SIOC English
有机化学
高级检索

有机化学 >

2026 , Vol. 46 >Issue 8: 3147 - 3157

DOI: https://doi.org/10.6023/cjoc202602012

研究论文

酰胺噁唑啉导向的铜催化[2.2]对环芳烷直接C—H酰氧基化反应

  • 韩银松 ,
  • 王东炜 ,
  • 肖佳怡 ,
  • 冯若昆 , *
展开
  • 绍兴大学化学化工学院 浙江绍兴 312000

收稿日期: 2026-02-10

  修回日期: 2026-04-05

  网络出版日期: 2026-05-19

基金资助

浙江省自然科学基金(LQ15B020002)

绍兴市重点科技创新团队(202034)

国家级大学生创新创业训练计划(202410349028)

收起

Amide-Oxazoline-Directed Copper-Catalyzed C—H Acyloxylation of [2.2]Paracyclophanes

  • Yinsong Han ,
  • Dongwei Wang ,
  • Jiayi Xiao ,
  • Ruokun Feng , *
Expand
  • College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, Zhejiang 312000
*E-mail:

Received date: 2026-02-10

  Revised date: 2026-04-05

  Online published: 2026-05-19

Supported by

Zhejiang Provincial Natural Science Foundation(LQ15B020002)

Shaoxing Key Science and Technology Innovation Team Project(202034)

National College Students’ Innovation and Entrepreneurship Training Program(202410349028)

Copyright

© 2026 Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Fold

摘要

报道了一种基于廉价金属铜催化、利用酰胺噁唑啉导向基团实现的[2.2]对环芳烷直接C(sp2)—H酰氧化反应. 该反应体系适用于芳香羧酸、烯基羧酸及烷基羧酸等多种羧酸底物, 能以中等到良好的产率获得目标产物. 克级规模实验及后续水解反应进一步证明了该方法的合成实用性. 本研究为[2.2]对环芳烷的选择性官能化提供了一种高效、便捷的合成策略, 具有潜在的应用前景.

关键词： 铜催化; 酰胺噁唑啉导向; C—H酰氧基化; [2.2]对环芳烷

本文引用格式

韩银松 , 王东炜 , 肖佳怡 , 冯若昆 . 酰胺噁唑啉导向的铜催化[2.2]对环芳烷直接C—H酰氧基化反应[J]. 有机化学, 2026 , 46(8) : 3147 -3157 . DOI: 10.6023/cjoc202602012

Abstract

A copper-catalyzed direct C—H acyloxylation of [2.2]paracyclophanes utilizing an oxazoline amide directing group has been developed. A range of carboxylic acid substrates, including aromatic, alkenyl, and alkyl carboxylic acids, are tolerated, delivering the corresponding acyloxylated products in moderate to good yields. Gram-scale reactions and subsequent hydrolysis experiments further demonstrate the synthetic utility of this method. This work provides an efficient and convenient strategy for the selective functionalization of [2.2]paracyclophanes, highlighting its potential for practical applications.

Key words： copper catalysis; amide oxazoline directing; C—H acyloxylation; [2.2]paracyclophanes

由于[2.2]对环芳烷分子具有独特的刚性骨架, 含有该骨架的分子具有优异的光物理与光电特性[1], 使其在材料科学、生物等多个领域得到广泛应用[2]; 同时因其固有的平面手性[3], 被大量用于不对称合成与手性功能材料构筑, 兼具材料科学与合成化学双重重要价值[4]. 因此, [2.2]对环芳烷衍生物的合成具有重要的研究意义.
单取代[2.2]对环芳烷的制备主要基于经典苯环化学方法实现[5]. 例如硝基、醛基、乙酰基等官能团可通过傅克反应、亲电取代等反应引入; 而引入氧、硫等杂原子则需经多步反应完成. 此类方法往往步骤繁琐, 且产物收率偏低.
近年研究发现, 通过过渡金属催化C(sp2)—H直接官能化可以实现对[2.2]对环芳烷的选择性修饰. 2012年, Bolm课题组[6]报道了酮肟导向的钯催化[2.2]对环芳烷C(sp2)—H键乙酰氧基化反应. 2014年, Bräse课题组[7]在钯催化体系下, 以N-甲氧基醛肟为导向基团, 实现[2.2]对环芳烷的直接卤化反应. 2019年, Benedetti等[8]以羟基取代的[2.2]对环芳烷与一系列丙炔酸缩合形成的酯化产物为原料, 氯化金为催化剂下实现了[2.2]对环芳烷的分子内环化反应. 2023年, Xu课题组[9]报道了钯催化[2.2]对环芳烷的直接芳基化. 尽管过渡金属催化的C(sp2)—H官能化在修饰[2.2]对环芳烷方面取得了一定进展, 但昂贵的金属催化剂及有限的底物适用性制约了该类反应的进一步发展.
近年来, 廉价金属催化的C(sp2)—H官能化取得了重要突破, 多种双齿导向基团因具备良好的配位能力和广泛的底物兼容性受到广泛关注[10]. 利用该策略实现[2.2]对环芳烷的直接官能化成为新的研究方向. 2022年, 史炳锋课题组[11]报道了以8-氨基喹啉为导向基团、钴催化实现[2.2]对环芳烷的C(sp2)—H官能化反应. 2025年, 该课题组[12]进一步发展了钴催化的电氧化及光氧化还原体系, 实现了外消旋[2.2]对环芳烷的对映选择性C(sp2)—H酰氧基化与烷氧基化, 为平面手性[2.2]对环芳烷衍生物的高效合成提供了新策略.
酰胺噁唑啉作为一类重要的分子骨架, 在合成化学中应用广泛. 特别是Yu、Zhang等[10,13]报道了一系列铜催化C—H炔基化及羟基化反应的工作后, 针对酰胺噁唑啉导向的C—H官能化研究受到了持续关注, 相关研究领域也得以不断拓展. 基于以上研究背景, 本课题组采用CuCl/Ag2CO3催化体系, 发展了以酰胺噁唑啉为双齿导向基团的直接C(sp2)—H酰氧基化反应, 为[2.2]对环芳烷的功能化修饰提供了新途径.

1 结果与讨论

首先, 利用酰胺噁唑啉作为底物模板, 使用20 mol%的溴化铜作为催化剂, 2 equiv.的碳酸银作为氧化剂, 甲苯和N,N-二甲基乙酰胺(DMA)作为混合溶剂, 在130 ℃的空气氛围下反应12 h, 以51%的产率得到了目标产物3aa(表1, Entry 1). 催化剂筛选结果表明, 氯化亚铜的催化活性高于其他铜盐(如乙酸铜、碘化亚铜、溴化亚铜、溴化铜和氯化铜), 在相同条件下产率提升至61%, 不添加催化剂则反应不发生(表1, Entries 2~7). 因此确定氯化亚铜作为该反应的最佳催化剂. 值得关注的是, 仅使用Ag2CO3作为氧化剂时, 才能获得目标产物(表1, Entries 8~12). 随后尝试改变甲苯和DMA的比例, 实验结果表明, 增加DMA的比例, 产率逐步下降(表1, Entries 13~15), 进一步优化溶剂发现: 使用单一甲苯或添加二甲基亚砜(DMSO)均未能提升反应效果; 而将DMA替换为N,N-二甲基甲酰胺(DMF)后, 产率提高至67%(表1, Entries 16~18). 此外, 对温度和时间的考察显示, 反应温度降至110 ℃或升至150 ℃, 均导致产率下降; 将反应时间缩短至8 h仍有原料残留, 延长至16 h则产率未进一步提升(表1, Entries 19~22). 在反应体系中加入1 equiv.碳酸钾, 反应产率下降至25%(表1, Entry 23), 根据实验结果, 加入碱并不能促进反应的进行. 因此, 确定该反应的最优条件为: 以氯化亚铜(20 mol%)为催化剂, 碳酸银(2.0 equiv.)为氧化剂, 甲苯/ DMF (V∶V=3∶1, 总量2 mL)为溶剂, 于130 ℃下反应12 h.
表1 反应条件优化a,

