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[ CAS No. 19227-13-5 ]

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2D
Chemical Structure| 19227-13-5
Chemical Structure| 19227-13-5
Structure of 19227-13-5 *Storage: {[proInfo.prStorage]}

Quality Control of [ 19227-13-5 ]

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Related Doc. of [ 19227-13-5 ]

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Product Details of [ 19227-13-5 ]

CAS No. :19227-13-5MDL No. :MFCD00019952
Formula :C8H10N2OBoiling Point :305.6°C at 760 mmHg
Linear Structure Formula :-InChI Key :N/A
M.W :150.18Pubchem ID :-
Synonyms :

Computed Properties of [ 19227-13-5 ]

TPSA : - H-Bond Acceptor Count : -
XLogP3 : - H-Bond Donor Count : -
SP3 : - Rotatable Bond Count : -

Safety of [ 19227-13-5 ]

Signal Word:WarningClassN/A
Precautionary Statements:P261-P305 P351 P338UN#:N/A
Hazard Statements:H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 19227-13-5 ]

  • Downstream synthetic route of [ 19227-13-5 ]

[ 19227-13-5 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 19227-13-5 ]
  • [ 79-04-9 ]
  • [ 50737-29-6 ]
YieldReaction ConditionsOperation 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%).
  • 2
  • [ 104-85-8 ]
  • [ 19227-13-5 ]
YieldReaction ConditionsOperation 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.

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    Zh. Org. Khim.,
  • 3
  • [ 19227-13-5 ]
  • [ 108-24-7 ]
  • [ 81386-30-3 ]
YieldReaction ConditionsOperation 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)
  • 4
  • [ 19227-13-5 ]
  • (S)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid [ No CAS ]
  • (S)-N-(4-chlorophenyl)-2-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
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.
  • 5
  • [ 108-55-4 ]
  • [ 19227-13-5 ]
  • sodium 4-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl]butanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
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.
  • 6
  • [ 19227-13-5 ]
  • 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
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%).
  • 7
  • [ 19227-13-5 ]
  • [ 94-41-7 ]
  • 4,6-diphenyl-2-p-methylphenylpyrimidine [ No CAS ]
YieldReaction ConditionsOperation 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.
  • 8
  • [ 19227-13-5 ]
  • [ 1124-65-8 ]
  • 4-methyl-N'-{[(2E)-3-(thiophen-2-yl)prop-2-enoyl]oxy}benzenecarboximidamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
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.
  • 9
  • [ 354-32-5 ]
  • [ 19227-13-5 ]
  • 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
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.
  • 10
  • [ 24424-99-5 ]
  • [ 19227-13-5 ]
  • 3-(4-methylphenyl)-1,2,4-oxadiazol-5-ol [ No CAS ]
YieldReaction ConditionsOperation 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.
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