螺[4,4]壬烷骨架广泛地存在于天然产物、药物分子及生物活性分子中.在近几十年里, 越来越多的化学家致力于此类分子的合成, 并发展出过渡金属催化[1]和有机小分子催化[2]等各种各样的合成策略.虽然对此类化合物的合成取得了令人瞩目的进展, 但这些方法的应用仍受原料合成困难、反应条件苛刻以及催化剂昂贵等条件限制.所以发展利用简单易得的催化剂和原料, 条件温和且高效合成出螺环化合物的方法仍十分具有挑战.
1995年, 陆熙炎等[3a]首先报道了三苯基磷催化的[3+2]环化反应, 到目前为止, 有机磷小分子作为一种有效的亲核催化剂已被广泛应用到环化反应中[4].此前的研究主要集中于2, 3-丁二烯酸酯与α-取代的联烯酸酯, 并发展出Lu’s [3+2][3], Kwon’s [4+2][5], Tong’s [4+1][6]等类型反应.由于γ-取代基的引入导致联烯酸酯的反应活性降低, 因此对γ-取代联烯酸酯的研究相对较少[7]. 2011年, 施敏等[8]报道了γ-取代联烯酸酯的γ位区域选择性[3+2]环化反应. 2013年, Marinetti课题组[9]发展了三苯基磷催化γ-取代联烯酸酯的α区域选择性[3+2]环化反应.这些研究表明, γ-取代联烯酸酯可以应用于有机磷催化的环化反应中.
2013年, 黄有等[10]通过γ-取代联烯酸酯与2-芳基- 1, 3-茚二酮的[4+2]环化反应, 合成出一系列螺环化合物(Scheme 1).作者在联烯酸酯的δ-位引入苯基基团, 利用芳环π-共轭效应稳定γ亚甲基上负电荷, 进而实现极性反转加成.本研究中, 我们发现了γ-甲基联烯酸酯与2-芳基-1, 3-茚二酮全新区域选择性串联反应.在三苯基磷催化下, 以中等到较好的产率和非对映选择性得到螺[4,4]壬烷类化合物(Scheme 1).
在最初的实验中, 以2-苯基烯基-1, 3-茚二酮(1a)和γ-甲基联烯酸酯为底物, PPh3 (20 mol%)为催化剂, 四氢呋喃(THF)为溶剂, 在室温的条件下, 反应12 h, 以72%的产率和9:1的非对映选择性获得产物3a.然后对反应条件进行了优化.首先筛选了不同亲核性能的有机磷催化剂(表 1, Entries 1~5).结果表明, 有机磷催化剂的亲核性对反应的产率和非对映选择性有很大影响, 催化剂亲核性过强[如PBu3和(4-MeOC6H4)3P, 表 1, Entries 3, 5]或过弱(表 1, Entry 2)都抑制该反应进行.室温条件下反应较好, 降低或者升高温度, 对反应不利(表 1, Entries 6, 7).提高或者降低催化剂的用量不能改善反应结果(表 1, Entries 8~10).最后, 考察了溶剂对反应的影响, 当使用1, 4-二氧六环作为溶剂时, 效果最好(表 1, Entries 11~15).选用的优化反应条件: PPh3 (20 mol%)作为催化剂, 1, 4-二氧六环为溶剂, 在室温的条件下反应4 h.产物3的结构和立体化学通过NMR, HRMS及单晶分析(3e)等手段表征[11].
