title: Biologically active compounds through catalysis: efficient synthesis of N-(heteroarylcarbonyl)-N'-(arylalkyl)piperazines.
abstract: 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.
authors.affiliation: Leibniz-Institut für Organische Katalyse an der Universität Rostock e.V., Buchbinderstrasse 5-6, 18055 Rostock, Germany.
authors.forename: Kamal
authors.initials: K
authors.lastname: Kumar
authors.forename: Dirk
authors.initials: D
authors.lastname: Michalik
authors.forename: Ivette
authors.initials: I
authors.lastname: Garcia Castro
authors.forename: Annegret
authors.initials: A
authors.lastname: Tillack
authors.forename: Alexander
authors.initials: A
authors.lastname: Zapf
authors.forename: Michael
authors.initials: M
authors.lastname: Arlt
authors.forename: Timo
authors.initials: T
authors.lastname: Heinrich
authors.forename: Henning
authors.initials: H
authors.lastname: Böttcher
authors.forename: Matthias
authors.initials: M
authors.lastname: Beller
mesh_terms: 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
chemical_list: D010879:Piperazines; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D010165:Palladium