Developing and Exploiting New Photoreductants in Radical Chemistry

The activation of typically inert organic compounds via SET reduction is a significant goal in synthetic chemistry. This doctoral thesis focused on studying and developing novel photochemical strategies to activate a wide range of such compounds and generate radical species. The objective was to utilize these radicals to facilitate synthetically valuable transformations, enabling the construction of useful chemical bonds. To achieve this target, we designed and developed organic catalysts and intermediates that, upon light excitation, access a highly reducing excited state and subsequently function as potent SET reductants.

Activating relatively inert substrates, such as fluoro- and chloro-arenes, alkyl chlorides, and unsubstituted arenes, via SET reduction is difficult due to their strong covalent bonds and low reduction potentials. Although a few strategies are available for the reduction of certain functional groups, each method typically targets only specific substrates. To develop a general and practical protocol based on a single photocatalyst capable of activating a wide variety of inert substrates, we identified a highly reducing anionic indole thiolate organocatalyst. Upon excitation with visible light, this catalyst can consistently achieve the activation of inert C–F, C–Cl, and C–O bonds, as well as the Birch-type reduction of unfunctionalized arenes, all through SET reduction.

Leveraging the strongly reducing anionic indole thiolate organocatalyst, which we previously designed for generating aryl radicals, we developed a thiol-free organocatalytic method that couples aryl chlorides with alkyl alcohols under mild conditions, producing a diverse array of aryl alkyl thioethers. A key aspect of this method was the discovery that 1,1,3,3-tetramethylthiourea can serve as a simple sulfur source, intercepting aryl radicals generated through SET activation of aryl chlorides. The subsequent SET oxidation forms aryl isothiouronium ions, known polar intermediates in the thiol-free synthesis of thioethers via deoxythiolation with nucleophilic alcohols. Formation of under photochemical conditions allows for an intersection with the deoxythiolation pathway, leading directly to thioethers in a mild and selective manner.

Traditional methods for their preparation predominantly rely on thiols, which often possess undesirable traits including unpleasant odor, limited commercial variety, and air instability. Building on our previous findings, where we demonstrated that isothiouronium salt can be easily generated by trapping aryl radicals with 1,1,3,3-tetramethylthiourea, we aimed to extend this strategy to thioester synthesis by substituting alcohols with carboxylic acids as nucleophiles in the deoxythiolation path. Surprisingly, we discovered that 1,1,3,3-tetramethylthiourea could be directly excited with light. Unlike the previous study, this protocol is centered on the direct excitation of 1,1,3,3-tetramethylthiourea and its versatile role as both a sulfur source and a photoreductant. It facilitates the generation of aryl radicals via SET activation of aryl halides, which are then trapped to form reactive isothiouronium ions. These intermediates, through the well-established polar deoxythiolation process, lead to the formation of the desired thioesters under mild conditions.