* 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] Journal of Biological Chemistry, 1952, vol. 195, p. 239,240
2
[ 15231-91-1 ]
[ 7499-66-3 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 150℃; for 48 h;
6-bromonaphthalen-2-amine (15)6-Bromonaphthalen-2-ol (1.5 g, 6.7 mmol) was heated with ammonium hydroxide (10ml) and ammonium sulfite (3.5 g, 26 mmol) in a seal tube at 150 0C for 48 h. After cooling to room temperature, ethyl acetate was added and organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated to obtain crude product 15 (1.4 g, Y; 94 percent), which was pure enough and can be used directly for next step without further purification. 1H NMR (CDCl3): δ 7.84 (IH, br), 7.56 (IH, d, J= 9.6 Hz), 7.43 (2H, m), 6.95 (2H, m), 3.87 (2H, b). Leigh C. Anderson and Donald G. Thomas: Quinoidation of Triaryl Compounds - Hydroxynaphthyldiphenylcarbinols J. Am. Chem. Soc; 65; 1943; 239, 241.
33%
With ammonium bisulfite; ammonia In water at 190℃; for 24 h;
Preparation of 6-Bromonaphthalen-2-amine (9) 6-Bromo-2-naphthol (2.0 g, 9 mmol), ammonium sulfite (10.4 g, 90 mmol) and 10 mL of ammonia solution were sealed in a tube. The reaction mixture was heated at 190° C. for 24 hrs and allowed to cool to room temperature, the reaction mixture was extracted with EtOAc. HCl (10percent) was added to the organic layer to give a precipitate. After filtration, the solid was dissolved in 10percent of Na2CO3 and extracted with EtOAc, the organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give the product as yellow solid (0.67 g, 33percent). MS [M++43]=265, LC-MS: tR=20.14 min.
21%
With ammonium hydroxide; ammonium sulfite monohydrate In water at 120℃; for 17 h;
General procedure: Ammonium hydroxide aqueous solution ( 841mg, 27.8 mmol, 2 equiv.) was added to a freshly prepared aqueous solution of ammonium sulfite monohydrate (3.2 g, 27.8 mmol, 2 equiv.) in a 35 ml high pressure reaction vessel. Appropriate 2-naphthol analog (1a or 1b) (13.9 mmol, 1 equiv.) was added, and the mixture was stirred for 17 h at 120 °C. The reaction mixture was filtered and the precipitate was washed with cold 5percent aq. NaOH and then dissolved in DCM. The organic layer was again washed with 5percent aq. NaOH (3×30 mL) and dried over anh. sodium sulfate to afford 2-naphthylamines after the removal of solvent in vacuo.
Reference：
[1] Patent: WO2008/124812, 2008, A1, . Location in patent: Page/Page column 53
[2] Chemistry - An Asian Journal, 2010, vol. 5, # 9, p. 2053 - 2061
[3] Patent: US2008/293766, 2008, A1, . Location in patent: Page/Page column 11
[4] Steroids, 2015, vol. 98, p. 107 - 113
[5] Journal of Organic Chemistry, 1960, vol. 25, p. 214 - 215
[6] Journal of the American Chemical Society, 1943, vol. 65, p. 239,241
[7] Journal of Organic Chemistry, 1960, vol. 25, p. 214 - 215
[8] Journal of Physical Chemistry, 1993, vol. 97, # 17, p. 4540 - 4547
[9] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 8, p. 1925 - 1930
3
[ 15231-91-1 ]
[ 13720-06-4 ]
Yield
Reaction Conditions
Operation in experiment
29%
Stage #1: With bromine; triphenylphosphine In acetonitrile at 20 - 70℃; for 2.5 h; Stage #2: at 300℃; for 1 h; neat (no solvent)
Bromine (78.8 g, 493 mmol) was added dropwise to a cooled (0 °C) solution of triphenylphosphine (129 g, 493 mmol) in anhydrous CH3CN (200 mL) and the solution was stirred for 30 min at rt. A solution of 6-bromo-2-naphthol (100 g, 448 mmol) in anhydrous acetonitrile (CH3CN) (200 mL) was added, and the reaction mixture was stirred for a further 2 h at 70 °C. After removal of the solvent (bath temp was increased to 140 °C), the residue was heated to 300 °C for 1 h. After being cooled to 100 °C, the black tar was dissolved in toluene (100 mL), and cooled to rt while stirring. The resulting solution was washed with 1 N NaOH and water, followed by drying over MgSO4. The solvent was removed in vacuo and the residue was dissolved in MeOH (50 mL). The precipitate was filtered and washed with MeOH (200 mL) and diisopropylether (iPr2O), successively, to give 2 (37.2 g, 29percent) as a grey powder. The analytical sample was obtained by recrystallization from AcOEt (light brown plates). 1H NMR (CDCl3) δ: 7.51-7.62 (4H, m), 7.94 (2H, s). IR (KBr): 1568, 1481, 1175, 1134, 1065, 885, 853, 816 cm-1. Anal. Calcd for C10H6Br2: C, 42.00; H, 2.11. Found: C, 42.28; H, 2.18.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1751 - 1770
[2] Synthesis, 1989, # 5, p. 356 - 359
[3] Patent: US6573289, 2003, B1,
4
[ 15231-91-1 ]
[ 1590-25-6 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6367 - 6371
5
[ 15231-91-1 ]
[ 74-88-4 ]
[ 17579-79-2 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 7, p. 2319 - 2323
6
[ 288-32-4 ]
[ 15231-91-1 ]
[ 18162-48-6 ]
[ 17579-79-2 ]
Reference：
[1] Patent: US6333435, 2001, B1,
7
[ 15231-91-1 ]
[ 75-16-1 ]
[ 17579-79-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 15, p. 2634 - 2638
With hydrogenchloride; N-Bromosuccinimide In water; acetone at 20℃; for 0.25 h;
6-Bromo-2-naphthol (500 mg, 2.242 mmol, 1 eq) and NBS (558.7 mg, 3.319 mmol, 1.4 eq) are stirred at RT in 4.4 ml of acetone and 22 μl of 1 N HCl for 15 min. Ethyl acetate is added, and this organic phase is washed three times with 1 N HCl. After drying over magnesium sulfate, filtering and concentrating in vacuum on a rotary evaporator, the desired product is obtained in quantitative yield (677 mg). C10H6Br2O; MW 300/302/304; 1H-NMR (CDCl3): δ 7.90 (d, J=1.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.59 (dd, J=2.1 Hz, J=9.1 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H); 13C-NMR (CDCl3): δ 177.5, 151.0, 131.0, 130.6, 130.1, 128.4, 128.3, 127.2, 118.0, 106.1; IR: 3443, 1688, 1617, 1586, 1382, 1209, 1183, 1130 1/cm
Reference：
[1] Patent: US2010/204234, 2010, A1, . Location in patent: Page/Page column 15
[2] RSC Advances, 2018, vol. 8, # 32, p. 17806 - 17812
[3] Synthetic Communications, 1996, vol. 26, # 13, p. 2597 - 2601
[4] Chemical Communications, 2018, vol. 54, # 39, p. 4935 - 4938
10
[ 109-65-9 ]
[ 15231-91-1 ]
[ 66217-20-7 ]
Reference：
[1] Journal of the American Chemical Society, 1996, vol. 118, # 29, p. 6841 - 6852
[2] Helvetica Chimica Acta, 1985, vol. 68, p. 1406 - 1426
[3] Pharmazie, 1977, vol. 32, # 12, p. 761 - 763
[4] Journal of Medicinal Chemistry, 1987, vol. 30, # 3, p. 574 - 580
11
[ 15231-91-1 ]
[ 324-41-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 8, p. 1925 - 1930
[2] Journal of Organic Chemistry, 1960, vol. 25, p. 214 - 215
12
[ 15231-91-1 ]
[ 64-19-7 ]
[ 5773-80-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
for 1.5 h; Large scale
6-bromo-2-naphthol crystals. Finally, the crude crystals were reintroduced to a mass fraction of 66.7percent with a mass of 2160 Kg Of the acetic acid solution in the re-dissolved, dissolved and then static 1. 5h, filtration, washing, After drying, a recrystallization of 6-bromo-2-naphthoic acid was obtained in a yield of 95. 3percent pure Degrees 99. 55percent, single miscellaneous 0. 45percent
Reference：
[1] Patent: CN106542971, 2017, A, . Location in patent: Paragraph 0035
13
[ 15231-91-1 ]
[ 33626-98-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 23, p. 2865 - 2870
14
[ 1123760-77-9 ]
[ 15231-91-1 ]
[ 91270-68-7 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 22, p. 9338 - 9343
15
[ 15231-91-1 ]
[ 17295-11-3 ]
Reference：
[1] Journal of the American Chemical Society, 1996, vol. 118, # 23, p. 5432 - 5442
16
[ 15231-91-1 ]
[ 17295-11-3 ]
Reference：
[1] Patent: US4374262, 1983, A,
17
[ 15231-91-1 ]
[ 616-38-6 ]
[ 17295-11-3 ]
[ 135-19-3 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 7, p. 2319 - 2323
18
[ 15231-91-1 ]
[ 78119-82-1 ]
Yield
Reaction Conditions
Operation in experiment
78.6%
With n-butyllithium In tetrahydrofuran; N,N-dimethyl-formamide at -78 - 20℃; for 2 h; Inert atmosphere
