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DOI: 10.1055/a-2017-4814
Regio- and Diastereoselective Synthesis of Substituted Triazolo [3,4-b]thiadiazin-6-ols and Triazolo[3,4-b]thiadiazines
We are grateful to the Faculty of Chemistry of Kharazmi University for supporting this work. We also thank the Alexander von Humboldt Foundation for supporting this work.
Abstract
An efficient, catalyst-free, regio- and diastereoselective approach for the synthesis of novel 7-aryl-3-alkyl(aryl)-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ols has been developed via the reaction of 4-amino-[1,2,4]triazole-3-thiols with nitroepoxides in methanol at room temperature. The products were simply dehydrated in the presence of PTSA in ethanol at 70 °C to afford the corresponding 7-aryl-3-alkyl(aryl)-6-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines in 91–98% yields. In addition, treatment of the product with acidic chloroform afforded the corresponding α-((4-amino-5-methyl-4H-1,2,4-triazol-3-yl)thio)-α-phenylpropan-2-one in quantitative yield.
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Key words
nitroepoxide - 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ols - 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines - diastereoselective - catalyst-freeThe chemistry of heterocyclic rings is rich and these compounds have found a wide range of applications in organic and medicinal chemistry, pharmaceuticals and industry.[1] Among heterocycles, those containing N,S-atoms are in the heart of research for finding novel drugs and biologically active compounds.[2] Among N,S-heterocycles, [1,2,4]-triazolo[3,4-b][1,3,4]thiadiazines are an interesting class of heterocyclic compounds possessing a wide range of pharmaceutical activities such as antimicrobial,[3] antifungal,[4] anticancer,[5] antidepressant,[6] antitumor,[7] analgesic,[8] anti-oxidant,[9] anti-inflammatory,[10] anti-HIV[11] agents. In addition, these compounds were extensively applied as inhibitor of various enzymes such as urease, alkaline phosphatase, acetyl choline sterase, and phosphodiesterase.[12] The wide spectra of biological activities of these compounds can be attributed to the fused triazole ring with thiadiazine, which have synergic effect on each other with enhanced biological activities.
In view of the importance of this heterocyclic core, many efforts have been devoted to find new synthetic methods to access this interesting scaffold. Among them, cyclocondensation of 4-amino-3-mercaptotriazoles with α-halocarbonyls,[13] with ketones containing active α-hydrogens in glacial acetic acid/sulfuric acid,[14] and with α-halonitriles[14] are noteworthy. In addition, intramolecular cyclization of 4-amino-3-propargylmercapto-1,2,4-triazole derivatives in acetic acid/heteropoly acid catalytic system[15] and condensation of 1,3,4-oxadiazole derivatives with hydrazine hydrate in refluxing acetic acid[16] were also reported. However, finding novel methods for the synthesis of these compounds to overcome the most of drawbacks associated with the present methods including low to moderate yields, harsh reaction conditions, using toxic α-halocarbonyl compounds, and difficulties associated with the preparation and isolation of α-halocarbonyls/nitriles especially those with a halogen group on the more hindered side is highly in demand for the synthesis of [1,2,4]-triazolo[3,4-b][1,3,4]thiadiazines of high diversity.
4-Amino-1,2,4-triazole-3-thiols have been widely used for synthesizing triazolothiadiazines.[13] They have the unique structural feature of proximity of amino and thiol groups, which could be utilized as an efficient N,S-dinucleophile in ring closure reactions leading to the formation of new heterocycles.[17]
Nitroepoxides have attracted the attention of organic chemists in recent years because of their unique and interesting reactivity in organic transformations.[18] These molecules have particular characteristics including two potential vicinal electrophilic centers, which makes them as efficient mono- and bis-electrophiles for the synthesis of various N,N- and N,S-heterocycles and substituted phenyl-2-propanone (P2P) derivatives.[19]
In continuation of our interest on the application of nitroepoxides for the synthesis of heterocyclic compounds, herein, we report an efficient, diastereo- and regioselective method for the synthesis of novel 7-aryl-3-alkyl(aryl)-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ols and their dehydration products, 7-aryl-3-alkyl(aryl)-6-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines using nitroepoxides (Scheme [1]).
Reaction of 4-amino-5-(4-fluorophenyl)-4H-1,2,4-triazole-3-thiol (1a) with nitroepoxide 2a was considered as a model reaction for optimization of the reaction conditions. By considering the successful cyclocondensation reaction of 1a with phenacyl bromides in refluxing ethanol,[13] the same conditions were applied for the reaction of 1a with nitroepoxide 2a. We observed that the product 3a was obtained in moderate yield (50%, Table [1], entry 1). By varying the reaction solvent to DMF, THF, MeOH, and water at 70 °C no improvement in reaction yield was obtained (entries 2–5). Using a base such as Et3N, DBU, and K2CO3 or an acid (PTSA) as a catalyst in ethanol at 70 °C did not improve the reaction yield (entries 6–9). In addition, low yield (32%) was obtained under neat conditions. By using K2CO3 in ethanol at room temperature, the yield was improved to 68% (entry 10). Surprisingly, we observed that performing the model reaction in ethanol at room temperature under base-free conditions afforded high yield (80%) of 3a (entry 11). By having this result in hand, we repeated the reaction in various solvents at room temperature under base-free conditions and the best yield (87%) was obtained in methanol (entries 12). It is notable that the product was precipitated in the reaction mixture and simply collected by filtration. In conclusion, reaction of one equivalent of 1a with one equivalent of nitroepoxide 2a in methanol at room temperature was considered as optimal reaction conditions for further derivatization.
After determination of optimal conditions, the generality of this protocol was examined using various nitroepoxides and 4-amino-3-mercaptotriazoles (Table [2]). Nitroepoxides with electron-donating and -withdrawing groups on the phenyl ring are suitable substrates in this protocol, albeit higher yields were observed for electron-withdrawing substituents. Naphthyl-substituted nitroepoxide gave also excellent yields (3v, 89%). In addition, various 4-amino-3-mercaptotriazoles with an aliphatic (methyl, cyclohexyl, or benzyl) or aromatic group at the position 5 of triazole ring afforded 73–97% yields. It is worth noting that this reaction is highly diastereoselective, and only a single diastereomer as racemic mixture was observed in high purity after purification, although two stereogenic centers were generated in this reaction. By the aid of 2D NOESY NMR, the stereochemistry of products was assigned as cis, in which the hydroxyl and the aryl groups in thiadiazine ring are in a cis configuration.
a Reaction conditions: 1a (1mmol), 2a (1 mmol), solvent (5 mL), 6 h, temperature (°C).
b Isolated yield. A diastereomeric ratio of >20:1 was observed in each case as determined by 1H NMR analysis.
