Oxazole Synthesis

An easy synthesis of 5-trifluoromethylated oxazole compounds as a building block which would be able to transform into effectively useful pharmaceuticals or chemicals can be achieved to improve the practical use. In this study, we describe the new synthesis of methyl 5-trifluoromethyl-2-phenyloxazole-4-carboxylate which derived from 4-alkoxy oxazole in one-pot by utilizing Cornforth rearrangement. At this time, we took an interest in the experimental result that no precursors of rearrangement were detected in this reaction. The strategy of designing and synthesizing compounds that inhibited reclosure from nitrile ylide resulted in successful capture of unstable precursors.

Introduction

The methods which substitute fluorine for proton at an

Namely, we would be able to prepare compounds (3) as precursors for Cornforth rearrangement reaction from 2-aryloxazoles (2) which are obtained by cyclization of the corresponding glycine (1). Then compounds (3) would be transformed to compounds (4) by optimization of the reaction conditions. First, 2-aryl-5-methoxyoxazoles (2) were prepared by the method of Wipf’s protocol12) from methyl N-arylcarbonyl glycine methyl esters (1) in the presence of Et3N in DCE with PPh3 and I2 at room temperature for 19-24hr. This reaction proceeded in mild condition and afforded compound (2) in 80-97% yield by column chromatography (Table 1). Subsequently, we attempted preliminary examination by choosing 5-methoxy -2-phenyl oxazole (2a) as starting material to proceed whether Friedel–Crafts reaction. Although the normal conditions which used Lewis acid such as AlCl3 or TiCl4 with TFAA in DCE did not proceed to acylation, the reaction of introducing trifluoroacetyl group at the C4-position of oxazole without Lewis acid gave substituted oxazole (4a). Contrary to our expectations, isolated oxazole had been not trifluoroacetylated derivative (3a), reaching rearrangement compound (4a) in one step．After our optimization of the acylated condition, the use of 1.3 equivalents of TFAA and THF as a solvent and condition of the temperature at 60 degrees for 22 hr led 90%