Synthesis of Imidazole-Based Molecules under Ultrasonic Irradiation Approaches

Imidazole-based compounds are a series of heterocyclic compounds that exhibit a wide range of biological and pharmaceutical activities. However, those extant syntheses using conventional protocols can be time-costly, require harsh conditions, and result in low yields. As a novel and green technique, sonochemistry has emerged as a promising method for organic synthesis with several advantages over conventional methods, including enhancing reaction rates, improving yields, and reducing the use of hazardous solvents. Contemporarily, a growing body of ultrasound-assisted reactions have been applied in the preparation of imidazole derivatives, which demonstrated greater benefits and provided a new strategy. Herein, we introduce the brief history of sonochemistry and focus on the discussion of the multifarious approaches for the synthesis of imidazole-based compounds under ultrasonic irradiation and its advantages in comparison with conventional protocols, including typical name-reactions and various sorts of catalysts in those reactions.

Gargantuan contributions to imidazole derivatives' synthesis were made by former trailblazers, leading those precursory strategies showing beneficial applications in pharmacy, organic chemistry, and material chemistry as well. Those classic trails, however, are faced with an increasing challenge since their drawbacks, for instance, pollution and low yield, need to be ameliorated in certain ways in order to keep pace with green chemistry ideology as well as cost reduction.
Consequently, a slew of emerging techniques, such as ultrasound, microwave, and radiant, have burgeoned on account of researchers painstakingly working hard to tackle the shortcomings mentioned. Amongst them, the utilization of sonochemistry has been receiving more attention from researchers as several predicaments are overcome by highly frequent mechanical waves. In other words, the simplification of tedious procedures, the trim of irrelevant reactions, and milder requisites for activating molecules are achieved by harnessing ultrasound as assistance. Eminent advantages of sonochemistry over traditional ways have successively stirred organic, pharmaceutical, and materials chemists' emotions to delve into its prospective application in synthetic approaches as well as making it a trend.
The ultrasonic irradiation reaction mixture produces a large number of cavitation bubbles, which grow rapidly and then collapse violently, forming microjets and producing fine emulsions between the reactants. Afterward, the collapse of the cavitation bubbles also increases the local temperature inside the reaction mixture and eventually causes the reaction mixture to pass through the activation energy barrier.
As a consequence of the principle that ultrasound is produced by a process converting mechanical or electrical energy into sound energy, the transferring device is obviously of vital importance [31]. This is the so-called ultrasonic transducer, and there are mainly three types of these: the liquid-driven type, the magnetostrictive type, and the piezoelectric type. The piezoelectric type, constructed of piezoelectric ceramic, is most prevalently utilized in the laboratory [32]. Furthermore, ultrasonic cleaning baths, ultra-Scheme 1. Typical synthetic methods for imidazole and its derivatives.
Gargantuan contributions to imidazole derivatives' synthesis were made by former trailblazers, leading those precursory strategies showing beneficial applications in pharmacy, organic chemistry, and material chemistry as well. Those classic trails, however, are faced with an increasing challenge since their drawbacks, for instance, pollution and low yield, need to be ameliorated in certain ways in order to keep pace with green chemistry ideology as well as cost reduction.
Consequently, a slew of emerging techniques, such as ultrasound, microwave, and radiant, have burgeoned on account of researchers painstakingly working hard to tackle the shortcomings mentioned. Amongst them, the utilization of sonochemistry has been receiving more attention from researchers as several predicaments are overcome by highly frequent mechanical waves. In other words, the simplification of tedious procedures, the trim of irrelevant reactions, and milder requisites for activating molecules are achieved by harnessing ultrasound as assistance. Eminent advantages of sonochemistry over traditional ways have successively stirred organic, pharmaceutical, and materials chemists' emotions to delve into its prospective application in synthetic approaches as well as making it a trend.
The ultrasonic irradiation reaction mixture produces a large number of cavitation bubbles, which grow rapidly and then collapse violently, forming microjets and producing fine emulsions between the reactants. Afterward, the collapse of the cavitation bubbles also increases the local temperature inside the reaction mixture and eventually causes the reaction mixture to pass through the activation energy barrier.
As a consequence of the principle that ultrasound is produced by a process converting mechanical or electrical energy into sound energy, the transferring device is obviously of vital importance [31]. This is the so-called ultrasonic transducer, and there are mainly three types of these: the liquid-driven type, the magnetostrictive type, and the piezoelectric type. The piezoelectric type, constructed of piezoelectric ceramic, is most prevalently utilized in the laboratory [32]. Furthermore, ultrasonic cleaning baths, ultrasonic horns, and probe systems are the most common devices for ultrasonic sources. Hitherto, the ultrasonic cleaning bath is the most widely spread and economical source of ultrasonic irradiation for chemical laboratories. In addition, the ultrasonic probe makes acoustic energy transfer directly into the system without the loss of energy.
The development of sonochemistry is not a walk in the park but the effort of several generations of researchers. The key point was first reported by Sir Galton, a British physiologist, who invented a silent whistle that is able to emit high-frequency waves, widely named ultrasound. It is virtually certain that the discovery of piezoelectricity by physicists Jacques Curie and Pierre Curie leads to the attainment of generating ultrasound in a water medium [33,34]. Albeit ultrasound was initially engaged in a sonar system for detecting objects, the cavitation phenomenon was observed by Sir Thornycoft and Barnably when noticing the erosion of their submarine propellers. The theory was then inducted by Lord Rayleigh, who formulated a mathematical model delineating cavitation in an incompressible fluid. The giant advantages of sonochemistry were first revealed by Wood and Loomis in 1927. By using ultrasound, they dealt with two types of reactions successfully, such as the redox of sulfite in an aqueous solvent and accelerating some conventional reactions, for example, the hydrolysis of dimethyl sulfate, demonstrating that ultrasound is a promising tool in chemical synthesis even without its mechanism [35]. In the following decades, a surge of research gradually detected the rationale of sonochemistry mentioned before. The sonolysis of an organic liquid was achieved by Schultz and Henglein in 1953 [36]. In 1967, Lierke and his colleague inspected that metal powders could be formed when they were using ultrasound to atomize molten metals [37]. During this period, ultrasound technology was improved significantly by the update of homogenizers, causing it to be more accessible to generate high-frequency ultrasound. This led to the evolution of new applications in sonochemistry, including synthesis, polymerization, and environmental remediation.
As far as the 1980s with the progress of ultrasonic generators, researchers surprisingly found that ultrasound indicated extraordinary applications in chemistry. The term "sonochemistry" was introduced by Neppiras when he traced back acoustic cavitation.
After the 21st century, just like a gusher, a huge number of ultrasound-assisted reactions were reported, particularly, and ultrasound has been playing an increasingly significant role, especially in the synthetic chemistry process.
In 2003, Phillippe inspected vesicle deformation with a powerful ultrasonic tool [38]. Three years later, Cintas and Pedro summarized existing applications that have an ecofriendly process [39]. In 2021, Machado and his colleagues presented the enhancement of the synthesis of N-and O-heterocyclic compounds, which play an eminent role in pharmaceutical chemistry by introducing sonochemistry and recyclable heterogeneous catalysts [40].
Following the development of sonochemistry, some famous conferences, associations, journals, and works on the topic of sonochemistry have been established or published ( Figure 1) [41,42].
On the basis of our preceding study, this work, which covers the research over the last two decades, will highlight recent developments in the ultrasound-assisted synthesis of imidazole-based compounds as well as the advantages they possess. Meanwhile, it is anticipated that this review will provide new opportunities for the investigation of a practical design for imidazole-containing compounds.
eco-friendly process [39]. In 2021, Machado and his colleagues presented the enhancement of the synthesis of N-and O-heterocyclic compounds, which play an eminent role in pharmaceutical chemistry by introducing sonochemistry and recyclable heterogeneous catalysts [40].
Following the development of sonochemistry, some famous conferences, associations, journals, and works on the topic of sonochemistry have been established or published ( Figure 1) [41,42].

Development of Ultrasound-Assisted Imidazole-Based Compounds Synthesis
As the significance of green chemistry and environmentally friendly principles has gradually grown, scientists have been searching for alternative trials to enhance the traditional but cumbersome reactions. With the superior features of sonochemistry, in other words, some extraordinary advances have been acquired by applying the ultrasoundassisted technique in conventional reactions in imidazole derivatives' synthesis, bringing surprising merits to the following reactions, including the Debus-Radziszewski reaction, the Phillip-Ladenburg reaction, the Ullmann reaction, as well as some other reactions.

Debus-Radziszewski Imidazole Synthesis
The illustrious Debus-Radziszewski reaction, originally claimed by Debus in 1858 and enhanced by Radziszewski in 1882, has been widely used in synthesizing a series of imidazole derivatives (Scheme 2) [17,18]. Typically, the D-R reaction proceeds via the dehydration condensation of a diketone, an aldehyde, and two equivalents of ammonia. This reaction can afford 1,2,4,5-tetrasubstituted imidazoles when one equivalent of ammonia could be an alternative to the primary amine.
Molecules 2023, 28, x FOR PEER REVIEW On the basis of our preceding study, this work, which covers the research last two decades, will highlight recent developments in the ultrasound-assisted sis of imidazole-based compounds as well as the advantages they possess. Mean is anticipated that this review will provide new opportunities for the investigat practical design for imidazole-containing compounds.

Development of Ultrasound-Assisted Imidazole-Based Compounds Synthes
As the significance of green chemistry and environmentally friendly princi gradually grown, scientists have been searching for alternative trials to enhance ditional but cumbersome reactions. With the superior features of sonochemistry, words, some extraordinary advances have been acquired by applying th sound-assisted technique in conventional reactions in imidazole derivatives' sy bringing surprising merits to the following reactions, including the Debus-Radzi reaction, the Phillip-Ladenburg reaction, the Ullmann reaction, as well as som reactions.