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a Reaction conditions: 1 (1mmol), 2 (1 mmol), solvent (5 mL), 6 h, rt. Isolated yields are reported. A diastereomeric ratio of >20:1 was observed for all derivatives as determined by 1H NMR spectra.
Due to the importance of triazolothiadiazines 4, the dehydration reaction of selected triazolothiadiazin-6-ols 3 was carried out in the presence of PTSA in ethanol at 70 °C. We found that the corresponding products 4a–m were obtained in 91–98% yields and desired regioselectivity toward imine bond formation. The starting materials with different substitution pattern are compatible in this reaction and afforded excellent yields (Table [3]). Attempt to prepare compound 4 directly from the starting materials 1 and 2 in a one-pot procedure by mixing the starting materials in methanol at room temperature for 6 hours, followed by the addition of PTSA and further stirring at 60 °C for 2 hours, afforded lower yield in comparison to the two-step reaction.
Phenyl-2-propanones (also known as P2P and phenylacetones) are versatile intermediates in synthetic organic chemistry for the preparation of biologically active compounds (e.g., amphetamine and methamphetamine), agrochemicals and fragrances.[20] By the reaction of 3h with a trace amount of hydrochloric acid in chloroform, the corresponding substituted 1-((4-amino-4H-1,2,4-triazol-3-yl)thio)-1-phenylpropan-2-one 5 was obtained in quantitative yield (Scheme [2]).
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a Reaction conditions: 3a (1 mmol), PTSA (10 mol%), 70 °C, 2 h, EtOH (5 mL). Isolated yields are reported.
In principle, by the reaction of nitroepoxides 2 with 4-amino-[1,2,4]triazole-3-thiols 1, two regioisomers 3i and 3i′ may be generated by different combinations as depicted in Scheme [3]. In addition, by the reaction of 3i and 3i′ with PTSA, three regioisomers (4g, 4g′, and 4g′′ may be produced during the dehydration reaction (Scheme [3]). In addition to 1H and 13C NMR analyses, HMBC (1H-13C) and NOE experiments were also carried out for the selected compounds to find the correct regioisomer and stereochemistry in each step.
The (1H-13C) HMBC of compound 3i showed cross peaks of the proton at position 7 (H7, δ 4.79) with the carbons 6-CH3 (δ 25.1), C6 (δ 80.2), C2′′ (δ 125.2), and C1′′ (δ 139.4). Carbon 7 is assigned by correlations with the protons of 6-CH3 (δ 1.24), OH (δ 6.56), NH (δ 7.36), H6′′ (δ 8.05), and H2′′ (δ 8.50). In addition, carbon 6 is assigned by interactions with protons 1.24 (6-CH3), 4.79 (H7), 6.56 (OH), and 7.36 (NH). Furthermore, C9 is assigned by interaction with proton 7. The absence of correlation between C6 (δ 80.2) with the protons of the nitro-substituted phenyl ring exclude the formation of structure 3i′. These selected assignments confirm the proposed regioisomer for the compound 3 (Figure [1]A, for full correlation analysis; see Table [1] and Figures 1–4 in SI). 1H NMR spectra of this compound in the presence of D2O also confirm the presence of two exchangeable hydrogens, which are related to the OH and NH groups. In addition, the stereochemistry of products 3 was determined as cis by the aid of NOE experiment. NOE experiment of 3i shows space correlations of H7 (δ 4.79) with methyl group 6-CH3 (δ 1.24) and NH group (δ 7.36), which confirm the cis orientation of H7 and methyl group in thiadiazine ring (Figure [1]B).
Although three possible regioisomers 4g, 4g′, and 4g′′can be obtained by dehydration reaction of compounds 3j with PTSA, but only regioisomer 4g was confirmed with the aid of NMR analyses. While there are two aliphatic peaks in 13C NMR at around 23 ppm (for 6-CH3) and 40 ppm (for carbon 7), the possibility of formation of the isomers 4g′ and 4g′′can be simply eliminated. In addition, the lack of any exchangeable proton with D2O in 1H NMR spectra confirms the proposed structure for compound 4g and imine bond formation. Furthermore, HMBC (1H-13C) shows the correlation of carbon of imine C6 (δ 159.9) with protons of methyl 6-CH3 (δ 2.38) and H7 (δ 5.58). Crossed peak between C7 (δ 41.2) and methyl protons 6-CH3 (δ 2.38) and the protons of phenyl ring H2′′/6′′ (δ 7.25) is another evidence for the structure 4g and structures 4g′ and 4g′′can be simply removed by this observation. In addition, C9 is simply assigned by interaction with H7 (δ 5.58) (Figure [2], for full correlation analysis; see Table [2] and Figures 5–7 in SI).
The structure of 5 is also confirmed by NMR analyses (1H, 13C and HMBC), which is another evidence for the formation of regioisomers 3 and 4. HMBC (1H-13C) shows the correlation of carbon of carbonyl C7 (δ 201.8) with protons of methyl H8 (δ 2.20, CH3) and H6 (δ 6.03). Crossed peak between C6 (δ 60.4) and methyl protons H8 (δ 2.20, CH3) and the proton of phenyl ring H6′′ (δ 7.37) is another evidence for the structure 5. In addition, C3 (δ 150.6) is simply assigned by interaction with H6 (δ 6.03) and NH2 (δ 4.97). Furthermore, C5 is assigned by correlations with H2′/6′ (δ 7.92) and NH2 (δ 4.97) (Figure [3], for full correlation; see Table [3] and Figures 8, 9 in SI).
A proposed mechanism for the formation of triazolothiadiazin-6-ols and triazolothiadiazines is depicted in Scheme [4]. Initially, nitroepoxide ring opening with the thiol group of 1 affords the intermediate I by the loss of nitric acid. Then, intramolecular addition of the amine group in triazole ring to the carbonyl affords the corresponding triazolothiadiazin-6-ol 3. The stereochemistry of products can be explained by two Newman projections Ia and Ib. Due to the gauche interaction between the methyl and aryl groups in Ib, the reaction proceeds via the conformer Ia to afford the products with the observed stereochemistry. In addition, heating of 3 in the presence of a catalytic amount of PTSA facilitates the dehydration reaction to provide the triazolothiadiazines 4, while by treating compound 3 with acidic chloroform at room temperature, the equilibrium favors the reverse reaction toward the formation of intermediate I.
In summary, reaction of 4-amino[1,2,4]triazole-3-thiols with nitroepoxides under catalyst-free conditions was introduced as efficient protocol for the synthesis of triazolothiadiazin-6-ols. In addition, we have shown that these compounds are efficient intermediates for the synthesis of triazolothiadiazines by dehydration reaction in the presence of PTSA and substituted P2P derivatives by ring opening reaction. The simplicity, regioselectivity and diastereoselectivity as well as being well-efficient in a short time, using nontoxic and expensive reagents and facile isolation of the products are the main advantages of this experiment.
