* 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.
Stage #1: With toluene-4-sulfonic acid In methanol for 0.166667 h; Stage #2: With N-Bromosuccinimide In methanol for 0.416667 h;
General procedure: A solution of the starting material (~10 mmol) and pTsOH (10 mol percent) in MeOH (1.0 mL per mmol starting material) was stirred for 10 min, then a solution of NBS (100 mol percent; recrystallized from H2O) in MeOH (0.1 M) was added dropwise over 20 min from a foiled reaction flask. The reaction mixture was stirred for a further 5 min and then concentrated in vacuo. The resultant residue was purified using column chromatography (CH2Cl2, or 1percent MeOH in CH2Cl2). 3.3. Characterization of Products2-Bromo-4-methylphenol (10) [23]: 10.1 mmol; 1.73 g (92percent);
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 27, p. 6733 - 6737
3
[ 98-54-4 ]
[ 2198-66-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With bromine In tetrachloromethane; chloroform at 0℃; Inert atmosphere
A solution of bromine (7.18 mL, 0.14 mol) in chloroform (25 mL) was added dropwise over 2 hours to a solution of 4-tert-butyl-phenol (20 g, 0.133 mol) in 1:1 v/v chloroform:carbon tetrachloride (64 mL) at 0° C. under nitrogen until a slight red coloration persisted (approximately 1 mL of bromine solution remained). The reaction mixture was then purged with nitrogen overnight. The resulting tan solution was diluted with dichloromethane (50 mL), washed with 1percent aqueous sodium thiosulfate solution (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)phenol (30.5 g, quantitative yield) as a colorless oil.
100%
With bromine In tetrachloromethane; chloroform at 0℃; for 2 h; Inert atmosphere
A solution of bromine (7.18 mL, 0.14 mol) in chloroform (25 mL) was added dropwise over 2 hours to a solution of 4-tert-butyl-phenol (20 g, 0.133 mol) in 1:1 v/v chloroform:carbon tetrachloride (64 mL) at 0° C. under nitrogen until a slight red coloration persisted (approximately 1 mL of bromine solution remained). The reaction mixture was then purged with nitrogen overnight. The resulting tan solution was diluted with dichloromethane (50 mL), washed with 1percent aqueous sodium thiosulfate solution (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)phenol (30.5 g, quantitative yield) as a colorless oil.
97%
With sodium chlorite; acetic acid; sodium bromide In water at 20℃;
A 2-bromo-4-tert-butyl phenol preparation method, comprising the following steps:S11. Under room temperature, 1mol dissolved in P-tert- ding Fen 300-500ml in of acetic acid, then adding 150-250ml water, stirring, add 1.01mol sodium bromide;S12. Room temperature, under stirring, 1-2 hours, dropping 10percent sodium chlorite solution (available chlorine 128,2.0 sodium bromide equivalent), stirring the mixture at room temperature for reaction 4-8 hours.The embodiment of the invention the 2-bromo-4-tert-butyl phenol product, the conversion is 99percent or more, the yield is 97percent, content 98.3percent.
83%
With N-Bromosuccinimide In dichloromethane at 20℃; for 4 h; Cooling with ice
A solution of 4-tert-butyl-phenol (5.070 g, 33.75 mmol) in DCM (200 mL) was cooled in ice-water bath. N-bromosuccinimide (5.020 g, 28.20 mmol) was added to the solution in three equal portions in 30 min intervals. The mixture was allowed to reach room temperature and was stirred for an additional 3 h. The mixture was concentrated under reduced pressure and the residue was triturated with MTBE (300 mL). The solid material was filtered off and the filtrate was washed with water (3.x.300 mL). The organic layer was separated, dried over sodium sulfate and concentrated to yield 8.3 g of oily residue. A 3.0 g sample of the residue was chromatographed on flash Silica (100 g), eluted with 10percent DCM in hexanes to afford 2-bromo-4-tert-butyl-phenol (2.33 g, 83percent). 1H NMR (400 MHz, CDCl3): δ 1.28 (9H, s), 5.37 (1H, bs), 6.95 (1H, d, J=8.4 Hz), 7.24 (1H, dd, J=8.4, 2.8 Hz), 7.44 (1H, d, J=2.8 Hz). ESI-MS: 227.2.
