图1 杂环烯酮缩胺的结构
Figure 1. Structure of heterocyclic ketene aminals
引用本文:
罗大云, 崔时胜, 胡兴梅, 林军, 严胜骄. 酰胺类杂环烯酮缩胺的合成[J]. 有机化学,
2017, 37(1): 166-175.
doi:
10.6023/cjoc201607002
Citation: Luo Dayun, Cui Shisheng, Hu Xingmei, Lin Jun, Yan Shengjiao. Synthesis of Amide Class Heterocyclic Ketene Aminals[J]. Chinese Journal of Organic Chemistry, 2017, 37(1): 166-175. doi: 10.6023/cjoc201607002
Citation: Luo Dayun, Cui Shisheng, Hu Xingmei, Lin Jun, Yan Shengjiao. Synthesis of Amide Class Heterocyclic Ketene Aminals[J]. Chinese Journal of Organic Chemistry, 2017, 37(1): 166-175. doi: 10.6023/cjoc201607002
酰胺类杂环烯酮缩胺的合成
English
Synthesis of Amide Class Heterocyclic Ketene Aminals
Abstract:
In this paper, a concise protocol for synthesis of possess potential pharmacological active amide class heterocyclic ketene aminals (HKAs) has been developed, which based on the six or seven-membered HKAs 1~2, using aryl isocyanate 4 as acylation agent.The regioselective acylation reaction of HKAs in 1, 4-dioxane at room temperature gave compounds 5~6 with 90%~98% yields.However, the five-membered HKAs 3 and aryl isocyanate 4 reacted in 1, 4-dioxane catalyzed by Cs2CO3 at room temperature to obtain compounds 7 in 78%~93% yields.
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Key words:
- heterocyclic ketene aminals
- / isocyanate
- / regioselective
- / acylation reaction
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从方法学上对杂环烯酮缩胺进行区域选择性酰化反应具有一定意义; 同时由于杂环烯酮缩胺具有广泛生物活性, 酰胺类化合物也具有广泛生物活性, 所以通过杂环烯酮缩胺的区域选择性酰化合成的新的酰胺类杂环烯酮缩胺将具有潜在的生物活性.本文以杂环烯酮缩胺1~3与苯基异氰酸酯4为反应原料, 在1, 4-二氧六环溶剂中室温条件下, 通过酰基化反应简洁、高效区域选择性合成一系列酰胺类杂环烯酮缩胺酰胺化合物5~6和苯基脲结构的杂环烯酮缩胺化合物7.该方法具有原料易得、合成路线简洁、产率高、反应条件温和等优点.合成路线见Scheme 1.
杂环烯酮缩胺(HKAs)是一种多功能的合成砌块[9~11], 已广泛用于合成结构多样的杂环化合物, 其中许多杂环化合物具有优异的多种生理活性, 如抗肿瘤[12]、除草、杀虫[13]、抗焦虑[14]、抗细菌等[15].杂环烯酮缩胺的结构如图 1所示, 由于结构中含有吸电子基(EWG)和供电性氨基导致碳-碳双键高度极化, 致使α-碳电子云密度增大, 使得α-碳具有较好亲电性, 可以与多种亲电试剂发生选择性反应, 如烷基化[16]、酰化[17]、糖基化[18]、卤化[19]、硝化反应[20]、芳硫基化[21].而通过与苯基异氰酸酯进行酰化合成具有潜在生物活性的酰胺类环烯酮缩胺化合物具有重要意义.从图 1可知, HKAs属于缺电子烯胺, 缺电子烯胺的合成多年来一直备受合成化学家们广泛关注[22].
酰胺衍生物是一类重要的杂环化合物, 由于其具有潜在的药理活性包括抗肺炎、抗肿瘤、抗真菌、抗痢疾、抗氧化、除草、杀虫等[1, 2], 同时可作为许多有机化合物及药物分子的合成中间体[3], 致使其在有机化学、药物学、植物学以及材料学等方面都有潜在的应用[4~6].酰胺衍生物中较为重要的一类化合物即苯基脲类化合物具有优异的除草性能[7, 8], 致使其在植物学以及农业等领域都有重要的应用价值, 也引起了研究者们的极大关注.如除草剂灭草隆、草不隆等均具有苯基脲结构.
图图式 1 目标化合物5~7的合成
Figure 图式 1. Synthesis of target compounds 5~7
1 结果与讨论
1.1 反应条件的筛选、制备和讨论
表3
反应条件的优化a
Table3.
Optimization of reaction conditions
Entry Solvent Catalyst t/℃ Time/h Yieldb/% 1 Acetone - r.t. 3 71 2 Acetonitrile - r.t. 3 42 3 EtOH - r.t. 3 13 4 1, 4-Dioxane - r.t. 3 73 5 Toluene - r.t. 3 68 6 Tetrahydrofuran - r.t. 3 56 7 Chloroform - r.t. 3 61 8 1, 4-Dioxane DIPEA r.t. 3 75 9 1, 4-Dioxane Et3N r.t. 3 77 10 1, 4-Dioxane K2CO3 r.t. 2.5 83 11 1, 4-Dioxane Cs2CO3 r.t. 2.5 91 12 1, 4-Dioxane t-BuOK r.t. 1.5 79 13 1, 4-Dioxane NaH r.t. 1.5 72 14 1, 4-Dioxane - 80 1.5 32 15 1, 4-Dioxane Cs2CO3 80 1.5 38 aThe reaction was performed with 3a (1 mmol), 4a (1.1 mmol), catalyst (0.5 mmol) and the solvent (15 mL). bIsolated yields based on HKAs 3a. 表3 反应条件的优化a
Table3. Optimization of reaction conditions
表1
反应条件的优化a
Table1.
Optimization of reaction conditions
Entry Solvent Catalyst T (℃) Time/h Yieldb/% 1 Acetone - r.t. 3 91 2 Acetonitrile - r.t. 3 79 3 EtOH - r.t. 3 21 4 1, 4-Dioxane - r.t. 3 96 5 Toluene - r.t. 3 93 6 THF - r.t. 3 87 7 1, 4-Dioxane DIPEA r.t. 3 89 8 1, 4-Dioxane Et3N r.t. 2 94 9 1, 4-Dioxane K2CO3 r.t. 2.5 81 10 1, 4-Dioxane Cs2CO3 r.t. 2 63 11 1, 4-Dioxane - 50 2.5 93 12 1, 4-Dioxane - 110 2.5 91 13 1, 4-Dioxane - r.t. 3 97c 14 1, 4-Dioxane - r.t. 3 94d aThe reaction was performed with 1a (1 mmol), 4a (1 mmol) and the solvent (15 mL). bIsolated yields. cThe reaction was performed with 1a (1 mmol), 4a (1.1 mmol), and the solvent (15 mL).dThe reaction was performed with 1a (1.1 mmol), 4a (1 mmol), and the solvent (15 mL). 表1 反应条件的优化a
Table1. Optimization of reaction conditions首先, 将杂环烯酮缩胺1a与4-氯苯基异氰酸酯(4a)按等物质的量溶解于丙酮中, 室温条件下反应3 h, 结果以91%的收率得目标化合物5a(表 1, Entry 1).在此基础上, 筛选了乙腈、乙醇、1, 4-二氧六环、甲苯、四氢呋喃五种溶剂(表 1, Entries 2~6).结果表明溶剂对反应收率有较大影响, 其中1, 4-二氧六环为溶剂时以96%的收率得目标化合物5a(表 1, Entry 4).从表 1可看出, 1, 4-二氧六环为最佳溶剂.对催化剂包括DIPEA, Et3N, K2CO3, Cs2CO3进行筛选.结果显示, 催化剂对反应速率有一定的提高, 但反应的副产物也随之增多, 致使反应的收率有所下降, 尤其是碳酸铯作为催化剂时反应收率下降到63%(表 1, Entries 10 vs 7~9).对反应温度进行筛选.反应在50 ℃或回流条件下, 温度提高虽可缩短反应时间, 但收率却有所降低(表 1, Entries 11, 12), 确定室温是最佳温度.最后, 对原料的物质的量比进行筛选.将HKAs (1a)与4-氯苯基异氰酸酯(4a)的物质的量比由1:1调整为1:1.1时, 反应进行较完全且目标化合物的收率也较高(表 1, Entries 4 vs 13 vs 14).最终确定最佳反应条件为: 1a与4a的物质的量比为1:1.1, 溶剂为1, 4-二氧六环, 室温条件下搅拌3 h.
