A Facile and Catalyst-Free Microwave-Promoted Multicomponent Reaction for the Synthesis of Functionalised 1,4-Dihydropyridines With Superb Selectivity and Yields

We report a highly efficient green protocol for developing a novel library of 1,2,4-triazole-tagged 1,4-dihydropyridine analogs through the one-pot process from the four-component fusion of the 1H-1,2,4-triazol-3-amine with different chosen aldehydes, diethyl acetylenedicarboxylate, and active methylene compounds in a water medium under microwave irradiation and catalyst-free conditions. Excellent yields (94–97%) of the target products were achieved with high selectivity with a short reaction time (<12 min) at room temperature. The structures of the synthesized pyrimidine analogs were established by NMR and HRMS spectroscopic analysis. Simple workup, impressive yields, no column chromatography, green solvent, rapid reaction, and excellent functional group tolerance are the benefits of this protocol.


INTRODUCTION
The green chemistry approach employing non-hazardous chemicals and eco-friendly reaction conditions is most motivating in preparing broadly used and pharmacologically significant organic compounds (Kerru et al., 2019a,b). The microwave irradiation (MW) technique mostly applies environmentally benign green technology in heating to speed up the organic reactions for value-added conversions. The MW-assisted organic synthesis has become a powerful tool and an excellent non-conventional approach in the green synthetic methodologies in modern drug discovery programs (Wathey et al., 2002;Mavandadi and Pilotti, 2006). MW induces the growth of oscillation excitation and mass transference in a microwave environment, which produces vigorous heating in reaction vessels, an alternative energy source of chemical reaction for enhanced reaction rate (Polshettiwar and Varma, 2008). Furthermore, the MW technique has attracted considerable interest in organic synthesis due to the higher selectivity, improved product yield, and atom economy, which reduce the by-product generation compared to conventional thermal heating techniques (Khumalo et al., 2019). Therefore, MW-mediated organic synthesis is the preferred green method over unconventional to classical thermal processes for the rapid synthesis of a series of bioactive heterocyclic compounds (Diaz-Ortiz et al., 2019). In recent years, multicomponent reactions (MCR) have also gained eminence as ecofriendly green procedures in synthetic organic chemistry (Kerru et al., 2020a,b). The one-pot processes afford a high atom economy, high functional group tolerance, avoidance of the separation and purification methods, and minimizing the chemical waste (Kerru et al., 2020c,d). Thus, the MCR strategy is an economical approach for the synthesis of libraries of heterocyclic molecules for medicinal chemistry benefits .

EXPERIMENTAL SECTION
General Procedure for the Synthesis of 1,2,4-Triazole-1,4-Dihydropyridine (5a-l) Under Microwave A solution of 1H-1,2,4-triazol-3-amine (1, 0.1 mmol), diethyl acetylenedicarboxylate (2, 0.1 mmol), chosen aldehydes (3a-l, 0.1 mmol), and malononitrile (4, 0.1 mmol) in water solvent (6 mL) were added in a 100 mL volume shielded combination vessel. The reaction mixture was MW aided by exploitation microwave irradiation power (150 W) at room temperature for 10-12 min. The reaction progress was monitored by TLC (Hexane: Ethyl acetate; 70:30). After the completion of the reaction, the reaction mixture was transferred to the beaker. The synthesized solid product was filtered by vacuum before being the product was recrystalised with hot ethanol to offer the corresponding pure product. The structural elucidation of all the novel compounds was accomplished by different spectroscopic methods ( 1 H NMR, 13 C NMR, and HRMS).

