* 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 aluminum (III) chloride; magnesium In tetrahydrofuran at 50 - 55℃; Reflux
The amount of methoxyphenylbromobenzene was increased to 243.2 g (1.3 mol), propionitrile 71.6 g (1.3 mol), the same as Example 1,The yield of methoxyphenylacetone was 88.6percent.;_In the presence of reflux condenser,The reaction flask of the dropping funnel was charged with 24.0 g (1.0 mol) of magnesium powder,Anhydrous aluminum trichloride 3.0 g,Tetrahydrofuran (THF) solution (300 mL)heating.In the dropping funnel, 187.1 g (1.0 mol) of m-methoxybenzene was slowly added,And 300 mL of tetrahydrofuran (THF)Control reaction liquid temperature 50-55 ,So that the solution has been kept in a state of slightly boiling,After the dropwise addition was heated under reflux 0.5-1.0h,To ensure that the magnesium reaction is complete,Get Grignard reagent.Stirring,55.1 g (1.0 mol) of propionitrile was slowly added to the Grignard reagent,After the dropwise addition,And then reaction 1.0-2.0h.Reaction is completed,Cold water bath slowly drop by adding 3.0mol / L hydrochloric acid,Decomposition of addition products,The inorganic phase is separated,The organic phase was subjected to atmospheric distillation to remove THF.Control the temperature to 180-185 ° C,The distillation was carried out under reduced pressure (reduced pressure at -0.095 MPa,Distillation temperature of 185 ° C),3-Methoxyphenylacetone was obtained in a yield of 78.3percent.
Reference：
[1] Patent: CN106518635, 2017, A, . Location in patent: Paragraph 0018-0033
With copper(I) bromide In acetonitrile at 80℃; for 2 h;
General procedure: A mixture of diaryliodonium salt (0.5 mmol), cuproushalide (0.75 mmol) and CH3CN (1mL) was taken in a 10mL reaction tube and heated at 80°C temperature for 2 hoursunder vigorous stirring. After completion of the reaction(observed on TLC or GC) the reaction mass was cooled toroom temperature, and 5 ml of water was added. The mixturewas stirred for 10 mins, the product was extracted with ethylacetate (3 * 10mL). The organic layer was washed withwater and dried over anhydrous sodium sulphate. Solventwas evaporated under reduced pressure to obtain the product.The crude product was purified on silica gel column by usingpetroleum ether and ethyl acetate as solvents to obtain thepure product. The obtained product was analyzed by 1HNMR, 13C NMR.
Reference：
[1] Letters in Organic Chemistry, 2013, vol. 10, # 8, p. 541 - 548
6
[ 536-90-3 ]
[ 2398-37-0 ]
Reference：
[1] Organic Letters, 2017, vol. 19, # 10, p. 2518 - 2521
[2] Annali di Chimica (Rome, Italy), 1959, vol. 49, p. 1237,1248
[3] Annali di Chimica (Rome, Italy), 1959, vol. 49, p. 1237,1248
7
[ 591-20-8 ]
[ 616-38-6 ]
[ 2398-37-0 ]
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1974 - 1978
[2] Organic Process Research and Development, 2012, vol. 16, # 5, p. 1150 - 1153
8
[ 67-56-1 ]
[ 585-79-5 ]
[ 2398-37-0 ]
Reference：
[1] Organic Process Research and Development, 2003, vol. 7, # 3, p. 303 - 305
9
[ 585-79-5 ]
[ 124-41-4 ]
[ 2398-37-0 ]
Reference：
[1] Organic Process Research and Development, 2003, vol. 7, # 3, p. 303 - 305
10
[ 591-20-8 ]
[ 77-78-1 ]
[ 2398-37-0 ]
Reference：
[1] Synlett, 2013, vol. 24, # 13, p. 1702 - 1706
[2] Journal of the American Chemical Society, 1939, vol. 61, p. 1001
[3] Journal of pharmaceutical sciences, 1972, vol. 61, # 12, p. 1936 - 1940
11
[ 67-56-1 ]
[ 2398-37-0 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 12, p. 6456 - 6466
12
[ 591-20-8 ]
[ 74-88-4 ]
[ 2398-37-0 ]
Reference：
[1] New Journal of Chemistry, 2006, vol. 30, # 1, p. 53 - 58
13
[ 591-19-5 ]
[ 2398-37-0 ]
Reference：
[1] Journal of the American Chemical Society, 1939, vol. 61, p. 1001
[2] Journal of the Chemical Society, 1936, p. 50
14
[ 870485-34-0 ]
[ 2398-37-0 ]
Reference：
[1] Australian Journal of Chemistry, 2010, vol. 63, # 12, p. 1619 - 1626
15
[ 578-57-4 ]
[ 2398-37-0 ]
[ 591-20-8 ]
Reference：
[1] Patent: US4447660, 1984, A,
16
[ 766-85-8 ]
[ 2398-37-0 ]
Reference：
[1] Letters in Organic Chemistry, 2013, vol. 10, # 8, p. 541 - 548
17
[ 89598-96-9 ]
[ 2398-37-0 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 12, p. 6456 - 6466
18
[ 591-20-8 ]
[ 80-48-8 ]
[ 2398-37-0 ]
Reference：
[1] Journal of the Chemical Society, 1936, p. 50
19
[ 67-56-1 ]
[ 108-86-1 ]
[ 2398-37-0 ]
Reference：
[1] American Chemical Journal, 1898, vol. 20, p. 236,238
20
[ 67-56-1 ]
[ 108-86-1 ]
[ 2398-37-0 ]
Reference：
[1] American Chemical Journal, 1898, vol. 20, p. 236,238
21
[ 1072-53-3 ]
[ 2398-37-0 ]
[ 5020-41-7 ]
Reference：
[1] Synthesis, 2008, # 11, p. 1793 - 1797
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 6293 - 6305
[3] Patent: WO2010/122134, 2010, A1, . Location in patent: Page/Page column 66
[4] Patent: WO2017/36880, 2017, A1, . Location in patent: Paragraph 202
22
[ 75-21-8 ]
[ 2398-37-0 ]
[ 5020-41-7 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1998, vol. 37, # 9, p. 929 - 932
[2] Chemical Communications, 2013, vol. 49, # 71, p. 7794 - 7796
23
[ 2398-37-0 ]
[ 768-70-7 ]
Reference：
[1] Organic and biomolecular chemistry, 2003, vol. 1, # 3, p. 498 - 506
24
[ 2398-37-0 ]
[ 1066-54-2 ]
[ 768-70-7 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 39, p. 6707 - 6712
25
[ 2398-37-0 ]
[ 106-95-6 ]
[ 24743-14-4 ]
Yield
Reaction Conditions
Operation in experiment
76%
Stage #1: With magnesium In tetrahydrofuran for 4 h; Heating / reflux Stage #2: With water; ammonium chloride In tetrahydrofuran
Intermediate 1 l-AUyl-3-methoxy-benzene (Ha)A solution of 3-bromoanisole (4Og, 0.2138mol) dissolved in dry THF (220 rnL) was added dropwise to a solution of magnesium (7.9g, 0.328mol) activated by pinch of iodine in dry THF (20 ml) and the reaction was shortly heated with a heat -gun to get the reaction started. After 1 hr, when the solution was gray and most of the magnesium was dissolved, allyl bromide (28.4 mL, 0.328 mol) was added. After 3 h the reaction was quenched by a saturated NH4Cl solution and the organic layer was extracted with diethyl ether. The organic phase was dried over anhydrous Na2SO4, the solvent was evaporated and the crude product was subjected to flash chromatography on silica gel (230-400 mesh) using 3-4percent ethyl acetate in petroleum ether which gave the allyl compound as yellow viscous liquid (24 g, 76percent).
