Skip to main content

CO2 as a traceless directing group for catalytic meta C-H olefinations

Periodic Reporting for period 1 - metaC-Hfunct (CO2 as a traceless directing group for catalytic meta C-H olefinations)

Reporting period: 2015-04-01 to 2017-03-31

The objectives of this project are in line with the development of meta-functionalized fluoroarenes and other substituted arenes from their corresponding arene precursors via C–H bond functionalization.
Fluorinated biaryl motifs are a particularly important class within fluorinated compounds, with widespread presence in pharmaceuticals and agrochemicals. The methods currently utilized to access fluorinated arene motifs suffer from major drawbacks such as the need to use prefunctionalized molecules that either have elevated costs or require synthetic steps for their preparation and also lead to the generation of significant amounts of waste. The project we have developed allows for the use of inexpensive and readily available fluoroarenes as precursors for the synthesis of fluorinated biaryl motifs leading to greener and faster protocols towards such motifs. This project also contributes to create accelerated synthetic routes towards compounds with pharmaceutical and agrochemical interest.
From the beginning of the project we have been working towards the development of novel methods to provide access to meta-functionalized of fluoroarenes, aryl alkyl arenes and acetals in a more sustainable manner compared to the current methods. Our work is based on the introduction of carboxylic acids from CO2 to the substrates to direct the functionalization prior to the release of the carboxylic acid as CO2. Methods for the meta-arylation and meta-olefination of fluoroarenes and aryl alkyl ethers and acetals have been successfully developed. We have demonstrated that these methods tolerate many functional groups in most positions of the aromatic rings, being electron-donating and electron-withdrawing groups compatible with the methods. Also we have been able to develop a synthetic route towards a γ-secretase inhibitor, currently under testing for Alzheimer’s disease treatment by putting our method into use. This new synthetic route accelerates the previously patented route for the target compound.
We have started the dissemination of the results of this project, and we have recently published a review article in the chemistry journal Chemical Communications on the use of carboxylic acids as traceless directing groups that summarizes the background of the funded project. The results of this project will be submitted for publication in a leading scientific chemistry journal in the near future. The beneficiary has presented the results of the project at the Sheffield Hallam University where he was invited to deliver an oral communication. Prof. Igor Larrosa will present the results in conferences, talks in research and industry, as appropriate.
The direct ortho- and para-functionalization of fluoroarenes, following the inherent selectivity of such molecules had been previously achieved. However, non-inherent meta selectivity in the functionalization of fluoroarenes lacked precedent. Our method has been able to tackle the meta-arylation and alkenylation of fluoroarenes for the first time (see Scheme). This leads to more economically and environmentally sustainable methods for the production of chemicals that have minimal impact in the environment.
Summary of the chemical transformations carried out within the project