Abstract
Based on readily available N-(2,2,2-trichloro-1-hydroxyethyl)carboxamides, N-(2,2,2-trichloro-1-(3-(3-mercapto-4H-1,2,4-triazol-4-yl)thioureido)ethyl) carboxamides, dehydrosulfurization–under the influence of excess HgO–led to the formation of N-(1-([1,2,4] triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)carboxamides. The reaction was carried out in boiling glacial acetic acid for 1-1.5 hours. The cyclization products were obtained in 42-62% yields and easily isolated from the reaction mixture. The structure of all synthesized compounds was confirmed by complex spectral studies.
Introduction
Heterocyclic systems containing a 1,3,4-thiadiazole or 1,2,4-triazole ring are of great importance for medical chemistry and the pharmaceutical industry [1, 2, 3]; they are widely used in agriculture [1,4] and in the production of polymers, semiconductors [1,5,6] and dyes [1, 7, 8, 9, 10].
Of particular interest are the [1,2,4]triazolo[3,4-b][1,3,4] thiadiazole derivatives, which are condensed heterocyclic systems containing both a 1,3,4-thiadiazole ring and a 1,2,4-triazole ring. A large number of studies are devoted to the antimicrobial activity of these compounds, including antibacterial [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22], antifungal [16, 17, 18, 19, 20, 21] and antitubercular [23,24] one. Among the derivatives of [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazole, there are substances having an inhibitory effect on certain enzymes, for example, acetylcholinesterase [25] and protein tyrosine phosphatase 1B [26]. These compounds are very promising as antioxidants and cytotoxic agents [12, 27, 28, 29]. The presence of activity against HIV-1 and HIV-2 [20,21], herpes viruses [30], JC and BK viruses [31] in these compounds is of particular note. In addition, the use of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives as ligands makes it possible to create a number of complexes of Terbium, Copper and Cadmium having luminescent activity [32,33].
In this article, we report the synthesis of a number of new [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives containing an alkylamide fragment, which in our view can enhance their biological activity.
Results and Discussion
Based on readily available N-(2,2,2-trichloro-1-hydroxyethyl)carboxamides 1 [34], we obtained a series of N-(2,2,2-trichloro-1-isothiocyanatoethyl)carboxamides 2 (Scheme 1). As a result of the addition of 4-amino-4H-1,2,4-triazole-3-thiol 3 [35] to isothiocyanates 2 [36], N-amidoalkylated thioureas 4 were synthesized (Scheme 1). The addition reaction was carried out in acetonitrile, which greatly facilitated the isolation of products 4a-f and allowed yields of 61-72% with sufficient purity for use in further conversions without further purification. Compounds 4 are promising polyfunctional reagents, and we successfully used them as starting reagents for the preparation of new [1,2,4] triazolo[3,4-b][1,3,4]thiadiazole derivatives.
Synthesis of N-(2,2,2-trichloro-1-(3-(3-mercapto-4H-1,2,4-triazol-4-yl)thioureido)ethyl)carboxamides 4. Reagents and conditions: a: SOCl2, CCl4, reflux, 1-1.2 h; b: KSCN, acetonitrile, stirring for 1.5-2 h; c: acetonitrile, reflux 5-7 min., r.t., 48 h.
Dehydrosulfurization of thiourea 4 was carried out by refluxing glacial acetic acid with 20% excess HgO (yellow) for 1-1.5 hours. During the reaction, the mixture acquired a black color due to the formation of HgS. It was assumed that this reaction passed through the formation of a carbodiimide 5 intermediate (Scheme 2) [37]. N-Amidoalkylated derivatives of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-amine 6 were prepared in suitable yields and isolated, without special difficulty, from the reaction mixture.
![Scheme 2 Synthesis of N-(1-([1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)carboxamides 6.](/document/doi/10.1515/hc-2019-0020/asset/graphic/j_hc-2019-0020_fig_002.jpg)
Synthesis of N-(1-([1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)carboxamides 6.
We attempted to use dicyclohexylcarbodiimide as a dehydrosulfurization agent. The reaction was carried out in anhydrous 1,4-dioxane, but the dicyclohexylthiourea formed thereby greatly complicating the isolation and purification of the target products.
The structure of the compounds obtained was confirmed by complex spectral studies. In the 1Н NMR spectra of isothiocyanates 2, the N–H and C–H signals of the protons appeared as doublets in the ranges 10.4-9.2 ppm and 6.7-6.5 ppm, respectively. The isothiocyanate group in the IR spectra of compounds 2 appeared as an intense absorption band at 2060-2035 cm-1, and the carbon signal of this group in the 13C NMR spectra appeared at 140 ppm.
In the 1H NMR spectra of compounds 6, there were no signals of isolated S–H and N–H protons, characteristic for the starting thioureas 4, which appeared as singlets in the range 13.9-13.8 ppm and 11.5-11.0 ppm, respectively. In the 13C NMR spectra of compounds 4, a carbon signal C=S was observed at 185 ppm, which was absent in the spectra of compounds 6. At the same time, in the 13C NMR spectra of compounds 6, there were carbon signals of three imino groups located in the range 135-166 ppm. While there were only two signals for compounds 4 in this range.
In the mass spectra of all compounds 6, the molecular ion appeared in the protonated form [M+H]+ (Scheme 3).
![Scheme 3 Fragmentation of N-(1-([1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)carboxamides 6.](/document/doi/10.1515/hc-2019-0020/asset/graphic/j_hc-2019-0020_fig_003.jpg)
Fragmentation of N-(1-([1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)carboxamides 6.
Protonation was also characteristic for certain fragment ions. The decomposition of compounds 6 took place in two ways: in the first case, the elimination of N-(2,2,2-trichloroethylidene)carboxamide with the formation of the ion A (m/z = 142) was observed, and in the second case, the elimination of the carboxylic acid amide was observed, forming fragmental ion B (m/z = 270).
The spectral data confirmed the occurance of the dehydrosulfurization process followed by heterocyclization to the mercapto group and excluded any transformation involving the amide fragment, as in [38,39].
