During my doctoral thesis, we designed new C(sp3)-H functionalization using halogen catalysis. We developed various procedures using either molecular iodine or a bromide salt to perform new amination and oxygenation reactions. In particular, we focused on the so-called Hofmann-Löffler reaction to access valuable pyrrolidine formation.
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 key 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. As an extension of this work, oxaziridines were synthesized as well.
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. The light has a dual role in this procedure since it is exciting the organic dye TPT and promotes the cleavage of the N-I bond. After the final pyrrolidine formation, TPT oxidizes the HI extruded during the cyclization step. Remarkably, oxygen is the terminal oxidant of this transformation (re-oxidizing TPT). Using the same cooperative catalysis, lactonization could be achieved as well.
The major limitation of the 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 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. The mechanism remains the same but 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, a Ritter-type amination guided by the Hofmann-Löffler reaction was designed by using sulfamides directing group instead of sulfonamides.
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