Study of Fundamental Steps of Transition metal-Catalyzed Cross-coupling Reactions

Transition metal-catalyzed cross-coupling reactions with organometallic reagents or other nucleophiles have had a tremendous impact on the way organic chemists currently design synthetic strategies. These reactions deliver the possibility to create carbon-carbon bonds under mild reaction conditions with high functional group compatibility. The Nobel Prize 2010 awarded for the development of Pd-catalyzed cross-coupling reactions illustrates the importance of this methodology. Pd-catalyzed cross-coupling reactions are now used as standard for the synthesis and derivatization of scaffolds. Discovery programs in the fine chemicals industry make use of this synthetic tool to identify hits, leads and perform further lead optimization. The functionalized scaffolds are usually heterocycles due to their importance in the industry (APIs, agrochemicals, …).  Pd-catalyzed cross-coupling reactions have been developed for carbocycles. Application of these methods for the synthesis and functionalization of heterocycles therefore often requires very high catalyst loadings and in several cases the reaction does even not work at all. Clearly, the heteroatoms present can influence the catalysis significantly but the fundamental parameters responsible for this inhibition are just not understood/studied. A good example is the synthesis of [2-(3-methyl-3H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)amine, a VEGFR kinase inhibitor. Process chemists at Pfizer investigated the synthesis of the biaryl core 2-(3H-imidazol-4-yl)thieno[3,2-b]pyridine via Pd-catalyzed cross-coupling reactions with organometallic reagents at larger scale. A wide variety of Pd-catalyzed cross-coupling reactions were attempted (Suzuki-Miyaura, Hiyama, Kumada, Negishi and Stille reaction) but only the Stille reaction proved to be robust and scaleable on > 50g scale. No rationale for this remarkable observation could be given. Our research team has acquired a lot of experience in the use of transition metal-catalyzed cross-coupling reactions involving heterocycles. Similarly as in the Pfizer case, we experienced the limitations of transition metal catalysis for both heterocyclic scaffold synthesis and its derivatization. In order to gain insight into the limitations of the transfer of transition metal-catalyzed cross-coupling reactions of carbocycles to heterocycles, the effects of heteroatoms in the substrate (and organometallic reagent) on the fundamental steps of the catalytic cycle have to be studied. Therefore, a kinetic study of the fundamental steps of the catalytic cycle needs to be performed. In sharp contrast to the widespread application of transition metal-catalyzed cross-coupling reactions on heterocyclic substrates (mainly (pseudo)haloheteroarenes), experimental data regarding the effects of heteroatoms on the fundamental steps of the catalytic cycle are very scarce. This research is in collaboration with Prof. Anny Jutand of the Ecole Normale Supérieure.