Conclusion
By a chain of simple transformations, we synthesized a number of new [1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-6-amine derivatives 6. Initially, based on N-(2,2,2-trichloro-1-hydroxyethyl)carboxamides 1, N-(2,2,2-trichloro-1-isothiocyanatoethyl)carboxamides 2 were prepared. As a result of the addition of 4-amino-4H-1,2,4-triazole-3-thiol 3 to isothiocyanates 2, N-amidoalkylated thioureas 4 were synthesized. Dehydrosulfurization of the latter, under the influence of excess HgO, resulted in the formation of compounds 6. The cyclization products were obtained with acceptable yields and were isolated without special difficulty from the reaction mixture.
Experimental
Melting points were determined in open capillaries and are not corrected. IR spectra were recorded in KBr tablets using the device Spectrum BX II. The mass spectra of FAB were recorded on the device VG7070, desorption of ions from solution samples in meta-nitrobenzyl alcohol were conducted by beam of argon atoms with 8 keV energy. 1H NMR and 13C spectra were measured on spectrometer Varian VXR-400 (standard TMS). Chemical shifts (δ) are given in ppm downfield. The constants value of the spin-spin interaction (J) is given in Hz. Elemental analysis was performed on a LECO CHNS-900 instrument. The monitoring of the reaction progress and identity of the compounds obtained has been performed by TLC (Silufol UV-254, eluent – chloroform: acetone – 3:1).
The starting N-(2,2,2-trichloro-1-hydroxyethyl)carboxamides 1a-f were obtained according to the procedure described in [34]. The spectral characteristics for compounds 1a-e are described in [34], and for compound 1f, they are listed below and are described for the first time.
N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide (1f) [40]
Cream colored crystals; yield 84%; m.p. 153-155 °C; Rf = 0.36. 1H NMR (400 MHz, DMSO-d6): δ 8.77 (d, J = 8.3 Hz, 1H, OH), 7.90-7.87 (m, 2H, Harom. + NH), 7.45 (br. s, 1H, Harom.), 6.66 (br. s, 1H, Harom.), 5.93 (dd, J = 8.3, 5.9 Hz, 1H, CH); 13C NMR (100 MHz, DMSO-d6): δ 167.2 (C=O), 137.8, 132.6, 127.3, 118.8 (arom.), 102.24 (CCl3), 80.8 (CH); IR (KBr) (v cm-1): 3316 (OH), 3162, 3140 (NH), 2957, 2878, 2733, (CH), 1651 (C=O), 1572, 1527, 1471, 1348, 1293, 1149, 1196,1083, 1015, 940, 800, 752, 625, 599, 461; FAB-MS: m/z 258 [M+H]+. Anal. Calcd (%) for C7H6Cl3NO3 (258.48): C, 32.53; H, 2.34; Cl, 41.14; N, 5.42. Found: C, 32.50; H, 2.32; Cl, 41.17; N, 5.45.
General procedure for the synthesis of isothiocyanates (2a-e)
12 mmol (0.9 mL) of thionyl chloride was added to the suspension of 10 mmol N-(2,2,2-trichloro-1-hydroxyethyl)carboxamides (1) [34] in 30-35 mL of CCl4. The mixture was refluxed for 1-1.2 hours. After completion of the reaction, the still-warm solution was filtered, and the filtrate was evaporated on a rotary evaporator. The residue after evaporation was treated with hexane (2×10 mL), filtered and dissolved in 30-35 mL of anhydrous acetonitrile. 10 mmol (0.97 g) of carefully dried KSCN was added in portions to the resulting solution. The reaction mixture was stirred for 1.5-2 hours. The precipitated KCl was filtered off, the filtrate was evaporated on a rotary evaporator without raising the heating temperature above 55-60 °C. The residue after evaporation was treated with water (3×50 mL), filtered and dried at room temperature for 48 hours. The product was recrystallized from acetonitrile. The yields are given on a crystallized product. Compounds 2a, 2c and 2d were obtained previously. Compounds 2b, 2e and 2f were obtained for the first time.
N-(2,2,2-Trichloro-1-isothiocyanatoethyl)acetamide (2a) [41]
Light yellow solid; yield 82% (2.03 g); m.p. 93-95 °C; Rf = 0.71. Anal. Calcd (%) for C5H5Cl3N2OS (247.52): C, 24.26; H, 2.04; Cl, 42.97; N, 11.32; S, 12.95. Found: C, 24.23; H, 2.06; Cl, 42.95; N, 11.36; S, 12.98.
N-(2,2,2-Trichloro-1-isothiocyanatoethyl)acrylamide (2b)
Light yellow solid; yield 78% (4.87 g); m.p. 125-127 °C; Rf = 0.88. 1H NMR (400 MHz, DMSO-d6): δ 9.80 (d, J = 8.8 Hz, 1H, NH), 6.56 (d, J = 8.8 Hz, 1H, CH), 6.45 (dd, J = 9.8, 17.1 Hz, 1H, CH=CH2), 6.31 (d, J = 17.1 Hz, 1H, =CH2-trans), 5.85 (d, J = 9.8 Hz, 1H, =CH2-cis); 13C NMR (100 MHz, DMSO-d6): δ 164.4 (C=O), 140.3 (-N=C=S), 129.4 (CH=CH2), 129.2 (CH=CH2), 98.9 (CCl3), 72.5 (CH); IR (KBr) (v cm-1): 3227, 3192 (NH), 3017, 2933, 2742 (CH), 2057 (-N=C=S), 1667 (C=O), 1636, 1533, 1409, 1313, 1220, 1130, 1073, 982, 799, 758, 615, 547; FAB-MS: m/z 259 [M+H]+. Anal. Calcd (%) for C6H5Cl3 N2OS (259.53): C, 27.77; H, 1.94; Cl, 40.98; N, 10.79; S, 12.35. Found: C, 27.75; H, 1.96; Cl, 41.01; N, 10.81; S, 12.34.
N-(2,2,2-Trichloro-1-isothiocyanatoethyl)benzamide (2c) [42]
Light yellow solid; yield 75% (2.32 g); m.p. 152-154 °C; Rf = 0.83. Anal. Calcd (%) for C10H7Cl3N2OS (309.59): C, 38.80; H, 2.28; Cl, 34.35; N, 9.05; S, 10.36. Found: C, 38.78; H, 2.26; Cl, 34.38; N, 9.09; S, 10.38.
