Fluorinated derivatives of titanocene Y: Synthesis and cytotoxicity studies

Article abstract of DOI:10.1002/ejic.200800504

From the reaction of Super Hydride (LiBEt₃H) with 6-(2-fluoro-4-methoxyphenyl)fulvene (1a), 6-(4-trifluoromethoxyphenyl) fulvene (1b), and 6-(3-fluoro-4-methoxyphenyl)fulvene (1c) lithiated cyclopentadienide intermediates 2a-c were synthesised.

Full text of DOI:10.1002/ejic.200800504

FULL PAPER
DOI: 10.1002/ejic.200800504
Fluorinated Derivatives of Titanocene Y: Synthesis and Cytotoxicity Studies
James Claffey,[a] Brendan Gleeson,[a] Megan Hogan,[a] Helge Müller-Bunz,[a]
Denise Wallis,[a] and Matthias Tacke*[a]
Keywords: Anticancer drugs / Cisplatin / Titanocene / Hydridolithiation / Fulvenes / Fluorine / Cytotoxicity / LLC-PK
From the reaction of Super Hydride (LiBEt3H) with 6-(2-
(long-lasting cells–pig kidney) cell line in order to determine
fluoro-4-methoxyphenyl)fulvene (1a), 6-(4-trifluoromethoxy- the cytotoxicity of these compounds presented in this paper.
phenyl)fulvene (1b), and 6-(3-fluoro-4-methoxyphenyl)ful-
vene (1c) lithiated cyclopentadienide intermediates 2a–c
were synthesised. These intermediates were then trans-
metallated to titanium with TiCl4 to give the benzyl-substi-
The titanocenes 3a and 3b had their cytotoxicity inhibitory
concentration (IC50) values determined to be 6.0 and 7.3 µ
respectively. The cytotoxicity value of 3c could not be deter-
M,
mined accurately due to solubility problems of the compound
tuted titanocenes bis[(2-fluoro-4-methoxybenzyl)cyclopen- under standard test conditions. All three titanocene deriva-
tadienyl]titanium(IV) dichloride (3a), bis[(4-trifluoromethoxy-
benzyl)cyclopentadienyl]titanium(IV) dichloride (3b) and
tives show significant cytotoxicity improvement when com-
pared to unsubstituted titanocene dichloride, whereas titan-
bis[(3-fluoro-4-methoxybenzyl)cyclopentadienyl]titanium(IV) ocenes 3a and 3b show threefold cytotoxicity improvement
dichloride (3c). The three titanocenes 3a–c were character-
ised by single-crystal X-ray diffraction. Preliminary in vitro
cell tests were performed on the titanocenes on the LLC-PK
in comparison to previous class leader titanocene Y.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
ation or hydridolithiation of the fulvene followed by trans-
metallation with titanium tetrachloride in the latter two
cases.[7] Hydridolithiation of 6-anisylfulvene and subse-
quent reaction with TiCl4 led to bis[(p-methoxybenzyl)-
cyclopentadienyl]titanium(IV) dichloride (titanocene Y)
(Figure 1),[8] which has an IC50 value of 21 µ when tested
on the LLC-PK cell line. This particular cell line was chosen
as it has proven to be a good mimic of a kidney carcinoma
cell line and a reliable tool for the optimisation of titano-
cenes against this type of cancer.
In addition, the anti-proliferative activity of titanocene Y
and other titanocenes has been studied in 36 human tumor
cell lines[9] and against explanted human tumors.[10,11]
These in vitro and ex vivo experiments showed that renal
cell cancer is the prime target for this novel class of titano-
cenes, but there is significant activity against ovary, pros-
tate, cervix, lung, colon, and breast cancer as well. These
results were underlined by first mechanistic studies concern-
ing the effect of these titanocenes on apoptosis and the
apoptotic pathway in prostate cancer cells.[12] Furthermore,
it was shown, that titanocene derivatives give a positive im-
mune response by up-regulating the number of natural
killer (NK) cells in mice.[13] Recently, animal studies re-
ported the successful treatment of mice bearing xenografted
Caki-1 and MCF-7 tumors with titanocene Y.[14,15]
Introduction
Beyond the field of platinum anti-cancer drugs there is
significant unexplored space for further metal-based drugs
targeting cancer. Titanium-based reagents have significant
potential against solid tumors. Budotitane {[cis-diethoxy-
bis(1-phenylbutane-1,3-dionato)titanium(IV)]} (Figure 1)
looked very promising during its preclinical evaluation, but
did not go beyond Phase I clinical trials, although a Crem-
ophor EL® based formulation was found for this rapidly
hydrolysing molecule.[1] Much more robust in this aspect
of hydrolysis is titanocene dichloride (Cp2TiCl2) (Figure 1),
which shows medium anti-proliferative activity in vitro but
promising results in vivo.[2,3] Titanocene dichloride reached
clinical trials, but the efficacy of Cp2TiCl2 in Phase II clin-
ical trials in patients with metastatic renal cell carcinoma[4]
or metastatic breast cancer[5] was too low to be pursued.
The field gained renewed interest with McGowan’s ele-
gant synthesis of ring-substituted cationic titanocene di-
chloride derivatives, which are water-soluble and show sig-
nificant activity against ovarian cancer.[6] More recently,
novel methods starting from fulvenes and other precursors
allow direct access to antiproliferative titanocenes by re-
ductive dimerisation with titanium dichloride, carbolithi-
[a] Conway Institute of Biomolecular and Biomedical Research,
UCD School of Chemistry and Chemical Biology, Centre for
Synthesis and Chemical Biology (CSCB), University College
Dublin,
A simple anion-exchange reaction in thf employing silver
oxalate and the titanocene Y eliminates insoluble silver
chloride and produces oxali-titanocene Y (Figure 1).[16] De-
spite the addition of the oxalate bidentate ligand in replace-
Belfield, Dublin 4, Ireland
E-mail: matthias.tacke@ucd.ie
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Synthesis and Cytotoxicity of Fluorinated Titanocene Y Derivatives
Figure 1. Structures of budotitane, titanocene dichloride, titanocene Y and oxali-titanocene Y.
ment of the two chlorine atoms on the titanium centre there
is almost no apparent variance in the molecular structures.
