Zn/Y双金属接力催化:一锅法分子内环异构化/分子间阿尔德-烯反应构建α-羟基酰胺噁唑衍生物

张硕 楼建芳 王佳睿 宋子贺 彭丹 王峰 闫志旺 崔仕麒 刘一帆 牟秋红 李金辉

引用本文: 张硕, 楼建芳, 王佳睿, 宋子贺, 彭丹, 王峰, 闫志旺, 崔仕麒, 刘一帆, 牟秋红, 李金辉. Zn/Y双金属接力催化:一锅法分子内环异构化/分子间阿尔德-烯反应构建α-羟基酰胺噁唑衍生物[J]. 有机化学, 2020, 40(3): 704-713. doi: 10.6023/cjoc201909002 shu
Citation:  Zhang Shuo, Lou Jianfang, Wang Jiarui, Song Zihe, Peng Dan, Wang Feng, Yan Zhiwang, Cui Shiqi, Liu Yifan, Mu Qiuhong, Li Jinhui. Zn/Y Bimetallic Relay Catalysis: One Pot Intramolecular Cyclo-isomerization/Intermolecular Alder-Ene Reaction toward Oxazole α-Hydroxy Amide Derivatives[J]. Chinese Journal of Organic Chemistry, 2020, 40(3): 704-713. doi: 10.6023/cjoc201909002 shu

Zn/Y双金属接力催化:一锅法分子内环异构化/分子间阿尔德-烯反应构建α-羟基酰胺噁唑衍生物

    通讯作者: Lou Jianfang, E-mail: wangma@cau.edu.cn
  • 基金项目:

    山东省自然科学基金(No.ZR2017BB033)、山东省科学院青年基金(No.2018QN0030)、国家自然科学基金(No.51503118)资助项目

摘要: 报道了一种新型的Zn/Y双金属接力催化的串联反应,该方法通过Zn(OTf)2和Y(OTf)3接力催化,一锅法进行分子内环异构化/分子间阿尔德-烯反应构建α-羟基酰胺噁唑衍生物.产物的形成主要是由Zn(OTf)2活化炔丙基酰胺的叁键发生分子内的环化反应构建噁唑啉中间体,由Y(OTf)3催化1-苄基吲哚啉-2,3-二酮类化合物,继而由噁唑啉中间体与1-苄基吲哚啉-2,3-二酮类化合物发生分子间阿尔德-烯反应,实现了α-羟基酰胺噁唑衍生物的合成.优化部分的对比实验证实,Zn(OTf)2和Y(OTf)3的存在对于该串联反应都是必须条件.所有反应都是将各反应物和试剂一次性加入,在空气氛围下100℃加热进行反应.该方法反应条件简单、原子经济性高、官能团兼容性好,对噁唑衍生物合成具有重要的意义.

English

  • 噁唑化合物是很多天然产物和药物分子的基本骨架, 具有丰富的生物活性和功能[1].此外, 噁唑分子作为保护基团[2]、导向基团[3]以及配体[4]广泛应用于有机合成中.因此, 对噁唑化合物的合成引起了化学家的广泛关注.

    现有的合成方法中, 过渡金属比如Au[5], Pd[6], Cu[7], Ag[8], Fe[9], Zn[10]等催化炔丙基酰胺的分子内环化反应是构建噁唑衍生物的最有吸引力的策略之一.该方法具有良好的官能团兼容性和较好的原子经济性.如2012年, Hashmi课题组[5d]发展了Au(Ⅰ)催化的炔丙基酰胺发生分子内环化生成噁唑啉中间体, 而后氧气氧化到氢过氧化物, 硼氢化钠还原得到相应的噁唑醇类化合物的方法; 2014年, Moran课题组[7b]发展了一个CuI催化环化端位炔丙酰胺合成噁唑啉的方法; 2015年, 徐政虎课题组[10a]发展了Zn(OTf)2作为π酸和ơ酸催化剂进行串联的环异构化/烯丙基烷基化反应合成噁唑类衍生物的方法. 2016年, 该课题组[10b]发展了由Zn(OTf)2作为π酸催化剂催化炔丙酰胺发生5-exo-dig亲核环化产生一个噁唑啉中间体, 然后与Sc(OTf)3活化的醛基亲电试剂发生羰基-烯反应, 实现了碳-碳键的构建, 合成了噁唑醇类化合物.

    阿尔德-烯反应是构建C—C键的有效策略[11], 在有机合成中具有重要的意义. Mikami小组[12]、Feng小组[13]、Nakai小组[14]和Evans小组[15]分别报道了乙醛酸酯的阿尔德-烯反应, 这类反应通常需要有高活性的反应物, 高温的反应条件或者合适的路易斯酸催化.但是寻找高效地催化阿尔德-烯反应的过渡金属催化剂仍然是一个巨大的挑战[16].

    双金属接力催化反应体系可以实现单一催化剂不能完成的反应, 拓展反应的类型和底物范围; 提高反应的活性和效率, 有利于控制反应的选择性; 而且能将多步反应缩减为一步完成, 避免很多中间体的分离纯化, 减少反应过程中的后处理物质消耗和废物排放, 提高反应的经济性和效率, 减少环境伤害, 因此双金属接力催化体系成为了近年来的研究热点[17].

    在此背景下, 发展了新型的Zn/Y双金属接力催化体系, 由Zn(Ⅱ)催化炔丙基酰胺分子内环化反应构建噁唑啉, 由Y(Ⅲ)活化1-苄基吲哚啉-2, 3-二酮类化合物, 继而由噁唑啉中间体与活化的1-苄基吲哚啉-2, 3-二酮类化合物发生分子间阿尔德-烯反应实现了α-羟基酰胺噁唑衍生物的合成.

