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CAS No. : | 19227-13-5 | MDL No. : | MFCD06411167 |
Formula : | C8H10N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 150.18 | Pubchem ID : | - |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | General procedure: In 10 mL of dichloromethane 2 mmol of amidoxime 2 was dissolved and 2 mmol of anhydride 3 was added.The reaction mixture was stirred at room temperaturefor 2 h, then it was washed with 10 mL of NaHCO3 solution and 10 mL of water, the organic layer was dried with Na2SO4 and evaporated at a reduced pressure. The residue was dissolved in 1.52 mL of DMSO and 80 mg (2 mmol) of preliminary ground NaOH was added. The reaction mixture was stirred at room temperature for 1 h and diluted with 20 mL of cold water. The formed precipitate was filtered off. | |
for 1.5h;Heating / reflux; | 2.00 g of N'-hydroxy-4-methylbenzenecarboxyimidamide was dissolved in 40 ML of acetic anhydride, and this solution was stirred for 1.5 hours while heating it under reflux.. After the reaction mixture was cooled to room temperature, the solvent was distilled out thereof under reduced pressure, and then the resultant residue was purified by silica gel column chromatography to yield 1.20 g of 5-methyl-3-(4-methylphenyl)-1,2,4-oxadiazole as yellow solid. NMR(400MHz,CDCl3) delta value: 2.41(3H,s), 2.65(3H,s), 7.28(2H,d,J=8.0Hz), 7.94(2H,d,J=8.0Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydroxylamine; In ethanol; water; at 25 - 78℃; for 18h; | To a stirred solution of 4-methylbenzonitrile (1 g, 8.5 mmol) in ethanol (10 mL), 50% aqueous hydroxylamine (1.1 mL, 17.1 mmol) was added at 25 C and stirred at 78 C for 18 h. The reaction mixture was concentrated under reduced pressure to get ISP -hydrox -4-methylbenzimidamide (1.3 g, 8.5 mmol, 100 % yield). |
96% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 6h;Reflux; | General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL). |
96% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 6h;Reflux; | General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL). |
96% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 6h;Reflux; | General procedure: General procedure 1.To a stirred suspension of corresponding nitrile 1 and hydroxylamine hydrochloride(1.5 equiv.) in EtOH (10 mL per gram of nitrile) NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL). |
96% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 6h;Reflux; | General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL). N'-Hydroxy-4-methylbenzimidamide (AM-4). Compound was synthesized by following GP1 starting from 4-methylbenzonitrile (5 g, 0.043 mol) in 96% (6.15 g) yield |
96% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 6h;Reflux; | General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL). |
85.9% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; water; for 5h;Reflux; | Intermediate V-2; N'-hydroxy-4-methylbenzimidamide In a 500 ml round bottom flask, hydroxylamine hydrochloride (6.4 g, 92.1 mmol) and sodium bicarbonate (7.74 g, 92.1 mmol) were combined with ethanol (100ml) and water (20ml). The suspension was stirred for 15 min. 4-Methylbenzonitrile (9.81 g, 83.7 mmol) was added and the mixture was heated for 5 h at reflux. The reaction was cooled to room temperature. Ethanol was removed by evaporation. The solid residue was suspended in water (100ml), filtered off and washed with water (3x30ml) and heptane (3x40ml). The filter cake was dried in vacuo to yield, N'-hydroxy-4-methylbenzimidamide (10.8 g, 71.9 mmol, 85.9 % yield) as light blue solid. Melting point: 146.8-147.PC (Lit: 147C) |
78% | With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; water; for 3h;Reflux; | 4-Methylbenzonitrile 42b (940 mg, 8.0 mmol) in EtOH (30 mL) wasadded to NH2OH.HCl (3.34 g, 48 mmol) and NaHCO3 (2.54 g,24 mmol) in water (30 mL) and the mixture was boiled under reflux for 3 h. TheEtOH was evaporated and the residue was poured into water. The precipitatewas collected, washed (water) and dried to give 44b (940 mg, 78%) as awhite powder: mp 138-139C (lit.24 136-137C); 1H NMR d 2.37 (3 H, s, Me),5.77 (2 H, br, NH2), 7.22 (2H, d, J = 8.0 Hz, Ph 3,5-H2),7.61 (2 H, d, J = 8.0 Hz, Ph 2,6-H2), 9.55 (1H, s, OH); 13CNMR d 20.78 (Me), 125.24 (2,6-C2), 128.60(3,5-C2), 130.55 (1-C), 138.21 (4-C), 150.74 (C=N); MS m/z 151.0888(M + H)+ (C8H11N2O requires151.0871). |
68.94% | With hydroxylamine hydrochloride; potassium carbonate; In ethanol; for 24h;Reflux; | General procedure: The amidoximes were prepared as per procedure reported earlier in the literature [30]. Hydroxylamine hydrochloride (21.94 mmol, 1.518 g) and anhydrous potassium carbonate (43.8 mmol, 6.053 g) were added to ethanol (30 mL) at room temperature followed by the addition of acetonitrile/ appropriate aromatic nitrile (14.6 mmol). The mixture was refluxed till the completion of the reaction which was monitored by TLC. The solvent was evaporated and the residue was dissolved in EtOAc (50 mL). The organic layer was separated, washed twice with water and dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was left overnight at room temperature. The compound thus obtained was recrystallized using dichloromethane to give compounds 2a-f. |
66% | With hydroxylamine hydrochloride; triethylamine; In methanol; at 20℃;Reflux; | General procedure: A solution of the appropriate cyanophenyl 1a-1k (0.1 mol), hydroxylamine hydrochloride (0.2 mol), and TEA (0.2 mol) in methanol was left under stirring at room temperature for 1 h, then heated under reflux until the disappearance of the starting materials (TLC analysis). After cooling, the solvent was evaporated to dryness under reduced pressure to give the crude, which was dissolved in ethyl acetate (400 mL) and washed with brine (3 100 mL) and dried with Na2SO4. The ethyl acetate was evaporated under reduced pressure to yield the compounds 2a-2k. |
66% | With hydroxylamine hydrochloride; triethylamine; In methanol; at 20 - 65℃; | General procedure: A solution of the appropriate cyanophenyl 1a-1j (0.1mol), hydroxylamine hydrochloride (0.2 mol), and TEA (0.2 mol) in methanol was stirred at room temperature for 1 h, then heated under reflux until the disappearance of the starting materials (TLC analysis). After cooling, the solvent was evaporated to dryness under reduced pressure to give the crude, which was dissolved in ethyl acetate (400 mL) and washed with brine (3×100 mL) and dried with Na2SO4. Ethyl acetate was evaporated under reduced pressure to yield the compounds 2a-2j. |
64% | With hydroxylamine hydrochloride; triethylamine; In ethanol; at 50℃;Product distribution / selectivity; | To a stirred suspension OfNH2OH HCl (2.9 g, 43 mmol) in EtOH was added Et3N (5.3 g, 52 mmol), then it was stirred for 30 mins at ambient temperature. Compound 1.1 (5g, 43 mmol) was added and warmed to 500C overnight. The resulting solution was concentrated directly in vacuum to remove EtOH and residue was taken up by Et2O and extracted by 2N HCl solution. The HCl layer was adjusted to pH 7-8 with 2N sodium hydroxide solution and a white solid formed. This was filtrated and dried under vacuum at 500C overnight to give a pale solid (4.5 g). Yield: 64%.1H NMR (400 MHz, DMSO-d6) delta (ppm): 9.53 (IH, s, O-H), 7.56-7.54 (2H, dd, Ph-H), 7.18-7.16 (2H, dd, Ph-H), 5.74 (2H, s, -NH2). |
With hydroxylamine hydrochloride; sodium methylate; In methanol; at 20℃; for 3h; | 29.7 g of hydroxylamine hydrochloride was dissolved in 100 ML of methanol, to which 82.4 g of a 28% solution of sodium methoxide in methanol was added at room temperature, and this solution was stirred for one hour at the same temperature. 10.0 g of 4-methylbenzonitrile was added to this mixture, which was then stirred for 2 hours at room temperature.. The reaction mixture was concentrated under reduced pressure, to which water was added, and adjusted to PH 8 with 6M hydrochloric acid, followed by addition thereto of ethyl acetate, and the organic phase was separated therefrom.. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 11.6 g of N'-hydroxy-4-methylbenzenecarboxyimidamide as white solid. NMR(400MHz,CDCl3) delta value: 2.37(3H,s), 4.87(2H,brs), 8.31(1H,brs), 7.20(2H,d,J=8.0Hz), 7.51(2H,d,J=8.0Hz) | |
With hydroxylamine; In ethanol; water; for 1h;Reflux; | General procedure: 50 % Aq. Hydroxylamine (1.05 mmole) was added to a solution of nitrile (10, 1.0 mmole)in ethanol (10 vol) at room temperature. Reflux the reaction mass for 1 hr (TLC monitored).After completion of reaction, cooled to room temperature and concentrated under reducedpressure to get the corresponding amidoxime (7a-m) as a white to yellow colored solidwhich was used directly in the next step without further purification. | |
With hydroxylamine; In ethanol; water; for 1.5h;Reflux; Inert atmosphere; | General procedure: To the solution of nitrile (1) in EtOH (0.1 M) was added 50wt% aqueous hydroxylaminesolution (1.2 equiv). The mixture was stirred at reflux temperature for 1.5 h under nitrogen. After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The crude amidoxime (2) product was dissolved in CH2Cl2(0.1 M), and then ArSO2Cl (TsCl or o-NsCl, 1.05 equiv) and DIPEA (1.05 equiv)were added at 0 oC. The mixture was stirred under nitrogen atmosphere at room temperature for 3 h or at reflux temperature for 1 h (see reference 3 for details).3 Themixture was concentrated under reduced pressure. The crude cyanamide (3) productwas dissolved in the mixture of 1 N aqueous HCl solution and EtOH (1 N HCl / EtOH= 1 : 4, v/v, reaction concentration = 0.1 M). The mixture was stirred at reflux temperaturefor 3 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography. | |
With hydroxylamine; acetic acid; In neat (no solvent); at 150℃; for 0.666667h; | General procedure: A mixture of the appropriate nitrile (4, 2 mmol), hydroxylamine50% (0.132 g, 2 mmol), and a catalytic amount of AcOH was stirredat 150 C for 40 min. After nearly complete conversion to thecorresponding amidoxime, as was indicated by TLC monitoring, theappropriate 2,2-dialkoxyacetate (6, 2 mmol) and K2CO3 (0.276 g,2 mmol) were added to the reaction mixture which was stirred at100 C for further 6 h. After completion of the reaction as indicatedby TLC, the reaction mixture was cooled to room temperature andthe residue was purified by column chromatography using n-hexane-EtOAc (6:1) as eluent. The solvent was removed, and the product was obtained. | |
With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; for 18h;Reflux; | General procedure: An aqueous solution of sodium hydroxide (20 mmol in 10 ml)was added to a solution of benzonitrile 5 (10 mmol) and hydroxylaminehydrochloride 6 (20 mmol) in EtOH (50 ml) in a dropwisemanner at room temperature. Then, the mixture was heated underreflux for 18 h. After completion of the reaction (checked by TLC),the solvent was evaporated under reduced pressure, water (50 ml)was added to the residue, and the pH of solution was set at pH 2using HCl (1 N). The mixture was extracted using ethyl acetate(2 x 25 ml). The aqueous solution was cooled to 0 C andneutralized using sodium carbonate solution. The obtained precipitatewas filtered off, washed with water, and dried at 60 C toobtain compound 7. In the next step, chloroacetyl chloride 8(12 mmol) was added to a stirring solution of compound 7(11.2 mmol) and K2CO3 (11 mmol) in dry acetone (25 ml) in adropwise manner during 10 min. The reaction mixture was stirredat room temperature for 24 h. After reaction completion, the solventwas evaporated under reduced pressure, the obtained whiteprecipitate was dissolved in ethyl acetate (50 ml), and the organicphase was washed with water (4 x 20 ml) and brine (20 ml). Theorganic phase was dried over Na2SO4 and the solvent was evaporatedunder reduced pressure. The residue was recrystallized fromEtOH to obtain pure N'-(2-chloroacetoxy)-benzimidamide 9. Asuspension of compound 9 (8 mmol) in toluene (50 ml) was heatedunder reflux for 5 h. Then, the solvent was evaporated underreduced pressure and the obtained yellow oily residue wasrecrystallized from petroleum ether to give pure yellow 3-aryl-5-(chloromethyl)-1,2,4-oxadiazole derivative 10 (65-70%). | |
39.1 g | With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | Example 1 : Preparation of 2,2-dimethyl-N-[[4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]- propanamide (Compound 1.2 of Table 1 ) Step 1 : Preparation of N'-hvdroxy-4-methyl-benzamidine To a stirring suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water (0642) (440 mL) at RT were added hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80C for 4 hours. The mixture was cooled to RT and diluted with 2M HCI until pH 8. Ethanol was evaporated under reduced pressure. The mixture was filtered, washed with water and dried under vacuum to afford 39.1 g of the title compound. LC/MS (Method A) retention time = 0.23 minutes, 151.0 (M+H). |
With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | To a stirred suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water (440 mL) at RT was added hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80C for 4 hours. The mixture was cooled to RT and diluted with 2N HCI until pH 8. Ethanol was evaporated under reduced pressure. The mixture was filtered, washed with water and dried under vacuum to afford the title compound. LC/MS (Method A) retention time = 0.23 minutes, 151.0 (M+H). | |
