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Reactivity of allylic fluorides in the presence of palladium catalysts: synthesis and applications of fluorinated heterocycles

Final Activity Report Summary - MCPF-HETEROCYCLES (Reactivity of allylic fluorides in the presence of palladium catalysts: synthesis and applications of fluorinated heterocycles)

The main aim of the original project was the synthesis of fluorinated heterocycles via palladium-catalysed cyclisation of allylic fluorides featuring a nucleophilic group (OH, NHP; being P: protective group). These fluorinated heterocycles, despite their importance by their own in agrochemical and pharmaceutical industries, could undergo further manipulation to give fluorinated carbohydrates. So, the first step in our synthetic programme was the selection of an appropriate methodology for the preparation of nitrogen- and oxygen-containing allyl fluorides. Probably, the most used methodology for the preparation of allylic fluorides is the dehydroxyfluorination of the corresponding alcohols using diethylaminosulfur trifluoride (DAST). However, this nucleophilic fluorinating reagent could react with other functional groups present in the molecule, so it was necessary to search for another methodology. Finally, we decided to use the electrophilic fluorodesilylation of allylsilanes because of its high tolerance to different functional groups.

Thus, the following step was the synthesis of allylsilanes bearing a nucleophilic group. This kind of substrates could be obtained through cross-metathesis of allylsilane and the corresponding alcohols or N-protected amines. However, this synthetic route gave more problems than expected due to several side-reactions, such as isomerisation of the starting materials and reaction of the isomerised products, took place. These side-products complicated the purification step, and the development of a new methodology was in demand.

We postulated that the electrophilic fluorodesilylation of cyclic allylsiloxanes could also lead to desired allylic fluorides. This new method was based on the idea that after 'usual' fluorodesilylation, the ring would open giving a silyl-protected alcohol. So, finding the conditions where electrophilic fluorodesilylation and alcohol deprotection could be carried out one-pot was our aim. We were very pleased when cyclic allylsiloxanes led to the corresponding allylic fluorides after treatment with selectfluor in DMF. To the best of our knowledge, this was the first time that this transformation was carried out.

To finish with the objectives proposed for the first year of the project, the study of the reactivity of nitrogen- and oxygen-containing allylic fluorides was initiated. Some preliminary studies furnished products resulting of the formation of p-allylpalladium complexes. At the moment, experiments to favour the palladium-cyclisation over the p-allylpalladium complex formation are being conducted in our laboratory.