6-bromo-2-naphthol (0.91 g, 4.1 mmol) was dissolved in 20 mL of dry THF, protected under nitrogen, and n-BuLi (3.4 mL, 8.2 mmol) was added, stirred for 1 hour and then anhydrous DMF (0.941 mL, 12.3 mmol) was added dropwise at -78 ° C,The reaction was continued for 1 hour, raised to room temperature, acidified with 2N hydrochloric acid to pH = 5, extracted with ethyl acetate, washed with water, washed with saturated brine,Dried over anhydrous sodium sulfate, filtered and concentrated to give hexanesulfonic acid (8: 1) column chromatography to give 6-hydroxy-2-naphthaldehyde, yield 78.6percent
Reference：
[1] Journal of the American Chemical Society, 2010, vol. 132, # 41, p. 14625 - 14637
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 4, p. 690 - 705
[3] Journal of Organic Chemistry, 2018,
[4] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2660 - 2673
[5] Patent: US2005/65066, 2005, A1, . Location in patent: Page/Page column 68
[6] Patent: WO2004/80480, 2004, A1, . Location in patent: Page/Page column 149-150
[7] Patent: WO2006/5683, 2006, A1, . Location in patent: Page/Page column 150
[8] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8969 - 8973
[9] Angewandte Chemie - International Edition, 2014, vol. 53, # 14, p. 3722 - 3726[10] Angew. Chem., 2014, vol. 126, # 14, p. 3796 - 3800,5
20
[ 15231-91-1 ]
[ 109-72-8 ]
[ 78119-82-1 ]
Yield
Reaction Conditions
Operation in experiment
81%
With N,N,N,N,N,N-hexamethylphosphoric triamide; tert.-butyl lithium In tetrahydrofuran; N,N-dimethyl-formamide
Step a) N-Butyllithium (35.9 mL, 89.7 mmol) was added dropwise to a cold (-78° C.) solution of 6-bromo-2-naphthol (20.0 g, 89.7 mmol) in THF (200 mL). 6-Hydroxy-2-naphthaldehyde After stirring for 10 minutes, tert-butyllithium (52.76 mL, 89.7 mmol) was added dropwise. The mixture was stirred for 30 min at -78° C., and two hours at -20° C. Then, hexamethylphosphoramide (15.6 mL, 89.7 mmol) was added to the reaction mixture. After stirring for 20 minutes. N,N-dimethylformamide (6.94 mL, 89.7 mmol) was added dropwise. The mixture was allowed to come to room temperature, stirred for 1 hour, and quenched with aqueous ammonium chloride. The mixture was poured into water, acidified with 2N HCL and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexane/EtOAc 3/1), gave a yellow solid (12.5 g, 81percent yield, m.p. 173°-174°
Reference：
[1] Patent: US5399588, 1995, A,
21
[ 2591-86-8 ]
[ 15231-91-1 ]
[ 78119-82-1 ]
Reference：
[1] Dyes and Pigments, 2012, vol. 94, # 2, p. 175 - 182
[2] Tetrahedron, 1999, vol. 55, # 18, p. 5821 - 5830
22
[ 15231-91-1 ]
[ 173471-71-1 ]
Reference：
[1] Organic Letters, 2012, vol. 14, # 10, p. 2598 - 2601
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 17, p. 6972 - 6983
[3] Journal of the American Chemical Society, 2017, vol. 139, # 38, p. 13393 - 13403
[4] Patent: CN104140381, 2018, B,
[5] Patent: CN108218743, 2018, A,
23
[ 15231-91-1 ]
[ 768-95-6 ]
[ 128272-29-7 ]
Reference：
[1] Patent: US5952382, 1999, A,
[2] Patent: US5705167, 1998, A,
24
[ 15231-91-1 ]
[ 22635-62-7 ]
[ 128272-29-7 ]
Reference：
[1] Patent: US5015758, 1991, A,
25
[ 15231-91-1 ]
[ 173194-95-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 2 h; Inert atmosphere Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at -70 - 20℃; for 3.5 h; Inert atmosphere Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water at 20℃; for 2 h;
5.58 g (25 mmol) of 6-bromo-2-naphthol was dissolved in 125 ml of dehydrated tetrahydrofuran in an argon atmosphere. After cooling the solution to -70°C, 33 ml (55 mmol) of a hexane solution of n-butyllithium was slowly added dropwise to the solution over 30 minutes. The mixture was stirred at -70°C for 1.5 hours. After the addition of 11.5 ml (50 mmol) of triisopropyl borate, the mixture was stirred at -70°C for 30 minutes. The mixture was then stirred for 3 hours while allowing the mixture to slowly return to room temperature. After the addition of 100 ml of 2 M hydrochloric acid to the reaction mixture, the mixture was stirred at room temperature for 2 hours. The reaction solution was then separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was combined, washed with a saturated sodium chloride solution, and dried with anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with dichloromethane in a suspended state to obtain 4.02 g of 6-hydroxynaphthalen-2-ylboronic acid (yield: 85percent).
43%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.33333 h; Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at -78℃; for 0.25 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water at 0℃; for 0.25 h;
6-Hydroxynaphthalen-2-yI-2-boronic acid (TJA02057) Ci0H9BO3 MW 187.99. A dry 250 ml r.b. flask was loaded with 6-bromo-2-naphthol (5.38 g, 24.1 mmol) and purged with N2(g>. Anhydrous THF (80 mL) added with stirring and the vessel cooled to -78 0C (dry ice/acetone bath). After 30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was added dropwise over 20 min. The reaction was left to stir for 1 h. Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with the reaction still at -78 °C. After 15 min of stirring at this temperature the dry ice/acetone bath was removed. At 0 0C 2 M HCl(aq) (5 mL) was added and the reaction left to stir for a further 15 min. THF removed under vacuum and residues taken up in distilled water (20 mL) and dichloromethane (50 mL) added. The resulting white precipitate was filtered and washed with dichloromethane and distilled water. Dried under vacuum at 70 0C to give the title compound as an off white solid (1.88 g, 43 percent).1H NMR (270 MHz5 DMSCW6) δ 7.04-7.08 (2H, m, ArH), 7.58-7.61 (IH, d, J= 8.4 Hz, ArH), 7.73-7.76 (2H5 d, J= 8.4 Hz, ArH)5 7.72-7.73 (IH5 d5 J= 1.5 Hz5 ArH)5 8.06 (2H5 S5 ArB(OH)2), 8.23 (IH5 S5 ArH) and 9.83 (IH5 S5 ArOH); HPLC (70 percent CH3CN in H2O) tτ= 5.431 (97.67 percent); LCMS (APCI)5 m/z 187.04 (M" - H5 100 percent), 142.92 ((M" - H) - B(OH)2, 55).
With Selectfluor In acetonitrile at 60℃; for 12 h; Inert atmosphere
Under argon atmosphere, 4.46 g (0.02 mol) of 6-bromo-2-naphthol and 250 ml of acetonitrile were placed in a 250 ml three-necked flask under stirring,The solution was dissolved, followed by the addition of Selectfluor 8.50 g (0.024 mol). The mixture was heated to 60 ° C with stirring for 12 h.The reaction mixture was poured into 100 ml of water and added with 150 ml of ethyl acetate. The mixture was stirred and allowed to stand. The organic layer was separated, washed with water three times, dried over anhydrous sodium sulfate, filtered and concentrated. The crude mixture was stirred with petroleum ether / Ethyl ester system to do the agent, the silica gel column, after the column liquid was swirled to a yellow solid precipitation stopped rotating when placed at room temperature, precipitation of a large number of yellow solid, filtered dry yellow solid6-bromo-1-fluoro-2-naphthol 2.64 g, yield 54.6percent
Reference：
[1] Patent: CN106336350, 2017, A, . Location in patent: Paragraph 0082; 0087; 0088
[2] Patent: WO2006/52555, 2006, A2, . Location in patent: Page/Page column 28; 49
[3] Patent: WO2017/184476, 2017, A1, . Location in patent: Page/Page column 45
With ammonium bisulfite; ammonia; water; at 150℃; for 48h;
6-bromonaphthalen-2-amine (15)6-Bromonaphthalen-2-ol (1.5 g, 6.7 mmol) was heated with ammonium hydroxide (10ml) and ammonium sulfite (3.5 g, 26 mmol) in a seal tube at 150 0C for 48 h. After cooling to room temperature, ethyl acetate was added and organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated to obtain crude product 15 (1.4 g, Y; 94 %), which was pure enough and can be used directly for next step without further purification. 1H NMR (CDCl3): delta 7.84 (IH, br), 7.56 (IH, d, J= 9.6 Hz), 7.43 (2H, m), 6.95 (2H, m), 3.87 (2H, b). Leigh C. Anderson and Donald G. Thomas: Quinoidation of Triaryl Compounds - Hydroxynaphthyldiphenylcarbinols J. Am. Chem. Soc; 65; 1943; 239, 241.
