Recent Advances in Microwave ‐ Assisted Copper ‐ Catalyzed Cross ‐ Coupling Reactions

: Cross ‐ coupling reactions furnishing carbon–carbon (C–C) and carbon–heteroatom (C–X) bond is one of the most challenging tasks in organic syntheses. The early developed reaction protocols by Ullmann, Ullman–Goldberg, Cadiot–Chodkiewicz, Castro–Stephens, and Corey– House, utilizing elemental copper or its salts as catalyst have, for decades, attracted and inspired scientists. However, these reactions were suffering from the range of functional groups tolerated as well as severely restricted by the harsh reaction conditions often required high temperatures (150– 200 °C) for extended reaction time. Enormous efforts have been paid to develop and achieve more sustainable reaction conditions by applying the microwave irradiation. The use of controlled microwave heating dramatically reduces the time required and therefore resulting in increase in the yield as well as the efficiency of the reaction. This review is mainly focuses on the recent advances and applications of copper catalyzed cross ‐ coupling generation of carbon–carbon and carbon– heteroatom bond under microwave technology. catalyzed microwave ‐ assisted A 3 coupling for the synthesis of propargylamines.


Introduction
Carbon-carbon (C-C) and carbon-heteroatom (C-X) bond formations through crosscoupling reactions represents as one of the most useful strategy in the synthetic organic chemistry, hence many procedures and methodologies have been developed and published in the literature. Elemental copper (Cu) is the first transition metal element used to catalyze the formation of C-C and C-X bond. The first report of copper in catalyzing C-C bond formation was proposed by Fritz Ullman in 1901. Followed by the modification of the classical Ullmann reaction to include C-X bond, was reported by Ullman and Goldberg in the years from 1903 to 1906. The progress was followed by Cadiot-Chodkiewicz coupling reaction in 1957, Castro-Stephens coupling reaction in 1963, and Corey-House synthesis in 1967. In the 1970s, the cross coupling reaction entered a new era by introducing palladium (Pd) as one of the most powerful noble metal in the crosscoupling reactions. Many important chemical transformations to generate new organic molecules have been developed and these reactions being named after the person who discovered it, including Kumada and Heck (1972), Sonogashira (1975), Negishi (1977), Stille (1978), Suzuki (1979), Hiyama (1988), and Liebeskind-Srogl (2000). Despite the great advances in utilizing palladium as catalyst, copper is still very much used as one of the important catalyst, being non-noble metal, which is cheap and available in the most organic synthetic laboratories globally. However, in comparison with palladium, copper catalyzed reactions are often suffering from the tolerance to cover variety of functional groups as well as the stability of starting materials and products due to the essentially required harsh reaction conditions such as high temperatures-typically 150-200 °Cand for the extended reaction time from several hours to few days [1][2][3][4].
Upon the discovery of microwave technology, as an alternative heating source for organic reactions, it has gained much attention due to its high efficiency, reproducibility, and shortening the reaction time. This fulfills the requirements of green chemistry reactions as well as reducing solvents consumption, reaction temperature, and the extended reaction time to less than an hour, while many reactions are being done in few to several minutes. This is usually accompanied with significant reduction of energy consumption, raising the efficiency and yield of the desired product, through lowering the level of side reactions [5,6]. Therefore, the discovery of the microwave heating in organic chemistry has revived the application of copper in cross-coupling reaction to access novel organic compounds via the formation of new C-C and C-X bonds.
This review article is aiming to highlight the recent advances and perspectives of copper-catalyzed cross-coupling C-C and C-X bond formation under controlled microwave heating. Although it covers the most recent methodologies published in the last decade, but priority will be given to the protocols bearing transformation of widerange of substrates, emphasizing on their utility and restrictions to simplify the further development of this very attractive area of research.

