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Article

Regioselective Synthesis of 1,4-Disubstituted-1,2,3-triazole Hybrids Containing Isatin and 1,4-Dihydropyridines Mediated by Ionic Liquid/Water/Cu(I) System

by
Loredana Maiuolo
1,
Paola Costanzo
1,
Antonio Jiritano
1,
Federica Meringolo
1,
Giulia Fiorani
2,
Vincenzo Algieri
3,* and
Antonio De Nino
1,*
1
Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci, Cubo 12C, 87036 Rende, CS, Italy
2
Department of Molecular Sciences and Nanosystems, University Ca’Foscari Venezia, 30172 Mestre, VE, Italy
3
IRCCS NEUROMED—Istituto Neurologico Mediterraneo, Via Atinense, 18, 86077 Pozzilli, IS, Italy
*
Authors to whom correspondence should be addressed.
Reactions 2026, 7(3), 49; https://doi.org/10.3390/reactions7030049
Submission received: 13 July 2026 / Revised: 6 August 2026 / Accepted: 9 August 2026 / Published: 19 August 2026
(This article belongs to the Special Issue Cycloaddition Reactions at the Beginning of the Third Millennium, 2nd Edition)
Browse Figures
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Abstract

In the present work, we report the sustainable regioselective synthesis of a novel series of 1,2,3-triazole-based hybrid molecules containing isatins and 1,4-dihydropyridines by Copper(I)-catalyzed Azide-Alkyne 1,3-dipolar Cycloaddition (CuAAC). Our synthetic strategy provides mild reaction conditions, high reaction yields, a simple recovery procedure, and a reusable catalytic system based on an environmentally benign solvent mixture of ionic liquid/water. The latter was recovered together with the Cu(I) catalyst generated in situ and Na-ascorbate and reused up to six times, maintaining high efficacy in terms of regioselectivity and reaction yields. Finally, a mechanism of the reaction was proposed, involving the key role of IL.

Graphical Abstract

1. Introduction

In modern medicinal chemistry, the development of a new generation of multifunctional therapeutic agents based on hybrid molecules has emerged as an innovative and sustainable strategy [1,2,3,4]. Although classical combination drug therapies have historically proven effective in treating complex diseases [5,6], they show several disadvantages, including increased risk of adverse drug reactions in the patient and complexity in drug formulation and delivery. Recently, a sustainable alternative that integrates two or more pharmacophoric units into a single chemical framework emerged to overcome these limitations [7,8]. Hybrid molecules aim to enhance therapeutic efficacy, minimize side effects, simplify pharmacokinetics, and offer potential multitarget activity [9,10,11]. Among the several heterocycles with acclaimed biological activity [12,13,14], 1,2,3-triazoles have emerged as privileged scaffolds in drug discovery, owing to their synthetic accessibility, chemical stability, low toxicity, high bioavailability, and broad-spectrum biological activity [15,16,17,18]. Furthermore, the triazole ring facilitates strong interactions with biological targets through hydrogen bonding and π-stacking, making it an ideal core in the design of hybrid molecules. Recent advances in hybrid drug development focused on combining 1,2,3-triazoles with other bioactive heterocycles, such as isatins or 1,4-dihydropyridines (1,4-DHPs) [19,20]. Isatin, a versatile oxindole derivative, has been extensively investigated for its anticancer, antibacterial, and antiviral properties [21,22,23], and the presence of functional groups suitable for chemical transformations. In particular, the combination of 1,2,3-triazoles and isatins developed hybrids with antibacterial, anticancer, antioxidant, and free radical scavenging in a single molecular scaffold [24,25,26,27,28,29].
On the other hand, 1,4-DHPs, a class of nitrogen-containing heterocycles [30], are well known for their cardiovascular and antihypertensive properties, particularly as calcium channel blockers (i.e., nifedipine) [31], and are also used as antioxidants, anticancers, neuroprotectives, and antibacterials [32,33]. 1,4-DHP groups in triazole-based hybrids offer several advantages in terms of pharmacological sustainability due to multitargeted action. Furthermore, the 1,4-DHP ring promotes redox modulation by scavenging reactive oxygen species (ROS) and counteracting oxidative stress [34,35,36]. From this context comes our idea to construct oxyndole-1,2,3-triazole-1,4-DHP hybrids that may represent promising multifunctional therapeutic agents with potential and versatile applications in antibacterial, anticancer, and neurodegenerative diseases. In particular, the hypothesis to realize hybrids based on a core of 1,2,3-triazole, and especially the most synthesized 1,4-disubstituted, has been greatly facilitated by Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC) [37,38]. In particular, the 1,4-derivatives form a great number of secondary interactions with the active site of the enzyme target (dipole-dipole interactions, hydrogen bonds, π–stacking, etc.), probably due to their near-linear spatial geometry.
This reaction is highly efficient, regioselective, and works very well under mild conditions and in the presence of a broad range of functional groups without the use of protecting groups [39,40,41]. Some examples of 1,4-disubstituted-1,2,3-triazole-containing hybrids synthesized by CuAAC are reported in Figure 1a [15,16]. Performing organic reactions in alternative and eco-friendly reaction media [42,43] such as ionic liquids (ILs) can represent an additional advantage in CuAAC [44,45,46,47,48]. In fact, their negligible vapor pressure, thermal stability, and non-flammability permit simple post-reaction recycling and safe reaction conditions [49,50,51]. In addition, their ionic nature permits excellent solvation properties and promotes electrostatics-based intermolecular organization at medium range, improving reaction rates [52,53,54]. Considering our highly experience in the synthesis of biologically active heterocycle compounds [55,56,57] and use of eco-friendly conditions [58,59], in this study we report the sustainable synthesis of a novel series of 1,4-disubstituted-1,2,3-triazole-based hybrids that integrate triazoles, substituted isatins and 1,4-dihydropyridine motifs by CuAAC in presence of ionic liquid/water/Cu(I) as an efficient and reusable catalytic system (Figure 1b). This strategy permits us to obtain excellent regioselectivity, elevated yields, and a very good recovery of the catalytic system up to six times without loss of efficiency. More in detail, after a screening between some ILs, the best performances were obtained with 1-methyl pyridinium trifluoromethanesulfonate [mpy]OTf, which was chosen for its easy halogen-free synthesis [58].