我们以六元环的杂环烯酮缩胺1a与4-氯苯基异氰酸酯(4a)为模板反应, 分别对反应溶剂、催化剂、反应时间、温度等进行条件筛选与优化, 结果见表 1.
在获得最佳反应条件基础上, 我们考察不同取代的杂环烯酮缩胺和苯基异氰酸酯的反应情况.从表 4可看出, 供电子基HKAs反应的收率高于吸电基HKAs (表 4, Entries 2、3 vs 4 vs 5 vs 6).而苯基异氰酸酯苯环上的吸电子基有利于收率(表 4, Entries 1 vs 10~12).
当五元环杂环烯酮缩胺3a与4-氯苯基异氰酸酯(4a)在上述同样条件下反应, 以73%的收率获得杂环烯酮缩胺的氮酰基化产物7a.由于反应的收率还不够理想, 我们对溶剂、温度、催化剂等进行了筛选优化.首先, 3a与4a的物质的量比为1:1.1, 选择丙酮、乙腈等溶剂(表 3, Entries 1~7).结果发现1, 4-二氧六环仍然是较为理想的溶剂; 在催化剂筛选时发现, 随着催化剂碱性的增强, 目标化合物的收率有所提高, 但当我们使用碱性较强的叔丁醇钾和氢化钠作为催化剂时, 薄层色谱(TLC)检测表明该反应副产物增多导致目标化合物的收率降低(表 3, Entries 4 vs 8~13).温度的提高使得反应更为复杂, 收率大为下降(表 3, Entries 11 vs 15).据此, 反应的最佳条件是以1, 4-二氧六环为溶剂, 碳酸铯为催化剂, 室温下反应2.5 h.同时, 我们也利用该条件重新对六元环和七元环HKAs进行测试, 发现该条件下仅有少量的氮酰基化产物产生, 主产物依然是发生在HKAs的α-碳的酰基化产物.
此外, 我们用不同取代的苯基异氰酸酯4b~4d为反应底物与六~七元杂环烯酮缩胺反应.结果表明, 不同取代苯基异氰酸酯对产物收率有一定影响.供电子基苯基异氰酸酯比吸电子基苯基异氰酸酯有更高的收率(表 2, Entries 11 vs 1 vs 12 vs 13, Entries 18 vs 17 vs 19 vs 20).
在最佳条件基础上探索该反应的普适性.我们选择供电子的甲基、甲氧基和吸电子的氟、氯、溴取代的HKAs, 邻位和对位取代的HKAs, 六元和七元环的HKAs作为反应底物进行测试.研究结果表明, 对于六元环的HKAs而言, 供电子基团(Me, MeO)比吸电子基团(F、Cl、Br)取代的HKAs有更高的收率(表 2, Entries 1~6).此外, 对位取代较邻位取代的HKAs有较高的收率(表 2, Entries 4 vs 7; Entries 5 vs 8).噻吩杂环烯酮缩胺同样以优异的收率得到目标产物(表 2, Entry 9).七元环HKAs为底物时同样以优异的收率得到目标化合物6(表 2, Entries 14~20).从反应收率看, 给电子基略高于吸电子基HKAs (表 2, Entries 15 vs 16 vs 17).
表2
酰胺类杂环烯酮缩胺5~6的制备a
Table2.
Preparation of amide class heterocyclic ketene aminals 5~6
Entry 1/2 (EWG/n) 4 5/6 Yieldb/% 1 1a (PhCO/1) 4a 5a 97 2 1b (4-MeOC6H4CO/1) 4a 5b 95 3 1c (4-MeC6H4CO/1) 4a 5c 96 4 1d (4-FC6H4CO/1) 4a 5d 92 5 1e (4-ClC6H4CO/1) 4a 5e 90 6 1f (4-BrC6H4CO/1) 4a 5f 92 7 1g (2-FC6H4CO/1) 4a 5g 91 8 1h (2-ClC6H4CO/1) 4a 5h 90 9 1i (C4H3SCO/1) 4a 5i 97 10 1j (NO2/1) 4a 5j 95 11 1a (PhCO/1) 4b 5k 98 12 1a (PhCO/1) 4c 5l 96 13 1a (PhCO/1) 4d 5m 96 14 2a (PhCO/2) 4a 6a 94 15 2b (4-MeC6H4CO/2) 4a 6b 97 16 2c (4-FC6H4CO/2) 4a 6c 92 17 2d (4-ClC6H4CO/2) 4a 6d 94 18 2d (4-ClC6H4CO/2) 4b 6e 96 19 2d (4-ClC6H4CO/2) 4c 6f 95 20 2d (4-ClC6H4CO/2) 4d 6g 93 aThe reaction was performed with 1or 2 (1 mmol), 4 (1.1 mmol) and the solvent (15 mL). bIsolated yields based on HKAs 1 or 2. 表2 酰胺类杂环烯酮缩胺5~6的制备a
Table2. Preparation of amide class heterocyclic ketene aminals 5~6
表4
酰胺类杂环烯酮缩胺酰胺7的制备
Table4.
Preparation of amide class heterocyclic ketene aminals 7a
Entry 3 (EWG) 4 7 Yieldb/% 1 3a (PhCO) 4a 7a 91 2 3b (4-MeOC6H4CO) 4a 7b 90 3 3c (4-MeC6H4CO) 4a 7c 89 4 3d (4-FC6H4CO) 4a 7d 85 5 3e (4-ClC6H4CO) 4a 7e 87 6 3f (4-BrC6H4CO) 4a 7f 78 7 3g (2-ClC6H4CO) 4a 7g 79 8 3h (C4H3S) 4a 7h 91 9 3i (NO2) 4a 7i 90 10 3a (PhCO) 4b 7j 85 11 3a (PhCO) 4c 7k 91 12 3a (PhCO) 4d 7l 93 aThe reaction was performed with 3 (1 mmol), 4 (1.1 mmol), CsCO3 (0.5 mmol) and the solvent (15 mL). bIsolated yields based on HKAs 3. 表4 酰胺类杂环烯酮缩胺酰胺7的制备
Table4. Preparation of amide class heterocyclic ketene aminals 7a1.2 反应选择性
图2 杂环烯酮缩胺1a和3a的最优构象
Figure 2. Optimal conformations of heterocyclic ketene aminals 1a and 3a
对于六元环HKAs进行α-C选择性酰化反应, 而五元环HKAs进行氮原子的选择性酰化反应, 这主要受空间位阻作用.烯胺类化合物受位阻作用而进行选择性反应已有文献报道[23~25].我们利用高斯软件分别计算六元环HKAs 1a和五元环HKAs 3a的最优构象(图 2).从图 2可以看出化合物1a呈U型结构, 而化合物3a呈近似直线型分子.可看出, 六元环HKAs 1a的α-C (C3)的位阻比五元环HKAs 3a的α-C (C3)位阻小; 反之, 六元环HKAs 1a的氮原子(N4)的位阻比五元环HKAs 3a的氮原子(N4)位阻大; 在化合物1a和3a中羰基氧均与氮原子(N1)形成分子内氢键, 导致N1位很难参加反应.由上可知, 是位阻作用导致六元环杂环烯酮缩胺1在与苯基异氰酸酯4反应时优先进行的是α-C酰化反应; 而五元环杂环烯酮缩胺3在与苯基异氰酸酯4反应时优先进行的是氮原子(N4)的酰化反应.
