CN108250037B - 一种光催化Heck脱羧偶联合成顺式烯烃化合物的方法 - Google Patents

一种光催化Heck脱羧偶联合成顺式烯烃化合物的方法 Download PDF

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CN108250037B
CN108250037B CN201810191008.9A CN201810191008A CN108250037B CN 108250037 B CN108250037 B CN 108250037B CN 201810191008 A CN201810191008 A CN 201810191008A CN 108250037 B CN108250037 B CN 108250037B
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那日松
郑超
尚睿
成万民
刘佳
李洪连
郭线茹
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Henan Agricultural University
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Abstract

本发明涉及一种光催化Heck脱羧偶联合成顺式烯烃化合物的方法，具体涉及一种式I结构化合物的制备方法，其特征在于包括如下步骤：

Description

一种光催化Heck脱羧偶联合成顺式烯烃化合物的方法
技术领域
本发明属于有机合成领域，具体涉及一种光催化Heck脱羧偶联合成顺式烯烃化合物的方法。
背景技术
自然界中具有多种含有烯烃结构的活性天然产物，例如不饱和脂肪酸、花生四烯酸、以及植物和微生物中的一些不饱和脂肪酸代谢产物。这些化合物通常具有多样性的生物活性，例如消炎、抗真菌、抗肿瘤、杀虫、杀菌、免疫抑制、镇痛、抗过敏等作用。在医药、农药等领域具有极大的研究价值，基于对这些天然产物的仿生合成与生物活性研究，人们开发了多种药物和农药。其中，甲氧基丙烯酸酯类杀菌剂是近年来发展最为迅速的一类仿生杀菌剂。因此，具有生物活性的烯烃片段是广泛存在于天然产物和有机化合物的重要片段之一，如何高效地构建顺式烯烃分子结构，以及如何由此类烯烃衍生出具有良好生物活性的化合物，对于活性化合物筛选及绿色合成工艺具有重要意义。合成顺式烯烃的方法通常有氢化反应、Wittig反应和偶联反应方法。我们通过将过渡金属催化剂与光氧化还原催化剂合并，利用生物质衍生的羧酸作为原料在Heck交叉偶联反应中产生Z-选择性的取代乙烯衍生物。由于氧化还原中性脱羧的高能垒和烯烃产物的热力学有利的E-选择性，我们设计和实现了采用钯/铱双催化体系解决这个非常具有挑战性的问题。该方法具有条件温和、绿色环保的优点。
发明内容
本发明提供一种式I结构的化合物、立体异构体、互变异构体、几何异构体、其溶剂化物或其药学上可接受的盐，其特征在于所述式I结构如下：
Figure BDA0001591385180000011
R1选自卤素、C1-C4烷氧基、C1-C4烷基、卤代C1-C4烷基、卤代C1-C4烷氧基；
R2选自H、C1-C4烷基，R3、R4各自独立地选自任选被一个或多个Ra取代的C1-C4烷基、-NHBoc，或者R3与R4一起为任选被一个或多个Ra取代的五至六元环烷基或氮杂环烷基，每一个Ra彼此独立地选自Ts、Boc、C1-C4烷硫基、C1-C4烷氧基、-C(O)ORb、任选被一个或多个C1-C4烷基或C1-C4烷氧基取代的苯基或苯氧基；
或者R2、R3、R4一起形成任选被一个或多个C1-C4烷基、C1-C4烷氧基、羟基、-C(O)ORb取代的桥环烷烃，所述桥环优选二环或三环，每条桥上碳原子数为1-3个；
Rb选自C1-C4烷基；
n为0-5的整数。
本发明所述氮杂环烷基指环中含有1个氮原子的杂环烷基。
本发明的另一实施方案提供上述式I结构，其特征在于R1选自氟、氯、溴、甲氧基、三氟甲基。
本发明的另一实施方案提供上述式I结构，其特征在于R2选自H、甲基、乙基、丙基，R3、R4各自独立地选自-NHBoc、任选被一个或多个Ra取代的甲基、乙基、丙基、丁基，或者R3与R4一起为任选被一个或多个Ra取代的环己基、氮杂环戊基或氮杂环己基，每一个Ra彼此独立地选自Ts、Boc、甲硫基、甲氧基、-C(O)OMe、-COOt-Bu、二甲基苯氧基或叔丁氧基苯基。
本发明的另一实施方案提供上述式I结构，其特征在于R2、R3、R4一起形成任选被一个或多个-COOMe取代的二环桥环烷烃，每条桥上碳原子数为2个。
本发明的另一实施方案提供上述式I结构化合物，选自如下化合物1-15：
