CN115246795A - 4-苯基对位含有醚结构的异噁唑啉类化合物及其制备和作为杀虫、杀菌剂的应用 - Google Patents
4-苯基对位含有醚结构的异噁唑啉类化合物及其制备和作为杀虫、杀菌剂的应用 Download PDFInfo
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- CN115246795A CN115246795A CN202110452462.7A CN202110452462A CN115246795A CN 115246795 A CN115246795 A CN 115246795A CN 202110452462 A CN202110452462 A CN 202110452462A CN 115246795 A CN115246795 A CN 115246795A
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- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
本发明涉及一类新型4‑苯基对位含有醚结构的异噁唑啉类化合物及其制备方法和在防治害虫及植物病菌方面的应用。本发明的新型4‑苯基对位含有醚结构的异噁唑啉类化合物显示出很好的杀小菜蛾、东方粘虫、草地贪夜蛾、棉铃虫、玉米螟、蚊幼虫、蠕虫等活性及抑制植物病菌活性。
Description
技术领域
本发明涉及一类新型4-苯基对位含有醚结构的异噁唑啉类化合物及其制备和在防治害虫及抑制植物病菌方面的应用，属于农业防护与害虫防治技术领域。
背景技术
自2005年日本日产化学株式会社报道了异噁唑啉类化合物作为杀虫剂后(W.O.2005085216)，作为21世纪发现的一类新型杀虫剂，由于其独特的杀虫机制、高选择性，与现有杀虫剂无显著交互抗性等特点，已成为杀虫剂研究领域的热点和前沿(ChemMedChem 2016,11,270–276.)。众多研究机构对此异噁唑啉结构进行了大量的研究报道，在广泛筛选中发现了许多高活性化合物。
本课题组近年来开展了许多针对乙螨唑噁唑啉杀螨剂的结构改造和衍生工作，以2-(2,6-二氟苯基)-4-(4-取代苯基)-1,3-噁唑啉为重点研究方向，研究发现在4-苯基苄位连接不同的杂原子取代基，设计合成了在4-苯基苄位连接氧、氮、硫、肟醚、(亚)砜基、苯环以及杂环的多个系列化合物(J.Agric.Food.Chem.2021,69,3601–3606；J.Agric.Food.Chem.2019,67,13544–13549；J.Agric.Food.Chem.2019,67,4224–4231；J.Agric.Food Chem.2016,64,3034–3040；J.Agric.Food Chem.2015,63,9690–9695；J.Agric.Food Chem.2014,62,3064–3072.)，发现了许多比乙螨唑对朱砂叶螨的螨卵和幼螨活性更高的化合物。
异噁唑啉核心骨架与乙螨唑噁唑啉核心骨架具有很高的相似性，借鉴本课题组对于噁唑啉类杀螨剂的成功经验，我们认为在苯基苄位连接杂原子取代基，可能有利于其生物活性的提升。便设计合成在异噁唑啉环4-苯基苄位连接氧、氮杂原子基团(结构式一)，并进行杀虫活性研究。
发明内容
针对现有技术不足，本发明提供异噁唑啉衍生物及其制备方法和在防治害虫及抑制植物病菌的应用。本发明的异噁唑啉衍生物具有很好的杀虫和抗植物病菌活性。
本发明新型4-苯基苄位含有(肟)醚、氮杂环结构的异噁唑啉类化合物结构通式为(I)所示结构的化合物：
式中，W为氧(肟)、氮。R为氢、(卤代)烷基、芳基、杂环。Y为F、Br。
本发明所述的4-苯基苄位含有(肟)醚、氮杂环结构的异噁唑啉类化合物(通式I)为下述I-1～I-65所示的化合物(结构式二)。
上述化学结构式I-1～I-65的合成方法如下：
本发明的异噁唑啉衍生物I-1～I-3的合成：按照方程式一所示的方法制备，首先以3,5-二氯苯硼酸(1)和2-溴-3,3-三氟丙烯(2)为原料，碳酸钾为碱，双三苯基膦基氯化钯为催化剂，在四氢呋喃和水中回流得到偶联产物3,5-二氯-1-(1-三氟甲基乙烯基)苯(3)。4-氰基苄溴(4a)经二异丁基氢化铝(DIBAL-H)还原得到4-(溴甲基)苯甲醛(5a)，后在醋酸钠碱催化下，与盐酸羟胺反应生成4-(溴甲基)苯甲醛肟(6a)，然后与上面合成的3在水中，KCl存在下，Oxone氧化环化生成3-(4-(溴甲基)苯基)-5-(3,5-二氯苯基)-5-(三氟甲基)-4,5-二氢异噁唑(7a)。中间体7a与对应醇做溶剂在硫酸亚铁催化下加热回流生成I-1～I-3。
上述方程式中R1分别为I-1～I-3结构中所示基团。
本发明的异噁唑啉衍生物I-4～I-7的合成：按照方程式二所示的方法制备，中间体7a与相应醇，在乙腈做溶剂、氩气保护下，以氢氧化钠为碱、碘化钾为碘离子源，加热回流生成I-4～I-7。
上述方程式中R1分别为I-4～I-7结构中所示基团。
本发明的异噁唑啉衍生物I-8～I-15的合成：按照方程式三所示的方法制备，中间体7a与相应醇，在乙腈做溶剂、氩气保护下，以碳酸钾为碱、碘化钾为碘离子源，加热回流生成I-8～I-15。
上述方程式中R1分别为I-8～I-15结构中所示基团。
本发明的异噁唑啉衍生物I-16～I-17的合成：按照方程式四所示的方法制备，中间体7a与相应酮肟，在超干N,N-二甲基甲酰胺做溶剂，氢化钠为拔氢试剂，室温搅拌生成I-16～I-17。
上述方程式中R2和R3分别为I-16～I-17结构中所示基团。
本发明的异噁唑啉衍生物I-18～I-26的合成：按照方程式五所示的方法制备，中间体7a与相应醇肟，在超干N,N-二甲基甲酰胺做溶剂、氩气保护下，氢化钠为拔氢试剂，室温搅拌生成I-18～I-26。
上述方程式中R2和R3分别为I-18～I-26结构中所示基团。
本发明的异噁唑啉衍生物I-27～I-30的合成：按照方程式六所示的方法制备，中间体7a与相应苯并杂环肟，在乙腈做溶剂，碳酸钾为拔氢试剂，加热回流生成I-27～I-30。
上述方程式中R2和R3分别为I-27～I-30结构中所示基团。
本发明的异噁唑啉衍生物I-31～I-58的合成：按照方程式七所示的方法制备，中间体7a与相应氮杂环，在乙腈做溶剂、氩气保护下，以碳酸钾为碱、碘化钾为碘离子源，加热回流生成I-31～I-58。
上述方程式中R4和R5分别为I-31～I-58结构中所示基团。
本发明的异噁唑啉衍生物I-59～I-62的合成：按照方程式八所示的方法制备，4-氰基-2-氟苄溴(4b)经二异丁基氢化铝(DIBAL-H)还原得到4-(溴甲基)-3-氟苯甲醛(5b)，后在醋酸钠碱催化下，与盐酸羟胺反应生成4-(溴甲基)-3-氟苯甲醛肟(6b)，然后与上面合成的3在水中，KCl存在下，Oxone氧化环化生成3-(4-(溴甲基)-3-氟苯基)-5-(3,5-二氯苯基)-5-(三氟甲基)-4,5-二氢异噁唑(7b)。中间体7b与相应氮杂环，在乙腈做溶剂、氩气保护下，以碳酸钾为碱、碘化钾为碘离子源，加热回流生成I-59～I-62。
上述方程式中R4和R5分别为I-59～I-62结构中所示基团。
本发明的异噁唑啉衍生物I-63～I-65的合成：按照方程式九所示的方法制备，4-氰基-2-溴苄溴(4c)经二异丁基氢化铝(DIBAL-H)还原得到4-(溴甲基)-3-溴苯甲醛(5c)，后在醋酸钠碱催化下，与盐酸羟胺反应生成4-(溴甲基)-3-溴苯甲醛肟(6c)，然后与上面合成的3在水中，KCl存在下，Oxone氧化环化生成3-(4-(溴甲基)-3-溴苯基)-5-(3,5-二氯苯基)-5-(三氟甲基)-4,5-二氢异噁唑(7c)。中间体7c与相应氮杂环，在乙腈做溶剂、氩气保护下，以碳酸钾为碱、碘化钾为碘离子源，加热回流生成I-63～I-65。
上述方程式中R4和R5分别为I-63～I-65结构中所示基团。
本发明的4-苯基苄位含有(肟)醚、氮杂环结构的异噁唑啉类衍生物I-1～I-65表现出很好的杀虫活性，能很好地灭杀小菜蛾、东方粘虫、草地贪夜蛾、棉铃虫、玉米螟、蚊幼虫、跳蚤、蜱、蠕形螨、疥螨、耳螨等。
本发明的4-苯基苄位含有(肟)醚、氮杂环结构的异噁唑啉类衍生物I-1～I-65具有较好的抗植物病菌活性，能很好地抑制黄瓜枯萎、花生褐斑、苹果轮纹、小麦纹枯、玉米小斑、西瓜炭疽、水稻恶苗、番茄早疫、小麦赤霉、水稻稻瘟、辣椒疫霉、油菜菌核、黄瓜灰霉、水稻纹枯14种植物病菌。
具体实施方式
下述的实施例和生测试验结果可用来进一步说明本发明，但不意味着限制本发明。
实施例1：异噁唑啉衍生物I-1的合成。
第一步，中间体3的合成。将3,5-二氯苯基硼酸(1)(57.25g,300mmol)，二氯双(三苯基膦)钯(6.32g,9mmol)加入2L的干燥三口瓶中，氩气置换气三次，然后用注射器加入200mL 3.0M的碳酸钾水溶液及600mL四氢呋喃，随后加入2-溴-3,3,3-三氟丙烯(2)(37.4mL,360mmol)，加热回流搅拌4h。反应结束后，冷却至室温，加入冰水，水相用乙酸乙酯萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，减压浓缩，经石油醚柱层析得无色油状物45.92g，收率64％。
第二步，中间体5a的合成。将4-氰基苄溴(4a)(19.60g,100mmol)溶于300mL无水甲苯中，氩气置换气三次，冰浴冷却至0℃，然后缓慢滴加1M二异丁基氢化铝的正己烷溶液(150mL)。于0℃下再搅拌1h，升至室温继续搅拌1h，然后加入200mL的氯仿稀释。最后，再将混合物冰浴冷却，缓慢加入300mL 10％HCl，在室温继续搅拌1h。反应混合物用乙酸乙酯萃取，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，减压蒸馏，得到粗产物。经正己烷重结晶得到白色固体16.39g，产率83％，熔点94-95℃。1H NMR(400MHz,CDCl3)δ10.01(s,1H),7.86(d,J＝8.0Hz,2H),7.55(d,J＝8.0Hz,2H),4.51(s,2H).13C NMR(100MHz,CDCl3)δ191.7,144.4,136.2,130.3,129.8,32.1.
第三步，中间体6a的合成。在室温下，将中间体5a(19.80g,100mmol)加到乙酸钠(24.61g,300mmol)和盐酸羟胺(13.9g,200mmol)的乙醇：水(1:1)中的溶液中，室温搅拌，TLC监测直到反应示完成。减压旋除大部分乙醇，随后将反应液倒入400mL冰水中，析出大量白色固体，抽滤得蓬松的白色粉末18.24g，收率86％，熔点126-128℃，直接用于下一步。
第四步，中间体7a的合成。将中间体3(60.00g,250mmol)、6a(21.30g,100mmol)和KCl(7.46g,100mmol)加入1L圆底烧瓶中，然后加入750mL水，最后在搅拌下加入Oxone(92.2g,150mmol)，室温搅拌4h。水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，减压浓缩，经(V(石油醚):V(乙酸乙酯)＝60:1)柱层析得白色固体23.25g，收率51％，熔点106-108℃。
第五步：I-1合成。将中间体苄溴7a(451.0mg,1.0mmol)和硫酸亚铁(278.0mg,1.0mmol)加入甲醇(5.0mL)中加热回流，TLC监测。反应结束后，冷却至室温，过滤除去硫酸亚铁，并将残余物用10mL甲醇洗涤，减压浓缩，经(V(石油醚):V(乙酸乙酯)＝20:1)柱层析得无色油状物315.1mg，收率78％；1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.42(t,J＝1.6Hz,1H),7.40(d,J＝8.4Hz,2H),4.49(s,2H),4.09(d,J＝17.2Hz,1H),3.70(d,J＝17.3Hz,1H),3.41(s,3H).13C NMR(100MHz,CDCl3)δ156.0,141.9,139.3,135.7,129.8,128.0,127.1,126.9,125.5,123.9(q,J＝282.7Hz),87.1(q,J＝30.3Hz),74.1,58.5,44.3.19F NMR(376MHz,CDCl3)δ170.50(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C18H15Cl2F3NO2[M+H]+404.0426,found,404.0424.