    N-(2-炔-1-基)苯甲酰胺(1a)与1-苄基吲哚啉-2, 3-二酮(2a)为模板反应, Zn(OTf)2作为π酸催化剂催化炔丙基酰胺分子内环化反应, 其他路易斯酸作为另外一种催化剂, 令人高兴的是, 所试验的路易斯酸催化剂, 比如In(OTf)3、Y(OTf)3、Yb(OTf)3、La(OTf)3、Sc(OTf)3和Ni(ClO4)2•6H2O都可以得到目标产物3a, 其中以Y(OTf)3催化反应所得到的收率最高(表 1, Entries 1~6).而后考察了温度对反应的影响:反应温度降低至80 ℃, 反应收率降低至75%, 反应温度升高至120 ℃, 反应收率基本不变(表 1, Entries 6~8).控制实验表明, 反应需要Zn(OTf)2与Y(OTf)3同时催化时进行(表 1, Entries 9~10), 反应只单独使用Zn(OTf)2催化时收率只有27%, 反应只单独使用Y(OTf)3催化时, 薄层色谱分析显示没有检测到产物3a.随后对π酸催化剂进行了考察(表 1, Entries 11~12), 实验结果表明AgOTf和Cu(OTf)2都不能很好地催化反应的进行.紧接着对有不同极性的有机溶剂如甲苯(toluene)和乙腈(MeCN)分别作为介质进行了对比, 对比结果显示1, 2-二氯乙烷(DCE)仍然是最合适的反应介质(表 1, Entries 1, 13, 14).最终确定Zn(OTf)2和Y(OTf)3为共用的催化剂, DCE为溶剂, 反应温度为100 ℃是最优的反应条件.

    表 1

    表 1  反应条件优化a
    Table 1.  Optimization of reaction conditionsa
    下载: 导出CSV
    Entry Catalyst A Catalyst B Solvent Temp./℃ Yieldb/%
    1 Zn(OTf)2 In(OTf)3 DCE 100 25
    2 Zn(OTf)2 Y(OTf)3 DCE 100 87
    3 Zn(OTf)2 Yb(OTf)3 DCE 100 34
    4 Zn(OTf)2 La(OTf)3 DCE 100 28
    5 Zn(OTf)2 Sc(OTf)3 DCE 100 62
    6 Zn(OTf)2 Ni(ClO4)2•6H2O DCE 100 56
    7 Zn(OTf)2 Y(OTf)3 DCE 80 75
    8 Zn(OTf)2 Y(OTf)3 DCE 120 88
    9 Zn(OTf)2 DCE 100 27
    10 Y(OTf)3 DCE 100 0
    11 AgOTf Y(OTf)3 DCE 100 32
    12 Cu(OT)2 Y(OTf)3 DCE 100 28
    13 Zn(OTf)2 Y(OTf)3 Toluene 100 38
    14 Zn(OTf)2 Y(OTf)3 CH3CN 100 23
    General conditions: 1a (0.24 mmol), 2a (0.2 mmol), catalyst A (10 mol%), Catalyst B (10 mol%), solvent (2 mL), in sealed tube, overnight. b Isolated yield based on 2a.

    在确定了最优的反应条件后, 首先对不同的炔丙基酰胺(1)与1-苄基吲哚啉-2, 3-二酮(2a)之间的反应进行了考察(表 2).在最优条件下, 芳环上含有不同类型给电子取代基如烷基(3b, 3c)和甲氧基(3d), 含有不同富电子的芳环如呋喃环(3e)、噻吩环(3f)和萘环(3m), 含有不同吸电子取代基如硝基(3j)、氰基(3k)、卤素(3j~3i)和三氟甲基(3l), 烷基取代的炔丙基酰胺(3z)等均可以顺利地和2a反应得到相应的噁唑衍生物3.产率大多为良好到优秀.相比而言, 含有吸电子基团的炔丙基酰胺比含有给电子基团或富电子的炔丙基酰胺所得到的产物的收率要低一些, 这可能是因为含有吸电子基团的炔丙基酰胺所得到的烯基醚中间体M1活性较低, 因此相应的M12a反应时的收率较低.随后, 继续对不同的3-羟基- 2-苯甲基-异吲哚啉-1-酮类化合物参与的合成反应进行了研究.采用1-苄基-5-甲氧基吲哚啉-2, 3-二酮、1-苄基- 5-甲基吲哚啉-2, 3-二酮、1-苄基-5-硝基吲哚啉-2, 3-二酮、1-苄基-5-氯吲哚啉-2, 3-二酮、1-苄基-5-氟吲哚啉-2, 3-二酮、1-苄基-6-氯吲哚啉-2, 3-二酮、1-苄基-6-氟吲哚啉- 2, 3-二酮、1-苄基-7-氯吲哚啉-2, 3-二酮与1a进行反应, 均以良好到优秀的产率得到目标化合物3n~3u.其中, 2中含有吸电子取代基比含有给电子取代基所得到的相应的产物收率要高一些, 这可能是因为含有吸电子取代基的1-苄基吲哚啉-2, 3-二酮类化合物活性较高, 因此相应的反应收率较高. 1-(4-甲基)吲哚啉-2, 3-二酮、4-((2, 3-二氧代吲哚啉-1-基)甲基)苯甲腈、1-甲基吲哚啉-2, 3-二酮、1-异丙基吲哚啉-2, 3-二酮对反应同样表现出了良好的兼容性.

