R. V. Patil
,
J. U. Chavan
and
A. G. Beldar
*
PSGVPM’S Arts, Science & Commerce College, Shahada Dist.- Nandurbar, Maharashtra 425409, India. E-mail: dragbeldar@gmail.com
First published on 3rd May 2017
Aminothiazoles and their derivatives are of immense biological importance and have been consistently synthesized via various methods. However, the synthesis of aminothiazole derivatives has some problems such as poor yields, difficult isolation procedures, use of expensive catalysts etc. Recently, polymer or solid-supported synthetic protocols have attracted the attention from the research community because of their easy execution, increased product yields, greater selectivity, simple work-up procedures, and recoverability of the catalysts. In this study, we reported the polymer-supported approaches for the synthesis of differently substituted aminothiazoles.
In the present review, we attempted to highlight the synthesis of aminothiazoles using polymer-supported strategies. In addition, this review covers the use of polymer-supported catalysts in the synthesis of aminothiazoles and polymer-mediated or co-mediated synthesis. The nature of the polymeric support may be either organic (multi-functionalised resins, polyethylene glycol—PEG etc.) or inorganic (such as silica, alumina etc.). In some of methods, supramolecules, such as β-cyclodextrin, have been used as the catalyst, whereas some syntheses are microwave-assisted. This review will provide useful insights for the researchers from the area of polymer-supported synthesis of bioactive heterocyclic motifs.
Patrick C. Kearney, Monica Fernandez, and John A. Flygare have demonstrated a new method for the synthesis of 2-aminothiazoles (21)46 from a primary amine and α-bromo ketones (19), and aminothiazoles (21) was obtained in good yield and with a high degree of purity. The backbone of this method is the conversion of a resin-bound amino group to a thiourea 18 using Fmoc-NCS (17). Scheme 2 shows the steps for the synthesis of 2-aminothiazoles.
Herein, three different resin types (16) were employed in the same procedure. The use of Rink amide MBHA resin yielded thiazoles that were unsubstituted at the 2-amino position, whereas thiazoles substituted at the 2-amino position were generated from ArgoGel-MB-CHO resin that was reductively aminated in two steps. A compound was generated from glycine linked to Rink amide MBHA resin; in this case, the 2-amino group of thiazole did not serve as the point of attachment to the resin.
In 2000, M. Kidwai, B. Dave, and K. R. Bhushan firstly reported a basic alumina (inorganic polymer)-supported synthesis of 2-aminothiazoles from halo carbonyl compounds and substituted thiourea under solvent-free conditions using microwave radiations (Scheme 3).47
The reaction time was drastically reduced with improved yields as compared to that in the conventional method. Basic alumina was added to the solution of phenacyl bromide 22 and N-substituted thiourea 23 dissolved in dichloromethane at room temperature. The reaction mixture was thoroughly mixed, and the adsorbed material was dried in air (beaker) and placed in an alumina bath inside a microwave oven and irradiated.
Roman Baer and Thierry Masquelin in 2001 reported a novel solid-phase synthesis of 2,4-diaminothiazoles from a polymer-bound thiouronium salt 27. The synthetic strategy involved the formation of polymer-bound thioureido–thiourea intermediates 29, which upon treatment with α-bromo-ketones 30 underwent S-alkylation, followed by a base-catalyzed intramolecular ring closure/cleavage to provide 2,4-diaminothiazoles 32 (Scheme 4).48 The attractive feature of this method is the polymer-supported auto-scavenging strategy (PSAS), which provides a clean, high-yielding, and traceless synthesis towards 2,4-diaminothiazoles.
The diethylaminomethyl polystyrene resin 31 was used to activate the intermediate and isolate the HBr by-product. After the base-catalyzed intramolecular-cyclization/cleavage process, the resulting resin-bound thiol was used to remove the excess of the α-bromo ketones 30, affording the polymer-bound thioether derivatives 34. They effectively illustrated the concept of the polymer-supported auto-scavenging strategy (PSAS), affording highly pure 2,4-diaminothiazoles 32, separated from the polymer-bound derivatives 33 and 34 after simple filtration and evaporation. This was an advantage over other strategies for producing 2,4-diaminothiazoles.
