A Simple and Broadly Applicable C−N Bond Forming Dearomatization Protocol Enabled by Bifunctional Amino Reagents

Xiaofeng Ma,Natalie Fey,John F Bower,Tom A Young,Joshua J Farndon

doi:10.1002/ange.201708176

Abstract

AbstractA C−N bond forming dearomatization protocol with broad scope is outlined. Specifically, bifunctional amino reagents are used for sequential nucleophilic and electrophilic C−N bond formations, with the latter effecting the key dearomatization step. Using this approach, γ‐arylated alcohols are converted to a wide range of differentially protected spirocyclic pyrrolidines in just two or three steps.

Highlights

Electrophile-triggered dearomatization processes enable the direct conversion of readily prepared planar molecules to synthetically valuable three-dimensional scaffolds,[1] often
The process requires specific N-protecting groups, is most efficient under strongly acidic conditions (e.g. TFA as solvent) and can suffer from competing oxidation processes involving the arene.[5e]. Given the limitations associated with the state-of-the-art, we reasoned that the development of a CÀN bond forming dearomatization platform with broad scope would represent a significant and useful advance
We sought to circumvent the requirement of a strong external oxidant, and, at the same time, provide a pyrrolidine synthesis that can accommodate a variety of N-protecting groups and a range of nucleophilic arenes

Summary

Introduction

Electrophile-triggered dearomatization processes enable the direct conversion of readily prepared planar molecules to synthetically valuable three-dimensional scaffolds,[1] often. Chemie facilitates the Mitsunobu step and avoids protecting group manipulations,[8] 2) readily prepared enantiopure secondary alcohols can potentially be used as a starting point,[7] 3) the use of an NÀO bond as a mild internal oxidant should minimize competing oxidation processes involving the arene, 4) the leaving group derived byproduct (HOR) should be easy to remove during work-up, and 5) a wide range of Nprotecting groups should be tolerated because the dearomatization step relies on the electrophilicity of the nitrogen center, rather than on its nucleophilicity.

Results

Conclusion