56%
With magnesium In diethyl ether at 0 - 20℃; for 2 h; Inert atmosphere
To magnesium (290 g, 12 mmol), 1-bromo-3-methoxybenzene (1 mL, 8 mmol) in Et2O (40 mL) was added dropwise under nitrogen atmosphere. The mixture was refluxed until magnesium was consumed and cooled to 0°C subsequently. To the solution allylbromide (2.4 mL, 28 mmol) was added dropwise. After stirring for 2 h at room temperature, the mixture was quenched with sat. NH4Cl aq. and extracted with ether and the subsequent purification by flash column chromatography (hexane–ethyl acetate=19 : 1) afforded 1-allyl-3-methoxybenzene (667 mg, 56percent). To a stirred solution of 1-allyl-3-methoxybenzene (667 mg, 4.5 mmol) in CH2Cl2 (60 mL), an 1 M solution of BBr3 in CH2Cl2 5.5 mL (5.5 mmol) was added dropwise at−78°C under nitrogen atmosphere. The solution was allowed to warm up to 0°C and stirred for 2 h at room temperature. The reaction mixture was quenched with water and extracted with CH2Cl2, and the subsequent purification by flash column chromatography (hexane–diethyl ether=3 : 1) afforded 3-allylphenol (302 mg, 50percent).
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 19, p. 9772 - 9780
[2] Journal of Medicinal Chemistry, 1991, vol. 34, # 8, p. 2638 - 2643
[3] Patent: WO2008/135488, 2008, A1, . Location in patent: Page/Page column 43
[4] Tetrahedron, 2010, vol. 66, # 34, p. 6965 - 6976
[5] Chemical and Pharmaceutical Bulletin, 2018, vol. 66, # 7, p. 741 - 747
[6] Journal of the American Chemical Society, 2003, vol. 125, # 36, p. 10977 - 10996
[7] Helvetica Chimica Acta, 1977, vol. 60, p. 768 - 797
26
[ 2398-37-0 ]
[ 591-87-7 ]
[ 24743-14-4 ]
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 3, p. 1165 - 1168
27
[ 2398-37-0 ]
[ 79-10-7 ]
[ 6099-04-3 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: With potassium <i>tert</i>-butylate In water at 20℃; for 0.166667 h; Inert atmosphere; Green chemistry Stage #2: With bis-(1-methylimidazole)palladium(II) dichloride In water at 100℃; for 12 h; Green chemistry
General procedure: Under a N2 atmosphere, LiOtBu or KOtBu (3.0 mmol), H2O (2.0 mL) and acrylic acid (1.2 mmol) were added into a Schlenk reaction tube and the mixture was stirred at room temperature for 10 minutes. Then an aryl halide 2 (1.0 mmol) and Pd(II)–Im complex 1 (1.0 molpercent) were added. The mixture was stirred at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was acidified by HCl (4 M) to pH 1 and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel to afford the pure product 5.
Reference：
[1] New Journal of Chemistry, 2015, vol. 39, # 3, p. 2052 - 2059
[2] Journal of Chemical Research, 2013, vol. 37, # 5, p. 294 - 297
28
[ 2398-37-0 ]
[ 677-22-5 ]
[ 33733-83-4 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 22, p. 8478 - 8481
[2] Chemistry - A European Journal, 2011, vol. 17, # 22, p. 6052 - 6055
29
[ 2398-37-0 ]
[ 677-22-5 ]
[ 33733-83-4 ]
[ 100-66-3 ]
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 22, p. 6052 - 6055
30
[ 2398-37-0 ]
[ 75-36-5 ]
[ 30186-18-6 ]
Yield
Reaction Conditions
Operation in experiment
42%
With aluminum (III) chloride In 1,1-dichloroethane for 4 h; Heating / reflux
A dichloroethane solution (250 ml) of 1-bromo-3-methoxybenzene (30 g), acetyl chloride (15.5 g) and aluminum chloride (25.6 g) was refluxed for 4 hours. The reaction mixture was poured into ice water, and the organic layer was separated. The organic layer was washed with water, dried over magnesium sulfate and then concentrated. The residue was subjected to silica gel chromatography, and the title compound was obtained as a colorless oil (14.4 g, yield 42percent) from the diethyl ether-hexane (1:10) eluate. 1H-NMR (200MHz, CDCl3) δ: 2.61 (3H, s), 7.04 (1H, dd, J=1.9, 8.5Hz), 7.18 (1H, d, J=1.8Hz), 7.58 (1H, d, J=8.4Hz)
Reference：
[1] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 4, p. 1111 - 1114
32
[ 2398-37-0 ]
[ 547-63-7 ]
[ 32454-33-4 ]
Reference：
[1] Journal of the American Chemical Society, 2002, vol. 124, # 42, p. 12557 - 12565
[2] Organic Letters, 2008, vol. 10, # 8, p. 1545 - 1548
Reference：
[1] Tetrahedron Letters, 2007, vol. 48, # 24, p. 4179 - 4182
[2] Tetrahedron Letters, 2007, vol. 48, # 23, p. 4083 - 4086
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5917 - 5930
[4] Organometallics, 2014, vol. 33, # 11, p. 2806 - 2813
35
[ 2398-37-0 ]
[ 28547-28-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5917 - 5930
36
[ 2398-37-0 ]
[ 536-90-3 ]
[ 92248-06-1 ]
Reference：
[1] Synlett, 2008, # 12, p. 1870 - 1876
[2] Canadian Journal of Chemistry, 2005, vol. 83, # 6-7, p. 958 - 968
37
[ 2398-37-0 ]
[ 92248-06-1 ]
[ 536-90-3 ]
Yield
Reaction Conditions
Operation in experiment
5%
With lithium amide; N,N,N,N,-tetramethylethylenediamine; zinc(II) chloride In 1,2-dimethoxyethane at 80℃; for 24 h;
The advantageous effect of adding zinc chloride to an amination reaction was demonstrated in the amination reaction of 3-bromoanisole. the results of which are summarized in Table 10. When 3-bromoanisole was reacted under the standard lithium amide amination conditions, using lithium amide (10 eq.) in the presence of (CyPF-^-Bu)PdCl2 (1 molpercent) in DME gave a complicated mixture of products was obtained (Table 10, Entry 1). When conducted in the presence of zinc chloride and TMEDA, however, the reaction could successfully gave the desired monoarylation product, 3-methoxyaniline, although at high concentrationsN,N-dimethyl-3-methoxyaniline was formed in a significant amount as a by- <n="62"/>product (Table 10, Entries 3 and 4). Under optimized conditions (Table 10, Entries 8 and 9), 3-methoxyaniline was formed selectively in good yield.
Reference：
[1] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 60-61
[2] Australian Journal of Chemistry, 2015, vol. 68, # 12, p. 1842 - 1853
38
[ 2398-37-0 ]
[ 110-18-9 ]
[ 15799-79-8 ]
[ 92248-06-1 ]
[ 536-90-3 ]
Yield
Reaction Conditions
Operation in experiment
24%
With lithium amide; zinc(II) chloride In 1,2-dimethoxyethane at 80℃; for 24 h;
The advantageous effect of adding zinc chloride to an amination reaction was demonstrated in the amination reaction of 3-bromoanisole. the results of which are summarized in Table 10. When 3-bromoanisole was reacted under the standard lithium amide amination conditions, using lithium amide (10 eq.) in the presence of (CyPF-^-Bu)PdCl2 (1 molpercent) in DME gave a complicated mixture of products was obtained (Table 10, Entry 1). When conducted in the presence of zinc chloride and TMEDA, however, the reaction could successfully gave the desired monoarylation product, 3-methoxyaniline, although at high concentrationsN,N-dimethyl-3-methoxyaniline was formed in a significant amount as a by- <n="62"/>product (Table 10, Entries 3 and 4). Under optimized conditions (Table 10, Entries 8 and 9), 3-methoxyaniline was formed selectively in good yield.
