40.1.8 Product Subclass 8: Piperazines

Abstract

AbstractThe piperazine unit is widely distributed in natural products and life-saving small-molecule pharmaceuticals. It is the third most common nitrogen heterocycle occurring in pharmaceuticals approved by the U. S. Food and Drug Administration. This chapter covers strategies for the synthesis and transformations of piperazines, with both classical methods and recent developments reviewed. A major focus is on cyclization reactions such as intramolecular hydroaminations, multicomponent approaches, and routes from ethane-1,2-diamine substrates. Also discussed are approaches based on hydrogenation of (hydro)pyrazines by heterogeneous catalysis and by (asymmetric) homogeneous catalysis. Finally, a variety of transformations involving modification of a substituent on a piperazine ring are surveyed, including arylations, alkylations, and oxidations.