Piano Stool Aminoalkylidene-Ferracyclopentenone Complexes from Bimetallic Precursors: Synthesis and Cytotoxicity Data

Article abstract of DOI:10.1002/cplu.201900639

The reaction of pyrrolidine with a series of cationic diiron cyclopentadienyl complexes containing a bridging vinyliminium ligand gives access to piano stool monoiron complexes based on a five-membered metallacycle that includes a vinyl-aminoalkylidene mo

Full text of DOI:10.1002/cplu.201900639

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DOI: 10.1002/cplu.201900639
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Piano Stool Aminoalkylidene-Ferracyclopentenone
Complexes from Bimetallic Precursors: Synthesis and
Cytotoxicity Data
Dalila Rocco,[a, e] Lucinda K. Batchelor,[b] Eleonora Ferretti,[c, f] Stefano Zacchini,*[d]
Guido Pampaloni,[a] Paul J. Dyson,[b] and Fabio Marchetti*[a]
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The reaction of pyrrolidine with a series of cationic diiron
cyclopentadienyl complexes containing a bridging vinyliminium
ligand gives access to piano stool monoiron complexes based
on a five-membered metallacycle that includes a vinyl-amino-
alkylidene moiety, in moderate to high yields. The resulting
metallacyclic motif (aminoalkylidene-ferracyclopentenone) is
unique in organometallic chemistry and is partially pre-
constructed on the dinuclear frame. The monoiron products
were fully characterized by elemental analysis, IR and multi-
nuclear NMR spectroscopy, and in a number of cases by X-ray
diffraction and cyclic voltammetry. They are robust in aqueous
solutions and generally unreactive towards alkylating agents in
organic solvents. However, a cationic derivative was prepared in
high yield by methylation of a 2-pyridyl group. The cytotoxicity
of both neutral and ionic complexes was assessed on cancerous
(A2780 and A280cisR) and non-cancerous (HEK293) cell lines,
revealing the influence of local structural modifications on the
antiproliferative activity and the selectivity of the compounds.
Introduction
anticancer potential of ferrocene derivatives,[3] also as cytotoxic
agents.[4] In general, such class of compounds may be obtained
from commercially available Fe2Cp2(CO)4 or its simple deriva-
tives, via preliminary fragmentation of the dinuclear frame.
Thus, the smooth oxidation of Fe2Cp2(CO)4 by means of either
halogen-based oxidants (e.g. hydrogen halides[5] and I2[6]) or
silver salts[7] provides a facile entry into mononuclear species
based on the [FeCp(CO)2]+ core, to which a variety of ligands
can be added.[2a–b,d,4a,6,8] Small molecular units tethered to the
[Fe2Cp2(CO)3] framework prior to fragmentation may be pre-
served in the corresponding monoiron products, and examples
include isocyanides,[9] thiocarbonyl[10] and vinyl groups.[11] Alter-
native strategies for the synthesis of piano stool iron(II) carbonyl
Interest in developing new iron-based compounds is motivated
by the attractive characteristics of the metal, being abundant,
inexpensive and environmentally benign.[1] In particular, piano-
stool iron complexes containing the robust cyclopentadienyl
(Cp) ligand have been intensively investigated for their catalytic
applications,[2] and, following the interest aroused by the
[a] D. Rocco, Prof. G. Pampaloni, Prof. F. Marchetti
Dipartimento di Chimica e Chimica Industriale
Università di Pisa
Via G. Moruzzi 13
56124 Pisa (Italy)
compounds are constituted by Na(Hg) reduction of
E-mail: fabio.marchetti1974@unipi.it
Homepage: http://people.unipi.it/fabio_marchetti1974/
[b] Dr. L. K. Batchelor, Prof. P. J. Dyson
Institut des Sciences et Ingénierie Chimiques
Ecole Polytechnique Fédérale de Lausanne (EPFL)
CH-1015 Lausanne (Switzerland)
[c] Dr. E. Ferretti
Institut für Anorganische Chemie
Tammannstr. 4
37077 Göttingen (Germany)
[d] Prof. S. Zacchini
[12]
Fe2Cp2(CO)4
and the use of iron(II) chloride/sodium cyclo-
pentadienide systems.[2c] In general, Fischer alkylidene (Fischer
carbene) ligands, including aminoalkylidene ligands, need to be
built directly on monoiron complexes via modification of
hydrocarbyl ligands, thus determining intrinsic structural
limitations.[13] In this regard, (Cp)Fe-aminocarbene moieties
have been obtained by aminolysis of alkoxy-carbenes[14] and
vinylidenes,[15] modification of isocyanide ligands,[14a] and elec-
trophilic addition of imidoyl chlorides to suitable organoferrate
(I) anions.[16]
Dipartimento di Chimica Industriale “Toso Montanari”
Università di Bologna
Viale Risorgimento 4
40136 Bologna (Italy)
A more versatile approach would consist in the construction
of a functionalized ligand on the diiron scaffold Fe2Cp2(CO)x
(x=2-3), followed by cleavage of the latter and subsequent
inclusion of the pre-formed fragment in a monoiron compound.
In principle, this strategy takes advantage of the cooperative
effects provided by the two adjacent iron centres, exploiting
bridging and multisite coordination modes and allowing
reactivity patterns which are not available on homologous
mononuclear structures.[17]
E-mail: stefano.zacchini@unibo.it
[e] D. Rocco
Present address: Department of Chemistry
University of Basel, BPR 1096
Mattenstrasse 24a
4058 Basel (Switzerland)
[f] Dr. E. Ferretti
Present address: Institut für Chemie und Biochemie
Fabeckstr. 34–36
14195 Berlin (Germany)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cplu.201900639
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Diiron complexes with a bridging vinyliminium ligand, 2,
can be prepared on gram scales from Fe2Cp2(CO)4 through the
stepwise assembly of one isocyanide and one alkyne, proceed-
ing with the intermediate formation of the μ-aminocarbyne
species 1 (Scheme 1).[18,19] The diiron compounds 2 display
notable properties, including promising antiproliferative
potential,[20] and their versatile chemistry offers much oppor-
tunity for unusual and selective transformations of the vinyl-
iminium moiety;[17a,21] in general, the resulting organic fragments
remain anchored to the two iron atoms. Herein, we describe
the facile synthesis (tolerant of various functionalities) of a large
family of piano stool monoiron compounds incorporating the
N-C1-C2-C3 moiety and also report on their antiproliferative
potential.
rearrangement, terminating with the elimination of one iron
atom and cyclopentadiene.[22] These reactions require rigorously
anhydrous conditions: CoCp2 is air/moisture sensitive, therefore
the reaction solvent must be freshly distilled and, since the
diiron reactant is hydrophilic, this needs to be stored under
inert atmosphere or dried before use. Furthermore, the
reactions seem limited to specific R’ substituents. On the other
hand, the employment of a stronger reductant such as sodium
hydride, that is also an efficient Brönsted base, may favour
deprotonation pathways.[23]
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In order to find a convenient and general method to obtain
compounds of type 3, we considered the possibility of using an
amine in the place of cobaltocene; the reducing power of
amines is well documented in the literature.[24] To this purpose,
pyrrolidine was selected as the optimal reagent, due to its
favourable characteristics (liquid at ambient temperature,
relatively low boiling point and inexpensive); instead the use of
other amines was less satisfying (NH2Cy, NH2Et), or unsuccessful
Results and Discussion
i
Synthesis and Characterization of Compounds
(NEt3, NH2 Pr). Thus, the reactions of 2a–m with a ten-fold
excess of pyrrolidine in tetrahydrofuran afforded 3a–m in 40–
93% yields (referred to the C1-C3 chain); no significant amounts
of side-products were detected in all cases. The method
reported in Scheme 2 is not critically sensitive to air/moisture
(pyrrolidine is used from the bottle and 2a–m can be conserved
in air without any pre-treatment before reaction) and, notably,
can be broadly applied as it tolerates a variety of functional
groups.
Compounds 3a–m were purified by alumina chromatogra-
phy, and fully characterized by analytical and spectroscopic
methods. Furthermore, the molecular structures of 3b, 3f, 3g
and 3h were determined by single-crystal X-ray diffraction
(Figure 1, Table 1).
Complexes 3a-m are based on a five-membered metalla-
cycle, consisting of fused vinyl-aminoalkylidene and acyl units,
which is unique in organometallic chemistry. The formation of
this structure appears the consequence of the incorporation of
the C3 vinyliminium chain, pre-generated on the diiron skeleton
from isocyanide/alkyne combination, on the monoiron deriva-
tive. Ring closure is ensured by carbon-carbon bond coupling
A
series of vinyliminium compounds, [2a–m]CF3SO3, was
prepared as air stable triflate salts in 60–90% yield from the
parent aminocarbyne complexes, following a literature proce-
dure (Scheme 1).[20] Complexes [2b,d,g,i,j,l]CF3SO3 are unprece-
dented, and their IR and NMR features generally resemble those
typical of related species bearing a cis geometry of the Cp
ligands and E arrangement of the N-substituents (when R¼Me).
