The length of the bridging chain in ansa-metallocenes influences their antiproliferative activity against triple negative breast cancer cells (TNBC)

Article abstract of DOI:10.1039/c6dt01640e

In order to examine whether the length of the bridging chain in ansa-ferrocenes affects their antiproliferative activity against MDA-MB-231 triple negative breast cancer cell lines (TNBC), we synthesized derivatives of the type 1-[bis-(4-hydroxyphenyl)]me

Full text of DOI:10.1039/c6dt01640e

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Beaupérin, M. Richard, D. Plauk, P. Pigeon, S. Toma, V. Polackova and G. Jaouen, Dalton Trans., 2016,
DOI: 10.1039/C6DT01640E.
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The length of the bridging chain in ansaꢀmetallocenes influences their antiproliferative
activity against triple negative breast cancer cells (TNBC).
Matthieu Beauperin,a,b Siden Top,a,b* , MarieꢀAude Richard,a,b Damian Plażuk,c Pascal
Pigeon,a,b,d Stefan Toma,e Viera Poláčková,e and Gérard Jaouena,b,d*
a Sorbonne Universités, UPMC Univ Paris 6, UMR 8232, IPCM, Fꢀ75005 Paris, France
b CNRS, UMR 8232, IPCM, Fꢀ75005 Paris, France
c University of Lodz, Faculty of Chemistry, Department of Organic Chemistry, ul. Tamka 12,
Lodz 91ꢀ403, Poland
d PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, Fꢀ75005 Paris, France
e Faculty of Natural Sciences, Comenius University, SKꢀ84215 Bratislava, Slovakia
1

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CORRESPONDING AUTHORS
Siden Top, Gérard Jaouen
Sorbonne Universités, UPMC Univ Paris 6, UMR 8232, IPCM, Fꢀ75005 Paris, France
Eꢀmails: siden.top@upmc.fr; gerard.jaouen@chimieꢀparistech.fr
KEYWORDS: Bioorganometallic chemistry, ferrocenophanes, ruthenocenophanes, breast
cancer.
2

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ABSTRACT
In order to examine whether the length of the bridging chain in ansaꢀferrocenes affects their
antiproliferative activity against MDAꢀMBꢀ231 triple negative breast cancer cell lines
(TNBC), we synthesized derivatives of the type 1ꢀ[bisꢀ(4ꢀhydroxyphenyl)]methylideneꢀ
[n]ferrocenophane and 1ꢀ[(4ꢀhydroxyphenyl)ꢀphenyl]methylideneꢀ[n]ferrocenophane with n =
3, 4, 5. We found that the derivatives of [3]ferrocenophane, the compounds with the shortest
bridging chains, are the most active. IC50 values were 0.09 ± 0.01, 2.41 ± 0.10, and 1.85 ±
0.25 ꢀM for the dihydroxyphenyl derivatives, with n = 3, 4, 5, respectively. These differences
can be explained in terms of modification of the key metabolites (radical versus quinone
methides) within the ansa series depending on the length of the bridging chain. The derivative
of [5]ferrocenophane, possessing two –[bisꢀ(4ꢀhydroxyphenyl)]methylidene groups, was also
prepared. Surprisingly, this relatively large molecule is also active (IC50 = 2.7 ± 0.3 ꢀM). Two
ruthenocenophane analogs were also synthesized. These ruthenium compounds are practically
inactive against MDAꢀMBꢀ231 cells. The unusual chemistry of these different compounds is
discussed in terms of elucidating the mechanism underlying their diverse antiproliferative
activity, and their specific advantages are evaluated.