33%
With ammonium bisulfite; ammonia; In water; at 190℃; for 24h;
Preparation of 6-Bromonaphthalen-2-amine (9) 6-Bromo-2-naphthol (2.0 g, 9 mmol), ammonium sulfite (10.4 g, 90 mmol) and 10 mL of ammonia solution were sealed in a tube. The reaction mixture was heated at 190 C. for 24 hrs and allowed to cool to room temperature, the reaction mixture was extracted with EtOAc. HCl (10%) was added to the organic layer to give a precipitate. After filtration, the solid was dissolved in 10% of Na2CO3 and extracted with EtOAc, the organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give the product as yellow solid (0.67 g, 33%). MS [M++43]=265, LC-MS: tR=20.14 min.
21%
With ammonium hydroxide; ammonium sulfite monohydrate; In water; at 120℃; for 17h;
General procedure: Ammonium hydroxide aqueous solution ( 841mg, 27.8 mmol, 2 equiv.) was added to a freshly prepared aqueous solution of ammonium sulfite monohydrate (3.2 g, 27.8 mmol, 2 equiv.) in a 35 ml high pressure reaction vessel. Appropriate 2-naphthol analog (1a or 1b) (13.9 mmol, 1 equiv.) was added, and the mixture was stirred for 17 h at 120 C. The reaction mixture was filtered and the precipitate was washed with cold 5% aq. NaOH and then dissolved in DCM. The organic layer was again washed with 5% aq. NaOH (3×30 mL) and dried over anh. sodium sulfate to afford 2-naphthylamines after the removal of solvent in vacuo.
With potassium hydroxide; sulfur dioxide; In water;
EXAMPLE 1 Dissolve 3.4g (0.03 mol) of potassium hydroxide pellets in 25g (1.4 mols) of water, slowly introduce 0.8g (0.0125 mol) of sulfur dioxide, then add 3.0g (0.01 mol) of <strong>[16239-18-2]1,6-dibromo-2-naphthol</strong>, and heat the reaction mixture at 45 C. Analysis of the reaction mixture after one hour shows 99% conversion to 6-bromo-2-naphthol.
With sulfur dioxide; potassium carbonate; In methanol; water;
EXAMPLE 2 Dissolve 3.0g (0.01 mol) of <strong>[16239-18-2]1,6-dibromo-2-naphthol</strong> and 1.4g (0.01 mol) of potassium carbonate in a mixture of 29.9g (1.66 mols) of water and 48.6g (1.52 mols) of methanol at room temperature. Introduce 3.3g (0.05 mol) of sulfur dioxide into the resultant clear solution to form a milky mixture and then heat the mixture to 45-50C to form a clear solution. After two hours at 45-50C, no reaction has occurred. Add another 2.8g (0.02 mol) of potassium carbonate to effect an exothermic reaction that raises the temperature to 68C. Maintain the temperature at 65C for 1.5 hours while monitoring the reaction. GC analysis shows 84% conversion to 6-bromo-2-naphthol after 30 minutes at 65C and complete conversion after 1.5 hours.
at 87℃; under 760.051 Torr; for 0.583333h;Inert atmosphere; Large scale;
<strong>[16239-18-2]1,6-dibromo-2-naphthol</strong> was 96.8%. After the reaction, the nano-Pd / Fe with an iron element quality of 288Kg was added and the temperature was maintained at 87 C. At the same time, nitrogen was introduced into the standard atmospheric pressure for 35 min to obtain 6-bromo-2-naphthol solution. The temperature of the reactor was then reduced to 35 C using 2592 Kg of pure water The 6-bromo-2-naphthol solution was diluted and allowed to stand for 3 h and then filtered to give crude 6-bromo-2-naphthol crystals. Finally, the crude crystals were reintroduced into a acetic acid solution having a mass fraction of 66.7% by mass of 2160 Kg
Bromine (78.8 g, 493 mmol) was added dropwise to a cooled (0 C) solution of triphenylphosphine (129 g, 493 mmol) in anhydrous CH3CN (200 mL) and the solution was stirred for 30 min at rt. A solution of 6-bromo-2-naphthol (100 g, 448 mmol) in anhydrous acetonitrile (CH3CN) (200 mL) was added, and the reaction mixture was stirred for a further 2 h at 70 C. After removal of the solvent (bath temp was increased to 140 C), the residue was heated to 300 C for 1 h. After being cooled to 100 C, the black tar was dissolved in toluene (100 mL), and cooled to rt while stirring. The resulting solution was washed with 1 N NaOH and water, followed by drying over MgSO4. The solvent was removed in vacuo and the residue was dissolved in MeOH (50 mL). The precipitate was filtered and washed with MeOH (200 mL) and diisopropylether (iPr2O), successively, to give 2 (37.2 g, 29%) as a grey powder. The analytical sample was obtained by recrystallization from AcOEt (light brown plates). 1H NMR (CDCl3) delta: 7.51-7.62 (4H, m), 7.94 (2H, s). IR (KBr): 1568, 1481, 1175, 1134, 1065, 885, 853, 816 cm-1. Anal. Calcd for C10H6Br2: C, 42.00; H, 2.11. Found: C, 42.28; H, 2.18.
With bromine; triphenylphosphine; In methanol; dichloromethane; acetonitrile;
(i) Production of 2,6-Dibromonaphthalene To a solution of triphenylphosphine (64.5 g) in acetonitrile (150 ml) was added dropwise bromine (39 g) under ice cooling, and the mixture was stirred at room temperature for 30 min. To the mixture was added a solution of 6-bromo-2-naphthol (50.0 g) in acetonitrile (100 ml). The mixture was stirred at 70 C. for 2 h. The solvent was distilled off, and the residue was heated at 250 C. for 5 h. The obtained black solid was dissolved in dichloromethane, washed with IN-sodium hydroxide solution and dried. The solvent was distilled off, and to the residue was added methanol (50 ml). The mixture was subjected to filtration and the residue was washed with methanol. The resulting solid was purified by column chromatography (eluent, hexane:THF=1:1), then recrystallized from ethyl acetate to give the titled compound (17.5 g) as brown plates. 1H-NMR (CDCl3) delta: 7.51-7.62 (4H, m), 7.94 (2H, s). IR (KBr): 1769, 1568, 1481, 1175, 1134, 1065, 964, 885, 853, 816 cm-1.
EXAMPLE 94 6-Cyano-2-naphthol The noted compound was prepared from 6-bromo-2-naphthol according to the procedure of Aoyama et al., Chem. Pharm. Bull., 33, 1458 (1985) in 56% yield after flash chromatography.
In ethanol; N,N-dimethyl-formamide;
EXAMPLE 13A 6-hydroxy-2-naphthonitrile A solution of 6-bromo-2-naphthol (25.0 g, 112 mmol) and copper(I) cyanide (11 g, 123 mmol) in DMF (30 mL) was heated to 135 C., stirred for 18 hours, cooled to room temperature, diluted with ethyl acetate (50 mL), triturated with 10% sodium hydroxide, and filtered through diatomaceous earth (Celite). The filtrate was adjusted to pH 2 and extracted with ethyl acetate. The combined extracts were concentrated, dissolved in ethanol (150 mL), triturated with water, and filtered to provide the desired product. MS (DCI/NH3) m/e 170 (M+H)+.
In ethanol; N,N-dimethyl-formamide;
EXAMPLE 28A 6-Hydroxy-2-naphthalenecarbonitrile A solution of 6-bromo-2-naphthol (25.0 g, 112 mmol) and copper(I) cyanide (11 g, 123 mmol) in DMF (30 mL) was heated at 135 C. for 18 h, cooled, diluted with ethyl acetate (50 mL), triturated with 10% aq sodium hydroxide and filtered through Celite. The filtrate was acidified to pH 2 and extracted with ethyl acetate. The combined extracts were concentrated, dissolved in ethanol (150 mL) and triturated with water to precipitate 14.01 g of the title compound. MS (DCI/NH3) m/e 170 (M+H)+.
