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

Temperature

-50 °C

A solution of 2,2,6,6-tetramethyl-4-piperidine (TMP) (550 mg, 3.93 mmol, 2.1 eq) in THF (5 ml) was cooled to −78° C. under nitrogen atmosphere. N-Butyl lithium (1.6 M in hexane, 1.52 ml, 3.96 mmol, 2.1 eq) was added slowly maintaining the temperature below −70° C. After addition, the reaction mixture was warmed to −50° C. and stirred for one hour. The clear solution became turbid indicating the salt formation. The reaction mixture was cooled to −80° C., and a solution of 2-fluoro-4-methylbenzonitrile (250 mg, 1.85 mmol, 1.0 eq) in THF (1 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 re-cooled to −78° C. and a saturated solution of iodine (516 mg, 2.03 mmol, 1.1 eq) in THF (1 ml) was added slowly maintaining the temperature below −70° C. After addition, the mixture was warmed to ambient temperature. The reaction mixture was poured into a saturated solution of Na2S2O3 (10 ml) and stirred for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over sodium sulphate. The volatiles were evaporated under reduced pressure. The crude product was purified under silica gel (60-120) column chromatography using 0.5% ethyl acetate/hexane as eluent. Yield: 187 mg (38%). 1H NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.13-7.15 (d, 1H, J=7.92 Hz), 7.48-7.50 (t, 1H, J=4.80 Hz).

1. temperaturemaintaining the temperature below −70° C
2. additionAfter addition
3. temperatureThe reaction mixture was cooled to −80° C.
4. temperaturemaintaining temperature below −70° C
5. temperatureThe mixture was then warmed to −50° C.
6. stirringstirred for 30 minutes
7. temperatureThe mixture was re-cooled to −78° C.
8. temperaturemaintaining the temperature below −70° C
9. additionAfter addition
10. temperaturethe mixture was warmed to ambient temperature
11. stirringstirred for 30 minutes
12. customThe organic layer was separated
13. extractionthe aqueous layer was extracted with ethyl acetate
14. washwashed with brine
15. dry with materialdried over sodium sulphate
16. customThe volatiles were evaporated under reduced pressure
17. customThe crude product was purified under silica gel (60-120) column chromatography

ORD record

ord-f474f8b91e2447c68148f10cf7b6b4d6

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08309558B2