Figure BDA0001591385180000021
在另一优选例中，式I结构化合物中R1、R2、R3、R4、n为上述化合物1-15中相应位置的具体基团。
在另一优选例中，所述的式I结构化合物选自上述化合物1-15、其立体异构体、互变异构体、几何异构体、溶剂化物或其药学上可接受的盐。
应理解，上述优选基团可相互组合以形成本发明的各种优选化合物，限于篇幅，在此不一一累述。
本发明的另一实施方案提供一种制备上述式I结构化合物的方法，其特征在于包括如下步骤：
Figure BDA0001591385180000032
光照下式II化合物与式III化合物于有机溶剂中，在催化剂、碱金属盐、配体作用下反应得到式I化合物；
其中催化剂选自钯催化剂和/或铱催化剂，所述钯催化剂选自0、+2、+3或+4价钯的配合物，优选Pd(TMP)(OAc)2、烯丙基氯化钯、环戊二烯基烯丙基钯、Pd(OAc)2、Pd2(dba)3、PdCl2、Pd(PPh3)4中的一种或多种；所述铱催化剂选自Ir[dF(CF3)ppy]2(dtbbpy)PF6、铱(III)吡啶基苯基络合物中的一种或多种；
碱金属盐选自碱金属的磷酸盐、硫酸盐、氟化物、氯化物、溴化物、碘化物中的一种或多种，优选K2PO4、KH2PO4、K2HPO4、KHSO4、KF、KCl、KBr中的一种或多种；
配体选自氮配体、膦配体中的一种或几种，优选1,10-phenanthroline、3,4,7,8-tetramethyl-1,10-phenanthroline(TMP)、联吡啶、双噁唑、单齿膦配体三苯基膦，双齿膦配体DPPE和DPPF、Xantphos、缺电子膦氧配体三异丙氧基膦中的一种或多种；
其中，基团R1、R2、R3、R4、n具有任一上文所述的定义。
本发明的另一实施方案提供一种制备上述式I结构化合物的方法，其特征在于式II化合物与式III化合物的摩尔比为1:1～4，优选1:2～3。
本发明的另一实施方案提供一种制备上述式I结构化合物的方法，其特征在于式II化合物与钯催化剂的摩尔比为1:0.01～0.5，优选1:0.05～0.1。
本发明的另一实施方案提供一种制备上述式I结构化合物的方法，其特征在于式II化合物与铱催化剂的摩尔比为1:0.005～0.5，优选1:0.02～0.05。
本发明的另一实施方案提供一种制备上述式I结构化合物的方法，其特征在于式II化合物与碱金属盐的摩尔比为1:1～4，优选1:2～3。
本发明的另一实施方案提供一种制备上述式I结构化合物的方法，其特征在于式II化合物与配体的摩尔比为1:0.01～0.5，优选1:0.06～0.1。
应理解，上述各实施方案(例如优选方案)可相互组合以形成本发明的各种优选技术方案，限于篇幅，在此不一一累述。
上述制备方法，可以在惰性气体(例如氩气)或氮气等保护下进行。
上述制备方法中的有机溶剂为有机合成领域常规的溶剂，对于所述有机溶剂没有特别限定，只要其对反应条件呈惰性即可。优选地，所述有机溶剂可以为极性非质子性溶剂，例如选自芳烃类溶剂、烃类溶剂、卤代烃类溶剂、酰胺类溶剂、砜类溶剂、亚砜类溶剂、杂环类溶剂、中的一种或多种。作为实例，所述溶剂可以选自氯苯、DCE(1,2-二氯乙烷)、氯仿、DMSO(二甲亚砜)、NMP(N-甲基吡咯烷酮)、DMF(N,N-二甲基甲酰胺)中的一种或多种。
本发明的另一实施方案提供一种药物组合物，其特征在于该药物组合物以本发明上述任一式I结构化合物或立体异构体、互变异构体、几何异构体、其溶剂化物或其药学上可接受的盐作为有效成分。该药物组合物还可包括农药学上可接受的辅料，例如载体、稀释剂、赋形剂等。上述药物组合物还可包括其他抗农业真菌药物和/或其他用于防治农业病害的药物。
本发明的另一实施方案提供上述任一式I结构化合物或立体异构体、互变异构体、几何异构体、其溶剂化物或其药学上可接受的盐在预防和/或治疗由农业真菌感染引起的农作物病害中的应用。所述农作物病害优选小麦根腐病，小麦赤霉病，小麦纹枯病，杏褐腐病和辣椒疫霉病中的一种或几种。
术语和定义
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请保护的范围内。
本发明中术语“药学上可接受的盐”可参见“Salt selection for basic drugs”,Int.J.Pharm.(1986),33,201–217。例如与如下无机酸形成的酸加成盐：例如盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸，或者与如下有机酸形成的酸加成盐：例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
