* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Heterocycles, 2004, vol. 64, p. 193 - 198
2
[ 704-14-3 ]
[ 93735-22-9 ]
Reference：
[1] Patent: US2008/64871, 2008, A1,
3
[ 704-14-3 ]
[ 6529-94-8 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2006, vol. 54, # 4, p. 991 - 1000
[2] Journal of Agricultural and Food Chemistry, 2005, vol. 53, # 3, p. 538 - 548
[3] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 3, p. 561 - 566
[4] Tetrahedron, 2011, vol. 67, # 6, p. 1187 - 1192
[5] European Journal of Medicinal Chemistry, 2017, vol. 132, p. 90 - 107
[6] Patent: US2008/64871, 2008, A1,
4
[ 150-19-6 ]
[ 3114-61-2 ]
[ 16292-95-8 ]
[ 704-14-3 ]
Yield
Reaction Conditions
Operation in experiment
29%
With bismuth (III) nitrate pentahydrate In acetone at 0℃; for 20 h;
General procedure: To a solid mixture of phenol (1–3 equiv) and Bi(NO3)35H2O (1 equiv) or Fe(NO3)39H2O (1 equiv) was added acetone (10 ml/mmol). The resulting mixture was stirred at room temperature under air or at reflux for 2–24 hours, Tables 1 and 2. When the reaction was completed the insoluble materials were filtered off using a pad of Celite and the residue was washed by acetone (ca. 5 ml/mmol). The filtrate was treated by NaHCO3 (0.1 g/mmol) until evolution of CO2 stopped. Insoluble material was filtered off again, and the solvent was removed under vacuum in a water bath 25–35°C. The nitrated products were separated or purified using silica gel chromatography, to give pure phenolic compounds. All products were characterized by 1H NMR,13C NMR and IR and were identified by comparison of the spectral data and melting points with those reported in literature and characterized.
Reference：
[1] Journal of the Chemical Society, 1929, p. 2778
[2] Monatshefte fuer Chemie, 1880, vol. 1, p. 887[3] Monatshefte fuer Chemie, 1881, vol. 2, p. 369 Anm. 3
6
[ 150-19-6 ]
[ 60-29-7 ]
[ 7697-37-2 ]
[ 7782-77-6 ]
[ 16292-95-8 ]
[ 704-14-3 ]
Reference：
[1] Monatshefte fuer Chemie, 1880, vol. 1, p. 887[2] Monatshefte fuer Chemie, 1881, vol. 2, p. 369 Anm. 3
7
[ 4920-84-7 ]
[ 704-14-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
With aluminum (III) chloride In dichloromethane for 5.5 h; Reflux
A solution of 2,4-dimethoxynitrobenzene (2.0 g, 10.9 mmol) in 360 mL of CH2Cl2 was cooled to 0 °C and 2.91 g of AlCl3 (21.3 mmol) were portionwise added. The mixture was heated to reflux for 5.5 h (development of a bright red color). After cooling to RT, 10percent aqueous HCl was added dropwise and the mixture was extracted three times with CH2Cl2. The combined organic layers were dried with MgSO4. After solvent removal under reduced pressure the crude product was purified bychromatography (c-hex/EtOAc = 10:1) to afford 5-methoxy-2-nitrophenol (11) as ayellow solid (1.64 g, 9.69 mmol, 89percent).
Stage #1: With propionic acid; sodium nitrite In water at -5℃; for 1 h; Stage #2: With nitric acid In water at -5 - 20℃; for 16 h;
Benzoxazole Formation Procedures: Compound 3: A solution of 3-methoxyphenol (10 g, 80.55 mmol) in propionic acid (80 mL) was treated at -5° C. with a solution of NaNO2 (5.61 g, 81.30 mmol) in water (13 mL). After stirring for 1 h at -5° C., nitric acid (6.7 mL, 161.10 mmol) was added. The slurry was stirred for 1 h at -5° C., and then at room temperature for 16 h. Water (80 mL) was then added in a dropwise fashion at room temperature. The resultant solid was filtered, washed with 50percent aqueous propionic acid, and dried to give 7.47 g (55percent) of 5-methoxy-2-nitro-phenol.
36%
at 20℃; for 0.5 h; Inert atmosphere
To a solution of3-methoxyphenol (6.0 g, 48.33 mmol) in AcOH (70 ml) was added HNO3 (60percent,5.08 g, 48.33 mmol) at 0 °C under nitrogenatmosphere and the mixture was stirred at RT for 30 min. The aqueous layer wasfurther extracted with EtOAc, and the combined organic solutions were driedover MgSO4, filtered and concentrated in vacuo. The residuewas purified by flash column chromatography (n-hexane:EtOAc = 20:1) toafford the 1a (2.84 g, 17.40 mmol,36percent) as an orange solid: Rf = 0.9 (n-hexane:EtOAc =3:1); 1H NMR (400 MHz, CDCl3) δ 11.05 (1H, s), 8.04 (1H,d, J = 8.0 Hz), 6.53 (1H, d, J= 2.4 Hz), 6.52 (1H,dd, J = 2.4, 8.0Hz), 3.89 (3H, s); 13C NMR (100 MHz, CDCl3) δ 166.9, 157.8,127.5, 126.8, 109.3, 101.2, 56.0.
