Organometallic SERMs (selective estrogen receptor modulators): Cobaltifens, the (cyclobutadiene)cobalt analogues of hydroxytamoxifen

Article abstract of DOI:10.1016/j.jorganchem.2009.11.003

The McMurry coupling of (tetraphenylcyclobutadiene)cobalt(cyclopentadienyl) ketones, (C₄Ph₄)Co[C₅H₄C({double bond, long}O)R], where R = Me, 3a, or Et, 3b, with a range of substituted benzophenones furnished a se

Full text of DOI:10.1016/j.jorganchem.2009.11.003

Journal of Organometallic Chemistry 695 (2010) 595–608
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Organometallic SERMs (selective estrogen receptor modulators): Cobaltifens,
the (cyclobutadiene)cobalt analogues of hydroxytamoxifen
Kirill Nikitin a, Yannick Ortin a, Helge Müller-Bunz a, Marie-Aude Plamont b, Gérard Jaouen b,
a,
Anne Vessières b, , Michael J. McGlinchey
*
*
a School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
b Laboratoire Charles Friedel, UMR CNRS 7223, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, F-75231 Paris Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The McMurry coupling of (tetraphenylcyclobutadiene)cobalt(cyclopentadienyl) ketones, (C4Ph4)Co-
[C5H4C(@O)R], where R = Me, 3a, or Et, 3b, with a range of substituted benzophenones furnished a series
of cobaltifens, organometallic analogues of tamoxifen whereby a phenyl ring has been replaced by an org-
Received 7 September 2009
Received in revised form 21 October 2009
Accepted 3 November 2009
Available online 10 November 2009
ano-cobalt sandwich moiety. These systems of the general formula (g
4-C4Ph4)Co[g5-C5H4C(R)@C(Ar)Ar0],
where R = Me or Et, and Ar = Ar0 = p-C6H4X where X is OH, 2a and 2b, OMe, 2c and 2d, OBn, 2e and 2f, or
O(CH2)2NMe2, 12a and 12b, and where Ar = C6H4OH and Ar0 = C6H4O(CH2)2NMe2, 2g and 2h, have been
characterised by NMR spectroscopy and/or X-ray crystallography. The effect of 2a and 2b, 2g and 2h,
and 12a and 12b on the growth of MCF-7 (hormone-dependent) and MDA-MB-231 (hormone-indepen-
dent breast cancer cells) was studied. The dihydroxycobaltifens 2a and 2b exhibit a strong estrogenic
effect on MCF-7 cells while the aminoalkyl-hydroxycobaltifens, 2g and 2h, were found to be only slightly
Keywords:
Bioorganometallic chemistry
Cobalt
Breast cancer
Tamoxifen
cytotoxic on MDA-MB-231 cells (IC50 = 27.5 and 17
ethoxy)cobaltifens, 12a and 12b were shown to be highly cytotoxic towards both cell lines (IC50 = 3.8 and
2.5 M).
lM); surprisingly, however, the bis-(dimethylamino-
SERM
l
Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction
tamoxifen-type systems containing such metals as titanium and
manganese [7], iron [8], rhenium [9], ruthenium [10], or platinum
[11] have been reported. At present, the most promising candi-
dates are the ferrocifens [8] in which a b-phenyl ring in tamoxifen
has been replaced by a ferrocenyl moiety (Chart 1). The antiprolif-
erative effect of the ferrocifens matches the efficacy of tamoxifen
on hormone-dependent breast cancer cells (MCF7), but they show
an additional strong cytotoxicity on hormone-independent (MDA-
MB-231) breast cancer cells.
Currently, the ferrocifens, 1, in particular the hydroxyferrocifen,
1b, are the most well-studied and potentially most biologically via-
ble metal-containing analogues of tamoxifen [6,12]. It has been
suggested that the strong antiproliferative effect of the hydroxyfer-
rocifens is based on their facile oxidation to the ferrocinium ion
[13], and the consequent generation of hydroxyl radicals which
are known to be very genotoxic. However, the mode of action of
the ferrocifens has yet to be fully elucidated.
In the continuing battle against breast cancer, tamoxifen
remains a vital component in the physician’s armoury. However,
approximately 40% of tumours are resistant to this drug, and mod-
ifications of the molecule that involve the incorporation of organo-
metallic substituents are attracting considerable attention. Of
course, metallo-drugs such as cis-platin and its successors are in
wide clinical use, but biologically-active systems in which the me-
tal is directly linked to a carbon atom – bio-organometallics – have
been intensively studied only in recent years [1]. Early work fo-
cussed on the synthesis of organometallic derivatives of estradiol
[2], alkynyl-estradiols [3] and related steroidal frameworks [4],
and was concerned primarily with the development of the metal-
carbonyl-immuno-assay technique that uses infrared spectroscopy
and electrochemical techniques rather than radiochemical meth-
ods [5].
However, since that time, the focus has moved more towards
the development of therapeutic agents, and the current status of
organometallic SERMs has been reviewed recently [6]. Thus,
We here describe the syntheses, structural characterisation and
preliminary biological activity of the first cobaltifens, 2, whereby
the b-phenyl ring in tamoxifen has been replaced by a (tetraphe-
nylcyclobutadiene)cobalt(cyclopentadienyl) group, an organo-co-
balt sandwich unit capable of ready multiple functionalisation
allowing exquisite tuning of its electronic character, redox proper-
ties and steric parameters [14].
* Corresponding authors. Tel.: +353
1 716 2880; fax: +353 1 716 1178
(M.J. McGlinchey).
E-mail address: michael.mcglinchey@ucd.ie (M.J. McGlinchey).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.11.003

596
K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
R1
R1
7
6
R
3
Me
7
6
3
1
2
2
1
4
4
R2
Co
Ph
Ph
Fe
R2
Ph
Ph
1
2
2a: R = H, R1 = R2 = OH
1a: R1 = H, R2 = O(CH2)3NMe2
1b: R1 = OH, R2 = O(CH2)3NMe2
1c: R1 = R2 = OH
2f: R = Me, R1 = R2 = OBn
2b: R = Me, R1 = R2 = OH
2c: R = H, R1 = R2 = OMe
2d: R = Me, R1 = R2 = OMe
2e: R =H, R1 = R2 = OBn
2g: R = H, R1 = OH, R2 =OCH2CH2NMe2
2h: R = Me, R1 = OH, R2 = OCH2CH2NMe2
2i: R = H, R1= R2 =H
2j: R = Me, R1 = R2 = H
Chart 1. Ferrocifens (1) and cobalt analogues (2).
such is not the case in (g g
4-cyclobutadiene)cobalt( 5-cyclopentadi-
2. Results and discussion
enyl) sandwich compounds where the four-membered ring is the
favoured site of attack. In very simplistic terms, the cobalt sand-
wich can be considered as [(C4H4)2ꢀ][Co3+][(C5H5)1ꢀ] such that
2.1. Synthetic aspects
both rings are 6
the greater negative charge. Moreover, even in (
C5H5), Friedel–Crafts acylation occurs primarily on the phenyls
[16].
p
aromatic, but the four-membered ring possesses
The syntheses of organometallic SERMs related to tamoxifen
have focussed on the replacement of a phenyl ring by an organo-
metallic moiety. The most straight forward routes to such mole-
cules involve the coupling of the organometallic fragment to the
diaryl component. At present, it appears that generation of the cen-
tral double bond is most efficiently accomplished by use of a
McMurry coupling, as in Scheme 1, rather than by a Horner–Wittig
or other synthetic procedure.
The initial problem was to generate the required organometallic
ketone, 3, for reaction with the appropriately substituted benzo-
phenone, ArC(@O)Ar0. In the ferrocifen series, Friedel–Crafts acyla-
tion of one of the rings in ferrocene is particularly facile since the
molecule is mirror-symmetric with respect to the iron and the
cyclopentadienyl moieties are rather electron-rich [15]. However,
g
4-C4Ph4)Co(g5
-
Consequently, it is necessary to functionalise the five-mem-
bered ring prior to attachment of the organo-cobalt fragment. Early
routes [17] to these cobalt sandwich compounds involved the reac-
tion, and subsequent coupling, of two alkynes with (C5H5)Co(CO)2,
but Richards and co-workers [18] have reported that higher yields
are achievable by use of chlorotris(triphenylphosphine)cobalt(I), as
depicted in Scheme 1. By using this latter approach, we have pre-
viously described the syntheses and X-ray crystallographic charac-
terisations of the organometallic ketones (C4Ph4)Co[C5H4C(@O)R],
where R = Me, 3a, or Et, 3b [19,20]. Moreover, McMurry coupling
of 3a with benzophenone furnished (C4Ph4)Co[C5H4C(Me)@CPh2]
along with several other coupling and rearrangement products
[20]. However, the challenge lay in successfully carrying out a
McMurry coupling when the benzophenone partner possessed
oxygen or nitrogen substituents that might compete with the ke-
tonic moiety for complexation with the low-valent titanium re-
agent, thus lowering the efficiency of the C@C coupling process.
As illustrated in Scheme 2, one can envisage a number of poten-
tially viable synthetic routes to 2. In principle, the target cobalti-
fens, 2g and 2h, might be prepared as E/Z mixtures in one step
from the ketones 3a and 3b, respectively. However, this would in-
volve the realisation of a McMurry coupling with 4-hydroxy-40-
dimethylaminoethoxybenzophenone, 4a. Alternatively, a synthetic
route via the 4-benzyloxy-40-dimethylaminoethoxycobaltifen, 2k,
requires the protection/deprotection of the phenolic hydroxyl.
Since it has been shown that the hydrogenolysis of O-benzylated
O
R
(Ph3P)3CoCl
O
1. Na
R
2. RCOOEt
Co(PPh3)2
Na
R
R
Ar
Ar
O
Ar2C=O
Zn/TiCl4
Ph
Ph
Co
Ph
Co
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
2
Scheme 1. Scheme 1. General route to the organocobalt ketone precursors (3), and
subsequent McMurry coupling.

