5 - Category Ii Cyclization—The Hemetsberger Synthesis

Abstract

A solution of sodium methoxide (25% w, 115 ml, 532 mmol) in methanol (187 ml) was cooled to -8 OC under nitrogen. A solution of 2,4,5-trimethoxybenzaldehyde (25 g, 128 mmol) and methyl azidoacetate (59 g, 513 mmol) in a 1:2 mixture of methanol–THF (50ml + 100ml) was added dropwise to the sodium methoxide solution with stirring at 8OC over a period of 45 min. The solution was stirred and kept below 5 OC for 2 h. The mixture was then poured onto ice (1 kg) and stirred. The precipitate, which resulted was collected by filtration, washed with water and dried over CaCl2 in a vacuum desiccator. The dried precipitate was dissolved in EtOAc (600ml) and dried over Na2SO4. Evaporation of the solvent gave the product as bright yellow crystals (27.6 g) in 74% yield. The cinnamate ester prepared as above (23.2 g, 79 mmol) was added as a solid slowly to refluxing xylene (500 ml) over a period of 3 h at a rate that prevented accumulation of unreacted azidocinnamate in the solution. The reaction mixture was cooled and the solvent removed in vacuo. The residue was recrystallized from methanol to give pure product (20.7 g, 99% yield).