Amine-cation-driven heteroannulation of halomaleimides with C–N cleavage : metal-free access to heterobicyclic frameworks

Ciber, Luka (author), Brodnik, Helena (author), Petek, Nejc (author), Svete, Jurij (author), Grošelj, Uroš (author), Štefane, Bogdan (author)

Maleimides and their derivatives are highly versatile scaffolds with broad applications in synthetic chemistry, medicinal chemistry, and materials science; however, methods to expand their structural diversity remain limited. Here, we present a so far undescribed, metal-free, and mild strategy for the rapid construction of functionalized maleimides from readily available dihalomaleimide derivatives. The reaction is initiated by tertiary amine-mediated formation of an ammonium cation, which directs heteroannulation to efficiently generate heterobicyclic scaffolds. This modular approach also enables the synthesis of 3,4-diamino-substituted maleimides, including challenging second halogen substitutions with weak nucleophiles. Mechanistic studies indicate that a quaternary enamine intermediate plays a central role in steering the transformation, providing broad functional group tolerance and synthetically useful yields. Overall, this strategy offers a versatile platform for accessing structurally diverse maleimides, unlocking new opportunities in bioconjugation, medicinal chemistry, and materials science.

• Language: English
• Keywords: heterobicyclic and 3, 4-diamino-substituted maleimides, halomaleimides, C-N cleavage, quaternary enamine intermediate, mechanistic studies, metal-free mild conditions, heterocycles
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: Str. 2114-2121
• Numbering: Vol. 13, iss. 7
• PID: 20.500.12556/RUL-180117
• UDC: 547.7
• ISSN on article: 2052-4129
• DOI: 10.1039/D6QO00010J
• COBISS.SI-ID: 268833795
• Publication date in RUL: 03.03.2026

Record is a part of a journal

• Title: Organic Chemistry Frontiers
• Publisher: Royal Society of Chemistry
• ISSN: 2052-4129
• COBISS.SI-ID: 1109854

Licences

• License: CC BY-NC 3.0, Creative Commons Attribution-NonCommercial 3.0 Unported
• Link: http://creativecommons.org/licenses/by-nc/3.0/
• Description: You are free to reproduce and redistribute the material in any medium or format. You are free to remix, transform, and build upon the material. You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.

Secondary language

• Language: Slovenian
• Keywords: heterobiciklični in 3, 4-diamino-substituirani maleimidi, halomaleimidi, cepitev vezi C-N, kvaternarni enaminski intermediati, mehanistične študije, blagi pogoji brez kovin, heterocikli

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P1-0179-2020
• Name: Napredna organska sinteza in kataliza

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: I0-0022-2022
• Name: Mreža raziskovalnih infrastrukturnih centrov Univerze v Ljubljani (MRIC UL)