Debus-Radziszewski Imidazole Synthesis
The illustrious Debus-Radziszewski reaction, originally claimed by Debus and enhanced by Radziszewski in 1882, has been widely used in synthesizing a imidazole derivatives (Scheme 2) [17,18]. Typically, the D-R reaction proceeds dehydration condensation of a diketone, an aldehyde, and two equivalents of am This reaction can afford 1,2,4,5-tetrasubstituted imidazoles when one equivalen monia could be an alternative to the primary amine. However, this classic method has many drawbacks, for instance, harsh conditions, hazardous chemicals, expensive acid catalysts, complicated working rification procedures, and a long reaction period, with side reactions leading to m yields.
With the ultrasonic irradiation utilized in the D-R reaction, a more compac prepare imidazole-based compounds was discovered. The desirable advantages ultrasound-based conditions mentioned, such as, briefly speaking, in compa conventional ways that synthesize promising imidazole and its derivatives, dem that a higher yield, milder conditions, and shorter reaction time are achieved w lution and expenses are diminished.
Bandyopadhyay and his co-workers reported a method with the D-R pr synthesize 2-aryl-4-phenyl-1H-imidazoles 17 under ultrasound irradiation by densation of phenylglyoxal monohydrate 14, aldehyde 15, and ammonium ac without using any catalyst/solid support (Scheme 3) [43]. This sonicated a proved to be milder, more rapid, and more eco-friendly compared to the traditio However, this classic method has many drawbacks, for instance, harsh reaction conditions, hazardous chemicals, expensive acid catalysts, complicated working and purification procedures, and a long reaction period, with side reactions leading to mediocre yields.
With the ultrasonic irradiation utilized in the D-R reaction, a more compact way to prepare imidazole-based compounds was discovered. The desirable advantages of those ultrasound-based conditions mentioned, such as, briefly speaking, in comparison to conventional ways that synthesize promising imidazole and its derivatives, demonstrate that a higher yield, milder conditions, and shorter reaction time are achieved while pollution and expenses are diminished.
Bandyopadhyay and his co-workers reported a method with the D-R process to synthesize 2-aryl-4-phenyl-1H-imidazoles 17 under ultrasound irradiation by the condensation of phenylglyoxal monohydrate 14, aldehyde 15, and ammonium acetate 16 without using any catalyst/solid support (Scheme 3) [43]. This sonicated approach proved to be milder, more rapid, and more eco-friendly compared to the traditional D-R reactions.
However, the results of these reactions were not satisfactory in the yields of 57~73% at room temperature after 25~60 min, which may be attributed to the lack of an appropriate supplementary catalyst. To improve the effectiveness of ultrasound-assisted D-R reactions, researchers have investigated modifying the conditions of D-R reactions, including using nano-catalysts metal complexes catalysts, ionic liquids catalysts, organic catalysts, inorganic catalysts and oxidants.

Nano-catalysts
Magnetic nano-particles (MNPs) were applied for the one-pot three-componen sonochemical method to synthesize 2,4,5-trisubstituted imidazoles 19 by Safari and hi group in 2012 (Scheme 4) [44]. This ultrasound-assisted protocol afforded the corre sponding imidazoles in high yields of up to 97% under the catalysis of Fe3O4 MNP which was previously synthesized through the coprecipitation method. The effect of ul trasound was validated by observing significant reductions in reaction time with the as sistance of ultrasound, compared to cases under the conventional condition in the ab sence of sonication (25~45 min for the ultrasonic condition and 120~180 min for the reflux condition). In addition, this type of reaction, catalyzed by Fe3O4 MNPs, demonstrated wide applicability to substrates. One year later, they reported the methods that applied ionic liquid to support th Fe3O4 MNPs catalyst in the synthesis of multi-substituted imidazoles 21 (Scheme 5) [45] The modified heterogeneous catalyst showed comparably great activity, as the yields in this approach could reach 95%. In addition, the MNPs-IL catalyst can be easily recycled and reused with only a 7% loss in activity after five cycles. Avoiding the use of harmfu catalysts, an optimal reaction temperature, a high yield, and a simple method makes it a more effective alternative than the conditions from conventional methods. In 2013, they continued to report a synthesis of 1,2,4,5-tetrasubstituted imidazoles 21 To improve the effectiveness of ultrasound-assisted D-R reactions, researchers have investigated modifying the conditions of D-R reactions, including using nano-catalysts, metal complexes catalysts, ionic liquids catalysts, organic catalysts, inorganic catalysts, and oxidants.

Nano-Catalysts
Magnetic nano-particles (MNPs) were applied for the one-pot three-component sonochemical method to synthesize 2,4,5-trisubstituted imidazoles 19 by Safari and his group in 2012 (Scheme 4) [44]. This ultrasound-assisted protocol afforded the corresponding imidazoles in high yields of up to 97% under the catalysis of Fe 3 O 4 MNPs which was previously synthesized through the coprecipitation method. The effect of ultrasound was validated by observing significant reductions in reaction time with the assistance of ultrasound, compared to cases under the conventional condition in the absence of sonication (25~45 min for the ultrasonic condition and 120~180 min for the reflux condition). In addition, this type of reaction, catalyzed by Fe 3 O 4 MNPs, demonstrated wide applicability to substrates.
To improve the effectiveness of ultrasound-assisted D-R reactions, researchers h investigated modifying the conditions of D-R reactions, including using nano-catal metal complexes catalysts, ionic liquids catalysts, organic catalysts, inorganic catal and oxidants.

Nano-catalysts
Magnetic nano-particles (MNPs) were applied for the one-pot three-compo sonochemical method to synthesize 2,4,5-trisubstituted imidazoles 19 by Safari and group in 2012 (Scheme 4) [44]. This ultrasound-assisted protocol afforded the co sponding imidazoles in high yields of up to 97% under the catalysis of Fe3O4 M which was previously synthesized through the coprecipitation method. The effect o trasound was validated by observing significant reductions in reaction time with th sistance of ultrasound, compared to cases under the conventional condition in the sence of sonication (25~45 min for the ultrasonic condition and 120~180 min for the re condition). In addition, this type of reaction, catalyzed by Fe3O4 MNPs, demonstr wide applicability to substrates. One year later, they reported the methods that applied ionic liquid to suppor Fe3O4 MNPs catalyst in the synthesis of multi-substituted imidazoles 21 (Scheme 5) The modified heterogeneous catalyst showed comparably great activity, as the yield this approach could reach 95%. In addition, the MNPs-IL catalyst can be easily recy and reused with only a 7% loss in activity after five cycles. Avoiding the use of har catalysts, an optimal reaction temperature, a high yield, and a simple method make more effective alternative than the conditions from conventional methods. In 2013, they continued to report a synthesis of 1,2,4,5-tetrasubstituted imidazole by a one-step condensation of four components of benzil 18, aryl aldehyde 15, am nium acetate 16, and aniline 22 (Scheme 6) [46]. These reactions were promoted by One year later, they reported the methods that applied ionic liquid to support the Fe 3 O 4 MNPs catalyst in the synthesis of multi-substituted imidazoles 21 (Scheme 5) [45]. The modified heterogeneous catalyst showed comparably great activity, as the yields in this approach could reach 95%. In addition, the MNPs-IL catalyst can be easily recycled and reused with only a 7% loss in activity after five cycles. Avoiding the use of harmful catalysts, an optimal reaction temperature, a high yield, and a simple method makes it a more effective alternative than the conditions from conventional methods.
To improve the effectiveness of ultrasound-assisted D-R reactions, researchers investigated modifying the conditions of D-R reactions, including using nano-catal metal complexes catalysts, ionic liquids catalysts, organic catalysts, inorganic catal and oxidants.

