Stereoselective Nickel(II)-Catalyzed Addition of Aryl Grignards to Diphenylacetylene in the Synthesis of Zuclomiphene

Stereoselective synthesis of zuclomiphene was developed using nickel-catalyzed addition of 4-fluorophenylmagnesium bromide to 1,2-diphenylacetylene, followed by quenching with a chlorinating reagent. Since the aryl fluoride addition and chlorination reactions occur consecutively in one pot, the cis orientation of the two phenyl groups of 1,2-diphenylacetylene is conserved, leading to the highly selective synthesis of zuclomiphene. The use of the Grignard reagent resulted in the presence of bromide ions in the reaction mixture, which led to the formation of the bromo-analog of zuclomiphene. Alternative routes were then explored to overcome this issue to yield high-purity zuclomiphene.