Current Microwave Chemistry - Volume 7, Issue 1, 2020

This review deals with the recent advances on the microwave-assisted synthesis of bioactive heterocycles without using any catalyst under various reaction conditions. Synthesis of various biologically promising N-heterocycles, O-heterocycles, S-heterocycles, N as well as O- or S-heterocycles reported so far under catalyst-free microwave-irradiated conditions are discussed in this review.

Multi-Component Reactions (MCRs) have emerged as an excellent tool in organic chemistry for the synthesis of various bioactive molecules. Among these, one-pot MCRs are included, in which organic reactants react with domino in a single-step process. This has become an alternative platform for the organic chemists, because of their simple operation, less purification methods, no side product and faster reaction time. One of the important applications of the MCRs can be drawn in carbon- carbon (C-C) and carbon-heteroatom (C-X; X = N, O, S) bond formation, which is extensively used by the organic chemists to generate bioactive or useful material synthesis. Some of the key carbon- carbon bond forming reactions are Grignard, Wittig, Enolate alkylation, Aldol, Claisen condensation, Michael and more organic reactions. Alternatively, carbon-heteroatoms containing C-N, C-O, and C-S bond are also found more important and present in various heterocyclic compounds, which are of biological, pharmaceutical, and material interest. Thus, there is a clear scope for the discovery and development of cleaner reaction, faster reaction rate, atom economy and efficient one-pot synthesis for sustainable production of diverse and structurally complex organic molecules. Reactions that required hours to run completely in a conventional method can now be carried out within minutes. Thus, the application of microwave (MW) radiation in organic synthesis has become more promising considerable amount in resource-friendly and eco-friendly processes. The technique of microwaveassisted organic synthesis (MAOS) has successfully been employed in various material syntheses, such as transition metal-catalyzed cross-coupling, dipolar cycloaddition reaction, biomolecule synthesis, polymer formation, and the nanoparticle synthesis. The application of the microwave-technique in carbon-carbon and carbon-heteroatom bond formations via MCRs with major reported literature examples are discussed in this review.

The carbon-chalcogen bond formation is of much importance as organochalcogenides scaffold, and in general, it shows by organochalcogenide scaffolds, in general, show promising biological activities and many compounds containing chalcogenide units are currently used as drugs, agrochemicals and useful materials. Thus, a plethora of methods has been developed for the formation of carbonchalcogen bonds. This review covers the recent developments on the formation of carbon-chalcogen bonds under microwave irradiation and synthesis of useful chalcogenides by employing this process.

Background: Amide bond plays a key role in medicinal chemistry, and the analysis of bioactive molecular database revealed that the carboxamide group appears in more than 25% of the existing database drugs. Typically amide bonds are formed from the union of carboxylic acid and amine; however, the product formation does not occur spontaneously. Several synthetic methods have been reported for amide bond formation in literature. Present work demonstrated simple and eco-friendly amide bond formation using carboxylic acid and primary amines through in situ generation of O-acylurea. The reaction was found to be more efficient, faster reaction rate; simple work-up gave pure compound isolation in moderate to excellent yield using microwave irradiation as compared to conventional heating. Methods: Developed one-pot synthesis of amide compounds using agro-waste derived greener catalyst under microwave irradiation. Results: Twenty amide bond containing organic compounds are synthesized from carboxylic acid with primary amine catalyzed by agro-waste derived medium under microwave irradiation. First, the reaction involved carboxylic acid activation using EDC.HCl, which is the required base for the neutralization and coupling. The method employed natural agro-waste derived from banana peel ash (WEB) for the coupling gave target amide product without the use of an external organic or inorganic base. Conclusion: In the present work, we demonstrated that agro-waste extract is an alternative greener catalytic medium for the condensation of organic carboxylic acid and primary amine under microwave irradiation. The method found several advantages compared to reported methods like solventfree, non-toxic, cheaper catalyst, and simple reaction condition. The final isolated product achieved chromatographically pure by simple recrystallization and did not require further purification.