1.3 反应机理
我们以化合物5a为例阐明该反应的可能机理:首先杂环烯酮缩胺1a对4-氯苯基异氰酸酯(4a)加成得中间体8, 中间体8经过亚胺-烯胺[11a]互变形成中间体9, 化合物9经过酮-烯醇互变形成化合物5a.反应机理如Scheme 2所示.
图图式 2 推测的反应机理
Figure 图式 2. Proposed mechanism
2 结论
总之, 本文成功建立了区域选择性简洁、高效合成具有潜在生物活性的酰胺类杂环烯酮缩胺化合物库的方法.该方法以六元或七元环杂环烯酮缩胺1~2与异氰酸酯4在1, 4-二氧六环溶剂中室温下反应3 h后以优异的收率(90%~98%)得到杂环烯酮缩胺α-碳酰基化产物5~6; 而五元环杂环烯酮缩胺3与异氰酸酯4在1, 4-二氧六环溶剂中, 用碳酸铯为催化剂, 室温下反应2.5 h后以良好的收率(78%~93%)得杂环烯酮缩胺氮酰基化产物7.该方法具有操作简便、合成路线简洁、产率高、区域选择性好等优点.所合成的酰胺类杂环烯酮缩胺化合物具有潜在的生物活性, 这将为今后进一步进行活性筛选打下基础.
3 实验部分
3.1 仪器和试剂
控温型电磁搅拌器; 傅里叶红外光谱仪(Thermo Nicolet Avatar 360型); 高分辨质谱仪(Agilent CL/Msd TOF); 核磁共振仪Bruck DRX300 (1H: 300 MHz, 13C: 75 MHz)或DRX500 (1H: 500 MHz, 13C: 125 MHz); 熔点仪(XT-4A控温型显微熔点测定仪).试剂用分析纯或化学纯(无水硫酸钠干燥处理). GF254高效薄层层析板及柱层析硅胶(200~300目, 青岛海洋化工厂).反应原料1~3按文献[26]制备.
3.2 化合物5~6的合成方法
N, 3-双(4-氯苯基)-3-氧代-2-[四氢嘧啶-2(1H)-亚基]丙酰胺(5e):得351 mg, 白色固体, 产率90%. m.p. 232.4~234.4 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.87~1.95 (m, 2H, CH2), 3.33 (t, J=4.5 Hz, 4H, 2CH2), 6.81 (d, J=8.7 Hz, 2H, ArH), 7.05 (d, J=8.7 Hz, 2H, ArH), 7.22 (d, J=8.4 Hz, 2H, ArH), 7.43 (d, J=8.1 Hz, 2H, ArH), 9.96 (br, 2H, 2NH); 13C HMR (75 MHz, CDCl3) δ: 19.6, 38.3, 38.3, 90.9, 120.8, 128.6, 128.7, 128.7, 129.3, 136.0, 136.8, 141.3, 159.9, 169.8, 187.7; IR (KBr) v: 3425, 1621, 1591, 1526, 1491, 1400, 1320, 1203, 1174, 1090, 1014, 827, 780 cm-1; HRMS (TOF ES+) calcd for C19H16Cl2-N3O2 [M-H]- 388.0625, found 388.0622.
N-(4-氯苯基)-2-硝基-2-[四氢嘧啶-2(1H)-亚基]乙酰胺(5j):得281 mg, 白色固体, 产率95%. m.p. 206.7~208.7 ℃; 1H NMR (300 MHz, DMSO-d6) δ: 1.81~1.89 (m, 2H, CH2), 3.36~3.42 (m, 4H, 2CH2), 7.34 (d, J=8.7 Hz, 2H, ArH), 7.63 (d, J=8.7 Hz, 2H, ArH), 9.85 (br, 2H, 2NH), 11.76 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 17.8, 38.4, 38.4, 108.7, 121.2, 126.7, 128.6, 137.6, 155.5, 161.4; IR (KBr) v: 3208, 3088, 2879, 1626, 1582, 1534, 1444, 1363, 1316, 1277, 1157, 1099, 830, 771, 511 cm-1; HRMS (TOF ES+) calcd for C12H12ClN4O3 [M-H]- 295.0603, found 295.0603.
3-(4-氯苯基)-2-(1, 3-安定-2-亚基)-3-氧代-N-(对甲苯基)丙酰胺(6e):得368 mg, 白色固体, 产率96%. m.p. 204.4~206.4 ℃; 1H NMR (300 MHz, DMSO-d6) δ: 1.50~1.54 (m, 4H, 2CH2), 2.21 (s, 3H, CH3), 2.95~2.99 (m, 4H, 2CH2), 7.01 (d, J=8.1 Hz, 2H, ArH), 7.32~7.43 (m, 6H, ArH), 8.85 (br, 2H, 2NH), 11.21 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6) δ: 20.3, 26.7, 26.7, 44.9, 44.9, 93.9, 119.0, 127.5, 128.9, 129.3, 130.8, 133.2, 137.4, 142.5, 167.3, 169.1, 186.5; IR (KBr) v: 3425, 3297, 3037, 2945, 1626, 1591, 1514, 1488, 1439, 1404, 1360, 1248, 1173, 1109, 1072, 1040, 845, 814, 789 cm-1; HRMS (TOF ES+) calcd for C21H22ClN3O2 [M+H]+ 383.1473, found 383.1473.
N-(4-氟苯基)-3-氧代-3-苯基-2-[四氢嘧啶-2(1H)-亚基]丙酰胺(5l):得325 mg, 白色固体, 产率96%. m.p. 204.5~206.5 ℃; 1H NMR (300 MHz, CDCl3) δ: 2.00~2.04 (m, 2H, CH2), 3.43~3.47 (m, 4H, 2CH2), 6.80~6.86 (m, 4H, ArH), 7.37~7.41 (m, 3H, ArH), 7.57~7.61 (m, 2H, ArH), 10.24 (br, 2H, 2NH); 13C HMR (75 MHz, CDCl3) δ: 19.7, 38.2, 38.2, 90.7, 115.0, 115.3, 121.6 (d, J=7.5 Hz), 127.7, 128.7, 130.0, 134.2, 143.2, 159.6 (d, J=240.7 Hz), 160.1, 160.7, 170.1, 189.4; IR (KBr) v: 3425, 3248, 3059, 2924, 2871, 1626, 1590, 1536, 1503, 1445, 1366, 1322, 1208, 1145, 834, 776, 735, 700 cm-1; HRMS (TOF ES+) calcd for C19H18FN3O2 [M+H]+ 340.1456, found 340.1460.
N-(4-氯苯基)-2-(1, 3-安定-2-亚基)-3-氧代-3-(对甲苯基)丙酰胺(6b):得372 mg, 白色固体, 产率97%. m.p. 180.1~182.1 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.62~1.68 (m, 4H, 2CH2), 2.37 (s, 3H, CH3), 3.03~3.09 (m, 4H, 2CH2), 7.18~7.32 (m, 6H, ArH), 7.46~7.52 (m, 2H, ArH), 8.67 (br, 2H, 2NH), 10.06 (br, 1H, NH); 13C HMR (75 MHz, CDCl3)δ: 21.4, 27.4, 27.4, 45.9, 45.9, 93.1, 121.4, 128.0, 128.6, 129.2, 137.6, 140.2, 140.8, 169.0, 170.4, 191.6; IR (KBr) v: 3426, 3313, 2944, 1628, 1528, 1492, 1438, 1399, 1345, 1211, 1088, 1008, 829, 789 cm-1; HRMS (TOF ES+) calcd for C21H21ClN3O2 [M-H]- 382.1328, found 382.1329.
