吖啶二酮类化合物具有广泛的生物活性, 如消炎[1]、抗菌[2]、抗真菌[3]、组蛋白脱乙酰基酶(SITR1)抑制剂[4]、钙钾离子通道调节作用[5]、碳酸酐酶抑制作用[6]等.此外, 吖啶二酮类化合物具有优良的光学性能, 如作为化学传感器[7]、激光染料[8]、染料敏化剂[9]和光聚合引发剂[10]等.因而, 吖啶二酮类化合物的合成方法受到人们的广泛关注.
吖啶二酮类化合物通常由醛、二酮和胺三组分的Hantzsch缩合反应合成.本反应所用的催化剂既有季铵盐[11]、质子酸[12]、Lewis酸[13-15]以及离子液体[16-19]等均相催化体系, 又有固体强酸[20-24]、纳米或介孔材料负载活性物质[25-32]等异相催化体系.此外, 微波辐射[33-34]对Hantzsch反应合成吖啶二酮也有较好的促进作用.虽然人们开发了多种催化体系, 但是一些催化剂存在制备工艺复杂、原料昂贵不易获得、反应条件苛刻或反应过程需要有机溶剂等问题, 有必要发展材料易得、操作简单、条件温和、更加绿色高效的合成方法.
低共熔溶剂(DESs)是本世纪初发展起来的一种低熔点混合物溶剂, 具有制备简单、价格便宜、无毒、能生物降解、稳定性好、组成原料可以再生等优点[35-36], 是一种新型的绿色溶剂.低共熔溶剂由氢键受体(HBA, 主要是季铵盐)与氢键供体(HBD)或季铵盐与金属盐组成, 各组分间的键合形式以氢键为主[37-38], 与传统的离子液体有明显不同.当前, 低共熔溶剂已经成功应用于吸附、分离等诸多领域[39], 尤其是低共熔溶剂作为有机反应的溶剂[40-41]或催化剂[42-43]而倍受关注.氯化胆碱(ChCl)是最早作为氢键受体用于制备低共熔溶剂的季铵盐, 具有便宜易得、兼容性好等优点, 是制备低共熔溶剂常用的原料[44-45].
以芳醛、环己二酮、醋酸铵或苯胺为原料, 在氯化胆碱/氯化锌组成的低共熔溶剂体系中, 通过多组分一锅法合成了一系列N-取代十氢吖啶-1, 8-二酮(Scheme 1), 反应在1~2 h内完成, 操作简单, 反应条件温和, 对反应底物包容性好, 产物收率均达到中等以上.
以5, 5-二甲基-1, 3-环己二酮、苯甲醛和各种氮源化合物之间的反应为模板, 考察DES组成、温度以及不同的氮源底物等对反应的影响.低共熔溶剂作为反应的溶剂, 其用量以能够完全覆盖反应物为宜.经过探索其用量确定为2 mL.如表 1所示, 70 ℃条件下, 不加任何催化剂和溶剂, 反应收率极低(表 1, Entry 1), 说明本反应活化能较高, 必需加入合适的催化剂降低活化能, 或采用更高的反应温度反应才能顺利进行.将反应置于几种不同组成的DES (ChCl/Urea, ChCl/Oxalic acid, ChCl/ PEG, ChCl/p-TsOH, ChCl/ZnCl2)中, 无须另加催化剂, 反应即能顺利进行, 说明DES对本反应兼具催化剂和溶剂双重功能.上面几种DES体系对反应均表现出不同程度的促进作用, 其中ChCl/ZnCl2的催化效率最高(表 1, Entry 6).
