CN115850111A - 一种镍催化含偕二氟烯烃结构脂肪胺的制备方法 - Google Patents
一种镍催化含偕二氟烯烃结构脂肪胺的制备方法 Download PDFInfo
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Abstract
本发明涉及一种镍催化含偕二氟烯烃结构脂肪胺的制备方法，在氩气氛围下使用乙二醇二甲醚溴化镍作为催化剂，浴铜灵作为配体，氟化钠作为碱，三甲氧基硅烷为氢源，乙二醇二甲醚作为溶剂，在70℃下反应18 h。在温和的条件下实现了迁移脱氟烯丙基化反应，分离收率最高可达93%。本发明利用镍催化未活化烯烃以及三氟甲基取代烯烃为原料发生迁移脱氟烯丙基化反应来高效合成偕二氟烯烃化合物，其显著优点包括：本发明方法避免传统方法中贵金属催化剂的使用，具有高区域选择性，且反应条件温和、操作简单、具有广泛的底物普适性和官能团兼容性，合成效率高。合成的一系列含偕二氟烯烃的胺产物在农药、医药及材料领域有广泛的应用。
Description
技术领域
本发明属于有机化学技术领域，特别是涉及一种镍催化的偕二氟烯烃化合物的制备方法，该方法在相同条件下，烯丙基酰胺衍生物作为烯烃底物时得到迁移脱氟烯丙基化产物，并且具有优异的区域选择性。
背景技术
偕二氟烯烃是多种有机氟化合物的合成前体，在农业化学、药物化学、材料科学中有着广泛的应用。由于它们与酮、醛和酯的空间和电子具有相似性，因而是理想的羰基生物电子等排体，同时它们的代谢稳定性也得到了增强，所以被广泛地用于现代药物的研究。由于偕二氟烯烃特殊的性质，因此，开发合成偕二氟烯烃一直是化学家们研究的热点。一方面，烯烃来源丰富且容易制备，发展烯烃作为起始原料的反应，一直是化学家们研究的热门领域。另一方面，链行走和交叉偶联反应的结合是实现远程 C-H 键官能团化的有效方法，与传统的导向基定位的 C-H 键活化相比，该方法条件温和、无需安装/脱除导向基。
过去几十年来，发展合成结构多样的偕二氟烯烃的方法引起了广泛关注，比如：2015年, Ichikawa课题组报道了一例镍催化脱氟环化构建偕二氟烯烃的反应。该反应中炔烃与三氟甲基取代的烯烃在镍催化下发生环金属化, 随后经β-F消除得到偕二氟烯烃。参见： J. Ichikawa. J. Fluorine Chem. [J].2000, 105, 257-263. 传统上制备偕二氟烯烃是通过羰基或重氮化合物的偕二氟烯基化反应来实现的，比如：2019年，天津大学马军安课题组通过本实验室开发的新型二氟烷基化试剂——苯砜基二氟重氮乙烷，开发出构建手性和非手性偕二氟烯丙基胺的通用有效方法。参见： J.-L. Zeng, Y. Zhang, M.-M.Zheng, Z.-Q. Zhang, X.-S. Xue, F.-G. Zhang, J.-A. Ma. Org.Lett. [J]. 2019,21, 8244-8249. 此外，通过有机金属试剂为亲核试剂对α-三氟甲基取代的烯烃发生SN2型加成消除反应为合成偕二氟烯烃化合物提供了一条新途径。比如，2020年华南理工大学江焕峰课题组报道了SN2型的1,1-双亲核试剂与(三氟甲基)烯烃的双烯丙基脱氟烷基化反应， 参见：Y.-Y. Cai, H. Zeng, C.-L. Zhu, C. Liu, G.-Y. Liu, H.-F. Jiang.Org.Chem.Front. [J]. 2020, 7, 1260-1264. 在光催化或过渡金属催化的温和条件下，α-三氟甲基烯烃脱氟交叉偶联构建偕二氟乙烯基团的策略，已成功应用于合成不同的偕二氟烯烃中在这些反应中α-三氟甲基烯烃可以高效地捕获自由基，并通过β-氟消除将三氟甲基转化为偕二氟乙烯基。比如：2016年，中山大学周磊课题组利用自由基/极***叉的策略，实现了首例可见光促进酮酸与三氟甲基烯烃的脱羧/脱氟偶联反应，合成了一系列γ,γ-偕二氟烯丙基酮化合物，参见：T. Xiao, L. Li, L. Zhou J. Org. Chem. [J]. 2016，81, 7908–7916. 此外， 2020年，南开大学汪清民课题组在光催化条件下通过三苯基膦辅助的芳基羧酸脱羟基得到酰基自由基，此自由基通过和α-三氟甲基苯乙烯加成，然后通过还原氟消除的策略高效的合成γ,γ-偕二氟烯丙基酮。参见：Y.-Q. Guo, Y.-F. Wu, R.-G. Wang, H.-J. Song, Y.-X. Liu, Q.-M. Wang. Org.Lett. [J]. 2021, 23, 2353-2358.
经典的交叉偶联反应，是指亲核试剂（有机金属试剂为主）与亲电试剂之间的反应， 往往其中的有机金属试剂需要预先制备，这带来了操作与成本的问题，同时有机金属试剂对官能团的耐受性较差，并且对空气与湿气敏感。上述方法其需要昂贵金属催化剂、不同亲核试剂的区域选择性差以及官能团耐受性差等缺点，严重限制了该方法的普遍性以及潜在的工业应用。2020年，南京大学朱少林课题组开发了一种NiH体系实现了高效选择性催化不活泼烯烃与三氟甲基取代烯烃的迁移脱氟交叉偶联制备偕二氟烯烃，不幸的是烷基取代的三氟甲基烯烃在该条件下并不反应。参见：F.-L. Chen, X.-F. Xu, Y.-L. He, G.-P.Huang, S.-L. Zhu. Angew. Chem. Int. Ed. [J]. 2020, 59, 5398-5402.
有关偕二氟烯烃化合物的现有技术：
[1]黄帅,侯雪龙. 偕二氟烯丙基类化合物的制备方法[P].中国专利：CN114315726 A. 2022.04.12
[2]褚雪强,沈志良,孙莉雯,陈佳伟. 一种水相中制备磷酸化偕二氟二烯烃化合物的方法[P].中国专利：CN 115010753. A .2022.09.06
[3]褚雪强,沈志良,孙莉雯. 一种偕二氟烯烃化合物的制备方法[P].中国专利：CN 114409515. A 2022.04.29
[4]毕锡和,张欣宇,李林轩,张晓龙,宁永泉. 一种制备α ,α-偕二氟羰基类化合物的方法[P].中国专利：CN 114249679 A. 2022.03.29
本发明在廉价易得的乙二醇二甲醚溴化镍的催化下，70 ℃下反应18 h，即可实现烯丙基酰胺衍生物的迁移脱氟烯丙基化反应，并且对于烷基或芳基取代的三氟甲基烯烃底物均能兼容。该方法反应条件温和，简洁高效，底物适用范围广，官能团兼容性高，产物收率高，可以放大至克级规模生产合成，对于含氟药物的合成具有重大意义。
发明内容
本发明的目的是解决烯丙基酰胺类衍生物的高区域选择性问题，提供了一种在相同反应条件下，实现烯丙基胺类衍生物的迁移脱氟烯丙基化的方法。
为了解决未活化烯烃底物的区域选择性的迁移脱氟烯丙基化问题，本发明通过筛选催化剂、配体、碱的种类，溶剂，温度，反应时间等，可以在70 ℃下，实现偕二氟烯烃化合物的制备。该实验方法可用于含氟药物以及材料的合成。
为实现上述目的，本发明公开了如下的技术方案
一种镍催化含偕二氟烯烃结构脂肪胺的制备方法，其特征在于按如下的步骤进行：
（1）在充满氩气的手套箱中，向干燥的反应管中称量15 mol% 乙二醇二甲醚溴化镍, 15 mol% 浴铜灵(2,9-二甲基-4,7-联苯-1,10-邻二氮杂菲)、未活化的烯烃底物、3equiv三氟甲基取代烯烃、2.5 equiv 氟化钠，乙二醇二甲醚，2 equiv三甲氧基硅烷，将反应体系在70 ℃条件下搅拌反应18 h；
（2）反应结束后，将所得溶液真空浓缩，粗产物通过硅胶柱色谱纯化，用乙酸乙酯和正己烷的混合物作为洗脱剂，计算分离产率；
其中R1指的是：
R2指的是：Me；
R3指的是：Me，n-Pr；
R4指的是：
所述的未活化的烯烃底物为：
所述三氟甲基取代烯烃为
其中未活化烯烃底物与三氟甲基取代烯烃的摩尔比为1：3
所述催化剂为乙二醇二甲醚溴化镍；
所述配体为浴铜灵；
所述碱为氟化钠；
所述氢源为三甲氧基硅烷；
所述溶剂为乙二醇二甲醚；
所述时间为18小时；
所述作为洗脱剂的乙酸乙酯与正己烷的体积比1：10。
本发明烯丙基酰胺衍生物作为烯烃底物时得到迁移脱氟烯丙基化产物。
本发明进一步公开了所述方法在用于在温和条件下实现高分离率的偕二氟产物方面的应用。本发明同时也公开了采用本发明所述方法制备的典型化合物在用于含氟药物以及材料合成方面的应用。实验结果显示：该方法具有高区域选择性，且反应条件温和、操作简单、具有广泛的底物普适性和官能团兼容性，合成效率高。此外，偕二氟烯烃可以作为一个平台化合物来合成一系列官能团化的含氟化合物。
本发明更加详细的描述如下：
本发明涉及一种镍催化含偕二氟烯烃结构脂肪胺的制备方法，为了适应工业化的需要，开发了一种廉价、条件温和、操作方便，高收率且高区域选择性的制备方法。酰胺作为一种常见的导向基团，其来源广泛，存储运输方便，故本发明方案使用烯丙基酰胺衍生物作为导向基团来源参与三氟甲基取代烯烃的迁移脱氟烯丙基化反应；
其中R1指的是：
R2指的是：Me；
R3指的是：Me，n-Pr；
R4指的是：
所述的未活化的烯烃底物为：
所述三氟甲基取代烯烃为
其中未活化烯烃底物与三氟甲基取代烯烃的摩尔比为1：3
具体制备步骤如下：
（1）将催化剂、配体、碱、溶剂、硅烷、未活化的烯烃底物和三氟甲基取代烯烃加入到反应管中，混匀后70 ℃搅拌反应18 h；
（2）反应结束后，将所得溶液真空浓缩，粗产物通过硅胶柱色谱纯化，分离迁移脱氟烯丙基化产物，计算分离收率。
其中，催化剂为乙二醇二甲醚溴化镍；配体为浴铜灵(2,9-二甲基-4,7-联苯-1,10-邻二氮杂菲)；碱为氟化钠；三氟甲基取代烯烃选用一种；硅烷为三甲氧基硅烷；反应体系中的溶剂选择乙二醇二甲醚。
本发明具有的优点和积极效果在于：
1、预先安装的导向基团可以调控区域选择性，并且易于脱除，适用于烯丙基酰胺类衍生物；
