English

• 喹啉-2, 4-二酮结构单元广泛分布于天然产物及人工合成的化合物中, 许多喹啉-2, 4-二酮类化合物具有重要的生物及药物活性^[1].一些喹啉-2, 4-二酮衍生物还可作为有机合成中间体用于合成其它具有生物活性的含氮稠杂环化合物^[2].目前, 文献报道了多种合成喹啉-2, 4-二酮类化合物的方法, 常见的有过渡金属催化4-羟基喹啉-2-酮的偶联反应^[3]、喹啉-2, 4-二醇的3, 3-二烷基化反应^[4]、靛红酸酐的Mukaiyama反应^[5]等.虽然这些方法大大促进了对喹啉-2, 4-二酮类化合物的应用研究, 但同时它们也存在着反应条件苛刻、反应时间长、收率低和适用范围窄等明显的缺陷.近年来, 以N-(2-氰基芳基)丙烯酰胺为底物的自由基加成环化反应为多官能团化喹啉-2, 4-二酮的合成提供了一种新方法^[6], 然而这种方法通常需要使用过渡金属催化剂和过量的氧化剂, 不可避免的会对产物造成金属污染.因此, 发展简洁、高效的喹啉-2, 4-二酮衍生物合成方法仍然具有重要的意义.

  图 1

  

  图 1.  一些具有生物活性的喹啉-2, 4-二酮类化合物

  Figure 1.  Some bioactive quinoline-2, 4-diones

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  另一方面, Houben-Hoesch反应是通过芳烃与腈的亲电取代合成芳香酮或稠环酮类化合物的经典反应^[7].然而, 由于腈基的亲电性较弱, 该反应主要用于富电子芳烃的酰基化, 且在反应过程中通常需要过量强酸活化氰基^[8].严苛的反应条件不仅为反应的操作与后处理造成不便, 也进一步限制了反应的适用范围.因此, 开发温和高效的Houben-Hoesch反应条件并拓展其适用范围是非常必要的. 2010年, Kobayashi等^[9]报道了氰基乙酰芳胺类化合物在三氟乙酸酐(TFAA)/N, N-二甲基甲酰胺(DMF)体系中的分子内Houben-Hoesch反应.在该体系中, 氰基乙酰芳胺首先发生α-三氟乙酰化反应转化为烯醇中间体, 给电子的烯醇片段活化氰基从而使得该中间体在温和的条件下发生环化反应转化为3-三氟乙酰基-4-羟基喹啉-2-酮类化合物(Scheme 1).随后, 他们进一步利用给电子基团活化氰基的策略发展了氰基乙酰芳胺化合物在三氟甲磺酸酐(Tf₂O)/DMF体系中的分子内Houben-Hoesch反应, 合成了3-甲酰基-4-羟基喹啉-2-酮类化合物^[10].然而, 对于非活化的氰基乙酰芳胺衍生物, TFAA/DMF及Tf₂O/DMF体系都难以使其发生Houben-Hoesch反应.为此, 有必要继续探索新的反应条件以弥补文献报道的不足.在我们课题组前期研究工作的基础上^[11], 报道一例以三氟甲烷磺酸甲酯(TfOMe)为促进剂的α, α-二烃基氰基乙酰芳胺化合物的分子内Houben-Hoesch反应.该反应具有底物范围宽泛、产物收率高等优点, 不仅拓展了Houben-Hoesch反应的应用范围, 也为合成喹啉-2, 4-二酮类化合物提供了简便的新途径.

  图式 1

  

  图式 1.  三氟乙酰化诱导的氰基乙酰芳胺的Houben-Hoesch反应

  Scheme 1.  Trifluoroacetylation-induced Houben-Hoesch reaction of cyanoacetanilides

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  1.   结果与讨论

  1.1   反应条件的优化

  我们以带有五元环的氰基乙酰芳胺(1a)为底物对反应条件进行了优化, 主要的实验结果如表 1所示.当以无水DMF为溶剂, TFAA、Tf₂O或三氟甲烷磺酸甲酯(TfOMe)为促进剂时, 1a不发生反应(表 1, Entries 1~3).改用无水二氯乙烷为溶剂, 1.2 equiv.的TfOMe为促进剂时, 反应在100 ℃条件下进行2 h可以顺利地以78%的收率得到预期的喹啉-2, 4-二酮产物2a(表 1, Entry 4).反应在其它的溶剂如甲苯、乙酸乙酯或普通的二氯乙烷中也可进行, 但它们的效果都不如无水二氯乙烷(表 1, Entries 5~7).值得注意的是, 在无溶剂的条件下, 反应仍可以68%的收率获得目标产物2a.我们也考察了温度对反应的影响, 发现当温度降低至80 ℃时, 反应时间延长且产物2a的收率下降(表 1, Entry 9), 而当升高温度至120 ℃时, 反应效果更好(表 1, Entry 10).对物料比的考察表明1.2 equiv.的TfOMe对反应非常适合, 增加TfOMe的用量到1.3 equiv.不能提高产物2a的收率(表 1, Entry 11), 但降低TfOMe的用量会使2a的收率明显下降(表 1, Entry 12).

