catalysts Synthesis of 1,5-Functionalized 1,2,3-Triazoles Using Ionic Liquid/Iron(III) Chloride as an Efﬁcient and Reusable Homogeneous Catalyst

: An efﬁcient, eco-compatible, and very cheap method for the construction of triazoles via eliminative azide–oleﬁn cycloaddition (EAOC) reaction has been developed by a catalytic system, IL/FeCl 3 , offering a highly regioselective approach to structurally diverse 1,5-disubstituted 1,2,3-triazoles in up to 95% yield. This strategy features the reuse of a catalytic system through simple operations. Mechanistic studies indicated that an asynchronous concerted dipolar cycloaddition–elimination process might be involved.


Introduction
Triazoles are five-member N-heterocyclic compounds bearing three nitrogen atoms in the ring. They exist in two isomeric forms, namely, 1,2,3-triazoles and 1,2,4-triazoles, and are an important nucleus for the development of drugs, mainly because they are resistant to oxidation, reduction, and hydrolysis in both acidic and basic conditions because of their aromatic nature [1]. Their active participation in hydrogen bond formation, dipole-dipole, and π-stacking interactions can mimic peptide bonds, enhancing their binding ability with different biological targets [2]. Therefore, triazoles represent a significant class of nitrogen compounds with important biological properties, such as antibacterial, anticancer, antivirus, antimalarial, anti-inflammatory, and antituberculosis [3,4]. In particular, 1,2,3-triazoles have found a broad spectrum of biological applications such as β-lactum antibiotic tazobactum, cefatrizine, and anticancer compound carboxyamidotriazole (CAI), which are some drugs available on the market [5].
Considering the importance of 1,2,3-triazoles and in continuation of our experience in catalysis [22][23][24][25], herein we report the application of FeCl 3 in ionic liquid (ILs) as a reusable homogeneous catalyst system. To our knowledge, this is the first EAOC of nitroolefins by using iron catalyst in ionic liquid.
ILs have recently received a good deal of attention since classical organic reactions, including cycloadditions reactions, can be performed in these media with great advantages (yield and selectivity) as compared to conventional conditions [26][27][28][29][30]. Ionic liquids are distinguished by the advantages pertaining to these solvents, such as no measurable vapor pressure, easy solvent recover/recycle, and high solubility of the Lewis acids in these solvents [31][32][33].
Recently, among the plethora of Lewis acids reported in the literature, iron catalysts have been identified as important and effective catalysts in various organic reactions because of their low price, easy availability, sustainability, nontoxicity, and environmentally friendly characteristics [34][35][36][37][38][39][40].
In this paper, we investigated a number of catalyzed-EAOC reactions of nitroolefins in different ionic liquids and Lewis acids. Finally, we selected the [mpy]OTf/FeCl 3 system considering both the strong coordination of the NO 2 group to the Fe-catalyst and the use of 1-methyl pyridinium trifluoromethanesulfonate ([mpy]OTf) as an ideal reaction medium due the strong stabilization of reaction intermediates. The major advantages of using this ionic liquid are the low cost and the easy one-step preparation through halide-free direct synthesis by adding methyl trifluoromethane sulfonate directly to dry pyridine.