Background: A Lewis acid promoted efficient and facile procedure for one-pot synthesis of a novel series of fluoroquinolone clubbed with thiadiazoles motifs under microwave irradiation is described here. This technique has more advantages such as high yield, a clean procedure, low reaction time, simple work-up and use of Lewis acid catalyst. Objective: Our aim is to generate a biologically active 1,3,4- thiadiazole ring system by using a onepot synthesis method and microwave-assisted heating. High yield and low reaction time were the main purposes to synthesize bioactive fluoroquinolone clubbed 1,3,4- thiadiazole moiety. Methods: Fluoroquinolone Clubbed 1,3,4-Thiadiazole Motifs was prepared by Lewis acid promoted, one-pot synthesis, under microwave irradiation. All the synthesized molecules were determined by IR, 1H NMR, 13C NMR, and Mass spectra. The antimicrobial activity of synthesized compounds was examined against two Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), two Gram-positive bacteria (Staphylococcus aureus, Streptococcus pyogenes), and three fungi (Candida albicans, Aspergillus niger, Aspergillus clavatus) using the MIC (Minimal Inhibitory Concentration) method and antitubercular activity H37Rv using L. J. Slope Method. Results: Lewis acid promoted, one-pot synthesis of Fluoroquinolone clubbed 1,3,4-Thiadiazole motifs under microwave irradiation is an extremely beneficial method because of its low reaction time and good yield. Some of these novel derivatives showed moderate to good in vitro antibacterial, antifungal, and antitubercular activity. Conclusion: One-pot synthesis of 1,3,4-Thiadiazole by using Lewis acid catalyst gives a good result for saving time and also getting more production of novel heterocyclic compounds with good antimicrobial properties via microwave heating method.

Background: Higher temperature regions (hot spots) have been observed in organic reactions and are attributed to microwave selective heating. The accumulated heat in reaction systems accelerates certain reactions. Methods: The theoretical calculation was applied to select a suitable Diels-Alder reaction as a molecular probe to determine the microwave thermal effect on Diels-Alder reaction, one class of bimolecular reactions. The kinetic investigations were utilized to determine the reaction activation energies and further to calculate the actual reaction temperatures under different microwave conditions from the Arrhenius equation. Results: On the basis of the theoretical calculational results, Diels-Alder reaction of furan and maleimide was selected as a molecular probe to determine the microwave thermal effect in Diels- Alder reaction. Their activation energies under thermal conditions were determined from kinetic data by using the Arrhenius equation. The actual reaction temperatures under different microwave conditions were further deduced from their activation energies and the Arrhenius equation. Conclusion: Higher temperature regions (hot spots) were observed in Diels-Alder reaction, and they are more obvious in less polar solvents than those in more polar solvents in the microwave irradiated reactions.

Background: Microwave selective heating thermal effect is obvious in unimolecular organic reactions. However, it is unclear whether it exists in bimolecular organic reactions under strictly controlled reaction temperature conditions. Objective: To determine whether microwave selective heating effect exists in the microwave-assisted bimolecular reactions. Methods: Hammett linear relationships in “one-pot” aminolyses of mixed 4-nitrophenyl substituted benzoates with benzylamine and 4-nitrophenyl benzoate with mixed substituted anilines were selected as molecular level probes to explore the thermal effect in the microwave-assisted bimolecular reactions. Results: In less polar solvent, there is an obvious “hot spots” effect. “One-pot” aminolyses of mixed 4-nitrophenyl substituted benzoates with benzylamine and 4-nitrophenyl benzoate with mixed substituted anilines were performed in less polar solvent toluene under oil-bath and microwave heating conditions. Generally, slopes of Hammett plots or effect of substituents on reaction rates decrease along with temperature increases under oil-bath heating conditions. Under microwave irradiation conditions, slopes of Hammett plots or effect of substituents on reaction rates decrease in comparison with those under oil-bath heating conditions at the same setting temperature, revealing that higher temperature regions (“hot spots”) still exist in intermolecular organic reactions. Conclusion: Microwave selective heating thermal effect still exists in bimolecular organic reactions under strictly controlled reaction temperature conditions, revealing that higher temperature regions (“hot spots”) do exist in intermolecular organic reactions.