Recent Advances in C–C and C–N Bond Forming Reactions Catalysed by Polystyrene-Supported Copper Complexes

This present mini-review covers recently published results on Cu(I) and Cu(II) complexes immobilized on polystyrene carriers, which are used as heterogeneous, eco-friendly reusable catalysts applied for carbon–carbon and carbon–nitrogen forming reactions. Recent advances and trends in this area are demonstrated in the examples of oxidative homocoupling of terminal alkynes, the synthesis of propargylamines, nitroaldolization reactions, azide alkyne cycloaddition, N-arylation of nitrogen containing compounds, aza-Michael additions, asymmetric Friedel–Crafts reactions, asymmetric Mukaiyama aldol reactions, and asymmetric 1,3-dipolar cycloaddition of azomethine ylides. The type of polystyrene matrix used for the immobilization of complexes is discussed in this paper, and particularly, the efficiency of the catalysts from the point of view of the overall reaction yield, and possible enantioselectivity and potential reusing, is reviewed.


Introduction
Preservation of the current standard of living for the human population is not further possible without the development of ecologically sustainable chemical processes and technologies [1,2]. One of the methods for contributing to responsible handling with raw materials and energy resources is the utilization of recyclable catalysts [1][2][3][4][5]. The strategy of how to obtain recyclable catalysts belongs the immobilization of known homogeneous catalysts to the solid carriers [3][4][5]. Organic polymers, especially commercially available cross-linked pearl-like copolymers of styrene e.g., Merrifield resin™ [6] and JandaJel resin™ [7] belong among the most relevant carriers. The remarkable advantage of polymer-supported catalysts lies in their simple separation and reusability, their low price, and also in the possibility of their usage in selective continuous-flow procedures [5,7]. The immobilization of the catalyst can be performed by the reaction of ligands or catalysts with suitably chemically activated polystyrene (post-modification strategy) [7]. Another possibility is the grafting of the ligand or catalyst containing a double bond from the reaction, with monomers generating the scaffold of the polymeric carrier (copolymerization strategy) [7]. The convenience of one or other strategies cannot be generally stated-it depends on many factors for each concrete case. Nowadays, there are many examples in chemical databases of recyclable catalysts based on complex compounds immobilized on different polymers. This review is focused on the area of highly efficient recyclable catalysts based on Cu(I) and Cu(II) complexes immobilized on polystyrene carriers. The aim of this review was to summarize, discuss and evaluate recently published results of catalysts, which were designed particularly for reactions, where new carbon-carbon respective carbon-nitrogen bonds are formed.

Oxidative Homocoupling of Terminal Alkynes
Carbon-carbon bond forming reactions are essential tools for building the carbon skeleton of organic compounds, and therefore they represent an elemental content of organic synthesis. Copper-catalysed oxidative homocoupling of terminal alkynes known also as Glaser coupling [8] introduce a suitable method for the preparation of 1,3-diynes, which are needful basic building blocks in the synthesis of many natural and pharmaceutical products, as well as some advanced functional materials [9]. A successful application of the heterogeneous catalyst intended for this reaction can be documented on the example of recyclable catalyst 1, which is based on the complex consisting of N,N,N′,N′tetraethyldiethylenetriamine and CuSO4, anchored on polystyrene cross-linked with 1% divinylbenzene (DVB) (Scheme 1) [10]. The efficiency of catalyst 1 was confirmed from the syntheses of 20 substituted symmetrical 1,3-diynes, where high yields of isolated products were achieved (58-99%). During the reuse of catalyst 1, release of small amount of Cu(II) ions was observed, however this did not affect significantly the yield of 1,4-diphenylbutane-1,3-diyne, even after nine cycles [10]. Another recently published successful heterogeneous catalyst [11] for Glaser coupling was based on the Cu(II) complex of copolymer N- (1,10-phenanthroline-5-yl)acrylamide and DVB. This catalyst was also used for Huisgen 1,3-dipolar cycloaddition [11]. For oxidative C-C homocoupling of acetylenes, a heterogeneous catalyst based on copper nanoparticles (3-9 nm), stabilized onto nitro functionalized polystyrene resin, was prepared. This catalyst was tested in the synthesis of seven 1,4-disubstituted-1,3-diynes (92-95%) [12].
The main advantage of this system lies in easy preparation of the catalyst from inexpensive and commercially available starting materials. Moreover, a significant benefit is the possibility of reusing of the catalyst, and the eco-friendly performance of the reaction in aqueous media [13].

