Novel achiral indole-substituted titanocenes: Synthesis and preliminary cytotoxicity studies

Article abstract of DOI:10.1016/j.jorganchem.2010.10.039

A series of eight new titanocene dichloride derivatives has been synthesised and characterized. Four compounds from the series are lypophilic indole-functionalised titanocenes and four are hydrochloride salts of their dimethylaminomethyl-functionalised counterparts, which are water soluble. The compounds were tested for their in vitro cytotoxicities against the human kidney cancer cell line CAKI-1 and their results are compared with previously synthesised structural analogues. Surprisingly, two of the compounds showed no activity against the CAKI-1 cell line; however six compounds exhibited medium to high potency with IC50 values as low as 7.0 μM. These six complexes were tested further on this cell line using the co-solvent Soluphor P, which has been shown to improve both solubility and cytotoxicity of similar complexes. One of the compounds carrying a N-methylindole-substituent was obtained in the form of single crystals and allowed for the characterisation by X-ray crystallography; the compound crystallised in the space group P2₁/n (#14) with four molecules present in the monoclinic unit cell.

Full text of DOI:10.1016/j.jorganchem.2010.10.039

Journal of Organometallic Chemistry 696 (2011) 1072e1083
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Novel achiral indole-substituted titanocenes: Synthesis and preliminary
cytotoxicity studies
*
Anthony Deally, Brendan Gleeson, Helge Müller-Bunz, Siddappa Patil, Donal F. O’Shea, Matthias Tacke
Conway Institute of Biomolecular and Biomedical Research, Centre for Synthesis and Chemical Biology (CSCB), UCD School of Chemistry and Chemical Biology, University College
Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of eight new titanocene dichloride derivatives has been synthesised and characterized. Four
compounds from the series are lypophilic indole-functionalised titanocenes and four are hydrochloride
salts of their dimethylaminomethyl-functionalised counterparts, which are water soluble. The
compounds were tested for their in vitro cytotoxicities against the human kidney cancer cell line CAKI-1
and their results are compared with previously synthesised structural analogues. Surprisingly, two of the
compounds showed no activity against the CAKI-1 cell line; however six compounds exhibited medium
Received 25 August 2010
Received in revised form
11 October 2010
Accepted 18 October 2010
Keywords:
to high potency with IC50 values as low as 7.0 mM. These six complexes were tested further on this cell
Titanocene dichloride
Renal-cell cancer
CAKI-1
Cytotoxicity
Indole
line using the co-solvent Soluphor P, which has been shown to improve both solubility and cytotoxicity
of similar complexes. One of the compounds carrying a N-methylindole-substituent was obtained in the
form of single crystals and allowed for the characterisation by X-ray crystallography; the compound
crystallised in the space group P21/n (#14) with four molecules present in the monoclinic unit cell.
Ó 2010 Elsevier B.V. All rights reserved.
Soluphor P
1. Introduction
was the first non-platinum metal complex to enter phase I
clinical trials in 1993 [9]. The compound exhibited hydrolytic
Ever since the discovery of cisplatin for the treatment of
a variety of tumours, there has been an increased effort devoted to
the identification and clinical development of novel organometallic
compounds which overcome cross resistance in patients and have
more favourable toxicity profiles [1,2]. Despite this effort, move-
ment of other transition-metal antitumour agents toward the clinic
has been extremely slow. This is perhaps due to the assumption
that organometallic chemistry and biology are mutually incom-
patible with many organometallic compounds being sensitive to
water and oxidation. Research over the last decade by Alberto [3]
and Jaouen [4] has shown that organometallic pharmaceuticals
can infact be formulated.
Köpf first identified the antitumour activity of metallocenes
[5], most notably of which is titanocene (bis-cyclopentadienyl
titanium) dichloride or Cp2TiCl2 and has been investigated for
use against various animal and xenografted human tumours
including fluid and solid sarcoma 180 [6], colon 38 and B16
melanoma [7] and fluid and solid Ehrlich ascites tumour (EAT)
[8]. Based on these encouraging results titanocene dichloride
instability under a pH of 5, which held back the identification of
the active species responsible for antitumour activity. A formu-
lation of titanocene dichloride in malic acid was required for
administration of the compound in clinical trials [10]. The
maximum tolerated dose was an IV injection of 560 mg/kg,
contrary to preclinical trials where liver toxicity was the dose-
limiting effect, renal toxicity was identified as the dose-limiting
side effect. Two minor responses out of the 40 patients were
observed, those with bladder carcinoma and non-small cell lung
cancer [10]. Despite this low rate of success the compound
proceeded to phase II clinical trials in 1998 for patients with
metastatic renal cell Carcinoma [11]. Previous to this study
Kurbacher et al. showed that the in vitro activity of titanocene
dichloride in renal cell carcinoma (RCC) specimens was more
favourable over conventional antineoplastic agents such as
cisplatin, doxorubicin, mitoxantrone and vinblastine [12]. The
results from phase II trials indicated that using titanocene
dichloride as a single agent in chemotherapy was not sufficiently
promising to warrant further studies and titanocene dichloride
has been discontinued from further clinical trials.
As previously stated, a limiting property of titanocene dichloride
is its very lowaqueous solubility, generally requiring formulation for
administration as a drug. Derivatives of titanocene dichloride can be
* Corresponding author.
E-mail address: matthias.tacke@ucd.ie (M. Tacke).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.10.039

A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
1073
N
N
N
N
N
H
H
Cl
O
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Ti
Ti
Ti
Ti
Cl
N
N
N
N
N
1a
1b
1c
1d
Fig. 1. Previously synthesised indole-substituted titanocenes.
generated either by substitution of the chloride anions or through
alteration of the cyclopentadienyl ring to increase water solubility.
One approach has involved the substitution of the chlorides anions
by thiols, this improved the hydrolytic stabilityof the compound and
increased cell growth inhibition in both the HeLa and COLO 320DM
cell lines [13]. Baird [14,15] and McGowan [16,17] have both
exploited the use of aryl and alkyl ammonium salts to produce water
soluble derivatives of titanocene dichloride. These compounds were
shown to have significantly better activity and stability than their
nonfunctionalized counterpart titanocene dichloride and gave
a potent cytotoxic effect on cisplatin-resistant ovarian tumour cell
lines. Another importantobservation made bybothgroupsis the fact
that the dicationic analogues demonstrated quite significant
potency when compared to their monocationic counterparts [18].
Gansäuer et al. synthesised water soluble carbonyl-substituted
titanocenes and tested their activity for apoptosis on a range of cells
including A375, MCF-7 cells and Jurkat cells. These compounds
showed promising in vivo activity on SCID mice bearing human
lymphomas [19]. Melëndez et al. have showed that incorporation of
various steroidal esters into titanocene dichloride have potential as
vectors for anticancer compounds such as these [20].
Soluphor P increased the cytotoxicity of compound 1a ten-fold to
give an IC50 value of 0.71 M against CAKI-1 cells in vitro.
m
This paper is now reporting the synthesis and cytotoxicity of
achiral indole-substituted titanocene dichloride derivatives, which
explore structural analogues of compounds 1a and 1b. Where these
compounds were substituted to the CP on the 5-membered ring of
the indole, we wished to investigate substitution of the CP to all
available positions of the indoles 6-membered ring. Structure and
shape of complexes such as these is of utmost importance for
biological activity. Varying the position of attachment of the CP ring
would give us an insight into the difference in activity of these
compounds and allow us to build on these results for future work.
Both the indole-substituted titanocenes and corresponding “gra-
mine” substituted titanocenes have been synthesised for compar-
ison purposes.
2. Results and discussion
2.1. Synthesis
1H-Indole-4-carbaldehyde, 1H-Indole-5-carbaldehyde and 6-
Bromo-1H-indole were available commercially and used as
received. The methylation of indoles was achieved by N-alkylation
with NaH and methyliodide [23]. Introduction of an aldehyde group
into indoles 3c and 3d was achieved using a halogen-lithium
exchange with n-BuLi followed by a DMF quench and subsequent
work up in aq HCl [24]. The Bartoli indole synthesis, whereby 2-
nitrobromobenzene and three equivalents of vinyl magnesium
bromide were used to generate indole 2, Scheme 1 [25]. The
Mannich reaction, whereby an indole is reacted with formaldehyde
and dimethylamine in the presence of acetic acid was used to
incorporate the dimethylaminomethyl functionality to the four
indoles 3aed to give compounds 3eeh [26] (Fig. 3).
In an attempt to exploit this alkyl ammonium substituent for the
development of new water soluble drug candidates, we recently
reported the use of indole-substituted titanocenes [21]. Substitu-
tion of the Cp ring with a gramine side arm was the most logical
choice for this type of compound to give a dihydrochloride deriv-
ative of bis[(1-methyl-3-dimethylaminomethylindol-2-yl)cyclo-
pentadienyl]titanium(IV) dichloride 1a (Fig. 1). This compound was
tested on the CAKI-1 cell line, to give an IC50 value of 13
mM when
tested without any solubilising agent, and 8.2 M when 0.7% DMSO
m
was used as a co-solvent, which is five-fold increase in cytotoxicity
when compared to indole-substituted titanocene 1c. A compli-
mentary study also carried out within our research group was to
compare the cytotoxic behaviour of compound 1a with different
formulation reagents such as the non-ionic surfactants Cremophor
EL and Tween 80, pegylated reagents PEG-400 and Solutol HS 15,
and the co-solvent Soluphor P (Fig. 2) [22]. It was found that
The synthesis of fulvenes 4aeh (Fig. 4) from aldehydes 3aeh is
based on a modified version of the Stone and Little method [27] and
MgBr
3x
THF, -40oC
NO2
N
Br
O
H
Br
N
2
Fig. 2. Soluphor P.
Scheme 1. Bartoli synthesis of indole 2.

