Recent advances in copper-catalyzed C-S cross-coupling reactions

Copper-catalyzed cross-coupling reactions offer a powerful tool for the formation of carbon-heteroatom bonds. Copper catalysis has an indisputable advantage over the other catalytic systems due to its low cost and the use of readily accessible and stable ligands. Among the various copper-catalyzed coupling reactions, C-S bond forming reactions have gained much attention due to its applications in the synthesis of molecules having biological and pharmaceutical impact. This review illustrates the current strategies and applications of Cu-catalyzed C-S cross coupling reactions.


Introduction
2][3][4] The transition metal catalyzed cross-coupling reactions offer a powerful strategy for the construction of aryl-sulfur bonds.This approach involves the coupling of organic halides with thiols.Despite the importance of this reaction protocol in organic synthesis, transition metal catalyzed thioetherification received lesser attention, compared to other carbon-heteroatom bond forming reactions.The strong chelating property of sulfur causes catalyst poisoning, rendering the catalytic reaction ineffective.However, recently there has been considerable progress in the area of transition metal catalyzed organosulfur chemistry.
Migita et al. used Pd(PPh 3 ) 4 as a catalyst for the coupling reaction between aryl iodides and bromides with thiols under mild conditions. 57][8][9] But these systems have limitations since they require the preparation and use of PR 3 ligands which are not eco-friendly.Catalytic systems based on other transition metals such as nickel [10][11][12][13] , cobalt 14 and iron 15 have also been studied.These catalytic systems also suffer from certain disadvantages like metal toxicity, low turnover numbers etc.But there is much interest in the development of copper based catalytic systems because of the low cost of Cu and use of readily accessible and stable ligands.Many attractive Cu-catalyzed coupling processes have been reported by various research groups.7][18][19][20] This review highlights the existing strategies for copper-catalyzed C-S bond forming reactions and covers the literature from 2004-2014.
The classical Cu-catalyzed reaction between thiols and aryl halides required stoichiometric amounts of copper salts, polar solvents and high temperature. 21In recent years there is an upsurge of reports on C-S bond formation using various ligands such as phosphazene P 2 -Et base, neocuproine etc., primarily due to the high stability and low cost of copper.

Different Catalytic Systems
In this review we classify the catalyst systems according to the nature of the ligand present in the complex

