Synthesis and preliminary cytotoxicity studies of achiral pyrrolyl-substituted titanocenes

Article abstract of DOI:10.1016/j.poly.2010.05.018

From the reaction of various 6-pyrrolylfulvenes (3a-3d) with Super Hydride (LiBEt₃H), lithiated cyclopentadienide intermediates (4a-4d) were synthesised. These intermediates were then transmetallated with titanium tetrachloride TiCl₄

Full text of DOI:10.1016/j.poly.2010.05.018

Polyhedron 29 (2010) 2445–2453
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Polyhedron
journal homepage: www.elsevier.com/locate/poly
Synthesis and preliminary cytotoxicity studies of achiral pyrrolyl-substituted
titanocenes
Anthony Deally, James Claffey, Brendan Gleeson, Megan Hogan, Helge Müller-Bunz, Siddappa Patil,
*
Donal F. O’Shea, Matthias Tacke
UCD School of Chemistry and Chemical Biology, Centre for Synthesis and Chemical Biology (CSCB), Conway Institute of Biomolecular and Biomedical Research,
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:
From the reaction of various 6-pyrrolylfulvenes (3a–3d) with Super Hydride (LiBEt3H), lithiated cyclo-
pentadienide intermediates (4a–4d) were synthesised. These intermediates were then transmetallated
with titanium tetrachloride TiCl4 to yield the pyrrolyl-substituted titanocenes bis-[((1-(4-methoxyben-
zyl)-pyrrole)2-)cyclopentadienyl]titanium(IV) dichloride (5a), bis-[((1-(4-methoxyphenyl)-pyrrole)2-)
cyclopentadienyl]titanium(IV) dichloride (5b), bis-[((2,4-bis(4-methoxyphenyl)-1-methyl-pyrrole)2-)
cyclopentadienyl]titanium(IV) dichloride (5c), bis-[((2-(4-methoxyphenyl)-1-methyl-pyrrole)2-)cyclo-
pentadienyl]titanium(IV) dichloride (5d). Titanocene 5b crystallised and was characterised by X-ray crys-
tallography. The four titanocenes 5a–5d were tested for their cytotoxicity through MTT-based in vitro
tests on CAKI-1 cell lines in order to determine their IC50 values. Titanocenes 5a–5d were found to have
Received 18 December 2009
Accepted 19 May 2010
Available online 26 May 2010
Keywords:
Anticancer drug
Titanocene dichloride
Pyrrole
Renal-cell cancer
CAKI-1
IC50 values of 440 ( 35), 68 ( 14), 105 ( 30), and 36 ( 7) lM.
Ó 2010 Elsevier Ltd. All rights reserved.
Cytotoxicity
1. Introduction
nium dichloride, hydridolithiation or carbolithiation of the fulvene
followed by transmetallation with titanium tetrachloride in the
latter two cases.
Hydridolithiation of 6-anisyl fulvene and subsequent reaction
with titanium tetrachloride led to bis-[(p-methoxybenzyl)cyclo-
pentadienyl] titanium(IV) dichloride (titanocene Y) [7], which has
Renal cell carcinoma (RCC) is the most common malignant dis-
ease of the adult kidney, which accounts for approximately 3% of
adult malignancies [1]. If not detected early, these cancers develop
to an invasive adenocarcinoma, which have very limited treatment
options and poor outcomes. New targeted compounds like Bev-
acizumab, Sunitinib, Sorafenib, Temsirolimus and others offer
some therapeutic potential for advanced renal-cell cancer, since
these compounds can block the VEGF or mTOR pathway and are
therefore anti-angiogenic [2]. These clinical facts suggest new ther-
apeutic regimens must be explored in the quest to develop an
effective therapy for these metastatic or advanced forms of renal-
cell cancer.
There is significant unexplored space for titanium-based drugs
targeting cancer. Titanocene dichloride reached clinical trials, but
the efficacy of this compound in Phase II clinical trials in patients
with metastatic renal cell carcinoma [3] or metastatic breast can-
cer [4] was too low to be pursued. The field got renewed interest
with McGowan et al. elegant synthesis of ring-substituted cationic
titanocene dichloride derivatives, which are water-soluble and
show significant activity against ovarian cancer [5]. More recently,
novel methods starting from fulvenes [6] allow direct access to
antiproliferative titanocenes via reductive dimerisation with tita-
an IC50 value of 21 lM when tested on the LLC-PK cell line. In addi-
tion, the antiproliferative activity of titanocene Y and other tita-
nocenes has been studied in 36 human tumour cell lines [8] and
against explanted human tumours [9,10]. Previous work has dem-
onstrated that titanocene Y induces apoptosis in a caspase-inde-
pendent manner in a range of prostate cancer cells and it
maintained its cytotoxic effects in Bcl-2 over expressing PC-3 cells
[11]. Besides the direct apoptosis-inducing effects these titanocene
derivatives give a positive immune response by up-regulating the
number of natural killer (NK) cells in mice [12] and titanocene Y
proved itself as a strong anti-angiogenic compound with an IC50
value of 4.9 lM shown in a spheroid-based cellular angiogenesis
assay [13]. Recently, animal studies reported the successful treat-
ment of mice bearing xenografted A431 [14], PC-3 [15], Caki-1
[16] and MCF-7 [17] tumours with titanocene Y or its oxalate
[18,19]. The chemistry was then extended to racemic mixtures of
chiral pyrrolyl-substituted titanocenes (titanocene C) [20] which
showed a high cytotoxic activity against LLC-PK cells with an IC50
value of 5.5 and share therefore the activity level of clinically used
platinum-based anticancer drugs. The structures of titanocene Y,
titanocene C and our proposed new class are shown in Fig. 1.
* Corresponding author.
E-mail address: matthias.tacke@ucd.ie (M. Tacke).
0277-5387/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2010.05.018

2446
A. Deally et al. / Polyhedron 29 (2010) 2445–2453
R3
Me2N
O
R2
N
N
Cl
Cl
Cl
Ti
Cl
R1
Ti
Ti
R1
N
Cl
Cl
N
R2
O
NMe2
R3
a: R1 = -CH2-p-MeOC6H4, R2 + R3 = H;
b: R1 = p-MeOC6H4, R2 + R3 = H;
c
: R1 = CH3, R2 + R3 = p-MeOC6H4;
d: R1 = CH3, R2 = p-MeOC6H4, R3 = H
Fig. 1. Molecular structures of titanocene Y, titanocene C and titanocenes 5a–5d.