Carbene Transfer Reaction
Reactions where carbenes were transferred onto unsaturated substrates (alkenes, alkynes, arenes, imines, aldehydes etc.), have provided a number of useful products [14][15][16][17][18][19]. The mentioned carbenes can be generated in situ from diazo compounds by the application of transition metal-based catalysis [14]. The most widespread example of such reaction implemented at large scale is copper-catalysed cyclopropanation of substituted alkenes with alkyl diazoacetates. Therefore, many homogeneous as well as heterogeneous catalytic systems have been developed for this reaction [14][15][16][17][18][19][20]. In the case of Cu(I) complexes, bisoxazoline ligands [15][16][17][18] and azabisoxazoline ligands [19] were used, anchored on pearl-like polystyrenes. For the immobilization of ligands either a copolymerization strategy (catalysts 3 and 4) or post-modification strategy (catalysts 5-7) was utilized. The catalysts were generated in situ by the coordination of copper(II) triflate and consequent reduction with phenylhydrazine (Scheme 3) [15][16][17][18][19][20]. The main advantage of this system lies in easy preparation of the catalyst from inexpensive and commercially available starting materials. Moreover, a significant benefit is the possibility of reusing of the catalyst, and the eco-friendly performance of the reaction in aqueous media [13].

Nitroaldolization Reaction
The nitroaldolization (Henry) reaction catalysed by chiral optically pure catalysts is important among reactions; it involves the formation of a new carbon-carbon bond [32][33][34][35][36][37][38][39]. This reaction occurs in the synthesis of substituted 2-nitroalcohols used e.g., for the preparation of biologically active compounds and medicinal drugs [34]. A recently published comprehensive paper [35] covers works concerning catalysts based on supported transition metal complexes aimed for an asymmetric variant of the Henry reaction. Three recent works were not covered in the above mentioned review [36,38,39]. The first work [39] included a study of a library of substituted polystyrylsulfonyl-imidazolineaminophenol copper complexes as solid supported catalysts for the Henry reaction. The selected complex of copper(II) acetate, based on (S,S)-diphenylethylenediamine-derived imidazoline, Scheme 6. Addition of terminal alkynes to imines catalysed by catalysts 2 and 11.
From the presented results, the prepared heterogeneous catalysts 2, 9-11 represent highly efficient catalytic systems. Particularly, catalyst 11 showed itself to be an eco-friendly variant that allowed the synthesis of propargylamines in aqueous media. From the chemical structure of catalyst 9, it contains a defined stereogenic centre. However, the eventual optical purity of chiral propargylamines prepared with the use of this catalyst was not discussed in the cited paper [23]. Elsewhere, e.g., in [27][28][29][30], several enantioselective homogeneous catalysts based on Cu(II) complexes designed for the synthesis of optically pure propargylamines were described. For the heterogeneous variant of enantioselective synthesis of propargylamines, only a version of a Cu(I) pybox complex anchored on magnetic nanoparticles (Fe 3 O 4 @SiO 2 ) have been described so far [31].

