One-Pot Synthesis of Novel Isoxazoline, Pyrazines, Bypyrimidine and Oxime Templates

Abstract

Retrieval of low bioactivity phytochemicals and activity optimization through semi-synthetic derivatization is currently the most promising route to drug development. The flavonoids, especially chalcones, from Polygonum senegalense are biologically active. However, they have not been commercialized as drugs because of their low therapeutic value, as guided by the World Health Organization (WHO). In the current study, the flavonoids were derivatised to new isoxazoline, pyrazole, oxime, and bypyrimidine. Two isoxazoline analogues, 4-(4,5-dihydro-5-phenylisoxazol-3-yl)-5-methoxybenzene-1,3-diol (1), and 2-(4,5-dihydro-3-phenylisoxazol-5-yl)-3,6-dimethoxyphenol (2) were successfully afforded by reactions of two chalcones, (E)-1-(2,4-dihydroxy-6-methoxyphenyl)-3-phenyprop-2-en-1-one and (E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-en-1-one with hydroxylamine hydrochloride in pyridine respectively.  A similar reaction between 1',4'-dihydroxy-6'-methoxychalcone (or (E)-1-(2,4-dihydroxy-6-methoxyphenyl)-3-phenyprop-2-en-1-one) and hydroxylamine hydrochloride in ethanol, adopted for synthesis of oxazole derivative, yielded an oxime instead (3). to introduce heteroatomic Sulphur on a six-membered ring and obtain a bypyrimidine derivative, 4,5-dihydro-6-(2,4- dihydroxy-3,6-dimethoxyphenyl)-4-phenylpyrimidine-2-(1H)-thione (4) -unsaturated chalcone was reacted with thiourea. The structure elucidation was done using ESIHRMS, ¹H-NMR, ¹³C-NMR, and DEPT spectral data analyses.  The study revealed that it is possible to generate several semi-synthetic products, most of which are heterocyclic, with improved functionality and bioactivity from natural products by leveraging -unsaturation and other active sites.