1074
A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
O
O
O
N
N
N
N
3c
3b
3a
3d
O
O
O
N
N
N
N
O
N
N
N
N
3g
3f
3e
3h
O
Fig. 3. The structure of indoles 3aeh.
described in [28]; the corresponding aldehyde was reacted with
freshly cracked cyclopentadiene in the presence of pyrrolidine as
a base catalyst to yield the desired product in yields of 47e92%.
The exocyclic double bond in the fulvenes is more reactive and
allows for selective hydride insertion at this double bond and not
at the diene component of the fulvenes. Hydride insertion was
achieved using LiBEt3H (superhydride) in diethyl ether to obtain
the correspondingly functionalised lithium cyclopentadienide
intermediate. These intermediates were then isolated by filtration,
dried in vacuo and re-dissolved in THF. Two equivalents of the
lithium cyclopentadienide intermediate were then trans-
metallated with one equivalent of TiCl4, resulting in the formation
of one equivalent of the appropriately substituted titanocenes
5aeh (Figs. 5 and 6) in yields of 41e81% and the by-product
lithium chloride. Titanocenes 5eeh were then treated with 2
equivalents of HCl in DCM/diethyl ether to produce the water
soluble dihydrochloride salt of their dimethylaminomethyl func-
tionalised parent (Table 1).
2.2. Structural discussion
A single crystal of titanocene 5a suitable for X-ray diffraction
experiments was obtained by the slow diffusion of pentane into
saturated solutions of the compound in chloroform. Selected bond
lengths and angles are displayed in Table 2, while the crystal data
and refinement details for 5a are found in Table 3.
This crystal was compared to a previously synthesised indole-
substituted titanocene 1d [19]. The indole component of this tita-
nocene is attached to the cyclopentadienyl ring on the 5-membered
“pyrrole” unit, namely position 3 of the indole. Its structure can be
seen in Fig. 7. Compound 5a is bound to the cyclopentadienyl ring at
position 4 of the 6-membered ring of the indole. The length of
bonds between the metal centre and the carbon atoms of the
cyclopentadienyl rings bound to the metal ion are similar for both
titanocenes. They vary between 233.6 and 244.6 ppm for 1d and
233.5(2)e240.9(2) for 5a. The length of the carbonecarbon bonds
of the cyclopentadienyl rings vary between 140.0 and 142.5 ppm for
N
N
N
N
4c
4b
4a
4d
N
N
N
N
N
N
N
N
4g
4f
4e
4h
Fig. 4. The structure of fulvenes 4aeh.

A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
1075
N
N
Ti
N
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Ti
Ti
Ti
N
N
5a
5c
5d
5b
Fig. 5. The structure of titanocenes 5aed.
1d and 137.7(3)e143.0(2) for 5a. The bond lengths in the indole are
similar for both compounds, with 1d varying between 136.0(3)e
145.4(3) and 5a between 136.8(2)e143.2(2) ppm. The dihedral
angle created by C(1)eC(6)eC(7)eC(8) is 123.3(2)ꢀ for 1d and for 5a
C(1)eC(6)eC(7)eC(15) is 102.8(1)ꢀ, whereas the dihedral angle C
(17)eC(22)eC(23)eC(24) is 119.2ꢀ for 1d and for 5a C(16)eC(21)eC
(22)eC(230) is 112.4(5)ꢀ. These values show that for 1d, the indole
substituents are orientated at a more obtuse angle to reduce steric
strain between both rings. The titaniumechlorine bond lengths are
almost identical for both structures with values between 236.3 and
237.3 ppm. The CleTieCl’ angle was measured for 1d as 92.34(2)ꢀ
and for 5a is 94.66(3) for Cl(1)eTieCl(2A) and 98.4(2) for Cl(2B)e
TieCl(1). The two structures show similar conformations as the
indole substituents in both cases are orientated away from each
other, to reduce steric hindrance.
2.3. Cytotoxicity studies
The cytotoxic effects of titanocenes 5aeh were determined
using in vitro cultured human renal cell carcinoma CAKI-1 cells. The
cell line was obtained from the ATCC (American Tissue Cell Culture
Collection) (HTB-47) in 2001 and maintained in Dulbecco’s modi-
fied eagle medium containing 10% (v/v) FBS (Foetal Bovine Serum),
1% (v/v) penicillin streptomycin, and 1% (v/v) L-glutamine. Cyto-
toxicities of the various titanocenes were determined by an MTT-
based assay.
This series described comprises of
a range of structural
analogues of 1b (with two distinct subsets; indole-substituted
titanocenes 5aed and a dihydrochloride salt of their dimethyla-
minomethyl functionalised counterpart 5eeh) which complement
and add to the previously reported series of indole-substituted
H
N
Cl
H
N
Cl
N
N
N
H
N
Cl
Cl
H
N
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Ti
Ti
Ti
Ti
H
Cl
N
Cl
N
H
N
N
N
Cl
Cl
N
H
H
5e
5f
5g
5h
Fig. 6. The structures of titanocenes 5eeh.

1076
A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
Table 1
Table 3
Cytotoxicities of titanocenes 5aeh on CAKI-1 cell lines using DMSO and Soluphor P
Crystal data and structure refinement for 5a.
based formulations.
Identification code
5a
Compound
IC-50
m
M (DMSO)
IC-50 mM (Soluphor P)
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C30 H28 N2 Cl2 Ti
535.34
100(2) K
5a
5b
5c
5d
5e
5f
13(ꢄ1)
85 (ꢄ5)
98 (ꢄ5)
NA
180 (ꢄ6)
24 (ꢄ3)
27 (ꢄ4)
NA
18 (ꢄ3)
No cell death
39 (ꢄ3)
0.71073 Å
Monoclinic
P21/n (#14)
a ¼ 7.1999(2) Å,
7 (ꢄ0.9)
19 (ꢄ4)
Unit cell dimensions
a
¼ 90ꢀ.
5g
5h
No cell death
25 (ꢄ4)
b ¼ 24.9674(6) Å,
c ¼ 14.0664(4) Å,
2465.24(11) Å3
4
b
¼ 102.855(3)ꢀ.
¼ 90ꢀ.
40 (ꢄ1)
g
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to theta ¼ 26.43ꢀ
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodnesseofefit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
Largest diff. peak and hole
1.442 Mg/m3
0.587 mmꢁ1
1112
titanocenes [19]. Compounds 5eeh were tested with and without
DMSO, the results of which showed little or no variation in cyto-
toxicity. For comparative purposes only the tests carried out using
DMSO are shown. The IC50 data obtained are shown in Figs. 8
and 9, and it is clear there is little variation in potency for
compounds 5a,b,d and 5e,f,h. However there is one striking
observation, compound 5c and its dimethylaminomethyl func-
tionalised equivalent 5g (which are both attached to the cyclo-
pentadienyl ring at position six of the indole) both show a complete
lack of cytotoxic activity. This was unexpected as this series of
compounds exhibit very subtle structural differences. This differ-
ence in reactivity may be due to instability of the titanocenes as
unidentified decomposition products could be seen in solution
after one day.
0.2229 ꢂ 0.1673 ꢂ 0.0374 mm3
3.33e29.52ꢀ.
ꢁ9ꢃhꢃ9,e34ꢃkꢃ31,e18ꢃlꢃ18
25,876
6230 [R(int) ¼ 0.0253]
99.7%
Analytical
0.980 and 0.912
Full matrix least squares on F2
6230/3/328a
1.022
R1 ¼ 0.0376, wR2 ¼ 0.1024
R1 ¼ 0.0501, wR2 ¼ 0.1067
0.699 and e0.315 e.Åꢁ3
a
Ordered and disordered TieCl bond lengths were restrained to be equal using
SADI.
Indole-substituted titanocenes all show a medium level of
cytotoxicity when tested against the CAKI-1 cell line, with IC50
values for 5a,b,d as 13, 18 and 39
comparable to compound 1b (21
position three of the indole. As expected, incorporation of a dime-
thylaminomethyl group into position two of the indole, compounds
5e and 5h exhibited higher potencies when compared to their more
hydrophobic counterparts with values of 7 mM and 25 mM. Infact
compound 5e was the most potent of the series. Titanocene 5f did
not show a marked improvement in cytotoxicity when compared to
its lypophilic counterpart 5b with an IC50 value of 19
m
M respectively. These values are
mM), which is bonded to the CP on
With the exception of compounds 5c and 5g (which showed no
activity) the titanocenes were further tested on the CAKI-1 cell line
using the solubilising agent Soluphor P (2-pyrrolidone). Soluphor P
is a low molecular weight cyclic amide which is water-miscible, and
liquid at room temperature with solubilising properties. The
toxicity of Soluphor P is attractively low; its oral LD50 in rats is
5000 mg/kg. In one study it was concluded that it is a better co-
solvent than commonly used pharmaceutical co-solvents such as
propylene glycol or glycerine [29]. Compound 1a was tested on the
CAKI-1 cell line using Soluphor P as the solubilising agent, the result
mM versus
18 M. It did however become water soluble, which is an obvious
m
advantage when administering compounds such as these in the
clinic.
of which was a ten-fold increase in cytotoxicity from 8.2
0.71 M when tested with DMSO.
mM to
m
Surprisingly, when all six titanocenes of the series were solubi-
lised using Soluphor P and tested on the CAKI-1 cell line the
potencies exhibited were lower when compared to the tests using
DMSO as the solubilising agent. Readilyevident in Figs. 8 and 9, it can
be seen that titanocenes 5a,b,d suffered a greater loss in potency
when compared to their more hydrophilic counterparts 5e,f,h with
compound 5a showing a 7-fold decrease in activity. It is not clear
why compound 1a should undergo a ten-fold increase in activity
while compounds substituted to the CP through the 6-membered
ring of the indole all show a decrease in activity. Further studies into
this trend are ongoing and will be reported in due course.
Table 2
Selected bond lengths and angles for crystal structures of titanocenes 1d and 5a.
Bond lengths (ppm)
1d
5a
240.9(2)
TieC(17)
TieC(18)
TieC(19)
TieC(20)
240.6(2)
241.0(2)
239.8(2)
233.7(2)
236.9(2)
141.7(2)
140.7(2)
142.5(2)
140.4(2)
140.9(2)
237.7(1)
237.2(1)
NA
TieC(16)
TieC(17)
TieC(18)
TieC(19)
TieC(20)
C(1)eC(2)
C(2)eC(3)
C(3)eC(4)
C(4)eC(5)
C(5)eC(1)
TieCl(1)
TieCl(2A)
TieCl(2B)
C(1)eC(6)
C(6)eC(7)
TieCent1
TieCent2
240.1(2)
238.0(2)
233.5(2)
237.0(2)
140.6(2)
142.7(2)
138.7(3)
141.4(2)
141.6(2)
236.4(5)
238.4(8)
233.2(8)
150.1(2)
151.4(2)
206.4(1)
205.4(1)
TieC(21)
C(1)eC(2)
C(2)eC(3)
C(3)eC(4)
C(4)eC(5)
C(5)eC(1)
TieCl(1)
TieCl(2A)
TieCl(2B)
C(1)eC(6)
C(6)eC(7)
TieCent1
3. Conclusion and outlook
Eight new titanocenes, all similar in functionality to previous
compounds which exhibit promising cytotoxic activities, have been
synthesised and characterized. The eight compounds have been
assessed for their cytotoxicities against the human kidney cancer
cell line CAKI-1 with and without DMSO and Soluphor P. The
150.6(2)
150.0(2)
206.0(1)
206.0(1)
TieCent2
Bond angles [ꢀ]
Cent1eTieCent2
Cl(2)eTieCl(1)
Cl(2B)eTieCl(1)
130.8(2)
92.3 (2)
NA
Cent1eTieCent2
Cl(2A)eTieCl(1)
Cl(2B)eTieCl(1)
131.09(1)
94.66(3)
98.4(2)
compounds display medium to high cytotoxicity (7e39
tested using DMSO and lower activity when tested with Soluphor P
(24e180 M). The IC50 values of the compounds are consistent
mM) when
m

