Developments in Phosphiranium Ions Chemistry – DePhI

Our method to carry out this exploratory study is to interface in-depth investigations of organic physical chemistry with the development of a variety of novel synthetic transformations, begining with the implementation of reliable access methods to phosphiranes and phosphiraniums, followed by the development of ambitious C-centered ring opening reactions of phosphiraniums, in polar or photoredox catalytic situations. The primary objectives of the physicochemical studies are to determine the nuclephilicity parameters of phosphiranes, the P- and C-electrophilicity parameters of phosphiraniums, as well as to study the redox behaviour under photocatalytic conditions of phosphiranes and phosphiraniums. The study of opening reactions shall be based, in accordance with data from physico-chemical studies, on the comprehensive preparation of a variety of phosphiranium ions, and on methodical screening of different sets of nucleophiles meeting predefined criteria. The ring opening experiments should be carry out through the evaluation of various parameters and conditions rationally designed to facilitate the site-selective, C-centered opening process.

1-Central to the DephI project is the identification of new reaction partners capable of opening phosphiranium salts with high site-selectivity (C-centered). With this in mind, we were able to demonstrate from a few model phosphiraniums that highly C-selective ring-opening processes were possible by other nitrogenous nucleophiles than aniline derivatives, in particular O-protected hydroxylamine derivatives. 2-The phosphiranium access approach selected and used to date requires a synthesis and then a quaternarization of phosphiranes, which are obtained from a primary phosphine. Diversification of the phosphiranium salts structures by modulation of primary phosphine was rapidly shown to be limited ; on the other hand, starting from mesityl phosphine, a complementary strategy based on diversification through quaternarization has proved successful and has enabled quick access to a relatively comprehensive set of structure phosphiranium salts covering a broad reactivity spectrum that we have been able to begin exploring and mapping. One of the highlights is the identification of a category of quaternarizing agents causing an exacerbated phosphiranium reactivity towards the nucleophile components. 3-During this study, we also developed monotopic triflation/quaternarization and in situ ring opening sequences, which not only greatly facilitate syntheses of beta-functionalized phosphines, but also especially enable to overcome limitations encountered at various stages of conventional step-by-step approaches.

• Synthetic studies : Comprehensive exploration of the strategy based on «second generation« quaternarisation/opening sequences Concomitant intensification of the exploration of the range of nucleophilic partners. Evaluation of dipolar partners for the development of quaternarization/opening cascading sequences • Physico-chemical studies of model phosphiranes and phosphiraniums: UV/Visible spectroscopy, fluorescence and laser pulse photolysis (device handling and preliminary studies) Evaluation of phosphirane nucleophilicity by polar reaction with a,ß-unsaturated iminium electrophilic species Study of the reactivity of phosphiranes by photoredox catalysis

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Despite the prominence of phosphorus chemistry in modern science, phosphiranes and phosphiranium salts remain elusive species although these strained rings constitute appealing units with high potential for direct incorporation as phosphino ethylene units in molecules. Unlike their aziridinium analogues, which are transiently generated as synthetic intermediates of reasonable stability and always undergo selective nucleophilic ring-openings on carbons, phosphiraniums were shown in a very few number of seminal studies to be more unstable and prone to P-selective attacks by nucleophiles. The DePhI project aims at designing and revealing the chemistry of and phosphiranium salts in full, by interfacing in depth physical organic chemistry investigations with the development of a variety of completely new transformations, covering developments of reliable methods for phosphiraniums synthesis as well as original and very challenging C centered ring-openings or annulations under either polar or catalytic photoredox situations. We do hope to invert the trend to make phosphiranium ions a much more attractive target for both academia and industry.
In a preliminary phase we plan to prepare an extended range of phosphiranium salts which will be used in extensive physicochemical studies and mechanistic investigations. From this crossover experimental/mechanistic approach should emerge new leads of electrophilic phosphiraniums and nucleophiles combinations, which are expected to perform efficiently in the C-selective ring-opening of phosphiraniums, and will thus be tested. A next phase of the project will address diverse and complementary strategies aimed at offering new opportunities in reaction couplings of phosphiraniums, with as three main objectives to solve site-selectivity issues (C- versus P-attack) of certain reactive nucleophiles, to enable reactions of weaker nucleophiles that normally display poor/no reactivity, and also to propose innovative annulation processes. The intermolecular ring-opening processes to be investigated will mostly stage the vectorization of nucleophiles by an organocatalyst or a directing group suitably chosen according to the nucleophile used. Regarding the annulation reactions, a diversity of sequences consisting in phosphirane quaternarization by a selection of 1,n-dipolar reaction partners, followed by subsequent intramolecular ring-opening of the in situ generated phosphiraniums by the nucleophilic fragment of the dipoles, are proposed. In a next phase we will address the potential of phosphiranes and phosphiraniums in photoredox catalysis. First of all and in a view of complementarity with our usual polar approaches,, we propose the original synthesis of phosphiranium ions by photoredox arylative and alkylative quaternarization of phosphiranes. Next, assuming that phosphiraniums hold promise for radical fragmentations, we will look at a variety of crossover radical-polar ring-opening/annulation sequences with diverse unsaturated partners. Interestingly, these reducing quenching photoredox processes should provide a new catalytic, mild access to diverse phosphorus scaffolds in a complementary way to polar methods considered in the preceding tasks. A closing task will be ultimately intended to emphasize both the synthetic and application potential of phosphiranium ions chemistry developped throughout the DePhI project.