Microwave-Mediated, Catalyst-Free Synthesis of 1,2,4-Triazolo[1,5-a]pyridines from Enaminonitriles

Abstract

A catalyst-free, additive-free, and eco-friendly method for synthesizing 1,2,4-triazolo[1,5-a]pyridines under microwave conditions has been established. This tandem reaction involves the use of enaminonitriles and benzohydrazides, a transamidation mechanism followed by nucleophilic addition with nitrile, and subsequent condensation to yield the target compound in a short reaction time. The methodology demonstrates a broad substrate scope and good functional group tolerance, resulting in the formation of products in good-to-excellent yields. Furthermore, the scale-up reaction and late-stage functionalization of triazolo pyridine further demonstrate its synthetic utility. A plausible reaction pathway, based on our findings, has been proposed.

1. Introduction

The synthesis of heterocyclic compounds holds enormous applications in medicinal and pharmaceutical chemistry [1]. Nitrogen-containing heterocyclic compounds are found in numerous natural products exhibiting immense biological activities [2]. Developing sustainable methodologies for the synthesis of fused heterocyclic compounds is an actively pursued area of research. 1,2,4-triazolo[1,5-a]pyridine, with a bridge-headed nitrogen atom, is usually found in medicinal and biologically active compounds [3,4,5,6]. It exhibits numerous activities, including acting as RORγt inverse agonists [7], PHD-1 [8], JAK1 [9], and JAK2 inhibitors [10] (Figure 1). Also, these compounds are utilized in the treatment of cardiovascular disorders [11], type 2 diabetes [12], and hyperproliferative disorders [13]. Additionally, these types of compounds have various applications in the material sciences fields as well [14].

Thus, due to the importance of these compounds, a number of methods have been developed for constructing this useful framework (Scheme 1). In 2009, the Nagasawa group first disclosed a facile synthesis of 1,2,4-triazolo[1,5-a]pyridines from 2-amino pyridine with nitrile in the presence of CuBr via consecutive addition–oxidative cyclization [15]. Subsequently, numerous research groups have achieved the target compound either by using a transition metal catalyst or through the utilization of external oxidants at the stoichiometric level, such as NaClO/base [16], Pb(OAc)₄ [17], and MnO₂ [18]. In 2014, Zhao et al. reported the formation of 1,2,4-triazolo[1,5-a]pyridines through the reaction between 2-aminopyridine and nitriles in the presence of Cu-Zn/Al-Ti, a heterogeneous catalyst system under atmospheric air [19].

Zhao et al. described the PIFA-mediated intramolecular annulation of N-(2-pyridyl)amidine by forming an oxidative N-N bond [20]. In 2015, Chang and coworkers reported the same reaction in an I₂/KI reagent system [21]. On the other hand, Zhang and colleagues reported the same intramolecular annulation under metal- and additive-free electrolytic conditions, utilizing nBu₄Br as both a redox mediator and electrolyte [22]. Bartels et al. developed a CuBr-catalyzed synthesis of 2-amino-triazolopyridine from quanidylpyridines through oxidative cyclization under an air atmosphere [23]. In 2021, Chattopadhyay et al. reported the annulation between 1,2,3,4-tetrazole and nitriles in the presence of a Mn–Porphyrin catalytic system [24]. In 2022, Liu and coworkers developed a mechanochemical method to obtain 1,2,4-triazolo[1,5-a]pyridines by the reaction between azinium-N-imines and nitriles via a [3 + 2] cycloaddition reaction in the presence of copper acetate [25]. Zhuo et al. developed the reaction from 1,2,4-oxadiazol-3-amines and 2-flouropyidines in a basic medium via tandem S_NAr/Boulton–Katritzky rearrangement [26]. Zhuo’s group further developed a palladium-catalyzed tandem reaction between 1,2,4-oxadiazol-3-amines and 2-pyridyl triflate. This cascade reaction proceeds via C-N coupling, followed by Boulton–Kartritzky rearrangement [27]. In 2022, Cao and coworkers reported the reaction of N-iminoisoquinolinium ylides with dioxazolone as an acyl nitrile source in the presence of copper acetate, providing 1,2,4-triazolo[1,5-a]pyridines via C-H amidation and cyclization [28], and so on [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48]. Despite the efficiency of these methods in several aspects, there are still some limitations, including the use of solvent in large quantities, longer reaction times, multistep processes, and, in several cases, the requirement for either metal or external catalysts, which will come out as chemical hazards. To overcome these issues, it is crucial to develop more sustainable methods.

In the past two decades, microwave chemistry has attracted significant attention in synthetic organic chemistry due to its rapidity, reproducibility, and efficiency in shorter timeframes compared to conventional approaches [49,50,51]. Moreover, microwave methods play an important role in reducing unwanted byproducts, eliminating the need for hazardous solvents and mitigating harsh reaction conditions. Considering the green chemistry perspective, these types of reactions are environmentally benign, requiring a minimal amount of solvent, enhancing the reaction rates, and profiting from the cost of the overall process.

The nitrile group is an important precursor capable of being transformed into various molecules via reduction, hydration, hydrolysis, nucleophilic addition, and [3 + 2] cycloaddition, leading to the formation of nitrogen-containing heterocyclic compounds [52,53,54]. Enaminonitrile, in particular, is a highly reactive and versatile intermediate utilized for the synthesis of novel heterocyclic compounds [55]. In the course of our investigation into novel metal-free synthesis in our research group [55,56,57,58,59,60,61], we herein present a microwave-mediated cascade reaction to develop 1,2,4-triazolo[1,5-a]pyridine (3) through the reaction between enaminonitriles (1) and benzohydrazides (2), as depicted in Scheme 1. To the best of our knowledge, there is no report available to date on the synthesis of triazolo pyridine without use of the catalysts or additives.

2. Results and Discussion

In order to find out the optimal reaction conditions, we used enaminonitrile 1m (1.0 equiv.) and 4-methoxybenzohydrazide 2a (2.0 equiv.) as starting materials in toluene, stirring at 120 °C for 24 h. Pleasingly, the expected 1,2,4-triazolo[1,5-a]pyridine 3m was obtained with an 83% yield (Table 1, entry 1). Encouraged by this outcome, and aiming to improve the yield of the reaction, we conducted solvent screening, and the results are summarized in Table 1. Solvents such as THF, DMSO, EtOH, and MeOH did not afford the expected product, while a lower yield was observed in the case of DMF and ACN (Table 1, entries 2–4). Notably, pyridine (76%), xylene (69%), and chlorobenzene (79%) delivered 3m in good yields (Table 1, entries 5–7). To our delight, performing the reaction in dry toluene (86%) and incorporating molecular sieves led to an enhanced yield of 89% under a shorter reaction time of 5 h (Table 1, entries 8, 9). Subsequently, we investigated the impact of varying the equivalence of hydrazide (2a). When the equivalence 2a was reduced from 2.0 equiv. to 1.0 equiv. or 1.5 equiv., the yield of 3a was significantly dropped to 27% and 51%, respectively (Table 1, entries 10, and 11). We also checked the reaction with different additives; the use of TFA afforded a good yield of 79%, and p-TSA resulted in 72% (Table 1, entries 12, and 13). In contrast, the reaction with different bases, including Cs₂CO₃, K₂CO₃, and KOtBu, failed to afford the product (Table 1, entry 15).

After examining various solvents and additives, we conducted further investigations focusing on the role of reaction temperature. Interestingly, when the reaction was performed in a microwave medium at 140 °C, the desired product 3m was obtained with an 89% yield within 3 h (Table 1, entry 16). However, we observed that reducing the temperature from 140 °C resulted in a slightly lower yield at both 100 °C and 120 °C (Table 1, entries 17–18). On the other hand, by increasing the reaction temperature to 160 °C and 180 °C, the reactions were completed in 90 min and 40 min, affording 3m with yields of 81% and 76%, respectively (Table 1, entries 18 and 19). Finally, upon switching to a green solvent such as TBME, a 69% yield of 3m was obtained. Based on the above screening, we have determined that the optimal reaction conditions for this tandem reaction involve using 1 (1.0 equiv.) and 2 (2.0 equiv.) in dry toluene (1.5 mL) under microwave conditions at 140 °C.

With the optimized conditions in hand, we explored the substrate scope of this methodology. Initially, numerous benzohydrazides were reacted with 4-methoxy enaminonitrile under the standard reaction conditions, and the outcomes are summarized in Table 2. Unsubstituted benzohydrazide worked well under this condition, delivering the anticipated product 3a in an 83% yield. EDGs on the benzohydrazide, such as methoxy and methyl-substituted derivatives, were well tolerated, affording the desired triazolopyridines in high yields of 3b-89% and 3c-82%. Substrates containing strong EWG were then examined, and the CF₃ group was well tolerated in our optimized conditions, yielding 3d in 73%. However, the NO₂ group delivered the equivalent product 3e in only 24% yield.