Results and Discussion
Synthesis
When tested on LLC-PK cells, oxali-titanocene Y is 13-fold
more cytotoxic against LLC-PK as titanocene Y itself and
exhibits an IC50 value of 1.6 µ. Oxali-titanocene Y is twice
as cytotoxic as cisplatin, which has an IC50 value of 3.3 µ
on the LLC-PK cell line.[8]
The general synthetic method of the three fluorine-sub-
stituted titanocenes is shown in Scheme 1.
The syntheses of the three fulvenes 1a–c (Figure 2) were
all done by well-established analogous synthetic methods of
Stone and Little[19] by the condensation of freshly cracked
cyclopentadiene in the presence of a base in yields of 78–
86%. Pyrrolidine was used as the base to catalyse this reac-
tion.
The introduction of fluorine in medicinal compound
classes has been shown to lead to an enhancement of the
pharmaceutical properties in comparison to the parent
compound in many cases.[17,18] Fluorine is a small atom
with the highest electronegativity, and covalently bound fluo-
rine occupies a smaller volume than a methyl, amino, or
hydroxy group but is significantly larger than a hydrogen
atom. Fluorine introduction can lead to an increase in lipo-
philicity, an increase in resistance to metabolic decomposi-
tion and an increase in pharmacokinetic properties through
possible different intrinsic activity. All of these can contrib-
ute to a potential improvement in activity vs. the parent
compound.
Figure 2. Structures of fulvenes 1a–1c.
Within this paper we present the synthesis and prelimi-
The three lithium cyclopentadienide intermediates were
nary cytotoxicity studies of a series of three fluorinated de- synthesised by the nucleophilic addition of hydride to the
rivatives of titanocene Y. exocyclic double bond of the fulvenes, which then can be
Scheme 1. Synthesis of benzyl-substituted titanocenes from fulvenes by using the hydridolithiation reaction.
Figure 3. Structures of titanocenes 3a–3c.
Eur. J. Inorg. Chem. 2008, 4074–4082
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M. Tacke et al.
FULL PAPER
isolated in yields of 35–97%. These exocyclic double bonds
The length of the bond between the titanium centre and
in the fulvenes have increased polarity, due to the inductive the carbon atoms of the cyclopentadienyl rings bound to
effects of their respective phenyl groups. This increased po- the metal atom are very similar for 3a–c. They vary from
larity allows for selective nucleophilic attack at this double 2.34 Å to 2.43 Å for 3a, from 2.35 Å to 2.42 Å in the case of
bond and not at the diene component of the fulvenes.
3b and from 2.35 Å to 2.42 Å for 3c. The titanium–centroid
Two equivalents of this lithium cyclopentadienide inter- distances of the three titanocenes are also highly compar-
mediate can be transmetallated to one equivalent of TiCl4 able with 3a–c having titanium–centroid distances of
resulting in the formation of one equivalent of the required 2.06 Å. The centroid–titanium–centroid angle was mea-
benzyl-substituted titanocene 3a–c (Figure 3) in yields of sured to be 131.53° for 3a, 131.73° for 3b and 132.51° for
38–64% and two equivalents of the by-product of lithium 3c. The carbon–carbon bond lengths of the cyclopen-
chloride following a 16 h reflux.
tadienyl rings are once again very similar for all three titan-
ocenes; 3a has carbon–carbon bond lengths for the cyclo-
pentadienyl rings of 1.40–1.42 Å, whereas 3b has bond
lengths of 1.40–1.41 Å, and 3c has bond lengths of 1.40–
1.42 Å. The titanium–chlorine bond lengths are very similar
for 3a–c with them varying from 2.37 Å to 2.38 Å. The Cl–
Ti–ClЈ bond angle was measured at 93.73° for 3a, 93.93°
for 3b and 93.45° for 3c. The bond lengths and bond angles
are shown in Table 2.
Structural Discussion
The benzyl-substituted titanocenes are a class of titano-
cenes that are very promising for crystallisation experiments
due to not being contaminated by stereoisomers. Crystals
suitable for X-ray crystallography of 3a (Figure 4) were
grown by slow infusion of pentane into a saturated dichlo-
The packing in 3a and 3c features pronounced Z-shapes in
romethane solution, crystals of 3b (Figure 5) were grown the molecules. Despite the introduction of the fluorine atom
from a saturated trichloromethane solution, and 3c (Fig- into the phenyl ring, there is almost no difference in the mo-
ure 6) formed crystals from a saturated dichloromethane lecular structures of 3a and 3c in comparison to titanocene Y
solution.
with only minimal structural change having occurred.
Figure 4. X-ray diffraction structure of bis[(2-fluoro-4-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride (3a); thermal ellipsoids
are drawn at the 50% probability level.
Figure 5. X-ray diffraction structure of bis{[4-(trifluoromethoxy)benzyl]cyclopentadienyl}titanium(IV) dichloride (3b); thermal ellipsoids
are drawn at the 50% probability level.
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Synthesis and Cytotoxicity of Fluorinated Titanocene Y Derivatives
Figure 6. X-ray diffraction structure of bis[(3-fluoro-4-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride (3c); thermal ellipsoids
are drawn at the 50% probability level.
Figure 7. X-ray diffraction structure of two molecules of bis{[4-(trifluoromethoxy)benzyl]cyclopentadienyl}titanium(IV) dichloride (3c)
connected by π–π interaction; thermal ellipsoids are drawn at the 50% probability level.