39.1 g | With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | Preparation of N'-hvdroxy-4-methyl-benzamidine To a stirring suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water (440 mL) was added at RT hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80C for 4 hours. The mixture was cooled to RT and diluted with 2N HCI until pH 8. Ethanol was evaporated under reduced pressure then the mixture was filtered, washed with water, and dried under vacuum to afford 39.1 g of the title compound which was used without further purification. LC/MS (Method A) retention time = 0.23 minutes, 151.0 (M+H). |
39.1 g | With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | To a stirred suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water(440 mL) was added at room temperature hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassiumcarbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80 C for 4 hours. The mixture was cooled to room temperature and diluted with 2N HCI until pH 8. Ethanol was evaporated under reduced pressure. The mixture was filtered, washed with water and dried under vacuum to afford 39.1 g of the title compound. LC/MS (Method A) retention time =0.23 minutes, 151.0 (M+H). |
39.1 g | With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 22 - 80℃; for 4h; | To a stirred suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water (440 mL) was added at 22C hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 20 80C for 4 hours. The mixture was cooled to 22C and diluted with 2N HCI until pH 8. Ethanol was evaporated under reduced pressure. The mixture was filtered, washed with water and dried under vacuum to afford 39.1 g of N'-hydroxy-4-methyl-benzamidine. LC/MS (Method A) retention time = 0.23 minutes, 151 .0 (M+H). |
With hydroxylamine hydrochloride; sodium carbonate; In ethanol;Reflux; | General procedure: A round-bottom flask equipped with a magnetic stir bar and a reflux condenser was charged withbenzonitrile (1.03 g, 10.0 mmol), sodium carbonate (2.0 equiv.), hydroxylamine hydrochloride (2.0equiv.), and EtOH (15 mL). The mixture was heated to reflux overnight. After cooling to roomtemperature, the solvent was removed under reduced pressure. The resulting solid was suspendedin EtOAc and filtered over a pad of Celite. The filtrate was evaporated to dryness to give crudebenzamidoxime. Pivalic anhydride (1.1 equiv.) was added and the mixture was heated at 130 C for 1 h. Aftercooling to room temperature, the mixture was diluted with EtOAc and the resulting solution waswashed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4 and thesolvent was evaporated. The residue was subjected to column chromatography (eluent:hexane/EtOAc = 40/1) and subsequent Kugelrohr distillation gave 1a as colorless oil (1.31 g, 65%). | |
39.1 g | With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | To a stirring suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water (440 mL) was added at room temperature hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80C for 4 hours. The mixture was cooled to room temperature and diluted with 2N HCl until pH 8. Ethanol was evaporated under reduced pressure then the mixture was filtered, washed with water, and dried under vacuum to afford 39.1 g of N-hydroxy-4-methyl-benzamidine which was usedwithout further purification.LC/MS (Method A) retention time = 0.23 minutes, 151.0 (M+H). |
With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | To a stirred suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water (440 mL) at rt was added hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80C for 4 hours. The mixture was cooled to rt and diluted with 2N HCI until pH 8. Ethanol was evaporated underreduced pressure. The mixture was filtered, washed with water and dried under vacuum to afford the title compound.LC/MS (Method A) retention time = 0.23 minutes, 151.0 (M+H). | |
With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | To a suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water (440 mL) at RT was added hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80C for 4 h. The mixture was cooled to RT, diluted with 2N HCI until pH 8 and the ethanol was removed under reduced pressure. The resultant mixture was filtered, washed with water and dried under vacuum to afford the title compound which was used without further purification. LC/MS (Method A) retention time = 0.23 minutes, 151 .0 (M+H). | |
With hydroxylamine hydrochloride; potassium hydroxide; In methanol; at 60℃; | General procedure: A 1.0 M solution of hydroxylamine hydrochloride in MeOH (2.0eq) and a 1.0 M solution of KOH in MeOH (2.0 eq) were combined at 0C and stirred for ~30 min (slowly warming from 0C to rt). The potassium chloride salt formed was removed by filtration. The filtrate was added to the nitrile 21 [1.0 eq; the corresponding nitrile was either purchased from commercial source (analogs 21a-l and 21o), or synthesized starting from a commercial nitrile, which was further modified via a Suzuki coupling reaction using established methods (21m-n)] and the mixture was heated at 60C for 17-24h. MeOH was removed under vacuum and the residue was diluted with EtOAc, washed with brine, and the organic layer was concentrated. The product 22 was typically obtained in quantitative yield and >90% purity, and was used in the next step without further purification. | |
39.1 g | With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | To a suspension of 4-methylbenzonitrile (35.0 g, 0.29 mol) in ethanol (220 mL) and water (440 mL) at rt was added hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80C for 4 hours then cooled to rt and diluted with 2N HCI until pH 8. Ethanol was removed under reduced pressure. The mixture was filtered, washed with water and dried under vacuum to afford 39.1 g of N'-hydroxy-4-methyl- benzamidine as a pale gum then used directly in the next preparation step without further purification. LC/MS retention time = 0.23 minutes, 151 .0 (M+H). |
39.1 g | With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | To a suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water (440 mL) was added at room temperature hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80C for 4 hours. The mixture was then allowed to reach room temperature and diluted with 2N HCI until pH 8. The volatiles were removed under reduced pressure and the reaction contents were filtered, washed with water, and dried under vacuum to afford 39.1 g of the title compound. LC/MS (Method A) retention time = 0.23 minutes, 151.0 (M+H). |
39.1 g | With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | To a suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 mL) and water (440 mL) was added at room temperature hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol), and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80C for 4 hours, then cooled to room temperature, and diluted with 2N HCI until pH 8. The volatiles were removed under reduced pressure and the reaction contents were filtered, washed with water, and dried under vacuum to afford 39.1 g of the title compound. LC/MS (Method A) retention time = 0.23 minutes, 151 .0 (M+H). |
With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | To a stirred suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 imL) and water (440 mL) at RT was added hydroxylamine hydrochloride (41.1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1 .5 mmol). The reaction mixture was heated at 80C for 4 hours. The mixture was cooled to RT and diluted with 2N HCl until pH 8. Ethanol was evaporated under reduced pressure. The mixture was filtered, washed with water and dried under vacuum to afford the title compound. LC/MS (Method A) retention time = 0.23 minutes, 151.0 (M+H). | |
With 8-quinolinol; hydroxylamine hydrochloride; potassium carbonate; In ethanol; water; at 80℃; for 4h; | a stirred suspension of 4-methylbenzonitrile (35 g, 0.29 mol) in ethanol (220 imL) and water (440 mL) at room temperature was added hydroxylamine hydrochloride (41 .1 g, 0.58 mol), potassium carbonate (65.4 g, 0.47 mol) and 8-hydroxyquinoline (0.22 g, 1.5 mmol). The reaction mixture was heated at 80 C for 4 hours. The mixture was cooled to room temperature and diluted with 2N HCI until pH 8 and volatiles were then removed under reduced pressure. The reaction contents were filtered, washed with water, and dried under reduced pressure to afford the title compound. LC/MS (Method A) retention time = 0.23 minutes, 151 .0 (M+H). | |
With hydroxylamine hydrochloride; triethylamine; In ethanol; for 18h;Reflux; | General procedure: To a stirred solution of appropriate nitrile (a-e)(50 mmol) in EtOH (100 mL) was added hydroxylaminehydrochloride (2.2 equiv) and then Et3N (2.3 equiv). This solution was stirred under reflux for 18 h and then diluted with water. The solvent (EtOH) was removed under reduced pressure, and the aqueous layer extracted 2 times DCM. The organic layer was dried over MgSO4 and concentrated undervacuum. The crude product was purified by recrystallizationusing chloroform-heptane or column chromatography oversilica gel using a mixture of hexane/EtOAc as the eluent toafford pure aryl amidoximes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | (Z)-/V (2-chloroacetoxy)-4-methylbenzimidamide (SO3-004) (8a): To a solution of N- hydroxy-4-methylbenzamidine (0.50 g, 3.30 mmol) in acetone (20 ml) chloroacetyl chloride(0.37 g, 3.30 mmol) was added slowly and the mixture was stirred at rt for 30 min. Acetone was evaporated and the residue was washed with sodium bicarbonate solution (5 ml) and water (1 0 ml) . The compound SO3-004 8a was dried and obtained as a white solid. (0.70 g,88%). 1 H NM R (400 M Hz, DMSO) delta 7.05 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 4.58(s, 2H), 2.20 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With formaldehyd; sodium hydroxide In dimethyl sulfoxide at 20℃; for 22h; | General procedure for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from amidoximes and aldehydes in the superbasic system NaOH/DMSO. A 10-mL flask was charged with 1 mmol of amidoximewhich was dissolved in 1.5 mL of DMSO, and2.2 mmol of aldehyde 2 and 0.05 mmol (2 mg) ofpowdered sodium hydroxide were added each in oneportion. The mixture was stirred for 1 h, 1.75 mol(70 mg) of powdered sodium hydroxide was added,and the mixture was stirred for 21 h more. After completionof the reaction (TLC), the resulting suspensionwas diluted with 7 mL of distilled water, and theprecipitate was filtered off and washed with 2 mL ofwater. If a tarry material was formed, the supernatantwas separated by decanting, and the residue waswashed with three 2-4-mL portions of water. Theproducts were purified by chromatography using acetone-toluene-petroleum ether (5:3:5) as eluent. |
15% | With 4-bromobenzenecarbonitrile; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 48h; | |
With sodium hydroxide In dimethyl sulfoxide at 20℃; for 24h; |
