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With manganese(IV) oxide In dichloromethane at 20℃; for 12 h;
Step 3: Preparation of 4-bromo-3-methylbenzaldehyde To a solution of (4-bromo-3-methylphenyl)methanol (420 mg, 2.09 mmol) in DCM (6 mL) at rt was added MnO2 (1.82 g, 20.9 mmol). The reaction mixture was stirred for 12 h, filtered and concentrated under reduced pressure to give 4-bromo-3-methyl-benzaldehyde (372 mg; yield 89percent) as an oil.
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 13, p. 3774 - 3789
[2] Tetrahedron Letters, 2007, vol. 48, # 52, p. 9144 - 9147
[3] Patent: US2013/131016, 2013, A1, . Location in patent: Paragraph 0191
[4] Organic and Biomolecular Chemistry, 2011, vol. 9, # 11, p. 4276 - 4286
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 3973 - 4001
[6] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2651 - 2656
[7] Patent: WO2006/18326, 2006, A1, . Location in patent: Page/Page column 44
[8] Organic Letters, 2014, vol. 16, # 9, p. 2318 - 2321
With sodium tetrahydroborate; ethanol In tetrahydrofuran at 20℃; for 4 h; Inert atmosphere
NaBH4 (4.27 g, 2.50 mmol,2.5 eq) was added to a solution of 4-bromo-3-methylbenzaldehyde (9.00 g, 45.21 mmol, 1.0 eq)in THF and EtOH (10:1, 150 mL) under nitrogen atmosphere and the solution was stirred at ambient temperature for 4 h. After complete consumption of starting material, the reaction mixture was diluted with EtOAc and washed with 0.5 N aq HC1 followed by water and brine. The organic extract was then dried over anhydrous sodium sulfate, filtered, and solvents evaporated from the filtrate under reduced pressure to afford (4-bromo-3-methylphenyl)methanol (9.0 g, 100percent) as yellow oil.
Preparation of Intermediate 4-Bromo-3-methyl-benzaldehvde (l-2a):The starting material (4-bromo-3-methyl-benzonitrile, 12.8g, 65.3 mmol) was dissolved in toluene (120 ml_) and dichloromethane (20 mL) and cooled to -600C as a 1.5M diisobutylaluminum hydride in toluene (67 mL, 100 mmol) was added dropwise over 30 minutes keeping the temperature between -60 and -500C. The reaction was allowed to warm slowly to room temperature and stirred for an additional 3 hours. The reaction was quenched by adding ethyl acetate and stirring for 20 minutes before the addition of 1 N aqueous hydrochloric acid at 0°C. The reaction mixture was then allowed to warm slowly to room temperature before extractive workup in the usual manner using ethyl acetate (2 times). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with 5percent ethyl acetate in heptane to yield 5.6 g of the title compound (l-2a).1H NMR (CDCI3): delta 2.47 (s, 3H), 7.54 (dd, 1 H), 7.69-7.72 (m, 2H), 9.94 (s, 1H)
Example II: Preparation of 4-bromo-3-methyl-benzaldehvde; A solution of 4-bromo-3-methyl-benzonitrile (500 mg) in dichloromethane was added at 0°C to a solution of diisobutylaluminium hydride ("DIBAL-H") in hexanes (IM) (2.6 ml). The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was poured on a mixture of ice (10 g) and aqueous hydrobromic acid (6M) (10 ml). The mixture was allowed to warm to ambient temperature and then extracted twice with dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-bromo-3-methyl-benzaldehyde (0.419 g) as a colorless oil. 1H-NMR (400 MHz, CDCl3): 9.95 (s, IH), 7.72 (m, 2H), 7.55 (d, IH), 2.50 (s, 3H) ppm.
Example Il : Preparation of 4-bromo-3-methyl-benzaldehyde; A solution of 4-bromo-3-methyl-benzonitrile (commercially available) (500 mg) in dichloromethane was added at 0°C to a solution of diisobutylaluminium hydride ("DIBAL- H") (2.6.ml) in hexanes (IM). The mixture was stirred at 0°C for 2 hours. The reaction mixture was poured on a mixture of ice (10 g) and aqueous hydrobromic acid (6M) (10 ml). The mixture was allowed to warm to ambient temperature and then extracted twice with dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-bromo-3-methyl-benzaldehyde (0.419 g) as a colorless oil. 1H-NMR (400 MHz, CDCl3): 9.95 (s, IH), 7.72 (m, 2H), 7.55 (d, IH), 2.50 (s, 3H) ppm.
