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Article

Synthesis of 4-(Phenylchalcogenyl)tetrazolo[1,5-a]quinolines by Bicyclization of 2-Azidobenzaldehydes with Phenylchalcogenylacetonitrile

by
Loana I. Monzon
1,
Nicole C. M. Rocha
1,
Gabriela T. Quadros
1,
Pâmela P. P. Nunes
1,
Roberta Cargnelutti
2,
Raquel G. Jacob
1,
Eder J. Lenardão
1,
Gelson Perin
1,* and
Daniela Hartwig
1,*
1
Laboratório de Síntese Orgânica Limpa-LaSOL-CCQFA, Universidade Federal de Pelotas—UFPel, P.O. Box 354, Pelotas 96010-900, RS, Brazil
2
Departamento de Química, Universidade Federal de Santa Maria—UFSM, Av. Roraima, Building 18, Santa Maria 97105-900, RS, Brazil
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(13), 5036; https://doi.org/10.3390/molecules28135036
Submission received: 30 May 2023 / Revised: 19 June 2023 / Accepted: 23 June 2023 / Published: 27 June 2023
(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)
Browse Figures
Versions Notes

Abstract

:
A general methodology to access valuable 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines was developed by the reaction of 2-azidobenzaldehyde with phenylchalcogenylacetonitriles (sulfur and selenium) in the presence of potassium carbonate (20 mol%) as a catalyst. The reactions were conducted using a mixture of dimethylsulfoxide and water (7:3) as solvent at 80 °C for 4 h. This new methodology presents a good functional group tolerance to electron-deficient and electron-rich substituents, affording a total of twelve different 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines selectively in moderate to excellent yields. The structure of the synthesized 4-(phenylselanyl)tetrazolo[1,5-a]quinoline was confirmed by X-ray analysis.

Graphical Abstract

1. Introduction

Tetrazoles and quinolines are members of the important class of the azaheterocycles, which have a wide variety of applications. The first ones consist in a five-membered ring with four nitrogen and one carbon atom. Even though they cannot be found in nature, tetrazoles are very stable considering the number of nitrogen atoms. Tetrazole derivatives are used as explosives and fuels in the arms industry and as agrochemicals, and they can be found in over 40 commercial drugs as antibiotic, antiallergic, analgesic, and antihypertensive agents (Figure 1) [1,2,3,4].
On the other hand, quinoline scaffold is a benzene ring-fused pyridine mostly found in various natural products, particularly in alkaloids. Quinolines have multipurpose applications in medicinal chemistry, such as anticancer, antibacterial, antifungal, anthelmintic, antiprotozoal, anticonvulsant, antitubercular, anti-inflammatory, analgesic, antimalarials, and antiviral agents (Figure 1) [5,6,7].
Tetrazoloquinolines are molecular hybrids that contain both quinoline and tetrazole systems in the same molecule, and they have received much attention due to their biological activities and synthetic usefulness [8,9,10,11]. Despite the significant advances toward the synthesis of new azaheterocycles, the need for a new study on the combinations of substrates for the synthesis of new tetrazoloquinolines and more complex structures is still an open issue.
In this context, chalcogen–tetrazolo[1,5-a]quinolines constitute an interesting class of molecules, which combine the importance of a tetrazoloquinoline nucleus [8,9,10,11] with an organochalcogen moiety [12,13,14]. Selenium and sulfur are important essential elements, playing important roles in metabolic pathways [15,16,17,18,19,20], and the interest in chalcogen chemistry [21,22,23] and pharmacology [24,25,26,27] has increased in this century.
Several methodologies [28,29,30,31,32,33,34] have been reported for the synthesis of a range of tetrazolo[1,5-a]quinolines such as (i) from the reaction of 2-chloroquinoline with sodium azide (Scheme 1, Method A) [32]; (ii) from the diazotization of 2-hydrazinylquinoline derivatives (Scheme 1, Method B) [29]; and (iii) from the intramolecular cyclocondensation of 2-azidoarylidenes (Scheme 1, Method C) [31,34]. However, to the best of our knowledge, there are no procedures to directly prepare 4-(phenylchalcogenyl)tetrazol[1,5-a]quinolines. Additionally, most of the described synthetic routes to obtain tetrazolo[1,5-a]quinolines involve high temperatures, long reaction times, harsh catalysis, and toxic solvents [28].
Tetrazole or triazole nucleus can be formed in very good yields through the fast, concerted and regioselective [3 + 2] cycloaddition between arylazides and acetonitrile-bearing active CH groups [33,34,35,36]. Heating is necessary for poorly reactive substrates, but if strong electron-withdrawing groups are present in the acetonitrile counterpart, the reaction takes place rapidly. In the same way, the intramolecular cycloaddition can occur quickly in molecules that have these two groups (nitrile and azide) in the same chain [33,34,35].
Polycyclic tetrazoles can be obtained when various arylazides containing an electrophilic group at the ortho position are used. Thus, cyclocondensation of 2-azidobenzaldehydes with acetonitrile derivatives under base catalysis have been used to produce tetrazolo[1,5-a]quinoline derivatives [28]. However, with 2-azidobenzaldehyde 1a, the active methylene anion of acetonitrile I reacts with both the aldehyde and azide sites, resulting in two reaction pathways (Scheme 2) [34]. Subsequent cyclization of the respective intermediates II and III formed in situ leads to two different heterocyclic compounds. The pathway cyclization depends on the reaction conditions and are subject to solvent effects [34]. Usually, in the presence of protic solvents and heating, tetrazolo[1,5-a]quinolines IV were synthesized, whereas in aprotic solvent and at low temperature, 1,2,3-triazolo[1,5-a]quinazolines V were obtained [34,35,36].
In path A, the first step of the reaction involves the Knoevenagel condensation of aldehyde with the methylene anion of acetonitrile, formed in the presence of a base. In the second step, the intramolecular [3 + 2] cycloaddition of II occurs, affording the tetrazolo[1,5-a]quinoline IV. Pathway B, instead, starts with the attack of acetonitrile carbanion on the azide function followed by the intramolecular cyclocondensation between the amino and carbonyl groups of the aminotriazole intermediate III, affording the 1,2,3-triazolo[1,5-a]quinazoline V (Scheme 2).
Based on what was described so far, and in our interest in developing new strategies to prepare potentially bioactive organochalcogen compounds, we decided to explore the reaction of Scheme 2 to create so far unprecedented hybrid molecules containing both the tetrazolo[1,5-a]quinoline and organochalcogen moieties under green conditions. Therefore, herein we describe the synthesis of 4-(arylchalcogenyl)tetrazolo[1,5-a]quinoline 3a–l through the intramolecular cyclocondensation between 2-azidobenzaldehydes 1 and appropriate 2-(arylchalcogenyl)acetonitriles 2, using K2CO3 as base in a mixture of DMSO:H2O as solvent (Scheme 1, Method D).