Table 1 Optimization of reaction conditions

Entry Cu Oxidant Solvent Temp./℃ Time/h Yieldb/%
1 CuBr2 Ag2CO3 V(Toluene)∶V(DMA)=3∶1 130 12 51
2 CuCl2 Ag2CO3 V(Toluene)∶V(DMF)=3∶1 130 12 54
3 Cu(OAc)2 Ag2CO3 V(Toluene)∶V(DMA)=3∶1 130 12 37
4 CuI Ag2CO3 V(Toluene)∶V(DMA)=3∶1 130 12 41
5 CuCl Ag2CO3 V(Toluene)∶V(DMA)=3∶1 130 12 61
6 CuBr Ag2CO3 V(Toluene)∶V(DMA)=3∶1 130 12 58
7 — Ag2CO3 V(Toluene)∶V(DMA)=3∶1 130 12 NRc
8 CuCl Ag2SO4 V(Toluene)∶V(DMA)=3∶1 130 12 NR
9 CuCl AgOAc V(Toluene)∶V(DMA)=3∶1 130 12 NR
10 CuCl O2 V(Toluene)∶V(DMA)=3∶1 130 12 NR
11 CuCl Ag2CO3 V(Toluene)∶V(DMA)=3∶1 130 12 42
12 CuCl — V(Toluene)∶V(DMA)=3∶1 130 12 NR
13 CuCl Ag2CO3 V(Toluene)∶V(DMA)=1∶1 130 12 43
14 CuCl Ag2CO3 V(Toluene)∶V(DMA)=1∶2 130 12 40
15 CuCl Ag2CO3 V(Toluene)∶V(DMA)=1∶3 130 12 34
16d CuCl Ag2CO3 Toluene 130 12 47
17 CuCl Ag2CO3 V(Toluene)∶V(DMSO)=3∶1 130 12 67
18 CuCl Ag2CO3 V(Toluene)∶V(DMF)=3∶1 130 12 50
19 CuCl Ag2CO3 V(Toluene)∶V(DMF)=3∶1 110 12 32
20 CuCl Ag2CO3 V(Toluene)∶V(DMF)=3∶1 150 12 39
21 CuCl Ag2CO3 V(Toluene)∶V(DMF)=3∶1 130 8 58
22 CuCl Ag2CO3 V(Toluene)∶V(DMF)=3∶1 130 16 66
23e CuCl Ag2CO3 V(Toluene)∶V(DMF)=3∶1 130 12 25

a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (20 mol%), oxidant (2.0 equiv.), and solvent (2 mL) in air. b Isolated yield. c NR means no reaction. d Ag2CO3 (1.0 equiv.). e K2CO3 (1.0 equiv.).

在已优化的反应条件下, 为进一步提升[2.2]对环芳烷甲酰胺邻位酰氧基化反应的产率, 考察了不同取代基修饰的酰胺噁唑啉作为双齿导向基团的效果(Scheme 1). 结果表明, 噁唑啉五元环上取代基的空间位阻对反应影响显著: 当在噁唑啉的4位或5位引入甲基时, 产率分别下降至47% (3ba)和59% (3ea). 相比之下, 氨基对位引入溴原子对产率影响较小(3ca). 值得注意的是, 当使用氨基对位氯代的酰胺噁唑啉作为导向基团时, 酰氧基化反应的产率可提升至75% (Scheme 1, 3da).
图式1 导向基团筛选

Scheme 1 Screening of directing groups

基于上述结果, 选用N-4-氯-2-(4,5-二氢噁唑-2-基)苯基酰胺作为最优导向基团, 系统考察了不同取代苯甲酸底物的适用性(Scheme 2). 对位和间位引入甲基的苯甲酸均能顺利反应, 分别以75% (3da)和70% (3db)的收率得到相应产物. 当对位引入大位阻基团(如叔丁基、苯基)时, 产率有所下降(3dd, 3de). 苯甲酸对位被吸电子基(如氰基、硝基、三氟甲基、乙酰基)取代时, 目标产物的收率普遍较低(3df~3di). 值得注意的是, 含强配位性氧原子的底物, 如4-乙酰氧基苯甲酸和2,3-二甲氧基苯甲酸, 可能因与铜中心竞争配位而导致产率进一步降低(3di和3dj). 尽管如此, 具有较大空间位阻的2,4,6-三甲基苯甲酸仍能以52%的收率得到目标产物(3dk), 天然产物胡椒酸也可顺利参与反应, 以69%的收率获得酰氧基化产物(3dl). 此外, 杂芳酸(如呋喃-2-甲酸、噻 吩-2-甲酸)及稠环酸(1-萘甲酸)也能以37%~61%的收率得到相应产物(3dm~3do). 在考察的肉桂酸类底物中, 不同取代基的肉桂酸均能以41%~56%的收率获得目标化合物(3dp~3ds), 其产率变化趋势符合电子效应的影响. 富电子的特戊酸亦可作为酰氧基化底物, 但产率仅为37% (3dt). 其他脂肪酸如乙酸、丙酸、环己基甲酸, 在标准条件下未获得目标产物. 将反应放大到克级, 在标准条件下可以以54%产率得到目标产物; 该产物在AlCl3, 四氢呋喃(THF)/H2O体系中反应可以以90%产率得到噁唑啉开环产物4. 此外, 在碱作用下, 可以实现酯的水解反应, 并以87%产率得到产物5 (Scheme 3).
图式2 酸的底物范围

Scheme 2 Substrate scope of acids

图式3 反应的应用与放大研究

Scheme 3 Application and scale-up study of the reaction

根据实验事实及文献报道[14-15], 提出了如下可能的反应机理(Scheme 4). 一价铜在碳酸银氧化作用下, 转化为二价铜物种, 该二价铜与底物中的N,N-双齿导向基团配位, 形成铜(II)络合物A. 随后, 络合物A通过导向基辅助活化[2.2]对环芳烷甲酰胺的邻位C(sp2)—H键, 生成环金属中间体B. 中间体B经氧化过程进一步转化为铜(III)物种C, 后者通过配体交换与还原消除反应, 一步生成邻位酰氧基化目标产物, 并再生一价铜催化剂, 完成催化循环. 在该体系中, 碳酸银不仅作为氧化剂, 还与芳基羧酸(ArCOOH)作用生成相应的芳基羧酸根(ArCOO－), 参与后续反应步骤.
图式4 可能的反应机理

Scheme 4 Proposed reaction mechanism

2 结论

综上所述, 发展了一种基于廉价金属铜催化的双齿配体导向的C(sp2)—H活化酰氧基化反应, 实现[2.2]对环芳烷的选择性修饰的新策略. 该反应体系展现出优异的底物普适性, 能够兼容多种芳基及杂环取代酸底物, 以中等到良好的收率获得结构多样的目标产物. 所得[2.2]对环芳烷衍生物在作为多功能材料或生物方面具有潜在应用价值.

3 实验部分

3.1 仪器与试剂

核磁共振氢谱(1H NMR)、碳谱(13C NMR)检测均使用布鲁克AVANCE III 400或500 MHz核磁共振仪完成, 溶剂为氘代氯仿(CDCl3); 高分辨质谱(HRMS)数据通过沃特世GCT Premier质谱仪采集获得; 熔点测定使用显微熔点测定仪(WRS-1C)测量(数据未经温度校正). 相关起始原料参照已知文献方法制备完成. 除非另有说明, 所有试剂及溶剂均购自商业渠道并直接使用, 未经进一步纯化处理. 常规条件反应进程采用硅胶F254薄层色谱板进行监测. 柱层析分离操作以300~400目硅胶为填料, 以石油醚(PE)/乙酸乙酯(EA)体系作为洗脱剂开展.

