| 75.2% |
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.333333h; |
General procedure: In a round bottom flask, 10mmol aniline derivitives (4a-n) and 20mmol potassium carbonate were suspended in 15mL DMF and cooled to 0C. Then 12mmol chloroacethylchloride was added. The reaction mixture was then stirred at room temperature for 20min; quenched with saturated sodium hydrogen carbonate (10mL) and washed with water. The organic layer was separated and dried over sodium sulfate. The organic layer was evaporated under reduced pressure, and the crude reaction mixture was purified by column chromatography using chloroform and methanol as a mobile phase to obtain a pure compound [36-39]. The CAS-numbers and yield of synthesized compounds were reported in the supplementary file (Table S1). |
| 75.8% |
With triethylamine; In dichloromethane; at 0℃; for 4h; |
General procedure: Weigh 0.51g (5mmol) of aniline (5mmol) and triethylamine in a 50mL round bottom flask, add 10mL of dichloromethane, use nitrogen protection, add 0.56g (5mmol) of chloroacetyl chloride, and place in an ice-water bath at 0 and stir. After reacting for 4 hours, add 20mL of dichloromethane to dilute the reaction, wash with 1M hydrochloric acid, saturated sodium bicarbonate solution and brine successively, and use rotary evaporation to remove dichloromethane to obtain substituted aniline (7) |
| 70% |
|
General procedure: To a solution of substituted aniline (compounds 1a-1t) or 5-aminoindole and 6-aminoquinoline (1.0 equiv.) in dichloromethane (CH2Cl2) (15mL) at 0C, potassium carbonate (K2CO3) (2.0 equiv.) was added. The reaction was stirred at 0C for 15min. Into this stirring solution, chloroacetyl chloride (1.0 equiv.) was added dropwise at 0C. The mixture was stirred for 2hat room temperature. After completion of the reaction, water (20mL) was added, and the mixture was extracted with dichloromethane. The organic solvent phase was concentrated under vacuum to afford the desired compounds 2a-2t, 5a and 5b. |
| 53.01% |
|
General procedure: Step 1. To the stirred solution of Aniline (1.0 equiv) in acetone was added K2CO3 (1.2 equiv.) at RT and stirred for 30min. Chloroacetyl chloride/substituted acetylchloride (1.1 equiv.) was then added at 0C and stirred for additional 3h at room temperature. After completion of the reaction (monitored by TLC), volatiles were removed on rotary evaporator and ethyl acetate was added. Organic layer were washed with water, aq NaHCO3, brine. Organic layer was dried over sodium sulfate and evaporated on rotary evaporator and the crude residue was purified by flash chromatography to give the desired product. |
|
With pyridine; In water; at 0℃; for 1h; |
General procedure: Generalprocedure: To a solution of aniline or benzylamine (10 mmol) inwater (20 ml) and pyridine (1.6 ml) was added chloracetyl chloride(1.69 g, 15 mmol) slowly at 0 C. The reaction mixture was stirredat 0 C for 1.0 h and then diluted with water (50 ml). The precipitatewas collected by filtration, washed with water and dried undervacuum. N-substituted-2-chloroacetamides 3a-3r were obtainedas solid (yield 50-80%). |
|
In N,N-dimethyl-formamide; at 20℃; for 0.333333h; |
General procedure: To a stirred solution of substituted aniline (1 mmol) and chloroacetyl chloride (1 mmol) which was stirred in 5 mL DMF for 20 min, were added benzyl amine derivatives (1.3 mmol) and CS2 (5 mmol). The reaction mixture was allowed to stir for required additional time (Table 2). Then, 5 mL of water was added and the solution was extracted with ethyl acetate and dried over sodium sulfate and purified by passing over a silica gel column chromatography using petroleum ether/ethyl acetate (8:2). |
|
With triethylamine; In dichloromethane; at 20℃; for 0.5h; |
General procedure: To a solution of the appropriate amine (50 mmol) in triethylamine (5.1 mg, 50.5 mmol) and dichloromethane (50 mL), chloroacetyl chloride (70 mmol) was added dropwise, and the mixture was allowed to stir at room temperature for 30 min. Then, it was slowly poured into a saturated solution of NaHCO3 (100 mL). The layers were separated, and the aqueous layer was extracted with CH2-Cl2 (30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The product was dried and recrystallized from ethyl acetate andpetroleum ether to obtain 2-chloro-N-substituted acetamides. The properties and analytical data for these compounds 15a-v were listed in the supporting information. |
|
|
General procedure: Under nitrogen atmosphere, dry CH2Cl2 (30 mL), amine (0.02 mol), and Et3N (0.05 mol) wereadded to a three-necked round bottom ask and stirred for 0.5 h, then chloroacetyl chloride droppedslowly and reacted for 3 h at room temperature. Then, the solution was washed with 2 mol L1hydrochloric acid (30 mL), saturated aq NaHCO3 solution (30 mL), and brine (40 mL), successively,then dried over anhydrous Na2SO4 and filtered. After evaporating CH2Cl2 in vacuum, the obtainedcrude product was rened by recrystallization using ethyl acetate/petroleum ether. |
|
In N,N-dimethyl-formamide; at 20℃; for 0.5h; |
General procedure: Mixture of amines 6 and chloroacetyl chloride 7 in DMF werestirred at room temperature for 30 min. At the end of the reaction(checked by TLC), the reaction mixture was diluted with water, pouredinto ice, and the obtained white precipitate was filtered off. The residuewas washed with water to obtain pure N-phenyl (or benzyl)-2-chloroacetamide8. |
|
With triethylamine; In dichloromethane; at 0 - 25℃; for 20h; |
General procedure: 2-Chloroacetyl chloride (24 mmol) wasslowly added dropwise to a mixture of various anilines(20 mmol) and Et3N (24 mmol) in anhydrous CH2Cl2(20 mL) at 0 C. The reaction mixture was warmed to roomtemperature and stirred for an additional 20 h. After the solventwas removed under reduced pressure, the residue waswashed with ice water, and the precipitate was separatedby filtration. The crude product was purified by crystallizationusing a mixture of ether/hexane (2a-r). |
|
In acetic acid; at 0 - 20℃; |
General procedure: Various substituted anilines were dissolved in glacial acetic acidat 0 C, to this was added over 30 min choloroacetylchloride (2equivalents). The reaction mixture was brought to room temperatureand stirred overnight. Saturated sodium bicarbonate solutionwas added till complete neutralization. The resulting precipitatewas filtered off and washed with n-hexane and dried. The resultantproduct was used further without any purification. Either of 3-hydroxy benzaldehyde, 4-hydroxy benzaldehyde, vanillin or isovanillin(1 equivalent) was dissolved in acetone and potassiumcarbonate (2 equivalents) was added. Then correspondingsubstituted acetamide was mixed to the stirring solution. Finally,potassium iodide (1.5 equivalent) was added. The reaction mixturewas refluxed for 8-10 h. After completion of reaction, the resultantmixture was concentrated and treated with water and extractedwith ethyl acetate (3 x 20 mL). The organic layers were combinedand treated with brine and dried over sodium sulfate andconcentrated. The crude mixture was purified over silica gel(60-120) using petroleum ether: ethyl acetate (9:1). |
|
With acetic acid; at 0 - 20℃; |
General procedure: Various substituted anilines were dissolved in glacial acetic acid at0 C, to this was added over 30 min choloroacetyl chloride (2 equivalents).The reaction mixture was brought to room temperature andstirred overnight. Saturated sodium bicarbonate solution was added tillcomplete neutralization. The resulting precipitate was filtered off andwashed with n-hexane and dried. The resultant product (1) was usedfurther without any purification. Either of 4-hydroxy benzaldehyde(2a), vanillin (2b) or isovanillin (2c) (1 equivalent) was dissolved inacetone and potassium carbonate (2 equivalents) was added. Thencorresponding substituted acetamide (1) was mixed to the stirring solution.Finally, potassium iodide (1.5 equivalent) was added. The reactionmixture was refluxed for 8-10 h. After completion of reaction,the resultant mixture was concentrated and treated with water andextracted with ethyl acetate (3×20 mL). The organic layers werecombined and treated with brine and dried over sodium sulfate andconcentrated. The crude mixture was purified over silica gel (60-120)using petroleum ether: ethyl acetate (9:1). |
|
With triethylamine; at 0 - 20℃; for 4h; |
General procedure: In a round bottom flask, primary or secondary amines (0.1 mol) and triethyl amine weredissolved in DCM and stirred at 0 C. 2-Chloroacetyl chloride (0.1 mol) was added to reaction mixture drop wise with continuous stirring on magnetic stirrer. After the addition,the ice bath was removed and the reaction mixture was stirred at room temperature for 4 h.The progress of the reaction was monitored by TLC using ethyl acetate: hexane (1:9) as asolvent system. After completion of the reaction, the reaction mixture was poured on crushedice and neutralised by adding acetic acid to it. The obtained solid intermediates of respectiveamines were filtered, dried and crystallised in ethanol. |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 12h; |
General procedure: A stirred solution of aniline derivatives 1a-h (0.05 mol) in dichloromethane DCM (50 mL) was cooled to 0 C, and chloroacetyl chloride (0.06 mol) and triethylamine (0.06 mol) was added dropwise to the solution. The resulting mixture was warmed to room temperature and stirred overnight. The organic phase was diluted with DCM (50 mL) and washed with 0.5 M HCl (50 mL), then saturated with NaHCO3 and brine. The organic layer was collected and dried over anhydrous Na2SO4. Then, the solvent was removed under reduced pressure. The 2-chloro-N-phenylancetamide derivatives (5 mmol) obtained by recrystallization were refluxed with potassium iodide (7.5 mmol) in acetone (10 mL) for 6 h, and the solvent was evaporated in vacuo. Water (50 mL) was added to the reaction mixture, and the organic phase extracted with ethyl acetate was washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated, then recrystallized from ethyl acetate to obtain Compounds 2a-h [1-3]. Moxifloxacin (2 mmol) and TEA (4.4 mmol) were added to a stirred solution of 2-iodo-N-phenylancetamide derivatives 2a-h (2.2 mmol) in acetonitrile (10 mL). The mixture was heated under reflux for 12 h, then the solvent was removed under vacuum. The resulting solid was recrystallized using acetonitrile to afford eight 4a-h [4]. |
|
With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; |
General procedure: The corresponding amine was dissolved in anhydrous dichloromethane at 0C, and then triethylamine (1.1 eq) was added under a nitrogen atmosphere. Chloroacetyl chloride (1.1 eq) diluted with anhydrous dichloromethane was slowly added to the reaction mixture in an ice bath. The reaction stirred at 0C for 30min, after which the reaction slowly warmed to room temperature overnight. TLC was used to monitor the reaction. After the reaction was complete, it was quenched with water and extracted with dichloromethane. The organic phase was retained and washed with an aqueous hydrochloric acid solution, an aqueous saturated sodium hydrogen carbonate solution, and brine three times. Anhydrous sodium sulfate was used to dry the organic phase, after which the solvent was removed under reduced pressure with a rotary evaporator to obtain crude product. The crude product was dissolved in ethyl acetate and recrystalized with petroleum ether to afford the final product. Compounds 5-14 were in 58-86% yield. |
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