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| Entry | Catalyst (mol%) | Solvent | Time/h | dr | Yieldb/% |
| 1 | Ph3P (20) | THF | 12 | 9:1 | 72 |
| 2 | (4-FC6H4)3P (20) | THF | 23 | 3.8:1 | 33 |
| 3 | (4-MeOC6H4)3P (20) | THF | 24 | — | Trace |
| 4 | Ph2PMe (20) | THF | 23 | 1.7:1 | 12 |
| 5 | PBu3 (20) | THF | 24 | — | Trace |
| 6c | Ph3P (20) | THF | 30 | — | 0 |
| 7d | Ph3P (20) | THF | 2 | 5.9:1 | 61 |
| 8 | Ph3P (10) | THF | 28 | — | Trace |
| 9 | Ph3P (30) | THF | 20 | 5.6:1 | 50 |
| 10 | Ph3P (50) | THF | 2 | 3.6:1 | 34 |
| 11 | Ph3P (20) | CHCl3 | 18 | 5.5:1 | 13 |
| 12 | Ph3P (20) | CH2Cl2 | 18 | 1.6:1 | 6 |
| 13 | Ph3P (20) | Toluene | 20 | 5.2:1 | 72 |
| 14 | Ph3P (20) | CH3CN | 20 | — | Trace |
| 15 | Ph3P (20) | 1, 4-Dixoane | 4 | 6.4:1 | 82 |
| a Unless otherwise mentioned, the reaction was performed with 1a (0.1 mmol), 2a (0.2 mmol) in 2.0 mL of solvent. b Isolated yield. c Reaction temperature: 0 ℃. d Reaction temperature: 50 ℃. | |||||
接着对合成螺环化合物的反应进行拓展.分别考察了芳基烯基茚二酮上芳基取代基及联烯酸酯上酯基对反应的影响, 反应结果如表 2所示.此类反应有很好的底物适用性.对于底物1, 无论芳基上的取代基是吸电子基还是供电子基, 这类反应均能顺利进行, 并以中等到较好的产率及非对映选择性得到目标产物(表 2, Entries 1~19).研究发现芳基上取代基的位置对产率有影响.当取代基在对位时, 反应产率较低(表 2, Entries 4 vs. 2, 3; 7 vs. 5, 6; 10 vs. 9; 12 vs. 11).当使用强供电子基或者强吸电子基时, 此类反应仍能顺利地进行, 并给出较好的产率和非对映选择性(表 2, Entries 8, 13).值得一提的是, 当芳基为稠环(1-萘基、2-萘基)、杂环(2-噻吩基、3-噻吩基、2-呋喃基)或者苯乙烯基等时, 该反应以中等到较好收率和非对映选择性得到相应螺环化合物(表 2, Entries 14~19).当使用γ-甲基联烯酸苄酯时, 所得到的螺环化合物的产率和非对映选择性有一定的降低(表 2, Entry 20).当使用γ-甲基联烯酸甲酯时, 得到78%的产率和4:1的非对映选择性(表 2, Entry 21).然而, 当使用γ-异丙基联烯酸乙酯时, 没有目标产物生成.
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| Entry | Ar | R | Time/h | Yieldb/% | dr |
| 1 | Ph | Et | 4 | 82 | 6.4:1 |
| 2 | 2-MeC6H4 | Et | 34 | 57 | 9:1 |
| 3 | 3-MeC6H4 | Et | 2 | 67 | 4:1 |
| 4 | 4-MeC6H4 | Et | 23 | 39 | 5:1 |
| 5 | 2-BrC6H4 | Et | 48 | 66 | 10:1 |
| 6 | 3-BrC6H4 | Et | 20 | 68 | 5:1 |
| 7 | 4-BrC6H4 | Et | 17 | 47 | 7:1 |
| 8 | 4-MeOC6H4 | Et | 21 | 75 | 5:1 |
| 9 | 2-ClC6H4 | Et | 17 | 79 | 10:1 |
| 10 | 4-ClC6H4 | Et | 12 | 57 | 5:1 |
| 11 | 2-FC6H4 | Et | 24 | 76 | 9:1 |
| 12 | 4-FC6H4 | Et | 7 | 38 | 10:1 |
| 13 | 2, 4-Cl2C6H3 | Et | 24 | 87 | ＞20:1 |
| 14 | 1-Naphthyl | Et | 24 | 79 | 8:1 |
| 15 | 2-Naphthyl | Et | 34 | 42 | 11:1 |
| 16 | 2-Thienyl | Et | 24 | 74 | ＞20:1 |
| 17 | 3-Thienyl | Et | 34 | 54 | ＞20:1 |
| 18 | 2-Furyl | Et | 24 | 84 | 10:1 |
| 19 | 2-Styryl | Et | 34 | 41 | 3:1 |
| 20 | Ph | Bn | 22 | 40 | 3:1 |
| 21 | Ph | Me | 10 | 78 | 4:1 |
| a Unless otherwise stated, the reactions were performed with 1 (0.1 mmol), 2 (0.2 mmol) in 2.0 mL of solvent. b Isolated yield. | |||||
根据实验结果和文献报道[12], 我们推测了反应机理.首先, 三苯基磷亲核进攻γ-甲基联烯酸酯的β位, 生成两性离子中间体A和B, 接下来, 两性离子中间体进攻烯基茚二酮生成α区域选择性中间体C, 随后的关环反应产生中间体D, 分子内1, 2-H迁移给出中间体E, 最后, 脱去催化剂得到最终的产物(Scheme 2).
发展了一种有机磷催化的基于γ-取代联烯酸酯α区域选择性[3+2]环加成反应, 在此类反应中, 通过使用芳基烯基茚二酮作为缺电子烯烃, 成功地以中等到较好的产率和非对映选择性得到一系列的螺环化合物.此类反应具有操作简单、反应条件温和和底物适用性广等优点, 对于此类反应的后续研究仍在进行当中.
1H NMR (300 MHz)和13C NMR (75 MHz)采用Bruker AV300核磁共振仪测定, 所用溶剂为CDCl3, 核磁校正以CDCl3为内标; 所有的测试在298 K的温度下.熔点测定仪使用SGW X-4B型熔点测定仪; 未知化合物的高分辨数据采用Agilent 1290-6540 UHPLC Q-Tof高分辨质谱仪配合ESI源测定, 已知化合物的物理数据和核磁数据氢谱均经与已知文献比对确认.实验所用试剂均为分析纯试剂, 从安耐吉和百灵威等试剂公司购买; 柱层析使用200~300目硅胶(青岛海洋), 洗脱剂为石油醚(b.p. 60~90 ℃)和乙酸乙酯.底物1[13]和2[14]的合成均参考已知的文献.
取2-芳基-1, 3-茚二酮1 (0.1 mmol)与γ-甲基联烯酸酯2 (0.2 mmol)于10 mL圆底烧瓶中, 加入2 mL的1, 4-二氧六环作为溶剂, 加入PPh3 (0.02 mmol)作为催化剂, 室温条件下反应, 薄层色谱(TLC)跟踪监测.当反应完全后, 减压除去溶剂, 柱层析分离(石油醚/乙酸乙酯, V:V＝15:1), 得到最终的目标产物.
5-甲基-2-苯基-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-烯-3-甲酸乙酯(3a):白色固体, 产率82%. m.p. 105.7~105.9 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.96 (d, J＝7.5 Hz, 1H, ArH), 7.77~7.57 (m, 3H, ArH), 7.12~6.97 (m, 3H, ArH), 6.95~6.79 (m, 3H, ArH, C＝CH), 4.77 (t, J＝2.5 Hz, 1H, CHPh), 4.13~3.99 (m, 2H, OCH2), 3.60~3.52 (m, 1H, CHCH3), 1.11~1.04 (m, 6H, CHCH3, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 202.8, 198.0, 164.1, 147.1, 142.9, 141.8, 137.1, 135.9, 135.3, 134.5, 128.5, 127.8, 127.0, 123.0, 122.9, 68.7, 60.3, 59.4, 45.8, 14.7, 14.0; HRMS (ESI) calcd for C23H21O4 [M+ H]+ 361.1434, found 361.1433.
5-甲基-2-(邻甲苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3b):白色固体, 产率57%; m.p. 143.1~143.5 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.77~7.61 (m, 3H, ArH), 7.59~7.46 (m, 2H, ArH), 7.01 (d, J＝7.7 Hz, 1H, C＝CH), 6.87~6.69 (m, 3H, ArH), 3.97 (q, J＝7.1 Hz, 2H), 3.69~3.66 (m, 1H, CHAr), 2.75~2.53 (m, 3H, CHCH3), 2.17 (s, 3H, CH3), 1.89~1.71 (m, 1H, CHCH3), 0.99 (t, J＝7.1 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 202.7, 202.0, 165.4, 146.7, 142.4, 142.3, 137.7, 135.6, 134.6, 134.5, 130.6, 129.6, 127.3, 126.7, 125.8, 122.6, 122.0, 61.2, 61.0, 42.6, 26.7, 25.1, 19.5, 13.7; HRMS (ESI) calcd for C24H23O4 [M+H]+ 375.1591, found 375.1590.
5-甲基-2-(间甲苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3c):白色固体, 产率67%; m.p. 112.9~113.1 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.84~7.50 (m, 5H, ArH), 6.93~6.64 (m, 4H, ArH, C＝CH), 3.99 (q, J＝7.1 Hz, 2H, OCH2), 3.31 (d, J＝12.4 Hz, 1H, CHAr), 2.86~2.47 (m, 3H, CHCH3), 2.10 (s, 3H, CH3), 1.99~1.82 (m, 1H, CHCH3), 1.01 (t, J＝7.1 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 203.15, 201.38, 165.45, 146.76, 142.86, 141.79, 138.72, 137.52, 134.43, 128.97, 128.81, 127.97, 127.80, 125.10, 122.36, 122.00, 61.40, 60.97, 47.78, 26.38, 23.42, 21.06, 13.63; HRMS (ESI) calcd for C24H23O4 [M+H]+ 375.1591, found 375.1591.
5-甲基-2-(对甲苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3d):黄色黏性液体, 产率39%; 1H NMR (300 MHz, CDCl3) δ: 7.71 (dd, J＝5.9, 2.0 Hz, 1H), 7.63~7.49 (m, 4H), 6.77 (dd, J＝26.9, 8.1 Hz, 4H), 3.95 (q, J＝7.1 Hz, 2H, OCH2), 3.38~3.23 (m, 1H, CHAr), 2.81~2.46 (m, 3H, CHCH3), 2.05 (s, 3H, CH3), 1.92~1.80 (m, 1H, CHCH3), 0.96 (t, J＝7.1 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 203.3, 201.6, 165.5, 146.8, 142.9, 141.8, 136.7, 135.8, 134.5, 134.4, 129.0, 128.6, 127.9, 122.5, 122.1, 61.3, 61.0, 47.5, 26.4, 23.6, 20.7, 13.6; HRMS (ESI) calcd for C24H23O4 [M+ H]+ 375.1591, found 375.1591.
5-甲基-2-(2-溴苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3e):白色固体, 产率66%; m.p. 133.2~133.5 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.02 (d, J＝7.4 Hz, 1H), 7.83~7.67 (m, 3H), 7.32~7.20 (m, 3H), 7.05~6.97 (m, 2H), 5.15 (s, 1H, CHAr), 4.19~3.94 (m, 2H, OCH2), 3.51~3.35 (m, 1H, CHCH3), 1.10~1.06 (m, 6H, CHCH3, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 202.5, 197.2, 163.7, 147.4, 142.5, 141.5, 137.8, 135.7, 135.4, 134.9, 132.2, 130.6, 128.6, 127.0, 125.0, 123.5, 122.8, 65.4, 60.4, 56.7, 47.5, 16.0, 13.9; HRMS (ESI) calcd for C23H20BrO4 [M+H]+ 439.0539, found 439.0539.
5-甲基-2-(3-溴苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3f):黄色黏性液体, 产率68%; 1H NMR (300 MHz, CDCl3) δ: 7.99 (d, J＝7.4 Hz, 1H), 7.83~7.60 (m, 3H), 7.19 (d, J＝7.9 Hz, 1H), 7.05~6.80 (m, 4H, ArH, C＝CH), 4.71 (t, J＝2.6 Hz, 1H, CHAr), 4.17~4.02 (m, 2H, OCH2), 3.62~3.46 (m, 1H, CHCH3), 1.13~1.08 (m, 6H, CH2CH3, CHCH3); 13C NMR (75 MHz, CDCl3) δ: 202.5, 197.8, 163.8, 147.6, 142.8, 141.7, 139.6, 136.1, 135.6, 134.0, 131.6, 130.2, 129.3, 127.3, 123.2, 123.1, 121.9, 68.3, 60.5, 58.5, 46.1, 14.7, 14.0; HRMS (ESI) calcd for C23H20BrO4 [M+H]+ 439.0539, found 439.0536.
5-甲基-2-(4-溴苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3g):黄色黏性液体, 产率47%; 1H NMR (300 MHz, CDCl3) δ: 7.96 (d, J＝7.3 Hz, 1H), 7.82~7.59 (m, 3H), 7.19 (d, J＝8.4 Hz, 2H), 6.86 (t, J＝2.3 Hz, 1H), 6.78 (d, J＝8.3 Hz, 2H), 4.73 (t, J＝2.6 Hz, 1H, CHAr), 4.20~3.94 (m, 2H, OCH2), 3.61~3.44 (m, 1H, CHCH3), 1.15~1.02 (m, 6H, CHCH3, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 202.6, 197.9, 163.8, 147.4, 142.8, 141.7, 136.3, 136.1, 135.6, 134.1, 130.9, 130.3, 123.1, 123.1, 121.0, 68.4, 60.4, 58.4, 46.2, 14.6, 14.0; HRMS (ESI) calcd for C23H20BrO4 [M+H]+ 439.0539, found 439.0536.
5-甲基-2-(4-甲氧基苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3h):黄色固体, 产率75%; 1H NMR (300 MHz, CDCl3) δ: 7.78~7.69 (m, 1H), 7.64~7.51 (m, 4H), 6.85 (d, J＝8.7 Hz, 2H), 6.46 (d, J＝8.7 Hz, 2H), 3.95 (q, J＝7.1 Hz, 2H, OCH2), 3.58 (s, 3H, OCH3), 3.28 (d, J＝12.4 Hz, 1H, CHAr), 2.81~2.45 (m, 3H, CHCH3), 1.88~1.83 (m, 1H, CHCH3), 0.97 (t, J＝7.1 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 203.4, 201.64, 165.4, 158.5, 146.8, 142.9, 141.8, 134.6, 134.5, 131.0, 129.1, 129.0, 122.5, 122.1, 113.4, 61.4, 61.0, 55.1, 47.0, 26.4, 23.8, 13.6; HRMS (ESI) calcd for C24H23O5 [M+H]+ 391.1540, found 391.1540.