3.2 实验方法

3.2.1 [2.2]对环芳烷酰氧基化产物的制备

向配备四氟旋塞的35 mL耐压反应管中依次加入对应的化合物1 (0.2 mmol)、2 (0.4 mmol, 2.0 equiv.)、碳酸银(Ag2CO3, 110.3 mg, 0.2 mmol, 2.0 equiv.)、氯化亚铜(CuCl, 4.0 mg, 0.04 mmol, 20 mol%)、甲苯(1.5 mL)以及DMF (0.5 mL). 将反应管置于预热的130 ℃平行反应模块中, 反应12 h. 待反应结束并冷却至室温, 向反应液中加入饱和食盐水(10 mL), 用乙酸乙酯(5 mL)进行萃取, 水相再用乙酸乙酯(5 mL×3)萃取. 合并有机相, 经无水硫酸镁干燥后, 通过硅藻土垫过滤, 滤液经旋转蒸发仪浓缩. 最后以石油醚/乙酸乙酯(V∶V=10∶1)为洗脱剂进行柱层析分离, 获得[2.2]对环芳烷酰氧基化产物3aa~3dt.
4-[N-(2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-甲基苯甲酸酯(3aa): 白色固体, 71.0 mg, 产率67%. m.p. 151.3~152.1 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.07 (s, 1H), 8.98~8.91 (m, 1H), 8.04~7.96 (m, 2H), 7.65 (dd, J=8.0, 1.6 Hz, 1H), 7.43~7.48 (m, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 2H), 6.98~7.03 (m, 1H), 6.84 (dd, J=8.0, 2.0 Hz, 1H), 6.75~6.61 (m, 3H), 6.54 (d, J=8.0 Hz, 1H), 4.14~4.21 (m, 1H), 4.04~4.11 (m, 1H), 4.01~3.91 (m, 1H), 3.91~3.77 (m, 1H), 3.42 (d, J=8.8 Hz, 2H), 3.16~2.85 (m, 6H), 2.40 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 165.4, 163.9, 163.7, 145.7, 144.3, 141.1, 139.7, 139.6, 139.5, 136.7, 132.9, 132.7, 132.6, 132.2, 132.2, 132.1, 129.9, 129.6, 129.2, 128.8, 128.6, 126.5, 122.2, 119.6, 113.3, 66.1, 54.3, 35.3, 34.4, 33.7, 31.2, 21.7; HRMS (ESI) calcd for C34H31N2O4 [M＋H]＋ 531.2278, found 531.2278.
4-[(S)-N-(2-(4-甲基-4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-甲基苯甲酸酯(3ba): 白色固体, 51.1 mg, 产率47%. m.p. 146.5~147.4 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 8.91~8.82 (m, 1H), 8.09~8.02 (m, 2H), 7.65~7.73 (m, 1H), 7.41~7.47 (m, 1H), 7.28~7.19 (m, 3H), 7.08~7.00 (m, 1H), 6.86~6.92 (m, 1H), 6.72~6.61 (m, 3H), 6.55 (d, J=8.0 Hz, 1H), 4.37~4.10 (m, 2H), 3.82~3.72 (m, 1H), 3.45~3.26 (m, 2H), 3.17~2.94 (m, 5H), 2.94~2.81 (m, 1H), 2.42 (s, 3H), 1.16 (dd, J=6.4, 4.0 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 165.3, 164.0, 162.6, 145.9, 145.8, 144.3, 144.2, 140.5, 140.3, 139.8, 139.7, 139.5, 139.5, 139.4, 136.5, 132.8, 132.8, 132.7, 132.4, 132.4, 132.4, 132.3, 132.2, 132.1, 132.1, 130.2, 130.1, 129.8, 129.8, 129.2, 129.0, 128.8, 126.6, 126.5, 122.3, 122.2, 119.8, 119.7, 113.4, 72.7, 72.6, 61.9, 61.4, 35.3, 34.5, 34.4, 33.9, 33.7, 31.2, 31.1, 21.7, 21.3, 21.1; HRMS (ESI) calcd for C35H33- N2O4 [M＋H]＋ 545.2435, found 545.2436.
4-[N-(4-溴-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-甲基苯甲酸酯(3ca): 白色固体, 80.52 mg, 产率66%. m.p. 183.1~184.1 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.98 (s, 3H), 8.87 (d, J=9.2 Hz, 3H), 8.01~7.93 (m, 6H), 7.75 (d, J=2.4 Hz, 3H), 7.56 (dd, J=9.2, 2.4 Hz, 3H), 7.24 (dd, J=8.0, 2.0 Hz, 3H), 7.17 (d, J=8.0 Hz, 6H), 6.82 (dd, J=8.0, 2.0 Hz, 3H), 6.71 (dd, J=8.0, 2.4 Hz, 6H), 6.64 (dd, J=8.0, 2.0 Hz, 3H), 6.54 (d, J=8.0 Hz, 3H), 4.13~4.20 (m, 3H), 4.03~4.11 (m, 3H), 3.89~3.98 (m, 3H), 3.77~3.86 (m, 3H), 3.47~3.33 (m, 6H), 3.15~2.97 (m, 14H), 2.97 (d, J=2.4 Hz, 1H), 2.95~2.84 (m, 4H), 2.42 (s, 9H); 13C NMR (100 MHz, Chloroform-d) δ: 165.5, 163.8, 162.6, 145.8, 144.5, 141.2, 139.5, 139.5, 138.8, 136.9, 134.8, 133.0, 132.7, 132.6, 132.2, 132.1, 131.4, 129.8, 129.5, 129.2, 128.3, 126.4, 121.1, 114.9, 114.4, 66.3, 54.4, 35.3, 34.4, 33.6, 31.1, 21.7; HRMS (ESI) calcd for C34H29BrN2- NaO4 [M＋Na]＋ 633.1183, found 633.1196.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基 4-甲基苯甲酸酯(3da): 白色固体, 84.6 mg, 产率75%. m.p. 148.7~149.5 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.96 (s, 1H), 8.92 (d, J=9.2 Hz, 1H), 8.01~7.93 (m, 2H), 7.60 (d, J=2.4 Hz, 1H), 7.42 (dd, J=9.2, 2.4 Hz, 1H), 7.24 (dd, J=8.0, 2.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 2H), 6.82 (dd, J=8.0, 2.0 Hz, 1H), 6.70 (dd, J=8.0, 2.4 Hz, 2H), 6.64 (dd, J=8.0, 2.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 4.14~4.21 (m, 1H), 4.04~4.11 (m, 1H), 3.89~3.98 (m, 1H), 3.77~3.86 (m, 1H), 3.46~3.33 (m, 2H), 3.14~2.84 (m, 5H), 2.42 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 165.5, 163.8, 162.7, 145.8, 144.5, 141.2, 139.5, 139.5, 138.3, 136.8, 133.0, 132.7, 132.6, 132.1, 132.1, 131.9, 129.8, 129.5, 129.2, 128.5, 128.3, 127.1, 126.4, 120.9, 114.5, 66.3, 54.4, 35.3, 34.4, 33.6, 31.1, 21.7; HRMS (ESI) calcd for C34H30ClN2O4 [M＋H]＋ 565.1889, found 565.1893.
4-[N-(4-氯-2-(5-甲基-4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]-对环芳烷-4-基 4-甲基苯甲酸酯(3ea): 白色固体, 68.3 mg, 产率59%. m.p. 145.5~146.4 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.03 (s, 1H), 8.92 (dd, J=11.6, 9.2 Hz, 1H), 7.96 (dd, J=8.0, 6.4 Hz, 2H), 7.60 (dd, J=10.4, 2.8 Hz, 1H), 7.40 (dd, J=9.2, 2.4 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.19~7.13 (m, 2H), 6.80 (dt, J=8.0, 1.6 Hz, 1H), 6.71~6.65 (m, 2H), 6.62 (dd, J=7.6, 2.0 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 4.47~4.53 (m, 1H), 3.87~4.04 (m, 1H), 3.51~3.30 (m, 4H), 3.12~2.83 (m, 8H), 2.40 (s, 4H), 1.28 (d, J=6.4 Hz, 3H), 1.18 (d, J=6.4 Hz, 1H); 13C NMR (125 MHz, Chloroform-d) δ: 165.6, 163.9, 162.2, 162.1, 145.8, 144.6, 141.3, 139.6, 139.6, 139.6, 138.5, 138.5, 136.9, 133.1, 133.0, 132.8, 132.7, 132.2, 132.2, 131.9, 131.9, 130.1, 130.0, 129.6, 129.6, 129.3, 129.3, 128.7, 128.6, 128.4, 127.1, 126.5, 120.9, 120.8, 114.9, 75.2, 75.1, 61.1, 35.4, 34.5, 33.7, 31.3, 31.2, 21.8, 20.9, 20.8; HRMS (ESI) calcd for C35H32ClN2O4 [M＋H]＋ 579.2045, found 579.2047.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基3-甲基苯甲酸酯(3db): 白色固体, 80.0 mg, 产率70%. m.p. 157.3~157.9 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.00 (s, 1H), 8.95 (d, J=9.2 Hz, 1H), 7.86~7.89 (m, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.42 (dd, J=9.2, 2.4 Hz, 1H), 7.38~7.30 (m, 1H), 7.30~7.19 (m, 2H), 6.78 (dd, J=8.0, 2.0 Hz, 1H), 6.73~6.67 (m, 2H), 6.63 (dd, J=8.0, 2.0 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 4.11~4.17 (m, 1H), 4.05~3.86 (m, 2H), 3.75~3.84 (m, 1H), 3.47~3.33 (m, 2H), 3.13~2.85 (m, 6H), 2.25 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 165.5, 163.9, 162.8, 145.7, 141.3, 139.6, 139.5, 138.4, 138.3, 136.9, 134.4, 133.1, 132.8, 132.7, 132.2, 132.1, 131.9, 130.3, 129.6, 129.1, 128.5, 128.4, 128.0, 127.1, 127.0, 120.9, 114.5, 66.2, 54.3, 35.3, 34.4, 33.7, 31.1, 21.1; HRMS (ESI) calcd for C34H30ClN2O4 [M＋H]＋ 565.1889, found 565.1896.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基苯甲酸酯(3dc): 白色固体, 72.1 mg, 产率63%. m.p. 152.0~152.7 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.98 (s, 1H), 8.93 (d, J=9.2 Hz, 1H), 8.14~8.05 (m, 2H), 7.64~7.53 (m, 2H), 7.46~7.35 (m, 3H), 7.24 (dd, J=8.0, 2.0 Hz, 1H), 6.82 (dd, J=8.0, 2.0 Hz, 1H), 6.71 (dd, J=8.0, 1.6 Hz, 2H), 6.65 (dd, J=7.6, 2.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 4.13~4.20 (m, 1H), 4.01~4.08 (m, 1H), 3.89~3.97 (m, 1H), 3.77~3.86 (m, 1H), 3.47~3.34 (m, 2H), 3.17~2.86 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.4, 163.8, 162.8, 145.7, 141.2, 139.5, 139.5, 138.3, 136.9, 133.6, 133.0, 132.7, 132.2, 132.1, 132.0, 129.8, 129.5, 129.2, 128.6, 128.5, 128.2, 127.2, 120.9, 114.5, 66.3, 54.3, 35.3, 34.4, 33.7, 31.1; HRMS (ESI) calcd for C33H27ClN2NaO4 [M＋Na]＋ 573.1552, found 573.1555.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-叔丁基苯甲酸酯(3dd): 白色固体, 66.67 mg, 产率55%. m.p. 176.3~176.9 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.99 (s, 1H), 8.97 (d, J=9.2 Hz, 1H), 8.04~7.97 (m, 2H), 7.55 (d, J=2.4 Hz, 1H), 7.44 (dd, J=9.2, 2.4 Hz, 1H), 7.40~7.33 (m, 2H), 7.30~7.20 (m, 1H), 6.82 (dd, J=8.0, 2.0 Hz, 1H), 6.72 (dd, J=8.0, 2.0 Hz, 2H), 6.65 (dd, J=8.0, 2.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 4.10~4.17 (m, 1H), 4.01~4.08 (m, 1H), 3.88~3.97 (m, 1H), 3.75~3.84 (m, 1H), 3.49~3.35 (m, 2H), 3.17~2.86 (m, 6H), 1.35 (s, 9H); 13C NMR (100 MHz, Chloroform-d) δ: 165.5, 163.7, 162.7, 157.4, 145.9, 141.3, 139.5, 138.4, 136.9, 133.1, 132.8, 132.6, 132.2, 132.1, 131.9, 129.7, 129.5, 128.5, 128.2, 127.0, 126.3, 125.4, 120.8, 114.5, 66.2, 54.3, 35.3, 35.1, 34.4, 33.7, 31.2, 31.1; HRMS (ESI) calcd for C37H36ClN2O4 [M＋H]＋ 607.2358, found 607.2362.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-联苯羧酸酯(3de): 白色固体, 71.4 mg, 产率57%. m.p. 172.3~172.9 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.03 (s, 1H), 8.98 (d, J=9.2Hz, 1H), 8.19~8.12 (m, 2H), 7.65~7.56 (m, 5H), 7.52 (dd, J=8.4, 6.4 Hz, 2H), 7.48~7.42 (m, 2H), 7.28 (dd, J=8.0, 2.0 Hz, 1H), 6.87 (dd, J=8.0, 2.0 Hz, 1H), 6.76~6.70 (m, 2H), 6.67 (dd, J=8.0, 2.0 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 4.04~4.20 (m, 2H), 3.91~4.00 (m, 1H), 3.78~3.87 (m, 1H), 3.50~3.36 (m, 2H), 3.20~2.88 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.5, 163.6, 162.8, 146.4, 145.8, 141.2, 139.8, 139.5, 139.5, 138.4, 136.9, 133.0, 132.8, 132.7, 132.2, 132.1, 132.0, 130.3, 129.6, 129.1, 129.0, 128.6, 128.3, 128.3, 127.8, 127.4, 127.2, 120.9, 114.6, 66.3, 54.4, 35.3, 34.4, 33.7, 31.2; HRMS (ESI) calcd for C39H32ClN2O4 [M＋H]＋ 627.2045, found 627.2048.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-氟苯甲酸酯(3df): 白色固体, 38.6 mg, 产率34%. m.p. 188.2~188.9 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.01 (s, 1H), 8.93 (d, J=9.2 Hz, 1H), 8.17~8.08 (m, 2H), 7.65 (d, J=2.4 Hz, 1H), 7.44 (dd, J=9.2, 2.4 Hz, 1H), 7.23 (dd, J=8.0, 2.0 Hz, 1H), 7.13~7.02 (m, 2H), 6.82 (dd, J=8.0, 2.0 Hz, 1H), 6.74~6.68 (m, 2H), 6.65 (dd, J=8.0, 2,0 Hz, 1H), 6.56 (d, J=8.0 Hz, 1H), 4.13~4.21 (m, 1H), 4.04~4.11 (m, 1H), 4.00~3.78 (m, 2H), 3.46~3.33 (m, 2H), 3.16~2.86 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 167.4, 165.3, 164.8, 162.9, 162.8, 145.6, 141.2, 139.5, 139.5, 138.2, 136.9, 132.9, 132.8, 132.8, 132.5, 132.4, 132.2, 132.1, 132.0, 129.5, 128.6, 128.3, 127.3, 125.5, 125.4, 120.9, 115.9, 115.7, 114.5, 66.3, 54.4, 35.3, 34.4, 33.7, 31.1; HRMS (ESI) calcd for C33H27ClFN2O4 [M＋H]＋ 569.1638, found 569.1648.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-溴苯甲酸酯(3dg): 白色固体, 49.0 mg, 产率39%. m.p. 187.2~187.8 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.95 (s, 1H), 8.87 (d, J=9.2 Hz, 1H), 7.97~7.89 (m, 2H), 7.64 (d, J=2.4 Hz, 1H), 7.56~7.48 (m, 2H), 7.41 (dd, J=9.0, 2.4 Hz, 1H), 7.18 (dd, J=8.0, 2.0 Hz, 1H), 6.78 (dd, J=8.0, 2.0 Hz, 1H), 6.68 (dd, J=8.0, 1.6 Hz, 2H), 6.62 (dd, J=8.0, 2.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 4.26~4.06 (m, 2H), 3.97~3.77 (m, 2H), 3.41~3.29 (m, 2H), 3.12~2.83 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.3, 163.2, 162.9, 145.5, 141.2, 139.5, 139.4, 138.2, 136.9, 132.8, 132.8, 132.2, 132.1, 131.9, 131.3, 129.5, 128.9, 128.7, 128.3, 128.1, 127.4, 120.9, 114.5, 66.3, 54.4, 35.3, 34.4, 33.7, 31.1; HRMS (ESI) calcd for C33H27BrClN2O4 [M＋H]＋ 629.0837, found 629.0835.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-氰基苯甲酸酯(3dh): 白色固体, 35.7 mg, 产率31%. m.p. 189.5~189.9 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.03 (s, 1H), 8.88 (d, J=9.2 Hz, 1H), 8.24~8.17 (m, 2H), 7.76~7.69 (m, 2H), 7.66 (d, J=2.4 Hz, 1H), 7.43 (dd, J=9.2, 2.4 Hz, 1H), 7.19 (dd, J=8.0, 2.0 Hz, 1H), 6.81 (dd, J=8.0, 2.0 Hz, 1H), 6.75~6.67 (m, 2H), 6.65 (dd, J=8.0, 2.0 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 4.17~4.24 (m, 1H), 4.07~4.15 (m, 1H), 3.96~3.81 (m, 2H), 3.29~3.38 (m, 2H), 3.15~2.86 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.1, 162.9, 162.4, 145.4, 141.2, 139.5, 139.3, 138.1, 137.0, 133.1, 133.1, 132.8, 132.6, 132.4, 132.2, 132.2, 132.1, 130.3, 129.5, 128.7, 128.4, 127.5, 120.8, 117.8, 117.0, 114.4, 66.3, 54.4, 35.3, 34.4, 33.7, 31.0; HRMS (ESI) calcd for C34H27Cl- N3O4 [M＋H]＋ 576.1685, found 576.1691.