Chemoselective Oxidation of Thiols with Oxoammonium Cations

Abstract

The oxidation of various aryl and aliphatic thiols with the commercially available and environmentally benign reagent Bobbitt's salt (1) has been investigated. The reaction affords the corresponding disulfide products in good to excellent yields (71−99%) and can be accomplished in water, methanol, or acetonitrile solvent. Moreover, the process is highly chemoselective, tolerating traditionally oxidation-labile groups such as free amines and alcohols. Combined experimental and computational studies reveal that the oxidation takes place via a polar two-electron process with concomitant and unexpected deoxygenation of the oxoammonium cation through homolysis of the weak N−O bond, differing from prototypical radical-based thiol couplings. This unusual consumption of the oxidant has significant implications for the development of new nitroxide-based radical traps for probing S-centered radicals, the advancement of new electrochemical or catalytic processes involving nitroxide/oxoammonium salt redox couples, and applications to biological systems.

Organic Synthesis Using Nitroxides

“…1109 In the oxidative homocoupling of thiols using an oxoammonium salt, N−O bond cleavage was also observed, and by using 0.55 equiv of Bobbitt's salt, near quantitative yields were obtained for formation of disulfides. 1110 Arylthiol coupling was also achieved with a catalytic amount of TEMPO under oxygen atmosphere upon light irradiation 1111 or at elevated temperature (Scheme 59b). In the presence of amines, S−N bond formation was realized (Scheme 59c).…”

Recent advancements in the use of Bobbitt's salt and 4-acetamidoTEMPO

“…The oxidation of sulfur-containing functional groups using both nitroxyl radicals and oxoammonium salts has also been investigated, but is much less developed when compared to alcohol and amine oxidations. 8,43–50 Nitroxyl radicals were reported to react with thiols to afford disulfide and sulfonic acid products decades ago by Morrisett and Drott, 43 but the chemistry was not further developed or understood for some time. In the early 1990's Osa, Bobbitt, and co-workers harnessed this reactivity and used an 4-amido-TEMPO-modified graphite electrode to electrochemically oxidize thiols to disulfides through a proposed one-electron oxidation mediated by the nitroxyl radical.…”

“…46 The mechanism of how thiols undergo oxidation by oxoammonium cations to afford disulfide products was not well-understood until very recently (Schemes 12–14). 8…”

“…During development of a protocol for the oxidation of thiols to disulfides using 1 , Weierbach, Lambert, and co-workers noted that the oxidation was remarkably chemoselective for the thiol functionality, even in the presence of other traditionally oxidation-labile groups such as alcohols or free amines. 8 Furthermore, the experimental observation that the recovered, reduced form of the oxoammonium cation was not the prototypical hydroxylamine ( 32 ), but rather a piperidinium tetrafluoroborate salt ( 50 ), a result of a deoxygenation event, led them to conduct experimental and computational mechanistic studies to investigate the nature of disulfide bond formation by 1 .…”

“…Given the growing and wide-ranging application of Bobbitt's salt ( 1 ) and ACT ( 2 ) across several fields, this feature article aims to highlight recent advancements in their use, mechanistic underpinnings, and application. Our contributions 4–14 in expanding the utility, accessibility, and understanding of these two oxidants over the past 10 years and continued exploration of these reagents will offer a first-hand perspective towards the past and current trajectory of these oxidants as they proliferate into several fields of chemistry.…”