2、本发明可以在乙二醇二甲醚溴化镍的促进下，烯丙基酰胺类衍生物得到偕二氟产物；
3、本方法能够在较为温和的条件下实现烯丙基酰胺类衍生物得到迁移脱氟烯丙基化产物，反应温度温和，反应迅速，制备过程简单，实验操作过程较为安全；
4、底物适用范围广，一系列烷基取代的酰胺以及各种芳香酰胺均能兼容，烷基、芳香烃和杂环取代三氟甲基烯烃均能适用。
具体实施方式
下面通过具体的实施方案叙述本发明。除非特别说明，本发明中所用的技术手段均为本领域技术人员所公知的方法。另外，实施方案应理解为说明性的，而非限制本发明的范围，本发明的实质和范围仅由权利要求书所限定。对于本领域技术人员而言，在不背离本发明实质和范围的前提下，对这些实施方案中的物料成分和用量进行的各种改变或改动也属于本发明的保护范围。
其中发明中用到的浴铜灵(2,9-二甲基-4,7-联苯-1,10-邻二氮杂菲)、乙二醇二甲醚、三甲氧基硅烷、乙二醇二甲醚溴化镍、等均有市售；未活化的烯烃底物的合成参见文献: Triandafillidi, I., Kokotou, M. G., Kokotos. C. G. Org. Lett.2018, 20, 36−39. 以及 Alhalib, A., Kamouka, S., Moran. W. J. Org. Lett.2015, 17, 1453−1456.三氟甲基取代烯烃底物的合成参见文献：Y. Lan, F. Yang, C.Wang, ACS Catal.2018, 8, 9245–9251.以及 T. Ichitsuka, T. Fujita, J. Ichikawa, ACS Catal.2015, 5, 5947-5950.
实施例1
未活化的烯烃底物种类对迁移脱氟烯丙基化反应的影响
一种镍催化的偕二氟烯烃化合物的制备方法，拓展了未活化烯烃底物范围，其中烯烃底物拓展为含有β-取代基以及内烯烃，具体步骤为：
（1）在充满氩气的手套箱中，向干燥的反应管中称量15 mol% (0.0093 g) 乙二醇二甲醚溴化镍, 15 mol% (0.0101 g) 浴铜灵(2,9-二甲基-4,7-联苯-1,10-邻二氮杂菲),加入0.2 mmol未活化的烯烃底物（见表1）、0,06 mmol 2-萘-3,3,3-三氟丙烯、0.05mmol(0.0210 g) 氟化钠，1 mL，0.04 mmol (51 µL) 三甲氧基硅烷，将反应体系在70 ℃条件下搅拌反应18 h；
（2）反应结束后将所得溶液真空浓缩，粗产物通过硅胶柱色谱纯化，用乙酸乙酯和正己烷的混合物作为洗脱剂，计算分离收率。
表1 未活化烯烃种类对迁移脱氟烯丙基化反应的影响
本实施例所得产物的结构表征数据如下所示：
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)acetamide (3a)
1H NMR (400 MHz, CDCl3) δ 7.87–7.78 (m, 4H), 7.52–7.39 (m, 3H), 5.03(d, J = 8.6 Hz, 1H), 4.06–3.87 (m, 1H), 2.75–2.60 (m, 2H), 1.72 (s, 3H),1.61–1.52 (m, 1H), 1.42–1.33 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR (101MHz, Chloroform-d) δ 169.70, 154.56 (t, J = 289.5 Hz), 133.28, 132.51,130.97, 128.24, 128.00, 127.60, 127.43 (t, J = 3.1 Hz), 126.39, 126.28,126.04 (t, J = 3.0 Hz), 89.98 (t, J = 18.0 Hz), 49.97, 32.82, 27.18, 23.23,10.23; 19F NMR (376 MHz, CDCl3) δ -90.04 (s, 2F). HRMS (ESI) m/z calculatedfor C18H20F2NO+ [M+H]+ : 304.1507, found: 304.1513.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)pivalamide (3b)
δ 7.88–7.77 (m, 4H), 7.53–7.41 (m, 3H), 5.23 (d, J = 8.4 Hz, 1H),4.01–3.91 (m, 1H), 2.73–2.60 (m, 2H), 1.63–1.53 (m, 1H), 1.47–1.37 (m, 1H),1.00 (s, 9H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ177.81, 154.57 (dd, J = 291.4, 287.2 Hz), 133.32, 132.59, 131.03 (dd, J =4.2, 2.9 Hz), 128.36, 127.99, 127.59, 127.48 (t, J = 3.2 Hz), 126.36, 126.26,126.10 (t, J = 3.0 Hz), 90.06 (dd, J = 21.5, 14.4 Hz), 49.56, 38.56, 33.00,27.43, 27.35, 10.25; 19F NMR (376 MHz, Chloroform-d) δ -89.97 (d, J = 41.0 Hz,1F), -90.33 (d, J = 41.0 Hz, 1F). HRMS (ESI) m/z calculated for C21H26F2NO+ [M+H]+ : 346.1977, found: 346.1985.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)tetrahydro-2H-pyran- 4-carboxamide (3c)
1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 16.2, 8.6 Hz, 1H), 7.61–7.33(m, 1H), 4.99 (d, J = 8.1 Hz, 1H), 3.97 (d, J = 6.2 Hz, 1H), 3.82 (d, J =10.6 Hz, 1H), 3.16 (t, J = 11.3 Hz, 1H), 2.68 (s, 1H), 1.93 (t, J = 11.4 Hz,1H), 1.66–1.45 (m, 1H), 1.48–1.34 (m, 1H), 0.87 (t, J = 7.2 Hz, 1H); 13C NMR(101 MHz, CDCl3) δ 173.64, 154.54 (dd, J = 291.5, 287.4 Hz), 133.29, 132.54,131.14 (dd, J = 4.0, 2.9 Hz), 128.39, 127.93, 127.58, 127.47 (d, J = 3.1 Hz),126.50, 126.38, 126.04 (t, J = 2.9 Hz), 89.91 (dd, J = 21.5, 14.7 Hz), 67.15(d, J = 9.9 Hz), 49.80, 42.21, 32.87, 29.06, 27.34, 10.30; 19F NMR (376 MHz,Chloroform-d) δ -89.82 (d, J = 40.3 Hz, 1F), -90.11 (d, J = 40.4 Hz, 1F).HRMS (ESI) m/z calculated for C22H26F2NO+ [M+H]+ : 407.1788, found: 407.1787.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)-2,2- diphenylacetamide (4d)
1H NMR (400 MHz, CDCl3) δ 7.83–7.76 (m, 3H), 7.70 (s, 1H), 7.51–7.45(m, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.28–7.18 (m, 6H), 7.16–7.07 (m, 4H), 5.24(d, J = 8.6 Hz, 1H), 4.71 (s, 1H), 4.03–3.92 (m, 1H), 2.66–2.54 (m, 2H),1.57–1.47 (m, 1H), 1.37–1.29 (m, 1H), 0.78 (t, J = 7.4 Hz, 3H); δ 171.42,154.49 (t, J = 289.6 Hz), 139.43 (d, J = 5.3 Hz), 133.32, 132.61, 130.61,128.90, 128.83, 128.75 (d, J = 2.4 Hz), 128.33, 128.11, 127.64, 127.46 (t, J= 3.2 Hz), 127.22, 126.35 (d, J = 4.2 Hz), 126.03 (t, J = 3.0 Hz), 89.93 (t,J = 17.8 Hz), 59.41, 49.98, 32.66, 27.27, 10.18; 19F NMR (376 MHz, Chloroform-d) δ -89.73 (s, 2F). HRMS (ESI) m/z calculated for C30H28F2NO+ [M+H]+ :456.2133, found: 456.2142.
