The target indole analog of 4-hydroxy Tamoxifen® was determined via a structure-based approach. 4-Hydroxy Tamoxifen® is of interest due to its increased affinity to bind with the estrogen receptor relative to Tamoxifen®. The Hemetsberger-Knittel indole synthesis methodology provides an effective and efficient procedure to substituted indoles via vinyl azides. Two approaches were examined in this project, “the benzophenone” approach and “the benzaldehyde” approach. The benzophenone approach allows for the synthesis of the indole analog of 4-hydroxy Tamoxifen® with a direct approach. The benzaldehyde approach was used to test reaction conditions, such as temperature and addition method. The reactions of benzophenone or certain benzaldehydes in the Aldol condensation reaction with an azido ester using potassium tert-butoxide and sodium methoxide at low temperatures were examined. The reaction of 3,4,5-trimethoxybenzaldehyde with ethyl azidoacetate with potassium tert-butoxide produced the vinyl azide precursor to the trisubstituted indole as determined by 1H-NMR data. It is speculated that benzophenone’s lower reactivity and steric hinderance hindered its ability to react with the ethyl azidoacetate. Complications of the reactions performed to produce vinyl azides will be discussed in more detail.