  表 1

  

  表 1  1a的Houben-Hoesch反应条件优化^a

  Table 1.  Optimization of the reaction conditions for the Houben-Hoesch reaction of 1a

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  Entry	Solvent	Additive (equiv.)	Time/h	T/℃	Yield/%
  1	DMF	TFAA (1.2)	10	100	0b
  2	DMF	Tf2O (1.2)	10	100	0c
  3	DMF	TfOMe (1.2)	10	100	0d
  4	ClCH2CH2Cl	TfOMe (1.2)	2	100	78
  5	Toluene	TfOMe (1.2)	20	100	46
  6	CH3CO2C2H5	TfOMe (1.2)	8	100	60
  7	ClCH2CH2Cle	TfOMe (1.2)	2	100	75
  8	__f	TfOMe (1.2)	2	100	68
  9	ClCH2CH2Cl	TfOMe (1.2)	5	80	53
  10	ClCH2CH2Cl	TfOMe (1.2)	1	120	80
  11	ClCH2CH2Cl	TfOMe (1.3)	1	120	79
  12	ClCH2CH2Cl	TfOMe (1.1)	2	120	71
  a Unless otherwise noted, all the reactions were conducted in anhydrous solvent (2.0 mL) with 1.0 mmol of 1a, and the yields were calculated based on the weight of the isolated products. b 92% of 1a was recovered. c 93% of 1a was recovered. d 93% of 1a was recovered. e common ClCH2CH2Cl.f solvent free.

  1.2   底物的拓展

  在确立了最佳反应条件后(表 1, Entry 10), 考察了一系列具有多种取代模式和不同电子效应的α, α-二烃基氰基乙酰芳胺化合物在TfOMe作用下的反应, 结果列于表 2中.实验结果表明, 芳环上取代基的电子效应和空间效应都对反应的产率有一定的影响.例如, 相比于电中性的原料1a(表 2, Entry 1), 苯环对位被吸电子的氯或者硝基取代时, 产物2b和2c的产率略有下降(表 2, Entries 2, 3), 而当对位取代基是给电子基团如甲氧基或甲基时, 反应仍以较高的产率生成相应的产物2d和2e(表 2, Entries 4, 5).当甲基处于苯环邻位时, 其具有的空间位阻使得产物2f的产率较低(表 2, Entry 6).对于间甲基取代的底物1g(表 2, Entry 7), 反应以5：1的区域选择性得到一对难以分离的混合物, 其中主要成分为7-甲基喹啉-2, 4-二酮(2g), 次要组分为5-甲基-4-甲亚胺基喹啉-2-酮化合物.可能因为邻甲基和环戊基的空间效应阻碍了亚胺中间体的水解.此外, 反应也受到酰胺氮原子上R²取代基的影响. R²为乙基或有一定空间位阻的异丙基时(表 2, Entries 8, 9), 产率略有降低, 但是当R²为氢时(表 2, Entry 10), 只能以25%的产率获得产物2j, 且薄层色谱(TLC)监测发现有较多难以分离鉴定的副产物, 可能是由于TfOMe与未经保护的酰胺发生副反应导致的.除了上述带有五元环的氰基乙酰芳胺类化合物以外, α, α-二甲基或二乙基取代的氰基乙酰芳胺在TfOMe作用下也可以顺利地转化为相应的喹啉-2, 4-二酮产物(表 2, Entries 11, 12).然而, 当用TfOMe处理α, α-二炔丙基取代的底物1m时, 所得产物并非预期的3, 3-二炔丙基喹啉-2, 4-二酮, 而是3-炔丙基-3-丙酮基喹啉-2, 4-二酮(2m) (Eq. 1).显然, 炔丙基在环化反应的副产物三氟甲烷磺酸(TfOH)的催化下进一步发生了水解反应^[12].

  (1)

  表 2

  

  表 2  反应底物的拓展^a

  Table 2.  Substrate scope of the reaction

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  Entry	1	R1	R2	R3 (or R3…R3)	2	Yield/%
  1	1a	H	Me	(CH2)4	2a	80
  2b	1b	4-Cl	Me	(CH2)4	2b	76
  3b	1c	4-NO2	Me	(CH2)4	2c	75
  4	1d	4-MeO	Me	(CH2)4	2d	83
  5	1e	4-Me	Me	(CH2)4	2e	80
  6	1f	2-Me	Me	(CH2)4	2f	71
  7	1g	3-Me	Me	(CH2)4	2g+3c	77
  8	1h	H	Et	(CH2)4	2h	75
  9	1i	H	i-Pr	(CH2)4	2i	63
  10	1j	H	H	(CH2)4	2j	25
  11	1k	H	Me	Me	2k	78
  12	1l	H	Me	Et	2l	76
  a Unless otherwise noted, all the reactions were conducted in anhydrous ClCH2CH2Cl (2.0 mL) with 2 (1.0 mmol) and TfOMe (1.2 mmol) at 120 ℃ for 1~2 h, and the yields were calculated based on the weight of the products. b To the reaction mixture was added 20 mmol of H2O, after 1b/1c was consumed as monitored by TLC analysis, and the reaction was carried on for another 1 h.c n(2g):n(3)＝5:1, identified by 1H NMR.

  1.3   反应机理研究

  在上述实验结果的基础上, 结合有关Houben-Hoesch反应以及腈类化合物与TfOMe反应的文献报道^{[9, 10, 13]}, 我们提出了α, α-二烃基氰基乙酰芳胺化合物在TfOMe作用下转化为喹啉-2, 4-二酮类化合物的可能反应机理, 如Scheme 2所示, 首先, α, α-二烃基氰基乙酰芳胺化合物1的氰基氮原子被TfOMe甲基化形成腈鎓离子中间体A, 然后A发生分子内的芳烃亲电取代反应转化为酮亚胺中间体B, B水解得到喹啉-2, 4-二酮类化合物2.值得注意的是, 在上述反应过程中, 底物1分子内R³取代基的空间位阻越大, 其对腈鎓离子中间体A的形成越不利; 而R¹取代基的电子效应虽然对芳环的亲电取代反应活性有一定影响, 但由于腈鎓离子的强亲电性, 即使硝基取代的芳环也能很好地发生亲电环化反应; 相比之下, 取代基R¹尤其是R²的空间位阻对该反应过程的影响更加明显.

