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Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic Chemistry
Volume 38, 2008 - Issue 21
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Original Articles

Practical Synthesis of 1-(7-Fluoro-naphthalen-1-yl)piperazine Hydrochloride

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Pages 3631-3639 | Received 18 Apr 2008, Published online: 14 Oct 2008
 

Abstract

A practical and scalable preparation of 1-(7-fluoronaphthalen-1-yl)-piperazine hydrochloride (1) is reported. The original route for the synthesis of this compound involved the use of 1-amino-7-fluoronaphthalene and bis(2-chloroethyl)amine hydrochloride, two highly toxic compounds. A new protocol has been developed that employs a palladium-catalyzed Buchwald–Hartwig cross-coupling reaction between 1-Boc-piperazine and 1-bromo-7-fluoronaphthalene followed by piperazine deprotection with HCl gas. In addition, an efficient palladium removal protocol allowed for the preparation of the target molecule with less than 20 ppm of this metal. This methodology has been successfully implemented to produce multigram quantities of 1 with excellent purity and low palladium content.

ACKNOWLEDGMENTS

We thank Dr. Nabil Ghazal for providing information on this methodology and for helpful discussions during the implementation of this project. We also thank Drs. Dan Belmont, Sally Gut, Cheryl Hayward, Russ Linderman, and John Ragan for reviewing this manuscript.

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