* 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 the American Chemical Society, 2014, vol. 136, # 7, p. 2711 - 2714
[2] Patent: WO2005/63239, 2005, A1, . Location in patent: Page/Page column 134
2
[ 4654-39-1 ]
[ 98-80-6 ]
[ 37729-18-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 14, p. 4199 - 4203
3
[ 4654-39-1 ]
[ 1553-60-2 ]
Reference：
[1] Organic Process Research and Development, 2006, vol. 10, # 5, p. 1076 - 1079
4
[ 41841-16-1 ]
[ 4654-39-1 ]
Yield
Reaction Conditions
Operation in experiment
85.5%
With lithium borohydride In tetrahydrofuran at 0 - 20℃; for 2 h;
5.5a (6 g, 26.2 mmol, 1.0equiv) was dissolved in THE (100 mL) and cooled toO °C. LiBH4 (2M in THE) (1.41 g, 52.4 mmol, 2.0 equiv) was added drop wise at 0 °C and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 5.5b (4.5 g, 85.5 percent yield). LCMS (mlz): 204.8 [M+H]. 1H NMR (400 MHz, DMSO) 6 7.56 — 7.35 (m, 2H), 7.27 — 7.07 (m, 2H), 4.67 (t, J = 5.2 Hz, 1 H), 3.58 (td, J = 6.8, 5.4 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H).
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5627 - 5631
[2] Patent: WO2015/66413, 2015, A1, . Location in patent: Page/Page column 164; 165
[3] Chemistry - A European Journal, 2015, vol. 21, # 42, p. 14737 - 14741
[4] Advanced Synthesis and Catalysis, 2012, vol. 354, # 10, p. 1879 - 1884
[5] Synthesis, 2011, # 18, p. 2935 - 2940
5
[ 75-21-8 ]
[ 106-37-6 ]
[ 4654-39-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With n-butyllithium In diethyl ether; hexane at -40 - 20℃; for 3 h; Inert atmosphere Stage #2: at -40 - 20℃; for 1 h; Inert atmosphere
The solution of 1,4-dibromobenzene (40 g, 0.17 mol) in drydiethyl ether (200 mL) was cooled to 40 C and n-buthyllithium(105.6 mL, 1.6 M in hexanes, 0.17 mol) was added dropwise for1 h. The mixture was allowed to warm up to rt and stirred for2 h. The reaction was once again cooled to 40 C and a solutionof ethylene epoxide (8.46 mL, 0.17 mol) in 40 mL of diethyl etherwas added slowly to the mixture. The reaction mixture was slowlywarmed to room temperature and stirred for 1 h at room temperature.Then 40 mL of NH4Cl was added to quench the reaction. Theproduct was extracted with diethyl ether (3 100 mL). Theorganic layers were dried over MgSO4, filtered and concentrated.Distillation afforded 28.63 g (85percent) of a colourless liquid of 10.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 12, p. 3465 - 3472
[2] Organic and Biomolecular Chemistry, 2010, vol. 8, # 15, p. 3552 - 3562
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1977, p. 2357 - 2364
6
[ 1878-68-8 ]
[ 4654-39-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 3 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0 - 80℃; for 0.5 h;
4-r2-(2-Bromoethoxy)ethvnbenzonitrile(T) 2-(4-BromophenvDethanol To a chilled solution (about O0C) of 4-bromophenyl acetic acid (25 g, 0.116 mol) in THF (250 mL), borane methyl sulphide (13.2 g, 0.174 mol) was added, dropwise, under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h. After cooling the mixture to between 0 and 5°C, the reaction was quenched by adding 1.5 NHCl (80 mL), dropwise. After warming for 30 min at about 800C, the reaction mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water and brine and then dried. The product was obtained as colourless liquid after concentration (yield: 23.3 g, 99percent).
18.7g
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 30℃; for 2 h;
The specific operation is as follows: The bromophenylacetic acid was added to 200ml of tetrahydrofuran,Stirring cooled to 0 ° C after adding lithium aluminum hydride in batches, the end of the addition,After the reaction was heated to 25 ~ 30 ° C for 2h, 300ml of water and 400ml of dichloromethane were separated,The organic phase was added to 20g of anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure at 30-35 ° C.Obtained light yellow oil (brominated S1-1): 18.7g, under ice bath,To bromine S1-1 was added dropwise phosphorus tribromide, dropping temperature during the control at 0 ~ 10 ,Dropping is completed, incubated 10min insulation, a white smoke generated, stirring, warming to 75 ~ 80 ,After stirring for 2h, 30ml of saturated sodium bicarbonate solution, 200ml of ethyl acetate,Stirring 20min liquid separation, the organic phase 40 ~ 45 filtrate was concentrated under reduced pressure,A yellow liquid (bromination S2) was obtained: 22.1 g. Yield: 90.0percent.
Reference：
[1] Patent: WO2006/135316, 2006, A1, . Location in patent: Page/Page column 64
[2] European Journal of Inorganic Chemistry, 2011, # 14, p. 2238 - 2246
[3] Advanced Synthesis and Catalysis, 2016, vol. 358, # 3, p. 452 - 458
[4] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 85, p. 10514 - 10516,3
[5] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 786 - 801
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 756 - 760
[7] Journal of Organic Chemistry, 1964, vol. 29, # 8, p. 2109 - 2116
[8] Chemical and Pharmaceutical Bulletin, 1977, vol. 25, # 7, p. 1732 - 1739
[9] Tetrahedron, 1990, vol. 46, # 20, p. 7247 - 7262
[10] Tetrahedron Letters, 1989, vol. 30, # 46, p. 6291 - 6294
[11] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2882 - 2891
[12] Bulletin of the Chemical Society of Japan, 2005, vol. 78, # 10, p. 1856 - 1861
[13] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4752 - 4756
[14] Synthetic Communications, 1998, vol. 28, # 5, p. 823 - 832
[15] Journal of the American Chemical Society, 2010, vol. 132, # 12, p. 4076 - 4077
[16] European Journal of Organic Chemistry, 2011, # 17, p. 3178 - 3183
[17] Synthesis, 2011, # 18, p. 2935 - 2940
[18] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13349 - 13357
[19] Patent: WO2015/66413, 2015, A1,
[20] Chemistry - A European Journal, 2014, vol. 20, # 47, p. 15325 - 15329
[21] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
[22] Patent: CN106478506, 2017, A, . Location in patent: Paragraph 0133; 0134
7
[ 50-00-0 ]
[ 589-17-3 ]
[ 4654-39-1 ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 70℃; for 2 h; Schlenk technique; Inert atmosphere Stage #2: at 70℃; for 6 h; Schlenk technique; Inert atmosphere
General procedure: Phenethyl alcohol (3a) A two neck Schlenk flask equipped with a magnetic stirring bar and septum was heated with heat gun (~400 °C) for 10 min under high vacuum. After cooling to room temperature, the flask was flushed with argon (3 times). Zn-dust (654 mg, 2.0 equiv, 10.0 mmol) was added followed by THF (20 mL). 1,2-Dibromoethane (5 molpercent) was added and the reaction mixture was heated until ebullition occurs. After cooling to rt, chlorotrimethylsilane (1 molpercent) was added and the mixture was heated again till ebullition occurs. The flask was again cooled to rt and benzyl chloride (633 mg, 5.0 mmol, 1 equiv) was added as a solution in THF (10 mL) and it was heated at 70 °C for 2 h and cooled to rt. Paraformaldehyde (450 mg, 3.0 equiv. 15.0 mmol) was slowly added at rt and the flask was again heated at 70 °C for 6 h. The solution was cooled to rt and saturated NH4Cl solution was added. The phases were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (20 mL), brine (10 mL) and then dried over Na2SO4. The solvents were evaporated under reduced pressure and the residue was purified by silica gel column chromatography using cyclohexane or cyclohexane/ethyl acetate as an eluent to obtain phenethyl alcohol (3a) (510 mg, 83percent) as a colourless liquid.
Reference：
[1] Journal of Physical Organic Chemistry, 2008, vol. 21, # 11, p. 945 - 953
22
[ 99-90-1 ]
[ 4654-39-1 ]
Reference：
[1] Organic Process Research and Development, 2006, vol. 10, # 5, p. 1076 - 1079
23
[ 32017-76-8 ]
[ 4654-39-1 ]
[ 5391-88-8 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1987, vol. 60, p. 1813 - 1818
24
[ 1122-91-4 ]
[ 4654-39-1 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 31, p. 4308 - 4311
25
[ 16532-79-9 ]
[ 4654-39-1 ]
Reference：
[1] Journal of Organic Chemistry, 1964, vol. 29, # 8, p. 2109 - 2116
26
[ 589-15-1 ]
[ 4654-39-1 ]
Reference：
[1] Journal of Organic Chemistry, 1964, vol. 29, # 8, p. 2109 - 2116
27
[ 104-10-9 ]
[ 4654-39-1 ]
Reference：
[1] Journal of the Chemical Society, 1936, p. 181,183
[2] Journal of the Chemical Society, 1935, p. 1819
28
[ 4654-39-1 ]
[ 75-86-5 ]
[ 57775-08-3 ]
Reference：
[1] Patent: US6335350, 2002, B1, . Location in patent: Example 78
[2] Patent: EP1137645, 2004, B1, . Location in patent: Page 45
29
[ 4654-39-1 ]
[ 57775-08-3 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1977, p. 2357 - 2364
30
[ 60-12-8 ]
[ 4654-39-1 ]
[ 1074-16-4 ]
Reference：
[1] Synlett, 2004, # 15, p. 2739 - 2745
31
[ 4654-39-1 ]
[ 46112-46-3 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 4177
32
[ 109-72-8 ]
[ 60-29-7 ]
[ 124-38-9 ]
[ 4654-39-1 ]
[ 46112-46-3 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 4177
[2] Iowa State College Journal of Science, 1943, vol. 18, p. 65
33
[ 4654-39-1 ]
[ 149910-98-5 ]
Reference：
[1] Pharmazie, 1996, vol. 51, # 9, p. 641 - 644
[2] Tetrahedron Letters, 2013, vol. 54, # 30, p. 3962 - 3964
[3] Tetrahedron Letters, 2014, vol. 55, # 50, p. 6821 - 6826
[4] Chemistry - A European Journal, 2014, vol. 20, # 47, p. 15325 - 15329
[5] Advanced Synthesis and Catalysis, 2016, vol. 358, # 12, p. 1880 - 1885
[6] Journal of Organic Chemistry, 2016, vol. 81, # 15, p. 6463 - 6471
[7] Organic and Biomolecular Chemistry, 2016, vol. 14, # 44, p. 10366 - 10370
[8] Chemistry - A European Journal, 2017, vol. 23, # 45, p. 10871 - 10877
[9] Organic Letters, 2018,
34
[ 3970-21-6 ]
[ 4654-39-1 ]
[ 149910-98-5 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 7, p. 3104 - 3112
35
[ 4654-39-1 ]
[ 137756-89-9 ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5 h; Stage #2: With hydrogenchloride; Triisopropyl borate In tetrahydrofuran; hexane; water at -78 - 20℃; for 1 h;
To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9 mmol) in THF (80 ml) was added a solution of 1.5M n-BuLi in hexane (39.8 ml, 59.7 mmol) at -78° C. over 30 min. After 1 hour, a solution of B(OiPr)3 (8.61 ml, 37.3 mmol) in THF (20 ml) was added slowly to the mixture at -78° C. The resultant mixture was warmed to room temperature, and treated with 2M HCl (100 ml) for 1 hour. This was extracted with CH2Cl2 and dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with CH2Cl2/MeOH=20/1 to afford 2.61 g (63percent) of the title compound. [2789] 1H-NMR (CD3OD) δ: 7.64-7.48 (2H, m), 7.19-7.13 (2H, m), 3.70 (2H, t, J=7.2 Hz), 2.77 (2H, t, J=7.2 Hz) MS (ESI) m/z: 165 ([M-H]-)
63%
With n-butyllithium; Triisopropyl borate In tetrahydrofuran; hexane at -78 - 20℃; for 1.5 h;
To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9 mmol) in tetrahydrofuran (80 mL) was added a solution of 1.5 M n-butyl lithium in hexane (39.8 mL, 59.7 mmol) at -78° C. over 30 min. After 1 h, a solution of triisopropyl borate (8.61 mL, 37.3 mmol) in tetrahydrofuran (20 mL) was added slowly to the mixture at -78° C. The resultant mixture was warmed to room temperature, and treated with 2 M HCl (100 mL) for 1 h. This mixture was extracted with dichloromethane and dried (MgSO4). After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (20:1) to afford 2.61 g (63percent) of the title compound as white solids
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 35℃; for 1.5 h; Stage #2: at -78 - 35℃; Stage #3: With ammonium chloride In tetrahydrofuran; hexane
(Step 1) To a solution of 2-(4-bromophenyl)ethanol (3.00 g, 14.9 mmol) in THF (60 mL) was added 1.6 M butyllithium/hexane solution (23.3 mL, 37.3 mmol) at -78° C. and the mixture was stirred at -78° C. for 1 hr and then at room temperature for 30 min. The reaction mixture was cooled again to -78° C. and triisopropylboric acid (7.02 g, 37.3 mmol) was added. The mixture was gradually heated to room temperature. Saturated aqueous ammonium chloride solution (150 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous-sodium sulfate. The solvent was evaporated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (67-100percent ethyl acetate/hexane-9percent methanol/ethyl acetate) to give [4-(2-hydroxyethyl)phenyl]boronic acid as a colorless amorphous form (925 mg, 37percent).