Nitroaldolization Reaction
The nitroaldolization (Henry) reaction catalysed by chiral optically pure catalysts is important among reactions; it involves the formation of a new carbon-carbon bond [32][33][34][35][36][37][38][39]. This reaction occurs in the synthesis of substituted 2-nitroalcohols used e.g., for the preparation of biologically active compounds and medicinal drugs [34]. A recently published comprehensive paper [35] covers works concerning catalysts based on supported transition metal complexes aimed for an asymmetric variant of the Henry reaction. Three recent works were not covered in the above mentioned review [36,38,39]. The first work [39] included a study of a library of substituted polystyrylsulfonyl-imidazoline-aminophenol copper complexes as solid supported catalysts for the Henry reaction. The selected complex of copper(II) acetate, based on (S,S)-diphenylethylenediamine-derived imidazoline, (S)-phenylethylamine, and dibromophenol, was highly efficient and provided the products of the reaction (nitromethane with substituted aldehydes) in high yields (76-99%) and high enantioselectivity (75-95% ee). The same ligand as a complex with copper(II) triflate was examined in the Friedel-Crafts alkylation of indole by substituted nitroalkenes, to give the adducts in high yields (86-99%) and high enantioselectivity-up to 83% ee [39]. The second variant of immobilization represented recyclable the heterogeneous catalyst 12 (Scheme 7), containing imidazolidine-4-one covalently bound on swellable pearl-like polystyrene having an -SH group (200-800 µm) [36]. Covalent anchoring of the ligand was performed by radical thiol-alkene click reaction, initiated thermally (azobisisobutyronitrile (AIBN), toluene, reflux 24 h), as well as photochemically (2,2-dimethoxy-2-phenylacetophenone, λ max = 365 nm, 40 W, DCM, 25 • C, 24 h). For the subsequent reaction of the copolymer with copper(II) acetate, heterogeneous catalyst 12 was prepared, and was characterized by elemental microanalysis and Raman spectroscopy [36]. Henry reactions proceeded in the polymeric matrix of swellable catalyst 12 with a rate comparable with the use of catalyst 13 in homogeneous media [37]. The corresponding substituted (R)-2-nitroethanols were produced in high yields (65-99%) and with high enantioselectivity (up to 92% ee) comparable with the homogeneous catalyst 13 (up to 96% ee). The reuse of catalyst 12 was studied for the reaction of pivalaldehyde with nitromethane. After five-fold recovery and reuse of heterogeneous catalyst 12, a decrease in yield of about 24% occurred; on the other hand, the decrease in enantioselectivity was negligible (3% ee) (Scheme 7) [36]. (S)-phenylethylamine, and dibromophenol, was highly efficient and provided the products of the reaction (nitromethane with substituted aldehydes) in high yields (76-99%) and high enantioselectivity (75-95% ee). The same ligand as a complex with copper(II) triflate was examined in the Friedel-Crafts alkylation of indole by substituted nitroalkenes, to give the adducts in high yields (86-99%) and high enantioselectivity-up to 83% ee [39]. The second variant of immobilization represented recyclable the heterogeneous catalyst 12 (Scheme 7), containing imidazolidine-4-one covalently bound on swellable pearl-like polystyrene having an -SH group (200-800 µm) [36]. Covalent anchoring of the ligand was performed by radical thiol-alkene click reaction, initiated thermally (azobisisobutyronitrile (AIBN), toluene, reflux 24 h), as well as photochemically (2,2-dimethoxy-2-phenylacetophenone, λmax = 365 nm, 40 W, DCM, 25 °C, 24 h). For the subsequent reaction of the copolymer with copper(II) acetate, heterogeneous catalyst 12 was prepared, and was characterized by elemental microanalysis and Raman spectroscopy [36]. Henry reactions proceeded in the polymeric matrix of swellable catalyst 12 with a rate comparable with the use of catalyst 13 in homogeneous media [37]. The corresponding substituted (R)-2-nitroethanols were produced in high yields (65-99%) and with high enantioselectivity (up to 92% ee) comparable with the homogeneous catalyst 13 (up to 96% ee). The reuse of catalyst 12 was studied for the reaction of pivalaldehyde with nitromethane. After five-fold recovery and reuse of heterogeneous catalyst 12, a decrease in yield of about 24% occurred; on the other hand, the decrease in enantioselectivity was negligible (3% ee) (Scheme 7) [36]. The third variant represented heterogeneous catalysts 14a,b based on Cu(II) complexes of substituted imidazolidine-4-thiones immobilized by means of sulfur atoms on different types of polystyrene carriers (poly[styrene-co-4-vinylbenzyl chloride-co-tetra(ethylene glycol)-bis(4-vinylbenzyl)ether), Merrifield resin™ and JandaJel resin™ (Scheme 8) [38]. It was found, that catalysts 14a,b catalyse the Henry reaction with high yields and high enantioselectivity, regardless of the polymeric carrier used (up to 98% ee). The obtained yields and enantioselectivities were comparable with the individual cases of reactions catalysed by analogical homogeneous catalysts 15a,b (Scheme 8). Beside monitoring the yields and enantioselectivity, the possibility of recovery and reusing of catalysts 14a,b was also studied. For instance, in the reaction of 2-methoxybenzaldehyde with nitromethane, the catalyst was reused more than 10 times without any decrease in enantioselectivity (81% ee) (Scheme 8) [38]. The third variant represented heterogeneous catalysts 14a,b based on Cu(II) complexes of substituted imidazolidine-4-thiones immobilized by means of sulfur atoms on different types of polystyrene carriers (polystyrene-co-4-vinylbenzyl chloride-co-tetra(ethylene glycol)-bis(4-vinylbenzyl) ether), Merrifield resin™ and JandaJel resin™ (Scheme 8) [38]. It was found, that catalysts 14a,b catalyse the Henry reaction with high yields and high enantioselectivity, regardless of the polymeric carrier used (up to 98% ee). The obtained yields and enantioselectivities were comparable with the individual cases of reactions catalysed by analogical homogeneous catalysts 15a,b (Scheme 8). Beside monitoring the yields and enantioselectivity, the possibility of recovery and reusing of catalysts 14a,b was also studied. For instance, in the reaction of 2-methoxybenzaldehyde with nitromethane, the catalyst was reused more than 10 times without any decrease in enantioselectivity (81% ee) (Scheme 8) [38].