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INTRODUCTION
Cancer remains, despite therapeutic advances, one of the foremost multifactorial diseases in
terms of mortality. In 2012, 14.1 million worldwide new cases were reported, with 8.2 million
deaths.1 According to literature, metallodrugs are considered to be promising anticancer
agents.2ꢀ17 The development of these products was initially stimulated by the discovery of
cisplatin, which is currently used to treat various types of cancer, in particular testicular,
ovarian and nonꢀsmallꢀcell lung cancers.18ꢀ20 New classes of platinum complexes with lower
toxicity or better activity have been synthesized. More than 50% of current treatments for
cancer involve coordination compounds of platinum.20ꢀ22 However, it has not been possible to
eradicate a number of serious secondary effects caused by these medications, in particular
their high level of general toxicity and tendency to induce resistance.20 Inspired by the success
of platinum compounds, other transition metals have been intensively studied, most recently
13, 16, 23ꢀ26
27ꢀ30
in organometallic form, for example with Fe,12,
Ru,3,
Au,8 Os,15, 31 Ir,32
rhodium,33, 34 and some of these have now reached the clinical trial stage.6, 35
OH
Fe
O(CH2)3NMe2
Fc-OH-TAM
Chart 1. FcꢀOHꢀTAM
In the case of ferrocene compounds, we found that substituting ferrocenyl for the βꢀaryl group
of hydroxytamoxifen, an antiestrogenic drug for treatment of hormone dependent breast
cancer, gave the organometallic compound (FcꢀOHꢀTAM), which bears a [ferrocenylꢀeneꢀ
4

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phenol] redox motif (JaouenꢀTop redox motif) and shows good activity against MDAꢀMBꢀ
231 triple negative breast cancer cells (TNBC) (Chart 1). The IC50 value of FcꢀOHꢀTAM is
0.5 ꢀM.36 An update on this series of compounds, including the latest mechanistic results, was
recently published by Jaouen et al..37 We also studied the series of ansaꢀferrocenes bearing a
threeꢀcarbon bridge. These compounds showed higher efficacity in vitro than those of the
acyclic ferrocene series. For example, compounds 1b, 2b, 3b, and 4b are respectively 7, 3, 8
and 9 times more active than 1a, 2a, 3a, and 4a (Table 1).38
Table 1. IC50 values of selected acyclic ferrocenyl and ansa ferrocenyl complexes
R1
R1
R2
R2
Fe
Fe
Series a
Series b
R1
R2
Compound
IC50 (ꢀM)
IC50 (ꢀM)
OH
OH
H
OH
H
0.64±0.06[a]
1.54±0.13[c]
7.54±0.7[c]
0.55±0.05[c]
0.09±0.01[b]
0.47±0.06[c]
0.92±0.11[c]
0.061±0.005[c]
1a, 1b
2a, 2b
3a, 3b
4a, 4b
H
NH2
OH
[a] Data from ref 39, [b] Data from ref 40, [c] Data from ref 38.
The ansa compounds shown in Table 1 still display the above redox motif and are
characterized by a threeꢀcarbon bridge. Ansa ferrocenes may exist and do exist in fact with
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different bridging chain lengths. One might assume in principle that the antiproliferative
activity of these compounds would vary according to the length of the intercyclopentadienyl
bridge, thus it is important to study ansa compounds with each length of bridging chain. We
present here the syntheses and antiproliferative results of compounds with 4ꢀ and 5ꢀcarbon
chains. In addition, we found that the ruthenocene derivatives are much less active than their
41
ferrocene analogs.30,
contextualized.
These characteristics as a whole have been evaluated and
RESULTS AND DISCUSSION
Synthesis
Compounds 8ꢀ12 were prepared via a McMurry crossꢀcoupling reaction between two
appropriate ketones (Scheme 1).
R1
R1
O
TiCl4, Zn
O
Fe
n
THF, reflux
R2
R3
Fe
n
R2
R3
5
6
7
n = 1, R3 = Me
n = 2, R3 = H
n = 3, R3 = H
8
9
n = 2, R1 = R2 = OH, R3 = H
n = 2, R1 = OH, R2 = H, R3 = H
n = 3, R1 = R2 = OH, R3 = H
n = 3, R1 = OH, R2 = H, R3 = H
n = 1, R1 = R2 = OH, R3 = Me
10
11
12
Scheme 1. Synthesis of [n]ferrocenophane compounds.
The compounds 3ꢀmethylꢀ[3]ferrocenophanꢀ1ꢀone, 5 42 and [5]ferrocenophanꢀ1ꢀone 7 43 were
prepared according to literature methods. [4]ferrocenophanꢀ1ꢀone, 6, was originally
synthesized via a homologation reaction using diazomethane as reagent44. However for safety
reasons we chose to replace the diazomethane with TMSCHN2/BF3.Et2O in the synthesis of 6
6

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44. The coupling reaction of these ketones with benzophenones via a McMurry reaction gave
compounds 8ꢀ12. Yields were moderate (14 to 24%).
HO
OH
O
TiCl4, Zn
O
Ru
THF, reflux
OH
Ru
OH
13
Scheme 2. Synthesis of ruthenocenophane 13.
Coupling between [3]ruthenocenophanꢀ1ꢀone and 4,4’ꢀdihydroxybenzophenone gave
compound 13 in 77% yield (Scheme 2).
HO
OH
OH
O
O
TiCl4, Zn
M
M
O
THF, reflux
OH
OH
M = Fe, Ru
14 M = Fe 2% yield
HO
M = Ru 28% yield
15
Scheme 3. Synthesis of tetraphenols 14 and 15.
