Titanocene dihalides and ferrocenes bearing a pendant α-d- xylofuranos-5-yl or α-d-ribofuranos-5-yl moiety. synthesis, characterization, and cytotoxic activity

Article abstract of DOI:10.1021/om500200r

Titanocene dichlorides of general formula [(η⁵-C ₅H₅)(η⁵-C₅H₄R) TiCl₂] (where R = 5-deoxy-1,2-di-O-isopropylidene-3-O-benzyl-α- d-xylofuranos-5-yl (Xylf) (8a); R = 5-deoxy-1,2-di-O-isopropylidene-3-O-benzyl- α-d-ribofuranos-5-yl (Ribf) (8b)) and [(η⁵-C ₅H₄R)₂TiCl₂] (R = Xylf (9a); R = Ribf (9b)) were prepared by reaction of the corresponding lithium cyclopentadienides 7a,b with an equimolar amount of [(η⁵-C ₅H₅)TiCl₃] or a 0.5 mol amount of [TiCl ₄(THF)₂]. Titanocene difluorides of the general formula [(η⁵-C₅H₄R¹)(η⁵- C₅H₄R²)TiF₂] (R¹ = H and R² = Ribf (10); R¹ = R² = Xylf (11a); R ¹ = R² = Ribf (11b)) were obtained by fluorination of the corresponding titanocene dichlorides 8b and 9 with the fluorinating agent {2-(CH₂NMe₂)C₆H₄-κC,N}(n-Bu) ₂SnF in high yields. Alternatively, complexes 11 were prepared in a straightforward way by direct reaction of [TiF₄(THF)₂] with 2 equiv of the corresponding lithium cyclopentadienide 7a,b. Ferrocene complexes [(η⁵-C₅H₄R)₂Fe] (R = Xylf (12a); R = Ribf (12b)) were synthesized by metathesis of 2 equiv of lithium cyclopentadienide 7a,b and 1 equiv of anhydrous FeCl₂. Deprotection of the benzyl group in ferrocenes 12 proceeded cleanly by a catalytic hydrogenation on Pd/C and afforded the ferrocene diols [(η⁵- C₅H₄R)₂Fe] (R = 5-deoxy-1,2-di-O- isopropylidene-α-d-xylofuranos-5-yl (Xylf-OH) (14a); R = 5-deoxy-1,2-di-O-isopropylidene-α-d-ribofuranos-5-yl (Ribf-OH) (14b)). A scaled up benzyl deprotection with Et₃SiH as a hydrogen source led to the replacement of only one benzyl group, which gave the ferrocene alcohol [(η⁵-C₅H₄R¹)(η⁵- C₅H₄R²)Fe] (R¹ = Xylf and R ² = Xylf-OH (13)). The prepared complexes were characterized by elemental analysis, melting point determination, NMR, IR, and ESI-MS, and the molecular structure of 9b was determined by X-ray diffraction analysis. The cytotoxic activity of complexes 8-14 against A2780 and A2780cis cancer cells was evaluated by MTT tests. Titanocene difluorides 10 and 11 and ferrocene diol 14a showed cytotoxicity against A2780 cells in the medium to low micromolar range, while the most active species, 11b, displayed about 40% higher cytotoxicity against A2780cis in comparison to a cisplatin standard.

Full text of DOI:10.1021/om500200r

Article
pubs.acs.org/Organometallics
Titanocene Dihalides and Ferrocenes Bearing a Pendant
α‑D‑Xylofuranos-5-yl or α‑D‑Ribofuranos-5-yl Moiety. Synthesis,
Characterization, and Cytotoxic Activity
†
†
‡
‡
§
̌
̌
Tomas Hodík, Martin Lamac, Lucie Cervenkova St’astna, Jindrich Karban, Lucie Koubkova,
́
̌
̌
́
́
̌
́
Roman Hrstka,§ Ivana Císarova,∥ and Jirí Pinkas*,†
̌
́
̌
†J. Heyrovsky Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Dolejsk
̌
ova 2155/3, 182 23 Prague 8,
́
Czech Republic
‡Institute of Chemical Process Fundamentals, Academy of Sciences of the Czech Republic, v.v.i., Rozvojova
́
135, 165 02 Prague 6,
Czech Republic
§
̌
Regional Centre for Applied and Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653 Brno, Czech
́
Republic
∥Department of Inorganic Chemistry, Charles University, Hlavova 2030, 128 43 Prague 2, Czech Republic
S
* Supporting Information
ABSTRACT: Titanocene dichlorides of general formula [(η5-
C5H5)(η5-C5H4R)TiCl2] (where R = 5-deoxy-1,2-di-O-iso-
propylidene-3-O-benzyl-α-D-xylofuranos-5-yl (Xylf) (8a); R =
5-deoxy-1,2-di-O-isopropylidene-3-O-benzyl-α-D-ribofuranos-
5-yl (Ribf) (8b)) and [(η5-C5H4R)2TiCl2] (R = Xylf (9a); R =
Ribf (9b)) were prepared by reaction of the corresponding
lithium cyclopentadienides 7a,b with an equimolar amount of
[(η5-C5H5)TiCl3] or a 0.5 mol amount of [TiCl4(THF)2].
Titanocene difluorides of the general formula [(η5-C5H4R1)(η5-C5H4R2)TiF2] (R1 = H and R2 = Ribf (10); R1 = R2 = Xylf (11a);
R1 = R2 = Ribf (11b)) were obtained by fluorination of the corresponding titanocene dichlorides 8b and 9 with the fluorinating
agent {2-(CH2NMe2)C6H4-κC,N}(n-Bu)2SnF in high yields. Alternatively, complexes 11 were prepared in a straightforward way
by direct reaction of [TiF4(THF)2] with 2 equiv of the corresponding lithium cyclopentadienide 7a,b. Ferrocene complexes [(η5-
C5H4R)2Fe] (R = Xylf (12a); R = Ribf (12b)) were synthesized by metathesis of 2 equiv of lithium cyclopentadienide 7a,b and 1
equiv of anhydrous FeCl2. Deprotection of the benzyl group in ferrocenes 12 proceeded cleanly by a catalytic hydrogenation on
Pd/C and afforded the ferrocene diols [(η5-C5H4R)2Fe] (R = 5-deoxy-1,2-di-O-isopropylidene-α-D-xylofuranos-5-yl (Xylf-OH)
(14a); R = 5-deoxy-1,2-di-O-isopropylidene-α-D-ribofuranos-5-yl (Ribf-OH) (14b)). A scaled up benzyl deprotection with
Et3SiH as a hydrogen source led to the replacement of only one benzyl group, which gave the ferrocene alcohol [(η5-C5H4R1)(η5-
C5H4R2)Fe] (R1 = Xylf and R2 = Xylf-OH (13)). The prepared complexes were characterized by elemental analysis, melting
point determination, NMR, IR, and ESI-MS, and the molecular structure of 9b was determined by X-ray diffraction analysis. The
cytotoxic activity of complexes 8−14 against A2780 and A2780cis cancer cells was evaluated by MTT tests. Titanocene
difluorides 10 and 11 and ferrocene diol 14a showed cytotoxicity against A2780 cells in the medium to low micromolar range,
while the most active species, 11b, displayed about 40% higher cytotoxicity against A2780cis in comparison to a cisplatin
standard.
giving rise to a structure−activity concept similar to that used in
tailoring active catalysts for polymerization or organic syn-
thesis.11 In this respect, titanocene dichlorides bearing
cyclopentadienyl rings substituted by alkyl and alkenyl,12−14
methoxyalkyl,15 substituted aryl,16 silyl,17 and carboxylic acid
esters18 were prepared and evaluated. Similarly, the effect of the
bridge between cyclopentadienyl rings on the biological
performance of ansa-titanocene dichlorides was recently
elucidated.12,13,19,20 The Baird21−24 and McGowan groups25−27
INTRODUCTION
■
The discovery of the cytotoxic properties of cisplatin1 initiated
the search for other transition-metal antitumor complexes.
Despite steady effort, only a few nonplatinum complexes have
entered clinical trials,2 the first among them being titanocene
dichloride.3,4 However, the clinical trials of titanocene
dichloride were discontinued due to nephrotoxicity and other
side effects together with low efficacy.5 The last two decades
have seen a renewed research interest in titanium anticancer
compounds, as documented by several reviews in recent
years.6−10 The substitution of the cyclopentadienyl moiety was
found to be a useful tool to modulate biological properties,
Received: February 26, 2014
Published: April 9, 2014
© 2014 American Chemical Society
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Chart 1
have synthesized a family of water-soluble titanocene
dichlorides bearing ionic alkyl and arylammonium substituents.
These ionic complexes showed a remarkable cytotoxic activity
against human ovarian cancer cell lines A2780, which was
retained even against the cisplatin-resistant cell line A2780cis.
Tacke and co-workers introduced a modular synthesis of
titanocene dichlorides bearing a modified benzyl28−31 or
methyleneheteroaryl group32,33 starting from substituted
fulvenes. Among these series, titanocene Y, [{η5-
C5H4CH2C6H4-(p-OMe)}2TiCl2)], was found to be a promis-
ing drug candidate toward a wide range of human tumor cells.34
A recent study showed that the increased cytotoxity of
titanocene Y toward HT-29 colon carcinoma cells in
comparison to titanocene dichloride is directly related to a
higher cellular uptake of the former species,35 where human
serum albumin acts as an active transporter for titanocene Y.36
Transferrin, another serum protein, has been implicated in the
delivery of Ti(IV) compounds into the cell.37−39 The
aforementioned examples indicate that the efficient transport
of titanocene into a carcinogenic cell is a crucial parameter for
its biological performance.
(benzyl protected vs deprotected), and σ ligand (chlorido vs
fluorido) on the antiproliferative activity of the complexes.
Various tumors show increased D-glucose uptake in vivo
(known as the Warburg effect)40 in comparison to that of the
normal tissue by 1 order of magnitude.41 This leads to an
overexpression of the D-glucose transporters (GLUTs) in
cancer cells, which makes GLUT receptors another prospective
target for the transport of anticancer drugs selectively into
cancerous cells.42 It should be noted that the transport via
GLUT receptors is not restricted to D-glucose; other simple
monosacharides are transported as well. Among others, D-
xylose and D-ribose were found to be transported into the cell
by means of GLUT, a slightly higher affinity to the transporter
being found for the former species.43 Generally, conjugation of
a transition-metal complex to a carbohydrate moiety leads to its
reduced toxicity, better biocompatibility, and increased
solubility in aqueous media. Several reviews dealing with
carbohydrate−metal conjugates published in the last 14 years
show an increasing interest in the field.44−48 Whereas numerous
ferrocene−carbohydrate conjugates have been described,49−58
there are very few examples of carbohydrate-modified cyclo-
pentadienyl ligands in titanocene dichlorides. Titanocene
dichlorides (see Chart 1) bearing cyclopentadienyl rings
modified with D-mannitol (I),59 α-D-xylofuranose (II),60 and
α-D-galactopyranose (III)61,62 have been reported, although no
cytotoxicity data were presented. A family of titanocene
dichlorides bearing one (IV and V) or two (VI and VII)
modified ribofuranose moieties was recently patented.63
Complexes IV−VII were tested against L929, KB 3.1, A-431,
and A-498 cell lines with the cytotoxicity increasing in the order
VII < IV < V < VI, the last one having a cytotoxicity (IC50 = 5.5
μM for L929 and 5.3 μM for KB 3.1) comparable with that of
cisplatin (IC50 = 2.2 μM for L929 and 1.2 μM for KB 3.1).
