDCl3),:170.7,163.5,141.9,138.8,137.6,133.1,133.0,132.5,131.2,130.9,130.1,129.3,129.2,129.1,129.1,129.0,128.9,128.8,128.6,127.0,126.6,126.4,66.7,64.9,51.9,35.2.ESI-HRMS:m/zM+H+C30H24Cl2NO3计算值：516.1133；测量值：516.1137.1-氧代-2-(3,4-二氯苯基)-3-苯基-1,2,3,4-四氢异喹啉-4-羧酸环己酯(7e)：白色固体，产率 92%；熔点 137139。1HNMR(400MHz,CDCl3),:8.238.22(m,1H),7.537.46(m,3H),7.407.39(m,1H),7.267.21(m,5H),7.157.14(m,2H),5.59(s,1H),4.874.84(m,1H),4.01(d,J=1.2Hz,1H),1.791.24(m,10H).13CNMR(100MHz,CDCl3),:170.2,163.7,142.0,139.0,133.0,133.0,131.2,130.9,