2. Results and Discussion

Initially, we chose 2-azidobenzaldehyde 1a and 2-(arylselanyl)acetonitrile 2a as model substrates to establish the best conditions for this reaction, and some experiments were performed to synthesize the corresponding tetrazolo[1,5-a]quinoline 3a (Table 1). We started our studies by reacting 1a (0.25 mmol) with 2a (0.25 mmol) at 80 °C for 4 h, using K2CO3 (20 mol%) as a catalyst in 1.0 mL of DMSO as solvent. Under these conditions, the desired product 3a was obtained in 21% yield (Table 1, entry 1). When water was used as the solvent, only traces of 3a were detected by GC/MS (Table 1, entry 2). An excellent result was obtained when a mixture of DMSO:H2O (7:3) was used as solvent, leading to the expected product 3a in 98% yield (Table 1, entry 3), showing that a small amount of water is needed to dissolve the potassium carbonate.
Next, we investigated the use of different solvents; water was mixed with glycerol, DMF, toluene and acetonitrile. Unfortunately, a decrease in the yield of 3a was observed in all cases, with glycerol being the best in class (Table 1, entries 4–7). When the reaction was performed without solvent, the expected product 3a was obtained in only 10% yield (Table 1, entry 8). Hence, a 7:3 mixture of DMSO and water was chosen as the best solvent for this reaction.
As a way to verify how different bases can affect the reaction, cesium carbonate (Cs2CO3), potassium hydroxide (KOH), triethylamine (Et3N), and 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) were tested in the reaction of 1a with 2a (Table 1, entries 9–12). However, except for Cs2CO3 (92% yield), the observed results were not satisfactory, and lower yields of 3a were obtained in all cases. When the amount of K2CO3 was reduced to 10 mol%, the desired product 3a was obtained in only 10% yield, while no product was observed in the absence of base, demonstrating the crucial role of the base (Table 1, entries 13 and 14). Thus, K2CO3 that is considered a green catalyst, [37] was set as the best base for this reaction. When the reactions were performed at 60 °C and 100 °C, the desired product 3a was obtained in 30% and 62% yield, respectively (Table 1, entries 15 and 16). The tetrazolo[1,5-a]quinoline 3a was respectively obtained in 68% and 22% yield after 3 and 2 h of reaction (Table 1, entries 17 and 18). Finally, a reaction was performed at room temperature, to verify the possibility of preparing the respective 1,2,3-triazolo[1,5-a]quinazoline V (see Scheme 2, Pathway B). After 4 h of reaction, only 50% of the starting aldehyde was consumed, and a mixture of triazole 8a and tetrazole derivative 3a was obtained in a 2:8 ratio (Table 1, entry 19).
Based on the results shown in Table 1, the best reaction conditions involve stirring a mixture of 2-azidobenzaldehyde (1a, 0.25 mmol) and 2-(arylselanyl)acetonitrile (2a, 0.25 mmol) in the presence of K2CO3 (20 mol%) as base in a 7:3 mixture of DMSO:H2O (1.0 mL) as solvent for 4 h at 80 °C.
