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Enantioselective, palladium-catalyzed alpha-arylation of N-Boc-pyrrolidine.

Journal of the American Chemical Society (2006-03-16)
Kevin R Campos, Artis Klapars, Jacob H Waldman, Peter G Dormer, Cheng-yi Chen
ABSTRACT

This communication discloses the first instance of the enantioselective Pd-catalyzed alpha-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 degrees 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Tri-tert-butylphosphonium tetrafluoroborate, 97%
Sigma-Aldrich
(R)-(+)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane, 98%