Five-component synthesis of dihydropyridines based on diketene

The 1,4-dihydropyridine (1,4-DHP) skeleton is one of the most versatile heterocyclic pharmacophores since it has been found as the central fragment in many clinical pharmaceuticals.[1] The most notable examples are the series of 1,4-DHP-based calcium channel blocker drugs such as nifedipine, felodipine, and nicardipine, which are still widely prescribed for the treatment of hypertension and related cardiovascular diseases.[1,2] In addition, the results obtained from a study with 1,4- DHPs as an a1aadrenoceptorselective antagonist discloses their promising potential in treating benign prostatic hyperplasia.[3] A novel five-component strategy involving commercially available diketene, primary amines, malononitrile and various benzaldehydes for the synthesis of densely functionalized 1,4-dihydropyridines in good yields was achieved. The reaction pathway involves a sequential ring-opening of diketene/enamine formation/Knoevenagel-condensation/Michael addition and 6-exo-tet cyclization,resulting in multiple bond-formation events including two C-C and three C-N bonds ultimately leading to the formation of the respective 1,4-dihydropyridines.