The research originated from the reaction of phenylpropiolic acid 1a with sodium benzenesulfinate 2a. β-Ketosulfone product 3aa was generated in 32% yield in hexafluoroisopropanol (HFIP) at room temperature for 10 hours. Motivated by this initial result, various conditions were screened to promote the isolated yield to 93% (Table 1, Supporting Information (SI)). We then set out to investigate the generality of this method. First, a vast array of alkynyl carboxylic acids were tested (Fig. 2). Methyl, methoxyl, and phenyl substituted substrates were well-tolerated to give corresponding products in 81%-91% yields. Product with bromo group (3af) was prepared in 90% yield. Electron-withdrawing groups such as cyano, trifluoromethyl, ester, and aldehyde groups were compatible with the conditions, and the corresponding products were synthesized in the yields of 73–86% (3ae, 3ag-3ai). Thienyl and naphthyl propiolic acids were also suitable substrates, and offering 3am and 3an in 88% and 90% yields, respectively. Next, the scope of sodium sulfinates were evaluated. Benzenesulfinates bearing electron-donating groups such as -tBu, -OMe, and -NHAc provided up to 90% yields (3bb-3bd). Sulfinates with moderate to strong electron-withdrawing groups (e.g., halogen, OCF3, CN, NO2) remained suitable under the conditions (3be-3bi, 69%-85%). Naphthyl and thiophenyl-substitued counterparts took part in this transformation equally well, leading to 3bj and 3bq in the yields of 81% and 92%, respectively. Further efforts were made to evaluate the alkyl sulfinates. Pleasingly, both cyclic and acyclic alkyl sulfinates delivered products in nearly quantitive yields (3bl-3bm).
To demonstrate the synthetic utility of the developed chemistry, the reaction was carried out in 10 mmol scale, and the target product was synthesized without loss of efficiency. Following similar procedures, some representative biologically active molecules such as 3af (anti-analgesic agents) (Abdel-Aziz et al. 2014), 3ag (11β-hydroxysteroid dehydrogenase type I inhibitors) (Xiang et al. 2007), and 3an (carboxylesterase 1) (Han et al. 2018) were also obtained in gram scale from the corresponding arylpropiolic acids (Fig.3a). It is noteworthy that, the estrone unit, which broadly exist in drugs and bioactive molecules, could be efficiently assembled into 5 in over 90% yield (Fig.3b). This outcome highlighted the applicability and versatility of the present protocol.
Next, some experiments were carried out to probe the possible mechanism. The addition of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) into the reaction mixture gave no desired products (Fig. 1a., SI), which indicated that the reaction might be involved in a radical pathway. Then, in the presence of diphenylethene, a sulfonylative adduct 6 was detected by HRMS (Fig. 1b., SI), inferring the generation of sulfonyl radical. Moreover, when butylated hydroxytoluene (BHT) was added to this reaction system, the desired reaction was diminished dramatically and the capture of the superoxide radical anion (O2·−) was observed by HRMS (BHT-OOH, 7) (Fig. 1c., SI). On the other hand, the oxo-sulfonylation did not occur under nitrogen atmosphere (Fig. 1d., SI). When we studied the reaction under 18O2 (97%) atmosphere, the 18O-labled ratio of the ketone 3aa was 68% (Fig. 1e., SI). Furthermore, performing the reaction in the presence of H218O (10 equiv.) under the optimal conditions, only 6% 3aa was labled with 18O (Fig. 1f., SI). These results indicated that the molecular oxygen was the oxidant as well as the O-source of the products.
Based on the aforementioned results and previous works (Chen et al. 2020; Lu et al. 2013; Lu et al. 2015), a tentative reaction pathway is depicted in Fig. 4. Initially, sodium sulfinate was activated by oxygen via autoxidation with formation of oxygen radical A, resonating with sulfonyl radical B, while producing superoxide radical anion O2·−. Subsequently, the addition of B to alkynyl acids 1 offered vinyl radical C, which could be further trapped by dioxygen to form the peroxy radical D. Afterwards, intermediate D undergoes a single electron transfer (SET) to generate peroxide anion intermediate E. Besides, the capture of O2·− by the intermediate C may also generated the intermediate E, which further went through intramolecular proton transfer (PT) to render the hydroperoxide intermediate F. Finally, the reduction of intermediate F furnished species G, followed by isomerization to give the desired β‑keto sulfone 3.