Cu-Nitrogen complexes
Venkataraman et al. have used CuI-neocuproine (2,9-dimethyl-1,10-phenanthroline) complex for the coupling of aryl iodides with aryl and alkyl thiols in presence of NaO t Bu in toluene at 110 o C, affording the products in excellent yields (Scheme 1).Scheme 1. Cu-catalyzed synthesis of sulfides using neocuproine as ligand.
Electron-rich aryl iodides gave better yields in this reaction.The substituents on the oposition of the aryl iodide or thiol did not affect the rate of the reaction.
Electron-withdrawing and electron donating groups as well as ortho substituents on the aryl iodide are tolerated in the reaction affording moderate yields of the thioether.
A copper-catalyzed cross-coupling of heterocyclic thiols with aryl iodides was reported by Niu et al. 24 The reaction was carried out in the presence of CuI, 1,10-phenanthroline and K2CO3 in DMF at 120 ºC, affording the heterocyclic sulfides in high selectivities and yields.(Scheme 3) Scheme 3. CuI-catalyzed carbon-sulfur bond formation of heterocyclic thiols with aryl iodides.
Electronic and steric effects of the substituents on the thiol did not affect the rate of the reaction.Heterocyclic thiols also gave excellent yields.
Electron rich and electron poor aryl boronic acids afforded good yields of the products.However alkylboronic acids are found to be unsuitable for this transformation.A number of functional groups such as Me, OMe, F, Cl, CF3, NO2, CO2H, on the arylboronic acid are tolerated in the reaction.
Sekar et al. synthesized diarylthioethers from thiols and aryliodides in presence of BINAM-Cu(OTf)2 complex and Cs2CO3 in DMF at 110 o C (Scheme 6). 27The reaction was unaffected by the position of substituents on the aryl iodide.Scheme 6. Cu-catalyzed synthesis of sulfides using BINAM ligand.
Electron donating and weakly electron withdrawing groups on aryl chloride failed to give the thioether and aryl halides containing strong electron withdrawing groups afforded the thioether product by nucleophilic substitution reaction in the absence of BINAM-Cu catalyst.
Benzotriazole was also found to be an efficient ligand for C-S coupling reactions. 28Aryl iodides and aryl bromides coupled with aryl thiols and alkyl thiols in presence of 0.5 mol% CuI and 1 mol% benzotriazole in DMSO at 100 ºC affording the sulfides in >90% yield (Scheme 7).Aryl bromides required only 80 ºC for the reaction to get good yields.Scheme 7. Cu-catalyzed synthesis of sulfides using benzotriazole as ligand.
A variety of functional groups were found to be compatible with the reaction.
An environmentally benign diaryl thioether coupling in water has been reported recently. 29nder the optimized reaction conditions, aryl thiol and aryl iodide or aryl bromide were heated in water at 120 ºC in the presence of CuCl and trans-1,2-diaminocyclohexane (Scheme 8).A large variety of functional groups, both electron donating and electron withdrawing as well as free NH2 and -OH on the aryl iodide partner and aryl thiol partner were found to be compatible with the reaction.Scheme 8. Cu-catalyzed synthesis of sulfides using trans-1,2-diaminocyclohexane ligand in water.
Steric effects arising from o-substitution has not shown much influence on the product yield.Aryl bromides are also good substrates for this reaction but restricted to those containing electron withdrawing groups like NO2, Ac, CF3 and F. To accommodate electron rich aryl bromides, an in situ halogen exchange (Br-I) was carried out on 4-bromoaniline in presence of CuCl, diamine and NaI in water followed by treatment with thiol and diamine, which led to the product (phenyl 4-aminophenyl sulfide) in good yield (84%).The green coloured aqueous solution obtained after removing the product could be further used for three consecutive reaction cycles without isolation and reactivation of the catalyst and without any loss of activity.Scheme 9. Cu-catalyzed coupling of thiol with aryl halide using tris-(2-aminoethyl)amine ligand.
Shingare and co-workers developed an efficient methodology for the copper-catalyzed C-S cross-coupling reactions of aryl halides with thiols using a tripodal ligand, tris-(2aminoethyl)amine. 30 (Scheme 9)
A variety of functional groups in the phenylboronic acid such as methoxy, nitro, CF3, fluoro etc. were tolerated in the reaction.Notably, functional groups sensitive to reducing conditions (eg.NO2) were unaffected in this reaction.
At the same time, Buchwald and Kwong reported a simple thioether formation protocol from aryl iodides and aryl/alkyl thiols using CuI, ethyleneglycol and K2CO3 in isopropanol at 80 o C (Scheme 11). 32Functional groups such as cyano, nitro, keto, amino, hydroxyl, carboxylic acid, aldehyde, on the aryl iodide are compatible with the reaction.The reaction is also tolerant of steric hindrance as many o-substituted aryl iodides yielded the thioethers in excellent yields.Aliphatic thiols are also found to be efficient nucleophiles in this reaction.Buchwald then used the protocol in the coupling of 6-iodoimidazo[1,2-a]pyridine with thiophenols and obtained the products in moderate yields. 33cheme 11.Cu-catalyzed synthesis of sulfides using ethyleneglycol as ligand.
The β-ketoester used in C-N and C-O coupling reaction was also found to be an efficient ligand for C-S bond formation. 34Aryl iodides containing electron donating and electron neutral groups reacted with electron rich and electron neutral thiols in the presence of CuBr, β-ketoester ligand and Cs2CO3 in DMSO at 60-75 o C affording very high yields of the corresponding diarylthioethers (Scheme 12).Scheme 12. Cu-catalyzed synthesis of sulfides using ethyl 2-oxocyclohexanecarboxylate.
The S-arylation reactions of thiols with aryl halides catalyzed by N,N′-dioxide/ CuI catalytic system was reported by Chen et al. 35 The reaction was carried out in presence of Cs2CO3 in DME at 80 o C.(Scheme 13) Scheme 13.Cu-catalyzed S-arylation of thiols with aryl halides using N,N′-dioxide as ligand.
In the limited examples studied, methoxy and keto groups on the aryl iodide and methoxy and chloro on the aryl thiol were found to be compatible with the reaction.
Biologically active thioethers were synthesized by CuI catalyzed coupling of aryl or heteroaryl chlorides with aryl mercaptan using racemic trans-cyclohexane-1,2-diol. 37asu et al. have used catechol violet as a ligand for the CuI catalyzed thioether formation in DMF at 70-90 ºC in which electron rich and electron deficient aryl iodides afforded good yields of the products. 38

