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Article

Microwave-Assisted “Libraries from Libraries” Approach toward the Synthesis of Allyl- and C-Cyclopropylalkylamides

Supporting Info

Peter Wipf,*^†^§ Claire M. Coleman,^†^§ Jelena M. Janjic,^‡^§ Pravin S. Iyer,^§ Matthew D. Fodor,^§ Yvonne A. Shafer,^§ Corey R. J. Stephenson,^† Christopher Kendall,^† and Billy W. Day^†^‡

Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and Center for Chemical Methodologies & Library Development, University of Pittsburgh, Pennsylvania 15260

J. Comb. Chem., 2005, 7 (2), pp 322–330

DOI: 10.1021/cc049842a

Publication Date (Web): February 19, 2005

Author to whom correspondence should be addressed. E-mail: pwipf@pitt.edu; fax: +1-412-624-0787; tel: +1-412-624-8606.

†

Department of Chemistry.

Center for Chemical Methodologies & Library Development.

‡

Department of Pharmaceutical Sciences.

Abstract

Cascade reactions of internal and terminal alkynes, zirconocene hydrochloride, dimethylzinc, and phosphinoyl imines (prepared in one step from aldehydes and diphenylphosphinoyl amide) lead to allylic phosphinoyl amides after aqueous workup. Microwave acceleration allows the completion of this one-pot reaction sequence in 10 min. These allylic amides can be converted into a variety of derivatives, including carbamates and sulfonamides, or reacted prior to workup with diiodomethane to give novel C-cyclopropylalkylamides. A solution-phase “libraries from libraries” approach was used to generate an intermediate 20-member library which was subsequently expanded to a 100-member library by a series of N-functionalizations. The biological activity was evaluated in an assay for competitive binding to the estrogen receptor (ERα), revealing three potent lead compounds of a new structural type.

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