| 88.7% |
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 35℃; for 3.0h; |
In a three-necked flask, <strong>[459-23-4]p-fluorobenzaldehyde oxime</strong> (5 g, 35.9 mmol) was dissolved in N,N-dimethylformamide (100 mL), added in batches to the NCS (4.8 g, 35.9 mmol), and reacted at 35 C. for 3 h.After the reaction was completed, the reaction solution was poured into 200 ml of ethyl acetate, washed with pure water (100 mL×4), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 5.5 g of chloroquinone, with a yield of 88.7%. |
| 76% |
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 0 - 20℃; |
General procedure: general procedure. Each oxime (0.50 g, 4.50 mmol)was dissolved inanhydrous DMF (5 mL) in a round-bottom flask equipped withmagnetic stirrer and cooled at 0 C. N-chlorosuccinimide (NCS)(0.60 g, 4.50 mmol) was slowly added, and the obtained suspensionwas stirred at room temperature. When the reaction wascompleted, Et2O was added and the solution was washed withwater until the removal of DMF. The combined organic extractswere dried over anhydrous Na2SO4, and the solvent was distilled invacuum. |
| 42% |
With N-chloro-succinimide; In acetonitrile; at 20℃; for 19.0h; |
N-chlorosuccinimide (1.30 g, 9.72 mmol) was added to a solution of <strong>[459-23-4]4-fluorobenzaldoxime</strong> in acetonitrile (15 mL), followed by stirring at room temperature for 19 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), whereby 4-fluorobenzhydroxymoyl chloride (649 mg, yield: 42%) was obtained as a white solid. 1H-NMR (400 MHz, CDCl3): delta7.08-7.13 (m, 2H), 7.83-7.87 (m, 3H). 19F-NMR (376 MHz, CDCl3): delta-109 (s, 1F). |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 50℃; for 3.0h; |
Part C; A solution of <strong>[459-23-4]4-fluorobenzaldehyde oxime</strong> (222 mg, 1.60 mmol) dissolved in 3 mL of DMF was treated with JV-chlorosuccinimide (212 mg, 1.60 mmol) and the reaction mixture was heated at 50 C for 3 hours. The reaction mixture was diluted with 25 mL of ethyl acetate and then washed with H2O (4 x 20 mL). The organic portion was washed with brine, dried over Na2SO4, filtered and concentrated to give 4-fluoro-N- hydroxybenzenecarboximidoyl chloride as a white solid. The material was dissolved in 10 mL Of CH2Cl2 and the solution was cooled to 0 C. A solution of (HS)-11-ethynyl- 10,11- dihydro-8H-[l,4]oxazino[4',3':l,2]imidazo[4,5-c]quinoline (190 mg, 0.76 mmol) dissolved in 3 mL Of CH2Cl2 was then added followed by triethylamine (318 muL, 2.29 mmol). The reaction was allowed to warm to ambient temperature overnight. The reaction mixture was concentrated and chromatography (0-2% methanol/CHCl3) gave (1 li?)-l l-[3-(4- fluorophenyl)isoxazol-5-yl]- 10, 11 -dihydro-8H-[l ,4]oxazino[4',3': 1 ,2]imidazo[4,5- c]quinoline as a light-brown solid. |
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With hydrogenchloride; N-chloro-succinimide; In N,N-dimethyl-formamide; at 20 - 35℃; |
A solution of <strong>[459-23-4]4-fluorobenzaldoxime</strong> (1.0 g, 7.19 mmol) in DMF (6 mL) at room temperature was treated with HCl gas, collected from the head space of a bottle of 12M HCl, (5 mL) and N-chlorosuccinimide (0.960 g, 7.19 mmol) such that the reaction temperature was below 35 C., cooled to room temperature, treated with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. |
|
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.0h; |
Part DA solution of <strong>[459-23-4]4-fluorobenzaldehyde oxime</strong> (0.97 g, 7.0 mmol), see International Publication No. WO2006/065280 (Moser et al) Example 11, in DMF (14 mL) was chilled in an ice/water bath. iV-Chlorosuccinimide (0.93 g, 7.0 mmol) was added in a single portion. The ice bath was removed; the solution was stirred at ambient temperature for 2 hours and then partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide about 1.2 g of 4-fluoro-iV- hydroxybenzenecarboximidoyl chloride as a light yellow solid |
|
|