Cu-N and O bidentate ligand complexes.
Guo et al. reported a thioether synthesis using CuI-N-methylglycine system in presence of KOH in dioxane at 100 o C (Scheme 15). 39heme 15.Cu-catalyzed synthesis of sulfides using methylglycine as ligand.
Aryl iodides having electron donating or electron withdrawing groups gave very good yields with alkyl and aryl thiols.Aryl bromides also afforded the sulfide but the rate of reaction was low.The reaction could also be carried out in DMF solvent and with K3PO4 as base.
This procedure was then modified by Ma et al. using L-proline at lower temperature. 40Thus aryl iodides reacted with aryl and alkyl thiols in presence of 10 mol% CuI, 20 mol% L-proline and K2CO3 (or K3PO4 for aliphatic thiols) in DME at 80 ºC affording excellent yields of the products.(Scheme16) Scheme 16.Cu-catalyzed synthesis of sulfides using L-proline as ligand.
Both electron withdrawing and electron donating groups on the aryl iodide as well as osubstituted aryl iodides afforded very high yields of the thioether products with both aryl and alkyl thiols.

Cu nanoparticles
Cu nanoparticles have excellent catalytic activity because of their high surface to volume ratios.A ligand-free diaryl or aryl alkyl thioether formation was achieved between aryl iodides and aryl/alkyl thiols using Cu nanoparticles under microwave irradiation (120 ºC) in less than 10 min.in presence of K2CO3 in DMF. 41Many functional groups including free NH2 and OH were tolerated in the reaction.Substituents at the ortho position of the aryl iodide did not affect the reaction.
CuO nanoparticles are also found to be efficient catalyst for C-S bond formation. 42Aryl and alkyl thiols underwent coupling reaction with aryl iodides in presence of 1.26 mol% CuO nanoparticles and KOH in DMSO at 80 ºC affording in most cases quantitative yields of the products in less than 10h (Table 1).Electron donating groups on thiols were found to be more reactive than electron withdrawing groups.Electron withdrawing groups on the aryl iodides enhanced the yield of the sulfide product.The catalyst was found to be suitable for reuse up to three cycles without appreciable loss of activity.
Babu and Karvembu reported a nano CuO-catalyzed C-S cross coupling of aryl halides with thiophenol in presence of KOH as a base in dimethylacetamide (DMAc) at room temperature under ligand-free conditions (Scheme 17). 43Another nano copper oxide catalyzed cross coupling reaction of thiols with aryl iodides in [bmmim]BF4 was reported by Braga et al (Scheme 18). 44Compared to the usual organic solvents, [bmmim]BF4 exhibited more efficiency as it can be reused up to four successive runs.

Scheme 18. CuO nanoparticle-catalyzed S-arylation of thiols with aryl iodides.
This reaction offers a strategy to obtain diaryl or alkyl aryl sulfides from aryl iodides and thiols using CuO nanopowder in ionic liquid as a reusable medium.
Kamal and coworkers developed a method for C-S bond forming reactions, catalyzed by copper oxide nanoparticles supported on graphene oxide, employing weak bases like triethyl amine. 45A variety of aryl sulfides were synthesized using this strategy.The authors extended the scope of this method for the synthesis of symmetrical diaryl sulfides from thiourea and aryl iodides.

Ligand free catalytic systems
The general approach for Cu-catalyzed C-S cross coupling reactions is the use of a catalytic amount of copper salt, always in presence of a ligand and a base under relatively mild conditions.But in some cases the coupling can even be carried out under ligand-free conditions.The ligandfree catalytic procedures are interesting since it avoids the use of expensive and time consuming preparation of ligands.
van Koten and coworkers reported an efficient C-S bond forming reaction of aryl iodides and thiophenol under ligand free conditions. 46The reaction was catalyzed by CuI in presence of K2CO3 base in N-methylpyrrolidinone at 100 ºC (Scheme 19).A variety of diaryl thioethers were synthesized with good functional group tolerance.Another ligand-free protocol for C-S coupling of thiols with aryl iodides was reported by Wang et al. 47 The reaction was catalyzed by CuI-PEG or CuI-PEG-H 2 O system (Scheme 20).A variety of functionalized aryl sulfides were synthesized in excellent yields by this method.Both aryl thiols and aliphatic thiols reacted well with the aryl iodides.
For iodochalcogenophenes, 5 mol% CuI and KOH base and for bromo derivatives, 10 mol% CuI and K3PO4 were found to be the best reagents.The reaction was found to be insensitive to the electronic nature of thiol and also the nature of the substitution at the ortho position.Notably, no ligand was used in this reaction.
Feng et al. explained a ligand-free copper-catalyzed C-S cross coupling of thiols with aryl iodide using KF/Al2O3 as base. 49The reaction was carried out in DMF at 110 ºC (Scheme 22).Scheme 22. Cu-catalyzed C-S cross coupling of thiols with aryl iodide using KF/Al2O3 as base.
Feng et al. also reported a ligand-free copper-catalyzed C-S cross coupling of benzothiazole with aryl iodides in aqueous solution to form 2-aminophenyl sulfide derivatives (Scheme 23). 50he reactions were catalyzed by CuCl with tetrabutylammonium hydroxide as base and water as the solvent at 50 ºC.

Scheme 23. Cu-catalyzed C-S cross coupling of benzothiazole with aryl iodides.
Recently, Peters et al. reported the first photo-induced copper-catalyzed cross coupling reaction between aryl thiols and aryl halides via single electron transfer under mild conditions (0 o C) (Scheme 24). 51The inexpensive CuI was used as the precatalyst without the need of any ligand.This new strategy can be applied for the efficient cross coupling of a broad range of aryl thiols with a wide array of functionalized aryl halides.
Scheme 24.Photo-induced Cu-catalyzed C-S cross coupling reaction of aryl thiols with aryl halides.

Supported Cu catalysts
Islam et al. reported the synthesis of a furfural functionalized polymer-amine grafted with copper which was used as an excellent catalyst for S-arylation reactions of various aryl halides with aryl thiols in water medium (Scheme 25). 52The catalyst could be reused for several consecutive cycles with consistent catalytic activity.A copper modified amine-functionalized zirconia which could be used as an efficient catalyst for C-S coupling reactions was developed by Parida and co-workers. 54The amine functionalization provides a better loading and uniform distribution of the Cu particle in the zirconia surface.The catalyst shows good catalytic activity and recycling efficiency.

Mechanism
Although the mechanism of Cu-catalyzed C-N coupling has been extensively studied, the corresponding C-S bond formation has not received much attention.
The copper(I)-catalyzed Ullmann-type C-S coupling reaction generally consists of a ligand, a base and a copper salt.Better yields are obtained when a ligand was used in combination with a copper(I) catalyst indicating that the proposed intermediate of the reaction could be a Cu(I) complex chelated with the additive ligand. 55n the proposed mechanism of copper(I)-catalyzed C-S coupling reaction, the base deprotonates the thiol generating a thiolate, which may then replace the counter anion of the copper source and produce a copper complex Cu(I)L(SR) with the thiolate and the ligands. 56An oxidative addition of the aryl halide (ArI) to the complex takes place to produce the intermediate Cu(III)LArI(SR).This intermediate regenerates the Cu(I)LI and the desired product ArSR by reductive elimination.Another proposed mechanism involves the oxidative addition of the aryl halide to form Cu(III)LArI followed by the substitution of the I-with the RS-to form Cu(III)LAr(SR). [57][58][59][60] However, the intermediates from the catalytic reaction has not been directly observed or isolated, and the mechanism of the catalytic reaction has not been well established so far.
An in situ electrospray ionization mass spectrometry (ESI-MS) study of the copper(I)catalyzed Ullmann-type C-S coupling reaction under catalytic reaction condition was carried out by Shyu and coworkers. 61Thus coupling reaction between iodobenzene and thiophenol was studied using catalytic CuI in presence of potassiun tert-butoxide as base and 1,10 phenanthroline as ligand in toluene at 120 o C for 6h.Complexes [Cu(SPh)2] -, [Cu(SPh)I] -and K[Cu(SPh)2(Ph)] + were observed under the catalytic reaction conditions indicating that they are intermediates in the reaction.A reaction mechanism was proposed based on these observations (Scheme 27).
The reaction of thiophenol with potassium tert-butoxide and CuI generates the complex [Cu(SPh)2] -which on reaction with iodobenzene produces the intermediate [Cu(SPh)2(Ph)I] - through an oxidative addition reaction.Reductive elimination of diphenyl thioester generates [Cu(SPh)I] -which subsequently reacts with PhS -to form [CuSPh)2] -and completes the catalytic cycle.