Multi-step reaction with 2 steps 1: sodium hydroxide / dimethyl sulfoxide / 4 h / 20 °C 2: sodium hydroxide / dimethyl sulfoxide / 24 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / dimethyl sulfoxide / 4 h / 20 °C 2: sodium hydroxide / dimethyl sulfoxide / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | General procedure: b. In 10 mL of dichloromethane was dissolved 2 mmol of amidoxime 2, 185 mg (2.2 mmol) of NaHCO3 was added. The reaction mixture was cooled to 0 and by portions maintaining the reaction mixture temperature below 5 2 mmol of acyl chloride 3 was added. The reaction mixture was warmed to room temperature, stirred for 2 h, then it was washed with 10 mL of NaHCO3 solution and 10 mL of water, the organic layer was dried with Na2SO4 and evaporated at a reduced pressure. The residue was dissolved in 1.52 mL of DMSO and 80 mg (2 mmol) of preliminary ground NaOH was added. The reaction mixture was stirred at room temperature for 1 h and diluted with 20 mL of cold water. The formed precipitate was filtered off. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20 - 100℃; for 4.5h; Microwave irradiation; | 7 The starting material (9) was prepared as follows: A mixture of 1 (see Example 1) (0.200g, 0. 369mmol) and 4-methylbenzamidoxime (0. 1 lOg, 0. 733mmol) in methylene chloride (5ml) were stirred for 3 hours at room temperature. The solution was then heated to 100°C in a microwave for 90 minutes. After cooling, methylene chloride (50ml) was added and the solution was washed with aqueous sodium hydroxide (50ml, 2M). The residue was purified by flash chromatography eluting with methylene chloride to give 4- (2-chloroethyl)-5- (3, 5-dimethylphenyl)-2- { 1-methyl-1- [3- (4- methylphenyl)-1, 2,4-oxadiazol-5-yl] ethyl}-6H-thieno [2, 3-b] pyrrole (9) as a yellow oil (0.130g, 72%). MS-ESI: 490 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With pyridine In toluene at 20 - 105℃; for 9h; | 5-Adamantan-l-yI-3-p-tolyl-[l,2,4]oxadiazole (XDS031S0, STX1599 ); To a solution of adamantan-1-yl-carbonyl chloride (99 mg, 0.50 mmol) in toluene (5 mL) was added pyridine (1 mL), followed by 4-methylbenzamide oxime (75 mg, 0.5 mmol). The reaction mixture was stirred at ambient temperature under nitrogen for 3h, at 105°C for 6h and then partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over sodium sulphate and evaporated to give a yellow solid that was purified by flash chromatography (Ethyl acetate-hexane gradient elution) to give the title compound as crystalline solid (98 mg, 67%). TLC single spot at Rf. 0.77 (30% EtOAc/hexane); 1H NMR (270 MHz5 CDCl3) δ 1.80 (6H, broad, 3 x CH2), 2.13 (9H, s, 3 x CH2 and 3 x CH)5 2.39 (3H5 s5 CH3), 7.25 (2H, dt, J= 8.1, 1.2 Hz5 ArH) and 7.95 (2H, EPO dt, J= 8.2, 1.2 Hz, ArH); LC/MS (APCI) m/z 295 (M+H-H); HPLC tr = 5.9 min (>98%) in 6% water-acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 192℃; for 0.05h; Microwave irradiation; | 5-Adamantan-l-ylmethyl-3-p-tolyl-[l,2,4]oxadiazoIe (XDS03187, STX1620 ); To a solution of adamantan-1-yl-acetic acid (87 mg, 0.50 mmol) in DMF (3 mL) was added diisopropylethylamine (0.22 mL, 1.25 mmol), followed by HBTU and 4- methylbenzamide oxime (75 mg, 0.5 mmol). The reaction mixture was irradiated with microwave at 192°C for 3 minutes and evaporated in vacuo to give a residue which was partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over sodium sulphate and evaporated to give a yellow solid that was purified by flash chromatography (Ethyl acetate-hexane gradient elution) to give the title compound as yellow solid (59 mg, 38%). TLC single spot at Rf. 0.55 (20% EtOAc/hexane); 1H NMR (270 MHz, CDCl3) δ 1.52-1.67 (12H, m, 6 x CH2), 1.93 (3H, broad, 3 x CH), 2.33 (3H3 s, CH3), 2.65 (2H, s, CH2), 7.25 (2H, d, J= 8.8 Hz, ArH) and 7.90 (2H, d, J= 8.8 Hz, ArH); LC/MS (APCI) m/z 309 (M+H-H); HPLC tr = 5.24 min (>96%) in 10% water- acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With aluminum oxide; potassium fluoride; thiourea In N,N-dimethyl-formamide at 100 - 110℃; for 24h; | |
62% | In N,N-dimethyl-formamide at 120℃; for 0.166667h; Sealed tube; Microwave irradiation; | General procedure for synthesis of 1,2,4-oxadiazole (2a-i) General procedure: To a solution of arylamidoximes 1a-i (1 mmol) in DMF (0.5 mL) dicyclohexylcarbodiimideDDC (1.5 or 2.0 mmol) was added. The mixture was irradiated in a closed vesselat 120 C and 150W for a specific time. The reaction was monitored each 5 min usingTLC (hexane:ethyl acetate 7:3). After it cooled, the residue was evaporated underreduced pressure. The crude material was purified using column chromatography on silicagel (eluents, hexane:EtOAc gradient from 8:2 to 7:3) to give the products 2a-i. |
0.47 g | at 150℃; for 3h; Molecular sieve; Neat (no solvent); |
In N,N-dimethyl-formamide for 0.166667h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In benzene; for 10h;Reflux; | General procedure: A solution of chloroacetyl chloride (0.813 g, 7.2 mmol) in benzene (10 mL) was added dropwise to a solution of benzamidoxime (2a) (2.448 g, 18.0 mmol) in benzene (100 mL) and the mixture was heated under reflux for 10 h. The reaction was monitored by TLC. The reaction mixture was concentrated in vacuo, and the crude residue was purified by flash column chromatography (FCC) using n-hexane:ethyl acetate (2:1) mixture to give(3a) as a white solid (1.245 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydrogencarbonate In ethanol at 60℃; for 2h; regioselective reaction; | Synthesis of chromeno [4, 3-d] pyrimidine 3-oxide derivatives (3a-n) General procedure: A solution of 4-chloro-3-formyl coumarin (1 mmol), hydroxybenzimidamide (1 mmol) and sodium bicarbonate (1 equivalent) in 5ml EtOH was heated at 60°C for 2h. After completion of the reaction the precipitate obtained was filtered and washed thoroughly with water and re-crystallized from ethanol to afford pure products 3a-n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: 3beta-Acetoxyandrost-5-ene-17 beta-carboxylic acid (4, 288mg, 0.80mmol) or 3beta-acetoxyandrost-5,16-diene-17-carboxylic acid (6, 287mg, 0.80mmol) was dissolved in dry CH2Cl2 (10mL) and CDI (195mg, 1.2mmol) was added. The solution was stirred for 2h at room temperature until completion of the coupling reaction, and 3equiv. of benzamidoxime (IIa), substituted benzamidoxime (IIb-d) or acetamidoxime (IIe) was then added. After stirring for 2h at room temperature, the mixture was evaporated and subjected to flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 3β-acetoxyetienic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2h; Stage #2: p-toluamidoxime In dichloromethane at 20℃; for 2h; | 4.1.2 General procedure for the O-acylation of amidoximes (IIa-e) General procedure: 3β-Acetoxyandrost-5-ene-17 β-carboxylic acid (4, 288mg, 0.80mmol) or 3β-acetoxyandrost-5,16-diene-17-carboxylic acid (6, 287mg, 0.80mmol) was dissolved in dry CH2Cl2 (10mL) and CDI (195mg, 1.2mmol) was added. The solution was stirred for 2h at room temperature until completion of the coupling reaction, and 3equiv. of benzamidoxime (IIa), substituted benzamidoxime (IIb-d) or acetamidoxime (IIe) was then added. After stirring for 2h at room temperature, the mixture was evaporated and subjected to flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With p-toluenesulfonyl chloride In pyridine at 0 - 20℃; Inert atmosphere; | |
With N-ethyl-N,N-diisopropylamine In dichloromethane Inert atmosphere; | [Method c] General procedure for one-pot synthesis of N-monosubstituted urea (4)from nitrile (1) (Scheme 3) General procedure: To the solution of nitrile (1) in EtOH (0.1 M) was added 50wt% aqueous hydroxylaminesolution (1.2 equiv). The mixture was stirred at reflux temperature for 1.5 h under nitrogen. After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The crude amidoxime (2) product was dissolved in CH2Cl2(0.1 M), and then ArSO2Cl (TsCl or o-NsCl, 1.05 equiv) and DIPEA (1.05 equiv)were added at 0 oC. The mixture was stirred under nitrogen atmosphere at room temperature for 3 h or at reflux temperature for 1 h (see reference 3 for details).3 Themixture was concentrated under reduced pressure. The crude cyanamide (3) productwas dissolved in the mixture of 1 N aqueous HCl solution and EtOH (1 N HCl / EtOH= 1 : 4, v/v, reaction concentration = 0.1 M). The mixture was stirred at reflux temperaturefor 3 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography. | |
113.5 mg | With fluorosulfonyl fluoride; triethylamine In dichloromethane at 20℃; for 2h; Schlenk technique; |
With fluorosulfonyl fluoride; triethylamine In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium hydroxide; In 1,4-dioxane; at 100℃;Inert atmosphere; | General procedure: To a stirred solution of 3-ferrocenylpropynal (6) (0.25 mmol) in dioxane (7.5 mL) under argon was added the proper amidoxime 2 (0.32 mmol) and KOH (0.25 mmol) and the resulting mixture was heated under reflux for appropriate time. The progress of the reaction was monitored by routine TLC for the disappearance of 3-ferrocenylpropynal (6). After the reaction was over, the mixture was allowed to cool to room temperature and filtrated to remove undissolved KOH. Organic solvent was then removed on a rotary evaporator to give the crude product, which was purified by flash column chromatography on silica gel using hexane/ethyl acetate (9:1) as the eluent to afford the corresponding 5-ferrocenyl-1,2,4-oxadiazole derivative 10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 10% w/w sulfonic acid on Wang resin In 1,4-dioxane at 80℃; for 2h; | 3.2.1. General Procedure for the Synthesis of 2-substituted Quinazolinones (8a-k) General procedure: To a stirred solution of isatoic anhydride (1 mmol.) and amidoxime (1.1 mmol.) in 1,4-dioxane (10 vol.), Wang-OSO3H resin (10% w/w) was added, and the mixture was stirred at 80 °C for 2-6 h. After completion of the reaction, as indicated by TLC, it was cooled to room temperature, and the catalyst was filtered and then washed with 1,4-dioxane. The filtrate was concentrated to get the crude product. Column chromatographic purification of crude on silica gel (25% ethyl acetate in hexanes) afforded the product. |
86% | With sulfonic acid on Wang resin In 1,4-dioxane at 80℃; for 2h; | 3.2.1. General Procedure for the Synthesis of 2-substituted Quinazolinones (8a-k) General procedure: To a stirred solution of isatoic anhydride (1 mmol.) and amidoxime (1.1 mmol.) in 1,4-dioxane (10 vol.), Wang-OSO3H resin (10% w/w) was added, and the mixture was stirred at 80 °C for 2-6 h. After completion of the reaction, as indicated by TLC, it was cooled to room temperature, and the catalyst was filtered and then washed with 1,4-dioxane. The filtrate was concentrated to get the crude product. Column chromatographic purification of crude on silica gel (25% ethyl acetate in hexanes) afforded the product. |
83.2% | With ferric(III) chloride In 1,4-dioxane at 80℃; for 6h; | General procedure for synthesis of 2-aryl Quinazolinones(8a- 8m) General procedure: To a solution of isatoic anhydride (1 mmol.) in 1, 4-dioxane (10 vol.) was added amidoxime(1.1 mmol.) followed by FeCl3 (10 mol %). The reaction mixture was stirred at 80 °C for 2-9 h (TLC monitored). After completion of reaction, diluted with EtOAc (10 vol.) andwashed with water (2 x 5 vol.). The organic layer was dried over anhydrous Na2SO4,filtered, and concentrated under reduced pressure to give the crude product. Columnchromatographic purification of crude on silica gel (30% EtOAc in hexanes) afforded the product (8a-m) in 79-93% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate In neat (no solvent) for 0.133333h; Microwave irradiation; | General Procedure for the Synthesis of 3-aryl -5-pentyl-1,2,4-oxadiazoles (3a-f) General procedure: A mixture of ethyl hexanoate 2 (0.22 g, 1.54 mmol), appropriate arylamidoximes 1a-f (1.00 mmol) and K2CO3 (0.12g, 0.85 mmol) was well triturated and placed in a small glass test tube followed by irradiation in a domestic microwave oven (100% potency, 650 W) for 8 min and then cooled. After that, the crude product was purified by chromatography on silica gel 60 (Merck 70-230 mesh) using hexanes/EtOAc (9:1) to yield the corresponding 3-aryl-5-pentyl-1,2,4-oxadiazoles, 3a-f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 4-Methylbenzyl bromide With potassium carbonate; dimethyl sulfoxide at 110℃; for 4h; Stage #2: p-toluamidoxime With dimethyl sulfoxide at 110℃; for 4h; | Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles derivatives 3a-h;general procedure General procedure: A mixture of benzyl bromide 1 (1 mmol) and K2CO3 (1.5 mmol) in dimethyl sulfoxide (DMSO) (1 mL) was stirred for 4 h at 110 °C. Then, benzamidoxime 2 (1 mmol) were added to the reaction mixture and stirring was continued at 110 °C for 4 h. The reaction mixture was cooled to room temperature and H2O (3 mL) was added. The precipitate was filtered, washed with H2O (2 mL) and dried. The crude products were purified by column chromatography using diethyl ether/ethyl acetate(5:1) as an eluent to give pure 3,5-diphenyl-1,2,4-oxadiazole 3a-h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 2,4-dichlorobenzyl bromide With potassium carbonate; dimethyl sulfoxide at 110℃; for 4h; Stage #2: p-toluamidoxime With dimethyl sulfoxide at 110℃; for 4h; | Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles derivatives 3a-h;general procedure General procedure: A mixture of benzyl bromide 1 (1 mmol) and K2CO3 (1.5 mmol) in dimethyl sulfoxide (DMSO) (1 mL) was stirred for 4 h at 110 °C. Then, benzamidoxime 2 (1 mmol) were added to the reaction mixture and stirring was continued at 110 °C for 4 h. The reaction mixture was cooled to room temperature and H2O (3 mL) was added. The precipitate was filtered, washed with H2O (2 mL) and dried. The crude products were purified by column chromatography using diethyl ether/ethyl acetate(5:1) as an eluent to give pure 3,5-diphenyl-1,2,4-oxadiazole 3a-h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetone at 20℃; for 12h; | 13 5.1.12 General procedure for the synthesis of 5-(chloromethyl)-3-aryl -1,2,4-oxadiazoles 4a-4j General procedure: Potassium carbonate (13.8 g, 0.10 mol) was added to a solution of N′-hydroxybenzimidamides 2a-2j (0.10 mol) in dry acetone (250 mL). Chloroacetyl chloride (9.68 mL, 13.56 g, 0.12 mol) was added dropwise over a period of 1 h to the stirred reaction mixture, and the reaction was allowed to stir overnight at room temperature. Solvent was then removed under reduced pressure to give the product. This solid was dissolved in ethyl acetate (400 mL) and was partitioned once with water (100 mL). The organic layer was then washed with water (3×100 mL), brine (3×100 mL), dried over Na2SO4, and concentrated under reduced pressure to give the O-acyl products 3a-3j. The O-acyl adducts 3a-3j were added to 200 mL of toluene and were heated to reflux for 5 h. Removal of the solvent under reduced pressure gave the crude products, which were chromatographed on silica gel using ethyl acetate/petroleum ether as an eluent to afford the products 4a-4j. | |
With potassium carbonate at 20℃; | ||