5-甲基-2-(2-氯苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3i):白色固体, 产率79%; m.p. 103.4~103.8 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.01 (d, J＝7.5 Hz, 1H), 7.85~7.61 (m, 3H), 7.19 (d, J＝2.8 Hz, 2H), 7.08 (t, J＝3.0 Hz, 2H), 6.96 (t, J＝2.2 Hz, 1H), 5.16 (t, J＝2.0 Hz, 1H, CHAr), 4.14~4.00 (m, 2H, OCH2), 3.50~3.43 (m, 1H), 1.12~1.01 (m, 6H, CH2CH3, CHCH3); 13C NMR (75 MHz, CDCl3) δ: 202.5, 197.4, 163.7, 147.6, 142.3, 141.5, 136.0, 135.7, 135.4, 134.5, 133.9, 130.5, 128.8, 128.3, 126.4, 123.4, 122.8, 65.7, 60.4, 54.2, 47.3, 15.8, 13.9; HRMS (ESI) calcd for C23H20ClO4 [M+H]+ 395.1045, found 395.1042.
5-甲基-2-(4-氯苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3j):黄色黏性液体, 产率57%; 1H NMR (300 MHz, CDCl3) δ: 7.95 (d, J＝7.5 Hz, 1H), 7.79~7.61 (m, 3H), 7.02 (d, J＝8.2 Hz, 2H), 6.85~6.81 (m, 3H), 4.73 (t, J＝2.6 Hz, 1H, CHAr), 4.14~3.97 (m, 2H, OCH2), 3.57~3.48 (m, 1H, CHCH3), 1.13~1.01 (m, 6H, CHCH3, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 202.6, 198.0, 163.9, 147.4, 142.8, 141.7, 136.1, 135.8, 135.5, 134.2, 132.8, 129.9, 128.0, 123.1, 68.5, 60.4, 58.4, 46.1, 26.9, 14.6, 14.0; HRMS (ESI) calcd for C23H20ClO4 [M+H]+ 395.1045, found 395.1045.
5-甲基-(2-氟苯基)-1', 3'-二氧-2-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3k):黄色黏性液体, 产率76%; 1H NMR (300 MHz, CDCl3) δ: 8.04 (m, 1H), 7.85~7.65 (m, 3H), 7.19~6.98 (m, 3H), 6.95 (t, J＝2.3 Hz, 1H), 6.74~6.68 (m, 1H), 5.05 (s, 1H, CHAr), 4.22~4.04 (m, 2H, OCH2), 3.62~3.53 (m, 1H, CHCH3), 1.18~1.08 (m, 6H, CHCH3, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 202.2, 197.8, 163.9, 160.2 (d, J＝245.7 Hz), 147.7, 142.0 (d, J＝44.1 Hz), 135.8, 135.5, 133.5, 130.4 (d, J＝3.9 Hz), 128.7 (d, J＝8.3 Hz), 124.9, 124.7, 123.6 (d, J＝3.4 Hz), 123.3, 122.8, 114.7, 114.4, 66.7, 60.4, 46.5, 15.0, 14.0; HRMS (ESI) calcd for C23H20FO4 [M+H]+ 379.1340, found 379.1339.
5-甲基-2-(4-氟苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3l):黄色黏性液体, 产率38%; 1H NMR (300 MHz, CDCl3) δ: 7.97 (d, J＝7.3 Hz, 1H), 7.82~7.56 (m, 3H), 6.89~6.84 (m, 3H), 6.75 (t, J＝8.7 Hz, 2H), 4.76 (t, J＝2.6 Hz, 1H, CHAr), 4.24~3.92 (m, 2H, OCH2), 3.59~3.52 (m, 1H, CHCH3), 1.14~1.02 (m, 6H, CHCH3, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 202.7, 198.1, 164.0, 161.7 (d, J＝245.5 Hz), 147.3, 142.9, 141.8, 136.0, 135.5, 134.3, 132.9 (d, J＝3.2 Hz), 130.1 (d, J＝8.1 Hz), 123.0 (d, J＝3.9 Hz), 114.9, 114.6, 68.6, 60.4, 58.5, 45.9, 14.6, 14.0; HRMS (ESI) calcd for C23H20FO4 [M+H]+ 379.1340, found 379.1340.
