2005年第25卷有机化学V ol. 25, 2005第7期, 826～829 Chinese Journal of Organic Chemistry No. 7, 826～829* E-mail: fengchao@; Tel.: 8627-83692749.Received October 15, 2004; revised December 9, 2004; accepted January 24, 2005.No. 7 成冲云等：无溶剂条件下微波辐射合成2-氨基噻唑衍生物827图1 目标化合物的合成路线Figure 1The synthetic rout of target compounds司, 噻吩乙酮来自Avoco公司, 4-甲基苯乙酮自制; 其余均为市售试剂.1.2 2-氨基-4,5,6,7-四氢苯并噻唑(1)的合成将硫脲7.6 g (0.1 mol)、碘12.7 g (0.05 mol)和环己酮5.2 mL (0.05 mol)混合, 搅拌下在195 W微波辐射反应40 s后接着130 W反应5 min. 反应完毕加热水200 mL,趁热过滤, 滤液用Na2CO3处理, 得黄色固体, 冷却减压过滤, 滤饼用蒸馏水洗涤两次, 真空干燥后得6.4 g 淡黄色针状晶体1, 产率88%. m.p. 86～87 (℃文献值[4] 87～88 );℃1H NMR (CDCl3, 300 MHz) δ: 1.80 (s, 4H), 2.55 (s, 4H), 4.89 (d, J＝32 Hz, 2H); IR (KBr) ν: 3373, 3283, 3169, 3087, 2933, 2844, 2741, 1637, 1584, 1524, 1442, 1367, 1311, 1277, 1239, 1181, 1113, 1062, 1018, 892, 725, 695, 650, 630, 537 cm－1.1.3 2-氨基-4-苯基噻唑(2)的合成将硫脲7.6 g (0.1 mol)、碘12.7 g (0.05 mol)和苯乙酮5.2 mL (0.05 mol)混合, 搅拌下在130 W微波辐射反应2 min后接着65 W反应10 min. 反应完毕加乙醚50 mL洗涤, 滤除乙醚, 残留物加热水200 mL, 趁热过滤,滤液用氨水调至中性, 得白色絮状固体, 冷却过滤,滤饼用蒸馏水洗涤两次, 真空干燥得5.7 g微黄色针状晶体2, 产率67%. m.p. 149～150 (℃文献值[8] 146～148 );℃1H NMR (CDCl3, 300 MHz) δ: 7.78 (d, J＝8 Hz, 2H), 7.47 (t, J＝27 Hz, 2H), 7.28 (t, J＝15 Hz, 1H), 6.73 (s, 1H), 5.11 (s, 2H); IR (KBr)ν: 3435, 3254, 3155, 3114, 3068, 1599, 1516, 1482, 1441, 1338, 1319, 1202, 1040, 769, 716, 667, 578 cm－1.1.4 2-氨基-4-[4-甲氧基-苯基]噻唑(3)的合成将硫脲2.4 g (32 mmol)、碘3.9 g (16 mmol)和对甲氧基苯乙酮2.4 g (16 mmol)混合, 搅拌下在65 W微波辐射反应11 min 40 s. 反应完毕加乙醚30 mL洗涤,除去乙醚, 残留物加热水200 mL, 趁热过滤,滤液用氨水调至中性, 冷却过滤,滤饼用蒸馏水洗涤两次, 真空干燥得2.1 g白色粉末3, 产率64%. m.p. 206～208 (℃文献值[4] 204～205 );℃ 1H NMR (CDCl3, 300 MHz) δ: 7.70 (d, J＝9 Hz, 2H), 7.26 (s, 1H), 6.91 (d, J＝9 Hz, 1H), 6.59 (s, 1H), 4.98 (s, 2H), 3.85 (d, J＝13 Hz, 3H); IR (KBr) ν: 3441, 3119, 1626, 1538, 1523, 1494, 1452, 1417, 1327, 1291, 1246, 1179, 1037, 836, 738, 700, 602 cm－1.1.5 化合物4～9的合成参考1.4合成化合物4～9, 微波辐射反应条件和产率见表1.表1微波辐射合成化合物3～9的反应条件及产率aTable 1 The reaction condition and yield of compounds 3～9 Compd.R1R2t/min 产率/%3 p-CH3OC6H4 H11.6 644 p-ClC6H4 H15445 p-CH3C6H4 H20 126 p-H2NC6H4 H 5 217 p-O2NC6H4 H 5 268 2-Thieyl H20379 α-Naphthyl H20 17a微波辐射功率均为65 W (10%).2-氨基-4-[4-氯-苯基]噻唑(4): m.p. 169～170 (℃文献值[4] 163～164 );℃1H NMR (CDCl3, 300 MHz) δ: 7.70 (d, J＝8 Hz, 2H), 7.34 (d, J＝24 Hz, 2H), 6.71 (s, 1H),5.12 (s, 2H); IR (KBr) ν: 3441, 3114, 2345, 1635, 1536, 1478, 1403, 1341, 1089, 1040, 1011, 823, 730, 574, 486cm－1.2-氨基-4-[4-甲基-苯基]噻唑(5): m.p. 125～126(℃文献值[4] 124～125 );℃1H NMR (CDCl3, 300 MHz) δ: 