K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
597
OBn
Alk
NMe2
Co
O
Ph
Ph
Ph
Ph
OBn
4b
2k
O
iii
NMe2
O
OH
OH
O
i
Alk
O
4a
Alk
Co
O
NMe2
O
NMe2
Co
Ph
Ph
Ph
i
Ph
Ph
Ph
Ph
Ph
OH
5a
2g,h
3a: Alk = Me
3b: Alk = Et
O
ii
OH
i
NMe2
OH
Cl
Alk
6
Co
OH
Ph
Ph
Ph
Ph
2a,b
Scheme 2. Potential routes to cobaltifens (2). Reagents/solvents: (i) Zn/TiCl4/THF; (ii) Na2CO3/acetone; (iii) H2, Pd/C, ethanol.
tamoxifens does not affect the double bond [21], this approach can
be used for the preparation of Z-isomers of tamoxifen and similar
OBn
systems. However, this route would still involve a McMurry cou-
Et
Et
4b
pling with
a dimethylaminoalkoxy-substituted benzophenone,
O
4b. To avoid this potential difficulty, the amine functionality could
be introduced at the final step leading to an E/Z mixture; we note
that this latter approach has been successful for the ferrocifens, 1a
and 1b [8]. In the present work we describe the preparation of the
bis(4-hydroxyphenyl)-, 2a and 2b, bis(4-methoxyphenyl-), 2c and
2d, and bis(4-benzyloxyphenyl)-substituted cobalt complexes, 2e
and 2f, and also the 2-dimethylaminoethoxycobaltifens, 2g and
2h. Moreover, we report the X-ray crystallographic characterisa-
tions of 2c, 2d, 2e, 2f, 2g, and 2h, as well as of the already known,
but not previously structurally studied, 1,1-bis(4-hydroxyphenyl)-
2-ferrocenylbutene, 1c.
TiCl4, Zn,THF
Ph
Ph
7a
8 (52%) OCH2CH2NMe2
Fe
Et
O
4b
Et
TiCl4, Zn,THF
Et
Fe
Fe
7b
The feasibility of McMurry coupling with aminoalkoxy-ketones
was initially studied. When a 2:1 mixture of propiophenone, 7a
and 4b was heated for four days in the presence of zinc and tita-
nium tetrachloride, the anticipated O-benzyltamoxifen, 8, was sep-
arated as an E/Z mixture in a reasonable yield of 52% (Scheme 3).
However, this encouraging result could not be extended to the
organometallic systems 1 and 2. Thus, when a 2:1 mixture of pro-
pionylferrocene, 7b, and the ketone 4b was subjected to the same
conditions, the anticipated 4-benzyloxyferrocifen was not isolated.
Instead a significant quantity of homo-coupled 2,3-diferrocenyl-2-
butene and a mixture of unidentified amine products, presumably
homocoupling products of 4b, were obtained. Likewise, reaction of
the organo-cobalt ketones 3a, 3b with 4b also led predominantly to
homo-coupled products, and no cross-coupling products, e.g. 2k,
were isolated.
Scheme 3. McMurry couplings with the amino-ketone (4b).
Nevertheless, before discarding this route, the direct one-step
approach to cobaltifens, 2, from the corresponding ketones, 3a or
3b was examined. It was found that treatment of the methyl ke-
tone 3a with an excess of the non-protected 4-hydroxy-40-dim-
ethylaminoalkoxybenzophenone, 4a, at 50 °C over four days
yielded cobaltifen 2g in just 9% yield. Unfortunately, the yield of
this reaction could not be further optimised; moreover, a similar
attempt to couple 4a with the less soluble ethyl ketone, 3b, failed
completely.
Having concluded that McMurry coupling involving aminoalk-
oxy-substituted benzophenones does not proceed satisfactorily

598
K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
R
R
R
R
R
[Co]
Alk
Alk
Zn,TiCl 4
Alk
O
+
3
[Co]
[Co]
R
R
R
10a: Alk = Me
10b: Alk = Et
2a (90%)
9a: R = OMe
9b: R = OBn
5a: R = OH
5b: R = OMe
5c: R = OBn
2b (26%) + 10b
2c (12%) + 9a
2d (13%) + 9a + 10 b
2e (40%) + 10a
2f (20%) + 10b
Co
Ph
[Co] =
Ph
Ph
Ph
Scheme 4. McMurry couplings of benzophenones (5) with organo-cobalt ketones (3).
NMe2
NMe2
OH
O
O
Alk
Alk
6
2a
or
2b
+
NMe2
K2CO3, acetone
Co
O
Co
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Z,E-2g
Z,E-2h
12a: Alk = Me
12b: Alk = Et
Scheme 5. Alkylation of dihydroxy derivatives (2a) or (2b), leading to mono- and di-amines (2g) or (2h), and (12a) or (12b).
for the cobalt sandwich complexes, 2, we focussed on the two-step
procedure involving dihydroxycobaltifens, 2a, 2b and their subse-
quent alkylation with 2-chloroethyl-N,N-dimethylamine, 6. Ini-
tially, the coupling of the organo-cobalt ketones 3a, 3b with 4,40-
dihydroxybenzophenone, 5a, its 4,40-dimethoxy analogue, 5b,
and 4,40-dibenzyloxybenzophenone, 5c, was studied (Scheme 4).
When a mixture of the methyl ketone, 3a, and 4,40-dimethoxy-
benzophenone, 5b, was heated at reflux overnight the cross-cou-
pling product 2c was obtained in 12% yield, while the homo-
coupled material tetra(anisyl)ethylene, 9a, was formed in 4% yield.
A reaction of the ethyl ketone 3b with 5b under the same condi-
tions led to the cross product 2d in 13% yield, but was accompanied
by a higher amount of the organic homo-coupled alkene 9a (15%),
and the dicobalt complex (C4Ph4)Co(C5H4)C(Et)@C(Et)(C5H4)-
Co(C4Ph4), 10b (10%) [20].
When a mixture of the methyl ketone, 3a, and the dibenzyloxy
ketone, 5c, was heated at 65 °C for one day with zinc and titanium
tetrachloride, the hetero-coupling product, 2e, was formed in 40%
yield (Scheme 4). However, the reaction also generated a consider-
able amount (15%) of the homo-coupled organic product tetra-(4-
benzyloxyphenyl)ethylene, 9b. Furthermore, the yield could not be
significantly improved by running the reaction for a longer period
of time; instead the formation of 9b becomes predominant.
It was further noted that attempted coupling of 5c with the
ethyl ketone, 3b, led mainly to the homo-coupled dicobalt product,
10b, presumably because of the decreased reactivity and solubility
of the ethyl ketone relative to the analogous methyl derivative, 3a.
Nevertheless, when the coupling of 3b with 5c was carried out at
50 °C over four days, a 20% yield of 2f was obtained; moreover, it
was possible to recover the 80% of unreacted starting material,
3b. Interestingly, McMurry couplings with 5c also yielded the
reduction product (C6H5CH2OC6H4)2CH2, 11, that was also charac-
terised by X-ray crystallography (see Fig. 8 below).
The dihydroxycobaltifen, 2a, was successfully prepared by care-
fully heating a mixture of the methyl ketone, 3a, and the unpro-
tected 4,40-dihydroxybenzophenone, 5a, at 50 °C in THF in the
presence of zinc and titanium chloride for four days. The desired
cross product, 2a, was isolated in high yield (90%). However, the at-
tempted coupling of the ethyl ketone, 3b, with 5a under the same
conditions led mainly to the formation of homo-coupled product,
10b. To increase the solubility of 3b, THF/dichloromethane
(1:1 v/v) was used as solvent and the mixture was heated at
50 °C in a sealed tube. In this case it was possible to obtain the co-
balt complex 2b in a modest yield (26%) and to recover most (73%)
of the remaining cobalt starting material, 3b.
The target hydroxycobaltifens 2f and 2g, that also bear an
O(CH2)2NMe2 group, were finally prepared by alkylation of one of
the two available hydroxyl groups of 2a or 2b with 2-chloro-
ethyl-N,N-dimethylamine, 6, (Scheme 5). Consequently both, 2f
and 2g, were obtained as 1:1 E/Z diastereomeric mixtures in mod-
erate yields, 30–39%, and up to 50% of the unreacted 2a or 2b could
be recovered. The remaining organo-cobalt species undergo double
alkylation leading to the diamines 12a or 12b. Thus, it has been
established that the cobaltifens, 2f and 2g, are readily preparable
via a reliable two-step protocol involving a McMurry coupling fol-
lowed by the alkylation of hydroxyl group.
2.2. X-ray crystal structures of organometallic SERMs
The structures of the cobalt sandwich complexes 2c, 2d, 2e, 2f,
2g, and 2h have all been determined by X-ray diffraction, and the
crystallographic collection data are listed in Tables 1 and 2. In

