Ming-Phos/铜催化的甲亚胺叶立德与三氟甲基烯酮的不对称[3+2]环加成反应

武力左 张峰源 章振涛 尚垒 刘宇

引用本文: 武力左, 张峰源, 章振涛, 尚垒, 刘宇. Ming-Phos/铜催化的甲亚胺叶立德与三氟甲基烯酮的不对称[3+2]环加成反应[J]. 有机化学, 2020, 40(8): 2460-2467. doi: 10.6023/cjoc202004038 shu
Citation:  Wu Lizuo, Zhang Fengyuan, Zhang Zhentao, Shang Lei, Liu Yu. Ming-Phos/Copper(I)-Catalyzed Asymmetric Intermolecular[3+2] Cycloaddition of Azomethine Ylides with Trifluoromethyl Enones[J]. Chinese Journal of Organic Chemistry, 2020, 40(8): 2460-2467. doi: 10.6023/cjoc202004038 shu

Ming-Phos/铜催化的甲亚胺叶立德与三氟甲基烯酮的不对称[3+2]环加成反应

    通讯作者: 尚垒, shanglei@ccut.edu.cn; 刘宇, yuliu@ccut.edu.cn
  • 基金项目:

    吉林省科技发展计划(No.20170520137JH)和国家自然科学基金青年基金(No.21602015)资助项目

摘要: 含有三氟甲基的手性吡咯烷骨架是许多天然产物和药物的重要中间体,其高效的不对称合成方法是有机化学研究热点之一.通过Ming-Phos手性配体实现了铜催化的甲亚胺叶立德与β-三氟甲基-αβ-不饱和酮的不对称[3+2]环加成反应,以较高的产率和对映选择性合成了一系列含三氟甲基的手性吡咯烷化合物(ee值高达98%,产率高达99%).该方法条件温和,操作简单,配体简单易得,且具有良好的底物普适性和官能团兼容性.

English

  • 近年来, 有机氟化学领域一直在快速发展.随着氟原子的引入, 使得许多有机化合物表现出独特的理化性质、药理及生物活性[1], 因此有机氟化合物在材料化学、生物医学和药物化学等领域被广泛应用[2].随着含氟有机化合物需求的日益增加, 发展新的含氟有机化合物合成方法也显得更为迫切[3].在一系列有机氟分子中, 手性三氟甲基作为常见的官能团, 广泛出现于农业和药物化学领域[4].

    过渡金属催化甲亚胺叶立德与缺电子烯烃的不对称1, 3-偶极环加成反应, 是构建吡咯烷环高效的合成方法之一[5, 6].由于手性三氟甲基吡咯烷类化合物表现出的独特生物活性, 其不对称合成也备受化学家们的关注[7](图 1).

    图 1

    图 1.  带有CF3立体中心的农业和药物化学杂环化合物
    Figure 1.  Asymmetric [3+2] cycloaddition of azomethine ylides with electron-deficient alkenes

    将三氟甲基烯烃引入到该反应体系, 可以高效地实现三氟甲基吡咯烷的合成. 1985年, Bonnet-Delpon课题组[8]使用化学计量的AgOAc, 成功地实现了反式二取代三氟甲基烯酯与甲亚胺叶立德的1, 3-偶极环加成反应, 得到了系列endo-选择性的消旋三氟甲基化吡咯烷类化合物.直到二十多年以后, 王春江课题组[9]才首次报道了铜催化的反/顺式二取代三氟甲基烯酯和甲亚胺叶立德的1, 3-偶极的不对称[3+2]环加成反应, 该催化体系表现出高反应活性, 优异的非对映选择性和良好的对映选择性(图 2a). 2016年, 周志明课题组[10]也以非常优秀的产率、对映和非对映选择性完成了β-三氟甲基-β, β-二取代硝基烯烃与甲亚胺叶立德的不对称[3+2]环加成反应(图 2b).近期, 张俊良课题组[11]通过使用自主开发的Ming-Phos等配体, 成功实现了铜催化的甲亚胺叶立德和三取代三氟甲基烯酯/酮(β-三氟甲基-β, β-二取代烯酮、α-三氟甲基-α, β-不饱和酯)不对称环加成反应, 以非常高的产率、出色的对映和非对映选择性, 获得了含三氟甲基季碳全碳手性中心的吡咯烷化合物(图 2c)[11c, 12].我们与张俊良课题组[13]合作, 将Ming-Phos配体应用于甲亚胺叶立德与环内烯烃的不对称环加成反应, 也表现出色的催化活性.鉴于上述反应体系中未考查β-单取代三氟甲基烯酮的反应性, 本工作对该体系进行了扩展, 探索了甲亚胺叶立德与反式三氟甲基烯酮的1, 3-偶极不对称环加成反应(图 2d).

    图 2

    图 2.  甲亚胺叶立德与三氟甲基烯烃的[3+2]不对称环加成反应
    Figure 2.  Asymmetric [3+2] cycloaddition of azomethine ylides with trifluoromethyl alkenes

    首先以反式三氟甲基烯酮(1a)和甲亚胺叶立德2a为模板底物, Cu(CH3CN)4BF4为催化剂, 甲基叔丁基醚为溶剂, 碳酸铯为碱, 反应温度为-30℃, 对Ming- Phos配体进行了筛选, 结果如表 1所示:当使用M1作为配体时, 反应能以3:1的dr值, 70%的产率和92% ee得到endo构型的产物(Entry 1);随后, 使用位阻较小的M2作为配体时, 反应结果较差, dr值为1:1, ee值也降至86% (Entry 2);当使用含有叔丁基的M3时, 反应的选择性有了明显的提升(Entry 3);当使用苯基取代的配体M4时, 反应的dr值为2:1, ee值为98% (Entry 4);当使用萘基配体M5时, 反应的选择性有了明显降低, ee值降到了12% (Entry 5);最后使用构型相反的M6配体时, 反应的产率和选择性都明显降低(Entry 6).

