* 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 medicinal chemistry, 1970, vol. 13, # 6, p. 1040 - 1042
[2] Patent: US5639780, 1997, A,
2
[ 31938-07-5 ]
[ 1878-67-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3018 - 3022
[2] Journal fuer Praktische Chemie (Leipzig), 1932, vol. <2> 133, p. 331,346
[3] Journal of the Chemical Society, 1948, p. 1251,1254
[4] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1880, p. 481
With lithium aluminium tetrahydride; sulfuric acid In tetrahydrofuran at -5 - 20℃; for 2 h;
A suspension of LiAlH4 (3.04 g, 80 mmole) in dry THF ( 100 ml) was cooled to -5 0C. Concentrated H2SO4 (3.9 g, 40 mmole) was added dropwise, and the resulting mixture was stirred at -5 0C for 1 hour. A solution of 3-bromo-benzenacetontrile (9.80 g, 50 mmole) in THF (5 ml) was added dropwise, and the reaction was allowed to warm to room temperature when the addition was complete. The reaction was stirred at room temperature for 1 hour, and then cooled back to 0 0C and quenched by the addition of a 1 : 1 THF: H2O mixture (12.4 ml). Et2O was added (50 ml), followed by a 3.6 M solution of NaOH (24.4 ml). The mixture was filtered through Celite, and the solids were washed well with additional Et2O. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound (9.7 g, 97percent). The crude compound was used in subsequent steps. 1H NMR (400 MHz, CDCl3) δ 7.38-7.30 (m, 2H), 7.20-7.10 (m, 2H), 2.96 (t, 2H), 2.72 (t, 2H), 1.35 (br s, 2H). MS (ESI) m/z: Calculated: 199; Observed: 200/202 (M++.).
96%
With lithium aluminium tetrahydride; sulfuric acid In tetrahydrofuran at 0 - 20℃; for 1 h;
A suspension of LIALH4 (1.24 g, 32.7 mmol) in dry THF (50 mL) was cooled to 0 °C. Concentrated H2SO4 (1.6 g, 16.3 mmol) was added dropwise, and the resulting mixture was stirred at 0 °C for 30 min. A solution of 3-bromo- benzeneacetonitrile (4.01 g, 20.4 mmol) in THF (5 mL) was added dropwise, and the reaction was allowed to warm to room temperature when the addition was complete. The reaction was stirred at room temperature for lh, and then cooled back to 0 °C and quenched by the addition of a 1: 1 THF: H20 mixture (5 mL). Et2O was added (20 mL), followed by a 3.6 M solution OF NAOH (10 mL). The mixture was filtered through Celite, and the solids were washed well with additional ET2O. The organic phase was dried over NA2S04, filtered, and concentrated in vacuo to provide the title compound (3.91 g, 96percent). The crude compound was used in subsequent STEPS. 1H- NMR (CDC13); 8 7.38-7. 30 (overlapping s at 7.35 and d, J=7. 2 Hz for d, 2H), 7.20- 7.10 (m, 2H), 2. 96 (t,. J=6. 8 Hz, 2H), 2.72 (t, J=6. 4 Hz, 2H), 1. 35 (br s, 2H). MS (ESI) (M+H) += 200/202.
93%
With lithium aluminium tetrahydride; sulfuric acid In tetrahydrofuran at 20℃; for 1 h;
A suspension of LiAH4 (2.5 g, 66 mmol, 1.6 eq) in dry THF (100 mL) was cooled to -5° C. and concentrated H2SO4 (3.2 g, 33 mmol, 0.8 eq) was added drop wise while the temperature was maintained below 3° C. The reaction mixture was stirred at 5° C. for 40 minutes and a solution of intermediate I-59 (8.0 g, 41 mmol, 1.0 eq) in THF was added drop wise. The reaction mixture was warmed to room temperature and stirred for additional 60 minutes. The reaction mixture was cooled to 0° C. and quenched by adding a mixture of THF (5 mL) and water (5 mL). Ether was added followed by a solution of sodium hydroxide (20 mL, 3.6M in water) and the crude reaction mixture was filtered through short plug of Celite. The combined organic layers were dried over anhydrous MgSO4, the solids were removed by filtration and the filtrate was concentrated by evaporation to give intermediate I-60 (8.0 g, 93percent). MS (ESI): m/z 200 (M+H+).
93.4%
With raney nickel In ethanol at 20℃; for 10 h;
Add 300 mL of ethanol to the three-neck bottle.35.0 g of 3-bromophenylacetonitrile and 5.0 g of Raney nickel were reacted at 20 ° C for 10 h.Filter and concentrate the filtrate to give a crude product.Recrystallization from petroleum ether gave 34.7 g (93.4percent) of 3-bromophenylethylamine.
92%
Stage #1: With lithium aluminium tetrahydride; sulfuric acid In tetrahydrofuran at 20℃; for 1 h; Stage #2: With sodium hydroxide; water In tetrahydrofuran; diethyl ether
Step 1: 2-(3-bromophenyl)ethanamine To a solution of 2M LAH (31 mL) in THF (37 mL) at 0° C. was added sulfuric acid (1.6 mL) dropwise. This mixture was allowed to stir for 30 min and then (3-bromophenyl)-acetonitrile (30.6 mmol) in THF (7.5 mL) was slowly added. The reaction mixture was allowed to warm to rt and stir for 1 hr. The reaction was cooled to 0° C. and then a 1:1 v:v mixture of THF:water (20 mL) was added, followed by diethyl ether (40 mL). A precipitate formed. 4N NaOH was added until the solution reached pH=9. The mixture was filtered and the solid was washed with ether. The solution was dried over Na2SO4 and concentrated to give 2-(3-bromophenyl)ethanamine (28.1 mmol, 92percent) as an oil, which was used without further purification.
83.3%
Stage #1: With borane-THF In tetrahydrofuran at 0℃; for 24.5 h; Reflux Stage #2: for 4 h; Reflux
General procedure: Toa solution of 2-bromobenzyl cyanide (20.0 g, 0.1 mol) in THF (100 mL) was added1M BH3·THF (200 mL, 0.2 mol) dropwise at 0 oCover 30 min and then heated to reflux for 24 h. After quenchedwith MeOH (50 mL) and 6M HCl (50 mL) at 0 oC, the reaction mixturewas heated to reflux for another 4 h and concentrated under reduced pressure.The residue was diluted with H2O (300 mL) and washed with EA (75 mL×2). The aqueous layer was then neutralized by 15percent NaOH, extracted with EA (75mL ×2). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford compound 2a as yellow oil (17.4 g, 85.2percent).
73%
Stage #1: With borane-THF In tetrahydrofuranHeating / reflux Stage #2: With hydrogenchloride; water In tetrahydrofuran at 20℃;
2-(3-Bromophenyl) ethylamine To a solution of 3-bromophenyl acetonitrile (9.8 g, 50 mmol) in THF (20 mL) is added a solution of borane (.1 M in THF, 150 mL) under a nitrogen atmosphere. The reaction mixture is refluxed overnight. It is cooled to room temperature and treated with 6 N HCl (150 mL). The resulting mixture is washed with ethyl acetate and ethyl acetate is discarded. The aqueous layer is basifed with sodium carbonate and then extracted with ethyl acetate several times. The combined organic layer is washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure to obtain colorless viscous oil without further purification (7.3 g, 73percent).
With potassium hydroxide;tetrabutylammomium bromide; In water; toluene; for 1.5h;Reflux;
To a solution of 3-bromobenzeneacetonitrile (6.480 g, 33.054 mmol), potassium hydroxide (14.8 g, 26.4 mmol), and tetrabutylammonium bromide (0.107 g, 0.331 mmol) in toluene (90 mL) and H2O (4 mL) was added 1,3-dibromopropane (3.4 mL, 33.0 mmol). The resulting mixture was then refluxed for 1.5 h. Then, the mixture was cooled to room temperature and H2O (100 mL) was added. The mixture was then extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was then mixed with silica gel and the solid mixture was purified by silica gel flash column chromatography using ISCO instrument (solid loading, 0%-100% EtOAc/hexane) to give l-(3-bromophenyl)cyclobutanecarbonitrile as a yellow oil. MS (ESI, positive ion) m/z: 236 (M+l).
methyl [2-(3-bromophenyl)-2-cyano]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 2-<strong>[31938-07-5](3-bromophenyl)acetonitrile</strong> (5 g) in tetrahydrofuran (50 mL) was added sodium hydride (3.00 g) portion wise at 23 C. The mixture was heated to 50 C. for 20 minutes. Dimethyl carbonate (8.60 mL) was added dropwise. The mixture was heated at reflux for 2 hours. The mixture was poured into cold and slightly acidic water. The aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through a Buchner funnel and concentrated to give a residue, which was purified by silica gel column chromatography, eluting with 0%-25% dichloromethane/petroleum ether to afford the title compound. MS (LC-MS) m/e 256.0 (M+H)+
To a solution of 2-<strong>[31938-07-5](3-bromophenyl)acetonitrile</strong> (5 g) in tetrahydrofuran (50 mL) was added sodium hydride (3.00 g) portion wise at 23C. The mixture was heated to 50 C for 20 minutes. Dimethyl carbonate (8.60 mL) was added dropwise. The mixture was heated at reflux for 2 hours. The mixture was poured into cold and slightly acidic water. The aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through a Buchner funnel and concentrated to give a residue, which was purified by silica gel column chromatography, eluting with 0%-25% dichloromethane/ petroleum ether to afford the title compound. MS (LC-MS) m/e 256.0 (M+H) +
To a solution of 2-<strong>[31938-07-5](3-bromophenyl)acetonitrile</strong> (5 g) in tetrahydrofuran (50 mL) was addedsodium hydride (3.00 g) portion wise at 23C. The mixture was heated to 50 oc for 20 minutes.10 Dimethyl carbonate (8.60 mL) was added dropwise. The mixture was heated at reflux for 2 hours.The mixture was poured into cold and slightly acidic water. The aqueous layer was extracted withethyl acetate (2 x 200 mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered through a Buchner funnel and concentrated to give a residue,which was purified by silica gel column chromatography, eluting with 0%-25% dichloromethane/15 petroleum ether to afford the title compound. MS (LC-MS) m/e 256.0 (M+H) +
With potassium phosphate;palladium diacetate; johnphos; In 1,2-dimethoxyethane; for 20h;Heating / reflux;
(3-bromo-phenyl)-acetonitrile (5.1g, 25.5mMol) is dissolved in dimethoxyethane (54ml). After addition of piperazine-1-carboxylic acid benzylester (11.4g, 5I mMoI), potassium phosphate (10.8g, 5I mMoI), (2-biphenyl)di-tert butylphosphine (2.28g, 7.6mMol) and palladium-ll- acetate (573mg, 2.55mMol) the mixture is refluxed for 20 hours. After cooling to room temperature the mixture is filtered and the brown filtrate is evaporated in vacuo to give a brown oil. The crude mixture is separated by flash chromatography (gradient of ethyl acetate/hexane 1 :9 to 1 :1) yielding the pure product as a dark yellow oil (M+H+ 336.2).
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