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-乙酰氧基苯甲酸酯(3di): 白色固体, 45.0 mg, 产率37%. m.p. 161.5~162.4 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.01 (s, 1H), 8.91 (d, J=9.2 Hz, 1H), 8.17~8.09 (m, 2H), 7.66 (d, J=2.4 Hz, 1H), 7.43 (dd, J=9.2, 2.4 Hz, 1H), 7.21 (dd, J=8.0, 2.0 Hz, 1H), 7.19~7.10 (m, 2H), 6.81 (dd, J=8.0, 2.0 Hz, 1H), 6.74~6.67 (m, 2H), 6.64 (dd, J=8.0, 2.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 4.15~4.22 (m, 1H), 4.05~4.12 (m, 1H), 4.00~3.78 (m, 2H), 3.44~3.32 (m, 2H), 3.15~2.85 (m, 6H), 2.36 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 168.8, 165.3, 163.1, 162.9, 154.8, 145.5, 141.1, 139.5, 139.5, 138.2, 136.9, 132.9, 132.8, 132.7, 132.2, 132.1, 132.0, 131.4, 129.5, 128.7, 128.3, 127.3, 126.7, 121.8, 120.9, 114.6, 66.3, 54.4, 35.3, 34.4, 33.7, 31.1, 21.2; HRMS (ESI) calcd for C35H30ClN2O6 [M＋H]＋ 609.1787, found 609.1793.
4-(N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基)[2,2]对环芳烷-4-基2,3-二甲氧基苯甲酸酯(3dj): 白色固体, 37.8 mg, 产率31%. m.p. 157.5~158.4 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.09 (s, 1H), 8.95 (d, J=9.2 Hz, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.44 (dd, J=9.2, 2.8 Hz, 1H), 7.36 (dd, J=8.0, 1.6 Hz, 1H), 7.20 (dd, J=8.0, 2.0 Hz, 1H), 7.07 (dd, J=8.0, 1.6 Hz, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.83 (dd, J=8.0, 2.0 Hz, 1H), 6.69 (dd, J=8.0, 2.0 Hz, 2H), 6.63 (dd, J=8.0, 2.0 Hz, 1H), 6.53 (d, J=8.0 Hz, 1H), 4.07~4.21 (m, 2H), 3.95~4.01 (m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.88~3.79 (m, 1H), 3.44~3.26 (m, 2H), 3.20~2.86 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.5, 163.3, 162.7, 153.6, 149.8, 145.8, 141.0, 139.5, 139.5, 138.4, 136.8, 132.8, 132.7, 132.7, 132.2, 132.1, 131.9, 129.8, 128.6, 128.3, 127.1, 124.6, 123.9, 122.5, 121.0, 116.5, 114.7, 66.4, 61.6, 56.1, 54.5, 35.3, 34.4, 33.7, 30.9; HRMS (ESI) calcd for C35H32Cl- N2O6 [M＋H]＋ 611.1943, found 611.1949.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基2,4,6-三甲基苯甲酸酯(3dk): 白色固体, 61.6 mg, 产率52%. m.p. 158.0~158.9 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.12 (s, 1H), 8.90 (d, J=9.2 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.47 (dd, J=9.2, 2.4 Hz, 1H), 7.17 (dd, J=8.0, 2.0 Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J=8.0, 2.0 Hz, 1H), 6.71~6.62 (m, 3H), 6.55 (d, J=8.0 Hz, 1H), 4.31~4.17 (m, 2H), 4.04~3.84 (m, 2H), 3.33~2.87 (m, 8H), 2.39 (s, 6H), 2.31 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 167.7, 165.7, 162.8, 145.5, 140.2, 139.3, 138.3, 136.8, 136.7, 132.8, 132.7, 132.5, 132.4, 132.1, 132.0, 130.1, 129.7, 129.1, 128.9, 128.8, 127.5, 121.3, 115.0, 66.3, 54.7, 35.2, 34.5, 33.6, 30.9, 21.1, 20.7; HRMS (ESI) calcd for C36H33ClN2NaO4 [M＋Na]＋ 615.2021, found 615.2025.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基胡椒酸酯(3dl): 白色固体, 82.0 mg, 产率69%. m.p. 144.0~145.0 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.97 (s, 1H), 8.94 (d, J=9.2 Hz, 1H), 7.71 (dd, J=8.0, 1.6 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.43 (dd, J=9.2, 2.4 Hz, 1H), 7.22 (dd, J=8.0, 2.0 Hz, 1H), 6.81 (dd, J=8.0, 2.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.74~6.66 (m, 2H), 6.64 (dd, J=8.0, 2.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 6.00~6.04 (m, 2H), 4.09~4.23 (m, 2H), 3.80~3.99 (m, 2H), 3.45~3.32 (m, 2H), 3.15~2.84 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.4, 163.1, 162.8, 152.2, 147.8, 145.8, 141.2, 139.5, 139.5, 138.4, 136.9, 133.0, 132.8, 132.7, 132.2, 132.0, 132.0, 129.5, 128.5, 128.3, 127.1, 125.9, 123.0, 120.9, 114.5, 109.5, 108.1, 102.0, 66.3, 54.4, 35.3, 34.4, 33.6, 31.1; HRMS (ESI) calcd for C34H27ClN2O6 [M＋H]＋ 595.1630, found 595.1639.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基1-萘甲酸酯(3dm): 白色固体, 73.2 mg, 产率61%. m.p. 148.8~149.6 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.08 (s, 1H), 9.05~8.95 (m, 2H), 8.39 (dd, J=7.2, 1.4 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.95~7.86 (m, 1H), 7.64~7.52 (m, 3H), 7.43 (dd, J=9.2, 2.4 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.31~7.24 (m, 1H), 6.85 (dd, J=8.0, 2.0 Hz, 1H), 6.79~6.70 (m, 2H), 6.67 (dd, J=7.6, 2.0 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 3.98~4.04 (m, 1H), 3.82~3.91 (m, 1H), 3.85~3.62 (m, 2H), 3.41 (t, J=9.6 Hz, 2H), 3.26~2.93 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.6, 164.4, 162.7, 145.8, 141.2, 139.5, 139.5, 138.3, 136.8, 134.3, 133.8, 133.1, 132.8, 132.8, 132.2, 131.9, 131.6, 131.3, 129.7, 128.7, 128.6, 128.5, 128.0, 127.2, 126.3, 125.4, 125.2, 124.5, 121.0, 114.7, 66.1, 54.5, 35.3, 34.4, 33.7, 31.1; HRMS (ESI) calcd for C37H30ClN2O4 [M＋H]＋ 601.1889, found 601.1892.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基呋喃-2-甲酸酯(3dn): 白色固体, 60.5 mg, 产率56%. m.p. 178.2~179.1 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.98 (s, 1H), 8.95 (d, J=9.2 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.57 (dd, J=2.0, 0.8 Hz, 1H), 7.44 (dd, J=9.2, 2.4 Hz, 1H), 7.25~7.16 (m, 2H), 6.78 (dd, J=8.0, 2.0 Hz, 1H), 6.73~6.66 (m, 2H), 6.64 (dd, J=7.6, 2.