  图式 2

  

  图式 2.  可能的反应机理

  Scheme 2.  Proposed mechanism

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  2.   结论

  报道了一种合成喹啉-2, 4-二酮类化合物的新方法.以廉价易得的α, α-二烃基氰基乙酰芳胺化合物为原料, 在TfOMe的促进下, 经Houben-Hoesch反应合成了一系列多取代的喹啉-2, 4-二酮化合物.该方法具有适用范围广、反应条件温和、产物收率较高等优点.不仅拓展了Houben-Hoesch反应的应用范围, 也丰富了通过非环反应前体一步构建喹啉-2, 4-二酮杂环的合成策略, 可为其它杂环化合物的设计与合成提供实验支持和理论指导.

  3.   实验部分

  3.1   仪器与试剂

  实验所用试剂均购于阿拉丁试剂公司.氰基乙酰芳胺的制备按照文献[9]合成.柱层析使用200~300目硅胶, 以石油醚和乙酸乙酯为展开剂.熔点采用X-4型熔点仪(温度未经校正)测定. ¹H NMR(300 MHz或600 MHz)和¹³C NMR (75 MHz或150 MHz)采用Bruker Advance 300或UltraShield 600核磁共振仪测定, CDCl₃或DMSO-d₆为溶剂, TMS为内标. IR采用Spectrum One型红外光谱仪经KBr压片法测定.元素分析采用PerkineElmer PE-2400分析仪.高分辨质谱采用LTQ Orbitrp质谱仪测定.

  3.2   实验方法

  3.2.1   α, α-二烃基氰基乙酰芳胺1a~1j的合成

  以1a的合成为例.室温下, 向50 mL圆底烧瓶中加入15 mL DMF、10 mmol N-甲基-N-苯基氰基乙酰胺和22 mmol无水K₂CO₃, 搅拌反应1 h后, 向圆底烧瓶中缓慢滴加11 mmol 1, 4-二溴丁烷, 5 min内滴加完毕, 室温下继续搅拌反应约20 h, 薄层色谱(TLC)监测反应完全后, 将反应混合物倒入300 mL饱和食盐水中, 用CH₂Cl₂ (30 mL×3)萃取, 合并有机相, 用无水MgSO₄干燥, 真空浓缩除去CH₂Cl₂后, 粗产品经硅胶柱层析[V(石油醚)：V(EtOAc)＝12：1)分离纯化, 得白色固体产物1a.

  1-氰基-N-甲基-N-苯基环戊甲酰胺(1a):白色固体, 产率90%. m.p. 58~59 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 1.63~1.72 (m, 4H), 1.88 (s, 2H), 2.28 (s, 2H), 3.26 (s, 3H), 7.42 (s, 3H), 7.45~7.48 (t, J＝7.2 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 24.8, 30.9, 32.4, 39.1, 40.4, 47.4, 121.7, 129.0, 129.6, 142.1, 167.4; IR ν: 3061, 2981, 2954, 2877, 2235, 1655, 1593, 1496, 1452, 1421, 1370, 1288, 705, 680 cm^-1. Anal. calcd for C₁₄H₁₆N₂O: C 73.66, H 7.06, N 12.27; found C 73.80, H 7.03, N 12.23.

  N-(4-氯苯基)-1-氰基-N-甲基环戊甲酰胺(1b):白色固体, 产率67%. m.p. 60~61 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 1.79 (s, 4H), 2.04 (s, 2H), 2.32 (s, 2H), 3.31 (s, 3H), 7.28 (s, 2H), 7.42 (d, J＝8.4 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 24.8, 30.9, 32.5, 38.9, 40.3, 47.2, 121.7, 129.7, 130.4, 134.6, 140.7, 167.2; IR ν: 3086, 3057, 2980, 2951, 2872, 2234, 1652, 1591, 1490, 1453, 1416, 1366, 1284, 842 cm^-1. Anal. calcd for C₁₄H₁₅ClN₂O: C 64.00, H 5.75, N 10.66; found C 63.92, H 5.77, N 10.70.

  N-(4-硝基苯基)-1-氰基-N-甲基环戊甲酰胺(1c):淡黄色固体, 产率70%. m.p. 67~68 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 1.82~1.89 (m, 4H), 2.14~2.22 (m, 2H), 2.34~2.46 (m, 2H), 3.47 (s, 3H), 7.48~7.53 (m, 2H), 8.30~8.34 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 25.1, 38.8, 39.9, 46.8, 121.4, 124.8, 128.6, 146.8, 148.5, 167.2; IR ν: 3107, 3078, 2978, 2947, 2881, 2234, 1658, 1608, 1592, 1519, 1493, 1371, 1349, 1289, 864 cm^-1. Anal. calcd for C₁₄H₁₅N₃O₃: C 61.53, H 5.53, N 15.38; found C 61.58, H 5.55, N 15.34.