79.6%
With bromine In tetrachloromethane; chloroform at 0 - 20℃; for 6 h;
Example 31: 2-(2-Bromo-4-tert-butyI-phenoxy)-N-(3-fluoro-4- methanesulfonySamno-benzyl)-acetamide <n="105"/>Step 1 : 2-Bromo-4-tert-butyl-phenol; To a suspension of t-buthylphenol (7 g, 46.6 mmol) in CHCI3(H ml) / CCI4 (11 ml) was slowly added bromine (8.2 g, 51.3 mmol) at 0 0C. The mixture was stirred for 6 hrs at room temperature. The reaction mixture was diluted with ether, then washed three times with 10percent Na2S2Oa and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was distilled (10 torr, 120 - 130 0C) to yield 2-bromo-4-tert-butyl-phenol (8.5 g, 79.6percent).1H-NMR (300MHz, CDCI3): δ 7.44 (d, 1 H, J = 2.4 Hz), 7.23 (dd, 1 H, J = 8.4, 2.4 Hz), 6.95 (d, 1 H, J = 8.4 Hz), 5.36 (s, 1 H), 1.28 (s, 9H).
62%
With bromine In tetrahydrofuran; tetrachloromethane; chloroform at 0℃; for 2 h; Inert atmosphere
To a solution of bromine (15 mL) in chloroform(10 g, 62.5 mmol) The solution 0°C And 1: 1 v / v chloroform under argon: carbon tetrachloride (30 mL)4-tert-butylphenol (8.48 g, 56.5 mmol) dissolved in tetrahydrofuran Solution Slowly for 2 hours.The reaction mixture was stirred overnight.The reaction mixture was diluted with dichloromethane (50 mL) and washed with 1percent Na2SO3Aqueous solution and brine.The organic layers were combined, treated with Na2SO4, filtered and evaporated.The residue was purified by flash chromatography (eluent: normal-hexane) to give 2-bromo-4-tert-butylphenol.Yield 8.04 g (62percent).
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 5, p. 1362 - 1368
[2] Chemistry - A European Journal, 2012, vol. 18, # 11, p. 3286 - 3291
[3] Patent: US2014/135320, 2014, A1, . Location in patent: Page/Page column 0219
[4] Patent: US2014/135360, 2014, A1, . Location in patent: Paragraph 0147
[5] Tetrahedron Asymmetry, 1999, vol. 10, # 3, p. 411 - 427
[6] Tetrahedron Letters, 2010, vol. 51, # 2, p. 340 - 342
[7] Tetrahedron, 2010, vol. 66, # 34, p. 6906 - 6911
[8] Organic Process Research and Development, 1999, vol. 3, # 1, p. 5 - 9
[9] Patent: CN105315135, 2016, A, . Location in patent: Paragraph 0026; 0035; 0048; 0049; 0050; 0051; 0052
[10] Angewandte Chemie - International Edition, 2012, vol. 51, # 27, p. 6733 - 6737
[11] Canadian Journal of Chemistry, 1989, vol. 67, p. 2061 - 2066
[12] Journal of the American Chemical Society, [13] Journal of the American Chemical Society, 2010, vol. 132, p. 5566 - 5567
[14] Synthetic Communications, 2007, vol. 37, # 21, p. 3815 - 3826
[15] Journal of the American Chemical Society, 2014, vol. 136, # 21, p. 7662 - 7668
[16] Synlett, 2011, # 15, p. 2265 - 2269
[17] Journal of the American Chemical Society, 1981, vol. 103, p. 3782
[18] Synthetic Communications, 2007, vol. 37, # 8, p. 1381 - 1388
[19] Chemistry - A European Journal, 2004, vol. 10, # 17, p. 4115 - 4125
[20] Tetrahedron, 2009, vol. 65, # 22, p. 4429 - 4439
[21] Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 11, p. 4187 - 4189
[22] Organic Letters, 2006, vol. 8, # 19, p. 4291 - 4293
[23] Patent: US2010/210577, 2010, A1, . Location in patent: Page/Page column 27-28
[24] Tetrahedron Letters, 1995, vol. 36, # 35, p. 6261 - 6262
[25] Tetrahedron, 1999, vol. 55, # 28, p. 8377 - 8384
