Desarrollo de nuevas funcionalizaciones c(sp3)-h a través de catálisis de halógenos
- Autores: Thomas Duhamel
- Directores de la Tesis: Ruben Martin Romo (dir. tes.)
- Lectura: En la Universidad de Oviedo ( España ) en 2020
- Idioma: español
- Tribunal Calificador de la Tesis: José Manuel González Díaz (presid.), Eduardo Rubio Royo (secret.), Daniele Leonori (voc.), Philippe Dauban (voc.), Olivier Baudoin (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: RUO
- Resumen
During my doctoral thesis, I designed new C(sp3)-H functionalization using halogen catalysis.
I developed various procedures using either molecular iodine or a bromide salt to perform new amination and oxygenation reactions. In particular, I focused on the so-called Hofmann-Löffler reaction to access valuable pyrrolidine formation.
When I started, no bromide catalysis was developed for the latter. We found out that a combination of an ammonium bromide salt with mCPBA could provide the corresponding pyrrolidines. Using sulfonamides as starting materials, we could generate in-situ the N-Br bond.
A homolytic cleavage by daylight irradiation affords the nitrogen-centered radical. Subsequent 1,5-HAT occurs followed by a bromination to selectively provide an alkylbromide intermediate.
Further cyclization process yields the final pyrrolidines. For the first time, the N-brominated intermediate could be isolated and fully characterized. As an extension of this work, when the 1,5-HAT could not proceed, oxaziridines were synthesized instead.
Then, a cooperative catalysis between molecular iodine and an organic dye was designed. The mechanism is similar to the one described above. It was found that hypoiodite, formed from the disproportionation of iodine in the presence of water, was the active species generating the N-I bond in-situ. Calculations have been carried out on the N-I bond on sulfonamides to know their exact cleavage condition. It was found out that blue LEDs could undergo the homolytic cleavage of such N-I bond. Therefore, the light has a dual role in this procedure since it is also exciting the organic dye TPT which has its maximum absorption wavelength in the blue region of the visible spectrum. After the final pyrrolidine formation, TPT oxidizes the HI extruded during the cyclization step. Remarkably, oxygen is the terminal oxidant of this transformation since it is re- oxidizing TPT.
Using the same cooperative catalysis, lactonization could be achieved as well.
The major limitation of this two precedent procedures is the requirement of an activated carbon position to have a rapid cyclization step. The idea, to accelerate the formation of the pyrrolidines is to implement an oxidant in the reaction system which is able to oxidize the alkyliodine intermediate. As a result, we would have a alkyliodine(III) intermediate, well known to be an excellent nucleofuge. After an extensive optimization, we found out that the combination of molecular iodine and mCPBA using tert-butanol as co-solvent was efficient. As previously, molecular iodine in the presence of water disproportionates in hypoiodite HOI. This inorganic species with tert-butanol generates tert-butyl hypoiodite thus leading to the in-situ formation of the N-I bond. Following the same mechanism than above-mentioned, the alkyliodine intermediate is generated. An extra oxidation step by mCPBA forms the alkyliodine(III) intermediate crucial for the access of non-activated carbon position for the formation of pyrrolidines.
Finally, as my last project, we wondered whether another protecting group than sulfonamides could undergo selective amination reaction. We focused on sulfamides that are well-known to perform 1,6-HAT. While trying to cyclize on activated benzylic position, we could access 1,3- diamines easily. But, at non-activated secondary position, the reaction did not proceed. The alkyliodine intermediate was isolated instead. As a result, we tried at the slightly more activated tertiary non-activated position. A new aminated product coming from a Ritter-type amination was isolated. Therefore, after the selective 1,6-HAT followed by the iodination at the targeted tertiary position, a molecule of acetonitrile, used as solvent, displaces the iodine to generate in the presence of water an acetamide. Using this protocol, oxygenation have been performed as well.
