Activation chimiosélective et dérivatisation d’amides et d'alcools : synthèse de plusieurs groupements fonctionnels et hétérocycles
A major objective in organic chemistry is the development of methods for general, simple and cost-effective transformations allowing for the efficient modification of natural resources into different products of public interest. In particular, the research of chemoselective and “green” methods represents a growing interest for the industrial sector. In fact, the synthetic application on large-scale of catalytic and selective processes using mild conditions allows the reduction of wastes and energy usage, minimizing the cost of production and the harmful effects to the environment. In this context, the research group of Professor André B. Charette from Université de Montréal is interested in the development of general and chemoselective methods for the derivatization of readily available functionalities, such as amides and alcohols.  The amide function, also named peptide bond in proteins, is identified in diverse families of natural products and is commonly used as synthetic intermediate in the synthesis of pharmaceutical leads. The alcohol function is one of the most abundant functionalities in nature, intrinsically and largely used in synthetic chemistry.   In the context of this thesis, simple, general and chemoselective transformations were applied to secondary and tertiary amides, as well as to primary and secondary alcohols. The first part of the thesis relies on the activation of amides mediated by triflic anhydride, followed by the nucleophilic addition of different reagents, allowing for the formation of several key functional groups in organic chemistry, such as aldimines, aldehydes, amines, ketones, ketimines, and amidrazone derivatives. The latter functionality has been used in successive reactions towards the formation of heterocycles, such as 1,2,4-triazoles via a cyclodehydration reaction and 3-aminoindazoles via a palladium-catalyzed C–H functionalization reaction.   The second part of the thesis is based on an acid mediated Mitsunobu reaction allowing the nucleophilic substitution of alcohols in the presence of free carbamines (which doesn’t contain any electron-withdrawing substituents), normally basic entities with pKa over 13 (in DMSO), which are intrinsically unaccepted in standard Mitsunobu conditions. Contrary to the usual multi-step synthesis of amines using the Mitsunobu reaction, this method allows the formation of substituted amines in a single step without the need of protecting groups.
Activation Amide