Halogen-containing substrates also efficiently underwent this tandem reaction to deliver the expected products in moderate yields (3f, 41%, 3g, 43%). Similar to the aromatic rings, heteroaromatic compounds such as 3-nicotinic hydrazide (76% (3h)), 2-thiophenecarboxylic acid hydrazide (94% (3i)), and 2-furoic hydrazide (73% (3j)) gave the final products in good-to-excellent yields. Additionally, aliphatic acyl hydrazides are compatible under these reactions and displayed good yields (3k, 67%, and 3l, 46%). Along with optimized microwave reaction conditions, we also carried out the reflux reaction at 120 °C with 100 mg of 3Å MS; almost all the obtained products showed similar yields with microwave conditions but with a slightly prolonged reaction time (details are given in Table 2, in the parenthesis).

Encouraged by these outcomes, we next investigated our standard conditions with various enaminonitriles. Almost all the enaminonitriles successfully delivered the final product in very high yield (Table 3). Enaminonitriles with EDGs such as propyl (80%, 3n) and thiomethyl (71%, 3o) delivered the products in higher yield. EWGs such as nitro groups delivered the corresponding product 3p in a slightly moderate yield of 48%. Enaminonitrile with halogens delivered the equivalent products in excellent yields (3q, 91%; 3r, 94%; 3s, 90%; 3t, 71%; and 3u, 67%). These products have the potential to undergo various expansions through coupling reactions with the halogen functional groups. Similar to Table 2, here also, reflux reactions were conducted for some substrates (at 120 °C with 100 mg of 3Å MS, data are in parenthesis of Table 3), which produced the corresponding products in comparable yields with microwave reaction conditions but required a little extra time to complete.

To further expand the synthetic utility of this method, we conducted a scale-up reaction (Scheme 2). An amount of 1.54 mmol of 1m efficiently reacted with 2.0 equiv. of 2a to afford the corresponding product 3m in 88%. We performed a control experiment to gain a deeper insight into the reaction pathways. In the presence of the radical scavenger BHT, 3m was obtained in an excellent yield of 89%, indicating that this reaction did not go through a radical pathway. From the application point of view, we explored some coupling reactions [62]. Initially, a Suzuki–Miyaura cross-coupling reaction was performed. A triazolopyridine derivative with a bromo functional group (3s) reacted with 4-methoxyphenylboronic acid (4) in the presence of Pd(PPh₃)₄ to afford the coupling product 5 in an 88% yield. Later, we carried out a Sonogashira coupling reaction between the iodo compound (3t) and 4-ethylnylanisole (6), resulting in the coupling product 7 in a 61% yield.

Based on the above results, we propose a reaction pathway to explain the possible formation of product 3 (Scheme 3). Initially, compound 1 undergoes transamidation with 2 to deliver the intermediate A by the removal of dimethyl amine. The nitrogen lone pair attacks the nitrile moiety of A, affording the intermediate B, which subsequently undergoes condensation with the carbonyl group to provide intermediate C. Finally, the elimination of water leads to the formation of the 1,2,4-triazolo[1,5-a]pyridine 3 product.

3. Materials and Methods

3.1. General Information

Unless noted otherwise, all reagents were purchased from commercial sources and used as received. Reaction progress was monitored using thin-layer chromatography (TLC) using silica gel F₂₅₄ plates. Products were purified using flash column chromatography using silica gel 60 (70–230 mesh) or by using the Biotage ‘Isolera One’ system with indicated solvents. NMR spectra were recorded on a Jeol RESONANCE ECZ 400S (400 MHz for ¹H NMR and 100 MHz for ¹³C NMR). Chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance resulting from incomplete deuteration as the internal reference (CDCl₃: 7.26 ppm, DMSO-d₆: 2.5 ppm, 3.33 ppm of water peak) or relative to TMS (δ 0.0). Data are reported as follows: chemical shift δ, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, td = triplet of doublet, ddd = doublet of doublets of doublets, ddt = doublet of doublet of triplets), coupling constants (Hz), number of protons. High-resolution mass spectra (HRMS) were recorded on either Bruker BioSciences maXis 4G or Thermo Vanquish uhplc system. Melting points were recorded in a Stuart Cole-Parmer SMP30 apparatus. All the microwave reactions were conducted in a Biotage initiator+. The parameters were at 140 °C (pressure 0 bar, power 145–160 W), at 160 °C (pressure 1 bar, power 180–200 W), at 180 °C (pressure 2 bar, power 250–265 W), and at 140 °C in TBME (pressure 6 bar, power 175–190 W).

3.2. Typical Procedure for the Preparation of Enaminonitriles [55]

The synthesis of enaminonitriles consists of two steps. The general procedure for step 1, Horner–Wadsworth–Emmons (HWE) reaction with acetophenone: In a 50 mL oven-dried round-bottom flask, sodium hydride (60%, 9.1 mmol, 2.2 equiv.) was added, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, dry tetrahydrofuran (0.5 M) was added, and the mixture was cooled to 0 °C. Diethyl cyanomethylphosphonate (9.1 mmol, 2.2 equiv.) was then slowly added to the reaction mixture and allowed to stir for 30 min. The ice bath was removed, and acetophenone (4.15 mmol, 1.0 equiv.) was added to the reaction mixture, which was then stirred at room temperature. Once the reaction was completed, as monitored using TLC, solvents were evaporated, and the residue was diluted with 30 mL of water. The reaction mixture was extracted three times (20 mL × 3) with ethyl acetate (EtOAc), and the combined organic layers were washed with a sodium chloride (NaCl) solution and dried with Na₂SO₄. The solvent was evaporated to obtain the crude product. Purification was carried out using silica gel chromatography using a hexanes/ethyl acetate (9:1) mixture to yield substituted α,β-unsaturated 3-phenylbut-2-enenitrile in an E/Z mixture (92% yield, 546 mg).

General procedure for step 2, synthesis of enaminonitrile: In a 50 mL oven-dried round-bottom flask, α,β-unsaturated 3-phenylbut-2-enenitrile (0.69 mmol, 1.0 equiv) and NH₄OAc (0.84 mmol, 1.2 equiv.) in DMSO (0.69 mL) were combined, followed by the addition of DMF-DMA (3.49 mmol, 5.0 equiv.). The resulting reaction mixture was stirred at 120 °C until completion, as monitored using TLC. Subsequently, the reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with chloroform (20 mL × 3). The combined organic layers were washed with a saturated NaCl solution, dried over anhydrous Na₂SO₄, and then evaporated. The crude product was purified using silica gel chromatography using a hexanes/ethyl acetate mixture (9:1 to 8:2) to yield the (4E)-5-(dimethylamino)-3-phenylpenta-2,4-dienenitrile (86%, 118 mg).

3.3. Typical Procedure for the Preparation of 1,2,4-triazolo[1,5-a]Pyridines in Microwave Conditions

In an oven-dried microwave vial (0.5–2.0 mL), enaminonitriles (1, 0.175 mmol, 1.0 equiv.) and benzohydrazides (2, 0.35 mmol, 2.0 equiv.) were added. After evacuation and backfilling with nitrogen three times, dry toluene 1.5 mL was added. The reaction vial was then closed and microwave heating was performed at 140 °C. Once the reaction was completed, as indicated by TLC, the reaction mixture was cooled to room temperature and directly purified using silica gel column chromatography using chloroform/ethyl acetate 10:1 as the eluent.

3.4. Typical Procedure for the Preparation of 1,2,4-triazolo[1,5-a]Pyridines in Reflux Conditions

In an oven-dried 25 mL round-bottom flask, enaminonitriles (1, 0.175 mmol, 1.0 equiv.), benzohydrazides (2, 0.35 mmol, 2.0 equiv.), and 100 mg of 3Å MS were added. After evacuation and backfilling with nitrogen three times, dry toluene 2.0 mL was added. Then, Dean–Stark apparatus was fixed and refluxed at 120 °C. Once the reaction was completed, as monitored using TLC, the reaction mixture was cooled to room temperature and directly purified using silica gel column chromatography using chloroform/ethyl acetate 10:1 as the eluent.

