* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
General procedure: A stirring mixture of benzoic acid (0.2442 g, 2.0 mmol), thiosemicarbazide (0.1823 g, 2.0 mmol) and POCl3 (1.2 ml) was heated at 80 oC for 2.5 h. After cooling down to room temperature, water (2.5 mL) was added. The reaction mixture was refluxed for 4 h. After cooling, the mixture was basified to pH 8 by the dropwise addition of 40percent NaOH solution under stirring. The precipitate was filtered and recrystallized from ethanol to yield 0.3130 g of the target compound 1a as a white solid ,Yield: 88.3percent.
82%
Stage #1: at 75℃; for 0.5 h; Stage #2: for 4 h; Reflux
General procedure: 5.1.1 5-(4-Morpholinophenyl)-1,3,4-thiadiazol-2-amine (59) A mixture of 4-morpholinobenzoic acid (5.18 g, 25 mmol) and N-aminothiourea (2.28 g, 25 mmol) in POCl3 (7 ml) was stirred vigorously at 75 °C for 0.5 h. After addition of H2O (30 ml), the reaction mixture was heated under reflux for 4 h and basified to pH 8 by 50percent NaOH solution. The mixture was filtered and the filter cake was recrystallized from ethanol to yield 3.90 g of compound 59 as a yellow crystal. Yield: 59percent; The synthetic procedures of compounds 60–81 were the same as that described above. 5.1.1.2 5-(4-Methoxyphenyl)-1,3,4-thiadiazol-2-amine (61) Yield: 82percent, mp: 219-220 °C (EtOH). ESI-MS m/z: 208.2 [M+H]+; 1H NMR (DMSO-d6) δ 3.80 (s, 3H), 7.01-7.03 (m, 2H), 7.23 (s, 2H), 7.67-7.69 (m, 2H).
81.3%
at 75℃; for 0.5 h;
General procedure: A stirring mixture of benzoic acid (7.32 g, 60 mmol), N-aminothiourea(6.38 g, 70 mmol) and POCl3 (20 ml) washeated at 75 °C for 0.5 h. After cooling down to room temperature,water was added. The reaction mixture was refluxedfor 4 h. After cooling, the mixture was basified to pH8 by the drop-wise addition of 50percent NaOH solution understirring. The precipitate was filtered and re-crystallized from ethanol
76.09%
at 85℃; for 10 h;
p-Anisic acid (3.04 g, 20 mmol) and thiosemicarbazide (1.82 g,20 mmol) were dissolved in 30 mL of phosphorus oxychloride, thereaction mixture was refluxed at 85 °C for 10 h. After the reactionfinished, the mixture was poured into ice water slowly and thensaturate NaOH solution was added to adjust the pH value to 8.0under vigorous stirring. The mixture was extracted with ethyl acetatethree times, the organic layer was washed with brine anddried over anhydrous sodium sulfate. After solvent evaporation, thecrude product was purified by recrystallization from anhydrousethanol to get 3.15 g white powder, yield: 76.09percent. Melting point:188.1-189.5 °C. FT-IR (KBr, Disc, cm1): 3409.28 (m, ν NH2), 3377.72(m,ν NH2), 3304.97 (w), 3105.35 (m), 1647.15 (m), 1608.48 (m, ν CN),1578.80 (w), 1511.49 (s, ν benzene), 1465.51(s), 1304.97 (w), 1267.34(w), 1246.65 (s, ν OCH3), 1174.54 (m, ν OCH3), 1128.97 (w), 1052.67 (w),1031.98 (m), 978.88 (w), 829.22 (m), 658.86 (w), 520.48 (w). 1HNMR (DMSO-d6, 400 MHz, ppm) δ: 7.69-7.67 (d, J= 8.0 Hz, 2H),7.28 (s, 2H, NH2), 7.03-7.01 (d, J =8.0 Hz, 2H), 3.80 (s, 3H, OCH3). 13CNMR (100 MHz, DMSO) δ 167.85, 160.24, 156.25, 127.77, 123.61,144.46, 55.27. MS (ESI) m/z: found, [M+H]+, 208.0542; molecularformula C9H9N3OS requires [M+H]+, 208.0544.
65%
Stage #1: for 5 h; Reflux Stage #2: for 7 h; Cooling; Reflux
General procedure: A mixture ofappropriate 4-n-alkoxybenzoic acid (10 mmol) and (0.91 g, 10 mmol) of thiosemicarbazidewith 5 mL of phosphorus oxychloride was refluxed gently for 5 hr. After cooling 50 mL of water was added, the mixture was then refluxed for 7 hr and filtered, neutralizedwith potassium hydroxide. The precipitate was washed with water and recrystallized fromethanol-water to give titled compound [III]n.
