Carbo-silylation Reactions as Central Tool for the Synthesis of Complex Silaheterocycles – C-Sil

In order to achieve our general objective of developing simple and efficient synthesis of azasilheterocycles we will have to achieve 3 clear sub-objectives:

1- The development of new building blocks bearing one silicon and one nitrogen atom,
2- The development of carbosilylation reactions,
3- The development of original domino sequences leading to mixed N/Si

The team worked on several aspects of the project in parallel. In particular, objective 1 has been partially achieved while objective 2 has been fully achieved over the past period. This progress of the work is partially in agreement with the planning which had been initially established.

1/ Development of new synthons carrying a silicon atom and a nitrogen atom:

In the framework of our studies we have realized the first efficient synthesis of N/Si synthons based on a nitrogen heterocycle. This was made possible by directed lithiation and then trapping with a silylated group. Finally, after an intensive study, we performed the deprotection of the nitrogenous group to reach the targeted synthons. However, the second approach envisaged and involving a key hydrosilylation step has been abandoned for the moment in order to concentrate on the two other objectives of the project.

2/ Development of original carbosilylation reactions:

Over the past period we have fully achieved our goals in terms of carbosilylation of polarized alkynes. Thus we have developed an efficient toolbox for the synthesis of silylated compounds in a fully controlled manner. We have developed the first silylcyanation of ynamides. This pallado-catalyzed reaction is totally regioselective, delivering exclusively tetrasubstituted 2-aminoacrylonitriles. Unexpectedly, the nature (aryl or alkyl) of the substituent located at the ß-position of the ynamide directly controls the stereoselectivity. This reaction can be considered the first general access to fully substituted 2-aminoacrylonitriles. Mechanistic studies (including DFT) were also conducted. On the other hand, we have also developed the silylformylation of ynamide without CO. This is the first regio- and stereoselective silylformylation of ynamides. This reaction has been shown to be tolerant of a wide range of functional groups and the substitution of CO (conventionally used) with isonitrile has made this reaction safer and more convenient than standard silylformylation reactions. This reaction represents a versatile and simple access to various hard-to-access tetrasubstituted 3-silyl-2-amidoacrolein derivatives. The synthetic potential of these new building blocks was evaluated by performing several post functionalizations.

In the coming period we will focus on the 3rd objective of the project, namely : The development of original domino sequences leading to mixed N/Si

1. Versatile Access to Tetrasubstituted 2-Amidoacroleins through Formal Silylformylation of Ynamides, Stéphane Golling, Frédéric R. Leroux, Morgan Donnard* Org. Lett. 2021, 23, 8093–8097 pubs.acs.org/doi/10.1021/acs.orglett.1c03141
hal.archives-ouvertes.fr/hal-03369636

No patent for the moment.

Silicon-containing heterocycles are highly valuable scaffolds as they have shown specific properties in very different fields such as, non-exhaustively, materials, fragrances and pharmaceuticals. Notably, most of the time these specificities are due to the silicon atom itself as it changes dramatically the polarity as well as the conformational characteristics of an organic compound compared to its carbon analog. However, the number of efficient synthetic methodologies to reach these scaffolds remains low in comparison to other heterocycles and it undoubtedly represents the main barrier to the use of such molecules in many fields. In this research program, we propose to manage a global and systematic synthesis program to access azasilaheterocycles as they represent the most promising family of silamolecules in terms of biological activity. The goal is to offer a reliable and versatile synthetic toolbox to access a wide scope of such compounds. These chemical scaffolds should be of high interest in diverse fields such as the pharmacy, the agrochemistry, and the materials.