Hexamethylphosphoramide → 2-(2'-Chloro-3-methylbiphenyl-4-yl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)-ethoxy]phenyl}propanenitrile

Participants

Reaction Conditions

Reaction Steps

To a solution (2′-chloro-3-methylbiphenyl-4-yl)acetonitrile (1 eq.) from step 1 in THF (0.10M) at −78° C. was added hexamethylphosphoramide (HMPA; 4 eq.) then lithium hexamethyldisilazide (LiHMDS; 1.2 eq.). The reaction mixture was stirred 30 min at −78° C. To the resulting solution was cannulated over 10 min a solution of 1,3-dichloro-2-{2-[4-(iodomethyl)phenoxy]ethoxy}-5-methylbenzene (II.1; 1.05 eq.). The final mixture was allowed to warm slowly to 0° C., stiffed an extra 2 h, poured in saturated aqueous NH4Cl and finally extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 20% in 30 min) afforded the desired compound as a colorless oil.

Provenance & Evidence