Compounds 14 and 15 were obtained by performing a double coupling reaction between 4,4’ꢀ
dihydroxybenzophenone and [5]ferrocenophanꢀ1,5ꢀdione (compound 14), and
[5]ruthenocenophanꢀ1,5ꢀdione (compound 15) (Scheme 3). Compound 14 was obtained in
only 2% yield (Scheme 2). This very low yield is due to the nature of the McMurry reaction,
as the result tends to be a mixture of homocoupling and crossꢀcoupling products. The double
coupling reaction on the same ketone increases the number of compounds that may be
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formed. It should be noted that the coupling reaction of [5]ruthenocenophanꢀ1,5ꢀdione gave
15 in better yield (28%). The low yield of 14 (2%), may arise from the difference in reactivity
between [5]ferrocenophanꢀ1,5ꢀdione and [5]ruthenocenophanꢀ1,5ꢀdione in McMurry coupling
or from the difficulty in purification of this compound. In fact, 14 was only obtained in pure
form after several successive purifications by column chromatography including HPLC that
causes important yield loss.
Antiproliferative activity
The antiproliferative activity of the compounds synthesized was measured on the TNBC
(Triple Negative Breast Cancer) cell line MDAꢀMBꢀ231. The IC50 and log Po/w values are
listed in Table 2.
Table 2. IC50 values of compounds 1b, 2b, and 7ꢀ12 for MDAꢀMBꢀ231 cells and log Po/w
values.
Compound
IC50 (µM)[a]
0.09 ± 0.01[b]
0.47 ± 0.06[c]
0.78 ± 0.12
2.7 ± 0.03
log Po/w
4.6[b]
5.6
1b
2b
5.1
(R)ꢀ12
(S)ꢀ12
8
5.0
2.41 ± 0.10
4.53 ± 0.62
1.85 ± 0.25
4.13 ± 0.18
5.1
ꢀ
9
5.4
10
6.4
11
[a] Mean of two independent experiments; [b] Data from ref 40; [c] Data from ref 38.
Comparison of the antiproliferative activity of the diphenols 1b, 8, and 10 on the one hand,
and compounds 2b, 9, and 11, on the other, clearly shows that the compounds bearing the
shortest bridging chains are the most active while the compounds with 4ꢀ and 5ꢀcarbon
bridges have similar activities to one another although higher than those of the previous
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series. In fact, 1b and 2b (n = 1) are respectively 27 and 9 times more active than 8 and 9 (n =
2). Conversely, 10 and 11 (n = 3) are slightly better than 8 and 9. It is surprising to note that
the presence of a small lipophilic group, such as the methyl radical, on the bridge decreases
the activity of the compound. This is the case for compound 12, which becomes less active
than 1b. Moreover, we observed a clear difference between the two chiral isomers (R)ꢀ12 and
(S)ꢀ12. This result seems to show that the steric effect created in cells by the compound plays
an important role in its antitumoral activity. The log Po/w values of compounds 1b, 8 and 10
are respectively 4.6, 5.1 and 5.4. These values show that the lipophilicity of the compound
increases with the length of the bridging chain.
We next compare the antiproliferative activity of the ferrocenophane series with that of the
ruthenocenophane series. Table 3 shows the corresponding IC50 values.
Table 3. Antiproliferative activity of 1b, 13, 14, and 15 against hormoneꢀindependent breast
cancer cells (MDAꢀMBꢀ231)
Compound
1b (Fe)
13 (Ru)
14 (Fe)
15 (Ru)
0.09 ± 0.01[b]
> 30
2.7 ± 0.3
> 10
IC50 (ꢀM)[a]
[a] Mean of two independent experiments in quadruplicate. [b] Data from ref 40;
The results clearly show a significant difference in antiproliferative activity between the two
series. In fact, unlike ferrocenophane 1b, the ruthenocenophane equivalent 13 is practically
inactive, and the IC50 value is estimated in this case at more than 30 ꢀM. In addition, it is
surprising that compound 14, which is bulkier than 1b due to the presence of the second –
[bis(hydroxyphenyl)]methylidene group, still remains distinctly active (IC50 = 2.7 ± 0.3 ꢀM).
This can be explained by the effect induced by the phenols. In fact, we have previously shown
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that for this type of compounds, the presence of two phenols resulted in an improvement in
the antiproliferative effect compared to compounds bearing only one phenol, or indeed no
phenol.38, 45, 46 The low activity of ruthenocene compounds compared to that of ferrocene
compounds, is confirmed yet again by the low activity of compound 15. Its IC50 value is
estimated to be around 10 ꢀM.
