Selective Fluorination of 2-Aminopyrazine Derivatives in Aqueous Phase

doi:10.6023/A18070307

Acta Chim. Sinica ›› 2018, Vol. 76 ›› Issue (12): 962-966.DOI: 10.6023/A18070307 Previous Articles Next Articles

Special Issue: 有机氟化学

Communication

2-氨基吡嗪衍生物在水相中的选择性氟化反应研究

田亚伟, 周刚, 赵晓明, 淡文彦

同济大学化学科学与工程学院上海 200092

投稿日期:2018-07-30 发布日期:2018-10-08
通讯作者: 赵晓明,E-mail:xmzhao08@mail.tongji.edu.cn E-mail:xmzhao08@mail.tongji.edu.cn
基金资助:
项目受国家自然科学基金（No.21272175）和同济大学中央高校基础研究基金资助.

Selective Fluorination of 2-Aminopyrazine Derivatives in Aqueous Phase

Tian Yawei, Zhou Gang, Zhao Xiaoming, Dan Wenyan

Tongji University, School of Chemical Science & Engineering, Shanghai 200092

Received:2018-07-30 Published:2018-10-08
Contact: 10.6023/A18070307 E-mail:xmzhao08@mail.tongji.edu.cn
Supported by:
Project supported by the National Natural Science Foundation of China (No. 21272175) and the Fundamental Research Funds for the Central Universities.

1. Selective Fluorination of 2-Aminopyrazine Derivatives in Aqueous Phase.PDF(2155KB)

Abstract

2-Aminopyrazines are widely found in naturally occurring compounds, drugs and biologically active ingredients. Especially, the compounds containing a fluorinated aminopyrazine have been applied in the pharmaceutical industry. The introduction of a fluorine atom into organic compounds generally leads to a significant change in the chemical, physical and biological properties. Therefore, new method for introducing a fluorine atom into the aminopyrazine ring is highly desirable. Traditional Balz-Schiemann reaction is difficult to employ in the preparation of fluorinated aminopyrazines because of the decomposition of pyrazine derivatives under strong acidic conditions. In general, pyrazines can take place nucleophilic fluorination; aminopyrazines, which is activated by an amino group, can occur electronphilic halogenation; the radical fluorination of pyrazine derivatives has not reported yet. We envisage a direct fluorination of 2-aminopyrazines with Selectfluor may proceed under mild conditions. In this paper, the fluorination of 2-aminopyrazine derivatives with Selectfluor in aqueous phase was studied, and a transition-metal free fluorination of 2-aminopyrazine derivatives was developed. The method affords 5-fluoro-2-aminopyrazines in good yield with excellent chemoselectivity and high regioselectivity. The results suggested that the fluorination may undergo a radical process. Using this method, an enzyme inhibitor having a certain inhibitory effect on analog of B-Raf enzyme was synthesized. The synthesis was as follows: 6-phenyl-2-aminopyrazine (1a, 0.2 mmol), selectfluor (2a, 0.1 mmol), toluene:water [V(toluene):V(water)＝1:1, 2 mL] in a reaction tube. The reaction was carried out at room temperature, monitoring by ¹⁹F NMR. After the completion of the reaction, the reaction mixture was cooled, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give 5-fluoro-2-aminopyrazines 3 and 3-fluoro-2-aminopyrazines 3'.

Key words: 2-aminopyrazine, selectfluor, fluorination, chemoselectivity, regioselectivity

Cite this article

Tian Yawei, Zhou Gang, Zhao Xiaoming, Dan Wenyan. Selective Fluorination of 2-Aminopyrazine Derivatives in Aqueous Phase[J]. Acta Chim. Sinica, 2018, 76(12): 962-966.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

