Methyl iodide → 2-Isopropylpyridine

Temperature

-45 °C

2-Isopropylpyridine was prepared by the method of P. Rocca, et. al. (Tetrahedron Vol. 54, pp. 8771-8782 (1998). A solution of 2-ethylpyridine (1000 g, 9.332 moles) in anhydrous Tetrahydrofuran (6000 mL) was cooled to −35° C. by a dry ice/acetone bath. n-Butyllithium (3970 mL of 2.5 Molar, 9.925 moles) was added at a fast drop wise rate over a period of 1.5 hours, while maintaining the internal temperature at −20° C. to −25° C. Stirring was continued for an additional 1.5 hours at −20° C., then the reaction was cooled to −45° C. Iodomethane (642 mL, 1458 g, 10.272 moles) was added at a moderate drop wise rate over a period of 1.5 hours, while maintaining the reaction temperature between −40° C. and −45° C. After the addition was complete, the mixture was allowed to stir for an additional 2 hours at −40° C., then was quenched by the fast drop wise addition of water (4000 mL) added over a period of 30 minutes. The reaction mixture was cooled to 0° C. and treated with concentrated Hydrochloric acid (1150 mL) added over a period of 15 minutes. The mixture was allowed to stir for an additional hour while warming to 15° C., then was transferred to a separatory funnel with diethyl ether (2000 mL), and the layers separated. The aqueous phase was further washed with diethyl ether (3×1000 mL), then made basic (pH=9) by treatment with solid potassium carbonate. The aqueous mixture was extracted with diethyl ether (4×1000 mL). The combined extracts were washed with saturated brine (1000 mL) then dried (anhydrous magnesium sulfate). Filtration, followed by removal of the solvent under reduced pressure at room temperature, gave the crude product as a reddish-orange liquid (˜2000 mL). This crude product was distilled (twice) at atmospheric pressure through a three inch, glass vigreaux column, collecting the desired 2-isopropylpyridine (b.p. 158-163° C.) as a light yellow liquid (926 g, 82% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.53 (d, J=4.22 Hz, 1 H) 7.59 (td, J=7.59, 1.69 Hz, 1 H) 7.16 (d, J=8.01 Hz, 1 H) 7.08 (ddd, J=7.38, 4.85, 0.84 Hz, 1 H) 2.94-3.25 (m, J=6.91, 6.91, 6.91, 6.91, 6.91, 6.74 Hz, 1 H) 1.31 (d, J=6.74 Hz, 6 H).

1. temperaturewhile maintaining the internal temperature at −20° C. to −25° C
2. temperaturewhile maintaining the reaction temperature between −40° C. and −45° C
3. additionAfter the addition
4. stirringto stir for an additional 2 hours at −40° C.
5. customwas quenched by the fast drop wise addition of water (4000 mL)
6. additionadded over a period of 30 minutes
7. temperatureThe reaction mixture was cooled to 0° C.
8. additiontreated with concentrated Hydrochloric acid (1150 mL)
9. additionadded over a period of 15 minutes
10. stirringto stir for an additional hour
11. temperaturewhile warming to 15° C.
12. customwas transferred to a separatory funnel with diethyl ether (2000 mL)
13. customthe layers separated
14. washThe aqueous phase was further washed with diethyl ether (3×1000 mL)
15. extractionThe aqueous mixture was extracted with diethyl ether (4×1000 mL)
16. washThe combined extracts were washed with saturated brine (1000 mL)
17. dry with materialthen dried (anhydrous magnesium sulfate)
18. filtrationFiltration
19. customfollowed by removal of the solvent under reduced pressure at room temperature

ORD record

ord-ed0f09751b7449918f5fdd470122e876

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08013165B2