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| Entry | Madiab | Nitrogen source | T/℃ | Yield/% |
| 1 | Free solvent | NH4OAc | 70 | Trace |
| 2 | ChCl/Urea | NH4OAc | 70 | 67.2 |
| 3 | ChCl/Oxalic acid | NH4OAc | 70 | 65.4 |
| 4 | ChCl/p-TsOH | NH4OAc | 70 | 71.9 |
| 5 | ChCl/PEG | NH4OAc | 70 | 68.2 |
| 6 | ChCl/ZnCl2 | NH4OAc | 70 | 78.4 |
| 7 | ChCl/ZnCl2 | NH4OAc | 60 | 67.8 |
| 8 | ChCl/ZnCl2 | NH4OAc | 80 | 90.2 |
| 9 | ChCl/ZnCl2 | NH4OAc | 90 | 91.6 |
| 10 | ChCl/ZnCl2 | NH4HCO3 | 80 | 83.3 |
| 11 | ChCl/ZnCl2 | (NH4)2CO3 | 80 | 78.2 |
| 12 | ChCl/ZnCl2 | NH4Cl | 80 | 80.7 |
| 13 | ChCl/ZnCl2 | (NH2)2CO | 80 | 77.9 |
| 14 | ChCl/ZnCl2 | C6H5NH2 | 80 | 73.1 |
| 15b | ChCl/ZnCl2 | C6H5NH2 | 90 | 88.7 |
| 16c | ChCl/ZnCl2 | NH4OAc | 80 | 81.2 |
| a Reaction conditions: diketone (2 mmol), aromatic aldehyde (1 mmol), ammonium acetate ((2 mmol), aromatic amine (1 mmol), DES (2 mL), reaction time: 1~2 h. b Reaction time 2 h. c ChCl/ZnCl2 was reused three times. | ||||
反应在ChCl/ZnCl2体系中进行, 当反应温度低于60 ℃, 反应收率较低(表 1, Entry 7), 可能是由于低温时DES粘度大, 双酮溶解性不好的缘故.反应收率随着温度的升高而提高, 当反应温度升到80 ℃时, 产率达90%以上(表 1, Entry 8), 继续升高温度到90 ℃, 收率略有升高, 但是提高幅度不大(92%, 表 1, Entry 9).实验中, 选用不同的含氮化合物如铵盐、尿素和芳胺等作为氮源, 发现铵盐尤其是醋酸铵效果较尿素及芳胺要好(表 1, Entries 1~12).醋酸铵为氮源时, 反应相对容易进行, 一般在80 ℃反应1~2 h即能达到很高收率(表 1, Entry 8).芳胺的反应活性相对较低, 如苯胺在80 ℃时收率只有73%(表 1, Entry 14).反应温度提高到90 ℃, 收率接近90%(表 1, Entry 15).综合各种因素, 当醋酸铵为氮源时, 反应在80 ℃温度下进行, 而芳胺为氮源时, 反应温度则设定为90 ℃.与无溶剂反应条件下(120 ℃)[28]相比, 在DES介质中进行时本反应条件更加温和.此外, 醋酸铵作氮源时过量1倍, 而芳胺的投料无需过量, 可能因为醋酸铵易分解且产生的氨气易挥发, 而芳胺挥发性较低.反应结束后, DES经简单干燥处理可以循环使用3次, 产率仍在80%以上(表 1, Entry 16), 这也是DES作为反应介质的优势之一.
为了考察ChCl/ZnCl2体系对Hantzsch缩合反应的适用性, 在优化的反应条件下选用含有不同取代基的双酮、芳醛、醋酸铵或芳胺等进行反应, 合成了一系列N-取代十氢吖啶-1, 8-二酮, 反应结果如表 2所示.产物的结构经过氢谱、碳谱、红外和质谱等方法鉴定, 其数值与文献的报道能较好地吻合.
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| Compd. | R1 | R2 | R3 | Yield/% |
| 1a | H | C6H5 | H | 85.6 |
| 1b | H | 4-MeC6H4 | H | 83.2 |
| 1c | H | 4-MeOC6H4 | H | 81.4 |
| 1d | H | 4-NO2C6H4 | H | 92.6 |
| 1e | CH3 | C6H5 | H | 90.2 |
| 1f | CH3 | 4-BrC6H4 | H | 83.9 |
| 1g | CH3 | 4-MeC6H4 | H | 82.6 |
| 1h | CH3 | 4-MeOC6H4 | H | 80.5 |
| 1i | CH3 | 4-NO2C6H4 | H | 91.7 |
| 1j | CH3 | 3-NO2C6H4 | H | 86.6 |
