* 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.
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 1 h; Reflux
To a solution of 2-chloro-5-methylanisole (11) (274 g, 1.75 mol) in CC14 (2.5 L) was added benzoyl peroxide (4.23 g, 0.02 mol) and NBS (321 g, 1.80 mol). The reaction mixture was heated to reflux for 1 h with mechanical stirring. The reaction mixture was cooled, washed with IN HCl (2 L), satd NaHC03 (2 L) and brine (2 L), dried over MgS04, filtered and concentrated under reduced pressure to give the 5-(bromomethyl)-3- chloroanisole (12) as a light yellow solid (412 g, quantitative). 1H NMR (400MHz, CDC13): δ 7.30-7.34 (d, 1H), 6.95 (s, 1H), 6.91-6.93 (d, 1H), 4.45 (s, 2H), 3.92 (s, 3H).
100%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 1 h; Reflux
To a solution of 2-chloro-5-methylanisole (11) (274 g, 1.75 mol) in CCl4 (2.5 L) was added benzoyl peroxide (4.23 g, 0.02 mol) and NBS (321 g, 1.80 mol). The reaction mixture was heated to reflux for 1 h with mechanical stirring. The reaction mixture was cooled, washed with IN HCl (2 L), satd NaHCO3 (2 L) and brine (2 L), dried over MgSO4, filtered and concentrated under reduced pressure to give the 5-(bromomethyl)-3- chloroanisole (12) as a light yellow solid (412 g, quantitative). 1H NMR (400MHz, CDCl3): δ 7.30-7.34 (d, IH), 6.95 (s, IH), 6.91-6.93 (d, IH), 4.45 (s, 2H), 3.92 (s, 3H).
92%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3 h; Heating / reflux
To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92percent). 1H NMR (400 MHz, CDCl3) δ 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H).
92%
With N-Bromosuccinimide; azobisisobutyronitrile In tetrachloromethane
4-Bromomethyl-1-chloro-2-methoxy-benzene To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92percent). 1H NMR (400 MHz, CDCl3) δ 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H).
92%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3 h; Reflux
4-Bromomethyl-1-chloro-2-methoxy-benzene To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92percent). 1H NMR (400 MHz, CDCl3) δ 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H).
With ammonium cerium(IV) nitrate; acetic acid In water at 100℃; for 1.25 h;
Step 2;. 4-Chloro-3- (methyloxy) benzaldehyde; Ceric ammonium nitrate (43.3 g, 79.0 mmol, 4.00 equiv) was dissolved in 1: 1 HOAc/H2O (200 mL). This solution was added dropwise over one hour to a stirred solution of the product from Step 1 (3.09g, 19 7 mmol, 1.00 equiv) in 1: 1 HOAc/H2O (100 mL) at 100 °C. After the addition was complete, the reaction was stirred for an additional 15 minutes. The reaction was cooled, diluted with H20 and extracted twice with Et20. The combined organic extracts were washed three times with H20, three times with satd. NaHC03, and once with brine. The organic phase was dried over MgS04 and concentrated en vacuo to afford the title compound (3. 00g, 89percent) as an amber oil. 1H NMR (400 MHz, CDCL3) 9.97 (s, 1H), 7. 57 (d, 1H), 7.46 (s, 1H), 7.43 (d, 1H), 4.00 (s, 3H).
Reference：
[1] Patent: WO2005/82890, 2005, A1, . Location in patent: Page/Page column 88
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1887 - 1891
[3] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4408 - 4414
[4] Russian Chemical Bulletin, 2012, vol. 61, # 8, p. 1616 - 1621[5] Izv. Akad. Nauk, Ser. Khim., 2012, # 8, p. 1599 - 1604
[6] Patent: EP2314593, 2016, B1,
5
[ 73909-16-7 ]
[ 13726-17-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1887 - 1891
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4408 - 4414
[3] Tetrahedron Letters, 1986, vol. 27, # 45, p. 5397 - 5400
[4] Russian Chemical Bulletin, 2012, vol. 61, # 8, p. 1616 - 1621[5] Izv. Akad. Nauk, Ser. Khim., 2012, # 8, p. 1599 - 1604
[6] Patent: US5554620, 1996, A,
[7] Patent: EP2314593, 2016, B1,
With pyridine; potassium permanganate In water at 50℃; for 24 h;
A stirred mixture of compound 2 (11.17 g, 71 mmol), potassium permanganate (35.0 g, 221 mmol), pyridine (36 mL), and water (107 mL) was heated at 50 °C for 24 h. The mixture was then stirred at room temperature for 13 h. The mixture was filtered and MnO2 was suspended in hot water and again filtered off. The combined aqueous filtrates were washed with ethyl acetate (3 x 75 mL), and then acidified with 2 N H2SO4. The precipitate was filtered off, washed with water, and dried to give the title compound (11.98 g, 90percent). mp: 215-216 °C (lit. mp: 217-219 °C refPreviewPlaceHolder[22]).
