Reactivity and mechanistic study of the Sonogashira coupling and Grignard-Sonogashira coupling reactions

Abstract

The interest in studying enediyne systems was stimulated by the discovery of anti-cancer agents containing enediyne functionalities, such as esperamicin and dynemicin. These compounds have potential for use as anti-tumour antibiotics, however, they are not sufficiently selective to he used clinically. Many attempts to synthesize analogs of the natural enediynes with improved selectivity and reduced toxicity have been made. A number of synthetic methodologies have been employed toward the synthesis of the analogs, including Stephens- Castro Coupling and Sonogashira Coupling. In this thesis, a reactivity study involving coupling reactions using Pd(PPh3)4 and a series of electron donating and electron withdrawing substituted aryl halides is presented. The positions of these substituents relative to the coupled alkyne (i.e., ortho, meta, para) were studied and the changes these substituents had on reactivity (i.e., electronic and steric effects) were investigated. All of the substituted alkynyl benzenes were successfully synthesized in all positions and fully characterized. High yields were obtained for both electron withdrawing and electron donating substituents. In competitive reactions electron withdrawing groups in the para position reacted preferentially over electron donating groups. In general, substituents in the ortho position decreased the rate of reaction. When the starting halides were converted to Grignard reagents, high yields were obtained for electron donating groups as well as some hindered electron withdrawing groups. Mechanistic studies for the Grignard coupling reaction reveal that a transmetallation reaction occurs, and the same catalytic intermediate that is present in the standard Sonogashira coupling reaction also exists in the modified Grignard coupling process.