A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
1077
Fig. 7. Crystal structure of 5a. Thermal ellipsoids are drawn on the 50% probability level, disorder neglected.
with similar titanocenes in the literature, however titanocenes 5c
and 5g exhibit no potency when compared to their structural
analogues. In agreement with previous findings on similar
compounds but for reasons which at present are unknown, there
are remarkable variations in the potencies of titanocenes exhibiting
similar structural features.
titanocene-based anticancer drugs remains very deserving of
attention.
4. Experimental
4.1. General conditions
Although Soluphor P increased the potency of compound 1a
ten-fold, it did not achieve the desired effect on this series of tita-
nocenes which is a surprising result. However we have shown that
it is possible to synthesise analogues of titanocenes that are water
soluble and do not require the need for solubilising agents such as
Soluphor P. Addition of a dimethylaminomethyl group to the indole
increases the activity of the compounds as well as removes the
need for formulating agents, which is of a great advantage in the
clinic. This is most evident in compound 5a and its dimethylami-
nomethyl functionalised counterpart 5e. Formulation of 5a with
Soluphor P causes a 7-fold decrease in activity, whereas the addi-
tion of the dimethylaminomethyl group to give 5e causes the
compound to become water soluble and increases activity by
a whole order of magnitude. Nonetheless the potency of 1a
demonstrates that this approach to the development of new
Titanium tetrachloride (1.0 M solution in toluene), Super
Hydride (LiBEt3H, 1.0 M solution in THF), and all chemicals were
obtained commercially from Aldrich Chemical Co. and used
without any further purification. 1H-indole-4-carbaldehyde, 1H-
indole-5-carbaldehyde and 6-bromo-1H-indole were purchased
from Apollo Scientific and used as received. Solvents were dried in
a Grubbs apparatus and collected under an atmosphere of nitrogen
prior to use. All spectroscopic data of titanocenes 5eeh are of the
hydrochloride salts of the parent compound. Manipulations of air
and moisture sensitive compounds were done using standard
Schlenk techniques, under a nitrogen atmosphere. NMR spectra
were measured on a Varian 300, 400, or 500 MHz spectrometer.
Chemical shifts are reported in ppm and are referenced to TMS. IR
spectra were recorded on a Varian 3100 FT-IR Excalibur Series
1.2
1.0
0.8
0.6
1.2
1.0
0.8
0.6
0.4
5e, 7.0 (+/- 0.9) 10-6
M
0.4
0.2
0.0
5a, 13 (+/- 1) 10-6
M
M
5f, 19 (+/- 4) 10-6
5g, No cell death
M
5b, 18 (+/- 3) 10-6
5c, No cell death
0.2
0.0
5h, 25 (+/- 4) 10-6
M
5d, 39 (+/- 3) 10-6
M
1E-10
1E-9
1E-8
1E-7
1E-6
1E-5
1E-4
1E-3
1E-10
1E-9
1E-8
1E-7
1E-6
1E-5
1E-4
1E-3
Log10 Drug Concentration (M)
Log10 Drug Concentration (M)
Fig. 8. Cytotoxicity studies of titanocenes 5aeh against CAKI-1 cells using DMSO as co-solvent.

1078
A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1.2
1.0
0.8
0.6
5a, 85 (+/- 5) 10-6
5b, 98 (+/- 5) 10-6
M
0.4
5e, 24 (+/- 3) 10-6
M
M
5f, 27 (+/- 4) 10-6
5h, 40 (+/- 1) 10-6
M
5d, 180 (+/- 6) 10-6
M
0.2
0.0
M
1E-10
1E-9
1E-8
1E-7
1E-6
1E-5
1E-4
1E-3
1E-10
1E-9
1E-8
1E-7
1E-6
1E-5
1E-4
1E-3
Log10 Drug Concentration (M)
Log10 Drug Concentration (M)
Fig. 9. Cytotoxicity studies of titanocenes against CAKI-1 cells using Soluphor P as co-solvent.
employing a KBr disk. UVeVis spectra were recorded on a Cary
50 Scan UVeVisible Spectrophotometer, in nm, in
incubation at 37 ꢀC, individual wells were treated with 200
mL of
(l
3
a solution of MTT in medium (5 mg MTT per 11 mL medium). The
dm3 molꢁ1 cmꢁ1). A single crystal of titanocene 5a suitable for X-
ray diffraction experiments was grown by the diffusion of pentane
into a saturated solution of 5a in chloroform at room temperature.
X-ray diffraction data for the compound was collected on a BRUKER
Smart Apex diffractometer at 100 K. A semi-empirical absorption
correction on the raw data was performed using the program
SADABS [30]. The crystal structure was then solved by direct
methods (SHELXS-NT97) [31] and refined by full matrix least
squares methods against F2. Further details about the data collec-
tion are listed in Table 2, as well as reliability factors. Additional
details are available free of charge from the Cambridge Structural
Database under the CCDC No. 789464. The formulations were
sonicated using a VWR Ultrasonic Cleaner (45 kHz). MS data was
collected on a quadrupole tandem mass spectrometer (Quattro
Micro, Micromass/Water’s Corp., USA), and prepared as solutions of
tetrahydrofuran (THF). C,H,N analysis was carried out with an
Exeter-CE-440 elemental analyser, and Cl was determined by mer-
curimetric titrations.
cells were incubated for 3 h at 37 ꢀC. The mediumwas then removed,
and the purple formazan crystals weredissolved in 200 mL DMSO per
well. Absorbance was then measured at 540 nm by a Wallac-Victor
(Multilabel HTS Counter) plate reader or a SpectraMax 190 Microplate
Reader. Cell viability was expressed as a percentage of the absor-
bance recorded for control wells. The values used for the dose
response curves of Figs. 8 and 9 represent the values obtained from
four consistent MTT-based assays for each compound tested.
4.3. Synthesis
4.3.1. 4-(Cyclopenta-2,4-dienylidenemethyl)-1-methylindole (4a)
1-Methylindole-4-carbaldehyde (3a) (2.2 g, 13.8 mmol) was
dissolved in MeOH (70 mL). Freshly cracked cyclopentadiene
(1.5 mL, 18 mmol) was added to the solution followed by pyrroli-
dine (1.2 mL, 15 mmol) and the colour immediately changed from
light yellow to red. The reaction was left to stir whilst being
monitored by thin layer chromatography (silica/DCM), which
showed consumption of starting material after 4 h. Acetic acid
(1 mL) was added to quench the reaction and the product was
extracted with DCM (2 ꢂ 50 mL). The organic layers were combined
and washed with H2O (2 ꢂ 50 mL) and brine (2 ꢂ 50 mL). The DCM
was dried over sodium sulphate and the solvent removed at
reduced pressure to give a red oil in 77% yield. (2.2 g, 10.6 mmol).
4.2. MTT-based assay (MTT ¼ 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyl-2H-tetrazolium bromide)
Preliminary in vitro cell tests were performed on CAKI-1 cells to
compare the cytotoxicity of the compounds presented in this work.
The cell line was obtained from the ATCC (American Tissue Cell
Culture Collection) (HTB-47) in 2001 and maintained in Dulbecco’s
modified eagle medium containing 10% (v/v) FBS (Foetal Bovine
1H NMR (300 MHz, CDCl3)
d
7.66 (s, 1H), 7.46 (d, J ¼ 7.2, 1H),
7.35e7.31 (m, 1H), 7.28 (d, J ¼ 7.2, 1H), 7.10 (m, 1H), 6.79e6.75
(m, 1H), 6.67e6.62 (m, 2H), 6.55e6.51 (m, 1H), 6.44e6.39 (m, 1H),
3.79 (s, 3H).
Serum), 1% (v/v) penicillin streptomycin, and 1% (v/v) L-glutamine.
The cytotoxicities of titanocenes 5aeh were determined by an
13C NMR (75 MHz, CDCl3)
d 145.1, 136.9, 136.4, 134.5, 130.6, 129.7,
MTT-based assay [32].
128.9, 128.9, 126.9, 122.5, 121.7, 121.4, 110.4, 99.5, 33.0 [NeCH3].
Specifically, cells wereseeded in 96-well platescontaining200 mL
ES-MS: m/z 208 [M þ H]þ.
of medium, and were incubated at 37 ꢀC and 5% carbon dioxide for
24 h to allow for exponential growth. The compounds used for
HRMS: m/z calcd for C15H14N [M þ H]þ, 208.1126, found
208.1118. lmax [nm], (3
) [L molꢁ1 cmꢁ1], CHCl3: 274 (10600), 386
testing were dissolved in dimethyl sulfoxide (70
m
L DMSO) and
(9000).
diluted with medium to obtain stock solutions of 5 ꢂ 10ꢁ4 M in
IR (KBr disk, cmꢁ1): 3100, 3065, 2941, 2911, 1619, 1597, 1511,
1493, 1466, 1435, 1417, 1342, 1292, 1086, 996, 895.
concentration. In the case of formulations using Soluphor P, the
compounds were dissolved in 50 mL Soluphor P and sonicated at
room temperature for 5 min. The cells were then treated with
varying concentrations of the compounds and incubated for 48 h at
37 ꢀC. At that time, the solutions were removed from the wells, the
cells were washed with PBS (phosphate buffer solution), and fresh
medium was added to the wells. Following a recovery period of 24 h
4.3.2. Bis-[((1-methylindole)-4)-cyclopentadienyl]titanium (IV)
dichloride (5a)
1 M Solution of Super Hydride (LiBEt3H) (11.50 mL, 11.50 mmol)
in THF was concentrated by removal of the solvent by heating at
60 ꢀC under reduced pressure of 10ꢁ2 mbar for 40 min and then to

A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
1079
90 ꢀC for 20 min in a Schlenk flask. 4-(Cyclopenta-2,4-dien-
ylidenemethyl)-1-methylindole (4a) (2.10 g, 10.15 mmol) was
added to a Schlenk flask and dissolved in dry diethyl ether (100 mL)
to give a red solution. The red fulvene solution was transferred to
the Super Hydride solution via cannula. The solution was left to stir
for 16 h, in which time a white precipitate of the lithium cyclo-
pentadienide intermediate formed and the solution had changed
its colour from orange/red to white. The precipitate was filtered on
to a frit. The white precipitate was dried under reduced pressure
and transferred to a Schlenk flask under nitrogen. The lithium
cyclopentadienide intermediate was dissolved in dry THF (50 mL)
to give a colourless solution. Titanium tetrachloride (2.60 mL,
2.60 mmol) was added to the lithium cyclopentadienide interme-
diate solution to give a dark brown solution. The dark brown tita-
nium solution was refluxed for 16 h. The solution was then cooled
and the solvent was removed under reduced pressure. The
remaining residue was extracted with DCM (50 mL) and filtered
through celite to remove the remaining LiCl. The solvent was
removed under reduced pressure to yield a brown solid. This was
then washed with pentane (3 ꢂ 50 mL) and diethyl ether
(2 ꢂ 50 mL) to give a brown solid in 44% yield (1.2 g, 2.24 mmol).
90 ꢀC for 20 min in a Schlenk flask. 5-(Cyclopenta-2,4-dien-
ylidenemethyl)-1-methylindole (4b) (1.90 g, 9.18 mmol) was added
to a Schlenk flask and dissolved in dry diethyl ether (100 mL) to give
a red solution. The red fulvene solution was transferred to the Super
Hydride solution via cannula. The solution was left to stir for 16 h,
in which time a white precipitate of the lithium cyclopentadienide
intermediate formed and the solution had changed its colour from
orange/red to white. The precipitate was filtered on to a frit. The
white precipitate was dried briefly under reduced pressure and was
transferred to a Schlenk flask under nitrogen. The lithium cyclo-
pentadienide intermediate was dissolved in dry THF (50 mL) to give
a colourless solution. Titanium tetrachloride (3.74 mL, 3.74 mmol)
was added to the lithium cyclopentadienide intermediate solution
to give a dark red solution. The dark red titanium solution was re-
fluxed for 16 h. The solution was then cooled and the solvent was
removed under reduced pressure. The remaining residue was
extracted with DCM (100 mL) and filtered through celite to remove
the remaining LiCl. The solvent was removed under reduced pres-
sure to yield a red solid. This was then washed with pentane
(3 ꢂ 50 mL) and diethyl ether (2 ꢂ 50 mL) to give a red solid in 61%
yield (1.5 g, 2.80 mmol).
1H NMR (400 MHz, CDCl3)
d
7.22e7.18 (m, 2H), 7.14 (t, 2H), 7.04
1H NMR (400 MHz, CDCl3)
d 7.45 (s, 2H), 7.27e7.24 (m, 2H),
(d, J ¼ 2.8, 2H), 6.92e6.87 (m, 2H), 6.54 (d, J ¼ 2.8, 2H), 6.36 (s, 4H),
7.13e7.08 (m, 2H), 7.05 (d, J ¼ 3.0, 2H), 6.44 (d, J ¼ 3.0, 2H), 6.35 (s,
6.20 (s, 4H), 4.32 (s, 4H), 3.76 (s, 6H).
4H), 6.25 (s, 4H), 4.17 (s, 4H), 3.77 (s, 6H).
13C NMR (101 MHz, CDCl3)
d
136.8, 136.8, 131.9, 128.7, 127.9,
13C NMR (101 MHz, CDCl3)
d
138.6, 135.7, 130.5, 129.4, 128.9,
122.7 [C5H4eCH2], 121.7, 119.6, 116.3 [C5H4eCH2], 107.9, 99.6, 34.6
123.1, 122.2 [C5H4eCH2], 121.1, 116.8 [C5H4eCH2], 109.4, 100.9, 37.3
[C5H4eCH2], 33.0 [NeCH3]. lmax [nm], (
3
) [L molꢁ1 cmꢁ1], CHCl3:
[C5H4eCH2], 33.1 [NeCH3]. lmax [nm], (3
) [L molꢁ1 cmꢁ1], CHCl3:
268 (13,600).
268 (28,300).
IR (KBrdisk, cmꢁ1):3552, 3481, 3424, 3094, 3045, 2916,1637,1616,
1509, 1491, 1446, 1416, 1344, 1303, 1232, 1082, 1057, 833, 721, 711.
Anal. Calc. for C30H28Cl2N2Ti: C, 67.3; H, 5.27; N, 5.23; Cl, 13.2;
found: C, 67.58; H, 5.50; N, 5.38; Cl, 12.96.
IR (KBr disk, cmꢁ1): 3548, 3472, 3424, 2918, 1637, 1617, 1489,
1444, 1422, 1336, 1301, 1242, 1079, 831, 800, 729.
Anal calculated for C30H28Cl2N2Ti: C, 67.3; H, 5.27; N, 5.23; Cl,
13.2; found: C, 68.6; H, 5.64; N, 5.19; Cl, 12.1.
4.3.3. 5-(Cyclopenta-2,4-dienylidenemethyl)-1-methylindole (4b)
1-Methylindole-5-carbaldehyde (3b) (2.24 g, 14.08 mmol) was
dissolved in MeOH (70 mL). Freshly cracked cyclopentadiene
(1.50 mL, 18.38 mmol) was added to the solution followed by pyr-
rolidine (1.20 mL,14.63 mmol) and the colour immediately changed
from light yellow to red. The reaction was left to stir whilst being
monitored by thin layer chromatography (silica/DCM), which
showed consumption of starting material after 6 h. Acetic acid
(1 mL) was added to quench the reaction and the product was
extracted with DCM (2 ꢂ 50 mL). The organic layers were combined
and washed with H2O (2 ꢂ 50 mL) and brine (2 ꢂ 50 mL). The DCM
was dried over sodium sulphate and the solvent removed at
reduced pressure to give a red oil in 72% yield. (2.10 g, 10.14 mmol).
4.3.5. 6-(Cyclopenta-2,4-dienylidenemethyl)-1-methylindole (4c)
1-Methylindole-6-carbaldehyde (3c) (1.3 g, 8.18 mmol) was
dissolved in MeOH (70 mL). Freshly cracked cyclopentadiene
(0.8 mL, 9.80 mmol) was added to the solution followed by pyr-
rolidine (0.8 mL, 9.76 mmol) and the colour immediately changed
from light yellow to red. The reaction was left to stir whilst being
monitored by thin layer chromatography (silica/DCM), which
showed consumption of starting material after 3 h. Acetic acid
(1 mL) was added to quench the reaction and the product was
extracted with DCM (2 ꢂ 50 mL). The organic layers were combined
and washed with H2O (2 ꢂ 50 mL) and brine (2 ꢂ 50 mL). The DCM
was dried over sodium sulphate and the solvent removed at
reduced pressure to give a red oil. The red oil was purified by
column chromatography with dichloromethane used as the eluent.
The dichloromethane was removed at reduced pressure to yield
a red oil in 47% yield. (0.8 g, 3.86 mmol).
1H NMR (400 MHz, CDCl3)
d
7.90 (s, 1H), 7.56 (dd, J ¼ 8.6, 1.3, 1H),
7.38 (s, 1H), 7.33 (d, J ¼ 8.6, 1H), 7.07 (d, J ¼ 3.1, 1H), 6.86 (d, J ¼ 5.1,
1H), 6.71e6.65 (m, 1H), 6.53 (d, J ¼ 3.1, 1H), 6.49 (d, J ¼ 5.1, 1H),
6.40e6.35 (m, 1H), 3.79 (s, 3H).
1H NMR (400 MHz, CDCl3)
d
7.62 (d, J ¼ 8.3, 1H), 7.57 (s, 1H), 7.41
13C NMR (101 MHz, CDCl3)
d
142.67, 140.94, 137.22, 134.44
(d, J ¼ 8.3,1H), 7.39 (s,1H), 7.12 (m,1H), 6.87e6.82 (m,1H), 6.70e6.65
[C5H4eCH2], 129.94, 129.18 [C5H4eCH2], 128.83, 128.38, 127.50
[C5H4eCH], 124.72, 124.68, 120.34 [C5H4eCH], 109.59, 102.10, 32.97
(NeCH3).
(m, 1H), 6.52e6.46 (m, 2H), 6.39e6.34 (m, 1H), 3.82 (s, 3H).
13C NMR (101 MHz, CDCl3)
d 143.3, 140.7, 136.9, 134.7, 131.1,
130.4, 129.5, 127.4, 122.5, 121.0, 120.4, 112.4, 101.4, 32.9 [NeCH3].
ES-MS: m/z 208 [M þ H]þ.
ES-MS: m/z 208 [M þ H]þ.
HRMS: m/z calcd for C15H14N [M þ H]þ, 208.1126, found 208.1117.
HRMS: m/z calcd for C15H14N [M þ H]þ, 208.1126, found
lmax [nm], (
3
) [L molꢁ1 cmꢁ1], CHCl3: 273 (11,300), 382 (9000).
208.1116. lmax [nm], (3
) [L molꢁ1 cmꢁ1], CHCl3: 272 (11,400), 377
IR (KBr disk, cmꢁ1): 3466, 3384, 1616, 1603, 1486, 1372, 1331,
1304, 1245, 1160, 1099, 1077, 994, 897, 773.
(19,700).
IR (KBr disk, cmꢁ1): 3097, 2925, 1623, 1613, 1506, 1469, 1419,
1382, 1345, 1314, 1252, 1202, 1089, 994, 898, 811, 761.
4.3.4. Bis-[((1-Methylindole)-5)-cyclopentadienyl]titanium (IV)
dichloride (5b)
1 M Solution of Super Hydride (LiBEt3H) (11.00 mL, 11.00 mmol)
in THF was concentrated by removal of the solvent by heating it to
60 ꢀC under reduced pressure of 10ꢁ2 mbar for 40 min and then to
4.3.6. Bis-[((1-methylindole)-6)-cyclopentadienyl]titanium (IV)
dichloride (5c)
1 M Solution of Super Hydride (LiBEt3H) (3.00 mL, 3.00 mmol) in
THF was concentrated by removal of the solvent by heating it to

