Synthesis and cytotoxicity studies of silyl-substituted titanocene dichloride derivatives

Article abstract of DOI:10.1021/om300227h

Six new titanocene compounds have been isolated and characterized. These compounds were synthesized from their silyl-substituted fulvene or cyclopentadiene precursors using Super Hydride (LiBEt₃H) or n-BuLi, followed by transmetalation with titanium tetrachloride, to yield the corresponding titanocene dichloride derivatives. These complexes are bis-[((phenyl)dimethylsilane)cyclopentadienyl] titanium(IV) dichloride (3a), bis-[((4-methoxyphenyl)dimethylsilane)cyclopentadienyl] titanium(IV) dichloride (3b), bis-[((4-N,N-dimethylmethanamine)dimethylsilane)cyclopentadienyl] titanium(IV) dichloride (3c), bis-[((4-N,N-diethylmethanamine)dimethylsilane) cyclopentadienyl] titanium(IV) dichloride (3d), bis-[((1-methyl-5- trimethylsilyl)indol-3-yl)methylcyclopentadienyl] titanium(IV) dichloride (4e), and bis-[((1-methyl-3-diethylaminomethyl-5-trimethylsilyl)indol-2-yl) methylcyclopentadienyl] titanium(IV) dichloride (4f). The two titanocenes 3a and 3b were crystallized and characterized by X-ray crystallography, while all six titanocenes were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines in order to determine their IC₅₀ values. Titanocenes were found to have IC₅₀ values of 139 (±5), 106 (± 4), 127 (±4), 104 (±9), 90 (±6), and 15 (±2) μM.

Full text of DOI:10.1021/om300227h

Article
pubs.acs.org/Organometallics
Synthesis and Cytotoxicity Studies of Silyl-Substituted Titanocene
Dichloride Derivatives
Anthony Deally, Frauke Hackenberg, Grainne Lally, Helge Muller-Bunz, and 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
S
* Supporting Information
ABSTRACT: Six new titanocene compounds have been
isolated and characterized. These compounds were synthesized
from their silyl-substituted fulvene or cyclopentadiene
precursors using Super Hydride (LiBEt3H) or n-BuLi, followed
by transmetalation with titanium tetrachloride, to yield the
corresponding titanocene dichloride derivatives. These com-
plexes are bis-[((phenyl)dimethylsilane)cyclopentadienyl]
titanium(IV) dichloride (3a), bis-[((4-methoxyphenyl)-
dimethylsilane)cyclopentadienyl] titanium(IV) dichloride
(3b), bis-[((4-N,N-dimethylmethanamine)dimethylsilane)cyclopentadienyl] titanium(IV) dichloride (3c), bis-[((4-N,N-
diethylmethanamine)dimethylsilane)cyclopentadienyl] titanium(IV) dichloride (3d), bis-[((1-methyl-5-trimethylsilyl)indol-3-
yl)methylcyclopentadienyl] titanium(IV) dichloride (4e), and bis-[((1-methyl-3-diethylaminomethyl-5-trimethylsilyl)indol-2-
yl)methylcyclopentadienyl] titanium(IV) dichloride (4f). The two titanocenes 3a and 3b were crystallized and characterized by
X-ray crystallography, while all six titanocenes were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell
lines in order to determine their IC50 values. Titanocenes were found to have IC50 values of 139 ( 5), 106 ( 4), 127 ( 4), 104
( 9), 90 ( 6), and 15 ( 2) μM.
back the identification of the active species responsible for
antitumor activity. A formulation 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
nonsmall 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 favorable over conventional antineoplastic agents,
such as cisplatin, doxorubicin, mitoxantrone, and vinblastine.12
However, 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.
Interest in the field was renewed with McGowan et al.'s
synthesis of ring-substituted cationic titanocene dichloride
derivatives, which are water-soluble and were shown to have
significant activity against ovarian cancer.13 Incorporation of
one or two trimethylsilyl groups into the cyclopentadienyl rings
1. INTRODUCTION
Although most new drugs entering the clinic are organic-based
compounds, there is an increasing recognition that many metal
ions are involved in natural biological processes and that there
is much scope for the design of metal-based therapeutic
agents.1,2 In fact, platinum complexes, particularly cisplatin and
its second-generation counterparts, have become established as
highly effective antitumoral agents, and they have revolution-
ized the treatment of testicular cancer, which is still one of their
most successful applications.3 Despite this resounding success,
these compounds cause serious side effects, such as
nephrotoxicity, and chemists continue their quest to find
other metal complexes as potential anticancer agents.
In this context, various organometallic complexes of Ti, Fe,
Mo, V, and Ru, which contain one or more cyclopentadienyl
rings, have been assessed for their antitumor capabilities.4 Most
notable of these metallocene dihalide complexes is titanocene
(bis-cyclopentadienyl titanium) dichloride or Cp2TiCl2, which
has been investigated for use against various animal and
xenografted human tumors, including fluid and solid sarcoma
180, colon 38, and B16 melanoma and fluid and solid Ehrlich
ascites tumor (EAT).5−7 The compound was also shown to
treat cisplatin-resistant ovarian cells A2780CP, which suggests
that the compound has a different mechanism of action than
cisplatin itself.8 On the basis of these encouraging results,
titanocene dichloride was the first nonplatinum metal complex
to enter phase I clinical trials in 1993.9 The compound
exhibited hydrolytic instability under a pH of 5, which held
Special Issue: Organometallics in Biology and Medicine
Received: March 20, 2012
Published: July 2, 2012
© 2012 American Chemical Society
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Figure 1. Molecular structures of Titanocene Y, Titanocene Y*, and previously synthesized indole-substituted titanocene.
