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Article

Regioselective Synthesis of NO-Donor (4-Nitro-1,2,3-triazolyl)furoxans via Eliminative Azide–Olefin Cycloaddition

by
Irina A. Stebletsova
1,2,
Alexander A. Larin
1,
Ivan V. Ananyev
3 and
Leonid L. Fershtat
1,*
1
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospect, 119991 Moscow, Russia
2
D.I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Square, 125047 Moscow, Russia
3
N.S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, GSP-1, Leninsky Prospect, 31, 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(19), 6969; https://doi.org/10.3390/molecules28196969
Submission received: 1 September 2023 / Revised: 29 September 2023 / Accepted: 1 October 2023 / Published: 7 October 2023
(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)
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Abstract

:
A facile and efficient method for the regioselective [3 + 2] cycloaddition of 4-azidofuroxans to 1-dimethylamino-2-nitroethylene under p-TSA catalysis affording (4-nitro-1,2,3-triazolyl)furoxans was developed. This transformation is believed to proceed via eliminative azide–olefin cycloaddition resulting in its complete regioselectivity. The developed protocol has a broad substrate scope and enables a straightforward assembly of the 4-nitro-1,2,3-triazole motif. Moreover, synthesized (4-nitro-1,2,3-triazolyl)furoxans were found to be capable of NO release in a broad range of concentrations, thus providing a novel platform for future drug design and related biomedical applications of heterocyclic NO donors.

1. Introduction

Nitrogen heterocycles are the most frequently occurring structural motifs in various pharmaceuticals and promising drug candidates [1,2,3,4]. According to the U.S. FDA database, >59% of clinically used small-molecule medicines incorporate a nitrogen heterocycle subunit [5,6]. However, the construction of individual pharmaceutical scaffolds using known synthetic methodologies often involves multi-step and energy-consuming procedures or suffers from a lack of reproducibility and scalability. Therefore, the creation of novel step-economy protocols for the assembly of various nitrogen-containing heterocyclic scaffolds remains highly urgent [7,8,9].
Among pharmacologically active substances, heterocyclic NO donors have become an important subclass in organic and medical chemistry [10,11,12,13,14]. In contrast to widely known vasodilator nitroglycerin, heterocyclic NO donors are hydrolytically stable, do not stimulate nitrate tolerance and demonstrate improved pharmacological profiles. Moreover, biomedical applications of simple heterocyclic NO donors along with their hybridization with other pharmacophoric scaffolds were found to be promising for the creation of new medications to overcome the issue of multidrug resistance [15,16,17]. A variety of heterocyclic NO donors (furoxans [18,19,20,21,22], azasydnones [23,24], sydnone imines [25], triazole oxides [26] and pyridazine dioxides [27]) were synthesized and evaluated for their pharmacological potency so far (Figure 1).
In this series, furoxan (1,2,5-oxadiazole 2-oxide) derivatives exhibit a broad range of pharmacological activities including antibacterial [28], antiparasitic [29] and cytotoxic [30,31,32,33] activities. Due to exogenous NO release, furoxans possess promising antiaggregant properties [34,35,36].
In a series of nitrogen heterocycles, 1,2,3-triazoles have become of paramount importance over the past two decades due to their universal application in diverse fields, such as drug development and medicinal chemistry [37,38,39], materials science and polymers [40,41]. In addition, they contribute to organic synthesis by acting as synthetic precursors to many valuable compounds [42,43,44]. In this regard, nitro-1,2,3-triazoles acquire additional significance due to their potential application in energetic materials science and for medicinal chemistry needs [45,46,47]. Taking into account the potency of the molecular hybridization tool in the development of new drug candidates, a method for the synthesis of previously unknown (nitro-1,2,3-triazolyl)furoxans is desired.
Previously, a couple of synthetic approaches toward the construction of a (1,2,3-triazolyl)-1,2,5-oxadiazole biheterocyclic core were proposed. [3 + 2] Cycloaddition of azidofuroxans to acetylenes proceeded under substantially harsh conditions and provided mixtures of regioisomeric 1,2,3-triazoles, while an analogous reaction with 1,3-dicarbonyl compounds had a narrow substrate scope (Scheme 1a) [48,49]. Moreover, this approach did not allow the installation of the nitro group onto the 1,2,3-triazole core. [3 + 2] Cycloaddition of 4-amino-3-azidofurazan to 1-nitro-2-morpholinoethylene contributed to the formation of 4-nitro-1,2,3-triazole with a furazan moiety, which, however, is not capable of NO release (Scheme 1b) [50]. In addition, this reaction proceeded under prolonged heating in an ionic liquid medium and suffered both from a narrow substrate scope and low yields. These examples clearly demonstrate that the fine tunability of the reactivity of 4-azidofuroxans may be achieved by introducing various additives to achieve both high regioselectivity and a broad scope. Herein, we report on a regioselective, p-TSA-catalyzed eliminative azide–olefin cycloaddition of 4-azidofuroxans to 1-dimethylamino-2-nitroethylene for the synthesis of (4-nitro-1,2,3-triazolyl)furoxans (Scheme 1c).