    表 2

    表 2  分子内环异构化/阿尔德-烯反应底物扩展
    Table 2.  Application scope of the intramolecular cycloisomerization/intermolecular Alder-ene reaction a
    下载: 导出CSV

    进行了控制实验对反应机理进行了研究:化合物1a在Zn(OTf)2催化条件下进行分子内环化反应, 以74%的收率顺利得到了噁唑啉中间体M1, M1在Y(OTf)3催化条件下与2a反应, 以73%的收率得到了预期的最终产物3a.根据控制实验的结果以及已有的文献报道[10], 提出了可能的反应机理:以模型反应为例, 该反应是由Zn(OTf)2和Y(OTf)3接力催化的一锅法分子内环异构化/分子间阿尔德-烯反应构建α-羟基酰胺噁唑衍生物. Zn(OTf)2活化化合物1a的叁键, 发生分子内的环化反应构建噁唑啉中间体M1, Y(OTf)3活化化合物2a, 继而由噁唑啉中间体M1与活化的化合物2a发生分子间阿尔德-烯反应实现了噁唑分子的合成.

    探索并建立了一种Zn(OTf)2和Y(OTf)3接力催化的分子内环异构化/分子间阿尔德-烯反应构建噁唑衍生物的合成方法.该方法由Zn(OTf)2活化化合物1a发生分子内的环化反应构建噁唑啉中间体, Y(OTf)3活化化合物2a, 继而由噁唑啉中间体与活化的化合物2a发生分子间阿尔德-烯反应, 实现了噁唑分子的合成.该方法反应条件简单、原子经济性高、对官能团兼容性好, 对噁唑衍生的合成具有重要的意义.

    Bruker AV400型核磁共振仪, 以CDCl3或DMSO-d6为溶剂, TMS为内标; Agilent Q-TOF 6510型高分辨质谱仪, 电喷雾离子化技术(ESI), 直接进样法进样.柱层析使用200~300目硅胶.

    在38 mL厚壁耐压瓶中加入炔丙基酰胺类化合物1 (0.24 mmol)、1-苄基吲哚啉-2, 3-二酮类化合物2 (0.2 mmol)、Zn(OTf)2 (7.2 mg, 10 mol%)、Y(OTf)3 (11.7 mg, 10 mol%)和1, 2-二氯乙烷(2.0 mL), 然后在100 ℃温度下封管搅拌反应过夜.反应停止后, 自然降温至室温, 而后向反应液中加入6 mL水, 再用二氯甲烷(6 mL×3)萃取, 有机相用无水Na2SO4干燥, 过滤后, 所得滤液旋蒸除去溶剂得到粗产品.粗产品经柱层析提纯得到目标化合物3.洗脱剂为石油醚和乙酸乙酯.薄层色谱(TLC)检测洗脱进程, 合并收集液并旋蒸除去洗脱剂得到相应的纯品, 计算收率.所有目标化合物的结构经核磁共振氢谱、碳谱以及高分辨质谱表征.

    1-苄基-3-羟基-3-[(2-苯基噁唑-5-基)甲基]吲哚啉-2-酮(3a):产率87%. 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, J=6.3 Hz, 2H), 7.51~7.27 (m, 4H), 7.19 (t, J=7.7 Hz, 1H), 7.16~7.05 (m, 4H), 7.04~6.91 (m, 2H), 6.73 (s, 1H), 6.60 (d, J=7.8 Hz, 1H), 4.94 (d, J=15.7 Hz, 1H), 4.62 (d, J=15.8 Hz, 1H), 4.32 (s, 1H), 3.51 (dd, J=31.7, 14.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.28, 142.54, 134.93, 130.16, 130.04, 129.24, 128.78, 128.67, 127.63, 127.20, 126.84, 126.10, 124.34, 123.32, 109.75, 75.67, 43.91, 34.87; HRMS (ESI) calcd for C25H21N2O3 [M+H]+ 397.1547, found 397.1548.

    图式 2

    图式 2.  控制实验及反应机理研究
    Scheme 2.  Control experiments and proposed reaction mechanism

    1-苄基-3-羟基-3-[(2-(间甲苯基)噁唑-5-基)甲基]吲哚啉-2-酮(3b):产率89%. 1H NMR (400 MHz, CDCl3) δ: 7.62~7.52 (m, 2H), 7.40 (d, J=7.2 Hz, 1H), 7.32~6.95 (m, 9H), 6.74 (s, 1H), 6.61 (d, J=7.7 Hz, 1H), 4.94 (d, J=15.7 Hz, 1H), 4.64 (d, J=15.7 Hz, 1H), 4.03 (s, 1H), 3.50 (dd, J=34.4, 14.6 Hz, 2H), 2.34 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 177.19, 161.52, 145.88, 142.58, 138.39, 134.94, 130.97, 130.06, 129.21, 128.79, 128.58, 127.63, 127.10, 126.85, 126.83, 126.71, 124.37, 123.29, 123.26, 109.75, 75.64, 43.92, 34.91, 21.29; HRMS (ESI) calcd for C26H23N2O3 [M+H]+ 411.1703, found 411.1703.

    1-苄基-3-羟基-3-((2-(邻甲苯基)噁唑-5-基)甲基)吲哚啉-2-酮(3c):产率90%. 1H NMR (400 MHz, CDCl3) δ: 7.63 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.0 Hz, 1H), 7.25 (t, J=7.0 Hz, 1H), 7.20~7.04 (m, 7H), 7.00 (dd, J=6.0, 2.3 Hz, 2H), 6.78 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 4.94 (d, J=15.8 Hz, 1H), 4.60 (d, J=15.8 Hz, 2H), 3.52 (q, J=14.6 Hz, 2H), 2.42 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 177.45, 161.83, 145.64, 142.52, 137.18, 134.94, 131.47, 130.00, 129.78, 129.33, 128.77, 128.75, 128.72, 127.63, 126.86, 126.67, 126.24, 126.24, 125.84, 124.37, 123.42, 109.79, 75.79, 43.90, 34.77, 21.79; HRMS (ESI) calcd for C26H23N2O3 [M+H]+ 411.1703, found 411.1704.

    1-苄基-3-羟基-3-((2-(4-甲氧基苯基)噁唑-5-基)甲基)吲哚啉-2-酮(3d):产率89%. 1H NMR (400 MHz, CDCl3) δ: 7.68 (d, J=8.8 Hz, 2H), 7.39 (d, J=7.2 Hz, 1H), 7.17 (t, J=7.7 Hz, 1H), 7.09 (dt, J=9.8, 4.4 Hz, 4H), 7.02~6.95 (m, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.64 (s, 1H), 6.58 (d, J=7.8 Hz, 1H), 4.93 (d, J=15.8 Hz, 1H), 4.60 (d, J=15.8 Hz, 2H), 3.81 (s, 3H), 3.48 (dd, J=31.8, 14.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.38, 161.40, 161.19, 145.43, 142.54, 134.96, 129.95, 129.39, 128.77, 127.77, 127.60, 126.81, 126.56, 124.35, 123.26, 120.05, 114.08, 109.71, 75.70, 55.35, 43.87, 34.84; HRMS (ESI) calcd for C26H23N2O4 [M+H]+ 427.1652, found 427.1650.

    1-苄基-3-((2-(呋喃-2-基)噁唑-5-基)甲基)-3-羟基吲哚啉-2-酮(3e):产率92%. 1H NMR (400 MHz, CDCl3) δ: 7.47 (d, J=0.8 Hz, 1H), 7.34 (d, J=7.3 Hz, 1H), 7.21~7.11 (m, 4H), 7.06 (dd, J=8.4, 4.8 Hz, 3H), 6.74 (d, J=3.2 Hz, 1H), 6.71 (s, 1H), 6.63 (d, J=7.8 Hz, 1H), 6.44 (dd, J=3.4, 1.7 Hz, 1H), 4.94 (d, J=15.7 Hz, 1H), 4.66 (d, J=15.7 Hz, 1H), 4.28 (dd, J=23.8, 17.0 Hz, 1H), 3.46 (dd, J=42.4, 14.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.20, 154.12, 145.75, 144.20, 142.71, 142.47, 135.00, 130.06, 129.05, 128.80, 127.69, 126.95, 126.66, 124.32, 123.32, 111.72, 111.21, 109.72, 75.48, 43.93, 34.68; HRMS (ESI) calcd for C23H19N2O4 [M+H]+ 387.1339, found 387.1340.

    1-苄基-3-羟基-3-((2-(噻吩-2-基)噁唑-5-基)甲基)吲哚啉-2-酮(3f):产率93%. 1H NMR (400 MHz, CDCl3) δ: 7.36 (ddd, J=13.0, 12.4, 6.1 Hz, 3H), 7.22~7.05 (m, 5H), 7.05~6.97 (m, 3H), 6.66 (s, 1H), 6.61 (d, J=7.8 Hz, 1H), 4.95 (d, J=15.7 Hz, 1H), 4.63 (d, J=15.7 Hz, 1H), 4.43 (s, 1H), 3.47 (dd, J=34.2, 14.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.29, 157.52, 145.66, 142.50, 134.96, 130.06, 129.75, 129.20, 128.79, 128.06, 127.85, 127.66, 127.54, 126.88, 126.76, 124.37, 123.33, 109.74, 75.61, 43.93, 34.75; HRMS (ESI) calcd for C23H19N2O3S [M+H]+ 403.1111, found 403.1112.

    1-苄基-3-((2-(3-氟苯基)噁唑-5-基)甲基)-3-羟基吲哚啉-2-酮(3g):产率80%. 1H NMR (400 MHz, CDCl3) δ: 7.54 (d, J=7.7 Hz, 1H), 7.35 (ddd, J=21.6, 14.5, 7.5 Hz, 3H), 7.21 (t, J=7.6 Hz, 1H), 7.17~6.92 (m, 7H), 6.76 (s, 1H), 6.63 (d, J=7.7 Hz, 1H), 4.96 (d, J=15.7 Hz, 1H), 4.62 (d, J=15.7 Hz, 1H), 4.26 (s, 1H), 3.51 (q, J=14.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.18, 162.80 (d, J=244.8 Hz), 160.16 (d, J=3.2Hz), 146.51, 142.53, 134.91, 130.36 (d, J=8 Hz), 130.15, 129.19, 129.10, 128.78, 127.66, 127.12, 126.84, 124.33, 123.39, 121.77 (d, J=2.9 Hz), 117.10 (d, J21.2 Hz), 113.04 (d, J=23.8 Hz), 109.78, 75.63, 43.92, 34.88; 19F NMR (376 MHz, CDCl3) δ: -112.27; HRMS (ESI) calcd for C25H20FN2O3 [M+H]+ 415.1452, found 415.1453.

