Iodine → 2-Fluoro-3-iodo-4-methylbenzonitrile

Temperature

-50 °C

A solution of 2,2,6,6-tetramethyl-4-piperidine (TMP) (45 mL, 267 mmol) in THF (400 mL) was cooled to −78° C. under an atmosphere of nitrogen. n-Butyl lithium (2.5 M in hexane, 110 mL, 275 mmol) was added slowly maintaining the temperature below −70° C. After addition, the reaction mixture was warmed to −50° C. and stirred for 30 minutes. The clear solution became turbid indicating the salt formation. The reaction mixture was recooled to −80° C., and a solution of 2-fluoro-4-methylbenzonitrile (32.4 g, 240 mmol) in THF (150 mL) was slowly added maintaining temperature below −70° C. The mixture was then warmed to −50° C. and stirred for 30 minutes. The mixture was recooled to −70° C. and a saturated solution of iodine (67 g, 264 mmol) in THF (150 mL) was added slowly maintaining the temperature at −70° C. After addition, the mixture was warmed to ambient temperature. The reaction mixture was poured into a solution of Na2S2O3 (160 g in 1.5 L of water) and stirred for 1 h. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. The volatiles were evaporated under reduced pressure. The crude product was subjected to vacuum distillation, and at about 60° C., the excess TMP was removed, at about 100° C., the starting compound 2-fluoro-4-methylbenzonitrile and a small amount of 2-fluoro-3-iodo-4-methylbenzonitrile were removed and, finally at 115° C., pure 2-fluoro-3-iodo-4-methylbenzonitrile was obtained as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 261.9 (M+1).

1. temperaturemaintaining the temperature below −70° C
2. additionAfter addition
3. customwas recooled to −80° C.
4. temperaturemaintaining temperature below −70° C
5. temperatureThe mixture was then warmed to −50° C.
6. stirringstirred for 30 minutes
7. customwas recooled to −70° C.
8. temperaturemaintaining the temperature at −70° C
9. additionAfter addition
10. temperaturethe mixture was warmed to ambient temperature
11. stirringstirred for 1 h
12. customThe organic layer was separated
13. extractionthe aqueous layer was extracted with ethyl acetate
14. washwashed with brine
15. dry with materialdried over Na2SO4
16. filtrationfiltered
17. customThe volatiles were evaporated under reduced pressure
18. distillationThe crude product was subjected to vacuum distillation
19. customat about 60° C., the excess TMP was removed, at about 100° C.
20. customthe starting compound 2-fluoro-4-methylbenzonitrile and a small amount of 2-fluoro-3-iodo-4-methylbenzonitrile were removed and, finally at 115° C.

ORD record

ord-bc6b647777c1419291ee1aaaf131a195

Source dataset

uspto-grants-2010_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07759337B2