Ullmann-Type Cross-Coupling Reactions
Ullmann coupling reaction is the first reported cross-coupling reaction that uses a transition metal as catalyst. It has been developed by Fritz Ullmann for the synthesis of symmetrical biaryl compounds via the generation of new Ar-Ar (C-C) bond starting from an aryl halide and mediated by elemental copper (Cu0) [7]. In the next few years, Ullmann reaction has been modified to involve the coupling of aryl halides and various nucleophiles for the generation of other carbon-heteroatom (C-X) bonds, such as C-N, C-O, and C-S [8][9][10][11].
For the last 20 years, Müller and coworkers are been interested in the synthesis of diverse range of anthraquinone derivatives for their pharmacological activity as antagonists for purinergic P2 receptors as well as ectonucleotidases inhibitors [12][13][14][15][16][17][18][19][20]. However, the anthraquinone chemistry undergo Ullmann coupling reaction under classical conventional heating were very much limited to the activated amines and anilines with significant low yield and extended reaction times for up to 48 h under harsh reaction conditions. Baqi, Y. et al. were the first to systematically investigate the effect of microwave irradiation on the Cu-catalyzed Ullmann coupling reaction using three different oxidation states of copper, namely elemental copper (0) powder (Cu), copper(I) chloride (CuCl), and copper (II) sulfate (CuSO4). The three oxidation states of copper (0, I, and II) were investigate, in a comparison manner, under conventional heating and microwave technology [21,22]. The most significant achievement was when they employed a catalytic amount (5 mol%) of elemental copper in phosphate buffer (NaH2PO4 and Na2HPO4) at pH 6-7, as solvent under microwave irradiation, Scheme 1. The developed protocol has been successfully employed for the synthesis of a small library (about 200 compounds) of amino-and anilino-anthraquinones, where most of these compounds were previously inaccessible under classical Ullmann reaction using conventional heating. Scheme 1. Elemental copper (Cu) catalyzed microwave-assisted synthesis of the anthraquinones.
The generality of this protocol was further examined on other aryl halide scaffold and found to be useful. For example, Georg and his coworkers have employed the above mentioned protocol for the synthesis of 8-anilinonaphthalene-1-sulfonic acid derivatives. Similarly they have found that the use of elemental copper in phosphate buffer to be superior over other used copper based catalysts [23]. However, the reaction has relatively taken longer time, about 60-90 min, compared to the same reactions being performed under microwave heating. The product was obtained in low to good yields, Scheme 2. This low yield is probably due to the halide used, a chloride ion being less effective leaving group compared with bromide ion, while the presence of a carbonyl function in the anthraquinone core might have a direct impact on the stabilization of the intermediate generated in the catalytic cycle through possible coordination bond between the free lone pair on the oxygen atom of the carbonyl group and copper surface thus facilitate the reaction towards the desired product in shorter reaction time, therefore, it may minimize any competitive side reactions, which is the main cause of losing the yields. Park, A.R. and Yum, E.K. have developed microwave assisted synthesis of isoquinolines using copper(I) oxide (Cu2O) [24]. They have systematically optimized the reaction using different kind and equivalent of the catalyst, base, solvent, and reaction time. They have concluded that the optimal conditions for N-arylation of isoquinolines were using catalytic amount (10 mol %) of Cu2O, in the presence of Cs2CO3 as a base in N,N-dimethylacetamide (DMA) as solvent. The resulting mixture was then heated at 120 °C for 60 min in a microwave reactor leading to the desired products in moderate to very good yields, Scheme 3. Similarly, Gavade, S.N. et al. has developed copper(I) oxide (Cu2O) as useful catalyst for the N-arylation of phenylurea to produce novel diphenylurea derivatives under microwave irradiation [25,26]. The diphenylurea compounds were obtained via Narylation of phenylurea using aryl halides in the presence of catalytic amount (20 mol %) of copper(I) oxide (Cu2O). Two protocols were published; first one using solvent-and ligand-free condition with the yields ranging from 35-90% [25] and the second reaction condition was a ligand-free with the yields ranging from 60-85% [26], Scheme 4. In another study utilizing microwave irradiation, Bolm and coworkers have reported on the amination reaction between of 3-halopyridines and amines as nucleophile under solvent-and ligand-free conditions that lead to novel N-heteroarylated derivatives of aniline at 3-position [27]. They have systematically examined different kind and amount of the copper catalysts and bases. The best reaction conditions was achieved when a catalytic amount (10 mol %) of copper(I) oxide (Cu2O) in the presence of K3PO4 as base was employed. The reaction mixture was then heated in a microwave oven at 100 °C for 60 min to obtain N-heteroarylated aniline derivatives in moderate to excellent yields, Scheme 5. In a microwave reactor, Oh and Yum have reported on the use of copper(I) oxide (Cu2O) to catalyze the synthesize of 1,3-diarylated indazoles [28]. They have reported on the use of catalytic amount (10 mol %) of Cu2O, and Cs2CO3 as a base in N,Ndimethylacetamide (DMA) as solvent, the resulting mixture was then heated in a microwave oven at 200 °C for 1 h, the optimized reaction conditions resulted in moderate to good yields, Scheme 6. Under controlled microwave technology, Sakhuja and coworkers have reported on the synthesis of N-coumaryl amino acids by coupling reaction between 4-chlorocoumarin with N-terminus unprotected amino acids following the Ullmann coupling reaction, the optimized reaction condition suggest the use of copper(I) iodide (CuI) in basic condition (K2CO3) and water as solvent [29]. The resulting mixture was then heated in a microwave oven at 80 °C for 10-15 min to produce a series of N-coumaryl amino acids in very high yields, Scheme 7. Scheme 7. CuI catalyzed microwave-assisted reaction between 4-chlorocoumarin and amino acids.
Recently, Kwon, J.-K. et al. have developed a simple and efficient copper(I) oxide (Cu2O) catalyst system for the N-arylation reaction of various indole derivatives with divers aryl halides (Ar-X) under microwave irradiation technology [30]. The reaction has been optimized with regards copper salts, bases and solvents. The most effective reaction condition was achieved by the use of catalytic amount (10 mol %) of Cu2O and cesium carbonate (Cs2CO3) as base in dimethylacetamide (DMA) as solvent to produce the desired products, N-heteroarylated indoles, in moderate to excellent yields via ligand-free coppercatalyzed Ar-N bond formation. The reaction carried out in a microwave oven at 200 °C for 20-60 min, Scheme 8. Scheme 9 summarizes the proposed mechanism for Ullmann-type cross-coupling reaction. In the first step copper(I) halide (Cu-X) react with a nucleophile (HNu) in the presence of base to facilitate the removal of the acid (HX). This step will lead for the formation of a complex between copper and nucleophile (Cu-Nu). Followed by an oxidative addition of aryl halide (Ar-X), which proceed via the accommodation of Ar and X functions on the catalyst surface through oxidizing Cu(I) to Cu(III). Copper(III) is unstable species and will undergo a reductive elimination reaction to produce the Ullmann coupling product and to regenerate the catalyst (Cu-X) to be reused in the next catalytic cycle.

Scheme 9.
A proposed mechanism pathway for the Ullmann-type cross-coupling reaction.