Asymmetric Friedel-Crafts Reaction
Beletskaya et al. [40] studied asymmetric Friedel-Crafts alkylation of indole and its derivatives in the presence of complex of Cu(OTf)2 with chiral isopropyl bis(oxazoline) ligand immobilized on Merrifield resin™ according to the "click" procedure 16. The target products were obtained with a yield of up to 99% and up to 97% ee. Catalyst 16 ensured high yield and enantioselectivity even after five-fold reuse (Scheme 9) [40]. The heterogeneous catalyst 16 was also tested in the alkylation of N-methylindole by methyl (E)-2-oxo-4-phenylbut-3-enoate with yields of 22-94% and lower enantioselectivity (49% ee) [40].

Asymmetric Friedel-Crafts Reaction
Beletskaya et al. [40] studied asymmetric Friedel-Crafts alkylation of indole and its derivatives in the presence of complex of Cu(OTf) 2 with chiral isopropyl bis(oxazoline) ligand immobilized on Merrifield resin™ according to the "click" procedure 16. The target products were obtained with a yield of up to 99% and up to 97% ee. Catalyst 16 ensured high yield and enantioselectivity even after five-fold reuse (Scheme 9) [40].

Asymmetric Friedel-Crafts Reaction
Beletskaya et al. [40] studied asymmetric Friedel-Crafts alkylation of indole and its derivatives in the presence of complex of Cu(OTf)2 with chiral isopropyl bis(oxazoline) ligand immobilized on Merrifield resin™ according to the "click" procedure 16. The target products were obtained with a yield of up to 99% and up to 97% ee. Catalyst 16 ensured high yield and enantioselectivity even after five-fold reuse (Scheme 9) [40]. The heterogeneous catalyst 16 was also tested in the alkylation of N-methylindole by methyl (E)-2-oxo-4-phenylbut-3-enoate with yields of 22-94% and lower enantioselectivity (49% ee) [40].

Asymmetric Mukaiyama Aldol Reaction
The enantioselective Mukaiyama aldol reaction of methyl pyruvate with silylated ketene thioacetal was tested with a heterogeneous polystyrene copper complex catalyst based on chiral bis(oxazoline) [41] (Scheme 10). The highly-crosslinked polymer 3 was prepared by a copolymerization strategy in the presence of toluene as a porogen agent [41]. The heterogeneous catalyst 3/Cu(OTf)2 was less active than the analogous homogeneous catalysts, and aldol products were formed after a longer time; however, high overall yield (90%) and with an enantiomeric excess comparable to those obtained with the soluble ligands (90% ee), was obtained. Moreover, the catalyst based on polymer complex 3 was easily recovered by simple filtration and was reused several times without any loss of activity or stereoselectivity (Scheme 10) [41]. In the second work, the azabis(oxazoline) complexes 17 bonded to Merrifield resin™ were confirmed for the aldol reaction of different α-ketoesters with silylated ketone enolates [42]. The catalysis results showed that these heterogeneous complexes 17 accomplished enantioselectivities only slightly lower than those obtained in solution. Catalyst recovery depends on the ligand, so whereas polymers (R 3 : Ph) and (R 3 : i-Pr) were recovered with the same unsatisfactory results (51%, 38-39% ee), the recovered catalyst coming from (R 3 : t-Bu) led to even slightly lower yields (25%) but with the higher enantioselectivity (85% ee) (Scheme 10) [42].