4-Methyl-N-(2,2,2-trichloro-1-isothiocyanatoethyl) benzamide (2d) [42]
Light yellow solid; yield 80% (3.03 g); m.p. 119-121 °C; Rf = 0.89. Anal. Calcd (%) for C11H9Cl3N2OS (323.62): C, 40.83; H, 2.80; Cl, 32.86; N, 8.66; S, 9.91. Found: C, 40.79; H, 2.78; Cl, 32.89; N, 8.70; S, 9.93.
2,4-Dichloro-N-(2,2,2-trichloro-1-isothiocyanatoethyl) benzamide (2e)
Light yellow crystals; yield 78% (2.95 g); mp. 113-115 °C (MeCN); Rf = 0.72. 1H NMR: δ 10.39 (d, J = 8.8 Hz, 1Н, NH), 7.76 (s, 1H, Harom.), 7.57-7.55 (m, 1H, Harom.), 7.50-7.48 (m, 1H, Harom.), 6.68 (d, J = 8.8 Hz, 1H, CH). 13C NMR: δ 165.6 (C=O), 140.7 (-N=C=S), 135.4, 133.5, 131.2, 130.3, 129.2, 127.3, (arom.), 98.8 (CCl3), 72.4 (CH). IR: νmax 3226, 3188 (NH), 3024, 2927, 2852 (CH), 2033 (-N=C=S), 1667 (C=O), 1591, 1533, 1283, 1220, 1163, 1129, 1001, 813, 795, 624, 509 cm-1. MS (FAB): m/z 377 [M+H]+. Anal. Calcd (%) for C10H5Cl5N2OS (378.47): C, 31.74; H, 1.33; Cl, 46.83; N, 7.40; S, 8.47. Found: C, 31.71; H, 1.35; Cl, 46.87; N, 7.44; S, 8.51.
N-(2,2,2-trichloro-1-isothiocyanatoethyl)furan-2-carboxamide (2f)
Yellow crystals; yield 75% (2.25 g); mp. 165-167 °C (EtOH); Rf = 0.63. 1H NMR: δ 9.24 (d, J = 8.8 Hz, 1Н, NH), 8.52-8.50 (m, 1H, Harom.), 7.79 (br. s, 1H, Harom.), 7.29-7.28 (m, 1H, Harom.), 6.72 (br. s, 1H, CH). 13C NMR: δ 166.2 (C=O), 142.8 (-N=C=S), 137.6, 129.3, 127.4, 111.4 (arom.), 95.4 (CCl3), 79.4 (CH). IR: νmax 3354, 3321 (NH), 2990, 2961 (CH), 2055 (-N=C=S), 1668 (C=O), 1572, 1533, 1495, 1355, 1288, 1209, 1135, 1014, 945, 800, 757, 662, 547 cm-1. MS (FAB): m/z 299 [M+H]+. Anal. Calcd (%) for C8H5Cl3N2O2S (299.55): C, 32.08; H, 1.68; Cl, 35.50; N, 9.35; S, 10.70. Found: C, 32.05; H, 1.66; Cl, 35.54; N, 9.37; S, 10.73.
General procedure for the synthesis of thioureas (4a-f)
10 mmol (1.16 g) of 4-amino-4H-1,2,4-triazole-3-thiol 3 [35] dissolved in 15-18 mL of acetonitrile were added to 10 mmol of N-(2,2,2-trichloro-1-isothiocyanatoethyl)carboxamide 2 dissolved in 10-12 mL of acetonitrile. The mixture was refluxed for 5-7 minutes, filtered and left for 48 hours at room temperature. The precipitate formed was filtered and washed with acetonitrile 2×5 mL. The product was first dried at room temperature for 24 hours, and then, at 100-110 °C - for an additional 3 hours. The resulting crude product is suitable for use in further conversions without further purification. Analytical samples were purified by recrystallization from acetonitrile. The yields are given on a crystallized product.
N-(2,2,2-Trichloro-1-(3-(3-mercapto-4H-1,2,4-triazol-4-yl) thioureido)ethyl)acetamide (4a)
Light yellow solid; yield 67% (2.44 g); m.p. 147-149 °C; Rf = 0.32. 1H NMR (400 MHz, DMSO-d6): δ 13.82 (s, 1H, SH), 11.01 (s, 1H, NH), 8.98 (br. s, 1H, NH), 8.84 (br. s, 1H, NH), 8.58 (s, 1H, -N=CH-N=), 7.20 (dd, J = 9.3, 8.8 Hz, 1H, CH), 1.95 (s, 1H, CH3); 13C NMR (100 MHz, DMSO-d6): δ 185.0 (C=S), 168.9 (C=O), 166.3 (C=N), 141.9 (C=N), 101.0 (CCl3), 69.9 (CH), 22.5 (CH3). IR (KBr) (v cm-1): 3592 (SH), 3470, 3418, 3256, 3206 (NH), 3095, 3006, 2928, 2852, 2791 (CH), 1650 (C=O), 1590, 1562, 1489, 1420, 1309, 1221, 1110, 1043, 918, 869, 820, 798, 721, 662, 559; FAB-MS: m/z 363 [M+H]+. Anal. Calcd (%) for C7H9Cl3N6OS2 (363.66): C, 23.12; H, 2.49; Cl, 29.24; N, 23.11; S, 17.63. Found: C, 23.09; H, 2.47; Cl, 29.27; N, 23.15; S, 17.65.