The molecule of 3b has a conformation, which as of yet is centre and the next carbon atom of the other ring are
unique among the benzyl-substituted titanocenes. The two 3.46 Å and 3.51 Å. In the literature, a distance of 3.41 Å
substituted cyclopentadienyl ligands are orientated at an has been reported for π–π interaction in titanium 4-acyl-5-
angle of 90° to each other, leading to an angular shape (Fig- pyrazolonates[20] between the pyrazolonato and the phenyl
ure 7). This, however, does not affect the packing efficiency. moiety, which compares very favourably to our observed π–
The volume per non-hydrogen atom is 16.1 Å3 of 3b, which π interaction. The titanocenes 3a and 3c feature distances
is somewhat smaller than is found in titanocene Y, the value between the two adjacent phenyl rings that are larger than
of which is 18.1 Å3.[8]
4.2 Å. As the rings are oriented in a head-to-tail manner,
It might be expected that the strongly electron-with- one might think that the π–π interaction is enhanced by a
drawing trifluoromethoxy group would induce an electric dipole–dipole interaction. On closer inspection, this seems
dipole moment within the phenyl ring, especially consider- unlikely to be the case. The positive end of each ring is
ing the electron-donating methylenecyclopentadienyl group situated above the centre of the other ring and is thus as
in para position. The electron-depleted carbon atom in the close to the negative end as to the positive one of the phenyl
trifluoromethoxy group might also attract one of the nega- ring.
tively polarised atoms, e.g. a fluorine atom. This is clearly
The unit cell has a monoclinic pseudosymmetry. It can
not the case. Instead, the fluorine atoms come quite close be transformed into a C-centred lattice with the lattice pa-
to each other. The shortest intermolecular fluorine–fluorine rameters: a = 38.645, b = 6.532, c = 22.824 Å, α = 89.30°,
distance is 2.96 Å between F2 and F6, which shows a β = 124.17°, γ = 90.80°, space group C2/c (#15). Most crys-
van der Waals interaction. In fact, they come so close that tals of 3b are twinned according to this pseudosymmetry.
they cause repulsion strong enough that the oxygen atom is As the lattice parameters of twinned crystals of 3b refine to
pushed out of the phenyl ring plane (see Figures 6 and 8). the ideal monoclinic unit cell (i.e. α = γ = 90°), all the bond
There is some π–π interaction between the two adjacent lengths and angles result distorted, even though the refine-
phenyl rings (see Figure 8). The distances between the ring ment is good. Interestingly, even with this nontwinned spec-
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M. Tacke et al.
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imen a refinement in C2/c leads to a reasonable model, al- chloride (IC50 value of 2000 µ), the newly synthesised tit-
beit without entirely satisfactory R values (wR2 = 0.35; R1 anocenes 3a and 3b show a larger than 280-fold decrease in
= 0.14). All relevant bond lengths and bond angles can be magnitude in terms of the IC50 value. These titanocenes 3a
found in Table 1.
and 3b, which incorporate fluorine in the phenyl ring, show
a threefold decrease in cytotoxicity with respect to the for-
mer class leader titanocene Y with an IC50 value of 21 µ
on the LLC-PK cell line. They have a twofold higher cyto-
toxicity in comparison to cisplatin with an IC50 value of
3.3 µ on the LLC-PK cell line. The improved cytotoxicities
of these benzyl-substituted titanocenes may be due to the
increased lipophilicity induced in comparison to titano-
cene Y through the incorporation of fluorine into these
compounds. Also the existing dipole moment of titano-
cene Y becomes larger due to the incorporation of fluorine
into the phenyl ring or the methoxy group itself; 3c is not
as successful in terms of cytotoxicity, in comparison to 3a
and 3b, probably due to the loss of solubility of this titano-
cene through the incorporation of fluorine in the 3-position
of the phenyl ring.
The fluorinated titanocenes 3a and 3b because of their
promising IC50 values, obtained from cell tests performed
on the LLC-PK cell line, were treated with silver oxalate to
produce bis[(2-fluoro-4-methoxybenzyl)cyclopentadienyl]ti-
tanium(IV) oxalate and bis[(4-trifluoromethoxybenzyl)cy-
clopentadienyl]titanium(IV) oxalate, respectively. It was
hoped that a similar 13-fold increase in cytotoxicity, which
was seen with titanocene Y in going to oxali-titanocene Y,
would be also seen with the fluorinated derivatives of titan-
ocene Y. This was not achieved as the IC50 values for these
anion-exchanged titanocenes were found to be larger than
100 µ due to a dramatic loss in solubility. These com-
pounds could not be fully characterized spectroscopically
due to a lack of solubility even in common deuterated sol-
vents.
Table 1. Selected bond lengths and angles from crystallographic
structures of titanocenes 3a–c.
3a
3b
3c
Bond lengths
Ti–C(1)
Ti–C(2)
Ti–C(3)
Ti–C(4)
2.4102(15)
2.3399(16)
2.3536(16)
2.3862(15)
2.4281(14)
1.404(2)
1.405(2)
1.420(3)
1.398(2)
1.419(2)
1.495(2)
1.515(2)
2.3652(4)
2.3652(4)
2.061(2)
2.422(3)
2.393(3)
2.348(3)
2.352(3)
2.408(3)
1.413(4)
1.402(4)
1.414(4)
1.396(4)
1.412(4)
1.492(4)
1.522(4)
2.3816(8)
2.3396(8)
2.062(1)
2.065(1)
2.415(2)
2.393(3)
2.352(2)
2.350(2)
2.395(3)
1.416(4)
1.393(4)
1.413(4)
1.399(4)
1.404(4)
1.499(3)
1.514(4)
2.3679(7)
2.3523(8)
2.059(3)
2.058(2)
Ti–C(5)
C(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(5)–C(1)
C(1)–C(6)
C(6)–C(7)
Ti–Cl(1)
Ti–Cl(2)
Ti–Cent(1)
Ti–Cent(2)
2.061(2)
Bond angles
Cent(1)–Ti–Cl(1)
Cent(1)–Ti–Cl(2)
Cent(1)–Ti–Cent(2) 131.53(1)
Cl(1)–Ti–Cl(2) 93.73(2)
105.88(1)
106.71(1)
105.49(3)
105.99(2)
131.73(2)
93.93(3)
106.24(2)
105.62(2)
132.51(2)
93.45(3)
Cytotoxicity Studies
The values used for the dose response curves of Figure 8
represent the values obtained from four consistent MTT-
based assays for each compound tested.