General procedure: Benzaldehyde oxime (467.2 mg, 3.861 mmol) was dissolved in DMF (10.0 mL) at rt in the two-neck round buttom flask attached with a thermometer. A portion of N-chlorosuccinimide (NCS) about one-tenth of the total of 515.6 mg (3.861 mmol) was slowly added under the temperature control of 30-35 C. After 10 min, HCl gas (~ 20 mL) was bubbled into the reaction mixture. The remaining of NCS was added and left to stir for a further 1 h at 30 C. The reaction mixture was quenched with ice/H2O and extracted with diethyl ether (3 x 20 mL). The combined organic extracts were washed with H2O and dried (Na2SO4). The extracts were concentrated under reduced pressure to give a yellow oil (404.7 mg). The crude product was of >90% purity from 1H NMR analysis and was used in the next step without purification. |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 1.0h; |
General procedure: To a solution of an appropriate aryloxime 1a-j (4.0 mmol) in 20 mL of dimethylformamide (DMF), 4.8 mmol (0.64 g) of N-clorosuccinimide (NCS) was added dropwise in 30 minutes. The resulting solution was stirred at room temperature until TLC analysis confirmed the disappearance of the starting oxime. The mixture was diluted with water (20 mL) and ethyl acetate (20 mL). The organic layer was separated, and the aqueous phase was extracted again with AcOEt (20 mL). Drying of the combined organic layers over anhydrous Na2SO4 and solvent removal in vacuo furnished the crude imidoyl chloride which was used in the next step without further purification (3a-j). 4-Pentyn-1-ol (4, 0.4 g, 4.8 mmol) and the imidoyl chloride (3a-j, 4.0 mmol) were suspended in 1:1 mixture of tert-butanol and water (10 mL). To this solution, a mixture of Cu(OAc)2 (40 mg, 0.2 mmol) and sodium ascorbate (120 mg, 0.6 mmol) was added followed by the dropwise addition of an aqueous solution of KHCO3 (18.0 mmol) to it. The contents were allowed to stir at room temperature until TLC analysis indicated the complete consumption of imidoyl chloride. The mixture was then diluted with water (10 mL) and AcOEt (10 mL). The organic layer was separated, and the water phase was extracted with AcOEt (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the solvent evaporated under reduced pressure. The residue was chromatographed over silica gel using cyclohexane:EtOAc as eluant (1:1, v/v), crystallized from chloroform and hexane, which after work-up furnished the desired 3-(3-aryl-isoxazol-5-yl)-propan-1-ol. |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20 - 35℃; for 2.0h; |
To a solution of (E)- and/or (Z)-<strong>[459-23-4]4-fluoro-benzaldehyde oxime</strong> (23.3 g, 167 mmol) (6.9 g, 50 mmol) in DMF (50 mL) was added N-chlorosuccinimide (6.6 g, 50 mmol) portionwise over 1 h, keeping the temperature below 35 C. The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured onto ice- water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (25.9 g, 89%) which was obtained as an off white solid. MS: m/e = 173.0 [M]+. |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 0℃; for 12.0h; |
General procedure: At 0 C, the syn and anti oxime 18-23 (7.0 mmol) was dissolved in dry DMF (30 mL) and the N-chlorosuccinimide (1.03 g, 7.7 mmol) was slowly added. The reaction was stirred for 12 h and the solvent was carefully evaporated under reduced pressure (without heating above 40 C). The residue was solubilized into ethyl acetate (30 mL) and washed five times with water (50 mL). The organic layer was dried over anhydrous MgSO4 and carefully concentrated under vacuum to afford the crude chlorooxime 24-29. Their purities were verified by 1H NMR prior to use the chlorooximes in the next cycloaddition step. |
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With hydrogenchloride; N-chloro-succinimide; In dichloromethane; water; |
General procedure: Representative procedurefor compound 4d. In a round bottom flask, were added 4-methylbenzaldehyde oxime(2d) (2.03 g, 15.00 mmol), N-chlorossuccinimide (2.20 g, 16.50 mmol), dichloromethane(45 mL) and a drop of HClconc, the mixture was stirred for 4 hours to form the oximoylchloride. After the formation of the intermediate the mixture was cooled in ice bath, andto the solution were added 4-tert-butoxystyrene (3a) (2.82 mL, 15.00 mmol) and triethylamine(6.27 mL, 45.00 mmol) dropwise, then the mixture was stirred at room temperaturefor 24 hours. After the reaction time the mixture was washed with 1M HCl (2 × 20 mL)and brine (2 × 20 mL), the organic layer was dried over Na2SO4 and the solvent wasremoved under reduced pressure giving the crude material. The product was purified byrecrystallization in ethanol. |
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With chlorine; In chloroform;Cooling with ice; |