2. Results and Discussion

Generally, hybrid molecules are divided into three types: fused, merged, and conjugated [60,61]. In particular, in the latter type, the different pharmacophoric groups are usually separated by a central core that can be constituted by an alkyl chain, an aryl system, a heterocycle, or a combination of them. As already commented, 1,2,3-triazoles can represent a building block strategically useful for their chemical stability and their facile preparation by CuAAC reaction. With the goal of realizing conjugated hybrids with potential biological activity, in this work, we present an innovative and eco-sustainable methodology to synthesize, for the first time, to our knowledge, hybrid molecules with a central 1,4-disubstituted 1,2,3-triazole core linked to two important pharmacophoric groups, such as substituted isatins and 1,4-DHPs.
We innovatively decided to prepare these hybrid molecules with the additional purpose of improving the interactions with the different active sites of biological targets, selecting functional groups of different chemical nature on their skeleton (i.e., ester, carbonyl, amine, amide), and varying the spacers to make the final hybrids more adaptable to the enzymatic cavities.
With such objectives, this study commenced with the evaluation of a suitable synthetic strategy for the construction of the 1,4-disubstituted-1,2,3-triazole-based hybrids described in Figure 1b, and the choice fell on a CuAAC reaction between an azide as a 1,3-dipole and a propargyl derivative as a dipolarophile, to achieve, in a simple manner, the 1,2,3-triazole hybrid (Scheme 1).