    表 1

    表 1  Ming-phos配体筛选a
    Table 1.  Screening of Ming-phos ligands
    下载: 导出CSV
    Entry Ligand drb Yieldc/% eed/%
    1 M1 3:1 70 92
    2 M2 1:1 43 86
    3 M3 4:1 78 98
    4 M4 2:1 63 98
    5 M5 1:1 70 12
    6 M6 1:1 40 34
    a All reactions were carried out with 0.1 mmol of 1a, 0.2 mmol of 2a, 5 mol% catalyst ([Cu] to ligand=1:1.1) in 2.0 mL of MTBE at -30 ℃ for 6 h. b The diastereomeric ratios were determined by 1H NMR analysis of the crude products. c The yield of 3aa was determined by 1H NMR analysis using CH2Br2 as the internal reference. d The ee values were determined by chiral HPLC.

    接下来考察了其他条件对反应的影响(表 2).首先对催化剂铜盐进行了考察, 结果显示:当使用Cu(CH3- CN)4ClO4、Cu(CH3CN)4PF6、[Cu(OTf)2]•Tol、Cu(CF3- SO3)2、Cu(CH3CN)4NTF2时, 并未得到更好的结果(Entries 1~6).接着考察了其他的无机碱和有机碱, 当使用叔丁醇钾时, 对映选择性大幅度降低; 而使用1, 5-二氮杂二环[5.4.0]十一烯-5 (DBU)作为碱时, 完全失去了选择性(Entry 7~10).最后考察了溶剂对反应的影响, 与叔丁基甲基醚相比, 以四氢呋喃为溶剂时, 非对映选择性略有提升, 而对映选择性保持不变(Entry 11).然而, 换作其他醚类溶剂或甲苯作为溶剂时, 均没有得到更好的结果(Entries 12~14).通过对反应条件的系统优化, 最终确定了反应的最优条件: M3 (5.5 mol%)作为配体, Cu(CH3CN)4BF4 (5 mol%)作为催化剂, 碳酸铯作为碱, 四氢呋喃作为溶剂, 反应温度为-30 ℃.

    表 2

    表 2  反应条件优化a
    Table 2.  Optimization of the reaction conditions
    下载: 导出CSV
    Entry [Cu] Base Solvent dr b Yield c (ee) d/%
    1 Cu(CH3CN)4ClO4 Cs2CO3 MTBE 5:1 74 (98)
    2 Cu(CH3CN)4PF6 Cs2CO3 MTBE 5:1 80 (98)
    3 [Cu(OTf)]2"Tol Cs2CO3 MTBE 5:1 77 (96)
    4 Cu(CF3SO3)2 Cs2CO3 MTBE 5:1 76 (96)
    5 Cu(CH3CN)4NTf2 Cs2CO3 MTBE 4:1 78 (93)
    6 Cu(CH3CN)4BF4 Cs2CO3 MTBE 5:1 79 (98)
    7 Cu(CH3CN)4BF4 tBuOK MTBE 3:1 56 (11)
    8 Cu(CH3CN)4BF4 DBU MTBE 1:1 35 (0)
    9 Cu(CH3CN)4BF4 Et3N MTBE 4:1 66 (96)
    10 Cu(CH3CN)4BF4 K2CO3 MTBE 5:1 78 (98)
    11 Cu(CH3CN)4BF4 Cs2CO3 THF 6:1 85 (96)
    12 Cu(CH3CN)4BF4 Cs2CO3 iPr2O 5:1 78 (98)
    13 Cu(CH3CN)4BF4 Cs2CO3 Et2O 4:1 74 (97)
    14 Cu(CH3CN)4BF4 Cs2CO3 Toluene 6:1 77 (96)
    a All reactions were carried out with 0.1 mmol of 1a, 0.2 mmol of 2a 5 mol% of catalyst ([Cu] to ligand=1:1.1) in 2.0 mL solvent at -30 ℃ for 6 h. b The diastereomeric ratios were determined by 1H NMR analysis of the crude products. c The yields were determined by 1H NMR analysis using CH2Br2 as the internal reference. d The ee values were determined by chiral HPLC.

    在此条件下, 对底物的范围进行了考察(表 3).结果表明, 当三氟甲基烯酮底物的苯环上4-位是氟、氯、溴、三氟甲基、硝基等吸电子基团时, 反应能以较好的产率和优秀的选择性得到产物(3aa~3ea).当苯环上不含取代基或带有给电子的甲氧基时, 反应同样以优异的产率和对映选择性得到目标产物, 但非对映选择性大幅度降低(3fa, 3ga).以邻位和间位取代的三氟甲基烯酮作为底物时, 反应均可顺利进行并都给出了较好的产率和优秀的选择性(3ha, 3ia).另外, 还考察了苯环上含多个取代基的底物, 当2, 4-位或3, 4-位为氯原子取代时, 能以良好的产率和优异的选择性得到产物(3ja, 3ka).最后考察了甲亚胺叶立德上苯环取代基的影响, 当没有取代基时, 能以84%的产率和97%的ee值得到产物(3eb).当取代基为甲基和甲氧基的时候, 反应顺利进行, 并以良好到优秀的产率和优异的选择性得到目标产物(3ec, 3ed).

    表 3

    表 3  底物范围a, b
    Table 3.  Substrate scope
    下载: 导出CSV
    a All reactions were carried out with 0.3 mmol of 1, 0.6 mmol of 2, 5 mol% of catalyst ([Cu] to ligand=1:1.1) in 6.0 mL THF at -30 ℃ for 2~8 h. b Isolated yield. The ee values were determined by chiral HPLC. The diastereomeric ratios were determined by 1H NMR analysis of the crude products.

    研究了铜催化的甲亚胺叶立德与β-三氟甲基-α, β-不饱和酮的不对称[3+2]环加成反应, 通过使用张俊良课题组发展的Ming-Phos手性配体, 以中等到优秀的产率、优异的对映选择性得到目标产物.该方法条件温和, 操作简单, 配体合成简单, 底物普适性较好.因此为含三氟甲基的吡咯烷类化合物的合成提供了一种较为有效的方法.课题组将继续从事进一步的体系扩展和优化.