Discussion
We have recently shown that in oxidative activation of ferrocenes, the key metabolite,
responsible for the majority of the antiproliferative activity, can differ.12, 37 This sometimes
arises because of the nature of the metal; for example with FcꢀOHꢀTam 16 the key metabolite
is the moderately electrophilic quinone methide 17 (Scheme 4).47ꢀ50 But if the ferrocene is
replaced by an osmocene 18 the active electrophilic species becomes a stabilized carbenium
ion 19, and the IC50 of the precursor on MDAꢀMBꢀ231 goes from 0.5 µM to 3 µM.51 In this
situation the substituents also play a role, since if the alkyl chain in FcꢀdiOH 1a is substituted
by –CH2CH2CH2OH, compound 20, the quinone methide is obtained with generation of a
tetrahydrofuranylꢀtype heterocycle 21 and the IC50 value on MDAꢀMBꢀ231 goes from 0.6 µM
to 0.11 µM.52 In fact this new type of quinone methide permits only 1,6 Michael adducts and
not 1,8 as with FcꢀdiOH 1a.49
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OH
O
Ag2O
or microsomes
Fe
Fe
O(CH2)3NMe2
Fc-OH-TAM
O(CH2)3NMe2
16
17
OH
O
H2O2/HRP
Os
Os
O(CH2)3NMe2
O(CH2)3NMe2
18
Fc-OH-TAM
19
OH
O
HO
Ag2O
O
or microsomes
Fe
Fe
OH
OH
20
Fc-OH-TAM
21
Scheme 4. Oxidation of 16, 18 and 20.
In the case of 3ꢀcarbon ansa derivatives, a certain number of parallels with FcꢀdiOH 1a can be
seen. The two compounds generate ROS53 and offer dual mechanisms, senescence and
apoptosis54, 55 depending on concentration.37 They can be formulated as lipoid nanocapsules
(LNC) and are active on cancer cells.56ꢀ59 They also possess an electrochemically oxidizable
Fe (II).48, 60, 61 However the 3ꢀcarbon ansa derivative 1b remains more active on MDAꢀMBꢀ
231, as well as on the NCIꢀ60 cell lines,38, 45, 46 than the acyclic form.38, 46 In the case of the
ansa derivative we were unable to characterize or isolate a species of the quinone methide
type60 suggesting that the oxidized form is more active and less stable than in the acyclic
series. Indeed the Xꢀray crystal structure of a 3ꢀcarbon ansa species reveals a constrained
arrangement in which the two Cp rings are not parallel but instead make an angle of 10°.45
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This nonꢀplanar arrangement is an indication of significant internal energy stored in the active
intermediate that could be the constrained radical species below, 22, which is probably very
active (Chart 2).
O
OH
Fe
22
Chart 2. Major reactive intermediate for 1b.62
Theoretical studies of this novel intermediate species confirm this idea.62 The ferrocifens have
already demonstrated their ability to change their key active species during oxidation but
overall a fairly high level of cytotoxic activity is always observed.
HO
O
Ag2O
Acetone
Fe
Fe
n
n
9
11
n = 2
n = 3
23
24
n = 2
n = 3
Scheme 5. Oxidation of 9 and 11 by Ag2O.
Lengthening the chain to relieve the crowding of the ansa molecule leads to behavior closer to
that of the acyclic system. In fact chemical oxidation by silver oxide of compound 9 with 4
carbons and compound 11 with 5 carbons gives, as in the case of the acyclic series, quinone
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methides 23 and 24, respectively (Scheme 5). This behavior is consistent with the observed
biological results.
With the derivatives of Ru, IC50 values on cancer cells are found to be considerably superior
to those obtained with Fe (for example with 13). Ruthenocene’s lower anticancer activation
relative to ferrocene in ferrocifenꢀtype systems has already been reported.51, 63 It may be
linked to a redox system with less favorable reversibility. This difference may however be
useful one. It has recently been shown that ferrocifens, in addition to their anticancer effect, in
fact also show antiproliferative activity on plasmodium falciparum.64
Indeed certain Ru complexes that are less active on cancer cells conserve good antimalarial
properties.46 We are actively searching for molecules where the two properties are well
differentiated. The Ru products reported here could form a part of this research into
differentiated effects,64 with a focus on antimalarial properties which have not previously
been seen in the metallocifens.
This contribution is an illustration of the richness of the metallocifen series, as part of the
exponentially developing branch of chemical biology that is the bioorganometallic chemistry
of transition metals.
