Development of Emergent Fluorinated Intermediates of High Added Value in Synthesis – DEFIS

The research program consists in three independent modules.
The first work module tackles the synthesis of optically enriched organic compounds incorporating a CHF2 group. The proposed strategy is based on the use of organometallic nucleophiles generated from enantioenriched difluoromethylsulfoxides. After adding organometallic species to various electrophiles, cleavage of the sulfoxide or subsequently functionalization of the C-S bond should lead to a large diversity of optically enriched CHF2 compounds.
The second module extends the previously developed strategy to the synthesis of optically enriched chiral compounds incorporating asymmetric carbon substituted by an OCF3 or SF5 group. Pathways to enantioenriched sulfoxides with an adjacent carbon substituted by an OCF3 group, or to alpha or beta-SF5 substituted vinyl sulfoxides, will first be developed. Then, the resulting building blocks will be functionalized, capitalizing on the very rich synthetic potential of chiral sulfoxide chemistry.
The third module is specifically dedicated to organic compounds substituted by the SF5 group. SF5-azadienes will be prepared from vinamidinium salts or SF5-alkynes. Azirines substituted by an SF5 group will also be synthesized by addition of the SF5 radical to unsaturated acceptors or by using aldolization reactions involving alpha-SF5-acetates. Functionalized azadienes will then be engaged in pericyclic reaction sequences to prepare unsaturated nitrogen-containing heterocyclic compounds. The previously prepared azirines will be involved in addition reactions of organometallic nucleophiles or transition metal-catalyzed processes to access saturated or aromatic nitrogen-containing heterocycles.

Fluorine chemistry lies at the heart of highly competitive economic activities. The objective of the DEFIS project is to create original molecules incorporating emerging fluorinated groups, such as CF2H, OCF3 and SF5, in order to obtain new molecular building blocks that will be at the origin of the future agrochemical or pharmacological ingredients. These emerging fluorinated groups may have novel physico-chemical and biological properties and constitute an alternative to the CF3 group. Finally, these emerging fluorinated groups may eventually lead to improved biological activity or even a new mode of action with a minor impact on the environment.
The DEFIS project is at the forefront of innovation in modern fluorine organic chemistry and has multiple socio-economic interests: 1) significantly increase the international visibility and performance of French chemical R&D in strategic areas of the pharmaceutical, agrochemical and materials industries; 2) enable innovation in synthetic methods in a highly competitive field at the international level; 3) ensure, at a relatively early stage of potential industrial exploitation, many possible short-term applications, applications that primarily concern companies such as Sanofi; 4) enable the development of new therapeutic or agrochemical molecules, potentially more effective, more benign to the environment, and displaying new modes of action to allow for new treatments.

Organofluorine chemistry is nowadays an important part of Life Science-oriented research. Hence, the development of new and more efficient methods for the introduction of fluorinated groups is a major challenge. From an industrial perspective, CHF2, OCF3, and SF5 groups are quite seldom encountered and there is an urgent need to develop efficient and selective approaches towards scaffolds substituted by these Emergent Fluorinated Substituents (EFS). These EFS might provide new reactivities and functions to man-made molecules and may also lead to improved biological activity or even a new mode of action. Quite importantly, novel EFS would also avoid patent restrictions and thus provide an advantage over competitors in the field, a consideration of prime importance for the chemical industry. Thus, the discovery of innovative molecules bearing emergent fluorinated groups is of utmost importance for leading companies in this field.
The project lies at the forefront of innovation in modern organofluorine chemistry. Besides the innovation in synthetic methods in a highly internationally competitive area, at a relatively early stage of a potential industrial exploitation, numerous possible applications in the short term will be generated by this project.
This project will contribute to guiding further research topics by devising new tools leading to applications in fields that constitute essential assets for the industrial revival of our country.
The three main objectives for a company are: (1) to obtain a way to rapidly access specific technologies in fluorine chemistry; (2) to get a clear advantage over competitors in the field and
(3) to possess a library of new building-blocks unavailable by competitors.

1. Blanchard, N.; Bizet, V. Angew. Chem. Int. Ed. 2019, 58, 6814.
2. C. Batisse, M. F. Céspedes Dávila, M. Castello, A. Messara, B. Vivet, G. Marciniak, A. Panossian, G. Hanquet, F. R. Leroux, Tetrahedron 2019, 75, 3063-3079.
3. C. Batisse, A. Panossian, G. Hanquet, F. R. Leroux, Chem. Commun. 2018, 54, 10423-10426.

Decades of chemical research have shown that the fluorine atom and the fluorine-containing motifs profoundly impact the structure, reactivity and function of organic and inorganic molecules. Fluorine containing compounds are nowadays synthesized in pharmaceutical, agrochemical, polymer and electronic research on a routine basis. As an example, it is well established that fluorine atom(s) and/or fluoroalkyl group(s) can lead to many beneficial effects in a biologically active molecule. A logical consequence of these highly desirable properties is that more than 200 pharmaceuticals and 155 agrochemicals (among the 920 registered) containing at least one fluorine atom are currently on the market, which account for approximately 25% of the bioactive compounds. Material sciences are also deeply impacted by fluorine as exemplified by the annual growth rate of the fluoropolymer market estimated at 6.5% through 2016.
In the past decade, Fluorine chemistry greatly expanded with insightful contributions from research groups aiming at developing novel synthetic methods and reagents for the regio- and stereoselective introduction of fluorine or fluorine-containing groups into molecular scaffolds. Indeed, the fluorine chemistry field is still developing at a rapid pace and one of the current challenges is the search for Emergent Fluorinated Substituents (EFS) that would not only give new reactivities and functions to man-made molecules but also eventually lead to improved biological activity or even a novel mode of action. Quite importantly, novel EFS would also avoid patent restrictions and thus provide an advantage over competitors in the field, a consideration of prime importance for the chemical industry. Such EFS are based on carbon (CHF2), linked to a heteroatom (O-CF3, S-CF3), or based on sulfur (SF5). From an industrial perspective, it should be noted that CHF2, OCF3 and SF5 groups are quite rarely encountered and there is an urgent need to develop academic as well as industrial viable approaches towards scaffolds substituted by these EFS.
The project DEFIS belongs to "Challenge 3: Stimulate industrial renewal - Research focus 4: Sustainable chemistry, products, associated processes". In the DEFIS project, we have created a consortium of two partners gathering three teams, sharing common research interests but also possessing different specific expertises, which aims to investigate the synthesis and reactivity of three different types of emergent fluorinated substituents (CHF2, OCF3 and SF5) incorporated in a broad array of cyclic and acyclic chemical motifs. The proposal is organized in three objectives: in the first objective, we will develop an access to enantioenriched difluoromethylated compounds and in the second objective, we will focus on enantioenriched building blocks incorporating OCF3 and SF5 substituents. Finally, in the third objective, we will tackle the synthesis of SF5-substituted nitrogen heterocycles.
The overall goals of the project have been defined to address the crucial challenges that lay ahead for the chemical industry in terms of innovation and intellectual property in the field of EFS, that will ultimately translate to numerous areas of our daily life, from life- to material sciences. Finally, a special attention has been paid to the management of the proposal in order to prevent dead ends and excessive delays in the realization of the different tasks.