(3r,5r,7r)-N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl) adamantane-1-carboxamide (3e)
1H NMR (400 MHz, CDCl3) δ 7.88–7.78 (m, 4H), 7.51–7.40 (m, 3H), 5.08(d, J = 8.6 Hz, 1H), 4.04–3.93 (m, 1H), 2.73–2.60 (m, 2H), 1.80 (s, 3H), 1.57(d, J = 10.7 Hz, 4H), 1.53 (s, 1H), 1.51–1.48 (m, 2H), 1.43 (d, J = 12.2 Hz,7H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) 13C NMR (101 MHz,Chloroform-d) δ 177.20, 154.53 (dd, J = 291.3, 287.4 Hz), 133.40, 132.60,131.37 (dd, J = 4.3, 2.9 Hz), 128.47, 127.96, 127.56, 127.52, 126.43, 126.30,126.14 (t, J = 2.9 Hz), 89.94 (dd, J = 21.7, 14.5 Hz), 49.47 (t, J = 2.6 Hz),40.35, 38.88, 36.34, 32.79, 28.00, 27.38, 10.32; 19F NMR (376 MHz, Chloroform-d) δ -89.64 (d, J = 39.6 Hz, 1F), -89.90 (d, J = 39.8 Hz, 1F). HRMS (ESI) m/zcalculated for C27H32F2NO+ [M+H]+ : 424.2446, found: 424.2451.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)-2-methylbenzamide (3f)
1H NMR (400 MHz, CDCl3) δ 7.88–7.80 (m, 4H), 7.52–7.45 (m, 3H), 7.23–7.19 (m, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.90 (t, J = 7.3 Hz, 1H), 6.80 (d, J= 7.1 Hz, 1H), 5.36 (d, J = 9.1 Hz, 1H), 4.20–4.12 (m, 1H), 2.85–2.72 (m,2H), 2.38 (s, 3H), 1.73–1.66 (m, 1H), 1.54–1.48 (m, 1H), 0.95 (t, J = 7.4 Hz,3H); 13C NMR (101 MHz, CDCl3) δ 169.63, 136.54, 135.95, 133.37, 132.65,130.87, 129.64, 128.45, 128.04, 127.60, 127.57, 127.54, 126.38, 126.28,126.18, 126.08 (t, J = 2.9 Hz), 125.50, 90.10 (dd, J = 16.6, 12.0 Hz), 50.10,33.30, 27.59, 19.62, 10.34; 19F NMR (376 MHz, Chloroform-d) δ -89.78 (d, J =40.5 Hz, 1F), -89.93 (d, J = 40.6 Hz, 1F). HRMS (ESI) m/z calculated forC24H24 F2NO+ [M+H]+ : 380.1820, found: 380.1828.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)benzamide (3g)
1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.81–7.76 (m, 3H), 7.49–7.43(m, 3H), 7.36–7.31 (m, 1H), 7.28–7.25 (m, 2H), 7.14 (t, J = 7.8 Hz, 2H), 5.67(d, J = 8.7 Hz, 1H), 4.24–4.15 (m, 1H), 2.82–2.80 (dd, J = 5.2, 2.8 Hz, 2H),1.72–1.63 (m, 1H), 1.58–1.49 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (101MHz, CDCl3)δ 166.99, 154.60 (dd, J = 291.3, 287.9 Hz), 134.43, 133.38,132.59, 131.17, 131.13, 128.56, 128.26, 128.00, 127.60, 127.51 (t, J = 3.1Hz), 126.52, 126.44, 126.32, 126.03 (t, J = 2.9 Hz), 89.93 (dd, J = 21.1,15.1 Hz), 50.55, 32.78, 27.37, 10.38.; 19F NMR (376 MHz, CDCl3) δ -89.75 (d, J= 40.1 Hz, 1F), -89.97 (d, J = 40.1 Hz, 1F). HRMS (ESI) m/z calculated forC23H22F2NO+ [M+H]+ : 366.1664, found: 366.1670.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)-4-methoxybenzamide(3h)
1H NMR (400 MHz, CDCl3) δ 7.83–7.76 (m, 4H), 7.49–7.43 (m, 3H), 7.24–7.17 (m, 2H), 6.65–6.57 (m, 2H), 5.56 (d, J = 8.8 Hz, 1H), 4.23–4.14 (m, 1H),3.75 (s, 3H), 2.80 (dd, J = 5.4, 2.4 Hz, 2H), 1.70–1.62 (m, 1H), 1.58–1.48(m, 1H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.45, 161.86,154.57 (dd, J = 291.5, 287.7 Hz), 133.38, 132.55, 131.27 (dd, J = 3.9, 2.7Hz), 131.26, 128.56, 128.28, 128.01, 127.59, 127.49 (t, J = 3.1 Hz), 126.65,126.34 (d, J = 16.1 Hz), 126.03 (t, J = 2.9 Hz), 113.38, 89.94 (dd, J = 21.4,14.8 Hz), 55.30, 50.46, 32.74, 27.38, 10.41; 19F NMR (376 MHz, CDCl3) δ -89.79(d, J = 40.2 Hz, 1F), -90.04 (d, J = 40.2 Hz, 1F). HRMS (ESI) m/z calculatedfor C24H24F2NO+ [M+H]+ : 396.1770, found: 396.1778.
4-chloro-N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)benzamide (3i)
1H NMR (400 MHz, CDCl3) δ 7.81–7.74 (m, 4H), 7.52–7.45 (m, 2H), 7.42(d, J = 8.5 Hz, 1H), 7.14–7.09 (m, 2H), 7.08–7.00 (m, 2H), 5.56 (d, J = 8.8Hz, 1H), 4.22–4.14 (m, 1H), 2.88–2.81 (m, 1H), 2.81–2.73 (m, 1H), 1.70–1.66(m, 1H), 1.59–1.50 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3)δ 165.83, 154.57 (dd, J = 291.6, 287.9 Hz), 137.34, 133.32, 132.60, 132.51,131.25 (dd, J = 4.0, 2.7 Hz), 128.62, 128.39, 127.91, 127.88, 127.59, 127.44(t, J = 3.0 Hz), 126.57, 126.41, 125.92 (t, J = 2.8 Hz), 89.80 (dd, J = 21.4,15.0 Hz), 50.86, 32.60, 27.33, 10.43; 19F NMR (376 MHz, CDCl3) δ -89.63 (d, J= 39.6 Hz, 1F), -89.91 (d, J = 39.7 Hz, 1F). HRMS (ESI) m/z calculated forC23H21ClF2NO+ [M+H]+ : 400.1274, found: 400.1282.