另外，具有足够酸性的本发明的化合物的另一种适合的药学上可接受的盐是碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如钙盐或镁盐)、铵盐，或与提供生理学可接受的阳离子的有机碱形成的盐，例如与如下物质形成的盐：N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。另外，碱性含氮基团可用如下试剂季铵化：低级烷基卤化物，例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物；硫酸二烷基酯，例如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯；长链卤化物，例如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物；芳烷基卤化物如苄基和苯乙基溴化物等。并且，所述药学上可接受的盐还应当包括部分为内盐形式的化合物的药学上可接受的盐。
本领域技术人员还会认识到，所要求保护的化合物的酸加成盐可通过多种已知方法中的任意一种使所述化合物与适当的无机酸或有机酸反应来制备。或者，本发明的酸性化合物的碱金属盐和碱土金属盐通过各种已知的方法使本发明的化合物与适当的碱反应来制备。
本发明所述卤素优选氟、氯、溴、碘，所述C1-C4烷基优选甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等。
术语“农药学上可接受的辅料”是指可药用惰性成分。赋形剂种类的实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的药学上可接受的载体的实例为：糖类，例如乳糖、蔗糖、甘露醇和山梨醇；淀粉类，例如玉米淀粉、木薯淀粉和土豆淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和甲基纤维素；磷酸钙类，例如磷酸二钙和磷酸三钙；硫酸钠；硫酸钙；聚乙烯吡咯烷酮；聚乙烯醇；硬脂酸；硬脂酸碱土金属盐，例如硬脂酸镁和硬脂酸钙；硬脂酸；植物油类，例如花生油、棉籽油、芝麻油、橄榄油和玉米油；非离子、阳离子和负离子表面活性剂；乙二醇聚合物；β-环糊精；脂肪醇类；和谷物水解固形物以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外，应理解，在阅读了本发明所记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本发明所限定的范围。
本发明实施例中使用的化学原料(式II和式III)可自己合成、商业定制或通过商业途径直接购买，除非另有说明，本发明使用的商品化试剂购自Adamas-beta，TCI和Aldrich。快速柱层析使用青岛海洋化工厂生产的200-300目硅胶。1H NMR、13C NMR和19F NMR均以四甲基硅烷(TMS)为内标，氘代氯仿(CDCl3)为溶剂，使用Bruker-400型核磁共振仪测定。HRMS分析数据使用Finnigan LCQ advantage Max Series仪器测定，ESI质谱数据使用Thermo LTQ Orbitrap XL仪器测定。
实施例1
合成如下式的化合物1：
Figure BDA0001591385180000071
取2-甲基-环己基甲酸(0.2mmol)，4-氟苯乙烯(0.4mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.4mmol)溶于氯苯(2mL)中，在光照下(由36WBlue LED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(32.7mg,75％)，即为化合物1，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为96/4。1H NMR(400MHz,CDCl3)δ7.17–7.10(m,2H),7.00–6.92(m,2H),6.41(d,J＝12.7Hz,1H),5.53(d,J＝12.7Hz,1H),1.51–1.04(m,10H),1.00(s,3H).19F NMR(376MHz,CDCl3)δ-116.63.13C NMR(100MHz,CDCl3)δ161.5(d,J＝244.7Hz),142.0,135.4(d,J＝3.5Hz),130.2(d,J＝7.8Hz),127.4,114.5(d,J＝21.2Hz),39.2,37.4,29.3,26.1,22.7.HRMS(EI)Calcd for C15H19F+[M]+:218.1471,found:218.1466.
