Sustainable synthesis of imidazoles using a catalyst-free approach and ethyl lactate as a bio-based green solvent in the Debus-Japp-Radziszewski reaction

Abstract A highly substituted family of imidazoles is effectively obtained through the Debus-Japp-Radziszewski reaction. In this process, benzil, ammonium acetate, and various benzaldehydes react in a particularly notable solvent: ethyl lactate (EL). This bio-based solvent, derived from biomass fermentation, stands out not only for its sustainable origin but also for its remarkable properties. Ethyl lactate is biodegradable, health-risk-free, is easily recyclable, and is non-corrosive, categorizing it as an exemplary green solvent. The multicomponent reaction, carried out under these conditions, eliminates the need for a catalyst, resulting in products with good yields. The isolation of the products is very simple, requiring only filtration, as they are insoluble in the solvent. In this way, this methodology aligns with various principles of green chemistry, emphasizing the strategic choice of ethyl lactate. This choice has a positive impact on the synthesis of imidazoles, well-known for their pharmacological properties. Graphical Abstract


Introduction
The compounds containing an imidazole nucleus have attracted great interest due to reports in the literature of imidazoles exhibiting various pharmacological and biological activities.Examples include metronidazole and nitrosoimidazole, as bactericides, 1-vinyl-imidazole with fungicidal properties, megazol as a trypanocidal agent, and imidazole-2-one as an anti-leishmaniasis agent, among other antimicrobial activities. [1]n addition, lophine derivatives (2,4,5-triphenyl-1H-imidazole) exhibit an appealing fluorescence attributed to their enduring chemiluminescent properties.Ravichandran and Hariharasubramanian conducted an extensive study of the electrochemical properties of this family of molecules. [2]Studies show that lophine materials can be potential candidates in optoelectronic applications. [2,3]Therefore, this compound family has been considered a synthetically interesting target.
Among the most used reactions, the Debus-Japp-Radziszewski reaction stands out, as it is multicomponent and, therefore, convergent, a highly relevant aspect from the perspective of green chemistry.
Historically, in 1858, Debus [4] reported the synthesis of glyoxaline from the reaction of glyoxal with ammonia.At that time, the author deduced the minimum formula of the compound (C 3 H 4 N 2 ), which we now classify as imidazole.Twenty years later, in 1882, Japp [5][6][7] and Radziszewski [8,9] reported, almost simultaneously, the first synthesis of highly substituted imidazoles through an analogous reaction involving a 1,2-dicarbonyl compound 1, aldehydes 2, and ammonia.The use of this reaction allows the synthesis of imidazole derivatives with a broad structural diversity, depending on the chosen substrates.Furthermore, it is known that the use of primary amines 3 results in the formation of the corresponding N-substituted imidazole derivatives 4. Thus, we can represent, in Scheme 1, the general Debus-Japp-Radziszewski reaction.
Several reaction parameters have been modified with the aim of improving yield and exploring the applicability of the method for obtaining structurally diverse imidazole derivatives using this reaction.Among them are solvent-free reactions using catalysts such as iodine, [10] SBA-Pr-SO 3 H, [11] and ionic liquids. [12]In our group, we contributed to two papers in which we demonstrated the use of green solvents -water and propylene carbonate (PC) -for the synthesis of imidazoles, in the absence of a catalyst. [13,14]We also published an extensive review of this reaction. [15]n this article, we highlight the advantages of applying the Debus-Japp-Radziszewski reaction using ethyl lactate as an environmentally friendly solvent.Ethyl lactate (EL) stands out as a highly suitable choice for a green solvent, meeting various criteria for this classification.Notably, it is 100% biodegradable, health-risk-free, is easily recyclable, non-corrosive, among other highly interesting physical and chemical properties.[18][19][20] Moreover, under the provided conditions, there is no need to use additional catalysts.