Copper(I)-Catalysed Azide Alkyne Cycloaddition
Beside the reactions leading to carbon-carbon bond formation, the reactions providing new carbon-nitrogen bond also play a relevant role in organic synthesis. Particularly, this includes the Huisgen 1,3-dipolar cycloaddition of alkynes with azides providing 1,4-and 1,5-isomers of 1,2,3triazole [43]. Copper(I)-catalysed azide alkyne cycloaddition (CuAAC) represents a current variant, which converse to the original thermic version, proceeds quickly, regiospecifically (1,4-), and with high yields [44,45]. These properties rank this reaction among the most significant "near-perfect" bond-forming reactions known as "click" reactions [46]. The importance of this reaction consists not only in the efficient preparation of substituted 1,2,3-triazoles, but especially in the possibility for connecting different molecules and macromolecules, or to functionalize surfaces in a controlled way. The first polystyrene-supported copper(I) catalyst for CuAAC was based on the Amberlyst A21-CuI complex and was published in 2006 [47]. This and many further papers are discussed in a recently published review concerning immobilized copper complexes anchored on polystyrene and other heterogeneous carriers [48]. Also, two other papers deal with CuAAC [49,50].
The authors [49] prepared the catalyst 18 based on copper(I) iodide complex with cryptand-22 immobilized on commercial chloromethylated polystyrene (1% DVB) (Scheme 11). This heterogeneous heat-and air-stable catalyst 18 was used for a two-component CuAAC reaction of substituted organic azides with substituted alkynes, and this provided excellent yields of 1,4-disubstituted 1,2,3-triazoles (78-99%). The second three-component variant of this reaction involving organic halides, sodium The highly-crosslinked polymer 3 was prepared by a copolymerization strategy in the presence of toluene as a porogen agent [41]. The heterogeneous catalyst 3/Cu(OTf) 2 was less active than the analogous homogeneous catalysts, and aldol products were formed after a longer time; however, high overall yield (90%) and with an enantiomeric excess comparable to those obtained with the soluble ligands (90% ee), was obtained. Moreover, the catalyst based on polymer complex 3 was easily recovered by simple filtration and was reused several times without any loss of activity or stereoselectivity (Scheme 10) [41]. In the second work, the azabis(oxazoline) complexes 17 bonded to Merrifield resin™ were confirmed for the aldol reaction of different α-ketoesters with silylated ketone enolates [42]. The catalysis results showed that these heterogeneous complexes 17 accomplished enantioselectivities only slightly lower than those obtained in solution. Catalyst recovery depends on the ligand, so whereas polymers (R 3 : Ph) and (R 3 : i-Pr) were recovered with the same unsatisfactory results (51%, 38-39% ee), the recovered catalyst coming from (R 3 : t-Bu) led to even slightly lower yields (25%) but with the higher enantioselectivity (85% ee) (Scheme 10) [42].

Copper(I)-Catalysed Azide Alkyne Cycloaddition
Beside the reactions leading to carbon-carbon bond formation, the reactions providing new carbon-nitrogen bond also play a relevant role in organic synthesis. Particularly, this includes the Huisgen 1,3-dipolar cycloaddition of alkynes with azides providing 1,4-and 1,5-isomers of 1,2,3-triazole [43]. Copper(I)-catalysed azide alkyne cycloaddition (CuAAC) represents a current variant, which converse to the original thermic version, proceeds quickly, regiospecifically (1,4-), and with high yields [44,45]. These properties rank this reaction among the most significant "near-perfect" bond-forming reactions known as "click" reactions [46]. The importance of this reaction consists not only in the efficient preparation of substituted 1,2,3-triazoles, but especially in the possibility for connecting different molecules and macromolecules, or to functionalize surfaces in a controlled way. The first polystyrene-supported copper(I) catalyst for CuAAC was based on the Amberlyst A21-CuI complex and was published in 2006 [47]. This and many further papers are discussed in a recently published review concerning immobilized copper complexes anchored on polystyrene and other heterogeneous carriers [48]. Also, two other papers deal with CuAAC [49,50].
Halligudi et al. studied biomimetic oxidative coupling of 2-aminophenol to phenoxazine-2-one catalysed by bis(2′-[2-hydroxyethyl]benzimidazolato)copper(II) complex anchored onto chloromethylated polystyrene [53]. The kinetics and the effects of the catalyst concentration, substrate concentration, air pressure and temperature on the reaction course were studied. 2-Aminophenol in the presence of air (70 °C, 800 psig, DMF, 8 h) gave 62% conversion and the immobilized catalyst was more stable and more active than its homogeneous analogue. The catalyst recycling study demonstrated that the anchored catalyst did not leach out the metal complex during the reaction, and thus its catalytic activity was reproducible [53].

N-Arylation of Amines, Amides and Nitrogen Containing Heterocycles
Aryl-nitrogen bonds formed via cross-coupling reactions represent a powerful tool for the production of a number of compounds with practical uses [54]. The original variant of the Ullmann reaction is still utilized for this purpose [55]. However, this method of performing of the reaction is constrained by several disadvantages, e.g., it needs high temperature (150-200 °C) and the use of stoichiometric amounts of copper [54,55]. A remarkable simplification was achieved by the use of substituted phenylboronic acids for N-arylation of imidazole catalysed by copper(II) salts [56]. The next facilitation was the utilization of heterogeneous catalyst 22 (Scheme 14) [57]. Catalyst 22 was prepared from commercial chloromethylated polystyrene (5.5% DVB), on which β-alanine was attached through Interestingly, 20 showed much better catalytic performance than 21 (in all cases from 91 to >99% ee). Furthermore, the polystyrene-supported Fesulphos ligand 20 were recovered and reused in successive catalytic 1,3-dipolar cycloadditions without further addition of Cu(I), maintaining excellent enantioselectivity in up to three runs (Scheme 13) [52].
Halligudi et al. studied biomimetic oxidative coupling of 2-aminophenol to phenoxazine-2-one catalysed by bis(2 -[2-hydroxyethyl]benzimidazolato)copper(II) complex anchored onto chloromethylated polystyrene [53]. The kinetics and the effects of the catalyst concentration, substrate concentration, air pressure and temperature on the reaction course were studied. 2-Aminophenol in the presence of air (70 • C, 800 psig, DMF, 8 h) gave 62% conversion and the immobilized catalyst was more stable and more active than its homogeneous analogue. The catalyst recycling study demonstrated that the anchored catalyst did not leach out the metal complex during the reaction, and thus its catalytic activity was reproducible [53].