1080
A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
60 ꢀC under reduced pressure of 10ꢁ2 mbar for 40 min and then to
90 ꢀC for 20 min in a Schlenk flask. 6-(Cyclopenta-2,4-dien-
ylidenemethyl)-1-methylindole (4c) (0.60 g, 2.89 mmol) was added
to a Schlenk flask and dissolved in dry diethyl ether (40 mL) to give
a red solution. The red fulvene solution was transferred to the Super
Hydride solution via cannula. The solution was left to stir for 16 h, in
which time a white precipitate of the lithium cyclopentadienide
intermediate formed and the solution had changed its colour from
orange to white. The precipitate was filtered on to a frit. The white
precipitate was dried briefly under reduced pressure and was
transferred to a Schlenk flask under nitrogen. The lithium cyclo-
pentadienide intermediate was dissolved in dry THF (50 mL) to give
a colourless solution. Titanium tetrachloride (1.06 mL, 1.06 mmol)
was added to the lithium cyclopentadienide intermediate solution
to give a dark red solution. The dark red titanium solution was re-
fluxed for 16 h. The solution was then cooled and the solvent was
removed under reduced pressure. The remaining residue was
extracted with DCM (100 mL) and filtered through celite to remove
the remaining LiCl. The solvent was removed under reduced pres-
sure to yield a red solid. This was then washed with pentane
(3 ꢂ 50 mL) and diethyl ether (3 ꢂ 50 mL) to give a red solid in 65%
yield (0.51 g, 0.96 mmol).
60 ꢀC under reduced pressure of 10ꢁ2 mbar for 40 min and then to
90 ꢀC for 20 min in a Schlenk flask. 7-(Cyclopenta-2,4-dien-
ylidenemethyl)-1-methylindole (4d) (0.65 g, 3.14 mmol) was added
to a Schlenk flask and dissolved in dry diethyl ether (40 mL) to give
a red solution. The red fulvene solution was transferred to the Super
Hydride solution via cannula. The solution was left to stir for 16 h, in
which time a white precipitate of the lithium cyclopentadienide
intermediate formed and the solution had changed its colour from
orange to white. The precipitate was filtered on to a frit. The white
precipitate was dried under reduced pressure and was transferred
to a Schlenk flask under nitrogen. The lithium cyclopentadienide
intermediate was dissolved in dry THF (50 mL) to give a colourless
solution. Titanium tetrachloride (0.95 mL, 0.95 mmol) was added to
the lithium cyclopentadienide intermediate solution to give a dark
red solution. The dark red titanium solution was refluxed for 16 h.
The solution was then cooled and the solvent was removed under
reduced pressure. The remaining residue was extracted with DCM
(100 mL) and filtered through celite to remove the remaining LiCl.
The solvent was removed under reduced pressure to yield a red
solid. This was then washed with pentane (3 ꢂ 50 mL) and diethyl
ether (3 ꢂ 50 mL) to give a red solid in 48% yield (0.41 g,
0.76 mmol).
1H NMR (400 MHz, CDCl3)
d
7.53 (d, J ¼ 8.1, 2H), 7.17 (s, 2H), 7.01
1H NMR (400 MHz, CDCl3)
d
7.42 (d, J ¼ 7.6, 2H), 6.90 (m, 2H),
(d, J ¼ 3.1, 2H), 6.94 (d, J ¼ 8.1, 2H), 6.43 (d, J ¼ 3.1, 2H), 6.36e6.33
6.85 (d, J ¼ 2.6, 2H), 6.76 (d, J ¼ 7.6, 2H), 6.38 (d, J ¼ 2.6, 2H), 6.18 (s,
(m, 4H), 6.30e6.27 (m, 4H), 4.20 (s, 4H), 3.75 (s, 6H).
4H), 6.14 (s, 4H), 4.52 (s, 4H), 3.83 (s, 6H).
13C NMR (101 MHz, CDCl3)
d
138.4, 137.2, 133.0, 129.1, 127.3,
13C NMR (101 MHz, CDCl3)
d
136.4, 133.7, 129.9, 129.3, 123.3,
122.4, 121.1 [C5H4eCH2], 121.0, 116.6 [C5H4eCH2], 109.9, 101.0, 37.7
121.4, 121.3 [C5H4eCH2], 119.1, 118.6, 115.6 [C5H4eCH2], 100.2, 35.8
[C5H4eCH2], 33.1 [NeCH3]. lmax [nm], (
3
) [L molꢁ1 cmꢁ1], CHCl3:
[C5H4eCH2], 32.4 [NeCH3]. lmax [nm], (3
) [L molꢁ1 cmꢁ1], CHCl3:
278 (12,600).
263 (25600).
IR (KBr disk, cmꢁ1): 3542, 3479, 3413, 2921, 1617, 1510, 1470,
1420, 1340, 1316, 1085, 808.
IR (KBr disk, cmꢁ1): 3537, 3474, 3417, 3097, 2956, 2920, 2848,
1617, 1489, 1474, 1407, 1314, 1261, 1113, 1087, 1061, 821.
Anal. Calc. for C30H28Cl2N2Ti: C, 67.3; H, 5.27; N, 5.23; Cl, 13.25;
found: C, 65.66; H, 5.48; N, 4.89; Cl 12.09.
Anal calculated for C30H28Cl2N2Ti: C, 67.3; H, 5.27; N, 5.23;
found: C, 67.31; H, 5.60; N, 5.99.
4.3.7. Synthesis of 7-(cyclopenta-2,4-dienylidenemethyl)-1-
methylindole (4d)
4.3.9. 3-((Dimethylamino)-methyl)-1-methylindole-4-
carbaldehyde (3e)
1-Methylindole-7-carbaldehyde (3d) (0.70 g, 4.40 mmol) was
dissolved in MeOH (70 mL). Freshly cracked cyclopentadiene
(0.50 mL, 6.12 mmol) was added to the solution followed by pyr-
rolidine (0.25 mL, 3.05 mmol) and the colour immediately changed
from light yellow to red. The reaction was left to stir whilst being
monitored by thin layer chromatography (silica/DCM), which
showed consumption of starting material after 3 h. Acetic acid
(0.50 mL) was added to quench the reaction and the product was
extracted with DCM (2 ꢂ 50 mL). The organic layers were combined
and washed with H2O (2 ꢂ 50 mL) and brine (2 ꢂ 50 mL). The DCM
was dried over sodium sulphate and the solvent removed at
reduced pressure to give a red oil in 83% yield. (0.76 g, 3.67 mmol).
1-Methylindole-4-carbaldehyde (2.6 g, 16.35 mmol) was dis-
solved in acetic acid (40 mL), dimethylamine (4 mL, 32.70 mmol)
was added and the solution was cooled to 30 ꢀC. Formaldehyde
(2.60 mL, 32.70 mmol) was added and the solution was allowed to
stand for 2 h. The mixture was then added to an ice/NaOH (100 mL,
9 M) solution and stirred vigorously for 10 min until a white
precipitate formed. This was filtered, washed with water and
suction dried to give a white solid in 67% yield (2.4 g, 11.11 mmol).
1H NMR (400 MHz, CDCl3)
7.53 (d, J ¼ 7.7, 1H), 7.31 (t, J ¼ 7.7, 1H), 7.13 (s, 1H), 3.81 (s, 3H), 3.65
(s, 2H), 2.23 (s, 6H). 13C NMR (101 MHz, CDCl3)
194.4 [CHO], 138.9,
d
10.69 (s, 1H), 7.79 (d, J ¼ 7.7, 1H),
d
131.8, 130.2, 127.1, 121.3, 121.1, 114.9, 112.9, 56.9 [CH2N(CH3)2], 44.9
[CH2N(CH3)2], 32.9 [NeCH3].
1H NMR (400 MHz, CDCl3)
d
7.92 (s, 1H), 7.62 (d, J ¼ 7.7, 1H), 7.21
(d, J ¼ 7.7, 1H), 7.11 (m, 1H), 6.98 (d, J ¼ 3.1, 1H), 6.66e6.60 (m, 1H),
6.58 (d, J ¼ 5.1, 1H), 6.54 (d, J ¼ 5.1, 1H), 6.50 (d, J ¼ 3.1, 1H),
6.43e6.37 (m, 1H), 3.99 (s, 3H).
ES-MS: m/z 217 [M þ H]þ.
HRMS: m/z calcd for C13H17N2O [M þ H]þ, 217.1341, found
217.1340.
13C NMR (101 MHz, CDCl3)
d
145.9, 135.9, 134.7, 134.4, 131.5,
IR (KBr disk, cmꢁ1): 2939, 2777, 1689, 1638, 1606, 1555, 1459,
1414, 1340, 1314, 1243, 1017, 924, 835, 749.
130.7, 129.8, 127.2, 125.6, 122.3, 121.8 [C5H4eCH], 121.6, 119.4, 101.5,
37.2 [NeCH3].
ES-MS: m/z 208 [M þ H]þ.
4.3.10. 1-(4-(Cyclopenta-2,4-dienylidenemethyl)-1-methylindol-3-
yl)-N,N-dimethylmethanamine (4e)
HRMS: m/z calcd for C18H17NO [M]þ, 263.1310, found 263.1297.
lmax [nm], (
3
) [L molꢁ1 cmꢁ1], CHCl3: 274 (14,100), 377 (9400).
3-((Dimethylamino)-methyl)-1-methyl-indole-4-carbaldehyde
(3e) (2.50 g, 11.57 mmol) was dissolved in MeOH (70 mL). Freshly
cracked cyclopentadiene (1.50 mL, 18.38 mmol) was added to the
solution followed by pyrrolidine (1.00 mL, 12.11 mmol) and the
colour immediately changed from colourless to red. After 6 h acetic
acid (1 mL) was added to quench the reaction and the product was
extracted with DCM (2 ꢂ 50 mL). The organic layers were combined
and washed with H2O (2 ꢂ 50 mL) and brine (2 ꢂ 50 mL). The DCM
IR (KBr disk, cmꢁ1): 3478, 3396, 3235, 2915, 1637, 1617, 1517,
1486, 1463, 1445, 1336, 1297, 1280, 1211, 1077, 798, 765, 722.
4.3.8. Bis-[((1-methylindole)-7)-cyclopentadienyl]titanium (IV)
dichloride (5d)
1 M Solution of Super Hydride (LiBEt3H) (6.2 mL, 6.2 mmol) in
THF was concentrated by removal of the solvent by heating it to

A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
1081
was dried over sodium sulphate and the solvent removed at
reduced pressure to give a red oil in 69% yield. (2.10 g, 7.95 mmol).
was added and the solution was cooled to 30 ꢀC. Formaldehyde
(2.60 mL, 32.70 mmol) was added and the solution was allowed to
stand for 2 h. The mixture was then added to an ice/NaOH (100 mL,
9 M) solution and stirred vigorously for 10 min until a white
precipitate formed. This was filtered, washed with water and
suction dried to give a white solid in 74% yield (2.61 g, 12.08 mmol).
1H NMR (400 MHz, CDCl3)
d 8.49 (s, 1H), 7.36e7.31 (m, 1H), 7.29
(m, 1H), 7.26 (s, 1H), 6.98 (s, 1H), 6.71e6.67 (m, 1H), 6.67e6.63 (m,
1H), 6.58e6.54 (m, 1H), 6.47e6.43 (m, 1H), 3.78 (s, 3H), 3.46 (s, 2H),
2.30 (s, 6H).
13C NMR (101 MHz, CDCl3)
d
144.9,140.3,137.8,133.8 [C5H4eCH],
1H NMR (300 MHz, CDCl3)
d
10.04 (s, 1H), 8.24 (d, J ¼ 1.2, 1H),
130.6, 130.2, 129.9, 127.2, 126.6 [C5H4eCH], 123.7, 121.6, 121.5
[C5H4eCH], 113.5, 110.0, 55.9 [CH2N(CH3)2], 44.8 [CH2N(CH3)2], 32.8
[NeCH3].
7.79 (dd, J ¼ 8.6, 1.2, 1H), 7.36 (d, J ¼ 8.6, 1H), 7.07 (s, 1H), 3.80
(s, 3H), 3.63 (s, 2H), 2.28 (s, 6H).
13C NMR (75 MHz, CDCl3)
d 192.6 [CHO], 140.3, 129.9, 128.9,
ES-MS: m/z 265 [M þ H]þ.
128.1, 125.1, 121.9, 114.5, 109.7, 54.4[CH2N(CH3)2], 45.4 [CH2N
(CH3)2], 32.9 [NeCH3].
HRMS: m/z calcd for C18H21N2 [M þ H]þ, 265.1705, found
265.1714. lmax [nm], (
3
) [L molꢁ1 cmꢁ1], CHCl3: 265 (13,000), 386
ES-MS: m/z 217 [M þ H]þ.
(9100).
HRMS: m/z calcd for C13H17N2O [M þ H]þ, 217.1341, found
217.1337.
IR (KBr disk, cmꢁ1): 2933, 2852, 2809, 2762, 1624, 1600, 1553,
1449, 1419, 1340, 1315, 1255, 1202, 1075, 1044, 1075, 1009, 889, 771,
761.
IR (KBr disk, cmꢁ1): 2940, 2855, 2812, 2764, 1689, 1611, 1569,
1493, 1458, 1385, 1356, 1309, 1190, 1140, 1095, 1027, 1003, 801 763.
4.3.11. Bis-[((1-methyl-indol-3-yl-N,N-dimethylmethana-
miniumchloride)-4)-cyclopentadienyl]titanium (IV) dichloride (5e)
4.3.13. 1-(5-(Cyclopenta-2,4-dienylidenemethyl)-1-methylindol-3-
yl)-N,N-dimethylmethanamine (4f)
1
M
Solution of Super Hydride (LiBEt3H) (10.00 mL,
3-((Dimethylamino)-methyl)-1-methylindole-5-carbaldehyde
(3f) (2.50 g, 11.57 mmol) was dissolved in MeOH (70 mL). Freshly
cracked cyclopentadiene (1.50 mL, 18.38 mmol) was added to the
solution followed by pyrrolidine (1.00 mL, 12.11 mmol) and the
colour immediately changed from colourless to red. After 6 h acetic
acid (1 mL) was added to quench the reaction and the product was
extracted with DCM (2 ꢂ 50 mL). The organic layers were combined
and washed with H2O (2 ꢂ 50 mL) and brine (2 ꢂ 50 mL). The DCM
was dried over sodium sulphate and the solvent removed at
reduced pressure to give a red oil in 72% yield. (2.20 g, 8.33 mmol).
10.00 mmol) in THF was concentrated by removal of the solvent by
heating it to 60 ꢀC under reduced pressure of 10ꢁ2 mbar for 40 min
and then to 90 ꢀC for 20 min in a Schlenk flask. 1-(4-(Cyclopenta-
2,4-dienylidenemethyl)-1-methylindol-3-yl)-N,N-dimethylme-
thanamine (4e) (2.00 g, 7.57 mmol) was added to a Schlenk flask
and dissolved in dry diethyl ether (100 mL) to give a red solution.
The red fulvene solution was transferred to the Super Hydride
solution via cannula. The solution was left to stir for 16 h, in which
time a white precipitate of the lithium cyclopentadienide inter-
mediate formed and the solution had changed its colour from
orange/red to white. The precipitate was filtered on to a frit. The
white precipitate was dried briefly under reduced pressure and
was transferred to a Schlenk flask under nitrogen. The lithium
cyclopentadienide intermediate was dissolved in dry THF (50 mL)
to give a colourless solution. Titanium tetrachloride (1.62 mL,
1.62 mmol) was added to the lithium cyclopentadienide interme-
diate solution to give a dark red solution. The dark red titanium
solution was refluxed for 16 h. The solution was then cooled and
the solvent was removed under reduced pressure. The remaining
residue was extracted with DCM (100 mL) and filtered through
celite to remove the remaining LiCl. The solvent was removed
under reduced pressure to yield an orange solid in 41% yield
(1.00 g, 1.54 mmol). A portion of this solid (0.1 g, 0.15 mmol) was
then dissolved in DCM (10 mL) and an ethereal solution of
hydrogen chloride (0.15 mL, 2 M) was added and a precipitate
immediately formed. Diethyl ether (30 mL) was then added. After
15 min stirring, the solid was filtered to give a brown powder in
45% yield (0.05 g, 0.07 mmol).
1H NMR (400 MHz, CDCl3)
d
7.94 (s, 1H), 7.57 (dd, J ¼ 8.6, 1.3, 1H),
7.40 (s, 1H), 7.30 (d, J ¼ 8.6, 1H), 7.00 (s, 1H), 6.87e6.81 (m, 1H),
6.70e6.65 (m, 1H), 6.50e6.46 (m, 1H), 6.39e6.34 (m, 1H), 3.76 (s,
3H), 3.61 (s, 2H), 2.28 (s, 6H).
13C NMR (101 MHz, CDCl3)
d 142.6, 141.1, 137.5, 134.4 [C5H4eCH],
129.3, 129.1, 128.7, 128.1, 127.5 [C5H4eCH], 124.6, 123.5, 120.3
[C5H4eCH], 113.2, 109.6, 54.3 [CH2N(CH3)2], 45.4 [CH2N(CH3)2], 32.8
[NeCH3].
ES-MS: m/z 265 [M þ H]þ.
HRMS: m/z calcd for C18H17NO [M]þ, 263.1310, found 263.1297.
lmax [nm], (3
) [L molꢁ1 cmꢁ1], CHCl3: 275 (13,800), 380 (8900).
IR (KBr disk, cmꢁ1): 3062, 2939, 2812, 2765, 1735, 1619, 1569,
1487, 1456, 1387, 1350, 1312, 1265, 1196, 1151, 1086, 1027, 995, 924,
848, 798, 763.
4.3.14. Bis-[((1-methyl-indol-3-yl-N,N-dimethylmethana
miniumchloride)-5)-cyclopentadienyl]titanium (IV) dichloride (5f)
1 M Solution of Super Hydride (LiBEt3H) (9.00 mL, 9.00 mmol) in
THF was concentrated by removal of the solvent by heating at 60 ꢀC
under reduced pressure of 10ꢁ2 mbar for 40 min and then to 90 ꢀC
1H NMR (400 MHz, D2O)
d
7.39 (s, 2H), 7.25 (d, J ¼ 8.0, 2H), 6.83
(m, 2H), 6.55 (d, J ¼ 8.0, 2H), 6.02 (s, 4H), 5.94 (s, 4H), 4.23 (s, 4H),
for 20 min in
a Schlenk flask. 1-(5-(Cyclopenta-2,4-dien-
3.69 (s, 6H), 3.65 (s, 4H), 2.63 (s, 12H).
ylidenemethyl)-1-methyl-1H-indol-3-yl)-N,N-dimethylmethan-
amine (4f) (2.00 g, 7.57 mmol) was added to a Schlenk flask and
dissolved in dry diethyl ether (100 mL) to give a red solution. The
red fulvene solution was transferred to the Super Hydride solution
via cannula. The solution was left to stir for 16 h, in which time
a white precipitate of the lithium cyclopentadienide intermediate
formed and the solution had changed its colour from orange/red to
white. The precipitate was filtered on to a frit. The white precipitate
was dried briefly under reduced pressure and was transferred to
a Schlenk flask under nitrogen. The lithium cyclopentadienide
intermediate was dissolved in dry THF (50 mL) to give a colourless
solution. Titanium tetrachloride (2.13 mL, 2.13 mmol) was added to
the lithium cyclopentadienide intermediate solution to give a dark
13C NMR (101 MHz, D2O)
d 137.9, 137.6, 134.7, 133.7, 129.5, 122.4,
122.3, 118.2[C5H4eCH2], 115.8 [C5H4eCH2], 108.9, 101.7, 54.4 [CH2N
(CH3)2], 41.3 [CH2N(CH3)2], 32.6 [C5H4eCH2], 32.5 [NeCH3].
IR (KBr disk, cmꢁ1): 3476, 3048, 2938, 2695, 1609, 1543, 1453,
1420, 1372, 1330, 1088, 1012, 923, 798, 747.
Anal calculated for C36H44Cl4N4Ti: C, 59.8; H, 6.14; N, 7.76; found
C, 59.83; H, 5.74; N, 6.92.
4.3.12. 3-((Dimethylamino)-methyl)-1-methylindole-5-
carbaldehyde (3f)
1-Methylindole-5-carbaldehyde (2.6 g, 16.35 mmol) was dis-
solved in acetic acid (30 mL), dimethylamine (4 mL, 32.70 mmol)

1082
A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
red solution. The dark red titanium solution was refluxed for 16 h.
The solution was then cooled and the solvent was removed under
reduced pressure. The remaining residue was extracted with DCM
(100 mL) and filtered through celite to remove the remaining LiCl.
The solvent was removed under reduced pressure to yield an
orange solid in 44% yield (1.10 g, 1.69 mmol). A portion of this solid
(0.1g, 0.15 mmol) was then dissolved in DCM (10 mL) and an
ethereal solution of hydrogen chloride (0.15 mL, 2 M) was added
and a precipitate immediately formed. Diethyl ether (30 mL) was
then added. After 15 min stirring, the solid was filtered to give
a brown powder in 54% yield (0.06 g, 0.08 mmol).
ES-MS: m/z 265 [M þ H]þ.
HRMS:m/zcalcdforC18H21N2 [Mþ H]þ, 265.1705, found265.1701.
lmax [nm], (e
) [L molꢁ1 cmꢁ1], CHCl3: 282 (13,100), 378 (8900).
IR (KBr disk, cmꢁ1): 2940, 2858, 2772, 1604, 1471, 1389, 1342,
1217, 1087, 995, 908, 812, 758, 649.
4.3.17. Bis-[((1-methylindol-3-yl-N,N-dimethylmethana-
miniumchloride)-6)-cyclopentadienyl]titanium (IV) dichloride (5g)
1 M Solution of Super Hydride (LiBEt3H) (9.00 mL, 9.00 mmol) in
THF was concentrated by removal of the solvent by heating it to
60 ꢀC under reduced pressure of 10ꢁ2 mbar for 40 min and then to
90 ꢀC for 20 min in a Schlenk flask. 1-(6-(cyclopenta-2,4-dien-
ylidenemethyl)-1-methylindol-3-yl)-N,N-dimethylmethanamine
(4g) (2.20 g, 8.33 mmol) was added to a Schlenk flask and dissolved
in dry diethyl ether (100 mL) to give a red solution. The red fulvene
solution was transferred to the Super Hydride solution via cannula.
The solution was left to stir for 16 h, in which time a white
precipitate of the lithium cyclopentadienide intermediate formed
and the solution had changed its colour from orange/red to white.
The precipitate was filtered on to a frit. The white precipitate was
dried briefly under reduced pressure and was transferred to
a Schlenk flask under nitrogen. The lithium cyclopentadienide
intermediate was dissolved in dry THF (50 mL) to give a colourless
solution. Titanium tetrachloride (3.13 mL, 3.13 mmol) was added to
the lithium cyclopentadienide intermediate solution to give a dark
red solution. The dark red titanium solution was stirred for 16 h.
The solvent was removed under reduced pressure. The remaining
residue was extracted with DCM (100 mL) and filtered through
celite to remove the remaining LiCl. The solvent was removed
under reduced pressure to yield an orange solid in 45% yield (1.20 g,
1.84 mmol). A portion of this solid (0.1 g, 0.15 mmol) was then
dissolved in DCM (10 mL) and an ethereal solution of hydrogen
chloride (0.15 mL, 2 M) was added and a precipitate immediately
formed. Diethyl ether (30 mL) was then added. After 15 min stir-
ring, the solid was filtered to give a brown powder in 72% yield
(0.08 g, 0.11 mmol).
1H NMR (400 MHz, D2O)
d 7.33 (s, 2H), 7.31 (s, 2H), 7.25 (d,
J ¼ 8.1, 2H), 6.87 (d, J ¼ 8.1, 2H), 6.31 (s, 4H), 6.21 (s, 4H), 4.27 (s, 4H),
3.63 (s, 4H), 3.60 (s, 6H), 2.64 (s, 12H).
13C NMR (101 MHz, D2O)
d 139.7, 135.6, 133.4, 131.1, 127.5, 123.3,
118.8,117.9,116.4,110.5,101.2, 51.8 [CH2N(CH3)2], 41.3 [CH2N(CH3)2],
35.2 [C5H4eCH2], 32.4 [NeCH3].
IR (KBr disk, cmꢁ1): 3491, 2941, 2701, 1618, 1546, 1487, 1474,
1457, 1428, 1382,1325, 1256, 1212, 1152, 1060, 1022, 924, 805.
Anal. Calc. for C36H44Cl4N4Ti: C, 59.8; H, 6.14; N, 7.76; found C,
59.69; H, 5.54; N, 7.82.
4.3.15. 3-((Dimethylamino)-methyl)-1-methylindole-6-
carbaldehyde (3g)
1-Methylindole-6-carbaldehyde (1.9 g, 11.90 mmol) was dis-
solved in acetic acid (30 mL), dimethylamine (3 mL, 23.80 mmol)
was added and the solution was cooled to 30 ꢀC. Formaldehyde
(1.79 mL, 23.80 mmol) was added and the solution was allowed to
stand for 2 h. The mixture was then added to an ice/NaOH (80 mL,
9 M) solution and stirred vigorously for 10 min until a white
precipitate formed. This was filtered, washed with water and
suction dried to give a white solid in 43% yield (1.13 g, 5.23 mmol).
1H NMR (400 MHz, CDCl3)
d 10.06 (s, 1H), 7.86 (s, 1H), 7.78 (d,
J ¼ 8.2, 1H), 7.63 (d, J ¼ 8.2,1H), 7.22 (s,1H), 3.85 (s, 3H), 3.60 (s, 2H),
2.27 (s, 6H).
13C NMR (101 MHz, CDCl3)
d 192.6 [CHO], 136.6, 133.2, 132.8,
130.6, 120.6, 119.7, 112.9, 111.9, 54.2 [CH2N(CH3)2], 45.3 [CH2N
(CH3)2], 32.9 [NeCH3].
1H NMR (400 MHz, CDCl3)
d
7.48 (d, J ¼ 8.2, 2H), 7.29 (s, 2H), 7.07
(s, 2H), 6.86 (d, J ¼ 8.2, 2H), 6.34 (s, 4H), 6.21 (s, 4H), 4.25 (s, 4H),
ES-MS: m/z 217 [M þ H]þ.
3.63 (s, 6H), 3.58 (s, 4H), 2.56 (s, 12H).
HRMS: m/z calcd for C13H17N2O [M þ H]þ, 217.1341, found
217.1331.
13C NMR (101 MHz, CDCl3)
d 141.9, 139.5, 135.9, 135.6, 128.6,
124.1, 121.5, 121.0 [C5H4eCH2], 118.9 [C5H4eCH2], 112.8, 103.9,
54.4[CH2N(CH3)2], 43.8 [CH2N(CH3)2], 37.8 [C5H4eCH2], 34.9
[NeCH3].
IR (KBr disk, cmꢁ1): 2939, 2855, 2812, 1688, 1612, 1562, 1543,
1478, 1383, 1341, 1319, 1212, 1180, 1147, 1061, 1004, 852, 816, 744.
IR (KBr disk, cmꢁ1): 3412, 2942, 2702, 1618, 1547, 1473, 1424,
1385, 1337, 1175, 1066, 925, 819, 608.
4.3.16. 1-(6-(Cyclopenta-2,4-dienylidenemethyl)-1-methylindol-3-
yl)-N,N-dimethylmethanamine (4g)
Anal calculated for C36H44Cl4N4Ti: C, 59.8; H, 6.14; N, 7.76; found
C, 59.93; H, 5.74; N, 6.9.
3-((Dimethylamino)-methyl)-1-methylindole-6-carbaldehyde
(3g) (1.10 g, 5.09 mmol) was dissolved in MeOH (70 mL). Freshly
cracked cyclopentadiene (0.82 mL, 10.18 mmol) was added to the
solution followed by pyrrolidine (0.84 mL, 10.18 mmol) and the
colour immediately changed from colourless to red. After 2 h acetic
acid (0.5 mL) was added to quench the reaction and the product
was extracted with DCM (2 ꢂ 50 mL). The organic layers were
combined and washed with H2O (2 ꢂ 50 mL) and brine (2 ꢂ 50 mL).
The DCM was dried over sodium sulphate and the solvent removed
at reduced pressure to give a red oil in 92% yield (1.24 g,
4.69 mmol).
4.3.18. 3-((Dimethylamino)-methyl)-1-methylindole-7-
carbaldehyde (3h)
1-Methyl-indole-7-carbaldehyde (2.0 g, 12.57 mmol) was dis-
solved in acetic acid (30 mL), 40% aqueous dimethylamine
(3.2 mL, 25.60 mmol) was added and the solution was cooled to
30 ꢀC. Formaldehyde (1.90 mL, 25.70 mmol) was added and the
solution was allowed to stand for 2 h. The mixture was then
added to an ice/NaOH (80 mL, 9 M) solution and stirred vigorously
for 10 min until a brown suspension formed. This was extracted
with DCM (2 ꢂ 50 mL). The organic layers were combined and
washed with H2O (2 ꢂ 50 mL) and brine (2 ꢂ 50 mL). The
DCM was dried over sodium sulphate and the solvent removed
at reduced pressure to give a brown oil in 74% yield (2 g,
9.25 mmol).
1H NMR (400 MHz, CDCl3)
d
7.61 (d, J ¼ 8.3, 1H), 7.46 (s, 1H), 7.35
(m, 1H), 7.31 (s, 1H), 6.99 (s, 1H), 6.79e6.74 (m, 1H), 6.62e6.58 (m,
1.8, 1H), 6.45e6.38 (m, 1H), 6.32e6.25 (m, 1H), 3.70 (s, 3H), 3.51 (s,
2H), 2.19 (s, 6H).
13C NMR (101 MHz, CDCl3)
d 143.3, 140.7, 137.2, 134.7 [C5H4eCH],
130.6, 130.4, 129.5 [C5H4eCH], 129.4, 127.5, 122.3, 120.4 [C5H4eCH],
119.6, 112.5, 112.4, 54.3 [CH2N(CH3)2], 45.3 [CH2N(CH3)2], 32.8
[NeCH3].
1H NMR (300 MHz, CDCl3)
d
10.19 (s, 1H), 7.97 (dd, J ¼ 7.6, 1.1,
1H), 7.68 (dd, J ¼ 7.6, 1.1, 1H), 7.21 (t, 1H), 6.98 (s, 1H), 4.08 (s, 3H),
3.57 (s, 2H), 2.24 (s, 6H).

