A novel route to 5-substituted 3-isoxazolols. Cyclization of N, O-DiBoc beta-keto hydroxamic acids synthesized via acyl Meldrum's acids.
3-Isoxazolols are most often synthesized from a beta-keto ester and hydroxylamine. This cyclization typically gives rise to a major byproduct, the corresponding 5-isoxazolone. We have found that N, O-diBoc-protected beta-keto hydroxamic acids can be synthesized and cyclized to 5-substituted 3-isoxazolols without formation of any byproduct. We present a novel and versatile three-step procedure in which carboxylic acid derivatives are converted into acyl Meldrum's acids which, upon aminolysis with N, O-bis(tert-butoxycarbonyl)hydroxylamine, lead to the N, O-diBoc-protected beta-keto hydroxamic acids. These hydroxamic acid analogues were then, upon treatment with hydrochloric acid, cyclized to the corresponding 5-substituted 3-isoxazolols.
Sørensen
U S
US
NeuroScience PharmaBiotec Research Centre, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
Falch
E
E
Krogsgaard-Larsen
P
P
D000363:Agaricales / Q000737:chemistry; D003500:Cyclization; D004146:Dioxanes / Q000737:chemistry* / Q000378:metabolism; D018755:GABA Agonists / Q000138:chemical synthesis; D006851:Hydrochloric Acid / Q000378:metabolism; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000378:metabolism; D007306:Insecticides / Q000138:chemical synthesis; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009118:Muscimol / Q000138:chemical synthesis
D004146:Dioxanes; D018755:GABA Agonists; D006877:Hydroxamic Acids; D007306:Insecticides; D007555:Isoxazoles; D009118:Muscimol; C076489:Meldrum's acid; D006851:Hydrochloric Acid