7.66 (d, J＝8 Hz, 2H), 7.21 (d, J＝9 Hz, 2H), 6.67 (s,1H), 5.03 (s, 2H), 2.36 (s, 3H); IR (KBr) ν: 3455, 3118, 1638, 1539, 1522, 1490, 1401, 1333, 1113, 1037, 824, 730,694 cm－1.2-氨基-4-[4-氨基-苯基]噻唑(6): m.p. 168～170(℃文献值[4] 174～175 );℃1H NMR (CDCl3, 300 MHz) δ: 7.55 (b, 2H), 6.68 (t, J＝19 Hz, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 4.65 (b, 2H), 4.05 (b, 2H); IR (KBr) ν: 3370, 1608, 1509, 1402, 1277, 1181, 833, 755 cm－1.2-氨基-4-[4-硝基-苯基]噻唑(7): m.p. 283～285(℃文献值[4] 285～286 );℃ 1H NMR (CDCl3, 300 MHz) δ: 8.24 (d, J＝9 Hz, 2H), 7.94 (d, J＝8 Hz, 2H), 6.97 (s,1H), 5.02 (s, 2H); IR (KBr) ν: 3401, 3154, 1694, 1642, 1595, 1539, 1505, 1404, 1322, 1261, 1206, 1110, 1039, 854, 843, 748, 720, 619 cm－1.2-氨基-4-噻吩基噻唑(8): m.p. 127～130 (℃文献值[4] 131～132 ℃); 1H NMR (CDCl3, 300 MHz) δ: 7.33 (d, J＝3 Hz, 1H), 7.25 (t, J＝9 Hz, 1H), 7.03 (t, J＝8 Hz,1H), 6.62 (s, 1H), 5.02 (s, 2H); IR (KBr) ν: 3424, 3116, 2341, 1627, 1548, 1522, 1401, 1364, 1115, 800, 703 cm－1.828有机化学V ol. 25, 20052-氨基-4-萘基噻唑(9): m.p. 153～156 ,℃1H NMR (CDCl3, 300 MHz) δ: 8.33 (t, J＝9 Hz 1H), 7.86 (t, J＝8 Hz, 2H), 7.63 (d, J＝7 Hz, 1H), 7.48 (t, J＝8 Hz, 2H), 7.26 (s, 1H), 6.65 (s, 1H), 5.22 (d, J＝16 Hz, 2H); IR (KBr) ν: 3430, 3078, 1628, 1528, 1392, 1345, 1021, 810, 781, 722, 646 cm－1.2 结果与讨论在普通加热条件下，酮、硫脲和碘反应需数十小时以上, 在微波辐射条件下, 利用硫脲和酮反应合成2-氨基噻唑衍生物的文献未见报道. 本文利用微波反应合成了9种化合物, 其性状与熔点与文献报道一致. 并利用IR和1H NMR对化合物结构进行了确证.2.1 最佳反应条件的筛选为了寻找微波辐射反应的最佳条件, 在预试验的基础上, 本文对微波辐射功率、辐射时间和投料比进行研究. 以环己酮为例(表2), 应用正交设计方法, 以产率为考核指标, 设计考察了它们的影响.表2 正交设计的因素与水平的选择(L34)aTable 2 The factor and level of orthogonal test (L34)因素 A/WB/minC D水平1 130 10 1∶2 1∶1水平2 195 151.2∶2 1.2∶1水平3 65 201.4∶2 1.4∶1a A: 辐射功率, B: 反应时间, C: 环己酮和硫脲投料比, D: 环己酮和碘投料比.利用《正交设计助手oea》软件将实验数据处理(表3). 实验表明反应最优水平组合为A1B2C2D1.由表3可看出四因素中影响最大的是酮/碘投料比;表明碘在环化反应中起主导作用, 既可催化引发反应又参与了反应过程, 是反应原料之一. 依据表3最佳反应条件, 经多次验证, 表明微波辐射法比普通加热法反应时间缩短48倍, 产率与文献值[4]相当.2.2 微波辐射功率和时间的影响提高微波辐射功率、延长辐射反应时间, 有利于促表3 正交设计处理直观分析表aTable 3 Results and calculation of orthogonal testFactornA/W B/min C DYield/%1 13010 0.5 1 692 13015 0.6 1.2 553 13020 0.7 1.4 514 19510 0.6 1.4 605 19515 0.7 1 606 19520 0.5 1.2 267 6510 0.7 1.2 378 6515 0.5 1.4 619 6520 0.6 1 53I 58.355.3 52 60.7II 48.758.7 56 39.3III 50.343.3 49.357.3极差9.615.4 6.721.4a A, B, C, D同表2.进环合作用; 然而功率过高反而导致产率降低. 实验过程中发现, 功率高时, 反应体系易干燥结块黏附于瓶壁,使反应物不能充分均匀接触, 导致反应进行不完全, 副反应增多, 后处理困难, 产率大幅度降低. 微波辐射功率较低时, 达不到环合条件, 即使延长辐射时间也不能达到理想产率甚至得不到目标化合物. 因此, 本文采用双功率微波辐射法. 即先以适宜的高功率反应一段时间,目的在于诱发反应进行; 接着低功率长时间辐射以保证环合反应充分进行.