An Efficient Synthesis of a Dual PPAR α/γ Agonist and the Formation of a Sterically Congested α-Aryloxyisobutyric Acid via a Bargellini Reaction

• Published in: Journal of organic chemistry Vol. 70; no. 21; pp. 8560 - 8563
• Main Authors: Cvetovich, Raymond J, Chung, John Y. L, Kress, Michael H, Amato, Joseph S, Matty, Louis, Weingarten, M. David, Tsay, Fuh-Rong, Li, Zhen, Zhou, George
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.10.2005; Amer Chemical Soc
• Subjects: Butyrates - chemical synthesis; Butyrates - chemistry; Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Molecular Structure; Organic chemistry; Physical Sciences; PPAR alpha - agonists; PPAR gamma - agonists; Preparations and properties; Propionates - chemical synthesis; Propionates - chemistry; Science & Technology; BENZOXAZOLES; OXIMES; AGENTS; DERIVATIVES; BECKMANN REARRANGEMENT; CHLORIDE; Isobutyric acid; Agonist; Steric hindrance; Oxime; Aromatic compound; Fluorine Organic compounds; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo051027+

A practical synthesis of benzisoxazole 1 and its conversion to α-aryloxyisobutyric acid 2 using 1,1,1-trichloro-2-methyl-2-propanol (chloretone) was developed. Benzisoxazole 1 was formed in high yields by the action of either methanesulfonyl chloride/base upon intermediate oxime 8 or with thionyl chloride/base, which initially forms cyclic sulfite 10. A highly reactive, short-lived intermediate derived from chloretone was detected by ReacIR and its half-life determined to be ∼5 min. Reaction conditions for the Bargellini reaction were developed that resulted in a 95% yield of 2 from the reaction of highly hindered phenol 1 with chloretone hemihydrate and powdered NaOH in acetone. Thus highly hindered α-aryloxyisobutyric acids can be made in a single step in high yield.