During the last years, transition metal-catalyzed C–H activation has emerged as a powerful method for the selective construction of C–C and C–Het bonds and has greatly expanded the toolbox of synthetic chemistry.[12, 21, 25] Ruthenium catalyst were recognized as a potent alternative to costly palladium or rhodium catalysts and have enabled a number of unique transformations, especially in terms of remote σ-activation.[27, 71] However, a detailed mechanistic understanding of these transformations is often lacking and thus impedes the improvement of established catalytic systems as well as the rational design of novel synthetic protocols. Therefore, the main objective of this thesis was directed towards detailed mechanistic investigations of various C–H and C–C activation processes by means of experiment and computation.
Protocols for ruthenium-catalyzed meta-selective C–H activations are frequently restricted to strongly coordinating, nitrogen-containing heterocycles as directing groups, thereby limiting the applicability towards biologically relevant structures (vide supra). With this in mind, a method for the meta-C–H bromination of bioactive purines should be investigated and used as a platform for further diversifications (Scheme 51).
Scheme 51: meta-C–H bromination of purines 148 under ruthenium catalysis.
Furthermore, based on the ruthenium-catalyzed meta-C–H alkylation strategies developed by Ackermann,[77, 78] the application of ketimines as easily transformable directing groups in meta-selective C–H alkylations should be explored. In addition to the development of a novel synthetic
2 Objectives
Scheme 52: Ruthenium catalysis for remote C–H alkylation of ketimines 151.
In the context of remote C–H activations, the prediction of ortho/meta-selectivities by means of computational chemistry could contribute to a deeper understanding of the reaction mechanism and to the identification of potential key intermediates. To this end, various conceivable cyclometalated complexes with different substrates and coordination environments should be evaluated and compared to experimental observations.
The use of easily accessible carboxylic acids as traceless directing groups in transition metal-catalyzed C–H activation holds enormous potential.[56] So far, detailed insights into the reaction mechanism of decarboxylative C–H activations under ruthenium catalysis remained scarce and should prove instrumental to the development of novel transformations. Especially the competition between decarboxylative and annulative processes is worth investigating (Scheme 53).
Scheme 53: Decarboxylative C–H activation of benzoic acids 31 under ruthenium catalysis.
The C–H activation of weakly coordinating aryl acetamides 153 was previously achieved by palladium catalysis, but was thus far not explored with less costly ruthenium catalysts.[110, 111] Due to a presumed formation of an unusual and challenging six-membered ruthenacycle, the utilization of these substrates in ruthenium-catalyzed C–H activation should be experimentally studied and a comparison with the corresponding, more commonly occuring five-membered metalacycle conducted (Scheme 54).
2 Objectives
Scheme 54: Ruthenium-catalyzed distal C–H activation of aryl acetamides 153.
Furthermore, the development of sustainable protocols for the diversification of ferrocenes via a C–H activation approach is highly desirable due to the application of substituted ferrocenes as inter alia ligands[112] and bioactive molecules.[113] Different weakly coordinating directing groups for direct C–H arylations of ferrocenes under ruthenium catalysis should be investigated with respect to the C–H ruthenation step and the stability of the generated metalacycle (Scheme 55).
Scheme 55: C–H arylation of ferrocenes 156 with ruthenium catalysts.
During the last years, transition metal-catalyzed C–H activation was recognized as a convenient strategy for the last-stage diversification of peptides and amino acids.[114] Computational studies on the hydroarylation with indoles 125 as a model substrate for tryptophan should be conducted to gain insight into the catalytic pathway. In addition, an analysis of the ligand influences on the energy profile could lead to the identification of more efficient catalysts (Scheme 56).
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In an earlier report on ruthenium-catalyzed C–H arylations with aryl halides, the group of Ackermann observed a competing oxidative C–H/C–H activation process, in which the aryl halide acts as the oxidant.[115] However, no explanation concerning this change in mechanism was presented at that time and the selectivity-controlling parameters remained unclear. An in-depth study on the rate- and selectivity-controlling factors as well as the catalyst’s mode of action should be performed and should prove invaluable, not only to the understanding of oxidative C–H/C–H activations with ruthenium catalysts, but also in providing new insights into well-established C–H arylation processes (Scheme 57).
Scheme 57: Ruthenium-catalyzed C–H/C–H activation and C–H arylation.
Throughout the last years, a trend towards the use of earth-abundant, inexpensive[86] base metal catalysts for C–H activation could be witnessed (Figure 4). In that regard, the potential of manganese catalysis for the late-stage diversification of tryptophan-containing peptides was revealed in a previous report on C–H alkynylation (vide supra).[95] Consequently, computational investigation of the key elementary steps of a related manganese-catalyzed C–H allylation of tryptophan 160 should contribute to a deeper understanding of the turnover-limiting steps of the reaction mechanism (Scheme 58).
Figure 4: Prices of commonly employed metals in € per kg.
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2 Objectives
Scheme 58: Manganese-catalyzed C–H allylation of tryptophan 160.
Through transition metal-catalyzed C–C activation strategies a number of C–C and C–Het bond formations can be achieved, which cannot be realized by other methods.[96] The use of benzylic alcohols 142 as substrates in the context of manganese-catalyzed C–C allylations with cyclic carbonates and carbamates should be explored. In addition to the user-friendly access to synthetically useful allylated arenes, detailed studies of the manganese-catalyzed C–C activation process could provide novel insights into the fundamental differences of C–C and C–H activation reactions (Scheme 59).
Scheme 59: C–C allylation of benzylic alcohols 142 under manganese catalysis.