Herein we present the preparation of titanocene dichlorides,
titanocene difluorides, and ferrocenes bearing a cyclopenta-
dienyl ring modified with a substituent derived from protected
α-D-xylofuranose or α-D-ribofuranose (epimers differing in
stereochemistry at the C(3) stereogenic center in the furanose
ring). The cytotoxic activity of the prepared complexes against
A2780 and A2780cis cell lines was determined with the aim of
evaluating the effect of the carbohydrate configuration (α-D-
xylofuranose vs α-D-ribofuranose), the number of carbohydrate
units in the complex (one vs two), carbohydrate protection
RESULTS AND DISCUSSION
■
Synthesis of Cyclopentadienyl Ligands 6. The starting
material for the preparation of protected 5-deoxypentofuranos-
5-yl cyclopentadienes 6a,b was the readily available diacetone
glucose 1,64 which was converted into tosylates 4 and 5 using a
reaction sequence based mostly on literature procedures
(Scheme 1). Reaction of tosylates 5 and 4 with sodium
cyclopentadienide in dimethylformamide provided pentofur-
anosyl cyclopentadienes 6a/6a′ and 6b/6b′, which were
obtained as inseparable mixtures of 1,3- and 1,4-cyclo-
pentadienes in yields 65% and 68%, respectively.
Synthesis and Characterization of Titanocene Diha-
lides 8−11. Deprotonation of cyclopentadienes 6a/6a′ and
6b/6b′ with n-BuLi in Et2O (Scheme 2) cleanly afforded
corresponding lithium cyclopentadienides 7a,b as white or
slightly pink solids in 92% and 75% yields, respectively. The
proposed structures of the lithium cyclopentadienides 7a,b
1
were supported by their H and 13C NMR spectra in THF-d8.
Reaction of [(η5-C5H5)TiCl3] with an equimolar amount of
lithium cyclopentadienides 7a,b in THF (Scheme 2) afforded
the corresponding heterosubstituted titanocene dichlorides
8a,b in 64% and 75% yields, respectively. Reaction of
[TiCl4(THF)2] with 2 equiv of lithium cyclopentadienides
7a,b in THF (Scheme 2) led after workup to the
homosubstituted titanocene dichlorides 9a,b in 40 and 72%
yields, respectively. Complexes 8 and 9 were obtained as red or
red-orange solids, stable in air and moderately stable to
humidity.
The replacement of σ-bonded chloride ligands with fluoride
ligands in the titanocene moiety resulted in specific cases in an
increased cytostatic efficiency against cancer cells.70 To date,
the preparation of titanocene difluorides has been based solely
on fluorination of the respective dichloro- or dimethyltitano-
cenes with one of the following fluorinating agents: NaF,71
Me3SnF,70,72 BF3·OEt2,73 AgF,74 and {2-(CH2NMe2)C6H4-
κC,N}(n-Bu)2SnF.75−77
We have explored the reaction of titanocene dichloride 8b
with 2 equiv of {2-(CH2NMe2)C6H4-κC,N}(n-Bu)2SnF in
CH2Cl2 at room temperature (Scheme 3, top). The reaction
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a
Scheme 1. Preparation of Protected 5-Deoxypentofuranos-5-ylcyclopentadienes 6a,b
a
Reagents: (i) acetone, ZnCl2;64 (ii) CrO3, acetic anhydride, pyridine;65 (iii) NaBH4, EtOH, H2O;66 (iv) BnBr, NaH, THF;67 (v) AcOH, H2O;67,68
(vi) NaIO4, MeOH, H2O, then NaBH4, MeOH, H2O;67,68 (vii) TsCl, pyridine, for 5 see ref 69 and for 4 see the Supporting Information; (viii)
C5H5Na, DMF.
Scheme 2. Preparation of Titanocene Dichlorides 8 and 9
Scheme 3. Preparation of Titanocene Difluorides 10 and 11
proceeded smoothly within 3 days, and the progress of the
reaction could be monitored by a color change of the solution
from red to orange. The formed byproduct {2-(CH2NMe2)-
C6H4-κC,N}(n-Bu)2SnCl was removed by repeated washing
with pentane, and titanocene difluoride 10 was obtained in high
yield (86 and 93% in two independent experiments) as a yellow
solid. The fluorination method was extended to symmetrically
substituted titanocenes 9. The reaction of titanocene
dichlorides 9a,b with 2 equiv of {2-(CH2NMe2)C6H4-κC,N}-
(n-Bu)2SnF (Scheme 3, left side) in CH2Cl2 at room
temperature afforded titanocene difluorides 11a,b in 88% and
94% yields, respectively. In an alternative approach, we have
tested the fluorination of 9a with NaF in water,71,78 which
could be advantageous because it is a cheap, commercially
available reagent. However, the reaction of titanocene
dichloride 9a with an excess of NaF (see the Supporting
Information) in water for 3 h led only to ca. 10% conversion to
titanocene difluoride 11a (unreacted starting 9a and several
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Figure 1. Molecular structure of 9b at the 40% probability level with atom-labeling scheme. Hydrogen atoms are omitted for clarity.
Scheme 4. Preparation of Ferrocenes 12−14
3
unidentified titanium species were also present, as determined
with 1H and 19F NMR spectroscopy). Unfortunately, a
prolonged reaction time led to hydrolytic decomposition of
9a rather than to an increased yield of 11a.
coupling constant JHH in the range 4.3−4.5 Hz, the inversion
of configuration at the C(3) stereogenic center (giving rise to a
xylofuranose moiety) resulted in no measurable coupling.
Signals of the ribofuranose moiety (in complexes 8b, 9b, 10,
and 11b) were shifted to a higher field in comparison to the
corresponding methine groups in the xylofuranose moiety (in
Although the fluorinating agent {2-(CH2NMe2)C6H4-κC,N}-
(n-Bu)2SnF gave satisfactory results, we were looking for an
alternative route, which would afford titanocene difluorides in a
single step without the necessity of corresponding titanocene
dichloride preparation. Complex [TiF4(THF)2] was proposed
as a convenient precursor for titanocene difluorides.79
Surprisingly, its use for cyclopentadienyllithium to titanium
transmetalation (widely applied for the preparation of
titanocene dichlorides from [TiCl4(THF)2]) has not been
reported in the literature so far. The reaction of 2 equiv of
lithium cyclopentadienides 7a,b with [TiF4(THF)2] (Scheme 3,
right side) in THF proceeded at room temperature and
afforded titanocene difluorides 11a,b in 84% and 68% yields,
respectively.
complexes 8a, 9a, and 11a) in both H and 13C NMR spectra.
1
Chemical shifts of the furanose methine groups (C(1)H−
C(4)H) are not sensitive to coordination of the cyclo-
pentadienylfuranose ligand to titanium in titanocene dichlor-
ides and difluorides, which indicates only negligible mutual
interaction between the titanocene and the carbohydrate
fragment in solution. The signals of fluoride ligands in 19F
NMR spectra were found as singlets at 64.18 ppm for 11a and
63.57 ppm for 11b and as two closely positioned doublets
centered at 64.10 and 64.23 ppm for 10. These values are close
to the value found for titanocene difluoride (64.2 ppm),72
which also points to negligible interaction between the Ti−F
bond and the carbohydrate moiety.
ESI-MS spectra of all studied titanocene dihalides corrobo-
rated the proposed structure, showing [M + K]+, [M + Na]+,
and [M − halide]+ ions as the characteristic species. Generally,
the [M − Cl]+ ion in titanocene dichlorides 8 and 9 possesses
higher relative abundance in comparison to the [M − F]+ ion in
titanocene difluorides 10 and 11, which roughly reflects the
greater stability of the Ti−F bond. The IR spectra of titanocene
difluorides 10 and 11 show characteristic medium to strong
bands at 549−582 cm−1 due to Ti−F stretching vibrations.
Molecular Structure of Titanocene Dichloride 9b.
Titanocene dichloride 9b crystallized in orthorhombic space
group P21212 (No. 18) with one chiral molecule in the
asymmetric unit. Selected geometric parameters are given in the
The prepared titanocene dihalides 8−11 were characterized
by elemental analysis, melting points, NMR, IR, and ESI-MS.
The presence of four chiral centers in the furanose moiety gave
rise to an ABCD spin system for the methine signals CH in
1
monosubstituted cyclopentadienyl ring(s) in both H and 13C
NMR (see the Experimental Section and Supporting
Information) spectra of all complexes, while the methine signal
of the unsubstituted cyclopentadienyl ring in complexes 8 and
1
10 appears as a singlet in both H and 13C NMR spectra. The
carbohydrate part displays qualitatively the same spectral
pattern for both furanose rings in all complexes, except for
the multiplicity of the vicinal proton signals of C(3)H and C(2)
H. While a dihedral angle between these two protons in
ribofuranose moiety led to their mutual splitting with a
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Supporting Information, and the molecular structure is
depicted in Figure 1. The molecule has C2 symmetry with a
2-fold rotation axis passing through the titanium atom and
bisecting the Cl−Ti−Cl′ angle. The metallocene complex
possesses a bent structure (the dihedral angle between Cp
planes is 51.4(1)°), where the Cp rings are close to an eclipsed
conformation (torsion angle φ = 3.1(4)°). The pendant
carbohydrate moieties are oriented toward the opened side of
the metallocene wedge, and they are pointing away from the
metal center, showing no intramolecular interaction with the
titanium atom. The molecular packing (see the Supporting
Information) further supports the absence of any intermo-
lecular interactions, as the carbohydrate and titanocene
domains are separated from each other. The furanose ring
acetone, or THF afforded a crystalline material; however, it was
not suitable for X-ray analysis.
All prepared ferrocenes 12−14 were characterized by
elemental analysis, NMR, IR, and ESI-MS, and in addition,
1
melting points were determined for diols 14. The H and 13C
NMR spectra (see the Experimental Section and Supporting
Information) of ferrocenes 12−14 corroborated the proposed
structures. The signal of the hydroxyl group(s) appeared as a
doublet spanning the region 5.10−5.23 ppm (5.21 ppm, 3JHH
=
5.1 Hz for 13; 5.23 ppm, 3JHH = 5.1 Hz for 14a; 5.10 ppm, 3JHH
= 6.9 Hz for 14b) in 1H NMR spectra of DMSO-d6 solutions of
the ferrocenyl alcohols 13 and 14. The equivalence of both
hydroxyl protons in diols 14 indicates that both substituted
cyclopentadienyl rings freely rotate in solution and formation of
intramolecular hydrogen bonds is suppressed.
3
adopts a conformation close to the twist T4 conformation
(ring puckering parameter Φ = 311.8(3)°)80 and retains the α-
D-ribo absolute configuration, which proves that no racemiza-
tion at stereogenic centers occurred during the whole synthesis.
Synthesis and Characterization of Ferrocenes 12−14.
The transmetalation from lithium to iron was used for the
preparation of homoleptically substituted ferrocenes. The
reaction of 2 equiv of lithium cyclopentadienides 7a,b with
anhydrous FeCl2 in THF (Scheme 4, middle) afforded
substituted ferrocenes 12a,b in 68% and 64% yields,
respectively. The ferrocenes could be easily purified by column
chromatography on silica gel with a hexane−ethyl acetate
mixture as an eluent. The products were obtained as yellow-
orange oils or waxes, stable to air and humidity. They were
soluble in most organic solvents (toluene, ethyl acetate, THF,
dichloromethane, chloroform) but only sparingly soluble in
water. In an alternative route to 12a, we have tested the
reaction of the in situ prepared 1,1′-dilithioferrocene with 2
equiv of tosylate 5 in boiling THF (for details see the
Supporting Information). However, the reaction did not
proceed, probably due to the low nucleophilicity of 1,1′-
dilithioferrocene.
The poor solubility of ferrocenes 12 in water is undesirable
for their use in biological assays. In order to improve their
solubility in protic solvents (mainly water), deprotection of the
benzyl group at the C(3) carbon was attempted. In an initial
effort, a hydrogenation catalyzed by Pd/C with triethylsilane as
a hydrogen source was carried out according to a literature
procedure.81 The screening experiment utilizing 12a on a ca. 1
mmol scale with an excess of triethylsilane (Scheme 4, right
side) in methanol led to complete removal of benzyl groups in
1 h, affording diol 14a in 86% yield.