实施例2
合成如下式的化合物2：
Figure BDA0001591385180000072
取5-(2,5-二甲基苯氧基)-2,2-二甲基戊酸(0.2mmol)，4-氟苯乙烯(0.6mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.01mmol)，钯催化剂PdCl2(0.02mmol),PPh3(0.02mmol)和KCl(0.6mmol)溶于1,2-二氯乙烷(2mL)中，在光照下(由36W Blue LED灯提供)室温反应过夜，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(50.9mg,78％)，即为化合物2，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为96/4。1H NMR(400MHz,CDCl3)δ7.16–7.10(m,2H),7.03–6.92(m,3H),6.65(d,J＝7.5Hz,1H),6.59(s,1H),6.42(d,J＝12.6Hz,1H),5.54(d,J＝12.6Hz,1H),3.82(t,J＝6.4Hz,2H),2.31(s,3H),2.18(s,3H),1.82–1.69(m,2H),1.50–1.40(m,2H),0.95(s,6H).19F NMR(376MHz,CDCl3)δ-116.55.13C NMR(100MHz,CDCl3)δ161.6(d,J＝244.8Hz),157.1,141.8,136.5,135.1(d,J＝3.4Hz),130.4,130.3(d,J＝5.0Hz),127.2,123.6,120.7,114.5(d,J＝21.1Hz),112.0,68.4,40.6,37.1,29.1,25.1,21.5,15.8.HRMS(ESI)Calcd for C22H28FO+[M+H]+:327.2119,found:327.2105.
实施例3
合成如下式的化合物3：
Figure BDA0001591385180000081
取2,2-二甲基丁酸(0.2mmol)，4-甲氧基苯乙烯(0.2mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.1mmol)，钯催化剂Pd(PPh3)4(0.1mmol),1,10-phenanthroline(0.1mmol)和KH2PO4(0.2mmol)溶于氯仿(3mL)中，在光照下(由36W Blue LED灯提供)室温反应过夜，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(23.3mg,57％)，即为化合物3，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为94/6。1H NMR(400MHz,CDCl3)δ7.09(d,J＝8.1Hz,2H),6.86–6.77(m,2H),6.41(d,J＝12.6Hz,1H),5.45(d,J＝12.6Hz,1H),3.80(s,3H),1.32(q,J＝7.5Hz,2H),0.90(s,6H),0.82(t,J＝7.5Hz,3H).13C NMR(100MHz,CDCl3)δ158.0,141.4,131.7,129.9,127.6,112.9,55.2,37.3,36.7,28.5,9.2.HRMS(ESI)Calcd for C14H21O+[M+H]+:205.1587,found:205.1599.
实施例4
合成如下式的化合物4：
Figure BDA0001591385180000082
取2-甲基-环己基甲酸(0.2mmol)，4-甲氧基苯乙烯(0.8mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.001mmol)，钯催化剂Pd2(dba)3(0.002mmol),Xantphos(0.002mmol)和Na2HPO4(0.2mmol)溶于NMP(2mL)中，在光照下(由36W Blue LED灯提供)室温反应过夜，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(29.5mg,64％)，即为化合物4，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为90/10。1H NMR(400MHz,CDCl3)δ7.11(d,J＝8.2Hz,2H),6.81(d,J＝8.3Hz,2H),6.42(d,J＝12.7Hz,1H),5.48(d,J＝12.7Hz,1H),3.80(s,3H),1.57–1.05(m,10H),1.03(s,3H).13C NMR(100MHz,CDCl3)δ158.0,141.3,131.9,129.8,128.1,113.0,55.2,39.2,37.3,29.4,26.1,22.7.HRMS(ESI)Calcd for C16H23O+[M+H]+:231.1743,found:231.1756.