5-甲基-2-(2, 4-二氯苯基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3m):白色固体, 产率87%; m.p. 109.4~109.7 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.01 (d, J＝7.1 Hz, 1H), 7.87~7.66 (m, 3H), 7.21~7.11 (m, 3H), 6.96 (t, J＝2.3 Hz, 1H), 5.10 (t, J＝2.0 Hz, 1H, CHAr), 4.20~3.99 (m, 2H, OCH2), 3.50~3.41 (m, 1H, CHCH3), 1.12 (t, J＝7.1 Hz, 3H, CH2CH3), 1.07 (d, J＝7.4 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ: 202.2, 197.4, 163.5, 147.9, 142.2, 141.4, 135.9, 135.7, 134.8, 134.4, 134.2, 133.4, 131.3, 128.6, 126.8, 123.5, 122.9, 65.4, 60.6, 53.6, 47.5, 15.8, 14.0; HRMS (ESI) calcd for C23H19Cl2O4 [M+H]+ 379.1340, found 379.1340.
5-甲基-2-(1-萘基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3n):白色固体, 产率79%; m.p. 106.8~107.1 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.88 (d, J＝7.5 Hz, 1H), 7.66~7.49 (m, 5H), 7.42~7.12 (m, 5H), 6.99 (s, 1H), 5.64 (s, 1H, CHAr), 4.19~3.92 (m, 2H, OCH2), 3.64 (d, J＝7.1 Hz, 1H, CHCH3), 1.13 (d, J＝7.3 Hz, 3H, CHCH3), 1.00 (t, J＝7.0 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 203.6, 197.6, 164.2, 146.9, 142.3, 141.6, 135.7, 135.2, 135.0, 133.5, 133.4, 131.5, 128.7, 127.6, 127.5, 125.7, 125.0, 125.0, 122.9, 122.7, 122.6, 67.6, 60.3, 53.7, 46.7, 15.2, 14.0; HRMS (ESI) calcd for C27H23O4 [M+H]+ 411.1591, found 411.1592.
5-甲基-2-(2-萘基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3o):黄色黏性液体, 产率42%; 1H NMR (300 MHz, CDCl3) δ: 7.99 (d, J＝7.6 Hz, 1H), 7.77~7.46 (m, 6H), 7.42~7.29 (m, 3H), 7.09 (dd, J＝8.5, 1.5 Hz, 1H), 6.92 (t, J＝2.3 Hz, 1H), 4.98 (t, J＝2.6 Hz, 1H, CHAr), 4.14~3.95 (m, 2H, OCH2), 3.67~3.54 (m, 1H, CHCH3), 1.13 (d, J＝7.4 Hz, 3H, CHCH3), 1.04 (t, J＝7.1 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 203.0, 198.0, 164.2, 147.1, 142.9, 141.8, 135.9, 135.3, 134.9, 134.7, 132.9, 132.5, 127.8, 127.5, 127.5, 127.4, 126.8, 125.7, 125.6, 123.1, 123.0, 68.7, 60.4, 59.2, 46.2, 14.7, 14.0; HRMS (ESI) calcd for C27H23O4 [M+H]+ 411.1591, found 411.1591.
5-甲基-2-(2-噻吩基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3p):黄色固体, 产率74%; 1H NMR (300 MHz, CDCl3) δ: 7.99 (d, J＝6.8 Hz, 1H), 7.85~7.68 (m, 3H), 7.01 (d, J＝4.5 Hz, 1H), 6.85 (t, J＝2.2 Hz, 1H), 6.77 (dd, J＝5.0, 3.6 Hz, 1H), 6.62 (d, J＝3.3 Hz, 1H), 4.96 (t, J＝2.2 Hz, 1H, CHAr), 4.19~4.01 (m, 2H, OCH2), 3.52~3.45 (m, 1H, CHCH3), 1.15~1.10 (m, 6H, CH2CH3, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 202.3, 197.6, 163.8, 146.8, 143.0, 141.7, 140.2, 136.0, 135.5, 134.5, 126.8, 126.6, 124.5, 123.2, 123.1, 67.8, 60.4, 53.5, 45.9, 15.2, 14.0; HRMS (ESI) calcd for C21H19SO4 [M+H]+ 367.0999, found 367.0999.