However, scaling up the reaction 4 times led to only partial
deprotection and formation of ferrocenyl alcohol 13 (Scheme
4, left side) in 78% yield. We assume that the Pd/C catalytic
dehydrogenation of triethylsilane (i.e., hydrogen evolution) is
considerably faster than the Pd/C catalytic debenzylation;
therefore, an excess of triethylsilane should be occasionally
added to achieve a sufficient concentration of hydrogen in the
reaction mixture to complete the debenzylation (for details see
the Experimental Section). While this was rather impractical,
molecular hydrogen was further used for debenzylation of
ferrocenes 12. The Pd/C-catalyzed hydrogenation of 12a,b
under atmospheric pressure of molecular hydrogen in THF or
methanol afforded the corresponding diols 14a,b in 82% and
70% yields (Scheme 4, right side). The diols 14 were obtained
as yellow solids stable in air and soluble in most organic
solvents. Repeated recrystallizations of 14a from methanol,
The situation is more complex in the solid state, as was
indicated by IR spectroscopy (see the Supporting Information).
A unique absorption band for valence −OH vibration was
found at 3467 cm−1 for 13 and at 3459 cm−1 for 14b, which is
consistent with the presence of only terminal hydroxyl groups
in the structure. In contrast to that, two absorption bands at
3457 and 2565 cm−1 were found for two distinct hydroxyl
groups in 14a. We suggest that the former could be attributed
to a terminal hydroxyl group and the latter to a hydrogen-
bonded hydroxyl group, constituting an intramolecular bridge
between both carbohydrate moieties (see the Supporting
Information).
Cytotoxicity Studies. The cytotoxic properties of com-
plexes 8−14 against A2780 and A2780cis cells were evaluated
by MTT tests. IC50 values of 24 h and 72 h treatments for
A2780 and 24h treatment for A2780cis are summarized in
Table 1. A 24 h assay for the A2780 cell line shows no
Table 1. Cytotoxic Activity (IC50 Values (μM)) of
Carbohydrate-Modified Titanocene Dihalides 8−11 and
Ferrocenes 12 and 14 against A2780 and A2780cis
compd
8a
A2780 (24 h)
A2780 (72 h)
A2780cis (24 h)
a
>100
>100
NT
NT
8b
NT
NT
NT
b
9a
55
NT
9b
>100
38
17
30
5
4
3
65 12
48 12
>100
10
36.4 1.1
11a
11b
12a
12b
14a
14b
cisplatin
60
9
19.6 1.3
>100
8.5 1.5
NT
31
6
NT
NT
NT
NT
50
>100
NT
38.3 1.1
>100
26 12
a
NT
c
12.9 1.5
1.74 0.27
9
a
b
c
Not tested. Performed only once. cis-[PtCl2(NH3)2].
cytostatic effect (IC50 > 100 μM) for titanocene dichlorides 8
and 9 or for fully protected ferrocenes 12 and ferrocene diol
14b. On the other hand, the titanocene difluoride complexes 10
and 11a possessed cytotoxicity in a moderate micromolar range
(36.4 1.1 μM for 10; 60 9 μM for 11a), and the most
active complex 11b showed a cytotoxicity value of the same
order of magnitude as Cisplatin (19.6 1.3 μM for 11b; 12.9
1.5 μM for cisplatin). In the prolonged 72 h assay, titanocene
difluoride 11b attained the highest cytotoxicity among the
tested complexes (IC50 = 8.5 1.5 μM), the value being ca. 4-
fold lower in comparison to that of its chlorido analogue 9b (38
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5 μM). Generally, the prolonged assay for the A2780 cell line
led to a decrease in IC50 values by about half for titanocene
difluorides 10 and 11 (36.4 1.1 μM (24 h) vs 17 4 μM (72
h) for 10; 60 9 μM (24 h) vs 30 3 μM (72 h) for 11a; 19.6
1.3 μM (24 h) vs 8.5 1.5 μM (72 h) for 11b) and by about
one-third for ferrocene diol 14a (38.3 1.1 μM (24 h) vs 26
12 μM (72 h)), which indicates their capability of prolonged
residing in cells during the assay. The titanocene complexes
active against the A2780 cell line (9b, 10, and 11) were further
evaluated against the A2780cis cell line in a 24 h assay.
Complexes 9b and 10 showed cytotoxicity comparable to that
of cisplatin, while the most active 11b has about 40% higher
cytotoxicity than cisplatin (31 6 μM for 11b and 50 9 μM
for cisplatin).
dichlorides 8 and 9 or ferrocenes 12, respectively. Ferrocene
diols 14 were obtained from ferrocenes 12 by deprotection of
the benzyl group at the C(3) carbon of the furanose ring.
Nevertheless, a scaled up benzyl deprotection with Et3SiH as a
hydrogen source led to the removal of only one benzyl group to
give ferrocene alcohol 13. Fluorination using the fluorinating
agent {2-(CH2NMe2)C6H4-κC,N}(n-Bu)2SnF was found to be
an easy and clean procedure for the generation of titanocene
difluorides 10 and 11 from the corresponding dichlorides 8b
and 9 in excellent yields. However, a direct reaction of lithium
cylopentadienides 7 with [TiF4(THF)2] was found to be a
straightforward way for the preparation of symmetrically
substituted titanocene difluorides 11 in a single step in yields
comparable to those achieved for the analogous titanocene
dichlorides from [TiCl4(THF)2]. As titanocene difluorides are
important catalytic precursors in many catalytic processes (e.g.,
defluorination, hydrosilylation; for a complete listing see a
recent review article),84 we suggest that the described
metathesis method of their preparation may find a widespread
use.
An evaluation of the cytotoxic activity of the prepared
complexes against A2780 and A2780cis cell lines revealed an
increased activity of titanocene difluorides in comparison to the
corresponding dichlorides. Furthermore, an increase in
cytotoxicity has been achieved by the incorporation of two
carbohydrate moieties into the titanocene framework, in
comparison to the titanocene complexes bearing only a single
carbohydrate moiety. Therefore, titanocene difluorides bearing
two carbohydrate molecules seem to be the most promising
species for future investigations. The most cytotoxic complex,
11b, reached about 5-fold lower activity against A2780 cell line
in comparison to cisplatin, while about 40% higher activity was
reached against the cisplatin-resistant A2780cis cell line. This
seems to imply a different mechanism of action of the species in
comparison to cisplatin, which would be advantageous in the
treatment of cisplatin-resistant cancers. Studies on the
mechanism of action of active compounds (mainly 11b) and
elucidation of function of the carbohydrate moiety in the
cellular uptake are currently under way.
The function of fluoride σ ligands is not clear from the
literature. Kopf-Maier et al. proposed only a negligible effect of
̈
halide ligands in Cp2TiX2 (X = F, Cl, Br, I) against EAT
tumors, although a slightly higher activity was found for the
fluoro analogue (LD50 = 60 mg/kg for Cp2TiF2 vs LD50 = 100
mg/kg for Cp2TiCl2).4 On the other hand, a 3−5-fold decrease
in activity against several cell lines going from fluorido to
chlorido titanocenes Cp′2TiX2 (X = F, Cl; Cp′ =
C4H4CH3−n{C6H4(p-OMe)}n, n = 1, 2) was reported by
Tacke et al.70 A greater bond strength of the Ti−F bond (569
34 kJ mol−1) in comparison to the Ti−Cl bond (494 kJ
mol−1) would lead to a slower solvolysis of the fluoride, while
not completely preventing the solvolysis (the Ti−O bond
strength is 666.5 6.3 kJ mol−1).82 Therefore, we tentatively
suggest that a slower decay of titanocene difluorides into
biologically inactive insoluble species with multiple Ti−O−Ti
bonds takes place in an aqueous environment. It should be
mentioned that the cytotoxicity of titanocene difluorides does
not arise from the toxicity of the fluoride anion itself, as fluoride
anions (e.g., in NaF solutions) revealed significant cytotoxicity
only at relatively high concentrations above milimolar values.83
The effect of the configuration of the carbohydrate
substituent on the metallocene biological performance is not
obvious, as the ribofuranose moiety enhanced the activity of
titanocene difluorides 11 (A2780(72 h), 30 3 μM for 11a, 8.5
1.5 μM for 11b; A2780cis, >100 μM for 11a, 31 6 μM for
11b) while it decreased the activity of ferrocene diols 14
(A2780(24 h), 38.3 1.1 μM for 14a, >100 μM for 14b) in
comparison to the xylofuranose analogues in both studied cell
lines. Nevertheless, a roughly 2-fold higher cytotoxicity of
EXPERIMENTAL SECTION
■
General Considerations. All manipulations with air-sensitive
compounds were carried out under an argon atmosphere using
standard Schlenk techniques. 1H (299.98 or 499.87 MHz), 13C (75.44
or 125.71 MHz), and 19F (282.22 or 470.37 MHz) NMR spectra were
measured on a Varian Mercury 300 or Varian Innova 500 spectrometer
titanocene difluoride 11b (A2780(72 h), 8.5
1.5 μM;
A2780cis, 31 6 μM) bearing two ribofuranose moieties in
comparison to the titanocene difluoride 10 bearing only one
ribofuranose moiety (A2780(72 h), 17 4 μM; A2780cis, 48
12 μM) implies a strengthening effect of two carbohydrate
substituents attached to a metallocene moiety on the cytostatic
activity.
1
at 25 °C. H and 13C chemical shifts (δ/ppm) are given relative to
solvent signals (δH/δC: CDCl3, 7.26/77.16; THF-d8, 3.58/67.21;
DMSO-d6, 2.50/39.52). The 19F NMR spectra were referenced to
external CFCl3. EI-MS spectra were measured using an Agilent 6890
gas chromatograph coupled to an Agilent 5973 mass spectrometer
operating in 70 eV ionization mode. Electrospray mass spectra (ESI-
MS) were measured with a Bruker Esquire 3000 instrument on
dichloromethane/acetonitrile solutions. IR spectra of samples in KBr
pellets were measured on a Nicolet Avatar FTIR spectrometer in the
range 400−4000 cm−1. Melting points were determined on a Kofler
block and were uncorrected. Elemental analyses were carried out on a
FLASH EA1112 CHN-O Automatic Elemental Analyzer (Thermo
Scientific).
Chemicals. Solvents were appropriately dried (THF, diethyl ether,
toluene by refluxing with Na/benzophenone; dichloromethane by
refluxing with CaH2) distilled, and stored over 4Å molecular sieves.
MeLi (1.6 M solution in diethyl ether), [(η5-C5H5)TiCl3],
[TiCl4(THF)2], and Pd/C (palladium on carbon, 10 wt % Pd) were
purchased from Aldrich and used as received. Et3SiH was dried by
CONCLUSIONS
■
A synthetic protocol for the preparation of titanocenene
dichlorides and ferrocenes bearing a fully protected 5-
deoxyxylofuranose or 5-deoxyribofuranose moiety has been
developed. The synthesis started from D-glucose, and the
cyclopentadiene moiety was attached to the 5-position of 5-
deoxyxylofuranose or 5-deoxyribofuranose in eight steps.
Deprotonation of the corresponding cyclopentadienes 6
followed by a metathesis reaction between lithium cyclo-
pentadienide-carbohydrate 7 and [(η5-C5H5)TiCl3],
[TiCl4(THF)2], and FeCl2 gave the corresponding titanocene
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Organometallics
Article
refluxing over LiAlH4 and distilled prior to use. [TiF4(THF)2]79 and
{2-(CH2NMe2)C6H4-κC,N}(n-Bu)2SnF75 were prepared by literature
methods.
