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

Temperature

-78 °C

An oven-dried, 3-necked 500 ml round bottom flask with magnetic stirrer, thermometer, addition funnel, and nitrogen inlet was purged with N2 for 20 min. 2,2,6,6-tetramethylpiperidine (41.84 ml, 241 mmol) was introduced into flask via syringe, followed by 100 ml of anhydrous THF. The reaction mixture was cooled to −78° C., and n-BuLi (2.5M solution in hexane, 102 ml, 254 mmol) was introduced via cannula. The addition was done slowly, drop-wise, making sure that temperature stayed in the −70° C. to −80° C. range. (˜40 min). The addition flask was washed with 100 ml of anhydrous THF and the reaction mixture warmed to −50° C. for 30 min. during which time the clear solution became turbid. The reaction mixture was cooled to −78° C. again and 2-fluoro-4-methylbenzonitrile (30 g, 222 mmol) dissolved in 80 ml of anhydrous THF was added drop wise to the stirred solution while the internal temperature was maintained below −70° C. (approx 20 min). The addition funnel was washed once with 100 ml portion of THF and the reaction mixture was warmed up to −50° C. for 60 min. The reaction mixture was cooled again to −78° C. and a saturated solution of iodine (62 g, 244 mmol) in 100 ml of THF was introduced into the addition funnel. The quench was done stepwise, and the resulting yellow mixture was kept at an internal temperature below −60° C. (approx 20 min). The addition funnel was washed twice with 50 ml of THF and then the mixture was allowed to warm-up to room temperature. After stirring overnight, the entire mixture was added to a solution of 20 g thiosulfite in 1000 ml of water, stirred for 1 hour, and washed with ethyl acetate 3×250 ml. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified using an ISCO system. The product fractions were combined and concentrated. The product was re-crystallized from ether/hexane to give 33 g (57%) of the product. 1H NMR (CDCl3, 400 MHz) δ 7.50 (dd, 1H), 7.16 (d, 1H), 2.50 (s, 3H). LC-MS (M+1)=262 M/Z.

1. additionAn oven-dried, 3-necked 500 ml round bottom flask with magnetic stirrer, thermometer, addition funnel, and nitrogen inlet
2. customwas purged with N2 for 20 min
3. additionThe addition
4. customstayed in the −70° C. to −80° C. range
5. custom(˜40 min)
6. washThe addition flask was washed with 100 ml of anhydrous THF
7. temperaturethe reaction mixture warmed to −50° C. for 30 min. during which time the clear solution
8. temperatureThe reaction mixture was cooled to −78° C. again
9. additionwas added drop wise to the stirred solution while the internal temperature
10. temperaturewas maintained below −70° C. (approx 20 min)
11. washThe addition funnel was washed once with 100 ml portion of THF
12. temperaturethe reaction mixture was warmed up to −50° C. for 60 min
13. temperatureThe reaction mixture was cooled again to −78° C.
14. customwas kept at an internal temperature below −60° C. (approx 20 min)
15. washThe addition funnel was washed twice with 50 ml of THF
16. temperatureto warm-up to room temperature
17. additionthe entire mixture was added to a solution of 20 g thiosulfite in 1000 ml of water
18. stirringstirred for 1 hour
19. washwashed with ethyl acetate 3×250 ml
20. dry with materialThe combined organic layers were dried over magnesium sulfate
21. filtrationfiltered
22. concentrationconcentrated
23. customThe residue was purified
24. concentrationconcentrated
25. customThe product was re-crystallized from ether/hexane

ORD record

ord-c3752a80b85d416ab83684144345d9c1

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09127024B2