Nano copper oxide catalyzed synthesis of symmetrical diaryl sulfides under ligand free conditions

Potassium thiocyanate acts as an efficient sulfur surrogate in C–S cross-coupling reactions mediated by recyclable copper oxide nanoparticles under ligand free conditions. This protocol avoids foul smelling thiols, for the synthesis of a variety of symmetrical diaryl sulfides, via the cross-coupling of different aryl halides with potassium thiocyanate, affording corresponding products in moderate to excellent yields.


Introduction
After the discovery of copper-promoted Ullmann reaction [1][2][3] for the construction of carbon-hetero atom bonds, several protocols have been reported over the years to establish C-N, C-O, and C-S linkages. Carbon-sulfur bonds are widespread, occurring in numerous pharmaceutically and biologically active compounds [4][5][6][7][8]. A large variety of aryl sulfides are in use for diverse clinical applications in the treatment of cancer [9], HIV [10,11], Alzheimer's and Parkinson's diseases [12].
These recently developed protocols involve expensive catalytic systems and ligands [43], long reaction times [43,44], metal contamination of the final product, and non recyclability of the catalyst. This leads to increased costs as well as limiting the scope of the reaction. From the synthetic point of view, it is desirable to find novel recyclable catalytic systems, especially under ligand-free conditions, for the synthesis of such highly useful organic compounds.
In the past few years, considerable efforts have been made in the area of heterogeneous catalysis for various organic transformations. In general, heterogeneous catalysts offer higher surface area and lower coordinating sites, which are responsible for their higher catalytic activity [45][46][47]. Furthermore, heterogeneous catalysis has the advantage of high atom efficiency, easy product purification, and reusability of the catalyst. However, up until now, the investigation of nanoparticles as catalysts has been limited and will be widely studied in future.

Results and Discussion
In continuation of our investigations on metal-catalyzed crosscoupling reactions, we have explored the CuO-catalyzed synthesis of diaryl sulfides under ligand-free conditions (Scheme 1). To the best of our knowledge, this is the first recyclable copper oxide nanoparticle-catalyzed cross-coupling of aryl halides with potassium thiocyanate [46][47][48][49][50][51]. Initially, the reaction between potassium thiocyanate and iodobenzene was selected as the model reaction for optimizing the reaction conditions involving various copper sources, bases, solvents, and temperature (Table 1).  entries 1 and 2). The ideal temperature for the reaction was found to be 130 °C.
A study was conducted on C-S cross-coupling reaction using various sulfur sources under these conditions ( Table 2). Among these sulfur surrogates potassium thiocyanate gave good yields in this C-S cross-coupling reaction.
While expanding the scope of this nano CuO catalyzed tandem cross-coupling, the reaction of potassium thiocyanate with various aryl halides was examined under the optimized conditions. In general, all the reactions were very clean, and the  symmetrical aryl sulfides were obtained in moderate to good yields. This protocol efficiently coupled iodobenzenes with electron donating groups (e.g., Me, OMe and Et) with potassium thiocyanate to produce the corresponding products in excellent yields (Table 3, entries 4, 6 and 8), whereas in the presence of an electron withdrawing group (CF 3 , NO 2 ) a slight decrease in the yield of the diaryl sulfide (Table 3, entries 12 and 13) was observed. Under these reaction conditions, various hetero aromatic iodides were reacted with potassium thiocyanate and gave the corresponding diaryl sulfides in appreciable yields (Table 3, entries 15, 16 and 17). In case of the reactions of aromatic and hetero aromatic bromides with potassium thiocyanate, longer reaction times were required in order to obtain reasonable yields of diaryl sulfides (Table 3, entry 2, 5, 7 and 18). Iodobenzene was found to be a more reactive substrate than bromo, and chloro benzenes (Table 3, entries 1, 2 and 3).

Conclusion
We have developed a CuO nanoparticles catalyzed synthesis of symmetrical diaryl sulfides via cascade reaction of aryl halides with potassium thiocyanate under ligand free conditions. The reaction avoids foul smelling thiols and the catalyst is economical, air stable, functions under ligand free conditions and is recyclable for up to four cycles without loss of catalytic activity [20,[39][40][41] (Table 4). The progress of the reaction was monitored by TLC. When the reaction was complete, the reaction mixture was allowed to cool, a 1:1 mixture ethyl acetate and water (20 mL) was added and the CuO was removed by centrifugation. The organic layer was washed successively with brine and water, and dried with Na 2 SO 4 . The solvent and volatiles were completely removed under vacuum to give the crude product, which was purified by column chromatography on silica gel to yield the analytically pure product in up to 94% yield. The identity and purity of the product was confirmed by 1 H and 13 C NMR spectroscopy.

Supporting Information
Supporting Information File 1 Experimental details and spectroscopic data for new compounds.