含氮杂环的N—H和O—H二氟甲基化反应

doi:10.6023/A18070265

化学学报 ›› 2018, Vol. 76 ›› Issue (12): 972-976.DOI: 10.6023/A18070265 上一篇下一篇

所属专题：有机氟化学

研究通讯

含氮杂环的N—H和O—H二氟甲基化反应

马星星^a,b, 轩晴晴^b, 宋秋玲^a,b

a. 华侨大学材料科学与工程学院厦门 361021;
b. 华侨大学化学化工学院新一代物质转化研究所厦门 361021

投稿日期:2018-07-11 发布日期:2018-11-08
通讯作者: 宋秋玲,E-mail:qsong@hqu.edu.cn E-mail:qsong@hqu.edu.cn
基金资助:
项目受国家自然科学基金（No.21772046）、中组部青年千人计划和福建省自然科学基金（No.2016J01064）资助.

N—H and O—H Difluoromethylation of N-Heterocycles

Ma Xingxing^a,b, Xuan Qingqing^b, Song Qiuling^a,b

a. College of Materials Science & Engineering at Huaqiao University, Xiamen 361021;
b. Institute of Next Generation Matter Transformation, College of Chemical Engineering at Huaqiao University, Xiamen 361021

Received:2018-07-11 Published:2018-11-08
Contact: 10.6023/A18070265 E-mail:qsong@hqu.edu.cn
Supported by:
Project supported by the National Natural Science Foundation of China (No. 21772046), the Recruitment Program of Global Experts and the Natural Science Foundation of Fujian Province (No. 2016J01064).

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1. 含氮杂环的N—H和O—H二氟甲基化反应.PDF(6846KB)

摘要/Abstract

有机氟化合物具有独特的化学、物理和生物性能，被广泛应用于医药、农药、新型功能材料、生命科学等领域.因此，发展便捷高效的合成方法，将单个的氟原子（—F）、二氟甲基（—CF₂H）或者三氟甲基（—CF₃）引入有机小分子，是有机合成领域的热点.相对于发展相对成熟的三氟甲基化反应，二氟甲基化反应发展相对滞后.利用廉价、易保存的溴二氟乙酸乙酯在Na₂CO₃的条件下产生二氟卡宾，并顺利发生N—H，O—H的二氟甲基化反应，成功的将二氟甲基引入到有机小分子中.该反应的底物适用性很广，官能团的兼容性也很好，卤素、醛基、硝基、腈基等取代的底物均能顺利的发生反应.

关键词: 含氟化合物, 有机氟化学, 碱催化, 二氟卡宾, 含氮杂环化合物

It is known that fluorine is the strongest in electronegativity and a peculiar element. Fluorinated compounds are extensively applied in the areas of pharmaceuticals, agrochemical, materials, life sciences, etc., due to the unique chemical, physical and biological properties of fluorine-containing compounds. Therefore, the development of expedient synthetic strategies for the introduction of —F, —CF₂H and —CF₃ into organic compounds has attracted much attentions of chemists. Although trifluoromethylation has been well developed, difluoromethylation has been less reported. We found that difluorocarbene (:CF₂) could be generated in situ from ethyl bromodifluoroacetate (BrCF₂COOEt) in the presence of Na₂CO₃, which could go through N—H, O—H difluoromethylation smoothly. The scope of substrates was broad, and various functional groups, such as halogen, formyl group, nitro-group, nitrile and so on could be tolerated well. This would be a potential and practical reaction in modification of various bioactive drugs beause benzimidazole, indazole and pyridine are the skeleton of medicine and nature molecule. In addition, a representative procedure for this reaction is as following: An oven-dried Schlenk tube (10 mL) was equipped with a magnetic stir bar, the substrates of nitrogen-containing or oxygen-containing (0.3 mmol), the base (Na₂CO₃,2 equiv., 0.6 mmol), ethyl bromodifluoroacetate (1.2 equiv., 0.36 mmol). The flask was evacuated and backfilled with N₂ for 3 times, acetone or acetonitrile as a solvent for 24 h under N₂ atmosphere. Where after the solvent concentrated in vacuo and the residue was purified by chromatography on silica gel with ethyl acetate:petroleum ether (EA:PE＝1:30) to afford the corresponding products.

Key words: fluorine-containing compounds, organofluorine chemistry, base-catalyzed, difluorocarbene, difluoromethylation, nitrogen-containing, oxygen-containing, heterocyclic compounds

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马星星, 轩晴晴, 宋秋玲. 含氮杂环的N—H和O—H二氟甲基化反应[J]. 化学学报, 2018, 76(12): 972-976.

Ma Xingxing, Xuan Qingqing, Song Qiuling. N—H and O—H Difluoromethylation of N-Heterocycles[J]. Acta Chim. Sinica, 2018, 76(12): 972-976.