General procedure: p-Chlorobenzaldehyde oxime (2a-i) (39mmol, 6.08 g) wasdissolved in anhydrous chloroform (100mL). After cooling the solution in an ice bath, chlorine gas was passed through the solution until the determination of the 3.20-g weight increase. The solution was refrigerated for one night. Then the solution was evaporated under reduced pressure at 40 C. The formed p-chloro-N-hydroxybenzimidoyl chloride was dissolved in dry benzene (30mL), and to the solution aniline (78mmol, 7.28 g) was added dropwise in dry benzene (20mL) with constant stirring at room temperature for 24 h. After this the mixture was refrigerated for 1 h. The salt precipitated was removed by filtration. The residual solid was subjected to flash column chromatography (eluant:ethyl acetate:petroleum ether). The crude product was crystallized from ethyl acetate:petroleum ether (1:6) mixture to give N-phenyl-p-chlorobenzamidoxime (3d) (5.24 g, 54 %). |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃;Microwave irradiation; |
General procedure: The compounds were synthesised based on procedure reportedin the literature [38]. For the preparation of the imidoyl chloride, N-chlorosuccinimide (0.1 mmol) was slowly added to a solution of analdoxime (0.105 mmol) in DMF (1 mL) and the reaction was stirreduntil the starting material was not visible on the TLC analysis. After,the reaction was diluted with brine (15 mL), extracted with ethylether (3 x10 mL), dried over Na2SO4, concentrated under vacuumand utilized without any purification in the next step. Following,propargylic alcohol (0.105 mmol), copper (II) sulphate (2 mol%),sodium ascorbate (10 mol%), sodium bicarbonate (0.4 mmol) and4mL of H2O:t-BuOH were added to the product obtained in the firstpart, and the reaction was further stirred for 4 h. Next, the reactionwas diluted with brine (15 mL), extracted with ethyl acetate(3 x 10 mL), dried over Na2SO4, concentrated under vacuum andthe crude extract was purified by flash column chromatography onsilica (hexane:ethyl acetate 6:4) yielding the expected product.After purification, they were compared via TLC analysis to therespecting compounds synthesized under microwave irradiation,when this comparison was desired, and characterized by NMR andmass spectrometry. |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 6.0h; |
General procedure: To a mixture of aldehyde derivative (8.0 mmol, 1.0 equiv) and hydroxylamine hydrochloride (8.0 mmol, 1.0 equiv) in THF-H2O (20 mL, 1:1v/v) at 0 C, NaOH (8.0 mmol, 1.0 equiv) was added and the mixture and stirred for 10 min. Upon completion of the reaction, the organic phase was removed under vacuum and H2O (10 mL) was added. The aqueous phase was extracted with EtOAc (3 × 10 mL) and the combined organic phase was washed with brine, dried over Na2SO4, and removed under vacuum to afford the crude product, which was directly used for the next step without purification. The crude product was added into a mixture of NCS (8.4 mmol, 1.05 equiv) in DMF (20 mL) at r.t. and the mixture was stirred for 6 h. Upon completion of the reaction, the organic phase was removed under vacuum and H2O (10 mL) was added. The aqueous phase was extracted with EtOAc (3 × 30 mL) and the combined organic phase was washed with brine, dried over Na2SO4, and removed under vacuum to afford the crude product, which was directly used for the next step without purification. |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 35℃; for 2.0h; |
General procedure: Substituted-benzene formaldehyde oxime (compound 2) (2.0 mmol) was dissolved in dimethylformamide (10.0 mL). Then the N-chlorosuccinimide (2.2 mmol) was added with stirring over a period of 2 hours at 35C. The mixture was extracted with EtOAc (3×10 mL). After washing with water and brine, the solvent was evaporated in vacuums to afford the crude N-hydroxybenzimidoyl chloride derivatives (compound 3). Consecutively, the derivatives and compound 7 (1.0 mmol) were dissolved in tetrahydrofuran (10.0 mL). Then the triethylamine (2.0 mmol) was dropped carefully with ZnCl2 (2.0 mmol) added quickly. The reaction mixture was stirred at 35C in anhydrous under nitrogen atmosphere for 16-20 hours until the starting material disappeared (monitored by TLC with dichloromethane/methanol = 20/1, V/V). The products were purified by chromatography (dichloromethane/methanol = 100:1). The crude was crystallized by EtOAc/petroleum ether to afford the target compound a1-21 and b1-8. |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 35℃; for 3.0h; |