of compounds such as these was also shown to significantly
improve the cytotoxicity.14 More recently, novel methods
starting from fulvenes allow direct access to antiproliferative
titanocenes via reductive dimerization with titanium dichloride,
hydridolithiation, or carbolithiation of the fulvene, followed by
transmetalation with titanium tetrachloride in the latter two
cases.15
Scheme 1. Synthesis of the Cyclopentadiene Precursors 2a−
2d to Titanocenes 3a−3d
Hydridolithiation of 6-anisyl fulvene and subsequent reaction
with titanium tetrachloride led to bis-[(p-methoxybenzyl)-
cyclopentadienyl] titanium(IV) dichloride (Titanocene Y,
Figure 1), which has an IC50 value of 30 μM when tested on
the renal cell carcinoma cell line, CAKI-1.16 In addition, the
antiproliferative activity of Titanocene Y and other titanocenes
has been studied in 36 human tumor cell lines and against
explanted human tumors.17−19 Previous work has demonstrated
that Titanocene Y induces apoptosis in a caspase-independent
manner in a range of prostate cancer cells, and it maintained its
cytotoxic effects in Bcl-2 overexpressing PC-3 cells.20 Besides
the direct apoptosis-inducing effects, these titanocene deriva-
tives give a positive immune response by up-regulating the
number of natural killer (NK) cells in mice, and Titanocene Y
proved itself as a strong antiangiogenic compound with an IC50
value of 4.9 μM shown in a spheroid-based cellular angiogenesis
assay.21,22 Recently, animal studies reported the successful
treatment of mice bearing xenografted A431, PC-3, CAKI-1,
and MCF-7 tumors with Titanocene Y.23−25
Following the success of Titanocene Y in both in vivo and in
vitro testing, it was determined necessary to explore further
derivatives of Titanocene Y and measure their preliminary in
vitro biological activity. This work led to the synthesis of water-
soluble derivatives of Titanocene Y and indole-substituted
titanocenes (Figure 1).26,27 This paper is presenting work that
builds on these compounds, incorporating silyl groups similar
to that of McGowan et al., with a key difference: the production
of symmetrical titanocenes that have been shown to be more
active than their asymmetrical counterparts.
intermediates would polymerize upon removal of solvent; this
was most likely caused by attack of the nucleophilic amine at
the susceptible silicon−chlorine center. The products obtained
were of a high purity and could be easily handled. They were
converted to their corresponding titanocene (Figure 2) in the
same fashion as 2a and 2b.
Several efforts were made to incorporate a bridging
dimethylsilyl group at position 5 of the indole using the same
process as 1a and 1b, but all attempts were futile. Instead, we
decided to incorporate the trimethylsilyl group at position 5 of
the indole and compare its cytotoxicity against its non-
functionalized counterparts. The methylation of 5-bromoindole
was achieved by N-alkylation with NaH and methyliodide.28
Addition of the trimethylsilyl group was carried out using a
bromine−lithium exchange using n-BuLi, followed by addition
of trimethylsilyl chloride. Incorporation of the aldehyde group
to position 3 of the indole 2e was carried out using the
Vilsmeier−Haack reaction with phosphorus oxychloride and
DMF, followed by a basic workup.29 Introduction of an
aldehyde group into indole 2f was achieved using n-BuLi,
followed by a DMF quench, and a subsequent workup in aq
HCl.30 Incorporation of the diethylaminomethyl moiety to
compound 1f was done using the Mannich reaction.31
The synthesis of fulvenes 3e and 3f from aldehydes 2e and 2f
is based on a modified version of the Stone and Little
method.32 The aldehyde was reacted with freshly cracked
cyclopentadiene in the presence of pyrrolidine as a base catalyst
to yield the desired product in yields of 82 and 86%. Hydride
insertion was achieved using LiBEt3H (Super Hydride) in
diethyl ether to obtain the correspondingly functionalized
lithium cyclopentadienide intermediate. These intermediates
were then captured on a Schlenk glass frit, dried in vacuo, and
redissolved in THF. Two equivalents of the lithium cyclo-
pentadienide intermediate was then transmetalated with 1 equiv
of TiCl4, resulting in the formation of 1 equiv of the
appropriately substituted titanocenes 4e and 4f (Figure 2) in
yields of 80% and 45% and the byproduct lithium chloride,
which was removed by filtration through a Celite plug.
2. RESULTS AND DISCUSSION
2.1. Synthesis. Compounds 1a and 1b were synthesized
using the appropriately substituted Grignard reagents and
dichlorodimethyl silane. They were purified using vacuum
distillation and were further reacted with sodium cyclo-
pentadienide to give 2a and 2b, the precursors to the
corresponding titanocene (Scheme 1). Conversion to the
titanocene (Figure 2) was done by reacting 2 equiv of precursor
with 2 equiv of n-BuLi, followed by the addition of 1 equiv of
titanium tetrachloride (Scheme 1). The byproduct LiCl was
removed by passing the compounds through a plug of Celite.
Compounds 2c and 2d (Scheme 2) were synthesized in a
one-pot fashion. This was due to the fact that their
2.2. Structural Discussion. A single crystal of titanocene
3a suitable for X-ray diffraction experiments was obtained by
the slow diffusion of pentane into saturated solutions of the
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Figure 2. Structures of titanocenes 3a−3d, 4e, and 4f.
Scheme 2. Synthesis of Titanocenes 3a−3d, 4e, and 4f
compound in chloroform, whereas a single crystal of 3b was
obtained by the slow evaporation of chloroform from a
saturated solution. Selected bond lengths and angles are
displayed in Table 1, while the crystal data and refinement
details for 3a and 3b can be found in the Supporting
Information.33
The length of bonds between the metal center and the
carbon atoms of the cyclopentadienyl rings bound to the metal
ion are similar for Titanocene Y and 3a and 3b (Figures 3 and
4). They vary between 233.6(3) and 242.8(3) pm for
Titanocene Y, between 235.3(5) and 241.6(7) pm for 3a,
and between 234.1(2) and 244.9(2) pm for 3b. The Ti−
Cp(centroid) distances are similar for all three compounds,
which shows that the less electron-withdrawing silicon does not
affect the binding of the Cp to the metal center. The same
applies to the carbon−carbon bonds of the cyclopentadienyl
rings with bond lengths between 138.1(4) and 141.7(4) pm for
Titanocene Y. For 3a, it is between 139.6(2) and 143.2(2) pm,
and for 3b, it is between 139.8(3) and 142.3(3) pm. Neither
Titanocene Y nor 3a nor 3b have any internal crystallographic
symmetry, although these molecules have potential mirror and
2-fold symmetry. This is shown by similar compounds, where
the benzene ring is replaced by a furan, pyrrole, or thiophene
group.34 The titanium−chlorine bond lengths are approx-
imately equal for all three compounds, with Ti−Cl(1) being
236.8(1) pm and Ti−Cl(2) being 236.6(1) pm for Titanocene
Y. For 3a, Ti−Cl(1) is 237.5(6) pm and Ti−Cl(2) is 235.9(1)
pm, and for 3b, Ti−Cl(1) is 236.0(1) pm and Ti−Cl(2) is
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compact than 3b, which appears to be more stretched. There
are no π−π interactions to be seen between the groups.
2.3. Cytotoxicity Studies. The cytotoxic effects of
titanocenes 3a−3d, 4e, and 4f 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
modified eagle medium containing 10% (v/v) FBS (Foetal
Bovine Serum), 1% (v/v) penicillin streptomycin, and 1% (v/v)
L-glutamine. Cytotoxicities of the various titanocenes were
determined by an MTT-based assay.
The series described is composed of a range of titanocenes,
with two distinct subsets: structural analogues of Titanocene Y,
which contain a bridging dimethylsilyl group, and indole-
substituted titanocenes, which contain a trimethylsilyl group in
position 5 of the indole. These titanocenes complement and
add to the previously reported series of indole-substituted
titanocenes. As seen in Figure 5, titanocenes 3a−3d, 4e, and 4f
exhibited an illustrative spectrum of activity with IC50 values of
139, 106, 127, 104, 90, and 15 μM against CAKI-1 cells,
respectively. The results of the cell test proved to be
disappointing, with the incorporation of the bridging
dimethylsilyl group causing a decrease in activity in all
compounds when compared with their nonsilylated counter-
parts. This is particularly evident in compound 3d, which has an
almost 200-fold decrease in activity when compared with its
nonsilylated counterpart (Table 2). This decrease in activity is
unfortunate, but not wholly unexpected. We envisaged that the
less electron-withdrawing silicon (compared to carbon) atom
adjacent to the cyclopentadienide ring might have a positive
effect on the binding of the Cp ring to the titanium center;
however, upon closer inspection of the crystal structure, we can
see that this was not the case, with the Ti−Cp(centroid)
distances almost equal (∼206 pm) to those of titanocenes
bearing no silicon.
Table 1. Selected Bond Lengths and Angles for Crystal
Structures of Titanocene Y and 3a and 3b
bond lengths
(pm)
Titanocene Y
3a
242.4(6)
3b
244.9(2)
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)
236.8(1)
236.6(1)
150.9(4)
239.4(7)
235.8(6)
235.3(4)
240.3(2)
142.5(4)
139.8(2)
142.0(2)
139.6(2)
142.1(2)
237.5(6)
237.5(6)
239.6(8)
235.4(2)
234.1(2)
241.0(2)
141.5(3)
140.8(3)
140.6(4)
140.3(3)
141.9(3)
236.0(6)
237.5(6)
Ti−C(5)
C(1)−C(2)
C(2)−C(3)
C(3)−C(4)
C(4)−C(5)
C(5)−C(1)
Ti−Cl(1)
Ti−Cl(2)
C(1)−C(6)
C(1)−Si(1)
C(1)−Si(1)
187.6(0)
187.2(5)
C(6)−C(7)
151.7(4)
150.2(4)
151.9(4)
C(8)−Si(1)
C(8)−Si(1)
188.0(1)
188.6(2)
C(17)−C(22)
C(22)−C(23)
C(14)−Si(2)
C(15)−Si(2)
188.5(9)
188.3(2)
C(21)−Si(2)
C(22)−Si(2)
187.2(8)
187.9(2)
Ti−Cent1
Ti−Cent2
206.1
206.1
206.3(<1)
207.1(<1)
206.8(1)
207.2(1)
The introduction of a trimethylsilyl group onto position 5 of
the indole does not have a dramatic effect on the efficacy of the
indole-substituted titanocenes on the CAKI-1 cell line.
Titanocene 4e has a 5-fold decrease in activity when compared
with its nonfunctionalized counterpart; however, the com-
pound does have reduced solubility in an aqueous medium. As
a result, the IC50 values for this compound may not be a true
reflection of its cytotoxic activity. However, titanocene 4f (IC50
= 15 μM), which is the most active compound in this study, has
relatively the same activity as its nonsilylated counterpart (IC50
= 10 μM).35
Figure 3. Molecular structure of 3a; thermal ellipsoids are drawn at the
50% probability level.
3. CONCLUSION AND OUTLOOK
In conclusion, we have synthesized a range of titanocenes with
bridging dimethylsilyl groups, and indole-substituted titano-
cenes, which contain a trimethylsilyl group in position 5 of the
indole. These compounds have been evaluated for their
cytotoxic properties on the CAKI-1 cell line. The compounds
display a range of activity, from titanocenes with low activity to
indole-substituted titanocenes that have high cytotoxicity.
Unfortunately, incorporation of silicon into these compounds
did not have the desired effect on cytotoxicity that we had
hoped for. However, we have shown that it is possible to
synthesize unique compounds, such as these titanocenes. The
design, synthesis, and biological testing of further structural
analogues based upon McGowan’s unsymmetrical silyl-
substituted titanocenes is ongoing, the results of which will
be reported upon in due course.
Figure 4. Molecular structure of 3b; thermal ellipsoids are drawn at
the 50% probability level.
239.5(2) pm. The Cl−Ti−Cl′ angle was measured for
Titanocene Y as 95.94(3)°. For 3a, it is 94.91(4)°, and for
3b, it is 93.84(2)°. The three structures show similar
conformations as the benzyl substituents are orientated away
from each other so that steric hindrances are minimized.
However, as can be seen in Figure 3, titanocene 3a is more
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Figure 5. Cytotoxicity curves from typical MTT assays showing the effect of compounds 3a−3d, 4e, and 4f on the viability of CAKI-1 cells.
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
Table 2. Cytotoxicities of Titanocenes 3a−3d, 4e, and 4f and
their Nonsilylated Counterparts on CAKI-1 Cells Using
DMSO
10% (v/v) FBS (Foetal Bovine Serum), 1% (v/v) penicillin
streptomycin, and 1% (v/v) L-glutamine. The cytotoxicities of
titanocenes 3a−d, 4e, and 4f were determined by an MTT-based
assay.38
IC50 CAKI-1
nonsilylated equivalent IC50 CAKI-1 [μM]
26,34
compound
[μM]
3a
3b
3c
3d
4e
4f
139 ( 5)
106 ( 4)
127 ( 4)
104 ( 9)
90 ( 6)
15 ( 2)
not measured
30 ( 2)
Specifically, cells were seeded in 96-well plates containing 200 μL of
medium and were incubated at 37 °C and 5% carbon dioxide for 24 h
to allow for exponential growth. The compounds used for testing were
dissolved in dimethyl sulfoxide (70 μL DMSO, 0.7% of final
concentration) and diluted with medium to obtain stock solutions of
5 × 10−4 M in concentration. Negative controls were done using only
70 μL of DMSO and no drug. 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 buffered saline), and fresh medium was
added to the wells. Following a recovery period of 24 h incubation at
37 °C, individual wells were treated with 200 μL of a solution of MTT
in medium (5 mg of MTT per 11 mL of medium). The cells were
incubated for 3 h at 37 °C. The medium was then removed, and the
purple formazan crystals were dissolved in 200 μL of 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 absorbance recorded for control wells. IC50 values were
determined using the Origin “50” program. The graphs were
constructed by plotting normalized absorbance versus concentration.