Results
To begin, we chose the cycloaddition reaction between (E)-nitrostyrene 1a and benzylazide 2a in the presence of both imidazolium-based and pyridinium-based ionic liquids and some Lewis acid catalysts as the model system to optimize the reaction conditions for an efficient synthesis of the product 3a (Table 1). In an initial experiment, the reaction was performed in 1-methyl pyridinium trifluoromethanesulfonate ([mpy]OTf) at 60 • C catalyzed by 20 mol % FeCl 3 in a 1:1 ratio of reagents, isolating 1,5-disubstituted triazole 3a in 24% yield after 48-h reaction due to degradation of benzylazide 2a (Table 1, entry 1). The use of 1.2 eq. or 1.5 eq. of azide at 100 • C did not lead to satisfactory results. A doubling of azide concentration revealed an increase of yield to 40% (Table 1, entry 2). Subsequently, when the reaction temperature was raised to 100 • C, the yield of the product improved significantly, also reducing the reaction time (Table 1, entry 3). Any attempt to reduce the amount of catalyst did not provide improvements of the product yield (Table 1, entry 4).
Further screening of Lewis acids (Table 1, entries 5-8) revealed that the optimal results were obtained in the presence of FeCl 3 as catalyst (Table 1, entry 3). Moreover, without any catalyst, the reagents 1a and 2a in same reaction conditions gave the 1,5-disubstituted triazole 3a in very low yield after a long reaction time (Table 1, entry 9). This last result highlights that the catalyst accelerates the reaction by increasing the electrophilicity of the nitroolefin through coordination, but it is not involved in the elimination step.

Discussion
In order to confirm the eliminative azide-olefin cycloaddition (EAOC) mechanism, we investigated the possible reaction pathway.
To gain deeper insight into the mechanism, the reaction was studied at the B3LYP-D3BJ/Def2SVP level of theory to calculate geometries and then single point calculations at the B3LYP-D3BJ/Def2TZVP level of theory were performed (for details, see Supplementary Materials). We studied as a model the reaction between phenyl azide PA and (E)-nitrostyrene NS to give compound 3h. Initially, we calculated the direct cycloaddition between PA and NS without any catalyst to give the two intermediate cycloadducts. We considered two channels corresponding to the obtention of 1,4-(channel 1) and 1,5-adducts (channel 2). Two different relative orientations between the nitroolefin and the azide (endo/exo) were taken into account, thus having a total of four initial approaches (Scheme 2). The different approaches for each regioisomer actually lead to different isomers connected by a pyramidal inversion at the azide nitrogen. The analysis of the optimized transition structures and the corresponding IRCs revealed concerted processes in all cases. The preferred one, TS2x, corresponded to channel 2/exo (energy barrier of 29.3 kcal/mol), with differences of 0.2, 2.1, and 2.3 kcal/mol with respect to channel 2/endo (TS2n), channel 1/endo (TS1n), and channel 1/exo (TS1x), respectively (Scheme 2). Next, we evaluated the same reaction catalyzed by iron(III) chloride, which is coordinated at the nitro group. The same trend was observed for the catalyzed reaction. In the presence of iron(III) chloride, the barrier was reduced to 23.6 kcal/mol ( Figure 1).
Denitration reaction is a well-known process that takes place through the thermal elimination of nitrous acid. The electronic nature of the reaction resembles a typical Cope elimination. Accordingly, a previous de-coordination is required to form P15. A barrier of 22.5 kcal/mol was found, the formation of the final product 3h being thermodynamically favored by 25 kcal/mol ( Figure 1). Consequently, for the iron-catalyzed process, the cycloaddition step is the rate-limiting one and it should be expected that the observed product of the reaction is 3h in agreement with experimental observations. The geometries of TS2x-Fe and TS3 are shown in Figure 2. The geometry of the former reflects the higher asynchronicity of the catalyzed cycloaddition, in which the N1-C5 bond of the triazoline is formed earlier that the N3-C4 bond. According to these findings, it is possible to propose the catalytic cycle illustrated in Scheme 3. The first step of the reaction is the coordination of iron(III) chloride to nitroolefin compound NS to form an activated intermediate NS-Fe that reacts with the azide derivative PA to produce a triazoline intermediate P15-Fe through a transition state TS2n-Fe. The final step consists of the production of FeCl 3 in its original quantity and elimination of HNO 2 to afford the 1,5-disubstituted 1,2,3-triazole 3h via a transition state TS3. Scheme 3. Proposed mechanism of EAOC reaction.
Moreover, considering that the used ionic liquid ([mpy]OTf) was an excellent reaction medium, we suppose that this IL may stabilize the coordinated intermediates by general electrostatic interactions [28,[41][42][43], favoring both the cycloaddition reaction with azide compound and the transformation of triazoline derivative in triazole substrate. In fact, the weak interaction between 1-methyl pyridinium cation and trifluoromethanesulfonate anion due to their dimension favors the possibility for the cation (or anion) to solvate the transition state (ionic coordinated intermediate) [44,45].
The catalytic system IL/FeCl 3 has been analyzed also with respect to recovery and reuse in the reaction between (E)-nitrostyrene 1a and benzylazide 2a and the results are shown in Figure 3. As shown in Figure 3, similar conversions were obtained, showing that the ionic liquid/FeCl 3 system remains active until six cycles and that it can be recovered efficiently in this way.

