A general strategy for the amination of electron-rich and electron- poor heteroaromatics by desaturative catalysis Javier Corpas a , Henry Caldora b , Ester Maria Di Tommaso a , Augusto Hernandez c , Oliver Turner d , Luis Miguel Azofra e , Alessandro Ruffoni* a , Daniele Leonori* a a Institute of Organic Chemistry, RWTH Aachen University, Germany, b Department of Chemistry, University of Manchester, UK, c XChem Inc., Montreal, QC Canada, d Oncology RD Medicinal Chemistry, AstraZeneca, Cambridge, UK, e Instituto de Estudios Ambientales y Recursos Naturales (i-UNAT), Campus Universitario de Tafira, Las Palmas de Gran Canaria, Spain Aminated heterocycles are high value targets in industrial sectors (pharmaceutical and fine chemicals), but their preparation still represents a remarkable synthetic challenge. [1] Disclosed in this poster is a general platform for the synthesis of aminated heterocycles whereby a single catalytic manifold can be used to selectively aminate pyridines, pyrroles, furans, thiophenes and pyrazoles at their most deactivated positions. The mechanistic blueprint for this transformation unveils a brand-new and distinct approach to the preparation of aminated heterocycles that nitration and/or cross-coupling strategies cannot access. Here, our approach harnesses the same amine building blocks that are used in cross-couplings but exploits piperidones, pyrrolidinones etc. as heteroaryl halide surrogates. This addresses simultaneously two key challenges in the formation of heteroaryl C-N bonds: As the carbonyl group acts as formal handle for C–N cross-coupling, we by-pass completely electrophilic aromatic chemistry for either nitration or halogenation and then cross-coupling. Instead, we use carbonyl chemistry, possibly the most generalised and robust reactivities known, to introduce functionalities across the “future” aromatic ring.With this approach we replace the challenging reductive elimination from heteroaryl-organometallic intermediates with a simple condensation between an amine and a carbonyl group, which operates under mild conditions. [2] It is widely known that cross-coupling aminations fail on “real-world” substrates and reaction conditions cannot be translated from one class of heteroaromatics to another, especially going from electron-poor to electron-rich systems. [3] This novel desaturative methodology provides an unprecedented and unified approach to the synthesis of C4 and C3-aminated pyridines (electron-poor) as well as C3-aminated pyrroles, furans, thiophenes and pyrazoles (electron-rich) with over 30 complex primary and secondary amines showcased. Key to the success of this process is the catalytic activity of our cobaloxime which has a dual sequential role, acting first as a H-atom abstractor and then as an oxidant. Evidence for this novel mechanistic interplay will be discussed in detail. [4] References 1. Vitaku, E., Smith, D. T. Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 57, 10257-10274, (2014). 2. Reichert, E. C., Feng, K., Sather, A. C. Buchwald, S. L. Pd-Catalyzed Amination of Base-Sensitive Five-Membered Heteroaryl Halides with Aliphatic Amines. J. Am. Chem. Soc. 145, 3323-3329, (2023). 3. Ruiz-Castillo, P. Buchwald, S. L. Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions. Chem. Rev. 116, 12564-12649, (2016). 4. U. Dighe, S., Juliá, F., Luridiana, A., Douglas, J. J. Leonori, D. A photochemical dehydrogenative strategy for aniline synthesis. Nature 584, 75-81, (2020).
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