Synthesis and cytotoxicity evaluation of 2-benzoylbenzoxazoles by Reaction of o-aminophenol with Acetophenone Catalyzed by Sulfur in DMSO
Main Article Content
Abstract
The 2-benzoylbenzoxazole derivatives were known for their significant biological activities such as anti-proliferative activity, inhibition of FAAH enzyme (fatty acid amide hydrolase). Synthesis of biologically active 2-benzoylbenzoxazole motifs often relies on a multi-step process or precursors carrying active groups. In this study, we report a simple and efficient method for the synthesis of such compounds by the direct reaction of o-aminophenol with acetophenone catalyzed by sulfur in DMSO. The reaction was found to take place via benzoxazolation in the Willgerodt rearrangement of acetophenone, followed by benzylic oxidation to restore the carbonyl functional group. With the optimized reaction conditions, we have synthesized a number of 2-benzoylbenzoxazoles 3aa - 3ae derivatives with good yield from 60 to 75%. Several synthetic derivatives have shown cancer cell growth inhibitory activity with IC50 values ranging from 36.37 to 56.08 µM. The cytotoxicity of some resulting compounds was evaluated and showed that the ellipticine positive control was stable in the experiment.
Keywords
benzoylbenzoxazole, Willgerodt, sulfur, DMSO, oxidation
Article Details
References
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6. T. Guntreddi, R. Vanjari, S. Kumar, R. Singh, N. Singh, P. Kumar, K. N. Singh, Elemental sulfur mediated synthesis of benzoxazoles, benzothiazoles and quinoxalines via decarboxylative coupling of 2-hydroxy/mercapto/amino-anilines with cinnamic acids, RSC Adv., 6, 81013-81016, 2016. https://doi.org/10.1039/C6RA17491D
7. T.B. Nguyen, P. Retailleau, Elemental sulfur-promoted oxidative rearranging coupling between o-aminophenols and ketones: a synthesis of 2-alkyl benzoxazoles under mild conditions, Org. Lett., 19, 3887, 2017. https://doi.org/10.1021/acs.orglett.7b01775
8. T.B. Nguyen, J. Cheung-Lung, Iron-catalyzed sulfur-promoted decyanative redox condensation of o-nitrophenols and arylacetonitriles: an unprecedented route to 2-arylbenzoxazoles, Eur. J. Org. Chem., 5815, 2018. https://doi.org/10.1002/ejoc.201701607
9. T. B. Nguyen, L. Ermolenko, W. A. Dean, A. Almourabit, Benzazoles from aliphatic amines and o-amino/mercaptan/hydroxyanilines: elemental sulfur as a highly efficient and traceless oxidizing agent, Org. Lett., 14, 5948, 2012. https://doi.org/10.1021/ol302856w
10. Z. Li, J. Dong, J. Wang, D. Yang, Z. Weng, Elemental sulfur-promoted one-pot synthesis of 2-(2,2,2-trifluoroethyl)-benzoxazoles and their derivatives, Chem. Commun., 55, 13132, 2019. https://doi.org/10.1039/C9CC06822H
11. N. Aljaar, R. Gujjarappa, M. Al-Refai, M. Shtaiwi, C. C. J. Malakar, Overview on recent approaches towards synthesis of 2-keto-annulated oxazole derivatives, Heterocycl. Chem., 56, 2730, 2019. https://doi.org/10.1002/jhet.3673
12. H. Wang, J. Liu, J. P. Qu, Y. B. Kang, Overcoming electron-withdrawing and product-inhibition effects by organocatalytic aerobic oxidation of alkylpyridines and related alkylheteroarenes to ketones, J. Org. Chem., 85, 394, 2020. https://doi.org/10.1021/acs.joc.9b03205
13. J. Kumar, A. Gupta, S. Bhadra, Pd II-Catalyzed methoxylation of C (sp 3)–H bonds adjacent to benzoxazoles and benzothiazoles, Org. Biomol. Chem., 17, 3314, 2019. https://doi.org/10.1039/C9OB00337A