Deaminative functionalization of aromatic amines: Current advances, challenges, and future horizons

Amines are ubiquitous functional groups in both nature and medicinal chemistry, and their synthetic utility has made deaminative functionalization an important area of research in organic chemistry. However, activating the inherently stable C–N bond remains a significant challenge, particularly within aromatic systems, where the bond dissociation energy (BDE) of the C(sp2)–NH2 is approximately 102.6 ± 1.0 kcal mol−1. An ideal strategy to address this hurdle involves the conversion of the unprotected NH2 group into a modular and efficient leaving group. In this regard, while aliphatic deaminative functionalization chemistry has been extensively developed and proceeds through mechanisms such as polar pathway, radical deamination, deaminative oxidation, and transition-metal-catalyzed processes, aromatic C–N bond-breaking transformations still rely heavily on classical aryldiazonium chemistry. Aryldiazonium salts, first discovered in 1858, have long served as key intermediates in deaminative processes. These compounds have proven to be highly versatile precursors, facilitating the development of several important named reactions, including the Sandmeyer, Pschorr cyclization, Gomberg-Bachmann, Balz-Schiemann fluorination, and Meerwein arylation reactions. Furthermore, aryldiazonium salts are employed as flexible aryl building blocks, finding widespread application in modern radical-mediated transformations and transition-metal-catalyzed coupling reactions (Figure 1A). Notably, the Sandmeyer reaction remains a well-established method for synthesizing aryl halides and continues to be an indispensable tool in modern synthesis, garnering significant attention. However, classical Sandmeyer chemistry faces several limitations: (1) the inherent instability of diazonium salts and their highly reactive nature, which pose significant explosion risks during synthesis, storage, and use; (2) the requirement for stoichiometric amounts of copper, leading to heavy metal waste; and (3) poor compatibility with electron-deficient or sterically hindered aromatic systems. As a result, there is a growing need for safer and more efficient alternatives to these compounds. Despite substantial efforts over the last 30 years toward activating C(sp2)–NH2 bonds via polyalkylation of anilines followed by transition-metal-catalyzed cleavage, these tactics have been restricted to the activation of simple and specific anilines (Figure 1B).

In response to the shortcomings of these preactivation strategies, recent research has increasingly focused on innovative direct deamination routes. Newly developed approaches efficiently convert (hetero)aromatic amines into distinct reactive intermediates (e.g., pyridinium, isodiazene, transient aryldiazonium, and N-nitroamine species) using simple reagents. The formation of these intermediates provides new avenues for overcoming the challenges posed by the high BDE of the C(sp2)–NH2 bond and the poor leaving ability of the NH2 group, ultimately enabling selective derivatization across a wide range of NH2-containing molecules (Figure 1C). In parallel, significant progress has also been made in aliphatic C–N bond cleavage,5,6 further underscoring that deaminative functionalization is a rapidly advancing field.

Current advances in deaminative functionalization of aromatic amines

Pyrylium salts have long been used to activate C(sp3)–NH2 bonds, converting aliphatic amines into Katritzky-type pyridinium salts, which are widely employed in substitution chemistry. Building on this progress, the Cornella group developed a practical deaminative chlorination protocol for amino heterocycles using simple pyrylium reagents and readily available chloride sources.7 This method provides a robust strategy for the chlorination of electron-deficient (hetero)aromatic systems, relying on in-situ-generated pyridinium intermediates that undergo a nucleophilic aromatic substitution (SNAr) pathway.

The Levin group described a facile deaminative method utilizing a rationally designed anomeric amide reagent.8 This reagent facilitates radical C–N bond cleavage, offering a practical radical-based deamination pathway that proceeds under mild conditions. This method has been shown to apply to both aromatic and aliphatic amines. Mechanistic investigations reveal that carbon-centered radical species are formed via an in-situ-formed isodiazene intermediate, which readily undergoes N2 extrusion.

Inspired by nitrate reduction chemistry, the Ritter group conceived a safety-enhanced Sandmeyer protocol that employs transient aryldiazonium intermediates, preventing the accumulation and isolation of diazonium salts.9 This strategy enables direct deaminative halogenation of anilines with readily available nitrate sources, common reductants, and conventional halide donors. They further established this nitrate reduction strategy as a general platform for safer aryldiazonium chemistry, demonstrating its utility in versatile deaminative transformations of anilines, including Suzuki-Miyaura coupling, sulfonylation, fluorination, and cyanation.