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2
[ 4334-74-1 ]
[ 1014-25-1 ]
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[1] Asian Journal of Chemistry, 2011, vol. 23, # 3, p. 1305 - 1308
5
[ 833-84-1 ]
[ 1014-25-1 ]
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6
[ 79-19-6 ]
[ 874-90-8 ]
[ 1014-25-1 ]
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7
[ 123-11-5 ]
[ 1014-25-1 ]
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8
[ 4334-74-1 ]
[ 1014-25-1 ]
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9
[ 54998-29-7 ]
[ 1014-25-1 ]
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[4] Journal of the Chemical Society, 1957, p. 2858,2860
10
[ 99-96-7 ]
[ 1014-25-1 ]
Reference：
[1] Molecular Crystals and Liquid Crystals, 2014, vol. 593, # 1, p. 34 - 42
With iodosylbenzene; dihydrogen peroxide; acetic acid; In dimethyl sulfoxide; at 60℃; for 4h;Green chemistry;
General procedure: To a mixture of thiosemicarbazide (3, 0.5mmol), sodiumacetate (0.5mmol), aldehyde (2, 0.5mmol), 3mL of solvent(vH2O:vEtOH=1:1) was successively added into the tube andstirred for 15min at room temperature. After the reactionwas completed, the solvent was evaporated under reducedpressure and the residue was redissolved in DMSO (3mL),followed by addition of acetic acid (2 equiv), PhI (10mol%)and H2O2(2 equiv) in sequence, and then stirred at 60Cfor 4h (monitored by TLC). After allowing to attain roomtemperature, the saturated solution of Na2S2O3(5mL) wasadded to the reaction mixture in order to quench and then themixture was extracted with ethyl acetate (3 × 10mL). Thecombined organic layer was dried over anhydrous MgSO4and concentrated. Finally, the residue was purified by flashcolumn chromatography on silica gel using a mixture of ethylacetate and petroleum ether as eluent to give the products.
With triethylamine; In 1,4-dioxane; at 20℃; for 4.16667h;
To a mixture of 2-amino-5-(4-methoxyphenyl)-1 ,3,4-thiadiazole (417 mg, 2.03 mmol) and triethylamine (425 muIota, 3.05 mmol) in 15 ml dioxane was added drop-wise chloroacetyl chloride (206 muIota, 2.54 mmol) in 10 ml dioxane over a period of 10 min. The reaction was stirred at room temperature for 4 hours and then poured into 75 ml of water. The resulting precipitate was filtered off and washed with water and dried to give the title product (525 mg, 95%). (0296) LC-MS (ES): 284.1 (M+H), 1H NMR (DMSO-d6) delta 12.96 (s, 1 H), 7.89 (d, 2H), 7.09 (d, 2H), 4.46 (s, 2H), 3.83 (s, 3H).
In benzene;Reflux;
General procedure: Compound 1a (1.15g, 10mmol) was stirred in dry benzene (15mL). Chloroacetyl chloride (1.3mL, 16mmol, 1.6 equv.) in dry benzene (10mL) was added in a dropwise manner. The reaction mixture was refluxed for 3-5h. The reaction was monitored by TLC using ethyl acetate: hexane (1:1 v/v) system. The products were filtered while hot and washed with a small amount of cold methanol. The The reaction mixture was filtered while hot, washed with a small amount of cold methanol and recrystallized from dioxane-water to give white crystalline solid. Yield (89.5%); mp decompose at 236C; IR (cm-1, KBr): 3434(NH), 1698 (C=O), 1580 (C=N); 1H NMR (90MHz, delta ppm DMSO-d6): 2.6 (s, 3H, CH3), 4.4 (s, 2H, CH2), 12.9 (br. s, 1H, NH), Elemental analysis for C5H6ClN3OS (191.64): Calculated/Found: 31.34/31.49 (%C), 3.16/3.28 (%H), 21.93/21.87 (%N) and 16.73/16.94 (%S).
General procedure: A stirring mixture of benzoic acid (0.2442 g, 2.0 mmol), thiosemicarbazide (0.1823 g, 2.0 mmol) and POCl3 (1.2 ml) was heated at 80 oC for 2.5 h. After cooling down to room temperature, water (2.5 mL) was added. The reaction mixture was refluxed for 4 h. After cooling, the mixture was basified to pH 8 by the dropwise addition of 40% NaOH solution under stirring. The precipitate was filtered and recrystallized from ethanol to yield 0.3130 g of the target compound 1a as a white solid ,Yield: 88.3%.
82%
General procedure: 5.1.1 5-(4-Morpholinophenyl)-1,3,4-thiadiazol-2-amine (59) A mixture of 4-morpholinobenzoic acid (5.18 g, 25 mmol) and N-aminothiourea (2.28 g, 25 mmol) in POCl3 (7 ml) was stirred vigorously at 75 C for 0.5 h. After addition of H2O (30 ml), the reaction mixture was heated under reflux for 4 h and basified to pH 8 by 50% NaOH solution. The mixture was filtered and the filter cake was recrystallized from ethanol to yield 3.90 g of compound 59 as a yellow crystal. Yield: 59%; The synthetic procedures of compounds 60-81 were the same as that described above. 5.1.1.2 5-(4-Methoxyphenyl)-1,3,4-thiadiazol-2-amine (61) Yield: 82%, mp: 219-220 C (EtOH). ESI-MS m/z: 208.2 [M+H]+; 1H NMR (DMSO-d6) delta 3.80 (s, 3H), 7.01-7.03 (m, 2H), 7.23 (s, 2H), 7.67-7.69 (m, 2H).
81.3%
With trichlorophosphate; at 75℃; for 0.5h;
General procedure: A stirring mixture of benzoic acid (7.32 g, 60 mmol), N-aminothiourea(6.38 g, 70 mmol) and POCl3 (20 ml) washeated at 75 C for 0.5 h. After cooling down to room temperature,water was added. The reaction mixture was refluxedfor 4 h. After cooling, the mixture was basified to pH8 by the drop-wise addition of 50% NaOH solution understirring. The precipitate was filtered and re-crystallized from ethanol
76.09%
With trichlorophosphate; at 85℃; for 10h;
p-Anisic acid (3.04 g, 20 mmol) and thiosemicarbazide (1.82 g,20 mmol) were dissolved in 30 mL of phosphorus oxychloride, thereaction mixture was refluxed at 85 C for 10 h. After the reactionfinished, the mixture was poured into ice water slowly and thensaturate NaOH solution was added to adjust the pH value to 8.0under vigorous stirring. The mixture was extracted with ethyl acetatethree times, the organic layer was washed with brine anddried over anhydrous sodium sulfate. After solvent evaporation, thecrude product was purified by recrystallization from anhydrousethanol to get 3.15 g white powder, yield: 76.09%. Melting point:188.1-189.5 C. FT-IR (KBr, Disc, cm1): 3409.28 (m, nu NH2), 3377.72(m,nu NH2), 3304.97 (w), 3105.35 (m), 1647.15 (m), 1608.48 (m, nu CN),1578.80 (w), 1511.49 (s, nu benzene), 1465.51(s), 1304.97 (w), 1267.34(w), 1246.65 (s, nu OCH3), 1174.54 (m, nu OCH3), 1128.97 (w), 1052.67 (w),1031.98 (m), 978.88 (w), 829.22 (m), 658.86 (w), 520.48 (w). 1HNMR (DMSO-d6, 400 MHz, ppm) delta: 7.69-7.67 (d, J= 8.0 Hz, 2H),7.28 (s, 2H, NH2), 7.03-7.01 (d, J =8.0 Hz, 2H), 3.80 (s, 3H, OCH3). 13CNMR (100 MHz, DMSO) delta 167.85, 160.24, 156.25, 127.77, 123.61,144.46, 55.27. MS (ESI) m/z: found, [M+H]+, 208.0542; molecularformula C9H9N3OS requires [M+H]+, 208.0544.
75%
With trichlorophosphate; at 75℃; for 4h;Inert atmosphere;
General procedure: A mixture of the opportune substituted benzoic acid (6.57 mmol), thiosemicarbazide (9.85 mmol) and phosphorus oxychloride (5 mL) was stirred at 75 C for 4 h under N2atmosphere. After cooling to room temperature, water was added and the reaction mixture was further refluxed for 4 h. The mixture was cooled and basified to pH 8 by the addition of 1N NaOH(aq)solution. The resulting mixture was then extracted three times with EtOAc and then washed with water. Organic layer was dried over Na2SO4and evaporated under reduced pressure. The crude mass was recrystallized from EtOH. The compounds were obtained as light-yellow solids in a yield of 75-80%. 5-(4-Methoxyphenyl)-1,3,4-thiadiazol-2-amine(5): crystallization in EtOH. Yellow solid, yield 75%.1H-NMR (400 MHz, Acetone): delta 7.73-7.71 (d,J= 8.0 Hz, 2H), 7.01-6.99 (d,J= 8.0 Hz, 2H), 6.56 (bs, 2H), 3.84 (s, 3H) ppm. LC-MS (ES):m/z230 [M + Na]+.