N-(2,2,2-Trichloro-1-(3-(3-mercapto-4H-1,2,4-triazol-4-yl) thioureido)ethyl)acrylamide (4b)
Light yellow solid; yield 64% (2.40 g); m.p. 165-167 °C; Rf = 0.29. 1H NMR (400 MHz, DMSO-d6): δ 13.81 (s, 1H, SH), 11.00 (s, 1H, NH), 9.13 (br. s, 1H, NH), 8.86 (br. s, 1H, NH), 8.59 (s, 1H, -N=CH-N=), 7.30 (dd, J = 8.8, 8.3 Hz, 1H, CH), 6.40 (dd, J = 16.6, 9.8 Hz, 1H, CH=CH2), 6.23 (d, J = 16.6 Hz, 1H, =CH2-trans), 5.77 (d, J = 9.8 Hz, 1H, =CH2-cis); 13C NMR (100 MHz, DMSO-d6): δ 185.0 (C=S), 166.3 (C=O), 163.8 (C=N), 143.3 (C=N), 130.2 (-CH=CH2), 128.0 (-CH=CH2), 100.8 (CCl3), 70.1 (CH); IR (KBr) (v cm-1): 3282 (SH), 3243, 3160, 3126, (NH), 3092, 2993, 2953, 2931, 2876, 2834, 2792 (CH), 1671 (C=O), 1637, 1552, 1503, 1482, 1414, 1323, 1302, 1215, 1120, 994, 929, 843, 797, 722, 683, 662, 549; FAB-MS: m/z 375 [M+H]+. Anal. Calcd (%) for C8H9Cl3N6OS2 (375.67): C, 25.58; H, 2.41; Cl, 28.31; N, 22.37; S, 17.07. Found: C, 25.54; H, 2.39; Cl, 28.36; N, 22.40; S, 17.10.
N-(2,2,2-Trichloro-1-(3-(3-mercapto-4H-1,2,4-triazol-4-yl) thioureido)ethyl)benzamide (4c)
Light yellow solid; yield 61% (2.60 g); m.p. 158-160 °C; Rf = 0.45. 1H NMR (400 MHz, DMSO-d6): δ 13.87 (s, 1H, SH), 11.43 (s, 1H, NH), 9.39 (br. s, 1H, NH), 8.64 (m, 2H, NH+-N=CH-N=), 7.88-7.87 (m, 2H, Harom.), 7.63-7.47 (m, 4H, 3Harom.+CH); 13C NMR (100 MHz, DMSO-d6): δ 185.0 (C=S), 166.5 (C=O), 165.7 (C=N), 143.2 (C=N), 133.0, 132.1, 128.5, 127.5 (arom.), 101.3 (CCl3), 70.5 (CH); IR (KBr) (v cm-1): 3252 (SH), 3090 (NH), 2925, 2854 (CH), 1673 (C=O), 1646, 1506, 1485, 1323, 1224, 1141, 1116, 1027, 924, 798, 710, 685, 561; FAB-MS: m/z 425 [M+H]+. Anal. Calcd (%) for C12H11Cl3N6OS2 (425.73): C, 33.86; H, 2.60; Cl, 24.98; N, 19.74; S, 15.06. Found: C, 33.84; H, 2.58; Cl, 25.01; N, 19.77; S, 15.09.
4-Methyl-N-(2,2,2-trichloro-1-(3-(3-mercapto-4H-1,2,4-triazol-4-yl)thioureido)ethyl)benzamide (4d)
Light yellow solid; yield 72% (3.17 g); m.p. 198-200 °C; Rf = 0.34. 1H NMR (400 MHz, DMSO-d6): δ 13.87 (s, 1H, SH), 11.48 (s, 1H, NH), 9.29 (br. s, 1H, NH), 8.63 (m, 2H, NH+-N=CH-N=), 7.80-7.78 (m, 2H, Harom.), 7.48 (dd, J = 8.8, 8.8 Hz, 1H, CH), 7.35-7.33 (m, 2H, Harom.), 2.38 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): δ 185.0 (C=S), 166.5 (C=O), 165.5 (C=N), 143.1 (C=N), 142.3, 130.1, 129.0, 127.5 (arom.), 101.4 (CCl3), 70.5 (CH), 21.1 (CH3). IR (KBr) (v cm-1): 3288 (SH), 3169, 3114, 3071 (NH), 3004, 2944, 2853, 2775, 2616 (CH), 1644 (C=O), 1610, 1546, 1495, 1479, 1419, 1309, 1149, 1032, 925, 797, 754, 661, 565; FAB-MS: m/z 439 [M+H]+. Anal. Calcd (%) for C13H13Cl3N6OS2 (439.76): C, 35.51; H, 2.98; Cl, 24.18; N, 19.11; S, 14.58. Found: C, 35.48; H, 2.95; Cl, 24.21; N, 19.15; S, 14.61.
2,4-Dichloro-N-(2,2,2-trichloro-1-(3-(3-mercapto-4H-1,2,4-triazol-4-yl)thioureido)ethyl)benzamide (4e)
Light yellow solid; yield 71% (3.51 g); m.p. 162-164 °C; Rf = 0.37. 1H NMR (400 MHz, DMSO-d6): δ 13.86 (s, 1H, SH), 11.09 (s, 1H, NH), 9.73 (br. s, 1H, NH), 8.90 (br. s, 1H, NH), 8.63 (s, 1H, -N=CH-N=), 7.74 (s, 1H, Harom.), 7.56-7.54 (m, 1H, Harom.), 7.47-7.45 (m, 1H, Harom.), 7.34 (dd, J = 8.8, 9.3 Hz, 1H, CH); 13C NMR (100 MHz, DMSO-d6): δ 185.2 (C=S), 166.4 (C=O), 164.8 (C=N), 143.2 (C=N), 135.2, 134.1, 131.4, 130.3, 129.3, 127.3 (arom.), 100.5 (CCl3), 70.4 (CH). IR (KBr) (v cm-1): 3545 (SH), 3345, 3213, 3150 (NH), 3080, 3010, 2947, 2866, 2642 (CH), 1679 (C=O), 1539, 1497, 1319, 1218, 1124, 936, 805, 761, 735, 552; FAB-MS: m/z 493 [M+H]+. Anal. Calcd (%) for C12H9Cl5N6OS2 (494.62): C, 29.14; H, 1.83; Cl, 35.84; N, 16.99; S, 12.96. Found: C, 29.11; H, 1.80; Cl, 35.87; N, 17.04; S, 12.98.