With hydrogenchloride; N-Bromosuccinimide; In water; acetone; at 20℃; for 0.25h;
6-Bromo-2-naphthol (500 mg, 2.242 mmol, 1 eq) and NBS (558.7 mg, 3.319 mmol, 1.4 eq) are stirred at RT in 4.4 ml of acetone and 22 mul of 1 N HCl for 15 min. Ethyl acetate is added, and this organic phase is washed three times with 1 N HCl. After drying over magnesium sulfate, filtering and concentrating in vacuum on a rotary evaporator, the desired product is obtained in quantitative yield (677 mg). C10H6Br2O; MW 300/302/304; 1H-NMR (CDCl3): delta 7.90 (d, J=1.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.59 (dd, J=2.1 Hz, J=9.1 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H); 13C-NMR (CDCl3): delta 177.5, 151.0, 131.0, 130.6, 130.1, 128.4, 128.3, 127.2, 118.0, 106.1; IR: 3443, 1688, 1617, 1586, 1382, 1209, 1183, 1130 1/cm
With ferrous perchlorate; (1R,2R)‐N1,N2‐di(quinolin‐8‐yl)cyclohexane‐1,2‐diamine; oxygen; In chlorobenzene; at 50℃; under 760.051 Torr;Schlenk technique; Molecular sieve;
General procedure: (S)-[1,1′-Binaphthalene]-2,2′-diol (2a) [47]: Fe(ClO4)2 (12.7 mg, 10 mol%; NOTE: perchlorate salt isa potential explosive [72] and should be handled with extreme caution) and L1 (9.2 mg, 5 mol%) weredissolved in anhydrous PhCl (5 mL) in a 25 mL Schlenk tube, and the mixture was stirred at roomtemperature for 30 min. Then, 2-naphthol (72.3 mg, 0.5 mmol, 1.0 equiv) and MS 4Å (152.7 mg) wereadded. The reaction mixture was quickly evacuated and refilled with oxygen (1 atm), and thisoperation was repeated for three cycles. Then the mixture was stirred at 50 C under oxygen, asmonitored by TLC. The desired product was obtained (60.6 mg, 84% yield) as a pale yellow solid afterpurification by silica gel chromatography (PE to PE/EA = 10/1 to 5/1). 80:20 er (HPLC: Chiralpak ASH,hexane/propan-2-ol = 90/10, 0.5 mL/min, λ = 230 nm, tR (min): major = 24.9, minor = 38.9). 1H-NMR(400 MHz, Chloroform-d) δ 7.99 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 7.9 Hz, 2H), 7.38 (td, J = 7.7, 1.6 Hz, 4H),7.31 (ddd, J = 8.2, 6.9, 1.4 Hz, 2H), 7.19-7.12 (m, 2H), 5.04 (s, 2H).
5.58 g (25 mmol) of 6-bromo-2-naphthol was dissolved in 125 ml of dehydrated tetrahydrofuran in an argon atmosphere. After cooling the solution to -70C, 33 ml (55 mmol) of a hexane solution of n-butyllithium was slowly added dropwise to the solution over 30 minutes. The mixture was stirred at -70C for 1.5 hours. After the addition of 11.5 ml (50 mmol) of triisopropyl borate, the mixture was stirred at -70C for 30 minutes. The mixture was then stirred for 3 hours while allowing the mixture to slowly return to room temperature. After the addition of 100 ml of 2 M hydrochloric acid to the reaction mixture, the mixture was stirred at room temperature for 2 hours. The reaction solution was then separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was combined, washed with a saturated sodium chloride solution, and dried with anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with dichloromethane in a suspended state to obtain 4.02 g of 6-hydroxynaphthalen-2-ylboronic acid (yield: 85%).
43%
6-Hydroxynaphthalen-2-yI-2-boronic acid (TJA02057) Ci0H9BO3 MW 187.99. A dry 250 ml r.b. flask was loaded with 6-bromo-2-naphthol (5.38 g, 24.1 mmol) and purged with N2(g>. Anhydrous THF (80 mL) added with stirring and the vessel cooled to -78 0C (dry ice/acetone bath). After 30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was added dropwise over 20 min. The reaction was left to stir for 1 h. Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with the reaction still at -78 C. After 15 min of stirring at this temperature the dry ice/acetone bath was removed. At 0 0C 2 M HCl(aq) (5 mL) was added and the reaction left to stir for a further 15 min. THF removed under vacuum and residues taken up in distilled water (20 mL) and dichloromethane (50 mL) added. The resulting white precipitate was filtered and washed with dichloromethane and distilled water. Dried under vacuum at 70 0C to give the title compound as an off white solid (1.88 g, 43 %).1H NMR (270 MHz5 DMSCW6) delta 7.04-7.08 (2H, m, ArH), 7.58-7.61 (IH, d, J= 8.4 Hz, ArH), 7.73-7.76 (2H5 d, J= 8.4 Hz, ArH)5 7.72-7.73 (IH5 d5 J= 1.5 Hz5 ArH)5 8.06 (2H5 S5 ArB(OH)2), 8.23 (IH5 S5 ArH) and 9.83 (IH5 S5 ArOH); HPLC (70 % CH3CN in H2O) ttau= 5.431 (97.67 %); LCMS (APCI)5 m/z 187.04 (M" - H5 100 %), 142.92 ((M" - H) - B(OH)2, 55).
Example 1 Synthesis of methyl 3-[4-cyclohexylmethyloxy-3-(6-hydroxynaphthalen-2-yl)-phenyl]Propionate (Compound No. 001) (Preparation Method 4, Step d-1) A solution of 2-bromo-6-hydroxynaphthalene (1.15 g, TCI) in anhydrous THF (50 ml) was cooled to -78 C. under argon atmosphere, added dropwise with 1.6 M solution of n-butyllithium in hexane (6.88 ml, Ald) over 20 minutes and stirred for 30 minutes.The reaction mixture was added dropwise with triisopropyloxyborane (henceforth abbreviated as "(IPrO)3B, 1.73 ml, Ald) over 10 minutes, stirred for 30 minutes, then warmed to room temperature and further stirred for 2 hours.The reaction mixture was added with 0.5 M aqueous sulfuric acid (10 ml) and extracted with diethyl ether (100 ml*3).The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 6-hydroxy-2-naphthaleneboronic acid (1.85 g).A solution of this product in ethanol (5.0 ml), Intermediate 7 (1.16 g) and 2 M aqueous sodium carbonate (12.0 ml) were added with toluene (10.0 ml) and tetrakistriphenylphosphine palladium (0) (henceforth abbreviated as "(Ph3P)4Pd", 570 mg, Nacalai Tesque) and stirred at 100 C. for 25 hours.The reaction mixture was added with ethyl acetate (300 ml) and washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine.The organic layer was dried, and then the solvent was evaporated under reduced pressure.The residue was purified by flash column chromatography (hexane:ethyl acetate=6:1) to obtain the title compound (Compound No. 001, 1.04 g).
With oxygen;C26H28N2O9V2; In tetrachloromethane; at 0℃; for 96h;Product distribution / selectivity;
EXAMPLE 11 Oxidative Coupling of 2-naphthol and its Derivatives Catalyzed by 1c A reaction flask described in example 9 was charged with a solution of catalyst 1c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 6-bromo-2-naphthol (44 mg, 0.2 mmol) in anhydrous CCl4 (1 mL) under 0 C. The reaction mixture was stirred at 0 C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether-1/3) to give (R)-BINOL 3c, Yield 99%. [α]D25=-33.7 (c=0.4 in EtOAc), 1H NMR (300 MHz, CDCl3) δ (ppm) 8.06 (d, J=1.8 Hz, 2H, 2*HC (4)), 7.89 (d, J=9.0 Hz, 2H, 2*HC (5)), 7.37 (d, J=6.9 Hz, 2H, 2*HC (8)), 7.36 (dd, J=9.0 Hz, 1.8 Hz, 2H, 2*HC (7)), 6.96 (d, J=9.0 Hz, 2H, 2*HC (3)), 5.08 (s, 2H, 2*OH). e.e. 90%, and the configuration was R (Kromasil CHI-TBB column, Hexane/propan-2-ol=80: 20; flow rate 1 mL/min; S-isomer, tR 6.68 min and R-isomer, tR 7.51 min).
