N-nitroamine: Open a new era for direct deaminative functionalization

Aryl amines are ubiquitous in natural products and medicinal compounds. Deaminative functionalization has been regarded as a cornerstone of synthetic chemistry and would greatly enhance the development of dyes, pharmaceuticals, and agrochemicals. The classic process, Sandmeyer reaction, reported in 1884 by Traugott Sandmeyer, provided one of the earliest and most powerful methods for transforming aryl amines into aryl halides through copper(I)-mediated substitution of diazonium salts. This discovery revolutionized aromatic substitution chemistry, allowing for the conversion of abundant aniline derivatives into diverse building blocks for further functionalization. Yet, despite its longevity, the Sandmeyer reaction has long been burdened by intrinsic issues: the need to generate and handle diazonium salts, which are often unstable and shock sensitive, resulting in potential detonation upon contact with air and even in solution; limited substrate scope, particularly for heteroaromatic or electron-poor systems; and the requirement for stoichiometric copper salts, producing metal waste and complicating purification. Moreover, the multistep diazotization-functionalization workflow is operationally cumbersome, often unsuitable for scale-up.

Previously, the assumption on the use of the tetrafluoroborate (BF4−) counterion to prevent explosions of diazonium salts has been proven to be incorrect. Efforts on the modification of reaction setup via using continuous-flow technology provided an alternative to decrease the explosive risk, whereas it is only suitable for some diazonium salts. In addition, new protocols to lower the concentration of diazonium salts inspired by nitrate reductase-involved process,1 or to produce pyridine salts as the leaving group2 or diazenes as intermediates3 to avoid the generation of diazonium salts, have been developed well, giving rise to deaminative functionalization under safer conditions. However, in view of atom economy, operational simplicity, and substrate compatibility, it is highly desirable to search for more general and sustainable strategies for deaminative functionalization.