Final Report Summary - DASCA (Direct Alkylation of Saturated Cyclic Amines via catalytic C-H Functionalization.)
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. 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. The overall objective of DASCA project was to develop direct transition metal-catalyzed functionalizations of C(sp3)–H bonds in saturated nitrogen-based heterocycles, with a particular focus on broad scope and regioselectivity. The major scientific achievements are:
1) Development of a direct ruthenium-catalyzed C(sp3)-H alpha–alkylation of cyclic amines using dioxolane protected alkenones. This new method permits one to efficiently introduce oxygen functionality (3-oxoalkyl) into the alpha–alkyl chain of various cyclic amines (piperidines, bicyclic amines, featuring a bis-substituted piperidine entity, and other cyclic systems such as pyrrolidine and azepane). The utility of the alpha-alkylation methodology was demonstrated by the possibility to efficiently remove the pyridin-2-yl directing group as well as the ketal protective group in the reaction products. After all, post-transformation of the secondary amine and ketone functionalities will allow one to access a variety of hitherto unknown substituted cyclic amines, which are valuable targets for drug discovery research.
2) Development of new directing groups for direct functionalization of cyclic amines. The above mentioned achievement of the DASCA project demonstrated the applicability of a pyridin-2-yl directing group (DG) for the efficient alpha-alkylation of piperidines and other cyclic amines. However, the pyridin-2-yl DG is not free of limitations. When the substrate possesses two equally active alpha-positions at the piperidine site, a mixture comprising mono- and bis-functionalized products is typically obtained. Additionally, the removal of the pyridin-2-yl DG is not trivial, even though the procedures developed recently by the Antwerp team provide a huge progress in that area. Therefore, the focus of the DASCA project was on the development of alternative DG groups, which were free of these disadvantages. The new DGs are still based on a pyridine moiety, but comprise an additional linker and extra substituents. We developed a flexible synthetic approach for the synthesis of a library of new directing groups, and have undertaken the extensive optimization of the reaction conditions for the Pd-catalyzed arylation and alkylation of five- and six-membered cyclic amines. This allows for the first time to achieve regioselective mono alpha-arylation via C-H activation in cyclic amines.
3) An alternative approach for alpha-functionalization of cyclic amines investigated is the use of a a directing group attached to the carbon skeleton of the cyclic amine, rather than to the nitrogen atom. As substituted cyclic amines are readily available, their derivatization with pyridine-containing directing groups was studied. By the variation of the position of the DG, also selective introduction of the aryl group in other positions was achieved. Most importantly, this approach allows for the first time to achieve a diastereoselective mono arylation in cyclic amines. Further, substitution patterns hitherto inaccessible via transition metal catalysis and only achievable through long synthetic routes via classical synthesis, are achieved with this method.
1) Development of a direct ruthenium-catalyzed C(sp3)-H alpha–alkylation of cyclic amines using dioxolane protected alkenones. This new method permits one to efficiently introduce oxygen functionality (3-oxoalkyl) into the alpha–alkyl chain of various cyclic amines (piperidines, bicyclic amines, featuring a bis-substituted piperidine entity, and other cyclic systems such as pyrrolidine and azepane). The utility of the alpha-alkylation methodology was demonstrated by the possibility to efficiently remove the pyridin-2-yl directing group as well as the ketal protective group in the reaction products. After all, post-transformation of the secondary amine and ketone functionalities will allow one to access a variety of hitherto unknown substituted cyclic amines, which are valuable targets for drug discovery research.
2) Development of new directing groups for direct functionalization of cyclic amines. The above mentioned achievement of the DASCA project demonstrated the applicability of a pyridin-2-yl directing group (DG) for the efficient alpha-alkylation of piperidines and other cyclic amines. However, the pyridin-2-yl DG is not free of limitations. When the substrate possesses two equally active alpha-positions at the piperidine site, a mixture comprising mono- and bis-functionalized products is typically obtained. Additionally, the removal of the pyridin-2-yl DG is not trivial, even though the procedures developed recently by the Antwerp team provide a huge progress in that area. Therefore, the focus of the DASCA project was on the development of alternative DG groups, which were free of these disadvantages. The new DGs are still based on a pyridine moiety, but comprise an additional linker and extra substituents. We developed a flexible synthetic approach for the synthesis of a library of new directing groups, and have undertaken the extensive optimization of the reaction conditions for the Pd-catalyzed arylation and alkylation of five- and six-membered cyclic amines. This allows for the first time to achieve regioselective mono alpha-arylation via C-H activation in cyclic amines.
3) An alternative approach for alpha-functionalization of cyclic amines investigated is the use of a a directing group attached to the carbon skeleton of the cyclic amine, rather than to the nitrogen atom. As substituted cyclic amines are readily available, their derivatization with pyridine-containing directing groups was studied. By the variation of the position of the DG, also selective introduction of the aryl group in other positions was achieved. Most importantly, this approach allows for the first time to achieve a diastereoselective mono arylation in cyclic amines. Further, substitution patterns hitherto inaccessible via transition metal catalysis and only achievable through long synthetic routes via classical synthesis, are achieved with this method.