Preparation of Carbo- and Heterocycles via novel Environmentally Friendly Radical Processes. – UZFUL-Chem

This study will examine the scope and limitations of the reaction with a short selection of original reagents, which were expected to be capable of mediating the desired radical cascade, under environmentally friendly conditions (e.g. in the absence of transition metal). The first part of our study will be conducted on a model substrate in close collaboration with the laboratory CEISAM (University of Nantes, France) and the University of Berne (Switzerland). In the second part of the program, the scope will be then extended to include various types of precursors. The complementary skills of the different partners involved will be the key for the success of this second part. The use of highly reactive nitrogen-based substrates will be conducted with the University of Brussels (Belgium), while the synthesis of sulphur-containing heterocycles will be carried out with Trinity College Dublin (Ireland). The results collected during the whole program will be analysed and rationalised thanks to high-level computational methods, in collaboration with the University of Melbourne (Australia). This will allow us to propose a model to explain, and ideally, predict the behaviour of each class of substrates under our optimised reaction conditions.

we have determined a selection of reagents, with complementary behaviours, allowing for the desired radical cascade to proceed in good yields and, sometimes, very high levels of selectivity. Some of these reagents are commercially available, others have been designed and their synthesis optimised to meet our requirements. A series of carbocycles presenting a alkenyl side chain, allowing for further transformations, have been successfully prepared in one step from terminal alkynes, under mild reaction conditions (room temperature, no need for inert atmosphere). We could also prepared advanced intermediates presenting a useful sulfone moiety, which offers many opportunities for further functionalization.

The work developed in the frame of this ANR program have led so far to 8 publications in high quality peer-reviewed journals with a broad readership (Chemistry: a European Journal, Angewandte Chemie International Edition...) or targeted to the organic chemists community (Organic Letters, Free Radical Research...). Almost all of these publications have been co-authored between the CEISAM laboratory and one of the foreign collaborators involved in the project. The results that have been secured with publication have been presented at international scientific meetings, COST workshops or invited lectures.

1) Beginning of a new research program with Prof. E. M. Scanlan (Trinity College Dublin) on the preparation of new heterocycles.

2) Integration into the european COST ''CHAOS'' program (2016-2019) on ''CH activation in organic synthesis''

3) PICS CNRS ''CASCHEM'' (2018-2020) (development of new radical cascades based on CH activation reactions), collaboration with P. Renaud (Berne, Switzerland).
Porteur: F. Dénès.

1. Bénéteau, R.; Despiau, C. F.; Rouaud, J.-C.; Boussonnière, A.; Silvestre, V.; Lebreton, J.; Dénès, F.* Chem. Eur. J. 2015, 21, 11378-11386. (IF = 5.317).

2. Bénéteau, R.; Despiau, C. F.; Rouaud, J.-C.; Boussonnière, A.; Silvestre, V.; Lebreton, J.; Dénès, F.* Chem. Eur. J. 2015, 21, 11378-11386.Bénéteau, R.;, Boussonnière, A.; Rouaud, J.-C.; Lebreton, J.; Graton, J.; Jacquemin, D.; Sebban, M.; Oulyadi, H.; Hamdoun, G.; Hancock, A. N.; Schiesser, C. H.; Dénès, F.* Chem. Eur. J. 2016, 22, 4809 (IF = 5.317).

3. Gloor, C. S.; Dénès, F.; Renaud, P.* Free Rad. Res. 2016, 50, S102-S111 (IF = 3.188)

4. Soulard, V.; Dénès, F.*; Renaud, P.* Free Rad. Res. 2016, 50, S2–S5 (IF = 3.188)

5. McSweeney, L.; Dénès, F.; Scanlan, E. M.* Eur. J. Org. 2016, 2080-2095 (IF = 2.882)

6. Gloor, C. S.; Dénès, F.*; Renaud, P.* Angew. Chem. Int. Ed. 2017, 56, 13329-13332 (IF = 11.994)

7. McCourt, R. O.; Dénès, F.; Sanchez-Sanz, G.; Scanlan, E. M.* Org. Lett. 2018, 20, 2948-2951 (IF = 6.492).

8. McCourt R. O.; Dénès F.; Scanlan E. M. Molecules 2018, 23, 897 (IF = 3.098)

The preparation of 5- and 6-membered rings (cyclopentanes, tetrahydrofurans, and pyrrolidine derivatives) having a pendant alkenyl side chain will be carried out via a novel radical cascade based upon intramolecular hydrogen shifts. The study will examine the scope and limitations of various reagents to mediate these radical cascades under environmentally friendly, tin-free conditions. The range of substrates suitable for this reaction will be investigated and general conditions will be developed and optimized. The cyclic compounds resulting from this radical cascade will serve as precursors for the development of new methodologies, such as new types of ring-expansions or selective cross-coupling reactions. Applications will be directed towards the preparation of useful building blocks for the synthesis of more complex targets.