    仪器: SHZ-D(III)型循环水式真空泵, X-5型显微熔点测定仪, N-1100型旋转蒸发仪, OSB-2100型油浴锅, DL-400型循环冷却器, 2XZ-2型旋片式真空泵, ZF-20D型暗箱式紫外分析仪, DZTW型调温电热套, RCT B S025型磁力搅拌器, AV-400型核磁共振谱仪Q-TRA- PLC/MS/MS system型质谱仪, LC-2030C 3D高效液相色谱仪.

    试剂:苯甲醛, 4-氯苯甲醛, 4-溴苯甲醛, 4-氰基苯甲醛, 4-氟苯甲醛, 4-硝基苯甲醛, 4-甲氧基苯甲醛, 4-甲基苯甲醛, 3-硝基苯甲醛, 2-硝基苯甲醛, 2, 4-二氯苯甲醛, 3, 4-二氯苯甲醛, 二异丙胺, 2-溴-3, 3, 3-三氟丙烯, 正丁基锂, 三乙胺, 甘氨酸甲酯盐酸盐, 无水硫酸镁, 四氢呋喃,碳酸铯.

    在室温下将M3 (5.5 mol%)和Cu(CH3CN)4BF4 (5 mol%)在四氢呋喃(THF, 6 mL)中搅拌2 h.将反应温度降至-30 ℃后, 依次加入甲亚胺叶立德2 (0.6 mmol), Cs2CO3 (0.15 mmol)和三氟甲基烯酮1 (0.3 mmol).薄层色谱(TLC)监测三氟甲基烯酮1完全反应后, 减压除去溶剂.粗产物用1H NMR分析以确定非对映体选择性, 然后将粗产物通过硅胶快速柱色谱纯化(石油醚/乙酸乙酯, V:V=8:1)得到产物3.使用手性柱进行HPLC检测, 测定产物的对映选择性.

    (2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(4-氯苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3aa): 125.1 mg白色固体, 85%产率, 6:1 dr, 96% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=90:10, 0.8 mL/min, 210 nm]; major enantiomer tR=33.6 min, minor enantiomer tR=14.2 min]. m.p. 142~143 ℃; [α]D20-0.22 (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.44 (d, J=8.6 Hz, 2H), 7.25~7.18 (m, 4H), 6.99 (d, J=8.4 Hz, 2H), 4.70 (d, J=7.5 Hz, 1H), 4.37~4.35 (m, 1H), 4.13 (d, J=6.2 Hz, 1H), 3.91 (s, 3H), 3.77~3.69 (m, 1H), 2.98 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 197.3, 171.2, 139.9, 135.2, 134.9, 131.4, 129.4, 128.7, 128.7, 126.6 (q, JC-F=278.3 Hz), 122.1, 66.4, 60.4, 53.0, 51.3, 50.7 (q, J=27.1 Hz); 19F NMR (376 MHz, CDCl3) δ: 68.87; ESI-MS calcd for C20H16BrClF3NNaO3 [M+Na+] 511.9852, found 511.9856.

    (2S, 3S, 4S, 5R)-甲基-4-(4-溴苯甲酰基)-5-(4-溴苯基)-3- (三氟甲基)吡咯烷-2-羧酸酯(3ba): 136.4 mg白色固体, 85%产率, 8:1 dr, 97% ee [Chiralpak AD-H column [V(he-xanes):V(2-propanol)=90:10, 0.8 mL/min, 210 nm]; minor enantiomer tR=36.5 min, major enantiomer tR=14.6 min]. m.p. 137~138 ℃; [α]D20-0.26 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.42~7.35 (m, 4H), 7.19 (d, J=8.5 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 4.70 (d, J=7.5 Hz, 1H), 4.37~4.35 (m, 1H), 4.13 (d, J=6.2 Hz, 1H), 3.92 (s, 3H), 3.77~3.68 (m, 1H), 2.99 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 197.5, 171.2, 135.3, 135.2, 131.6, 131.3, 129.4, 128.7, 128.6, 128.0 (t, JC-F=278.4 Hz), 122.1, 66.3, 60.3, 52.9, 51.2, 50.5 (q, J=27.1 Hz); 19F NMR (376 MHz, CDCl3) δ: -68.86; ESI-MS calcd for C20H16Br2F3NNaO3 [M+Na+] 555.9347, found 555.9345.

    (2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(4-氟苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ca): 101.0 mg白色固体, 71%产率, 3:1 dr, 94% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=90:10, 0.8 mL/min, 210 nm]; major enantiomer tR=29.3 min, minor enantiomer tR=14.1 min]. m.p. 165~166 ℃; [α]D20-0.08 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.56~7.52 (m, 2H), 7.19 (d, J=8.5 Hz, 2H), 7.01~6.91 (m, 4H), 4.70 (d, J=7.3 Hz, 1H), 4.39~4.36 (m, 1H), 4.14 (d, J=6.0 Hz, 1H), 3.92 (s, 3H), 3.78~3.68 (m, 1H), 3.00 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 196.9, 171.2, 165.7 (d, J=256.5 Hz), 135.2, 133.1, 131.3, 130.8 (d, J=9.5 Hz), 128.7, 126.7 (q, JC-F=278.3 Hz), 122.0, 115.5 (d, J=21.9 Hz), 66.5, 60.4, 53.0, 51.2, 50.7 (q, J=26.9 Hz); 19F NMR (376 MHz, CDCl3) δ: -68.88, -103.90; ESI-MS calcd for C20H16BrF4NNaO3 [M+Na+] 496.0147, found 496.0151.

    (2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(4-氰基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3da): 131.4 mg白色固体, 91%产率, 12:1 dr, 98% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=90:10, 0.8 mL/ min, 233 nm]; minor enantiomer tR=57.7 min, major enantiomer tR=31.4 min]. m.p. 135~136 ℃; [α]D20-0.24 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.55 (s, 4H), 7.16 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 4.74 (d, J=7.6 Hz, 1H), 4.42~4.39 (m, 1H), 4.14 (d, J=6.3 Hz, 1H), 3.92 (s, 3H), 3.85~3.75 (m, 1H), 2.94 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 198.1, 171.4, 144.4, 135.4, 134.1, 131.3 (2 C), 129.1, 128.8, 128.3, 126.7 (q, JC-F=278.4 Hz), 121.9, 66.6, 60.6, 53.0, 51.1, 51.0 (q, J=27.0 Hz); 19F NMR (376 MHz, CDCl3) δ: -68.84; ESI-MS calcd for C21H16BrF3N2NaO3 [M+Na+] 503.0194, found 503.0190.

    (2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(4-硝基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ea): 120.3 mg白色固体, 80%产率, 10:1 dr, 98% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=80:20, 0.8 mL/min, 233 nm]; major enantiomer tR=26.8 min, minor enantiomer tR=16.0 min]. m.p. 149~150 ℃; [α]D20-0.47 (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 8.09 (d, J=8.9 Hz, 2H), 7.62 (d, J=8.9 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 7.00 (d, J=8.5 Hz, 2H), 4.76 (d, J=7.6 Hz, 1H), 4.42~4.41 (m, 1H), 4.15 (d, J=6.3 Hz, 1H), 3.93 (s, 3H), 3.84~3.78 (m, 1H), 2.94 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 197.2, 171.1, 150.0, 141.0, 135.0, 131.6, 129.0, 128.8, 126.5 (q, JC-F=278.3 Hz), 123.5, 122.4, 66.2, 60.2, 53.1, 52.0, 50.2 (q, J=27.3 Hz); 19F NMR (376 MHz, CDCl3) δ: -68.87; ESI-MS calcd for C20H16Br- F3N2NaO5 [M+Na+] 523.0092, found 523.0096.

    (2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(苯甲酰基)- 3-(三氟甲基)吡咯烷-2-羧酸酯(3fa): 117.6 mg白色固体, 86%产率, 1:1 dr, 91% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=90:10, 0.5 mL/min, 210 nm]; minor enantiomer tR=32.2 min, major enantiomer tR=20.6 min]. m.p. 164~165 ℃; [α]D20-0.10 (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.50 (d, J=8.2 Hz, 2H), 7.43 (t, J=7.4 Hz, 1H), 7.26~7.24 (m, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 4.70 (d, J=7.5 Hz, 1H), 4.45~4.43 (m, 1H), 4.14 (d, J=6.2 Hz, 1H), 3.92 (s, 3H), 3.76~3.73 (m, 1H), 3.01 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 198.6, 171.3, 136.6, 135.3, 133.3, 131.2, 128.8, 128.3, 128.1, 126.5 (q, J=278.4 Hz), 121.9, 66.5, 53.0, 51.3, 50.7 (q, J=27.0 Hz); 19F NMR (376 MHz, CDCl3) δ: -68.76; ESI-MS calcd for C20H17Br- F3NNaO3 [M+Na+] 478.0242, found 478.0239.

    (2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(4-甲氧基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ga): 128.3 mg白色固体, 88%产率, 2:1 dr, 94% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=90:10, 0.8 mL/ min, 210 nm]; minor enantiomer tR=37.4 min, major enantiomer tR=18.7 min]. m.p. 124~125 ℃; [α]D20-0.28 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.52 (d, J=8.9 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.73 (d, J=8.9 Hz, 2H), 4.67 (d, J=7.3 Hz, 1H), 4.39~4.36 (m, 1H), 4.13 (d, J=6.1 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.74~3.65 (m, 1H), 3.06 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 196.8, 171.3, 163.7, 135.5, 131.2, 130.5, 129.6, 128.7, 126.75 (q, J=278.6 Hz), 121.7, 113.5, 60.6, 55.4, 52.9, 50.9 (q, J=26.8 Hz), 50.75; 19F NMR (376 MHz, CDCl3) δ: -68.89; ESI-MS calcd for C21H19BrF3NNaO4 [M+ Na+] 508.0347, found 508.0345.

    (2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(2-硝基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ha): 108.3 mg白色固体, 72%产率, 10:1 dr, 93% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=80:20, 0.8 mL/min, 210 nm]; minor enantiomer tR=24.1 min, major enantiomer tR=14.2 min]. m.p. 123~124 ℃; [α]D20-0.20 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.00 (d, J=9.1 Hz, 1H), 7.50~7.45 (m, 1H), 7.32 (d, J=8.5 Hz, 3H), 7.04 (d, J=8.2 Hz, 2H), 5.95 (d, J=9.0 Hz, 1H), 4.64 (d, J=5.9 Hz, 1H), 4.17 (d, J=4.5 Hz, 1H), 3.95 (s, 3H), 3.83~3.77 (m, 2H), 3.16 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 196.2, 171.1, 147.7, 137.5, 135.0, 133.4, 131.5, 129.5, 128.7, 127.2, 126.5 (q, JC-F=278.3 Hz), 123.0, 122.3, 66.2, 60.0, 53.0, 51.8, 49.9 (q, J=27.4 Hz); 19F NMR (376 MHz, CDCl3) δ: -69.03; ESI-MS calcd for C20H16BrF3N2NaO5 [M+Na+] 523.0092, found 523.0095.

    (2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(3-硝基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ia): 133.8 mg白色固体, 89%产率, 9:1 dr, 96% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=80:20, 0.8 mL/min, 233 nm]; minor enantiomer tR=13.4 min, major enantiomer tR=14.2 min]. m.p. 125~126 ℃; [α]D20-0.18 (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 8.27~8.24 (m, 2H), 7.81 (d, J=7.8 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 4.80~4.79 (m, 1H), 4.41~4.40 (m, 1H), 4.16 (d, J=6.1 Hz, 1H), 3.93 (s, 3H), 3.87~3.81 (m, 1H), 2.91 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 196.1, 171.0, 147.7, 137.5, 135.0, 133.4, 131.4, 129.5, 128.7, 127.2, 126.5 (q, J=278.4 Hz), 123.0, 122.2, 66.2, 60.0, 53.0, 51.8, 49.8 (q, J=27.4 Hz); 19F NMR (376 MHz, CDCl3) δ: -68.93; ESI-MS calcd for C20H16BrF3N2NaO5 [M+Na+] 523.0092, found 523.0090.

    (2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(2, 4-二氯苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ja): 132.3 mg浅黄色固体, 84%产率, 8:1 dr, 97% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=90:10, 0.5 mL/min, 210 nm]; minor enantiomer tR=21.4 min, major enantiomer tR=17.2 min]. m.p. 98~99 ℃; [α]D20-0.11 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.27 (s, 3H), 6.99 (t, J=8.8 Hz, 3H), 6.40 (d, J=8.4 Hz, 1H), 4.69~4.61 (m, 2H), 4.14 (d, J=5.6 Hz, 1H), 3.91 (s, 3H), 3.77~3.69 (m, 1H), 2.97 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 200.1, 171.1, 137.9, 136.8, 134.9, 131.87, 131.6, 130.5, 130.0, 128.3, 127.1, 126.6 (d, JC-F=278.4 Hz), 122.1, 66.0, 60.5, 55.5, 53.1, 50.6 (q, J=27.4 Hz); 19F NMR (376 MHz, CDCl3) δ: -68.71; ESI-MS calcd for C20H15BrCl2- F3NNaO3 [M+Na+] 545.9462, found 545.9466.

    (2S, 3S, 4S, 5R)-甲基-5-(4-溴苯基)-4-(3, 4-二氯苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ka): 137.1 mg浅黄色固体, 87%产率, 7:1 dr, 96% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=90:10, 0.5 mL/ min, 210 nm]; major enantiomer tR=32.5 min, minor enantiomer tR=17.2 min]. m.p. 143~144 ℃; [α]D20-0.23 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.49 (d, J=15.3 Hz, 1H), 7.33 (s, 2H), 7.22 (d, J=7.2 Hz, 2H), 7.00 (d, J=7.1 Hz, 2H), 4.73~4.72 (m, 1H), 4.29 (s, 1H), 4.13 (s, 1H), 3.92 (s, 3H), 3.75 (s, 1H), 2.95 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 196.3, 171.2, 138.0, 136.1, 135.1, 133.1, 131.5, 130.4, 130.1, 128.7, 127.0, 126.6 (q, JC-F=278.3 Hz), 122.4, 66.4, 60.3, 53.1, 51.6, 50.3 (q, J=27.3 Hz); 19F NMR (376 MHz, CDCl3) δ: -68.85; ESI-MS calcd for C20H15BrCl2F3NNaO3 [M+Na+] 545.9462, found 545.9464.

    (2S, 3S, 4S, 5R)-甲基-4-(4-硝基苯甲酰基)-5-苯基- 3-(三氟甲基)吡咯烷-2-羧酸酯(3eb): 106.4 mg浅黄色固体, 84%产率, 10:1 dr, 97% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=90:10, 0.8 mL/min, 233 nm]; minor enantiomer tR=31.9 min, major enantiomer tR=24.8 min]. m.p. 135~136 ℃; [α]D20-0.12 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.02 (d, J=8.9 Hz, 2H), 7.58 (d, J=8.9 Hz, 2H), 7.10 (d, J=7.4 Hz, 2H), 7.03 (q, J=7.2, 5.9 Hz, 3H), 4.80 (d, J=7.5 Hz, 1H), 4.43~4.40 (m, 1H), 4.16 (d, J=6.1 Hz, 1H), 3.94 (s, 3H), 3.82~3.77 (m, 1H), 3.09 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 197.5, 171.2, 149.8, 141.1, 135.5, 129.0, 128.5 (2C), 127.1, 126.6 (q, JC-F=278.3 Hz), 123.3, 67.2, 60.4, 53.1, 52.4, 50.5 (q, J=27.1 Hz); 19F NMR (376 MHz, CDCl3) δ: -68.83; ESI-MS calcd for C20H17F3N2NaO5 [M+Na+] 445.0987, found 445.0982.

    (2S, 3S, 4S, 5R)-甲基4-(4-硝基苯甲酰基)-5-(对甲苯基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ec): 121.8 mg浅黄色固体, 93%产率, 15:1 dr, 98% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=90:10, 0.8 mL/ min, 233 nm]; minor enantiomer tR=33.4 min, major enantiomer tR=23.6 min]. m.p. 113~114 ℃; [α]D20-0.18 (c 0.3, CHCl3); 1 H NMR (400 MHz, CDCl3) δ: 8.02 (d, J=8.9 Hz, 2H), 7.58 (d, J=8.9 Hz, 2H), 7.10 (d, J=7.4 Hz, 2H), 7.03 (q, J=7.2, 5.9 Hz, 2H), 4.80 (d, J=7.5 Hz, 1H), 4.41~4.39 (m, 1H), 4.16 (d, J=6.1 Hz, 1H), 3.94 (s, 3H), 3.80~3.75 (m, 1H), 3.03 (s, 1H), 2.11 (s, 3H); 13C NMR (126 MHz, CDCl3) δ: 197.7, 171.3, 149.8, 141.1, 138.3, 132.4, 129.1, 129.1, 127.0, 126.6 (q, JC-F=278.2 Hz), 123.2, 67.0, 60.4, 53.0, 52.6, 50.6 (q, J=27.2 Hz), 20.88; 19F NMR (376 MHz, CDCl3) δ: -68.81; ESI-MS calcd for C21H19F3N2NaO5 [M+Na+] 459.1144, found 459.1147.

    (2S, 3S, 4S, 5R)-甲基-5-(4-甲氧基苯基)-4-(4-硝基苯甲酰基)-3-(三氟甲基)吡咯烷-2-羧酸酯(3ed): 112.6 mg黄色固体, 83%产率, 11:1 dr, 91% ee [Chiralpak AD-H column [V(hexanes):V(2-propanol)=90:10, 0.8 mL/ min, 254 nm]; minor enantiomer tR=61.6 min, major enantiomer tR=43.2 min]. m.p. 134~135 ℃; [α]D20-0.16 (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 8.05 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.01 (d, J=8.6 Hz, 2H), 6.55 (d, J=8.6 Hz, 2H), 4.76 (d, J=7.7 Hz, 1H), 4.40~4.38 (m, 1H), 4.13 (d, J=6.2 Hz, 1H), 3.93 (s, 3H), 3.80 (d, J=15.9 Hz, 1H), 3.61 (s, 3H), 2.94 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 197.6, 171.2, 159.5, 149.7, 141.0, 129.0, 128.2, 127.5, 126.6 (q, JC-F=278.3 Hz), 123.2, 113.7, 66.6, 55.1, 53.0, 52.4, 50.4, 50.3 (q, J=27.1 Hz); 19F NMR (376 MHz, CDCl3) δ: -68.78; ESI-MS calcd for C21H19F3N2NaO6 [M+Na+] 475.1093, found 475.1089.

