Synthesis and cytotoxicity studies of new (dimethylamino)-functionalised and 7-azaindole-substituted 'titanocene' anticancer agents (7-azaindole = 1H-pyrrolo[2,3-b]pyridine)

Article abstract of DOI:10.1002/hlca.200890191

From the carbolithiation of 1-(cyclopenta-2,4-dien-1-ylidene)-N,N- dimethylmethanamine (=6-(dimethylamino)fulvene; 3) and different lithiated azaindoles 2 (1-methyl-7-azaindol-2-yl, 1-[(diethylamino) methyl]-7-azaindol-2- yl, and 1-(methoxymethyl)-7-azaindol-2-yl), the corresponding lithium cyclopentadienide intermediates 4a-4c were formed (7-azaindole=1H-pyrrolo[2,3-b] pyridine). The latter underwent a transmetallation reaction with TiCl ₄ resulting in the (dimethylamino)-functionalised 'titanocenes' 5a-5c. When the 'titanocenes' 5a-5c were tested against LLC-PK cells, the IC₅₀ values obtained were of 8.8, 12, and 87 μM, respectively. The most cytotoxic 'titanocene', 5a, with an IC₅₀ value of 8.8 μM is nearly as cytotoxic as cis-platin, which showed an IC₅₀ value of 3.3 μM when tested on the epithelial pig kidney LLC-PK cell line, and ca. 200 times better than 'titanocene dichloride' itself.

Full text of DOI:10.1002/hlca.200890191

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Synthesis and Cytotoxicity Studies of New (Dimethylamino)-Functionalised
and 7-Azaindole-Substituted ꢀTitanoceneꢁAnticancer Agents (7-Azaindole ¼
1H-Pyrrolo[2,3-b]pyridine)
by Megan Hogan, Juliet Cotter, James Claffey, Brendan Gleeson, Denise Wallis, Donal OꢁShea*, and
Matthias Tacke*
UCD School of Chemistry and Chemical Biology, Conway Institute of Biomolecular and Biomedical
Research, Centre for Synthesis and Chemical Biology (CSCB), University College Dublin, Belfield,
Dublin 4, Ireland (e-mail: donal.f.oshea@ucd.ie or matthias.tacke@ucd.ie)
From the carbolithiation of 1-(cyclopenta-2,4-dien-1-ylidene)-N,N-dimethylmethanamine (¼6-
(dimethylamino)fulvene; 3) and different lithiated azaindoles 2 (1-methyl-7-azaindol-2-yl, 1-[(dieth-
ylamino)methyl]-7-azaindol-2-yl, and 1-(methoxymethyl)-7-azaindol-2-yl), the corresponding lithium
cyclopentadienide intermediates 4a – 4c were formed (7-azaindole ¼ 1H-pyrrolo[2,3-b]pyridine). The
latter underwent a transmetallation reaction with TiCl4 resulting in the (dimethylamino)-functionalised
ꢀtitanocenesꢁ 5a – 5c. When the ꢀtitanocenesꢁ 5a – 5c were tested against LLC-PK cells, the IC50 values
obtained were of 8.8, 12, and 87 mm, respectively. The most cytotoxic ꢀtitanoceneꢁ, 5a, with an IC50 value
of 8.8 mm is nearly as cytotoxic as cis-platin, which showed an IC50 value of 3.3 mm when tested on the
epithelial pig kidney LLC-PK cell line, and ca. 200 times better than ꢀtitanocene dichlorideꢁ itself.
Introduction. – Titanium-based reagents have significant potential activity against
solid tumors. Budotitane (¼cis-diethoxybis(1-phenylbutane-1,3-dionato)titani-
um(IV)) looked very promising during its preclinical evaluation but did not go beyond
phase-I clinical trials, although a Cremophor ELꢂ based formulation was found for this
rapidly hydrolyzing molecule [1]. Much more robust in this aspect of hydrolysis is
ꢀtitanocene dichlorideꢁ ([TiCl2Cp2]), which shows medium antiproliferative activity in
vitro but promising results in vivo [2][3]. ꢀTitanocene dichlorideꢁ reached clinical trials,
but the efficacy of [TiCl2Cp2] in phase-II clinical trials in patients with metastatic renal
cell carcinoma [4] or metastatic breast cancer [5] was too low to be pursued.