| 1k | CH3 | 2-Thienyl | H | 78.6 |
| 1l | CH3 | 2-Pyridyl | H | 81.2 |
| 1m | H | C6H5 | 3-O2NC6H4 | 76.1 |
| 1n | H | C6H5 | 4-MeC6H4 | 84.7 |
| 1o | CH3 | C6H5 | C6H5 | 83.6 |
| 1p | CH3 | C6H5 | 3-O2NC6H4 | 75.1 |
| 1q | CH3 | C6H5 | 4-MeC6H4 | 82.7 |
| 1r | CH3 | 4-ClC6H4 | C6H5 | 81.3 |
| 1s | CH3 | C6H5 | 4-ClC6H4 | 79.8 |
| 1t | CH3 | C6H5 | 2-Pyridyl | 76.5 |
| a Dketone (2 mmol), aromatic aldehyde (1 mmol), ammonium acetate (2 mmol), aromatic amine (1 mmol), DES (2 mL), reaction time: 1~2 h, reaction temperature: 1a~1l 80 ℃, 1m~1t 90 ℃. | ||||
从表 2可以看出, 含不同取代基的各种反应底物在ChCl/ZnCl2体系中均能顺利进行反应, 但底物上取代基的电子性质对反应的影响略有不同.含吸电子基团的芳醛(表 2, 1d, 1i, 1j)较供电子基团的芳醛(表 2, 1b, 1c, 1g, 1h)产率相对略高.芳胺中所含取代基的电子性质对反应的影响与芳醛相反, 含供电子基团的芳胺(表 2, 1n, 1q)较含吸电子基团的芳胺(表 2, 1m, 1p, 1s)产率相对略高.此外, 采用含杂环的芳醛(表 2, 1k, 1l)和芳胺(表 2, 1t)进行上述反应, 同样获得了中等以上的收率, 说明ChCl/ZnCl2体系对各种反应底物均有较好的包容性.
以苯甲醛、5, 5-二甲基-1, 3-环己二酮和醋酸铵的反应为例说明Hantzsch缩合反应可能的机理.在低共熔溶剂活化下, 双酮发生互变异构形成烯醇异构体, 一分子异构体与活化的芳醛缩合形成中间体A, 另一分子异构体与醋酸铵分解放出的氨作用形成中间体B, 中间体A和B之间通过缩合脱去一分子水而形成产物.
以双酮、芳醛、醋酸铵或芳胺等为原料, 在ChCl/ ZnCl2组成的低共熔溶剂作用下合成了一系列N-取代十氢吖啶-1, 8-二酮类化合物.该方法条件温和、反应时间短、环境友好、产率高.所用的ChCl/ZnCl2低共熔溶剂制备简单, 可以多次重复使用, 为低共熔溶剂应用于合成稠合含氮杂环化合物进行了有益的尝试.
熔点由XT4A型显微熔点仪(北京科仪电光仪器厂)测定, 氢谱和碳谱由Ascend-400 MHz型超导核磁共振波谱仪测定(Bruker公司), 红外光谱由Prestige-21型傅立叶变换红外光谱仪(岛津制作所)测定, 质谱由安捷伦5973型质谱仪(Agilent公司)测定.实验所用化学试剂均为分析纯, 使用前未进一步纯化.
低共熔溶剂(ChCl/ZnCl2)的制备参照文献[44]进行. 150 mL圆底烧瓶中加入氯化胆碱13.96 g (0.1 mol)和氯化锌27.26 g (0.2 mol), 于80 ℃油浴下不断搅拌至透明(约2 h).停止加热冷却至室温, 真空干燥5 h后密封保存备用.
50 mL圆底烧瓶中加入2 mmol环己二酮, 1 mmol芳醛, 2 mmol醋酸铵或1 mmol芳胺以及2 mL低共熔溶剂充分混合, 于80 ℃或90 ℃油浴中加热搅拌1~2 h.反应进程由薄层色谱跟踪(石油醚/乙酸乙酯, V:V＝4:1).反应结束后, 加水充分搅拌过滤.或加乙酸乙酯和水混合物(V:V＝1:1)进行萃取, 分液, 有机层干燥, 浓缩, 溶剂回收.滤饼用水洗涤, 晾干, 乙醇重结晶得纯品, 产率达75%~93%.水层浓缩除水得DES (ChCl/ZnCl2), 经真空干燥, 纯化, 重复使用.
9-苯基-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1a):黄色固体, m.p. 277~278 ℃ (Lit.[13] 279~281 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.24~7.13 (m, 4H), 7.06~7.02 (m, 1H), 4.74 (s, 1H), 2.60~2.50 (m, 4H), 2.30~2.24 (m, 4H), 1.96~1.88 (m, 4H); 13C NMR (101 MHz, CDCl3) δ: 195.5, 162.9, 143.3, 127.3, 127.1, 125.4, 115.9, 35.9, 30.6, 26.11, 19.3; IR (KBr) ν: 3048, 2995, 1655, 1560, 1235, 1185 cm－1; MS (70 eV) m/z (%): 293 (M+, 56), 216 (100).
