Formal Synthesis of Ortho-Cyanated N-Heterocycles via Direct, Metal-Free Cyanation of N-Oxides Under Benign Conditions

TL;DR

A new metal-free method allows efficient and mild synthesis of cyanated heterocycles, useful in pharmaceuticals and agrochemicals.

Contribution

A unified, metal-free strategy for ortho-C-H cyanation of N-oxides under mild conditions is introduced.

Findings

The method works for various heterocyclic N-oxides like pyridine and quinoline derivatives.

It offers advantages like mild conditions, no catalysts, and broad substrate scope.

The approach is efficient and scalable for complex, biologically relevant molecules.

Abstract

The introduction of cyano groups into aza-heterocyclic compounds plays a pivotal role in accessing diverse derivatives that are essential for the development of natural products, pharmaceuticals, and agrochemicals. Herein, we report a unified strategy for the direct ortho-C-H cyanation of a broad range of heterocyclic N-oxides, including pyridine, quinoline, isoquinoline, and pyrimidine derivatives. This transformation proceeds under mild conditions without the need for external activating agents or catalysts, and has been successfully applied to structurally complex, biologically relevant molecules. Compared to existing methodologies, our approach offers several distinct advantages: the use of non-prefunctionalized heteroarene substrates, environmentally benign reaction solvents, operational simplicity, broad substrate scope, and high efficiency in generating diverse ortho-cyanated heterocyclic compounds. Moreover, the method demonstrates considerable potential for scalable synthesis.

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