5-fluoro-2-(6-hydroxy-2-naphthyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 80.0℃; for 17h;
Step 1: 6-(2-Cvano-4-fluorophenyl)-2-naphtfayl trifluorometfaanesulfonate; A mixture of 6-bromo-2-naphthol (12.0 g, 52.2 mmol), 5-fluoro-2-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)benzonitrile (16.7 g, 67.6 mmol, prepared according to the method disclosed in patent WO/2003099816), sodium carbonate solution (2M, 75 mL) and tetrakis(triphenylphosphine)palladium (0) (1.2 g, 1.0 mmol) in 1,4-dioxane (360 mL) was heated at 8O0C for 17 hours. It was allowed to cool then poured into dilute hydrochloric acid (1 M, 360 mL) and extracted with ethyl acetate (3 x 200 mL). These extracts were washed with water and brine then dried (MgSO4), filtered and the solution concentrated in vacuo to a volume of ~100 mL. Solid was filtered off and sucked dry to give 5-fluoro-2-(6-hydroxy-2-naphthyl)benzamide as a white solid. This solid (6.3 g, 22.4 mmol) was suspended in dichloromethane (130 mL)/ pyridine (11 mL) at O0C under nitrogen, and trifluoromethane sulfonic anhydride (11 mL, 65.5 mmol) added gradually over 40 minutes before leaving overnight to return to ambient temperature. Solvent was removed in vacuo, water (400 mL) added and extracted into ethyl acetate (2 x 300 mL). These extracts were washed with water and brine then dried(MgSO4), filtered and solvent removed in vacuo. Purification by flash column chromatography eluting with 10% ethyl acetate/isohexane gave 6-(2-cyano-4-fluorophenyl)-2-naphthyl trifluoromethanesulfonate (8.0 g, 38%). 1H NMR (500 MHz, CDCl3) delta 8.06 (1 H, s), 8.01 (2 H, dd, J = 4.0, 9.0 Hz), 7.82 (1 H, d, J = 2.3 Hz), 7.73 (1 H, dd, J = 1.7, 8.5 Hz), 7.60 (1 H, dd, J = 5.2, 8.6 Hz), 7.53 (1 H, dd, J = 2.6, 7.9 Hz), 7.47 - 7.41 (2 H, m).
With potassium fluoride; In methanol; acetonitrile;
Production Example 6-1 2-(6-bromo-2-naphthyloxy)-4-nitrobenzonitrile After heating to reflux <strong>[34667-88-4]2-fluoro-4-nitrobenzonitrile</strong> (1 g), 6-bromo-2-naphthol (1.41 g), potassium fluoride/alumina (0.7 g) and 18-crown-6 (0.16 g) in acetonitrile, the mixture was reacted for 12 hours. It was then cooled to room temperature, the insoluble portion was filtered using celite, the ethyl acetate layer was washed with water and saturated saline and then dried over magnesium sulfate, and the solvent was distilled off. Methanol was added to the residue for crystallization to obtain 1.43 g of 2-(6-bromo-2-naphthyloxy)-4-nitrobenzonitrile. 1H-NMR (CDCl3) delta:7.31 (1H, dd, J=2.4, 8.8 Hz), 7.54 (1H, d, J=2.0 Hz), 7.62-7.70 (3H, m), 7.88 (1H, s), 7.90 (1H, s), 8.01 (1H, dd, J=2.0, 8.4 Hz), 8.08 (1H, s).
tetrakis(triphenylphophine)palladium (0)[ No CAS ]
[ 247924-47-6 ]
[ 588-93-2 ]
[ 247924-46-5 ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In ethanol; toluene;
Synthesis of 6-(4-propylphenyl)-2-naphthol 50 g of 6-bromo-2-naphthol and 48 g of 4-propylphenylboric acid (synthesised by reacting a Grignard reagent prepared from 4-propylbromobenzene with trimethyl borate, and then subjecting the reaction product to hydrolysis with hydrochloric acid) were dissolved in a mixture of 200 ml of toluene and 100 ml of ethanol. To the solution was then added 200 ml of a 2 N aqueous solution of potassium carbonate. To the reaction mixture was then added 2.6 g of tetrakis(triphenylphophine)palladium (0). The reaction mixture was then heated under reflux for 6 hours. The reaction solution was then allowed to cool to room temperature. The resulting organic phase was then separated. The resulting aqueous phase was then extracted with toluene The material thus extracted and the organic phase ware together washed sequentially with diluted hydrochloric acid, water and saturated brine, and then dehydrated and dried over anhydrous sodium sulfate, The solvent was then distilled off to obtain 47 g of 6-(4-propylphenyl)-2-naphthol in crystal form.
With sulfuric acid; In diethyl ether; n-heptane; dichloromethane;
(a) Preparation of 3-(1-adamantyl)-6-bromo-2-naphthol 56 g (0.25 mol) of 6-bromo-2-naphthol, 38.2 g (0.25 mol) of 1-adamantanol and 500 ml of a mixture of dichloromethane and heptane (40/60) were introduced into a round-bottomed flask. 15 ml of concentrated sulfuric acid were added and the reaction mixture was stirred at room temperature for 48 hours. The solid was filtered off, washed with heptane (3*100 ml) and dissolved in ethyl ether and the organic phase was washed with water, separated by settling, dried over magnesium sulfate and evaporated. 60.1 g (67%) of the expected compound were collected, which compound had a melting point of 215-6 C.
With hydrogenchloride; In n-heptane; dichloromethane; water;
(a) Synthesis of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene: 22.3 g (0.1 mol) of 6-bromo-2-naphthol, 15.2 g (0.1 mol) of 1-adamantanol and 100 ml of dichloromethane were introduced into a round-bottomed flask. 5.5 ml of concentrated hydrochloric acid were added and the mixture was stirred at room temperature for twelve hours. The mixture was evaporated to dryness and the residue was taken up in water and neutralized with sodium bicarbonate. The resulting mixture was extracted with ethyl acetate and the organic phase was separated out after settling of the phases had taken place, dried over magnesium sulfate and evaporated. The residue obtained was triturated in a mixture of dichloromethane and heptane (30/70), filtered and dried. 19 g (53%) of the expected compound, with a melting point of 215-6 C., were collected.
With sodium acetate; aniline; In 5,5-dimethyl-1,3-cyclohexadiene; ethanol; water;
EXAMPLE I N-Phenyl-6-bromo-2-naphthylamine Xylene was distilled from a mixture of 6-bromo-2-naphthol (16.4 g., 0.0735 mol.), aniline (25 ml, 0.274 mol.), xylene (25 ml), and p-toluene sulfonic acid monohydrate (2.7 g., 0.014 mol.) until the reaction temperature reached 190 C. The mixture was held at this temperature for 5 hours, and then cooled to 85 C. Sodium acetate (3.7 g.) and ethanol (100 ml) were added and the mixture was heated to reflux. The solution was cooled to 5 C. and the resulting slurry was filtered. The solids were washed with cold ethanol (50 ml). The air-dried solids (19.5 g.) were reslurried in hot water (150 ml) and filtered to give a gray solid, 19.3 g, 88% yield, m.p. 126.2-128.3 C.
With Selectfluor; In acetonitrile; at 60℃; for 12.0h;Inert atmosphere;
Under argon atmosphere, 4.46 g (0.02 mol) of 6-bromo-2-naphthol and 250 ml of acetonitrile were placed in a 250 ml three-necked flask under stirring,The solution was dissolved, followed by the addition of Selectfluor 8.50 g (0.024 mol). The mixture was heated to 60 C with stirring for 12 h.The reaction mixture was poured into 100 ml of water and added with 150 ml of ethyl acetate. The mixture was stirred and allowed to stand. The organic layer was separated, washed with water three times, dried over anhydrous sodium sulfate, filtered and concentrated. The crude mixture was stirred with petroleum ether / Ethyl ester system to do the agent, the silica gel column, after the column liquid was swirled to a yellow solid precipitation stopped rotating when placed at room temperature, precipitation of a large number of yellow solid, filtered dry yellow solid6-bromo-1-fluoro-2-naphthol 2.64 g, yield 54.6%
With Selectfluor; 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2,2,2]octane-1,4-bis(tetrafluoroborate); In methanol; at 0 - 25℃; for 15.0h;
Commercially available 6-bromo-2-hydroxynaphthalene (3 g, 13.5 mmol) in 100 mL of methanol was treated with SELECTFLUOR (4 1 g, 11.5 mmol) and ACCUFLUOR (0.63 g, 1.9 mmol) at 0 0C, warmed to room temperature, aged for 15 h, and the mixture concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, diethyl ether/hexanes) to give the desired 6-bromo-1-fluoro-2-hydroxynaphthalene product EXAMPLE 19 was prepared from this intermediate in a manner similar to EXAMPLE 17 above and illustrated in Scheme 5. The desired product was purified via preparative RPHPLC. 1H NMR (CD3OD, 600 MHz) delta 8.51 (d, 1H), 8.02 (dd, 1H), 7.82 (d, 1H), 7.61 (s, 1H), 7.51 (t, 1H), 7.42 (d, 1H), 7.38 (dd, 1H), 7.13- 7.08 (m, 2H), 3.14 (t, 2H), 2.79 (t, 2H); LCMS m/z 354 (M++1).