Reference：
[1] Tetrahedron, 1998, vol. 54, # 27, p. 7843 - 7848
[2] Patent: US2011/224269, 2011, A1, . Location in patent: Page/Page column 20
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 13, p. 3067 - 3072
[4] Journal of the Chemical Society, 1935, p. 946
[5] Yakugaku Zasshi, 1959, vol. 78, p. 931[6] Chem.Abstr., 1960, p. 497
[7] Bulletin de la Societe Chimique de France, 1972, p. 4061 - 4067
[8] Journal of Organic Chemistry, 1991, vol. 56, # 5, p. 1788 - 1800
[9] Phytochemistry, 1994, vol. 37, # 2, p. 297 - 300
[10] Scientia Pharmaceutica, 2005, vol. 73, # 3, p. 95 - 100
[11] Journal fuer Praktische Chemie/Chemiker-Zeitung, 1993, vol. 335, # 1, p. 103 - 104
[12] Synthetic Communications, 1993, vol. 23, # 3, p. 343 - 348
[13] Patent: US2003/216582, 2003, A1, . Location in patent: Page/Page column 4
9
[ 446-36-6 ]
[ 704-14-3 ]
Yield
Reaction Conditions
Operation in experiment
93%
With hydrogenchloride; sodium methylate In methanol
Part A 5-Fluoro-2-nitrophenol (5.00 g, 31.8 mmol) and methanol (120 mL) were combined and the mixture was treated with sodium methoxide (4.6 mL, 190.8 mmol, 25percent w/w solution in MeOH). The reaction mixture was heated at 60° C. for 40 h. The mixture was transferred to a separatory funnel containing cold 1 N HCl and the aqueous layer was extracted with EtOAc (3*). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford 5-methoxy-2-nitrophenol (5.0 g, 93percent yield) as a yellow solid: mp 93.0-94.0° C., 1H NMR (300 MHz, CDCl3): δ 11.05 (s, 1H), 8.03 (d, J=10.3 Hz, 1H), 6.55-6.51 (m, 2H), 3.89 (s, 3H).
Reference：
[1] Patent: US2003/171380, 2003, A1,
10
[ 13895-38-0 ]
[ 704-14-3 ]
Reference：
[1] Synthetic Communications, 1995, vol. 25, # 15, p. 2327 - 2335
[2] Organic and Biomolecular Chemistry, 2007, vol. 5, # 3, p. 531 - 546
[3] Journal of the Chemical Society, 1929, p. 2778
[4] Journal of the Chemical Society, 1929, p. 2778
[5] Journal fuer Praktische Chemie/Chemiker-Zeitung, 1993, vol. 335, # 1, p. 103 - 104
[6] Synthetic Communications, 1993, vol. 23, # 3, p. 343 - 348
[7] Scientia Pharmaceutica, 2005, vol. 73, # 3, p. 95 - 100
11
[ 150-19-6 ]
[ 3114-61-2 ]
[ 16292-95-8 ]
[ 704-14-3 ]
Yield
Reaction Conditions
Operation in experiment
29%
With bismuth (III) nitrate pentahydrate In acetone at 0℃; for 20 h;
General procedure: To a solid mixture of phenol (1–3 equiv) and Bi(NO3)35H2O (1 equiv) or Fe(NO3)39H2O (1 equiv) was added acetone (10 ml/mmol). The resulting mixture was stirred at room temperature under air or at reflux for 2–24 hours, Tables 1 and 2. When the reaction was completed the insoluble materials were filtered off using a pad of Celite and the residue was washed by acetone (ca. 5 ml/mmol). The filtrate was treated by NaHCO3 (0.1 g/mmol) until evolution of CO2 stopped. Insoluble material was filtered off again, and the solvent was removed under vacuum in a water bath 25–35°C. The nitrated products were separated or purified using silica gel chromatography, to give pure phenolic compounds. All products were characterized by 1H NMR,13C NMR and IR and were identified by comparison of the spectral data and melting points with those reported in literature and characterized.
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 13, p. 4199 - 4208
13
[ 116668-84-9 ]
[ 59-51-8 ]
[ 704-14-3 ]
Reference：
[1] Patent: US2003/4202, 2003, A1,
14
[ 6627-53-8 ]
[ 704-14-3 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1902, vol. 21, p. 325
15
[ 5451-83-2 ]
[ 704-14-3 ]
Reference：
[1] Journal of Organic Chemistry, 1957, vol. 22, p. 220
16
[ 150-19-6 ]
[ 16292-95-8 ]
[ 704-14-3 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 2778
[2] Monatshefte fuer Chemie, 1880, vol. 1, p. 887[3] Monatshefte fuer Chemie, 1881, vol. 2, p. 369 Anm. 3
17
[ 28987-59-9 ]
[ 704-14-3 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 2778
18
[ 3163-07-3 ]
[ 77-78-1 ]
[ 704-14-3 ]
Reference：
[1] Proceedings - Indian Academy of Sciences, Section A, 1953, vol. 37, p. 765,768[2] Proceedings - Indian Academy of Sciences, Section A, 1953, vol. 38, p. 31,35
19
[ 20278-59-5 ]
[ 704-14-3 ]
Reference：
[1] P. Ch. S., p. 238
[2] Chem. Zentralbl., 1901, vol. 72, # I, p. 739
20
[ 66910-71-2 ]
[ 704-14-3 ]
Reference：
[1] Chem. Zentralbl., 1901, vol. 72, # I, p. 739
21
[ 6627-53-8 ]
[ 124-41-4 ]
[ 704-14-3 ]
[ 4920-84-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1902, vol. 21, p. 325
22
[ 67764-33-4 ]
[ 20278-59-5 ]
[ 64-19-7 ]
[ 704-14-3 ]
Reference：
[1] Journal of the Chemical Society, 1901, vol. 79, p. 1077
[2] Chem. Zentralbl., 1901, vol. 72, # I, p. 739
23
[ 150-19-6 ]
[ 7664-93-9 ]
[ 64-19-7 ]
[ 704-14-3 ]
Reference：
[1] Journal of the Chemical Society, 1935, p. 946
24
[ 58243-21-3 ]
[ 7722-84-1 ]
[ 704-14-3 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 2778
25
[ 58243-21-3 ]
[ 7697-37-2 ]
[ 704-14-3 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 2778
26
[ 150-19-6 ]
[ 60-29-7 ]
[ 7697-37-2 ]
[ 7782-77-6 ]
[ 16292-95-8 ]
[ 704-14-3 ]
Reference：
[1] Monatshefte fuer Chemie, 1880, vol. 1, p. 887[2] Monatshefte fuer Chemie, 1881, vol. 2, p. 369 Anm. 3
Benzoxazole Formation Procedures: Compound 3: A solution of 3-methoxyphenol (10 g, 80.55 mmol) in propionic acid (80 mL) was treated at -5 C. with a solution of NaNO2 (5.61 g, 81.30 mmol) in water (13 mL). After stirring for 1 h at -5 C., nitric acid (6.7 mL, 161.10 mmol) was added. The slurry was stirred for 1 h at -5 C., and then at room temperature for 16 h. Water (80 mL) was then added in a dropwise fashion at room temperature. The resultant solid was filtered, washed with 50% aqueous propionic acid, and dried to give 7.47 g (55%) of 5-methoxy-2-nitro-phenol.
36%
With nitric acid; acetic acid; at 20℃; for 0.5h;Inert atmosphere;
To a solution of3-methoxyphenol (6.0 g, 48.33 mmol) in AcOH (70 ml) was added HNO3 (60%,5.08 g, 48.33 mmol) at 0 C under nitrogenatmosphere and the mixture was stirred at RT for 30 min. The aqueous layer wasfurther extracted with EtOAc, and the combined organic solutions were driedover MgSO4, filtered and concentrated in vacuo. The residuewas purified by flash column chromatography (n-hexane:EtOAc = 20:1) toafford the 1a (2.84 g, 17.40 mmol,36%) as an orange solid: Rf = 0.9 (n-hexane:EtOAc =3:1); 1H NMR (400 MHz, CDCl3) delta 11.05 (1H, s), 8.04 (1H,d, J = 8.0 Hz), 6.53 (1H, d, J= 2.4 Hz), 6.52 (1H,dd, J = 2.4, 8.0Hz), 3.89 (3H, s); 13C NMR (100 MHz, CDCl3) delta 166.9, 157.8,127.5, 126.8, 109.3, 101.2, 56.0.
[0039] 5-Methoxy-2-nitrophenol (B from Scheme I with R4=methoxy and R3 and both R5=H): To a 2 liter round bottom flask, fit with a mechanical stirrer and an additional funnel, add propionic acid (300 mL) and 3-methoxyphenol (37.2 g, 0.3 mol). The resulting mixture is cooled to 0 C. and a solution of sodium nitrite (21 g, 0.304 mol) in water (50 ml) is slowly added. After stirring for 1 hr at 0 C., fuming nitric acid (40 mL) is slowly added. The resulting slurry is stirred at 0 C. for 1 hour and then warmed to room temperature over 2 hours. Water (250 mL) is added dropwise at room temperature, and the resulting solid is filtered and washed with 300 mL 50% aqueous propionic acid to provide, after drying, 5-methoxy-2-nitrophenol as a solid.