The identity of the new 4-(arylchalcogenyl)tetrazolo[1,5-a]quinolines was confirmed by HRMS, and 1H, 13C and 77Se-NMR analysis. In the 1H-NMR spectrum of all the prepared compounds, a characteristic signal is a doublet (J ≅ 8.0 Hz) around 8.5 ppm, referring to H-6, while in the 13C-NMR the characteristic tetrazole ring Csp2 appears at 146.5–147.0 ppm. In addition, the chemical structure of 4-(phenylselanyl)tetrazolo[1,5-a]quinoline 3a was confirmed by a single crystal X-ray diffraction analysis (Figure 2) (for details, see the Supplementary Materials). Colorless crystals of compound 3a were obtained by the slow evaporation of the dichloromethane/ethyl acetate (1:1) mixture, in the refrigerator. The obtained crystals were analyzed by single crystal X-ray diffraction analysis (Figure 2). The distance between Se(1)–C(1) and Se(1)–C(7) is 1.916(2) and 1.899(2) Å, respectively. The N–N and N–C distance in the tetrazol portion of the structure is N(1)–N(2) 1.364(3); N(3)–N(2) 1.304(4), N(3)–N(4) 1.358(4); N(1)–C(15) 1.349(3) and N(4)–C(15) 1.327(3) Å. The angle between the C(7)–Se(1)–C(1) is 100.23(9)°.
The scope of the proposed methodology was then extended to differently substituted arylselanyl-acetonitrile 2a–h, in the reaction with 2-azidobenzaldehyde 1a, aiming to investigate the generality and limitations of the method (Scheme 3). Interestingly, the presence of substituents in the benzene ring of the arylselanyl-acetonitrile counterpart decreases the reactivity compared to the unsubstituted 2a, but a clear electronic effect could not be observed. For instance, electron-rich 2-(p-tolylselanyl)acetonitrile 2b, 2-(o-tolylselanyl)acetonitrile 2c, and 2-(mesitylselanyl)acetonitrile 2d reacted smoothly with 1a to afford the respective tetrazolo[1,5-a]quinolines 3b, 3c, and 3d in 60%, 63%, and 45% yield. Similarly, the electron-poor 2-((4-chlorophenyl)selanyl)acetonitrile 2f and 2-((3-(trifluoromethyl)phenyl)selanyl)acetonitrile 2g produced the expected products 3f and 3g in 52% and 50% yield, respectively. A remarkable result was obtained in the reaction of 2-((4-fluorophenyl)selanyl)acetonitrile 2e, which afforded 4-((4-fluorophenyl)selanyl)tetrazolo[1,5-a]quinoline 3e in 80% yield under optimal conditions. Satisfactorily, the protocol was suitable for the heteroaromatic derivative 2h, and 4-(thiophen-2-ylselanyl)tetrazolo[1,5-a]quinoline 3h was synthesized in 70% yield.
Subsequently, we investigated the reactivity of a variety of arylthioacetonitriles 2i–l with 2-azidobenzaldehyde 1a under the optimized conditions (Scheme 4). In contrast to the observed for the selenium analogs, the presence of substituents in para-position of the benzene ring of the thioacetonitrile did not strongly influence the reactivity. Thus, unsubstituted 2-(phenylthio)acetonitrile 2i afforded 3i in 62% yield, while the substituted derivatives 3j, 3k, and 3l were obtained in 60%, 55%, and 55% yield, respectively.
Based on the literature [33,34,35,36] and our own results, we believe that the reaction probably proceeds via path A (Scheme 2), suggesting that the plausive mechanism for the formation of 4-(arylchalcogenyl)tetrazolo[1,5-a]quinoline 3 is that of Scheme 5. Initially, in the presence of K2CO3, the Knoevenagel condensation between 2-azidobenzaldehyde 1a and 2-(phenylselanyl)-acetonirile 2a occurs, leading to the intermediate I. Then, an intramolecular [3 + 2] cycloaddition of the azido group to the nitrile group in intermediate I furnishes the 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinoline 3a.