With N-fluorobis(benzenesulfon)imide; In N,N-dimethyl-formamide; at 25℃; for 48.0h;
Step 1 (0294) 6-bromonaphthalen-2-ol (5 g, 22.41 mmol) was dissolved in DMF (50 mL) in a 250 mL flask. N-fluorobenzenesulfonimide (21.20 g, 67.2 mmol) was added and the solution was stirred at 25C for 2 days. The solution was concentrated . The residue was purified by column chromatography on silica gel (120 g), eluting with Hexane and EtOAc (0% to 50%) to give 6-bromo-l-fluoronaphthalen-2-ol (6.1 g, purity: 88%, yield: 99%).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water;Heating / reflux;
5a Preparation of the phenolic ligand[0081] 6-bromo-2-naphthol 6.1 g, 0.0273 mol; 3,5-trifluoromethylphenylboronic acid 7.6g, 0.0295 mol; potassium carbonate 18.6 g, 0.1346 mol; water 18OmL; ethyleneglycoldimethylether 18OmL were combined and sparged with nitrogen for 45 minutes. Tetrakistriphenylphosphine Pd(O) (1.2g, 0.001 mol) was then added and the mixture was refluxed overnight. Upon cooling to room temperature 50OmL of acidic water was added and extracted with dichloromethane. The organic layer was preabsorbed onto silica gel and eluted down a silica column with hexanes 80%/ethylacetate 20%. The eluted organic material was concentrated and taken up in ethanol and stirred with activated carbon, filtered and concentrated_to precipitate the desired phenolic ligand in 75% yield.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 48h;
0074] A degassed solution of K2CO3 (8.2 g, 5.9 mmol) in H2O (100 ml_) was added to a mixture of 6-bromo-2-naphthol (3.43 g, 1.54 mmol), 4-(t-butylphenyl)boronic acid (3.21 g, 1.80 mmol) and Pd(PPh3)4 (0.89 g, 0.77 mmol) in monoglyme (100 ml_) and then heated to 800C for two days. Upon cooling, the mixture was diluted with diethylether and 1M HCI (~20mL) was added. After neutralization with a saturated solution of NaHCO3, the organic layer was separated and dried over MgSO4. Upon evaporation of the solvent a yellow solid was obtained which was purified by chromatography on silica (hexane) to obtain the desired product as a tan powder (3.8 g, 89%).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 6h;Reflux;
Take a 100ml single-necked round bottom flask and add a stir bar,Add a certain amount of 6-bromo-2-naphthol in sequence,Tetrakis (triphenylphosphine) palladium, sodium carbonate, then add a mixed solution of toluene and water,Finally, an ethanol solution in which arylboronic acid is dissolved is added to the round bottom flask,The mixed solution was refluxed at 85C for 6h. After the reaction was completed, part of the solvent was removed. The residue was extracted with ethyl acetate and water. The pH of the mixed solution was adjusted to 2 with hydrochloric acid solution. The aqueous layer in the mixed solution was extracted with at least ethyl acetate. Three times, the organic phase obtained by extraction was washed with water and brine successively, and then dried over anhydrous sodium sulfate, added to silica gel to spin dry, and purified by flash preparative chromatography to obtain the product.
With sulfuric acid; In hexane; n-heptane; water; ethyl acetate;
EXAMPLE 9 Preparation of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene In a 100 ml flask, under a nitrogen atmosphere, are placed 2 g of 1-acetoxyadamantane and 20 ml of n-heptane, and 0.5 g of concentrated sulfuric acid is introduced drop by drop. At a temperature of about 22.C, 2.3 of 6-hydroxy-2-bromonaphthalene are added slowly and the mixture is left in vigorous agitation. The solvent is eliminated by filtration and the solid residue in suspension in the water is collected. The residue is filtered and then washed until neutrality is obtained. The resulting reddish solid is washed again with hexane until a colorless filtrate is obtained. After drying in a vacuum oven for 24 hours at 30 C one obtains a raw product which is chromatographed with a silica column using an ethyl acetate and hexane mixture of 1:9 as the eluent. After evaporation of the solvents, 1.3 g of desired raw product were obtained (Melting point: 218-224 C.).
EXAMPLE 7 3-(6-Bromo-2-naphthyloxy)-4-nitropyridine-N-oxide To 6-bromo-2-naphthol (8.43 g) in 80 ml DMF at room temperature was added sodium carbonate (8.0 g) portionwise, and after the addition was complete, the mixture was stirred for 10 minutes, and then a solution of <strong>[769-54-0]3-fluoro-4-nitropyridine-N-oxide</strong> (6.0 g) in 40 ml DMF was added dropwise. The reaction mixture was then stirred for six hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with sat. NaCl solution and dried over Na2 SO4. The filtrate was concentrated to yield a solid (31 g). This material was triturated with methanol to yield a solid, 10.0 g, m.p. 175-177 C. Analysis: Calculated for C15 H9 BrN2 O4: 49.89% C, 2.51% H, 7.76% N; Found: 49.60% C, 2.44% H, 7.55% N.
With sodium hydroxide; sodium carbonate;palladium-carbon; In ethanol; water;
EXAMPLE 3. Preparation of 6-carboxy-2-naphthol (CHN). A four-necked flask was charged with: 16.4g of 6-bromo-2-naphthol (0.074 moles), 6.33g Na2CO3(0.06 moles), 351.4mg Pd/C (3.2%) and 120 ml 2-ethyl-1-hexanol. Nitrogen was flushed through the system for 20 mins., then replaced by CO at atmospheric pressure (20 ml/min. flow). The carbonylation process was carried out at 160oC for 7 hrs. with stirring whereupon the conversion of 6-bromo-2-naphthol to the 2-ethyl-1-hexyl ester of 2-hydroxy-6-naphthol acid was 96.2%, and only 0.3% of starting material was detected. After the reaction, the flask was cooled and vented. 50cc water was added to the reaction mixture, which was then filtered in order to remove the heterogeneous catalyst. The excess of octanol was distilled from the organic layer. The product, a viscous oil, was dissolved in 80cc 95% ethanol. 8.9 g NaOH in 40 ml water was added, and the mixture was refluxed for 2.5 hrs. The hydrolysis mixture was allowed to cool and the ethanol was stripped off by distillation followed by the addition of 40cc water. The resulting 2-phase system was separated. The aqueous layer was further extracted with ethyl acetate (20ml) to remove all traces of organic materials, then acidified with aqueous HCl (37%), to bring the pH to 3.0-3.5. The heavy white-grey precipitate was filtered, washed with water and dried in an oven under vacuum to give 12.6 g of 2-hydroxy-6-naphthoic acid (90.3%). Crystallization from hot water and acetone yielded a white solid with a melt-. ing of of 250oC. The above ester, as well as the acid, were characterised by IR, NMR and Gas Chromatography-Mass Spectrometry.
With hydrogenchloride; iron(III) chloride; In N-methyl-acetamide; water;
(1) Into 80 ml of anhydrous dimethylformamide (hereinafter referred to as DMF), were dissolved 50 g of 6-bromo-2-naphthol and 24.1 g of cuprous cyanide, and heated under reflux for 6 hours. After cooling, an aqueous solution containing 100 g of ferric chloride and 25 g of 35 % hydrochloric acid dissolved in 200 ml of water was added and stirred for 20 minutes at 60C. After cooling to the room temperature, the product was extracted twice with 300 ml of ether. The organic layer was washed with water, followed by removing the ether. The resulting solid was recrystallized with toluene to obtain 26.2 g of brown 6-cyano-2-naphthol.
Preparative Example 1 6-Methyl-2-Naphthol React 6-bromo-2-naphthol with t-butyl dimethylsilyl chloride and imidazole, followed by adding n-BuLi and CH3I. Deprotect the hydroxyl group by reacting with n-Bu4F to produce the title compound.
