Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - BiMetArylation (Bimetallic catalytic arylation of simple arenes)

Teaser

The development of new methodologies for the preparation of biologically and industrially interesting compounds remains one of the fundamental challenges in chemistry. Aryl-aryl bond formation is one of the most important tools in modern organic synthesis. These biaryl motifs...

Summary

The development of new methodologies for the preparation of biologically and industrially interesting compounds remains one of the fundamental challenges in chemistry. Aryl-aryl bond formation is one of the most important tools in modern organic synthesis. These biaryl motifs are very often found in pharmaceutical, agrochemicals, organic materials and natural products. Given the abundance of C–H bonds in organic molecules, the selective activation and use of these bonds in controlled synthetically useful transformations is an immensely important topic. In this context, direct C–H arylation has emerged as a powerful methodology for the synthesis of biaryls. However, in most methodologies described so far, the arene substrate must fulfil certain requirements such as containing strong electron-withdrawing or electron-donating groups, or bearing special directing groups. Substrates lacking this feature either are unreactive or must be used in large excess. The coupling of ‘simple arenes’, which are not considered as π-electron-deficient or -rich remains challenging.
On this basis we envisioned a methodology in which the π-coordination of non-activated arenes to a metal fragment promotes the C-H arylation reaction catalysed by palladium. We designed a new approach based on a system fully catalytic in both transition metals, Pd used for mediating the cross-coupling and Ru used for enhancing the reactivity of the arene via π-complexation.
To develop this new catalytic methodology three milestones have to be met. First, a suitable method for stoichiometric C-H arylation of π-coordinated arenes has to be found. Then, conditions for effective arene exchange between the bisarylated complex and simple arenes have to be developed. Finally, these two steps have to be merged together to develop a methodology that is catalytic in both Pd and the π-arene metal complex.
Unfortunately, it was impossible to achieve enough catalytic activity for this process. Nevertheless, we applied the knowledge acquired during the process along with the group experience to develop a direct arylation‐cyclisation reaction for the construction of medium‐sized rings promoted by π-complexation of fluoroarenes to chromium tricarbonyl fragment and a catalytic asymmetric C-H arylation of (π-arene)-chromium complexes which allows facile access to planar-chiral phosphines.

Work performed

With the aim of finding suitable co-catalyst able to enhance reactivity of non-activated arenes towards the arylation reaction we synthesised a range of published and unpublished (π-benzene)-metal complexes of several transition metals and tested them towards stoichiometric C-H arylation conditions. Then we tried stoichiometric arylation of these compounds under the Pd-catalysed arylation conditions. We also did an exhaustive screening of catalytic conditions. Best results were found with [Ru(η5-C5Me5)(η6-C6H6)]PF6 giving 45% of monoarylated product.
Then we investigated the stoichiometric arene exchange between metallated-biaryl complexes and other arenes. After evaluating different parameters such as temperature influence, the use of polar solvents and additives, and the use of UV irradiation, we found suitable conditions in which product of arene exchange was obtained in 96% yield.
Finally we tried to develop a system fully catalytic in both transition metals, Pd used for mediating the cross-coupling and Ru (or other Transition Metal) used for enhancing the reactivity of the arene via π-complexation. We explored several approaches including solvent, temperature, additives, nature and amount of catalysts, as well as the influence of the UV radiation. The best of these combinations gave 5 turnover of the catalytic cycle meaning that catalysis is operating but product was obtained only in 5% yield. When the ruthenium catalyst is added in 30% mol the yield of the product increased up to 15%. Among all the π-arene complexes tested best results were obtained with [Ru(η5-C5Me5)(η6-C6H6)]PF6 and similar results observed with other two similar cyclopentadienyl-derivative ruthenium complexes.
With these results we demonstrated that the bimetallic catalytic process is possible, but unfortunately it was not possible to achieve good yields of the products. However, the knowledge and experience acquired during the development of this project allowed us to discover a new approach for the construction of medium‐sized rings promoted by π-complexation of fluoroarenes to chromium tricarbonyl fragment by direct arylation/cyclisation reactions and the first catalytic asymmetric C-H arylation of (π-arene)-chromium complexes which provides facile access to planar-chiral phosphines.

Final results

Medium-ring structures are abundant in natural products; however their presence in drugs molecules remains rare, potentially due to the limited availability of methods for their synthesis. Research carried out during the reporting period has provided a new strategy for the one-pot construction of bridged biaryl molecules based on the dual increased reactivity of fluoroarenes towards both C–H activation and SNAr on coordination to chromium tricarbonyl. This method will contribute to create accelerated synthetic routes towards target compounds.
On the other hand, planar-chiral transition-metal species have extensively been applied as stoichiometric auxiliaries and/or suitable starting materials for asymmetric synthesis of biologically interesting substances. Sandwich type compounds like ferrocene have been extensively investigated as optically active ligands in catalysis; by contrast, the application of (Ï€-arene)-chromium complexes as chiral ligands have drawn less attention and there are only few examples where (Ï€-arene)-Cr(CO)3 derivatives have been successfully used in asymmetric catalysis, possibly because the reported methods to synthesise enantioenriched (Ï€-arene)-chromium complexes involve either the use of stoichiometric amount of chiral reagent or prefunctionalization of the (Ï€-arene)-chromium complex. With the aim of enhancing the usefulness of planar-chiral chromium complexes we have developed the first catalytic asymmetric C-H arylation of (Ï€-arene) chromium tricarbonyl complexes to generate planar-chirality providing facile access to new planar-chiral mono- and diphosphine ligands by derivatisation of the catalysis products. This new synthetic approach opens the door to an array of new chiral-planar phosphines which can be used as ligands in a variety of asymmetric catalysis.
The work carried out during this project is a small step towards one of the most ambitious goals that organic chemistry is facing today; developing more sustainable synthetic routes for the synthesis of molecules of interest, from plastics and materials to pharmaceuticals, preservatives or agrochemicals. In line with this, organic chemistry has long moved towards catalysis. Nonetheless, most synthetic routes currently at work in industry are long and generate a large amount of waste. In this scenario C–H bond functionalization, a concept that we applied in all the projects carried out during the reporting period, constitute an alternative to traditional synthetic organic chemistry aimed at accelerating synthetic routes and lowering the amount of waste generation. The results contained in this report contribute to lower the impact that the agrochemical and pharmaceutical industries have in the environment in accordance to the EU policy objectives.

Website & more info

More info: https://personalpages.manchester.ac.uk/staff/igor.larrosa/index.html.