2. Results and Discussion

Recently, our research group created direct methods for the synthesis of various functionally substituted furoxans. It is also known that the nitro group in 4-nitrofuroxans is prone to nucleophilic displacement due to high electrophilicity of ring carbon atoms [51,52]. In particular, a couple of azidofuroxans were recently prepared upon treatment of 4-nitrofuroxans with NaN3 [48]. Using this furoxan reactivity pattern, we prepared a series of starting 4-azidofuroxans 2a–v from the readily available nitro derivatives 1a–v in good and high yields (Scheme 2).
4-Azido-3-(p-tolyl)furoxan (2a) was chosen as a model substrate to optimize the reaction conditions for the synthesis of target (4-nitro-1,2,3-triazolyl)furoxans 3a–v (Table 1). 1-Dimethylamino-2-nitroethylene was used as a convenient dipolarophile in all reactions. Refluxing of substrate 2a with 1-dimethylamino-2-nitroethylene in various ratios and solvents afforded target 4-nitro-1,2,3-triazole 3a in low yields (up to 30%, entries 1–8). Interestingly, an addition of Lewis acids did not improve the reaction outcome but resulted in a yield decrease (entries 9–13). Utilization of mCPBA as an oxidizer to convert the dimethylamino group to the corresponding N-oxide was also inefficient (entry 14). To our delight, more fruitful results were obtained upon p-toluenesulfonic acid (p-TSA) catalysis (entries 15–18). The optimal amount of p-TSA was found to be 15 mol.% (entries 16–18). Interestingly, commercially available pyridinium p-toluenesulfonate (PPTS) also catalyzed the studied transformation, albeit the yield of 3a was lower (entry 19). Therefore, the optimal conditions for the synthesis of (4-nitro-1,2,3-triazolyl)furoxan 3a were found to be a utilization of 5 equiv. of dipolarophile, 15 mol.% of p-TSA in refluxing MeCN (entry 16). It should also be noted, that in all cases, the formation of regioisomeric 5-nitro-1,2,3-triazole 3a′ was not observed.
Having established optimal conditions, we next surveyed the substrate scope of our eliminative azide–olefin cycloaddition by employing an array of azides 2a–v and 1-dimethylamino-2-nitroethylene, and the results are summarized in Scheme 3. It was found that azidofuroxans 2c–m bearing an o-, m- or p-substituted phenyl ring underwent cycloaddition smoothly, although nitrotriazoles 3k,l possessing a strongly electron-withdrawing CF3 or NO2 group at the para-position were formed in lower yields. To our delight, (4-nitro-1,2,3-triazolyl)furoxans 3n–q incorporating di- and trisubstituted phenyl rings were also obtained in good yields. Moreover, a variety of heteroaromatic substituents such as 2-pyridyl-, 6-nitropiperonyl- and 5-nitrofuryl- well tolerated the investigated protocol resulting in a formation of corresponding (4-nitro-1,2,3-triazolyl)furoxans 3r–t. 3-Alkyl-4-azidofuroxans 2u,v underwent eliminative azide–olefin cycloaddition providing target products 3u,v confirming broad applicability of the developed method. It should also be emphasized that in all cases, reaction proceeded regioselectively and the formation of regioisomeric 5-nitro-1,2,3-triazoles was not observed.
All synthesized compounds were characterized by multinuclear (1H, 13C, 14N) NMR spectroscopy, IR spectroscopy, high-resolution mass spectrometry and elemental analysis. The structures of 2a, 3a and 3c were additionally confirmed by X-ray diffraction study (Figure 2).
The molecule of 2a is nearly planar in crystal: the mean deviation from the mean-square plane composed by non-hydrogen atoms is only 0.032 Å. This conformation is expected owing to the combination of π-donor (4-methylphenyl) and π-acceptor (azidofuroxane) fragments in 2a. In its turn, the crystal packing of 2a is of a layer type (Figure S1): planar molecules are bound into layers by the CH…O and CH…N interactions (C…O 3.353(2) and 3.394(2) Å, C…N 3.361(2) Å), whereas the π…π stacking interactions are formed between the layers.
The formal replacement of the azido group with the nitrotriazole fragments in 3a and 3c results in the steric repulsion between substituted phenyl rings and triazole moieties. For instance, the C6-C5-C1-C2 and C1-C2-N3-N4 torsion angles in 3a equal 64.8(2)° and 40.0(2)°, respectively. It is interesting to note that the conjugation of the central furoxan fragment in 3a with its substituents can be considered as saturable: the C6-C5-C1-C2 and C1-C2-N3-N4 torsion angles are respectively equal to 38.8° and 59.8° in the equilibrium isolated molecule of 3a modelled at the PBE0-D3/def2TZVP level. In other words, the rotation of one substituent induced by crystal packing effects upon the formal gas-to-crystal transition is totally compensated by the rotation of the other one.
This saturability is further observed in the crystal of 3c. The bromophenyl substituent in 3c is disordered over two places with the C6-C5-C1-C2 torsion angles being equal to 118.8(2)° and 96.5(2)°. Owing to this nearly perpendicular arrangement of the phenyl and furoxan cycles, the conjugation within the furoxan–triazole fragment becomes substantial: the C1-C2-N3-N4 torsion angle is only 9.3(2)°. In the isolated molecule of 3c, the conjugation within the furoxan–triazole fragment again becomes smaller (the C1-C2-N3-N4 torsion angle is 29.1°), whereas the conjugation between the furoxan and bromophenyl moieties becomes larger (the C6-C5-C1-C2 torsion angle is 58.7°).
Nevertheless, despite this significant non-planarity of the molecules of 3a and 3c, the layer-type packing motifs are observed in both crystals (Figures S2 and S3). The intralayer binding is achieved by a number of the O…π interactions between the furoxane and nitro groups in 3a (the shortest O…O distances are 2.953(1) and 3.033(1) Å), and by the O…π (the shortest O…X distances are 2.748(2), 3.008(2) and 3.142(3) Å) and the CH…O interactions (C…O 3.203(3)–3.248(3) Å) in 3c. The hydrophobic contacts are found between the layers in both 3a and 3c.
A plausible reaction mechanism of eliminative azide–olefin cycloaddition is outlined in Scheme 4. We assume that there are two different ways toward the formation of 1,2,3-triazoline intermediate A. Firstly, p-TSA as a Brønsted acid coordinates with the dimethylamino group of the dipolarophile, enabling regioselective [3 + 2] cycloaddition. Thus, generated 1,2,3-triazoline intermediate A undergoes elimination of dimethylamine (HNMe2) providing 4-nitro-1,2,3-triazole 3 and dimethylamine, which couples with anion B, that occurred from p-TSA deprotonation, and forms the salt C. Since catalytic amounts of p-TSA are sufficient for the transformation to occur, we propose that dimethylammonium p-toluenesulfonate C is also able to catalyze the cycloaddition step, forming a catalytic cycle.
Since furoxans correspond to NO donors, we investigated the ability of the synthesized (4-nitro-1,2,3-triazolyl)furoxans 3 to release NO. The formation of the nitrite anion as a result of the oxidation of NO can be quantified in accordance with the Griess assay and thus can serve as a reliable tool for measuring the NO release. Synthesized (4-nitrotriazolyl)furoxans 3 were subjected to 1 h incubation in the presence of L-cystein under physiological conditions (pH 7.4; 37 °C), and the amount of NO2 formed was measured using the spectrophotometric method. It was found that (4-nitrotriazolyl)furoxans containing aromatic or heteroaromatic substituents emit NO fluxes in a broad range of 8.5–72.4%. Interestingly, compounds bearing aliphatic substituents or electron-withdrawing moieties in the aromatic ring (3j, 3o, 3s) release smaller amounts of NO (8.5–12.1%). It is important to note that furoxanyltriazole 3p incorporating 3,4-dimethoxyphenyl group demonstrated the highest NO-donor ability (72.4%). Overall, these results might be helpful in the development of novel NO-donor drug candidates with various pharmacological activities (Figure 3).

3. Conclusions

In summary, we developed a convenient and straightforward approach to an assembly of (4-nitro-1,2,3-triazolyl)furoxans based on eliminative azide–olefin cycloaddition of 4-azidofuroxans and 1-dimethylamino-2-nitroethylene under p-TSA catalysis. The reported method has a number of advantages including a broad substrate scope and complete regioselectivity resulting in the construction of the 4-nitro-1,2,3-triazole motif. Synthesized (4-nitro-1,2,3-triazolyl)furoxans were found to be capable of NO release in a broad range of concentrations under physiological conditions. Therefore, our results contribute to the enlargement of the available libraries of NO-donor substances and unveil novel opportunities in drug design and related biomedical applications.

4. Materials and Methods

4.1. General Methods

  • CAUTION! Although we have encountered no difficulties during preparation and handling of azides 1a–w described in this paper, they are potentially explosive and may be sensitive to impact and friction. Mechanical actions of these species, involving scratching or scraping, must be avoided. Any manipulations must be carried out by using appropriate standard safety precautions.
All reactions were carried out in well-cleaned, oven-dried glassware with magnetic stirring. 1H, 13C NMR spectra were recorded on a Bruker AM-300 (300.13 and 75.47 MHz, respectively) spectrometer and referenced to residual solvent peak. 14N NMR spectra were measured on a Bruker AM-300 (21.69 MHz) spectrometer using MeNO2 (δ14N = 0.0 ppm) as an external standard. The chemical shifts are reported in ppm (δ). Mass spectra were measured using a Finnigan MAT INCOS-50 instrument. The IR spectra were recorded on the Simex FT-801 IR-Fourier spectrometer in the 4000–550 cm−1 region (spectral resolution 4 cm−1) using the universal optical attenuated total reflection (ATR) accessory with ZnSe crystal plate. ZaIR 3.5 software (Simex, Russia) was used to carry out baseline correction and normalization of FEAR spectra. A background (air) measurement was taken for every sample processed. The peaks corresponding to CO2 vibrations were removed using the “straight line generation” option in the ZaIR 3.5 software (Simex). Raw spectra were preprocessed using a simple two-point linear subtraction baseline correction method. Two points, 900 and 1850 cm−1, were selected outside the wavenumber region of interest that showed no variation across all samples. Spectra were the vector normalized. Spectrum smoothing was not performed. High-resolution mass spectra were recorded on a Bruker microTOF spectrometer with electrospray ionization (ESI). All measurements were performed in a positive (+MS) ion mode (interface capillary voltage: 4500 V) with scan range m/z: 50–3000. External calibration of the mass spectrometer was performed with Electrospray Calibrant Solution (Fluka). A direct syringe injection was used for all analyzed solutions in MeCN (flow rate: 3 μL min−1). Nitrogen was used as nebulizer gas (0.4 bar) and dry gas (4.0 L∙min−1); interface temperature was set at 180 °C. All spectra were processed by using Bruker Data Analysis 4.0 software package. Elemental analyses were performed by the CHN Analyzer Perkin-Elmer 2400. Analytical thin-layer chromatography (TLC) was carried out on Merck 25 TLC silica gel 60 F254 aluminum sheets. The visualization of the TLC plates was accomplished with a UV light. All standard reagents were purchased from Aldrich or Acros Organics and used without further purification. 4-Azido-3-phenylfuroxan 1b was obtained according to the previously described procedure [48].