4.53 or 4.54 (d, 2JHH = 12.0 Hz, 1H, CH2Ph); 4.76 or 4.77 (d, JHH
=
2
3
12.0 Hz, 1H, CH2Ph); 5.71 (d, JH1H2 = 3.8 Hz, 1H, C(1)H); 6.18,
1
6.27, 6.40 (3 × m, 3 × 1H, =CH, C5H5); 7.30−7.37 (m, 5H, Ph). H
Preparation of Cyclopentadienes 6a/6a′. A solution of sodium
cyclopentadienide in tetrahydrofuran (6 mL, 2 M, 12 mmol) was
added dropwise with cooling (−50 °C) and stirring to a solution of 3-
O-benzyl-1,2-di-O-isopropylidene-5-O-(p-toluenesulfonyl)-α-D-xylo-
furanose (5;69 2.945 g, 6.78 mmol) in anhydrous dimethylformamide
(10 mL). The mixture was warmed to room temperature, and stirring
was continued for 2 h while a fine precipitate formed. The reaction
mixture was then kept at 5 °C overnight. TLC in ethyl acetate/light
petroleum (1/5) indicated the absence of the starting compound. The
unreacted cyclopentadienide was decomposed by addition of 5 mL of
water, and after 10 min the reaction mixture was poured onto ice. The
water phase was extracted three times with ethyl acetate/diethyl ether
(1/1) and then once with diethyl ether. The organic extracts were
combined, dried over sodium sulfate, and concentrated to afford 2.4 g
of the crude product. Chromatography on silica gel in ethyl acetate/
light petroleum (1/5) afforded the crystalline product as an
inseparable mixture of 6a and 6a′ in a 5/4 molar ratio. Yield 1.454
NMR (500 MHz, CDCl3) for 6b′: 1.35, 1.59 (2 × s, 2 × 3H, CMe2);
2.56, 2.80 (2 × m, 2 × 1H, CH2C5H5); 2.91 (m, 2H, CH2, C5H5); 3.43
3
3
(dd, JH4H3 = 8.8 Hz and JH2H3 = 8.8 Hz, 1H, C(3)H); 4.28 (ddd,
3
3
3JH4H5 = 3.6 Hz, JH4H5′ = 7.1 Hz and JH4H3 = 8.8 Hz, 1H, C(4)H);
3
3
4.53 (dd, JH1H2 = 3.8 Hz and JH2H3 = 8.8 Hz, 1H, C(2)H); 4.53 or
4.54 (d, 2JHH = 12.0 Hz, 1H, CH2Ph); 4.76 or 4.77 (d, 2JHH = 12.0 Hz,
1H, CH2Ph); 5.71 (d, 3JH1H2 = 3.8 Hz, 1H, C(1)H); 6.05, 6.37, 6.45 (3
× m, 3 × 1H, =CH, C5H5); 7.30−7.37 (m, 5H, Ph). 13C NMR (126
MHz, CDCl3) for 6b: 26.57, 26.74 (CMe2); 32.81 (CH2C5H5); 44.26
(CH2, C5H5); 72.02 or 72.04 (CH2Ph); 77.04 or 77.06 (C(2)); 77.74
(C(4)); 80.92 (C(3)); 103.88 or 103.91 (C(1)); 112.70 (CMe2);
127.94 or 127.98, 128.02 or 128.07, 128.40 or 128.42 (CH, Ph);
129.02, 131.73, 132.15 (CH, C5H5); 137.57 or 137.64 (Cipso, Ph);
144.62 (Cipso, C5H5). 13C NMR (126 MHz, CDCl3) for 6b′: 26.57,
26.74 (CMe2), 31.78 (CH2C5H5); 41.28 (CH2, C5H5); 72.02 or 72.04
(CH2Ph); 77.04 or 77.06 (C(2)); 77.32 (C(4)); 80.69 (C(3)); 103.88
or 103.91 (C(1)); 112.70 (CMe2);); 127.94 or 127.98, 128.02 or
128.07, 128.40 or 128.42 (CH, Ph); 128.87, 133.41, 135.18 (CH,
C5H5); 137.57 or 137.64 (Cipso, Ph); 142.42 (Cipso, C5H5). EI-MS (m/z
(%)): 313 (1), 270 (8), 269 (7), 248 (3), 179 (7), 91 (100). Anal.
Calcd for C20H24O4 (328.39): C, 73.15; H, 7.37. Found: C, 72.94; H,
7.43.
1
g (65%). Mp: 68 °C. H NMR (500 MHz, CDCl3) for 6a: 1.31, 1.49
(2 × s, 2 × 3H, CMe2); 2.84 (m, 2H, CH2C5H5); 2.87, 2.97 (2 × m, 2
3
× 1H, CH2, C5H5); 3.83 (dd, JH4H3 = 3.1 Hz, 1H, C(3)H); 4.36
(pseudo td, 3JH4H3 = 3.1 Hz, 3JH4H5 = 7.0 Hz and 3JH4H5′ = 7.1 Hz, 1H,
2
3
C(4)H); 4.48 (d, JHH = 11.8 Hz, 1H, CH2Ph); 4.62 (d, JH1H2 = 3.9
Hz, 1H, C(2)H); 4.68 (d, 2JHH = 11.8 Hz, 1H, CH2Ph); 5.93 (d, 3JH1H2
= 3.9 Hz, 1H, C(1)H); 6.22, 6.27, 6.41 (3 × m, 3 × 1H, CH, C5H5);
Preparation of Lithium Cyclopentadienide 7a. To a mixture of
cyclopentadienes 6a/6a′ (1.429 g, 4.36 mmol) in Et2O (50 mL) was
slowly added dropwise a solution of n-BuLi in hexane (2.00 mL, 2.5 M,
5.00 mmol), which caused immediate precipitation of a white solid.
The suspension was stirred for 12 h and then filtered. The obtained
white solid was washed with Et2O (2 × 10 mL) and dried under
vacuum to constant weight. Yield: 1.338 g (92%). 1H NMR (300
MHz, THF-d8): 1.23 (s, 3H, CMe2); 1.39 (s, 3H, CMe2); 2.85 (dd,
1
7.28−7.37 (m, 5H, Ph). H NMR (500 MHz, CDCl3) for 6a′: 1.31,
1.49 (2 × s, 2 × 3H, CMe2); 2.56, 2.84 (2 × m, 2 × 1H, CH2C5H5);
2.93 (m, 2H, CH2, C5H5); 3.81 (d, 3JH4H3 = 3.1 Hz, 1H, C(3)H); 4.40
(pseudo td, 3JH4H3 = 3.1 Hz, 3JH4H5 = 7.2 Hz and 3JH4H5′ = 7.1 Hz, 1H,
2
3
C(4)H); 4.48 (d, JHH = 11.8 Hz, 1H, CH2Ph); 4.62 (d, JH1H2 = 3.9
Hz, 1H, C(2)H); 4.67 (d, 2JHH = 11.8 Hz, 1H, CH2Ph); 5.94 (d, 3JH1H2
= 3.9 Hz, 1H, C(1)H); 6.07, 6.42, 6.45 (3 × m, 3 × 1H, CH, C5H5);
7.28−7.37 (m, 5H, Ph). 13C NMR (126 MHz, CDCl3) for 6a: 25.89,
26.40 (CMe2); 28.84 (CH2C5H5); 43.72 (CH2, C5H5); 71.71
(CH2Ph); 79.79 (C(4)); 82.00 (C(3)); 82.10 (C(2)); 104.87 or
104.89 (C(1)); 111.44 (CMe2); 127.85, 128.05 or 128.09, 128.52 or
128.69 (CH, Ph); 128.65, 131.50, 132.63 (CH, C5H5); 137.86 or
137.89 (Cipso, Ph); 145.31 (Cipso, C5H5). 13C NMR (126 MHz, CDCl3)
for 6a′: 25.89, 26.40 (CMe2), 28.00 (CH2C5H5); 41.23 (CH2, C5H5);
71.65 (CH2Ph); 79.79 (C(4)); 81.84 (C(3)); 82.10 (C(2)); 104.87 or
104.89 (C(1)); 111.44 (CMe2); 127.85, 128.05 or 128.09, 128.52 or
128.69 (CH, Ph); 128.20, 134.14, 135.02 (CH, C5H5); 137.86 or
137.89 (Cipso, Ph); 143.09 (Cipso, C5H5). EI-MS (m/z (%)): 328 (M•+,
3), 249 (7), 211 (6), 164 (8), 91 (100), 79 (10). Anal. Calcd for
C20H24O4 (328.39): C, 73.15; H, 7.37. Found: C, 73.07; H, 7.42.
Preparation of Cyclopentadienes 6b/6b′. A solution of sodium
cyclopentadienide in tetrahydrofuran (3.8 mL, 2 M, 7.6 mmol) was
added dropwise with cooling (−50 °C) and stirring to a solution of 3-
O-benzyl-1,2-di-O-isopropylidene-5-O-(p-toluenesulfonyl)-α-D-ribofur-
anose (4; 1.939 g, 4.46 mmol) in anhydrous dimethylformamide (9
mL). The mixture was warmed to room temperature, and stirring was
continued for 2 h while a fine precipitate formed. The reaction mixture
was then kept at 5 °C overnight. TLC in ethyl acetate/light petroleum
(1/2 and 1/5) indicated the absence of the starting compound. The
unreacted cyclopentadienide was decomposed by addition of 4 mL of
water, and after 10 min the reaction mixture was poured onto ice. The
water phase was extracted three times with ethyl acetate. The organic
extracts were combined, washed with brine, dried over sodium sulfate,
and concentrated to afford 1.7 g of the crude product. Chromatog-
raphy on silica gel in ethyl acetate/light petroleum (1/5) yielded a
syrupy product as an inseparable mixture of 6b and 6b′ in an
equimolar ratio, which crystallized spontaneously upon storing
overnight at room temperature. Yield: 0.993 g (68%). Mp: 58−65
3
2
2JHH = 13.6 Hz, JHH = 7.5 Hz, 1H, CH2C5H4); 2.94 (dd, JHH = 13.6
3
3
Hz, JHH = 7.5 Hz, 1H, CH2C5H4); 3.78 (d, JHH = 3.0 Hz, 1H, C(3)
H); 4.39 (td, 3JHH = 7.5 Hz, 3JHH = 3.0 Hz, 1H, C(4)H); 4.55 (d, 2JHH
= 11.8 Hz, 1H, CH2Ph); 4.61 (d, 3JHH = 3.9 Hz, 1H, C(2)H); 4.64 (d,
2JHH = 11.8 Hz, 1H, CH2Ph); 5.53 − 5.63 (m, 4H, C5H4); 5.72 (d,
3JHH = 3.9 Hz, 1H, C(1)H), 7.18 − 7.39 (m, 5H, Ph). 13C NMR (75
MHz, THF-D8): 26.64, 27.27 (CMe2); 29.55 (CH2C5H4); 72.38
(CH2Ph); 83.09 (C(3)); 83.92 (C(2)); 84.27 (C(4)); 103.26, 103.45
(CH, C5H4); 105.59 (C(1)); 111.55 (CMe2); 114.54 (Cipso, C5H4);
128.16, 128.36, 129.03, (CH, Ph); 140.00 (Cipso, Ph).
Preparation of Lithium Cyclopentadienide 7b. To a mixture
of cyclopentadienes 6b/6b′ (1.848 g, 5.63 mmol) in Et2O (60 mL)
cooled to 0 °C was slowly added dropwise a solution of n-BuLi in
hexane (2.40 mL, 2.5 M, 6.00 mmol), which caused precipitation of a
slightly pink waxy solid within several minutes. The resulting
suspension was stirred for 12 h. The solution was removed by reverse
filtration, and the obtained slightly pink gel was washed with Et2O (2
× 15 mL) and dried under vacuum to constant weight. Yield: 1.403 g
1
(75%). H NMR (300 MHz, THF-d8): 1.28 (s, 3H, CMe2); 1.47 (s,
2
3H, CMe2); 2.67 (dd, JHH = 13.8 Hz, 3JHH = 7.2 Hz, 1H, CH2C5H4);
2
3
2.88 (dd, JHH = 13.8 Hz, JHH = 5.7 Hz, 1H, CH2C5H4); 3.52 (dd,
3
3JHH = 8.7 Hz, JHH = 4.5 Hz, 1H, C(3)H); 4.06−4.16 (m, 1H, C(4)
2
3
H); 4.49 (d, JHH = 11.4 Hz, 1H, CH2Ph); 4.61 (pseudo t, JHH = 4.5
Hz, 3JHH = 3.9 Hz, 1H, C(2)H); 4.66 (d, 2JHH = 11.4 Hz, 1H, CH2Ph);
5.52 − 5.56 (m, 2H, C5H4); 5.56−5.61 (m, 2H, C5H4); 5.60 partially
3
overlapped (d, JHH = 3.9 Hz, 1H, C(1)H); 7.20−7.40 (m, 5H, Ph).