CONCLUSION
The antiproliferative effect of the diphenolic ansa derivatives of ferrocene on TNBCꢀtype
cancer cells such as MDAꢀMBꢀ231 is largely dependent on the length of the carbon chain
linking the two cyclopentadienyl rings, and occurs via an evolution of the mechanism of
action that depends on the nature of the key metabolite. In the case of a threeꢀcarbon chain
which constrains the molecule internally, the active species is not a moderately
electrophophilic quinone methide such as that identified for FcꢀdiOH 1a but rather a
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constrained intermediate, probably of the radical type, which is more active than a neutral
quinone methide. This constraint can be released by lengthening the chain to 4 or 5 carbons,
which gives access to a quinone methide whose effect can be modulated by steric means.
Replacing Fe with Ru gives entities with a greatly reduced antiproliferative effect, confirming
the better access to reversible redox of Fe relative to Ru in the action of ferrocifens. However
Ru complexes may be of use in offering antimalarial effects dissociated from antitumoral
activity. This will be the subject of further studies.
EXPERIMENTAL
All reactions and manipulations were carried out under a nitrogen atmosphere using
standard Schlenk techniques. THF was distilled over sodium/benzophenone prior to use. Thin
1
layer chromatography was performed on silica gel 60 GF254. H and 13CꢀNMR spectra were
acquired on a Bruker 300, 400, 600, and 700 MHz spectrometers. Mass spectrometry was
carried out at the “Service de Spectrométrie de Masse” at ENSCP, Paris. Microanalyses were
performed by the “Service de Microanalyse ICSN” at Gif sur Yvette, France. High resolution
mass spectra (HRMS) were performed at IMAGIF (ICSN, Gif sur Yvette, France) and the
“Institut Parisien de Chimie Moléculaire” (IPCMꢀUMR 8232, Université Pierre et Marie
Curie). [5]Ferrocenophanꢀ1,5ꢀdione,65, 66 [3]ruthenocenophanꢀ1ꢀone 67 and Rꢀ and Sꢀ3ꢀmethylꢀ
[3]ferrocenophanꢀ1ꢀone42 were prepared according to the literature procedures. Determination
of the cytotoxicity of 2b, 7, 8, 9, 10, and 11 was performed at IMAGIF (ICSN, Gif sur Yvette,
France), the procedure was described in ref68. The IC50 values of (R)ꢀ12 and (S)ꢀ12, 13, 14,
and 15 were measured according to the published procedures51. The log Po/w values of the
compounds were determined by reverseꢀphase HPLC according to the method previously
described by Minick69and Pomper70.
14

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[5]ruthenocenophanꢀ1,5ꢀdione
To a solution of acetylruthenocene (0.625 g, 2.3 mmol) in anhydrous CH2Cl2 (15 mL), a
solution of distilled 3ꢀchloropropionyl chloride (0.54 g, 0.41 mL, 3.4 mmol) in CH2Cl2 (5
mL) was added at room temperature. The reaction mixture was cooled in an ice bath and
AlCl3 (1.1 g, 8.3 mmol) was added slowly over 1 h. The solution was stirred for 1.5 h at 0° C
until no starting material was detected by TLC. The content of the flask was then poured into
300 g of crushed ice. After the ice melted, the layers were separated and the aqueous phase
was extracted with CH2Cl2 (3×20 mL). Combined organic extracts were dried (Na2SO4), and
the solvent was evaporated. The crude product was used in the next step without further
purification. The crude product was dissolved in boiling MeOH (10 mL). To the solution was
added 10% aq NaOH (5 mL). The reaction mixture was stirred and heated at reflux for 30
min. Then the mixture was cooled in an ice bath and the precipitate was filtered off, washed
with water (2×10 mL), and dried under vacuum. Product [5]ruthenocenophanꢀ1,5ꢀdione was
obtained as yellow crystals (0.56 g, 74%). 1H NMR (300 MHz, CDCl3): δ 2.24 (m, 4H, CH2),
13
2.41 (m, 2H, CH2), 4.88 (t, J = 1.9 Hz, 4H, C5H4), 5,07 (t, J = 1.9 Hz, 4H, C5H4). C NMR
(75 MHz, CDCl3): δ 26.7 (1 CH2), 35.1 (2 CH2), 72.5 (8 CH, C5H4), 87.2 (2C, C5H4), 199.9
(2CO). IR (neat): 3292, 3105, 2977, 2943, 2918, 1660, 1651, 1458, 1397, 1262, 1093, 1057,
901, 817. Anal. Calcd for C15H14O2Ru: C, 55.04; H, 4.31. Found: C, 54.69; H, 4.39. Melting
point 220ꢀ221⁰C.
