Solid supported FeCl3 has been widely used as a reusable and efficient heterogeneous catalyst in organic syntheses. For example, polyaniline nano-fiber supported FeCl3 was used as the catalyst for the acylation of alcohols and amines [1]. Rice husk supported FeCl3 nanoparticles was used for the chemoselective 1,1-diacetate protection and deprotection of aldehydes [2]. Polymer supported FeCl3 was used as the catalyst for the high yield synthesis of 1,5-benzodiazepine derivatives under solvent free conditions and microwave irradiation [3]. Silica supported FeCl3 was used in various organic reactions [4, 5, 6]. Recently, we used FeCl3-SiO2 as a reusable heterogeneous catalyst for the synthesis of 5-substituted 1H-tetrazoles via [2+3] cycloaddition of nitriles and sodium azide [7].
Currently, nano-particles have attracted considerable research interest as an efficient support for homogeneous catalysts in synthetic chemistry due to their high specific surface areas [8]. The advantages of these nano-particles include high activity, strong oxidizing ability, moderate to high Lewis acidity, non-toxicity, reusability, and long term stability [9, 10]. The size of the nano particle as adsorbent determines its adsorption capacity [11].
Recently, the use of silica supported reagents has received considerable importance in organic syntheses because of their ease of handling, enhanced reaction rates, better selectivity, simple workup, low cost, ease of preparation, and recoverability of catalysts. In the past few years, silica supported acids like silica sulfuric acid [12], BF3·SiO2 [13], silica gel/NaHSO4 [14] or HClO4-SiO2 [15], have received significant attention as efficient catalysts in various organic transformations due to their high acidity, easy handling, and low cost.
Most heterocycles participate in the metabolic pathway of live organisms and perform several biochemical functions and are widely used in medicine industry. Nearly 60% of the pharmaceuticals used in therapeutic systems are N-functionalized heterocycles. One of the important type of the N-functionalized heterocycles are 1,2,4-triazines. It has been reported that the 1,2,4-triazine derivatives possess a broad spectrum of biological activities. For example, they have shown antifungal [16], anti-cancer [17], anti-bacterial [18], analgesic [19], and anti-tumor activities [20, 21].
The reactions of α,β-dicarbonyl compounds with various α,γ-nucleophiles like semicarbazide or thiosemicarbazide are important procedures for the synthesis of triazines [22, 23, 24, 25]. Many of these methods have drawbacks such as low yields or prolonged time period and application of hazardous and expensive catalysts or solvents. Therefore, the development of greener, clean, and environmentally friendly approaches is desirable.
Unfortunately, the adsorption capacity of the adsorbent was not calculated, and the precise amount of FeCl3 on the catalyst was not known in most reactions. Also, the leaching probability of FeCl3 from the surface of the catalyst was not investigated in most reports. So there are demands for preparing the right supported catalyst with the most efficient content of FeCl3 for synthesizing organic intermediates and fine chemicals.
Concerning the versatility and high efficiency of solid supported FeCl3, and the importance of the substituted 1,2,4-triazines, here we report the one-pot synthesis of a series of 1,2,4-triazines from the reactions of semicarbazide or thiosemicarbazide with various α,β-dicarbonyl compounds under reflux in a EtOH-H2O (9:1) mixture as solvent with a FeCl3@SiO2 catalyst (Scheme 1).
Semicarbazide HCl, thiosemicarbazide, SiO2 of various particle sizes and α,β-dicarbonyl compounds, were purchased from Merck Chemical Company and used without further purification. IR spectra were recorded on a Bruker 500 spectrophotometer with KBr pellets. 1H and 13C NMR spectra were obtained on a Bruker 300 MHz Avance spectrometer with DMSO-d6 as solvent. Ultrasonication was performed in a TRANSSONI 660/H ultrasound cleaner with a frequency of 35 KHz and an output power of 70 W.