4-bromo-N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)benzamide (3j)
1H NMR (400 MHz, CDCl3) δ 7.81–7.74 (m, 4H), 7.52–7.47 (m, 2H), 7.43(d, J = 8.5 Hz, 1H), 7.25–7.18 (m, 2H), 7.04 (d, J = 8.5 Hz, 2H), 5.50 (d, J= 8.7 Hz, 1H), 4.23–4.15 (m, 1H), 2.89–2.82 (m, 1H), 2.81–2.74 (m, 1H), 1.71–1.65 (m, 1H), 1.57–1.51 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz,CDCl3) δ 165.84, 154.59 (dd, J = 291.5, 287.9 Hz), 133.34, 133.09, 132.53,131.37, 131.26 (dd, J = 3.8, 2.5 Hz), 128.60, 128.01, 127.89, 127.57, 127.43(t, J = 3.0 Hz), 126.55, 126.39, 125.90 (t, J = 2.9 Hz), 125.79, 89.79 (dd, J= 21.2, 15.2 Hz), 50.88, 32.60, 27.35, 10.37; 19F NMR (376 MHz, Chloroform-d)δ -89.65 (d, J = 39.7 Hz, 1F), -89.90 (d, J = 39.7 Hz, 1F). HRMS (ESI) m/zcalculated for C23H20F2NO+ [M+H]+ : 444.0769, found: 444.0769
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)-2-naphthamide (3k)
1H NMR (400 MHz, CDCl3) δ 8.29–8.18 (m, 1H), 7.90 (s, 1H), 7.86–7.76(m, 5H), 7.54–7.47 (m, 5H), 7.14–7.07 (m, 1H), 6.98 (dd, J = 7.0, 0.9 Hz,1H), 5.61 (d, J = 9.0 Hz, 1H), 4.34–4.26 (m, 1H), 2.90–2.80 (m, 2H), 1.77–1.70 (m, 1H), 1.60–1.52 (m, 1H), 1.01 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz,CDCl3) δ 169.12, 154.67 (dd, J = 291.4, 287.9 Hz), 134.55, 133.62, 133.39,132.65, 130.98 (dd, J = 3.5, 2.7 Hz), 130.37, 130.06, 128.51, 128.19, 128.05,127.61, 127.57, 127.03, 126.41, 126.34, 126.30, 126.10 (t, J = 3.0 Hz),125.38, 124.47, 124.35, 90.11 (dd, J = 20.9, 15.0 Hz), 50.45, 33.24, 27.62,10.43; 19F NMR (376 MHz, Chloroform-d) δ -89.58 (d, J = 40.2 Hz, 1F), -89.82(d, J = 40.2 Hz, 1F). HRMS (ESI) m/z calculated for C27H24F2NO+ [M+H]+ :416.1820, found: 416.1827.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)-4-(trifluoromethyl) benzamide (3l)
1H NMR (400 MHz, CDCl3) δ 7.80–7.71 (m, 4H), 7.50–7.40 (m, 3H), 7.31(d, J = 8.3 Hz, 2H), 7.27–7.24 (m, 2H), 5.58 (d, J = 8.7 Hz, 1H), 4.26–4.17(m, 1H), 2.93–2.84 (m, 1H), 2.82–2.75 (m, 1H), 1.73–1.67 (m, 1H), 1.61–1.53(m, 1H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.53, 154.59(dd, J = 291.7, 288.1 Hz), 137.38, 133.34, 132.82 (d, J = 32.7 Hz), 132.50,131.27 (dd, J = 4.0, 2.6 Hz), 128.65, 127.84, 127.56, 127.42 (t, J = 3.0 Hz),126.85, 126.62, 126.48, 125.86, 125.16 (q, J = 3.7 Hz), 122.21, 89.73 (dd, J= 21.4, 15.1 Hz), 51.08, 32.53, 27.35, 10.43; 19F NMR (376 MHz, Chloroform-d)δ -63.06(s, 3), -89.58 (d, J = 39.5 Hz, 1F), -89.85 (d, J = 39.5 Hz, 1F).HRMS (ESI) m/z calculated for C24H21F5NO+ [M+H]+ : 434.1538, found: 434.1544.
N-(5,5-difluoro-2,2-dimethyl-4-(naphthalen-2-yl)pent-4-en-1-yl) benzamide (3m)
1H NMR (400 MHz, CDCl3) δ 7.82–7.74 (m, 4H), 7.46–7.40 (m, 3H), 7.38–7.32 (m, 3H), 7.24–7.18 (m, 2H), 5.66 (t, J = 5.5 Hz, 1H), 3.13 (d, J = 6.6Hz, 2H), 2.51–2.42 (m, 2H), 0.85 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 167.44,154.73 (dd, J = 291.4, 288.3 Hz), 134.59, 133.31, 132.72 (dd, J = 4.7, 2.5Hz), 132.52, 131.30, 128.62, 128.48, 127.91, 127.75, 127.44–127.17 (m),126.67, 126.65, 126.48, 126.29 (t, J = 2.5 Hz), 90.21 (dd, J = 21.9, 13.9Hz), 48.54, 37.88, 37.40 (t, J = 2.4 Hz), 25.72; 19F NMR (376 MHz, Chloroform-d) δ -88.39 (d, J = 39.0 Hz, 1F), -90.61 (d, J = 39.0 Hz, 1F). HRMS (ESI) m/zcalculated for C24H24F2NO+ [M+H]+ : 380.1820, found: 380.1819.
N-(1,1-difluoro-2-(naphthalen-2-yl)hept-1-en-4-yl)benzamide (3n)
1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.81–7.77 (m, 3H), 7.49–7.43(m, 3H), 7.33 (t, J = 7.4 Hz, 1H), 7.25 (dd, J = 6.2, 2.1 Hz, 2H), 7.13 (t, J= 7.8 Hz, 2H), 5.62 (d, J = 8.7 Hz, 1H), 4.31–4.26 (m, 1H), 2.86–2.76 (m,2H), 1.68–1.55 (m, 2H), 1.41–1.31 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR(101 MHz, CDCl3) δ 166.84, 154.61 (dd, J = 291.3, 287.8 Hz), 134.39, 133.37,132.57, 131.22 (dd, J = 5.1, 2.6 Hz), 131.16, 128.56, 128.25, 127.99, 127.59,127.50 (t, J = 3.1 Hz), 126.48, 126.43, 126.30, 126.03 (t, J = 2.9 Hz), 89.92(dd, J = 21.0, 15.2 Hz), 48.91, 36.66, 33.18, 19.22, 13.94; 19F NMR (376 MHz,Chloroform-d) δ -89.79 (d, J = 40.1 Hz, 1F), -89.99 (d, J = 40.1 Hz, 1F).HRMS (ESI) m/z calculated for C24H24F2NO+ [M+H]+ : 380.1820, found: 380.1820.
N-(1,1-difluoro-2-(naphthalen-2-yl)non-1-en-4-yl)benzamide (3o)
1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.81–7.77 (m, 3H), 7.49–7.44(m, 3H), 7.34 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 3.6 Hz, 2H), 7.14 (t, J = 7.7Hz, 2H), 5.60 (d, J = 8.8 Hz, 1H), 4.32–4.25 (m, 1H), 2.81 (dd, J = 5.4, 2.1Hz, 2H), 1.69–1.61 (m, 1H), 1.53–1.45 (m, 1H), 1.37–1.32 (m, 2H), 1.27–1.23(m, 4H), 0.84 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.78, 159.11–149.27 (m), 134.48, 133.39, 132.59, 131.27–131.15 (m), 131.11, 128.53,128.23, 127.98, 127.57, 127.51 (t, J = 3.0 Hz), 126.48, 126.40, 126.27,126.03 (t, J = 2.7 Hz), 89.95 (dd, J = 21.1, 15.3 Hz), 49.14, 34.46, 33.15,31.64, 25.58, 22.47, 13.92. 19F NMR (376 MHz, Chloroform-d) δ -89.79 (d, J =40.1 Hz, 1F), -90.00 (d, J = 40.1 Hz, 1F). HRMS (ESI) m/z calculated forC26H28F2NO+ [M+H]+ : 408.2133, found: 408.2141
N-(1,1-difluoro-2-(naphthalen-2-yl)non-1-en-4-yl)benzamide (3p)
1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.81–7.77 (m, 3H), 7.49–7.44(m, 3H), 7.33 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 6.7 Hz, 2H), 7.14 (t, J = 7.7Hz, 2H), 5.63 (d, J = 8.8 Hz, 1H), 4.31–4.23 (m, 1H), 2.81 (dd, J = 5.2, 2.2Hz, 2H), 1.65–1.60 (m, 1H), 1.55–1.45 (m, 1H), 1.38–1.31 (m, 2H), 1.28–1.21(m, 4H), 0.83 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.79, 154.61(dd, J = 291.4, 288.1 Hz), 134.48, 133.39, 132.59, 131.20 (dd, J = 3.6, 2.3Hz), 131.12, 128.53, 128.24, 127.98, 127.58, 127.51 (t, J = 3.1 Hz), 126.49,126.41, 126.27, 126.03 (t, J = 2.9 Hz), 89.96 (dd, J = 21.0, 15.2 Hz), 49.14,34.46, 33.14, 31.64, 25.59, 22.48, 13.94. 19F NMR (376 MHz, Chloroform-d) δ -89.79 (d, J = 40.1 Hz, 1F), -90.00 (d, J = 40.1 Hz, 1F). HRMS (ESI) m/zcalculated for C26H28F2NO+ [M+H]+ : 408.2133, found: 408.2138.
