Green Chemistry: Air-Triggered Catalyst- and Oxidant-Free Decarboxylative Oxysulfonylation of Arylpropiolic Acids With Sodium Sulnates

The exploration of novel green synthetic strategies to obtain useful organic molecules is one of the most important missions for sustainable development. Herein, an ecient and sustainable decarboxylative oxysulfonylation between arylpropiolic acids and sodium sulnates has been established, providing a broad scope of β-ketosulfones in excellent yields. The reactions proceed at room temperature employing air as the only oxidant and oxygen source without extra catalyst, oxidant, and additive. Additionally, the reaction is scalable, and the products have been easily isolated by simple recrystallization, avoiding the chromatographic purication. Mechanistic studies have also been conducted to reveal that the reaction proceed via a radical mechanism.


Introduction
Over the last few decades, decarboxylative-coupling reaction of carboxylic acids has become an important and robust instrument in the synthetic chemist's toolkit (Goossen et  The eld of decarboxylative C-S bond-forming reactions remained relatively quiet. In 2009, Duan (Duan et al. 2009) reported the rst direct decarboxylative coupling between ortho-substituted aryl carboxylic acids with thiols to produce aryl sul des. Later, a number of processes have been devised in the C-S bond construction through decarboxylative strategy (Shen et al. 2015;Hosseinian et al. 2018). In this context, most of these cases could be summarized into two patterns ( Fig. 1a): (i) The cross-coupling reactions of C-M species with various sulfurative reagents after transition-metal-mediated decarboxylation of carboxylic acids; (ii) The oxidants triggered radical coupling reactions of carbon radical with sulfur radicals through the decarboxylation of carboxyl radical. However, these methods always required expensive and toxic metal catalysts, photoredox catalysts, and external oxidants, which severely limited their application in pharmaceutical and industrial manufacturing. Hence, the catalyst-and oxidant-free decarboxylative C-S bond forming reactions are incontrovertibly in great demand but remain largely underdeveloped. General procedure for the synthesis of Arylpropiolic Acids (1) A 10 mL vessel was charged with caesium carbonate (6 mmol), silver (I) oxide (1 mol%) and dimethyl sulfoxide (DMSO) (5 mL). The reaction vessel was purged with carbon dioxide, and the alkyne (5 mmol) was added via syringe. The resulting mixture was stirred for 16 h at 50 ℃ at ambient CO 2 pressure. At the end of the reaction, the reaction mixture was cooled to room temperature and diluted with water. Then the aqueous layer was acidi ed with aqueous HCl and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO 4 ), ltered and the volatiles were removed in vacuo to afford the corresponding arylpropiolic acids 1.
General procedure for the synthesis of sodium sul nate substrates (2) A 25 mL round bottom ask was charged with sodium sul te (20 mmol), sodium bicarbonate (20 mmol) and deionized H 2 O (10 mL). After stirring for 5 min, the sulfonyl chloride (10 mmol) was added portionwise to the ask. The mixture was heated to 80 o C in an oil bath for 12 h. After cooling to room temperature, water was removed under vacuum, affording the crude sul nate salt. Recrystallization of the residue in ethanol afforded the corresponding sodium sul nates 2.
General procedure for the synthesis of β-keto sulfones (3) A mixture of aryl alkynes 1 (1 mmol), sul nates 2 (10 mmol) and HFIP was stirred at 25 °C under air atmosphere for 6 h. Upon completion, the solvent was removed by rotary evaporation. The residue was extracted with EA (3 × 30 mL). The organic phase was washed with water and brine, respectively. The solvent was concentrated in vacuo and puri ed by recrystallization to give the desired β-keto sulfones 3.

Results And Discussion
The research originated from the reaction of phenylpropiolic acid 1a with sodium benzenesul nate 2a. β-Ketosulfone product 3aa was generated in 32% yield in hexa uoroisopropanol (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, tri uoromethyl, 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 sul nates were evaluated. Benzenesul nates bearing electron-donating groups such ast Bu, -OMe, and -NHAc provided up to 90% yields (3bb-3bd). Sul nates with moderate to strong electronwithdrawing groups (e.g., halogen, OCF 3 , CN, NO 2 ) 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 sul nates. Pleasingly, both cyclic and acyclic alkyl sul nates 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 e ciency. 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 e ciently 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 2,2,6,6tetramethyl-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 (O 2 ·− ) 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 18 O 2 (97%) atmosphere, the 18 O-labled ratio of the ketone 3aa was 68% (Fig. 1e., SI). Furthermore, performing the reaction in the presence of H 2 18 O (10 equiv.) under the optimal conditions, only 6% 3aa was labled with 18 O (Fig. 1f., SI).
These results indicated that the molecular oxygen was the oxidant as well as the O-source of the products.

Conclusion
In summary, we have developed a practical and green decarboxylative oxysulfonylation between arylpropiolic acids and sodium sul nates that allows the rapid synthesis of diversely functionalized βketosulfones. This reaction features mild and sustainable conditions, simple operation, good functional group tolerance, and broad substrate scope. Moreover, this is the rst solely dioxygen triggered decarboxylative oxysulfonylation reaction of arylpropiolic acids, which enriches the repertoire of the molecular oxygen in the decarboxylative coupling reactions toward sustainable synthesis of various valuable compounds. General information, general experimental procedure, mechanism studies, characterization data for compounds and NMR spectra of compounds (PDF)

Notes
The authors declare no competing nancial interest. The recent C-S bond-forming process via decarboxylative-coupling transformations and strategies for the β-keto sulfone synthesis.

Figure 3
Gram-scale reaction and late-stage oxy-sulfonylation of bioactive molecules. Plausible mechanism.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. SupportingInformation.pdf