实施例2：I-2的合成。将中间体苄溴7a(451.0mg,1.0mmol)和硫酸亚铁(278.0mg,1.0mmol)加入乙醇(5.0mL)中加热回流，TLC监测。反应结束后，冷却至室温，过滤除去硫酸亚铁，并将残余物用10mL甲醇洗涤，减压浓缩，经(V(石油醚):V(乙酸乙酯)＝20:1)柱层析得无色油状物300.6mg，收率76％；1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.44–7.38(m,3H),4.53(s,2H),4.09(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H),3.55(q,J＝7.2Hz,2H),1.26(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ156.0,142.3,139.3,135.7,129.8,127.9,127.1,126.8,125.4,123.9(q,J＝282.7Hz),87.1(q,J＝30.2Hz),72.1,66.2,44.3,15.3.19F NMR(376MHz,CDCl3)δ170.49(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C19H17Cl2F3NO2[M+H]+418.0583,found,418.0580.
实施例3：I-3的合成。将中间体苄溴7a(451.0mg,1.0mmol)和硫酸亚铁(278.0mg,1.0mmol)加入异丙醇(5.0mL)中加热回流，TLC监测。反应结束后，冷却至室温，过滤除去硫酸亚铁，并将残余物用10mL甲醇洗涤，减压浓缩，经(V(石油醚):V(乙酸乙酯)＝20:1)柱层析得无色油状物310.4mg，收率75％；1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.43–7.38(m,3H),4.53(s,2H),4.09(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H),3.44(t,J＝6.8Hz,2H),1.69–1.60(m,2H),0.95(t,J＝7.2Hz,3H3).13C NMR(100MHz,CDCl3)δ156.0,142.4,139.3,135.7,129.8,127.9,127.0,126.7,125.4,123.9(q,J＝282.6Hz),87.1(q,J＝30.5Hz),72.5,72.2,44.3,23.0,10.7.19F NMR(376MHz,CDCl3)δ170.50(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C20H19Cl2F3NO2[M+H]+432.0739,found,432.0738.
实施例4：I-4的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，氢氧化钠(48.0mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，三氟乙醇(120.1mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得无色油状物471.0mg，收率95％；1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.4Hz,2H),7.52(d,J＝1.2Hz,2H),7.44–7.39(m,3H),4.71(s,2H),4.10(d,J＝17.2Hz,1H),3.86(q,J＝8.8Hz,2H),3.71(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.9,140.0,139.2,135.7,129.9,128.1,127.6,127.3,125.5,124.1(q,J＝277.7Hz),123.9(q,J＝282.7Hz),87.2(q,J＝30.4Hz),73.5(s),67.7(q,J＝34.1Hz),44.3.19F NMR(376MHz,CDCl3)δ176.01(s),170.45(s).Mass Spectrometry:HRMS-ESI(m/z):calcd forC19H14Cl2F6NO2[M+H]+472.0300,found,472.0296.
实施例5：I-5的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，氢氧化钠(48.0mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-氟乙醇(76.9mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝20:1)柱层析得无色油状物271.2mg，收率62％；1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.44–7.40(m,3H),4.66(t,J＝4.4Hz,1H),4.63(s,2H),4.54(t,J＝4.4Hz,1H),4.09(d,J＝17.2Hz,1H),3.78(t,J＝4.4Hz,1H),3.73–3.67(m,2H).13CNMR(100MHz,CDCl3)δ156.0,141.5,139.3,135.7,129.8,128.0,127.1,127.0,125.4,123.9(q,J＝282.6Hz),87.1(q,J＝30.2Hz),83.2(d,J＝168.3Hz),72.7,69.7(d,J＝19.6Hz),44.3.19FNMR(376MHz,CDCl3)δ170.48(s),26.97(s).MassSpectrometry:HRMS-ESI(m/z):calcd for C19H16Cl2F4NO2[M+H]+436.0489,found,436.0486.
实施例6：I-6的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，氢氧化钠(48.0mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，3-丁炔-1-醇(84.1mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝30:1)柱层析得无色油状物257.2mg，收率58％；1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.4Hz,2H),7.51(d,J＝1.6Hz,2H),7.45–7.39(m,3H),4.59(s,2H),4.09(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,1H),3.61(t,J＝6.8Hz,2H),2.51(td,J＝6.8,2.4Hz,2H),2.00(t,J＝2.4Hz,1H).13C NMR(100MHz,CDCl3)δ156.0,141.7,139.3,135.7,129.8,128.0,127.1,127.0,125.5,123.9(q,J＝282.7Hz),87.1(q,J＝30.2Hz),81.3,72.4,69.6,68.6,44.3,20.0.19F NMR(376MHz,CDCl3)δ170.49(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C21H17Cl2F3NO2[M+H]+442.0583,found,442.0580.
实施例7：I-7的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，氢氧化钠(48.0mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-噻吩甲醇(137.0mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得无色油状物273.6mg，收率56％；1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.44–7.40(m,3H),7.32(dd,J＝4.8,1.2Hz,1H),7.03–6.98(m,2H),4.73(d,J＝0.4Hz,2H),4.59(s,2H),4.09(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ156.0,141.6,140.7,139.3,135.7,129.8,128.2,127.1,127.0,126.8,126.8,126.2,125.5,123.9(q,J＝282.8Hz),87.1(q,J＝30.4Hz),71.0,66.9,44.30(s).19F NMR(376MHz,CDCl3)δ170.51(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C22H17Cl2F3NO2S[M+H]+486.0304,found,486.0300.
实施例8：I-8的合成。于100mL三口烧瓶中加入中间体苄溴7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，对氟苯酚(134.5mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得白色固体463.5mg，收率96％，熔点102-104℃；1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.48(d,J＝8.4Hz,2H),7.42(t,J＝1.6Hz,1H),7.00–6.94(m,2H),6.92–6.86(m,2H),5.07(s,2H),4.09(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ157.6(d,J＝237.5Hz),155.9,154.6(d,J＝1.8Hz),140.4,139.2,135.7,129.9,127.8,127.3,127.3,125.4,123.9(q,J＝282.8Hz),116.1(d,J＝15.5Hz),116.0(d,J＝15.4Hz),87.2(q,J＝30.4Hz),70.0,44.3.19F NMR(376MHz,CDCl3)δ170.49(s),126.68(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C23H16Cl2F4NO2[M+H]+484.0489,found,484.0484.
实施例9：I-9的合成。于100mL三口烧瓶中加入中间体苄溴7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，对氯苯酚(154.3mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得白色固体367.7mg，收率74％，熔点114-115℃；1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.48(d,J＝8.4Hz,2H),7.42(t,J＝1.6Hz,1H),7.24(dt,J＝8.8,3.6Hz,2H),6.88(dt,J＝8.8,3.6Hz,2H),5.08(s,2H),4.09(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ157.1,155.9,140.1,139.2,135.7,129.9,129.6,127.8,127.4,127.3,126.3,125.4,123.9(q,J＝282.6Hz),116.3,87.2(q,J＝30.3Hz),69.7,44.3.19F NMR(376MHz,CDCl3)δ170.51(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C23H16Cl3F3NO2[M+H]+500.0193,found,500.0188.
实施例10：I-10的合成。于100mL三口烧瓶中加入中间体苄溴7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，对氯苯酚(154.3mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得白色固体416.2mg，收率83％，熔点109-111℃；1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.4Hz,2H),7.56–7.51(m,4H),7.42(t,J＝1.6Hz,1H),7.39(dd,J＝8.4,1.6Hz,1H),7.18(td,J＝16.0,1.6Hz,1H),6.95–6.90(m,2H),5.18(s,2H),4.09(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.9,154.0,140.0,139.2,135.7,130.6,129.8,127.8,127.5,127.3,125.4,123.9(q,J＝282.8Hz),123.4,122.15(s),114.2,87.2(q,J＝30.3Hz),70.2,44.2.19F NMR(376MHz,CDCl3)δ170.51(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C23H16Cl3F3NO2[M+H]+500.0193,found,500.0187.
实施例11：I-11的合成。于100mL三口烧瓶中加入中间体苄溴7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，对溴苯酚(207.6mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得白色固体525.5mg，收率97％，熔点133-134℃；1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.47(d,J＝8.4Hz,2H),7.42(t,J＝1.6Hz,1H),7.37(dt,J＝8.8,2.8Hz,2H),6.83(dt,J＝8.8,2.8Hz,2H),5.07(s,2H),4.10(d,J＝17.2Hz,1H),3.71(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ157.6,155.8,140.0,139.2,135.7,132.5,129.8,127.8,127.4,127.3,125.4,123.9(q,J＝282.8Hz),116.8,113.6,87.2(q,J＝30.4Hz),69.6,44.2.19F NMR(376MHz,CDCl3)δ170.49(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C23H16BrCl2F3NO2[M+H]+543.9688,found,543.9682.
实施例12：I-12的合成。于100mL三口烧瓶中加入中间体苄溴7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，对三氟甲基苯酚(194.5mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得白色固体468.0mg，收率87％，熔点117-118℃；1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.50(d,J＝8.4Hz,2H),7.42(t,J＝1.6Hz,1H),7.02(d,J＝8.4Hz,2H),5.15(s,2H),4.10(d,J＝17.2Hz,1H),3.73(s,1H).13C NMR(100MHz,CDCl3)δ160.9,155.9,139.9,139.2,135.7,129.9,127.8,127.5,127.4,127.1(q,J＝3.7Hz),125.4,124.5(q,J＝269.5Hz),124.0(q,J＝282.6Hz),123.5(q,J＝32.5Hz),115.0,87.3(q,J＝30.3Hz),69.5,44.2.19F NMR(376MHz,CDCl3)δ188.43(s),170.50(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H16Cl2F6NO2[M+H]+534.0457,found,534.0452.
实施例13：I-13的合成。于100mL三口烧瓶中加入中间体苄溴7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-羟基吡啶(114.1mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(二氯甲烷):V(甲醇)＝80:1)柱层析得棕色固体362.9mg，收率78％，熔点131-133℃；1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.4Hz,2H),7.49(d,J＝1.6Hz,2H),7.40(t,J＝1.8Hz,1H),7.36–7.29(m,3H),7.26(dd,J＝6.8,2.0Hz,1H),6.60(d,J＝8.8Hz,1H),6.16(td,J＝6.8,0.8Hz,1H),5.14(s,2H),4.04(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.8,139.8,139.7,139.1,137.3,135.6,129.8,128.5,127.4,127.3,125.4,123.9(q,J＝282.6Hz),121.4,106.6,87.2(q,J＝30.2Hz),51.9,44.1.19F NMR(376MHz,CDCl3)δ170.45(s).Mass Spectrometry:HRMS-ESI(m/z):calcd forC22H16Cl2F3N2O2[M+H]+467.0535,found,467.0531.
实施例14：I-14的合成。于100mL三口烧瓶中加入中间体苄溴7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，3-氟-2-羟基吡啶(135.7mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(二氯甲烷):V(甲醇)＝80:1)柱层析得白色固体312.3mg，收率65％，熔点72-74℃；1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.4Hz,2H),7.48(d,J＝1.6Hz,2H),7.38(t,J＝1.6Hz,1H),7.34(d,J＝8.4Hz,2H),7.12(td,J＝7.2,1.6Hz,1H),7.08(td,J＝8.4,1.6Hz,1H),6.10(td,J＝7.2,4.4Hz,1H),5.18(s,2H),4.05(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(101MHz,CDCl3)δ156.53(s),156.28(s),155.78(s),153.95(s),151.46(s),139.05(d,J＝3.8Hz),135.63(s),132.49(d,J＝4.8Hz),129.78(s),128.71(s),127.56(d,J＝4.6Hz),125.31(d,J＝13.8Hz),122.41(s),120.35(d,J＝17.1Hz),119.58(s),104.37(d,J＝5.8Hz),87.67(s),87.37(s),87.07(s),86.77(s),51.92(s),44.07(s).19F NMR(376MHz,CDCl3)δ170.44(s),120.60(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C22H15Cl2F4N2O2[M+H]+485.0441,found,485.0436.
