CN111592519B - 一种含氟羧酸类化合物及其制备方法 - Google Patents

一种含氟羧酸类化合物及其制备方法 Download PDF

Info

Publication number
CN111592519B
CN111592519B CN201910261590.6A CN201910261590A CN111592519B CN 111592519 B CN111592519 B CN 111592519B CN 201910261590 A CN201910261590 A CN 201910261590A CN 111592519 B CN111592519 B CN 111592519B
Authority
CN
China
Prior art keywords
nmr
compound
cdcl
difluoroolefin
bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201910261590.6A
Other languages
English (en)
Other versions
CN111592519A (zh
Inventor
余达刚
李静
颜思顺
吴东山
叶剑衡
龚莉
曾昕
冉川昆
贵永远
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan University
Original Assignee
Sichuan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan University filed Critical Sichuan University
Priority to CN201910261590.6A priority Critical patent/CN111592519B/zh
Priority to CN202011620309.2A priority patent/CN112794782B/zh
Publication of CN111592519A publication Critical patent/CN111592519A/zh
Application granted granted Critical
Publication of CN111592519B publication Critical patent/CN111592519B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
    • C07B41/12—Formation or introduction of functional groups containing oxygen of carboxylic acid ester groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/65—Halogen-containing esters of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明提供了一种含氟羧酸类化合物及其制备方法和应用，制备方法包括：将含氟烯烃类化合物与CO2在铜催化剂、配体、碱和硼试剂的存在下于溶剂中发生反应，反应温度为50‑100℃，反应时间为2‑28h，制得。本发明所用原料来源广泛，反应条件温和，并且避免了有毒物质及贵金属的使用，同时为温室气体的合理高效利用开辟了一条重要的途径。