The exact IC50 values were based on a fit of this graph. Titanocene Y
(IC50 = 30 ( 2) μM) was used as a positive control in each test.
The values used for the dose response curves of Figure 5 represent
the values obtained from four consistent MTT-based assays for each
compound tested.
6.7 ( 0.9)
0.55 ( 0.32)
21 ( 5)
10 ( 2)
4. EXPERIMENTAL SECTION
4.1. General Conditions. 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. 5-Bromo-1H-indole was
purchased from Apollo Scientific and used as received. Solvents
were dried in a Grubbs solvent system and collected under an
atmosphere of nitrogen prior to use. 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 parts per million and are referenced to TMS. IR
spectra were recorded on a Varian 3100 FT-IR Excalibur Series
employing a KBr disk. UV−vis spectra were recorded on a Cary 50
Scan UV−visible spectrophotometer (λ in nm, ε in dm3 mol−1 cm−1).
A single crystal of titanocene 3a suitable for X-ray diffraction
experiments was obtained by the slow diffusion of pentane into
saturated solutions of the compound in chloroform, whereas a single
crystal of 3b suitable for X-ray diffraction experiments was obtained by
the slow evaporation of chloroform from a saturated solution. X-ray
diffraction data for 3a and 3b were collected on an Agilent
Technologies (former Oxford Diffraction) Super Nova A diffrac-
tometer at 100 K. 3a was measured with Mo Kα (0.71073 Å) and 3b
with Cu Kα (1.54184 Å). A complete data set was collected, assuming
that the Friedel pairs are not equivalent. An analytical absorption
correction based on the shape of the crystal was performed.36 The
crystal structure was then solved by direct methods (SHELXS-97) and
refined by full-matrix least-squares methods against F2 (SHELXL-
97).37 Additional details are available free of charge from the
Cambridge Structural Database under the CCDC Nos. 870549 (3b)
and 87550 (3a). MS data were collected on a quadrupole tandem mass
spectrometer (Quattro Micro, Micromass/Water’s Corp., Milford,
MA) and prepared as solutions of tetrahydrofuran (THF). CHN
analysis was carried out with an Exeter-CE-440 elemental analyzer.
MTT-Based Assay (MTT = 3-(4,5-Dimethylthiazol-2-yl)-2,5-
diphenyl-2H-tetrazolium Bromide). Preliminary in vitro cell tests
4.2. Synthesis. Preparation of Chloro(phenyl)dimethyl Silane
(1a). To a solution of dichlorodimethyl silane (1.15 mL, 9.6 mmol) in
Et2O (5 mL) was added dropwise (phenyl)magnesium bromide,
prepared from 4-bromobenzene (1.0 mL, 9.6 mmol) and magnesium
turnings (0.25 g, 10.6 mmol) in THF (25 mL) at 0 °C. The reaction
mixture was warmed to room temperature. After stirring for 24 h,
pentane was added to the reaction mixture, and the resulting
precipitate was filtered off. After evaporation of the volatile materials,
the residue was purified by vacuum distillation (85 °C/6 mmHg) to
afford a light yellow oil (1.3 g, 7.6 mmol, 82%).
39
1
Confirmed by H NMR. 1H NMR (300 MHz, CDCl3): δ 7.66−
7.57 (m, 2H), 7.45−7.39 (m, J = 6.3 Hz, 3H), 0.68 (s, 6H).
Preparation of Cyclopenta-1,3-dienyl(phenyl)dimethyl Silane
(2a). To a solution of freshly cracked cyclopentadiene (1.0 mL, 12
mmol) in THF (33 mL) was added dropwise n-BuLi (1.6 M in hexane,
7.5 mL, 12.0 mmol) at −78 °C, and the mixture was stirred at the
same temperature for 0.5 h. To the mixture, chloro(phenyl)dimethyl
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silane (1a) (2.0 g, 12 mmol) was added dropwise, and the resulting
mixture was allowed to warm to room temperature. After stirring for 4
h, the reaction was quenched with saturated NH4Cl aqueous solution
and extracted with pentane (50 mL). The organic layer was washed
with brine, dried over MgSO4, and evaporated to give a brownish oil
(2.10 g, 10.5 mmol, 89%).
removed. The resulting red solid was washed with pentane (40 mL)
and dried under vacuum to give a red crystalline powder (0.20 g, 0.34
mmol, 26%).
1H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8.5 Hz, 4H, C6H4),
6.89 (d, J = 8.4 Hz, 4H, C6H4), 6.68 (t, J = 2.2 Hz, 4H, C5H4), 6.30 (t,
J = 2.2 Hz, 4H, C5H4), 3.79 (s, 6H, OCH3), 0.54 (s, 12H, Si(CH3)2).
13C NMR (101 MHz, CDCl3): δ 160.90 (q-C6H4), 135.83 (C6H4),
40
1
Confirmed by H NMR. 1H NMR (400 MHz, CDCl3): δ 7.58−
7.51 (m, 2H), 7.42−7.35 (m, 3H), 6.62−6.52 (m, 4H), 3.61 (s, 1H),
0.20 (s, 6H).
130.77, 130.09 (C5H4), 128.69, 121.03 (C5H4), 113.91 (C6H4), 55.27
(OCH3), −1.28 (Si(CH3)2). 29Si NMR (79 MHz, CDCl3): δ 31.85. IR
(KBr disk, cm−1): 3463, 3110, 2965, 2834, 1590, 1562, 1501, 1457,
1402, 1278, 1245, 1182, 1106, 1047, 1026, 835, 818, 783. λmax [nm],
(ε) [L mol−1 cm−1], CHCl3: 233 (26 048), 258 (15 238), 404 (2144).
Anal. Calcd for C28H34O2Cl2Si2Ti: C, 58.23; H, 5.93. Found: C, 57.90;
H, 5.60.
Preparation of 1-(4-(Cyclopenta-2,4-dienyldimethylsilyl)phenyl)-
N,N-dimethylmethanamine (2c). To a solution of dichlorodimethyl
silane (1.58 mL, 13 mmol) in Et2O (5 mL) was added dropwise (4-
((dimethylamino)methyl)phenyl) magnesium bromide, prepared from
1-(4-bromophenyl)-N,N-dimethylmethanamine (2.6 g, 12 mmol) and
magnesium turnings (0.32 g, 13 mmol) in THF (25 mL) at 0 °C. The
reaction mixture was warmed to room temperature and stirred for 24
h. To this was added a solution of freshly cracked cyclopentadiene (1.0
mL, 12 mmol) and n-BuLi (1.6 M in hexane, 7.6 mL, 12 mmol) in
THF (30 mL), and the resulting yellow solution was stirred for a
further 16 h. Saturated aqueous NH4Cl (50 mL) was added, and the
product was extracted with pentane (3 × 20 mL). The organic layer
was washed with brine (50 mL), dried over MgSO4, and evaporated to
give a light yellow oil. This oil was left in an exsiccator overnight to
give the product (2.80 g, 10.9 mmol, 90%).