All chemicals and solvents were obtained from commercial sources and used as received. The 1H and 13C NMR spectra of products were recorded on a Bruker AMX 300, 400, and 500 MHz spectrometers referenced to internal Me4Si at 0.00 ppm. Reaction monitoring was carried out by TLC using TLC silica gel 60 F254 plates. HRMS (High-Resolution Mass Spectra) were measured on a THERMO SCIENTIFIC Advantage and a THERMO SCIENTIFIC Exactive instrument equipped with an APCI source in the positive-ion mode. Nitroepoxides[18] [19] and 4-amino[1,2,4]triazole-3-thiols[13,14] were prepared according to the literature procedures (see also SI).
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7-Aryl-3-alkyl(aryl)-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ols 3a–v; General Procedure
To a solution of a 4-amino-5-aryl(alkyl)-4H-1,2,4-triazole-3-thiol 1 (1 mmol) in MeOH (5 mL) was added a nitroepoxide 2 (1 mmol) and the mixture was stirred at rt for 6 h (completion of reaction was checked by TLC, EtOAc/n-hexane 1:3). The resulting precipitate was filtered, washed with cold MeOH, and dried to give pure products 3a–v as colorless powders.
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7-(4-Chlorophenyl)-3-(4-fluorophenyl)-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3a)
Colorless solid; yield: 327 mg (87%); mp 144–146 °C.
IR (KBr): 3409, 3250, 1609, 1484, 1454, 1235, 1161, 1016, 838 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.08 (dd, J = 8.7, 5.7 Hz, 2 H), 7.61 (d, J = 8.2 Hz, 2 H), 7.46 (d, J = 8.5 Hz, 2 H), 7.38 (t, J = 8.9 Hz, 2 H), 7.30 (s, 1 H), 6.44 (s, 1 H), 4.58 (s, 1 H), 1.19 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 164.1 (d, 1 J = 268 Hz), 151.0, 143.9, 135.5, 133.3, 131.9, 130.0 (d, 3 J = 8.7 Hz), 128.4, 123.3 (d, 4 J = 3 Hz), 115.7 (d, 2 J = 21 Hz), 79.7, 49.4, 24.5.
HRMS (ESI): m/z calcd for C17H14ClFN4OS [M + H]+: 377.0639; found: 377.0636.
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7-(2-Chlorophenyl)-3-(4-fluorophenyl)-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3b)
Colorless solid; yield: 320 mg (85%); mp 139–141 °C.
IR (KBr): 3334, 3253, 1608, 1534, 1475, 1455, 1232, 1160, 1036, 841, 754 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.07 (dd, J = 8.7, 5.6 Hz, 2 H), 7.96 (dd, J = 7.2, 2.3 Hz, 1 H), 7.54–7.35 (m, 5 H), 7.48 (s, 1 H), 6.53 (s, 1 H), 5.21 (s, 1 H), 1.23 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 164.9 (d, 1 J = 273 Hz), 151.1, 143.5, 133.8, 133.7, 131.9, 130.3, 130.0, 129.9 (d, 3 J = 8.5 Hz), 127.70, 123.3 (d, 4 J = 3 Hz), 115.7 (d, 2 J = 21.6 Hz), 80.0, 44.9, 23.9.
HRMS (ESI): m/z calcd for C17H14ClFN4OS [M + H]+: 377.0639; found: 377.0637.
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7-(2-Chlorophenyl)-3,6-dimethyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3c)
Colorless solid; yield: 257 mg (87%); mp 117–119 °C.
IR (KBr): 3370, 3183, 1546, 1473, 1431, 1173, 1118, 1032, 753, 700 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.92 (m, 1 H), 7.51 (dd, J = 7.2, 1.9 Hz, 1 H), 7.43–7.37 (m, 2 H), 7.11 (s, 1 H), 6.35 (s, 1 H), 5.14 (s, 1 H), 2.27 (s, 3 H), 1.21 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 150.2, 141.3, 134.0, 133.6, 133.1, 130.1, 129.2, 127.5, 79.8, 45.0, 23.8, 9.5.
HRMS (ESI): m/z calcd for C12H13ClN4OS [M + H]+: 297.0577; found: 297.0574.
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7-(4-Chlorophenyl)-3,6-dimethyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3d)
Colorless solid; yield: 266 mg (90%); mp 107–109 °C.
IR (KBr): 3410, 1634, 1547, 1491, 1427, 1274, 1167, 1124, 1016, 798 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.56 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 7.5 Hz, 2 H), 6.92 (s, 1 H), 6.27 (s, 1 H), 4.53 (s, 1 H), 2.27 (s, 3 H), 1.17 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 150.2, 141.7, 135.7, 133.2, 131.8, 128.4, 79.6, 49.5, 24.6, 9.7.
HRMS (ESI): m/z calcd for C12H13ClN4OS [M + H]+: 297.0577; found: 297.0575.
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3,6-Dimethyl-7-(p-tolyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3e)
Colorless solid; yield: 201 mg (73%); mp 99–102 °C.
IR (KBr): 3410, 3177, 1608, 1471, 1379, 1231, 1168, 1033, 841, 773 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.42 (d, J = 8.1 Hz, 2 H), 7.17 (d, J = 7.9 Hz, 2 H), 6.88 (s, 1 H), 6.15 (s, 1 H), 4.45 (s, 1 H), 2.29 (s, 3 H), 2.26 (s, 3 H), 1.15 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 150.0, 142.1, 137.8, 133.6, 129.7, 128.9, 79.6, 50.1, 24.5, 20.7, 9.66.
HRMS (ESI): m/z calcd for C13H16N4OS [M + H]+: 277.1123; found: 277.1120.
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3,6-Dimethyl-7-(3-nitrophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3f)
Colorless solid; yield: 276 mg (90%); mp 159–162 °C.
IR (KBr): 3412, 3184, 1631, 1532, 1428, 1352, 1168, 1125, 1029, 734, 689 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.46 (d, J = 2.0 Hz, 1 H), 8.24 (dd, J = 8.2, 1.4 Hz, 1 H), 8.01 (d, J = 7.9 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 6.97 (s, 1 H), 6.40 (s, 1 H), 4.73 (s, 1 H), 2.29 (s, 3 H), 1.21 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 150.3, 147.6, 141.3, 139.0, 136.9, 129.7, 124.6, 123.4, 79.7, 49.2, 24.7, 9.6.
HRMS (ESI): m/z calcd for C12H13ClN5O3S [M + H]+: 308.0817; found: 308.0811.
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7-(2,4-Dichlorophenyl)-3,6-dimethyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3g)
Colorless solid; yield: 300 mg (91%); mp 133.5–135.5 °C.