Description

一种含氟羧酸类化合物及其制备方法
技术领域
本发明属于有机化学技术领域，具体涉及一种含氟羧酸类化合物及其制备方法。
背景技术
有机氟化合物在医药、农药、含氟芳香族中间体等方面具有不可取代的地位。在医药中，含氟基团的引入可以有效改善药物的代谢途径和速度，使药物具有更好的生物利用度和生物选择性，而含有α-氟代羧基结构的分子，在药物、活性分子中具有重要地位。以下均为含有的α-氟代羧基结构的药物分子：
Figure BDA0002015459890000011
但目前合成该类化合物的方法往往存在步骤繁琐、官能团兼容性差、底物适用范围窄、选择性差、收率低、底物获取难等缺点，而且含氟砌块的引入、羧基的形成以及当量试剂的使用均大大限制了该类反应的应用。因此，从来源较为广泛的全氟或多氟分子，直接通过惰性C-F的选择性羧基化反应，构建众多重要的α-氟代羧酸类化合物在现代有机合成和药物化学中具有重要的学术意义和应用前景。但由于C-F键的强惰性，更难以实现其活化。而在温和条件下，对多氟化合物C-F键的选择性催化转化更是极为困难。值得一提的是：对于有机金属催化的惰性碳氟键选择性断裂的交叉偶联反应，虽然目前在国内外均有相关研究，但反应往往仅限于硼化、氢化或硅化等过程。总的来说，目前惰性碳氟键的催化转化还未涉及到与CO2的偶联羧基化反应。
另一方面，随着近年来环境和资源问题越来越突出，化石资源消耗巨大，资源短缺，大量CO2废气的排放引起温室效应，导致全球海平面上升。而可循环再生、廉价易得、无毒害的CO2不仅仅只是一种温室气体，同时也是良好的C1资源，利用其制备有机物具有重要的学术和环保价值。但CO2本身的性质又成为其利用的挑战。在CO2的各种化学转化中，化学工作者相应地发展了多种CO2参与合成高附加值化学品的新途径，获得许多种类的化学品。尽管在CO2化学转化方面已开展了大量研究工作，但在温和条件下实现CO2的转化利用仍存在着诸多挑战。
发明内容
针对现有技术中存在的上述问题，本发明提供一种含氟羧酸类化合物及其制备方法，在 CO2参与的温和条件下，由二氟烯烃类、α-三氟甲基苯乙烯类化合物制备α-氟代羧酸类化合物，其原料来源广泛，反应条件温和，并且避免了有毒物质及贵金属的使用，同时为温室气体的合理高效利用开辟了一条重要的途径。
为实现上述目的，本发明解决其技术问题所采用的技术方案是：
一种含氟羧酸类化合物，结构通式为：
Figure BDA0002015459890000021
其中，R1为芳基、杂芳基、酯基、烯基及其衍生物，R2为H、烷基、芳基及其衍生物， R3为H、卤素、甲氧基、氰基，烷基、羰基、酯基、芳基和杂芳基及其衍生物。
进一步地，烷基为具有1-20个碳原子的直链烷基、支链烷基、环烷基，如甲基、乙基、异丙基、正丁基、环戊基等；芳基为具有6-20个碳原子的芳基，如苯基、苄基、萘基等；杂芳基为具有6-20个碳原子的杂芳基，如喹啉、异喹啉、吡啶、噻吩等。
进一步地，含氟羧酸类化合物的具体结构式为：
Figure BDA0002015459890000022
Figure BDA0002015459890000031
上述含氟羧酸类化合物的制备方法包括：将含氟烯烃类化合物与CO2在铜催化剂、配体、碱和硼试剂的存在下于溶剂中发生反应，反应温度为50-100℃，反应时间为2-28h，制得。
上述式1化合物的制备方法包括：二氟烯烃类化合物与CO2在铜催化剂、配体、碱和硼试剂的存在下于溶剂中发生反应，反应温度为50-100℃，反应时间为2-28h，制得氟代丙烯酸类化合物；其中二氟烯烃类化合物与铜催化剂的摩尔比为40:1-5:1，二氟烯烃类化合物与配体的摩尔比为40:1-5:1，二氟烯烃类化合物与碱的摩尔比为1:1-1:6，二氟烯烃类化合物与硼试剂的摩尔比为1:1-1:5，反应式如下：
Figure BDA0002015459890000041
进一步地，二氟烯烃类化合物与铜催化剂的摩尔比为20:1，二氟烯烃类化合物与配体的摩尔比为20:1，二氟烯烃类化合物与碱的摩尔比为1:3.5，二氟烯烃类化合物与硼试剂的摩尔比为1:1.5。
进一步地，铜催化剂为有机铜催化剂，如噻吩-2-甲酸亚铜(CuTc)或醋酸亚铜(CuOAc)；以及无机铜催化剂，如氯化亚铜(CuCl)、溴化亚铜(CuBr)或碘化亚铜(CuI)；优选为为噻吩-2-甲酸亚铜(CuTc)。
进一步地，配体为双磷配体，如4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)、双(2-二苯基磷苯基)醚(DPEphos)、4,6-双(二苯基膦)吩嗪(Nixantphos)、双二苯基膦乙烷(dppe)、双二苯基膦丁烷(dppb)等；优选为4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)、双(2-二苯基磷苯基)醚(DPEphos)、4,6-双(二苯基膦)吩嗪(Nixantphos)；更优选为4,5-双二苯基膦-9,9- 二甲基氧杂蒽(Xantphos)。
进一步地，碱为强碱或弱碱，如氟化钾(KF)、氟化铯(CsF)、甲醇钾(KOMe)、醋酸钾(KOAc)、叔丁醇锂(LiOtBu)、叔丁醇钾(KOtBu)等；优选为叔丁醇锂(LiOtBu)。
进一步地，硼试剂为联硼酸频那醇酯(B2Pin2)、联硼酸新戊二醇酯(B2nep2)、联硼酸邻苯二酚酯、双联(2,4-二甲基-2,4-戊二醇)硼酸酯等；优选为联硼酸频那醇酯(B2Pin2)。
进一步地，溶剂为非极性溶剂或强极性有机溶剂，如邻二甲苯(o-xylene)、N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮(NMP)等；优选为N,N-二甲基甲酰胺(DMF)。
在制备式1化合物时，当底物中苯环上存在取代基时，甲氧基、苯氧基、氰基、卤素取代的邻、间、对底物都可以很好兼容。对于萘环取代二氟烯烃类化合物，不论是1位还是2位，反应都可以顺利地进行，但是当R2为甲基等位阻较大的底物时，相对位阻小的底物，反应性能较差。另外，杂芳环的底物也可以较好的收率得到目标产物，对于底物中同时存在芳基二氟烯烃和烷基二氟烯烃，反应可以专一的实现芳基二氟烯烃的C-F键羧基化，而没有检测到烷基二氟烯烃官能团羧基化的产物，显示了反应的化学选择性。
上述式2化合物的制备方法包括：α-三氟甲基苯乙烯类化合物与CO2在铜催化剂、配体、碱和硼试剂的存在下于溶剂中发生反应，反应温度为50-100℃，反应时间为2-28h，制得α- 二氟代丁烯酸酯类化合物；其中α-三氟甲基苯乙烯类化合物与铜催化剂的摩尔比为40:1-5:1，α-三氟甲基苯乙烯类化合物与配体的摩尔比为40:1-5:1，α-三氟甲基苯乙烯类化合物与碱的摩尔比为1:1-1:6，α-三氟甲基苯乙烯类化合物与硼试剂的摩尔比为1:1-1:5，反应式如下：
Figure BDA0002015459890000051
进一步地，α-三氟甲基苯乙烯类化合物与铜催化剂的摩尔比为10:1，α-三氟甲基苯乙烯类化合物与配体的摩尔比为10:1，α-三氟甲基苯乙烯类化合物与碱的摩尔比为1:3.0，α-三氟甲基苯乙烯类化合物与硼试剂的摩尔比为1:1.5。
进一步地，铜催化剂为有机铜催化剂，如噻吩-2-甲酸亚铜(CuTc)、乙酰丙酮酸铜、醋酸亚铜(CuOAc)或醋酸铜(Cu(OAc)2)；以及无机铜催化剂，如氯化亚铜(CuCl)、氟化铜(CuF2)、溴化铜(CuBr2)或氯化铜(CuCl2)；优选为氯化亚铜(CuCl)。
进一步地，配体为双磷配体，如4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)、双(2-二苯基磷苯基)醚(DPEphos)、4,6-双(二苯基膦)吩嗪(Nixantphos)、双二苯基膦乙烷(dppe)、双二苯基膦丁烷(dppb)等；优选为4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)、双(2-二苯基磷苯基)醚(DPEphos)、4,6-双(二苯基膦)吩嗪(Nixantphos)；更优选为4,5-双二苯基膦-9,9- 二甲基氧杂蒽(Xantphos)。
进一步地，碱为强碱或弱碱，如氟化钾(KF)、碳酸铯(Cs2CO3)、甲醇钾(KOMe)、甲醇钠(NaOMe)、叔丁醇锂(LiOtBu)、叔丁醇钾(KOtBu)等；优选为甲醇钾(KOMe)、叔丁醇锂(LiOtBu)、叔丁醇钾(KOtBu)；更优选为甲醇钾(KOMe)。
进一步地，硼试剂为联硼酸频那醇酯(B2Pin2)、联硼酸新戊二醇酯(B2nep2)、联硼酸邻苯二酚酯、双联(2,4-二甲基-2,4-戊二醇)硼酸酯等；优选为双联(2-甲基-2,4-戊二醇)硼酸酯。
进一步地，溶剂为极性溶剂，如N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮(NMP)等；优选为N-甲基吡咯烷酮(NMP)。
在制备式2化合物时，当底物中苯环上存在取代基时，甲基、苯基、甲氧基、苯氧基、酯基、羰基、氰基、卤素取代的底物都能很好的兼容。对于萘环取代的α-三氟甲基乙烯类化合物，不论是1位还是2位，反应都可以顺利地进行。对于所有底物均实现了一个C-F键的羧基化反应，显示了反应专一的化学选择性。
本发明提供的含氟羧酸类化合物及其制备方法，具有以下有益效果：
本发明通过铜硼物质B对不饱和键加成，而后发生β-F消除形成硼中间体D，进而与铜发生进一步的转金属化，生成活性的有机铜亲核试剂E，而后对二氧化碳进攻，生成α-氟代羧酸类目标产物。具体反应过程如下：
Figure BDA0002015459890000061
本发明在温和条件下，实现α-氟代羧酸类化合物的构建，并且本发明合成方法中利用了温室气体二氧化碳，有一定的学术价值和经济环境意义。本发明对于合成α-氟代丙烯酸和α- 二氟代丁烯酸酯类化合物具有高的化学、区域和非对映异构体选择性，良好的官能团兼容性，较宽的底物范围以及容易实现克级规模及衍生等优点，为其在医药、材料等领域的应用奠定了坚实的基础。
具体实施方式
实施例1 Z-2-氟-3-(4-苯基苯基)丙烯酸(以下称为化合物2a)的制备
将二氟烯烃类化合物(1a，0.4mmol)、硼试剂(0.4mmol，2mL)、铜催化剂(0.02mmol)、配体(0.02mmol)和碱(1.4mmol)混合，然后充入CO2(1个大气压)，在CO2气氛下加入有机溶剂，在80℃搅拌反应24h，最后冷却至室温，用乙酸乙酯和盐酸淬灭反应产物，再用乙酸乙酯萃取3次后浓缩旋干，纯化，制得最终纯的目标产物。具体反应原料见下表，反应式如下：
Figure BDA0002015459890000071
序号 硼试剂 配体 铜催化剂 碱 溶剂 产率[％]<sup>[b]</sup>
1 B<sub>2</sub>Pin<sub>2</sub> Xantphos CuTc KOAc DMF N.D.
2 B<sub>2</sub>Pin<sub>2</sub> Xantphos CuTc CsF DMF Trace
3 B<sub>2</sub>Pin<sub>2</sub> Xantphos CuTc LiO<sup>t</sup>Bu DMF 88(85)
4 B<sub>2</sub>Pin<sub>2</sub> Xantphos CuTc NaO<sup>t</sup>Bu DMF 59
5 B<sub>2</sub>Pin<sub>2</sub> Xantphos CuTc KO<sup>t</sup>Bu DMF 44
6 B<sub>2</sub>Pin<sub>2</sub> Xantphos CuI LiO<sup>t</sup>Bu DMF 73
7 B<sub>2</sub>Pin<sub>2</sub> Xantphos CuOAc LiO<sup>t</sup>Bu DMF 83
8 B<sub>2</sub>Pin<sub>2</sub> Xantphos CuTc LiO<sup>t</sup>Bu DMAc 70
9 B<sub>2</sub>Pin<sub>2</sub> Xantphos CuTc LiO<sup>t</sup>Bu o-xylene 65
10 B<sub>2</sub>Pin<sub>2</sub> Xantphos - LiO<sup>t</sup>Bu DMF N.D.
11 B<sub>2</sub>Pin<sub>2</sub> Xantphos CuTc - DMF N.D.
12[c] B<sub>2</sub>Pin<sub>2</sub> Xantphos CuTc LiO<sup>t</sup>Bu DMF 85％
上表中，[b]为以茴香醚为内标的UPLC收率，括号内为分离收率；[c]为反应时间为2h；Trace为痕量，N.D.为未检出。
由上表可知，序号为12的反应过程时间短，所得目标产物的产率较大，其具体操作过程如下：
向含有磁子的干燥的史莱克(Schlenk)管(25mL)中加入反应底物(86.5mg，0.4mmol， 1equiv)，联硼酸频哪醇酯(B2Pin2)(152mg，0.6mmol，1.5equiv)，然后将史莱克管转入手套箱中，再加入噻吩-2-甲酸亚铜(CuTc)(3.8mg，0.02mmol，5mol％)，4,5-双二苯基膦-9,9- 二甲基氧杂蒽(Xantphos)(11.6mg，0.02mmol，5mol％)，叔丁醇锂(LiOtBu)(112mg，1.4mmol， 3.5equiv)。将Schlenk管封死后从手套箱中取出并连接到连有CO2钢瓶的双排管上，拧松盖子并在双排管上抽充置换CO2 3次，使其管中充满CO2气体，然后在CO2气氛下加入超干N,N- 二甲基甲酰胺(DMF)(2mL)。最后，将反应管置于金属浴上，于80℃下搅拌反应2h。冷却至室温后用2mL乙酸乙酯，2mL盐酸水溶液(2mol/L)猝灭混合物，然后用6mL乙酸乙酯萃取三次后将萃取液合并浓缩旋干。残余物通过快速柱层析纯化(PE/EA＝10:1～1:1)，最终得到纯的所需产物，产物为白色固体，质量为82.3mg，产率为85％，Rf(PE/EA 1:1):0.20；1H NMR (400MHz,DMSO-d6)δ13.66(s,1H),7.85–7.75(m,4H),7.75–7.69(m,2H),7.54–7.46(m, 2H),7.45–7.36(m,1H),7.10(d,J＝36.8Hz,1H)；19F NMR(376MHz,DMSO-d6)δ-123.47；13C NMR(101MHz,DMSO-d6)δ162.45(d,J＝34.7Hz),147.78(d,J＝265.4Hz),141.60(d,J＝2.5 Hz),139.62,131.16(d,J＝8.0Hz),130.55(d,J＝4.0Hz),129.49,128.44,127.53,127.17,116.70 (d,J＝4.2Hz).HRMS(ESI-):calcd for C15H10FO2 -[M-H]-241.0670,found 241.0671.
实施例2-33 α-氟代丙烯酸(酯)类化合物(化合物2b-2ag)的制备
该类化合物的合成步骤与化合物2a的合成步骤一致，仅为原料不同，具体反应式和化合物具体结构如下：
Figure BDA0002015459890000081
上述[b]为CuTc(0.04mmol)，Xantphos(0.04mmol)。[c]为碘甲烷酯化后的分离收率。[d] 为19F-NMR分析得到Z/E选择性的结果。
所得α-氟代丙烯酸(酯)类化合物(化合物2b-2ag)的结构式和参数如下：
Z-2-氟-3-(4-苯基苯基)丙烯酸甲酯(2a')
结构式为：
Figure BDA0002015459890000091
其为白色固体，质量为78mg，收率为76％，Rf(PE/EA 10:1):0.50；1H NMR(400MHz,CDCl3)δ7.73–7.69(m,2H),7.66–7.59(m,4H),7.49–7.42(m,2H).,7.42–7.33(m,1H),6.97(d,J＝35.3Hz,1H),3.90(s,3H)；19F NMR(376MHz,CDCl3)δ-125.44.13C NMR(101MHz,CDCl3)δ161.90(d,J＝34.4Hz),146.82(d,J＝267.2Hz),142.42(d,J＝2.7Hz),140.08,130.81 (d,J＝7.9Hz),130.00(d,J＝5.0Hz),128.90,127.86,127.43,127.05,117.47(d,J＝4.1Hz),52.69. HRMS(ESI+):calcd for C16H13FNaO2 +[M+Na]+279.0792,found279.0786.