    1-苄基-3-((2-(3-氯苯基)噁唑-5-基)甲基)-3-羟基吲哚啉-2-酮(3h):产率82%. 1H NMR (400 MHz, CDCl3) δ: 7.64 (d, J=7.4 Hz, 2H), 7.42 (d, J=7.2 Hz, 1H), 7.35~7.21 (m, 3H), 7.17~7.05 (m, 4H), 7.05~6.97 (m, 2H), 6.78 (s, 1H), 6.64 (d, J=7.8 Hz, 1H), 4.96 (d, J=15.7 Hz, 1H), 4.62 (d, J=15.7 Hz, 1H), 4.19~3.77 (m, 1H), 3.50 (q, J=14.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.09, 159.97, 146.53, 142.55, 134.91, 134.74, 130.22, 130.11, 129.97, 129.16, 128.79, 127.67, 127.12, 126.86, 126.11, 124.34, 124.09, 123.40, 109.78, 75.61, 43.93, 34.92; HRMS (ESI) calcd for C25H19ClN2O3 [M+H]+ 430.1084, found 430.1085.

    1-苄基-3-((2-(4-溴苯基)噁唑-5-基)甲基)-3-羟基吲哚啉-2-酮(3i):产率83%. 1H NMR (400 MHz, CDCl3) δ: 7.57 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.39 (d, J=7.2 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 7.09 (dd, J=7.4, 4.2 Hz, 4H), 7.02~6.91 (m, 2H), 6.72 (s, 1H), 6.60 (d, J=7.8 Hz, 1H), 4.94 (d, J=15.7 Hz, 1H), 4.59 (d, J=15.7 Hz, 2H), 3.49 (q, J=14.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.30, 160.45, 146.42, 142.51, 134.89, 131.92, 130.06, 129.31, 128.78, 127.68, 127.52, 127.04, 126.81, 126.06, 124.61, 124.33, 123.35, 109.75, 75.65, 43.90, 34.85; HRMS (ESI) calcd for C25H20BrN2O3 [M+H]+ 475.0652, found 475.0652.

    1-苄基-3-羟基-3-((2-(2-硝基苯基)噁唑-5-基)甲基)吲哚啉-2-酮(3j):产率78%. 1H NMR (400 MHz, CDCl3) δ: 7.75~7.67 (m, 1H), 7.66~7.59 (m, 1H), 7.53 (p, J=6.6 Hz, 2H), 7.32 (d, J=7.2 Hz, 1H), 7.25~7.05 (m, 7H), 6.84 (s, 1H), 6.67 (d, J=7.8 Hz, 1H), 4.92 (d, J=15.7 Hz, 1H), 4.74 (d, J=15.7 Hz, 1H), 3.91 (s, 1H), 3.44 (dd, J=50.8, 14.9 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.00, 156.67, 148.40, 147.73, 142.41, 135.08, 131.89, 130.76, 130.11, 130.09, 128.88, 128.83, 127.72, 127.46, 127.06, 124.35, 123.74, 123.46, 120.83, 109.79, 75.34, 43.93, 34.61; HRMS (ESI) calcd for C25H20N3O5 [M+H]+ 442.1397, found 442.1397.

    4-(5-[(1-苄基-3-羟基-2-氧代吲哚啉-3-基)甲基]噁唑-2-基)苯甲腈(3k):产率80%. 1H NMR (400 MHz, CDCl3) δ: 7.79 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.41 (d, J=7.2 Hz, 1H), 7.23 (dd, J=11.2, 4.3 Hz, 1H), 7.17~7.02 (m, 4H), 7.02~6.94 (m, 2H), 6.83 (s, 1H), 6.64 (d, J=7.8 Hz, 1H), 4.97 (d, J=15.7 Hz, 1H), 4.60 (d, J=15.7 Hz, 1H), 4.43 (s, 1H), 3.52 (q, J=14.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.16, 159.43, 147.50, 142.50, 134.87, 132.49, 130.85, 130.17, 129.20, 128.79, 127.69, 127.68, 126.82, 126.37, 124.30, 123.44, 118.30, 113.35, 109.80, 75.59, 43.92, 34.88; HRMS (ESI) calcd for C26H20N3O3 [M+H]+ 422.1499, found 422.1499.

    1-苄基-3-羟基-3-((2-(3-(三氟甲基)苯基)噁唑-5-基)甲基)吲哚啉-2-酮(3l):产率76%. 1H NMR (400 MHz, CDCl3) δ: 7.90 (d, J=7.8 Hz, 1H), 7.80 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.3 Hz, 2H), 7.22 (t, J=7.7 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.06 (dd, J=4.9, 1.3 Hz, 3H), 6.99~6.92 (m, 2H), 6.81 (s, 1H), 6.63 (d, J=7.8 Hz, 1H), 4.95 (d, J=15.7 Hz, 1H), 4.72 (s, 1H), 4.57 (d, J=15.7 Hz, 1H), 3.68~3.41 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.30, 159.86, 146.83, 142.49, 134.89, 131.18 (q, J=32.5 Hz), 130.16, 129.41, 129.22, 129.09, 128.75, 127.88, 127.60, 127.15, 126.84, 126.53 (q, J=3.6 Hz), 125.07, 124.37, 123.42, 122.91 (q, J=3.8 Hz), 109.73, 75.73, 43.9, 34.9; 19F NMR (376 MHz, CDCl3) δ: -62.82; HRMS (ESI) calcd for C26H20F3N2O3 [M+H]+ 465.1421, found 465.1422.