Synthesis of (R)ꢀ1ꢀ[bisꢀ(4ꢀhydroxyphenyl)methylidene]ꢀ3ꢀmethylꢀ[3]ferrocenophane, (R)ꢀ
12
Titanium (IV) chloride (0.564 g, 0.326 mL, 3 mmol) was added dropwise to a suspension of
zinc powder (0.384 g, 5.9 mmol) in 12 mL of dry THF at 0°C. The mixture was heated at
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reflux for 1 hour. After cooling to room temperature anhydrous pyridine (0.472 mg, 0.482
mL, 6 mmol) and a solution of (R)ꢀ3ꢀmethylꢀ[3]ferrocenophanꢀ1ꢀone (0.254 g, 1 mmol) and
4,4’ꢀdihydroxybenzophenone (0.214 g, 1 mmol) in 4 mL of THF were successively added and
the resulting mixture was refluxed for 2h. After cooling to room temperature 30 ml of 8%
potassium carbonate was added and the product was extracted with several portions of 50 ml
of diethyl ether. The organic solution was washed with water and brine, dried, and
evaporated. Pure product Rꢀ12 was obtained as a yellow powder in 24% yield (105 mg) by
1
chromatography on silica gel (200 ml) using nꢀpentane/diethyl ether 3/2 as eluent. . H NMR
(600 MHz, acetoneꢀd6): δ 1.14 (d, J = 6.8 Hz, 3H, CH3), 2.67ꢀ2.57 (m, 3H, CH2ꢀCH), 3.71ꢀ
3.70 (m, 1H, C5H4), 3.83ꢀ3.82 (m, 1H, C5H4), 3.85ꢀ3.84 (m, 1H, C5H4), 4.02ꢀ4.01 (m, 1H,
C5H4), 4.08ꢀ4.07 (m, 1H, C5H4), 4.23ꢀ4.22 (m, 1H, C5H4), 4.32ꢀ4.31 (m, 1H, C5H4), 4.33ꢀ4.32
(m, 1H, C5H4), 6.53 (d, J = 8.5 Hz, 2H, C6H4), 6.83 (d, J = 8.5 Hz, 4H, C6H4), 7.06, (d, J = 8.5
13
Hz, 2H, C6H4), 8.09 (s, 1H, OH), 8.30 (s, 1H, OH). C NMR (151 MHz, acetoneꢀd6): δ 22.6
(CH3), 36.4 (CH), 50.4 (CH2), 67.0 (CH, C5H4), 67.7 (CH, C5H4), 68.9 (CH, C5H4), 69.4 (CH,
C5H4), 69.9 (CH, C5H4), 70.1 (CH, C5H4), 71.9 (CH, C5H4), 72.0 (CH, C5H4), 87.1 (C, C5H4),
92.8 (C, C5H4), 115.0 (2CH, C6H4), 115.8 (2CH, C6H4), 131.4 (2CH, C6H4), 132.6 (2CH,
C6H4), 133.9 (C), 136.0 (C), 136.2 (C), 141.6 (C), 156.6 (C), 157.1 (C). HRMS (ESI,
C27H24FeO2: [M]+•] calcd: 436.11202, found: 436.11203. |α|18D +110° (c 0.268, MeOH).
Synthesis of (S)ꢀ1ꢀ[bisꢀ(4ꢀhydroxyphenyl)methylidene]ꢀ3ꢀmethylꢀ[3]ferrocenophane, (S)ꢀ
12
The synthetic procedure of Sꢀ12 is similar to that of Rꢀ12, starting from (S)ꢀ3ꢀmethylꢀ
1
[3]ferrocenophanꢀ1ꢀone. H NMR (600 MHz, acetoneꢀd6): δ 1.14 (d, J = 6.8 Hz, 3H, CH3),
2.67ꢀ2.57 (m, 3H, CH2ꢀCH), 3.71ꢀ3.70 (m, 1H, C5H4), 3.83ꢀ3.82 (m, 1H, C5H4), 3.85ꢀ3.84 (m,
1H, C5H4), 4.02ꢀ4.01 (m, 1H, C5H4), 4.08ꢀ4.07 (m, 1H, C5H4), 4.23ꢀ4.22 (m, 1H, C5H4), 4.32ꢀ
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4.31 (m, 1H, C5H4), 4.33ꢀ4.32 (m, 1H, C5H4), 6.53 (d, J = 8.5 Hz, 2H, C6H4), 6.83 (d, J = 8.5
Hz, 4H, C6H4), 7.06, (d, J = 8.5 Hz, 2H, C6H4), 8.09 (s, 1H, OH), 8.30 (s, 1H, OH). 13C NMR
(151 MHz, acetoneꢀd6): δ 22.6 (CH3), 36.4 (CH), 50.4 (CH2), 67.0 (CH, C5H4), 67.7 (CH,
C5H4), 68.9 (CH, C5H4), 69.4 (CH, C5H4), 69.9 (CH, C5H4), 70.1 (CH, C5H4), 71.9 (CH,
C5H4), 72.0 (CH, C5H4), 87.1 (C, C5H4), 92.8 (C, C5H4), 115.0 (2CH, C6H4), 115.8 (2CH,
C6H4), 131.4 (2CH, C6H4), 132.6 (2CH, C6H4), 133.9 (C), 136.0 (C), 136.2 (C), 141.6 (C),
156.6 (C), 157.1 (C). HRMS (ESI, C27H24FeO2: [M] +•) calcd: 436.11202, found: 436.11207.
|α|18D ꢀ110° (c 0.278, MeOH).
