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

Temperature

-50 °C

Morpholine (2.05 g, 24 mmol) and THF (40 mL) were placed in a 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 1 (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 stirred for 35 min. A solution of nitrobenzene (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). Pure 2 was obtained (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 CDEPT135 (500 MHz, CDCl3): δ: 196.11 (CHO), 107.93 (C-6), 103.90 (C-4), 56.29 (OMe), 55.83 (OMe).

1. customequipped with a stirring bar
2. customseptum cap
3. additionwas then added dropwise over 45 min
4. customat −75° C
5. customat −75° C
6. stirringThe resulting dark mixture was stirred at −75° C. for 4 h
7. temperatureto warm to room temperature
8. stirringstirred for 15 min
9. customAfter dilution with brine (100 mL), THF was removed in vacuo
10. extractionThe aqueous solution was extracted with diethyl ether (4×40 mL)
11. extractionThe combined organic layers were extracted with 2 N NaOH (3×40 mL)
12. washThe combined NaOH extracts were washed with diethyl ether (3×20 mL)
13. extractionThe resulting mixture was extracted with CH2Cl2 (3×20 mL)
14. washthe combined organic extracts were washed with brine
15. dry with materialdried (MgSO4)
16. customThe product was purified by flash chromatography
17. washeluting with EtOAc/hexane (1:2)
18. customPure 2 was obtained (2.0 g, 55%) as a yellow solid

ORD record

ord-da3628e903ae48d98d503e0d2e6e4f42

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08283340B2