A. Deally et al. / Journal of Organometallic Chemistry 696 (2011) 1072e1083
1083
13C NMR (75 MHz, CDCl3)
d
191.3 [CHO],131.9, 130.6, 126.9, 123.1,
1H NMR (400 MHz, CD3OD)
7.27e7.14 (m, 4H), 6.51 (s, 4H), 6.30 (s, 4H), 4.64 (s, 4H), 4.56 (s, 4H),
d
7.73 (d, J ¼ 7.8, 2H), 7.50 (s, 2H),
121.7, 118.8, 113.4, 109.3, 54.5 [CH2N(CH3)2], 45.6 [CH2N(CH3)2], 39.0
[NeCH3].
4.04 (s, 6H), 2.94 (s, 12H).
ES-MS: m/z 217 [M þ H]þ.
13C NMR (101 MHz, CD3OD)
d 135.1, 134.7, 134.1, 129.4, 125.3,
HRMS: m/z calcd for C13H17N2O [M þ H]þ, 217.1341, found
217.1349.
123.4, 120.6, 117.0, 116.2 [C5H4eCH2], 115.6 [C5H4eCH2], 101.9, 51.8
[CH2N(CH3)2], 41.1 [CH2N(CH3)2], 35.9 [C5H4eCH2], 31.9 [NeCH3].
IR (KBr disk, cmꢁ1): 3400, 2930, 2720, 1635, 1559, 1472, 1458,
1411, 1384, 1354, 1329, 1214, 1166, 1102, 1068, 1014, 922, 801, 751.
Anal calculated for C36H44Cl4N4Ti: C, 59.8; H, 6.14; N, 7.76; found
C, 58.57; H, 6.94; N, 7.3.
IR (KBr disk, cmꢁ1): 2941, 2856, 2812, 2764, 1690, 1602, 1548,
1463, 1375, 1293, 1244, 1205, 1169, 1133, 1042, 1017, 955, 797, 744.
4.3.19. 1-(7-(Cyclopenta-2,4-dienylidenemethyl)-1-methylindol-3-
yl)-N,N-dimethylmethanamine (4h)
Acknowledgements
3-((Dimethylamino)-methyl)-1-methylindole-7-carbaldehyde
(3h) (1.20 g, 5.55 mmol) was dissolved in MeOH (70 mL). Freshly
cracked cyclopentadiene (0.42 mL, 5.55 mmol) was added to the
solution followed by pyrrolidine (0.45 mL, 5.55 mmol) and the
colour immediately changed from colourless to red. After 6 h acetic
acid (0.5 mL) was added to quench the reaction and the product
was extracted with DCM (2 ꢂ 50 mL). The organic layers were
combined and washed with H2O (2 ꢂ 50 mL) and brine (2 ꢂ 50 mL).
The DCM was dried over sodium sulphate and the solvent removed
at reduced pressure to give a brown oil in 75% yield (1.10 g,
4.16 mmol).
The authors thank the Higher Education Agency (HEA), the
Centre for Synthesis and Chemical Biology (CSCB), University
College Dublin (UCD) and COST D39 for funding.
Appendix A. Supplementary material
CCDC-789464 contains the supplementary crystallographic data
for compound 5a. This data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
1H NMR (300 MHz, CDCl3)
d
7.90 (s, 1H), 7.69 (dd, J ¼ 7.7, 0.8,1H),
7.20 (m, 1H), 7.12 (d, J ¼ 7.7, 1H), 6.92 (s, 1H), 6.64e6.59 (m, 1H),
6.59e6.51 (m, 2H), 6.39 (dt, J ¼ 5.1, 1.7, 1H), 3.96 (s, 3H), 3.58 (s, 2H),
2.26 (s, 6H).
References
13C NMR (75 MHz, CDCl3)
d 145.9, 135.9, 135.0, 134.4 [C5H4eCH],
[1] Y.K. Yan, M. Melchart, A. Habtemariam, P.J. Sadler, Chem. Commun. (2005)
4764.
[2] A. Harstrick, H.T. Schmoll, G. Sass, H. Poliwoda, Y. Rustum, Eur. J. Cancer 29A
(1993) 1000.
[3] R. Alberto, R. Schibli, R. Waibel, U. Abram, A.P. Schubiger, Coord. Chem. Rev.
190e192 (1999) 901e919.
[4] F. Le Bideau, M. Salmain, S. Top, G. Jaouen, Chem. Eur. J. 7 (2001) 2289e2294.
[5] P. Köpf-Maier, H. Köpf, Angew. Chem. Int. Ed. Engl. 18 (1979) 477.
[6] P. Köpf-Maier, T. Klapötke, H. Köpf, F. Preiss, T. Marx, Anticancer Res. 6 (1986)
33e37.
131.4 [C5H4eCH], 130.1, 129.6, 127.3, 125.6 [C5H4eCH], 121.8, 121.6,
120.7, 119.2, 109.9, 54.3 [CH2N(CH3)2], 45.4 [CH2N(CH3)2], 37.0
[NeCH3].
ES-MS: m/z 265 [M þ H]þ.
HRMS: m/z calcd for C18H21N2 [M þ H]þ, 265.1705, found
265.1715. lmax [nm], (e
) [L molꢁ1 cmꢁ1], CHCl3: 272 (11,200), 379
(10,200).
IR (KBr disk, cmꢁ1): 2975, 2945, 2862, 2817, 2773, 1622, 1469,
1457, 1410, 1376, 1336, 1306, 1204, 1174, 1159, 1064, 901, 846, 710.
[7] P. Köpf-Maier, T. Klapötke, Arzneim.-Forsch. 37 (1987) 532e534.
[8] P. Köpf-Maier, B. Hesse, H. Köpf, J. Cancer Res. Clin. Oncol. 96 (1980) 43e51.
[9] W.E. Berdel, H.J. Schmoll, M.E. Scheulen, A. Korfel, M.F. Knoche, A. Harstrick,
F. Bach, J. Baugmart, G. Sab, Onkologie 16 (1993) 172.
[10] A. Korfel, M.E. Scheulen, H.J. Schmoll, O. Gründel, A. Harstrick, M. Knoche,
L.M. Fels, M. Skorzec, F. Bach, J. Baumgart, G. Sass, S. Seeber, E. Thiel,
W.E. Berdel, Clin. Cancer Res. 4 (1998) 2701.
[11] G. Lümmen, S. Sperling, H. Luboldt, T. Otto, H. Rubben, Cancer Chemother.
Pharmacol. 42 (1998) 415.
[12] C.M. Kurbacher, W. Nagel, P. Mallmann, J.A. Kurbacher, G. Sass, H. Hubner,
P.E. Andreotti, D. Krebs, Anticancer Res. 14 (1994) 1529.
[13] R. Meyer, S. Brink, C.E.J. van Rensburg, G.K. Joone, H. Görls, S. Lotz,
J. Organomet. Chem. 117 (2005) 690.
4.3.20. Bis-[((1-methyl-indol-3-yl-N,N-dimethylmethana-
miniumchloride)-7)-cyclopentadienyl]titanium (IV) dichloride (5h)
1 M Solution of Super Hydride (LiBEt3H) (4.00 mL, 4.00 mmol) in
THF was concentrated by removal of the solvent by heating at 60 ꢀC
under reduced pressure of 10ꢁ2 mbar for 40 min and then to 90 ꢀC
for 20 min in
a Schlenk flask. 1-(7-(Cyclopenta-2,4-dien-
ylidenemethyl)-1-methylindol-3-yl)-N,N-dimethylmethanamine
(1.0 g, 3.78 mmol) was added to a Schlenk flask and dissolved in dry
diethyl ether (100 mL) to give a red solution. The red fulvene
solution was transferred to the Super Hydride solution via cannula.
The solution was left to stir for 16 h, in which time a white oily
residue of the lithium cyclopentadienide intermediate formed and
the solution had changed its colour from orange/red to white. The
ether was removed under reduced pressure and dissolved in dry
THF (50 mL) to give a colourless solution. Titanium tetrachloride
was added to the lithium cyclopentadienide intermediate solution
to give an orange solution. The orange titanium solution was stirred
for 16 h and the solvent was removed under reduced pressure. The
remaining residue was extracted with DCM (100 mL) and filtered
through celite to remove the remaining LiCl. The solvent was
removed under reduced pressure to yield an off white solid in 81%
yield (1.0 g, 1.54 mmol). A portion of this solid (0.1 g, 0.15 mmol)
was then dissolved in DCM (10 mL) and an ethereal solution of
hydrogen chloride (0.15 mL, 2 M) was added and a brown precip-
itate immediately formed. Diethyl ether (30 mL) was then added.
After 15 min stirring, the solid was filtered to give a brown powder
in 62% yield (0.08 g, 0.09 mmol).
[14] P.W. Causey, M.C. Baird, S.P.C. Cole, Organometallics 23 (2004) 4486.
[15] G.D. Potter, M.C. Baird, S.P.C. Cole, J. Organomet. Chem. 692 (2007)
3508e3518.
[16] O.R. Allen, L. Croll, A.L. Gott, R.J. Knox, P.C. McGowan, Organometallics 23 (2004)
288.
[17] O.R. Allen, A.L. Gott, J.A. Hartley, J.M. Hartley, R.J. Knox, P.C. McGowan, Dalton
Trans. (2007) 5082e5090.
[18] G.D. Potter, M.C. Baird, M. Chan, S.P.C. Cole, Inorg. Chem. Commun. 9 (2006)
1114e1116.
[19] A. Gansäuer, I. Winkler, D. Worgull, T. Lauterbach, D. Franke, A. Selig,
L. Wagner, A. Prokop, Chem. Eur. J. 14 (2008) 4160e4163.
[20] L. Gao, J.L. Vera, J. Matta, E. Melendez, J. Biol. Inorg. Chem. 15 (2010) 851e859.
[21] M. Hogan, B. Gleeson, M. Tacke, Organometallics 29 (2010) 1032e1040.
[22] M. Hogan, B. Gleeson, M. Tacke, Lett. Drug Des. Discov. 7 (2010) 310e317.
[23] X. Luan, L. Wu, E. Drinkel, R. Mariz, M. Gatti, R. Dorta, Org. Lett. 12 (9) (2010)
1912e1915.
[24] M.P. Moyer, J.F. Shiurba, H. Rapoport, J. Org. Chem. 51 (1986) 5106e5110.
[25] M.S. Mudadu, A. Singh, R.P. Thummel, J. Org. Chem. 71 (2006) 7611e7617.
[26] H.R. Snyder, E.L. Eliel, J. Am. Chem. Soc. 70 (5) (1948) 1703e1705.
[27] K.J. Stone, R.D. Little, J. Org. Chem. 49 (1984) 1849e1853.
[28] M. Tacke, L.P. Cuffe, W.M. Gallagher, Y. Lou, O. Mendoza, H. Müller-Bunz,
J. Organomet. Chem. 689 (2004) 2242e2249.
[29] J. Parijat, S.H. Yalkowsky, Int. J. Pharm 342 (2007) 1e5.
[30] G.M. Sheldrick, SADABS Version 2.03. University of Göttingen, Germany, 2002.
[31] G.M. Sheldrick, SHELXS97 and SHELXL97. University of Göttingen, Germany,
1997.
[32] T. Mossman, J. Immunol. Methods 65 (1983) 55e63.