65%
General procedure: A mixture ofappropriate 4-n-alkoxybenzoic acid (10 mmol) and (0.91 g, 10 mmol) of thiosemicarbazidewith 5 mL of phosphorus oxychloride was refluxed gently for 5 hr. After cooling 50 mL of water was added, the mixture was then refluxed for 7 hr and filtered, neutralizedwith potassium hydroxide. The precipitate was washed with water and recrystallized fromethanol-water to give titled compound [III]n.
General procedure: A stirring mixture of substituted benzoic acid (10 mmol), thiosemicarbazide (10 mmol) and POCl3 (10 mL) was heated at 75-80 C for 6 h. After cooling down to room temperature, water was added. The reaction mixture was refluxed for 1 h. After cooling, the mixture was basified to pH 8-9 by the dropwise addition of 50% NaOH solution under ice bath. The precipitate was filtered and recrystallized from ethanol to gain compounds 6-10.
General procedure: A stirring mixture of substituted benzoic acid (10 mmol), thiosemicarbazide (10 mmol) and POCl3 (10 mL) was heated at 75-80 C for 6 h, The reaction was monitored by TLC. After cooling down to room temperature, water was added. The reaction mixture was refluxed for 1 h. After cooling, the mixture was basified to pH 8-9 by the dropwise addition of 50% NaOH solution under ice bath. The precipitate was filtered and recrystallized from ethanol to gain compounds 3.
With trichlorophosphate; at 80℃; for 2h;
General procedure: A mixture of substituted benzoic acid (40.61 mmol) and thiosemicarbazide (48.73 mmol) in POCl3 (45 mL) was stirring for 2 h at 80C. After cooling to room temperature, water (60 mL)was added in 30 min. Ice-water was added, and the pH was adjusted to 8 with 1 M sodium hydroxide solution. The mixture was filtered. The obtained solid was crystallized from DMF-H2O to give 3a-k.
General procedure: Substituted-5-phenyl-1, 3, 4-thiadiazol-2-amine (5)was synthesized by according to reportedliterature 2 Equimolar mixture of substituted benzoicacid and semicarbazide in 100ml round bottom flask,POCl3(13 ml) were added to it and heated at 75 0Cfor half an hour. After cooling down to roomtemperature then add water. The reaction mixturewas reflux for 4 hr, after cooling the mixture wasbasified to PH-8 by drop wise addition of 50 %NaOH solution under the stirring. The precipitatewas filtered and recrystallized from ethanol toobtained pure yield of compounds. 5-phenyl-1,3,4-thiadiazol-2-amine
General procedure: The synthetic approach to 5-substituted-1,3,4-thiadiazol-2-amine derivatives wasadapted from the literature (Foronmadi et al. 1999). Briefly, a mixture of carboxylicacid derivatives (50 mmol), POCl3 (13 ml) and N-aminothiourea (50 mmol) wasreacted for 0.5 h at 75 C. After cooling down to 0 C, water was added. The reactionmixture was refluxed for 4 h. After reaction, the mixture was basified to pH 8 by thedropwise addition of 50% NaOH solution. The precipitate was filtered and recystallizedfrom ethanol to get the title compounds.
General procedure: 0.1 M of aromatic carboxylic acid 1a-l was refluxed with 0.2 M of thiosemicarbazide 2 and 5 mLof phosphorous oxytrichloride for 2 h. After 2 h the mixture was cooled and diluted with 10 mL ofwater and again refluxed for additional 4 h. Then the mixture was filtered hot and the filtrate was 0.1 M of aromatic carboxylic acid 1a-l was refluxed with 0.2 M of thiosemicarbazide 2 and 5 mLof phosphorous oxytrichloride for 2 h. After 2 h the mixture was cooled and diluted with 10 mL ofwater and again refluxed for additional 4 h. Then the mixture was filtered hot and the filtrate was neutralized with a solution of 10% potassium hydroxide. The formed precipitate was filtered off andrecrystallized from absolute ethanol.
General procedure: A mixture ofcorresponding acid, 1 (2.00 mmol), and POCl3 (0.80 ml) wasstirred for 20 min at room temperature. Then, thiosemicarbazide(2.0 mmol, 0.182 g) was added, and theresulting suspension was refluxed for 1 h. After cooling theflask in an ice bath, 2.4 ml of distilled water was addedcarefully, and refluxwas continued for 1 h. The mixturewasthen cooled to the room temperature, saturated aqueoussolution of NaOH was added until pH 8.5 was reached, andthe suspensionwas stirred for 1 h at the room temperature.The formed precipitate of the corresponding 2-amino-1,3,4-thiadiazole derivative (2aeo) was then filtrated, driedover CaCl2, and recrystallized from hot 50% aqueous EtOH.
