Methodology - Synthesis


4-exo-dig cyclocarbopalladation for the synthesis of complex molecules

4exodig


Metal-catalyzed reactions for the synthesis of sulfur heterocycles

Palladium-catalyzed Domino Reactions for the Synthesis of Sulfur-based Heterocycles

Cyclocarbopalladation/cross-coupling cascade reactions were applied for the first time in a sulfur series and represent an efficient route to access sulfur heterocycles. Stille or Suzuki-Miyaura cross-coupling was successfully used as the final reaction. The products are original benzothiolane and isothiochromane scaffolds with a stereodefined tetrasubstituted exocyclic double bond. To illustrate the application of this method to the synthesis of bioactive molecules, a sulfur analogue of the anticancer agent tamoxifen was prepared as a potential selective estrogen-receptor modulator.

 

cascade soufre palladium


Organometallic chemistry applied to cyanated heteroatoms

At the present time, there is a real need for new transformations (greener, safer, cheaper) and original molecules bearing unprecedented scaffolds ( bearing new properties or modulating existing ones).
In order to contribute to the general effort made to face this two challenges, we propose to apply organometallic transformations to under investigated substrates, namely heteroatom-susbtituted nitriles (=cyanated heteroatoms).

This project could give rise to discovery of new concepts and approaches for bond construction and the design of new tools and catalytic systems for organic chemistry. Developed reactions will be then applied to think up substrates in order to generate original scaffolds that will be submitted to the expertise of potential partners in order to initiate collaborations that could result in valuable scientific outcomes across disciplines.

Recent Results

Copper-mediated oxidative cyanation of heteroatoms

The practical and mild aerobic oxidative CuCN-mediated cyanation of thiophenols and diaryl disulfides was investigated. The reaction was performed in air at room temperature and reached aromatic thiocyanates in moderate to good yields starting from a broad range of diversely functionalized substrates.

 

cyanation de soufre méfiée au cuivre

 

Aerobic Copper-Mediated Domino Three-Component Approach to 2-Aminobenzothiazole Derivatives

An unprecedented three-component reaction involving a 2,2′-diaminodiaryl disulfide, copper cyanide, and an electrophile is described. This transformation is based on an oxidative copper-mediated S-cyanation as a key step and involves a cyanation/cyclization/acylation domino sequence enabling a rapid and efficient synthesis of diversely substituted 2-aminobenzothiazole derivatives. Notably, this reaction proceeds via an original mechanism involving an intermolecular migration of the acyl group.



Hydroformylation and domino processes

In the last time the group is working on the development of new synthetic routes towards nitrogen heterocycles within the concept of step economy.  To achieve this goal, we have developed a method based on hydroformylation, a fundamental reaction in homogeneous catalysis, which was used to triggered domino reactions. 

A. In the first time, we have developed a methodology of synthesis of piperidine core via a hydroformylation of homoallylazides (Scheme).

hydroformylation

Unexpectedly, homoallylic azide allows to obtain the corresponding d-azidoalkyl aldehydes in the hydroformylation conditions.
Thus, we have synthesized original way (S)-anabasine, (S)-nicotine and (±)-sedamine.

B. In the second time, we have studied the hydroformylation of linear amide features a vinylacetamide and an additional nucleophile (Scheme). The transient N-acyliminium ion obtained after cyclohydrocarbonylation reaction can be trapped by various nucleophiles to give, according to a domino process, several aza-heterocylic scaffolds.

 

hydroformylation

 

Our strategy allows full control over product formation: by fine-tuning of the reaction conditions, various heterocycles can be obtained from simple, readily available materials from the feedstock. Moreover, complex, aza-polycyclic systems can be efficiently built in a diastereoselective fashion.

C. Still in respect to the step economy concept we have developed a multi-component domino reaction based on the hydroformylation between H2, CO, an unsaturated carboxylic acid derivative and a bi-nucleophile (Scheme).

 

hydroformylation

 

From O-succinimydil ester of vinylacetic acid and either amino-acid, amino-alcohol or aromatic amine, this reaction allowed to deliver fused heterocycles in single step and with good diastereoselectivity.