Synthesis of 1ꢀ[bisꢀ(4ꢀhydroxyphenyl)methylidene]ꢀ[4]ferrocenophane, 8
Titanium (IV) chloride (0.24 mL, 2.2 mmol) was added dropwise to a suspension of zinc
powder (0.51 g, 7.8 mmol) in 10 mL of THF at 0°C. The mixture was heated at reflux for 1
hour. A second solution was prepared by dissolving [4]ferrocenophanꢀ1ꢀone (0.34 g, 1.3
mmol) and 4,4’ꢀdihydroxybenzophenone (0.56 g, 2.7 mmol) in THF. This latter solution was
added dropwise to the first solution and then the reflux was continued for 2 hours. After
cooling to room temperature, the mixture was stirred with water and dichloromethane. The
organic layer was acidified with a 1 N HCl solution, washed with brine, then dried over
magnesium sulfate. After concentration under reduced pressure, the crude product was
chromatographed on silica gel column, with a mixture of cyclohexane/ethyl acetate (4:1) as an
eluent. 8 was isolated as a yellow powder (80 mg, 14 % yield). 1H NMR (400 MHz, acetoneꢀ
d6): δ 1.94ꢀ2.05 (m, 2H, CH2CH2CH2C=), 2.43ꢀ2.47 (m, 4H, CH2CH2CH2C=), 3.921 (s,2H,
C5H4), 3.96 (s, 2H, C5H4), 4.03 (s, 2H, C5H4), 4.14 (s, 2H, C5H4), 6.55 (d, J = 8.5 Hz, 4H,
C6H4), 6.73 (d, J = 8.5 Hz, 4H, C6H4), 6.81 (d, J = 8.5 Hz, 4H, C6H4), 7.03 (d, J = 8.5 Hz, 4H,
C6H4), 8.13 (s, 1H, OH), 8.34 (s, 1H, OH). 13C NMR (75 MHz, acetoneꢀd6): δ 27.7 (CH2,
CH2CH2CH2C=), 29.4 (CH2, CH2CH2CH2C=), 33.0 (CH2, CH2CH2CH2C=), 68.4 (2CH,
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C5H4), 68.8 (2CH, C5H4), 68.9 (2CH, C5H4), 70.2 (2CH, C5H4), 88.3 (C, C5H4), 89.0 (C,
C5H4), 114.9 (2CH, C6H4), 115.4 (2CH, C6H4), 131.0 (2CH, C6H4), 132.2 (2CH, C6H4), 134.7
(C, CH2ꢀC=C), 136.0 (C, C6H4), 136.2 (C, C6H4), 140.3 (C, CH2ꢀC=C), 156.1 (C, CꢀOH),
156.7 (C, CꢀOH). MS (CI, NH3): m/z 436.9 [M+H]+. HRMS (ESI, C27H24FeO2: [M]+•) calcd:
436.1126, found: 436.1133.
Synthesis of 1ꢀ[(4ꢀhydroxyphenyl)phenylmethylidene]ꢀ[4]ferrocenophane, 9
The synthetic procedure of 9 is similar to that of 8. Titanium(IV) chloride (0.25 mL, 2.3
mmol); zinc powder (0.4 g, 6.1 mmol); [4]ferrocenophanꢀ1ꢀone (0.25 g, 1.0 mmol; 4ꢀ
hydroxybenzophenone (0.4 g, 2.0 mmol). 9 was isolated as an orange powder in almost one
1
pure isomer (80 mg, 19 % yield). H NMR (300 MHz, acetoneꢀd6): δ 1.90ꢀ2.00 (m, 2H,
CH2CH2CH2C=), 2.41 (t, J = 6.2 Hz, 2H, CH2CH2CH2C=), 2.46ꢀ2.49 (m, 2H,
CH2CH2CH2C=), 3.94 (t, J = 1.7 Hz, 2H, C5H4), 3.97 (t, J = 1.9 Hz, 2H, C5H4), 4.04 (t, J =