Part B The product from Part A (3.0 g, 17.7 mmol) was dissolved in methanol (120 mL). The reaction vessel was evacuated and flushed with nitrogen and 10% Pd/C (600 mg) was added. The mixture was placed under an H2 atmosphere on the Parr shaker for 1 h. The catalyst was removed by filtration through a pad of Celite and the filtrate was concentrated to give 2-amino-5-methoxyphenol (2.52 g, 100% yield) as a brown solid which was used directly in the next step without further purification: 1H NMR (300 MHz, CDCl3): delta 6.78 (d, J=8.4 Hz, 1H), 6.44 (d, J=2.9 Hz, 1H), 6.35 (dd, J=8.4, 2.9 Hz, 1H), 3.73 (s, 3H).
98%
With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate; at 20℃; for 3.5h;Product distribution / selectivity;
Subsequently, a mixture of <strong>[704-14-3]5-methoxy-2-nitrophenol</strong> (7.47 g) and 10% Pd/C (1.87 g) was prepared in an ethyl acetate/ethanol (100 mL, 1:1 v/v) mixture. The resulting slurry was stirred under an H2 atmosphere for 3.5 h at room temperature. Hydrogen was subsequently purged from the reaction flask and the reaction mixture was filtered through Celite. After washing the celite pad with additional solvent, volatiles in the resultant filtrate were removed in vacuo to give 2-amino-5-methoxyphenol (6.03 g, 98%).
95.7%
With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃;
A mixture of Example 15a (40 g, 230 mmol), Pd/C (4.0 g, 10%) was stirred under the hydrogen balloon (15psi) in MeOH (600 mL) at 25 C for 16 hrs. After the reaction (detected by TLC) was completed, the black suspension was filtered through celite, then concentrated at 45 C under reduced pressure to give the desired product (Example 15b, 31.5 g, yield 95.7%) as brown solid. LCMS [M+1]+= 140
80%
With palladium carbon (20 wt%); hydrogen; In methanol; at 20℃; for 2h;Inert atmosphere;
To a mixture of 1a (2.84 g, 17.40 mmol) in MeOH (35 ml) was addedPd/C (568.2 mg, 20% w/w) under argon atmosphere, then the reaction mixture washydrogenated at RT for 2 h under H2. The resulting mixture wasfiltered through a short Celite pad. The filtrate was concentrated in vacuoto provide 2a (1.94 g, 13.92 mmol, 80%) as a crude pink solid withoutany further purification: Rf = 0.45 (n-hexane:EtOAc =1:2); 1H NMR (400 MHz, DMSO-d6) delta6.49 (1H, d, J = 8.4 Hz), 6.30 (1H, d, J = 2.8 Hz), 6.16 (1H, dd,J = 2.8, 8.4 Hz), 4.10 (2H, br s), 3.58 (3H, s); 13C NMR (100MHz, DMSO-d6) delta 151.2, 144.9, 130.1, 114.7, 103.8, 102.0,55.0.
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran;
2-Nitro-5-methoxyphenol (prepared from 3-methoxyphenol, R. J. Maleski, Synthetic Communications, 1993,23, 343-348) (48. 5g, 0.287 mol) dissolved in THF (1.5 L) was hydrogenated at ambient temperature over night with 10% palladium on carbon (10 g) until 20.3 L of hydrogen was consumed. After filtration and evaporation the residue was suspended in degased water (1.7 L) and acetic anhydride (42.5 mL) was added with stirring. The mixture was heated to 60 C for lh and then cooled to room temperature. The volatiles were removed in vacuo and the solid was washed thoroughly with water and dried in vacuo to give brick-red crystals (41.7 g, 80 %).tH-NMR (400 MHz,CDCI3) :8 8.98 (s, 1H) ; 7.34 (br. s, 1H); 6,81 (d, 1H); 6.58 (d, 1H); 6.44 (dd,1H) ; 3.78 (s,-3H) ; 2, 26 (s,-3H)
palladium-carbon; In tetrahydrofuran;
Step 1 Production of 2-amino-5-methoxyphenol <strong>[704-14-3]5-Methoxy-2-nitrophenol</strong> (1.059 g) was dissolved in tetrahydrofuran (30 mL). 7.5% Palladium-carbon (0.1 g) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 3 hrs. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washing solution were combined and the mixture was concentrated under reduced pressure to give the title compound (0.9615 g) as a pale-orange solid.
