Citation: Ren Zhiwen, Ren Nan, Zhang Faguang, Ma Junan. Facile Synthesis of Fluorinated Isoxazoles via Consecutive Double C—F Bond Cleavage[J]. Acta Chimica Sinica, ;2018, 76(12): 940-944. doi: 10.6023/A18070279 shu

Facile Synthesis of Fluorinated Isoxazoles via Consecutive Double C—F Bond Cleavage

Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin Collaborative Innovation Center of Chemical Science & Engineering, Tianjin University, Tianjin 300072

Corresponding author: Zhang Faguang, zhangfg1987@tju.edu.cn Ma Junan, majun_an68@tju.edu.cn
Received Date: 17 July 2018
Available Online: 14 December 2018
Fund Project: the National Natural Science Foundation of China 21532008the National Natural Science Foundation of China 21472137Project supported by the National Natural Science Foundation of China (Nos. 21472137, 21532008, 21772142) and the National Basic Research Program of China (973 Program, No. 2014CB745100)the National Basic Research Program of China 973 Programthe National Basic Research Program of China 2014CB745100the National Natural Science Foundation of China 21772142

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Fluorinated heterocycles represent a ubiquitous structural motif found in numerous pharmaceuticals, agrochemicals, and functional materials. This is especially true for fluorine-containing five-membered heteroaromatic compounds that have been widely investigated in various fields for a long time. In this context, fluorinated isoxazoles have emerged as valuable scaffolds owing to their diverse biological properties. Among various approaches that have been developed for the synthesis and functionalization of isoxazoles, efficient and modular route to fluorine-substituted isoxazoles are still limited. Traditional methods include the condensation of 2-fluoro-1, 3-dicarbonyl derivatives with hydroxylamine, Au-catalyzed fluorocyclization of 2-alkyne O-methyloximes, and direct fluorination of isoxazoles. However, the wide applicability of these approaches often suffers from low chemical yields, harsh reaction conditions, and limited substrate scope. Herein, we describe a one-pot protocol for the construction of fluorinated isoxazoles from CF₃-containing precursors with hydroxylammonium chloride. Typical features of this reaction include mild conditions, simple operations, and good functional group compatibility. This method provides facile access to a series of 3-F-5-aryl-isoxazoles in moderate to good yields from easily available α-CF₃-β-keto esters. Moreover, further synthetic transformations of obtained isoxazoles to important bio-active molecular derivatives have also been demonstrated. A representative procedure for this reaction is as following: α-CF₃-β-keto ester 1 (0.2 mmol, 1.0 equiv.), HONH₂·HCl (46 mg, 0.66 mmol), pyridine (71 μL, 0.88 mmol), and CH₃CN (3.0 mL) were added into an oven-dried vial equipped with a magnetic stir bar. The mixture was stirred at 75 ℃ for 12 h and monitored by thin-layer chromatography (TLC). After completion, 10 mL of water was added and the mixture was extracted with EtOAc for three times. The combined organic layers were washed with saturated NaCl and dried over Na₂SO₄. The mixture was evaporated under reduced pressure and residue was purified by flash chromatography on silica gel eluting with petroleum ether/ethyl acetate (V:V＝30:1) to afford the 3-F-5-aryl-isoxazole 2.
- C—F bond cleavage,
- isoxazole,
- one-pot reaction,
- F-containing heterocycle,
- hydroxylammonium chloride
1. [1]
  (a) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432. (b) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (e) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (f) Fluorinated Hetreocycles, ACS Symp. Ser. No. 1003, Eds.: Gakh, A. A.; Kirk, K. L. ACS, Washington, DC, 2009, pp. 3~20. (g) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (h) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Chem. Soc. Rev. 2011, 40, 3496. (i) Li, S.; Ma, J.-A. Chem. Soc. Rev. 2015, 44, 7439. (j) Jeschke, P. Pest Manage. Sci. 2017, 73, 10536. (k) Chen, C.; Fu, L.; Chen, P.; Liu, G. Chin. J. Chem. 2017, 35, 1781. (l) Yang, Q.-L.; Fang, P.; Mei, T.-S. Chin. J. Chem. 2018, 36, 338.
2. [2]
  (a) Fluorine in Heterocyclic Chemistry, Vol. 1, Eds.: Nenajdenko, V., Springer International Publishing, 2014. (b) Giornal, F.; Pazenok, S.; Rodefeld, L.; Lui, N.; Vors, J.-P.; Leroux, F. R. J. Fluorine Chem. 2013, 152, 2.
3. [3]
  (a) Cordero, F. M.; Giomi, D.; Lascialfari, L. In Progress in Heterocyclic Chemistry, Vol. 27, Eds.: Gribble, G. W.; Joule, J. A. Elsevier Ltd., 2015, p. 321. (b) Agrawal, N.; Mishra, P. Med. Chem. Res. 2018, 27, 1309.
4. [4]
  (a) Pinho, M.; Teresa, M. V. D. Curr. Org. Chem. 2005, 9, 925. (b) Kaur, K.; Kumar, V.; Sharma, A. K.; Gupta, G. K. Eur. J. Med. Chem. 2014, 77, 121. (c) Hu, F.; Szostak, M. Adv. Synth. Catal. 2015, 357, 2583. (d) Morita, T.; Yugandar, S.; Fuse, S.; Nakamura, H. Tetrahedron Lett. 2018, 59, 1159.
5. [5]
  (a) Fluorine in Medicinal Chemistry and Chemical Biology, Eds.: Ojima, I., Wiley-Blackwell, Chichester, UK, 2009. (b) Isanbora, C.; O'Hagan, D. J. Fluorine Chem. 2006, 127, 303.
6. [6]
  (a) Peng, W.-M.; Zhu, S.-Z. Acta Chim. Sinica 2003, 61, 455. (彭卫民, 朱仕正, 化学学报, 2003, 61, 455.) (b) Kumar, V.; Kaur, K. J. Fluorine Chem. 2015, 180, 55.
7. [7]
  (a) Bumgardner, C. L.; Sloop, J. C. J. Fluorine Chem. 1992, 56, 141. (b) Sloop, J. C.; Bumgardner, C. L.; Loehle, W. D. J. Fluorine Chem. 2002, 118, 135.
8. [8]
  (a) Stephens, C. E.; Blake, J. A. J. Fluorine Chem. 2004, 125, 1939. (b) Sato, K.; Sandford, G.; Shimizu, K.; Akiyama, S.; Lancashire, M. J.; Yufit, D. S.; Tarui, A.; Omote, M.; Kumadaki, I.; Harusawa, S.; Ando, A. Tetrahedron 2016, 72, 1690.
9. [9]
  Jeong, Y.; Kim, B.-I.; Lee, J. K.; Ryu, J.-S. J. Org. Chem. 2014, 79, 6444. doi: 10.1021/jo5008702
10. [10]
  (a) Dighe, S. U.; Mukhopadhyay, S.; Kolle, S.; Kanojiya, S.; Batra, S. Angew. Chem., Int. Ed. 2015, 54, 10926. (b) Yuan, X.; Yao, J.-F.; Tang, Z.-Y. Org. Lett. 2017, 19, 1410.
11. [11]
  (a) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119. (b) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. Chem. Rev. 2015, 115, 931. (c) Shen, Q.; Huang, Y.-G.; Liu, C.; Xiao, J.-C.; Chen, Q.-Y.; Guo, Y. J. Fluorine Chem. 2015, 179, 14.
12. [12]
  Ohtsuka, Y.; Uraguchi, D.; Yamamoto, K.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2016, 181, 1. doi: 10.1016/j.jfluchem.2015.10.013
13. [13]
  Okamoto, K.; Nanya, A.; Eguchi, A.; Ohe, K. Angew. Chem., Int. Ed. 2018, 57, 1039. doi: 10.1002/anie.201710920
14. [14]
  CCDC 1843944 contains the supplementary crystallographic data for this compound 2f, these data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
15. [15]
  (a) Watterson, S. H.; Guo, J.; Spergel, S. H.; Langevine, C. M.; Moquin, R. V.; Shen, D. R.; Yarde, M.; Cvijic, M. E.; Banas, D.; Liu, R.; Suchard, S. J.; Gillooly, K.; Taylor, T.; Rex-Rabe, S.; Shuster, D. J.; McIntyre, K. W.; Cornelius, G.; D'Arienzo, C.; Marino, A.; Balimane, P.; Warrack, B.; Salter-Cid, L.; McKinnon, M.; Barrish, J. C.; Carter, P. H.; Pitts, W. J.; Xie, J.; Dyckman, A. J. J. Med. Chem. 2016, 59, 2820. (b) Hou, X.; Zhang, H.; Chen, B.-C.; Guo, Z.; Singh, A.; Goswami, A.; Gilmore, J. L.; Sheppeck, J. E.; Dyckman, A. J.; Carter, P. H.; Mathur, A. Org. Process Res. Dev. 2017, 21, 200.
16. [16]
  (a) Menozzi, G.; Schenone, P.; Mosti, L. J. Heterocycl. Chem. 1983, 20, 645. (b) Strah, S.; Golobič, A.; Golobič, L.; Stanovnik, B. J. Heterocycl. Chem. 1997, 34, 1511. (c) Tang, X.-H.; Hu, C.-M. J. Fluorine Chem. 1995, 74, 9. (d) Ohtsuka, Y.; Uraguchi, D.; Yamamoto, K.; Tokuhisa, K.; Yamakawa, T. Tetrahedron 2012, 68, 2636. (e) Xu, L.; Zhang, Q.; Xie, Q.; Huang, B.; Dai, J.-J.; Xu, J.; Xu, H.-J. Chem. Commun. 2018, 54, 4406.
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