Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.
Procedure: A solution of potassium tert-butoxide (20.0 g, 0.78 mol) at 55° C. in t-BuOH (249 mL) was treated with a premixed solution of diethyl succinate (40.4 mL, 0.243 mol) and 3-bromobenzaldehyde (18.9 mL, 0.162 mol) dropwise. Upon completion of the addition, the reaction mixture was warmed to 85° C. and stirred for 2 h. After 2 h, the reaction mixture was cooled to 25° C. The reaction mixture was acidified to pH<4 with 2 N aqueous HCl and concentrated. The aqueous suspension was then extracted with ethyl acetate (3×). The organic layers were combined and washed with saturated aqueous NaHCO3 (5×). The basic aqueous washes were combined and reacidified with 2 N aqueous HCl to pH 1. Finally, the aqueous phase was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure, which afforded the desired half ester (39.1 g, 77%) as an orange oil. The half ester (39.1 g, 0.124 mol) was dissolved in acetic anhydride (178 mL) and NaOAc (18.7 g, 0.137 mol) was added. The reaction mixture was warmed to 140° C. and stirred for 6 h. Upon completion, the reaction mixture was cooled to 25° C. and poured into H2O. The aqueous layer was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in anhydrous ethanol (620 mL). K2CO3 (104 g, 0.624 mol) was added, and the reaction mixture was warmed at 80° C. for 1 h. The reaction mixture was cooled and acidified to pH 1 with 2 N aqueous HCl. The ethanol was removed under reduced pressure and the aqueous suspension was extracted with ethyl acetate (3×). The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography (SiO2, 16×30 cm, 0-15% EtOAc/hexanes gradient elution) provided 7 (5.4 g, 15% over 3 steps) as a yellow solid and its 7-bromo isomer (12.4 g, 34% over 3 steps). 1H NMR (CDCl3, 500 MHz) δ 8.16 (s, 1H), 8.07 (s, 1H), 7.89 (d, J=6.5 Hz, 1H), 7.73 (d, J=6.5 Hz, 1H), 7.63 (s, 1H), 7.29 (t, J=10 Hz, 1H), 4.43 (q, J=6.0 Hz, 2H) 1.44 (t, J=6.0 Hz, 3H). 13C NMR (CDCl3, 125 MHz) δ 165.9, 152.7, 136.3, 133.6, 130.6, 129.2, 126.7, 123.6, 122.7, 115.2, 112.3, 61.3, 14.3. IR (film) νmax3367, 2979, 1690, 1227 cm−1. ESI-TOF HRMS m/z 294.9959 (M+H+, C13H11BrO3 requires 294.9964).
Upon completion of the addition
After 2 h
the reaction mixture was cooled to 25° C
concentrated
The aqueous suspension was then extracted with ethyl acetate (3×)
washed with saturated aqueous NaHCO3 (5×)
Finally, the aqueous phase was extracted with ethyl acetate (3×)
dried over Na2SO4
concentrated under reduced pressure, which
afforded the
The reaction mixture was warmed to 140° C.
stirred for 6 h
Upon completion, the reaction mixture was cooled to 25° C.
The aqueous layer was extracted with ethyl acetate (3×)
dried over Na2SO4
concentrated under reduced pressure
The residue was dissolved in anhydrous ethanol (620 mL)
the reaction mixture was warmed at 80° C. for 1 h
The reaction mixture was cooled
The ethanol was removed under reduced pressure
the aqueous suspension was extracted with ethyl acetate (3×)
dried over Na2SO4
concentrated under reduced pressure
Flash chromatography (SiO2, 16×30 cm, 0-15% EtOAc/hexanes gradient elution)
provided 7 (5.4 g, 15% over 3 steps) as a yellow solid and its 7-bromo isomer (12.4 g, 34% over 3 steps)
Source ID: ord-9466291e9c494c2395a17f79409ba87d