Tetrahydropyranoquinolinone via a Knoevenagel Reaction

Significance

Reported is the synthesis of 2-amino-3-cyano-1,4,5,6-tetrahydropyrano[3,2-c]quinolin-5-ones via a mild ammionium acetate catal­yzed multicomponent cyclodehydration. Exami-nation of potential catalyst systems showed that a wide range of protic (e.g. TsOH) and Lewis acid (e.g. ZnCl₂) catalysts had no demonstrable efficacy in the desired process. However, basic (e.g. Et₃N) or neutral (e.g. ammonium acetate) systems were shown to afford the desired product in good yield and short reaction times. Investigation of catalyst loading revealed that yields were not significantly increased at levels above 20 mol%. Solvent screens established the suitability of ethanol and DMF for the transformation. Examination of the substrate scope demonstrated that variation of the aldehyde component was well tolerated across both aromatic and aliphatic examples.