9-(4-甲基苯基)-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1b):黄色固体, m.p.＞300 ℃ (Lit.[18] 332 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.02 (d, J＝8.0 Hz, 2H), 6.94 (d, J＝8.0 Hz, 2H), 4.85 (s, 1H), 2.29~1.78 (m, 7H), 1.75~1.73 (m, 4H), 1.24~0.85 (m, 4H); 13C NMR (101 MHz, CDCl3) δ: 195.3, 151.6, 145.0, 128.8, 128.5, 127.8, 126.0, 113.1, 37.3, 32.1, 26.8, 21.3; IR (KBr) ν: 3055, 2992, 1645, 1565, 1183, 1085 cm－1; MS (70 eV) m/z (%): 307 (M+, 78), 216 (100), 91 (55).
9-(4-甲氧基苯基)-3, 4, 6, 7, 9, 10-六氢吖啶- 1, 8(2H, 5H)-二酮(1c):黄色固体, m.p.＞300 ℃ (Lit.[16] 303~305 ℃); 1H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 7.04 (d, J＝8.0 Hz, 2H), 6.71 (d, J＝8.0 Hz, 2H), 4.84 (s, 1H), 3.68 (s, 3H), 2.19~2.16 (m, 4H), 1.92~1.75 (m, 4H), 1.24~1.00 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ: 195.3, 157.6, 151.5, 140.2, 128.9, 113.6, 113.2, 55.4, 37.3, 26.8, 21.3; IR (KBr) ν: 3065, 3030, 2938, 1640, 1577, 1122 cm－1; MS (70 eV) m/z (%): 323 (M+, 70), 43 (100).
9-(4-硝基苯基)-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1d):黄色固体, m.p. 281~282 ℃ (Lit.[16] 283~284 ℃); 1H NMR (400 MHz, DMSO-d6) δ: 9.54 (s, 1H), 8.01 (d, J＝8.6 Hz, 2H), 7.37 (d, J＝8.6 Hz, 2H), 4.95 (s, 1H), 2.60~2.46 (m, 4H), 2.35~2.25 (m, 4H), 1.91~1.68 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ: 195.2, 155.3, 152.4, 146.0, 129.3, 123.6, 111.9, 37.1, 33.7, 26.8, 21.2; IR (KBr) ν: 3064, 3031, 2958, 1641, 1570, 1140 cm－1; MS (70 eV) m/z (%): 338 (M+, 58), 216 (100).
3, 3, 6, 6-四甲基-9-苯基-3, 4, 6, 7, 9, 10-六氢吖啶- 1, 8(2H, 5H)-二酮(1e):黄色晶体, m.p. 279~280 ℃ (Lit.[27] 277~279 ℃); 1H NMR (400 MHz, CDCl3) δ: 9.32 (brs, 1H), 7.28~7.27 (m, 2H), 7.14~7.10 (m, 2H), 7.02~7.00 (m, 1H), 5.02 (s, 1H), 2.27~2.06 (m, 8H), 1.00 (s, 6H), 0.89 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 194.5, 147.2, 145.4, 127.0, 126.9, 125.0, 112.5, 49.7, 39.9, 32.6, 31.6, 28.5, 26.1; IR (KBr) ν: 3058, 3030, 2961, 1642, 1575, 1125 cm－1; MS (70 eV) m/z (%): 349 (M+, 20), 269 (100), 77 (34).
3, 3, 6, 6-四甲基-9-(4-溴苯基)-3, 4, 6, 7, 9, 10-六氢吖啶- 1, 8(2H, 5H)-二酮(1f):黄色固体, m.p. 242~243 ℃ (Lit.[27] 240~242 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.31 (d, J＝8.3 Hz, 2H), 7.22 (d, J＝8.3 Hz, 2H), 5.02 (s, 1H), 2.43~2.20 (m, 8H), 1.16 (s, 6H), 0.97 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 195.2, 147.4, 131.0, 129.9, 128.6, 119.8, 113.5, 50.6, 41.3, 33.4, 31.4, 29.5, 27.2; IR (KBr) ν: 3054, 2991, 1642, 1568, 1465, 1123 cm－1; MS (70 eV) m/z (%): 429 (49), 427 (M+, 51), 267 (100).
