Process Development for a Large Scale Stereoselective Synthesis of (Z)-(1-Bromobut-1-ene-1,2-diyl)dibenzene, a Key Intermediate of a Selective Estrogen Receptor Modulator

Two efficient large scale syntheses of (Z)-(1-bromobut-1-ene-1,2-diyl)dibenzene are described. The first is a three-step synthetic sequence from trimethyl(phenylethynyl)silane in 63% overall yield. The key transformations involved the stereospecific carbometalation reaction of trimethyl(phenylethynyl)silane followed by a bromination. Subsequent Miyaura−Suzuki coupling with phenylboronic acid and transformation of the vinyltrimethylsilane to a vinyl bromide afforded the target. In an improved synthesis, a stereoselective nickel acetylacetonate catalyzed PhZnEt addition to but-1-ynylbenzene, generated an organozincate intermediate, which was brominated in 58−62% overall yield. A key feature of this work was the production of highly regiopure olefin. The optimization effort that resulted in the utilization of substoichiometric amounts of Ph2Zn and the safety precautions taken to facilitate process scale-up are discussed.