以化合物1,2的合成为例(如表4所示), 实验证明双功率微波合成法既能诱发反应进行又避免反应过度,使产率显著提高.2.3 微波辐射合成2-氨基噻唑衍生物反应机理的初步探讨碘存在下酮与硫脲反应生成氨基噻唑衍生物的机理未见文献探讨. 实验结果(表3)显示碘/酮投料比是该反应的重要影响因素, 表明碘除起催化作用外, 同时也参与了反应. 同时双功率实验结果(表4)表明高功率引发有利于促进碘分子进攻酮的α碳原子, 但辐射时间太表4 单、双功率微波辐射合成反应比较Table 4 A comparison of single-time and double-time microwave irradiation of compounds 1 and 2单功率反应双功率反应P/W t/min 产率/% P1/W t1/min P2/W t2/min 产率/%1 130 15 63 1950.6 130 5 882 130 6 58 130 2 65 10 67No. 7成冲云等：无溶剂条件下微波辐射合成2-氨基噻唑衍生物829长会导致碘升华和反应体系炭化而阻碍进一步环合, 所以还需在低功率下使环合反应充分进行. 参照氯乙醛和硫脲反应制备2-氨基噻唑的反应机理[9], 结合实验结果分析, 作者认为该反应可能机理是: 碘分子首先与酮的α碳作用生成不稳定的中间物α-碘代酮, 再与硫脲反应,所得产物再经环化、脱水等步骤得到终产物, 假设历程如图2. 另外以2-戊酮、丙酮、环戊酮等为原料进行微波辐射反应, 均未得到目标产物, 可能因为原料不易生成α-碘代酮(如烷基酮)或者生成的α-碘代酮不稳定(环张力较大), 反应不能继续进行, 从侧面证实反应生成了α-碘代酮中间体的假设.关于微波辐射加速有机合成反应的原因, 目前尚无定论[10]. 本文采用微波辐射法反应, 体系温度远低于普通加热法, 初步判断微波非热效应可能对加速此类反应起决定作用. 然而微波致热效应也有一定作用; 一般所需温度较高的常规反应, 利用微波辐射法反应时需功率也较高.总之, 利用微波辐射法合成2-氨基噻唑衍生物具有反应时间短、无需溶剂、减少污染、产品易分离和后处理简单等优点. 特别是利用双功率微波辐射催化有机合成反应可大大提高反应产率和纯度.图2 假定的环合反应机理Figure 2 The ratiocinative mechanism of cyclization reactionReferences1 Zhang, A.; Xiong, W. N.; Hilbert, J. E.; DeWita, E. K.;Bidlack, J. M.; Neumeyer, J. L. J . Med . Chem . 2004, 47, 1886.2 Schneider, C. S.; Mierau, J. J . Med . Chem . 1987, 30, 494.3 Pratt, J.; Jae, H.-S.; Rosenberg, S.; Spina, K.; Winn, M.;Buchner, S.; Novosad, E.; KerKman, D.; Shiosaki, K.; Opgenorth, T.; DeBernardis, J. Bioorg . Med . Chem . Lett . 1994, 4, 169.4 King, L. C.; Hlavacek, R. J. J . Am . Chem . Soc . 1950, 72,3732.5 Yuan, K.-J.; Xia, P. Organic Heterocyclic Chemistry ,Peoples Medical Publishing House, Beijing, 1984, p. 95 (in Chinese).(袁开基, 夏鹏, 有机杂环化学, 人民卫生出版社, 北京, 1984, p. 95.)6 (a) Kodomari, M.; Aoyama, T.; Suzuki, Y . Tetrahedron Lett . 2002, 43, 1717.(b) Flygare, J. A.; Kearney, P. C.; Fernandez, M. J . Org . Chem . 1998, 63, 196.(c) Dane, G .; Juan, F. Tetrahedron Lett . 1999, 40, 423. 7 Varma, R. S. Green Chem . 1999, 1, 43.8 Liu, H.-L.; Li, Z.-C.; Anthonsen, T. Molecules 2000, 5,1055.9 Roberts, R. M.; Rodewald, L. B.; Wingrove, A. S. AnIntroduction to Moderny. Experimental Organic Chemistry , Translated by: Cao, X.-G .; Hu, C.-Q., Shanghai Scientific and Technical Publishers, Shanghai, 1981, pp. 208～209 (in Chinese).(Roberts R. M., Rodewald L. B., Wingrove A. S, 近代实验有机化学导论, 曹显国, 胡昌奇译, 上海科学技术出版社, 上海, 1981, pp. 208～209.)10 Wang, J.; Jiang, F.-C. Chin . J . Org . Chem . 2002, 22, 212 (inChinese).(王静, 姜凤超, 有机化学, 2002, 22, 212.)