C-F Borylation of Unsaturated Fluorocarbons

Lead Research Organisation: Imperial College London
Department Name: Dept of Chemistry

Abstract

The overall goal of the project is to develop methods to convert environmentally persistent fluorocarbons into reactive chemical building blocks that can be used in synthesis.

Objective 1 (Months 1-12). Catalytic Generation of Boron Dihydrides
Despite the extensive application of pinacolborane, bis(pinacol)diborane, catecholborane and bis(catechol)diborane in synthesis related boron reagents containing two hydrides are understudied. We proposed to develop a series of amine stabilised boron dihydrides by catalytic dehydrogenation of amine-borane precursors. The ligand precursors will be synthesized by Buchwald-Hartwig coupling of commercial starting materials.[1] Following coordination to BH3, we will investigate group 2 and 3 pre-catalysts to effect the dehydrogenative cyclisation of these substrates to provide a new route to hitherto inaccessible boron dihydrides.[2-5]

Objective 2 (Months 13-24). Catalytic C-F Borylation of Fluoroalkenes
The new reagents described above will be applied in the C-F borlyation of hydrofluoroolefins. We will hunt for catalysts capable of operating by a selective addition elimination reaction. Based on current unpublished mechanistic analysis from the group, three early transition metal catalysts are proposed as a starting points. All contain the following design features (i) solubilising and kinetically stabilising Cp ligands, (ii) electrophilic early TM to promote beta-fluoride elimination, (iii) a single reactive hydride site capable of hydrometallation of unsaturated systems.[6-8]

Objective 3 (Months 25-36). Mechanistic Studies
Understanding factors that control Regioselectivity and Chemoselectivity Following the development of the new catalytic reaction we will study the mechanism. This will be achieved by (i) isolating reactive intermediates and catalyst resting states and testing their reactivity, (ii) competition and mechanistic probe experiments including where applicable D-labelling experiments, (iii) kinetic analysis and (iv) DFT studies (in collaboration with a computational group). We will question our hypothesis of an addition-elimination process and whether or not this is truly operating under the conditions that we develop. We will seek to understand the steps that control the regio- and chemoselectivity of catalysis. If these steps are under catalyst or substrate control, we will aim to design additional experiments to see if we can switch the regiochemistry of the reaction.

Backup Plans: Should we not be able to access the boron dihydride reagents we will investigate the established aluminium dihydride complexes BDIAlH2 to the same end. We can also investigate the application of the new fluorine containing building blocks in synthesis and specifically in cross-coupling.. Depending on the chemo- and regioselectivity of the proposed reaction we can also think about developing chiral catalysts such as ansa-metallocences to try and generate enantiomerically pure products.[9]

References: [1] Feng and coworkers, J. Med. Chem. 2015, 1846. [2] (a) Hill and coworkers, Chem. Commun. 2010, 46, 7587; (b) Hill and coworkers, Chem. Eur. J. 2010, 16, 8505; (c) Hill and coworkers, Chem. Commun. 2013, 49, 1960. [3] (a) Crimmin and coworkers, Chem. Commun. 2014, 50, 9536; (b) Crimmin and coworkers, Organometallics, 2015, DOI: 10.1021/acs.organomet.5b00607. [4] Chen and coworkers, ACS Catalysis, 2013, 3, 521. [5] (a) Sabo-Etienne and coworkers, Angew. Chem., Int. Ed. 2012, 51, 3646; (b) Sabo-Etienne and coworkers, Chem. Eur. J. 2015, 21, 13080. [6] (a) Lentz and coworkers, Angew. Chem., Int. Ed. 2010, 49, 2933; (b) Lentz and coworkers, Chem. Eur. J. 2012, 18, 10701. [7] Jones and coworkers, J. Am. Chem. Soc. 2002, 124, 8681. [8] Andersen and coworkers, J. Am. Chem. Soc. 2005, 127, 7781. [9] Buchwald and coworkers, J. Am. Chem. Soc. 1992, 114, 7562.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509486/1 01/10/2016 31/03/2022
1805058 Studentship EP/N509486/1 01/10/2016 30/09/2019 Gregory Coates