  1-氰基-N-(4-甲氧基苯基)-N-甲基环戊甲酰胺(1d):白色固体, 产率78%. m.p. 75~76 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 1.76 (s, 4H), 1.98 (s, 2H), 2.28 (d, J＝4.2 Hz, 2H), 3.27 (s, 3H), 3.84 (s, 3H), 6.94 (d, J＝8.4 Hz, 2H), 7.25 (d, J＝8.4 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 24.6, 38.9, 40.5, 47.4, 55.4, 114.5, 121.9, 130.3, 134.5, 159.7, 167.6; IR ν: 3068, 2983, 2952, 2873, 2843, 2230, 1650, 1606, 1509, 1454, 1419, 1373, 1300, 1036, 852 cm^-1. Anal. calcd for C₁₅H₁₈N₂O₂: C 69.74, H 7.02, N 10.84, found C 69.80, H 7.00, N 10.88.

  1-氰基-N-甲基-N-对甲苯基环戊甲酰胺(1e):白色固体, 产率75%. m.p. 76~77 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 1.76 (s, 4H), 2.00 (s, 2H), 2.29 (s, 2H), 2.40 (s, 3H), 3.28 (s, 3H), 7.21 (s, 2H), 7.25 (d, J＝7.8 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 21.1, 24.7, 29.6, 39.0, 40.4, 47.4, 121.8, 128.8, 130.1, 138.9, 139.4, 167.4; IR ν: 2982, 2950, 2876, 2232, 1651, 1604, 1510, 1449, 1417, 1373, 1284, 833 cm^-1. Anal. calcd for C₁₅H₁₈N₂O: C 74.35, H 7.49, N 11.56; found C 74.28, H 7.52, N 11.52.

  1-氰基-N-甲基-N-邻甲苯基环戊甲酰胺(1f):白色固体, 产率88%. m.p. 33~34 ℃; 1f为旋转异构体, 主要构型与次要构型之比约为5.2：1. ¹H NMR (600 MHz, CDCl₃) δ: 1.74~1.82 (m, 4.46H), 1.89~1.93 (m, 1.37H), 2.16~2.19 (m, 2.59H), 2.34 (s, 3.35H), 2.47~2.49 (m, 1.41H), 3.21 (s, 3.00H), 3.52 (s, 0.54H), 7.10 (d, J＝5.8 Hz, 0.18H), 7.19 (d, J＝7.6 Hz, 0.98H), 7.26 (t, J＝7.5 Hz, 1.82H), 7.31~7.35 (m, 1.95H); ¹³C NMR (150 MHz, CDCl₃) δ: 17.0, 17.8, 24.6, 24.8, 25.3, 37.4, 37.5, 38.4, 39.0, 39.2, 39.9, 45.5, 47.3, 120.9, 121.8, 126.4, 126.7, 127.2, 127.9, 129.2, 129.4, 131.1, 131.7, 134.7, 137.2, 140.6, 142.6, 166.2, 167.7; IR ν: 3060, 3026, 2958, 2876, 2232, 1653, 1603, 1581, 1494, 1455, 1418, 1368, 1275, 770, 730 cm^-1. Anal. calcd for C₁₅H₁₈N₂O: C 74.35, H 7.49, N 11.56; found C 74.41, H 7.52, N 11.52.

  1-氰基-N-甲基-N-间甲苯基环戊甲酰胺(1g):白色固体, 产率78%. m.p. 33~34 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 1.77 (s, 4H), 2.00 (s, 2H), 2.31 (s, 2H), 2.39 (s, 3H), 3.30 (s, 3H), 7.14 (s, 2H), 7.22 (s, 1H), 7.33 (t, J＝7.8 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 21.2, 24.7, 30.9, 32.4, 39.0, 40.3, 47.4, 121.8, 125.8, 129.3, 129.5, 139.5, 141.9, 167.3; IR ν: 2958, 2876, 2232, 1659, 1607, 1589, 1491, 1453, 1418, 1368, 1293, 794, 707 cm^-1. Anal. calcd for C₁₅H₁₈N₂O: C 74.35, H 7.49, N 11.56, found C 74.45, H 7.45, N 11.52.

  1-氰基-N-乙基-N-苯基环戊甲酰胺(1h):无色油状液体, 产率81%. ¹H NMR (600 MHz, CDCl₃) δ: 1.15 (t, J＝7.2 Hz, 3H), 1.78 (d, J＝7.2 Hz, 4H), 1.99 (s, 2H), 2.30 (s, 2H), 3.76 (s, 2H), 7.31 (s, 2H), 7.43~7.47 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 12.4, 24.7, 30.9, 32.4, 39.1, 47.2, 47.6, 121.8, 128.9, 129.4, 130.0, 140.2, 166.7; IR ν: 3063, 3041, 2971, 2876, 2232, 1652, 1596, 1495, 1453, 1394, 1281, 769, 737 cm^-1. Anal. calcd for C₁₅H₁₈N₂O: C 74.35, H 7.49, N 11.56; found C 74.43, H 7.46, N 11.53.

  1-氰基-N-异丙基-N-苯基环戊甲酰胺(1i):白色固体, 产率73%. m.p. 56~57 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 1.07 (d, J＝6.6 Hz, 6H), 1.74 (s, 4H), 1.92 (d, J＝12.0 Hz, 2H), 2.27 (d, J＝12.0 Hz, 2H), 4.87~4.95 (m, 1H), 7.28 (s, 2H), 7.45 (d, J＝6.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 20.5, 24.6, 39.1, 48.2, 48.8, 122.0, 128.6, 129.3, 132.4, 135.7, 166.6; IR ν: 2975, 2875, 2228, 1647, 1592, 1494, 1454, 1394, 1332, 765, 713 cm^-1. Anal. calcd for C₁₆H₂₀N₂O: C 74.97, H 7.86, N 10.93; found C 74.84, H 7.90, N 10.97.