Synthesis of Bis-[((phenyl)dimethylsilane)cyclopentadienyl]
Titanium(IV) Dichloride (3a). To a solution of cyclopenta-2,4-
dienyl(phenyl)dimethyl silane (2a) (1.0 mL, 5.0 mmol) in THF (30
mL) was added dropwise n-BuLi (2.5 M in hexane, 2.0 mL, 5 mmol)
at −78 °C, and the solution was stirred at the same temperature for 0.5
h. The solution was allowed to warm to room temperature, and TiCl4
(1 M in toluene, 2.5 mL, 2.5 mmol) was added. The resulting red
solution was heated at 50 °C for 4 h. The solution was then cooled
and the solvent removed under reduced pressure. The remaining
residue was extracted with DCM (30 mL) and filtered through Celite
to remove the remaining LiCl. The solvent was removed under
reduced pressure to yield a brown waxy solid. This was dissolved in
Et2O (60 mL) and suction-filtered, and the solvent was removed. The
resulting red solid was washed with pentane and dried under vacuum
to give a red crystalline powder (0.50 g, 1.0 mmol, 38%).
1H NMR (300 MHz, CDCl3): δ 7.48 (s, 4H), 7.36 (s, 6H), 6.70 (s,
4H, C5H4), 6.32 (s, 4H, C5H4), 0.59 (s, 12H). 13C NMR (75 MHz,
CDCl3): δ 138.06, 134.32, 130.45, 130.15 (C5H4), 129.64, 128.15,
120.87 (C5H4), −1.49 (Si(CH3)2). 29Si NMR (99 MHz, CDCl3): δ
31.16. IR (KBr disk, cm−1): 3053. 2985, 2360, 2340, 1427, 1265, 1177.
1110, 1044, 895. Anal. Calcd for C26H30Cl2Si2Ti: C, 60.35; H, 5.84.
Found: C, 60.58; H, 5.44.
Preparation of Chloro(4-methoxyphenyl)dimethyl Silane (1b).
To a solution of dichlorodimethyl silane (3.0 mL, 25 mmol) in Et2O
(5 mL) was added dropwise (4-methoxyphenyl) magnesium bromide,
prepared from 4-bromoanisole (2.1 mL, 17 mmol) and magnesium
turnings (0.61 g, 25 mmol) in THF (25 mL) at 0 °C. The reaction
mixture was warmed to room temperature. After stirring for 24 h,
pentane was added to the reaction mixture, and the resulting
precipitate was filtered off. After evaporation of the volatile materials,
the residue was purified by vacuum distillation (100 °C/6 mmHg) to
afford a light yellow oil (2.6 g, 13 mmol, 77%).
1H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.5 Hz, 4H), 7.21 (d, J
= 8.5 Hz, 4H), 6.38−6.59 (m, 4H), 3.53 (s, 1H), 3.39 (s, 2H), 2.20 (s,
6H), 0.24 (s, 6H). 13C NMR (101 MHz, CDCl3): δ148.12, 143.35,
138.81, 138.31, 137.12 (C6H4), 133.55, 125.56 (C6H4), 64.12 (CH2),
45.45(CH3), −1.35 (Si(CH3)2). ES-MS: m/z 258 [M + H]+. HRMS:
m/z calcd for C16H24NSi [M + H]+, 258.1678; found, 258.1665. IR
(KBr disk, cm−1): 3051, 2957, 2821, 2305, 1602, 1458, 1396, 1363,
1265, 1173, 1112, 1036, 1017, 900, 843.
Synthesis of Bis-[((4-N,N-dimethylmethanamine)dimethylsilane)-
cyclopentadienyl] Titanium(IV) Dichloride (3c). To a solution of 1-
(4-(cyclopenta-2,4-dienyldimethylsilyl)phenyl)-N,N-dimethylmethan-
amine (2c) (1.0 g, 3.9 mmol) in THF (30 mL) was added dropwise n-
BuLi (1.6 M in hexane, 2.67 mL, 4.27 mmol) at −78 °C, and the
solution was stirred at the same temperature for 0.5 h. The solution
was allowed to warm to room temperature, and TiCl4 (1 M in toluene,
1.95 mL, 1.95 mmol) was added. The resulting orange solution was
stirred for 8 h. The solvent was then removed under reduced pressure.
The remaining residue was extracted with DCM (30 mL) and filtered
through Celite to remove the remaining LiCl. The solvent was
removed under reduced pressure to yield an orange solid. This was
dissolved with DCM (20 mL), and the product was precipitated using
Et2O (12 mL) and filtered. The resulting orange solid was washed with
Et2O (50 mL) and dried under vacuum to give an orange crystalline
powder (0.73 g, 1.2 mmol, 60%).
Confirmed by 1H NMR.41 1H NMR (400 MHz, CDCl3): δ 7.47 (d,
J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 3.74 (s, 3H), 0.58 (s, 6H).
Preparation of Cyclopenta-1,3-dienyl(4-methoxyphenyl)dimethyl
Silane (2b). To a solution of freshly cracked cyclopentadiene (0.98
mL, 12.0 mmol) in THF (33 mL) was added dropwise n-BuLi (1.6 M
in hexane, 7.5 mL, 12.0 mmol) at −78 °C, and the mixture was stirred
at the same temperature for 0.5 h. To the mixture, chloro(4-
methoxyphenyl)dimethyl silane (1b) (2.4 g, 12 mmol) was added
dropwise, and the resulting mixture was allowed to warm to room
temperature. After stirring for 4 h, the reaction was quenched with
saturated NH4Cl aqueous solution and extracted with pentane (50
mL). The organic layer was washed with brine, dried over MgSO4, and
evaporated to give a light yellow oil (2.60 g, 11.4 mmol, 95%).
Confirmed by 1H NMR.42 1H NMR (400 MHz, CDCl3): δ 7.46 (d,
J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.63−6.43 (broad m, 4H),
3.82 (s, 3H), 3.56 (s, 1H), 0.14 (s, 6H).
