利用串联的Staudinger/aza-Wittig/芳构化反应合成1,2,4-三取代咪唑衍生物

doi:10.6023/cjoc202306022

摘要/Abstract

报道了一种合成1,2,4-三取代咪唑衍生物的方法, 即通过含有烯基叠氮基的苯甲酰胺衍生物为关键中间体, 用三苯基膦处理, 发生串联的Staudinger/aza-Wittig/芳构化反应, 合成得到1,2,4-三取代咪唑衍生物. 该反应具有原料廉价易得, 反应条件温和, 无需使用金属催化剂, 操作简便的特点, 这是一种理想、高效的1,2,4-三取代咪唑杂环化合物的合成策略.

关键词: Staudinger反应, aza-Wittig反应, 芳构化反应, 1,2,4-三取代咪唑

An efficient and convenient route for the synthesis of 1,2,4-trisubstituted imidazole derivatives was described. Benzamide derivatives containing alkenylazide as the basic raw materials were treated with triphenyl phosphorus, and subsequently 1,2,4-trisubstituted imidazole derivatives were synthesized by a sequential Staudinger/aza-Wittig/aromatization reaction. The reaction is characterized by cheap and easy to obtain starting materials, mild reaction conditions, metal-free catalysts, and simple operation. It is an ideal and efficient synthesis strategy of 1,2,4-trisubstituted imidazole heterocyclic compounds.

Key words: Staudinger reaction, aza-Wittig reaction, aromatization reaction, 1,2,4-trisubstituted imidazole

引用此文

解海, 张雅丽, 秦秀婷, 谷永新. 利用串联的Staudinger/aza-Wittig/芳构化反应合成1,2,4-三取代咪唑衍生物[J]. 有机化学, 2024, 44(2): 525-532.

Hai Xie, Yali Zhang, Xiuting Qin, Yongxin Gu. Synthesis of 1,2,4-Trisubstituted Imidazoles via Sequential Staudinger/aza-Wittig/Aromatization Reaction[J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 525-532.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 6

图1. 含1,2,4-咪唑核心结构的药物活性分子举例

Figure 1. Examples of drugs containing 1,2,4-imidazole core structures

图式1. 苯基叠氮基烯丙基苯胺(2a)的制备路线优化

Scheme 1. Optimization of preparation route of N-(2-azido-3- phenylallyl)aniline (2a)

Compd.	R¹	R²	R³	Yield^a/%
3a	C₆H₅	C₆H₅	C₆H₅	88
3b	C₆H₅	C₆H₅	4-MeC₆H₄	84
3c	C₆H₅	C₆H₅	4-ClC₆H₄	89
3d	C₆H₅	C₆H₅	4-BrC₆H₄	81
3e	C₆H₅	C₆H₅	4-FC₆H₄	90
3f	C₆H₅	C₆H₅	4-NO₂C₆H₄	80
3g	C₆H₅	4-ClC₆H₄	C₆H₅	86
3h	C₆H₅	4-MeC₆H₄	C₆H₅	85
3i	C₆H₅	2-ClC₆H₄	C₆H₅	84
3j	C₆H₅	4-ClC₆H₄	4-MeOC₆H₄	83
3k	C₆H₅	2-Furyl	C₆H₅	80
3l	4-FC₆H₄	C₆H₅	4-MeC₆H₄	86
3m	Me	C₆H₅	C₆H₅	79

