Enantioselective, Palladium-Catalyzed α-Arylation of N-Boc-pyrrolidine

Kevin R. Campos,* Artis Klapars, Jacob H. Waldman, Peter G. Dormer, and Cheng-yi Chen
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065
J. Am. Chem. Soc., 2006, 128 (11), pp 3538–3539
DOI: 10.1021/ja0605265
Publication Date (Web): March 1, 2006
Copyright © 2006 American Chemical Society
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, kevin_campos@merck.com

Abstract

Abstract Image

This communication discloses the first instance of the enantioselective Pd-catalyzed α-arylation of N-Boc-pyrrolidine. The methodology relies on Beak's sparteine-mediated, enantioselective deprotonation of N-Boc-pyrrolidine to form the 2-pyrrolidinolithium specices in high enantiomeric ratio (er). Transmetalation of this intermediate with zinc chloride generates the stereochemically rigid, 2-pyrrolidinozinc reagent, which was readily coupled to a variety of functionalized aryl halides at room temperature using a catalyst generated from Pd(OAc)2 and PtBu3−HBF4. A diverse array of 2-aryl-N-Boc-pyrrolidines was synthesized using this methodology, providing adducts consistently in a 96:4 er. A survey of the stoichiometry revealed that as little as 0.3 equiv of zinc could be used in the coupling reaction, and the 2-pyrrolidinozinc reagent was found to exhibit stereochemical stability up to 60 °C. The method allows for the most convergent and reliable preparation of a broad range of functionalized 2-aryl-N-Boc-pyrrolidines in high enantioselectivity, which is highlighted in this report by the enantioselective synthesis of (R)-nicotine.

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  • Published In Issue March 22, 2006
  • Received January 23, 2006

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