Recent Advances in Piperazine Synthesis

Piperazine ranks as the third most common N-heterocycle appearing in small-molecule pharmaceuticals. This review highlights recent advances in methods development for the construction of the piperazine­ ring system with particular emphasis on preparing carbon-substituted piperazines. 1 Introduction 2 Reduction of (Di)ketopiperazine 3 N-Alkylation 4 Transition-Metal-Catalyzed/Mediated Piperazine Synthesis 4.1 The SnAP and SLAP Methods 4.2 Palladium-Catalyzed Cyclization 4.3 Gold-Catalyzed Cyclization 4.4 Other Metal-Catalyzed/Mediated Cyclization 4.5 Borrowing Hydrogen Strategy 4.6 Imine Reductive Cyclization 5 Reduction of Pyrazines 6 Miscellaneous 7 Conclusion