Development of New Multicomponent Processes based on Unexplored Chemistry of Isocyanides: Access to Heterocyclic Scaffolds and Applications
- Autores: Ouldouz Ghashghaie
- Directores de la Tesis: Rodolfo Lavilla Grifols (dir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Pedro Miguel Carda Usó (presid.), Ana Estévez Braun (secret.), Mercedes Álvarez Domingo (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: Dipòsit Digital de la UB
- Resumen
1. It was observed that the interaction of imines and isocyanides in the presence of a Lewis acid can lead to a variety of scaffolds including α-aminoamides, α-aminoamidines, indoles and diiminoazetidines. The reaction conditions were optimized to yield the later as the main product. Screening the scope of amines, aldehydes and isocyanides led to a small library of azetidine adducts. Also, a few spiro-azetidine adducts were prepared using isatine ketimines. A unified mechanism was proposed to explain the structural diversity that the process offers. In case of the main azetidine adduct, the process goes through consecutive insertion of two isocyanides followed by a 4-exo-dig cyclization. The structural elucidation of the azetidine compounds confirms the unexpected syn nature of the formed imine bonds.
2. It was shown that N-insertion of isocyanides to N-substituted propargylamines in the presence of HCl yields 1,3,4,5-tetrasubstituted imidazoliums salts. As the propargylamines arise from A3 reactions, the scope of the process in terms of aldehydes, amines, alkynes, and isocyanides was studied. The described conditions do not apply for aliphatic amines as opposed to the Zhu reaction [1] who used a different activation method (dual metallic catalysis). However, mild reaction conditions allow the incorporation of tert-Bu isocyanide, avoiding undesired elimination, as in Zhu conditions. Furthermore, the A3 reaction was successfully combined with the new reaction to obtain the imidazolium salts in a one pot process. We also explored the properties of the MCR adducts: As a proof of concept, an adduct was used as an NHC ligand for to catalyze a standard Suzuki coupling. Interestingly, some of the obtained compounds displayed potent antiparasitic activity against Trypanosoma brucei and T. cruzi at nanomolar level.
3. A TMSCl- catalyzed Reissert type MCR was studied. The process features insertion of isocyanide to N-Si bond as the mechanistical key step. Computational and experimental methods were applied to study this novel interaction of isocyanides and N-Si bonds. The reaction yields aminoimidazolium salts from the incorporation of two isocyanide units into azines. The new activation mode offers significantly wider scope. Regioselective incorporation of two distinct isocyanides was successfully performed. Furthermore, some obtained adducts demonstrated potent antiparasitic properties against Trypanosoma Brucei and Cruzi.
[1] S. Tong, Q. Wang, M.-X. Wang, J. Zhu, Angew. Chem. Int. Ed. 2015, 54, 1293–1297.
The paper of Zhu group was published when the project was in the course of manuscript writing.
4. The application of multiple Groebcke-Bienaymé-Blackburn reactions on di- and triaminoazines leads to the formation of a variety of new N-fused heterocyclic scaffolds (aminoimidazopyridines) with several diversity points. The selective reactivity mode of diaminopyrimidine provides controlled synthesis of non-symmetrical adducts. The scope of reaction was studied (analyzing the range of the aldehyde, isocyanide and aminoazine components) and post- modifications were applied to further diversify the rich structural outcome of the process. Adducts arising from melamine were structurally enlarged, exploiting cross-coupling reactions to achieve nanosized tripodal structures.
The synthesized adducts displayed interesting pH and environment sensitive fluorescent properties. Interestingly, a novel borylated BODYPY-type adduct was successfully synthesized and used for staining lysosomes in mammal cells Moreover, some adducts demonstrated potent antiviral activity against Adenovirus. Furthermore, selected compounds they showed selective affinity to G-quadruplex DNA sequences, suggesting potential applications in medicinal and biological chemistry.