3, 3, 6, 6-四甲基-9-(4-甲基苯基)-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1g):黄色晶体, m.p. 290~292 ℃ (Lit.[12] 293~294 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.22 (d, J＝7.9 Hz, 2H), 6.99 (d, J＝7.7 Hz, 2H), 5.03 (s, 1H), 2.38~2.19 (m, 8H), 2.23 (s, 3H), 1.08 (s, 6H), 0.97 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 196.02, 149.44, 143.75, 135.23, 128.71, 127.91, 113.30, 50.88, 40.64, 33.23, 32.61, 29.56, 27.12, 21.11; IR (KBr) ν: 3064, 3031, 2958, 1641, 1577, 1145 cm－1; MS (70 eV) m/z (%): 363 (M+, 35), 91 (53), 43 (58).
3, 3, 6, 6-四甲基-9-(4-甲氧基苯基)-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1h):黄色固体, m.p. 276~279 ℃ (Lit.[27] 277~280 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.25 (d, J＝8.5 Hz, 2H), 6.73 (d, J＝8.5 Hz, 2H), 5.02 (s, 1H), 3.75 (s, 3H), 2.47~2.45 (m, 2H), 2.38~2.03 (m, 6H), 1.09 (s, 6H), 0.97 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 196.0, 157.7, 149.0, 139.2, 128.9, 113.3, 55.0, 50.9, 40.7, 32.7, 29.6, 27.1; IR (KBr) ν: 3055, 3035, 2943, 1642, 1568, 1125 cm－1; MS (70 eV) m/z (%): 379 (M+, 60), 269 (100), 77 (60).
3, 3, 6, 6-四甲基-9-(4-硝基苯基)-3, 4, 6, 7, 9, 10-六氢吖啶(2H, 5H)-1, 8-二酮(1i):黄色固体, m.p. 285~287 ℃ (Lit.[25] 286~288 ℃); 1H NMR (400 MHz, CDCl3) δ: 8.08 (d, J＝8.4 Hz, 2H), 7.52 (d, J＝8.4 Hz, 2H), 5.15 (s, 1H), 2.45~2.42 (m, 2H), 2.30~2.14 (m, 6H), 1.04 (s, 6H), 0.96 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 195.2, 161.9, 150.5, 145.5, 128.3, 122.4, 113.6, 49.6, 39.9, 31.3, 28.2, 26.3; IR (KBr) ν: 3092, 2955, 1640, 1525, 1340, 1140, 875 cm－1; MS (70 eV) m/z (%): 394 (M+, 65), 272 (100), 43 (65).
3, 3, 6, 6-四甲基-9-(3-硝基苯基)-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1j):黄色晶体, m.p.＞300 ℃ (Lit.[18] 307~309 ℃); 1H NMR (400 MHz, CDCl3) δ: 8.03~7.92 (m, 2H), 7.39 (m, 2H), 5.11 (s, 1H), 2.46~2.14 (m, 8H), 1.04 (s, 6H), 0.96 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 195.2, 148.1, 135.5, 128.7, 122.3, 121.3, 112.9, 50.6, 41.2, 34.1, 32.8, 29.4, 27.1; IR (KBr) ν: 3090, 2952, 1643, 1560, 1365, 1235, 880 cm－1; MS (70 eV) m/z (%): 394 (M+, 38), 43 (100).
3, 3, 6, 6-四甲基-9-(噻吩-2-基)-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1k):黄色晶体, m.p.＞300 ℃ (Lit.[31] 330~333 ℃); 1H NMR (400 MHz, DMSO-d6) δ: 10.23 (s, 1H), 7.01~7.25 (m, 3H), 4.73 (s, 1H), 1.96~2.50 (m, 8H), 1.08 (s, 6H), 0.88 (s, 6H); 13C NMR (101 MHz, DMSO-d6) δ: 196.3, 157.0, 134.0, 131.5, 128.5, 112.9, 111.7, 54.8, 50.3, 40.1, 40.0, 31.8, 27.5; IR (KBr) ν: 3064, 2953, 1640, 1535, 1475, 1130 cm－1; MS (70 eV) m/z (%): 355 (M+, 43), 44 (100).
