New Free-radical Multicomponent Processes – RAD-MCR

Olefins are a cheap raw material derived from petroleum, the chemical processing of which provides access to a wide variety of chemical compounds used in the composition of finished products marketed and used daily. The elaboration of these olefins occurs most often through the use of rare-metal catalysts (palladium, platinum,....), whose sources are in the process of drying up. As part of this research program, our laboratory has proposed new ways to elaborate these olefins using methods avoiding the use of metals. This technique, called radical allows the assembly of several molecules in a single chemical reaction. The saving of time and matter is the main advantage of this approach which fully meets the principles of green chemistry. This strategy avoids indeed multiple purifications and the high consumption of solvents and reagents caused by the so-called multi-step approach. It also minimizes the production of undesirable materials.

This project has enabled the development of a new method for transforming olefins resulting from an assembly between an olefin and two chemical components linked by this method called radical. This approach is efficient in terms of operation since several carbon-carbon and carbon-heteroatom bonds (oxygen, nitrogen) are sequentially formed in a single step (in one reactor) from distinct molecules (building blocks). New molecules were thus generated and elaborated in turn to access targets that can later serve as intermediates in the synthesis of active pharmaceutical ingredients.

The results obtained in this project have allowed the development of international collaborations, including the exchange of young researchers between the French laboratory and foreign universities (e.g. the Integrated Action French-Japanese Program (Sakura) in collaboration with Prof. I. Ryu in Osaka «Development of Novel Multi-Component Radical Reactions and Their Application to Microflow Synthesis« or the Integrated Action France-Germany Program (Procope) in collaboration with Prof. Dr. Heinrich (University of Erlanger-Nuremberg) «Photocatalyzed Free-radical Reactions«.

This research has led to several publications in internationally renowned journals (including «Organic Letters« a journal of the American Chemical Society), but also to a chapter of a book dedicated to the chemistry of multicomponent reactions and a chapter in the journal « Techniques de l’Ingénieur » for a wider audience. The researchers involved in this work have reported this work in several national (The Organic Chemistry Day (JCO), Palaiseau) and international conferences (XXIII French-Japanese Symposium on Medecinal and Fine Chemistry, Nagasaki (Japan). The results were also the subject of lectures by the project developer in symposium in France, Germany (17th International Symposium on Organosilicon Chemistry (ISOS XVII). Berlin, Germany, 03-08 / 08/2014) and Japan (The 9th International Symposium on Integrated Synthesis - ISIS-9, Awaji Island, Hyogo, Japan, November 14-15, 2014).

Multicomponent reactions (MCR) have recently garnered a lot of attention, these processes offering an efficient access to a broad range of molecular diversity in a limited number of operations. While MCRs based on ionic and organometallic reactions have enjoyed a wide interest, such is not the case for multicomponent reactions relying on free-radical processes. In this project, we propose two novel free-radical mediated three-component processes that we called carbo-alkenylation and alkynylation. These reactions are based on the coupling between an electrophilic radical species, generated from the corresponding halide or xanthate, an electron-rich olefin and an electron-poor acceptor (unsaturated sulfones and nitroolefins). In the first part of the program, the nature of the different partners will be varied as to determine the best reacting system. In parallel, DFT calculations will be performed to establish a reactivity scale between the different components and to study the mechanism of the addition of nucleophilic radicals onto vinyl- and alkynylsulfones. Experimental and theoretical reactivity scale will be compared as to establish a predictive tool for these free-radical MCRs. A diastereocontrolled version of the carbo-alkenylation and alkynylation above will then be devised using chiral allylsilanes and allylic alcohols that should provide an access to enantioenriched adducts. We also envision, as a long-term objective, developing organocatalyzed enantiocontrolled carbo-alkenylation and alkynylation. Such a process has no precedent in the literature and appears as very challenging. We will thus start our study by devising an enantioselective version of a carbo-oximation reaction that we developed recently. Enantioselective carbo-alkenylation and alkynylation will be studied subsequently based on these preliminary results. For this purpose, activation of the electrophilic radical precursor and/or activation of the acceptor will be investigated using chiral Lewis and Brønsted acids. The last part of the project will finally focus on the development of new domino processes involving two successive multicomponent reactions. Our objective is to perform such post-functionalizations in a single pot, the adduct generated during the first MCR serving as a new component for a second MCR. Three different types of domino processes will be investigated. We will first study a free-radical carbo-alkenylation/1,4-addition/olefination domino process, relying on Julia or Horner-Emmons olefinations. Using acylsilanes as radical precursors, we will also develop an unprecedented cascade where a 1,4-addition of a nucleophile onto a vinylsulfone, followed by a cyclisation onto the acylsilane, will trigger a Brook rearrangement, to eventually provide functionalized silyl enol ethers. Finally, a third domino process will be developed based on an intramolecular Michael-type cyclisation/olefination sequence that should afford new unsaturated cyclic or polycyclic systems. These domino processes will be first tested on model compounds and their value illustrated with straightforward synthesis of small natural products. As a summary, we plan developing new free-radical additions of functionalized carbon fragments across the pi-system of non activated olefins. Such processes result in the neat formation of two new C-C bonds and the generation of a stereogenic center, which stereochemistry should be controlled using organocatalysis. On the whole, this project proposes to tackle fundamental aspects of radical chemistry, including the reactivity of olefins and the enantiocontrol in C-C bond formation under radical conditions.