Glycol methyl ether and glycol amine substituted titanocenes as antitumor agents

Article abstract of DOI:10.1002/ejic.200600586

6-[4-(2-Methoxyethoxy)phenyl]fulvene (3a) and 6-{4-[2-(dimethylamino) ethoxy]phenyl}fulvene (3b) were prepared as the starting materials for the synthesis of three different classes of titanocenes, which are ansa-titanocenes, diarylmethyl-substituted titanocenes and benzyl-substituted titanocenes. Because the synthetic possibilities seem to be limited, only ansa-titanocene {1,2-bis(cyclopentadienyl)-1,2-bis[4-(2-methoxyethoxy)phenyl]ethanediyl} titanium dichloride (4a) and benzyl-substituted titanocene bis-{[4-(2- methoxyethoxy)benzyl]cyclopentadienyl}titanium(IV) dichloride (6a) were obtained and characterised. The change in the substitution pattern of the phenyl moiety from an oxygen atom to a nitrogen atom had such a big influence on the reaction that not one compound of the three titanocene classes could be synthesised, and it was also not possible to obtain diarylmethyl-substituted titanocenes with the use of either of the fulvenes. When benzyl-substituted titanocene 6a was tested against pig kidney cells (LLC-PK), an antiproliferative effect that results in an IC₅₀ value of 43 μM, was observed. This IC₅₀ value is in the lower range of the cytotoxicities evaluated for titanocenes up to now. ansa-Titanocene 4a surprisingly showed, when tested on the same cell line, a proliferative effect together with a fast rate of hydrolysis. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejic.200600586

FULL PAPER
DOI: 10.1002/ejic.200600586
Glycol Methyl Ether and Glycol Amine Substituted Titanocenes as Antitumor
Agents
Katja Strohfeldt,[a] Helge Müller-Bunz,[a] Clara Pampillón,[a] Nigel J. Sweeney,[a] and
Matthias Tacke*[a]
Keywords: Anticancer drugs / cis-Platin / Titanocene / Super hydride / Lithiation / Titanium
6-[4-(2-Methoxyethoxy)phenyl]fulvene (3a) and 6-{4-[2-(di-
methylamino)ethoxy]phenyl}fulvene (3b) were prepared as
the starting materials for the synthesis of three different
classes of titanocenes, which are ansa-titanocenes, di-
arylmethyl-substituted titanocenes and benzyl-substituted ti-
tanocenes. Because the synthetic possibilities seem to be lim-
ited, only ansa-titanocene {1,2-bis(cyclopentadienyl)-1,2-
bis[4-(2-methoxyethoxy)phenyl]ethanediyl}titanium dichlo-
ride (4a) and benzyl-substituted titanocene bis-{[4-(2-meth-
oxyethoxy)benzyl]cyclopentadienyl}titanium(IV) dichloride
(6a) were obtained and characterised. The change in the sub-
stitution pattern of the phenyl moiety from an oxygen atom
to a nitrogen atom had such a big influence on the reaction
that not one compound of the three titanocene classes could
be synthesised, and it was also not possible to obtain di-
arylmethyl-substituted titanocenes with the use of either of
the fulvenes. When benzyl-substituted titanocene 6a was
tested against pig kidney cells (LLC-PK), an antiproliferative
effect that results in an IC50 value of 43 µM, was observed.
This IC50 value is in the lower range of the cytotoxicities
evaluated for titanocenes up to now. ansa-Titanocene 4a sur-
prisingly showed, when tested on the same cell line, a prolif-
erative effect together with a fast rate of hydrolysis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
with fulvenes.[8–19] By using this method we have synthe-
sised {1,2-bis(cyclopentadienyl)-1,2-bis[4-(dimethylamino)-
phenyl]ethanediyl}titanium dichloride (titanocene X),
which showed an IC50 value of 2.7×10–4  when tested for
cytotoxic effects on the LLC-PK cell line.[16]
The diarylmethyl-substituted titanocene analogues were
synthesized and they showed a significant increase in their
cytotoxicity. These titanocenes can be obtained by a carbo-
lithiation reaction of 6-arylfulvene with the corresponding
aryllithium species followed by transmetallation with tita-
nium tetrachloride.[20] With this new method, bis{bis[4-(di-
methylamino)phenyl]methylcyclopentadienyl}titanium(IV)
dichloride has been synthesised, which shows an IC50 value
of 3.8×10–5  when tested for cytotoxic effects on the LLC-
PK cell line.[20]
Introduction
The introduction of cis-platin into clinics in 1978 started
a broad search for other cytotoxic metal complexes. Despite
the resounding success of cis-platin and closely related plati-
num antitumor agents, the movement of other transition-
metal anticancer drugs towards the clinic has been excep-
tionally slow.[1–3] In general, metallocene dichlorides
(Cp2MCl2) with M = Ti, V, Nb and Mo show remarkable
antitumor activity,[4,5] and titanocene dichloride, Cp2TiCl2,
has especially become a very promising candidate as an an-
ticancer drug. Cp2TiCl2 shows medium–high cytotoxicity in
vitro and a high efficacy in the animal models. Unfortu-
nately, the efficacy in Phase II clinical trials in patients with
metastatic renal-cell carcinoma[6] or metastatic breast can-
cer[7] was too low to be pursued.
A third method that is used for the preparation of ben-
zyl-substituted titanocenes allowed for the synthesis of tit-
anocene Y, which is so far our best titanocene in terms of
cytotoxicity.[21] Bis-[(4-methoxybenzyl)cyclopentadienyl]-
titanium(IV) dichloride (titanocene Y), which has an IC50
value of 2.1×10–5  when tested on the LLC-PK cell line,
was synthesised from fulvene and super hydride (LiBEt3H)
followed by transmetallation with titanium tetrachloride.