More recently, novel methods starting from fulvenes [6 – 17] and other precursors
[18 – 20] allow direct access to highly substituted ꢀtitanocenesꢁ via reductive dimerisa-
tion, carbolithiation, or hydridolithiation of the fulvene followed by transmetallation in
the last two cases.
Titanocene
Y
(¼dichloridobis{(1,2,3,4,5-h)-1-[(4-methoxyphenyl)methyl]cyclo-
penta-2,4-dien-1-yl}titanium), which has an IC50 value of 21 mm when tested on the
LLC-PK cell line, was synthesised through hydridolithiation of 6-(p-anisyl)fulvene and
Superhydride (Li[BEt3H]) followed by transmetallation with TiCl4 [12]. The anti-
proliferative activity of titanocene Y has been studied in 36 human tumor cell lines [21]
and in explanted human tumors [22]. These in vitro and ex vivo experiments showed
that prostate, cervix, and renal cell cancer are prime targets for these novel classes of
ꢀtitanocenesꢁ, whereas the IC50 values for the breast-cancer cell lines were very
ꢃ 2008 Verlag Helvetica Chimica Acta AG, Zürich

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promising as well. These results were underlined by first mechanistic studies concerning
the effect of these ꢀtitanocenesꢁ on apoptosis and the apoptotic pathway in prostate-
cancer cells [23]. Furthermore, first animal studies have been published recently
reporting the successful treatment of xenografted Ehrlichꢁs ascites tumor in mice with
an ansa-titanocene [24] and xenografted Caki-1 [25], A431 [26], and MCF-7 [27]
tumors with titanocene Y. The effect of titanocene Yagainst xenograft Caki-1 tumors in
mice was shown to be superior to cis-platin and in the MCF-7 experiment, the tumors
could even be shrunk by titanocene Y.
In an alternative synthesis, by means of the carbolithiation of 6-(dimethylamino)-
fulvene (¼1-(cyclopenta-2,4-dien-1-ylidene)-N,N-dimethylmethanamine; 3) with lithi-
ated heterocycles, titanocene C [28] and titanocene M [29] (Fig. 1), and others [30 – 34]
were obtained and showed IC50 values as low as 5.4 mm when tested on the LLC-PK cell
line. This was a significant progress, since [TiCl2Cp2] exhibits an IC50 value of only
2000 mm against LLC-PK [8], which explains partly the failed phase-II clinical trials
against renal cell carcinoma.
Fig. 1. Structures and IC50 values of titanocenes Y, C, and M
The main idea behind the research presented in this work was to evaluate the
cytotoxic effects of (dimethylamino)-functionalised and azaindolyl-substituted titano-
cenes with respect to the corresponding free 7-azaindole (¼1H-pyrrolo[2,3-b]pyridine)
species, as well as ꢀtitanocene dichlorideꢁ and other previously synthesised ꢀtitanocenesꢁ
within our group, such as titanocene C. It is believed that suitable modification of the
cyclopentadienyl rings may help to overcome problems associated with the stability of
ꢀtitanoceneꢁ compounds under biological conditions, as kinetic and mechanistic studies
of the hydrolysis and uptake of ꢀtitanocene dichlorideꢁ and its derivatives under
physiological conditions give evidence towards the rapid hydrolysis of the chlorido
ligands and less rapid hydrolysis of the cyclopentadienyl rings at physiological pH [35].
The 7-azaindoles are the most widely studied one-N-atom analogue of the indole
ring system, with the replacement of the indole C(7) by an sp2-hybridised N-atom
providing a construct containing a H-bond donor and acceptor in a rigid 3-atom
arrangement. In recent years, numerous potential pharmaceutical applications have
been investigated for this class of heterocyclic compounds including as antitumor

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agents. As azaindoles have been shown to have high biological activity [36][37], it is
hoped that their incorporation into the ꢀtitanoceneꢁ will synergistically enhance the
activity of the drugs.