Nano-catalysts
Magnetic nano-particles (MNPs) were applied for the one-pot three-compo sonochemical method to synthesize 2,4,5-trisubstituted imidazoles 19 by Safari and group in 2012 (Scheme 4) [44]. This ultrasound-assisted protocol afforded the c sponding imidazoles in high yields of up to 97% under the catalysis of Fe3O4 M which was previously synthesized through the coprecipitation method. The effect o trasound was validated by observing significant reductions in reaction time with th sistance of ultrasound, compared to cases under the conventional condition in the sence of sonication (25~45 min for the ultrasonic condition and 120~180 min for the re condition). In addition, this type of reaction, catalyzed by Fe3O4 MNPs, demonstr wide applicability to substrates. One year later, they reported the methods that applied ionic liquid to suppor Fe3O4 MNPs catalyst in the synthesis of multi-substituted imidazoles 21 (Scheme 5) The modified heterogeneous catalyst showed comparably great activity, as the yield this approach could reach 95%. In addition, the MNPs-IL catalyst can be easily recy and reused with only a 7% loss in activity after five cycles. Avoiding the use of har catalysts, an optimal reaction temperature, a high yield, and a simple method make more effective alternative than the conditions from conventional methods. In 2013, they continued to report a synthesis of 1,2,4,5-tetrasubstituted imidazol by a one-step condensation of four components of benzil 18, aryl aldehyde 15, am nium acetate 16, and aniline 22 (Scheme 6) [46]. These reactions were promoted by function of ultrasonic irradiation and nano-magnesium aluminate spinel MgAl2O4 Lewis acid catalyst, affording 23 products with great effectiveness. After the assay In 2013, they continued to report a synthesis of 1,2,4,5-tetrasubstituted imidazoles 21 by a one-step condensation of four components of benzil 18, aryl aldehyde 15, ammonium acetate 16, and aniline 22 (Scheme 6) [46]. These reactions were promoted by the function of ultrasonic irradiation and nano-magnesium aluminate spinel MgAl 2 O 4 as a Lewis acid catalyst, affording 23 products with great effectiveness. After the assays for the optimization of the temperature and frequency of ultrasound, 60 • C and 50 kHz were determined to be the most satisfied conditions with a yield of up to 98%.
Molecules 2023, 28, x FOR PEER REVIEW 7 the optimization of the temperature and frequency of ultrasound, 60 °C and 50 kHz w determined to be the most satisfied conditions with a yield of up to 98%. Safa and his co-workers published three new methods for synthesizing m ti-substituted imidazoles 25 and 28 in 2015. As shown in Scheme 7, in method (a), utilized a string of M-SAPO-34 as acidic zeolite nano-catalysts of the one-pot conde tion [47]. In the evaluation of the catalytic efficiency of various kinds of M-SAPO-34 Cu, Fe, Co, Mn), the best outcome was observed under the catalysis of Cu-SAPO-34, a yield of 95% within 5 min. In method (b), the catalyst was replaced by Fe-Cu/ZS another metal-based zeolite catalyst, showing the greatest catalytic efficiency amo string of monometallic and bimetallic catalysts on the support of ZSM-5 zeolite Benzoin 26 can serve as the substrate of this process as an alternative to benzil 18, comparable reaction times (8 min for 26 and 2~3 min for 18) and yields (88~93% fo and 97~99% for 18). In addition, the Fe-Cu/ZSM-5 catalyst can be easily recycled wit an obvious loss in activity. In further research, this approach has yielded products are utilized to synthesize organosilicon-containing imidazole substrates 29-31, offeri wide range of chemical variety and biological functions that may be valuable for n drug development. In method (c), these researchers applied a series of cata (LaxSr1−xFeyCo1−yO3 nano-perovskites) in the synthesis of 28 [49]. La0.8Sr0.2Fe0.34Co0.66O3 reported as the most efficient one among these multi-component oxides that were pared by the sol-gel auto-combustion. With the function of La0.8Sr0.2Fe0.34Co0.66O3 and trasound, 28 were synthesized in great yields above 92%. Safa and his co-workers published three new methods for synthesizing multi-substituted imidazoles 25 and 28 in 2015. As shown in Scheme 7, in method (a), they utilized a string of M-SAPO-34 as acidic zeolite nano-catalysts of the one-pot condensation [47]. In the evaluation of the catalytic efficiency of various kinds of M-SAPO-34 (M = Cu, Fe, Co, Mn), the best outcome was observed under the catalysis of Cu-SAPO-34, with a yield of 95% within 5 min. In method (b), the catalyst was replaced by Fe-Cu/ZSM-5, another metal-based zeolite catalyst, showing the greatest catalytic efficiency among a string of monometallic and bimetallic catalysts on the support of ZSM-5 zeolite [48]. Benzoin 26 can serve as the substrate of this process as an alternative to benzil 18, with comparable reaction times (8 min for 26 and 2~3 min for 18) and yields (88~93% for 26 and 97~99% for 18). In addition, the Fe-Cu/ZSM-5 catalyst can be easily recycled without an obvious loss in activity. In further research, this approach has yielded products that are utilized to synthesize organosilicon-containing imidazole substrates 29-31, offering a wide range of chemical variety and biological functions that may be valuable for novel drug development. In method (c), these researchers applied a series of catalysts (La x Sr 1−x Fe y Co 1−y O 3 nanoperovskites) in the synthesis of 28 [49]. La 0.8 Sr 0.2 Fe 0.34 Co 0.66 O 3 was reported as the most efficient one among these multi-component oxides that were prepared by the sol-gel auto-combustion. With the function of La 0.8 Sr 0.2 Fe 0.34 Co 0.66 O 3 and ultrasound, 28 were synthesized in great yields above 92%.
In 2015, the γ-Al 2 O 3 NPs-catalyzed method for the synthesis of highly substituted imidazoles was introduced by Reddy and colleagues (Scheme 8) [50]. They allocated γ-Al 2 O 3 NPs to catalyze the multi-component reaction of benzil 18, arylaldehyde 15, amines 20, and NH 4 OAc 16, which afforded 1,2,4,5-tetrasubstituted imidazoles 21 with great yields of up to 95%. With the application of ultrasonic irradiation, the reactions showed higher yields and shorter times compared to the cases under traditional conditions. Moreover, Al 2 O 3 NPs catalysts exhibited great reusability, which was validated to have comparable activities for four cycles after separation.
In 2016, Sanasi and his co-workers introduced the application of nano-copper ferrite (CuFe 2 O 4 ) with a spinel structure in the one-pot, three-and four-component synthesis of substituted imidazoles 19 and 21 (Scheme 9) [51]. This type of novel catalyst showed high efficiency, bringing great yields of about 90%. The reusability accomplished by the simple operation of the catalyst is one of the major features of this reaction.
Meanwhile, Doustkhah and his co-workers found a great system combining mesoporous nano-reactor SBA-SO 3 H and ultrasonic radiation, which is used to synthesize heterocycles with biologically active ones (Scheme 10) [52]. In the system, highly substituted imidazole 19 and 21 are synthesized through the multi-component coupling method. SBA-SO 3 H induced by ultrasound can accelerate the mass transfer of mesoporous remarkably, leading to great yields and short reaction periods. When Ar was phenyl, the ultrasound-assisted synthesis of 21 obtained a yield of 94% in 8 min, while the same case In 2015, the γ-Al2O3 NPs-catalyzed method for the synthesis of highly substituted imidazoles was introduced by Reddy and colleagues (Scheme 8) [50]. They allocated γ-Al2O3 NPs to catalyze the multi-component reaction of benzil 18, arylaldehyde 15, amines 20, and NH4OAc 16, which afforded 1,2,4,5-tetrasubstituted imidazoles 21 with In 2016, Sanasi and his co-workers introduced the application of nano-copper ferrite (CuFe2O4) with a spinel structure in the one-pot, three-and four-component synthesis o substituted imidazoles 19 and 21 (Scheme 9) [51]. This type of novel catalyst showed high efficiency, bringing great yields of about 90%. The reusability accomplished by the sim ple operation of the catalyst is one of the major features of this reaction. Meanwhile, Doustkhah and his co-workers found a great system combining meso porous nano-reactor SBA-SO3H and ultrasonic radiation, which is used to synthesize heterocycles with biologically active ones (Scheme 10) [52]. In the system, highly substi tuted imidazole 19 and 21 are synthesized through the multi-component coupling method. SBA-SO3H induced by ultrasound can accelerate the mass transfer of mesopo rous remarkably, leading to great yields and short reaction periods. When Ar was phe nyl, the ultrasound-assisted synthesis of 21 obtained a yield of 94% in 8 min, while the same case under the condition of high-speed stirring as the alternative to ultrasound only achieved a yield of 80%, costing 4 h. Other imidazole derivatives, 19 and 21, were af forded in the yields of 80~92%. Notably, splendid selectivity and tolerance, and access to various functional groups are realized in this refined trial. In 2016, Sanasi and his co-workers introduced the application of nano-copper ferrite (CuFe2O4) with a spinel structure in the one-pot, three-and four-component synthesis of substituted imidazoles 19 and 21 (Scheme 9) [51]. This type of novel catalyst showed high efficiency, bringing great yields of about 90%. The reusability accomplished by the simple operation of the catalyst is one of the major features of this reaction. Meanwhile, Doustkhah and his co-workers found a great system combining mesoporous nano-reactor SBA-SO3H and ultrasonic radiation, which is used to synthesize heterocycles with biologically active ones (Scheme 10) [52]. In the system, highly substituted imidazole 19 and 21 are synthesized through the multi-component coupling method. SBA-SO3H induced by ultrasound can accelerate the mass transfer of mesoporous remarkably, leading to great yields and short reaction periods. When Ar was phenyl, the ultrasound-assisted synthesis of 21 obtained a yield of 94% in 8 min, while the same case under the condition of high-speed stirring as the alternative to ultrasound only achieved a yield of 80%, costing 4 h. Other imidazole derivatives, 19 and 21, were afforded in the yields of 80~92%. Notably, splendid selectivity and tolerance, and access to various functional groups are realized in this refined trial. Eidi and co-workers published the synthesis of 2,4,5-trisubstituted imidazoles 19 with the catalysis of CoFe2O4 NPs (Scheme 11) [53]. The spinel CoFe2O4 NPs were synthesized by the coprecipitation of Co 2+ and Fe 3+ in ammonia under the N2 atmosphere. They applied the CoFe2O4 nano-catalyst in one-step condensations of diketone 18, aldehyde 15, and ammonium acetate 16, with sonication. These reactions obtained high yields of up to 95% within 20 min under the function of ultrasonic irradiation and paramagnetic nano-CoFe2O4. In addition, the catalyst exhibited good reusability in the protocol mentioned, with few losses in catalytic activity after four cycles. Eidi and co-workers published the synthesis of 2,4,5-trisubstituted imidazoles 19 with the catalysis of CoFe 2 O 4 NPs (Scheme 11) [53]. The spinel CoFe 2 O 4 NPs were synthesized by the coprecipitation of Co 2+ and Fe 3+ in ammonia under the N 2 atmosphere. They applied the CoFe 2 O 4 nano-catalyst in one-step condensations of diketone 18, aldehyde 15, and ammonium acetate 16, with sonication. These reactions obtained high yields of up to 95% within 20 min under the function of ultrasonic irradiation and paramagnetic nano-CoFe 2 O 4 . In addition, the catalyst exhibited good reusability in the protocol mentioned, with few losses in catalytic activity after four cycles. thesized by the coprecipitation of Co 2+ and Fe 3+ in ammonia under the N2 atmosph They applied the CoFe2O4 nano-catalyst in one-step condensations of diketone 18, a hyde 15, and ammonium acetate 16, with sonication. These reactions obtained high yi of up to 95% within 20 min under the function of ultrasonic irradiation and paramagn nano-CoFe2O4. In addition, the catalyst exhibited good reusability in the protocol m tioned, with few losses in catalytic activity after four cycles. Scheme 11. Synthesis of 17.
In 2017, Esmaeilpour developed a green one-pot method to synthesize a strin 2,4,5-trisubstituted 32 and 1,2,4,5-tetrasubstituted imidazole 25 (Scheme 12) [54]. T prepared nano-silica dendritic polymer-supported H3PW12O40 NPs (Dendrimer-PWA the reusable catalyst of the ultrasound-assisted reaction. Dendritic-PWA n played the of the potent acid catalyst that highly promoted dehydration condensation with synergetic effect of ultrasound, leading to excellent yields of up to 95%. This appro demonstrated wide applicability to a variety of substrates as well. In 2017, Esmaeilpour developed a green one-pot method to synthesize a string of 2,4,5-trisubstituted 32 and 1,2,4,5-tetrasubstituted imidazole 25 (Scheme 12) [54]. They prepared nano-silica dendritic polymer-supported H 3 PW 12 O 40 NPs (Dendrimer-PWA n ) as the reusable catalyst of the ultrasound-assisted reaction. Dendritic-PWA n played the role of the potent acid catalyst that highly promoted dehydration condensation with the synergetic effect of ultrasound, leading to excellent yields of up to 95%. This approach demonstrated wide applicability to a variety of substrates as well.
hyde 15, and ammonium acetate 16, with sonication. These reactions obtained high yields of up to 95% within 20 min under the function of ultrasonic irradiation and paramagnetic nano-CoFe2O4. In addition, the catalyst exhibited good reusability in the protocol mentioned, with few losses in catalytic activity after four cycles. In 2017, Esmaeilpour developed a green one-pot method to synthesize a string of 2,4,5-trisubstituted 32 and 1,2,4,5-tetrasubstituted imidazole 25 (Scheme 12) [54]. They prepared nano-silica dendritic polymer-supported H3PW12O40 NPs (Dendrimer-PWA n ) as the reusable catalyst of the ultrasound-assisted reaction. Dendritic-PWA n played the role of the potent acid catalyst that highly promoted dehydration condensation with the synergetic effect of ultrasound, leading to excellent yields of up to 95%. This approach demonstrated wide applicability to a variety of substrates as well. In 2018, the Ghasemzadeh group reported a concise and efficient method to prepare Co 3 O 4 NPs via a one-pot reaction (Scheme 13) [55]. At that point, they investigated the catalytic effects of the nano-catalyst on the one-pot reaction of synthesizing a series of 1,2,4,5-tetrasubstituted imidazole 36 using ultrasonic irradiation. Simple work-up, neutral conditions, short reaction times (12~28 min), and excellent yields (91~97%) make it a meaningful alternative to traditional procedures that synthesize biologically active imidazole.
The antimicrobial activity of imidazole compounds against some common pathogenic bacteria was studied by a paper diffusion method in vitro, such as, Escherichia coli, Bacillus subtillis, Staphylococcus aureus, Salmonella Typhi, and Shigella dysentrae species. The results showed that compounds 36c, 36f, and 36h had the highest contents against all bacteria, compound 36a had the highest activity against Bacillus subtilis, and compound 36g possessed the highest antioxidant activity in Salmonella dysentery.
Varzi and his colleagues introduced a new approach to producing mixed nano-catalyst ZnS-ZnFe 2 O 4 in 2019 (Scheme 14) [56]. The nano-ZnS-ZnFe 2 O 4 was synthesized through the chemical coprecipitation method and then using the Lewis acidic catalyst to promote the sonicated synthesis of 19. The yields in this approach reached 95%, with a reaction time of 15 min. This hybrid nano-catalyst exhibited great effectiveness and recyclability and could be reused for six cycles with subtle activity loss. The reaction even obtained an 86% yield in the sixth cycle of catalyst utilization.
The antimicrobial activity of imidazole compounds against some common pathogenic bacteria was studied by a paper diffusion method in vitro, such as, Escherichia coli, Bacillus subtillis, Staphylococcus aureus, Salmonella Typhi, and Shigella dysentrae species. The results showed that compounds 36c, 36f, and 36h had the highest contents against all bacteria, compound 36a had the highest activity against Bacillus subtilis, and compound 36g possessed the highest antioxidant activity in Salmonella dysentery. Scheme 13. Synthesis of 36a-36h.
Varzi and his colleagues introduced a new approach to producing mixed nano-catalyst ZnS-ZnFe2O4 in 2019 (Scheme 14) [56]. The nano-ZnS-ZnFe2O4 was synthesized through the chemical coprecipitation method and then using the Lewis acidic catalyst to promote the sonicated synthesis of 19. The yields in this approach reached 95%, with a reaction time of 15 min. This hybrid nano-catalyst exhibited great effectiveness and recyclability and could be reused for six cycles with subtle activity loss. The reaction even obtained an 86% yield in the sixth cycle of catalyst utilization. Varzi and his colleagues introduced a new approach to producing mixed nano-catalyst ZnS-ZnFe2O4 in 2019 (Scheme 14) [56]. The nano-ZnS-ZnFe2O4 was synthe sized through the chemical coprecipitation method and then using the Lewis acidic cat alyst to promote the sonicated synthesis of 19. The yields in this approach reached 95% with a reaction time of 15 min. This hybrid nano-catalyst exhibited great effectiveness and recyclability and could be reused for six cycles with subtle activity loss. The reaction even obtained an 86% yield in the sixth cycle of catalyst utilization. Despite the laborious preparation of the catalyst, this ultrasound-assisted approach using MNP@LADES afforded substituted imidazoles in great yields of up to 94% without byproducts being observed. In addition, the catalyst can be easily recovered by magnetic separation and reused for five cycles without attrition of catalytic activity.
In 2020, Hajizadeh and her co-workers developed a one-pot three-component reaction by using a novel and green NiFe 2 O 4 -geopolymer nano-catalyst to prepare imidazole derivatives 32, which was accelerated by ultrasonic irradiations (Scheme 16) [58]. The nano-NiFe 2 O 4 supported on geopolymer exhibited great catalytic effects, validated by comparison to other catalysts, including, bentonite, geopolymer, and NiFe 2 O 4 NPs, and stable recyclability. and then coated with tetraethylorthosilicate. MNP@LADES was obtained after the intermediate product underwent the process of functionalization and a reaction with [Urea]4[ZnCl2]. Despite the laborious preparation of the catalyst, this ultrasound-assisted approach using MNP@LADES afforded substituted imidazoles in great yields of up to 94% without byproducts being observed. In addition, the catalyst can be easily recovered by magnetic separation and reused for five cycles without attrition of catalytic activity.

Scheme 15. Synthesis of 19 and 28.
In 2020, Hajizadeh and her co-workers developed a one-pot three-component reaction by using a novel and green NiFe2O4-geopolymer nano-catalyst to prepare imidazole derivatives 32, which was accelerated by ultrasonic irradiations (Scheme 16) [58]. The nano-NiFe2O4 supported on geopolymer exhibited great catalytic effects, validated by comparison to other catalysts, including, bentonite, geopolymer, and NiFe2O4 NPs, and stable recyclability. One year later, Kohan et al., published the synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives 28 catalyzed by a Bi1.5(Lu,Er)0.5O3 nano-catalyst via ultrasonic assistance (Scheme 17) [59]. This Lewis acidic heterogeneous catalyst possessed good catalytic activity and simple reusability. With the presence of nano-Bi1.5(Lu,Er)0.5O3 and the application of ultrasound, this method afforded imidazole-based compounds in great yields of roughly 90% within 5 min at room temperature. In 2020, Hajizadeh and her co-workers developed a one-pot three-component r tion by using a novel and green NiFe2O4-geopolymer nano-catalyst to prepare imida derivatives 32, which was accelerated by ultrasonic irradiations (Scheme 16) [58]. nano-NiFe2O4 supported on geopolymer exhibited great catalytic effects, validated comparison to other catalysts, including, bentonite, geopolymer, and NiFe2O4 NPs, stable recyclability. One year later, Kohan et al., published the synthesis of 1,2,4,5-tetrasubstituted idazole derivatives 28 catalyzed by a Bi1.5(Lu,Er)0.5O3 nano-catalyst via ultrasonic a tance (Scheme 17) [59]. This Lewis acidic heterogeneous catalyst possessed good cata activity and simple reusability. With the presence of nano-Bi1.5(Lu,Er)0.5O3 and the a cation of ultrasound, this method afforded imidazole-based compounds in great yield roughly 90% within 5 min at room temperature.  trasonic irradiation in 2021 (Scheme 18) [60]. They began with the synthesis of HMS, fol lowed by the functionalization of HMS with sulfamic acid groups, forming HMS-SA. Th fabricated materials, as catalysts, were introduced in the one-pot three-component syn thesis of trisubstituted imidazoles 38 and could be recovered and reused with almos negligible losses in efficacy. These ultrasonic-assisted reactions afforded 38 in great yield (92~99%).

Scheme 18. Synthesis of 38.
In early 2023, Kermanizadeh and Naeimi reported the design and preparation o modified silica-coated cobalt ferrite nano-particles (CoFe2O4@SiO2@(-CH2)3OWO3H NPs for the synthesis of trisubstituted imidazoles 19 (Scheme 19) [61]. Prepared via a four-step process, this novel catalyst exhibited solid stability and potent catalytic efficacy. Th 2,4,5-aryl imidazoles 19 were afforded through this method in yields of up to 95% within 8 min. After reactions, the solid acid catalyst could be easily recycled and reused for fiv cycles with consistent activity.

Metal Complex Catalysts
In 2008, Khosropour et al., introduced a simple and green ultrasonic-assisted syn thesis of 2,4,5-trisubstituted imidazole 40, with zirconium (IV) acetylacetonate (Zr(acac)4 as the catalyst and with aldehydes 24, benzils 39, and ammonium acetate 16 as the start ing materials (Scheme 20) [62]. In this approach, the best yield reached 97%. Compared t the cases under the reflux condition that took around 3 h with a maximum yield of 84% these ultrasound-assisted reactions typically finished in 20~50 min. In early 2023, Kermanizadeh and Naeimi reported the design and preparation of modified silica-coated cobalt ferrite nano-particles (CoFe 2 O 4 @SiO 2 @(-CH 2 ) 3 OWO 3 H NPs) for the synthesis of trisubstituted imidazoles 19 (Scheme 19) [61]. Prepared via a four-step process, this novel catalyst exhibited solid stability and potent catalytic efficacy. The 2,4,5aryl imidazoles 19 were afforded through this method in yields of up to 95% within 8 min. After reactions, the solid acid catalyst could be easily recycled and reused for five cycles with consistent activity. fabricated materials, as catalysts, were introduced in the one-pot three-component synthesis of trisubstituted imidazoles 38 and could be recovered and reused with almost negligible losses in efficacy. These ultrasonic-assisted reactions afforded 38 in great yields (92~99%). In early 2023, Kermanizadeh and Naeimi reported the design and preparation of modified silica-coated cobalt ferrite nano-particles (CoFe2O4@SiO2@(-CH2)3OWO3H NPs) for the synthesis of trisubstituted imidazoles 19 (Scheme 19) [61]. Prepared via a four-step process, this novel catalyst exhibited solid stability and potent catalytic efficacy. The 2,4,5-aryl imidazoles 19 were afforded through this method in yields of up to 95% within 8 min. After reactions, the solid acid catalyst could be easily recycled and reused for five cycles with consistent activity.

Metal Complex Catalysts
In 2008, Khosropour et al., introduced a simple and green ultrasonic-assisted synthesis of 2,4,5-trisubstituted imidazole 40, with zirconium (IV) acetylacetonate (Zr(acac)4) as the catalyst and with aldehydes 24, benzils 39, and ammonium acetate 16 as the starting materials (Scheme 20) [62]. In this approach, the best yield reached 97%. Compared to the cases under the reflux condition that took around 3 h with a maximum yield of 84%, these ultrasound-assisted reactions typically finished in 20~50 min.

Metal Complex Catalysts
In 2008, Khosropour et al., introduced a simple and green ultrasonic-assisted synthesis of 2,4,5-trisubstituted imidazole 40, with zirconium (IV) acetylacetonate (Zr(acac) 4 ) as the catalyst and with aldehydes 24, benzils 39, and ammonium acetate 16 as the starting materials (Scheme 20) [62]. In this approach, the best yield reached 97%. Compared to the cases under the reflux condition that took around 3 h with a maximum yield of 84%, these ultrasound-assisted reactions typically finished in 20~50 min. In 2011, the Damavandi group reported that bis [N-(3,5-dicumylsalicylidene)-2,6fluoroanilinato] zirconium(IV) dichloride was a highly interesting catalyst, using ultrasonic irradiation for the synthesis of 2-aryl-1H-phenanthro[9,10-d]imidazole derivatives 42 (Scheme 21) [63]. A novel one-pot method was brought out in the efficient synthesis of 42 under ultrasound with yields of up to 93%, bringing compact reaction procedures, lenient conditions, and affordable materials.
In 2011, a productive one-pot procedure of the synthesis of the 2,4,5-trisubstituted imidazoles 38 was published by the Safari group (Scheme 22) [64]. The condensation reaction was catalyzed by Zinc (II) [tetra-(4-methylphenyl)] porphyrin, which is a repeatable and new product, using 1,2-diketones 37 or α-hydroxyketones 43 with aromatic aldehydes 15 and ammonium acetate 16 as the starting source. Excellent yields of 87~97% were obtained in this method.

Ionic Liquids Catalysts
In 2010, the Zang group found that the ionic liquid 1-ethyl-3methylimidazole acetate ([EMIM]OAc) is a functional catalyst for the one-step synthesis of 2-aryl-4,5-diphenyl imidazole 19 (Scheme 23) [65]. With the utilization of ionic liquid [EMIM][Oac] and ultrasound, the yields significantly increased to a maximum of 96% compared with a method involving the absence of the catalyst (15%) or ultrasonication (18%). This procedure possesses obvious advantages, such as avoiding the use of harmful catalysts or reagents, reactions at room temperature, and simple steps for the separation process.

8, x FOR PEER REVIEW
15 of 31 trasound, the yields significantly increased to a maximum of 96% compared with a method involving the absence of the catalyst (15%) or ultrasonication (18%). This procedure possesses obvious advantages, such as avoiding the use of harmful catalysts or reagents, reactions at room temperature, and simple steps for the separation process.

Scheme 23. Synthesis of 19.
In 2013, the Saffari Jourshari group reported an interesting method for imidazole synthesis by the condensation of benzil 18 or 9,10-phenanthrenequinone 41 with aldehydes 15 and ammonium acetate 16, catalyzed via ultrasound in an ionic liquid-like phase (SILLP) (Scheme 24) [66]. The products 44 and 45 were afforded in great yields of around 90% with a short reaction time of 3~6 min. Additionally, many of the products they synthesized exhibited potent antimicrobial activity, such as 44a, 44b, 44c, and 44a In 2013, the Saffari Jourshari group reported an interesting method for imidazole synthesis by the condensation of benzil 18 or 9,10-phenanthrenequinone 41 with aldehydes 15 and ammonium acetate 16, catalyzed via ultrasound in an ionic liquid-like phase (SILLP) (Scheme 24) [66]. The products 44 and 45 were afforded in great yields of around 90% with a short reaction time of 3~6 min. Additionally, many of the products they synthesized exhibited potent antimicrobial activity, such as 44a, 44b, 44c, and 44a, 44b. This perhaps needs further and future in-depth research and excavation to find novel drugs for clinical applications of great value.

