* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With borane-THF In tetrahydrofuran at 14℃; for 18 - 22 h; Heating / reflux
To a solution of 3-(3-bromophenyl)propionic acid (10.0 g, 43.7 mmol) in anhydrous THF (150 mL) was added 1.0 M BH3.THF (150 mL, 150 mmol) via addition funnel. After BH3.THF was added, the reaction was refluxed for 18 hrs. The reaction was quenched with water (100 mL) and 1N HCl (300 mL). The solution was saturated with sodium chloride and extracted with ethyl acetate. The organic extract was washed with brine and dried over magnesium sulfate. The organic material was purified by chromatography on silica gel eluting with ethyl acetate in hexane to produce 9.39 g (100percent) of the desired alcohol as a colorless oil. NMR (CDCl3) δ 1.82-1.89 (m, 2H), 2.67 (t, 2H), 3.64 (t, 2H), 7.11 7.15 (m, 1H), 7.29-7.31 (m, 1H), 7.34 (s, 1H).Part A. Preparation of: To a solution of 3-(3-bromophenyl)propionic acid (15.0 g, 65.5 mmol) in anhydrous THF (200 mL) at 5° C. was added, via addition funnel, 1.0 M BH3-THF (200 mL, 200 mmol). The reaction temperature was kept below 14° C. during the addition of the BH3THF. After all the BH3THF was added, the reaction was refluxed for 22 hr and then quenched with water (100 mL) and 1N HCl (300 mL). The solution was saturated with sodium chloride and extracted with ethyl acetate (3.x.300 mL). The organic extract was washed with brine, dried over magnesium sulfate, and concentrated providing 14.4 g (100percent) of crude alcohol as a colorless oil. NMR(CDCl3) δ 1.82-1.89 (m, 2H), 2.67 (t, 2H), 3.64 (t, 2H), 7.11-7.15 (m, 1H), 7.29-7.31 (m, 1H), 7.34 (s, 1H).
98%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 3 h; Stage #2: With sodium hydroxide; water In tetrahydrofuran
Example 36. 3-(3-Bromo-plienvr)-propan-l-oI (23); [0173] 3-(3-Bromo-phenyl)-propionic acid (3.88 g, 16.9 mmol, 1 equiv) was diluted with THF (50 mL) and chilled to O0C. IM LAH solution added slowly so as to not allow internal reaction temperature to climb above 10-15°C. Once LAH addition was complete, reaction allowed to come to room temperature and stir for 3h. Reaction then quenched with sequential addition of water (0.5 mL), 15percent NaOH (0.5 mL) and water again(1.5 mL). This was then filtered and solvents evaporated to provide the product as a pale oil (2.75g, 98percent). Ri = 0.42 (30percent EtOAc/hexanes).
28%
With borane-THF In tetrahydrofuran at 0 - 20℃; Inert atmosphere
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(3-bromophenyl)propanoic acid (5 g, 21.83 mmol, 1.00 equiv) in THF (50 mL). This was followed by the addition of borane tetrahydrofuran complex solution (1 moL/L, 75 mL, 74.22 mmoL, 3.40 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction mixture was poured into 150 mL of HCl (1 moL/L), extracted with 3×200 mL of DCM, washed with 300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (10:1). The collected fraction was concentrated to afford 3-(3-bromophenyl)propan-1-ol (1.3 g, 28percent) as colorless oil. 1H-NMR (DMSO, 400 MHz) δ(ppm): 7.41-7.20 (m, 4H), 4.51-4.48 (t, 1H), 3.41-3.34 (m, 2H), 2.67-2.59 (m, 2H), 1.73-1.66 (m, 2H).
9.8 g
With borane-THF In tetrahydrofuran at 0℃; for 17 h; Inert atmosphere; Reflux
To a cooied (ice bath) soiution of 3-(3-bromophenyi)propanoic acid (8.0 g,35 mmoi) in anhydrous THF (100 mL) was added BH3-THF (100 mL, 1.0 M) via addition funnei under a nitrogen atmosphere. The reaction was stirred at 0 °C for 1 h then at refiux for 16 h. The reaction was carefuiiy quenched with HCi (37 mL, 2 M) then concentrated to remove THF. The suspension was diiuted withDCM (300 mL) then fiitered to remove the soiids. The iayers were separatedand the organic phase was washed with water (50 mL) and brine (50 mL) then dried over anhydrous Na2SO4, filtered, and concentrated to give 3-(3-bromophenyl)propan-1-ol (9.8 g, >100percent) as a yellow oil, which was used for next step without further purification.
Reference：
[1] Patent: US2004/10019, 2004, A1, . Location in patent: Page 160; 167
[2] Patent: WO2006/101977, 2006, A2, . Location in patent: Page/Page column 56
[3] Journal of Organic Chemistry, 2010, vol. 75, # 15, p. 5178 - 5194
[4] Angewandte Chemie - International Edition, 2018, vol. 57, # 15, p. 4058 - 4062[5] Angew. Chem., 2018, vol. 130, p. 4122 - 4126,5
[6] Patent: US2016/264518, 2016, A1, . Location in patent: Paragraph 0969; 0970
[7] Patent: US2007/27141, 2007, A1, . Location in patent: Page/Page column 9
[8] Patent: WO2016/147144, 2016, A1, . Location in patent: Page/Page column 113; 114
4
[ 14473-91-7 ]
[ 65537-54-4 ]
Yield
Reaction Conditions
Operation in experiment
74%
Stage #1: With lithium aluminium tetrahydride In diethyl ether at 20℃; for 3 h; Stage #2: With sodium hydroxide; water In diethyl ether
To suspension Of LiAlH4 (0.5 g, 1.3 mmol) in diethyl ether (25 mL) was added 3- bromocinnamic acid (83, 1.0 g, 4 mmol), in portions, at RT. The resulting suspension was stirred for 3 hours. The reaction was quenched by the successive addition of 15percent aq. NaOH solution (1 mL) and water. The resulting white suspension was filtered through a pad of Celite. The filter cake was washed with ether and then ethyl acetate. The filtrate was concentrated to afford crude 8 as yellow oil. Yield (0.7g, 74percent). 1H NMR (400 MHz, CDCl3) δ 7.10-7.35 (m, 4H), 3.65 (t, J = 6.5 Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H), 1.82-1.91 (m, 2H).
Stage #1: With 9-borabicyclo[3.3.1]nonane dimer In tetrahydrofuran at 20℃; Stage #2: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; water at 20℃; for 4 h; Cooling with ice
A solution of 1-allyl-3-bromobenzene (998 mg, 5.1 mmol) in THF (2 mL + 0.5 mL) was added to a solution of 9-BBN dimer (806 mg, 3.3 mol) in THF (6.6 mL). The mixture was stirred overnight at room temperature, then 3.0 M NaOH (2 mL) and 30percent H2O2 (2 mL) were added while cooling the reaction mixture in an ice bath to control the exotherm. The mixture was stirred at room temperature for 4 h and then partitioned between brine (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried (Na2Sψ4), filtered and concentrated in vacuo. Purification of the crude residue by chromatography on 80 g silica gel (hexanes --> 60percent EtOAc/hexanes, gradient) afforded 637 mg (58percent) of 3-(3-bromophenyl)propan-1-ol.
With borane-THF; In tetrahydrofuran; at 14℃; for 18 - 22h;Heating / reflux;
To a solution of <strong>[42287-90-1]3-(3-bromophenyl)propionic acid</strong> (10.0 g, 43.7 mmol) in anhydrous THF (150 mL) was added 1.0 M BH3.THF (150 mL, 150 mmol) via addition funnel. After BH3.THF was added, the reaction was refluxed for 18 hrs. The reaction was quenched with water (100 mL) and 1N HCl (300 mL). The solution was saturated with sodium chloride and extracted with ethyl acetate. The organic extract was washed with brine and dried over magnesium sulfate. The organic material was purified by chromatography on silica gel eluting with ethyl acetate in hexane to produce 9.39 g (100%) of the desired alcohol as a colorless oil. NMR (CDCl3) delta 1.82-1.89 (m, 2H), 2.67 (t, 2H), 3.64 (t, 2H), 7.11 7.15 (m, 1H), 7.29-7.31 (m, 1H), 7.34 (s, 1H).Part A. Preparation of: To a solution of <strong>[42287-90-1]3-(3-bromophenyl)propionic acid</strong> (15.0 g, 65.5 mmol) in anhydrous THF (200 mL) at 5 C. was added, via addition funnel, 1.0 M BH3-THF (200 mL, 200 mmol). The reaction temperature was kept below 14 C. during the addition of the BH3THF. After all the BH3THF was added, the reaction was refluxed for 22 hr and then quenched with water (100 mL) and 1N HCl (300 mL). The solution was saturated with sodium chloride and extracted with ethyl acetate (3×300 mL). The organic extract was washed with brine, dried over magnesium sulfate, and concentrated providing 14.4 g (100%) of crude alcohol as a colorless oil. NMR(CDCl3) delta 1.82-1.89 (m, 2H), 2.67 (t, 2H), 3.64 (t, 2H), 7.11-7.15 (m, 1H), 7.29-7.31 (m, 1H), 7.34 (s, 1H).
98%
Example 36. 3-(3-Bromo-plienvr)-propan-l-oI (23); [0173] 3-(3-Bromo-phenyl)-propionic acid (3.88 g, 16.9 mmol, 1 equiv) was diluted with THF (50 mL) and chilled to O0C. IM LAH solution added slowly so as to not allow internal reaction temperature to climb above 10-15C. Once LAH addition was complete, reaction allowed to come to room temperature and stir for 3h. Reaction then quenched with sequential addition of water (0.5 mL), 15% NaOH (0.5 mL) and water again(1.5 mL). This was then filtered and solvents evaporated to provide the product as a pale oil (2.75g, 98%). Ri = 0.42 (30% EtOAc/hexanes).
98%
With dimethylsulfide borane complex; In tetrahydrofuran; at 20 - 22℃; for 4.5h;Inert atmosphere;
Borane dimethyl sulfide complex (3.0 mL, 6.1 mmol) was added to a solution of <strong>[42287-90-1]3-(3-bromophenyl)propionic acid</strong> (308 mg, 1.34 mmol) in dry THF (15 mL) at room temperature under inert atmosphere. The mixture was stirred at room temperature for 4.5 h and thereafter diluted with CH2Cl2 and added dropwise to ice-cold 1 M HCl (aq, ~80 mL). NaOH (aq., 10%) was added until pH = 10. The phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over MgSO4 and concentrated under reduced pressure affording 3-(3-bromophenyl)propanol (282 mg, 98%) as a transparent oil. DMSO (0.28 mL, 3.9 mmol) was added dropwise to a solution of oxalyl chloride (0.14 mL, 1.6 mmol) in dry THF (19 mL) at -78 C under inert atmosphere. The mixture was stirred for 1 h. A solution of the crude alcohol obtained in the previous step (282 mg, 1.31 mmol) in THF (1.5 mL) was added dropwise to the mixture, which was stirred for 1 h at -78 C. Et3N (0.91 mL, 6.6 mmol) was added dropwise and stirring was continued for 20 min at -78 C. Thereafter the mixture was allowed to reach room temperature. Water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (10% EtOAc in pentane) affording 17c (209 mg, 73% over two steps) as transparent oil. 1H NMR (400 MHz, CDCl3) delta 9.82 (t, J = 1.2 Hz, 1H), 7.36-7.32 (m, 2H), 7.19-7.10 (m, 2H), 2.97-2.89 (m, 2H), 2.82-2.75 (m, 2H). 13C NMR (100 MHz, CDCl3) delta 200.9, 142.8, 131.5, 130.3, 129.6, 127.2, 122.8, 45.1, 27.8.
28%
With borane-THF; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of <strong>[42287-90-1]3-(3-bromophenyl)propanoic acid</strong> (5 g, 21.83 mmol, 1.00 equiv) in THF (50 mL). This was followed by the addition of borane tetrahydrofuran complex solution (1 moL/L, 75 mL, 74.22 mmoL, 3.40 equiv) dropwise with stirring at 0 C. The resulting solution was stirred overnight at room temperature. The reaction mixture was poured into 150 mL of HCl (1 moL/L), extracted with 3×200 mL of DCM, washed with 300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (10:1). The collected fraction was concentrated to afford 3-(3-bromophenyl)propan-1-ol (1.3 g, 28%) as colorless oil. 1H-NMR (DMSO, 400 MHz) delta(ppm): 7.41-7.20 (m, 4H), 4.51-4.48 (t, 1H), 3.41-3.34 (m, 2H), 2.67-2.59 (m, 2H), 1.73-1.66 (m, 2H).
A suspension of 1.84 g (8 mmol) of <strong>[42287-90-1]3-(3-bromophenyl)propionic acid</strong> and 0.91 g (24 mmol) of sodium borohydride in 20 ml of THF, cooled to 0 C., is admixed in small portions with 3.2 ml (25 mmol) of trifluoroborane-diethyl ether complex. Stirring is continued in the cold for 1 hour, and then at ambient temperature for 16 hours. The reaction mixture is cooled to 0 C. and neutralized to a pH of 7~8 by adding a 1N solution of aqueous sodium hydroxide. It is concentrated under reduced pressure and then the residue is taken up in water. It is extracted with dichloromethane and dried over sodium sulphate. Following filtration, the organic phase is concentrated under reduced pressure. This gives 1.62 g (7.53 mmol) of product in the form of an oil, which is used as it is in the following step.
9.8 g
With borane-THF; In tetrahydrofuran; at 0℃; for 17h;Inert atmosphere; Reflux;
To a cooied (ice bath) soiution of 3-(3-bromophenyi)propanoic acid (8.0 g,35 mmoi) in anhydrous THF (100 mL) was added BH3-THF (100 mL, 1.0 M) via addition funnei under a nitrogen atmosphere. The reaction was stirred at 0 C for 1 h then at refiux for 16 h. The reaction was carefuiiy quenched with HCi (37 mL, 2 M) then concentrated to remove THF. The suspension was diiuted withDCM (300 mL) then fiitered to remove the soiids. The iayers were separatedand the organic phase was washed with water (50 mL) and brine (50 mL) then dried over anhydrous Na2SO4, filtered, and concentrated to give 3-(3-bromophenyl)propan-1-ol (9.8 g, >100%) as a yellow oil, which was used for next step without further purification.
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃; for 18h;
General procedure: To a stirred solution of 3- or 4-substituted phenylpropanoic acid 51-63 (7.0 mmol) in dry THF (35 ml), borane dimethyl sulfide (21.0 mmol) was added dropwise at 0 oC. The reaction mixture was stirred for 18h at room temperature, quenched with H2O and concentrated in vacuo. The resulting residue was re-dissolved in diethyl ether (25 ml), and washed with 10%NaOH (30ml) and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated in vacuo to give 3-phenylpropan-1-ol derivatives that were used in the next step without further purification.
Stage #1: 1-allyl-3-bromo-benzene With 9-borabicyclo[3.3.1]nonane dimer In tetrahydrofuran at 20℃;
Stage #2: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; water at 20℃; for 4h; Cooling with ice;
10.1
A solution of 1-allyl-3-bromobenzene (998 mg, 5.1 mmol) in THF (2 mL + 0.5 mL) was added to a solution of 9-BBN dimer (806 mg, 3.3 mol) in THF (6.6 mL). The mixture was stirred overnight at room temperature, then 3.0 M NaOH (2 mL) and 30% H2O2 (2 mL) were added while cooling the reaction mixture in an ice bath to control the exotherm. The mixture was stirred at room temperature for 4 h and then partitioned between brine (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried (Na2Sθ4), filtered and concentrated in vacuo. Purification of the crude residue by chromatography on 80 g silica gel (hexanes → 60% EtOAc/hexanes, gradient) afforded 637 mg (58%) of 3-(3-bromophenyl)propan-1-ol.
To suspension Of LiAlH4 (0.5 g, 1.3 mmol) in diethyl ether (25 mL) was added 3- bromocinnamic acid (83, 1.0 g, 4 mmol), in portions, at RT. The resulting suspension was stirred for 3 hours. The reaction was quenched by the successive addition of 15% aq. NaOH solution (1 mL) and water. The resulting white suspension was filtered through a pad of Celite. The filter cake was washed with ether and then ethyl acetate. The filtrate was concentrated to afford crude 8 as yellow oil. Yield (0.7g, 74%). 1H NMR (400 MHz, CDCl3) delta 7.10-7.35 (m, 4H), 3.65 (t, J = 6.5 Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H), 1.82-1.91 (m, 2H).
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