    辅助材料(Supporting Information) 化合物31H NMR, 19F NMR, 13C NMR和HPLC谱图.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.


    1. [1]

      (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
      (b) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432.
      (c) Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27.
      (d) Bégué, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992.
      (e) Petrov, V. A. Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications, John Wiley & Sons, Inc, Hoboken, NJ, 2009.
      (f) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology, John Wiley & Sons, Ltd, Chichester, 2009.
      (g) Zhu, W.; Wang, J.; Wang, S. J. Fluorine Chem. 2014, 167, 37.
      (h) Zhang, J.; Jin, C.; Zhang, Y. Chin. J. Org. Chem. 2014, 34, 662(in Chinese).
      (张霁, 金传飞, 张英俊, 有机化学, 2014, 34, 662.)
      (i) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
      (j) Ji, X. M.; Shi, G. F.; Zhang, Y. H. Chin. J. Org. Chem. 2019, 39, 929(in Chinese).
      (季小明, 史广法, 张扬会, 有机化学, 2019, 39, 929.)
      (k) Meng, Y.; Li, E.; Zhang, Y.; Liu, S.; Bao, C.; Yang, P.; Zhang, L.; Zhang, D.; Wang, J.; Chen, Y.; Li, N.; Xin, J.; Zhao, P.; Ke, Y.; Zhang, Q.; Liu, H. Chin. J. Org. Chem. 2019, 39, 2541(in Chinese).
      (孟娅琪, 李二冬, 张洋, 刘栓, 包崇男, 杨鹏, 张路野, 张丹青, 王继宽, 陈雅欣, 栗娜, 辛景超, 赵培荣, 可钰, 张秋荣, 刘宏民, 有机化学, 2019, 39, 2541.)
      (l) Hu, J.; Ding, K.-L. Acta Chim. Sinica 2018, 76, 905(in Chinese).
      (胡金波, 丁奎岭, 化学学报, 2018, 76, 905.

    2. [2]

      (a) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
      (b) Li, Y.; Wu, Y.; Li, G.-S.; Wang, X.-S. Adv. Synth. Catal. 2014, 356, 1412.
      (c) Jeschke, P. ChemBioChem 2004, 5, 570.
      (d) O'Hagan, D.; Harper, D. B. J. Fluorine Chem. 1999, 100, 127.
      (e) Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364.
      (f) Li, Y.-Y.; Wang, Y.; Zhu, L.; Qu, L.; Lan, Y. Chin. J. Org. Chem. 2019, 39, 38(in Chinese).
      (李园园, 王元鉴, 朱磊, 屈凌波, 蓝宇, 有机化学, 2019, 39, 38.)
      (g) Jin, W.; Lu, G.; Li, Y.; Huang, X. Acta Chim. Sinica 2018, 76, 739(in Chinese).
      (金维则, 陆国林, 李永军, 黄晓宇, 化学学报, 2018, 76, 739.)
      (h) Zhang, J.; Wu, Z.; Xie, F.; Zhang, W. Chin. J. Org. Chem. 2018, 38, 1319(in Chinese).
      (张金刚, 吴正兴, 谢芳, 张万斌, 有机化学, 2018, 38, 1319.)
      (i) Xu, H.; Tan, Z.; Zhang, Y.; Fan, W. Guangzhou Chem. Ind. 2019, 47, 42(in Chinese).
      (许桓, 谭政, 张艳, 范为正, 广州化工, 2019, 47, 42.

    3. [3]

      (a) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432.
      (b) Purse, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
      (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
      (d) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
      (e) Prakash, G. K. S.; Wang, F. Chim. Oggi 2012, 30, 30.
      (f) Wang, J.; Liu, H. Chin. J. Org. Chem. 2011, 31, 1785(in Chinese).
      (王江, 柳红, 有机化学, 2011, 31, 1785.)
      (g) Lundgren, R. J.; Stradiotto, M. Angew. Chem., Int. Ed. 2010, 49, 9322.
      (h) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475.
      (i) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Asian J. 2012, 7, 1744.
      (j) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed. 2012, 51, 5048.
      (k) Ye, Y.; Sanford, M. S. Synlett 2012, 2005.
      (l) Qing, F.-L. Chin. J. Org. Chem. 2012, 32, 815(in Chinese).
      (卿凤翎, 有机化学, 2012, 32, 815.)
      (m) Pan, F.; Shi, Z. Acta Chim. Sinica 2012, 70, 1679(in Chinese).
      (潘菲, 施章杰, 化学学报, 2012, 70, 1679.)
      (n) Wang, X.; Zhang, Y.; Wang, J. Sci. Sin.: Chim. 2012, 42, 1417(in Chinese).
      (王兮, 张艳, 王剑波, 中国科学: 化学, 2012, 42, 1417.)
      (o) Chen, P.; Liu, G. Synthesis 2013, 45, 2929.
      (p) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214.
      (q) Xu, J.; Liu, X.; Fu, Y. Tetrahedron Lett. 2014, 55, 585.
      (r) Wang, G.; He, X.; Dai, J.; Xu, H. Chin. J. Org. Chem. 2014, 34, 837(in Chinese).
      (王光祖, 赫侠平, 戴建军, 许华建, 有机化学, 2014, 34, 837.)
      (s) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598.
      (t) Chu, L.; Qing, F.-L. Acc. Chem. Res. 2014, 47, 1513.
      (u) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.

    4. [4]

      (a) Kukhar, V. P.; Soloshonok, V. A. Fluorine Containing Amino Acids——Synthesis and Properties, Wiley, Chichester, 1995.
      (b) Nie, J.; Guo, H.-C.; Cahard D.; Ma, J.-A. Chem. Rev. 2010, 111, 455.
      (c) Hiyama, T. Organofluorine Compounds: Chemistry and Applications, Springer, New York, 2000.
      (d) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity and Applications, 2nd ed., Wiley-VCH, Weinheim, 2013.
      (e) Bégué, J. P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine, Wiley-VCH, Weinheim, 2008.
      (f) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, Chichester, 2009.
      (g) Gouverneur, V.; Muller, K. Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications, Imperial College Press, London, 2012.