The compound <strong>[459-23-4]4-fluorobenzaldehyde oxime</strong> (1 mmol)Dissolved in 10 mL of DMF,NCS (1.1 mmol) was added,35 C for 3 h.TCL monitoring reaction is complete,Extracted three times with ethyl acetate,Combine organic phase,Washed twice with saturated NaCl,Anhydrous Na2SO4 dried,Spin dry,To obtain the compound 4-chlorobenzaldehyde oxime chloride. |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 1.0h; |
General procedure: To a solution of the oxime (1.00 mmol, 1.0 equiv) in DMF (2.0mL) at r.t. was added N-chlorosuccinimide (1.10 mmol, 1.10equiv) and the mixture was stirred for 60 min. To the reactionmixture was added the alkene in one portion (1.10 mmol, 1.1equiv) followed by a solution of triethylamine (1.00 mmol, 1.00equiv) in DMF (1.0 mL). After complete addition, the reactionmixture was stirred at 23-25 C until complete conversion ofthe in situ formed chlorooxime intermediate (reaction wasmonitored by TLC). After complete conversion, the reaction waspoured into cold water (30.0 mL) and stirred for 10 min. Theaqueous phase was extracted with ethyl acetate (3 × 20.0 mL),the combined organic layers were washed with brine (20.0 mL),dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to yield the crude product which waspurified by flash chromatography. |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; |
General procedure: Benzaldoxime (50 mmol) and N-chlorosuccinimide (50 mmol) were dissolved in 40mL DMF and placed into a 125 mL round-bottom flask and the mixture was stirred at room temperature for 2-4 h. The completion of the reaction was monitored by TLC. Water was added, and the mixture was extracted with ethyl acetate, dried over Na2SO4, and concentrated and purified by flash column chromatography to yield the intermediate 1a-q (92-95% yields). |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; |
General procedure: A solution of DMF dissolved Benzaldoxime (50mmol), and N-Chlorosuccinimide (50mmol) were placed into a 125mL round-bottom flask. After stirring for 2-4hat room temperature, completion of the reaction was monitored by TLC. The organic phase was extracted with ethyl acetate, washed with saturated NaCl solution and dried over anhydrous NaSO4. The solvent was removed from the rotary evaporator, obtaining Hydroxybenzimidoyl Chloride (92-95% yields). |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20℃; for 3.0h;Inert atmosphere; |
General procedure: A solution of arylaldehyde (40 mmol), hydroxylamine hydrochloride (80 mmol, 2 equiv) and sodium hydroxide (80 mmol, 2 equiv) in EtOH (50 mL) was stirred at r.t. for 1 h. The solution was evaporated and the residue dissolved in EtOAc (150 mL). The organic layer was washed with water (3 x 70 mL), dried (Na2SO4), filtered and evaporated to dryness. A portion of the crude arylaldoxime (7 mmol) was then dissolved in DMF (10 mL) and NCS (7.4 mmol, 1.2 equiv) was added in 8-10 portions. The reaction was slightly exothermic and NCS portions were added slowly in order to maintain the temperature at 35- 40oC. The reaction was then stirred for 3 h at r.t. and poured into EtOAc (100 mL). The organic layer was washed with water (3 x 50 mL), dried (Na2SO4), filtered and evaporated to dryness. The hydroximoyl chlorides were used for cycloadditions without further purification. |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20 - 40℃; for 1.0h; |
General procedure: NCS (0.29 g, 2.2 mmol) was added to a stirred solution of the corre-sponding carbaldehyde oxime (22 mmol) in anhydrous DMF (30 mL)at room temperature. The reaction mixture was heated to 35-40 C(to initiate the chlorination), further NCS (2.65 g, 19.9 mmol) wasadded and the mixture was cooled to 30 C. The resulting solutionwas stirred at room temperature for 1 h (TLC monitoring), then cooledto 0 C and dinitromethane sodium salt (6.2 g, 48.4 mmol) was added.The mixture was stirred for an additional 30 min and left to stand in arefrigerator for 36 h. Next, anhydrous AcONa (5.7 g, 70 mmol) wasadded portionwise to the reaction mixture at 0-5 C. The resultingmixture was stirred for 30 min and then AcOH (35 mL) was addeddropwise at 0-5 C. NaNO 2 (7.59 g, 110 mmol) was added portion-wise, the reaction mixture was stirred for 30 min at 0-5 C, then the cooling bath was removed and stirring was continued at room tem-perature for 3 h. The reaction mixture was poured into H2O (300 mL)and stirred for 30 min. The obtained solid was filtered off, washedwith H 2 O and dried in air. |