3, 3, 6, 6-四甲基-9-(吡啶-2-基)-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1l):黄色晶体, m.p. 284~285 ℃ (Lit.[30] 285~286 ℃); 1H NMR (400 MHz, DMSO-d6) δ: 9.20 (s, 1H), 8.30 (d, J＝4.0 Hz, 1H), 7.55 (d, J＝6.4 Hz, 1H), 7.30 (d, J＝7.6 Hz, 1H), 7.03 (d, J＝5.2 Hz, 1H), 4.96 (s, 1H), 2.50~1.92 (m, 8H), 1.00 (s, 6H), 0.87 (s, 6H); 13C NMR (101 MHz, DMSO-d6) δ: 193.8, 163.3, 149.4, 147.9, 134.5, 122.4, 120.6, 109.8, 49.7, 34.9, 31.6, 28.6, 25.6; IR (KBr) ν: 3072, 2960, 1634, 1530, 1485, 1145 cm－1; MS (70 eV) m/z (%): 350 (M+, 45), 269 (80), 44 (100).
9-苯基-10-(3-硝基苯基)-3, 4, 6, 7, 9, 10-六氢吖啶- 1, 8(2H, 5H)-二酮(1m):黄色晶体, m.p. 280~282 ℃ (Lit.[16] 282~284 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.37~7.29 (m, 6H), 7.25~7.20 (m, 2H), 7.13~7.10 (m, 1H), 4.82 (s, 1H), 2.68~2.57 (m, 4H), 2.37~2.31 (m, 4H), 2.04~1.99 (m, 4H); 13C NMR (101 MHz, CDCl3) δ: 196.7, 163.9, 144.4, 128.4, 128.1, 126.4, 116.9, 37.0, 31.1, 27.2, 20.3; IR (KBr) ν: 3085, 2953, 1645, 1525, 1340, 1180, 840 cm－1; MS (70 eV) m/z (%): 414 (M+, 32), 337 (78).
9-苯基-10-(4-甲基苯基)-3, 4, 6, 7, 9, 10-六氢吖啶- 1, 8(2H, 5H)-二酮(1n):黄色晶体, m.p. 272~274 ℃ (Lit.[16] 273~276 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.34~7.27 (m, 4H), 7.25~7.10 (m, 5H), 4.82 (s, 1H), 2.61~2.34 (m, 6H), 2.32 (s, 3H), 2.01~1.87 (m, 6H); 13C NMR (101 MHz, CDCl3) δ: 196.5, 163.9, 144.4, 128.4, 128.1, 126.4, 116.9, 37.0, 31.6, 27.2, 20.3; IR (KBr) ν: 3048, 2953, 1650, 1578, 1153 cm－1; MS (70 eV) m/z (%): 383 (M+, 45), 292 (100), 91 (75).
3, 3, 6, 6-四甲基-9, 10-二苯基-3, 4, 6, 7, 9, 10-六氢吖啶- 1, 8(2H, 5H)-二酮(1o):黄色晶体, m.p. 251~253 ℃ (Lit.[29] 254~255 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.65~7.43 (m, 4H), 7.63 (d, J＝6.0 Hz, 2H), 7.26 (t, J＝8.0 Hz, 2H), 7.11 (t, J＝8.0 Hz, 2H), 5.10 (s, 1H), 2.26~2.10 (m, 4H), 2.02 (d, J＝15.8 Hz, 2H), 1.78 (d, J＝15.8 Hz, 2H), 0.88 (s, 6H), 0.72 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 195.5, 150.7, 146.7, 138.9, 130.5, 129.8, 128.3, 128.0, 126.2, 113.4, 50.0, 41.45, 32.4, 29.8, 26.5; IR (KBr) ν: 3058, 3025, 2948, 1641, 1545, 1182 cm－1; MS (70 eV) m/z (%): 425 (M+, 60), 347 (100), 327 (30).
3, 3, 6, 6-四甲基-9-苯基-10-(3-硝基苯基)- 3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1p):黄色固体, m.p. 195~197 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.44~7.28 (m, 5H), 7.24~7.20 (m, 3H), 7.18~7.16 (m, 1H), 4.75 (s, 1H), 2.52~2.48 (m, 4H), 2.25~2.14 (m, 4H), 1.05 (s, 6H), 0.96 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 195.4, 147.7, 146.4, 128.0, 126.0, 113.8, 50.8, 41.2, 33.6, 32.7, 29.5, 27.2; IR (KBr) ν: 3052, 3025, 2952, 1643, 1583, 1178 cm－1; MS (70 eV) m/z (%): 470 (M+, 35), 344 (100). Anal. calcd for C29H30N2O4: C 74.02, H 6.43, N 5.95, O 13.60; found C 74.08, H 6.45, N 5.91, O 13.56.