This paper is now investigating the synthesis and cytotoxicity of
O
achiral pyrrolyl-substituted titanocene dichloride derivatives,
which explore structural analogues combining the pyrrole unit of
titanocene C with the p-methoxy aryl ring of titanocene Y. Four
aryl-substituted pyrroles were selected with varying N and C
bonded aryl-substituents as an initial structure activity
investigation.
N
O
N
2a
1b
O
O
2. Results and discussion
2.1. Synthesis
N
N
O
O
The synthesis of pyrroles 1c and 1d was achieved using a con-
densation reaction with ammonia and the appropriately substi-
tuted 1,4-keto-aldehyde species [21,22] followed by methylation
using MeI [23]. Pyrrole 1b was synthesised using the same proce-
dure as 1c and 1d, with p-anisidine acting as the nitrogen source
[24].
The synthesis of 2a was achieved using 4-methoxybenzyl bro-
mide and pyrrole-2-carbaldehyde (Scheme 1) [25]. The structures
of these pyrroles are shown in Fig. 2.
1c
1d
Fig. 2. Structure of pyrroles 2a and 1b–1d.
resulting in the formation of 1 equiv. of the appropriately pyrrol-
yl-substituted titanocene 5a–5d (Fig. 3) in yields of 55–83% and
the by-product lithium chloride following a 16 h reflux.
The synthesis of pyrrole 2-carboxaldehydes was achieved by
the Vilsmeier–Haack reaction with phosphorous oxychloride and
DMF [26].
2.2. Structural discussion
The synthesis of fulvenes 3a–3d is based on a modified version
of the Stone and Little method [27] and described in Ref. [28]; the
corresponding aldehyde was reacted with cyclopentadiene in the
presence of pyrrolidine as a base catalyst to yield the desired prod-
uct in yields of 49–86%. Their structures can be seen in Scheme 2.
Using the method described in Ref. [7] and depicted in Scheme
1 these fulvenes were reacted with LiBEt3H to obtain the corre-
spondingly functionalised lithium cyclopentadienide intermedi-
ates 4a–4d. The exocyclic double bonds in the fulvenes have
increased polarity due to the inductive effects of their respective
pyrrolyl groups. This increased polarity allows for selective nucle-
ophilic attack at this double bond and not at the diene component
of the fulvenes. Two equivalents of the lithium cyclopentadienide
intermediate were then transmetallated with 1 equiv. of TiCl4,
A single crystal of titanocene 5b 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 1, while the crystal data
and refinement details for 5b are found in Table 2.
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 titanocene Y and 5b (Figs. 1 and 4). They vary be-
tween 233.6(3) and 242.8(3) pm for titanocene Y and between
233.1(2) and 245.4(2) pm for 5b. The same applies for the car-
bon–carbon bonds of the cyclopentadienyl rings with bonds length
between 138.1(4) and 141.7(4) pm for titanocene Y and for 5b be-
tween 139.0(4) and 141.9(3) pm. The dihedral angles created by
C(1)–C(6)–C(7)–C(8) and C(10)–C(60)–C(70)–C(80) is 100.6(3)° for
i) NaH
O
ii) HCl
O
Br
N
N
THF, rt, 24 h
O
H
O
2a
Scheme 1. Synthesis of 2a.

A. Deally et al. / Polyhedron 29 (2010) 2445–2453
2447
R3
R3
R3
i) cyclopentadiene
i) DMF, POCl3
ii) NaOH, H2O
O
ii) pyrrolidine
MeOH
R2
R2
R2
N
N
R1
N
R1
DMF
R1
1b,1c,1d
2a,2b,2c,2d
3a,3b,3c,3d
R3
R3
LiBEt3H
Et2O
+ BEt3
R2
N
R2
N
Li
R1
R1
3a,3b,3c,3d
4a,4b,4c,4d
R3
R2
N
R3
TiCl4
THF, reflux
16 h
Cl R1
Ti
+ 2 LiCl
2
R2
R1
N
Cl
N
R1
Li
R2
4a,4b,4c,4d
5a,5b,5c,5d
R3
a: R1 = -CH2-p-MeOC6H4, R2 + R3 = H;
b
c
: R1 = p-MeOC6H4, R2 + R3 = H;
: R1 = CH3, R2 + R3 = p-MeOC6H4;
d: R1 = CH3, R2 = p-MeOC6H4, R3 = H
Scheme 2. Synthesis of titanocenes 5a–5d.
O
N
N
O
Cl
Cl
Cl
Ti
Ti
Cl
O
N
N
5a
5b
O
O
N
N
O
Cl
Cl
Cl
Cl
O
Ti
Ti
O
O
N
N
5d
5c
O
Fig. 3. Structures of pyrrolyl-substituted titanocenes 5a–5d.

2448
A. Deally et al. / Polyhedron 29 (2010) 2445–2453
Table 1
mately perpendicular in their arrangement. These values also show
that for titanocene Y there is no plane of symmetry bisecting the
Cl(1)–Ti–Cl(2) plane and that the structure exhibits C2 symmetry
only. However, in structure 5b the bond lengths and angles for
the Cp and Cp0 rings are identical causing a mirror plane through
the Cl(1)–Ti–Cl(1) axis and therefore giving the structure a C2/c
space group.The titanium–chlorine bond lengths are slightly short-
er for 5b, with Ti–Cl(1) being 234.8(0) pm and Ti–Cl(2) as 234.8(1)
pm whereas for titanocene Y the Ti–Cl(1) bond length is 236.8(1)
and Ti–Cl(2) is 236.6(1) pm. The Cl–Ti–Cl0 angle was measured
for titanocene Y as 95.94(3)° and for 5b to be 93.95(4)°. The two
structures show similar conformations. The benzyl substituents,
in the case of titanocene Y, and the pyrrole substituents in the case
of 5b, are orientated away from each other, so that steric hin-
Selected bond lengths and angles for crystal structures of titanocene Y and 5b.
