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CAS No. : | 3959-07-7 | MDL No. : | MFCD00047931 |
Formula : | C7H8BrN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XRNVSPDQTPVECU-UHFFFAOYSA-N |
M.W : | 186.05 | Pubchem ID : | 77571 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 41.82 |
TPSA : | 26.02 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.07 cm/s |
Log Po/w (iLOGP) : | 1.82 |
Log Po/w (XLOGP3) : | 1.92 |
Log Po/w (WLOGP) : | 1.76 |
Log Po/w (MLOGP) : | 2.3 |
Log Po/w (SILICOS-IT) : | 2.13 |
Consensus Log Po/w : | 1.99 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.63 |
Solubility : | 0.436 mg/ml ; 0.00234 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.09 |
Solubility : | 1.51 mg/ml ; 0.00813 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.3 |
Solubility : | 0.0941 mg/ml ; 0.000506 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3259 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In dichloromethane at 0 - 20℃; | (c) A solution of Boc2O (1.29g, 5.91mmol) in CH2Cl2 (10ml) was added to a suspension of 4-bromobenzylamine (1.00g, 5.38mmol) and Et3N (0.60g, 5.91mmol) in CH2Cl2 (10ml) for 5min at 0°C with a CaCl2 tube. The reaction mixture was stirred overnight at room temperature. Then, H2O (50ml) was added to the mixture, and the organic layer was separated. The aqueous layer was extracted with CHCl3 (50ml×3). The combined organic layer was washed with H2O (50ml×1) and then brine (50ml×1), dried over Na2SO4 (anhyd), filtered, and concentrated under reduced pressure to afford (4-bromobenzyl)carbamic acid tert-butyl ester (1.63g, quant. y.) as a colorless solid. Colorless powder (n-hexane). Mp 73–74°C. 1H NMR (300MHz/CDCl3) δ 1.46 (9H, s, t-Bu), 4.26 (2H, d, J=6.0Hz, CH2), 4.84 (1H, br s, NH), 7.16 (2H, d, J=8.4Hz, ArH), 7.45 (2H, d, J=8.4Hz, ArH). |
96% | With sodium hydroxide In 1,4-dioxane; water at 20℃; for 12 h; | / Bromobenzylamine (0.93 g, 5 mmol) was dissolved in 1,4-dioxane (20 mL) and was treated with 10percent aq. NaOH (5 mL). To the stirred solution was added (Boc)20 (1.1 g, 5 mmol) dissolved in dioxane (10 mL). The mixture was stirred at room temperature for 12 hours. Water was added (20 mL) and the reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was collected, washed with brine, dried over MgS04, filtered, and the solvent was evaporated to give the product as a white solid (1.37 g, 96percent).1H NMR (400 MHz, CDC13) δ (ppm) 7.44 (d, J= 8.1 Hz, 2H), 7.15 (d, J= 8.0 Hz, 2H), 4.86 (br s, 1H), 4.26 (d, J= 6.1 Hz, 2H), 1.45 (s, 9H). ESI-MS (m/z): 287 [M+2]+. |
95% | at 20℃; for 1 h; | A solution of 4-bromobenzylamine (40.0g, 217.0 mmol) in THF (150 mL) was treated with di-tert-butyl dicarbonate (46.0g, 217 mmol) and stirred at rt for 1 h. The reaction mixture was concentrated in vacuo to afford a solid which was purified bychromatography (80:20 Hexanes: EtOAc) afforded the Boc protected amine (63.0 g, 95percent) as a white solid. A solution of the aryl bromide (30.0g, 98.0 mmol) in DMSO (100 mL) was treated with bis(pinacolato)diboron (30.0g, 118 mmol), KOAc (30.0g, 306 mmol), and PdCl2(dppf) (0.2 mmol) and warmed to 85 °C for 12 h. The reaction mixture was diluted with EtOAc (250 mL) and washed with water (2 x 150 mL) and brine (100 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford a solid which was purification by chromatography (80:20 hexanes: EtOAc) afforded the desired cmpd (31.0 g, yield 97percent) as a white solid. ESI-MS (M+H)+: 334. |
90% | at 20℃; Cooling with ice | Dissolve 10 mL of p-bromobenzylamine (1.0 g, 5.37 mmol) in a 100 mL round bottom flaskIn dichloromethane (DCM),Further, di-tert-butyl dicarbonate ((Boc) 2O (1.29 g, 5.91 mmol)) was gradually added dropwise.The DCM solution was stirred for 5 minutes under ice salt bath conditions and stirred at room temperature overnight.After the reaction was completed, the solvent was evaporated under reduced pressure, and water (40 mL) was added.The organic layer was combined and dried over anhydrous sodium sulfate.Evaporate the solvent and purify it by silica gel column chromatography. Eluent: petroleumEther (PE) / ethyl acetate (EA) = (20:1),A white solid (1.30 g, 90percent) was obtained. |
89% | With sodium carbonate In tetrahydrofuran; water for 12 h; Reflux | General procedure: p-bromobenzamine (1 g, 5.37 mmol) was dissolved in THF:Water 2:5. Boc2O (1.41 g, 6.45 mmol) and Na2CO3 ( 1.67 g, 12.09 mmol) were then added and the mixture was refluxed for 12 h. Extraction was performed with 3x50 mL of EtOAc. The organic phase was dried with Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography using heptane : EtOAc 10:1. Yield: 1.36 g (89percent, 4.79 mmol). 1H-NMR (CDCl3, 400MHz) δ: 7.74 (dt, 2H), 7.18 (d, 2H), 4.28 (d, 2H), 1.48 (s, 9H). 13C-NMR (CDCl3, 400MHz) δ: 156, 138, 132, 129, 121, 80, 44, 28. GC-MS: 285 m/z. Analytical data can be found in literature.2 Tert-butyl-4-bromobenzylcarbamate (400 mg, 1.40 mmol) was dissolved in 10 mL of dry dioxane, potassium acetate (165 mg, 1.68 mmol), bis(pinacolato)diboron (426 mg, 1.68 mmol) and Pd(dppf)Cl2 (10 mg, 0.01 mmol) were added and the reaction was stirred at 100 ºC for 12 h. The mixture was stirred with 10 mL of sat. NaCl aqueous solution for 10 min. and extracted with 3x50 mL EtOAc. The combined organic phases were dried with Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography using heptane : EtOAc 10:1. The pure compound was treated with 2.0 M HCl in diethyl ether and the resulting deprotected HCl salt was filtered off. Yield: 276 mg (73percent, 1.039 mmol). 1H-NMR (CDCl3 400MHz) δ: 7.69 (d, 2H), 7.48 (d, 2H), 4.03 (s, 2H), 1.29 (s, 12H). Analytical data can be found in literature.3 |
89% | With triethylamine In dichloromethane at 0 - 20℃; for 1 h; | General procedure: To a solution of (6chioropyridin3yl)methanamine (3.30 g, 23.1 mmol) inDCM (30 inL) was added TEA (4.84 mL. 34.7 rnmoi) and BOC2O (6.72 mL, 28.9 mrnol), at 0 °C. The resulting mixture was stirred at ambient temperature for iii. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with DCM (3x l0() rnL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Intermediate 2A (5.50 g, 98.0percent) as a yellow oil. ‘H NMR (300 MHz, DMSO-.ck) ö ppm1.38 (s, 9 H), 4,14 (d, J= 6.04 Hz, 2 H), 7.48 (d, J= 7.93 Hz, 2 H), 771 (dd, J= 8.12,2.46 Hz, I H), 8.28 (d, J = 189 Hz, I H). LCMS ,MethodD): retention time 2.31 mm,jM-H1-{i 243. 1. |
78% | With triethylamine In dichloromethane at 0 - 20℃; | General procedure: The hydrogenation of 3-phenylpropylazide (Table 2, entry 1) is given as an example. 3-Phenylpropylazide (3a) (207.2 mg, 1.29 mmol) was charged into an Ar-filled 100 mL glass autoclave equipped with a Teflon-coated magnetic stirring bar. THF (1.2 mL) degassed by three freeze–thaw cycles was introduced via a Teflon cannula, followed by the addition of a solution of the Pd NPs catalyst in DMF (5.0 mM, 20 μL, 0.10 μmol, S/Pd = 12,900:1). Hydrogen was introduced into the reaction vessel until the pressure gauge indicated 8 atm, and then the pressure was carefully released to 1 atm by opening the stop valve. This procedure was repeated five times,and finally hydrogen was pressurized to 8 atm. The vessel was placed in a water bath controlled at 50 °C, and the reaction mixture was vigorously stirred for 16 h. After careful venting of the hydrogen, the reaction mixture was concentrated under reduced pressure. 1,1,2,2-Tetrachloroethane (124.0 mg, 0.739 mmol) was added as an internal standard for the NMR analysis, and the produced 3-phenylpropylamine (4a) was quantified (99.5percent). The reaction mixture was carefully concentrated under reduced pressure to remove THF. To this crude mixture were added dichloromethane (5 mL) and triethylamine (0.45 mL, 3.2 mmol), and the mixture was cooled to 0 °C. Boc2O (726.7 mg, 3.3 mmol) was added at 0 °C, and the solution was stirred at room temperature over night. The reaction mixture was diluted by addition of dichloromethane (10 mL). The solution was washed 3 times successively with water, then once with brine, and dried over magnesium sulfate. After removal of the drying agent by filtration, the solution was concentrated under reduced pressure. The residual oil was purified by silica gel column chromatography (hexane : ethyl acetate = 20:1), giving pure carbamate Boc-4a as a colorless oil (248.3 mg, 87percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrazine hydrate; In methanol; for 1h;Reflux; | (b) The reaction mixture of <strong>[153171-22-3]2-(4-bromobenzyl)isoindole-1,3-dione</strong> (5.01g, 15.83mmol) and H2NNH2·H2O (100%) (1.59g, 31.67mmol) in MeOH (50ml) was stirred for 1h at reflux. After cooling, MeOH was removed under reduced pressure. Concentrated HCl (20ml) was then added and the resulting mixture was stirred for 1.5h at reflux. After cooling, 2N NaOH (200ml) was added to the mixture, and the insoluble matters were removed by filtration. The filtrate was extracted with AcOEt (100ml×3). The combined organic layer was washed with H2O (100ml×1) and then brine (100ml×1), dried over Na2SO4 (anhyd), filtered, and concentrated under reduced pressure to afford 4-bromobenzylamine (2.73g, 14.65mmol, y. 93%) as a yellow oil. 1H NMR (300MHz/CDCl3) delta 3.83 (2H, s, CH2), 7.20 (2H, d, J=8.4Hz, ArH), 7.45 (2H, d, J=8.4Hz, ArH). |
With hydrazine hydrate; In ethanol; at 20℃; for 1h; | To a solution of 2-(4-bromo-benzyl)-isoindole-l ,3-dione (4.1 g, 13.1 mmol, 1.0 eq) in EtOH (50 mL) was added the Nu2 Eta42Omicron (3.3 g, 65.5 mmol, 5.0 eq). The reaction mixture was stirred for 1 h at rt The solvent was evaporated and water was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2S04 and evaporated to give 4-bromo-benzylamine which was used without purified as a white solid (2.83 g, quant). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | at 50℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 0 - 20℃; | (c) A solution of Boc2O (1.29g, 5.91mmol) in CH2Cl2 (10ml) was added to a suspension of 4-bromobenzylamine (1.00g, 5.38mmol) and Et3N (0.60g, 5.91mmol) in CH2Cl2 (10ml) for 5min at 0C with a CaCl2 tube. The reaction mixture was stirred overnight at room temperature. Then, H2O (50ml) was added to the mixture, and the organic layer was separated. The aqueous layer was extracted with CHCl3 (50ml×3). The combined organic layer was washed with H2O (50ml×1) and then brine (50ml×1), dried over Na2SO4 (anhyd), filtered, and concentrated under reduced pressure to afford (4-bromobenzyl)carbamic acid tert-butyl ester (1.63g, quant. y.) as a colorless solid. Colorless powder (n-hexane). Mp 73-74C. 1H NMR (300MHz/CDCl3) delta 1.46 (9H, s, t-Bu), 4.26 (2H, d, J=6.0Hz, CH2), 4.84 (1H, br s, NH), 7.16 (2H, d, J=8.4Hz, ArH), 7.45 (2H, d, J=8.4Hz, ArH). |
96% | With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 12h; | / Bromobenzylamine (0.93 g, 5 mmol) was dissolved in 1,4-dioxane (20 mL) and was treated with 10% aq. NaOH (5 mL). To the stirred solution was added (Boc)20 (1.1 g, 5 mmol) dissolved in dioxane (10 mL). The mixture was stirred at room temperature for 12 hours. Water was added (20 mL) and the reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was collected, washed with brine, dried over MgS04, filtered, and the solvent was evaporated to give the product as a white solid (1.37 g, 96%).1H NMR (400 MHz, CDC13) delta (ppm) 7.44 (d, J= 8.1 Hz, 2H), 7.15 (d, J= 8.0 Hz, 2H), 4.86 (br s, 1H), 4.26 (d, J= 6.1 Hz, 2H), 1.45 (s, 9H). ESI-MS (m/z): 287 [M+2]+. |
95% | In tetrahydrofuran; at 20℃; for 1h; | A solution of 4-bromobenzylamine (40.0g, 217.0 mmol) in THF (150 mL) was treated with di-tert-butyl dicarbonate (46.0g, 217 mmol) and stirred at rt for 1 h. The reaction mixture was concentrated in vacuo to afford a solid which was purified bychromatography (80:20 Hexanes: EtOAc) afforded the Boc protected amine (63.0 g, 95%) as a white solid. A solution of the aryl bromide (30.0g, 98.0 mmol) in DMSO (100 mL) was treated with bis(pinacolato)diboron (30.0g, 118 mmol), KOAc (30.0g, 306 mmol), and PdCl2(dppf) (0.2 mmol) and warmed to 85 C for 12 h. The reaction mixture was diluted with EtOAc (250 mL) and washed with water (2 x 150 mL) and brine (100 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford a solid which was purification by chromatography (80:20 hexanes: EtOAc) afforded the desired cmpd (31.0 g, yield 97%) as a white solid. ESI-MS (M+H)+: 334. |
90% | In dichloromethane; toluene; at 20℃;Cooling with ice; | Dissolve 10 mL of p-bromobenzylamine (1.0 g, 5.37 mmol) in a 100 mL round bottom flaskIn dichloromethane (DCM),Further, di-tert-butyl dicarbonate ((Boc) 2O (1.29 g, 5.91 mmol)) was gradually added dropwise.The DCM solution was stirred for 5 minutes under ice salt bath conditions and stirred at room temperature overnight.After the reaction was completed, the solvent was evaporated under reduced pressure, and water (40 mL) was added.The organic layer was combined and dried over anhydrous sodium sulfate.Evaporate the solvent and purify it by silica gel column chromatography. Eluent: petroleumEther (PE) / ethyl acetate (EA) = (20:1),A white solid (1.30 g, 90%) was obtained. |
89% | With sodium carbonate; In tetrahydrofuran; water; for 12h;Reflux; | General procedure: p-bromobenzamine (1 g, 5.37 mmol) was dissolved in THF:Water 2:5. Boc2O (1.41 g, 6.45 mmol) and Na2CO3 ( 1.67 g, 12.09 mmol) were then added and the mixture was refluxed for 12 h. Extraction was performed with 3x50 mL of EtOAc. The organic phase was dried with Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography using heptane : EtOAc 10:1. Yield: 1.36 g (89%, 4.79 mmol). 1H-NMR (CDCl3, 400MHz) delta: 7.74 (dt, 2H), 7.18 (d, 2H), 4.28 (d, 2H), 1.48 (s, 9H). 13C-NMR (CDCl3, 400MHz) delta: 156, 138, 132, 129, 121, 80, 44, 28. GC-MS: 285 m/z. Analytical data can be found in literature.2 Tert-butyl-4-bromobenzylcarbamate (400 mg, 1.40 mmol) was dissolved in 10 mL of dry dioxane, potassium acetate (165 mg, 1.68 mmol), bis(pinacolato)diboron (426 mg, 1.68 mmol) and Pd(dppf)Cl2 (10 mg, 0.01 mmol) were added and the reaction was stirred at 100 ºC for 12 h. The mixture was stirred with 10 mL of sat. NaCl aqueous solution for 10 min. and extracted with 3x50 mL EtOAc. The combined organic phases were dried with Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography using heptane : EtOAc 10:1. The pure compound was treated with 2.0 M HCl in diethyl ether and the resulting deprotected HCl salt was filtered off. Yield: 276 mg (73%, 1.039 mmol). 1H-NMR (CDCl3 400MHz) delta: 7.69 (d, 2H), 7.48 (d, 2H), 4.03 (s, 2H), 1.29 (s, 12H). Analytical data can be found in literature.3 |
89% | With triethylamine; In dichloromethane; at 0 - 20℃; for 1h; | General procedure: To a solution of (6chioropyridin3yl)methanamine (3.30 g, 23.1 mmol) inDCM (30 inL) was added TEA (4.84 mL. 34.7 rnmoi) and BOC2O (6.72 mL, 28.9 mrnol), at 0 C. The resulting mixture was stirred at ambient temperature for iii. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with DCM (3x l0() rnL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Intermediate 2A (5.50 g, 98.0%) as a yellow oil. ?H NMR (300 MHz, DMSO-.ck) oe ppm1.38 (s, 9 H), 4,14 (d, J= 6.04 Hz, 2 H), 7.48 (d, J= 7.93 Hz, 2 H), 771 (dd, J= 8.12,2.46 Hz, I H), 8.28 (d, J = 189 Hz, I H). LCMS ,MethodD): retention time 2.31 mm,jM-H1-{i 243. 1. |
81.7% | With triethylamine; In dichloromethane; at 20℃; for 2h; | Weigh 10 g of p-bromobenzylamine into a 250 ml single-mouth bottle.50 ml of dichloromethane was added, followed by Et3N (5.98 g) and (Boc) 2 O (12.9 g).The reaction was stirred at room temperature for 2 h. Add 200 ml of water to the reaction system.Extracted with dichloromethane (50 ml × 3), combined with dichloromethane, water,100 ml of saturated brine was washed successively, and the dichloromethane layer was dried over anhydrous sodium sulfate.Filtration and concentration of the organic layer gave a white solid. Dryed to a solid 12.56g,The yield was 81.7%. |
78% | With triethylamine; In dichloromethane; at 0 - 20℃; | General procedure: The hydrogenation of 3-phenylpropylazide (Table 2, entry 1) is given as an example. 3-Phenylpropylazide (3a) (207.2 mg, 1.29 mmol) was charged into an Ar-filled 100 mL glass autoclave equipped with a Teflon-coated magnetic stirring bar. THF (1.2 mL) degassed by three freeze-thaw cycles was introduced via a Teflon cannula, followed by the addition of a solution of the Pd NPs catalyst in DMF (5.0 mM, 20 muL, 0.10 mumol, S/Pd = 12,900:1). Hydrogen was introduced into the reaction vessel until the pressure gauge indicated 8 atm, and then the pressure was carefully released to 1 atm by opening the stop valve. This procedure was repeated five times,and finally hydrogen was pressurized to 8 atm. The vessel was placed in a water bath controlled at 50 C, and the reaction mixture was vigorously stirred for 16 h. After careful venting of the hydrogen, the reaction mixture was concentrated under reduced pressure. 1,1,2,2-Tetrachloroethane (124.0 mg, 0.739 mmol) was added as an internal standard for the NMR analysis, and the produced 3-phenylpropylamine (4a) was quantified (99.5%). The reaction mixture was carefully concentrated under reduced pressure to remove THF. To this crude mixture were added dichloromethane (5 mL) and triethylamine (0.45 mL, 3.2 mmol), and the mixture was cooled to 0 C. Boc2O (726.7 mg, 3.3 mmol) was added at 0 C, and the solution was stirred at room temperature over night. The reaction mixture was diluted by addition of dichloromethane (10 mL). The solution was washed 3 times successively with water, then once with brine, and dried over magnesium sulfate. After removal of the drying agent by filtration, the solution was concentrated under reduced pressure. The residual oil was purified by silica gel column chromatography (hexane : ethyl acetate = 20:1), giving pure carbamate Boc-4a as a colorless oil (248.3 mg, 87%). |
With triethylamine; In dichloromethane; at 20℃; for 16h; | (i) (4-Bromo-benzyl)-carbamic acid tert-butyl ester To a solution of 5 g 4-Bromo-benzylamine and 7 ml NEt3 in 30 ml DCM 5.4 g Boc2O were added. After stirring for 16 h at RT the reaction mixture was concentrated and the precipitate was collected by filtration. The solid product was dried under reduced pressure and was used in the subsequent reaction without further purification. Yield: 6.5 g. | |
In ethanol; at 15 - 25℃;Inert atmosphere; | To a solution of (4-bromophenyl)methanamine (1.0 g, 5.4 mmol) in ethanol (20 mL) was added Boc20 (2.0 g, 6.4 mmol). The resulting mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the resulting residue purified by column chromatography on silica gel (petroleum ether/EtOAc: 4/1) to afford iert-butyl 4- bromobenzylcarbamate. LRMS (ESI) calc'd. for Ci2Hi7BrN02 [M+H]+: 286, found 286. 1H NMR (400 MHz, CDC13): delta 7.44 (d, / = 6.0 Hz, 2H), 7.14 (d, / = 8.4 Hz, 2H), 4.85 (br s, 1H), 4.25 (d, / = 6.0 Hz, 2H), 1.45 (s, 9H). | |
In ethanol; at 20℃;Inert atmosphere; | To a solution of (4-bromophenyl)methanamine (1.0 g, 5.4 mmol) in ethanol (20 mL) wasadded Boc2O (2.0 g, 6.4 mmol). The resulting mixture was stirred overnight at roomtemperature. The solvent was removed in vacuo and the resulting residue was purified by column chromatography on silica gel (pet ether/EtOAc: 4/1) to afford tert-butyl 4- bromobenzylcarbamate. LRMS (ESI) calcd. for C,2H,7BrNO2 [M+H]: 286, found 286. ?H NMR (400 MHz, CDC13): oe 7.44 (d, J= 6.0 Hz, 2H), 7.14 (d, J= 8.4 Hz, 2H), 4.85 (br s, 1H),4.25 (d, J= 6.0 Hz, 2H), 1.45 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In isopropyl alcohol at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 3-chloro-n-propanesulfonyl chloride; 4-Bromobenzylamine With triethylamine In N,N-dimethyl-formamide for 0.666667h; Inert atmosphere; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; | 15 A solution of 4-bromobenzylamine (1.85 g, 10 mmol) and triethylamine (2 g, 20 mmol) in dimethylformamide (30 ml) was treated with 3-chloropropanesulfonyl chloride (1.78 g, 10 mmol) by dropwise addition over 10 minutes with stirring under argon. This mix was stirred for 30 minutes before being treated with a 60% suspension of sodium hydride in mineral oil (1.2 g, 30 mmol of NaH) portionwise and the whole mix stirred at room temperature for 3 days. The reaction mixture was partitioned between water (50 ml) and dichloromethane (30 ml). The organic layer was dried over sodium sulphate and reduced to minimum volume by rotary evaporation. The residue was added to a 20 g pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.72 g, 94%).1H-NMR (400 MHz, CDCl3) δ: 7.49 (2H, m), 7.24 (2H, m), 3.21 (2H, m), 3.13 (2H, s), 3.11 (2H, m), 2.32 (2H, m); LC/MS Retention time 2.68 mins/(ES+) 290 (M+H, C10H1279BrNO2S requires 289). |
94% | Stage #1: 3-chloro-n-propanesulfonyl chloride; 4-Bromobenzylamine With triethylamine In N,N-dimethyl-formamide for 0.666667h; Inert atmosphere; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 72h; | |
94% | Stage #1: 3-chloro-n-propanesulfonyl chloride; 4-Bromobenzylamine With triethylamine In N,N-dimethyl-formamide for 0.666667h; Stage #2: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 72h; | 28 A solution of 4-bromobenzylamine (1.85g, 10mmol) and triethylamine (2g, 20mmol) in dimethylformamide (30ml) was treated with 3-chloropropanesulfonyl chloride (1.78g,10mmol) by dropwise addition over 10 minutes with stirring under argon. This mix was stirred for 30 minutes before being treated with a 60% suspension of sodium hydride in mineral oil (1.2g, 30mmol of NaH) portionwise and the whole mix stirred at room temperature for 3 days. The reaction mixture was partitioned between water (50ml) and dichloromethane (30ml). The organic layer was dried over sodium sulphate and reduced to minimum volume by rotary evaporation. The residue was added to a 2Og pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.72g, 94%).LC/Mass Spec (ES): Found 290 (ES+), retention time 2.68mins. Ci0H1279BrNO2S requires 289. 1 H-NMR (400MHz, CDCI3): 2.32 (2H, m), 3.1 1 (2H, m), 3.21 (2H, m), 3.13 (2H, s), 7.24 (2H, m), 7.49 (2H, m). |
94% | Stage #1: 3-chloro-n-propanesulfonyl chloride; 4-Bromobenzylamine With triethylamine for 0.666667h; Stage #2: With sodium hydride at 20℃; for 72h; | 20 Description 20: 2-[(4-bromophenyl)methyl]isothiazolidine 1,1 -dioxide (D20); A solution of 4-bromobenzylamine (1.85g, lOmmol) and triethylamine (2g, 20mmol) in dimethylformamide (30ml) was treated with 3-chloropropanesulfonyl chloride (1.78g, l Ommol) by dropwise addition over 10 minutes with stirring under argon. This mixture was stirred for 30 minutes before being treated with a 60% suspension of sodium hydride in mineral oil (1.2g, 30mmol of NaH) portionwise and the whole mixture stirred at room temperature for 3 days. The reaction mixture was partitioned between water (50ml) and dichloromethane (30ml). The organic layer was dried over sodium sulphate and reduced to minimum volume by rotary evaporation. The residue was added to a 2Og pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.72g, 94%).1 H-NMR (400MHz, CDCI3) δ: 7.49 (2H, m), 7.24 (2H, m), 4.13 (2H, s) 3.21 (2H, m), 3.11 (2H, m), 2.32 (2H, m); LC/MS Retention time 2.68mins/(ES+) 290 & 292 (M+H, Ci0H12BrNO2S requires 289 & 291 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrakis(2-{(E)-[(2-[(E)-(2-hydroxyphenyl)methylidene]amino}phenyl)imino]methyl}phenol)cobalt(II); ammonia; hydrogen In tetrahydrofuran; lithium hydroxide monohydrate at 120℃; for 24h; Autoclave; | |
91% | With ammonia; hydrogen In methanol at 89.84℃; for 3h; High pressure; | |
91% | With ammonium hydroxide; hydrogen In ethanol at 130℃; for 12h; Autoclave; | 2.4. General procedure of the reductive amination General procedure: The reductive amination of carbonyl compounds was performed in a 50 mL stainless steel autoclave reactor. In a typical run, benzaldehyde (1 mmol), Co(at)NC-800 (20 mg), ethanol (8 mL) and NH3.H2O (26.5 wt%, 2 mL) were charged into the reactor, and then the autoclave reactor was closed. The reactor was flushed with H2 for several times to remove air, and then charged with 1 MPa H2 at room temperature. The reaction was then carriedout at 130 °C for 12 h with a stirring rate of 1000 RPM. After reaction,the reaction mixture was cooled down to room temperature and then depressurized. Then, the products in the reaction mixture were detected by gas chromatography by the use of ethylbenzene as the internal standard. The products were also identified by GC/MS (Shimadzu GCMS-QP2010) equipped with Agilent capillary column DB-5MS. |
86% | With ammonia; hydrogen In <i>tert</i>-butyl alcohol at 120℃; for 15h; | |
86% | With ammonia; hydrogen In methanol at 30℃; for 24h; Autoclave; | |
Multi-step reaction with 2 steps 1: 1) hexamethyldisilazane, BuLi / 1) THF, hexane, 40 min, RT; 2) THF, hexane, 2 h 2: 8 percent / Mg, TiCl4 / tetrahydrofuran / 2.75 h / -70 °C | ||
With ammonia; hydrogen In ethanol at 20℃; for 16h; | 6.ii (ii) General Procedure for the Reduction of Aldehydes using Catalytic Hydrogenation:; A solution ammonia in ethanol (ca. 7N in EtOH, 2.0 ml_) was added to the aldehyde (11) (0.5 mmol). To this solution was added palladium on carbon (10% w/w, 186 mg, 0.05 mmol). The round bottom flask was flushed with hydrogen and then sealed with a rubber septa. The reaction mixture was then stirred for 16 h at room temperature under 1 atmosphere pressure of hydrogen (hydrogen-filled ballon). All volatiles were subsequently removed under reduced pressure. The residue was taken up in MeOH (20 ml_) and filtered. The filtrate was concentrated in vacuo to afford a pale yellow oil, which was subjected to silica gel chromatography (EtOAc/hexanes/Et3lM) to afford the primary carbinamine (8c).8c isolated as a clear, colorless oil. 1H NMR (CDCI3, 300 MHz) δ 7.42 (2H, d, J = 8.0 Hz), 7.22 (2H, d, J = 8.0 Hz), 3.95 (2H, H), 1.70 (2H, br s). | |
Multi-step reaction with 3 steps 1: sodium tetrahydridoborate / methanol / 1 h / 0 - 20 °C 2: glacial acetic acid; hydrogen bromide / 0.5 h / 0 °C 3: ammonia / ethanol; lithium hydroxide monohydrate / 4 h / 20 °C | ||
Multi-step reaction with 3 steps 1: sodium tetrahydridoborate / methanol / 1 h / 0 - 20 °C 2: hydrogen bromide / glacial acetic acid / 0.5 h / 0 °C 3: ammonium hydroxide / ethanol / 4 h / 20 °C | ||
93 %Chromat. | With ruthenium; ammonia; hydrogen In methanol at 89.84℃; for 2h; | |
95 %Chromat. | With ammonia; hydrogen In <i>tert</i>-butyl alcohol at 120℃; for 24h; Autoclave; High pressure; | |
With ammonium hydroxide; hydrogen at 130℃; for 20h; | ||
With ammonium hydroxide; hydrogen In methanol at 90℃; for 6h; Autoclave; Sealed tube; | ||
With ammonia; hydrogen In isopropanol at 100℃; for 16h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; | 4-Bromobenzylamine hydrochloride (1. 11 g) is dissolved in water (25 mL). The solution is adjusted to pH 12 with 2 [NNAOH] and extracted with CH2Cl2 (25 [ML).] The organic layer is concentrated in vacuo and the resulting free base is combined with ethyl 2-((((2R)-2-hydroxy-2-pyridin-2-ylethyl((methyl)amino)methyl)-7-methyl-4-oxo- 4,7-dihydrothieno [2, 3-b]pyridine-5-carboxylate (Preparation 55,0. 200 g) and heated to [190 C FOR] 1 h. The reaction [MIXTURE] is allowed to cool for several minutes and toluene (150 mL) is added. The mixture is concentrated in vacuo. The resulting residue is dissolved in [CH2C12] (50 mL) and washed with water [(50] mL). The organic layer is dried [(MGSO4),] filtered, and concentrated in vacuo. The crude product is purified by column chromatography (CH2Cl2/methanol, 99/1; 98/2 ; 97/3) followed by recrystallization from EtOAc to yield [0.] 061 g of the title compound as a white solid. Physical characteristics. M.p. 151-153 C; 1H NMR (400 MHz, DMSO-d6) delta 10.61, 8.69, 8.47-8.46, 7.79-7.76, 7.54-7. 48, 7.29-7.24, 7.19-7.14, 5.37, 4.83-4.79, 4.53, 3.92, 3.89-3.81, 2.84-2.80, 2.72-2.67, 2.32; MS (ESI+) m/z 541(M + H)+. ANAL. Found: C, 55.11 ; H, 4.42 ; N, 10.24 ; Br, 14.60; S, 5.85. | |
With sodium hydroxide; In water;pH 12.0; | <strong>[26177-44-6]4-bromobenzylamine hydrochloride</strong> (5 g) was dissolved in water (100 mL); adjusted to pH 12 with NaOH solution, and the mixture extracted with DCM, dried and evaporated to give the free base as a clear oil (2.5 g). 1-(Phenylsulfonyl)-1H-indole-2-sulfonyl chloride (2 g) was dissolved in DCM (40 mL) and cooled in a water bath. 4-Bromobenzylamine (2.5 g) was added, followed by pyridine (1 mL) and the mixture stirred overnight. The mixture was poured into acidified water (250 mL) and extracted with ethyl acetate (200 mL). The organic was washed with water (4 x 200 mL), dried and evaporated to an oil and crystallised from ether / petrol to give the title compound as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine In dichloromethane at 0 - 20℃; | 1. Typical procedure of preparation of N-benzylacetamide General procedure: To a stirring solution of benzylamine (4.29 g, 40 mmol), Et3N (4.45 g, 45 mmol) in CH2Cl2 (45 mL), was added acetyl chloride (3.53 g, 45 mmol) at 0 °C (ice/water bath). The reaction mixture was stirred at 0 °C for 10 minutes. Then, the reaction mixture was stirred at room temperature overnight. After the completion, the mixture was washed with NaHCO3 (3 times) and brine, and dried over MgSO4. Then, the organic layer was concentrated and recrystallized from PE-EtOAc (v/v=6/1), affording the N-benzylacetamide (1a) (5.13 g, yield 86%). |
76% | With triethylamine In tetrahydrofuran; dichloromethane at 0℃; for 3h; | N-(4-bromobenzyl)acetamide (14) To the solution of (4-bromophenyl)methanamine (114 mg, 0.613 mmol) in dry DCM (2 mL) and dry THF (1 mL) was added trimethylamine (342 µL, 2.464 mmol). To the resulting mixture was added acetyl chloride dropwise at 0 . The mixture solution was stirred for 3 h and concentrated under a vacuum. To the residue was added DCM (20 mL), and the organic phase was washed twice with 1 N hydrochloric acid (9 mL) and saturated sodium chloride aqueous solution (10 mL). The combined organic layers were dried over Na2SO4, concentrated in a vacuum and purified by column chromatography (silica gel, DCM MeOH = 200 : 1) to give compound 14 (106 mg, 76% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 5.89 (s, 1H), 4.39 (d, J = 5.8 Hz, 2H), 2.03 (s, 3H). ESI-MS: m/z 228.0 [M+H]+. |
15.a EXAMPLE 15 N-Butyloxycarbonyl-3- [4-(N-acetylaminomethyl)phenyl]-5-iso-butylthio- phene-2-sulfonamide (a) 3- [4- (N-ACETYLAMINOMETHYL) PHENYL]-5-ISO-BUTYL-N-TERT-BUTYLTHIOPHENE- 2-sulfonamide To a nitrogen-flushed solution OF PD (OAC) 2 (17.5 mg, 0. 078 mmol) in DME (2 mL), was added triphenylphosphine (82 mg, 0.312 mmol). The solution was flushed with nitrogen again and stirred under a N2 atmosphere for 30 minutes. The brownish suspension was transferred to a nitrogen-flushed mixture of 5-ISO-BUTYL-2- (N-TERT-BUTYLAMINOSULFONYL) thiophene-3-boronic acid (0.50 g, 1.56 mmol, see Preparation A, step (c)), N-(4- bromobenzyl) acetamide (0.71 g, 3.12 mmol, prepared form 4- BROMOBENZYLAMINE and acetyl chloride), and potassium carbonate (0. 86 g, 6.24 mmol) in DME: H20 : EtOH (3.5 : 1.5 : 1 mL). The mixture was refluxed overnight under a N2 atmosphere, washed with aqueous NAOH solution (1M), water and brine, dried over anhydrous MGS04 and concentrated to afford the residue which was purified by circular chromatography (50% acetone in pet. ether) to afford pure sub-title product as a colourless solid (0.43 g, 65%). mp 171-172oC H NMR (270 MHz, CDC13) : 8 0.97 (d, 6H, J= 6.60 Hz), 1.0 (s, 9H), 1.91 (M, 1H), 2.07 (s, 3H), 2.67 (d, 2H, J = 6. 93 HZ), 4.47 (d, 2H, J = 5. 61 Hz), 6.20 (br s, 1H), 6.73 (s, 1H), 7.37 (d, 2H, J = 7.92 Hz), 7.53 (d, 2H, J = 7.92 Hz) 13C NMR (67.5 MHz, CDCl3) : 6 22.13, 23.21, 29. 48, 30.50, 39. 169 43. 28, 54. 51, 127. 76, 128. 94, 129.25, 133. 88, 136. 11, 138.61, 143.14, 148. 53, 170. 18 IR (neat, cm-1): v 3314,2963, 1650,1535, 1432, 1308, 1136,1049, 1009, 844 MS (ESI+) : INLZ at 423.1 (MI++1) Anal. Calcd for C2LH30N203S2 : C, 58. 44; H, 7.24 ; N, 6.49 ; Found: C, 58.1 ; H, 7.0 ; N, 6.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With 4-methyl-morpholine; In dichloromethane; | EXAMPLE 48 N-(4-Bromophenylmethyl)-3-(4'-trifluoromethylbiphenyl-2-carbonylamino)-benzoic acid amide Prepared analogously to Example 7 from 3-(4'-trifluoromethylbiphenyl-2-carbonylamino)-benzoic acid and 4-bromobenzylamine in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine. Yield:51% of theory Rf value:0.64 (silica gel; dichloromethane/ethanol=9:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 19h; | 3.1 A solution of 4-bromobenzylamine (5g, 26.9mmol) in THF (50ml) and water (50ml) was cooled down to O0C with sodium hydroxide (1.13g, 28.2mmol). Benzyl chloroformate (4.0ml, 28.2mmol) was added slowly and the reaction mixture was stirred at O0C for 1h and at r.t. for 18 hours. Brine (50ml) and EtOAc (5OmL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (4OmL). The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to yield a light pink solid (9.27g, 100%). 1H NMR (300 MHz, CDCI3), δ: 4.34 (2 H, d, J=6.0 Hz, CH2NH), 5.14 (2 H, s, OCH2), 7.17 (2 H, d, J=8.1 Hz, Ar), 7.33 - 7.40 (5 H, m, Ar), 7.46 (2 H, d, J=8.3 Hz, Ar) |
82% | In toluene at 20℃; for 4 - 6h; | 4 To a stirred suspension of 4-bromobenzyl amine 56 (1 equiv.) and sodium carbonate (1.5 equiv.) in anhydrous toluene at room temperature was added ethyl or benzyl chloroformate.Stirring was continued for 4-6 hours at the same temperature, insoluble materials were filtered off, and the filtrate was washed with water and dried over MgSO-I. Solvent evaporation under reduced pressure and purification by flash column chromatography on silica gel (diethyl ether-hexane) gave pure product (57.1 or 57.2 respectively) in 82-90% yields.Selected data of synthesized carbamates (57). (4-Bromobenzyl)carbamic acid benzyl ester (57.2).1H NMR (500 MHz5 CDCl3) δ 7.44 (d, J = 7.7 Hz5 2H), 7.38-7.30 (m, 5H), 7.16 (d, J = 7.7 Hz, 2H), 5.13 (s, 2H), 5.09 (br s, IH, NH), 4.32 (d, J = 5.5 Hz, 2H). |
With sodium carbonate In toluene at 20℃; for 4 - 6h; | To a stirred suspension of 4-bromobenzyl amine 56 (1 equiv.) and sodium carbonate (1.5 equiv.) in anhydrous toluene at RT was added ethyl or benzyl chloroformate. Stirring was continued for 4-6 hours at the same temperature, insoluble materials were filtered off, and the filtrate was washed with water and dried over MgSO4. Solvent evaporation under reduced pressure and purification by flash column chromatography on silica gel (diethyl ether-hexane) gave pure product (57.1 or 57.2 respectively) in 82-90% yields. |
23 g | With sodium carbonate In tetrahydrofuran; water at 0 - 25℃; for 2h; | 22.1 Step 1: preparation of benzyl N-[(4-bromophenyl)methyl]carbamate (compound 22a) To a solution of 4-bromobenzylamine (20.00 g, 107.50 mmol) and sodium carbonate (34.18 g, 322.49 mmol) in THF/ water (450 mL, v/v = 2/1) was added benzyl chloroformate (36.68 g, 215.00 mmol) at 0 °C. After being stirred at 25 °C for 2 hrs, the reaction mixture was quenched by addition of water (200 mL) and extracted with EA (200 mL) twice. The combined organic layer was dried over Na2S04, filtered and concentrated. The residue was purified by flash column (EtO Ac/isohexane = 30%) to give compound 22a (23.00 g) as a white solid. MS: calc’d 320 (MH+), measured 320 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | A mixture of 4-bromobenzylamine (0.99Og, 5.32mmol), DIEA (0.84mL, 4.84mmol) and DMAP (0.01 Og, 0.08mmol) in dry dichloromethane (3OmL) were stirred nitrogen at O0C. 2-Methoxybenzene sulfonyl chloride (1.0Og, 4.84mmol) was added and the reaction mixture slowly warmed up to room temperature for overnight. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/hexanes, 1 : 1) to yield 1.707g (99%) of [(4-bromophenyl)methyl][(2- methoxyphenyl)sulfonyl]amine (43) as a white solid. MS (M+H)+ 356, 358; (M-H)" 354, 356 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;acetic acid; In ethanol; for 2h;Reflux; | To a solution of methyi-4-oxo-tetrahydrofuro-3-carboxylate (1.0 g, 6.94 mmol) in ethanol (16 niL) was added 4-bromobenzylamme (1.621 g5 7.29 mmol) followed by triethylamine (0.919 niL, 6.59 mmol) and acetic acid (0.119 mL, 2.082 mmol). The mixture was refluxed for 2 h. The mixture was concentrated in vacuo, taken up in EtOAc (30 mL) and water (30 mL). The <n="35"/>organic layer was then washed with saturated NaHCC>3 (20 mL). The aqueous layer was then extracted with EtOAc (3 x 40 mL) and the combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and concentrated in vacuo to give a brown oil which solidified over time to an oily brown solid, which was taken on crude to the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine In dichloromethane at 20℃; Cooling with ice; Inert atmosphere; | 25 A solution of 4-bromobenzylamine (2.50 g, 13.5 mmol) and triethylamine (14.9 mmol, 1.5 g, 2.1 ml) in dichloromethane (50 ml) was cooled in an ice bath with stirring under argon. Methanesulfonyl chloride (1.55 g, 13.7 mmol, 1.05 ml) was added dropwise and the resulting mix was allowed to warm up to room temperature and stirred for 1 hour. The reaction mix was washed 3 times with water (20 ml) and the organic layer deied over sodium sulphate and reduced to minimum volume under reduced pressure to give the title compound as a colourless solid (3.45 g, 97%).1H-NMR (400 MHz, CDCl3) δ: 7.51 (2H, m), 7.25 (2H, m), 4.67 (1H, m), 4.29 (2H, d, J=6 Hz), 2.90 (3H, s); LC/MS Retention time 2.39 mins/(ES-) 262 & 264 (M-H, C8H10BrNO2S requires 263 & 265). |
95% | With pyridine at 0℃; for 1h; | 4.1 Step 1 Step 1: To a stirred solution of No.78 (4-bromophenyl)methanamine (500 mg, 2.687 mmol) in No.64 pyridine were added No.47 methanesulfonyl chloride (0.4 mL, 5.106 mmol) at 0° C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. No.79 N-(4-bromobenzyl)methane-sulfonamide (675 mg) was obtained in 95% yield.[0419]Step 2: To a stirred solution of No.79 N-(4-bromobenzyl)methanesulfonamide (675 mg, 2.555 mmol) in No.56 dimethylformamide were added No.81 ethyl 2-chloropropionate (0.42 mL), No.82 manganese (280 mg) and No.83 (2,2′-bipyridine)nickel(II)-dibromide (67 mg, 0.17885 mmol). No.84 Trifluoroacetic acid (2 drops) was added. The reaction mixture was stirred for 36 h at 60° C. After cooling down to room temperature, the mixture was hydrolysed by 1N No.85 HCl and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to obtain No.86 ethyl 2-(4-(methylsulfonamidomethyl)phenyl)propanoate (325 mg).[0420]Step 3: To a stirred solution of No.86 ethyl 2-(4-(methylsulfonamidomethyl)phenyl)propanoate (325 mg, 1.139 mmol) in co-solvent with No.27 tetrahydrofuran and No.37 water (1:1) were added No.88 sodium hydroxide (114 mg, 2.8475 mmol). The reaction mixture was refluxed for 16 h, then cooled to room temperature, acidified to pH 3-4 with acetic acid. The residue dissolved in No.43 ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to give No.89 2-(4-(methylsulfonamidomethyl)phenyl)propanoic acid (74 mg, 25%).[0421]Step 4: To a stirred solution of No.89 2-(4-(methylsulfonamidomethyl)phenyl)propanoic acid (60 mg, 0.233 mmol) and No.36 (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (62 mg, 0.233 mmol) in No.71 acetonitrile were added No.33 N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (67 mg, 0.349 mmol), No.34 1-hydroxybenzotriazole (47 mg, 0.349 mmol) and No.35 triethylamine (0.08 mL, 0.582 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in No.43 ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to obtain No.91 2-(4-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 4) (81 mg, 69%).[0422]1H NMR (300 MHz, CDCl3) 7.75 (d, 1H, J=8.07 Hz, Ar), 7.57 (d, 1H, J=8.07 Hz, Ar), 7.26 (m, 8H, Ar), 5.54 (t, 1H, NH), 4.63 (t, 1H, NH), 4.45 (d, 2H, CH2), 4.30 (d, 2H, CH2), 3.50 (q, 1H, CH), 2.91 (s, 3H, mesyl), 2.38 (s, 3H, methyl), 1.47 (d, 3H, methyl). |
95% | With pyridine at 0℃; for 1h; | 4.1 Step 1 : To a stirred solution of (4-bromophenyl)methanamine (500 mg, 2.687 mmol) in pyridine were added methanesulfonyl chloride (0.4 mL, 5.106 mmol) at 0 °C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(4-bromobenzyl)methane- sulfonamide (675 mg) was obtained in 95 % yield. |
95% | With pyridine at 0℃; for 1h; | B5.1 Step 1 : To a stirred solution of (4-bromophenyl)methanamine (500 mg, 2.687 mmol) in pyridine were added methanesulfonyl chloride (0.4 mL, 5.106 mmol) at 0°C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried (MgSO4) and filtered. The solvent removed in vacuo. The crude was purified by CC. N-(4-bromobenzyl)methanesulfonamide (675 mg) was obtained (95 % yield). |
93% | With pyridine at 0℃; for 1h; | 6.1 Step 1: (4-Bromophenyl)methanamine (500 mg, 2.687 mmol) was dissolved in pyridine (5 mL) and methanesulfonyl chloride (0.4 mL, 5.106 mmol) was added to the solution at 0° C. The mixture was stirred for 1 h at 0° C. Then, the mixture was quenched with 1N HCl solution and extracted with ethyl acetate. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography (silica gel: 100-200 mesh, eluent: n-hexane/etyl acetate 1:1) gave N-(4-bromobenzyl)methanesulfonamide in pure form (663 mg, 93%). |
93% | With pyridine at 0℃; for 1h; | 6.1 Step 1 : (4-Bromophenyl)methanamine (500 mg, 2.687 mmol) was dissolved in pyridine (5 ml_) and methanesulfonyl chloride (0.4 ml_, 5.106 mmol) was added to the solution at 0 °C. The mixture was stirred for 1 h at 0 °C. Then, the mixture was quenched with 1 N HCI solution and extracted with ethyl acetate. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography (silica gel: 100 - 200 mesh, eluent: n- hexane / etyl acetate 1 :1 ) gave N-(4-bromobenzyl)methanesulfonamide in pure form (663 mg, 93 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tert.-butylhydroperoxide; 2,3-dicyano-5,6-dichloro-p-benzoquinone In toluene at 90 - 95℃; for 9.5h; | |
88% | With tert.-butylhydroperoxide; ammonium cerium (IV) nitrate In water; acetonitrile at 80 - 85℃; for 7h; Inert atmosphere; | |
87% | With tert.-butylhydroperoxide In water; acetonitrile at 70 - 75℃; for 6h; | General procedure for the synthesis of 2-phenylquinazolines: General procedure: To a magnetically stirred 2-amino benzo/acetophenone (1.0 mmol) in acetonitrile (10 mL), benzylamine (2.5 mmol), graphite oxide 10 wt % (with respect to 2-amino benzo/acetophenone), and TBHP (200 μL of 70 % aqueous solution) were added at 70-75 ° C until the reaction goes for completion as indicated by TLC. After completion of the reaction, the catalyst was separated by filtration and washed with water for reuse. The reaction mixture was concentrated to remove acetonitrile. After evaporation of the solvent under reduced pressure, the crude residue was extracted with ethylacetate and the combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, evaporated to get crude product and purified by column chromatography by using hexane and ethylacetate (9:1) as eluent to give the titled compound 2-phenylquinazoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol at 20℃; for 1h; | 3 To lOg of montelukast acid from Example 1, 200ml of methanol was introduced, and the mixture was stirred. At room temperature, to the resultant product, 3.2g of 4-bromo benzylamine was introduced, followed by stirring for 1 hour. Then, methanol was vacuum-concentrated, and 100ml of isopropyl alcohol was introduced, followed by stirring. When crystallized, the reaction mixture was heated up to 50°C Then, the reaction mixture was stirred while 100ml of normal hexane was dropped into it. The resultant product was stirred at 50°C for 3 hours, gradually cooled to room temperature, further stirred for 3 hours, and f i ltered. Through vacuum-drying at 50°Cfor 12 hours, 10.9g of montelukast 4-bromo benzylamine salt was obtained (yield: 88%, purity: 98.3%, HPLC wavelength: 238nm, Phenyl column, 4.6X250mm, moving phase A: 0.1% TFA in water, B: 0.1% TFA in ACN, flowing at 6:4 to 1:9 for 20min at a flow rate 1.5mL/min). H-NMR(300MHz, CDC13) δ (ppm) : 8.13(d, 1H), 8.04(d, 1H), 7.79-7.61(m, 4H),7.51~7.08(m, 13H), 4.01(t, 1H), 3.83(s, 2H), 3.22-3.14(m, 1H), 2.98~2.91(m, 1H), 2.73(d, 1H), 2.62-2.16(m, 5H) , 1.63(d, 6H) , 0.58~0.46(m, 4H) | |
9.3 g | In methanol; hexane at 20℃; | 3 Example 3 Preparation of 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-bromo benzylamine salt Example 3 Preparation of 1-(((1(R)-(3-(2-(7-chloro-2-quinolinil)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid 4-bromo benzylamine salt To 10 g of montelukast acid from Example 1, 200 ml of methanol was introduced, and the mixture was stirred. At room temperature, to the resultant product, 3.2 g of 4-bromo benzylamine was introduced, followed by stirring for 1 hour. Then, methanol was vacuum-concentrated, and 100 ml of isopropyl alcohol was introduced, followed by stirring. When crystallized, the reaction mixture was heated up to 50° C. Then, the reaction mixture was stirred while 100 ml of normal hexane was dropped into it. The resultant product was stirred at 50° C. for 3 hours, gradually cooled to room temperature, further stirred for 3 hours, and filtered. Through vacuum-drying at 50° C. for 12 hours, 10.9 g of montelukast 4-bromo benzylamine salt was obtained (yield: 88%, purity: 98.3%, HPLC wavelength: 238 nm, Phenyl column, 4.6*250 mm, moving phase A: 0.1% TFA in water, B: 0.1% TFA in ACN, flowing at 6:4 to 1:9 for 20 min at a flow rate 1.5 mL/min). 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.13 (d, 1H), 8.04 (d, 1H), 7.797.61 (m, 4H), 7.517.08 (m, 13H), 4.01 (t, 1H), 3.83 (s, 2H), 3.223.14 (m, 1H), 2.982.91 (m, 1H), 2.73 (d, 1H), 2.622.16 (m, 5H), 1.63 (d, 6H), 0.580.46 (m, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation; | General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium carbonate / tetrahydrofuran; water / 12 h / Reflux 2: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 12 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Cooling with ice; | -tert-butyl 2-((4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-l-carboxylate An ice-cooled mixture of (2S,4R)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (commercially available from for example Aldrich) (7.95 g, 34 mmol) and (4- bromophenyl)methanamine (commercially available from for example Fluorochem) (6.4 g, 34 mmol) in DMF (200 mL) was treated with DIPEA (18 mL, 103 mmol) and then with HATU (14.4 g, 38 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The mixture was treated with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic phase was washed with saturated aqueous sodium bicarbonate (2 x 300 mL), water (100 mL), brine (200 mL), dried over magnesium sulfate and evaporated to dryness. The product was purified by flash chromatography (750 g silica cartridge) using a gradient elution from 0% to 10% methanol in dichloromethane to afford the title compound (12.9 g, 94% yield). LCMS RT= 0.87 min, ES+ve m/z 401 [M+H]+. |
94% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Cooling with ice; | (2S,4R)-tert-butyl 2-(( 4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate An ice-cooled mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (commercially available from for example Aldrich) (7.95 g, 34.4 mmol) and (4- bromophenyl)methanamine (commercially available from for example FluroChem) (6.4 g, 34.4 mmol) in DMF (200 mL) was treated with DIPEA (18.02 mL, 103 mmol) and then with HATU (14.39 g, 37.8 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 x 300 mL), water (100 mL), brine (200 mL), dried over magnesium sulphate and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution from 0% to 10% methanol in DCM to afford the title compound (12.9 g, 32.3 mmol, 94% yield). LCMS RT= 0.87 min, ES+ve m/z 399.2/401.2 [M+H]+. |
94% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h; Cooling; | (2S,4R)-tert-butyl 2-((4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate An ice-cooled mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (commercially available from for example Aldrich) (7.95 g, 34 mmol) and (4-bromophenyl)methanamine (commercially available from for example Fluorochem) (6.4 g, 34 mmol) in DMF (200 mL) was treated with DIPEA (18 mL, 103 mmol) and then with HATU (14.4 g, 38 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The mixture was treated with water (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with saturated aqueous sodium bicarbonate (2×300 mL), water (100 mL), brine (200 mL), dried over magnesium sulfate and evaporated to dryness. The product was purified by flash chromatography (750 g silica cartridge) using a gradient elution from 0% to 10% methanol in dichloromethane to afford the title compound (12.9 g, 94% yield). LCMS RT=0.87 min, ES+ve m/z 401 [M+H]+. |
94% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Cooling with ice; | (25,47?) -ieri-Butyl 2-((4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-l-carboxylate (25,47?) -ieri-Butyl 2-((4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-l-carboxylate An ice-cooled mixture of (25,4fi)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (commercially available from for example Aldrich) (7.95 g, 34 mmol) and (4- bromophenyl)methanamine (commercially available from for example FluroChem) (6.4 g, 34 mmol) in DMF (200 mL) was treated with DIPEA (18 mL, 103 mmol) and then with HATU (14.4 g, 38 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 x 300 mL), water (100 mL), brine (200 mL), dried over magnesium sulphate and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution from 0% to 10% methanol in DCM to afford the title compound (12.9 g, 32 mmol, 94% yield). LCMS RT= 0.87 min, ES+ve m/z 399.2/401.2 [M+H]+. |
94% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h; Cooling with ice; | (2S,4R)-tert-Butyl 2-((4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate An ice-cooled mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (commercially available from for example Aldrich) (7.95 g, 34.4 mmol) and (4-bromophenyl)methanamine (commercially available from for example FluroChem) (6.4 g, 34.4 mmol) in DMF (200 mL) was treated with DIPEA (18.02 mL, 103 mmol) and then with HATU (14.39 g, 37.8 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2×300 mL), water (100 mL), brine (200 mL), dried over magnesium sulphate and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution from 0% to 10% methanol in DCM to afford the title compound (12.9 g, 32.3 mmol, 94% yield). LCMS (Method A) RT=0.87 min, ES+ve m/z 399.2/401.2 [M+H]+. |
94% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Cooling with ice; | (2S,4R)-tert-butyl 2-((4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (2S,4R)-tert-butyl 2-((4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate An ice-cooled mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (Aldrich) (7.95 g, 34 mmol) and (4-bromophenyl)methanamine (Fluorochem) (6.4 g, 34 mmol) in DMF (200 mL) was treated with DIPEA (18 mL, 103 mmol) and then with HATU (14.4 g, 38 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The mixture was treated with water (200 mL) and extracted with ethyl acetate (2*200 mL). The combined organic phase was washed with saturated aqueous sodium bicarbonate (2*300 mL), water (100 mL), brine (200 mL), dried over magnesium sulfate and evaporated to dryness. The product was purified by flash chromatography (750 g silica cartridge) using a gradient elution from 0% to 10% methanol in dichloromethane to afford the title compound (12.9 g, 94% yield). LCMS RT=0.87 min, ES+ve m/z 401 [M+H]+. |
77% | Stage #1: (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 0.5h; Inert atmosphere; Stage #2: 4-Bromobenzylamine In N,N-dimethyl-formamide at 0 - 25℃; for 0.5h; Inert atmosphere; | Ligase 1a: tert-butyl (2S,4R)-2-[(4-bromophenyl)methylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate To a solution of N-Boc-4-hydroxy-L-proline (60 g, 259.46 mmol, 1.0 eq), N,N-diisopropylethylamine (135.58 mL, 778.38 mmol, 3.0 eq) in DMF (500 mL) was added O- (7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (118.39 g, 311.35 mmol, 1.2 eq) at 25 °C. After stirring for 0.5 h, 4-bromobenzylamine (53.1 g, 285.41 mmol, 1.1 eq) was added to the mixture at 0 °C. Then the mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated sodium bicarbonate, water and brine, then dried over anhydrous sodium sulfate and evaporated to dryness. The product was triturated in methyl tert-butyl ether (500 mL) to afford the title compound (80 g, 201 mmol,77% yield) as a yellow solid. MS (ESI): 421.0 ([M+Na]+). |
Stage #1: 4-Bromobenzylamine; (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With iron(III) chloride; 3-methyl-4-oxa-5-azahomoadamantane; oxygen In water at 100℃; for 10h; | Typical procedure for oxidative synthesis of benzimidazoles, benzoxazolesor benzothiazoles General procedure: A mixture of 1.2 mmol o-phenylenediamine, 2-aminophenol or 2-aminothiophenol and 1 mmol primary amine, 10 mol % FeCl3, 1 mol % 3-methyl-4-oxa-5-azahomoadamantane, 5 ml H2O were mixed in a 10-ml three-necked flask, then O2 was bubbled into the flask at flow rate of 20 ml/min. The reaction mixture was stirred at 100 C for several hours, and reaction progress was monitored by TLC. The final reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was directly purified by column chromatography on silica gel using hexane/ethyl acetate (7:3) as eluent to afford the pure product. |
91% | With 2,2,6,6-tetramethyl-piperidine-N-oxyl; ferric nitrate In neat (no solvent) at 110℃; for 24h; Green chemistry; | |
90% | With 4-tert-butyl-5-methoxy-1,2-benzoquinone; oxygen; toluene-4-sulfonic acid In acetonitrile at 60℃; for 24h; Schlenk technique; |
85% | With tert.-butylhydroperoxide In water at 100℃; for 6h; | Experimental General procedure: A mixture of 1.5 mmol aromatic amines, 1 mmol o-phenylenediamine, and 4 mmol TBHP were prepared in a 10-ml, three-necked flask, stirred at 100 °C for several hours, and the reaction progress was monitored by TLC. After completionof the reaction, the reaction mixture was cooled to room temperature. The pure product was isolated after a simple filtration. When necessary, the crude product was purified by chromatography using hexane/ethyl acetate (7:3) as eluent. |
85% | With iron(III) sulfate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In neat (no solvent) at 110℃; for 24h; Green chemistry; | Typical procedure for aerobic oxidative synthesisof benzimidazoles, benzoxazoles, or benzothiazoles General procedure: A mixture of 6 mmol of the alcohol or the amine and5 mmol o-phenylenediamine, o-aminophenol or o-aminothiophenol,10 mol % Fe2(SO4)3, 10 mol % TEMPO wasprepared in a 10 ml three-necked flask, and then stirred inopen air at 110 °C for several hours, The reaction progresswas monitored by TLC. When the final reaction mixturecooled to room temperature, the crude products was directlypurified by column chromatography on silica gel using hexane/ethyl acetate (7:3) as eluent to afford the pure product. |
84% | With Al cations incorporated into the Si framework; open air In neat (no solvent) at 100℃; for 15h; Green chemistry; | |
83% | With copper(ll) bromide In toluene at 100℃; for 24h; | |
65% | With phosgene; oxygen In toluene at 110℃; for 24h; | |
With copper(ll) bromide In toluene at 100℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With iodine; triethylamine; In dimethyl sulfoxide; at 120℃; for 3h; | A round bottom flask was charged with <strong>[211693-73-1]2,3-difluoro-6-nitroaniline</strong> (0.50 g, 2.87 mmol, 1.00 equiv.) and 4-bromobenzylamine (0.959 g, 5.15 mmol, 1.80 equiv.). Dimethyl sulfoxide (2.5 mL) was then added flowed by Et3N (0.968 mL, 6.88 mmol, 2.40 equiv.) and I2 (catalytic, 10 mg). The reaction mixture was heated to 120 C. and stirred for 3 h. The reaction mixture was then cooled to ambient temperature, diluted with water (75 mL) and extracted with Ethyl acetate (2*60 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude material, which was purified by silica gel column chromatography (10% ethyl acetate/hexane) to afford compound 3 as the desired product (0.869 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 89% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); palladium(II) hydroxide; In water; butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; Sealed tube; | Step 8: (4-bromophenyl)methanamine (1.00 g, 5.37 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). K3P04 (2.28 g, 10.75 mmol), Pd2(dba)3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added in under N2. The reaction mixture was sealed in a pressure tube and heated up to 125C for lh. After cooling down the reaction to RT, the mixture was poured into the water and extracted by lOOmL x 3 EA. The combined organic layer was washed with brine, dried over Na2SCand concentrated under the vacuum to give the crude product. The solid was purified by silicone gel column with 10% MeOH (containing ~2N N) in DCM to get the pure (4-(2-memylpyridin-4-yl)phenyl)methanamine (yield ~ 89%). MS m/z 199.1 (M + 1). |
Ca. 89% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; Sealed tube; | (4-bromophenyl)methanamine (1.00 g, 5.37 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). K3P04 (2.28 g, 10.75 mmol), Pd2(dba)3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added in under N2. The reaction mixture was sealed in a pressure tube and heated up to 125C for lh. After cooling down the reaction to RT, the mixture was poured into the water and extracted by 1 OOmL x 3 EA. The combined organic layer was washed with brine, dried over Na2S04, and concentrated under the vacuum to give thecrude product. The solid was purified by silicone gel column with 10% MeOH (containing ~2N NH3) in DCM to get the pure (4-(2-methylpyridin-4-yl)phenyl)methanamine (yield ~ 89%). MS m/z 199.1 (M + |
Ca. 89% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; Sealed tube; | 4-bromophenyl)methanamine (1.00 g, 5.37 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). K3PO4 (2.28 g, 10.75 mmol), Pd2(dba)3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added in under N2. The reaction mixture was sealed in a pressure tube and heated up to 125 C. for 1 h. After cooling down the reaction to RT, the mixture was poured into the water and extracted by 100 mL*3 EA. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under the vacuum to give the crude product. The solid was purified by silicone gel column with 10% MeOH (containing ~2N NH3) in DCM to get the pure (4-(2-methylpyridin-4-yl)phenyl)methanamine (yield ~89%). MS m/z 199.1 (M+1). |
Ca. 89% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; Sealed tube; | (4-bromophenyl) methanamine (1.00 g, 5.37 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (883.30 mg, 6.45 mmol) was dissolved in BuOH (10.0 mL) and water (2.0 mL) . K 3 PO 4 (2.28 g, 10.75 mmol), Pd 2 (dba) 3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added under N 2. The reaction mixture was sealed in a pressure tube and heated to 125 C. for 1 hour. After cooling the reaction to RT, the mixture was poured into water and extracted with 100 ml × 3 EA. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo A crude product was obtained. The solid was washed with 10% MeOH in DCM (containing ~ 2 N NH3) With a silicone gel column to give pure (4- (2-methylpyridin-4-yl) Phenyl) methanamine (yield ~ 89%). |
89% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; In butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; | (4-bromophenyl) methanamine (1.00 g, 5.37 mmol) and 2-methylpyridin-4-ylboronic acid (883.30 mg, 6.45 mmol) were dissolved in butanol mL).K3PO4 (2.28 g, 10.75 mmol), Pd2 (dba) 3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added under N2.The reaction mixture was sealed in a pressure tube and heated to 125 C for 1 h.After the reaction cooled to RT, the mixture was poured into water and extracted with 100 mL x 3EA. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the crude product. The solid was purified by silica gel column with DCM in 10% methanol containing ~ 2N ammonia to obtain pure(4- (2-methylpyridin-4-yl) phenyl) methanamine(Yield ~ 89%) |
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 1.0h;Inert atmosphere; Sealed tube; | [0173] (4-bromophenyl)methanamine (1.00 g, 5.37 mmol) and <strong>[579476-63-4]2-methylpyridin-4-yl-4-boronic acid</strong> (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). K3P04 (2.28 g, 10.75 mmol), Pd2(dba)3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added in under N2. The reaction mixture was sealed in a pressure tube and heated up to 125C for lh. After cooling down the reaction to RT, the mixture was poured into the water and extracted by 1 OOmL x 3 EA. The combined organic layer was washed with brine, dried over Na2S04, and concentrated under the vacuum to give the crude product. The solid was purified by silicone gel column with 10% MeOH (containing ~2N NH3) in DCM to get the pure (4-(2-methylpyridin-4-yl)phenyl)methanamine (yield ~ 89%). MS m/z 199.1 (M + 1). | |
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 1.0h;Sealed tube; Inert atmosphere; | (4-bromophenyl)methanamine (1 .00 g, 5.37 mmol) and 2-methylpyridin-4-yl-4- boronic acid (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). K3P04 (2.28 g, 10.75 mmol), Pd2(dba)3 (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added in under N2. The reaction mixture was sealed in a pressure tube and heated up to 125C for 1 h. After cooling down the reaction to RT, the mixture was poured into the water and extracted by 10OmL x 3 EA. The combined organic layer was washed with brine, dried over Na2S04, and concentrated under the vacuum to give the crude product. The solid was purified by silicone gel column with10% MeOH (containing ~2N NH3) in DCM to get the pure (4-(2-methylpyridin-4-yl)phenyl)methanamine (yield ~ 89%). MS m/z 199.1 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 1,4-diaza-bicyclo[2.2.2]octane; 1,10-Phenanthroline; copper(II) acetate monohydrate; sulfur In dimethyl sulfoxide at 100℃; | General experimental procedure: General procedure: A mixture of 2-iodoaniline 1 (1 mmol), benzylamine 2 (1.2 mmol), sulfur powder (6 mmol), DABCO (2 mmol), Cu(OAc)2·H2O (0.02 mmol), and 1,10-phenanthroline (0.02 mmol) was stirred in DMSO (5mL) at 100 °C. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature, water (20 mL) was added, and then the aqueous solution was extracted with ethyl acetate (3×15 mL). The organic layers were combined, dried over anhydrous MgSO4, the filtrate was concentrated under vacuum and then the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate (10:1 to 14:1) on silica gel to provide the desired product. |
76% | With 1,4-diaza-bicyclo[2.2.2]octane; 1,10-Phenanthroline; copper(II) acetate monohydrate; sulfur In dimethyl sulfoxide at 100℃; | General experimental procedure: General procedure: A mixture of 2-iodoaniline 1 (1 mmol), benzylamine 2 (1.2 mmol), sulfur powder (6 mmol), DABCO (2 mmol), Cu(OAc)2.H2O (0.02 mmol), and 1,10-phenanthroline (0.02 mmol) was stirredin DMSO (5 mL) at 100 °C. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature, water (20 mL) was added, and then the aqueous solution was extracted with ethyl acetate (3 15 mL). The organic layers were combined, dried over anhydrous MgSO4, the filtrate was concentrated under vacuum and then the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate (10:1 to 14:1) on silicagel to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In dichloromethane; at 20℃; for 1h; | To a solution of (4-bromophenyl)methanamine (0.93 g, 5 mmol) and triethyl amine (1.05 mL, 7.5 mmol) in dichloromethane, was added 2,4,6- trimethylbenzene- l-sulfonyl chloride (1.09 g, 5 mmol) portion wise. The mixture was allowed to stir for 1 h at ambient temperature. The reaction mixture was washed with HC1 (2N) (3 x 50 mL), water and brine. The organic layer was dried over anhydrous MgS04 and concentrated in vacuo to obtain the title compound as colorless prisms (98%); 1 H NMR (400 MHz, Chloroform-if) delta (ppm) 7.38 - 7.32 (m, 2H), 7.07 - 7.01 (m, 2H), 6.94 (s, 2H), 4.90 (t, J= 6.2 Hz, 1H), 4.03 (d, J= 6.2 Hz, 2H), 2.61 (s, 6H), 2.31 (s, 3H); 13C NMR (100 MHz, Chloroform-i/) delta (ppm) 142.6, 139.2, 135.6, 133.7, 132.1, 131.8, 129.6, 121.9, 46.3, 23.1, 21.1 ; HRMS calculated for Ci6Hi8BrN02S (M+H)+ : 368.0314, Found: 368.0319. |
With triethylamine; In dichloromethane; at 20℃; for 1h; | To a solution of 2,4,6-trimethylbenzenesulfonyl chloride (5.86 g, 27 mmol) and TEA (4.1 g, 40 mmol) in DCM (100 mL) was added (4-bromophenyl)methanamine (5.0 g, 27 mmol) portionwise. The mixture was allowed to stir for 1 h at rt, washed with HCI (2N, 100 mL), water and brine. The organic layer was dried over Na2S04 and concentrated to obtain compound 1a. 1H-NMR (CDCI3, 300 MHz): delta 7.38-7.35 (m, 2H), 7.05-7.02 (m, 2H), 6.94 (s, 2H), 4.76 (t, J = 6.0 Hz, 1H), 4.04 (d, J = 6.0 Hz, 2H), 2.62 (s, 6H), 2.31 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Cooling with ice 2: palladium diacetate; potassium acetate / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C / Inert atmosphere 3: hydrogenchloride / methanol; dichloromethane; 1,4-dioxane / 2 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C | ||
Multi-step reaction with 4 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C / Cooling 2: palladium diacetate; potassium acetate / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C / Inert atmosphere 3: hydrogenchloride / dichloromethane; methanol; 1,4-dioxane / 2 h / 20 °C 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C | ||
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Cooling with ice 2: palladium diacetate; potassium acetate / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C / Inert atmosphere 3: hydrogenchloride / methanol; 1,4-dioxane / 2 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C |
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C / Cooling with ice 2: potassium acetate; palladium diacetate / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C / Inert atmosphere 3: hydrogenchloride / 1,4-dioxane; methanol; dichloromethane / 2 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.5 h / 20 °C | ||
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 1 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl-formamide / 2 h / 90 °C / Inert atmosphere 3: dichloromethane / 0.5 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 6 steps 1: triethylamine / acetonitrile / 15 h / 20 °C 2: palladium diacetate; potassium acetate / N,N-dimethyl acetamide / 15 h / 120 °C / Inert atmosphere 3: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C 5: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 6: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 25 °C / Inert atmosphere 1.2: 0.5 h / 0 - 25 °C / Inert atmosphere 2.1: palladium diacetate; potassium acetate / 1-methyl-pyrrolidin-2-one / 16 h / 120 °C / Inert atmosphere 3.1: hydrogenchloride / methanol; dichloromethane; water; 1,4-dioxane / 2 h / 20 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 4.2: 1.5 h / 25 °C / Inert atmosphere | ||
Multi-step reaction with 6 steps 1: sodium hydroxide / methanol / 5 h / 0 - 20 °C 2: potassium acetate; palladium diacetate / N,N-dimethyl acetamide / 10 h / 150 °C / Inert atmosphere 3: hydrogenchloride / methanol 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / tetrahydrofuran / 2 h / 0 - 20 °C 5: hydrogenchloride / methanol 6: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 64h; | Step A: 4-((4-Bromobenzyl)amino)-3-nitrophenol To a solution of <strong>[2105-96-6]4-<strong>[2105-96-6]fluoro-3-nitrophenol</strong></strong> (20 g, 127 mmol) in acetonitrile (50 mL) were added 4-(bromophenyl)methanamine (23.7 g, 127 mmol) followed by DIPEA (44 mL, 255 mmol). The mixture was heated to 90° C. for 64 h. The mixture was cooled to RT and concentrated to dryness. The residue was dissolved in DCM (500 mL) and washed with water (2*100 mL). The organics were dried with Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC to afford the title compound. 1H NMR (300 MHz, DMSO-d6) delta 9.37 (s, 1H), 8.41-8.37 (m, 1H), 7.51 (d, J=8.4, 2H), 7.42 (d, J=2.9, 1H), 7.29 (d, J=8.4, 2H), 7.03 (dd, J=9.2, 2.9, 1H), 6.76 (d, J=9.3, 1H), 4.54 (d, J=6.2, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 90℃; for 12h;Inert atmosphere; | General procedure: To an oven dried three neck RB containing 2-Iodobenzoic acid (1) (2mmol), benzyl amine (2) (4mmol) and CuI(0.4mmol) in DMSO(3ml) was added 0.55g of K2CO3. Then, the reaction mixture was allowed to stir at 90C under air atmosphere for 12h.The completion of the reaction was monitored by TLC. After being cooled at room temperature the reaction mixture was poured in to ice cooled water and extracted with ethyl acetate two times. The combined organic layer was washed with brine and then dried over anhydrous Na2SO4. The solvent was evaporated and the crude product was purified by column chromatography (hexane(80)/ ethyl acetate (20)) on silica gel to afford 2-phenyl-4H-benzo[d][1,3]oxazine-4-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 1-methyl-pyrrolidin-2-one; copper(II) ferrite; oxygen; at 130℃; for 16h;Schlenk technique; Green chemistry; | General procedure: An oven dried Schlenk Tube equipped with a magnetic stirring bar charged under air with 2-nitrophenol (1mmol), benzyl amine (1.5mmol),Copper ferrite NPs(10%),followed by 2mL of NMP (N-methyl pyrollidone) as a solvent. Reaction mixture was heated in a oil bathe at 130oC and was stirred for 16h.The reaction was monitored by GC and TLC. After completion of reaction the reaction mixture was cooled to room temperature and the reaction mass was diluted with ethyl acetate .Copper ferrite NPs was separated by using external magnet. Then the solution was filtered through the plug of cellite .The filtrate washed with water (3x10mL).The organic layer was separated and dried over anhydrous sodium sulphate. The solvent remove under vacuum to get the crude product which was purified by column chromatography on silica gel eluting with the mixture of pet ether/ethyl acetate (20:1) mixture to afford pure product.The purity and identity of known product are confirmed by 1HNMR and GC-MS spectroscopic Techniques. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With anhydrous silver carbonate In 1,4-dioxane at 50℃; for 12h; | General procedure for the synthesis of 2,4,5-trisubstituted oxazoles (2a-2t): General procedure: A mixture of 1,2-diketone (1.5 mmol), primary amine (1 mmol) and silver carbonate (2.0 equiv.)in 5 ml 1,4-dioxane was stirred at 50 C for 12 hrs. The reaction progress was monitored by TLC.After completion of the reaction, the solid was filtrated out and was washed withdichloromethane. Finally the solvent of the filtrate was removed under vacuum and the resultingcrude product was purified by column chromatography over 60-120 mesh silica gel [ethylacetate/ petroleum ether (60-80°C)]. No further purification was needed. |
69.1% | With anhydrous silver carbonate In 1,4-dioxane at 50℃; for 48h; | 10 (Synthesis of Intermediate (29)) 10.0 g (53.75 mmol) of 4-bromobenzylamine in a 1 mL 500 mL flask, Phenanthrene-9,10-dione 11.2 g (53.75 mmol), 22.2 g (80.62 mmol) of Ag 2 CO 3 and 100 mL of 1,4-dioxane were mixed and then stirred at 50 ° C. for 2 days. After the reaction was completed, the reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. Concentrate the Column Chromatography Purification using (CHCl 3). Solidification with methanol yielded 12.3 g (yield: 69.1%) of a pale yellow solid compound (intermediate (29)). |
With anhydrous silver carbonate In 1,4-dioxane at 80℃; for 8h; |
With anhydrous silver carbonate In 1,4-dioxane at 50℃; for 12h; Inert atmosphere; | ||
With anhydrous silver carbonate In 1,4-dioxane | ||
With anhydrous silver carbonate In 1,4-dioxane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 2,8-dibromo-10-(4-bromophenyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-dipyrrolo[1,2-c:2′,1′-f ][1,3,2]diazaborinin-4-ium-5-uide In acetonitrile at 50℃; for 5h; Irradiation; Green chemistry; | Typical Procedures for Photocatalytic Oxidation of Amine with 2-Aminothiophenol General procedure: Amine (1 mmol), 2-aminothiophenol (2 mmol), BODIPY photosensitizer (0.01 mmol, 1.0 mol%), and acetonitrile (5 mL) were added to a dry 10-mL flask. The flask was pressurized with air (2 bar) and then heated to 50 C. The solution was then irradiated using a 35-W xenon lamp through a cutoff filter (0.72M NaNO2 aqueous solution, which is transparent for light >385nm, because lamps could emit a small amount of ultraviolet light). After the reaction was completed, the solvent was evaporated under reduced pressure. The crude product was further purified using column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 0 - 20℃; for 3h;Inert atmosphere; | 2-Amino-4,5-difluorobenzoic acid (5.0 g; 28.9 mmol), 50 ml of DCM, TEA (12.1 ml; 87 mmol), and (4-bromophenyl)methanamine (4.0 ml; 31.8 mmol) were placed in a reaction flask under nitrogen and cooled to 0 C. T3P (34 ml; 57.8 mmol; 50 % in EtOAc) was added slowly. The reaction mixture was stirred at it for 3 h. DCM was added and the mixture was washed twice with water, dried with a phase separator, and evaporated to dryness to give 12.48 g of crude 2-amino-N-(4-bromobenzyl)-4,5-difluorobenzamide. The product was used in the next step without purification. ^-NMR (400 MHz, cfc-DMSO): delta 4.37 (d, 2H), 3.87 (br s, 2H), 6.66 (dd, 2H), 6.88 (d, 1H), 7.23-7.31 (m, 2H), 7.47-7.55 (m, 2H), 7.67 (dd, 1H), 8.85 (t, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.44 g | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | <strong>[108288-16-0]2-Amino-4-chloro-5-fluorobenzoic acid</strong> (2.5 g; 13.2 mmol), 20 ml of DCM, TEA (5.5 ml; 39.6 mmol), and (4-bromophenyl)methanamine (1.83 ml; 14.5 mmol) were placed in a reaction flask under nitrogen and cooled to 0 C. T3P (9.4ml; 15.8 mmol) was added slowly. The reaction mixture was allowed to warm to rt after 30 min and stirred overnight. Water (15 ml) was added and the precipitation formed was filtered, washed three times with 10 ml of water, and dried under vacuum at 50 C to give 3.01 g of the product. Additional product was precipitated from the filtrate, filtered, washed, and dried to give 0.44 g of the product. 1H-NMR (400 MHz, 6-DMSO): delta 4.37 (d, 2H), 6.54 (br s, 2H), 6.88 (d, IH), 7.24- 7.29 (m, 2H), 7.49-7.54 (m, 2H), 7.61 (d, IH), 8.92 (t, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.03 g | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃;Inert atmosphere; | 2-Amino-3,5-difluorobenzoic acid (1.0 g; 5.78 mmol), 10 ml of dry DCM, and TEA (2.415 ml; 17.33 mmol) were placed in a reaction flask under nitrogen. 4-Bromobenzylamine (0.803 ml; 6.35 mmol) was added slowly and then T3P (4.12 ml; 6.93 mmol; 50 % in EtOAc) was added keeping the temperature at rt. The mixture was stirred at rt over three nights. Water was added to the mixture and the precipitation formed was filtered, washed with water, and dried in a vacuum oven to yield 1.03 g of 2-amino-N-(4-bromobenzyl)-3,5- difluorobenzamide. LC-MS (ES) [M+l]: 343.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With copper(l) iodide; di-tert-butyl peroxide; copper(II) acetate monohydrate In dimethyl sulfoxide at 110℃; for 24h; | 1.1 (1) Preparation of compound ET-Y1 The cuprous iodide (19g, 0.1mol, 1eq),And copper acetate monohydrate (20g, 0.1mol, 1eq)Dissolved in DMSO (750ml),Then 4-bromobenzylamine (55.5g, 0.3mol, 3eq),2-methylquinoline (14.3g, 0.1mol, 1eq),Di-tert-butyl peroxide DTBP (29.2g, 0.2mol, 2eq)Add to the reaction system.Heat the oil bath to 110°C for 24 hours,TLC monitors the completion of the reaction.Cool the reaction solution to room temperature,1.5L water was added and extracted with ethyl acetate (1L*3).Combine the ethyl acetate phases,Dry with anhydrous sodium sulfate, filter with suction,Rotate to remove ethyl acetate,The obtained crude product was purified by column chromatography to obtain intermediate ET-Y1 (27.2 g, yield 80%). |
72% | With ammonium iodide In N,N-dimethyl-formamide at 100℃; for 15h; Electrochemical reaction; | |
60% | With copper(l) iodide; di-tert-butyl peroxide; copper(II) acetate monohydrate In dimethyl sulfoxide at 110℃; for 24h; |
With copper(l) iodide; di-tert-butyl peroxide; copper(II) acetate monohydrate In dimethyl sulfoxide at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrogen In ethanol at 110℃; for 24h; Autoclave; | 7 Example 7 Weighing 186 mg of p-bromobenzylamine,6.1 mg of Ru catalyst, 3.0 mL of ethanol,The 290 mg of 5-HMF was weighed and mixed in a 10 mL autoclave,The system was replaced with 10 bar of hydrogen for 3 times, the reaction initial hydrogen pressure was 25 bar, the temperature was 110 ° C, and the reaction time was 24h.After the completion of the reaction, the ethanol was removed under reduced pressure, and the residue was separated by silica gel column to give 325 mg of a yellow solid in a yield of 80%. |
79.7% | With [ruthenium(2,9-dimethyl[1,10]phenanthroline)2(chloride)2]; hydrogen In ethanol for 12h; Heating; High pressure; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: 4-Bromobenzylamine With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 2-fluoroprop-2-enoate In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | 4.2.1 General procedure for the synthesis of N-substituted -fluoroacrylamides (2a-i) General procedure: A solution of 2.0 M NaHMDS in THF (7.5 mL, 15.0 mmol) was added to the solution of RNH2 (1.2 equiv) in THF (25 mL) at 0 °C under Ar atmosphere. The reaction solution was then stirred for 30 min at room temperature, after that, methyl 2-fluoroacrylate (0.91 mL, 10.0 mmol) was added dropwise at 0 °C. The resulting solution was then warmed to room temperature and stirred for overnight. After quenched with saturated NH4Cl aqueous solution, the mixture was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with brine (20mL) and dried over NaSO4. After filtration and concentration, the residue was purified by column chromatography, and the isolated yields were shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With 1,1'-bis-(diphenylphosphino)ferrocene; potassium phosphate; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; water; at 100℃;Inert atmosphere; | p-bromobenzylamine (800mg, 4.30mmol) were dissolved in dioxane / water, was added A39-1 (1.52g, 12.1mmol), potassium phosphate (1.82 g of,8.58mmol), Pd (dppf) 2Cl2 (176mg, 0.22mmol), dppf (119mg, 0.22mmol), purged with nitrogen, stirred overnight at 100 deg.] C, cooledCooling to room temperature, suction filtered through Celite, and the filtrate was added water (30 mL), dichloromethane (50mL × 6). The organic phase was dried over anhydrous sodium sulfate, filtered sulfurSodium, spin dry the solvent, the residue was purified by column chromatography (dichloromethane: methanol = 50: 1-20: 1 plus ammonia) to give a brown oil (410mg, 51%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium carbonate; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; water; at 80℃;Inert atmosphere; | The crude intermediate A1-2 (8g, 27%, 9.86mmol) dissolved in dioxane / water (100mL / 20mL), was added to the bromonemzylamine (1.65g, 8.88mmol),potassium carbonate (2.72g, 19.73mmol), Pd (dba)2 (567mg, 0.99mmol) and SPhos (810mg, 1.97mmol), purged with nitrogen, 80C, the reaction overnight. Cooled to room temperature, suction filtered through Celite, and the filtrate was added 100mL of water, ethyl acetate (150mL × 3) and the combined organic phase was washed with a saturated brine (300mL × 2) washing the organic phase with anhydrous sodium sulfate, and sodium sulfate was filtered, spin dry ethyl acetate, the residue was purified by column chromatography (dichloromethane:Methanol = 50: 1-30: 1 ammonia water) to give a brown solid (1.27g, 72%). |
800 mg | With potassium phosphate; bis(dibenzylideneacetone)-palladium(0); In water; tert-butyl alcohol; at 100℃; for 12h;Inert atmosphere; | To a suspension of 17 (5.1 g, crude), (4-bromophenyl)methanamine (1.8 g, 9.68 mmol) and Pd(dba)2 (557 mg, 0.97 mmol) in t-BuOH (40 mL) and H2O (10 mL) were added K3PO4 (4.1 g, 19.4 mmol) and Xphos (397 mg, 0.97 mmol). The mixture was stirred at 100 C under N2 for 12 h. After cooling to room temperature, the mixture was evaporated and the residue was purified by silicagel column chromatography (dichloromethane/methanol = 10:1) to give the desired product (800 mg, 42%) as a yellow solid. 1HNMR (400 MHz, CDCl3) d 8.53 (d, J = 5.2 Hz, 1H), 7.61 (d,J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.37 (s, 1H), 7.31 (d,J = 5.2 Hz, 1H), 3.94 (s, 2H), 2.62 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With 1,1'-bis-(diphenylphosphino)ferrocene; potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,4-dioxane; water at 105℃; Inert atmosphere; | 1.9.1 Synthesis of B9-2 The B9 - 1 (1 g, 5.38 mmol) and phenyl boronic acid (787 mg, 6 . 45 mmol) is dissolved in dioxane (40 ml) and water (10 ml) in, Pd (dppf) Cl added2 (176 mg, 0 . 22 mmol), dppf (119 mg, 0 . 22 mmol) and potassium phosphate (2.28 mg, 10 . 75 mmol), under the protection of nitrogen, replace the nitrogen five times, heating to 105 °C, the reaction overnight. After cooling to room temperature the filtering, the filtrate is concentrated under reduced pressure. Column chromatography (dichloromethane: methanol=20:1) to obtain brown oil of (390 mg, 40%). |
13 %Chromat. | With potassium phosphate; palladium diacetate In water at 100℃; for 1h; Inert atmosphere; Green chemistry; | |
94 %Chromat. | With palladium diacetate In water at 100℃; for 24h; Inert atmosphere; |
92 %Chromat. | With palladium diacetate In water at 100℃; for 4h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2h; | Procedure 1 General procedure: In a 100 mL flask equipped with magnetic stirring, the organic acid (1.35 mmol, 200 mg) was dissolved in dimethylformamide (DMF, 2.7 mL) and trimethylamine (0.14 mL, 1.35 mmol). The solution was cooled in an ice bath (0 °C). Then, 4-chlorobenzylamine (1.35 mmol) was added. Soon after a 1.35 mmol solution of BOP in CH2Cl2 (10 mL) was added to the flask. The reaction was stirred at 0 °C for 30 min, and then for an additional period, at room temperature for 2 h. After the reaction, the CH2Cl2 was removed under reduced pressure and the solution was poured into a separatory funnel containing water (10 mL) and EtOAc (10 mL). The product was extracted with EtOAc (3 × 10 mL). The organic phase was washed sequentially with 1 N HCl, water, 1 M NaHCO3 and water (10 mL of each); dried with Na2SO4, filtered and concentrated in a rotavapor. The amide was purified by gel chromatography on a silica gel column using as the mobile phase an EtOAc:Hex mixture gradient of increasing polarity. |
With benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; In N,N-dimethyl-formamide; for 4.0h;Reflux; | General procedure: Compound 4 (1.84 g, 0.01 mol) was mixed with (1.06 g, 0.01 mol) of trimethylamine and (0.01 mol)of the appropriate aromatic amine in 5 mL of dimethylformamide (DMF). The mixture was refluxedfor 4 h, cooled, and poured on crushed ice. The crystals were collected and crystallized from ethylalcohol. The melting points for all synthesized compounds were above 300 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.69 g | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere; | A mixture of <strong>[1046832-21-6]1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (2.0 g), (4-bromophenyl)methanamine (1.52 g), tetrakis(triphenylphosphine)palladium(0) (0.28 g), 2 M aqueous sodium carbonate solution(8.19 mL) and DME (30 mL)-water (3 mL) was stirred under an argon atmosphere at 90C overnight. The reaction mixturewas concentrated, and THF was added to the residue. The insoluble material was filtered off. The filtrate was concentrated,and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound(0.69 g).1H NMR (300 MHz, CDCl3) delta 1.73 (2H, s), 2.39 (3H, s), 3.88 (5H, d, J = 4.7 Hz), 7.29-7.43 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.4% | Stage #1: bromostyrene; 4-Bromobenzylamine With sodium hexametaphosphate; ammonium cerium (IV) nitrate; 1,3-bis(3-cyanopropyl)-1H-imidazol-3-ium chloride; dinitrodiammine platinum In toluene at 80℃; for 4h; Stage #2: acetic acid In water; toluene at 80℃; for 0.666667h; | 3 S1: To the appropriate amount of organic solvent toluene, 100 mmol of the compound of the above formula (I), 250 mmol of the compound of the above formula (III), 300 mmol of the amine source cerium ammonium nitrate, 3 mmol of the catalyst dinitrodiammine platinum, 10 mmol of the ligand (3-cyanopropyl) imidazole chloride and 300 mmol sodium hexametaphosphate were added and the temperature was raised to 80 ° C and the reaction was stirred at that temperature for 4 hours. S1100mmol(I)250mmol(III)300mmol3mmol10mmolL140mmol1,3-(3-)300mmol80°C4 Submit CorrectionsCloseS2: After the reaction of Step S2 was completed, an aqueous solution of acetic acid having a mass percentage of 40% was added dropwise to the resulting system until the total molar amount of acetic acid added was 200 mmol, and the reaction was stirred at 80 ° C for 40 minutes. S2S240200mmol80°C40 Submit CorrectionsCloseAfter completion of the reaction at step S2, the mixture was poured into ethyl acetate, washed successively with saturated aqueous NaHCO3 and brine, and the aqueous layer was extracted with ethyl acetate. The washed organic layers and the extracted organic layers were combined with anhydrous Na2 SO 4, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (using n-hexane-ethyl acetate mixture as eluent, volume ratio of 1: 3) to give the compound of formula (III) The yield was 95.4% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | General procedure: A solution of 1,3-benzodioxole-5-propanoic acid (20mmol) in anhydrous DMF (30ml) was treated with PyBOP (22mmol) followed by DIEPA (60mmol). After stirring at room temperature for 20 min, the corresponding amine (20mmol) was added, and the solution was stirred at room temperature overnight. The reaction was diluted with dichloromethane (100 ml) and water (100 ml). The layers were separated and the organic layer was washed with water (3 x 25 ml). The combined aqueous washes were then back-extracted with dichloromethane (50 ml), The combined organic layers were washed with brine (50 ml) and dried over magnesium sulfate, filtered and finally evaporated in vacuo. The crude material was purified by column chromatography over silica gel(dichloromethane/methanol: 100/0 to 92/8) to give the title compound (2a-2f). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 20h; | Synthesis ofELT-BBA adduct was achieved by initial epoxidation of ELT using m-CPBA, basedon a reported method about peroxidation studies of acetylenes (McDonald andSchwab, 1964). ELT (4 mg, 10.2 mmol) was dissolved in dichloromethane (10 ml),and m-CPBA (20 mg, 116.3 mmol) and BBA (20 mg, 107.5 mmol) were then added.After being stirred for 20 hours at room temperature, the reaction mixtures werecentrifuged, and the supernatants were condensed under nitrogen stream. Theresulting sample was reconstituted with acetonitrile-water (1:9) for LC-MS/MSanalysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.3% | General procedure: The compounds 5-13 were synthesized using the mixed anhydrides method (21) of peptide synthesis. The suitable acid (10 mmol) was dissolved in dry tetrahydrofuran (THF) or a mixture of dimethylformamide (DMF)/tetrahydrofuran (30 mL). Next, N-methylmorpholine (NMM) (10 mmol, 1.1 mL) was added and the mixture was stirred under nitrogen and chilled to -20C. Isobutyl chloroformate (IBCF) (10 mmol, 1.3 mL) was added dropwise to keep the temperature below -15C. Then the suitable amine: 2- or 4-fluorobenzylamine; 2- trifluoromethoxybenzylamine; 2-trifluoromethylbenzylamine, 4-bromobenzylamine or 1-naphthylmethylamine (10 mmol) in THF was added in small portions and the reaction mixture was stirred at -15C for 30 min. and at room temperature for 1 h. The solution was concentrated in vacuo and the residue was dissolved in CHCl3 (40 mL). This solution was washed with 20 mL portions of 1 M HCl, saturated NaHCO3 solution and saturated NaCl solution, then dried with anhydrous MgSO4, filtered and concentrated in vacuo. The obtained compounds were purified as follows: 5, 6, 8, 11, 12 and 13 by crystallization from ethyl acetate/hexane, 10 by crystallization from ethyl acetate and 7, 9 by column chromatography in chloroform as eluent and then by crystallization from ethyl acetate/hexane. All stages of the synthesis were controlled by the thin-layer chromatography. The general procedure for the synthesis of the obtained compounds is shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tert.-butylhydroperoxide; copper diacetate; In water; at 30℃; for 12h; | General procedure: A mixture of N-benzyl enaminoketone (1.0 mmol), di-alkylacetylenedicarboxylate (1.0 mmol), benzyl amine (1.0 mmol), Cu(OAc)2 (8 mol%) and TBHP (4.0 mmol, 0.56 mL of a 70% aqueous solution) in water (0.5 mL) was stirred at 30 C for 12 h under air. The reaction progress was monitored by TLC. After completion of the reaction, the solid was filtrated out and washed with hot ethyl acetate. Finally the solvent of the filtrate was removed under vacuum and the resulting crude product was purified by column chromatography over 60-120 mesh silica gel [ethyl acetate/petroleum ether (60-80 C)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tert.-butylhydroperoxide; copper diacetate; In water; at 30℃; for 12h; | General procedure: A mixture of N-benzyl enaminoketone (1.0 mmol), di-alkylacetylenedicarboxylate (1.0 mmol), benzyl amine (1.0 mmol), Cu(OAc)2 (8 mol%) and TBHP (4.0 mmol, 0.56 mL of a 70% aqueous solution) in water (0.5 mL) was stirred at 30 C for 12 h under air. The reaction progress was monitored by TLC. After completion of the reaction, the solid was filtrated out and washed with hot ethyl acetate. Finally the solvent of the filtrate was removed under vacuum and the resulting crude product was purified by column chromatography over 60-120 mesh silica gel [ethyl acetate/petroleum ether (60-80 C)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | Preparation of Compound 11-4 A mixture of 4-bromobenzylamine (1.0 g, 5.4 mmol), triethylamine (1.50 mL, 10.7 mmol) in anhydrous DCM (50 mL) was cooled to 0° C. under argon atmosphere. A solution of 1,2-bis(chlorodimetylsilyl)ethane (1.16 g, 5.4 mmol) in anhydrous DCM (20 mL) was added via cannula. The mixture was stirred for 1 h at 0° C. and then 1 h at room temperature. The solvent was removed in vacuo, the residue was suspended in hexanes and filtered. Filtrate was concentrated in vacuo and used in the next step without further purification. | |
With triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | Preparation of Compound 11-4 A mixture of 4-bromobenzylamine (1.0 g, 5.4 mmol), triethylamine (1.50 mL, 10.7 mmol) in anhydrous DCM (50 mL) was cooled to 0° C. under argon atmosphere. A solution of 1,2-bis(chlorodimetylsilyl)ethane (1.16 g, 5.4 mmol) in anhydrous DCM (20 mL) was added via cannula. The mixture was stirred for 1 h at 0° C. and then 1 h at room temperature. The solvent was removed in vacuo, the residue was suspended in hexanes and filtered. Filtrate was concentrated in vacuo and used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.3% | In acetonitrile; at 90℃; | 4-Chlorobenzofuro[3,2-djpyrimidine (110 mg, 0.537 mmol) was added to astirring solution of(4-bromophenyl)methanamine (100 mg, 0.537 mmol) in ACN (2.7 ml)at rt. The reaction was stirred at 90 C overnight. The reaction was concentrated,adsorbed onto celite and was purified on silica gel (Biotage, EtOAc/hexanes gradient, 0-100% over 10 CVs) to afford N-(4-bromobenzyl)benzofuro[3,2-djpyrimidin-4-amine (130 mg, 0.367 mmol, 68.3 % yield). LCMS (M+H) = 353.85 and 355.85. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With C30H29BrMnNO2P2; potassium carbonate In neat (no solvent) at 150℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; | To a solution of 2-methyl-1 -naphthoic acid (500 mg, 2.69 mmol) and (4-bromophenyl)methan- amine (500 mg, 2.69 mmol) in DMF (20 mL) was added TEA (543 mg, 5.38 mmol) and HATU (1.23 g, 3.23 mmol) at 0C. The mixture was stirred at rt overnight, diluted with H20 and extracted with EA (3 x). The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the crude compound 8a as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h; | General procedure: To a solution of2(5 mmol,1equiv) in DMF (10 mL) was added 3-bromobenzylamine (5 mmol, 1equiv) and K2CO3(5 mmol, 1equiv).Then the reaction mixture was stirred for 4 h at 90C. Then the mixture was quenched with water (50ml) and extracted with ethyl acetate (2×50 mL).The combined organic layers werewashed with saturated NaCl solution anddried overanhydrous Na2SO4and concentrated under vacuumto give the corresponding target product3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.1 g | With triethylamine; In ethanol; water; at 75℃; for 16h; | To a stirred solution of compound 08-01-2 (5 g, 0.0141 mol) in 65% aq. ethanol (50 mL) was added EhN (6 mL, 0.0424 mol), compound 08-01-6 (3.3 g, 0.0184 mol) slowly at RT. The resulting mixture was stirred at 75C for 16 h. The reaction was monitored by LCMS. The reaction mixture was neutralized with 1.5 N HC1, precipitated solid was filtered, washed with water and dried to get the product 08-01-7 as an off white solid. (5.1 g, 85 %) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: DIPEA (7.2 mmol, 2.5 eq), PyBOP (3.6 mmol, 1.25 eq) and 6a-b(2.9 mmol, 1.0 eq) in CH2Cl2 (20 mL) was stirred at 25 C for 2 h. then,7a-l (3.2 mmol, 1.1 eq) was added. The mixture was stirred for another13 h and quenched with H2O (100 mL). The aqueous layer was extractedwith CH2Cl2 (30 mL X 3) and the combined organic layers werewashed with brine, and dried over anhydrous Na2SO4. Purification ofthe crude reaction mixture was progressed by column chromatography(5-30% EtOAc/PE). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In acetonitrile; at 80℃; for 16h; | To a solution of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (1.0 g, 4.452 mmol, 1.00 equiv) and l-(4-bromophenyl)methanamine (0.99 g, 5.342 mmol, 1.20 equiv) in acetonitrile (50 mL) was added potassium carbonate (1.85 g, 13.355 mmol, 3.00 equiv). After stirring at 80 C for 16 h, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (1 :20)) to afford 1.5 g (81%) of N-((4- bromophenyl)methyl)-6,7-dimethoxyquinazolin-4-amine as an white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With 1-methyl-pyrrolidin-2-one; potassium carbonate at 225℃; for 5h; Microwave irradiation; | General procedure: To a 10-20 mL capacity microwave vial was added 1-fluoro-2- nitrobenzene (0.400 g, 2.830 mmol, 1 equiv.), benzylamine (0.330 g, 3.120 mmol, 1.1 equiv.) and potassium carbonate (0.978 g, 7.092 mmol, 2.5 equiv.) in N-methylpyrrolidone (15 mL). The vial was properly closed and irradiated in microwave reactor at 225 C for 4 h. The vial was then cooled to ambient temperature and water (30 mL) was added to it, followed by extraction with ethyl acetate (200 mL). The organic extract was washed with water (150 mL), brine (25 mL), and dried over anhydrous sodium sulfate. Subsequently, it was filtered and concentrated to obtain a dark brown sticky mass. The crude material obtained was loaded on a pre packed silica gel 50 g SNAP cartridge and purified by flash chromatography on a Biotage instrument using 50-60% gradient of ethyl acetate in hexane to obtain pure 2- phenyl-1H-benzo[d]imidazole as a light brown solid (0.358 g, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With ammonium iodide; sulfur In sulfolane at 175℃; for 48h; Inert atmosphere; Sealed tube; | 2. General Procedure for Benzothiazole Synthesis In a 15 mL oven-dried reaction vessel, nitrobenzene 1 (2.0 mmol), benzylamine 2 (4.0mmol), powdered sulfur (321 mg, 10.0 mmol), NH4I (435 mg, 3.0 mmol), and sulfolane(2.0 mL) were charged under an argon atmosphere. The sealed reaction vessel wasstirred at 200 °C (oil bath) for 24 h. After cooling to ca. 120 °C, the reaction mixturewas poured into a 5% acetic acid aqueous solution and the resulting solid was collectedby filtration. The solid was washed with water and extracted with ethyl acetate. Theorganic layer was washed with water and brine and dried over anhydrous MgSO4. Thesolvent was removed under reduced pressure. The crude product was further puri fiedby column chromatography on silica gel (hexane/ethyl acetate). |
Tags: 3959-07-7 synthesis path| 3959-07-7 SDS| 3959-07-7 COA| 3959-07-7 purity| 3959-07-7 application| 3959-07-7 NMR| 3959-07-7 COA| 3959-07-7 structure
[ 26177-44-6 ]
(4-Bromophenyl)methanamine hydrochloride
Similarity: 0.97
[ 376646-62-7 ]
(4-Bromo-2-methylphenyl)methanamine
Similarity: 0.94
[ 1171381-49-9 ]
(4-Bromo-2-methylphenyl)methanamine hydrochloride
Similarity: 0.92
[ 699-03-6 ]
1-(4-Bromophenyl)-N-methylmethanamine
Similarity: 0.92
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