Furthermore, the (dimethylamino)-functionalisation of the ꢀtitanocenesꢁ is believed
to be related to the cytotoxicity of this class of ꢀtitanocenesꢁ. It is possible that once
these ꢀtitanocenesꢁ have passed the cell membrane, a mono-or dication is formed by
hydrolysis of one or two of the Cl-ligands. At this point, the coordination of the extra
Me2N donor groups to the Ti centre could stabilise these cationic intermediates and
finally increase the number of ꢀtitanoceneꢁ – DNA interactions leading to cell death at a
lower concentration. Within this article, we present a new series of 7-azaindol-2-yl-
substituted and (dimethylamino)-functionalised ꢀtitanocenesꢁ, their syntheses, and
preliminary cytotoxicity studies.
Results and Discussion. – Synthesis of ꢀTitanocenesꢁ 5a – 5c (Scheme 1). The
required 6-(dimethylamino)fulvene (3) was synthesised according to the already
published procedure in 82% yield [38]. The syntheses of azaindoles 1a and 1c were
achieved by the N-alkylation with the corresponding alkyl halide [39], and azaindole 1b
was synthesised by a Mannich reaction with HCHO and Et2NH [40].
Scheme 1. Synthesis of ꢀTitanocenesꢁ 5a – 5c
The use of ArLi in the synthesis of other metallocenes is well known [41 – 45], and it
has recently been used for the syntheses of achiral ꢀtitanocene dichloridesꢁ [13][14].
This time, the carbolithiation method led to the synthesis of a new group of
ꢀtitanocenesꢁ that contain stereogenic centres, i.e., to 5a – 5c. The first step of this one-
pot procedure consisted in the formation of the functionalised lithium intermediates

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t
2a – 2c by treating the corresponding heterocycles 1a – 1c with BuLi (Scheme 1). Side
reactions were avoided by cooling the mixtures down to À 788 during the addition of
tBuLi and subsequent warming to 08. This step was followed by a nucleophilic addition
of the lithiated intermediate to the C¼C bond of 3 at À 788 and subsequent warming to
08, resulting in the formation of the appropriately substituted lithium cyclopentadienyl
intermediates 4a – 4c after 40 min at 08. This reaction occurred with no stereoselectivity,
and the intermediates 4a – 4c already contain a stereogenic centre. The next step was a
transmetallation reaction of 4a – 4c (2 mol-equiv.) with TiCl4 under reflux over 20 h in
THF to give ꢀtitanocenesꢁ 5a – 5c as shiny dark solids.
All three ꢀtitanocenesꢁ 5a – 5c were mixtures of different isomers (cf. Fig. 2). Hence,
three different signals should be seen for every H-and C-atom in the 1H-and 13C-NMR
spectra. The (R,R) and (S,S) isomers are enantiomers and thus give identical NMR
spectra, whereas for the H-or C-atoms of the ( R,S) (¼(S,R)) isomer, two signals are
observed, as the environment of the two cyclopentadienyl moieties is different. A ratio
of 2 :1:1 for the signals of the (S,S) and (R,R) isomer to the two signals of the (S,R)
(¼ R,S)) isomers is observed in the integration pattern.
Fig. 2. Expected isomers for ꢀtitanoceneꢁ 5a (note that in this case (R,S) ¼ (S,R))
MTT-Based Assay (MTT¼ 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazo-
lium Bromide). Preliminary in vitro cell tests were performed on LLC-PK cells to
compare the cytotoxicity of the compounds presented in this work. This cell line was
chosen based on their long-lasting growth behaviour, similar to the one shown in
carcinoma cells. It was obtained from the ATCC (American Tissue Cell Culture
Collection) and maintained in Dulbeccoꢁs modified eagle medium containing 10% (v/v)
FCS (foetal calf serum), 1% (v/v) penicillin streptomycin, and 1% (v/v) l-glutamine.
The cytotoxic activities of azaindoles 1a – 1c and ꢀtitanocenesꢁ 5a – 5c were determined
by an MTT-based assay [45].