Michael C. Pirrung and Sunil V. Pansare demonstrated the synthesis of 2-aminothiazole-5-carboxylates using trityl chloride resin49 (35) as the starting solid support, which was subsequently converted to the trityl isothiocyanate (TrITC) resin 36. The polymer-supported thiourea 37 prepared from 36 was subjected to condensation with a methyl 2-chloroacetoacetate50 38 and released the 2-aminothiazole-5-carboxylic acid methyl esters as their hydrochloride salts 39, which were converted to their free bases 40 by a solid-supported neutralization with sodium carbonate (Scheme 5).
In 2002, Frank Stieber and co-workers reported51 a new method for the polymer-supported synthesis of 2-amino thiazoles, which involved a traceless hydrazide linker,52 as well as the biological evaluation of the synthesized aminothiazoles. The polymer bound amide 43 was synthesized by coupling monomethyl adipicate 42 with amino-functionalized polystyrene 41 and the subsequent saponification of the methyl ester upon treatment with LiOH (Scheme 6). The acid-functionalized resin 43 was then converted into the p-nitrophenylhydrazides 45 upon activation with N,N-diisopropylcarbodiimide (DIC) and N-hydroxybenzotriazole (HOBt) and treatment with differently substituted 4-nitrophenylhydrazines 44. The two hydrazide nitrogen atoms in 45 were acylated with Fmoc-Cl (Fmoc = fluorenylmethoxycarbonyl) before reduction of the nitrobenzene groups to anilines, as shown in Scheme 6. The polymer-bound thiourea 50 was further reacted with α-bromoketone 19 to produce polymer bound aminothiazoles 51. Finally, the targeted aminothiazoles 52 were sequestered from the solid support upon treatment with a catalytic amount of Cu(OAc)2 in n-propylamine and purging with O2 for the reoxidation of Cu+ formed in the oxidation of the linker group. The traceless cleavage of the linker was achieved via oxidation of phenylhydrazide to acyldiazene and subsequent nucleophilic attack on the carbonyl group (Scheme 7). Although this novel synthetic strategy involved a large number of steps to synthesize the aminothiazoles, it has contributed a diverse range of new structural motifs to the library of aminothiazoles, which show potential bioactivity.
Mitsuo Kodomari, Tadashi Aoyama, and Yoshitada Suzuki developed a method for the synthesis of 2-aminothiazoles from α-bromo ketones in one-pot using a supported-reagent system, KSCN/SiO2–R1NH3OAc/Al2O3, in which the α-bromo ketone 19 reacted first with KSCN/SiO2 (ref. 53) and the product α-thiocyano ketone reacted with R1NH3OAc/Al2O3 to provide the final product 2-aminothiazole 21 in high yield. This synthesis involved two steps in one-pot (Scheme 8).54 After completion of the reaction, the used solid reagents were removed by filtration. The filtrate was then evaporated to obtain the crude products, which were purified by column chromatography over silica gel. The authors also employed α-chloro ketones as the substrate in the one-pot procedure to produce their corresponding 2-aminothiazoles in high yields as in the case of the α-bromo ketones. Although this solid-supported strategy is simple and efficient, both supported reagents were required in a large excess to obtain high yields.
Said El Kazzouli and co-workers in 2002 demonstrated that the α-bromo ketone derived from the Rink amide resin loaded with 3-iodobenzoic acid after two steps could be subsequently treated with thiourea to obtain a variety of 2-aminothiazoles (Scheme 9).55 The resin 53 was deprotected with 20% piperidine in N,N-dimethylacetamide. 3-Iodobenzoic acid was bound onto the Rink amide resin 54 under standard peptide coupling conditions.56
A palladium(0)-mediated coupling reaction was performed on resin 55 in the presence of tributyl(1-ethoxyvinyl)tin, triphenylarsine,56 and tris(dibenzylidene acetone)dipalladium(0) as the catalyst via heating at 50 °C under argon in 1,4-dioxane to obtain the resin 56. The conversion of 56 to α-bromoketone 57 was achieved upon treatment with N-bromosuccinimide in a mixture of THF and water (4:1). 2-Aminothiazoles 58 were obtained by treating the resin 57 with an ethanol solution of thiourea at 50 °C. The resin bound aminothiazoles 58 were derivatized at the –NH2 position upon reaction with an acyl chloride or p-toluenesulfonyl chloride in a mixture of pyridine/dichloromethane (1/1) at room temperature. Resin cleavage using TFA provided 2-aminothiazoles 59. After seven steps, the yields varied from 33 to 78% with excellent purity.
