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Merging visible-light photocatalysis and C-H activation: new strategy towards all-carbon quaternary stereogenic centres – 2al-VisPhot-CH

Dual catalysis merging visible-light photocatalysis and C-H activation: new strategy towards all-carbon quaternary stereogenic centres.

C-C couplings are fundamental reactions allowing construction of complex molecular scaffolds from simple starting materials. However, such couplings frequently require rather harsh reaction conditions. We propose therefore to develop a conceptually new approach implying dual catalysis. Each coupling partner could therefore be activated selectively via either organometallic catalysis or photocatalysis, yet pawing a way towards challenging transformations under mild reaction conditions.

Asymmetric, mild and eco-compatible alkylations

Developing conceptually novel, more eco-reliable transformations, building up molecular scaffolds inaccessible via standard methodologies and designing unprecedented catalytic systems: these are urgent challenges of the fundamental research in organic chemistry. The objective of the herein presented project is to respond to these important issues by devising an original dual catalysis. We propose to employ synergistic catalysis merging visible-light photoredox catalysis and transition-metal catalyzed C-H activation to perform highly challenging sp2-sp3 and sp3-sp3 couplings. Metal catalyzed C-H activation will therefore be used to generate key sp2 and sp3-metallacyclic intermediates, prompt to trap hindered alkyl radicals, resulting from the photoredox activation. Such complementary and specific activation modes, well adapted to each coupling partner should allow the targeted transformations to occur under mild reaction conditions, giving therefore promise for an efficient transfer of chiral information during the stereoselective transformations. Accordingly, the supreme goal of the herein presented work is to perform asymmetric transformations thus paving the way towards original synthetic routes to access highly valuable all-carbon quaternary stereogenic centers. Both diastereoselective (use of stereogenic directing groups on C-H substrates) and enantioselective transformations (utilization of chiral C-H activation catalysts) will be investigated. <br />In addition, a synthesis of original photocatalysts based on Cu is envisioned in order to bring an alternative solution to broadly used but very expensive Ir and Ru-based complexes.

During this project we propose developing unprecedented alkylation reactions of simple, non prefunctionalized starting materials by means of C-H activation. In order to reach this goal, we envision performing C-H activation by using organometallic, homogenous catalysts, hence generating metallacyclic intermediates. In parallel, the second, aliphatic coupling partner, will be converted into highly reactive radical moieties under visible light photoactivation. Such an approach will therefore be employed to accomplish, firstly, C(sp2)-C(sp3) couplings (aromatic substrate for C-H activation), and, secondly, even more challenging C(sp3)-C(sp3) couplings. Subsequently, we will endeavor on building up chiral molecules by means of stereoselective bond formation reactions, with an ultimate goal to synthesize skeletons containing enantiopure quaternary carbon motifs.
The starting point of this work consists on determining two independent catalytic cycles, ie. C-H activation and photoinduced formation of aliphatic radicals, occurring under similar reaction conditions (solvent, temperature, additives). Based on literature several C-H activation partners have been selected, as prompt to undergo room temperature metallation. Also several families of aliphatic derivatives such as silicates, trifluoroborates and carboxylic acids have been chosen as precursors of aliphatic radicals. Consequently, the initial work concerns merging of such two independent catalytic systems in order to allow the direct coupling between such substrates. Importantly, Pd-catalysts seem privileged to mediate the C-H activation event. The successful development of such couplings will inspire further developments. Accordingly, diastereoselective transformations, implying use of C-H activation substrates bearing a chiral directing group, and enantioselective couplings, based on a formation of metallacyclic intermediates bearing a stereogenic external ligand, will be explored.

The herein presented project foresees participation of one PhD student. This PhD student was hired in October 2016 and therefore he has been involved in the experimental work since only 8 months.
The work on the projected debuted by in-depth literature study in order to select both C-H activation reactions and photocatalytic transformations efficient under comparable reaction conditions. Accordingly, few C-H activation substrates (benzamides, hydrazines, sulfoxides) and aliphatic radical precursors (trifluoroborates, silicates, carboxylic acids) have been selected; also few reaction protocols potentially allowing activation of both substrates have been determined. The experimental work started by synthesis of required C-H activation substrates and aliphatic coupling partners as well as Ir- and Ru-based photocatalysts. Subsequently, the desired C-C bond formations via dual catalysis have been explored under an array of different reaction conditions (mainly Pd-catalyst has been explored to perform direct metallation). Unhopefully, no desired couplings could be achieved for the moment.
However, during this experimental work we have discovered that under dual-catalysis reaction conditions 8-amidoquinolines undergoes direct C-H functionalization at C5 position. Surprisingly, optimization of the reaction conditions clearly indicated that this direct coupling does not require neither C-H activation catalyst nor photosensitizer and only visible light irradiation is necessary. Accordingly, extremely mild and eco-compatible perfluoroalkylation of amidoquinolines could be achieved (transition metal and oxidant free, acetone as solvent, K2CO3 as sole additive, room temperature) affording often-unprecedented perfluoroalkylated heterocycles. Remarkably, this transformation is compatible with and array of quinoline derivatives and enables regiodivergent functionalization at both C5 and C8 positions.