由表1中数据得出，在温和条件下，上述各类未活化的烯烃均适用于本发明方案，大多数可以得到80%及以上产率。分析表1中数据可以得到以下结论，一级、二级、和三级烷基取代的酰胺(3a-3e)均能以良好的收率得到目标产物。用N-烯丙基苯甲酰胺作为供体时可得到93%的迁移脱氟烯丙基化产物(3f)；该反应适用多种官能团化的芳烃，包括芳基环上带有给电子、中性以及吸电子取代基(3g-3l)。此外，β-取代的末端烯烃(3m)和内烯烃底物(3n-3p)，无论是Z或E构型的异构体都是能够兼容的。
实施例2
三氟甲基取代的烯烃对迁移脱氟烯丙基化反应的影响
一种镍催化的偕二氟烯烃化合物的制备方法，拓展了三氟甲基取代的烯烃底物范围。具体步骤为：
（1）在充满氩气的手套箱中，向干燥的反应管中称量15 mol% (0.0093 g) 乙二醇二甲醚溴化镍, 15 mol% (0.0101 g) 浴铜灵(2,9-二甲基-4,7-联苯-1,10-邻二氮杂菲),0.2 mmol (0.0322 g) N-烯丙基苯甲酰胺、0,06 mmol三氟甲基取代烯烃（见表2）、0.05mmol (0.0210 g) 氟化钠，1 mL乙二醇二甲醚，0.04 mmol (51 µL) 三甲氧基硅烷，将反应体系在70 ℃条件下搅拌反应18 h；
（2）反应结束后将所得溶液真空浓缩，粗产物通过硅胶柱色谱纯化，用乙酸乙酯和正己烷的混合物作为洗脱剂，计算分离收率。
表2 三氟甲基取代的烯烃底物对反应的影响
N-(6,6-difluoro-5-(4-methoxyphenyl)hex-5-en-3-yl)benzamide (4a)
1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.4 Hz, 2H), 7.43 (t, J = 7.4Hz, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.8Hz, 2H), 5.90 (d, J = 8.5 Hz, 1H), 4.16–4.06 (m, 1H), 3.74 (s, 3H), 2.68–2.57(m, 2H), 1.68–1.59 (m, 1H), 1.54–1.45 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H); 13CNMR (101 MHz, CDCl3) δ 167.05, 158.94, 154.26 (dd, J = 289.8, 286.7 Hz),134.68, 131.23, 129.50 (t, J = 3.0 Hz), 128.35, 126.73, 125.61 (dd, J = 3.5,2.2 Hz), 114.22, 89.36 (dd, J = 20.9, 15.4 Hz), 55.19, 50.32, 32.85, 27.26,10.32. 19F NMR (376 MHz, CDCl3) δ -91.30 (d, J = 3.4 Hz, 1F), -91.44 (d, J =43.8 Hz, 1F). HRMS (ESI) m/z calculated for C20H22F2NO2 + [M+H]+ : 346.1613,found: 346.1619.
N-(6,6-difluoro-5-(4-(trifluoromethoxy)phenyl)hex-5-en-3-yl)benzamide (4b)
1H NMR (400 MHz, CDCl3) δ 7.54–7.52 (m, 2H), 7.50–7.45 (m, 1H), 7.42–7.35 (m, 4H), 7.18 (d, J = 8.1 Hz, 2H), 5.70 (d, J = 8.7 Hz, 1H), 4.17–4.08(m, 1H), 2.73–2.63 (m, 2H), 1.71–1.64 (m, 1H), 1.55–1.46 (m, 1H), 0.95 (t, J= 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.17, 154.50 (dd, J = 291.0, 288.6Hz), 148.45, 134.55, 132.14 (d, J = 1.6 Hz), 131.42, 129.84 (t, J = 3.2 Hz),128.53, 126.55, 120.42 (q, J = 257.5 Hz), 120.42 (d, J = 257.5 Hz), 89.12(dd, J = 20.4, 16.3 Hz), 50.20 (t, J = 2.7 Hz), 33.07, 27.45, 10.27; 19F NMR(376 MHz, CDCl3) δ -57.80 (s, 3F), -89.55 (d, J = 2.2 Hz, 2F). HRMS (ESI) m/zcalculated for C20H19F2NO2 + [M+H]+ : 400.1330, found: 400.1335.
N-(6,6-difluoro-5-(4-(methylthio)phenyl)hex-5-en-3-yl)benzamide (4c)
1H NMR (400 MHz, CDCl3) δ 7.48–7.43 (m, 3H), 7.40–7.33 (m, 2H), 7.30–7.26 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 5.67 (d, J = 8.7 Hz, 1H), 4.18–4.08(m, 1H), 2.75–2.63 (m, 2H), 2.44 (s, 3H), 1.67–1.62 (m, 1H), 1.55–1.45 (m,1H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.98, 154.35 (dd,J = 290.9, 287.6 Hz), 138.13, 134.56, 131.34, 130.11 (dd, J = 3.4, 2.4 Hz),128.71 (t, J = 3.2 Hz), 128.46, 126.63, 126.61, 89.36 (dd, J = 21.0, 15.2Hz), 50.35, 32.64, 27.31, 15.54, 10.35; 19F NMR (376 MHz, Chloroform-d) δ -90.08 (d, J = 41.2 Hz, 1F), -90.25 (d, J = 41.2 Hz, 1F). HRMS (ESI) m/zcalculated for C20H22F2NOS+ [M+H]+ : 362.1385, found: 362.1390.
N-(6,6-difluoro-5-(3-fluoro-4-methoxyphenyl)hex-5-en-3-yl)benzamide (4d)
1H NMR (400 MHz, CDCl3) δ 7.57–7.54 (m, 2H), 7.49–7.45 (m, 1H), 7.40–7.36 (dm, 2H), 7.12–7.08 (m, 2H), 6.92–6.86 (m, 1H), 5.72 (d, J = 8.7 Hz,1H), 4.16–4.07 (m, 1H), 3.84 (s, 3H), 2.66–2.62 (m, 2H), 1.70–1.63 (m, 1H),1.54–1.45 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ167.07, 154.42 (dd, J = 291.5, 286.9 Hz), 146.98 (d, J = 10.7 Hz), 134.63,131.35, 128.46, 126.62, 124.31 (q, J = 3.2 Hz), 116.08 (dt, J = 19.4, 3.4Hz), 113.59 (d, J = 2.3 Hz), 88.89 (dd, J = 22.3, 14.4 Hz), 56.21, 50.21,32.84, 27.36, 10.28; 19F NMR (376 MHz, Chloroform-d) δ -89.94 (d, J = 41.4 Hz,1F), -90.28 (dt, J = 41.7, 2.4 Hz, 1F), -130.78–-139.64 (m, 1F). HRMS (ESI)m/z calculated for C20H21F3NO2 + [M+H]+ : 364.1519, found: 364.1524.
