Facile construction of densely functionalized 4H-chromenes via three-component reactions catalyzed by l-proline

Abstract

Three-component reactions of salicylaldehydes, 1,3-cyclohexanediones and a sulfur, carbon, or nitrogen-based nucleophile were developed, for the first time, by using L-proline as a catalyst, which generated various substituted 4H-chromene derivatives in good to excellent yields. The reactions were performed in ethanol under mild and metal-free conditions. In these reactions, the use of L-proline as a catalyst was proven to be key for rendering the reactions possible because replacing L-proline with other acids or bases resulted in the generation of many side products. Many nucleophiles, such as thiophenols, mercaptans, indoles, sulfinic acid, benzotriazole, 2-naphthol, 5-methyl-2-phenyl-1,2-dihydropyrazol-3-one, 6-aminouracil, 6-amino-1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione and some commonly used C–H acids including 4-hydroxycoumarin, 2-hydroxy-1,4-naphthoquinone and barbituric acid could be successively used to assemble with dimedone and salicylaldehyde. Particularly, the product generated from the reaction of benzotriazole, 3-methoxysalicylaldehyde and dimedone can also be used as a starting material, in which the fragment of benzotriazole acts as a leaving group, for the synthesis of some important compounds by reacting with many carbon-based nucleophiles, such as dibenzoylmethane, ethyl benzoylacetate, 1,3-cyclohexanedione, N,N-dimethylaniline, 2-methylfuran and sesamol in acidic conditions. This offers a complementary route to access some 4H-chromenes that cannot be attained with the above-mentioned three-component reactions.