Synthesis Of β-Keto Sulfones By Directly Using Sulfonyl Chloride As A Sulfur Source

The development of mild and general methods for C-S bond formation has received significant attention because the C-S bond is indispensable in many important biological and pharmaceutical compounds. As traditionally cheap and commercially available sulfur sources, sulfonyl chlorides are usually employed to form C-O and C-N bonds by the reactions with nucleophiles, like alcohols and amines (For example, Hinsberg test), affording corresponding sulfonate esters and sulfonamides, respectively. The only example concerning using sulfonyl chlorides as electrophiles to form C-S bonds is Friedel-Crafts reaction, in which sulfonyl chlorides react with arenes under metal-catalyzed condition, affording aromatic sulfones. By far, no report has been found concerning utilization of sulfonyl chlorides as electrophiles to react with alkenes to form C-S bonds under metal-free reaction conditions, in which alkenes acting as nucleophiles.β-ketosulfones are widely used as building blocks in synthetic organic chemistry. β-ketosulfones are highly desirable materials owing to their useful fungicidal, antibacterial, as well as other important biological properties. They are widely used in the construction of natural products and various important organic compounds, such as disubstituted acetylenes, allenes, chiral vinyl sulfones, ketones polyfunctionalized 4H-pyrans, lycopodine alkaloid, quinolines and optically active β-hydroxysulfones.Owing to a variety of their biological activities and synthetic utility, numerous methods have been reported in the literature. The traditionally available methodologies for β-ketosulfones mainly include the following:(1) the alkylation sodium sulfinates with a-halo ketones; (2) the oxidation of sodium sulfinates with unsaturated hydrocarbons; (3) the oxidation of the corresponding β-keto sulfides; (4) the oxidation of the vinyl sulfones. However, most of these developed methods still have associated limitation, such as inaccessible starting materials, expensive and relatively harsh reaction conditions. And most important of these mothods employ sulfinic acids or its salts as their sulfonylating agents to synthesize their target β-ketosulfones. However, it especially needs to point out here that sulfinic acids or its salts have very limited commercial availability, and are often prepared from the corresponding sulfonyl chlorides. Thus, the development of new synthetic methods using commercially available and less expensive sulfonyl chlorides as the sulfonylation reagents and a simple, cheap, highly effective new synthesis method toward β-ketosulfones would have genuine synthetic value.Herein, we disclose an efficient one-pot procedure to build a large variety of β-ketosulfones, via direct oxysulfonylation reaction of aromatic alkenes with sulfonyl chlorides in the presence of tert-butyl hydroperoxide (TBHP) under mild and metal-free reaction conditions. The whole methodology has simple process, easy operation, high atom economy, cheap and accessible raw materials and catalysts. In mechanism research, through the isotope labeling, radicals block experiment means, etc, the mechanism of the reaction was in-depth studied.The main contents of this paper are as follows:1. The bio active, chemcial properties and methodologies for the synthesis of β-ketosulfones were introduced and summarized.2. The reaction conditions were optimized:the amount of sulfonyl chlorides, base, solvent, oxidant, temperature and the time with the template reaction of styrene (la)and TsCl(2a).3. Under the optimized conditions, the substrate scope was examined, by employing a large variety of aryl-alkenes as well as aryl or alkyl sulfonyl chlorides. And 25 compounds were synthesized with structural elucidation by NMR and HRMS.4. The mechanism of the reaction was explored by variety of means. Trough the isotope labeling, radicals block experiment means, etc, the mechanism of the reaction was in-depth studied.