Diaryl sulfides constitute an important class of therapeutic agents in medicinal chemistry ^[1,2,3,4,5]. Therefore,the development of efficient and mild methods for the synthesis of these compounds represents a broad area of organic chemistry. In recent years,C-S cross-coupling reaction has drawn high attention due to their promise in numerous bioactive natural products and pharmaceuticals.

    Traditional methods for the synthesis of diaryl/aryl alkyl sulfides involve reduction of aryl sulfones or aryl sulfoxides using strong reducing agents ^[6]. To overcome these harsh conditions, transition-metal compounds via catalyzed cross-coupling systems, such as nickel ^[7,8,9,10],palladium ^[11,12],lanthanum ^[13],indium ^[14],have been developed.

    Some of the methods for the C-S bond formation using crosscoupling systems involves reaction of aryl diazoniumfluoroborate and diaryl disulfides ^[15],coupling of aryl or alkyl thiols with aryl halides ^{[8,16,17,18,19,20]},cross-coupling reaction of aryl halides and ethyl potassium xanthogenate ^[21,22],reaction of phenolic esters such as acetates,triflates,tosylates and phosphonates with alkyl halides by using thiourea as a sulfur source ^[23],reaction of aryl halides with aminothiourea ^[24],oxidative sulfidation of diaryl disulfides with aryltrimethoxysilanes ^[25],reaction of thiourea with aryl halides ^[26].

    Previous approaches to the synthesis of diaryl/aryl alkyl sulfides usually require more drastic conditions,such as high reaction temperature,use of stoichiometric amounts of the catalyst,use of ligands together with highly toxic metals. Also,it must be noted that all of the previous methods suffer from the lack of recyclability,which represent more obstacles for the utility of this chemistry in parallel synthesis.

    Heterogeneous catalysis is of paramount importance in many are as ^{[27,28,29,30,31,32]}. Heterogeneously catalyzed processes have recently been brought to many scientists as comparatively more efficient methodologies because facile recovery and reusability of the catalysts can be done with these processes. Also stability of the catalyst and even sometimes its activity will be improved when heterogeneously a catalytic system is used ^[33,34]. Among these heterogeneous catalysts,magnetic nanoparticles have emerged as an attractive method due to their numerous applications in organic synthesis ^{[35,36,37,38,39,40,41,42,43,44]}. Copper/iron oxide based catalysts are environmentally compatible,air and moisture insensitive,and separation from reaction mixture is very simple by means of an external magnetic field ^[45,46,47].

    Only two new reports of magnetically separable CuFe₂O₄ as a catalyst in synthesis of diaryl chalcogenides has been published in the literature. The first report on magnetically separable,recyclable nano-CuFe₂O₄ catalyzed reaction of aryl/alkyl iodides with aryl/alkyl thiols has been published by Nageswar and co-workers in 2011 ^[48]. Two years later,organoselenides and organotellurides have been synthesized by a simple reaction of organoboronic acids and dichalcogenides using CuFe₂O₄ nanoparticles without any ligand ^[49]. These two works encouraged us to use copper/iron oxide based nanoparticles for S-arylation reaction of thiourea by aryl halides.

    On the direct synthesis of diaryl sulfides from the reaction of thiourea and aryl halides,few reports have been published in literatures ^{[23,26,50,51,52,53,54]}. In this paper,we describe a methodology for the synthesis of these symmetrical sulfides using a ligand-free and high-recyclable magnetic catalyst. This methodology gives access to a wide variety of symmetrical aryl sulfide derivatives under milder conditions (Scheme 1).

Scheme 1

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Scheme 1.S-Arylation of thiourea by aryl halides in the presence of nano-CuFe2O4.

    Nano-CuFe₂O₄ was prepared with a modified method according to the literature ^[55]. Both 1.51 g Cu(NO₃)₂.3H₂O and 5.04 g Fe(NO₃)₃.9H₂O were dissolved in 100 mL distilled water,then added to 50 mL of 4 mol/L NaOH solution followed by heating and aging at 90 ℃ for 2 h. The prepared nanoparticles were centrifuged, washed by water and dried at 80 ℃ overnight. Finally the powder was calcined at 800 ℃ for 2 h. X-ray diffraction,FT-IR,SEM and EDX analyses confirmed the formation of the nano-CuFe₂O₄(Figs. S1-S6 in Supporting information). The average particles size was 23.5 nm by the Scherrer equation. 2.2. General procedure for the synthesis of diphenyl sulfane

    In a typical experiment,a flask equipped with a magnetic stirrer was charged with 0.2 mmol base,0.25 mmol thiourea (1 equiv.), 0.5 mmol iodobenzene (1 equiv.),1 mL DMF and 10 mol% nano-CuFe₂O₄ catalyst. This mixture was heated at 120 ℃ in an oil bath for 12 h. The progress of the reaction was monitored by TLC (n-hexane). Then the reaction mixture was cooled to room temperature,and the catalyst was separated magnetically. The supernatant was extracted with 10 mL n-hexane (for five times). The organic layer was dried with CaCl₂ and then the solvent removed under reduced-pressure to give the product. In some cases,derivatives of diphenyl sulfide were purified by column chromatography on silica gel (with n-hexane) to give the pure diaryl sulfide. All products are known compounds and were identified by comparison of their properties (¹H NMR and ¹³C NMR) with those of authentic samples ^{[26,56,57,58,59,60]}; these data were given in the Supporting information. 3. Results and discussion

