反应详情

A solution of 4-bromotoluene (310 g, 1.81 moles) in 1500 ml of anhydrous ether was cooled to an internal temperature of -65° C. (slurry forms at ~-6° C.) under nitrogen. A solution of t-butyllithium (1.7 M in pentane, 2.2 L, 3.74 moles) was added over a period of ~90 minutes (internal temperature maintained below -55° C.). The cooling bath was then replaced with water baths which brought the reaction mixture up to +20° C. over 45 minutes and the white slurry was stirred an additional 2 hours at room temperature (most solids dissolved). The contents of this flask were then transferred under nitrogen pressure via a 1/8" plastic cannula to a stirred solution of ZnCl2 in ether (1M, 1.86 L) and THF (3.7 L) over 25 minutes (a cool water bath was used to maintain an internal temperature of 25° C.). The reaction mixture was stirred at room temperature for 2 hours. The appearance may vary from a clear solution with white flocculent precipitate to a mixture with heavy white solids. The reaction mixture was then transferred via a 1/4" cannula under vacuum) to a solution of 2-bromobenzonitrile (220 g, 1.2 moles) and bis(triphenylphosphine) nickel (II) chloride (22 g, 0.0337 moles) in THF (3.1 L) at room temperature over 20 minutes. The internal temperature rose to 35° C. during additions but subsided when complete. The dark red solution was stirred at room temperature overnight. The reaction mixture was then added carefully in portions to ice cold 1N HCl (~15 L) stirred rapidly in a large extractor. The organic layer was separated and the aqueous phase extracted with ether (3×2 L). The organic layers were combined and washed with water (2×2 L), brine, dried over MgSO4 and filtered through a plug of silica gel. The solution was concentrated to give the crude product as an oily solid (275 g). The material was then purified on a silica gel column (3 kg of E. Merck SiO2 60, 70-230 mesh) using methylene chloride-hexane (1:4 ) to give 196 g (85%) of the title compound as a low melting (46°-49.5° C.) solid. NMR (CDCl3): 2.22 (s, 3H), 7.24-7.78 (8H).

1. temperature(internal temperature maintained below -55° C.)
2. customup to +20° C.
3. customover 45 minutes
4. dissolutiondissolved)
5. customThe contents of this flask were then transferred under nitrogen
6. temperatureto maintain an internal temperature of 25° C.)
7. stirringThe reaction mixture was stirred at room temperature for 2 hours
8. customat room temperature
9. customover 20 minutes
10. customrose to 35° C. during additions
11. stirringThe dark red solution was stirred at room temperature overnight
12. stirringstirred rapidly in a large extractor
13. customThe organic layer was separated
14. extractionthe aqueous phase extracted with ether (3×2 L)
15. washwashed with water (2×2 L), brine
16. dry with materialdried over MgSO4
17. filtrationfiltered through a plug of silica gel
18. concentrationThe solution was concentrated
19. customto give the crude product as an oily solid (275 g)
20. customThe material was then purified on a silica gel column (3 kg of E. Merck SiO2 60, 70-230 mesh)