58%
With potassium permanganate In water
(b) A mixture of 3-methoxy-4-chlorotoluene (25.5 g, 0.163 mol) and KMnO4 (62 g, 0.392 mol) in 1.2 L of water was refluxed with stirring for 16 hours. The mixture was filtered, the filtrate was neutralized with cone. HCl solution (to pH=2), and the resulting solid was filtered, washed with water, and dried to afford 3-methoxy-4-chlorobenzoic acid (17.5 g,58percent).
58%
With potassium permanganate In water; toluene for 17 h; Reflux
B. Synthesis of 4-chloro-3-methoxybenzoic acid (0200) To the crude toluene (7.8 g, 50 mmol) was added a solution KMnO4 (19.8 g, 125 mmol) in water (300 mL). The reaction mixture was stirred vigorously at reflux for 17 hr and filtered warm through Celite, washing the cake with 200 mL hot water. The clear filtrate was washed with ethyl ether (2 x 150 mL), acidified with cone. HCl (9 mL) and filtered to give pure white solid 4-chloro-3-methoxybenzoic acid (5.36 g, 58percent). ES-MS (M+H)+ = 187.
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4408 - 4414
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 12, p. 5754 - 5762
[3] Archiv der Pharmazie, 2011, vol. 344, # 11, p. 745 - 754
[4] Chemical Biology and Drug Design, 2013, vol. 82, # 3, p. 336 - 347
[5] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 315 - 322
[6] Journal of Enzyme Inhibition and Medicinal Chemistry, 2016, vol. 31, p. 111 - 122
[7] European Journal of Medicinal Chemistry, 1990, vol. 25, # 3, p. 267 - 270
[8] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1887 - 1891
[9] Patent: US5554620, 1996, A,
[10] Patent: EP2314593, 2016, B1, . Location in patent: Paragraph 0200
[11] Tetrahedron Letters, 1986, vol. 27, # 45, p. 5397 - 5400
[12] Patent: US2007/88036, 2007, A1, . Location in patent: Page/Page column 25
[13] Russian Chemical Bulletin, 2012, vol. 61, # 8, p. 1616 - 1621[14] Izv. Akad. Nauk, Ser. Khim., 2012, # 8, p. 1599 - 1604
With pyridine; potassium permanganate; In water; at 50℃; for 24h;
A stirred mixture of compound 2 (11.17 g, 71 mmol), potassium permanganate (35.0 g, 221 mmol), pyridine (36 mL), and water (107 mL) was heated at 50 C for 24 h. The mixture was then stirred at room temperature for 13 h. The mixture was filtered and MnO2 was suspended in hot water and again filtered off. The combined aqueous filtrates were washed with ethyl acetate (3 x 75 mL), and then acidified with 2 N H2SO4. The precipitate was filtered off, washed with water, and dried to give the title compound (11.98 g, 90%). mp: 215-216 C (lit. mp: 217-219 C refPreviewPlaceHolder[22]).
58%
With potassium permanganate; In water;
(b) A mixture of 3-methoxy-4-chlorotoluene (25.5 g, 0.163 mol) and KMnO4 (62 g, 0.392 mol) in 1.2 L of water was refluxed with stirring for 16 hours. The mixture was filtered, the filtrate was neutralized with cone. HCl solution (to pH=2), and the resulting solid was filtered, washed with water, and dried to afford 3-methoxy-4-chlorobenzoic acid (17.5 g,58%).
58%
With potassium permanganate; In water; toluene; for 17h;Reflux;
B. Synthesis of 4-chloro-3-methoxybenzoic acid (0200) To the crude toluene (7.8 g, 50 mmol) was added a solution KMnO4 (19.8 g, 125 mmol) in water (300 mL). The reaction mixture was stirred vigorously at reflux for 17 hr and filtered warm through Celite, washing the cake with 200 mL hot water. The clear filtrate was washed with ethyl ether (2 x 150 mL), acidified with cone. HCl (9 mL) and filtered to give pure white solid 4-chloro-3-methoxybenzoic acid (5.36 g, 58%). ES-MS (M+H)+ = 187.
