|
With thionyl chloride; In dichloromethane; |
(1) Production of 2,5-dimethoxybenzoyl chloride: <strong>[2785-98-0]2,5-dimethoxybenzoic acid</strong> (643 mg, 3.53 mmols) was put into a 30-ml two-neck flask, purged with argon, and dissolved in 1 ml of dry methylene chloride. Next, thionyl chloride (0.5 ml, 7.05 mmols) was added to the flask, and heated under reflux at 70 C. for 5 hours. Next, the solvent was removed by evaporation under reduced pressure, using an aspirator. |
|
With thionyl chloride; for 1h;Heating / reflux; |
A mixture of <strong>[2785-98-0]2,5-dimethoxybenzoic acid</strong> (5.0 g, 27.5 mmol) and thionyl chloride (15 mL) was refluxed for 1 hour. The volatiles then were removed under vacuum.The residue was dissolved in THF (20 mL) and added into a cold (0 C.) solution of 2,5-dimethoxyaniline (4.6 g, 30.2 mmol), triethylamine (5 mL, 35.9 mmol) and THF (40 mL). The reaction mixture was stirred for 30 mins., poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 2/1) gave a white solid (8.1 g, 93% yield, m.p. 121-123 C.); MS m/e 318 (M+H)+. Analysis for: C17H19NO5 Calc'd: C, 64.34; H, 6.03; N, 4.41 Found: C, 64.29; H, 5.95; N, 4.44 |
|
With oxalyl dichloride; In dichloromethane; at 20℃; for 24h; |
General procedure: To a solution of dimethoxylbenzoic acid (2.39 g, 13.14 mmol) in dry dichlormethane (60 mL) was added oxalyl chloride (5.73 mL, 65.7 mmol). The mixture was stirred at room temperature for 24 h and then concentrated under reduced pressure to afford dimethoxylbenzoyl chloride 3a-d as colorless residue. To a solution of 3a-d and 1,2,3-trimethoxybenzene (2, 2.43 g, 14.45 mmol) in 20 mL anhydrous ether, aluminum trichloride (5.26 g, 39.42 mmol) was added at 0 C. The resulting mixture was stirred for 12 h at room temperature under N2 protection. Then a mixture of 15% hydrochloric acid and ethyl acetate (100 mL, V/V = 1:1) were added. The ethyl acetate layer was partitioned, washed with brine (30 mL × 3), dried over magnesium sulfate and concentrated under reduced pressure. The residue was suspended in a solution that contained methanol (22.4 mL), water (14.9 mL) and sodium hydrate (4.9 g, 0.12 mol) at 0 C. Then the reaction mixture was heated to 110 C for next 36 h. After cooled to 0 C, the mixture was acidified with 2 mol/L HCl solution till pH = 2-3. The precipitation was formed, filtered, washed with cold water and dried to provide 4a-d, respectively. |
|
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; |
To a solution of <strong>[2785-98-0]2,5-dimethoxybenzoic acid</strong> (6.00 g, 33.0 mmol) in DCM (100 mL) was added oxalyl chloride (3.6 mL, 41.3 mmol) and then DMF (0.2 mL). The solution was stirred at room temperature for 2 h, and the solvent was removed under reduced pressure. The crude material was placed under vacuum for 30 min to remove all of the oxalyl chloride. To a mixture of the residue and N, O-dimethylhydroxylamine hydrochloride (4.03 g, 41.32 mmol) in DCM (100 mL) at 0 C, triethylamine (6.8 mL, 48.78 mmol) was added dropwise. The solution was stirred at 0 C for 30 min and then at room temperature for additional 30 min. The reaction was diluted with DCM (50 mL), washed (2x100 mL H20, 100 mL brine), dried over Na2S04, and concentrated under reduced pressure. The crude material was purified on a silica gel column to yield N,2,5-trimethoxy-N-methylbenzamide (7.32 g, 99%) as clear oil which solidified over time. 1H NMR (CDC13): delta 7.90 (m, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.58 (br s, 3H), 3.32 (br s, 3H). |
|
With thionyl chloride; In chloroform; for 8h;Reflux; |
General procedure: To a solution of an appropriate substituted carboxylic acid (10 mmol) in CHCl3 (50 mL) was added thionyl chloride (3.6 mL, 50 mmol), dropwise over 10 min. The resulting solution was refluxed for 8 h and then concentrated in vacuo. The residual light brown oil was dissolved in THF (50 mL), diluted with a solution of 30% NH4OH (6 mL), and stirred at room temperature for an additional 2 h. At that point, saturated aqueous NaHCO3 (10 mL) was added and the reaction mixture was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude amide was carried directly to the next step without further purification. |
|
With thionyl chloride; at 75℃; for 6h;Inert atmosphere; |
General procedure: The mixture of suitable substituted benzoic acid (5a-5d, 0.01 mol) and thionyl chloride (5 ml) was stirred at 75 C for 6 h under nitrogen. After removal of excess thionyl chloride in vacuo, 4-methoxy-2-nitroaniline (1b, 0.01 mol) and anhydrous Na2CO3 (0.1 mol) were added to the reaction mixture dissolved in anhydrous acetone (50 ml). After stirring at 54 C for 1 h, the solvent was removed under vacuum and the residue was poured into ice water with stirring. The precipitated solid was fitered, washed with ice water and dried to obtain the corresponding N-phenylbenzamide derivatives (7a-7d). To a solution of N-phenylbenzamide derivatives (7a-7d, 0.01 mol) in anhydrous acetic acid (50 ml) was added iron powder (0.03 mol), and then the mixture was refluxed at 100 C. After completion of the reaction as indicated by TLC, the solvent was evaporated under reduced pressure and the residue was extracted with CH2Cl2 (3 × 20 mL). The combined organic fractions were washed with saturated NaHCO3, brine, dried (Na2SO4), and evaporated in vacuo. The residue was chromatographed on silica gel using petroleum ether/EtOAc (10:1-4:1). |
|
With thionyl chloride; at 70℃; for 1h; |
A solution of <strong>[2785-98-0]2,5-dimethoxybenzoic acid</strong> (5.00 g) in thionyl chloride (20 mL) was heated to 70 C. for 1 h. The volatiles were removed under reduced pressure and the residue was dissolved in CH2Cl2 (20 mL). This solution was added to a solution of N,O-dimethylhydroxylamine hydrochloride (2.95 g) and NEt3 (4.12 mL) in CH2Cl2 (40 mL) at 0 C. and the resulting mixture was stirred at ambient temperature overnight. Saturated ammonium chloride solution was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated sodium bicarbonate solution and brine and were dried. The volatiles were removed under reduced pressure to yield the desired product (80% yield). |
|
With thionyl chloride; at 75℃; for 1h; |
A solution of <strong>[2785-98-0]2,5-dimethoxybenzoic acid</strong> (100 mg, 0.549 mmol) in SOCl2 (1 mL) at 75C was stirred magnetically for 1 h, then cooled and concentrated in vacuo to remove excess thionylchloride. |
|
With thionyl chloride; at 75℃; for 1h; |
A solution of <strong>[2785-98-0]2,5-dimethoxybenzoic acid</strong> (100 mg, 0.549 mmol) in SOCI2(1 mL) at 75C was stirred magnetically for 1 h, then cooled and concentrated in vacuo to remove excess thionylchloride. To a mixture of this acid chloride in 1 mL CH2CI2 was added drop wise 1-phenylpiperazine (89 mg, 0.549 mmol, 120 mu) solution in 1 mL CH2CI2followed by ethyldiisopropylamine (0.2 mL). The mixture was stirred for a further 18.5 hours before being concentrated in vacuo. The residue was purified over silica gel with 0-100% ethyl acetate in cyclohexane to yield (2,5-dimethoxyphenyl)-(4-phenylpiperazin-1 -yl)methanone (170 mg, 0.521 mmol) in 95 % yield. |
|
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; |
Oxalyl chloride (3.6 mL, 41.3 mmol) was added to a solution of <strong>[2785-98-0]2,5-dimethoxybenzoic acid</strong> (6.00 g, 33.0 mmol) in DCM (100 mL) at room temperature. Then, DMF (0.2 mL) was added to the mixture. The resulting solution was stirred at room temperature for 2 h, and the solvent was removed on a rotary evaporator. The crude material was placed under vacuum for 30 minutes to remove the residual oxalyl chloride to give the crude acid chloride. Crude material was dissolved in DCM (100 mL) and cooled to 0 C. To this solution, Nu,Omicron- dimethylhydroxylamine hydrochloride (4.03 g, 41.32 mmol) and triethylamine (6.8 mL, 48.78 mmol) were added. The resulting mixture was stirred at 0 C for 30 min and then at room temperature for additional 30 min. The reaction was diluted with DCM (50 mL), washed with H20 (2x100 mL), washed with brine (100 mL), dried over a2S04, filtered, and concentrated on a rotary evaporator. The crude material was purified by silica gel chromatography to yield N,2,5- trimethoxy-N-methylbenzamide (7.32 g, 99%) as clear oil which solidified over time. 1H NMR (CDC13): delta 7.90 (m, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.58 (br s, 3H), 3.32 (br s, 3H). |
|
With thionyl chloride;Reflux; |
General procedure: A mixture of benzoic acid 8 (10 mmol) in sulfinyl dichloride (SOCl2, 20-50 mmol) was stirred under reflux condition for 3-8 h, and then the solvent was removed under reduced pressure to afford crude chlorides 9. Ammonium thiocyanate (15 mmol) and PEG-400 (0.18 g) were added to the solution of benzoyl chloride 9 (10 mmol) in dichloromethane (25 mL). The mixture was stirred at room temperature for 1 h. Then the precipitate was filtered off, the filtrate containing compounds 10 was collected to be used in next step directly. |
|
With thionyl chloride; at 79℃; for 4h;Inert atmosphere; |
Based on a method reported in the literature, a flame-dried round bottom flask was charged with 2, 5-dimethoxybenzoic acid 21 (1 equiv) and thionyl chloride (10 equiv), and the mixture was refluxed for 4 h at 79 C. The reaction was concentrated under reduced pressure to furnish the desired acid chloride, which was carried on to the next step without further purification |