Specifically, cells were seeded in 96-well plates containing 200 ml microtitre wells at a density of 5000
cells/200 ml of medium, and were incubated at 378 for 24 h to allow for exponential growth. Then, the

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compounds used for the testing were dissolved in the minimal amount of dimethyl sulfoxide (DMSO)
possible and diluted with medium to obtain stock solutions of 5 · 10À4 m in concentration and less than
0.7% of DMSO. The cells were then treated with varying concentrations of the compounds and incubated
for 48 h at 378. Then, the solutions were removed from the wells, and the cells were washed with PBS
(phosphate buffer solution), and fresh medium was added to the wells. Following a recovery period of
24 h incubation at 378, individual wells were treated with a 200 ml of a solution of MTT in medium
(solution of 30 mg of MTT in 30 ml of medium). The cells were incubated for 3 h at 378. The medium was
then removed, and the purple formazan crystals were dissolved in 200 ml of DMSO per well. Absorbance
was then measured at 540 nm by a Wallac-Victor (Multilabel HTS Counter) plate reader. Cell viability
was expressed as a percentage of the absorbance recorded for control wells. The values used for the dose
response curves of Figs. 3 and 4 represent the values obtained from four consistent MTT-based assays for
each compound tested.
As seen in Fig. 3, azaindoles 1a and 1c show negligible cytotoxic behaviour, and
only at their highest concentrations, while compound 1b shows significant cell death
with an IC50 value of 22 mm. Fig. 4 depicts a clear increase in cytotoxicity for the
corresponding ꢀtitanocenesꢁ 5a – 5c with IC50 values of 8.8 mm, 12 mm, and 87 mm,
respectively. What is more, when compared to unsubstituted ꢀtitanocene dichlorideꢁ,
ꢀtitanoceneꢁ 5a has a 200-fold decrease in magnitude in terms of the IC50 value, and is
similar to both cis-platin (IC50 ¼ 3.3 mm) [8] and titanocene C [28]. Additionally,
ꢀtitanoceneꢁ 5a shows a nine-fold increase in cytotoxicity with respect to its indolyl-
substituted counterpart (an analogue of titanocene C), with an IC50 value of 71 mm
[30]. As aforementioned, the possible intramolecular stabilisation of the mono-or
dication of such titanocenes, illustrated in Scheme 2, is believed to play a role in the
cytotoxicity of these compounds.
Fig. 3. Cytotoxicity studies of azaindoles 1a – 1c against LLC-PK cells

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Fig. 4. Cytotoxicity studies of ꢀtitanocenesꢁ 5a – 5c against LLC-PK cells
Scheme 2. Proposed Intramolecular Stabilisation of the Mono- or Dications of (Dimethylamino)-
Functionalised ꢀTitanocenesꢁ
Structural DFT Discussion. Despite our efforts to crystallise the three ꢀtitanocenesꢁ
5a – 5c, no suitable crystals were obtained. This might be explained by the existence of
different isomers in the racemic mixture. To overcome this problem, density-functional-
theory (DFT) calculations were carried out for ꢀtitanoceneꢁ 5a at the B3LYP level with
the 6-31G** basis set [46]1). Selected bond lengths of the optimised structure of 5a are
listed in the Table (for atom numbering, see Fig. 5). The calculated structure of (S,S)-
ꢀtitanoceneꢁ 5a is presented in Fig. 6.
The length of the bond between the metal centre and the cyclopentadienyl C(1) or
C(1’) atom of the two Cp rings of 5a is 250.1 and 247.0 pm, respectively, whereas the
CÀC bonds of the two cyclopentadienyl rings show bond lengths between 140.1 and
1
)
Supplementary information (coordinates and energy) is available upon request from M. T.