Synthesis of Bis-[((4-methoxyphenyl)dimethylsilane)-
cyclopentadienyl] Titanium(IV) Dichloride (3b). To a solution of
cyclopenta-2,4-dienyl(4-methoxyphenyl)dimethyl silane (2b) (0.60
mL, 2.6 mmol) in THF (30 mL) was added dropwise n-BuLi (1.6
M in hexane, 1.7 mL, 2.7 mmol) at −78 °C, and the solution was
stirred at the same temperature for 0.5 h. The solution was allowed to
warm to rt, and TiCl4 (1 M in toluene, 1.3 mL, 1.3 mmol) was added.
The resulting red solution was heated at 50 °C for 4 h. The solution
was then cooled and the solvent removed under reduced pressure. The
remaining residue was extracted with DCM (30 mL) and filtered
through Celite to remove the remaining LiCl. The solvent was
removed under reduced pressure to yield a brown waxy solid. This was
dissolved in Et2O (50 mL) and suction-filtered, and the solvent was
1H NMR (300 MHz, D2O): δ 7.43 (broad d, 4H, C6H4), 7.20
(broad d, 4H, C6H4), 6.60−6.48 (m, 4H, C5H4), 6.03−5.92 (m, 4H,
C5H4), 4.01 (s, 4H, CH2), 2.55 (s, 12H, CH3), 0.09 (s, 12H,
Si(CH3)2). 13C NMR (75 MHz, D2O): δ 142.65, 136.26, 135.25
(C6H4), 132.13, 131.89, 131.56 (C6H4), 130.66, 62.30 (CH2), 43.50
(CH3), −0.01 (Si(CH3)2). 29Si NMR (99 MHz, CDCl3): δ 31.15. IR
(KBr disk, cm−1): 3054, 2985, 2685, 2305, 1605, 1421, 1264, 1048,
895. Anal. Calcd for C32H44N2Si2Cl2Ti: C, 60.85; H, 7.02; N, 4.43.
Found: C, 60.32; H, 7.74; N, 4.04.
1-(4-(Cyclopenta-2,4-dienyldimethylsilyl)phenyl)-N,N-diethylme-
thanamine (2d). To a solution of dichlorodimethyl silane (2.0 mL, 16
mmol) in Et2O (5 mL) was added dropwise (4-((diethylamino)-
methyl)phenyl) magnesium bromide, prepared from 1-(4-bromophen-
yl)-N,N-diethylmethanamine (4.0 g, 16 mmol) and magnesium
turnings (0.39 g, 16 mmol) in THF (25 mL) at 0 °C. The reaction
mixture was warmed to room temperature and stirred for 24 h. To this
was added a solution of freshly cracked cyclopentadiene (1.3 mL, 16
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mmol) and n-BuLi (1.6 M in hexane, 10 mL, 16 mmol) in THF (30
mL), and the resulting yellow solution was stirred for a further 16 h.
Saturated aqueous NH4Cl (50 mL) was added, and the product was
extracted with pentane (3 × 20 mL). The organic layer was washed
with brine (50 mL), dried over MgSO4, and evaporated to give a light
yellow oil. This oil was left in an exsiccator overnight to give the
product (3.5 g, 12 mmol, 88%).
filtered and washed with water (100 mL) to give a white solid. This
was purified by flash column chromatography (silica) with Et2O as the
eluent. The solvent was removed at reduced pressure to yield a white
solid (1.5 g, 6.5 mmol, 90%).
1H NMR (400 MHz, CDCl3): δ 9.99 (s, 1H, CHO), 8.46 (s, 1H, H-
4), 7.65 (s, 1H, H-2), 7.49 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.2 Hz,
1H), 3.88 (s, 3H, NCH3), 0.31 (s, 9H, Si(CH3)3). 13C NMR (101
MHz, CDCl3): δ 184.62 (CHO), 139.40, 138.65, 134.46, 128.95,
127.56, 125.34, 118.31, 109.56, 33.83 (NCH3), −0.51(Si(CH3)2). ES-
MS: m/z 254 [M + Na]+. HRMS: m/z calcd for C13H17NOSiNa [M +
Na]+, 254.0977; found, 254.0971. IR (KBr disk, cm−1): 3053, 2986,
2957, 2359, 2306, 1664, 1536, 1422, 1265, 1153, 1101, 985.
Synthesis of 3-(Cyclopenta-2,4-dienylidenemethyl)-1-methyl-5-
(trimethylsilyl)-indole (3e). 1-Methyl-5-(trimethylsilyl)-indole-3-car-
baldehyde (2e) (2.1 g, 9.1 mmol) was dissolved in MeOH (70 mL).
Freshly cracked cyclopentadiene (0.76 mL, 9.1 mmol) was added to
the solution, followed by pyrrolidine (0.75 mL, 9.1 mmol), and the
color immediately changed from colorless to red. The reaction was left
to stir while being monitored by thin-layer chromatography (silica/
DCM), which showed only one product spot after 3 h. 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 was removed
at reduced pressure to give a red oil. This was purified by flash column
chromatography (silica) with pentane as the eluent. The solvent was
removed at reduced pressure to yield a red solid (2.1 g, 7.5 mmol,
82%). 1H NMR (300 MHz, CDCl3): δ 7.98 (s, 1H), 7.55 (s, 1H), 7.51
(s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 6.77−6.72
(m, 1H), 6.63−6.60 (m, 1H), 6.44−6.40 (m, 2H), 3.85 (s, 3H,
NCH3), 0.32 (s, 9H, Si(CH3)3). 13C NMR (75 MHz, CDCl3): δ
140.75, 137.77, 133.38, 131.93, 131.81, 130.46, 128.67, 128.14, 127.80,
127.08, 124.46, 119.62, 113.56, 109.55, 33.54 (NCH3), −0.46
(Si(CH3)2). ES-MS: m/z 280 [M + H]+. IR (KBr disk, cm−1): 2954,
2926, 1611, 1530, 1454, 1420, 1340, 1265, 1245, 1126, 1076, 875, 836,
738.
1H NMR (400 MHz, CDCl3): δ 7.5 (d, J = 8.5 Hz, 2H, C6H4), 7.34
(d, J = 8.5 Hz, 2H, C6H4), 6.41−6.622 (m, 4H), 3.56 (s, 2H),3.42 (s,
1H), 2.45 (q, 4H, CH2), 2.01 (t, 6H, CH3), 0.10 (s, 6H, Si(CH3)2).
13C NMR (101 MHz, CDCl3): δ147.82, 145.25, 142.21, 140.13,
138.31, 137.12, 132.65, 62.12, 52.45, 12.23, −3.35. ES-MS: m/z 286
[M + H]+. HRMS: m/z calcd for C18H28NSi [M + H]+, 285.1991;
found, 286.1980. IR (KBr disk, cm−1): 3406, 2957, 1737, 1642, 1594,
1503, 1463, 1363, 1279, 1249, 1182, 1114, 1032, 833, 808, 724.
