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Late-stage C-H Arylation of Thiazolo[5,4-f]quinazolin-9(8H)-one Backbone: Synthesis of an Array of Potential Kinase Inhibitors
1 , 1 , 2 , 1 , * 1
1  Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA UMR 6014, F-76000 Rouen, France
2  Manros Therapeutics, Centre de Perharidy, 29680 Roscoff, France.

Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Our research group focuses on the synthesis of thiazolo[5,4-f]quinazolin-9(8H)-one derivatives as potential kinase inhibitors involved in Alzheimer's disease.[1] Previous in vitro results led us to intensively study the backbone for further SAR investigations. In order to establish SAR studies, C-H arylation methods were investigated. [2] The regioselective C-H bond activation of the thiazole moieties was developed to furnish the corresponding valuable C2-arylated compounds.


Herein, we report an extension of this methodology to thiazolo[5,4-f]quinazolin-9(8H)-ones in order to functionalize regioselectively at C2 and C7 positions.[3] A metal-free synthesis of the tricyclic starting material was also described giving access to these compounds in a facile manner.[4] Two monoarylated compounds show high inhibition values for kinases of the DYRK's family,  involved in Alzheimer's disease.


[1]    (a) Chaikuad, A.; Diharce, J.; Schröder, M.. Foucourt, A.; Leblond, B.; Casagrande, A.-S.; Désiré, L.; Bonnet, P.; Knapp, S.; Besson, T. J. Med. Chem. 2016, 59, 10315; (b) Hédou, D.; Dubouilh-Benard, C.; Loaëc, N.; Meijer, L.; Fruit, C.; Besson, T. Molecules 2016, 21, 794; (c) Courtadeur, S.; Benyamine, H.; Delalonde, L.; de Oliveira, C.; Leblond, B.; Foucourt, A.; Besson, T.; Casagrande, A.-S.; Taverne, T.; Girard, A.; Pando, M.P.; Désiré, L. J. Neurochem. 2015, 133, 440; (d) Thompson, B.; Bhansali, R.; Diebold, L.; Cook, D. E.; Stolzenburg, L.;Casagrande, A. –S.; Besson, T.; Leblond, B.; Desire, L.; Malinge, S.; Crispino, J. D. J. Exp. Med. 2015, 212, 723.

[2]    (a) Laclef, S.; Harari, M.; Godeau, J.; Schmitz-Afonso, I.; Bischoff, L.; Hoarau, C.; Levacher, V.; Fruit, C.; Besson, T. Org. Lett. 2015, 17, 1700 ; (b) Godeau, J.; Harari, M.; Laclef, S.; Deau, E.; Fruit, C.; Besson, T. Eur. J. Org. Chem. 2015, 7705.

[3]    Harari, M.; Couly, F.; Fruit, C.; Besson, T. Org. Lett. 2016, 18, 3282.

[4]    Couly, F.; Dubouilh-Benard, C.; Besson, T.; Fruit, C. Synthesis 2017, in press, DOI: 10.1055/s-0036-1588434.

Comments on this paper
Andrea Porcheddu
impressed, a great job!
A curiosity, can you prepare the library (double arylation) via two-steps, one-pot process? in this way the procedure would be much more interesting ...


Thierry Besson
Dear Andrea,

Thanks for your comments,

Yes selective and regioselective arylation of the starting scafold was also realized in one pot procedure, see:
Org. Lett. 2016, 18, 3282−3285 DOI: 10.1021/acs.orglett.6b01552, but with lower yields compared to the overal yield of the sequential procedure.

It is also possible to obtain bis-arylated derivatives in one experiment with 3 equiv of the starting aryl iodide (described in this presentation).

best regards
Andrea Porcheddu
thanks Thierry