3. Materials and Methods

3.1. General Information

Reactions were carried out in a two-necked round-bottomed flask with a Teflon-coated magnetic stirring bar. Solvents and reagents were used as received unless otherwise noted. The reactions were monitored by thin-layer chromatography (TLC), which was performed using Merck (Merck, Darmstadt, Germany) silica gel (60 F254), with a 0.25 mm thickness. For visualization, TLC plates were either exposed to UV light, or stained with iodine vapor or in a 5% vanillin solution in 10% aqueous H2SO4 and heat. Hydrogen nuclear magnetic resonance spectra (1H NMR) were obtained on a Bruker Avance III HD 400 MHz employing a direct broad-band probe at 400 MHz. The spectra were recorded in CDCl3 or DMSO-d6 solutions. The chemical shifts (δ) are reported in ppm, referenced to tetramethylsilane (TMS) as the internal reference. Coupling constants (J) are reported in Hertz. Carbon-13 nuclear magnetic resonance spectra (13C NMR) were obtained on Bruker Avance III HD 400 MHz employing a direct broad-band probe at 100 MHz. The chemical shifts (δ) are reported in ppm, referenced to the solvent peak of CDCl3 (δ 77.0 ppm) or DMSO-d6 (39.7 ppm). Selenium-77 nuclear magnetic resonance spectra (77Se NMR) were obtained on a Bruker Avance III HD 400 MHz employing direct broad-band probe at 76 MHz. The chemical shifts (δ) are reported in ppm, using as solvent CDCl3 and diphenyl diselenide as an internal standard (δ 463 ppm). Figures of the NMR spectra are presented in the Supplementary Materials. High-resolution mass spectra (HRMS) were recorded in positive ion mode (APCI) using a Q-TOF or a Quadrupole-Orbitrap spectrometer. Melting point (mp) values were measured in a Marte PFD III instrument with a 0.1 °C precision. The starting 2-azidobenzaldehydes 1 [38] and 2-(arylchalcogenyl)acetonitriles 2a–l [39] were synthesized according to the literature.

3.2. Synthesis of 2-Azidobenzaldehyde 1a

2-Azidobenzaldehyde (1a) was synthesized according to the methodology proposed by Qiu et al., with some modifications [38]. In a 100 mL two-necked round-bottomed flask equipped with magnetic stirring and at 60 °C (oil bath), 15 mmol (2.26 g) of 2-nitrobenzaldehyde and 25 mL of dimethylformamide (DMF) were added. The solution was stirred for 5 min and after that, 30 mmol (1.95 g) of sodium azide (NaN3) was added under air atmosphere. The resulting mixture was stirred at 60 °C for 48 h. After this time, the resulting solution was received into water (150 mL) and the product was extracted with ethyl acetate (3 × 50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure (rotary evaporator). The crude oil was purified by column chromatography using silica gel and hexane–ethyl acetate (98:02) as the eluent. The respective product was obtained in 54% of yield (1.19 g).

3.3. General Procedure for the Synthesis of (Arylchalcogenyl)acetonitriles 2a–l

The (arylchalcogenyl)acetonitriles 2a–l were synthesized according to the methodology proposed by Alves et al., with some modifications [39]. In a 25 mL round-bottomed reaction flask equipped with magnetic stirring, 1.2 mmol of diaryl chalcogenide (RSeSeR or RSSR), 5 mL of tetrahydrofuran (THF) and 2 mL of ethanol were added. The resulting mixture was stirred for a few minutes at 0 °C under N2 atmosphere. Then, 3 mmol (0.11 g) of sodium borohydride was slowly added. After that, the reaction color changed from yellow to white. In the sequence, 2.5 mmol of the respective chloronitrile was added and stirred at room temperature under N2 atmosphere for 8 h. After this time, the reaction mixture was received into water (150 mL) and the product was extracted with ethyl acetate (3 × 25 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum (rotary evaporator). The residue was purified by column chromatography using silica gel and hexane–ethyl acetate as the eluent. The products 2a–l were obtained in good to excellent yields.