K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
599
Table 1
Crystallographic data for 1c, 2c, 2d and 2e.
1c
2c
2d
2e
Formula
C26H24O2Fe
424.30
100(2)
(C50H41O2Co)3ꢁ(C3H6O)2
2314.43
100(2)
C51H43O2CoꢁCH2Cl2
831.71
100(2)
C62H49O2Co
884.94
100(2)
Formula mass
Temperature (K)
Crystal system
Space group
a (Å)
Triclinic
Triclinic
Triclinic
Triclinic
ꢀ
ꢀ
ꢀ
ꢀ
P1 (#2)
P1 (#2)
P1(#2)
P1 (#2)
8.8583(8)
10.2256(10)
12.0578(11)
71.964(2)
71.182(2)
88.455(2)
970.80(16)
2
11.3339(11)
21.423(2)
24.868(2)
97.422(2)
97.733(2)
93.868(2)
5910.8(10)
2
10.1984(11)
11.3127(13)
18.320(2)
78.127(2)
82.695(2)
75.604(2)
1997.0(4)
2
10.3106(7)
16.2302(11)
16.3893(11)
60.586(1)
74.897(1)
79.745(1)
2302.5(3)
2
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
V (Å3)
Z
qcalc (g cmꢀ3
)
1.438
0.790
1.300
0.479
1.383
0.607
1.276
0.419
l
(mmꢀ1
)
F(0 0 0)
444
2432
868
928
Crystal size (mm)
h Range (°)
Index ranges
0.40 ꢂ 0.20 ꢂ 0.10
1.88–30.40
ꢀ12 6 h 6 12
ꢀ14 6 k 6 14
ꢀ16 6 l 6 16
10352
1.00 ꢂ 0.20 ꢂ 0.20
1.67–28.53
ꢀ15 6 h 6 15
ꢀ27 6 k 6 27
ꢀ32 6 l 6 33
101683
0.60 ꢂ 0.50 ꢂ 0.10
1.89–28.28
ꢀ13 6 h 6 13
ꢀ15 6 k 6 15
ꢀ24 6 l 6 24
20492
0.50 ꢂ 0.20 ꢂ 0.10
1.46–26.43
ꢀ12 6 h 6 12
ꢀ20 6 k 6 20
ꢀ20 6 l 6 20
40852
Reflections collected
Independent reflections (Rint
Maximum and minimum
transmission
)
5290, 0.0147
0.9252 and 0.7764
27660, 0.0253
0.9102 and 0.7848
9792, 0.0264
0.9418 and 0.7132
9413, 0.0341
0.9593 and 0.8809
Refinement method
full-matrix least squares on
F2
full-matrix least squares on
F2
full-matrix least squares on
F2
full-matrix least squares on
F2
Data/restraints/parameters
5290/0/358
1.091
27660/0/1517
1.033
9792/0/694
1.040
9413/0/782
1.060
Goodness-of-fit (GOF) on F2
Final R values [I > 2
r
(I)]: R1, wR2
0.0348, 0.0909
0.0391, 0.0937
0.824 and ꢀ0.262
0.0395, 0.1001
0.0478, 0.1052
0.618 and ꢀ0.420
0.0435, 0.1126
0.0530, 0.1183
0.645 and ꢀ0.478
0.0388, 0.0930
0.0463, 0.0972
0.610 and ꢀ0.214
R values (all data): R1, wR2
Largest diff. peak/hole (e Åꢀ3
)
Table 2
Crystallographic data for 2f, 2g, 2h and 11.
2f
2g
2h
11
Formula
C63H51O2Co
898.97
100(2)
C52H46NO2CoꢁC2H3N
816.88
100(2)
(C53H48NO2Co)2ꢁC3H6O
1637.79
100(2)
Monoclinic
P21/c (#14)
18.3577(18)
11.6278(12)
20.016(2)
90
93.247(3)
90
4265.8(7)
2
1.275
0.447
C27H24O2
380.46
100(2)
Monoclinic
Pn (#7)
5.6638(13)
39.604(9)
8.938(2)
90
97.882(5)
90
1985.9(8)
4
1.273
0.079
Formula mass
Temperature (K)
Crystal system
Space group
a (Å)
Triclinic
Triclinic
ꢀ
ꢀ
P1 (#2)
P1 (#2)
11.6305(9)
14.1404(11)
14.3467(11)
85.896(2)
86.497(2)
76.234(2)
2283.4(3)
2
11.4356(16)
13.1927(19)
15.491(2)
81.510(4)
75.332(4)
71.893(4)
2142.9(5)
2
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
V (Å3)
Z
q calc (g cmꢀ3
)
1.307
0.423
1.266
0.445
l
(mm–1
)
F(0 0 0)
944
860
1728
808
Crystal size (mm)
h Range (°)
Index ranges
0.20 ꢂ 0.20 ꢂ 0.05
1.80–26.00
ꢀ14 6 h 6 14
ꢀ17 6 k 6 17
ꢀ17 6 l 6 17
39461
0.20 ꢂ 0.20 ꢂ 0.05
1.36–23.36
ꢀ12 6 h 6 12
ꢀ14 6 k 6 14
ꢀ17 6 l 6 17
14357
0.20 ꢂ 0.10 ꢂ 0.02
2.03–22.06
ꢀ19 6 h 6 19
ꢀ12 6 k 6 12
ꢀ21 6 l 6 21
25269
0.70 ꢂ 0.40 ꢂ 0.01
0.51–24.14
ꢀ6 6 h 6 6
ꢀ45 6 k 6 45
ꢀ10 6 l 6 10
13370
Reflections collected
Independent reflections (Rint
Maximum and minimum
transmission
)
8979, 0.0388
0.9792 and 0.9136
6174, 0.0513
0.9781 and 0.8041
5251, 0.0545
0.9911 and 0.9032
3194, 0.0730
0.9992 and 0.6436
Refinement method
Full-matrix least squares on
F2
8979/0/799
Full-matrix least squares on
F2
6174/0/537
Full-matrix least squares on
F2
Full-matrix least squares on
F2
Data/restraints/parameters
5251/222/556a,b
1.013
3194/148/523a
1.108
Goodness-of-fit (GOF) on F2
1.044
0.985
Final R values [I > 2
r
(I)]: R1, wR2
0.0400, 0.0903
0.0500, 0.0946
0.712 and ꢀ0.224
0.0486, 0.1001
0.0754, 0.1097
0.491 and ꢀ0.339
0.0419, 0.0953
0.0613, 0.1029
0.613 and ꢀ0.273
0.0509, 0.1064
0.0602, 0.1095
0.204 and ꢀ0.245
R values (all data): R1, wR2
Largest diff. peak/hole (e Åꢀ3
)
a
DELU (rigid bonds) restraints were applied to all thermal displacement parameters.
The solvent acetone was restrained to be planar and symmetrical using CHIZ and SADI.
b

600
K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
Table 3
Bond length, bond angle and torsional angles for iron (1a–1c) and cobalt (2c–2j) sandwich complexes.
Parameter
1a (Z)
1b (E)
1c
2c
2d
2e
2f
2g (Z)
2h (Z)
2i
2j
13(Z)
C(3)–C(2)–C(1) (°)
C(4)–C(2)–C(1) (°)
C(6)–C(1)–C(2) (°)
C(7)–C(1)–C(2) (°)
115.3
129.0
122.0
125.0
87
94
108
0.8
118.7
126.5
124.2
121.5
58.6
75.5
79.8
18.5
2.8
122.4
120.9
122.0
124.6
61.0
61.3
77.1
32.9
11.9
121.7
122.6
124.3
123.1
83.0
59.6
83.4
34.0
6.4
120.4
124.3
124.5
123.1
85.0
66.7
72.5
6.5
17.1
122.1
121.6
124.4
120.5
45.9
69.3
87.8
45.7
4.9
120.6
123.7
125.1
122.0
79.5
77.6
73.5
15.8
11.5
121.3
124.9
124.9
120.5
55.0
57.5
82.8
11.5
9.2
120.4
124.4
125.2
120.6
83.9
89.7
64.9
13.4
3.6
122.4
122.0
121.9
124.4
66.1
45.4
82.6
26.4
1.3
120.4
124.8
124.7
123.0
66.9
66.4
86.2
7.6
123.4
121.4
124.8
121.5
52.5
77.2
84.7
–
Z-aryl twist anglea (°)
E-aryl twist anglea (°)
E/Z-aryl dihedral (°)
Cp-ring twist anglea (°)
Plane C(3)–C(2)–C(4) versus plane C(6)–C(1)–C(7) (°)
C(1)@C(2) (Å)
5.2
1.347
–
12.8
1.358
–
13.1
1.360
9.25
1.353
9.65
1.478
9.18
1.347
8.98
1.345
9.46
1.341
9.56
1.354
9.30
1.365
9.49
1.338
9.59
1.37
–
O(1)ꢁ ꢁ ꢁO(2) (Å)
a
Torsion angle relative to the plane of the central double bond.
Fig. 1. Molecular structure of (C5H5)Fe[(C5H4C(Et)@C(C6H4OH)2] (1c).
Fig. 2. Molecular structure of (C4Ph4)Co[C5H4C(Me)@C(C6H4OMe)2] (2c).
addition, we have previously reported [19,20] the structures of the
unsubstituted phenyl analogues, 2i and 2j, and selected distances,
angles and torsional parameters for all of these molecules are col-
lected in Table 3. In particular, these data may be compared with
the published structures [8c,22] of the ferrocifens, 1a and 1b, as
well as of the known complex 1,1-bis(dihydroxyphenyl)-2-ferro-
cenylbutene, 1c, whose structure had not previously been re-
ported. Structures of E- and Z- tamoxifens reveal that all three
phenyl rings are twisted 52°-55° out of the plane of the central
double bond [23,24]. In contrast, in the Z-ferrocifen, 1a, both the
phenyl and the alkylamino-substituted rings are almost perpendic-
ular to the central plane [22]; moreover, the angle C(4)–C(2)–C(1)
between the bulky sandwich moiety and the double bond has
opened up to 129°. In the E-hydroxyferrocifen, 1b, the phenolic
ring makes an angle of 59° with the double bond plane, whereas
the alkylamino-substituted ring adopts a dihedral angle of 76° [8c].
The structure of the ferrocenyl complex 1c appears as Fig. 1. The
geometric parameters are very similar to those of the previously
reported ferrocifens; the central double bond length is 1.36 Å,
and the Fe–C distances are 2.05–2.06 Å. As with the E-hydroxyfer-
rocifen, 1b, the carbon atoms linking the four substituents to the
central double bond are not coplanar; the twist angle between
the planes defined by C(3)–C(2)–C(4) and by C(6)–C(1)–C(7) is
13.2° (12.8° in 1b). The two phenolic rings in 1c make almost iden-
tical dihedral angles of 61.0° and 61.3° with the plane of the double
bond.
Fig. 3. Molecular structure of (C4Ph4)Co[C5H4C(Et)@C(C6H4OMe)2] (2d).
from 120° to 125°, and the considerable bulk of the tetraphenylcy-
clobutadiene-cobalt sandwich moiety apparently does not cause
major angle distortion. However, there are some noticeable differ-
ences between methyl (2c, 2e, 2g, and 2i) and ethyl (2d, 2f, 2h, and
2j) systems: in the former cases, the twist angle between the
planes – C(3)–C(2)–C(4) and C(6)–C(1)–C(7) – made by the substit-
uents at the termini of the double bond ranges up to 17°, whereas
in the ethyl complexes this dihedral angle is generally much closer
to co-planarity. In contrast, in the ethyl systems, especially those
The molecular structures of cobalt complexes 2c through 2h are
shown in Figs. 2–7, and the metrical parameters listed in Table 2
reveal a number of general features. Unlike the Z-ferrocifen, 1b,
the in-plane angles around the central double bond range only

