Authors:

Kien Nguyen

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About Paper:

Nitrogen-nitrogen (N-N) bonds are relatively rare in nature, with only about 300 bioactive natural products containing this moiety [1]. Many clinically approved drugs, including antihypertensives, antidepressants, and antibiotics, also contain N-N bonds [2]. Despite the medicinal relevance of this motif, directly coupling two nitrogen atoms is fundamentally challenging because of the inherently electron-rich nature of nitrogen (polarity mismatch). As such, established methods often rely on the formation of transient electron-deficient nitrogen intermediates that can react with electron-rich nitrogen partners. While successful, these strategies require at least one sp? nitrogen source. N-N bond formation between two sp* nitrogen coupling partners is rare, with only a few reported examples and limited structural diversity. These methods often suffer from competing oxidative elimination due to weak adjacent carbon-hydrogen (C-H) bonds, leading to decomposition of N(sp*) intermediates. To address these challenges, this project employs electrochemistry to generate an N(sp*)-centered radical cation from quinuclidine, a nitrogen-containing bicyclic amine. Of note, this intermediate resists the typical decomposition pathway because the bicyclic structure disfavors elimination. We hypothesized that the electron-deficient N-radical cation could couple with nucleophilic quinuclidine to form N,N'-bisquinuclidinium (the N-N dimer). Optimized electrochemical conditions successfully produced the desired N,N'-bisquinuclidinium in high yield. We further demonstrated the synthetic utility of this transformation by performing ring-opening reactions on the N-N dimer with various oxygen-, nitrogen-, and sulfur-based nucleophiles to generate a wide array of nonsymmetrical N,N'-bispiperidines. Preliminary mechanistic studies suggest that N-N bond formation proceeds through polarity-matched hypervalent N(sp*}-N(sp") intermediate formation between the N-radical cation and neutral quinuclidine. This represents a unique mechanism for bond formation between an N-radical cation and a nitrogen nucleophile, and potentially with other heteroatom nucleophiles such as sulfur and phosphorus.

Source:

Northwestern University

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Co-authors:

Kien Nguyen