实施例15：I-15的合成。于100mL三口烧瓶中加入中间体苄溴7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-羟基嘧啶(115.3mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(二氯甲烷):V(甲醇)＝80:1)柱层析得白色固体427.7mg，收率92％，熔点196-198℃；1H NMR(400MHz,CDCl3)δ8.59(s,1H),7.72–7.59(m,1H),7.49(s,1H),7.45–7.33(m,1H),7.26(s,1H),6.31(dd,1H),5.11(s,1H),4.06(d,J＝17.2Hz,1H),3.68(d,J＝17.2Hz,1H).13CNMR(100MHz,CDCl3)δ166.4,156.4,155.7,147.5,139.1,138.1,135.7,129.9,129.1,128.0,127.7,125.4,123.8(q,J＝282.5Hz),104.6,87.3(q,J＝30.4Hz),54.0,44.1.19F NMR(376MHz,CDCl3)δ170.42(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C21H15Cl2F3N3O2[M+H]+468.0488,found,468.0484.
实施例16：I-16的合成。将氢化钠(33.0mg,1.5mmol)和丙酮肟(80.84mg,1.1mmol)溶解于无水DMF(5mL)中。搅拌30min后，加入中间体7a(451.0mg,1.0mmol)，室温搅拌，TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝20:1)柱层析得无色油状物303.8mg，收率68％；1HNMR(400MHz,CDCl3)δ7.64(d,J＝8.4Hz,2H),7.51(d,J＝1.6Hz,2H),7.43–7.39(m,3H),5.08(s,2H),4.08(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H),1.90(s,3H),1.86(s,3H).13C NMR(100MHz,CDCl3)δ156.0,155.9,142.1,139.3,135.7,129.8,128.2,127.0,126.8,125.4,123.9(q,J＝282.6Hz),87.1(q,J＝30.3Hz),74.5,44.3,22.0,15.9.19F NMR(376MHz,CDCl3)δ170.52(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C20H18Cl2F3N2O2[M+H]+445.0692,found,445.0688.
实施例17：I-17的合成。将氢化钠(33.0mg,1.5mmol)和环己酮肟(124.5mg,1.1mmol)溶解于无水DMF(5mL)中。搅拌30min后，加入中间体7a(451.0mg,1.0mmol)，室温搅拌，TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得无色油状物352.8mg，收率73％；1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.4Hz,2H),7.43–7.36(m,3H),5.07(s,2H),4.09(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,1H),2.51(t,J＝6.0Hz,2H),2.18(t,J＝6.0Hz,2H),1.70–1.55(m,6H).13C NMR(100MHz,CDCl3)δ161.4,156.0,142.2,139.3,135.7,129.8,128.2,127.0,126.8,125.4,123.9(q,J＝282.6Hz),87.1(q,J＝30.3Hz),74.4,44.3,32.3,27.2,25.9,25.6.19F NMR(376MHz,CDCl3)δ170.52(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C23H22Cl2F3N2O2[M+H]+485.1005,found,485.1001.
实施例18：I-18的合成。将中间体7a(451.0mg,1.0mmol)，4-氟苯甲醛肟(153.0mg,1.1mmol)，氢氧化钠(48.0mg,1.2mmol)加入50mL单口瓶中，氩气置换气三次，后加入5mL甲醇，室温搅拌48h，通过TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝30:1)柱层析得白色固体309.5mg，收率61％，熔点95-96℃；1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.66(d,J＝8.4Hz,2H),7.5–7.52(m,2H),7.51(d,J＝1.6Hz,2H),7.46(d,J＝8.4Hz,2H),7.42(t,J＝1.6Hz,1H),7.05(tt,J＝8.4,2.0Hz,2H),5.21(s,2H),4.08(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ163.91(d,J＝248.9Hz),156.0,148.4,141.2,139.3,135.7,129.9,129.08(d,J＝8.3Hz),128.8,128.34(d,J＝3.3Hz),127.2,127.1,125.5,123.9(q,J＝282.7Hz),116.0(d,J＝21.8Hz),87.2(q,J＝30.3Hz),75.7,44.3.19F NMR(376MHz,CDCl3)δ170.51(s),139.81(s).MassSpectrometry:HRMS-ESI(m/z):calcd for C24H17Cl2F4N2O2[M+H]+511.0598,found,511.0594.
实施例19：I-19的合成。将中间体7a(451.0mg,1.0mmol)，3-氟苯甲醛肟(153.0mg,1.1mmol)，氢氧化钠(48.0mg,1.2mmol)加入50mL单口瓶中，氩气置换气三次，后加入5mL甲醇，室温搅拌48h，通过TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得白色固体312.4mg，收率61％，熔点69-70℃；1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.67(d,J＝8.4Hz,2H),7.52(s,2H),7.47(d,J＝8.4Hz,2H),7.42(t,J＝1.6Hz,1H),7.36–7.26(m,3H),7.06(t,J＝8.0Hz,1H),5.23(s,2H),4.09(d,J＝17.2Hz,1H),3.70(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ163.1(d,J＝245.0Hz),155.9,148.4(d,J＝2.9Hz),141.1,139.34(s),135.7,134.4(d,J＝8.0Hz),130.4(d,J＝8.3Hz),129.9,128.8,127.3,127.2,125.5,124.0(q,J＝282.6Hz),123.4(d,J＝2.9Hz),117.1(d,J＝21.5Hz),113.4(d,J＝22.7Hz),87.2(q,J＝30.2Hz),75.8,44.3.19F NMR(376MHz,CDCl3)δ170.51(s),137.43(s).Mass Spectrometry:HRMS-ESI(m/z):calcd forC24H17Cl2F4N2O2[M+H]+511.0598,found,511.0596.
实施例20：I-20的合成。将中间体7a(451.0mg,1.0mmol)，2-氟苯甲醛肟(153.0mg,1.1mmol)，氢氧化钠(48.0mg,1.2mmol)加入50mL单口瓶中，氩气置换气三次，后加入5mL甲醇，室温搅拌48h，通过TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得无色油状物214.8mg，收率42％；1H NMR(400MHz,CDCl3)δ8.40(s,1H),7.78(t,J＝7.6Hz,1H),7.66(d,J＝7.6Hz,2H),7.51(s,2H),7.47(d,J＝7.6Hz,2H),7.42(s,1H),7.34(dd,J＝9.2,7.6Hz,1H),7.12(t,J＝7.6Hz,1H),7.06(t,J＝9.2Hz,1H),5.24(s,2H),4.08(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ161.0(d,J＝250.8Hz),156.0,143.3(d,J＝4.3Hz),141.2,139.4,135.8,131.7(d,J＝8.4Hz),129.9,128.7,127.3,127.2,127.0(d,J＝2.2Hz),125.3,124.5(d,J＝3.3Hz),124.0(q,J＝282.8Hz),120.0(d,J＝10.8Hz),116.01(d,J＝21.0Hz),87.2(q,J＝30.2Hz),75.8,44.4.19F NMR(376MHz,CDCl3)δ170.51(s),137.43(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H17Cl2F4N2O2[M+H]+511.0598,found,511.0595.
实施例21：I-21的合成。将中间体7a(451.0mg,1.0mmol)，4-氯苯甲醛肟(170.5mg,1.1mmol)，氢氧化钠(48.0mg,1.2mmol)加入50mL单口瓶中，氩气置换气三次，后加入5mL甲醇，室温搅拌48h，通过TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得白色固体287.2mg，收率55％，熔点107-109℃；1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.66(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.49(d,J＝8.4Hz,2H),7.46(d,J＝8.4Hz,2H),7.42(d,J＝1.6Hz,1H),7.33(d,J＝8.4Hz,2H),5.22(s,2H),4.09(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.9,148.4,141.1,139.3,136.0,135.7,130.6,129.8,129.1,128.7,128.4,127.2,127.1,125.5,123.9(q,J＝282.6Hz),87.2(q,J＝30.1Hz),75.7,44.3.19F NMR(376MHz,CDCl3)δ170.51(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H17Cl3F3N2O2[M+H]+527.0302,found,527.0297.
实施例22：I-22的合成。将中间体7a(451.0mg,1.0mmol)，4-溴苯甲醛肟(218.9mg,1.1mmol)，氢氧化钠(48.0mg,1.2mmol)加入50mL单口瓶中，氩气置换气三次，后加入5mL甲醇，室温搅拌48h，通过TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得白色固体304.4mg，收率53％，熔点106-108℃；1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.65(d,J＝8.4Hz,2H),7.51(d,J＝1.6Hz,2H),7.50–7.43(m,4H),7.43–7.39(m,3H),5.21(s,2H),4.08(d,J＝17.2Hz,1H),3.68(d,J＝17.2Hz,1H).13CNMR(100MHz,CDCl3)δ155.9,148.5,141.1,139.3,135.7,132.1,131.0,129.8,128.7,128.6,127.2,127.1,125.4,124.3,123.9(q,J＝282.7Hz),87.2(q,J＝30.3Hz),75.8,44.3.19F NMR(376MHz,CDCl3)δ170.53(s).Mass Spectrometry:HRMS-ESI(m/z):calcd forC24H17BrCl2F3N2O2[M+H]+570.9797,found,570.9791.
实施例23：I-23的合成。将中间体7a(451.0mg,1.0mmol)，4-三氟甲基苯甲醛肟(208.0mg,1.1mmol)，氢氧化钠(48.0mg,1.2mmol)加入50mL单口瓶中，氩气置换气三次，后加入5mL甲醇，室温搅拌48h，通过TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得白色固体341.5mg，收率61％，熔点94-95℃；1H NMR(400MHz,CDCl3)δ8.17(s,1H),7.70–7.64(m,4H),7.61(d,J＝8.4Hz,2H),7.51(d,J＝1.6Hz,2H),7.47(d,J＝8.4Hz,2H),7.42(t,J＝1.6Hz,1H),5.25(s,2H),4.09(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.9,148.1,140.9,139.3,135.7,135.6,131.7(q,J＝32.7Hz),129.8,128.8,127.4,127.4,127.2,125.8(q,J＝3.8Hz),125.5,124.0(q,J＝270.6Hz),123.9(q,J＝282.7Hz),87.2(q,J＝30.6Hz),76.0,44.3.19F NMR(376MHz,CDCl3)δ187.11(s),170.50(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C25H17Cl2F6N2O2[M+H]+561.0566,found,561.0560.
实施例24：I-24的合成。将中间体7a(451.0mg,1.0mmol)，4-三氟甲氧基苯甲醛肟(225.5mg,1.1mmol)，氢氧化钠(48.0mg,1.2mmol)加入50mL单口瓶中，氩气置换气三次，后加入5mL甲醇，室温搅拌48h，通过TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得无色液体354.1mg，收率61％；1HNMR(400MHz,CDCl3)δ8.13(s,1H),7.66(d,J＝8.4Hz,2H),7.59(dt,J＝8.0,2.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.46(d,J＝8.4Hz,2H),7.42(t,J＝1.6Hz,1H),7.20(d,J＝8.0Hz,2H),5.23(s,2H),4.09(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.9,150.4,148.1,141.1,139.3,135.7,130.8,129.9,128.8,128.7,127.3,127.2,125.5,123.9(q,J＝282.6Hz),121.2,120.5(q,J＝256.2Hz),87.2(q,J＝30.1Hz),75.8,44.3.19F NMR(376MHz,CDCl3)δ192.14(s),170.49(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C25H17Cl2F6N2O3[M+H]+577.0515,found,577.0508.
