Revisiting the three component synthesis of isoxazolo[5,4-b]pyridines, 4-aryl-3,7,7-trimethyl-isoxazolo[5,4-b]quinolin-5(6H)-ones and related heterocycles

The one-step three-component microwave assisted synthesis between aromatic aldehydes with tetronic acid or indan-1,3-dione readily formed the Knoevenagel adducts that underwent addition of 3-methylisoxazol-5-amine 1 to form the isoxazolo[5,4-b]pyridine products 8[a,b,d,e,g] in 67-90% yield. The multicomponent reaction using dimedone formed the respective addition products 4-aryl-3,7,7-trimethyl-isoxazolo[5,4-b]quinolin-5(6H)-ones 8[c,f,h] (36-79%). In contrast, the sonication of an aryl aldehyde and dimedone with an equivalent amount of 2-hydroxyammonium formate exclusively generated the Knoevenagel adduct 4c via hydro-4c. When microwaved either with 3-amino-5-methylisoxazole 1 or 3,4,5-trimethoxyaniline 14 in ethanoic acid-ethylacetate (1:1), tetrahydroacridones 15[a,b] formed in high yields (88-92%). Importantly, this two-step reaction sequence generates highly reproducible and pure products.