In 2003, Alan R. Katritzky, Xiaohong Cai, and Boris V. Rogovoy synthesized trisubstituted resin bound thioureas and demonstrated their applications in the synthesis of triazoles and thiazoles.57 Resin-bound amines 63 were obtained in three steps:58 the conversion of Wang resin 60 into the brominated resin 61; its subsequent nucleophilic substitution with 4-hydroxybenzaldehyde in the presence of potassium tert-butoxide; and a standard reductive amination in the presence of an amine and sodium triacetoxyborohydride (Scheme 10). 63 condensed with acyl isothiocyanates to provide N-acylated thiourea resins 64 (R1 = H). Condensation of resins 64 with 2-bromoacetophenones in the presence of TEA affords thiazoles 65. After cleavage of the solid support, the desired substituted aminothiazoles 66 were obtained in 62–80% isolated yields. The steps in Scheme 10 were also performed using Merrifield resin instead of Wang resin and resulted in similar results.
Ill Young Lee and co-workers in 2005 reported a solid-phase synthetic strategy for the synthesis of trisubstituted aminothiazoles using resin-bound cyanodithioimidocarbonic acid and α-bromoketone.59 The resin-bound thiazole was treated with acyl chlorides or isocyanates.
After oxidation–activation of a thioether linker to a sulfone linker, traceless cleavage was achieved with nucleophiles to obtain trisubstituted aminothiazoles (Scheme 11). Merrifield resin 25 was treated with dipotassium cyanodithioimidocarbonate, which was prepared from CS2, KOH, and cyanamide in aqueous ethanol.60 The obtained resin 66 requires to be washed with water because the salt form of the resin-bound cyanodithioimidocarbonic acid is difficult to filter with organic solvents. Subsequently, resin 66 was reacted with 2-bromoacetophenone or ethyl bromoacetate and triethylamine to obtain the polymer bound 4-aminothiazoles 67. Sulfonyl resin 68 was obtained by MCPBA oxidation, an application of the solution-phase thiazole synthesis.61,62 The desired thiazoles 69 were liberated from resin 68 using the nucleophilic addition of amines (primary and secondary) and anilines. The reaction of thiazole resin 67 with isocyanate or acid chloride gave the desired resin-bound thiazole urea 70. Then, oxidation and amine addition gave the corresponding thiazoles 71. Some new differently substituted aminothiazoles were synthesized in 28–42% yield after four steps.
In 2006, Tadashi Aoyama and co-workers reported a method for the synthesis of 2-aminothiazoles in one pot using a supported reagents system, KSCN/SiO2–NH4OAc/Al2O3, in which an α-halo ketone 72 (X = Cl and Br) reacted first with KSCN/SiO2 and the product α-thiocyanatoketone 73 reacted with NH4OAc/Al2O3 to provide the final product 2-aminothiazoles 74 in good yield (Scheme 12).63
Kumaran G. Sreejalekshmi and co-workers in 2006, efficiently synthesized 2,4-diamino-5-ketothiazoles 78 using polymer-supported amidinothioureas 77 derived from aminomethylpolystyrene 75. The resin 75 was prepared from Merrifield resin using a standard literature procedure.64 Amidinothioureas 77 were treated with α-haloketones 30 to produce 78, an approach involving traceless cleavage from the support in good yield. It was reported that the second step tracelessly removes the solid support via eliminative aromatization to afford the 2,4-diamino-5-ketothiazoles 78 (Scheme 13).65 Although this strategy involved a solid-support protocol, the targeted products were purified by column chromatography. Reuse of the resin was found to be inefficient and it enormously affected the yield.
In 2007, Tadashi Aoyama and co-workers demonstrated a one-pot three-step synthetic strategy for the synthesis of aminothiazoles using an inorganic-supported reagents system.66 The effectiveness of the one-pot three-step reaction was compared with the reaction of 79 with solid-supported reagents in a sequence of steps and also in one pot (Scheme 14); the yields obtained from the one-pot strategy were found to be higher than those obtained from the stepwise method.
After optimization of the reagent system, differently substituted diones 83 were subjected to react with all the required reagents in one-pot to form aminothiazoles 84 (Scheme 15). This reported one-pot method provides a highly efficient synthesis of 2-aminothiazoles when compared to the stepwise method, and all three reagents were uneventfully removed from the crude products by simple filtration.
