Copper Catalyzed Synthesis of Heterocyclic Molecules via C–N and C–O Bond Formation under Microwaves: A Mini-Review

Abstract

Heterocyclic moieties play a significant role in the field of drug discovery. C–N and C–O bond formation reactions are the primary synthetic sequence for the generation of heterocyclic molecules. The generation of C–N and C–O bonds involves the use of mostly Pd or Cu catalysts although other transition metal catalyst’s are also involved. However, in C–N and C–O bond formation reactions, several problems were faced such as catalytic systems containing costly ligands, lack of substrate scope, lots of waste generation, and high temperature conditions. So it is imperative to uncover new eco-friendly synthetic strategies. In view of enormous drawbacks, it is important to develop an alternate microwave-assisted synthesis of heterocycles via C–N and C–O bond formation, which provides a short reaction time, tolerance for functional groups, and less waste production. Numerous chemical reactions have been accelerated using microwave irradiation which provides a cleaner reaction profile, lower energy consumption, and higher yields. This review article highlights a comprehensive overview on the potential application of microwave assisted synthetic routes for the synthesis of diverse heterocycles via mechanistic pathways covering the year ranges from 2014 to 2023, along with possible biological interests.

1. Introduction

C–N and C–O bonds are the most omnipresent and important bonds found in organic materials, natural products, drugs, and agricultural chemicals.^1a Almost 80% of marketed drugs contain either C–N or C–O bond. Nitrogen and oxygen containing heterocycles stand out among the many types of heterocyclic compounds due to their diverse nature. Further these heterocycles are particularly important in the pharmaceutical industry due to their excellent solubility and salt forming capacity. To synthesize nitrogen and oxygen containing heterocycles, one important step is the formation of C–N or C–O bonds, for which many synthetic strategies have been developed using transition metal catalysts.^1b,1c For the first time the Ullmann group,^2a and the Goldberg group^2b discovered the Cu-catalyzed C–N and C–O bond forming reactions. Later on, Buchwald^2c and Hartwig groups^2d demonstrated the Pd catalyzed C–N bond formation reaction. Of late the Chan and Lam group achieved a major breakthrough on the Cu-catalyzed C–N bond formation reactions.^2e,2f It has been noticed that other than palladium or copper, several other transition metals such as nickel, zinc, iron, cobalt, and manganese are also used for C–N and C–O bond forming reactions.³ However, all those methods suffer various drawbacks such as the high reaction temperature, use of costly ligands, lack of substrate scope, and lots of waste generation, etc. Consequently, the development of environmentally friendly, simple, and straightforward C–N or C–O bond forming procedures is advantageous for a wide range of organic synthesis applications.

In heterocyclic chemistry, palladium is one of the most popular metal catalysts employed for the generation of C–N and C–O bonds. These catalysts are costly and unstable, and have poor functional group compatibility. Given the requirement to provide versatile, affordable, multipurpose, and eco-friendly catalytic systems, copper has become an attractive and diverse catalysts. More prominently, Cu-catalyzed reactions are widely used in organic synthesis because of their accessibility, safety, and cost-effectiveness. Copper has been shown to be a viable substitute for costly noble metals like palladium in catalysis. The relevance of copper in transition metal catalysis has been shown by the reports of several new processes during the past decade.⁴ Being the most versatile and efficient catalyst among transition metals, copper is a very good redox catalyst. Both Cu(I) and Cu(II) species react efficiently with chemicals for the formation of diverse heterocycles. In addition to their traditional uses as metals, copper salts and complexes are now widely used for their exceptional catalytic properties in a wide range of chemical processes. Further, there is a huge urgency to develop organic synthesis in sustainable pathways. Microwave chemistry is an established field with several well-established applications and a number of benefits in terms of reaction rate and yield. As a result, microwave assisted organic synthesis has become a handy tool for sustainable organic synthesis because of its reliability and efficiency. Researchers were given newfound freedom to make significant advances in the design and development of cutting-edge heterocyclic molecules, thanks to microwave aided chemistry. Starting from heterocyclic synthesis, metal-mediated chemistry, and industrial preparation of aromatic compounds using microwaves, this technology has been extended to continuous-flow organic synthesis also. Lastly the wide application of microwaves in organic synthesis can enhance its value for the synthesis of high-value organic chemicals, polymers, and nanomaterials in much less time than would be required using conventional heating methods.⁵ Recently, Szostak and his group reviewed the synthesis of privileged heterocyclic moieties which could be amenable to microwave irradiation also.⁶

To the best of our knowledge, no specialized review has been focused on highlighting the advancements in Cu-catalyzed synthesis of heterocycles via C–N and C–O bond formation under microwaves, despite numerous reviews about Cu-catalyzed C–N and C–O bond forming reactions published until date. In this review, we have covered the synthesis of five and six membered heterocycles such as triazoles, tetrazoles, isoxazoles, pyrroles, napthofuranones benzofuran linked aminothiazoles, lactones, furoquinoxalines, quinolones, quinazolinones, 2-iminopyrans, and fused quinazoline, respectively. The review focuses particularly on the mechanism of these microwave-assisted copper-catalyzed heterocyclisation to ignite readers’ curiosity about the creation of greener and more useful C–N and C–O bond forming methods covering the year ranges from 2014 to 2023.