IR (KBr): 3370, 3176, 1591, 1548, 1471, 1426, 1387, 1277, 1170, 1124, 1049, 1006, 808, 696 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.92 (d, J = 8.7 Hz, 1 H), 7.70 (d, J = 2.2 Hz, 1 H), 7.53 (dd, J = 8.6, 2.2 Hz, 1 H), 7.13 (s, 1 H), 6.45 (s, 1 H), 5.10 (s, 1 H), 2.27 (s, 3 H), 1.20 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 150.3, 141.1, 134.6, 133.9, 133.2, 133.1, 128.7, 127.9, 79.8, 44.5, 23.9, 9.6.
HRMS (ESI): m/z calcd for C12H12Cl2N4OS [M + H]+: 331.0187; found: 331.0182.
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7-(2-Chlorophenyl)-6-methyl-3-(p-tolyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3h)
Colorless solid; yield: 320 mg (86%); mp 214–216 °C.
IR (KBr): 3411, 3251, 1615, 1473, 1455, 1445, 1277, 1176, 1122, 1037, 822, 751 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.97–7.82 (m, 3 H), 7.52 (d, J = 6.9 Hz, 1 H), 7.43–7.37 (m, 3 H), 7.34 (d, J = 7.8 Hz, 2 H), 6.50 (s, 1 H), 5.21 (s, 1 H), 2.36 (s, 3 H), 1.23 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 152.0, 143.2, 139.2, 133.9, 133.7, 131.9, 130.2, 129.3, 129.0, 127.7, 127.6, 123.9, 80.0, 44.9, 23.93, 20.9.
HRMS (ESI): m/z calcd for C18H17ClN4OS [M + H]+: 373.0890; found: 373.0884.
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6-Methyl-7-(3-nitrophenyl)-3-(p-tolyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3i)
Colorless solid; yield: 322 mg (84%); mp 199–203 °C.
IR (KBr): 3533, 3239, 1614, 1528, 1445, 1350, 1173, 1111, 970, 821 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.49 (s, 1 H), 8.24 (d, J = 8.3 Hz, 1 H), 8.04 (d, J = 7.7 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 2 H), 7.70 (t, J = 8.0 Hz, 1 H), 7.33–7.32 (m, 3 H), 6.54 (s, 1 H), 4.77 (s, 1 H), 2.36 (s, 3 H), 1.22 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 152.0, 147.6, 143.2, 139.2, 138.9, 136.7, 129.9, 129.0, 127.7, 124.7, 123.9, 123.6, 79.8, 49.2, 24.3, 20.9.
HRMS (ESI): m/z calcd for C18H17N5O3S [M + H]+: 384.1130; found: 384.1128.
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7-(4-Chlorophenyl)-6-methyl-3-(p-tolyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3j)
Colorless solid; yield: 338 mg (91%); mp 190–191 °C.
IR (KBr): 3411, 3258, 1612, 1489, 1426, 1377, 1273, 1169, 1144, 1089, 1014, 823 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.90 (d, J = 8.1 Hz, 2 H), 7.61 (d, J = 8.5 Hz, 2 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.25 (s, 1 H), 6.39 (s, 1 H), 4.57 (s, 1 H), 2.36 (s, 3 H), 1.19 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 151.9, 143.6, 139.2, 135.6, 133.3, 131.9, 129.0, 128.4, 127.7, 124.0, 79.7, 49.5, 24.6, 21.0.
HRMS (ESI): m/z calcd for C18H17ClN4OS [M + H]+: 373.0890; found: 373.0887.
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6-Methyl-7-phenyl-3-(p-tolyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3k)
Colorless solid; yield: 296 mg (87%); mp 113–114 °C.
IR (KBr): 3382, 3176, 1635, 1455, 1412, 1179, 1122, 1034, 816, 698 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.90 (d, J = 8.0 Hz, 2 H), 7.63–7.53 (m, 2 H), 7.44–7.36 (m, 3 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.23 (s, 1 H), 6.32 (s, 1 H), 4.55 (s, 1 H), 2.36 (s, 3 H), 1.19 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 151.8, 143.8, 139.0, 136.5, 129.9, 128.9, 128.6, 128.3, 127.6, 124.0, 79.7, 50.2, 24.5, 20.9.
EI-MS: m/z (%) = 338 (M•+), 320 (120), 296, 202, 117, 91.
HRMS (ESI): m/z calcd for C18H18N4OS [M + H]+: 339.1280; found: 339.1272.
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7-(4-Chlorophenyl)-3-cyclohexyl-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3l)
Colorless solid; yield: 321 mg (88%); mp 193–195 °C.
IR (KBr): 3413, 3232, 1636, 1492, 1448, 1170, 1089, 1031, 800 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.56 (d, J = 8.3 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2 H), 6.87 (s, 1 H), 6.23 (s, 1 H), 4.53 (s, 1 H), 2.78 (t, J = 10.3 Hz, 1 H), 1.99–1.21 (m, 10 H), 1.17 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 157.0, 141.7, 135.8, 133.2, 131.8, 128.4, 79.6, 49.5, 33.0, 31.0, 29.6, 25.5, 24.6.
HRMS (ES+): m/z calcd for C17H22ClN4OS [M + H]+: 365.9008; found: 365.8993.
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3-Cyclohexyl-6-methyl-7-(3-nitrophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3m)
Colorless solid; yield: 341 mg (91%); mp 108–110 °C.
IR (KBr): 3458, 3172, 1618, 1534, 1448, 1353, 1168, 1028, 735 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.45 (s, 1 H), 8.23 (d, J = 8.1 Hz, 1 H), 7.99 (d, J = 7.6 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 6.94 (s, 1 H), 6.37 (s, 1 H), 4.72 (s, 1 H), 2.81 (d, J = 11.3 Hz, 1 H), 2.02–1.24 (m, 10 H), 1.20 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 157.2, 147.6, 141.3, 139.1, 136.9, 129.9, 124.7, 123.5, 79.7, 49.3, 33.0, 31.0, 29.6, 25.5, 24.6.
HRMS (ES+): m/z calcd for C17H22N5O3S [M + H]+: 376.1443; found. 376.1439.
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3-(4-Methoxyphenyl)-6-methyl-7-(3-nitrophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3n)
Colorless solid; yield: 335 mg (84%); mp 121–122 °C.
IR (KBr): 3410, 3305, 1615, 1480, 1280, 1150, 1030, 830 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.50 (s, 1 H), 8.24 (d, J = 8.3 Hz, 1 H), 8.05 (d, J = 7.6 Hz, 1 H), 7.98 (d, J = 8.5 Hz, 2 H), 7.70 (t, J = 8.0 Hz, 1 H), 7.33 (s, 1 H), 7.08 (d, J = 8.2 Hz, 2 H), 6.55 (s, 1 H), 4.78 (s, 1 H), 3.81 (s, 3 H), 1.23 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 160.2, 151.9, 147.6, 142.9, 138.9, 137.0, 129.9, 129.2, 124.8, 123.6, 119.2, 113.9, 79.8, 55.3, 49.2, 24.6.