N-Arylation of Amines, Amides and Nitrogen Containing Heterocycles
Aryl-nitrogen bonds formed via cross-coupling reactions represent a powerful tool for the production of a number of compounds with practical uses [54]. The original variant of the Ullmann reaction is still utilized for this purpose [55]. However, this method of performing of the reaction is constrained by several disadvantages, e.g., it needs high temperature (150-200 • C) and the use of stoichiometric amounts of copper [54,55]. A remarkable simplification was achieved by the use of substituted phenylboronic acids for N-arylation of imidazole catalysed by copper(II) salts [56]. The next facilitation was the utilization of heterogeneous catalyst 22 (Scheme 14) [57]. Catalyst 22 was prepared from commercial chloromethylated polystyrene (5.5% DVB), on which β-alanine was attached through the oxygen atom, and copper(II) acetate was coordinated. Less efficient variants of this catalyst were prepared by the coordination with CuCl 2 and CuI. Catalyst 22 was successfully tested for the reaction of substituted phenylboronic acids with nitrogen containing heterocycles (imidazole, benzimidazole; 65-98%) and with amides (phthalimide, benzamide, benzenesulfonamide; 37-98%) under very mild conditions (methanol, 40 • C, 10-20 h). The reaction with amines was performed in DMSO in the presence of K 2 CO 3 at 140 • C (aniline, benzylamine; 58-91%) (Scheme 14) [57]. The recovery and reuse of catalyst 22 was studied for the reaction of phenylboronic acid with imidazole (Cycle 1: 98%; Cycle 6: 90%) and aniline (Cycle 1: 86%; Cycle 4: 82%). In both cases, only a slight decrease in yields was observed (Scheme 14) [57]. Under comparable conditions as in [57]  The recovery and reuse of catalyst 22 was studied for the reaction of phenylboronic acid with imidazole (Cycle 1: 98%; Cycle 6: 90%) and aniline (Cycle 1: 86%; Cycle 4: 82%). In both cases, only a slight decrease in yields was observed (Scheme 14) [57]. Under comparable conditions as in [57]  The recovery and reuse of catalyst 22 was studied for the reaction of phenylboronic acid with imidazole (Cycle 1: 98%; Cycle 6: 90%) and aniline (Cycle 1: 86%; Cycle 4: 82%). In both cases, only a slight decrease in yields was observed (Scheme 14) [57]. Under comparable conditions as in [57]  Catalyst 23 was prepared from commercial chloromethylated polystyrene (2% DVB), on which 5-phenyl-1H-tetrazole was attached, and CuCl 2 was coordinated (Scheme 15). The reactions were performed in DMSO at 120 • C for 12-16 h in the presence of K 2 CO 3 (N-heterocycles; 67-95%), or in the presence of KOH (amines; 67-85%). In different solvents (THF, MeCN, DME, N-methylpyrrolidone (NMP), DMF) and under different conditions (Cs 2 CO 3 , NaHCO 3 , K 3 PO 4 , TEA; 80 • C, 130 • C) N-arylation of 1H-imidazole with iodobenzene occurred with lower yields than the reaction in DMSO. The recovery and reusing of catalyst 23 was tested with success for the reaction of imidazole with iodobenzene (Cycle 1: 94%; Cycle 6: 89%). The N-arylation of amides and lactams with substituted iodobenzenes, bromobenzene, 2-bromopyridine or 2-iodopyridine catalysed by 24 was also successful (Scheme 16) [61]. Catalyst 24 was prepared from commercial chloromethylated polystyrene, where the chloromethyl group was transformed to an aldehydic group. Subsequent reaction with β-alanine led to the production of an imine, which was then coordinated with Cu(II) acetate. N-arylations were performed without a solvent and in the presence of K2CO3 at 120 °C, for 15-20 h, with yields in the range of 62-92%. The recovery and reusing of catalyst 24 was successfully tested for the reaction of benzamide with iodobenzene (Cycle 1: 92%; Cycle 8: 89%) (Scheme 16) [61]. Further examples of reactions proceeding in aqueous media were N-arylation of substituted bromobenzenes with substituted anilines and (cyclo)alkylamines, catalysed by catalyst 25 in the presence of tetrabutylammonium bromide (TBAB) (Scheme 17) [62]. Catalyst 25 was prepared by the sequence of reactions from atactic polystyrene. Firstly, polystyrene was nitrated, reduced to amine, diazotated, and reduced to hydrazine, which was then acylated by 1H-pyrrole-2-carboxylic acid. The catalyst 25 itself was generated directly in the reaction mixture from the functionalized polystyrene and Cu(I) iodide. Catalyst 24 was prepared from commercial chloromethylated polystyrene, where the chloromethyl group was transformed to an aldehydic group. Subsequent reaction with β-alanine led to the production of an imine, which was then coordinated with Cu(II) acetate. N-arylations were performed without a solvent and in the presence of K 2 CO 3 at 120 • C, for 15-20 h, with yields in the range of 62-92%. The recovery and reusing of catalyst 24 was successfully tested for the reaction of benzamide with iodobenzene (Cycle 1: 92%; Cycle 8: 89%) (Scheme 16) [61]. Further examples of reactions proceeding in aqueous media were N-arylation of substituted bromobenzenes with substituted anilines and (cyclo)alkylamines, catalysed by catalyst 25 in the presence of tetrabutylammonium bromide (TBAB) (Scheme 17) [62]. Catalyst 25 was prepared by the sequence of reactions from atactic polystyrene. Firstly, polystyrene was nitrated, reduced to amine, diazotated, and reduced to hydrazine, which was then acylated by 1H-pyrrole-2-carboxylic acid. The catalyst 25 itself was generated directly in the reaction mixture from the functionalized polystyrene and Cu(I) iodide. Catalyst 24 was prepared from commercial chloromethylated polystyrene, where the chloromethyl group was transformed to an aldehydic group. Subsequent reaction with β-alanine led to the production of an imine, which was then coordinated with Cu(II) acetate. N-arylations were performed without a solvent and in the presence of K2CO3 at 120 °C, for 15-20 h, with yields in the range of 62-92%. The recovery and reusing of catalyst 24 was successfully tested for the reaction of benzamide with iodobenzene (Cycle 1: 92%; Cycle 8: 89%) (Scheme 16) [61]. Further examples of reactions proceeding in aqueous media were N-arylation of substituted bromobenzenes with substituted anilines and (cyclo)alkylamines, catalysed by catalyst 25 in the presence of tetrabutylammonium bromide (TBAB) (Scheme 17) [62]. Catalyst 25 was prepared by the sequence of reactions from atactic polystyrene. Firstly, polystyrene was nitrated, reduced to amine, diazotated, and reduced to hydrazine, which was then acylated by 1H-pyrrole-2-carboxylic acid. The catalyst 25 itself was generated directly in the reaction mixture from the functionalized polystyrene and Cu(I) iodide. The reaction of substituted bromobenzenes with benzylamine and substituted anilines (70 • C, 16 h) proceeded with very good yields of up to 82%. The lowest yield was attained in the reaction of 4-bromonitrobenzene with benzylamine (44%), while the reaction with sterically demanding 2,4,6-trimethylaniline did not proceed. Analogical reactions with (cyclo)alkylamines (90 • C, 16 h) provided yields of up to 93%, while the lowest yield was achieved in the reaction of 4-bromonitrobenzene with butylamine (51%). Substituted bromopyridines provided products with yields of 33-85%. The reactions of substituted iodobenzenes with imidazole (120 • C, 16 h) led to products with yields ranging from 65% to 87%. The lowest yield was obtained for iodobenzene itself (65%), while the reaction with 2-methoxyiodobenzene did not proceed. Catalyst 25 was also applied in the intramolecular N-arylation of N-(2-iodophenyl)-1H-imidazole-2-carboxamide giving imidazo[1,2-a]quinoxaline. The recovery and reusing of catalyst 25 was successfully tested for the reaction of 4-methoxyiodobenzene with imidazole (Cycle 1: 79%; Cycle 5: 82%) (Scheme 17) [62].

