5-Nitroguaiacol

Yellow to light brown powder

2-Methoxy-5-nitrophenol is a member of 3-nitrophenols.

To a suspension of 2-methoxy-5-nitrophenol (525g, 3.104 mol) and potassium carbonate (643. 5g, 4.66 mol) in [DIMETHYLFOLMAMIDE] (1 L), under N2 protection, was added cyclopentyl bromide (499.2 [ML, ] 4.66 mol). The suspension was heated to [100C] for [6H.] Potassium carbonate (85.8g, 0.62 mol) and cyclopentyl bromide (50 [ML, ] 0.46 mol) were added. The suspension was heated to [100C] for 4h. TLC indicated the reaction was complete (9: 1 DCM: MeOH). The reaction mixture was cooled to room temperature and diluted with water (3L) and ether (3L). The layers were separated and the aqueous layer was [RE-EXTRACTED] with ether (2L). The combined organic layers were washed with 1N [NAOH] (2L), water [(2L), ] and brine (2L). The organic layer was dried over sodium sulfate, filtered, and evaporated. The resulting solid was azeotrope with toluene (2 x 300 mL) to obtain 736.7g (99.6% yield) as a yellow solid.To a solution of the commercially available reagent 2-methoxy-5-nitrophenol (19.4g, 111 mmol) in anhydrous CH3CN (300 mL)was added bromocyclopentane (20.34 g, 140 mmol), K2003 (30 g, 222 mmol), the reaction mixture was stirred at 90 00 overnight. The mixture was diluted with EA and washed with brine, dried over anhydrous Na2SO4 and concentrated togive the crude product which was purified by column chromatography to give I-71a (20 g, 76.9% yield) as a yellow solid. ESI-M (Mi-i): 238 calc. for C12H15N04: 237.1.1-Cyclopentyloxy-2-methoxy-5-nitrobenzene To a suspension of 2-methoxy-5-nitrophenol (525g, 3.104 mol) and potassium carbonate (643.5 g, 4.66 mol) in dimethylformamide (1 L), under N2 protection, was added cyclopentyl bromide (499.2 mL, 4.66 mol). The suspension was heated to 100 C. for 6 h. Potassium carbonate (85.8 g, 0.62 mol) and cyclopentyl bromide (50 mL, 0.46 mol) were added. The suspension was heated to 100 C. for 4 h. TLC indicated the reaction was complete (9:1 DCM:MeOH). The reaction mixture was cooled to room temperature and diluted with water (3L) and ether (3L). The layers were separated and the aqueous layer was re-extracted with ether (2L). The combined organic layers were washed with 1N NaOH (2L), water (2L), and brine (2L). The organic layer was dried over sodium sulfate, filtered, and evaporated. The resulting solid was azeotroped with toluene (2*300 mL) to obtain 736.7 g (99.6% yield) as a yellow solid. The following compounds were prepared in a similar manner as described above:(1) Synthesis of 3-cyclopentyloxy-4-methoxynitrobenzene 10.00 g (59 mmole) of 2-methoxy-5-nitrophenol, 11.01 g (74 mmole) of bromocyclopentane, 10.21 g (74 mmole) of potassium carbonate, and 0.98 g of potassium iodide were added in 50 ml of N, N-dimethylformamide and the mixture was stirred for one night at room temperature. This solution was diluted with 200 ml of methylene chloride and washed with water. The organic solution was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, to obtain a residue as a yellow solid. This residue was purified by flash chromatography (SiO2: eluted by gradient of range from 40% ethyl acetate/hexane to 45% ethyl acetate/hexane). The solvent was removed and the residue dried in vacuo to obtain 3-cyclopentyloxy-4-methoxynitrobenzene 12.52 g (yield 89.3%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) delta 1.64-1.68 (2H, m), 1.83-1.92 (4H, m), 1.99-2.05 (2H, m), 3.95 (3H, s), 4.85 (1H, m), 6.89 (1H, d, J=8.79 Hz), 7.74 (1H, d, J=2.44 Hz), 7.88 (1H, dd, J=8.79, 2.44 Hz)Step 1: preparation of 2-ethoxy-1-methoxy-4-nitro-benzene Method 2: -5-nitrophenol (244 g, S .44 mol) is placed in a flask (5 L) under nitrogen at rt. Toluene (2.0 L) is added, followed by benzyl bromide (258.6 g, 1.51 moles). TBAB ( 12.3 g) and NaOH (20% in water, 1.0 L) to give a red suspension. The reaction mixture is slow ly heated to 50-55 0C. After 1 h, the mixture converts from suspension to a two phase solution. The reaction is complete in 3 h. The reaction mixture is cooled to 25 0C, and the two phases are separated. The organic phase is washed once with NaOH (2.5 N, 300 mL) and then evaporated directly to give 372.5 g ( 100%) of the title compound as a j ellow solid.[01021 LCMS (Standard Method): 2.81 min, 260 (M+H/ . 1H NMR (300 MHz. CDCh) delta 7.87 (dd, J = 2.5, 8.8 I Iz, 1 H), 7.64 (d, J = 2.5 Hz, I H), 7.48-7.34 (m, 5H), 6.92 (d. J = 9.1 Hz. I H), 5.20 (s. 2H). 3.98 (s. 3H).Under the room temperature condition, the 2 - methoxy -5 - nitro phenol (5g, 29.6mmol) dissolved in 60 ml N, N - dimethyl formamide (DMF), magnetic stirring, adding anhydrous K2CO3(6.1g, 44 . 