N-(4-氯苯基)-3-(2-氟苯基)-3-氧代-2-[四氢嘧啶-2(1H)-亚基]丙酰胺(5g):得340 mg, 白色固体, 产率91%. m.p. 154.2~156.2 ℃; 1H NMR (300 MHz, CDCl3) δ: 1.89~1.96 (m, 2H, CH2), 3.32~3.38 (m, 4H, 2CH2), 6.80~6.86 (m, 2H, ArH), 6.92 (t, J=9 Hz, 1H, ArH), 7.03 (d, J=8.4 Hz, 2H, ArH), 7.11 (t, J=7.5 Hz, 1H, ArH), 7.19~7.24 (m, 1H, ArH), 7.46 (t, J=6.9 Hz, 1H, ArH), 10.18 (br, 2H, 2NH); 13C HMR (75 MHz, CDCl3) δ: 19.5, 38.2, 38.2, 93.1, 116.2 (d, J=22.5 Hz), 120.8, 124.8, 128.5, 128.7, 129.5, 130.9, 131.2 (d, J=8.3 Hz), 136.7, 156.9, 160.1 (d, J=22.5 Hz), 169.5, 182.6; IR (KBr) v: 3431, 1619, 1492, 1451, 1399, 1366, 1321, 1241, 1094, 827, 772 cm-1; HRMS (TOF ES+) calcd for C19H16Cl-FN3O2 [M-H]- 372.0921, found 372.0919.
3-(2-氯苯基)-N-(4-氯苯基)-3-氧代-2-[四氢嘧啶-2(1H)-亚基]丙酰胺(5h):得351 mg, 白色固体, 产率90%. m.p. 136.0~138.0 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.87~1.93 (m, 2H, CH2), 3.31~3.37 (m, 4H, 2CH2), 6.68 (br, 1H, NH), 6.78~6.84 (m, 2H, ArH), 7.01 (d, J=8.4 Hz 2H, ArH), 7.12~7.17 (m, 2H, ArH), 7.27~7.33 (m, 2H, ArH), 10.24 (br, 2H, 2NH); 13C HMR (75 MHz, CDCl3) δ: 19.4, 38.2, 38.2, 92.7, 120.6, 127.6, 128.2, 128.4, 128.6, 129.9, 130.2, 136.7, 142.6, 160.0, 169.2, 185.6; IR (KBr) v: 3427, 2969, 1619, 1492, 1399, 1367, 1320, 1238, 1200, 1092, 1056, 828, 775 cm-1; HRMS (TOF ES+) calcd for C19H16Cl2N3O2 [M-H]- 388.0625, found 388.0627.
N-(4-氯苯基)-2-(1, 3-安定-2-亚基)-3-(4-氟苯基)-3-氧代丙酰胺(6c):得356 mg, 白色固体, 产率92%. m.p. 168.4~170.4 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.65~1.71 (m, 4H, 2CH2), 3.08~3.14 (m, 4H, 2CH2), 7.05~7.26 (m, 6H, ArH), 7.59~7.66 (m, 2H, ArH), 8.77 (br, 2H, 2NH), 9.65 (br, 1H, NH); 13C HMR (75 MHz, CDCl3) δ: 27.3, 27.3, 45.9, 45.9, 93.2, 115.5 (d, J=21.8 Hz), 121.3, 128.3, 128.7, 130.2 (d, J=8.3 Hz), 137.3, 139.1, 165.6, 168.9, 170.0, 189.9; IR (KBr) v: 3429, 3308, 3044, 2934, 2853, 1629, 1599, 1528, 1492, 1400, 1344, 1283, 1221, 1154, 1131, 1090, 1011, 849, 826, 790, 609 cm-1; HRMS (TOF ES+) calcd for C20H18ClFN3O2 [M-H]- 386.1077, found 386.1075.
N, 3-双(4-氯苯基)-2-(1, 3-安定-2-亚基)-3-氧代丙酰胺(6d):得380 mg, 白色固体, 产率94%. m.p. 198.6~200.6 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.65~1.71 (m, 4H, 2CH2), 3.07~3.14 (m, 4H, 2CH2), 7.21~7.30 (m, 4H, ArH), 7.37 (d, J=8.1 Hz, 2H, ArH), 7.55 (d, J=8.1 Hz, 2H, ArH), 8.72 (br, 2H, 2NH), 9.75 (br, 1H, NH); 13C HMR (75 MHz, CDCl3) δ: 27.3, 27.3, 45.9, 45.9, 93.3, 121.3, 128.3, 128.8, 128.8, 129.4, 136.4, 137.3, 141.4, 168.8, 169.9, 189.7; IR (KBr) v: 3428, 3306, 2930, 1625, 1532, 1491, 1438, 1345, 1282, 1192, 1090, 1012, 844, 789 cm-1; HRMS (TOF ES+) calcd for C20H18Cl2N3O2 [M-H]- 402.0782, found 402.0781.
3-(4-氯苯基)-2-(1, 3-安定-2-亚基)-N-(4-氟苯基)-3-氧代丙酰胺(6f):得368 mg, 白色固体, 产率95%. m.p. 214.6~216.6 ℃; 1H NMR (300 MHz, DMSO-d6) δ: 1.51~1.55 (m, 4H, 2CH2), 2.96~3.00 (m, 4H, 2CH2), 7.04 (t, J=8.9 Hz, 2H, ArH), 7.36~7.49 (m, 6H, ArH), 8.84 (br, 2H, 2NH), 11.32 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 26.7, 26.7, 44.9, 44.9, 93.8, 114.8, 115.1, 120.5 (d, J=7.5 Hz), 127.5, 129.3, 133.3, 136.3, 142.4, 157.3 (d, J=237.0 Hz), 167.4, 168.9, 186.5; IR (KBr) v: 3426, 3307, 3040, 2947, 1785, 1627, 1603, 1570, 1507, 1485, 1439, 1346, 1284, 1207, 1159, 1090, 1034, 878, 834, 791, 722 cm-1; HRMS (TOF ES+) calcd for C20H19ClFN3O2 [M+H]+ 388.1223, found 388.1224.
称取1 mmol杂环烯酮缩胺1~2加入到25 mL圆底烧瓶中, 再加入15 mL溶剂搅拌溶解.搅拌下, 缓慢加入1.1 mmol苯基异氰酸酯4, 室温下搅拌3 h, TLC监测直至杂环烯酮缩胺反应完全后, 停止反应.密封圆底烧瓶后于冰箱内静置约0.5 h后, 反应液中有固体析出, 抽滤.滤液经过减压蒸馏并留少量液体接着加入一定量的石油醚, 析出固体, 再抽滤.合并两次抽滤所得固体用适量丙酮重结晶得目标产物5~6.
3-氧代-3-苯基-2-[四氢嘧啶-2(1H)-亚基]-N-[4-(三氟甲基)苯基]丙酰胺(5m):得373 mg, 白色固体, 产率96%. m.p. 211.7~213.7 ℃; 1H NMR (300 MHz, CDCl3) δ: 2.00~2.05 (m, 2H, CH2), 3.44~3.48 (m, 4H, 2CH2), 7.02 (d, J=8.4 Hz, 2H, ArH), 7.18 (br, 1H, NH), 7.37~7.43 (m, 5H, ArH), 7.58~7.61 (m, 2H, ArH), 10.21 (br, 2H, 2NH); 13C HMR (75 MHz, CDCl3)δ: 19.7, 38.3, 38.3, 90.8, 118.9, 124.7~125.8 (m), 127.7, 128.8, 130.2, 141.5, 143.0, 160.2, 170.1, 189.9; IR (KBr) v: 3422, 3293, 3066, 2931, 2882, 1634, 1618, 1598, 1512, 1472, 1445, 1364, 1321, 1258, 1163, 1068, 870, 841, 776, 705 cm-1; HRMS (TOF ES+) calcd for C20H18F3N3O2 [M+H]+ 390.1424, found 390.1425.
