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CAS No. : | 589-10-6 | MDL No. : | MFCD00000234 |
Formula : | C8H9BrO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JJFOBACUIRKUPN-UHFFFAOYSA-N |
M.W : | 201.06 | Pubchem ID : | 68526 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 45.61 |
TPSA : | 9.23 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) : | -5.68 cm/s |
Log Po/w (iLOGP) : | 2.31 |
Log Po/w (XLOGP3) : | 2.6 |
Log Po/w (WLOGP) : | 2.46 |
Log Po/w (MLOGP) : | 2.61 |
Log Po/w (SILICOS-IT) : | 2.7 |
Consensus Log Po/w : | 2.53 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.97 |
Solubility : | 0.215 mg/ml ; 0.00107 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.44 |
Solubility : | 0.725 mg/ml ; 0.00361 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.8 |
Solubility : | 0.0316 mg/ml ; 0.000157 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.37 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362+P364 | UN#: | N/A |
Hazard Statements: | H315-H319 | Packing Group: | N/A |
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 |
---|---|---|
94% | With potassium carbonate In acetonitrile at 80℃; for 6 h; | General procedure: The compounds were synthesized according to Scheme 1. A suspension of phenol (10mmol), 1,2-dibromoethane(50mmol), and anhydrous K2CO3 (30mmol) in dry acetonitrile(50mL) was stirred at 80°C for 6 h.The reaction mixturewas filtered, and the K2CO3 was recovered, reactivated (in vacuum at 120°C, 5 h), and the solvent was concentratedunder reduced pressure.The residue was purified by columnchromatography over silica gel using petroleum ether aseluent to give the product as a solid (Scheme 1, Table 4). 1-(2-Bromoethoxy)-benzene [22, 23] (Entry 1). mp: 33-34°C.1H NMR (400MHz, CDCl3), δ: 7.29–7.26 (m, 2H), 6.95–6.92(m, 3H), 4.26–4.23 (t, J = 3.6Hz, 2H), 3.61–3.58 (t, J = 3.6Hz,2H).13C NMR (100MHz, CDCl3) δ: 158, 129.5, 121.4, 114.8,67.8, 29.1. MS m/z (I): 202 (50, M+2), 200 (48, M+), 109 (97),107 (100), 94 (60), 77 (29), 65 (38), 51 (22), 39 (52). |
85% | With sodium hydroxide In water | 1-(2-Bromoethyl)piperidine hydrobromide In a mixed solution consisting of 50 g of 1,2-dibromoethane, 18.5 g of phenol and 100 ml of water was added dropwise 30 ml of water containing therein 7.9 g of sodium hydroxide at a temperature of 130° C. over 30 minutes with stirring. The reaction solution was further stirred for 6 hours. After completion of the reaction, the organic layer was separated from the reaction solution, washed twice with a saturated aqueous potassium carbonate solution, washed twice with water and dried with anhydrous sodium sulfate. The organic layer was separated by filtration and condensed under reduced pressure to give 34.3 g of 2-phenoxyethyl bromide having a boiling point of 105° C. to 107° C. at 6 mmHg in a yield of 85percent. |
85% | With sodium hydroxide In water | REFERENTIAL EXAMPLE 1 1-(2-Bromoethyl)piperidine hydrobromide In a mixed solution consisting of 50 g of 1,2-dibromoethane, 18.5 g of phenol and 100 ml of water was added dropwise 30 ml of water containing therein 7.9 g of sodium hydroxide at a temperature of 130° C. over 30 minutes with stirring, and the reaction solution was further stirred for 6 hours. After completion the reaction, the organic layer was separated from the reaction solution, washed twice with a saturated aqueous potassium carbonate solution, washed twice with water and dried over anhydrous sodium sulfate. The organic layer was separated by filtration and condensed under reduced pressure to give 34.3 g of 2-phenoxyethyl bromide having a boiling point of 105° C. to 107° C. at 6 mmHg in a yield of 85percent. |
67% | With sodium hydroxide In water for 5 h; Reflux | Example 11 Synthesis of N-ethyl-N-(2-phenoxy)ethylcyclohexylamine A 22.5percent aqueous sodium hydroxide solution (135 mL) was added to a mixture of phenol (30.0 g (0.32 mol)) and 1,2-dibromoethane (237 g (1.28 mol)), and the mixture was stirred 5 hours under heating at reflux. The temperature was returned to room temperature, and the mixture was then extracted three times with dichloromethane (100 mL). The whose organic layer was dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. The residue was purified by a silica gel chromatography (petroleum ether : ethyl acetate = 10 : 1) to obtain (2-bromoethoxy)benzene (compound-01) (43.0 g, 0.215 mol, yield 67percent). |
64% | With potassium carbonate; potassium iodide In acetone at 60℃; | General procedure: A solution of 1,2-dibromoethane (0.02 mol) in 40 ml ofacetone was added dropwise into the mixture of respective phenol (0.08 mol) andK2CO3 (0.04 mol) in 30 ml of acetone. Subsequently, acatalytic amount of KI (0.3 mmol) was added and the resulting mixture wasstirred at 60°C for 24–72 hours. After the completion of the reaction theinorganic residues were filtrated off and organic mixture was concentrated undervacuum. The obtained crude product was purified on silica gel with AcOEt/hexaneas eluting system. 2.1. (2-Bromoethoxy)benzene 16{1}Yellow oil(6 g, 64percent yield), following chromatographic purification over silica gel with AcOEt/hexane (0.5/9.5 v/v); UPLC/MSpurity 97percent, tR = 7.98. C8H9BrO, MW 201.06, MonoisotopicMass 199.98, [M+H]+ 200.2. 1H NMR (300 MHz, CDCl3)δ 3.43 (t, J = 6.5Hz, 2H), 4.28 (t, J = 6.5 Hz, 2H), 6.81 (dd, J = 5.2,1.0 Hz, 1H), 6.95 (td, J = 7.6, 1.1 Hz, 1H), 7.02 (m, 1H),7.14 (td, J = 8.0, 1.8 Hz, 1H), 7.21–7.25 (m, 1H). |
64% | With potassium iodide; sodium hydroxide In methanol for 8 h; Reflux | This compound was made according to the previous work [1]. Phenol (2.35 g, 25 mmol), NaOH (1 g,25 mmol), 1,2-dibromoethane (10.8 mL, 125 mmol) and a catalyzed amount of KI were added into 50 mL methanol. The solution was refluxed for 8 h. Then the solvent was evaporated and the crude product was purified on column chromatography by using petroleum ether as eluent. The yield was 64percent. |
63% | With potassium carbonate In acetonitrile at 100℃; | General procedure: 1,2-dibromoethane (573mL, 6.62mmol) was added to a mixture of 2-hydroxybenzthiazole (500mg, 3.31mmol) and potassium carbonate (1.37g, 9.93mmol) in acetonitrile, which were then refluxed (oil bath temp 100°C) till the consumption of benzthiazole (TLC, 7h). The reaction mixture was allowed to cool at room temperature and diluted with water. Further extraction was done using EtOAc (3×5mL). The organic layer was combined and washed with 4N NaOH solution and then with brine. Organic layer was then dried (anh Na2SO4), filtered and concentrated under vacuum. The resulting mixture was purified using column chromatography (ethyl acetate: hexane, 3:97). This resulted in white solid intermediate, 2-(benzthiazol-2-yloxy)ethyl bromide (11b) in 70percent (597mg) yield. |
58% | With potassium carbonate; potassium iodide In acetone at 60℃; | General procedure: A solution of 1,2-dibromoethane (0.02 mol) in 40 ml of acetone was added dropwise into the mixture of respective phenol 1–11 (0.08 mol) and K2CO3 (0.04 mol) in 30 ml of acetone. Subsequently a catalytic amount of KI (0.3 mmol) was added and the resulting mixture was stirred at 60°C for 24–72 hours. After the completion of the reaction the inorganic residues were filtrated off and organic mixture was concentrated under vacuum. The obtained crude product was purified on silica gel with AcOEt/hexane as eluting system.#10;#10; |
54% | With tetrabutylammomium bromide; sodium hydroxide In waterReflux | Phenol 1.0g (10.6mmol) was dissolved in 20mL of water was added NaOH 0.64g (15,8mmol), was added with stirring 1,2-dibromoethane 1.83mL (21,3mmol), was added a catalytic amount of TBAB, was heated to reflux. After the reaction was cooled to room temperature, ethyl acetate (20mL × 3). The combined organic phases, the organic phase was washed with 1N HCl × 2, water × 2, 1N NaOH × 2, × 2 was washed with saturated sodium chloride, dried over anhydrous Na2SO4 dry. Filtration, column chromatography (petroleum ether: ethyl acetate = 50) to give a white solid 1.2g, Yield: 54percent. |
52% | With sodium hydroxide In water for 12 h; Reflux | Equipped with a stirrer, reflux condenser, drying tube, thermometer 100ml three-necked flask was added phenol (1g,8.2mmol), water (14mL) and 1,2-dibromoethane (1.4mL, 16.4mmol), with vigorous stirring, was heated to reflux. Was added dropwise aqueous NaOH (3mL, 3M), the reaction 12h. After the reaction was cooled to room temperature and extracted with ethyl acetate (20mL × 3), washed with saturated brine, dried over anhydrous MgSO4. Column chromatography on silica gel, eluent petroleum ether: ethyl acetate = 20:1 (v / v), to give a pale yellow oil 1.1g (5.47mmol), Yield: 52percent |