With potassium permanganate; tetrabutyl-ammonium chloride; water; for 3h;Heating / reflux;
Step 2: 2-chloro-5-methylanisole (31.2 g, 1 equiv) and Bu4NCl (2 g, cat.) in 500 mL of water was treated with 95 g of KMnO4 at reflux for 3 hours. The mixture was then filtered through celite, acidified with conc. HCl and the white solid was collected after filtration and air dry to give 4-chloro-3-methoxybenzoic acid.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 1h;Reflux;
To a solution of 2-chloro-5-methylanisole (11) (274 g, 1.75 mol) in CC14 (2.5 L) was added benzoyl peroxide (4.23 g, 0.02 mol) and NBS (321 g, 1.80 mol). The reaction mixture was heated to reflux for 1 h with mechanical stirring. The reaction mixture was cooled, washed with IN HCl (2 L), satd NaHC03 (2 L) and brine (2 L), dried over MgS04, filtered and concentrated under reduced pressure to give the 5-(bromomethyl)-3- chloroanisole (12) as a light yellow solid (412 g, quantitative). 1H NMR (400MHz, CDC13): delta 7.30-7.34 (d, 1H), 6.95 (s, 1H), 6.91-6.93 (d, 1H), 4.45 (s, 2H), 3.92 (s, 3H).
100%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 1h;Reflux;
To a solution of 2-chloro-5-methylanisole (11) (274 g, 1.75 mol) in CCl4 (2.5 L) was added benzoyl peroxide (4.23 g, 0.02 mol) and NBS (321 g, 1.80 mol). The reaction mixture was heated to reflux for 1 h with mechanical stirring. The reaction mixture was cooled, washed with IN HCl (2 L), satd NaHCO3 (2 L) and brine (2 L), dried over MgSO4, filtered and concentrated under reduced pressure to give the 5-(bromomethyl)-3- chloroanisole (12) as a light yellow solid (412 g, quantitative). 1H NMR (400MHz, CDCl3): delta 7.30-7.34 (d, IH), 6.95 (s, IH), 6.91-6.93 (d, IH), 4.45 (s, 2H), 3.92 (s, 3H).
95%
With N-Bromosuccinimide;
(ii)3-methoxy-4-chlorobenzyl Bromide A mixture of 3-methoxy-4-chlorotoluene (9.62 g) and N-bromosuccinimide (12.05 g) was refluxed whilst being irradiated with light using a photoflood lamp for 2 hours. The mixture was cooled, filtered and evaporated to give an oil which was purified by column chromatography eluding with diethyl ether to give the desired product as an oil (14.67 g, 95%). NMR (CDCl3): d 3.9 (s, 3H), 4.45 (s, 2H), 6.9-7.0 (m, 2H), 7.3-7.4 (m, 1H).
92%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 3h;Heating / reflux;
To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCl3) delta 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H).
92%
With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane;
4-Bromomethyl-1-chloro-2-methoxy-benzene To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCl3) delta 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H).
92%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 3h;Reflux;
4-Bromomethyl-1-chloro-2-methoxy-benzene To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCl3) delta 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H).
78%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 3h;Reflux;
To a stirred solution of 2-chloro-5-methylanisole (16-1, 20.0 g, 127.71 mol) in CCl4 (200 mL) was added AIBN (4.19 g, 25.54 mol) and NBS (22.7 g, 127.7 mol). The resulting reaction mixture was heated under reflux for 3 hours. Then, the reaction mixture was cooled, washed with a 1N HCl aqueous solution, NaHCO3 saturated aqueous solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give 22g (yield = 78%) of a light yellow solid corresponding to 2-chloro-5-(bromomethyl)anisole (16-2). 1H NMR (400 MHz, CDCl3)
With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; for 3h;Heating / reflux;
A solution of 4-chloro-3-methoxytoluene (36; 0.5 g; 3.2 mmol), NBS (0.57 g; 3.2 mmol) and benzoyl peroxide (0.031 g; 0.13 mmol) and 32 mL of DCE were heated at reflux for 3 h. The reaction mixture was cooled, diluted with CH2Cl2 and washed with water and brine. The organic extract was dried, filtered and evaporated to yield the bromomethyl compound 38b which was used without further purification.
With N-Bromosuccinimide; dibenzoyl peroxide; In ethyl acetate; for 3h;Irradiation with halogen lamp;
(i) 4-(BromomethyI)-l-chIoro-2-methoxybenzene 2-Chloro-5-methylrhohenol (20 g), K2CO3 (30 g), acetone (200 ml) and methyl iodide (9.4 ml) were charged to a flask and stirred for 24 h. The solvent was removed under reduced pressure and the residue partitioned between ether and water. The organics were separated, washed with 2 M sodium hydroxide, water, dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in EtOAc, then NBS (25 g) and benzoyl peroxide (0.5 g) was added and the reaction mixture irradiated with a halogen lamp for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography(eluent isohexane) to give the subtitle compound (30 g) used directly without further purification or characterisation.