2. Synthesis of Cu-Catalyzed Heterocyclic Moieties via Microwave Assisted C–N Bond Formation Reaction

Among the nitrogen-containing heterocyclic compounds, five-membered triazoles are known for their greater pharmaceutical applications. Structurally, 1,2,3-triazole and 1,2,4-triazole are the two types of five-membered triazoles with profound bioactivity. Numerous synthetic protocols have been devised for their preparation. In 2014, Ma and his group hypothesized the synthesis of 1,2,4-triazoles via a tandem double addition-oxidative cyclization method using Cu catalysts. The synthetic sequence involved the reaction of two molecules of aryl nitrile and an amine 1 to form 1,2,4-triazoles 2 in the presence of Cu(OAc)₂ at 120 °C in microwaves for 30 min (Scheme 1). Here interestingly aryl nitrile was used as solvent and reagents. Using primary amines and aryl nitriles as the starting ingredients, this method has the advantage of forming simultaneously C–N and N–N bonds in one single reaction. A variety of aryl amines and n-alkyl amines were used to generate the corresponding substituted 1,2,4-triazoles in low to moderate yields. The anticipated product was not detected when alkyl nitriles were used which specifies that aromatic nitrile is critical for this transformation. Here the microwave irradiation reduced the reaction time drastically.⁷

Scheme 1. Microwave-Assisted Synthesis of 1,2,4-Triazoles Using Cu(II) Catalyst.

Mechanistically, aryl nitrile activated by Cu(OAc)₂ reacts with amine to form the imidamide A by Cu²⁺ mediated direct addition. Addition of another molecule of aryl nitrile activated by Cu(OAc)₂ generated intermediate B. The intermediate B was converted to the cyclic intermediate C upon releasing one molecule of acetic acid followed by the reductive cyclization to generate the 1,2,4-functionalized triazoles 2 (Figure 1). In the same year, Narender et al. reported a Cu(OTf)₂ catalyzed multicomponent coupling reaction to produce biologically important polysubstituted furoquinoxalines under microwaves. Here, the synthetic protocol demonstrated an effective method for producing good to exceptional yields of furoquinoxalines 6 from o-phenylenediamine 3, and keto esters 4, and alkynes 5 using Cu(OTf)₂ as the catalyst at 80 °C under microwaves for 10 min (Scheme 2). In optimization studies, the importance of temperature and catalyst concentration for increased yield was noted. The yields of the electron-rich diamines were only moderately greater than those of diamines with low electron density. The target furoquinoxalines 6 were smoothly and efficiently generated by both the electron rich and electron withdrawing aromatic alkynes. The synthetic scheme created an easy, unique, and effective approach for the single-step, Cu(II)-catalyzed synthesis of compound 6 using the A³-coupling reaction in moderate to exceptional productivity under microwaves.⁸

Figure 1.

Plausible mechanism for the formation of 1,2,4-triazoles under microwaves.

Scheme 2. Microwave-Assisted Synthesis of Furoquinoxalines Using Cu(II) Catalyst.

Mechanistically in the A³-coupling reaction, the o-phenylenediamine 3a reacts with ketoester 4a to result in an imine intermediate A which upon reaction with Cu-acetylide B forms the propargylamine C. The intermediate C subsequently transformed to cyclized intermediate E via 5-endo-dig cyclization followed by oxidation of the resulting furoquinoxaline 6a (Figure 2).

Figure 2.

Plausible mechanism of synthesis of furoquinoxalines via intermediates A–E.

In 2015, Singh and his group developed a simple one-pot sequential method for the production of thiazolidinone-linked 1,2,3-functionalized triazole 10 using Cu (I) catalysis. Thaizolidinones linked triazoles 10 were synthesized from propargyloxybenzaldehyde 7, aryl azide 8 using CuSO₄·5H₂O as catalyst and d-glucose as reducing agent in H₂O-THF (1:2) solvent in microwaves at 70 °C for 55 min followed by reacting thioglycollic acid and aniline 9 (Scheme 3). Both EDG and EWG groups on anilines were found to generate moderate to good yield (62–87%).⁹

Scheme 3. Microwave-Assisted Synthesis of Thiazolidinone-Linked 1,2,3-Triazole Using Cu(II) Catalyst.