The structures of the three mentioned titanocene classes are
shown in Figure 1.
In order to increase the cytotoxicity of Cp2TiCl2, dif-
ferent highly substituted analogues were synthesised.
Within this paper we introduce three different types of
substituted titanocenes: ansa-titanocenes, diarylmethyl-
substituted titanocenes, and benzyl-substituted titanocenes.
ansa-Titanocenes, which contain
a
carbon–carbon
bridge, can be synthesised by reacting titanium dichloride
[a] UCD School of Chemistry and Chemical Biology, Conway In-
stitute of Biomolecular and Biomedical Research, Centre for
Synthesis and Chemical Biology (CSCB), University College
Dublin,
The first in vitro and ex vivo tests with titanocenes X
and Y showed that prostate, cervix and renal cell cancer are
prime targets for these types of titanocenes. Both titano-
Belfield, Dublin 4, Ireland
E-mail: matthias.tacke@ucd.ie
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K. Strohfeldt, H. Müller-Bunz, C. Pampillón, N. J. Sweeney, M. Tacke
FULL PAPER
Figure 1. Molecular structures of the titanocenes.
cenes have been studied in a 36 human carcinoma cell panel These fulvenes can be synthesised according to the pub-
for their antiproliferative activity.[22] Furthermore, titano- lished procedure[18] by reacting the corresponding benzalde-
cene X has been tested on four freshly explanted human hyde with cyclopentadiene in the presence of pyrrolidine as
tumors.[23] First mechanistic studies showed that both titan- a base. Benzaldehydes 2a and 2b were not commercially
ocenes induce apoptosis, especially in prostate cancer available, and therefore, they were synthesised from 4-hy-
cells.[24] Furthermore, very successful animal studies with droxybenzaldehyde (1) and the corresponding alkyl chlo-
the use of titanocene Y on Caki-1 tumor-bearing mice and ride.[27] Afterwards, 6-[4-(2-methoxyethoxy)phenyl]fulvene
xenograft Ehrlich’s ascites tumor in mice were per- (3a) and 4-[2-(dimethylamino)ethoxy]benzaldehyde (3b)
formed.[25,26]
were obtained in the described condensation reaction as
The main idea behind the research presented in this pa- orange solids in yields of 78% and 51%, respectively
per was to convert the methoxy group of titanocene Y, our (Scheme 1).
most cytotoxic titanocene, into a glycol methyl ether or
glycol amine side chain in order to improve the cytotoxicity
and availability in the cell. Within this paper, we present
the synthetic possibilities and limits of introducing a glycol
methyl ether or a glycol amine group in all three mentioned
classes of titanocenes and comparing the antiproliferative
effects of the new synthesised titanocenes.
Results and Discussion
Synthesis
6-Arylfulvenes are the starting materials for all three
classes of titanocenes and their main function is to intro-
duce the substitution pattern at the cyclopentadienide rings. Scheme 1. Synthesis of fulvenes 3a and 3b.
Scheme 2. Synthesis of ansa-titanocene 4a.
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Glycol-Substituted Titanocenes as Antitumor Agents
FULL PAPER
ansa-Titanocenes can be obtained by the reductive di-
merisation of the corresponding fulvene with titanium di-
chloride (Scheme 2), which is synthesised by the reduction
of TiCl4 with nBuLi as described in refs.[12,13]
With the use of this method, fulvenes 3a and 3b were
tested for the synthesis of the corresponding ansa-
titanocenes. ansa-Titanocene 4a was obtained from fulvene
3a as a black solid in a yield of 22%, and the determined
cis–trans ratio at the carbon–carbon bridge was 44:56. Sur-
prisingly, with the use of fulvene 3b and the above-described
procedure, no ansa-titanocene was formed and merely a
black polymer was obtained.
A second synthetic pathway starting with 6-arylfulvenes
leads to the corresponding benzyl-substituted titanocenes.
This method includes a hydride transfer to the exocyclic
double bond of the fulvene with the use of LiBEt3H (super
hydride) and results in the formation of the appropriate
substituted lithium cyclopentadienyl intermediate. Two
moles of this lithium intermediate undergo a transmetalla-
Scheme 3. Synthesis of benzyl-substituted titanocene 6a.
tion reaction with TiCl4 to give the corresponding un- pentadienide 5b could not be isolated and consequently re-
bridged substituted titanocenes (Scheme 3).[21]
acted with TiCl4.
These benzyl-substituted titanocenes do not have ste-
A third synthetic route that leads to the formation of
reocentres; therefore, unlike their ansa analogues, stereoiso- achiral diarylmethyl-substituted titanocenes was evaluated
mers of this compound do not exist, which, in terms of in again for both fulvenes 3a and 3b.[20] The first step was
vivo and in vitro cell testing, is advantageous. Our most a bromine–lithium exchange reaction and resulted in the
cytotoxic titanocene, titanocene Y, has been synthesised by formation of lithiated intermediates 9a and 9b. Bromine
this reaction.
compounds 8a and 8b were synthesised beforehand by re-
Again, both fulvenes 3a and 3b were tested for their abil- fluxing 4-hydroxyphenylbromide (7) with the appropriate
ity to form the corresponding benzyl-substituted titanoc- alkyl chloride.[28] Afterwards, lithium intermediates 9a and
enes. With the use of this method, unbridged titanocene 6a 9b were intended to undergo a carbolithiation reaction that
was obtained as a brown solid in a yield of 67% from 3a. would result in the formation of corresponding substituted
Again, the use of fulvene 3b did not lead to any success; lithium cyclopentadienide 5a and 5b, which could then be
therefore, the unbridged titanocene substituted with a transmetallated with TiCl4 (Scheme 4). However, neither
glycol amine group could not be formed. The reactivity of the use of fulvene 3a nor the use of fulvene 3b led to the
lithium intermediate 5b was so high that it immediately de- formation of the expected diarylmethyl-substituted titano-
composed after its formation and substituted lithium cyclo- cene.
Scheme 4. Synthesis of diarylmethyl-substituted titanocene.
Eur. J. Inorg. Chem. 2006, 4621–4628
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K. Strohfeldt, H. Müller-Bunz, C. Pampillón, N. J. Sweeney, M. Tacke
FULL PAPER
Closer investigations of the lithium–bromine exchange Table 1. Selected bond lengths and angles for 4a.
reaction showed that the para-substituted lithium interme-
diate was not the only product formed. The formation of a
mixture of lithium compounds might be due to the ortho-
directing property of the glycol methyl ether or glycol amine
Bond lengths [Å]
Cl1–Ti
Cl2–Ti
Ti–C1
2.3553(11)
2.3559(11)
2.352(3)
2.397(3)
2.391(3)
2.360(3)
2.367(3)
2.054(3)
2.359(4)
2.401(4)
2.394(4)
2.341(3)
2.383(3)
2.058(2)
1.406(5)
1.418(5)
C2–C3
C3–C4
C4–C5
C5–C6
1.375(5)
1.399(5)
1.387(5)
1.522(5)
1.397(5)
1.408(5)
1.377(6)
1.399(5)
1.394(5)
1.508(5)
1.521(5)
1.564(10)
1.467(7)
1.252(9)
1.374(7)
side chain. To carry out these investigations the bromine Ti–C2
Ti–C3
C16–C17
C16–C20
C17–C18
C18–C19
C19–C20
C20–C21
C6–C21
C29–O4A
C29–O4B
O4A–C30
O4B–C30
compound was treated with tert-butyllithium in THF and
Ti–C4
afterwards reacted with chlorotrimethylsilane.
Ti–C5
Ti–Cent1
Ti–C16
Ti–C17
Ti–C18
Ti–C19
Ti–C20
Ti–Cent2
Structural Discussion
Suitable single-crystals of titanocene 4a for X-ray diffrac-
tion experiments were obtained by the slow diffusion of
pentane into a saturated solution of dichloromethane. The C1–C2
collection and refinement data for 4a are shown in Table 2.
C1–C5
Because of the presence of stereoisomers, ansa-
Bond angles [°]
titanocenes seem to be a difficult class of compounds in
Cl1–Ti–Cl2
Cent1–Ti–Cent2
C28–C29–O4A
C28–C29–O4B
C29–O4A–C30
C29–O4B–C30
95.04(4)
128.15(3)
86.8(5)
119.8(5)
109.9(7)
109.1(4)
terms of crystallisation experiments. Therefore, there are
very few examples of molecular structures of titanocenes in
the crystal form and their crystallisation behaviour strongly
depends on the substitution pattern. In the crystal structure
of titanocene 4a, only the trans isomer is found, and in ac-
¯
cordance with the centrosymmetric space group P1, the
(R,R)- and (S,S) isomers are present in equal amounts. The
molecule itself has a pseudo-C2 symmetry in the solid state.
The cyclopentadienyl bond lengths are of the expected val-
ues for titanocenes and range from 138 pm to 142 pm, as
well as the ring centroid distances to the metal centre (205
and 206 pm). The Ti–Cl bond lengths, both of them being
236 pm, and the Cl–Ti–Cl angle, being 95.0°, are also typi-
cal of titanocenes (Table 1). The carbon–carbon ansa-
bridge has a length of 152 pm and is therefore in the ex-
pected range for a carbon–carbon single bond. Despite the
ansa-bridge, the angle centroid–metal–centroid is 128°,
which is nearly the same as that in unbridged titanocene Y
(131°)[21] and suggests that there is no strain on the ethylene
bridge.
known to be of high purity and the cytotoxic effects that
are observed can not be due to the presence of chlorinated
solvents.
Cell Tests
The in vitro cytotoxicity of compounds 4a and 6a was
determined by MTT-based assays[29] that involves a 48 hour
drug exposure period, followed by 24 hours of recovery
time. Compounds were tested for their activity on pig kid-
ney cells (LLC-PK) and the results are shown in Figures 2
and 3.
One of the glycol methyl ether side chains shows an ori-
entational disorder with O4 and is distributed over two po-
sitions. In the final refinement, the position of the two adja-
cent carbon atoms, C29 and C30, has been treated as unaf-
fected and leads to some unusual bond lengths and angles
(Table 1). These unusual bond lengths and angles show that
C29 is, in fact, disordered as well and that the two positions
are very close to each other (Ͻ20 pm). Therefore, the data-
set with a resolution of 87 pm does not allow a separate
refinement of the two C29 sites.
The unit cell of the determined structure of 4a shows an
absence of any solvent molecules; the assumed free space
between the titanocenes is filled by the glycol methyl ether
group. This is in contrast to the molecular structure of an
analogue of ansa-titanocene that is substituted with a
pentamethyl phenyl group at the cyclopentadienyl rings. In
Figure 2. Molecular structure of a crystal of 4a, thermal ellipsoids
are drawn at the 50% probability level and disorder has been ne-
glected.