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参考文献

[1] (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881;
(b) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470;
(c) Hiyama, T. Organofluorine Compounds Chemistry and Applications, Springer-Verlag, Berlin Heidelberg, 2000;
(d) O'Hagan, D. Chem. Soc. Rev. 2008, 37, 308;
(e) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320;
(e) Wang, J.; Sanchez-Rosello, M.; Acen, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432;
(f) Brahms, D.; Dailey, W. Chem. Rev. 1996, 96, 1585;
(g) Dolbier, W.; Battiste, M. Chem. Rev. 2003, 103, 1071;
(h) Fedoryński, M. Chem. Rev. 2003, 103, 1099;
(i) Ed.:Hiyama, T., Organofluorine Compounds:Chemistry and Applications, Springer, New York, 2000;
(j) Hong, M.; Min, J.; Wang, S. Chin. J. Org. Chem. 2018, 38, 1907. (洪梅, 闵洁, 王石发, 有机化学, 2018, 38, 1907.)
[2] (a) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626;
(b) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529;
(c) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305;
(d) Prakash, G. K. S.; Chacko, S. Curr. Opin. Drug Discovery Dev. 2008, 11, 793;
(e) Feng, Z.; Min, Q.-Q.; Fu, X-P.; An, L.; Zhang, X. Nature Chem. 2017, 9, 918;
(f) Ge, S.; Chaladaj, W.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 4149;
(g) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. J. Med. Chem. 2017, 60, 797;
(h) Xu, C.; Guo, W-H.; He, X.; G, Y-L.; Zhang, X.-Y.; Zhang, X. Nat. Commun. 2018, 9, 1170;
(i) Gu, Y.; Leng, X.; Shen, Q. Nat. Commun. 2014, 5, 5405;
(j) Ran, Y.; Lin, Q.-Y.; Xu, X.-H.; Qing, F.-L. J. Org. Chem. 2016, 81, 7001.
[3] (a) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465;
(b) Hu, J.; Ni, C. Synthesis 2014, 46, 842;
(c) Leo, A.; Hansch, C.; Elkins, D. Chem. Rev. 1971, 71, 525;
(d) Hansch, C.; Leo, A.; Taft, R.W. Chem. Rev. 1991, 91, 165;
(e) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827;
(f) Manteau, B.; Pazenok, S.; Vors, J. P.; Leroux, F. R. J. Fluorine Chem. 2010, 131, 140.
(g) Rong, J.; Ni, C.; Wang, Y.; Kuang, C.; Gu, Y.; Hu, J. Acta Chim. Sinica 2017, 75, 105. (荣健, 倪传法, 王云泽, 匡翠文, 顾玉诚, 胡金波, 化学学报, 2017, 75, 105);
(h) Sun, X.; Wang, W.; Ma, J.; Yu, S. Acta Chim. Sinica 2017, 75, 115. (孙晓阳, 王文敏, 马晶, 俞寿云, 化学学报, 2017, 75, 115);
(i) Zhou, N.; Xu, P.; Li, W.; Cheng, Y.; Zhu, C. Acta Chim. Sinica 2017, 75, 60. (周能能, 胥攀, 李伟鹏, 成义祥, 朱成建, 化学学报, 2017, 75, 60);
(j) Zhang, L.; Wu, B.; Chen, Z.; Hu, J. Chin. J. Org. Chem. 2018, 38, 2028. (章吕烨, 吴彬强, 陈张涛, 胡锦锦, 曾晓飞, 钟国富, 有机化学, 2018, 38, 2028);
(k) Chen, C.; Fu, L.; Chen, P.; Liu, G. Chin. J. Chem. 2017, 35, 1781.
[4] (a) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470;
(b) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475;
(c) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed. 2012, 51, 5048;
(d) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2015, 115, 765;
(e) Ni, C.; Zhu, L.; Hu, J. Acta Chim. Sinica 2015, 73, 90. (倪传法, 朱林桂, 胡金波, 化学学报, 2015, 73, 90);
(f) Zhang, P.; Lu, L.; Shen, Q. Acta Chim. Sinica 2017, 75, 744. (张盼盼, 吕龙, 沈其龙, 化学学报, 2017, 75, 744);
(g) Chachignon, H.; Cahard, D. Chin. J. Chem. 2016, 34, 445.
[5] (a) Xie, Q.; Ni, C.; Zhang, R.; Li, L.; Rong, J.; Hu, J. Angew. Chem., Int. Ed. 2017, 56, 3206;
(b) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem., Int. Ed. 2013, 52, 12390;
(c) Gu, J-W.; Zhang, X. Org. Lett. 2015, 17, 5384;
(d) Flynn, R. M.; Burton, D. J. J. Fluorine Chem. 2011, 132, 815;
(e) Feng, Z.; Min, Q.-Q.; Zhang, X. Org. Lett. 2016, 18, 44;
