3-tert-butyl-5-fluorobenzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-tert-Butyl-5-fluoro-benzaldehyde (252 g, 1.4 moles) was dissolved in methanol (4 vol, 1000 ml) and trimethyl orthoformate (1 vol, 252 ml). Toluenesulfonic acid (3.4% w/w, 6 g) was added in one portion and the resulting solution stirred at rt for 1 hour. Triethylamine (0.12 vol, 30 mL) was added and the reaction concentrated to an oil, and then re-suspended in ethyl acetate (3 L) and NaHCO3 (aq. sat., 1 L) and water (1 L) with vigorous mixing. The organic phase was washed with additional water (1 L), polish filtered and then concentrated to provide an orange oil (311.2 g, 98.5%), used directly in the next reaction. the reaction concentrated to an oil The organic phase was washed with additional water (1 L) polish filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bromo-3-tert-butyl-5-fluorobenzene (323.2 g, 1.4 moles) was dissolved in THF (3.3 L) and cooled −10° C. iPrMgCl (2M solution in THF, 0.5 eq, 350 mL) was added over 20 min, followed by nBuLi (2.5M solution in hexanes, 1.0 eq, 560 mL) over two hours. DMF (4 eq, 450 mL) was added over one hour then stirred for 45 minutes and quenched with 3M HCl (1000 mL). The layers were separated and the aqueous fraction was diluted with water (1 L) and extracted with ethyl acetate (1 L). The organic fractions were combined and washed with water (2×2 L). The organic fraction was concentrated to provide an orange oil (252 g, quant), used directly in the next reaction. was added over 20 min quenched with 3M HCl (1000 mL) The layers were separated the aqueous fraction was diluted with water (1 L) extracted with ethyl acetate (1 L) washed with water (2×2 L) The organic fraction was concentrated to provide an orange oil (252 g, quant) used directly in the next reaction

Conditions: temp:0.00; pressure:0.00; stir: