Ring-Opening Fluorination of Isoxazoles
Masaaki Komatsuda, Hugo Ohki, Hiroki Kondo Jr., Ayane Suto and Junichiro Yamaguchi*
*Department of Applied Chemistry, Waseda University, 513 Wasedatsurumakicho, Shinjuku, Tokyo 162-0041, Japan,
Email: junyamaguchi
waseda.jp
M. Komatsuda, H. Ohki, H. Kondo Jr., A. Suto, J. Yamaguchi, Org. Lett., 2022, 24, 3270-3274.
DOI: 10.1021/acs.orglett.2c01149
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Abstract
A convenient reaction of isoxazoles with an electrophilic fluorinating agent (Selectfluor) provides tertiary fluorinated carbonyl compounds under mild reaction conditions and with good functional group tolerance. Diverse transformations of the resulting α-fluorocyanoketones furnish a broad range of fluorinated compounds.
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Details
The document discusses the development of a ring-opening fluorination method for isoxazoles, resulting in tertiary fluorinated carbonyl compounds. This process uses an electrophilic fluorinating agent, Selectfluor, under mild conditions with good functional group tolerance. The method efficiently converts isoxazoles into α-fluorocyanoketones, which can undergo various transformations to produce diverse fluorinated compounds. The study highlights the importance of fluorine in pharmaceuticals due to its unique properties, such as higher liposolubility and metabolic stability. The research explores different fluorinating agents and reaction conditions, finding that Selectfluor at 80°C in MeCN yields the best results. The substrate scope includes various 4-methylisoxazoles with different substituents at the C5 position, showing good yields and functional group compatibility. The study also examines the reactivity of 5-phenylisoxazoles and C3-substituted isoxazoles, noting that the reaction requires C4-substituted isoxazoles for successful ring-opening fluorination. The document concludes with the potential for further studies to expand the generality of this functionalization method using other aromatic compounds and electrophilic participants.
Key Words
fluorides, nitriles, isoxazoles, Selectfluor
ID: J54-Y2022
