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.

Formal anti-Markovnikov hydroamination of terminal olefins

“…12 More recently, some success in the metal-catalyzed intermolecular anti-Markovnikov hydroamination of unactivated olefins has been reported. For example, the Hultzsch and Beller groups have both performed the base-catalyzed anti-Markovnikov hydroamination of styrenes using LiN(SiMe 3 ) 2 and TMEDA 13 or n -BuLi 14 catalytic systems. Similarly, the Hartwig group has reported the rhodium-catalyzed anti-Markovnikov hydroamination of styrenes with secondary amines, 15 while the Marks group has demonstrated that organolanthanide-catalysis is conducive to the anti-Markovnikov hydroamination of styrenes and two additional substrates bearing directing groups.…”

A Formal Total Synthesis of Taxol Aided by an Automated Synthesizer

“…Since the first report of a solid‐phase synthesis by Merrifield,2 simply repeated cycles of coupling reactions and deprotections have been applied to the automated syntheses of biopolymers such as oligopeptides,2 oligonucleotides,3 and, more recently, oligosaccharides 4. 5 In recent years, automation has also been utilized for applications such as the optimization of reaction conditions, routine syntheses of structurally similar compounds, such as building blocks for combinatorial synthesis,6 and the bulk synthesis of important intermediates. In the total syntheses of complex molecules, however, one needs long sequences that include not only simple transformations but also challenging key reactions.…”

Lithium‐Catalyzed anti‐Markovnikov Intermolecular Hydroamination Reactions of Vinylarenes and Simple Secondary Amines

“…Although the field of alkali‐metal‐promoted hydroamination emerged in the early 1950s, most of the reported studies have been limited in terms of scope to a few amine/olefin partners and have been conducted under harsh reactions conditions. It was only recently that the groups of Beller and later Hultzsch truly explored the scope of the alkali‐metal‐catalyzed anti‐Markovnikov hydroamination of vinylarenes with N ‐benzylpiperazine and primary/secondary amines, respectively, under gentler conditions (Scheme ). Besides the fact that these studies provided useful protocols for the preparation of a range of linear amine products, there is still room for improvement in terms of catalyst efficiency and scope.…”

“…and styrene (2 equiv.) catalyzed by n BuLi (20 mol %) in THF at room temperature provided the linear product in 80 % yield after 24 h …”