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.
Evdokimov
Nikolai M
NM
Department of Organic Chemistry, Timiryazev Agriculture Academy, Moscow 127550, Russia.
Kireev
Artem S
AS
Yakovenko
Andrey A
AA
Antipin
Mikhail Yu
MY
Magedov
Igor V
IV
Kornienko
Alexander
A
D000447:Aldehydes / Q000737:chemistry*; D002625:Chemistry, Organic / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D004095:Dihydropyridines / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods
D000447:Aldehydes; D004095:Dihydropyridines; D006571:Heterocyclic Compounds; D009570:Nitriles; D011725:Pyridines; D013438:Sulfhydryl Compounds; C038806:1,4-dihydropyridine; C000945:dicyanmethane; C023666:pyridine