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

Citations Over TimeTop 10% of 2006 papers

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.

Related Papers

• → A Neutral Gold(III)–Boron Transmetalation(2014)70 cited
• → Mechanistic Exploration of the Transmetalation and Reductive Elimination Events Involving PdIV–Abnormal NHC Complexes in Suzuki–Miyaura Coupling Reactions: A DFT Study(2018)33 cited
• → Directed Deprotonation−Transmetalation as a Route to Substituted Pyridines(2001)62 cited
• → Recent Trends in Enantioselective Diorganozinc-Additions to Aldehydes(2006)25 cited
• → Transmetalation Reactions Producing Organocopper Reagents(2002)16 cited