| 90% |
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol at 90℃; for 3h; |
21.1 Step 1:
4-bromobenzonitrile (3 g, 16.48 mmol), hydroxylamine hydrochloride (1.49 g, 21.4 mmol) and NaHCO3 (2.08 g, 25 mmol) were dissolved in ethanol (70 mL), and the solution was warmed to 90° C., followed by reaction for 3 hours. After completion of the reaction was confirmed by TLC, extraction was carried out with water (100 mL) and ethyl acetate (250 mL). The organic layer was washed with brine and distilled under reduced pressure. The resulting solids were washed with hexane, filtered and dried under vacuum to afford the title compound 4-bromo-N'-hydroxybenzimidamide (16a). Yield: 90%.MS (ESI+) m/z 215.1 (M+1) |
| 90% |
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol; water monomer for 3h; Reflux; |
N-Hydroxy-4-methylbenzimidamide(44b).
General procedure: 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. |
| 90% |
With ethanol; hydroxylamine; Sodium hydrogenocarbonate at 90℃; for 3h; |
21.1
Step 1: Preparation of 4-bromo-Nr-hydroxybenzimidamide (16a)4-bromobenzonitrile (3 g, 16.48 mmol), hydroxylamine hydrochloride (1.49 g, 21.4 mmol) and NaHCO3 (2.08 g, 25 mmol) were dissolved in ethanol (70 mL), and the solution was warmed to 90 °C, followed by reaction for 3 hours. After completion of the reaction was confirmed by TLC, extraction was carried out with water (100 mL) and ethyl acetate (250 mL). The organic layer was washed with brine and distilled under reduced pressure. The resulting solids were washed with hexane, filtered and dried under vacuum to afford the title compound 4-bromo-N'-hydroxybenzimidamide (16a). Yield: 90%. MS(ESI+) m/z 215.1 (M+1) |
| 90% |
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol at 78℃; for 6h; |
|
| 87% |
With hydroxyamino hydrochloride In ethanol; water monomer Reflux; |
|
| 79% |
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol; water monomer at 25℃; for 70h; |
|
| 72.95% |
With hydroxyamino hydrochloride; potassium carbonate In ethanol for 29h; Reflux; |
2.1.2. General Method for the Synthesis of methyl/arylamidoximes (2a-f)
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. |
| 67.8% |
With hydroxyamino hydrochloride; potassium carbonate In ethanol at 20℃; for 12.5h; Reflux; |
4.1.1. Synthesis of the compound 2 series.
General procedure: Hydroxylamine hydrochloride (200 mmol) and K2CO3(200 mmol) were dissolved in 200 mL of alcohol and stirred for30 min at room temperature. The corresponding nitriles (75 mmol)1 were added and the reaction mixture was heated to reflux for12 h. After filtration of inorganic salts, the solvent was evaporatedunder reduced pressure. The products 2 were purified by columnchromatography (petroleum ether/acetone, 2:1, v/v). |
|
With ethanol; hydroxylamine |
|
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With hydroxylamine; acetic acid at 100℃; for 0.0166667h; microwave irradiation; |
|
|
With hydroxyamino hydrochloride In dimethyl sulfoxide at 0 - 20℃; |
2 Laboratory Example 2
Hydroxylamine hydrochloride was suspended in anhydrous dimethylsulfoxide (DMSO) and the mixture was cooled in an ice bath. Potassium tert-butoxide (KOBut) was added in a portionwise fashion under a nitrogen atmosphere and the solution was stirred at room temperature for one hour. Then, p-bromobenzonitrile was added at once and the reaction mixture was stirred overnight at room temperature. It was poured over ice-water, the product was filtered and the p-bromobenzamidoxime was recrystallized from ethanol. |
|
With hydroxyamino hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 150℃; for 0.2h; |
|
|
With potassium fluoride; hydroxyamino hydrochloride at 100℃; for 0.0833333h; Microwave irradiation; Neat (no solvent); |
|
|