实施例25：I-25的合成。将中间体7a(451.0mg,1.0mmol)，4-甲硫基苯甲醛肟(183.8mg,1.1mmol)，氢氧化钠(48.0mg,1.2mmol)加入50mL单口瓶中，氩气置换气三次，后加入5mL甲醇，室温搅拌48h，通过TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得白色固体357.1mg，收率66％，熔点100-101℃；1H NMR(400MHz,CDCl3)δ8.09(s,1H,CH),7.65(d,J＝8.4Hz,2H),7.52(d,J＝1.6Hz,2H),7.49–7.44(m,4H),7.42(t,J＝1.6Hz,1H),7.21(d,J＝8.4Hz,2H),5.21(s,2H),4.08(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H),2.48(s,3H).13C NMR(100MHz,CDCl3)δ156.0,149.1,141.4,141.3,139.3,135.7,129.8,128.7,127.5,127.2,127.1,126.2,125.5,123.9(q,J＝282.7Hz),87.2(q,J＝30.4Hz),75.6,44.3,15.4.19F NMR(376MHz,CDCl3)δ170.52(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C25H20Cl2F3N2O2S[M+H]+539.0569,found,539.0562.
实施例26：I-26的合成。将中间体7a(451.0mg,1.0mmol)，2-吡啶甲醛肟(134.3mg,1.1mmol)，氢氧化钠(48.0mg,1.2mmol)加入50mL单口瓶中，氩气置换气三次，后加入5mL甲醇，室温搅拌48h，通过TLC监测反应进程。反应结束后，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝40:1)柱层析得无色液体301.0mg，收率61％；1HNMR(400MHz,CDCl3)δ8.60(d,J＝4.8Hz,1H),8.24(s,1H),7.75(d,J＝8.0Hz,1H),7.69–7.63(m,3H),7.50(d,J＝1.6Hz,2H),7.46(d,J＝8.0Hz,2H),7.40(t,J＝1.6Hz,1H),7.25(ddd,J＝7.6,4.8,1.2Hz,1H),5.27(s,2H),4.08(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.9,151.5,150.3,149.8,140.9,139.3,136.6,135.7,129.8,128.7,127.3,127.1,125.4,124.2,123.9(q,J＝282.8Hz),121.2,87.2(q,J＝30.4Hz),76.0,44.3.19F NMR(376MHz,CDCl3)δ170.52(s).Mass Spectrometry:HRMS-ESI(m/z):calcd forC23H17Cl2F3N3O2[M+H]+494.0644,found,494.0640.
实施例27：I-27的合成。将中间体7a(451.0mg,1.0mmol)，苯并呋喃-2-甲醛肟(193.3mg,1.2mmol)，碳酸钾(359.3mg,2.6mmol)加入50mL单口瓶中，并加入6mL乙腈，加热回流12h。反应结束后冷却至室温，加入水和乙酸乙酯分层，水相用乙酸乙酯萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝30:1)柱层析得白色固体224.2mg，收率42％，熔点88-90℃；1HNMR(400MHz,CDCl3)δ8.16(s,1H),7.67(d,J＝8.4Hz,2H),7.58(d,J＝7.6Hz,1H),7.55–7.50(m,3H),7.48(d,J＝8.4Hz,2H),7.41(t,J＝1.6Hz,1H),7.35(td,J＝7.6,0.8Hz,1H),7.25(d,J＝7.6Hz,1H),6.95(s,1H),5.31(s,2H),4.08(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.9,155.6,148.6,140.6,140.2,139.3,135.7,129.8,128.8,127.8,127.4,127.2,126.4,125.5,123.9(q,J＝282.8Hz),123.6,121.7,111.8,110.3,87.2(q,J＝30.2Hz),76.2,44.3.19F NMR(376MHz,CDCl3)δ170.49(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C26H18Cl2F3N2O3[M+H]+533.0641,found,533.0636.
实施例28：I-28的合成。将中间体7a(451.0mg,1.0mmol)，苯并噻吩-2-甲醛肟(212.4mg,1.2mmol)，碳酸钾(359.3mg,2.6mmol)加入50mL单口瓶中，并加入6mL乙腈，加热回流12h。反应结束后冷却至室温，加入水和乙酸乙酯分层，水相用乙酸乙酯萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝30:1)柱层析得白色固体346.7mg，收率63％，熔点153-155℃；1H NMR(400MHz,CDCl3)δ8.37(s,1H),7.78(dd,J＝6.0,2.0Hz,1H),7.73(dd,J＝6.0,2.0Hz,1H),7.66(d,J＝8.4Hz,2H),7.52(d,J＝0.8Hz,2H),7.48(d,J＝8.4Hz,2H),7.42(t,J＝1.6Hz,1H),7.38(s,1H),7.37–7.31(m,2H),5.24(s,2H),4.08(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.9,144.8,140.8,140.1,139.3,139.2,135.9,135.7,129.8,128.9,127.3,127.1,126.1,125.4,124.8,124.2,123.9(q,J＝282.7Hz),122.5,87.2(q,J＝30.2Hz),76.0,44.3.19F NMR(376MHz,CDCl3)δ170.52(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C26H18Cl2F3N2O2S[M+H]+549.0413,found,549.0408.
实施例29：I-29的合成。将中间体7a(451.0mg,1.0mmol)，1-(苯并噻吩-2-基)乙烷-1-酮肟(229.2mg,1.2mmol)，碳酸钾(359.3mg,2.6mmol)加入50mL单口瓶中，并加入6mL乙腈，加热回流12h。反应结束后冷却至室温，加入水和乙酸乙酯分层，水相用乙酸乙酯萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝30:1)柱层析得白色固体344.8mg，收率61％，熔点167-168℃；1H NMR(400MHz,CDCl3)δ7.78–7.70(m,2H),7.66(d,J＝8.4Hz,2H),7.55–7.39(m,6H),7.37–7.29(m,2H),5.26(s,2H),4.08(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H),2.33(s,3H).13C NMR(100MHz,CDCl3)δ156.0,151.9,141.2,140.6,140.1,139.4,139.3,135.7,129.8,128.9,127.2,127.1,125.8,125.5,124.5,124.0,123.9(q,J＝282.8Hz),123.6,122.3,87.1(q,J＝30.3Hz),75.9,44.3,12.8.19F NMR(376MHz,CDCl3)δ170.54(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C27H20Cl2F3N2O2S[M+H]+563.0569,found,563.0561.
实施例30：I-30的合成。将中间体7a(451.0mg,1.0mmol)，1-甲基吲哚-2-甲醛肟(208.9mg,1.2mmol)，碳酸钾(359.3mg,2.6mmol)加入50mL单口瓶中，并加入6mL乙腈，加热回流12h。反应结束后冷却至室温，加入水和乙酸乙酯分层，水相用乙酸乙酯萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝30:1)柱层析得白色固体183.8mg，收率34％，熔点128-130℃；1H NMR(400MHz,CDCl3)δ8.26(s,1H),7.67(d,J＝8.4Hz,2H),7.60(d,J＝8.0Hz,1H),7.52(s,,J＝0.8Hz,2H),7.49(d,J＝8.4Hz,2H),7.42(t,J＝2.0Hz,1H),7.30(td,J＝7.2,2.0Hz,2H),7.11(td,J＝7.2,2.0Hz,1H),6.71(s,1H),5.24(s,2H),4.09(d,J＝17.2Hz,1H),3.93(s,3H),3.70(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.9,143.5,141.3,139.8,139.3,135.7,131.1,129.8,128.8,127.3,127.2,127.1,125.4,123.9(q,J＝282.7Hz),123.8,121.4,120.2,109.6,108.2,87.2(q,J＝30.4Hz),75.9,44.3,32.3.19F NMR(376MHz,CDCl3)δ170.54(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C27H21Cl2F3N3O2[M+H]+546.0957,found,546.0956.
实施例31：I-31的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-羟基噻唑(121.4mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体425.0mg，收率90％，熔点84-86℃；1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.4Hz,2H),7.50(d,J＝1.6Hz,2H),7.40(t,J＝1.6Hz,1H),7.30(d,J＝8.4Hz,2H),6.50(d,J＝5.2Hz,1H),6.13(d,J＝5.2Hz,1H),4.88(s,2H),4.07(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ172.1,155.7,139.2,139.1,135.7,129.8,128.4,127.6,127.5,125.4,124.0,123.8(q,J＝282.6Hz),102.1,87.2(q,J＝30.4Hz),48.3,44.1.19F NMR(376MHz,CDCl3)δ170.48(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C20H14Cl2F3N2O2S[M+H]+473.0100,found,473.0095.
实施例32：I-32的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-羟基苯并噻唑(181.4mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体483.8mg，收率93％，熔点74-75℃。1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.0Hz,2H),7.49(d,J＝1.6Hz,2H),7.44(d,J＝7.6Hz,1H),7.39(t,J＝1.6Hz,1H),7.34(d,J＝8.1Hz,2H),7.21(t,J＝7.6Hz,1H),7.14(t,J＝7.6Hz,1H),6.89(d,J＝7.6Hz,1H),5.17(s,2H),4.05(d,J＝17.2Hz,1H),3.66(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ170.4,155.7,139.1,138.5,136.7,135.7,129.8,127.8,127.6,127.4,126.6,125.4,123.8(q,J＝282.6Hz),123.6,122.9,122.7,111.1,87.2(q,J＝30.4Hz),45.9,44.1.19F NMR(376MHz,CDCl3)δ170.54(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H16Cl2F3N2O2S[M+H]+523.0256,found,523.0250.
实施例33：I-33的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，4-氟苯并噻唑-2-酮(203.0mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体512.3mg，收率95％，熔点75-77℃。1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.0Hz,2H),7.49(d,J＝1.6Hz,2H),7.40(t,J＝1.6Hz,1H),7.37(d,J＝8.0Hz,2H),7.21(d,J＝7.5Hz,1H),7.09(td,J＝8.0,4.4Hz,1H),6.97(dd,J＝12.0,8.0Hz,1H),5.33(s,2H),4.05(d,J＝17.2Hz,1H),3.66(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ169.9,155.8,148.2(d,J＝244.6Hz),139.7,139.2,135.7,129.8,127.9(d,J＝1.3Hz),127.4,127.2,125.4,124.8(d,J＝3.6Hz),124.6(d,J＝10.1Hz),123.9(d,J＝7.4Hz),123.8(q,J＝282.6Hz),118.7(d,J＝3.6Hz),114.2(d,J＝20.1Hz),87.2(q,J＝30.3Hz),47.7(d,J＝7.3Hz),44.2.19F NMR(376MHz,CDCl3)δ170.55(s),119.82(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H15Cl2F4N2O2S[M+H]+541.0162,found,541.0159.
实施例34：I-34的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，6-氯苯并噻唑-2-酮(222.8mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体447.8mg，收率81％，熔点153-154℃。1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.0Hz,2H),7.49(d,J＝1.6Hz,2H),7.41(d,J＝2.0Hz,1H),7.39(t,J＝1.6Hz,1H),7.31(d,J＝8.0Hz,2H),7.15(dd,J＝8.8,2.0Hz,1H),6.80(d,J＝8.8Hz,1H),5.14(s,2H),4.05(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ169.7,155.6,139.1,138.0,135.7,135.2,129.8,129.0,127.7,127.7,127.6,126.8,125.4,124.1,123.8(q,J＝282.7Hz),122.7,111.9,87.25(q,J＝30.4Hz),46.1,44.1.19F NMR(376MHz,CDCl3)δ170.53(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H15Cl3F3N2O2S[M+H]+556.9866,found,556.9864.
实施例35：I-35的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-氯苯并噻唑-2-酮(222.8mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体469.0mg，收率84％，熔点92-94℃。1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.4Hz,2H),7.50(d,J＝1.6Hz,2H),7.41(t,J＝1.6Hz,1H),7.38–7.32(m,3H),7.13(dd,J＝8.0,2.0Hz,1H),6.89(d,J＝2.0Hz,1H),5.14(s,2H),4.06(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ170.4,155.6,139.1,137.9,137.6,135.7,132.6,129.9,127.8,127.7,125.4,123.8,123.8(q,J＝282.7Hz),123.7,120.9,111.5,87.3(q,J＝30.3Hz),46.1,44.2.19F NMR(376MHz,CDCl3)δ-79.38(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H15Cl3F3N2O2S[M+H]+556.9866,found,556.9863.
