Strategies for oxidative synthesis of N-triflyl sulfoximines.

The oxidation of various structurally different N-trifluoromethylthio sulfoximines was investigated using different oxidizing agents and conditions. Mono- and disubstituted phenyl methyl and phenyl cyclopropyl N-trifluoromethylthio sulfoximines were oxidized with NaOCl·5H2O in water, while sterically hindered substrates bearing bulkier alkyl chains or two phenyl rings required the addition of MeCN to the reaction mixture. Chloro-, bromo-, and cyano-substituted substrates, as well as substrates bearing the benzyl groups, required a completely different approach using m-CPBA in DCM. Each method was tested on a gram-scale, with almost no difference in yield or reaction profile. The methods were also tested on N-p-tolylthio sulfoximine where successful oxidation to the corresponding sulfone derivative was observed. Finally, the N-triflyl sulfoximines acquired in the oxidations were examined in terms of stability and reactivity in Suzuki-Miyaura and Sonogashira coupling reactions, as well as many others. The selective mono- and dinitration of 4-methoxyphenyl N-triflyl sulfoximine was demonstrated by using nitric and sulfuric acid. N-triflyl sulfoximines were found to be stable in concentrated aqueous NaOH and HCl solutions and at elevated temperatures.

Oxidation of N-trifluoromethylthio sulfoximines using NaOCl·5H2O.

N-Trifluoromethylthio sulfoximines are biologically interesting compounds, but their potential is still poorly understood. The oxidation of N-trifluoromethylthio sulfoximines led to their corresponding sulfoxide derivatives as a new class of compounds, when using sodium hypochlorite pentahydrate (NaOCl·5H2O) as a green and relatively unexplored reagent. The reactions took place with a small excess of oxidant under environmentally friendly conditions in EtOAc for 16 h at room temperature. Noteworthy distinctions of this transformation are the simplicity, high selectivity, energy and cost efficiency, minimal amounts of non-hazardous waste, isolation of most of the products without the additional need for chromatographic purification, and simple scalability to gram reactions without deterioration of the yield. The reaction exhibited excellent green chemistry metrics with high atom economy (82.0%), actual atom economy (79.5%), reaction mass efficiency (79.7%), E-factor (16.48) and a very high EcoScale score (84.5). Competitive experiments demonstrated that electron-rich substrates are more reactive than their electron-poor counterparts. Furthermore, the Suzuki-Miyaura functionalization of N-trifluoromethylsulfaneylidene sulfoximine could be achieved depending on the conditions, resulting in coupling products with or without an introduced sulfoxide moiety. Sonogashira coupling of N-trifluoromethylsulfaneylidene sulfoximine furnished the expected acetylene derivative in high yield, and the reaction conditions are compatible with the newly introduced sulfaneylidene functionality. Bromine and nickel catalysts were also shown to be deprotecting agents of the sulfoxide group. A selected N-trifluoromethylsulfaneylidene sulfoximine demonstrated its stability in water in the presence of air and in dilute hydrochloric acid, while it converted back to the parent sulfoximine under basic conditions.