K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
601
Fig. 4. Molecular structure of (C4Ph4)Co[C5H4C(Me)@C(C6H4OCH2Ph)2] (2e).
Fig. 7. Molecular structure of Z-(C4Ph4)Co[C5H4C(Et)@C(C6H4OH)(C6H4OCH2CH2-
NMe2)] (2h).
2.3. Hydrogen bonding within the crystal structures
In the crystalline state, molecules of 1,1-bis(4-hydroxyphenyl)-
2-ferrocenylbutene, 1c, are linked in a head-to-tail fashion via
hydrogen bonds (O–Hꢁ ꢁ ꢁO = 2.209 Å) between the hydroxyl sub-
stituents (Fig. 9), and there is no solvent incorporated in the unit
cell.
In contrast, the methyl-cobaltifen, 2g and the ethyl-cobaltifen,
2h, which were recrystallised from acetonitrile and acetone,
respectively, show very different packing motifs. In the ethyl com-
plex, 2h, hydrogen bonds are formed between the phenolic hydro-
xyl of one molecule and the dimethylamino nitrogen of its
neighbour such that the O–Hꢁ ꢁ ꢁN distance is 1.915 Å. This results
in the formation of large, centrosymmetric rhomboidal cavities that
are occupied by disordered acetone molecules (Fig. 10). In the
methyl-cobaltifen, 2g, the hydrogen bonds (O–Hꢁ ꢁ ꢁN = 1.902 Å)
form a much flatter assembly (Fig. 11), and the acetonitrile solvent
molecules are positioned outside the cavities. The central cores of
the hydrogen-bonded dimers of 2h and 2g are shown in Figs. 12a
and 12b, respectively.
Fig. 5. Molecular structure of (C4Ph4)Co[C5H4C(Et)@C(C6H4OCH2Ph)2] (2f).
2.4. Biological activity
Previous studies of the bioactivity of cobalt-containing organo-
metallics have focussed on (alkyne)dicobalt-hexacarbonyls which
have shown antiproliferative activity against LAMA-84 leukaemia
cells [25]. However, we are unaware of any prior reports on the
use of cobalt sandwich complexes in this context, and we here de-
scribe our results on the recognition of cobaltifens by the estrogen
receptor (ER
a) together with the study of their antiproliferative
behaviour against standard hormone-dependent (MCF-7) and hor-
mone-independent (MDA-MB-231) breast cancer cells.
Fig. 6. Molecular structure of Z-(C4Ph4)Co[C5H4C(Me)@C(C6H4OH)(C6H4OCH2CH2-
NMe2)] (2g).
2.4.1. Determination of the relative binding affinity (RBA) values of the
with bulky substituents such as benzyloxy or dimethylaminoeth-
oxy, the two aryl groups at C(1) are rotated out of the plane of
the double bond to a much greater extent (ꢃ83 7°) than is the
case for the methyl complexes (ꢃ57° 11°).
compounds for the alpha form of the estrogen receptor (ERa)
The RBA values obtained for the cobaltifens are reported in Ta-
ble 4. These affinities are quite low (below 1%) for all the com-
plexes and significantly lower than the values found for the
ferrocenyl derivatives (RBA around 10–15%) [8c,8d]. This may be
a consequence of the size of the organometallic (cyclobutadi-
ene)cobalt units which, with their four phenyl groups, are signifi-
cantly more bulky than the unsubstituted cyclopentadienyl ring
of ferrocene.
Both hydroxycobaltifens, 2g and 2h, were isolated in crystalline
form as their Z-isomers, but one can assume that the interconver-
sion of Z- and E-rotamers would be a facile process since any trace
of acid would generate a cobalt-stabilised cation [19], thus allow-
ing rotation about the C(1)–C(2) bond.

602
K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
Fig. 8. X-ray crystal structure of bis-(4-benzyloxyphenyl)methane (11).
Fig. 9. Intermolecular Oꢁ ꢁ ꢁH hydrogen bonding in (C5H5)Fe(C5H4)C(Et)C@C(C6H4OH)2 (1c).
Fig. 10. Intermolecular OHꢁ ꢁ ꢁN hydrogen bonding in ethyl hydroxycobaltifen (2h) showing disordered acetone solvent molecules encapsulated inside the cavities.
2.4.2. Cell proliferation
logues of tamoxifen and ferrocifen, are weakly cytotoxic towards
both cell lines. This effect seems to be connected to the cytotoxicity
rather than to an antiestrogenic effect of these molecules, as the
IC50 values found for the two complexes on MDA-MB-231 cells
The effect of the cobaltifens on the proliferation of cancer cells
has been tested on the hormone-dependent MCF-7 and on the hor-
mone-independent MDA-MB-231 breast cancer cells and the re-
sults are also given in Table 4. The rate of cell growth after
culturing for five days was compared to that of the control cells,
whereby nothing was added, and whose values were set at 100%.
These data appear to suggest that there is no significant differ-
ence between the activity of compounds containing methyl or
ethyl substituents adjacent to the double bond in the cobaltifens
2 and 12. The dihydroxycobaltifens, 2a and 2b, were found to be
estrogenic on MCF-7 cells and not, or only slightly, cytotoxic on
MDA-MB-231 cells. This result is in accord with that found for
the sandwich or half-sandwich diphenol complexes of ruthenium,
rhenium or manganese [26]. It also confirms that even compounds
with low RBA values can express a significant estrogenic effect
[27]. The aminoalkyl-hydroxycobaltifens, 2g and 2h, direct ana-
(27.5 and 17.5
lM, respectively) are in the same range than the va-
lue of 30 M found for hydroxytamoxifen [28]. Rather unexpect-
l
edly, it transpired that the bis-(diaminoethoxy)cobaltifens, 12a
and 12b, are highly cytotoxic on both cell lines, and low IC50 values
of 3.8 and 2.5 lM, respectively, were found for these two com-
plexes. In light of this observation, we sought literature precedents
and noted a very recent report by Nagahara [29] which described
the bioactivity of the corresponding organic system, 13a, which
possesses two alkylamino chains. Interestingly, it was reported
that this compound is highly cytotoxic against two leukaemia cell
lines, HL-60 and Jurkat, described as ER positive (HL-60) and ER
negative (Jurkat). It was suggested that the mechanism of action
of these bis(alkylamino) chain systems does not involve an interac-

K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
603
tion with the estrogen receptor but depends rather on mitochon-
drial perturbation, as has been invoked for some cationic gold sys-
tems [30].
O(CH ) N(CH )
2 n
3 2
13a : n=2
13b : n=3
O(CH ) N(CH )
2 n
3 2
Molecules 13a and 13b
Fig. 11. Intermolecular OHꢁ ꢁ ꢁN hydrogen bonding in the methyl hydroxycobaltifen
(2g) showing acetonitrile solvent molecules in the voids outside the cavities.
We have now extended this study by evaluating the cytotoxic-
ity of 13b against standard breast cancer cells, MCF-7 and MDA-
Fig. 12. (a) The central cavity in ethyl hydroxycobaltifen dimer (2h) with acetone inside the cavity. (b) The core of methyl hydroxycobaltifen (2g). In each case, the
(C4Ph4)Co(C5H4) moieties have been removed for clarity.
Table 4
Relative binding affinity for the estrogen receptor (ERa) and effect on the growth of breast cancer cells of compounds (2) and (12).
R
2
R
1
Co
Ph
Ph
Ph
Ph
R
3
R1
R2
R3
RBA for ERa (%)a
Effect of 10
MCF-7c
l
M of the compounds on the growth of cancer cells (%)b
MDA-MB-231d (IC50 M))e
(l
2a
2b
2g
2h
12a
12b
Me
Et
Me
Et
Me
Et
OH
OH
OH
OH
OH
OH
0.3 0.1
0.08
0.31 0.01
124
191
64
89
12
75
93
*
O(CH2)2NMe2
O(CH2)2NMe2
O(CH2)2NMe2
O(CH2)2NMe2
78 [27.5 1]
71 [17 5]
5 [3.8 0.4]
6 [2.5 0.4]
0.25
0
O(CH2)2NMe2
O(CH2)2NMe2
0.047 0.003
0.035 0.005
18
a
b
c
Mean of two experiments range, except when an asterisk (*) appears.
Control = cells without added compound, set at 100% after 5 days of culture.
Hormone-dependent breast cancer cells.
Hormone-independent breast cancer cells.
Mean of two experiments range.
d
e