表1. 苯甲酰胺衍生物3的制备

Table 1. Preparation of benzamide derivatives 3

图式2. 6a的合成路线

Scheme 2. Synthesis route of 6a

表2. 1,2,4-三取代咪唑6 的制备

Table 2. Preparation of 1,2,4-trisubstituted imidazoles 6

图式3. 可能的反应机理

Scheme 3. Proposed reaction mechanism

参考文献 53

[1]	Jin Z. Nat. Prod. Rep. 2011, 28, 1143. doi: 10.1039/c0np00074d
[2]	Hoffmann, H.; Lindel, T. Synthesis-stuttgar. 2003, 12, 1753.
[3]	Gaba, M.; Mohan, C. Med. Chem. Res. 2003, 25, 173. doi: 10.1007/s00044-015-1495-5
[4]	Franchetti, P.; Marchetti, L. S.; Cappaellaci, J. A.; Yalowitz, H. N.; Jayaram, B. M.; Glodstein, M.; Grafantini, A. Bioorg. Med. Chem. Lett. 2001, 11, 67. pmid: 11140736
[5]	Baraldi, P. G.; Beria, I.; Cozzi, P.; Bianchi, N.; Gambari, R.; Romagnoli, R. Bioorg. Med. Chem. 2003, 11, 965.
[6]	Vlahakis, J. Z.; Kinobe, R. T.; Nakatsu, K.; Szarek, W. A.; Crandall, I. E. Bioorg. Med. Chem. Lett. 2006, 16, 296.
[7]	Lagu, B.; Kluge, A. F.; Tozzo, E.; Fredenburg, R.; Bell, E. L.; Goddeeris, M. M.; Dwyer, P.; Basinski, A.; Senaiar, R. S.; Jaleel, M.; Tiwari, N. K.; Panigrahi, S. K.; Krishnamurthy, N. R.; Takahashi, T.; Patane, M. A. ACS Med. Chem. Lett. 2018, 9, 935. doi: 10.1021/acsmedchemlett.8b00287
[8]	Zhu, H. Y.; Cooper, A. B.; Desai, J.; Njoroge, G.; Kirschmeier, P.; Bishop, W. R.; Strickland, C.; Hruza, A.; Doll, R. J.; Girijavallabhan, V. M. Bioorg. Med. Chem. Lett. 2010, 20, 1134. doi: 10.1016/j.bmcl.2009.12.013
[9]	Mishra, R.; Ganguly, S. Med. Chem. Res. 2012, 21, 3929. doi: 10.1007/s00044-012-9972-6
[10]	Rani, N.; Sharma, A.; Gupta, G. K.; Singh, R. Mini-Rev. Med. Chem. 2013, 13, 1626. doi: 10.2174/13895575113139990069
[11]	Chen, Y.; Wei, Y. F.; Li, J. X.; Luo, W. Q.; Jin, C. M. Chin. J. Inorg. Chem. 2021, 37, 235 (in Chinese).
	(陈雨, 卫杨帆, 李嘉欣, 罗文琦, 金传明, 无机化学. 2021, 37, 235.)
[12]	Luo, H. B.; Ren, Q.; Wang, P.; Zhang, J.; Wang, L. F.; Ren, X. M. ACS Appl. Mater. Interface. 2019, 11, 9164. doi: 10.1021/acsami.9b01075
[13]	Ye, Y. X.; Guo, W. G.; Wan, L. H.; Li, Z. Y.; Song, Z. J.; Chen, J.; Zhang, Z. J.; Xiang, S. C.; Chen, B. L. J. Am. Chem. Soc. 2017, 139, 15604. doi: 10.1021/jacs.7b09163
[14]	Tseng, C. C.; Chen, K. L.; Lee, K. W.; Takayam, H.; Lin, C. Y; Wong, F. F. Prog. Org. Coat. 2019, 127, 385.
[15]	Wang, X. J.; Xu, T.; Duan, H. D. Sens. Actuators. B 2015, 214, 138. doi: 10.1016/j.snb.2015.03.022
[16]	Cheng, D. D.; Liu, X. L.; Yang, H. Z.; Zhang, T.; Han, A. X.; Zang, L. Sensor. 2017, 17, 35. doi: 10.3390/s17010035
[17]	Xu, Z. X.; Wang, S. M.; Zhao, L.; Zhang, S. L.; Li, J. B. Chin. J. Org. Chem. 2003, 23, 950 (in Chinese).
	(许祖勋, 王世敏, 赵雷, 张胜利, 黎俊波, 有机化学. 2003, 23, 950.)
[18]	Zhao, Y.; Chen, P. P.; Li, G. N.; Niu, Z. G.; Wang, E. J. Chin. J. Org. Chem. 2023, 43, 2156 (in Chinese). doi: 10.6023/cjoc202210002
	(赵洋, 陈盼盼, 李高楠, 钮智刚, 王恩举, 有机化学. 2023, 43, 2156.)
[19]	He, Y.; Chai, Y. Q.; Yuan, R.; Wang, H. J.; Bai, L. J.; Cao, Y. L.; Yuan, Y. L. Biosens. Bioelectron. 2013, 50, 294. doi: 10.1016/j.bios.2013.05.041
[20]	Debus H. Justus Liebigs Ann. Chem. 1858, 107, 199. doi: 10.1002/jlac.v107:2
[21]	Radzisewski B. Ber. Dtsch. Chem. Ges. 1882, 15, 2706. doi: 10.1002/cber.v15:2
[22]	Bredereck, H.; Theilig, G. Chem. Ber. 1953, 86, 88. doi: 10.1002/cber.v86:1
[23]	Gupta, G. K.; Rani, N.; Kumar, V. Mini-Rev. Org. Chem. 2012, 9, 270.
[24]	Patel, S. R.; Patil, R. V.; Chavan, J. U.; Beldar, A. G. Turk. J. Chem. 2022, 46, 624. doi: 10.55730/1300-0527.3357