3.4. General Reaction Procedure for the Synthesis of 4-(Arylchalcogenyl)tetrazolo[1,5-a]quinolines 3a–l

2-Azidobenzaldehyde 1a (0.037 g, 0.25 mmol), 2-(arylchalcogenyl)acetonitrile 2 (0.25 mmol), K2CO3 (0.007 g, 20 mol%) and DMSO:H2O (7:3, 1 mL) were added to a 25 mL two-necked round-bottomed flask. The system was then immersed in a preheated oil bath at 80 °C and stirred at this temperature until total disappearance of the starting materials. Reactions were monitored by thin-layer chromatography (TLC). After the completion of the reaction, the reaction mixture was cooled to room temperature and extracted with EtOAc (3 × 10 mL), dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by preparative chromatographic plate using ethyl acetate/hexane as the eluent. Spectral data for the prepared products are listed below.
4-(Phenylselanyl)tetrazolo[1,5-a]quinoline (3a): Brown solid, mp: 171–174 °C. Yield: 98%. 1H NMR (400 MHz, CDCl3) δ: 8.57 (d, J = 8.3 Hz, 1H), 7.77 (dd, J = 14.9 and 7.5 Hz, 3H), 7.67 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.49 (dt, J = 14.1 and 7.0 Hz, 3H), 7.37 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 147.1, 136.5 (2C), 130.9, 130.1 (2C), 130.0, 129.8, 129.2, 127.9, 127.7, 125.2, 124.6, 119.7, 116.6. 77Se NMR (76 MHz, CDCl3) δ: 397.49. HRMS m/z: [M + H]+ Calcd. for C15H10N4Se: 327.0143. Found: 327.0134.
4-(p-Tolylselanyl)tetrazolo[1,5-a]quinoline (3b): Brown solid, mp: 123–125 °C. Yield: 60%.
1H NMR (400 MHz, CDCl3) δ: 8.56 (d, J = 8.3 Hz, 1H), 7.74 (t, J = 8.3 Hz, 1H), 7.66 (d, J = 8.0 Hz, 3H), 7.58 (t, J = 7.6 Hz, 1H), 7.31 (s, 1H), 7.27 (d, J = 7.9 Hz, 2H), 2.24 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 147.0, 140.2, 136.7 (2C), 131.0 (2C), 130.2, 129.8, 129.1, 127.9, 127.6, 124.6, 121.3, 120.4, 116.6, 21.3. 77Se NMR (76 MHz, CDCl3) δ: 353.31. HRMS m/z: [M + H]+ Calcd. for C16H12N4Se: 341.0300. Found: 341.0290.
4-(o-Tolylselanyl)tetrazolo[1,5-a]quinoline (3c): White solid, mp: 167–169 °C. Yield: 63%. 1H NMR (400 MHz, CDCl3) δ: 8.56 (d, J = 8.3 Hz, 1H), 7.77–7.72 (m, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 4.2 Hz, 2H), 7.28–7.24 (m, 1H), 7.14 (s, 1H), 2.51 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 147.0, 142.9, 137.9, 130.9, 130.5, 129.8, 129.1, 129.0, 127.9, 127.6, 127.5, 125.7, 124.6, 119.3, 116.5, 22.7. 77Se NMR (76 MHz, CDCl3) δ: 354.05. HRMS m/z: [M + H]+ Calcd. for C16H12N4Se: 341.0300. Found: 341.0287.
4-(Mesitylselanyl)tetrazolo[1,5-a]quinoline (3d): White solid, mp: 184–186 °C. Yield: 45%. 1H NMR (400 MHz, CDCl3) δ: 8.49 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.03 (s, 2H), 6.83 (s, 1H), 2.41 (s, 6H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 147.09, 144.1 (2C), 140.61, 129.4 (2C), 129.38, 128.89, 127.80, 127.44, 127.08, 124.89, 122.94, 119.82, 116.61, 23.9 (2C), 21.15. 77Se NMR (76 MHz, CDCl3) δ: 280.22. HRMS m/z: [M + H]+ Calcd. for C18H16N4Se: 369.0613. Found: 369.0608.
4-((4-Fluorophenyl)selanyl)tetrazolo[1,5-a]quinoline (3e): Yellow solid, mp: 163–167 °C. Yield: 80%. 1H NMR (400 MHz, CDCl3) δ: 8.55 (d, J = 8.3 Hz, 1H), 7.79–7.72 (m, 3H), 7.66 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 8.1 Hz, 1H), 7.52–7.44 (m, 2H), 7.36 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 163.8 (d, J = 251.8 Hz), 146.3, 137.4 (d, J = 8.6 Hz, 2C), 130.1, 129.0, 128.1, 127.8, 127.8, 125.4, 124.3, 124.0 (d, J = 3.4 Hz), 117.4 (d, J = 22.1 Hz, 2C), 116.7. 77Se NMR (76 MHz, CDCl3) δ: 388.82. HRMS m/z: [M + H]+ Calcd. for C15H9FN4Se: 345.0049. Found: 345.0052.
