Biologically active compounds through catalysis: efficient synthesis of N-(heteroarylcarbonyl)-N'-(arylalkyl)piperazines.
A practical route for the synthesis of new biologically active 5-HT(2 A) receptor antagonists has been developed. In only three catalytic steps, this class of central nervous system (CNS) active compounds can be synthesized efficiently with high diversity. As the initial step, an anti-Markovnikov addition of amines to styrenes provides an easy route to N-(arylalkyl)piperazines, which constitute the core structure of the active molecules. Here, base-catalyzed hydroamination reactions of styrenes with benzylated piperazine proceeded in high yield even at room temperature. After catalytic debenzylation, the free amines were successfully carbonylated with different aromatic and heteroaromatic halides and carbon monoxide to yield the desired compounds in good to excellent yields. The two key reactions, base-catalyzed hydroamination of styrenes and palladium-catalyzed aminocarbonylation of haloarenes/heterocycles, showed tolerance towards various functional groups, thereby demonstrating the potential to synthesize a wide variety of new derivatives of this promising class of pharmaceuticals.
Kumar
Kamal
K
Leibniz-Institut für Organische Katalyse an der Universität Rostock e.V., Buchbinderstrasse 5-6, 18055 Rostock, Germany.
Michalik
Dirk
D
Garcia Castro
Ivette
I
Tillack
Annegret
A
Zapf
Alexander
A
Arlt
Michael
M
Heinrich
Timo
T
Böttcher
Henning
H
Beller
Matthias
M
D000586:Amination; D002384:Catalysis; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology
D010879:Piperazines; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D010165:Palladium