5-甲基-2-(3-噻吩基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3q):黄色黏性液体, 产率54%; 1H NMR (300 MHz, CDCl3) δ: 7.96 (d, J＝6.9 Hz, 1H), 7.82~7.66 (m, 3H), 7.02 (dd, J＝4.9, 3.0 Hz, 1H), 6.82 (t, J＝2.3 Hz, 1H), 6.76~6.69 (m, 1H), 6.65 (dd, J＝5.0, 1.2 Hz, 1H), 4.85 (t, J＝2.7 Hz, 1H, CHAr), 4.20~3.97 (m, 2H, OCH2), 3.61~3.47 (m, 1H, CHCH3), 1.13~1.09 (m, 6H, CHCH3, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 202.7, 198.2, 164.0, 146.6, 142.9, 141.8, 137.8, 136.0, 135.4, 134.5, 128.1, 124.7, 123.0, 122.9, 122.7, 68.5, 60.3, 54.2, 45.5, 14.6, 14.0; HRMS (ESI) calcd for C21H19SO4 [M+H]+ 367.0999, found 367.0998.
5-甲基-2-(2-呋喃基)-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3r):黄色固体, 产率84%; 1H NMR (300 MHz, CDCl3) δ: 8.07~7.95 (m, 1H), 7.92~7.73 (m, 3H), 7.14 (s, 1H), 6.86 (t, J＝2.1 Hz, 1H), 6.20~6.11 (m, 1H), 5.93 (d, J＝3.1 Hz, 1H), 4.75 (s, 1H, CHAr), 4.28~4.03 (m, 2H, OCH2), 3.45~3.38 (m, 1H, CHCH3), 1.19 (t, J＝7.1 Hz, 3H, CH2CH3), 1.13 (d, J＝7.4 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ: 202.1, 197.3, 163.6, 151.1, 147.0, 142.8, 141.6, 141.4, 135.9, 135.5, 132.7, 123.4, 123.1, 110.3, 108.0, 65.9, 60.5, 51.3, 46.5, 15.3, 14.1; HRMS (ESI) calcd for C21H19O5 [M+H]+ 351.1227, found 351.1230.
(E)-5-甲基-2-苯乙烯基-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-甲酸乙酯(3s):黄色固体, 产率41%; 1H NMR (300 MHz, CDCl3) δ: 8.01~7.95 (m, 1H), 7.94~7.88 (m, 1H), 7.84~7.75 (m, 2H), 7.23~7.09 (m, 5H), 6.74 (t, J＝2.1 Hz, 1H), 6.22 (t, J＝6.6 Hz, 2H), 4.33~4.05 (m, 3H, CHAr, OCH2), 3.48~3.41 (m, 1H, CHCH3), 1.27~1.21 (m, , 3H, CH2CH3), 1.10 (d, J＝7.4 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ: 202.7, 199.0, 163.9, 146.0, 142.9, 142.1, 136.7, 136.1, 135.8, 135.6, 134.9, 132.5, 128.3, 127.4, 127.2, 126.4, 123.3, 67.7, 60.4, 55.7, 46.4, 14.9, 14.2; HRMS (ESI) calcd for C25H23O4 [M+H]+ 387.1591, found 387.1591.
5-甲基-2-苯基-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-烯-3-甲酸苄酯(3t):黄色黏性液体, 产率40%; 1H NMR (300 MHz, CDCl3) δ: 7.97 (d, J＝7.5 Hz, 1H), 7.80~7.65 (m, 2H), 7.59 (d, J＝7.5 Hz, 1H), 7.30~6.85 (m, 11H), 5.06 (dd, J＝45.0, 12.6 Hz, 2H, OCH2), 4.81 (t, J＝2.6 Hz, 1H, CHAr), 3.63~3.51 (m, 1H, CHCH3), 1.11 (d, J＝7.4 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ: 202.8, 198.0, 163.9, 148.1, 142.9, 141.8, 137.0, 135.9, 135.7, 135.3, 134.1, 128.6, 128.3, 127.9, 127.8, 127.1, 123.02, 122.9, 68.7, 66.1, 59.4, 45.8, 14.7; HRMS (ESI) calcd for C28H23O4 [M+H]+ 423.1591, found 423.1591.
5-甲基-2-苯基-1', 3'-二氧-1', 3'-二氢螺[环戊[3]烯-1, 2'-茚]-3-烯-3-甲酸甲酯(3u):黄色油状物, 产率78%; 1H NMR (300 MHz, CDCl3) δ: 7.97 (d, J＝7.5 Hz, 1H), 7.76 (td, J＝7.4, 1.2 Hz, 1H), 7.69 (td, J＝7.4, 1.2 Hz, 1H), 7.59 (d, J＝7.5 Hz, 1H), 7.08~7.04 (m, 3H, ), 6.91~6.84 (m, 3H, Ar, CH＝C), 4.78 (t, J＝2.6 Hz, 1H, CHAr), 3.63 (s, 3H, OCH3), 3.56 (dt, J＝7.4, 2.6 Hz, 1H, CHCH3), 1.11 (d, J＝7.5 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ: 202.8, 198.0, 164.6, 147.6, 142.9, 141.8, 136.9, 135.9, 135.3, 134.1, 128.5, 127.9, 127.1, 123.0, 122.9, 68.6, 59.3, 51.6, 45.8, 14.7; HRMS (ESI) calcd for C28H23O4 [M+ H]+ 347.1278, found 347.1261.
