From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines

Frédéric Lassagne (1) , Timothy Langlais (1) , Elsa Caytan (1) , Emmanuelle Limanton (1) , Ludovic Paquin (1) , Manon Boullard (1) , Coline Courtel (1) , Idriss Curbet (1) , Clément Gédéon (1) , Julien Lebreton (1) , Laurent Picot (2) , Valérie Thiéry (2) , Mohamed Souab (3) , Blandine Baratte (4, 5, 6, 7) , Sandrine Ruchaud (6, 8) , Stéphane Bach (4, 5, 6, 7) , Thierry Roisnel (1) , Florence Mongin (1)

1 ISCR - Institut des Sciences Chimiques de Rennes
2 LIENSs - LIttoral ENvironnement et Sociétés
3 P3H - Phophorylation de protéines et Pathologies Humaines
4 LBI2M - Laboratoire de Biologie Intégrative des Modèles Marins
5 KISSf - Plate-forme de criblage d'inhibiteurs de protéines kinases=Kinase Inhibitor Specialized Screening facility
6 SBR - Station biologique de Roscoff = Roscoff Marine Station
7 FR2424 - Fédération de recherche de Roscoff
8 LBI - Laboratoire de Biologie Intégrative

2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodoquinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[2 ,3 :5,6] pyrido[4,3-b]indole and pyrazino[2 ,3 :4,5]pyrido[2,3-d]indole, respectively. 8-Iodopyrido[2,3-b] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition).

Mots clés: pyrazine; deprotometalation; coupling; N-arylation; palladium; copper

Domaines: Chimie thérapeutique; Chimie organique

Frédéric Lassagne, Timothy Langlais, Elsa Caytan, Emmanuelle Limanton, Ludovic Paquin, et al.. From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines. Molecules, 2018, 23 (11), pp.2961. ⟨10.3390/molecules23112961⟩. ⟨hal-03867783⟩