Aza-Michael Addition
Nucleophilic addition of N-nucleophiles on activated multiple bonds (aza-Michael addition) is a significant reaction in the synthesis of β-amino carbonyl compounds as crucial intermediates in the synthesis of β-amino acids, β-lactam antibiotics, and chiral auxiliaries [63]. Simple, green and efficient preparation of N-alkylated imidazoles was tested, with a reaction of substituted imidazoles with different α,β-unsaturated compounds catalysed by polystyrene-supported CuI-imidazole complex catalyst 26 (Scheme 18) [64]. Catalyst 26 was prepared via surfactant free emulsion polymerization with 4-VBC (4-vinylbenzylchloride) and DVB (2%), whereby uniform globular particles (400-500 nm) with high Cl content (21.5%) were obtained initially. Afterwards, these particles were highly functionalized by imidazole and coordinated by CuI. The efficiency of catalyst 26 was firstly confirmed for the addition of imidazole on acrylonitrile (8.5 mol% Cu; 60 °C; 4-10 h); while the influence of the solvent was studied: methanol (58%); MeCN (63%); DMSO (52%); DMF (71%); acetone (47%); THF (58%). The reactions were then performed in DMF and the temperature optimized to 75 °C. The addition of substituted imidazoles on α,β-unsaturated substrates proceeded with very good yields up to 74-84%. The lowest yield was achieved for the addition of 4-nitro-1H-imidazole on acrylonitrile. Catalyst 26 was separated by filtration and was further recycled for the reaction of imidazole with acrylonitrile (Cycle 1: 92%; Cycle 2: 91%; Cycle 5: 89%). The given results show that catalyst 26 represents an excellent reusable catalyst; which could be potentially applied at an industrial scale [64].