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Table. Selected Bond Lengths [pm] from the DFT-Calculated Structure of 5a and X-Ray Crystal
Structure of 6
DFT Structure X-Ray structure
DFT Structure X-Ray structure
of 5a
of 6
of 5a
of 6
TiÀC(1)
TiÀC(2)
TiÀC(3)
TiÀC(4)
TiÀC(5)
TiÀC(1’)
TiÀC(2’)
TiÀC(3’)
TiÀC(4’)
TiÀC(5’)
C(1)ÀC(2)
250.1
242.5
239.9
238.1
244.3
247.0
239.8
234.6
244.5
249.1
143.3
252.8
243.1
232.6
234.2
243.6
249.3
239.3
232.7
239.4
244.6
C(1’)ÀC(2’) 141.6
C(2’)ÀC(3’) 142.2
C(3’)ÀC(4’) 142.2
C(4’)ÀC(5’) 140.1
C(5’)ÀC(1’) 143.0
C(1)ÀC(6)
152.4
C(1’)ÀC(6’) 152.0
C(6)ÀC(6’)
C(6)ÀC(7)
560.0
152.4
C(6’)ÀC(7’) 152.0
C(6)ÀN(1)
C(6’)ÀN(2)
TiÀCl(1)
147.7
148.2
236.5
234.4
149.8
149.6
235.7
237.2
C(2)ÀC(3) 141.3
C(3)ÀC(4) 141.5
C(4)ÀC(5) 142.0
C(5)ÀC(6) 141.4
TiÀCl(2)
Fig. 5. Atom numbering of 5a and 6 for the structural DFT discussion of 5a
143.3 pm. The bond lengths between the two N-substituted C-atoms C(6) and C(6’) and
the C-atoms of the Cp groups are very similar, i.e., 152.4 and 152.0 pm, respectively. As
well, the lengths of the bonds between the two N-substituted C-atoms and the N-atoms
of the Me2N groups are similar, i.e., 147.7 and 148.2 pm. The steric hindrance of the Ar
and Me2N groups attached to these N-substituted C-atoms causes a lengthening of the
bond, to relieve the resultant steric strain.
The ClÀTiÀCl angle is calculated to be 95.78. The angles formed between C(1) or
C(1’), the corresponding N-substituted C(6) or C(6’), and C(7) or C(7’) are almost
identical, measuring 114.48 and 114.58, respectively. The angles formed between the N-
atom of the two Me2N groups, C(6) or C(6’), and C(1) or C(1’) measure 110.88 and
108.78, respectively.
The DFT-calculated structure of 5a was then compared to the X-ray structure of a
TiIV complex found in the literature, [TiCl2(Me2NCMe2ÀC5H4)2] (6) [47] (see Fig. 5
and Table). In this complex, the length of the bond between the Ti-centre and the two
Cl-atoms differ by only ca. 1 pm from the one found for 5a (see Table). The same
applies to the bond length between N(1) or N(2) and C(6) or C(6’), respectively, and to

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Fig. 6. DFT-Calculated structure of the (S,S) isomer of 5a
the bond length between the Cp C-atom and the Ti-centre. The ClÀTiÀCl angle of 6
(94.98) is very similar to the one calculated for 5a (95.78), and so is the angle formed
between the Ti-centre and the centre of the Cp rings (with a difference of 0.68).
Conclusions and Outlook. – The carbolithiation of 6-(dimethylamino)fulvene (3)
with the lithiated 7-azaindol-2-yl species 2 followed by transmetallation offers a general
synthesis of the new chiral 7-azaindol-2-yl-substituted and (dimethylamino)-function-
alised ꢀmetallocenesꢁ 5. The most promising compound 5a exhibits one of the so far
highest cytotoxicity of a ꢀtitanoceneꢁ against LLC-PK, indicating its potential as an
anticancer drug. We aim at employing the carbolithiation of 6-(dimethylamino)fulvene
(3) for future syntheses of ꢀtitanocenesꢁ with even improved cytotoxicities enabling
chemotherapy against renal cell cancer (RCC) in the nearby future.
The authors thank the Higher Education Authority (HEA), the Centre for Synthesis and Chemical
Biology (CSCB), University College Dublin (UCD), and COST D39 for funding.