    5. [5]

      For recent reviews about 1, 3-dipolar cycloadditions of iminoesters, see: (a) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
      (b) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887.
      (c) Álvarez-Corral, M.; Muñoz-Dorado, M.; Rodríguez-García, I. Chem. Rev. 2008, 108, 3174.
      (d) Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132.
      (e) Engels, B.; Christl, M. Angew. Chem., Int. Ed. 2009, 48, 7968.
      (f) Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784.
      (g) Moyano, A.; Rios, R. Chem. Rev. 2011, 111, 4703.
      (h) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2011, 50, 8492.
      (i) Maroto, E. E.; Izquierdo, M.; Reboredo, S.; Marco-Martínez, J.; Filippone, S.; Martín, N. Acc. Chem. Res. 2014, 47, 2660.
      (j) Hashimoto, T.; Maruoka, K. Chem. Rev. 2015, 115, 5366.
      (k) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10.
      (l) Dickstein, J. S.; Kozlowski, M. C. Chem. Soc. Rev. 2008, 37, 1166.
      (m) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626.

    6. [6]

      (a) Kim, H. Y.; Li, J.-Y.; Kim, S.; Oh, K. J. Am. Chem. Soc. 2011, 133, 20750.
      (b) Yamashita, Y.; Imaizumi, T.; Kobayashi, S. Angew. Chem., Int. Ed. 2011, 50, 4893.
      (c) Xu, H.; Golz, C.; Strohmann, C.; Antonchick, A. P.; Waldmann, H. Angew. Chem., Int. Ed. 2016, 55, 7761.
      (d) Pascual-Escudero, A.; de Cózar, A.; Cossío, F. P.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2016, 55, 15334.
      (e) Yamashita, Y.; Guo, X.-X.; Takashita, R.; Kobayashi, S. J. Am. Chem. Soc. 2010, 132, 3262.
      (f) Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H. J. Am. Chem. Soc. 2010, 132, 5338.
      (g) Potowski, M.; Schürmann, M.; Preut, H.; Antonchick, A. P.; Waldmann, H. Nat. Chem. Biol. 2012, 8, 428.
      (h) Awata, A.; Arai, T. Angew. Chem., Int. Ed. 2014, 53, 10462.
      (i) Narayan, R.; Bauer, J. O.; Strohmann, C.; Antonchick, A. P.; Waldmann, H. Angew. Chem., Int. Ed. 2013, 52, 12892.
      (j) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.; Schürmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2, 735.
      (k) Liu, T.-L.; He, Z.-L.; Wang, C.-J. Chem. Commun. 2011, 47, 9600.
      (l) Li, Q.; Huang, R.; Wang, C.-J. Acta Chim. Sinica 2014, 72, 830(in Chinese).
      (李清华, 黄蓉, 王春江, 化学学报, 2014, 72, 830.)
      (m) Xu, S.; Zhang, Z. M.; Xu, B.; Liu, B.; Liu, Y. Zhang, J. J. Am. Chem. Soc. 2018, 140, 2272.
      (n) Xu, B.; Zhang, Z. M.; Liu, B.; Xu, S.; Zhou, L. J.; Zhang, J. Chem. Commun., 2017, 53, 8152.
      (o) Bai, X.-F.; Song, T.; Xu, Z.; Xia, C.-G.; Huang, W.-S.; Xu, L.-W Angew. Chem., Int. Ed. 2015, 54, 5255.
      (p) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979.
      (q) Feng, B.; Chen, J.-R.; Yang, Y.-F.; Lu, B.; Xiao, W. J. Chem. Eur. J. 2018, 24, 1714.

    7. [7]

      (a) Zhi, Y.; Zhao, K.; Liu, Q.; Wang, A.; Enders, D. Chem. Commun. 2016, 52, 14011.
      (b) Huang, B.; Li, C.; Wang, H.; Wang, C.; Liu, L.; Zhang, J., Org. Lett. 2017, 19, 5102.
      (c) Wang, H.; Zhang, L.; Tu, Y.; Xiang, R.; Guo, Y.-L.; Zhang, J., Angew. Chem. Int. Ed. 2018, 57, 15787.
      (d) Ponce, A.; Alonso, I.; Adrio, J.; Carretero, J. C. Chem.-Eur. J. 2016, 22, 4952.
      (e) Dong, Z.; Zhu, Y.; Li, B.; Wang, C.; Yan, W.; Wang, K.; Wang, R. J. Org. Chem. 2017, 82, 3482.

    8. [8]

      (a) Bonnet-Delpon, D.; Chennoufi, A.; Rock, M. H. Bull. Soc. Chim. Fr. 1985, 132, 402.
      (b) Bégué, J.-P.; Bonnet-Delpon, D.; Chennoufi, A.; Ourévitch, M. K.; Ravikumar, S.; Rock, A. H. J. Fluorine Chem., 2001, 107, 275.

    9. [9]

      (a) Li, Q.-H.; Tong, M.-C.; Li, J.; Tao, H.-Y.; Wang, C.-J. Chem. Commun., 2011, 47, 11110.
      (b) Li, Q.-H, ; Xue, Z.-Y, ; Li, J, ; Tao, H.-Y, ; Wang, C.-J. Tetrahedron Lett. 2012, 53, 3650.