In our workgroup, ansa-titanocenes have been synthe-
this analogue, the aromatic substituents form a channel in sised which show cytotoxic effects with IC50 values in the
which the solvent molecules are situated.[18] In terms of bio- range of 930 to 210 µ when tested on the LLC-PK cell
logical applications, the absence of solvent molecules in the line, depending on the substitution pattern of the phenyl
obtained crystals is advantageous as the compounds are ring. Most of the ansa-titanocenes show poor water solubil-
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Glycol-Substituted Titanocenes as Antitumor Agents
FULL PAPER
Figure 3. Cytotoxicity curve from typical MTT assays that show the effect of compound 4a on the viability of pig kidney (LLC-PK)
cells.
ity, and therefore, the introduction of the glycol methyl amount of the white precipitate. Nevertheless, there might
ether group was supposed to improve the water solubility still be a rapid rate of hydrolysis, which has a counter-
and the availability of the titanocene in the cell.
productive impact on the cytotoxic effect.
The water solubility of ansa-titanocene 4a was signifi-
cantly improved, but unfortunately a few seconds after the
titanocene dissolved in the medium, a white solid precipi-
tated despite the fact that the titanocene is completely solu-
ble in 0.7% DMSO. Cell tests with this solution showed
very surprising results. ansa-Titanocene 4a, which was dis-
solved in the medium with 0.7% DMSO, showed nearly no
cytotoxic effect under physiological conditions. Quite the
opposite result, a proliferative effect, was observed and the
cell growth was significantly increased when tested on the
LLC-PK cell line. Only at very low concentrations in the
range of 10–5 to 10–8  can a small cytotoxic effect be no-
ticed (Figure 3). The proliferative result can be explained by
a very fast hydrolysis rate of the ansa-titanocene, which re-
sults from the substitution pattern of the phenyl rings.
A similar unexpected proliferate effect was observed by
G. Jaouen and coworkers when a titanocene derivative of
the anticancer drug tamoxifen was tested on the human
hormone-dependent breast cancer cell line MCF-7. This
compound contains an analogous glycol amine group and
further explanations concerning the hydrolysis process can
be found within the literature[30] and the studies of P.
Sadler.[31]
Figure 4. Cytotoxicity curve from typical MTT assays that show
the effect of compound 6a on the viability of pig kidney (LLC-PK)
cells.
Furthermore, benzyl-substituted titanocene 6a does not
have stereocentres, and therefore, stereoisomers do not ex-
ist, unlike their ansa analogue 4a. In terms of in vivo and
in vitro cell testing, this is advantageous. Previously, the
presence of unseparated stereoisomers meant that the issue
of whether the compounds’ cytotoxicities were related to
specific isomers was not addressed. This is not of concern
for achiral compound 6a.
Cytotoxic studies with the use of analogous benzyl-sub-
stituted titanocene 6a were undertaken in order to deter-
mine whether the hydrolysis rate is dependant only on the
side chain of the phenyl moiety or whether there is an ad-
ditional correlation with the structure of the titanocene.
Titanocene 6a was tested in the typical MTT-based assay
with the use of the LLC-PK cell line and it showed an IC50
value of 43 µ (Figure 4). However, this value, when com-
pared with that of benzyl-substituted titanocene Y, is twice
Conclusions and Outlook
6-Arylfulvenes can be very useful starting materials for
as large. In comparison to cis-platin, this represents an ap- the synthesis of different types of titanocenes. Fulvenes 3a
proximate thirteen-fold increase. Nevertheless, this value and 3b, which have a glycol methyl ether or a glycol amine
shows an approximate fifty-fold decrease in magnitude side chain at the phenyl moiety, were obtained in good
when compared with that of titanocene dichloride; its IC50 yields as orange solids. Their application towards the syn-
value is 2.0×10–3  when tested on the same cell line.[16] thesis of titanocenes was very limited. Only the glycol
Samples prepared for the cell tests showed a significantly methyl ether analogues of ansa-titanocene and of benzyl-
slower rate of hydrolysis compared with that of ansa- substituted titanocene were obtained, whereas it was not
titanocene 4a. This resulted in the formation of a lesser possible to synthesise any of the three types of titanocenes
Eur. J. Inorg. Chem. 2006, 4621–4628
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K. Strohfeldt, H. Müller-Bunz, C. Pampillón, N. J. Sweeney, M. Tacke
FULL PAPER
fractometer. A semi-empirical absorption correction on the raw
data was performed with the program SADABS.[32] The crystal
structure was then solved by direct methods (SHELXS-NT 97)[33]
and refined by full-matrix least-squares methods against F2. Fur-
ther details about the data collection are listed in Table 2, as well
as reliability factors. CCDC-610549 contains 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_request/cif.
bearing a glycol amine side chain. Both fulvenes could not
be used for the successful synthesis of a diarylmethyl-substi-
tuted titanocene. This study shows how limited the various
methods are and that not every 6-arylfulvene can be used
for the synthesis of the corresponding titanocenes.
When tested for cytotoxicity on the LLC-PK cell line, the
IC50 value of 6a was in the lower 10–5  range and showed
a clear dose dependent antiproliferative effect. This repre-
sents an increase in cytotoxicity when compared to that of
unsubstituted titanocene dichloride; however, 6a is two
times less cytotoxic than the most cytotoxic of the titanoc-
enes so far, titanocene Y, which has a methoxybenzyl func-
tionality. Compound 6a is also approximately fifteen times
less cytotoxic than cis-platin when tested on the LLC-PK
cell line.
Table 2. Crystal data and structure refinements for 4a.
Empirical formula
Formula weight
Temperature [K]
Wavelength [Å]
C30H32O4Cl2Ti
575.36
100(2)
0.71073
Crystal system
Space group
triclinic
P1(#2)
¯
Surprisingly, ansa-titanocene 4a showed a proliferative
effect when tested on the same cell line. This might be due
to the fast rate of hydrolysis, which was observed during
the preparation of the sample for the cell tests. Nevertheless,
this was the first time that a proliferative effect with this
class of titanocenes was observed. We could show that a
glycol methyl ether side chain at the phenyl moiety helps to
improve the water solubility, but unfortunately it increases
the hydrolysis rate as well. Furthermore, we were able to see
that the hydrolysis rate is strongly dependent on the class of
titanocenes.
Unit cell dimensions [Å], [°]
a = 7.7841(11), α = 102.085(2)
b = 13.0191(18), β = 100.794(3)
c = 14.358(2), γ = 102.998(3)
1343.7(3)
Volume [Å3]
Z
2
Densitycalcd. [Mg/m3]
Absorption coefficient [mm–1
F(000)
1.422
0.552
600
]
Crystal size [mm3]
0.20×0.10×0.02
1.66 to 24.00
–8 Յ h Յ 8, –14 Յ k Յ 14, –16
Յ l Յ 16
θ range for data collection [°]
Index ranges
Reflections collected
14440
Future work will focus on the exchange of the chlorines Independent reflections
4207 [R(int) = 0.0460]
99.8
Semi-empirical from equivalents
0.9890 and 0.8143
Full-matrix least–squares on F2
4207/0/345
Completeness to θ = 24.00° [%]
in order to decrease the hydrolysis rate. If this can be
achieved, both titanocenes might be very interesting com-
pounds for further studies in terms of their availability in
the cell.
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
1.052
Final R indices [IϾ2σ(I)]
R indices (all data)
R1 = 0.0468, wR2 = 0.1177
R1 = 0.0680, wR2 = 0.1312
0.717 and –0.328
Largest diff. peak and hole [e/Å–3
]
Experimental Section
General Conditions: Titanium tetrachloride, n-butyllithium (2.0 
in cyclohexane), tert-butyllithium (1.7  in pentane), 4-hydroxy-
benzaldehyde, 4-bromophenol, K2CO3, NaI, DMF, (2-chloroethyl)-
methyl ether, 2-(dimethylamino)ethyl chloride and super hydride
(LiBEt3H, 1.0  solution in THF) were obtained commercially
from Aldrich Chemical Co. THF, toluene, pentane and diethyl
ether were dried with Na and benzophenone. Solvents were freshly
distilled and collected under an atmosphere of argon prior to use.
Cyclopentadiene was collected under an atmosphere of nitrogen
from freshly cracked dicyclopentadiene and pyrrolidine was dis-
tilled under an atmosphere of argon prior to use. Manipulations of
air- and moisture-sensitive compounds were done with the use of
standard Schlenk techniques, under an argon atmosphere. NMR
spectra were measured with either a Varian 300 or a Varian 400
spectrometer. Chemical shifts are referenced to TMS. IR spectra
were recorded with a Perkin–Elmer Paragon 1000 FT-IR Spectrom-
eter. UV/Vis spectra were recorded with a Unicam UV2 Spectrome-
ter. Electron spray mass spectrometry of 4a and 6a were performed
with a quadrupole tandem mass spectrometer (Quattro Micro,
Micromass/Water’s Corp., USA) with the use of solutions that were
made up in 50% dichloromethane and 50% methanol.
In vitro cell tests were performed on LLC-PK cells obtained from
the ATCC (American Tissue Cell Culture Collection) and main-
tained in Dulbecco’s Modified Eagle Medium containing FCS (foe-
tal calf serum) [10% (v/v)], penicillin streptomycin [1% (v/v)] and
-glutamine [1% (v/v)]. Cells were seeded in 96-well plates contain-
ing 200-µL-microtitre wells at a density of 5,000 cells/200 µL of
medium and were incubated at 37 °C for 24 h to allow for ex-
ponential growth. The compounds used for the testing were then
dissolved in a medium solution containing DMSO (0.7%) to obtain
stock solutions of 5×10–4  in concentration. The cells were then
treated with varying concentrations of the compounds and incu-
bated for 48 h at 37 °C. The solutions were then removed from the
wells and the cells were washed with PBS (phosphate buffer solu-
tion) and fresh medium was added to the wells. After a recovery
period of 24 h incubation at 37 °C, individual wells were treated
with a solution of MTT (200 µL) [3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide] in medium. The solution consisted
of MTT (30 mg) in the medium (30 mL). The cells were incubated
for 3 h at 37 °C. The medium was then removed and the purple
formazan crystals were dissolved in DMSO (200 µL per well). Ab-
sorbance was then measured at 540 nm by a Wallac Victor
(Multilabel HTS Counter) Plate Reader. Cell viability was ex-
pressed as a percentage of the absorbance recorded for control
wells. The mean values used for the dose response curves represent
Single-crystals of 4a suitable for X-ray diffraction experiments were
grown by the diffusion of pentane into a saturated solution of
dichloromethane at room temperature. X-ray diffraction data for
the compound was collected with a BRUKER Smart Apex dif-
4626
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2006, 4621–4628

Glycol-Substituted Titanocenes as Antitumor Agents
FULL PAPER
the values obtained from four consistent MTT-based assays for
each compound tested.