2.1. Obtaining Precursors for Hybrid Molecules by CuAAC Reaction: Dipoles and Dipolarophiles

2.1.1. Synthesis of 1,3-Dipoles: N-1-Azidoalkyl-isatins 16–22

In this direction, we started by preparing the appropriate 1,3-dipoles by changing the electronic effect through variation of the substituents. In Scheme 2, we report the synthetic procedure to prepare the N-1-azidoalkyl-isatins 16–22.
The procedure provided the synthesis of intermediate N-haloalkyl derivatives by a modified literature methodology [62]. Considering our extensive experience in syntheses in non-conventional solvents, we performed both reaction steps in an ionic liquid with the purpose of making the whole procedure of hybrid molecule synthesis more efficient. Moreover, we projected the variation of the linkers on this part of the hybrid skeleton for the highly performing alkylation reaction on isatin derivatives.
In detail, suitable isatins 1–3 were reacted with alkyl dihalides 4–8 and anhydrous potassium carbonate in [mPy]OTf at 60 °C to give the corresponding N-1-haloalkyl-isatins 9–15 with excellent yields. As observed in Scheme 2, the presence of different substituents on the C5-position does not seem to deeply affect the reactivity of the isatins 1–3 towards alkylation, considering that comparable yields were observed for all cases. Moreover, an excess of dihalides was used to avoid products of double substitution. The isolated N-1-haloalkyl products 9–15 were subsequently reacted with NaN3 in [mPy]OTf at 60 °C to form corresponding N-1-azidoalkyl-isatins 16–22 in high yields [63].

2.1.2. Synthesis of Dipolarophiles: Propargyloxyphenyl-1,4-dihydropyridines 27–29

Successively, propargyloxyphenyl-1,4-dihydropyridines 27–29 were synthesized as dipolarophiles, and the results are illustrated in Scheme 3.
The synthesis of substituted propargyloxyphenyl-1,4-dihydropyridines 27–29 was conducted via the Hantzsch reaction between ethyl acetoacetate 23 and the prepared aldehydes 24–26, using ammonium chloride as an N-source in aqueous basic media at 60 °C and different reaction times (see Supplementary Materials for experimental details of all intermediates and final products).

2.2. Synthesis of Hybrid Molecules 30–50 by CuAAC Reaction

With the precursors in our hands, we selected the 1,3-dipolar cycloaddition between 1-(2-azidoethyl)isatin 16 and propargyloxyphenyl-1,4-dihydropyridine 27 as a model system to optimize the reaction conditions. To enhance the sustainability and recyclability of our reaction, we explored ionic liquid (IL)/water mixtures as reaction media. In further detail, we investigated the variation of ILs, catalysts, and catalyst molar ratios. Moreover, we applied 65 °C and 5 h for temperature and reaction time, respectively, considering that increasing them did not furnish significant changes. The results are summarized in Table 1.
We initially employed various ILs as solvent and a catalytic system consisting of CuSO4·5H2O (as Cu(II) source) and sodium ascorbate to generate Cu(I) in situ [64].
As can be observed from Table 1 in entries 1–4, changes in the anion of the employed ionic liquid furnished the final compound 30 in good and encouraging yields (71–76%). When we used 1-n-butyl-2,3-dimethylimidazolium hexafluorophosphate ([bdmim]PF6) as solvent, we observed a similar yield (Table 1, Entry 5). To refine the optimal reaction conditions, we examined the system 1-methylpyridinium trifluoromethanesulfonate [mPy]OTf and H2O 9:1 v/v (Table 1, Entry 6), which yielded the desired product in an excellent way (96%). Specifically, we selected 1-methyl pyridinium trifluoromethanesulfonate [mPy]OTf as an ionic liquid also for its easy one-step preparation through halide-free direct synthesis, by adding directly methyltrifluoromethane sulfonate to dry pyridine (see Supplementary Materials). This very high purity provides a more uniform action of the ionic couple of IL, avoiding formation of by-products. The 9:1 ratio of [mPy]OTf/water was derived from our previous evaluation of the minimum water amount to afford better solubilization of this IL, which is still solid at around 60 °C. So, we have maintained the same water amount with other ILs to apply the same reaction conditions. Attempts to lower the catalyst loading led to a significant reduction in yield (Table 1, Entry 7).
Further investigations into copper sources (Table 1, Entries 8–12) confirmed that CuSO4·5H2O combined with sodium ascorbate offers superior performance compared to other Cu(II) or Cu(I) salts in the absence of sodium ascorbate. Therefore, the presence of sodium ascorbate was found to be essential not only for in situ reduction of Cu(II) to Cu(I), but also to suppress re-oxidation.
Finally, to assess the goodness of our method, we performed the model reaction in some of the most used organic solvents for synthesis of hybrid molecules by CuAAC (i.e., DMF, EtOH and t-BuOH) [20]. As you can see in Entries 13–16 of Table 1, the yields obtained in these solvents were lower with respect to our system. Further attempts to improve the yield by enhancing the reaction temperature in DMF failed, with by-product formation observed (Entry 14, Table 1).
It is noteworthy that product 30, as expected, showed complete regioselectivity toward the 1,4-disubstituted isomer.
Then, to fully explore the potential of our reaction protocol, we extended the investigation to all synthesized N-1-azidoalkylisatins 16–22 and propargyloxyphenyl-1,4-dihydropyridines 27–29, constructing 1,4-disubstituted 1,2,3-triazole hybrid molecules 30–50, as summarized in Scheme 4. As you can see, the reaction worked very well in all cases, with a successful transformation of the reagents to yield the desired products in near-quantitative yields, even if with azides 21 and 22 as 1,3-dipoles, a slight reduction in yields was observed, probably due to the increased degree of freedom of selected spacers. It is worth noting that only the 1,4-disubstituted 1,2,3-triazole regioisomer was obtained for all synthesized compounds, demonstrating an elevated regioselectivity.
Finally, with the aim of validating the scalability of our synthetic procedure, the reaction was successfully scaled from milligrams to 5 g, starting from azide 16 and alkyne 27 and affording the product 30 in 96% yield (see Scheme 4), also without any compromise in the regioselectivity. These results confirmed the high quality, scalability, and facile practicality of our developed method.

