Diisopropylamine → 1-Bromo-3-fluorobenzaldehyde

Participants

Reaction Conditions

Reaction Steps

To a solution of diisopropylamine (2.27 mol, 320 mL) in anhydrous tetrahydrofuran (800 mL) in a 5 L flask at 0° C. add 1.6 M butyllithium (1.16 L, 1.86 mol) in hexanes dropwise over 1.5 h. Stir the resulting yellow solution at 0° C. for 30 min. In a separate 12 L flask dissolve 1-bromo-3-fluorobenzene (203 mL, 1.86 mol) in anhydrous tetrahydrofuran (650 mL) and cool to −78° C. Transfer the preformed LDA solution to an addition funnel via cannula and add dropwise to the 1-bromo-3-fluorobenzene solution over 2 h so the temperature does not rise above −70° C. Stir the resulting slurry at −78° C. for 30 min. Add a solution of N-methyl-N-phenyl formamide (230 mL, 1.86 moles, 1.00 equiv.) in anhydrous tetrahydrofuran (1.15 L) dropwise at −78° C. over one hour while maintaining the temperature below −70° C. Stir the reaction cold for 2 h while slowly allowing it to rise to room temperature overnight. Dilute the reaction with methyl tert-butyl ether (3 L), quench with 1M hydrochloric acid (4 L) and stir vigorously for 3 h. Separate the layers and extract the aqueous layer with methyl tert-butyl ether (1 L). Wash the combined organic phases with 1M hydrochloric acid (2×1 L), water (1 L), brine (1 L), dry over magnesium sulfate, filter and concentrate to an orange oil that slowly solidifies to obtain the title compound (394 g, 105%). 1H NMR (CDCl3) δ 10.37 (s, 1H), 7.50 (d, 1H), 7.44 (m, 1H), 7.17 (t, 1H).

Provenance & Evidence