  1-氰基-N-苯基环戊甲酰胺(1j):白色固体, 产率89%. m.p. 56~57 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 1.90~1.99 (m, 4H), 2.26~2.45 (m, 4H), 7.18 (t, J＝7.5 Hz, 1H), 7.36 (t, J＝7.8 Hz, 2H), 7.53 (d, J＝7.8 Hz, 2H), 7.97 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 25.4, 37.8, 48.6, 120.4, 122.6, 125.1, 128.9, 136.9, 166.2; IR ν: 3338, 3059, 2957, 2876, 2234, 1703, 1602, 1547, 1491, 1441, 1314, 1249, 755, 694 cm^-1. Anal. calcd for C₁₃H₁₄N₂O C 72.87, H 6.59, N 13.07; found C 72.99, H 6.56, N 13.02.

  3.2.2   α, α-二烃基氰基乙酰芳胺1k~1m的合成

  以1k的合成为例, 室温下, 向50 mL圆底烧瓶中加入15 mL DMF、10 mmol N-甲基-N-苯基氰基乙酰胺和22 mmol无水K₂CO₃, 搅拌反应1 h后, 向圆底烧瓶中滴加30 mmol碘甲烷, 滴加完毕后, 继续在室温下搅拌反应约20 h, TLC监测反应完全后, 将反应混合物倒入300 mL饱和食盐水中, 用CH₂Cl₂ (30 mL×3)萃取, 合并有机相, 用无水MgSO₄干燥, 真空浓缩除去CH₂Cl₂后, 粗产品经硅胶柱层析[V(石油醚)：V(EtOAc)＝30：1)纯化, 得白色固体产物1k.

  2-氰基-N, 2-二甲基-N-苯基丙酰胺(1k):淡黄色固体, 产率79%. m.p. 44~45 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 1.60 (s, 6H), 3.34 (s, 3H), 7.33 (dd, J＝7.2, 2.4 Hz, 2H), 7.44~7.50 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 27.3, 37.3, 40.8, 121.2, 128.6, 129.1, 129.7, 142.4, 168.0; IR ν: 3059, 3017, 2985, 2940, 2238, 1651, 1593, 1497, 1464, 1421, 1390, 1371, 1281, 778, 746 cm^-1. Anal. calcd for C₁₂H₁₄N₂O: C 71.26, H 6.98, N 13.85, found C 71.34, H 6.97, N 13.80.

  2-氰基-2-乙基-N-甲基-N-苯基丁酰胺(1l):由N-甲基-N-苯基氰基乙酰胺与溴乙烷反应制备.无色油状液体, 产率27%. ¹H NMR (300 MHz, CDCl₃) δ: 1.06 (t, J＝7.5 Hz, 6H), 1.71~1.83 (m, 2H), 2.04~2.16 (m, 2H), 3.34 (s, 3H), 7.24~7.28 (m, 2H), 7.44~7.47 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 9.8, 32.5, 40.6, 49.6, 119.2, 128.8, 129.3, 129.7, 142.3, 167.2; IR ν: 3064, 3040, 2976, 2940, 2882, 2230, 1639, 1597, 1495, 1463, 1416, 1383, 1277, 774, 731 cm^-1. Anal. calcd for C₁₄H₁₈N₂O: C 73.01, H 7.88, N 12.16; found C 72.90, H 7.91, N 12.20.

  2-氰基-N-甲基-N-苯基-2-炔丙基-4-戊炔酰胺(1m):由N-甲基-N-苯基氰基乙酰胺与3-溴丙炔反应制备.白色固体, 产率73%. m.p. 63~64 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 2.22 (t, J＝2.4 Hz, 2H), 2.75 (d, J＝16.5 Hz, 2H), 3.00 (dd, J＝16.5, 2.4 Hz, 2H), 3.36 (s, 3H), 7.43~7.48 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ: 27.4, 41.0, 45.9, 73.3, 77.1, 117.5, 123.6, 127.4, 128.9, 129.5, 129.8, 141.4, 163.8; IR ν: 3300, 3250, 3072, 2957, 2239, 1647, 1595, 1497, 1433, 1386, 1271, 700, 664 cm^-1. Anal. calcd for C₁₆H₁₄N₂O: C 76.78, H 5.64, N 11.19；found C 76.87, H 5.62, N 11.15.

  3.2.3   喹啉-2, 4-二酮2的合成

  以2a的合成为例, 室温下, 向干燥的15 mL厚壁耐压瓶中加入2 mL无水1, 2-二氯乙烷、1 mmol底物1a和1.2 mmol TfOMe, 密封后升温至120 ℃搅拌反应约1 h, TLC监测反应完成, 待反应体系冷却至室温后将反应液倒入30 mL饱和食盐水中, 用CH₂Cl₂ (15 mL×3)进行萃取, 合并有机相, 用无水MgSO₄干燥, 真空浓缩除去CH₂Cl₂后, 粗产品经硅胶柱层析[V(石油醚)：V(EtOAc)＝14：1)纯化, 得灰白色固体产物2a.

