סמינר בכימיה אורגנית: Enhancing Structural Complexity via Dearomative Functionalization of N-Heterocycles

Abstract:

Nitrogen heterocycles play a vital role in pharmaceuticals and natural products, with the six-membered aromatic and aliphatic architectures being commonly used.1 The current toolbox of synthetic methods has greatly contributed to the construction of these molecules by providing robust transformations for carbon-carbon (C–C) and carbon-heteroatom (C–X) bond formation.2 However, these methods predominantly produce libraries of aromatic N-heterocycles, such as pyridine derivatives, with diverse functionalities.

In contrast, the synthesis of functionalized aliphatic N-heterocycles, particularly piperidine derivatives, is more challenging. Current procedures often rely on substrate-specific cyclization of amino-olefins, C–N coupling methodologies, and hydrogenation reactions, which necessitate the pre-decoration of suitable precursors prior to the construction of functionalized piperidine scaffolds.

We therefore believe that dearomative functionalization reaction could represent an ideal solution, since it allows the introduction of functional groups within the synthetic process.3 Despite promising research, the current strategies are limited to the introduction of a single functionality. To the best of our knowledge, dearomative functionalization of heterocycles that could install multiple functionalities is highly underdeveloped.

In this context, we propose unique dearomative functionalization reactions for the construction of highly decorated aliphatic N-heterocycles with diverse functional handles.4 Challenges related to site-selectivity, regio- and diastereoselectivity will be discussed and insights into the reactions mechanism through mechanistic studies will be provided.

References

1. a) Vitaku E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257; b) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845.

2. a) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Nat. Chem. 2018, 10, 383; b) Campos, K. R.; Coleman, P. J.; Alvarez, J. C.; Dreher, S. D.; Garbaccio, R. M.; Terrett, N. K.; Tillyer, R. D.; Truppo, M. D.; Parmee, E. R. Science 2019, 363, eaat0805.

3. Huck, C. J.; Sarlah, D. Chem 2020, 6, 1589.

4. a) Agbaria, M.; Egbaria, N.; Nairoukh, Z. Chem. Sci. 2024, 15, 19136; b) Mondal, R.; Agbaria, M.; Cohen, O.; Nairoukh, Z. Chem. Eur. J. 2024, 30, e202303588; c) Hu, M.; Ding, H.; DeSnoo, W.; Tantillo, D. J.; Nairoukh, Z. Angew. Chem. Int. Ed. 2023, 62, e202315108.