Materials and Methods
All reagents and commercial ionic liquids were purchased from Sigma-Aldrich (St. Gallen, Switzerland) or Alfa Aesar (Karlsruhe, Germany) and used without purification. Reactions were monitored by TLC using silica plates 60-F264 commercially available from Merck (Darmstadt, Germany). 1 H and 13 C NMR spectra were recorded at 300 and 75 MHz, respectively, in CDCl 3 using tetramethylsilane (TMS) as the internal standard (Bruker (Billerica, MA, USA) ACP 300 MHz). Chemical shifts are given in parts per million and coupling constants in Hertz. LC-MS analyses were carried using an Agilent 6540 UHD Accurate-Mass Q-TOF LC-MS (Agilent, Santa Clara, CA, USA) fitted with a electrospray ionization source (Dual AJS ESI) operating in positive ion mode. Chromatographic separation was achieved using a C18 RP analytical column (Poroshell 120, SB-C18, 50 × 2.1 mm, 2.7 mm) at 30 • C with an elution gradient from 5% to 95% of B over 13 min, a being H 2 O (0.1% FA) and B CH 3 CN (0.1% FA). Flow rate was 0.4 mL min −1 .

General Procedure for Synthesis of 1,5-Disubstituted-1,2,3-Triazoles 3a-n
In a two-necked round bottom flask, equipped with bubble condenser and magnetic stir bar, ionic liquid (5 mL), FeCl 3 (20 mol %), (E)-nitrostyrene 1a-n (1 eq.), and azide 2a-b (2 eq.) were placed. The reaction was conducted at 100 • C for the appropriate time. The crude was extracted with dichloromethane (3 × 5 mL) and the combined organic layer was evaporated under vacuum. The crude product was purified on a flash silica gel column by using hexane/ethyl acetate (9:1 v/v) to obtain the desired product (3a-n). Complete characterization of all products is reported in Appendix A.

Procedure of Recycling of the Catalytic System IL/FeCl 3
After the polar phase was extracted three times by dichloromethane, the ionic liquid/FeCl 3 mixture was washed with hexane and dried at 65 • C under vacuum condition. Successive runs were performed in the recycled ionic liquid/FeCl 3 by reacting fresh reagents at the usual conditions.

Conclusions
In conclusion, we have reported an efficient approach to prepare 1,5-disubstitued-1,2,3-triazole derivatives via FeCl 3 -mediated eliminative azide-olefin cycloadditions (EAOC) in ionic liquid as a solvent. The principle features of this synthetic method are high atom economy, simple operation, high yields, and the reuse of catalytic system IL/FeCl 3 until six cycles. The nature of the Lewis acid and ionic liquid appears to have a large impact to the regiocontrol of the reaction, where the ionic liquid anion might stabilize the cationic transition state, allowing formation of the triazoline intermediate. Theoretical calculations indicate that an asynchronous concerted dipolar cycloaddition-elimination process might be involved in the formation of 1,5-functionalized triazoles. Moreover, they support the hypothesis that the subsequent elimination step to carry out triazoles proceeds without iron coordination.

Data for the Products
All products were characterized by ESI(+)-MS, 1 H and 13 C NMR. The regioisomery was attributed by comparison with literature data [17].