(NE)-N-benzylidenehydroxylamine

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a colorless, homogeneous solution of (E)-benzaldehyde oxime (24.4 g, 201 mmol) in N,N-dimethylformamide (60 mL) at room temperature was added N-chlorosuccinimide (26.9 g, 201 mmol) portion-wise over 30 min. During each addition, the reaction mixture became yellow and then gradually returned to near colorlessness. Additionally, an exotherm was noted with each portion added. (It was extremely important to make sure the reaction initiates after the addition of the first ˜⅕ of the NCS; an ice-bath was readily available.) After the addition was complete, the homogeneous reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 250 mL of water and extracted with ether (3×100 mL). The organic layers were combined, washed with water (2×100 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), and washed with brine (100 mL). The aqueous layers were back extracted with ether (100 mL), and the combined organic layers (400 mL) were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (Z)—N-hydroxybenzimidoyl chloride (30.84 g, 198 mmol, 98% yield) as a fluffy, pale yellow solid. The product had an HPLC ret. time=1.57 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=155.8. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.30-7.64 (m, 3H), 7.73-7.87 (m, 2H), and 12.42 (s, 1H). During each addition added the reaction initiates an ice-bath was readily available ) After the addition extracted with ether (3×100 mL) washed with water (2×100 mL) washed with a 10% aqueous solution of lithium chloride (2×100 mL) washed with brine (100 mL) The aqueous layers were back extracted with ether (100 mL) the combined organic layers (400 mL) were dried over anhydrous sodium sulfate Concentration under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-benzaldehyde oxime (Sigma Aldrich; 3.3 g, 20 mmol) in tert butanol and water (1:1) 80 mL, is treated with chloramine T trihydrate (Sigma Aldrich; 5.9 g, 21 mmol) in small, portions over 5 min. The reaction is then treated with copper sulfate pentahydrate (0.15 g, 0.6 mmol) and copper turnings ˜50 mg and tributylethynylstannane (6.3 g, 20 mmol). The reaction is then adjusted to pH 6 with sodium hydroxide solution and stirred for 6 h. The reaction mixture is treated with dilute ammonium hydroxide solution to remove all copper salts. The product is collected by filtration, redissolved in ethyl acetate and filtered through a short plug of silica gel. The filtrate is concentrated in vacuo to give 3-phenyl-5-(tributylstannyl) isoxazole. to remove all copper salts The product is collected by filtration redissolved in ethyl acetate filtered through a short plug of silica gel The filtrate is concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-benzaldehyde oxime (Sigma Aldrich; 3.3 g, 20 mmol) in tert butanol and water (1:1) 80 mL, is treated with chloramine T trihydrate (Sigma Aldrich; 5.9 g, 21 mmol) in small, portions over 5 min. The reaction is then treated with copper sulfate pentahydrate (0.15 g, 0.6 mmol) and copper turnings ˜50 mg and tributylethynylstannane (6.3 g, 20 mmol). The reaction is then adjusted to pH 6 with sodium hydroxide solution and stirred for 6 h. The reaction mixture is treated with dilute ammonium hydroxide solution to remove all copper salts. The product is collected by filtration, redissolved in ethyl acetate and filtered through a short plug of silica gel. The filtrate is concentrated in vacuo to give 3-phenyl-5-(tributylstannyl) isoxazole. to remove all copper salts The product is collected by filtration redissolved in ethyl acetate filtered through a short plug of silica gel The filtrate is concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-benzaldehyde oxime (Sigma Aldrich; 3.3 g, 20 mmol) in tert butanol and water (1:1) 80 mL, is treated with chloramine T trihydrate (Sigma Aldrich; 5.9 g, 21 mmol) in small, portions over 5 min. The reaction is then treated with copper sulfate pentahydrate (0.15 g, 0.6 mmol) and copper turnings ˜50 mg and tributylethynylstannane (6.3 g, 20 mmol). The reaction is then adjusted to pH 6 with sodium hydroxide solution and stirred for 6 h. The reaction mixture is treated with dilute ammonium hydroxide solution to remove all copper salts. The product is collected by filtration, redissolved in ethyl acetate and filtered through a short plug of silica gel. The filtrate is concentrated in vacuo to give 3-phenyl-5-(tributylstannyl) isoxazole. to remove all copper salts The product is collected by filtration redissolved in ethyl acetate filtered through a short plug of silica gel The filtrate is concentrated in vacuo

