Crossed coupling of functionalised ketones by low valent titanium (the McMurry reaction): a new stereoselective synthesis of tamoxifen

Abstract

Low valent titanium-mediated crossed coupling of substituted benzophenones of the type 4-XPhCOPh, where X = MeO, ClCH₂CH₂O, BrCH₂CH₂O, CF₃C₆H₄O, HO and Me₂NCH₂CH₂O, with propiophenone affords the corresponding but-1-enes in high yield with a marked preponderance of the Z-isomer in most cases. Remarkably, when X = OH the Z:E ratio is 9:1. The value of this method is illustrated by simple syntheses of (Z)-1-{4-[2-(N,N-dimethylamino)ethoxy]phenyl}-1,2-diphenylbut-1-ene (Tamoxifen) a drug widely used in the treatment of oestrogen-dependent breast tumours.