Solution

Decarboxylative C(sp3)‐N and C(sp3)‐O Cross Coupling

Runze Mao, Johnathan Balon, Adrian Frey and Xile Hu*

Laboratory of Inorganic Synthesis and Catalysis, EPFL, 1015 Lausanne, Switzerland

C(sp3)-heteroatom (N, O) bond are ubiquitous in medicinal, material and agro chemistry. Catalytic C(sp3)-heteroatom cross coupling of alkyl electrophiles with heteroatom

nucleophiles is an underdeveloped disconnection strategy to forge C(sp3)-heteroatom bonds, with the potential to overcome major limitations of existing methods. Here we

employ tandem photoredox and copper catalysis to achieve decarboxylative C(sp3)-heteroatom coupling of alkyl N-hydroxyphthalimide (NHPI) esters with heteroatom

nucleophiles under mild conditions. This method can be used to synthesize a diverse set of valuable products using readily available alkyl carboxylic acids, including many

natural products and drugs. Complementarity in scope and functional group tolerance to existing methods, and proposed mechanism were demonstrated.

Introduction

Acknowledgments

References:

ConclusionsDecarboxylative C(sp3)-heteroatom coupling of alkyl NHPI esters has beenachieved using tandem photoredox and copper catalysis. This coupling methodallows for rapid transformation of readily available alkyl carboxylic acids into alkylaryl amines, primary amines or alkyl aryl ethers, which are important compounds inmedicinal chemistry. This method provides a new disconnection strategy andexhibits complementary scope and functional group tolerance compared totraditional C(sp2)-heteroatom cross coupling and SN2 reactions.

[1] R. Mao, A. Frey, J. Balon, X. Hu, Nat. Catal. 2018, 1, 120. [2] R. Mao, J. Balon, X. Hu, Angew. Chem., Int. Ed. 2018, 57, 9501. [3] R. Mao, J. Balon, X. Hu, Angew. Chem., Int. Ed. 2018, just accepted

Challenge Hypothetical Pathway

This work is supported by the NoNoMeCat Marie Skłodowska-Curietraining network funded by the European Union under the Horizon 2020Program (675020-MSCA-ITN-2015-ETN). We also thank SCNAT andSCS for a financial support through a «Chemistry Travel Award»

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Mechanistic Studies and Applications

Late-Stage Modification of Natural Products and Drugs