Bond lengths (pm)
Titanocene Y
5b
Ti–C(1)
Ti–C(2)
Ti–C(3)
Ti–C(4)
238.5(3)
240.9(3)
240.3(3)
234.4(3)
237.2(3)
141.2(4)
139.3(4)
140.5(4)
140.9(4)
140.5(4)
141.7(4)
140.1(4)
138.1(4)
141.6(4)
139.6(4)
236.8(1)
236.6(1)
150.9(4)
151.7(4)
150.2(4)
151.9(4)
206.1
245.4(2)
242.3(2)
233.1(2)
233.6(3)
238.6(3)
140.1(4)
140.6(3)
141.3(4)
139.0(4)
141.9(3)
141.9(2)
140.5(2)
140.0(3)
140.7(3)
142.5(3)
234.8(0)
234.8(1)
149.7(3)
149.6(4)
149.8(3)
150.6(3)
206.5(2)
206.5(2)
131.39(1)
106.45(1)
106.17(1)
93.95(4)
Ti–C(5)
C(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(5)–C(1)
C(17)–C(18)
C(18)–C(19)
C(19)–C(20)
C(20)–C(21)
C(21)–C(17)
Ti–Cl(1)
drances are minimised. There are no
p–p interactions to be seen
between the substituted pyrrole groups but some soft Van der
Waals interactions are present. The absence of solvent molecules
present in the crystal unit cells is a particular advantage when it
comes to biological testing.
Ti–Cl(2)
C(1)–C(6)
C(6)–C(7)
C(17)–C(22)
C(22)–C(23)
Ti–Cent1
2.3. Cytotoxicity studies
Ti–Cent2
206.1
Cent–Ti–Cent
Cl1–Ti–Cent1
Cl2–Ti–Cent1
Cl2–Ti–Cl1
130.68(2)
105.89(2)
106.50(3)
95.94(3)
As seen in Figs. 5 and 6, titanocenes 5a–5d exhibited an illustra-
tive spectrum of activity with IC50 values of 440, 68, 105 and 36
against Caki-1 cells, respectively. Encouragingly 5d had compara-
ble activity to that of titanocene Y (IC50 of 30 M) and can be
lM
l
viewed as a heterocyclic version of this compound. Structural anal-
ysis of 5a–5d shows, that the most active 5d most closely resem-
bles titanocene Y. This fact is particularly evident when
compared to the structural isomer 5a which has the poorest re-
corded efficacy of the series with a greater than 12-fold lower effi-
cacy than 5d. The titanocene derived from the N-aryl-substituted
Table 2
Crystal data and structure refinement for 5b.
Identification code
5b
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
C
34H32N2O2Cl2Ti
pyrrole 5b, provided intermediate activity (68 lM) within the ser-
619.42
100(2)
0.71073
monoclinic
C2/c (#15)
ies but offers less scope for further development. Titanocene 5c
also shows a 3-fold decrease in cytotoxicity with respect to titano-
cene Y in spite of the fact that it contains all the structural units of
5d, with an additional aryl ring at pyrrole C-4 position. The in-
crease in lipophilicity of 5c when compared to 5d may account
for this decrease in cytotoxicity, as titanocene 5d (which has the
substituent at position 4 of the pyrrole removed) has improved
32.539(4)
6.6075(8)
13.3422(16)
90
91.285(3)
90
2867.9(6)
4
1.435
b (Å)
c (Å)
a
(°)
cytotoxicity of 36 lM.
b (°)
c
(°)
V (Å3)
3. Conclusions and outlook
Z
Dcalc (Mg/m3)
Absorption coefficient (mmꢀ1
F(0 0 0)
)
0.520
1288
The hydridolithiation of 6-substituted fulvenes has been found
to be a very effective and reproducible way to generate low to
medium cytotoxic aryl-substituted and heteroaryl-substituted
titanocenes of high purity. Following these investigative studies
into the synthesis and cytotoxicity of these pyrrolyl-substituted
titanocenes, we have been able to identify a specific aryl-hetero-
aryl substitution pattern that establishes a new achiral class with
comparable activity of titanocene Y. The design, synthesis and bio-
logical testing of further structural analogues based upon 5d is on-
going, the results of which will be reported upon in due course.
Crystal size (mm3)
0.60 ꢁ 0.10 ꢁ 0.10
2.50–26.49
ꢀ40 6 h 6 40, ꢀ8 6 k 6 8,
ꢀ16 6 l 6 16
12,042
2955 (0.0387)
99.3%
semi-empirical from equivalents
h Range for data collection (°)
Index ranges
Reflections collected
Independent reflections (Rint
Completeness to h = 26.43°
Absorption correction
Maximum and minimum transmission 0.9498 and 0.6722
Refinement method
)
full-matrix least-squares on F2
2955/0/250
1.149
R1 = 0.0489, wR2 = 0.1070
R1 = 0.0586, wR2 = 0.1113
0.571 and ꢀ0.421
Data/restraints/parameters
Goodness-of-fit on F2
4. Experimental
Final R indices [I > 2
R indices (all data)
r(I)]
Largest difference in peak and hole
4.1. General conditions
(e Å-3
)
Titanium tetrachloride (1.0 M solution in toluene), Super Hy-
dride (LiBEt3H, 1.0 M solution in THF), and all chemicals were ob-
tained commercially from Aldrich Chemical Co. and used without
any further purification. Solvents were dried in a Grubbs apparatus
and collected under an atmosphere of nitrogen prior to use. Manip-
ulations of air and moisture sensitive compounds were done using
5b, whereas the dihedral angle C(1)–C(6)–C(7)–C(8) for titanocene
Y is 101.4(3)° and for C(17)–C(22)–C(23)–C(24) is 88.7(3)°. These
values show that for titanocene Y and 5b the ring substituents
are not co-planar with the cyclopentadienyl rings, but approxi-

A. Deally et al. / Polyhedron 29 (2010) 2445–2453
2449
O
C14
C17
C13
C4
C3
C5
C12
Ti
C2
C15
C1
C11
C10
C1
N
C16
C6
Cl
C7
C9
Cl
C8
Fig. 4. Molecular structure of 5b, thermal ellipsoids are drawn on the 50% probability level.
Series employing a KBr disc. UV–Vis spectra were recorded on a
Cary 50 Scan UV–Visible Spectrophotometer, (k in nm, in
1.3
1.2
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
e
dm3 molꢀ1 cmꢀ1). A single crystal of titanocene 5b suitable for X-
ray diffraction experiments was grown by the diffusion of pentane
into a saturated solution of 5b in chloroform at room temperature.