With hydrogen;palladium-carbon; In tetrahydrofuran; at 20℃; for 3h;
Step 1 Production of 2-amino-5-methoxyphenol <strong>[704-14-3]5-Methoxy-2-nitrophenol</strong> (1.059 g) was dissolved in tetrahydrofuran (30 mL). 7.5% Palladium-carbon (0.1 g) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 3 hrs. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran The filtrate and washing solution were combined and the mixture was concentrated under reduced pressure to give the title compound (0.9615 g) as a pale-orange solid.
With hydrogen;palladium-carbon; In tetrahydrofuran; at 0 - 40℃; for 3h;
Step 1 Production of 2-amino-5-methoxyphenol <strong>[704-14-3]5-Methoxy-2-nitrophenol</strong> (1.059 g) was dissolved in tetrahydrofuran (30 mL). 7.5% Palladium-carbon (0.1 g) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 3 hrs. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washing solution were combined and the mixture was concentrated under reduced pressure to give the title compound (0.9615 g) as a pale-orange solid.
3-Chloro-2-hydroxy-4-methoxy-nitrobenzene[ No CAS ]
[ 37742-67-9 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hypochlorite; In water; at 20℃; for 24h;
To a flask containing <strong>[704-14-3]3-methoxy-6-nitro-phenol</strong> (0.5 g) is added aqueous sodium hypochlorite (5.25% aqueous solution, 21 mL) and the mixture is stirred at room temperature for approximately 24 hours. The mixture is then cooled in an ice-bath, acidified by addition of concentrated hydrochloric acid, then extracted twice with ethyl acetate. These organic extracts are dried over anhydrous magnesium sulfate, the solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silca gel (15% acetone in hexanes is used as the eluant) to provide both the mono- and di-chlorinated products as yellow solids.
With sodium hydrogencarbonate; N,N,N-trimethylbenzenemethanaminium dichloroiodate; In methanol; dichloromethane; at 20℃; for 24h;
To a solution of 5-methoxy-2-nitro-phenol (0.25 g) in dichloromethane (15 mL) and methanol (6 mL) is added benzyltrimethylammonium dichloroiodate (1.08 g) and sodium bicarbonate (0.85 g) and the mixture is allowed to stir at room temperature for 24 hours. The solution is then filtered, the filtrate is concentrated under reduced pressure, the residue is dissolved in ethyl acetate and then washed successively with 5% aqueous sodium bicarbonate, 5% aqueous sodium bisulfite, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate the solvent is removed by evaporation under reduced pressure and the residue is recrystallized from toluene to provide the desired product as yellow needles.
(2R) -2- [ (5-Methoxy-2-nitrophenoxy) methyl] oxirane To a stirred solution of <strong>[704-14-3]5-methoxy-2-nitrophenol</strong> (2.11 g, 12.5 mmol) and 2 (S)-oxyran-2- methanol (0.926 g, 12.5 mmol) in CH2C12 (150 mL) was added polymer bound triphenylphosphine (6.2 g, 18.7 mmol). The mixture was stirred at room temperature for 15 minutes, then cooled to O C, DEAD (3.65 g, 18.7 mmol) was added dropwise. After addition was completed the reaction mixture was stirred at 0 C for 2 hours. Then ice-bath was removed and the reaction mixture was stirred at room temperature over the week end. The polymer bound reagent was removed by filtration through celite. The filtrate was concentrated in vacuo, tert.-butyl methyl ether (100 mL) was added and stirred at room temperature for 30 minutes to obtain a precipitation and clear solution. The precipitate was filtered off and washed with ter-butyl methyl ether. The filtrate was concentrated in vacuo the residue was purified by silica gel flash chromatography (heptane/ethyl acetate) to give the sub-title compound (1.45 g). 1H-NMR (CDC13, 400 MHz): 8 8. 00 (d, J= 9.1 Hz, 1H) ; 6.60 (d, J= 2.5 Hz, 1H); 6.55 (dd, J= 2.5, 9.1 Hz, 1H); 4.42 (dd, J= 2.7, 11.2 Hz, 1H); 4.13 (dd, J= 5.1, 11. 2 Hz, 1H) ; 3.88 (s, 3H); 3.41 (m, 1H) ; 2.92 (m, 2H).