2mmol). Then in the system slowly adding bromination animal pen (5.56g, 32 . 5mmol), raising the temperature to 40 C, the reaction overnight, TLC monitoring (petroleum ether: acetone=20:5, Rf=0.4). Most of the DMF removed by reduced pressure distillation, under the stirring condition, poured into ice water in the remaining system, a large number of solids are separated out. Filtering, the filter cake is washed with alkali solution, until the filtrate is colorless, drying filter cake, shall be red solid, yield: 99%.The 10.0g 2-methoxy-5-nitrophenol and 12.2g of anhydrous potassium carbonate was added in 250ml three-neck flask, then add 150ml N, N- dimethylformamide, was slowly added dropwise under magnetic stirring. 11.1g benzyl bromide, about ten minutes after the dripping, the system was heated to 40 C overnight reaction, spin off part of the solvent under reduced pressure, poured into ice water, large amount of solid precipitation, filtration, the filter cake washed with water until the filtrate with a base not yellow So far, dried to give 2-benzyloxy-1-methoxy-4-nitrobenzene 15.1g, 98% yield.To a solution of 2-methoxy-5-nitrophenoI (5.0 g, 29.6 mmol) in anhydrous DMF (60 ml) was added K2CO3 (4.49 g, 32.5 mmol) and benzyl bromide (3.87 ml, 32.5 mmol). The mixture was stirred at ambient temperature under argon atmosphere for 18 hours. The reaction mixture was poured into water (100 ml) and extracted with DCM (3x100 ml). The combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography (2:8 EtOAc:Heptane) to provide the title compound as a yellow solid (7.46 g, 97 % yield).1H NMR (300 MHz, DMSO-d6), delta: 7.93 (1H, dd, J=2.6, 9.3 Hz), 7.85 (1 H, d, J=2.6 Hz), 7.5- 7.3 (5H, m), 7.2 (1H, d, J=9.3 Hz), 5.22 (2H, s), 3.91 (1H, s).A) 1-Benzyloxy-2-methoxy-5-nitrobenzene; Potassium carbonate (1.65 gm; 12 mmol) was added to a solution of 2- methoxy-5-nitro phenol (1.69 g; 10 mmol) and benzyl bromide (1.71 gm; 10 mmol) in acetone (60 ml). The reaction mixture was refluxed for l2hours. The solvent was . removed under reduced pressure and the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was separated, washed with water (2 x 50 ml), dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 2.5 g of l-Benzyloxy-2-methoxy-5-nitrobenzene (Yield = 96.5 %) 'H NMR CDC13 7.95 (1H, d, J 8Hz) 7.81 (1H, s) 7.3-7.5 (5H, m) 6.92 (1H, d, J 8Hz) 5.15 (2H, s) 3.95 (3H, s).A mixture of 2-methoxy-5-nitrophenol 1 (20g, 118mmol), benzyl bromide (177mmol) and K2CO3 (355mmol) in DMF (200mL) was stirred at 90C for 5h. The reaction was cooled to room temperature and poured into a mixture of ice and water (1000mL). The solid was collected by filtration, washed with water and dried in vacuo to give the title compound. 2 as a white solid (28.8g, 94%). m.p. 93-94C (91-92C, ref [26]); 1H NMR (400MHz, DMSO-d6) delta 7.91 (dd, J=8.8, 2.6Hz, 1H, Ar-H), 7.83 (d, J=2.6Hz, 1H, Ar-H), 7.45 (d, J=7.2Hz, 2H, Ar-H), 7.40 (t, J=7.2Hz, 2H, Ar-H), 7.35 (d, J=7.0Hz, 1H, Ar-H), 7.18 (d, J=9.0Hz, 1H, Ar-H), 5.21 (s, 2H, PhCH2-), 3.91 (s, 3H, -OCH3). MS (ESI) m/z: 260.1 [M+H]+.2-methoxy-5-nitrophenol (10.0 g, 59.2 mmol) was added sequentially to a 250 ml three-necked flask aAnhydrous potassium carbonate(12.2 g, 88.4 mmol) and N, N-dimethylformamide 100 ml, benzyl bromide(11.1 g, 64.9 mmol) was added dropwise with stirring, and the temperature was raised to 40 C for 4 hours. The reaction was complete by thin layer chromatography (ethyl acetate: petroleum ether (V: V) = 2: 1). After completion of the reaction, the reaction mixture was cooled to room temperature and the reaction solution was poured into 500 ml of ice water, stirred, dried to give 14.1 g of a pale yellow solid in a yield of 93.1%.The starting material was prepared as follows: A mixture of 2-methoxy-5-nitrophenol (6 g, 35 mmol), 2-bromoethyl methyl ether (4 ml, 40 mmol), potassium carbonate (5.8 g, 40 mmol) and potassium iodide (0.5 g) in DMF (50 ml) was heated at 80 C. for 1 hour.. The mixture was allowed to cool and poured into water (400 ml).. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 4-methoxy-3-(2-methoxyethoxy)nitrobenzene (7.75 g, 98%). 1H NMR Spectrum: (CDCl3) 3.46 (s, 3H); 3.82 (t, 2H); 3.96 (s, 3H); 4.25 (t, 2H); 6.91 (d, 1H); 7.79 (d, 1H); 7.92 (dd, 1H); MS-ESI: 227 [MH]+;

Molecular Weight:169.13
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:169.03750770
Monoisotopic Mass:169.03750770
Topological Polar Surface Area:75.3
Heavy Atom Count:12
Complexity:167
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes