Abstract

Carbon-carbon (C-C) bonds are one of the most common bonds in nature and hence, the formation of C-C bond has always been of interest in synthetic chemistry. Consequently, numerous Pd-catalyzed C-C bond forming reactions, such as Kumada, Heck, Suzuki, Negishi, and Stille couplings, have been developed during the last decades. The majority of these methods can be used in the formation of biaryls and hetero-biaryls that are important moieties in pharmaceuticals and materials due to their special properties such as conjugated π systems and planar structures. Thiophene is one of the most important heteroarenes and is frequently used in the synthesis of biologically active compounds and fine chemicals.

As an example, the biologically active thienoisoquinoline scaffold (160), discovered by Wyeth, can be used as a potential therapeutic for inflammatory-related diseases such as atherosclerosis, type II diabetes, and cancer through the inhibition of nuclear factor NF-κB. The patented synthetic route to access the desired scaffold involves an eight-step reaction sequence including two Pd-catalyzed Suzuki coupling reactions. With increased emphasis on green chemistry, modular environmentally-friendly Pd-catalyzed C-C bond forming reactions, such as decarboxylative cross-coupling and C-H activation, have received increased attention in the past decade. These reactions do not require pre-functionalization of the coupling partners and do not produce high mass and stoichiometric by-products, therefore they can be employed to access scaffold (160) more efficiently. We developed two experimental approaches towards these thienoisoquinoline systems. A 5-step synthesis employing a Pd-catalyzed intramolecular decarboxylative cross-coupling (158 → 159) followed by direct C-H arylation (159 → 160). Alternatively, the palladium-catalyzed reactions can be telescoped to produce a one-pot sequence that provides efficient access to aryl-substituted thienoisoquinolines (158 → 160 directly). The work presented in this thesis demonstrates the applicability of decarboxylative and C-H activation couplings in the efficient synthesis of biologically important compounds. The synthesis of several analogues using both described methods will be presented and the advantages will be described. The one-pot method offers a convenient way to access this scaffold in excellent yields that avoids the longer synthetic route previously reported.