Z-2-氟-3-苯基丙烯酸(2b)
结构式为：
Figure BDA0002015459890000092
其为白色固体，质量为46mg，收率为70％，Rf(PE/EA 1:1):0.20；1H NMR(400MHz,DMSO-d6)δ7.76–7.66(m,2H),7.52–7.40(m,3H),7.05(d,J＝36.7Hz,1H)；19F NMR(376 MHz,DMSO-d6)δ-123.74；13C NMR(101MHz,DMSO-d6)δ162.43(d,J＝34.8Hz),147.68(d, J＝264.4Hz),131.42(d,J＝4.0Hz),130.52(d,J＝7.9Hz),130.16(d,J＝2.1Hz),129.38,117.02 (d,J＝4.2Hz).LRMS(ESI-):calcd for C9H6FO2 -[M-H]-165.04,found 164.83.
Z-2-氟-3-(4-甲基苯基)丙烯酸(2c)
结构式为：
Figure BDA0002015459890000093
其为白色固体，质量为43mg，收率为60％，Rf(PE/EA 1:1):0.20；1H NMR(400MHz,DMSO-d6)δ13.57(s,1H),7.56(d,J＝8.2Hz,2H),7.23(d,J＝8.0Hz,2H),6.96(d,J＝37.0Hz, 1H),2.30(s,3H)；19F NMR(376MHz,DMSO-d6)δ-124.73；13C NMR(101MHz,DMSO-d6)δ162.48(d,J＝34.3Hz),147.12(d,J＝262.5Hz),140.05(d,J＝2.7Hz),130.48(d,J＝7.9Hz), 129.96,128.58(d,J＝4.1Hz),117.05(d,J＝4.3Hz),21.43.LRMS(ESI-):calcdfor C10H8FO2 - [M-H]-179.05,found 178.86.
Z-2-氟-3-(4-异丙基苯基)丙烯酸(2d)
结构式为：
Figure BDA0002015459890000101
其为白色固体，质量为50mg，收率为60％，Rf(PE/EA 1:1):0.25；1H NMR(400MHz,DMSO-d6)δ7.63(d,J＝8.1Hz,2H),7.33(d,J＝8.1Hz,2H),7.01(d,J＝36.9Hz,1H),2.97–2.85(m,1H),1.21(d,J＝6.9Hz,6H)；19F NMR(376MHz,DMSO-d6)δ-124.79；13C NMR(101 MHz,DMSO-d6)δ162.55(d,J＝34.6Hz),150.80(d,J＝2.4Hz),147.23(d,J＝263.7Hz), 130.65(d,J＝7.9Hz),129.02(d,J＝4.1Hz),127.35,117.06(d,J＝4.4Hz),33.82,24.02.HRMS(ESI-):calcd for C12H12FO2 -[M-H]-207.0827,found 207.0825.
Z-2-氟-3-(4-叔丁基苯基)丙烯酸(2e)
结构式为：
Figure BDA0002015459890000102
其为白色固体，质量为67mg，收率为76％，Rf(PE/EA 1:1):0.25；1H NMR(400MHz,DMSO-d6)δ7.63(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),7.01(d,J＝36.9Hz,1H),1.29(s,9H)；19F NMR(376MHz,DMSO-d6)δ-124.72；13C NMR(101MHz,DMSO-d6)δ162.49(d,J＝34.6Hz),152.94(d,J＝2.4Hz),147.28(d,J＝263.9Hz),130.33(d,J＝7.8Hz),128.60(d,J＝4.0 Hz),126.14,116.91(d,J＝4.5Hz),34.96,31.27.HRMS(ESI-):calcd for C13H14FO2 -[M-H]- 221.0983,found 221.0983.
Z-2-氟-3-(4-甲氧基苯基)丙烯酸(2f)
结构式为：
Figure BDA0002015459890000103
其为白色固体，质量为44mg，收率为55％，Rf(PE/EA 1:1):0.18；1H NMR(400MHz,DMSO-d6)δ13.44(s,1H),7.66(d,J＝8.7Hz,2H),7.08–6.91(m,3H),3.80(s,3H)；19F NMR(376MHz,DMSO-d6)δ-127.14；13C NMR(101MHz,DMSO-d6)δ167.34(d,J＝35.7Hz), 165.45(d,J＝3.1Hz),151.02(d,J＝262.8Hz),137.04(d,J＝8.0Hz),128.61(d,J＝4.1Hz),121.73(d,J＝4.4Hz),119.61,60.45.LRMS(ESI-):calcd for C10H8FO3 -[M-H]-195.05,found 194.83.
Z-2-氟-3-(4-苯氧基苯基)丙烯酸(2g)
结构式为：
Figure BDA0002015459890000111
其为白色固体，质量为85mg，收率为82％，Rf(PE/EA 1:1):0.20；1H NMR(400MHz,DMSO-d6)δ13.61(s,1H),7.78–7.73(m,2H),7.51–7.43(m,2H),7.28–7.20(m,1H),7.16–6.99(m,5H)；19F NMR(376MHz,DMSO-d6)δ-125.64；13C NMR(101MHz,DMSO-d6)δ 162.51(d,J＝34.7Hz),158.48(d,J＝3.3Hz),156.08,146.98(d,J＝263.8Hz),132.59(d,J＝8.1 Hz),130.68,126.35(d,J＝4.0Hz),124.70,119.89,118.72,116.50(d,J＝4.3Hz).HRMS(ESI-):calcd for C15H10FO3 -[M-H]-257.0619,found 257.0618.
Z-2-氟-3-(4-三氟甲氧基苯基)丙烯酸(2h)
结构式为：
Figure BDA0002015459890000112
其为白色固体，质量为64mg，收率为64％，Rf(PE/EA 1:1):0.18；1H NMR(400MHz,DMSO-d6)δ7.85(d,J＝8.8Hz,2H),7.45(d,J＝8.3Hz,2H),7.12(d,J＝36.1Hz,1H)；19F NMR(376MHz,DMSO-d6)δ-56.86,-123.14；13C NMR(101MHz,DMSO-d6)δ162.16(d,J＝34.8Hz),149.11(q,J＝1.6Hz),148.05(d,J＝264.8Hz),132.40(d,J＝8.1Hz),130.64(d,J＝3.8Hz), 121.60,120.39(q,J＝256.9Hz),115.43(d,J＝4.2Hz).HRMS(ESI-):calcd forC10H5F4O3 - [M-H]-249.0180,found 249.0179.
Z-2-氟-3-(4-氟苯基)丙烯酸(2i)
结构式为：
Figure BDA0002015459890000113
其为白色固体，质量为50mg，收率为68％，Rf(PE/EA 1:1):0.22；1H NMR(400MHz,DMSO-d6)δ7.83–7.73(m,2H),7.36–7.25(m,2H),7.08(d,J＝36.4Hz,1H)；19F NMR(376 MHz,DMSO-d6)δ-110.29,-124.87；13C NMR(101MHz,DMSO-d6)δ162.89(dd,J＝248.6,3.8 Hz),162.33(d,J＝34.6Hz),147.34(d,J＝265.3Hz),132.82(t,J＝8.4Hz),127.99(t,J＝3.6Hz), 116.38(d,J＝21.7Hz),115.90(d,J＝4.1Hz).HRMS(ESI-):calcd for C9H5F2O2 -[M-H]- 183.0263,found 183.0270.
Z-2-氟-3-(4-氯苯基)丙烯酸(2j)
结构式为：
Figure BDA0002015459890000121
其为白色固体，质量为52mg，收率为65％，Rf(PE/EA 1:1):0.18；1H NMR(400MHz,DMSO-d6)δ7.73(d,J＝8.5Hz,2H),7.52(d,J＝8.5Hz,2H),7.08(d,J＝36.3Hz,1H)；19F NMR(376MHz,DMSO-d6)δ-122.77；13C NMR(101MHz,DMSO-d6)δ162.24(d,J＝34.7Hz),148.00(d,J＝266.4Hz),134.69(d,J＝3.7Hz),132.18(d,J＝8.1Hz),130.34(d,J＝4.0Hz),129.44, 115.81(d,J＝4.0Hz).HRMS(ESI-):calcd for C9H5ClFO2 -[M-H]-198.9968,found198.9970.
Z-2-氟-3-(4-溴苯基)丙烯酸(2k)
结构式为：
Figure BDA0002015459890000122
其为白色固体，质量为69mg，收率为70％，Rf(PE/EA 1:1):0.18；1H NMR(400MHz,DMSO-d6)δ7.66(s,4H),7.06(d,J＝36.2Hz,1H)；19F NMR(376MHz,DMSO-d6)δ-122.41；13CNMR(101MHz,DMSO-d6)δ162.25(d,J＝34.8Hz),148.07(d,J＝267.1Hz),132.38, 132.37(d,J＝8.0Hz),130.66(d,J＝3.9Hz),123.51(d,J＝3.7Hz),115.89(d,J＝4.0Hz). HRMS(ESI-):calcd for C9H5BrFO2 -[M-H]-242.9462,found 242.9467.
Z-2-氟-3-(4-(N,N-二苯胺基)苯基)丙烯酸(2l)
结构式为：
Figure BDA0002015459890000123
其为白色固体，质量为113mg，收率为85％，Rf(PE/EA 1:1):0.25；1H NMR(400MHz,DMSO-d6)δ7.57(d,J＝8.9Hz,2H),7.44–7.28(m,4H),7.19–7.03(m,6H),7.00–6.83(m,3H)；19F NMR(376MHz,DMSO-d6)δ-126.67；13C NMR(101MHz,DMSO-d6)δ162.65(d,J＝34.3Hz),148.97(d,J＝2.9Hz),146.80,146.43(d,J＝261.7Hz),131.91(d,J＝8.0Hz),130.21, 125.61,124.66,124.30(d,J＝4.1Hz),121.40,116.94(d,J＝4.5Hz).HRMS(ESI-):calcd for C21H15FNO2 -[M-H]-332.1092,found 332.1087.
Z-2-氟-3-(4-三氟甲基苯基)丙烯酸(2m)
结构式为：
Figure BDA0002015459890000131
其为白色固体，质量为69mg，收率为69％，Rf(PE/EA 5:1):0.60；1H NMR(400MHz,CDCl3) δ7.74(d,J＝8.2Hz,2H),7.66(d,J＝8.3Hz,2H),6.95(d,J＝34.3Hz,1H),3.92(s,3H)；19F NMR(376MHz,CDCl3)δ-62.98,-122.36；13C NMR(101MHz,CDCl3)δ161.37(d,J＝34.5Hz), 147.95(d,J＝271.5Hz),134.37(dd,J＝4.3,1.4Hz),131.18(qd,J＝32.7,2.9Hz),130.36(d,J＝ 8.3Hz),125.70(q,J＝3.7Hz),123.74(q,J＝272.2Hz),116.08(d,J＝4.3Hz),52.89.GC-MS (EI):calcd for C11H8F4O2m/z 248.0,found 248.1.
Z-2-氟-3-(4-(甲氧基羰基)苯基)丙烯酸甲酯(2n)
结构式为：
Figure BDA0002015459890000132
其为白色固体，质量为72mg，收率为75％，Rf(PE/EA 30:1):0.60；1H NMR(400MHz,CDCl3)δ8.11–8.02(m,2H),7.74–7.65(m,2H),6.95(d,J＝34.5Hz,1H),3.93(s,3H),3.91(s, 3H)；19F NMR(376MHz,CDCl3)δ-122.22；13C NMR(101MHz,CDCl3)δ166.41,161.49(d,J＝34.5Hz),147.87(d,J＝271.5Hz),135.29(d,J＝4.5Hz),130.80(d,J＝2.8Hz),130.12(d,J＝8.3 Hz),129.95,116.56(d,J＝4.4Hz),52.86,52.30.HRMS(ESI+):calcd for C12H12FO4 +[M+H]+ 239.0714,found 239.0717.
Z-2-氟-3-(4-氰基苯基)丙烯酸甲酯(2o)
结构式为：
Figure BDA0002015459890000141
其为白色固体，质量为58mg，收率为70％，Rf(PE/EA 5:1):0.55；1H NMR(400MHz,CDCl3) δ7.71(q,J＝8.3Hz,4H),6.94(d,J＝33.9Hz,1H),3.93(s,3H)；19F NMR(376MHz,CDCl3)δ -120.49；13C NMR(101MHz,CDCl3)δ161.13(d,J＝34.5Hz),148.44(d,J＝273.7Hz),135.34 (d,J＝4.4Hz),132.49,130.55(d,J＝8.5Hz),118.34,115.66(d,J＝4.2Hz),112.89(d,J＝3.3 Hz),53.04.GC-MS(EI):calcd for C11H8FNO2m/z 205.0found205.0.
Z-2-氟-3-(4-甲砜基苯基)丙烯酸甲酯(2p)
结构式为：
Figure BDA0002015459890000142
其为白色固体，质量为68mg，收率为66％，Rf(PE/EA 5:1):0.30；1H NMR(400MHz,CDCl3) δ8.01–7.94(m,2H),7.87–7.77(m,2H),6.98(d,J＝33.8Hz,1H),3.93(s,3H),3.08(s,3H)；19F NMR(376MHz,CDCl3)δ-120.53；13C NMR(101MHz,CDCl3)δ161.11(d,J＝34.5Hz),148.53(d,J＝273.6Hz),140.88(d,J＝3.0Hz),136.23(d,J＝4.4Hz),130.81(d,J＝8.3Hz), 127.82,115.49(d,J＝4.3Hz),53.01,44.39.HRMS(ESI+):calcd for C11H11FNaO4S+[M+Na]+ 281.0254,found 281.0257.
Z-2-氟-3-(4-吡啶基2-苯基)丙烯酸甲酯(2q)
结构式为：
Figure BDA0002015459890000143
其为白色固体，质量为76mg，收率为73％，Rf(PE/EA 5:1):0.40；1H NMR(400MHz,CDCl3) δ8.70(s,1H),8.04(d,J＝8.0Hz,2H),7.79–7.67(m,4H),7.24(d,J＝2.9Hz,1H),6.97(d,J＝ 35.2Hz,1H),3.89(s,3H)；19F NMR(376MHz,CDCl3)δ-124.56；13C NMR(101MHz,CDCl3)δ 161.76(d,J＝34.4Hz),156.20,149.77,147.01(d,J＝268.2Hz),140.34(d,J＝1.7Hz),136.84, 131.54(d,J＝4.5Hz),130.71(d,J＝8.2Hz),127.15,122.57,120.61,117.33(d,J＝4.6Hz),52.67. HRMS(ESI+):calcd for C15H13FNO2 +[M+H]+258.0925,found258.0915.
Z-2-氟-3-(3-甲基苯基)丙烯酸(2r)
结构式为：
Figure BDA0002015459890000151
其为白色固体，质量为53mg，收率为74％，Rf(PE/EA 1:1):0.20；1H NMR(400MHz,DMSO-d6)δ7.53–7.46(m,2H),7.37–7.32(m,1H),7.26–7.22(m,1H),6.99(d,J＝36.7Hz,1H),2.34(s,3H)；19F NMR(376MHz,DMSO-d6)δ-123.75；13C NMR(101MHz,DMSO-d6)δ 162.45(d,J＝33.7Hz),147.60(d,J＝266.0Hz),138.56,131.33(d,J＝4.0Hz),131.00(d,J＝7.6Hz),130.86(d,J＝2.0Hz),129.27,127.70(d,J＝8.0Hz),117.10(d,J＝4.2Hz),21.39.HRMS (ESI-):calcd for C10H8FO2 -[M-H]-179.0514,found 179.0523.
Z-2-氟-3-(3-甲氧基苯基)丙烯酸(2s)
结构式为：
Figure BDA0002015459890000152
其为白色固体，质量为56mg，收率为71％，Rf(PE/EA 1:1):0.17；1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),7.37–7.32(m,1H),7.28–7.21(m,2H),7.06–6.93(m,2H),3.74(s,3H)；19F NMR(376MHz,DMSO-d6)δ-123.00；13C NMR(101MHz,acetone-d6)δ161.24(d,J＝35.0Hz),159.91,132.45(d,J＝4.1Hz),129.86,122.56(d,J＝8.2Hz),117.17(d,J＝4.1Hz), 115.49(d,J＝2.2Hz),115.27(d,J＝8.0Hz),54.69.HRMS(ESI-):calcd forC10H8FO3 -[M-H]- 195.0463,found 195.0464.
Z-2-氟-3-(3-氯苯基)丙烯酸(2t)
结构式为：
Figure BDA0002015459890000153
其为白色固体，质量为54mg，收率为78％，Rf(PE/EA 1:1):0.20；1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.71–7.64(m,1H),7.54–7.44(m,2H),7.08(d,J＝36.1Hz,1H)；19FNMR(376MHz,DMSO-d6)δ-121.61；13C NMR(101MHz,DMSO-d6)δ162.09(d,J＝34.9Hz),148.39(d,J＝266.8Hz),133.94,133.46(d,J＝3.9Hz),131.16,129.86(d,J＝10.2Hz),129.83, 128.96(d,J＝8.4Hz),115.54(d,J＝3.9Hz).HRMS(ESI-):calcd for C9H5ClFO2 -[M-H]- 198.9968,found 198.9967.
Z-2-氟-3-(3-氰基苯基)丙烯酸甲酯(2u)
结构式为：
Figure BDA0002015459890000161
其为白色固体，质量为58mg，收率为70％，Rf(PE/EA 5:1):0.55；1H NMR(400MHz,CDCl3) δ7.93(s,1H),7.85(d,J＝8.0Hz,1H),7.69–7.64(m,1H),7.54(t,J＝7.8Hz,1H),6.91(d,J＝ 33.8Hz,1H),3.93(s,3H)；19F NMR(376MHz,CDCl3)δ-121.86；13C NMR(101MHz,CDCl3)δ 161.15(d,J＝34.4Hz),148.10(d,J＝272.0Hz),134.10(d,J＝8.1Hz),133.38(d,J＝8.7Hz), 132.75(d,J＝2.6Hz),132.22(d,J＝4.2Hz),129.74,118.16,115.29(d,J＝4.3Hz),113.28, 52.99.GC-MS(EI):calcd for C11H8FNO2m/z 205.0found 205.0.
Z-2-氟-3-(2-氟苯基)丙烯酸(2v)
结构式为：
Figure BDA0002015459890000162
其为白色固体，质量为62mg，收率为84％，Rf(PE/EA 1:1):0.20；1H NMR(400MHz,DMSO-d6)δ13.87(s,1H),7.81(td,J＝7.7,1.5Hz,1H),7.50–7.43(m,1H),7.33–7.24(m,2H), 7.03(d,J＝35.4Hz,1H)；19F NMR(376MHz,DMSO-d6)δ-115.01(d,J＝7.2Hz),-121.35(d,J ＝7.0Hz)；13C NMR(101MHz,DMSO-d6)δ161.93(d,J＝34.8Hz),159.97(dd,J＝250.5,1.7 Hz),148.75(d,J＝268.3Hz),132.33(dd,J＝8.8,1.8Hz),130.93(dd,J＝12.5,1.8Hz),125.48(d, J＝3.5Hz),118.90(dd,J＝12.1,4.2Hz),116.21(d,J＝21.8Hz),108.04(dd,J＝6.8,4.9Hz). LRMS(ESI-):calcd for C9H5F2O2 -[M-H]-183.03,found182.84.
Z-2-氟-3-(2-甲基苯基)丙烯酸(2w)
结构式为：
Figure BDA0002015459890000163
其为白色固体，质量为38mg，收率为52％，Rf(PE/EA 1:1):0.20；1H NMR(400MHz,DMSO-d6)δ7.68(d,J＝6.8Hz,1H),7.42–7.23(m,3H),7.11(d,J＝35.3Hz,1H),2.35(s,3H)；19F NMR(376MHz,DMSO-d6)δ-125.59；13C NMR(101MHz,acetone-d6)δ161.43(d,J＝35.7Hz),147.22(d,J＝265.2Hz),137.40(d,J＝1.2Hz),130.46,129.71(d,J＝11.5Hz),129.71(d,J ＝3.8Hz),129.46(d,J＝1.5Hz),126.19,114.37(d,J＝5.1Hz),19.16.HRMS(ESI-):calcd for C10H8FO2 -[M-H]-179.0514,found 179.0522.
Z-2-氟-3-(2-甲氧基苯基)丙烯酸(2x)
结构式为：
Figure BDA0002015459890000171
其为白色固体，质量为52mg，收率为66％，Rf(PE/EA 1:1):0.18；1H NMR(400MHz,DMSO-d6)δ7.77(dd,J＝7.8,1.7Hz,1H),7.45–7.39(m,1H),7.27(d,J＝37.2Hz,1H),7.11(d, J＝8.4Hz,1H),7.04(t,J＝7.6Hz,1H),3.86(s,3H)；19F NMR(376MHz,DMSO-d6)δ-125.36；13C NMR(101MHz,DMSO-d6)δ162.43(d,J＝35.7Hz),157.34,147.61(d,J＝263.1Hz), 131.83(d,J＝1.5Hz),130.51(d,J＝13.4Hz),121.17,119.47(d,J＝4.7Hz),111.86,110.44(d,J ＝3.5Hz),56.17.LRMS(ESI-):calcd for C10H8FO3 -[M-H]-195.05,found 194.83.
Z-2-氟-3-萘-2-丙烯酸(2y)
结构式为：
Figure BDA0002015459890000172
其为白色固体，质量为71mg，收率为82％，Rf(PE/EA 1:1):0.22；1H NMR(400MHz,DMSO-d6)δ13.74(s,1H),8.27(s,1H),8.09–7.93(m,3H),7.84(d,J＝8.6Hz,1H),7.68–7.52(m,2H),7.22(d,J＝36.5Hz,1H)；19F NMR(376MHz,DMSO-d6)δ-123.41；13C NMR(101 MHz,DMSO-d6)δ162.44(d,J＝35.7Hz),147.84(d,J＝266.4Hz),133.48(d,J＝1.4Hz), 133.18,130.79(d,J＝7.8Hz),129.00(d,J＝4.2Hz),128.90,128.87,128.01,127.83,127.19,127.08(d,J＝8.1Hz),117.10(d,J＝4.1Hz).LRMS(ESI-):calcd for C13H8FO2 -[M-H]-215.05, found 214.85.
Z-2-氟-3-萘-1-丙烯酸(2z)
结构式为：
Figure BDA0002015459890000173
其为白色固体，质量为57mg，收率为66％，Rf(PE/EA 1:1):0.22；1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝8.1Hz,1H),8.06–7.96(m,2H),7.92(d,J＝7.2Hz,1H),7.77–7.56(m,4H)；19F NMR(376MHz,DMSO-d6)δ-123.86；13C NMR(101MHz,DMSO-d6)δ162.35(d,J＝35.1Hz),148.56(d,J＝265.9Hz),133.62,131.13,130.26,129.13,128.67(d,J＝10.1Hz),127.54, 127.30(d,J＝3.3Hz),126.74,125.98,123.98,113.52(d,J＝5.9Hz).HRMS(ESI-):calcd for C13H8FO2 -[M-H]-215.0514,found 215.0515.
Z-2-氟-3-(4-氟-2-甲氧基苯基)丙烯酸(2aa)
结构式为：
Figure BDA0002015459890000181
其为白色固体，质量为57mg，收率为67％，Rf(PE/EA 1:1):0.18；1H NMR(400MHz,DMSO-d6)δ7.50(dd,J＝8.6,1.9Hz,1H),7.36–7.25(m,2H),7.05(d,J＝36.3Hz,1H),3.88(s, 3H)；19F NMR(376MHz,DMSO-d6)δ-124.52,-132.26；13C NMR(101MHz,DMSO-d6)δ 162.32(d,J＝34.6Hz),152.38(dd,J＝249.0,3.6Hz),147.58(d,J＝10.8Hz),147.31(d,J＝264.3Hz),128.35(t,J＝3.9Hz),123.56(dd,J＝9.2,7.3Hz),116.80(d,J＝18.6Hz),116.31(d,J ＝2.4Hz),115.87(dd,J＝7.5,2.2Hz),56.36.HRMS(ESI-):calcd forC10H7F2O3 -[M-H]- 213.0369,found 213.0365.
Z-2-氟-3-苯并噻吩-2-丙烯酸(2ab)
结构式为：
Figure BDA0002015459890000182
其为浅黄色固体，质量为62mg，收率为70％，Rf(PE/EA 1:1):0.16；1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),8.08(t,J＝7.4Hz,2H),7.54–7.46(m,2H),7.39(d,J＝35.2Hz,1H)；19F NMR(376MHz,DMSO-d6)δ-120.10；13C NMR(101MHz,DMSO-d6)δ162.26(d,J＝34.3 Hz),148.61(d,J＝265.3Hz),139.10,137.83,131.36(d,J＝14.9Hz),125.83(d,J＝3.3Hz),125.49,125.36,123.38,122.00,108.39(d,J＝7.3Hz).HRMS(ESI-):calcd for C11H6FO2S-[M-H]-221.0078,found 221.0074.
Z-2-氟-3-喹啉-3-丙烯酸(2ac)
结构式为：
Figure BDA0002015459890000191
其为浅黄色固体，质量为48mg，收率为52％，Rf(PE/EA 5:1):0.30；1H NMR(400MHz,CDCl3)δ9.05(d,J＝1.5Hz,1H),8.48(d,J＝1.2Hz,1H),8.10(d,J＝8.5Hz,1H),7.85(d,J＝8.1Hz,1H),7.79–7.73(m,1H),7.63–7.53(m,1H),7.09(d,J＝35.0Hz,1H),3.94(s,3H)；19FNMR(376MHz,CDCl3)δ-121.87；13C NMR(101MHz,CDCl3)δ161.27(d,J＝34.3Hz), 151.08(d,J＝6.6Hz),148.27(d,J＝270.1Hz),147.88(d,J＝2.3Hz),137.22(d,J＝10.8Hz),130.79,129.29,128.48,127.56,127.36,124.40(d,J＝5.0Hz),114.49(d,J＝5.4Hz),52.89. HRMS(ESI+):calcd for C13H11FNO2 +[M+H]+232.0768,found 232.0758.
Z-2-氟-3-(4,4-二氟-3-丁烯基苯基)丙烯酸(2ad)
结构式为：
Figure BDA0002015459890000192
其为白色固体，质量为70mg，收率为68％，Rf(PE/EA 1:1):0.20；1H NMR(400MHz,DMSO-d6)δ7.64(d,J＝7.9Hz,2H),7.30(d,J＝7.8Hz,2H),7.02(d,J＝36.8Hz,1H),4.47(m,J ＝26.9,2.8Hz,1H),2.70(t,J＝7.5Hz,2H),2.27(q,J＝7.7Hz,2H)；19F NMR(376 MHz,DMSO-d6)δ-89.37(d,J＝49.4Hz),-91.58(d,J＝49.5Hz),-124.45；13C NMR(101MHz, DMSO-d6)δ162.45(d,J＝34.7Hz),155.78(dd,J＝286.3,283.5Hz),147.30(d,J＝264.0Hz),143.22(d,J＝2.5Hz),130.55(d,J＝7.9Hz),129.42,129.23(d,J＝4.1Hz),116.93(d,J＝4.4Hz), 78.38(dd,J＝21.5,19.1Hz),34.87(t,J＝2.3Hz),23.75(d,J＝4.4Hz)；HRMS(ESI-):calcd for C13H10F3O2 -[M-H]-255.0638,found 255.0638.
(2Z,4E)-2-氟-5-苯基-2,4-戊二烯酸甲酯(2ae)
结构式为：
Figure BDA0002015459890000193
其为浅黄色油状液体，质量为63mg，收率为76％，Rf(PE/EA 5:1):0.60；
1H NMR(400MHz,CDCl3)δ7.50–7.43(m,2H),7.39–7.27(m,3H),7.14–7.02(m,1H),6.89–6.70(m,2H),3.85(s,3H)；19F NMR(376MHz,CDCl3)δ-128.82；13C NMR(101MHz, CDCl3)δ161.52(d,J＝33.7Hz),146.55(d,J＝264.3Hz),139.12(d,J＝4.6Hz),136.03(d,J＝1.8Hz),129.17,128.85,127.28(d,J＝0.9Hz),119.20(d,J＝8.8Hz),118.76(d,J＝2.0Hz), 52.47.GC-MS(EI):calcd for C12H11FO2m/z 206.1found 206.1.
Z-2-氟-5,5-二苯基-2,4-戊二烯酸甲酯(2af)
结构式为：
Figure BDA0002015459890000201