[25]	Rani, N.; Kumar, P.; Singh, R.; de Sousa, D. P.; Sharma, P. Curr. Drug Target. 2020, 21, 1130. doi: 10.2174/1389450121666200530203247
[26]	Kamijo, S.; Yamamoto, Y. Chem.-Asian J. 2007, 2, 568. doi: 10.1002/asia.v2:5
[27]	Heravi, M. M.; Daraie, M.; Zadsirjan, V. Mol. Diversit. 2015, 19, 577.
[28]	Tolomeu, H. V.; Fraga, C. A. M. Molecule. 2023, 28, 838. doi: 10.3390/molecules28020838
[29]	Punia, S.; Verma, V.; Kumar, D.; Singh, G.; Sahoo, S. C. Synth. Commun. 2020, 50, 700. doi: 10.1080/00397911.2020.1712608
[30]	Salfeena, C.T. F.; Jalaja, R.; Davis, R.; Suresh, E.; Somappa, S. B. ACS Omeg. 2018, 3, 807.
[31]	Yu, H. H.; Xiao, L.; Yang, X. C.; Shao, L. M. Chem. Commun. 2017, 53, 9745. doi: 10.1039/C7CC05315K
[32]	Huang, X. S.; Cong, X. F.; Mi, P. B.; Bi, X. H. Chem. Commun. 2017, 53, 3858. doi: 10.1039/C7CC00772H
[33]	Wu, P.; Zhang, L. T.; Zhang, X. G.; Guo, X.; Chen, B. H. Chin. J. Chem. 2016, 34, 363. doi: 10.1002/cjoc.v34.4
[34]	Cao, J. H.; Zhou, X. Q.; Ma, H. J.; Shi, C.; Huang, G. S. RSC Adv. 2016, 6, s7232.
[35]	Tang, D.; Guo, X.; Wang, Y.; Wang, J.; Li, J. H.; Huang, Q. W.; Chen, B. H. Tetrahedron Lett. 2015, 56, 5982. doi: 10.1016/j.tetlet.2015.09.034
[36]	Li, Y. X.; Fu, Y. J.; Ren, C. J.; Tang, D.; Wu, P.; Meng, X.; Chen, B. H. Org. Chem. Front. 2015, 2, 1632.
[37]	Liu, X.; Wang, D.; Chen, Y. X.; Tang, D.; Chen, B. H. Adv. Synth. Catal. 2013, 355, 2798. doi: 10.1002/adsc.v355.14/15
[38]	Xiao, L. W.; Peng, X. X.; Zhou, Q. X.; Kou, W.; Shi, Y. R. Chin. J. Org. Chem. 2015, 35, 1204 (in Chinese). doi: 10.6023/cjoc201412012
	(肖立伟, 彭晓霞, 周秋香, 寇伟, 时亚茹, 有机化学. 2015, 35, 1204.) doi: 10.6023/cjoc201412012
[39]	Zhao, M. N.; Yang, Z. M.; Yang, D. S. Chin. J. Org. Chem. 2022, 42, 111 (in Chinese). doi: 10.6023/cjoc202107014
	(赵咪娜, 杨梓墨, 杨得锁, 有机化学. 2022, 42, 111.) doi: 10.6023/cjoc202107014
[40]	Staudinger, H.; Meyer, J. Helv. Chim. Act. 1919, 2, 635. doi: 10.1002/hlca.v2:1
[41]	Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; Santos, J. M. Tetrahedro. 2007, 63, 523. doi: 10.1016/j.tet.2006.09.048
[42]	Pedrood, K.; Montazer, M. N.; Larijani, B.; Mahdavi, M. Synthesis-stuttgar. 2021, 53, 2342. doi: 10.1055/a-1394-7511
[43]	Lao, Z. Q.; Toy, P. H. Beilstein J. Org. Chem. 2016, 12, 2577. doi: 10.3762/bjoc.12.253
[44]	Lebedev, R.; Dar’in, D.; Kantin, G.; Bakulina, O.; Krasavin, M. Molecule. 2022, 27, 8130. doi: 10.3390/molecules27238130
[45]	Xie, H.; Hu, Q. Q.; Zhang, Y. L.; Qin, X. T.; Li, L. Curr. Org. Synth. 2023, 20, 589. doi: 10.2174/1570179420666221006113032
[46]	Xie, H.; Hu, Q. Q.; Qin, X. T.; Liang, J. M.; Li, L.; Zhang, Y. L.; Lu, Z. Heterocycle. 2022, 104, 585. doi: 10.3987/COM-21-14600
[47]	Xie, H.; Rao, Y.; Ding, M. W. Dyes Pigm. 2017, 139, 440. doi: 10.1016/j.dyepig.2016.12.040
[48]	Xie, H.; Yuan, D.; Ding, M. W. J. Org. Chem. 2012, 77, 2954. doi: 10.1021/jo202588j
[49]	Xie, H.; Liu, J. C.; Ding, M. W. Synthesi. 2016, 48, 4541. doi: 10.1055/s-0036-1588308
[50]	Xie, H.; Ding, M. W. Tetrahedro. 2012, 68, 7984. doi: 10.1016/j.tet.2012.07.002
[51]	McGonagle, F. I.; MacMillan, D. S.; Murray, J.; Sneddon, H. F.; Jamieson, C.; Watson, A. J. B. Green Chem. 2013, 15, 1159. doi: 10.1039/c3gc40359a
[52]	Ding M. W. Sci. Sin. Chim. 2010, 40, 869 (in Chinese). doi: 10.1360/zb2010-40-7-869
	(丁明武, 中国科学: 化学. 2010, 40, 869.)
[53]	Nie, Y. B.; Duan, Z.; Ding, M. W. Tetrahedro. 2012, 68, 965. doi: 10.1016/j.tet.2011.12.005