A solution of 4-bromo-3-methyl-benzonitrile (commercially available) (500 mg) in dichloromethane (7.5 ml) was added at 00C to a solution of diisobutylaluminium hydride ("DIBAL-H") (2.6. ml) in hexanes (IM). The reaction mixture was stirred at 00C for 2 hours. The reaction mixture was poured on a mixture of ice (10 g) and aqueous hydrobromic acid (6M) (10 ml). The mixture was allowed to warm to ambient temperature and then extracted twice with dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-bromo-3-methyl-benzaldehyde (0.419 g) as a colorless oil. 1H-NMR (400 MHz, CDCl3): 9.95 (s, IH), 7.72 (m, 2H), 7.55 (d, IH), 2.50 (s, 3H) ppm.
With diisobutylaluminium hydride; In hexane; at -40 - 20℃; for 1.5h;
To a solution of 4-bromo-3-methylbenzonitrile (0.975 g; 5.00 mmol) in anhyd CH2Cl2(7.5 mL) at ?40° C. was added DIBAL-H (7.5 mL of a 1M solution in hexanes; 7.5 mmol), dropwise over 5 min. The mixture was stirred 30 min at ?40° C., removed from the cooling bath and stirred 1 h at rt. The mixture was cooled in an ice bath, and excess hydride was quenched by dropwise addition of MeOH. After stirring 20 min, Rochelle's salt (satd aq. solution) was added, the mixture was stirred at rt overnight, and the layers were separated. The aqueous layer was extracted with CH2Cl2(×2), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid (Note 1). Note 1 The title compound was oxidized rapidly on standing in air to a mixture of benzaldehyde and benzoic acid.
EXAMPLE 13 4-Bromo-3-methyl benzaldehyde. N-4-chlorobenzyl-N-(4-bromo-3-methylbenzoyl)-4-O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1percent-divinylbenzene)-resin (0.2 g, 0.5 mmol/g 0.1 mmol), prepared as in Example 11, is suspended in diethyl ether for 10 minutes and then cooled to 5° C. in an orbital shaker. The suspension is treated with LiAlH3 OMe (0.46 M in diethyl ether, 0.2 mL, 0.092 mmol) and agitated for 30 minutes at this temperature. The reaction mixture is quenched by the addition of aqueous 2 M HCl and vortexed for 30 minutes. Sodium potassium tartrate is added and the mixture is vortexed for a further 10 minutes. Sodium sulfate is added and the mixture is filtered through a plug of silica gel, washing thoroughly with dichloromethane. The filtrate is concentrated to give 4-bromo-3-methyl benzaldelhyde. GC MS: EI Area=99.5percent, m/z 179/199 (Br)[M]+; 1 H NMR (CDCl3) delta 9.94 (1H,s), 7.70 (2H,d), 7.52 (1H,d), 2.45 (3H,s); MS (EI): m/z=199 [M+H]+.
43
[ 78775-11-8 ]
[ 21204-67-1 ]
[ 877064-90-9 ]
Yield
Reaction Conditions
Operation in experiment
In toluene; at 90℃; for 1h;
2.1 g (6.45 mmol, 1.5 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 900 mg of <strong>[78775-11-8]4-bromo-3-methylbenzaldehyde</strong> in 5 ml of toluene. The reaction mixture is heated at 90°C for 1 hour. The solvent is evaporated off and the residual oil is chromatographed on silica gel (8/2 heptane/ethyl acetate). 610 mg of methyl (E)-3-(4-bromo-3-methylphenyl)acrylate are obtained in oil form. Yield = 55percent over steps a, b and c
With hydroxylamine hydrochloride; triethylamine; In ethanol; for 2h;Reflux;
Step 4: Preparation of <strong>[78775-11-8]4-bromo-3-methylbenzaldehyde</strong> oxime To a mixture of <strong>[78775-11-8]4-bromo-3-methyl-benzaldehyde</strong> (372 mg, 1.87 mmol) and hydroxylamine hydrochloride (306.5 mg, 4.41 mmol) in ethanol (5 mL) at rt was added Et3N (0.15 mL). The reaction mixture was heated under reflux for 2 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in EA (10 mL), washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give <strong>[78775-11-8]4-bromo-3-methylbenzaldehyde</strong> oxime (384 mg; yield 96percent) as a white solid.
