The advent of new synthetic strategies has enriched the synthetic organic chemistry to access molecules with tremendous complexity. In this context, transition metal-catalyzed C−H activation has emerged as a powerful tool for highly step- and atom- economical synthesis that avoids laborious prefunctionalizations of starting materials.[27, 56] In this thesis, the primary focus was the development of novel and sustainable methods by direct C−H activation to synthesize value-added synthetic targets of biological importance.
In the first project, the unprecedented use of a manganese(I) complex was demonstrated for challenging C−F/C−H functionalizations (Scheme 129).[283] Robust reaction conditions and ample substrate scope are some of the key characteristics of this approach. This method proved to be viable for synthetically meaningful ketimines. Thus, versatile manganese(I)-catalyzed C−F/C−H functionalization allowed for the synthesis of diverse fluorinated scaffolds. In addition to allylations and alkenylations, we also identified the potential of manganese catalysis in C−H perfluoroalkenylation using challenging perfluoroalkenes. It is noteworthy that even amino acids and peptides underwent C−F/C−H functionalizations under racemization-free conditions.
Scheme 129. Manganese(I)-catalyzed C−F/C−H functionalizations.
In the second project, the versatility of ruthenium catalysis was shown towards C–F/C–H functionalization (Scheme 130).[284] Previously our group reported on the ruthenium-catalyzed C–H hydroarylations with unactivated alkenes and perfluoroalkenes. In the present method, by
the judicious choice of a tertiary phosphine ligand, a switch in chemoselectivity was observed towards challenging C–F functionalization. More pleasingly, ketimines were found as amenable substrates for the envisioned C–F/C–H functionalization to synthesis fluorinated ketones by a one-pot hydrolysis. This approach allowed for highly chemo- and position-selective β-fluorine eliminations with a broad range of substituted ketimines and perfluoroalkenes. Considering the importance of fluorinated building blocks, these studies are expected to inspire related developments in the field of transition metal catalysis.
Scheme 130. E-selective C–H/C–F functionalization by ruthenium(II) catalysis.
As with fluorinated scaffolds, chiral molecules represent a class of highly desirable building blocks. Thus, the next part of the thesis focused on the development of sustainable enantioselective transformations using cost-effective transition metals. In the third project, we developed a novel chiral carboxylic acid CA5 to realize the first cobalt(III)-catalyzed enantioselective C–H activation (Scheme 131).[270] Initial studies with commonly used mono protected amino acids and chiral phosphoric acids failed to provide high levels of enantiocontrol. In contrast, the design of novel chiral carboxylic acid CA5 enabled the first highly enantioselective cobalt(III)-catalyzed C–H alkylation with unactivated alkenes 223 by organometallic chelation assisted C–H activation. The mild Grignard-free reaction conditions tolerated a wide array of sensitive functional groups on the indoles 354 as well as on the alkene coupling partners 223. Moreover, the directing groups were removed in a traceless fashion
under hydrogenation conditions without any erosion of the enantiomeric excess. Detailed mechanistic studies by kinetic experiments and non-linear effect studies provided evidence for dimeric hydrogen bond stabilized resting state of the chiral carboxylic acid. This study on co-operative cobalt(III)/chiral acid manifold set the stage for subsequent developments in the enantioselective cobalt(III)-catalyzed C–H activation, as further reports were documented by Matsunaga[271a] and Cramer.[285]
Scheme 131. Enantioselective cobalt(III)-catalyzed C–H alkylation by chiral carboxylic acid cooperation.
Thereafter, we became interested in the development of ruthenium-catalyzed enantioselective organometallic C−H activation with the combination of a chiral acid. In contrast to the significant advances in the ruthenium catalyzed C−H activation, organometallic enantioselective transformations remain largely underdeveloped. In this project we succeeded to achieve enantioselective ruthenium-catalyzed organometallic C−H alkylation, employing a C2 symmetrical chiral acid CA14 to control the enantio-induction (Scheme 132).[286] Cost-effective and bench-stable [RuCl2(p-cymene)]2 was successfully employed with a chiral carboxylic acid to synthesis enantioenriched tetrahydrocarbazoles and cyclohepta[b]indoles derivatives by intramolecular cyclization at room temperature. C2-symmetric chiral acid was found to be crucial for enantioselective intramolecular C−H alkylation while other commonly used chiral acids failed in this protocol. Detailed kinetic and DFT studies unraveled a reversible C−H metalation step and an enantio-determining proto-demetalation step by the chiral acid.
DFT studies provided support for the presence of weak secondary dispersive interactions to control enantio-induction.
Scheme 132. Enantioselective ruthenium-catalyzed organometallic C−H alkylation Resource-economy is another important aspect in molecular syntheses.[224] Consequently, a large portion of the doctoral thesis was focused on addressing improved sustainability and resource-economy for the activation of inert C–H bonds. Over the past years, early examples of electrochemical C−H activations were largely restricted to the use of palladium. In 2017, Ackermann realized the first electrochemical 3d transition metal-catalyzed C−H activation using inexpensive cobalt as a catalyst for oxygenation reactions,[246] which has set the stage for the development of electrochemical transformations with Earth-abundant transition metals.[232]
In the fifth project, we realized electrochemical copper-catalyzed sequential alkyne annulations with benzamides to synthesis isoindolone motifs 256 in the absence of any chemical oxidants (Scheme 133).[287] Inexpensive Cu(OAc)2 was employed as the catalyst for the electrooxidative alkynylation protocol by the assistance of 8-aminoquinoline as the directing group.
Furthermore, our reaction conditions were found to be suitable for the decarboxylative C–H/
C–C cleavage with alkynyl carboxylic acids. This study showed the unique potential of copper catalysts in electrochemical transformations, which is expected to inspire related developments in the near future.
Scheme 133. Copper-catalyzed electrochemical alkyne annulation.
Thus far, all the reported electrochemical transformations with precious 4d and 5d transition metals were limited to activated alkenes, such as styrenes and acrylates. In the subsequent project, we showed the versatility of oxidative cobalt catalysis in electrocatalytic C−H allylations with unbiased olefins (Scheme 134).[288] A key characteristic of our strategy was the use of the biomass-derived solvent -valerolactone as the reaction media. Electro-oxidative cobalt catalysis provided the chelation-assisted ortho-C−H allylation by the assistance of 8-aminoquinoline as the directing group, generating molecular hydrogen as the sole stoichiometric by-product. A plethora of sensitive functional groups were fully tolerated, providing exclusively the allylic selectivity. Competition experiment provided evidence for a base-assisted internal electrophilic-type substitution mechanism for the C–H metalation event.
This turns out to be one of the scarce example for the application of unactivated olefins in electrochemical C−H activation reactions.
Scheme 134. Cobalt-catalyzed electrochemical C−H allylation
The merger of electrosynthesis with transition metal catalysis provides enormous potential towards perfect resource economy. Despite substantial progress, enantioselective metallaelectro-catalyzed C–H activation was not realized before. To address the full potential of electrochemistry and considering practical importance of chiral building blocks, we achieved the first asymmetric metallaelectro-catalyzed C–H activation under exceedingly mild reaction conditions (Scheme 135).[289] We employed inexpensive L-tert-leucine as a transient directing group to enable electrochemical atroposelective organometallic C–H activation. This was the unprecedented report for the application of transient directing group in electrochemical transformations. The combination of Pd(OAc)2 and L-tert-leucine provided excellent enantioselectivities for the atroposelective olefination reactions to furnish axially-chiral biaryls. On a pleasing note, similar reaction conditions were also effective for the synthesis of N−C axially-chiral motifs in excellent enantioselectivities. Detailed kinetic studies shed light on the C−H metalation step, being suggestive of the C–H activation as the rate-determining step. In addition, DFT studies showed preference for the formation of seven membered ring over the five-membered metallacycle to enable the axial chirality. This metallaelectro-catalyzed enantioselective protocol provided a step-economical strategy to the synthesis of highly enantio-enriched BINOLs, dicarboxylic acids and helicenes. Given the topical interest in the development of new approach for enantioselective transformations, this sustainable protocol paves the path for further developments in this research area.
Scheme 135. Metallaelectro-catalyzed enantioselective C−H activation.
5. Experimental Part