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

Abstract

A practical synthesis of benzisoxazole 1 and its conversion to alpha-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 approximately 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 alpha-aryloxyisobutyric acids can be made in a single step in high yield.

Recent applications of gem-dichloroepoxide intermediates in synthesis

“…However, researchers at Merck thoroughly investigated several procedures for the preparation of dual PPAR α/ agonist 54 and found the direct conversion of benzisoxazole 53 to target 54 by way of an optimized Bargellini reaction offered superior results in terms of yield and step economy (Scheme 14). 31 Mesityl oxide formation and exothermicity were not problematic under the optimized conditions. During their investigation, the authors also established the half-life of the presumptive kinetically reactive 1,1-dichloro-2,2-dimethyloxirane in basic acetone as approximately five minutes based upon ReactIR studies.…”

Efficient and Versatile Synthesis of 2,3-Dialkylimidazo[4,5-b]quinolin-9-ols by Microwave-Assisted One-Pot Beckmann Rearrangement

“…Yield: 11%; waxy solid; R f = 0.11 (CH 2 Cl 2 -MeOH, 30:1 152.082, 150.226, 146.126, 128.608, 126.810, 124.918, 122.213, 119.832, 113.226, 42.674, 23.022, 14.468, 11.598 13 C NMR: d = 161.748,149.544,138.381,131.617,125.730,124.644,124.384,111.038,42.340,23.408,21.824,21.202,14.730.…”

“…13 C NMR: d = 168.623,150.519,145.925,143.362,135.478,134.265,126.684,122.078,115.214,114.897,54.864,14.056.…”

“…13 C NMR: d = 166.072,150.645,146.739,144.176,134.910,125.321,122.779,121.422,125.352,111.776,54.564,35.192,31.506,30.664,18.102,14. …”

“…1 H NMR: d = 7.84 (s,1 H),7.78 (d,J = 8.7 Hz,1 H),7.62 (d,J = 8.7 Hz,1 H),10 H),5.16 (t,J = 5.7 Hz,1 H),4.45 (d,J = 5.7 Hz, 2 H), 2.65 (s, 3 H), 1.85 (s, 3 H), 1.41 (s, 9 H). 13 C NMR: d = 147.519,145.477,144.325,128.578,127.814,127.264,126.694,126.491,115.484,50.064,47.762,34.903,31.663,26.784,14. 13 C NMR: d = 167.093,151.906,149.439,142.176,130.979,128.810,125.221,121.779,118.752,114.422,42.764,22.812,22.233,11.192 13 C NMR: d = 168.992,156.249,154.218,146.971,131.266,128.005,125.147,121.638,113.906,108.408,66.880,51.187,12.566. MS (EI): m/z = 269 (M + ), 238,224,…”