N-(2,2,2-trichloro-1-(3-(3-mercapto-4H-1,2,4-triazol-4-yl) thioureido)ethyl)furan-2-carboxamide (4f)
Yellow solid; yield 67% (2.79 g); m.p. 178-180 °C; Rf = 0.35. 1H NMR (400 MHz, DMSO-d6): δ 13.86 (s, 1H, SH), 11.44 (s, 1H, NH), 9.39 (br. s, 1H, NH), 8.64-8.44 (m, 3H, -N=CH-N= + NH + Harom.), 8.03 (brs, 1H, Harom.), 7.39-7.37 (m, 1H, Harom.), 7.03 (dd, J = 8.8, 6.8 Hz, 1H, CH); 13C NMR (100 MHz, DMSO-d6): δ 184.6 (C=S), 164.6 (C=O), 152.4 (C=N), 146.1 (C=N), 136.7, 131.9, 129.5, 112.18 (arom.), 101.6 (CCl3), 70.2 (CH). IR (KBr) (v cm-1): 3458 (SH), 3315, 3270, 3086 (NH), 3000, 2979, 2811 (CH), 1665 (C=O), 1531, 1475, 1333, 1136, 1013, 934, 702, 628, 483; FAB-MS: m/z 415 [M+H]+. Anal. Calcd (%) for C10H9Cl3N6O2S2 (415.69): C, 28.89; H, 2.18; Cl, 25.58; N, 20.22; S, 15.42. Found: C, 28.86; H, 2.16; Cl, 25.61; N, 20.24; S, 15.45.
General procedure for the synthesis of [1,2,4] triazolo[3,4-b][1,3,4]thiadiazol-6-amine derivatives (6a-f)
A mixture of 10 mmol of thiourea 4, 12 mmol (2.60 g) of HgO (yellow) and 10-12 mL of glacial acetic acid was boiled under reflux for 1-1.5 hours. The reaction mixture was cooled to room temperature and filtered twice from the resulting HgS. 15-18 mL of H2O was added to the filtrate. The precipitate formed was filtered and treated with a 10% Na2CO3 solution of 2×15 mL, and then washed with 15-20 mL of water. The resulting product was dried at room temperature for 48 hours and then purified by recrystallization from ethanol. The yields are given on a crystallized product.
N-(1-([1,2,4]Triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)acetamide (6a)
White solid; yield 58% (1.91 g); m.p. 178-180 °C; Rf = 0.31. 1H NMR (400 MHz, DMSO-d6): δ 9.17 (s, 1H, NH), 9.13 (br. s, 1H, NH), 9.04 (s, 1H, -N=CH-N=), 6.57 (d, J = 8.8 Hz, 1H, CH), 1.98 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): δ 169.5 (C=O), 163.6, 150.1, 135.4 (C=N), 100.2 (CCl3), 69.0 (CH), 22.3 (CH3). IR (KBr) (v cm-1): 3253, 3232, 3088 (NH), 2998, 2929, 2855, 2795 (CH), 1673 (C=O), 1584, 1514, 1491, 1371, 1238, 1113, 1040, 976, 821, 801, 620, 506; FAB-MS: m/z 329 [M+H]+. Anal. Calcd (%) for C7H7Cl3N6OS (329.58): C, 25.51; H, 2.14; Cl, 32.27; N, 25.50; S, 9.73. Found: C, 25.48; H, 2.12; Cl, 32.31; N, 25.53; S, 9.76.
N-(1-([1,2,4]Triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)acrylamide (6b)
White solid; yield 55% (1.88 g); m.p. 184-186 °C; Rf = 0.27. 1H NMR (400 MHz, DMSO-d6): δ 9.35 (d, J = 8.8 Hz, 1H, NH), 9.27 (br. s, 1H, NH), 9.22 (s, 1H, -N=CH-N=), 6.66 (br.s, 1H, CH), 6.48 (dd, J = 16.8, 10.3 Hz, 1H, CH=CH2), 6.25 (d, J = 16.8 Hz, 1H, =CH2-trans), 5.77 (d, J = 10.3 Hz, 1H, =CH2- cis); 13C NMR (100 MHz, DMSO-d6): δ 164.4 (C=O), 163.5, 150.1, 135.4 (C=N), 129.9 (CH=CH2), 128.3 (CH=CH2), 100.0 (CCl3), 69.2 (CH). IR (KBr) (v cm-1): 3251, 3090 (NH), 2998, 2928, 2852 (CH), 1674 (C=O), 1639, 1582, 1511, 1490, 1410, 1323, 1248, 1224, 1106, 976, 958, 823, 799, 735, 679, 628, 565; FAB-MS: m/z 341 [M+H]+. Anal. Calcd (%) for C8H7Cl3N6OS (341.60): C, 28.13; H, 2.07; Cl, 31.13; N, 24.60; S, 9.39. Found: C, 28.10; H, 2.09; Cl, 31.15; N, 24.62; S, 9.42.
N-(1-([1,2,4]Triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)benzamide (6c)
White solid; yield 42% (1.65 g); m.p. 160-162 °C; Rf = 0.29. 1H NMR (400 MHz, DMSO-d6): δ 9.38 (d, J = 8.6 Hz, 1H, NH), 9.01 (br. s, 1H, NH), 8.99 (s, 1H, -N=CH-N=), 7.92-7.90 (m, 2H, Harom.), 7.54-7.50 (m, 1H, Harom.), 7.46-7.42 (m, 2H, Harom.), 6.83 (dd, J = 8.6, 8.6 Hz, 1H, CH); 13C NMR (100 MHz, DMSO-d6): δ 166.2 (C=O), 163.3, 150.1, 134.8 (C=N), 133.0, 131.4, 127.8, 127.7 (arom.), 100.4 (CCl3), 69.6 (CH). IR (KBr) (v cm-1): 3329, 3224, 3186, 3096 (NH), 2946, 2929, 2851 (CH), 1672 (C=O), 1584, 1491, 1327, 1236, 1118, 1077, 962, 870, 796, 694, 611, 543; FAB-MS: m/z 391 [M+H]+. Anal. Calcd (%) for C12H9Cl3N6OS (391.66): C, 36.80; H, 2.32; Cl, 27.15; N, 21.46; S, 8.19. Found: C, 36.78; H, 2.30; Cl, 27.18; N, 21.49; S, 8.21.
N-(1-([1,2,4]Triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)-4-methylbenzamide (6d)
White solid; yield 62% (2.52 g); m.p. 141-143 °C; Rf = 0.28. 1H NMR (400 MHz, DMSO-d6): δ 9.15 (br. s, 1H, NH), 8.68 (br. s, 1H, -N=CH-N=), 7.81-7.79 (m, 2H, Harom.), 7.61 (br. s, 1H, NH), 7.36-7.34 (m, 2H, Harom.), 6.68 (dd, J = 8.8, 8.8 Hz, 1H, CH), 2.38 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): δ 166.5 (C=O), 163.6, 150.2, 142.1 (C=N), 135.4, 130.1, 128.7, 127.9 (arom.), 100.3 (CCl3), 69.7 (CH), 21.0 (CH3). IR (KBr) (v cm-1): 3255, 3154 (NH), 2995, 2925, 2855 (CH), 1670 (C=O), 1575, 1486, 3123, 1239, 1142, 1097, 1039, 802, 749, 638, 547; FAB-MS: m/z 405 [M+H]+. Anal. Calcd (%) for C13H11Cl3 N6OS (405.68): C, 38.49; H, 2.73; Cl, 26.22; N, 20.72; S, 7.90. Found: C, 38.47; H, 2.75; Cl, 26.25; N, 20.71; S, 7.92.
N-(1-([1,2,4]Triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)-2,4-dichlorobenzamide (6e)
White solid; yield 61% (2.81 g); m.p. 121-123 °C; Rf = 0.23. 1H NMR (400 MHz, DMSO-d6): δ 9.92 (d, J = 8.8 Hz, 1H, NH), 9.33 (d, J = 8.8 Hz, 1H, NH), 9.26 (s, 1H, -N=CH-N=), 7.73 (s, 1H, Harom.), 7.53-7.52 (m, 1H, Harom.), 7.46-7.43 (m, 1H, Harom.), 6.68 (dd, J = 8.8, 8.8 Hz, 1H, CH); 13C NMR (100 MHz, DMSO-d6): δ 165.7 (C=O), 163.5, 150.2, 135.5 (C=N), 135.0, 134.3, 131.2, 130.3, 129.1, 127.2 (arom.), 99.7 (CCl3), 69.5 (CH). IR (KBr) (v cm-1): 3285, 3241, 3078 (NH), 3008, 2944, 2855 (CH), 1660 (C=O), 1590, 1505, 1482, 1299, 1247, 1136, 1106, 822, 804, 733, 664; FAB-MS: m/z 459 [M+H]+. Anal. Calcd (%) for C12H7Cl5N6OS (460.54): C, 31.30; H, 1.53; Cl, 38.49; N, 18.25; S, 6.96. Found: C, 31.27; H, 1.51; Cl, 38.52; N, 18.28; S, 6.99.
N-(1-([1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)furan-2-carboxamide (6f)
White solid; yield 44% (1.68 g); m.p. 168-170 °C; Rf = 0.30. 1H NMR (400 MHz, DMSO-d6): δ 9.63 (d, J = 8.6 Hz, 1H, NH), 9.13 (d, J = 5.8 Hz, 1H, NH), 9.03 (s, 1H, -N=CH-N=), 7.79 (br. s, 1H, Harom.), 7.46-7.43 (m, 1H, Harom.), 6.72 (br. s, 1H, Harom.), 6.11 (dd, J = 8.6, 5.8 Hz, 1H, CH); 13C NMR (100 MHz, DMSO-d6): δ 166.4 (C=O), 156.4, 148.1, 138.2 (C=N), 134.2, 132.5, 127.2, 118.8 (arom.), 103.8 (CCl3), 73.0 (CH). IR (KBr) (v cm-1): 3329, 3277, 3112 (NH), 3062, 2950 (CH), 1667 (C=O), 1601, 1501, 1483, 1320, 1214, 1139, 1015, 925, 822, 795, 678, 517; FAB-MS: m/z 381 [M+H]+. Anal. Calcd (%) for C10H7Cl3 N6O2S (381.62): C, 31.47; H, 1.85; Cl, 27.87; N, 22.02; S, 8.40. Found: C, 31.45; H, 1.86; Cl, 27.90; N, 22.06; S, 8.43.
References
[1] Hu Y, Li C-Y, Wang X-M, Yang Y-H, Zhu H-L. 1,3,4-Thiadiazole: synthesis, reactions, and applications in medicinal, agricultural, and materials chemistry. Chem. Rev. 2014;114:5572-5610.10.1021/cr400131uSearch in Google Scholar PubMed
[2] Jain AK, Sharma S, Vaidya A, Ravichandran V, Agrawal RK. 1,3,4-Thiadiazole and its derivatives: a review on recent progress in biological activities. Chem. Biol. Drug. Des. 2013;81:557-576.10.1111/cbdd.12125Search in Google Scholar PubMed
[3] Maddila S, Pagadala R, Jonnalagadda SB. 1,2,4-Triazoles: A Review of Synthetic Approaches and the Biological Activity. Lett. Org. Chem. 2013;10:693-714.10.2174/157017861010131126115448Search in Google Scholar
[4] Stankovský Š, Špirková K, Jedlovska E, Konečný V. Preparation and Pesticide Properties of Some 1-Substituted (1H)-1,2,4-Triazoles. Chem. Pap. 1994;48:347-350.Search in Google Scholar
[5] Huo J, Hu H, Zhang M, Hu X, Chen M, Chen D, Liu J, Xiao G, Wang Y, Wen Zh. A mini review of the synthesis of poly-1,2,3-triazole-based functional materials. RSC Adv. 2017;7:2281-2287.10.1039/C6RA27012CSearch in Google Scholar
[6] Savateev A, Pronkin S, Epping JD, Willinger MG, Antoniettia M, Dontsova D. Synthesis of an electronically modified carbon nitride from a processable semiconductor, 3-amino-1,2,4-triazole oligomer, via a topotactic-like phase transition. J. Mater. Chem. A. 2017;5:8394-8401.10.1039/C7TA01714FSearch in Google Scholar
[7] Dilworth JR, Pascu SI, Waghorn PhA, Vullo D, Bayly SR, Christlieb M, Suna X, Supuranc CT. Synthesis of sulfonamide conjugates of Cu(II), Ga(III), In(III), Re(V) and Zn(II) complexes: carbonic anhydrase inhibition studies and cellular imaging investigations. Dalton Trans. 2015;44:4859-4873.10.1039/C4DT03206CSearch in Google Scholar PubMed
[8] Erfantalab M, Khanmohammadi H. New 1,2,4-triazole-based azo-azomethine dye. Part III: Synthesis, characterization, thermal property, spectrophotometric and computational studies. Spectrochim. Acta A. Mol. Biomol. Spectrosc. 2014;125:345-352.10.1016/j.saa.2014.01.113Search in Google Scholar PubMed