Conclusions
The hydridolithiation of aryl-substituted fulvenes has
been found to be a very effective and reproducible way to
medium to highly cytotoxic benzyl-substituted titanocenes
of high purity. Following these investigative studies into the
synthesis and cytotoxicity of these fluorinated benzyl-sub-
stituted titanocenes, we have been able to establish that flu-
orinated titanocene Y derivatives have further cytotoxic po-
tential to be achieved through the incorporation of fluorine
in the correct positions of the phenyl ring. However, the
incorporation of a chelating oxalate anion instead of the
two chloride anions does not lead to an enhancement of
cytotoxicity as was seen with titanocene Y, as there is a sig-
nificant loss of solubility within this series. The optimum
positioning of fluorine on the phenyl ring can lead to a
threefold decrease in cytotoxicity in comparison to titano-
Figure 8. Cytotoxicity curves from typical MTT assays showing the
effect of compounds 3a and 3b on the viability of LLC-PK cells.
As seen in Figure 8, the titanocenes 3a and 3b showed cene Y, but these fluorinated derivatives of titanocene Y do
IC50 values of 6.0 and 7.3 µ, respectively. The cytotoxicity not appear to be candidates for anion exchange. Neverthe-
value of titanocene 3c could not be determined accurately less, with 3a and 3b there are now two nonchiral titano-
due to solubility problems of the compound under the stan- cene Y derivatives, which exhibit a cytotoxicity almost
dard test conditions but had an IC50 value larger than equal to cisplatin and are simple to prepare, available for
100 µ. When compared to unsubstituted titanocene di- future evaluation against renal-cell cancer.
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Synthesis and Cytotoxicity of Fluorinated Titanocene Y Derivatives
by column chromatography with dichloromethane as the eluent.
The dichloromethane was removed at reduced pressure to yield
2.24 g of a red oil (80.2% yield, 11.0 mmol). 1H NMR (CDCl3,
400 MHz): δ = 3.84 (s, 3 H, C6H3F-OCH3), 6.32 (m, 1 H, C5H4),
Experimental Section
General Conditions: Titanium tetrachloride (1.0  solution in tolu-
ene), Super Hydride (LiBEt3H, 1.0  solution in thf), dicyclopenta-
diene, 2-fluoro-4-methoxybenzaldehyde and 3-fluoro-4-methoxy-
benzaldehyde were obtained from Aldrich Chemical Company. 4-
(Trifluoromethoxy)benzaldehyde was obtained from FluoroChem
and was used without further purification. Diethyl ether and thf
were dried with sodium and benzophenone, and they were freshly
distilled and collected under nitrogen prior to use. Pentane was
dried with sodium, benzophenone and bis(ethleneglycol)ethyl ether,
and it was freshly distilled and collected under nitrogen prior to
use. Manipulations of air- and moisture-sensitive compounds were
carried out under nitrogen by using standard Schlenk techniques.
NMR spectra were measured with either a Varian 300, 400 or
500 MHz spectrometer. Chemical shifts are reported in ppm and
are referenced to TMS. IR spectra were recorded with a Perkin–
Elmer Paragon 1000 FT-IR Spectrometer by employing a KBr disk
or a liquid IR cell. UV/Vis spectra were recorded with a Unicam
UV4 Spectrometer. C,H,N analysis was carried out with an Exeter
Analytical CE-440 Elemental Analyser, whereas Cl was determined
by mercurimetric titrations, and F was determined by using an
Orion Fluoride Electrode following combustion in O2. Suitable
crystals of 3a were grown by slow infusion of pentane into a satu-
rated dichloromethane solution, crystals of 3b were grown by slow
concentration of a saturated trichloromethane solution, and 3c
formed crystals from of a saturated dichloromethane solution. X-
ray diffraction data for the compounds 3a, 3b and 3c were collected
with a Bruker SMART APEX CCD area detector diffractometer.
A full sphere of reciprocal space was scanned by φ-ω scans. Pseudo-
empirical absorption correction based on redundant reflections was
performed by the program SADABS.[21] The structures were solved
by direct methods using SHELXS-97[22] and refined by full-matrix
least squares on F2 for all data using SHELXL-97.[22] In 3a all
hydrogen atoms were located in the difference fourier map and al-
lowed to refine freely. In 3b and 3c hydrogen atoms were added at
calculated positions and refined by using a riding model. Their
isotropic temperature factors were fixed to 1.2 times (1.5 times for
methyl groups) the equivalent isotropic displacement parameters of
their parent atoms. Anisotropic thermal displacement parameters
were used for all non-hydrogen atoms. Further details about the
data collection are listed in Table 2, as well as reliability factors.
CCDC-688693, -688695 and -688694 for 3a, 3b and 3c, respectively,
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_requ-
est/cif.
3
4
6.44 (m, 1 H, C5H4), 6.64 (dd, JH3-F = 11.3, JH3-H5 = 2.0 Hz, 1
3
H, C6H3F-OCH3), 6.65 (m, 2 H, C5H4), 6.77 (dd, JH5-H6 = 11.4,
4JH5-H3 =2.4 Hz, 1 H, C6H3F-OCH3),7.30 (s, 1 H, C5H4-CH), 7.64 (t,
JH6-F = 8.4 Hz, 1 H, C6H3F-OCH3) ppm. 13C NMR (CDCl3,
100 MHz, proton-decoupled): δ = 54.7, 101.0 (d, J2CF = 26 Hz),
109.6, 110.2, 117.0 (d, J2CF = 13 Hz), 118.9, 126.1, 128.7, 129.4 (d,
J3CF = 5 Hz), 131.6, 134.3, 160.2, 161.8 (d, J1CF = 252 Hz) ppm.