13C NMR (75 MHz, THF-d8): 27.09, 27.14 (CMe2); 34.64
(CH2C5H4); 72.46 (CH2Ph); 78.80 (C(2)); 81.37 (C(4)); 83.70
(C(3)); 103.54, 103.81 (CH, C5H4); 104.99 (C(1)); 112.86 (CMe2);
113.44 (Cipso, C5H4); 128.59, 129.09, 129.13 (CH, Ph); 139.08 (Cipso
,
Ph).
1
Preparation of Titanocene Dichloride 8a. A solution of lithium
cyclopentadienide 7a (0.210 g, 0.63 mmol) in THF (10 mL) was
dropped into a solution of [(η5-C5H5)TiCl3] (0.137 g, 0.63 mmol) in
THF (10 mL) cooled to −20 °C. The reaction mixture was warmed to
room temperature and stirred for 1 h. Volatiles were evaporated under
°C. H NMR (500 MHz, CDCl3) for 6b: 1.35, 1.59 (2 × s, 2 × 3H,
CMe2); 2.60, 2.82 (2 × m, 2 × 1H, CH2C5H5); 2.93 (m, 2H, CH2,
3
3
C5H5); 3.43 (dd, JH2H3 = 8.8 Hz and JH3H4 = 8.8 Hz, 1H, C(3)H);
4.21 (ddd, JH4H5 = 3.6 Hz, 3JH4H5′ = 7.1 Hz and JH4H3 = 8.8 Hz, 1H,
C(4)H); 4.53 (dd, JH1H2= 3.8 Hz and JH2H3 = 8.8 Hz, 1H, C(2)H);
3
3
3
3
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vacuum, and the residue was extracted with chloroform (6 mL). The
chloroform extract was layered with heptane (20 mL), which afforded
a red oil after several days in the refrigerator (4 °C). The oil was
isolated, and crystallization was attempted from a toluene/heptane
mixture (4 mL/2 mL) at low temperature (4 °C). Nevertheless, the
product again appeared as a red oil after several days. The oil was
separated and dried under vacuum for several hours, which caused its
solidification to a red solid. Yield: 0.205 g (64%). Mp: 48 °C. 1H NMR
(300 MHz, (CD3)2SO): 1.24, 1.37 (2 × s, 2 × 3H, CMe2); 2.95−3.00
436 (vw), 415 (w). Anal. Calcd for C25H28Cl2O4Ti (511.27): C, 58.73;
H, 5.52. Found: C, 59.12; H, 5.81.
Preparation of Titanocene Dichloride 9a. A solution of lithium
cyclopentadienide 7a (0.600 g, 1.79 mmol) in THF (15 mL) was
dropped into a solution of TiCl4(THF)2 (0.270 g, 0.81 mmol) in THF
(15 mL) cooled to −78 °C. The resulting red solution was stirred for 1
h and then allowed warmed to room temperature and stirred for an
additional 14 h. After evaporation of THF under vacuum, the crude
product was extracted with dichloromethane (8 mL and 2 × 2 mL).
The volume of the collected dichloromethane fraction was reduced to
half, and the obtained dark red solution was layered with hexane (20
mL). A dark red-brown oil separated after several days at 4 °C. The oil
was isolated, washed with 4 × 2 mL of pentane, and dried under
vacuum for several hours, which caused its solidification to a brown
powder. The mother liquor and collected washings gave an additional
3
(m, 2H, CH2C5H4); 3.73 (d, JHH = 3.3 Hz, 1H, C(3)H); 4.21−4.26
2
(m, 1H, C(4)H); 4.47, 4.69 (2 × d, 2 × JHH = 11.7 Hz, 2 × 1H,
CH2Ph); 4.74 (d, 3JHH = 3.9 Hz, 1H, C(2)H); 5.85 (d, 3JHH = 3.9 Hz,
1H, C(1)H); 6.33−6.42 (m, 2H, C5H4); 6.65 (s, 5H, C5H5); 6.67−
1
6.75 (m, 2H, C5H4); 7.30−7.38 (m, 5H, Ph). H NMR (300 MHz,
2
CDCl3): 1.31, 1.47 (2 × s, 2 × 3H, CMe2); 3.07 (dd, JHH = 15.6 Hz,
1
crop of the product. Overall yield: 0.252 g (40%). Mp: 110 °C. H
2
3
3JHH = 5.4 Hz, 1H, CH2C5H4); 3.12 (dd, JHH = 15.6 Hz, JHH = 8.3
NMR (300 MHz, CDCl3): 1.31, 1.46 (2 × s, 2 × 6H, CMe22); 3.05 (dd,
3
Hz, 1H, CH2C5H4); 3.82 (d, JHH = 3.0 Hz, 1H, C(3)H); 4.28 (ddd,
3
2JHH = 15.4 Hz, JHH = 5.4 Hz, 2H, CH2C5H4); 3.12 (dd, JHH = 15.4
3JHH = 8.3 Hz, 3JHH = 5.4 Hz, 3JHH = 3.0 Hz, 1H, C(4)H); 4.51 (d, 2JHH
= 11.9 Hz, 1H, CH2Ph); 4.62 (d, 3JHH = 4.0 Hz, 1H, C(2)H); 4.71 (d,
3
3
Hz, JHH = 8.0 Hz, 2H, CH2C5H4); 3.81 (d, JHH = 3.1 Hz, 2H, C(3)
H); 4.30 (ddd, 3JHH = 8.0 Hz, 3JHH = 5.4 Hz, 3JHH = 3.1 Hz, 2H, C(4)
H); 4.51 (d, 2JHH = 11.9 Hz, 2H, CH2Ph); 4.61 (d, 3JHH = 4.0 Hz, 2H,
C(2)H); 4.70 (d, 2JHH = 11.9 Hz, 2H, CH2Ph); 5.94 (d, 3JHH = 4.0 Hz,
2H, C(1)H); 6.31−6.36 (m, 2H, C5H4); 6.37−6.44 (m, 4H, C5H4);
6.44−6.49 (m, 2H, C5H4); 7.27−7.38 (m, 10H, Ph). 13C NMR (75
MHz, CDCl3): 26.32 (CMe2); 30.17 (CH2C5H4); 72.05 (CH2Ph);
80.06 (C(4)); 82.24 (C(2)); 82.66 (C(3)); 105.09 (C(1)); 111.53
(CMe2); 115.21, 118.63, 121.98, 123.33 (CH, C5H4); 127.92, 128.13,
128.72 (CH, Ph); 134.46 (Cipso, C5H4); 137.53 (Cipso, Ph). ESI-MS
(m/z; ESI+, relative abundance): 811 ([M + K]+, 6); 795 ([M + Na]+,
12); 737 ([M − Cl]+, 100). IR (KBr, cm−1): 3107 (vw), 3089 (vw),
3062 (vw), 3031 (w), 2985 (m), 2932 (m), 1689 (vw), 1581 (vw),
1497 (m), 1454 (m), 1374 (sh, s), 1350 (w), 1298 (vw), 1255 (m),
1214 (s), 1164 (s), 1076 (vs), 1027 (vs), 960 (w), 887 (m), 856 (s),
827 (m), 738 (s), 699 (s), 634 (w), 514 (vw). Anal. Calcd for
C40H46Cl2O8Ti (773.57): C, 62.10; 5.99 H, . Found: C, 62.23; H, 6.08.
Preparation of Titanocene Dichloride 9b. To a solid mixture of
lithium cyclopentadienide 7b (0.508 g, 1.52 mmol) and TiCl4(THF)2
(0.241 g, 0.72 mmol) cooled to −78 °C was added THF (15 mL). The
mixture was warmed to room temperature and stirred for 12 h.
Volatiles were evaporated under vacuum, and the solid residue was
extracted with dichloromethane (14 mL). The resulting dark red-
brown solution was evaporated to dryness, and the residue was
redissolved in a minimal amount of dichloromethane (4 mL) and
layered with heptane (14 mL). After the mixture was stored for several
days in the refrigerator (4 °C), a red crystalline solid appeared
(suitable crystals for X-ray analysis were chosen). The material was
isolated, washed consecutively with a dichloromethane−heptane
mixture and heptane, and dried under vacuum. The combined mother
liquid and washings gave another crop of the product after several days
in the freezer (−28 °C). Overall yield: 0.401 g (72%). Mp: 168 °C. 1H
NMR (300 MHz, CDCl3): 1.34, 1.56 (2 × s, 2 × 6H, CMe22); 2.77 (dd,
2JHH = 11.9 Hz, 1H, CH2Ph); 5.96 (d, JHH = 4.0 Hz, 1H, C(1)H);
3
6.34−6.38 (m, 1H, C5H4); 6.43−6.47 (m, 1H, C5H4); 6.48−6.52 (m,
2H, C5H4); 6.55 (s, 5H, C5H5); 7.29−7.41 (m, 5H, Ph). 13C NMR (75
MHz, CDCl3): 26.28, 26.82 (CMe2); 30.19 (CH2C5H4); 72.04
(CH2Ph); 79.96 (C(4)); 82.18 (C(2)); 82.65 (C(3)); 105.09
(C(1)); 111.54 (CMe2); 115.75, 119.07 (CH, C5H4); 120.03
(C5H5); 122.30, 123.36 (CH, C5H4); 127.94, 128.18, 128.74 (CH,
Ph); 135.11 (Cipso, C5H4); 137.46 (Cipso, Ph). ESI-MS (m/z; ESI+,
relative abundance): 549 ([M + K]+, 93); 533 ([M + Na]+, 90); 475
([M − Cl]+, 100). IR (KBr, cm−1): 3110 (w), 3063 (w), 3029 (w),
2984 (m), 2931 (m), 2873 (w), 1603 (vw), 1496 (w), 1454 (sh, m),
1382 (m), 1374 (m), 1350 (w), 1300 (sh, w), 1248 (s), 1214 (s), 1164
(s), 1076 (vs), 1027 (s), 961 (w), 887 (w), 851 (m), 822 (vs), 737
(m), 698 (m), 669 (vw), 635 (vw), 603 (vw), 512 (vw), 466 (vw).
Anal. Calcd for C25H28Cl2O4Ti (511.27): C, 58.73; H, 5.52. Found: C,
58.95; H, 5.68.
Preparation of Titanocene Dichloride 8b. To a solid mixture of
lithium cyclopentadienide 7b (0.262 g, 0.78 mmol) and [(η5-
C5H5)TiCl3] (0.155 g, 0.71 mmol) cooled to −78 °C was added
THF (10 mL). The mixture was warmed to room temperature and
stirred for an additional 12 h. Volatiles were removed under vacuum,
and the residue was extracted with dichloromethane (15 mL).
