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Synthesis 2010(17): 2859-2883  
DOI: 10.1055/s-0030-1257906
REVIEW
© Georg Thieme Verlag Stuttgart ˙ New York

Piperazine Scaffolds via Isocyanide-Based Multicomponent Reactions

Alexander Dömling*, Yijun Huang
University of Pittsburgh, Drug Discovery Institute, Pittsburgh, PA 15261, USA
Fax: +1(412)3835298; e-Mail: asd30@pitt.edu;
Further Information

Publication History

Received 25 March 2010
Publication Date:
30 July 2010 (online)

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Abstract

Piperazine scaffolds are amongst the most extensively used backbones in medicinal chemistry and many bioactive compounds are built upon this template. The physicochemical properties and the three-dimensional structures of the different piperazine chemotypes are of utmost importance to understanding its biological activities. Knowing the synthetic access to this chemical space of piperazines is of great importance to designing compounds with better properties. Isocyanide-based multicomponent reactions (IMCRs) allow for the truly convergent and efficient access to not less than 35 different piperazine derived scaffolds. These are reviewed, and their scopes and limitations are discussed.

1 Piperazine Scaffolds in Chemistry and Medicine

2 Chemical Space of Piperazines via Isocyanide-Based ­Multicomponent Reactions

3 Monocyclic Piperazines

3.1 Piperazine

3.2 Ketopiperazine

3.3 2,5-Diketopiperazine

3.4 2,6-Diketopiperazine

4 Bicyclic Fused Piperazines

5 Polycyclic Fused Piperazines

6 Introduction of the Piperazine Moiety via a Starting ­Material

7 Conclusions and Outlook

Key words

piperazine - diketopiperazine - heterocycles - multicomponent reaction - isocyanide

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3

Khoury, K.; Dömling, A.; ChemMedChem in press.

4

Dömling, A.; Wang, K.; Wang, W. Chem. Rev. submitted for publication.

63

Liu, H. X.; William, S.; Herdtweck, E; Botros, S.; Dömling, A. Bioorg. Med. Chem. submitted for publication.

64

Cao, H.; Liu, H. X.; Dömling, A. Chem. Eur. J. in press