Conclusions
In this mini-review, we focused on Cu(I) and Cu(II) complexes anchored on pearl-like polystyrenes. The prepared heterogeneous catalysts were beneficially used for oxidative homocoupling of terminal alkynes, synthesis of propargylamines, nitroaldolization reaction, azide alkyne cycloaddition, Narylation of nitrogen containing compounds, aza-Michael addition asymmetric Friedel-Crafts reactions, asymmetric Mukaiyama aldol reactions, and asymmetric 1,3-dipolar cycloaddition of azomethine ylides. In several given examples, any difference between the efficiency of individual catalysts was not found depending on the method of their preparation (copolymerization strategy or post-modification strategy) [15][16][17][18][19]. In a prevalent number of examples, any significant decrease in chemical yields was not observed in the comparison of heterogeneous catalysts with corresponding The efficiency of catalyst 26 was firstly confirmed for the addition of imidazole on acrylonitrile (8.5 mol % Cu; 60 • C; 4-10 h); while the influence of the solvent was studied: methanol (58%); MeCN (63%); DMSO (52%); DMF (71%); acetone (47%); THF (58%). The reactions were then performed in DMF and the temperature optimized to 75 • C. The addition of substituted imidazoles on α,β-unsaturated substrates proceeded with very good yields up to 74-84%. The lowest yield was achieved for the addition of 4-nitro-1H-imidazole on acrylonitrile. Catalyst 26 was separated by filtration and was further recycled for the reaction of imidazole with acrylonitrile (Cycle 1: 92%; Cycle 2: 91%; Cycle 5: 89%). The given results show that catalyst 26 represents an excellent reusable catalyst; which could be potentially applied at an industrial scale [64].

Conclusions
In this mini-review, we focused on Cu(I) and Cu(II) complexes anchored on pearl-like polystyrenes. The prepared heterogeneous catalysts were beneficially used for oxidative homocoupling of terminal alkynes, synthesis of propargylamines, nitroaldolization reaction, azide alkyne cycloaddition, N-arylation of nitrogen containing compounds, aza-Michael addition asymmetric Friedel-Crafts reactions, asymmetric Mukaiyama aldol reactions, and asymmetric 1,3-dipolar cycloaddition of azomethine ylides. In several given examples, any difference between the efficiency of individual catalysts was not found depending on the method of their preparation (copolymerization strategy or post-modification strategy) [15][16][17][18][19]. In a prevalent number of examples, any significant decrease in chemical yields was not observed in the comparison of heterogeneous catalysts with corresponding homogeneous catalysts. The advantages of discussed heterogeneous catalysts consisted in their simple preparation from inexpensive and easily available starting materials, their simple isolation, and the possibility of reuse. Easy performance of the reaction in aqueous media brings great benefits in the case of cross-coupling reactions [13], Huisgen cycloaddition [49], N-arylation [62], and solvent-free N-arylation [61]. Most of the mentioned reactions possess high potential for industrial usage, hence the catalytic systems presented in this review significantly contribute to further development of ecologically sustainable chemical processes and technologies.