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

• Published in: Chemistry : a European journal Vol. 10; no. 3; pp. 746 - 757
• Main Authors: Kumar, Kamal, Michalik, Dirk, Garcia Castro, Ivette, Tillack, Annegret, Zapf, Alexander, Arlt, Michael, Heinrich, Timo, Böttcher, Henning, Beller, Matthias
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 06.02.2004; WILEY‐VCH Verlag; Wiley
• Subjects: Amination; amphetamines; carbonylation; Catalysis; Chemistry; Chemistry, Multidisciplinary; homogeneous catalysis; hydroamination; Molecular Structure; palladium; Palladium - chemistry; Physical Sciences; Piperazines - chemical synthesis; Piperazines - pharmacology; Science & Technology; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - pharmacology; UNSATURATED-COMPOUNDS; BETA-PHENYLETHYLAMINES; ANTI-MARKOVNIKOV-FUNCTIONALIZATIONS; amphetamines; hydroamination; FINE CHEMICALS; homogeneous catalysis; COUPLING REACTIONS; AROMATIC OLEFINS; ARYL HALIDES; TRANSITION-METAL; palladium; carbonylation; OXIDATIVE AMINATION
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200305327

A practical route for the synthesis of new biologically active 5‐HT2 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. Just three catalytic steps are required to synthesize a variety of 5‐HT2 A receptor antagonist molecules, which are otherwise very expensive and tedious to produce. Starting with substituted styrenes and piperazines, an easy and cheap route to the potentially active molecules has been developed (see scheme). The target molecules were obtained in good to excellent overall yields through the use of base‐catalyzed hydroamination and Pd‐catalyzed aminocarbonylation as the key reaction steps.