实施例5
合成如下式的化合物5：
Figure BDA0001591385180000091
取1-叔丁氧羰基-4-甲基-4-哌啶甲酸(0.2mmol)，4-甲氧基苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),三异丙氧基膦(0.012mmol)和NaCl(0.5mmol)溶于氯苯(2mL)中，在光照下(由36W Blue LED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(36.5mg,55％)，即为化合物5，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为94/6。1H NMR(400MHz,CDCl3)δ7.09(d,J＝8.1Hz,2H),6.87–6.76(m,2H),6.52(d,J＝12.6Hz,1H),5.45(d,J＝12.6Hz,1H),3.81(s,3H),3.57–3.48(m,2H),3.02–2.94(m,2H),1.60–1.51(m,2H),1.42(s,9H),1.24–1.16(m,2H),1.11(s,3H).13C NMR(100MHz,CDCl3)δ158.3,155.0,138.8,131.2,129.8,129.7,113.3,79.1,55.2,40.5,37.9,35.9,28.9,28.5.HRMS(ESI)Calcd for C20H30NO3 +[M+H]+:332.2220,found:332.2208.
实施例6
合成如下式的化合物6：
Figure BDA0001591385180000092
取二环[2,2,2]辛烷-1,4-环己二羧酸单甲酯(0.2mmol)，4-甲氧基苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP 3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.5mmol)溶于氯苯(2mL)中，在光照下(由36W Blue LED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(24.0mg,40％)，即为化合物6，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为89/11。1H NMR(400MHz,CDCl3)δ7.06(d,J＝8.1Hz,2H),6.83–6.79(m,2H),6.37(d,J＝12.6Hz,1H),5.39(d,J＝12.6Hz,1H),3.81(s,3H),3.60(s,3H),1.72–1.65(m,6H),1.56–1.49(m,6H).13C NMR(100MHz,CDCl3)δ178.5,158.0,140.3,131.5,130.0,128.0,113.0,55.2,51.6,38.6,34.0,31.6,28.4.HRMS(ESI)Calcd for C19H25O3 +[M+H]+:301.1798,found:301.1786.
实施例7
合成如下式的化合物7：
取2-乙基己酸(0.2mmol)，2-氯苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.5mmol)溶于氯苯(2mL)中，在光照下(由36W BlueLED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(23.2mg,49％)，即为化合物7，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为90/10。1H NMR(400MHz,CDCl3)δ7.36(dd,J＝7.3,2.0Hz,1H),7.28(dd,J＝7.2,2.1Hz,1H),7.23–7.14(m,2H),6.51(d,J＝11.6Hz,1H),5.48(dd,J＝11.6,10.2Hz,1H),2.38–2.25(m,1H),1.47–1.14(m,8H),0.89–0.81(m,6H).13CNMR(100MHz,CDCl3)δ139.2,136.5,133.7,130.5,129.2,127.8,126.6,126.1,39.0,35.0,29.4,28.3,22.9,14.1,11.7.HRMS(EI)Calcd for C15H21Cl+[M]+:236.1332,found:236.1330.
实施例8
合成如下式的化合物8：
Figure BDA0001591385180000102
取1-对甲苯磺酰基-4-哌啶甲酸(0.2mmol)，2-氯苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP 3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.5mmol)溶于氯苯(2mL)中，在光照下(由36W Blue LED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(37.6mg,50％)，即为化合物8，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为90/10。1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.2Hz,2H),7.37–7.27(m,3H),7.19–7.09(m,3H),6.43(d,J＝11.5Hz,1H),5.55(dd,J＝11.4,10.1Hz,1H),3.78–3.72(m,2H),2.42(s,3H),2.26–2.13(m,3H),1.74–1.67(m,2H),1.62–1.54(m,2H).13C NMR(100MHz,CDCl3)δ143.5,137.0,135.8,133.5,133.0,130.0,129.6,129.5,128.3,127.7,126.4,126.3,45.8,34.4,31.3,21.5.HRMS(ESI)Calcd for C20H23ClNO2S+[M+H]+:376.1133,found:376.1140.
实施例9
合成如下式的化合物9：
Figure BDA0001591385180000111
取Boc-丙氨酸(0.2mmol)，2-三氟甲基苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.5mmol)溶于氯苯(2mL)中，在光照下(由36WBlue LED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(45.4mg,72％)，即为化合物9，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为94/6。1H NMR(400MHz,CDCl3)δ7.68–7.50(m,3H),7.36(t,J＝8.0Hz,1H),6.65(dd,J＝11.6,2.2Hz,1H),5.64(dd,J＝11.5,9.0Hz,1H),4.60–4.34(m,2H),1.41(s,9H),1.15(d,J＝6.3Hz,3H).13C NMR(100MHz,CDCl3)δ154.8,135.8,135.4(q,J＝2.0Hz),131.8,131.0,128.3(q,J＝30.3Hz),127.2,126.3,125.7(q,J＝6.0Hz),124.2(q,J＝273.8Hz),79.3,44.6,28.4,21.7.HRMS(ESI)Calcd forC16H21F3NO2 +[M+H]+:316.1519,found:316.1506.