    10. [10]

      Tang, L.-W.; Zhao, B.-J.; Dai, L.; Zhang, M.; Zhou, Z.-M. Chem.-Asian J. 2016, 11, 2470. doi: 10.1002/asia.201600941

    11. [11]

      For applications of Ming-Phos in asymmetric catalysis, see: (a) Zhang, Z.-M.; Chen, P.; Li, W.; Niu, Y.; Zhao, X. L.; Zhang, J. Angew. Chem., Int. Ed. 2014, 53, 4350.
      (b) Chen, M.; Zhang, Z.-M.; Yu, Z.; Qiu, H.; Ma, B.; Wu, H.-H.; Zhang, J. ACS Catal. 2015, 5, 7488.
      (c) Zhang, Z.-M.; Xu, B.; Xu, S.; Wu, H.-H.; Zhang, J. Angew. Chem., Int. Ed. 2016, 55, 6324.
      (d) Xu, B.; Zhang, Z.-M.; Xu, S.; Liu, B.; Xiao, Y.; Zhang, J. ACS Catal. 2017, 7, 210.
      (e) Di, X.; Wang, Y.; Wu, L.; Zhang, Z.-M.; Dai, Q.; Li, W.; Zhang, J. Org. Lett. 2019, 21, 3018.
      (f) Wang, Y.; Zhang, Z.-M.; Liu, F.; He, Y.; Zhang, J. Org. Lett. 2018, 20, 6403.
      (g) Zhou, L.; Li, S.; Xu, B.; Ji, D.; Wu, L.; Liu, Y.; Zhang Z.-M.; Zhang, J. Angew. Chem., Int. Ed. 2020, 59, 2769.
      (h) Zhou, L.; Xu, B.; Ji, D.; Zhang, Z.-M.; Zhang, J. Chin. J. Chem. 2020, 38, 577.

    12. [12]

      For applications of Ming-Phos in[3+2] cycloadditions, see: (a) Xu, B.; Zhang, Z.-M.; Xu, S.; Liu, B.; Xiao, Y. Zhang, J. ACS Catal. 2017, 7, 210.
      (b) Liu, B, ; Zhang, Z.-M.; Xu, B.; Xu, S, ; Wu, H.-H, ; Zhang, J. Adv. Synth. Catal. 2018, 360, 2144.
      (c) Zhang, R.; Xu, B.; Zhang, Z.-M.; Zhang, J. Acta Chim. Sinica 2020, 78, 245(in Chinese).
      张荣华, 许冰, 张展鸣, 张俊良, 化学学报, 2020, 78, 245.

    13. [13]

      Wu, Y.; Xu, B.; Liu, B.; Zhang, Z. M.; Liu, Y. Org. Biomol. Chem. 2019, 17, 1395. doi: 10.1039/C8OB02922A

  • 图 1  带有CF3立体中心的农业和药物化学杂环化合物

    Figure 1  Asymmetric [3+2] cycloaddition of azomethine ylides with electron-deficient alkenes

    图 2  甲亚胺叶立德与三氟甲基烯烃的[3+2]不对称环加成反应

    Figure 2  Asymmetric [3+2] cycloaddition of azomethine ylides with trifluoromethyl alkenes

    表 1  Ming-phos配体筛选a

    Table 1.  Screening of Ming-phos ligands

    Entry Ligand drb Yieldc/% eed/%
    1 M1 3:1 70 92
    2 M2 1:1 43 86
    3 M3 4:1 78 98
    4 M4 2:1 63 98
    5 M5 1:1 70 12
    6 M6 1:1 40 34
    a All reactions were carried out with 0.1 mmol of 1a, 0.2 mmol of 2a, 5 mol% catalyst ([Cu] to ligand=1:1.1) in 2.0 mL of MTBE at -30 ℃ for 6 h. b The diastereomeric ratios were determined by 1H NMR analysis of the crude products. c The yield of 3aa was determined by 1H NMR analysis using CH2Br2 as the internal reference. d The ee values were determined by chiral HPLC.
    下载: 导出CSV

    表 2  反应条件优化a

    Table 2.  Optimization of the reaction conditions

    Entry [Cu] Base Solvent dr b Yield c (ee) d/%
    1 Cu(CH3CN)4ClO4 Cs2CO3 MTBE 5:1 74 (98)
    2 Cu(CH3CN)4PF6 Cs2CO3 MTBE 5:1 80 (98)
    3 [Cu(OTf)]2"Tol Cs2CO3 MTBE 5:1 77 (96)
    4 Cu(CF3SO3)2 Cs2CO3 MTBE 5:1 76 (96)
    5 Cu(CH3CN)4NTf2 Cs2CO3 MTBE 4:1 78 (93)
    6 Cu(CH3CN)4BF4 Cs2CO3 MTBE 5:1 79 (98)
    7 Cu(CH3CN)4BF4 tBuOK MTBE 3:1 56 (11)
    8 Cu(CH3CN)4BF4 DBU MTBE 1:1 35 (0)
    9 Cu(CH3CN)4BF4 Et3N MTBE 4:1 66 (96)
    10 Cu(CH3CN)4BF4 K2CO3 MTBE 5:1 78 (98)
    11 Cu(CH3CN)4BF4 Cs2CO3 THF 6:1 85 (96)
    12 Cu(CH3CN)4BF4 Cs2CO3 iPr2O 5:1 78 (98)
    13 Cu(CH3CN)4BF4 Cs2CO3 Et2O 4:1 74 (97)
    14 Cu(CH3CN)4BF4 Cs2CO3 Toluene 6:1 77 (96)
    a All reactions were carried out with 0.1 mmol of 1a, 0.2 mmol of 2a 5 mol% of catalyst ([Cu] to ligand=1:1.1) in 2.0 mL solvent at -30 ℃ for 6 h. b The diastereomeric ratios were determined by 1H NMR analysis of the crude products. c The yields were determined by 1H NMR analysis using CH2Br2 as the internal reference. d The ee values were determined by chiral HPLC.
    下载: 导出CSV

    表 3  底物范围a, b

    Table 3.  Substrate scope

    a All reactions were carried out with 0.3 mmol of 1, 0.6 mmol of 2, 5 mol% of catalyst ([Cu] to ligand=1:1.1) in 6.0 mL THF at -30 ℃ for 2~8 h. b Isolated yield. The ee values were determined by chiral HPLC. The diastereomeric ratios were determined by 1H NMR analysis of the crude products.
    下载: 导出CSV
  • 加载中
计量
  • PDF下载量:  3
  • 文章访问数:  105
  • HTML全文浏览量:  9
文章相关
  • 发布日期:  2020-08-01
  • 收稿日期:  2020-04-25
  • 修回日期:  2020-04-29
  • 网络出版日期:  2020-05-25
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

/

返回文章