(f) Ke, M.; Song, Q. J. Org. Chem. 2016, 81, 3654;
(g) Ke, M.; Song, Q. Chem. Commun. 2017, 53, 2222;
(h) Ke, M.; Song, Q. Adv. Synth. Catal. 2017, 359, 384;
(i) Ke, M.; Feng, Q.; Yang, K.; Song, Q. Org. Chem. Front. 2016, 3, 150;
(j) Taguchi, T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.; Uehara, H.; Endo, H.; Kobayashi, Y. Tetrahedron Lett. 1986, 27, 6103;
(k) Araki, K.; Inoue, M. Tetrahedron 2013, 69, 3913;
(l) Belhomme, M.-C.; Poisson, T.; Pannecoucke, X. Org. Lett. 2013, 15, 3428;
(m) Feng, Z.; Min, Q.-Q.; Fu, X-P.; An, L.; Zhang, X. Nature Chem. 2017, 9, 918.
[6] (a) Burton, D. J.; Wiemers, D. M. J. Am. Chem. Soc. 1985, 107, 5014;
(b) Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108, 832;
(c) Zheng, J.; Lin, J.-H.; Deng, X.-Y.; Xiao, J.-C. Org. Lett. 2015, 17, 532;
(d) Brooks, A. F.; Topczewski, J. J.; Ichiishi, N.; Sanford, M. S.; Scott, P. J. H. Chem. Sci. 2014, 5, 4545;
(e) Huiban, M.; Tredwell, M.; Mizuta, S.; Wan, Z.; Zhang, X.; Collier, T. L.; Gouverneur, V.; Passchier, J. Nat. Chem. 2013, 5, 941;
(f) van der Born, D.; Sewing, C.; Herscheid, J. D. M.; Windhorst, A. D.; Orru, R. V. A.; Vugts, D. J. Angew. Chem., Int. Ed. 2014, 53, 11046;
(g) Ivashkin, P.; Lemonnier, G.; Cousin, J.; Grégoire, V.; Labar, D.; Jubault, P.; Pannecoucke, X. Chem.-Eur. J. 2014, 20, 9514;
(h) Ruhl, T.; Rafique, W.; Lien, V. T.; Riss, P. J. Chem. Commun. 2014, 50, 6056.
[7] See reviews for the formation of:CF₂H (a) Fu, X.-P.; Xiao, Y.-L.; Zhang, X. Chin. J. Chem. 2018, 36, 143;
(b) Zhang, W.; Zhu, L.; Hu, J. Tetrahedron 2007, 63, 10569. See reviews for difluoro-cyclopro-panes:(c) Toshiyuki, I. Current Fluoroorganic Chemistry, Vol. 949, ACS Symposium Series, American Chemical Society, 2007, pp. 352-362;
(d) Burch, J. D.; Barrett, K.; Chen, Y.; DeVoss, J.; Eigenbrot, C.; Goldsmith, R.; Ismaili, M. H. A.; Lau, K.; Lin, Z.; Ortwine, D. F.; Zarrin, A. A.; McEwan, P. A.; Barker, J. J.; Ellebrandt, C.; Kordt, D.; Stein, D. B.; Wang, X.; Chen, Y.; Hu, B.; Xu, X.; Yuen, P.-W.; Zhang, Y.; Pei, Z. J. Med. Chem. 2015, 58, 3806;
(e) Dantzig, A. H.; Shepard, R. L.; Law, K. L.; Tabas, L.; Pratt, S.; Gillespie, J. S.; Binkley, S. N.; Kuhfeld, M. T.; Starling, J. J.; Wrighton, S. A. J. Pharmacol. Exp. Ther. 1999, 290, 854;
(f) Itoh, T.; Kanbara, M.; Ohashi, M.; Hayase, S.; Kawatsura, M.; Kato, T.; Miyazawa, K.; Takagi, Y.; Uno, H. J. Fluorine Chem. 2007, 128, 1112.
[8] (a) Fuchibe, K.; Aono, T.; Hu, J.; Ichikawa, J. Org. Lett. 2016, 18, 4502; see reviews for[3+2] and[2+2+1] cyclizations:(b) Coscia, R. W.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 2496 and refs therein;
(c) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49;
(d) Frü hauf, H.-W. Chem. Rev. 1997, 97, 523; see reviews for Junji Ichikawa's previous works about transition metal difluorocarbene complexes:(e) Aono, T.; Sasagawa, H.; Fuchibe, K.; Ichikawa, J. Org. Lett. 2015, 17, 5736.
[9] Imidazole derivatives play an important role in chemical and biological systems, see reviews:(a) Bando, T.; Sugiyama, H. Acc. Chem. Res. 2006, 39, 935;
(b) Breslow, R. Acc. Chem. Res. 1991, 24, 317;
(c) Townsend, L. B. Chem. Rev. 1967, 67, 533;
(d) Palui, G.; Aldeek, F.; Wang, W.; Mattoussi, H. Chem. Soc. Rev. 2015, 44, 193.
[10] (a) Ma, X.; Zhou, Y.; Song, Q. Org. Lett. 2018, 20, 4777;
(b) Ma, X.; Mai, S.; Zhou, Y.; Cheng, G.-J.; Song, Q. Chem. Commun. 2018, 54, 8960.

含氮杂环的N—H和O—H二氟甲基化反应

N—H and O—H Difluoromethylation of N-Heterocycles

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