Microwave-assisted C-H arylation of Quinazolin-4-one-type Precursors of Bioactive Heterocycles

Our group is focused on the synthesis of C,N,S- or C,N,O-containing heterocyclic precursors of bioactive molecules able to modulate the activity of kinases involved to some extent in Alzheimer's disease.¹ Previous biological results lead us to intensively study thiazoloquinazolin-4-one backbone especially modulations of positions 1 and 2. Following our effort for the construction of a broad range of substituted thiazoloquinazolin-4-one derivatives as potential kinase inhibitors,² modulating the position 3 was further explored. As an efficient and versatile approach in complex molecules synthesis palladium-catalyzed, C–H functionalization of heteroarenes³ represents an extremely attractive approach.

Our presentation describes the first extensive study of palladium-catalyzed direct C-H (hetero)-arylation of quinazolin-4(3H)-ones with aryl iodides, bromides and chlorides under microwave irradiation.⁴ This innovative methodology tolerates a broad range of heteroaryl and aryl halides substituted by electronically different groups. The scope of substrates was extended to pyridinopyrimidin-4-ones. This method provides an efficient, versatile, and rapid access to 2-arylquinazolin-4-one backbone and will be extended to our thiazoloquinazolin-4-one derivatives.

References

1. (a) Schmitt, C.; Miralinaghi, P.; Mariano, M.; Hartmann, R.W. ; Engel, M. ACS Med. Chem. Lett. 2014, 5, 963. (b) Dehbi, O.; Tikad, A.; Bourg, S.; Bonnet, P.; Lozach, O.; Meijer, L.; Aadil, M.; Akssira, M.; Guillaumet, G.; Routier, S. Eur. J. Med. Chem. 2014, 80, 352.
2. (a) Foucourt A.; Hédou, D.; Dubouilh-Benard, C.; Girard, A.; Taverne, T.; Désiré, L.; Casagrande, A.-S.; Leblond, B.; Loaëc, N.; Meijer, L.; Besson, T. Molecules 2014, 19, 15546. (b) Foucourt A.; Hédou, D.; Dubouilh-Benard, C.; Girard, A.; Taverne, T.; Casagrande, A.-S.; Désiré, L.; Leblond, B.; Besson, T. Molecules 2014, 19, 15411. (c) Deau, E.; Hédou, D.; Chosson, E.; Levacher, V.; Besson. T. Tetrahedron Letters 2013, 54, 3518. (d) C. Schmitt, P. Miralinaghi, M. Mariano, R.W. Hartmann, M. Engel, ACS Med. Chem. Lett. 2014, 5, 963.
3. (a) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth. Catal. 2014, 356, 17. (b) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. (c) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed. 2012, 51, 8960. (d) Ackermann, L. Chem. Rev. 2011, 111, 1315.
4. (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, in press.