With potassium carbonate In acetone at 20℃; for 24h; | 5.3. General procedure for the synthesis of 3-aryl-5-(chloromethyl)-1,2,4-oxadiazole derivatives 10 General procedure: An aqueous solution of sodium hydroxide (20 mmol in 10 ml)was added to a solution of benzonitrile 5 (10 mmol) and hydroxylaminehydrochloride 6 (20 mmol) in EtOH (50 ml) in a dropwisemanner at room temperature. Then, the mixture was heated underreflux for 18 h. After completion of the reaction (checked by TLC),the solvent was evaporated under reduced pressure, water (50 ml)was added to the residue, and the pH of solution was set at pH 2using HCl (1 N). The mixture was extracted using ethyl acetate(2 x 25 ml). The aqueous solution was cooled to 0° C andneutralized using sodium carbonate solution. The obtained precipitatewas filtered off, washed with water, and dried at 60 °C toobtain compound 7. In the next step, chloroacetyl chloride 8(12 mmol) was added to a stirring solution of compound 7(11.2 mmol) and K2CO3 (11 mmol) in dry acetone (25 ml) in adropwise manner during 10 min. The reaction mixture was stirredat room temperature for 24 h. After reaction completion, the solventwas evaporated under reduced pressure, the obtained whiteprecipitate was dissolved in ethyl acetate (50 ml), and the organicphase was washed with water (4 x 20 ml) and brine (20 ml). Theorganic phase was dried over Na2SO4 and the solvent was evaporatedunder reduced pressure. The residue was recrystallized fromEtOH to obtain pure N'-(2-chloroacetoxy)-benzimidamide 9. Asuspension of compound 9 (8 mmol) in toluene (50 ml) was heatedunder reflux for 5 h. Then, the solvent was evaporated underreduced pressure and the obtained yellow oily residue wasrecrystallized from petroleum ether to give pure yellow 3-aryl-5-(chloromethyl)-1,2,4-oxadiazole derivative 10 (65-70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In neat (no solvent); at 100℃; for 6h; | General procedure: A mixture of the appropriate nitrile (4, 2 mmol), hydroxylamine50% (0.132 g, 2 mmol), and a catalytic amount of AcOH was stirredat 150 C for 40 min. After nearly complete conversion to thecorresponding amidoxime, as was indicated by TLC monitoring, theappropriate 2,2-dialkoxyacetate (6, 2 mmol) and K2CO3 (0.276 g,2 mmol) were added to the reaction mixture which was stirred at100 C for further 6 h. After completion of the reaction as indicatedby TLC, the reaction mixture was cooled to room temperature andthe residue was purified by column chromatography using n-hexane-EtOAc (6:1) as eluent. The solvent was removed, and the product was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In neat (no solvent); at 100℃; for 6h; | General procedure: A mixture of the appropriate nitrile (4, 2 mmol), hydroxylamine50% (0.132 g, 2 mmol), and a catalytic amount of AcOH was stirredat 150 C for 40 min. After nearly complete conversion to thecorresponding amidoxime, as was indicated by TLC monitoring, theappropriate 2,2-dialkoxyacetate (6, 2 mmol) and K2CO3 (0.276 g,2 mmol) were added to the reaction mixture which was stirred at100 C for further 6 h. After completion of the reaction as indicatedby TLC, the reaction mixture was cooled to room temperature andthe residue was purified by column chromatography using n-hexane-EtOAc (6:1) as eluent. The solvent was removed, and the product was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: 7-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 90℃; for 1.5h; Stage #2: p-toluamidoxime In N,N-dimethyl-formamide at 110℃; for 6h; | 378A Example 378A Tert-butyl 4-{2-methyl-3-[3-(4-methylphenyl)-l,2,4-oxadiazol-5-yl]-5-oxo-4,5-dihydropyrazolo[l,5- a]pyrimidin-7-yl Jpiperidine- 1 -carbox late 7-[l-(tert-butoxycarbonyl)piperidin-4-yl]-2-methyl-5-oxo-4,5-dihydropyrazolo[l,5-a]pyrimidine-3- carboxylic acid (150 mg, 398 μιηο) was dissolved in N,N-Dimethylformamid (2 ml) and treated with N,N-Diisopropylethylamine (210 μ, 1.2 mmol) and Ι ,Γ-Carboyldiimidazol (129 mg, 797 μιηο). The mixture was stirred at 90 °C for 1.5h N'-hydroxy-4-methylbenzenecarboximidamide (120 mg, 797 μιηο) was dissolved in N,N-Dimethylformamid (1 ml) and added dropwise. The mixture was then stirred at 110 °C for 6h. The mixture was purified via reverse phase HPLC (Method: column: Reprosil C18; 10 μιη; 125x30 mm / flow: 50 ml/min / solvents: A = water (0,01% formic acid), B = acetonitrile / gradient: 0.00-5.00 min = 10%B, 6.50min = 20%B, 17.0-19.75min = 100%B, 19.75.00-23.00min = 90%B) to afford the product. The obtained amount was 68.5 mg (100 % purity, 35 % of theory). LC-MS (Method 11B): Rt = 2.51 min; MS (ESIneg): m z = 489 [M-H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: 7-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid; 1,1'-carbonyldiimidazole With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 90℃; for 1h; Stage #2: p-toluamidoxime In N,N-dimethyl-formamide at 110℃; for 5.5h; | 49A Example 49A 7rt-butyl 4-{3-[3-(4-methylphenyl)-l,2,4-oxadiazol-5-yl]-5-oxo-4,5-dihydropyrazolo[l,5-a]pyrimidin- 7-yl}piperidine-l-carboxylate To a solution of compound 7-[l-(iert-Butoxycarbonyl)piperidin-4-yl]-5-oxo-4,5-dihydropyrazolo[l,5- a]pyrimidine-3-carboxylic acid (150 mg, 0.41 mmol) in 3 ml dimethylformamide was added 1,1 '- carbonyldiimidazole (134 mg, 0.83 mmol) and N,N-diisopropylethylamine (106 mg, 0.83 mmol) and then the reaction mixture was stirred lh at 90 C. After this time N'-hydroxy-4- methylbenzenecarboximidamide (124 mg, 0.83 mmol) was added and the mixture was stirred for 5.5 h at 110 C. After cooling to RT, the mixture was diluted with 2 ml acetonitrile and purified by preparative HPLC (Method 1A). After evaporating acetonitrile from the combined product fractions a white solid precipitated in the aqueous phase which was collected by filtration and dried for 2h at 60 C under vacuo to yield the title compound (92 mg, 47% of theory). LC-MS (Method IB): Rt = 1.28 min, MS (ESIPos): m/z = 477 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tris(acetonitrile)(η5-pentamethylcyclopentadienyl)rhodium(III) hexafluoroantimonate; copper diacetate In tert-Amyl alcohol at 130℃; for 18h; Sealed tube; Inert atmosphere; | 19 Example 19 0.25 mmol of a benzamidine derivative of formula (I), 0.80 mmol of an alkyne compound of formula (II), 6.0 mol % of [Cp*Rh(CH3CN)3](SbF5)2 (Cp* represents pentamethylcyclopentadienyl), and 1.12 mmol (4.5 equivalents) of copper (II) acetate were added into a sealed tube. The sealed tube was then evacuated and purged with nitrogen gas three times. 3.5 ml of 2-methyl-2-butanol was subsequently added into the sealed tube via a syringe under a nitrogen atmosphere to obtain a reaction mixture, which was stirred at 130°C. for l8hours. Themixturewasthencooledanddiluted with CH2C12 (10 ml), followed by filtration through a Celite pad. The Celite pad was washed with CH2C12 (50 ml) to obtain a filtrate. The filtrate was concentrated in vacuo and the residue was purified by a silica gel colunm using hexaneEtOAc (5-15%) as eluent to give a product of formula (III). 10057] The definitions of R’, R2, R3, X, R, Y’, andY2 in formulae (I), (II), and (III) in Examples 1-23 are listed in Table 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 4h; | General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. 4.2.1. 5-Methyl-3-(4-methylphenyl)-1,2,4-oxadiazole8 (3a)White solid; yield 86% (299 mg); mp 77e78 C (lit.8 mp77.6e78.2 C). IR (neat): 1591, 1566, 1481, 1409, 1362, 827, 720, 707,cm1. 1H NMR (DMSO-d6, 400 MHz): d 7.77 (d, J 8.1 Hz, 2H), 7.34(d, J 7.6 Hz, 2H), 2.64 (s, 3H), 2.36 (s, 3H). 13 NMR (DMSO-d6,100 MHz): d 177.2, 167.6, 141.4, 129.8, 126.9, 123.6, 21.1, 12.0. MS(ESI): m/z 175 [MH]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 4h; | General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydroxide In dimethyl sulfoxide at 20℃; for 4h; | 4.2. General procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 4h; | General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium hydroxide; In dimethyl sulfoxide; at 20.0℃; for 4.0h; | General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 4h; | General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium hydroxide In dimethyl sulfoxide at 20℃; for 4h; | 4.2. General procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydroxide In dimethyl sulfoxide at 20℃; for 16h; | 4.2. General procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With sodium hydroxide In dimethyl sulfoxide at 20℃; for 16h; | 4.2. General procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 4h; | General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 4h; | General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 4h; | General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydroxide In dimethyl sulfoxide at 20℃; for 4h; | 4.2. General procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles General procedure: To a solution of amidoxime 1 (2 mmol) and ester 2 (3 mmol) inDMSO (2 mL) 120 mg (3 mmol) powdered NaOH was rapidlyadded.The reaction mixture was stirred at room temperature for therequired time (TLC or precipitation of the product). The reactionmixture was diluted with cold water (30e50 mL). The resultingprecipitate was ltered off, washed with water (30 mL) and dried inair at 50 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In tetrahydrofuran at 0 - 25℃; for 16h; | 10.b.2 b) Step 2: 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a stirred solution of N'-hydroxy-4-methylbenzimidamide (6 g, 40 mmol) in tetrahydrofuran (60 mL), trifluoroacetic anhydride (8.46 mL, 59.9 mmol) was added dropwise at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (100 mL) and the product was extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed by saturated aqueous solution of sodium bicarbonate (2 X 50 mL), water (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 3-(p-tolyl)-5- (trifluoromethyl)-1,2,4-oxadiazole (8.9 g, 98 % yield). |
98% | In tetrahydrofuran at 0 - 25℃; for 16h; | 10.b.2 b) Step 2: 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a stirred solution of N'-hydroxy-4-methylbenzimidamide (6 g, 40 mmol) in tetrahydrofuran (60 mL), trifluoroacetic anhydride (8.46 mL, 59.9 mmol) was added dropwise at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (100 mL) and the product was extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed by saturated aqueous solution of sodium bicarbonate (2 X 50 mL), water (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 3-(p-tolyl)-5- (trifluoromethyl)-1,2,4-oxadiazole (8.9 g, 98 % yield). |
98% | In tetrahydrofuran at 0 - 25℃; for 16h; | 10.b.2 b) Step 2: 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a stirred solution of N'-hydroxy-4-methylbenzimidamide (6 g, 40 mmol) in tetrahydrofuran (60 mL), trifluoroacetic anhydride (8.46 mL, 59.9 mmol) was added dropwise at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (100 mL) and the product was extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed by saturated aqueous solution of sodium bicarbonate (2 X 50 mL), water (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 3-(p-tolyl)-5- (trifluoromethyl)-1,2,4-oxadiazole (8.9 g, 98 % yield). |
75.2% | In tetrahydrofuran at 0 - 20℃; for 3h; | |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole To a stirred solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2- methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C for two hours and diluted with water. The organic layer was separated, washed successively with sodium bicarbonate solution, ammonium chloride solution and water, dried over sodium sulfate, filtered and evaporated to dryness. The crude was subject to combiflash chromatography over silica gel with heptane/EtOAc 99: 1 to 90: 10 to afford 54.1 g of the title compound as clear oil, which solidified upon storage. LC/MS (Method A) retention time = 1.15 minutes, mass not detected. H NMR (400 MHz, CDCI3) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H). 9F NMR (400 MHz, CDCI3) δ ppm: -65.41 (s). |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a stirring solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2- methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C for two hours then diluted with water. The organic layer was separated, washed successively with an aqueous sodium bicarbonate solution, aqueous ammonium chloride solution, and water. The organic phase was then dried over sodium sulfate, filtered and evaporated to dryness. The crude was subject to flash chromatography over silica gel (750 g prepacked column; eluent heptane/EtOAc 99: 1 to 90: 10) to afford 54.1 g of the title compound as clear oil, which solidified after storage. LC/MS (Method A) retention time = 1.15 minutes, mass not detected. 1NMR (400 MHz, CDCl3) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H). 19F NMR (400 MHz, CDCI3) δ ppm: -65.41 (s). |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 2.