2,6-DIMETHYLANILINE HYDROCHLORIDE synthesis
- Product Name:2,6-DIMETHYLANILINE HYDROCHLORIDE
- CAS Number:21436-98-6
- Molecular formula:C8H12ClN
- Molecular Weight:157.64
2198-53-0
925-90-6
21436-98-6
The general procedure for the synthesis of 2,6-dimethylaniline hydrochloride from 2,6-dimethylacetanilide and ethylmagnesium bromide was as follows: trifluoromethanesulfonic anhydride (Tf2O, 185 μL, 1.1 mmol) was added slowly and dropwise to a cooled-to-0°C dichloromethane ( 4 mL) solution. The reaction mixture was stirred at 0 °C for 30 min, then transferred to -78 °C and a solution of tetrahydrofuran (THF, 15 mL) of freshly prepared organocerium reagent/complex (3.0 mmol) was added, and stirring was continued for 2 hours. Upon completion of the reaction, the reaction was quenched by the addition of a 3 mol/L aqueous hydrochloric acid solution (5 mL) and the mixture was gradually warmed to room temperature with continued stirring for 2 hours. Subsequently, 25% ammonium hydroxide solution (5 mL) was added to the mixture. The organic layer was separated and the aqueous phase was extracted with ether (3 x 10 mL). The organic layers were combined, washed with saturated saline (3 x 3 mL) and concentrated under reduced pressure to about 1/3 of the original volume. the residual organic phase was extracted with 3 mol/L aqueous hydrochloric acid solution (3 x 5 mL). The separated organic phase was washed with saturated saline (5 mL), dried with anhydrous magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure, and the residue was purified by silica gel fast column chromatography to obtain the target ketone product. All aqueous phases were combined, washed with ether (5 mL) and alkalized with 25% ammonium hydroxide solution (5 mL), then back-extracted with ether (5×20 mL). The ether layers were combined, washed with saturated saline (5 mL), dried over anhydrous magnesium sulfate (MgSO4), filtered and acidified with 3 mol/L ethyl acetate hydrochloride solution (5 mL), and finally concentrated under reduced pressure to give 2,6-dimethylaniline hydrochloride.
2198-53-0
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Yield: 84%
Reaction Conditions:
Stage #1:N-(2,6-dimethylphenyl)acetamide with 2-fluoropyridine;trifluoromethylsulfonic anhydride in dichloromethane at 0; for 0.5 h;
Stage #2:ethylmagnesium bromide with cerium(III) chloride in tetrahydrofuran;dichloromethane at -78; for 2 h;
Stage #3: with hydrogenchloride in ethyl acetate
Steps:
General procedure for N-deacylation of secondary amides
General procedure: Tf2O (185μL, 1.1mmol) was added dropwise to a cooled (0°C) solution of amide (1.0mmol) and 2-fluoropyridine (103μL, 1.2mmol) in dichloromethane (4mL). After stirring at 0°C for 30min, the mixture was cannulated to a freshly prepared organocerium reagent/complex (3.0mmol) in THF (15mL) at -78°C and stirred for 2h. Aqueous HCl solution (3mol/L, 5mL) was added to quench the reaction and the mixture was allowed to warm to r.t. and stirred for 2h. Ammonium hydroxide solution (25%, 5mL) was then added to the mixture. The organic layer was separated and the aqueous phase was extracted with diethyl ether (3× 10mL). The combined organic layers were washed with brine (3× 3mL) and concentrated under reduced pressure to about 1/3 volume. The residual organic phase was then extracted with aqueous HCl solution (3mol/L, 3× 5mL). The separated organic phase was washed with brine (5mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to afford ketone. The aqueous phases were combined, washed with diethyl ether (5mL), basified with an ammonium hydroxide solution (25%, 5mL) and back-extracted with diethyl ether (5× 20mL). The ether layers were combined, washed with brine (5mL), dried over anhydrous MgSO4, filtered, acidified with a solution of HCl in ethyl acetate (3mol/L, 5mL) and concentrated under reduced pressure to afford the desired amine hydrochloride salt.
References:
Wang, Ai-E.;Chang, Zong;Liu, Yong-Peng;Huang, Pei-Qiang [Chinese Chemical Letters,2015,vol. 26,# 9,p. 1055 - 1058] Location in patent:supporting information
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