[9] Khanmohammadi H, Erfantalab M, Bayat A, Babaei A, Sohrabi M. New 1,2,4-triazole-based azo-azomethine dyes. Part II: synthesis, characterization, electrochemical properties and computational studies. Spectrochim. Acta A. Mol. Biomol. Spectrosc. 2012;97:876-884.10.1016/j.saa.2012.07.041Search in Google Scholar PubMed
[10] Khanmohammadi H, Erfantalab M. New 1,2,4-triazole-based azo-azomethine dyes. Part I: Synthesis, characterization and spectroscopic studies. Spectrochim. Acta A. Mol. Biomol. Spectrosc. 2012;86:39-43.10.1016/j.saa.2011.09.053Search in Google Scholar PubMed
[11] Zhang J, Liu H, Zhu K, Gong Sh, Dramsi Sh, Wang Y-T, Li J, Chen F, Zhang R, Zhou L, Lan L, Jiang H, Schneewind O, Luo C, Yang C-G. Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase. Proc. Natl. Acad. Sci. U.S.A. 2014;111:13517-13522.10.1073/pnas.1408601111Search in Google Scholar PubMed PubMed Central
[12] Seelolla G, Ponneri V. Synthesis, Antimicrobial, and Antioxidant Activities of Some Fused Heterocyclic [1,2,4] Triazolo[3,4-b][1,3,4]thiadiazole Derivatives. J. Heterocyclic Chem. 2016;53:929-936.10.1002/jhet.2348Search in Google Scholar
[13] Xiao H, Li P, Guo D, Hu J, Chai Yu, He W. Synthesis and antibacterial activity evaluation of 2,6-bis(6-substituted-1,2,4-triazolo[3,4-b][1,3,4]thiadiazol-3-yl)pyridine derivatives. Med. Chem. Res. 2014;23:1941-1949.10.1007/s00044-013-0790-2Search in Google Scholar
[14] Naveena ChSh, Poojary B, Chandrashekhar Ch, Kumari NS. Synthesis and Biological Evaluation of Some [1,2,4] Triazolo[3,4-b][1,3,4]Thiadiazoles and [1,2,4]Triazolo [3,4-b][1,3,4]Thiadiazines. Lett. Drug Des. Discovery. 2011;8:189-200.10.2174/157018011794183806Search in Google Scholar
[15] Almajan GL, Barbuceanu SF, Bancescu G, Saramet I, Saramet G, Draghici C. Synthesis and antimicrobial evaluation of some fused heterocyclic [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives. Eur. J. Med. Chem. 2010;45:6139-6146.10.1016/j.ejmech.2010.10.007Search in Google Scholar PubMed
[16] Khalil NS. Novel Simple Efficient Synthetic Approach Toward 6-Substituted-2H-[1,2,4]Triazolo[3,4-b][1,3,4]Thiadiazole-3-Thiones and First Synthesis and Biological Evaluation of N-and S-β-D-Glucosides of the[1,2,4]Triazolo[3,4-b][1,3,4] Thiadiazole Ring System. Nucleosides Nucleotides Nucleic Acids. 2007;26:347-359.10.1080/15257770701296978Search in Google Scholar PubMed
[17] Pundeer R, Ranjan P, Prakash R, Joshi R. Synthesis of Novel 6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles as Potential Antimicrobial Agents. Lett. Org. Chem. 2018;15:92-98.10.2174/1570178614666170907121125Search in Google Scholar
[18] Li D, Fu H. The Synthesis and Antibacterial Activities of 2,5-Bis[(3-aryl)-1,2,4-triazolo[3,4-b][1,3,4] thiadiazole-6-yl]thiophenes. Phosphorus, Sulfur Silicon Relat. Elem. 2008;183:2229-2236.10.1080/10426500701852794Search in Google Scholar
[19] Taha MAM. Convenient Synthesis of Some 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines Bearing 3-Methylthio{7H-1,2,4-triazolo[1,5-d]tetrazol-6-yl} moiety as Possible Antimicrobial Activity. Phosphorus, Sulfur Silicon Relat. Elem. 2008;183:2525-2533.10.1080/10426500801967773Search in Google Scholar
[20] Invidiata FP, Furnò G, Simoni D, Lampronti I, Musiu C, Milia C, Scintu F, La Colla P. 3,6-Disubstituted 1,2,4-triazolo[3,4-b] [1,3,4]thiadiazoles: synthesis and evaluation for antimicrobial and antiviral activity. III. Farmaco 1997;52:259-261.Search in Google Scholar
[21] Invidiata FP, Simoni D, Scintu F, Pinna N. 3,6-Disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles: synthesis, antimicrobial and antiviral activity. II. Farmaco 1996;51:659-664.Search in Google Scholar
[22] Li D, Bi X, Fu H. The Synthesis and Antibacterial Activities of 1,4-Bis[(3-aryl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole-6-yl]Butanes. Phosphorus, Sulfur Silicon Relat. Elem. 2007;182:1307-1314.10.1080/10426500601160850Search in Google Scholar
[23] Li Z, Liu Y, Bai X, Deng Q, Wang J, Zhang G, Xiao Ch, Mei Y, Wang Yu. SAR studies on 1,2,4-triazolo[3,4-b][1,3,4] thiadiazoles as inhibitors of Mtb shikimate dehydrogenase for the development of novel antitubercular agents. RSC Adv. 2015;5:97089-97101.10.1039/C5RA19334FSearch in Google Scholar
[24] Bonde CG, Peepliwal A, Gaikwad NJ. Synthesis and Antimycobacterial Activity of Azetidine-, Quinazoline-, and Triazolo-thiadiazole-containing Pyrazines. Arch. Pharm. (Weinheim) 2010;343:228-236.10.1002/ardp.200900165Search in Google Scholar PubMed
[25] Liu X-J, Wang L, Yin L, Cheng F-Ch, Sun H-M, Liu W-W, Shi D-H, Cao Zh-L. Synthesis and biological evaluation of novel glycosyl-containing 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole derivatives as acetylcholinesterase inhibitors. J. Chem. Res. 2017;41:571-575.10.3184/174751917X15064232103047Search in Google Scholar