[26] Chemische Berichte, 1986, vol. 119, # 11, p. 3507 - 3514
[27] Patent: WO2007/120012, 2007, A1, . Location in patent: Page/Page column 104
[28] Patent: KR2018/22137, 2018, A, . Location in patent: Paragraph 0143-0147
[29] Journal of the Chemical Society, 1941, p. 358,359
[30] Tetrahedron, 1991, vol. 47, # 10/11, p. 1911 - 1924
[31] Tetrahedron Letters, 2001, vol. 42, # 45, p. 7925 - 7928
[32] Polish Journal of Chemistry, 2009, vol. 83, # 3, p. 493 - 502
[33] Organic Letters, 2009, vol. 11, # 11, p. 2441 - 2444
[34] Journal of Organic Chemistry, 2018, vol. 83, # 15, p. 7867 - 7877
4
[ 98-54-4 ]
[ 98-22-6 ]
[ 2198-66-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With toluene-4-sulfonic acid In methanol for 0.166667 h; Stage #2: With N-Bromosuccinimide In methanol for 0.416667 h;
General procedure: A solution of the starting material (~10 mmol) and pTsOH (10 mol percent) in MeOH (1.0 mL per mmol starting material) was stirred for 10 min, then a solution of NBS (100 mol percent; recrystallized from H2O) in MeOH (0.1 M) was added dropwise over 20 min from a foiled reaction flask. The reaction mixture was stirred for a further 5 min and then concentrated in vacuo. The resultant residue was purified using column chromatography (CH2Cl2, or 1percent MeOH in CH2Cl2). 3.3. Characterization of Products2-Bromo-4-methylphenol (10) [23]: 10.1 mmol; 1.73 g (92percent);
General procedure: A solution of the starting material (~10 mmol) and pTsOH (10 mol %) in MeOH (1.0 mL per mmol starting material) was stirred for 10 min, then a solution of NBS (100 mol %; recrystallized from H2O) in MeOH (0.1 M) was added dropwise over 20 min from a foiled reaction flask. The reaction mixture was stirred for a further 5 min and then concentrated in vacuo. The resultant residue was purified using column chromatography (CH2Cl2, or 1% MeOH in CH2Cl2). 3.3. Characterization of Products2-Bromo-4-methylphenol (10) [23]: 10.1 mmol; 1.73 g (92%);
With potassium carbonate In acetone for 22h; Inert atmosphere; Reflux;
5.1 2-Bromo-4-(tert-butyl)-1-methoxybenzene
Iodomethane (10.0 mL, 0.161 mol) was added to a mixture of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (29.5 g, 0.129 mol) and potassium carbonate (42.7 g, 0.309 mol) in dry acetone (400 mL) and the reaction mixture refluxed under nitrogen for 22 hours. The cooled reaction mixture was then concentrated and the residue partitioned between ethyl acetate (400 mL) and 0.3 M aqueous sodium hydroxide solution (300 mL). The organic phase was separated, washed with water (300 mL) and saturated brine (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-methoxybenzene (32.09 g, 100% yield) as a light yellow oil. HPLC/MS Rt=7.47 min.
97%
With potassium carbonate In acetone Reflux;
1.b Step (b):2-bromo-4-tert-butyl-1-methoxybenzeneManufacturing
2-Bromo-4-tert-butylphenol (8.04 g) prepared in the above step (a) K2CO3 (11.6 g) and anhydrous acetone(120 mL)Methyl iodide (6.23 g) was slowly added to the mixture.The reaction mixture was refluxed overnight, cooled to room temperature and filtered.The filtrate was evaporated and purified by column chromatography (eluent: normal-hexane) to obtain 2-bromo-4-tert-butyl-1-methoxybenzene. Yield 8.27 g (97%).