With hydroxyamino hydrochloride; triethylamine In ethanol for 3h; Heating / reflux; |
44
Description 44 4-Bromo-N-hydroxy-benzenecarboximidamide (D44); 4-Bromophenylcarbonitrile (10.2g), hydroxylamine hydrochloride (7.8g) and triethylamine (11.3g) were dissolved in EtOH (250ml) and the reaction mixture was heated at reflux for 3h, after which it was evaporated to form a white precipitate of the desired amidoxime, which was filtered and washed with water (25ml). The filtrate was extracted into EtOAc (2χ25ml), and the combined organic extracts were dried (Na2SO4) and evaporated to give a second crop of the title compound (D44) (combined yield = 11.1g). LCMS electrospray (+ve) 215 and 217 (MH+). |
|
With hydroxyamino hydrochloride; N-ethyl-N,N-diisopropylamine In ethanol at 20 - 90℃; for 5h; |
12 Preparation of 4-bromo-N'-hydroxybenzimidamide (15)
Example 12 Preparation of 4-bromo-N'-hydroxybenzimidamide (15) To a solution of 4-bromobenzonitrile (5.0 g, 27.5 mmol) in ethanol (42 ml) at room temperature, hydroxylamine hydrochloride (1.91 g, 27.5 mmol) and DIPEA (4.8 ml, 27.5 mmol) were added. The reaction mixture was stirred at 90° C. for 5 hours. After cooled to room temperature, the resulting mixture was concentrated to yield a colorless viscous liquid. The liquid was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and then concentrated to give a crude compound, which was washed with n-hexane to yield product 15 as a white solid (5.0 g). |
|
With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol; water monomer at 20℃; |
General procedure for the preparation of amidoximes 1
General procedure: To a solution of 0.01 mol of nitrile in 200 mL of ethanol was added a solution of 0.695 g (0.01 mol) of hydroxylamine hydrochloride in 10 mL of water, followed by the further addition of 0.420 g (0.005 mol) of sodium carbonate in 10 mL of water. The reaction mixture was stirred overnight at rt. The mixture was then concentrated to small volume under vacuum, diluted with cold water, and placed in refrigerator overnight. The precipitate that formed was recovered and recrystallized from ethanol. All amidoximes were known and characterized by comparison of their physical data with those prepared in accordance with literature procedures.1 |
|
With hydroxylamine |
|
|
With hydroxyamino hydrochloride; sodium hydroxide In ethanol for 12h; Reflux; |
General Procedure for Synthesis of Oxadiazole Compounds
General procedure: (1) Nitrile compound (10.0 mmol), Hydroxyl amine hydrochloride (11.0 mmol, 754.0 mg), NaOH (11.0 mmol, 440.0 mg) and EtOH (20.0 mL) were added to a 50.0 mL RBF. The resulting mixture was stirred reflux ov ernight. After the reaction complete (Monitored by TLC), ethanol was removed under vacuum and the residue was purified by a silica-gel chromatography to give a white solid amidoxime product. |
|
With hydroxyamino hydrochloride; anhydrous sodium carbonate In methanol; water monomer for 4h; Reflux; |
|
|
With hydroxyamino hydrochloride; triethylamine In ethanol at 70℃; for 48h; Inert atmosphere; |
1 4.3.1
N'-Hydroxybenzimidamide (22)
General procedure: Triethylamine (42 mL, 0.3 mol) was added to a solution of benzonitrile (21, 10.3 g, 0.1 mol), hydroxylamine hydrochloride (20.9 g, 0.3 mol) and ethanol (150 mL) and stirred for 12 h at 75 °C. The reaction mixture was cooled to room temperature and evaporated to dryness, extracted with DCM (300 mL)/water (100 mL). The organic layer dried with MgSO4, filtered and evaporated to dryness yielding the desired product 22 as a primrose yellow liquid (10.6 g, yield 78%). 1H NMR (300 MHz, DMSO-d6): δ = 9.59 (s, 1H), 7.62-7.67 (m, 2H), 7.32-7.37 (m, 3H), 5.77 (s, 2H); LC/MS (ESI): m/z 137 [M + H]+. |
|
With hydroxylamine In ethanol; water monomer for 1h; Reflux; |
General procedure for Synthesis of Amidoximes (7a-m).