    1-苄基-3-羟基-3-((2-(萘-1-基)噁唑-5-基)甲基)吲哚啉-2-酮(3m):产率91%. 1H NMR (400 MHz, CDCl3) δ: 8.99 (d, J=8.4 Hz, 1H), 7.84 (t, J=8.2 Hz, 2H), 7.76 (d, J=7.3 Hz, 1H), 7.58~7.41 (m, 3H), 7.37 (t, J=7.8 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.07~6.93 (m, 5H), 6.89 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 4.92 (d, J=15.8 Hz, 1H), 4.75 (s, 1H), 4.61 (d, J=15.8 Hz, 1H), 3.58 (q, J=14.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.57, 161.37, 145.88, 142.54, 134.90, 133.84, 130.99, 130.02, 129.96, 129.39, 128.78, 128.73, 128.46, 127.75, 127.60, 127.49, 126.96, 126.86, 126.82, 126.19, 126.15, 124.90, 124.44, 123.70, 123.45, 109.84, 75.89, 43.93, 34.86; HRMS (ESI) calcd for C29H23N2O3 [M+H]+447.1703, found 447.1705.

    1-苄基-3-羟基-5-甲氧基-3-[(2-苯基噁唑-5-基)甲基]吲哚啉-2-酮(3n):产率82%. 1H NMR (400 MHz, CDCl3) δ: 7.76 (dd, J=7.6, 1.6 Hz, 2H), 7.45~7.29 (m, 3H), 7.08 (dd, J=5.0, 1.7 Hz, 3H), 7.05~6.95 (m, 3H), 6.74 (s, 1H), 6.68 (dd, J=8.5, 2.5 Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 5.17~4.79 (m, 2H), 4.57 (d, J=15.7 Hz, 1H), 3.70 (s, 3H), 3.58~3.39 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.28, 161.30, 156.51, 146.15, 135.70, 135.02, 130.66, 130.17, 128.75, 128.66, 127.58, 127.18, 126.85, 126.12, 114.63, 111.33, 110.31, 76.07, 55.82, 43.98, 34.92; HRMS (ESI) calcd for C26H23N2O4 [M+H]+ 427.1652, found 427.1652.

    1-苄基-3-羟基-5-甲基-3-((2-苯基噁唑-5-基)甲基)吲哚啉-2-酮(3o):产率85%. 1H NMR (400 MHz, CDCl3) δ: 7.83~7.69 (m, 2H), 7.42~7.30 (m, 3H), 7.07 (dd, J=10.1, 5.1 Hz, 3H), 7.04~6.90 (m, 3H), 6.75 (s, 1H), 6.68 (dd, J=8.5, 2.5 Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 4.90 (d, J=15.8 Hz, 2H), 4.58 (d, J=15.7 Hz, 1H), 3.71 (s, 3H), 3.51 (q, J=14.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.26, 161.31, 156.52, 146.13, 135.71, 135.01, 130.63, 130.17, 128.75, 128.66, 127.59, 127.19, 126.89, 126.85, 126.12, 114.64, 111.33, 110.31, 76.07, 55.82, 43.99, 34.93; HRMS (ESI) calcd for C26H23N2O3 [M+H]+ 411.1703, found 411.1704.

    1-苄基-3-羟基-5-硝基-3-[(2-苯基噁唑-5-基)甲基]吲哚啉-2-酮(3p):产率92%. 1H NMR (400 MHz, CDCl3) δ: 8.35 (d, J=2.1 Hz, 1H), 8.10 (dd, J=8.7, 2.1 Hz, 1H), 7.68 (d, J=6.9 Hz, 2H), 7.36 (tt, J=14.2, 7.1 Hz, 3H), 7.17~7.03 (m, 3H), 6.96 (d, J=6.6 Hz, 2H), 6.82 (s, 1H), 6.64 (d, J=8.7 Hz, 1H), 5.13 (d, J=13.9 Hz, 1H), 4.95 (d, J=15.8 Hz, 1H), 4.64 (d, J=15.8 Hz, 1H), 3.64~3.45 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.47, 161.73, 148.06, 145.13, 143.87, 133.79, 130.58, 130.49, 129.06, 128.81, 128.14, 127.24, 126.86, 126.77, 126.63, 126.03, 120.35, 109.48, 75.22, 44.26, 34.68; HRMS (ESI) calcd for C25H20N3O5 [M+H]+ 442.1397, found 442.1398.

    1-苄基-5-氯-3-羟基-3-[(2-苯基噁唑-5-基)甲基]吲哚啉-2-酮(3q):产率89%. 1H NMR (400 MHz, CDCl3) δ: 7.84~7.61 (m, 2H), 7.44 (d, J=1.4 Hz, 1H), 7.37 (d, J=6.2 Hz, 3H), 7.19~7.03 (m, 4H), 6.97 (d, J=5.1 Hz, 2H), 6.80 (s, 1H), 6.49 (d, J=8.3 Hz, 1H), 4.91 (d, J=15.8 Hz, 1H), 4.61 (d, J=15.8 Hz, 1H), 4.43 (s, 1H), 3.64~3.38 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 176.90, 161.55, 145.52, 141.00, 134.43, 130.96, 130.32, 129.91, 128.89, 128.73, 127.82, 127.10, 127.02, 126.78, 126.12, 125.02, 110.80, 75.70, 44.03, 34.87; HRMS (ESI) calcd for C25H20ClN2O3 [M+H]+ 431.1157, found 431.1158.