604
K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
MB-231, and have confirmed the cytotoxic behaviour of this purely
organic molecule with an IC50 value of 0.34 0.05 M. It may be
cyclobutadiene)cobalt] (3b) [20], propionylferrocene (7b) [7], and
1,1-bis(4-dimethylaminoethoxyphenyl)-2-phenyl-1-butene (13b)
[32], were prepared as described elsewhere.
l
that the decreased bioactivity of the cobaltifen systems described
here (about a log factor from the parent organic compound) is
attributable to the presence of the bulky tetraphenylcyclobutadi-
ene moiety. However, we have recently described a convenient
route to tetramethyl- and tetraethylcyclobutadiene-cobalt com-
plexes [31] which, if used in future McMurry reactions, may lead
to cobaltifen systems with enhanced bioactivity.
4.3. Preparationof 1,1-bis-(4-methoxyphenyl)-2-[(
4-tetraphenylcyclobutadiene)cobalt]-1-butene (2d)
g
5-cyclopentadienyl)-
(g
To activated zinc (0.6 g, 9.2 mmol) in THF (30 mL) at 0 °C was
added TiCl4 (10 mL, 1 M solution in CH2Cl2), and the solution be-
came yellow after 10 min. Upon warming to room temperature
the mixture became green and, after being heated at reflux for
2.5 h, yielded a dark blue solution. The reaction mixture was al-
lowed to cool to room temperature whereupon 3b (1.2 g,
2.25 mmol) and 5b (1.75 g, 7.2 mmol) were added together and
the reaction was allowed to reflux overnight. After quenching with
saturated sodium carbonate (80 mL), the resulting solution was
transferred to a separation funnel and extracted with ether until
the organic layer was no longer yellow. The product was concen-
trated under reduced pressure, and diluted in the minimum
amount of ether. Chromatographic separation on alumina was car-
ried out initially with pentane, increasing to 30% ether in pentane
solution in 1% increments.
We are unaware of any previous studies on organometallic
sandwich compounds with two dialkylaminoalkoxy chains. A re-
port on the bioactivity of the corresponding ferrocenyl system pos-
sessing two side chains will be the subject of a future publication
[32], and we feel confident that these molecules will continue to
attract the attention of the bioorganometallic community.
3. Conclusions
Several synthetic approaches to the target novel cobaltifen
structures have been compared, and have revealed that the methyl
hydroxycobaltifen, 2g, is formed in low yield under McMurry
cross-coupling conditions directly from the organo-cobalt ketone
3
and 4-dimethylaminoethoxy-4-hydroxybenzophenone. How-
ever, the more practical synthetic approach, proceeds via a high
yield coupling of the ketones 3a and 3b and dihydroxybenzophe-
none, with subsequent alkylation of a phenolic hydroxyl by using
an appropriate halogenated alkylamine. This procedure also yields
the novel, and previously little studied, organometallic diamines,
12. The structures of the cobalt sandwich complexes 2c, 2d, 2e,
2f, 2g, and 2h, as well as the dihydroxyferrocifen, 1c, were charac-
terised by X-ray crystallography, and compared with the previ-
ously reported data on tamoxifens.
4.3.1. Fraction 1
1,1,2,2-tetra(methoxyphenyl)ethene, 9a, (0.25 g, 15%) was
eluted by using a mixture of ether/pentane (6/94) and was isolated
as a white solid. 1H NMR (500 MHz, CDCl3, 25 °C) d 6.92 (d, 8H,
J = 8 Hz), 6.63 (d, 8H, J = 8 Hz), 3.74 (s, OCH3); 13C NMR
(125 MHz, CDCl3, 25 °C): d 157.8, 136.9 (Cipso), 132.6, 113.1 (CH
aromatic), 128.8, 128.2 (C@C), 55.1 (OCH3).
4.3.2. Fraction 2
The effect of the (cyclobutadiene)cobalt compounds 2g and 2h,
and of 12a and 12b, on the growth of MCF-7 (hormone-dependent
breast cancer cells) and MDA-MB-231 (hormone-independent
breast cancer cells) has been studied. While the hydroxycobaltifens
2g and 2h are only slightly cytotoxic, their counterparts 12a and
12b, which possess two dimethylaminoethoxy sidechains, are
unexpectedly highly cytotoxic. This finding poses interesting ques-
tions as to the mechanism of antiproliferative activity in ferroci-
fens, cobaltifens and related families of SERMS, and further
investigation of these molecules is continuing.
In particular, a more extensive investigation of the scope and
bioactivity of cobaltifens with differing numbers of chains (and
lengths of chains), and also with a range of electronically disparate
substituents on the cyclobutadiene ring will be the subject of a fu-
ture report. These cobalt sandwich molecules will also be tested for
activity against prostate cancer cell lines, for which ferrocenyl-
substituted aryl-hydantoins have recently been shown to be anti-
proliferative [33].
2d (0.21 g, 13%) was eluted by using a mixture of ether/pentane
(6/94) and was isolated as an orange solid. 1H NMR (300 MHz,
CDCl3, 25 °C): d 7.44 (d, 8H, J = 7.5 Hz, C4Ph4), 7.20 (m, 12H,
C4Ph4), 6.95, 6.87, 6.78, 6.69 (each d, 8H, J = 8 Hz, C6H4OMe),
4.39, 4.37 (each d, 2 Hz, Cp), 3.79, 3.76 (each s, OCH3), 1.83 (q,
J = 7.5 Hz, CH2), 0.77 (t, J = 7.5 Hz, CH3); 13C NMR (75 MHz, CDCl3,
25 °C): d 156.9, 156.8 (Cipso, C–OMe), 137.8, 136.1 (Cpara, C6H4OMe),
136.6, 132.9 (C@C), 135.6 (Cipso, C4Ph4), 129.9, 129.2, 112.7, 112.4
(CH, C7H7O), 127.8, 126.9, 125.1 (CH, Ph4), 99.3 (Cp Cipso), 82.7,
81.5 (CH, Cp), 73.9 (C4Ph4), 54.1 (OCH3), 25.6 (CH2), 14.1 (CH3);
MS (ES) 746 (100%). Anal. Calc. for C51H43CoO2 (746.83): C, 82.02,
H 5.80. Found: C, 81.88; H, 5.86%. X-ray quality crystals were
grown from acetonitrile-dichloromethane.
4.3.3. Fraction 3
Trans-2,3-bis[(g g
5-cyclopentadienyl)( 4-tetraphenylcyclobut-
adiene)cobalt]-3-hexene (10b 0.24 g, 10%) was eluted using a mix-
ture of ether/pentane (9/91) and was isolated as a yellow solid. 1H
NMR (500 MHz, CDCl3, 25 °C): d 7.39–7.13 (m, 20H, C4Ph4), 4.47,
4.31 (each d, J = 2 Hz, Cp), 1.80 (q, J = 7 Hz, CH2), 0.87 (t, J = 7 Hz,
CH3); 13C NMR (100 MHz, CDCl3, 25 °C): d 136.9 (Cipso, Ph4), 134.3
(C@C), 129.1, 128.1 (CHortho–meta, Ph4), 126.2.
4. Experimental
4.1. General methods
4.4. Preparation of 1,1-bis-(4-methoxyphenyl)-2-[(g5
cyclopentadienyl)(
4-tetraphenylcyclobutadiene)cobalt]-propene (2c)
-
All reactions were carried out under an atmosphere of dry nitro-
gen. NMR spectra were acquired on Varian Inova spectrometers.
Assignments were based on standard 1H–1H and 1H–13C two-
dimensional techniques, and nOe measurements. Elemental analy-
ses are from the University College Dublin Microanalytical Service.
g
Compound 2c was prepared analogously and isolated as an or-
ange powder (0.22 g, 12%). X-ray quality crystals were grown from
acetone/cyclohexane. 1H NMR (500 MHz, CDCl3, 25 °C): d 7.45 (d,
8H, J = 8 Hz, CHortho, C4Ph4), 7.22 (m, 12H, C4Ph4), 6.95, 6.80, 6.78,
6.59 (each d, 2H, J = 8Hz, C6H4OMe), 4.44, 4.47 (each d, 2H,
J = 2 Hz, Cp), 3.85, 3.80 (each s, OCH3), 1.57 (s, CH3); 13C NMR
(125 MHz, CDCl3, 25 °C): d 163.2 (COMe), 137.5(Cpara, C6H4OMe),
4.2. Preparation of 3a, 3b, 7b and 13b
[(
g
5-Acetylcyclopentadienyl)(
g
4-tetraphenylcyclobutadiene)-
4-tetraphenyl-
cobalt] (3a) [19], [(
g
5-propionylcyclopentadienyl)(
g

K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
605
136.8, 129.1 (CHortho, C4Ph4), 128.5 (CHmeta, C4Ph4), 128.2 (Cmeta
,
4.9. Preparation of 1,1-bis(4-benzyloxyphenyl)-2-[(
g
5-cyclopentadienyl)
C6H4OMe), 127.3, 126.4 (C@C), 126.2 (CHpara
,
C4Ph4), 113.4
(g
4-tetraphenylcyclobutadiene)cobalt]-1-butene (2f)
(CHortho, C6H4OMe), 103.4, 83.4, 82.8 (CH, Cp), 75.2 (C4Ph4), 55.7
(OMe), 20.4 (CH3). Anal. calc. for C50H41CoO2ꢁ0.5C6H12) (774.89):
C, 82.15, H 6.11. Found: C, 82.54; H, 6.06%.
Compound 2f was prepared from 3b (0.107 g, 0.2 mmol) and 5c
(0.079 g, 0.2 mmol) in the presence of Zn (0.078 g, 1.2 mmol) and
TiCl4 (0.09 mL, 0.8 mmol). The reaction was run in THF (8 mL) at
50 °C over 4 days, and 2f was isolated (0.036 g, 20%) as a red solid,
m.p. 206 °C. 1H NMR (400 MHz, CDCl3, 25 °C): d 7.43 (d, 8H,
J = 7.7 Hz), 7.5–7.3 (8H, m), 7.25–7.15 (6H, m), 7.22 (8H, t,
J = 7.7 Hz), 6.95 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.78
(2H, d, J = 8.8 Hz), 6.73 (2H, d, J = 8.8 Hz), 5.03 (2H, s), 4.99 (2H,
s), 4.39 (2H, d, J = 2.0 Hz), 4.37 (2H, d, J = 2.0 Hz), 1.83 (2H, q,
J = 6.6 Hz), 0.78 (3H, t; J = 6.6 Hz); MS (ES) 899 (100%). Anal. Calc.
for C63H51CoO2 (899.03): C, 84.17; H, 5.72. Found: C, 84.04; H,
5.74. X-ray quality crystals were grown from acetone. Additionally,
unreacted 3b (85 mg, 80%) was recovered. When an analogous
reaction was run at 65 °C the yield of 2f was 6.5% while accompa-
nied by (C6H5OC6H4)2CH2, 11, 25%).
4.5. McMurry reactions
The following McMurry coupling reactions were carried out in
sealed vessels charged with freshly made zinc filings and dried sol-
vent. The vessel was cooled to ꢀ20 °C, titanium tetrachloride was
added, and the mixture was stirred at 60 °C under a nitrogen atmo-
sphere for 2 h. The appropriate ketone was dissolved in the re-
quired solvent and the solution was added to the reaction vessel
after which time the reaction mixture was sealed and stirred at
the required temperature. The reaction mixture was then diluted
with dichloromethane (200 mL), washed with 0.5 m HCl
(2 ꢂ 50 mL), sodium hydrocarbonate (20 mL) and dried over
Na2CO3. The organic phase was concentrated and the residue was
4.10. Preparation of 1,1-bis(4-hydroxyphenyl)-2-[(
4-tetraphenylcyclobutadiene)cobalt]propene (2a)
g
5-cyclopentadienyl)-
separated (silica 40–63 lm) using a Buchi Sepacor setup.
(g
4.6. Preparation of bis-1,1-(4-hydroxyphenyl)-2-ferrocenyl-1-butene
Compound2a wasprepared from3a(0.104 g, 0.2 mmol)and4,40-
(1c)
dihydroxybenzophenone 5a (0.107 g, 0.5 mmol) using Zn (0.2 g,
3 mmol) and TiCl4 (0.22 mL, 2 mmol). The reaction was run in THF
(8 mL) at 50 °C over 4 days, and 2a was isolated (0.13 g, 90%) as a
red solid, m.p. 246 °C. 1H NMR (400 MHz, CDCl3, 25 °C): dH 7.43 (d,
8H, J = 8.0 Hz), 7.15–7.25 (12H, m), 6.86 (2H, d, J = 8.8 Hz), 6.69
(4H, d, J = 8.8 Hz), 6.61 (2H, d, J = 8.8 Hz), 4.90 (1H, s), 4.86 (1H, s),
4.38 (2H, d, J = 2.0 Hz), 4.36 (2H, d, J = 2.0 Hz), 1.47 (3H, s); 13C
NMR (100 MHz, CDCl3, 25 °C): dC 153.9 (2Cipso, (PhOMe)2), 138.4,
127.2 (C@C), 137.3, 137.0 (Cpara, C(PhOBn)2), 136.5 (Cipso, C4Ph4),
Compound 1c was prepared from 7b (0.24 g, 1 mmol) and 4,40-
dihydroxybenzophenone 5a (0.214 g, 1 mmol) using Zn (0.39 g,
6 mmol) and TiCl4 (0.33 mL, 3 mmol). The reaction was run in
THF (25 mL) at 65 °C over 2 days yielding 1c (0.235 g, 56%) as a
red solid. The characteristics of the material were consistent with
the published data [7]. X-ray quality crystals were grown from
acetone.
4.7. Preparation of (Z,E)-1-[4-(benzyloxy)phenyl]-1-[4-(2-
dimethylaminoethoxy)phenyl)]-2-phenylbut-1-ene (8)
131.5, 131.1 (Cmeta, C(PhOBn)2), 128.8 (Cortho, C4Ph4), 127.9 (Cmeta
,
C4Ph4), 126.1 (Cpara, C4Ph4), 115.0, 114.6 (Cortho, C(PhOBn)2), 100.4
(Cq, Cp), 83.8, 82.3 (CH, Cp), 75.0 (C4Ph4), 20.3 (CH3); MS (ES) 704
(68%). Anal. Calc. for C48H37CoO2ꢁ0.5C6H12 (746.83): C, 82.02; H,
5.80. Found: C, 82.49; H, 5.59%.
Compound 8 was prepared from 7a (0.134 g, 1 mmol) and 4-
benzyloxy-40-(2-dimethylaminoethoxy)benzophenone, 4b, (0.188 g,
0.5 mmol) using Zn (0.33 g, 5 mmol) and TiCl4 (0.27 mL, 2.5 mmol).
The reaction was run in THF (10 mL) at 65 °C over 4 days yielding 8
(0.125 g, 52%) as a white solid. The characteristics of the material 8
were consistent with the published data [21].
4.11. Preparation of 1,1-bis(4-hydroxyphenyl)-2-[(
4-tetraphenylcyclobutadiene)cobalt]-1-butene (2b)
g
5-cyclopentadienyl)-
(g
Compound 2b was prepared from 3b (0.107 g, 0.2 mmol) and 5a
4.8. Preparation of 1,1-bis(4-benzyloxyphenyl)-2-[(g5
cyclopentadienyl)(
4-tetraphenylcyclobutadiene)cobalt]propene (2e)
-
(0.128 g, 0.6 mmol) using Zn (0.26 g, 4 mmol) and TiCl4 (0.22 mL,
2 mmol). The reaction was run in the mixture of THF (6 mL) and
dichloromethane (6 mL) at 50 °C over 4 days, and 2b was isolated
g
Compound2ewasprepared from3a (0.104 g, 0.2 mmol)and 4,40-
dibenzyloxy-benzophenone 5c (0.079 g, 0.2 mmol) in the presence
of Zn (0.078 g, 1.2 mmol) and TiCl4 (0.09 mL, 0.8 mmol). The reaction
was run in THF (8 mL) at 65 °C over 2 days, and 2e was isolated
(0.070 g, 40%) as a red solid, m.p. 184–186 °C. 1H NMR (400 MHz,
CDCl3, 25 °C): d 7.42 (d, 8H, J = 7.7 Hz), 7.5–7.3 (8H, m), 7.25–7.15
(6H, m), 7.21 (8H, t, J = 7.7 Hz), 6.92 (2H, d, J = 8.8 Hz), 6.84 (2H, d,
J = 8.8 Hz), 6.77 (2H, d, J = 8.8 Hz), 6.74 (2H, d, J = 8.8 Hz), 5.03 (2H,
s), 5.00 (2H, s), 4.38 (2H, d, J = 2.0 Hz), 4.35 (2H, d, J = 2.0 Hz), 1.49
(0.038 g, 26%) as
a
red solid, m.p. >260 °C (dec.). 1H NMR
(400 MHz, CDCl3, 25 °C): dH 7.44 (d, 8H, J = 8.0 Hz), 7.15–7.30 (12H,
m), 6.87 (2H, d, J = 8.8 Hz), 6.70 (4H, d, J = 8.8 Hz), 6.61 (2H, d,
J = 8.8 Hz), 4.40 (2H, d, J = 2.0 Hz), 4.36 (2H, d, J = 2.0 Hz), 1.82 (2H,
q, J = 7.5 Hz), 0.75 (3H, t, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3,
25 °C): dC 154.0 (2Cipso, (PhOMe)2), 138.7 (C@C), 137.9, 137.4 (Cpara
,
C(PhOBn)2), 136.7 (Cipso, C4Ph4), 131.3, 130.0 (Cmeta, C(PhOBn)2),
129.0 (Cortho, C4Ph4), 128.2 (Cmeta, C4Ph4), 126.4 (Cpara, C4Ph4),
115.4, 115.2 (Cortho, C(PhOBn)2), 100.4 (Cq, Cp), 83.9, 82.7 (CH, Cp),
75.1 (C4Ph4), 27.1 (@C–CH2), 15.3 (CH3); MS (ES) 718 (70%). Anal.
Calc. for C49H39CoO2 (718.78): C, 81.88; H, 5.47. Found: C, 81.97; H,
5.49%. Additionally, unreacted 3b (78 mg, 73%) was recovered.
(3H, s); 13C NMR (100 MHz, CDCl3, 25 °C): d 157.2, 157.2 (Cipso
PhOMe), 138.4, 127.2 (C@C), 137.4, 137.1 (Cpara, C(PhOBn)2), 137.1,
137.0 (Cipso, CH2Ph), 136.5 (Cipso, C4Ph4), 131.3, 131.0 (Cmeta
,
,
C(PhOBn)2), 128.8 (Cortho, C4Ph4), 128.6, 128.5 (Cortho, CH2Ph),
128.0 (Cpara, CH2Ph, Cmeta, C4Ph4), 126.1 (Cpara, C4Ph4), 114.5, 114.0
(Cortho, C(PhOBn)2), 100.4 (Cipso, Cp), 83.8, 82.3 (CH, Cp), 75.0
(C4Ph4), 69.9 (CH2), 20.4 (CH3). MS (ES) 885 (100%). Anal. Calc. for
C62H49CoO2 (885.00): C, 84.14; H, 5.58. Found: C, 83.88; H, 5.86%.
X-ray quality crystals were grown from acetone. Addition-
4.12. Preparation of Z,E-1-(4-hydroxyphenyl)-1-[4-(2-dimethylamino-
ethoxy)phenyl)]-2-[(g g
5-cyclopentadienyl)( 4-tetraphenylcyclobutadiene)-
cobalt]propene (2g)
ally trans-2,3-bis-[(
g
5-cyclopentadienyl)(
g
4-tetraphenylcyclobut-
4.12.1. Method A
adiene)cobalt]-2-butene, 10a, (15 mg, 15%) was isolated as a red
solid [20].
From 3a (0.107 g, 0.2 mmol) and 4-(2-dimethylaminoethoxy)-
40-hydroxybenzophenone 4a (0.114 g, 0.4 mmol) using Zn (0.26 g,

606
K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
4 mmol) and TiCl4 (0.22 mL, 2 mmol). The reaction was run in THF
(12 mL) at 50 °C over 4 days, and Z,E-2g was isolated (0.014 g, 9%)
as a red solid.
(Cmeta, C(PhOBn)2), 128.8 (Cortho, C4Ph4), 127.8 (Cmeta, C4Ph4),
126.0 (Cpara, C4Ph4), 115.1, 114.2 (Cortho, C(PhOBn)2), 100.3 (Cq,
Cp), 83.6, 82.4 (CH, Cp), 74.9 (C4Ph4), 65.3 (CH2O), 58.0 (CH2N),
45.4 (CH3N), 26.7 (@C–CH2), 15.0 (CH3); MS (ES) 790 (100%). Anal.
Calc. for C53H48CoNO2ꢁ0.5C3H6O (818.94): C, 79.93; H, 6.28, N 1.71.
Found: C, 79.90; H, 6.07%; N 1.70. X-ray quality crystals were
grown from acetone.
4.12.2. Method B
The diol 2a (0.07 g, 0.1 mmol) was dissolved in acetone (10 mL),
potassium carbonate (0.097 g, 0.7 mmol) was added, and the mix-
ture was stirred for 1 h after which time a solution of hydrochlo-
ride 6 (0.0173 g, 0.12 mmol) in acetone/water (1.2 mL, 9/1 v/v)
was added. The reaction mixture was stirred at 50 °C for 6 h, fil-
tered, concentrated and separated by chromatography using
dichloromethane, and then 5% methanol in dichloromethane.
The first fraction contained unreacted 2a (25 mg, 36%).
The second fraction contained Z,E-2g (30 mg, 50:50 ratio, 39%)
as a red solid, m.p. 168 °C. 1H NMR (300 MHz, CDCl3, 25 °C): dH
7.42 (m, 8H), 7.15–7.25 (12H, m), 6.84, 6.82, 6.69, 6.67, 6.66,
6.58, 6.57, 6.52 (8H, each d, J = 8.7 Hz), 4.35–4.40 (4H, m), 4.05,
4.00 (2H, each t, J = 5.2 Hz), 2.78, 2.84 (2H, each t, J = 5.2 Hz),
2.42, 2.41 (6H, each s), 1.47 (3H, s); 13C NMR (100 MHz, CDCl3,
25 °C, only one isomer given): dC 156.9, 154.6 (2Cipso, (PhOMe)2),
The third fraction contained 1,1-bis-[4-(2-dimethylaminoethoxy)-
phenyl)]-2-[(g g
5-cyclopentadienyl)( 4-tetraphenylcyclobutadiene)-
cobalt]-1-butene, 12b, (19 mg, 20%) as a red glassy solid. 1H NMR
(400 MHz, CDCl3, 25 °C): dH 7.43 (d, 8H, J = 7.6 Hz), 7.15–7.25
(12H, m), 6.92 (2H, d, J = 8.7 Hz), 6.79 (2H, d, J = 8.7 Hz), 6.77 (2H,
d, J = 8.7 Hz), 6.70 (2H, d, J = 8.7 Hz), 4.39 (2H, d, J = 1.8 Hz), 4.36
(2H, d, J = 1.8 Hz), 4.05 (2H, t, J = 6.0 Hz), 4.01 (2H, t, J = 6.0 Hz),
2.73 (2H, t, J = 6.0 Hz), 2.71 (2H, t, J = 6.0 Hz), 2.33 (6H, s), 2.34
(6H, s), 1.82 (2H, q, J = 7.6); 1.80 (2H, q, J = 7.6); 0.76 (3H, t,
J = 7.6); 13C NMR (100 MHz, CDCl3, 25 °C) dC 157.0, 156.8 (2Cipso
(PhOMe)2), 138.3 (C@C), 137.0, 136.5 (Cpara, C(PhOBn)2), 136.3 (Cipso
,
,
C4Ph4), 131.3, 130.8 (Cmeta, C(PhOBn)2), 128.8 (Cortho, C4Ph4), 127.9
(Cmeta, C4Ph4), 126.1 (Cpara, C4Ph4), 114.6, 113.9 (Cortho, C(PhOBn)2),
100.5 (Cq, Cp), 83.7, 82.3 (CH, Cp), 75.0 (C4Ph4), 65.5 (CH2O), 58.1
(CH2N), 45.4 (CH3N), 26.6 (@C–CH2), 15.1 (CH3); HRMS (ES) Anal.
Calc. for C57H58CoN2O2: 861.3830. Found: 861.3928 (M+H, 100%).
138.6, 127.0 (C@C), 137.1, 136.7 (Cpara, C(PhOBn)2), 136.5 (Cipso
C4Ph4), 131.4, 131.0 (Cmeta, C(PhOBn)2), 128.8 (Cortho, C4Ph4),
127.9 (Cmeta, C4Ph4), 126.0 (Cpara, C4Ph4), 115.3, 114.0 (Cortho
,
,
C(PhOBn)2), 100.6 (Cq, Cp), 83.7, 82.3 (CH, Cp), 75.0 (C4Ph4), 65.0
(CH2O), 58.0 (CH2N), 45.3 (CH3N), 20.3 (CH3); MS (ES) 775
(100%). Anal. Calc. for C52H46CoNO2 (775.88): C, 80.50; H, 5.98, N
1.81. Found: C, 80.42; H, 6.02%; N 1.83. X-ray quality crystals of
Z-2g were grown from acetonitrile.
4.14. Biochemical experiments
4.14.1. Materials
Stock solutions (1 ꢂ 10ꢀ3 M) and serial dilutions of the cobalti-
fens to be tested were prepared in DMSO just prior to use. Dul-
becco’s modified eagle medium (DMEM) was purchased from
Gibco BRL, foetal calf serum from Dutscher, Brumath, France, glu-
tamine, E2 and protamine sulphate were from Sigma. MCF-7 and
MDA-MB-231 cells were from the Human Tumor Cell Bank. Sheep
uteri weighing approximately 7 g were obtained from the slaugh-
terhouse at Mantes-la-Jolie, France. They were immediately frozen
and kept in liquid nitrogen prior to use.
The third fraction contained 1,1-bis-[4-(2-dimethylaminoeth-
oxy)phenyl)]-2-[g g
5-cyclopentadienyl)( 4-tetraphenylcyclobutadi-
ene)cobalt]propene, 12a (20 mg, 24%) as a red glassy solid: 1H NMR
(300 MHz, CDCl3, 25 °C): dH 7.42 (d, 8H, J = 7.6 Hz), 7.15–7.25 (12H,
m), 6.90 (2H, d, J = 8.7 Hz), 6.78 (2H, d, J = 8.7 Hz), 6.72 (2H, d,
J = 8.7 Hz), 6.69 (2H, d, J = 8.7 Hz), 4.37 (2H, d, J = 1.8 Hz), 4.34
(2H, d, J = 1.8 Hz), 4.05 (2H, t, J = 6.0 Hz), 4.01 (2H, t, J = 6.0 Hz),
2.73 (2H, t, J = 6.0 Hz), 2.71 (2H, t, J = 6.0 Hz), 2.338 (6H, s), 2.343
(6H, s), 1.47 (3H, s); 13C NMR (100 MHz, CDCl3, 25 °C): dC 157.0,
156.9 (2Cipso, (PhOMe)2), 138.4, 127.2 (C@C), 137.0, 136.4 (Cpara
,
C(PhOBn)2), 136.4 (Cipso, C4Ph4), 131.3, 130.9 (Cmeta, C(PhOBn)2),
128.8 (Cortho, C4Ph4),127.9 (Cmeta, C4Ph4), 126.0 (Cpara, C4Ph4),
114.1, 113.7 (Cortho, C(PhOBn)2), 100.4 (Cq, Cp), 83.7, 82.3 (CH,
Cp), 74.9 (C4Ph4), 65.4 (CH2O), 58.0 (CH2N), 45.5 (CH3N), 20.2
(CH3); HRMS (ES) Anal. Calc. for C56H56CoN2O2: 847.3674. Found:
847.3698 (M+H, 100%).
4.14.2. Determination of the Relative Binding Affinity (RBA) of the
compounds for ER
RBA values were measured on ER from lamb uterine cytosol
prepared in buffer A (0.05 M Tris–Hcl, 0.25 M sucrose, 0.1% b-
mercaptoethanol, pH 7.4 at 25 °C) as described previously [34]. Ali-
quots (200 lL) of cytosol were incubated for 3 h at 0 °C with
[6,7-3H]-E2 (2 ꢂ 10ꢀ9 M, specific activity 1.62 TBq/mmol, NEN Life
Science, Boston MA) in the presence of nine concentrations of the
complexes to be tested (between 6 ꢂ 10ꢀ6 M and 6 ꢂ 10ꢀ8 M), or
of 17b-E2 (between 8 ꢂ 10ꢀ8 M and 7.5 ꢂ 10ꢀ10 M). At the end of
the incubation period, the fractions of [3H]-E2 bound to the estro-
gen receptors (Y values) were precipitated by addition of a
200 mL of a cold solution of protamine sulphate (1 mg/mL in
water). After a 10 min period of incubation at 4 °C, the precipitates
were recovered by filtration on 25 mm circle glass microfibre fil-
ters GF/C filters using a Millipore 12 well filtration ramp. The filters
were rinsed twice with cold phosphate buffer and then transferred
in 20 mL plastic vials. After addition of 5 mL of scintillation liquid
(BCS Amersham) the radioactivity of each fraction was counted
in a Packard tri-carb 2100TR liquid scintillation analyser. The con-
centration of unlabeled steroid required to displace 50% of the
bound [3H]-E2 was calculated for 17b-E2 and for each complex by
plotting the logit values of Y [logit Y = ln(Y/100 ꢀ Y)] versus the
mass of the competing complex. The RBA (relative binding affinity)
was calculated as follows: RBA of a compound = concentration of
E2 required to displace 50% of [3H]-E2 ꢂ 100/concentration of the
compound required to displace 50% of [3H]-E2. The RBA value of
E2 is by definition equal to 100%.
4.13. Preparation of Z,E-1-(4-hydroxyphenyl)-1-[4-(2-dimethylamino-
ethoxy)phenyl)]-2-[(
cobalt]-1-butene (2h)
g g
5-cyclopentadienyl)-( 4-tetraphenylcyclobutadiene)-
The diol 2b (0.072 g, 0.1 mmol) was dissolved in acetone
(10 mL), potassium carbonate (0.097 g, 0.7 mmol) was added, and
the mixture was stirred for 1 h after which time a solution of 6
(0.0145 g, 0.1 mmol) in acetone/water (1 mL, 9/1 v/v) was added.
The reaction mixture was stirred at 50 °C for 6 h, filtered, concen-
trated and separated by chromatography using dichloromethane,
then 5% methanol in dichloromethane.
The first fraction contained unreacted 2b (36 mg, 50%).
The second fraction contained Z,E-2h (23 mg, 50:50 ratio, 30%)
as a red solid, m.p. 226 °C. 1H NMR (400 MHz, CDCl3, 25 °C): dH
7.43 (d, 8H), 7.15–7.25 (12H, m), 6.87, 6.85, 6.73, 6.71, 6.68, 6.63,
6.59, 6.55 (4H, each d, J = 8.7 Hz), 4.35–4.44 (4H, m), 4.05, 4.00
(2H, each t, J = 5.2 Hz), 2.84, 2.80 (2H, each t, J = 5.2 Hz), 2.43,
2.40 (6H, each s), 1.81 (2H, q, J = 7.6), 0.75, 0.74 (3H, each t,
J = 7.6 Hz); 13C NMR (100 MHz, CDCl3, 25 °C, only one isomer gi-
ven): dC 156.8, 154.7 (2Cipso, (PhOMe)2), 138.6, 133.7 (C@C),
137.9, 136.8 (Cpara, C(PhOBn)2), 136.5 (Cipso, C4Ph4), 130.9, 130.3

K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
(c) N. Metzler-Nolte, Angew. Chem., Int. Ed. 40 (2001) 1040–1043;
607
4.14.3. Culture conditions
(d) K. Severin, R. Bergs, W. Beck, Angew. Chem., Int. Ed. 37 (1998) 1634–
1654;
Cells were maintained in monolayer culture in DMEM with phe-
nol red/Glutamax I, supplemented with 9% of decomplemented
foetal calf serum and 0.9% kanamycine, at 37 °C in a 5% CO2 air
humidified incubator. For proliferation assays, cells were plated
in 24-well sterile plates at a density of 1.1 ꢂ 104 cells for PC-3 or
MDA-MB-231 and of 3 ꢂ 104 cells for MCF-7 in 1 mL of DMEM
without phenol red, supplemented with 9% of foetal calf serum
desteroided on dextran charcoal, 0.9% Glutamax I and 0.9% kanam-
ycine, and were incubated for 24 h. The following day (D0), 1 mL of
the same medium containing the compounds to be tested diluted
in DMSO, was added to the plates (final volumes of DMSO: 0.1%;
4 wells for each conditions). After three days (D3), the incubation
medium was removed and 2 mL of fresh medium containing the
compounds was added. At different days (D3, D4, D5 and D6),
the protein content of each well was quantified by methylene blue
staining as follows. Cell monolayers were fixed and stained for 1 h
in methanol with methylene blue (2.5 mg/mL), and then washed
thoroughly with water. Two millilitres of HCl (0.1 M) was then
added, and the plate was incubated for 1 h at 37 °C. Then the absor-
bance of each well was measured at 655 nm with a Biorad spectro-
photometer (microplate reader). The results are expressed as the
percentage of proteins versus the control. Experiments were per-
formed at least in duplicate.
(e) C.G. Hartinger, P.J. Dyson, Chem. Soc. Rev. 38 (2009) 391–401.
[2] (a) S. Top, G. Jaouen, A. Vessières, J.-P. Abjean, D. Davoust, C.A. Rodger, B.G.
Sayer, M.J. McGlinchey, Organometallics 4 (1985) 2143–2150;
(b) H. El Amouri, A. Vessières, D. Vichard, S. Top, M. Gruselle, G. Jaouen, J. Med.
Chem. 35 (1992) 3130–3135;
(c) D. Osella, G. Dutto, G. Jaouen, A. Vessières, P.R. Raithby, L. De Benedetto,
M.J. McGlinchey, Organometallics 12 (1993) 4545–4552;
(d) D. Osella, G. Dutto, C. Nervi, M.J. McGlinchey, A. Vessières, G. Jaouen, J.
Organomet. Chem. 533 (1997) 97–102.
[3] (a) M. Savignac, G. Jaouen, C.A. Rodger, R.E. Perrier, B.G. Sayer, M.J.
McGlinchey, J. Org. Chem. 51 (1986) 2328–2332;
(b) A. Vessières, G. Jaouen, M. Gruselle, J.L. Rossignol, M. Savignac, S. Top, S.
Greenfield, J. Steroid Biochem. 30 (1988) 301–306;
(c) A. Vessières, S. Top, C. Vaillant, D. Osella, J.P. Mornon, G. Jaouen, Angew.
Chem., Int. Ed. Engl. 31 (1992) 753–755;
(d) S. Tondu, G. Jaouen, M.F. D’Agostino, K.L. Malisza, M.J. McGlinchey, Can. J.
Chem. 70 (1992) 1743–1749;
(e) S. Top, M. Gunn, G. Jaouen, J. Vaissermann, J.-C. Daran, M.J. McGlinchey,
Organometallics 11 (1992) 1201–1209;
(f) S. Top, H. El Hafa, A. Vessières, J. Quivy, J. Vaissermann, D.W. Hughes, M.J.
McGlinchey, J.-P. Mornon, E. Thoreau, G. Jaouen, J. Am. Chem. Soc. 117 (1995)
8372–8380;
(g) D. Osella, C. Nervi, F. Gaelotti, A. Vessières, G. Jaouen, Helv. Chim. Acta 84
(2001) 3289–3298;
(h) S. Top, H. El Hafa, A. Vessières, M. Huché, J. Vaissermann, G. Jaouen, Chem.
Eur. J. 8 (2002) 5241–5249;
(i) A. Vessières, D. Spera, S. Top, B. Misterkiewicz, J.M. Heldt, E.A. Hillard, M.
Huché, M.A. Plamont, E. Napolitano, R. Fiaschi, G. Jaouen, Chem Med Chem 1
(2006) 1275–1281.
[4] (a) R.M. Moriarty, Y.-Y. Ku, U.S. Gill, R. Gilardi, R.E. Perrier, M.J. McGlinchey,
Organometallics 8 (1989) 960–967;
4.15. Crystallographic data for 1c, 2c, 2d, 2e, 2f, 2g, 2h, and 11
(b) G. Jaouen, S. Top, A. Vessières, B.G. Sayer, C.S. Frampton, M.J. McGlinchey,
Organometallics 11 (1992) 4061–4068.
Data were collected using a Bruker SMART APEX CCD area
detector diffractometer. A full sphere of the reciprocal space was
scanned by phi-omega scans. A semi-empirical absorption correc-
tion, based on redundant reflections, was performed by the pro-
gram SADABS [35]. The structure was solved by direct methods and
refined by full-matrix least-squares on F2 for all data using the pro-
gram library SHELXTL [36,37]. Hydrogen atoms in 1c, 2d, 2e, and 2f
were located in the unit cell and allowed to refine freely with iso-
tropic thermal displacement parameters. All other hydrogen atoms
were added at calculated positions and refined using a riding mod-
el. Their isotropic thermal displacement parameters were fixed to
1.2 times (1.5 times for methyl groups and OH groups) the
equivalent thermal displacement parameter of the parent atom.
Anisotropic displacement parameters were refined for all non-
hydrogen atoms.
[5] (a) G. Jaouen, A. Vessières, S. Top, A.A. Ismail, I.S. Butler, C.R. Seances Acad. Sci.,
Ser. 2 298 (1984) 683–686;
(b) G. Jaouen, A. Vessières, S. Top, A.A. Ismail, I.S. Butler, J. Am. Chem. Soc. 107
(1985) 4778–4780.
[6] G. Jaouen, S. Top, A. Vessières, G. Leclercq, M.J. McGlinchey, Curr. Med. Chem.
11 (2004) 2505–2517.
[7] (a) S. Top, E.B. Kaloun, S. Toppi, A. Herrbach, M.J. McGlinchey, G. Jaouen,
Organometallics 20 (2001) 4554–4561;
(b) S. Top, E.B. Kaloun, A. Vessières, I. Laïos, G. Leclercq, G. Jaouen, J.
Organomet. Chem. 643–644 (2002) 350–356.
[8] (a) G. Jaouen, S. Top, A. Vessières, G. Leclerq, J. Quivy, L. Jin, A. Croisy, C.R. Acad.
Sci. Paris Série IIc (2000) 89–93;
(b) S. Top, A. Vessières, C. Cabestaing, I. Laïos, G. Leclerq, C. Provot, G. Jaouen, J.
Organomet. Chem. 637 (2001) 500–506;
(c) S. Top, A. Vessières, G. Leclercq, J. Quivy, J. Tang, J. Vaissermann, M. Huché,
G. Jaouen, Chem Eur. J. 9 (2003) 5223–5236;
(d) A. Vessières, S. Top, P. Pigeon, E.A. Hillard, L. Boubeker, D. Spera, G. Jaouen,
J. Med. Chem. 48 (2005) 3937–3940.
[9] S. Top, A. Vessières, P. Pigeon, M.N. Rager, M. Huché, E. Salomon, C. Cabestaing,
J. Vaissermann, G. Jaouen, Chem. Biol. Chem. 5 (2004) 1104–1113.
[10] P. Pigeon, S. Top, A. Vessières, M. Huché, E.A. Hillard, E. Salomon, G. Jaouen, J.
Med. Chem. 48 (2005) 2814–2821.
Acknowledgements
[11] S. Top, E.B. Kaloun, A. Vessières, G. Leclercq, I. Laïos, M. Ourevitch, C. Deuschel,
M.J. McGlinchey, G. Jaouen, Chem Bio Chem 4 (2003) 754–761.
[12] (a) A. Vessières, S. Top, W. Beck, E.A. Hillard, G. Jaouen, Dalton Trans. 4 (2006)
529–541;
(b) A. Nguyen, A. Vessières, E.A. Hillard, S. Top, P. Pigeon, G. Jaouen, Chimia 61
(2007) 725–761.
[13] E.A. Hillard, A. Vessières, L. Thouin, G. Jaouen, C. Amatore, Angew. Chem., Int.
Ed. Engl. 45 (2006) 285–290.
We thank Science Foundation Ireland, University College Dub-
lin, the Ministère de la Recherche (France) and the Centre Natio-
nale de la Recherche Scientifique and for generous financial
support.
[14] A.R. Kudinov, E.V. Mutsenek, D.A. Loginov, Coord. Chem. Rev. 248 (2004) 571–
585.
Appendix A. Supplementary material
[15] R.B. Woodward, M. Rosenblum, M.C. Whiting, J. Am. Chem. Soc. 74 (1952)
3458–3459.
[16] M.D. Rausch, R.A. Genetti, J. Org. Chem. 35 (1970) 3888–3897.
[17] W.P. Hart, D.W. Macomber, M.D. Rausch, J. Am. Chem. Soc. 102 (1980) 1196–
1198.
[18] A.M. Stevens, C.J. Richards, Organometallics 18 (1999) 1346–1348.
[19] Y. Ortin, K. Ahrenstorf, P. O’Donohue, D. Foede, H. Mueller-Bunz, P. McArdle,
A.R. Manning, M.J. McGlinchey, J. Organomet. Chem. 689 (2004) 1657–1664.
[20] Y. Ortin, J. Grealis, C. Scully, H. Müller-Bunz, A.R. Manning, M.J. McGlinchey, J.
Organomet. Chem. 689 (2004) 4683–4690.
[21] A. Detsi, M. Koufaki, T. Calogeropoulou, J. Org. Chem. 67 (2002) 4608–4611.
[22] S. Top, B. Dauer, J. Vaissermann, G. Jaouen, J. Organomet. Chem. 541 (1997)
355–361.
CCDC 739363, 739362, 739369, 739366, 739365, 739367,
739368 and 739364 contain the supplementary crystallographic
data for compounds (1c), (2c), (2d), (2e), (2f), (2g), (2h) and (11),
respectively. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.jorganchem.2009.11.003.
[23] B.T. Kilbourn, P.G. Owston, J. Chem. Soc. B (1970) 1–5.
[24] G. Precigoux, C. Courseille, S. Geoffre, M. Hospital, Acta Crystallogr., Sect. B 35
(1979) 3070–3072.
[25] I. Ott, B. Kircher, C.P. Bagowski, D.H.W. Vlecken, E.B. Ott, J. Will, K. Bensdorf,
W.S. Sheldrick, R. Gust, Angew. Chem., Int. Ed. 48 (2009) 1160–1163.
References
[1] (a) G. Jaouen (Ed.), Bioorganometallics: Biomolecules, Labelling, Medicine,
Wiley-VCH, Weinheim, 2006;
(b) D.R. van Staveren, N. Metzler-Nolte, Chem. Rev. 104 (2004) 5931–5985;

608
K. Nikitin et al. / Journal of Organometallic Chemistry 695 (2010) 595–608
[26] E.A. Hillard, A. Vessières, S. Top, P. Pigeon, K. Kowalski, M. Huché, G. Jaouen, J.
Organomet. Chem. 692 (2007) 1315–1326.
[27] J.B. Heilmann, E.A. Hillard, M.A. Plamont, A. Vessières, P. Pigeon, M. Bolte, G.
Jaouen, J. Organomet. Chem. 693 (2008) 1716–1722.
[31] P. O’Donohue, S.A. Brusey, C.M. Seward, Y. Ortin, B.C. Molloy, H. Müller-
Bunz, A.R. Manning, M.J. McGlinchey, J. Organomet. Chem. 694 (2009)
2536–2547.
[32] P. Pigeon, personal communication.
[28] F. Zhang, P.W. Fan, X. Liu, L. Shen, R.B. van Breeman, J.L. Bolton, Chem. Res.
Toxicol. 13 (2000) 53–62.
[29] Y. Nagahara, I. Shiina, K. Nakata, A. Sasaki, T. Miyamoto, M. Ikekita, Cancer Sci.
99 (2008) 608–614.
[33] O. Payen, S. Top, A. Vessières, E. Brulé, M.-A. Plamont, M.J. McGlinchey, H.
Müller-Bunz, G. Jaouen, J. Med. Chem. 51 (2008) 1791–1799.
[34] A. Vessières, S. Top, A.A. Ismail, I.S. Butler, M. Loüer, G. Jaouen, Biochemistry 27
(1988) 6659–6666.
[30] (a) S. Mahepal, R. Bowen, M.A. Mamo, M. Layh, C.E.J. Van Rensburg, Met.-based
Drugs (2008) 864853;
[35] G.M. Sheldrick, SADABS, Bruker AXS Inc., Madison, WI 53711, 2000.
[36] G. M. Sheldrick, SHELXS-97, University of Göttingen, 1997.
[37] G.M. Sheldrick, SHELXL-97-2, University of Göttingen, 1997.
(b) O. Rackham, S.J. Nichols, P.J. Leedman, S.J. Berners-Price, A. Filipovska,
Biochem. Pharmacol. 74 (2007) 992–1002.