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 24-oxadiazole To a stirred solution of N-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2-methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C fortwo hours and diluted with water. The organic layerwas separated, washed successively with sodium bicarbonate solution, ammonium chloride solution and water, dried over sodium sulfate, filtered and evaporated to dryness. The crude was subject to flash chromatography over silica gel (750g prepacked column) with heptane/EtOAc 99:1 to 90:10 to afford 54.1 g of the title compound as clearoil, which solidified after storage.LC/MS (Method A) retention time = 1.15 minutes, mass not detected.1H NMR (400 MHz, CDCI3) ö ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s,3H).19F NMR (400 MHz, CDCI3) ö ppm: -65.41 (s). |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 3.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole To a stirred solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2- methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C for 30 two hours and diluted with water. The organic layer was separated, washed successively with sodium bicarbonate solution, ammonium chloride solution and water, dried over sodium sulfate, filtered and evaporated to dryness. The crude residue was subject to flash chromatography over silica gel (heptane: EtOAc eluent gradient 99: 1 to 90: 10) to afford 54.1 g of 3-(p-tolyl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole as clear oil, which solidified after storage. LC/MS (Method A) retention time = 1.15 minutes, mass not detected. NMR (400 MHz, CDCIs) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H). 9F NMR (400 MHz, CDCI3) δ ppm: -65.41 (s). |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 3.2 Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 24-oxadiazole To a stirring solution of N-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2- methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C for two hours then diluted with water. The organic layer was separated, washed successively with anaqueous sodium bicarbonate solution, aqueous ammonium chloride solution, and water. The organic phase was then dried over sodium sulfate, filtered and evaporated to dryness. The crude was subject to flash chromatography over silica gel (750 g prepacked column; eluent heptane/EtOAc 99:1 to 90:10) to afford 54.1 g of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole as clear oil, which solidified after storage.LC/MS (Method A) retention time = 1.15 minutes, mass not detected.1H NMR (400 MHz, CDCI3) ö ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H).19F NMR (400 MHz, CDCI3) δ ppm: -65.41 (s). |
In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 9.2 Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 24-oxadiazole To a stirred solution of N-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2- methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C fortwo hours and then diluted with water. The organic layer was separated, washed successively with sodium bicarbonate solution, ammonium chloride solution and water, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography over silica gel (750 g pre-packed column) with heptane/EtOAc 99:1 to 90:10 to afford the title compound as a clear oil, which solidified upon storage.1H NMR (400 MHz, CDCI3) ö ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s,3H).19F NMR (400 MHz, CDCI3) ö ppm: -65.41 (s).LC/MS (Method A) retention time = 1.15 minutes, mass not detected. | |
In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole To a stirred solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2- methyltetrahydrofuran (750 mL) was added TFAA (49 mL, 0.35 mol) at 0°C. The reaction mixture was stirred for 2 h at 15°C and then diluted with water. The organic layer was separated, washed successively with sodium bicarbonate solution, saturated aqueous ammonium chloride solution, then water and dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was subjected to flash chromatography over silica gel (750g pre-packed column) with heptane/EtOAc 99: 1 to 90: 10 to afford the title compound as a clear oil, which solidified after storage. LC/MS (Method A) retention time = 1.15 minutes, mass not detected. NMR (400 MHz, CDCIs) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s,3H). 19F NMR (400 MHz, CDCI3) δ ppm: -65.41 (s). | |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole To a solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2-methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C for two hours and diluted with water. The organic layers were separated, washed successively with sodium bicarbonate solution, saturated aqueous ammonium chloride solution, and water then dried over sodium sulfate, filtered and evaporated to dryness. The crude residue was subject to flash chromatography over silica gel using a heptane/EtOAc 99: 1 to 90: 10 eluent gradient to afford 54.1 g of the title compound as a clear oil, which solidified after storage. LC/MS retention time = 1 .15 minutes, mass not detected NMR (400 MHz, CDCIs) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H). 9F NMR (376 MHz, CDCIs) δ ppm: -65.41 (s). |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2-methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C for 2 hours then diluted with water. The organic layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel (heptane/EtOAc eluent gradient 99:1 to 90:10) to afford 54.1 g of the title compound as clear oil, which solidified after storage. LC/MS (Method A) retention time = 1 .15 minutes, mass not detected. NMR (400 MHz, CDCIs) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H). (0411) 9F NMR (400 MHz, CDCI3) δ ppm: -65.41 (s). |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2-methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C for two hours then diluted with water. The organic layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and water then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resultant crude residue was purified by flash chromatography over silica gel (heptane/EtOAc eluent gradient 99: 1 to 90: 10) to afford 54.1 g of the title compound as clear oil, which solidified after storage. LC/MS (Method A) retention time = 1.15 minutes, mass not detected.NMR (400 MHz, CDCIs) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H). 'F NMR (400 MHz, CDCIs) δ ppm: -65.41 (s). |
In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a stirred solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2- methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C for two hours and then diluted with water. The organic layer was separated, washed successively with sodium bicarbonate solution, ammonium chloride solution and water, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography over silica gel (750 g pre-packed column) with heptane/EtOAc 99: 1 to 90: 10 to afford the title compound as a clear oil, which solidified upon storage.LC/MS (Method A) retention time = 1.15 minutes, mass not detected. NMR (400 MHz, CDCIs) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s,3H).9F NMR (400 MHz, CDCI3) δ ppm: -65.41 (s). | |
In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a stirred solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2-methyltetrahydrofuran (750 mL) was added TFAA (49.9 mL, 349.9 mmol) at 0 °C. The reaction mixture was stirred at 15 °C for two hours and then diluted with water. The organic layer was separated, washed successively with a saturate sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (heptane: EtOAc eluent gradient 99: 1 to 90: 10) to afford the title compound as a clear oil, which solidified upon storage. LC/MS (Method A) retention time = 1.15 minutes, mass not detected.1H NMR (400 MHz, CDCI3) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H).19F NMR (400 MHz, CDCl3) δ ppm: -65.41 (s). | |
In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole To a stirred solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2- methyltetrahydrofuran (750 mL) was added TFAA (49.9 mL, 349.9 mmol) at 0°C. The reaction mixture was stirred at 15°C for two hours and then diluted with water. The organic layer was separated, washed successively with a saturate sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (heptane: EtOAc eluent gradient 99: 1 to 90: 10) to afford the title compound as a clear oil, which solidified upon storage. LC/MS (Method A) retention time = 1.15 minutes, mass not detected. NMR (400 MHz, CDCIs) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H. 9F NMR (400 MHz, CDCI3) δ ppm: -65.41 (s). | |
In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 24-oxadiazole To a solution of W-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2-methyltetrahydrofuran (750 mL) was added TFAA (49.9 mL, 349.9 mmol) at 0°C. The reaction mixture was stirred at 15°C fortwo hours and then diluted with water. The organic layer was separated, washed successively with a saturate sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (heptane:EtOAc eluent gradient 99:1 to 90:10) to afford the title compound as a clear oil, which solidified upon storage. LC/MS (Method A) retention time = 1.15 minutes,mass not detected.1H NMR (400 MHz, CDCI3) ö ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H).19F NMR (400 MHz, CDCI3) ö ppm: -65.41 (s). | |
In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolyl) To a stirred solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2- methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C for 2 hours and then diluted with water. The organic layer was separated, washed successively with a saturate sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (heptane: EtOAc eluent gradient 99: 1 to 90:10) to afford 56.0 g of the title compound as a clear oil, which solidified upon storage. LC/MS (Method A) retention time = 1.15 minutes, mass not detected. (0347) NMR (400 MHz, CDCIs) δ ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, (0348) 9F NMR (400 MHz, CDCI3) δ ppm: -65.41 (s). | |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3- (p-tolyl) -5- (trifluoromethyl) -1,2,4-oxadiazole TFAA was added to a stirred solution of N'-hydroxy-4-methyl-benzidine (38.7 g, 0.25 mol) in 2-methyltetrahydrofuran (750 mL) at 0 ° C. The reaction mixture was stirred at 15 ° C for two hours and diluted with water. The organic layer was separated, washed sequentially with sodium bicarbonate solution, ammonium chloride solution, and water, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was subjected to flash chromatography on silica gel (750 g pre-packed column) with heptane / EtOAc 99: 1 to 90:10 to provide 54.1 g of the title compound as a clear oil, which solidified after storage |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 2.2 Step 2: Preparation of 3-(p-tolvD-5-(trifluoronnethvD-1.2.4-oxadiazole To a solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2-methyltetrahydrofuran (750 ml_) was added trifluoracetic anhydride at 0°C. The reaction mixture was stirred at 15°C for two hours then diluted with water. The organic layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and water then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resultant crude residue was purified by flash chromatography over silica gel (heptane/EtOAc eluent gradient 99: 1 to 90: 10) to afford 54.1 g of the title compound as clear oil, which solidified after storage. LC/MS (Method A) retention time = 1.15 minutes, mass not detected. NMR (400 MHz, CDCIs) d ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H). 19F NMR (400 MHz, CDCIs) d ppm: -65.41 (s). |
54.1 g | In 2-methyltetrahydrofuran at 0 - 15℃; for 2h; | 1.2 Step 2: Preparation of 3-(p-tolvn-5-(trifluoromethvn-1 ,2.4-oxadiazole To a solution of N'-hydroxy-4-methyl-benzamidine (38.7 g, 0.25 mol) in 2-methyltetrahydrofuran (750 mL) was added TFAA at 0°C. The reaction mixture was stirred at 15°C for two hours then diluted with water. The organic layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and water, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel (heptane/EtOAc eluent gradient 99:1 to 90:10) to afford 54.1 g of the title compound as clear oil, which solidified after storage. LC/MS (Method A) retention time = 1 .15 minutes, mass not detected. (0453) 1H NMR (400 MHz, CDCb) d ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H). (0454) 19F NMR (400 MHz, CDCb) d ppm: -65.41 (s). |
76 g | In 2-methyltetrahydrofuran at 0 - 20℃; for 19h; | 1.B Step B: Preparation of 3-(4-methylphenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of N-hydroxy-4-methyl-benzenecarboximidamide (i.e. the product of Step A) (56 g, 0.37 mol) in 2-methyltetrahydrofuran (560 mL) at 0° C. was added trifluoroacetic anhydride (63 mL, 0.45 mol). The reaction mixture was stirred at 0° C. for 3 h, warmed to room temperature and stirred for an additional 16 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate solution followed by saturated aqueous sodium chloride solution. The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (eluting with petroleum ether) to provide the title compound as an oil (76 g). 1H NMR (CDCl3, 400 MHz) δ 7.99 (d, 2H), 7.31 (d, 2H), 2.43 (s, 3H). |