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of NaH (60% dispersion in mineral oil (17 mg, 423 μmol)) in dioxane (2.5 mL) was treated with a solution of (E)-benzaldehyde oxime (51 mg, 423 μmol) in DMF (1.5 mL). The reaction was stirred at 23° C. under nitrogen. After 30 minutes, the reaction was cooled to 0° C. and then a solution of 1-tert-butyl ethyl 4-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)piperidine-1,4-dicarboxylate (157 mg, 338 μmol) in DMF (3.5 mL) was added in a dropwise fashion over 10 minutes. After 1 hour, the reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO3 solution (75 mL), water (75 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 1-8% MeOH/DCM), affording the cyclized product. The cyclized product was mixed with glycine methyl ester hydrochloride (28 mg, 220 μmol) and DIPEA (48 μL, 275 μmol) in 1,4-dioxane (4 mL) and heated to 95° C. in a sealed vessel. After 18 hours, the reaction was cooled to 23° C., diluted with EtOAc (75 mL) and washed with saturated NaHCO3 solution (50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 28-100% EtOAc/hexane) affording the title compound in 40 mg. MS m/e=501.2 (M+Na)+. the reaction was cooled to 0° C. After 1 hour washed with saturated NaHCO3 solution (75 mL), water (75 mL) and brine (75 mL) dried over MgSO4 concentrated in vacuo purified by silica gel chromatography (eluant: 1-8% MeOH/DCM) affording the cyclized product heated to 95° C. in a sealed vessel After 18 hours the reaction was cooled to 23° C. washed with saturated NaHCO3 solution (50 mL) and brine (50 mL) dried over MgSO4 concentrated in vacuo purified by silica gel chromatography (eluant: 28-100% EtOAc/hexane)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (E)-benzaldehyde oxime (234 mg, 1.93 mmol) in dry DMF (9 mL) was added to a suspension of NaH (46 mg, 1.93 mmol) in dioxane (9 mL) at room temperature. The mixture was stirred for 30 minutes and then cooled to 0° C. A solution of ethyl 3-(2-chloro-6-(1-ethoxy-2-methyl-1-oxopropan-2-yl)phenyl)propiolate (520 mg, 1.61 mmol) in dry DMF (9 mL) was added, and the mixture was stirred at 0° C. for 3 hours and then at room temperature for 1 hour. The mixture was quenched with water and then washed with EtOAc (2×). The aqueous layer was made acidic with 10% HCl and then extracted with EtOAc (2×). The extracts were dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography to give 210 mg of ethyl 5-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate as a colorless oil. MS m/e=295 (M+H)+. the mixture was stirred at 0° C. for 3 hours at room temperature for 1 hour The mixture was quenched with water washed with EtOAc (2×) extracted with EtOAc (2×) The extracts were dried over anhydrous MgSO4 concentrated under vacuum The residue was purified by flash chromatography

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of NaH (60% dispersion in mineral oil (0.39 mL, 9.3 mmol)) in 40 mL dioxane at room temperature, was treated with a mixture of (E)-benzaldehyde oxime (1.0 g, 8.6 mmol) in 40 mL DMF. The resulting mixture was stirred for 30 minutes. The mixture was then cooled to 0° C. and treated with a mixture of ethyl 4′-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)-5,5-dimethyl-spiro[1,3-dioxane-2,1′-cyclohexane]-4′-carboxylate (3.6 g, 7.8 mmol) in 30 mL DMF. The resulting mixture was stirred for 1 hour. The mixture was then carefully quenched with 10 mL H2O and brought to a pH of 5 by addition of 10% HCl. The mixture was extracted with ethyl ether (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 20-30% EtOAc to give 2.2 g of the product as a pale yellow solid. MS (m/z)=435 (M+H)+. The resulting mixture was stirred for 1 hour The mixture was then carefully quenched with 10 mL H2O brought to a pH of 5 by addition of 10% HCl The mixture was extracted with ethyl ether (3×50 mL) The combined organic layers were washed with brine (20 mL) dried over anhydrous Na2SO4 concentrated in vacuo purified by column chromatography eluting with 20-30% EtOAc

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of NaH (60% dispersion in mineral oil (36 mg, 895 μmol)) in dioxane (5 mL) in an oven-dried round-bottomed flask was treated with a solution of (E)-benzaldehyde oxime (108 mg, 895 μmol) in DMF (4 mL) in a dropwise fashion. The reaction was stirred at 23° C. under nitrogen. After 30 minutes, the reaction was cooled to 0° C., and was then treated with a solution of ethyl 1-benzyl-4-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)piperidine-4-carboxylate (325 mg, 716 mmol) in DMF (4 mL) which was added in a dropwise fashion over 10 minutes. After 1 hour, the solution was diluted with EtOAc (150 mL) and washed with a saturated NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 2-10% MeOH/DCM), affording the cyclized product, a solution of which (160 mg, 376 mmol) in 1,4-dioxane (7 mL) was treated with glycine tert-butyl ester hydrochloride (94.5 mg, 564 μmol) and DIPEA (131 μL, 751 μmol). The reaction was heated to 120° C. After 19 hours, the reaction was cooled to 23° C., diluted with EtOAc (50 mL) and washed with a saturated NaHCO3 solution (50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0-5% MeOH/EtOAc+1% TEA), affording 120 mg (62%, 2 steps) of 1,1-dimethylethyl N-((6-chloro-4-hydroxy-2-oxo-1′-(phenylmethyl)-4H-spiro[naphthalene-1,4′-piperidin]-3-yl)carbonyl)glycinate. MS m/e=512.2 (M+H)+. the reaction was cooled to 0° C. was added in a dropwise fashion over 10 