Experimental Part
t
General. TiCl4 (1.0m in toluene) and BuLi (1.7m in pentane) were obtained commercially from
Aldrich Chemical Co. THF was dried over Na and benzophenone, and freshly distilled and collected
under Ar prior to use. Manipulations of air-and moistures-ensitive compounds were done by using
standard Schlenk techniques under Ar. CC ¼ Column chromatography. UV/VIS Spectra: Unicam UV4
spectrometer; lmax in nm (e in dm3 molÀ1 cmÀ1), in CH2Cl2. IR Spectra: Perkin-Elmer Paragon-1000 FT-
IR spectrometer; in KBr disk, ˜n in cmÀ1. 1H-and 13C-NMR Spectra: Varian 300 or 400 spectrometer; d in
ppm rel. to Me4Si as internal standard, J in Hz. MS: quadrupole tandem mass spectrometer (Quattro
Micro, Micromass/Waterꢁs Corp., USA); solns. in CH2Cl2/MeOH 1:1; in m/z. Elemental analyses: anal.
Exeter-CE-440 elemental analyser for C, H, and N.

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1-Methyl-1H-pyrrolo[2,3-b]pyridine (1a). mixture of 1H-pyrrolo[2,3-b]pyridine (1.70 g,
A
14.4 mmol), NaH (691 mg, 17.2 mmol; 60% in oil), and DMF (30 ml) was stirred under N2 at 08 for
30 min, until the evolution of H2 was complete. MeI (2.00 g, 14.4 mmol) was added dropwise over 10 min,
and the mixture was allowed come to r.t. over 3 h. The solvent was evaporated and the residue purified by
1
CC (silica gel, pentane/Et2O 4 :1): 1a (1.46 g, 77%). Yellow oil. H-NMR (400 MHz, CDCl3): 3.89 (s,
3 H); 6.44 (d, J ¼ 3.3, 1 H); 7.04 (dd, J ¼ 7.8, 4.8, 1 H); 7.18 (d, J ¼ 3.3, 1 H); 7.89 (dd, J ¼ 7.8, 1.5, 1 H); 8.34
(dd, J ¼ 4.8, 1.5, 1 H). 13C-NMR (75 MHz, CDCl3): 31.5; 99.5; 115.9; 120.7; 128.9; 129.2; 143.0; 148.0. ES-
MS: 133.0 ([M þ H]þ). HR-MS (neg.): 131.0610 ([M À H]À, C8H7NÀ2 ; calc. 131.0609).
1-[(Diethylamino)methyl]-1H-pyrrolo[2,3-b]pyridine (1b). To a suspension of 1H-pyrrolo[2,3-
b]pyridine (2.00 g, 16.9 mmol) in H2O (5 ml), HCHO (1.2 ml, 4.23 mmol; 37% aq. soln.) and Et2NH
(0.30 g, 4.23 mmol; 20% (w/w) aq. soln.) were simultaneously added over 30 min at 08. The mixture was
stirred for 3 h at 08 and warmed to r.t. over 18 h, during which time an oil precipitated. The crude was
extracted with Et2O (50 ml), and the Et2O layer was re-extracted with 2m aq. HCl (3 ꢀ 20 ml). The aq.
extract was immediately made alkaline with 40% NaOH soln. (40 ml) and extracted with Et2O (3 ꢀ
20 ml), the org. phase dried (Na2SO4), the solvent evaporated, and the crude purified by CC (alumina,
pentane/Et2O 3 :1): 1b (2.0 g, 60%). Yellow oil. 1H-NMR (300 MHz, CDCl3): 0.93 (t, 6 H); 2.43 (q, 4 H);
5.0 (s, 2 H); 6.26 (d, J ¼ 3.3, 1 H); 6.82 (dd, J ¼ 7.8, 4.8, 1 H); 7.11 (d, J ¼ 3.3, 1 H); 7.67 (dd, J ¼ 7.8, 1.6,
1 H); 8.15 (dd, J ¼ 4.8, 1.6, 1 H). 13C-NMR (75 MHz, CDCl3): 11.6; 44.3; 45.6; 60.2; 98.6; 114.6; 119.2;
127.4; 141.7; 147.4. ES-MS: 204.1 ([M þ H]þ). HR-MS: 204.1507 ([M þ H]þ, C12H18Nþ3 ; calc. 204.1501).