  1'-甲基-1'H-螺[环戊烷-1, 3'-喹啉]-2', 4'-二酮(2a)^[14]:灰白色固体, m.p. 51~52 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 1.82~1.91 (m, 4H), 2.16~2.23 (m, 4H), 3.47 (s, 3H), 7.17 (t, J＝7.8 Hz, 2H), 7.61 (dd, J＝6.6, 1.1 Hz, 1H), 7.99 (dd, J＝7.8, 1.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 26.9, 29.8, 36.6, 63.5, 114.6, 120.2, 122.6, 127.9, 135.5, 143.2, 174.3, 196.8; IR ν: 3046, 3026, 2952, 2865, 1694, 1660, 1603, 1473, 1418, 1354, 1302, 756 cm^-1; HRMS (ESI) calcd for C₁₄H₁₆NO₂ [M+H]⁺ 230.1181, found 230.1176.

  6'-氯-1'-甲基-1'H-螺[环戊烷-1, 3'-喹啉]-2', 4'-二酮(2b):白色固体, m.p. 56~57 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 1.67~1.75 (m, 4H), 2.03~2.05 (m, 4H), 3.36 (s, 3H), 7.41 (dd, J＝6.9, 2.4 Hz, 1H), 7.74 (dd, J＝6.9, 2.4 Hz, 2H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 26.8, 30.2, 36.2, 63.4, 118.1, 121.4, 126.3, 127.1, 135.3, 142.4, 173.5, 195.3; IR ν: 3116, 3049, 2960, 2867, 1658, 1598, 1485, 1467, 1428, 1382, 1336, 1290, 906, 863, 826 cm^-1; HRMS (ESI) calcd for C₁₄H₁₅ClNO₂ [M+H]⁺ 264.0791, found 264.0785.

  6'-硝基-1'-甲基-1'H-螺[环戊烷-1, 3'-喹啉]-2', 4'-二酮(2c):浅黄色固体, m.p. 104~105 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 1.84~1.92 (m, 4H), 2.20~2.23 (m, 4H), 3.56 (s, 3H), 7.34 (d, J＝9.1 Hz, 1H), 8.44 (dd, J＝9.1, 2.7 Hz, 1H), 8.78 (d, J＝2.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 25.1, 26.8, 30.5, 36.6, 64.1, 115.5, 120.0, 123.8, 130.0, 142.6, 147.6, 174.0, 194.5; IR ν: 3123, 3099, 3079, 2965, 2863, 1795, 1672, 1606, 1523, 1486, 1442, 1327, 1310, 876, 835 cm^-1; HRMS (ESI) calcd for C₁₄H₁₅N₂O₄ [M+H]⁺ 275.1032, found 275.1028.

  6'-甲氧基-1'-甲基-1'H-螺[环戊烷-1, 3'-喹啉]-2', 4'-二酮(2d):浅黄色固体, m.p. 74~75 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 1.65~1.80 (m, 4H), 2.02~2.06 (m, 4H), 3.36 (s, 3H), 3.80 (s, 3H), 7.28~7.35 (m, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 26.6, 29.8, 36.1, 55.5, 62.8, 109.6, 117.2, 120.5, 122.8, 137.2, 154.6, 173.0, 196.2; IR ν: 3060, 3040, 2952, 2866, 2838, 1646, 1616, 1590, 1499, 1471, 1433, 1418, 1350, 1303, 1119, 1027, 875, 827 cm^-1; HRMS (ESI) calcd for C₁₅H₁₈NO₃ [M+H]⁺ 260.1287, found 260.1282.

  1', 6'-二甲基-1'H-螺[环戊烷-1, 3'-喹啉]-2', 4'-二酮(2e):白色固体, m.p. 59~60 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 1.65~1.77 (m, 4H), 1.96~2.11 (m, 4H), 2.32 (s, 3H), 3.36 (s, 3H), 7.27 (d, J＝8.4 Hz, 1H), 7.51~7.54 (m, 1H), 7.64 (d, J＝1.8 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 19.9, 26.6, 29.7, 36.0, 63.0, 115.6, 119.6, 127.0, 131.8, 136.5, 141.0, 173.3, 196.3; IR ν: 3126, 3080, 3050, 3018, 2950, 2866, 1644, 1613, 1585, 1503, 1467, 1372, 1348, 1262, 906, 829 cm^-1; HRMS (ESI) calcd for C₁₅H₁₈NO₂ [M+H]⁺ 244.1338, found 244.1332.

  1', 8'-二甲基-1'H-螺[环戊烷-1, 3'-喹啉]-2', 4'-二酮(2f):白色固体, m.p. 85~86 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 1.55~1.60 (m, 2H), 1.63~1.69 (m, 2H), 1.95~1.99 (m, 2H), 2.05~2.09 (m, 2H), 2.46 (s, 3H), 3.31 (s, 3H), 7.16 (t, J＝7.5 Hz, 1H), 7.51 (d, J＝7.5 Hz, 1H), 7.55 (d, J＝7.5 Hz, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 21.5, 26.3, 34.3, 37.0, 63.6, 124.0, 124.7, 127.9, 139.0, 144.3, 173.9, 197.0; IR ν: 3080, 2951, 2867, 1698, 1660, 1584, 1488, 1453, 1408, 1380, 1297, 803, 788, 761 cm^-1; HRMS (ESI) calcd for C₁₅H₁₈NO₂ [M+H]⁺ 244.1338, found 244.1333.

  1', 7'-二甲基-1'H-螺[环戊烷-1, 3'-喹啉]-2', 4'-二酮(2g): ¹H NMR (600 MHz, DMSO-d₆) δ: 1.68~1.76 (m, 4H), 2.00~2.07 (m, 4H), 2.42 (s, 3H), 3.37 (s, 3H), 7.02 (d, J＝7.8, 1H), 7.20 (s, 1H), 7.73 (d, J＝7.8 Hz, 1H); 13C NMR (150 MHz, DMSO-d₆) δ: 22.1, 26.9, 30.0, 36.4, 63.1, 116.1, 117.8, 123.7, 127.4, 143.5, 147.1, 174.0, 196.0; HRMS (ESI) calcd for C₁₅H₁₈NO₂ [M+H]⁺ 244.1338, found 244.1330.

  1'-乙基-1'H-螺[环戊烷-1, 3'-喹啉]-2', 4'-二酮(2h):灰白色固体, m.p. 64~65 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 1.15 (t, J＝7.2 Hz, 3H), 1.58~1.85 (m, 4H), 2.05 (t, J＝6.6 Hz, 4H), 4.03 (q, J＝7.2 Hz, 2H), 7.19 (t, J＝7.2 Hz, 1H), 7.40 (d, J＝8.4 Hz, 1H), 7.70 (t, J＝7.8 Hz, 1H), 7.85 (d, J＝7.8 Hz, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 12.4, 26.8, 36.0, 37.2, 63.3, 115.6, 120.3, 122.7, 127.8, 136.2, 142.3, 173.3, 196.4; IR ν: 3115, 3082, 3048, 2961, 2869, 1656, 1602, 1467, 1323, 1259, 753 cm^-1; HRMS (ESI) calcd for C₁₅H₁₈NO₂ [M+H]⁺ 244.1338, found 230.1329.

  1'-异丙基-1'H-螺[环戊烷-1, 3'-喹啉]-2', 4'-二酮(2i):白色固体, m.p. 50~51 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 1.46 (d, J＝6.0 Hz, 6H), 1.65~1.74 (m, 4H), 1.99~2.08 (m, 4H), 4.83~4.93 (m, 1H), 7.18 (t, J＝7.8 Hz, 1H), 7.50 (d, J＝8.4 Hz, 1H), 7.66~7.69 (m, 1H), 7.83 (dd, J＝7.8, 1.7 Hz, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 19.6, 26.7, 35.6, 47.6, 64.1, 116.1, 121.2, 122.5, 127.8, 135.8, 142.9, 173.5, 196.5; IR ν: 3116, 3073, 3013, 2961, 2938, 2867, 1666, 1602, 1587, 1485, 1455, 1404, 1380, 1344, 1280, 754 cm^-1; HRMS (ESI) calcd for C₁₆H₂₀NO₂ [M+H]⁺ 258.1494, found 258.1489.

  1'H-螺[环戊烷-1, 3'-喹啉]-2', 4'-二酮(2j):白色固体, m.p. 170~171 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 1.70~1.77 (m, 4H), 2.00~2.06 (m, 4H), 7.09~7.11 (m, 2H), 7.58 (t, J＝7.8 Hz, 1H), 7.75 (d, J＝7.2 Hz, 1H); 10.73 (s, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 27.0, 36.2, 63.1, 116.5, 118.5, 122.6, 127.2, 136.0, 142.5, 174.9, 197.2; IR ν: 3300, 3198, 3120, 3066, 3004, 2958, 2937, 2868, 1662, 1615, 1600, 1508, 1485, 1435, 1321, 1261, 757 cm^-1; HRMS (ESI) calcd for C₁₃H₁₄NO₂ [M+H]⁺ 216.1025, found 216.1019.

  1, 3, 3-三甲基喹啉-2, 4(1H, 3H)-二酮(2k)^[5a]:白色固体. m.p. 45~46 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 1.49 (s, 6H), 3.48 (s, 3H), 7.18 (t, J＝7.8 Hz, 2H), 7.61~7.66 (m, 1H), 8.01 (dd, J＝7.8, 1.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 23.9, 29.6, 29.8, 53.1, 114.7, 119.8, 123.0, 128.2, 135.8, 143.0, 174.2, 197.7; IR ν: 3087, 2983, 2970, 2936, 2894, 2868, 1698, 1663, 1606, 1589, 1494, 1473, 1416, 1382, 1303, 757 cm^-1; HRMS (ESI) calcd for C₁₂H₁₄NO₂ [M+H]⁺ 204.1025, found 204.1019.

  1-甲基-3, 3-二乙基喹啉-2, 4(1H, 3H)-二酮(2l):无色油状液体. ¹H NMR (300 MHz, CDCl₃) δ: 0.74 (t, J＝7.5 Hz, 6H), 1.94~2.12 (m, 4H), 3.51 (s, 3H), 7.16~7.20 (m, 2H), 7.63 (t, J＝7.8 Hz, 1H), 8.04 (d, J＝7.8 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 9.5, 29.4, 32.5, 63.1, 114.7, 121.2, 122.9, 127.5, 136.1, 143.4, 173.3, 197.9; IR ν: 3085, 2969, 2937, 2880, 1694, 1660, 1603, 1471, 1417, 1360, 1302, 755 cm^-1; HRMS (ESI) calcd for C₁₄H₁₈NO₂ [M+H]⁺ 232.1338, found 232.1331. Anal. calcd for C₁₄H₁₇NO₂: C 72.70, H 7.41, N 6.06; found C 72.77, H 7.38, N 6.08.

  1-甲基-3-(2-氧代丙基)-3-炔丙基喹啉-2, 4(1H, 3H)-二酮(2m):白色固体, m.p. 105~106 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 1.91 (t, J＝2.6, 1H), 2.13 (s, 3H), 2.59 (d, J＝1.2 Hz, 2H), 3.50 (s, 3H), 3.57 (d, J＝5.1 Hz, 2H), 7.15~7.22 (m, 2H), 7.61~7.67 (m, 1H), 8.02 (dd, J＝7.8, 1.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ: 28.2, 28.8, 29.8, 50.6, 55.4, 72.6, 76.8, 114.8, 120.6, 122.9, 127.8, 136.0, 143.4, 171.7, 194.7, 205.8; IR (KBr) ν: 3294, 2997, 2914, 2852, 1692, 1655, 1599, 1494, 1472, 1422, 1395, 1368, 1304, 773 cm^-1; HRMS (ESI) calcd for C₁₆H₁₆NO₃ [M+H]⁺ 270.1130, found 270.1128. Anal. calcd for C₁₆H₁₅NO₃: C 71.36, H 5.61, N 5.20; found C 71.27, H 5.63, N 5.22.

  1', 5'-二甲基-4'-甲亚胺基-1'H-螺[环戊烷-1, 3'-喹啉]-2'(4'H)-酮(3): ¹H NMR (600 MHz, DMSO-d₆) δ: 1.39~1.63 (m, 5H), 2.09~2.15 (m, 4H), 2.55~2.59 (m, 1H), 3.11 (s, 3H), 3.23 (s, 3H), 7.05 (d, J＝7.2 Hz, 1H), 7.07 (d, J＝7.8, 1H), 7.38 (t, J＝7.8, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 20.3, 24.8, 25.3, 27.6, 30.5, 35.9, 41.3, 60.8, 113.1, 122.0, 125.0, 130.2, 136.0, 140.0, 165.3, 173.3; HRMS (ESI) calcd for C₁₆H₂₁N₂O [M+H]⁺ 257.1654, found 257.1639.

  辅助材料(Supporting Information)  化合物1a~1m, 2a~2m和3的核磁共振谱图.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 1  一些具有生物活性的喹啉-2, 4-二酮类化合物

  Figure 1  Some bioactive quinoline-2, 4-diones

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  图式 1  三氟乙酰化诱导的氰基乙酰芳胺的Houben-Hoesch反应

  Scheme 1  Trifluoroacetylation-induced Houben-Hoesch reaction of cyanoacetanilides

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  图式 2  可能的反应机理

  Scheme 2  Proposed mechanism

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  表 1  1a的Houben-Hoesch反应条件优化^a

  Table 1.  Optimization of the reaction conditions for the Houben-Hoesch reaction of 1a

  Entry	Solvent	Additive (equiv.)	Time/h	T/℃	Yield/%
  1	DMF	TFAA (1.2)	10	100	0b
  2	DMF	Tf2O (1.2)	10	100	0c
  3	DMF	TfOMe (1.2)	10	100	0d
  4	ClCH2CH2Cl	TfOMe (1.2)	2	100	78
  5	Toluene	TfOMe (1.2)	20	100	46
  6	CH3CO2C2H5	TfOMe (1.2)	8	100	60
  7	ClCH2CH2Cle	TfOMe (1.2)	2	100	75
  8	__f	TfOMe (1.2)	2	100	68
  9	ClCH2CH2Cl	TfOMe (1.2)	5	80	53
  10	ClCH2CH2Cl	TfOMe (1.2)	1	120	80
  11	ClCH2CH2Cl	TfOMe (1.3)	1	120	79
  12	ClCH2CH2Cl	TfOMe (1.1)	2	120	71
  a Unless otherwise noted, all the reactions were conducted in anhydrous solvent (2.0 mL) with 1.0 mmol of 1a, and the yields were calculated based on the weight of the isolated products. b 92% of 1a was recovered. c 93% of 1a was recovered. d 93% of 1a was recovered. e common ClCH2CH2Cl.f solvent free.

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  表 2  反应底物的拓展^a

  Table 2.  Substrate scope of the reaction

  Entry	1	R1	R2	R3 (or R3…R3)	2	Yield/%
  1	1a	H	Me	(CH2)4	2a	80
  2b	1b	4-Cl	Me	(CH2)4	2b	76
  3b	1c	4-NO2	Me	(CH2)4	2c	75
  4	1d	4-MeO	Me	(CH2)4	2d	83
  5	1e	4-Me	Me	(CH2)4	2e	80
  6	1f	2-Me	Me	(CH2)4	2f	71
  7	1g	3-Me	Me	(CH2)4	2g+3c	77
  8	1h	H	Et	(CH2)4	2h	75
  9	1i	H	i-Pr	(CH2)4	2i	63
  10	1j	H	H	(CH2)4	2j	25
  11	1k	H	Me	Me	2k	78
  12	1l	H	Me	Et	2l	76
  a Unless otherwise noted, all the reactions were conducted in anhydrous ClCH2CH2Cl (2.0 mL) with 2 (1.0 mmol) and TfOMe (1.2 mmol) at 120 ℃ for 1~2 h, and the yields were calculated based on the weight of the products. b To the reaction mixture was added 20 mmol of H2O, after 1b/1c was consumed as monitored by TLC analysis, and the reaction was carried on for another 1 h.c n(2g):n(3)＝5:1, identified by 1H NMR.

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•