3.5. Procedure for the Scale-Up Reaction

In an oven-dried microwave vial (2.0–5.0 mL), enaminonitrile (1m, 1.54 mmol, 1.0 equiv.) and 4-methoxybenzohydrazide (2a, 3.08 mmol, 2.0 equiv.) were added. After evacuation and backfilling with nitrogen three times, 4.0 mL of dry toluene was added. The reaction vial was then closed and microwave heating was performed at 140 °C. Once the reaction was completed, as monitored using TLC, the reaction mixture was cooled to room temperature and directly purified using silica gel column chromatography using chloroform/ethyl acetate 10:1 to afford the 3m in an 88% yield (406 mg).

3.6. Procedure for the Reaction with Radical Scavenger

In an oven-dried microwave vial (0.5–2.0 mL), enaminonitrile (1m, 0.225 mmol, 1.0 equiv.), benzohydrazide (2a, 0.45 mmol, 2.0 equiv.), and BHT (0.09 mmol, 4.0 equiv.) were added. After evacuation and backfilling with nitrogen three times, 2.0 mL of dry toluene was added. The reaction vial was then closed, and microwave heating was performed at 140 °C. Once the reaction was completed, as monitored using TLC, the reaction mixture was cooled to room temperature and directly purified using silica gel column chromatography using chloroform/ethyl acetate (10:1) to afford the 3m in an 89% (60 mg).

3.7. Procedure for the Suzuki–Miyaura Coupling Reaction

A reaction mixture of 7-(4-bromophenyl)-2-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3s, 18.1 mg, 0.0476 mmol, 1.0 equiv.), 4-methoxyphenylboronic acid (4, 14.5 mg, 2.0 equiv.), Pd(PPh₃)₄ (5.5 mg, 0.1 equiv.), and K₂CO₃ (9.9 mg, 1.5 equiv.) in degassed ethanol (1.0 mL) was stirred at 80 °C for 12 h using sand bath. The reaction progress was monitored using TLC, and once the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (10 mL), and washed with brine (5 mL × 2). The aqueous layer was extracted with DCM (10 mL × 2). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure to give the crude product, which was purified using silica gel column chromatography using DCM: EtOAc (0 -> 5%) to afford the coupled product 5 in an 88% yield (17.1 mg) as a pale-yellow solid.

3.8. Procedure for the Sonogashira Coupling Reaction

A mixture of 7-(4-iodophenyl)-2-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3t, 16.1 mg, 0.0377 mmol, 1.0 equiv), 4-ethynylanisole (6, 6.0 mg, 1.2 equiv.), Pd(PPh₃)₂Cl₂ (2.6 mg, 0.1 equiv.), CuI (0.7 mg, 0.1 equiv.), and Et₃N (0.5 mL) in toluene (1.0 mL) was stirred at 100 °C for 9 h under nitrogen atmosphere. The reaction progress was monitored using TLC, and once the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (10mL), and washed with brine (5 mL × 2). The water layer was extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure to give the crude product, which was purified using silica gel column chromatography by using DCM: EtOAc (0 to 5%) to afford the coupled product 7 in 61% yield (9.9 mg) as a pale-yellow solid.

3.9. Anlytical Data of Synthezised Compounds

7-(4-methoxyphenyl)-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (3a)

M.W: yield 82.6% (43.0 mg, SM was used 39.5 mg), reflux: yield 85.1% (39.2 mg, SM was used 39.5 mg); pale yellow solid; mp: 141–143 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.59 (dd, J = 4.6, 2.4 Hz, 1H), 8.32–8.29 (m, 2H), 7.89 (dd, J = 3.2, 0.8 Hz, 1H), 7.65–7.60 (m, 2H), 7.54–7.47 (m, 3H), 7.25 (td, J = 7.9, 2.0 Hz, 1H), 7.04 (dd, J = 5.6, 3.4 Hz, 2H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 160.7, 160.7, 152.0, 130.4, 130.2, 128.9, 128.4, 128.1, 127.5, 114.8, 113.7, 113.6, 112.0, 111.9, 55.6; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₉H₁₆N₃O: 302.1293; Found: 302.1289.

2,7-bis(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3b)

M.W: yield 88.3% (51.2 mg, SM was used 40.0 mg), reflux: yield 88.3% (67.5 mg, SM was used 52.7 mg); pale yellow solid; mp: 188–190 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.56 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 8.8 Hz, 2H), 7.88 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 6.8 Hz, 1H), 7.05–7.01 (m, 4H), 3.88 (s, 3H), 3.88 (S, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 164.0, 161.6, 160.7, 151.7, 143.1, 130.2, 129.0, 128.4, 128.0, 122.9, 114.8, 114.3, 113.5, 111.6, 55.6, 55.5; HRMS (ESI) m/z [M + H]⁺: calcd for C₂₀H₁₈N₃O₂: 332.1399; Found: 332.1393.

7-(4-methoxyphenyl)-2-(p-tolyl)-[1,2,4]triazolo[1,5-a]pyridine (3c)

Yield 81.3% (48.9 mg, SM was used 43.5 mg); yellow solid; mp: 155–157 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.55 (d, J = 6.8 Hz, 1H), 8.18 (d, J = 7.6 Hz, 2H), 7.84 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 7.19 (dd, J = 5.6, 1.6 Hz, 1H), 7.01 (d, J = 8.4 Hz, 2H), 3.86 (S, 3H), 2.41 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 164.7, 160.5, 152.1, 142.6, 140.4, 130.3, 129.6, 128.3, 128.0, 127.9, 127.3, 114.8, 113.3, 111.9, 55.5, 21.6; HRMS (ESI) m/z [M + H]⁺: calcd for C₂₀H₁₈N₃O: 316.1449; Found: 316.1445.

7-(4-methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (3d)

Yield 73.2% (60.3 mg, SM was used 50.8 mg); pale yellow solid; mp: 219–221 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.61 (d, J = 7.2 Hz, 1H), 8.43 (d J = 7.6 Hz, 2H), 7.90 (s, 1H), 7.77 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 161.7, 152.0, 143.3, 139.4, 135.3, 130.1, 129.1, 128.0, 127.1, 123.4, 119.5, 114.4, 113.5, 112.4, 55.5, 21.3. ¹⁹F NMR (376 MHz, CDCl₃): δ -62.7; HRMS (ESI) m/z [M + H]⁺: calcd for C₂₀H₁₅F₃N₃O: 370.1167; Found: 370.1165.

7-(4-methoxyphenyl)-2-(4-nitrophenyl)-[1,2,4]triazolo[1,5-a]pyridine (3e)

M.W: yield 24.0% (5.6 mg, SM was used 15.3 mg), reflux: yield 23.8% (8.6 mg, SM was used 24.0 mg); pale yellow solid; mp: 177–179 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.62 (d, J = 7.2 Hz, 1H), 8.48 (d, J = 8.8 Hz, 2H), 8.36 (d, J = 8.8 Hz, 2H), 7.91 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.33 (dd, J = 5.6, 1.6 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 161.4, 160.0, 151.6, 148.2, 142.0, 136.4, 128.4, 127.9, 127.5, 123.6, 114.4, 113.7, 111.1, 54.9; HRMS (ESI) m/z [M + H]⁺: calcd for C₂₀H₁₅N₄O₃: 347.1144; Found: 347.1135.

2-(4-chlorophenyl)-7-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3f)

M.W: yield 40.8% (28.8 mg, SM was used 48.2 mg), reflux: yield 42.1% (14.5, SM was used 23.5 mg); pale yellow solid; mp: 202–204 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.57 (d, J = 6.4 Hz, 1H), 8.23 (dt, J = 8.8, 2.2 Hz, 2H), 7.86 (q, J = 0.9 Hz, 1H), 7.62 (dt, J = 9.2, 2.6 Hz, 2H), 7.47 (dt, J = 8.8, 2.2 Hz, 2H), 7.26 (dd, J = 4.4, 2.4 Hz, 1H), 7.04 (dt, J = 8.8, 2.7 Hz, 2H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 163.5, 160.7, 152.1, 143.1, 136.4, 130.1, 129.2, 129.2, 128.8, 128.4, 128.0, 114.9, 113.8, 112.0, 55.6; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₉H₁₅ClN₃O: 336.0904; Found: 336.0899.

2-(4-bromophenyl)-7-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3g)

Yield 43.0% (31.3 mg, SM was used 43.8 mg); pale yellow solid; mp: 209–211 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.60 (d, J = 7.2 Hz, 1H), 8.26 (d, J = 9.2 Hz, 2H), 7.91 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.22–7.20 (m, 1H), 7.03 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 163.5, 160.6, 151.2, 140.2, 136.2, 131.5, 128.7, 128.3, 128.0, 123.0, 122.0, 114.0, 112.3, 111.7, 54.9; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₉H₁₅BrN₃O: 380.0398; Found: 380.0390.