1-(Methoxymethyl)-1H-pyrrolo[2,3-b]pyridine (1c). As described for 1a, with 1H-pyrrolo[2,3-
b]pyridine (2.00 g, 16.9 mmol), NaH (813 mg, 20.3 mmol; 60% in oil), DMF (40 ml), and MeOCH2Cl
(1.36 g, 16.9 mmol). The solvent was evaporated and the residue extracted with Et2O (3 ꢀ 20 ml). The
extract was washed with H2O (20 ml) and evaporated, and the residue purified by CC (alumina, pentane/
Et2O 1:2): 1c (2.19 g, 80%). Yellow oil. 1H-NMR (300 MHz, CDCl3): 3.25 (s, 3 H); 5.59 (s, 2 H); 6.46 (d,
J ¼ 3.6, 1 H); 7.01 (dd, J ¼ 7.8, 4.8, 1 H); 7.26 (d, J ¼ 3.6); 7.84 (dd, J ¼ 7.8, 1.6, 1 H); 8.27 (dd, J ¼ 4.8, 1.6,
1 H). 13C-NMR (75 MHz, CDCl3): 56.2; 74.7; 101.1; 116.4; 120.6; 127.8; 128.8; 143.2; 148.1. ES-MS (neg.):
161.1 ([M À H]À). HR-MS: 163.0870 ([M þ H]þ, C9H11N2Oþ; calc. 163.0871).
Dichloridobis{(1,2,3,4,5-h)-1-[(dimethylamino)(1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]cy-
clopenta-2,4-dien-1-yl}titanium(IV) ([TiCl2{h5-C5H4ÀCH(NMe2)(C7H4N2ÀMe)}2]; 5a). To 1a (0.70 g,
5.3 mmol) in a Schlenk flask, THF (20 ml) was added until a transparent soln. was formed, while stirring
at r.t. The soln. was cooled down to À 788, and tBuLi (3.1 ml, 5.3 mmol) was added. The soln. was allowed
to warm to 08 for 20 min, resulting in the formation of the yellow lithium intermediate. In a second
Schlenk flask, 3 (0.64 g, 5.3 mmol) was dissolved in THF, and the resultant orange soln. was added via
cannula at À 788 to the Schlenk flask containing the lithiated intermediate. The mixture was then allowed
to warm to 08 and left stirring for 40 min. TiCl4 (2.6 ml, 2.6 mmol) was added in situ at r.t., and the mixture
was refluxed for 20 h. Subsequently, the solvent was evaporated, resulting in the formation of a black
solid that was dissolved in CH2Cl2. The soln. was filtered through Celite to remove LiCl, the black filtrate
filtered additionally twice by gravity filtration, the solvent removed, and the black solid washed with
pentane and then dried in vacuo: 5a (1.25 g, 75%). UV/VIS: 261 (97200), 369 (91808), 416 (71534), 483
(weak). IR: 3050, 2958, 2773, 1619, 1456, 1292, 1020, 800. 1H-NMR (300 MHz, CDCl3): 8.36 – 6.91 (m, 2
C7H4N2); 6.86 – 6.35 (m, 2 C5H4); 5.37, 5.35, 5.29 (3s, 2 Me2NCH); 3.95, 3.90 (2s, 2 C7H4N2ÀMe); 2.70,
2.87 (br. s, 2 Me2NCH). 13C-NMR (100 MHz, CDCl3): 99.5, 105.3, 115.7, 116.8, 120.5, 124.5, 126.6, 128.9,
132.0, 136.1, 142.9, 144.7, 151.3 (C5H4, C7H4N2); 64.7 (Me2NCH); 34.9, 35.0, 41.8 (Me2NCH); 28.6, 30.9,
31.5 (C7H4N2ÀMe). ES-MS: 623.5 ([M þ H]þ). Anal. calc. for C32H36Cl2N6Ti (623.44): C 61.64, H 5.82, Cl
11.37, N 13.48; found: C 61.88, H 6.17, Cl 11.33, N 12.99.