19F NMR (CDCl3, 282 MHz): δ = –112.65 (t, J = 10.3 Hz, 1 F,
C H F-OCH ) ppm. IR (CH Cl ): ν = 3059, 1705, 1410, 1281,
˜
6
3
3
2
2
1262, 1244, 889, 745, 727, 704 cm–1. UV/Vis (CH2Cl2): λ (ε) = 250
(6300), 296 (6400), 332 (6800), 357 (6000) nm; λmax (ε) = 369 (6800)
nm. C13H11FO (202.23): calcd. C 77.21, H 5.48, F 9.39; found C
76.97, H 5.50, F 9.40.
Bis[(2-fluoro-4-methoxybenzyl)cyclopentadienyl]titanium(IV)
Di-
chloride, [(η5-C5H4–CH2–C6H3F–OCH3)]2TiCl2 (3a): A 1  solu-
tion of Super Hydride (LiBEt3H) (15.2 mL, 15.2 mmol) in thf was
concentrated by removal of the solvent by heating it to 60 °C under
reduced pressure of 10–2 mbar for 40 min and then to 90 °C for
20 min in a Schlenk flask. The concentrated Super Hydride was
dissolved in dry diethyl ether (20 mL) to give a cloudy white sus-
pension. The red oil of 1a (2.04 g, 10.0 mmol) was added to a
Schlenk flask and dissolved in dry diethyl ether (60 mL) to give a
red solution. The red fulvene solution was transferred to the Super
Hydride solution through a cannula. The solution was stirred for
8 h to give a white precipitate of the lithium cyclopentadienide in-
termediate, and the solution had changed from orange/red to faint
yellow. The precipitate was filtered through a frit and was washed
with pentane (10 mL). The white precipitate was dried briefly under
reduced pressure and was transferred to a Schlenk flask under ni-
trogen. 1.76 g (8.35 mmol, 83.4% yield) of the lithiated cyclopen-
tadienide intermediate was obtained. Titanium tetrachloride
(4.20 mL, 4.20 mmol) was dissolved in dry thf (30 mL) to give a
yellow solution in a Schlenk flask. The lithium cyclopentadienide
intermediate was dissolved in dry thf (70 mL) to give a colourless
solution. The titanium tetrachloride solution was added to the lith-
ium cyclopentadienide intermediate solution through a cannula to
give a dark brown/red solution. The dark brown/red titanium solu-
tion was refluxed at 85 °C for 16 h. The solution was then cooled,
and the solvent was removed under reduced pressure. The remain-
ing brown residue was extracted with trichloromethane (50 mL)
and filtered through Celite to remove the remaining LiCl. The
brown filtrate was filtered two more times by gravity filtration. The
solvent was removed under reduced pressure to yield 1.41 g of a
brown solid (2.69 mmol, 64.0% yield). 1H NMR (CDCl3,
500 MHz): δ = 3.79 (s, 6 H, C6H3F-OCH3), 4.03 (s, 4 H, C5H4-
Synthesis
3
4
6-(2-Fluoro-4-methoxyphenyl)fulvene,
C5H4–CH–C6H3F–OCH3
CH2), 6.34 (m, 8 H, C5H4), 6.61 (dd, JH3-F = 12.8, JH3-H5
=
=
3
4
(1a): 2-Fluoro-4-methoxybenzaldehyde was purified by sublimation
before any use in reactions. 2-Fluoro-4-methoxybenzaldehyde
(2.12 g, 13.7 mmol) was dissolved in methanol (50 mL) to give a
colourless solution. Freshly cracked cyclopentadiene (3.3 mL,
40 mmol) was added to the reaction solution, which remained
colourless. Pyrrolidine (2.5 mL, 30 mmol) was added to the solu-
tion. The solution slowly changed from colourless to yellow and
finally reached a red/orange colour. The reaction mixture was
stirred for 3 h. Acetic acid (1.8 mL) was added to quench the reac-
tion. Water (100 mL) was added to the reaction mixture, and the
organic product was extracted with diethyl ether (3ϫ30 mL). The
diethyl ether layer was dried with magnesium sulfate and concen-
trated at reduced pressure to yield a red oil, which was purified
2.3 Hz, 2 H, C6H3F-OCH3), 6.64 (dd, JH5-H6 = 8.8, JH5-H3
2.3 Hz, 2 H, C6H3F-OCH3), 7.16 (t, JH6-F = 8.5 Hz, 1 H, C6H4-
OCH3) ppm. 13C NMR (CDCl3, 125 MHz, proton-decoupled): δ
= 30.0 (C5H4-CH2), 55.6 (C6H3F-OCH3), 101.7 (d, J2CF = 25 Hz),
109.8 (d, J4CF = 3 Hz), 115.0, 116.3 (d, J2CF = 16 Hz), 118.5 (d,
J2CF = 16 Hz), 122.3, 131.6 (d, J3CF = 7 Hz), 136.3, 159.8 (d, J3CF
= 10 Hz), 161.4 (d, J1CF = 245 Hz) ppm. 19F NMR (CDCl3,
282 MHz): δ = –115.68 (t, J = 10.3 Hz, 1 F, C6H3F-OCH3) ppm.
IR (KBr): ν = 3107, 2834, 1624, 1584, 1507, 1428, 1295, 1248, 1156,
˜
1103, 1031, 849, 785 cm–1. UV/Vis (CH2Cl2): λ (ε) = 209 (800), 214
(1000), 219 (1700), 263 (4200), 319 (1700) nm; λmax (ε) = 403 (600)
nm. C26H24Cl2F2O2Ti (525.26): calcd. C 59.45, H 4.60, Cl 13.49, F
7.23; found C 58.79, H 4.81, Cl 13.04, F 6.92.
Eur. J. Inorg. Chem. 2008, 4074–4082
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4079

M. Tacke et al.
FULL PAPER
Table 2. Crystallographic refinement data for titanocenes 3a–c.
