Butanal → Ethyl 4-butyrylbenzoate

Temperature

-40 °C

At −40° C., isopropylmagnesium chloride lithium chloride (15.3 mL, 1.3M in THF, 19.9 mmol) was added dropwise to a solution of ethyl 4-iodobenzoate (5.00 g, 18.11 mmol) in tetrahydrofuran (30 mL). The solution was stirred at −40° C. for 40 minutes. Butyraldehyde (1830 mg, 25.4 mmol) was added. The reaction was allowed to warm to room temperature over 3 hours. The reaction was quenched with 1N HCl and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue (1.0 g, 4.5 mmol) was combined with dichloromethane (16.7 mL), dimethylsulfoxide (4.79 mL), and triethylamine (2.28 g, 22.5 mmol) and cooled to 0° C. Sulfur trioxide pyridine complex (2.15 g, 13.5 mmol) was added in portions and the mixture was stirred at 0° C. for 1 hour. The reaction was allowed to gradually warm to room temperature and stir over 2 hours. The reaction was quenched with brine and diluted with dichloromethane. The layers were separated and the aqueous layer was extracted again with dichloromethane (20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave ethyl 4-butyrylbenzoate. 1H NMR (400 MHz, CDCl3, δ): 8.05-8.17 (m, 2 H), 7.92-8.04 (m, 2 H), 4.40 (q, J=7.15 Hz, 2 H), 2.96 (t, J=7.22 Hz, 2 H), 1.69-1.86 (m, 2 H), 1.40 (t, J=7.12 Hz, 3 H), 1.00 (t, J=7.22 Hz, 3 H).

1. temperatureto warm to room temperature over 3 hours
2. customThe reaction was quenched with 1N HCl
3. extractionextracted with ethyl acetate three times
4. dry with materialThe combined organic layers were dried over sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated
7. temperaturecooled to 0° C
8. additionSulfur trioxide pyridine complex (2.15 g, 13.5 mmol) was added in portions
9. stirringthe mixture was stirred at 0° C. for 1 hour
10. temperatureto gradually warm to room temperature
11. stirringstir over 2 hours
12. customThe reaction was quenched with brine
13. additiondiluted with dichloromethane
14. customThe layers were separated
15. extractionthe aqueous layer was extracted again with dichloromethane (20 mL)
16. dry with materialThe combined organic layers were dried over sodium sulfate
17. filtrationfiltered
18. concentrationconcentrated
19. customPurification by column chromatography (0-30% ethyl acetate in heptane)

ORD record

ord-bcc628fa40a344a1a2a626eb6bddc80d

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08809342B2