Scheme 23. Synthesis of 19.
In 2013, the Saffari Jourshari group reported an interesting method for imidazole synthesis by the condensation of benzil 18 or 9,10-phenanthrenequinone 41 with aldehydes 15 and ammonium acetate 16, catalyzed via ultrasound in an ionic liquid-like phase (SILLP) (Scheme 24) [66]. The products 44 and 45 were afforded in great yields of around 90% with a short reaction time of 3~6 min. Additionally, many of the products they synthesized exhibited potent antimicrobial activity, such as 44a, 44b, 44c, and 44a, 44b. This perhaps needs further and future in-depth research and excavation to find novel drugs for clinical applications of great value.
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Scheme 24. Synthesis of 44(a-c) and 45(a-b).
After four years, 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]), an efficient ionic liquid catalyst, was applied to synthesize imidazole compounds via ultrasonic irradiation by the Shirole group (Scheme 25) [67]. Compared to the cases of the conventional reflux condition, the yields in ultrasound-assisted reactions increased by around 10%, and the reaction time decreased by two thirds, validating the efficacy of ultrasound.

Scheme 24. Synthesis of 44(a-c) and 45(a-b).
After four years, 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]), an efficient ionic liquid catalyst, was applied to synthesize imidazole compounds via ultrasonic irradiation by the Shirole group (Scheme 25) [67]. Compared to the cases of the conventional reflux condition, the yields in ultrasound-assisted reactions increased by around 10%, and the reaction time decreased by two thirds, validating the efficacy of ultrasound.
After four years, 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]), an efficient ionic liquid catalyst, was applied to synthesize imidazole compounds via ultrasonic irradiation by the Shirole group (Scheme 25) [67]. Compared to the cases of the conventional reflux condition, the yields in ultrasound-assisted reactions increased by around 10%, and the reaction time decreased by two thirds, validating the efficacy of ultrasound.

Scheme 25. Synthesis of 47.
In 2018, Arafa and colleagues introduced the [DABCO-DOL][OAc], a DABCO-based ionic liquid catalyst, which was a powerful and eco-friendly catalyst for this one-pot multi-component imidazole-based compounds' synthesis (Scheme 26) [68]. Through the substitution reaction of DABCO and 2-chloro-1,3-propandiol, followed by the anion exchange, this ionic liquid catalyst was quickly prepared. Compared with traditional methods, the proposed method afforded 19 more effectively, with a simple operation and high yields of up to 99%. In addition, the ionic liquid catalyst can be reused with comparable efficacy after seven cycles.

In 2018, Arafa and colleagues introduced the [DABCO-DOL][OAc]
, a DABCO-based ionic liquid catalyst, which was a powerful and eco-friendly catalyst for this one-pot multi-component imidazole-based compounds' synthesis (Scheme 26) [68]. Through the substitution reaction of DABCO and 2-chloro-1,3-propandiol, followed by the anion exchange, this ionic liquid catalyst was quickly prepared. Compared with traditional methods, the proposed method afforded 19 more effectively, with a simple operation and high yields of up to 99%. In addition, the ionic liquid catalyst can be reused with comparable efficacy after seven cycles. sonic irradiation by the Shirole group (Scheme 25) [67]. Compared to the cases o conventional reflux condition, the yields in ultrasound-assisted reactions increase around 10%, and the reaction time decreased by two thirds, validating the efficacy o trasound. In 2018, Arafa and colleagues introduced the [DABCO-DOL][OAc], a DABCO-b ionic liquid catalyst, which was a powerful and eco-friendly catalyst for this on multi-component imidazole-based compounds' synthesis (Scheme 26) [68]. Throug substitution reaction of DABCO and 2-chloro-1,3-propandiol, followed by the anio change, this ionic liquid catalyst was quickly prepared. Compared with tradit methods, the proposed method afforded 19 more effectively, with a simple operation high yields of up to 99%. In addition, the ionic liquid catalyst can be reused with parable efficacy after seven cycles. In 2020, Hilal and his colleagues reported a novel acidic ionic liquid, [2-(imm)-4-{b(immh)m}c][HSO 4 ] 3 , which was applied as the catalyst in the synthesis of 2,4,5-trisubstituted imidazole derivatives 19 (Scheme 27) [69]. With auxiliary ultrasonication, this ionic liquid catalyst was prepared via a five-step procedure and significantly promoted the condensation of aldehydes 15, ammonium acetate 16, and benzil 18/benzoin 26. These ultrasoundassisted reactions obtained yields of 73~98% with a reaction time of 35~60 min, while the methods under the conventional reflux condition obtained lower yields (38~86%) and a longer reaction time (120~190 min). In addition, the ionic liquid catalyst could be easily recycled for three cycles.
In is regarded as an eco-compatible and highly efficient catalyst under ultrasound irradiation, bringing a convenient isolation process for the products. The catalyst could be reused for five cycles with limited loss in catalytic activity.

Organic Catalysts
In 2011, Damavandi developed a satisfactory one-step multi-component method for the synthesis of 2-aryl-1H-phenanthro[9,10-d] imidazoles 42 through ultrasonic irradiation (Scheme 29) [71]. To investigate the most suitable catalyst for the condensation of aldehydes 15, 9,10-phenanthrenequinone 41, and ammonium acetate 16, researchers examined several organic acids and their salts. The highest yield (94%) was obtained under ultrasonic irradiation and the catalysis of p-toluenesulfonic acid (p-TSA), using EtOH as the solvent.
This p-TSA-catalyzed approach offered a simple and efficient way to synthesize 42 with the facile operation to purify.

Organic Catalysts
In 2011, Damavandi developed a satisfactory one-step multi-component metho the synthesis of 2-aryl-1H-phenanthro[9,10-d] imidazoles 42 through ultrasonic irra tion (Scheme 29) [71]. To investigate the most suitable catalyst for the condensatio aldehydes 15, 9,10-phenanthrenequinone 41, and ammonium acetate 16, researc examined several organic acids and their salts. The highest yield (94%) was obta under ultrasonic irradiation and the catalysis of p-toluenesulfonic acid (p-TSA), u EtOH as the solvent. This p-TSA-catalyzed approach offered a simple and efficient w synthesize 42 with the facile operation to purify.

Scheme 29. Synthesis of 42.
Five years later, this group continued to use L-proline as the catalyst, which convenient and user-friendly reagent with great catalytic activity. Previous rese published by Shitole et al., in 2009 reported the application of L-proline in the stan D-R reaction, in which L-proline served as a bifunctional catalyst containing both a b secondary amine group and an acid carboxylic group (Scheme 30a) [72]. These reac obtained great yields (75~94%) but cost several hours (120~300 min) to undergo comp progression. Furthermore, in 2016, Damavandi  In 2014, the Heravi group developed an interesting one-pot three-component rou tine to synthesize 2,4,5-trisubstituted imidazoles 32, using ultrasound irradiation withou a solvent in the presence of Selectfluor™ (Scheme 31) [74]. The Selectfluor TM served as the Lewis acidic catalyst in the reaction that activated the carbonyl group, effectively pro moting the three-component condensation under sonication. These ultrasonic-assisted reactions offered 32 in great yields of 82~99% within 3~15 min. In 2014, the Heravi group developed an interesting one-pot three-component routine to synthesize 2,4,5-trisubstituted imidazoles 32, using ultrasound irradiation without a solvent in the presence of Selectfluor™ (Scheme 31) [74]. The Selectfluor TM served as the Lewis acidic catalyst in the reaction that activated the carbonyl group, effectively promoting the three-component condensation under sonication. These ultrasonic-assisted reactions offered 32 in great yields of 82~99% within 3~15 min.
In 2014, the Heravi group developed an interesting one-pot three-component tine to synthesize 2,4,5-trisubstituted imidazoles 32, using ultrasound irradiation wit a solvent in the presence of Selectfluor™ (Scheme 31) [74]. The Selectfluor TM served a Lewis acidic catalyst in the reaction that activated the carbonyl group, effectively moting the three-component condensation under sonication. These ultrasonic-ass reactions offered 32 in great yields of 82~99% within 3~15 min. Devkate and his co-workers claimed an enthralling one-pot three-component tion that synthesizes 2,4,5-triaryl-1H-imidazole 19 via a novel approach, in 2017 (Sch 32) [75]. They utilized polyethylene glycol PEG-400 as an effective and recoverable lyst to promote the condensation of the benzil 18, aromatic aldehydes 15, and ammon acetate 16. Compared to the traditional reflux condition, every reaction using auxi ultrasound afforded product 19 higher yields and a shorter reaction time. The yields risen significantly for most reactions (87~95% for the ultrasonic method and 67~75% the conventional method) and remarkably reduced the reaction time (8~15 min fo ultrasonic method and 53~80 min for the conventional method). Devkate and his co-workers claimed an enthralling one-pot three-component reaction that synthesizes 2,4,5-triaryl-1H-imidazole 19 via a novel approach, in 2017 (Scheme 32) [75]. They utilized polyethylene glycol PEG-400 as an effective and recoverable catalyst to promote the condensation of the benzil 18, aromatic aldehydes 15, and ammonium acetate 16. Compared to the traditional reflux condition, every reaction using auxiliary ultrasound afforded product 19 higher yields and a shorter reaction time. The yields have risen significantly for most reactions (87~95% for the ultrasonic method and 67~75% for the conventional method) and remarkably reduced the reaction time (8~15 min for the ultrasonic method and 53~80 min for the conventional method). In 2020, Khandebharad and his co-workers reported an eco-compatible procedu synthesize tetrasubstituted imidazole-based compounds 25 in w 3-(N-morpholino)propane sulfonic acid (MOPS) was utilized as a green and effic acidic catalyst (Scheme 33) [76]. With the effect of ultrasonic irradiation and MOPS one-pot four-component condensation of benzil 18, aldehydes 15, primary amine 20, ammonium acetate 16 afforded product 25 in great yields within a short reaction t Notably, the MOPS catalyst could be recycled and reused for three cycles. Accordin their statistics, the majority of the yields were promoted from approximately 80% to and the reaction time was roughly halved from 20~60 min to 10~30 min with the he ultrasound.

Scheme 33. Synthesis of 25.
In the same year, the Behrouz group reported the phenylphosphine(PPh3)-catalyzed ultrasound-assisted reaction to synthe 2,4,5-trisubstituted imidazole 32 efficiently (Scheme 34) [77]. They found that PPh hibited great catalysis activity in the D-R reaction at room temperature, which prov an effective and eco-friendly method with a cheap and harmless catalyst for the prep In 2020, Khandebharad and his co-workers reported an eco-compatible procedure to synthesize tetrasubstituted imidazole-based compounds 25 in which 3-(N-morpholino)propane sulfonic acid (MOPS) was utilized as a green and efficient acidic catalyst (Scheme 33) [76]. With the effect of ultrasonic irradiation and MOPS, the one-pot four-component condensation of benzil 18, aldehydes 15, primary amine 20, and ammonium acetate 16 afforded product 25 in great yields within a short reaction time. Notably, the MOPS catalyst could be recycled and reused for three cycles. According to their statistics, the majority of the yields were promoted from approximately 80% to 90% and the reaction time was roughly halved from 20~60 min to 10~30 min with the help of ultrasound. In 2020, Khandebharad and his co-workers reported an eco-compatible procedure to synthesize tetrasubstituted imidazole-based compounds 25 in which 3-(N-morpholino)propane sulfonic acid (MOPS) was utilized as a green and efficient acidic catalyst (Scheme 33) [76]. With the effect of ultrasonic irradiation and MOPS, the one-pot four-component condensation of benzil 18, aldehydes 15, primary amine 20, and ammonium acetate 16 afforded product 25 in great yields within a short reaction time. Notably, the MOPS catalyst could be recycled and reused for three cycles. According to their statistics, the majority of the yields were promoted from approximately 80% to 90% and the reaction time was roughly halved from 20~60 min to 10~30 min with the help of ultrasound.