16.1 g
With potassium carbonate In acetone at 65℃; for 20h; Inert atmosphere;
With potassium carbonate
4-Methyl-2-bromoanisole and 4-(tert-butyl)-2-bromoanisole were prepared from 4-Methyl-2-bromophenol and 4-(tert-butyl)-2-bromophenol by reaction with MeI in the presence of K2CO3 following literature procedure. (Lygo, Tetrahedron Lett., 1999, 40, 1389)
5.29 g
With potassium carbonate In acetone at 20℃; for 72h;
1.vii (vii) 2-Bromo-4-(tert-butyl)-1-methoxybenzene
(vii) 2-Bromo-4-(tert-butyl)-1-methoxybenzeneA mixture of 2-bromo-4-(tert-butyl)phenol (5 g, 21.82 mmol), K2CO3 (4.52 g, 32.7 mmol) and Mel (1.5 mL, 23.99 mmol) in acetone (70 mL) was stirred at rt for 3 days. The solvent was evaporated and the residue partitioned between DCM (200 mL) and water (200 mL). The organic layer was washed with brine, dried (MgSCv), filtered and evaporated under reduced pressure to afford the sub-title compund (5.29 g) as an oil. 1H NMR (400 MHz, CDCl3) δ: 7.54 (s, 1 H), 7.27 (d, 1 H), 6.83 (d, 1 H), 3.87 (s, 3H), 1.29 (s, 9H).
With potassium carbonate
235A 2-bromo-4-(tert-butyl)-1-methoxybenzene
Example 235A 2-bromo-4-(tert-butyl)-1-methoxybenzene To 2-bromo-4-(tert-butyl)phenol [CASNo.2198-66-5] (5 g, 21.82 mmol) and potassium carbonate (6.03 g, 43.6 mmol) in N,N-dimethylformamide (12 mL) was added iodomethane (2.72 mL, 43.6 mmol) slowly at room temperature. The mixture was stirred at room temperature for 10 minutes and 40° C. overnight. The mixture was filtered and the cake was washed with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified via chromatography on a 40 g silica gel cartridge, eluting with ethyl acetate in heptane at 0-25% gradient to provide the title compound. MS (APCI+) m/z 244 (M+H)+.
2-([2,2'-bipyridin]-6-yl)-4-tert-butylphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
Stage #1: 2-bromo-4-tert-butylphenol With n-butyllithium In diethyl ether at -30.16 - 19.84℃; Schlenk technique; Inert atmosphere;
Stage #2: [2,2]bipyridinyl In diethyl ether; toluene at 49.84℃; for 48h; Schlenk technique; Inert atmosphere; Further stages;
2 4.2 Synthesis of 2-([2,2′-bipyridin]-6-yl)-4-di-tert-butylphenol (BpyPh4-tBu-H, 4)
n-BuLi (8.8mL, 22mmol of a 2.5M solution) was added dropwise at 243K under inert atmosphere to a anhydrous diethyl ether solution (20mL) of 2-bromo-4-di-tert-butylphenol (2.29g, 10mmol). After one night stirring at room temperature the white suspension was slowly added to a warm solution (323K) of 2,2-bipyridine (0.64g, 4mmol) in 20mL of anhydrous toluene. Immediately, a red color was obtained. The solution was maintained at 323K for 48h and then cooled to 273K and hydrolyzed slowly with H2O (30mL). The mixture was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4 for 3h. Following filtration, 2.5g of MnO2 were added. The reaction mixture was stirred for 24h at room temperature and filtered thorough Celite. The solution was evaporated to dryness with a rotary evaporator. The mixture was purified by column chromatography (silica gel, hexane/EtOAc=6:1) to give ligand as a pale yellow oil which was recrystallized in methanol gave pale yellow solid (0.58g, 48%). 1H NMR (400MHz, CDCl3): δ 8.01-7.97 (2H, m, ArH), 7.87 (1H, d, J=8Hz, ArH), 7.81 (1H, d, J=4Hz, ArH), 7.66-7.62 (2H, m, ArH) 7.24-7.23 (1H, m, ArH) 6.87 (1H, dd, J=8.8, 2.8Hz, ArH) 6.81-6.78(1H, m, ArH), 6.14 (1H, d, J=8Hz, ArH), 1.27 (9H, s, Ar-C(CH3)3). 13C NMR (100MHz, CDCl3): δ 157.70, 157.32, 154.68, 153.35, 149.56, 141.50, 138.72, 137.32, 129.02, 124.17, 122.80, 120.79, 119.26, 119.24, 118.08, 117.94, 34.20, 31.56. Mass spectrum (EI, m/z) 304.1571, calc. exact mass C20H20N2O 304.16. Anal. Calcd. (found) for C20H20N2O: N, 9.25 (9.20); C, 81.16 (78.92); 6.82 (6.62)%.