Azide-Alkyne Huisgen [2 + 3] Cycloaddition Reaction
The azide-alkyne Huisgen (3 + 2) cycloaddition is one of the most versatile synthetic methods in heterocyclic chemistry. It is a 1,3-dipolar cycloaddition reaction between an organoazides (R-N3) and a terminal or internal alkyne (C≡C) to produce mixtures of the two regioisomers when using asymmetric alkynes. In this respect, the classic Huisgen (3 + 2) cycloaddition fails as a true click reaction. A copper-catalyzed variant can be conducted in aqueous conditions, even at room temperature. Additionally, whereas the classic Huisgen 1,3-dipolar cycloaddition often produces mixtures of regioisomers, the copper-catalyzed reaction allows the synthesis of the 1,4-disubstituted regioisomers specifically [31].
Under controlled microwave irradiation condition, Raju and coworkers have developed new derivatives of 1,2,3-triazolyl-pyrrolidinyl-quinolinolines using copper as catalysts and evaluated these derivatives for their antibacterial activity [32]. They have examined two oxidation state of copper, namely copper(I) iodide (CuI) and copper(II) sulfate pentahydrate (CuSO4•5H2O). CuI found to be superior with respect to yields, in which the desired products were obtained in very good to excellent yield, Scheme 10. In another study utilizing microwave irradiation, Arrjane, M. et al. have synthesized and evaluated new acridone derivatives as antibacterial agent, in vitro [33]. The proposed derivatives were prepared via click chemistry using copper sulfate pentahydrate (CuSO4•5H2O) and sodium ascorbate (VcNa) in DMF as solvent. The reaction was performed in conventional and microwave heating. The authors have concluded that the use of microwave irradiation has dramatically reduced the reaction time to 10 min with great improvements in the yields, Scheme 11. Scheme 11. CuSO4•5H2O catalyzed microwave-assisted synthesis of acridone-1,2,3-triazole derivatives.
A microwave-assisted protocol for the synthesis of 7-triazol-1-yl-fluoroquinolone using copper(II) sulfate (CuSO4) as catalyst for the azide-alkyne cycloaddition has been proposed by Cardoso-Ortiz and coworkers [34]. Two reaction procedures were employed, one under conventional heating, while the other one performed under microwave irradiation. It has been noticed that the extended reaction time, under conventional heating, for 7 days were accomplished in very short time (ca. 5 min) under microwave irradiation, with significant improvement in the yield of the desired product, Scheme 12. Lima and coworkers have developed novel copper-II oxide nanoparticles (CuO NPs) to catalyze the synthesis of 1,2,3-triazoles starting from divers dicarbonyl compounds and aryl azides under microwave technology [35]. The reaction proceed using a catalytic amount (30 mol %) of the copper nanoparticles (CuO NPs) in dimethyl sulfoxide (DMSO) as solvent, the resulting mixture was then heated in a microwave oven at 80 °C for 15 min to produce 1,4,5-trisubstituted 1,2,3-triazoles in low to excellent yields, Scheme 13. Under controlled microwave irradiation conditions, Ashok and coworkers have developed new 2-indolinone-based bis-1,2,3-triazole derivatives as antioxidant and antimicrobial agents [36]. The chemical syntheses were performed in direct comparison between conventional and microwave heating in the presence of two oxidation state of copper catalysts (I & II), namely copper(I) iodide (CuI) with sodium ascorbate (VcNa) and copper(II) sulfate pentahydrate (CuSO4•5H2O). CuIfound to be superior over CuSO4•5H2O that produces the desired products in higher yields. Both reactions were achieved in short reaction times (3-12 min), Scheme 14. Four novel hydrosoluble Cu(I)-DAPTA complexes have been synthesized and characterized for their efficiency in a microwave-assisted three-component azide-alkyne cycloaddition click reaction [37]. One of these novel catalysts found to be more effective that leads to higher yields of the desired products. The reaction mixture was heated in a microwave oven at 125 °C for 15 min in mixture of equal amount (1:1) of water and acetonitrile as solvent furnishing the desired products in good to excellent yields, Scheme 15. Using a dedicated microwave oven, Yuan and Qu have reported on the functionalization of β-sitosterols [38]. In which a mixture of β-sitosterol-3-yl azide, phenylacetylene, catalytic amount (10 mol %) of CuSO4•5H2O and sodium L-ascorbate (VcNa), were all mixed in the presence of water as solvent. The resulting mixture was then heated in a microwave oven as 40 °C for 30 min, to produce the desired product in low to excellent isolated yields, Scheme 16. Scheme 16. CuSO4 catalyzed microwave-assisted synthesis of β-sitosterol derivatives bearing a 1,2,3-triazole substituents.
Alves and coworkers have reported on the synthesis of (arylselanyl)phenyl-1H-1,2,3triazoles under copper catalyzed microwave assisted reaction [39]. The reaction proceed with excellent yield when they used copper(II) acetate (Cu(OAc)2) and sodium ascorbate in a mixture of water and THF, the mixture was heated in a microwave oven at 70 °C for 30 min to produce the target compound in excellent yield, Scheme 17. Scheme 17. Cu(OAc)2 catalyzed microwave assisted synthesis of (arylselanyl)phenyl-1H-1,2,3triazoles.
Using a microwave-assisted protocol, Van der Eycken and coworkers have systematically improved the construction of 2-amino-1H-imidazole/triazole conjugates, the target compounds showed moderate to high preventive activity against biofilms of S.
Typhimurium, E. coli, P. aeruginosa, and S. aureus. [40]. They have optimized the synthesis using a catalytic amount (5 mol %) of copper(II) acetate nanoparticles [Cu(OAc)2 NPs] to catalyze the azide-alkyne cycloaddition in the presence of hydrazine (N2H4) as solvent, the resulting mixture was then heated in a microwave oven at 100 °C for short reaction time (2 min) to produce 2-amino-1H-imidazole/triazole conjugates in moderate to excellent yield, Scheme 18. In another study utilizing microwave irradiation, Carvalho and coworkers have reported on the use of copper(II) sulfate (CuSO4) to catalyze the cycloaddition reaction between azide and alkyne [41]. The reaction was achieved using catalytic amount (3 mol %) of CuSO4 and DMF as solvent, the resulting mixture was then heated in microwave oven at 70 °C for 10 min to produce benznidazole derivatives in moderate to excellent yields, Scheme 19. Scheme 19. CuSO4 catalyzed microwave-assisted synthesis of benznidazole analogues.
In a systematic investigation using microwave technology, Khan, A.N. et al. has reported on the use of copper salts to catalyze the synthesis of β-1,2,3-triazolyl-α-amino esters [42]. They have reported on the use of several kind of copper catalysts in different solvents and in the presence or absence of the base pentamethyldiethylenetriamine (PMDTA). A catalytic amount (10 mol %) of copper(I) iodide (CuI) in the presence of PMDTA in THF were the most effective combination. The reaction mixture was then heated in a microwave oven at 100 °C for short reaction time (5 min), to offer β-1,2,3triazolyl-α-amino esters in moderate to good isolated yields, Scheme 20. Scheme 20. CuI catalyzed microwave-assisted synthesis of β-1,2,3-triazolyl-α-amino esters.
Under microwave assisted reaction conditions, Liu and coworkers have reported on the use of copper(II) sulfate to catalyze the one-pot synthesis of α-propargyl 3-tosylamino-2,3-dideoxyglycosides [43]. A systematic strategy were employed to access these very important kind of organic molecules. They have concluded that the most effective reaction pathway found to be the use of a catalytic amount (1 mol %) of CuSO4 in DMF as solvent, the reaction mixture was then heated in a microwave oven at 70 °C for 15 min, the desired products were obtained in moderate to excellent yields, Scheme 21.
In another study by Barros and coworkers reported on the derivatization of sucrose were sucrose derived azides reacted with diverse terminal alkynes to produce 1,2,3triazole-sucrose derivatives [44]. They have reported on the use of catalytic amount (20 mol %) of copper sulfate (CuSO4) in the presence of sodium ascorbate (VcNa) in equal amount (1:1) of tert-butanol and water (tBu:H2O), the resulting mixture was then heated in a microwave oven at 70 °C for a short reaction time (5 min), and 1,2,3-triazole-sucrose derivatives were produced in excellent yields, Scheme 22.