3, 3, 6, 6-四甲基-9-苯基-10-(4-甲基苯基)- 3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1q):黄色晶体, m.p. 263~265 ℃ (Lit.[26] 261~263 ℃); 1H NMR (400 MHz, DMSO-d6) δ: 7.65~7.42 (m, 5H), 7.23 (d, J＝6.0 Hz, 2H), 7.06 (d, J＝6.0 Hz, 2H), 5.05 (s, 1H), 2.36~2.17 (m, 4H), 2.32 (s, 3H), 2.01~1.96 (m, 2H), 1.74~1.72 (m, 2H), 0.88 (s, 6H), 0.72 (s, 6H); 13C NMR (101 MHz, DMSO-d6) δ: 195.4, 150.6, 143.8, 138.9, 135.0, 130.5, 129.9, 128.8, 127.9, 113.5, 50.0, 41.4, 32.4, 31.9, 29.8, 26.5, 21.1; IR (KBr) ν: 3092, 3056, 2955, 1640, 1576, 1156 cm－1; MS (70 eV) m/z (%): 439 (M+, 68), 43 (52).
3, 3, 6, 6-四甲基-9-(4-氯苯基)-10-苯基-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1r):黄色晶体, m.p. 260~262 ℃ (Lit.[26] 259~261 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.56~7.50 (m, 6H), 7.44~7.42 (m, 1H), 7.25~7.23 (m, 2H), 5.30 (s, 1H), 2.28~2.19 (m, 6H), 1.88~1.80 (m, 2H), 0.95 (s, 6H), 0.79 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 195.6, 150.3, 132.1, 129.7, 129.3, 128.8, 113.7, 50.6, 50.1, 41.9, 33.7, 32.5, 29.7, 27.3, 26.7; IR (KBr) ν: 3060, 2956, 1639, 1576, 1144, 1087 cm－1; MS (70 eV) m/z (%): 459 (M+, 55), 282 (100), 344 (70).
3, 3, 6, 6-四甲基-9-苯基-10-(4-氯苯基)-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1s):黄色晶体, m.p.＞300 ℃ (Lit.[25] 300~302 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.68 (d, J＝8.8 Hz, 2H), 7.48 (d, J＝5.6 Hz, 2H), 7.21~7.32 (m, 4H), 7.07~7.12 (m, 1H), 5.05 (s, 1H), 2.16~2.22 (m, 4H), 2.00~1.78 (m, 4H), 0.88 (s, 6H), 0.72 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 195.5, 150.6, 146.6, 137.8, 134.4, 130.6, 128.4, 128.0, 126.3, 113.6, 50.0, 41.4 32.4, 32.3, 29.7, 26.5; IR (KBr) ν: 3085, 3046, 2937, 1645, 1570 cm－1; MS (70 eV) m/z (%): 459 (M+, 83), 379 (100), 344 (25).
3, 3, 6, 6-四甲基-9-苯基-10-(吡啶-2-基)-3, 4, 6, 7, 9, 10-六氢吖啶-1, 8(2H, 5H)-二酮(1t):黄色晶体, m.p. 253~255 ℃ (Lit.[27] 255~257 ℃); 1H NMR (400 MHz; DMSO-d6) δ: 8.75 (s, 1H), 8.14~8.10 (m, 1H), 7.66~7.62 (m, 2H), 7.40~7.37 (m, 2H), 7.27~7.22 (m, 2H), 7.11 (t, J＝6.0 Hz, 1H), 5.04 (s, 1H), 2.25~2.18 (m, 4H), 1.98 (d, J＝18.0 Hz, H), 1.71 (d, J＝18.0 Hz, H), 0.88 (6H, s), 0.72 (s, H); 13C NMR (101 MHz; DMSO-d6) δ: 195.5, 151.8, 150.6, 149.9, 146.7, 140.1, 128.2, 128.2, 126.2, 125.5, 125.4, 113.5, 50.0, 40.8, 32.6, 32.5, 29.6, 21.6; IR (KBr) ν: 3051, 3025, 2958 1640, 1584, 1122 cm－1; MS (70 eV) m/z (%): 426 (M+, 46), 345 (82), 44 (100).