X-ray diffraction data for the compound was collected on a BRU-
KER Smart Apex diffractometer at 100 K. A semi-empirical absorp-
tion correction on the raw data was performed using the program
SADABS [29]. The crystal structure was then solved by direct methods
(
SHELXS-NT97) [30] and refined by full-matrix least-squares methods
against F2. Further details about the data collection are listed in Ta-
ble 2, as well as reliability factors. Additional details are available
free of charge from the Cambridge Structural Database under the
CCDC No. 757646. 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 mercurimetric titrations.
5a IC50 = 44 (+/-5.7) E-5
5b IC50 = 6.8 (+/-1.4) E-5
1E-10 1E-9 1E-8 1E-7 1E-6 1E-5 1E-4 1E-3
Log10Drug Concentration (M)
4.2. MTT-based assay (MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyl-2H-tetrazolium bromide)
Fig. 5. Cytotoxicity studies of titanocenes 5a and 5b against CAKI-1 cells.
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 American Tissue Cell Culture
Collection (ATCC) (HTB-47) in 2001 and maintained in Dulbecco’s
modified eagle medium containing 10% (v/v) foetal bovine serum
1.3
1.2
1.1
1.0
0.9
(FBS), 1% (v/v) penicillin–streptomycin, and 1% (v/v) L-glutamine.
The cytotoxicities of titanocenes 5a–5d were determined by an
MTT-based assay [31].
Specifically, cells were seeded in 96-well plates containing
200 lL of medium, and were incubated at 37 °C and 5% carbon
dioxide for 24 h to allow for exponential growth. Then the com-
pounds used for the testing were dissolved in the minimal amount
of dimethyl sulfoxide (70 lL DMSO) possible and diluted with
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
medium to obtain stock solutions of 5 ꢁ 10ꢀ4 M in concentration
and less than 0.7% of DMSO. The cells were then treated with vary-
ing 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 phosphate buffer solution (PBS), and
fresh medium was added to the wells. Following a recovery period
of 24 h incubation at 37 °C, individual wells were treated with
5c IC50= 10.5 (+/-3.1)E-5
5d IC50= 3.6 (+/-0.7)E-5
1E-10 1E-9 1E-8 1E-7 1E-6 1E-5 1E-4 1E-3
Log10 Drug Concentration (M)
Fig. 6. Cytotoxicity studies of titanocenes 5c and 5d against CAKI-1 cells.
200 lL of a solution of MTT in medium (5 mg MTT per 11 mL med-
ium). The cells were incubated for 3 h at 37 °C. The medium was
then removed, and the purple formazan crystals were dissolved
standard Schlenk techniques, under a nitrogen atmosphere. NMR
spectra were measured on a Varian 300, 400, or 500 MHz spec-
trometer. Chemical shifts are reported in ppm and are referenced
to TMS. IR spectra were recorded on a Varian 3100 FT-IR Excalibur
in 200 lL 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 ex-
pressed as a percentage of the absorbance recorded for control

2450
A. Deally et al. / Polyhedron 29 (2010) 2445–2453
wells. The values used for the dose–response curves of Figs. 5 and 6
represents the values obtained from four consistent MTT-based as-
says for each compound tested.
heating it to 60 °C under reduced pressure of 10ꢀ2 mbar for
40 min and then to 90 °C for 20 min in a Schlenk flask. 2-(Cyclo-
penta-2,4-dienylidenemethyl)-1-(4-methoxybenzyl)-pyrrole
(2.1 g, 7.9 mmol) was added to a Schlenk flask and dissolved in dry
diethyl ether (150 mL) to give a red solution. The red fulvene solu-
tion 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 yellow. The
precipitate was filtered onto a frit. The white precipitate was dried
briefly under reduced pressure and was transferred to a Schlenk
flask under nitrogen. The lithium cyclopentadienide intermediate
4a (0.92 g, 3.4 mmol, 42%) was dissolved in dry THF (30 mL) to give
a colourless solution. Titanium tetrachloride (0.9 mL, 0.9 mmol)
was added to the lithium cyclopentadienide intermediate solution
to give a dark green solution. The dark green titanium solution was
refluxed for 16 h. The solution was then cooled and the solvent was
removed under reduced pressure. The remaining residue was ex-
tracted with DCM (30 mL) and filtered through Celite to remove
the remaining LiCl. The solvent was removed under reduced pres-
sure to yield a green/black solid in 83% yield (0.92 g, 1.42 mmol).
1H NMR (400 MHz, CDCl3) d 6.88 (d, J = 8.3 Hz, 4H, C6H4), 6.79
(d, J = 8.3 Hz, 4H, C6H4), 6.61 (s, 2H, C4H3N), 6.22 (d, J = 18.5 Hz,
4H), 6.08 (s, 2H, C4H3N), 5.83 (s, 2H, C4H3N), 4.95 (s, 4H, CH2),
3.92 (s, 4H, CH2), 3.76 (s, 6H, OCH3).
4.3. Synthesis
4.3.1. Synthesis of 1-(4-methoxybenzyl)-pyrrole-2-carbaldehyde (2a)
1H-Pyrrole-2-carbaldehyde (1.5 g, 16 mmol) in THF (60 mL)
was treated with sodium hydride (1.9 g, 45 mmol) and the solution
was stirred for 30 min. 1-(Bromomethyl)-4-methoxybenzene
(2.2 mL, 18 mmol) was added and the solution was stirred for
24 h, treated with 2 M HCl (2 mL) and extracted with DCM
(2 ꢁ 50 mL). The organic layers were combined and washed with
H2O (2 ꢁ 50 mL) and brine (2 ꢁ 50 mL). The DCM was dried over
sodium sulfate and the solvent was removed at reduced pressure
to give a brown oil. The brown oil was purified by column chroma-
tography using silica and cyclohexane/dichloromethane (7:3) as
the eluent. The solvent was removed at reduced pressure to yield
the product as a brown oil in 61% yield (2.10 g, 10.5 mmol).
1H NMR (400 MHz, CDCl3) d 9.54 (s, 1H, CHO), 7.12 (d, J = 7.0 Hz,
2H, C6H4), 6.96–6.94 (m, 2H, C4H3N), 6.83 (d, J = 7.0 Hz, 2H, C6H4),
6.23 (dd, J = 2.6, 0.9 Hz, 1H, C4H3N), 5.47 (s, 2H, CH2), 3.76 (s, 3H,
OCH3).
13C NMR (101 MHz, CDCl3) d 179.66, 159.35, 131.62, 131.31,
129.72, 129.06, 125.04, 114.23, 110.19, 55.41, 51.62.