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;
To a mixture of (2S)-oxiran-2-ylmethanol (445 mg, 6.0 mmol), <strong>[704-14-3]5-methoxy-2-nitrophenol</strong> (1.02 g, 6.0 mmol) and triphenylphosphine (1.57 g, 6.0 mmol) in THF (10 mL) was added DEAD (0.95 mL, 6.0 mmol) in THF (5 mL) dropwise at 0 C. After addition was completed the ice bath was removed and the mixture was stirred at room temperature over night. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum spirit) to give the sub-title compound (820 mg). 1H-NMR (CDC13, 400 MHz): 6 8. 00 (d, J= 9.1 Hz, 1H); 6.60 (d, J= 2.5 Hz, 1H); 6.54 (dd, J= 2.5, 9.1 Hz, 1H); 4.41 (dd, J= 2. 7,11. 3 Hz, 1H); 4.12 (dd, J= 5.0, 11.3 Hz, 1H) ; 3.88 (s, 3H); 3.41 (m, 1H); 2.92 (m, 2H). APCI-MS: m/z 226 (MH.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃;
To a mixture of (2S) -oxiran-2-ylmethanol (296.3 mg, 4.0 mmol), <strong>[704-14-3]5-methoxy-2-nitrophenol</strong> (676.6 mg, 4.0 mmol) and triphenyl phosphine (1.05 g, 4.0 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD, 704.6 mg, 4.0 mmol) in THF (5 mL) dropwise at room temperature. After addition was completed the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum spirit) to give the subtitled compound (650 mg). 1H-NMR (CDCl3, 400 MHz): delta 8.00 (d, J = 9.0 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H) ; 6.55 (dd, J = 2.5, 9.2 Hz, 1H) ; 4.41 (dd, J = 2.7, 11.3 Hz, 1H) ; 4.12 (dd, J = 5.0, 11.3 Hz, 1H) ; 3.90 (s, 3H); 3.41 (m, 1H); 2.93 (m, 2H).
b 2-Hydroxy-4-methoxynitrobenzene To a solution of dimethoxynitrobenzene (30.0 g, 0.163 mol) in 99% methanesulfonic acid (300 ml) was added dl-methionine (31.8 g, 0.212 mol) and the mixture was stirred at rt for 24 h. The solution was poured onto ice and stirred with water (1.5 l). The precipitate was filtered and washed with water. The title compoundcompound was collected as a yellow solid (23.1 g, 84%).
With hydrogenchloride; sodium methylate; In methanol;
Part A 5-Fluoro-2-nitrophenol (5.00 g, 31.8 mmol) and methanol (120 mL) were combined and the mixture was treated with sodium methoxide (4.6 mL, 190.8 mmol, 25% w/w solution in MeOH). The reaction mixture was heated at 60 C. for 40 h. The mixture was transferred to a separatory funnel containing cold 1 N HCl and the aqueous layer was extracted with EtOAc (3*). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford 5-methoxy-2-nitrophenol (5.0 g, 93% yield) as a yellow solid: mp 93.0-94.0 C., 1H NMR (300 MHz, CDCl3): delta 11.05 (s, 1H), 8.03 (d, J=10.3 Hz, 1H), 6.55-6.51 (m, 2H), 3.89 (s, 3H).
2-Amino-6-methoxy-4-phosphonomethoxybenzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step A. 2-Hydroxy-4-methoxy nitrobenzene was subjected to Step B of Example 32, Step B of Example 27, Step B of Example 29, Step D of Example 27 to give 2-Amino-6-methoxy-4-phosphonomethoxybenzothiazole (45.1) mp. >230 C.(dec.). Anal. calcd. for C9H11N2O5PS+0.5H2O: C: 36.12; H: 4.04; N: 9.36. Found: C: 36.18; H: 3.81; N: 9.47.
3-Chloro-2-hydroxy-4-methoxy-nitrobenzene[ No CAS ]
[ 37742-67-9 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In acetone;
EXAMPLE 27 (METHOD 7A) 2-Chloro-<strong>[704-14-3]3-methoxy-6-nitro-phenol</strong> and 2,4-Dichloro-<strong>[704-14-3]3-methoxy-6-nitro-phenol</strong> To a flask containing <strong>[704-14-3]3-methoxy-6-nitro-phenol</strong> (0.5 g) is added aqueous sodium hypochlorite (5.25% aqueous solution, 21 mL) and the mixture is stirred at room temperature for approximately 24 hours. The mixture is then cooled in an ice-bath, acidified by addition of concentrated hydrochloric acid, then extracted twice with ethyl acetate. These organic extracts are dried over anhydrous magnesium sulfate, the solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silca gel (15% acetone in hexanes is used as the eluant) to provide both the mono- and di-chlorinated products as yellow solids. Using the above procedure and appropriate starting materials the following compounds were prepared: 3-Chloro-2-hydroxy-4-methoxy-nitrobenzene 3,5-Dichloro-2-hydroxy-4-methoxy-nitrobenzene
With sodium hydrogencarbonate; In methanol; dichloromethane; ethyl acetate;
EXAMPLE 32 (METHOD 7F) 2,4-Diiodo-<strong>[704-14-3]3-methoxy-6-nitro-phenol</strong> To a solution of 5-methoxy-2-nitro-phenol (0.25 g) in dichloromethane (15 mL) and methanol (6 mL) is added benzyltrimethylammonium dichloroiodate (1.08 g) and sodium bicarbonate (0.85 g) and the mixture is allowed to stir at room temperature for 24 hours. The solution is then filtered, the filtrate is concentrated under reduced pressure, the residue is dissolved in ethyl acetate and then washed successively with 5% aqueous sodium bicarbonate, 5% aqueous sodium bisulfite, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate the solvent is removed by evaporation under reduced pressure and the residue is recrystallized from toluene to provide the desired product as yellow needles.