50 g | In tetrahydrofuran at 0 - 25℃; for 6h; Inert atmosphere; | 3.b.2 b) Step 2:- 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of N-hydroxy-4-methylbenzimidamide (38 g, 253 mmol) in tetrahydrofuran (150 mL), trifluoroacetic anhydride (53.6 mL, 380 mmol) was added at 0-5 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at 25 °C for 6 h. After completion of the reaction, ethyl acetate (150mL) was added to the reaction mixture. Saturated sodium bicarbonate solution (150mL) was added slowly with stirring until all the effervences stops. The ethyl acetate layer was isolated, washed with water (100 mL) followed by brine solution (50mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude obtained was purified by column chromatography by using hexane to 5% ethyl acetate in hexane as an eluent to obtain 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4- oxadiazole (50 g, 219 mmol, 87 % yield). |
Yield | Reaction Conditions | Operation in experiment |
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77% | General procedure: b. In 10 mL of dichloromethane was dissolved 2 mmol of amidoxime 2, 185 mg (2.2 mmol) of NaHCO3 was added. The reaction mixture was cooled to 0 and by portions maintaining the reaction mixture temperature below 5 2 mmol of acyl chloride 3 was added. The reaction mixture was warmed to room temperature, stirred for 2 h, then it was washed with 10 mL of NaHCO3 solution and 10 mL of water, the organic layer was dried with Na2SO4 and evaporated at a reduced pressure. The residue was dissolved in 1.52 mL of DMSO and 80 mg (2 mmol) of preliminary ground NaOH was added. The reaction mixture was stirred at room temperature for 1 h and diluted with 20 mL of cold water. The formed precipitate was filtered off. |
Yield | Reaction Conditions | Operation in experiment |
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70% | With potassium carbonate; copper(II) oxide In dimethyl sulfoxide at 110℃; for 24h; | 8 Synthesis of a 5- (p-methylphenyl) -3-methyl-1H-1,2,4-triazole comprising the steps of: A, take 0.5 mmol of acetamidine hydrochloride and 0.6 mmol 4-methyl-N-hydroxyphenylcarboximide In the reaction tube,And then to its addition of 0.08mmol CuO,1.25 mmol K2CO3 and 3 mL DMSO,The reaction was stirred at 110 ° C for 24 hours;B, the product was extracted with ethyl acetate,Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product,The crude product was purified by silica gel column chromatography (solvent volume ratio petroleum ether: ethyl acetate = 5: 1) to give a white solid5- (p-methylphenyl) -3-methyl-1H-1,2,4-triazole in 70% yield, m.p. 155-156 ° C. |
Yield | Reaction Conditions | Operation in experiment |
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62% | Stage #1: p-toluamidoxime; homophthalic anhydride In dimethyl sulfoxide at 20℃; for 2h; Stage #2: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 1h; | General procedure for the synthesis of 1,2,4-oxadiazoles 4a-u from amidoximes 1 and cyclic anhydrides 2 in DMSO. Method A. General procedure: To a solution of amidoxime 1 (2.5 mmol) in DMSO (2-3 mL) a cyclic anhydride 2 (2.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Next, to the reaction mixture powdered NaOH (5 mmol) was rapidly added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with cold water (30 mL) followed by the addition of hydrochloric acid to pH ~1. The resulting precipitate was filtered off, washed with cold water (25 mL) and dried in air at 50 °C. |
Yield | Reaction Conditions | Operation in experiment |
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91% | With iodine; potassium carbonate In water at 60℃; for 4h; Green chemistry; | |
76% | In water at 80℃; for 1h; | General procedure for the preparation of product 3a-3j General procedure: The mixture of amidoximes (1.0 mmol) and isothiocyanate (1.0 mmol) in water (2.0 mL)was stirred magnetically at 80 C for the stipulated period (1 (amidoximes) and 2 (isothiocyanates)both are organic compounds, they are soluble in the aqueous medium atheating conditions).After completion of the reaction as monitored by TLC, the reaction mixture wascooled to room temperature, excess water (30 mL) was added and extracted with ethyl acetate (230 mL) and the combined organic layer was washed with brine (30 mL),dried over Na2SO4 and solvent was evaporated under reduced pressure to get crude.Crude was purified by silica gel column chromatography using hexane and ethylacetate(10:1) as eluent to afford corresponding products 3a-3j |
Yield | Reaction Conditions | Operation in experiment |
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53.1% | General procedure: 3,4-difluorobenzoic acid (0.46g, 2.92mmol, 1.0 equiv) was dissolved in DMF (3.0mL) treated with carbonyldiimidazole (0.48g, 2.92mmol, 1.0 equiv) and stirred at room temperature for 1h. 45 (0.4g, 2.92mmol, 1.0 equiv) was added in the mixed solution and another 3mL DMF was added in the system. Then the temperature was increased to 110C and stirring was continued for 12-18h. After cooling, the mixture was diluted by means of water and saturated aqueous NaHCO3 solution. The generated solid product was collected by filtration and washed with saturated aqueous NaHCO3 solution. Yield: 0.345g (45.6%). |
Yield | Reaction Conditions | Operation in experiment |
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40% | With sodium ethanolate; copper diacetate In toluene at 110℃; for 24h; | 9 Example 9 0.5 mmol of 4-methylbenzamide oxime, 1.0 mmol of 4-bromobenzyl alcohol was placed in the reaction tube, and then 0.05 mmol of Cu(OAc) 2, 0.5 mmol of C2H5ONa, 2.5 mL of toluene were added in sequence, and stirred at 110 ° C. After reacting for 24 h, the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate.Ethyl acetate = 20:1) purified to a white solid.That is, 5-(4-bromophenyl)-3-(4-methylphenyl)-1,2,4-oxadiazole. Yield 40%, |
Yield | Reaction Conditions | Operation in experiment |
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56% | With sodium ethanolate; copper diacetate In dimethyl sulfoxide at 110℃; for 24h; | 7 Example 7 take 0.5 mmol of 4-methylbenzamide oxime, 1.0 mmol of 2,4-dichlorobenzyl alcohol in a reaction tube, and then Add 0.05mmol Cu(OAc)2, 0.5mmol C2H5ONa, 2.5mL DMSO in turn, stir the reaction at 110 ° C for 24h, and produce The extract was extracted with ethyl acetate, dried over anhydrous sodium The volume ratio of the agent was petroleum ether: ethyl acetate = 20:1) purified to a white solid.That is, 5-(2,4-dichlorophenyl)-3-(4-methylphenyl)-1,2,4-oxadiazole. Yield 56% |
Yield | Reaction Conditions | Operation in experiment |
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48% | With sodium ethanolate; copper(II) oxide In toluene at 110℃; for 24h; | 8 Example 8 0.5 mmol of 4-methylbenzamide oxime, 1.0 mmol of benzyl alcohol was placed in a reaction tube, and then 0.05 mmol of CuO, 0.5 mmol of C2H5ONa, 2.5 mL of toluene were added in sequence, and the reaction was stirred at 110 ° C for 24 h to obtain acetic acid. The ethyl ester was extracted, dried over anhydrous sodium sulfate and evaporated to dryness crystals crystals.That is, 5-phenyl-3-(4-methylphenyl)-1,2,4-oxadiazole. Yield 48%, |
Yield | Reaction Conditions | Operation in experiment |
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74% | Stage #1: p-toluamidoxime; chloroformic acid ethyl ester With sodium hydrogencarbonate In dichloromethane at 0 - 20℃; for 2h; Stage #2: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 1h; | 1,2,4-Oxadiazoles (5-5m). General procedure. b. General procedure: b. In 10 mL of dichloromethane was dissolved 2 mmol of amidoxime 2, 185 mg (2.2 mmol) of NaHCO3 was added. The reaction mixture was cooled to 0° and by portions maintaining the reaction mixture temperature below 5° 2 mmol of acyl chloride 3 was added. The reaction mixture was warmed to room temperature, stirred for 2 h, then it was washed with 10 mL of NaHCO3 solution and 10 mL of water, the organic layer was dried with Na2SO4 and evaporated at a reduced pressure. The residue was dissolved in 1.52 mL of DMSO and 80 mg (2 mmol) of preliminary ground NaOH was added. The reaction mixture was stirred at room temperature for 1 h and diluted with 20 mL of cold water. The formed precipitate was filtered off. |
Yield | Reaction Conditions | Operation in experiment |
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48% | Stage #1: p-toluamidoxime; cyclopropanecarboxylic acid chloride With sodium hydrogencarbonate In dichloromethane at 0 - 20℃; for 2h; Stage #2: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 1h; | 1,2,4-Oxadiazoles (5-5m). General procedure. b. General procedure: b. In 10 mL of dichloromethane was dissolved 2 mmol of amidoxime 2, 185 mg (2.2 mmol) of NaHCO3 was added. The reaction mixture was cooled to 0° and by portions maintaining the reaction mixture temperature below 5° 2 mmol of acyl chloride 3 was added. The reaction mixture was warmed to room temperature, stirred for 2 h, then it was washed with 10 mL of NaHCO3 solution and 10 mL of water, the organic layer was dried with Na2SO4 and evaporated at a reduced pressure. The residue was dissolved in 1.52 mL of DMSO and 80 mg (2 mmol) of preliminary ground NaOH was added. The reaction mixture was stirred at room temperature for 1 h and diluted with 20 mL of cold water. The formed precipitate was filtered off. |
Yield | Reaction Conditions | Operation in experiment |
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72% | Stage #1: p-toluamidoxime; Hexanoyl chloride With sodium hydrogencarbonate In dichloromethane at 0 - 20℃; for 2h; Stage #2: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 1h; | 1,2,4-Oxadiazoles (5-5m). General procedure. b. General procedure: b. In 10 mL of dichloromethane was dissolved 2 mmol of amidoxime 2, 185 mg (2.2 mmol) of NaHCO3 was added. The reaction mixture was cooled to 0° and by portions maintaining the reaction mixture temperature below 5° 2 mmol of acyl chloride 3 was added. The reaction mixture was warmed to room temperature, stirred for 2 h, then it was washed with 10 mL of NaHCO3 solution and 10 mL of water, the organic layer was dried with Na2SO4 and evaporated at a reduced pressure. The residue was dissolved in 1.52 mL of DMSO and 80 mg (2 mmol) of preliminary ground NaOH was added. The reaction mixture was stirred at room temperature for 1 h and diluted with 20 mL of cold water. The formed precipitate was filtered off. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: p-toluamidoxime; m-Chlorobenzoyl chloride With sodium hydrogencarbonate In dichloromethane at 0 - 20℃; for 2h; Stage #2: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 1h; | 1,2,4-Oxadiazoles (5-5m). General procedure. b. General procedure: b. In 10 mL of dichloromethane was dissolved 2 mmol of amidoxime 2, 185 mg (2.2 mmol) of NaHCO3 was added. The reaction mixture was cooled to 0° and by portions maintaining the reaction mixture temperature below 5° 2 mmol of acyl chloride 3 was added. The reaction mixture was warmed to room temperature, stirred for 2 h, then it was washed with 10 mL of NaHCO3 solution and 10 mL of water, the organic layer was dried with Na2SO4 and evaporated at a reduced pressure. The residue was dissolved in 1.52 mL of DMSO and 80 mg (2 mmol) of preliminary ground NaOH was added. The reaction mixture was stirred at room temperature for 1 h and diluted with 20 mL of cold water. The formed precipitate was filtered off. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: p-toluamidoxime; benzoic acid anhydride In dichloromethane at 20℃; for 2h; Stage #2: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 1h; | 1,2,4-Oxadiazoles (5-5m). General procedure. a. General procedure: In 10 mL of dichloromethane 2 mmol of amidoxime 2 was dissolved and 2 mmol of anhydride 3 was added.The reaction mixture was stirred at room temperaturefor 2 h, then it was washed with 10 mL of NaHCO3 solution and 10 mL of water, the organic layer was dried with Na2SO4 and evaporated at a reduced pressure. The residue was dissolved in 1.52 mL of DMSO and 80 mg (2 mmol) of preliminary ground NaOH was added. The reaction mixture was stirred at room temperature for 1 h and diluted with 20 mL of cold water. The formed precipitate was filtered off. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | General procedure: In 10 mL of dichloromethane 2 mmol of amidoxime 2 was dissolved and 2 mmol of anhydride 3 was added.The reaction mixture was stirred at room temperaturefor 2 h, then it was washed with 10 mL of NaHCO3 solution and 10 mL of water, the organic layer was dried with Na2SO4 and evaporated at a reduced pressure. The residue was dissolved in 1.52 mL of DMSO and 80 mg (2 mmol) of preliminary ground NaOH was added. The reaction mixture was stirred at room temperature for 1 h and diluted with 20 mL of cold water. The formed precipitate was filtered off. |
Yield | Reaction Conditions | Operation in experiment |