4.2. X-ray Crystallography

X-ray diffraction studies were carried out at 100K using the four-circle Rigaku Synergy S diffractometer equipped with a HyPix6000HE area-detector (kappa geometry, shutterless ω-scan technique, monochromatized Cu Kα-radiation) for 1a and the Bruker D8 Quest diffractometer equipped with a PhotonIII area-detector (ω- and φ-scan technique, monochromatized Mo Kα-radiation) for 3a and 3c. The intensity data were integrated and corrected for absorption and decay by the CrysAlisPro program for 1a and by the APEX3 program (SAINT [53], SADABS [54]) for 3a and 3c. All structures were solved by dual-space method SHELXT [55] and refined against F2 using SHELXL-2018 software (version 2014/6) [56]. All non-hydrogen atoms were refined with individual anisotropic displacement parameters. All hydrogen atoms were found in the difference Fourier synthesis and refined as riding atoms with relative isotropic displacement parameters. A rotating group model was applied for methyl groups. The bromophenyl substituent in the 3c structure was found to be disordered over two places with population ratio 95:5. All relevant crystal data and refinement details are listed in Table S1. The CCDC 2290794–2290796 contain all additional information on crystal structures and refinement.
The density functional theory calculations for 3a and 3c were performed using the Gaussian program [57] at the PBE0-D3 [58,59,60]/def2TZVP level. Equilibrium structures of both compounds correspond to minimums on the potential energy surface according to the calculations of the Hessian of electronic energy (ultrafine grids, no imaginary modes were found).

