Selective remote functionalizations of conjugated aldehydes – RemotAld
RemotAld : Selective remote functionalizations of conjugated aldehydes
The project seeks to develop a selective synthesis of gamma-functionalized enals
Regioselective and stereoselective functionalization of enals in gamma position
The initial objective of this research project is to develop a general radical method for the selective functionalization of alpha,beta-unsaturated aldehydes in the gamma position. This method is based on the use of photoredox catalysis and should allow the selective construction of C-C, C-O, C-N, or C-S bonds at this position at a distance, and an enantioselective version is also envisaged through the use of chiral organocatalysts.
The methodology used consists of the mildand controlled generation of oxygen-, nitrogen-, sulphur- or carbon-centered radicals through the use of photoredox catalysis. These radicals are then selectively added to the gamma position of dienolates such as silylated dienol ethers to form the desired products. A flow chemistry approach is also envisaged to optimise and scale up these photochemical transformations.
As originally planned in the project, we first started to work on C-O bond formation. The envisaged approach requires the generation of oxygen-centred radicals, in particular alkoxy RO radicals. In order to develop this reaction on alpha,beta-unsaturated carbonyl compounds, we first worked on simpler substrates, namely carbonyl compounds. We were able to show that if these carbonyl compounds are activated in the form of silylated enol ethers, we could carry out the alkoxylation in the alpha position in very good yields by using pyridinium salts as sources of RO- radicals (work recently published in Org. Lett.).
We then generalized this study by trying to apply it to the synthesis of gamma-alkoxylated compounds. For this purpose, we synthesized a whole range of silylated dienol ethers and by adapting the operating conditions very slightly, in particular the choice of photocatalyst, we managed to functionalize our substrates remotely, with perfect selectivity for the gamma compound compared to the alpha compound, in coherence with our initial working hypothesis.
This reaction could also be generalised to nitrogen-centred radicals. Among the sources tested, the N-amino pyridinium salts were also the most efficient for this transformation, and we can also note a total selectivity for the gamma position.
Finally, we also sought to generalise the reaction with carbon radicals. Here again, after modification of the operating conditions (solvent and base were changed), a large number of gamma-alkylated enals could be isolated in good yields. In particular, we focused on the introduction of perfluorinated groups (CF3, C4F9, CF2H, CF2CO2Et), which constitutes a completely new synthesis in this field of interest. All these results will be published in the coming months (two manuscripts are in preparation), and correspond more or less to the initial plan of the project, especially in WP1.
For the second part of the project, we still have to adapt the reactions in flow chemistry, generalise the methodology for the introduction of sulphur groups, and tackle the enantioselective version, corresponding to WP2 of the project.
C. Banoun, F. Bourdreux, E. Magnier, G. Dagousset, Org. Lett. 2021, 23, 8926
Unlike most methodologies of organic synthesis, remote functionalization allows for a selective reaction to proceed at a distal and less reactive position of an organic molecule. This is a very powerful concept, which would in principle provide solutions to almost every synthetic challenge faced by organic chemists. The inherent difficulty is however to be able to distinguish among all potential reactive sites of the molecule. In particular, enolizable alpha,beta-unsaturated aldehydes (enals) are valuable substrates which can undergo such remote functionalization in their gamma position. The goal of this project is to bring solutions to the two major challenges encountered in this field: 1) the alpha/gamma selectivity issue: we propose an innovative and general radical approach based on photoredox catalysis. 2) the stereoselectivity issue: we plan here to use a dual catalytic system, by merging photoredox catalysis with aminocatalysis.
Monsieur GUILLAUME DAGOUSSET (Institut Lavoisier de Versailles)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
ILV Institut Lavoisier de Versailles
Help of the ANR 195,156 euros
Beginning and duration of the scientific project: October 2020 - 48 Months