Synthesis and cytotoxicity studies of achiral azaindole‐substituted titanocenes

From the reaction of 1‐methyl‐1 H‐pyr‐rolo[2,3‐b]pyridine ( 1a ),1‐(methoxymethyl)‐1 H‐pyrrolo[2,3‐b]pyridine ( 1b ), 1‐isopropyl‐1 H‐pyrrolo[2,3‐b]pyridine (1c ), and 1‐(4‐methoxybenzyl)‐1 H‐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, µM respectively, whereas 4d showed no cytotoxic activity. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:148–157, 2011; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20668