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Synfacts 2006(2): 0184-0184  
DOI: 10.1055/s-2005-921770
Polymer-Supported Synthesis
© Georg Thieme Verlag Stuttgart · New York

Gram-Scale Synthesis of N-Aryl- and N-Aryl-N¢-methylpiperazines on PEG

Contributor(s): Yasuhiro Uozumi, Ray Kawade, Toshimasa Suzuka
H. C. Rudbeck, I. Johannsen, O. Nielsen, T. Ruhland, M. B. Sommer, D. Tanner, R. Dancer*
H. Lundbeck A/S, Valby, VersaMatrix A/S, Valby and Technical University of Denmark, Lyngby, Denmark
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Publication History

Publication Date:
23 January 2006 (online)

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Significance

A new methodology for the gram-scale synthesis of N-arylpiperazines was developed. Thus, bis(chloroethyl)amine anchored on PEG resin 2 was prepared from chloroformate 1 with bis(chloroethyl)amine hydrochloride salt. The reaction resin 2 and 3,4-disubstituted anilines proceeded at 100 ºC to give the corresponding resin-bound N-arylpiperazines 3a-d. Reductive cleavage of the piperazine moieties of 3a-d with lithium aluminum hydride gave N-aryl-N¢-methylpiperazines 4a-d in low to moderate yields. The desired N-arylpiperidine oxalates 5a-d were obtained in low yields by base-mediated cleavage of 3a-d using potassium tert-butoxide.