3a
3b
3c
Empirical formula
Formula mass
Temperature [K]
Wavelength [Å]
Crystal system
Space group
Unit cell dimensions
a [Å]
α [°]
b [Å]
β [°]
c [Å]
C26H2Cl24F2O2Ti
525.25
100(2) K
0.71073
monoclinic
C2/c (#15)
C26H20Cl2F6O2Ti
597.22
100(2) K
C26H24Cl2F2O2Ti
525.25
100(2) K
0.71073 Å
triclinic
0.71073 Å
triclinic
¯
¯
P1 (#2)
P1 (#2)
18.1465(16)
90
6.6132(6)
91.559(2)
18.8496(17)
90
2261.2(4)
4
1.543
6.5322(3)
107.035(1)
19.5513(10)
99.262(1)
20.2369(10)
98.814(1)
2383.3(2)
4
6.6427(8)
70.168(3)
13.3484(16)
76.633(3)
13.6491(16)
81.645(3)
1104.7(2)
2
1.579
0.670
γ [°]
Volume [Å3]
Z
Density (calcd.) [Mg/m3]
1.664
0.655
Absorption coefficient [mm–1] 0.654
F(000)
Crystal size [mm]
θ range for data collection [°] 2.16 to 28.00
Index ranges
1080
0.60ϫ0.15ϫ0.10
1208
540
0.40ϫ0.20ϫ0.03
1.11 to 24.11
–7ՅhՅ7
–22ՅkՅ22
–23ՅlՅ23
35458
0.25ϫ0.03ϫ0.02
1.62 to 25.00
–7ՅhՅ7
–15ՅkՅ15
–16ՅlՅ16
17596
3890 [R(int) = 0.0452]
100.0%
semiempirical from equivalents
0.9867/0.8427
full-matrix least squares on F2
3890/0/300
–23ՅhՅ23
–8ՅkՅ8
–24ՅlՅ24
10462
Reflections collected
Independent reflections
Completeness to θmax
Absorption correction
Max./min. transmission
Refinement method
2722 [R(int) = 0.0287]
99.7%
semiempirical from equivalents semiempirical from equivalents
0.9375/0.7415 0.9806/0.8631
full-matrix least squares on F2 full-matrix least squares on F2
2722/0/198
1.037
7585 [R(int) = 0.0401]
99.8%
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I Ͼ 2σ(I)]
R indices (all data)
7585/0/667
1.054
R1 = 0.0385, wR2 = 0.0876
R1 = 0.0488, wR2 = 0.0918
0.603/–0.270
1.051
R1 = 0.0311, wR2 = 0.0781
R1 = 0.0357, wR2 = 0.0810
R1 = 0.0406, wR2 = 0.0911
R1 = 0.0516, wR2 = 0.0957
0.574/–0.294
Largest diff. peak/hole [eÅ–3] 0.411/–0.231
6-[4-(Trifluoromethoxy)phenyl]fulvene,
C5H4–CH–C6H4–OCF3 Bis{[4-(trifluoromethoxy)benzyl]cyclopentadienyl}titanium(IV) Di-
(1b): 4-(Trifluoromethoxy)benzaldehyde (2.48 g, 13.0 mmol) was
dissolved in methanol (80 mL) to give a colourless solution. Freshly
cracked cyclopentadiene (3.00 mL, 36.3 mmol) was added to the
reaction solution, which remained colourless. Pyrrolidine (2.0 mL,
24.0 mmol) was then added to the solution. The solution changed
very slowly from colourless to yellow and finally reached a red/
orange colour. The reaction mixture was stirred for 28 h. Acetic
acid (1.80 mL) was added to quench the reaction. Water (100 mL)
was added to the reaction mixture, and the organic product was
extracted with diethyl ether (3ϫ50 mL). The diethyl ether solution
was dried with magnesium sulfate, and then the solvent was re-
moved at reduced pressure to yield a red oil. The red oil was puri-
fied by column chromatography with dichloromethane as the elu-
ent. The dichloromethane was removed at reduced pressure to yield
chloride, [(η5-C5H4–CH2–C6H4–OCF3)]2TiCl2 (3b): A 1  solution
of Super Hydride (LiBEt3H) (12.6 mL, 12.6 mmol) in thf was con-
centrated by removal of the solvent by heating it to 60 °C under
reduced pressure of 10–2 mbar for 40 min and then to 90 °C for
10 min in a Schlenk flask. The concentrated Super Hydride was
dissolved in dry diethyl ether (20 mL) to give a cloudy white sus-
pension. The red oil of 1b (2.104 g, 8.83 mmol) was added to a
Schlenk flask and was dissolved in dry diethyl ether (50 mL) to
give a red/orange solution. The red/orange fulvene solution was
transferred to the Super Hydride solution through a cannula. The
solution was stirred for 6 h during which time a white precipitate
of the lithium cyclopentadienide intermediate formed and the solu-
tion had changed from red/orange to yellow. Dry pentane (20 mL)
was added to the solution to improve the precipitation of the lith-
2.41 g (78.2% yield, 10.1 mmol) of a red oil. 1H NMR (CDCl3, ium cyclopentadienide intermediate. The precipitate was filtered
400 MHz): δ = 6.31 (m, 1 H, C5H4), 6.51 (m, 1 H, C5H4), 6.64 (m, through a frit and was washed with diethyl ether (10 mL). The
2 H, C5H4), 7.15 (s, 1 H, C5H4-CH), 7.24 (d, J = 6.3 Hz, 2 H, white precipitate was dried briefly under reduced pressure and was
C6H4-OCH3), 7.58 (d, J = 6.9 Hz, 2 H, C6H4-OCH3) ppm. 13C transferred to
a Schlenk flask under nitrogen. Yield 0.77 g
NMR (CDCl3, 100 MHz, proton-decoupled): δ = 120.2, 121.17,
121.18, 127.4, 131.6, 132.2, 136.29, 136.31, 147.2 ppm. 19F NMR
(CDCl3, 282 MHz): δ = –58.1 (s, 3 F, C6H4-OCF3) ppm. IR
(3.14 mmol, 35.6%) of the lithiated cyclopentadienide intermediate.