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 6.45 (dd, J=3.6, 1.8 Hz, 1H), 4.11~4.24 (m, 2H), 3.95~4.04 (m, 1H), 3.77~3.86 (m, 1H), 3.46~3.33 (m, 2H), 3.17~2.86 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.2, 162.8, 155.6, 147.3, 144.9, 143.8, 141.4, 139.5, 139.4, 138.3, 136.9, 133.0, 132.9, 132.7, 132.2, 132.0, 132.0, 129.5, 128.6, 128.1, 127.1, 120.9, 119.2, 114.6, 112.1, 66.3, 54.4, 35.3, 34.3, 33.7, 31.1; HRMS (ESI) calcd for C31H26ClN2O5 [M＋H]＋ 541.1525, found 541.1533.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基噻吩-2-甲酸酯(3do): 白色固体, 41.1 mg, 产率37%. m.p. 182.1~182.9 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.01 (s, 1H), 8.95 (d, J=9.0 Hz, 1H), 7.83 (dd, J=3.6, 1.2 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.57 (dd, J=4.8, 1.3 Hz, 1H), 7.43 (dd, J=9.2, 2.4 Hz, 1H), 7.21 (dd, J=8.0, 2.0 Hz, 1H), 7.05 (dd, J=5.2, 3.6 Hz, 1H), 6.81 (dd, J=8.0, 2.0 Hz, 1H), 6.70 (dd, J=8.0, 1.6 Hz, 2H), 6.63 (dd, J=8.0, 2.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 4.10~4.23 (m, 2H), 3.94~4.02 (m, 1H), 3.79~3.88 (m, 1H), 3.47~3.34 (m, 2H), 3.19~2.84 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.2, 162.8, 159.2, 145.4, 141.5, 139.5, 139.4, 138.4, 136.9, 134.3, 133.7, 133.0, 132.8, 132.7, 132.6, 132.2, 132.0, 132.0, 129.5, 128.5, 128.2, 128.0, 127.1, 120.9, 114.5, 66.3, 54.4, 35.3, 34.3, 33.7, 31.2; HRMS (ESI) calcd for C31H26Cl- N2O4S [M＋H]＋ 577.1296, found 557.1300.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基肉桂酸酯(3dp): 白色固体, 56.4 mg, 产率49%. m.p. 189.2~190.0 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.00 (s, 1H), 8.97 (d, J=9.2 Hz, 1H), 7.74 (d, J=16.0 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.49~7.36 (m, 6H), 7.18 (dd, J=8.0, 2.0 Hz, 1H), 6.81 (dd, J=8.0, 2.0 Hz, 1H), 6.73~6.61 (m, 3H), 6.56~6.48 (m, 2H), 4.16~4.27 (m, 2H), 3.94~4.03 (m, 1H), 3.83~3.92 (m, 1H), 3.44~3.31 (m, 2H), 3.20~2.84 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.5, 164.2, 162.9, 146.5, 145.6, 141.0, 139.5, 139.5, 138.3, 136.8, 133.9, 132.7, 132.7, 132.2, 132.1, 132.1, 130.8, 129.5, 128.9, 128.8, 128.3, 128.2, 127.3, 121.0, 116.9, 114.7, 66.4, 54.5, 35.3, 34.4, 33.7, 31.0; HRMS (ESI) calcd for C35H30ClN2O4 [M＋H]＋ 577.1889, found 577.1892.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-甲基肉桂酸酯(3dq): 白色固体, 64.9 mg, 产率53%. m.p. 172.8~173.7 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.99 (s, 1H), 8.97 (d, J=9.2 Hz, 1H), 7.75~7.66 (m, 2H), 7.44 (dd, J=9.2, 2.4 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.23~7.17 (m, 3H), 6.81 (dd, J=8.0, 2.0 Hz, 1H), 6.73~6.60 (m, 3H), 6.52 (d, J=8.0 Hz, 1H), 6.47 (d, J=16 Hz, 1H), 4.15~4.26 (m, 2H), 3.95~4.03 (m, 1H), 3.96~3.83 (m, 1H), 3.44~3.31 (m, 2H), 3.20~2.84 (m, 6H), 2.41 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 165.6, 164.3, 162.9, 146.5, 145.6, 141.3, 141.0, 139.5, 138.4, 136.8, 132.8, 132.6, 132.6, 132.2, 132.1, 132.0, 131.2, 129.7, 129.5, 128.8, 128.3, 128.2, 127.3, 121.0, 115.7, 114.7, 66.4, 54.5, 35.3, 34.4, 33.7, 31.0, 21.5; HRMS (ESI) calcd for C36H31ClN2NaO4 [M＋Na]＋ 613.1865, found 613.1870.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-甲氧基肉桂酸酯(3dr): 白色固体,67.9 mg, 产率56%. m.p. 176.1~176.8 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.96 (s, 1H), 8.95 (d, J=9.0 Hz, 1H), 7.70~7.61 (m, 2H), 7.42 (dd, J=9.2, 2.4 Hz, 1H), 7.38~7.32 (m, 2H), 7.16 (dd, J=8.0, 2.0 Hz, 1H), 6.93~6.85 (m, 2H), 6.78 (dd, J=8.0, 2.0 Hz, 1H), 6.71~6.58 (m, 3H), 6.49 (d, J=8.0 Hz, 1H), 6.35 (d, J=16 Hz, 1H), 4.28~4.11 (m, 2H), 4.05~3.93 (m, 1H), 3.85 (s, 4H), 3.42~3.28 (m, 2H), 3.18~2.81 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.6, 164.4, 162.9, 161.8, 146.2, 145.7, 140.9, 139.5, 139.5, 138.4, 136.8, 132.8, 132.6, 132.5, 132.1, 132.1, 132.0, 130.0, 129.5, 128.8, 128.3, 127.2, 126.7, 121.0, 114.8, 114.4, 114.2, 66.4, 55.4, 54.5, 35.3, 34.4, 33.6, 31.0; HRMS (ESI) calcd for C36H32- ClN2O5 [M＋H]＋ 607.1994, found 607.1997.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基4-氯肉桂酸酯(3ds): 白色固体, 50.0 mg, 产率41%. m.p. 177.4~178.2 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.97 (s, 1H), 8.94 (d, J=9.2 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.42 (dd, J=9.2, 2.4 Hz, 1H), 7.39~7.30 (m, 4H), 7.15 (dd, J=8.0, 2.0 Hz, 1H), 6.77 (dd, J=8.0, 2.0 Hz, 1H), 6.71~6.58 (m, 3H), 6.50 (d, J=7.8 Hz, 1H), 6.46 (d, J=16.0 Hz, 1H), 4.29~4.14 (m, 2H), 4.03~3.80 (m, 2H), 3.40~3.28 (m, 2H), 3.17~2.82 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 165.5, 163.9, 162.9, 145.5, 145.0, 141.0, 139.5, 139.4, 138.3, 136.8, 136.8, 132.7, 132.7, 132.4, 132.2, 132.1, 129.5, 129.3, 129.2, 128.8, 127.3, 121.0, 117.5, 114.7, 66.4, 54.5, 35.3, 34.4, 33.6, 30.9; HRMS (ESI) calcd for C35H29Cl2N2O4 [M＋H]＋ 611.1499, found 611.1499.
4-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷-4-基特戊酸酯(3dt): 白色固体, 39.22 mg, 产率37%. m.p. 175.1~175.9 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 11.88 (s, 1H), 8.97 (d, J=9.2 Hz, 1H), 7.82 (d, J=2.4 Hz, 1H), 7.48 (dd, J=9.2, 2.4 Hz, 1H), 7.21 (dd, J=8.0, 2.0 Hz, 1H), 6.76 (dd, J=8.0, 2.0 Hz, 1H), 6.65 (dd, J=7.6, 5.6 Hz, 2H), 6.59 (dd, J=7.6, 2.0 Hz, 1H), 6.51 (d, J=8.0 Hz, 1H), 4.35~4.21 (m, 2H), 4.06~3.82 (m, 2H), 3.41~3.24 (m, 2H), 3.10~2.97 (m, 3H), 2.97~2.76 (m, 3H), 1.22 (s, 9H); 13C NMR (100 MHz, Chloroform-d) δ: 175.6, 165.4, 162.7, 145.8, 140.9, 139.5, 139.2, 138.4, 136.8, 132.9, 132.3, 132.3, 132.2, 132.1, 132.0, 129.5, 128.8, 128.4, 127.3, 120.9, 114.6, 66.4, 54.6, 39.0, 35.2, 34.3, 33.4, 30.8, 27.1; HRMS (ESI) calcd for C31H32ClN2O4 [M＋H]＋ 531.2045, found 531.2047.