With N-Bromosuccinimide; dibenzoyl peroxide; In ethyl acetate; for 3h;Irradiation;
(i) 4-(Bromomethyl)-1-chloro-2-methoxybenzene 2-Chloro-5-methylphenol (20 g), K2CO3 (30 g), acetone (200 ml) and methyl iodide (9.4 ml) were charged to a flask and stirred for 24 h. The solvent was evaporated under reduced pressure and the residue partitioned between ether and water. The organics were separated, washed with 2 M NaOH then water, dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, then NBS (25 g) and benzoyl peroxide (0.5 g) were added and the reaction mixture irradiated with a halogen lamp for 3 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (eluent isohexane) to give the subtitle compound (30 g) used directly without further purification or characterisation.
With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; for 3h;Heating / reflux;
A solution of 4-chloro-3-methoxytoluene (9a; 0.5 g; 3.2 mmol), NBS (0.57 g; 3.2 mmol) and benzoyl peroxide (0.031 g; 0.13 mmol) and 32 mL of DCE were heated at reflux for 3 h. The reaction mixture was cooled, diluted with CH2Cl2 and washed with water and brine. The organic extract was dried filtered and evaporated to yield the bromomethyl compound 9b which was used without further purification.
With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; for 3h;Heating / reflux;
A solution of 4-chloro-3-methoxytoluene (9a; 0.5 g; 3.2 mmol), NBS (0.57 g; 3.2 mmol) and benzoyl peroxide (0.031 g; 0.13 mmol) and 32 mL of DCE were heated at reflux for 3 h. The reaction mixture was cooled, diluted with CH2Cl2 and washed with water and brine. The organic extract was dried filtered and evaporated to yield the bromomethyl compound 9b which was used without further purification.
With ammonium cerium(IV) nitrate; acetic acid; In water; at 100℃; for 1.25h;
Step 2;. 4-Chloro-3- (methyloxy) benzaldehyde; Ceric ammonium nitrate (43.3 g, 79.0 mmol, 4.00 equiv) was dissolved in 1: 1 HOAc/H2O (200 mL). This solution was added dropwise over one hour to a stirred solution of the product from Step 1 (3.09g, 19 7 mmol, 1.00 equiv) in 1: 1 HOAc/H2O (100 mL) at 100 °C. After the addition was complete, the reaction was stirred for an additional 15 minutes. The reaction was cooled, diluted with H20 and extracted twice with Et20. The combined organic extracts were washed three times with H20, three times with satd. NaHC03, and once with brine. The organic phase was dried over MgS04 and concentrated en vacuo to afford the title compound (3. 00g, 89percent) as an amber oil. 1H NMR (400 MHz, CDCL3) 9.97 (s, 1H), 7. 57 (d, 1H), 7.46 (s, 1H), 7.43 (d, 1H), 4.00 (s, 3H).
2,2'-azolbis(4-methoxy-2,4-diaethylvaleronitrile)[ No CAS ]
[ 73909-16-7 ]
[ 103347-14-4 ]
Yield
Reaction Conditions
Operation in experiment
With N-Bromosuccinimide; In dichloromethane;
PREPARATION 91(2) To a solution of 4-chloro-3-methoxytoluene (5.65 g) and N-bromosuccinimide (6.74 g) in anhydrous dichloromethane (60 mL) was added 2,2'-azolbis(4-methoxy-2,4-diaethylvaleronitrile) (674 mg). After stirring for 3 hours under reflux, the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with hexane to give 4-chloro-3-methoxybenzyl bromide as white powders (2.00 g). NMR (CDCl3, delta): 3.92 (3H, s), 4.46 (2H, s), 6.91-6.96 (2H, m), 7.32 (1H, d, J=8 Hz).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2h;Reflux;
Preparation 574-(Bromomethyl)-1 -chloro-2-methoxybenzeneTo a solution of 4-chloro-3-methoxytoluene (200 mg, 1 .28 mmol) in carbon tetrachloride (12 mL) was added /V-bromosuccinimide (228 mg, 1 .28 mmol) and benzoyl peroxide (31 mg, 0.128 mmol). The mixture was heated at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was partitioned between DCM and water. The organic layer was separated, dried over sodium sulphate and evaporated to yield an orange oil. The oil was purified by silica gel chromatography eluting with 30% heptanes in DCM to afford the title compound (45 mg) as a 3.5:1 :1 mixture with 4-chloro-3-methoxytoluene and 1 - chloro-4-(dibromomethyl)-2-methoxybenzene respectively, which was used in the next step without further purification.1H NMR (400 MHz, CDCI3): delta 3.95 (s, 3H), 4.45 (s, 2H), 6.75 (s, 1 H), 6.95 (d, 1 H), 7.33 (d, 1 H).LCMS Rt = 3.17 minutes Molecular ion not observed
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