N-(5-(3,4-dichlorophenyl)-6,6-difluorohex-5-en-3-yl)benzamide (4e)
1H NMR (400 MHz, CDCl3) δ 7.58–7.52 (m, 2H), 7.50–7.45 (m, 2H), 7.38(t, J = 8.0 Hz, 3H), 7.27–7.19 (m, 1H), 5.74 (d, J = 8.7 Hz, 1H), 4.24–3.86(m, 1H), 2.87–2.50 (m, 2H), 1.74–1.60 (m, 1H), 1.50 (m, 1H), 0.95 (t, J = 7.4Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.19, 154.53 (dd, J = 293.0, 288.4 Hz),134.37, 133.60 (dd, J = 4.4, 3.1 Hz), 132.81, 131.67, 131.52, 130.64, 130.15(t, J = 3.4 Hz), 128.55, 127.76 (t, J = 3.2 Hz), 126.58, 88.69 (dd, J = 22.8,14.3 Hz), 50.21, 32.90, 27.44, 10.38.; 19F NMR (376 MHz, Chloroform-d) δ -88.22 (d, J = 37.1 Hz, 1F), -88.50 (d, J = 37.1 Hz, 1F). HRMS (ESI) m/zcalculated for C19H18Cl2F2NO+ [M+H]+ : 384.0728, found: 384.0735.
N-(5-(4-bromophenyl)-6,6-difluorohex-5-en-3-yl)benzamide (4f)
1H NMR (400 MHz, CDCl3) δ 7.52–7.42 (m, 5H), 7.39 (t, J = 7.5 Hz, 2H),7.24 (t, J = 7.3 Hz, 2H), 5.67 (d, J = 8.6 Hz, 1H), 4.15–4.04 (m, 1H), 2.73–2.61 (m, 2H), 1.68–1.63 (m, 1H), 1.55–1.45 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.08, 154.31 (dd, J = 291.6, 288.1 Hz), 134.49,132.51 (dd, J = 3.7, 2.3 Hz), 131.92, 131.45, 130.01 (t, J = 3.1 Hz), 128.54,126.59, 121.62, 89.24 (dd, J = 21.4, 15.2 Hz), 50.23, 32.84, 27.39, 10.34; 19FNMR (376 MHz, Chloroform-d) δ -89.43 (d, J = 39.5 Hz, 1F), -89.60 (d, J =39.5 Hz, 1F). HRMS (ESI) m/z calculated for C19H19BrF2NO+ [M+H]+ : 394.0613,found: 394.0620.
N-(5-([1,1'-biphenyl]-4-yl)-6,6-difluorohex-5-en-3-yl)benzamide (4g)
1H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 8.3 Hz, 4H), 7.46–7.42 (t, J =6.4 Hz, 6H), 7.40–7.33 (m, 2H), 7.28 (dd, J = 14.0, 6.5 Hz, 2H), 5.69 (d, J =8.6 Hz, 1H), 4.25–4.13 (m, 1H), 2.83–2.67 (m, 2H), 1.74–1.64 (m, 1H), 1.59–1.49 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ167.01, 157.34, 154.44 (d, J = 4.2 Hz), 151.58, 140.43, 134.60, 132.61,131.29, 128.81, 128.72 (t, J = 3.1 Hz), 128.45, 127.48, 127.05, 126.61, 89.56(dd, J = 18.5, 17.6 Hz); 19F NMR (376 MHz, CDCl3) δ -89.83 (s, 2F). HRMS (ESI)m/z calculated for C25H24F2NO+ [M+H]+ : 392.1820, found: 392.1826.
N-(5-(9,9-dimethyl-9H-fluoren-2-yl)-6,6-difluorohex-5-en-3-yl) benzamide (4h)
1H NMR (400 MHz, CDCl3) δ 7.72–7.68 (m, 2H), 7.41–7.38 (m, 2H), 7.35–7.26 (m, 6H), 7.13 (t, J = 7.7 Hz, 2H), 5.69 (d, J = 8.8 Hz, 1H), 4.26–4.16(m, 1H), 2.78–2.76 (m, 2H), 1.68–1.63 (m, 1H), 1.59–1.51 (m, 1H), 1.45 (s,3H), 1.29 (s, 3H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ166.82, 154.45 (dd, J = 290.7, 287.9 Hz), 138.90, 138.52, 134.49, 132.73 (dd,J = 3.1, 2.1 Hz), 131.20, 128.30, 127.51, 127.23 (t, J = 2.9 Hz), 127.05,126.56, 122.62, 122.59, 120.32, 120.06, 90.12 (dd, J = 20.6, 15.4 Hz), 50.64,46.91, 32.77, 27.37, 27.23, 26.74, 10.43; 19F NMR (376 MHz, CDCl3) δ -90.50(d, J = 42.7 Hz, 1F), -91.11 (d, J = 42.8 Hz, 1F). HRMS (ESI) m/z calculatedfor C28H28F2NO+ [M+H]+ : 432.2133, found: 432.2133.
N-(5-(benzo[d][1,3]dioxol-5-yl)-6,6-difluorohex-5-en-3-yl)benzamide (4i)
1H NMR (400 MHz, CDCl3) δ 7.57–7.51 (m, 2H), 7.48–7.44 (m, 1H), 7.37(t, J = 7.5 Hz, 2H), 6.83–6.74 (m, 3H), 5.92 (d, J = 1.4 Hz, 1H), 5.87 (d, J= 1.4 Hz, 1H), 5.74 (d, J = 8.7 Hz, 1H), 4.17–4.08 (m, 1H), 2.66–2.59 (m,2H), 1.71–1.60 (m, 1H), 1.55–1.46 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR(101 MHz, CDCl3) δ 166.98, 154.32 (dd, J = 290.4, 286.6 Hz), 147.92, 147.00,134.62, 131.31, 128.43, 127.11 (dd, J = 4.4, 2.8 Hz), 126.66, 121.92 (t, J =3.0 Hz), 108.90 (t, J = 3.2 Hz), 108.55, 101.18, 89.61 (dd, J = 22.0, 14.9Hz), 50.24, 33.05, 27.37, 10.34; 19F NMR (376 MHz, CDCl3) δ -82.25 (d, J =28.6 Hz, 1F), -87.11 (d, J = 28.6 Hz, 1F). HRMS (ESI) m/z calculated forC20H20F2NO3 + [M+H]+ : 360.1406, found: 360.1412.
methyl 4-(4-benzamido-1,1-difluorohex-1-en-2-yl)benzoate (4j)
1H NMR (400 MHz, CDCl3) δ 8.01–7.96 (m, 2H), 7.51–7.49 (m, 2H), 7.46–7.42 (m, 3H), 7.37–7.33 (m, 2H), 5.68 (d, J = 8.7 Hz, 1H), 4.16–4.07 (m, 1H),3.91 (s, 3H), 2.74–2.71 (m, 2H), 1.69–1.65 (m, 1H), 1.54–1.45 (m, 1H), 0.94(t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.09, 166.57, 154.58 (dd, J= 292.1, 289.9 Hz), 138.39, 134.51, 131.35, 129.93, 129.19, 128.45, 128.28(t, J = 3.2 Hz), 126.59, 89.72 (dd, J = 19.9, 16.2 Hz), 52.07, 50.31, 32.74,27.39, 10.29; 19F NMR (376 MHz, Chloroform-d) δ -88.30(s, 2F). HRMS (ESI) m/zcalculated for C21H22F2NO3 + [M+H]+ : 374.1562, found: 374.1564.
N-(5-(4-cyanophenyl)-6,6-difluorohex-5-en-3-yl)benzamide (4k)
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 7.3Hz, 2H), 7.52–7.47 (m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 5.76 (d, J = 8.6 Hz,1H), 4.12–4.03 (m, 1H), 2.75–2.66 (m, 2H), 1.70–1.64 (m, 1H), 1.55–1.47 (m,1H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.27, 154.71 (dd,J = 294.3, 289.4 Hz), 138.48 (dd, J = 4.2, 3.4 Hz), 134.31, 132.36, 131.65,129.03 (t, J = 3.4 Hz), 128.58, 126.58, 118.54, 111.13, 89.52 (dd, J = 22.4,13.8 Hz), 50.19, 32.81, 27.38, 10.39; 19F NMR (376 MHz, CDCl3) δ -87.11 (d, J= 34.2 Hz, 1F), -87.33 (d, J = 34.3 Hz, 1F). HRMS (ESI) m/z calculated forC20H19F2N2O+ [M+H]+ : 341.1460, found: 341.1460.
