Strategies for oxidative synthesis of N-triflyl sulfoximines

Abstract

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.

Scheme 1. Previous and current work.

Scheme 2. Proposed mechanism for the oxidation of sulfides 2 to their corresponding sulfones 3 with NaOCl·5H₂O.

Scheme 3. Removal of trifluoromethythio group with concomitant chlorination.

Scheme 4. Proposed mechanism for the oxidation of sulfides 2 with m-CPBA.

Scheme 5. Gram scale reactions.

Scheme 6. Further functionalizations of 3x.

Scheme 7. Nitration of 3b.

Scheme 8. Oxidation of N-sulfenylated sulfoximine.