实施例10
合成如下式的化合物10：
Figure BDA0001591385180000121
Boc-脯氨酸(0.2mmol)，2-三氟甲基苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.5mmol)溶于氯苯(2mL)中，在光照下(由36W BlueLED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(51.2mg,75％)，即为化合物10，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为94/6。1H NMR(400MHz,CDCl3)δ7.71–7.47(m,3H),7.36(t,J＝8.0Hz,1H),6.65(d,J＝11.6Hz,1H),5.75(dd,J＝11.8,9.1Hz,1H),4.68–4.61(m,1H),3.45(t,J＝6.6Hz,2H),2.07–1.67(m,4H),1.40(s,9H).19F NMR(376MHz,CDCl3)δ-75.98.13C NMR(100MHz,CDCl3)δ155.5,135.5,135.3,131.5,130.7,128.4(q,J＝29.7Hz),127.1,125.9(q,J＝4.8Hz),125.2,124.2(q,J＝273.8Hz),81.2,55.0,46.7,33.3,28.4,23.6.HRMS(ESI)Calcd for C18H23F3NO2 +[M+H]+:342.1675,found:342.1661.
实施例11
合成如下式的化合物11：
Figure BDA0001591385180000122
取3-(4-(叔丁氧基)苯基)-2-((叔丁氧羰基)氨基)丙酸(0.2mmol)，2-三氟甲基苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP 3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.5mmol)溶于氯苯(2mL)中，在光照下(由36W Blue LED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(67.7mg,73％)，即为化合物11，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为90/10。1H NMR(400MHz,CDCl3)δ7.61(d,J＝7.8Hz,1H),7.44(t,J＝7.5Hz,1H),7.33(t,J＝7.6Hz,1H),7.15(d,J＝6.7Hz,1H),6.99(d,J＝8.4Hz,2H),6.91–6.86(m,2H),6.69(dd,J＝11.6,1.8Hz,1H),5.65(dd,J＝11.5,9.2Hz,1H),4.60–4.38(m,2H),2.85–2.65(m,2H),1.38(s,9H),1.32(s,9H).19F NMR(376MHz,CDCl3)δ-60.63.13C NMR(100MHz,CDCl3)δ154.8,154.0,135.2(q,J＝2.0Hz),133.5,132.0,131.6,130.7,130.0,128.2(d,J＝28.0Hz),127.8,127.3,125.7(q,J＝5.05Hz),124.2(q,J＝273.9Hz),124.1,79.3,78.3,49.6,41.1,28.8,28.3.HRMS(ESI)Calcd for C26H33F3NO3 +[M+H]+:464.2407,found:464.2402.
实施例12
合成如下式的化合物12：
Figure BDA0001591385180000131
取5-(叔丁氧基)-2-((叔丁氧羰基)氨基)-5-氧代戊酮酸(0.2mmol)，2-三氟甲基苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP 3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.5mmol)溶于氯苯(2mL)中，在光照下(由36W Blue LED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(68.7mg,80％)，即为化合物12，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为96/4。1H NMR(400MHz,CDCl3)δ7.70–7.47(m,3H),7.36(t,J＝7.7Hz,1H),6.73(dd,J＝11.6,2.0Hz,1H),5.61(dd,J＝11.6,9.5Hz,1H),4.60(s,1H),4.42–4.27(m,1H),2.22–2.12(m,2H),1.84–1.67(m,2H),1.43–1.36(m,18H).19F NMR(376MHz,CDCl3)δ-60.58.13C NMR(100MHz,CDCl3)δ172.6,154.9,135.1(q,J＝2.0Hz),134.1,131.9,131.0,128.3(q,J＝33.0Hz),127.7,127.3,125.7(q,J＝7.1Hz),124.2(d,J＝273.8Hz),80.4,79.3,48.3,31.7,30.6,28.3,28.0.HRMS(ESI)Calcd for C22H31F3NO4 +[M+H]+:430.2200,found:430.2178.