In a typical procedure, nano-sized SiO2 (0.25 g) was added to a solution (1250 ppm) of FeCl3 (31.25 mg) in dried EtOAc (25 mL) and the mixture was stirred for 24 h at 20 °C. The resulting mixture was centrifuged and filtered and the solid material was stirred in fresh EtOAc (25 mL) for a further 1 h. The concentration of the remaining Fe3+ in the separated solution was determined by atomic absorption. The FeCl3 content of the prepared catalyst was 66.9 mg of FeCl3 per g of FeCl3@SiO2. As indicated in the TEM image of FeCl3@SiO2 (Fig. 1), no detectable change in the size was observed after the adsorption of FeCl3 on the nano-sized silica.
A mixture of α,β-dicarbonyl substrates (1 mmol), semicarbazide or thiosemicarbazide (1 mmol) and FeCl3@SiO2 (25 mg) in EtOH-H2O (9:1, 5 mL) mixture as a solvent was refluxed. After completion of the reaction, which was monitored with TLC, the resulting mixture was filtered and the solid was washed with EtOAc and H2O. The structures of the resulting products were established on the basis of their 1H NMR, 13C NMR, and CHN analysis.
6,7-Dihydro-5-methyl-5H-cyclopenta[e][1,2,4]triazine-3- ol (Entry 1). Pale yellow solid; mp = 250-252 ᵒC; IR (KBr, cm-1): ν 3500, 3000, 1689; 1H NMR (DMSO, 90 MHz): δ 6.4 (m, 5H), 1.09 (d, 3H), 11.03 (s, 1H) and 9.5 (s, 1H); 13C NMR (DMSO, 22.5 MHz): δ 11, 22.5, 27, 32.7, 137.5, 148 and 154; Anal. Calcd for C7H9N3O (%): C 55.62, H 6.00, N 27.80, O 10.58; Found (%): C 54.43; H 5.2, N 31.51, O 8.86.
5,6-Diphenyl-1,2,4-triazine-3-ol (Entry 2). Pale white solid; mp = 231-233 ᵒC; IR (KBr, cm-1): ν 3500, 3300, 1687; 1H NMR (DMSO, 90 MHz): δ 7.0 (m, 11H) and 13.51 (s, 1H); 13C NMR (DMSO, 22.5 MHz): δ 127.99, 128.16, 128.77, 128.93, 129.28, 130.78, 134.48, 135.73, 142.30, 153.35 and 167.28; Anal. Calcd for C15H11N3O (%): C 72.28, H 4.45, N 16.86, O 6.42; Found (%): C 71.12, H 4.61, N 17.51, O 6.76.
5H-[1,2,4]triazino[5,6-b]indol-3-ol (Entry 3). Pale yellow solid; mp = 281-283 ᵒC; IR (KBr, cm-1): ν 3470, 3300, 1700; 1H NMR (DMSO, 90 MHz): δ 7.12 (m, 5H), 11.02 (s, 1H) and 11.72 (s, 1H); 13C NMR (DMSO, 22.5 MHz): δ 110.77, 120.15, 122.16, 130.32, 130.92, 1414.42, 154.95 and 162.66; Anal. Calcd for C9H6N4O (%): C 58.06, H 3.25, N 30.09, O 8.59; Found (%): C 59.04, H 2.82, N 30.38, O 7.76.
Snaphto[1,2-e](1,2,4)-triazin-9-ol (Entry 4). Pale white solid; mp = 281-283 ᵒC; IR (KBr, cm-1): ν 3470, 3300, 1700; 1H NMR (DMSO, 90 MHz): δ 6.8-8.3 (m, 6H), 10 (s, 1H) and 11.73 (s, 1H); 13C NMR (DMSO, 22.5 MHz): δ 123.17, 126.9, 127.99, 128.16, 128.52, 130.4, 133.54, 135.43, 136.87, 142.79, 155.40 and 156.15; Anal. Calcd for C13H7N3O (%): C 70.58, H 3.19, N 19.00, O 7.23; Found (%): C 69.73, H 3.82, N 18.89, O 7.74.
