Hydrochloric Acid → 2-Trimethylacetyl-4-dimethylaminopyridine

Temperature

0 °C

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:

1. customA slightly cloudy colorless solution was obtained
2. temperatureIt was then warmed to room temperature in about 20 min
3. customwas formed
4. customprepared in the second flask) via cannula in 0.5 hr with vigorous stirring
5. additionafter the addition
6. stirringit was stirred for 30 min at -78° C
7. additionThe reaction turned orange during the addition
8. temperatureto warm slowly to room temperature in 5 hr
9. stirringThe solution was stirred at 35°-40° C. overnight
10. customThe volatile solvents were removed by aspirator
11. extractionextracted with diethyl ether (3×150 mL) and THF (150 mL)
12. dry with materialCombined organic solution was dried with MgSO4
13. customAfter removal of solvent (aspirator)
14. customthe residue was purified by flash chromatography on silica gel (20×5 cm), 1:3 EtOAc/hexane eluent

ORD record

ord-f197326b13b34856a86157e65530eefb

Source dataset

uspto-grants-1997_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05646287