Site-Selective Copper-Catalyzed Amination and Azidation of Arenes and Heteroarenes via Deprotonative Zincation

Abstract

Arene amination is achieved by site-selective C-H zincation followed by copper-catalyzed coupling with O-benzoylhydroxylamines under mild conditions. Key to this success is ortho-zincation mediated by lithium amidodiethylzincate base that is effective for a wide range of arenes, including nonactivated arenes bearing simple functionalities such as fluoride, chloride, ester, amide, ether, nitrile, and trifluoromethyl groups as well as heteroarenes including indole, thiophene, pyridine, and isoquinoline. An analogous C-H azidation is also accomplished using azidoiodinane for direct introduction of a useful azide group onto a broad scope of arenes and heteroarenes. These new transformations offer rapid access to valuable and diverse chemical space of aminoarenes. Their broad applications in organic synthesis and drug discovery are demonstrated in the synthesis of novel analogues of natural product (-)-nicotine and antidepressant sertraline by late-stage amination and azidation reactions.

Figure 1

Representative examples of functionalized aminoarenes in natural products and pharmaceuticals

Scheme 1

Arene C–H Amination Reactions

Scheme 2

Lithium Diethyl Amido Zincate Complex for Selective and Effective C–H Zincation of Indole

Scheme 3

Late-stage Amination of Bioactive Molecules

Scheme 4

Rapid Synthesis of Novel Analogs of Sertraline via Arene Azidation