3-(4-氯苯基)-2-(1, 3-安定-2-亚基)-3-氧代-N-[4-(三氟甲基)苯基]丙酰胺(6g):得407 mg, 白色固体, 产率93%. m.p. 236.2~238.2 ℃; 1H NMR (300 MHz, DMSO-d6) δ: 1.51~1.55 (m, 4H, 2CH2), 2.93~2.97 (m, 4H, 2CH2), 7.38~7.42 (m, 4H, ArH), 7.57 (d, J=8.7 Hz, 2H, ArH), 7.72 (d, J=8.4 Hz, 2H, ArH), 8.75 (br, 2H, 2NH), 12.08 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 26.5, 26.5, 45.0, 45.0, 94.3, 118.5, 121.4~122.8 (m), 125.8, 127.6, 129.1, 133.3, 142.4, 143.8, 167.3, 169.0, 186.2; IR (KBr) v: 3425, 3315, 3048, 2950, 1781, 1633, 1593, 1575, 1489, 1410, 1362, 1281, 1159, 1108, 1067, 1013, 841, 786, 720 cm-1; HRMS (TOF ES+) calcd for C21H19ClF3N3O2 [M+H]+, 438.1191, found 438.1192.
N-(4-氯苯基)-3-氧代-3-苯基-2-[四氢嘧啶-2(1H)-亚基]丙酰胺(5a):得345 mg, 白色固体, 产率97%. m.p. 186.3~188.3 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.97~2.05 (m, 2H, CH2), 3.41~3.47 (m, 4H, 2CH2), 6.83 (d, J=8.4Hz, 2H, ArH), 6.94 (br, 1H, NH), 7.11 (d, J=8.4 Hz, 2H, ArH), 7.36~7.42 (m, 3H, ArH), 7.58 (d, J=3.9 Hz, 2H, ArH), 10.21 (br, 2H, 2NH); 13C HMR (75 MHz, CDCl3) δ: 19.7, 38.2, 38.2, 90.8, 120.8, 127.7, 128.3, 128.5, 128.7, 130.1, 136.9, 143.1, 160.1, 170.0, 189.5; IR (KBr) v: 3282, 2869, 1628, 1488, 1367, 1321, 1284, 1245, 1196, 1145, 1094, 1046, 826, 777, 749, 702, 507 cm-1; HRMS (TOF ES+) calcd for C19H17ClN3O2 [M-H]- 354.1015, found 354.1013.
N-(4-氯苯基)-3-氧代-2-[四氢嘧啶-2(1H)-亚基]-3-(噻吩-2-基)丙酰胺(5i):得350 mg, 黄色固体, 产率97%. m.p. 182.3~184.3 ℃; 1H NMR (300 MHz, DMSO-d6) δ: 1.81~1.87 (m, 2H, CH2), 3.28~3.34 (m, 4H, 2CH2), 6.92 (t, J=4.1 Hz, 1H, ArH), 7.11 (d, J=3.0 Hz, 1H, ArH), 7.24 (d, J=8.7 Hz, 2H, ArH), 7.47~7.53 (m, 3H, ArH), 9.31 (br, 2H, 2NH), 11.12 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 18.7, 38.2, 38.2, 91.8, 120.2, 125.2, 126.3, 126.7, 128.3, 128.3, 139.3, 147.9, 159.9, 167.7, 175.0; IR (KBr) v: 3431, 1619, 1492, 1451, 1399, 1366, 1321, 1241, 1094, 827, 772 cm-1; HRMS (TOF ES+) calcd for C17H15ClN3O2S [M-H]- 360.0579, found 360.0579.
N-(4-氯苯基)-3-(4-甲氧基苯基)-3-氧代-2-[四氢嘧啶-2(1H)-亚基]丙酰胺(5b):得366 mg, 白色固体, 产率95%. m.p. 168.0~170.0 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.97~2.03 (m, 2H, CH2), 3.40~3.46 (m, 4H, 2CH2), 3.82 (s, 3H, OCH3), 6.86~7.15 (m, 7H, ArH+NH), 7.53~7.59 (m, 2H, ArH), 10.15 (br, 2H, 2NH); 13C HMR (75 MHz, CDCl3) δ: 19.8, 38.3, 38.3, 55.4, 90.2, 113.9, 120.9, 128.2, 128.6, 129.9, 135.3, 137.1, 160.1, 161.2, 170.3, 189.1; IR (KBr) v: 3427, 1622, 1602, 1492, 1362, 1321, 1251, 1168, 1032, 782 cm-1; HRMS (TOF ES+) calcd for C20H19ClN3O3 [M-H]- 384.1120, found 384.1121.
N-(4-氯苯基)-3-氧代-2-[四氢嘧啶-2(1H)-亚基]-3-(对甲苯基)丙酰胺(5c):得355 mg, 白色固体, 产率96%. m.p. 190.1~192.1 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.97~2.03 (m, 2H, CH2), 2.36 (s, 3H, CH3), 3.41~3.47 (m, 4H, 2CH2), 6.83~7.17 (m, 7H, ArH+NH), 7.44~7.50 (m, 2H, ArH), 10.20 (br, 2H, 2NH); 13C HMR (75 MHz, CDCl3) δ: 19.7, 21.4, 38.2, 38.2, 90.6, 120.8, 127.8, 128.2, 128.5, 129.3, 137.1, 140.2, 140.3, 160.1, 170.2, 189.7; IR (KBr) v: 3286, 1626, 1591, 1526, 1491, 1401, 1361, 1320, 1245, 1172, 831, 780 cm-1; HRMS (TOF ES+) calcd for C20H19ClN3O2 [M-H]- 368.1171, found 368.1170.
3-氧代-3-苯基-2-[四氢嘧啶-2(1H)-亚基]-N-(对甲苯基)丙酰胺(5k):得328 mg, 白色固体, 产率98%. m.p. 200.9~202.9 ℃; 1H NMR (300 MHz, CDCl3) δ: 1.99~2.03 (m, 2H, CH2), 2.26 (s, 3H, CH3), 3.43~3.47 (m, 4H, 2CH2), 6.76 (d, J=8.1 Hz, 2H, ArH), 6.97 (d, J=7.8 Hz, 2H, ArH), 7.37~7.41 (m, 3H, ArH), 7.58~7.62 (m, 2H, ArH), 10.33 (br, 2H, 2NH); 13C HMR (75 MHz, CDCl3) δ: 19.7, 20.8, 38.2, 38.2, 90.9, 120.0, 127.7, 128.7, 129.1, 129.9, 133.2, 135.6, 143.2, 160.1, 170.1, 189.3 cm-1; HRMS (TOF ES+) calcd for C20H21N3O2 [M+H]+ 336.1707, found 336.1710.
N-(4-氯苯基)-2-(1, 3-安定-2-亚基)-3-氧代-3-苯基丙酰胺(6a):得347 mg, 白色固体, 产率94%. m.p. 174.5~176.5 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.64~1.70 (m, 4H, 2CH2), 3.04~3.10 (m, 4H, 2CH2), 7.22~7.61 (m, 9H, ArH), 8.71 (br, 2H, NH), 9.88 (br, 1H, NH); 13C HMR (75 MHz, CDCl3) δ: 27.3, 27.3, 45.9, 45.9, 93.4, 121.4, 127.8, 128.1, 128.7, 128.7, 130.4, 137.4, 143.1, 169.0, 170.3, 191.5; IR (KBr) v: 3300, 3059, 2946, 1632, 1492, 1438, 1399, 1343, 1281, 1244, 1213, 1132, 1087, 1011, 821, 766, 703, 665, 507 cm-1; HRMS (TOF ES+) calcd for C20H19ClN3O2 [M-H]- 368.1171, found 368.1174.