HRMS (ESI): m/z calcd for C18H17N5O4S [M + H]+: 400.1079; found: 400.1077.
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7-(4-Chlorophenyl)-3-(4-methoxyphenyl)-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3o)
Colorless solid; yield: 357 mg (92%); mp 141–144 °C.
IR (KBr): 3431, 3257, 1612, 1489, 1256, 1177, 1091, 1029, 837 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.96 (d, J = 8.6 Hz, 2 H), 7.61 (d, J = 8.5 Hz, 2 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.23 (s, 1 H), 7.07 (d, J = 8.9 Hz, 2 H), 6.39 (s, 1 H), 4.56 (s, 1 H), 3.81 (s, 3 H), 1.19 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 160.1, 151.7, 143.3, 135.6, 133.3, 131.9, 129.2, 128.4, 119.2, 113.9, 79.7, 55.3, 49.4, 24.6.
HRMS (ESI): m/z calcd for C18H17ClN4O2S [M + H]+: 389.0839; found: 389.0834.
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7-(2-Chlorophenyl)-3-(4-methoxyphenyl)-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3p)
Colorless solid; yield: 349 mg (90%); mp 76–79 °C.
IR (KBr): 3324, 3265, 1611, 1476, 1439, 1251, 1175, 1125, 1030, 834, 747 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.03–7.89 (m, 3 H), 7.51 (m, 1 H), 7.47–7.35 (m, 3 H), 7.08 (d, J = 8.5 Hz, 2 H), 6.48 (s, 1 H), 5.21 (s, 1 H), 3.82 (s, 3 H), 1.23 (s, 3 H)
13C NMR (75 MHz, DMSO-d 6): δ = 160.1, 151.7, 142.9, 133.9, 133.7, 130.2, 129.3, 129.0, 127.6, 119.2, 114.0, 113.8, 80.0, 55.2, 44.9, 24.0.
HRMS (ESI): m/z calcd for C18H17ClN4O2S [M – H]–: 387.0682; found: 387.0690.
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6-Methyl-7-(3-nitrophenyl)-3-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol) (3q)
Colorless solid; yield: 344 mg (93%); mp 133–135 °C.
IR (KBr): 3410, 3225, 1615, 1536, 1477, 1351, 1180, 1127, 1014, 911, 770, 697 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.50 (s, 1 H), 8.24 (d, J = 7.6 Hz, 1 H), 8.03 (d, J = 6.3 Hz, 3 H), 7.70 (t, J = 8.0 Hz, 1 H), 7.52 (d, J = 7.2 Hz, 3 H), 7.36 (s, 1 H), 6.55 (s, 1 H), 4.78 (s, 1 H), 1.23 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 152.0, 147.6, 143.5, 138.9, 136.9, 129.9, 129.5, 128.4, 127.7, 126.7, 124.7, 123.6, 79.8, 49.2, 24.6.
HRMS (ESI): m/z calcd for C17H15N5O3S [M + H]+: 370.0974; found: 370.0971.
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3-Benzyl-6-methyl-7-(3-nitrophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3r)
Colorless solid; yield: 344 mg (90%); mp 116–117 °C.
IR (KBr): 3519, 3264, 1588, 1528, 1354, 1174, 1100, 1029, 729 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.44 (s, 1 H), 8.23 (d, J = 7.8 Hz, 1 H), 7.99 (s, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.40–7.22 (m, 5 H), 6.95 (s, 1 H), 6.47 (s, 1 H), 4.78 (s, 1 H), 4.22–3.92 (ABq, J = 15.5 Hz, 2 H), 1.20 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 152.8, 147.6, 141.9, 139.0, 136.9, 136.6, 133.2, 128.7, 128.4, 126.5, 124.6, 123.5, 79.9, 49.2, 29.3, 24.6.
HRMS (ESI): m/z calcd for C18H17N5O3S [M + H]+: 384.1130; found: 384.1126.
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3-Benzyl-7-(4-chlorophenyl)-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3s)
Colorless solid; yield: 350 mg (94%); mp 184–187 °C.
IR (KBr): 3420, 3179, 1600, 1491, 1464, 1273, 1169, 1132, 1015, 722 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.55 (d, J = 8.5 Hz, 2 H), 7.50–7.36 (m, 2 H), 7.38–7.19 (m, 5 H), 6.86 (s, 1 H), 6.31 (s, 1 H), 4.60 (s, 1 H), 4.17–3.93 (ABq, J = 15.5 Hz, 2 H), 1.18 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 152.7, 142.3, 136.7, 135.7, 133.2, 131.8, 128.8, 128.5, 128.4, 126.5, 79.8, 49.4, 29.4, 24.5.
HRMS (ESI): m/z calcd for C18H17ClN4OS [M + H]+: 373.0890; found: 373.0887.
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3-Benzyl-7-(2-chlorophenyl)-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3t)
Colorless solid; yield: 342 mg (92%); mp 135–136 °C.
IR (KBr): 3337, 3175, 1635, 1472, 1275, 1173, 1120, 1033, 749 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.98–7.92 (m, 1 H), 7.50 (dd, J = 7.0, 2.3 Hz, 1 H), 7.45–7.20 (m, 7 H), 7.08 (s, 1 H), 6.41 (s, 1 H), 5.24 (s, 1 H), 4.15–3.95 (ABq, J = 15.4 Hz, 2 H), 1.22 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 154.6, 152.7, 142.0, 136.7, 134.1, 133.7, 130.1, 129.2, 128.7, 128.4, 127.5, 126.5, 80.1, 44.8, 29.3, 24.0.
HRMS (ESI): m/z calcd for C18H17ClN4OS [M + H]+: 373.0890; found: 373.0887.
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3-Benzyl-7-(2,4-dichlorophenyl)-6-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3u)
Colorless solid; yield: 373 mg (92%); mp 98–100 °C.
IR (KBr): 3370, 3164, 1620, 1587, 1470, 1385, 1274, 1163, 1101, 1049, 866, 725 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.94 (d, J = 8.6 Hz, 1 H), 7.71 (m, 1 H), 7.53 (d, J = 8.5 Hz, 1 H), 7.37–7.20 (m, 5 H), 7.07 (s, 1 H), 6.48 (s, 1 H), 5.21 (s, 1 H), 4.14–3.95 (ABq, J = 15.4 Hz, 2 H), 1.21 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 152.8, 141.7, 136.7, 134.6, 133.9, 133.4, 128.7, 128.5, 128.3, 127.9, 127.9, 126.5, 80.0, 47.5, 30.1, 24.0.
