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Accueil > Les équipes > Réactivité organométallique et catalyse pour la synthèse (ROCS) > Thèmes de recherche

New Catalytic Transformations

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Our team is trying to develop new catalytic transformations enabling us to limit the number of synthetic steps through the development of domino processes and/or C-H activation. We are also trying to develop new metal-catalyzed reactions from biomass-derived molecules. In case of success, these developed transformations can be subjected to a stereoselective version (if possible), to a mechanistic study and can be applied to the total synthesis of a molecule of interest.

Development of C-H bond functionalization reactions

Functionalization of allylic C-H bonds : C-H activation vs. nucleopalladation

A few years ago, our team started to develop new C-H functionalization reactions. We also developed a Pd(II)-catalyzed direct allylic amination in the presence of benzoquinone playing the role of the oxidant. During the course of our studies, we demonstrated that the use of acetic acid as the solvent enabled to accelerate and to considerably improve the reaction. This solvent may assist benzoquinone during the reoxidantion and the ionization of intermediate palladium complexes. The mechanistic aspects of these steps of the catalytic cycle have been determined with a detailed DFT study.

More recently, we continued this study and we established that if we change the oxidant (using diacetoxyiodobenzene instead of benzoquinone), the Pd(II) species formed after the aminopalladation step could be oxidized into a Pd(IV) intermediate instead of being subjected to a β-H elimination step followed by a reductive elimination. In that case, cyclic adducts (lactams and cyclic carbamates) resulting from the double functionalization of the double bond could be obtained with good yields. A detailed mechanistic study has been done to get a better understanding on which parameters could influence going through an aminopalladation/β-H elimination/reductive elimination mechanism type, an aminopalladation/oxidative addition/reductive elimination mechanism type or a direct C-H activation mechanism type eventually followed by a sigmatropic rearrangement. The same kind of reaction and mechanistic study has been done in the case of the cyclization of terminal alkenylcarboxylic acids. Starting from these substrates, it appears that the reactivity is similar to the one with the substrates bearing an amide or carbamate nucleophilic functionnality.

This kind of reaction has also been developed starting from unsaturated N-sulfonamides using hypervalent iodine reagents playing the role of the terminal oxidant. Different reactivities have been observed according to the nature of the alkene (terminal or internal) or according to the nature of terminal oxidant used (diacetoxyiodobenzene or bistrifluoroacetoxyiodobenzene). This modulation of the reaction conditions enables us to prepare N-tethered heterocyclic compounds through an allylic amination mechanism via aminopalladation or via a C-H activation mechanism.

Our team has then reported a dehydrogenative allylic amination starting from 3-butenoic acid derivatives. Thanks to two different procedures involving palladium complexes, several sulfonamides can carry out the intermolecular functionalization of the γ-position of the 3-butenoic acid derivatives via a C-H activation mechanism.

Functionalization of C(sp2)-H bonds

  • Synthesis of methylidene-γ-lactams by C-H functionalization of terminal alkenes

Recently, thanks to a cyclizing aminopalladation/peroxycyclic dehydropalladation, we described an efficient synthesis of methylidene-γ-lactams. In the presence of oxygen gas playing the role of the terminal oxidant, optimal yields can only be obtained with triphenylphosphine and chloride ligands. We also proposed a mechanism based on experimental observations as well as DFT calculations.

  • Direct allylation of pyridine-N-oxides by Pd-catalyzed C-H activation

Not long ago, we found reaction conditions enabling us to do the palladium-catalyzed C2-alkenylation of azine-N-oxides by C-H activation. The desired compounds were formed according to a cascade allylation/isomerization process with moderate to good yields. Optimal yields were obtained using a tri-tert-butylphosphine ligand, prepared in situ from a tri-tert-butylphosphonium salt and potassium fluoride.

Synthesis of heterocycles by a Pd-catalyzed cyclization of allenes

Following our work reported in 2009 (J. Organomet. Chem. 2012, 714, 53) on the preparation of lactones by a Pd-catalyzed cyclization between an activated methylene moiety and an allene function, we continued the synthesis of heterocyclic compounds with the ruthenium-catalyzed preparation of oxazolidines (collaboration with Prof. Gianluigi Broggini).

Development of Palladium-catalyzed domino processes

Domino processes enable the generation of several new chemical bonds during single synthetic step, starting from simple substrates. Our group’s projects deals with the study of original catalytic sequences generally involving one or more transition metals.

Development of domino processes involving allenes

Our group is involved in developing domino processes using palladium-catalyzed transformations. The aminoallene cyclization reactions described above have been integrated in a Pd-catalyzed allene carbopalladation/amination domino process for the preparation of 1,4-benzodiazepinones.

Synthesis of 1,2-dihydroquinolines

Thanks to a domino procedure involving a Buchwald-Hartwig coupling and a Tsuji-Trost reaction, several N-aryl-1,2-dihydroquinolines have been efficiently prepared from anilines and Morita-Baylis-Hillmann adducts possessing an ortho-bromoaryl functionality in the allylic position. The reaction order in the domino sequence depends on the nature of the adduct. If the latter is bearing an alcohol function, then the Buchwald-Hartwig amination of the ortho-bromoaryl moiety occurs first. On the contrary, if the adduct is bearing an acetoxy functionality, then the Tsuji-Trost allylic amination occurs first.

Synthesis of 2-carboxyl-6-hydroxy-octahydroindole motifs

Following previous work from our group (J. Organomet. Chem., 2003, 687, 291 and Eur. J. Org. Chem., 2004, 2840 on the total synthesis of (±)-isoretronecanol), 2-carboxyl-6-hydroxy-octahydroindole (CHOI) derivatives have been prepared with a Pd-catalyzed domino process involving an intramolecular Tsuji-Trost reaction between an activated methylene moiety and an allylacetate (or benzoate) followed by an amination in the allylic position. After an homologation step and an epoxidation (or a syn-dihydroxylation step), advanced precursors of natural molecules from the aeruginosins family could be efficiently synthesized.

Following on from this work, we developed a new method to generate bi- or tricyclic molecules from resonance-stabilized acetamides and α,β-unsaturated cyclic ketones. The bicyclic compounds are prepared with a Pd-catalyzed domino sequence involving an intermolecular Tsuji-Trost allylation followed by an aza-Michael reaction. The tricyclic compounds are synthesized using the same reaction sequence but adding a Pd-catalyzed α-arylation of the ketone function thanks to the presence of the ortho-bromoaryl core on the nitrogen atom of the amide.

Development of more environment-friendly processes

A couple of years ago, we interested in developing more environment-friendly processes, especially through the preparation of recyclable catalysts and through the valorization of biomass-derived molecules. In the latter aspect, we do have a particular interest in finding step-economical processes, especially in the development of C-H activation processes.

Development of supported catalysts

In collaboration with Dr. Jutta Rieger’s team at Laboratoire de Chimie des Polymères, we made our contribution to the development of Pd(0) nanoparticular catalysts, which are stabilized in a core-shell nanogel capsule. These solid- and solution-stable catalysts have been used efficiently in Mizoroki-Heck reactions between n-butyl acrylate and several aryl halides. Although there is an activity loss, these catalysts are easily recyclable and can be used three times.

Valorization of biomass-derived molecules

We recently engaged in a new project dealing with the valorization of furfural, which is a product of lignocellulose degradation. We efficiently prepared high added-value C-3 alkylated furfural derivatives with ruthenium-catalyzed Murai reaction conditions. A mechanistic proposal (collaboration with Prof. Luis Veiros – ULisboa) has been done on the basis of DFT calculations.