7-(4-methoxyphenyl)-2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (3h)

Yield 76.3% (48.4 mg, SM was used 47.8 mg); pale yellow solid; mp: 173–175 °C; ¹H NMR (400 MHz, CDCl₃): δ 9.53 (s, 1H), 8.71 (d, J = 5.2 Hz, 1H), 8.61–8.58 (m, 2H), 7.88 (q, J = 0.9 Hz, 1H), 7.64 (dt, J = 8.8, 2.7 Hz, 2H), 7.48 (dd, J = 5.2, 5.0 Hz, 2H), 7.29 (dd, J = 5.6, 1.8 Hz, 1H), 7.05 (dt, J = 9.2, 2.5 Hz, 2H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 162.2, 160.7, 152.4, 150.3, 148.2, 143.1, 135.2, 130.1, 128.4, 128.1, 127.4, 124.0, 114.9, 114.0, 112.2, 55.6; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₈H₁₅N₄O: 303.1245; Found: 303.1242.

7-(4-methoxyphenyl)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (3i)

M.W: yield 94.1% (57.2 mg, SM was used 45.1 mg), reflux: yield 85.2% (28.0 mg, SM was used 24.4 mg); pale yellow solid; mp: 150–152 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.54 (d, J = 6.8 Hz, 1H), 7.90 (dd, J = 2.8, 0.8 Hz,1H), 7.82 (d, J = 0.8 Hz, 1H), 7.60 (dt, J = 8.4, 2.6 Hz 2H), 7.45 (dd, J = 3.6, 1.4 Hz, 1H), 7.22 (dd, J = 5.2, 1.8 Hz, 1H), 7.17 (dd, J = 3.6, 1.6 Hz, 1H), 7.02 (dt, J = 9.2, 2.4 Hz, 2H), 3.86 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 160.6, 152.0, 143.0, 133.6, 130.1, 128.4, 128.2, 128.0, 127.9, 127.8, 114.8, 113.5, 111.7, 55.5; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₇H₁₄N₃OS: 308.0857; Found: 308.0852.

2-(furan-2-yl)-7-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3j)

Yield 72.5% (46.6 mg, SM was used 50.5 mg); pale yellow solid; mp: 137–139 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.59 (d, J = 6.8 Hz, 1H), 7.87 (s,1H), 7.64–7.62 (m, 3H), 7.30–7.26 (m, 2H), 7.05 (d, J = 6.8 Hz, 2H), 6.60 (s, 1H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 160.7, 157.2, 151.7, 146.1, 144.4, 143.4, 130.1, 128.5, 128.1, 114.8, 113.9, 112.0, 111.9, 111.7, 55.6; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₇H₁₄N₃O₂: 292.1086; Found: 292.1081.

7-(4-methoxyphenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (3k)

M.W: yield 66.7% (30.6 mg, SM was used 43.8 mg), reflux: 65.5% (13.8 mg, SM was used 20.0 mg); brown solid; mp: 192–194 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.47 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 0.8 Hz, 1H), 7.58 (dt, J = 9.2, 2.5 Hz, 2H), 7.17 (dd, J = 5.2, 2.0 Hz, 1H), 7.01 (dt, J = 9.2, 2.6 Hz, 2H), 3.86 (s, 3H), 2.60 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 164.4, 160.6, 151.7, 142.6, 130.3, 128.4, 127.6, 114.7, 112.9, 111.5, 55.5, 14.6; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₄H₁₄N₃O: 240.1136; Found: 240.1131.

2-heptyl-7-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3l)

Yield 46.2% (31.4 mg, SM was used 48.0 mg); pale yellow solid; mp: 224–226 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.47 (d, J = 7.2 Hz, 1H), 7.74 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.15 (dd, J = 5.6, 1.6 Hz, 1H), 7.00 (d, J = 4.4 Hz, 2H), 3.84 (s, 3H), 2.90 (t, J = 7.8 Hz, 2H), 1.86 (p, J = 5.8 Hz, 2H), 1.41–1.26 (m, 9H), 0.85 (t, J = 6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 168.3, 160.5, 151.7, 142.4, 130.4, 128.3, 127.7, 114.7, 112.8, 111.7, 55.5, 31.8, 29.5, 29.2, 29.0, 28.5, 22.7, 14.2; HRMS (ESI) m/z [M + H]⁺: calcd for C₂₀H₂₆N₃O: 324.2075; Found: 324.2070.

2-(4-methoxyphenyl)-7-phenyl-[1,2,4]triazolo[1,5-a]pyridine (3m)

M.W: yield 89.0% (64.9 mg, SM was used 48.0 mg), reflux: yield 89.0% (39.7 mg, SM was used 29.4 mg); pale yellow solid; mp: 179–181 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.60–8.57 (m, 1H), 8.24 (d, J = 8.4 Hz, 2H), 7.90 (s, 1H), 7.69–7.61 (m, 2H), 7.55–7.44 (m, 3H), 7.27–7.23 (m, 1H), 7.03 (dd, J = 6.8, 2.0 Hz, 2H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 164.6, 161.4, 152.0, 143.0, 138.1, 129.4, 129.1, 128.9, 128.0, 127.2, 123.3, 114.2, 113.4, 112.8, 55.5; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₉H₁₆N₃O: 302.1293; Found: 302.1288.

2-(4-methoxyphenyl)-7-(4-propylphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3n)

M.W: yield 80.0% (48.0 mg, SM was used 42.0 mg), reflux: yield 84.1% (24.8 mg, SM was used 20.7 mg); pale yellow solid; mp: 158–160 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.58 (d, J = 7.6 Hz, 1H), 8.24 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 3.88 (s, 3H), 2.66 (t, J = 7.6 Hz, 2H), 2.04 (h, J = 3.6 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 164.5, 161.4, 152.0, 144.1, 143.1, 135.3, 129.5, 128.9, 127.9, 127.0, 123.3, 114.2, 113.4, 112.3, 55.4, 37.8, 24.5, 13.9; HRMS (ESI) m/z [M + H]⁺: calcd for C₂₂H₂₂N₃O: 344.1763; Found: 344.1755.

2-(4-methoxyphenyl)-7-(4-(methylthio)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (3o)

M.W: yield 70.5% (59.0 mg, SM was used 58.8 mg), reflux: yield 54.2% (16.7 mg, SM was used 21.7 mg); pale yellow solid; mp: 201–203 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.57 (d, J = 7.6 Hz, 1H), 8.23 (d, J = 8.0 Hz, 2H), 7.88 (s, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.23–7.21 (m, 1H), 7.01 (d, J = 8.8 Hz, 2H) 3.87 (s, 3H), 2.53 (S, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 164.5, 161.7, 151.9, 142.7, 140.7, 134.6, 129.2, 128.1, 127.5, 127.2, 123.2, 114.4, 113.2, 112.1, 55.5, 15.7; HRMS (ESI) m/z [M + H]⁺: calcd for C₂₀H₁₈N₃OS: 348.1170; Found: 348.1168.

2-(4-methoxyphenyl)-7-(2-nitrophenyl)-[1,2,4]triazolo[1,5-a]pyridine (3p)

M.W: yield 48.2% (27.5, SM was used 40.1 mg), reflux: yield 47.1% (29.0 mg, SM was used 43.3 mg); pale yellow solid; mp: 170–172 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.57 (d, J = 6.8 Hz, 1H), 8.23 (d, J = 9.2 Hz, 2H), 8.04 (d, J = 7.2 Hz 1H), 7.71 (td, J = 7.6, 1.3 Hz, 1H), 7.68 (s, 1H), 7.61 (td, J = 7.6, 1.1 Hz, 1H), 7.50 (dd, J = 6.8, 0.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 5.6, 1.6 Hz, 1H), 3.88 (S, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 164.7, 161.5, 151.4, 148.5, 140.1, 134.0, 133.4, 131.8, 129.8, 129.0, 127.9, 125.0, 123.0, 114.7, 114.3, 114.2, 55.5; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₉H₁₅N₄O₃: 347.1144; Found: 347.1138.

7-(4-fluorophenyl)-2-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3q)

Yield 91.1% (62.8 mg, SM was used 46.6 mg); pale yellow solid; mp: 197–199 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.59 (d, J = 6.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 2H), 7.87 (s, 1H), 7.67–7.63 (m, 2H), 7.23–7.18 (m, 3H), 7.03 (d, J = 9.2 Hz, 2H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 164.8, 164.4, 162.3, 161.6, 151.7, 142.3, 134.2, 129.1, 129.0, 129.0, 128.2, 123.0, 116.4 (d, J = 21.1 Hz), 114.3, 113.4, 112.6, 55.5; ¹⁹F NMR (376 MHz, CDCl₃): δ -112.7; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₉H₁₅FN₃O: 320.1199; Found: 320.1194.