3.2.2 克级反应的制备方法

将1d (1.0 g, 2.3 mmol)、对甲基苯甲酸(625.6 mg, 4.6 mmol, 2.0 equiv.)、氯化亚铜(CuCl, 45.5 mg, 0.46 mmol, 20 mol%)、碳酸银(Ag2CO3, 1268.5 mg, 4.6 mmol, 2.0 equiv.)、甲苯(15 mL)和DMF (5 mL)依次加入125 mL带四氟旋塞的耐压反应瓶. 将反应瓶置于130 ℃油浴中反应24 h. 冷却至室温后, 加入饱和食盐水(100 mL), 用乙酸乙酯(20 mL)萃取, 水相再用乙酸乙酯(10 mL×3)萃取. 合并所有有机相, 经无水硫酸镁干燥并过滤, 旋蒸除去溶剂. 通过石油醚/乙酸乙酯柱层析分离, 获得克级规模的目标化合物700.5 mg, 产率为54%.

3.2.3 开环产物的制备方法

在50 mL圆底烧瓶中依次加入反应产物3da (113.0 mg, 0.2 mmol)、AlCl3 (52.4 mg, 0.4 mmol, 2.0 equiv.)、水(18.0 mg, 1.0 mmol, 5.0 equiv.)以及THF (2 mL). 在室温条件下反应0.5 h. 用TCL监测, 反应结束后, 向体系中加入碳酸氢钠的饱和溶液(10 mL)淬灭反应, 用乙酸乙酯(10 mL×3)萃取, 合并有机层, 无水硫酸镁干燥, 经硅藻土垫过滤并浓缩后, 通过石油醚/乙酸乙酯(V∶V=5∶1)柱层析分离, 得到开环产物4-[N-(4-氯-2-((2-氯乙基)-氨基甲酰基)-苯基)-氨基甲酰基][2,2]对环芳烷- 4-基4-甲基苯甲酸酯(4), 黄色油状物, 108.1 mg, 产率90%; 1H NMR (500 MHz, Chloroform-d) δ: 10.40 (s, 1H), 8.63 (d, J=9.0 Hz, 1H), 8.07 (d, J=8.3 Hz, 2H), 7.38 (dd, J=9.0, 2.5 Hz, 1H), 7.32 (d, J=2.5 Hz, 1H), 7.23~7.25 (d, J=2.5 Hz, 2H), 7.11 (dd, J=8.0, 2.0 Hz, 1H), 6.97 (dd, J=8.0, 2.0 Hz, 1H), 6.67~6.63 (m, 2H), 6.60 (dd, J=8.0, 2.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 6.40 (s, 1H), 3.59~3.63 (m, 4H), 3.36~3.22 (m, 2H), 3.12~2.95 (m, 5H), 2.84~2.76 (m, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 167.5, 165.2, 165.0, 145.8, 145.0, 140.9, 139.6, 139.4, 137.2, 137.2, 133.1, 133.0, 132.8, 132.5, 132.3, 131.9, 130.3, 129.9, 129.5, 129.1, 128.3, 126.9, 126.0, 122.9, 122.4, 43.3, 41.6, 35.3, 34.5, 33.5, 30.8, 21.8; HRMS (ESI) calcd for C34H30Cl2N2NaO4 [M＋Na]＋ 623.1475, found 623.1474.

3.2.4 水解产物的制备方法

在35 mL耐压反应管中依次加入反应产物3da (113.0 mg, 0.2 mmol)、碳酸钾(K2CO3, 110.4 mg, 0.8 mmol, 4.0 equiv.)、水(18.0 mg, 1.0 mmol, 5.0 equiv.)以及甲醇(5 mL). 反应管在预热的120 ℃平行反应模块中反应4 h. 反应液冷却后, 先旋蒸除去甲醇, 加入饱和食盐水(10 mL), 用乙酸乙酯(10 mL×3)萃取. 合并有机层, 用无水硫酸镁干燥, 经硅藻土垫过滤并浓缩, 通过石油醚/乙酸乙酯柱层析分离, 得到酯水解产物4-羟基- 5-[N-(4-氯-2-(4,5-二氢噁唑-2-基)苯基)氨基甲酰基][2,2]对环芳烷(5), 白色固体, 71.7 mg, 产率87%. m.p. 199.6~200.5 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 12.71 (s, 1H), 11.38 (s, 1H), 8.81 (dd, J=8.4, 1.2 Hz, 1H), 7.90 (dd, J=8.0, 1.6 Hz, 1H), 7.53~7.58 (m, 1H), 7.20~7.08 (m, 2H), 6.59~6.64 (m, 2H), 6.53 (d, J=7.6 Hz, 1H), 6.48 (dd, J=8.0, 2.0 Hz, 1H), 6.36 (d, J=7.6 Hz, 1H), 4.30~4.43 (m, 2H), 3.97~4.13 (m, 2H), 3.80~3.87 (m, 1H), 3.41~3.49 (m, 1H), 3.17~3.24 (m, 1H), 3.10~2.96 (m, 2H), 2.86~2.94 (m, 1H), 2.76~2.84 (m, 1H), 2.53~2.61 (m, 1H); 13C NMR (100 MHz, Chloroform- d) δ: 169.7, 164.4, 159.8, 140.0, 139.4, 139.3, 138.0, 138.0, 132.9, 132.5, 131.9, 131.3, 129.4, 128.7, 127.7, 127.4, 122.9, 120.3, 119.3, 114.0, 66.3, 54.5, 36.3, 35.3, 33.9, 30.3; HRMS (ESI) calcd for C26H24N2NaO3 [M＋Na]＋ 435.1679, found 435.1684.
辅助材料(Supporting Information) 化合物3aa~3dt、4、5的核磁共振氢谱和碳谱图. 这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.
(Cheng, F.)

