Direct synthesis of tamoxifen and related triaryl-substituted alkenes via two-fold extrusion reactions

CHED 297

Ian R. Bothwell, bothweli@southwestern.edu and Frank Guziec Jr., guziecf@southwestern.edu. Department of Chemistry and Biochemistry, Southwestern University, 1001 E. University Ave., Georgetown, TX 78626
The two-fold extrusion reaction has proven to be an effective means of synthesizing highly substituted, sterically hindered olefins. The mechanism for this reaction involves loss of sulfur and diatomic nitrogen from the 1,3,4-thiadiazoline intermediate formed by a 1,3-dipolar cycloaddition between a thione and a diazo compound. In order to determine the potential of this reaction in the synthesis of biologically important molecules, we have applied it to the preparation of the selective estrogen receptor modulator: tamoxifen. We have successfully produced a mixture of the Z- and E- isomers of tamoxifen in good yield by combining the diazo compound derived for propiophenone tosylhydrazone with 4-(2-dimethylamino)ethoxythiobenzophenone. Our synthetic route could prove to be advantageous over currently used methods due to the possibility for a direct synthesis of various tamoxifen metabolites and related compounds under mild reaction conditions. Details of the synthesis of the required precursors will also be presented.