EXAMPLE 1 Preparation of 6-methoxy-2-mercaptobenzoxazole Carbon disulphide (9 ml, 0.15 mol) was added dropwise over a period of 1 minute to a solution of potassium hydroxide (6.5 g, 0.12 mol) in a mixture of water (10 ml) and methanol (100 ml), followed by <strong>[704-14-3]2-nitro-5-methoxyphenol</strong> (16.9 g, 0.1 mol). ]The <strong>[704-14-3]2-nitro-5-methoxyphenol</strong> required as starting material was prepared by nitration of 3-methoxyphenol as described in Synthetic Communications, 1993, 23(3) 343-348.] To this mixture was added dropwise a solution of potassium hydroxide (39 g, 0.7 mol) and sodium dithionite (65 g, 0.3 mol), over a period of 15 minutes, so that the temperature did not exceed 40 C. The reaction mixture was then cooled to room temperature and carbon disulphide (0.9 ml, 0.15 mol) added and the resulting solution heated to 80 C. for 2 hours. The mixture was then cooled and acidified with concentrated hydrochloric acid to a pH of 3. The pale yellow precipitate was collected and air dried to yield 6-methoxy-2-mercaptobenzoxazole (16.6 g, 89%). Proton NMR (CDCl3): delta 2.85(3H, OCH3); 6.9(1H, dd, aromatic C--H); 6.95(1H, d, aromatic C--H); 7.13(H, d, aromatic C--H); 11.0 (H, bs, SH).
EXAMPLE 3 Preparation of 5-methoxy-2-mercaptobenzoxazole Carbon disulphide (886 mg, 0.7 ml, 11.6 mmol) was added dropwise to KOH (800 mg, 14.3 mmol) dissolved in methanol (8 ml) and water (15 ml), and the resulting yellow solution stirred for 4 minutes at room temperature. This was added to a mixture of 3-methoxy-6-nitrophenol (1.2 g, 7.1 mmol), KOH (2.0 g, 35.7 mmol) and water (35 ml), followed by the addition of first solid sodium dithionite (3.7 g, 21.2 mmol), then carbon disulphide (760 mg, 9.9 mmol). The resulting mixture was stirred at 70 C. for 20 hours. The reaction mixture was cooled to room temperature, acidified with concentrated HCl and the resulting precipitated solid collected by filtration and air dried. The yield was 980 mg (76%). Proton NMR (CDCl3 /D6 -DMSO): delta 3.80 (3H, s, OCH3), 6.75 (2H, m, aromatic C--H), 7.50 (1H, d, aromatic C--H), and 13.20 (1H, bs, SH).
2-carbamoylmethoxy-4-methoxynitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;
Reaction of 0.84 g of <strong>[704-14-3]5-methoxy-2-nitrophenol</strong>, 1.66 g of potassium carbonate and 1.84 g of iodoacetamide by the process described in Example 55) gives 2-carbamoylmethoxy-4-methoxynitrobenzene: mp 185-7 C.; Rf (O)=0.58.
O-ethyl N-sec-butyl phosphoramidochloridothionate[ No CAS ]
[ 584-08-7 ]
[ 88276-24-8 ]
Yield
Reaction Conditions
Operation in experiment
72.1%
With sodium hydroxide; In water; toluene; acetonitrile;
EXAMPLE 1 <strong>[704-14-3]5-Methoxy-2-nitrophenol</strong> (1.69 g; 0.01 mole) was dissolved in acetonitrile (25 ml), and anhydrous potassium carbonate powder (1.40 g) was added thereto. The mixture was stirred at 50-60 C. for 30 minutes. Then, O-ethyl N-sec-butyl phosphoramidochloridothionate (2.15 g; 0.01 mole) was added dropwise at the same temperature to the mixture, which was refluxed for 4 hours with stirring. After the inorganic salt was filtered off, the solvent was evaporated. The residue was dissolved in toluene and washed with dilute hydrochloric acid, an aqueous solution of sodium hydroxide and water in order. After being dried over anhydrous sodium sulfate, toluene was evaporated, followed by purification with silica gel column chromatography to obtain 2.51 g of O-ethyl O-(5-methoxy-2-nitrophenyl) N-sec-butyl phosphoramidothionate (Compound No. 33). Yield, 72.1%; nD26.0, 1.5353.
