Synthesis and Cytotoxicity Studies of Achiral Azaindole-Substituted Titanocenes

From the reaction of 1-methyl-1H-pyrrolo[2,3-b]pyridine (1a), 1-(methoxymethyl)-1H-pyrrolo[2,3-b]pyridine (1b), 1-isopropyl-1H-pyrrolo[2,3b]pyridine (1c), and 1-(4-methoxybenzyl)-1H-pyrrolo [2,3-b]pyridine (1d) under Vilsmeier-Haak conditions, the corresponding aldehydes in position 3 (2a-2d) were synthesized. These aldehydes were transformed in the corresponding fulvenes (3a-3d) by the Knoevenagel condensation and treated with Li[BEt3H] to obtain the corresponding lithiated cyclopentadienide intermediates (3'a-3'd). These intermediates were, finally transmetallated to titanium with TiCl4 to yield the 7-azaindol-3-yl-substituted titanocenes bis {[(1-methyl-1-H-pyrrolo[2,3-b]pyridin-3-yl)methyl]cyclopentadienyl} titanium(IV) dichloride (4a), bis{[(1-methoxymethyl-1-H - pyrrolo[2,3-b]pyridin-3-yl) methyl] cyclopentadienyl} titanium(IV) dichloride (4b), bis{[(1-Isopropyl-1-H-pyrrolo[2,3-b] pyridin-3-yl) methyl] cyclopentadienyl} titanium(IV) dichloride (4c), and bis{[(4-methoxybenzyl-1-H-pyrrolo[2,3-b] pyridin-3-yl) methyl] cyclopentadienyl} titanium(IV) dichloride (4d). All the titanocenes had their cytotoxicity investigated through MTT-based preliminary in vitro testing on the Caki-1 cell lines to determinate their IC50 values. Titanocenes 4a-4c were found to have IC50 values of 120 +/- 10, 83 +/- 13, and 54 +/- 12, mu M respectively, whereas 4d showed no cytotoxic activity. (C) 2011 Wiley Periodicals, Inc. Heteroatom Chem 22: 148-157, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20668