实施例13
合成如下式的化合物13：
Figure BDA0001591385180000141
取Boc-甲硫氨酸(0.2mmol)，2-三氟甲基苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.5mmol)溶于氯苯(2mL)中，在光照下(由36WBlue LED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(24.8mg,33％)，即为化合物13，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为95/5。1H NMR(400MHz,CDCl3)δ7.68–7.51(m,3H),7.37(t,J＝7.9Hz,1H),6.75(dd,J＝11.6,2.3Hz,1H),5.64(dd,J＝11.5,9.3Hz,1H),4.62–4.37(m,2H),2.47–2.34(m,2H),1.98(s,3H),1.84–1.65(m,2H),1.42(s,9H).19F NMR(376MHz,CDCl3)δ-60.53.13C NMR(100MHz,CDCl3)δ154.9,135.1(q,J＝1.9Hz),133.9,131.9,131.0,128.8(q,J＝30.6Hz),128.0,127.4,125.8(q,J＝6.0Hz),124.2(q,J＝273.9Hz),79.4,48.0,35.3,30.0,28.4,15.3.HRMS(ESI)Calcd for C18H25F3NO2S+[M+H]+:376.1553,found:376.1535.
实施例14
合成如下式的化合物14：
Figure BDA0001591385180000142
取Boc-丙氨酸(0.2mmol)，五氟苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.5mmol)溶于氯苯(2mL)中，在光照下(由36W BlueLED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(53.3mg,79％)，即为化合物14，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为93/7。1H NMR(400MHz,CDCl3)δ6.06(d,J＝11.3Hz,1H),5.87(dd,J＝11.2,9.2Hz,1H),4.50(s,1H),4.24–4.09(m,1H),1.37(s,9H),1.26(d,J＝6.7Hz,3H).19F NMR(376MHz,CDCl3)δ-139.97,-155.72,-162.56.13C NMR(100MHz,CDCl3)δ154.7,143.9(dm,J＝249.0Hz),140.9,140.4(d,J＝253.5Hz),137.5(dm,J＝250.0Hz),112.9,111.1(td,J＝19.1,3.8Hz),79.5,45.7,28.2,20.6.HRMS(ESI)Calcdfor C15H17F5NO2 +[M+H]+:338.1174,found:338.1166.
实施例15
合成如下式的化合物15：
Figure BDA0001591385180000151
取2-((叔丁氧羰基)氨基)-2-甲基丙酸(0.2mmol)，4-甲氧基苯乙烯(0.5mmol)，铱催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6(0.004mmol)，钯催化剂Pd(OAc)2(0.01mmol),TMP 3,4,7,8-tetramethyl-1,10-phenanthroline(0.012mmol)和K2HPO4(0.5mmol)溶于氯苯(2mL)中，在光照下(由36W Blue LED灯提供)室温反应24小时，反应结束后，加水淬灭，乙酸乙酯提取三次，合并有机相，浓缩后通过柱层析分离获得无色油状液体(35.0mg,60％)，即为化合物15，Z/E构型比例通过1H-NMR分析，使用二苯甲烷作为内标物，比例为94/6。1H NMR(400MHz,CDCl3)δ7.18(d,J＝8.3Hz,2H),6.87–6.79(m,2H),6.42(d,J＝12.6Hz,1H),5.69(d,J＝12.6Hz,1H),4.56(s,1H),3.81(s,3H),1.40(s,6H),1.32(s,9H).13C NMR(101MHz,CDCl3)δ)δ158.3,153.9,137.5,130.2,130.0,127.9,113.3,78.6,55.2,53.0,29.3,28.4.HRMS(ESI)Calcd for C17H26NO3 +[M+H]+:292.1907,found:292.1918.