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In ethanol; water; for 4h;Reflux;
In a reaction container, 3.17 g (14.2 mmol) of 6-bromo-2-naphthol, 5.00 g (15.6 mmol) of 2- (9, 9-dimethyl-9H-fluoren-2-yl) -4 , 4 , 5, 5-tetramethyl- [1, 3, 2] doxaborane, 96.0 ml of ethanol, 6.78 g (21.3 mmol) of sodium carbonate, 48.0 ml of pure water, and 30 mg (14.2 x 10"3 mmol) of Pd(PPh3J2Cl2 were placed, and heat-refluxing was performed for 4 hours. After cooling, pure water was added thereto, and filtration was performed to give crude crystals. The resulting crude crystals were washed with pure water and heptane, and thereby 3.94 g (yield 82.5%) of fluorenyl naphthol was obtained. Next, 10.5 g (31.2 mmol) of fluorenyl naphthol and 100 ml of pyridine were placed in a reaction container, and 15.5 ml (93.6 mmol) of trifluoromethanesulfonic anhydride was added dropwise thereto in an ice bath. Then, stirring was performed for 3 hours, and the reaction solution was poured into ice water, followed by filtration. The resulting crude crystals were washed with methanol to thereby obtain 6.99 g (yield 64.7%) of an intermediate c.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene;
EXAMPLE 1: Synthesis of Compound (2); [0062] Compounds (16) and (17) were synthesized in the manners described below and were subsequently subjected to coupling described below.
4-Trifluoromethyl-cyclohexanol (1170 mg, 0.00697 mol, TCI) and 2-naphthalenol, 6-bromo- (1.30 g, 0.00581 mol, Aldrich) and triphenylphosphine (1.83 g, 0.00697 mol, Aldrich) were dissolved in toluene (36.8 mL, Aldrich) and the mixture was stirred. Then diisopropyl azodicarboxylate (1.37 mL, 0.00697 mol, Acros) was added. After 4d, the reaction was evaporated to dryness, then taken up in methylene chloride. Silica gel was added and the solvent was removed. The residue was purified on a silica gel column using 0-100% ethyl acetate in hexanes as eluent. Appropriate fractions combined and concentrated to give the product as a 3:1 mixture of cis and trans isomers (minor: Rf=O.65 and major: Rf=O.52 in 7:1 hexanes/ethyl acetate) in 1.6202 g yield.The material was repurified using silica gel chromatography (dry load) using 0-5% ethyl acetate in hexanes as eluent but no resolution of cis and trans was seen. 1.548 g isolated (71%).
bis-(2,4-dimethyl-8-quinolinolato)(6-bromo-2-naphtholato)-aluminum-(III)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Synthetic Example 13; In a three-necked flask were placed 3.5 g of <strong>[115310-98-0]2,4-dimethyl-8-quinolinol</strong> obtained in Synthetic Example 7, 4.1 g of aluminum isopropoxide and 150 ml of anhydrous ethanol and the mixture was heated to the reflux temperature in an atmosphere of nitrogen and stirred for 1 hour. The reaction mixture was cooled to room temperature and the insoluble matters were removed by filtration through Celite. To the filtrate at room temperature was added slowly with stirring a solution of 3.5 g of <strong>[115310-98-0]2,4-dimethyl-8-quinolinol</strong> and 4.5 g of 6-bromo-2-naphthol in 100 ml of anhydrous ethanol and the mixture was stirred for 1 hour. The precipitates were collected by filtration, washed with ethanol, then washed with methanol and dried at 70 C. under reduced pressure for 5 hours to give 14 g of BDQMA.
With potassium phosphate; copper(l) iodide; (E)-1-(2-pyridinyl)methylene-2-phenylhydrazine; In 1,4-dioxane; at 95 - 105℃;Inert atmosphere;
General procedure: To a solution of 8aa or 8ab (30 mmol) and substituted naphthols(20 mmol) in dioxane (20 mL) was added CuI (0.38 g, 2 mmol), (E)-1-(2-pyridinyl)methylene-2-phenyl hydrazine (0.39 g, 2 mmol) and K3PO4 (8.49 g, 40 mmol) under N2 atmosphere. The mixture was stirred and heated to 95-105 C for 36-48 h. Then the mixture was filtered, and the filter cake was washed with n-hexane(4 × 10 mL). The combined filtrate and wash liquor was evaporated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (60-90 C petroleum ether as eluent) to obtain 9a-t as pure white solids in the yield of 11-52%.
With potassium phosphate; copper(l) iodide; (E)-1-(2-pyridinyl)methylene-2-phenylhydrazine; In 1,4-dioxane; at 95 - 105℃;Inert atmosphere;
General procedure: To a solution of 8aa or 8ab (30 mmol) and substituted naphthols(20 mmol) in dioxane (20 mL) was added CuI (0.38 g, 2 mmol), (E)-1-(2-pyridinyl)methylene-2-phenyl hydrazine (0.39 g, 2 mmol) and K3PO4 (8.49 g, 40 mmol) under N2 atmosphere. The mixture was stirred and heated to 95-105 C for 36-48 h. Then the mixture was filtered, and the filter cake was washed with n-hexane(4 × 10 mL). The combined filtrate and wash liquor was evaporated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (60-90 C petroleum ether as eluent) to obtain 9a-t as pure white solids in the yield of 11-52%.
With aluminum (III) chloride; In 1,2-dichloro-ethane; at 80℃; for 1h;Inert atmosphere;
General procedure: A mixture of 2,3-dichloropyrazine or its derivatives (1, 1.0 equiv), substituted phenols (2a-p) (1.0 equiv) and anhydrous AlCl3 (1.0 equiv) in dichloroethane (5 mL) was stirred at 80 oC for 30 min. Then the mixture was cooled to room temperature and additional quantity of AlCl3 (1.0 equiv) was added. The mixture was stirred again at 80 oC for another 30 min. After completion of the reaction, the mixture was poured into ice-cold water (15 mL), stirred for 10 min and then extracted with ethyl acetate (3.x.5 mL). The organic layers were collected, combined, washed with water (3.x.10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to afford the expected products.
With palladium diacetate; triethylamine; diphenylphosphinopropane; In ethylene glycol; at 145℃; for 4h;Inert atmosphere;
10109] Compound 4a, 1 -(6-hydroxynaphthalen-2-yl)etha-none, was synthesized by the inventors.10110] Specifically, starting materials for synthesis such as6-bromo-2-naphthol (2.0 g, 8.97 mmol), Pd(OAc)2 (100mg,0.45 mmol), DPPP (370 mg, 0.9 mmol), and ethylene glycol (3 mE) were added to an oven-dried flask with two necks and charged with argon gas. Oxygen present in the mixture was removed by adding the argon gas to the resulting mixture, and ethyleneglycolvinylether (2.41 mE, 27 mmol) and Et3N obtained distillation (3.12 mE, 22.4 mmol) were sequentially added. The mixture was stirred at 145 C. for 4 hours using a silicone oil containet The mixture was cooled to room temperature and stirred with dichloromethane (15 mE) and a 5% HC1 aqueous solution (30 mE) at room temperature for 1 hout The resulting mixture was extracted with dichioromethane (2x30 mE), and an organic layer was washed with water (30 mE) and dehydrated with anhydrous sodium sulfate (6 g). The solvent was removed under a reduced pressure condition of 40 mbar, and the resulting product was purified by column chromatography through a silica gel (Merck-silicagel 60, 230-400 mesh; using CH2C12 as a developer), thereby obtaining a solid, Compound 4a(1.33 g, 80%).10111] ?H NMR (CDC13, 300 MHz, 298 K, oe): 8.41 (1H, s), 7.98 (1H, dd, J=8.7, 1.6 Hz), 7.87 (1H, d, J=8.7 Hz), 7.70 (1H, d, J=8.7 Hz), 7.16 (1H, dd, J=8.7, 1.6 Hz), 5.4 (1H, s), 2.71 (3H, s); mp 172 C.
A solution of n-BuLi (11.76mL, 18.82mmol, 1.6M in hexane) was added dropwise to a cold (-78C) stirred solution of 6-bromo-2-naphthol (2g, 8.96mmol) in anhydrous THF (50mL). After 30min <strong>[116332-54-8]4-fluoro-N-methoxy-N-methylbenzamide</strong> 7a (1.640g, 8.96mmol) in anhydrous THF (20mL) was added slowly over 20min. The resulting mixture was stirred for 2h whilst warming to room temperature. Water (100mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×50mL), and the combined organic extracts were dried over anhydrous Na2SO4, removal of the solvent under vacuum afforded the crude 6-(4-fluorobenzoyl)-2-naphthol8a. The crude product was purified by crystallisation from ethyl acetate and hexane, 52% yield, m. p. 142-143C; numax 531, 769, 804, 1127, 1299, 1458, 1648, 3271, 3550cm-1; deltaH 5.97 (1H, s, OH), 7.19 (4H, m, Ar-H), 7.75 (1H, d, J=8.6Hz, 4-H), 7.83 (1H, d, J=8.7Hz, 8-H), 7.88 (3H, m, Ar-H), 8.17 (1H, d, J=1.0Hz, 5-H); deltaC 109.61, 115.53 (d, J=21.7Hz), 119.10, 126.36, 126.81, 127.34, 131.54, 132.17, 132.27, 132.63, 132.72, 134.18 (d, J=3.1Hz), 137.09, 156.21, 165.30 (d, J=254Hz), 195.84; deltaF-106.58; Found [M+H]+=267.0821, C17H11FO2 requires [M+H]+=267.0816.
