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

Temperature

-78 °C

To a mixture of 2,2,6,6-tetramethyl-piperidine (4.50 mL, 26.6 mmol) and tetrahydrofuran (40 mL, 500 mmol) at −78° C. was slowly added n-butyllithium (2.5 mol/L in hexane, 11.5 mL, 28.8 mmol). The reaction vessel was transferred to a 0° C. ice bath for 60 minutes and then recooled at −78° C. 2-fluoro-4-methylbenzonitrile (3.1095 g, 23.010 mmol) as a solution in tetrahydrofuran (20 mL, 200 mmol) was then slowly added. The reaction mixture was stirred at −78° C. for 2 hours, and then a solution of iodine (7.33 g, 28.9 mmol) in tetrahydrofuran (10 mL, 100 mmol) was slowly added and then the reaction mixture was allowed to warm to room temperature. After 1.5 hours the reaction mixture was poured into a solution of sodium thiosulfate (20 g) in water (40 mL) and stirred at room temperature for 15 minutes. The layers were separated, and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (80 g silica, solvent gradient 0-10% ethyl acetate in heptanes) to yield a mixture of regioisomeric products, with the desired product as the major component (3.9385 g, 76% pure). LCMS (ESI): M+H=262.1; 1H NMR (400 MHz, CDCl3) δ 7.51-7.44 (m, 1H), 7.14 (d, J=7.9 Hz, 1H), 2.56 (s, 3H).

1. customwas transferred to a 0° C.
2. customfor 60 minutes
3. customrecooled at −78° C
4. temperatureto warm to room temperature
5. stirringstirred at room temperature for 15 minutes
6. customThe layers were separated
7. extractionthe aqueous layer extracted with ethyl acetate
8. dry with materialdried over MgSO4
9. filtrationfiltered
10. customevaporated in vacuo
11. customThe crude product was purified via flash chromatography on silica gel (80 g silica, solvent gradient 0-10% ethyl acetate in heptanes)
12. customto yield
13. additiona mixture of regioisomeric products

ORD record

ord-bdb262713e0f476b9be1bc1dfe9eb04b

Source dataset

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08623889B2