Hydrochloric Acid → 2-Trimethylacetyl-4-dimethylaminopyridine

Participants

Reaction Conditions

Reaction Steps

To a solution of4-dimethylaminopyridine (DMAP) (6.892 g, 56.4 mmol) in dry THF (200 mL) at 0° C. was added BF3 etherate (7.3 mL, 59.4 mmol) dropwise via a syringe. A slightly cloudy colorless solution was obtained. It was stirred at 0° C. for 0.5 hr. To a solution of 2,2,6,6-tetramethyl piperidine (10.0 mL, 59.2 mmol) in dry THF (100 mL) at -78° C. in a second flask was added n-butyllithium (58.5 mL, 1.06 M in hexane, 62.0 mmol) via syringe. It was then warmed to room temperature in about 20 min. The DMAP-BF3 salt solution was cooled to -78° C. upon which a white suspension was formed. To this suspension was added lithium tetramethylpiperidide solution (prepared in the second flask) via cannula in 0.5 hr with vigorous stirring. A clear dark tan solution was observed after the addition was complete and it was stirred for 30 min at -78° C. This solution at -78° C. was then transferred dropwise to a solution of trimethylacetyl chloride (13.9 mL, 112.6 mmol) in dry THF (50 mL) at -78° C. via cannula in 1 hr. The reaction turned orange during the addition. It was allowed to warm slowly to room temperature in 5 hr. The final solution was brown. Water (50 mL), methanol (50 mL) and 6 N HCl (30 mL) were added sequentially to the reaction mixture. The solution was stirred at 35°-40° C. overnight. The volatile solvents were removed by aspirator. The residue was made basic with 6 N NaOH (ca. pH>11) and extracted with diethyl ether (3×150 mL) and THF (150 mL). Combined organic solution was dried with MgSO4. After removal of solvent (aspirator), the residue was purified by flash chromatography on silica gel (20×5 cm), 1:3 EtOAc/hexane eluent to give 7.10 g of 2-Trimethylacetyl-4-dimethylaminopyridine (1) (61% ). Characterization of the product (1) was as follows:

Provenance & Evidence