Hydrochloric Acid → 6-bromo-3,4-dihydro-1H-2-benzopyran-1-one

Participants

Reaction Conditions

Reaction Steps

A solution of DIPA (4 M, 270 mL, 1080 mmol) in THF (900 mL) was cooled to −65° C. and HexLi (2.1 M, 505 mL, 1061 mmol) was added dropwise over 15 minutes maintaining the internal temp <−55° C. Upon completion the reaction mixture was warmed up to −40° C. where it was stirred for 30 minutes. To the resulting solution of LDA was added 4-bromo-2-methylbenzoic acid (90 g, 419 mmol) slowly (over 15 minutes) as a solution in THF (400 mL) during which time the reaction mixture turned into a bright red suspension. The reaction mixture was stirred for 30 minutes at −40° C. and then warmed to 15° C. at which point paraformaldehyde (50.3 g, 1674 mmol) was added in 3 portions as a solid keeping the internal temperature (ice water bath) below <18° C. Stirring was then continued at room temperature for 1 hour during which time the mixture turned an orange-yellow color. After a second hour of stirring, the vessel was immersed in an ice water bath and 3N HCl (650 mL) was added at such a rate to keep the internal temperature less than 30° C. The contents of the reaction vessel were subsequently transferred to a separatory funnel where it was extracted 3×400 mL EtOAc and the combined organic phases were then concentrated to ˜800 mL total volume. To this was added Amberlyst® 15 ion exchange resin (12 g) and the resulting mixture stirred at 48° C. overnight (˜14 h). HPLC analysis the following morning indicated that cyclization to the desired halolactone was nearly complete. The resin was removed by filtration and the yellow solution concentrated to ˜200 mL total volume at which point the desired product began to crystallize as a yellow solid which was then collected by filtration. The cake was subsequently washed with MTBE (2×80 mL) to give the first crop of product. Additional material was salvaged by washing the collected supernatant 2× with 200 mL 10% K2CO3,aq followed by 200 mL 1M H3PO4. After concentration to −100 mL the crystallized material was collected by filtration, washed with MTBE and then combined with the first crop and dried to afford the title compound.

Provenance & Evidence