辅助材料(Supporting Information) 所有产物1a~1t的核磁共振氢谱和碳谱图谱.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 低共熔溶剂中N-取代十氢吖啶-1, 8-二酮类化合物的合成
Scheme 1 Synthesis of N-substituted decahydroacridine-1, 8- diones in deep eutectic solvents
图 1 DES催化Hantzsch反应可能的机理
Figure 1 Plausible mechanism for the DES catalyzed Hantzsch reaction
表 1 合成十氢吖啶-1, 8-二酮反应条件的优化a
Table 1. Optimization of reaction conditions for the synthesis of decahydroacridine-1, 8-diones
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| Entry | Madiab | Nitrogen source | T/℃ | Yield/% |
| 1 | Free solvent | NH4OAc | 70 | Trace |
| 2 | ChCl/Urea | NH4OAc | 70 | 67.2 |
| 3 | ChCl/Oxalic acid | NH4OAc | 70 | 65.4 |
| 4 | ChCl/p-TsOH | NH4OAc | 70 | 71.9 |
| 5 | ChCl/PEG | NH4OAc | 70 | 68.2 |
| 6 | ChCl/ZnCl2 | NH4OAc | 70 | 78.4 |
| 7 | ChCl/ZnCl2 | NH4OAc | 60 | 67.8 |
| 8 | ChCl/ZnCl2 | NH4OAc | 80 | 90.2 |
| 9 | ChCl/ZnCl2 | NH4OAc | 90 | 91.6 |
| 10 | ChCl/ZnCl2 | NH4HCO3 | 80 | 83.3 |
| 11 | ChCl/ZnCl2 | (NH4)2CO3 | 80 | 78.2 |
| 12 | ChCl/ZnCl2 | NH4Cl | 80 | 80.7 |
| 13 | ChCl/ZnCl2 | (NH2)2CO | 80 | 77.9 |
| 14 | ChCl/ZnCl2 | C6H5NH2 | 80 | 73.1 |
| 15b | ChCl/ZnCl2 | C6H5NH2 | 90 | 88.7 |
| 16c | ChCl/ZnCl2 | NH4OAc | 80 | 81.2 |
| a Reaction conditions: diketone (2 mmol), aromatic aldehyde (1 mmol), ammonium acetate ((2 mmol), aromatic amine (1 mmol), DES (2 mL), reaction time: 1~2 h. b Reaction time 2 h. c ChCl/ZnCl2 was reused three times. | ||||
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表 2 DES促进系列十氢吖啶-1, 8-二酮的合成a
Table 2. Synthesis of decahydroacridine-1, 8-diones promoted by DES
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| Compd. | R1 | R2 | R3 | Yield/% |
| 1a | H | C6H5 | H | 85.6 |
| 1b | H | 4-MeC6H4 | H | 83.2 |
| 1c | H | 4-MeOC6H4 | H | 81.4 |
| 1d | H | 4-NO2C6H4 | H | 92.6 |
| 1e | CH3 | C6H5 | H | 90.2 |
| 1f | CH3 | 4-BrC6H4 | H | 83.9 |
| 1g | CH3 | 4-MeC6H4 | H | 82.6 |
| 1h | CH3 | 4-MeOC6H4 | H | 80.5 |
| 1i | CH3 | 4-NO2C6H4 | H | 91.7 |
| 1j | CH3 | 3-NO2C6H4 | H | 86.6 |
| 1k | CH3 | 2-Thienyl | H | 78.6 |
| 1l | CH3 | 2-Pyridyl | H | 81.2 |
| 1m | H | C6H5 | 3-O2NC6H4 | 76.1 |
| 1n | H | C6H5 | 4-MeC6H4 | 84.7 |
| 1o | CH3 | C6H5 | C6H5 | 83.6 |
| 1p | CH3 | C6H5 | 3-O2NC6H4 | 75.1 |
| 1q | CH3 | C6H5 | 4-MeC6H4 | 82.7 |
| 1r | CH3 | 4-ClC6H4 | C6H5 | 81.3 |
| 1s | CH3 | C6H5 | 4-ClC6H4 | 79.8 |
| 1t | CH3 | C6H5 | 2-Pyridyl | 76.5 |
| a Dketone (2 mmol), aromatic aldehyde (1 mmol), ammonium acetate (2 mmol), aromatic amine (1 mmol), DES (2 mL), reaction time: 1~2 h, reaction temperature: 1a~1l 80 ℃, 1m~1t 90 ℃. | ||||
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