Subsequently in 2016, Cui et al. proposed a synthetic protocol for completely functionalized pyrroles via microwave-assisted copper-catalyzed synthesis. In this regard, β-enamino compounds 11 and propargyl acetates 12 underwent microwave irradiation at 150 °C for 20 min in the presence of 5 mol % of Cu(OTf)₂ in toluene to form substituted pyrroles 13 (Scheme 4). Moreover, expected products were obtained in 70–80% yield using both electron-donating and electron-withdrawing substituents on the aromatic ring system of β-enamino ester. Similarly, propargyl acetates with terminal alkyne and aryl or heteroaryl groups as substituents yielded pyrroles in moderate to excellent results (54–75%).¹⁰

Scheme 4. Microwave-Assisted Synthesis of Pyrroles under Microwaves.

Initially, Cu(II) activated propargyl esters reacted with compound 11 to form an intermediate A which upon electron reorganization followed by 5-exo-dig intramolecular cyclization resulted in the intermediate B. The intermediate B underwent isomerization to obtain substituted pyrrole derivatives 13 as shown in Figure 3.

Figure 3.

Plausible mechanism for the synthesis of pyrroles under microwaves.

In 2016, Miura and his co-worker reported an intramolecular Cu-catalyzed benzylic sp³ C–H amination of ortho-methylbenzamides to develop isoindolinones synthesis, which had significant importance in medicinal chemistry. Isoindolinones 15 was obtained from 2,6-disubstituted benzamide 14 after treatment with Cu(OAc)₂ (20 mol %), 1-AdCOOH (40 mol %), and MnO₂ in diglyme for 2 h at 200 °C under microwave irradiation (Scheme 5). It was found electron-donating substituents (15a, 15b, 15c, 15d) yielded well to generate the appropriate isoindolinones in comparison of electron withdrawing group (15e, 15f, 15g).

Scheme 5. Cu(II) Catalyzed Synthesis of Isoindolinones under Microwaves.

Mechanistically, first, benzamide 14 was activated by Cu(OR)₂ to result an N,N-bidentately coordinated Cu species A. Next, the cyclo-metalated complex B is produced at the proximal benzylic site by the irreversible and rate-limiting C–H cleavage. Finally, the intermediate C underwent disproportionation and reductive elimination to generate the isoindolinone 15 (Figure 4).¹¹

Figure 4.

Plausible mechanism of synthesis of isoindolinones under microwaves.

Subsequently, in 2017, our group established a very effective and environment-friendly technique for the synthesis of 5-substituted 1H-tetrazole derivatives using Cu(I) catalyst. As depicted in Scheme 6, substituted nitriles 16 and sodium azide underwent (3 + 2) cycloaddition reaction to form 5-substituted 1H-tetrazole 17 in the presence of 10 mol % [Cu(phen)(PPh₃)₂]NO₃ catalyst in green media under microwaves at 65 °C for 15 min. Outstanding yields of the corresponding 1H-tetrazole derivatives were obtained from the reaction of aromatic nitriles having unsubstituted or electron-withdrawing groups as opposed to the lower yields obtained from aromatic nitriles containing electron-donating substituents.^12a In the same year, we have utilized CuO nanoparticles for the synthesis of 5-substituted 1H-tetrazoles under microwave irradiation.^12b

Scheme 6. Synthesis of 5-Substituted 1H-Tetrazole under Microwaves in Green Media.

In 2018, Murthy and his group synthesized benzofuran linked aminothiazoles derivatives 25 via microwave irradiation. Initially, two equivalents of benzaldehyde were reacted with starting material 18 to generate the intermediate 19 under basic conditions. Subsequent hydrogenation of compound 19 using 10% Pd/C in ethyl acetate generated the intermediate 20 which upon reacting with chloroacetone generated furan derivatives 21. Further the intermediate 21 reacted with NH₂OH·HCl in EtOH medium under microwaves from dioxime 22 in the presence of K₂CO₃. Under microwave (MW) irradiation, compound 21 was utilized to react with NH₂OH·HCl in EtOH to form dioxime 22. The compound 22 was then subjected to acetylation in EtOH medium under microwaves generating compound 23. Further the acetylated derivative 23 underwent Cu(I) catalyzed heterocyclization with substituted isothicynates using Cs₂CO₃ as base resulting in benzodifuran linked aminothiazoles derivatives 25 under microwaves for 15–25 min with excellent yields (Scheme 7). Ironically the same reaction took 12–18 h under refluxing dioxane solution to generate benzodifuran linked aminothiazoles derivatives 25. Antibacterial and antimycobacterial testing was performed in vitro on the synthesized products. The derivatives 25b, 25c, and 25d demonstrated superior growth inhibition against a Gram-positive B. subtilis strain. Antibacterial activity of the studied compounds against B. subtilis and M. bovis strains was enhanced by the presence of Br and F atoms in the ortho position of aromatic rings.¹³

Scheme 7. Microwave Assisted Synthesis of Functionalized Benzodifuran Linked Aminothiazoles Derivatives.

Further, in 2018, Choudhury et al. reported the synthesis of pyrimidine fused quinolines 28 via copper-catalyzed domino reactions. Pyrimidine fused quinoline derivatives 28 were achieved in 30 min under microwaves by reacting substituted 2-bromo benzaldehyde 26 with enaminone 27 using K₂CO₃ as base and 10 mol % of cupric chloride as Cu(II) source in DMF solvent at 150 °C (Scheme 8). Excellent results were obtained when the reaction is carried out in DMF as solvent without the use of any additive or ligand because DMF has both reducing and coordinating properties. Using various substituted 2-bromo benzaldehyde having electron-donating and pulling substituents at various positions on the phenyl ring, moderate to good yields of target compounds were obtained.¹⁴

Scheme 8. Synthesis of Pyrimidine Fused Quinolones under Microwaves Using Cu(II) Catalyst.

Subsequently, in the same year, Cho and his group reported the Cu-catalyzed coupling and cyclization reaction to synthesize quinazoline derivatives 32. Primary amides 31 were reacted with different benzimidazole derivatives 29 or 30 at 130 °C for 1 h in the presence of CuI, l-proline, and Cs₂CO₃ in DMF under microwave irradiation (100 W) to produce quinazoline derivatives 32a–p with modest to good yields (66–83%) (Scheme 9).¹⁵

Scheme 9. Synthesis of Pyrimidine Fused Quinolones under Microwaves.

In 2018, Fang et al. reported the synthesis of quinazolinone derivatives 36 in water via a microwave-assisted copper-catalyzed cascade reaction. To generate quinazolinone derivatives 36, Cu-catalyzed cascade reaction of amidines 35 with functionalized 2-halobenzoic acids 34 in water as solvent under microwaves is described here (Scheme 10). Consequently, the best catalytic conditions were achieved by heating CuCl₂ (10 mol %), ligand 33 (10 mol %), and sodium hydroxide in H₂O at ambient condition for 20 min under microwaves. A wide range of substrates with functional groups such as methoxy, methyl, nitro, and bromo were successfully subjected to the catalytic processes with good to excellent yields of 55% to 94%. When compared to aryl bromide and aryl chloride, aryl iodide reacted more strongly. The substituted 2-halobenzoic acids 34 and amidines 35 with electron-withdrawing groups were somewhat more reactive than those with electron-donating groups.¹⁶

Scheme 10. Cu(II) Catalyzed Synthesis of Quinazolinones under Microwaves.

The intermediate amide A synthesized from 2-halobenzoic acid 34a and amidine 35a, underwent Cu(II) catalyzed intramolecular C–N bond forming reaction to provide the desired product 36a (Figure 5).

Figure 5.

Plausible mechanism of synthesis of quinazolinone.

In 2018, Nagavelli and his co-worker synthesized quinolinone derivatives 39 by using copper catalyst via one-pot synthesis. The synthetic scheme initiated from the reaction of iodoalkynes 37 and aryl azides 38 using CuI as catalyst (10 mol %) with t-BuOK (2 equiv) in [Bmim]PF₆ under microwaves for 0.5 h (Scheme 11). High yields, a simple workup, and rapid reactions are just a few of the benefits of this one-pot approach. In vitro cytotoxic assays were performed on the A549, MCF-7, IMR-32, and HeLa human cancer cell lines to determine the efficacy of each compound. Among them, high activity was observed for both 39b and 39c against the MCF-7 and A-549 cell lines.¹⁷

Scheme 11. Synthesis of Benzothiazino[1,2,3]triazolo[4,5-c]quinolinone in Microwaves.

The [3 + 2] cycloaddition of an aryl azide and the Cu(I)-acetylide intermediate of iodoalkyne 37 yielded the 5-iodo-1,2,3-triazole intermediate A. The mechanism involved the activation of iodoalkyne 37 by Cu(I) catalyst to form the Cu(I)-acetylide intermediate. Further C–H activation of triazole-iodide bond by Cu(I) catalyst led to the generation of intermediate B which upon intramolecular electrophilic aromatic substitution/direct arylation generated the intermediate C. The seven-membered intermediate D was created by the removal of proton from intermediate C using t-BuOK. Finally, the reductive elimination of intermediate D obtained benzothiazino[1,2,3-triazolo[4,5-c]quinolinone 39. (Figure 6).¹⁷

Figure 6.

Plausible mechanism for the synthesis of benzothiazino[1,2,3]triazolo[4,5-c]quinolinone.

In the year 2020, our group demonstrated the synthesis of 1,4-disubstituted 1,2,3-triazoles 43 using ionic liquid supported Cu(II) catalyst 42 under microwaves. The synthetic scheme commenced by reacting various benzyl bromide 40 with sodium azide followed by the addition of alkynes derivatives 41 and ionic liquid supported Cu(II) catalyst 42 in MeOH solvent (Scheme 12). Here the solvent MeOH acts as a reducing agent. The reaction was accomplished at 65 °C for 8 min under microwave irradiation. Substituted benzyl bromide bearing an electron-donating group interacted favorably, resulting in high yields of the corresponding triazoles. Likewise, slow reaction rates were seen when similar triazoles were prepared from benzyl bromides or substituted benzyl bromides bearing electron withdrawing groups.¹⁸ This methodology was further extended to the synthesis of rufinamide, an antiepileptic drug.

Scheme 12. Synthesis of 1,4-Disubstituted 1,2,3-Triazoles by Cu(II) Catalyst.

This synthetic process began with the in situ formation of azides from the interaction of organic halides and NaN₃ in methanol. A five-membered copper metallacycle was generated with the addition of a Cu(I) catalyst, which was reduced from Cu(II) species through methanol. The triazole derivative 43 was synthesized by a further protonolysis of intermediate A, and the catalytic cycle is closed via arial oxidation to the Cu(II) species (Figure 7). In 2021, Nanduri and his group designed a unique microwave-assisted tandem process for the synthesis of fused quinazoline derivatives, which involved the production of new C–N bonds. 2-Bromoquinazolinone/2-bromobenzimidazole 44 reacted with substituted aldehyde 45 using Cu₂O (10 mol %) as catalyst with NH₄OAc in isopropanol medium for 30 min at 120 °C under microwaves to form fused quinazoline derivatives 46 (Scheme 13). Results showed that various substituted heterocyclic aldehydes and benzaldehydes were well tolerated and yielded the expected products in moderate to excellent proportions (73–85%). Better yields were obtained from benzaldehydes that had electron-donating substituents rather than those that included electron-withdrawing groups.¹⁹

Figure 7.

Plausible mechanism for the synthesis of 1,4-disubstituted 1,2,3-triazoles by Cu(II) catalyst.

Scheme 13. Synthesis of Fused Quinazoline Using Cu(I) Catalyst under Microwaves.

Mechanistically the final compound fused quinazoline could be produced in two different pathways. In route A, the activation of compound 44 by Cu(I) catalyst followed by reacting with NH₃ generated from NH₄OAc which upon reacting with aldehydes obtained imine intermediate D. Finally, the intermediate D underwent intramolecular nucleophilic addition reaction resulting in the formation target compound 46. In Path B, the reaction of aldehyde 45 with NH₃ followed by the reduction generated the intermediate F. Subsequently, the reaction of compound 44 with the intermediate F under Cu(I) catalyzed conditions followed by in situ generated benzyl amines resulted the intermediate G which on rearrangement resulted in intermediate H. The intermediate G upon oxidation followed by intramolecular nucleophilic addition resulted in the target moiety in good to excellent yields (Figure 8).

Figure 8.

Plausible mechanism of synthesis of fused quinazoline using microwaves.

In 2021, Kumbar and his group developed a rapid and selective synthesis of quinoline-linked triazoles in microwave condition (Scheme 14). The synthesis of quinolin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones 51 was achieved via Click chemistry, representing the pinnacle of the approach where [3 + 2] cycloaddition of azides with terminal alkynes was established. The reported protocol was environmentally friendly for the rapid and efficient regioselective synthesis of quinolinyl-1,2,3-triazolyl-1,2,4-triazol-3 (4H)-one 51 with high yields and excellent purity. The compound 48 synthesized using the Vilsmeier–Haack reaction was reduced with NaBH₄ to the corresponding alcohol followed by treatment with PBr₃ in DCM to obtain the bromo-substituted quinoline. After reacting 3-(bromomethyl)-2-chloro-6/7/8-substituted quinoline with NaN₃ in aqueous acetone at ambient conditions, the corresponding azide 49 was produced. The compound 49 subsequently underwent (3 + 2) cycloaddition with acetylenic dipolarophiles 50 under click conditions using microwaves to synthesize quinoline-linked triazoles 51 (Scheme 14).²⁰

Scheme 14. Synthesis of Quinoline-Linked Triazoles under Microwaves.

In 2022, Cho et al. developed the synthesis of indole-fused quinazolinones by using copper-catalyzed nucleophilic addition followed by a C–N coupling reaction. Irradiating the mixture of 2-(2-bromoaryl)indoles 52 with aryl isocyanates 53 under microwaves in the presence of CuI and Cs₂CO₃ using DMF as solvent at 130 °C for 2 h yielded 5-arylindolo[1,2-c]quinazolin-6(5H)-ones 54 (Scheme 15). The synthetic manipulation was also possible with straight and branched alkyl chains at position 3 of the indole moiety in 2-(2-bromoaryl)indoles. Similarly, both electron-withdrawing and electron-donating substituents on bromophenyl and indole moieties were resulted in good yield.²¹

Scheme 15. Microwave-Assisted Synthesis of Indole-Fused Quinazolinones.

