Biologically Active Compounds through Catalysis: Efficient Synthesis of N-(Heteroarylcarbonyl)-N′-(arylalkyl)piperazines

Kamal Kumar, Dirk Michalik, Ivette Garcia Castro, Annegret Tillack, Alexander Zapf, Michael Arlt, Timo Heinrich, Henning Böttcher, Matthias Beller

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

A practical route for the synthesis of new biologically active 5-HT 2A 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.

Original languageEnglish
Pages (from-to)746-757
Number of pages12
JournalChemistry - A European Journal
Volume10
Issue number3
DOIs
StatePublished - 6 Feb 2004
Externally publishedYes

Keywords

  • Amphetamines
  • Carbonylation
  • Homogeneous catalysis
  • Hydroamination
  • Palladium

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