A highly site-selective radical sp3 C-H amination of azaheterocycles.

Keith W Bentley,Krysta A Dummit,Jeffrey F Van Humbeck

doi:10.1039/c8sc00590g

Abstract

This report describes the development of a novel C-H amination strategy using both a Cu(ii) Lewis acid and an organic hydrogen atom transfer catalyst to activate benzylic C-H bonds adjacent to aromatic N-heterocycles. This simple methodology demonstrates very high selectivity towards azaheterocycles without using exogenous directing groups and affords excellent site selectivity in substrates with more than one reactive position. A wide range of heterocyclic structures not compatible with previously reported catalytic systems have proven to be amenable to this approach. Mechanistic investigations strongly support a radical-mediated H-atom abstraction, which explains the observed contrast to known closed-shell Lewis acid catalyzed processes.

Highlights

Nitrogen-containing heterocycles are pervasive in natural products,[1] functional materials,[2] agrochemicals,[3] and small molecule pharmaceuticals.[4]
Speci cally in the case of copper, the Huang and Guo groups used diethyl azodicarboxylate (DEAD) for pyridine amination, where the mechanism was proposed to involve a dearomatized nucleophile that forges the new C–N bond by a two electron pathway.9h,9i the Rueping group developed a Cu(II) system for C–C bond formation that was amenable to several classes of heterocycles.9g In general, for all types of catalysts relatively forcing conditions involving high reaction temperatures and non-polar solvents have been required unless acidifying substituents are present.9k It was our view that highly desirable polar and functionalized molecules may not have sufficient solubility or stability under such conditions
Underpinning our own work, the Inoue group reported the use of N-hydroxypthalimide (NHPI, 1) as a hydrogen atom transfer (HAT) catalyst for benzylic C–N bond formation in alkyl benzenes using DEAD as the nitrogen source.[13]

Summary

Introduction

Nitrogen-containing heterocycles are pervasive in natural products,[1] functional materials,[2] agrochemicals,[3] and small molecule pharmaceuticals.[4]. This report describes the development of a novel C–H amination strategy using both a Cu(II) Lewis acid and an organic hydrogen atom transfer catalyst to activate benzylic C–H bonds adjacent to aromatic Nheterocycles.

Results

Conclusion