The NMR spectra of [2d]CF3SO3 and [2j]CF3SO3 (in acetone-d6)
contain two sets of resonances, attributed to E/Z and trans/cis
isomers, respectively. Complex [2g]CF3SO3 also exists in solution
as a mixture of two species, differing in the spatial orientation
of the Me and Cl substituents on the N-bound arene. The
reaction involving [1c]CF3SO3 and 2-ethynylpyridine was not
selective, and two geometric isomers were obtained (head-
head and head-tail alkyne insertion modes), as evidenced by
NMR spectroscopy. The structures of [2i]CF3SO3 and trans-[2j]
CF3SO3 were ascertained by single-crystal X-ray diffraction
(views of the structures are provided as Supporting Information,
see Figures S1 and S2).
We recently described the cobaltocene-induced fragmenta-
tion of some diiron vinyliminium compounds, leading to the
monoiron [FeCp(CO){C1N(Me)(Xyl)C2HC3(R’)C(=O)}] (R’=Ph, 3a;
R’=CH2OH, 3n; R’=Et, 3o).[22,20] A detailed investigation on the
synthetic pathway to 3o indicated that initial single electron
transfer from CoCp2 to the diiron complex triggers a multistep
Scheme 1. Synthesis of diiron μ-vinyliminium complexes (counter
-
anion=CF3SO3 ; R’=H, alkyl, aryl, SiMe3, CO2Me, N- or S-heterocycle; R’’=H,
Scheme 2. Synthesis of piano-stool vinyl-aminoalkylidene iron complexes
from dinuclear precursors; Xyl=2,6-C6H3Me2, Xyl-Cl=2,6-C6H3MeCl.
alkyl or aryl).
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3g and 3h, respectively]. The Fe-carbene and N-carbene
distances in 3b, 3f, 3g and 3h [e.g. for 3b, Fe(1)-C(5)=1.912(4)
Å and C(5)-N(1)=1.321(5) Å] resemble the values reported for
other Fe(II)-aminoalkylidene complexes, including 3a and
3o.[20,22] The C2-C3 and C1-C2 distances [e.g. in 3b: C(3)-C(4)=
1.326(6) Å, C(5)-C(4)=1.458(6) Å] are in agreement with typical
Csp2=Csp2 and Csp2À Csp2 bond lengths, respectively.[26] In 3b,
3f and 3g, the two different N-substituents are oriented in an
E-configuration.
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In the IR spectra of 3a–m (in CH2Cl2), the carbonyl ligand
and the acyl group are clearly recognized by two distinct
absorptions falling in within the ranges 1909–1922 cmÀ 1 and
1602–1619 cmÀ 1, respectively. The NMR spectra of 3a–f and
3h–l contain a single set of resonances which, in the cases of
3a–f, reasonably correspond to the E configuration of the
aminoalkylidene group, consistent with the X-ray structures
(see above). Compounds 3a–m contain one stereogenic iron
centre, and in principle they exist as a racemic mixture of
enantiomers. Instead, two isomers, in nearly 1:1 ratio, were
observed for 3g and 3m. In 3g, probably corresponding to the
two possible orientations adopted by the methyl and chlorine
arene substituents. Instead, E and Z isomers are expected in the
case of 3m, due to the comparable steric demands of the
methyl and benzyl groups, which bind the nitrogen atom. In
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Figure 1. Molecular structures of [FeCp(CO){η2-C1Me(Xyl)C2HC3(tBu)C(=O)}],
3b, [FeCp(CO){η2-C1Me(Xyl)C2HC3(3-tiophenyl)C(=O)}], 3f, [FeCp(CO){η2-C1Me
(Xyl-Cl)C2HC3(Ph)C(=O)}], 3g, [FeCp(CO){η2-C1Me2C2HC3(Ph)C(=O)}], 3h. Dis-
placement ellipsoids are at the 30% probability level. H-atoms, except H(4),
have been omitted for clarity.
°
Table 1. Selected bond distances (Å) and angles ( ) for 3b, 3f, 3g, 3h and
[4]CF3SO3.
3b
3f
3g
3h
[4]CF3SO3
1
the H NMR spectra, the vinyl C2-H protons are observed in the
Fe(1)-C(5)
Fe(1)-C(4)
Fe(1)-C(1)
C(5)-O(1)
C(4)-O(2)
C(1)-N(1)
C(3)-C(4)
C(2)-C(3)
C(1)-C(2)
Fe(1)-C(5)-O
(1)
1.739(7) 1.739(3)
1.937(5) 1.939(3)
1.912(4) 1.913(3)
1.166(7) 1.148(3)
1.208(5) 1.218(3)
1.321(5) 1.318(3)
1.521(6) 1.525(3)
1.326(6) 1.336(4)
1.458(6) 1.458(4)
175.1(6) 178.1(3)
1.746(2)
1.936(2)
1.905(2)
1.154(3)
1.218(3)
1.325(3)
1.529(3)
1.336(3)
1.463(3)
178.2(2)
1.723(7) 1.740(3)
1.938(6) 1.928(3)
1.946(6) 1.920(3)
1.156(9) 1.142(3)
1.216(8) 1.217(3)
1.307(8) 1.323(3)
1.519(8) 1.524(4)
1.329(9) 1.330(4)
1.468(9) 1.490(3)
178.6(6) 178.5(3)
range 6.45–8.05 ppm, while the two N-bound methyl groups
give rise to two signals (e.g. at 3.77 and 3.57 ppm in 3h), due
to the partial double bond nature of C1-N. Salient 13C NMR
features are supplied by the resonances of the metallacyclic
carbons. Hence, C1 and C2 are observed in the ranges 256.6–
268.3 ppm and 146.2–150.5 ppm, in accordance with their
amino-alkylidene[21,27] and vinyl character, respectively. The C3
carbon atoms are observed in the range 162.1–183.6 ppm,
being significantly affected by the nature of R’.
At variance with the general observation that late metal-
acyl groups are susceptible to alkylation to afford alkoxy-
alkylidene derivatives,[17a,28] 3h is unreactive towards meth-
ylating agents (MeI, CF3SO3Me). Otherwise, the reaction of 3e
with methyl triflate was straightforward and led to selective
methylation of the pyridyl nitrogen, affording the pyridinium
salt [4]CF3SO3 (Scheme 3). The latter was isolated in 80% yield
after chromatographic purification and characterized by X-ray
diffraction and IR and NMR spectroscopy.
Fe(1)-C(4)-C(3) 113.1(3) 112.79(18) 112.97(15) 112.9(4) 112.19(18)
C(4)-C(3)-C(2)
C(3)-C(2)-C(1)
112.1(4) 112.3(2)
117.0(4) 116.1(2)
112.2(2)
115.6(2)
113.0(6) 114.3(2)
116.0(6) 114.8(2)
C(2)-C(1)-Fe(1) 114.0(3) 114.32(18) 114.80(16) 113.5(4) 113.61(18)
C(1)-Fe(1)-C(5) 88.2(2) 89.17(11) 83.12(9) 82.9(2) 89.61(12)
between the C3 carbon and one carbonyl ligand originally
present in 2a–m, forming the acyl group. In analogy with
former findings (see above), we propose that the process is
initiated by electron transfer from the amine to 2a–m, to form
diiron radical species undergoing intramolecular rearrangement
until the loss of the {FeCp} unit.[22] Accordingly, when the
reaction of [2a]CF3SO3 with pyrrolidine was carried out in air,
the IR spectrum of the mixture after 36 hours evidenced only
limited conversion of [2a]+ to 3a, suggesting some O2
interference.
It has to be noted that the previously reported generation
of vinyl-aminoalkylidene ligands on monoiron compounds
suffers from important limitations (see Introduction), including
complicated synthetic protocols and restrictions on the nature
of the vinyl substituents.[25]
A view of the structure of the cation is shown in Figure 2,
with relevant bonding parameters listed in Table 1. The most
salient aspect of the X-ray structure of [4]+ is the orientation
The five-membered ring in 3b,f,g,h is almost perfectly
planar mean deviations from the Fe(1) C(2) C(3) C(4) C(5) least
square planes 0.0170, 0.0565, 0.0549 and 0.0606 Å for 3b, 3f,
Scheme 3. Selective methylation of a pyridyl function in the piano-stool
vinyl-aminoalkylidene iron complex 3e.
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Table 2. Overview of the first oxidation and reduction potentials (V vs.
Fc+/Fc) at a scan rate of 100 mV/s determined by cyclic voltammetry for a
selection of monoiron complexes. The peak-to peak separation (ΔEp) is
defined by the difference between the two peak potentials for a given
redox couple.
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3
4
Compound
Solvent
Oxidation
ΔEp(ox)
Reduction
ΔEp[red]
5
6
7
8
9
3a
3a
3b
3c
3d
3e
3f
3h
3i
3i
MeCN
THF
À 0.160
À 0.135
À 0.105
À 0.029
À 0.015
À 0.008
À 0.145
À 0.370
À 0.435
À 0.155
À 0.200
(2 steps)
À 0.080
À 0.180
83
–
À 1.940
À 2.000
À 2.135
À 1.860
À 1.745
À 1.764
À 1.935
À 2.090
À 2.020
À 1.830
À 2.240
(irr)
70
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
100
65
85
100
96
80
91
–
80
80
80
80
95
83
80
–
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3j
MeCN
100
–
Figure 2. Structure of the cation of [FeCp(CO){C1NMe(Xyl)C2HC3(2-methyl-
pyridinium)C(=O)}]CF3SO3, [4]CF3SO3. Displacement ellipsoids are at the 30%
probability level. H-atoms, except H(4), have been omitted for clarity.
3l
MeCN
MeCN
81
81
À 1.795
82
90
3n22
À 2.070
adopted by the N-substituents (Z configuration), which is
opposite to that observed in the solid state for 3b,f,g (E
configuration). On the other hand, the main bond lengths and
angles in [4]+ do not significantly differ from those in 3b,f,g,h.
Methylation of the pyridyl moiety in 3e produces a notable
variation of the electron density at the iron atom, as evidenced
by the IR stretching frequency of the carbonyl ligand which
moves from 1919 in 3e to 1939 cmÀ 1 in [4+]. Conversely, the
conversion of 3e to [4]CF3SO3 does not give rise to major
changes in the NMR spectrum. In particular, the C1, C2 and C3
resonance values of [4+] (262.8, 149.9 and 167.0 ppm, respec-
tively, dmso-d6 solution) are close to the corresponding ones
observed for 3e (263.2, 152.5 and 161.4 ppm, respectively,
CD2Cl2 solution).
Relevant to the biological studies, the stability of com-
pounds 3a–m and [4]CF3SO3 was monitored in D2O/dmso-d6
solutions by 1H NMR spectroscopy, after storing the solutions at
Figure 3. Cyclic voltammogram of 3d recorded in MeCN at a scan rate of
100 mV/s with NBu4PF6 (0.1 M) as the supporting electrolyte; potentials vs
Fc+/Fc.
°
37 C for 72 hours: all the compounds are substantially stable,
since only traces (<10%) of additional species were NMR
detected at the end of treatment. Moreover, the compounds
showed robustness even in dmso/cell culture medium mixture
(ascribable to the FeII/FeIII couple) and one reduction in the
potential ranges À 0.435 V to 0.015 V and À 2.240 V to À 1.675 V,
respectively. Both anodic and cathodic processes are generally
reversible in the time scale of the experiment, as suggested by
the peak-to-peak separation for each couple being lower than
100 mV (The theoretical value is 59 mV at room temperature for
a reversible one-electron event with fast electron-transfer
kinetics).[29] The only exception is given by complex 3j, showing
°
(RPMI-1640), and were cleanly recovered after 72 hours at 37 C
following dichloromethane extraction (see Experimental for
details).
Electrochemistry
The electrochemical behaviour of selected monoiron com-
pounds was investigated in acetonitrile solution (and also in
tetrahydrofuran in some cases) by cyclic voltammetry at
ambient temperature. The results are summarized in Table 2; as
a representative example, the voltammogram of 3d in MeCN is
reported in Figure 3, while all cyclic voltammetry profiles are
supplied as Supporting Information (Figures S44–S56).
In general, two main electron transfers were observed with
respect to the ferrocene/ferrocenium redox couple. More
precisely, the compounds (in acetonitrile) exhibit one oxidation
a
two-step electrochemical oxidation at À 0.20 V and an
irreversible reduction at À 2.24 V. This peculiar behaviour may
be related to the combination of electron donor R and R’
substituents (i.e., methyl and tert-butyl), probably affecting the
stability of the formally reduced species [3j]À , this latter
undergoing chemical transformation after electron transfer.
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Cytotoxicity Studies
vary across the series of compounds. The inactivity of [4]CF3SO3
may be related to its ionic nature, disfavouring both cellular
uptake and oxidation. It should also be noted that 3a–n tend to
be less cytotoxic than their bimetallic precursors, 2a–n,[20] and
that the trends in cytotoxicities between the two groups of
complexes deviate substantially, despite the bimetallic com-
plexes potentially undergoing fragmentation in vitro to form
mononuclear species. In general, bimetallic complexes are often
more cytotoxic than mononuclear complexes, irrespective of
whether they remain intact or fragment following cellular
uptake,[34] although many highly cytotoxic mononuclear iron-
based organometallic complexes are known.[3b,35]
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The cytotoxicity of the new compounds 3b–m and [4]SO3CF3
was assessed against cisplatin sensitive and cisplatin resistant
human ovarian carcinoma (A2780 and A2780cisR) cell lines and
the non-tumorigenic human embryonic kidney (HEK-293) cell
line. Cisplatin and [RuCl2(η6-p-cymene)(kP-pta)] (RAPTA-C)[30]
were evaluated as positive and negative controls, respectively.
The obtained IC50 values are presented in Table 3, where they
are compared to those previously determined for 3a and 3n.
The compounds display a range of cytotoxicities, with 3b
displaying the lowest IC50 values in the two cancer cell lines
(6.7�1.2 μM in A2780 cells and 11�1 μM in A2780cisR cells)
together with reasonable degree of cancer cell selectivity (41�
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10 μM in HEK-293 cells). Compound 3f contains a thiophenyl Conclusion
group, which is known to impart various pharmacological
properties to organic scaffolds, including anticancer activity.[31]
In keeping with 3a, the presence of a phenyl ring attached to
the metallacycle appears to favourably affect the selectivity (3g
and 3h), with the compounds being essentially inactive in the
HEK-293 cell line.
Bimetallic complexes are ideal for constructing functionalized
organic and organometallic architectures and the readily
available dimer Fe2Cp2(CO)4 represents a versatile starting
material. In particular, bridging vinyliminium ligands with
unusual coordination fashion can be fabricated on a diiron
frame by stepwise assembly of one isocyanide and one alkyne.
Herein, we have described the amine-promoted selective
fragmentation of easily available diiron vinyliminium complexes
into piano stool complexes featuring a unique structural motif,
which arises from the adaptation of the intact vinyliminium
moiety to the monoiron species. Structural variation is guaran-
teed by the general character of the reaction, and the
availability of a large number of alkynes. In particular, the
introduction of a pyridyl group allows subsequent derivatization
via alkylation. The series of piano stool iron compounds exhibits
a variable cytotoxic activity, and a selectivity against cancer cell
lines seems favoured by the presence on the vinyl moiety of a
phenyl substituent rather than other groups.
Previous studies on 3a (R’=Ph) indicated that the anti-
proliferative activity is likely related to a combination of the
accessible oxidation potential, triggering the production of ROS,
and the compact, hydrophobic structure, allowing DNA
binding.[20] Accordingly, the lack of cytotoxicity detected for 3n
(R’=CH2OH) was ascribed to a less favourable DNA binding,
obstructed by the hydrophilic hydroxyl unit.[20] Based on the
electrochemical results, all the neutral compounds (3) might be
prone to oxidation inside the cells, and thus represent further
examples of anticancer metal-based compounds that are
potentially activated via an oxidation mechanism,[3a–b,32] as
opposed to the more commonly encountered activation by
reduction mechanism.[33] It should be noted, however, that
there is not a clear correlation between the oxidation and
reduction potentials of 3a–n (Table 2) and their cytotoxicities
(Table 3). Such disparity is not unexpected as other factors Experimental Section
which also impact on cytotoxicity, such as cellular uptake, will
Materials and Methods
All manipulations were carried out under N2 atmosphere using
Table 3. IC50 values (μM) determined for compounds 3a–n, [4]CF3SO3 and
cisplatin on human ovarian carcinoma (A2780), human ovarian carcinoma
cisplatin resistant (A2780CisR) and human embryonic kidney (HEK-293) cell
lines after 72 h exposure. Values are given as the mean �SD.
standard Schlenk techniques. The reaction vessels were oven dried
at 120 C prior to use, evacuated (10À 2 mmHg) and then filled with
°
N2. Organic reactants (TCI Europe or Sigma Aldrich) and Fe2Cp2(CO)4
(Strem) were commercial products of the highest purity available.
Compounds [Fe2Cp2(CO)2(μ-CO){μ-CNMe(R)}]CF3SO3 (R=Xyl=2,6-
C6H3Me2, [1a]CF3SO3; R=Xyl-Cl=2,6-C6H3MeCl, [1b]CF3SO3; R=Me,
[1c]CF3SO3; R=CH2Ph, [1d]CF3SO3),[18] [2a,c,e,f,h,k]CF3SO3,[20] and
3n[22] were prepared according to published procedures. Solvents
were distilled before use under N2 from appropriate drying agents.
Chromatography was carried out under N2 on deactivated alumina
columns (Sigma Aldrich, 4% w/w water). Infrared spectra of solid
samples were recorded on a Perkin Elmer Spectrum One FT-IR
spectrometer, equipped with a UATR sampling accessory (4000–
400 cmÀ 1 range). Infrared spectra of solutions were recorded on a
Perkin Elmer Spectrum 100 FT-IR spectrometer with a CaF2 liquid
transmission cell (2300–1500 cmÀ 1 range). NMR spectra were
recorded at 298 K on a Bruker Avance II DRX400 instrument
equipped with a BBFO broadband probe. Chemical shifts (ex-
pressed in parts per million) are referenced to the residual solvent
Compound
A2780
A2780cisR
HEK-293
3a[20]
3b
3c
3d
3e
3f
3g
3h
3i
16�2
6.7�1.2
11�2
46�3
31�1
8�2
26�3
11�1
31�3
46�3
31�2
>200
17.7�1.1
30�2
19�2
22�3
34�2
>200
>200
41�10
7.0�1.3
34�3
69�6
37�2
>200
20�2
44�3
31�4
37�3
21�2
>200
>200
43�7
44�10
24�3
170�15
38�3
>200
>200
8.4�0.9
3j
3k
3l
3m
3n[20]
[4]CF3SO3
cisplatin
13.4�0.8
180�1
>200
2.3�0.6
9.4�1.1
>200
>200
31�3
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peaks[36] (1H, 13C) or to external standard (19F, CFCl3). NMR spectra
were assigned with the assistance of 1H-13C (gs-HSQC and gs-HMBC)
correlation experiments.[37] NMR signals due to a second isomeric
form (where relevant) are italicized. Carbon, hydrogen and nitrogen
analyses were performed on a Vario MICRO cube instrument
(Elementar).
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Synthesis and Characterization of [2]CF3SO3
General procedure: The appropriate precursor [1]CF3SO3 (ca.
0.5 mmol) was dissolved into acetonitrile (10 mL), then Me3NO
(1.3 eq.) was added. The resulting mixture was stirred for 1 h, and
progressive darkening of the solution was observed. The conversion
of the starting material into the acetonitrile adduct [Fe2Cp2(CO)(μ-
CO)(NCMe){μ-CNMe(R)}]CF3SO3 (Scheme 1) was confirmed by IR
spectroscopy. The volatiles were removed under vacuum, and the
residue was dissolved in dichloromethane (ca. 20 mL). The solution
was treated with the appropriate alkyne (ca. 1.3 eq.), and the
mixture was stirred at room temperature for 48 h under a N2
atmosphere. The final mixture was charged on an alumina column.
Elution with CH2Cl2 and CH2Cl2/THF mixtures allowed unreacted
alkyne and impurities to be removed, then a fraction corresponding
to the desired product was collected using a CH3CN/MeOH mixture
(9:1 v/v) as eluent. Removal of the solvent under reduced pressure
afforded an air stable solid.
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From [1a]CF3SO3 and 3-ethynylpyridine. Brown-green solid, yield
90%. Anal. calcd. for C30H27F3Fe2N2O5S: C, 51.75; H, 3.91; N, 4.02.
Found: C, 51.61; H, 3.86; N, 4.13. IR (CH2Cl2): ῦ/cmÀ 1 =2004 vs (CO),
1
1820 s (μ-CO), 1632 m (C2C1N). H NMR (acetone-d6): δ/ppm=8.70,
8.11, 7.60–7.06 (m, 7 H, C5H4N+C6H3Me2); 5.72, 5.45, 5.39, 5.11 (s, 10
H, Cp); 4.44 (s, 3 H, NMe); 3.77 (s, 1 H, C2H); 2.35, 1.89 (s, 6 H,
C6H3Me2). E/Z ratio=ca. 4. 13C{1H} NMR (dmso-d6): δ/ppm=232.1
(C1); 210.0 (CO); 148.2-123.1 (C5H4N+C6H3Me2); 92.4, 88.3 (Cp); 54.2
(C2); 45.6 (NMe); 17.4, 16.6 (C6H3Me2).
[Fe2Cp2(CO)(μ-CO){μ-η1:η3-C3(Ph)C2HC1N(Me)(XylCl)}]CF3SO3, [2 g]
CF3SO3
[Fe2Cp2(CO)(μ-CO){μ-η1:η3-C3(tBu)C2HC1N(Me)(Xyl)}]CF3SO3,
[2b]
CF3SO3
From [1b]CF3SO3 and phenylacetylene. Greenish-brown solid, yield
75%. Anal. calcd. for C30H25ClF3Fe2NO5S: C, 50.34; H, 3.52; N, 1.96.
Found: C, 50.16; H, 3.61; N, 2.07. IR (CH2Cl2): ῦ/cmÀ 1 =2005 vs (CO),
1
1822 s (μ-CO), 1607 s (C2C1N). H NMR (acetone-d6): δ/ppm=7.60,
From [1a]CF3SO3 and 3,3-dimethyl-1-butyne. Brown-yellow solid,
yield 58%. Anal. calcd. for C29H32F3Fe2NO5S: C, 51.58; H, 4.78; N, 2.07.
Found: C, 51.37; H, 4.88; N, 1.98. IR (CH2Cl2): ῦ/cmÀ 1 =1999 vs (CO),
7.50, 7.37 (m, 8H, Ph+C6H3ClMe); 5.72, 5.45, 5.41 (s, 10 H, Cp); 4.77
(s, 1 H, C2H); 4.48 (s, 3 H, NMe); 2.45, 2.10, 1.98 (s, 3H, C6H3Me).
Isomer ratioffi1. 13C{1H} NMR (acetone-d6): δ/ppm=253.3, 252.5 (μ-
CO); 235.5, 234.3 (C1); 210.6, 210.3, 204.9, 208.2 (CO+C3); 156.2
(ipso-C6H3); 143.0, 135.5, 131.1-126.9 (C6H3); 92.8, 92.6, 88.6, 88.4
(Cp); 54.6, 54.3 (C2); 53.9, 45.6 (NMe); 18.0, 16.9 (C6H3Me).
1
1804 s (μ-CO), 1635 m (C2C1N). H NMR (acetone-d6): δ/ppm=7.25–
7.03 (m, 3 H, C6H3Me2); 5.75, 5.53 (s, 10 H, Cp); 4.40 (s, 3 H, NMe);
4.29 (s, 1 H, C2H); 2.33, 1.89 (s, 6 H, C6H3Me2); 1.76 (s, 9 H, CMe3). 13C
{1H} NMR (acetone-d6): δ/ppm=256.6 (μ-CO); 231.2 (C1); 225.4 (C3);
211.2 (CO); 145.4 (ipso-C6H3Me2); 131.7, 131.6, 129.5, 129.3
(C6H3Me2); 90.9, 87.2 (Cp); 49.4 (CMe3); 49.1 (C2); 45.2 (NMe); 34.5
(CMe3); 17.2, 16.6 (C6H3Me2).
[Fe2Cp2(CO)(μ-CO){μ-η1:η3-C3(3,5-C6H3(CF3)2)C2HC1NMe2}]CF3SO3,
[2i]CF3SO3
[Fe2Cp2(CO)(μ-CO){μ-η1:η3-C3(3-Py)C2HC1N(Me)(Xyl)}]CF3SO3, [2d]
CF3SO3
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From [1c]CF3SO3 and 1-ethynyl-3,5-bis(trifluoromethyl)benzene.
1
2
Brown solid, yield 65%. Anal. calcd. for C26H20F9Fe2NO5S: C, 42.13; H,
2.72; N, 1.89. Found: C, 42.25; H, 2.60; N, 1.94. IR (CH2Cl2): ῦ/cmÀ 1
=
1996 vs (CO), 1813 s (μ-CO), 1696 m-s (C2C1N). 1H NMR (dmso-d6): δ/
ppm=8.31, 8.14 (m, 3 H, arom); 5.40, 5.27 (s, 10 H, Cp); 4.71 (s, 1 H,
C2H); 3.86, 3.42 (s, 6 H, NMe2). 13C{1H} NMR (dmso-d6): δ/ppm=256.1
(μ-CO); 223.4 (C1); 209.9 (CO); 194.8 (C3); 158.4 (ipso-C6H3); 135.6–
120.7 (aromatics); 91.9, 88.4 (Cp); 54.0 (C2); 51.8, 44.8 (NMe2); CF3 not
observed. 19F{1H} NMR (dmso-d6): δ/ppm=À 60.8 (CF3); À 77.8
(CF3SO3). Crystallization from a CH2Cl2 solution layered with Et2O
3
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5
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7
8
°
and stored at À 30 C afforded red-brown crystals of 2i.
9
From [1c]CF3SO3 and 2-ethynylpyridine. Green-brown solid, yield
61%. Anal. calcd. for C23H21F3Fe2N2O5S: C, 45.57; H, 3.49; N, 4.62.
Found: C, 45.32; H, 3.45; N, 4.50. IR (CH2Cl2): ῦ/cmÀ 1 =1990vs (CO),
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[Fe2Cp2(CO)(μ-CO){μ-η1:η3-C3(tBu)C2HC1NMe2}]CF3SO3, [2j]CF3SO3
1
1808 s (μ-CO), 1684 m (C2C1N). H NMR (dmso-d6): δ/ppm=12.84 (s,
1 H, C3H); 8.76, 7.97, 7.79, 7.43 (m, 4 H, C5H4N); 5.60, 5.29, 5.19, 4.92
(s, 10 H, Cp); 4.71 (C2H); 3.83, 3.28 (s, 6 H, NMe2). Isomer ratio=ca. 5.
13C{1H} NMR (dmso-d6): δ/ppm=257.1 (μ-CO); 224.4 (C1); 210.6 (CO);
200.2, 171.7 (C3); 149.3, 137.3, 122.6, 122.4 (C5H4N); 91.4, 90.8, 88.4,
88.1 (Cp); 52.7 (C2); 51.4, 44.9 (NMe2).
Synthesis and Characterization of 3a–m
General procedure. The appropriate precursor [2]CF3SO3 (ca.
0.5 mmol) was dissolved in tetrahydrofuran (15–20 mL), then
pyrrolidine (ca. 10 eq.) was added. The mixture was stirred at room
temperature overnight, then it was passed through a short alumina
pad using neat acetonitrile as eluent. The filtrated solution was
dried under vacuum. The residue was dissolved in diethyl ether or
diethyl ether/dichloromethane mixture and charged on alumina
column. Elution with petroleum ether/diethyl ether mixtures
allowed any impurities to be removed, then the fraction corre-
sponding to the desired product was collected. Removal of the
solvent under reduced pressure afforded an air stable solid. Yields
are given with respect to C1.
From [1c]CF3SO3 and 3,3-dimethyl-1-butyne. Brown-green solid,
yield 90%. Anal. calcd. for C22H26F3Fe2NO5S: C, 45.15; H, 4.48; N, 2.39.
Found: C, 44.72; H, 4.73; N, 2.50. IR (CH2Cl2): ῦ/cmÀ 1 =1980 vs (CO),
1810 s (μ-CO), 1682 m (C2C1N). 1H NMR (dmso-d6): δ/ppm=5.53,
5.22, 5.03, 4.76 (s, 10 H, Cp); 4.88, 4.54 (s, 1 H, C2H); 3.92, 3.81, 3.16
(s, 6 H, NMe2); 1.76, 1.73 (s, 9 H, CMe3). trans/cis ratio=2.5.
Crystallization from a CH2Cl2 solution layered with Et2O and stored
°
at À 30 C afforded X-ray quality crystals of 2j.
[Fe2Cp2(CO)(μ-CO){μ-η1:η3-C3(3-Py)C2HC1NMe2}]CF3SO3, [2 l]CF3SO3
[FeCp(CO){C1N(Me)(Xyl)C2HC3(Ph)C(=O)}], 3a
From [1c]CF3SO3 and 3-ethynylpyridine. Dark green solid, yield
61%. Anal. calcd. for C23H21F3Fe2N2O5S: C, 45.57; H, 3.49; N, 4.62.
Found: C, 45.69; H, 3.55; N, 4.78. IR (CH2Cl2): ῦ/cmÀ 1 =1994 vs (CO),
1809 s (μ-CO), 1683 m (C2C1N). 1H NMR (dmso-d6): δ/ppm=9.00,
8.68, 8.22, 7.60 (m, 4 H, C5H4N); 5.39, 5.26 (s, 10 H, Cp); 4.61 (s, 1 H,
C2H); 3.86, 3.32 (s, 6 H, NMe2). 13C{1H} NMR (dmso-d6): δ/ppm=256.8
(μ-CO); 224.0 (C1); 210.2 (CO); 198.2 (C3); 148.0, 135.5, 125.2, 122.7,
119.5 (C5H4N); 91.9, 88.3 (Cp); 53.9 (C2); 51.8, 44.8 (NMe2).
From [2a]CF3SO3. Brown solid, yield 93%. Eluent for chromatog-
raphy: Et2O. Anal. calcd. for C25H23FeNO2: C, 70.60; H, 5.45; N, 3.29.
Found: C, 70.50; H, 5.48; N, 3.21. IR (CH2Cl2): ῦ/cmÀ 1 =1919 vs (CO),
1612 m (COacyl), 1571 m. IR (solid state): ῦ/cmÀ 1 =3082 w, 3029 w,
2925 w, 1907 vs, 1614 m (COacyl), 1571 w-m (C1N), 1471 m, 1383 m,
1352 w, 1299 w, 1084 s-br, 1015 s-br, 879 w, 798 vs, 774 vs, 719 w,
696 m, 656 w. 1H NMR (acetone-d6): δ/ppm=7.38–7.22 (m, 8 H,
C6H3Me2 +Ph); 6.96 (s, 1 H, C2H); 4.73 (s, 5 H, Cp); 3.96 (s, 3 H, NMe);
2.32, 2.17 (s, 6 H, C6H3Me2).[20] 13C{1H} NMR (acetone-d6): δ/ppm=
264.7, 264.6 (COacyl +C1); 221.9 (CO); 168.7 (C3); 147.5 (C2); 145.5
(ipso-C6H3); 132.9, 132.7, 132.4, 129.1, 129.0, 128.9, 128.8, 128.7,
127.9 (C6H3Me2 +Ph); 85.1 (Cp); 48.8 (NMe); 17.0, 16.6 (C6H3Me2).[20]
[Fe2Cp2(CO)(μ-CO){μ-η1:η3-C3(2-Py)C2HC1NMe2}]CF3SO3,
[2n–2]
CF3SO3
[FeCp(CO){C1N(Me)(Xyl)C2HC3(tBu)C(=O)}], 3b
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From [2d]CF3SO3. Brown solid, yield 65%. Eluent for chromatog-
raphy: CH2Cl2. Anal. calcd. for C24H22FeN2O2: C, 67.62; H, 5.20; N, 6.57.
Found: C, 67.51; H, 5.28; N, 6.49. IR (CH2Cl2): ῦ/cmÀ 1 =1922 vs (CO),
1607 m (COacyl), 1564w. IR (solid state): ῦ/cmÀ 1 =1914vs (CO),
1601 m (COacyl), 1561w, 1489 m, 1471 m, 1438 w, 1416 w, 1394 m,
1262 m, 1241 m, 1187 m, 1168 m, 1089 vs, 1139 m-s, 1053 s, 1025 s,
986 m, 920 w, 885 w-m, 840 w-m, 816 s, 804 s, 703 m-s, 682 m,
655 m. 1H NMR (dmso-d6): δ/ppm=8.42, 7.64, 7.29 (m, 7 H, C5H4N+
C6H3Me2); 6.89 (s, 1 H, C2H); 4.74 (s, 5 H, Cp); 3.86 (s, 3 H, NMe); 2.24,
2.10 (s, 6 H, C6H3Me2). 13C{1H} NMR (dmso-d6): δ/ppm=266.1 (COacyl);
262.9 (C1); 222.3 (CO); 165.5 (C3); 150.0, 149.2, 145.4, 136.5, 132.8,
132.4, 129.5, 129.4, 129.2, 128.5, 123.8 (C5H4N+C6H3Me2); 148.3 (C2);
85.7 (Cp); 49.7 (NMe); 17.7, 17.3 (C6H3Me2).
From [2b]CF3SO3. Brown solid, yield 40%. Eluent for chromatog-
raphy: Et2O/CH2Cl2 1:1 v/v (quick chromatography). Anal. calcd. for
C22H29FeNO2: C, 66.84; H, 7.39; N, 3.54. Found: C, 66.70; H, 7.46; N,
3.61. IR (CH2Cl2): ῦ/cmÀ 1 =1913 vs (CO), 1616 m (COacyl), 1598w. IR
(solid state): ῦ/cmÀ 1 =2907 w, 1915 m-sh, 1906 vs (CO), 1614 m
(COacyl), 1599 w-m, 1568w, 1477 m, 1429 w-m, 1381 m, 1359 w-m,
1243 w, 1143 w, 1087 m, 1068 m-s, 1014 m-s, 881 w, 854 m, 803 vs,
744w, 724 m, 709 m, 688 w, 658 w. 1H NMR (dmso-d6): δ/ppm=
7.29–7.24 (m, 3 H, C6H3Me2); 6.45 (s, 1 H, C2H); 4.60 (s, 5 H, Cp); 3.78
(s, 3 H, NMe); 2.18, 2.03 (s, 6 H, C6H3Me2); 0.92 (s, 9 H, CMe3). 13C{1H}
NMR (dmso-d6): δ/ppm=267.8 (COacyl); 264.4 (C1); 222.6 (CO); 183.6
(C3); 146.3 (C2); 145.4 (ipso-C6H3Me2); 132.6, 132.4, 129.3, 129.1
(C6H3Me2); 85.5 (Cp); 49.1 (NMe); 34.2 (CMe3); 29.1 (CMe3); 17.7, 17.2
(C6H3Me2). Crystals of 3b suitable for X-ray analysis were collected
from a diethyl ether solution layered with pentane, stored at
[FeCp(CO){C1N(Me)(Xyl)C2HC3(2-pyridine)C(=O)}], 3e
°
À 30 C.
[FeCp(CO){C1N(Me)(Xyl)C2HC3(2-naphthyl)C(=O)}], 3c
From [2e]CF3SO3. Red solid, yield 68%. Eluent for chromatography:
CH2Cl2. Anal. calcd. for C24H22FeN2O2: C, 67.62; H, 5.20; N, 6.57.
Found: C, 67.41; H, 5.23; N, 6.64. IR (CH2Cl2): ῦ/cmÀ 1 =1919 vs (CO),
1608 s (COacyl), 1561 m. IR (solid state): ῦ/cmÀ 1 =3075 w, 3029 w,
2944 w, 2924 w, 1916 vs (CO), 1605 m (COacyl), 1578w-m, 1558w-m,
1494 m, 1459 w-m, 1426 m, 1391 m, 1383 m, 1273 w, 1237 w,
1140 w, 1083 m, 1054 w, 1007 m, 986 w-m, 891w, 843w, 818w-m,
From [2c]CF3SO3. Brown solid, yield 55%. Eluent for chromatog-
raphy: Et2O/CH2Cl2 1:1 v/v. Anal. calcd. for C29H25FeNO2: C, 73.27; H,
5.30; N, 2.95. Found: C, 73.10; H, 5.41; N, 3.06. IR (CH2Cl2): ῦ/cmÀ 1
=
1
1920 vs (CO), 1610s (COacyl). IR (solid state): ῦ/cmÀ 1 =2922vw,
1908vs (CO), 1610 m (COacyl), 1558 w, 1486 m, 1434 w-m, 1388 w-m,
1353 w, 1238 w, 1164 w, 1135 w-m, 1079vs, 1018 s, 959 w, 846 w,
801 vs, 734 w, 712 w, 658 w. 1H NMR (dmso-d6): δ/ppm=7.88, 7.46–
7.39, 7.23, 7.02 (m, 10 H, C10H7 +C6H3Me2); 6.72 (s, 1 H, C2H); 4.80 (s,
5 H, Cp); 3.90 (s, 3 H, NMe); 2.27, 2.15 (s, 6 H, C6H3Me2). 13C{1H} NMR
(dmso-d6): δ/ppm=264.7, 263.2 (COacyl +C1); 222.5 (CO); 171.2 (C3);
150.5 (C2); 145.5 (ipso-C6H3Me2); 132.9, 132.8, 132.3, 131.2, 129.5,
129.4, 129.2, 128.7, 128.6, 126.5, 126.4, 126.3, 125.9, 125.5 (C10H7 +
C6H3Me2); 85.7 (Cp); 49.5 (NMe); 17.7, 17.3 (C6H3Me2).
809w-m, 789 s, 779 s, 741 m, 723 w, 697 w, 682 w, 654 w. H NMR
(dmso-d6): δ/ppm=8.44, 7.85, 7.74, 7.30 (m, 7 H, C5H4N+C6H3Me2);
7.38 (s, 1 H, C2H); 4.74 (s, 5 H, Cp); 3.83 (s, 3 H, NMe); 2.22, 2.08 (s, 6
H, C6H3Me2). 13C{1H} NMR (dmso-d6): δ/ppm=267.3 (COacyl); 262.8
(C1); 222.6 (CO); 167.0 (C3); 150.4, 150.1, 145.6, 136.5, 132.8, 132.4,
129.6, 129.5, 129.2, 125.8, 124.5 (C5H4N+C6H3Me2); 149.9 (C2), 85.8
(Cp); 49.7 (NMe); 17.7, 17.3 (C6H3Me2).
[FeCp(CO){C1N(Me)(Xyl)C2HC3(3-thiophene)C(=O)}], 3f
[FeCp(CO){C1N(Me)(Xyl)C2HC3(3-pyridine)C(=O)}], 3d
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From [2h]CF3SO3. Dark-red solid, yield 66%. Eluent for chromatog-
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raphy: CH2Cl2/THF 1:1 v/v. Anal. calcd. for C18H17FeNO2: C, 64.50; H,
5.11; N, 4.18. Found: C, 64.36; H, 5.23; N, 4.26. IR (CH2Cl2): ῦ/cmÀ 1
=
=
From [2f]CF3SO3. Brown solid, yield 70%. Eluent for chromatog-
raphy: CH2Cl2. Anal. calcd. for C23H21FeNO2S: C, 64.05; H, 4.91; N,
3.25. Found: C, 63.91; H, 4.98; N, 3.35. IR (CH2Cl2): ῦ/cmÀ 1 =1918 vs
(CO), 1615 m (COacyl), 1596 s. IR (solid state): ῦ/cmÀ 1 =3075w,
3030 vw, 2944 w, 1908 vs (CO), 1616 m-sh, 1594 m-s, 1483 m,
1471 m, 1441 w, 1418 w, 1387 m, 1380 m, 1364 w, 1352 w, 1284 w,
1263 w, 1238 w, 1140 w-m, 1085 w-m, 1074 w-m, 1050 w, 1003 m,
1915 vs (CO), 1602 m (COacyl), 1526 m. IR (solid state): ῦ/cmÀ 1
3104 vw, 2969 vw, 2941 vw, 1893 vs (CO), 1588 s (COacyl), 1524 m-s,
1488 w, 1442 w-m, 1409 m, 1398 m, 1356 w, 1320 w, 1299 w,
1260 w, 1238 w-m, 1177 w-m, 1150 w-m, 1114 w-m, 1088 w-m,
1073 w-m, 1030 m, 1006 m, 869 m, 845 w-m, 817 m, 773 s, 738 w,
1
716 m, 701 s, 648 w-m, 628 w-m, 592 m, 576 s. H NMR (dmso-d6):
δ/ppm=7.70 (s, 1 H, C2H); 7.56, 7.36 (m, 5 H, Ph); 4.57 (s, 5 H, Cp);
3.77, 3.57 (s, 6 H, NMe). 13C{1H} NMR (CDCl3): δ/ppm=270.0 (COacyl);
262.1 (C1); 221.9 (CO); 169.5 (C3); 146.3 (C2); 132.8 (ipso-Ph); 129.1,
128.2 (Ph); 85.2 (Cp); 51.7, 43.0 (NMe). Crystallization from a CH2Cl2
1
900 w, 885 w, 873 w, 845 w, 823 m, 799 s, 716 w-m, 696 m. H NMR
(dmso-d6): δ/ppm=8.04, 7.43, 7.34–7.25, 6.96 (m, 6 H, C4H3S+
C6H3Me2); 6.86 (s, 1 H, C2H); 4.70 (s, 5 H, Cp); 3.81 (s, 3 H, NMe); 2.22,
2.07 (s, 6 H; C6H3Me2). 13C{1H} NMR (dmso-d6): δ/ppm=267.3 (COacyl),
261.8 (C1); 222.6 (CO); 162.1 (C3); 150.0 (C2); 145.5 (ipso-C6H3Me2);
133.1, 132.9, 132.4, 129.5, 129.4, 129.1, 127.9, 126.7 (C4H3S+
C6H3Me2); 85.6 (Cp); 49.4 (NMe); 17.7, 17.3 (C6H3Me2). Crystals of 3f
suitable for X-ray analysis were collected from a dichloromethane
°
solution layered with pentane and stored at À 30 C afforded dark
red crystals of 3h.
[FeCp(CO){C1N(Me)2C2HC3(3,5-C6H3(CF3)2)C(=O)}], 3i
°
solution layered with pentane, stored at À 30 C.
[FeCp(CO){C1N(Me)(XylCl)C2HC3(Ph)C(=O)}], 3 g
From [2i]CF3SO3. Brown solid, yield 45%. Eluent for chromatog-
raphy: CH2Cl2 (quick chromatography). Anal. calcd. for
C20H15F6FeNO2: C, 50.98; H, 3.21; N, 2.97. Found: C, 51.15; H, 3.15; N,
2.94. IR (CH2Cl2): ῦ/cmÀ 1 =1921vs (CO), 1612 m (COacyl), 1530w. IR
(solid state): ῦ/cmÀ 1 =2930 w, 1908 s (CO), 1608 w-m (COacyl),
1594 w-sh, 1531 w-m, 1410 w, 1400 w, 1373 m-s, 1276 vs, 1247 w-
m, 1169 m-s, 1124 vs, 1025 s, 898 w-m, 873 w-m, 844 m, 810 m-s,
From [2g]CF3SO3. Brown solid, yield 75%. Eluent for chromatog-
raphy: CH2Cl2/Et2O 1:1 v/v. Anal. calcd. for C24H20ClFeNO2: C, 64.67;
H, 4.52; N, 3.14. Found: C, 64.50; H, 4.64; N, 3.06. IR (CH2Cl2): ῦ/
cmÀ 1 =1922vs (CO), 1615 m (COacyl), 1571w. IR (solid state): ῦ/
cmÀ 1 =3078 vw, 2964 w-m, 1912 m-s (CO), 1615 m (COacyl), 1570 w,
1477 w-m, 1382 w-m, 1302 w, 1260 s, 1243 w-m, 1186 w, 1161 w,
1079 s, 1015 vs, 989 s, 886 m, 865 m, 848 m, 796 vs, 779 vs, 714 m,
1
717 w-m, 700 m, 681 s. H NMR (dmso-d6): δ/ppm=8.33, 8.25 (m, 3
H, C6H3); 8.05 (s, 1 H, C2H); 4.58 (s, 5 H, Cp); 3.71, 3.67 (s, 6 H, NMe).
13C{1H} NMR (dmso-d6): δ/ppm=268.6 (COacyl); 256.6 (C1); 222.8 (CO);
2
163.2 (C3); 150.5 (C2); 135.3, 130.0, 125.2, 130.5, 122.3 (d, JCF
=
1
32 Hz) (aromatics); 125.8 (q, JCF =418 Hz, CF3); 85.5 (Cp); 52.2, 44.7
(NMe). 19F{1H} NMR (dmso-d6): δ/ppm=À 61.3.
1
700 m, 693 m-s, 667 m. H NMR (CDCl3): δ/ppm=7.45–7.26 (m, 8 H,
C6H3ClMe+Ph); 6.88, 6.85 (s, 1 H, C2H); 4.73, 4.72 (s, 5 H, Cp); 3.91,
3.90 (s, 3 H, NMe); 2.31, 2.21 (C6H3ClMe). Isomer ratio=1. 13C{1H}
NMR (CDCl3): δ/ppm=269.0, 268.6, 268.3, 267.9 (COacyl +C1); 221.0
(CO); 170.0, 169.8 (C3); 147.5, 147.4 (C2); 143.3, 143.0 (ipso-C6H3ClMe);
135.5, 135.0, 132.5, 130.1, 129.8, 129.7, 129.6, 129.2, 129.1, 128.5,
128.2, 128.1 (C6H3ClMe+Ph); 85.4, 85.3 (Cp); 48.9, 48.6 (NMe); 18.1,
17.9 (C6H3ClMe). Crystallization from a CH2Cl2 solution layered with
[FeCp(CO){C1N(Me)2C2HC3(tBu)C(=O)}], 3j
°
pentane and stored at À 30 C afforded dark-red crystals of 3g.
[FeCp(CO){C1N(Me)2C2HC3(Ph)C(=O)}], 3 h
From [2j]CF3SO3. Brown solid, yield 43%. Eluent for chromatog-
raphy: CH2Cl2. Anal. calcd. for C16H21FeNO2: C, 60.97; H, 6.72; N, 4.44.
Found: C, 60.81; H, 6.80; N, 4.30. IR (CH2Cl2): ῦ/cmÀ 1 =1909vs (CO),
1619 m (COacyl), 1528w. IR (solid state): ῦ/cmÀ 1 =2956 w, 2867 w,
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1890 vs (CO), 1601 s (COacyl), 1541 m-s, 1481 w, 1455 w, 1435 w,
1407 m, 1387 w, 1358 w-m, 1242 m, 1166 w, 1098 w, 1063 m-s,
1018 w-m, 874 w-m, 865 m, 846 m-s, 818 m, 806 m-s, 743 m-s,
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720 w-m, 704 m. H NMR (dmso-d6): δ/ppm=7.46 (s, 1 H, C2H); 4.42
(s, 5 H, Cp); 3.63, 3.50 (s, 6 H, NMe); 1.12 (s, 9 H, CMe3). 13C{1H} NMR
(dmso-d6): δ/ppm=270.2 (COacyl); 258.4 (C1); 223.2 (CO); 182.7 (C3);
146.2 (C2); 85.3 (Cp); 51.7, 43.6 (NMe); 34.4 (CMe3); 29.3 (CMe3).
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[FeCp(CO){C1N(Me)2C2HC3(2-naphthyl)C(=O)}], 3k
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From [2m]CF3SO3. Brown solid, yield 80%. Eluent for chromatog-
raphy: CH2Cl2/Et2O 1:1 v/v. Anal. calcd. for C24H21FeNO2: C, 70.09; H,
5.15; N, 3.41. Found: C, 70.31; H, 5.16; N, 3.50. IR (CH2Cl2): ῦ/cmÀ 1
=
1917vs (CO), 1605 m (COacyl), 1571w, 1509 m. IR (solid state): ῦ/
cmÀ 1 =3029 vw, 2929 vw, 1897 vs (CO), 1599 m (COacyl), 1569 w,
1507 m, 1496 m, 1453 w, 1443 w, 1398 w-m, 1351 w, 1242 w,
1201 w, 1130 w, 1090 w-m, 1032 w, 1005 m, 996 m, 970 w, 871 w,
842 w, 812 m, 773 m-s, 735 m, 720 m, 695 s. 1H NMR (CDCl3): δ/
ppm=7.79, 7.72 (s, 1 H, C2H); 7.62-7.17 (m, 10 H, Ph+CH2Ph); 5.65,
From [2k]CF3SO3. Brown solid, yield 48%. Eluent for chromatog-
raphy: Et2O (quick chromatography). Anal. calcd. for C22H19FeNO2: C,
68.59; H, 4.97; N, 3.64. Found: C, 68.50; H, 5.06; N, 3.48. IR (CH2Cl2):
ῦ/cmÀ 1 =1916vs (CO), 1608 m (COacyl), 1530w. IR (solid state): ῦ/
cmÀ 1 =2925 w, 2855 w, 1896 vs (CO), 1604 m (COacyl), 1531 m,
1505 m, 1447 m, 1407 m, 1394 m, 1358 w, 1331 w, 1178 w, 1152 m,
1082 s, 1051 s, 963 m-s, 917 w, 864 m-s, 843 m-s, 800 vs, 728 m-s,
2
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5.28 (d, JHH =14.2 Hz, CH2); 5.20, 5.06 (d, 2 H, JHH =15.8 Hz, CH2);
4.62, 4.57 (s, 5 H, Cp); 3.73, 3.38 (s, 3 H, NMe). Isomer ratio=ca. 1.2.
13C{1H} NMR (CDCl3): δ/ppm=269.9 (COacyl); 264.4, 264.0 (C1); 222.1,
221.8 (CO); 170.3, 169.9 (C3); 146.6 (C2); 134.7, 134.4, 132.8, 132.7
(ipso-Ph); 129.4, 129.3, 129.2, 128.4, 128.3, 128.2, 127.5, 126.4 (Ph+
CH2Ph); 85.4, 85.2 (Cp); 67.9, 59.1 (CH2); 49.9, 40.6 (NMe).
1
710 s, 666 m. H NMR (dmso-d6): δ/ppm=7.94, 7.53 (m, 7 H, C10H7);
7.21 (s, 1 H, C2H); 4.63 (s, 5 H, Cp); 3.74, 3.58 (s, 6 H, NMe). 13C{1H}
NMR (dmso-d6): δ/ppm=266.9 (COacyl); 257.0 (C1); 223.2 (CO); 171.0
(C3); 151.3 (ipso-C10H7); 150.5 (C2); 134.0, 133.4, 131.6, 128.4, 126.7,
126.3, 125.5 (C10H7); 85.5 (Cp); 52.0, 44.3 (NMe).
Synthesis and characterization of [FeCp(CO){C1NMe(Xyl)C2HC3(2-
methyl-pyridinium)C(=O)}]CF3SO3, [4]CF3SO3
[FeCp(CO){C1N(Me)2C2HC3(3-pyridine)C(=O)}], 3 l
A solution of 3d (80 mg, 0.188 mmol) in CH2Cl2 (10 mL) was treated
with methyl triflate (0.025 mL, 0.22 mmol). The resulting solution
was allowed to stir at room temperature for 1 hour, then it was
charged on a short alumina pad. Quick elution with MeCN/MeOH
mixture (9:1 v/v) gave a brown fraction. The title product was
obtained as a brown solid upon removal of the volatiles under
vacuum. Yield 89 mg, 80%. Anal. calcd. for C26H25F3FeN2O5S: C,
52.89; H, 4.27; N, 4.75. Found: C, 52.77; H, 4.36; N, 4.85. IR (CH2Cl2):
From [2l]CF3SO3. Brown solid, yield 55%. Eluent for chromatog-
raphy: THF/CH2Cl2 1:1 v/v (quick chromatography). Anal. calcd. for
C17H16FeN2O2: C, 60.74; H, 4.80; N, 8.33. Found: C, 60.54; H, 4.81; N,
8.25. IR (CH2Cl2): ῦ/cmÀ 1 =1918vs (CO), 1664 m-s, 1604 m (COacyl),
1528w-m. IR (solid state): ῦ/cmÀ 1 =2981 s, 2971 s, 1885 vs (CO),
1604 m (COacyl), 1578 w, 1560 w, 1531 m, 1470 w, 1405 w-m,
1394 w, 1237 w, 1151 w, 1085 w, 1049 w, 1026 w-m, 994 w-m,
ῦ/cmÀ 1 =1939vs (CO), 1610 m (COacyl). IR (solid state): ῦ/cmÀ 1
=
1
881 w, 810 m, 784 m, 712 m, 702 w-m. H NMR (dmso-d6): δ/ppm=
8.74, 8.54, 7.93, 7.41 (m, 4 H, C5H4N); 8.15 (s, 1 H, C2H); 4.56 (s, 5 H,
Cp); 3.70, 3.63 (s, 6 H, NMe). 13C{1H} NMR (dmso-d6): δ/ppm=268.6
(COacyl); 256.6 (C1); 222.9 (CO); 164.5 (C3); 149.7 (C2); 148.9, 136.8,
129.1, 125.4, 123.7 (C5H4N); 85.5 (Cp); 52.0, 44.3 (NMe).
3553 w, 3490 w, 3089 w, 3067 w, 2932 vw, 1918 s (CO), 1622 m
(COacyl), 1604 m, 1587 m, 1505 m-s, 1483 m, 1398 m, 1360 w, 1277 s,
1252 vs, 1226 s, 1154 vs, 1087 m, 1030 vs, 1010 s, 964 m, 893 w-m,
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813 m-s, 789 s, 768 s, 715 m. H NMR (CD2Cl2): δ/ppm=8.84, 8.29,
7.90, 7.52, 7.29 (m, 7 H, C5H4N+C6H3Me2); 7.07 (s, 1 H, C2H); 4.83 (s,
5 H, Cp); 4.10, 3.92 (s, 6 H, NMe); 2.29, 2.20 (s, 6 H, C6H3Me2). 13C{1H}
NMR (CD2Cl2): δ/ppm=264.2, 263.2 (COacyl +C1); 220.2 (CO); 161.4
(C3); 152.5 (C2); 146.8, 145.4, 145.0, 144.3, 132.0, 129.6, 129.3, 128.8,
126.9 (C5H4N+C6H3Me2); 85.6 (Cp); 50.2, 47.4 (NMe); 17.5, 17.3
(C6H3Me2). Crystals of [4]CF3SO3 suitable for X-ray analysis were
collected from a dichloromethane solution layered with hexane,
[FeCp(CO){C1N(Me)(CH2Ph)C2HC3(Ph)C(=O)}], 3 m
°
stored at À 30 C.
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X-Ray Crystallography
Electrochemistry
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Crystal data and collection details for [2i]CF3SO3, [2j]CF3SO3, 3b, 3f,
3g, 3h and [4]CF3SO3·CH2Cl2 are reported in Table 4. Data were
recorded on a Bruker APEX II diffractometer equipped with a
PHOTON100 detector using MoÀ Kα radiation. Data were corrected
for Lorentz polarization and absorption effects (empirical absorp-
tion correction SADABS).[38] The structures were solved by direct
methods and refined by full-matrix least-squares based on all data
using F2.[39] Hydrogen atoms were fixed at calculated positions and
refined by a riding model. All non-hydrogen atoms were refined
with anisotropic displacement parameters.
Cyclic voltammograms were measured in a N2 glovebox (MBRAUN
LABmaster) with levels of H2O and O2 below 0.1 ppm using a Gamry
Interface 1000b potentiostat controlled by Gamry Framework
software. Solvents were dried and distilled under Ar from the
appropriate drying agent (THF from Na/K and benzophenone,
MeCN from CaH2), stored over 3 Å molecular sieves and thoroughly
deoxygenated with Ar prior use. The samples were measured in
acetonitrile or tetrahydrofuran at a concentration of 1 mM of
complex and 0.1 M of Bu4NPF6 as conductive salt. A glassy carbon
electrode was used as working electrode, a platinum disk as
counter electrode and a silver wire as a pseudo-reference electrode.
Ferrocene (or decamethylferrocene) was added as an internal
standard and all spectra were referenced to the ferrocene/
ferrocenium redox couple (Fc/Fc+).
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Stability Studies
a) Stability in D2O/dmso-d6: Each compound (3b–m and [4]CF3SO3,
ca. 3 mg) was dissolved in dmso-d6/D2O (ca. 3:1 v/v). The
resulting solutions were analysed by 1H NMR and then
In Vitro Cytotoxicity Study
°
maintained at 37 C for 72 h. After cooling to room temperature,
the final solutions were analysed by H NMR: the resonances of
the starting compound were clearly recognized, with no
significant variations (total amount of other species <10%
respect to the starting compound).
Human ovarian carcinoma (A2780 and A2780cisR) cell lines were
obtained from the European Collection of Cell Cultures. The human
embryonic kidney (HEK-293) cell line was obtained from ATCC
(Sigma, Buchs, Switzerland). Penicillin streptomycin, RPMI 1640
GlutaMAX (where RPMI=Roswell Park Memorial Institute), and
DMEM GlutaMAX media (where DMEM=Dulbecco’s modified Eagle
medium) were obtained from Life Technologies, and fetal bovine
serum (FBS) was obtained from Sigma. The cells were cultured in
RPMI 1640 GlutaMAX (A2780 and A2780cisR) and DMEM GlutaMAX
(HEK-293) media containing 10% heat-inactivated FBS and 1%
1
b) Stability in cell culture medium: Each compound (3b–m and [4]
CF3SO3, ca. 6 mg) was dissolved in dmso (ca. 4 mL) in a glass
tube, then 2 mL of RPMI-1640 medium (Merck; modified with
sodium bicarbonate, without L-glutamine and phenol red,
liquid, sterile-filtered, suitable for cell culture) were added. The
°
resulting mixture was maintained at 37 C for 72 h, then allowed
°
penicillin streptomycin at 37 C and CO2 (5%). The A2780cisR cell
line was routinely treated with cisplatin (2 μM) in the media to
maintain cisplatin resistance. The cytotoxicity was determined using
to cool to room temperature and extracted with CH2Cl2 (5–
10 mL). Removal of the volatiles from the organic phase gave a
residue (3–4 mg) which was analysed by IR spectroscopy
(CH2Cl2 solution), the IR spectrum being superimposable with
that of the starting material.
the
3-(4,5-dimethyl
2-thiazolyl)-2,5-diphenyl-2H-tetrazolium
bromide (MTT) assay.40 Cells were seeded in flat-bottomed 96-well
plates as a suspension in a prepared medium (100 μL aliquots and
Table 4. Crystal data and measurement details for [2i]CF3SO3, [2j]CF3SO3·solv, 3b, 3f, 3g, 3h and [4]CF3SO3·CH2Cl2.
[2i]CF3SO3
[2j]CF3SO3·solv
3b
3f
3g
3h
[4]CF3SO3·CH2Cl2
Formula
FW
T, K
C26H20F9Fe2NO5S C22H26F3Fe2NO5S C23H27FeNO2
C23H21FeNO2S
431.32
293(2)
C24H20ClFeNO2
445.71
100(7)
C18H17FeNO2
335.17
100(7)
0.71073
Orthorhombic
Fdd2
26.648(3)
28.827(3)
7.8480(8)
90
C27H27FeCl2N2O2S
675.31
100(2)
741.19
295(2)
0.71073
Monoclinic
P21/c
12.8947(8)
12.1379(7)
18.0241(11)
90
585.20
100(2)
0.71073
Monoclinic
P21/n
7.8885(5)
10.0925(7)
32.409(2)
90
405.30
293(2)
0.71073
Monoclinic
P21/c
9.7227(10)
23.904(2)
10.1857(10)
90
λ, Å
0.71073
Monoclinic
C2/c
17.6422(7)
11.5607(5))
20.0757(8)
90
0.71073
Monoclinic
C2/c
18.6544(13)
11.4297(8)
19.6644(14)
90
0.71073
Crystal system
Space group
a, Å
b, Å
c, Å
Triclinic
�
P1
8.1984(8))
8.9595(8)
21.115(2)
80.077(3)
84.622(3)
66.656(3)
1402.1(2)
2
°
α,
°
β,
γ,
96.610(2)
90
2802.3(3)
95.162(2)
90
2569.8(3)
117.240(3)
90
2104.8(4)
96.7890(10)
90
4065.9(3)
99.767(2)
90
4132.0(5)
90
90
°
Cell Volume, Å3
Z
6028.8(11)
16
1.477
1.006
4
4
4
8
8
Dc, g·cmÀ 3
1.757
1.513
1.279
1.409
1.433
1.600
0.865
692
μ, mm-1
1.209
1.264
0.733
0.863
1792
0.879
1840
F(000)
Crystal size, mm
1488
1200
856
2784
0.22×0.19×0.14 0.21×0.16×0.13 0.25×0.21×0.14 0.16×0.14×0.11 0.24×0.21×0.14 0.18×0.16×0.12 0.22×0.18×0.14
°
θ limits,
1.590–27.101
38900
6182
[Rint =0.0403]
6182/318/453
2.114–26.994
33066
5608
[Rint =0.0521]
5608/0/312
1.704–25.998
25609
4119
[Rint =0.0981]
4119/162/278
2.043–24.998
24198
2.098–26.998
28059
2.081–26.997
16704
3265
[Rint =0.0768]
3265/67/202
1.959–27.997
20270
6718
[Rint =0.0378]
6718/0/374
Reflections collected
Independent reflec-
tions
3577
[Rint =0.0417]
3577/211/269
4498
[Rint =0.0332]
4498/4/270
Data/restraints/pa-
rameters
Goodness on fit on F2 1.047
1.294
1.144
1.103
0.0413
1.200
0.0444
1.185
0.0656
0.1226
0.986/À 1.043
1.144
0.0537
0.1021
0.804/À 0.686
R1 (I>2σ(I))
wR2 (all data)
0.0565
0.1487
0.0727
0.1442
0.0902
0.1804
0.0969
0.302/À 0.258
0.0923
0.451/À 0.464
Largest diff. peak and 1.129/À 0.533
0.990/À 0.831
0.804/À 0.351
hole, e ÅÀ 3
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approximately 4300 cells/well) and preincubated for 24 h. Stock
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positive (0À 100 μM) and negative (200 μM) controls respectively.
The compounds were added to the preincubated 96-well plates in
100 μL aliquots, and the plates were incubated for a further 72 h.
MTT (20 μL, 5 mg/mL in Dulbecco’s phosphate buffered saline) was
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The culture medium was aspirated and the purple formazan
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absorbance of wells corresponding to the untreated control cells.
The reported IC50 values are based on the means from two
independent experiments, each comprising four tests per concen-
tration level.
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Supporting Information Available
Views of X-ray structures (Figures S1-S2); NMR spectra (Figur-
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1944512 ([4]CF3SO3) contain the supplementary crystallographic
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Acknowledgements
We gratefully thank the University of Pisa for financial support
(PRA_2017_25, “composti di metalli di transizione come possibili
agenti antitumorali”) and the Swiss National Science Foundation
for financial support.
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Keywords: cytotoxicity · iron · metal-based drugs · piano stool
complexes · vinyliminium ligands
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Revised manuscript received: November 14, 2019
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FULL PAPERS
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Amine-promoted selective fragmen-
tation of readily available diiron vi-
nyliminium complexes can be
D. Rocco, Dr. L. K. Batchelor, Dr. E.
Ferretti, Prof. S. Zacchini*, Prof. G.
Pampaloni, Prof. P. J. Dyson, Prof. F.
Marchetti*
broadly applied to the synthesis of
piano-stool monoiron products
featuring a unique structural motif,
which is partially constructed by ex-
ploiting FeÀ Fe cooperativity. The
compounds display a variable cyto-
toxicity against cancer (A2780 and
A280cisR) and non-cancerous
1 – 14
Piano Stool Aminoalkylidene-Ferra-
cyclopentenone Complexes from Bi-
metallic Precursors: Synthesis and
Cytotoxicity Data
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(HEK293) cell lines, and a significant
selectivity has been observed with a
phenyl ring as vinyl substituent.