ES-MS: m/z 216 [M+H]+.
13C NMR (101 MHz, CDCl3) d 159.13, 135.59, 130.74, 130.19,
128.07, 123.15, 121.64 (C4H3N), 115.67, 114.30, 108.30, 107.43,
55.50, 50.24, 28.14.
HRMS: m/z calcd for
215.0942.
C
13H13NO2 [M]+, 215.0946: found
IR (KBr disc, cmꢀ1): 2933, 2832, 1658, 1605, 1512, 1470, 1404,
1365, 1305, 1247, 1190, 1090, 1031, 840, 751.
IR (KBr disc, cmꢀ1): 2930, 1611, 1530, 1451, 1289, 1246, 1174,
1126, 1084, 1032, 820.
kmax [nm],
(15 238), 404 (2144).
(e)
[L molꢀ1 cmꢀ1], CHCl3: 233 (26 048), 258
4.3.2. Synthesis of 2-(cyclopenta-2,4-dienylidenemethyl)-1-(4-
methoxybenzyl)-pyrrole (3a)
Anal. Calc. for C36H36Cl2N2O2Ti: C, 66.78; H, 5.6; N, 4.33; Cl,
1-(4-Methoxybenzyl)-pyrrole-2-carbaldehyde (2.1 g 9.7 mmol)
was dissolved in MeOH (50 mL). Freshly cracked cyclopentadiene
(1.4 mL, 17 mmol) was added to the solution followed by pyrroli-
dine (1.6 mL, 20 mmol) and the colour immediately changed from
colourless to red. The reaction was left to stir whilst being moni-
tored by thin layer chromatography (silica/DCM), which showed
only one product spot after 2 days. Acetic acid (1 mL) was added
to quench the reaction and the product was extracted with DCM
(2 ꢁ 50 mL). The organic layers were combined and washed with
H2O (2 ꢁ 50 mL) and brine (2 ꢁ 50 mL). The DCM was dried over
sodium sulfate and the solvent removed at reduced pressure to
give a red oil. The red oil was purified by column chromatography
with DCM used as the eluent. The dichloromethane was removed
at reduced pressure to yield a red oil in 86% yield (2.2 g, 8.4 mmol).
1H NMR (400 MHz, CDCl3) d 7.00 (d, J = 8.8 Hz, 2H, C6H4), 6.91 (s,
1H), 6.88–6.84 (m, 4H), 6.78–6.76 (m, 1H), 6.60–6.57 (m, 1H,
C4H3N), 6.41–6.38 (m, 1H), 6.29 (dd, J = 3.5 Hz, 3.0 Hz, 1H,
C4H3N), 6.19 (dt, J = 5.0 Hz, 1.8 Hz, 1H), 5.14 (s, 2H, CH2), 3.77 (s,
3H, OCH3).
10.95. Found: C, 64.14; H, 5.47; N, 3.94; Cl, 9.47%.
4.3.4. Synthesis of 1-(4-methoxyphenyl)-pyrrole-2-carbaldehyde (2b)
Prepared as per literature procedure [32] and confirmed via 1H
NMR.
1H NMR (400 MHz, CDCL3) d 9.52 (s, 1H), 7.31 – 7.20 (m, 2H,
C6H4), 7.14 – 7.11 (m, 1H), 7.03–7.01 (m, 1H), 6.98 – 6.93 (m, 2H,
C6H4), 6.42 – 6.32 (m, 1H), 3.84 (s, 3H, OCH3).
4.3.5. Synthesis of 2-(cyclopenta-2,4-dienylidenemethyl)-1-(4-
methoxyphenyl)-pyrrole (3b)
1-(4-Methoxyphenyl)-pyrrole-2-carbaldehyde (2.0 g, 9.9 mmol)
was dissolved in MeOH (40 mL) to give a clear solution. Freshly
cracked cyclopentadiene (0.80 mL, 9.90 mmol) was added to the
reaction solution, which remained colourless. Pyrrolidine
(0.90 mL, 11.0 mmol) was added to the solution. The solution
immediately changed colour from colourless to yellow and finally
reached a red colour. The reaction was left to stir for 24 h, after
which a light orange precipitate formed. This was filtered to yield
an orange solid in 74% yield (1.86 g, 7.40 mmol).
13C NMR (101 MHz, CDCl3) d 159.40, 140.61, 133.98, 130.55,
129.49, 129.24, 127.98, 126.98, 126.63, 125.33, 119.69, 116.44,
114.51, 110.8, 55.50, 50.52 .
1H NMR (400 MHz, CDCl3) d 7.26 (d, J = 6.6 Hz, 2H, C6H4), 7.01–
6.98 (m, 3H), 6.95–6.92 (m, 1H), 6.82 (d, J = 4.6 Hz, 1H), 6.73 (s, 1H,
–CH), 6.63–6.60 (m, 1H), 6.42–6.39 (m, 2H), 6.17–6.14 (m, 1H),
3.87 (s, 3H, C6H4).
kmax [nm], (e
) [L molꢀ1 cmꢀ1], CHCl3: 235 (13 819), 280 (7282),
330 (6472), 385 (17 085).
ES-MS: m/z 264 [M+H]+.
13C NMR (101 MHz, CDCl3) d 159.40, 140.46, 133.92, 132.13,
131.58, 129.24, 127.93, 126.96, 126.88, 126.74, 119.60, 116.19,
114.64, 111.25, 55.80.
HRMS: m/z calcd for C18H17NO [M]+, 263.1310, found 263.1297.
IR (KBr disc, cmꢀ1): 3055, 1611, 1511, 1463, 1401, 1264, 1187,
1074, 1036, 895, 738.
ES-MS: m/z 250 [M+H]+.
HRSM: m/z calcd for
250.1236.
kmax [nm], (
C
17H16NO [M+H]+ 250.1232, found
4.3.3. Synthesis of bis-[((1-(4-methoxybenzyl)-pyrrole)2-)-
cyclopentadienyl]titanium(IV) dichloride (5a)
One molar solution of Super Hydride (LiBEt3H) (9.6 mL,
9.6 mmol) in THF was concentrated by removal of the solvent by
e
) [L molꢀ1 cmꢀ1], CHCl3: 385 (33 146), 270 (6817).
IR (KBr disc, cmꢀ1): 2912, 1732, 1699, 1617, 1558, 1514, 1448,
1411, 1321, 1253, 1174, 1081, 1027, 994, 885, 842, 776, 732.

A. Deally et al. / Polyhedron 29 (2010) 2445–2453
2451
4.3.6. Synthesis of Bis-[((1-(4-methoxyphenyl)-pyrrole)2-)-
cyclopentadienyl]titanium(IV) dichloride (5b)
phenyl)-1-methyl-pyrrole (0.58 g 2.00 mmol) in DMF (0.5 mL)
was added dropwise and stirred for 1 h to give a dark green solu-
tion. This solution was then stirred at 35 °C for 1 h. The solution
was cooled to rt and 5 g of ice in 9 M NaOH (5 mL) was added
slowly, causing a green precipitate to form. This precipitate was fil-
tered and washed with H2O (100 mL) to give a dark green solid in
57% yield (0.36 g, 1.1 mmol).
One molar solution of Super Hydride (LiBEt3H) (12 mL,
12 mmol) in THF was concentrated by removal of the solvent by
heating it to 60 °C under reduced pressure of 10ꢀ2 mbar for
40 min and then to 90 °C for 20 min in a Schlenk flask. 2-(Cyclo-
penta-2,4-dienylidenemethyl)-1-(4-methoxyphenyl)-pyrrole
(1.5 g, 6.0 mmol) was added to a Schlenk flask and dissolved in dry
diethyl ether (50 mL) to give an orange solution. The fulvene solu-
tion 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 yellow. The precip-
itate was filtered onto a frit. The white precipitate was dried briefly
under reduced pressure and was transferred to a Schlenk flask un-
der nitrogen. The lithium cyclopentadienide intermediate 4b
(0.55 g 2.1 mmol, 35%) was dissolved in dry THF (30 mL) to give
a light yellow solution. Titanium tetrachloride (1.1 mL, 1.1 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 ex-
tracted with DCM (30 mL) and filtered through Celite to remove
the remaining LiCl. The solvent was removed under reduced pres-
sure to yield a brown solid in 75% yield (0.50 g, 0.80 mmol).
1H NMR (400 MHz, CDCl3) d 7.10 (d, J = 6.9 Hz, 4H, C6H4), 6.89
(d, J = 6.9 Hz, 4H, C6H4), 6.69 (d, J = 1.7 Hz, 2H), 6.24–6.21 (m,
4H), 6.14 (s, 2H), 6.04 (s, 4H), 5.95 (s, 2H), 3.92 (s, 4H), 3.82 (s,
6H, OCH3).
1H NMR (300 MHz, CDCl3) d 9.63 (s, 1H, CHO), 7.41 (d, J = 8.0 Hz,
2H, C6H4), 7.38 (d, J = 8.0 Hz, 2H, C6H4), 7.01 (d, J = 8.8 Hz, 2H,
C6H4), 6.97 (d, J = 8.8 Hz, 2H, C6H4), 6.28 (s, 1H, C4HN), 3.95 (s,
3H, NCH3), 3.87 (s, 3H, OCH3), 3.86 (s, 3H, OCH3).
13C NMR (75 MHz, CDCl3) 13C NMR (300 MHz, CDCl3) d 180.66,
160.21, 159.57, 143.24, 139.95, 130.90, 130.81, 128.37, 126.62,
123.54, 114.38, 114.20, 110.86, 55.61, 55.58, 35.04.
ES-MS: m/z 322 [M+H]+.
HRSM: m/z calcd for C20H20NO3 [M+H]+ 322.1443, found:
322.1450.
IR (KBr disc, cmꢀ1): 2924, 1691, 1497, 1462, 1363, 1246, 1771,
1037, 836.
4.3.9. Synthesis of 2-(cyclopenta-2,4-dienylidenemethyl)-3,5-bis(4-
methoxyphenyl)-1-methyl-pyrrole (3c)
3,5-Bis(4-methoxyphenyl)-1-methyl-pyrrole-2-carbaldehyde
(0.62 g, 1.93 mmol) was dissolved in MeOH (40 mL) to give a deep
green solution. Freshly cracked cyclopentadiene (0.16 mL,
1.90 mmol) was added to the reaction solution, which remained
colourless. Pyrrolidine (0.15 mL, 1.90 mmol) was added to the
solution and the colour changed from green to yellow and finally
reached a red colour. The reaction was left to stir whilst being
monitored by thin layer chromatography (silica/dichloromethane),
which showed only one product spot after 5 days. Acetic acid
(1 mL) was added to quench the reaction. The product was ex-
tracted with DCM (2 ꢁ 50 mL). The organic layers were combined
and washed with H2O (2 ꢁ 50 mL) and brine (2 ꢁ 50 mL). The
DCM was dried over sodium sulfate and the solvent removed at re-
duced 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 49% yield (0.35 g, 1.0 mmol).
13C NMR (101 MHz, CDCl3) d 159.03, 135.80, 133.11, 131.79,
127.82, 123.22, 122.82, 115.22, 114.47, 108.51, 107.94, 55.75,
28.60.
IR (KBr disc, cmꢀ1): 3100, 2900, 1604, 1517, 1464, 1294, 1249,
1181, 1168, 1100, 1033, 833.
kmax [nm], (e
) [L molꢀ1 cmꢀ1], CHCl3: 404 (3630), 233 (37 652).
Anal. Calc. for C34H32Cl2N2O4Ti: C, 65.93; H, 5.21; N, 4.52; Cl,
11.45. Found: C, 61.32; H, 5.07; N, 3.99; Cl, 8.32%.
4.3.7. Synthesis of 2,4-bis(4-methoxyphenyl)-1-methyl-1H-pyrrole
(1c)
1H NMR (400 MHz, CDCl3) d 7.44 (d, J = 8.8 Hz, 2H, C6H4), 7.40
(d, J = 8.8 Hz, 2H, C6H4), 7.09 (s, 1H, –CH), 6.99 (d, J = 8.8 Hz, 2H,
C6H4), 6.91 (d, J = 8.8 Hz, 2H, C6H4), 6.53–6.51 (m, 1H, C5H4),
6.43–6.40 (m, 1H, C5H4), 6.40 (s, 1H, NCH3), 6.33 (s, 1H, C5H4),
6.32 (s, 1H, C5H4), 3.87 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.60 (s,
3H, NCH3).