辅助材料(Supporting Information) 产物3的1H NMR、13C NMR和产物3e的单晶结构.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 1 磷催化γ-取代联烯酸酯的Domino反应的不同类型
Scheme 1 Different styles for phosphine-catalyzed domino reaction with γ-substituted allenoates
表 1 反应条件优化a
Table 1. Optimization of reaction conditions
| |||||
| Entry | Catalyst (mol%) | Solvent | Time/h | dr | Yieldb/% |
| 1 | Ph3P (20) | THF | 12 | 9:1 | 72 |
| 2 | (4-FC6H4)3P (20) | THF | 23 | 3.8:1 | 33 |
| 3 | (4-MeOC6H4)3P (20) | THF | 24 | — | Trace |
| 4 | Ph2PMe (20) | THF | 23 | 1.7:1 | 12 |
| 5 | PBu3 (20) | THF | 24 | — | Trace |
| 6c | Ph3P (20) | THF | 30 | — | 0 |
| 7d | Ph3P (20) | THF | 2 | 5.9:1 | 61 |
| 8 | Ph3P (10) | THF | 28 | — | Trace |
| 9 | Ph3P (30) | THF | 20 | 5.6:1 | 50 |
| 10 | Ph3P (50) | THF | 2 | 3.6:1 | 34 |
| 11 | Ph3P (20) | CHCl3 | 18 | 5.5:1 | 13 |
| 12 | Ph3P (20) | CH2Cl2 | 18 | 1.6:1 | 6 |
| 13 | Ph3P (20) | Toluene | 20 | 5.2:1 | 72 |
| 14 | Ph3P (20) | CH3CN | 20 | — | Trace |
| 15 | Ph3P (20) | 1, 4-Dixoane | 4 | 6.4:1 | 82 |
| a Unless otherwise mentioned, the reaction was performed with 1a (0.1 mmol), 2a (0.2 mmol) in 2.0 mL of solvent. b Isolated yield. c Reaction temperature: 0 ℃. d Reaction temperature: 50 ℃. | |||||
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表 2 反应底物拓展a
Table 2. Scope of reaction substrates
| |||||
| Entry | Ar | R | Time/h | Yieldb/% | dr |
| 1 | Ph | Et | 4 | 82 | 6.4:1 |
| 2 | 2-MeC6H4 | Et | 34 | 57 | 9:1 |
| 3 | 3-MeC6H4 | Et | 2 | 67 | 4:1 |
| 4 | 4-MeC6H4 | Et | 23 | 39 | 5:1 |
| 5 | 2-BrC6H4 | Et | 48 | 66 | 10:1 |
| 6 | 3-BrC6H4 | Et | 20 | 68 | 5:1 |
| 7 | 4-BrC6H4 | Et | 17 | 47 | 7:1 |
| 8 | 4-MeOC6H4 | Et | 21 | 75 | 5:1 |
| 9 | 2-ClC6H4 | Et | 17 | 79 | 10:1 |
| 10 | 4-ClC6H4 | Et | 12 | 57 | 5:1 |
| 11 | 2-FC6H4 | Et | 24 | 76 | 9:1 |
| 12 | 4-FC6H4 | Et | 7 | 38 | 10:1 |
| 13 | 2, 4-Cl2C6H3 | Et | 24 | 87 | ＞20:1 |
| 14 | 1-Naphthyl | Et | 24 | 79 | 8:1 |
| 15 | 2-Naphthyl | Et | 34 | 42 | 11:1 |
| 16 | 2-Thienyl | Et | 24 | 74 | ＞20:1 |
| 17 | 3-Thienyl | Et | 34 | 54 | ＞20:1 |
| 18 | 2-Furyl | Et | 24 | 84 | 10:1 |
| 19 | 2-Styryl | Et | 34 | 41 | 3:1 |
| 20 | Ph | Bn | 22 | 40 | 3:1 |
| 21 | Ph | Me | 10 | 78 | 4:1 |
| a Unless otherwise stated, the reactions were performed with 1 (0.1 mmol), 2 (0.2 mmol) in 2.0 mL of solvent. b Isolated yield. | |||||
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