Small HeteroAromatic Ring Synthesis: A Unified Approach

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.

The first 2 months were dedicated to the synthesis of the starting alkynyl epoxides. Whilst seemingly simple, such compounds were found to be hard to synthesise. We thus developed a second organocatalytic approach that easily delivered the expected products in only 2 steps. Despite average overall yields (40-50%), this method allowed us to easily access several grams of alkynyl epoxides from cheap and commercially available starting materials in less than one day and with only one purification needed.

The next 9 months were dedicated to finding an appropriate catalytic system that will meet our requirements in terms of efficacy and cost. Whilst preliminary results from our group described Pd(PPh3)4 as a good catalyst, the need for elevated temperatures (100 °C) and high catalyst loadings (10 mol%) urged us to try to find milder conditions, and more reactive catalyst. This turned out to be extremely time-consuming, given the myriad parameters that could get tuned, but we managed to find out conditions that allowed us to synthesise the corresponding furan in almost quantitative yields, with low catalyst loadings (1.25 mol%), and at room temperature without the need of solvent. Key to these findings were three essential parameters: the presence of a benzoic acid additive, the use of a specific ligand, and the degree of oxidation of palladium. The reaction scope encompassed ~30 different substrates; this would be reported in a publication within the next few months, which will be the first dissemination of our work.

The last part of the project was focused on the development of another set of conditions because our previous method proved not to be tolerant to a lot of functionnalities. Whilst 1,2-disubstituted epoxides worked extremely well, changes in this substitution patterns resulted in a loss of reactivity. Moreover, our first set of conditions did not seem to work well with aziridines, even though small quantities of the corresponding pyrroles could be isolated. Once again, screening conditions proved to be tedious, but we discovered that replacing our benzoic acid additive with a copper source had a drastic influence on the epoxide reactivity, allowing us to obtain good yields of furans that were unaccessible previously. Those conditions are still not totally optimised, but seem to tolerate more substrates than before, albeit with inferior yields.

As a conclusion, this funding allowed us to develop two parallel approaches to furans from alkynyl epoxides. Both of those methods utilise cheap reagents and are complimentary to each other: the first one gives excellent yields under mild conditions, but proved to be limited in scope; the second one offers more functional group and substitution pattern tolerance, but is still to be optimised to access publishable, and thus useful, yields.

Both of our methods progress from the classical ways of making furans, in the sense that they do not necessitate elevated temperatures, harsh additives, complex catalytic systems or expensive chemicals. To the best of our knowledge, none of these strategies were previously reported, and should give new insights into the chemistry of palladium. More specifically, our first method triggered an extensive NMR study of the reaction that would potentially help rationalising our observations and allow us to better understand this chemistry. We believe that this will in turn benefit the scientific community, whether it is the academic or the industrial field.

Periodic Reporting for period 1 - SHARS (Small HeteroAromatic Ring Synthesis: A Unified Approach)

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