2,4-Bis(4-methoxyphenyl)-1H-pyrrole (2.35 g, 8.40 mmol) in
THF (50 mL) was treated with sodium hydride (1.35 g, 33.7 mmol)
and stirred for 30 min. MeI (2.70 mL 43.3 mmol) was added and
stirred for a further 1 h. The excess MeI was quenched with 4 M
NaOH (5 mL). The product was extracted with DCM (2 ꢁ 50 mL).
The organic layers were combined and washed with H2O
(2 ꢁ 50 mL) and brine (2 ꢁ 50 mL). The DCM was dried over so-
dium sulfate and the solvent removed at reduced pressure to give
a dark brown solid in 98% yield (2.4 g, 8.2 mmol).
13C NMR (101 MHz, CDCl3) d 159.57, 158.63, 142.59, 141.31,
133.05, 130.61, 130.39, 129.93, 129.87, 129.46, 128.79, 127.34,
126.31, 125.32, 122.13, 114.32, 114.17, 110.48, 55.59, 55.51, 35.92.
ES-MS: m/z 370 [M+H]+.
1H NMR (400 MHz, CDCl3) d 7.43 (d, J = 8.7 Hz, 2H, C6H4), 7.34
(d, J = 8.7 Hz, 2H, C6H4), 6.94 (d, J = 8.7 Hz, 2H, C6H4), 6.89 (s, 1H,
C4H2N), 6.87 (d, J = 8.7 Hz, 2H, C6H4), 6.38 (d, J = 2.0 Hz, 1H,
C4H2N), 3.83 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.62 (s, 3H, –CH3).
13C NMR (101 MHz, CDCl3) d 159.00, 157.88, 135.47, 130.23,
128.81, 126.29, 125.92, 124.12, 119.25, 114.28, 114.07, 106.10,
55.54, 55.52, 35.18.
HRSM: m/z calcd for C25H24NO2 [M+H]+ 370.1807 found:
370.1809.
kmax [nm], (e
) [L molꢀ1 cmꢀ1], CHCl3: 431 (9880), 286 (14 366).
IR (KBr disc, cmꢀ1): 2926, 1607, 1515, 1502, 1402, 1288, 1248,
1175, 1036, 834, 802, 760.
4.3.10. Synthesis of bis-[((3,5-bis(4-methoxyphenyl)-1-methyl-
pyrrole)2-)cyclopentadienyl]titanium(IV) dichloride (5c)
Anal. Calc. for C19H19NO2: C, 77.79: H, 6.53: N, 4.77. Found: C,
77.01: H, 6.65: N, 4.81.
One molar solution of Super Hydride (LiBEt3H) (4.8 mL,
4.8 mmol) in THF was concentrated by removal of the solvent by
heating it to 60 °C under reduced pressure of 10ꢀ2 mbar for
40 min and then to 90 °C for 20 min in a Schlenk flask. 2-(Cyclo-
penta-2,4-dienylidenemethyl)-3,5-bis(4-methoxyphenyl)-1-
methyl-pyrrole (1.2 g, 3.3 mmol) was added to a Schlenk flask and
dissolved in dry diethyl ether (50 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
IR (KBr disc, cmꢀ1): 2924, 2853, 1610, 1568,1504, 1465, 1385,
1290, 1252, 1771, 1037, 836.
4.3.8. Synthesis of 3,5-bis(4-methoxyphenyl)-1-methyl-pyrrole-2-
carbaldehyde (2c)
DMF (0.71 mL) was stirred at 0 °C for 30 min and to this POCl3
(0.19 mL, 2.00 mmol) was added and the solution was stirred for
a further 15 min at 0 °C, following which 2,4-bis(4-methoxy-

2452
A. Deally et al. / Polyhedron 29 (2010) 2445–2453
white precipitate of the lithium cyclopentadienide intermediate
formed and the solution had changed its colour from orange/red
to yellow. The precipitate was filtered onto a frit. The white precip-
itate was dried briefly under reduced pressure and was transferred
to a Schlenk flask under nitrogen. The lithium cyclopentadienide
intermediate 4c (0.55 g, 1.40 mmol, 44%) was dissolved in dry
THF (30 mL) to give a light yellow solution. Titanium tetrachloride
(0.7 mL, 0.7 mmol) was added to the lithium cyclopentadienide
intermediate solution to give a dark red solution. The dark red tita-
nium solution was refluxed for 16 h. The solution was then cooled
and the solvent was removed under reduced pressure. The remain-
ing residue was extracted with DCM (30 mL) and filtered through
Celite to remove the remaining LiCl. The solvent was removed un-
der reduced pressure to yield a brown/purple solid in 57% yield
(0.35 g, 0.40 mmol).
(m, 1H), 6.59 (d, J = 4.0 Hz, 1H), 6.42 (d, J = 4.0 Hz, 1H), 6.32–6.27
(m, 2H), 3.86 (s, 3H, OCH3), 3.66 (s, 3H, N–CH3).
13C NMR (101 MHz, CDCl3) d 159.33, 139.92, 139.62, 133.46,
131.91, 130.33, 128.64, 126.54, 125.61, 124.85, 119.30, 116.07,
114.01, 111.22, 55.35, 31.95.
ES-MS: m/z 264 [M+H]+.
HRSM: m/z calcd for C18H17NO [M]+ 263.1297, found 263.1304.
kmax [nm],
(46 946).
(e)
[L molꢀ1 cmꢀ1], CHCl3: 276 (14 418), 250
IR (KBr disc, cmꢀ1): 1596, 1535, 1431, 1389, 1345, 1339, 1251,
1179, 1057, 994, 899.
4.3.13. Synthesis of bis-[((5-(4-methoxyphenyl)-1-methyl-pyrrole)2-)-
cyclopentadienyl]titanium(IV) dichloride (5d)
One molar Super Hydride (6 mL, 6 mmol) in THF was concen-
trated by removal of the solvent by heating it to 60 °C under re-
duced pressure of 10ꢀ2 mbar for 40 min and then to 90 °C for
20 min in a Schlenk flask. 2-(Cyclopenta-2,4-dienylidenemethyl)-
5-(4-methoxyphenyl)-1-methyl-pyrrole (0.8 g, 3.0 mmol) was
added to a Schlenk flask and was dissolved in dry diethyl ether
(50 mL) to give a red solution. The red fulvene solution was trans-
ferred 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 chan-
ged its colour from red to cream. The precipitate was filtered onto a
frit. The white precipitate was dried briefly under reduced pressure
and was transferred to a Schlenk flask under nitrogen. The lithium
cyclopentadienide intermediate 4d (0.57 g 2.10 mmol, 69%) was
dissolved in of dry THF (30 mL) to give a colourless solution. Tita-
nium tetrachloride (1 mL, 1 mmol) was added to the lithium cyclo-
pentadienide 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 (30 mL) and fil-
tered through Celite to remove the remaining LiCl. The solvent
was removed under reduced pressure to yield a brown solid in
55% yield (0.38 g, 0.60 mmol).
