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Decarboxylative fluorination and trifluoromethylation of benzoic acids


Project Description

In 2018, >40% of FDA approved small molecule drugs contained fluorinated aromatics. This is explained through a wide range of effects that fluorine can impart on drug molecules, such as modulating lipophilicity, basicity and bioavailability, among others. However, fluorinated compounds are generally much costlier to produce due to the requirement for expensive or toxic reagents. Over the last decade, benzoic acids have emerged as an attractive feedstock for synthesis, due to their wide availability at relatively low cost, their chemical stability and the easiness for preparing derivatives. Thus methodologies for the preparation of fluorinated compounds via decarboxylative processes are highly sought after. Our group has pioneered Ag-catalyzed decarboxylative transformations of benzoic acids (for a review, see: Synthesis 2012, 653; citations: 245). More recently we have developed transition-metal free methods for decarboxylative iodination (JACS 2017) and bromination (Chem Sci 2018) of benzoic acids. However, decarboxylative fluorinations of benzoic acids are largely unknown.

In this collaborative project with Vertex Pharmaceuticals, we will develop a catalytic process capable of carrying out decarboxylative fluorinations and trifluoromethylations on benzoic acids, under mild-conditions, capable of operating on already functionalized ‘real-world’ molecules. Such methods will allow the easy introduction of fluorine atoms at specific positions in aromatic rings at the end of a synthesis, affording compounds with potentially enhanced biological properties and allowing the late stage installation of 18F for PET imaging.
The student will become proficient in organic synthesis, organometallic chemistry and in their application to pharmaceutically relevant challenges. Transferable and leadership skills such as reporting of results orally and in writing, time management, project planning and management will be developed.

Academic background of candidates:
Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in Chemistry. A Masters degree in organic or organometallic chemistry and/or equivalent experience is desirable.

Contact for further Information:
Prof. Igor Larrosa

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

Funding Notes

This is a 3.5 year EPSRC CASE studentship with Vertex Pharmaceuticals. Funding will cover fees and stipend (£15,009 in 2019-20).

Restricted to UK/EU applicants with 3 years residency in the UK

We expect the programme to commence in September 2020.

References

“Decarboxylative Suzuki–Miyaura coupling of (hetero)aromatic carboxylic acids using iodine as the terminal oxidant”, Jacob M. Quibell, Guojian Duan, Gregory J. P. Perry and Igor Larrosa Chem. Commun. 2019, 55, 6445-6448. (Highlighted in Synfacts 2019,6445.)
“meta-C–H Arylation of fluoroarenes via traceless directing group relay strategy”, Marc Font, Andrew R. A. Spencer and Igor Larrosa Chem. Sci. 2018, 9, 7133-7137. (Highlighted in Synfacts 2018, 7133.)
“Transition Metal-Free Decarboxylative Bromination of Aromatic Carboxylic Acids”, Jacob M. Quibell, Greg J. P. Perry, Diego M. Cannas and Igor Larrosa Chem. Sci. 2018, 9, 3860-3865.
“Transition Metal-Free Decarboxylative Iodination: New Routes for Decarboxylative Oxidative Cross-Couplings”, Greg J. P. Perry, Jacob M. Quibell, Adyasha Panigrahi and Igor Larrosa J. Am. Chem. Soc. 2017, 139, 11527-11536. (Most downloaded article in August and September 2017).

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