2.3. Hypothesis of Mechanism

At this stage, we turned our attention to hypothesize a plausible catalytic cycle for our reaction (Scheme 5), analogously to the mechanism proposed by Fokin et al. for the CuAAC reaction [65].
The developed reaction begins with in situ reduction of Cu(II) by sodium ascorbate, generating the catalytically active Cu(I) species (A). The catalytic cycle starts with π-coordination of the Cu(I) complex to the alkyne 27, followed by deprotonation and formation of a σ-bond copper acetylide (C). At this stage, it is plausible to think that the adduct C and azide 16 are completely solvated by the ionic liquid, which plays a crucial role in this fundamental step of cycloaddition, providing for the alignment of the dipole and the dipolarophile on two parallel planes with a highly ordered system and a low degree of entropy. More in detail, the ionic liquids are characterized by a so-called ionic self-assembly (ISA) structure, in which the noncovalent electrostatic interactions act as the primary driving force, and π-π interactions serve as secondary driving forces. Therefore, the combination of cations and anions of IL highly organized in hierarchical superstructures might hold the reagents firmly, favouring their alignment and improving the HOMOdipole/LUMOdipolarophile interaction [66,67,68]. In the subsequent step, β-carbon of acetylide C attacks at N-3 of azide 16 to form the first C-N covalent bond and N-1 of azide coordinates Cu(I), producing the intermediate D. Then, nucleophilic attack of N-1 on α-C of acetylide generates the second C–N covalent bond, forming intermediate E. Final protonation of the copper-bound triazole furnishes the desired 1,4-disubstituted 1,2,3-triazole 30 and regenerates the active Cu(I) catalyst [69,70].

2.4. Recovery and Reuse of Catalytic System

Lastly, the recyclability of the catalytic system [mPy]OTf/H2O/Cu(I) recovered with Na-ascorbate as an insoluble fraction in the extraction phase by diethyl ether was assessed through successive reaction cycles using the model reaction between 1-(2-azidoethyl)isatin 16 and propargyloxyphenyl-1,4-dihydropyridine 27, and the results are reported in Figure 2.
As depicted in Figure 2, the catalytic system maintained high activity and selectivity over six consecutive cycles without appreciable loss in efficiency. Before making any comment, it is necessary to illustrate the reaction workup. In fact, the use of [mPy]OTf, practically insoluble in organic solvents, permits the recovery of the final hybrid in the organic phase, while the [mPy]OTf/H2O/Cu(I) system and sodium ascorbate remain in the polar phase. The latter, washed with diethyl ether, is reused by adding only fresh dipole and dipolarophile in each cycle. It is noteworthy that the Cu(I) remains active considering the presence of excess sodium ascorbate in the recovered polar phase, which prevents the oxidation of Cu(I) to Cu(II) for several consecutive reaction cycles.
These excellent recovery and reuse results, combined with high reaction yields, elevated regioselectivity, low catalyst loading, operational simplicity, and good scalability, highlight the sustainability and practicality of our proposed synthetic method.

3. Materials and Methods

Commercial starting materials were purchased from Merck (Milano, Italy) or Alfa Aesar (Karlsruhe, Germany) and were used without further purification. Reactions were monitored by TLC using silica plates 60-F264, commercially available from Merck (Milano, Italy). Mono- and bidimensional 1H and 13C NMR experiments were recorded at 500 and 125.7 MHz, respectively, in CDCl3 and DMSO-d6 as solvent using tetramethylsilane (TMS) as an internal standard (Bruker Avance 500 MHz with a 5 mm TBO probe, Rheinstetten, Germany). Chemical shifts are given in parts per million and coupling constants in Hertz. Regiochemistry was established by NMR techniques. High-resolution mass spectra (HRMS) were recorded with a Bruker Compact QTOF instrument (Bruker, Billerica, MA, USA). HRMS spectra were acquired in positive ion mode, with a mass resolution of 30,000. Mass calibration was performed with a solution of sodium formate clusters and processed in HPC mode. Spectra acquisition was performed in flow injection, with a full scan mode in the range from 30 to 1000 m/z. N2 was the source of dry gas (V = 4 L/min, T = 180 °C). The ion formula of each compound was calculated with the Smart Formula tool of the Bruker software platform, analyzing the isotopic pattern ratio with 4 mDa mass confidence. All samples were dissolved in CH3CN. Synthesis and characterization of substituted haloalkylisatin 9–15 and azidoalkylisatin 16–22 were realized by modified literature procedures and reported in the Supplementary Materials [62,63]. Propargyloxyphenyl-1,4-dihydropyridines 27–29 and precursors were prepared according to procedures in the literature (see Supplementary Materials for procedures and characterization) [71,72]. [mPy]OTf was prepared according to procedures in the literature (see Supplementary Materials for the synthetic procedure) [73]. Melting points of all intermediates and products were obtained on a Kofler apparatus and compared with literature data, where present [74,75,76,77,78,79,80,81,82].

3.1. General Procedure for Synthesis of 1,4-Disubstituted 1,2,3-Triazole Hybrid Molecules 30–50

In a 25 mL two-necked round-bottom flask, equipped with a bubble condenser and magnetic stir bar, CuSO4·5 H2O (0.033 g, 0.13 mmol, 0.2 eq), sodium ascorbate (0.103 g, 0.522 mmol, 0.8 eq), propargyloxyphenyl-1,4-dihydropyridine 27–29 (0.65 mmol, 1 eq) and azidoalkylisatin 16–22 (0.65 mmol, 1 eq) were mixed with 10 mL of [mPy](OTf)/H2O (9:1 v:v). The reaction was heated at 65 °C for 5 h. The mixture was extracted with ethyl acetate (3 × 20 mL) and the combined organic layer was washed with brine solution (3 × 10 mL), dried with anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude was purified by flash chromatography (CHCl3/MeOH 9:1 v:v), isolating products 30–50 (see Supplementary Materials for the characterization).

3.2. Gram Scale Procedure for Compound 30

In a 500 mL three-necked round-bottom flask equipped with a bubble condenser and magnetic stir bar, CuSO4·5H2O (0.65 g, 2.6 mmol, 0.2 eq), Na-Ascorbate (2.07 g, 10.45 mmol, 0.8 eq), propargyl 1,4-dihydropyridine 27 (5.0 g, 13.05 mmol, 1 eq), and azidoalkylisatin 16 (3.27 g, 13.05 mmol, 1 eq) were mixed with 250 mL of [mPy]OTf/H2O (9:1 v:v). The reaction was heated at 65 °C for 5 h. The mixture was extracted with ethyl acetate (3 × 50 mL), and the combined organic layers were washed with brine solution (3 × 30 mL), dried with anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude was purified by flash chromatography (CHCl3/CH3OH 9:1 v:v), isolating product 30 as an orange solid with 96% yield (7.54 g).