O-methyl N-(3-methoxypropyl)phosphoramidochloridothionate[ No CAS ]
[ 704-14-3 ]
[ 88276-49-7 ]
Yield
Reaction Conditions
Operation in experiment
70%
With sodium hydroxide; potassium carbonate; In water; toluene; acetonitrile;
EXAMPLE 3 <strong>[704-14-3]5-Methoxy-2-nitrophenol</strong> (3.38 g; 0.02 mole) was dissolved in acetonitrile (50 ml), and anhydrous potassium carbonate (2.76 g; 0.02 mole) was added to the solution and stirred at 50-60 C. for 30 minutes. Then, at the same temperature, O-methyl N-(3-methoxypropyl)phosphoramidochloridothionate (4.35 g; 0.02 mole) was added dropwise to the mixture, which was then refluxed with stirring. After the inorganic salt was filtered off, the solvent was evaporated. The residue was dissolved in toluene, and the resultant solution was washed with dilute hydrochloric acid, an aqueous solution of sodium hydroxide and water. After being dried over anhydrous sodium sulfate, toluene was evaporated. The residue was purified by silica gel column chromatography to obtain 4.90 g of O-methyl O-(5-methoxy-2-nitrophenyl) N-(3-methoxypropyl)phosphoramidothionate (Compound No. 58). Yield, 70%; n24, 1.5425.
methyl 6-(2-nitro-5-methoxyphenoxy)hexanoate[ No CAS ]
[ 14273-90-6 ]
[ 704-14-3 ]
[ 244632-93-7 ]
methyl 6-(2-amino-5-methoxyphenoxy)hexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate;palladium; In N-methyl-acetamide;
TB 595 6-(2-isothiocyanoto-5-methoxphenoxy)hexanoic acid, represented as TB595 and shown in FIG. 3Lwas prepared by a number of steps. The first step involves the reaction of <strong>[704-14-3]2-nitro-5-methoxyphenol</strong> (1.69 g, 10 mmol) with methyl 6-bromohexanoate (2.08 g, 10 mmol) in dry dimethylformamide and anhydrous potassium carbonate (2.0 g, 14.5 mmol) at 60 C. for 12 hours to produce the intermediate ester, methyl 6-(2-nitro-5-methoxyphenoxy)hexanoate. Hydrogenation of methyl 6-(2-nitro-5-methoxyphenoxy)hexanoate using palladium-on-carbon as catalyst afforded the isolation of methyl 6-(2-amino-5-methoxyphenoxy)hexanoate which was saponified in 10% water/ethanol (1:1) solution of potassium hydroxide to give 6-(2-amino-5-methoxyphenoxy)hexanoic acid in 95% yield.
With aluminum (III) chloride; In dichloromethane; for 5.5h;Reflux;
A solution of 2,4-dimethoxynitrobenzene (2.0 g, 10.9 mmol) in 360 mL of CH2Cl2 was cooled to 0 C and 2.91 g of AlCl3 (21.3 mmol) were portionwise added. The mixture was heated to reflux for 5.5 h (development of a bright red color). After cooling to RT, 10% aqueous HCl was added dropwise and the mixture was extracted three times with CH2Cl2. The combined organic layers were dried with MgSO4. After solvent removal under reduced pressure the crude product was purified bychromatography (c-hex/EtOAc = 10:1) to afford 5-methoxy-2-nitrophenol (11) as ayellow solid (1.64 g, 9.69 mmol, 89%).
With potassium carbonate; In acetone;Inert atmosphere; Reflux;
General procedure: In an oven dried round-bottom flask, under a nitrogen atmosphere, ortho-nitrophenol 2a (556 mg, 4.0 mmol, 1 equiv) was dissolved in dry acetone (5 mL) and stirred with anhydrous K2CO3 (829 mg, 1.5 equiv) and bromoacetonitrile (575 mg, 1.2 equiv) was added, then the reaction mixture was refluxed for overnight. TLC analysis indicated all the starting materials had been consumed. After removal of acetone under reduced pressure, the reaction mixture was poured in water (15 mL) and extracted with ethyl acetate (2x30 mL), washed with brine (2x15 mL), and dried over Na2SO4. The solvent was evaporated and the crude product was purified by flash column chromatography on silica gel (Yield 76-93%).
With potassium carbonate; In acetone;Inert atmosphere; Reflux;
General procedure: In an oven dried round-bottom flask,under a nitrogen atmosphere, 2-nitrophenol derivative (2.0 mmol, 1 equiv) was dissolved in dry acetone (5 mL) and stirred with anhydrous K2CO3 (2.6 mmol, 1.3 equiv). 2-bromocetonitrile (2.4 mmol, 1.2 equiv) was added to the reaction mixture and refluxed fluxed until the completion of the reaction. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate (25 mL), washed with water (3×10 mL), brine (2×10 mL), and dried over Na2SO4. The solvent was evaporated and the 2-(2-nitrophenoxy)acetonitrile product was purified by flash chromatography on silica gel.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
