An efficient access to β-ketosulfones via β-sulfonylvinylamines: metal–organic framework catalysis for the direct C–S coupling of sodium sulfinates with oxime acetates

A copper-based framework Cu2(OBA)2(BPY) was synthesized and used as a recyclable heterogeneous catalyst for the synthesis of β-sulfonylvinylamines from sodium sulfinates and oxime acetates via direct C–S coupling reaction. The transformation was remarkably affected by the solvent, and chlorobenzene emerged as the best option. This Cu-MOF displayed higher activity than numerous conventional homogeneous and MOF-based catalysts. The catalyst was reutilized many times in the synthesis of β-sulfonylvinylamines without considerably deteriorating in catalytic efficiency. These β-sulfonylvinylamines were readily converted to the corresponding β-ketosulfones via a hydrolysis step with aqueous HCl solution. To the best of our knowledge, this direct C–S coupling reaction to achieve β-sulfonylvinylamines was not previously conducted with a heterogeneous catalyst.


Introduction
Sulfone derivatives have emerged as essential intermediates for the synthesis of numerous compounds with potentially valuable biological activities. [1][2][3][4] Diverse synthetic protocols have been developed for the construction of these skeletons owing to their signicance. Tang et al. previously reported the synthesis of bketosulfones via a tetrabutylammonium iodide-mediated oxidative coupling reaction of sulfonylhydrazides with enamides. 5 Kumar and Muthyala employed 1-butyl-3methylimidazolium p-toluenesulnate as a reagent to afford the corresponding b-ketosulfones. 6 Loghmani-Khouzani and Hajiheidari prepared b-ketosulfones by the reaction of thiols with a-bromoacetophenones, subsequently followed by an oxidation step. 7 Yang et al. demonstrated an efficient protocol to achieve b-ketosulfones via a visible-light initiated direct oxysulfonylation between alkenes and sulnic acids under transition-metal-free conditions. 8 Xie et al. synthesized b-ketosulfones based on a photoinduced radical fragmentation and rearrangement of vinyl tosylates. 9 Recently, Tang et al. reported for the rst time the Cu(OAc) 2 -catalyzed synthesis of b-sulfonylvinylamines from oxime acetates and sodium sulnates, and upon hydrolysis, corresponding b-ketosulfones were readily achieved in high yields. 10 To establish greener pathways to b-ketosulfones, heterogeneous catalysts should be utilized for the formation of b-sulfonylvinylamines to achieve easy catalyst recovery and recycling, as well as facile product isolation and purication.
Metal-organic frameworks (MOFs) are crystalline and selforganizing reticular materials, consisting of metal cations sharing polytopic organic linkers. [11][12][13][14][15] Applications of MOFs in the eld of catalysis are somewhat delaying behind other domains. 16,17 With remarkably high porosity and almost innite synthetic tunability, MOFs have exhibited several advantages in catalysis over non-porous and zeolitic materials. 18,19 Generally, catalytically active sites on MOFs could originate from the metal-based building units or from functional groups on the organic linkers. [20][21][22] The isolation of metal points in the networks would provide a greater number of active sites for the reactants. 23,24 Many organic reactions conducted with MOFsbased catalysts have been declared in the literature. 20,[25][26][27][28] Nevertheless, b-sulfonylvinylamines and b-ketosulfones were not previously synthesized utilizing heterogeneous catalysts, and the exploration of recyclable catalysts should be necessary for the construction of these skeletons. In this manuscript, we would like to illustrate an efficient access to b-sulfonylvinylamines from sodium sulnates and oxime acetates via direct C-S coupling reaction utilizing Cu 2 (OBA) 2 (BPY) metal-organic framework catalysis. The Cu-MOF catalyst was reutilized many times without a noticeably deterioration in catalytic efficiency. These b-sulfonylvinylamines were readily converted to b-ketosulfones with a hydrolysis step with aqueous HCl solution.

Synthesis of metal-organic framework Cu 2 (OBA) 2 (BPY)
In a typical procedure, 4,4 0 -oxybis(benzoic) acid (H 2 OBA) (0.258 g, 1 mmol), copper(II) nitrate trihydrate (Cu(NO 3 ) 2 $3H 2 O) (0.242 g, 1 mmol), and 4,4 0 -bipyridine (BPY) (0.078 g, 0.5 mmol) were dissolved in the mixture of DMF and distilled water (14 mL, 11 : 3 v/v). The mixture was magnetically stirred for 30 min to obtain a clear solution. The solution was subsequently distributed to three 10 mL vials. The vials were carefully capped and heated at 85 C in an isothermal oven for 48 h. Green crystals were formed during the experiment. Aer the vials were cooled to ambient temperature, the solid product in each vial was collected by decantation, and washed in DMF (3 Â 10 mL). Solvent exchange was consequently performed with methanol (3 Â 10 mL) at room temperature. The framework was then dried at 150 C for 6 h under vacuum on a Shlenkline to have 0.29 g of Cu 2 (OBA) 2 (BPY) in the form of green crystals (75% yield regarding H 2 OBA).
In order to achieve 2-(phenylsulfonyl)-1-(thiophen-2-yl) ethanone, aer the rst step, the reaction mixture was cooled to room temperature and ltered to remove the Cu 2 (OBA) 2 (BPY) catalyst. The ltrate was then magnetically stirred with aqueous HCl solution (1 M, 1 mL) at 80 C for 3 h. The resulting mixture was quenched with brine (5 mL), and the organic ingredients were extracted into ethyl acetate (3 Â 5 mL). The combined ethyl acetate solution was dried over anhydrous Na 2 SO 4 . The solvent was subsequently removed under vacuum, and the crude product was puried by silica gel column chromatography utilizing hexane and ethyl acetate (3 : 1, v/v) as eluent to obtain the expected b-ketosulfone. Product structure was subsequently conrmed by GC-MS, 1 H NMR, and 13 C NMR.

Results and discussion
The Cu 2 (OBA) 2 (BPY) was synthesized in 75% yield from 4,4 0oxybis(benzoic) acid, copper(II) nitrate trihydrate, and 4,4 0bipyridine following a literature approach. 29,30 The copperorganic framework was consequently characterized by utilizing conventional analysis methods ( Fig. S1-S7 †). The Cu-MOF was initially used as a heterogeneous catalyst for the direct C-S coupling reaction between 1-(thiophen-2-yl)ethanone O-acetyl oxime and sodium benzenesulnate to produce (Z)-2-(phenylsulfonyl)-1-(thiophen-2-yl)ethenamine (Scheme 1a). First, the inuence of temperature on the reaction yield was explored. The reaction was performed in toluene under argon for 3 h, at 10 mol% catalyst, with reactant molar ratio of 1 : 1 and reactant concentration of 0.25 M, at room temperature, 60 C, 80 C, 100 C, and 120 C, respectively. The reaction did not proceed at room temperature and 60 C with no trace quantity of product being noted. Increasing the temperature to 80 C resulted in only 10% yield. The reaction yield was remarkably improved to 60% for the reaction conducted at 100 C. Boosting the temperature to 120 C did not led to higher yield of the desired product ( Fig. 1). It was noted that the yield of the expected product was improved by changing the reactant molar ratio, having investigated the reaction with 1-(thiophen-2-yl)ethanone O-acetyl oxime : sodium benzenesulnate molar ratio of 2 : 1, 1 : 1, 1 : 1.2, and 1 : 1.5, respectively. The reaction utilizing two equivalents of 1-(thiophen-2-yl)ethanone O-acetyl oxime afforded 69% yield. Similar yield was achieved by employing 1.2 equivalents of sodium benzenesulnate. Increasing the amount of sodium benzenesulnate to 1.5 equivalents was not necessary as the yield of (Z)-2-(phenylsulfonyl)-1-(thiophen-2-yl)ethenamine was not enhanced noticeably (Fig. 2).
As the direct C-S coupling reaction using the copper-based framework catalyst proceeded in solution, changing the solvent could led to higher yield. Tang et al. previously reported for the rst time the Cu(OAc) 2 -catalyzed synthesis of b-sulfonylvinylamines from oxime acetates and sodium sulnates, and pointed out that toluene was the best solvent for this transformation. 10 We consequently studied the impact of different solvents on the yield of (Z)-2-(phenylsulfonyl)-1-(thiophen-2-yl) ethenamine. The reaction was conducted at 100 C in each solvent under argon for 3 h, in the presence of 10 mol% catalyst, with 1.2 equivalents of sodium benzenesulnate and at reactant concentration of 0.25 M. DMSO and DMF were not appropriate for the reaction, producing the b-sulfonylvinylamine product in 18% and 36% yields, respectively. Changing the solvent to mesitylen, 64% yield was observed, while 68% and 66% yields were detected to the case of toluene and cumene, respectively. The yield was upgraded to 86% for the reaction carried out in oxylene. Similarly, 85% and 84% yields were obtained for the reaction in p-xylene and m-xylene, respectively. Moving to 1,4dioxane, the yield was decreased to 65% yield. n-Butanol and ethyl acetate should not be used for this reaction. Compared to these solvents, chlorobenzene emerged as the solvent of choice, affording 87% yield of (Z)-2-(phenylsulfonyl)-1-(thiophen-2-yl) ethenamine (Fig. 3).
One more factor that should be explored is the reactant concentration. We consequently conducted the reaction with various concentrations of 1-(thiophen-2-yl)ethanone O-acetyl oxime, ranging from 0.05 M to 0.50 M. Very low yield of the bsulfonylvinylamine product was detected with reactant concentration of 0.05 M. Extending the concentration to 0.17 M afforded 39% yield. Interestingly, increasing the reactant concentration to 0.25 M signicantly accelerated the transformation, affording 87% yield of (Z)-2-(phenylsulfonyl)-1-(thiophen-2-yl)ethenamine. However, lower yield of the desired product was observed for the reaction with higher reactant concentration (Fig. 4). This could be explained due to the mass transfer of the reactants when a solid catalyst was employed. Having these results, the impact of catalyst quantity on the reaction was consequently explored. The reaction was performed at 100 C in chlorobenzene under argon for 3 h, with 1.2 equivalents of sodium benzenesulnate and reactant    This journal is © The Royal Society of Chemistry 2018 concentration of 0.25 M, in the presence of 5 mol%, 7.5 mol%, 10 mol%, 12.5 mol%, and 15 mol% catalyst, respectively. It was noted that no trace evidence of the b-sulfonylvinylamine product was detected in the absence of the catalyst. Utilizing 5 mol% catalyst resulted in 67% yield, while 73% yield was obtained for the case of 7.5 mol% catalyst. The yield of (Z)-2-(phenylsulfonyl)-1-(thiophen-2-yl)ethenamine was improved to 87% for the reaction utilizing 10 mol% catalyst. Extending the catalyst amount to 15 mol% did not led to higher yield of the desired product (Fig. 5). Noted that benzenesulnic acid was inactive in this reaction, with the desired product being detected in trace amount. Additionally, potassium benzenesulnate was signicantly less reactive than the sodium salt, affording only 16% yield.
To highlight the benet of the Cu 2 (OBA) 2 (BPY) in the direct C-S coupling reaction, its catalytic efficiency was compared to other homogeneous and heterogeneous catalysts. The reaction was conducted at 100 C in chlorobenzene under argon for 3 h, with 1.2 equivalents of sodium benzenesulnate and reactant concentration of 0.25 M, in the presence of 10 mol% catalyst. Several homogeneous copper catalysts displayed reasonable activity for the reaction. The CuCl-catalyzed transformation progressed to 63% yield, while 65% yield was detected for the case of CuBr. Utilizing Cu(OAc) 2 as catalyst, the yield was improved to 72% (Fig. 6). Noted that in the rst Cu(OAc) 2catalyzed synthesis of b-sulfonylvinylamines from oxime acetates and sodium sulnates, Tang et al. pointed out that thiophene oxime acetate was less reactive than benzene oxime acetate. 10 Moving to copper-based MOFs as catalysts, it was noted that MOF-199 and VNU-18 exhibited very low activity towards the direct C-S coupling reaction, with less than 10% yield being recorded. Cu(OBA) was more active, affording the bsulfonylvinylamine product in 55% yield. This value was improved to 71% for the reaction utilizing Cu 2 (BPDC) 2 (DABCO) catalyst, while 74% yield was observed for that employing Cu 2 (BPDC) 2 (BPY) catalyst. Compared to these homogeneous and heterogeneous catalysts, Cu 2 (OBA) 2 (BPY) displayed higher performance, generating the expected product in 87% yield (Fig. 7).
Since the direct C-S coupling reaction between 1-(thiophen-2-yl)ethanone O-acetyl oxime and sodium benzenesulnate proceeded in chlorobenzene, the leaching experiment was then carried out to conrm that if any copper species in the liquid phase contributed to the yield of (Z)-2-(phenylsulfonyl)-1-   (thiophen-2-yl)ethenamine. The reaction was performed at 100 C in chlorobenzene under argon for 3 h, with 1.2 equivalents of sodium benzenesulnate and reactant concentration of 0.25 M, in the presence of 10 mol% catalyst. Upon the completion of the reaction, the copper-based framework catalyst was removed from the reactor by centrifugation. The liquid phase was subsequently transferred to a new and clean screwcap vial. Fresh reagents were consequently added to this vial. The resulting mixture was magnetically stirred at 100 C under argon for 3 h. Under these conditions, no additional (Z)-2-(phenylsulfonyl)-1-(thiophen-2-yl)ethenamine was detected. This result veried that the direct C-S coupling reaction utilizing Cu 2 (OBA) 2 (BPY) catalyst progressed under truly heterogeneous catalysis (Fig. 8).
To gain more information about the pathway of the reaction, (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) was utilized as a radical scavenger. In the rst experiment, TEMPO was added at the beginning of the reaction, and no trace amount of product was detected. In the second experiment, aer the rst 1 h reaction time, TEMPO was introduced to the reactor, and the reaction mixture was magnetically stirred under argon at 100 C for further 2 h. Under these conditions, no additional b-sulfonylvinylamine product was observed. Furthermore, the direct C-S coupling reaction was also allowed to proceed in the presence of 1,1-diphenylethylene. It was noted that the transformation was considerably affected by this radical scavenger. These observations veried that radical species should be involved in the catalytic cycle. With these data, and based on previous report, 10 a plausible pathway was proposed (Scheme 2). Initially, a copper enamide intermediate was produced from the oxime acetate, while copper(II) were converted to copper(III) species. A sulfonyl free radical was then formed via a singleelectron-transfer (SET) process, releasing the copper(II) species. Next, the sulfonyl free radical attacked to the enamide intermediate, followed by the regeneration of the copper(II) species. Finally, tautomerization of the imine intermediate afforded the corresponding b-sulfonylvinylamine.
As mentioned previously, the Cu 2 (OBA) 2 (BPY) displayed higher catalytic performance than numerous homogeneous and MOF-based catalysts. To emphasize the signicance of this catalyst, one important issue would be its reusability. The copper-based framework was accordingly explored for reusability in 10 sequential catalytic runs. The reaction was carried out at 100 C in chlorobenzene under argon for 3 h, with 1.2 equivalents of sodium benzenesulnate and reactant concentration of 0.25 M, in the presence of 10 mol% catalyst. Aer each catalytic cycle, the copper-based catalyst was collected by centrifugation, washed extensively with DMF and methanol, dried at 150 C under vacuum on a Shlenkline for 6 h. This catalyst sample was subsequently utilized for next catalytic run with the same reaction conditions. It was noted that the Cu 2 (-OBA) 2 (BPY) was reusable many times without a substantial deterioration in catalytic efficiency. Certainly, 86% yield of the desired product was still obtained for the 10 th catalytic run (Fig. 9). Additionally, the reutilized catalyst was characterized by XRD ( Fig. 10) and FT-IR (Fig. 11). Analysis results veried that the catalyst structure was preserved during the experiments.

Conclusions
The copper-organic framework Cu 2 (OBA) 2 (BPY) was utilized as a recyclable heterogeneous catalyst for the direct C-S coupling reaction between sodium sulnates and oxime acetates to produce b-sulfonylvinylamines. The solvent expressed a remarkable impact on the transformation, and chlorobenzene emerged as the best option. This Cu-MOF was more active towards the coupling reaction than a series of copper-based homogeneous and MOF-based catalysts. The coupling reaction utilizing Cu 2 (OBA) 2 (BPY) catalyst progressed under truly heterogeneous catalysis. The catalyst was reutilized many times in the synthesis of b-sulfonylvinylamines without a considerably deterioration in catalytic efficiency. These b-sulfonylvinylamines were promptly converted to corresponding b-ketosulfones via a hydrolysis step with aqueous HCl solution. The fact that b-sulfonylvinylamines were generated under a heterogeneous catalysis approach, and readily converted to b-ketosulfones upon hydrolysis, was consequently protable to pharmaceutical and agrochemical industries.

Conflicts of interest
There are no conicts to declare.