[26] Baburajeev CP, Mohan ChD, Ananda H, Rangappa Sh, Fuchs JE, Jagadish S, Siveen KS, Chinnathambi A, Alharbi SA, Zayed ME, Zhang J, Li F, Sethi G, Girish KS, Bender A, Basappa, Rangappa KS. Development of Novel Triazolo-Thiadiazoles from Heterogeneous “Green” Catalysis as Protein Tyrosine Phosphatase 1B Inhibitors. Sci. Rep. 2015;5:14195.10.1038/srep14195Search in Google Scholar PubMed PubMed Central
[27] Sunil D, Isloor AM, Shetty P, Satyamoorthy K, Prasad ASB. Synthesis, characterization, antioxidant, and anticancer studies of 6-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-3-[(2-naphthyloxy)methyl][1,2,4]triazolo[3,4-b][1,3,4]thiadiazole in HepG2 cell lines. Med. Chem. Res. 2011;20:1074-1080.10.1007/s00044-010-9436-9Search in Google Scholar
[28] Ding H-Y, Li D-J. Synthesis and anticancer activities of 1,4-bis(6-aryl-1,2,4-triazolo[3,4-b]-[1,3,4]thiadiazole-3-yl) benzene derivatives. Heterocycl. Commun. 2011;17:69-71.Search in Google Scholar
[29] Al-Soud YA, Al-Masoudi NA, Loddo R, La Colla P. In-Vitro Anti- HIV and Antitumor Activity of New 3,6-Disubstituted [1,2,4] Triazolo[3,4-b][1,3,4]thiadiazoles and Thiadiazine Analogues. Arch. Pharm. (Weinheim) 2008;341:365-369.10.1002/ardp.200700272Search in Google Scholar PubMed
[30] Farghaly A-R, Clercq ED, El-Kashef H. Synthesis and antiviral activity of novel [1,2,4]triazolo[3,4-b][1,3,4] thiadiazoles, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and [1,2,4]triazolo[3,4-b][1,3,4] thiadiazepines. Arkivoc 2006;10:137-151.10.3998/ark.5550190.0007.a17Search in Google Scholar
[31] Bonafoux D, Nanthakumar S, Bandarage UK, Memmott Ch, Lowe D, Aronov AM, Bhisetti GR, Bonanno KC, Coll J, Leeman J, Lepre ChA, Lu F, Perola E, Rijnbrand R, Taylor WP, Wilson D, Zhou Y, Zwahlen J, ter Haar E. Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors. J. Med. Chem. 2016;59:7138-7151.10.1021/acs.jmedchem.6b00486Search in Google Scholar PubMed
[32] Zhang W, Chai,Y, Li K, Chen Y,Yan D, Guo D. Synthesis and fluorescence properties of 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol derivatives and their terbium complexes. Luminescence 2014;29:1113-1122.10.1002/bio.2668Search in Google Scholar PubMed
[33] Fan J-Zh, Li J-P, Zhang L-P, Zhang L-G, Wang D-Zh. New CuII and CdII Metal-organic Coordination Polymers with 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole Ligands: Syntheses, Structures and Luminescent Properties. J. Chin. Chem. Soc. 2015;62:786-792.10.1002/jccs.201400496Search in Google Scholar
[34] Pokotylo IO, Zadorozhnii PV, Kiselev VV, Kharchenko AV. Solvent-free synthesis and spectral characteristics of N-(2,2,2-trichloro-1-hydroxyethyl)carboxamides. Chem. Data Collect. 2018;15-16:62-66.10.1016/j.cdc.2018.04.002Search in Google Scholar
[35] Shaker RM, Aly AA. Recent Trends in the Chemistry of 4-Amino-1,2,4-triazole-3-thiones. Phosphorus, Sulfur Silicon Relat. Elem. 2006;181:2577-2613.10.1080/10426500600775922Search in Google Scholar
[36] Zadorozhnii PV, Kiselev VV, Kharchenko AV. Synthesis of nitrogen-containing heterocycles based on N-(isothiocyanatoalkyl)carboxamides. In Modern Directions in Chemistry, Biology, Pharmacy and Biotechnology. Novikov, VP., Ed. Lviv Polytechnic Publishing House: Lviv, 2015; pp 212-219.Search in Google Scholar
[37] Ulrich H. Chemistry and Technology of Carbodiimides; Wiley-VCH: New York, 2007.10.1002/9780470516683Search in Google Scholar
[38] Zadorozhnii PV, Kiselev VV, Pokotylo IO, Kharchenko AV. A new method for the synthesis of 4H-1,3,5-oxadiazine derivatives. Heterocycl. Commun. 2017;23:369-374.Search in Google Scholar
[39] Zadorozhnii PV, Kiselev VV, Pokotylo IO, Okhtina OV, Kharchenko AV. Synthesis and mass spectrometric fragmentation pattern of 6-(4-chlorophenyl)-N-aryl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amines. Heterocycl. Commun. 2018;24:273-278.10.1515/hc-2018-0082Search in Google Scholar
[40] Willard JR, Hamilton CS. Studies in the Furan Series. Chloralfuramides and Some of their Reactions. J. Am. Chem. Soc. 1953;75:2370-2373.10.1021/ja01106a025Search in Google Scholar
[41] Drach BS, Sinitsa AD, Kirsanov AV. N-(1,2,2,2-Tetrachloroethyl) amides. Zhurn. Obshch. Khim. 1970;40:1933-1937; Chem. Abstr. 1971;75:63069.Search in Google Scholar
[42] Altenbach RJ, Bai H, Brioni JD, Carroll WA, Gopalakrishnan M, Gregg RJ, Holladay MW, Huang PP, Kincaid JF, Kort ME, Kym PR, Lynch JK, Perez-Medrano A, Zhang HQ. US2002/28836 2002 A1; Chem. Abstr. 2002;136:231935.Search in Google Scholar
© 2019 Pavlo V. Zadorozhnii et al., published by De Gruyter
This work is licensed under the Creative Commons Attribution 4.0 Public License.