48%
Stage #1: 2-bromo-4-tert-butylphenol With n-butyllithium In diethyl ether at 243 - 293℃; Inert atmosphere;
Stage #2: [2,2]bipyridinyl In diethyl ether; toluene at 293 - 323℃; Inert atmosphere;
Stage #3: With manganese(IV) oxide In diethyl ether; ethyl acetate; toluene at 20℃; for 24h;
4 4.4 Synthesis of 2-([2,2′-bipyridin]-6-yl)-4-tert-butylphenol (BpyPh4-tBu-H, L2)
n-BuLi (4.4 mL, 11 mmol of a 2.5 M solution) was added dropwise at 243 K under inert atmosphere to a anhydrous diethyl ether solution (20 mL) of 2-bromo-4-tert-butylphenol (2.29 g, 10 mmol). After one night stirring at room temperature the white suspension was slowly added to a warm solution (323 K) of 2,2-bipyridine (1.60 g, 10 mmol) in 20 mL of anhydrous toluene. Immediately, a red color was obtained. The solution was maintained at 323 K for 48 h and then cooled to 273 K and hydrolyzed slowly with H2O (30 mL). The mixture was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4 for 3 h. Following filtration, 2.5 g of MnO2 were added. The reaction mixture was stirred for 24 h at room temperature and filtered through Celite. The solution was evaporated to dryness with a rotary evaporator. The mixture was purified by column chromatography (silica gel, hexane/EtOAc = 6:1) to give ligand as a pale yellow oil which was recrystallized in methanol gave pale yellow solid (1.46 g, 48%).
Stage #1: 2-bromo-4-tert-butylphenol With n-butyllithium In hexane; tert-butyl methyl ether at -20℃; for 0.25h;
Stage #2: carbon dioxide In hexane; tert-butyl methyl ether at 0 - 20℃; for 0.75h;
4 Procedure for the synthesis of 5-(tert-hutyl)-2-hydroxyhenzoic acid (25)
nBuLi 1.6 M in hexanes (3.49 g) was added to a round bottom flask equipped with a magnetic stirbar, a thermocouple, and a N2 bubbler. The round bottom flask was cooled down to -20 °C and stirring started. A solution of 2-bromo-4-tert- butylphenol (26) (5.00 g) in MTBE (12.5 mL) was prepared, cooled to - 20 °C, and charged to the round bottom flask drop wise while maintaining the temperature at -20 °C +/- 5 °C. The reaction mixture was stirred at -20 °C +/- 5 °C for 15 min then allowed to warm up to 23 °C. The completeness of the lithiation was measured by 'H NMR (200 pL reaction mixture diluted into 0.75 mL d4-MeOH) after 15 min at room temperature. The reaction was considered complete when less than 1% 2-bromo-4-tert-butylphenol was observed. The reaction mixture was cooled down to 0 °C, dry ice (solid CO2) was added, and the reaction was stirred at room temperature for 45 min. Water (50.0 mL) was added to quench the reaction. The mixture was transferred into a separatory funnel, the phases were separated, and the organic phase was discarded. The aqueous phase was acidified to pH ~2 with 1 M HC1 (15.0 mL), then extracted with MTBE (25.0 mL) three times. The combined organic extracts were concentrated under reduced pressure to yield 5-(tert- butyl)-2-hydroxybenzoic acid (25) as a yellow solid (2.25 g, 53.15% yield); NMR (400 MHz, d4-MeOH): 7.86 (1H, d, J = 2.6 Hz), 7.54 (1H, dd, J = 8.7, 2.6 Hz), 6.85 (1H, d, J = 2.7 Hz), 1.30 (9H, s).
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