EI-MS: m/z (%) = 406 (M•+), 388, 355, 312, 229, 202, 116, 91 (100).
HRMS (ESI): m/z calcd for C18H16Cl2N4OS [M + H]+: 407.0500; found: 407.0492.
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3-(4-Fluorophenyl)-6-methyl-7-(naphthalen-1-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-ol (3v)
Colorless solid; yield: 349 mg (89%); mp 132–134 °C.
IR (KBr): 3420, 3239, 1607, 1481, 1447, 1347, 1269, 1232, 1176, 1085, 1032, 836, 775 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.21 (d, J = 8.5 Hz, 1 H), 8.16–8.06 (m, 3 H), 7.99 (dd, J = 14.5, 8.1 Hz, 2 H), 7.67 (dd, J = 8.4, 6.9 Hz, 1 H), 7.59 (q, J = 7.1, 6.6 Hz, 2 H), 7.40 (t, J = 8.9 Hz, 2 H), 7.34 (s, 1 H), 6.51 (s, 1 H), 5.69 (s, 1 H), 1.17 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 164.3 (d, 1 J = 245 Hz), 150.9, 144.4, 133.1, 132.2, 131.7, 129.9 ((d, 3 J = 8.2 Hz), 129.1, 128.8, 128.3, 127.0, 125.8, 125.5, 123.4 (d, 4 J = 3 Hz), 122.1, 115.7 (d, 2 J = 21 Hz), 80.2, 43.0, 24.1.
HRMS (ES+): m/z calcd for C21H17FN4OS [M + H]+: 393.1185; found: 393.1174.
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7-Aryl-3-alkyl(aryl)-6-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 4a–m; General Procedure
To a suspension of 3 (1 mmol) in EtOH (5 mL) was added PTSA (10 mol%) and the mixture was stirred at 70 °C for 2 h until the reaction was complete (TLC, EtOAc/n-hexane 1:3). The reaction mixture was quenched with H2O (10 mL) and the product was extracted with EtOAc (3 × 10 mL). The organic extracts were combined, washed with H2O (2 × 10 mL), dried (anhyd Na2SO4) and evaporated under reduced pressure to afford the pure product 4.
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7-(4-Chlorophenyl)-3-(4-fluorophenyl)-6-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4a)
Colorless solid; yield: 347 mg (97%); mp 152–154 °C.
IR (KBr): 1606, 1479, 1456, 1222, 1161, 1094, 1016, 845, 598 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.16–8.06 (m, 2 H), 7.49–7.35 (m, 4 H), 7.24 (d, J = 8.6 Hz, 2 H), 5.58 (s, 1 H), 2.36 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 164.8 (d, 1 J = 247.5 Hz), 159.6, 149.8, 140.0, 134.3, 133.5, 130.3, 129.4 ((d, 3 J = 8.3 Hz), 129.0, 122.3 (d, 4 J = 3 Hz, 116.1 (d, 2 J = 28.6 Hz), 40.7, 23.3.
EI-MS: m/z (%) = 358 (M•+, 100), 282, 168, 121, 89.
HRMS (ESI): m/z calcd for C17H12ClFN4S [M + H]+: 359.0533; found: 359.0527.
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7-(2-Chlorophenyl)-3,6-dimethyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4b)
Colorless solid; yield: 264 mg (95%); mp 147–148 °C.
IR (KBr): 1637, 1531, 1466, 1437, 1390, 1378, 1037, 736 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.60 (d, J = 8.0 Hz, 1 H), 7.40 (dd, J = 7.6, 1.5 Hz, 1 H), 7.25 (t, J = 7.6 Hz, 1 H), 6.77 (d, J = 7.7 Hz, 1 H), 5.62 (s, 1 H), 2.50 (s, 3 H), 2.30 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 157.4, 149.8, 136.8, 132.7, 131.8, 130.7, 130.7, 128.2, 127.4, 40.3, 23.0, 9.9.
EI-MS: m/z (%) = 278 (M•+, 100), 202, 168, 115, 99, 89.
HRMS (ESI): m/z calcd for C12H11ClN4S [M + H]+: 279.0471; found: 279.0464.
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7-(4-Chlorophenyl)-3,6-dimethyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4c)
Colorless solid; yield: 253 mg (91%); mp 104–105 °C.
IR (KBr): 1633, 1538, 1469, 1359, 1091, 1015, 809, 740 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.41 (d, J = 8.5 Hz, 2 H), 7.18–7.11 (m, 2 H), 5.49 (s, 1 H), 2.47 (s, 3 H), 2.28 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 158.2, 149.6, 137.5, 134.7, 133.4, 129.3, 129.0, 41.1, 23.1, 9.9.
HRMS (ES+): m/z calcd for C12H12ClN4S [M + H]+: 279.0471; found: 279.0466.
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7-(2,4-Dichlorophenyl)-3,6-dimethyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4d)
Colorless solid; yield: 302 mg (97%); mp 136–138 °C.
IR (KBr): 1629, 1584, 1462, 1435, 1389, 1363, 1109, 844, 810 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.79 (s, 1 H), 7.32 (dd, J = 8.3, 2.1 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 5.63 (s, 1 H), 2.51 (s, 3 H), 2.31 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 157.2, 149.9, 136.7, 134.4, 133.9, 131.0, 130.5, 128.8, 128.3, 40.4, 23.0, 9.9.
HRMS (ESI): m/z calcd for C12H10Cl2N4S [M + H]+: 313.0081; found: 313.0078.
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7-(2-Chlorophenyl)-6-methyl-3-(p-tolyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4e)
Colorless solid; yield: 340 mg (96%); mp 125–127 °C.
IR (KBr): 1610, 1477, 1450, 1378, 1183, 1049, 964, 821, 770, 743 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.99 (d, J = 7.0 Hz, 2 H), 7.62 (d, J = 7.6 Hz, 1 H), 7.39–7.37 (m, 3 H), 7.25 (m, 1 H), 6.86 (d, J = 6.9 Hz, 1 H), 5.71 (s, 1 H), 2.38 (d, J = 5.7 Hz, 6 H).
13C NMR (75 MHz, DMSO-d 6): δ = 158.4, 150.7, 140.1, 138.9, 132.9, 131.4, 131.0, 130.7, 129.3, 128.2, 127.8, 127.3, 122.9, 39.4, 23.30, 21.00.
HRMS (ESI): m/z calcd for C18H15ClN4S [M + H]+: 355.0784; found: 355.0781.
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6-Methyl-7-(3-nitrophenyl)-3-(p-tolyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4f)
Colorless solid; yield: 346 mg (95%); mp 175–179 °C.