Scheme 33. Synthesis of 25.
In the same year, the Behrouz group reported the triphenylphosphine(PPh3)-catalyzed ultrasound-assisted reaction to synthesize 2,4,5-trisubstituted imidazole 32 efficiently (Scheme 34) [77]. They found that PPh3 exhibited great catalysis activity in the D-R reaction at room temperature, which provided an effective and eco-friendly method with a cheap and harmless catalyst for the preparation of 32. Disparate from other typical D-R reactions, these researchers employed urea 52 as the nitrogen source, resulting in higher yields (up to 95%) compared to the assays of NH4OAc (up to 87%). In this approach, imidazole derivatives 32 were obtained in excel- In the same year, the Behrouz group reported the triphenylphosphine(PPh 3 )-catalyzed ultrasound-assisted reaction to synthesize 2,4,5-trisubstituted imidazole 32 efficiently (Scheme 34) [77]. They found that PPh 3 exhibited great catalysis activity in the D-R reaction at room temperature, which provided an effective and eco-friendly method with a cheap and harmless catalyst for the preparation of 32. Disparate from other typical D-R reactions, these researchers employed urea 52 as the nitrogen source, resulting in higher yields (up to 95%) compared to the assays of NH 4 OAc (up to 87%). In this approach, imidazole derivatives 32 were obtained in excellent yields of 80~95%. phenylphosphine(PPh3)-catalyzed ultrasound-assisted reaction to synthe 2,4,5-trisubstituted imidazole 32 efficiently (Scheme 34) [77]. They found that PPh hibited great catalysis activity in the D-R reaction at room temperature, which prov an effective and eco-friendly method with a cheap and harmless catalyst for the prep tion of 32. Disparate from other typical D-R reactions, these researchers employed 52 as the nitrogen source, resulting in higher yields (up to 95%) compared to the assay NH4OAc (up to 87%). In this approach, imidazole derivatives 32 were obtained in e lent yields of 80~95%. Scheme 34. Synthesis of 32.

Inorganic Catalysts
In 2009, Shelke and his co-workers synthesized the structurally div 2,4,5-trisubstituted imidazole 19 via the one-pot three-component method, catalyze non-toxic ceric (IV) ammonium nitrate (CAN), assisted by ultrasound, benzil 18/ben 26, aldehydes 15, and ammonium acetate 16 as the starting material (Scheme 35) CAN exerted its catalysis activity as a Lewis acid that activated the carbonyl. In that y they continued to utilize boric acid as the acidic catalyst in the synthesis of 2,4,5-tr imidazole derivatives 19 under sonication [79]. Boric acid with the supplementary Scheme 34. Synthesis of 32.

Inorganic Catalysts
In 2009, Shelke and his co-workers synthesized the structurally diverse 2,4,5-trisubstituted imidazole 19 via the one-pot three-component method, catalyzed by non-toxic ceric (IV) ammonium nitrate (CAN), assisted by ultrasound, benzil 18/benzoin 26, aldehydes 15, and ammonium acetate 16 as the starting material (Scheme 35) [78]. CAN exerted its catalysis activity as a Lewis acid that activated the carbonyl. In that year, they continued to utilize boric acid as the acidic catalyst in the synthesis of 2,4,5-triaryl imidazole derivatives 19 under sonication [79]. Boric acid with the supplementary ultrasound irradiation ameliorated the three-component condensation with great effectiveness, offering an efficient and convenient protocol for the preparation of imidazole-based compounds with yields above 85%. In 2014, Safari and his co-workers formulated a one-pot synthesis of substitut imidazoles based on the ultrasound method and the SiO2-OSbCl2 catalyst (Scheme 3 [80]. The synthesis of 2,4,5-trisubstituted imidazoles 19 and 1,2,4,5-tetrasubstituted 21 v a multi-compound condensation was accelerated by using assisted ultrasonication a antimony(III) chloride with the support of silica gel (SiO2-OSbCl2) as a Lewis acid ca lyst, under a solvent-free condition. This protocol demonstrated great applicability various substrates with comparable effectiveness. Most reactions obtained great yields above 80% with a short reaction time (10~33 min). In 2014, Safari and his co-workers formulated a one-pot synthesis of substituted imidazoles based on the ultrasound method and the SiO 2 -OSbCl 2 catalyst (Scheme 36) [80]. The synthesis of 2,4,5-trisubstituted imidazoles 19 and 1,2,4,5-tetrasubstituted 21 via a multi-compound condensation was accelerated by using assisted ultrasonication and antimony(III) chloride with the support of silica gel (SiO 2 -OSbCl 2 ) as a Lewis acid catalyst, under a solvent-free condition. This protocol demonstrated great applicability to various substrates with comparable effectiveness. Most reactions obtained great yields of above 80% with a short reaction time (10~33 min).
In 2020, Dastmard and her co-workers reported a one-pot, four-component method using acidic KHSO 4 as an effective catalyst under ultrasonic irradiations to synthesize 4,5-diphenyl-1H-imidazol-1-yl-1H-1,2,4-triazole derivatives 54 (Scheme 37) [81]. The yields were obtained in 70~96%, and the reaction time ranged from 10 min to 25 min. Based on the results from trials in Scheme 37, they continued to sift several bioactivity compounds after they obtained the results. The antimicrobial activities of compounds that they synthesized against Gram-negative bacteria (Escherichia coli., Pseudomonas aeruginosa.) and Gram-positive bacteria (Bacillus subtilis., Micrococcus luteinis.) were screened below. They evaluated the compounds' antioxidant activities and then found that many of the products have promising potential regarding antibacterial activity and high antioxidant activity.

Scheme 35. Synthesis of 19.
In 2014, Safari and his co-workers formulated a one-pot synthesis of substituted imidazoles based on the ultrasound method and the SiO2-OSbCl2 catalyst (Scheme 36) [80]. The synthesis of 2,4,5-trisubstituted imidazoles 19 and 1,2,4,5-tetrasubstituted 21 via a multi-compound condensation was accelerated by using assisted ultrasonication and antimony(III) chloride with the support of silica gel (SiO2-OSbCl2) as a Lewis acid catalyst, under a solvent-free condition. This protocol demonstrated great applicability to various substrates with comparable effectiveness. Most reactions obtained great yields of above 80% with a short reaction time (10~33 min).

Scheme 36. Synthesis of 19 and 21.
In 2020, Dastmard and her co-workers reported a one-pot, four-component method using acidic KHSO4 as an effective catalyst under ultrasonic irradiations to synthesize 4,5-diphenyl-1H-imidazol-1-yl-1H-1,2,4-triazole derivatives 54 (Scheme 37) [81]. The yields were obtained in 70~96%, and the reaction time ranged from 10 min to 25 min. Based on the results from trials in Scheme 37, they continued to sift several bioactivity compounds after they obtained the results. The antimicrobial activities of compounds that they synthesized against Gram-negative bacteria (Escherichia coli., Pseudomonas aeruginosa.) and Gram-positive bacteria (Bacillus subtilis., Micrococcus luteinis.) were screened

Oxidant
In 2012, the Nagargoje group used diethyl bromophosphate (DEP) as the oxidant for a one-pot three-component condensation to obtain 2,4,5-triaryl-imidazole compounds 19 (Scheme 38) [82]. The oxidant agent DEP enabled benzoin to serve as a feasible alternative to benzil as the substrate of the D-R reaction, and the cases of both benzoin and benzil afforded the product 19 in great yields (91~97%) under an ultrasound-assisted condition.

Oxidant
In 2012, the Nagargoje group used diethyl bromophosphate (DEP) as the oxidant for a one-pot three-component condensation to obtain 2,4,5-triaryl-imidazole compounds 19 (Scheme 38) [82]. The oxidant agent DEP enabled benzoin to serve as a feasible alternative to benzil as the substrate of the D-R reaction, and the cases of both benzoin and benzil afforded the product 19 in great yields (91~97%) under an ultrasound-assisted condition.

Phillips-Ladenburg Imidazole Synthesis
In 1875, Ladenburg reported the synthesis of benzimidazole via the condensation of 1,2-diaminobenzens (1,2-DAB) and aldehydes [19,20]. Around 1928, Phillips enhanced the Ladenburg method by using carboxylic acids as substitutes for aldehydes [21][22][23]. Scheme 39 shows the typical type of the Phillips-Ladenburg reaction that affords benzimidazoles from 1,2-DAB. The conventional Phillips reaction usually requires harsh reaction conditions, for example, a combination of high temperature (170 • C) and microwave irradiation, which, definitely suffers high-energy consumption, an expensive apparatus, and verbose reaction times.
In 2012, the Nagargoje group used diethyl bromophosphate (DEP) as the oxidan a one-pot three-component condensation to obtain 2,4,5-triaryl-imidazole compound (Scheme 38) [82]. The oxidant agent DEP enabled benzoin to serve as a feasible alte tive to benzil as the substrate of the D-R reaction, and the cases of both benzoin benzil afforded the product 19 in great yields (91~97%) under an ultrasound-ass condition.