Mechanistically the nucleophilic addition of compound 52a with compound 53a led to the formation of the intermediate A. The intermediate A then underwent an intramolecular C–N bond formation by an addition–elimination nucleophilic aromatic substitution via Meisenheimer complexes B, C, D, E and a copper-catalyzed Ullmann-type coupling to obtain the compound 54a (Figure 9).

Figure 9.

Plausible mechanism for the synthesis of indole-fused quinazolinones in microwaves.

In 2022, Sridharan et al. reported the microwave-assisted Cu(II) catalyzed cascade cyclization reaction to synthesize oxazepines derivatives 60 and diazepines derivatives 61. The corresponding oxazepane/diazepines derivatives 60/61 were synthesized by a cascade reaction of various O/N-propargylated 2-hydroxybenzaldehydes 55/56 and o-phenylenediamines 57 in the presence of 10 mol % of Cu(OTf)₂ and K₂CO₃ as base in DMF under microwave irradiation at 100 °C for 15 min (Scheme 16). Both electron withdrawing and electron donating groups showed good to excellent yield.²²

Scheme 16. Synthesis of Benzo[f]imidazo[1,2-d][1,4]oxazepines and Benzo[f]imidazo[1,2-d][1,4]diazepines under Microwaves.

The intermediate imine A produced from the reaction between aldehyde 55/56 and o-phenylenediamine 57 underwent Cu(II) catalyzed intramolecular 5-endo-trig cyclization, followed by aerial oxidation/aromatization, to provide the imidazole intermediate 58/59 through species B. The internal alkyne of 58/59 is activated by the copper(II) catalyst in the presence of a base, resulting in the production of desired products 60/61 followed by 7-exo-dig cyclization (Figure 10).

Figure 10.

Plausible mechanism for the synthesis of benzo[f]imidazo[1,2-d][1,4]oxazepines and benzo[f]imidazo[1,2-d][1,4]diazepines.

Further in the same year, Sushmita and her group reported the synthesis of a novel series of N-substituted indole derivatives 66 using both conventional and microwave heating techniques. It was observed that microwave irradiation yielded a higher percentages of yields (72–96%) and shorter reaction times compared to the conventional approach (64–94%). The indole derivatives 66 were obtained by a three-step synthetic route beginning with the N-alkylation of tetrahydro-1H-carbazoles, followed by copper-catalyzed Huisgen [3 + 2] cycloaddition reaction with aromatic azides 65 in the presence of CuSO₄ and sodium ascorbate in DMF-H₂O (2:1) for 6 min under microwave irradiation (Scheme 17). Among the synthesized compounds, 66b, 66d, and 66e were found to exhibit good antioxidant, anticancer, and antimicrobial activities.²³

Scheme 17. Synthesis of 1,2,3-Triazolylmethyl Indole Using Microwaves.

3. Synthesis of Cu-Catalyzed Heterocyclic Moieties via Microwave Assisted C–O Bond Formation Reaction

The preference of copper (in the form of oxides, salts, and complexes) over palladium in C–O cross coupling reaction could be due to the low cost, ease of handling, and nontoxicity. In many cases, it has been observed that particularly in the formation of C–O bond via substitution reactions copper catalysis demonstrated excellent results. Cu-catalyzed cross-coupling reactions are sometimes more selective than Pd-catalyzed reactions as these reactions can produce the desired products with a smaller amount of undesirable side products. In terms of compatibility, Cu-catalyzed cross-coupling reactions are compatible with a greater variety of functional groups compared to those of Pd-catalyzed reactions.

In the year 2015, Lopez et al. established a fast and effective protocol for the regio- and diastereoselective cycloisomerization of compound 67. The cycloisomerization of compound 67 catalyzed by CuBr (5 mol %) in water under microwave irradiation at 100 °C for 8 min was presented a diastereo and regioselective approach for gaining access to a wide range of highly functionalized lactones 68 in excellent yields (Scheme 18). For a wide range of highly functionalized compound 68, this approach allows for high yields under moderate reaction conditions.²⁴

Scheme 18. Microwave-Assisted Synthesis of Functionalized-Lactones via Cu Catalyst.

In the same year, Punniyamurthy and his group reported a Cu(I) catalyzed multicomponent tandem synthesis of coumarins derivative 73 using microwaves. In order to synthesize 3-N-sulfonylamidine coumarin, a four-component tandem synthesis was planned using salicylaldehydes 69, propiolates 70, sulfonyl azides 71, and secondary amines 72. The multicomponent reaction was carried out in the presence of CuI (10 mol %), K₂CO₃ as base in 1,4-dioxane medium at 130 °C under microwave irradiation for 1 h (Scheme 19). Aldehydes with substitution at the 3/5-position resulted products in good yield compared to the substitution at the 4-position. Using electron-withdrawing groups such as CHO and NO₂ at 5-position produced final products in lower yields. Similarly, both aliphatic and aromatic sulfonyl asides were useful in the process with satisfactory yields, and the coupling process is very selective to the propiolate and secondary amine species.²⁵

Scheme 19. Microwave-Assisted Synthesis of 3-N-Sulfonylamidine Coumarins via Cu(I) Catalyst.