实施例16
采用菌丝生长法(NY/T 1156.2-2006)，化合物1-15(50μg/mL)在小麦根腐病，小麦赤霉病，小麦纹枯病，杏褐腐病和辣椒疫霉病等真菌离体抑制活性如下：
I＝(D1-D2)D1╳100％
其中I为抑制率，D1为空白对照样品的菌斑平均直径，D2为待测样品菌斑的平均直径。
“++++”表示抑制率在70％以上，“+++”抑制率为50％-60％，“++”表示抑制率为30％-40％，“+”表示抑制率为10％-20％。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (13)

1.一种式I结构化合物的制备方法，其特征在于包括如下步骤：
Figure FDA0002278198290000011
光照下式II化合物与式III化合物于有机溶剂中，在催化剂、碱金属盐、配体作用下反应得到式I化合物；
其中催化剂选自钯催化剂和铱催化剂，所述钯催化剂选自0、+2、+3或+4价钯的配合物；所述铱催化剂选自Ir[dF(CF3)ppy]2(dtbbpy)PF6、铱(III)吡啶基苯基络合物中的一种或多种；
碱金属盐选自碱金属的磷酸盐、硫酸盐、氟化物、氯化物、溴化物、碘化物中的一种或多种；
配体选自氮配体、膦配体中的一种或几种；
其中，R1选自卤素、C1-C4烷氧基、C1-C4烷基、卤代C1-C4烷基、卤代C1-C4烷氧基；
R2选自H、C1-C4烷基，R3、R4各自独立地选自任选被一个或多个Ra取代的C1-C4烷基、-NHBoc，或者R3与R4一起为任选被一个或多个Ra取代的五至六元环烷基或氮杂环烷基，每一个Ra彼此独立地选自Ts、Boc、C1-C4烷硫基、C1-C4烷氧基、-C(O)ORb、任选被一个或多个C1-C4烷基或C1-C4烷氧基取代的苯基或苯氧基；
或者R2、R3、R4一起形成任选被一个或多个C1-C4烷基、C1-C4烷氧基、羟基、-C(O)ORb取代的桥环烷烃，所述桥环选自二环或三环，每条桥上碳原子数为1-3个；
Rb选自C1-C4烷基；
n为0-5的整数。
2.权利要求1所述的制备方法，其特征在于所述钯催化剂选自Pd(TMP)(OAc)2、烯丙基氯化钯、环戊二烯基烯丙基钯、Pd(OAc)2、Pd2(dba)3、PdCl2、Pd(PPh3)4中的一种或多种。
3.权利要求1所述的制备方法，其特征在于所述配体选自1,10-phenanthroline、3,4,7,8-tetramethyl-1,10-phenanthroline(TMP)、联吡啶、双噁唑、单齿膦配体三苯基膦，双齿膦配体DPPE和DPPF、Xantphos、缺电子膦氧配体三异丙氧基膦中的一种或多种。
4.权利要求1所述的制备方法，其特征在于所述碱金属盐选自K2PO4、KH2PO4、K2HPO4、KHSO4、KF、KCl、KBr中的一种或多种。
5.权利要求1所述的制备方法，其特征在于R1选自氟、氯、溴、甲氧基、三氟甲基。
6.权利要求1所述的制备方法，其特征在于R2选自H、甲基、乙基、丙基，R3、R4各自独立地选自-NHBoc、任选被一个或多个Ra取代的甲基、乙基、丙基、丁基，或者R3与R4一起为任选被一个或多个Ra取代的环己基、氮杂环戊基或氮杂环己基，每一个Ra彼此独立地选自Ts、Boc、甲硫基、甲氧基、-C(O)OMe、-COOt-Bu、二甲基苯氧基或叔丁氧基苯基。
7.权利要求1所述的制备方法，其特征在于R2、R3、R4一起形成任选被一个或多个-COOMe取代的二环桥环烷烃，每条桥上碳原子数为2个。
8.权利要求1所述的制备方法，其特征在于式I结构化合物选自化合物1-15：
Figure FDA0002278198290000021
Figure FDA0002278198290000031
9.权利要求1-8任一项所述的制备方法，其特征在于式II化合物与式III化合物的摩尔比为1:1～4。
10.权利要求1-8任一项所述的制备方法，其特征在于式II化合物与钯催化剂的摩尔比为1:0.01～0.5。
11.权利要求1-8任一项所述的制备方法，其特征在于式II化合物与铱催化剂的摩尔比为1:0.005～0.5。
12.权利要求1-8任一项所述的制备方法，其特征在于式II化合物与碱金属盐的摩尔比为1:1～4。
13.权利要求1-8任一项所述的制备方法，其特征在于式II化合物与配体的摩尔比为1:0.01～0.5。
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