实施例36：I-36的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，4-氯苯并噻唑-2-酮(222.8mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体483.5mg，收率87％，熔点76-77℃。1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.0Hz,2H),7.50(d,J＝1.6Hz,2H),7.39(d,J＝1.6Hz,1H),7.36(d,J＝8.0Hz,1H),7.24–7.18(m,3H),7.07(t,J＝8.0Hz,1H),5.65(s,2H),4.05(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ170.4,155.8,140.4,139.2,135.6,132.9,129.7,129.5,127.3,126.8,125.4,125.0,124.0,123.8(q,J＝282.7Hz),121.6,117.0,87.1(q,J＝30.3Hz),47.7,44.1.19F NMR(376MHz,CDCl3)δ-79.31(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H15Cl3F3N2O2S[M+H]+556.9866,found,556.9863.
实施例37：I-37的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，6-硝基苯并噻唑-2-酮(235.4mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体407.1mg，收率72％，熔点108-110℃；1H NMR(400MHz,CDCl3)δ8.37(d,J＝2.0Hz,1H),8.12(dd,J＝9.2,2.0Hz,1H),7.65(d,J＝8.4Hz,2H),7.48(d,J＝1.6Hz,2H),7.40(t,J＝1.6Hz,1H),7.34(d,J＝8.4Hz,2H),7.01(d,J＝9.2Hz,1H),5.23(s,2H),4.05(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ170.0,155.5,143.8,141.4,139.0,137.2,135.7,129.9,127.9,127.8,127.8,125.4,123.8(q,J＝282.9Hz),123.6,122.9,118.9,110.7,87.3(q,J＝30.4Hz),46.5,44.0.19F NMR(376MHz,CDCl3)δ170.48(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H15Cl2F3N3O4S[M+H]+568.0107,found,568.0111.
实施例38：I-38的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-甲氧基苯并噻唑-2-酮(217.5mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体505.5mg，收率91％，熔点89-91℃。1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.4Hz,2H),7.49(d,J＝1.6Hz,2H),7.39(t,J＝1.6Hz,1H),7.33(d,J＝8.4Hz,2H),7.30(d,J＝8.4Hz,1H),6.71(dd,J＝8.4,2.4Hz,1H),6.46(d,J＝2.4Hz,1H),5.12(s,2H),4.05(d,J＝17.2Hz,1H),3.73(s,3H),3.66(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ171.3,159.1,155.7,139.1,138.5,137.7,135.6,129.8,127.7,127.6,127.4,125.4,123.8(q,J＝282.7Hz),123.4,113.6,109.1,98.6,87.2(q,J＝30.3Hz),55.7,45.9,44.1.19F NMR(376MHz,CDCl3)δ170.54(s).MassSpectrometry:HRMS-ESI(m/z):calcd for C25H18Cl2F3N2O3S[M+H]+553.0362,found,553.0359.
实施例39：I-39的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，6-甲氧基苯并噻唑-2-酮(217.5mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体481.0mg，收率87％，熔点78-79℃。1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.0Hz,2H),7.49(d,J＝1.6Hz,2H),7.39(t,J＝1.6Hz,1H),7.32(d,J＝8.0Hz,2H),7.00(d,J＝2.0Hz,1H),6.80–6.73(m,2H),5.13(s,2H),4.04(d,J＝17.2Hz,1H),3.77(s,3H),3.66(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ170.0,156.4,155.7,139.1,138.6,135.7,130.4,129.8,127.8,127.6,127.3,125.4,123.8(q,J＝282.8Hz),123.7,113.0,111.7,108.2,87.2(q,J＝30.4Hz),55.9,45.9,44.1.19F NMR(376MHz,CDCl3)δ170.53(s).Mass Spectrometry:HRMS-ESI(m/z):calcd forC25H18Cl2F3N2O3S[M+H]+553.0362,found,553.0359.
实施例40：I-40的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，6-乙氧基苯并噻唑-2-酮(234.3mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体460.1mg，收率81％，熔点176-177℃。1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.0Hz,2H),7.49(d,J＝1.6Hz,2H),7.41(t,J＝1.6Hz,1H),7.33(d,J＝8.0Hz,2H),7.00(s,1H),6.79–6.72(m,2H),5.13(s,2H),4.04(d,J＝17.2Hz,1H),3.98(q,J＝6.8Hz,2H),3.65(d,J＝17.2Hz,1H),1.39(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ170.0,155.72,155.70,139.1,138.6,135.7,130.4,129.8,127.8,127.5,127.3,125.4,123.8(q,J＝282.6Hz),123.6,113.7,111.7,108.9,87.2(q,J＝30.4Hz),64.3,45.9,44.1,14.9.19F NMR(376MHz,CDCl3)δ-79.40(s).MassSpectrometry:HRMS-ESI(m/z):calcd for C26H20Cl2F3N2O3S[M+H]+567.0518,found,567.0510.
实施例41：I-41的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，苯并噁唑-2-酮(162.1mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体359.5mg，收率71％，熔点153-155℃；1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.4Hz,2H),7.49(d,J＝1.6Hz,2H),7.44–7.37(m,3H),7.24–7.19(m,1H),7.14–7.06(m,2H),6.82–6.77(m,1H),5.03(s,2H),4.06(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.7,154.7,142.7,139.1,138.0,135.7,130.6,129.8,128.2,127.7,127.6,124.1,123.8(q,J＝282.7Hz),122.9,110.3,108.8,87.3(q,J＝30.4Hz),45.7,44.1.19F NMR(376MHz,CDCl3)δ170.50(s).MassSpectrometry:HRMS-ESI(m/z):calcd for C24H16Cl2F3N2O3[M+H]+507.0485,found,507.0484.
实施例42：I-42的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-氟苯并噁唑-2-酮(183.7mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体501.1mg，收率96％，熔点85-86℃；1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.4Hz,2H),7.50(d,J＝1.6Hz,2H),7.44–7.37(m,3H),7.15(dd,J＝8.8,4.0Hz,1H),6.79(td,J＝8.8,2.4Hz,1H),6.54(dd,J＝7.6,2.4Hz,1H),5.01(s,2H),4.07(d,J＝17.2Hz,1H),3.68(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ159.5(d,J＝241.0Hz),155.6,155.0,139.1,138.7(d,J＝1.7Hz),137.4,135.7,131.4(d,J＝12.8Hz),129.9,128.3,128.1,127.8,125.4,123.8(q,J＝282.7Hz),110.9(d,J＝9.4Hz),109.2(d,J＝24.4Hz),97.5(d,J＝29.6Hz),87.4(q,J＝30.5Hz),46.0,44.2.19FNMR(376MHz,CDCl3)δ-79.41(s),-116.21(s).Mass Spectrometry:HRMS-ESI(m/z):calcdfor C24H15Cl2F4N2O3[M+H]+525.0390,found,525.0388.
实施例43：I-43的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，6-氯苯并噁唑-2-酮(203.5mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体493.7mg，收率91％，熔点71-73℃；1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.4Hz,2H),7.49(d,J＝1.6Hz,2H),7.41(t,J＝1.6Hz,1H),7.38(d,J＝8.4Hz,2H),7.24(d,J＝2.0Hz,1H),7.07(dd,J＝8.4,2.0Hz,1H),6.70(d,J＝8.4Hz,1H),5.02(s,2H),4.06(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13CNMR(100MHz,CDCl3)δ155.6,154.4,143.0,139.1,137.5,135.7,129.9,129.3,128.5,128.3,128.0,127.8,125.4,124.2,123.8(q,J＝282.7Hz),111.3,109.4,87.3(q,J＝30.3Hz),46.0,44.1.19F NMR(376MHz,CDCl3)δ-79.42(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H15Cl3F3N2O3[M+H]+541.0095,found,541.0091.
实施例44：I-44的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-氯苯并噁唑-2-酮(203.5mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体498.8mg，收率92％，熔点68-70℃；1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.4Hz,2H),7.50(d,J＝1.6Hz,2H),7.42–7.38(m,3H),7.14(d,J＝8.4Hz,1H),7.08(dd,J＝8.4,2.0Hz,1H),6.79(d,J＝2.0Hz,1H),5.01(s,2H),4.07(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.6,154.6,141.2,139.1,137.4,135.8,131.6,129.9,129.7,128.2,128.1,127.8,125.4,123.8(q,J＝282.7Hz),122.9,111.2,109.3,87.3(q,J＝30.2Hz),46.0,44.2.19F NMR(376MHz,CDCl3)δ-79.40(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H15Cl3F3N2O3[M+H]+541.0095,found,541.0092.
实施例45：I-45的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，6-溴苯并噁唑-2-酮(256.8mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体535.6mg，收率92％，熔点77-78℃；1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.0Hz,2H),7.49(d,J＝1.6Hz,2H),7.40(t,J＝1.6Hz,1H),7.39–7.35(m,3H),7.21(dd,J＝8.4,2.0Hz,1H),6.66(d,J＝8.4Hz,1H),5.01(s,2H),4.06(d,J＝17.2Hz,1H),3.68(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.6,154.2,143.1,139.0,137.4,135.7,129.9,129.8,128.2,128.0,127.7,127.0,125.4,123.8(q,J＝282.8Hz),115.3,113.9,109.9,87.3(q,J＝30.6Hz),45.9,44.1.19F NMR(376MHz,CDCl3)δ-79.43(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H15BrCl2F3N2O3[M+H]+587.9590,found,587.9582.
实施例46：I-46的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-溴苯并噁唑-2-酮(256.8mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体571.4mg，收率98％，熔点77-79℃；1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.4Hz,2H),7.50(d,J＝1.6Hz,2H),7.43–7.36(m,3H),7.23(dd,J＝8.4,2.0Hz,1H),7.08(d,J＝8.4Hz,1H),6.94(d,J＝2.0Hz,1H),5.00(s,2H),4.07(d,J＝17.2Hz,1H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.6,154.4,141.7,139.1,137.3,135.7,131.9,129.9,128.2,128.0,127.8,125.8,125.4,123.8(q,J＝282.7Hz),116.7,112.0,111.7,87.3(q,J＝30.4Hz),45.9,44.1.19F NMR(376MHz,CDCl3)δ-79.39(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H15BrCl2F3N2O3[M+H]+587.9590,found,587.9589.
实施例47：I-47的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，6-硝基苯并噁唑-2-酮(216.1mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体483.1mg，收率88％，熔点105-107℃；1H NMR(400MHz,CDCl3)δ8.13–8.08(m,2H),7.68(d,J＝8.4Hz,2H),7.48(d,J＝1.6Hz,2H),7.45–7.38(m,3H),6.91(d,J＝9.2Hz,1H),5.10(s,2H),4.06(d,J＝17.2Hz,1H),3.68(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.5,154.2,143.6,142.1,139.0,136.6,136.0,135.7,129.9,128.3,127.9,125.4,123.8(q,J＝282.7Hz),121.1,108.1,106.6,87.2(q,J＝30.4Hz),46.3,44.0.19F NMR(376MHz,CDCl3)δ-79.45(s).MassSpectrometry:HRMS-ESI(m/z):calcd for C24H15Cl2F3N3O5[M+H]+552.0335,found,552.0334.
实施例48：I-48的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-羟基苯并咪唑(161.0mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝3:1)柱层析得白色固体381.1mg，收率87％，熔点193-195℃。1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.0Hz,4H),7.50(d,J＝1.6Hz,4H),7.41(t,J＝1.6Hz,2H),7.38(d,J＝8.0Hz,4H),7.02–6.96(m,2H),6.87–6.81(m,2H),5.14(s,4H),4.05(d,J＝17.2Hz,2H),3.67(d,J＝17.2Hz,2H).13C NMR(100MHz,CDCl3)δ155.7,154.5,139.6,139.2,135.7,129.9,129.1,128.1,127.5,127.3,125.4,123.9(q,J＝282.6Hz),121.9,108.4,87.2(q,J＝30.3Hz),44.8,44.2.19F NMR(376MHz,CDCl3)δ170.50(s).MassSpectrometry:HRMS-ESI(m/z):calcd for C41H27Cl4F6N4O3[M+H]+877.0736,found,877.0734.