In 2009, Andrew Cole and co-workers reported the synthesis of 2-amino-5-benzoyl-4-(2-furyl) thiazoles 90, adenosine A2A receptor antagonists.67 The amino-functionalized polystyrene resin 85 was acylated with an acid-cleavable linker, 4-(4′-formyl-3′-methoxy)phenoxybutyric acid, to obtain the aldehyde 86 (Scheme 16).68 A resin-bound secondary amine 87 was generated by reductive alkylation of a series of primary amines (R1NH2) with 86. Subsequently, the reaction of 87 with different acylisothiocyanates gave the N-acyl thioureas 88. The resin-bound 2-aminothiazoles 89 were obtained upon the S-alkylation of 88 with a series of α-bromoketones and their subsequent cyclization. Finally, cleavage of the aminothiazoles from the resin using trifluoroacetic acid provided 2-aminothiazoles 90. The antagonists were further characterized via the A2A binding assay and an A1 selectivity assay.
It is observed from the literature that, some research groups utilized polymer-supported brominating reagents, bases, and scavengers to quantitatively produce corresponding aminothiazoles with high degrees of purity. Jorg Habermann and co-workers reported the synthesis of aminothiazoles; the synthesis involved an effective α-bromination of differently substituted acetophenones using polymer-supported pyridinium bromide perbromide 92 (PSPBP).69 The targeted aminothiazoles were prepared in high yield using a sequence of polymer-supported reagents without any chromatographic purification step. The α-bromo acetophenones 93 obtained from 91 using PSPBP 92 were treated with thiourea (26) in the presence of polymer-supported 1,5,7-triazabicyclo[4.4.0]-dec-5-ene 94 (TBD-P)70 as a base in THF and the mixture was refluxed for 30 minutes; then, the cyclodehydration reaction was conducted to obtain the desired aminothiazoles 95 (Scheme 17).
The same group has also demonstrated the synthesis of aminothiazoles 97 using sulfonamidated α-bromo piperidones 96, which were treated with thiourea 26 in the presence of TBD-P 94 in refluxing THF over 4 hours (Scheme 18). The corresponding 2-amino-1,3-thiazoles 97 were obtained in high yield and high purity.71
Young K. Yun and co-workers synthesized 2-aminothiazoles hydrobromide monohydrates (99) by the reaction of thioureas 98 and α-bromoketones 30 in dry acetone using a Quest 205 Organic Synthesizer72 and free-based the compounds (100) in the same reaction vessel using polymer-supported bases (Scheme 19). Herein, two polymeric bases were found to be effective: MP-carbonate (macroporous triethylammonium methyl polystyrene carbonate resin) 101, a resin-bound equivalent of potassium carbonate (K2CO3),73–75 and PS-DIEA (N,N-(diisopropyl)aminomethyl-polystyrene) resin 102.76 The polymer-supported bases successfully neutralized the 2-aminothiazole hydrobromide monohydrates to produce the free-based aminothiazoles.
In 2005, K. Rama Rao and co-workers demonstrated β-cyclodextrin in water as a catalyst for the first time in the synthesis of thiazoles. This method claimed efficient and user-friendly reactions conditions such as the use of a hazard-free solvent, low temperatures, fast reactions, high yields, and no unwanted side products. Phenacyl bromides 103 and thioamide/thiourea 104 react in the presence of β-CD in water, and the β-CD complex of 103 was formed in situ to obtain the corresponding thiazole or aminothiazoles 105 in high yield. It was found that the reaction smoothly proceeded without the formation of by-products or rearranged products (Scheme 20).78 After completion of the reaction, the organic material was extracted with ethyl acetate, the organic phase was separated and washed with brine, dried over Na2SO4, filtered, and the solvent was removed under vacuum. The crude product was purified by silica gel column chromatography.