The future work on this project will concern several different approaches:
1) We will continue our efforts on the initially proposed dual catalysis implying Pd-mediated C-H activation and photocatalysis. In this context mainly new substrates for the C-H activation event will be designed targeting very fast metallation step what should facilitate trapping of the aliphatic radicals by such species
2) Design of diastereoselectives transformations implying synergistic Ni-catalyzed couplings and photocatalysis. Indeed, since 2015 remarkable advances have been achieved in this field and an array of transformations occurring via Ni-catalyzed coupling and photocatalysis have been reported. However, stereoselective version of such bond forming reactions remains elusive. Accordingly, we envision using such an approach to access asymmetric molecules described in the project.
3) Design of other reactions allowing direct functionalization of quinolines by means of photoactivation. In particular, we would like to focus on photocatalytic transformations allowing introduction of a coordinating moieties on the quinoline scaffold. Subsequently, the newly installed motifs will be used as the directing groups to enhance metal-catalyzed direct C-H activation on several other positions.

«Regiodivergent Visible Light Induced C-H Functionalization of Quinolines at C-5 and C-8 under Metal-, Photosensitizer- and Oxidant-Free Conditions«, P. B. Arockiam, L. Guillemard, J. Wencel-Delord, Adv. Synth. Catal. 2017, doi.: 10.1002/adsc.201700471

Developing conceptually novel, more eco-reliable transformations, building up molecular scaffolds inaccessible via standard methodologies and designing unprecedented catalytic systems: these are urgent challenges of the fundamental research in organic chemistry. In particular, alkylation reactions involving sterically hindered coupling partners, with, ideally, concomitant formation of stereogenic centers, remain particularly demanding. The objective of the herein presented project is to respond to this important issue by devising an original dual catalysis benefiting from two expanding fields of organic chemistry: C-H activation and photoactivation. The direct functionalization establishes itself as sustainable strategy to convert latent C-H bonds into desired C-C and C-X bonds. However, such transition metal-catalysis is less suited for the activation of aliphatic substrates, in particular if hindered C(sp3)-H bonds are considered. In contrast, visible light photoredox activation has recently emerged as an appealing strategy to access sterically congested, highly active aliphatic species. The ambition of 2al-VisPhot-CH project is to merge such two complementary activation modes in a synergistic catalysis to reach challenging sp2-sp3 and sp3-sp3 couplings. In such transformations, one aromatic or aliphatic non-prefunctionalized substrate will be activated via direct insertion of the metal into a C-H bond, whereas a sterically congested aliphatic active moiety will be generated via single electron transfer (SET). Subsequently, the action of such two distinct catalytic cycles will converge by intercepting the aliphatic radical (resulting from photoredox catalysis) by a metallacyclic intermediate generated in the C-H activation process.

Our initial efforts will concern the couplings between aromatic C-H activation substrates, bearing a modular coordinating group, with alkyl radical precursors. Subsequently, sp3-sp3 couplings will be targeted by merging more challenging C(sp3)-H activation and photocatalysis. These preliminary studies should unlock the door towards appealing asymmetric transformations. Indeed, the synergistic catalysis gives the promise of transformations compatible with extremely mild reaction conditions hence creating an opportunity to impart stereocontrol during the bond-forming step. In this context, both diastereo- and enantioselective reactions will be studied. Our supreme goal is to apply such unique dual catalysis to build-up difficult to access all-carbon quaternary stereogenic centers. Importantly, if such challenging target can be reasonably envisaged, it is because the single electron transfer approach will be employed to access tertiary aliphatic species, extremely difficult to generate via classical transition-metal catalysis.

An important part of this project will also be dedicated to the design, synthesis, characterization and evaluation of original photosensitizers. Inspired by the potential of the Cu-based complexes to advantageously replace Ru and Ir photosensitizers, the preparation of innovative chromophores based on this inexpensive metal will be undertaken. Synthesis of Cu(I) complexes bearing 4,5-diazafluoren-9-one derivative ligands and copper salts coordinated by carbazole-type bicoordinating N,N ligands seems particularly appealing. Importantly, the successful development of this part of the project might have a major impact on the general development of the visible-light induced photocatalysis with possible implementation in a variety of transformations.

Project coordinator

Madame Joanna Wencel-Delord (Laboratoire de Chimie Moléculaire)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


UMR 7509 Laboratoire de Chimie Moléculaire

Help of the ANR 174,000 euros
Beginning and duration of the scientific project: October 2015 - 48 Months

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