3-(4-溴苯基)-N-(4-氯苯基)-3-氧代-2-[四氢嘧啶-2(1H)-亚基]丙酰胺(5f):得399 mg, 白色固体, 产率92%. m.p. 179.2~181.2 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.97~2.03 (m, 2H, CH2), 3.40~3.46 (m, 4H, 2CH2), 6.91 (d, J=7.8 Hz, 2H, ArH), 7.03 (br, 1H, NH), 7.16 (d, J=7.8 Hz, 2H, ArH), 7.44~7.50 (m, 4H, ArH), 10.03 (br, 2H, 2NH); 13C HMR (75 MHz, CDCl3)δ: 19.6, 38.3, 38.3, 90.9, 120.8, 124.3, 128.6, 128.7, 129.5, 131.7, 136.8, 141.7, 159.9, 169.8, 187.7; IR (KBr) v: 3426, 3298, 2964, 1620, 1594, 1524, 1490, 1400, 1364, 1322, 1245, 1204, 1173, 1092, 1010, 828, 779, 765 cm-1; HRMS (TOF ES+) calcd for C19H16BrClN3O2 [M-H]- 432.0119, found 432.0118.
N-(4-氯苯基)-3-(4-氟苯基)-3-氧代-2-[四氢嘧啶-2(1H)-亚基]丙酰胺(5d):得343 mg, 白色固体, 产率92%. m.p. 176.9~178.9 ℃; 1H NMR (300 MHz, CDCl3)δ: 1.97−2.03 (m, 2H, CH2), 3.40~3.46 (m, 4H, 2CH2), 6.90~7.17 (m, 7H, ArH+NH), 7.57~7.63 (m, 2H, ArH), 10.08 (br, 2H, NH); 13C HMR (75 MHz, CDCl3) δ: 19.7, 38.3, 38.3, 90.7, 115.5 (d, J=21.0 Hz), 120.7, 128.7, 130.1 (d, J=8.3 Hz), 136.8, 139.1, 159.9, 169.9, 187.9; IR (KBr) v: 33284, 1621, 1598, 1491, 1402, 1319, 1232, 1092, 831, 783 cm-1; HRMS (TOF ES+) calcd for C19H16ClFN3O2 [M-H]- 372.0921, found 372.0923.
3.3 化合物7的合成方法
称取1 mmol杂环烯酮缩胺3加入到25 mL圆底烧瓶中, 加入15 mL溶剂搅拌溶解, 并在搅拌下缓慢加入1.1 mmol苯基异氰酸4.充分搅拌后加入0.5 mmol Cs2CO3, 室温下搅拌2.5 h, TLC监测直至杂环烯酮缩胺反应完全后停止反应.加水淬灭反应时析出固体, 搅拌10 min左右后静置0.5 h后抽滤.抽滤所得固体用适量丙酮重结晶得目标产物7.
(E)-N-(4-氯苯基)-2-[2-(4-氯苯基)-2-氧代亚乙基]咪唑烷-1-甲酰胺(7e):得327 mg, 白色固体, 产率87%. m.p. 192.7~194.7 ℃; 1H NMR (300 MHz, DMSO-d6)δ: 3.70~3.76 (m, 2H, CH2), 4.06~4.12 (m, 2H, CH2), 6.74 (s, 1H, CH), 7.39 (d, J=8.1 Hz, 2H, ArH), 7.48 (d, J=7.5 Hz, 2H, ArH), 7.60 (d, J=7.8 Hz, 2H, ArH), 7.79 (d, J=7.5 Hz, 2H, ArH), 9.09 (br, 1H, NH), 10.32 (br, 1H, ArNH); 13C HMR (75 MHz, DMSO-d6)δ: 41.8, 45.0, 77.9, 122.5, 127.2, 128.2, 128.2, 128.4, 134.9, 137.5, 139.3, 151.0, 159.8, 183.7; IR (KBr) v: 3310, 3140, 2974, 2897, 1689, 1601, 1570, 1494, 1474, 1399, 1313, 1281, 1245, 1176, 1088, 1057, 1029, 1014, 964, 903, 879, 854, 825, 772, 754, 683, 634, 549, 502 cm-1; HRMS (TOF ES+) calcd for C18H14Cl2N3O2 [M-H]- 374.0469, found 374.0469.
(E)-N-(4-氯苯基)-2-(硝基亚甲基)咪唑烷-1-甲酰胺(7i):得254 mg, 黄色固体, 产率90%. m.p. 170.2~172.2 ℃; 1H NMR (300 MHz, DMSO-d6)δ: 3.76 (t, J=8.4 Hz, 2H, CH2), 4.15 (t, J=8.6 Hz, 2H, CH2), 7.39 (d, J=8.4 Hz, 2H, ArH), 7.54 (d, J=8.4 Hz, 2H, ArH), 7.66 (s, 1H, CH), 9.17 (br, 1H, NH), 9.70 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6) δ: 42.5, 45.7, 100.8, 122.8, 127.6, 128.4, 137.1, 150.5, 155.4; IR (KBr) v: 3300, 3179, 3108, 3054, 2981, 2906, 1707, 1597, 1538, 1488, 1461, 1420, 1382, 1321, 1240, 1215, 1095, 1075, 1013, 995, 946, 833, 807, 790, 766, 743, 594, 506 cm-1; HRMS (TOF ES+) calcd for C11H10ClN4O3 [M-H]- 281.0446, found 281.0445.
(E)-N-(4-氯苯基)-2-[2-(2-氯苯基)-2-氧代亚乙基]咪唑烷-1-甲酰胺(7g):得297 mg, 白色固体, 产率79%. m.p. 170.1~172.1 ℃; 1H NMR (300 MHz, DMSO-d6)δ: 3.74 (t, J=8.4 Hz, 2H, CH2), 4.09 (t, J=8.6 Hz, 2H, CH2), 6.21 (s, 1H, CH), 7.33~7.44 (m, 6H, ArH), 7.54 (d, J=9.0 Hz, 2H, ArH), 9.08 (br, 1H, NH), 10.09 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6) δ: 41.9, 44.9, 82.0, 122.4, 126.9, 127.2, 128.4, 128.6, 129.4, 129.7, 129.8, 137.5, 142.4, 150.9, 159.0, 186.6; IR (KBr) v: 3259, 3187, 3118, 3063, 2977, 2897, 1706, 1601, 1564, 1543, 1490, 1396, 1317, 1239, 1177, 1094, 1074, 1045, 1013, 968, 907, 828, 750, 688, 637, 509 cm-1; HRMS (TOF ES+) calcd for C18H14Cl2N3O2 [M-H]- 374.0469, found 374.0468.
(E)-N-(4-氯苯基)-2-[2-氧代-2-(噻吩-2-基)亚乙基]咪唑烷-1-甲酰胺(7h):得316 mg, 黄色固体, 产率91%. m.p. 180.4~182.4 ℃; 1H NMR (300 MHz, DMSO-d6)δ: 3.68~3.74 (m, 2H, CH2), 4.05~4.09 (m, 2H, CH2), 6.63 (s, 1H, CH), 7.07~7.11 (m, 1H, ArH), 7.40~7.46 (m, 3H, ArH), 7.57~7.65 (m, 3H, ArH), 9.09 (br, 1H, NH), 10.00 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 41.8, 45.0, 77.8, 122.5, 126.6, 127.2, 127.9, 128.4, 129.7, 137.5, 147.8, 151.0, 159.1, 178.8; IR (KBr) v: 3378, 3152, 3101, 3061, 2977, 2890, 1697, 1594, 1491, 1421, 1399, 1318, 1279, 1250, 1231, 1090, 1075, 1058, 1035, 1010, 967, 871, 853, 829, 772, 714, 613, 509 cm-1; HRMS (TOF ES+) calcd for C16H13ClN3O2S [M-H]- 346.0422, found 346.0422.
辅助材料(Supporting Information) 化合物的1H NMR和13C NMR谱图.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.