Reference：
[1] Arzneimittel-Forschung, 1959, vol. 9, p. 715 - 717
[2] Journal of Organic Chemistry, 1998, vol. 63, # 4, p. 930 - 937
40
[ 2398-37-0 ]
[ 29949-84-6 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1964, vol. 25, p. 294 - 300
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2018, vol. 56, # 10, p. 1100 - 1110
41
[ 2398-37-0 ]
[ 98447-30-4 ]
[ 103966-66-1 ]
Reference：
[1] Tetrahedron, 2009, vol. 65, # 7, p. 1281 - 1286
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 7, p. 1475 - 1491
42
[ 2398-37-0 ]
[ 10365-98-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere; Schlenk technique Stage #2: With Trimethyl borate In tetrahydrofuran at -78 - 20℃; for 16 h; Inert atmosphere; Schlenk technique
1-bromo-3-methoxybenzene (20 g, 107 mmol) was dissolved in dry THF (200 mL) in a Schlenk tube. The solution was purged with N2 and cooled to -78 ºC. n-Butyllithium (2.5 mol/L, 64.2 mL) was added slowly. A white precipitate was formed during the addition. The mixture was stirred for 1 h at the same temperature and then trimethyl borate (74 mL, 321.0 mmol) was added. The resulting clear solution was slowly warmed to room temperature and stirred for 16 h. Concentrated hydrochloric acid was added until a pH of 3-4 was reached. The reaction mixture was poured into ethyl acetate (200 mL) and the aqueous layer was discarded. The organic layer was washed three times with saturated salt water, dried over anhydrous Na2SO4 and filtered. The solvent was removed and the product was recrystallized from ethyl acetate/petroleum ether (1:10) to afford the title compound (13.8 g, 85 percent). 1H NMR (DMSO-d6, 400 MHz, ppm): δ 8.02 (s, 2H, OH-H), 7.36 (d, J = 4.0 Hz, 2H, Ar-H), 7.25 (t, J= 8.0 Hz, 1H, Ar-H), 6.95 (d, J = 8.0 Hz, 2H, Ar-H), 3.75 (s, 3H, CH3-H); 13C NMR (CDCl3, 100 MHz, ppm): δ 158.55, 128.48, 126.32, 118.98, 115.72, 54.78.
78%
Stage #1: With n-butyllithium In tetrahydrofuran; hexaneInert atmosphere Stage #2: With Trimethyl borate In tetrahydrofuran; hexaneInert atmosphere
General procedure: Under an argon atmosphere a solution of the appropriate bromobenzene (1 equivalent) dissolved in anhydrous THF (approximately 30 mL per mmol bromobenzene) is cooled to -78 °C using a nitrogen-ethanol-bath. A solution of 2.3 equivalents of n-butyllithium in hexane is added drop wise keeping the temperature below -78 °C. After completion the mixture is stirred for one hour at this temperature. Then 1.5 equivalents of trimethyl borate are added slowly and the reaction mixture is stirred at -78 °C for another hour. The cooling bath is then removed, the reaction mixture is stirred until room temperature is reached and quenched with a saturated solution of ammonium chloride. THF and the major part of the water is removed under reduced pressure, the residue is laced with 3M hydrochloric acid until a pH of 3 is reached. After extraction with DCM (3 x) the organic phases are collected, washed with brine, dried over sodium sulphate and filtered. DCM is removed under reduced pressure, the resulting solid is washed first with ice cold water and then with PE and dried.
Reference：
[1] Tetrahedron, 2013, vol. 69, # 19, p. 3934 - 3941
[2] Patent: US6342610, 2002, B2, . Location in patent: Page column 75
[3] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 590 - 603
[4] Journal of Organic Chemistry, 2008, vol. 73, # 11, p. 4212 - 4218
[5] Journal of the American Chemical Society, 2013, vol. 135, # 4, p. 1264 - 1267
[6] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6427 - 6439
43
[ 2398-37-0 ]
[ 121-43-7 ]
[ 10365-98-7 ]
Yield
Reaction Conditions
Operation in experiment
92.1%
With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane
1st Stage 3-Methoxybenzeneboronic Acid 41.3 g (220 mmol) 3-bromoanisole were dissolved in 880 ml tetrahydrofuran and the solution was cooled to -70° C. in a cooling bath (ethanol/dry ice). 160 ml (250 mmol) butyllithium solution (1.6 M in hexane) were added dropwise under nitrogen such that the temperature did not rise above -60° C. After stirring at -70° C. for 1.5 hours, 75 ml (660 mmol) trimethyl borate were also added dropwise such that the temperature did not rise above -60° C. After stirring in the cold for a further hour, the mixture was warmed to 25° C. in the course of two hours, 720 ml hydrochloric acid (1 M) were added and the mixture was stirred at 25° C. for 15 hours. For working up, the mixture was extracted three times with 300 ml ether each time, the organic phases were combined, washed with 100 ml each of water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered and the filtrate was concentrated on a rotary evaporator (500-10 mbar). In this manner, 30.8 g 3-methoxybenzeneboronic acid (92.1percent of theory) were obtained.
80%
Stage #1: With magnesium In tetrahydrofuran; toluene at 60 - 80℃; Inert atmosphere Stage #2: at 0℃; Inert atmosphere Stage #3: With sulfuric acid In tetrahydrofuran; toluene at 20℃; Inert atmosphere
To a mixture of magnesium (2.95 g, 121mmol), THF (35mL), and toluene (35 mL)was added dropwise 3-bromoanisole 2(13.0 mL, 103mmol)with keeping temperature at 60 ºC. The reaction mixture was stirred at 80 ºC for 2hours. Prepared Grignard reagent was slowly dropwise to a toluene solution (20 mL) of trimethyl borate (11.4 mL, 102 mmol) at 0 ºC. The reaction mixture was stirred at 0 ºC for 2 hours, then neutralized with 10percent sulfuric acid, and stirred at r.t. overnight. Organic phase was separated, dried over MgSO4, and evaporated to give 3-methoxyphenylboronic acid (12.36 g, 80percent) as white powder.
Reference：
[1] Patent: US2002/198251, 2002, A1,
[2] Tetrahedron Letters, 2012, vol. 53, # 46, p. 6182 - 6185,4
[3] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 17, p. 2513 - 2523
[4] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1919 - 1922
44
[ 2398-37-0 ]
[ 5419-55-6 ]
[ 10365-98-7 ]
Yield
Reaction Conditions
Operation in experiment
156.1 g
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 1 h; Inert atmosphere Stage #2: at 20℃; for 18 h; Inert atmosphere Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water
n-Butyllithium in n-hexane (925.0 mL, 1.59 M) was added dropwise to a mixture of THF (1,000 mL) and 1-bromo-3-methoxybenzene (T-1) (250.0 g, 1.34 mol) at -70° C. under an atmosphere of nitrogen. After the addition had been completed, the reaction mixture was stirred at the same temperature for 1 hour. Triisopropyl borate (300.9 g, 1.60 mol) was added dropwise, and then the mixture was warmed slowly to room temperature. The stirring was continued at room temperature for 18 hours, and the reaction mixture was poured into 6M-hydrochloric acid. The mixture was extracted with ethyl acetate (500 mL) four times, and the organic layer was washed with water. After the organic layer had been dried over anhydrous magnesium sulfate, the organic solvent was distilled off under reduced pressure. The residue was sufficiently washed with heptane to leave colorless solids (156.1 g) of 3-methoxyphenylboronic acid (T-2).
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 23, p. 5612 - 5615
[2] Chemistry - A European Journal, 2017, vol. 23, # 4, p. 935 - 945
[3] Patent: US8394468, 2013, B2, . Location in patent: Page/Page column 52; 53
[4] Organic Letters, 2015, vol. 17, # 2, p. 346 - 349
[5] Journal of Materials Chemistry C, 2015, vol. 3, # 22, p. 5754 - 5763
45
[ 13675-18-8 ]
[ 2398-37-0 ]
[ 10365-98-7 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 9, p. 2985 - 2988
With N-Bromosuccinimide; iodine In acetonitrile for 12 h; Darkness
General procedure: To a reaction tube charged with NBS (1.5 equiv, 0.3 mmol), catalyst (10 molpercent, 0.02 mmol) and CH3CN (1.0 mL),was added para-chloroanisole 1a (0.2 mmol). After being stirred at room temperature for 12 h in dark, the reaction was quenched by saturated aq. solution of Na2S2O3 (2 mL). The resulting mixture was extracted by ethyl acetate (3 5 mL). The combined organic extracts were washed by brine (10 mL), dried over Na2SO4 and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residuewas purified by flash chromatography on a silica gel column with petroleum ether/dichloromethane (5:1) as the eluent to give 4.3.1. 2-Bromo-4-chloroanisole (2a)
Reference：
[1] Tetrahedron, 2017, vol. 73, # 50, p. 7105 - 7114
[2] Bulletin de la Societe Chimique de France, 1981, vol. 1, # 1-2, p. 42 - 48
[3] Synthetic Communications, 2000, vol. 30, # 12, p. 2091 - 2098
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In methanol; toluene at 100℃; for 16 h; Inert atmosphere
General procedure: According to a procedure by Oxford et al.,[3] furan-2-boronic acid (168 mg, 1.5 mmol, 1.5 eq), aryl halide (1.0 mmol, 1.0 eq), Pd(PPh3)4 (116 mg, 0.1 mmol, 10 molpercent) and cesium carbonate (350 mg, 1.1 mmol, 1.1 eq) were suspended in a toluene/MeOH mixture (4:1, 10 mL). The reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was diluted with EtOAc (8 mL) and the organic layer was extracted was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography.
