Synthesis of functionalized 4,5-dihydroisoxazoles decorated with the dimethylphosphinoyl group

Abstract

Aim. To synthesize a hybrid molecular platform incorporating dimethylphosphinoyl and 4,5-dihydroisoxazole moieties suitable for the creation of focused combinatorial libraries of compounds.Results and discussion. The base-promoted interaction of halogenoxides with dimethyl(vinyl)phosphine oxide under mild conditions allowed us to obtain 11 isoxazoline–dimethylphosphine oxide hybrids in moderate yields. The reaction was found to be regio- though non-stereoselective. Furoxans were identified as possible side products of the reaction.Experimental part. The one-pot interaction with dimethyl(vinyl)phosphine oxide was used for the synthesis of the target compounds. Nitrile oxides were obtained in situ from the corresponding halogenoximes by base-promoted generation. The ADME parameters for a synthesized 5-P(O)Me2-isoxazoline compared to its isosters with the same core structure were predicted using a SwissADME Web Tool. The compounds obtained were characterized by 1H, 13C, 19F, 31P NMR spectroscopy and HPLC-MS spectrometry methods, as well as the elemental analysis.Conclusions. A practical approach to the isoxazoline platform decorated with a 5-P(O)Me2 “magic” group and containing 3-substituent with an easy-to-modify functionality has been developed. On example of the piperidine derivative, the effect of the dimethylphosphinoyl group on physicochemical properties and ADME parameters compared to its isosters has been determined.