Synthesis of Isoxazolylvinyl Ketones from Substituted Furans
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Synthesis of isoxazolylvinyl ketones from substituted furans Olga V. Serdyuk1*, Frank Hampel1, Vladimir T. Abaev2,3 1
Department of Chemistry and Pharmacy, Institute of Organic Chemistry I, Friedrich-Alexander University of Erlangen-Nürnberg, 10 Nikolaus-Fiebiger-St., Erlangen 91058, Germany; e-mail: [email protected] 2 North Ossetian State University named after K. L. Khetagurov, 43–46 Vatutina St., Vladikavkaz 362025, Russia 3 Department of Chemistry, North Caucasus Federal University, 1a Pushkina St., Stavropol 355009, Russia Published in Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(11), 1477–1484
Submitted October 13, 2020 Accepted November 11, 2020
A new method for the preparation of isoxazolylvinyl ketones related to potential cytotoxic agents has been developed. In the first step, the reaction of furfuryl ketones with hydroxylamine hydrochloride affords the corresponding oximes. Further, the oxidative ring opening – ring closure reaction of oximes leads to isoxazoles with an α,β-unsaturated carbonyl motif. The developed procedure is metal-free and does not require expensive starting materials. Keywords: chalcone, furan, isoxazole, ring opening – ring closure reaction.
Cancer is the second leading cause of death worldwide. In 2018, 18.1 million new cases and 9.6 million cancer deaths were reported according to the World Health Organization.1 Despite of the huge breakthroughs in the development of anticancer drug therapy, some drawbacks, e.g., high toxicity of anticancer agents toward normal cells and the rise of multidrug resistance, remain. Therefore, the discovery of new effective cytotoxic agents is still highly desired.2 Isoxazole derivatives are known to reveal promising activity against breast cancer (MCF-7), prostate cancer (PC3),3 the human central nervous system glioma (SNB-19),4 lung adenocarcinoma (A549), colon cancer (Colo-205),5 and other tumor cell lines.6 In medicinal chemistry, chalcones and their heterocyclic analogs bearing α,β-unsaturated fragments are known as important scaffolds with potent anticancer activity.7 In particular, isoxazolylvinyl ketones and isoxazole-chalcones demonstrate activity against lung cancer cell lines H1792, H157, A549, Calu-18 and prostate DU-145 cancer cell lines (Fig. 1).9 Additionally, the enone motif in these structures can be further modified, giving access to various linked heterocycles. We have recently reviewed application of this concept to some related systems through functionalization of the enone fragment.10 Since the common approach to heterocyclic chalcones is the Claisen–Schmidt conden0009-3122/20/56(11)-1477©2020 Springer Science+Business Media, LLC
sation, the discovery of new cytotoxic agents based on chalcone scaffold has long been focused on easily available heterocyclic aldehydes and ketones.8,9 To the best of our knowledge, the only isoxazole-chalcones that have been reported up to now are those depicted in Figure 1. We suggested that easily available furfuryl ketones 111 could serve as a starting point for the synthesis of isoxazolylvi
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