Studies toward improving the reactivity and chemoselectivity of chloroarenes in palladium-catalyzed cross-coupling processes

Palladium-catalyzed cross-coupling reactions are a powerful tool for the practicing organic chemist. It is a rare occurrence to find an issue of the current organic synthesis literature which does not contain several articles related to this ever expanding field. Recently, much attention has been paid to developing methodology for the use of chloroarenes as substrates for these processes. These efforts are certainly worthwhile when one considers that chloroarenes are easier to obtain and considerably less expensive than other commonly used substrates. However, this task is not without its challenges, due to the inert nature of the carbon-chlorine bond.;We show through catalyst recycling studies that the Pd/C precatalyst can be reused up to four times without any significant loss in efficiency. Analysis of residual palladium levels of several products result in a range from 9 to 30 ppm. Filtration and split tests reveal that product formation continues after the removal of the solid Pd/C from the reaction mixture. Through the use of a combination mercury poisoning and filtration test we conclude that the reaction is catalyzed by a soluble zero valent molecular palladium species.;By instituting an incubation period for the Pd/C precatalyst before the addition of the ligand we are able to significantly reduce the ligand loading. Analysis of soluble palladium levels of a product prepared in this manner result in < 5 ppm palladium. This method is shown to superior to those which use traditional homogeneous precatalysts for the preparation of three biphenyl products. A catalytic cycle is proposed in which ligand free and ligand assisted pathways combine to give practical yields of coupling products but also result in low levels of Pd contamination.;The palladium-catalyzed amination reaction is used to prepare the quinolone antibacterial Norfloxacin from the fluorochloroarene precursor. Selective substitution at the chlorine atom is achieved. This method is shown to have practical advantages over the current methodology for the preparation of these compounds.;We have succeeded in developing a technique which utilizes Pd/C as a precatalyst in combination with a phosphine ligand for the Suzuki cross-coupling reaction. We are the first to demonstrate the broad scope of this process by reacting a variety of chloroarenes and aryl boronic acids which are difficult to couple under ligandless Pd/C conditions. In doing so, we obtain product yields of 30--91% in comparison to the 0--36% yields obtained with Pd/C in the absence of ligand.;The palladium-catalyzed cyanation of bromo and chloroarenes is performed in the presence of tri-t-butylphosphine tetrafluoroborate salt. Preliminary results show the complete conversion of bromobenzene at 80°C in two hours. The rationale behind the preparation of a novel azaphosphine ligand based on a non-biaryl atropisomeric backbone is discussed along with the progress achieved toward that end.