With sulfuric acid; In ethanol; water; at 80 - 90℃; for 4h;
General procedure: An aromatic carboxylic acid (0.05 mol) and an aqueous solution of thiosemicarbazide (0.05 mol) were added into ethanol with constant starring. Now few drops of concentric sulfuric acid mixed and heated under reflux (80-90 C) for 4 h, till the completion ofthe reaction as indicated by TLC. The reaction mixtures were cool and poured to ice-cold water, basified with 10% Na2CO3 solution, filter, dried, and recrystallized from a suitable solvent.
With trichlorophosphate; for 6h;Reflux;
General procedure: A mixture of acetic acid (1mL, 16.6mmol,), thiosemicarbazide (1.5g, 16.6mmol, 1 equv.) and phosphorus oxychloride (7.5mL, 80.2mmol, 8.2 equv.) were refluxed for 2h. The reaction mixture was cooled to room temperature, ice water (25mL) was added, and the reaction was refluxed for further 4h. After cooling the reaction mixture was alkalinized by conc ammonium hydroxide solution (20%), the formed precipitate was filtered off and washed with cold water. The product used for the next step without further purification. Brownish solid; Yield (52%); mp 224-225C; IR (cm-1, KBr): 3259, 3069 (NH2), 1640 (C=N); 1H NMR (60MHz, delta ppm DMSO-d6): 2.6 (s, 3H, CH3), 7.1 (br. s, 2H, NH2), EI-MS [m/z (%)]: 115.29 (M+, 48.11%), 45.98 (100% base peak); Elemental analysis for C3H5N3S (115.16): Calculated/Found: 31.29/31.53 (%C), 4.38/4.61(%H), 36.49/36.70 (%N) and 27.84/27.69 (%S).
With trichlorophosphate; at 20 - 70℃; for 2.5h;
General procedure: 10 mL of phosphorus oxychloride was added to the raw materials of acetic acid (10mmol) and hydrazinecarbothioamine in a 50 mL flask. The mixture was stirred at room temperature for 0.5 h, and then heated up to 70C for 2 h. After cooling to room temperature, 40 mL of distilled water was added slowly to quench the phosphorus oxychloride. Then, the mixture was heated and refluxed for 5 h. When the solution was neutralized by adding 50% NaOH solution to pH=8, the product was precipitated. The raw product was purified by MeOH or flash column chromatography. Yield: 75%.
General procedure: Trifluoroacetic acid (4 mL) was added to a mixture of nitrile(1.0 mmol) and thiosemicarbazide (1.1 mmol). The reaction mixturewas stirred and refluxed for 6 h. Then, it was cooled to roomtemperature and aqueous ammonia was added. The precipitatedsolidwas filtered,washed with hot water and air-dried. It should benoted that the compounds f1-f35 were directly used for the nextreaction without further purification.
2-(4-methoxyphenyl)-6-phenylimidazo[2,1-b]-1,3,4-thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In ethanol; for 18h;Reflux;
General procedure: To a solution of 5-(4-substituted phenyl)-1,3,4-thiadiazole-2-amine 3a-l (0.01 mol) in 10 mLabsolute ethanol, the corresponding phenacyl bromide was added (0.02 mol). The mixture wasrefluxed for 18 h or more, depending of the reaction progress, monitored by TLC. After the reactionwas complete, the mixture was filtered and the solid hydrobromide was collected. The precipitatewas neutralized by aqueous sodium carbonate solution, filtered and purified by recrystallization or bycolumn chromatography to remove unwanted products. The purification method is indicated belowfor each individual compound.
2-(p-methoxphenyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester[ No CAS ]
[ 1014-25-1 ]
[ 762-21-0 ]
[ 68787-55-3 ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In ethanol; water;
EXAMPLE 12 11.5 g of <strong>[1014-25-1]2-amino-5-(p-methoxyphenyl)-1,3,4-thiadiazole</strong> are reacted with 9.5 g of acetylene dicarboxylic acid diethyl ester in 100 ml of ethanol in the same way as described in Example 11. 7 g of the crude 2-(p-methoxphenyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester thus obtained, melting at 216-218 C., are introduced into a solution of 1.3 g of potassium hydroxide in 200 ml of ethanol. The reaction mixture is briefly boiled and then left standing overnight. The crystals precipitated are dissolved by the addition of water. After acidification with hydrochloric acid to approximately pH 2, the crystals are filtered off under suction, washed with water and dried. 2-(p-Methoxyphenyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid melting with decomposition at 227-230 C. is thus obtained.
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