其为浅黄色油状液体，质量为81mg，收率为72％，Rf(PE/EA 5:1):0.60；1H NMR(400MHz, CDCl3)δ7.44–7.40(m,3H),7.34–7.29(m,5H),7.24–7.20(m,2H),7.02(dd,J＝11.9,0.4Hz, 1H),6.72(dd,J＝31.1,11.9Hz,1H),3.79(s,3H)；19F NMR(376MHz,CDCl3)δ-132.82；13C NMR(101MHz,CDCl3)δ161.56(d,J＝34.1Hz),150.13(d,J＝5.2Hz),147.32(d,J＝265.0 Hz),141.20(d,J＝1.3Hz),138.41,130.35,128.78,128.45,128.39,128.37,128.21,117.41(d,J＝ 1.9Hz),116.77(d,J＝7.0Hz),52.43.HRMS(ESI+):calcd forC18H16FO2 +[M+H]+283.1129, found 283.1137.
(2Z,4E)-2-氟-4-甲基-5-苯基-2,4-戊二烯酸甲酯(2ag)
结构式为：
Figure BDA0002015459890000202
其为浅黄色油状液体，质量为54mg，收率为61％，Rf(PE/EA 30:1):0.40；1H NMR(400 MHz,CDCl3)δ7.41–7.23(m,5H),6.80(s,1H),6.69(dd,J＝35.3,0.6Hz,1H),3.86(s,3H),2.22 (dd,J＝2.8,1.3Hz,3H)；19F NMR(376MHz,CDCl3)δ-128.08；13C NMR(101MHz,CDCl3)δ 162.18(d,J＝34.6Hz),145.60(d,J＝266.3Hz),137.51(d,J＝6.4Hz),136.44(d,J＝1.5Hz), 131.34(d,J＝5.9Hz),129.37(d,J＝1.0Hz),128.30,127.67,122.73(d,J＝3.9Hz),52.55(d,J＝ 0.6Hz),16.46(d,J＝7.2Hz).HRMS(ESI+):calcd for C13H13FNaO2 +[M+Na]+243.0792,found 243.0790.
实施例34-48 2,2-二氟-3-丁烯酸正己酯类化合物(4a-4o)的制备
具体制备过程为：
向含有磁子的干燥的史莱克(Schlenk)管(25mL)中加入反应底物(0.2mmol)，双联(2-甲基-2,4-戊二醇)硼酸酯(76.2mg，0.3mmol，1.5equiv)，然后将史莱克(Schlenk)管转入手套箱中，再加入氯化亚铜(CuCl)(2.0mg，0.02mmol，10mol％)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)(11.6mg，0.02mmol，10mol％)，甲醇钾(KOMe)(42mg，0.6mmol，3.0equiv)。将Schlenk管封闭后从手套箱中取出并连接到连有CO2钢瓶的双排管上，拧松盖子并在双排管上抽置换CO2 3次，使其管中充满CO2气体，然后在CO2气氛下加入超干N- 甲基吡咯烷酮(NMP)(2mL)。最后，将反应管置于金属浴上，于80℃下搅拌反应24h。冷却至室温后用微量进样器加入1-碘己烷(127mg(88uL)，0.6mmol，3.0equiv)，于80℃继续反应4小时，冷却室温后用6mL乙酸乙酯萃取3次后将萃取液浓缩旋干。残余物通过快速柱层析纯化(石油醚：乙酸乙酯50:1～10:1梯度洗脱)，最终得到纯的所需产物。
具体反应式和化合物具体结构如下：
Figure BDA0002015459890000211
2,2-二氟-3-(4-苯基苯基)-3-丁烯酸正己酯(4a)
结构式为：
Figure BDA0002015459890000221
其为浅黄色油状液体，质量为50mg，收率为70％，Rf(PE/EA30:1):0.55；1H NMR(400MHz,CDCl3)δ7.61–7.55(m,4H),7.52–7.40(m,4H),7.37–7.34(m,1H),5.92(t,J＝1.6Hz,1H),5.79(t,J＝1.6Hz,1H),4.18(t,J＝6.6Hz,2H),1.57–1.49(m,2H),1.26–1.17(m,6H),0.83(t,J＝6.8Hz,3H)；19F NMR(376MHz,CDCl3)δ-102.01；13C NMR(101MHz,CDCl3)δ 163.73(t,J＝33.9Hz),141.49,140.88(t,J＝22.1Hz),140.26,133.63(t,J＝1.3Hz),128.83,128.08,127.61,127.09,127.01,119.91(t,J＝8.6Hz),113.11(t,J＝252.1Hz),67.09,31.23,28.16, 25.21,22.43,13.93.HRMS(ESI+):calcd for C22H24F2NaO2 +[M+Na]+381.1637,found 381.1625. 2,2-二氟-3-(4-甲氧基苯基)-3-丁烯酸正己酯(4b)
结构式为：
Figure BDA0002015459890000222
其为浅黄色油状液体，质量为35mg，收率为56％，Rf(PE/EA 30:1):0.45；1H NMR(400 MHz,CDCl3)δ7.35(d,J＝8.7Hz,2H),6.86(d,J＝8.8Hz,2H),5.82(t,J＝1.6Hz,1H),5.66(t,J ＝1.6Hz,1H),4.16(t,J＝6.6Hz,2H),3.81(s,3H),δ1.58–1.48(m,2H),1.29–1.16(m,6H), 0.87(t,J＝6.9Hz,3H)；19F NMR (376MHz,CDCl3)δ-102.26；13C NMR(101MHz,CDCl3)δ 163.80(t,J＝33.5Hz),159.89,140.57(t,J＝21.9Hz),128.96,127.06(t,J＝1.3Hz),118.64(t,J ＝8.6Hz),113.77,113.16(t,J＝251.9Hz),66.99,55.22,31.23,28.16,25.19,22.42,13.96.HRMS (ESI+):calcd for C17H22F2NaO3 +[M+Na]+335.1429,found335.1411.
2,2-二氟-3-(4-氯苯基)-3-丁烯酸正己酯(4c)
结构式为：
Figure BDA0002015459890000223
其为浅黄色油状液体，质量为41mg，收率为64％，Rf(PE/EA30:1):0.50；1H NMR(400MHz,CDCl3)δ7.37–7.29(m,4H),5.91(t,J＝1.6Hz,1H),5.72(t,J＝1.3Hz,1H),4.17(t,J＝6.6Hz,2H),1.58–1.49(m,2H),1.31–1.16(m,6H),0.87(t,J＝6.9Hz,3H)；19F NMR(376MHz,CDCl3)δ-102.37；13C NMR(101MHz,CDCl3)δ163.49(t,J＝33.9Hz),140.23(t,J＝22.4Hz),134.87,133.16(t,J＝1.4Hz),129.10(t,J＝1.2Hz),128.65,120.60(t,J＝8.5Hz),112.83(t,J＝ 252.3Hz),67.17,31.21,28.14,25.20,22.44,13.96.HRMS(ESI+):calcd forC16H19ClF2NaO2 + [M+Na]+339.0934,found 339.0927.
2,2-二氟-3-(4-溴苯基)-3-丁烯酸正己酯(4d)
结构式为：
Figure BDA0002015459890000231
其为浅黄色油状液体，质量为45mg，收率为62％，Rf(PE/EA30:1):0.50；1H NMR(400MHz,CDCl3)δ7.50–7.46(m,2H),7.30–7.25(m,2H),5.92(t,J＝1.5Hz,1H),5.73(t,J＝1.4Hz,1H),4.17(t,J＝6.6Hz,2H),1.58–1.50(m,2H),1.30–1.15(m,6H),0.88(t,J＝7.0Hz,3H)；19F NMR(376MHz,CDCl3)δ-102.34；13C NMR(101MHz,CDCl3)δ163.47(t,J＝33.9Hz),140.30(t,J＝22.4Hz),133.64(t,J＝1.4Hz),131.61,129.38(t,J＝1.2Hz),123.11,120.64(t,J＝ 8.5Hz),112.77(t,J＝252.3Hz),67.18,31.21,28.14,25.20,22.44,13.97.HRMS(ESI+):calcd for C16H19BrF2NaO2 +[M+Na]+383.0429,found 383.0421.
2,2-二氟-3-(4-叔丁基苯基)-3-丁烯酸正己酯(4e)
结构式为：
Figure BDA0002015459890000232
其为浅黄色油状液体，质量为38mg，收率为56％，Rf(PE/EA30:1):0.60；1H NMR(400MHz,CDCl3)δ7.39–7.32(m,4H),5.85(t,J＝1.6Hz,1H),5.71(t,J＝1.5Hz,1H),4.16(t,J＝6.6Hz,2H),1.58–1.46(m,2H),1.31(s,9H),1.29–1.17(m,6H),0.86(t,J＝6.9Hz,3H)；19FNMR(376MHz,CDCl3)δ-102.12；13C NMR(101MHz,CDCl3)δ163.82(t,J＝34.0Hz),151.72,140.96(t,J＝22.1Hz),131.71(t,J＝1.4Hz),127.28,125.35,119.33(t,J＝8.6Hz),113.16(t,J＝ 251.8Hz),66.97,34.58,31.20,28.08,25.15,22.42,13.97.HRMS(ESI+):calcd for C20H28F2NaO2 +[M+Na]+361.1950,found 361.1945.
2,2-二氟-3-(3-甲氧基苯基)-3-丁烯酸正己酯(4f)
结构式为：
Figure BDA0002015459890000241
其为浅黄色油状液体，质量为33mg，收率为52％，Rf(PE/EA 30:1):0.45；1H NMR(400 MHz,CDCl3)δ7.25(t,J＝8.0Hz,1H),7.00–6.96(m,1H),6.95–6.93(m,1H),6.91–6.86(m, 1H),5.90(t,J＝1.6Hz,1H),5.74(t,J＝1.5Hz,1H),4.16(t,J＝6.6Hz,2H),3.80(s,3H),1.58– 1.48(m,2H),1.31–1.14(m,6H),0.87(t,J＝6.9Hz,3H)；19F NMR(376MHz,CDCl3)δ-102.06；13C NMR(101MHz,CDCl3)δ163.69(t,J＝33.9Hz),159.48,141.16(t,J＝22.1Hz),136.10, 129.47,120.12,120.12(t,J＝8.6Hz),114.22,113.45,113.02(t,J＝252.0Hz),67.06,55.22,31.24, 28.17,25.20,22.42,13.96.HRMS(ESI+):calcd for C17H22F2NaO3 +[M+Na]+335.1429,found 335.1418.
2,2-二氟-3-(3-氯苯基)-3-丁烯酸正己酯(4g)
结构式为：
Figure BDA0002015459890000242
其为浅黄色油状液体，质量为39mg，收率为62％，Rf(PE/EA 30:1):0.6；1H NMR(400MHz, CDCl3)δ7.40(s,1H),7.37–7.27(m,3H),5.94(t,J＝1.6Hz,1H),5.74(t,J＝1.5Hz,1H),4.18(t, J＝6.6Hz,2H),1.60–1.50(m,2H),1.31–1.16(m,6H),0.87(t,J＝6.9Hz,3H)；19F NMR(376 MHz,CDCl3)δ-102.31；13C NMR(101MHz,CDCl3)δ163.44(t,J＝33.9Hz),140.29(t,J＝22.6 Hz),136.55((t,J＝1.3Hz)),134.39,129.70,128.84,128.04,125.99,121.21(t,J＝8.5Hz),112.79 (t,J＝252.4Hz),67.22,31.23,28.17,25.22,22.43,13.96.HRMS(ESI+):calcd for C16H19ClF2NaO2 +[M+Na]+339.0934,found339.0935.
2,2-二氟-3-(3-苯基苯基)-3-丁烯酸正己酯(4h)
结构式为：
Figure BDA0002015459890000243
其为浅黄色油状液体，质量为49mg，收率为68％，Rf(PE/EA 30:1):0.55；1H NMR(400 MHz,CDCl3)δ7.62(s,1H),7.60–7.54(m,3H),7.46–7.33(m,5H),5.95(t,J＝1.7Hz,1H), 5.79(t,J＝1.5Hz,1H),4.16(t,J＝6.6Hz,2H),1.56–1.46(m,2H),1.23–1.12(m,6H),0.83(t,J ＝6.8Hz,3H)；19F NMR(376MHz,CDCl3)δ-101.99；13C NMR(101MHz,CDCl3)δ163.71(t,J ＝33.9Hz),141.44,141.31(t,J＝22.2Hz),140.59,135.29(t,J＝1.5Hz),128.86,128.82,127.55, 127.46,127.14,126.66–126.52(m,2C),120.32(t,J＝8.5Hz),113.08(t,J＝252.1Hz),67.09, 31.20,28.15,25.17,22.38,13.93.HRMS(ESI+):calcd forC22H24F2NaO2 +[M+Na]+381.1637, found 381.1635.
2,2-二氟-3-(3,5-二甲基苯基)-3-丁烯酸正己酯(4i)
结构式为：
Figure BDA0002015459890000251
其为浅黄色油状液体，质量为26mg，收率为42％，Rf(PE/EA 30:1):0.60；1H NMR(400 MHz,CDCl3)δ7.01–6.97(m,3H),5.86(t,J＝1.5Hz,IH),5.69(d,J＝1.5Hz,IH),4.17(t,J＝ 6.6Hz,2H),2.31(s,6H),1.58–1.50(m,2H),1.30–1.17(m,6H),0.87(t,J＝6.8Hz,3H)；19F NMR(376MHz,CDCl3)δ-101.99；13C NMR(101MHz,CDCl3)δ163.77(t,J＝33.9Hz),141.43 (t,J＝21.9Hz),137.87,134.68(t,J＝1.5Hz),130.31,125.50(t,J＝1.0Hz),119.64(t,J＝8.6 Hz),113.11(t,J＝252.0Hz),66.95,31.26,28.16,25.19,22.41,21.28,13.95HRMS(ESI+): calcd for C18H24F2NaO2 +[M+Na]+333.1637,found 333.1624.
2,2-二氟-3-(3,4-亚甲基二氧代苯基)-3-丁烯酸正己酯(4j)
结构式为：
Figure BDA0002015459890000252
其为浅黄色油状液体，质量为43mg，收率为65％，Rf(PE/EA30:1):0.30；
1H NMR(400MHz,CDCl3)δ6.92–6.85(m,2H),6.77(d,J＝8.0Hz,1H),5.97(s,2H),5.83 (t,J＝1.6Hz,1H),5.65(t,J＝1.6Hz,1H),4.17(t,J＝6.6Hz,2H),1.59–1.51(m,2H),1.30– 1.16(m,6H),0.87(t,J＝6.9Hz,3H)；19F NMR(376MHz,CDCl3)δ-102.18；13C NMR(101MHz,CDCl3)δ163.66(t,J＝34.0Hz),148.00,147.66,140.69(t,J＝22.1Hz),128.58(t,J＝1.5 Hz),121.70(t,J＝1.2Hz),119.33(t,J＝8.5Hz),113.01(t,J＝252.0Hz),108.28(t,J＝1.4Hz), 108.17,101.26,67.03,31.23,28.17,25.20,22.41,13.94.HRMS(ESI+):calcdfor C17H20F2NaO4 + [M+Na]+349.1222,found 349.1219.