Evaporation of dichloromethane afforded the crude product as an
orange-red fluffy solid, which was recrystallized from a dichloro-
methane/heptane mixture at low temperature (4 °C). The precipitated
red-orange solid was isolated, washed with heptane (2 × 2 mL), and
1
dried under vacuum. Yield: 0.297 g (75%). Mp: 172 °C. H NMR
(300 MHz, CDCl3): 1.34, 1.56 (2 × s, 2 × 3H, CMe2); 2.79 (dd, 2JHH
3
2
= 15.1 Hz, JHH = 8.1 Hz, 1H, CH2C5H4); 3.17 (dd, JHH = 15.1 Hz,
3JHH = 3.1 Hz, 1H, CH2C5H4); 3.40 (dd, 3JHH = 8.9 Hz, 3JHH = 4.4 Hz,
1H, C(3)H); 4.15 (pseudo td, 3JHH = 8.9 Hz, 3JHH = 8.1 Hz, 3JHH = 3.1
Hz, 1H, C(4)H); 4.53 (d, 2JHH = 11.9 Hz, 1H, CH2Ph); 4.55 (pseudo
t, 3JHH = 4.4 Hz, 3JHH = 3.8 Hz, 1H, C(2)H); 4.79 (d, 2JHH = 11.9 Hz,
3
2JHH = 15.0 Hz, JHH = 8.0 Hz, 2H, CH2C5H4); 3.14 (dd, JHH = 15.0
Hz, 3JHH = 3.1 Hz, 2H, CH2C5H4); 3.39 (dd, 3JHH = 8.9 Hz, 3JHH = 4.4
Hz, 2H, C(3)H); 4.15 (pseudo td, 3JHH = 8.9 Hz, 3JHH = 8.0 Hz, 3JHH
3
1H, CH2Ph); 5.70 (d, JHH = 3.8 Hz, 1H, C(1)H); 6.25−6.28, 6.34−
2
= 3.1 Hz, 2H, C(4)H); 4.53 (d, JHH = 11.9 Hz, 2H, CH2Ph); 4.53
6.37, 6.39−6.42, 6.42−6.45 (4 × m, 4 × 1H, C5H4); 6.54 (s, 5H,
C5H5); 7.32−7.40 (m, 5H, Ph). 13C NMR (75 MHz, CDCl3): 26.60,
26.82 (CMe2); 33.48 (CH2C5H4); 72.29 (CH2Ph); 77.00 (C(2));
77.78 (C(4)); 81.00 (C(3)); 104.05 (C(1)); 112.96 (CMe2); 116.27,
116.36 (CH, C5H4); 119.93 (CH, C5H5); 124.07, 124.42 (CH, C5H4);
(pseudo t, 3JHH = 4.4 Hz, 3JHH = 3.8 Hz, 2H, C(2)H); 4.78 (d, 2JHH
=
11.9 Hz, 2H, CH2Ph); 5.69 (d, 3JHH = 3.8 Hz, 2H, C(1)H); 6.19−6.23,
6.29−6.32 (2 × m, 2 × 2H, C5H4); 6.35−6.40 (m, 4H, C5H4); 7.31−
7.40 (m, 5H, Ph). 13C NMR (75 MHz, CDCl3): 26.63, 26.86 (CMe2);
33.47 (CH2C5H4); 72.32 (CH2Ph); 77.06 (C(2)); 77.88 (C(4)); 80.99
(C(3)); 104.07 (C(1)); 112.96 (CMe2); 115.96, 116.20, 123.72,
128.28, 128.40, 128.70 (CH, Ph); 133.53 (Cipso, C5H4); 137.45 (Cipso
,
Ph). ESI-MS (m/z; ESI+, relative abundance): 549 ([M + K]+, 95);
533 ([M + Na]+, 100); 475 ([M − Cl]+, 97). IR (KBr, cm−1): 3114
(w), 3107 (w), 3064 (vw), 3034 (vw), 2986 (w), 2976 (w), 2950 (w),
2931 (w), 2895 (w), 2885 (w), 1627 (vw), 1498 (w), 1453 (m), 1434
(m), 1384 (m), 1372 (m), 1329 (w), 1307 (w), 1263 (m), 1240 (m),
1224 (s), 1207 (m), 1169 (m), 1132 (s), 1102 (s), 1072 (s), 1061
(m), 1041 (s), 1010 (s), 974 (w), 962 (m), 923 (vw), 891 (w), 874
(s), 858 (s), 838 (s), 822 (vs), 786 (vw), 760 (m), 741 (w), 706 (vs),
688 (w), 618 (w), 608 (m), 588 (vw), 559 (w), 514 (w), 495 (vw),
124.03 (CH, C5H4); 128.30, 128.43, 128.72 (CH, Ph); 132.94 (Cipso
,
C5H4); 137.50 (Cipso, Ph). ESI-MS (m/z; ESI+, relative abundance):
811 ([M + K]+, 100); 795 ([M + Na]+, 27); 737 ([M − Cl]+, 17). ESI-
MS (m/z; ESI−, relative abundance): 809 ([M + Cl]−, 100); 482 ([M
+ Cl − Cp]́
−, 20). IR (KBr, cm−1): 3116 (sh, w), 3089 (vw), 3065
(vw), 3027 (vw), 2988 (w), 2974 (w), 2957 (vw), 2924 (m), 2898
(w), 2865 (vw), 1627 (vw), 1608 (vw), 1498 (m), 1454 (m), 1432
(m), 1373 (sh, s), 1350 (w), 1307 (m), 1252 (m), 1209 (s), 1167 (s),
1141 (s), 1093 (vs), 1027 (vs), 997 (s), 943 (vw), 926 (vw), 907 (w),
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871 (s), 854 (s), 830 (m), 734 (s), 698 (m), 658 (vw), 611 (w), 547
(vw), 513 (w), 460 (vw), 433 (vw). Anal. Calcd. for C40H46Cl2O8Ti
(773.57): C, 62.10; 5.99 H, . Found: C, 62.15; H, 5.96.
(m), 832 (m), 739 (m), 699 (m), 582 (sh, m). Anal. Calcd for
C40H46F2O8Ti (740.67): C, 64.86; H, 6.26. Found: C, 65.03; H, 6.41.
Preparation of Titanocene Difluoride 11b. Route 1. A solution
of 9b (0.080 g, 103 μmol) and {2-(CH2NMe2)C6H4-κC,N}(n-
Bu)2SnF (0.081 g, 210 μmol) in dichloromethane (15 mL) was
stirred for 2 days. Volatiles were removed under vacuum, and the
residual yellow wax was triturated five times with pentane (5 × 10 mL)
under sonification and finally dried under vacuum. The yield of a
yellow solid was 0.072 g (94%).
Preparation of Titanocene Difluoride 10. A solution of 8b
(0.120 g, 0.24 mmol) and {2-(CH2NMe2)C6H4-κC,N}(n-Bu)2SnF
(0.188 g, 0.48 mmol) in dichloromethane (10 mL) was stirred for 3
days, whereupon the mixture gradually changed color from red to
orange and finally to yellow. All volatiles were removed under vacuum,
and a sticky yellow residue was triturated five times with pentane (5 ×
10 mL) in an ultrasonic bath for 10 min. The resulting yellow solid
Route 2. A solution of 7b (0.260 g, 0.78 mmol) in THF (15 mL)
was gradually dropped into a cold (−78 °C) solution of [TiF4(THF)2]
(0.094 g, 0.35 mmol) in THF (20 mL). The mixture was warmed to
room temperature and stirred for an additional 12 h. Volatiles were
removed under vacuum, and the residue was extracted with
dichloromethane (in total 18 mL). Evaporation of the solvent gave
11b as a yellow-brown solid. Yield: 0.176 g (68%).
1
was dried under vacuum. Yield: 0.105 g (93%). Mp: 122−125 °C. H
NMR (300 MHz, CDCl3): 1.34, 1.56 (2 × s, 2 × 3H, CMe22); 2.60 (dd,
3
2JHH = 15.3 Hz, JHH = 8.1 Hz, 1H, CH2C5H4); 2.94 (dd, JHH = 15.3
Hz, 3JHH = 3.1 Hz, 1H, CH2C5H4); 3.36 (dd, 3JHH = 8.9 Hz, 3JHH = 4.3
Hz, 1H, C(3)H); 4.15 (pseudo td, 3JHH = 8.9 Hz, 3JHH = 8.1 Hz, 3JHH
2
= 3.1 Hz, 1H, C(4)H); 4.52 (d, JHH = 11.9 Hz, 1H, CH2Ph); 4.52
1
(pseudo t, 3JHH = 4.3 Hz, 3JHH = 3.8 Hz, 1H, C(2)H); 4.76 (d, 2JHH
=
Mp: 153 °C. H NMR (300 MHz, CDCl3): 1.33, 1.55 (2 × s, 2 ×
2
6H, CMe2); 2.59 (dd, JHH = 15.3 Hz, 3JHH = 8.4 Hz, 2H, CH2C5H4);
11.9 Hz, 1H, CH2Ph); 5.68 (d, 3JHH = 3.8 Hz, 1H, C(1)H); 5.98−6.02,
6.10−6.14 (2 × m, 2 × 1H, C5H4); 6.33−6.37 (m, 2H, C5H4); 6.40 (br
s, 5H, C5H5); 7.32−7.39 (m, 5H, Ph). 13C NMR (75 MHz, CDCl3):
26.66, 26.86 (CMe2); 31.82 (CH2C5H4); 72.29 (CH2Ph); 77.00
(C(2)); 77.78 (C(4)); 81.07 (C(3)); 104.11 (C(1)); 112.93 (CMe2);
115.75, 116.60 (CH, C5H4); 118.53 (CH, C5H5); 118.64, 118.85, (CH,
2
3
2.93 (dd, JHH = 15.3 Hz, JHH = 3.0 Hz, 2H, CH2C5H4); 3.34 (dd,
3JHH = 8.7 Hz, 3JHH = 4.5 Hz, 2H, C(3)H); 4.14 (pseudo td, 3JHH = 8.7
Hz, 3JHH = 8.4 Hz, 3JHH = 3.0 Hz, 2H, C(4)H); 4.49 (pseudo t, 3JHH
=
3
2
4.5 Hz, JHH = 3.6 Hz, 2H, C(2)H); 4.50 (d, JHH = 12.0 Hz, 2H,
CH2Ph); 4.74 (d, 2JHH = 12.0 Hz, 2H, CH2Ph); 5.67 (d, 3JHH = 3.6 Hz,
2H, C(1)H); 5.94−5.99, 6.05−6.10 (2 × m, 2 × 2H, C5H4); 6.26−
6.34 (m, 4H, C5H4); 7.20−7.40 (m, 10H, Ph). 13C NMR (75 MHz,
CDCl3): 26.66, 26.85 (CMe2); 31.80 (CH2C5H4); 72.26 (CH2Ph);
77.03 (C(2)); 77.48 (C(4)); 81.07 (C(3)); 104.08 (C(1)); 112.87
(CMe2); 115.24, 116.14, 118.39, 118.44 (CH, C5H4); 128.22, 128.35,
128.66 (CH, Ph); 136.68 (Cipso, C5H4); 137.58 (Cipso, Ph). 19F NMR
(282 MHz, CDCl3): 63.57 (s, 2F, TiF2). ESI-MS (m/z; ESI+, relative
abundance): 779 ([M + K]+, 100); 763 ([M + Na]+, 68); 721 ([M −
F]+, 5). IR (KBr, cm−1): 3089 (vw), 3064 (vw), 3031(vw), 2986 (m),
2934 (m), 1497 (w), 1455 (m), 1435 (vw), 1373 (sh, m), 1350 (vw),
1306 (w), 1249 (m), 1215 (s), 1168 (s), 1136 (s), 1092 (sh, s), 1023
(vs), 872 (m), 831 (m), 741 (m), 700 (m), 655 (vw), 609 (w), 581
(m), 559 (m), 513 (vw), 418 (w). Anal. Calcd for C40H46F2O8Ti
(740.67): C, 64.86; H, 6.26. Found: C, 65.09; H, 6.39.
C5H4); 128.26, 128.38, 128.69 (CH, Ph); 137.40 (Cipso, C5H4); 137.56
2
(Cipso, Ph). 19F NMR (282 MHz, CDCl3): 64.10, 64.23 (2 × d, JFF
=
23.6 Hz, 2 × 1F, TiF2). ESI-MS (m/z; ESI+, relative abundance): 517
([M + K]+, 100); 501 ([M + Na]+, 51); 459 ([M − F]+, 6). IR (KBr,
cm−1): 3109 (w), 3030 (vw), 2989 (w), 2886 (w), 1633 (vw), 1498
(w), 1454 (sh, w), 1373 (sh, w), 1349 (vw), 1302 (vw), 1252 (w),
1215 (m), 1167 (m), 1135 (m), 1091 (m), 1025 (m), 914 (vw), 872
(m), 816 (m), 750 (m), 701 (m), 655 (w), 610 (m), 581 (s), 567 (vs),
549 (vs), 513 (w), 457 (vw), 417 (m). Anal. Calcd for C25H28F2O4Ti
(478.37): C, 62.76; H, 5.90. Found: C, 62.91; H, 6.07.