Mechanistically, the Cu(I) catalyzed (3 + 2) cycloaddition reaction between alkyne 70 and azides 71 resulted in the generation of ketenimine B via A which underwent nucleophilic addition with amine resulting in the intermediate C. The intermediate C further reacted with aldehyde 69 to obtain intermediate D which underwent transesterification leading to the formation of 3-N-sulfonylamidine coumarin 73 (Figure 11).

Figure 11.

Plausible mechanism for the synthesis of 3-N-sulfonylamidine coumarins.

In 2015, Ahmed and his co-worker synthesized napthofuranones 78 via microwave irradiation with or without the metal salt. In path I, 2-oxoaldehydes 75, pyrrolidine 76, and β- naphthol 74 in toluene (1 mL) underwent microwave irradiation (50 W) at 100 °C for 10 min to form tetrahydrofuro[3,2-d]oxazoles 77. Subsequently, tetrahydrofuro[3,2-d]oxazoles 77 converted to napthofuranones using Cu(II) catalyst under microwave irradiation at 100 °C in toluene solvent for 20 min. In path II, napthofuranones 78 were synthesized straightforwardly from 2-oxoaldehydes 75, pyrrolidine 76, and β- naphthol 74 in the presence of Cu(II) catalyst at 100 °C for 15 min via microwave irradiation (50 W) with excellent yields (81–92%) (Scheme 20).²⁶

Scheme 20. Microwave-Assisted Synthesis of Napthofuranones via Cu(II) Catalyst.

Synthesis of compound 78 began with the formation of 2-oxoiminium ion (intermediate A) through the interaction of 2-oxoaldehyde 75 and pyrrolidne 76. The behavior of this intermediate A changes between metallic pathway (path A), and nonmetallic pathway (path B). In path-A, the 2-oxoiminium ion A underwent ene reaction and O- cyclization to form intermediate C. Later intermediate C underwent aerial oxidation followed by Cu(II) catalyzed reaction resulting in the target compound 78. Likewise in path B, ammoniumyl radical cation (intermediated D) derived via single electron transfer (SET) from intermediate-A and compound 74. In the end, Cu(II) mediated cyclization and hydrolysis of the iminium intermediate yielded the target compound 78 (Figure 12).

Figure 12.

Plausible mechanism of synthesis of napthofuranones.

In 2016, our group established a microwave assisted telescopic synthetic protocol to develop 3,5-disubstituted isoxazoles 82 from N-hydroxyl imidoyl chlorides 80 with substituted alkynes 81 in water medium with 2 mol % of [Cu(phen)(PPh₃)₂]NO₃ as catalyst. N-hydroxybenzimidoyl chloride 80 was obtained by condensing benzaldehyde 79 with hydroxylamine hydrochloride using NaOH as base in aqueous medium under microwaves for 7 min at 65 °C followed by subsequent reaction with N-chlorosuccinimide. Further, N-hydroxybenzimidoyl chloride 80 underwent Cu(I) catalyzed 1,3-dipolar cycloaddition with alkyne 81 at 65 °C for 5 min under microwaves resulting into 3,5-diphenylisoxazole 82 with excellent yield. Aromatic aldehydes having electron-donating substituents could not react efficiently to obtain corresponding isoxazoles as compared to electron-withdrawing substituents. Similarly, this reaction was unaffected by the presence of electron-withdrawing groups or electron-donating substituents at the aromatic terminal alkyne. Microwave irradiation utilizing a green solvent such as water, significantly speeds the reaction with less time and provides excellent yields (Scheme 21).²⁷

Scheme 21. Microwave-Assisted Synthesis of 3,5-Disubstituted Isoxazoles in Green Media.

In 2018, Zhang and his group reported a comparison study to synthesize a new 1,2,3-triazoles linked with an isoxazole ring by conventional heating and microwave irradiation. The reaction improves with microwave irradiation compared to conventional heating methods. Click chemistry was used to synthesize 1,2,3-triazoles with isoxazole ethers 85/87 from substituted isoxazolyl alkyne 84 and substituted benzyl azide 83 or neopentylglycol diazide 86 using Cu(OAc)₂/sodium ascorbate as the catalyst in aqueous THF at 50 °C for 10 min in microwaves. The higher yields were observed for electron donating groups owing to the electron-rich property as compared to that of the electron withdrawing substituents in the 1,3-dipolar cycloaddition reaction (Schemes 22 and 23).²⁸

Scheme 22. Synthesis of 1,2,3-Triazoles Fused Isoxazoles.