Carbon-Carbon (C-C) Bond Formation
Copper and its salts have been widely involved as co-catalyst along with palladium for the Heck and Sonogashira coupling reactions furnishing carbon-carbon (C-C) bond. For example palladium/copper-II oxide nanoparticles (Pd/CuO NPs) were developed and widely used for the Heck coupling reactions under microwave irradiation [46]. The reaction was performed using catalytic amount (2 mol %) of Pd/CuO in the presence of base (K2CO3) and equal volume (1:1) of ethanol/water as solvent, the reaction mixture was then heated in a microwave oven at 150 °C for a short reaction time (10 min) to produce the desired products in good to excellent yield, Scheme 24. Scheme 24. Pd/CuO NPs catalyzed microwave-assisted Heck coupling reaction.
The authors have employed the same catalyst (Pd/CuO NPs) under microwave irradiation conditions to explore its efficiency towards the Sonogashira coupling between phenylacetylene and iodobenzene [47]. The catalyst found to be effective for the synthesis of diphenylacetylene in high yield, Scheme 25. Tsai, W.-T. et al. improved the coupling reaction between aryl halides, vinyl iodides, and bromides with aryl-and alkyl-alkynes under controlled microwave irradiation condition [48]. The reaction was proceed using catalytic amount (2-5 mol %) of the copper complex [CuI(xantphos)] in the presence of cesium carbonate (Cs2CO3) as base in DMF as solvent, the resulting mixture was then heated in a microwave oven at 135 °C for 10-30 min, furnishing the desired alkyne derivatives in low to excellent isolated yields, Scheme 26. In another study utilizing copper/palladium to catalyze Sonogashira cross-coupling reaction between aryl halides and trimethylsilylacetylene has been described by Lei, Y. et al. [49]. The reaction was optimized utilizing a catalytic amount (10 mol %) of copper(I) iodide (CuI), triethylamine (Et3N) as base in acetonitrile as solvent, the resulting mixture was then heated in a microwave oven at 120 °C for a short reaction time (5 min) leading to the desired products in high yields, Scheme 27. Scheme 27. Cu/Pd-catalyzed microwave-assisted Sonogashira-type coupling reaction between aryl halide and trimethylsilylacetylene.
Under controlled microwave process, Anilkumar and coworkers have developed environmentally friendly catalytic method of copper based catalyst to catalyze Suzuki cross-coupling reaction of alkynyl bromides with boronic acid derivatives [50]. The Suzuki-type reaction proceed smoothly using a catalytic amount (10 mol %) of copper(I) iodide (CuI) in the presence of potassium phosphate (K3PO4) as base and ethanol as solvent, the combined mixture was then heated in a microwave oven at 130 °C for 15 min furnishing 1,2-diarylacetylenes in moderate to excellent yield, Scheme 28. Bimetallic catalysts composed of palladium and copper(II) oxide (Pd/CuO) have been developed by Elazab, H.A. et al. as efficient and recyclable catalyst for the Suzuki-type cross-coupling reaction [50]. The reaction proceed using a catalytic amount (1 mol %) of Pd/CuO in the presence of potassium carbonate (K2CO3) as base and in equal amount (1:1) of water and ethanol (H2O:EtOH) as solvent, the reaction mixture was then heated in a microwave oven at 150 °C for 10 min furnishing biphenyl derivatives in moderate to excellent yields, Scheme 29. The developed Suzuki coupling reaction found to be applicable for a wide varieties of aryl halides and the desired products were obtained in good to excellent yields. It has been also noticed that the catalyst can be fully recycled up to five times while keeping its efficiency. Scheme 29. Pd/CuO catalyzed microwave-assisted Suzuki cross-coupling reaction.
Using microwave technology, Ibrahim, M.A. has reported the use of copper(II) triflate Cu(OTf)2 for the coupling reaction between a wide range of aryl halides and diethyl malonate esters furnishing α-aryl malonates, as important intermediate in the synthesis of azaheterocycles, such as benzodiazepine, isoquinoline, and pyrrolopyridine derivatives [51]. The reaction have been properly optimized to use catalytic amount (10 mol %) of Cu(OTf)2, picolinic acid as ligand and toluene as solvent, the resulting mixture was then heated in a microwave oven at 90 °C for 20 min to obtain α-aryl malonates in moderate to excellent yields, Scheme 30. Under controlled microwave irradiation conditions, Jha and Jain described a regioselective cross-coupling reaction of N-tosylhydrazones with azine N-oxides [52]. The reaction proceed using copper(I) iodide (CuI) and LiOtBu as a base in toluene as solvent, the resulting mixture was then irradiated in a microwave reactor at 100 °C for 60 min and the desired products were obtained in moderate to excellent yields, Scheme 31.

Synthesis of Propargylamines
Propargylamines are versatile building blocks and key intermediates for the synthesis of important scaffolds bearing nitrogen function, such as natural products, heterocycles, and biologically active molecules [53]. Therefore, scientists are interested in the development of new methods for the synthesis of this important class of intermediates [54][55][56][57]. The synthesis started under classical pathway followed by transition-metalcatalyzed three-component coupling reactions under conventional heating. While, in the last decade, more emphasize was given for the preparation of propargylamines under microwave irradiation, including the use of copper to catalyze their syntheses. One of the most convenient and general approach to produce propargylamine derivatives is the three-component coupling of an amine, an aldehyde, and an alkyne, commonly called A 3 coupling.
Van der Eycken and co-workers described the synthesis of secondary alkylpropargylamines via A 3 coupling reaction with primary aliphatic amines under microwave heating [56]. A catalytic amount (20 mol %) of copper(I) iodide (CuI) was used for the three component cross-coupling reaction among cyclic ketone, primary amine, and terminal alkyne under solvent free condition, the resulting mixture was then heated in a microwave oven at 100 °C for 25 min to produce propargylamine derivatives from low to very good yields, Scheme 32. Scheme 32. CuI catalyzed microwave-assisted A 3 coupling for the synthesis of propargylamines.
Shimpi and coworkers have developed new heterogeneous catalyst (CuNPs@ZnO-PTh) which composed of copper nanoparticles (CuNPs) loaded on zinc oxidepolythiophene (ZnO-PTh) [58]. The catalyst then applied to the synthesis of number of propargylamine derivatives, such as tetra substituted propargylamine and pyrrolo [1,2-a]quinolone in ethylene glycol as a solvent and heated in a dedicated microwave reactor, the desired products were obtain in high yields, Scheme 33. to produce propargylamine derivatives [59]. The reaction proceed smoothly using very low catalytic amount (0.1 mol %) of the copper based complex in acetonitrile as solvent (CH3CN), the reaction mixture was then heated in a microwave oven at 85 °C for short reaction time (5 min) to generate the propargylamine derivatives in good to excellent yields, Scheme 34. In another study utilizing microwave technology, polystyrene resin supported copper nanoparticles (Cu NPs@Resin) have been developed by Kaur and coworkers for the synthesis of propargylamine derivatives via A 3 coupling reaction of aldehyde, alkynes, and amines [60]. Cu NPs@Resin was used to catalyze the reaction in toluene as solvent. The reaction mixture was then heated at 100 °C in a microwave oven for 25 min to produce the desired products in moderate to excellent yields, Scheme 35. Xu and coworkers have developed novel strategy of the three-component coupling among divers amino alcohols, aldehydes and alkynes using copper(I) chloride (CuCl) as catalyst under microwave irradiation condition [61]. The reaction has proceeded smoothly to provide the desired propargylamines in low to excellent yields, Scheme 36. Van der Eycken and coworkers have systematically examined several copper salt catalysts in different catalytic amount for the synthesis of secondary alkylpropargylamines via A 3 coupling reaction with primary aliphatic amines under microwave conditions [62]. The most effective reaction conditions were achieved using a catalytic amount (20 mol %) of copper(I) bromide (CuBr) in toluene as solvent, the reaction mixture was then heated in a microwave oven at 100 °C for 25 min to produce propargylamine derivatives in moderate to excellent yield, Scheme 37. Scheme 37. CuBr catalyzed microwave-assisted A 3 coupling for the synthesis of propargylamines.
A decarboxylative A 3 coupling reaction of an alkynylcarboxylic acid with a secondary amine and an aldehyde forming tertiary propargylamines in high yields has been described [63]. The reaction was optimized include the use of catalytic amount (20 mol %) of copper(I) iodide (CuI) for the decarboxylative cross-coupling reaction in toluene as solvent, the reaction mixture was then heated in microwave oven at 100 °C for 15 min to produce propargylamine derivatives in low to excellent yield, Scheme 38. In a similar study same author have reported on the synthesis of propargylamine based 1,4-diamino-2-butynes via one pot Cu(I)-catalyzed A 3 decarboxylative coupling of a propiolic acid, an aldehyde, and substituted amines [64]. Moreover, polysubstituted propargylamines have been synthesized using decarboxylative three-component coupling of a 2-oxoacetic acid, substituted amine and an alkyne [65]. On the other hand, Tong and coworkers have reported the synergistic effect of dual copper catalysts to catalyzed A 3 cross coupling/decarboxylative domino reactions [66]. While Organ and coworkers have reported on the preparation of propargylamines using microwaveassisted continuous-flow organic synthesis (MACOS) technology for the reaction among aldehydes or ketone with amines and terminal alkynes [67].
Scheme 39 summarizes the proposed catalytic cycle for the preparation of propargylamine derivatives. The mechanism starts from the condensation of an amine with an aldehyde leading to the formation of imine (Schiff base), followed by coordination of alkyne and Cu(I) to generate an alkenyl-copper complex along with the imine designated intermediate (I). Intermediate (II) is resulted from nucleophilic alkyne attack on activated imine carbon to generate a new C-C bond leading finally to form the highly substituted propargylamines (III) by decomplexation step and regeneration of the active species of the catalyst [59].

Scheme 39.
A proposed mechanism for copper-catalyzed microwave-assisted synthesis of propargylamines.

Synthesis of Heterocyclic Systems
Heterocyclic compounds are cyclic aliphatic or aromatic organic molecules that at least one of the carbons in the ring being replaced with a heteroatom-such as N, O, S, P, etc. A heterocyclic ring system has been reported to be part of many natural product compounds, pharmaceuticals, and biologically active compounds. Therefore, and due to its important applications, several organic synthetic methodologies have been developed for the synthesis of this important class of molecules, among these recently developed methodologies is the use of copper under microwave irradiation technology.
Sayyad, N. et al. have reported on a dimerization reaction of two molecules of orthohallobenzamides furnishing new quinazolinone derivatives via intramolecular cyclization reaction using copper iodide under microwave irradiation [68]. The hallobenzamides were treated in different alcohol-namely methanol, ethanol, or propanol-as solvent in the presence of copper(I) iodide (CuI) as catalyst and cesium carbonate (Cs2CO3) as base, the resulting mixture was then heated in a microwave oven at 120 °C for 10 min to produce quinazolinones in low to very good yield, Scheme 40. The reaction proceeds via two intermediates pathway in which the solvent used in the reaction (methanol, ethanol, and propanol) acts as a nucleophile generating alkoxy substitution.

Scheme 40. CuI catalyzed microwave-assisted dimerization of ortho-hallobenzamides.
Under controlled microwave processes, Cho and coworkers have developed a new synthetic method for the synthesis of novel azole-fused pyrimidinones starting from βbromo-α,β-unsaturated amides and different azoles, e.g., imidazole, pyrazole, and benzimidazole [69]. The reaction proceeds via intermolecular C-N bond formation. Elemental copper (Cu) powder was used under microwave irradiation in the presence of K2CO3 as base and DMF as solvent, the resulting mixture was then heated in a microwave oven at 100 °C for 1 h yielding the desired product in low to very good yield, Scheme 41. A microwave-assisted cross-coupling reaction using copper(I) iodide (CuI) was proposed by Jacob and coworkers as an efficient method to access fused 1,2,3-triazolo-1,3,6-triazonine derivatives [70]. The authors have reported on the reaction between 5iodo-1,2,3-triazoyl benzaldehyde derivatives and substituted ortho-diaminobenzenes in the presence of catalytic amount (5 mol %) of CuI in DMSO as solvent, the reaction mixture was then heated in a microwave oven at 100 °C for 1 h and the desired novel heterocycles were obtained in moderate to excellent yields, Scheme 42.  [1,4]diazepin-6-ones by post-Ugi copper-catalyzed intramolecular coupling reaction [71]. The desired products were obtain in moderate to high yield using copper-I iodide (CuI) via cycloaddition reaction of four components under microwave irradiation, the reaction proceed smoothly using Cs2CO3 as base in DMSO as solvent, the resulting mixture was then heated in a microwave oven at 100 °C for 30 min to produce 4H-benzo[f]imidazo [1,4]diazepin-6-ones in low to very good yields, Scheme 43. In another study, Rout, L. et al. have developed new Cu@Ag core-shell nanoparticles (Cu@Ag NPs) and they have explored their application to catalyze the synthesis of octahydroquinazolinone derivatives [72]. The newly developed nanoparticles (Cu@Ag NPs) have been used for the synthesis of the target compounds via one-pot condensation reaction of three components; aromatic aldehydes, cyclic-diketones, and urea in solvent free condition to obtain octahydroquinazolinone in moderate to excellent yield in short reaction time (1-5 min), Scheme 44. Under controlled microwave-assisted copper-catalyzed reaction condition, Ke and coworkers have developed new strategy for the synthesis of quinazolinone derivatives in aqueous media [73]. They have systematically improved the reaction utilizing different copper oxidation states, such as CuI, CuCl2, CuO, CuSO4, and Cu(OAc)2. The optimized reaction conditions suggests that a catalytic amount (10 mol %) of CuCl2 and 10 mol % of 8hydroxyquinoline as ligand in water as solvent is the most effective combination to access the target compounds. The reaction mixture was then stirred at room temperature for 20 min under microwave irradiation with cooling to maintain the reaction at room temperature, furnishing quinazolinone derivatives in moderate to excellent yields, Scheme 45. formation followed by ring closure. The reaction proceeds smoothly starting from orthohalo (Cl or Br) aromatic carboxylic acids with guanidine hydrochloride in ligand free conditions [74]. The mixture of starting materials, catalytic amount (10 mol %) of Cu2O, and Cs2CO3 as base in DMF as solvent was heated in a microwave oven at 120 °C for 20 min to produce the quinazoline derivatives in moderate to very good yields, Scheme 46. On the other hand, Bhanage and coworkers have developed new copper(I) oxide nanocubes (Cu2O-nanocubes) and utilized it for the synthesis of quinazoline derivatives starting from 2-bromobenzaldehydes and amidine hydrochloride derivatives [75]. The reactants were treated with catalytic amount (5 mol %) of Cu2O-nanocubes, Cs2CO3 as base and ethylene glycol ((CH2OH)2), the reaction mixture was then irradiated at 360 Watt in a microwave oven for 2 min furnishing 2-phenylquinazoline derivatives in moderate to excellent yields, Scheme 47. Xu and coworkers have reported on the syntheses of 1,4-oxathiines and 1,4-dioxines under microwave irradiation [76,77]. The reaction proceed via ring expansion of thiiranes and oxiranes with α-diazo-β-dicarbonyl moieties. They have examined two types of copper catalysts, namely CuSO4•5H2O and Cu(hfacac)2•xH2O in dichloroethane (DCE) as solvent and microwave heating at 100-150 °C for 20 min, Scheme 48. In spite of the fact that this reaction produces the desired compounds in only low to moderate yields, but it is considered as one of the most important method described to access such biologically important heterocyclic compounds.
A new series of benzodifuran-based bis(N-(het)arylthiazol-2-amine) derivatives have been developed as antibacterial agents. These compounds were synthesized starting from O,O-diacetyl dioxime and aryl-isothiocyanates under microwave irradiation. The reaction produced higher yield within short reaction time compared to conventional heating [78]. A catalytic amount (20 mol %) of CuI, in the presence of Cs2CO3 as a base and dioxane as solvent, the resulting mixture was then heated in a microwave oven at 100 °C for 15-25 min to produce benzodifuran-based bis(N-(het)arylthiazol-2-amine) derivatives in high yields, Scheme 49. A silver/copper cocatalyst has been developed by Wang and coworkers for the synthesis of substituted carbazoles via cascade intramolecular cyclization/desulfinamide/dehydrogenation in one pot reaction under microwave irradiation [79]. The author has optimized the reaction condition to the use of catalytic amounts of the both cocatalysts, 20 mol % of copper(II) acetate (Cu(OAc)2) and 10 mol % of silver hexafluoroantimonate (AgSbF6) in the presence of chloranil as oxidizing agent in dichloroethane (DCE) as solvent, the reaction mixture was then heated in a microwave oven at 80 °C for 2.5 h furnishing substituted carbazoles in moderate to very good yields, Scheme 50. Under controlled microwave irradiation condition, Cho and coworkers have prepared indolo[2,1-a]isoquinolines using copper(I) iodide to catalyze the intermolecular cyclization of 2-(2-bromoaryl)-1H-indoles with 1,3-diketones [80]. The reaction proceed smoothly using a very low catalytic amount (0.03 mol %) of copper(I) iodide (CuI) and potassium phosphate (K3PO4) as base in N,N-dimethylformamide (DMF) as solvent, the reaction mixture was heated in a microwave oven at 130 °C for 1 h to produce the corresponding indolo[2,1-a]isoquinoline derivatives in low to good isolated yields, Scheme 51. The reaction proceed via cycloaddition reaction of various substituted nitriles with sodium azide (NaN3) in equal volume (1:1) of water and isopropanol (H2O:IPA) as solvent, the resulting mixture was then heated in a microwave oven at 65 °C for 15 min to produce the target compounds in good to excellent yields, Scheme 52.

Carbon-Hydrogen (C-H) Bond Functionalization
The ability to selectively generate new aryl-carbon (Ar-C) bond is one of the longstanding challenges for the organic chemist community. One of these strategies is to activate the non-reactive C-H bond by applying novel catalyst that work in a regioselective manner.
Under microwave-assisted synthesis C-H bond arylation have been reported using copper catalysts for the synthesis of substituted pivanilides by Yang, H.J. et al. [112]. The authors have found that pivanilides selectively direct the arylation reaction towards the meta-position by using homogeneous or heterogeneous copper based catalyst, Cu(OTf)2/DTBP and Cu-β zeolite/DTBP respectively, the reaction proceed in dichloroethane (DCE) as solvent, the reaction mixture was then irradiated in a microwave oven at 80 °C for 30-60 min to produce pivanilide derivatives in moderate to excellent yields, Scheme 53.

Scheme 53.
Homogeneous and heterogeneous copper catalyzed microwave-assisted synthesis of pivanilides.
Besson and coworkers have developed thiazolo [5,4-f]quinazolin-9(8H)-one in two step C-H activation under microwave irradiation [113]. Regioselective C-2 and C-7 arylation of thiazolo[5,4-f]quinazolin-9(8H)-one has been achieved using cocatalysts between copper and palladium, in the presence of base (DBU and LiOtBu). The resulting mixture was then heated in a microwave oven at 120 °C for relatively long reaction time (5 h) to introduce divers aryl moieties at position C-2 and C-7 of the thiazolo[5,4f]quinazolin-9(8H)-one core in moderate to high yields, Scheme 54. In another study, by same authors, a direct arylation of quinazolin-4-one under microwave-assisted process has been described [114]. The arylation reaction proceed via cocatalysts using mixture of copper(I) iodide (CuI) and palladium(II) acetate (Pd(OAc)2) in the presence of lithium tert-butoxide (LiOtBu) as base in DMF as solvent. The reaction mixture was then heated in a microwave oven at 120 °C for 30 min to produce C-2 substituted (2H)-quinazolin-4-ones in low to excellent yields, Scheme 55. Under controlled microwave heating condition, Yuan, J. et al. have carried out C-H amidation of quinoxalin-2(1H)-ones using copper catalyst [115]. The reaction proceed with catalytic amount (4 mol %) of copper(I) bromide (CuBr) in the presence of K2S2O8 as oxidizing agent in CH3CN as solvent, the reaction mixture was then heated in a microwave oven at 80 °C for 30 min. The authors found that this reaction being tolerated for divers functional groups, including (hetero)aryl amides (primary and secondary) and aliphatic amides (cyclic and acyclic) to produce amidated quinoxalin-2(1H)-ones in good to excellent yields, Scheme 56. Scheme 56. CuBr catalyzed microwave-assisted amidation of quinoxalin-2(1H)-ones.
A microwave-assisted regioselective alkenylation at C-8 position in purines and azoles, such as caffeine, 1,3,4-oxadiazole, 5-phenyloxazole, N-methylbenzimidazole, benzothiazole, 1,2,4-triazole, and oxazole using microwave reactor has been described by Piguel and coworkers [116]. The reaction has been carried out using cocatalyst composed of copper(I) iodide (CuI) and palladium(II) acetate (Pd(OAc)2), in the presence of phenantroline as ligand, LiOtBu as base in dioxane as solvent, the resulting mixture was then heated in a microwave oven at 120 °C for 30 min to produce the target compounds in low to very good yields, Scheme 57. Scheme 57. CuI and Pd(OAc)2 cocatalyzed microwave-assisted alkenylation at C-8 position in purines and azoles.