7-(4-chlorophenyl)-2-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3r)

Yield 93.6% (57.4 mg, SM was used 42.5 mg); pale yellow solid; mp: 231–233 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.59 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 2H), 7.89 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 6.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 164.7, 161.8, 151.8, 142.0, 136.6, 135.6, 129.7, 129.2, 128.5, 128.3, 123.2, 114.4, 113.2, 112,9 55.5; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₉H₁₅ClN₃O: 336.0903; Found: 336.0898.

7-(4-bromophenyl)-2-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3s)

Yield 90.1% (58.6 mg, SM was used 47.5 mg); pale yellow solid; mp: 220–222 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.61 (d, J = 6.8 Hz, 1H), 8.23 (dt, J = 8.8, 2.6 Hz, 2H), 7.19 (s, 1H), 7.65 (dt, J = 8.4, 2.0 Hz, 2H), 7.54 (dt, J = 8.4, 2.1 Hz, 2H), 7.19 (dd, J = 5.6, 1.8 Hz, 1H), 7.03 (dt, J = 8.8, 2.5 Hz, 2H), 3.88 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 163.5, 160.6, 151.2, 140.2, 136.1, 131.6, 128.6, 128.3, 128.0, 122.9, 122.0, 114.0, 112.3, 111.6, 54.9; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₉H₁₅BrN₃O: 380.0398; Found: 380.0393.

7-(4-iodophenyl)-2-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3t)

Yield 70.7% (50.1 mg, SM was used 53.9 mg), reflux: yield 75.6% (28.7 mg, SM was used 28.7 mg); pale yellow solid; mp: 228–230 °C; M.W: ¹H NMR (400 MHz, CDCl₃): δ 8.60 (d, J = 6.8 Hz, 1H), 8.23 (dt, J = 9.2, 2.6 Hz, 2H), 7.88 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.20 (dd, J = 5.2, 1.8 Hz, 1H), 7.03 (dt, J = 8.8, 2.4 Hz, 2H), 3.87 (S, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 163.5, 160.6, 151.1, 140.4, 137.5, 136.5, 128.6, 128.3, 128.0, 123.0, 113.9, 112.2, 111.5, 94.6, 54.9; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₉H₁₅IN₃O: 428.0259; Found: 428.0254.

7-(2,5-dichlorophenyl)-2-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3u)

Yield 67% (38.9 mg, SM was used 41.9 mg); pale yellow solid; mp: 225–227 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.60 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.36 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 7.05 (dd, J = 7.2 Hz, J = 2.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 165.1, 161.7, 151.5, 139.9, 139.3, 133.4, 131.7, 131.0, 130.9, 130.0, 129.2, 127.7, 123.4, 116.5, 115.2, 114.4, 55.5; HRMS (ESI) m/z [M + H]⁺: calcd for C₁₉H₁₄Cl₂N₃O: 370.0514; Found: 370.0508.

7-(4′-methoxy-[1,1′-biphenyl]-4-yl)-2-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (5)

Yield 88% (17.1 mg, SM used 18.1 mg); pale yellow solid; mp: 208–210 °C; NMR was conducted at 373 K because of poor solubility of 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.91 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.51 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 163.4, 160.5, 159.0, 151.2, 141.0, 140.0, 134.9, 131.3, 128.1, 127.9, 127.2, 126.9, 126.3, 123.0, 114.2, 113.9, 112.3, 111.1, 54.9, 54.8; HRMS (ESI) m/z [M + H]⁺: calcd for C₂₆H₂₂N₃O₂: 408.1712; Found: 408.1707.

2-(4-methoxyphenyl)-7-(4-((4-methoxyphenyl)ethynyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (7)

Yield 61% (9.9 mg, SM used 16.1 mg); pale yellow solid; mp: 233–235 °C; NMR was conducted at 413 K because of poor solubility of 7. ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.09 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.50 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 163.4, 160.5, 159.3, 151.0, 140.3, 136.3, 132.2, 131.1, 127.9, 127.8, 126.4, 123.0, 122.9, 114.0, 113.9, 113.8, 112.0, 111.4, 90.4, 87.0, 54.8 (two methoxy groups appeared at one peak); HRMS (ESI) m/z [M + H]⁺: calcd for C₂₈H₂₂N₃O₂: 432.1712; Found: 432.1707.

4. Conclusions

We demonstrated a microwave-mediated cascade synthesis of 1,2,4-triazolo [1,5-a]pyridines in good-to-excellent yields. Various enaminonitriles and benzo- and hetero- hydrazides successfully yielded the final products. Additionally, our protocol can be used for scale-up synthesis, and facile transformation of the resulting triazolopyridines was explored. This strategy operates without the need for catalysts, additives, or workups and utilizes a minimal amount of solvent. These features make this methodology highly attractive.

Author Contributions

Formal analysis, writing—original draft preparation, K.L. and Y.-A.K.; investigation, C.J., J.S., S.R., and J.-H.K.; writing—review and editing, conceptualization, supervision, M.V. and J.-K.J. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

Footnotes

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Figure, Schemes and Tables

Figure 1. Representative examples of bioactive 1,2,4-triazolo[1,5-a]pyridines.

Scheme 1. Reported strategies for the synthesis of triazolopyridines and our approach.

Scheme 2. Scale-up and derivatization.

Scheme 3. Plausible mechanism of the synthesis of 1,2,4-triazolo[1,5-a]pyridine.

Table 1

Optimization of reaction conditions ^a.

Scheme 3. Plausible mechanism of the synthesis of 1,2,4-triazolo[1,5-a]pyridine.

Entry	Solvent	Additive	Time (h)	Yield (%) b
1	Toluene		24	83
2	Solvents c		24	NR d
3	DMF		24	20
4	ACN		24	17
5	Pyridine		24	76
6	Xylene		24	69
7	Chlorobenzene		24	79
8	Dry Toluene		12	86
9 e	Dry Toluene	3Å MS	5	89
10 f	Dry Toluene		13	27
11 g	Dry Toluene		26	51
12 h	Dry Toluene	TFA	2	79
13 h	Dry Toluene	p-TSA	1	72
14 h	Dry Toluene	MsOH	0.5	50
15 h	Dry Toluene	Bases i	2	NR
16 j,k	Dry Toluene		3	89
17 l,k	Dry Toluene		6	28
18 m,k	Dry toluene		6	62
19 n,k	Dry Toluene		90 min	81
20 o,k	Dry Toluene		40 min	76
21 p,k	TBME		3	69

^a Unless otherwise mentioned, all reactions were performed in 1m (0.10 mmol, 1.0 equiv.), 2a (0.20 mmol, 2.0 equiv.), and solvent (2.0 mL), stirred at 120 °C under conventional heating for the indicated time. ^b Isolated yield. ^c Solvents: THF, DMSO, EtOH, MeOH. ^d NR—No reaction. ^e An amount of 100 mg of 3Å MS was used. ^f Used 1.0 equiv. of 2a. ^g Used 1.5 equiv. of 2a. ^h An amount of 1.5 equiv. of additive was used and stirred at 140 °C. ⁱ Bases: Cs₂CO₃, K₂CO₃, and KOtBu. ^j Conducted under microwave conditions at 140 °C (pressure 0 bar, power 145–160 W). ^k An amount of 1.5 mL of solvent was used. ^l Conducted under microwave conditions at 100 °C (pressure 1 bar, power 92–105 W). ^m Conducted under microwave conditions at 120 °C (pressure 0 bar, power 105–115 W). ⁿ Conducted under microwave conditions at 160 °C (pressure 1 bar, power 180–200 W). ^o Conducted under microwave conditions at 180 °C (pressure 2 bar, power 250–265 W). ^p Conducted under microwave conditions at 140 °C (pressure 6 bar, power 175–190 W).

Table 2

Substrate scope of acylhydrazides ^a.

Scheme 3. Plausible mechanism of the synthesis of 1,2,4-triazolo[1,5-a]pyridine.