4.3. Synthetic Procedures

4.3.1. General Procedure for the Synthesis of 4-Azidofuroxans 2a–v

Sodium azide (20.4 mmol, 1.328 g) was added in one portion to a vigorously stirred, ice-cooled solution of the corresponding 4-nitrofuroxan 1 (8.2 mmol) in DMSO (15 mL). Then the reaction mixture was stirred for 3 h at 20 °C until the consumption of substrate 1 (TLC monitoring, eluent CHCl3/CCl4, 1:1). The resulting mixture was poured onto 30 g of ice and extracted with CH2Cl2 (3 × 15 mL), and combined organic layers were washed with H2O (3 × 15 mL) and dried over MgSO4. Filtration of the drying agent and evaporation of the solvent afforded target 4-azidofuroxans 1.
  • 4-Azido-3-(p-tolyl)furoxan (2a): yield 1.72 g (97%), light yellow solid; mp 100–101 °C, Rf (CH2Cl2) = 0.85. 1H NMR (300 MHz, DMSO-[d6]) δ, ppm: 7.85 (d, 2H, J = 8.4 Hz, Ar), 7.41 (d, 2H, J = 8.4 Hz, Ar), 2.39 (s, 3H, CH3); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.7, 141.5, 129.7, 126.5, 118.5, 108.9, 21.6; 14N NMR (21.7 MHz, DMSO-[d6]): δ = −145.8 (br s, N3). IR (KBr), ν: 2918, 2148, 1922, 1592, 1518, 1450, 1404, 1331, 1317, 1289, 1238, 1111, 1066, 971, 854, 821, 735 cm−1. HRMS (ESI) calcd. for C9H8N5NaO2+: 240.0492. Found: 240.0485 [M+Na]+.
  • 4-Azido-3-(2-bromophenyl)furoxan (2c): yield 1.75 g (76%), yellow oil; Rf (CHCl3/CCl4, 4:1) = 0.79. 1H NMR (300 MHz, CDCl3) δ, ppm: 7.72–7.75 (m, 1H, Ar), 7.36–7.51 (m, 3H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 148.5, 128.9, 128.1, 127.3, 123.2, 119.4, 117.7, 105.2; 14N NMR (21.7 MHz, CDCl3): δ = −152.3 (s, N3). IR (KBr), ν: 2144, 1608, 1497, 1438, 1331, 1259, 1133, 1071, 969, 837, 759 cm−1. MS (70 eV, m/z (%)): 225 (1) [M–NO]+, 195 (3) [M−2NO]+, 281 (4) [M]+, 144 (10) [M–Br–N3–O]+, 114 (19) [M–Br–N3–NO2]+, 30 (100) [NO]+. Calcd. for C8H4BrN5O2 (%): C, 34.07; H, 1.43; N, 24.83. Found (%): C, 33.89; H, 1.59; N, 24.59.
  • 4-Azido-3-(2-fluorophenyl)furoxan (2d): yield 1.27 g (70%), yellow solid; mp 122–124 °C, Rf (CH2Cl2) = 0.93. 1H NMR (300 MHz, DMSO-[d6]) δ, ppm: 7.66–7.75 (m, 2H, Ar), 7.42–7.51 (m, 2H, Ar); 13C NMR (75.5 MHz, DMSO-[d6]) δ, ppm: 159.9 (d, J = 253.3 Hz), 158.2, 134.6 (d, J = 8.5 Hz), 131.7 (d, J = 1.9 Hz), 125.6 (d, J = 3.5 Hz), 117.0 (d, J = 20.0 Hz), 109.1 (d, J = 14.2 Hz), 107.1; 14N NMR (21.7 MHz, DMSO-[d6]): δ = −148.9 (s, N3). IR (KBr), ν: 2924, 2141, 1805, 1725, 1599, 1550, 1502, 1453, 1404, 1326, 1271, 1092, 970, 846, 753 cm−1. Calcd. for C8H4FN5O2 (%): C, 43.45; H, 1.82; N, 31.67. Found (%): C, 43.52; H, 1.93; N, 31.50.
  • 4-Azido-3-(2-nitrophenyl)furoxan (2e): yield 1.60 g (79%), orange solid; mp 100–102 °C, Rf (CH2Cl2) = 0.88. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.27 (d, 1H, J = 8.1 Hz, Ar), 7.87–7.68 (m, 3H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.8, 147.5, 134.1, 132.3, 131.6, 125.8, 116.1, 107.9; 14N NMR (21.7 MHz, CDCl3): δ = −13.5 (s, NO2), δ = −147.8 (s, N3). IR (KBr), ν: 2976, 2152, 1611, 1553, 1517, 1481, 1383, 1323, 1207, 1128, 1049, 964, 847, 727 cm−1. HRMS (ESI) calcd. for C8H8N7O4+: 266.0625. Found: 266.0632 [M+NH4]+. HRMS (ESI) calc. for C8H4N6NaO4+: 271.0181. Found: 271.0186 [M+Na]+.
  • 4-Azido-3-(2-(trifluoromethyl)phenyl)furoxan (2f): yield 1.97 g (89%), white solid; mp 116–118 °C, Rf (CH2Cl2) = 0.83. 1H NMR (300 MHz, CDCl3) δ, ppm: 7.86–7.89 (m, 1H, Ar), 7.71–7.78 (m, 2H, Ar), 7.43–7.49 (m, 1H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 153.4, 132.7, 132.3, 131.9, 130.8, 127.5 (q, J = 4.6 Hz), 124.9, 119.5 (q, J = 92.7 Hz), 108.1; 14N NMR (21.7 MHz, CDCl3): δ = −147.3 (s, N3). IR (KBr), ν: 2978, 2148, 1606, 1566, 1484, 1422, 1316, 1273, 1226, 1128, 1051, 967, 844, 786 cm−1. HRMS (ESI) calcd. for C9H4F3NaN5O2+: 294.0221. Found: 294.0209 [M+Na]+.
  • 4-Azido-3-(3-bromophenyl)furoxan (2g): yield 1.50 g (65%), beige solid; mp 124–126 °C, Rf (CHCl3/CCl4, 4:1) = 0.85. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.22 (t, 1H, J = 1.9 Hz, Ar), 8.01–8.05 (m, 1H, Ar), 7.63–7.67 (m, 1H, Ar), 7.41 (t, 1H, J = 8.0 Hz, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.5, 133.9, 130.5, 129.2, 125.0, 123.4, 123.1, 107.8; 14N NMR (21.7 MHz, CDCl3): δ = −147.4 (s, N3). IR (KBr), ν: 2922, 2153, 1593, 1485, 1393, 1334, 1272, 1211, 1078, 985, 857, 751 cm−1. HRMS (ESI) calcd. for C8H479BrN5NaO2+: 303.9432. Found: 303.9441 [M+Na]+.
  • 4-Azido-3-(3-chlorophenyl)furoxan (2h): yield 0.60 g (31%), white solid; mp 65–66 °C, Rf (CH2Cl2) = 0.92. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.06–8.10 (m, 1H, Ar), 7.95–8.02 (m, 1H, Ar), 7.44–7.51 (m, 2H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.5, 135.2, 131.0, 130.3, 126.4, 124.5, 123.2, 107.8; 14N NMR (21.7 MHz, CDCl3): δ = −146.0 (s, N3). IR (KBr), ν: 2973, 2923, 2852, 2150, 1642, 1562, 1486, 1395, 1335, 1274, 1220, 1122, 1055, 899, 752 cm−1. HRMS (ESI) calcd. for C8H4ClN5NaO2+: 259.9957 (35Cl), 261.9924 (37Cl). Found: 259.9946 (35Cl), 261.9917 (37Cl) [M+Na]+.
  • 4-Azido-3-(3-methoxyphenyl)furoxan (2i): yield 0.99 g (52%), white solid; mp 116–118 °C, Rf (CH2Cl2) = 0.84. 1H NMR (300 MHz, CDCl3) δ, ppm: 7.62–7.65 (m, 2H, Ar), 7.41–7.46 (m, 1H, Ar), 7.03–7.07 (m, 1H, Ar), 3.88 (s, 3H, OCH3); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 159.8, 152.8, 130.1, 122.6, 119.0, 116.9, 111.7, 108.8; 14N NMR (21.7 MHz, CDCl3): δ = −146.3 (s, N3). IR (KBr), ν: 2947, 2918, 2144, 1631, 1547, 1503, 1481, 1383, 1322, 1274, 1134, 1028, 962, 873, 777 cm−1. Calcd. for C9H7N5O3 (%): C, 46.36; H, 3.03; N, 30.03. Found (%): C, 46.18; H, 3.09; N, 29.88.
  • 4-Azido-3-(3-nitrophenyl)furoxan (2j): yield 1.48 g (73%), yellow solid; mp 120–122 °C, Rf (CHCl3/CCl4, 4:1) = 0.83. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.95–8.96 (m, 1H, Ar), 8.46–8.49 (m, 1H, Ar), 8.35–8.38 (m, 1H, Ar), 7.73–7.79 (m, 1H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.4, 148.5, 131.7, 130.3, 125.3, 123.4, 121.5, 107.5; 14N NMR (21.7 MHz, CDCl3): δ = −14.3 (s, NO2), δ = −148.2 (s, N3). IR (KBr), ν: 2925, 2150, 1659, 1593, 1530, 1492, 1467, 1350, 1286, 1216, 1080, 999, 876, 794 cm−1. HRMS (ESI) calcd. for C8H4N6NaO4+: 271.0184. Found: 271.0186 [M+Na]+.
  • 4-Azido-3-(4-(trifluoromethyl)phenyl)furoxan (2k): yield 1.31 g (59%), light yellow solid; mp 122–124 °C, Rf (CH2Cl2) = 0.88. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.23 (d, 2H, J = 8.3 Hz, Ar), 7.79 (d, 2H, J = 8.3 Hz, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.6, 132.5 (d, J = 33.0 Hz), 128.3 (d, J = 52.0 Hz), 126.9, 125.9 (q, J = 3.7 Hz), 125.1, 108.0; 14N NMR (21.7 MHz, CDCl3): δ = −147.8 (s, N3). IR (KBr), ν: 2976, 2921, 2152, 1629, 1563, 1514, 1485, 1390, 1323, 1237, 1173, 1054, 955, 846, 771 cm−1. Calcd. for C9H4F3N5O2 (%): C, 39.87; H, 1.49; N, 25.83. Found (%): C, 40.04; H, 1.33; N, 25.69.