实施例49：I-49的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-氟-1,3-二氢苯并咪唑-2-酮(182.6mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝3:1)柱层析得白色固体256.6mg，收率59％，熔点119-120℃。1H NMR(400MHz,CDCl3)δ7.67–7.60(m,4H),7.53–7.47(m,4H),7.42–7.40(m,2H),7.39–7.33(m,4H),6.75–6.65(m,2H),6.58(dd,J＝8.0,1.6Hz,1H),5.15–5.08(m,4H),4.12–4.00(m,2H),3.72–3.63(m,2H).13C NMR(100MHz,CDCl3)δ160.1,157.7,155.7,154.8,139.3,139.2,139.0,135.7,129.9,129.8,129.7,128.1,128.1,127.6,127.6,127.5,127.5,125.4,125.3,125.2,123.9(q,J＝282.7Hz),108.8,108.7,108.4,108.2,97.2,96.9,87.3(q,J＝30.3Hz),45.0,44.9,44.2.19F NMR(376MHz,CDCl3)δ-79.39(s),-79.41(s),-119.60(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C41H26Cl4F7N4O3[M+H]+895.0642,found,895.0643.
实施例50：I-50的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-氯-1,3-二氢苯并咪唑-2-酮(202.3mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝3:1)柱层析得白色固体297.0mg，收率65％，熔点121-122℃。1H NMR(400MHz,CDCl3)δ7.68–7.59(m,4H),7.54–7.46(m,4H),7.43–7.39(m,2H),7.39–7.33(m,4H),6.95(dd,J＝8.4,1.2Hz,1H),6.83(d,J＝1.2Hz,1H),6.73(d,J＝8.4Hz,1H),5.12(s,2H),5.10(s,2H),4.12–4.01(m,2H),3.74–3.62(m,2H).13C NMR(100MHz,CDCl3)δ155.7,154.4,139.1,139.1,139.0,138.9,135.7,130.0(s),129.9,128.0,127.7,127.6,127.6,127.5,127.5,127.4,125.4,123.9(q,J＝282.6Hz),121.9,109.1,108.8,87.3(q,J＝30.4Hz),44.9,44.2.19F NMR(376MHz,CDCl3)δ-79.38(s),-79.40(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C41H26Cl5F6N4O3[M+H]+911.0346,found,911.0342.
实施例51：I-51的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-溴-1,3-二氢苯并咪唑-2-酮(255.6mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝3:1)柱层析得白色固体368.4mg，收率77％，熔点127-129℃。1H NMR(400MHz,CDCl3)δ7.67–7.59(m,4H),7.53–7.48(m,4H),7.43–7.39(m,2H),7.39–7.31(m,4H),7.10(dd,J＝8.4,1.6Hz,1H),6.96(d,J＝1.6Hz,1H),6.68(d,J＝8.4Hz,1H),5.12(s,2H),5.10(s,2H),4.14–3.99(m,2H),3.74–3.59(m,2H).13C NMR(100MHz,CDCl3)δ155.7,155.7,154.3,139.1,139.1,139.0,138.9,135.7,130.3,129.9,128.2,128.1,128.0,127.7,127.6,127.5,127.5,125.4,124.7,123.9(q,J＝282.6Hz),114.6,111.5,109.6,87.3(q,J＝30.2Hz),44.9,44.2.19F NMR(376MHz,CDCl3)δ-79.38(s),-79.41(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C41H25BrCl4F6N4NaO3[M+Na]+976.9661,found,976.9663.
实施例52：I-52的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-硝基-1,3-二氢苯并咪唑-2-酮(215.0mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝3:1)柱层析得白色固体364.3mg，收率79％，熔点133-134℃。1H NMR(400MHz,CDCl3)δ7.97(dd,J＝8.4,1.6Hz,1H),7.74(d,J＝1.6Hz,1H),7.70–7.60(m,4H),7.52–7.46(m,4H),7.44–7.33(m,6H),6.90(d,J＝8.4Hz,1H),5.19(s,4H),4.12–4.00(m,2H),3.74–3.62(m,2H).13C NMR(100MHz,CDCl3)δ155.6,155.6,154.7,143.0,139.1,139.1,138.3,138.2,135.7,134.1,129.9,129.1,128.2,128.1,127.9,127.8,127.8,125.4,123.9(q,J＝282.7Hz),118.9,107.7,104.1,87.3(q,J＝30.2Hz),45.2,45.2,44.1.Mass Spectrometry:HRMS-ESI(m/z):calcd for C41H26Cl4F6N5O5[M+H]+922.0587,found,922.0583.
实施例53：I-53的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-氧代-2,3-二氢-1H-1,3-苯并咪唑-5-羧酸甲酯(230.6mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝3:1)柱层析得白色固体374.9mg，收率80％，熔点128-130℃。1H NMR(400MHz,CDCl3)δ7.75(dd,J＝8.4,1.2Hz,1H),7.66–7.59(m,4H),7.56(d,J＝1.2Hz,1H),7.52–7.46(m,4H),7.43–7.33(m,6H),6.87(d,J＝8.4Hz,1H),5.16(s,4H),4.05(d,J＝17.2Hz,2H),3.85(s,3H),3.67(d,J＝17.2Hz,2H).13C NMR(100MHz,CDCl3)δ166.8,155.7,155.7,154.7,139.1,139.1,139.1,138.9,135.7,132.9,129.85(s),129.0,128.1,127.6,127.5,127.5,125.4,124.5,124.1,123.9(q,J＝282.7Hz),109.4,107.8,87.2(q,J＝30.1Hz),52.3,45.0,44.9,44.2.19F NMR(376MHz,CDCl3)δ-79.39(s),-79.42(s).Mass Spectrometry:HRMS-ESI(m/z):calcd forC43H29Cl4F6N4O5[M+H]+935.0791,found,935.0786.
实施例54：I-54的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-甲基-1,3-二氢苯并咪唑-2-酮(177.8mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝3:1)柱层析得白色固体271.4mg，收率61％，熔点122-123℃。1H NMR(400MHz,CDCl3)δ7.68–7.59(m,4H),7.54–7.46(m,4H),7.43–7.40(m,2H),7.40–7.34(m,4H),6.80(d,J＝8.0Hz,1H),6.71(d,J＝8.0Hz,1H),6.66(s,1H),5.12(s,4H),4.14–3.98(m,2H),3.75–3.60(m,2H),2.29(s,3H).13C NMR(100MHz,CDCl3)δ155.8,155.8,154.6,139.7,139.2,1357,131.8,129.8,129.3,128.1,128.0,127.5,127.5,127.2,126.9,125.4,123.9(q,J＝282.7Hz),122.4,109.0,108.2,87.2(q,J＝30.3Hz),44.8,44.7,44.2,21.6.19F NMR(376MHz,CDCl3)δ-79.40(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C42H29Cl4F6N4O3[M+H]+891.0892,found,891.0889.
实施例55：I-55的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5,6-二甲基-2-苯并咪唑啉酮(194.6mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝3:1)柱层析得白色固体185.2mg，收率41％，熔点122-124℃。1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.4Hz,4H),7.50(d,J＝1.6Hz,4H),7.41(t,J＝1.6Hz,2H),7.36(d,J＝8.4Hz,4H),6.62(s,2H),5.11(s,4H),4.06(d,J＝17.2Hz,2H),3.67(d,J＝17.2Hz,2H),2.18(s,6H).13C NMR(100MHz,CDCl3)δ155.8,154.6,139.9,139.2,135.7,130.2,129.9,128.0,127.5,127.2,127.1,125.4,123.9(q,J＝282.6Hz),109.6,89.2(q,J＝30.4Hz),44.7,44.2,20.1.19F NMR(376MHz,CDCl3)δ-79.41(s).MassSpectrometry:HRMS-ESI(m/z):calcd for C42H29Cl4F6N4O3[M+H]+905.1049,found,905.1046.
实施例56：I-56的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，1-甲基-2-苯咪唑啉酮(177.8mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝3:1)柱层析得白色固体341.7mg，收率66％，熔点141-143℃。1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.4Hz,2H),7.49(d,J＝1.6Hz,2H),7.39(t,J＝1.6Hz,1H),7.36(d,J＝8.4Hz,2H),7.09(t,J＝7.2Hz,1H),7.00(t,J＝7.2Hz,2H),6.81(d,J＝7.2Hz,1H),5.09(s,2H),4.05(d,J＝17.2Hz,1H),3.66(d,J＝17.2Hz,1H),3.46(s,3H).13C NMR(100MHz,CDCl3)δ155.8,154.6,139.8,139.1,135.6,130.2,129.8,128.9,128.1,127.4,127.1,125.4,123.9(q,J＝282.6Hz),121.7,121.5,108.1,107.7,87.1(q,J＝30.5Hz),44.6,44.1,27.4.19F NMR(376MHz,CDCl3)δ-79.39(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C23H16Cl2F3N4O2[M+H]+520.0801,found,520.0799.
实施例57：I-57的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，吡啶三唑酮(162.1mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝1:1)柱层析得白色固体354.2mg，收率70％，熔点159-161℃。1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.2Hz,1H),7.63(d,J＝8.4Hz,2H),7.49(d,J＝1.6Hz,2H),7.44(d,J＝8.4Hz,2H),7.40(d,J＝1.4Hz,1H),7.11–7.03(m,2H),6.49(td,J＝6.4,1.6Hz,1H),5.17(s,2H),4.04(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ155.8,148.8,142.0,139.2,139.1,135.7,130.3,129.8,129.0,127.5,127.4,125.4,123.9,123.8(q,J＝282.8Hz),115.6,110.8,87.2(q,J＝30.3Hz),49.4,44.2.19F NMR(376MHz,CDCl3)δ-79.47(s).Mass Spectrometry:HRMS-ESI(m/z):calcd forC23H16Cl2F3N4O2[M+H]+507.0597,found,507.0594.
实施例58：I-58的合成。于100mL三口烧瓶中加入中间体7a(451.0mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-甲氧基-1,3,4-噻二唑-2-酮(158.6mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体404.6mg，收率80％。1HNMR(400MHz,CDCl3)δ7.64(d,J＝8.4Hz,2H),7.51(d,J＝1.6Hz,2H),7.43–7.37(m,3H),4.96(s,2H),4.08(d,J＝17.2Hz,1H),3.92(s,3H),3.69(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ167.3,158.3,155.8,139.2,139.1,135.7,129.8,128.9,127.4,125.4,123.9(q,J＝282.6Hz),87.2(q,J＝30.4Hz),57.3,49.9,44.2.19F NMR(376MHz,CDCl3)δ-79.40(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C20H15Cl2F3N3O3S[M+H]+504.0158,found,504.0157.
实施例59：异噁唑啉衍生物I-59的合成。
第一步，中间体5b的合成。将4-氰基-2-氟苄溴(4b)(8.56g,40mmol)溶于120mL无水甲苯中，氩气置换气三次，冰浴冷却至0℃，然后缓慢滴加1M二异丁基氢化铝的正己烷溶液(60mL)。于0℃下再搅拌1h，升至室温继续搅拌1h，然后加入200mL的氯仿稀释。最后，再将混合物冰浴冷却，缓慢加入150mL 10％HCl，在室温继续搅拌1h。反应混合物用乙酸乙酯萃取，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，减压蒸馏，得到粗产物。经正己烷重结晶得到白色固体7.53g，产率87％，熔点57-58℃。1H NMR(400MHz,CDCl3)δ9.96(s,1H),8.07(d,J＝1.6Hz,1H),7.80(dd,J＝8.0,1.6Hz,1H),7.63(d,J＝8.0Hz,1H),4.61(s,2H).