IR (KBr): 1610, 1532, 1478, 1446, 1349, 1188, 965, 827, 720 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.19 (d, J = 7.2 Hz, 1 H), 8.14 (s, 1 H), 7.92 (d, J = 8.1 Hz, 2 H), 7.74–7.58 (m, 2 H), 7.39 (d, J = 7.8 Hz, 2 H), 5.73 (s, 1 H), 2.41 (s, 3 H), 2.40 (s, 2 H).
13C NMR (75 MHz, DMSO-d 6): δ = 159.0, 150.9, 148.0, 140.2, 139.5, 137.3, 133.5, 131.0, 129.3, 127.8,127.6, 123.7, 122.8, 40.8, 23.3, 20.9.
HRMS (ESI): m/z calcd for C18H15N5O2S [M + H]+: 366.1025; found: 366.1023.
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7-(4-Chlorophenyl)-6-methyl-3-(p-tolyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4g)
Colorless solid; yield: 330 mg (93%); mp 130–132 °C.
IR (KBr): 1613, 1488, 1453, 1379, 1182, 1091, 1010, 966, 825 cm–1.
1H NMR (400 MHz, DMSO-d 6): δ = 7.94 (d, J = 8.1 Hz, 2 H), 7.46 (d, J = 8.5 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.25 (d, J = 8.5 Hz, 2 H), 5.58 (s, 1 H), 2.40 (s, 3 H), 2.38 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 159.32, 150.67, 140.09, 139.78, 134.29, 133.49, 129.33, 129.28, 128.96, 127.68, 122.94, 40.75, 40.33, 40.05, 39.77, 39.50, 39.22, 38.94, 38.66, 23.29, 20.96.
EI-MS: m/z (%) = 354 (M•+, 100), 278, 168, 117, 89.
HRMS (ESI): m/z calcd for C18H15ClN4S [M + H]+: 355.0784; found: 355.0779.
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7-(4-Chlorophenyl)-3-cyclohexyl-6-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4h)
Colorless solid; yield: 329 mg (95%); mp 58–60 °C.
IR (KBr): 1632, 1490, 1461, 1377, 1183, 1092, 1014, 824, 797 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 7.42 (d, J = 8.5 Hz, 2 H), 7.11 (d, J = 8.5 Hz, 2 H), 5.48 (s, 1 H), 3.00 (t, J = 11.1 Hz, 1 H), 2.30 (s, 3 H), 2,01–1.09 (m, 10 H).
13C NMR (75 MHz, DMSO-d 6): δ = 158.3, 155.8, 137.8, 134.6, 133.4, 129.3, 128.8, 79.1, 41.1, 33.6, 30.6, 29.4, 25.4, 25.2, 25.2, 23.2.
HRMS (ES+): m/z calcd for C17H20ClN4S [M + H]+: 347.1097; found: 347.1091.
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3-(4-Methoxyphenyl)-6-methyl-7-(3-nitrophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4i)
Colorless solid; yield: 358 mg (94%); mp 66–70 °C.
IR (KBr): 1610, 1530, 1479, 1453, 1350, 1253, 1176, 1100, 1027, 836, 722 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.17 (dd, J = 7.9, 1.9 Hz, 1 H), 8.10 (d, J = 2.2 Hz, 1 H), 8.00 (d, J = 8.9 Hz, 2 H), 7.75–7.52 (m, 2 H), 7.13 (d, J = 8.6 Hz, 2 H), 5.72 (s, 1 H), 3.84 (s, 3 H), 2.41 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 160.8, 159.0, 150.7, 148.1, 139.3, 137.4, 133.5, 131.1, 129.4, 123.7, 122.1, 118.0, 114.3, 55.4, 40.6, 23.4.
HRMS (ES+): m/z calcd for C18H16N5O3S [M + H]+: 382.0974; found: 382.0964.
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7-(2-Chlorophenyl)-3-(4-methoxyphenyl)-6-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4j)
Colorless solid; yield: 363 mg (98%); mp 68–69 °C.
IR (KBr): 1610, 1479, 1451, 1252, 1176, 1027, 834, 739 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.06 (d, J = 8.6 Hz, 2 H), 7.63 (d, J = 7.9 Hz, 1 H), 7.39 (m, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.14 (d, J = 8.7 Hz, 2 H), 6.85 (d, J = 7.7 Hz, 1 H), 5.70 (s, 1 H), 3.84 (s, 3 H), 2.37 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 160.8, 158.4, 150.5, 138.6, 132.9, 131.5, 131.0, 130.8, 129.5, 128.2, 127.2, 118.1, 114.3, 55.3, 39.4, 23.3.
EI-MS: m/z (%) = 370 (M•+, 100), 294, 168, 133, 115.
HRMS (ESI): m/z calcd for C18H15ClN4OS [M + H]+: 371.0733; found: 371.0729.
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3-Benzyl-6-methyl-7-(3-nitrophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4k)
Colorless solid; yield: 358 mg (98%); mp 124–126 °C.
IR (KBr): 1717, 1622, 1601, 1531, 1460, 1349, 718 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.13–8.09 (m, 2 H), 7.48–7.17 (m, 6 H), 6.92 (d, J = 7.6 Hz, 1 H), 5.62 (s, 1 H), 4.42–4.17 (ABq, J = 15.3 Hz, 2 H), 2.32 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 158.3, 151.7, 148.2, 138.0, 137.6, 136.0, 132.2, 130.5, 128.6, 128.5, 126.8, 123.5, 122.6, 40.8, 30.0, 23.1.
EI-MS m/z (%) = 365 (M•+), 338 (100), 115, 91.
HRMS (ESI): m/z calcd for C18H15N5O2SNa [M + Na]+: 388.0844; found: 388.0842.
#
3-(4-Fluorophenyl)-6-methyl-7-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4l)
Colorless solid; yield: 308 mg (95%); mp 196–198 °C.
IR (KBr): 1610, 1480, 1453, 1232, 1160, 1102, 837, 695 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.12 (dd, J = 8.3, 4.7 Hz, 2 H), 7.58–7.26 (m, 5 H), 7.26–7.10 (m, 2 H), 5.56 (s, 1 H), 2.36 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 164.8 (d, 1 J = 230 Hz), 160.1, 149.8, 140.3, 135.3, 130.2 (d, 3 J = 8.2 Hz, 129.4, 128.8, 127.1, 122.4 (d, 4 J = 3.0 Hz), 116.19 (d, 2 J = 25.5 Hz), 41.4, 23.4.
EI-MS: m/z (%) = 324 (M•+), 300 (100), 202, 121, 104, 77.
HRMS (ESI): m/z calcd for C17H13FN4S [M + H]+: 325.0923; found: 325.0916.
