Electron‐Deficient Alloxazinium Salts: Efficient Organocatalysts of Mild and Chemoselective Sulfoxidations with Hydrogen Peroxide

Abstract

A series of substituted alloxazinium perchlorates has been prepared and tested as catalysts for the oxidation of sulfides to sulfoxides with hydrogen peroxide. The logarithms of the observed rate constants of thioanisole oxidation correlate with the Hammett s constants of the substituents on the alloxazinium catalysts, as well as with their reduction potentials E 0' and their pK R+ values, representing the alloxazinium salt/pseudobase equilibrium. The stronger the electron-withdrawing substituent, the more efficient is the alloxazinium catalyst. The alloxazinium salts with a cyano or trifluoromethyl group in position 8 proved to be the most efficient, operating at room temperature at small loadings, down to 0.1 mol%, achieving turnover number values of up to 640 and acceleration by a factor of 350 relative to the non-catalyzed oxidation. The 8-cyanoalloxazinium perchlorate was evaluated as the best catalyst; however, due to its relatively good accessibility, the 8-(trifluoromethyl)alloxazinium perchlorate seems to be the catalyst of choice for sulfoxidations with hydrogen peroxide. It was successfully tested for the sulfoxidation of a series of aliphatic and aromatic sulfides on a preparative scale. It produced the corresponding sulfoxides in quantitative conversions and with high isolated yields (87-98%). No over-oxidation to sulfone was ever observed.

A Click Chemistry Approach towards Flavin-Cyclodextrin Conjugates—Bioinspired Sulfoxidation Catalysts

“…Probably, use of oxygen in place of hydrogen peroxide in oxidations with flavin-cyclodextrin conjugates, analogously to enzymes (combined with a sacrificial reducing agent [2]), would be a way to eliminate some background non-selective oxidations. The other way to improve our catalytic systems could be to optimize the solvent conditions or to increase the reactivity of flavin subunit by introduction of a strong electron-withdrawing group to flavin benzene ring [6].…”

“…Within the last three decades, flavinium salts have been shown as useful tools for the organocatalytic activation of hydrogen peroxide and oxygen allowing various oxidations to proceed under mild conditions [1,2,3]. In particular, extensive research on H 2 O 2 -sulfoxidations catalyzed by flavinium salts has resulted in several useful synthetic procedures for mild, chemoselective and stereoselective transformations of sulfides to sulfoxides [4,5,6,7,8,9]. In these artificial systems, flavinium salts Fl mimic the function of flavin co-factors in monooxygenases [10] via the in situ formation of flavin-4a-hydroperoxide FlOOH , which subsequently oxidizes the substrate (Scheme 1).…”

Artificial Flavin Systems for Chemoselective and Stereoselective Oxidations

“…Investigation of the effects of substituents in the 7‐ and 8‐positions on the behaviour of alloxazinium salts 2 in H 2 O 2 sulfoxidations showed that electron‐withdrawing groups improved the efficiencies of the catalysts (Figure 3). 36 Electron‐withdrawing groups significantly increase the electrophilicities of alloxazinium salts, as expressed by the reduction potentials E 0 and the p K R+ values (Table 3), thus enhancing their ability to add a neutral nucleophile. The catalytic activities of the alloxazinium salts without co‐catalysts correlate with their reduction potentials and p K R+ values, as well as with the Hammett constants.…”

“…No over‐oxidation to sulfone was observed. The stability of 2k was documented by three consecutive catalytic runs in methyl p ‐tolyl sulfide oxidation taking place without loss of activity 36…”

Thiosemicarbazone organocatalysis: tetrahydropyranylation and 2-deoxygalactosylation reactions and kinetics-based mechanistic investigation

“… 15 In spite of the widespread use of organocatalysts and the demand for insight into the way in which they operate, there are very few examples of Hammett analyses performed with focus on the organocatalyst, and none of these investigations were expanded to also include a Hammett analysis of the substrate. 16 …”