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

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.


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].
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.
Tetrazole or triazole nucleus can be formed in very good yields through the fast, concerted and regioselective [3 + 2] cycloaddition between arylazides and acetonitrilebearing 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 [1,5a]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]. 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 1D).

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.

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.
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[1,5a]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 [ 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 K 2 CO 3 as base in a mixture of DMSO:H 2 O as solvent (Scheme 1, Method D).

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 K 2 CO 3 (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 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. 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 (Cs 2 CO 3 ), potassium hydroxide (KOH), triethylamine (Et 3 N), 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 Cs 2 CO 3 (92% yield), the observed results were not satisfactory, and lower yields of 3a were obtained in all cases. When the amount of K 2 CO 3 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, K 2 CO 3 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 K 2 CO 3 (20 mol%) as base in a 7:3 mixture of DMSO:H 2 O (1.0 mL) as solvent for 4 h at 80 • C.

Scheme 3. 4-(Arylselanyl)tetrazolo[1,5-a]quinolines 3a-h: scope of 2-(arylselanyl)acetonitriles 2.
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 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.

General Information
Reactions were carried out in a two-necked round-bottomed flask with a Tefloncoated magnetic stirring bar. Solvents and reagents were used as received unless otherwise noted. The reactions were monitored by thin-layer chromatography (TLC), which 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- 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]

General Information
Reactions were carried out in a two-necked round-bottomed flask with a Tefloncoated magnetic stirring bar. Solvents and reagents were used as received unless other-Scheme 5. Plausible mechanism.

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 F 254 ), 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 H 2 SO 4 and heat. Hydrogen nuclear magnetic resonance spectra ( 1 H 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 CDCl 3 or DMSO-d 6 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 ( 13 C 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 CDCl 3 (δ 77.0 ppm) or DMSO-d 6 (39.7 ppm). Selenium-77 nuclear magnetic resonance spectra ( 77 Se 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 CDCl 3 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.

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 2nitrobenzaldehyde 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 (NaN 3 ) 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).

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 N 2 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 N 2 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 MgSO 4 , 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.

General Reaction Procedure for the Synthesis of 4-(Arylchalcogenyl)tetrazolo[1,5-a]quinolines3a-l
2-Azidobenzaldehyde 1a (0.037 g, 0.25 mmol), 2-(arylchalcogenyl)acetonitrile 2 (0.25 mmol), K 2 CO 3 (0.007 g, 20 mol%) and DMSO:H 2 O (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 MgSO 4 , 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.

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 1 H, 13 C, and 77 Se 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;