One-Step Synthesis of Heterocyclic Privileged Medicinal Scaffolds by a Multicomponent Reaction of Malononitrile with Aldehydes and Thiols

Heterocyclic privileged medicinal scaffolds involving pyridine, 1,4-dihydropyridine, chromeno[2,3-b]pyridine, and dihydro-1,4-dithiepine frameworks are prepared via a single-step multicomponent reaction
of structurally diverse aldehydes with various thiols and malononitrile. Mechanistic studies of the synthetic
pathway leading to pyridines reveal that 1,4-dihydropyridines undergo oxidation by the intermediate
Knoevenagel adducts rather than by air oxygen. The use of o,o‘-disubstituted aromatic aldehydes leads
to the corresponding 1,4-dihydropyridines, whereas salicylic aldehydes result in chromeno[2,3-b]pyridines.
Reactions of ethanedithiol as a thiol component produce dimeric pyridines with sterically unencumbered
aldehydes, while o,o‘-disubstituted aromatic aldehydes give dihydro-1,4-dithiepines. Thus, depending on
the aldehyde and thiol types, diverse libraries of medicinally relevant compounds can be prepared by a
simple one-step process involving no chromatography.

包含吡啶、1,4-二氢吡啶、色烯并[2,3-b]吡啶与二氢-1,4-二噻庚因骨架的药物优势杂环骨架，可通过结构多样的醛类与各类硫醇、丙二腈的单步多组分反应制备。针对吡啶合成路径的机理研究表明，1,4-二氢吡啶是由中间体克脑文盖尔（Knoevenagel）加合物氧化得到，而非空气中的氧气。使用邻,邻'-二取代芳香醛可得到对应的1,4-二氢吡啶，而水杨醛则生成色烯并[2,3-b]吡啶。以乙二硫醇作为硫醇组分时，空间位阻较小的醛会生成二聚吡啶类化合物，邻,邻'-二取代芳香醛则得到二氢-1,4-二噻庚因类产物。综上，根据醛类与硫醇的种类差异，通过无需色谱分离的简便单步反应，即可构建各类具有药用价值的化合物库。