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General procedure: In a sealed tube in amicrowave reactor, 0.8 mmol of L-N-protected amino acid(1-5) and DCC (0.96 mmol, 0.199 g) were dissolved in acetone(1.0 mL) and the mixture was magnetically stirred forapproximately 40 minutes to form the reactive intermediate. Then, 0.8 mmol of aryl amidoxime (a-e) was added, and themixture was homogenized. The acetone was removed inroute evaporator without heating, and H2O (1.0 mL) wasadded to the mixture, which was subjected to microwaveirradiation at 100W power, temperature of 115C, during15 min. Soon after, the reaction crude was dissolved in ethylacetate and washed with water. The organic phase was driedover magnesium sulfate, and the solvent was removed undervacuum. The residue was purified by column chromatographyon silica gel (hexane-ethyl acetate, 7 : 3) to afford pureproducts (1-5a-e). Detailed experimental procedures, 1Hand 13C NMR spectra for all compounds, are available in thesupporting information, ESI (available here). |
Yield | Reaction Conditions | Operation in experiment |
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91% | In 2-methyltetrahydrofuran; at 0 - 25℃; under 7425.74 Torr; for 5h; | 100 g (0.67 mol) /V-hydroxy-4-methyl-benzamidine were suspended in 450 g (5.22 mol) tetra- hydro-2-methylfuran (Me-THF). In total, 203 g (1.53 mol) trifluoroacetyl chloride were dosed in between 0C and 25C in 5 hours. Then, the volatiles were removed in vacuo (60C, 250 to 5 mbar) to yield 138 g (>99 % HPLC purity, 91 % yield) 3-( >tolyl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole. |
Yield | Reaction Conditions | Operation in experiment |
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85% | General procedure: Method A. An ethyl chloroformate (ECF, 3.0 mmol, 0.29 mL) was added, dropwise to a mixture of carboxylic acid (2.5 mmol) and TEA (3.0 mmol, 0.42 mL) in 1,4-dioxane (4 mL). The reaction mixture was stirred at room temperature for 15 min. An amidoxime 2 (2.5 mmol) in 1,4-dioxane (4 mL) was added and resulted mixture was stirred at room temperature for 15 min. The solvent was evaporated at reduced pressure and residue was diluted with water (25 mL). The precipitate was filtered off, washed with cold water (25 mL) and dried in air at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
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75% | With dmap; 1,10-Phenanthroline; iodine; iron(II) chloride In chlorobenzene at 120℃; for 8h; | 2. General procedure for the synthesis of (2,4-diphenyl-1H-imidazol-5-yl)(phenyl)methanone 3ab General procedure: The reactions were carried out in a round-bottom sidearm flask (10 mL). 1a (0.2 mmol), 2b (0.4 mmol), FeCl2 (10 mol%), 1,10-phen (10 mol%), I2 (60 mol%), DMAP (1 eq) and PhCl (1 mL) were added to the flask with magnetic stirring bar. The resulting mixture was stirred at 120 °C for 8 h. After cooling to room temperature, the mixture was filtered and extracted with ethyl acetate (3×10 mL). Then the filtrate was concentrated under reduced pressure in order to get the crude product, which was further purified by silica gel chromatography (petroleum/ethyl acetate = 10/1 as eluent) to obtain product 3ab. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,10-Phenanthroline; iron(III) chloride hexahydrate; potassium carbonate; In toluene; at 120℃; for 10h; | General procedure: The reactions were carried out in a round-bottom sidearm flask (10 mL). 1a (0.2 mmol), 2b (0.4 mmol), FeCl3.6H2O (10 mol%), 1,10-phen (10 mol%), K2CO3 (2 eq) and Toluene (2 mL) were added to the flask with magnetic stirring bar. The resulting mixture was stirred at 120 C for 10 h. After cooling to room temperature, the mixture was filtered and extracted with ethyl acetate (3×10 mL). Then the filtrate was concentrated under reduced pressure in order to get the crude product, which was further purified by silica gel chromatography (petroleum/ethyl acetate = 50/1 as eluent) to obtain product 4ab. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine In dichloromethane at 20℃; for 4h; | General procedure for Synthesis of N,N-dimethyl-1,2,4-oxadiazol-5-amine derivatives (3a to 3t) General procedure: 0.002 mol amidoximes and 0.008 mol triethylamine dissolved in 10 ml dichloromethane. The solution was then instilled to 10 ml dichloromethane containing 0.004 mol Vilsmeier salt and stirred for 4 h . The whole progress was monitored by TLC and evaporated the solvent then followed by column chromatography column chromatography to get terminated material. |
Yield | Reaction Conditions | Operation in experiment |
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88% | With trifluoroacetic acid; In tetrahydrofuran; at 0 - 25℃; for 6h;Inert atmosphere; | To a stirred solution of N? -hydro xy-4-methylbenzimidamide (0.9 g, 5.9 mmol) in tetrahydrofuran (15 mL) , trifluoroacetic acid (1.3 mL, 8.9 mmol) was added at 0-5 C under nitrogen atmosphere. The reaction mixture was then stirred at 25 C for 6 h. Ethyl acetate (50 mL) was added to the reaction mixture followed by the cautious addition of saturated solution of sodium bicarbonate. Ethyl acetate layer was separated washed with water (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 10% ethyl acetate in hexane to obtain 3-(p-tolyl)-5-(trifluoromethyl)-l,2,4-oxadiazole (1.2g, yield 88%). |
Yield | Reaction Conditions | Operation in experiment |
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57% | Stage #1: 2-pyridinecarboxylic acid N-oxide With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: p-toluamidoxime In dimethyl sulfoxide at 20℃; for 18h; Stage #3: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 2h; | 2.2 Synthesis and characterization of N-oxide 1a-i. General procedure 5 (GP5) General procedure: To a solution of a 2-carboxypyridine 1-oxide (10 mmol) in dry DMSO (5 mL) CDI (1.95 g, 12 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, and an amidoxime (10 mmol) was added. The reaction mixture was stirred at room temperature for another 18 h, after that to the reaction mixture powdered NaOH (12 mmol) was rapidly added. The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was diluted with cold water (80 mL). The resulting precipitate was filtered off, washed with cooled water (25 mL) and dried in air at 50 °C. 2-(3-(p-Tolyl)-1,2,4-oxadiazol-5-yl)pyridine 1-oxide 1f. According to GP5: white solid; 1.44 g (57%) yield |
Yield | Reaction Conditions | Operation in experiment |
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79% | In acetonitrile at 80℃; for 24h; | General procedure for the preparationof compounds 4 General procedure: Benzamidoximes 1 (1 mmol) and Erlenmeyer azlactones 2 (1 mmol) were dissolved in 5 cm3 MeCN and stirred at reflux. After completion of the reaction [about 24 h, TLC (n-hexane/EtOAc, 4:1) monitoring], the precipitated solids were filtered and washed with cold EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
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82% | In acetonitrile at 80℃; for 24h; | General procedure for the preparationof compounds 4 General procedure: Benzamidoximes 1 (1 mmol) and Erlenmeyer azlactones 2 (1 mmol) were dissolved in 5 cm3 MeCN and stirred at reflux. After completion of the reaction [about 24 h, TLC (n-hexane/EtOAc, 4:1) monitoring], the precipitated solids were filtered and washed with cold EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
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77% | In acetonitrile at 80℃; for 24h; | General procedure for the preparationof compounds 4 General procedure: Benzamidoximes 1 (1 mmol) and Erlenmeyer azlactones 2 (1 mmol) were dissolved in 5 cm3 MeCN and stirred at reflux. After completion of the reaction [about 24 h, TLC (n-hexane/EtOAc, 4:1) monitoring], the precipitated solids were filtered and washed with cold EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
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78% | In acetonitrile at 80℃; for 24h; | General procedure for the preparationof compounds 4 General procedure: Benzamidoximes 1 (1 mmol) and Erlenmeyer azlactones 2 (1 mmol) were dissolved in 5 cm3 MeCN and stirred at reflux. After completion of the reaction [about 24 h, TLC (n-hexane/EtOAc, 4:1) monitoring], the precipitated solids were filtered and washed with cold EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
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80% | In acetonitrile at 80℃; for 24h; | General procedure for the preparationof compounds 4 General procedure: Benzamidoximes 1 (1 mmol) and Erlenmeyer azlactones 2 (1 mmol) were dissolved in 5 cm3 MeCN and stirred at reflux. After completion of the reaction [about 24 h, TLC (n-hexane/EtOAc, 4:1) monitoring], the precipitated solids were filtered and washed with cold EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
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91% | General procedure: In a round-bottom flask, the respective 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoic acid (0.8 mmol) and 3.2 mL of 1% NaOH methanol solution(freshly prepared) were mixed and the reaction was allowed tostir for one hour. After the time, methanol was evaporated and theproduct was recrystallized from chloroform. |
Yield | Reaction Conditions | Operation in experiment |
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63% | General procedure: (4-Chlorophenyl)carbamoyl)-L-proline (115) (1.0 equiv), corresponding benzamidoxime (116-136) (1.0 equiv), EDCI (1.1 equiv), and HOAT (1.1 equiv) were dissolved in DCM (0.3 M) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Dioxane was added into the residue and the reaction mixture was heated at 100 C overnight. After completion, the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc, washed twice with water and once with brine. The combined organic layer was dried over MgSO4 and then evaporated under reduced pressure. The corresponding product was separated using silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: p-toluamidoxime; (E)-2-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)acetic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile for 1h; Stage #2: In toluene for 3h; Reflux; Stage #3: With lithium hydroxide monohydrate In tetrahydrofuran; water for 2h; | 4. General procedure for the synthesis of (E)-3-(4-((3-phenyl-1,2,4-oxadiazol-5-yl)methoxy)phenyl)acrylic acid (9): General procedure: E)-2-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)acetic acid (15) (2 g, 8.47 mmol, 1 equiv) and hydroxybenzotriazole (HOBt) (1.44 g,8.47 mmol, 1 equiv) were slurried in dry acetonitrile (20 mL). Addition of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) (1.6 g, 8.47 mmol) to this mixture was done at room temperature. To this solution, 4-chloro-N-hydroxybenzimidamide (17v,1.45 g, 8.47 mmol, 1 equiv) was added and stirred for 1 h. The solvent evaporated to afford the intermediate product and to this toluene was added and refluxed for 3 h. The reaction mixture was partitioned with ethyl acetate and aqueous bicarbonate solution. Then dried the organic layer and concentrated to afford the crude product which was purified by recrystallization in DCM to afford the desired product. Later 1 g of crude product was directly hydrolyzed by dissolving in 20 mL of THF and a suspension of LiOH·H2O (0.12 g, 2.97 mmol, 1.1 equiv) in THF:water (6 mL, 1:1, v/v) was added and then stirred for 2 hr. TLC was analyzed , then the lithium salt of carboxylic acid was converted to the corresponding acid by neutralizing with dil. HCl (1 N). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate In dimethyl sulfoxide at 100℃; for 24h; Sealed tube; regioselective reaction; | 3.2. Typical Experimental Procedure for the Synthesis of 2,4-Diphenyl-1H-imidazole (3aa) General procedure: A mixture of benzamidoxime (1a, 136.1 mg, 1.0 mmol), phenylacetylene (2a, 204.1 mg, 2.0 mmol)and Cs2CO3 (815.1 mg, 2.5 mmol) in DMSO (4.0 mL), in a 25 mL screw-capped thick-walled Pyrextube was stirred at 100 °C for 24 h in an oil bath. After the reaction mixture was cooled to roomtemperature, it was poured into a solvent mixture of water (50.0 mL) and ethyl acetate (20.0 mL), andthe two phases were then separated. The aqueous layer was extracted with ethyl acetate (3 × 20.0 mL).The combined organic extracts were dried over anhydrous Na2SO4. After removal of the solventunder reduced pressure, the residue was purified by column chromatography on silica gel withpetroleum ether/ethyl acetate (gradient mixture ratio from 100:0 to 70:20) as eluent, to afford 3aa as awhite solid (160.4 mg, 73%).The characterization data for known products of 3aa, 3ab, 3af, 3ah-3al, 3an, 3ao, 3aq, 3ar, 3ba,3ca and 3da reported in the Supplementary Materials. Each of 3ac, 3ad, 3ae, 3ag, 3am, 3ap and 3edare new compounds, and their spectroscopic data are reported below. |
Yield | Reaction Conditions | Operation in experiment |