With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane
Step. 4-(2-hydroxyethyl)phenylboronic acid To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9 mmol) in THF (80 ml) was added a solution of 1.5M n-BuLi in hexane (39.8 ml, 59.7 mmol) at -78° C. over 30 min. After 1 hour, a solution of B(OiPr)3 (8.61 ml, 37.3 mmol) in THF (20 ml) was added slowly to the mixture at -78° C. The resultant mixture was warmed to room temperature, and treated with 2M HCl (100 ml) for 1 hour. This was extracted with CH2Cl2 and dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluding with CH2Cl2/MeOH=20/1 to afford 2.61 g (63percent) of the title compound. 1H-NMR (CD3OD) δ: 7.64-7.48 (2H, m), 7.19-7.13 (2H, m), 3.70 (2H, t, J=7.2 Hz), 2.77 (2H, t, J=7.2 Hz) MS (ESI) m/z: 165 ([M-H]-)
Reference：
[1] Patent: US2002/77329, 2002, A1,
38
[ 4654-39-1 ]
[ 73183-34-3 ]
[ 651030-55-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 85℃; for 12 h; Inert atmosphere
Step 1: 2-(4-(4,4,5,5-Tetramethyl-l,3)2-dioxaborolan-2-yl)phenyl)ethanol Potassium acetate (4.88 g, 49.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (7.6 g, 30 mmol) and PdCl2(dppf) (0.91 g, 1.2 mmol) were added to a solution of 2-(4-bromophenyl)ethanoi (5.0 g, 25 mmol) in 1 ,4-dioxane (100 mL) under 2, The mixture was purged with N2 then stirred under N2 at about 85 °C for about 12 h. After cooling to rt, water (100 mL) was added and the mixture was extracted with EtOAc (2 χ 100 mL). The combined organic layers were washed with saturated aqueous NaCl (100 mL) and dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel (17percent EtOAc/petroleum ether). The appropriate fractions were collected and concentrated under reduced pressure to give the title compound (6.2 g, 100percent). NMR (400MHz, (.' )(. I :) δ 7.78 (d, J = 7.9 Hz, 2H), 7.29 - 7.23 (m, 2H), 3.87 (t, J= 6.6 Hz, 2H), 2.90 t, J = 6.6 Hz, 2H), 1.36 (s, 12H).
100%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 85℃; for 12 h; Inert atmosphere
Step 1: 2-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethanol KOAc (4.88 g, 49.7 mmol), 4,4,4,,4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-d.ioxaborolane) (7.6 g, 30 mmol) and PdCl2(dppf) (0.91 g, 1.2 mmol) were added to a solution of 2-(4-bromophenyl)ethanol (5.0 g, 25 mmol) in 1,4-dioxane (100 mL) under N2. The mixture was purged with N2 then stirred under N2 at about 85 °C for about 12 h. After cooling to rt, water (100 mL) was added and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with sat. aq.NaCl (100 mL) and dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (17percent EtO Ac/petroleum ether). The appropriate fractions were collected and concentrated under reduced pressure to afford the title product (6.2 g, 100percent). NMR (400MHz, CDC13) δ 7.78 (d, ,/ = 7.9 Hz, 2H), 7.29 - 7.23 (m, 2H), 3.87 (t, ,/ = 6.6 Hz, 2H), 2.90 (t, ,/ = 6.6 Hz, 2H), 1.36 (s, 12H).
100%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 85℃; for 12 h; Inert atmosphere
Potassium acetate (4.88 g, 49.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (7.6 g, 30 mmol) and PdCl2(dppf) (0.91 g, 1.2 mmol) were added to a solution of 2-(4-bromophenyl)ethanol (5.0 g, 25 mmol) in 1,4-dioxane (100 mL) under N2. The mixture was purged with N2 then stirred under N2 at about 85 °C for about 12 h. After cooling to rt, water (100 mL) was added and the mixture was extracted with EtOAc (2 χ 100 mL). The combined organic layers were washed with saturated aqueous NaCl (100 mL) and dried over Na2SOzi, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel (17percent EtO Ac/petroleum ether). The appropriate fractions were collected and concentrated under reduced pressure to give the title compound (6.2 g, 100percent). NMR (400MHz, CDC13) δ 7.78 (d, J= 7.9 Hz, 2H), 7.29 - 7.23 (m, 2H), 3.87 (t, J= 6.6 Hz, 2H), 2.90 (t, J= 6.6 Hz, 2H), 1.36 (s, 12H).
89%
With potassium acetate In dimethyl sulfoxide at 120℃; for 5 h;
To a solution of 2-(4-bromophenyl)ethanol (500mg, 2.49mmol) in dimethyl sulfoxide (5mL) were added bis (pinacolato) diboron (632mg, 2.49mmol), potassium acetate (733mg, 7.47mmol) and [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane (1:1) complex (102mg, 124μmol), and the mixture was stirred for 5 hours at 120°C. Ice water and toluene were added to the reaction mixture and the insolubles were filtered off. The organic layer was separated, washed with water, then dried over anhydrous sodium sulfate, and solvent was distilled off. The residue obtained was purified by silica gel column chromatography [hexane-ethyl acetate=1:1], thereby affording 455mg of the title compound as a pale yellow oil. Yield 89percent.1H-NMR (CDCl3, δ): 1.34(12H,s), 2.89(2H,t,J=6.3Hz), 3.87(2H,q, J=6.3Hz), 7.25(2H,d,J=7.8Hz), 7.77(2H,d,J=8.3Hz).
79%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere
PdCI2(dppf)-CH2Cl2 adduct (4.06 g, 4.97 mmol) was added to a solution of 2-(4- bromophenyl)ethanol (10.0 g, 49.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (25.3 g, 99 mmol) and potassium acetate (14.64 g, 149 mmol) in 1 ,4- dioxane (200 ml_) at room temperature under a nitrogen atmosphere and the reaction mixture was stirred at 80 °C overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (1 :6 EtOAc/petroleum ether) to give 2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethanol (10.5 g, 39.2 mmol, 79 percent yield) as a yellow oil. LCMS: [M+NH4] 266.2.
73%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane at 100℃; for 18 h; Inert atmosphere
To a 1L flask was added Bis(pinacolato)diboron (30.5 g, 0.12 mol), KOAc (29.44 g, 0.3 mol) and1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mmol, 0.05 eq.). The flask was charged under Ar and dioxane (250 mL) was introduced and the resulting mixture was purged with Ar for 15 mm. To it was added 2-(4-bromophenyl)-ethanol (14 ml, 0.1 mol) and the mixture was then heated at 100 °C for 18 h. It was cooled to room temperature and was filtered through celite.The filtrate was concentrated and the residue was diluted with EtOAc. The organic solution was washed with brine and driver over Mg504. Concentration afforded the crude product, which was further purified on a silica-gel column with 30-80percent EtOAc in hexane to give 18.1 g (73percent) of 2-(4- (4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenyl)ethanol
Reference：
[1] Patent: WO2016/168638, 2016, A1, . Location in patent: Page/Page column 30; 31
[2] Patent: WO2016/168633, 2016, A1, . Location in patent: Page/Page column 57
[3] Patent: WO2016/168641, 2016, A1, . Location in patent: Page/Page column 105
[4] Journal of the American Chemical Society, 2014, vol. 136, # 42, p. 14742 - 14745
[5] Patent: EP1544194, 2005, A1, . Location in patent: Page/Page column 37-38
[6] Patent: WO2017/98440, 2017, A1, . Location in patent: Page/Page column 150
[7] Patent: WO2016/11019, 2016, A1, . Location in patent: Page/Page column 160
With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at 0℃; for 1h;Inert atmosphere; Schlenk technique;
A solution of 2-(4-bromophenyl)ethanol (4.43 g, 0.0220 mol) dissolved in CH2Cl2 (50 mL) was cooled to 0C. Next, PPh3 (6.92 g, 0.0264 mol) was added, followed by NBS (4.70 g, 0.0264 mol), and vigorous effervescence in a yellow solution was observed. The mixture was allowed to stir at 0C for 60 minutes. After this time, the yellow solution was treated with saturated sodium bicarbonate solution (20 mL). The deep, dark blue organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The organic layers were combined and then the solvent was removed under reduced pressure to yield a deep, dark blue oil. The oil was purified on a column of silica (~1.5 cm × 20 cm) using EtOAc/hexanes (1:10) as an eluent and collecting the first nearly colourless fraction. Removal of the volatiles under reduced pressure yielded a very pale orange liquid. Yield: 5.38 g (93%). 1H NMR (500 MHz, 22C, CDCl3): 7.43 (d, 2H, 2JHH = 8 Hz, Ar), 7.08 (d, 2H, 2JHH = 8 Hz, Ar), 3.53 (t, 2H, 3JHH = 7 Hz, -CH2CH2-), 3.11 (t, 2H, 3JHH = 7 Hz, -CH2CH2-).
90%
With bromine; triphenylphosphine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; at 20℃; for 2h;
General procedure: To a stirred solution of triphenylphosphine (1.5 mmol) in dry dichloromethane was added iodine (1.5 mmol)and polymer supported 4-DMAP (0.4 mmol, 40 mol%). Stirring was continued for 2 min; alcohol (1mmol) was then added. The reaction was monitored by TLC. After complete conversion of the alcohol (as indicated byTLC), the reaction was quenched with an aqueous solution of sodium thiosulfate (20 mL). The organic solventswere removed and the aqueous solution extracted with ethylacetate (50 mL). The combined organic layers weredried using sodium sulfate (anhydrous), filtered and concentrated. The residue was purified by column chromatography (2% EtOAc in hexane) to get the desired iodide product.
90%
With phosphorus tribromide; at 0 - 80℃; for 2.16667h;
The specific operation is as follows: The bromophenylacetic acid was added to 200ml of tetrahydrofuran,Stirring cooled to 0 C after adding lithium aluminum hydride in batches, the end of the addition,After the reaction was heated to 25 ~ 30 C for 2h, 300ml of water and 400ml of dichloromethane were separated,The organic phase was added to 20g of anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure at 30-35 C.Obtained light yellow oil (brominated S1-1): 18.7g, under ice bath,To bromine S1-1 was added dropwise phosphorus tribromide, dropping temperature during the control at 0 ~ 10 ,Dropping is completed, incubated 10min insulation, a white smoke generated, stirring, warming to 75 ~ 80 ,After stirring for 2h, 30ml of saturated sodium bicarbonate solution, 200ml of ethyl acetate,Stirring 20min liquid separation, the organic phase 40 ~ 45 filtrate was concentrated under reduced pressure,A yellow liquid (bromination S2) was obtained: 22.1 g. Yield: 90.0%.
88.8%
Production Example 4 Synthesis of 4-bromophenethyl bromide 4-Bromophenethyl alcohol (1.3 ml) was treated as in Production Example 1 to give the title compound (2.345 g) as a pale yellow oil (yield: 88.8%). 1H-NMR (400 MHz, CDCl3): delta(ppm) 3.12(2H, t, J=7.4Hz), 3.54(2H, t, J=7.4Hz), 7.09(2H, d, J=8.4Hz), 7.45(2H, d, J=8.4Hz).
Part A. Employing method similar to Example 114 Part A but using 4-bromophenethylalcohol (5.0 gm, 24.9 mmol) 4-bromophenethylbromide was prepared as a clear oil. 1 H NMR (CDCl3): 3.15 (t, 2H), 3.58 (t, 2H), 7.10 (d, 2H), 7.45 (d, 2H).