  • 4-Azido-3-(4-nitrophenyl)furoxan (2l): yield 1.34 g (66%), yellow solid; mp 116–118 °C, Rf (CH2Cl2) = 0.78. 1H NMR (300 MHz, DMSO-[d6]) δ, ppm: 8.44 (d, 2H, J = 9.0 Hz, Ar), 8.22 (d, 2H, J = 9.0 Hz, Ar); 13C NMR (75.5 MHz, DMSO-[d6]) δ, ppm: 153.7, 148.6, 128.5, 128.1, 124.6, 109.2; 14N NMR (21.7 MHz, DMSO-[d6]): δ = −9.3 (s, NO2), −146.5 (s, N3). IR (KBr): 2924, 2138, 1709, 1598, 1520, 1457, 1404, 1330, 1196, 1065, 971, 847, 752 cm−1. Calcd. for C8H4N6O4 (%): C, 38.72; H, 1.62; N, 33.87. Found (%): C, 38.85; H, 1.87; N, 33.63.
  • 4-Azido-3-(4-fluorophenyl)furoxan (2m): yield 1.52 g (84%), light yellow solid; mp 103–105 °C, Rf (CH2Cl2) = 0.90. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.07–8.12 (m, 2H, Ar), 7.20–7.28 (m, 2H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 162.4 (d, J = 253.7 Hz), 152.5, 128.9 (d, J = 8.6 Hz), 117.6 (d, J = 3.4 Hz), 116.3 (d, J = 22.1 Hz), 108.3; 14N NMR (21.7 MHz, CDCl3): δ = −146.6 (s, N3). IR (KBr), ν: 2971, 2150, 1594, 1553, 1476, 1384, 1325, 1231, 1170, 1066, 964, 845, 771 cm−1. Calcd. for C8H4FN5O2 (%): C, 43.45; H, 1.82; N, 31.67. Found (%): C, 43.60; H, 1.93; N, 31.48.
  • 4-Azido-3-(2,4-dichlorophenyl)furoxan (2n): yield 1.53 g (69%), light yellow solid; mp 56–58 °C, Rf (CH2Cl2) = 0.95. 1H NMR (300 MHz, CDCl3) δ, ppm: 7.59 (d, 1H, J = 2.0 Hz, Ar), 7.42–7.45 (m, 1H, Ar), 7.28–7.35 (m, 1H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 153.1, 138.5, 135.7, 132.4, 130.6, 127.9, 118.9, 107.9; 14N NMR (21.7 MHz, CDCl3): δ = −147.0 (s, N3). IR (KBr), ν: 2926, 2150, 1725, 1586, 1490, 1370, 1259, 1104, 1052, 955, 855, 777 cm−1. Calcd. for C8H3Cl2N5O2 (%): C, 35.32; H, 1.11; N, 25.74. Found (%): C, 35.14; H, 1.18; N, 25.48.
  • 4-Azido-3-(3-chloro-4-nitrophenyl)furoxan (2o): yield 1.18 g (51%), orange solid; mp 122–124 °C, Rf (CH2Cl2) = 0.88. 1H NMR (300 MHz, acetone-[d6]) δ, ppm: 8.62 (d, 1H, J = 2.2 Hz, Ar), 8.37–8.41 (m, 1H, Ar), 7.83 (d, 1H, J = 8.7 Hz, Ar); 13C NMR (75.5 MHz, acetone-[d6]) δ, ppm: 153.1, 140.8, 136.4, 131.4, 123.4, 122.4, 118.7, 107.8; 14N NMR (21.7 MHz, acetone-[d6]): δ = −14.0 (s, NO2), −147.5 (s, N3). IR (KBr), ν: 2970, 2922, 2117, 1741, 1592, 1529, 1467, 1402, 1337, 1282, 1205, 1066, 997, 906, 860, 829 cm−1. Calcd. for C8H3ClN6O4 (%): C, 34.00; H, 1.07; N, 29.74. Found (%): C, 34.23; H, 0.93; N, 29.56.
  • 4-Azido-3-(3,4-dimethoxyphenyl)furoxan (2p): yield 1.76 g (82%), orange solid; mp 131–133 °C, Rf (CH2Cl2) = 0.90. 1H NMR (300 MHz, CDCl3) δ, ppm: 7.66–7.69 (m, 2H, Ar), 6.97–7.00 (d, 1H, J = 8.7 Hz, Ar), 3.96 (s, 6H, 2xOCH3); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.6, 151.0, 149.1, 120.4, 113.7, 111.1, 109.8, 109.0, 56.1, 56.0; 14N NMR (21.7 MHz, CDCl3): δ = −148.7 (s, N3). IR (KBr), ν: 2974, 2923, 2851, 2167, 1658, 1612, 1582, 1517, 1483, 1396, 1267, 1217, 1150, 1018, 921, 883, 807 cm−1. HRMS (ESI) calc. for C10H10N5O4+: 264.0727. Found: 264.0730 [M+H]+.
  • 4-Azido-3-(3,4,5-trimethoxyphenyl)furoxan (2q): yield 1.94 g (81%), beige solid; mp 120–121 °C. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.55 (s, 1H, Ar), 7.19 (s, 1H, Ar), 3.94 (s, 1H, OCH3), 3.93 (s, 1H, OCH3), 3.90 (s, 1H, OCH3); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.3, 150.0, 147.5, 145.9, 144.9, 125.2, 121.0, 104.6, 61.2, 56.1; 14N NMR (21.7 MHz, CDCl3): δ = −146.9 (s, N3). IR (KBr), ν: 2975, 2922, 2199, 1680, 1566, 1485, 1396, 1353, 1295, 1243, 1172, 1061, 970, 826, 713 cm−1. Calcd. for C11H11N5O5 (%): C, 45.06; H, 3.78; N, 23.88. Found (%): C, 44.89; H, 3.90; N, 23.62.
  • 4-Azido-3-(pyridin-2-yl)furoxan (2r): yield 1.15 g (69%), light yellow solid; mp 81–83 °C, Rf (CH2Cl2) = 0.91. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.81 (d, 1H, J = 4.9 Hz, Py), 8.22–8.25 (m, 1H, Py), 7.88–7.94 (m, 1H, Py), 7.41–7.45 (m, 1H, Py); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 153.0, 150.1, 142.7, 137.2, 125.0, 122.4, 118.9; 14N NMR (21.7 MHz, CDCl3): δ = −146.8 (s, N3). IR (KBr), ν: 2979, 2135, 1592, 1483, 1418, 1341, 1296, 1213, 1139, 1049, 993, 854 cm−1. HRMS (ESI) calc. for C7H5N6O2+: 205.0468. Found: 205.0474 [M+H]+.
  • 4-Azido-3-(6-nitro-1,3-benzodioxol-5-yl)furoxan (2s): yield 1.72 g (72%), brick solid; mp 166–168 °C, Rf (CH2Cl2) = 0.75. 1H NMR (300 MHz, CDCl3) δ, ppm: 7.73 (s, 1H, Ar), 6.99 (s, 1H, Ar), 6.26 (s, 2H, CH2); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.9, 152.3, 150.4, 111.4, 109.8, 108.2, 106.7, 104.1; 14N NMR (21.7 MHz, CDCl3): δ = −12.3 (s, NO2), −145.6 (s, N3). IR (KBr), ν: 2924, 2157, 1612, 1529, 1468, 1418, 1360, 1328, 1263, 1213, 1161, 1026, 919, 883, 783, 743 cm−1. HRMS (ESI) calc. for C9H5N6O6+: 293.0265. Found: 293.0259 [M+H]+.
  • 4-Azido-3-(5-nitrofuran-2-yl)furoxan (2t): yield 0.95 g (49%), beige solid; mp 121–123 °C, Rf (CH2Cl2) = 0.80. 1H NMR (300 MHz, CDCl3) δ, ppm: 7.48 (d, 1H, J = 3.9 Hz, Furan), 7.39 (d, 1H, J = 3.9 Hz, Furan); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.5, 151.0, 139.1, 114.6, 112.5, 103.5; 14N NMR (21.7 MHz, CDCl3): δ = −31.7 (s, NO2), −148.3 (s, N3). IR (KBr), ν: 2927, 2141, 1725, 1587, 1503, 1459, 1404, 1332, 1246, 1194, 1147, 1087, 1023, 996, 848, 812, 792, 752 cm−1. Calcd. for C6H2N6O5 (%): C, 30.26; H, 0.85; N, 35.29. Found (%): C, 30.12; H, 0.98; N, 35.03.
  • 4-Azido-3-methylfuroxan (2u): yield 0.75 g (65%), yellow oil; Rf (CHCl3) = 0.88. 1H NMR (300 MHz, CDCl3) δ, ppm: 2.08 (s, 3H, CH3); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 154.0, 107.3, 6.8. IR (KBr), ν: 2930, 2140, 1625, 1508, 1381, 1306, 1237, 1108, 1023, 880, 801 cm−1. Calcd. for C3H3N5O2 (%): C, 25.54; H, 2.14; N, 49.64. Found (%): C, 25.32; H, 2.31; N, 49.42.
  • 4-Azido-3-cyclohexylfuroxan (2v): yield 1.62 g (95%), yellow solid; mp 71–73 °C, Rf (CH2Cl2) = 0.94. 1H NMR (300 MHz, CDCl3) δ, ppm: 2.55–2.61 (m, 1H, Cy), 1.12–1.75 (m, 10H, Cy); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 154.2, 113.6, 33.1, 27.6, 25.6, 25.4; 14N NMR (21.7 MHz, CDCl3): δ = −146.6 (s, N3). IR (KBr), ν: 2927, 2856, 2142, 1708, 1599, 1496, 1451, 1367, 1306, 1251, 1201, 1048, 952, 883, 823, 761 cm−1. Calcd. for C8H11N5O2 (%): C, 45.93; H, 5.30; N, 33.48. Found (%): C, 45.64; H, 5.49; N, 33.16.

