New catalysis methods for pyridine synthesis

Background: Direct C-H functionalisation of pyridines is a challenging transformation, with few general, selective methods available. Despite significant advances in azine C-H activation chemistry over the past two decades, the pyridine C-H position remains difficult to manipulate under conditions that enable selective C-C bond formation. Given the exceptional prevalence of pyridines and related heteroarenes in pharmaceuticals (25 of the 200 top-selling small molecule drugs in 2022 incorporate at least one pyridine ring within their structure), new methods for pyridine functionalisation are central for the advance of drug discovery and chemical synthesis.
The ring-opening and closing of pyridiniums via Zincke imine ANRORC chemistry has been known for 100 years, but has seldom been used as a method for pyridine functionalization due to harsh reaction conditions. Inspired by recent developments in this area from McNally, we have found that triflic anhydride is very effective at generating Zincke imines 2 under mild conditions, and have demonstrated novel reactivity of the Zincke imine for Pd-catalysed arylation. For the first time, we have demonstrated selective, catalytic pyridine direct arylation is possible in one operation. Building on these results, our objective of this iCAT studentship is to explore Zincke imines as a general method for unprecedented pyridine functionalization.
Aims and programme of work: We will build our preliminary system into a general pyridine arylation method by optimising each step of the process guided by computational modelling of Zincke imine reactivity. Total yields from pyridine starting materials with simple aryl iodides are in the 40-60% range (1 mmol scale), which is encouraging for an unoptimized reaction, but we must understand the inefficiencies in the process if we are to build a robust method and extend the arylation to complex pyridine substrates. Our preliminary results point to a Heck-like mechanism of arylation, with selectivity for the C4 position in analogy to a classical Heck coupling on an enone. We will scrutinise this step with the aim of improving yields and reducing reaction temperature for better chemoselectivity on complex substrates. The process is currently three steps in one pot with a solvent change, removing the EtOAc from triflation step one for THF in step two (EtOH in the third step is simply added). We will study these solvent dependencies with the aim of achieving better integration to achieve a robust, general cross-coupling method for pyridine arylation.
The optimised system will then be applied to late-stage functionalisation problems (e.g. Vismodegib and chlorphenamine as examples in Scheme 2A). We believe that the introduction of computational methods to explore the reaction space around the Zincke imine structure will be transformative for pyridine syntheses, with the exciting prospect of uncovering new reactivity - existing applications of Zincke imines have concentrated on their use as dienophiles in Diels-Alder chemistry.
We have preliminary results for a regio-divergent 3-arylation, where a metal-free arylation with an electrophilic iodonium salt has captured enamine reactivity and created meta-product 10 in reasonable yield (Scheme 2B). We will extend this enamine chemistry to other reaction manifolds such as photoredox alkylation (e.g. synthesis of 11, proposed), with the aim of growing new pathways for Zincke chemistry beyond arylation. The PhD project will provide full training in catalysis methods that currently shape thinking in medicinal and process chemical industries, e.g. Pd-catalysed C-C and C-N bond formation and C-H activation, photoredox catalysed methods for C-C bond formation, along with DFT computational methods that are highly influential in the design of new methods for chemical synthesis.