Phototropin-Inspired Chemoselective Synthesis of Unsymmetrical Disulfides: Aerobic Oxidative Heterocoupling of Thiols Using Flavin Photocatalysis

Abstract

Inspired by the photochemical mechanism of a plant blue-light receptor, a unique flavin-based photocatalytic system was developed for the chemoselective heterocoupling of two different thiols, which enabled the facile synthesis of unsymmetrical disulfides. Owing to the redox- and photo-organocatalysis of flavin, the coupling reaction took place under mild metal-free conditions and visible light irradiation with the use of air, which is recognized as the ideal green oxidant.

Green Aerobic Oxidation of Thiols to Disulfides by Flavin–Iodine Coupled Organocatalysis

“…When the reaction was carried out in the absence of I 2 and under the strong visible-light irradiation from a white LED, poor yield and selectivity were observed (Scheme 3A, entry c). Unlike the previously reported photocatalyzed aerobic oxidation of thiols under basic conditions in the presence of 1a, 15 this reaction was carried out under neutral conditions and was not significantly influenced by photocatalysis.…”

“…The previously reported 1a-catalyzed photooxidation system required basic conditions (Scheme 1A); thus, acidic substrates such as 2q and 2r could not be used. 15 To our delight, however, the flaviniodine-catalyzed reaction tolerated a variety of functional groups, including basic amino groups and acidic hydroxy or carboxy groups, to give 3o-r.…”

“…13b,14 Furthermore, we recently reported the photocatalytic synthesis of symmetrical and unsymmetrical disulfides via aerobic oxidative coupling of thiols under visible light irradiation by using riboflavin tetraacetate (1a) as the photo-organocatalyst, which can be readily derived from inexpensive and commercially available riboflavin (vitamin B2) (Scheme 1A). 15 Herein, we report the novel aerobic oxidation of thiols via a dual catalytic system by using 1a and iodine, thus providing a facile synthesis procedure for disulfides under metal-free mild conditions without the need for light irradiation (Scheme 1B). First, we investigated the effects of various flavin catalysts, iodine sources, and solvents on the oxidation of 1-octanethiol (2a) under air (1 atm, balloon) in MeOH at 26 °C for 4 h (Tables 1, S1, and S2).…”

“…When the reaction was carried out in the absence of I2 and under the strong visible light irradiation of a white LED, poor yield and selectivity were observed (Scheme 3Ac). Unlike the previously reported photocatalysis of 1a, which was performed for the aerobic oxidation of thiols under basic conditions, 15 this study was carried out under neutral conditions and was not significantly influenced by photocatalysis. Based on the experimental results of this study and previous reports, we proposed a plausible catalytic cycle for the flaviniodine-catalyzed aerobic oxidation of thiols, as shown in Scheme 4.…”

Synthetic applications of flavin photocatalysis: a review

“…Iida et al 66 have developed the chemoselective synthesis of unsymmetrical disuldes using the oxidative heterocoupling reaction of two different thiols. The riboavin-based catalyst successfully promoted the formation of the phototropin-like avin-thiol adduct under visible light irradiation, the mild reactivity of adduct, played a crucial role in the chemoselective cross-coupling.…”