第二步，中间体6b的合成。在室温下，将中间体5b(3.46g,16mmol)加到乙酸钠(3.94g,48mmol)和盐酸羟胺(2.25g,32mmol)的乙醇：水(1:1)中的溶液中，室温搅拌，TLC监测直到反应完成。减压旋除大部分乙醇，随后将反应液倒入200mL冰水中，析出大量白色固体，抽滤得蓬松的白色粉末3.01g，收率81％，熔点127-129℃，直接用于下一步。
第三步，中间体7b的合成。将中间体3(7.80g,32.5mmol)、6b(3.00g,13mmol)和KCl(0.97g,1.3mmol)加入250mL圆底烧瓶中，然后加入78mL水，最后在搅拌下加入Oxone(12.0g,19.5mmol)，室温搅拌4h。水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，减压浓缩，经(V(石油醚):V(乙酸乙酯)＝60:1)柱层析得白色固体2.97g，收率49％，熔点103-105℃。
第四步：I-59合成。于100mL三口烧瓶中加入中间体7b(468.9mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-羟基噻唑(121.4mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体437.5mg，收率89％，熔点51-53℃。1H NMR(400MHz,CDCl3)δ7.48(d,J＝1.6Hz,2H),7.46(dd,J＝10.8,1.2Hz,1H),7.41(t,J＝1.6Hz,1H),7.38(d,J＝7.1Hz,1H),7.35(dd,J＝8.0,1.2Hz,1H),6.60(d,J＝5.2Hz,1H),6.14(d,J＝5.2Hz,1H),4.92(s,2H),4.04(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ172.1,160.7(d,J＝247.2Hz),155.0(d,J＝2.8Hz),138.8,135.8,131.4(d,J＝3.9Hz),129.9,129.8(d,J＝8.4Hz),126.18(d,J＝15.3Hz),125.4,124.3(d,J＝1.7Hz),123.7(q,J＝282.5Hz),123.4(d,J＝3.4Hz),114.0(d,J＝23.7Hz),102.0,87.6(q,J＝30.5Hz),43.90(s),42.37(d,J＝3.7Hz).19F NMR(376MHz,CDCl3)δ-79.53(s),-116.60(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C20H13Cl2F4N2O2S[M+H]+491.0005,found,491.0003.
实施例60：I-60的合成。于100mL三口烧瓶中加入中间体7b(468.9mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，5-甲氧基-1,3,4-噻二唑-2-酮(158.6mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝8:1)柱层析得无色油状物243.8mg，收率47％。1H NMR(400MHz,CDCl3)δ7.49(d,J＝1.6Hz,2H),7.45–7.37(m,3H),7.37–7.32(m,1H),5.03(s,2H),4.05(d,J＝17.2Hz,1H),3.91(s,3H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ167.3,160.7(d,J＝248.5Hz),158.4,155.1(d,J＝2.6Hz),138.9,135.8,130.9(d,J＝4.0Hz),130.0,129.5(d,J＝8.3Hz),126.2(d,J＝15.1Hz),125.4,123.8(q,J＝282.7Hz),123.0(d,J＝3.4Hz),114.1(d,J＝23.9Hz),87.6(q,J＝30.8Hz),57.4,44.0,43.8(d,J＝4.0Hz).19FNMR(376MHz,CDCl3)δ-79.49(s),-116.09(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C20H14Cl2F4N3O3S[M+H]+522.0064,found,522.0062.
实施例61：I-61的合成。于100mL三口烧瓶中加入中间体7b(468.9mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-羟基苯并噻唑(181.4mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝8:1)柱层析得白色固体425.5mg，收率79％，熔点72-73℃。1H NMR(400MHz,CDCl3)δ7.49–7.42(m,4H),7.41(t,J＝1.6Hz,1H),7.30(dd,J＝8.0,1.2Hz,1H),7.27(d,J＝7.2Hz,1H),7.23(dd,J＝8.0,1.2Hz,1H),7.16(td,J＝7.6,0.8Hz,1H),6.97(d,J＝8.0Hz,1H,),5.22(s,2H),4.02(d,J＝17.2Hz,1H),3.6(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ170.5,160.5(d,J＝246.7Hz),154.9(d,J＝2.6Hz),138.9,136.5,135.8,130.0(d,J＝4.0Hz),129.9,129.5(d,J＝8.3Hz),126.7,125.6(d,J＝14.7Hz),125.4,123.8,123.7(q,J＝282.7Hz),123.4(d,J＝3.2Hz),122.9,122.6,114.05(d,J＝23.8Hz),110.8,87.6(q,J＝30.4Hz),43.9,39.5(d,J＝4.6Hz).19F NMR(376MHz,CDCl3)δ-79.49(s),-116.24(s).Mass Spectrometry:HRMS-ESI(m/z):calcd forC24H15Cl2F4N2O2S[M+H]+541.0162,found,541.0160.
施例62：I-62的合成。于100mL三口烧瓶中加入中间体7b(468.9mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，苯并噁唑-2-酮(162.1mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝8:1)柱层析得白色固体346.2mg，收率66％，熔点68-70℃。1HNMR(400MHz,CDCl3)δ7.51–7.46(m,3H),7.44(d,J＝8.0Hz,1H),7.41(t,J＝1.6Hz,1H),7.36(dd,J＝8.0,1.6Hz,1H),7.23–7.19(m,1H),7.16–7.08(m,2H),6.96–6.92(m,1H),5.07(s,2H),4.04(d,J＝17.2Hz,1H),3.66(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ160.5(d,J＝247.3Hz),154.9(d,J＝2.8Hz),154.7,142.7,138.8,135.8,130.9(d,J＝3.8Hz),130.5,130.1(d,J＝8.3Hz),130.0,125.4,125.1(d,J＝14.9Hz),124.2,123.7(q,J＝282.5Hz),123.4(d,J＝3.5Hz),123.1,114.16(d,J＝23.8Hz),110.3,108.7(d,J＝2.5Hz),87.6(q,J＝30.6Hz),43.9,39.3(d,J＝4.4Hz).19F NMR(376MHz,CDCl3)δ-79.52(s),-116.01(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H15Cl2F4N2O3[M+H]+525.0390,found,525.0388.
实施例63：异噁唑啉衍生物I-63的合成。
第一步，中间体5c的合成。将4-氰基-2-溴苄溴(4c)(4.95g,18mmol)溶于54mL无水甲苯中，氩气置换气三次，冰浴冷却至0℃，然后缓慢滴加1M二异丁基氢化铝的正己烷溶液(27mL)。于0℃下再搅拌1h，升至室温继续搅拌1h，然后加入200mL的氯仿稀释。最后，再将混合物冰浴冷却，缓慢加入100mL 10％HCl，在室温继续搅拌1h。反应混合物用乙酸乙酯萃取，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，减压蒸馏，得到粗产物。经正己烷重结晶得到白色固体4.26g，产率86％，熔点88-89℃。1HNMR(400MHz,CDCl3)δ9.98(s,1H),7.66(dd,J＝8.0,1.2Hz,1H),7.61–7.55(m,2H),4.53(s,2H).
第二步，中间体6c的合成。在室温下，将中间体5c(4.14g,15mmol)加到乙酸钠(3.69g,45mmol)和盐酸羟胺(2.09g,30mmol)的乙醇：水(1:1)中的溶液中，室温搅拌，TLC监测直到反应示完成。减压旋除大部分乙醇，随后将反应液倒入200mL冰水中，析出大量白色固体，抽滤得蓬松的白色粉末3.89g，收率89％，熔点109-110℃，直接用于下一步。
第三步，中间体7c的合成。将中间体3(32.5g,32.5mmol)、6c(3.78g,13mmol)和KCl(0.97g,1.3mmol)加入250mL圆底烧瓶中，然后加入78mL水，最后在搅拌下加入Oxone(12.0g,19.5mmol)，室温搅拌4h。水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，减压浓缩，经(V(石油醚):V(乙酸乙酯)＝60:1)柱层析得白色固体3.55g，收率52％，熔点101-102℃。
第四步：I-63合成。于100mL三口烧瓶中加入中间体7c(528.8mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-羟基噻唑(121.4mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝5:1)柱层析得白色固体309.4mg，收率56％，熔点66-68℃。1H NMR(400MHz,CDCl3)δ7.88(d,J＝1.2Hz,1H),7.57(dd,J＝8.0,1.2Hz,1H),7.48(d,J＝1.6Hz,2H),7.41(t,J＝1.6Hz,1H),7.25(d,J＝8.0Hz,1H),6.59(d,J＝5.4Hz,1H),6.17(d,J＝5.4Hz,1H),4.98(s,2H),4.04(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ172.1,154.6,138.8,138.1,135.8,131.3,130.1,129.9,129.3,126.4,125.4,124.2,123.8,123.7(q,J＝282.7Hz),102.1,87.6(q,J＝30.5Hz),48.5,43.9.19F NMR(376MHz,CDCl3)δ-79.47(s).Mass Spectrometry:HRMS-ESI(m/z):calcd forC20H13BrCl2F3N2O2S[M+H]+550.9205,found,550.9203.
实施例64：I-64的合成。于100mL三口烧瓶中加入中间体7c(528.8mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，2-羟基苯并噻唑(181.4mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝8:1)柱层析得白色固体438.6mg，收率73％，熔点80-82℃；1H NMR(400MHz,CDCl3)δ7.93(d,J＝1.2Hz,1H),7.50–7.45(m,4H),7.41(t,J＝1.6Hz,1H),7.24–7.14(m,2H),6.96(d,J＝8.0Hz,1H),6.79(d,J＝8.0Hz,1H),5.24(s,2H),4.02(d,J＝17.2Hz,1H),3.64(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ170.3,154.6,138.9,137.1,136.5,135.8,131.4,129.9,129.0,127.9,126.8,126.4,125.4,123.9,123.8(q,J＝282.8Hz),123.2,123.0,122.6,111.2,87.6(q,J＝30.4Hz),46.2,43.9.19F NMR(376MHz,CDCl3)δ-79.46(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H14BrCl2F3N2NaO2S[M+Na]+622.9181,found,622.9172.
实施例65：I-65的合成。于100mL三口烧瓶中加入中间体7c(528.8mg,1.0mmol)，无水碳酸钾(165.9mg,1.20mmol)，碘化钾(199.2mg,1.20mmol)，苯并噁唑-2-酮(162.1mg,1.20mmol)和10mL乙腈，氩气保护下回流3h，TLC监测反应完全，加入水和二氯甲烷分层，水相用二氯甲烷萃取3次，合并有机相经水洗2次，饱和氯化钠洗涤1次，无水硫酸钠干燥，脱溶，经(V(石油醚):V(乙酸乙酯)＝8:1)柱层析得白色固体322.6mg，收率55％，熔点74-75℃；1H NMR(400MHz,CDCl3)δ7.93(d,J＝1.2Hz,1H),7.54(dd,J＝8.0,1.2Hz,1H),7.49((d,J＝1.6Hz,2H),7.41(t,J＝1.6Hz,1H),7.25–7.19(m,2H),7.16–7.07(m,2H),6.81(dd,J＝8.0,1.2Hz,1H),5.13(s,2H),4.04(d,J＝17.2Hz,1H),3.67(d,J＝17.2Hz,1H).13C NMR(100MHz,CDCl3)δ154.7,154.6,142.8,138.8,136.8,135.8,131.5,130.5,129.9,129.3,129.0,126.4,125.4,124.2,123.7(q,J＝282.6Hz),123.4,123.2,110.4,109.1,87.6(q,J＝30.5Hz),46.0,43.8.19F NMR(376MHz,CDCl3)δ-79.46(s).Mass Spectrometry:HRMS-ESI(m/z):calcd for C24H14BrCl2F3N2NaO3[M+Na]+606.9409,found,606.9405.