Phillips-Ladenburg Imidazole Synthesis
In 1875, Ladenburg reported the synthesis of benzimidazole via the condensatio 1,2-diaminobenzens (1,2-DAB) and aldehydes [19,20]. Around 1928, Phillips enha the Ladenburg method by using carboxylic acids as substitutes for aldehydes [21 Scheme 39 shows the typical type of the Phillips-Ladenburg reaction that affords zimidazoles from 1,2-DAB. The conventional Phillips reaction usually requires hars action conditions, for example, a combination of high temperature (170 °C) and m wave irradiation, which, definitely suffers high-energy consumption, an expensive paratus, and verbose reaction times.
Therefore, ultrasound-assisted methods are introduced by researchers, brin atom economic and eco-compatible effects to those conventional ones. Ultrasonic ir ation illustrates the P-L reaction, fueling higher yields, operating simplicity, and duction efficiency. In 2019, Nongrum and her co-workers, with ultrasonic assistance, brought abo green approach toward the fabrication of benzimidazole scaffolds 56 (Scheme 40) These researchers used meglumine as the green and harmless catalyst for the Phil Ladenburg reaction. The effect of ultrasound was evaluated by comparing it with cases under the condition of reflux which resulted in a longer reaction time (5 h for re stirring and 25~30 min for ultrasound) and lower yields (50~68% for reflux stirring 80~90% for ultrasound). In 2020, Karami and his co-workers reported a novel nano-catalyst, Co/Mn ported by GO (Graphene oxide) which was prepared by using metal oxide as a ca under ultrasound irradiation (Scheme 41) [84]. This reusable nano-catalyst has been to synthesize some benzimidazole from corresponding aldehydes 1,2-phenylene-diamine 56. Compared with applying a thermal condition at 80 °C ultrasonic way only required room temperature to undergo a reaction with compar yields. Therefore, ultrasound-assisted methods are introduced by researchers, bringing atom economic and eco-compatible effects to those conventional ones. Ultrasonic irradiation illustrates the P-L reaction, fueling higher yields, operating simplicity, and production efficiency.
In 2019, Nongrum and her co-workers, with ultrasonic assistance, brought about a green approach toward the fabrication of benzimidazole scaffolds 56 (Scheme 40) [83]. These researchers used meglumine as the green and harmless catalyst for the Phillips-Ladenburg reaction. The effect of ultrasound was evaluated by comparing it with the cases under the condition of reflux which resulted in a longer reaction time (5 h for reflux stirring and 25~30 min for ultrasound) and lower yields (50~68% for reflux stirring and 80~90% for ultrasound). In 2019, Nongrum and her co-workers, with ultrasonic assistance, brought green approach toward the fabrication of benzimidazole scaffolds 56 (Scheme These researchers used meglumine as the green and harmless catalyst for the P Ladenburg reaction. The effect of ultrasound was evaluated by comparing it w cases under the condition of reflux which resulted in a longer reaction time (5 h fo stirring and 25~30 min for ultrasound) and lower yields (50~68% for reflux stirr 80~90% for ultrasound). In 2020, Karami and his co-workers reported a novel nano-catalyst, Co/M ported by GO (Graphene oxide) which was prepared by using metal oxide as a under ultrasound irradiation (Scheme 41) [84]. This reusable nano-catalyst has be to synthesize some benzimidazole from corresponding aldehyde 1,2-phenylene-diamine 56. Compared with applying a thermal condition at 80 ultrasonic way only required room temperature to undergo a reaction with com yields. In 2020, Karami and his co-workers reported a novel nano-catalyst, Co/Mn supported by GO (Graphene oxide) which was prepared by using metal oxide as a carrier under ultrasound irradiation (Scheme 41) [84]. This reusable nano-catalyst has been used to synthesize some benzimidazole from corresponding aldehydes and 1,2-phenylene-diamine 56. Compared with applying a thermal condition at 80 • C, the ultrasonic way only required room temperature to undergo a reaction with comparable yields. ported by GO (Graphene oxide) which was prepared by using metal oxide as a ca under ultrasound irradiation (Scheme 41) [84]. This reusable nano-catalyst has been to synthesize some benzimidazole from corresponding aldehydes 1,2-phenylene-diamine 56. Compared with applying a thermal condition at 80 °C ultrasonic way only required room temperature to undergo a reaction with compar yields.

Scheme 41. Synthesis of 54.
In the same year, Godugu and his colleagues claimed an environmentally be protocol to synthesize 57, with the ancillary ultrasound and natural dolomitic limes catalyst, which was utilized as a heterogenous for the Philips reaction (Scheme 42) They surprisingly found that by employing ultrasound as well as the catalyst, stan refinements were acquired, such as non-toxic catalysts, a short reaction time (10~15 m excellent yields (94~98%), and an uncomplicated isolation of the products. In the same year, Godugu and his colleagues claimed an environmentally benign protocol to synthesize 57, with the ancillary ultrasound and natural dolomitic limestone catalyst, which was utilized as a heterogenous for the Philips reaction (Scheme 42) [85]. They surprisingly found that by employing ultrasound as well as the catalyst, standout refinements were acquired, such as non-toxic catalysts, a short reaction time (10~15 min), excellent yields (94~98%), and an uncomplicated isolation of the products.
to synthesize some benzimidazole from corresponding aldehydes 1,2-phenylene-diamine 56. Compared with applying a thermal condition at 80 °C ultrasonic way only required room temperature to undergo a reaction with compar yields. In the same year, Godugu and his colleagues claimed an environmentally be protocol to synthesize 57, with the ancillary ultrasound and natural dolomitic limes catalyst, which was utilized as a heterogenous for the Philips reaction (Scheme 42) They surprisingly found that by employing ultrasound as well as the catalyst, stan refinements were acquired, such as non-toxic catalysts, a short reaction time (10~15 m excellent yields (94~98%), and an uncomplicated isolation of the products. In 2022, Meeniga et al., emaciated an environmentally benign ionic liquid for the precursors of the synthesis of 2-aryl benzimidazoles 60 under ultrasonication (Scheme 43) [86]. The application of imidazole-and benzimidazole-based ionic liquids as the catalyst of the Phillips-Ladenburg reaction resulted in a brief reaction time (2~10 min), good yields (67~99%), and a great tolerance for various substrates. Compared to the conventional reaction, they sought a method that corresponds with green chemistry principles.
Molecules 2023, 28, x FOR PEER REVIEW yields (67~99%), and a great tolerance for various substrates. Compared to t tional reaction, they sought a method that corresponds with green chemistry p Scheme 43. Synthesis of 60.

Ullmann-Type Reaction
The Ullmann reaction is a broadly used method for carbon-nitrogen bo claimed by Ullmann in 1904 (Scheme 44) [87]. Though limited by large-tim high-energy-cost traditional reaction conditions (requiring copper for the cat high temperature of more than 180 °C), it is widely used for the synthesis of pounds such as imidazole. Though it was widely applied in labs, the classic annoying downsides, such as complex procedures, high pollution, and expen rials.

Ullmann-Type Reaction
The Ullmann reaction is a broadly used method for carbon-nitrogen bond-forming claimed by Ullmann in 1904 (Scheme 44) [87]. Though limited by large-timespan and highenergy-cost traditional reaction conditions (requiring copper for the catalyst and a high temperature of more than 180 • C), it is widely used for the synthesis of some compounds such as imidazole. Though it was widely applied in labs, the classic way shows annoying downsides, such as complex procedures, high pollution, and expensive materials. claimed by Ullmann in 1904 (Scheme 44) [87]. Though limited by large-timespan high-energy-cost traditional reaction conditions (requiring copper for the catalyst a high temperature of more than 180 °C), it is widely used for the synthesis of some pounds such as imidazole. Though it was widely applied in labs, the classic way sh annoying downsides, such as complex procedures, high pollution, and expensive m rials. Scheme 44. The Ullmann-type reaction.

Other Imidazole Synthesis
In 2008, Entezari and his co-workers delved into the synthesis 5-hydroxymethyl-2-mercapto-1-benzylimidazole 66 with an ultrasound-assisted (Scheme 46) [89]. They manipulated the conditions such as temperature and v pressure of the solvent in order to optimize the yields of the reactions, reaching a yie 90% after half an hour at 7°C, while the yields of the traditional trials reached only Scheme 44. The Ullmann-type reaction.
In 2019, Nematpour and her co-workers developed an alternative reaction routine for the novel synthesis of 2-(trichloromethyl)-benzimidazole 64 under ultrasound irradiation, with the aminetrichloroacetonitrile 62 adduct and 1,2-dihalo benzene 63 as the starting materials (Scheme 45) [88]. This improved Ullmann-type reaction only has one-pot, coppercatalyzed, and three-component conditions, offering a series of merits including more affordable raw materials, a short reaction time (30~35 min), and high yields (72~94%).
annoying downsides, such as complex procedures, high pollution, and expensive materials. In 2019, Nematpour and her co-workers developed an alternative reaction routine for the novel synthesis of 2-(trichloromethyl)-benzimidazole 64 under ultrasound irradiation, with the aminetrichloroacetonitrile 62 adduct and 1,2-dihalo benzene 63 as the starting materials (Scheme 45) [88]. This improved Ullmann-type reaction only has one-pot, copper-catalyzed, and three-component conditions, offering a series of merits including more affordable raw materials, a short reaction time (30~35 min), and high yields (72~94%).

Other Imidazole Synthesis
In 2008, Entezari and his co-workers delved into the synthesis of 5-hydroxymethyl-2-mercapto-1-benzylimidazole 66 with an ultrasound-assisted trial (Scheme 46) [89]. They manipulated the conditions such as temperature and vapor pressure of the solvent in order to optimize the yields of the reactions, reaching a yield of 90% after half an hour at 7°C, while the yields of the traditional trials reached only 70% Scheme 45. Synthesis of 64.

