Synthesis of 3,4,5‐Trisubstituted Isoxazoles via Sequential [3 + 2] Cycloaddition/Silicon‐Based Cross‐Coupling Reactions.

Abstract

All reactions were performed in oven (120 °C ) and/or flame dried glassware under an atmosphere of dry nitrogen or argon, unless noted. Reaction solvents tetrahydrofuran (HPLC grade), diethyl ether (BHT stabilized ACS grade) and methylene chloride (unstabilized HPLC grade) were dried by percolation through two columns packed with neutral alumina under a positive pressure of argon. Reaction solvents hexane (OPTIMA grade) and toluene (ACS grade) were dried by percolation through a column packed with neutral alumina and a column packed with Q5 reactant, a supported copper catalyst for scavenging oxygen, under a positive pressure of argon. Reaction solvent dioxane was distilled from sodium prior to use. Reaction solvent acetonitrile (HPLC grade) was used without further purification. Solvents for filtration and chromatography were certified ACS grade. "Brine" refers to a saturated solution of sodium chloride. All reaction temperatures correspond to internal temperatures measured with Teflon coated thermocouples.1 H and 13 C NMR were recorded on a 500 MHz, 1 H and 126 MHz, 13 C spectrometer. Spectra were referenced to residual chloroform (7.26 ppm, 1 H; 77.0 ppm, 13 C). Chemical shifts Denmark and Kallemeyn S2 are reported in ppm, multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), h (hextet), m (multiplet) and br (broad). Coupling constants, J, are reported in Hertz.All 1 H and 13 C NMR assignments are corroborated by 2D experiments (HETCOR and COSY).

The synthetic and therapeutic expedition of isoxazole and its analogs

“…Various methods have been reported to prepare isoxazoles with a variety of substituents at 3, 4, and 5 positions. Denmark and Kallemeyn (2005) first synthesized isoxazolylsilanols by [3+2] cycloaddition reaction between alkynyldimethylsilyl ethers and aryl and alkyl nitrile oxides (Route a, Fig. 3).…”