N-(5-(4-(dimethylamino)phenyl)-6,6-difluorohex-5-en-3-yl)benzamide (4l)
1H NMR (400 MHz, CDCl3) δ 7.38–7.33 (m, 3H), 7.26–7.20 (m, 2H), 7.15(d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 5.69 (d, J = 8.7 Hz, 1H),4.13–4.03 (m, 1H), 2.86 (s, 6H), 2.66–2.50 (m, 2H), 1.63–1.50 (m, 1H), 1.48–1.40 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.82,154.18 (dd, J = 288.8, 286.8 Hz), 149.72, 134.67, 131.16, 129.05 (t, J = 3.0Hz), 128.37 (d, J = 14.2 Hz), 126.76, 120.95, 112.62, 89.25 (dd, J = 20.0,16.1 Hz), 50.49, 40.41, 32.39, 27.19, 10.39; 19F NMR (376 MHz, Chloroform-d) δ-91.95 (d, J = 45.7 Hz, 1F), -92.10 (d, J = 45.7 Hz, 1F). HRMS (ESI) m/zcalculated for C21H25F2N2O+ [M+H]+ : 359.1929, found: 359.1936.
N-(6,6-difluoro-5-(3-formylphenyl)hex-5-en-3-yl)benzamide (4m)
1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.86 (s, 1H), 7.72 (d, J = 7.6Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.58–7.52 (m, 2H), 7.50–7.41 (m, 2H), 7.34(t, J = 7.6 Hz, 2H), 5.90 (d, J = 8.8 Hz, 1H), 4.26–3.93 (m, 1H), 2.73–2.70(m, 2H), 1.73–1.60 (m, 1H), 1.57–1.44 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H); 13CNMR (101 MHz, CDCl3) δ 192.03, 167.28, 154.63 (dd, J = 292.1, 288.6 Hz),136.67, 134.66 (dd, J = 3.8, 2.3 Hz), 134.42 (t, J = 3.0 Hz), 131.46, 129.54(t, J = 3.2 Hz), 129.45, 128.66, 128.49, 126.65, 89.37 (dd, J = 21.5, 15.0Hz), 50.21, 33.03, 27.47, 10.35; 19F NMR (376 MHz, Chloroform-d) δ -88.92 (d,J = 38.3 Hz, 1F), -89.08 (d, J = 38.4 Hz, 1F). HRMS (ESI) m/z calculated forC20H20F2NO2 + [M+H]+ : 344.1457, found: 344.1463.
N-(6,6-difluoro-5-(4-(trimethylsilyl)phenyl)hex-5-en-3-yl)benzamide (4n)
1H NMR (400 MHz, CDCl3) δ 7.30–7.21 (m, 5H), 7.16–7.09 (m, 4H), 5.52(d, J = 8.7 Hz, 1H), 4.00–3.90 (m, 1H), 2.58–2.44 (m, 2H), 1.51–41 (m, 1H),1.36–1.25 (m, 1H), 0.73 (t, J = 7.4 Hz, 3H), 0.04 (s, 9H); 13C NMR (101 MHz,CDCl3) δ 168.18, 155.56 (dd, J = 291.0, 288.1 Hz), 141.00, 135.79, 135.05(dd, J = 2.5, 1.7 Hz), 134.86, 132.39, 129.55, 128.66 (t, J = 3.0 Hz),127.78, 91.00 (dd, J = 20.0, 15.6 Hz), 51.58, 33.68, 28.46, 11.46, 0.00. 19FNMR (376 MHz, CDCl3) δ -89.94 (d, J = 40.9 Hz, 1F), -90.10 (d, J = 40.9 Hz,1F). HRMS (ESI) m/z calculated for C22H28F2NOSi+ [M+H]+ : 388.1903, found:388.1912.
N-(5-(benzofuran-2-yl)-6,6-difluorohex-5-en-3-yl)benzamide (4o)
The title compound was isolated as a white solid (78% yield, 93: 7rr) after chromatography on silica with ethyl acetate/hexane (1:10). 1H NMR(400 MHz, CDCl3) δ 7.55–7.50 (m, 3H), 7.41 (t, J = 8.2 Hz, 2H), 7.30–7.25 (m,3H), 7.23–7.20 (m, 1H), 6.85 (s, 1H), 5.99 (d, J = 8.4 Hz, 1H), 4.37–4.29 (m,1H), 2.82–2.72 (m, 2H), 1.80–1.72 (m, 1H), 1.68–1.60 (m, 1H), 1.02 (t, J =7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.37, 155.35 (dd, J = 300.8, 289.1Hz), 154.27, 149.34 (t, J = 6.5 Hz), 134.55, 131.31, 128.70, 128.45, 126.63,124.28, 123.11, 120.93, 110.93, 105.09 (dd, J = 8.8, 5.4 Hz), 83.90 (dd, J =28.2, 12.0 Hz), 50.99, 29.89, 27.52, 10.40; 19F NMR (376 MHz, Chloroform-d) δ-79.21 (d, J = 23.1 Hz, 1F), -85.71 (d, J = 23.0 Hz, 1F). HRMS (ESI) m/zcalculated for C21H20F2NO2 + [M+H]+ : 356.1457, found: 356.1464.
根据表2中数据分析可看出，芳环上的各种取代基都具有良好的耐受性，包括芳基环上带有富电子(4a-4f)或吸电子(4g-4m)取代基的底物。该反应可以兼容芳基氟(4d)、芳基氯(4e)以及芳基溴化物(4f)，它们可用于进一步衍生化反应，从而增加分子的复杂性。在这种温和的条件下，对于大位阻的联苯(4g)及芴(4h)也能适用，不仅可以耐受醚（4i）、酯（4j）和腈（4k），甚至还可以耐受通常容易被还原的官能团，如醛（4m）。另外，
在药物分子中常见的杂环呋喃（4o）也是可以兼容。幸运的是，烷基取代的三氟甲基烯烃(4p)在该条件下相容。
实施例3
本发明合成的系列偕二氟烯烃化合物的实际合成应用潜力：
其中典型化合物用于偕二氟烯烃的合成应用
表3 偕二氟烯烃的合成应用
N-(6,6-difluoro-5-(naphthalen-2-yl)hexan-3-yl)benzamide（5a）
1H NMR (400 MHz, CDCl3) δ 7.71–7.63 (m, 4H), 7.39–7.30 (m, 3H), 7.25(t, J = 7.4 Hz, 1H), 7.18 (d, J = 7.5 Hz, 2H), 7.06 (t, J = 7.6 Hz, 2H), 5.89(td, J = 56.6, 3.2 Hz, 1H), 5.50 (d, J = 8.8 Hz, 1H), 4.17–4.08 (m, 1H),3.33–3.21 (m, 1H), 2.30–2.20 (m, 1H), 2.11–2.01 (m, 1H), 1.71–1.59 (m, 1H),1.50–1.41 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H)；13C NMR (101 MHz, CDCl3) δ 166.00,133.45 (dd, J = 4.9, 2.9 Hz), 133.14, 132.41, 131.77, 130.15, 127.67, 127.15,126.98, 126.72, 126.54, 125.43, 125.28, 125.21, 125.02, 116.57 (t, J = 245.2Hz), 49.26, 46.84 (t, J = 19.8 Hz), 32.24 (dd, J = 4.3, 3.0 Hz), 27.18, 8.97；19F NMR (376 MHz, CDCl3) δ -119.12 (ddd, J = 276.4, 56.6, 15.2 Hz, 1F), -122.94 (ddd, J = 276.4, 56.6, 17.0 Hz, 1F). HRMS (ESI) m/z calculated forC23H24F2NO+ [M+H]+ : 368.1820, found: 368.1823.
N-(6-((4-(tert-butyl)phenyl)thio)-6,6-difluoro-5-(naphthalen-2-yl) hexan-3-yl)benzamide(5b)
1H NMR (400 MHz, CDCl3) δ 7.80–7.74 (m, 4H), 7.45–7.39 (m, 5H), 7.36–7.30 (m, 3H), 7.25–7.18 (m, 4H), 5.64 (d, J = 9.3 Hz, 1H), 3.96–3.83 (m, 1H),3.67–3.48 (m, 1H), 2.40–2.16 (m, 2H), 1.51–1.44 (m, 2H), 1.20 (s, 9H), 0.78(t, J = 7.4 Hz, 3H)；13C NMR (101 MHz, CDCl3) δ 167.03, 153.03, 136.58 (d, J =6.0 Hz), 136.04, 134.61, 134.08 (d, J = 4.4 Hz), 133.37, 133.15, 131.35,129.35, 128.62, 128.49, 128.18, 127.72, 126.88, 126.73, 126.30 (d, J = 2.6Hz), 126.03, 123.15, 51.36 (t, J = 22.3 Hz), 48.94, 35.19, 34.73, 31.20,28.46, 10.38；19F NMR (376 MHz, CDCl3) δ -74.06 (dd, J = 202.7, 11.1 Hz, 1F), -77.53 (dd, J = 202.7, 17.3 Hz, 1F). HRMS (ESI) m/z calculated for C33H36F2NOS+[M+H]+ : 532.2480, found: 532.2485.