4.3.2. General Procedure for the Synthesis of 4-(4-Nitro-1H-1,2,3-triazol-1-yl)furoxans 3a–v

N,N-Dimethylformamide dimethyl acetal (680 µL, 5.1 mmol) was added to a solution of nitromethane (270 μL, 5 mmol) in MeCN (10 mL). The reaction mixture was stirred for 3 h at 20 °C and volatiles were evaporated on a rotary evaporator affording 1-dimethylamino-2-nitroethylene. Thus obtained dipolarophile was dissolved in anhydrous MeCN (10 mL) followed by the addition of the corresponding 4-azidofuroxan 2 (1 mmol) and p-TSA monohydrate (29 mg, 0.15 mmol). The reaction mixture was stirred at 40 °C for 3 h and then refluxed for 69 h. After the disappearance of azides 2 on TLC, the solvent was distilled off under reduced pressure and the target product was purified by column chromatography (eluent CH2Cl2 or CHCl3/CCl4, 4:1).
  • 3-(4-p-Tolyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3a): yield 161 mg (56%), light yellow solid; mp 132–134 °C, Rf (CH2Cl2) = 0.7. 1H NMR (300 MHz, acetone-[d6]) δ, ppm: 9.68 (s, 1H, CH), 7.51 (d, 2H, J = 8.1 Hz, Ar), 7.37 (d, 2H, J = 8.1 Hz, Ar), 2.41 (s, 3H, CH3); 13C NMR (75.5 MHz, acetone-[d6]) δ, ppm: 154.0, 149.3, 142.1, 129.8, 128.1, 125.9, 117.5, 111.1, 20.6. IR (KBr), ν: 2922, 1623, 1549, 1523, 1486, 1389, 1325, 1273, 1137, 1112, 1027, 993, 955, 850, 786, 753 cm−1. HRMS (ESI) calcd. for C11H12N7O4+: 306.0945. Found: 306.0954 [M+NH4]+.
  • 4-(4-Nitro-1H-1,2,3-triazol-1-yl)-3-phenylfuroxan (3b): yield 140 mg (51%), white solid; mp 132–134 °C, Rf (CH2Cl2) = 0.7. 1H NMR (300 MHz, acetone-[d6]) δ, ppm: 9.69 (s, 1H, CH), 7.56–7.65 (m, 5H, Ar); 13C NMR (75.5 MHz, acetone-[d6]) δ, ppm: 155.0, 149.7, 131.9, 129.6, 128.7, 126.3, 121.1, 111.6. IR (KBr), ν: 2922, 1620, 1551, 1513, 1483, 1388, 1345, 1273, 1238, 1137, 1111, 1075, 1027, 1003, 955, 852, 825, 771 cm−1. HRMS (ESI) calcd. for C10H6N6NaO4+: 297.0343. Found: 297.0346 [M+Na]+.
  • 3-(2-Bromophenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3c): yield 144 mg (41%), yellow crystals; mp 122–124 °C, Rf (CHCl3/CCl4, 4:1) = 0.33. 1H NMR (300 MHz, acetone-[d6]) δ, ppm: 9.82 (s, 1H, CH), 7.86–7.89 (m, 1H, Ar), 7.81–7.84 (m, 1H, Ar), 7.63–7.66 (m, 2H, Ar); 13C NMR (75.5 MHz, acetone-[d6]) δ, ppm: 154.3, 149.8, 134.1, 133.8, 133.4, 128.9, 124.5, 124.4, 123.1, 111.3. IR (KBr), ν: 2923, 1612, 1554, 1502, 1468, 1386, 1326, 1277, 1182, 1138, 1048, 1026, 950, 864, 825, 771 cm−1. HRMS (ESI) calcd. for C10H5BrN6NaO4: 374.9448 (79Br), 376.9428 (81Br). Found: 374.9441 (79Br), 376.9423 (81Br) [M+Na]+.
  • 3-(2-Fluorophenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3d): yield 131 mg (45%), white solid; mp 148–150 °C, Rf (CH2Cl2) = 0.70. 1H NMR (300 MHz, acetone-[d6]) δ, ppm: 9.79 (s, 1H, CH), 7.81–7.87 (m, 1H, Ar), 7.70–7.78 (m, 1H, Ar), 7.45–7.50 (m, 1H, Ar), 7.34–7.40 (m, 1H, Ar); 13C NMR (75.5 MHz, acetone-[d6]) δ, ppm: 160.1 (d, J = 240.0 Hz), 153.8, 149.4, 134.4 (d, J = 8.6 Hz), 131.2,(d, J = 1.4 Hz), 125.3 (d, J = 3.6 Hz), 124.5, 116.3 (d, J = 21.4 Hz), 109.2 (d, J = 14.2 Hz), 107.3. IR (KBr), ν: 2924, 2855, 1725, 1710, 1597, 1550, 1502, 1453, 1404, 1326, 1214, 1197, 1066, 1026, 971, 847, 793 cm−1. Calcd. for C10H5FN6O4 (%): C, 41.11; H, 1.72; N, 28.76. Found (%): C, 41.34; H, 1.64; N, 28.52.
  • 3-(2-Nitrophenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3e): yield 217 mg (68%), yellow solid; mp 121–123 °C, Rf (CH2Cl2) = 0.70. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.11 (s, 1H, CH), 8.42–8.45 (m, 1H, Ar), 7.85–7.97 (m, 2H, Ar) 7.74–7.79 (m, 1H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 153.5, 148.7, 147.3, 135.0, 133.3, 132.6, 126.2, 121.2, 116.5, 108.5. IR (KBr), ν: 2922, 1620, 1553, 1485, 1388, 1322, 1170, 1133, 1067, 1027, 953, 824, 754 cm−1. HRMS (ESI) calcd. for C10H5N7NaO6+: 342.0194. Found: 342.0192 [M+Na]+.
  • 4-(4-Nitro-1H-1,2,3-triazol-1-yl)-3-(2-(trifluoromethyl)phenyl)furoxan (3f): yield 123 mg (36%), light yellow solid; mp 100–102 °C, Rf (CH2Cl2) = 0.62. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.02 (s, 1H, CH), 7.79–7.89 (m, 3H, Ar), 7.64–7.68 (m, 1H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 153.5, 148.7, 133.1, 132.7, 132.5, 130.6, 127.4 (q, J = 4.7 Hz), 124.9, 121.5, 118.6 (d, J = 2.0 Hz), 108.0. IR (KBr), ν: 2923, 2851, 1620, 1585, 1553, 1485, 1439, 1389, 1319, 1172, 1121, 1033, 951, 867, 824, 771 cm−1. Calcd. for C11H5F3N6O4 (%): C, 38.61; H, 1.47; N, 24.56. Found (%): C, 38.47; H, 1.64; N, 24.30.
  • 3-(3-Bromophenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3g): yield 208 mg (59%), yellow solid; mp 110–112 °C, Rf (CH2Cl2) = 0.65. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.97 (s, 1H, CH), 7.83 (t, 1H, J = 1.8 Hz, Ar), 7.70–7.74 (m, 1H, Ar), 7.36–7.50 (m, 2H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 156.3, 153.3, 135.1, 131.3, 130.8, 127.1, 123.4, 123.0, 121.6, 109.2. IR (KBr), ν: 2921, 1610, 1529, 1427, 1383, 1351, 1325, 1271, 1231, 1179, 1133, 1075, 1026, 960, 852, 826, 786 cm−1. HRMS (ESI) calcd. for C10H579BrN6NaO4: 374.9448. Found: 374.9456 [M+Na]+.
  • 3-(3-Chlorophenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3h): yield 117 mg (38%), light yellow solid; mp 1118–120 °C, Rf (CH2Cl2) = 0.54. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.96 (s, 1H, CH), 7.78 (t, 1H, J = 1.9 Hz, Ar), 7.56–7.63 (m, 2H, Ar), 7.49 (t, 1H, J = 7.9 Hz, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 144.4, 135.5, 132.2, 130.6, 129.3, 127.2, 124.0, 123.8, 116.6. IR (KBr), ν: 1620, 1547, 1504, 1477, 1387, 1322, 1302, 1278, 1176, 1135, 1066, 1025, 952, 840 cm−1. Calcd. for C10H5ClN6O4 (%): C, 38.92; H, 1.63; N, 27.23. Found (%): C, 39.09; H, 1.51; N, 26.99.
  • 3-(3-Methoxyphenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3i): yield 142 mg (47%), white solid; mp 116–118 °C, Rf (CH2Cl2) = 0.61. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.90 (s, 1H, CH), 7.41 (t, 1H, J = 8.1 Hz, Ar), 7.16 (t, 1H, J = 2.1 Hz, Ar), 7.06–7.10 (m, 1H, Ar), 7.00–7.04 (m, 1H, Ar), 3.83 (s, 3H, OCH3); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 160.1, 148.2, 130.6, 123.6, 120.5, 120.2, 117.8, 113.6, 110.2, 55.5. IR (KBr), ν: 2918, 2846, 1631, 1603, 1548, 1503, 1430, 1383, 1323, 1274, 1112, 1047, 1004, 977, 824, 784 cm−1. Calcd. for C11H8N6O5 (%): C, 43.43; H, 2.65; N, 27.63. Found (%): C, 43.29; H, 2.76; N, 27.41.
  • 3-(3-Nitrophenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3j): yield 163 mg (51%), light yellow solid; mp 121–123 °C, Rf (CH2Cl2) = 0.86. 1H NMR (300 MHz, acetone-[d6]) δ, ppm: 9.44 (s, 1H, CH), 8.52 (t, 1H, J = 2.0 Hz, Ar), 8.35–8.38 (m, 1H, Ar), 7.91–7.95 (m, 1H, Ar), 7.72–7.77 (m, 1H, Ar); 13C NMR (75.5 MHz, acetone-[d6]+CDCl3) δ, ppm: 154.0, 148.5, 148.4, 134.5, 130.6, 126.1, 124.6, 123.8, 122.3, 109.6. IR (KBr), ν: 2921, 1626, 1551, 1502, 1440, 1383, 1326, 1291, 1170, 1142, 1091, 1023, 960, 902, 844, 808 cm−1. Calcd. for C10H5N7O6 (%): C, 37.63; H, 1.58; N, 30.72. Found (%): C, 37.82; H, 1.42; N, 30.48.