Scheme 23. Synthesis of Dimeric 1,2,3-Triazoles Fused Isoxazoles under Microwaves.

Further, in 2021, Hajji et al. synthesized benzimidazolone linked isoxazoles which were known for their antioxidant and antimicrobial activities. The desired benzimidazolone tethered benzimidazolone 90 was synthesized from benzimidazol-2-one-alkyne 88 and various aryl nitrile oxides 89 in the presence of Cu(I) catalyst using Et₃N as base in DMF solvent under microwaves for 4–7 min. This procedure is attractive for the synthesis of putative active biological compounds because of the simple procedure, quick reaction time, and excellent yield of biheterocyclic products. The in vitro antibacterial and antioxidant properties of each of the freshly produced species 90 have been examined. Compounds 90d and 90e showed best antibacterial activity specifically against E. coli, P. aeruginosa, and S. aureus and showed the highest antifungal activity against C. albicans, A. fumigatus, and A. brasiliensis (Scheme 24).²⁹

Scheme 24. Microwave-Assisted Synthesis of Isoxazole Linked Benzimidazolones.

In 2022, Shanmugam et al. developed 2-iminopyrans 94 through microwave-assisted tandem Cu(I) catalyzed multicomponent reaction. 2-Iminopyrans 94 were synthesized by coupling the reaction of enaminones 91, phenyl acetylenes 92, and tosyl azide 93 in the presence of Cu(I) as catalyst and Et₃N as base in dichloroethane solvent under microwave conditions at 60 °C for 10 min. Good to modest yields of the corresponding 2-iminopyran were obtained from electron-donating and electron-withdrawing group substituted phenyl enaminones, respectively. Under the reported optimal conditions, several distinct styryl enaminones were tested, and all of them effectively formed the corresponding 2-iminopyran 94 (Scheme 25).³⁰

Scheme 25. Cu(I) Catalyzed Microwave Assisted Synthesis of 2-Iminopyrans.

Mechanistically, tosyl azide 93 and phenyl acetylene 92a produced metalated ketenimine intermediate via Cu(I) catalyst. Afterward, intermediate A was formed via addition of enaminone to ketenimine intermediate. Then the final compound 2-iminopyran 94a was formed via metal–carbon bond dissociation followed by 6π-electron cycloaddition reaction (Figure 13). Finally we have observed that the ligands have tremendous effect on the Cu-catalyzed reactions discussed in this review. The catalytic complexes have a wide range, excellent stability, and reactivity owing to the presence of electron-rich and highly adjustable ligands. The electron-rich ligands could greatly enhance the reducing capability of the copper catalyst, whereas coordination with copper enhances the good stability and solubility in organic solvents.

Figure 13.

Plausible mechanism of the synthesis of 2-iminopyrans.

Conclusion

Copper-catalyzed coupling processes have come a long way in the previous decade, and significant progress has been made in this area. A number of copper precursors, both metallic and salt-based, have been used effectively, with the latter having a noticeable impact on the transformation in the presence of microwaves heating. Microwave assisted organic reactions have clear advantages over conventional reaction conditions in terms of cleaner reaction profile, lower energy consumption, and higher yields. In this review, there are several metal species that have been shown to provide the greatest conversion of starting materials, and copper(I) is one of them. Further work is needed to produce environmentally friendly and sustainable procedures with a high degree of atom economy, such as by designing new ligands, synthesizing novel copper complexes, and using environmentally friendly solvents under microwave irradiation.

Biographies

Sushovan Jena received his B.Sc. degree in 2016 from the Department of Chemistry, M.P.C. Autonomous College, Baripada, Odisha and M.Sc. degree in 2019 from the School of Advanced Sciences, Vellore Institute of Technology, Vellore. He is currently pursuing his Ph.D. degree from Vellore Institute of Technology, Vellore, India under the supervision of Dr Kaushik Chanda. His research interests revolve around the development of new sustainable methodologies in heterocyclic organic chemistry and employing this methodology to make medicinally relevant compounds.

Dr Kaushik Chanda, obtained his MSc in Organic Chemistry from Gauhati University, India in 2001. Subsequently worked as a Senior Research Fellow in ICAR-NATP funded project in St Anthonys College, Shillong, India from 2002-2005. In 2006, he moved to Taiwan to pursue a Ph.D. in Applied Chemistry from National Chiao Tung University under the guidance of Prof Chung Ming Sun on a topic of Combinatorial Chemistry. In 2010, he moved to Department of Chemistry, National Tsing Hua University, Taiwan for NSC-postdoctoral fellowship in facet dependent organic catalysis with Prof Michael H Y Huang. Now he is working as an Associate Professor in the Department of Chemistry, Vellore Institute of Technology, Vellore. His research interest includes diversity oriented synthesis, anticancer drug design, drug delivery, sensing applications, and nanocatalysis.

The authors declare no competing financial interest.