4-((4-Chlorophenyl)selanyl)tetrazolo[1,5-a]quinoline (3f): White solid, mp: 146–149 °C. Yield: 52%. 1H NMR (400 MHz, CDCl3) δ: 8.58 (d, J = 8.3 Hz, 1H), 7.79 (t, J = 8.3 Hz, 1H), 7.71 (d, J = 8.5 Hz, 3H), 7.63 (t, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 147.1, 137.6 (2C), 136.2, 131.6, 130.4, 130.3 (2C), 129.4, 128.1, 127.9, 124.4, 123.6, 118.8, 116.7. 77Se NMR (76 MHz, CDCl3) δ: 391.28. HRMS m/z: [M + H]+ Calcd. for C15H9ClN4Se: 360.9754. Found: 360.9735.
4-((3-(Trifluoromethyl)phenyl)selanyl)tetrazolo[1,5-a]quinoline (3g): Yellow solid, mp: 145–149 °C. Yield: 50%. 1H NMR (400 MHz, CDCl3) δ: 8.62 (d, J = 8.3 Hz, 1H), 8.03 (s, 1H), 7.97 (dd, J = 7.8 Hz, 1H), 7.84 (td, J = 7.3 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.73–7.71 (m, 1H), 7.66 (td, J = 8.6 Hz, 1H), 7.58 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 147.3, 139.2, 133.1, 132.3 (q, J = 3.8 Hz), 132.2 (q, J = 32.8 Hz), 130.8, 130.4, 128.7, 128.4 (q, J = 266.0 Hz), 128.2, 128.1, 126.3 (q, J = 3.8 Hz), 124.7, 122.0, 117.6, 116.8. 77Se NMR (76 MHz, CDCl3) δ: 400.57. HRMS m/z: [M + H]+ Calcd. for C16H9F3N4Se: 395.0017. Found: 395.0017.
4-(Thiophen-2-ylselanyl)tetrazolo[1,5-a]quinoline (3h): White solid, mp: 160–163 °C. Yield: 70%. 1H NMR (400 MHz, CDCl3) δ: 8.54 (d, J = 8.3 Hz, 1H), 7.75 (td, J = 8.4 and 1.3 Hz, 1H), 7.70–7.66 (m, 2H), 7.59 (td, J = 8.2 and 1.2 Hz, 1H), 7.55 (dd, J = 3.5 and 1.2 Hz, 1H), 7.31 (s, 1H), 7.23–7.21 (m, 1H). 13C NMR (100 MHz, CDCl3) δ: 146.5, 139.4, 134.1, 130.10, 130.09, 129.1, 129.0, 127.9, 127.8, 124,5, 120.4, 117.9, 116.5. HRMS m/z: [M + H]+ Calcd. for C13H8N4SSe: 332.9708. Found: 332.9701.
4-(Phenylthio)tetrazolo[1,5-a]quinoline (3i): Brown solid, mp: 175–178 °C. Yield: 62%. 1H NMR (400 MHz, CDCl3) δ: 8.57 (d, J = 8.3 Hz, 1H), 7.75 (t, J = 8.3 Hz, 1H), 7.70–7.66 (m, 3H), 7.60 (t, J = 7.6 Hz, 1H), 7.51–7.49 (m, 3H), 7.24 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 146.4, 134.9 (2C), 130.1 (2C), 129.9, 129.9, 128.9, 128.8, 128.0, 127.8 (2C), 125.4, 124.3, 116.6. HRMS m/z: [M + H]+ Calcd. for C15H10N4S: 279.0699. Found: 279.0692.
4-(p-Tolylthio)tetrazolo[1,5-a]quinoline (3j): Brown solid, mp: 122–126 °C. Yield: 60%. 1H NMR (400 MHz, DMSO-d6) δ: 8.67 (d, J = 8.3 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.02 (t, J = 7.6 Hz, 1H), 7.87–7.83 (m, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 3.47 (s, 3H). 13C NMR (100 MHz, DMSO) δ: 146.3, 139.2, 133.4 (2C), 130.8 (2C), 130.7, 130.1, 128.8, 128.6, 128.3, 125.8, 124.1, 122.8, 116.1, 20.8. HRMS m/z: [M + H]+ Calcd. for C16H12N4S: 293.0855. Found: 293.0851.
4-((4-Methoxyphenyl)thio)tetrazolo[1,5-a]quinoline (3k): White solid, mp: 157–159 °C. Yield: 55%. 1H NMR (400 MHz, CDCl3) δ: 8.55 (d, J = 8.3 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.67–7.56 (m, 4H), 7.10–7.01 (m, 3H), 3.90 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 161.3, 146.1, 137.4 (2C), 129.5, 128.6, 127.9, 127.6, 127.1, 125.9, 124.4, 118.3, 116.5, 115.7 (2C), 55.5. HRMS m/z: [M + H]+ Calcd. for C16H12N4OS: 309.0805. Found: 309.0802.
4-((4-Chlorophenyl)thio)tetrazolo[1,5-a]quinoline (3l): White solid, mp: 174–177 °C. Yield: 55%. 1H NMR (400 MHz, CDCl3) δ: 8.61 (d, J = 8.2 Hz, 1H), 7.78 (dd, J = 15.2 and 7.6 Hz, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.36 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 146.5, 136.2, 135.8 (2C), 130.4, 130.3 (2C), 129.2, 129.0, 128.2, 127.9, 127.8, 124.4, 124.2, 116.7. HRMS m/z: [M + H]+ Calcd. for C15H9ClN4S: 313.0309. Found: 313.0300.