Synthesis of Bis-[((4-N,N-diethylmethanamine)dimethylsilane)-
cyclopentadienyl] Titanium(IV) Dichloride (3d). To a solution of 1-
(4-(cyclopenta-2,4-dienyldiethylsilyl)phenyl)-N,N-diethylmethan-
amine (2d) (1 g, 3.5 mmol) in THF (30 mL) was added dropwise n-
BuLi (1.6 M in hexane, 2.19 mL, 3.5 mmol) at −78 °C, and the
solution was stirred at the same temperature for 0.5 h. The solution
was allowed to warm to room temperature, and TiCl4 (1 M in toluene,
1.75 mL, 1.75 mmol) was added. The resulting orange solution was
stirred for 8 h. The solvent was then removed under reduced pressure.
The remaining residue was extracted with DCM (30 mL) and filtered
through Celite to remove the remaining LiCl. The solvent was
removed under reduced pressure to yield an orange solid. This was
dissolved with DCM (20 mL), and the product was precipitated using
Et2O (12 mL) and filtered. The resulting orange solid was washed with
Et2O and dried under vacuum to give an orange crystalline powder
(0.74 g, 1.1 mmol, 60%).
1H NMR (300 MHz, DMSO-d6): δ 7.67−7.65 (m, 4H, C6H4),
7.58−7.55 (m, 4H, C6H4), 6.18 (broad s, 8H, C5H4), 4.26 (s, 4H),
3.01−2.97 (m, 8H, CH2), 1.24 (t, J = 6.8 Hz, 12H, CH3), 0.04 (s, 12H,
Si(CH3)2). 13C NMR (101 MHz, D2O): δ 142.98, 135.79 (C6H4),
132.67, 132.51, 132.10 (C6H4), 131.88, 131.19, 57.64 (CH2), 48.72,
9.97 (CH3), 0.44 (Si(CH3)2). 29Si NMR (99 MHz, CDCl3): δ 31.13.
IR (KBr disk, cm−1): 3376, 2951, 2647, 2359, 2341, 1464, 1401, 1252,
1108, 1046, 963. Anal. Calcd for C36H52N2Si2Cl2Ti: C, 62.87; H, 7.62;
N, 4.07. Found: C, 62.71; H, 7.07; N, 4.02.
Synthesis of 1-Methyl-5-(trimethylsilyl)-indole (1e). To a solution
of 5-bromo-1-methyl-indole (2 g, 9.5 mmol) in THF (50 mL) was
added dropwise n-BuLi (2.5 M in hexane, 3.8 mL, 9.5 mmol) at −78
°C, and the solution was stirred at the same temperature for 1 h.
TMSCl (2.4 mL, 19 mmol) was then added, and the reaction was
allowed to come to room temperature over 24 h. The reaction was
quenched by addition of saturated ammonium chloride solution (30
mL). This 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 filtered, and the
solvent was removed at reduced pressure to give a yellow oil. This was
purified by column chromatography (silica) with DCM/pentane (1:1)
as the eluent. The solvent was removed at reduced pressure to yield a
yellow oil in 77% yield (1.5 g, 7.4 mmol).
Synthesis of Bis-[((1-methyl-5-trimethylsilyl)indol-3-yl)-
methylcyclopentadienyl] Titanium(IV) Dichloride (4e). Super Hy-
dride (LiBEt3H) (7.2 mL, 7.2 mmol, 1 M) in THF was concentrated
by removal of the solvent by heating it to 60 °C under a reduced
pressure of 10−2 mbar for 40 min and then to 90 °C for 20 min in a
Schlenk flask. 3-(Cyclopenta-2,4-dienylidenemethyl)-1-methyl-5-(tri-
methylsilyl)-indole (3e) (2.0 g, 7.2 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 color from red to white. 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 was dissolved in
dry THF (50 mL) to give a pale yellow solution. Titanium
tetrachloride (2.6 mL, 2.6 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
then 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 brown solid that was washed with pentane to give a brown
crystalline solid (1.9 g, 2.8 mmol, 80%).
1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H, H-4), 7.35 (q, J = 8.2
Hz, 2H), 7.03 (d, J = 3.1 Hz, 1H, H-2), 6.48 (d, J = 3.1 Hz, 1H, H-3),
3.80 (m, 3H, NCH3), 0.30 0 (s, 9H, Si(CH3)3). 13C NMR (101 MHz,
CDCl3): δ 137.41, 129.45, 128.96 (C-4), 128.64 (C-3), 126.62, 126.37,
109.02, 101.15 (C-2), 32.94 (CH3), −0.41 (Si(CH3)2). IR (KBr disk,
cm−1): 2952, 1606, 1513, 1478, 1422, 1322, 1275, 1245, 1073, 916,
836, 751.
Synthesis of 1-Methyl-5-(trimethylsilyl)-indole-3-carbaldehyde
(2e). DMF (1.15 mL) was stirred at 0 °C for 30 min, and to this
was added POCl3 (0.75 mL, 8 mmol). The solution was stirred for a
further 15 min at 0 °C, following which 1-methyl-5-(trimethylsilyl)-
indole (1e) (1.50 g, 7.40 mmol) in DMF (2 mL) was added dropwise,
and the solution was stirred for 1 h to give a dark red solution. This
solution was then stirred at 35 °C for 1 h. The solution was cooled to
room temperature, and 10 g of ice in 10 mL of NaOH (9M) was
added slowly, causing a white precipitate to form. This precipitate was
1H NMR (400 MHz, CDCl3): δ 7.70 (s, 2H, H-4), 7.37 (d, J = 8.1
Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 6.79 (s, 2H, H-2), 6.38 (s, 4H,
C5H4), 6.29 (s, 4H, C5H4), 4.21 (s, 4H, CH2), 3.70 (s, 6H, NCH3),
0.28 (s, 18H, Si(CH3)3). 13C NMR (101 MHz, CDCl3): δ 138.08,
137.74, 129.25, 127.75, 127.53, 126.62, 124.73, 122.60, 116.17, 112.89,
109.10, 32.80 (NCH3), 26.80 (CH2), −0.36 (Si(CH3)2). 29Si NMR
(99 MHz, CDCl3): δ 31.16. IR (KBr disk, cm−1): 3053, 2955, 2305,
1705, 1606, 1481, 1423, 1264, 1099, 835. Anal. Calcd for
C36H44N2Si2Cl2Ti: C, 63.61; H, 6.52; N, 4.12. Found: C, 63.39; H,
6.31; N, 3.98.