Titanium tetrachloride (1.6 mL, 1.6 mmol) was dissolved in dry thf
(40 mL) to give a yellow solution in a Schlenk flask. The lithium
(CH Cl ): ν = 2976, 1648, 1503, 1416, 1270, 894, 755, 744, cyclopentadienide intermediate was dissolved in dry thf (20 mL) to
˜
2
2
691 cm–1. UV/Vis (CH2Cl2): λ (ε) = 236 (7700), 251 (7300), 277 give a colourless solution. The titanium tetrachloride solution was
(7800), 287 (8400), 315 (6300) nm; λmax (ε) = 324 (5800) nm.
C13H9F3O (238.21): calcd. C 65.55, H 3.81, F 23.93; found C 64.94,
H 4.02, F 23.67.
added to the lithium cyclopentadienide intermediate solution
through a cannula to give a dark red/brown solution. The dark red/
brown titanium solution was refluxed at 85 °C for 16 h. The solu-
4080
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Eur. J. Inorg. Chem. 2008, 4074–4082

Synthesis and Cytotoxicity of Fluorinated Titanocene Y Derivatives
tion was then cooled, and the solvent was removed under reduced
pressure. The remaining residue was extracted with trichlorometh-
ane (40 mL) and filtered through Celite to remove the remaining
LiCl. The brown filtrate was filtered two more times by gravity
filtration. The solvent was removed under reduced pressure to yield
0.51 g of an orange/brown solid (0.849 mmol, 54.1% yield). 1H
trogen. Yield 1.47 g (7.01 mmol, 97.5%) of the lithiated cyclopen-
tadienide intermediate. Titanium tetrachloride (3.50 mL,
3.50 mmol) was dissolved in dry thf (20 mL) to give a yellow solu-
tion in a Schlenk flask. The lithium cyclopentadienide intermediate
was dissolved in dry thf (40 mL) to give a colourless solution. The
titanium tetrachloride solution was added to the lithium cyclopen-
NMR (CDCl3, 400 MHz): δ = 4.14 (s, 4 H, C5H4-CH2), 6.34 (m, tadienide intermediate solution through a cannula to give a dark
8 H, C5H4), 7.14 (d, J = 8.1 Hz, 4 H, C6H4OCF3), 7.25 (d, J =
8.1 Hz, 4 H, C6H4OCF3) ppm. 13C NMR (CDCl3, 100 MHz, pro-
ton-decoupled): δ = 36.2 (C5H4-CH2), 115.0, 121.2, 123.1, 123.1,
red solution. The dark red titanium solution was refluxed at 85 °C
for 16 h. The solution was then cooled, and the solvent was re-
moved under reduced pressure. The remaining brown residue was
130.3, 136.4, 138.2, 147.8, 147.9 ppm. 19F NMR (CDCl3, extracted with trichloromethane (80 mL) and filtered through Ce-
282 MHz): δ = –58.3 (s, 3 F, C H -OCF ) ppm. IR (KBr): ν = 2929,
lite to remove the remaining LiCl. The brown filtrate was filtered
two more times by gravity filtration. The solvent was removed un-
der reduced pressure to yield 0.712 g of a brown/pink solid
(1.36 mmol, 38.9% yield). H NMR (CDCl3, 500 MHz): δ = 3.79
(s, 6 H, C6H3F-OCH3), 4.03 (s, 4 H, C5H4-CH2), 6.34 (m, 8 H,
˜
6
4
3
2852, 1506, 1384, 1264, 1224, 1144, 809 cm–1. UV/Vis (CH2Cl2): λ
(ε) = 204 (1400), 209 (1900), 214 (1500), 220 (2100), 227 (1700),
265 (4900) nm; λmax (ε) = 396 (300) nm. C26H20Cl2F6O2Ti (597.22):
calcd. C 52.29, H 3.37, Cl 11.87, F 19.08; found C 51.14, H 3.39,
Cl 11.81, F 19.15.
1
3
4
C5H4), 6.61 (dd, JH5-F = 12.8, JH6-H5 = 2.3 Hz, 2 H, C6H3F-
3
4
OCH3), 6.64 (dd, JH2-F = 8.8, JH2-H6 = 2.3 Hz, 2 H, C6H3F-
OCH3), 7.16 (t, JH6-F = 8.5 Hz, 1 H, C6H4-OCH3) ppm. 13C NMR
(CDCl3, 125 MHz, proton-decoupled): δ = 30.0 (C5H4-CH2), 55.5
6-(3-Fluoro-4-methoxyphenyl)fulvene,
C5H4–CH–C6H3F–OCH3
(1c): 3-Fluoro-4-methoxybenzaldehyde (1.51 g, 9.76 mmol) was dis-
solved in methanol (70 mL) to give a colourless solution. Freshly
cracked cyclopentadiene (1.6 mL, 20 mmol) was added to the reac-
tion solution, which remained colourless. Pyrrolidine (1.3 mL,
15 mmol) was added to the solution. The solution slowly changed
from colourless to yellow and finally reached a red/orange colour.
