Ynamides and enamides: Enabling dienophiles for sydnone cycloadditions

Lead Research Organisation: University of Sheffield
Department Name: Chemistry


Pyrazoles are an important sub-class of organic molecules that are ubiquitous in bioactive and medicinally relevant compounds. Recent studies in our labs have highlighted sydnones as valuable precursors to a wide range of pyrazole products. Sydnones are easily prepared and stable molecules and we have a number of years' experience of studying these compounds. A limitation in this work currently is that it has largely been exploited to prepare relatively lipophilic compounds (pyrazoles bearing alkyl/aryl substituents). The potential of this chemistry to assemble heteroatom appended products is less clear at present.

One aspect of this project will aim to establish ynamides as effective substrates for sydnone cycloaddition reactions. Ynamides are easily prepared in a single step and are stable, and easy to use. To-date however, ynamides have not been employed in sydnone cycloaddition reactions, most likely because general routes to these substrates have only become available quite recently. We will investigate the sydnone cycloaddition chemistry of ynamides; i) to establish their relative reactivity; ii) to explore their reaction regioselectivity; iii) to explore their synthetic utility, in particular with respect to generating the free amine for further chemistry.

A second aspect of this work will study the scope of alkene cycloadditions with sydnones, as this process has been significantly less developed by comparison to alkynes. One of the reasons for the slower development of alkene cycloadditions is that the primary products are themselves unstable dipolar intermediates. These require further chemistries to generate stable pyrazolines (after proton transfer) or pyrazoles (after oxidation). Notably however, the alkene cycloaddition process appears to offer a rich opportunity to further extend the synthetic potential of sydnones for the generation of functionalised pyrazole intermediates. Specifically, a heteroatom bearing alkene should undergo elimination at the primary cycloadduct stage, thereby offering pyrazoles directly without the need for further oxidation steps. Having established heteroatom containing alkenes as viable substrates for pyrazole synthesis, we hope to further improve the scope of the method by introducing a new catalytic process that employs readily available carbonyl-containing substrates as dienophiles. For example, the successful employment of enamines provides the exciting prospect of devising an organocatalytic cycloaddition reaction of sydnones and ketones/aldehydes.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509735/1 01/10/2016 30/09/2021
1816703 Studentship EP/N509735/1 01/10/2016 31/03/2020 Christopher Paul Lakeland