The same group synthesized aminothiazoles in 2007 via the α-halogenation of β-keto esters using N-bromosuccinimide (NBS), followed by cyclization with thiourea in the presence of β-cyclodextrin in water at 50 °C. The β-keto esters 106 forms an in situ complex with β-cyclodextrin after the addition of NBS and thiourea (26); stirring the above mentioned mixture at the same temperature afforded the corresponding thiazoles 107 in excellent yield. The treatment of 106 with NBS may afford α-bromo β-keto esters as intermediates, which then undergo cyclization with thiourea to provide the corresponding thiazole derivatives (Scheme 21).79 The reaction smoothly occurred and succinimide was obtained as the by-product, which could be recycled to obtain NBS.80 After completion of the reaction, the mixture was then extracted with EtOAc and the extract was filtered. The organic layer was dried over anhyd. Na2SO4 and the solvent was removed under reduced pressure. The resulting product was further purified by column chromatography (EtOAc–hexane, 2:8). The aqueous layer was cooled to 5 °C, and β-CD was recovered from it by filtration. To the filtrate that contained succinimide, HBr, NaBrO3, and conc. H2SO4 were added,80 and the mixture was stirred for 30 min. Then, the mixture was extracted with EtOAc and the solvent was removed under vacuum to regenerate NBS in an isolated yield of 75–80%.
In the same year, K. Rama Rao and co-workers reported the supramolecular catalytic synthesis of thiazoles/aminothiazoles 109 from β-keto tosylates 108 and thioamide/thiourea 104 in water in the presence of β-cyclodextrin with impressive yields (Scheme 22).81 At room temperature, the planned reaction was performed, and after its completion, the products were isolated and purified by column chromatography. The catalyst β-cyclodextrin was recovered from aqueous solution cooled at 5 °C using filtration.
Biswanath Das, V. Saidi Reddy, and R. Ramu reported the synthesis of thiazoles and aminothiazoles via the treatment of phenacyl bromides 103 with thioamides/thiourea 104 in the presence of ammonium-12-molybdophosphate (AMP), [(NH4)3(PMo12O40)]82,83 at room temperature. They observed the completion of the reaction within 20 minutes in excellent yield. Recently, heteropoly acids and their salts have been used in the synthesis because of their interesting catalytic activity and capability of conducting the reaction in a cleaner manner when compared to conventional liquid acid catalysts.84 The heterogeneous catalyst AMP, the ammonium salt of a heteropoly acid, can easily be handled and removed from the reaction mixture using simple filtration.
To a mixture of 103 and 104 (1.2 mmol) in MeOH, AMP was added. The mixture was stirred at room temperature, and after 20 min, the mixture was filtered. The filtrate was concentrated and the residue was subjected to column chromatography over silica gel using hexane–EtOAc (4:1) as the eluent to afford the pure thiazole/aminothiazoles 105 (Scheme 23).85
Hitendra Karade, Manisha Sathe, and M.P. Kaushik demonstrated silica chloride as an effective heterogeneous catalyst for the synthesis of aminothiazoles. Many chemical transformations have been reported using silica gel as a support.86,87 The modified silica gel silica chloride (SiO2–Cl) has been reported to be an efficient reagent for the synthesis of many organic compounds.88–91 The silica chloride catalyst was prepared by stirring silica gel in DCM with thionyl chloride (SO2Cl) with the instantaneous liberation of HCl and SO2, and the catalyst prepared retained its activity for 6 months.
Silica chloride was added into ketone 110 and thiourea 26 in acetonitrile at 0 °C. The reaction mixture was brought to room temperature and refluxed for 1 h (Scheme 24).92 After completion of the reaction, the reaction mixture was filtered and the filtrate was washed with sodium bicarbonate solution and brine and extracted with ethyl acetate. The organic layer was separated, dried using anhydrous sodium sulphate, and concentrated under reduced pressure to afford the corresponding 2-aminothiazoles 74 in quantitative yield. It was noticeable that the original activity of the recovered silica chloride from recycle batch 3 could be restored by treatment with thionyl chloride under reflux.92 Studies on the application of this heterogeneous system have shown that silica chloride93,94 is an excellent source for the generation of HCl.
