An efficient one-pot and simple multicomponent approach to the synthesis of highly functionalized furans containing dialkyl phenol

In this study, arylglyoxals, acetylacetone, and 2,6-dimethyl phenol or 2,6-di-tert-butyl phenol are combined to efficiently synthesize a series of 1-(4-(3,5-dialkylphenyl)-2-methyl-5-phenylfuran-3-yl) ethan-1-one derivatives in excellent yields. These reactions were carried out in acetone at reflux under catalyst-free conditions in the presence of triethylamine as a base for 3 h. NMR, FT-IR, EI-MS, and elemental studies were used to characterize the products’ structural characteristics. The present study has also several benefits, such as excellent yields and the ease of workup procedure, making it an appealing, practical, and acceptable one-pot method for producing functionalized derivatives of dialkyl furan.


Experimental section 2.1. General information
All the chemicals used in this study were purchased from Merck (Darmstadt, Germany) and Fluka (Buchs, Switzerland) and were used without further purification.Melting points were determined using an Electrothermal 9100 apparatus.The mass spectra were obtained using a GCMS-QP5050A mass spectrometer operating at an ionization potential of 70 eV.Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer.The 1 H and 13 C NMR spectra were recorded using a BRUKER DRX-250 AVANCE instrument with CDCl 3 as the solvent and TMS as the internal standard at frequencies of 250.1 and 62.9 MHz, respectively.The IR spectra of products were measured with an FT-IR Perkin Elmer RXI.

General procedure for the synthesis of products (4a-h)
Arylglyoxal (1 mmol) and acetylacetone (1 mmol) were combined and agitated under reflux in acetone (10 mL) for 1 h.The reaction mixture was then supplemented with Et 3 N (1 mmol) and either 2,6-dimethyl phenol or 2,6-di-tert-butyl phenol (1 mmol) under the same conditions, and stirring was maintained for 2 h.The resulting product was a yellow solid.After the removal of the solvent, the product was rinsed with cold diethyl ether (5 mL).The residue was recrystallized from n-hexane/EtOAc 4:3 to yield 4.
Table 1.Optimization of the reaction conditions for the synthesis of compound 4a.

Synthesis and optimization of reaction conditions
As a model reaction for the synthesis of 1-(4-(4-hydroxy-3,5-dimethylphenyl)-2-methyl-5-phenyl furan-3-yl) ethan-1-one 4a, the one-pot reaction between arylglyoxals (1), acetylacetone (2), and 2,6-dimethylphenol (3) was selected (Table 1).The initial stages of the reaction occurred in water with one equimolar of Et 3 N present at room temperature.TLC was utilized to monitor the progress of the reaction.Upon compilation of the reaction, product 4a was isolated by filtration, yielding an orange powder.The reaction yield was 40%.In order to optimize the reaction conditions, the reaction was conducted in the presence of various bases and solvents.The results were presented in Table 1.As shown in Table 1, in the presence of 1,4-diazabicyclo [2.2.2] octane (DABCO), the reaction yield was 30% (Table 1, entries 1-5).The presence of KOH and K 2 CO 3 in water resulted in poor reaction yields, and pyridine in water did not facilitate the reaction.Consequently, Et 3 N was selected as the proper base for this reaction.The reaction yield could not be increased when using EtOH and CH 2 Cl 2 as solvents (Table 1, entries 6 and 7).Although the reaction yield increased in acetone, as well as in DMSO or CH 3 CN (Table 1, entries 8-10), the rise in acetone was more significant.Further research on the effect of temperature on reaction yield revealed that the reaction yield was higher when carried out in refluxing acetone (Table 1, entry 11).Therefore, the optimal temperature for the synthesis of 1-(4-(4-hydroxy-3,5dimethylphenyl)-2-methyl-5-phenylfuran-3-yl) ethan-1-one 4a is determined to be refluxing.Additionally, employing more Et 3 N did not impact the reaction yield, indicating that one equimolar of Et 3 N is the ideal amount of base for this reaction (Table 1, entries 11 and 12).In this reaction, no detectable byproducts were formed.Along with the desired product, small amounts of acetone-soluble dark materials were formed, which were separated from the main product by filtration.
In Scheme 2, the suggested mechanism for this reaction is depicted.Although the mechanistic specifics of the reaction are unknown, a credible explanation for the generation of product can be proposed.Initially, under reflux conditions for 1 h, arylglyoxal (1) and acetylacetone (2) undergo condensation by the Knoevenagel reaction to yield intermediate (5).Next, the Michael addition of phenol (3) to the intermediate (5) produces reactive 1,4-diketone (6).Triethylamine was used as a base during this stage, and the mixture was agitated under identical conditions for 2 h.The Paal-Knorr cyclization of the given 1,4-diketone yielded (8).Ultimately, this intermediate ( 8) is converted into product (4) via a formal [1,5] hydrogen shift [35].

Conclusion
The research was one of the first to use derivatives of high-function dialkyl furan instead of diene for a simple and easy one-pot synthesis method.In this method, the reaction between arylglyoxals, acetylacetone, 2,6-dimethyl phenol, or 2,6-di-tert-butyl phenol under reflux in the presence of triethylamine was used to yield 1-(4-(3,5-dialkylphenyl)-2methyl-5-phenylfuran-3-yl) ethan-1-one derivatives in excellent yields.The advantages of the present method include a straightforward procedure, an easy workup, a quick reaction time, readily accessible starting ingredients, and simple purification of products without using a chromatography column, which make it a new alternative route to other dialkyl furan syntheses.Scheme 2. The proposed mechanism for the preparation of compounds 4a-h.

Figure .
Figure.Furan-derived natural products and drugs.

Figure .
Figure.Furan-derived natural products and drugs.
[34]R spectrum of 4a, which displayed 21 different resonances.Additionally, product 4a exhibited 13 C NMR resonances for the 4Me, 2C-O, and Me-C=O carbons at 15.3, 19.1, 19.3, 30.2, 149.8, and 157.3 ppm, respectively[34].The 1 H NMR and13C NMR spectra of 4b-h are similar to those of 4a.The FT-IR spectrum of compound 4a showed an absorption band attributable to the carbonyl group at 1716 cm -1 .The mass spectrum of this compound displayed the molecular ion peak at 320 m/z, which is consistent with the proposed structure.