Phenanthro[9,10-e][1,2,4]triazin-3-ol (Entry 5). Pale light yellow solid; mp = 229-231 ᵒC; IR (KBr, cm-1): ν 3464, 3200, 1688; 1H NMR (DMSO, 90 MHz): δ 7.7-8.7 (m, 9H) and 14 (s, 1H); Anal. Calcd for C15H9N3O (%): C 72.87, H 3.67, N 16.99, O 6.47; Found (%): C 72.54, H 3.19, N 17.12, O 7.15.
(1,2,4)-Triazin-3-ol (Entry 6). Pale white solid; mp = 216-218 ᵒC; IR (KBr, cm-1): ν 3464, 3200, 1688; 1H NMR (DMSO, 90 MHz): δ 6.0 (s, 2H), 7.4 (s, 1H) and 10.33 (s, 1H); 13C NMR (DMSO, 22.5 MHz): δ 145.17, 150.9 and 161.99; Anal. Calcd for C3H3N3O (%): C 37.12, H 3.11, N 43.29, O 16.48; Found (%): C 37.45, H 3.82, N 42.71, O 16.02.
5,6-Diethyl(1,2,4)-triazin-3-ol (Entry 7). Pale light yellow solid; mp = 219-220 ᵒC; IR (KBr, cm-1): ν 3472, 3276, 1685; 1H NMR (DMSO, 90 MHz): δ 2.24-2.6 (m, 6H), 7.4 (m, 4H), 9.00 (s, 1H) and 10.22 (s, 1H); 13C NMR (DMSO, 22.5 MHz): δ 10.39, 10.7, 23.65, 129.65, 145.52 and 148.92; Anal. Calcd for C7H11N3O (%): C 54.89, H 7.24, N 27.43, O 10.44; Found (%): C 54.00, H 8.53, N 26.45, O 11.02.
2H-[1,2,4]triazino[5,6-b]indole-3(5H)-thione (Entry 8). Pale light yellow solid; mp = 254-257 ᵒC; IR (KBr, cm-1): ν 3395; 1H NMR (DMSO, 90 MHz): δ 8 (m, 4H), 11.5 (s, 1H) and 12.7 (s, 1H); 13C NMR (DMSO, 22.5 MHz): δ 107.89, 116.8, 117.82, 119.24, 126.12, 139.28, 159.58 and 175.74; Anal. Calcd for C9H6N4S (%): C 53.45, H 2.99, N 27.70, S 15.86; Found (%): C 53.10, H 3.2, N 27.53, S 16.17.
Phenanthro[9,10-e][1,2,4]triazine-3(2H)-thione (Entry 9). Pale light yellow solid; mp = 218-222 ᵒC; IR (KBr, cm-1): ν 3391; 1H NMR (DMSO, 90 MHz): δ 7.5-8.3 (m, 8H) and 13.8 (s, 1H); 13C NMR (DMSO, 22.5 MHz): δ 110.93, 119.87, 120.84, 122.25, 131.14, 131.97, 142, 26, 162.55 and 178.71; Anal. Calcd for C15H9N3S (%): C 68.42, H 3.45, N 15.96, S 12.18; Found (%): C 68.12, H 3.68, N 16.23, S 11.97.
5,6-Diphenyl-1,2,4-triazine-3(2H)-thione (Entry 10). Pale white solid; mp = 212-214 ᵒC; IR (KBr, cm-1): ν 3421; 1H NMR (DMSO, 90 MHz): δ 7.3 (m, 10H) and 15.2 (s, 1H); 13C NMR (DMSO, 22.5 MHz): δ 126.0, 128.75, 155.97, 157.63, 169.13 and 180.71; Anal. Calcd for C15H11N3S (%): C 67.9, H 4.18, N 15.84, S 12.08; Found (%): C 68.25, H 4.87, N 15.31, S 11.57.
To investigate the effect of the catalyst particle size on the rate and yield, the reaction between benzil (1 mmol) and semicarbazide HCl (1 mmol) in a EtOH-H2O (9:1) mixture as solvent was studied as the model reaction under reflux using various sizes of SiO2. The results are presented in Fig. 2.