#
6-Methyl-7-(naphthalen-1-yl)-3-(p-tolyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (4m)
Colorless solid; yield: 337 mg (91%); mp 199–200 °C.
IR (KBr): 1613, 1479, 1452, 1393, 1330, 1184, 1030, 960, 860, cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.32 (d, J = 8.5 Hz, 1 H), 8.02–8.00 (m, 3 H), 7.92 (d, J = 8.3 Hz, 1 H), 7.71 (t, J = 7.7 Hz, 1 H), 7.63 (t, J = 7.4 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 1 H), 6.93 (d, J = 7.2 Hz, 1 H), 6.33 (s, 1 H), 2.42 (s, 3 H), 2.40 (s, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 159.8, 150.6, 140.1, 140.0, 134.1, 129.7, 129.5, 129.3, 129.1, 128.9, 127.7, 127.0, 126.4, 125.3, 123.9, 123.5, 123.0, 38.7, 23.3, 20.9.
HRMS (ES+): m/z calcd for C22H18N4S [M + H]+: 371.1330; found: 371.1006.
#
Procedure for Conversion of 3h to 1-((4-Amino-5-(p-tolyl)-4H-1,2,4-triazol-3-yl)thio)-1-(2-chlorophenyl)propan-2-one (5)
In a test tube, 3h (1 mmol) was dissolved in commercial CHCl3 containing a trace amount of HCl and the mixture was stirred at rt for 24 h. The solvent was evaporated and the pure product 5 was obtained as a gummy solid; yield: 372 mg (~100%).
IR (KBr): 3334, 3173, 1714, 1608, 1475, 1232, 1160, 841, 754 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.92 (d, J = 8.2 Hz, 2 H), 7.48 (dd, J = 7.8, 1.5 Hz, 1 H), 7.36 (dd, J = 7.4, 1.9 Hz, 1 H), 7.33 (d, J = 2.0 Hz, 1 H), 7.30 (dd, J = 5.3, 1.8 Hz, 1 H), 7.28 (dt, J = 7.8, 1.3 Hz, 2 H), 6.03 (s, 1 H), 4.97 (s, 2 H), 2.41 (s, 3 H), 2.20 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 201.7, 154.6, 150.6, 140.5, 134.5, 132.1, 130.6, 130.6, 130.4, 129.3, 128.2, 127.8, 123.6, 60.5, 28.5, 21.6.
HRMS (ESI): m/z calcd for C18H17ClN4OS [M + H]+: 373.0890; found: 373.0885.
#
#
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
We are grateful to the staff of Freiburg University for HRMS analyses.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2017-4814.
- Supporting Information
-
References
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Corresponding Author
Publication History
Received: 16 March 2022
Accepted after revision: 22 January 2023
Accepted Manuscript online:
22 January 2023
Article published online:
15 February 2023
© 2023. Thieme. All rights reserved
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
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- 2a Jain AK, Vaidya A, Ravichandran V, Kashaw SK, Agrawal RK. Bioorg. Med. Chem. 2012; 20: 3378
- 2b Bruno G, Costantino L, Curinga C, Maccari R, Monforte F, Nicolo F, Ottana R, Vigorita M. Bioorganic Med. Chem. 2002; 10: 1077
- 3a Prakash O, Aneja DK, Hussain K, Lohan P, Ranjan P, Arora S, Sharma C, Aneja KR. Eur. J. Med. Chem. 2011; 46: 5065
- 3b Kouhkan M, Mahmoody M, Khalafy J, Pourali S, Samadi N. Med. Lab. J. 2020; 14: 20
- 4 Swamy SN, Basappa, Priya BS, Prabhuswamy B, Doreswamy BH, Prasad JS, Rangappa KS. Eur. J. Med. Chem. 2006; 41: 531
- 5 Holla BS, Sarojini B, Rao BS, Akberali PM, Kumari S, Shetty V. Farmaco 2001; 56: 565
- 6 Albrecht WL, Sweet FW. Patent US 3954983, 1976 ; Chem. Abstr. 1976, 85, 177510v
- 7 Holla BS, Poojary KN, Rao BS, Shivananda MK. Eur. J. Med. Chem. 2002; 37: 511
- 8 Aytaç P, Toskoparan B, Kaynak FB, Aktay G, Göktas O, Ȕnüvar S. Eur. J. Med. Chem. 2009; 44: 4528
- 9 Kaushik N, Kumar N, Kumar A. Int. J. Pharm. Pharm. Sci. 2015; 7: 120
- 10 Bhalla M, Hitkari A, Gujrati VR, Bhalla TN, Shanker K. Eur. J. Med. Chem. 1994; 29: 713
- 11 Farghaly AR, De Clercq E, El-Kashef H. ARKIVOC 2006; (x): 137
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- 12b Skoumbourdis AP, Le Clair CA, Stefan E, Turjanski AG, Maguire W, Titus SA, Huang R, Auld DS, Inglese J, Austin CP, Michnick SW, Xia M, Thomas CJ. Bioorg. Med. Chem. Lett. 2009; 19: 3686
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- 12d Gouda MA, Abu-Hashem AA, Hussein HA. R, Aly AS. Polycycl. Arom. Compd. 2022; 42: 2861
- 13a Khan I, Zaib S, Ibrar A, Rama NH, Simpson J, Iqbal J. Eur. J. Med. Chem. 2014; 78: 167
- 13b Li Z, Bai X, Deng Q, Zhang G, Zhou L, Liu Y, Wang J, Wang Y. Bioorg. Med. Chem. 2017; 25: 213
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- 18a Ranjbari MA, Tavakol H. J. Org. Chem. 2021; 86: 4756
- 18b Badali E, Rahimzadeh H, Sharifi A, Habibi A, Halimehjani AZ. Org. Biomol. Chem. 2020; 18: 4983
- 19a Guo X, Chen W, Chen B, Huang W, Qi W, Zhang G, Yu Y. Org. Lett. 2015; 17: 1157
- 19b Ziyaei Halimehjani A, Lotfi Nosood Y. Org. Lett. 2017; 19: 6748
- 19c Guo X, Shao J, Liu H, Chen B, Chen W, Yu Y. RSC Adv. 2015; 5: 51559
- 19d Vidal-Albalat A, Rodríguez S, González FV. Org. Lett. 2014; 16: 1752
- 19e Ibrahim MM, Grau D, Hample F, Tsogoeva SB. Eur. J. Org. Chem. 2014; 1401
- 19f Capel E, Vidal-Albalat A, Rodríguez S, González FV. Synthesis 2016; 48: 2572
- 19g Nosood YL, Ziyaei Halimehjani A, González FV. J. Org. Chem. 2018; 83: 1252
- 19h Guo S, Zhao D, Zhu Y, Yu Y, Chen W, Zhang G. Synth. Commun. 2017; 47: 1758