    1-苄基-5-氟-3-羟基-3-[(2-苯基噁唑-5-基)甲基]吲哚啉-2-酮(3r):产率91%. 1H NMR (400 MHz, CDCl3) δ: 7.74 (dd, J=7.7, 1.5 Hz, 2H), 7.40~7.30 (m, 3H), 7.18 (dd, J=7.5, 2.4 Hz, 1H), 7.12~7.01 (m, 3H), 6.95 (d, J=6.2 Hz, 2H), 6.86 (td, J=8.9, 2.5 Hz, 1H), 6.75 (s, 1H), 6.47 (dd, J=8.6, 4.0 Hz, 1H), 5.24 (s, 1H), 4.91 (d, J=15.8 Hz, 1H), 4.56 (d, J=15.8 Hz, 1H), 3.51 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.37, 161.48, 159.58 (d, J=241.3 Hz), 145.76, 138.30, 134.57, 131.25 (d, J=7.7 Hz), 130.32, 128.84, 128.73, 127.75, 126.99, 126.92, 126.77, 126.09, 116.19 (d, J=23.3 Hz), 112.54 (d, J=24.7 Hz), 110.48 (d, J=7.8 Hz), 75.96, 44.05, 34.83; 19F NMR (376 MHz, CDCl3) δ: -119.09; HRMS (ESI) calcd for C25H20FN2O3 [M+H]+ 415.1452, found 415.1453.

    1-苄基-6-氯-3-羟基-3-[(2-苯基噁唑-5-基)甲基]吲哚啉-2-酮(3s):产率88%. 1H NMR (400 MHz, CDCl3) δ: 7.84~7.68 (m, 2H), 7.44~7.33 (m, 3H), 7.30 (d, J=7.9 Hz, 1H), 7.10 (ddd, J=9.6, 6.5, 1.6 Hz, 4H), 7.04~6.92 (m, 2H), 6.78 (s, 1H), 6.60 (d, J=1.4 Hz, 1H), 4.90 (d, J=15.8 Hz, 1H), 4.58 (d, J=15.8 Hz, 1H), 4.21 (t, J=54.4 Hz, 1H), 3.47 (dd, J=32.9, 14.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.23, 161.49, 145.66, 143.79, 135.91, 134.35, 130.33, 128.93, 128.75, 127.88, 127.65, 127.03, 126.77, 126.08, 125.34, 123.25, 110.37, 75.29, 44.03, 34.86; HRMS (ESI) calcd for C25H20ClN2O3 [M+H]+ 431.1157, found 431.1157.

    1-苄基-6-氟-3-羟基-3-[(2-苯基噁唑-5-基)甲基]吲哚啉-2-酮(3t):产率92%. 1H NMR (400 MHz, CDCl3) δ: 7.76 (dd, J=7.6, 1.7 Hz, 2H), 7.42~7.28 (m, 4H), 7.16~7.03 (m, 3H), 7.03~6.89 (m, 2H), 6.84~6.64 (m, 2H), 6.32 (dd, J=8.8, 2.0 Hz, 1H), 4.90 (d, J=15.8 Hz, 1H), 4.69~4.32 (m, 2H), 3.48 (q, J=14.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.59, 163.93 (d, J=246.4 Hz), 161.45, 145.88, 144.28 (d, J=11.7 Hz), 134.39, 130.31, 128.92, 128.74, 127.87, 127.07, 126.94, 126.82, 126.07, 125.72, 125.62, 124.73 (d, J=3.0 Hz), 109.48 (d, J=22.3 Hz), 98.66 (d, J=27.6 Hz), 75.27, 44.06, 34.84; 19F NMR (376 MHz, CDCl3) δ: -108.85; HRMS (ESI) calcd for C25H20FN2O3 [M+H]+ 415.1452, found 415.1453.

    1-苄基-7-氯-3-羟基-3-[(2-苯基噁唑-5-基)甲基]吲哚啉-2-酮(3u):产率88%. 1H NMR (400 MHz, CDCl3) δ: 7.79 (d, J=7.1 Hz, 2H), 7.37 (d, J=6.7 Hz, 3H), 7.29 (d, J=7.2 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.11 (s, 3H), 7.04 (t, J=7.8 Hz, 1H), 6.98 (d, J=4.2 Hz, 2H), 6.76 (s, 1H), 5.22 (s, 2H), 4.32 (s, 1H), 3.46 (q, J=14.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.95, 161.53, 145.60, 138.65, 136.70, 132.60, 132.17, 130.30, 128.73, 128.58, 127.19, 127.12, 126.13, 126.07, 124.29, 123.03, 116.02, 74.87, 45.02, 35.02; HRMS (ESI) calcd for C25H20ClN2O3 [M+H]+ 431.1157, found 431.1158.

    3-羟基-1-(4-甲基苄基)-3-[(2-苯基噁唑-5-基)甲基]吲哚啉-2-酮(3v):产率85%. 1H NMR (400 MHz, CDCl3) δ: 7.82~7.63 (m, 2H), 7.43~7.28 (m, 4H), 7.18 (t, J=7.7 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 6.95~6.81 (m, 4H), 6.71 (s, 1H), 6.61 (d, J=7.8 Hz, 1H), 4.90 (d, J=15.6 Hz, 1H), 4.55 (d, J=15.6 Hz, 2H), 3.50 (q, J=14.6 Hz, 2H), 2.16 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 177.29, 161.29, 146.11, 142.60, 137.28, 131.90, 130.12, 129.98, 129.45, 129.34, 128.62, 127.23, 126.84, 126.10, 124.29, 123.26, 109.77, 75.69, 43.68, 34.85, 20.99; HRMS (ESI) calcd for C26H23N2O3 [M+H]+ 411.1703, found 411.1704.

