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

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.

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 microwavemediated 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.

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 Cs 2 CO 3 , K 2 CO 3 , and KOtBu, failed to afford the product (Table 1, entry 15). 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  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 methylsubstituted 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 CF 3 group was well tolerated in our optimized conditions, yielding 3d in 73%.However, the NO 2 group delivered the equivalent product 3e in only 24% yield.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.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.
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)), 2thiophenecarboxylic 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.

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.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.
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)  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.
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(PPh 3 ) 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.
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.

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 F 254 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 1 H NMR and 100 MHz for 13 C NMR).Chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance resulting from incomplete deuteration as the internal reference (CDCl 3 : 7.26 ppm, DMSO-d 6 : 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).

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 Na 2 SO 4 .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-2enenitrile in an E/Z mixture (92% yield, 546 mg).

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.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.

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).

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).

Scheme 2 .Scheme 2 .Scheme 2 .
Scheme 2. Scale-up and derivatization.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.

Table 1 .
Optimization of reaction conditions a .

Table 1 .
Optimization of reaction conditions a .

Table 2 .
Substrate scope of acylhydrazides a .

Table 2 .
Substrate scope of acylhydrazides a .

Table 3 .
Substrate scope of enaminonitriles a .

Table 3 .
Substrate scope of enaminonitriles a .