Pyrazine → (R)-3-Methyl-2-(pyrazin-2-yl)butan-2-ol

Participants

Reaction Conditions

Reaction Steps

A solution of 2,2,6,6-tetramethylpiperidine (282.2 g, 337.2 mL, 1.998 mol) in dry THF (1.400 L) was cooled to −35° C. under nitrogen. nBuLi (2.5M in hexanes) (799.2 mL of 2.5 M, 1.998 mol) was added over 30 minutes, keeping the internal temperature between −25 and −35° C. The mixture was allowed to warm to 0° (+/−1°) and stirred for 10 minutes. The mixture was then cooled to −78° C. and held at this temperature for 20 minutes. A solution of pyrazine (80 g, 998.9 mmol) in dry THF (200.0 mL) was then cannulated into the lithium amide mixture, keeping the internal temperature below −70° C. The deep red mixture was stirred for 20 minutes, then 3-methylbutan-2-one (430.1 g, 534.3 mL, 4.994 mol) (cooled in a −78° C. bath) was added as rapidly as possible, keeping the internal temperature below −60°. The mixture was then stirred at −78° C. (+/−5° C.) for 2 hrs. Lc/Ms after this time showed no pyrazine remaining. The reaction was quenched at −78° C. by slow addition of 2M HCl (2 L). Ethyl acetate (800 mL) was then added. The mixture was allowed to warm to ambient and the organic phase separated. The mixture was very dark but the phases were easily separated. The aqueous phase was extracted with ethyl acetate (2×500 ml). The combined organics were washed with sat NaHCO3 (800 ml), then water (1 L) then brine (500 ml). The mixture was then concentrated. The residue was dissolved in petrol (1.2 L). Some solid was present. MgSO4 was added and the mixture dried, filtered and concentrated. The crude was a dark red oil (260 g). The crude was purified on silica gel, eluting with 0-50% ethyl acetate/petrol). The title compound was obtained as a pale yellow oil (103.2 g, 62%); 1H NMR (CDCl3) 0.74 (3H, d), 1.01 (3H, d), 2.07 (1H, m), 4.19 (1H, s), 8.52 (2H, s), 8.73 (1H, s); MS ES(+) 167.35 (M+1).

Provenance & Evidence