minutes After 1 hour washed with a saturated NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL) dried over MgSO4 concentrated in vacuo purified by silica gel chromatography (eluant: 2-10% MeOH/DCM) affording the cyclized product The reaction was heated to 120° C After 19 hours the reaction was cooled to 23° C. washed with a saturated NaHCO3 solution (50 mL) and brine (50 mL) dried over MgSO4 concentrated in vacuo purified by silica gel chromatography (eluant: 0-5% MeOH/EtOAc+1% TEA)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: After dissolving (E)-benzaldehyde oxime (3.0 g, 25 mmol) in CH2Cl2 (30 ml), N-chlorosuccinimide (3.4 g, 25 mmol) was slowly added at 0° C. After stirring reaction solution for 2 hours, the reaction was completed by adding water (20 ml), and the reaction solution was extracted with dichloromethane. A pure compound of (E)-1-chloro-benzaldehyde oxime (3.30 g, 85%) was obtained by separating the residue with silica gel column chromatography. After dissolving the (E)- and (Z)-oxime mixtures (1.5 g, 9.64 mmol) in CH2Cl2 (30 ml), benzoylchloride (1.45 ml, 12.53 mmol) was slowly added at 0° C. under the presence of triethylamine (1.75 ml, 12.53 mmol). After stirring reaction solution for 1 hour, the reaction was quenched by 1 N hydrochloric acid, and the reaction solution was extracted with dichloromethane. A pure compound of (E)-1-chloro-benzaldehyde O-benzoyloxime (15) (1.9 g, 76%) was obtained by separating the residue with silica gel column chromatography. was slowly added at 0° C reaction solution for 2 hours the reaction solution was extracted with dichloromethane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: After dissolving (E)-benzaldehyde oxime (3.0 g, 25 mmol) in CH2Cl2 (30 ml), N-chlorosuccinimide (3.4 g, 25 mmol) was slowly added at 0° C. After stirring reaction solution for 2 hours, the reaction was completed by adding water (20 ml), and the reaction solution was extracted with dichloromethane. A pure compound of (E)-1-chloro-benzaldehyde oxime (3.30 g, 85%) was obtained by separating the residue with silica gel column chromatography. After dissolving the (E)- and (Z)-oxime mixtures (1.5 g, 9.64 mmol) in CH2Cl2 (30 ml), benzoylchloride (1.45 ml, 12.53 mmol) was slowly added at 0° C. under the presence of triethylamine (1.75 ml, 12.53 mmol). After stirring reaction solution for 1 hour, the reaction was quenched by 1 N hydrochloric acid, and the reaction solution was extracted with dichloromethane. A pure compound of (E)-1-chloro-benzaldehyde O-benzoyloxime (15) (1.9 g, 76%) was obtained by separating the residue with silica gel column chromatography. was slowly added at 0° C reaction solution for 2 hours the reaction solution was extracted with dichloromethane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a colorless, homogeneous solution of (E)-benzaldehyde oxime (24.4 g, 201 mmol) in N,N-dimethylformamide (60 mL) at room temperature was added N-chlorosuccinimide (26.9 g, 201 mmol) portion-wise over 30 min. During each addition, the reaction mixture became yellow and then gradually returned to near colorlessness. Additionally, an exotherm was noted with each portion added. (It is extremely important to make sure the reaction initiates after the addition of the first ˜⅕ of the NCS; an ice-bath was readily available.). After the addition was complete, the homogeneous reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 250 mL of water and extracted with ether (3×100 mL). The organic layers were combined, washed with water (2×100 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), and washed with brine (100 mL). The aqueous layers were back extracted with ether (100 mL), and the combined organic layers (400 mL) were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (Z)-N-hydroxybenzimidoyl chloride (30.84 g, 198 mmol, 98% yield) as a fluffy, pale yellow solid. The product had an HPLC ret. time=1.57 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=155.8. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.30-7.64 (m, 3H), 7.73-7.87 (m, 2H), and 12.42 (s, 1H). During each addition added the reaction initiates an ice-bath was readily available After the addition extracted with ether (3×100 mL) washed with water (2×100 mL) washed with a 10% aqueous solution of lithium chloride (2×100 mL) washed with brine (100 mL) The aqueous layers were back extracted with ether (100 mL) the combined organic layers (400 mL) were dried over anhydrous sodium sulfate Concentration under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (Z)-tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (330 mg, 1.56 mmol), (E)-benzaldehyde oxime (286 mg, 2.36 mmol) and DBU (0.007 mL, 0.05 mmol) were combined in MeCN (0.5 mL) and the mixture was stirred at room temperature for 48 hr. The solvent was removed under reduced pressure and the residue purified via preparative HPLC to give tert-butyl 5-(benzylideneaminooxy)-3-oxoazepane-1-carboxylate as a brown oil (127 mg). The solvent was removed under reduced pressure the residue purified via preparative HPLC