This project was originally intended to develop a new route to five-membered ring heteroaromatics, a class of chemicals that includes molecules such as pyrroles, furans, and thiophenes. Those structures form a cornerstone of medicinal research, exemplified by blockbuster drugs such as atorvastatin, a cholesterol lowering pyrrole with ~$125 billion sales; ranitidine, a histamine H2-receptor antagonist used to treat stomach ulcers which features on the World Health Organization's List of Essential Medicines, and clopidogrel, a platelet aggregation inhibitor used against coronary heart disease. These heterocycles also have a rich agrochemical history: the pyrethroid insecticide resmethrin and related furans (new variants of which are still coming to market) show for example that research into the furan scaffold remains an important activity; similarly, the pentasubstituted pyrrole pesticide chlorfenapyr is an example that illustrates the value of this core.
Despite this importance, the predominant methods used by both academic and industrial researchers to access these frameworks still rely on chemistry developed up to a century ago, which suffers from several drawbacks. Chief amongst these are restrictions on substituent patterns that are intrinsic to these classical routes, which prevents decoration of the ring with a full range of contemporary functionality. Whilst new methods to access such scaffolds are still published, they often use expensive catalysts, or harsh conditions.
The idea at the origin of this proposal was to address these shortcomings by developing a unified catalytic approach to these heterocycles through a fundamentally new ring synthesis mechanism. This chemistry would employ analogous reactions substrates, only differing by one heteroatom (either an oxygen, a nitrogen, or a sulfur), that could be easily access from cheap commercially-available materials. Moreover, it would offer an access to previously unattained substitution patterns, and permit the positioning of substituents at any or all of the 2-, 3- and 5-positions around the heteroaromatic ring. The conversion of the substrates to their corresponding five-membered rings would utilise a cheap source of palladium(0) with the idea of developing an inexpensive and robust method for heteroaromatic rings synthesis, such that this chemistry could be easily deployed by others. As mentioned earlier, the high pharmaceutical and agrochemical value of those structures led us to engage with industrial partners within Europe to initiate a knowledge transfer programme.
We dedicated most of our efforts to the synthesis of furans. Two sets of conditions were developed in parallel: one giving high yields (>90%) but displaying functional group tolerance issues, and another one with a broader scope, but inferior yields (40%-70%). The first method proved to be robust with a certain class of compounds (>20 examples), giving excellent yields at room temperature and in the absence of solvent which is exceptional for such a reaction, and interesting from an industrial point of view. However, varying the substitution pattern of the starting material caused a considerable drop in yield, a behaviour that we cannot yet explain. This urged us to develop a second route to more diverse furans that would come in complement of our first strategy. Preliminary results are encouraging, with a reaction now being more tolerant of diverse reactive groups, and allowing us to access furans that were previously unattainable in good yields (up to 73%). Whilst encouraging, this method still needs some optimisation to increase the yields in order to be industrially applicable. Whilst attempts at pyrrole formation proved unpractical when using either of those two methods, small amounts could still be isolated (<20%). Moreover, pyridine rings, another class of heteroaromatics, were also isolated, which could open up new horizons for the synthesis of such compounds.