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 20℃; for 2h;
Example 12: Preparation of 4-bromo-3-methyl-benzaldehvde oxime; To a solution of <strong>[78775-11-8]4-bromo-3-methyl-benzaldehyde</strong> (4.3 g) (Example II) in ethanol (50 ml), were added at ambient temperature hydroxylamine hydrochloride (1.75 g), sodium acetate (2.07 g) and water (15 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and aqueous sodium hydroxide (2M). The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 4:1) to give <strong>[78775-11-8]4-bromo-3-methyl-benzaldehyde</strong> oxime (3.65 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.05 (s, IH), 7.50 (m, 2H), 7.25 (d, IH), 2.40 (s, 3H) ppm.
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 20℃; for 3h;
Example 12: Preparation of <strong>[78775-11-8]4-bromo-3-methyl-benzaldehyde</strong> oxime; To a solution of <strong>[78775-11-8]4-bromo-3-methyl-benzaldehyde</strong> (4.3 g) (Example II) in ethanol (50 ml), were added at ambient temperature hydroxylamine hydrochloride (1.75 g), sodium acetate (2.07 g) and water (15 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and the residue diluted with ethyl acetate and aqueous sodium hydroxide (2M). The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 4:1) to give 4-bromo-3- methyl-benzaldehyde oxime (3.65 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.05 (s, IH), 7.50 (m, 2H), 7.25 (d, IH), 2.40 (s, 3H) ppm.
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 20℃; for 3h;
To a solution of <strong>[78775-11-8]4-bromo-3-methyl-benzaldehyde</strong> (4.3 g) (Example 1.1) in ethanol (50 ml), were added at ambient temperature hydroxylamine hydrochloride (1.75 g), sodium acetate (2.07 g) and water (15 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and aqueous sodium hydroxide (2M). The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 4:1) to give <strong>[78775-11-8]4-bromo-3-methyl-benzaldehyde</strong> oxime (3.65 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.05 (s, IH), 7.50 (m, 2H), 7.25 (d, IH), 2.40 (s, 3H) ppm.
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 20℃; for 0.166667h;
4-Bromo-3-methylbenzaldehyde (25 g) was dissolved in ethanol (285 ml) and water (85 ml) then sodium acetate (11.8 g) and hydroxylamine hydrochloride (10 g) were added. The reaction mixture was stirred at room temperature for lOmin, then ethanol was evaporated in vacuo. The residue was extracted with ethyl acetate, washed with water, then 2N sodium hydroxide, then water and brine. The organic layers were combined, dried over sodium sulfate, filtered and evaporated. The residue (yellow oil) was crystallised from cyclohexane to afford <strong>[78775-11-8]4-bromo-3-methylbenzaldehyde</strong> oxime as white crystals (19.2 g). LCMS (Method A) RT 1.63 min. [M+H]+ 215/216. lH NMR (400 MHz, CDC13) 2.45 (s, 3H), 7.30-7.60 (m, 4H), 8.10 (s, 1H).
19.2 g
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 20℃; for 0.166667h;
4-Bromo-3-methylbenzaldehyde (25 g) was dissolved in ethanol (285 ml) and water (85 ml) then sodium acetate (11.8 g) and hydroxylamine hydrochloride (10 g) were added. The reaction mixture was stirred at room temperature for lOmin, then ethanol was evaporated in vacuo. The residue was extracted with ethyl acetate, washed with water, then 2N sodium hydroxide, then water and brine. The organic layers were combined, dried over sodium sulfate, filtered and evaporated. The residue (yellow oil) was crystallised from cyclohexane to afford <strong>[78775-11-8]4-bromo-3-methylbenzaldehyde</strong> oxime as white crystals (19.2 g). LCMS (Method A) RT 1.63 min. [M+H]+ 215/216. lU NMR (400 MHz, CDC13) 2.45 (s, 3H), 7.30-7.60 (m, 4H), 8.10 (s, 1H).
(E)-N-[(4-bromo-3-methylphenyl)methylidene]hydroxylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 20℃;
Into a 500-mL round-bottom flask were placed water (30 mL), ethanol (150 mL), <strong>[78775-11-8]4-bromo-3-methylbenzaldehyde</strong> (10 g, 50.24 mmol, 1.00 equiv), H2OH.HCl (6 g) and CH3COONa (9 g). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The solids were collected by filtration. This resulted in 10 g (93percent) of (E)-N-[(4-bromo-3- methylphenyl)methylidene]hydroxylamine as a white solid. (ES, m/z): 213 [M+H]+.
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