Acid-promoted meta-C-H bond amination of aniline to directly synthesize m-diphenylamine

Recently, Professor Fei Wang's research group at Nankai University developed an aromatic radical substitution reaction based on aniline protonation-induced polarity reversal, achieving the direct meta-selective amination of aromatic amines to synthesize m-phenylenediamine compounds. The authors transformed the amine group, originally an ortho/para directing group, into a strongly electron-withdrawing ammonium functional group with meta-directing effects through aniline protonation. Simultaneously, they combined this with aryl hydrocarbon amination mediated by highly reactive ammonium radical cations/pyridinium radicals, thus solving the challenge of meta-selective hydrocarbon amination of aniline compounds. The article was published as an open access communication in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background information:
meta-Phenylenediamines are important organic intermediates widely used in the synthesis of pharmaceuticals, pesticides, and organic materials. Therefore, the efficient construction of m-phenylenediamine compounds has long been a focus of attention. Currently, these compounds mainly rely on the continuous nitration-reduction of aromatics, which involves harsh reaction conditions, poor atom economy, and limited product structures. meta-carbohydrogenation of aniline is the most direct and atom-economical method for synthesizing m-phenylenediamine compounds . However, due to the inherent ortho/para-directing effect of the amine group, existing methods mainly yield o-phenylenediamine and p-phenylenediamine. While the protonation strategy of aniline can achieve polarity reversal, the strong electron-withdrawing property of the ammonium group leads to insufficient nucleophilicity of the aromatic ring, making efficient conversion difficult. Therefore, developing a novel meta-carbohydrogenation method for aromatic amines with mild conditions, high selectivity, and broad applicability remains a pressing problem.

Highlights of this article:
To address the aforementioned challenges, Professor Fei Wang's group proposed an aromatic radical substitution strategy based on aniline protonation-induced polarity reversal, achieving meta-selective hydrocarbon amination of aromatic amines. Starting with aniline, the reaction proceeds via trifluoromethanesulfonate protonation, combined with ammonium radical cation/pyridinium radical-mediated aryl hydrocarbon amination, efficiently and regioselectively synthesizing a series of m-phenylenediamine compounds. This reaction exhibits good substrate versatility and functional group compatibility, including alcohols, ethers, nitriles, alkyl chlorides, morpholines, piperazines, oxazoles, thiazoles, pyridines, and alkylamines (Figure 2). A series of anilines substituted with electron-withdrawing or electron-donating groups at the para position all showed moderate to good yields and excellent meta-selectivity. The reaction selectivity of unsubstituted aniline derivatives was significantly reduced, accompanied by some para-amination products. Due to electronegativity, anilines substituted with electron-donating groups at the ortho position showed better reaction selectivity than substrates substituted with electron-deficient groups.

The reaction also provides an efficient method for the synthesis of bioactive molecules (Figure 3). For example, the original synthetic routes for intermediates 50, 54, 55, 59 and 62 depended on a multi-step nitration/reduction process, while this scheme can achieve direct one-step synthesis under mild conditions.

Summary and Outlook:
A research group led by Professor Fei Wang Fei at Nankai University developed a meta-selective carbohydrogen amination reaction of aromatic amines mediated by acid-promoted radicals. This method utilizes the high reactivity of cationic nitrogen-centered radicals (including ammonium and pyridinium radicals) and the protonation-induced polarity reversal effect of aromatic amines. The reaction is applicable to different types of aromatic amine substrates, enabling the construction of structurally diverse m-phenylenediamine products. The potential applications of this method are demonstrated through the concise formal synthesis of several bioactive molecules. More importantly, this protonation polarity reversal strategy holds promise for widespread application in aromatic radical substitution reactions.

Fei Wang, a researcher at the State Key Laboratory of Elemento-Organic Chemistry and the College of Chemistry at Nankai University, is the corresponding author of this paper, and Shi-Xiong Tang, a master's student at Nankai University, is the first author. Guan-Wang Huang, a doctoral student at Nankai University, and Jin-Kai Cheng, an undergraduate student, provided assistance for the successful completion of the work.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.