(E)-N-(4-氯苯基)-2-[2-(4-甲氧基苯基)-2-氧代亚乙基]咪唑烷-1-甲酰胺(7b):得334 mg, 白色固体, 产率90%. m.p. 158.6~160.0 ℃; 1H NMR (300 MHz, DMSO-d6) δ: 3.71 (t, J=8.1 Hz, 2H, CH2), 3.79 (s, 3H, OCH3), 4.08 (t, J=8.3 Hz, 2H, CH2), 6.72 (s, 1H, CH), 6.97 (d, J=8.7 Hz, 2H, ArH), 7.39 (d, J=8.7 Hz, 2H, ArH), 7.60 (d, J=8.7 Hz, 2H, ArH), 7.75 (d, J=8.4 Hz, 2H, ArH), 9.06 (br, 1H, NH), 10.26 (br, 1H, ArNH); 13C HMR (75 MHz, DMSO-d6)δ: 41.7, 45.0, 55.2, 77.5, 113.4, 122.5, 127.1, 128.2, 128.4, 133.2, 137.6, 151.1, 159.2, 161.0, 184.8; IR (KBr) v: 3429, 2895, 2838, 1702, 1598, 1575, 1489, 1392, 1319, 1243, 1169, 1094, 1060, 1030, 966, 906, 827, 776, 708, 604, 508 cm-1; HRMS (TOF ES+) calcd for C19H17ClN3O3 [M-H]-, 370.0963, found 370.0964.
(E)-2-(2-氧代-2-苯基亚乙基)-N-[4-(三氟甲基)苯基]咪唑烷-1-甲酰胺(7l):得349 mg, 白色固体, 产率93%. m.p. 154.2~156.2 ℃; 1H NMR (300 MHz, DMSO-d6) δ: 3.75 (t, J=8.3 Hz, 2H, CH2), 4.14 (t, J=8.4 Hz, 2H, CH2), 6.78 (s, 1H, CH), 7.42~7.45 (m, 3H, ArH), 7.69~7.84 (m, 6H, ArH), 9.31 (br, 1H, NH), 10.36 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 41.8, 45.0, 78.1, 120.4, 122.6~123.5 (m), 125.7, 126.4, 128.2, 130.3, 140.6, 142.5, 151.0, 159.5, 185.5; IR (KBr) v: 3423, 3282, 3061, 2951, 2898, 1606, 1578, 1500, 1485, 1440, 1322, 1244, 1115, 1067, 1031, 1019, 840, 801, 746, 724, cm-1; HRMS (TOF ES+) calcd for C19H16F3N3O2 [M+H]+ 376.1267, found 376.1270.
(E)-2-(2-氧代-2-苯基亚乙基)-N-(对甲苯基)咪唑烷-1-甲酰胺(7j):得273 mg, 白色固体, 产率85%. m.p. 175.1~177.1 ℃; 1H NMR (300 MHz, DMSO-d6) δ: 2.27 (s, 3H, CH3), 3.72 (t, J=8.4 Hz, 2H, CH2), 4.08 (t, J=8.5 Hz, 2H, CH2), 6.75 (s, 1H, CH), 7.14 (d, J=8.1 Hz, 2H, ArH), 7.41~7.44 (m, 5H, ArH), 7.76~7.80 (m, 2H, ArH), 8.91 (br, 1H, NH), 10.34 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 20.4, 41.7, 45.0, 77.9, 121.2, 126.4, 128.2, 128.9, 130.2, 132.5, 135.9, 140.7, 151.2, 159.8, 185.2; IR (KBr) v: 3422, 3328, 3085, 3042, 2976, 2900, 1782, 1687, 1599, 1576, 1496, 1439, 1396, 1318, 1243, 1105, 1023, 814, 743, 727 cm-1; HRMS (TOF ES+) calcd for C19H19N3O2 [M+H]+ 322.1550, found 322.1555.
(E)-N-(4-氯苯基)-2-(2-氧代-2-苯基亚乙基)咪唑烷-1-甲酰胺(7a):得311 mg, 白色固体, 产率91%. m.p. 142.3~144.3 ℃; 1H NMR (500 MHz, DMSO-d6)δ: 3.74 (t, J=8.4 Hz, 2H, CH2), 4.10 (t, J=8.4 Hz, 2H, CH2), 6.76 (s, 1H, CH), 7.39~7.44 (m, 5H, ArH), 7.60 (d, J=8.7 Hz, 2H, ArH), 7.78 (t, J=3.7 Hz, 2H, ArH), 9.09 (br, 1H, NH), 10.33 (br, 1H, NH); 13C HMR (125 MHz, DMSO-d6)δ: 42.1, 45.4, 78.5, 122.9, 126.8, 127.6, 128.6, 128.8, 130.6, 138.0, 141.1, 151.5, 160.0, 185.8; IR (KBr) v: 3434, 2925, 2855, 16998, 1599, 1577, 1494, 1439, 1397, 1317, 1239, 1176, 1094, 1059, 907, 826, 726, 696, 648, 507 cm-1; HRMS (TOF ES+) calcd for C18H15ClN3O2 [M-H]- 340.0858, found 340.0859.
(E)-N-(4-氯苯基)-2-[2-氧代-2-(对甲苯基)亚乙基]咪唑烷-1-甲酰胺(7c):得316 mg, 白色固体, 产率89%. m.p. 194.0~196.0 ℃; 1H NMR (300 MHz, DMSO-d6)δ: 2.33 (s, 3H, CH3), 3.69~3.75 (m, 2H, CH2), 4.05~4.09 (m, 2H, CH2), 6.74 (s, 1H, CH), 7.23 (d, J=7.2 Hz, 2H, ArH), 7.39 (d, J=8.1 Hz, 2H, ArH), 7.60 (d, J=7.8 Hz, 2H, ArH), 7.68 (d, J=7.2 Hz, 2H, ArH), 9.07 (br, 1H, NH), 10.30 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 20.9, 41.7, 45.0, 77.8, 122.5, 126.4, 127.1, 128.4, 128.7, 137.8 (d, J=22.5 Hz) 140.0, 151.1, 159.4, 185.2; IR (KBr) v: 3303, 3138, 3106, 2975, 2942, 2898, 1690, 1599, 1571, 1491, 1476, 1392, 1353, 1313, 1283, 1244, 1091, 1057, 1017, 903, 854, 826, 771, 752, 550, 503 cm-1; HRMS (TOF ES+) calcd for C19H17ClN3O2 [M-H]- 354.1014, found 354.1011.
(E)-2-[2-(4-溴苯基)-2-氧代亚乙基]-N-(4-氯苯基)咪唑烷-1-甲酰胺(7f):得328 mg, 白色固体, 产率78%. m.p. 251.3~253.3 ℃; 1H NMR (300 MHz, DMSO-d6)δ: 3.70~3.76 (m, 2H, CH2), 4.06~4.12 (m, 2H, CH2), 6.74 (s, 1H, CH), 7.37~7.43 (m, 2H, ArH), 7.57~7.63 (m, 4H, ArH), 7.67~7.73 (m, 2H, ArH), 9.09 (br, 1H, NH), 10.32 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 41.8, 45.0, 77.8, 122.5, 123.8, 127.2, 128.4, 128.5, 131.2, 137.5, 139.7, 151.0, 159.8, 183.8; IR (KBr) v: 3435, 3308, 3140, 2974, 2896, 1689, 1630, 1600, 1567, 1493, 1473, 1399, 1312, 1244, 1176, 1091, 1069, 1054, 1010, 903, 878, 851, 824, 771, 752, 634, 542, 502 cm-1; HRMS (TOF ES+) calcd for C18H14BrClN3O2 [M-H]- 417.9963, found 417.9965.