References

[1] (a) Vollhardt, P.; Schore, N. Organic Chemistry, Freeman Palgrave Macmillan, New York, 2011.
(b) Wang, M.; Zhang, Y.; Wang, T.; Wang, C.; Xue, D.; Xiao, J. Org. Lett. 2016, 18, 1976.
(c) Jean, B.; Marc, L.; Guy, Q. J. Heterocycl. Chem. 1980, 17, 257.
(d) Gainer, H.; Kokorudz, M.; Langdon, W. K. J. Org. Chem. 1961, 26, 2360.
(e) Bourguignon, J.; Lemarchand, M.; Quéquiner, G. J. Heterocycl. Chem. 1980, 17, 257.
[2] (a) Hart, B. P.; Haile, W. H.; Licato, N. J.; Bolanowska, W. E.; Mcguire, J. J.; Coward, J. K. J. Med. Chem. 1996, 27, 56.
(b) Jhulki, I.; Chanani, P. K.; Abdelwahed, S. H.; Begley, T. P. J. Am. Chem. Soc. 2016, 138, 8324.
[3] (a) Zou, Y.; Zhao, D.; Yan, C.; Ji, Y.; Liu, J.; Xu, J.; Lai, Y.; Tian, J.; Zhang, Y.; Huang, Z. J. Med. Chem. 2018, 61, 1821.
(b) Cheng, X. C.; Liu, X. Y.; Xu, W. F.; Guo, X. L.; Ou, Y. Bioorg. Med. Chem. 2007, 15, 3315.
(c) Zhao, Y.; Qian, G.; Ye, Y.; Wright, S.; Chen, H.; Shen, Y.; Liu, F.; Du, L. Org. Lett. 2016, 18, 2495.
(d) Wächter, G. A.; Davis, M. C.; Martin, A. R.; Franzblau, S. G. J. Med. Chem. 1998, 41, 2436.
(e) Kalinowski, D. S.; Sharpe, P. C.; Bernhardt, P. V.; Richardson, D. R. J. Med. Chem. 2008, 51, 331.
[4] (a) Liu, L. W.; Wang, F. Y.; Tian, F.; Peng, L.; Wang, L. X. Org. Process Res. Dev. 2016, 20, 320.
(b) Ashley, J. D.; Stefanick, J. F.; Schroeder, V. A.; Suckow, M. A.; Kiziltepe, T.; Bilgicer, B. J. Med. Chem. 2014, 57, 5282.
(c) Wang, G.; Wan, J.; Hu, Y.; Wu, X.; Prhavc, M.; Dyatkina, N.; Rajwanshi, V. K.; Smith, D. B.; Jekle, A.; Kinkade, A. J. Med. Chem. 2016, 59, 4611.
(d) Asaki, T.; Kuwano, K.; Morrison, K.; Gatfield, J.; Hamamoto, T.; Clozel, M. J. Med. Chem. 2015, 58, 7128.
(e) Guillotin, D.; Austin, P.; Begum, R.; Freitas, M. O.; Merve, A.; Brend, T.; Short, S. C.; Marino, S.; Martin, S. A. Clin. Cancer Res. 2016, 23, 2880.
(f) Wang, G.; Wan, J.; Hu, Y.; Wu, X.; Prhavc, M.; Dyatkina, N.; Rajwanshi, V. K.; Smith, D. B.; Jekle, A.; Kinkade, A. J. Med. Chem. 2016, 59, 4611.
[5] (a) Ryan, S. J.; Schimler, S. D.; Bland, D. C.; Sanford, M. S. Org. Lett. 2015, 46, 1866.
(b) Schimler, S. D.; Ryan, S. J.; Bland, D. C.; Anderson, J. E.; Sanford, M. S. J. Org. Chem. 2015, 80, 12137.
(c) Sun, H.; DiMagno, S. G. Angew. Chem., Int. Ed. 2006, 45, 2720.
(d) Kindon, N.; Andrews, G.; Baxter, A.; Cheshire, D.; Hemsley, P.; Johnson, T.; Liu, Y.; McGinnity, D.; McHale, M.; Mete, A.; Reuberson, J.; Roberts, B.; Steele, J.; Teobald, B.; Unitt, J.; Vaughan, D.; Walters, I.; Stocks, M. J. ACS Med. Chem. Lett. 2017, 8, 981.
[6] Fier, P. S.; Hartwig, J. F. Science 2013, 342, 956.
[7] Selectfluor made from F₂ and 1,4-diazabicyclo[2.2.2] octane in the presence of CH₂Cl₂ and BF₃ was reported, see:(a) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.; Syvret, R. G. J. Chem. Soc., Chem. Commun. 1992, 23, 595.
(b) Review:Nyffeler, P. T.; Durón, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C. H. Angew. Chem., Int. Ed. 2004, 36, 192.
(c) Account:Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31.
[8] CCDC 1826147 for 3a contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center.
[9] CCDC 1847836 for 3a' contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center.
[10] (a) Gahman, T. C.; Lang, H.; Davis, R. L.; Scranton, S. A. WO 2006124874, 2006[Chem. Abstr. 2006, 146, 13164].
(b) Yin, J.; Zhao, M. M.; And, M. A. H.; Mcnamara, J. M. Org. Lett. 2002, 4, 3481.