RESULTS AND DISCUSSION
To examine the solvent effect and reaction conditions for the synthesis of 1,2,4-triazole tagged 1,4-dihydropyridine 4a on the reaction rate and yield of the desired product and results are illustrated in Tables 1, 2. Initially, the typical reaction between the equimolar mixture of 3-amino-1,2,4-triazole (1), diethyl acetylene dicarboxylate (2), para-methoxy benzaldehyde (3a), and malononitrile (4)   Moreover, water is eco-friendly and inexpensive than the other organic solvents. With water as the solvent, the classical heating reaction required a longer time (1.5 h) and gave 81% of the target product (Table 1, entry 6). The overall results revealed that the microwave irradiation protocol provided high yields of the corresponding products in less time than the classical heating. Thus, water was shown to be the best medium for product yield and reaction time for synthesizing 1,2,4-triazole-tagged 1,4-dihydropyridine scaffolds under microwave irradiation at RT.
Additionally, we investigated the catalysts' ability to enhance the yield. Runs were conducted with NaOH, KOH, Cs 2 CO 3 , K 2 CO 3 , trimethylamine, and ammonium acetate as a catalyst under otherwise similar conditions ( Table 2). Lesser yields were detected under MW (73-94%) for 10 min and under classical heating for 90 min (68-83%) ( Table 2, entries 2-7) as compared to the catalyst-free condition ( Table 2, entry 1). The reaction without catalyst provided superior yields under both conditions. Under these optimized conditions (water and catalyst-free), we explored the scope and efficacy of this procedure, engaging different aldehyde substrates (3a-l) and C-H active compounds, (4) acetylenedicarboxylate (2) and reacting with 3-amino-1,2,4triazole (1) under MW conditions (Scheme 1). A total of 12 of the 1,2,4-triazole-linked 1,4-dihydropyridine analogs (5a-l) were synthesized in excellent yields (94-97%) within a reaction time of <12 min (Table 3), and all were novel compounds. We observed that the different electron-deficient and electron-rich functional groups on the aldehydes' phenyl moiety were welltolerated and performed effectively, offering the desired product's excellent yields.
All the synthesized scaffold structures were elucidated and confirmed by 1 H and 13 C NMR and HRMS spectroscopic analysis (Supplementary Material). For example, the synthesized compound 5a exhibited two prominent signals at δ 4.96 and δ 7.68 ppm due to the CH and NH 2 protons of the 1,4-dihydropyridine moiety. The quartet and triplet peaks appeared at δ 4.38 and δ 2.34 ppm attributed to the acetate (COOCH 2 CH 3 ) group protons. The two singlet signals at δ 6.55 and δ 8.36 ppm are due to the NH and CH protons of the SCHEME 1 | Synthesis of 1,2,4-triazole-1,4-dihydropyridine derivatives (5a-l). 1,2,4-triazole ring moiety. Another singlet was appeared at δ 3.94 ppm belongs to the three protons of the methoxy group (OCH 3 ) on the phenyl ring. The other residual phenyl ring protons appeared at their corresponding aromatic positions in the 1 H NMR spectrum. The acetate moiety's carbonyl carbon exhibited at δ 174.38 and 170.30 ppm in the 13 C NMR spectrum. The HRMS spectrum further confirmed the formation of the condensation product 5a with the molecular-ion peak (M+H) at m/z 439.1517. All the synthesized derivatives were established as the 1,2,4-triazole-linked 1,4-dihydropyridine analogs based on the structural characterization data. Table 4 illustrates the comparison of the results from the proposed green method and literature reported protocols in terms of experimental conditions, reaction time, and yield. An observation of the table's data indicates that eco-friendly solvent water provides superior results under microwave irradiation at RT in all respects compared to the reported methods. Thus, the MW method offers higher yields, excellent selectivity, simple workup, and a rapid reaction under catalyst-free green solvent conditions.

CONCLUSION
We described the procedure for synthesizing 12 novel biologically imperative 1,2,4-triazole-tagged 1,4-dihydropyridine analogs with excellent yields (94-97%) under microwave irradiation conditions. The one-pot reaction between the 3-amino-1,2,4-triazole, diethyl acetylenedicarboxylate, malononitrile, and various selected aldehydes was effectively accomplished in a water medium at RT in <12 min reaction time. The structural elucidation of the synthesized derivatives was achieved by HRMS, 1 H, and 13 C NMR spectral analysis. The method's various benefits are catalyst-free and show swift reactions, high selectivity, excellent yields, green solvents, and avoidance of column chromatography and hazardous reagents.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

AUTHOR CONTRIBUTIONS
NK performed experimental studies and wrote the original draft. SM performed validation and spectral characterization of synthesized molecules. SJ designed project planning, proofreading, and editing. All authors contributed to the article and approved the submitted version.