3.3. Recovery and Recycling Procedure for Catalytic System ([mPy]OTf/H2O/Cu(I))

The recovering and recycling procedures were performed on the model reaction between propargyloxyphenyl-1,4-dihydropyridine 27 (0.25 g, 0.65 mmol, 1 eq), azidoalkylisatin 16 (0.141 g, 0.65 mmol, 1 eq), CuSO4 5H2O (0.033 g, 0.13 mmol, 0.2 eq), Na-ascorbate (0.103 g, 0.52 mmol, 0.8 eq), and [mPy]OTf/H2O (9:1 ratio; 10 mL) at 65 °C for 5 h.
At the end of the reaction, the [mPy]OTf/H2O/Cu(I) mixture, also containing sodium ascorbate, recovered as residue insoluble in the extraction phase by ethyl acetate (3 × 10 mL), was washed with diethyl ether (2 × 5 mL) and dried at 50 °C under vacuum conditions (0.15 bar) for 15 min. Successive runs were performed in the recycled system after the addition only of fresh dipole 16 (0.141 gr, 0.65 mmols) and dipolarophile 27 (0.250 g, 0.65 mmols).

4. Conclusions

In this study, a novel library of hybrid molecules, incorporating a 1,2,3-triazole linker between isatin derivatives and dihydropyridine scaffolds, was successfully designed and developed. Initially, seven N-1-azidoalkylisatins and three propargyl-substituted 1,4-dihydropyridines were synthesized in good to excellent yields. These building blocks were subsequently employed in copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reactions to identify optimal, sustainable conditions for the regioselective synthesis of 1,4-disubstituted 1,2,3-triazole hybrids. After optimization of reaction conditions, twenty-one triazole-based hybrid compounds were obtained with high 1,4-regioselectivity and in excellent yields of up to 99%, except for a slight variation (84–88%) probably due to increased degree of freedom of employed spacers. Notably, the use of an ionic liquid/water medium proved critical for both reactivity and selectivity, likely due to its ability to stabilize reaction intermediates and facilitate 1,3-dipolar cycloaddition. Furthermore, the [mPy]OTf/H2O/catalyst system demonstrated high recyclability, maintaining excellent efficiency after multiple cycles, thereby enhancing the sustainability of the reaction. Finally, we performed the gram-scale reaction to verify the potential of our proposed method for wider applications, obtaining the same excellent results as in the testing phase.
In conclusion, we developed a novel protocol to synthesize 1,4-disustituted-1,2,3-triazole hybrids containing isatins and 1,4-dihydropyridines that offers several advantages, including operational simplicity, short reaction times, elevated regioselectivity, negligible formation of by-products, as well as an eco-sustainable approach that is highly reproducible and efficient even on a larger scale.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/reactions7030049/s1; S1: Synthesis of [mPy]OTf; S1–S6: Synthesis of azidoalkylisatins 16–22 and their precursors; S7–S13: Synthesis of 1,4-dihydropyridines 27–29 and their precursors; S13: gram-scale reaction; S14–S22: characterization data of hybrid molecules 30–50; S23–S54: characterization spectra of azidoalkylisatins 19–22 and their precursors (1H NMR, 13C NMR, COSY NMR and HRMS); S55–S78: characterization spectra of 1,4-dihydropyridines 27–29 and their precursors; S79–S163: characterization spectra of hybrid molecules 30–50 (data and spectra 1H NMR, 13C NMR, COSY NMR and HRMS). S164: references.

Author Contributions

Conceptualization, L.M., V.A. and A.D.N.; methodology, A.J., F.M. and V.A.; validation, L.M., P.C. and V.A.; investigation, A.J., F.M. and V.A.; resources, L.M., P.C. and A.D.N.; data curation, G.F. and V.A.; writing—original draft preparation, V.A.; writing—review and editing, L.M., P.C. and A.D.N.; supervision, L.M., P.C. and A.D.N.; funding acquisition, L.M., P.C. and A.D.N. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding authors.

