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Catalytic Methods for Sustainable Synthesis. A Merged Experimental and Computational Approach

Periodic Reporting for period 2 - CATMEC (Catalytic Methods for Sustainable Synthesis. A Merged Experimental and Computational Approach)

Reporting period: 2019-01-01 to 2021-02-28

CATMEC addresses smart synthetic route design, development of new catalytic reactions and computer modelling of chemical processes which have all been highlighted in developing and growing the knowledge base in the Fine chemicals sector and Reaction and Process Design while contributing to the goals of sustainability of Europe 2020.

The overall objectives are to:
1. Develop a doctoral programme that addresses interdisciplinary and intersectoral experiential development contributing to EU policy objectives in scientific training and degree assessment.
2. To deliver 6 research graduates who will become highly skilled professional researchers in state-of-the-art approaches in catalysis with a platform to advance contemporary chemical science.
3. Apply and develop novel and robust synthetic methods that will contribute powerful new strategies for the discovery of bioactive small molecules.
4. Transfer between the Host and Secondment-Host in both the academic and non-academic sectors, ensuring lasting collaboration beyond the lifetime of the action.
• ESR1 - This project will investigate the formation and benzannulation of aza-metallocycles that are formed from isatoic anhydrides and phthalimides to allow access to heterocyclic boronates that have not yet been prepared by transition metal catalysis.

An aza Diels-Alder cycloaddition leads to a difluoroboron intermediate. The substituents on the aryl groups provide atropisomerism, and at this stage it is possible to resolve the atropisomers by reacting this intermediate with a chiral ligand. The photocatalytic oxidative coupling of two different amines catalyzed by the MOF PCN-222(M) [M = Co, Ni, Cu, Zn, Pd] to identify which metal (M) on the PCN-222 give the best performance, with a view to developing a protocol that gives high selectivity (cross-condensation vs self-condensation). thereby increasing the scope and advantages of the reaction.

• ESR2 - This project will involve a detailed computational study focused on the M-X triple bond insertion step to help guide the design of more effective and selective catalysts for some transformations in the mechanism of many organometallic catalytic processes.

Computational methods to study insertion reactions of oxygen and nitrogen based nucleophiles into triple bonds, catalyzed by different transition metals have been applied. The gold catalyzed formation of N-heterocycles and other fused derivatives by the addition of amines to alkynes have been experimentally and computationally studied. The use of a bifunctional Brønsted base/H-bond donor ensures the formation of the product with high enantioselectivity. The computational analysis provides insights on the interactions between the catalyst and the substrates, as well as on the reactivity of the substrates.

•ESR3 - In this project, the potential of multifunctionalised metal-organic frameworks (MOFs), as catalytic reactors in organic synthesis was investigated.

Scanning Electron Microscopy and Powder X-ray Diffraction has been used to analyse different MOFs such as UiO-67, MIL-88B and MIL-101 for the application of the new MOF in the base-cataysed isomerization of allylic alcohols. DFT calculations revealed that the reaction followed a [1,3]-proton shift or a direct [1,n]-proton shift. The activation energies involve in the reaction are very similar which suggest that all the possible adducts formed in the reaction are under thermodynamic equilibrium. A kinetic simulation showed that the reaction goes until the formation of the most thermodynamically stable product and a theoretical study of the Kinetic Isotope Effect (KIE) confirmed that the rate-determining step (RDS) is the deprotonation step.

• ESR4 - This project will introduce a new Pd-catalysed annulation strategy for the synthesis of polycyclic piperidines that generates low molecular weight functionalised compounds with the potential to generate sp3-rich products in a stereocontrolled manner.

A palladium-catalysed allylation-condensation sequence allows the synthesis of a library of novel sp3-rich N heterocycles containing orthogonal functionality. The use of a readily available cyclic carbamate in the presence of a palladium catalyst generates a palladium-stabilised zwitterion, which reacts with a wide range of carbonyl substrates to provide the corresponding α-allylated compounds. These products can be further converted into six-membered N heterocycles through a TFA mediated deprotection-condensation step. The scope of this methodology to 1-aryl-2-indanones, 1-aryl-2-tetralones, α-fluoro-β-ketoesters and α- trifluoromethylthio-ketones and the potential of the final heterocyclic compounds to undergo further derivatisation has been demonstrated.

• ESR5 - This project will continue investigations on selective transition metal-catalysed halogenation reactions by applying this methodology to the synthesis of highly substituted α-haloketones and the development of an enantioselective version by using chiral halogenating reagents, chiral ion pairs or using transition-metal complexes bearing chiral ligands.

The base-catalyzed isomerization of allylic alcohols and ethers have been shown under metal-free conditions and the simple guanidine type base TBD (triazabicyclodecene) showed high levels of chirality transfer. Using this methodology, synthesis of g-trifluoromethylated ketones and ethers with excellent enantiomeric excesses has been demonstrated. This methodology has been applied to other allylic systems and when the optimized conditions were applied to enantiomerically enriched allylic chlorides, the formation of chiral ion pairs resulted in outstanding levels of chirality transfer.

• ESR6 - This project applies existing, or new, chiral thioureas, squaramides, and related H-bond donors in combination with achiral, simple Brønsted acids for the asymmetric protonation of enol derivatives in different ways, constituting a powerful strategy that can help make reaction development (discovery) more efficient.

The formation of esters in a three-component reaction, namely terminal alkynes with CO2 and organochlorides has been investigated by DFT and the limitations of the reaction have been explained thanks to the comparison of the different transition state energies. An understanding of an umpolung a-functionalization of allylic alcohols in a domino reaction and of the selectivity of the reaction was obtained using DFT studies.

Project dissemination can be viewed at:
CATMEC offered an excellent and innovative doctoral training programme with complementary, synergistic and multi-disciplinary skills in the scientific fields of synthesis, catalysis and computational studies, within a framework of sustainable chemistry. All ESRs have been jointly enrolled in their home and seconded institutions PhD programme and will follow the standard course of doctoral development with further opportunity to grow their skills and knowledge in non-academic environments offering an aspirational illustration of the opportunities available for young scientists,

The new technologies arising from this EJD have the potential to make a significant impact on the fine chemicals sector by delivering efficient and sustainable methods for the generation of novel small molecules. CATMEC also makes a contribution to the skills shortage in Europe of highly trained chemists.