    4-((3-羟基-2-氧代-3-((2-苯基噁唑-5-基)甲基)吲哚啉-1-基)甲基)苯甲腈(3w):产率90%. 1H NMR (400 MHz, CDCl3) δ: 7.66 (d, J=6.9 Hz, 2H), 7.49 (t, J=8.7 Hz, 1H), 7.42~7.15 (m, 7H), 7.01 (d, J=8.1 Hz, 2H), 6.70 (s, 1H), 6.52 (d, J=7.6 Hz, 1H), 5.03 (d, J=16.3 Hz, 1H), 4.57 (d, J=16.3 Hz, 1H), 4.55~4.17 (m, 1H), 3.62~3.44 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 177.24, 161.34, 145.81, 142.06, 140.33, 132.62, 130.46, 130.21, 129.30, 128.79, 127.38, 126.90, 126.87, 125.94, 124.59, 123.84, 118.28, 111.65, 109.24, 75.78, 43.48, 34.90; HRMS (ESI) calcd for C26H20N3O3 [M+H]+ 422.1499, found 422.1498.

    3-羟基-1-甲基-3-[(2-苯基噁唑-5-基)甲基]吲哚啉-2-酮(3x):产率88%. 1H NMR (400 MHz, CDCl3) δ: 7.81 (dd, J=6.5, 3.0 Hz, 2H), 7.41~7.36 (m, 3H), 7.34~7.26 (m, 2H), 7.09 (t, J=7.5 Hz, 1H), 6.75 (s, 1H), 6.73 (d, J=8.0 Hz, 1H), 4.37 (s, 1H), 3.42 (dd, J=50.2, 14.7 Hz, 2H), 3.10 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 177.32, 161.27, 146.29, 143.18, 130.18, 130.09, 129.13, 128.70, 127.22, 126.63, 126.07, 124.30, 123.26, 108.58, 75.57, 34.85, 26.23; HRMS (ESI) calcd for C26H23N2O4 [M+H]+ 427.1652, found 427.1650.

    1-苄基-3-羟基-3-((2-(4-甲氧基苯基)噁唑-5-基)甲基)吲哚啉-2-酮(3y):产率87%. 1H NMR (400 MHz, CDCl3) δ: 7.77 (dd, J=6.6, 2.9 Hz, 2H), 7.46~7.33 (m, 4H), 7.27 (dd, J=5.3, 2.3 Hz, 1H), 7.11 (t, J=7.4 Hz, 1H), 6.87 (d, J=7.9 Hz, 1H), 6.69 (s, 1H), 4.42 (dd, J=14.0, 7.0 Hz, 1H), 4.30~3.78 (m, 1H), 3.43 (q, J=14.5 Hz, 2H), 1.35 (d, J=7.1 Hz, 3H), 1.25 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 176.88, 161.22, 146.24, 141.98, 130.14, 129.84, 129.66, 128.64, 127.22, 126.59, 126.09, 124.48, 122.76, 110.19, 75.47, 44.14, 35.33, 19.20, 19.06; HRMS (ESI) calcd for C19H16N2O3 [M+H]+ 320.1161, found 320.1162.

    1-苄基-3-((2-(叔丁基)噁唑-5-基)甲基)-3-羟基吲哚啉-2-酮(3z):产率83%. 1H NMR (400 MHz, CDCl3) δ: 7.35 (d, J=7.3 Hz, 1H), 7.29~7.11 (m, 4H), 7.06 (dd, J=10.8, 7.6 Hz, 3H), 6.58 (d, J=8.7 Hz, 2H), 4.94 (d, J=15.7 Hz, 1H), 4.63 (d, J=15.7 Hz, 1H), 4.30 (s, 1H), 3.40 (q, J=14.5 Hz, 2H), 1.07 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ: 177.33, 170.85, 145.18, 142.37, 135.05, 129.84, 129.29, 128.88, 127.66, 127.00, 124.83, 124.51, 123.21, 109.56, 75.80, 43.89, 34.68, 33.42, 28.16; HRMS (ESI) calcd for C23H24N2O3 [M+H]+376.1787, found 376.1788.

    辅助材料(Supporting Information) 目标化合物的氢谱和碳谱核磁共振数据.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.


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  • 图式 2  控制实验及反应机理研究

    Scheme 2  Control experiments and proposed reaction mechanism

    表 1  反应条件优化a

    Table 1.  Optimization of reaction conditionsa

    Entry Catalyst A Catalyst B Solvent Temp./℃ Yieldb/%
    1 Zn(OTf)2 In(OTf)3 DCE 100 25
    2 Zn(OTf)2 Y(OTf)3 DCE 100 87
    3 Zn(OTf)2 Yb(OTf)3 DCE 100 34
    4 Zn(OTf)2 La(OTf)3 DCE 100 28
    5 Zn(OTf)2 Sc(OTf)3 DCE 100 62
    6 Zn(OTf)2 Ni(ClO4)2•6H2O DCE 100 56
    7 Zn(OTf)2 Y(OTf)3 DCE 80 75
    8 Zn(OTf)2 Y(OTf)3 DCE 120 88
    9 Zn(OTf)2 DCE 100 27
    10 Y(OTf)3 DCE 100 0
    11 AgOTf Y(OTf)3 DCE 100 32
    12 Cu(OT)2 Y(OTf)3 DCE 100 28
    13 Zn(OTf)2 Y(OTf)3 Toluene 100 38
    14 Zn(OTf)2 Y(OTf)3 CH3CN 100 23
    General conditions: 1a (0.24 mmol), 2a (0.2 mmol), catalyst A (10 mol%), Catalyst B (10 mol%), solvent (2 mL), in sealed tube, overnight. b Isolated yield based on 2a.
    下载: 导出CSV

    表 2  分子内环异构化/阿尔德-烯反应底物扩展

    Table 2.  Application scope of the intramolecular cycloisomerization/intermolecular Alder-ene reaction a

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  • 发布日期:  2020-03-01
  • 收稿日期:  2019-09-02
  • 修回日期:  2019-10-23
  • 网络出版日期:  2019-11-07
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