Mazaahir Kidwai, Ritika Chauhan, and Divya Bhatnagar employed recyclable solid-supported Nafion-H using a polyethylene glycol (PEG)–water solvent system in the synthesis of 2-aminothiazoles with improved efficiency and reduced waste production.95 The high catalytic activity of Nafion-H, its selectivity, recyclability, inertness, thermal stability, and ease of separation from the reaction mixture makes it an attractive candidate for organic synthesis.96–98 Nafion-H, a perflourinated sulfonic acid resin, is a useful solid acid catalyst for a variety of acid-catalyzed organic transformations.99–101 It consists of a polymeric backbone with highly acidic sulfonic acid groups and possesses hydrophobic (–CF2CF2) as well as hydrophilic regions (–SO3H). Optimization of the reaction medium was performed by comparing the yields obtained with different solvents such as ethanol, acetonitrile, THF, toluene, ethylene glycol, PEG-400, and PEG–H2O. The PEG–H2O (60:40) combination was found to be most impressive as far as the yield was concerned. A mixture of phenacyl bromide 22 (1 mmol), thiourea 26 (1 mmol), and Nafion-H (1 bead) in 5 mL of the PEG:water (60:40) solvent system was stirred at 50 °C for 10–30 min (Scheme 25).
After completion of the reaction, the catalyst was physically removed by forceps. Then, to the reaction mixture, 50 mL of ice-cold water was added. The resulting solid 2-aminothiazole products were filtered, then washed with water, and dried. The crude products were purified by column chromatography on silica gel to yield the 2-aminothiazoles 24. The catalyst showed excellent recyclability in this reaction. The catalyst was successively washed with acetone and deionized water and then dried overnight at 105 °C. The obtained catalyst had the same catalytic activity as the fresh catalyst.95
Recently, Javad Safari and Masoud Sadeghi employed starch nanoparticles (NPs) as an efficient catalyst for the synthesis of 2-aminothiazoles using methylcarbonyl compounds 110 and thiourea 26 as the precursors. Starch is a natural, renewable, biocompatible, and biodegradable polymer, which is produced by many plants as a source of stored energy. Starch or amylum is a carbohydrate that consists of glucose monomer units, which have two types of arrangements, amylose and amylopectin. Amylose is a linear polymer of glucose units that are connected to each other through an a-link. Amylopectin is a large and branched polysaccharide whose main structure is similar to that of amylose. In total, starch is formed from 20 to 30% amylose and 70 to 80% amylopectin.102–105
Starch NPs were prepared using the precipitation of amorphous starch.106 A mixture of methylcarbonyl 110, thiourea 26, iodine, DMSO, and 10 mg of starch NPs was stirred at 80 °C (Scheme 26). After completion of the reaction (as monitored by TLC, petroleum:ethyl acetate, 4:1), the reaction was quenched upon the addition of 10 mL distilled water. The aqueous solution was extracted with EtOAc and the combined extract was dried with anhydrous Na2SO4. The solvent was removed by vaccum, and finally, the resulting precipitated aminothiazoles 74 were recrystallized from EtOH.106
In 2009, Pei-Ying Lin and co-workers synthesized 2-aminothiazoles from β-keto tosylates and thioureas using PEG-400 as the medium.119 A comparison between acetonitrile and PEG as the medium was performed; the PEG medium results in an enhancement in the product yield. α-Toxyloxyacetophenone 108, thiourea 23, and sodium carbonate were added to PEG-400 (Scheme 27). The resulting mixture was stirred at room temperature for 1 h. Subsequently, the reaction mixture was extracted with Et2O. The remaining PEG suspension was filtered and recycled. The combined ethereal solution was evaporated under reduced pressure. The resulting residue was purified by column chromatography to obtain the aminothiazoles 111.
The PEG-400 can be typically recovered by first extracting the product, and the recovered solvent can be reused with retained activity. The authors reported the synthesis of the anti-inflammatory drug Fanetizole (111, Ar = Ph; R = CH2CH2Ph) with excellent yield using a PEG-mediated approach.
Dhanaji V. Jawale and co-workers reported the reactions of acetophenones 112, N-bromosuccinimide (NBS), and thiourea or aryl thioureas 23 in PEG-400 as a green reaction medium at room temperature (rt) with excellent yields of the corresponding 2-aminothiazole derivatives 113 (Scheme 28).120 In situ α-bromination of 112 was observed with (i) KBr, KBrO3 and a catalytic amount of acetic acid, (ii) bromine, and (iii) NBS. Among these brominating reagents, NBS shows an attractive combination with PEG; no radical initiator was needed and the reaction completed within 6 h. Subsequently, the brominated product underwent cyclocondensation to produce the aminothiazoles 113 in high yield. From these reported synthetic strategies, PEG has been proven as an attractive choice as a mediator.
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