N-(Hetero)Arylation and N-Alkylation Reaction
N-(Hetero)Aryl-and N-alkyl-substituted heterocycles are common pharmacophores in natural products and biologically active synthesized compounds. Therefore, scientists keep interest in the development of novel methodologies for N-(hetero)arylation and Nalkylation. Mild and efficient N-(hetero)arylation and N-alkylation of heterocycles has been developed with palladium and copper catalysts. Using palladium to catalyze N-(hetero)arylation and N-alkylation are encountered with some limitations mainly due to the high cost of the catalyst. Therefore, copper-catalyzed reactions received significant attention for such kind of reactions [106,112].
Using microwave heating technique, Abe, T. et al. have reported on the arylation reaction of 2-azabicyclo[2.2.1]hept-5-en-3-ones with arylboronic acids with copper catalyst to produce the related N-aryl compounds [117]. The reaction optimized to the use of a catalytic amount (10 mol %) of copper(II) acetate (Cu(OAc)2), in the presence of arylboronic acids and KOH as base in acetonitrile, the reaction mixture was then heated in a microwave oven at 80 °C for 30-120 min producing the title compounds in moderate to very good yield, Scheme 58. On the other hands, the N-cyclopropylation of pyridinols promoted by copper(II) acetate (Cu(OAc)2) under microwave irradiation have been described by Sharma and coworkers [118]. Pyridinols were reacted with cyclopropylboronic acid in the presence of equimolar concentration of Cu(OAc)2, with pyridine and NaHMDS as a base in toluene as solvent, the reaction mixture was then heated in a microwave oven at 120 °C for relatively a long reaction time (2-2.5 h) leading to the synthesis of the desired products in moderate to very good yields, Scheme 59. Under microwave irradiation, Al-Masum, M. et al. have reported on the use of dual catalysts composed of copper and palladium as useful cocatalyst for the amide styrylation reaction starting from potassium styryltrifluoroborates and amide compounds [119]. They have concluded the optimal conditions to be the use of catalytic amount of the dual catalysts, which is composed of copper(I) iodide (CuI) and [1,1′-Bis(di-tertbutylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dtbpf)) in the presence of potassium carbonate (K2CO3) as base in 1,4-dioxane as solvent, the resulting reaction mixture was then heated in a microwave oven at 120 °C for 30 min to produce the amide styrylation derivatives in moderate to excellent yields, Scheme 60. In a similar reaction, Chang, R.K. et al. have reported the synthesis of aryl amides via a concurrent tandem catalytic methodology of converting aryl chloride to an aryl iodide using halogen exchange reaction under microwave irradiation [120]. The author systematically optimized the reaction by applying a catalytic amount (20 mol %) of copper(I) iodide (CuI) and N,N′-cyclohexane-1,2-diamine as ligand, in the presence of K2CO3 as base in acetonitrile as solvent, the reaction mixture was then heated in a microwave oven at 200 °C for 45-60 min, affording the title compounds in moderate to very good yields, Scheme 61. Under controlled microwave irradiation, Nishihara and coworkers have investigated the chloroamination reaction of styrene derivatives with chlorotrimethylsilane and Nfluorobenzenesulfonimide [121]. The reaction has successfully achieved using catalytic amount (10 mol %) of Cu(acac)2 in dichloromethane as solvent, the reaction mixture was then heated in a microwave oven at 120 °C for 1 h to produce the desired products in moderate to excellent yields in high regioselectivity, Scheme 62. Using microwave heating process, Taj and coworkers have synthesized novel N(N')arylbenzamidines starting from corresponding N-arylbenzamides with ammonia or aniline in a one-pot reaction. The synthesized compounds showed good inhibition activity against several enzymes including acetylcholinesterase, butyrylcholinesterase, lipoxygenase, α-glucosidase, urease, and reverse transcriptase with some selectivity for acetylcholinesterase, butyrylcholinesterase, and anti-HIV [122]. The reaction proceed smoothly using copper(II) oxide (CuO) powder in neat condition with heating in microwave oven at 80 °C for 15 min, furnishing N(N′)-arylbenzamidine derivatives in moderate to good yields, Scheme 63. Recyclable nanoparticles composed of three metals, nickel, copper, and iron (NiCuFe2O4) has been developed and utilized for a microwave-assisted neat synthesis of bis-amide derivatives have been reported by Sarada, R. et al. [123]. They have concluded that the optimal reaction conditions achieved using catalytic amount (10 mol %) of NiCuFe2O4 nanoparticles (NiCuFe2O4 NPs) in the presence of silica gel, the resulting mixture was heated in a microwave oven at 100 °C for 4 min to obtain the desired products in excellent yields, Scheme 64. Nematpour, M. and Abedi, E. have reported the synthesis of sulfonylidenesulfonamide derivatives via one-pot reaction among three components: Nsulfonylketenimine, sodium arylsulfinates, and terminal alkynes under microwave irradiation [124]. The reaction being optimized to use a catalytic amount (10 mol %) of copper(I) iodide (CuI), in the presence of triethyl amine (Et3N) as a base and DMF as a solvent, the reaction mixture was irradiated in microwave oven at 900 Watt for 1 h furnishing sulfonylidene-sulfonamide derivatives in good to excellent yields, Scheme 65. Under controlled microwave irradiation technique, Shankaraiah and coworkers have developed novel copper(I)-complex [bis(tetrabutylammonium)di-μ-iododiiododicuprate(I)] for the synthesis of α-ketoamides starting from aryl methyl ketones and amines [125]. The reaction proceeds smoothly using a catalytic amount (20 mol %) of the copper(I)-complex (Cu(I)-complex) in the presence of molecular oxygen as oxidizing agent, and water as solvent, the reaction mixture was then heated in a microwave oven at 60 °C for 10 min to produce the target compounds in moderate to excellent yields, Scheme 66.

Synthesis of Carbon-Chalcogen Bonds (C-O, C-S, C-Se, and C-Te)
Copper based catalysts were used for carbon-chalcogen bonds (C-O, C-S, C-Se, and C-Te) formation under microwave irradiation. The generation of carbon-oxygen (C-O) bond has been developed as an efficient strategy for the synthesis of diaryl and alkyl aryl ethers via O-arylation and O-alkylation of phenols [126,127]. Two reaction pathways were proposed; the first one utilizing catalytic amount (5 mol %) of copper(I) bromide (CuBr) and 1,1-azobis(cyclohexane carbonitrile) (ACHN) as ligand in DMF as solvent [126], while the second reaction pathway through the use of a catalytic amount (5 mol %) of copper(I) oxide with Cs2CO3 as base in N-methyl-2-pyrrolidinone (NMP) as solvent [127], both reaction mixtures were heated in a microwave oven at 170 °C for 30 min to produce the diaryl and alkyl aryl ethers in moderate to excellent yields, Scheme 67.  [128]. The authors have concluded that the best reaction conditions were to use a catalytic amount (5 mol %) of copper(II) oxide (CuO), 1,10-phenanthroline as ligand, and potassium tert-butoxide (KOt-Bu) as base in water as solvent, the resulting mixture was then heated in a microwave oven at 120 °C for 30 min to produce the desired products in good to excellent yields, Scheme 68. Using controlled microwave condition, Chiosis and coworkers have reported the use of a combination between copper(I) iodide (CuI) and phase transfer catalyst, such as tetrabutylammonium bromide [(n-Bu)4NBr] as useful reagent for S-arylation of 8mercaptoadenine [129]. The reaction proceed smoothly using sodium tert-butoxide (NaOt-Bu) as base in DMF as solvent, the reaction mixture was then heated under microwave irradiation at 190 °C, the reaction required 1.5 h furnishing the desired products in low to excellent yields, Scheme 69. Under controlled microwave-assisted synthesis, Braga and coworkers have developed copper(II) oxide nanoparticles (CuO NPs) to catalyze the generation of novel carbon-chalcogen bonds, such as C-S, C-Se, and C-Te [130]. Diselenides, ditellurides, and disulfides were prepared via one-pot dimerization of organoyl iodides with elemental chalcogen (Y°) using CuO NPs in the presence of KOH as base, DMSO as solvent, the resulting mixture was heated in a microwave oven at 80 °C for 7-15 min and the desired products were obtained in moderate to excellent yields, Scheme 70. Diaryl sulfide derivatives have been synthesized using cross-coupling reaction between trialkyltin arylselenides and arylbromides using copper catalyst resulted in unsymmetrical diarylselenides [131]. The reaction proceeds using a catalytic amount (5 mol %) of the copper catalyst ([(phen)CuI]2) in DMF as solvent, the reaction mixture was then heated in microwave oven at 140 °C for 15-50 min to produce diaryl sulfide derivatives in moderate to excellent yields, Scheme 71. In another study, Saba S. et al. have reported on the use of copper(I) iodide (CuI) for the synthesis of diorganyl chalcogenides (S/Se/Te) starting from arylboronic acid derivatives under ligand and solvent-free conditions [132]. The reaction was done using catalytic amount (3 mol %) of CuI in DMSO as solvent, the reaction mixture was then heated in a microwave oven at 100 °C for 15 min to obtain the diorganyl chalcogenide derivatives in moderate to excellent yields, Scheme 72. Under microwave assisted condition, Bhargava and coworkers have reported on the synthesis of solketal from glycerol using copper mordenite (Cu-Mor) [133]. Cu-Mor were used to promote the cycloaddition reaction between glycerol and acetone in a microwave oven at 100 °C for 15 min leading to 95% conversion with 98% selectively for solketal, Scheme 73.