132.7 (2 C) (C-3,5 OC6H4), 135.1, 138.5 (C5H4), 143.5 (C-1 C5H4),
160.1 (C-1 OC6H4) ppm. C16H19NO (241.15): calcd. C 79.63, H
7.94, N 5.80; found C 79.85, H 7.92, N 5.79.
4-(2-Methoxyethoxy)benzaldehyde (2a): This compound was syn-
thesised according to the published procedure and obtained as a
nearly colourless oil in a yield of 72%.[27] The spectroscopic data
were in correspondence to the published data.
{1,2-Dicyclopentadienyl-1,2-bis[4-(2-methoxyethoxy)phenyl]ethane-
diyl}titanium Dichloride, [1,2-{4-(2-MeO-C2H4O)-C6H2}2C2H2{η5-
C5H4}2]TiCl2 (4a): TiCl4 (0.46 mL, 0.79 g, 4.18 mmol) was added
to dry toluene (50 mL) and dry THF (5 mL). The solution turned
immediately from colourless to pale yellow. The solution was
stirred and cooled down to –78 °C and then was treated dropwise
with nBuLi (4.18 mL, 8.36 mmol). The solution turned from yellow
to brown during the addition. After this addition, the mixture was
warmed up slowly to room temp., and the solution finally turned
black. After 20 h of stirring, a solution of 6-[4-(2-methoxyethoxy)
phenyl]fulvene (1.91 g, 8.36 mmol) in dry toluene was added to the
solution of TiCl2·2THF at room temp. under an atmosphere of
argon. The mixture was then stirred under reflux for another 16 h.
The solvent was removed under vacuum. The resulting black solid
was extracted with CH3Cl (3×20 mL) and filtered through celite
and twice through a Whatman No. 1 filter paper. The solvent was
removed under vacuum, and the residue was triturated with pen-
tane (40 mL) to give 0.53 g (22% yield) of a black solid. The ratio
of trans and cis isomers was 44% to 56%. 1H NMR (CDCl3,
400 MHz): δ = 3.42–3.48 (m, 2 H, CH3), 3.69–3.79 (m, 4 H,
CH3OCH2CH2), 4.01–4.10 (m, 4 H, CH3OCH2CH2O), 4.68, 5.40
(s, 2 H, cis- and trans-PhCHCp), 6.12–6.33, 6.76–7.17 (m, 16 H,
C6H4, C5H4) ppm. 13C NMR (CDCl3, 100 MHz): δ = 49.0, 51.8 (2
C) (cis- and trans-PhCHCp), 57.2 (2 C) (OCH3), 65.1, 68.8 (4 C)
(OCH2CH2O), 107.1, 111.3, 111.6, 111.9, 114.1, 114.2, 123.4,
125.3, 125.6, 126.8, 127.1, 127.6, 129.6, 130.7, 134.4, 135.6, 153.9,
4-[2-(Dimethylamino)ethoxy]benzaldehyde (2b): 4-Hydroxybenzal-
dehyde (1.00 g, 8.19 mmol) was heated at 80 °C together with 2-
(dimethylamino)ethyl chloride (1.2 equiv., 1.41 g, 9.83 mmol) and
K2CO3 (4 equiv., 4.52 g, 32.76 mmol) in abs. DMF (50 mL) for 3 d
under an atmosphere of argon. H2O (30 mL) was added, and the
reaction mixture was extracted with diethyl ether (4×20 mL). The
combined organic layers were dried with Na2SO4 and the solvent
was removed in vacuo. A red oil was obtained in a yield of 76%.
1H NMR (CDCl3, 300 MHz): δ = 2.33 [s, 3 H, N(CH3)2], 2.75 [t,
3J = 5.7 Hz, 2 H, (CH3)2NCH2CH2], 4.14 [t, 3J = 5.7 Hz, 2 H,
(CH3)2NCH2CH2O], 7.02 (d, JA,B = 8.4 Hz, 2 H, OCCHCH), 7.81
(d, JA,B = 8.7 Hz, 2 H, CHC), 9.86 (s, 1 H, CHO) ppm.
6-[4-(2-Methoxyethoxy)phenyl]fulvene (3a): Pyrrolidine (2.58 mL,
2.20 g, 30.94 mmol) was added to a solution of 4-(2-methoxy-
ethoxy)benzaldehyde (5.20 g, 30.94 mmol) and cyclopentadiene
(5.11 mL, 77.34 mmol) in methanol (60 mL). After this addition,
the solution turned from colourless to deep red and a solid was
formed. After 12 h, acetic acid (1.86 g, 1.77 mL, 30.94 mmol) was
added. H2O (30 mL) was added, and the mixture was extracted
with CH2Cl2 (4×20 mL). The combined organic layers were dried
with Na2SO4, and the solvent was removed in vacuo to afford a
dark red oil. The crude product was purified on a silica column
(15–5 cm) with CH2Cl2 as the solvent. After removal of the solvent
under vacuum, the product was obtained as an orange solid in yield
of 78% (5.49 g, 24.07 mmol). 1H NMR (CDCl3, 300 MHz): δ =
2.43 (s, 3 H, OCH3), 2.74 (t, 3J = 5.7 Hz, 2 H, CH3OCH2CH2),
4.11 (t, 3J = 5.7 Hz, 2 H, CH3OCH2CH2), 6.30–6.31, 6.47–6.49,
6.64–6.67, 6.71–6.73 (m, 4 H, C5H4), 6.95 (d, JA,B = 8.7 Hz, 2 H,
OCCHCHC), 7.15 (s, 1 H, C6H4CHC5H4), 7.56 (d, JA,B = 8.7 Hz,
2 H, OCCHCHC) ppm. 13C NMR (CDCl3, 75 MHz): δ = 45.9
(OCH3), 58.2, 66.1 (2 C) (CH3OCH2CH2O), 114.9 (2 C) (C-2,6
OC6H4), 119.9 (C5H4CHC6H4), 127.4, 129.6, 134.9, 138.3 (4 C) (C-
2,3,4,5 C5H4), 132.4 (2 C) (C-3,5 OC6H4), 143.3 (C-1 C5H4), 159.9
(C-1 OC6H4) ppm. C15H16O2 (228.12): calcd. C 78.98, H 7.07;
found C, 78.68, H, 7.05.
154.5 (22 C) (cis- and trans-C H and C H ) ppm. IR (KBr): ν =
˜
6
4
5
4
3104 (m), 2924 (m), 1612 (s), 1514 (s), 1453 (s), 1440 (s), 1254 (w),
1180 (s), 1059 (s), 1037 (s), 860 (m), 771 (m) cm–1. UV/Vis
(CH2Cl2): λ (ε, Lmol–1 cm–1) = 227 (23600), 271 (19666), 378
(1666), 387 (1767), 524 (233) nm. MS (ESI–): m/z = 610.99 [M +
Cl]+. C30H32Cl2O4Ti (574.12): calcd. C 62.63, H 5.61; found C
65.65, H 6.14.
Bis{[4-(2-methoxyethoxy)benzyl]cyclopentadienyl}titanium(IV) Di-
chloride, [{η5-C5H4-CH2-C6H4–O(CH2)2OCH3}2Ti]Cl2 (6a): LiB-
Et3H (12.44 mL) was concentrated by removal of the solvent by
heating it to 90 °C under a vacuum of 10–2 mbar for 2 h. The con-
centrated reagent was dissolved in diethyl ether (30 mL) and trans-
ferred to
a solution of 6-[4-(2-methoxyethoxy)phenyl]fulvene
6-{4-[2-(Dimethylamino)ethoxy]phenyl}fulvene (3b): Pyrrolidine (2.25 g, 9.86 mmol) in diethyl ether (10 mL). The solution was
(4.97 mL, 4.24 g, 59.55 mmol) was added to a solution of 4-[2-(di-
methylamino)ethoxy]benzaldehyde (11.50 g, 59.55 mmol) and cy-
clopentadiene (9.84 g, 148.88 mmol) in methanol (100 mL). After
this addition, the solution turned from colourless to deep red. After
12 h, acetic acid (3.58 g, 3.41 mL, 59.55 mmol) was added. H2O
(40 mL) were added, and the mixture was extracted with CH2Cl2
(4×40 mL). The combined organic layers were dried with Na2SO4,
and the solvent was removed by vacuum to afford a dark red oil.
The crude product was purified on an aluminium oxide column
(15–5 cm) with CH2Cl2 as the solvent. After removal of the solvent
under vacuum, the product was obtained as an orange solid in yield
stirred for 20 min and then pentane (40 mL) was added, after which
point lithium cyclopentadienide intermediate 5a precipitated from
the solution. The precipitate was immediately filtered, and 5a was
then collected on a frit and washed with pentane (25 mL), dried
briefly in vacuo and transferred to a Schlenk flask under an atmo-
sphere of argon. White lithium cyclopentadienide intermediate 5a
(1.88 g, 7.96 mmol, 81% yield) was dissolved in THF (20 mL) and
was added dropwise to a solution of TiCl4 (0.44 mL, 3.98 mmol)
in THF (80 mL) at 0 °C. The resultant dark red solution was heated
under reflux for 16 h. The solution was then cooled, and the solvent
was removed under reduced pressure. The remaining residue was
of 51% (7.34 g, 30.44 mmol). 1H NMR (CDCl3, 400 MHz): δ = extracted with CH2Cl2 (75 mL) and filtered through celite to re-
2.35 [s, 6 H, N(CH3)2], 2.75 [t, 3J = 5.7 Hz, 2 H, (CH3)2NCH2CH2],
move the LiCl. The dark red filtrate was filtered twice more by
4.11 [t, 3J = 5.7 Hz, 2 H, (CH3)2NCH2CH2O], 6.30–6.35, 6.45– gravity filtration. The solvent was removed under reduced pressure
6.50, 6.65–6.67, 6.70–6.75 (m, 4 H, C5H4), 6.96 (d, JA,B = 8.6 Hz,
2 H, C-2,6 OC6H4), 7.15 (s, 1 H, C5H4CHC6H4), 7.56 (d, JA,B
to yield a brown solid, which was dried in vacuo (1.54 g,
1
=
2.67 mmol, 67% yield). H NMR (CDCl3, 300 MHz): δ = 3.44 (s,
3
8.6 Hz, 2 H, C-3,5 OC6H4) ppm. 13C NMR (CDCl3, 100 MHz): 6 H, OCH3), 3.74 (t, J = 4.6 Hz, 4 H, CH3OCH2CH2), 4.02 (s, 4
δ
=
46.2 (2 C) [N(CH3)2], 58.4 [(CH3)2NCH2CH2], 66.2
H, C6H4CH2C5H4), 4.09 (t, 3J = 4.6 Hz, 4 H, CH3OCH2CH2O),
6.29 (s, 8 H, C5H4), 6.86, 7.11 (d, JA,B = 8.4 Hz, 8 H, C6H4) ppm.