The reaction mixture was stirred for 16 h. Acetic acid (1.0 mL) was
added to quench the reaction. Water (50 mL) was added to the
reaction mixture, and the organic product was extracted with di-
ethyl ether (3ϫ40 mL). The diethyl ether layer was dried with mag-
nesium sulfate and was concentrated at reduced pressure to yield
an orange/red solid. The orange/red solid was purified by column
chromatography with dichloromethane as the eluent. The dichloro-
methane was removed at reduced pressure to yield 1.71 g of an
orange solid (86.5% yield, 8.45 mmol). M.p. 49 °C. 1H NMR
(CDCl3, 500 MHz): δ = 3.84 (s, 3 H, C6H3F-OCH3), 6.38 (m, 2 H,
(C6H3F-OCH3), 101.7 (d, J2CF = 25.8 Hz), 109.8 (d, J5CF
2.8 Hz), 116.0, 118.5 (d, J1CF = 16.6 Hz), 122.8, 131.5 (d, J6CF
6.4 Hz), 136.3, 159.8 (d, J4CF = 11.1 Hz), 161.4 (d, J3CF
=
=
=
245.8 Hz) ppm. 19F NMR (CDCl3, 282 MHz): δ = –134.67 (q, J =
8.9, 3.8 Hz, 1 F, C H -OCF ) ppm. IR (KBr): ν = 3114, 1515, 1431,
˜
6
4
3
1281, 1264, 1222, 1120, 1024, 860, 801, 763 cm–1. UV/Vis (CH2Cl2):
λ (ε) = 213 (11900), 217 (15100), 229 (44000), 261 (50000), 269
(48200) nm; λmax (ε) = 397 (7600) nm. C26H24Cl2F2O2Ti (525.26):
calcd. C 59.45, H 4.60, Cl 13.49, F 7.23; found C 58.42, H 4.73,
Cl 13.60, F 7.57.
Cytotoxicity Studies: Preliminary in vitro cell tests were performed
on the cell line LLC-PK (long-lasting cells–pig kidney) in order to
compare the cytotoxicity of the compounds presented in this paper.
This cell line was chosen based on their regular and long-lasting
growth behaviour, which is similar to the one shown in kidney car-
cinoma cells. It was obtained from the ATCC (American Tissue
Cell Culture Collection) and maintained in Dulbecco’s Modified
Eagle Medium containing 10% (v/v) FCS (foetal calf serum), 1%
(v/v) penicillin streptomycin and 1% (v/v) -glutamine. Cells were
seeded in 96-well plates containing 200 µL microtitre wells at a den-
sity of 5000 cells/200 µL of medium and were incubated at 37 °C
for 24 h to allow for exponential growth. Then the compounds used
for the testing were dissolved in the minimal amount of dmso (di-
methyl sulfoxide) possible and diluted with medium to obtain stock
solutions of 5ϫ10–4  in concentration and less than 0.7% of
dmso. The cells were then treated with varying concentrations of
the compounds and incubated at 37 °C for 48 h. Then, the solu-
tions 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 of incubation at
37 °C, individual wells were treated with 200 µL of a solution of
MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-
mide] in medium. The solution consisted of 30 mg of MTT in
30 mL of medium. The cells were incubated at 37 °C for 3 h. The
medium was then removed, and the purple formazan crystals were
dissolved in dmso (200 µL) per well. A Wallac Victor (Multilabel
HTS Counter) Plate Reader was used to measure the absorbance
at 540 nm. Cell viability was expressed as a percentage of the ab-
sorbance recorded for control wells. The values used for the dose
response curves represent the values obtained from four consistent
MTT-based assays[23] for each compound tested. Titanocenes 3a
and 3b were found to have IC50 values of 6.0 and 7.3 µ respec-
tively (Figure 2). The cytotoxicity value of titanocene 3c could not
3
C5H4), 6.67 (m, 2 H, C5H4), 6.97 (t, JH2-F = 8.8 Hz, 1 H, C6H3F-
OCH3), 7.06 (s, 1 H, C5H4-CH), 7.30 (d, JH2-F = 8.8 Hz, 1 H,
3
4
C6H3F-OCH3), 7.37 (dd, JH5-H6 = 10.3, JH6-F = 2.0 Hz, 1 H,
C6H3F-OCH3) ppm. 13C NMR (CDCl3, 125 MHz, proton-decou-
pled): δ = 56.3, 113.2, 117.8 (d, J2CF = 19 Hz), 119.6, 127.5 (d, J5CF
= 4 Hz), 130.0 (d, J6CF = 7 Hz), 135.6, 136.6, 144.4, 148.7 (d, J4CF
= 11 Hz), 152.3 (d, J3CF = 247 Hz) ppm. 19F NMR (CDCl3,
282 MHz): δ = –134.8 (q, J = 8.9, 3.8 Hz, 1 F, C6H4-OCF3) ppm.
IR (KBr): ν = 1614, 1518, 1475, 1442, 1388, 1285, 1227, 1150, 1095,
˜
1019, 891, 821, 768 cm–1. UV/Vis (CH2Cl2): λ (ε) = 214 (3700),
238 (1480), 326 (28800), 329 (30400), 335 (30100), 338 (29900), 342
(30000), 347 (28100) nm; λmax (ε) = 357 (26700) nm. C13H11FO
(202.23): calcd. C 77.21, H 5.48, F 9.39; found C 77.10, H 5.57, F
9.24.
Bis[(3-fluoro-4-methoxybenzyl)cyclopentadienyl]titanium(IV)
Di-
chloride, [(η5-C5H4–CH2–C6H3F–OCH3)]2TiCl2 (3c): A 1  solu-
tion of Super Hydride (LiBEt3H) (12.7 mL, 12.7 mmol) in thf was
concentrated by removal of the solvent by heating it to 60 °C under
reduced pressure of 10–2 mbar for 40 min and then to 90 °C for
20 min in a Schlenk flask. The concentrated Super Hydride was
dissolved in dry diethyl ether (20 mL) to give a cloudy white sus-
pension. The orange solid of 1c (1.507 g, 7.45 mmol) was added to
a Schlenk flask and was dissolved in dry diethyl ether (50 mL) to
give a red solution. The red fulvene solution was transferred to the
Super Hydride solution through a cannula. The solution was
stirred for 6 h to give a white precipitate of the lithium cyclopen-
tadienide intermediate, and the solution had changed from red to
a very faint yellow. The white precipitate was dried briefly under
reduced pressure and was transferred to a Schlenk flask under ni-
Eur. J. Inorg. Chem. 2008, 4074–4082
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4081

M. Tacke et al.
FULL PAPER
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Received: May 21, 2008
Published Online: August 8, 2008
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Eur. J. Inorg. Chem. 2008, 4074–4082