Entry No	Compound Code	R1	Time (h)	Yield (%)	Under Reflux Conditions b
1	3a	phenyl	3.5	83	8 h, 85%
2	3b	4-methoxyphenyl	3	89	6 h, 89%
3	3c	4-tolyl	3	82
4	3d	4-(trifluoromethyl)phenyl	3	74
5	3e	4-nitrophenyl	3.5	24	8 h, 24%
6	3f	4-chlorophenyl	3	41	6 h, 42%
7	3g	4-bromophenyl	3	43
8	3h	3-pyridinyl	3	77
9	3i	2-thiophenyl	2	94	5 h, 85%
10	3j	2-furanyl	2	73
11	3k	methyl	7	67	12 h, 66%
12	3l	heptyl	6	46

^a Reaction conditions: 4-methoxy enaminonitrile (0.2 mmol, 1.0 equiv.), acyl hydrazides (0.40 mmol, 2.0 equiv.), dry toluene (1.5 mL), microwave heating at 140 °C for the indicated time. ^b The reaction was performed under reflux conditions stirred at 120 °C, along with 100 g of 3Å MS in 2.0 mL dry toluene. Isolated yields.

Table 3

Substrate scope of enaminonitriles ^a.

Scheme 3. Plausible mechanism of the synthesis of 1,2,4-triazolo[1,5-a]pyridine.

Entry No	Compound Code	R1	Time (h)	Yield (%)	Under Reflux Conditions b
13	3m	H	3	89
14	3n	4-n-Pr	4.5	80	7 h, 84%
15	3o	4-SMe	3	71	5 h, 54%
16	3p	2-NO2	7	48	25 h, 47%
17	3q	4-F	5	91
18	3r	4-Cl	5	94
19	3s	4-Br	6	90
20	3t	4-I	7	71	12 h, 76%
21	3u	2,5-dichloro	7	67

^a Reaction conditions: enaminonitrile (0.20 mmol, 1.0 equiv.), 4-methoxy benzohydrazide (0.40 mmol, 2.0 equiv.), dry toluene (1.5 mL), microwave heating at 140 °C for the indicated time. ^b The reaction was performed under reflux conditions at 120 °C, along with 100 g of 3Å MS in 2.0 mL dry toluene. Isolated yields.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules29040894/s1. ¹H NMR and ¹³C-NMR are available online.

References

1. Maes, B.W. Microwave-Assisted Synthesis of Heterocycles; Eycken, E.; Kappe, C.O. Springer: Berlin/Heidelberg, Germany, 2006; 155.

2. Henary, M.; Kananda, C.; Rotolo, L.; Savino, B.; Owens, E.A.; Cravotto, G. Benefits and applications of microwave-assisted synthesis of nitrogen containing heterocycles in medicinal chemistry. RSC Adv.; 2020; 10, pp. 14170-14197. [DOI: https://dx.doi.org/10.1039/D0RA01378A]

3. Mohite, P.; Nahar, D.; Pawara, R.; Alqahtani, T.; Eldin, S.M.; Mukherje, N.; Rahman Mohammad Said Al-Tawaha, A.; Iqbal, R.; Bawazeer, S.; Ali, I. Triazolopyridine, a leitmotif of synthetic methods and pharmacological attributes: An extensive review. Arab. J. Chem.; 2023; 16, 105181. [DOI: https://dx.doi.org/10.1016/j.arabjc.2023.105181]

4. Jones, G. The chemistry of the triazolopyridines: An update. Advances in Heterocyclic Chemistry; Academic Press: Cambridge, MA, USA, 2002; Volume 83, pp. 1-70.

5. Vorob’ev, A.Y. Methods of synthesis of [1,2,4]triazolo[1,5-а]pyridines (microreview). Chem. Heterocycl. Compd.; 2019; 55, pp. 695-697. [DOI: https://dx.doi.org/10.1007/s10593-019-02522-5]

6. Fischer, G. Chapter One—Recent advances in 1,2,4-triazolo[1,5-a]pyrimidine chemistry. Advances in Heterocyclic Chemistry; Scriven, E.F.V.; Ramsden, C.A. Academic Press: Cambridge, MA, USA, 2019; Volume 128, pp. 1-101.

7. Nakajima, R.; Oono, H.; Sugiyama, S.; Matsueda, Y.; Ida, T.; Kakuda, S.; Hirata, J.; Baba, A.; Makino, A.; Matsuyama, R. et al. Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists. ACS Med. Chem. Lett.; 2020; 11, pp. 528-534. [DOI: https://dx.doi.org/10.1021/acsmedchemlett.9b00649] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32292560]

8. Ahmed, S.; Ayscough, A.; Barker, G.R.; Canning, H.E.; Davenport, R.; Downham, R.; Harrison, D.; Jenkins, K.; Kinsella, N.; Livermore, D.G. et al. 1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction. J. Med. Chem.; 2017; 60, pp. 5663-5672. [DOI: https://dx.doi.org/10.1021/acs.jmedchem.7b00352] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28594552]

9. Zhou, S.; Mao, W.; Su, Y.; Zheng, X.; Qian, W.; Shen, M.; Shan, N.; Li, Y.; Wang, D.; Wu, S. et al. Identification of TUL01101: A Novel Potent and Selective JAK1 Inhibitor for the Treatment of Rheumatoid Arthritis. J. Med. Chem.; 2022; 65, pp. 16716-16740. [DOI: https://dx.doi.org/10.1021/acs.jmedchem.2c01550] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36512734]

10. Siu, M.; Pastor, R.; Liu, W.; Barrett, K.; Berry, M.; Blair, W.S.; Chang, C.; Chen, J.Z.; Eigenbrot, C.; Ghilardi, N. et al. 2-Amino-[1,2,4]triazolo[1,5-a]pyridines as JAK2 inhibitors. Bioorg. Med. Chem. Lett.; 2013; 23, pp. 5014-5021. [DOI: https://dx.doi.org/10.1016/j.bmcl.2013.06.008] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23870430]

11. Englert, H.; Mania, D.; Wettlaufer, D.; Klaus, E. Arylcarbonylaminoalkyl-dihydro-oxo-pyridines, Their Production and Their Use. U.S. Patent; 5,360,808, 1 November 1994.

12. Edmondson, S.D.; Mastracchio, A.; Mathvink, R.J.; He, J.; Harper, B.; Park, Y.-J.; Beconi, M.; Di Salvo, J.; Eiermann, G.J.; He, H. et al. (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]- pyridin-6-ylphenyl)butanamide:  A Selective α-Amino Amide Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes. J. Med. Chem.; 2006; 49, pp. 3614-3627. [DOI: https://dx.doi.org/10.1021/jm060015t] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16759103]

13. Blake, J.; Lyssikatos, J.P.; Marlow, A.L.; Seo, J.; Wallace, E.; Yang, H.W. Heterocyclic Inhibitors of MEK And Methods of Use Thereof. International Patent; Application No. WO2005051301, 18 May 2006.

14. Song, W.; Shi, L.; Gao, L.; Hu, P.; Mu, H.; Xia, Z.; Huang, J.; Su, J. [1,2,4]Triazolo[1,5-a]pyridine as Building Blocks for Universal Host Materials for High-Performance Red, Green, Blue and White Phosphorescent Organic Light-Emitting Devices. ACS Appl. Mater. Interfaces; 2018; 10, pp. 5714-5722. [DOI: https://dx.doi.org/10.1021/acsami.7b18202] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29368499]

15. Ueda, S.; Nagasawa, H. Facile Synthesis of 1,2,4-Triazoles via a Copper-Catalyzed Tandem Addition−Oxidative Cyclization. J. Am. Chem. Soc.; 2009; 131, pp. 15080-15081. [DOI: https://dx.doi.org/10.1021/ja905056z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19799379]

16. Grenda, V.J.; Jones, R.E.; Gal, G.; Sletzinger, M. Novel Preparation of Benzimidazoles from N-Arylamidines. New Synthesis of Thiabendazole1. J. Org. Chem.; 1965; 30, pp. 259-261. [DOI: https://dx.doi.org/10.1021/jo01012a061]

17. Potts, K.T.; Burton, H.R.; Bhattacharyya, J. 1,2,4-Triazoles. XIII. Derivatives of the s-Triazolo[1,5-a]pyridine Ring System1a. J. Org. Chem.; 1966; 31, pp. 260-265. [DOI: https://dx.doi.org/10.1021/jo01339a058]

18. Raval, J.P.; Desai, K.R. Synthesis and antimicrobial activity of new triazolopyridinyl phenothiazines. ARKIVOC; 2005; 2005, pp. 21-28. [DOI: https://dx.doi.org/10.3998/ark.5550190.0006.d03]