As shown in Fig. 2, in comparison with the catalyst-free condition, the reaction rate and yield were both improved when the reaction was carried out in the presence of the catalyst. In addition, by supporting FeCl3 on SiO2 and decreasing the particle size of SiO2, the reactions were completed in shorter times. These results can be explained on the basis of the differences in the FeCl3 content on SiO2 with various particles sizes. To prove this, the amount of adsorbed FeCl3 per unit mass of the adsorbent SiO2 (mg/g), qe, was calculated using Eq. (1) where C0and Ce are the initial and final concentrations (mg/L = ppm) of FeCl3 respectively, V is the solution volume (L) and m is the mass of SiO2 as adsorbent (g).
qe = (C0-Ce)V/m (1)
By using the atomic absorption technique for determining Ce, the amount of FeCl3 adsorption on the various particle sizes of SiO2 was determined. The FeCl3 content per g of solid catalyst decreased as the particle size was increased (Fig. 3).
To study the effect of the solvent on the adsorption process, nano-sized SiO2 (0.25 g) was added to the solutions (1250 ppm) of FeCl3 (31.25 mg) in various solvents (25 mL) and stirred for 24 h. The resulting mixture was then worked-up and the catalyst separated by the procedure described above. The FeCl3 content of the catalyst was determined by Fe3+ atomic absorption from Ce in Eq. (1). The amount of FeCl3 adsorbed on the nano-sized SiO2 with different solvents indicated that EtoAc provided the highest FeCl3 content (Fig. 4).
In order to obtain a high efficiency of the FeCl3 concentration in providing the most adsorption on nano-sized SiO2, we examined the FeCl3 contents on the prepared catalysts using various concentrations of the FeCl3 solution. Different concentrations of FeCl3 in EtOAc (25 mL) were placed in six separate flasks containing nano-sized SiO2 (0.25 g) and stirred at room temperature for 24 h. The content of each flask was centrifuged and filtered to separate the solid catalyst which was dried in an oven at 100 ᵒC. Finally, the concentration of Fe3+ was determined by atomic absorption using Ce in Eq. (1). The results are summarized in Table 1.
It is evident that no significant change of the FeCl3 content of the FeCl3@SiO2 catalyst occurred with increase of the concentration of FeCl3 beyond 1250 ppm (Table 1, Fig. 5).
To optimize the reaction conditions, the effects of the FeCl3@SiO2 catalyst and other reaction parameters on the model reaction were studied (Table 2).
The results shown in Table 2 indicated that the best result in terms of the reaction rate and yield was obtained when the reaction was conducted under reflux in a EtOH-H2O (9:1) mixture as solvent with FeCl3@SiO2 with a FeCl3 content of 66 mg per g catalyst (Entry 5). A decrease in the yield was observed when the reaction was performed under ultrasound irradiation using a similar catalyst composition (Entries 13 and 14). When the reaction was carried out in the presence of unloaded nano-SiO2, the rate and yield were both reduced significantly (Entry 2). Moreover, in the absence of the catalyst, the yield was very low (Entry 1).
In order to establish the scope of this methodology, we conducted the reaction of semicarbazide or thiosemicarbazide with a series of α,β-dicarbonyl compounds with different substituents under the optimum conditions (Table 2, Entry 5). All the reactions proceeded smoothly to afford the corresponding products in quantitative yields as summarized in Table 3.
In order to study the stability and reusability of the catalyst, the reaction mixture was centrifuged after the completion of the reaction. The separated solid was washed with ethyl acetate (2 × 5 mL) and dried under vacuum (20 ᵒC). The recovered catalyst was reused for three consecutive runs without any significant loss of activity (Table 3, Entry 1).
FeCl3@SiO2 is a suitable solid catalyst for the synthesis of 1,2,4-triazine derivatives in EtOH/H2O mixture as solvent under reflux. In comparison with other reported methods, this procedure gave the products in shorter reaction times and quantitative yields.
The authors wish to thank from the Bu-Ali Sina University, Hamedan 6517838683 Iran for the financial support of this work.
2015, Vol. 36 Issue (4): 620-625
PDF (648 KB)
2015, Vol. 36 Issue (4): 620-625
PDF (648 KB)