((5S)-5-ethyl-2-(naphthalen-2-yl)-2-(trifluoromethyl)pyrrolidin-1-yl) (phenyl)methanone(5c)
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.6 Hz, 2H), 8.02 (s, 1H),7.86–7.75 (m, 3H), 7.65 (d, J = 8.7 Hz, 1H), 7.45–7.37 (m, 5H), 3.64–3.57 (m,1H), 2.83 (dd, J = 14.5, 5.0 Hz, 1H), 1.85–1.77 (m, 1H), 1.56–1.42 (m, 2H),1.01 (t, J = 7.3 Hz, 3H)；13C NMR (101 MHz, CDCl3) δ 150.54, 133.96, 132.33,132.21, 131.76, 129.74, 127.48, 127.33, 127.24, 126.55, 126.31, 125.86,125.54, 124.04, 121.66 (d, J = 0.9 Hz), 109.29 (dd, J = 26.5, 19.7 Hz), 77.08(q, J = 29.3 Hz), 49.39, 31.37, 29.16, 9.23；19F NMR (376 MHz, CDCl3) δ -76.33(s, 3F). HRMS (ESI) m/z calculated for C24H23F3NO+ [M+H]+ : 398.1726, found:398.1730.
(E)-N-(6-fluoro-6-(1H-imidazol-1-yl)-5-(naphthalen-2-yl)hex-5-en-3- yl)benzamide(5d)
1H NMR (400 MHz, CDCl3) δ 7.75–7.64 (m, 4H), 7.48–7.36 (m, 5H), 7.28–7.20 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.79 (s, 1H), 5.80 (d,J = 9.1 Hz, 1H), 4.35–4.24 (m, 1H), 3.03–2.92 (m, 2H), 1.77–1.68 (m, 1H),1.64–1.54 (m, 1H), 0.97 (t, J = 7.4 Hz, 3H), 13C NMR (101 MHz, CDCl3) δ167.05, 145.24, 142.66, 137.28, 134.39, 133.29, 132.72, 132.66, 131.35,129.64, 129.07, 128.42, 128.04, 127.65, 127.36 (d, J = 3.5 Hz), 126.62 (d, J= 3.3 Hz), 126.53, 125.59 (d, J = 2.7 Hz), 118.75 (d, J = 1.8 Hz), 112.39 (d,J = 24.0 Hz), 50.27 (d, J = 2.6 Hz), 36.05, 28.23, 10.48 ; 19F NMR (376 MHz,CDCl3) δ -91.75 (s, 1F). HRMS (ESI) m/z calculated for C26H25FN3O+ [M+H]+ :414.1976, found: 414.1980.
(S)-(2-ethyl-5-fluoro-4-(naphthalen-2-yl)-2,3-dihydro-1H-pyrrol-1-yl) (phenyl)methanone(5e)
1H NMR (400 MHz, CDCl3) δ 7.77 (t, J = 8.0 Hz, 3H), 7.65 (s, 1H),7.61–7.55 (m, 3H), 7.50 (d, J = 7.1 Hz, 1H), 7.45 (t, J = 6.1 Hz, 4H), 4.76–4.65 (m, 1H), 3.32–3.19 (m, 1H), 2.76–2.65 (m, 1H), 2.12–2.02 (m, 1H), 1.96–1.86 (m, 1H), 1.07 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.59 (d,J = 3.0 Hz), 147.17, 144.34, 135.22 (d, J = 3.4 Hz), 132.41, 130.87 (d, J =1.3 Hz), 129.64, 129.01 (d, J = 6.4 Hz), 127.04, 126.93, 126.71, 126.60–126.51 (m), 125.35, 124.74, 122.93, 122.86 (d, J = 2.5 Hz), 93.95 (d, J = 6.0Hz), 56.52, 29.09 (d, J = 4.6 Hz), 25.44, 7.37, -0.49–-5.78 (m); 19F NMR (376MHz, CDCl3) δ -110.52 . HRMS (ESI) m/z calculated for C23H21FNO+ [M+H]+ :346.1602, found: 346.1606.
N-(1-(naphthalen-2-yl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)pentan-3-yl) benzamide(5f)
1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.7 Hz, 2H), 7.69–7.61 (m, 4H),7.47 (d, J = 7.8 Hz, 2H), 7.37–7.32 (m, 4H), 7.28 (t, J = 7.7 Hz, 3H), 7.15(t, J = 7.5 Hz, 2H), 6.16 (d, J = 8.6 Hz, 1H), 4.55–4.48 (m, 1H), 4.21–4.13(m, 1H), 2.82–2.71 (m, 1H), 2.34–2.24 (m, 1H), 1.73–1.61 (m, 1H), 1.59–1.51(m, 1H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 166.92, 166.18,164.13, 135.39, 133.21, 132.40, 131.64, 130.49, 130.23, 127.93, 127.78,127.37, 127.28, 126.73, 126.58, 125.81, 125.70, 125.58, 125.40, 125.11,124.28, 122.68, 49.21, 39.75, 37.93, 26.81, 9.36. HRMS (ESI) m/z calculatedfor C30H28N3O2 + [M+H]+ : 462.2176, found: 462.2180.
表3中数据表明了偕二氟烯烃可以作为一个平台化合物来合成一系列官能团化的含氟化合物，化合物3f可成功转化为6个有用的官能团。常用的Pd/C催化剂即可实现该氢化反应(5a)；3f与对叔丁基甲苯硫醇在超干DCE中反应2小时可偶联得到(5b)，硫醇点击化学很容易制备氟烷基硫化物，而硫烷基硫化物在可见光作用下能够高效地形成氟烷基自由基，参见：M. O. Zubkov, M. D. Kosobokov, V. V. Levin, V. A. Kokorekin, A. A.Korlyukov, J. Hu and A. D. Dilman. Chem. Sci.2020, 11, 737–741.使用胡试剂参与反应，能以优秀的产率得到α-CF3取代的叔胺(5c)；用咪唑处理3f时，亲核乙烯基取代反应(SNV)效果良好，实现了偕二氟烯烃的双官能团化引入了羰基和咪唑官能团(5d)，在强碱NaH的作用下3f可以通过分子内SNV反应，以93%的收率转化为(5e)。此外，在Cs2CO3的辅助下，3f与苯甲酰肼的环化反应得到了不对称2,5-二取代1,3,4-恶二唑(5f)，产率为80%。这些偕二氟烯烃的合成转化进一步证明了该方法的实用性。
Claims (6)
1.一种镍催化含偕二氟烯烃结构脂肪胺的制备方法，其特征在于按如下的步骤进行：
（1）在充满氩气的手套箱中，向干燥的反应管中称量15 mol% 乙二醇二甲醚溴化镍,15 mol% (2,9-二甲基-4,7-联苯-1,10-邻二氮杂菲)、未活化烯烃底物、三氟甲基取代烯烃、2.5 equiv 氟化钠，乙二醇二甲醚，2 equiv三甲氧基硅烷，将反应体系在70 ℃条件下搅拌反应18 h；其中未活化烯烃底物与三氟甲基取代烯烃的摩尔比为1：3；
（2）反应结束后，将所得溶液真空浓缩，粗产物通过硅胶柱色谱纯化，用乙酸乙酯和正己烷的混合物作为洗脱剂，计算分离产率；
其中R1指的是：
R2指的是：Me；
R3指的是：Me，n-Pr；
R4指的是：
所述的未活化的烯烃底物为：
所述三氟甲基取代烯烃为
所述溶剂为乙二醇二甲醚；所述作为洗脱剂的乙酸乙酯与正己烷的体积比1：10。
2.权利要求1所述的一种镍催化含偕二氟烯烃结构脂肪胺的制备方法，其特征在于：反应温度为70℃；催化剂为乙二醇二甲醚溴化镍。
3.权利要求1所述的一种镍催化含偕二氟烯烃结构脂肪胺的制备方法，其特征在于：配体为浴铜灵；碱为氟化钠；氢源为三甲氧基硅烷。
4.权利要求1所述的一种镍催化含偕二氟烯烃结构脂肪胺的制备方法，其特征在于：烯丙基酰胺衍生物作为烯烃底物时得到迁移脱氟烯丙基化产物。
5.权利要求1所述方法在用于在温和条件下实现高分离率、高区域选择性产物方面的应用。
6.采用权利要求1所述方法制备的迁移化合物在用于含氟药物以及材料合成方面的应用。
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