Applications
Carbon-heteroatom bond forming reactions have emerged as one of the most versatile and powerful tool in organic synthesis.The products of such transformations are often used as fine chemicals, pharmaceuticals, dyes and polymers.Many synthetic methodologies involving carbon-heteroatom coupling reactions have been developed.Among them, C-S bond forming reaction gained much attention since thioethers are of great significance due to their broad spectrum of therapeutic activities.The C-S bond forming reactions are widely used in pharmaceutical research, material synthesis and process development in industry and academia.
Bardajee demonstrated an efficient synthesis of fluorescent naphthalimide dyes via a CuIcatalyzed C-S cross coupling reaction between benzylthiol and 4-bromo-N-isobutylnaphthalimide (Scheme 28). 62 Nowadays the significance of vinyl sulfides has increased greatly, since they can be used as complementary building blocks to carbonyl compounds and Michael acceptors for the synthesis of many polymeric materials, natural products and synthetic reagents.Conventional methods for the synthesis of vinyl sulfides require harsh reaction conditions.Liu et al. developed a novel method for the synthesis of aryl sulfides via a Cu-catalyzed decarboxylative cross coupling of aryl propiolic acids with thiols (Scheme 29). 63The reaction was catalyzed by CuI in presence of Cs2CO3.A broad range of thiols reacted with aryl propiolic acids to form the corresponding vinyl sulfides in good to excellent yields with high stereoselectivity for Z-isomers.Scheme 29.Cu-catalyzed synthesis of vinyl sulfides.
Compounds containing a cyanamide functional group gained attention in synthetic organic chemistry because of their unique structure and reactivity.Punniyamurthy and coworkers reported a one-pot synthesis of 2-(arylthio)aryl cyanamides using cheap and air stable CuSO4.5H2O as a catalyst by domino intra-and inter-molecular C-S cross coupling reactions of 2-(iodoaryl)thioureas with aryl iodides under ligand free conditions (Scheme 30). 64heme 30.Cu-catalyzed synthesis of 2-(arylthio)aryl cyanamides.
Another protocol for the synthesis of 2-(arylthio)aryl cyanamide derivatives was demonstrated by Shao et al (Scheme 31). 65They synthesized the cyanamides via a coppercatalyzed domino C-S cross coupling of 2-aminobenzothiazoles with aryliodides.This protocol was also applied to the regioselective copper(I) catalyzed C-H hydroxylation/ C-S coupling of aryl thiols with vinyl halides for the synthesis of 2-(styrylthio)phenol derivatives. 67(Scheme 32) The 2-(styrylthio)phenols have been employed in synthesis of many bioactive compounds.Scheme 32.Cu-catalyzed C-H hydroxylation/ C-S coupling of aryl thiols with aryl and styryl halides.

Conclusions
This review highlights the recent developments in copper-catalyzed carbon-sulfur bond forming reactions.The C-S bond forming reactions serve as powerful tools in synthetic organic chemistry for the synthesis of various molecules that are of biological, pharmaceutical and material interest.Even though various other transition metals are used for catalyzing C-S cross coupling reactions, copper is found to be the most suitable one, as it is less toxic and inexpensive.This review also demonstrates the use of copper nanoparticles as an efficient catalyst for C-S cross coupling reactions.

Scheme 27 .
Scheme 27.The proposed mechanism for Cu-catalyzed C-S coupling by Shyu et al.

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