参考文献

原文顺序 | 文献年度倒序 | 文中引用次数倒序
[1]
(a) Brown, C. J.; Farthing, A. C. Nature 1949, 164, 915.

(b) Cram, D. J.; Steinberg, H. J. Am. Chem. Soc. 1951, 73, 5691.

(c) Wu, S.; Felder, S.; Brom, J.; Pointillart, F.; Maury, O.; Micouin, L.; Benedetti, E. Adv. Optical Mater. 2024, 12, 2400934.

[2]
(a) Morisaki, Y.; Chujo, Y. Angew. Chem., Int. Ed. 2006, 45, 6430.

(b) Morisaki, Y.; Gon, M.; Chujo, Y. Polym. Chem. 2013, 51, 2311.

(c) Morisaki, Y.; Gon, M.; Sasamori, T.; Tokitoh, N.; Chujo, Y. J. Am. Chem. Soc. 2014, 136, 3350.

(d) Cakici, M.; Gu, Z. G.; Nieger, M.; Bürck, J.; Heinke, L.; Bräse, S. Chem. Commun. 2015, 51, 4796.

[3]
(a) Chinchilla, R.; Najera, C. Chem. Rev. 2014, 114, 1783.

(b) Zhang, Y.; Zheng, J.; Cui, S. L. J. Org. Chem. 2014, 79, 6490.

(c) Zhang, X. S.; Chen, K.; Shi, Z. J. Chem. Sci. 2014, 5, 2146.

(d) Ilies, L.; Arslanoglu, Y.; Matsubara, T.; Nakamura, E. Asian J. Org. Chem. 2018, 7, 1327.

(e) Zu, C.; Zhang, T.; Yang, F.; Wu, Y. S.; Wu, Y. J. J. Org. Chem. 2020, 85, 12777.

[4]
(a) Bräse, S.; Dahmen, S.; Höfener, S.; Lauterwasser, F.; Kreis, M.; Ziegert, R. E. Synlett 2004, 2004, 2647.

(b) Rowlands, G. J. Org. Biomol. Chem. 2008, 6, 1527.

(c) Paradies, J. Synthesis 2011, 2011, 3749.

(d) Hassan, Z.; Spuling, E.; Knoll, D. M.; Lahann, J.; Bräse, S. Chem. Soc. Rev. 2018, 47, 6947.

(e) Felder, S.; Wu, S.; Brom, J.; Micouin, L.; Benedetti, E. Chirality 2021, 33, 506.

(f) Liang, H.; Guo, W.; Li, J. X.; Jiang, J. J.; Wang, J. Angew. Chem., Int. Ed. 2022, 61, e202204926.

[5]
(a) Cram, D. J.; Allinger, N. L. J. Am. Chem. Soc. 1955, 77, 6289.

(b) Glover, J. E.; Martin, D. J.; Plieger, P. G.; Rowlands, G, J. Eur. J. Org. Chem. 2013, 2013, 1671.

(c) Vincent, A.; Deschamps, D.; Martzel, T.; Lohier, J. F.; Richards, C. J.; Gaumont, A. C.; Perrio, S. J. Org. Chem. 2016, 81, 3961.

(d) Gibson, S. E.; Knight, J. D. Org. Biomol. Chem. 2003, 1, 1256.

[6]
Lennartz, P.; Raabe, G.; Bolm, C. Adv. Synth. Catal. 2012, 354, 3237.

[7]
Kramer, J. P.; Yildiz, C.; Nieger, M.; Bräse, S. Eur. J. Org. Chem. 2014, 2014, 1287.

[8]
Delcourt, M. L.; Reynaud, C.; Turcaud, S.; Favereau, L.; Crassous, J.; Micouin, L.; Benedetti, E. J. Org. Chem. 2019, 84, 888.

[9]
Pu, J.; Chen, L.; Wu, R. R.; Ye, P.; Li, H. L.; Wang, S.; Xu, Z. Y.; Lou, S. J.; Xu, D. Q. Chem. Commun. 2023, 59, 9348.

[10]
(a) Li, J. M.; Wang, Y. H.; Yu, Y.; Wu, R. B.; Weng, J.; Lu, G. ACS Catal. 2017, 7, 2661.

(b) Aneeja, T.; Neetha, M.; Afsina, C. M. A.; Anilkumar, G. RSC Adv. 2020, 10, 34429.

(c) Zhang, Q.; Tong, S.; Wang, M. X. Acc. Chem. Res. 2022, 55, 2796.

(d) Moniwa, H.; Shintani, R. Org. Lett. 2025, 27, 1763.

(e) Shang, M.; Wang, H. L.; Sun, S. Z.; Dai, H. X.; Yu, J. Q. J. Am. Chem. Soc. 2014, 136, 11590.

(f) Li, J. J.; Wang, C. G.; Yu, J. F.; Wang, P.; Yu, J. Q. Org. Lett. 2020, 22, 4692.

(g) Kuang, X.; Li, J. J.; Liu, T.; Ding, C. H.; Wu, K.; Wang, P.; Yu, J. Q. Nat Commun. 2023, 14, 7698.

(h) Shang, M.; Sun, S. Z.; Dai, H. X.; Yu, J. Q. J. Am. Chem. Soc. 2014, 136, 3354.

(i) Mei, M. S.; Zhang, Y. H. Chin. J. Org. Chem. 2024, 44, 3263 (in Chinese).

(梅明顺, 张扬会, 有机化学, 2024, 44, 3263.)

(j) Shen, J. B.; Shen, C.; Zhang, P. F. Chin. J. Org. Chem. 2025, 45, 677 (in Chinese).

(沈佳斌, 沈超, 章鹏飞, 有机化学, 2025, 45, 677.)

[11]
Song, H.; Li, Y.; Yao, Q. J.; Shi, B. F. Org. Chem. Front. 2022, 9, 4823.

[12]
Huang, F. R.; Teng, M. Y.; Qiu, H.; Yao, Q. J.; Shi, B. F. Angew. Chem., Int. Ed. 2025, 64, e202506465.

[13]
(a) Xu, J.; Zhang, J. Y.; Wang, Z. X.; Li, J.; Shen, J. B.; Zhang, P. F. Org. Lett. 2026, 28, 2777.

(b) Zheng, K.; Chen, C.; Xu, H.; Mao, J. G.; Shen, C. J. Org. Chem. 2025, 90, 15567.

[14]
(a) Wang, T.; Wang, X. S.; Song, Y. W.; Huo, J. J.; Kang, J. S.; Kang, Q. W.; Liu, L. T. Chin. J. Org. Chem. 2021, 41, 1098 (in Chinese).

(王涛, 王晓莎, 宋雅雯, 霍晶晶, 周敬栓, 康庆伟, 刘澜涛, 有机化学, 2021, 41, 1098.)

(b) Xu, L. P.; Haines, B. E.; Ajitha, M. J.; Yu, J. Q.; Musaev, D. G. ACS Catal. 2021, 11, 12620.

(c) Shang, M.; Sun, S. Z.; Wang, H. L.; Wang, M. M.; Dai, H. X. Synthesis 2016, 48, 4381.

(d) Tan, M.; Gu, Y.; Luo, X. J.; Zhang, P. Chin. J. Org. Chem. 2015, 35, 781 (in Chinese).

(谭明雄, 顾运琼, 罗旭健, 张培, 有机化学, 2015, 35, 781.)

(e) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744.

[15]
(a) Li, Z.; Yu, H.; Bolm, C. Angew. Chem., Int. Ed. 2017, 56, 9532.

(b) Xu, L. L.; Wang, X.; Ma, B.; Yin, M. X.; Li, H. X.; Dai, H. X.; Yu, J. Q. Chem. Sci. 2018, 9, 5160.

Options
文章导航

/

〈 〉