Direct Functionalization via Transition Metal-Catalyzed C-H Bond Activation

Transition metal-catalyzed reactions involving C–C and C-X (heteroatom) bond formation are arguably indispensable in modern organic chemistry. They allow for the selective and efficient synthesis of organic compounds, which are otherwise only accessible via multi-step synthetic routes. The classical catalytic methods usually involve the reaction of a transition metal complex with a reactive group on the substrate. For instance, cross-coupling reactions require the use of a C–X bond (X = halogen or pseudohalogen) in the substrate to create a reactive organometallic intermediate. The installation of a reactive group (pre-activation) is a serious drawback, as several reaction steps are often required to synthesize the substrates from commercially available starting materials. If C–H bonds, ubiquitous in organic substances, can be used directly in transition metal-catalyzed carbon - carbon and carbon -  heteroatom bond forming reactions (direct activation), this would deliver synthetic methods which are step- and atom economical and therefore of utmost importance for organic chemistry. After all, such methods are inherently more sustainable, require less energy and create less waste. In addition, the wider availability of substrates for direct catalytic functionalization of C–H bonds provides a much broader scope. However, the implementation of this attractive concept is far from being self-evident: C–H bonds are ubiquitous in organic molecules and their dissociation energies are large. Hence, selective functionalization of C–H bonds remains a significant challenge. Moreover, there are concerns of feedstocks of noble transition metals on a mid-term basis and their geographical distribution of mining on earth poses potential price stability issues. This resulted in a strong request of the fine chemicals industry to develop protocols based on base metals.

C(sp2)-H Bond Activation

In our research we hitherto have been mainly working on the synthesis of (new) heteroaromatic scaffolds (= basic structures which are already known for their interesting properties or compounds hitherto unknown) via the development of cyclization reactions involving C(sp2)-H bond activation. Efficient and flexible synthetic methods for the production of functionalized bicyclic and tricyclic heteroarenes are important for the fine chemicals sector and this both on discovery and scale-up level. These methods preferentially have to allow a large diversity in the type of functional group which can be incorporated on the scaffolds. The synthesis of these heteroarenes is hitherto however based on classical heterocyclic chemistry starting from a correctly ortho disubstituted (hetero)arene. Based on the limited commercial availability of these ortho disubstituted (hetero)arenes, there is a limitation in the functional group which can be installed in the scaffold. Low yields often also form an (additional) problem. Synthetic methods based on bond formation via transition metal-catalyzed C(sp2)-H activation form a very attractive alternative since no pre-activation of two positions in the starting material is required. This methodology therefore offers more possibilities from the point of view of diversity due to a better availability of substrate (both commercially and via synthesis, both arenes and heteroarenes). Internationally, functionalizations through C(sp2)-H activation hitherto focused largely on carbon-carbon and less on carbon-heteroatom bond formations. In our group we currently focus on scaffold design based on intramolecular direct carbon - nitrogen bond formation via transition metal-catalyzed C(sp2)-H activation. This is a dehydrogenative coupling (C(sp2)-H and N-H) and therefore requires a stoichiometric oxidant. The choice of this oxidant is crucial for the sustainability of the reaction. Oxygen is very attractive as it is the most sustainable oxidant on earth (producing water) and there is no feedstock limitation.

C(sp3)-H Bond Activation

C-C Bond Formation

While the field of functionalization through C(sp2)-H bond activation is internationally already an active field of research, the corresponding process involving C(sp3)-H bonds is still far less explored and often lacks mechanistic understanding. Functionalizations via transition-metal catalyzed C(sp3)-H activation have to be considered as a research area with a high risk but with a huge potential, if successful. The research in our division is centered on the direct α-functionalization of cyclic amines. Transition metal-catalyzed C(sp3)-H activation represents an elegant alternative synthetic approach to the direct functionalization of saturated cyclic amines involving stoichiometric reagents. Nevertheless, only a limited number of reports have appeared in the literature wherein the main focus is on 5-membered cyclic substrates. This is remarkable given the importance of such cyclic amines in medicinal chemistry. After all, the 2011 top 200 selling APIs list in the USA contains 22 molecules with e.g. a piperidine core.

C-O bond formation

Transition metal-catalyzed oxidation is a key technology for the transformation of feedstock into basic bulk chemicals of a higher oxidation state. In the last decade also in the fine chemicals production the interest in transition metal-catalyzed oxidation reactions has rapidly grown. This is mainly due to the environmental legislation which gradually became (and still becomes) stricter. Classical inorganic oxidants such as permanganate and dichromate are considered not “green” because of their toxicity and the fact that they are used as reagents (in at least stoichiometric amount), generating a lot of waste. Alternative transition metal-catalyzed oxidation processes with a high atom economy, a low E-factor and based on the use of non-toxic and cheap transition metals, such as base metals, are therefore highly relevant to the fine chemicals production industry. These “greener” oxidation reactions should be preferentially based on O2 which is the cheapest and greenest oxidant available to chemists. For application in fine chemical synthesis, which typically involves a greater degree of functionality than bulk chemicals, the chemoselectivity of the oxidation reaction is of the utmost importance. By tuning the metal catalysts and their coordination sphere this is a challenging but feasible goal. In a broader context the direct oxygenation of C-H bonds belongs to the field of C-H activation with transition metals which is currently at the forefront of research in synthetic organic chemistry.