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Synthesis of N-Ethyl-N-((1-methyl-5-(trimethylsilyl)-indol-3-yl)-
methyl)ethanamine (1f). 1-Methyl-5-(trimethylsilyl)-indole (2.1 g,
10 mmol) was dissolved in acetic acid (40 mL). Diethylamine (2.2 mL,
21 mmol) was added, and the solution was cooled to 30 °C.
Formaldehyde (2.3 mL, 21 mmol, 30% in H2O) was added, and the
solution was allowed to stand for 2 h. The mixture was then added to
an ice/NaOH (100 mL, 9M) solution and stirred vigorously for 10
min until a yellow precipitate formed. This was filtered, washed with
water, and suction-dried to give a yellow solid (2.3 g, 8.0 mmol, 76%).
1H NMR (400 MHz, CDCl3): δ 7.88 (s, 1H), 7.36 (d, J = 7.8 Hz,
1H), 7.29 (d, J = 7.8 Hz, 1H), 6.96 (s, 1H), 3.79 (s, 2H), 3.73 (s, 3H),
2.55 (q, J = 7.2 Hz, 4H), 1.12 (t, J = 7.2 Hz, 6H), 0.30 (s, 9H). 13C
NMR (101 MHz, CDCl3): δ 137.68, 128.82, 128.68, 128.24, 126.29,
125.19, 122.66, 108.90, 47.80, 46.88, 32.78, 12.36, −0.39. ES-MS: m/z
216 [M − NCH2CH3]+. IR (KBr disk, cm−1): 2964, 2932, 2795, 2339,
1607, 1553, 1417, 1379, 1275, 1245, 1201, 1101, 1053, 866.
Synthesis of 3-((Diethylamino)methyl)-1-methyl-5-(trimethylsil-
yl)-indole-2-carbaldehyde (2f). To a solution of N-ethyl-N-((1-
methyl-5-(trimethylsilyl)-indol-3-yl)methyl)ethanamine (1f) (1.5 g,
5.2 mmol) in THF (50 mL) was added dropwise n-BuLi (2.5 M in
hexane, 2.1 mL, 5.2 mmol) at −78 °C, and the solution was stirred at
the same temperature for 2 h. DMF (0.8 mL, 10.4 mmol) was then
added, and the reaction was allowed to come to room temperature
over 24 h. The reaction was quenched by addition of saturated
ammonium chloride solution (30 mL). This 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 filtered, and the solvent was removed at reduced
pressure to give a yellow oil. This was purified by column
chromatography (alumina) with DCM/pentane (3:1) as the eluent.
The solvent was removed at reduced pressure to yield a yellow oil (1.1
g, 3.5 mmol, 67%).
dienylidenemethyl)-1-methyl-5-(trimethylsilyl)-indol-3-yl)methyl)-N-
ethylethanamine (3f) (1.0 g, 2.8 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 24 h, in which time a white
precipitate of the lithium cyclopentadienide intermediate formed and
the solution had changed its color 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 was dissolved in
dry THF (50 mL) to give a pale 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 stirred for 16 h. The solvent was
then 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 brown crystalline solid that was washed with pentane,
followed by Et2O, to give a brown solid (0.5 g, 0.6 mmol, 45%).
1H NMR (400 MHz, DMSO-d6): δ 7.59 (s, 2H), 7.17 (d, J = 8.1
Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 6.58 (s, 4H), 6.27 (s, 4H), 3.79 (s,
4H), 3.34 (s, 6H), 2.81 (s, 4H), 2.63 (s, 8H), 1.00 (s, 12H), −0.00 (s,
18H). 13C NMR (101 MHz, CD3OD): δ 139.08, 138.97, 138.56,
129.75, 129.58, 128.46, 126.78, 125.32, 123.01, 109.55, 109.41, 48.07,
47.76, 30.19, 26.40, 11.95, −0.27. 29Si NMR (99 MHz, DMSO-d6): δ
21.58. IR (KBr disk, cm−1): 3052, 2961, 2414, 1606, 1554, 1472, 1438,
1366, 1265, 1085, 1011, 837. UV−vis (CH2Cl2): λ 230 nm (ε = 70
240), λ 290 nm (ε = 22 500), λ 400 nm (weak). Anal. Calcd for
C46H66N4Si2Cl4Ti: C, 65.00; H, 7.83; N, 6.59. Found: C, 65.29; H,
7.61; N, 6.63.
ASSOCIATED CONTENT
* Supporting Information
■
1H NMR (400 MHz, CDCl3): δ 10.37 (s, 1H), 8.05 (s, 1H), 7.53
(d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 4.05 (s, 3H), 3.99 (s,
2H), 2.54 (q, J = 7.1 Hz, 4H), 1.06 (t, J = 7.1 Hz, 6H), 0.33 (s, 9H).
13C NMR (101 MHz, CDCl3): δ 183.68, 140.23, 132.47, 131.59,
131.12, 128.13, 127.91, 127.03, 109.90, 47.08, 47.05, 31.99, 12.18,
−0.60. ES-MS: m/z 244 [M − NCH2CH3]+. HRMS: m/z calcd for
C18H29N2OSi [M + H]+, 317.2049; found, 317.2058. IR (KBr disk,
cm−1): 2959, 2871, 2802, 1666, 1605, 1530, 1470, 1383, 1277, 1246,
1203, 1161, 1092, 1056, 885.
S
Details of crystallographic analyses and table of crystal data and
structure refinement for 3a and 3b. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: matthias.tacke@ucd.ie.
■
Synthesis of N-((2-(Cyclopenta-2,4-dienylidenemethyl)-1-methyl-
5-(trimethylsilyl)-indol-3-yl)methyl)-N-ethylethanamine (3f). 3-
((Diethylamino)methyl)-1-methyl-5-(trimethylsilyl)-indole-2-carbal-
dehyde (2f) (1.2 g, 3.8 mmol) was dissolved in MeOH (70 mL).
Freshly cracked cyclopentadiene (0.3 mL, 3.8 mmol) was added to the
solution, followed by pyrrolidine (0.3 mL, 3.8 mmol), and the color
gradually changed from yellow to red. 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 was removed at reduced pressure
to give a red-brown oil, which was purified by column chromatography
(alumina) with DCM as the eluent to yield a red oil (1.2 g, 3.3 mmol,
86%).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Higher Education Authority (HEA), the
Centre for Synthesis and Chemical Biology (CSCB), and the
UCD School of Chemistry and Chemical Biology for funding.
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