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Preparation of (S)-tert-ButylPyOx and Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids
- Source :
- Organic Syntheses
- Publication Year :
- 2015
- Publisher :
- Organic Syntheses, Inc., 2015.
-
Abstract
- A. (S)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)picolinamide (2). A 1 L one-necked round-bottomed flask equipped with a 3.0 cm x 1.4 cm, egg-shaped, Teflon-coated magnetic stirring bar is sealed with a septum and connected via needle adapter to a two-tap Schlenk adapter attached to an oil bubbler and a nitrogen/vacuum manifold (Note 1). The flask is dried with a heat gun under vacuum and cooled under a stream of nitrogen. The flask is charged with 2-picolinic acid (1) (6.15 g, 50.0 mmol, 1.00 equiv) (Note 2), evacuated and back-filled with nitrogen three times, then charged with dichloromethane (300 mL, 0.17 M) (Note 3) and N-methylmorpholine (7.59 g, 8.25 mL, 75.0 mmol, 1.50 equiv). The flask is cooled in an ice/water bath and iso-butylchloroformate (6.86 mL, 7.17 g, 52.5 mmol, 1.05 equiv) is added dropwise over 30 min by syringe pump. The reaction mixture is stirred for an additional 30 min while remaining submerged in the ice/water bath. A separate 100 mL one-necked round-bottomed flask is sealed with a septum and connected via needle adapter to the two-tap Schlenk adapter and manifold, dried with a heat gun under vacuum, and allowed to cool under a stream of nitrogen. This flask is charged with (S)-tert-leucinol (6.45 g, 55.0 mmol, 1.10 equiv), dichloromethane (40 mL), and N-methylmorpholine (6.07 mL, 5.56 g, 55.0 mmol, 1.10 equiv). The resulting clear solution is taken up in a syringe and transferred dropwise using a syringe pump over the course of 1 h to the stirring reaction mixture in the ice/water bath. The cooling bath is removed, and the pale gold colored reaction mixture is stirred for an additional 6 h at 23 °C. Upon consumption of starting material (Note 4), the mixture is quenched at ambient temperature with a single addition of an aqueous solution of saturated NH_4Cl (50 mL), diluted with additional H_2O (25 mL), and transferred into a 1 L separatory funnel. The phases are separated, and the aqueous phase is extracted with CH_2Cl_2 (3 x 100 mL). The combined organic phases are washed with an aqueous solution of saturated NaHCO_3 (1 x 50 mL) and brine (1 x 50 mL). The combined organic phases are dried over Na_2SO_4 (10 g, 15 min while agitating), filtered through a M pore glass frit, and concentrated by rotary evaporation (28 °C, 15 mmHg). Excess N-methylmorpholine is further removed by placing the crude residue under high vacuum (< 12 mmHg, 12 h) to provide a pale red solid (Note 5). The crude residue is dissolved in 10 mL of acetone and purified via silica gel flash chromatography (Note 6). The combined product-containing fractions are concentrated by rotary evaporation (40 °C, 15 mmHg) to yield a solid, which is dried under high vacuum (< 12 mmHg, 12 h) to afford (S)-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide (2) as a white amorphous solid (9.88-9.95 g, 44.4-44.8 mmol, 89-90% yield) (Note 7).
- Subjects :
- Aqueous solution
Chromatography
010405 organic chemistry
Silica gel
Organic Chemistry
Aqueous two-phase system
ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION
010402 general chemistry
Cooling bath
01 natural sciences
Article
0104 chemical sciences
chemistry.chemical_compound
N-Methylmorpholine
chemistry
Acetone
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING
Physical and Theoretical Chemistry
ComputingMilieux_MISCELLANEOUS
Nuclear chemistry
Separatory funnel
Dichloromethane
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Organic Syntheses
- Accession number :
- edsair.doi.dedup.....491ec7601e3371ea235521c0c393008c