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Convergent and Efficient Synthesis of Novel Heteroaromatics

Final Report Summary - SYNHET (Convergent and Efficient Synthesis of Novel Heteroaromatics)

Project Number: 301008
Project Acronyms: SynHet
Project Title: Convergent and Efficient Synthesis of Novel Heteroaromatics
Project Fellow: Dr Raju Jannapureddy
Project Coordinator: Dr Paul W Davies, School of Chemistry, University of Birmingham, UK. Email: p.w.davies@bham.ac.uk; Tel: +44(0)121 4144408

This project was intended to explore the wider viability of a new strategy that allowed rapid access into an important class of molecules called azoles. These are important molecule types as they are widely encountered within pharmaceuticals, agrochemicals and naturally occurring bioactive materials and are useful precursors to other important compounds. Generally, a process called a [3+2]–dipolar cycloaddition would be an attractive way to construct these 5-membered rings as two components of similar complexity (the alkyne and the dipole) are bought together to form a much more complex product in an efficient manner. This approach has been hugely successful as a method to generate 1,2,3-triazoles – a so-called ‘Click’ reaction - which has revolutionised diverse fields of research including materials, bio conjugates and sensing due to its ability to be applied widely and make complex species in a simply applied fashion.
One of the required components, the dipole, is highly reactive. For triazoles, the dipole is relativity stable so that it can be handled and widely use. This is not the general case, as the required dipoles are unstable, can only be formed transiently in a reaction mixture and have a tendency to react through competing undesirable pathways. As such the same type of [3+2]–dipolar cycloaddition cannot be applied as widely for other types of, potentially more important, azoles. The Host group (Davies) had discovered that the [3+2]-cycloaddition reaction could be accessed to form oxazoles by using a new activation type that uncovered the dipole during the reaction mixture. This used gold catalysis alongside specific type of alkynes, called ynamides, to provide a potentially powerful way to overcome inherent limitations of [3+2]-cycloaddition. In this project, the goal was to explore whether the observed reactivity could be accessed more generally, using different alkyne types and different ylide types, and to show how this approach can be used to rapidly assemble functional molecules useful across different research areas.
Over the course of the project, the original protocol for the novel [3+2]-cycloaddition approach has been refined, the amount of reagent and catalyst required to achieve the desired products has been decreased leading to overall cleaner, more efficient, less wasteful synthesis. Several new alkyne-ynamide types have been identified as being reactive. A detailed study was undertaken to enhance reactivity to achieve efficient outcomes and as a result significantly more diverse variation on the important azole product can now be achieved, incorporating functionality that will be useful in applications.
A significant break-through has been achieved following a detailed optimisation of reaction conditions and structural impact so that a new type of alkyne could be used. A challenge in these [3+2] processes is that there are two possible outcomes as a result of the dipole and ylide coming tougher in a head-to-tail or head-to-head fashion. In comparison to the results achieved beforehand (cf head-to-head), this showed that a head-to-tail approach could also be achieved. This break-through completely changes the type of substitution patterns that can be made across the azole products in the novel [3+2] cycloaddition and hence its potential applicability. The generality of this process was investigated in terms of substrate scope alongside potential manipulation of the azole products.
In addition to studying the alkyne partner, the ylide partner has been explored. Firstly, it was shown that the substitution pattern around the reacting centres could be varied significantly allowing much more complex fragments to be bought together in this new manner to access highly functional species. This was then demonstrated by the design and preparation of amino acid derived systems which allowed the preparation of new organic catalysts, which have been shown to be competent themselves. Importantly, this was shown to be possible on gram scale which means this chemistry can be applied more widely. Through the combination of this approach and alkyne modifications a library of highly functional species have been prepared to demonstrate the applicability of this new strategy
Secondly, several new types of ylides have been prepared and shown to be competent reagents. Following a reaction optimisation, the application of this new reaction has been undertaken to show potential substrate scope in this reaction. This highlights that the new approach to [3+2]-cycloadditions can be applied to other types of azoles and provides rapid access into new substitution patterns around important heterocyclic motifs.
The reactivity that has been uncovered can have important impacts on synthesis of functional molecules as well as the field of gold catalysis. The issue of regiochemistry (Head-to-tail or head-to-head) is crucial in intermolecular reactions and new profile has been discovered for gold catalysis. The resulting product types have potential use, as functional molecules such as organocatalyst, but also as fragments for pharmaceutical and agrochemical discovery programmes and have been submitted for assessment as such with partner organisations. The work from this project is being prepared for publication in several journals and will be advertised on the group website post publication.
As a conclusion, from this project we have been able to achieve the proposed objectives. The initial hypothesis that his [3+2] approach can be more widely applied has been confirmed and been applied successfully to access four different types of heteroaromatic compounds with very diverse substitution patterns including those needed to function as organocatalysts. As a result of this work the Research Fellow has acquired a strong intellectual knowledge and practical skills which have allowed him to consolidate his future career.