44% | With potassium carbonate In acetone at 80℃; for 24 h; | To a solution of phenol (1.88g, 20mmol) and 1,2-dibromoethane (22.56g, 120mmol) in 75 acetone (50mL) was added potassium carbonate (5.52g, 40mmol) under stirring. The mixture was refluxed at 80°C for 24h. After being cooled to room temperature, any insoluable solids were filtered off and the solvent was evaporated from the filtrate to give a residue which was purified by column chromatography (ethyl acetate/petroleum ether=1:50, v/v) to afford the desired product as pale-yellow oil (2b) (1.11g, 44percent). 1H NMR (400MHz, CDCl3, ppm): δ=7.29 (t, J=8.0Hz, 2H), 6.98 (t, J=7.4Hz, 1H), 6.91 (d, J=8.8Hz, 2H), 4.28 (t, J=6.2Hz, 2H), 3.63 (t, J=6.4Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.6% | With lithium bromide In acetone at 20℃; for 24 h; | 1L2 (6.49g, 30.0mmol) in acetone (20mL) was added dropwise to LiBr (13.0g, 150mmol) in 100mL acetone at room temperature. After stirring for 24h, a reaction was stopped by the addition of water (50mL) and the organic portion was separated. The aqueous layer was extracted three times with diethyl ether (3×50mL) and the combined organic portions were dried over MgSO4. Filtration followed by evaporation gave the desired product 1L3 (4.08g, yield=67.6percent) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | General procedure: A solution of anhydrous diisopropylamide (2.30 mL, 16.37 mmol) in anhydrous THF (34 mL) was cooled to-10C. To the solution was added n-BuLi (2.5 M in hexane, 7.00 mL) dropwise over 20 min. The resulting mixture was stirred at -10C for 55 min. To the mixture was added isobutyronitrile (1.22 mL, 13.57 mmol)dropwise over 15 min. After the mixture was stirred at -10C for 75 min, a solution of 2-bromomethylnaphthalene (16d, 2 g, 9.05 mmol) in anhydrous THF (2 mL) was added dropwise over 10 min. The reaction mixture was stirred at -10C for 20 min, then allowed at 0C for additional 2.5 h. The reaction was carefully quenched by saturated NH4Cl aqueous solution. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (30 mL × 5). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give a brown oil, which was recrystallized from petroleum ether (10mL) to give 16c as a white solid (0.91 g, 48 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethyl ether; phenyllithium; diethylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethyl ether; magnesium |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With chlorosulfonic acid; In dichloromethane; at -10 - 20℃; for 3h; | General procedure: Chlorosulfonic acid (20.00 mmol) was added dropwise to an ice-salt bath solution of the appropriate bromoalkoxyphenyl (1-3) (10.00 mmol) dissolved in dichloromethane (25 ml) at -10 C. After stirring for 2 h, the reaction mixture was allowed to warm to room temperature, and was stirred for an additional hour. The reaction mixture was then poured into 200 g of cracked ice and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to afford the corresponding 4-(bromoalkoxy)benzenesulfonyl chloride derivatives (4-6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reaktion von Natriumphenolat; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In acetonitrile; at 80℃; for 6h; | General procedure: The compounds were synthesized according to Scheme 1. A suspension of phenol (10mmol), 1,2-dibromoethane(50mmol), and anhydrous K2CO3 (30mmol) in dry acetonitrile(50mL) was stirred at 80C for 6 h.The reaction mixturewas filtered, and the K2CO3 was recovered, reactivated (in vacuum at 120C, 5 h), and the solvent was concentratedunder reduced pressure.The residue was purified by columnchromatography over silica gel using petroleum ether aseluent to give the product as a solid (Scheme 1, Table 4). 1-(2-Bromoethoxy)-benzene [22, 23] (Entry 1). mp: 33-34C.1H NMR (400MHz, CDCl3), delta: 7.29-7.26 (m, 2H), 6.95-6.92(m, 3H), 4.26-4.23 (t, J = 3.6Hz, 2H), 3.61-3.58 (t, J = 3.6Hz,2H).13C NMR (100MHz, CDCl3) delta: 158, 129.5, 121.4, 114.8,67.8, 29.1. MS m/z (I): 202 (50, M+2), 200 (48, M+), 109 (97),107 (100), 94 (60), 77 (29), 65 (38), 51 (22), 39 (52). |
85% | With sodium hydroxide; In water; | 1-(2-Bromoethyl)piperidine hydrobromide In a mixed solution consisting of 50 g of 1,2-dibromoethane, 18.5 g of phenol and 100 ml of water was added dropwise 30 ml of water containing therein 7.9 g of sodium hydroxide at a temperature of 130 C. over 30 minutes with stirring. The reaction solution was further stirred for 6 hours. After completion of the reaction, the organic layer was separated from the reaction solution, washed twice with a saturated aqueous potassium carbonate solution, washed twice with water and dried with anhydrous sodium sulfate. The organic layer was separated by filtration and condensed under reduced pressure to give 34.3 g of 2-phenoxyethyl bromide having a boiling point of 105 C. to 107 C. at 6 mmHg in a yield of 85%. |
85% | With sodium hydroxide; In water; | REFERENTIAL EXAMPLE 1 1-(2-Bromoethyl)piperidine hydrobromide In a mixed solution consisting of 50 g of 1,2-dibromoethane, 18.5 g of phenol and 100 ml of water was added dropwise 30 ml of water containing therein 7.9 g of sodium hydroxide at a temperature of 130 C. over 30 minutes with stirring, and the reaction solution was further stirred for 6 hours. After completion the reaction, the organic layer was separated from the reaction solution, washed twice with a saturated aqueous potassium carbonate solution, washed twice with water and dried over anhydrous sodium sulfate. The organic layer was separated by filtration and condensed under reduced pressure to give 34.3 g of 2-phenoxyethyl bromide having a boiling point of 105 C. to 107 C. at 6 mmHg in a yield of 85%. |
76.5% | With potassium carbonate; In acetonitrile; at 80℃; for 18h; | In a 250 mL four-necked flask, phenol (18.8 g, 0.2 mol)and 1,2-dibromoethane (131.6 g, 0.7 mol) were dissolved in acetonitrile (100 mL), then the potassiumcarbonate (80 g, 0.6 mol) was added. The reaction mixture was heated to 80 and stirred for 18 h. After completion of reaction (monitored by TLC), the mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated under reduced pressure.The residual was poured into H2O (200 mL) under stirring, then allowed to stand overnight. The solid was collected by filtration and dried under vacuum to afford 2a (30.8 g, yield 76.5%) as a white solid. 1 H NMR(400 MHz CDCl 3) delta 7.33-7.26 (m, 2H), 6.98 (t, J = 7.4,1.1 Hz, 1H), 6.94-6.88 (m, 2H), 4.29 (t, J = 6.3 Hz, 2H),3.64 (t, J = 6.3 Hz, 2H). Anal. Calcd. For C8H9BrO: C,47.78%, H, 4.52%, found: C, 48.58%, H, 4.59%. |
67% | With sodium hydroxide; In water; for 5h;Reflux; | Example 11 Synthesis of N-ethyl-N-(2-phenoxy)ethylcyclohexylamine A 22.5% aqueous sodium hydroxide solution (135 mL) was added to a mixture of phenol (30.0 g (0.32 mol)) and 1,2-dibromoethane (237 g (1.28 mol)), and the mixture was stirred 5 hours under heating at reflux. The temperature was returned to room temperature, and the mixture was then extracted three times with dichloromethane (100 mL). The whose organic layer was dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. The residue was purified by a silica gel chromatography (petroleum ether : ethyl acetate = 10 : 1) to obtain (2-bromoethoxy)benzene (compound-01) (43.0 g, 0.215 mol, yield 67%). |
64% | With potassium carbonate; potassium iodide; In acetone; at 60℃; | General procedure: A solution of 1,2-dibromoethane (0.02 mol) in 40 ml ofacetone was added dropwise into the mixture of respective phenol (0.08 mol) andK2CO3 (0.04 mol) in 30 ml of acetone. Subsequently, acatalytic amount of KI (0.3 mmol) was added and the resulting mixture wasstirred at 60C for 24-72 hours. After the completion of the reaction theinorganic residues were filtrated off and organic mixture was concentrated undervacuum. The obtained crude product was purified on silica gel with AcOEt/hexaneas eluting system. 2.1. (2-Bromoethoxy)benzene 16{1}Yellow oil(6 g, 64% yield), following chromatographic purification over silica gel with AcOEt/hexane (0.5/9.5 v/v); UPLC/MSpurity 97%, tR = 7.98. C8H9BrO, MW 201.06, MonoisotopicMass 199.98, [M+H]+ 200.2. 1H NMR (300 MHz, CDCl3)delta 3.43 (t, J = 6.5Hz, 2H), 4.28 (t, J = 6.5 Hz, 2H), 6.81 (dd, J = 5.2,1.0 Hz, 1H), 6.95 (td, J = 7.6, 1.1 Hz, 1H), 7.02 (m, 1H),7.14 (td, J = 8.0, 1.8 Hz, 1H), 7.21-7.25 (m, 1H). |
64% | With potassium iodide; sodium hydroxide; In methanol; for 8h;Reflux; | This compound was made according to the previous work [1]. Phenol (2.35 g, 25 mmol), NaOH (1 g,25 mmol), 1,2-dibromoethane (10.8 mL, 125 mmol) and a catalyzed amount of KI were added into 50 mL methanol. The solution was refluxed for 8 h. Then the solvent was evaporated and the crude product was purified on column chromatography by using petroleum ether as eluent. The yield was 64%. |
63% | With potassium carbonate; In acetonitrile; at 100℃; | General procedure: 1,2-dibromoethane (573mL, 6.62mmol) was added to a mixture of 2-hydroxybenzthiazole (500mg, 3.31mmol) and potassium carbonate (1.37g, 9.93mmol) in acetonitrile, which were then refluxed (oil bath temp 100C) till the consumption of benzthiazole (TLC, 7h). The reaction mixture was allowed to cool at room temperature and diluted with water. Further extraction was done using EtOAc (3×5mL). The organic layer was combined and washed with 4N NaOH solution and then with brine. Organic layer was then dried (anh Na2SO4), filtered and concentrated under vacuum. The resulting mixture was purified using column chromatography (ethyl acetate: hexane, 3:97). This resulted in white solid intermediate, 2-(benzthiazol-2-yloxy)ethyl bromide (11b) in 70% (597mg) yield. |
58% | With potassium carbonate; potassium iodide; In acetone; at 60℃; | General procedure: A solution of 1,2-dibromoethane (0.02 mol) in 40 ml of acetone was added dropwise into the mixture of respective phenol 1-11 (0.08 mol) and K2CO3 (0.04 mol) in 30 ml of acetone. Subsequently a catalytic amount of KI (0.3 mmol) was added and the resulting mixture was stirred at 60C for 24-72 hours. After the completion of the reaction the inorganic residues were filtrated off and organic mixture was concentrated under vacuum. The obtained crude product was purified on silica gel with AcOEt/hexane as eluting system. |
54% | With tetrabutylammomium bromide; sodium hydroxide; In water;Reflux; | Phenol 1.0g (10.6mmol) was dissolved in 20mL of water was added NaOH 0.64g (15,8mmol), was added with stirring 1,2-dibromoethane 1.83mL (21,3mmol), was added a catalytic amount of TBAB, was heated to reflux. After the reaction was cooled to room temperature, ethyl acetate (20mL × 3). The combined organic phases, the organic phase was washed with 1N HCl × 2, water × 2, 1N NaOH × 2, × 2 was washed with saturated sodium chloride, dried over anhydrous Na2SO4 dry. Filtration, column chromatography (petroleum ether: ethyl acetate = 50) to give a white solid 1.2g, Yield: 54%. |
52% | With sodium hydroxide; In water; for 12h;Reflux; | Equipped with a stirrer, reflux condenser, drying tube, thermometer 100ml three-necked flask was added phenol (1g,8.2mmol), water (14mL) and 1,2-dibromoethane (1.4mL, 16.4mmol), with vigorous stirring, was heated to reflux. Was added dropwise aqueous NaOH (3mL, 3M), the reaction 12h. After the reaction was cooled to room temperature and extracted with ethyl acetate (20mL × 3), washed with saturated brine, dried over anhydrous MgSO4. Column chromatography on silica gel, eluent petroleum ether: ethyl acetate = 20:1 (v / v), to give a pale yellow oil 1.1g (5.47mmol), Yield: 52% |
44% | With potassium carbonate; In acetone; at 80℃; for 24h; | To a solution of phenol (1.88g, 20mmol) and 1,2-dibromoethane (22.56g, 120mmol) in 75 acetone (50mL) was added potassium carbonate (5.52g, 40mmol) under stirring. The mixture was refluxed at 80C for 24h. After being cooled to room temperature, any insoluable solids were filtered off and the solvent was evaporated from the filtrate to give a residue which was purified by column chromatography (ethyl acetate/petroleum ether=1:50, v/v) to afford the desired product as pale-yellow oil (2b) (1.11g, 44%). 1H NMR (400MHz, CDCl3, ppm): delta=7.29 (t, J=8.0Hz, 2H), 6.98 (t, J=7.4Hz, 1H), 6.91 (d, J=8.8Hz, 2H), 4.28 (t, J=6.2Hz, 2H), 3.63 (t, J=6.4Hz, 2H). |
With potassium carbonate; In acetonitrile; at 60℃; | A suspension of phenol (5 g, 0.053 mol), 1,2-dibromethane (60 g, 0.319 mol) and K2C03 (22 g, 0.16 mol) in dry acetonitrile (100 ml) was stirred at 60 C overnight under nitrogen atmosphere. The reaction mixture was filtered and the solvent concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 10 % ethyl acetate in petroleum ether as eluent to yield (10 g) of the sub-title compound as a solid. | |
With potassium carbonate; In acetonitrile; at 50℃; for 24h;Reflux; | General procedure: K2CO3 (0.02 mol) was suspended in BrCH2CH2Br (30 mL, 0.06 mol), and dropwise added different substituted phenols (0.015 mol) in CH3CN (10 mL) at 50 C, then the mixture was refluxed for 24 h and filtered, the filtrate was concentrated and purified by CC (column chromatography) over silica gel (eluent, PE:EA= 10:1) to give the white solid 3a-3r in 40.28-74.32 % yields. | |
With potassium carbonate; In acetone; at 80℃; for 15h;Inert atmosphere; | A mixture of phenol (200 mg, 2.13 mmol, 187 uL, 1.00 eq), 1,2-dibromoethane (2.40 g, 12.8 mmol, 962 uL, 6.00 eq) and K2CO3 (1.76 g, 12.8 mmol, 6.00 eq) in acetone (200 mL) was stirred at 80 C. under N2 for 15 hours. After completion, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC(PE/EA 10/1) to give 2-bromoethoxybenzene (160 mg, 738 umol, 35% yield, 92.8% purity) as colorless oil. (0366) 1H NMR (400 MHz, METHANOL-d4) delta=7.29-7.25 (m, 2H), 6.94-6.91 (m, 3H), 4.30-4.27 (m, 2H), 3.69-3.63 (m, 2H). | |
With potassium carbonate; In acetone; at 45℃; for 12h; | General procedure: To a solution of various substituted phenol (1 equiv) and 1,2-dibromoethane or 1,3-Dibromopropane (5 equiv) in acetone was added K2CO3 (5 equiv) at room temperature. The reaction mixture was heated to 45 C for 12 h. Then the reaction mixture was cooled to room temprature followed by filtration and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a mixture of petroleum ether/ethyl acetate (20:1, v/v) as eluent to afford 2a-L. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(i) NaOMe, acetone, (ii) /BRN= 508290/; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(i) aq. Na2SO3, (ii) PCl5; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In diethyl ether; water; at 20℃; for 4h; | Same procedure as in lit.32 with modifications: a biphasic solution of 2-bromo-1-phenoxy ethane32b (20.0 g, 0.1 mol), NBu4HSO4 (33 g, 0.1 mol) in Et2O (400 mL) and 50% aqueous NaOH (100 mL) was vigorously stirred at rt for 4 h. The organic phase was washed with H2O (3 × 50 mL), the aqueous phases were extracted with Et2O (2 × 50 mL), the combined organic phases dried (MgSO4) and evaporated. 27b was purified by distillation (7.8 g, 65%) at 70 C, 28 Torr. The reaction in toluene as in lit.32b gave a weaker yield (40%).1H NMR (250 MHz, CDCl3): similar values as in lit.37 S.-R. Sheng, X.-L. Liu, X.-C. Wang, Q. Xin and C.-S. Song, Synthesis (2004), pp. 2833-2836. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (21)37 |
20.1% | With potassium tert-butylate; In tetrahydrofuran; for 2h;Inert atmosphere; Reflux; | 25 g of beta-bromophenethol and 25 g of t-BuOK were dissolved in THF (100 mL) and heated under reflux and inert atmosphere for 2 h. Afterwards the mixture was cooled, filtrated and concentrated. The mixture was diluted with diethyl ether and washed with water. The organic layer was dried over MgSO4. Finally, the colorless liquid was purified by distillation, yielding 3.01 g (20.1%) |
Yield | Reaction Conditions | Operation in experiment |
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With ethanol Behandeln des entstandenen Aethylesters mit alkoh. Kali; |
Yield | Reaction Conditions | Operation in experiment |
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95% | With 1,3-dimethylimidazolinium methanesulfonate at 90℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
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88% | With copper(l) iodide; zinc In N,N-dimethyl-formamide at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
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97% | With potassium carbonate; In acetonitrile; for 16.0h;Heating / reflux; | A solution of commercially available 4-methoxy-2-oxo-l,2-dihydro-pyridine-3- carbonitrile (4.0 g, 0.0266 mol), beta-bromophenetole (5.62 g, 0.0279 mol) and K2CO3 (11.0 g, 0.0799 mol) in CH3CN (150 ml) was heated at reflux for 16 hours. The reaction mixture was then filtered off and the filtrate concentrated in vacuo. The residue was recrystallised from ethylether to yield intermediate compound 17 (7 g, 97 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | at 85℃; for 19h; | Example 57A 4,5-Dimethyl-3-(2-phenoxy-ethyl)-3H-thiazol-2-ylideneamine hydrobromide A mixture of <strong>[2289-75-0]4,5-dimethylthiazol-2-ylamine</strong> (1.0 g, 7.8 mmol) and (2-bromo-ethoxy)benzene (1.9 g, 9.4 mmol) were heated neat to 85 C. for 19 hours. The mixture was cooled to ambient temperature and the residue was crystallized from isopropanol. The solid was collected by filtration and dried under vacuum to afford 1.3 g (50%) of the title compound. MS (DCI/NH3) m/z 249 (M+H)+. |
50% | at 85℃; for 19h; | A mixture of <strong>[2289-75-0]4,5-dimethylthiazol-2-ylamine</strong> (1.0 g, 7.8 mmol) and (2-bromo-ethoxy)benzene (1.9 g, 9.4 mmol) were heated neat to 85 0C for 19 hours. The mixture was cooled to ambient temperature and the residue was crystallized from isopropanol. The solid was collected by filtration and dried under vacuum to afford 1.3 g (50%) of the title compound. MS (DCIZNH3) mZz 249 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 90 percent / sodium methoxide / methanol / 2 h / Heating 2: 83 percent / conc. sulfuric acid / ethanol; H2O / 8 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 20h; | Potassium carbonate (52 mg, 0.376 mmol) and then 2-<strong>[589-10-6]phenoxyethyl bromide</strong> (38 mg, 0.189 mmol) were added to a suspension of the N-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (30 mg, 0.124 mmol) obtained in Example 525 in dimethylformamide (1 ml), and the resulting mixture was stirred at room temperature for 20 hours. After the solid was removed by filtration, the dimethylformamide was distilled off under reduced pressure as an azeotrope with toluene to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol/triethylamine = 20/1/1) to obtain N-(8-(2-phenoxyethyl)-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (40 mg, 89%). MS : m/z = 377 (M + 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS); | EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Upon stirring a solution of p-anisoyl chloride (8.53 g, 50 mmol) and beta-bromophenetole (10.05 g, 50 mmol) in 20 mL of anhydrous nitrobenzene at 5 C. under a nitrogen atmosphere, 7.33 g (55 mmol) of anhydrous aluminum chloride was added portionwise. The resulting mixture was stirred at room temperature for 1 hour then at a reduced pressure for 5 minutes to remove the HCl gas produced during the reaction. Stirring was continued at room temperature under the nitrogen atmosphere for another hour. Nitrobenzene was removed at 45 C./0.4 mmHg and the solids deposited were dissolved in 60 mL of chloroform. Upon stirring the solution in an ice bath, 25 mL of 2M HCl was added portionwise. The organic layer was separated and washed with 20 mL of saturated sodium hydrogencarbonate aqueous solution, dried over solid NaHCO3, and filtered through a filter paper. Solvent was removed from the filtrate using a rotary evaporator and the crude product was purified by silica gel column chromatography (particle size 32-63) in CHCl3. The product with Rf=0.26 was collected and recrystallized from chloroform/hexane to give 14.44 g (43 mmol, 86% yield) of white flakes. m.p. 112.2-113.3 C. E.A. C16H15BrO3, calculated C 57.32, H 4.52, Br 23.83; found C 57.40, H 4.55, Br 23.76. 1H-NMR (DMSO-d6) delta 3.86 (m, 5H, -OCH3, -OCH2CH2Br), 4.44 (t, 2H, J=5.40, 5.04 Hz, -OCH2CH2Br), 7.08 (d, 2H, J=8.64 Hz, aromatic H's), 7.11 (d, 2H, J=8.64 Hz, aromatic H's), 7.71 (d, 2H, J=2.52 Hz, aromatic H's), 7.73 (d, 2H, J=2.52 Hz, aromatic H's). 13C-NMR (DMSO-d6) 31.17, 55.51, 67.97, 113.75, 114.33, 129.88, 130.44, 131.84, 161.11, 162.54, 193.12. |
Yield | Reaction Conditions | Operation in experiment |
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91.5% | With potassium carbonate;potassium iodide; In acetonitrile; at 20℃; for 72h; | 0.5 g (0.0057 mol) of (3R)-pyrrolidin-3-ol (commercially available) were dissolved in 15 ml of acetonitrile. To this solution were added 1.32 g (0.0065 mol) of (2- bromoethoxy) benzene, 0.095 g (0.00057 mol) of KI and 1.57 g (0.0114 mol) of K2C03. This mixture was stirred during 72 h at room temperature. The solid was filtered and the solvent was evaporated to dryness. CHCI3 was added to the residue and the solution obtained was washed with water and brine, dried over Na2SO4 and the solvent was evaporated to obtain 1.43 g of an oil. This product was purified by chromatography on silica gel eluting with chloroform/methanol/NH40H (90: 10: 1). The yield was 1.08 g of the title compound (91. 5 %). MS [M+1] + : 208 'H-NMR (CDCI3) : No. 1.80 (m, 1H), 2.20 (m, 1H), 2.40 (m, 1H), 2.65 (m, 1H), 2.75-3. 10 (m, 4H), 4.10 (t, 2H), 4.35 (m, 1H), 6.95 (m, 3H), 7.30 (m, 2H). (3R)-1-(2-phenoxyethyl)pyrrolidin-3-ol is described in WO 9625417 A1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; triethylamine; In methanol; N,N-dimethyl-formamide; | EXAMPLE 20 A mixture of 4-(2-piperidinoethyl)piperidine (3.27 g), 2-bromoethyl phenyl ether (3.35 g), triethylamine (2.3 ml) and DMF (50 ml) was heated on a steam bath for 16 hours. The mixture was worked up as described in Example 16. The crude solid hydrochloride was treated with sodium bicarbonate solution and the mixture extracted with dichloromethane to give the free base which was purified by flash chromatography on silica using methanol/triethylamine, 99:1 as the mobile phase. The oil obtained was dissolved in ether and acidified with ethereal hydrogen chloride to give 1-(2-phenoxyethyl)-4-(2-piperidinoethyl)piperidine dihydrochloride, m.p. 285 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine In toluene | 2 EXAMPLE 2 EXAMPLE 2 A mixture of 4-aminomethylpiperidine (25.0 g), acetophenone (25.6 ml), toluene (1 l) and a catalytic amount of p-toluenesulphonic acid was boiled under reflux for 6 hours, removing the water formed using a Dean and Stark apparatus. The mixture was cooled to approximately 70° C. then molten 2-bromoethyl phenyl ether (44.1 g) and triethylamine (30.5 ml) were added. The mixture boiled under reflux for 5 hours, then cooled and evaporated. The residue was heated on a steam bath for 5 hours with 6M hydrochloric acid (400 ml), to give after work up, 4-aminomethyl-1-(2-phenoxyethyl)piperidine dihydrochloride, m.p. 212°-214° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium hydrogencarbonate; In tetrahydrofuran; diethyl ether; dichloromethane; | Preparatory Example 2 Synthesis of 1-(2-phenoxyethyl)piperazine Piperazine (2.15 g) and 2-<strong>[589-10-6]phenoxyethyl bromide</strong> (1.00 g) were dissolved in tetrahydrofuran (30 ml), and the mixture was stirred at 40 to 60 C for 36 hours. The reaction solution was evaporated, and aqueous saturated sodium bicarbonate and diethyl ether were added to the residue, and the aqueous layer was partitioned. Methylene chloride was added to the aqueous layer, and the organic layer was partitioned. The organic layer was dried over sodium sulfate anhydrous and evaporated, whereby the title compound (664 mg, 65 %) was obtained. |
With hydrogen bromide; In ethanol; water; at 20℃; for 48h;Reflux; | General procedure: HBr (aq. 40%, 0.02 mol and 2.60 mL) was dropwise added to a solution of piperazidine (0.02 mol) in EtOH (50 mL) at r.t., and then 3a-3r (0.01 mol) in EtOH (50 mL) was added. The mixture was refluxed for 48 h, filtered and concentrated. The residue was dissolved in water, acidified with 10% HCl aq. to pH = 5-6 and washed with CH2Cl2, water layer was basified by 10-50 % NaOH till pH > 9 and extracted with CH2Cl2, dried over NaSO4 and evaporated until dryness to obtain the compounds 4a-4r with colorless oil in 35.24-70.98 % yields. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In N,N-dimethyl-formamide; for 17.0h; | 31A: 6-[1-(2-Phenoxyethyl)piperidin-4-yloxy]-2H-isoquinolin-1-one 2-Phenoxyethyl bromide (1 mol eq) was added to a suspension of <strong>[923359-38-0]6-(piperidin-4-yloxy)-2H-isoquinolin-1-one</strong> (30 mg, 0.12 mmol) and potassium carbonate (50 mgs, 3 mol) in N, N-dimethylformamide (1 ml) and shaken for 17 hours. The reactions was quenched with hydrochloric acid (2M) and methanol and passed down an SCX cartridge. The product was purified by preparative HPLC under basic conditions. The clean product was isolated by evaporation under reduced pressure to afford 6-[1-(2-phenoxyethyl)piperidin-4-yloxy]-2H-isoquinolin-1-one: El-MS: m/z=365.1 [M+H]+. | |
With potassium carbonate; In N,N-dimethyl-formamide; for 17.0h; | Example 3131 A: 6-ri-(2-Phenoxyethyl)piperidin-4-yloxyl-2/-/-isoquinolin-1-one2-Phenoxyethyl bromide (1 mol eq) was added to a suspension of 6-(piperidin-4- yloxy)-2H-isoquinolin-1-one (30mg, 0.12mmol) and potassium carbonate (50mgs, 3 mol) in N, ?/-dimethylformamide (1 ml) and shaken for 17 hours. The reactions was quenched with hydrochloric acid (2M) and methanol and passed down an SCX cartridge. The product was purified by preparative HPLC under basic conditions. The clean product was isolated by evaporation under reduced pressure to afford 6-[1-(2- phenoxyethyl)piperidin-4-yloxy]-2H-isoquinolin-1-one: EI-MS: m/z = 365.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydrogencarbonate; In acetonitrile; at 100℃; for 16h; | To a stirred solution of (2-bromoethoxy)benzene (1 g, 5 mmol) in CH3CN (50 mL) wereadded methyl piperidine-4-carboxylate (0.715g, 5 mmol, 1 equiv) and sodium bicarbonate (1.26 g, 15 mmol, 3 equiv) at room temperature. The reaction mixture was heated atlOOand stirred for 16 h. After completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extract was washed with brine, filtered and dried over sodium sulphate. The solvent was removed under reduced pressure. Purificationusing silica gel column chromatography (20% EtOAc Hexanes as eluent) afforded 1 gmethyl 1-(2-phenoxyethyl) piperidine-4-carboxylate (Yield = 76%). ESI+ MS: m/z: 264.1 ([M+Hj). |
65% | With sodium hydrogencarbonate; In acetonitrile; at 80℃; for 20h; | To a stirred solution of methyl isonipecotate (4. 00G, 28.00 mmol) and <strong>[589-10-6]phenoxyethyl bromide</strong> (4. 00g, 20.00 mmol) in acetonitrile (30 ml) was added sodium hydrogen carbonate (7. 00G, 84.00 mmol) and the reaction stirred at 80C for 20 hours. The reaction was cooled, filtered and concentrated under reduced pressure to give a crude brown oil. Purification by column chromatography (7% methanol: dichloromethane) gave the required compound as a light brown oil (4.8g, 65%). oH (270 MHz; CDCL3 ; ME4SI), 1.71-2. 37 (7H, m), 2.79 (2H, t, J 6. 0), 2.93-3. 0 (2H, m) 3.68 (3H, s), 4.10 (2H, t, J 6.0), 6.89-6. 97 (3H, m), 7.24-7. 32 (2H, m). HPLC 99%, m/z (APCI), 264.20 (100% [M+H] +), 232 (40, C14HL802N), 170 (47, C9H1602N). |
Yield | Reaction Conditions | Operation in experiment |
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~ 100% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a solution of lH-pyrrole-2-carbaldehyde (0.45 g, 4.8 mmol) and l-(2- bromoethoxy)benzene (1.1 g, 5.3 mmol) in DMF (20 mL) was added K2CO3 (3.3 g, 24 mmol). After stirring 16 hr at room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed with H2O ( 2 X 100 mL) then brine (100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 1.1 g (~100%) of crude l-(2-phenoxyethyl)-lH-pyrrole-2-carbaldehyde as a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
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75% | With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 55℃; for 21h; | To a solution of lH-indole-6-carboxylic acid methyl ester (0.5 g, 2.9 mmol) and l-(2- bromoethoxy)benzene (0.74 g, 3.7 mmol) in DMF (15 mL) was added K2CO3 (1.2 g, 8.6 mmol). After stirring at room temperature for 16 hr, the mixture was heated to 55 0C for 5 hr then cooled to room temperature and diluted with ethyl acetate (100 ml) and washed with water (3 X 50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was subjected to flash chromatography (20% ethyl acetate/hexane, then ethyl acetate) to provide 0.63 g (75%) of methyl l-(2-phenoxyethyl)-lH-indole-6-carboxylate. 1H nuMR (300 MHz, DMSO) S 8.26 (d, IH, J <n="142"/>= 1.0 Hz), 7.67-7.62 (m, 3H), 7.23 (td, 2H, J= 7.6 Hz5 J= 1.0 Hz), 6.92-6.84 (m, 3H), 6.55 (dd, IH, J- 3.0 Hz, J= 0.6 Hz), 4.66 (t, 2H, J= 4.9 Hz), 4.28 (t, 2H, J = 4.9 Hz), 3.86 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h; | Example 110 N'-[1-imadazol-1-yl-1-[1-(2-phenoxyethyl)imidazol-2-yl]methylidene]-N,N-dimethylhydrazine (compound Nos. 111, 112) To a solution of <strong>[33543-78-1]ethyl imidazole-2-carboxylate</strong> (0.505 g, 3.60 mmol) in N,N-dimethylformamide (6 ml) were added beta-bromophenetole (0.804 g, 4.00 mmol) and potassium carbonate (0.598 g, 4.32 mmol), and the mixture was stirred at 80°C for 1 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give ethyl 1-(2-phenoxyethyl)imidazole-2-carboxylate (0.869 g, 3.34 mmol, yield 93percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4.5h; | Example 101 N'-[1-imidazol-1-yl-1-[3-(2-phenoxyethoxy)thiophen-2-yl]methylidene]-N,N-dimethylhydrazine (compound No. 101) To a solution of methyl 3-hydroxythiophene-2-carboxylate (0.992 g, 6.27 mmol) in N,N-dimethylformamide (12 ml) were added beta-bromophenetole (1.268 g, 6.31 mmol) and potassium carbonate (1.059 g, 7.66 mmol), and the mixture was stirred at 80C for 4.5 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 3-(2-phenoxyethoxy)thiophene-2-carboxylate (1.624 g, 5.83 mmol, yield 93%). |
Yield | Reaction Conditions | Operation in experiment |
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44% | Step 2 : 5-(4-Methoxyphenyl)-l-(2-phenoxyethyl)pyridin-2(lH)-one; According to Scheme 5 Step 2: To a solution of 5-(4-methoxyphenyl)-(lH)-pyridin-2- one (leq, 0.30mmol, 60mg) in TEtaF (3mL) was added K2CO3 (10eq, 3.00mmol, 0.4Ig). The reaction was stirred at room temperature for 30 minutes then l-(2- bromoethoxy)benzene (3eq, 0.90mmol, 0.18g) was added. The reaction was stirred at 60C for 12 hours. After concentration of the solvent, acetonitrile (3mL) was added followed by K2CO3 (10eq, 3.00mmol, 0.4Ig) and l-(2-bromoethoxy)benzene (10eq, 3.00mmol, 0.60g) then the reaction was microwaved for 5 minutes at 180C. The reaction was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 10g SiO2) using CEta2Cl2/AcOEt (80/20) as the eluent to afford 5-(4-methoxyphenyl)-l- (2-phenoxyethyl)pyridin-2(lH)-one (0.13mmol, 42mg, 44%) as a yellow oil. Rf= 0.29 (CEta2Cl2/AcOEt 90/10); LC (XTerra RP18, 3.5mum, 3.0x50mm Column): RT = 4.31min; MS m/z (CI) [MH]+= 322; 1H NMR (500MHz, CDCl3) delta 3.86 (s, 3H), 4.33- 4.37 (m, 2H), 4.38-4.43 (m, 2H), 6.67 (d, J=10.1Hz, 1H), 6.87-6.90 (m, 2H), 6.95-6.99 (m, 3H), 7.25-7.30 (m, 2H), 7.32-7.35 (m, 2H), 7.59-7.62 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | EXAMPLE 2; PREPARATION OF 4-CHLORO-5-METHOXY-2-(2-PHENOXYETHYL)INDAN-l-ONE; 4-Chloro-5-methoxyindan-l-one (14.0 kg, 71.2 mol) (Example 1) was slurried in n- heptane (154 L). Glacial acetic acid (2.14 kg, 35.6 mol) was then added followed by 1,1- dimethylhydrazine (6.42 kg, 106.8 mol) such that the temperature remained <40C. The batch was then heated to 900C for 3 h. The batch was cooled to 600C, treated with THF (28 L) then concentrated to 40 L by distillation under atmospheric pressure. The resulting concentrate was cooled to 500C and diluted with THF (182 L). The THF solution was held overnight at <15C. The batch was cooled to -500C by direct injection of liquid N2, then n-hexyllithium (2.39 M in hexane, 21.2 kg, 71.2 mol) was added over 1.5 h, maintaining the internal temperature <-25C. The resulting slurry was aged between -30 and -200C for 30 min then a solution of beta-bromophenetole (14.4 kg) in THF (14 L) was added over 5 min, maintaining the internal temperature <-25C. The batch was then aged at -50C for 30 min. 6 N HCl (30 kg 37% HCl + 30 kg H2O) was charged to the mixture which was then aged at 500C until complete hydrolysis of the intermediate hydrazone was confirmed by HPLC (1.5 h). After cooling the batch to 200C, isopropyl acetate (56 L) was added and the aqueous layer was discarded. The organic phase was washed with water (75 L) then concentrated to 40 L using vacuum distillation at 4O0C. n-Heptane (40 L) was added and after aging for 30 min at 400C, 0.2% seed of the product ketone was added. The mixture was stirred for 1 h to allow a seed bed to develop, then a further 80 L of n-heptane was charged over 1 h at 400C. The resulting slurry was allowed to cool to 200C overnight then cooled to 5C over 1 h before filtering. The filter cake was washed with 4:1 heptanerisopropyl acetate (25 L), then sucked dry under a stream OfN2 for 3 h. The solid was dried in a vacuum oven at 45C for 48 h affording 20.2 kg of product as an off white solid in 88% yield. 1H NMR (400 MHz, CDCl3) delta 7.70 (IH, d, J = 8.4 Hz), 7.35-7.25 (2H, m), 7.04-6.88 (4H, m), 4.25-4.15 (2H, m), 4.00 (3H, s), 3.46-3.35 (IH, m)> 2.98-2.87 (2H, m), 2.54- <n="10"/>2.41 (IH, m), 2.03-1.89 (IH, m); 13C NMR (IOO MHz, CDCl3) delta 206J, 160.2, 158.8, 153.2, 130.8, 129.5, 123.6, 120.8, 119.7, 1 14.5, 111.6, 65.9, 56.8, 45.0, 32.2 <>31.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: Indole-3-carboxaldehyde With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: phenoxyethyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; | General procedure: The mixture of phenol (700 mg, 3.78 mmol), beta-bromophenetole (836 mg, 4.16 mmol) and cesium carbonate (1.838 mg, 5.67 mmol) in DMF (8 mL) was stirred overnight at 50 C. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over sodium sulfate and purified by recrystallization or flash chromatography. The compound 17b was synthesized starting from 17a following the general procedure H, as given in Example 9, as a white powder in 82% yield. 1H NMR (400 MHz, DMSO) delta 10.08 (s, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.37-7.25 (m, 3H), 7.16 (dd, J=8.6, 2.1 Hz, 1H), 7.00 (d, J=7.9 Hz, 2H), 6.95 (t, J=7.3 Hz, 1H), 4.38-4.28 (m, 4H), 2.05 (s, 3H). 13C NMR (101 MHz, DMSO) delta 168.49, 158.27, 153.57, 139.44, 129.77, 129.51, 120.79, 114.57, 112.10, 104.83, 67.44, 66.03, 24.07. HRMS (ESI) calculated for C16H16ClNO3 [M+Na]+: 328.0711. Found: 328.0720. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; | General procedure: The mixture of phenol (700 mg, 3.78 mmol), beta-bromophenetole (836 mg, 4.16 mmol) and cesium carbonate (1.838 mg, 5.67 mmol) in DMF (8 mL) was stirred overnight at 50° C. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over sodium sulfate and purified by recrystallization or flash chromatography. The compound 25b was prepared by using the general procedure H, as given in Example 9, starting from compound 25a as pale yellow solid in 80percent yield. 1H NMR (400 MHz, CDCl3) delta 7.86 (d, J=2.3 Hz, 1H), 7.77-7.66 (m, 2H), 7.33-7.26 (m, 2H), 7.00-6.93 (m, 3H), 4.49 (dd, J=5.6, 3.5 Hz, 2H), 4.41 (dd, J=6.0, 3.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) delta 158.37, 133.68, 129.55, 121.38, 120.28, 116.91, 114.73, 108.08, 68.58, 66.18. HRMS (ESI) calculated for C14H12BrNO4 [M+H]+: 359.9842. Found: 359.9855. |
50% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 24h; | To a solution of <strong>[52427-05-1]2-bromo-5-nitrophenol</strong> (9g, 0.041 28 mol) in anhydrous DMF (90 mL) at room temperature was added sodium hydride (1.82 g, 0.0454 mol). After stirring the resulting solution for 10 min, (2-bromoethoxy)benzene (9.96g, 0.04954 mol) was added slowly. The reaction was then stirred for 24 h and then quenched with water and diluted with DCM (150 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization from ethyl acetate to afford the title compound (6.95 g, 50percent yield). 1H NMR (399 MHz, DMSO) delta 7.94 (s, 1H), 7.87 (d, J=8.1Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.29 (t, J=6.8 Hz, 2H), 6.99 (d, J=7.6 Hz, 2H), 6.95 (s, 1H), 4.57 (s, 2H), 4.37 (s, 2H). 13C NMR (100 MHz, DMSO) delta 158.22, 155.20, 147.77, 133.77, 129.54, 120.87, 119.20, 116.83, 114.56, 108.28, 68.56, 66.10. HRMS (ESI) calcd for C14H12BrNO4 [M+Na]+ 359.9842; found 359.9855. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | To a flame dried flask back-filled with argon (*2) was added sodium hydride (26.5 g, 1.1 mol) and 325 mL of anhydrous DMF. A solution of N-(4-butyl-3-hydroxyphenyl)acetamide (120 g, 0.58 mol) dissolved in 325 mL of anhydrous DMF was added via dropping funnel over 30 min. at 0 C. The reaction was then brought to 75 C. and held for 4 hrs. Upon completion the reaction was cooled to room temperature and filtered over celite. The resulting solution was diluted with ethyl acetate (600 mL) and washed three times with ice-cold water and once with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude oil was purified further via flash chromatography with hexane:ethyl acetate (2:1) to obtain the title compound in 71% yield (132 g) as a light brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With copper; lithium methanolate In N,N-dimethyl-formamide at 25℃; for 3h; | |
70% | With lithium tert-butoxide In N,N-dimethyl-formamide at 30℃; for 4h; Irradiation; | 2.3. Photocatalytic reactions General procedure: Unless specified otherwise, the reactions were conducted underair with a pressure of 1 atm. A mixture of 1 mmol of alkyl halides,2 mmol of LiOtBu, 1.2 mmol of B2pin2 and 15 mg of Cu2.8Pd0.2/graphene catalyst was dissolved in DMF (10 mL) in a photocatalyticreactor equipped with a magnetic stirring bar. The reaction temperaturewas set at 30 C for alkyl bromides and 50 C for alkylchlorides, respectively, and controlled by a circulating water bath(RT4 circulator, ASONE). The mixture was stirred at 700 rpm during the reaction and exposed to a Xenon lamp (PLS-SXE300C/CUV, BeijingPerfect Light Scientific and Technical Co. Ltd). A low-pass opticalfilter was employed to block light with k < 400 nm. The lightintensity was maintained at 0.6 W/cm2. The effect of the wavelengthof light on catalytic performance was investigated usingvarious low pass optical filters to block light below specific cutoffwavelengths and using various light-emitting diode (LED) lampswith different wavelengths, respectively. For the former, employinga filter with a cut-off wavelength of 450 nm as an example,blocks light with wavelengths < 450 nm (the reaction mixturewas irradiated by light with wavelengths between 450 and800 nm). During this process, the light intensity without filteringfor the reaction remained unchanged.After reaction, the reaction mixture was diluted with dichloromethane(DCM, 10 mL), and filtered through a millipore filter (poresize: 0.22 lm), and n-dodecane (34 mg, 0.2 mmol) was added as aninternal standard. The product yields were determined by gaschromatography-mass spectrometry (GC-MS, BRUKER SCION SQ456 GC-MS) using n-dodecane as the internal calibration standard.The values given are the average of two experiments. The yieldswere calculated based on the amount of alkyl halide. The residuewas purified by column chromatography on silica gel (silica:200-300; eluant: hexane/ethyl acetate) to isolate the desiredproduct. |
69% | With chlorotris(triphenylphosphine)cobalt(I); sodium ethanolate; 1,3-dicyclohexylimidazol-2-ylidene In tert-butyl methyl ether at 50℃; for 16h; Inert atmosphere; |
51% | With potassium <i>tert</i>-butylate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; copper(l) chloride In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; | |
With copper(l) iodide; lithium methanolate In N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere; | ||
77 %Spectr. | Stage #1: bis(pinacol)diborane With potassium methanolate; [1,3-bis(2,4,6-trimethylphenyl)imidazol]-2-ylidene; zinc(II) chloride In tert-butyl methyl ether for 0.5h; Inert atmosphere; Schlenk technique; Glovebox; Stage #2: phenoxyethyl bromide In tert-butyl methyl ether at 20℃; for 1h; Inert atmosphere; Schlenk technique; Glovebox; | |
With potassium methanolate; [1,3-bis(2,4,6-trimethylphenyl)imidazol]-2-ylidene; copper dichloride In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With caesium carbonate In acetonitrile at 60℃; for 4h; Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.1% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | General procedure: Anhydrous K2CO3 (1.2 M equiv) was added to the solution of GA or compound 42 (0.2 mmol) and halogenating agents (1.2 M equiv) in dry DMF (5 mL). The reaction mixture was stirred at room temperature until the starting material was not observed by TLC. The mixture was treated with H2O (20 mL), the aqueous layer was extracted with EtOAc (2×20mL). The joined organic extracts were washed three times with H2O (60 mL) and saturated NaCl (60 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The residue was chromatographed using a silica gel column to afford the pure target products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Alternate synthesis: l-(2-phenoxyethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Sodium hydride (60percent>, 6.3 g, 1.0 eq) was added to a solution of lH-pyrazole-4- carbaldehyde (15 g, 156 mmol) in DMF (150 ml) at 0°C. The mixture was allowed to warm and was stirred at room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting mixture was stirred overnight at room temperature. It was quenched by addition of aqueous ammonium chloride, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography using a hexane/EtOAc gradient (10: 1 to 0: 100). Pure fractions were combined and evaporated under reduced pressure to yield l-(2-phenoxyethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (24 g, 71percent). | |
71% | Sodium hydride (60percent, 6.3 g, 1.0 eq) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (15 g, 156 mmol) in DMF (150 ml) at 0° C. The mixture was allowed to warm and was stirred at room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting mixture was stirred overnight at room temperature. It was quenched by addition of aqueous ammonium chloride, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using a hexane/ EtOAc gradient (10:1 to 0:100). Pure fractions were combined and evaporated under reduced pressure to yield 1-(2-phenoxyethyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (24 g, 71percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With caesium carbonate; In acetonitrile; at 20 - 80℃; | (E)-ethyl 3-(l-(2-phenoxyethyl)-lH-pyrazol-4-yl)acrylateCesium carbonate (0.490g, 1.5 mmol) and l-(2-bromoethoxy)benzene (0.261 g, 1.30 mmol) were added to a solution of (E)-ethyl 3-( H-pyrazol-4-yl)acrylate (0.167 g, 1 mmol) in ACN (8 mL) at room temperature. The suspension was stirred overnight at 80C. The reaction mixture was then cooled down to room temperature and the precipitated solids were filtered off. The filtrate was concentrated and purified by silica gel column chromatography using a gradient of 0-60% of EtOAc in hexanes to provide the title compound (0.203g, 71%) as a colorless oil. ES+ (M+H)+ 287 |
71% | With caesium carbonate; In acetonitrile; at 20 - 80℃; | Cesium carbonate (0.490 g, 1.5 mmol) and 1-(2-bromoethoxy)benzene (0.261 g, 1.30 mmol) were added to a solution of (E)-ethyl 3-(1H-pyrazol-4-yl)acrylate (0.167 g, 1 mmol) in ACN (8 mL) at room temperature. The suspension was stirred overnight at 80 C. The reaction mixture was then cooled down to room temperature and the precipitated solids were filtered off. The filtrate was concentrated and purified by silica gel column chromatography using a gradient of 0-60% of EtOAc in hexanes to provide the title compound (0.203 g, 71%) as a colorless oil. ES+(M+H)+287 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.6% | With lithium bromide; In acetone; at 20℃; for 24h; | 1L2 (6.49g, 30.0mmol) in acetone (20mL) was added dropwise to LiBr (13.0g, 150mmol) in 100mL acetone at room temperature. After stirring for 24h, a reaction was stopped by the addition of water (50mL) and the organic portion was separated. The aqueous layer was extracted three times with diethyl ether (3×50mL) and the combined organic portions were dried over MgSO4. Filtration followed by evaporation gave the desired product 1L3 (4.08g, yield=67.6%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; potassium iodide; In acetonitrile; at 160℃; for 0.166667h;Microwave irradiation; | General procedure: The title compound was synthesized in one step from commercially available starting materials according to the following procedure. Into a 20mL microwave reaction vial, containing a magnetic stir bar, were weighed 5-(trifluoromethoxy)isatin (460mg, 2.0mmol), K2CO3 (550mg, 4.0mmol), KI (33mg, 0.20mmol), followed by acetonitrile (20mL, 0.1M) and 2-bromoethyl phenyl ether (480mg, 2.4mmol). After being sealed with a crimp cap, the vessel was placed in a microwave reactor and heated to 160C for 10min, with magnetic stirring. After cooling to ambient temperature, the reaction was diluted with CH2Cl2 (?20mL) and washed with brine. The organic layer was separated and dried over Na2SO4. Solvent was removed under reduced pressure and the crude product was purified via flash column chromatography (silica gel, hexane/ethyl acetate, 0-50% ethyl acetate gradient). Product containing fractions were combined and the solvents removed under reduced pressure to obtain 583mg of ML326 (83% yield) as a red-orange powder. TLC Rf=0.79 (hexane/ethyl acetate 1:1); 1H NMR (400MHz, CDCl3 calibrated to 7.26) delta 7.52-7.46 (m, 2H), 7.31-7.25 (m, 3H), 6.98 (t, J=7.4Hz, 1H), 6.82 (d, 2H), 4.28 (t, J=5.0Hz, 2H), 4.17 (t, J=5.0Hz, 2H); 13C NMR (125MHz, CDCl3 calibrated to 77.16) delta 182.25, 158.27, 157.93, 150.01, 145.44, 131.02, 129.78, 121.75, 118.32, 114.39, 112.89, 65.94, 40.62; HRMS calcd for C17H13NO4F3[M+H+]; 352.0797 found: 352.0795. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / N,N-dimethyl-formamide / 100 °C 2: hydrazine hydrate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 2-ethylbenzimidazole With sodium hydride In N,N-dimethyl-formamide for 0.5h; Stage #2: phenoxyethyl bromide In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With (triphenylphosphine)silver(I) triflate; triphenylphosphine; 2-bromoethanol; In toluene; at 85.0℃; for 24.0h;Inert atmosphere; Sealed tube; | To a stirred solution of trifluoromethane sulfonic acid silver salt (0.14 g, 0.54 mmol, 0.03equiv) in toluene (10 mL) under argon atmosphere were added triphenyl phosphine (0.14 g,0.54 mmol, 0.03 equiv), AuC1(TPP) (0.27 g, 0.54 mmol, 0.03 equiv) and purged with argon for 5 mm in a sealed tube. To this cyclohexene (1.5 g, 18.25 mmol) and 2-bromo ethanol (4.52 g, 36.45 mmol, 2 equiv) were added at room temperature. The reaction mixture was heated at 85C and stirred for 24 h. After completion, the reaction mixture was diluted withdiethyl ether and filtered. The filtrate was concentrated under reduced pressure. Purification using silica gel column chromatography (2% EtOAc Hexanes) afforded 0.26 g of (2- bromoethoxy) cyclohexane (Yield = 10%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.6% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: To a solution of 1 (200 mg, 0.27 mmol) and K2CO3 (55 mg, 0.40 mmol) in DMF (5 mL), the corresponding bromoalkane derivative 2 or 3 (0.33 mmol) was added under a nitrogen atmosphere and the mixture was stirred at 90C. After the completion of the reaction, water (50 mL) was added and the product was extracted with ethyl acetate (20 mL×3). The combined organic phase was dried over anhydrous Na2SO4. The crude mixture was chromatographed over silica gel column using a mixture of ethyl acetate and petroleum ether. P5-C2-Ph: white solid, in 85.6 %, m.p. 130~131 C; IR (KBr) nu/cm-1: 3050 (C=C-H), 2936, 2853, 2830 (C-H), 1600, 1497, 1469 (Ar-C=C), 1212, 1048 (C-O); 1H NMR (600 MHz, CDCl3) delta/ppm: 7.32 - 7.30 (m, 2H, C3-H,C5-H), 6.98 - 6.96 (m, 3H, C2-H, C6-H, C4-H), 6.82-6.77 (m, 10H, Ca-H), 4.27 (t, J = 6.0 Hz, 2H, C8-H), 4.15 (t, J =6.0 Hz, 2H, C7-H), 3.82 (m, 10H, Cb-H), 3.68 -3.65 (m, 24H, Cc-H), 3.56 (s, 3H, Cc-H); 13C NMR (151 MHz, CDCl3) delta/ppm: 158.95 (C-1), 151.41, 150.93, 149.82, 129.66, 128.35, 116.08, 114.82, 114.27, 114.23, 114.20, 114.13, 114.10 (C-a), 129.24 (C-3,C-5), 121.18 (C-4), 114.41 (C-2,C-6), 67.88 (C-8), 67.08 (C-7), 55.99, 55.97, 55.95, 55.92, 55.90, 55.87, 55.86, 55.77, 53.03 (C-c), 32.02 , 29.86, 29.81, 29.73, 29.68, 22.79, 14.25 (C-b); ESI-MS m/z : 856.61 ([M]+), 874.74 ([M+NH4]+), 879.75([M+Na]+); HRESI-MS m/z : calcd for C52H56O11 856.3823, found 857.3876 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydride; In N,N-dimethyl-formamide; at 40℃; | To a solution of 2-methoxy-5-nitrophenol (3g, 0.017 74 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (0.85g, 0.02128 mmol) followed by (2-bromoethoxy)benzene. The reaction was stirred overnight at 40C. Upon completion, the reaction was quenched with DI H2O and extracted with dichloromethane. The organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was recrystallized in ethyl acetate to give the title product in 90% yield. 1H NMR (400 MHz, CDCl3) delta 7.92 (dd, J=8.9, 2.6 Hz, 1H), 7.87 (d, J=2.6 Hz, 1H), 7.32-7.24 (m, 2H), 6.99-6.92 (m, 3H), 6.90 (d, J=8.9 Hz, 1H), 4.47-4.42 (m, 2H), 4.40-4.36 (m, 2H). 13C NMR (101 MHz, CDCl3) delta 158.54, 155.17, 148.13, 141.42, 129.64, 121.35, 118.44, 114.78, 110.40, 108.73, 68.23, 66.35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate In N,N-dimethyl-formamide at 40℃; | |
With caesium carbonate In N,N-dimethyl-formamide at 40℃; | General Procedure E. General procedure: To N-(3-hydroxyphenyl)acetamide (15 mmol) was added (2-bromoethoxy)benzene (19.5 mmol) along with Cs2CO3 (45 mmol) and DMF (30 mL). The reaction was heated at 40°C. overnight. The reaction was extracted with DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was recrystallized in hexanes/ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 1h; | Compound 99 (100 mg, 0.371 mmol) to DCM (2 mL) the solution was dissolved in methyl isothiocyanate (30.0 , 0.446 mmol) was slowly added dropwise in a 0 and then, at room temperature two hours then stirred dongan. After checking the completion of the reaction by TLC, the solution was diluted with DCM and extracted with brine. The organic layer was dried over anhydrous Na2SO4, concentrated and filtered. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 1: 2) to give Compound 101 was synthesized via a (69.3 mg, 55%, colorless oil). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In acetonitrile Reflux; | General procedure: 2-(benzthiazol-2-yloxy)ethyl bromide (550mg, 2.13mmol) was then added to guanylthiourea (665mg, 1.92mmol) in acetonitrile and refluxed for 36h to obtain white precipitates. On complete consumption of guanylthiourea, the reaction mixture was cooled to room temperature and concentrated under vacuum. The semi-solid mass was washed with diethyl ether (2×5mL) and n-hexane and recrystallized from ethanol (3mL) to obtain white solid compound 11 in 72% yield (453mg). The remaining alkylated GTU derivatives were prepared following this typical procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 1h; | General procedure: To a stirred solution of 1-(2-pyridyl)-b-carboline (0.245 g,1 mmol) in 10 mL DMF, sodium hydride (50% in mineral oil, 0.048 g,1 mmol) and bromo-hydrocarbon (1 mmol) was added. The reactionmixturewas stirred at room temperature for 1 h. After reactionwas finished, the mixture was poured into ice water and extractedwith ethyl acetate. The organic layer was washed with water anddried. Removal of the solvent gave the crude product that waspurified by silica gel column (dichloromethane: methanol 100:1 as the eluent). The solvent was removed and the product wasobtained. |
63% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; | A solution of 0.24 g (10 mmol) of sodium hydride and15 ml of N, N-dimethylformamide was added50ml round bottom flask,Stirred at room temperature for 10 minutes, then 2.5 g (10 mmol) of compound 2 and 10 mmol were added2-<strong>[589-10-6]phenoxyethyl bromide</strong>,And followed by thin layer chromatography to the end of the reaction, and then the reaction solution into 500ml ice water,Extracted three times with 100 ml of ethyl acetate, the organic phases were combined, the solvent was evaporated,The resulting residue was purified by silica gel column chromatography (V dichloromethane: V methanol = 100: 1) to give Compound 3 (2.3 g, yield 63%). |
63% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; | 3)0.24 g (10 mmol) of sodium hydride and 15 ml of N, N-dimethylformamide were added to a 50 ml round bottom flask,Stirred at room temperature for 10 minutes,Another 2.5 g (10 mmol) of compound 2 was addedAnd 10 mmol of 2-phenoxybromoethane,And TLC detection to the end of the reaction,The reaction mixture was then poured into 500 ml of ice water, extracted three times with 100 ml of ethyl acetate,The organic phases are combined, the solvent is evaporated to dryness,The resulting residue was purified by silica gel column chromatography (V dichloromethane: V methanol = 100: 1)Compound 3 (2.3 g, yield 63%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.6% | With potassium carbonate; In acetonitrile; at 85℃; for 4h; | 4-hydroxy-1-indanone 1a (5 g, 33.78 mmol)Dissolved in 70 mL of acetonitrile,Potassium carbonate (8 g, 57.9 mmol)Phenoxyethyl bromide (8 g, 40 mmol) was added dropwise,85 stirring reaction 4h, the reaction is complete,The reaction solution was cooled to roomTemperature, filtration, concentration of filtrate under reduced pressure,Get black oil,And then dissolved in 100 mL of ethyl acetate, dried and dried, and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain intermediate product 1b(6.39 g, 23.85 mmol,White solid, the yield of 70.6%), directly into the next step. |
With potassium carbonate; In acetonitrile; at 85℃; for 3h; | General procedure: To a solution of 4-hydroxy-1-indanone (1a) (1.0 g, 1.0 equiv) and Potassium carbonate (1.2 g, 1.1 equiv) in acetonitrile (35 mL) was added R1-Br (1.1 equiv). The mixture was stirred for 3 h at 85C . After the reaction is completed, the reaction was cooled to room temperature and the Potassium carbonate was filtrated off and washed with ethyl acetate (2×15 mL). The combined organic phases were concentrated in vacuo and purified by silica gel chromatography to give corresponding target product (1b-10b, 16b and 18b-25b). To a solution of acetic acid (0.2 mL) and (1b-10b, 16b and 18b-25b) (0.95 g, 1.0 equiv) in CH2Cl2 was added propargylamine (0.35 mL, 0.77 equiv), the mixture was stirred for 2 h at room temperature. After that, sodium acetate (0.2 g, 0.82 equiv) was added to the mixture which was further stirred for 12 h at room temperature, followed by filtration. Then, the filtrate was stirred for 4 h at 25C with Sodium triacetoxyborohydride (STAB) (1.0 g, 0.75 equiv), followed by filtration. Adjusting pH < 2 by adding hydrogen chloride/methanol solution (10 mL), then the resultant was collected and washed with ethyl acetate, dried over MgSO4 and purified to afford the corresponding target product (D1-D10, D16 and D18-D25). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4,5-dichloroimidazole With potassium hydroxide In dimethyl sulfoxide at 35℃; for 0.25h; Stage #2: phenoxyethyl bromide In dimethyl sulfoxide at 45 - 50℃; for 0.5h; | General method for the synthesis of 1-(2-aryloxy)ethyl-4,5-dichloroimidazoles (IIf)-(IIn). General procedure: A mixtureof 4,5-dichloroimidazole (Ia) (1.37 g, 10 mmol)and finely ground KOH (10 mmol, taking intoaccount the 85% content) in DMSO (7 mL) wasstirred at 35 °C for 15 min, followed by the addition of2-aryloxybromide (11 mmol) at such a rate that thereaction temperature did not exceed 50°C. The reactionoccurred for 30 min at 45°C. After cooling, water(40 mL) was gradually added, and the resulting voluminousprecipitate of 1-aryloxyethyl-substitutedimidazoles (IIf)-(IIn) were filtered and washed with5% KOH (2 mL) and water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In toluene; at 80℃; for 0.333333h;Microwave irradiation; | General procedure: 1-Hexylimidazole (1 eq) and the appropriate alkyl halide (1 eq) were placed in a closed vessel and exposed to irradiation for 20 min at 80 C using a microwave irradiation. The product was then collected as described in the conventional procedure outlined earlier. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: carbon disulfide; L-homoserine lactone hydrochloride With sodium phosphate dodecahydrate In acetone for 0.5h; Stage #2: phenoxyethyl bromide In acetone | 4.7 General procedure for the synthesis of compounds 8a-j General procedure: Compounds 7a-7j were prepared following the literature reported methods in 54-83% yields [29]. To a solution of compound 3 (102mg, 0.74mmol) and Na3PO4·12H2O (423mg, 1.11mmol) in acetone (10mL) was added CS2 (94μL, 1.55mmol). After 0.5h stirring, the corresponding compounds 7a-7j were added. About 1-2h later, the solvent was removed under vacuum, the resulting residue was dissolved with DCM and then washed with brine. The organic layer was dried over MgSO4 and evacuated under vacuum to give the residue, which was then subject to column chromatography, affording the corresponding 8a-j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In acetonitrile for 0.05h; Microwave irradiation; | 4.1 4.2.3.2 Microwave irradiation (MWI) General procedure: Dipyridine Schiff base 4 and/or 5 (1mmol), acetonitrile (5mL), and the appropriate bromoalkoxybenzene derivatives (2mmol) were placed in closed borosilicate glass vessel fitted with a silicone cap and exposed to irradiation for 3-4min using a microwave reactor. The reaction was processed as described in the conventional procedure outlined earlier to give the same dicationic pyridinium bromides 6-11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In N,N-dimethyl-formamide; at 70 - 90℃; for 2h; | General procedure: 2-Phenoxyethylbromide (4.02 g, 20 mmol) and K2CO3 (2.76 g, 20 mmol) wereadded to the solution of the corresponding hydroxybenzaldehyde(2.44 g, 20 mmol) in DMF (20 mL). The reaction mixturewas stirredduring its heating from 70 to 90C within 1.5 h and incubated at90 for another 30 min. After cooling to room temperature, thevessel contents were poured into H2O (60 ml) and the suspensionwas stirred at 10C for 45 min; the precipitatewas filtered, air driedand washed 2 times on a filter with n-hexane (5 ml) and air dried.The yields of m- and p-PEGO-BA were 79 and 76%, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In toluene at 80℃; for 0.333333h; Microwave irradiation; Green chemistry; | 3.2.1. General procedures for the synthesis of imidazolium halides (1-17)using the microwave method General procedure: The alkyl halides (1.1 eq) were added to a solution of 1-pentyl-1Himidazole(1 eq) in toluene. The solution was then treated with irradiationfor 20 min in a closed vessel at 80 °C using a CEM Microwave. Thecompletion of the reaction was indicated by the formation of an oil orsolid phase from the initially clear homogenous mixture composed ofN,N-pentylimidazole and the alkyl halide in toluene. The product waseither filtered or extracted, and then washed with ethyl acetate. TheIL/salt was then dried at reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: 2,2'-bis(1,3,2-benzodioxaborole); phenoxyethyl bromide With tetrabutylammonium tetrafluoroborate In N,N-dimethyl acetamide at 25℃; for 0.316667h; Electrolysis; Inert atmosphere; Stage #2: 2,3-dimethyl-2,3-butane diol With triethylamine In N,N-dimethyl acetamide at 25℃; for 1h; Inert atmosphere; |
Tags: 589-10-6 synthesis path| 589-10-6 SDS| 589-10-6 COA| 589-10-6 purity| 589-10-6 application| 589-10-6 NMR| 589-10-6 COA| 589-10-6 structure
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