[(CH3)2NCH2CH2O], 115.1 (2 C) (C-2,6 OC6H4), 120.1
(C6H4CHC5H4), 127.6 (C5H4), 129.8 (C-4 OC6H4), 130.0 (C5H4), 13C NMR (CDCl3, 75 MHz): δ = 36.0 (2 C) (C6H4CH2C5H4), 59.2
Eur. J. Inorg. Chem. 2006, 4621–4628
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
4627

K. Strohfeldt, H. Müller-Bunz, C. Pampillón, N. J. Sweeney, M. Tacke
FULL PAPER
[7] N. Kröger, U. R. Kleeberg, K. B. Mross, L. Edler, G. Saß,
D. K. Hossfeld, Onkologie 2000, 23, 60–62.
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546, 105.
[9] F. Hartl, L. Cuffe, J. P. Dunne, S. Fox, T. Mahabiersing, M.
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[10] M. Tacke, J. P. Dunne, S. Fox, G. Linti, R. Teuber, J. Mol.
Struct. 2001, 570, 197–202.
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Eur. J. Inorg. Chem. 2002, 3039–3046.
(2 C) (OCH3), 67.3, 71.1 (4 C) (CH3OCH2CH2OC6H4), 114.7,
130.0 (4 C) (C-2,3,5,6 C6H4), 116.2, 122.2 (8 C) (C-2,3,4,5 C5H4),
131.7, 137.7 (4 C) (C-1 C5H4; C-6 C6H4), 157.5 (2 C) (C-1, OC6H4)
ppm. IR (KBr): ν = 3104 (m), 2924 (m), 1612 (s), 1514 (s), 1453
˜
(s), 1440 (s), 1254 (w), 1180 (s), 1059 (s), 1037 (s), 860 (m), 771
(m) cm–1. MS (ESI–): 611.05 [M + Cl]+. UV/Vis (CH2Cl2): λ (ε,
Lmol–1 cm–1) = 227 (26600), 262 (24600), 316 (8600), 396 (3500),
524(400) nm. C30H34Cl2O4Ti (576.13): calcd. C 62.41, H 5.99, Cl
12.28; found C 62.84, H 6.08, Cl 12.12.
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5219–5221.
1-Bromo-4-(2-methoxyethoxy)benzene (8a): This compound was
synthesised according to the known procedure and obtained as an
orange oil in a yield of 75%.[28] 1H NMR (CDCl3, 400 MHz): δ =
3.39 (s, 3 H, OCH3), 3.65–3.70 (m, 2 H, CH3OCH2CH2), 4.00–4.05
(m, 2 H, CH3CH2CH2O), 6.75 (d, JA,B = 9.1 Hz, 2 H, OCCHCH),
7.31 (d, JA,B = 8.9 Hz, 2 H, OCHCHC) ppm. 13C NMR (CDCl3,
100 MHz): δ = 59.4 (OCH3), 67.7, 71.1 (2 C) (OCH2CH2OCH3),
116.6 (2 C) (C-3,5 BrC6H4), 117.6 (C-1 BrC6H4), 132.4 (2 C) (C-
2,6 BrC6H4), 158.1 (C-4 BrC6H4). C9H11BrO2 (229.99): calcd. C
46.78, H 4.80; found C 46.80, H 4.81.
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1583–1585.
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Organometallics 1997, 16, 4567–4571.
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2004, 357, 225–234.
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Mendoza, H. Müller-Bunz, F.-J. K. Rehmann, N. Sweeney, J.
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1-Bromo-4-[2-(dimethylamino)ethoxy]benzene (8b): A mixture of 4-
bromophenol (3.75 g, 21.81 mmol), NaI (3.25 g, 21.68 mmol),
K2CO3 (4 equiv. 12.03 g, 87.24 mmol) and 2-(dimethylamino)ethyl
chloride (3.74 g, 26.17 mmol) in DMF (100 mL) was stirred at
80 °C for 4 d. H2O (50 mL) was added, and the reaction mixture
was extracted with diethyl ether (5×50 mL). The combined organic
layers were additionally washed with aq. KOH (3×20 mL). After-
wards, the aqueous layers were extracted with diethyl ether
(5×15 mL). The combined organic layers were dried with Na2SO4
and concentrated in vacuo to give a dark red oil. The oil was dis-
tilled at 96 °C (4×10–1 mbar) to afford a light yellow oil in a yield
of 52% (2.76 g, 11.34 mmol). 1H NMR (CDCl3, 400 MHz): δ =
2.31 [s, 6 H, N(CH3)2], 2.69 [t, 3J = 5.7 Hz, 2 H, (CH3)2NCH2CH2],
3.99 [t, 3J = 5.7 Hz, 2 H, (CH3)2NCH2CH2O], 6.78 (d, JA,B
=
9.1 Hz, 2 H, OCHCH), 7.34 (d, JA,B = 9.1 Hz, 2 H, OCHCHC)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 46.1 (2 C) [N(CH3)2], 58.4
[(CH3)2NCH2CH2], 66.4 [(CH3)2NCH2CH2O], 113.0 (C-1
BrC6H4), 116.6 (2 C) (C-3,5 BrC6H4), 132.4 (2 C) (C-2,6 BrC6H4),
158.2 (C-4 BrC6H4) ppm. C10H14BrNO: calcd. C 49.20, H 5.78, N
5.74; found C 48.90, H 5.68, N 5.65.
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Acknowledgments
The authors want to thank the Science Foundation Ireland (SFI)
for funding through grant (04/BRG/C0682). In addition, funding
from the Higher Education Authority (HEA) and the Centre for
Synthesis and Chemical Biology (CSCB) through the HEA PRTLI
cycle 3 as well as COST D39 was provided.
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Received: June 21, 2006
Published Online: September 20, 2006
4628
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2006, 4621–4628