Diisopropylamine → (R)-2-methyl-N-((S)-2-methyl-1-phenyl-2-(pyridine-2-yl)propyl)propane-2-sulfinamide

Participants

Reaction Conditions

Reaction Steps

To a 1.0 Molar solution of potassium t-butoxide in tetrahydrofuran (3000 mL, 3.000 moles) was added diisopropylamine (425 mL, 306.8 g, 3.032 moles). The resulting solution was cooled by a dry ice/acetone bath to −50° C. n-Butyllithium solution (980 mL of 2.5 Molar, 2.450 moles) was added drop wise over a period of 40 minutes, giving a bright orange solution. The mixture was allowed to stir for an additional 20 minutes at −25° C., then was cooled back down to −55° C. 2-isopropylpyridine (1) (240.0 g, 1.981 moles) was then added drop wise over a period of 20 minutes while maintaining the internal temperature between −50° C. to −55° C., giving a deep, reddish-purple solution. The mixture was allowed to stir for an additional 2 hours at −50° C., then was used directly in the next step. To the cooled (−50° C.) mixture containing the 2-Isopropylpyridyl anion was added a solution of (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide (2) (360.0 g, 1.720 moles) in anhydrous tetrahydrofuran (3000 mL), drop wise over a period of 3 hours while maintaining the internal temperature between −50° C. and −55° C. The reaction mixture was allowed to warm gradually over 3 hours to 0° C., then checked for completion by working up an aliquot and checking by HPLC. The reaction was quenched by treatment with saturated sodium bicarbonate solution (3000 mL), added drop wise over 20 minutes. After stirring for an additional 30 minutes, the mixture was further diluted with water (3000 mL), and divided into three portions (˜4500 mL each). Each portion was partitioned with ethyl acetate (1000 mL), and the layers separated. The combined aqueous layer was further extracted with ethyl acetate (3×1000 mL). The combined organic extracts were washed with saturated brine (1500 mL), then dried (anhydrous magnesium sulfate). Filtration, followed by removal of the solvent under reduced pressure, left the crude product as a cream-colored solid (575.8 g, 101.3% crude yield), which was a 9:1 mixture of diastereomers. The crude material was recrystallized from a mixture of Hexane/EtOAc (2:1) to give pure desired single diastereomer (371.9 g, 65.4% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.62 (dd, J=4.85, 1.05 Hz, 1 H) 7.52 (td, J=7.80, 2.11 Hz, 1H) 7.09-7.19 (m, 4 H) 6.99 (d, J=8.01 Hz, 1 H) 6.85-6.94 (m, 2 H) 5.80 (d, J=8.01 Hz, 1 H) 4.49 (d, J=8.43 Hz, 1 H) 1.46 (s, 3 H) 1.33 (s, 3 H) 1.10 (s, 9 H). MS: m/z 331.

Provenance & Evidence