5-bromo-3-tert-butyl-2-hydroxybenzaldehyde

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: step 1—To a solution of 3-tert-butyl-2-hydroxybenzaldehyde (CASRN 24623-65-2, 5.00 g) DCM (20 mL) at 0° C. was added dropwise a solution of Br2 (1.45 mL) in DCM (15 mL) over a period of 30 min. After the addition was complete the reaction was stirred for 1 h before the organic volatiles were removed under reduced pressure to afford 7.23 g of 5-bromo-3-tert-butyl-2-hydroxybenzaldehyde (B-1b, R4=tert-Bu) as a light yellowish solid. After the addition were removed under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 27 (3.83 g), MeI (2.32 mL) and K2CO3 (6.18 g) in DMF (50 mL) was heated at 50° C. for 1 h then cooled to RT and diluted with ether and water. The organic layer was thrice washed with water then brine, dried (MgSO4) and concentrated to afford 3.99 g of 5-bromo-3-tert-butyl-2-methoxybenzaldehyde (28) as a yellow solid. then cooled to RT The organic layer was thrice washed with water brine, dried (MgSO4) concentrated

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

Procedure: 5-bromo-3-tert-butyl-2-methoxybenzaldehyde (28)—To a solution of 3-tert-butyl-2-hydroxybenzaldehyde (CASRN 24623-65-2, 5.00 g) DCM (20 mL) at 0° C. was added dropwise a solution of Br2 (1.45 mL) in DCM (15 mL) over a period of 30 min. After the addition was complete the reaction was stirred for 1 h before the organic volatiles were removed under reduced pressure to afford 7.23 g of 5-bromo-3-tert-butyl-2-hydroxybenzaldehyde (27) as a light yellowish solid. After the addition were removed under reduced pressure

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-3-(tert-butyl)-2-hydroxybenzaldehyde (4.74 g, 18.42 mmol) and anhydrous potassium carbonate (2.83 g, 20.45 mmol) in anhydrous DMF (20.0 mL) was stirred under nitrogen in a water bath (20° C.) to give an orange-yellow suspension. After stirring for 20 min, 2-methoxyethoxymethyl chloride (2.40 mL, 21.19 mmol, technical grade) was added drop wise (20 min) to above suspension while maintaining an internal temperature of 20° C. The reaction mixture was stirred at room temperature for 3 h to give a canary yellow suspension. The reaction mixture was poured into ice-water (150 mL) and stirred at room temperature to give a yellow oily liquid, no solid formation was observed. After 30 min of stirring, the reaction mixture was extracted with dichloromethane (2×75 mL). The organic layer was removed, washed with water (1×50 mL) and dried over anhydrous magnesium sulfate, filtered and evaporated in-vacuo to give a pale yellow viscous liquid (6.7832 g). No purification was necessary and the crude product (purity >97%) was used directly in the next Step #3. to give an orange-yellow suspension After stirring for 20 min while maintaining an internal temperature of 20° C The reaction mixture was stirred at room temperature for 3 h to give a canary yellow suspension stirred at room temperature to give a yellow oily liquid After 30 min of stirring the reaction mixture was extracted with dichloromethane (2×75 mL) The organic layer was removed washed with water (1×50 mL) dried over anhydrous magnesium sulfate filtered evaporated in-vacuo

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

Procedure: To a stirred solution of 3-tert-butylsalicylaldehyde (5.13 g, 28.8 mmol) in acetic acid (15 mL) was added a solution of bromine (1.65 mL, 32.25 mmol) in acetic acid (7.0 mL) dropwise within 20 min. The reaction mixture was stirred at room temperature for 3 h. Analytical HPLC analysis after 3 h shows the desired product ˜72% and the unreacted starting material ˜28%. A second batch of bromine (0.5 mL) in acetic acid (3 mL) was added and the reaction mixture was stirred at room temperature for another 3 h. Analytical HPLC analysis of the reaction mixture after 3 h (6 h total) shows the desired product ˜85% and still shows the starting material ˜15%. After 6 h of stifling, the reaction mixture was diluted with dichloromethane (50 mL) and the organic layer was washed with 39% sodium bisulfite solution (1×10 mL), water, saturated NaHCO3 and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the desired product as a pale yellow crystalline solid (7.2421 g). Purification by silica-gel flash chromatography on silica gel column and elution with 0-5% ethyl acetate in n-heptane afforded the desired product as a pale yellow crystalline solid (4.792 g, 64% yield). LC-MS analysis of the product in negative mode shows the desired product's mass: m/z 255 (79BrM+−H) and m/z 257 (81BrM+−H). GC-MS analysis of the product in CI mode (Methane) shows the desired product's mass: m/z 256 (91BrM+) and m/z 258 (81BrM+), calc'd. for C11H13BrO2: 257.124. 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H, t-Bu-), 7.50 (s, 1H, H-4), 7.56 (s, 1H, H-6), 9.79 (s, 1H, —CHO), 11.70 (s, 1H, —OH). 1H NMR of the isolated product was identical with that of a previously reported sample of the product (Girsch et al., 2007). Analytical HPLC analysis after 3 h shows

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

Procedure: I-PrNEt2 (834 g, 6.46 g) and chloromethyl methyl ether (451 g, 5.60 mol) were gradually added to a solution of the 5-bromo-3-(tert-butyl)-2-hydroxybenzaldehyde (1333 g, 4.67 mol) in methylene chloride (4000 ml) while cooling on ice, and the mixture was stirred at room temperature for 2 days. After first distilling off the solvent under reduced pressure, ethyl acetate was added to the residue, washing was performed twice with brine, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1338 g) as a light yellow oil. while cooling on ice After first distilling off the solvent under reduced pressure, ethyl acetate was added to the residue washing the organic layer was dried over anhydrous magnesium sulfate concentrated under reduced pressure the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bromine (747 g) was gradually added to a solution of the 3-(tert-butyl)-2-(methoxymethoxy)benzaldehyde (1247 g, 4.67 mol) in methanol (4000 ml) while cooling on ice. After stirring at 20° C. for 1 hour, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, the mixture was washed with water, saturated sodium aqueous hydrogencarbonate and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to yield a crude product of the title compound (1333 g) as a red oil. while cooling on ice the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue the mixture was washed with water, saturated sodium aqueous hydrogencarbonate and brine in that order the organic layer was dried over anhydrous magnesium sulfate The organic layer was concentrated under reduced pressure