4. Conclusions

In summary, we have described here an efficient and environmentally friendly strategy to prepare 4-(arylselanyl)- and 4-(arylthiol)tetrazolo[1,5-a]quinoline starting from easily prepared and bench-stable 2-azidobenzaldehyde and 2-(arylchalcogenyl)acetonitriles. The reactions proceeded at a gentle heating of 80 °C for only 4 h, affording a total of 12 products 3a–l in good to excellent yields (50–98%). Further studies are ongoing to better characterize the pharmacological potential antinociceptive and antidepressive-like of these new compounds.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28135036/s1, Figure S1–S31: Selected 1H, 13C, and 77Se NMR spectra of the prepared compounds; Figure S32: Thermal ellipsoid plot at the 50% probability level for the compound 3a; Table S1: Crystal data and structure refinement for compound 3a; Figures S33–S43: Selected HRMS spectra of the new compounds.

Author Contributions

G.P., R.G.J., D.H. and E.J.L. conceived and designed the experiments; L.I.M., N.C.M.R., P.P.P.N. and G.T.Q. performed the experiments; G.P., R.G.J., D.H. and E.J.L. analyzed the data and wrote the paper, R.C. formal analysis. All authors have read and agreed to the published version of the manuscript.

Funding

This study was financed in part by the Coordenacão de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001. CNPq (Universal 422645/2021-4), FAPERGS, and FINEP are acknowledged for financial support. CNPq is also acknowledged for fellowships to E.J.L., G.P. and R.G.J.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The crystallographic information file (CIF) for the studied compound was deposited at the Cambridge Crystallographic Data Centre (CCDC) under identification number 2248272.

Acknowledgments

Thiago Barcellos, from University of Caxias do Sul, is acknowledged for providing the HRMS analysis.

Conflicts of Interest

The authors declare no conflict of interests.

Sample Availability

Samples of the compounds are available from the authors upon proper request.

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Molecules 28 05036 g001 550
Figure 1. Commercially available drugs containing the tetrazole or quinoline moiety.
Figure 1. Commercially available drugs containing the tetrazole or quinoline moiety.
Molecules 28 05036 g001
Molecules 28 05036 sch001 550
Scheme 1. Previous methods to prepare tetrazolo[1,5-a]quinolines. Method A: from 2-chloroquinoline and NaN3 [32]; Method B: from 2-hydrazinylquinoline [29]; Method C: from 2-azidoarylidenes [31,34]; Method D: this work.
Scheme 1. Previous methods to prepare tetrazolo[1,5-a]quinolines. Method A: from 2-chloroquinoline and NaN3 [32]; Method B: from 2-hydrazinylquinoline [29]; Method C: from 2-azidoarylidenes [31,34]; Method D: this work.
Molecules 28 05036 sch001
Molecules 28 05036 sch002 550
Scheme 2. Reaction pathways of the cyclization starting from 2-azidobenzaldehyde 1a. Path A: the first step is a Knoevenagel condensation to form II, followed by the cyclization to tetrazole IV. Path B: the first step is the formation of the triazole III, followed by the cyclization to quinazoline V.
Scheme 2. Reaction pathways of the cyclization starting from 2-azidobenzaldehyde 1a. Path A: the first step is a Knoevenagel condensation to form II, followed by the cyclization to tetrazole IV. Path B: the first step is the formation of the triazole III, followed by the cyclization to quinazoline V.
Molecules 28 05036 sch002
Molecules 28 05036 g002 550
Figure 2. Projection of the molecular structure of 4-(phenylselanyl)tetrazolo[1,5-a]quinoline (3a) obtained by X-ray crystallography.
Figure 2. Projection of the molecular structure of 4-(phenylselanyl)tetrazolo[1,5-a]quinoline (3a) obtained by X-ray crystallography.
Molecules 28 05036 g002
Molecules 28 05036 sch003 550
Scheme 3. 4-(Arylselanyl)tetrazolo[1,5-a]quinolines 3a–h: scope of 2-(arylselanyl)acetonitriles 2.
Scheme 3. 4-(Arylselanyl)tetrazolo[1,5-a]quinolines 3a–h: scope of 2-(arylselanyl)acetonitriles 2.
Molecules 28 05036 sch003
Molecules 28 05036 sch004 550
Scheme 4. 4-(Arylthio)tetrazolo[1,5-a]quinolines 3i–l: scope of 2-(arylthio)acetonitriles 2.
Scheme 4. 4-(Arylthio)tetrazolo[1,5-a]quinolines 3i–l: scope of 2-(arylthio)acetonitriles 2.
Molecules 28 05036 sch004
Molecules 28 05036 sch005 550
Scheme 5. Plausible mechanism.
Scheme 5. Plausible mechanism.
Molecules 28 05036 sch005
Table
Table 1. Optimization of the reaction conditions to prepare 3a a.
Table 1. Optimization of the reaction conditions to prepare 3a a.
Molecules 28 05036 i001
EntryBaseSolventTemperature (°C)Time (h)Yield (%) b
1K2CO3DMSO80421
2K2CO3H2O8043
3K2CO3DMSO:H2O80498
4K2CO3glycerol:H2O80446
5K2CO3DMF:H2O80420
6K2CO3toluene:H2O8042
7K2CO3CH3CN:H2O80415
8K2CO3-80410
9CsCO3DMSO:H2O80492
10KOHDMSO:H2O80421
11Et3NDMSO:H2O80430
12DBUDMSO:H2O80472
13K2CO3 cDMSO:H2O80410
14-DMSO:H2O804-
15K2CO3DMSO:H2O60430
16K2CO3DMSO:H2O100462
17K2CO3DMSO:H2O80255
18K2CO3DMSO:H2O80368
19K2CO3DMSO:H2O25450 d
a Reactions were performed using 2-azidobenzaldehyde 1a (0.037 g, 0.25 mmol), 2-(arylselanyl)acetonitrile 2a (0.049 g, 0.25 mmol) and base (0.007g, 20 mol%) in 1.0 mL of solvent under open atmosphere. b Yields are given for isolated product 3a. c Used 10 mol% of K2CO3. d Obtained as a mixture of 1,2,3-triazolo[1,5-a]quinazoline V and 3a (ratio V:3a = 2:8), as determined by 1H NMR and GC-MS analysis.
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Monzon, L.I.; Rocha, N.C.M.; Quadros, G.T.; Nunes, P.P.P.; Cargnelutti, R.; Jacob, R.G.; Lenardão, E.J.; Perin, G.; Hartwig, D. Synthesis of 4-(Phenylchalcogenyl)tetrazolo[1,5-a]quinolines by Bicyclization of 2-Azidobenzaldehydes with Phenylchalcogenylacetonitrile. Molecules 2023, 28, 5036. https://doi.org/10.3390/molecules28135036

AMA Style

Monzon LI, Rocha NCM, Quadros GT, Nunes PPP, Cargnelutti R, Jacob RG, Lenardão EJ, Perin G, Hartwig D. Synthesis of 4-(Phenylchalcogenyl)tetrazolo[1,5-a]quinolines by Bicyclization of 2-Azidobenzaldehydes with Phenylchalcogenylacetonitrile. Molecules. 2023; 28(13):5036. https://doi.org/10.3390/molecules28135036

Chicago/Turabian Style

Monzon, Loana I., Nicole C. M. Rocha, Gabriela T. Quadros, Pâmela P. P. Nunes, Roberta Cargnelutti, Raquel G. Jacob, Eder J. Lenardão, Gelson Perin, and Daniela Hartwig. 2023. "Synthesis of 4-(Phenylchalcogenyl)tetrazolo[1,5-a]quinolines by Bicyclization of 2-Azidobenzaldehydes with Phenylchalcogenylacetonitrile" Molecules 28, no. 13: 5036. https://doi.org/10.3390/molecules28135036

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