2,2-二氟-3-萘-2-(3-丁烯)酸正己酯(4k)
结构式为：
Figure BDA0002015459890000261
其为浅黄色油状液体，质量为39mg，收率为58％，Rf(PE/EA 30:1):0.50；1H NMR(400 MHz,CDCl3)δ7.88(s,1H),7.85–7.78(m,3H),7.57–7.44(m,3H),6.00(t,J＝1.6Hz,1H), 5.86(t,J＝1.5Hz,1H),4.13(t,J＝6.6Hz,2H),1.53–1.40(m,2H),1.20–1.01(m,6H),0.79(t,J ＝6.8Hz,3H)；19F NMR(376MHz,CDCl3)δ-101.77；13C NMR(101MHz,CDCl3)δ163.75(t,J ＝34.1Hz),141.13(t,J＝22.0Hz),133.10,132.97,132.04,128.39,128.14,127.55,127.02(d,J＝ 0.8Hz),126.64,126.45,125.28(d,J＝0.6Hz),120.35(t,J＝8.6Hz),113.13(t,J＝252.4Hz), 67.09,31.16,28.14,25.17,22.33,13.94.HRMS(ESI+):calcdfor C20H22F2NaO2 +[M+Na]+ 355.1480,found 355.1460.
2,2-二氟-3-(3-氟-4-苯基苯基)-3-丁烯酸正己酯(4l)
结构式为：
Figure BDA0002015459890000262
其为浅黄色油状液体，质量为50mg，收率为66％，Rf(PE/EA 30:1):0.55；1H NMR(400 MHz,CDCl3)δ7.59–7.51(m,2H),7.49–7.35(m,4H),7.29–7.22(m,2H),5.96(t,J＝1.5Hz, 1H),5.81(t,J＝1.6Hz,1H),4.21(t,J＝6.6Hz,2H),1.62–1.53(m,2H),1.29–1.17(m,6H), 0.84(t,J＝6.7Hz,3H)；19F NMR(376MHz,CDCl3)δ-102.14,-117.35；13C NMR(101MHz, CDCl3)δ163.52(t,J＝33.9Hz),159.38(d,J＝248.5Hz),139.93(td,J＝22.6,2.1Hz),135.51(d, J＝8.2Hz),135.01(d,J＝1.4Hz),130.70(d,J＝4.1Hz),129.33(d,J＝13.5Hz),128.91(d,J＝ 3.1Hz),128.52,127.98,123.65(d,J＝3.4Hz),120.85(t,J＝8.5Hz),115.72–115.39(m,1C), 112.85(t,J＝252.3Hz),67.24,31.22,28.16,25.22,22.43,13.94.HRMS(ESI+):calcd for C22H23F3NaO2 +[M+Na]+399.1542,found 399.1541.
2,2-二氟-3-(4-萘-2-苯基)-3-丁烯酸正己酯(4m)
结构式为：
Figure BDA0002015459890000263
其为浅黄色油状液体，质量为45mg，收率为55％，Rf(PE/EA 30:1):0.60；1H NMR(400 MHz,CDCl3)δ8.03(s,1H),7.94–7.83(m,3H),7.76–7.67(m,3H),7.56–7.45(m,4H),5.95(t, J＝1.6Hz,1H),5.81(t,J＝1.5Hz,1H),4.19(t,J＝6.6Hz,2H),1.59–1.49(m,2H),1.27–1.15 (m,6H),0.82(t,J＝6.9Hz,3H)；19F NMR(376MHz,CDCl3)δ-101.97；13C NMR(101MHz, CDCl3)δ163.76(t,J＝33.9Hz),141.38,140.87(t,J＝22.1Hz),137.57,133.70(t,J＝1.3Hz), 133.62,132.75,128.55,128.23,128.18,127.66,127.36,126.41,126.14,125.82,125.25,119.98(t, J＝8.6Hz),113.13(t,J＝252.1Hz),67.13,31.25,28.18,25.22,22.45,13.96.HRMS(ESI+): calcd for C26H26F2NaO2 +[M+Na]+431.1793,found431.1783.
2,2-二氟-3-(4-(4-氯苯)-苯基)-3-丁烯酸正己酯(4n)
结构式为：
Figure BDA0002015459890000271
其为浅黄色油状液体，质量为46mg，收率为59％，Rf(PE/EA 30:1):0.55；1H NMR(400 MHz,CDCl3)δ7.56–7.46(m,6H),7.43–7.38(m,2H),5.93(t,J＝1.6Hz,1H),5.78(t,J＝1.5 Hz,1H),4.18(t,J＝6.6Hz,2H),1.59–1.50(m,2H),1.26–1.12(m,6H),0.83(t,J＝6.8Hz,3H)；19F NMR(376MHz,CDCl3)δ-102.05；13C NMR(101MHz,CDCl3)δ163.67(t,J＝33.9Hz), 140.76(t,J＝22.3Hz),140.20,138.68,133.98(t,J＝1.3Hz),133.74,128.99,128.23,128.21(t,J ＝1.1Hz),126.91,120.13(t,J＝8.6Hz),113.05(t,J＝252.2Hz),67.11,31.21,28.15,25.19,22.42, 13.92.HRMS(ESI+):calcd for C22H23ClF2NaO2 +[M+Na]+415.1247,found 415.1246.
2,2-二氟-3-(9,9-二甲基芴-2-(3-丁烯)酸正己酯(4o)
结构式为：
Figure BDA0002015459890000272
其为浅黄色油状液体，质量为46mg，收率为58％，Rf(PE/EA 30:1):0.55；1H NMR(400 MHz,CDCl3)δ7.74–7.63(m,2H),7.46(s,1H),7.44–7.41(m,1H),7.38(dd,J＝7.9,1.6Hz, 1H),7.36–7.28(m,2H),5.93(t,J＝1.6Hz,1H),5.80(t,J＝1.5Hz,1H),4.14(t,J＝6.6Hz,2H), 1.48(s,8H),1.22–1.12(m,6H),0.79(t,J＝6.8Hz,3H)；19F NMR(376MHz,CDCl3)δ-101.62；13C NMR(101MHz,CDCl3)δ163.79(t,J＝33.9Hz),153.88,153.72,141.56(t,J＝21.9Hz), 139.77,138.42,133.61(t,J＝1.3Hz),127.63,127.05,126.70,122.62,121.87(t,J＝1.0Hz), 120.21,119.89,119.51(t,J＝8.6Hz),113.16(t,J＝252.0Hz),67.02,46.92,31.20,28.13,27.05, 25.16,22.36,13.89.HRMS(ESI+):calcd forC25H28F2NaO2 +[M+Na]+421.1950,found 421.1938.
实施例49产物Z-2-氟-3-(4-(N,N-二苯胺基)苯基)丙烯酸(2l)的克级规模合成
Figure BDA0002015459890000281
具体操作为：称量联硼酸频哪醇酯(1.52g，6mmol，1.5equiv)和4-N,N-二苯基二氟苯乙烯(1l)(1.23g，4mmol，1.0equiv)置于干燥的装有搅拌子的250mL史莱克瓶中，然后于手套箱中称取CuTc(38mg,0.2mmol,5mol％),Xantphos(116mg,0.2mmol,5mol％)和LiOtBu(1.12g,14mmol,3.5equiv)，然后抽置换CO2气体三次，使反应瓶中充满CO2气体，而后在 CO2氛围下通过注射器加入20mL超干DMF。拧紧反应瓶活塞，置于80℃下搅拌反应24h后拿出。待冷却至室温后依次加入20mL乙酸乙酯、20mL 2N的盐酸水溶液搅拌下猝灭反应，而后用50mL乙酸乙酯萃取3次，合并减压蒸馏浓缩后，残余物通过快速柱层析纯化 (PE/EA＝10:1)得黄色固体目标产物2l(1.04g，收率：78％)。
实施例50化合物2a'及2b的应用
Figure BDA0002015459890000282
通过化合物2a’可以以高产率获得化合物5和6，具体制备方法如下：
Z-2-氟-3-(4-苯基苯基)-2-烯丙醇(5)的制备：
依次称取Z-2-氟-3-(4-苯基苯基)丙烯酸甲酯(2a’)(51.3mg,0.2mmol,1.0equiv)，氢化铝锂(7.6mg,0.2mmol,1.0equiv)置于10mL事先干燥装有搅拌子的反应管中，抽充置换 N2三次后置于-10℃下搅拌冷却，通过注射器加入2mL无水乙醚，搅拌下反应6分钟。待TLC 点板监测原料反应完全后，依次加入H2O(11μL),15％NaOH(11μL)，H2O(33μL)。硅藻土过滤后减压蒸馏浓缩，残余物通过快速柱层析纯化(PE/EA:10/1至2/1梯度洗脱)得白色固体目标产物5，其为白色固体，质量为38.4mg，收率为84％，Rf(PE/EA 5/1):0.30；1HNMR(400 MHz,DMSO-d6)δ7.72–7.66(m,4H),7.61–7.57(m,2H),7.47(t,J＝7.6Hz,2H),7.39–7.33 (m,1H),5.98(d,J＝40.9Hz,1H),5.48(t,J＝5.9Hz,1H),4.14(dd,J＝13.3,5.9Hz,1H)；19F NMR(376MHz,DMSO-d6)δ-110.61；13C NMR(101MHz,DMSO-d6)δ160.73(d,J＝268.1 Hz),139.97,139.13(d,J＝2.2Hz),132.53(d,J＝2.3Hz),129.40,129.29(d,J＝7.2Hz),127.95, 127.24,126.92,105.66(d,J＝5.3Hz),60.10(d,J＝32.2Hz).HRMS(ESI-):calcd for C15H12FO- [M-H]-227.0878,found 227.0881.
1-苄基-3-氟-4-(4-苯基苯基)-3-甲酸甲酯-四氢吡咯(6)的制备：
称取Z-2-氟-3-(4-苯基苯基)丙烯酸甲酯(2a’)(51mg,0.2mmol,1.0equiv),N-(甲氧甲基)-N-(三甲基硅甲基)苄胺(190mg,0.8mmol,4.0equiv)于事先干燥的带有搅拌子的10mL 反应管中，加入1mL二氯甲烷配制成溶液，置于0℃下加入三氟乙酸(2.3mg,0.02mmol,10mol％)，而后移至25℃下搅拌反应3小时。冷却至室温后减压浓缩，残余物通过快速柱层析纯化(PE/EA＝30/1～5/1)得白色固体目标产物6，其为白色固体，质量为68mg，收率为87％， Rf(PE/EA 5/1):0.30；1H NMR(400MHz,CDCl3)δ7.58–7.49(m,4H),7.45–7.37(m,4H),7.36–7.24(m,6H),4.00–3.72(m,6H),3.62–3.48(m,1H),3.32–3.24(m,1H),3.17–2.99(m,2H)；19F NMR(376MHz,CDCl3)δ-160.62；13C NMR(101MHz,CDCl3)δ170.66(d,J＝28.1 Hz),138.43,133.66(d,J＝3.4Hz),129.53(d,J＝1.4Hz),128.75,128.69,128.44,127.28,127.09, 100.08(d,J＝199.7Hz),63.97(d,J＝24.6Hz),60.20,57.81,52.29(d,J＝20.1Hz).HRMS (ESI+):calc.for C25H25FNO2 +[M+H]+390.1864,found 390.1864.
通过化合物2b可以以高产率获得化合物7和8，具体制备方法如下：
Z-N-仲丁基-2-氟-3-苯基丙烯酰胺(7)的制备:
称取Z-2-氟-3-(4-苯基)丙烯酸(2b)(33mg,0.2mmol，1.0equiv),O-(7-氮杂苯并三唑 -1-基)-N,N,N’,N’-四甲基脲(152mg,0.4mmol,2equiv)置于事先干燥的带有搅拌子的10mL反应管中，抽充置换N2三次，而后依次在N2氛围下通过注射器加入2-氨基丁烷(22mg，0.3mmol， 1.5equiv)、三乙胺(60.6mg，0.6mmol，3equiv)。最后加入2mL DMF，置于25℃下搅拌反应5小时。TLC监测反应完成后，加H2O猝灭反应，乙酸乙酯萃取三次，合并后经无水硫酸钠干燥，减压蒸馏浓缩，残余物通过快速柱层析纯化(PE/EA＝10/1)得白色固体目标产物7，其为白色固体，质量为36mg，收率为82％，Rf(PE/EA 10/1):0.35；1H NMR(400MHz,CDCl3) δ7.64–7.55(m,2H),7.44–7.30(m,3H),6.93(d,J＝39.5Hz,1H),6.16(s,1H),4.11–4.00(m,1H),1.56(p,J＝7.3Hz,2H),1.22(d,J＝6.6Hz,3H),0.95(t,J＝7.4Hz,3H)；19F NMR(376MHz,CDCl3)δ-129.29；13C NMR(101MHz,CDCl3)δ159.81(d,J＝28.7Hz),150.21(d,J＝275.7Hz),131.44(d,J＝3.5Hz),130.01(d,J＝7.6Hz),129.07(d,J＝2.6Hz),128.70,113.27(d, J＝4.6Hz),46.91,29.63,20.37,10.37.HRMS(ESI+):calc.for C13H17FNO+[M+H]+222.1289, found 222.1285.
(R,Z)-2-氟-3苯基-N-(3-奎宁基)-丙烯酰胺(8)的制备
称取Z-2-氟-3-(4-苯基)丙烯酸(2b)(33mg,0.2mmol，1.0equiv),O-(7-氮杂苯并三唑 -1-基)-N,N,N’,N’-四甲基脲(152mg,0.4mmol,2equiv)置于事先干燥的带有搅拌子的10mL反应管中,抽充置换N2三次，而后依次在N2氛围下通过注射器加入R-3-氨基奎宁环二盐酸盐 (40mg，0.2mmol，1.0equiv)、三乙胺(80.8mg，0.8mmol，4equiv)。最后加入2mL DMF，置于25℃下搅拌反应6小时。TLC监测反应完成后，加2mL 1N NaOH猝灭反应，乙酸乙酯萃取三次，合并后经无水硫酸钠干燥，减压蒸馏浓缩，残余物通过快速柱层析纯化 (DCM/MeOH＝50/1～30/1)得目标产物8，其为淡黄色固体，质量为50mg，收率为91％，Rf (PE/EA 1/1):0.35；1H NMR(400MHz,CDCl3)δ7.61–7.55(m,2H),7.40–7.29(m,3H),6.91(d, J＝39.5Hz,1H),6.55(s,1H),4.05(s,1H),3.38(dd,J＝14.0,9.7Hz,1H),2.96–2.74(m,4H), 2.57(dd,J＝14.2,4.3Hz,1H),1.97(d,J＝2.8Hz,1H),1.74–1.63(m,3H),1.55–1.43(m,1H)；19F NMR(376MHz,CDCl3)δ-129.36；13C NMR(101MHz,CDCl3)δ160.33(d,J＝29.0Hz), 149.95(d,J＝275.1Hz),131.28(d,J＝3.5Hz),130.05(d,J＝7.6Hz),129.21(d,J＝2.5Hz), 128.73,113.53(d,J＝4.4Hz),55.83,47.36,46.82,46.60,25.72,25.65,20.08.HRMS(ESI+):calc.for C16H20FN2O+[M+H]+275.1554,found 275.1549。

