Pyridine → Chroman mesylate

Participants

Reaction Conditions

Reaction Steps

A suspension of the hydrochloride salt of 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (100 mg, 300 μmol), prepared as described in Example 1, in 1.5 mL MeCN was charged with pyridine (300 μL) followed by methanesulfonyl chloride (30 μL, 360 μmol). The suspension was stirred at 23° C. for 90 min, then diluted in isopropyl acetate (30 mL) and washed successively with 2.5 M aqueous sodium hydroxide, 1 M aqueous citric acid, and brine (1×15 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a yellowish oil. The oily residue was dissolved in methanol (3 mL), treated with concentrated HCl (approx. 30 μL), and the resulting mixture was warmed to 40° C. After 1 hr, the reaction was judged to be complete by TLC analysis, and was diluted into 50 mL EtOAc. The mixture was washed with 1 M aqueous sodium bicarbonate and brine (1×20 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient elution 20→60% EtOAc/Heptane) produced yellow solid chroman mesylate intermediate (48 mg). 1H NMR (CDCl3, 400 MHz) 3.31 (m, 2H), 2.90 (t, 2H), 2.78 (s, 2H), 2.67 (t, 2H), 2.14 (s, 3H), 2.09 (s, 3H), 1.76 (t, 2H), 1.22 (s, 6H) ppm. The resulting chroman was oxidized with CAN in a manner analogous to that used in Step 4 of Example 1. Silica gel purification (gradient elution 30→80% EtOAc/Heptane) afforded N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)methanesulfonamide as a yellow oil (25 mg). 1H NMR (CDCl3, 400 MHz) 4.82 (t, 2H), 3.26 (q, 2H), 2.92 (s, 3H), 2.78 (t, 2H), 2.61 (m, 2H), 1.99 (s, 6H), 1.59 (m, 2H), 1.26 (s, 6H) ppm.

Provenance & Evidence