Results and discussion
A synthetic method for the preparation of imidazoles based on the Debus-Japp-Radziszewski reaction was developed, using ethyl lactate (EL) as the solvent.The optimization of the reaction was carried out using benzil 5, ammonium acetate 6, and benzaldehyde 7 as a model.The variables studied included temperature versus reaction time (Table 1).
Table 2 shows the comparison of our already optimized methodology (entry 1), using ethyl lactate as a solvent, with conventional methods.The advantages are notable not only regarding the use of a green solvent, but also with respect to catalysts, reaction times, and yields.
Recently, there has been a great deal of effort in the literature toward the search for solvent-and catalyst-free reactions.The use of microwaves is an important tool to achieve good results; however, the reaction times and yields are comparable to those used in the methodology presented in this article.26] Continuing the search for solvent-free methodologies, researchers have utilized mandelic acid as an organo-catalyst in a reaction; however, with more extended reaction times (120 °C, 30 min). [27]Another approach involves using silica chloride as a heterogeneous catalyst in a solvent-free reaction.Nevertheless, the chlorination process of silica gel requires the use of thionyl chloride (SOCl 2 ), known for its high toxicity and challenging operational conditions. [28]hus, we have a potential method for synthesizing imidazoles under mild and environmentally friendly conditions.Based on Table 1, we defined the conditions to study the synthetic scope of the reaction using different aryl aldehydes.Table 3 presents the results obtained in the preparation of the respective 2,4,5-triaryl imidazoles 8a-g from benzil 5, aryl aldehydes 7a-g, and ammonium acetate 6, in the absence of a catalyst.The reaction was carried out at 110 °C using a "one-pot" procedure, with reaction times ranging from 3 to 20 minutes, leading to the production of imidazoles in good yields (46% to 91%).
The reactions were carried out on a scale of 3 mmol of aldehyde, 8 mmol of ammonium acetate, 3 mmol of benzil, and 0.8 mL of EL, in that order.It was observed that the precipitation of the products indicates the end of the reaction.The insolubility of the products in the reaction medium provides a significant advantage in the isolation of the products.The solid obtained in each reaction was filtered and washed with 8a [29] c 6 h 5 5 91 272-273 8b [29] 3-ohc 6 h 4 3 82 270-272 8c [21] 3,4-di-och 3 c 6 h 3 20 89 224-226 8d [30] 3-och 3 -4-ohc 6 h 3 4 89 264-266 8e [31] 4-Brc 6 h 4 6 80 268-269 8f [32] 2-naphthyl 4 46 278-281 8 g [29] 3-no 2 c 6 h 4 3 72 >300 warm distilled water to remove excess EL.Note that at this step, the product is isolated from the reaction medium by simple filtration.This shows potential for solvent recovery on a scale-up.It is interesting to observe that the yields are satisfactory and show little variation with the substituents of the aryl aldehydes.All products were characterized through infrared spectroscopy (IR), nuclear magnetic resonance (NMR), and gas chromatography-mass spectrometry (GC-MS).
It is interesting that the nature of the substituents on the aromatic aldehyde did not notably influence the reaction yield.This phenomenon can be attributed to the precipitation of the product during the reaction's progression, which shifts the reaction equilibrium.Except for product 8f, which is produced from 2-naphthylaldehyde, which can present steric impediment and has a π-system different from aldehydes derived from benzaldehyde.
Articles in the literature indicate the activation of carbonyl compounds, as well as nitrogenous nucleophiles, through hydrogen bonding, thereby favoring addition reactions. [20]However, we propose that the catalytic activity of ethyl lactate in the Debus-Japp-Radziszewski reaction may occur through the generation of the conjugate acid of ethyl lactate by protonation of one of the two basic centers of this solvent, namely, the carbonyl and hydroxyl oxygens.Moreover, this protonation reaction would shift the equilibrium of ammonia generation in situ.Based on this hypothesis, we propose an acidic catalysis as described in the mechanism of Scheme 2.

Conclusions
Highly substituted imidazoles can be obtained through the Debus-Japp-Radziszewski reaction, a multicomponent reaction involving benzil, aryl aldehydes, and ammonium acetate as a nitrogen source, thus constituting a convergent methodology.In the developed methodology, catalysts are not required.Moreover, the developed methodology utilizes a bio-based green solvent -ethyl lactate (EL).The yields are satisfactory and show minimal variation with the substituents of the aryl aldehydes.The isolation work-up involves a simple filtration.All of these attributes encompass several principles of Green Chemistry.

General
Unless otherwise noted, all materials were purchased from commercial suppliers and used without further purification.Reactions were monitored by thin layer chromatography (TLC) with silica gel-coated Merck 60 F254 plates, and compounds were visualized by irradiation with UV light (254 nm).Melting points were determined with a Thomas Model 40 Micro Hot Stage (Kofler-type) melting point apparatus and were corrected.IR spectra were recorded on a Nicolet Magna FT-IR spectrophotometer, and all compounds were examined as KBr pellets.Mass spectra were recorded on a Shimadzu GCMS-QP2010S mass-selective detector interfaced to a capillary gas chromatograph. 1 H-NMR spectra were recorded on 400 or 500 MHz Bruker spectrometers.Chemical shifts are reported in delta (δ) units relative to the singlet of tetramethylsilane (TMS) as the internal standard.Coupling constants are given in Hz.The following abbreviations are used to indicate peak multiplicity: s, singlet; d, doublet; t, triplet; m, multiplet; dd, doublet of doublets; and td, triplet of doublets. 13C-NMR spectra were recorded at 100 MHz or 125 MHz on complete hydrogen decoupling spectrometers.Chemical shifts are reported in delta (δ) units.

Procedure for the synthesis of 8a
In a round-bottom flask equipped with a condenser, a mixture of benzaldehyde (3 mmol), ammonium acetate (8 mmol), and benzil (3 mmol) in ethyl lactate (EL, 0.8 mL) was stirred magnetically in a pre-heated silicone oil bath at 110 °C for 5 minutes. [29]The reaction was monitored by TLC (silica, AcOEt/hexane − 5:1).The resulting precipitate was collected at room temperature, filtered, and washed with warm water.Subsequently, the air-dried solid was washed again with warm hexane.

Table 3 .
Scope of the Debus-Japp-Radziszewski Reaction in eL.

Table 2 .
methodologies in conventional solvents.