Claims (4)

1.一种含氟羧酸类化合物的制备方法，其特征在于，包括以下步骤：将含氟烯烃类化合物与CO2在铜催化剂、配体、碱和硼试剂的存在下于溶剂中发生反应，反应温度为50-100℃，反应时间为2-28h，制得，具体反应式如下：
Figure FDA0002883837340000011
其中，含氟烯烃类化合物为反应式中所示的二氟烯烃类化合物；R1为芳基、杂芳基、烯基及其衍生物，R2为H、烷基、芳基及其衍生物；所述烷基为具有1-20个碳原子的直链烷基、支链烷基、环烷基；芳基为具有6-20个碳原子的芳基；杂芳基为具有6-20个碳原子的杂芳基；
铜催化剂为噻吩-2-甲酸亚铜、醋酸亚铜、氯化亚铜、溴化亚铜或碘化亚铜；配体为4,5-双二苯基膦-9,9-二甲基氧杂蒽、双(2-二苯基磷苯基)醚、4,6-双(二苯基膦)吩嗪、双二苯基膦乙烷或双二苯基膦丁烷；碱为氟化钾、氟化铯、甲醇钾、醋酸钾、叔丁醇锂或叔丁醇钾；硼试剂为联硼酸频那醇酯、联硼酸新戊二醇酯、联硼酸邻苯二酚酯或双联(2,4-二甲基-2,4-戊二醇)硼酸酯；溶剂为邻二甲苯、N,N-二甲基甲酰胺或N-甲基吡咯烷酮。
2.根据权利要求1所述的含氟羧酸类化合物的制备方法，其特征在于，二氟烯烃类化合物与铜催化剂的摩尔比为40:1-5:1，二氟烯烃类化合物与配体的摩尔比为40:1-5:1，二氟烯烃类化合物与碱的摩尔比为1:1-1:6，二氟烯烃类化合物与硼试剂的摩尔比为1:1-1:5。
3.根据权利要求2所述的含氟羧酸类化合物的制备方法，其特征在于，二氟烯烃类化合物与铜催化剂的摩尔比为20:1，二氟烯烃类化合物与配体的摩尔比为20:1，二氟烯烃类化合物与碱的摩尔比为1:3.5，二氟烯烃类化合物与硼试剂的摩尔比为1:1.5。
4.根据权利要求1-3任一项所述的含氟羧酸类化合物的制备方法，其特征在于，制得的含氟羧酸类化合物的具体结构式为：
Figure FDA0002883837340000012
Figure FDA0002883837340000021
CN201910261590.6A 2019-04-02 2019-04-02 一种含氟羧酸类化合物及其制备方法 Active CN111592519B (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201910261590.6A CN111592519B (zh) 2019-04-02 2019-04-02 一种含氟羧酸类化合物及其制备方法
CN202011620309.2A CN112794782B (zh) 2019-04-02 2019-04-02 一种含氟羧酸类化合物及其制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910261590.6A CN111592519B (zh) 2019-04-02 2019-04-02 一种含氟羧酸类化合物及其制备方法