Other Imidazole Synthesis
In 2008, Entezari and his co-workers delved into the synthesis of 5-hydroxymethyl-2mercapto-1-benzylimidazole 66 with an ultrasound-assisted trial (Scheme 46) [89]. They manipulated the conditions such as temperature and vapor pressure of the solvent in order to optimize the yields of the reactions, reaching a yield of 90% after half an hour at 7 • C, while the yields of the traditional trials reached only 70% after 72 h. Apparently, applying the ultrasound-assisted procedure properly could achieve a high yield of the product.
Molecules 2023, 28, x FOR PEER REVIEW 25 after 72 h. Apparently, applying the ultrasound-assisted procedure properly c achieve a high yield of the product. In 2011, the Kargar group reported the synthesis of 2-substituted imidazole 6 the dehydrogenation of imidazolines [90]. Under the catalysis of [Mn(TPP)Cl@PSI oxidizing agent NaIO4 effectively promoted the dehydrogenation of 2-substituted i azolines 67 to form the corresponding product 68. This ultrasonic method afforded high yields of 74~94% after 1 h, while the same cases under magnetic stirring obta comparable yields but cost 10 h. In 2012, they continued to develop tetraphenylpor rinatomanganese(III) chloride, [Mn(TPP)Cl], as the catalyst of the oxidation proces those methods, 67 was oxidated by t-BuOOH with great effectiveness via ultrasonic in the presence of Mn(TPP)Cl supported on PSI or SiIm [91]. With a reaction period h, the yields of the Mn(TPP)@PSI-and Mn(TPP)Cl@SiIm-catalyzed reactions 68~90% and 75~95%, respectively. In the next year, researchers ap [Mn(TNH2PP)Cl@MWCNT] as the modified catalyst and NaIO4 as the new oxidant i dehydrogenation of 2-substituted imidazolines 67 [92]. The yields for this appr ranged from 71% to 93%. In these three catalytic systems, a variety of 2-imidaz compounds were effectively converted to the corresponding imidazoles, and all catalysts can be recycled five times without an undesirable loss in activity. Along In 2011, the Kargar group reported the synthesis of 2-substituted imidazole 68 via the dehydrogenation of imidazolines [90]. Under the catalysis of [Mn(TPP)Cl@PSI], the oxidizing agent NaIO 4 effectively promoted the dehydrogenation of 2-substituted imidazolines 67 to form the corresponding product 68. This ultrasonic method afforded 68 in high yields of 74~94% after 1 h, while the same cases under magnetic stirring obtained comparable yields but cost 10 h. In 2012, they continued to develop tetraphenylporphyrinatomanganese(III) chloride, [Mn(TPP)Cl], as the catalyst of the oxidation process. In those methods, 67 was oxidated by t-BuOOH with great effectiveness via ultrasonication in the presence of Mn(TPP)Cl supported on PSI or SiIm [91]. With a reaction period of 1 h, the yields of the Mn(TPP)@PSI-and Mn(TPP)Cl@SiIm-catalyzed reactions were 68~90% and 75~95%, respectively. In the next year, researchers applied [Mn(TNH 2 PP)Cl@MWCNT] as the modified catalyst and NaIO 4 as the new oxidant in the dehydrogenation of 2-substituted imidazolines 67 [92]. The yields for this approach ranged from 71% to 93%. In these three catalytic systems, a variety of 2-imidazoline compounds were effectively converted to the corresponding imidazoles, and all these catalysts can be recycled five times without an undesirable loss in activity. Along with making use of ultrasonic irradiation, complex procedures were simplified, and pollutants were diminished as well as energy was conserved, while yields were increased, and the reaction time was reduced under sonication (Scheme 47).
h, the yields of the Mn(TPP)@PSI-and Mn(TPP)Cl@SiIm-catalyzed reactions w 68~90% and 75~95%, respectively. In the next year, researchers app [Mn(TNH2PP)Cl@MWCNT] as the modified catalyst and NaIO4 as the new oxidant in dehydrogenation of 2-substituted imidazolines 67 [92]. The yields for this appr ranged from 71% to 93%. In these three catalytic systems, a variety of 2-imidazo compounds were effectively converted to the corresponding imidazoles, and all t catalysts can be recycled five times without an undesirable loss in activity. Along making use of ultrasonic irradiation, complex procedures were simplified, and pollut were diminished as well as energy was conserved, while yields were increased, and reaction time was reduced under sonication (Scheme 47). In 2013, Sadjadi and Eskandari published a novel approach to synthesize imidazo[1,2a]azine compounds 71 (Scheme 48) [93], taking the aldehydes 20, trimethyl-silylcyanide (TMSCN) 70, 2-aminopyrimidine or 2-aminopyridine 69 as the starting material. The imidazole scaffold was constructed with significant efficiency via a three-component condensation, facilitated by ultrasonic irradiation and the catalysis of ZnO nano-rods that had been previously prepared from the decomposition of Zn(OAc) 2 ·2H 2 O. Compared to the cases under conventional conditions, the method applying ultrasound irradiation received higher yields (83~90% for ultrasound, 65~76% for reflux, and 70~80% for stirring) and a shorter reaction time (7~12 min for ultrasound, 20~35 min for reflux, and 20~40 min for stirring). The ZnO nano-rod catalyst was able to be reused for three cycles. The reactions using the recycled catalyst obtained great yields of 88%, in addition to the typical features of ultrasound-assisted reactions, including a fast reaction time, a simple operation, and eco-compatibility.
Molecules 2023, 28, x FOR PEER REVIEW 26 plying ultrasound irradiation received higher yields (83~90% for ultrasound, 65~76% reflux, and 70~80% for stirring) and a shorter reaction time (7~12 min for ultraso 20~35 min for reflux, and 20~40 min for stirring). The ZnO nano-rod catalyst was ab be reused for three cycles. The reactions using the recycled catalyst obtained great y of 88%, in addition to the typical features of ultrasound-assisted reactions, includi fast reaction time, a simple operation, and eco-compatibility. In 2014, Khalili and Rimaz offered ultrasound promotion to the synthesis of ( 5)-aryl-2-aryloyl-1H-imidazoles 74 and 75, which were formed by the self-condensa reaction of arylglyoxal hydrates 73 in the presence of ammonium acetate, using wat solvent under irradiation by ultrasound (Scheme 49) [94]. The precursor could be der via the oxidation of acetophenones utilizing SeO2. The application of sonication le higher yields and shorter reaction periods compared to the conventional method. ultrasound-assisted reactions obtained yields of 72~95% in 4 min, while the cases wit ultrasound obtained yields of 55~86% after 45 min. In 2014, Khalili and Rimaz offered ultrasound promotion to the synthesis of (4 or 5)-aryl-2-aryloyl-1H-imidazoles 74 and 75, which were formed by the self-condensation reaction of arylglyoxal hydrates 73 in the presence of ammonium acetate, using water as solvent under irradiation by ultrasound (Scheme 49) [94]. The precursor could be derived via the oxidation of acetophenones utilizing SeO 2 . The application of sonication led to higher yields and shorter reaction periods compared to the conventional method. The ultrasound-assisted reactions obtained yields of 72~95% in 4 min, while the cases without ultrasound obtained yields of 55~86% after 45 min. reaction of arylglyoxal hydrates 73 in the presence of ammonium acetate, using wat solvent under irradiation by ultrasound (Scheme 49) [94]. The precursor could be der via the oxidation of acetophenones utilizing SeO2. The application of sonication le higher yields and shorter reaction periods compared to the conventional method. ultrasound-assisted reactions obtained yields of 72~95% in 4 min, while the cases wit ultrasound obtained yields of 55~86% after 45 min. In 2016, Phakhodee and his co-workers claimed ultrasound could be applied in synthesis method of substituted 2-aminobenzimidazoles 77 (Scheme 50) [95]. zene-1,2-diamine 55 and phenyl isothiocyanates 76 were coupled to create the inte diate mono-thiourea, which was similar to the Phillips-Ladenburg reaction. The i mediate then underwent cyclo-desulfurization via the function of PPh3-I2 system and converted into the product N-aryl-2-aminobenzimidazoles 77. This process was acc ated by ultrasonic irradiation, leading to higher efficiency in both time (10~25 min) yields (76~94%). In addition, benzene-1,2-diamine can be replaced by other sim compounds such as 2-aminophenol in this reaction, which provides a novel metho the construction of 2-amino benzoxazoles and other relative frameworks. In 2016, Phakhodee and his co-workers claimed ultrasound could be applied in the synthesis method of substituted 2-aminobenzimidazoles 77 (Scheme 50) [95]. Benzene-1,2diamine 55 and phenyl isothiocyanates 76 were coupled to create the intermediate monothiourea, which was similar to the Phillips-Ladenburg reaction. The intermediate then underwent cyclo-desulfurization via the function of PPh 3 -I 2 system and was converted into the product N-aryl-2-aminobenzimidazoles 77. This process was accelerated by ultrasonic irradiation, leading to higher efficiency in both time (10~25 min) and yields (76~94%). In addition, benzene-1,2-diamine can be replaced by other similar compounds such as 2-aminophenol in this reaction, which provides a novel method of the construction of 2-amino benzoxazoles and other relative frameworks.
via the oxidation of acetophenones utilizing SeO2. The application of sonication le higher yields and shorter reaction periods compared to the conventional method. ultrasound-assisted reactions obtained yields of 72~95% in 4 min, while the cases wit ultrasound obtained yields of 55~86% after 45 min. In 2016, Phakhodee and his co-workers claimed ultrasound could be applied in synthesis method of substituted 2-aminobenzimidazoles 77 (Scheme 50) [95]. zene-1,2-diamine 55 and phenyl isothiocyanates 76 were coupled to create the inte diate mono-thiourea, which was similar to the Phillips-Ladenburg reaction. The i mediate then underwent cyclo-desulfurization via the function of PPh3-I2 system and converted into the product N-aryl-2-aminobenzimidazoles 77. This process was acc ated by ultrasonic irradiation, leading to higher efficiency in both time (10~25 min) yields (76~94%). In addition, benzene-1,2-diamine can be replaced by other sim compounds such as 2-aminophenol in this reaction, which provides a novel metho the construction of 2-amino benzoxazoles and other relative frameworks. Three years later, Sreenivasulu et.al., published the preparation of pyridine-linked hydrazinylimidazoles 80 (Scheme 51) [96]. This part of the guanidyl group in the substrate can react with 4-substituted benzoyl bromine 79, forming the imidazole heterocycles under the irradiation of ultrasound. In comparison to the classic thermal method, the utilization of sonication resulted in a dramatically more rapid reaction (36~52 min for ultrasound and 300~540 min for reflux) and higher productivity (80~92% for ultrasound and 63~71% for reflux). Moreover, the majority of the products exhibited antimicrobial efficacy in the activity testing, indicating that these compounds could serve as an inspiration for the development of novel antibacterial or antifungal drugs. cles under the irradiation of ultrasound. In comparison to the classic thermal method, th utilization of sonication resulted in a dramatically more rapid reaction (36~52 min fo ultrasound and 300~540 min for reflux) and higher productivity (80~92% for ultrasound and 63~71% for reflux). Moreover, the majority of the products exhibited antimicrobia efficacy in the activity testing, indicating that these compounds could serve as an inspi ration for the development of novel antibacterial or antifungal drugs. Scheme 51. Synthesis of 80.

Conclusions
As mentioned, imidazole derivatives play a pivotal role in pharmaceutical, organic and material chemistry, commensurately boosting a thriving desire for both laboratorie and industrial companies. However, the conventional methods suffer significantly sinc they demonstrate a relatively low yield and are time-costly for most reactions, contrasted with the ultrasound-assisted protocols. The ultrasound-assisted synthesis, which meet the requirement of green chemistry and mitigates the above problems, has attracted mor and more researchers' attention.
Sonochemistry, as a nascent technique, demonstrates surprising advantages in th synthetic process, serving as a dramatical solution to those drawbacks mentioned in tra ditional reactions. Over the past two decades, plenty of new trials applying ultrasound to Scheme 51. Synthesis of 80.

Conclusions
As mentioned, imidazole derivatives play a pivotal role in pharmaceutical, organic, and material chemistry, commensurately boosting a thriving desire for both laboratories and industrial companies. However, the conventional methods suffer significantly since they demonstrate a relatively low yield and are time-costly for most reactions, contrasted with the ultrasound-assisted protocols. The ultrasound-assisted synthesis, which meets the requirement of green chemistry and mitigates the above problems, has attracted more and more researchers' attention.
Sonochemistry, as a nascent technique, demonstrates surprising advantages in the synthetic process, serving as a dramatical solution to those drawbacks mentioned in traditional reactions. Over the past two decades, plenty of new trials applying ultrasound to imidazole synthesis have been published, of which the majority were modified using ultrasonic irradiation on the basis of the classic conventional named reactions. These ultrasound-assisted modified syntheses exhibit excellent promise for the application of synthesis of imidazole compounds, with milder conditions, greater yields, and more significantly, higher atom economy and better eco-compatibility that conform to the principles of green chemistry.
In this review, we comprehensively traced back the enhancement of imidazole synthesis with the ancillary function of ultrasound. In the future, however, the enhancement of some ultrasonic reactions is not remarkable. Their reaction conditions should be further optimized, and more suitable reaction conditions under ultrasound-assisted synthesis, such as temperature, catalyst, oxidant, etc., should be explored or searched for. In addition, other typical imidazole syntheses based on ultrasound-assisted methods have not been reported yet. The optimization for the catalyst with a simpler structure and wider substrate tolerance needs more focus in future directions.
In summary, the ultrasound-assisted technique is able to enhance efficacy and selectivity and reduce cost and pollution. Ultrasound-assisted imidazole synthesis has shown its potential to innovate the field of synthetic chemistry by providing more efficient, ecofriendly, and sustainable approaches to heterocyclic compound synthesis.