19. Meng, X.; Yu, C.; Zhao, P. An efficient and recyclable heterogeneous catalytic system for the synthesis of 1,2,4-triazoles using air as the oxidant. RSC Adv.; 2014; 4, pp. 8612-8616. [DOI: https://dx.doi.org/10.1039/c3ra47029f]

20. Zheng, Z.; Ma, S.; Tang, L.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. PhI(OCOCF₃)₂-Mediated Intramolecular Oxidative N–N Bond Formation: Metal-Free Synthesis of 1,2,4-Triazolo[1,5-a]pyridines. J. Org. Chem.; 2014; 79, pp. 4687-4693. [DOI: https://dx.doi.org/10.1021/jo500298j] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24746013]

21. Song, L.; Tian, X.; Lv, Z.; Li, E.; Wu, J.; Liu, Y.; Yu, W.; Chang, J. I₂/KI-Mediated Oxidative N–N Bond Formation for the Synthesis of 1,5-Fused 1,2,4-Triazoles from N-Aryl Amidines. J. Org. Chem.; 2015; 80, pp. 7219-7225. [DOI: https://dx.doi.org/10.1021/acs.joc.5b01183]

22. Li, Y.; Ye, Z.; Chen, N.; Chen, Z.; Zhang, F. Intramolecular electrochemical dehydrogenative N–N bond formation for the synthesis of 1,2,4-triazolo[1,5-a]pyridines. Green Chem.; 2019; 21, pp. 4035-4039. [DOI: https://dx.doi.org/10.1039/C9GC01895F]

23. Bartels, B.; Bolas, C.G.; Cueni, P.; Fantasia, S.; Gaeng, N.; Trita, A.S. Cu-Catalyzed Aerobic Oxidative Cyclization of Guanidylpyridines and Derivatives. J. Org. Chem.; 2015; 80, pp. 1249-1257. [DOI: https://dx.doi.org/10.1021/jo502536t]

24. Khatua, H.; Das, S.K.; Roy, S.; Chattopadhyay, B. Dual Reactivity of 1,2,3,4-Tetrazole: Manganese-Catalyzed Click Reaction and Denitrogenative Annulation. Angew. Chem. Int. Ed.; 2021; 60, pp. 304-312. [DOI: https://dx.doi.org/10.1002/anie.202009078]

25. Zhu, B.; Li, W.; Chen, H.; Wu, M.; Hu, J.; Cao, H.; Liu, X. Mechanochemical Synthesis of 1,2,4-Triazoles via a [3+2] Cycloaddition of Azinium-N-Imines and Nitriles. Adv. Synth. Catal.; 2022; 364, pp. 2911-2915. [DOI: https://dx.doi.org/10.1002/adsc.202200463]

26. Li, Z.; Qiu, K.; Yang, X.; Zhou, W.; Cai, Q. Base-Promoted Tandem S_NAr/Boulton–Katritzky Rearrangement: Access to [1,2,4]Triazolo[1,5-a]pyridines. Org. Lett.; 2022; 24, pp. 2989-2992. [DOI: https://dx.doi.org/10.1021/acs.orglett.2c00863]

27. Xiong, H.; Li, Z.; Tang, H.; He, L.; Zhou, W. Tandem C–N coupling/Boulton–Katritzky rearrangement reactions of 3-aminoisoxazoles or 1,2,4-oxadiazol-3-amines with 2-pyridyl trifluoromethanesulfonate: A rapid access to [1,2,4]triazolo[1,5-a]pyridines. Org. Chem. Front.; 2022; 9, pp. 3527-3531. [DOI: https://dx.doi.org/10.1039/D2QO00514J]

28. Liu, X.; Li, W.; Jiang, W.; Lu, H.; Liu, J.; Lin, Y.; Cao, H. Cu(II)-Catalyzed C–H Amidation/Cyclization of Azomethine Imines with Dioxazolones via Acyl Nitrenes: A Direct Access to Diverse 1,2,4-Triazole Derivatives. Org. Lett.; 2022; 24, pp. 613-618. [DOI: https://dx.doi.org/10.1021/acs.orglett.1c04044]

29. Kujur, S.; Verma, S.; Kumar, A.; Sharma, R.; Pathak, D.D. A green polyol approach for the synthesis of Cu₂O NPs adhered on graphene oxide: A robust and efficient catalyst for 1,2,4-triazole and imidazo[1,2-a]pyridine synthesis. New J. Chem.; 2022; 46, pp. 8094-8104. [DOI: https://dx.doi.org/10.1039/D2NJ00831A]

30. Vorob′ev, A.Y.; Borodkin, G.I.; Andreev, R.V.; Shubin, V.G. 1,3-Dipolar cycloaddition of cyanopyridines to heterocyclic N-imines: Experimental and theoretical study. Chem. Heterocycl. Compd.; 2021; 57, pp. 284-291. [DOI: https://dx.doi.org/10.1007/s10593-021-02905-7]

31. Hassen, M.B.; Masmoudi, F.; Zribi, L.; Trigui, M.; Ismaili, L.; Marco-Contelles, J.; Chabchoub, F. Regioselective Synthesis of Novel [1,2,4]Triazolo[1,5-a]pyridine Derivatives. ChemistrySelect; 2021; 6, pp. 945-950. [DOI: https://dx.doi.org/10.1002/slct.202004577]

32. Ibrahim, H.M.; Behbehani, H.; Ahmed Arafa, W.A. A facile, practical and metal-free microwave-assisted protocol for mono- and bis-[1,2,4]triazolo[1,5-a]pyridines synthesis utilizing 1-amino-2-imino-pyridine derivatives as versatile precursors. RSC Adv.; 2020; 10, pp. 15554-15572. [DOI: https://dx.doi.org/10.1039/D0RA02256J] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35495427]

33. Xia, J.; Huang, X.; Cai, M. Heterogeneous Copper(I)-Catalyzed Cascade Addition–Oxidative Cyclization of Nitriles with 2-Aminopyridines or Amidines: Efficient and Practical Synthesis of 1,2,4-Triazoles. Synthesis; 2019; 51, pp. 2014-2022. [DOI: https://dx.doi.org/10.1055/s-0037-1611712]

34. Starosotnikov, A.M.; Bastrakov, M.A.; Knyazev, D.A.; Fedyanin, I.V.; Kachala, V.V.; Dalinger, I.L. Synthesis of N-Bridged 6,8-Dinitrotriazolo[1,5-a]pyridines. ChemistrySelect; 2019; 4, pp. 1510-1515. [DOI: https://dx.doi.org/10.1002/slct.201803068]

35. Nagaraju, T.; Krishna, P.R.; Sridhar, B.; Mangarao, N. PhI(OAc)₂-Mediated Regioselective Synthesis of 5-Guanidino-1,2,4-thiadiazoles and 1,2,4-Triazolo[1,5-a]pyridines via Oxidative N–S and N–N Bond Formation. Synthesis; 2019; 51, pp. 3600-3610. [DOI: https://dx.doi.org/10.1055/s-0037-1611854]

36. Bhatt, A.; Singh, R.K.; Sarma, B.K.; Kant, R. Trichloroisocyanuric acid-mediated synthesis of 1,5-fused 1,2,4-triazoles from N-heteroaryl benzamidines via intramolecular oxidative N–N bond formation. Tetrahedron Lett.; 2019; 60, 151026. [DOI: https://dx.doi.org/10.1016/j.tetlet.2019.151026]

37. Bhatt, A.; Singh, R.K.; Kant, R.; Sarma, B.K. A Convenient Synthesis of 1,5-Fused 1,2,4-Triazoles from N-Arylamidines via Chloramine-T Mediated Intramolecular Oxidative N–N Bond Formation. Synthesis; 2019; 51, pp. 3883-3890. [DOI: https://dx.doi.org/10.1055/s-0037-1611906]

38. Ayothiraman, R.; Bandaru, D.; Paranthaman, R.; Fenster, M.; Eastgate, M.D.; Vaidyanathan, R. T3P-Mediated N–N Cyclization for the Synthesis of 1,2,4-Triazolo[1,5-a]pyridines. Org. Process Res. Dev.; 2019; 23, pp. 2510-2515. [DOI: https://dx.doi.org/10.1021/acs.oprd.9b00396]

39. Lv, J.; He, Z.; Zhang, J.; Guo, Y.; Han, Z.; Bao, X. One-pot synthesis of [1,2,4]Triazolo[1,5-a]pyridines from azines and benzylidenemalononitriles via copper-catalyzed tandem cyclization. Tetrahedron; 2018; 74, pp. 3996-4004. [DOI: https://dx.doi.org/10.1016/j.tet.2018.06.002]

40. Hamdouchi, C.; Maiti, P.; Warshawsky, A.M.; DeBaillie, A.C.; Otto, K.A.; Wilbur, K.L.; Kahl, S.D.; Patel Lewis, A.; Cardona, G.R.; Zink, R.W. et al. Discovery of LY3104607: A Potent and Selective G Protein-Coupled Receptor 40 (GPR40) Agonist with Optimized Pharmacokinetic Properties to Support Once Daily Oral Treatment in Patients with Type 2 Diabetes Mellitus. J. Med. Chem.; 2018; 61, pp. 934-945. [DOI: https://dx.doi.org/10.1021/acs.jmedchem.7b01411]

41. Moloney, H.; Magnus, N.A.; Buser, J.Y.; Embry, M.C. Cyclization of Methyl-Coumalate-Derived Methyl 1-Benzamido-6-oxo-1,6-dihydropyridine-3-carboxylates: Assembly of the [1,2,4]Triazolo[1,5-a]pyridine Ring System. J. Org. Chem.; 2017; 82, pp. 6279-6288. [DOI: https://dx.doi.org/10.1021/acs.joc.7b00873]

42. Mammoliti, O.; Quinton, E.M.; Loones, K.T.J.; Nguyen, A.T.; Wouters, J.; Van Lommen, G. Direct access to 1-aryl-5-amino-1,2,4-triazoles and [1,2,4]triazolo[1,5-a]pyridines by two new single-step reactions from 1,3,4-thiadiazol-2-amines. Tetrahedron; 2013; 69, pp. 1669-1680. [DOI: https://dx.doi.org/10.1016/j.tet.2012.11.101]

43. Zhang, G.; Hu, Y. Synthesis and antitumor activities of 2-(substituted)phenyl-1,2,4-triazolo[1,5-a]pyridines. J. Heterocycl. Chem.; 2007; 44, pp. 919-922. [DOI: https://dx.doi.org/10.1002/jhet.5570440428]

44. Huntsman, E.; Balsells, J. New Method for the General Synthesis of [1,2,4]Triazolo[1,5-a]pyridines. Eur. J. Org. Chem.; 2005; 2005, pp. 3761-3765. [DOI: https://dx.doi.org/10.1002/ejoc.200500247]

45. Guba, W.; Nettekoven, M.; Püllmann, B.; Riemer, C.; Schmitt, S. Comparison of inhibitory activity of isomeric triazolopyridine derivatives towards adenosine receptor subtypes or do similar structures reveal similar bioactivities?. Bioorg. Med. Chem. Lett.; 2004; 14, pp. 3307-3312. [DOI: https://dx.doi.org/10.1016/j.bmcl.2004.03.104]

46. Brodbeck, B.; Püllmann, B.; Schmitt, S.; Nettekoven, M. Parallel iterative solution-phase synthesis of 5-amino-1-aryl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid amide derivatives. Tetrahedron Lett.; 2003; 44, pp. 1675-1678. [DOI: https://dx.doi.org/10.1016/S0040-4039(03)00062-5]

47. Kakehi, A.; Ito, S.; Uchiyama, K.; Konno, Y.; Kondo, K. Thermolysis and photolysis of various N-imidoyliminopyridinium ylides. J. Org. Chem.; 1977; 42, pp. 443-448. [DOI: https://dx.doi.org/10.1021/jo00423a012]

48. Kakehi, A.; Ito, S.; Uchiyama, K.; Konno, Y. Synthesis and Characterization of 1-imidoyliminopyridinium n-ylides. Chem. Lett.; 1976; 5, pp. 413-414. [DOI: https://dx.doi.org/10.1246/cl.1976.413]

49. Fairoosa, J.; Saranya, S.; Radhika, S.; Anilkumar, G. Recent Advances in Microwave Assisted Multicomponent Reactions. ChemistrySelect; 2020; 5, pp. 5180-5197. [DOI: https://dx.doi.org/10.1002/slct.202000683]

50. Kruithof, A.; Ruijter, E.; Orru, R.V.A. Microwave-Assisted Multicomponent Synthesis of Heterocycles. Curr. Org. Chem.; 2011; 15, pp. 204-236. [DOI: https://dx.doi.org/10.2174/138527211793979817]

51. Roberts, B.A.; Strauss, C.R. Toward Rapid, “Green”, Predictable Microwave-Assisted Synthesis. Acc. Chem. Res.; 2005; 38, pp. 653-661. [DOI: https://dx.doi.org/10.1021/ar040278m]

52. Rakshit, A.; Dhara, H.N.; Sahoo, A.K.; Patel, B.K. The Renaissance of Organo Nitriles in Organic Synthesis. Chem. Asian J.; 2022; 17, e202200792. [DOI: https://dx.doi.org/10.1002/asia.202200792] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36047749]

53. Cui, S.Q.; Liao, W.W. Recent Advances in Transition-Metal-Catalyzed C-H Addition to Nitriles. Synthesis; 2022; 54, pp. 33-48.

54. Xia, Y.; Jiang, H.; Wu, W. Recent Advances in Chemical Modifications of Nitriles. Eur. J. Org. Chem.; 2021; 2021, pp. 6658-6669. [DOI: https://dx.doi.org/10.1002/ejoc.202101196]

55. Sim, J.; Viji, M.; Rhee, J.; Jo, H.; Cho, S.J.; Park, Y.; Seo, S.Y.; Jung, K.Y.; Lee, H.; Jung, J.K. γ-Functionalization of α,β-Unsaturated Nitriles under Mild Conditions: Versatile Synthesis of 4-Aryl-2-Bromopyridines. Adv. Synth. Catal.; 2019; 361, pp. 5458-5465. [DOI: https://dx.doi.org/10.1002/adsc.201901002]

56. Jung, C.; Li, S.; Lee, K.; Viji, M.; Lee, H.; Hyun, S.; Lee, K.; Kang, Y.K.; Chaudhary, C.L.; Jung, J.K. Reagent-free intramolecular hydrofunctionalization: A regioselective 6-endo-dig cyclization of o-alkynoylphenols. Green Chem.; 2022; 24, pp. 2376-2384. [DOI: https://dx.doi.org/10.1039/D1GC04848A]

57. Viji, M.; Vishwanath, M.; Sim, J.; Park, Y.; Jung, C.; Lee, S.; Lee, H.; Lee, K.; Jung, J.K. α-Hydroxy acid as an aldehyde surrogate: Metal-free synthesis of pyrrolo[1,2-a]quinoxalines, quinazolinones, and other N-heterocycles via decarboxylative oxidative annulation reaction. RSC Adv.; 2020; 10, pp. 37202-37208. [DOI: https://dx.doi.org/10.1039/D0RA07093A] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35521290]

58. Lee, S.; Sim, J.; Jo, H.; Viji, M.; Srinu, L.; Lee, K.; Lee, H.; Manjunatha, V.; Jung, J.K. Transition metal-free synthesis of quinazolinones using dimethyl sulfoxide as a synthon. Org. Biomol. Chem.; 2019; 17, pp. 8067-8070. [DOI: https://dx.doi.org/10.1039/C9OB01629E] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31451812]

59. Viji, M.; Sim, J.; Li, S.; Lee, H.; Oh, K.; Jung, J.K. Organocatalytic and Regiodivergent Mannich Reaction of Ketones with Benzoxazinones. Adv. Synth. Catal.; 2018; 360, pp. 4464-4469. [DOI: https://dx.doi.org/10.1002/adsc.201800870]

60. Sim, J.; Jo, H.; Viji, M.; Choi, M.; Jung, J.A.; Lee, H.; Jung, J.K. Rapid, Operationally Simple, and Metal-free NBS Mediated One-pot Synthesis of 1,2-Naphthoquinone from 2-Naphthol. Adv. Synth. Catal.; 2018; 360, pp. 852-858. [DOI: https://dx.doi.org/10.1002/adsc.201701312]

61. Choi, M.; Viji, M.; Kim, D.; Lee, Y.H.; Sim, J.; Kwak, Y.S.; Lee, K.; Lee, H.; Jung, J.K. Metal-free approach for the ʟ-proline mediated synthesis of nitrones from nitrosobenzene. Tetrahedron; 2018; 74, pp. 4182-4187. [DOI: https://dx.doi.org/10.1016/j.tet.2018.06.001]

62. Oh, H.; Kim, H.; Kim, I. Regioselective Access to 1,2,4-Triazole-Fused N-Heterocycle, Pyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazine, via Double Dehydrative Cyclizations. J. Org. Chem.; 2023; 88, pp. 11748-11761. [DOI: https://dx.doi.org/10.1021/acs.joc.3c01044]