(E)-N-(4-氟苯基)-2-(2-氧代-2-苯基亚乙基)咪唑烷-1-甲酰胺(7k):得296 mg, 白色固体, 产率91%. m.p. 165.8~167.8 ℃; 1H NMR (300 MHz, DMSO-d6) δ: 3.73 (t, J=8.4 Hz, 2H, CH2), 4.09 (t, J=8.4 Hz, 2H, CH2), 6.77 (s, 1H, CH), 7.18 (d, J=8.9 Hz, 2H, ArH), 7.42~7.44 (m, 3H, ArH), 7.54~7.58 (m, 2H, ArH), 7.77~7.80 (m, 2H, ArH), 9.02 (br, 1H, NH), 10.34 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 41.7, 45.0, 78.0, 114.9, 115.2, 123.2 (d, J=7.5 Hz), 126.4, 127.9, 128.2, 130.2, 134.8, 140.7, 151.3, 158.4 (d, J=238.5 Hz), 159.7, 185.4; IR (KBr) v: 3421, 3295, 3076, 2976, 2900, 1690, 1599, 1577, 1500, 1480, 1405, 1316, 1253, 1177, 1058, 831, 802, 780, 747, 728 cm-1; HRMS (TOF ES+) calcd for C18H16FN3O2 [M+H]+ 326.1299, found 326.1302.
(E)-N-(4-氯苯基)-2-[2-(4-氟苯基)-2-氧代亚乙基]咪唑烷-1-甲酰胺(7d):得305 mg, 白色固体, 产率85%. m.p. 157.4~159.2 ℃; 1H NMR (300 MHz, DMSO-d6)δ: 3.73 (t, J=8.3 Hz, 2H, CH2), 4.10 (t, J=8.4 Hz, 2H, CH2), 6.73 (s, 1H, CH), 7.21~7.27 (m, 2H, ArH), 7.39 (d, J=8.7 Hz, 2H, ArH), 7.60 (d, J=8.7 Hz, 2H, ArH), 7.81~7.86 (m, 2H, ArH), 9.09 (br, 1H, NH), 10.28 (br, 1H, NH); 13C HMR (75 MHz, DMSO-d6)δ: 41.7, 45.0, 77.7, 115.0 (d, J=21.0 Hz), 122.5, 127.2, 128.4, 128.8 (d, J=9.0 Hz), 137.1, 137.6, 151.1, 159.6, 183.9; IR (KBr) v: 3425, 2975, 2901, 1691, 1598, 1510, 1491, 1401, 1317, 1285, 1244, 1155, 1093, 1058, 1013, 906, 828, 775, 597, 505 cm-1; HRMS (TOF ES+) calcd for C18H14ClFN3O2 [M-H]- 358.0764, found 358.0761.
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[1]
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图 2 杂环烯酮缩胺1a和3a的最优构象
Figure 2 Optimal conformations of heterocyclic ketene aminals 1a and 3a
表 1 反应条件的优化a
Table 1. Optimization of reaction conditions
Entry Solvent Catalyst T (℃) Time/h Yieldb/% 1 Acetone - r.t. 3 91 2 Acetonitrile - r.t. 3 79 3 EtOH - r.t. 3 21 4 1, 4-Dioxane - r.t. 3 96 5 Toluene - r.t. 3 93 6 THF - r.t. 3 87 7 1, 4-Dioxane DIPEA r.t. 3 89 8 1, 4-Dioxane Et3N r.t. 2 94 9 1, 4-Dioxane K2CO3 r.t. 2.5 81 10 1, 4-Dioxane Cs2CO3 r.t. 2 63 11 1, 4-Dioxane - 50 2.5 93 12 1, 4-Dioxane - 110 2.5 91 13 1, 4-Dioxane - r.t. 3 97c 14 1, 4-Dioxane - r.t. 3 94d aThe reaction was performed with 1a (1 mmol), 4a (1 mmol) and the solvent (15 mL). bIsolated yields. cThe reaction was performed with 1a (1 mmol), 4a (1.1 mmol), and the solvent (15 mL).dThe reaction was performed with 1a (1.1 mmol), 4a (1 mmol), and the solvent (15 mL). 
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表 2 酰胺类杂环烯酮缩胺5~6的制备a
Table 2. Preparation of amide class heterocyclic ketene aminals 5~6
Entry 1/2 (EWG/n) 4 5/6 Yieldb/% 1 1a (PhCO/1) 4a 5a 97 2 1b (4-MeOC6H4CO/1) 4a 5b 95 3 1c (4-MeC6H4CO/1) 4a 5c 96 4 1d (4-FC6H4CO/1) 4a 5d 92 5 1e (4-ClC6H4CO/1) 4a 5e 90 6 1f (4-BrC6H4CO/1) 4a 5f 92 7 1g (2-FC6H4CO/1) 4a 5g 91 8 1h (2-ClC6H4CO/1) 4a 5h 90 9 1i (C4H3SCO/1) 4a 5i 97 10 1j (NO2/1) 4a 5j 95 11 1a (PhCO/1) 4b 5k 98 12 1a (PhCO/1) 4c 5l 96 13 1a (PhCO/1) 4d 5m 96 14 2a (PhCO/2) 4a 6a 94 15 2b (4-MeC6H4CO/2) 4a 6b 97 16 2c (4-FC6H4CO/2) 4a 6c 92 17 2d (4-ClC6H4CO/2) 4a 6d 94 18 2d (4-ClC6H4CO/2) 4b 6e 96 19 2d (4-ClC6H4CO/2) 4c 6f 95 20 2d (4-ClC6H4CO/2) 4d 6g 93 aThe reaction was performed with 1or 2 (1 mmol), 4 (1.1 mmol) and the solvent (15 mL). bIsolated yields based on HKAs 1 or 2.
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表 3 反应条件的优化a
Table 3. Optimization of reaction conditions
Entry Solvent Catalyst t/℃ Time/h Yieldb/% 1 Acetone - r.t. 3 71 2 Acetonitrile - r.t. 3 42 3 EtOH - r.t. 3 13 4 1, 4-Dioxane - r.t. 3 73 5 Toluene - r.t. 3 68 6 Tetrahydrofuran - r.t. 3 56 7 Chloroform - r.t. 3 61 8 1, 4-Dioxane DIPEA r.t. 3 75 9 1, 4-Dioxane Et3N r.t. 3 77 10 1, 4-Dioxane K2CO3 r.t. 2.5 83 11 1, 4-Dioxane Cs2CO3 r.t. 2.5 91 12 1, 4-Dioxane t-BuOK r.t. 1.5 79 13 1, 4-Dioxane NaH r.t. 1.5 72 14 1, 4-Dioxane - 80 1.5 32 15 1, 4-Dioxane Cs2CO3 80 1.5 38 aThe reaction was performed with 3a (1 mmol), 4a (1.1 mmol), catalyst (0.5 mmol) and the solvent (15 mL). bIsolated yields based on HKAs 3a.
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表 4 酰胺类杂环烯酮缩胺酰胺7的制备
Table 4. Preparation of amide class heterocyclic ketene aminals 7a
Entry 3 (EWG) 4 7 Yieldb/% 1 3a (PhCO) 4a 7a 91 2 3b (4-MeOC6H4CO) 4a 7b 90 3 3c (4-MeC6H4CO) 4a 7c 89 4 3d (4-FC6H4CO) 4a 7d 85 5 3e (4-ClC6H4CO) 4a 7e 87 6 3f (4-BrC6H4CO) 4a 7f 78 7 3g (2-ClC6H4CO) 4a 7g 79 8 3h (C4H3S) 4a 7h 91 9 3i (NO2) 4a 7i 90 10 3a (PhCO) 4b 7j 85 11 3a (PhCO) 4c 7k 91 12 3a (PhCO) 4d 7l 93 aThe reaction was performed with 3 (1 mmol), 4 (1.1 mmol), CsCO3 (0.5 mmol) and the solvent (15 mL). bIsolated yields based on HKAs 3.
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