Miscellaneous Synthesis
Copper based catalysts have been utilized for a wide range of organic transformations; herby a selection of recently published important transformation carried out under microwave irradiation. Symmetrical and asymmetrical diaryl sulfones have been synthesized using copper(II) triflate (Cu(OTf)2) under microwave irradiation [134]. Nandi, G.C. has reported the coupling between sodium salt of sulfinic acids with aryl boronic acid derivatives in the presence of Cu(OTf)2 as catalyst and 2,2′-bipyridyl as ligand in dichloroethane (DCE) as solvent, the resulting mixture was then heated in a microwave oven at 120 °C for 20-30 min furnishing diaryl sulfones in moderate to very good yields, Scheme 74. Under controlled microwave irradiation condition, Jha and coworkers have developed new strategy for the synthesis of novel substituted acetophenones via hydration of terminal aryl acetylenes [135]. The authors have concluded that the reaction proceed smoothly using a catalytic amount (2.5 mol %) of Cu(OTf)2 in AcOH/H2O as a solvent, and the resulting mixture was then heated in a microwave oven at 110 °C for 2-15 min producing substituted acetophenones in low to excellent yields, Scheme 75. In another study, Silaghi-Dumitrescu and coworkers have synthesized aminophenothiazine derivatives under microwave-assisted amination procedure [136]. Various hallo substituted 10-alkyl-10H-phenothiazines were aminated using catalytic amount (5 mol %) of Cu2O, aqueous ammonia (NH3/H2O) solution and N-methyl-2-pyrrolidinone (NMP), the resulting mixture was then heated in a microwave oven at 120 °C for 2 h furnishing the target compounds in low to excellent yields, Scheme 76. Aryl halides have been converted into various derivatives of phenol using copper(II) catalyst under microwave-assisted hydroxylation reaction [137]. The reaction proceed smoothly using copper(II) chloride (CuCl2) as catalyst, KOH as base and tetrabutylammonium bromide [(n-Bu)4NBr] as phase transfer catalyst and L-proline lithium salt as ligand, the resulting mixture was then heated in a microwave at 120 °C for 40 min to produce phenol derivatives in moderate to excellent yield, Scheme 77. Aryl halides were converted into the corresponding nitro derivatives via coppercatalyzed microwave-assisted nitration using nitrite salts (n-Bu4NNO2) [138]. A systematic optimization of the reaction has resulted in the use of catalytic amount (10 mol %) of CuI, N,N'-dimethylethylenediamine as ligand, and n-Bu4NNO2 as nitrite salt, the reaction mixture was then heated in a microwave oven at 120 °C for 10 min to produce nitrobenzene derivatives in low to excellent yield, Scheme 78. Scheme 78. CuI catalyzed microwave-assisted nitration of aryl halides.
A combination between microwave and ultrasound irradiation (CMUI) was used to assist the reduction reaction of nitrobenzene derivatives to the corresponding anilines using copper(II) acetate nanoparticles (Cu(OAc)2 NPs) [139]. The reduction reaction has been optimized using 30 mol % of Cu(OAc)2 NPs, hydrazine hydrate (NH2-NH2•H2O) in ethylene glycol, the resulting mixture was then heated in a microwave oven at 120-125 °C for short reaction time (4-6.5 min), leading aniline derivatives in excellent yields, Scheme 79. Under controlled microwave-assisted reaction, Montel, S. et al. have reported the Conia-ene cyclization of tethered stabilized nucleophiles using neutral conditions, which is leading to obtain high selective 5-exo cyclized derivatives [140]. The reaction has proceed in an efficient way for both internal and terminal alkynes using catalytic amount (1 mol %) of the cationic copper catalyst ([Cu(Phen)(PPh3)2]NO3) and calcium hydride (CaH2) as a base in dioxane as solvent, the resulting mixture was then heated in a microwave oven at 150 °C for 20-180 min furnishing the desired cyclized product in low to excellent yields, Scheme 80. A hydrogenation reaction of furfural to furfuryl alcohol has been developed by Lopez-Sanchez and coworkers under microwave irradiation [141]. They have used a novel copper absorbed on titanium dioxide (Cu/TiO2) as catalyst in cyclopentyl methyl ether (CPME) as solvent, the resulting mixture was then heated in a microwave oven at 125 °C for relatively long reaction time (3 h), using 10 bar of the hydrogen gas (H2) pressure. The reaction showed 100% conversion and 99% selectivity of furfuryl alcohol under mild reaction conditions, Scheme 81. Scheme 81. Cu/TiO2 catalyzed microwave-assisted reduction of furfural to furfuryl alcohol.

Conclusions
Copper-catalyzed cross-coupling reactions to generate carbon-carbon (C-C) and carbon-heteroatom bonds, such as C-N, C-O, C-S, C-Se, and C-Te, under microwave controlled conditions has proved to be safe in handling and cost effectiveness compared with conventional heating method. Moreover, it has gain some advantageous in comparison to the use of noble metal such as palladium based catalyst for cross-coupling in both conventional or microwave heating, due to the low cost and ready availability of copper catalysts. In many discussed reactions, the use of the microwave heating technology have not only shorten the reaction time, but it was essential for a wider range of functional groups and to obtain the target compounds in higher yields. The catalytic materials showed variable catalyst loading, which ranging from little high load (30 mol %) to very low catalyst loading percentage (0.1 mol %). Several copper solid support catalysts, including nanomaterials, such as nanoparticles and nanocubes, have been developed for the microwave-assisted cross-coupling transformations. These solid support catalysts were found to be useful as homogenous as well as heterogeneous catalysts with advantage of being recyclable for consecutive use.