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80% | With trifluoroacetic acid at 20 - 60℃; for 0.583333h; | 3-(4-Methylphenyl)-1,2,4-oxadiazole (1u)37 Compound 1u was obtained according to the reported procedure.38 Toa solution of 4-methylbenzamide oxime (150 mg, 1.0 mmol) in trimethyl orthoformate (5 mL) was added a catalytic amount of trifluoroacetic acid at rt. After stirring for 5 min, the resulting solution was heated up to 60°C and stirred for additional 30 min. Then the mixture was concentrated and the residue was dissolved in EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried to graphed on silica gel (eluent hexane-EtOAc, 2:1) to give oxadiazole1u; yield: 150 mg (80%); colorless oil. IR (KBr): 2925, 1640, 1545, 1525, 1340 cm-1. 1H NMR (400 MHz, CDCl3): = 8.75 (s, 1 H), 8.03 (d, J = 8.1 Hz, 2 H),7.33 (d, J = 8.1 Hz, 2 H), 2.45 (s, 3 H). 13C NMR (100 MHz, CDCl3): = 167.7, 164.6, 141.8, 129.6, 127.5,123.4, 21.5. HRMS (ESI-TOF): m/z [M + H]+ calcd for C9H9N2O: 161.0709; found:161.0703. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.8% | With sodium methylate In methanol at 30℃; for 3.5h; | 1 Example 1) Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole A vessel was charged at 22°C with 40.0 g (256 mmol, purity 96.0%) of A/'-hydroxy-4-methyl- benzamidine and 181 g (1.28 mol) of ethyl trifluoroacetate. 27.6 g sodium methanolate (151 mmol, 30% w/w in methanol) was added within 30 minutes and the reaction mixture was stirred for 1.5 hours at 30°C. Then, another portion of 13.8 g sodium methanolate (75.5 mmol, 30% w/w in methanol) was added within 10 minutes and the mixture was stirred for additional 40 minutes. A final portion of 13.8 g sodium methanolate (75.5 mmol, 30% w/w in methanol) was added within 10 minutes and the mixture was stirred for additional 30 minutes. 2.3 g hydrochloric acid (32% w/w) was added and all volatiles were removed under reduced pressure. Water (60 g) was added and the phases were separated. 57.4 g (94.8%, HPLC purity (method 1): 96.3%) of the title compound was isolated from the organic phase. |
80% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 24℃; for 1.08333h; Molecular sieve; | 2 Example 2: This example illustrates the preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole: To a 50 mL flask was added N'-hydroxy-4-methyl-benzamidine (96% purity, 1 .0 g, 6.39 mmol), tetrahydrofuran (10 mL), 4A molecular sieves (150 mg). After cooling to 0°C, a 1 M tetrahydrofuran solution of potassium tert-butoxide (6.39 mL, 6.39 mmol) was introduced dropwise. To the resultant suspension, ethyl 2,2,2-trifluoroacetate (0.58 g, 4.40 mmol) was added over 5 minutes and the ice bath was removed. After 1 hour, the reaction conversion was 92% complete with a reaction mixture having a pH of 10.3 (measured using a pH meter). Citric acid (50 g) was added portionwise, and the contents stirred for 10 minutes to achieve a pH 5.9 reaction mixture. The crude reaction contents were filtered over celite, washed twice with tetrahydrofuran (20 mL), and the filtrate was concentrated under reduced pressure. The resultant crude mass was diluted with dichloromethane (20 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted twice with dichloromethane. The total combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 1 .22 g of the title compound as a pale yellow liquid (80% yield, QNMR purity 96%). (0290) NMR (400 MHz, CDCb) d ppm: 8.00 (d, 2H), 7.32 (d, 2H), 2.45 (s, 3H). (0291) 19F NMR (400 MHz, CDCb) d ppm: -65.41 (s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: (S)-2-[2-(phenylthio)acetamido]propanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetone at 20℃; for 0.333333h; Sealed tube; Green chemistry; Stage #2: p-toluamidoxime In water at 100℃; for 0.166667h; Sealed tube; Microwave irradiation; Green chemistry; | 2.6. General procedure for the synthesis of 1,2,4-oxadiazoles (7aa-fe) General procedure: In a sealed tube in a microwave reactor, 1.0 mmol of chalcogen α-acetamido acid derivatives (5a-f) was added to EDC*HCl (1.1 mmol, 0.199 g) and the two were dissolved in acetone (1.0 mL). The mixture was magnetically stirred for approximately 20 minutes to form the reactive intermediate. After this time, 1.1 mmol of arylamidoxime (6a-e) was added and the mixture was homogenized. The acetone was removed in a rotary evaporator without heating and H2O (1.0 mL) was added to the mixture. The tube was sealed and placed into a microwave irradiation CEM Discover at 100 W power, temperature of 100 °C for 10 minutes. Then, saturated NH4Cl and ethyl acetate (3 x 5.0 mL) were added. The combined organic layers were dried over MgSO4 and evaporated on a rotary evaporator. The crude products were purified by column chromatography on silica gel, using hexane/ethyl acetate as the eluent, furnishing the pure products 7aa-fe. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: (S)-4-methyl-2-[2-(phenylthio)acetamido]pentanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetone at 20℃; for 0.333333h; Sealed tube; Green chemistry; Stage #2: p-toluamidoxime In water at 100℃; for 0.166667h; Sealed tube; Microwave irradiation; Green chemistry; | 2.6. General procedure for the synthesis of 1,2,4-oxadiazoles (7aa-fe) General procedure: In a sealed tube in a microwave reactor, 1.0 mmol of chalcogen α-acetamido acid derivatives (5a-f) was added to EDC*HCl (1.1 mmol, 0.199 g) and the two were dissolved in acetone (1.0 mL). The mixture was magnetically stirred for approximately 20 minutes to form the reactive intermediate. After this time, 1.1 mmol of arylamidoxime (6a-e) was added and the mixture was homogenized. The acetone was removed in a rotary evaporator without heating and H2O (1.0 mL) was added to the mixture. The tube was sealed and placed into a microwave irradiation CEM Discover at 100 W power, temperature of 100 °C for 10 minutes. Then, saturated NH4Cl and ethyl acetate (3 x 5.0 mL) were added. The combined organic layers were dried over MgSO4 and evaporated on a rotary evaporator. The crude products were purified by column chromatography on silica gel, using hexane/ethyl acetate as the eluent, furnishing the pure products 7aa-fe. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: (S)-3-phenyl-2-[2-(phenylthio)acetamido]propanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetone at 20℃; for 0.333333h; Sealed tube; Green chemistry; Stage #2: p-toluamidoxime In water at 100℃; for 0.166667h; Sealed tube; Microwave irradiation; Green chemistry; | 2.6. General procedure for the synthesis of 1,2,4-oxadiazoles (7aa-fe) General procedure: In a sealed tube in a microwave reactor, 1.0 mmol of chalcogen α-acetamido acid derivatives (5a-f) was added to EDC*HCl (1.1 mmol, 0.199 g) and the two were dissolved in acetone (1.0 mL). The mixture was magnetically stirred for approximately 20 minutes to form the reactive intermediate. After this time, 1.1 mmol of arylamidoxime (6a-e) was added and the mixture was homogenized. The acetone was removed in a rotary evaporator without heating and H2O (1.0 mL) was added to the mixture. The tube was sealed and placed into a microwave irradiation CEM Discover at 100 W power, temperature of 100 °C for 10 minutes. Then, saturated NH4Cl and ethyl acetate (3 x 5.0 mL) were added. The combined organic layers were dried over MgSO4 and evaporated on a rotary evaporator. The crude products were purified by column chromatography on silica gel, using hexane/ethyl acetate as the eluent, furnishing the pure products 7aa-fe. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: (S)-2-[2-(phenylselenyl)acetamido]propanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetone at 20℃; for 0.333333h; Sealed tube; Green chemistry; Stage #2: p-toluamidoxime In water at 100℃; for 0.166667h; Sealed tube; Microwave irradiation; Green chemistry; | 2.6. General procedure for the synthesis of 1,2,4-oxadiazoles (7aa-fe) General procedure: In a sealed tube in a microwave reactor, 1.0 mmol of chalcogen α-acetamido acid derivatives (5a-f) was added to EDC*HCl (1.1 mmol, 0.199 g) and the two were dissolved in acetone (1.0 mL). The mixture was magnetically stirred for approximately 20 minutes to form the reactive intermediate. After this time, 1.1 mmol of arylamidoxime (6a-e) was added and the mixture was homogenized. The acetone was removed in a rotary evaporator without heating and H2O (1.0 mL) was added to the mixture. The tube was sealed and placed into a microwave irradiation CEM Discover at 100 W power, temperature of 100 °C for 10 minutes. Then, saturated NH4Cl and ethyl acetate (3 x 5.0 mL) were added. The combined organic layers were dried over MgSO4 and evaporated on a rotary evaporator. The crude products were purified by column chromatography on silica gel, using hexane/ethyl acetate as the eluent, furnishing the pure products 7aa-fe. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: (S)-4-methyl-2-[2-(phenylselenyl)acetamido]pentanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetone at 20℃; for 0.333333h; Sealed tube; Green chemistry; Stage #2: p-toluamidoxime In water at 100℃; for 0.166667h; Sealed tube; Microwave irradiation; Green chemistry; | 2.6. General procedure for the synthesis of 1,2,4-oxadiazoles (7aa-fe) General procedure: In a sealed tube in a microwave reactor, 1.0 mmol of chalcogen α-acetamido acid derivatives (5a-f) was added to EDC*HCl (1.1 mmol, 0.199 g) and the two were dissolved in acetone (1.0 mL). The mixture was magnetically stirred for approximately 20 minutes to form the reactive intermediate. After this time, 1.1 mmol of arylamidoxime (6a-e) was added and the mixture was homogenized. The acetone was removed in a rotary evaporator without heating and H2O (1.0 mL) was added to the mixture. The tube was sealed and placed into a microwave irradiation CEM Discover at 100 W power, temperature of 100 °C for 10 minutes. Then, saturated NH4Cl and ethyl acetate (3 x 5.0 mL) were added. The combined organic layers were dried over MgSO4 and evaporated on a rotary evaporator. The crude products were purified by column chromatography on silica gel, using hexane/ethyl acetate as the eluent, furnishing the pure products 7aa-fe. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Stage #1: (S)-3-phenyl-2-[2-(phenylselenyl)acetamido]propanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetone at 20℃; for 0.333333h; Sealed tube; Green chemistry; Stage #2: p-toluamidoxime In water at 100℃; for 0.166667h; Sealed tube; Microwave irradiation; Green chemistry; | 2.6. General procedure for the synthesis of 1,2,4-oxadiazoles (7aa-fe) General procedure: In a sealed tube in a microwave reactor, 1.0 mmol of chalcogen α-acetamido acid derivatives (5a-f) was added to EDC*HCl (1.1 mmol, 0.199 g) and the two were dissolved in acetone (1.0 mL). The mixture was magnetically stirred for approximately 20 minutes to form the reactive intermediate. After this time, 1.1 mmol of arylamidoxime (6a-e) was added and the mixture was homogenized. The acetone was removed in a rotary evaporator without heating and H2O (1.0 mL) was added to the mixture. The tube was sealed and placed into a microwave irradiation CEM Discover at 100 W power, temperature of 100 °C for 10 minutes. Then, saturated NH4Cl and ethyl acetate (3 x 5.0 mL) were added. The combined organic layers were dried over MgSO4 and evaporated on a rotary evaporator. The crude products were purified by column chromatography on silica gel, using hexane/ethyl acetate as the eluent, furnishing the pure products 7aa-fe. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine In acetonitrile at 0 - 20℃; for 1.5h; | Synthesis of O-acylamidoximes 4a-i (General method) General procedure: A solution of acyl chloride 3- (6.37 mmol) inanhydrous MeCN (15 ml) at 0°C was added dropwise to a stirred mixture of amidoxime 1-f (6.37 mmol) and Et3N(0.64 ml, 6.37 mmol) in anhydrous MeCN (15 ml). Thereaction mixture was stirred under the same conditions for30 min, then stirred for 1 h at 20°C and poured into cold water (150 ml), the white precipitate that formed was filtered off, washed with H2O, and dried at 80-90°. Theproduct was crystallized from MeOH or EtOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In water at 80℃; for 1h; | General procedure for the preparation of product 5a-5i General procedure: The mixture of amidoximes (1.0 mmol), isothiocyanate (1.0 mmol) and Et3N (1.0 mmol)base in water (2.0 mL) was stirred magnetically at 80 C for the stipulated period. Aftercompletion of the reaction as monitored by TLC, the reaction mixture was cooled toroom temperature, excess water (30 mL) was added and extracted with ethyl acetate(230 mL) and the combined organic layer was washed with brine (30 mL), dried overNa2SO4 and solvent was evaporated under reduced pressure to get crude. Crude waspurified by silica gel column chromatography using hexane and ethylacetate (10:1) aseluent to afford corresponding products 5a-5i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In water at 80℃; for 1h; | General procedure for the preparation of product 5a-5i General procedure: The mixture of amidoximes (1.0 mmol), isothiocyanate (1.0 mmol) and Et3N (1.0 mmol)base in water (2.0 mL) was stirred magnetically at 80 C for the stipulated period. Aftercompletion of the reaction as monitored by TLC, the reaction mixture was cooled toroom temperature, excess water (30 mL) was added and extracted with ethyl acetate(230 mL) and the combined organic layer was washed with brine (30 mL), dried overNa2SO4 and solvent was evaporated under reduced pressure to get crude. Crude waspurified by silica gel column chromatography using hexane and ethylacetate (10:1) aseluent to afford corresponding products 5a-5i |
Tags: 19227-13-5 synthesis path| 19227-13-5 SDS| 19227-13-5 COA| 19227-13-5 purity| 19227-13-5 application| 19227-13-5 NMR| 19227-13-5 COA| 19227-13-5 structure
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