Preparation of Titanocene Difluoride 11a. Route 1. A solution
of 9a (0.031 g, 40 μmol) and {2-(CH2NMe2)C6H4-κC,N}(n-Bu)2SnF
(0.035 g, 90 μmol) in dichloromethane (4 mL) was stirred for 12 h at
1
room temperature and then refluxed for 2 h. The H NMR of the
sample taken from the reaction mixture showed an accomplished
reaction. Volatiles were removed under vacuum, and the residual
yellow wax was triturated three times with hexane (3 × 5 mL) under
sonification for 10 min and finally dried under vacuum. The yield of a
yellow powder was 0.026 g (88%).
Preparation of Ferrocene 12a. Solid FeCl2 (0.127 g, 1.00 mmol)
was added to a solution of lithium cyclopentadienide 7a (0.701 g, 2.10
mmol) in THF (100 mL). The mixture was stirred for 20 h and then
refluxed for 5 h. After the mixture was cooled to room temperature,
volatiles were evaporated under vacuum. The orange-brown oily
residue was purified by column chromatography on silica gel using a
hexane/ethyl acetate mixture (from 10/1 to 10/4, v/v) to obtain the
desired compound as a yellow-orange oil. Yield 0.480 g (68%). Rf = 0.2
(hexane/ethyl acetate, 10/1). 1H NMR (300 MHz, CDCl3): 1.30, 1.47
Route 2. A mixture of 7a (0.285 g, 0.85 mmol) and [TiF4(THF)2]
(0.109 g, 0.41 mmol) was cooled to −78 °C, and THF (15 mL) was
added. The mixture was warmed to room temperature and stirred for
an additional 15 h. After this time the 1H NMR of the sample showed
that the reaction proceeded to completion. Volatiles were removed
under vacuum, and the residue was extracted with toluene (10 mL).
The volume of the yellow-orange toluene solution was reduced to ca. 4
mL, and the product was precipitated with heptane (10 mL), washed
with heptane (2 × 5 mL), and dried under vacuum. The yield of an
ocher powder was 0.257 g (84%).
2
(2 × s, 2 × 6H, CMe2)2; 2.75 (dd, JHH = 14.1 Hz, 3JHH = 6.3 Hz, 2H,
3
CH2C5H4); 2.80 (dd, JHH = 14.1 Hz, JHH = 7.8 Hz, 2H, CH2C5H4);
3.74 (d, 3JHH = 3.3 Hz, 2H, C(3)H); 3.93−3.95, 3.95−3.98, 3.98−4.02,
4.04−4.07 (4 × m, 4 × 2H, C5H4); 4.16−4.23 (m, 2H, C(4)H); 4.50
(d, 2JHH = 11.9 Hz, 2H, CH2Ph); 4.59 (d, 3JHH = 3.9 Hz, 2H, C(2)H);
2
3
4.68 (d, JHH = 11.9 Hz, 2H, CH2Ph); 5.92 (d, JHH = 3.9 Hz, 2H,
C(1)H); 7.28−7.42 (m, 10H, Ph). 13C NMR (75 MHz, CDCl3):
26.24, 26.76 (CMe2); 28.02 (CH2C5H4); 68.46, 68.54, 69.57, 69.76
(CH, C5H4); 71.64 (CH2Ph); 81.53 (C(4)); 81.92 (C(2)); 82.00
(C(3)); 84.41 (Cipso, C5H4); 104.87 (C(1)); 111.29 (CMe2); 127.65,
127.95, 128.61 (CH, Ph); 137.74 (Cipso, Ph). ESI-MS (m/z; ESI+): 733
([M + Na]+); 710 ([M]+). IR (KBr, cm−1): 3088 (w), 3066 (vw),
3031 (w), 2987 (m), 2958 (m), 2932 (s), 2884 (w), 1735 (m), 1497
(m), 1454 (s), 1440 (w), 1382 (s), 1374 (s), 1349 (m), 1332 (w),
1311 (vw), 1298 (w), 1245 (s), 1214 (s), 1165 (s), 1070 (vs), 1020
(vs), 959 (m), 924 (m), 887 (s), 860 (s), 827 (m), 809 (m), 737 (s),
697 (s), 636 (vw), 603 (vw), 504 (sh, m). Anal. Calcd for C40H46O8Fe
(710.62): C, 67.60; H, 6.53. Found: C, 67.43; H, 6.45.
Mp: 125−130 °C. 1H NMR (300 MHz, CDCl3): 1.30, 1.46 (2 × s,
2
3
2 × 6H, CMe2); 2.84 (dd, JHH = 15.4 Hz, JHH = 5.1 Hz, 2H,
2
3
CH2C5H4); 2.96 (dd, JHH = 15.4 Hz, JHH = 8.6 Hz, 2H, CH2C5H4);
3.79 (d, 3JHH = 3.1 Hz, 2H, C(3)H); 4.31 (ddd, 3JHH = 8.6 Hz, 3JHH
=
3
2
5.1 Hz, JHH = 3.1 Hz, 2H, C(4)H); 4.48 (d, JHH = 11.9 Hz, 2H,
CH2Ph); 4.60 (d, 3JHH = 4.0 Hz, 2H, C(2)H); 4.67 (d, 2JHH = 11.9 Hz,
2H, CH2Ph); 5.92 (d, 3JHH = 4.0 Hz, 2H, C(1)H); 6.06−6.10 (m, 2H,
C5H4); 6.10−6.14 (m, 2H, C5H4); 6.30−6.36 (m, 4H, C5H4); 7.29−
7.37 (m, 10H, Ph). 13C NMR (75 MHz, CDCl3): 26.34, 26.89
(CMe2); 28.55 (CH2C5H4); 71.94 (CH2Ph); 79.73 (C(4)); 82.20
(C(2)); 82.65 (C(3)); 105.07 (C(1)); 111.47 (CMe2); 114.84, 116.96,
117.32, 118.20 (CH, C5H4); 127.83, 128.08, 128.68 (CH, Ph); 137.61,
137.68 (2 × Cipso, C5H4 and Ph). 19F NMR (282 MHz, CDCl3): 64.18
(s, 2F, TiF2). ESI-MS (m/z; ESI+, relative abundance): 779 ([M + K]+,
100); 763 ([M + Na]+, 41); 721 ([M − F]+, 10). IR (KBr, cm−1):
3113 (vw), 3090 (vw), 3063 (vw), 3031 (vw), 2986 (m), 2933 (m),
1497 (w), 1455 (m), 1382 (m), 1374 (m), 1350 (w), 1299 (vw), 1257
(m), 1215 (s), 1165 (s), 1076 (vs), 1028 (vs), 960 (vw), 888 (m), 857
Preparation of Ferrocene 12b. To a mixture of FeCl2 (30 mg,
237 μmol) and lithium cyclopentadienide 7b (171 mg, 512 μmol) was
added THF (8 mL), and the mixture was stirred overnight. Volatiles
were removed under vacuum, and the residue was chromatographed
on silica gel using hexane/ethyl acetate (5/1, v/v). The title
compound was obtained as an orange wax. Yield: 0.118 g (64%). Rf
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= 0.2 (hexane/ethyl acetate, 5/1). 1H NMR (300 MHz, CDCl3): 1.33,
washed with methanol (5 mL), and volatiles were removed from the
collected methanol fractions. The solid residue was purified by column
chromatography on a silica gel with a chloroform/methanol mixture
(10/1, v/v) as an eluent. The crystallization of the obtained solid from
methanol gave 14a as a yellow crystalline solid. Yield: 0.045 g (86%).
Route 2. To a solution of 12a (0.060 g, 0.085 mmol) in THF (4
mL) was added a catalytic amount of Pd/C (10 wt % Pd, 0.015 g).
The reaction flask was attached to a latex balloon filled with hydrogen
gas, and the hydrogen was continuously refilled until the reaction
proceeded to completion (ca. 40 h) as detected by TLC. The
following workup was identical with that in the above experiment and
afforded 0.037 g (82%) of 14a.
1.58 (2 × s, 2 × 6H, CMe2); 2.46 (dd, 2JHH = 15.0 Hz, 3JHH = 6.3 Hz,
2
3
2H, CH2C5H4); 2.77 (dd, JHH = 15.0 Hz, JHH = 3.3 Hz, 2H,
3
3
CH2C5H4); 3.34 (dd, JHH = 9.0 Hz, JHH = 4.3 Hz, 2H, C(3)H);
3.80−3.84, 3.91−3.95, 3.95−3.98, 4.06−4.10 (4 × m, 4 × 2H, C5H4);
4.14 (ddd, 3JHH = 9.0 Hz, 3JHH = 6.3 Hz, JHH = 3.3 Hz, 2H, C(4)H);
3
3
2
4.45 (d, JHH = 3.9 Hz, 2H, C(2)H); 4.50 (d, JHH = 12.0 Hz, 2H,
CH2Ph); 4.76 (d, 2JHH = 11.9 Hz, 2H, CH2Ph); 5.64 (d, 3JHH = 3.9 Hz,
2H, C(1)H); 7.28−7.42 (m, 10H, Ph). 13C NMR (75 MHz, CDCl3):
26.72, 26.92 (CMe2); 31.53 (CH2C5H4); 68.34, 68.62, 70.27, 70.44
(CH, C5H4); 72.21 (CH2Ph); 77.14 (C(2)); 78.21 (C(4)); 80.37
(C(3)); 83.67 (Cipso, C5H4); 104.02 (C(1)); 112.76 (CMe2); 128.13,
128.29, 128.59 (CH, Ph); 137.85 (Cipso, Ph). ESI-MS (m/z; ESI+): 710
(M+). IR (KBr, cm−1): 3085 (vw), 3064 (vw), 3028 (vw), 2986 (m),
2933 (m), 2889 (w), 1634 (vw), 1496 (w), 1454 (m), 1427 (vw),
1382 (m), 1371 (s), 1350 (w), 1304 (m), 1248 (m), 1215 (s), 1167
(s), 1133 (s), 1103 (s), 1095 (s), 1026 (vs), 911 (w), 888 (w), 871
(m), 812 (w), 740 (m), 699 (m), 644 (vw), 611 (vw), 546 (vw), 523
(w), 498 (w), 451 (vw). Anal. Calcd for C40H46O8Fe (710.62): C,
67.60; H, 6.53. Found: C, 67.74; H, 6.59.
Rf = 0.6 (chloroform/methanol, 10/1). Mp: 200 °C. 1H NMR (300
MHz, DMSO-d6): 1.21, 1.34 (2 × s, 2 × 6H, CMe2); 2.49 partially
2
3
obscured by solvent signal (dd, JHH = 14.2 Hz, JHH = 7.1 Hz, 2H,
2
3
CH2C5H4); 2.62 (dd, JHH = 14.2 Hz, JHH = 6.6 Hz, 2H, CH2C5H4);
3.78 (dd, JHH = 5.1 Hz, JHH = 2.7 Hz, 2H, C(3)H); 3.97 partially
overlapped (pseudo td, JHH = 7.1 Hz, JHH = 6.6 Hz, JHH = 2.7 Hz,
3
3
3
3
3
2H, C(4)H); 3.99−4.02 (m, 4H, C5H4); 4.03−4.06 (m, 2H, C5H4);
3
4.09−4.12 (m, 2H, C5H4); 4.37 (d, JHH = 3.8 Hz, 2H, C(2)H); 5.23
Preparation of Ferrocene Alcohol 13. A catalytic amount of
Pd/C (10 wt % Pd, 0.045 g) was added to a solution of 12a (0.250 g,
0.35 mmol) in methanol (5 mL). Neat Et3SiH (3.5 mL, 22.0 mmol)
was dropped into the mixture, which caused an immediate hydrogen
evolution. The formed hydrogen overpressure was compensated by
attaching a latex balloon to the reaction flask. The mixture was stirred
for 5 h and then monitored with TLC. As the TLC analysis still
showed the presence of the starting ferrocene 12a, an additional
portion of Et3SiH (1.0 mL, 6.3 mmol) was added and the mixture was
stirred for a further 12 h. The mixture was filtered and the residue
washed with MeOH (5 mL). Combined methanol fractions were
evaporated to dryness, and the resulting orange-brown wax was
purified by column chromatography on silica gel (eluted with pure
chloroform followed by a chloroform/methanol mixture 10/1, v/v).
(d, 3JHH = 5.1 Hz, 2H, OH); 5.78 (d, 3JHH = 3.8 Hz, 2H, C(1)H). 13
C
NMR (75 MHz, DMSO-d6): 26.03, 26.60 (CMe2); 27.59 (CH2C5H4);
67.74, 67.77, 69.17, 69.54 (CH, C5H4); 73.78 (C(3)); 81.44 (C(4));
84.97 (Cipso, C5H4); 85.00 (C(2)); 104.04 (C(1)); 110.09 (CMe2).
ESI-MS, (m/z; ESI+): 553 ([M + Na]+); 530 ([M]+). ESI-MS (m/z;
ESI−): 529 ([M − H]−). IR (KBr, cm−1): 3457 (br w), 3103 (vw),
3090 (vw), 2992 (m), 2980 (m), 2965 (w), 2934 (m), 2888 (w), 2565
(br m), 1453 (vw),1442 (vw), 1385 (m), 1376 (s), 1332 (vw), 1291
(vw), 1251 (m), 1216 (s), 1164 (s), 1074 (vs), 1018 (vs), 955 (m),
927 (m), 884 (m), 859 (m), 823 (m), 751 (w), 634 (vw), 529 (vw),
509 (m), 499 (m). Anal. Calcd for C26H34O8Fe (530.38): C, 58.87; H,
6.46. Found: C, 58.82; H, 6.49.
Preparation of Ferrocene Diol 14b. The procedure described
above for 14a (Route 2) was used. Thus, 12b (0.139 g, 0.195 mmol)
was catalytically (0.030 g Pd/C) hydrogenated within 44 h to give 14b
as a yellow solid. Yield: 0.074 g (70%). Rf = 0.7 (chloroform/
methanol, 10/1). Mp: 175 °C. 1H NMR (300 MHz, DMSO-d6): 1.25,
1.43 (2 × s, 2 × 6H, CMe2); 2.33 (dd, 2JHH = 15.0 Hz, 3JHH = 8.4 Hz,
1
The H NMR showed 13 as the major product in addition to a small
amount of 14a. Further purification by column chromatography using
a hexane/ethyl acetate mixture (2/1, v/v) gave pure 13 as a brown
wax. Yield: 0.170 g (78%). Moreover, pure 14a (0.015 g, 8% yield) was
obtained by further column elution. Rf = 0.2 (hexane/ethyl acetate, 2/
1). 1H NMR (500 MHz, DMSO-d6): 1.21, 1.24, 1.34, 1.37 (4 × s, 4 ×
3H, CMe2); 2.45−2.52 obscured by solvent signal (m, 1H, CH2C5H4);
2
3
2H, CH2C5H4); 2.72 (dd, JHH = 15.0 Hz, JHH = 2.1 Hz, 2H,
3
CH2C5H4); 3.38−3.49 (m, 2H, C(3)H); 3.79 (pseudo td, JHH = 8.4
Hz, 3JHH = 8.7 Hz, 3JHH = 2.1 Hz, 2H, C(4)H); 4.00 (br s, 4H, C5H4);
3
3
2.55−2.71 (m, 3H, CH2C5H4); 3.71 (d, JHH = 2.9 Hz, 1H, C(3′)H);
4.04 (br s, 2H, C5H4); 4.06 (br s, 2H, C5H4); 4.41 (pseudo t, JHH
=
3
3
3.79 (dd, JHH = 5.1 Hz, JHH = 2.6 Hz, 2H, C(3)H); 3.96−4.02 (m,
6H, C5H4 and C(4)H); 4.03−4.05 (m, 1H, C5H4); 4.05−4.12 (m, 3H,
C5H4 and C(4′)H); 4.38 (d, 3JHH = 3.8 Hz, 1H, C(2)H); 4.48, 4.71 (2
× d, 2 × 2JHH = 11.7 Hz, 2 × 1H; CH2Ph); 4.72 (d, 3JHH = 3.8 Hz, 1H,
C(2′)H); 5.21 (d, 3JHH = 5.1 Hz, 1H, OH); 5.79 (d, 3JHH = 3.8 Hz, 1H,
3.9 Hz, 3JHH = 4.2 Hz, 2H, C(2)H); 5.10 (d, 3JHH = 6.9 Hz, 2H, OH);
5.62 (d, 3JHH = 3.9 Hz, 2H, C(1)H). 13C NMR (75 MHz, DMSO-d6):
26.34, 26.51 (CMe2); 31.33 (CH2C5H4); 67.73, 67.81, 69.05, 69.93
(CH, C5H4); 74.45 (C(3)); 78.71 (C(2)); 79.28 (C(4)); 85.02 (Cipso
,
C5H4); 103.12 (C(1)); 110.99 (CMe2). ESI-MS (m/z; ESI+): 562 ([M
− H + Na]+); 530 (M+·). IR (KBr, cm−1): 3459 (s), 3106 (vw), 3095
(vw), 3086 (vw), 2991 (m), 2937 (m), 2888 (w), 1733 (vw), 1454
(w), 1395 (m), 1388 (m), 1376 (m), 1318 (w), 1254 (m), 1216 (s),
1167 (m), 1121 (vs), 1099 (m), 1062 (vs), 1016 (vs), 926 (vw), 871
(s), 813 (w), 758 (vw), 689 (vw), 641 (vw), 620 (w), 585 (vw), 553
(vw), 505 (w), 494 (w), 450 (vw). Anal. Calcd for C26H34O8Fe
(530.38): C, 58.87; H, 6.46. Found: C, 59.01; H, 6.55.
3
C(1)H); 5.83 (d, JHH = 3.8 Hz, 1H, C(1′)H); 7.30−7.35 (m, 1H,
Ph); 7.36−7.43 (m, 4H, Ph). 13C NMR (125 MHz, DMSO-d6): 25.97,
26.00, 26.47, 26.56 (CMe2); 27.51 (CH2C5H4); 67.72, 67.75, 67.79,
67.81, 68.94, 69.15, 69.46, 69.47 (CH, C5H4); 70.63 (CH2Ph); 73.76
(C(3)); 80.83 (C(4′)); 81.11 (C(2′); 81.38 (C(4)); 81.60 (C(3′));
84.55 (Cipso, C5H4); 84.98 (C(2)); 85.01 (Cipso, C5H4); 104.02 (C(1));
104.16 (C(1′)); 110.05, 110.25 (CMe2); 127.61, 127.63, 128.32 (CH,
Ph); 137.92 (Cipso, Ph). ESI-MS (m/z; ESI+): 643 ([M + Na]+); 620
([M]+). IR (KBr, cm−1): 3467 (w), 3088 (vw), 3031 (vw), 2987 (s),
2958 (m), 2933 (s), 2888 (w), 1735 (w), 1497 (vw), 1455 (m), 1441
(vw), 1374 (sh, s), 1350 (vw), 1332 (w), 1296 (w), 1254 (s), 1216 (s),
1165 (s), 1070 (vs), 1024 (vs), 957 (m), 926 (w), 886 (s), 861 (s),
826 (sh, m), 739 (m), 698 (m), 668 (vw), 635 (w), 604 (vw), 527
(vw), 504 (sh, m), 444 (vw). Anal. Calcd. for C33H40O8Fe (620.50):
C, 63.87; H, 6.50. Found: C, 64.15; H, 6.77.
X-ray Crystallography. Single-crystal X-ray diffraction data for 9b
were obtained using a Nonius KappaCCD difractometer equipped
with a Bruker ApexII detector by monochromatized Mo Kα radiation
(λ = 0.71073 Å) at 150(2) K. The structure was solved by direct
methods (SHELXS)85 and refined by full-matrix least squares based on
F2 (SHELXL97).86 The hydrogen atoms were fixed into idealized
positions (riding model) and assigned temperature factors either
Hiso(H) = 1.2[Ueq(pivot atom)] or 1.5Ueq for the methyl moiety. The
determination of the absolute configuration was based on an
anomalous dispersion of heavy atoms. The graphic depiction of the
molecular structure was created using the PLATON program.87
Crystal data for 9b: C40H46Cl2O8Ti, M = 773.57, orthorhombic,
P21212 (No. 18), a = 10.5322(11) Å, b = 27.861(2) Å, c = 6.5319(6)
Å, V = 1916.7(3) Å3, Z = 2, Dx = 1.340 g mL−1, dark red crystal of
dimensions 0.38 × 0.33 × 0.32 mm, multiscan absorption correction
(μ = 0.41 mm−1), Tmin = 0.859, Tmax = 0.878. A total of 29069
Preparation of Ferrocene Diol 14a. Route 1. A catalytic amount
of Pd/C (10 wt % Pd, 0.015 g) was added to a solution of 12a (0.070
g, 0.99 mmol) in methanol (4 mL). Neat Et3SiH (1.0 mL, 6.3 mmol)
was dropped into the mixture, which caused an immediate hydrogen
evolution. The formed hydrogen overpressure was compensated by
attaching a latex balloon to the reaction flask. The mixture was stirred
for 1 h, while TLC analysis showed complete consumption of the
starting material. The mixture was filtered, the solid residue was
2068
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Organometallics
Article
reflections were measured (θmax= 27.5°), 4401 of which were unique
(Rint = 0.033) and 4181 were observed according to the I > 2σ(I)
criterion. The refinement converged (Δ/σmax< 0.002) to R = 0.029 for
observed reflections and Rw(F2) = 0.073; GOF = 1.06 for 233
parameters and all 4401 reflections. The final difference map displayed
no peaks of chemical significance (Δρmax = 0.32 e Å−3, Δρmin −0.19 e
Å−3). The chirality parameter was −0.01(2). Crystallographic data
(excluding structure factors) for the structure of 9b have been
deposited with the Cambridge Crystallographic Data Centre with
CCDC number 961600. Copies of the data can be obtained, free of
charge, on application to the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, U.K. (fax, +44-(0)1223-
336033; e-mail, deposit@ccdc.cam.ac.uk).
MTT Cytotoxicity Tests. Reagents. All tested compounds were
prepared as 65 mM stock solutions in DMSO and stored at −20 °C.
Cisplatin (cis-diamminedichloroplatinum(II)) was obtained from
Ebewe Pharma GmbH, Unterach, Austria.
Cell Line and Culture Condition. The A2780 and A2780cis ovarian
carcinoma cell lines were obtained from the American Type Culture
Collection (ATCC) and grown in RPMI 1640 medium supplemented
with 10% heat-inactivated fetal bovine serum (BIOCHROM AG;
Berlin, Germany), 100 U/mL of penicillin, and 0.1 mg/mL of
streptomycin (Hyclone Laboratories, Logan, UT, USA) and L-
glutamine 2 mM (Gibco) in a humidified incubator at 37 °C under
a 5% CO2 atmosphere and subcultured twice a week.
Education, Youth and Sport of the Czech Republic (Project
No. 0021620857). Dr. Lidmila Petrusova
the determination of melting points; Dr. Petr Svec and Prof.
Ales Ruzicka (University of Pardubice) are acknowledged for
́
is acknowledged for
̌
̌
̌
̌
̊
preparation and a generous gift of the fluorinating agent {2-
(CH2NMe2)C6H4-κC,N}(n-Bu)2SnF.
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J.P. and M.L. were supported by the Czech Science Foundation
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Czech Science Foundation (project P206/12/G151), the
European Regional Development Fund, and the State Budget
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