(Y0410151 QIN, X. Q.)No. 7Chinese Journal of Organic ChemistryIIIA New Synthetic Route of Disulfide Containing Aniline CompoundsDENG, Shi-Ren; HU, Gao-Qiang; YAN,Yong; GUO, Jian-Ping; HUANG, Wei-Guo; ZHOU, Yun-Hong; LI, Zao-Ying *Chin. J. Org. Chem. 2005, 25(7), 815Compound 1 was synthesized via a novel route by some cheap reagents in a relativelymild condition. At the same time, another new analogue 2 was prepared following the similar method. Thioacetalization Reaction of Odorlessα-Oxoketene Dithioacetals as 1,3-Propanedithiol EquivalentLIN, Chun; YU, Hai-Feng; LIU, Qun *; HOU, Dong-YanChin. J. Org. Chem. 2005, 25(7), 819Thioacetalization reaction of the selected aldehydes/ketones with 1a /1b was studied. Quantum Chemical Study on Asymmetric Allylation of BenzaldehydeCHEN, Wan-Suo *; CHEN, Zhi-Rong Chin. J. Org. Chem. 2005, 25(7), 822The quantum chemical method was employed to study the modified asymmetric allylation of benzaldehyde controlled by diisopropyl D -(－)-tartrate auxiliary. All the structures were optimized completely at the B3LYP/6-31G(d,p) level. The (R )-secondary alcohol could be achieved mainly through a six-membered ring chair-like transition state structure. From the relative reaction rate theory the main product predicted was in agreement with the experiment.Solvent Free Synthesis of 2-Aminothia-zole Derivatives under Microwave IrradiationCHENG, Chong-Yun; JIANG, Feng-Chao * Chin. J. Org. Chem. 2005, 25(7), 826Nine 2-aminothiazole derivatives were obtained under microwave irradiation condition by the reaction of thiourea, iodine and ketone in the absence of solvent. The reaction conditions were optimized by orthogonal design. The mechanism of the cyclization reaction under microwave irradiation was also suggested.Synthesis of Hydrogenated Quinolinesby Michael Addition of 1,3-Cyclohexane- dione with β,β-DicyanostyreneWANG, Jin-Jun *; XIE, Lei; KANG, Ming- Qin; ZHANG, Min; LI, Fu-Guo; CUI, Bing-CunChin. J. Org. Chem. 2005, 25(7), 830The hydrogenated quinolines were synthesized by Michael addition of1,3-cyclohexanedione with β,β-dicyanostyrene which was converted into 1,8-naphthridine derivative by the condensation with 1,3-cyclohexane-dione.Hydrogenated benzo[c ]acridin-5-one was obtained using one pot method by co-refluxing of aromatic aldehyde, α-naphthyl- amine and 1,3-cyclohexanedione. Synthesis of Cyclic Dienol Ether and Its PropertiesHUANG, Yan; LIN, Yong-Cheng * Chin. J. Org. Chem. 2005, 25(7), 835。
