Nitrogen → (r,r)-n-[3-(4-Methoxyphenyl)isothiazol-5-yl]-2-methyl-cyclopropanecarboxamide

Participants

Reaction Conditions

Reaction Steps

To a stirred suspension of 3-(4-methoxyphenyl)isothiazol-5-ylamine (5.0 g, 24.3 mmol) in anhydrous dichloromethane (230 mL), cooled to 0-5° C., is added trimethylaluminum (2.0 M in toluene, 12.1 mL, 24.2 mmol) by syringe. The solution is stirred 5 min, and benzyl (R,R)-2-methylcyclopropanecarboxylate (4.6 g, 24.21 mmol) is added with the aid of anhydrous dichloromethane (10 mL). The mixture is then warmed to 40-45° C. with N2 flow (needle bleed valve) to slowly remove solvent. After 2 h, most of the dichloromethane has been removed, and the internal temperature rises to about 50° C. The solution is stirred further for 3 h, cooled, and quenched cautiously with dropwise addition of water followed by 0.1 N HCl under a good N2 stream. The resulting residue is then partitioned between ethyl acetate (400 mL) and 0.1 N HCl (400 mL). The organic layer is dried over potassium carbonate, filtered, and evaporated to a low volume. The resulting suspension is diluted with hexanes and the solid filtered to afford 5.9 g of crude product which is re-suspended in MTBE (100 mL), warmed to mild reflux for 1 h, and cooled to room temperature. After standing 1 h, the solid was filtered and dried (20 mm Hg, 40° C.) to afford (R,R)—N-[3-(4-methoxyphenyl)isothiazol-5-yl]-2-methyl-cyclopropanecarboxamide (5.2 g, 75%). 1H NMR (DMSO-d6) 7.86 (d, J=8.8 Hz, 2H), 7.20 (s, 1H), 7.00 (d, J=8.8 Hz, 2H), 3.78 (s, 3H), 1.62 (m, 1H), 1.34 (m, 1H), 1.10 (d, J=6.0 Hz, 3H), 1.09 (m, 1H), 0.80 (m, 1H); ES-MS m/e 289 (m+H).

Provenance & Evidence