Reference：
[1] Chemistry - A European Journal, 2009, vol. 15, # 39, p. 10280 - 10290
[2] Synthesis, 1987, # 1, p. 51 - 53
63
[ 2398-37-0 ]
[ 75-36-5 ]
[ 89691-67-8 ]
[ 89368-12-7 ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: With triethylsilane In dichloromethane at 0℃; for 1.16667 h; Inert atmosphere Stage #2: for 2 h;
Friedel-Craft's Reaction Under inert atmosphere, to a solution of aluminium trichloride (1.25eq) in dichloromethane cooled at 0° C. was added the appropriate bromobenzene (1eq) drop by drop during 10 minutes. The reaction mixture was stirred at 0° C. for 1 hour then was added acyl chloride (1.05eq) in dichloromethane drop by drop. The reaction mixture was stirred for 2 hours then poured into ice. The phases were separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel. Example 10.1.3-Bromo-4-ethylanisole and 3-Bromo-6-ethylanisole10.1.11-(2-Bromo-4-methoxyphenyl)ethanone and 1-(4-Bromo-2-methoxyphenyl)ethanone Prepared following the Friede-Craft's method previously described (Method 10A) using 3-bromoanisole and acetyl chloride. The products were chromatographed over silica gel (elution gradient petroleum ether/ethyl acetate 98/2 to 90/10). 1-(2-bromo-4-methoxyphenyl)ethanone was obtained as a colorless oil and 1-(4-bromo-2-methoxyphenyl)ethanone was obtained as a white solid.Yield: 55percent (1-(2-bromo-4-methoxyphenyl)ethanone) and 18percent (1-(4-bromo-2-methoxyphenyl)ethanone)Rf (petroleum ether/ethyl acetate 95/5): 0.33 (1-(2-bromo-4-methoxyphenyl)ethanone) and 0.5 (1-(4-bromo-2-methoxyphenyl)ethanone)NMR 1H (CDCl3) (1-(2-bromo-4-methoxyphenyl)ethanone): 2.60 (s, 3H); 3.82 (s, 3H); 6.85 (d, 1H, J=1.9 Hz); 7.13 (s, 1H); 7.58 (d, 1H, J=5.0 Hz).NMR 1H (CDCl3) (1-(4-bromo-2-methoxyphenyl)ethanone): 2.61 (s, 3H); 3.94 (s, 3H); 7.15 (m, 2H); 7.64 (d, 1H, J=8.3 Hz).
Reference：
[1] Chinese Journal of Chemistry, 2018, vol. 36, # 11, p. 1003 - 1006
66
[ 2398-37-0 ]
[ 450412-22-3 ]
Reference：
[1] Journal of the American Chemical Society, 2002, vol. 124, # 29, p. 8514 - 8515
[2] Journal of the American Chemical Society, 2008, vol. 130, # 2, p. 472 - 480
[3] Beilstein Journal of Organic Chemistry, 2011, vol. 7, p. 1255 - 1260
[4] Journal of Organic Chemistry, 2007, vol. 72, # 14, p. 5113 - 5118
[5] Organic and Biomolecular Chemistry, 2010, vol. 8, # 17, p. 3860 - 3864
[6] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3416 - 3437
67
[ 2398-37-0 ]
[ 466639-53-2 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: With acetic anhydride; mercury(II) oxide In dichloromethane for 0.5 h; Reflux Stage #2: With iodine In dichloromethane for 12 h; Reflux
A stirred solution of 3-bromoanisole (10 g, 53.5 mmol), HgO (8.8 g, 40.6 mmol), Ac20 (1 mL) in CH2CI2 (100 mL) was refluxed for 30 mm. Then, 12(17.6 g, 69.5 mmol) was added by 6 portionsevery 30 mm. After refluxing for 12 h and filtration over a pad of celite, the filtrate was washed with a saturated Na2S2O3 solution. The aqueous layer was extracted with CH2CI2 (3 x 10 mL) and the combined organic layers were dried with MgSO4 and evaporated to dryness. Purification by flash chromatography (cyclohexane) afforded the titled compound.Colorless oil (yield = 94percent).1H NMR (300 MHz, CDCI3) 6 ppm 7.68 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 2.8 Hz, 1H), 6.59 (dd, J = 2.8 Hz, J = 8.8 Hz, 1 H), 3.77 (s, 3H).
35%
With iodine; silver trifluoroacetate In chloroform for 3 h; Inert atmosphere
A mixture of 3-bromophenol (0.53mmol, 1.0equiv), I2 (0.53mmol, 1.0equiv), and CF3COOAg (0.80mmol, 1.5equiv) in CHCl3 (5mL) was stirred under Ar atmosphere for 3h. The reaction was quenched with saturated Na2S2O3 (50mL) and extracted with CH2Cl2 (3×25mL). The solvent was then removed by rotary evaporation to give the brown crude oil. The crude product was purified by flash column chromatography (Hexane 100percent) to obtain product as pink oil (57mg, 35percent): Rf 0.51 (20percent EtOAc/Hexane). IR (UATR): νmax 2975, 1578, 1460, 1283, 1223, 1032, 840cm−1. 1H NMR (300MHz, CDCl3): δ 7.69 (d, J=8.7Hz, 1H), 7.20 (d, J=2.4Hz, 1H), 6.60 (dd, J=8.7, 2.1Hz, 1H), 3.78 (s, 3H); 13C NMR (75MHz, CDCl3): δ 160.1, 140.1, 129.8, 118.3, 115.3, 89.4, 55.5. EI-MS: m/z (percent) 312 (M+H+, 87), 297 (17), 172 (30), 63 (100). TOF-HRMS calcd for C7H6BrIO: 311.8641; found 311.8645, 313.8622.
Reference：
[1] European Journal of Medicinal Chemistry, 2010, vol. 45, # 9, p. 3617 - 3626
[2] Patent: WO2015/121785, 2015, A1, . Location in patent: Page/Page column 39; 41
[3] Journal of the American Chemical Society, 2012, vol. 134, # 22, p. 9291 - 9295
[4] Chemical Communications, 2017, vol. 53, # 44, p. 5970 - 5973
[5] Organic and Biomolecular Chemistry, 2018, vol. 16, # 38, p. 7019 - 7028
[6] Tetrahedron, 2013, vol. 69, # 44, p. 9277 - 9283
Intermediate 1 l-AUyl-3-methoxy-benzene (Ha)A solution of 3-bromoanisole (4Og, 0.2138mol) dissolved in dry THF (220 rnL) was added dropwise to a solution of magnesium (7.9g, 0.328mol) activated by pinch of iodine in dry THF (20 ml) and the reaction was shortly heated with a heat -gun to get the reaction started. After 1 hr, when the solution was gray and most of the magnesium was dissolved, allyl bromide (28.4 mL, 0.328 mol) was added. After 3 h the reaction was quenched by a saturated NH4Cl solution and the organic layer was extracted with diethyl ether. The organic phase was dried over anhydrous Na2SO4, the solvent was evaporated and the crude product was subjected to flash chromatography on silica gel (230-400 mesh) using 3-4% ethyl acetate in petroleum ether which gave the allyl compound as yellow viscous liquid (24 g, 76%).
56%
With magnesium; In diethyl ether; at 0 - 20℃; for 2h;Inert atmosphere;
To magnesium (290 g, 12 mmol), 1-bromo-3-methoxybenzene (1 mL, 8 mmol) in Et2O (40 mL) was added dropwise under nitrogen atmosphere. The mixture was refluxed until magnesium was consumed and cooled to 0C subsequently. To the solution allylbromide (2.4 mL, 28 mmol) was added dropwise. After stirring for 2 h at room temperature, the mixture was quenched with sat. NH4Cl aq. and extracted with ether and the subsequent purification by flash column chromatography (hexane-ethyl acetate=19 : 1) afforded 1-allyl-3-methoxybenzene (667 mg, 56%). To a stirred solution of 1-allyl-3-methoxybenzene (667 mg, 4.5 mmol) in CH2Cl2 (60 mL), an 1 M solution of BBr3 in CH2Cl2 5.5 mL (5.5 mmol) was added dropwise at-78C under nitrogen atmosphere. The solution was allowed to warm up to 0C and stirred for 2 h at room temperature. The reaction mixture was quenched with water and extracted with CH2Cl2, and the subsequent purification by flash column chromatography (hexane-diethyl ether=3 : 1) afforded 3-allylphenol (302 mg, 50%).
With potassium phosphate; copper(l) iodide; In diethylene glycol; at 70℃; for 14h;Sealed tube;
General procedure: A 10 mL vial was charged with CuI (9.5 mg, 0.05 mmol), PSAP (30 mg,0.05 mmol, > 100 mesh), K3PO4 (424 mg, 2 mmol), aryl bromides (1mmol), amines (1.5 mmol), DEG (2 mL), and a magnetic stir bar. The vessel was sealed with a septum and placed into a preheated oil batchat 70 C. The reaction mixture was held at this temperature for 14 hours. After cooling to r.t., the reaction mixture was filtered, and the precipitates were thoroughly washed with water and EtOAc (3 × 20mL). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Theresidue was purified using flash column chromatography on silica gel(eluting with petroleum ether/EtOAc) to afford the desired products.
78%
With copper(l) iodide; tetrabutylammomium bromide; potassium hydroxide; In water; at 70℃; for 16h;Green chemistry;
General procedure: A 10 mL of vial was charged with CuI (10 mg, 0.05 mmol), PSP (0.25 mmol, size less than 90 muM), TBAB (40 mg, 0.25 mmol), base (1.0 mmol), aryl halides (0.5 mmol), arylamine (2.0 mmol), H2O (1.0 mL), and a magnetic stir bar. The vessel was sealed with a septum and placed into an oil bath, which was preheated to 70 C (90 C for alkyl amine, 120 C for imidazole). The reaction mixture was stirred for another 16 h (8 h for imidazole). After allowing the mixture to cool to room temperature, the reaction mixture was filtrated, the precipitates were washed with water and ethyl acetate thoroughly. The filtrate was extracted with ethyl acetate (3×25 mL). The combined organic phases was washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatograph on silica gel to afford the desired products.
75%
With N-methoxy-1H-pyrrole-2-carboxamide; potassium phosphate; copper(II) acetate monohydrate; at 90℃; for 12h;Sealed tube;
General procedure: To a 10 mL sealed vial was added Cu(OAc)2·H2O (10 mg, 0.05mmol), N-methoxy-1H-pyrrole-2-carboxamide (7 mg, 0.05 mmol), aryl bromide (1.0 mmol), amine (3.0 mmol), K3PO4 (318 mg, 1.5 mmol),PEG-100 (2.0 g) and a magnetic stir bar. The reaction mixture was stirred in an oil bath preheated to 90 C for 12 h. After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 × 25 mL) and water (20 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product.
With lithium amide; zinc(II) chloride;[(CyPF-tBu)PdCl2]; In 1,2-dimethoxyethane; at 80℃; for 24h;Product distribution / selectivity;
The advantageous effect of adding zinc chloride to an amination reaction was demonstrated in the amination reaction of 3-bromoanisole. the results of which are summarized in Table 10. When 3-bromoanisole was reacted under the standard lithium amide amination conditions, using lithium amide (10 eq.) in the presence of (CyPF-^-Bu)PdCl2 (1 mol%) in DME gave a complicated mixture of products was obtained (Table 10, Entry 1). When conducted in the presence of zinc chloride and TMEDA, however, the reaction could successfully gave the desired monoarylation product, 3-methoxyaniline, although at high concentrationsN,N-dimethyl-3-methoxyaniline was formed in a significant amount as a by- <n="62"/>product (Table 10, Entries 3 and 4). Under optimized conditions (Table 10, Entries 8 and 9), 3-methoxyaniline was formed selectively in good yield.
7-methyl-1-(4-methylpiperazin-1-yl)naphthalene[ No CAS ]
bis(acetonitrile)palladium(II) dichloride[ No CAS ]
[ 2398-37-0 ]
[ 29949-84-6 ]
7-(3-Methoxyphenyl)-1-(4-methylpiperazin-1-yl)naphthalene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; ethyl acetate; N,N-dimethyl-formamide;
EXAMPLE 81 7-(3Methoxyphenyl)-1-(4-methylpiperazin-1-yl)naphthalene A mixture of 3-methoxy-1-bromobenzene (0.089 ml, 0.71 mmol), 7-trimethylstannyl-1-(4-methylpiperazin-1-yl)naphthalene (0.25 g, 0.64 mmol), bis-(acetonitrile) palladium chloride (0.0085 g, 0.032 mmol), <strong>[29949-84-6]tri(3-methoxyphenyl)phosphine</strong> (0.023 g, 0.064 mmol), and butylated hydroxytoluene (BHT, about 0.001 g, antioxidant) in dimethyl formamide (12 mL) was warned to 110 C. for 2 hours. The reaction was cooled to room temperature and diluted with 1 N aqueous lithium chloride (25 mL) and 1 N sodium hydroxide (2 mL); then extracted with ether (3*). The combined ether layer was washed with 1 N aqueous lithium chloride and brine. The organic phase was dried over calcium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (1*2.5 inches). Elution proceeded as follows: 75% ethyl acetate/hexane, 200 mL, nil; 2% methanol/ethyl acetate 200 mL and 10% methanol/ethyl acetate, 200 mL, 0.084 g of an oil. This oil was further purified by kugelrohr distillation (1 mm Hg). The distillation proceeded as follows: 110-130 C., 0.014 g of a mixture of the title product and 7-methyl-1-(4-methylpiperazin-1-yl)naphthalene: 200-220 C. 0.062 g (23%) of the title compound as a yellow oil: 1H NMR delta 8.43 (incompletely resolved dd, J=1.2Hz, 1 h), 7.90 (d, J=9 Hz, 1 H), 7.74 (dd, J=2,8.5 Hz, 1 H), 7.58 (d, J=8 Hz, 1 H), 7.43 (sym m, 2 H), 7.34 (dt, J=1.5, 7.5 Hz, 1 H), 7.29 (5, J=2 Hz, 1 H), 7.14 (dd, J=1, 7.5 Hz, 1 H), 6.96 (ddd, J=1, 2.5,8 Hz, 1H), 3.92 (s, 3 H) 3.20 (br s, 4 H), 2.75 (br s, 4 H), 2.44 (s, 3 H). The product was dissolved in chloroform and HCL gas was bubbled through the solution to form the hydrochloride salt. Concentration of this solution to about 1 mL. at the boil and addition of about 1 mL of ether caused the white crystalline product to precipitate. The hydrochloride salt weighted 0.057 g: mp 236-238 C. Analysis calculated for C22H24N2O·HCl: C, 71.63; H, 6.83; N, 7.59. Found: C, 71.31; H, 6.92; N, 7.59.
In methanol; ethyl acetate; N,N-dimethyl-formamide;
EXAMPLE 81 7-(3-Methoxyphenyl)-1-(4-methylpiperazin-1-yl)naphthalene A mixture of 3-methoxy-1-bromobenzene (0.089 mL, 0.71 mmol), 7-trimethylstannyl-1-(4-methylpiperazin-1-yl)naphthalene (0.25 g, 0.64 mmol), bis(acetonitrile) palladium chloride (0.0085 g, 0.032 mmol), <strong>[29949-84-6]tri(3-methoxyphenyl)phosphine</strong> (0.023 g, 0.064 mmol), and butylated hydroxytoluene (BHT, about 0.001 g, antioxidant) in dimethyl formamide (12 mL) was warned to 110 C. for 2 hours. The reaction was cooled to room temperature and diluted with 1N aqueous lithium chloride (25 mL) and 1 N sodium hydroxide (2 mL); then extracted with ether (3X). The combined ether layer was washed with 1N aqueous lithium chloride and brine. The organic phase was dried over calcium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (1*2.5 inches). Elution proceeded as follows: 75% ethyl acetate/hexane, 200 mL, nil; 2% methanol/ethyl acetate 200 mL and 10% methanol/ethyl acetate, 200 mL, 0.084 g of an oil. This oil was further purified by kugelrohr distillation (1 mm Hg). The distillation proceeded as follows: 110-130 C., 0.014 g of a mixture of the title product and 7-methyl-1-(4-methylpiperazin-1-yl)naphthalene: 200-220 C., 0.062 g (23%) of the title compound as a yellow oil: 1 H NMR delta 8.43 (incompletely resolved dd, J=1.2Hz, 1 h), 7.90 (d, J=9 Hz, 1 H), 7.74 (dd, J=2, 8.5 Hz, 1 H), 7.58 (d, J=8 Hz, 1 H), 7.43 (sym m, 2 H), 7.34 (dt, J=1.5, 7.5 Hz, 1 H), 7.29 (5, J=2 Hz, 1 H), 7.14 (dd, J=1, 7.5 Hz, 1 H), 6.96 (ddd, J=1,2.5, 8 Hz, 1H), 3.92 (s, 3 H) 3.20 (br s, 4 H), 2.75 (br s, 4 H), 2.44 (s, 3 H). The product was dissolved in chloroform and HCl gas was bubbled through the solution to form the hydrochloride salt. Concentration of this solution to about 1 mL. at the boil and addition of about 1 mL of ether caused the white crystalline product to precipitate. The hydrochloride salt weighted 0.057 g: mp 236-238 C. Analysis calculated for C22 H24 N2 O*HCl: C, 71.63; H, 6.83; N, 7.59. Found: C, 71.31; H, 6.92; N, 7.59.
tris-(dibenzylideneacetone)dipalladium(0); In o-xylene; water;
Comparative Example 7 A 100 ml Kjeldahl flask equipped with a cooling condenser and a thermometer was charged with 96 mg of tris(dibenzylideneacetone)dipalladium (supplied by Aldrich) and 10 ml of o-xylene at room temperature in a nitrogen atmosphere. 257 mg of tri-o-tolylphosphine was added to the content in the flask while being stirred, and maintained at 60 C. for 10 minutes with stirring in an oil, to give a catalyst. The content was then cooled to room temperature, and, in a nitrogen atmosphere, 1.36 g of 2-methylpiperazine, 2.0 g of m-bromoanisole as an aryl halide (the ratio of palladium atom/aryl halide=2.0% by mole) and 1.43 g of NaOBut were separately incorporated into the flask, each as a solution in 10 ml of o-xylene. The content in the flask was to 100 C. and maintained at that temperature for 3 hours with stirring. After completion of the reaction, the content was concentrated, water was added to the residue, and then, the mixture was extracted with ethyl acetate. The liquid extract was concentrated and dried in vacuum overnight to give brown oily N-(3-methoxyphenyl)-2-methylpiperazine. The result of the gas chromatographic analysis of the product is shown in Table 2.
tetrakis(triphenylphosphine)palladium (0); In ethanol; ethyl acetate; toluene;
c 3'-Methoxybiphenyl-4-ol A solution of <strong>[176672-49-4]4-tert-butoxybenzeneboronic acid</strong> (0.50 g), 3-bromoanisole (0.44 g), and tetrakis(triphenylphosphine)palladium(0) (0.09 g) in toluene (5 ml), ethanol(1.2 ml) and aqueous sodium carbonate (2 M, 2.4 ml) was heated at 100 C. for 19 hours. After cooling the reaction mixture was added to brine (50 ml) and ethyl acetate (50 ml). The organic layer was separated and dried over anhydrous magnesium sulfate. The solution was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluding with hexane:toluene 9:1 to give 4-tert-butoxy-3'-methoxybiphenyl (0.61 g). (MS (EI) 256 (M)+).
With sodium hydroxide; potassium carbonate;palladium; In hexane; ethyl acetate; toluene;
EXAMPLE 12 Synthesis of 3-(N,N-dimethylamino)anisole using aminoboranes. This example illustrates the preparation of arylamines from aminoboranes using a homogeneous palladium catalyst with sodium and potassium butoxide and potassium carbonate. A reaction mixture of tris(N,N-dimethylamino)borane (143 mg, 1.0 mmol), sodium t-butoxide (120 mg, 1.25 mmol), anhydrous potassium carbonate (175 mg, 1.25 mmol) PdCl2 (P(o-tolyl)3)2 (11 mg, 0.02 mmol), and 3-bromoanisole (0.12 ml, 0.95 mmol) in toluene (10 mL) was heated at ca. 105 C. under argon purge for ca. 10 h. The reaction mixture was cooled, diluted with ethyl ether (ca. 25 mL), washed with H2 O (ca. 15 mL) and then extracted with 4N HCl solution (2*15 mL). The aqueous fraction was cooled to 0 C., made alkaline with 4N NaOH solution (ca. 35 mL) and extracted with ethyl ether (2*25 mL). The organic fraction was dried with MgSO4, concentrated in vacuo and subjected to column chromatography on silica gel using hexane (ca. 75 mL) and then hexane:ethyl acetate (ca. 200 mL) to afford the title compound as a colorless oil (116 mg, 81%).
palladium-carbon; palladium; In potassium; toluene;
EXAMPLE 14 Synthesis of 3-(N,N-dimethylamino)anisole using aminoboranes. This example illustrates the preparation of arylamines from aminoboranes using a heterogeneous palladium catalyst in the absence of phosphine ligand and with potassium or sodium butoxide and demonstrates that complexing ligands are not necessary for the formation of the active catalytic form. A reaction mixture of tris(N,N-dimethylamino)borane (103 mg, 0.72 mmol), potassium t-butoxide (97 mg, 0.86 mmol), Pd/C (31 mg, 10% on C, 0.03 mmol), and 3-bromoanisole (0.07 ml, 0.58 mmol) in toluene (10 mL) was heated at ca. 105 C. under argon purge for ca. 10 h. The title compound was isolated as a colorless oil (67 mg, 81% yield) using the work-up described in Example 12.
80%
palladium-carbon; palladium; In toluene;
EXAMPLE 13 Synthesis of 3-(N,N-dimethylamino)anisole using aminoboranes. This example illustrates the preparation of arylamines from aminoboranes using a heterogeneous palladium catalyst in the presence of phosphine ligand and with potassium or sodium butoxide. A reaction mixture of tris(N,N-dimethylamino)borane (170 mg, 1.2 mmol), potassium t-butoxide (159 mg, 1.20 mmol), Pd/C (63 mg, 10% on C, 0.06 mmol), P(o-tolyl)3) (35 mg, 0.12 mmol), and 3-bromoanisole (0.12 ml, 0.95 mmol) in toluene (10 mL) was heated at ca. 105 C. under argon purge for ca. 10 h. The title compound was isolated as a colorless oil (114 mg, 80% yield) using the work-up described in Example 12.
With ammonium chloride; magnesium; In tetrahydrofuran; sodium hydroxide; diethyl ether; propionic acid anhydride;
A solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran (500 ml) was prepared from 3-methoxybromobenzene (187 g) and magnesium turnings (24 g) and was added over 1.5 hours to a mixture of propionic anhydride (260 g) and diethyl ether (500 ml) which had been cooled to -70 C. A saturated aqueous solution of ammonium chloride (500 ml) was added and the mixture was allowed to warm to ambient temperature. The organic layer was separated and washed in turn with a dilute aqueous sodium hydroxide solution and with a saturated aqueous sodium chloride solution. The organic layer was dried (Na2 SO4) and evaporated to give 3-methoxypropiophenone as a yellow oil (160 g).
With ammonium chloride; magnesium; In tetrahydrofuran; sodium hydroxide; diethyl ether; propionic acid anhydride;
A solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran (500 ml) was prepared from 3-methoxybromobenzene (187 g) and magnesium turnings (24 g) and was added over 1.5 hours to a mixture of propionic anhydride (260 g) and diethyl ether (500 ml) which had been cooled to -70C. A saturated aqueous solution of ammonium chloride (500 ml) was added and the mixture was allowed to warm to ambient temperature. The organic layer was separated and washed in turn with a dilute aqueous sodium hydroxide solution and with a saturated aqueous sodium chloride solution. The organic layer was dried (Na2SO4) and evaporated to give 3-methoxypropiophenone as a yellow oil (160 g).
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 4h;Heating / reflux;
[0136] To a solution of <strong>[14394-70-8]2-chloro-5-methylpyrimidin-4-amine</strong> (320 mg, 2.23 mmol) in 1,4- dioxane (40 mL) was added l-bromo-3-methoxybenzene (458.5 mg, 2.45 mmol), Cs2CO3 (2.9 g, 8.9 mmol), Pd2(dba)3 (201 mg, 0.22 mmol), and 4,5-bis(diphenylphosrhohino)-9,9- <n="89"/>dimethyxanthene (Xant Phos, 382 nig, 0.66 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine' (1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 24 (500 mg, 90%), was used for next reaction without further purification.
To a flask containing <strong>[86-90-8]4-bromophthalic anhydride</strong> (1) (25.65g, 0. 11mol) was added finely crushed aluminium chloride (30.13g, 0. 23mol). The solid mixture was further crushed and stirred using a spatula. To this mixture was added ANISOLE (85.53g, 86ml, 0. 79MOL) which initiated the production of HCI gas. Once gas evolution ceased the reaction was heated at 80C for 1.5 hours. The hot reaction mixture was poured into a solution of water: CONC. HYDROCHLORIDE acid (9: 1,600mL) and the aqueous layer extracted with ether (2 x 150ML). The organic layer was washed with water and then brine before being dried over magnesium sulphate, filtered and evaporated under reduced pressure to furnish the crude product. Overnight RECRYSTALLISATION from a mixture of ether (200ml) and hexane (400ml) yielded 14, after filtration, a white solid as a mixture of regio isomers. Yield 22.77g, 60%. 'H nmr (250MHz, CDC13) ; 9.28 (2H, brs, 2XCO2H), 8.19 (1H, D, J 1. 8, CHAR), 7. 92 (1 H, d, J 8.4, CHAR), 7.78 (1 H, d, J 1.8, CHar), 7. 74 (1 H, d, J 1.8, CHar), 7.69 (2H, d, J 2.0, CHar), 7.65 (2H, d, J 1.8, CHar), 7. 48 (1 H, d, J 1.8, CHar), 7.22 (I H, D, J B. 1 CHAR), 6.91 (2H, d, J2. 5, CHar), 6.88 (2H, d, J2. 5, CHar), 3. 86 (6H, s, 2XCH3).
With tris-(dibenzylideneacetone)dipalladium(0); (R)-(-)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; potassium tert-butylate; lithium chloride; In toluene; at 130℃; for 3h;Inert atmosphere;
General procedure: A flame-dried resealable Schlenk tube was charged with Pd2(dba)3 (0.025 mmol, 2.5 mol %), Josiphos (0.05 mmol, 5 mol %), the solid reactant(s) (1.0 mmol of the <strong>[53406-38-5]1-aminoindole</strong>, 2.0 mmol of the aryl halide), LiCl (2.0 mmol) and KOtBu (1.4 mmol). The Schlenk tube was capped with a rubber septum, evacuated, and backfilled with argon; this evacuation/backfill sequence was repeated one additional time. The liquid reactant(s) and toluene (2 mL/mmol) were added through the septum. The septum was replaced with a teflon screwcap. The Schlenk tube was sealed, and the mixture was stirred at 130 C for 3 h. The resulting suspension was cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate, and the inorganic salts were removed. The filtrate was concentrated and purification of the residue by silica gel column chromatography gave the desired product. All the compounds gave satisfactory spectroscopic data. Data for the selected compounds are given below:Compound 3a: Yield: 94%; TLC : Rf 0.39 (c-hexane/AcOEt 8:2). IR (neat): 3306, 1604, 1508, 1446, 1359, 1246, 1220, 1112, 1063, 832, 754 cm-1; 1H NMR (CDCl3, 300 MHz) : delta 7.55 (dd, 1H, J = 6.5, 2.3 Hz), 7.25-6.95 (m, 4H), 6.65 (d, 2H, J = 8.9 Hz), 6.42 (d, 1H, J = 3.3 Hz), 6.37 (d, 2H, J = 8.9 Hz), 6.32 (s, 1H), 3.62 (s, 3H).13C NMR (75 MHz, CDCl3) delta 154.5, 141.0, 135.9, 128.7, 126.6, 122.3, 121.1, 120.3, 114.7 (2C), 114.2 (2C), 109.5, 100.6, 55.6. m/z MS (ES+) 239.0 (M+H+).Compound 3i: Yield: 63%; TLC : Rf 0.40 (c-hexane/AcOEt 8:2). IR (neat): 3326, 1521, 1466, 1236, 1220, 1125, 1103, 832, 754 cm-1; 1H NMR (CDCl3, 300 MHz) : delta 7.79-7.61 (m, 1H), 7.33-7.10 (m, 4H), 6.99-6.83 (m, 2H), 6.55 (dd, 1H, J = 3.3, 0.7 Hz), 6.54, (br s, 1H), 6.46 (dd, 2H, J = 9.0, 4.4 Hz). 13C NMR (75 MHz, CDCl3) delta 159.4 (d, 1C, JC-F = 237.0 Hz), 143.4, 135.6, 128.5, 126.7, 122.5, 121.2, 120.4, 116.0 (d, 2C, JC-F = 23.5 Hz), 114.0 (d, 2C, JC-F = 8.3 Hz), 109.3, 100.9. m/z MS (ES+) 227.0 (M+H+).
General procedure: Under an argon atmosphere, to a solution of substituted bromobenzene (2.2 mmol) in THF (10 mL) was added dropwise n-BuLi (1.0 mL, 2.5 mmol) at -78 C and the mixture was stirred for 30 min. A solution of <strong>[67734-35-4](R)-tert-butyl tert-butanethiosulfinate</strong> 6 (0.39 g, 2.0 mmol) in THF (2 mL) was then added dropwise to the reaction mixture at -78 C. The temperature was allowed to slowly warm to room temperature. The reaction mixture was stirred overnight at room temperature, and then evaporated under reduced pressure. Saturated NH4Cl (10 mL) was added, and extracted with CH2Cl2 (10 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography with petroleum ether/EtOAc (4:1, V/V) to afford 7.13
With palladium; potassium carbonate; In methanol; acetonitrile; at 20℃; for 4.5h;
General procedure: To a freshly prepared solution of PdNPs (10 mL, 0.02 mmol), required amount of K2CO3 (2 mmol) was added followed by aryldihalides/ arylhalide (1 mmol) and arylboronic acid (3 mmol)/diboronic acid (0.75 mmol). Then, the reaction mixture was stirred at room temperature in open atmosphere. The reaction was monitored by TLC and was stopped after the complete consumption of starting material. The desired product got precipitated out which was separated by filtration and extracted with chloroform. The chloroform layer was evaporated to get the terphenyl in pure state.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.5h;Microwave irradiation;
General procedure: A mixture of aromatic trithiol (1 mmol), aryl bromide (3 mmol), K2CO3 (2.5 mmol) and PdnpnSTDP(0.05 mol% Pd) in DMF (3 mL) was stirred at 80 oC or subjected to MW irradiation(230 W, 80 oC) for the appropriate time according to Table 4. The work-up was performed asmentioned for synthesis of disulfides and the pure trisulfide was obtained by recrystallizationof the crude product from ethyl acetate.
With C20H12N2O8PdS2(2-)*2Na(1+); sodium hydroxide; In water; at 100℃; for 3h;
General procedure: A solution of aryl bromide (0.5 mmol), arylboronic acid (0.75 mmol), NaOH (1.0 mmol), and complex 1 (0.5 mol %) in H2O (1.0 mL) was stirred at 100 C for 5 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined EtOAc extracts were dried over anhydrous Na2SO4, filtrated, and then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE or PE/EtOAc as the eluent to obtain the desired products.
General procedure: (0013) A mixture of aryl halide (1 equiv), Cu(0) powder (10 equiv), and CuTC (2 equiv) in DMSO (0.2 mL/mmol of aryl halide) was stirred at 65-70 C for 15-72 h. Water and EtOAc were added, and the two phases were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by preparative TLC (EtOAc/hexanes) to furnish the desired product.
General procedure: (0013) A mixture of aryl halide (1 equiv), Cu(0) powder (10 equiv), and CuTC (2 equiv) in DMSO (0.2 mL/mmol of aryl halide) was stirred at 65-70 C for 15-72 h. Water and EtOAc were added, and the two phases were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by preparative TLC (EtOAc/hexanes) to furnish the desired product.
The amount of methoxyphenylbromobenzene was increased to 243.2 g (1.3 mol), propionitrile 71.6 g (1.3 mol), the same as Example 1,The yield of methoxyphenylacetone was 88.6%.;_In the presence of reflux condenser,The reaction flask of the dropping funnel was charged with 24.0 g (1.0 mol) of magnesium powder,Anhydrous aluminum trichloride 3.0 g,Tetrahydrofuran (THF) solution (300 mL)heating.In the dropping funnel, 187.1 g (1.0 mol) of m-methoxybenzene was slowly added,And 300 mL of tetrahydrofuran (THF)Control reaction liquid temperature 50-55 ,So that the solution has been kept in a state of slightly boiling,After the dropwise addition was heated under reflux 0.5-1.0h,To ensure that the magnesium reaction is complete,Get Grignard reagent.Stirring,55.1 g (1.0 mol) of propionitrile was slowly added to the Grignard reagent,After the dropwise addition,And then reaction 1.0-2.0h.Reaction is completed,Cold water bath slowly drop by adding 3.0mol / L hydrochloric acid,Decomposition of addition products,The inorganic phase is separated,The organic phase was subjected to atmospheric distillation to remove THF.Control the temperature to 180-185 C,The distillation was carried out under reduced pressure (reduced pressure at -0.095 MPa,Distillation temperature of 185 C),3-Methoxyphenylacetone was obtained in a yield of 78.3%.
With copper(l) iodide; L-lysine; potassium carbonate; In dimethyl sulfoxide; at 120℃; for 72h;Inert atmosphere;
2H-1,2,3-triazole (2.04 g, 30.0 mmol, 1.0 eq) was added to a 100 mL three-necked flask equipped with a magnetic rotor and a condenser, Cul (571.0 mg, 3.0 mmol, 0.10 eq), ligand L-lyine (690.0 mg, 6 mmol,0.20 eq) and K2CO3 (8 · 29 g, 60 · 0 mmol, 2.0 eq). Nitrogen exchange three times, then add 3-methoxybromobenzene (7 · 53mL,60.0 mmol, 2.0 eq) and solvent dimethyl sulfoxide (60 mL). The reaction mixture was placed in a 120 C oil bath for 3 days. The mixture was cooled to room temperature, quenched by adding 100 mL of water, diluted with 100 mL of ethyl acetate, filtered through Celite, and thoroughly washed with ethyl acetate. After the resulting liquid phase was separated, the aqueous phase was extracted with 50 mL of ethyl acetate three times, The organic phase is dried over anhydrous sodium sulphate. The filtrate was evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20: 1-1: 1) to give 2.30 g of 1A white solid in a yield of 44 %, 1A 'yellow liquid 1.79g, yield 34%.
44%; 34%
With potassium carbonate; copper(II) iodide; L-proline; In dimethyl sulfoxide; at 120℃; for 72h;Inert atmosphere;
Add 100ml three-necked bottle with magnetic rotor and condenser2H-1,2,3-triazole (2.04 g, 30.0 mmol, 1.0 eq), CuI (571.0 mg, 3.0 mmol, 0.10 eq),Ligand L-proline (690.0 mg, 6 mmol, 0.20 eq) and K2CO3 (8.29 g, 60.0 mmol, 2.0 eq).Nitrogen was purged three times and then 3-methoxybromobenzene (7.53 mL, 60.0 mmol, 2.0 eq) and solvent dimethyl sulfoxide (60 mL) were added. The reaction mixture was placed in a 120C oil bath for 3 days.Cool to room temperature, add 100mL of water to quench the reaction, add 100mL of ethyl acetate, diatomaceous earth, filter and wash thoroughly with ethyl acetate. After liquid separation, extract the aqueous phase with 50mL of ethyl acetate 3 times. The organic phase was dried over anhydrous sodium sulfate.Filtration, the filtrate was distilled under reduced pressure to remove the solvent, the crude product was separated and purified by silica gel column chromatography, eluent (petroleum ether / ethyl acetate = 20: 1-1: 1), to obtain 1A white solid 2.30g, yield 44% , 1A' Yellow liquid 1.79g, yield 34%.
methyl 4-(3-methoxyphenyl)-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38.7%
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene; at 100℃;
Pd2(dba)3 (35.5 mg, 0.04 mmol) and XPHOS (37.0 mg, 0.08 mmol) were added to a mixture of methyl 3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxylate (150 mg, 0.78 mmol), l-bromo-3- methoxybenzene (218 mg, 1.16 mmol) and K3PO4 (330 mg, 1.55 mmol) in toluene (5 mL) at room temperature. The mixture was stirred at 100 C overnight. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4. and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 25% EtOAc in hexane) to give white solids. The solids were washed with EtOAc-IPE and dried in vacuo to give the title compound (90 mg, 0.301 mmol, 38.7%) as a light brown oil. (3634) MS (ESI+), found 300.3 (M+H) (3635) 1H NMR (300 MHz, CDC13) 5:3.72-3.75 (2H, m) , 3.80 (3H, s) , 3.85 (3H, s), 4.28-4.35 (2H, m), 6.72-6.87 (4H, m) , 7.19-7.36 (1H, m) , 7.42 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 1.9 Hz).
tert-butyl 4-[(4-fluorophenyl)(hydroxy)(3-methoxyphenyl)methyl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
To a solution of 3-bromoanisole (487 mg, 2.6 mmol) in THF (40 mL) was added butyllithium (1.5 mL, 3.75 mmol, 2.5 M) at -78 C. After stirring for 1 h, tert- butyl 4-(4- fluorobenzoyl)piperidine-l -carboxylate (800 mg, 2.6 mmol) was added to the mixture and stirring was continued at -78 C for 1 h. Then the reaction was warmed to 25 C and stirred for another 13 h. The reaction was quenched with NH4C1 (sat. aq., 50 mL) and extracted with EtOAc (100 mL). The organic layer was separed, dried over Na^SCfi, filtered and concentrated under vacuum to afford tert- butyl 4-[(4- fluorophenyl)(hydroxy)(3-methoxyphenyl)methyl]piperidine-l -carboxylate (1100 mg, 63%) as yellow oil; LCMS: 438.l [M+Na]+.
With copper(I) oxide; 1,10-Phenanthroline; potassium carbonate; In N,N-dimethyl-formamide; for 48h;Inert atmosphere; Reflux;
A flask was charged with Cu 2O (10 mol%), 1, 10-phenanthroline (20 mol%), 3-bromoanisole (1 equiv.), K 2CO 3 (3 equiv.) and 2H-1, 2, 3-triazole (1.5 equiv.). Andydrous DMF (50 mL) was added to the flask and the mixture was refluxed for 48 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 100 mL dichloromethane and filtered through a plug of Celite. The filtrate was concentrated under reduced pressure and further purified by flash column chromatography on silica gel with n-hexane/EA (10: 1 to 8: 2) as eluent to afford the products. (h): Following the general procedure C. 2H-1, 2, 3-triazole (3g, 43.4 mmol) and 3-bromoanisole (3.7 mL, 29.0 mmol). Yield: 3.3 g, 65%. 1H NMR (400 MHz, CDCl 3) : delta 7.81 (s, 2H), 7.67 (d, J = 7.3 Hz, 2H), 7.38 (t, J = 8.0 Hz, 1H), 6.93-6.88 (m, 1H), 3.89 (s, 3H).
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