1-(6-bromonaphthalen-2-yl)pyrrolidin-3-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium hydrogensulfite; In water; at 120 - 130℃; for 72.0h;
General procedure: A steel bomb was charged with 6-bromo-2-naphthol (14), a secondary amine, sodium bisulfite, and water. The mixture was stirred at 120 C-130 C for 72 h. Upon cooling the reaction mixture was diluted with water, the product was extracted with CH2Cl2 or EtOAc, and the organic layer was washed with 5% NaOH solution, followed by washing with brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation. The crude product was purified by crystallization to give the corresponding naphthylamine.
With potassium carbonate; In N,N-dimethyl-formamide; at 180℃; for 8h;Microwave irradiation;
2-Bromo-6-cyclobutoxynaphthalene: 6-bromonaphthalene (700 mg, 3.1 mmol), K2C03 (2.140 g, 15.5 mmol), and bromocyclobutane (1.75 mL, 18.6 mmol) in dry DMF wereheated at 180 C in a microwave for 8 h. After completion, ethyl acetate and water were added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2xlOmL). The combined organic phases were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude product was then purified via flash chromatography over silica, eluting with a hexanes/EtOAc solvent gradient to afford 693 mg(80% yield) of pure product. ?H NMR (300 MHz, CDC1 ) 57.88 (s, 1H), 7.65-7.43 (m, 3H),7.10 (dd, 1H), 6.94 (s, 1H), 4.74 (m, 1H), 2.58-2.45 (m, 2H), 2.30-2.13 (m, 2H), 1.95-1.69 (m, 2H); MS (ESI) 278.5 m/z [MHj, C,4H,4BrO requires 278.2.
With potassium carbonate; palladium; In ethanol; water;Inert atmosphere; Heating;
In a reaction vessel compound 5.00g of formula (I-7-1) the compound represented by formula (I-6-1) 4.98g, potassium carbonate 4.65 g, ethanol 50mL, water 50mL was added. The inside of the system burged with nitrogen palladium catalyst was added. Hydrochloric acid and diluted with ethyl acetate after heating stirring, and washed with water and brine. This was purified by column chromatography and recrystallization to give the compound 5.03g of formula (I-8-1).
1-[(5-(benzyloxy)-4-oxo-4H-pyran-2-yl)(2,5-dibromophenylamino)methyl]-6-bromonaphthalen-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With boric acid functionalized silica supported Fe3O4 nanocatalyst; In neat (no solvent); at 40℃; for 0.916667h;Green chemistry;
General procedure: To a mixture of 2-naphthol (1 mmol), aniline derivatives(1 mmol) and Kojic aldehyde (1 mmol) was added nanoFe3O4(at)SiO2-boric acid (15 mg). The mixture was stirredat 40 C under solvent free condition in an oil bath and thecompletion of reaction was monitored by TLC (EtOAc / nhexane:1:4). After completion of the reaction, the mixturewas cooled to room temperature, ethanol (2 mL) was added,and themixture was stirred for 10 min. The catalyst was separatedout using an external magnet and the obtained solid wascollected by filtration and purified by recrystallization from(EtOH/acetone, 4:1) or was subjected to silica gel preparativelayer chromatography (EtOAc/n-hexane, 1:5) to give pyran asa pure solid. The recovered catalyst was washed with EtOH,dried and reused for the next run. The catalyst was recoveredand reused for five times without any significant changes inthe yield and the reaction time.
6-bromo-6′-cyano-1,1′-binaphthalene-2,2′-diol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With N,N,N,N,-tetramethylethylenediamine; copper dichloride; In methanol; at 20℃; for 10h;
A round-bottomed flask was charged with 6-cyano-2-naphthanol 1(1 mmol) and 6-bromo-2-naphthol 2 (1 mmol), CuCl2 (1 mmol),TMENDA (2 mmol) in MeOH (20 mL). The mixture was then stirred for10 h at room temperature. The solution was with ethyl acetate(2×20 mL). The combined organic layers were dried over Na2SO4 andfiltered. The solvent was removed under reduced pressure, and theresidue was subjected to column chromatography on silica gel(100-200 mesh) with a mixture of EtOAc-petroleum ether (1:2, v/v) aseluent. The pure product 3 was obtained as yellow solid.6-bromo-6?-cyano-1,1?-binaphthalene-2,2?-diol (3) Yield, 75%,1H NMR (300 MHz, Acetone-d6) delta: 8.42 (s, 1H), 8.12-8.08 (m, 2H), 7.94(d, J=9.0 Hz, 1H), 7.52-7.33 (m, 4H), 7.29 (d, J=9.0 Hz, 1H), 6.98(d, J=9.0 Hz, 1H). 13C NMR (75 MHz, Acetone-d6) delta: 157.36, 155.12,137.15, 135.11, 133.91, 131.57, 131.13, 130.89, 130.33, 130.22,128.88, 127.77, 127.31, 126.62, 121.38, 120.81, 120.08, 116.98,115.51, 114.49, 106.82.
({5-[(6-bromonaphthalen-2-yl)oxy]pentyl}oxy)(tert-butyl)dimethylsilane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; toluene; at 80℃; for 5h;
To a solution of 6-bromonaphthalen-2-ol (0.50 g), 5-[tert-butyl(dimethyl)silyl]oxypentan-l-ol (0.98 g) in THF (4.5 mL) and toluene (4.5 mL) were added DIAD (2.4 mL, 1.9 M solution in toluene) and PPh3 (1.2 g). After stirring for 5 hours at 80 C, the reaction mixture was concentrated in vacuo. The resulting residue was diluted with 25% EtOAc in /rhexane and the insoluble matters were filtered out. The filtrate was concentrated in vacuo. The residue was charged onto ISOLUTE HM-N and purified by OH-type silica gel column chromatography (2-8 % EtOAc in /2-hexane) to give the title compound (0.95 g, 100% yield) as colorless oil. NMR (400 MHz, CHLOROFORM-d) δ ppm 0.06 (s, 6 H), 0.90 (s, 9 H), 1.49- 1.65 (m, 4 H), 1.87 (quin, J=6.9 Hz, 2 H), 3.65 (t, J=6.2 Hz, 2 H), 4.06 (t, J=6.5 Hz, 2 H), 7.08 (d, J=2.2 Hz, 1H), 7.15 (dd, J=8.9, 2.4 Hz, 1H), 7.46-7.51 (m, 1H), 7.55- 7.66 (m, 2 H), 7.90 (d, J=1.5 Hz, 1H).
3-amino-8-bromo-1-(2,5-dichlorophenyl)-1H-benzo[f]chromene-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With piperidine; In ethanol; at 140℃; for 0.0333333h;Microwave irradiation;
General procedure: A reaction mixture of 6-bromo-2-naphthol (1) (0.01 mol), different aromatic aldehydes (2a-m) (0.01 mol), malononitrile (3) (0.01 mol),and piperidine (0.5 mL) in an ethanol solution (30 mL) was heated under microwave irradiation conditions for 2 min. at 140 C. After the reaction reached completion, the reaction mixture was cooled to room temperature, and the precipitated solid was filtered off, washed with methanol, and recrystallised from ethanol or ethanol/benzene. Thephysical and spectral data of compounds 4a-m and 5 are as follows:
2-bromo-6-(2-methyl-4-nitrophenoxy)naphthalene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96.4%
6-bromo-2-naphthol (2.68g, 12mmol), potassium carbonate (2.76g, 20mmol) and anhydrous N,N-dimethylformamide (15mL) were added to a 100mL single-necked bottle, After stirring at 25 C for 30 minutes, Add <strong>[455-88-9]1-fluoro-2-methyl-4-nitrobenzene</strong> (1.55g, 10mmol) dropwise Solution of N,N-dimethylformamide (5mL), After the dropwise addition, the reaction was carried out at 100 C for 10 hours under the protection of nitrogen. After the reaction was completed, the reaction mixture was cooled to 25 C and poured into ice water (100 mL) and stirred vigorously for 30 minutes, There is solid precipitation, filtration, The filter cake was washed with water (100mL x 3), Drying gave 3.45 g of light yellow solid, yield: 96.4%.
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