  • 4-(4-Nitro-1H-1,2,3-triazol-1-yl)-3-(4-(trifluoromethyl)phenyl)furoxan (3k): yield 112 mg (33%), light yellow solid; mp 145–147 °C, Rf (CH2Cl2) = 0.84. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.01 (s, 1H, CH), 7.75–7.84 (m, 4H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 148.0, 133.4, 129.8, 129.1, 126.4 (q, J = 3.6 Hz, CF3), 125.0, 123.8, 123.4, 123.1, 121.4, 109.5. IR (KBr), ν: 2922, 1620, 1551, 1519, 1486, 1388, 1322, 1164, 1111, 1066, 1027, 953, 823, 754 cm−1. HRMS (ESI) calcd. for C11H5F3N6NaO4+: 365.0217. Found: 365.0207 [M+Na]+.
  • 3-(4-Nitrophenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3l): yield 150 mg (47%), pale orange solid; mp 119–121 °C, Rf (CH2Cl2) = 0.55. 1H NMR (300 MHz, acetone-[d6]+CDCl3) δ, ppm: 9.77 (s, 1H, CH), 8.38–8.44 (m, 2H, Ar), 7.96–8.00 (m, 2H, Ar); 13C NMR (75.5 MHz, acetone-[d6]+CDCl3) δ, ppm: 149.2, 130.1, 127.8, 127.1, 125.6, 124.1, 123.43, 110.4. IR (KBr), ν: 1602, 1553, 1517, 1390, 1325, 1113, 1031, 987, 950, 854, 752 cm−1. Calcd. for C10H5N7O6 (%): C, 37.63; H, 1.58; N, 30.72. Found (%): C, 37.47; H, 1.67; N, 30.49.
  • 3-(4-Fluorophenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)-furoxan (3m): yield 146 mg (50%), light yellow solid; mp 120–122 °C, Rf (CH2Cl2) = 0.74. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.97 (s, 1H, CH), 7.61–7.65 (m, 2H, Ar), 8.25–8.29 (m, 2H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 164.4 (d, J = 255.5 Hz), 148.2, 130.8 (d, J = 9.0 Hz), 123.2, 117.0 (d, J = 22.5 Hz), 115.6 (d, J = 3.6 Hz), 109.8, 105.8. IR (KBr), ν: 2974, 2923, 1627, 1551, 1516, 1486, 1392, 1355, 1324, 1238, 1203, 1112, 1016, 954, 839, 752 cm−1. Calcd. for C10H5FN6O4 (%): C, 41.11; H, 1.72; N, 28.76. Found (%): C, 40.95; H, 1.90; N, 28.49.
  • 3-(2,4-Dichlorophenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3n): yield 212 mg (62%), pale yellow solid; mp 117–119 °C, Rf (CH2Cl2) = 0.84. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.06 (s, 1H, CH), 7.56–7.61 (m, 2H, Ar), 7.50–7.53 (m, 1H, Ar); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 153.7, 148.6, 139.4, 135.5, 132.7, 130.5, 128.5, 121.5, 118.4, 108.0. IR (KBr), ν: 2923, 2853, 1726, 1628, 1551, 1510, 1474, 1407, 1322, 1277, 1180, 1137, 1053, 950, 884, 788 cm−1. Calcd. for C10H4Cl2N6O4 (%): C, 35.01; H, 1.18; N, 24.50. Found (%): C, 34.83; H, 1.30; N, 24.32.
  • 3-(4-Chloro-3-nitrophenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3o): yield 191 mg (54%), yellow solid; mp 134–136 °C, Rf (CH2Cl2) = 0.45. 1H NMR (300 MHz, acetone-[d6]) δ, ppm: 9.10 (s, 1H, CH), 8.06 (br. s, 1H, Ar), 7.69 (br. s, 1H, Ar), 7.28 (s, 1H, Ar); 13C NMR (75.5 MHz, acetone-[d6]) δ, ppm: 156.5, 149.1, 149.0, 146.6, 138.0, 125.4, 117.7, 113.7, 104.9. IR (KBr), ν: 2978, 2901, 1613, 1592, 1553, 1480, 1384, 1278, 1080, 1023, 993, 908, 805, 725 cm−1. Calcd. for C10H4ClN7O6 (%): C, 33.96; H, 1.14; N, 27.73. Found (%): C, 34.13; H, 1.01; N, 27.51.
  • 3-(3,4-Dimethoxyphenyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3p): yield 167 mg (50%), white solid; mp 115–117 °C, Rf (CH2Cl2) = 0.86. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.92 (s, 1H, CH), 7.20 (d, 1H, J = 2.0 Hz, Ar), 7.02 (dd, 1H, J = 8.5, 2.0 Hz, Ar), 6.92–6.94 (d, 1H, J = 8.5 Hz, Ar), 3.92 (s, 3H, OCH3), 3.85 (s, 3H, OCH3); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 153.7, 151.9, 149.5, 148.3, 123.9, 121.7, 111.5, 111.1, 110.5, 110.4, 56.2, 56.1. IR (KBr), ν: 2921, 1580, 1517, 1484, 1433, 1387, 1324, 1221, 1149, 1115, 1012, 953, 860, 769 cm−1. Calcd. for C12H10N6O6 (%): C, 43.12; H, 3.02; N, 25.14. Found (%): C, 42.95; H, 3.15; N, 24.92.
  • 4-(4-Nitro-1H-1,2,3-triazol-1-yl)-3-(3,4,5-trimethoxyphenyl)furoxan (3q): yield 240 mg (66%), white solid; mp 138–140 °C, Rf (CHCl3/EtOAc, 15:1) = 0.38. 1H NMR (300 MHz, CDCl3) δ, ppm: 8.56 (s, 1H, CH), 7.27 (s, 2H, Ar), 3.91–3.95 (m, 9H, 3 OCH3); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 152.3, 150.0, 147.7, 145.4, 127.7, 124.2, 121.5, 111.5, 105.0, 61.3, 61.2, 56.3. IR (KBr), ν: 2924, 1591, 1565, 1488, 1426, 1352, 1296, 1201, 1110, 1061, 1013, 923, 825, 763 cm−1. Calcd. for C13H12N6O7 (%): C, 42.86; H, 3.32; N, 23.07. Found (%): C, 43.09; H, 3.16; N, 22.88.
  • 4-(4-Nitro-1H-1,2,3-triazol-1-yl)-3-(pyridin-2-yl)furoxan (3r): yield 137 mg (50%), pale yellow solid; mp 139–141 °C, Rf (CH2Cl2) = 0.86. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.13 (s, 1H, CH), 8.51–8.54 (m, 1H, Py), 8.25–8.29 (m, 1H, Py), 7.94–8.00 (m, 1H, Py), 7.43–7.48 (m, 1H, Py); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 150.2, 148.1, 141.2, 137.8, 125.9, 125.7, 122.5, 110.0. IR (KBr), ν: 2922, 1625, 1544, 1466, 1389, 1302, 1272, 1157, 1091, 1033, 989, 866, 785 cm−1. HRMS (ESI) calcd. for C9H5N7NaO4+: 298.0295. Found: 298.0306 [M+Na]+.
  • 3-(6-Nitro-1,3-benzodioxol-5-yl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3s): yield 260 mg (72%), brown solid; mp 138–140 °C, Rf (CH2Cl2) = 0.86. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.08 (s, 1H, CH), 7.84 (s, 1H, Ar), 7.06 (s, 1H, Ar), 6.32 (s, 2H, CH2); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 153.1, 151.2, 137.1, 131.6, 121.2, 118.5, 110.5, 110.2, 106.9, 104.5. IR (KBr), ν: 2923, 1712, 1625, 1588, 1503, 1481, 1391, 1331, 1265, 1110, 1024, 972, 881, 822 cm−1. HRMS (ESI) calcd. for C11H5N7NaO8+: 386.0081. Found: 386.0092 [M+Na]+.
  • 3-(5-Nitrofuran)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3t): yield 152 mg (52%), white solid; mp 139–141 °C, Rf (CH2Cl2) = 0.50. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.85 (s, 1H, CH Triazole), 7.77 (d, 1H, J = 4.0 Hz, CH Furan), 7.60 (d, 1H, J = 4.0 Hz, CH Furan); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 155.4, 153.9, 146.9, 137.9, 126.9, 116.2, 112.7, 105.9. IR (KBr), ν: 2925, 1796, 1725, 1630, 1503, 1475, 1394, 1310, 1244, 1155, 1025, 912, 856, 755 cm−1. Calcd. for C8H3N7O7 (%): C, 31.08; H, 0.98; N, 31.72. Found (%): C, 30.89; H, 1.11; N, 31.56.
  • 3-Metyl-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3u): yield 127 mg (60%), pale yellow solid; mp 129–131 °C, Rf (CH2Cl2) = 0.45. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.10 (s, 1H, CH), 2.63 (s, 3H, CH3); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 153.7, 149.8, 121.0, 107.5, 9.3. IR (KBr), ν: 2961, 2924, 2854, 1725, 1658, 1592, 1501, 1461, 1388, 1313, 1261, 1179, 1026, 950, 823, 752 cm−1. Calcd. for C5H4N6O4 (%): C, 28.31; H, 1.90; N, 39.62. Found (%): C, 28.09; H, 1.98; N, 39.39.
  • 3-(Cyclohexyl)-4-(4-nitro-1H-1,2,3-triazol-1-yl)furoxan (3v): yield 187 mg (67%), beige solid; mp 121–123 °C, Rf (CH2Cl2) = 0.76. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.03 (s, 1H, CH), 3.17–3.24 (m, 1H), 1.25–1.96 (m, 10H, Cy); 13C NMR (75.5 MHz, CDCl3) δ, ppm: 153.7, 148.8, 122.2, 113.4, 33.4, 26.4, 25.6, 25.0. IR (KBr), ν: 2929, 2854, 1726, 1608, 1547, 1491, 1449, 1387, 1313, 1270, 1180, 1105, 1049, 987, 881, 823 cm−1. Calcd. for C10H12N6O4 (%): C, 42.86; H, 4.32; N, 29.99. Found (%): C, 43.09; H, 4.18; N, 29.72.

