Hydrochloric Acid → 2-hydroxy-3,5-dimethoxybenzaldehyde

Temperature

-50 °C

Morpholine (2.05 g, 24 mmol) and THF (40 mL) were placed in a dry, three-necked, round bottomed flask equipped with a stirring bar, septum cap, dropping funnel, thermometer, and argon inlet. The flask was cooled in a dry ice-acetone bath to −50° C., and a solution of n-BuLi in hexane (1.6M, 15 mL, 24 mmol) was added all at once. After 10 min a solution of the 2-bromo-3,5-dimethoxybenzaldehyde 37 (4.9 g, 20 mmol) in THF (30 mL) was added dropwise via a syringe over a period of 4 min, and the mixture was cooled to ˜−75° C. over 20 min. n-BuLi in hexane (1.6M, 20 mL, 32 mmol) was then added dropwise over 45 min, keeping the temperature at −75° C. After complete addition of n-BuLi the solution was stritted for 35 min. A solution of nitrophenol (6.90 g, 46 mmol) in 10 mL THF was added from the dropping funnel, keeping the temperature at −75° C. The resulting dark mixture was stirred at −75° C. for 4 h and then allowed to warm to room temperature. It was acidified to pH 1 with 6N HCl and stirred for 15 min. After dilution with brine (100 mL), THF was removed in-vacuo. The aqueous solution was extracted with diethyl ether (4×40 mL). The combined organic layers were extracted with 2 N NaOH (3×40 mL). The combined NaOH extracts were washed with diethyl ether (3×20 mL) and then acidified to pH 1 with concentrated HCl. The resulting mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were washed with brine, dried (MgSO4) and adsorbed on silica gel. The product was purified by flash chromatography, eluting with EtOAc/hexane (1:2) to give 38 (2.0 g, 55%) as a yellow solid. m/z=183.06 (M+H). 1H NMR (500 MHz, CDCl3): δ: 10.71 (1H, s, OH), 9.91 (1H, s, CHO), 6.77 (1H, d, J4,6=2.8 Hz, H-6), 6.61 (1H, d, J4,6=2.8 Hz, H-4), 3.92 (3H, s, OMe), 3.84 (3H, s, OMe). 13C NMR CDEPT 135 (500 MHz, CDCl3): δ: 196.11 (CHO), 107.93 (C-6), 103.90 (C-4), 56.29 (OMe), 55.83 (OMe).

1. customthree-necked, round bottomed flask equipped with a stirring bar
2. customseptum cap
3. additionwas then added dropwise over 45 min
4. customat −75° C
5. customat −75° C
6. temperatureto warm to room temperature
7. stirringstirred for 15 min
8. customAfter dilution with brine (100 mL), THF was removed in-vacuo
9. extractionThe aqueous solution was extracted with diethyl ether (4×40 mL)
10. extractionThe combined organic layers were extracted with 2 N NaOH (3×40 mL)
11. washThe combined NaOH extracts were washed with diethyl ether (3×20 mL)
12. extractionThe resulting mixture was extracted with CH2Cl2 (3×20 mL)
13. washthe combined organic extracts were washed with brine
14. dry with materialdried (MgSO4)
15. customThe product was purified by flash chromatography
16. washeluting with EtOAc/hexane (1:2)

ORD record

ord-c525a322d8b440a7954a31c24c7d1ac2

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08283340B2