    To optimize reaction conditions,we undertook an intensive screening of reaction variables using iodobenzene as representative substrate (Table 1). These studies were carried out using a variety of different bases (Na₂CO₃,K₂CO₃,Cs₂CO₃,NaOH and KOH). Among the studied bases,Cs₂CO₃ and K₂CO₃ were the best (Table 1, entries 1 and 8). Replacing Cs₂CO₃ by the less expensive K₂CO₃ had no deleterious effect on the reaction. Yields of the product increased with increasing amounts of the base,so,three equivalents of K₂CO₃ were chosen as a standard amount of base for this reaction (Table 1,entry 13). Adjusting the reaction mixture showed that no product was formed in the absence of the base (Table 1,entry 15). Optimization with respect to the solvent showed that the reaction proceeds best in DMF (Table 1,entry 1). This solvent gave better results than other solvents,such as NMP, DMSO,CH₃CN (Table 1,entries 2-4). No product has been observed in the presence of water as a reaction medium (Table 1,entry 5). Screening was also performed at different temperatures and results showed that no reaction occurred below 100 ℃ (Table 1, entries 17 and 18). Ultimately,the optimal temperature was determined to be 120 ℃,and this was then used as a standard for the optimization of other parameters. The ratio of thiourea to aryl iodide was also optimized. An excess of thiourea is generally required to achieve the best coupling results. In our experiments,it was shown that a 100% excess of thiourea (2 equiv.) provided full conversion to the product in 24 h (Table 1,entry 16) when monitored by GC. Finally,the amounts of the catalyst were also examined in the range of 1-30 mol% of the nano-CuFe₂O₄ and it was found that 10 mol%,and in some cases 20 mol%,gave the most consistent results (Table 1,entries 13,14 and 16). Without nano-CuFe₂O₄,no product was observed and even running the reaction in the presence of low amounts of the catalyst (1-2 mol%) did not meet with success (Table 1,entries 10 and 11). To probe more fully the role of the copper in the reaction,we ran the coupling reaction in the presence of nano-CoFe₂O₄ as a source of cobalt and failed to obtain any product. This,therefore,suggests that copper is essential to the success of the reaction.

Table 1">Table 1

Table 1 Optimization of the nano-CuFe2O4catalyzed coupling of iodobenzene with thiourea under various conditions.a

Table 1 Optimization of the nano-CuFe2O4catalyzed coupling of iodobenzene with thiourea under various conditions.a

    We next decided to investigate the scope of the reaction via this modified procedure. The S-arylation reaction of thiourea was performed with a wide variety of aryl and alkyl halides (Table 2). Among all of the aryl halides studied by this reaction,both electron-donating substituents and electron-withdrawing substituents are found to be compatible. The reaction was found not to be sensitive to steric hindrance by a substituent ortho to the halide (Table 2,entry 4). Unfortunately,alkyl halides were unreactive under these conditions. We also investigated S-arylation of 2-bromopyridine as a heterocyclic compound due to their importance and found that this substrate successfully thio-etherified and afforded the corresponding symmetrical sulfides in good yields.

Table 1">Table 2

Table 2 Scope of the reaction of aryl halides and thiourea,catalyzed by CuFe2O4nanoparticles.a

Table 2 Scope of the reaction of aryl halides and thiourea,catalyzed by CuFe2O4nanoparticles.a

    The same protocol was also used in the presence of two different aryl halides to investigate a comparative study. Iodobenzene and 4-iodotoluene were used as substrates and finally both symmetrical and unsymmetrical aryl halides were synthesized (Scheme 2).

Scheme 2

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Scheme 2.Study of reactivity of S-arylation of thiourea with two different aryl halides.

    A comparison of the catalytic efficiency of CuFe₂O₄ with selected previously known catalysts is collected in Table 3. Diphenyl sulfane was produced in 12 h when our catalytic system was used,whereas when nano-CuO was used as catalyst,more reaction time was needed to produce diphenyl sulfane in good yields. Also,it should be mentioned that K₂CO₃ is preferred over Cs₂CO₃ due to the low cost of K₂CO₃,so the less expensive base was used in this work when it is compared with two other reported heterogeneous catalysts as shown in Table 3. Application of the cheaper base and shorter reaction time,along with the ability to separate the catalyst with an external magnet,make our conditions more suitable to other reported works ^[26,54].

Table 1">Table 3

Table 3 Comparison of protocols for the S-arylation of thiourea by iodobenzene.

Table 3 Comparison of protocols for the S-arylation of thiourea by iodobenzene.

    Finally,in order to examine the recyclability of the catalyst, spent CuFe₂O₄ was easily recovered from the reaction media and re-used. For recycling,after the first use,the catalyst was separated from the reaction mixture by a magnet,washed with ethanol successively,then with water and finally dried at 110 ℃ for 2 h. The regenerated CuFe₂O₄ was used for the S-arylation of thiourea by iodobenzene under the optimum reaction conditions to study the performance of the re-used catalyst (Table 4). No significant changes in yield of diphenylsulfane were observed after regeneration until the sixth cycle.

Table 1">Table 4

Table 4 The catalyst re-used under the optimum reaction conditions for acetylation of phenol.a

Table 4 The catalyst re-used under the optimum reaction conditions for acetylation of phenol.a