Acknowledgments

The authors would like to acknowledge the University of Calabria for financial support, the Italian Ministry of University and Research (MUR) for a doctoral grant, and the European Union (UE)-Next Generation EU-PNRR M6C2-Investimento 2.1 “Valorizzazione e potenziamento della ricerca bio medica del SSN”, PNRR-MAD-2022-12376295, CUP: F33C22001010006.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. (a) Examples of bioactive 1,4-disubstituted-1,2,3-triazole-based hybrids obtained by Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition. (b) Generic structure of 1,4-disubstituted-1,2,3-triazole-based hybrids synthesized by CuAAC and possible interactions with biological targets.
Figure 1. (a) Examples of bioactive 1,4-disubstituted-1,2,3-triazole-based hybrids obtained by Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition. (b) Generic structure of 1,4-disubstituted-1,2,3-triazole-based hybrids synthesized by CuAAC and possible interactions with biological targets.
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Reactions 07 00049 sch001
Scheme 1. Generic CuAAC reaction to form 1,2,3-triazole-hybrids.
Scheme 1. Generic CuAAC reaction to form 1,2,3-triazole-hybrids.
Reactions 07 00049 sch001
Reactions 07 00049 sch002
Scheme 2. Synthesis of 1,3-dipoles: substituted N-1-azidoalkylisatins 16–22.
Scheme 2. Synthesis of 1,3-dipoles: substituted N-1-azidoalkylisatins 16–22.
Reactions 07 00049 sch002
Reactions 07 00049 sch003
Scheme 3. Synthesis of dipolarophiles: substituted propargyloxyphenyl-1,4-dihydropyridine 27–29.
Scheme 3. Synthesis of dipolarophiles: substituted propargyloxyphenyl-1,4-dihydropyridine 27–29.
Reactions 07 00049 sch003
Reactions 07 00049 sch004aReactions 07 00049 sch004b
Scheme 4. Synthesis of hybrid molecules based on 1,4-disubstituted 1,2,3-triazoles by CuAAC a,b,c. a Reaction conditions: alkyne 27–29 (0.65 mmol, 1 eq), azide 16–22 (0.65 mmol, 1 eq), CuSO4·5H2O (0.033 g, 0.13 mmol, 0.2 eq), Na-ascorbate (0.103 g, 0.52 mmol, 0.8 eq), in [mPy]OTf/H2O 9:1 v/v (10 mL). b Isolated yield. c Gram-scale reaction conditions: alkyne 27 (5.0 g, 13.05 mmol, 1 eq), azide 16 (3.27 g, 13.05 mmol, 1 eq), CuSO4·5H2O (0.65 g, 2.6 mmol, 0.2 eq), Na-ascorbate (2.07 g, 10.45 mmol, 0.8 eq), in [mPy]OTf/H2O 9:1 v/v (250 mL).
Scheme 4. Synthesis of hybrid molecules based on 1,4-disubstituted 1,2,3-triazoles by CuAAC a,b,c. a Reaction conditions: alkyne 27–29 (0.65 mmol, 1 eq), azide 16–22 (0.65 mmol, 1 eq), CuSO4·5H2O (0.033 g, 0.13 mmol, 0.2 eq), Na-ascorbate (0.103 g, 0.52 mmol, 0.8 eq), in [mPy]OTf/H2O 9:1 v/v (10 mL). b Isolated yield. c Gram-scale reaction conditions: alkyne 27 (5.0 g, 13.05 mmol, 1 eq), azide 16 (3.27 g, 13.05 mmol, 1 eq), CuSO4·5H2O (0.65 g, 2.6 mmol, 0.2 eq), Na-ascorbate (2.07 g, 10.45 mmol, 0.8 eq), in [mPy]OTf/H2O 9:1 v/v (250 mL).
Reactions 07 00049 sch004aReactions 07 00049 sch004b
Reactions 07 00049 sch005
Scheme 5. Proposed reaction mechanism for regioselective synthesis of 1,4-disubstituted 1,2,3-triazole hybrid molecules by CuAAC in IL.
Scheme 5. Proposed reaction mechanism for regioselective synthesis of 1,4-disubstituted 1,2,3-triazole hybrid molecules by CuAAC in IL.
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Figure 2. Recovery and reuse of [mPy]OTf/H2O/Cu(I)/Na-ascorbate system until six cycles.
Figure 2. Recovery and reuse of [mPy]OTf/H2O/Cu(I)/Na-ascorbate system until six cycles.
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Table 1. Optimization of reaction conditions for the synthesis of the hybrid 30.
Table 1. Optimization of reaction conditions for the synthesis of the hybrid 30.
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Entry aSolventCatalytic SystemYield b
(%)
Copper Salt
(eq)		Na-Ascorbate
(eq)
1[bmim]OTf/H2O
9:1 		CuSO4·5H2O
(0.2)		0.8 76
2[bmim]Cl/H2O
9:1 		CuSO4·5H2O
(0.2)		0.8 71
3[bmim]BF4/H2O
9:1 		CuSO4·5H2O
(0.2)		0.8 74
4[bmim]lactate/H2O
9:1		CuSO4·5H2O
(0.2)		0.8 73
5[bdmim]PF6/H2O
9:1		CuSO4·5H2O
(0.2)		0.8 70
6[mPy]OTf/H2O
9:1 		CuSO4·5H2O
(0.2)		0.8 96
7 c[mPy]OTf/H2O
9:1 		CuSO4·5H2O
(0.1)		0.4 64
8[mPy]OTf/H2O
9:1 v/v		CuCl2·2 H2O
(0.2)		0.8 87
9[mPy]OTf/H2O
9:1 v/v		CuCl
(0.2)		-64
10[mPy]OTf/H2O
9:1 v/v		CuCl
(0.2)		0.8 84
11[mPy]OTf/H2O
9:1 v/v		CuI
(0.2)		-63
12[mPy]OTf/H2O
9:1 v/v		CuI
(0.2)		0.8 74
13DMFCuSO4·5H2O
(0.2)		0.873
14 dDMFCuSO4·5H2O
(0.2)		0.856
15EtOHCuSO4·5H2O
(0.2)		0.840
16t-BuOHCuSO4·5H2O
(0.2)		0.832
a Reaction conditions: alkyne 27 (0.25 g, 0.65 mmol, 1 eq), azide 16 (0.141 g, 0.65 mmol, 1 eq), copper salt (0.013 mmol, 0.2 eq), Na-ascorbate (0.103 g, 0.52 mmol, 0.8 eq), in solvent (10 mL), 65 °C, 5 h. b Isolated yield. c Reaction conditions: alkyne 27 (0.25 g, 0.65 mmol, 1 eq), azide 16 (0.141 g, 0.65 mmol, 1 eq), CuSO4·5H2O (0.017 g, 0.07 mmol, 0.1 eq), Na-ascorbate (0.052 g, 0.26 mmol, 0.4 eq), in [mPy]OTf/H2O (10 mL), 65 °C, 5 h. d Alkyne 27 (0.25 g, 0.65 mmol, 1 eq), azide 16 (0.141 g, 0.65 mmol, 1 eq), CuSO4·5H2O (0.033 g, 0.13 mmol, 0.2 eq), Na-ascorbate (0.103 g, 0.52 mmol, 0.8 eq), in DMF (10 mL), 85 °C, 5 h.
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Maiuolo, L.; Costanzo, P.; Jiritano, A.; Meringolo, F.; Fiorani, G.; Algieri, V.; De Nino, A. Regioselective Synthesis of 1,4-Disubstituted-1,2,3-triazole Hybrids Containing Isatin and 1,4-Dihydropyridines Mediated by Ionic Liquid/Water/Cu(I) System. Reactions 2026, 7, 49. https://doi.org/10.3390/reactions7030049