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With N-chloro-succinimide; In dichloromethane; at 20℃; for 3.0h; |
General procedure: To a mixture of aldehyde derivative (1.0 equiv) and hydroxylamine hydrochloride (1.5 equiv), KOH (1.5 equiv) in ethanol the mixture was stirred for 10 min, at 0 C. Upon completion of the reaction, the solvent was removed under vacuum and H2O (10 mL) was added. The aqueous phase was extracted with EtOAc (3 × 10 mL) and the combined organic phase was washed with brine, dried over Na2SO4, and removed under vacuum to afford the crude product, which was directly used for the next step without purification. The crude product was added into a mixture of NCS (1.05 equiv) in DCM (10 mL) at room temperature and the mixture was stirred for 3 h. Upon completion of the reaction, the organic phase was removed under vacuum and H2O (10 mL) was added. The aqueous phase was extracted with EtOAc (3 × 10 mL) and the combined organic phase was washed with brine, dried over Na2SO4, and removed under vacuum to afford the crude product, which was directly used for the next step without purification. To a mixture of compound (10) (1.0 equiv) and respective N hydroxybenzimidoyl chloride (1.5 equiv) was added EtOAc: H2O (1:1) and KHCO3 (2.0 equiv). The mixture was stirred at room temperature for 6 h. Extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified through silica gel (100-200) column chromatography using 10% ethyl acetate in petroleum ether (v/v) as eluent to obtain the desired products 17-23 (88-91% yields). |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 60℃; for 0.166667h; |
General procedure: To a solution of aromatic aldehyde (10 mmol) in 10 mL of ethanol, 10 mL of an aqueous solution of hydroxylamine hydrochloride (834 mg, 12 mmol) is added, the reaction is stirred for 5 minutes, and then neutralized to pH of 7 by a sodium carbonate solution to precipitate an aromatic aldehyde oxime, which is filtered and dried, and can be used directly for the next reaction. Aromatic aldehyde oxime (1.1 mmol), NCS (161 mg, 1.2 mmol), are added into 10 mL DMF and reacts for 10 minutes at 60 , then 4-alkynyl sinomenine (367 mg, 1 mmol) is added, and Et 3 N in 10 mL DMF is added dropwise in 30 minutes to give 1.3-dipole 7 in situ, the reaction of 7 and 4-alkynyl sinomenine produces sinomenine isoxazole 8. After being concentrated by evaporation in vacuo, 30 mL dichloromethane is added, the dichloromethane is then washed with water (15 mL x 3), dried over anhydrous sodium sulfate, and rotary evaporated to give crude product, purified by column chromatography (CH 2 Cl 2 /CH 3 OH/NH 3 ·H 2 O, 200:10:1-400:10:1, v/v) for characterization. |
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With pyridine; N-chloro-succinimide; at 20 - 40℃; |
General procedure: A drop of pyridine and then NCS (294 mg,2.2 mmol) with stirring were added to a suspension ofoxime 1 (2 mmol) in DCP (5 ml). Dissolution of the NCStook place, followed by precipitation of succinimide. Themixture was stirred at room temperature for 30 min, thenheated to 40 for 3-24 h (TLC control). A solution ofEt3N (455 mg, 4.5 mmol) in DCP (1 ml) was added withvigorous stirring to the mixture at room temperature.Heating of the mixture and precipitation occurred. Thereaction mixture was stirred for 1 h, DCP was distilled offunder reduced pressure, and the target compound wasisolated by flash chromatography on silica gel, eluentCH2Cl2 or CHCl3, Rf 0.6-0.8. |
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With N-chloro-succinimide; In N,N-dimethyl-formamide; at 35℃; for 3.0h; |
Dissolve the compound <strong>[459-23-4]4-fluorobenzaldehyde oxime</strong> (1 mmol) in 10 mL of DMF.Add NCS (1.1 mmol) and stir at 35 C for 3h.After the reaction was monitored by TLC, the reaction was extracted three times with ethyl acetate, and the organic phases were combined.Wash twice with saturated NaCl, dry with anhydrous Na2SO4, spin dry,The compound <strong>[459-23-4]4-fluorobenzaldehyde oxime</strong> chloride is obtained. |
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