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Exploring hypervalent iodine reagents: A powerful tool for sulfonylation reactions

Publication . Macara, João Cristóvão Santos Silva Pereira; Marques, Maria Manuel

Hypervalent iodine reagents are compounds bearing an iodine with a high oxidation state, commonly +3 or +5. Iodine(V) reagents are well documented as powerful mild oxidants, whereas iodine(III) reagents have a reactivity close to transition metals and can perform the electrophilic transfer of groups that are inherently nucleophilic - known as umpolung reactive-ty. Particularly, benziodoxolones and benziodoxoles, have shown great utility in the establishment of C-C, C-O, C-N bonds, among others.The last part of this thesis consisted on the investigation of the reactivity of the key sulfonyl benziodoxolone intermediate with carbon nucleophiles. Several nucleophiles were tested, and the use of enamines allowed the synthesis of sulfones. The work developed in this thesis represents a step-forward in the use of benziodoxolone-based reagents. In particular, the unprecedented synthesis of a PEG-bound benziodoxolone contributes to a sustainable synthesis of sulfonamides. The work presented in this thesis paves the way for future developments in the access of sulfonyl-containing compounds. In this thesis, the umpolung reactivity of benziodoxolones was investigated to address the establishment of N-S and C-S bonds. Given the medicinal interest in the sulfonyl-containing compounds, the potential of hypervalent iodine reagents was explored and several sulfonyl-containing compounds were synthesized, such as sulfonamides, sulfonyl hydrazides and sulfones. The first approach relied on the benziodoxolone-mediated sulfonylation of amines. Taking advantage of the umpolung reactivity of hypervalent iodine reagents, a key intermediate was synthesized using sodium sulﬁnate salts, and reacted with both aliphatic and aromatic amines. A total of 25 sulfonamides were obtained in moderate to quantitative yields, even in gram-scale. On the follow-up of this work, a benziodoxolone-based reagent was immobilized in a soluble polymer, polyethylene glycol (PEG-2000), to increase the sustainability of the synthesis of sulfonamides. The novel PEG-bound chlorobenziodoxolone was obtained in a simple six-step synthesis and used, applying the previously disclosed protocol, giving rise to sulfonamides in moderate to high yields. The polymer-immobilized reagent was recovered in high yields, recycled, and used in a second cycle with no loss of reactivity, constituting an improvement in the sustainability of this synthesis of sulfonamides. In a second part of this thesis, the previously established sulfonylation protocol mediated by a hypervalent iodine reagent was also investigated for the synthesis of sulfonyl hydrazides. Thus, the key intermediate generated in situ - hypervalent iodine reagent bearing a sulfonyl moiety - was reacted with mono- and disubstituted hydrazines, affording 18 sulfonyl hydrazides in yields up to 62%. Furthermore, a gram-scale reaction was performed, showing the robustness of the procedure. ESI-MS and DFT studies were performed to elucidate the reaction mechanism.

2023-05-30Tese de doutoramento

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

OE

Número da atribuição

PD/BD/142864/2018