AMA Style

Maiuolo L, Costanzo P, Jiritano A, Meringolo F, Fiorani G, Algieri V, De Nino A. Regioselective Synthesis of 1,4-Disubstituted-1,2,3-triazole Hybrids Containing Isatin and 1,4-Dihydropyridines Mediated by Ionic Liquid/Water/Cu(I) System. Reactions. 2026; 7(3):49. https://doi.org/10.3390/reactions7030049

Chicago/Turabian Style

Maiuolo, Loredana, Paola Costanzo, Antonio Jiritano, Federica Meringolo, Giulia Fiorani, Vincenzo Algieri, and Antonio De Nino. 2026. "Regioselective Synthesis of 1,4-Disubstituted-1,2,3-triazole Hybrids Containing Isatin and 1,4-Dihydropyridines Mediated by Ionic Liquid/Water/Cu(I) System" Reactions 7, no. 3: 49. https://doi.org/10.3390/reactions7030049

APA Style

Maiuolo, L., Costanzo, P., Jiritano, A., Meringolo, F., Fiorani, G., Algieri, V., & De Nino, A. (2026). Regioselective Synthesis of 1,4-Disubstituted-1,2,3-triazole Hybrids Containing Isatin and 1,4-Dihydropyridines Mediated by Ionic Liquid/Water/Cu(I) System. Reactions, 7(3), 49. https://doi.org/10.3390/reactions7030049

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