Part A. Employing method similar to Example 114 Part A but using 4-bromophenethylalcohol (5.0 gm, 24.9 mmol) 4-bromophenethylbromide was prepared as a clear oil. 1H NMR (CDCl3): 3.15 (t, 2H), 3.58 (t, 2H), 7.10 (d, 2H), 7.45 (d, 2H).
With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h;
To a solution of 2-(4-bromophenyl)ethanol (1.00 g) and tetrabromomethane (3.96 g) in tetrahydrofuran (10 ml) was added triphenylphosphine (2.87 g) at room temperature and the mixture was stirred at the same temperature for 1 hour under nitrogen. The mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-bromo-4-(2-bromoethyl)benzene (2.07 g). NMR (CDCl3, delta): 3.12 (2H, t, J=7.4 Hz), 3.54 (2H, t, J=7.4 Hz), 7.09 (2H, d, J=10.6 Hz), 7.45 (2H, d, J=10.6 Hz)
Stage #1: 1.4-dibromobenzene With n-butyllithium In diethyl ether; hexane at -40 - 20℃; for 3h; Inert atmosphere;
Stage #2: oxirane In diethyl ether; hexane at -40 - 20℃; for 1h; Inert atmosphere;
4.2.1. Synthesis of 2-(4-bromophenyl)ethanol 10
The solution of 1,4-dibromobenzene (40 g, 0.17 mol) in drydiethyl ether (200 mL) was cooled to 40 C and n-buthyllithium(105.6 mL, 1.6 M in hexanes, 0.17 mol) was added dropwise for1 h. The mixture was allowed to warm up to rt and stirred for2 h. The reaction was once again cooled to 40 C and a solutionof ethylene epoxide (8.46 mL, 0.17 mol) in 40 mL of diethyl etherwas added slowly to the mixture. The reaction mixture was slowlywarmed to room temperature and stirred for 1 h at room temperature.Then 40 mL of NH4Cl was added to quench the reaction. Theproduct was extracted with diethyl ether (3 100 mL). Theorganic layers were dried over MgSO4, filtered and concentrated.Distillation afforded 28.63 g (85%) of a colourless liquid of 10.
64%
Stage #1: 1.4-dibromobenzene With magnesium In diethyl ether at 20℃; Reflux;
Stage #2: oxirane With copper(I) bromide In tetrahydrofuran; diethyl ether at 20℃; Cooling with liquid nitrogen;
Stage #3: With water; acetic acid In tetrahydrofuran; diethyl ether
(i) nBuLi, hexane, Et2O, (ii) /BRN= 102378/; Multistep reaction;
With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 3h;
To a mixture of 2-(4- bromophenyl)ethanol (10.0 g, 49.7 mmol) in DCM (100 mL) were added imidazole (10.0 g, 149.2 mmol) and TBSC1 (8.2 g, 54.7 mmol) at 0 C. After stirring at room temperature for 3 h, the reaction mixture was quenched with water, extracted with DCM. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The crude was purified by silica gel column (PE: EA = 50: 1) to get (4-bromophenethoxy)(tert-butyl)dimethylsilane (16.2 g, 99%) as a colorless oil.
95.5%
With dmap; triethylamine; In dichloromethane; at 20℃;Large scale;
The reaction kettle was charged with <strong>[4654-39-1]4-bromophenethyl alcohol</strong> (1.0 kg, 5.0 mol) 10 times the volume of methylene chloride dissolved, Triethylamine (1.01 kg, 10.0 mol) And catalytic amount of DMAP, TBSCl (0.9 kg, 6.0 mol) was added in batches. Reaction to the disappearance of raw materials at room temperature, Washed, Saturated brine, After drying with anhydrous sodium sulfate, the liquid compound VA (1.5 kg, 95.5%) was obtained as a colorless oil. Directly into the next reaction.
76%
With 1H-imidazole; In dichloromethane;
3.0 g 2-(4-bromophenyl)ethanol (15 mmol) and 2.1 g imidazole (31 mmol) were dissolved in 20 mL dichloromethane. A solution of 2.3 g (tert-butyl)dimethylchlorosilane (15.5 mmol) dissolved in 20 mL dichloromethane was added and the mixture stirred overnight, forming a precipitate. The mixture was diluted with dichloromethane and washed three times with 4% w/v sodium carbonate solution, water and was dried over sodium sulphate. Evaporation and purification of the residue by chromatography (ethyl acetate-hexane gradient, 0:100 to 20:80) gave 3.6 g (76%) of [2-(4-bromophenyl)ethoxy](tert-butyl)dimethylsilane. 1H NMR (200 MHz, CHLOROFORM-d) ppm 7.42 (2 H, d, J=8.2 Hz), 7.11 (2 H, d, J=8.2 Hz), 3.80 (2 H, t, J=6.6 Hz), 2.79 (2 H, t, J=6.8 Hz), 0.89 (9 H, s), 0.01 (6 H, s)
With 1H-imidazole; In N,N-dimethyl-formamide; at 0℃;
1. Preparation of isopropyl 4-(2-oxoethyl)benzoate (14) - The synthesis of aldehyde 14 is illustrated in Scheme 4; Scheme 4; Step 1: [2-(4-bromophenyl)ethoxy](ter/-butyl)dimethylsilane; To a solution of 2-(4-bromophenyl)ethanol (5.3 g, 26.4 mmol) in DMF (50 mL) at OC was added imidazole (3.59 g, 52.8 mmol, 2 eq) and tert-Butyldimethylsilyl chloride (TBSCl) (4.18 g, 27.7 mmol, 1.05 eq) and the mixture was stirred at 0 0C until all starting material was consumed. The mixture was then diluted with water and extracted with ether (3x). The extracts were washed with water (3x) and brine and dried over MgSO4 to give the desired product. 1H NMR (400 MHz, acetone-d6) delta 7.46 (2H, d, J = 8Hz), 7.22 (2h, D, j = 8 Hz), 3.85 (t, 2H, J = 7Hz), 2.79 (t, 2H, J = 7 Hz), 0.87 (s, 9H) and - 0.01 (s, 6H).
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 3h;
Example 49 tert-butyl(dimethyl)[2-(4-methylphenyl)ethoxy]silane To N,N-dimethylformamide (6 mL) solution of 2-(4-bromophenyl)ethanol (552 mg), imidazole (248 mg) and tert-butyldimethylsilyl chloride (453 mg) were added. The reaction solution was stirred at room temperature for 3 hours. To the reaction solution, 1N-hydrochloric acid (10 mL) was added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0?97:3) to obtain the title compound (829 mg) having the following physical properties. TLC: Rf 0.51 (n-hexane:ethyl acetate=50: 1); NMR(CDCl3):delta 7.39 (d, J=8.4Hz, 2H), 7.08 (d, J=8.4Hz, 2H), 3.77 (t, J=6.9Hz, 2H), 2.76 (t, J=6.9Hz, 2H), 0.86 (s, 9H), -0.03 (s, 6H).
With 1H-imidazole; In tetrahydrofuran; at 20℃; for 2h;
To a solution of lH-imidazole (1.06 g, 15.6 mmol) and 2-(4- bromophenyl)ethanol (2.19 g, 10.9 mmol) in TetaF (20 mL) at room temperature was added /ert-butylchlorodimethylsilane (1.81 g, 12.0 mmol). The reaction mixture was stirred at room temperature for 2 h and diluted with hexanes. The organic phase was washed with water (2 x), brine (1 x), dried over MgSO4, filtered, and concentrated to give (4-bromophenethoxy)(;ert- butyl)dimethylsilane 65 which was used in the next step without further purification.
With 1H-imidazole; In tetrahydrofuran; at 20℃; for 1.5h;
1-Bromo-4-[2-(tert-butyldimethylsilyloxy)ethyl]benzene 70 g of 2-(4-bromophenyl)ethanol is dissolved in 350 ml of absolute tetrahydrofuran and mixed with 4.97 g of imidazole.. Then, 55 g of tert-butyldimethylsilyl chloride in 230 ml of absolute tetrahydrofuran is added in drops and stirred for 90 minutes at room temperature.. For working-up, the reaction mixture is added to ice water, extracted three times with diethyl ether, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum.. Preparative column chromatography on silica gel with hexane/ethyl acetate as an eluant yields 111 g of 1-bromo-4-[2-(tort-butyldimethyl-silyloxy)ethyl]benzene as a clear oil.
With dmap; triethylamine; In dichloromethane; at 17 - 25℃;Inert atmosphere;
Example 6 3-Amino-6-f4-{2-[f3-methoxypropyl)aminolethyl}phenyl)-N-pyridin-3-ylpyrazine-2- carboxamideThe title compound was prepared in accordance with the following procedure: (i) (4-Bromophenylethoxy)(tert-butyl)dimethylsilane To a solution of 2-(4-bromophenyl)ethanol (5 g, 25 mmol) in anhydrous dichloromethane (150 mL) was added triethylamine (7.5 g, 75 mmol), DMAP (300 mg, 2.5 mmol) and tert- butyldimethylsilyl chloride (7.5 g, 50 mmol) sequentially. The resulting pale brown solution was stirred at room temperature for overnight. The reaction mixture was extracted with dichloromethane and water three times. The combined organic layers were dried over anhydrous sodiumsulphate, filtered and concentrated in vacuo. The crude product was subjected to column chromatography with PE as eluant to afford the subtitle compound as a brown oil (7.1 g). 1H NMR (400 MHz, CDC13) delta 7.41 (dd, J = 6.4, 2.0 Hz, 2H), 7.10 (dd, J = 6.4, 2.0 Hz, 2H), 3.80 (t, J = 6.8 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 0.88 (s, 9H), 0.00 (s, 6H).
With triethylamine; In dichloromethane; at 0℃; for 0.5h;
Example 1.1: Preparation of Intermediate (lambda)-4-(2-(2-Methy]pyrrolidin-l- yl)ethyl)phenylboronic Acid; Step A: Preparation of Intermediate 4-Bromophenethyl Methanesulfonate;.4-Bromophenethyl alcohol (38.9 g, 193 mmol) was dissolved in DCM (193 mL). Triethylamine (40.4 mL, 290 mmol) was added and the mixture was cooled in an ice bath. Methanesulfonyl chloride (18 mL, 232 mmol) was added dropwise via an addition funnel. The ice bath was removed and the mixture was stirred for 30 min. The reaction mixture was diluted with 200 mL DCM, washed with 1 M HCl twice (100 mL each), followed by brine, saturated sodium bicarbonate, and brine. The organic phase was dried with sodium sulfate and filtered. Solvent was removed under reduced pressure to give the title compound (54.0 g) in quantitative yield. 1H NMR (400 MHz, CDCl3) delta 2.89 (s, 3 H), 3.02 (t, 7= 6.82 Hz, 2 H), 4.40 (t, J= 6.82 Hz, 2 H), 7.03 - 7.17 (m, 2 H), 7.43 - 7.47 (m, 2 H).
100%
With triethylamine; In dichloromethane; at 0℃; for 0.5h;
Step A: Preparation of Intermediate 4-Bromophenethyl Methanesulfonate. <n="56"/>4-Bromophenethyl alcohol (38.9 g, 193 mmol) was dissolved in DCM (193 mL).Triethylamine (40.4 mL, 290 mmol) was added and the mixture was cooled in an ice bath. Methanesulfonyl chloride (18 mL, 232 mmol) was added dropwise via an addition funnel. The ice bath was removed and the mixture was stirred for 30 min. The reaction mixture was diluted with DCM (200 mL), washed with 1 M HCl twice (100 mL each), followed by brine, saturated sodium bicarbonate, and brine. The organic phase was dried with sodium sulfate and filtered. The solvent was removed under reduced pressure to give the title compound (54.0 g) in quantitative yield. 1H NMR (400 MHz, CDCl3) delta ppm 2.89 (s, 3 H), 3.02 (t, J = 6.82 Hz, 2 H), 4.40 (t, J = 6.82 Hz, 2 H), 7.03 - 7.17 (m, 2 H), 7.43 - 7.47 (m, 2 H).
100%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
A solution of 2-(4-bromophenyl)ethanol (342 mul, 2.50 mmol), DIEA (653 mul, 3.75 mmol) and methanesulfonyl chloride (213 mul, 2.70 mmol) in DCM (12 ml) was stirred 1 h 30 at 0 C. and then overnight at rt. The solution was diluted with DCM, washed with a 0.5 N solution of HCl and brine. The organic phase was dried over Na2SO4 and concentrated to afford a yellow oil (700 mg, 100%).
100%
With triethylamine; In dichloromethane;Ice cooling;
Example 1.60: Preparation of Intermediate 4-Bromophenethyl Methanesulfonate. 4-Bromophenethyl alcohol (38.9 g, 193 mmol) was dissolved in DCM (193 mL).Triethylamine (40.4 mL, 290 mmol) was added and the mixture was cooled in an ice bath. Methanesulfonyl chloride (18 mL, 232 mmol) was added dropwise via an addition funnel. The ice bath was removed and the mixture was stirred for 30 min. The reaction mixture was diluted with DCM (200 mL), washed with 1 M HCl twice (100 mL each), followed by brine, saturated sodium bicarbonate, and brine. The organic phase was dried with sodium sulfate and filtered. The solvent was removed under reduced pressure to give the title compound (54.0 g) in quantitative yield. 1H NMR (400 MHz, CDCl3) delta ppm 2.89 (s, 3 H), 3.02 (t, J = 6.82 Hz, 2 H), 4.40 (t, J= 6.82 Hz, 2 H), 7.03 - 7.17 (m, 2 H), 7.43 - 7.47 (m, 2 H).
98%
With triethylamine; In dichloromethane; at 0 - 23℃;
Triethylamine (5.2 mL, 37.3 mmol) was added to a solution of <strong>[4654-39-1]4-bromophenethyl alcohol</strong> (5.0 g, 24.9 mmol) in CH2Cl2 (200 ml), and the resulting solution was cooled to 0 C. with an ice bath. Methanesulfonyl chloride (2.7 ml, 34.8 mmol) was added dropwise to the reaction mixture, and the resulting solution was allowed to warm slowly to room temperature overnight. The solution was washed with 0.1 N HCl and brine, and the combined organic extracts were dried over anhydrous MgSO4(s) and filtered, and the solvent was removed under reduced pressure. The crude yellow solid was purified by flash chromatography (silica gel, 70% v/v hexanes in CH2Cl2) to give mesylate 18 as a white solid in 98% yield. 1H NMR (CDCl3, 400 MHz) delta 7.46 (d, J) 8.5 Hz, 2H), 7.12 (d, J) 8.6 Hz, 2H), 4.39 (t, J) 6.9 Hz, 2H), 3.02 (t, J) 6.7 Hz, 2H), 2.89 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz) delta 135.55, 132.52, 130.92, 121.70, 69.83, 37.68, 35.31 ppm.
96%
With triethylamine; In dichloromethane; at 0 - 20℃; for 48h;Inert atmosphere;
To a solution of 10 (28.63 g, 0.142 mol) in 300 mL of CH2Cl2 wasadded triethylamine (29.5 mL, 0.21 mol), the mixture was cooledto 0 C and mesyl chloride (15.4 mL, 0.2 mol) was added dropwise.The reaction was stirred for 48 h at room temperature. Then 50 mLof a 0.1 N HCl solution was added and the mixture was extractedwith CH2Cl2 (3 150 mL). The organic layer was washed withbrine, dried over MgSO4, filtered and concentrated. The crude solidwas crystallized from a mixture of CH2Cl2 and hexane. The purecompound 11 was obtained as a pale white solid (38.3 g, 96%).
With triethylamine; In dichloromethane; at 20℃; for 2h;
EXAMPLE 10 This example demonstrates the preparation of 2-AMINO-2- [2- (2 , 3', 4'- trimethoxybiphenyl-4-yl) ETHYL]-1, 3-propanediol hydrochloride. (10-1) PREPARATION OF 2- (4-BROMOPHENYL) ETHYL IODIDE Methanesulfonylchloride (11.5 ml) was added to a solution of 2- (4- BROMOPHENYL) ethylalcohol (25.0 G) and triethylamine (22.6 ml) in dichloromethane (250 ml) at 0 C. The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was washed with brine and dried over sodium sulfate and concentrated in vacuo to yield a red oil (39. 1 g). Sodium iodide (18.6 g) was added to a solution of methanesulfonate in 2-butanone (400 ml), and the resulting suspension was heated under reflux for 4.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water, 10% aqueous sodium thiosulfate, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by silica-gel column chromatography using hexane/ethyl acetate 30: 1 gave the title compound (34.2 g) as a colorless oil.
With triethylamine; In chloroform; at 20℃; for 2h;Cooling with ice;
Under ice cooling, Et3N (1.3 mL) and methanesulfonyl chloride (0.64 mL) were sequentially added to a solution of 2-(4-bromophenyl)ethanol (1.5 g) in CHCl3 (10 mL), followed by stirring at room temperature for 2 hours. Under ice cooling, water was added thereto, followed by extraction with CHCl3. The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure. A mixture of the residue (light brown oil), 3-oxa-8-azabicyclo[3.2.1]octane (904 mg), 2,2,6,6-tetramethylpiperidine (2.0 mL), and MeCN (10 mL) was stirred at an outside temperature of 95 C. for 4 days. After cooling, water was added thereto, followed by extraction with CHCl3. The organic layer was filtered through a phase separator, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (SNAP Cartridge HP-Sil: 50 g, mobile phase: EtOAc/MeOH=99/1 to 90/10 (v/v)) to yield the title compound (1.47 g, light brown solid). MS (ESI pos.) m/z: 296, 298 ([M+H]+).
With triethylamine; at 5 - 20℃; for 3h;Inert atmosphere;
A solution of methane sulfonyl chloride (12.8 ml, 165.8 mmol, 1.1 eq) in methylisobutylketone (MIBK) (40 ml) was added dropwise to a cooled (5-10C) solution of bromophenethyl alcohol 12 (30.3 g, 150.7 mmol) and triethylamine (23.1 ml, 165.8 mmol, 1.1 eq) in MIBK (300 ml) an argon atmosphere within ca. 1 hour. Then, the reaction mixture was left to slowly heat up to the room temperature for ca. 2 h. After a check of the reaction by means of HPLC the reaction suspension was processed by addition of diluted aqueous HC1 (37 ml of 1M HC1 + 100 ml of H20) and intensively stirred for 15 min to achieve mixing of the phases; after stabilization and separation the aqueous phase was removed and the organic phase was still washed with 5% aqueous NaHC03 (50 ml), H20 ( 100 ml) and brine (100 ml). The crude mesylate solution was then heated up to boil under an argon atmosphere and dried by azeotropic distillation (ca. 50 ml of the H 0-MIBK mixture removed by distillation
With triethylamine; In chloroform; at 20℃; for 2h;Cooling with ice;
To a solution of 2-(4-bromophenyl)ethanol (1.50 g) in CHCl3 (10 mL), Et3N (1.30 mL) and MsCl (0.64 mL) were added sequentially under cooling with ice and the mixture was stirred at room temperature for 2 hours. After adding water under cooling with ice, extraction with CHCl3 was conducted. The organic layer was filtered with Phase Separator and the filtrate was concentrated under reduced pressure. A mixture of the resulting residue (2.40 g as a pale yellow oil), 3-oxa-8-azabicyclo[3.2.1]octane (904 mg), 2,2,6,6-tetramethylpiperidine (2.0 mL) and MeCN (10 mL) was stirred at an external temperature of 95C for 4 days. After leaving the mixture to cool, water was added for extraction with CHCl3. The organic layer was filtered with Phase Separator and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (SNAP Cartridge HP-Sil 50 g; mobile phase: EtOAc/MeOH = 99/1 - 90/10; v/v) to give the titled compound (1.47 g as a pale brown solid). MS (ESI pos.) m/z : 296, 298 ([M+H]+).
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.25h;
Methanesulfonyl chloride (0.43 mL, 5.47 mmol) was added to a solution of 2-(4- bromophenyl)-ethanol (1.0 g, 4.97 mmol) and triethylamine (0.84 mL, 5.96 mmol) in DCM (20 mL) at 0 C. The reaction mixture was stirred at 0 C for 15 minutes then at ambient temperature for 2 h. The reaction mixture was partitioned between water and DCM and the organic phase was dried over sodium sulfate, filtered and evaporated to give a colourless oil. The resultant residue was dissolved in acetonitrile (10 mL), piperidine (0.491 mL, 4.97 mmol) and potassium carbonate (0.823 g, 5.96 mmol) were added and the reaction mixture was heated at 70 C for 2.5 h. The reaction mixture was allowed to cool to ambient temperature then partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and evaporated and the resultant residue dissolved in methanol and loaded onto a 10 g SCX-2 cartridge. The column was washed with methanol then eluted with 2N ammonia in methanol and the basic fractions were evaporated to afford the title compound (1.27 g, 95%) as a colourless oil. 1H NMR (CDCl3, 300MHz): 7.41-7.36 (m, 2H), 7.10-7.04 (m, 2H), 2.79-2.71 (m, 2H), 2.54-2.40 (m, 6H), 1.66-1.56 (m, 4H), 1.50-1.40 (m, 2H).
Stage #1: 2-(4-bromophenyl)-acetic acid With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 3h;
Stage #2: With hydrogenchloride; water monomer In tetrahydrofuran at 0 - 80℃; for 0.5h;
H.i
4-r2-(2-Bromoethoxy)ethvnbenzonitrile(T) 2-(4-BromophenvDethanol To a chilled solution (about O0C) of 4-bromophenyl acetic acid (25 g, 0.116 mol) in THF (250 mL), borane methyl sulphide (13.2 g, 0.174 mol) was added, dropwise, under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h. After cooling the mixture to between 0 and 5°C, the reaction was quenched by adding 1.5 NHCl (80 mL), dropwise. After warming for 30 min at about 800C, the reaction mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water and brine and then dried. The product was obtained as colourless liquid after concentration (yield: 23.3 g, 99%).
92%
With lithium aluminium hydride In diethyl ether at 20℃; for 0.25h;
88%
With C25H42N6Rh(1+)*CF3O3S(1-); phenylsilane In tetrahydrofuran at 30℃; for 20h; Inert atmosphere;
83%
With Fe(CO)<SUB>3</SUB>(COD); phenylsilane In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; UV-irradiation; chemoselective reaction;
78%
In ethanol
27 4.1.4 Synthetic procedure 3: reduction of carboxylic acid with LiAlH4
In a 3-neck flask, LiAlH4 (8.0mmol) was dissolved in anhydrous tetrahydrofuran (THF) (10mL), under nitrogen atmosphere at 0°C. A solution of phenyl acetic acid (4.0mmol) in anhydrous THF (10mL), was added dropwise to the reaction mixture over 20min, followed by addition of 5mL of anhydrous THF. The mixture was allowed to warm to rt, after which the reaction was quenched with EtOAc (50mL) and water (50mL). The mixture was washed with water (3×50mL) and the organic layer was dried over MgSO4, filtered and the solvent was removed under reduced pressure.
77%
Stage #1: 2-(4-bromophenyl)-acetic acid With lithium aluminium hydride In diethyl ether at 0℃; for 1h; Inert atmosphere; Schlenk technique;
Stage #2: With sulfuric acid In diethyl ether Inert atmosphere; Schlenk technique;
76%
With dimethylsulfide borane complex In tetrahydrofuran
66%
Stage #1: 2-(4-bromophenyl)-acetic acid With phenylsilane; potassium-t-butoxide; C22H30ClN2RuS2(1+)*Cl(1-) In tetrahydrofuran at 60℃; for 18h; Inert atmosphere;
Stage #2: With water monomer; caesium fluoride In tert-butyl methyl ether at 20℃; for 3h; Inert atmosphere;
2-(4-Bromo-phenyl)-ethanol (2g):
To a stirred suspension of (4-bromo-phenyl)-aceticacid (1g) (500 mg, 2.3250 mmol,1equiv.) in degassed THF (10 V) was added ARP-03 (24.3 mg, 0.0465 mmol, 2 mol%)and again degassed for 10 minutes. After 10 minutes of degassing, PhSiH3 (0.87mL, 6.9750 mmol, 3 equiv.) and t-BuOK (1 M in THF) (0.23 mL, 0.2325 mmol, 10mol%) were added dropwise to reaction mixture at RT. The reaction mixture washeated to 60°C and stirred for 18 h. The reaction mixture was then evaporatedto remove volatiles, then suspended in MTBE and stirred with aq. CsF solution(10%, 10 V) for 3 h. The organic layer was then separated and concentrated invacuum to furnish the crude, which was purified by column chromatography on silica gel(eluent: Ethyl acetate / n-hexane = 1/4) to afford 2-(4-bromo-phenyl)-ethanol (2g) (206 mg, 66% brsm) as a yellowoil.1H NMR (300 MHz, DMSO- d6): 7.44 (d, J= 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.70 - 4.55 (m,1H), 3.70 - 3.50 (m, 2H), 2.68 (t, J= 6.9 Hz, 2H).13C NMR (100 MHz, DEPT - 135, CDCl3): δ 137.68 (C), 131.72 (CH×2),130.88 (CH×2), 120.42 (C), 63.47 (CH2), 38.62 (CH2).LCMS (EI, m/z) calcd for C8H9BrO [M - OH]: 184.06 Found: 184.98
55%
With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane In chloroform at 0 - 60℃; for 2.08333h; Schlenk technique; Inert atmosphere;
With lithium aluminium hydride
With sodium tetrahydridoborate; boron trifluoride diethyl ether complex In tetrahydrofuran
With lithium aluminium hydride In tetrahydrofuran for 12h; Heating;
With borane In tetrahydrofuran
With borane In tetrahydrofuran 1.) 0 deg C, 30 min, 2.) 25 deg C, 2 h;
77 % Spectr.
With diphenylsilane In tetrahydrofuran at 50℃; for 24h;
With lithium aluminium hydride In tetrahydrofuran Heating;
Multi-step reaction with 2 steps
1: tetrahydrofuran / 3 h
2: LiBH4 / tetrahydrofuran / 16 h
With lithium aluminium hydride In diethyl ether for 1h; Reflux;
119 mg
With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane In chloroform at 60℃; for 1h; Inert atmosphere;
Multi-step reaction with 2 steps
1: sulfuric acid / 3 h / Reflux
2: diisobutylaluminium hydride / tetrahydrofuran; toluene / 20 °C
Stage #1: 2-(4-bromophenyl)-acetic acid With lithium aluminium hydride In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; Cooling with water bath;
Stage #2: With water monomer In tetrahydrofuran
Multi-step reaction with 2 steps
1: sulfuric acid / 2 h / 20 °C
2: lithium tetrahydridoborate / tetrahydrofuran / 2 h / 0 - 20 °C
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃;
With lithium aluminium hydride In tetrahydrofuran at 0℃; for 4.5h; Reflux;
Preparation of phenylethyl alcohols
General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15%, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85% yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100% yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85% yield by column chromatography.
18.7g
With lithium aluminium hydride In tetrahydrofuran at 0 - 30℃; for 2h;
2.4
The specific operation is as follows: The bromophenylacetic acid was added to 200ml of tetrahydrofuran,Stirring cooled to 0 ° C after adding lithium aluminum hydride in batches, the end of the addition,After the reaction was heated to 25 ~ 30 ° C for 2h, 300ml of water and 400ml of dichloromethane were separated,The organic phase was added to 20g of anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure at 30-35 ° C.Obtained light yellow oil (brominated S1-1): 18.7g, under ice bath,To bromine S1-1 was added dropwise phosphorus tribromide, dropping temperature during the control at 0 ~ 10 ,Dropping is completed, incubated 10min insulation, a white smoke generated, stirring, warming to 75 ~ 80 ,After stirring for 2h, 30ml of saturated sodium bicarbonate solution, 200ml of ethyl acetate,Stirring 20min liquid separation, the organic phase 40 ~ 45 filtrate was concentrated under reduced pressure,A yellow liquid (bromination S2) was obtained: 22.1 g. Yield: 90.0%.
With CoxMnyO4 (x/y=10); In toluene; at 60℃; for 4h;
Add 1-(4-bromophenyl)ethanol (1 mmol) and toluene (2 mL) to a 10 mL reaction tube.The catalyst CoxMnyO4 (x/y=10) was added and the reaction mixture was reacted at 60 C for 4 h.After the reaction is completed, the target product is isolated by column chromatography.The target product VI was obtained in a yield of 99.9%.
89%
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; dihydrogen peroxide; In water; at 60℃; for 2h;
General procedure: A general experimental procedure is as follows: A mixtureof alcohol (1.0 mmol) and DBDMH (0.5 mmol, 0.14 g)in aqueous hydrogen peroxide (3.0 mmol, 35% aq. 0.09 mL)solution was stirred for 2 h at 60oC in the open vessel. Aftercooling the mixture to room temperature, the product wasextracted into dichloromethane (2 x 25 mL) and washed withwater. The combined organic layers were dried over MgSO4and evaporated under reduced pressure. The crude productwas purified by flash column chromatography (ethyl acetate/n-hexane = 1:3, v/v) to give the desired carbonyl compound.
71%
With Dess-Martin periodane; In dichloromethane; for 2h;Inert atmosphere;
General procedure: To a stirred solution of the Dess-Martin reagent (DMP) (1.5mmol) in CH2Cl2 (10mL) under nitrogen, the alcohol (1.0mmol) was added dropwise. The reaction mixture was stirred for 2h and subsequently quenched with saturated aqueous sodium thiosulfate (20mL). After 15min of stirring the layers were separated, the organic layer was washed with water (50mL) and brine (2×50mL) and the aqueous layer was washed with EtOAc (2×25mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The thus obtained semisolid was triturated with 10% EtOAc in hexanes. The solid was removed by filtration. The filtrate was concentrated under reduced pressure to yield the final product.
62%
With Dess-Martin periodane; In dichloromethane; at 20℃; for 1h;
A solution of 193 2-(4-bromophenyl)ethyl alcohol (2.00g, 10.0mmol) and 194 Dess-Martin periodinane (4.20g, 12.0mmol) in 113 CH2Cl2 (100mL) was stirred at room temperature for 1h. The reaction was quenched with 1M 195 aqueous Na2S2O3 solution and extracted with CH2Cl2. The organic layer was separated, washed with brine, and dried over Na2SO4, Filtration, evaporation in vacuo, and purification by silica gel column chromatography gave 196 30 (1.23g, 62%): 1H NMR (DMSO-d6, 300MHz, delta; ppm), 9.68 (1H, t, J=1.5Hz), 7.56-7.52 (2H, m), 7.22-7.18 (2H, m), 3.79 (2H, d, J=1.5Hz).
43%
With Dess-Martin periodane; In dichloromethane; at 20℃;
Synthesis of 2:A solution of p-bromophenethyl alcohol (2.23 g, 11.5 mmol) in dichloromethane (DCM) (20 mL) was treated with Dess-Martin reagent (6.5 g) at room temperature. After stirring at room temperature overnight, the solution was diluted with DCM (100 mL), washed with saturated NaHCO3, dried (Na2SO4), and purified by column chromatography (EtOAc:hexane=20:80) to provide the aldehyde 2 (1.0 g, 43%).
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide; In dichloromethane; water; at 0℃;
Step 1 : 2,2,6,6-Tetramethylpiperidine-l-oxyl (TEMPO; 1.6 g, 1.0 mmol, 0.002 eq.) and NaBr (6 g, 500 mmol, 1.0 eq.) were successively added under vigorous stirring to a solution of alcohol 1-1 ([CAS No.: 4654-39-1]; 100 g, 500 mmol, 1.0 eq.) in dichloromethane (2300 mL) at 0C. A solution of aqueous saturated NaHC03 and 10% NaOCl (400 mL) were added. The mixture was stirred for approximately ten minutes until thin- layer chromatography (TLC) indicated that the starting material had disappeared. The dichloromethane layer was separated. The aqueous layer was rapidly extracted with diethyl ether. The combined organic phases were washed with an aqueous solution of NaHS03 (10%) and KI (4%), brine, and dried with anhydrous sodium sulfate. After removing most of the volatiles under vacuum (keep temperature below 25C), the resulting solution of aldehyde 1-2 in dichloromethane (50 mL) was used as such directly in the next step.
97%Chromat.
With dihydrogen peroxide; In water; at 27℃; for 6h;
General procedure: A typical reaction scheme for the alcohol oxidation isgiven in Scheme 1. Au-MgO nanorods (30 mg) and H2O2(945 L, 15 equivalence) were stirred in 20 mL of waterand the substrate alcohol (1 mM) was slowly added to thereaction mixture and continuously stirred at room temperature.After the requisite time, the catalyst was separatedby centrifugation. The centrifugate was extracted usingdiethyl ether. The ether extract was dried over anhydroussodium sulphate and evaporated. Then the product was dissolvedin ethyl acetate and then analysed by GC. Authenticsamples of reactants and respective products were used toverify the retention time and to confirm the product formation.The used catalyst was washed with ethyl acetate and dried under vacuum. The dried catalyst was calcinedat 500 C before reuse.
3.51 mmol
With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 16h;
Step a. To a solution of 2-(4-bromophenyl)ethan-l-ol (4.97 mmol) in DCM (13 ml) was added Dess-Martin periodinane (6.2 mmol) at 0C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was partially evaporated and the obtained residue was filtered through celite hyflow. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (9-10% EtOAc in hexane) yielding 2-(4- bromophenyl) acetaldehyde (3.51 mmol). MS: ES- 197.10; XH MR (400 MHz, DMSO-d6) delta ppm 9.68 (s, 1 H), 7.54 (d, J=2.0 Hz, 2 H), 7.21 (d, J=8.4 Hz, 2 H), 3.79 (d, J=0.8 Hz, 2 H).
toluene-4-sulfonic acid; In dichloromethane; at 20℃;Inert atmosphere;
Into 3OmL OfCH2Cl2 in a 15OmL RB flask was dissolved <strong>[4654-39-1]4-bromophenethyl alcohol</strong> (7.0Og, 34.80 mmol) and 3,4-dihydro-2H-pyran (3.8OmL, 41.61 mmol). To this solution was added a few crystals ofp-toluenesulfonic acid monohydrate. The reaction mixture was then stirred at room temperature under a blanket of nitrogen overnight. Overnight the reaction mixture changed colour again to a deep brown colour. The reaction mixture was transferred to a 25OmL separating funnel and extracted with 15OmL of saturated NaEtaCO3(aq) solution during which time the brown colouration in the organic layer faded to an orange colour. The layers were separated and the organic layer was extracted again with 15OmL of brine. The organic layer was then separated and dried over anhydrous MgStheta4 for 1 hour at room temperature. The mixture was then filtered and the collected solid washed with 3>;<;30mL portions Of CH2Cl2. The filtrate and washings were combined and stripped to dryness on a rotary evaporator to yield an orange oil. Column chromatographic conditions for the remainder of the crude product were determined by TLC analysis (10% EtOAc / 90% H-hexane eluant) which indicated a major spot at R/ 0.5 with a few minor spots on and around the baseline. The crude product was then purified by dry column flash chromatography using a sinter of 80mm diameter and 80mm depth packed to a depth of 5.5cm with Merck 60 (15-40mum) silica gel, time per fraction: 4.00 minutes, crude product pre-loaded onto 12.5g of Merck 60 (15-40Dm) and this loaded on top of the column, n- Hexane / EtOAc elution in 10OmL fractions with the EtOAc component increasing in 1% increments from 0% (fraction 1) to 15% (fraction 16). Fractions' 9 &; 10 "foamed" on leaving the column and TLC (10% EtOAc / 90% H-hexane) of fractions' 8-15 indicated pure product was contained in fractions' 9-12 and these were combined and stripped to dryness on a rotary evaporator before being further dried in vacuo (oil immersion pump) overnight at room temperature. Yield: 9.82 Ig (98.9%, colourless liquid). 1H NMR (CDCl3) delta 1.40-1.88 (m, 6H, [3chi-CH2-]pyran), 2.86 (t, 2H, ArCH2-), 3.45 (m, IH, [OCHaHb-]pyran), 3.58 (q, IH, -Op^anCH3Hb-), 3.73 (m, IH, [OCHaHb-]pyran), 3.92 (q, IH, 4.57 (m, IH, [-OCHO-]pyran), 7.10 (d, 2H, ArH), 7.40 (d, 2H, ArH).
95%
With pyridinium p-toluenesulfonate; In dichloromethane; at 25℃; for 10h;
a) Preparation of intermediate 15; DHP (7 ml) and PPTS (0.58 g) were added to a solution of 4-bromo-benzeneethanol (9.4 g; 0.0467 mol) in DCM (q.s.) at 25 C. The solution was stirred at 25 C for 10 hours. The mixture was washed with water (3 x 50 ml), dried (MgS04), filtered and the solvent was evaporated. Yield: 12.63 g of intermediate 15 (95 % yield).
32.8%
With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃; for 3h;
1.31.a. 2-[2-(4-bromo-phenyl)-ethoxy]-tetrahydro-pyran 0.025 g of p-toluenesulphonic acid and 2.575 ml (28.22 mmol) of dihydropyran are added successively to a solution of 4.83 g (24.02 mmol) of 2-(4-bromo-phenyl)-ethanol in 12 ml dichloromethane at 0 C. Then the reaction mixture is stirred for three hours at ambient temperature. The reaction mixture is extracted with sodium hydrogen carbonate solution and the organic phase is dried over sodium sulphate. The purification is carried out by column chromatography on Alox (eluant: cyclohexane/ethyl acetate=8:2). Yield: 37 g (32.8% of theory); C13H17BrO2 (M=285.18); calc.: molar peak (M)+: 284/286 fnd.: molar peak (M)+: 284/286.
With sodium hydrogencarbonate; toluene-4-sulfonic acid; In dichloromethane;
Reference Example 1 Synthesis of 4-(2-(tetrahydropyran-2-yloxy)ethyl)bromobenzene p-Toluenesulfonic acid (0.30 g) was added to a solution of <strong>[4654-39-1]4-bromophenethyl alcohol</strong> (9.50 g, 47.24 mmol) in methylene chloride (50 ml), and the mixture was stirred under ice-cooling. To the mixture was added 3,4-dihydropyran (5.53 g, 65.74 mmol). After stirring under ice-cooling for 20 minutes, a saturated aqueous solution of sodium bicarbonate (40 ml) was added to the reaction mixture. The resulting mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)bromobenzene was obtained (13.40 g, 99%). NMR (delta ppm, TMS/CDCl3): 1.52-1.80 (6H,m), 2.85 (2H,t,J=7), 3.43-3.96 (4H,m), 4.57 (1H,t,J=4), 7.12 (2H,d, J=8), 7.39 (2H,d,J=8).
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0 - 20℃;
A solution of 2-(4~bromophenyi5thanol (20,0 g, 100 moi) in CH2CI2 (10 ml) was added dropwise io a solution of imidazole (22.4 mg, 0.33 mmoi), PPf (33.3 g, 127 mmoi), and 2 (32,5 g,130 mmoi) in CH2Ci2 (50 mL) at 0C, and the reaction was warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated aqueous sodium ihiosufaie {2 x 50 mL), brine, dried over Na?S04, filtered and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/ PE) to yield 1-bromo- - 2-iodoethyl)ben2ene (9.2. 22.7 g, 73%) as a white solid. NMR (400 MHz, CQGI3) d" 3.13 (t. J = 7.6 Hz, 2H), 3.32 (t, J = 7.6 Hz, 2H), 7,07 (d, J ~ 8,0 Hz, 2H). 7.44 (d: J = 8,2 Hz, 2H).
60%
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0 - 25℃; for 1h;
1 -Bromo-4-(2-iodoethyl)benzeneA solution of 2-(4-bromophenyl)ethanol (40.0 g, 0.199 mol) in dichloromethane (10 mL) was added dropwise to a solution of imidazole (22.4 mg, 0.329 mmol), triphenylphosphine (66.5 g, 0.254 mol), and iodine (65.0 g, 0.26 mol) indichloromethane (50 mL) at 0C. When the addition was complete it was warmed to rt. After 1 hour the reaction was filtered through celite, the filtrate was washed with saturated aqueous sodium thiosufate (2x100 mL), brine (100 mL), dried over MgS04, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (heptane/ethyl acetate 4: 1 ) afforded the title compound as a yellow-white solid (59.09 g, 60%). 1 HNMR (400 MHz, CHLOROFORM-d) delta ppm 3.14 (t, J=7.69 Hz, 2 H) 3.33 (t, J=7.69 Hz, 2 H) 7.08 (d, J=7.89 Hz, 2 H) 7.45 (d, J=8.31 Hz, 2 H)
(125a) 1-bromo-4-(2-methoxyethyl)benzene; N,N-dimethylformamide (20 mL) solution of <strong>[4654-39-1]4-bromophenethyl alcohol</strong> (2.01 g, 10.0 mmol) was cooled to 0C and was blended with sodium hydride (55% oily, 436 mg, 10.0 mmol) and the mixture was stirred at 0C for 10 minutes. The reaction mixture was blended with methyl iodide (0.75 mL, 12.0 mmol) and the mixture was stirred at room temperature for a further three hours. Water (50 mL) was added to the reaction liquid and extracted with ethyl acetate (50 mL) three times. The organic layers were combined and washed with water (50 mL) and a saturated saline solution (50 mL), and the solvent was evaporated under reduced pressure after drying over sodium sulfate and the title compound was obtained (2.15 g, yield 100%). Yellow liquid IR (film) numax 2925, 1489, 1382, 1191, 1117, 1011, 804 cm-1; 1H NMR(CDCl3, 400 MHz) delta 2.83 (2H, t, J = 7.0 Hz), 3.34 (3H, s), 3.58 (2H, t, J = 7.0 Hz), 7.10 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz); MS (EI) m/z: 214 [M+], 171, 169, 135, 104, 90, 45.
89%
[0010321 To a stirring mixture of 2-(4-brornophenyflethanol (2 g, 9.95 rnrnol) in DMF (20ml) at 0C was added sodium hydride (0.438 g of a 60% dispersion in mineral oil, 10.94mmol). After 45 mm, the cooling bath was removed and iodomethane (0.743 rnL, 11.94mrnol) was added to the reaction mixture. After 3 h, the mixture was poured onto water(150 rnL) and extracted with EA (3 x 50 mL).. The combined organic extracts were driedover MgSO4 and solvents evaporated. Column chromatography (Et20/iso-hexanes) gave1.9 g (89%) of 1 -bromo-4-(2-rnethoxyethyl)benzene) as an orange oil. LCMS-ESI (ni/z)calculated for C9H11BrNO: 214.0 not recorded. ?H NMR (400 MHz, Chloroform-d) oe7.50 - 7.38 (m, 2H), 7.15 - 7.07 (rn, 2H), 3.60 (t, J= 6.8 Hz, 2H), 3.37 (s, 3H), 2.85 (t, J= 6.9 Hz, 2H).
83%
5.5b (4.5 g, 22.4 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (50 mL)and cooled to 0 C. NaH (60%) (2.23 g, 55.9 mmol, 2.5 equiv) was added in portion wise and the reaction mixture was stirred at rt for 1 hour. Cooled the reaction mixture to 0C, iodomethane (4.76 g, 33.4 mmol, 1 .5 equiv) was added dropwise and the reaction mixture was stirred at rt for 24 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (5 % EtOAc in Hexane) to afford product 5.5c (4 g, 83 % yield). 1H NMR (400 MHz, DMSO) 6 7.50 - 7.44 (m, 2H), 7.25 - 7.16 (m, 2H), 3.51 (t, J = 6.7 Hz, 2H), 3.23 (d, J = 4.4 Hz, 3H), 2.82-2.75 (m, 2H).
In tetrahydrofuran; water;
Reference Example 98 In THF (100 ml) was dissolved <strong>[4654-39-1]4-bromophenethyl alcohol</strong> (10 g). To the mixture was added under ice-cooling 65% sodium hydride (1.7 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise under ice-cooling iodomethane (3.7 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1) to give 1-bromo-4-(2-methoxyethyl)benzene (8.3 g).
With triphenylphosphine; diethylazodicarboxylate; In diethyl ether; at 0 - 25℃; for 12h;
Diethylazodicarboxylate (5.2 g) is added dropwise to a solution of 4-bromophenethylalcohol (2.01 g), and triphenylphosphine (7.9 g) in diethyl ether (16 mL) at 0 C. The reaction mixture is stirred for 10 minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether (10 mL) is added. The clear orange solution is stirred for 5 minutes at 0 C and then at 25 C for 12 hours. The reaction mixture is then filtered, and washed with diethyl ether. The filtrate is concentrated under reduced pressure and chromatographed over silica gel (10% ethyl acetate-hexanes is used as the eluant) to provide the desired product as a pale yellow oil (2.04 g).
To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9 mmol) in THF (80 ml) was added a solution of 1.5M n-BuLi in hexane (39.8 ml, 59.7 mmol) at -78 C. over 30 min. After 1 hour, a solution of B(OiPr)3 (8.61 ml, 37.3 mmol) in THF (20 ml) was added slowly to the mixture at -78 C. The resultant mixture was warmed to room temperature, and treated with 2M HCl (100 ml) for 1 hour. This was extracted with CH2Cl2 and dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with CH2Cl2/MeOH=20/1 to afford 2.61 g (63%) of the title compound. [2789] 1H-NMR (CD3OD) delta: 7.64-7.48 (2H, m), 7.19-7.13 (2H, m), 3.70 (2H, t, J=7.2 Hz), 2.77 (2H, t, J=7.2 Hz) MS (ESI) m/z: 165 ([M-H]-)
63%
With n-butyllithium; Triisopropyl borate; In tetrahydrofuran; hexane; at -78 - 20℃; for 1.5h;
To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9 mmol) in tetrahydrofuran (80 mL) was added a solution of 1.5 M n-butyl lithium in hexane (39.8 mL, 59.7 mmol) at -78 C. over 30 min. After 1 h, a solution of triisopropyl borate (8.61 mL, 37.3 mmol) in tetrahydrofuran (20 mL) was added slowly to the mixture at -78 C. The resultant mixture was warmed to room temperature, and treated with 2 M HCl (100 mL) for 1 h. This mixture was extracted with dichloromethane and dried (MgSO4). After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (20:1) to afford 2.61 g (63%) of the title compound as white solids
TO A SLURRY OF SODIUM HYDRIDE (abt. 60% oil suspension, 4.58g) in N, N-dimethylformamide (150ML) was added dropwise 2- (4-BROMOPHENYL) ethanol (20g) in N, N-dimethylformamide (50ML) at 0C, and the mixture was stirred for 1HR at room temperature. To the mixture was added dropwise benzyl bromide (19.6g) at 0C, and the mixture was stirred at room temperature for 6hrs. The resulting mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound as a colorless oil (29. OG, 100%). 1H-NMR (300MHZ, CDCL3) : D 2.88 (2H, t, J=7Hz), 3.67 (2H, t, J=7Hz), 4.52 (2H, s), 7.11 (2H, d, J=8Hz), 7.27-7. 37 (5H, m), 7.41 (2H, d, J=8Hz).
100%
To a slurry of sodium hydride (abt. 60% oil suspension, 4.58 g) in N,N-dimethylformamide (150 ML) was added dropwise 2-(4-bromophenyl)ethanol (20 g) in N,N-dimethylformamide (50 ML) at 0 C., and the mixture was stirred for 1 hr at room temperature.To the mixture was added dropwise benzyl bromide (19.6 g) at 0 C., and the mixture was stirred at room temperature for 6 hrs. The resulting mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate.The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound as a colorless oil (29.0 g, 100%). 1H-NMR (300 MHz, CDCl3): delta 2.88(2H, t, J=7 Hz), 3.67(2H, t, J=7 Hz), 4.52(2H, s), 7.11(2H, d, J=8 Hz), 7.27-7.37(5H, m), 7.41(2H, d, J=8 Hz).
94%
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃;
4.1 g (102 mmol ; 2.2 eq) of a 60% dispersion of sodium hydride in mineral oil are washed twice with diethyl ether and then treated with 6.6 ml (55.6 mmol ; 1.2 eq) of benzyl bromide at 0C. 9.3 g (46.3 mmol ; 1.0 eq) OF 2- (4-BROMOPHENYL)- ethanol are added dropwise to a solution of 250 ml of N, N-dimethylformamide at 0C, after which the mixture is allowed to warm to room temperature overnight. The next day, the solution is diluted with ethyl acetate and then mixed cautiously with water, after which it is washed with 2.0 M sodium hydroxide solution and then with saline solution. The organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil is then puri- fied by flash chromatography on silica, first using hexane as eluent so as to elute all the residual benzyl bromide, and then using a mixture of ethyl acetate and hexane in a 1: 6 ratio so as to elute the expected product in the form of a colour- less oil (12. 67 G ; 94%).
41%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 16h;
2-(4-Bromophenyl)ethanol 8 (3.2g, 16mmol) and 43 (bromomethyl)benzene (1.9mL, 16mmol) were dissolved in 51 THF (50mL). 52 NaH (0.45g, 18mmol) was added (0C). The reaction mixture was stirred (from 0C to room temperature, 16h), quenched by pouring into water, extracted by EtOAc, dried (Na2SO4) and concentrated. The crude residue was purified by silica gel chromatography to provide 53 9b as a colorless oil (1.9g, 41% yield). 1H NMR (400MHz, CDCl3) delta 7.45-7.43 (m, 2H), 7.39-7.31 (m, 5H), 7.15-7.13 (m, 2H), 4.55 (s, 2H), 3.70 (t, J=6.9Hz, 2H), 2.91 (t, J=6.9Hz, 2H). 13C NMR (101MHz, CDCl3) delta 138.26, 138.13, 131.38 (2C), 130.72 (2C), 128.40 (2C), 127.61 (3C), 120.03, 73.03, 70.77, 35.80
Reference Example 75 4-(2-Benzyloxyethyl)-1-bromobenzene To a suspension of sodium hydride (60%, 1.09 g) in 1,2-dimethoxyethane (25 mL) was added 2-(4-bromophenyl)ethanol (5 g) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added benzyl bromide (3.25 mL), and the mixture was stirred at 80C overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane -n-hexane/ethyl acetate = 50/1 - 20/1) to give the title compound (6.8 g). 1H―NMR (CDCl3) delta ppm: 2.86 (2H, t, J=6.8Hz), 3.66 (2H, t, J=6.8Hz), 4.5 (2H, s), 7.05-7.15 (2H, m), 7.2-7.35 (5H, m), 7.35-7.45 (2H, m)
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃; for 12h;Inert atmosphere;
Step 1: 2-(4-(4,4,5,5-Tetramethyl-l,3)2-dioxaborolan-2-yl)phenyl)ethanol Potassium acetate (4.88 g, 49.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (7.6 g, 30 mmol) and PdCl2(dppf) (0.91 g, 1.2 mmol) were added to a solution of 2-(4-bromophenyl)ethanoi (5.0 g, 25 mmol) in 1 ,4-dioxane (100 mL) under 2, The mixture was purged with N2 then stirred under N2 at about 85 C for about 12 h. After cooling to rt, water (100 mL) was added and the mixture was extracted with EtOAc (2 chi 100 mL). The combined organic layers were washed with saturated aqueous NaCl (100 mL) and dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel (17% EtOAc/petroleum ether). The appropriate fractions were collected and concentrated under reduced pressure to give the title compound (6.2 g, 100%). NMR (400MHz, (.' )(. I :) delta 7.78 (d, J = 7.9 Hz, 2H), 7.29 - 7.23 (m, 2H), 3.87 (t, J= 6.6 Hz, 2H), 2.90 t, J = 6.6 Hz, 2H), 1.36 (s, 12H).
100%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃; for 12h;Inert atmosphere;
Step 1: 2-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethanol KOAc (4.88 g, 49.7 mmol), 4,4,4,,4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-d.ioxaborolane) (7.6 g, 30 mmol) and PdCl2(dppf) (0.91 g, 1.2 mmol) were added to a solution of 2-(4-bromophenyl)ethanol (5.0 g, 25 mmol) in 1,4-dioxane (100 mL) under N2. The mixture was purged with N2 then stirred under N2 at about 85 C for about 12 h. After cooling to rt, water (100 mL) was added and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with sat. aq.NaCl (100 mL) and dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (17% EtO Ac/petroleum ether). The appropriate fractions were collected and concentrated under reduced pressure to afford the title product (6.2 g, 100%). NMR (400MHz, CDC13) delta 7.78 (d, ,/ = 7.9 Hz, 2H), 7.29 - 7.23 (m, 2H), 3.87 (t, ,/ = 6.6 Hz, 2H), 2.90 (t, ,/ = 6.6 Hz, 2H), 1.36 (s, 12H).
100%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃; for 12h;Inert atmosphere;
Potassium acetate (4.88 g, 49.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (7.6 g, 30 mmol) and PdCl2(dppf) (0.91 g, 1.2 mmol) were added to a solution of 2-(4-bromophenyl)ethanol (5.0 g, 25 mmol) in 1,4-dioxane (100 mL) under N2. The mixture was purged with N2 then stirred under N2 at about 85 C for about 12 h. After cooling to rt, water (100 mL) was added and the mixture was extracted with EtOAc (2 chi 100 mL). The combined organic layers were washed with saturated aqueous NaCl (100 mL) and dried over Na2SOzi, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel (17% EtO Ac/petroleum ether). The appropriate fractions were collected and concentrated under reduced pressure to give the title compound (6.2 g, 100%). NMR (400MHz, CDC13) delta 7.78 (d, J= 7.9 Hz, 2H), 7.29 - 7.23 (m, 2H), 3.87 (t, J= 6.6 Hz, 2H), 2.90 (t, J= 6.6 Hz, 2H), 1.36 (s, 12H).
89%
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 120℃; for 5h;
To a solution of 2-(4-bromophenyl)ethanol (500mg, 2.49mmol) in dimethyl sulfoxide (5mL) were added bis (pinacolato) diboron (632mg, 2.49mmol), potassium acetate (733mg, 7.47mmol) and [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane (1:1) complex (102mg, 124mumol), and the mixture was stirred for 5 hours at 120C. Ice water and toluene were added to the reaction mixture and the insolubles were filtered off. The organic layer was separated, washed with water, then dried over anhydrous sodium sulfate, and solvent was distilled off. The residue obtained was purified by silica gel column chromatography [hexane-ethyl acetate=1:1], thereby affording 455mg of the title compound as a pale yellow oil. Yield 89%.1H-NMR (CDCl3, delta): 1.34(12H,s), 2.89(2H,t,J=6.3Hz), 3.87(2H,q, J=6.3Hz), 7.25(2H,d,J=7.8Hz), 7.77(2H,d,J=8.3Hz).
79%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere;
PdCI2(dppf)-CH2Cl2 adduct (4.06 g, 4.97 mmol) was added to a solution of 2-(4- bromophenyl)ethanol (10.0 g, 49.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (25.3 g, 99 mmol) and potassium acetate (14.64 g, 149 mmol) in 1 ,4- dioxane (200 ml_) at room temperature under a nitrogen atmosphere and the reaction mixture was stirred at 80 C overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (1 :6 EtOAc/petroleum ether) to give 2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)ethanol (10.5 g, 39.2 mmol, 79 % yield) as a yellow oil. LCMS: [M+NH4] 266.2.
75%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 24h;Inert atmosphere;
Bis(pinacolato)diboron (7.58 g, 29.85 mmol), potassium acetate (7.32 g, 74.58 mmol), Pd(dppf)Cl2 (50 mg) and 4-Bromophenethyl alcohol (5 g, 24.8 mmol) were dissolved in dry dioxane under nitrogen. After stirring at 100 C for 24 h, the mixture was transferred to a separatory funnel, extracted with dichloromethane (DCM) and then washed with brine and dried with anhydrous magnesium sulfate. The crude product was purified by silica gel column chromatography with a mixture of petroleum ether (PE): ethyl acetate (EA) = 4:1 as eluent to obtain the pure product 4.63 g (yield, 75%). 1H NMR (600 MHz, CDCl3): 2.84(1.9H, t, J=6.78 Hz), 3.79 (1.9H, t, J=6.78 Hz), 7.21 (1.9H, d, J=7.76 Hz), 7.75 (1.8H, d, J=7.76 Hz).
73%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
To a 1L flask was added Bis(pinacolato)diboron (30.5 g, 0.12 mol), KOAc (29.44 g, 0.3 mol) and1,1?-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mmol, 0.05 eq.). The flask was charged under Ar and dioxane (250 mL) was introduced and the resulting mixture was purged with Ar for 15 mm. To it was added 2-(4-bromophenyl)-ethanol (14 ml, 0.1 mol) and the mixture was then heated at 100 C for 18 h. It was cooled to room temperature and was filtered through celite.The filtrate was concentrated and the residue was diluted with EtOAc. The organic solution was washed with brine and driver over Mg504. Concentration afforded the crude product, which was further purified on a silica-gel column with 30-80% EtOAc in hexane to give 18.1 g (73%) of 2-(4- (4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenyl)ethanol
100 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃; for 16h;Inert atmosphere;
A mixture of 2-(4-bromophenyl)ethan-1-ol (CAS 4654-39-1) (60 g, 300 mmol), BISPIN (84 g, 330 mmol), KOAc (90 g, 900 mmol) and PdCI2(dppf) (6.6 g, 9 mmol) in dioxane (600 ml) was stirred under N2 at 85C for 16 h. Then, the RM was cooled down to RT and filtered. The resulting solution was concentrated under reduced pressure. Purification of the crude residue by chromatography on silica gel eluting with 0 - 30% EtOAc in petroleum ether afforded 100 g of the title compound as a colorless oil. LC-MS (Method I): Rt = 1.87 min, [M+NH4]+ = 266.
100 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃; for 16h;Inert atmosphere;
A mixture of 2-(4-bromophenyl)ethan-1-ol (60 g, 300 mmol), BISPIN (84 g, 330 mmol), KOAc (90 g, 900 mmol) and PdC (dppf) (6.6 g, 9 mmol) in 1 ,4-dioxane (600 ml) was stirred under N2at 85C for 16 h. The RM was cooled to RT, filtered, the filtrate was concentrated and the residue purified by chromatography on silica gel eluting with EtOAc in petroleum ether (from 0 to 30%) to afford of the title compound as an oil (100 g).Method J: Rt = 1.87 min, [M+NH4]+= 266.
With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 18h;
11.a
To a solution of 2- (4-BROMOPHENYL) ethanol (1.2 g, 6.0 mmol) in CH2CL2 (50 mL) at RT under nitrogen was added CBr4 (1.98 g, 5.8 mmol) and PPH3 (1.57 g, 5.8 mmol). After stirring at RT for 18 h the reaction mixture was concentrated and the residue diluted with ET20 (30 mL) resulting in precipitation of triphenylphosphine oxide. The ethereal solution was decanted, evaporated and purified by flash chromatography (silica, hexane) to provide the title compound as a clear oil (59%). 1H NMR (DMSO-d6) 8 7.45 (d, 2 H), 7.15 (d, 2 H), 3.51 (t, 2 H), 3.17 (t, 2 H); 13C NMR (DMSO-d6) 8 138.1, 133.4, 131.2, 122.5, 38.5, 27.2.
2-[4-(4-phenyl-1H-imidazol-1-yl)phenyl]ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With sodium carbonate; copper(I) bromide; In 1,3-dimethyl-2-imidazolidinone; at 180℃; for 36h;
STEP 1. 2-[4-(4-phenyl-1H-imidazol-1-yl)phenyl]ethanol A mixture of <strong>[670-95-1]4-phenylimidazole</strong> (4.32 g, 30 mmol), Bromophenethyl alcohol (10.5 ml, 75 mmol), CuBr (10.4 g, 72 mmol) and Na2CO3 (3.8 g, 36 mmol) in 1,3-dimethyl-2-imidazolidinone (100 mL) was stirred at 180 C. for 36 h. After cooling, to the mixture was added 25% NH3 aq. (50 mL). After 30 min, insoluble materials were removed by Celite filtration and washed with dichloromethane. The aqueous layer was extracted with dichloromethane. The organic phase was dried (MgSO4) and concentrated under reduced pressure. To the residue was added diisopropylether (100 mL) and the flask was cooled to 0 C. Filtration of the diisopropylether gave 4.01 g of the title compound as colorless solid (51%): MS (ESI) m/z 265 [M+H]+, 1H-NMR (CDCl3) delta2.94 (2H, t, J=6.4 Hz), 3.93 (2H, br), 7.26-7.30 (2H, m), 7.35-7.44 (5H, m), 7.55 (1H, d, J=1.2 Hz), 7.82-7.86 (3H, m).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 60℃;
The starting material, 2-(4-(thiophen-3-yl)phenyl)ethanol, was synthesized asfollows: In a sealed vessel was combined 2-(4-bromophenyl)ethanol (70 jxL), 4,4,5,5-tetramethyl-2-(thiophen-3-yl)-l,3,2-dioxaborolane (126 mg), K2CO3 (207 mg), catalyticPd(PPh3)4, 4.5 mL THF, and 0.5 mL H2O. The vessel was heated in an oil bath at 60 Covernight. The reaction mixture was diluted with water and DCM. The organic layerwas concentrated to yield 2-(4-(thiophen-3-yl)phenyl)ethanol (80 mg) as a solid whiteproduct. 80 mg tert-butyl (S)-2-(4-(4-(thiophen-3-yl)phenethyloxy)phenylcarbamoyl)-l-hydroxypropan-2-ylcarbamate was synthesized following the general procedureemploying 2-(4-(thiophen-3-yl)phenyl)ethanol (200 mg), 7V-(Boc)-a-methylserine (175mg), HATU (375 mg), and DIPEA (430 uL). MS (ESI, M+Na+) = 519. 2.6 mg of thephosphate was then synthesized from the carbamate (40 mg) as a solid white solid. MS(ESI, M+H+) = 477; *H NMR (400 MHz, DMSO-d6) 5 9.96 (br s, 1H), 7.81 (m, 1H),7.65 (m, 3H), 7.5 (m, 3H), 7.3 (m, 2H), 6.9 (m, 2H), 4.28 (m, 1H), 4.17 (m, 2H), 4.06(m, 1H), 3.04 (t, 2H), 1.48 (s, 3H).
11 Preparation 11
Preparation 11 2-(4-Benzoylphenyl)ethanol (40.12 g.), m.p. 78°-86° C., prepared by reaction of 130.69 g. (0.65 mole) of 2-(4-bromophenyl)ethanol with 109.2 g. (1.3 moles) of dihydropyran in the presence of a small amount of concentrated hydrochloric acid to give 189.63 g. of 2-(4-bromophenyl)ethanol tetrahydropyranyl ether; reaction of 85.5 g. (0.30 mole) of the latter with 178 ml. (0.39 mole) of a 2.18 molar solution of butyl lithium in anhydrous ether followed by reaction of the resulting lithio derivative with 40.26 g. (0.30 mole) of benzonitrile to give 43.64 g. of 2-(4-benzoylphenyl)ethanol, b.p. 201.0°-206.5° C./0.025-0.035 mm., nD23 =1.6087; and reaction of 29.4 g. (0.13 mole) of the latter with 29.4 g. (0.143 mole) of p-toluenesulfonyl chloride in 100 ml. of dry pyridine.
Reference Example 4 methyl 3-hydroxy-4-[4-(2-hydroxyethyl)benzyl]benzoate To a solution of 2-(4-bromophenyl)ethylalchol (1.7g) in tetrahydrofuran (100ML) was added 1.45mol/L tert-butyllithium n-pentane solution (12.6ML) under an argon atmosphere at -78C. After the mixture was stirred at -78C for 10 minutes, a solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (0.50g) in tetrahydrofuran (10ML) was added to the reaction mixture.. After the reaction mixture was stirred for 30 minutes under ice-cooling, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate.. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 1/3) to give a diphenylmethanol compound (0.28g).. The obtained diphenylmethanol compound (0.28g) was dissolved in methanol (5ML), and 10% palladium-carbon powder (0.14g) was added to the solution.. After the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 1/1) to give methyl 3-hydroxy-4-[4-(2-hydroxyethyl)benzyl]benzoate (0.26g).1H-NMR (CDCl3) delta ppm: 1.37 (1H, t, J=5.9Hz), 2.84 (2H, t, J=6.5Hz), 3.75-3.95 (5H, m), 4.01 (2H, s), 5.10 (1H, s), 7.05-7.25 (5H, m), 7.47 (1H, d, J=1.6Hz), 7.56 (1H, dd, J=1.6, 7.8Hz)
With zinc(II) fluoride;tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; at 80℃; for 18h;
Example 4: Preparation of2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid ethylester; In a reaction vessel, 4-bromo phenethyl alcohol(2.0g), Pd(dba)2(0.11g), f-Bu3P(0.08g), ZnF2(0.52g), ethyltrimethylsilyl dimethylketene acetal(2.7g) and DMF(20mL) were introduced, and the mixture was reacted at 80"C for 18 hours. Distilled water(50ml_) and ethylacetate(50mL) were added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated with Na2SO4, and then condensed by filtration, and purified to obtain 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid ethylester(2.3g, yield 92%).1H-NMR, 400 MHz, CDCI3, ppm : δ 1.25(t, 3H), 1.57(s, 6H), 2.82-2.84(t, 2H), 4.10-4.45(q, 2H), 3.83-3.86(t, 2H), 7.18-7.20(d, 2H), 7.27-7.29(d, 2H)
92%
With zinc(II) fluoride;tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; at 80℃; for 18h;
Example 4 Preparation of 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid ethylester In a reaction vessel, 4-bromo phenethyl alcohol (2.0 g), Pd(dba)2 (0.11 g), t-Bu3P (0.08 g), ZnF2 (0.52 g), ethyltrimethylsilyl dimethylketene acetal (2.7 g) and DMF (20 mL) were introduced, and the mixture was reacted at 80 C. for 18 hours. Distilled water (50 mL) and ethylacetate (50 mL) were added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated with Na2SO4, and then condensed by filtration, and purified to obtain 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid ethylester (2.3 g, yield 92%). 1H-NMR, 400 MHz, CDCl3, ppm: δ 1.25 (t, 3H), 1.57 (s, 6H), 2.82-2.84 (t, 2H), 4.10-4.45 (q, 2H), 3.83-3.86 (t, 2H), 7.18-7.20 (d, 2H), 7.27-7.29 (d, 2H)
With lithium borohydride; In tetrahydrofuran; at 0 - 20℃; for 2h;
5.5a (6 g, 26.2 mmol, 1.0equiv) was dissolved in THE (100 mL) and cooled toO C. LiBH4 (2M in THE) (1.41 g, 52.4 mmol, 2.0 equiv) was added drop wise at 0 C and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 5.5b (4.5 g, 85.5 % yield). LCMS (mlz): 204.8 [M+H]. 1H NMR (400 MHz, DMSO) 6 7.56 - 7.35 (m, 2H), 7.27 - 7.07 (m, 2H), 4.67 (t, J = 5.2 Hz, 1 H), 3.58 (td, J = 6.8, 5.4 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H).
(Step 1) To a solution of 2-(4-bromophenyl)ethanol (3.00 g, 14.9 mmol) in THF (60 mL) was added 1.6 M butyllithium/hexane solution (23.3 mL, 37.3 mmol) at -78 C. and the mixture was stirred at -78 C. for 1 hr and then at room temperature for 30 min. The reaction mixture was cooled again to -78 C. and triisopropylboric acid (7.02 g, 37.3 mmol) was added. The mixture was gradually heated to room temperature. Saturated aqueous ammonium chloride solution (150 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous-sodium sulfate. The solvent was evaporated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (67-100% ethyl acetate/hexane-9% methanol/ethyl acetate) to give [4-(2-hydroxyethyl)phenyl]boronic acid as a colorless amorphous form (925 mg, 37%).
1-(4-bromophenethyloxy)-3-(trifluoromethoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.2%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 15.5h;
(1) 17.42 g (66.42 mmol) of triphenylphosphine was added at room temperature to a solution having 9.21 g (45.81 mmol) of 2-(4-bromophenyl)ethanol and 8.61 g (48.34 mmol) of <strong>[827-99-6]3-(trifluoromethoxy)phenol</strong> dissolved in 160 ml of THF, followed by stirring for 10 minutes. Then, 31.23 ml (68.41 mmol) of DEAD (2.2 M toluene solution) was dropwise added over a period of 20 minutes, followed by stirring further for 15 hours. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (developing solvent: heptane/ethyl acetate=98/2 to 95/5, volume ratio, the same applies hereinafter) to obtain 14.10 g (yield: 85.2percent) of 1-(4-bromophenethyloxy)-3-(trifluoromethoxy)benzene as a colorless oil. 1H-NMR(300 MHz, CDCl3, deltappm): 7.44(d, 2H, J=8.1 Hz), 7.26(dd, 1H, J=8.1 Hz, 8.1 Hz), 7.16(d, 2H, J=8.1 Hz), 6.81(d, 1H, J=8.1 Hz), 6.80(d, 1H, J=8.1 Hz), 6.75-6.71(br, 1H), 4.14(t, 2H, J=6.9 Hz), 3.05(t, 2H, J=6.9 Hz)
With 1,3-bis-(diphenylphosphino)propane; potassium acetate; palladium diacetate; In tetrahydrofuran; at 80℃; under 2585.81 Torr; for 16h;
To a solution of 2-(4-bromophenyl)ethanol (500.00 mg, 2.49 mmol, 347.22 uL, 1.00 eq) in MeOH (20.00 mL) and THF (10.00 mL) were added KOAc (1.95 g, 19.92 mmol, 8.00 eq), Pd(OAc)2 (55.90 mg, 249.00 umol, 0.10 eq),and 3- diphenylphosphanylpropyl(diphenyl)phosphane (154.05 mg, 373.50 umol, 0.15 eq). The suspension was degassed and purged with CO. The mixture was stirred under an atmosphere of CO (50 psi) at 80 C for 16 h. The crude product was purified by silica gel column chromatography (Petroleum ethenEthyl acetate 20: 1 to 3: 1) to afford methyl 4-(2- hydroxyethyl)benzoate (425.00 mg) as a yellow oil. LCMS (M + H+) m/z: 181
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 5h;
General procedure: 2.5mmol thiazole-4-carboxyli acid and 2.0mmol alcohol were dissolved in 25mL dichloromethane (DCM) in a dry flask with continuous stirring, followed by the addition of 2.5mmol 3-(3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride. When the temperature of the reaction system cooled to 0°C, 0.2mmol 4-dimethylaminopyridine was added dropwise and reacted for 1hat 0°C. Then the temperature was elevated to room temperature for another 4h reaction. The reaction was stopped by adding 25mL saturated NaHCO3 solution and extracted twice with 20mL dichloromethane (2×20mL). The extracted organic layers were first dried by anhydrous Na2SO4, and then filtered and concentrated under vacuum distillation, obtaining the crude products. Finally, the crude products were further purified using column chromatography (ethy lacetate:petroleum ether, 1:5).
Step 2. 2-{4-[(7-Nitro-2,3-dihydro-1,4-benzodioxin-6-yl)amino]phenyl}ethanol The title compound was prepared according to the procedure described in step 1 of Example 45 from <strong>[62140-78-7]7-nitro-2,3-dihydro-1,4-benzodioxin-6-amine</strong> (step 1) and 4-bromophenylethyl alcohol. 1H-NMR (CDCl3) delta7.77 (1H, s), 7.26 (2H, d, J=8.4 Hz), 7.19 (2H, d, J=8.4 Hz), 6.64 (1H, s), 4.20-4.31 (4H, m), 3.89 (2H, t, J=6.4 Hz), 2.88 (2H, t, J=6.4 Hz).
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane;
Step. 4-(2-hydroxyethyl)phenylboronic acid To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9 mmol) in THF (80 ml) was added a solution of 1.5M n-BuLi in hexane (39.8 ml, 59.7 mmol) at -78 C. over 30 min. After 1 hour, a solution of B(OiPr)3 (8.61 ml, 37.3 mmol) in THF (20 ml) was added slowly to the mixture at -78 C. The resultant mixture was warmed to room temperature, and treated with 2M HCl (100 ml) for 1 hour. This was extracted with CH2Cl2 and dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluding with CH2Cl2/MeOH=20/1 to afford 2.61 g (63%) of the title compound. 1H-NMR (CD3OD) delta: 7.64-7.48 (2H, m), 7.19-7.13 (2H, m), 3.70 (2H, t, J=7.2 Hz), 2.77 (2H, t, J=7.2 Hz) MS (ESI) m/z: 165 ([M-H]-)
1-(7-bromoisochroman-1-yl)-N-methylmethanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trifluorormethanesulfonic acid; In dichloromethane; at 5 - 20℃; for 1h;
To a solution of 2-(4-bromophenyl)ethanol (2 g, 9.94 mmol) in DCM (20 mL) was added 2,2-dimethoxy-N-methylethanamine (2.35 g, 19.8 mmol). Trifluoromethane sulfonic acid (14.9 g, 99.3 mmol) was added dropwise into the mixture at 5~10C, and the mixture was warmed to 25 C and stirred for lh. Upon completion, ice water was added to quench the reaction, and the pH was adjusted to 8 using saturated NaHCC solution and extracted with DCM. The combined organic phases were dried over Na2S04, filtered and concentrated to dryness. The crude product was used for the next step without further purification. MS(ESI): m/z 256,258[M, M+2]+.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
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