1H NMR (400 MHz, CDCl3) d 7.32 (d, J = 9.0 Hz, 4H, C6H4), 7.30
(d, J = 9.0 Hz, 4H, C6H4), 6.94 (d, J = 8.7 Hz, 4H, C6H4), 6.90 (d,
J = 8.7 Hz, 4H, C6H4), 6.21 (s, 2H, C4H2N), 6.15 (t, 4H, C5H4), 6.11
(t, 4H, C5H4), 4.17 (s, 4H, –CH2), 3.84 (s, 6H, OCH3), 3.79 (s, 6H,
OCH3), 3.50 (s, 6H, N–CH3).
13C NMR (101 MHz, CDCl3) d 158.95, 158.05, 135.53, 134.40,
130.41, 129.64, 127.43, 126.03, 122.96, 122.91, 116.58, 114.16,
114.06, 108.31, 55.52, 55.49, 32.65, 26.80.
IR (KBr disc, cmꢀ1): 2931, 2833, 1521, 1451, 1289, 1175, 1036,
834, 795.
kmax [nm],
(45,378).
(e)
[L molꢀ1 cmꢀ1], CHCl3: 274 (43,531), 250
Anal. Calc. for C50H48Cl2N2O4Ti: C, 69.85; H, 5.63; N, 3.26; Cl,
8.25. Found: C,69.15; H, 6.02; N, 3.03; Cl, 5.73%.
4.3.11. Synthesis of 5-(4-methoxyphenyl)-1-methyl-pyrrole-2-
carbaldehyde (2d)
DMF (2 mL) was stirred at 0 °C for 30 min, following which
POCl3 (0.24 mL, 2.60 mmol) was added and the solution was stirred
for 15 min at 0 °C. 2-(4-Methoxyphenyl)-1-methylpyrrole (0.50 g,
2.60 mmol) in DMF (0.5 mL) was added dropwise and stirred for
2 h to give a dark red solution. Ice (5 g) and 9 M NaOH (5 mL)
was added slowly, giving a dark brown solution. The product was
extracted with DCM (2 ꢁ 50 mL). The organic layers were com-
bined and washed with H2O (2 ꢁ 50 mL) and brine (2 ꢁ 50 mL).
The DCM was dried over sodium sulfate and the solvent removed
at reduced pressure to give a dark brown oil in 56% yield (0.32 g,
1.50 mmol).
1H NMR (400 MHz, CDCl3) d 7.27 (d, J = 8.7 Hz, 4H, C6H4), 6.92
(d, J = 8.7 Hz, 4H, C6H4), 6.43 (s, 8H), 6.04 (d, J = 3.5 Hz, 2H), 5.79
(d, J = 3.5 Hz, 2H), 4.11 (s, 4H), 3.82 (s, 6H, OCH3), 3.50 (s, 6H, N–
CH3).
13C NMR (101 MHz, CDCl3) d 158.86, 135.12, 134.82, 132.01,
130.39, 126.36, 123.95, 115.40, 114.03, 107.16, 107.12, 55.53,
32.15, 29.10.
1H NMR (400 MHz, CDCl3) d 9.53 (s, 1H), 7.33 (d, J = 8.8 Hz, 2H),
6.97 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 4.1 Hz, 1H, C4H2N), 6.24 (d,
J = 4.1 Hz, 1H, C4H2N), 3.90 (s, 3H, N–CH3), 3.84 (s, 3H, OCH3).
13C NMR (101 MHz, CDCl3) d 179.59, 160.15, 144.54, 133.00,
131.63, 130.73, 123.63, 114.35, 110.62, 55.60, 34.52.
ES-MS: m/z 216 [M+H]+.
kmax [nm], (e
) [L molꢀ1 cmꢀ1], CHCl3: 273 (35 483), 258 (7015).
Anal. Calc. for C36H36Cl2N2O2Ti: C, 66.78; H, 5.6; N, 4.33; Cl,
10.95. Found: C, 65.3; H, 5.96; N, 3.78; Cl, 7.41%.
IR (KBr disc, cmꢀ1): 2929, 2851, 1611, 1520, 1457, 1384, 1285,
1250, 1176, 1032.
HRSM: m/z calcd for C13H14NO2 [M+H]+ 216.1025 found:
216.1026.
References
IR (KBr disc, cmꢀ1): 3053, 2930, 2841, 1655, 1611, 1465, 1358,
1258, 1178, 1047, 1030, 837, 777.
[1] Surveillance Epidemiology and End Results, National Cancer Institute 2007.
www.seer.cancer.gov.
[2] A.J. Schrader, R. Hofmann, Anti-cancer Drugs 19 (2008) 235.
[3] G. Lummen, H. Sperling, H. Luboldt, T. Otto, H. Rubben, Cancer Chemother.
Pharmacol. 42 (1998) 415.
[4] N. Kröger, U.R. Kleeberg, K.B. Mross, L. Edler, G. Saß, D.K. Hossfeld, Onkologie
23 (2000) 60.
4.3.12. Synthesis of 2-(cyclopenta-2,4-dienylidenemethyl)-5-(4-
methoxyphenyl)-1-methyl-pyrrole (3d)
5-(4-Methoxyphenyl)-1-methyl-pyrrole-2-carbaldehyde (1.3 g
6.0 mmol) was dissolved in MeOH (40 mL). Freshly cracked cyclo-
pentadiene (0.6 mL, 7.2 mmol) was added to the reaction solution,
which remained colourless. Pyrrolidine (0.5 mL, 6.0 mmol) was
added to the solution and the colour immediately changed from
colourless to red. The reaction was left to stir for 1 day, after which
a red precipitate formed. This was filtered to give the product as a
red solid in 50% yield (0.80 g, 3.0 mmol).
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d. 1H NMR (400 MHz, CDCl3) d 7.31 (d, J = 8.0 Hz, 2H, C6H4), 7.03
(s, 1H), 6.96 (d, J = 8.0 Hz, 2H, C6H4), 6.89–6.87 (m, 1H), 6.80–6.77

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