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN202011620309.2A Division CN112794782B (zh) 2019-04-02 2019-04-02 一种含氟羧酸类化合物及其制备方法

Publications (2)

Publication Number Publication Date
CN111592519A CN111592519A (zh) 2020-08-28
CN111592519B true CN111592519B (zh) 2021-03-23

Family

ID=72179314

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201910261590.6A Active CN111592519B (zh) 2019-04-02 2019-04-02 一种含氟羧酸类化合物及其制备方法
CN202011620309.2A Active CN112794782B (zh) 2019-04-02 2019-04-02 一种含氟羧酸类化合物及其制备方法

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN202011620309.2A Active CN112794782B (zh) 2019-04-02 2019-04-02 一种含氟羧酸类化合物及其制备方法

Country Status (1)

Country Link
CN (2) CN111592519B (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112321475B (zh) * 2020-11-13 2022-06-10 四川大学 一种γ-氨基酸类似物及其合成方法
CN113773201B (zh) * 2021-10-22 2023-09-15 天津医科大学 含三氟甲基的螺[4,5]癸烷类化合物及其制备方法
CN114605361B (zh) * 2022-04-14 2023-05-19 河南师范大学 一种合成γ-羟基-γ-全氟甲基丁烯内酯类化合物的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5972839A (en) * 1996-12-19 1999-10-26 Hoechst Schering Agrevo Gmbh 2-fluoroacrylic acid derivatives, novel mixtures of herbicides and antidotes, and their use

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664585B (zh) * 2012-08-30 2015-02-18 中国科学院上海有机化学研究所 一种三氟甲基羰基化合物的制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5972839A (en) * 1996-12-19 1999-10-26 Hoechst Schering Agrevo Gmbh 2-fluoroacrylic acid derivatives, novel mixtures of herbicides and antidotes, and their use

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
A novel reaction of β,β-dihydroxy acids or esters with vanadium(V) trichloride oxide. New entry to the stereoselective synthesis of α-fluoro-α,β-unsaturated acids and esters;Ishihara, Takashi等;《Tetrahedron Letters》;19990415;第4865-4868页 *
Pd- and Cu-Catalyzed Stereo- and Regiocontrolled Decarboxylative/C-H Fluoroalkenylation of Heteroarenes;Rousee, Kevin等;《Chemistry-A European Journal》;20141009;第15000-15004页 *
Preparation and proton, fluorine, and carbon-13 NMR spectra of m- and p-substituted α-fluorocinnamic acid esters;Elkik, Elias等;《Bulletin de la Societe Chimique de France》;19861231;第423-428页 *
Stereospecific Synthesis of Tri- and Tetrasubstituted α-Fluoroacrylates by Mizoroki-Heck Reaction;Rousee, Kevin等;《Organic Letters》;20160126;第540-543页 *
Synthetic utilization of 2-chloro-1,1,1,2-tetrafluoroethane;Notsu, Keiji等;《Chemistry-A European Journal》;20110705;第9200-9208页 *
The relationships between fluorine-19 substituent chemical shifts and electron populations in para and meta substituted α-fluoro-Z-cinnamic esters;Arnaud, Roger等;《Fluorine Chemistry》;20010607;第281-292页 *
Toward (Z)-selective Horner-Wadsworth-Emmons reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid;Sano, Shigeki等;《Tetrahedron Letters》;20021109;第9183-9186页 *

Also Published As

Publication number Publication date
CN112794782B (zh) 2022-06-17
CN112794782A (zh) 2021-05-14
CN111592519A (zh) 2020-08-28

Similar Documents

Publication Publication Date Title
CN111592519B (zh) 一种含氟羧酸类化合物及其制备方法
CN104803898B (zh) 芳基烷基、芳基芳基硫醚化合物及其合成方法
Mohan et al. Superparamagnetic copper ferrite nanoparticles catalyzed aerobic, ligand-free, regioselective hydroboration of alkynes: influence of synergistic effect
CN109293692B (zh) 一类偕二氟烷基硼酸酯类化合物及其制备方法和应用
CN108912042B (zh) 一种从芳香酸直接制备芳香酮的方法
CN113444005B (zh) 一种双芳基取代的非活化烯烃合成新型戊二酸类化合物的方法
CN105566021A (zh) 一种α，β-不饱和羧酸类化合物的制备方法
CN112442008B (zh) 一种温度调控单质硫与活泼内炔制备1,4-二噻烯和噻吩类化合物的方法及其转化反应
CN110590759B (zh) 一种水相合成含三氟甲基噻吩基非对称双吲哚化合物的新方法
CN111187130B (zh) 对位取代芳基化合物的制备方法
CN102942511B (zh) 一种环戊二烯的制备方法
CN105622625B (zh) 一种苯并吡喃酮并咪唑并吡啶类化合物的合成方法
CN115010600B (zh) 一种基于芳基碳氟键羧基化反应合成多氟芳基羧酸类化合物的方法
CN109734571B (zh) α-F-β-OH-羰基化合物的合成方法
CN105017043B (zh) α‑烷基支链取代的α‑氨基酸衍生物的合成方法
CN110003081A (zh) 一种多氟烷基取代的吲哚啉和四氢异喹啉的合成方法
CN113548965B (zh) 一种1,4烯炔类化合物的制备方法
CN105348044B (zh) 一种毒芹提取物(S)-Virol A的合成方法
CN108659028B (zh) 一种（z）式氟烷基化烯基硼酸酯及其制备方法和应用
CN102816116B (zh) 一种6-羟基-2（1h）-喹啉酮化合物的合成方法
CN104817483A (zh) 一种双羰基吲哚类化合物及其合成方法
CN108794420A (zh) 基于四甲基螺二氢茚骨架的双噁唑啉配体化合物及其中间体和制备方法与用途
CN114277389B (zh) 一种利用吡啶盐光电催化Minisci反应合成喹啉衍生物的方法
CN111138359A (zh) 制备3-羰基-4-叠氮基-n-苯磺酰基-1,2,3,4-四氢异喹啉类化合物的方法
CN113620795B (zh) 苯并环庚烯酮类化合物的合成方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant