Allyl bromide → 3-allyl-8-fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide

Participants

Reaction Conditions

Reaction Steps

Either cis (1-7) or trans-8-Fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-5, 4.8 g, 13.5 mmol) was dissolved in anhydrous THF (50 mL) and cooled to −78° C. in an acetone/dry ice bath under an N2 atmosphere. The resulting solution was treated with LHMDS (16.2 mL of a 1M toluene solution, 16.2 mmol) and stirred 2 minutes to produce a deep red color. Allyl bromide (2.3 mL, 26.9 mmol) was added neat and the solution was allowed to stir 10 minutes at −78° C. and then removed from the ice bath. Upon reaching ambient temperature, the reaction was judged complete by TLC and quenched by at addition of sat. aqueous NH4Cl (100 mL). The mixture was extracted with Et2O (3×100 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified using flash column chromatography (ISCO Redisep 120 g SiO2 column, 0-40% EtOAc/hexanes gradient) to provide pure 3-allyl-8-fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-6; a racemic mixture): 1H NMR (300 MHz, CDCl3) δ 7.40-7.22 (m, 3H), 7.20-7.12 (m, 3H), 6.77 (dd, J=8.9, 5.2 Hz, 1H), 6.53 (dt, J=8.6, 3.1 Hz, 1H), 5.57 (m, 1H), 5.27 (d, J=16.8 Hz, 1H), 5.22 (d, J=7.6 Hz, 1H), 4.12 (dd, J=10.5, 3.5 Hz, 1H), 3.90 (s, 3H), 3.63 (dd, J=11.0, 3.6 Hz, 1H), 3.37 (dd, J=13.7, 6.0 Hz, 1H), 3.32 (s, 3H), 2.96 (m, 2H); MS (M+H+, C22H22FN3O3) 396.3 found 396.4 required.

Provenance & Evidence