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 hydroxyamino hydrochloride; sodium hydroxide In water monomer for 3h; |
|
|
With hydroxyamino hydrochloride; sodium hydroxide In ethanol Reflux; |
|
|
With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol; water monomer at 20℃; |
Amidoximes 1; General Procedure
General procedure: The amidoximes were prepared according to our previous report. 16h To a solution of the appropriate nitrile (0.01 mol) in EtOH (200 mL)was added a solution of hydroxylamine hydrochloride (0.695 g, 0.01mol) in H2O (10 mL), followed by the addition of Na2CO3 (0.420 g, 0.005 mol) in H2O (10 mL). The reaction was stirred overnight at r.t. and then concentrated to a small volume under vacuum, diluted withcold H2O, and placed in a refrigerator overnight. The precipitate that formed was recovered and recrystallized from EtOH. All the prepared amidoximes are known and were characterized by comparison of their physical data with those prepared in accordance with literature procedures. |
|
With hydroxyamino hydrochloride; triethylamine In <i>tert</i>-butyl alcohol at 80℃; for 12h; |
|
|
With hydroxylamine for 4h; Reflux; |
|
|
With hydroxylamine In ethanol; water monomer for 3h; Reflux; Inert atmosphere; |
|
|
With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol Reflux; |
5-(tert-butyl)-3-phenyl-1,2,4-oxadiazole (1a)
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%). |
|
With hydroxylamine In ethanol at 20℃; Sonication; |
General procedure for synthesis of amidoximes under ultrasonic irradiation 2a-i
General procedure: The mixture of nitrile 1 (1 mmol) and hydroxylamine solution 50% (2 mmol) in ethanol (15 mL) was irradiated with ultrasound for 20-50 min. The progress of the reaction was monitored by TLC. After completion, the mixture was diluted with water (10 mL) and extracted with diethyl ether (2 × 10 mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated to afford the pure amidoxime. |
|
With hydroxyamino hydrochloride; potassium hydroxide In methanol at 60℃; |
Step 1: Preparation of amidoxime intemediates 22a-o
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 0°C and stirred for ~30 min (slowly warming from 0°C 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 60°C 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. |
|
With hydroxylamine In ethanol; water monomer Reflux; |
|
|
With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol Sonication; |
|
|
With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol at 80℃; |
|
|
With hydroxyamino hydrochloride; anhydrous Sodium acetate In ethanol; water monomer at 50 - 60℃; for 8h; |
General procedure for Synthesis of amidoxime derivatives(1a to 1p)
General procedure: 0.01mol nitrile dissolved in 10 ml ethanol. After that, 0.011 mol hydroxylamine hydrochloride, 10 ml water and 1.23g sodium acetate was added as followed, stirred in room temperature for 0.5 h then refluxed in 50-60 for 8 h. The ethanol was mostly evaporated in vacuum and then the aqueous residue was extracted with CH2Cl2 three times. The combined organic layer was dried over MgSO4 and evaporated to dryness to afford the desired product. |
|
With hydroxylamine In ethanol; water monomer for 3h; Reflux; |
|
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With hydroxyamino hydrochloride; sodium hydroxide In ethanol for 2h; Reflux; |
|
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With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol; water monomer at 20℃; |
|
|
With hydroxylamine In acetonitrile for 3h; Reflux; |
|
|
With hydroxylamine |
|
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With hydroxyamino hydrochloride; N-ethyl-N,N-diisopropylamine In ethanol for 4h; Reflux; |
|
|
With hydroxyamino hydrochloride; Sodium hydrogenocarbonate In ethanol; water monomer at 20℃; |
|
|
With hydroxyamino hydrochloride; triethylamine In ethanol at 80℃; |
General procedure for the preparation of benzamidoxime derivatives
General procedure: The mixture of benzonitrile(1.0 mmol), Et3N (2.0 mmol) and NH2OHHCl (1.0 mmol)was heated in solvent ethanol (2 mL) at 80 C for the stipulated period. After completionof the reaction as monitored by TLC, the reaction mixture was added to ice waterand the product was filtered off, washed with water (22 ml) and dried to afford corresponding benzamidoxime derivatives |
|
With hydroxyamino hydrochloride; potassium hydroxide In methanol at 20℃; Alkaline conditions; |
|
|
With hydroxylamine In ethanol; water monomer Reflux; |
3.2.2. General Procedure for Synthesis of Amidoximes (7a-k)
General procedure: To a stirred solution of nitrile (1.0 mmol.) in ethanol (10 vol), Hydroxylamine (1.05 mmol.) (50% aqueous solution) was added and refluxed. After completion of the reaction, as indicated by TLC, the reaction mixture was concentrated to get the corresponding amidoxime. |
|
With hydroxylamine In ethanol; water monomer Reflux; |
3.2.2. General Procedure for Synthesis of Amidoximes (7a-k)
General procedure: To a stirred solution of nitrile (1.0 mmol.) in ethanol (10 vol), Hydroxylamine (1.05 mmol.) (50% aqueous solution) was added and refluxed. After completion of the reaction, as indicated by TLC, the reaction mixture was concentrated to get the corresponding amidoxime. |
|
With hydroxyamino hydrochloride; anhydrous sodium carbonate In ethanol at 80℃; |
|
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