实施例66：季铵盐异噁唑啉类化合物I-1～I-65对小菜蛾(Plutellaxylostella)、粘虫(Mythimna separata)、草地贪夜蛾(Spodopterafrugiperda)、棉铃虫(Helicoverpa armigera)、玉米螟(0strinia nubilalis)、尖音库蚊淡色亚种(Culexpipienspallens)、蚜虫(Aphis laburniKaltenbach)的杀虫活性及朱砂叶螨成螨(Tetranychus cinnabarinus)的杀螨活性测定，测定程序如下：
草地贪夜蛾的活性测试：草地贪夜蛾Spodopterafrugiperda(J.E.Smith,1797)。试验方法：浸叶法。将大喇叭口期幼嫩玉米叶片剪为5cm叶段，浸渍药液10s,自然晾干后置于玻璃培养皿(直径75mm)中。选取发育整齐的2龄幼虫饥饿处理4h后接入处理后的叶片。以丙酮溶剂为对照。每处理幼虫10头,4次重复。处理后72h检查幼虫存活状态,以毛刷轻触幼虫体表，无反应判定为死亡，记录死亡数、存活数,计算死亡率及校正死亡率。
死亡率(％)＝(施药死亡虫数/施药总虫数)×100
校正死亡率(％)＝[(施药死亡率-空白死亡率)/(1-空白死亡率)]×100
粘虫的活性测试：粘虫(Mythimna separata Walker)，室内饲养的正常群体。试验方法：浸叶法，用玉米叶浸渍于丙酮配制的药液中，待药液干后接入10头3龄幼虫，主要为胃毒、触杀作用，同时观察幼虫取食现象。72h检查死亡率。每个化合物重复3次。
棉铃虫的活性测试：棉铃虫(Helicoverpa armigera)，室内饲养的正常群体。试验方法：浸叶法。用玉米叶浸渍于丙酮配制的药液中，待药液干后接入10头3龄幼虫，主要为胃毒、触杀作用，同时观察幼虫取食现象。72h后检查死亡率。每个化合物重复3次。
玉米螟的活性测试：玉米螟(0strinia nubilalis Hubner)，室内饲养的正常群体。试验方法：浸叶法。用玉米叶浸渍于丙酮配制的药液中，待药液干后接入10头3龄幼虫，主要为胃毒、触杀作用，同时观察幼虫取食现象。72小时后检查死亡率。每个化合物重复3次。
小菜蛾的活性测试：小菜蛾(Plutellaxylostella)，室内饲养的正常群体。试验方法：浸叶法。用直头眼科镊子浸渍甘蓝叶片到合适浓度的药液中，时间3-5秒，甩掉余液。每次一片，每个样品3片，按样品标记顺序依次放在处理纸上。待药液干后，放入具有标记的10cm长的直行管内，接入10头二龄幼虫用纱布盖好管口。将实验处理置于标准室内，4天后检查结果。每个化合物重复3次。
库蚊幼虫的活性测试：尖音库蚊淡色亚种(Culexpipienspallens)，室内饲养的正常群体。选取10头3龄库蚊幼虫，置于配制好的所需浓度100mL烧杯中。将处理放入标准处理室内，72h后检查死亡率。以含有1mL试验溶剂的水溶液为空白对照。每个化合物重复3次。
蚜虫的活性测试：蚜虫(Aphis laburniKaltenbach)，实验室蚕豆叶饲养的正常群体。称取药品，加1mLDMF溶解，加两滴吐温－20乳化剂，加入一定量的蒸馏水，搅拌均匀，配成所需浓度的药液。将带蚜虫(约60只)蚕豆叶片浸入药剂中5秒钟，拿出轻轻甩干，用滤纸吸干多余药剂，然后将蚕豆枝插入吸水海绵中，并用玻璃罩罩住枝条，用纱布封口，96h后检查结果，每个化合物重复3次。对照只向蒸馏水中加入乳化剂和溶剂，搅拌均匀。
朱砂叶螨成螨的活性测试：朱砂叶螨(Tetranychus cinnabarinus)供实验用的矮生菜豆长至两片真叶时，选择长势比较整齐、叶面积4-5平方厘米、株高10厘米左右的植株接虫，每株虫量控制在60-100头左右。接虫2h后，进行药剂处理。药剂处理采用植株浸渍法，浸渍时间5秒钟。植株从药液中取出后，轻轻抖动，甩掉多余药液，然后移入水培缸中，放置在室温下。处理后24h在双目镜下检查结果。每个化合物重复3次。
表1异噁唑啉衍生物I-1～I-65杀小菜蛾活性
表2异噁唑啉衍生物I-1～I-65杀粘虫、草地贪夜蛾、棉铃虫、玉米螟活性(致死率％)
aActivities at 200mg/L.bActivities at 100mg/L.cActivities at 50mg/L.dActivities at 25mg/L
eActivities at 10mg/L,fActivities at 5mg/L.gActivities at 2.5mg/L.hActivities at 1mg/L.
iActivities at 0.5mg/L,jActivities at 0.25mg/L.kActivities at 0.1mg/L.
表3异噁唑啉衍生物I-1～I-65杀蚊幼虫、蚜虫、朱砂叶螨活性(致死率％)
aActivities at 200mg/L.bActivities at 100mg/L.cActivities at 10mg/L.dActivities at 5mg/L,eActivities at 2.5mg/L.
fActivities at 1mg/L.gActivities at 0.5mg/L,hActivities at 0.25mg/L.iActivities at 0.1mg/L.jActivities at 0.05mg/L,
kActivities at 0.025mg/L.lActivities at 0.01mg/L.mActivities at0.005mg/L,nActivities at 0.0025mg/L.oActivities at 0.001mg/L.
杀小菜蛾活性：从表1中可看出，大部分衍生物均对小菜蛾表现了较好的灭杀活性，如I-4、I-24、I-28等在0.001mg/L下对小菜蛾亦有50％以上的抑制率，略微低于对照样fluralaner(65％，100mg/L)。
杀粘虫活性：大部分衍生物I在处理剂量为600μg/mL的浓度下都表现出不错的杀粘虫活性，其中化合物I-31、I-59、I-63在10mg/L下对粘虫有50％以上的抑制率。
杀草地贪夜蛾活性：大部分衍生物I在处理剂量为600mg/L的浓度下都表现出不错的杀草地贪夜蛾活性，其中化合物I-31、I-59、I-63在200mg/L下对粘虫有100％的抑制率
杀玉米螟、棉铃虫活性：大部分衍生物I在处理剂量为600mg/L的浓度下具有一定的杀玉米螟、棉铃虫活性。其中衍生物I-63表现出与fluralaner相当的杀玉米螟、棉铃虫活性。
杀蚊幼虫活性：大部分化合物均表现出不错的杀蚊幼虫活性，尤其是衍生物I-1、I-5、I-31、I-37、I-59、I-63、I-28在0.5mg/L下对蚊幼虫亦有100％的抑制率。
杀蚜虫活性：所有异噁唑啉衍生物I-1～I-65对蚜虫均无活性。
杀朱砂叶螨成螨活性：衍生物I-33、I-34、I-38、I-48、I-51、I-53、I-54、I-56、I-59、I-61、I-64在600mg/L下对朱砂叶螨成螨有80％以上的抑制率。
实施例67：抗菌活性测试，测定程序如下：
离体杀菌测试，菌体生长速率测定法(平皿法)：
将一定量药剂溶解在适量丙酮内，然后用含有200μg/mL乳化剂水溶液稀释至所需浓度，然后各吸取1mL药液注入培养皿内，再分别加入9mL培养基，摇匀后制成50μg/mL的含药平板，以添加1mL灭菌水的平板做空白对照。用直径4mm的打孔器沿菌丝外缘切取菌盘，移至含药平板上。每处理重复三次。将培养皿放在24±1℃恒温培养箱内培养。48小时后调查各处理菌盘扩展直径，求平均值，与空白对照比较计算相对抑菌率。
表4异噁唑啉衍生物I-1～I-65的离体杀菌活性测试结果
异噁唑啉衍生物在测试浓度为50mg/L的条件下对14种被测试菌都表现出广谱的抑制活性。化合物I-23对花生褐斑(48％)、苹果轮纹(92％)、小麦纹枯(90％)、玉米小斑(64％)、西瓜炭疽(60％)抑制率高于或相当于商品化品种多菌灵、百菌清；I-21与I-24也对花生褐斑表现出了较好的抑制率，分别为72％、40％；I-14与I-21对苹果轮纹有87％的抑制率，与多菌灵(85％)、百菌清(83％)相当；I-1对水稻稻瘟、辣椒疫霉表现出了较好的活性，抑制率达到50％、72％。
Claims (10)
1.如下所示结构的异噁唑啉类化合物I-1～I-65
2.权利要求1中所述的异噁唑啉类化合物I-1～I-3的制备方法：首先以3,5-二氯苯硼酸(1)和2-溴-3,3-三氟丙烯(2)为原料，碳酸钾为碱，双三苯基膦基氯化钯为催化剂，在四氢呋喃和水中回流得到偶联产物3,5-二氯-1-(1-三氟甲基乙烯基)苯(3)；4-氰基苄溴(4a)经二异丁基氢化铝(DIBAL-H)还原得到4-(溴甲基)苯甲醛(5a)，后在醋酸钠碱催化下，与盐酸羟胺反应生成4-(溴甲基)苯甲醛肟(6a)，然后与上面合成的3在水中，KCl存在下，Oxone氧化环化生成3-(4-(溴甲基)苯基)-5-(3,5-二氯苯基)-5-(三氟甲基)-4,5-二氢异噁唑(7a)；中间体7a与对应醇做溶剂在硫酸亚铁催化下加热回流生成I-1～I-3
上述方程式中R1分别为I-1～I-3结构中所示基团。
3.权利要求1中所述的异噁唑啉类化合物I-4～I-15的制备方法：其特征在于I-4～I-15按照如下方法制备：中间体7a与相应醇，在乙腈做溶剂、氩气保护下，以氢氧化钠或碳酸钾为碱、碘化钾为碘离子源，加热回流生成I-4～I-15
上述方程式中R1分别为I-4～I-15结构中所示基团。
4.权利要求1中所述的异噁唑啉类化合物I-16～I-26的制备方法：其特征在于I-16～I-26按照如下方法制备：中间体7a与相应酮肟，在超干N,N-二甲基甲酰胺做溶剂，氢化钠或氢氧化钠为拔氢试剂，室温搅拌生成I-16～I-26
上述方程式中R2和R3分别为I-16～I-26结构中所示基团。
5.权利要求1中所述的异噁唑啉类化合物I-27～I-30的制备方法：其特征在于I-27～I-30按照如下方法制备：中间体7a与相应苯并杂环肟，在乙腈做溶剂，碳酸钾为拔氢试剂，加热回流生成I-27～I-30
上述方程式中R2和R3分别为I-27～I-30结构中所示基团。
6.权利要求1中所述的异噁唑啉类化合物I-31～I-58的制备方法：其特征在于I-31～I-58按照如下方法制备：中间体7a与相应氮杂环，在乙腈做溶剂、氩气保护下，以碳酸钾为碱、碘化钾为碘离子源，加热回流生成I-31～I-58
上述方程式中R4和R5分别为I-31～I-58结构中所示基团。
7.权利要求1中所述的异噁唑啉类化合物I-59～I-62的制备方法：其特征在于I-59～I-62按照如下方法制备：4-氰基-2-氟苄溴(4b)经二异丁基氢化铝(DIBAL-H)还原得到4-(溴甲基)-3-氟苯甲醛(5b)，后在醋酸钠碱催化下，与盐酸羟胺反应生成4-(溴甲基)-3-氟苯甲醛肟(6b)，然后与上面合成的3在水中，KCl存在下，Oxone氧化环化生成3-(4-(溴甲基)-3-氟苯基)-5-(3,5-二氯苯基)-5-(三氟甲基)-4,5-二氢异噁唑(7b)；中间体7b与相应氮杂环，在乙腈做溶剂、氩气保护下，以碳酸钾为碱、碘化钾为碘离子源，加热回流生成I-59～I-62
上述方程式中R4和R5分别为I-59～I-62结构中所示基团。
8.权利要求1中所述的异噁唑啉类化合物I-63～I-65的制备方法：其特征在于I-63～I-65按照如下方法制备：4-氰基-2-溴苄溴(4c)经二异丁基氢化铝(DIBAL-H)还原得到4-(溴甲基)-3-溴苯甲醛(5c)，后在醋酸钠碱催化下，与盐酸羟胺反应生成4-(溴甲基)-3-溴苯甲醛肟(6c)，然后与上面合成的3在水中，KCl存在下，Oxone氧化环化生成3-(4-(溴甲基)-3-溴苯基)-5-(3,5-二氯苯基)-5-(三氟甲基)-4,5-二氢异噁唑(7c)；中间体7c与相应氮杂环，在乙腈做溶剂、氩气保护下，以碳酸钾为碱、碘化钾为碘离子源，加热回流生成I-63～I-65
上述方程式中R4和R5分别为I-63～I-65结构中所示基团。
9.权利要求1所述的异噁唑啉类化合物I-1～I-65在害虫防治中的应用，其特征在于它们作为杀虫剂，能灭杀小菜蛾、粘虫、草地贪夜蛾、棉铃虫、玉米螟、蚊幼虫、蚜虫、朱砂叶螨成螨、跳蚤、蜱、蠕形螨、疥螨、耳螨。
10.权利要求1所述的异噁唑啉类化合物I-1～I-65在防治植物病菌病中的应用，其特征在于它作为抗植物病菌剂，能抑制黄瓜枯萎、花生褐斑、苹果轮纹、小麦纹枯、玉米小斑、西瓜炭疽、水稻恶苗、番茄早疫、小麦赤霉、水稻稻瘟、辣椒疫霉、油菜菌核、黄瓜灰霉、水稻纹枯14种植物病菌。
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