Electrochemical Insertion of Ammonia into Cyclic Alkenes for the Synthesis of Aromatic N-Heterocycles

Aromatic N-heterocycles are prevalent in natural products and pharmaceuticals. Traditional synthetic methods often rely on condensation reactions using pre-oxidized materials, limiting functional group compatibility. For example, isoquinoline synthesis from indene typically involves oxidative cleavage of alkenes using ozone or OsO₄, restricting the scope of tolerated functional groups. In contrast, heteroatom insertion into carbon skeletons offers benefits such as atom economy, tolerance of oxidation-labile functional groups, and unexplored selectivity. However, cleaving C-C bonds, particularly in alkenes and alkynes, is far more challenging than oxidation. Dehydrogenation reactions offer a complementary route to oxygenation for regulating the oxidation state of organic molecules. Electrochemical dehydrogenative cross-coupling, specifically, has emerged as a powerful tool for oxidative bond formation without external oxidants. While electrochemical methods have advanced the construction of C-N bonds, the direct electrochemical synthesis of aromatic N-heterocycles from ammonia and alkenes remained elusive until this work. This research aimed to develop an efficient and versatile electrochemical method for the direct insertion of ammonia into carbon skeletons of cyclic alkenes, leading to the formation of various aromatic N-heterocycles. This method would represent a significant advancement in the field, offering advantages in atom economy, functional group tolerance, and synthetic accessibility.

The literature extensively details the synthesis of aromatic N-heterocycles, with classical methods frequently employing condensation reactions involving pre-oxidized starting materials. Oxidative cleavage of alkenes using reagents like ozone or OsO₄ has been a common strategy, but this approach has limitations in terms of functional group compatibility. Several studies have explored alternative approaches focusing on the advantages of heteroatom insertion into carbon skeletons. These methods aim to improve atom economy, enhance the tolerance of oxidation-sensitive functional groups, and potentially unlock new selectivities. The development of dehydrogenative cross-coupling reactions, particularly electrochemical methods, has shown promise in achieving oxidative bond formation without external oxidants. Electrochemical C-N bond formation has seen significant progress in recent years, with various protocols reported for aromatic C-H amination, benzylic C-H amination, alkyne amination, alkene azidation, and alkane amination. However, the direct electrochemical synthesis of aromatic N-heterocycles by inserting ammonia into alkenes had not been achieved before this study. This gap highlights the challenge in developing an efficient electrochemical approach that rivals the efficiency of oxidative methods for C-C bond cleavage.

The authors optimized the electrochemical insertion of ammonia into indene (1a), using various electrode materials (graphite felt, Pt, Ag) and solvents (methanol, dichloromethane, isopropanol). The best results were obtained with a graphite felt anode, a silver cathode, and a mixture of methanol and dichloromethane as the solvent, with Mg(ClO₄)₂ or LiBF₄ as the supporting electrolyte. The reaction was carried out at 0 °C under a constant cell voltage of 4 V for 3 hours. The yield of isoquinoline (2a) was significantly improved from 16% to 68% through optimization of the reaction conditions. The methodology was subsequently extended to a range of substrates, demonstrating its broad applicability and ability to synthesize various aromatic N-heterocycles. A gram-scale reaction was also successfully performed, confirming the scalability of the method. The reaction mechanism was investigated through the isolation and characterization of an intermediate aziridine, kinetic studies, and cyclic voltammetry. The proposed mechanism involves a four-electron oxidation process at the anode, followed by the evolution of hydrogen at the cathode. The intermediate aziridine was confirmed to be a key intermediate in the transformation. Controlled potential electrolysis experiments and kinetic studies provided evidence for the proposed multi-step electron transfer mechanism. Cyclic voltammetry experiments helped elucidate the roles of the substrate and ammonia in the electron transfer processes at the electrode surfaces. The overall reaction demonstrates high atom economy, with up to 99.2% theoretical atom economy being achieved.

The electrochemical method demonstrated the direct insertion of ammonia into cyclic alkenes, synthesizing various aromatic N-heterocycles. The reaction successfully employed electrochemical hydrogen evolution instead of oxygenation, eliminating the need for external oxidants. This approach exhibited high atom economy (up to 99.2% theoretical). Importantly, the method showed excellent tolerance towards oxidation-labile functional groups, a significant advantage over traditional oxidative methods. A wide range of substituted aromatic N-heterocycles were synthesized using this method. A key intermediate, an aziridine, was identified and characterized, offering insight into the reaction mechanism. Kinetic studies and cyclic voltammetry data provided supporting evidence for the proposed four-electron oxidation mechanism. The gram-scale synthesis of one product confirmed the scalability of this electrochemical approach. The synthesized compounds included a substituted 1,3-diazine, which is not accessible via other methods. A pharmaceutical compound, moxaverine, was synthesized using this methodology as a key step, demonstrating its practical utility.

This work successfully addresses the long-standing challenge of directly inserting ammonia into alkene skeletons to build aromatic N-heterocycles. The electrochemical approach presented here overcomes the limitations of traditional oxidative methods, offering several significant advantages. The high atom economy, avoidance of external oxidants, and tolerance of oxidation-labile functional groups greatly enhance the sustainability and scope of the synthesis. The identification of a key aziridine intermediate and the mechanistic studies using cyclic voltammetry provide valuable insights into the reaction pathway. The successful application of this method to the synthesis of moxaverine further demonstrates the practical implications of this approach. This method holds great potential for the efficient and sustainable synthesis of various complex aromatic N-heterocycles which are valuable in medicinal chemistry and materials science.

This study presents a novel and efficient electrochemical method for the direct insertion of ammonia into cyclic alkenes, leading to the synthesis of diverse aromatic N-heterocycles. This method offers advantages in atom economy, functional group tolerance, and scalability compared to traditional methods. The detailed mechanistic studies provide valuable insights into the reaction pathway. Future research could explore the application of this methodology to a broader range of substrates and functional groups, further expanding its utility in organic synthesis. Investigating the use of different electrode materials and reaction conditions to optimize the selectivity and efficiency of the process is also warranted.

While the methodology demonstrates broad applicability, further optimization might be necessary for specific substrates with steric hindrance or electron-withdrawing groups. The reaction conditions, particularly the solvent system and electrolyte, may need to be adjusted for optimal performance with different substrates. A more comprehensive understanding of the reaction mechanism and the effects of various reaction parameters on the selectivity could further improve the reaction efficiency and yield. Exploring the scalability of the process to industrial levels would also be a valuable future direction.