4.3.3. NO Release Assay

The test molecule (0.1 mmol) was dissolved in DMSO (50 mL). A 20 µL aliquot of the resulting solution was diluted with a phosphate buffer solution (180 µL, Ph 7.4). The final concentration of the tested compound was 2 × 10−4 M. The mixture was incubated at 37 °C for 1 h. A 50 µL aliquot of the Griess reagent (prepared by mixing sulfanilamide (4 g), N-naphthylethylenediamine dihydrochloride (0.2 g) and 85% H3PO4 (10 mL) in distilled and deionized water (final volume 100 mL)) was added and incubated for 10 min at 37 °C. UV absorbance at 540 nm was measured using a Multiskan GO Microplate Photometer and calibrated using a standard curve prepared from standard solutions of NaNO2 to give the nitrite concentration. All measurements were made in triplicate.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules28196969/s1: crystallographic data and copies of NMR spectra.

Author Contributions

Conceptualization, A.A.L. and L.L.F.; methodology, I.A.S.; investigation, I.A.S., A.A.L. and I.V.A.; writing—original draft preparation, A.A.L. and I.V.A.; writing—review and editing, L.L.F.; supervision, L.L.F.; project administration, L.L.F.; funding acquisition, L.L.F. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Russian Science Foundation (project 23-43-00090).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data obtained in this project are contained within this article and are available upon request from the authors.

Acknowledgments

Crystal structure determination procedures were performed at the Department of Structural Studies of the Zelinsky Institute of Organic Chemistry, Moscow, and at the Facilities of JRC PMR of the Kurnakov Institute of General and Inorganic Chemistry, Moscow. I.V. Ananyev is grateful to the support of the structural study by the Ministry of Science and Higher Education of the Russian Federation as part of the State Assignment of the N.S. Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Molecules 28 06969 g001
Figure 1. Heterocyclic NO donors.
Figure 1. Heterocyclic NO donors.
Molecules 28 06969 g001
Molecules 28 06969 sch001
Scheme 1. Previously known approaches toward the formation of (1,2,3-triazolyl)-1,2,5-oxadiazoles from 4-azidofuroxans with: (a) acetylenes and 1,3-dicarbonyl compounds, (b) 1-morpholino-2-nitroethylene and (c) newly developed protocol.
Scheme 1. Previously known approaches toward the formation of (1,2,3-triazolyl)-1,2,5-oxadiazoles from 4-azidofuroxans with: (a) acetylenes and 1,3-dicarbonyl compounds, (b) 1-morpholino-2-nitroethylene and (c) newly developed protocol.
Molecules 28 06969 sch001
Molecules 28 06969 sch002
Scheme 2. Synthesis of 4-azidofuroxans 2a–v.
Scheme 2. Synthesis of 4-azidofuroxans 2a–v.
Molecules 28 06969 sch002
Molecules 28 06969 sch003
Scheme 3. Substrate scope for the synthesis of (4-nitro-1,2,3-triazolyl)furoxans 3a–v.
Scheme 3. Substrate scope for the synthesis of (4-nitro-1,2,3-triazolyl)furoxans 3a–v.
Molecules 28 06969 sch003
Molecules 28 06969 g002
Figure 2. The crystal structures of 2a (upper), 3a (bottom left) and 3c (bottom right). All atoms are shown as probability ellipsoids of atomic displacements (p = 0.5).
Figure 2. The crystal structures of 2a (upper), 3a (bottom left) and 3c (bottom right). All atoms are shown as probability ellipsoids of atomic displacements (p = 0.5).
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Molecules 28 06969 sch004
Scheme 4. Plausible mechanism for the regioselective formation of 4-nitro-1,2,3-triazoles 3.
Scheme 4. Plausible mechanism for the regioselective formation of 4-nitro-1,2,3-triazoles 3.
Molecules 28 06969 sch004
Molecules 28 06969 g003
Figure 3. NO release data of 4-nitrotriazolylfuroxans 3a–v.
Figure 3. NO release data of 4-nitrotriazolylfuroxans 3a–v.
Molecules 28 06969 g003
Table 1. Optimization of the reaction conditions for the synthesis of 3a a.
Table 1. Optimization of the reaction conditions for the synthesis of 3a a.
Molecules 28 06969 i001
EntryEquiv. of DipolarophileAdditive
(mol. %)		SolventT, °CTime, hYield of 3a b, %
11—PhMe11072—
22—PhMe11072traces
33—PhMe1107224
45—PhMe1107230
55—CHCl360728
65—PhH807232
73—dioxane10272traces
85—MeCN8272traces
93BF3·OEt2 (15)PhMe1104823
103BF3·OEt2 (15)MeCN827212
113ZnCl2 (10)PhMe709618
123Yb(OTf)3 (15)PhMe1107215
133Yb(OTf)3 (15)MeCN8272traces
142mCPBA (10)PhMe11072traces
155p-TSA (15)PhH807248
165p- TSA (15)MeCN827251
175p-TSA (30)MeCN827249
185p-TSA (10)MeCN827232
195PPTS (15)MeCN827236
205p-TSA (15)PhMe1103636
a Reaction conditions: 1a (0.217 g, 1 mmol), dipolarophile, additive, stirring at indicated temperature for 36–96 h. b Isolated yields.
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MDPI and ACS Style

Stebletsova, I.A.; Larin, A.A.; Ananyev, I.V.; Fershtat, L.L. Regioselective Synthesis of NO-Donor (4-Nitro-1,2,3-triazolyl)furoxans via Eliminative Azide–Olefin Cycloaddition. Molecules 2023, 28, 6969. https://doi.org/10.3390/molecules28196969

AMA Style

Stebletsova IA, Larin AA, Ananyev IV, Fershtat LL. Regioselective Synthesis of NO-Donor (4-Nitro-1,2,3-triazolyl)furoxans via Eliminative Azide–Olefin Cycloaddition. Molecules. 2023; 28(19):6969. https://doi.org/10.3390/molecules28196969

Chicago/Turabian Style

Stebletsova, Irina A., Alexander A. Larin, Ivan V. Ananyev, and Leonid L. Fershtat. 2023. "Regioselective Synthesis of NO-Donor (4-Nitro-1,2,3-triazolyl)furoxans via Eliminative Azide–Olefin Cycloaddition" Molecules 28, no. 19: 6969. https://doi.org/10.3390/molecules28196969

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