Dichloridobis{(1,2,3,4,5-h)-1-{{1-[(diethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-2-yl}(dimethyl-
amino)methyl}cyclopenta-2,4-dien-1-yl}titanium(IV) ([TiCl2{h5-C5H4ÀCH(NMe2)(C7H4N2ÀCH2ÀN-
(CH2Me)2}2]; 5b). As described for 5a, with 1b (0.48 g, 2.5 mmol), THF (15 ml), tBuLi (1.5 ml,
2.5 mmol), 3 (0.31 g, 2.5 mmol), and TiCl4 (1.3 ml, 1.3 mmol). The final dark brown solid was washed
with pentane and then dried in vacuo: 5b (0.54 g, 54.6%). UV/VIS: 222 (87344), 312 (97292), 396
1
(57698), 564 (weak). IR: 2971, 2819, 1752, 1602, 1457, 1278, 1062, 800. H-NMR (300 MHz, CDCl3):
8.25 – 7.20 (m, 2 C7H4N2); 6.40 – 7.10 (m, 2 C5H4); 5.70 (s, 2 Me2NCH); 3.20 (s, 2 (MeCH2)2NCH2); 3.10 –
2.95 (br. s, 2 Me2NCH); 1.55 – 1.40 (m, 2 (MeCH2)2NCH2). 13C-NMR (100 MHz, CDCl3): 99.2, 110.8,

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Helvetica Chimica Acta – Vol. 91 (2008)
112.9, 118.4, 121.1, 123.4, 124.1, 127.9, 131.6, 131.9, 140.9, 147.7, 161.9 (C5H4, C7H4N2); 60.0 (Me2NCH);
42.3 (MeCH2)2NCH2); 41.3 (Me2NCH); 10.3, 13.0, 27.1, 29.8 ((MeCH2)2NCH2). ES-MS: 765.6 ([M þ
H]þ). Anal. calc. for C40H54Cl2N8Ti (765.68): C 62.74, H 7.11, Cl 9.26, N 14.64; found: C 62.38, H 7.54,
Cl 9.16, N 14.45.
Dichloridobis{(1,2,3,4,5-h)-1-{(dimethylamino)[1-methoxymethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-
methyl}cyclopenta-2,4-dien-1-yl}titanium(IV) ([TiCl2{h5-C5H4ÀCH(NMe2)(C7H4N2ÀCH2OMe)}2]; 5c).
t
As described for 5a, with 1c (0.86 g, 5.3 mmol), THF (20 ml), BuLi (3.2 ml, 5.3 mmol), 3 (0.64 g,
5.3 mmol), and TiCl4 (2.6 ml, 2.6 mmol). The final dark brown solid was washed with pentane and then
dried in vacuo: 5c (0.82 g, 46.1%). UV/VIS: 294 (97278), 397 (92208), 417 (76104), 440 (weak). IR: 3050,
2937, 1619, 1459, 1429, 1305, 1270, 1114, 1066, 840. 1H-NMR (300 MHz, CDCl3): 6.95 – 8.34 (m, 2
C7H4N2); 6.40 – 6.90 (m, 2 C5H4); 5.65, 5.80 (2s, 2 MeOCH2); 5.40, 5.49, 5.51 (3s, 2 Me2NCH); 3.19, 3.23,
3.25 (3s, 2 MeOCH2); 2.76 – 2.79, 2.84 (br. s, 2 Me2NCH). 13C-NMR (100 MHz, CDCl3): 101.2, 106.5,
116.4, 120.2, 126.6, 127.9, 129.0, 131.8, 135.9, 143.1, 146.8 (C5H4, C7H4N2); 71.9, 72.1, 74.8 (MeOCH2);
63.2, 63.3 (Me2NCH); 56.1, 56.2, 56.3 (MeOCH2); 34.1, 41.6, 41.9 (Me2NCH). ES-MS: 684.2 ([M þ Hþ]).
Anal. calc. for C34H40Cl2N6O2Ti (683.49): C 59.74, H 5.90, Cl 10.37, N 12.30; found: C 59.38, H 5.92, Cl
9.16, N 12.45.
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Received March 5, 2008