[1]	Huang Jiapian, Liu Fei, Wu Jie. Recent Advances in the Transformation of Difluorocyclopropenes^★ [J]. Acta Chimica Sinica, 2023, 81(5): 520-532.
[2]	Song Zhidong, Jiang Lvqi, Yi Wenbin. Fluorodecarboxylation of β,γ-Unsaturated Carboxylic Acids Using Trivalent Iodine and Hydrofluoric Acid-Based Fluorination Reagent [J]. Acta Chim. Sinica, 2018, 76(12): 967-971.
[3]	Fan Xuefeng, Zhao Huijun, Zhu Chen. Recent Advances in the Synthesis of Distal Fluorinated Ketones [J]. Acta Chim. Sinica, 2015, 73(10): 979-983.
[4]	Zhu Haitao, Liu Guosheng. Palladium-Catalyzed Oxidative Aminofluorination of Styrenes [J]. Acta Chimica Sinica, 2012, 70(23): 2404-2407.
[5]	Yan Zhaohua, Lai Kunmin, Tian Weisheng, Yu Zhangxin. Deoxyfluorination of Peracetylated Pyranose Hemiacetal with Fluoroalkanesulfonyl Fluoride [J]. Acta Chimica Sinica, 2012, 70(11): 1322-1326.
[6]	CAO Xiao-Hui, MA Yi, ZHOU Xiao-Li, CHEN Li-Gong. Synthesis of KAD-1229 through Amidation of Bis-activated Esters and Discussion of Regioselectivity of the Reactions [J]. Acta Chimica Sinica, 2009, 67(22): 2635-2640.
[7]	HU, Xiao-Xi ^a,b ZHANG, Jun-Xiang ^,a WANG, De-Cai ^,b LÜ, Long ^,a JIANG, Xue-Yin ^,c ZHANG, Zhi-Lin^c. Novel Blue-light-emitting Materials: Synthesis and Characterization of Fluorinated Ter(9,9-diphenylfluorenyl) [J]. Acta Chimica Sinica, 2008, 66(14): 1763-1769.
[8]	BI, Cheng-Liang ^*,a GUO, Ai-Hong ^b TANG, Xue-Jiao ^a GAO, Min ^a ZHANG, Bao-Gui ^a . Preparation and Performance of Lithium Perfluoroalkylphosphonate [J]. Acta Chimica Sinica, 2008, 66(12): 1441-1445.
[9]	SHI Min-Min, CHEN Hong-Zheng*, WANG Mang. Influences of Different Fluorinated Substituents on Electron Mobility of Perylene Diimides [J]. Acta Chimica Sinica, 2006, 64(8): 721-726.
[10]	. Pauson-Khand Approach towards Enantiopure C2-Symmetric Polycyclic Compound from D-Mannitol [J]. Acta Chimica Sinica, 2006, 64(2): 169-174.
[11]	LI Ming*^1,2, GUO Wei-Si, WEN Li-Rong, ZHONG Hui-Min, YANG Hua-Zheng². Regioselective Synthesis and 2D NMR Research of Ethyl 2-Methyl-thio-7(5)-substituted Pyrazolo[1,5-a]pyrimidine-3-carboxylate [J]. Acta Chimica Sinica, 2005, 63(9): 855-860.
[12]	ZHANG Yue-Mei, WANG Ruo-Xi, XU Wei-Ren², LIU Cheng-Bu*^{,1. Theoretical Study on the Regioselectivity of Nitrile Oxide 1,3-Dipolar Cycloaddition to Propyne [J]. Acta Chimica Sinica, 2005, 63(7): 567-571.}
[13]	LIANG Yun-Xiao*, SHANG Zhen-Feng², ZHAO Xue-Zhuang². Theoretical Studies on the Regioselectivity of Radical Addition to C₅₉XH (X＝N, B) [J]. Acta Chimica Sinica, 2005, 63(13): 1161-1166.
[14]	ZHANG JIANJUN;KONG FANZUO. A facile large scale synthesis of the core mannose pentasaccharide of N-linked glycoprotein and its isomer [J]. Acta Chimica Sinica, 2002, 60(1): 150-156.
[15]	ZENG FANXING;JIANG HUALIANG;YANG YUSHE;LIU DONGXIANG;CHEN JIANZHONG;TANG XICAN;LIU JING;SHEN JINGKANG;CHEN KAIXIAN;JI RUYUN. Syntheses and pharmacological studies of huperzine A analogues 1: (±)-14-fluorohuperzine A [J]. Acta Chimica Sinica, 1999, 57(5): 522-526.

2-氨基吡嗪衍生物在水相中的选择性氟化反应研究

Selective Fluorination of 2-Aminopyrazine Derivatives in Aqueous Phase

PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

Comments