1.7 Hz, 2H, C5H4), 4.15 (t, J = 1.9 Hz, 2H, C5H4), 6.56 (d, J = 8.7 Hz, 2H, C6H4), 6.75 (d, J =
8.7 Hz, 2H, C6H4), 7.02ꢀ7.26 (m, 3H, C6H5), 7.35 (t, J = 7.5 Hz, 2H, C6H5), 8.18 (s, 1H, OH).
13C NMR (75 MHz, acetoneꢀd6): δ 27.7 (CH2, CH2CH2CH2C=), 29.4 (CH2, CH2CH2CH2C=),
33.0 (CH2, CH2CH2CH2C=), 68.6 (2CH, C5H4), 69.0 (2CH, C5H4), 69.1 (2CH, C5H4), 70.5
(2CH, C5H4), 88.4 (C, C5H4), 88.7 (C, C5H4), 115.1 (2CH, C6H4), 127.1 (CH, C6H5), 128.8
(2CH, C6H5), 130.0 (2CH, C6H5), 132.2 (2CH, C6H4), 135.5 (C), 135.7 (C), 140.5.0 (C),
145.1 (C), 156.4 (C, CꢀOH). HRMS (ESI, C27H24FeO: [M] +•) calcd: 420.11711, found:
420.11665.
Synthesis of 1ꢀ[bisꢀ(4ꢀhydroxyphenyl)methylidene]ꢀ[5]ferrocenophane, 10
The synthetic procedure of 10 is similar to that of 8. Titanium (IV) chloride (1.061 g, 0.61
mL, 5.6 mmol.) was added dropwise to a suspension of zinc powder (0.512 g, 7.8 mmol.) in
dry THF (30 mL) at 10ꢀ20°C. The mixture was heated at reflux for 2 hours. A second solution
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was prepared by dissolving [5]ferrocenophanꢀ1ꢀone (0.3 g, 1.12 mmol.) and 4,4'ꢀ
dihydroxybenzophenone (0.36 g, 1.7 mmol.) in dry THF (15 mL). This latter solution was
added dropwise to the first solution and then the reflux was continued for 2 hours. After
cooling to room temperature, the mixture was stirred with water and dichloromethane. The
mixture was acidified with diluted hydrochloric acid until dark color disappeared and was
decanted. The aqueous layer was extracted with dichloromethane and the combination of
organic layers was dried on magnesium sulfate. After concentration under reduced pressure,
the crude product was chromatographed on silica gel column with
a 90/10
dichloromethane/acetone solution as an eluent to afford 10 as an orange solid (0.160 g, 32%
1
yield). H NMR (700.45 MHZ, acetoneꢀd6): δ 1.91 (m, 2H, CH2CH2CH2CH2C=), 2.27 (m,
2H, CH2CH2CH2CH2C=), 2.51 (t, J = 6.6 HZ, 2H, CH2CH2CH2CH2C=), 2.60 (t, J = 6.6 HZ,
2H, CH2CH2CH2CH2C=), 3.82 (t, J = 1.8 Hz, 2H, C5H4), 3.96 (t, J = 1.8 Hz, 2H, C5H4), 4.04
(t, J = 1.8 Hz, 2H, C5H4), 4.06 (t, J = 1.8 Hz, 2H, C5H4), 6.66 (d, J = 8.8 Hz, 2H, C6H4),
6.81(d, J = 8.8 Hz, 2H, C6H4), 6.82 (d, J = 8.8 Hz, 2H, C6H4), 7.06 (d, J = 8.8 Hz, 2H, C6H4),
8.12 (s, 1H, OH), 8.21 (s, 1H, OH). 13C NMR (75 MHz, acetoneꢀd6): δ 24.5
(CH2CH2CH2CH2C=), 26.0 (CH2CH2CH2CH2C=), 26.5 (CH2CH2CH2CH2C=), 32.4
(CH2CH2CH2CH2C=), 67.9 (2CH, C5H4), 68.2 (2CH, C5H4), 69.8 (2CH, C5H4), 70.8 (2CH,
C5H4), 86.8 (C, C5H4), 88.9 (C, C5H4), 115.7 (2x2CH, C6H4), 131.1 (2CH, C6H4), 131.4
(2CH, C6H4), 134.5 (C), 137.3 (C), 137.5 (C), 140.1 (C), 156.4 (C), 156.5 (C). HRMS (ESI,
C28H26FeO2: [M] +•) calcd: 450.12767, found: 450.12769.
Synthesis of 1ꢀ[(4ꢀhydroxyphenyl)phenylmethylidene]ꢀ[5]ferrocenophane, 11
The synthetic procedure of 11 is similar to that of 8. Titanium (IV) chloride (0.38 mL, 3.5
mmol), zinc powder (0.73 g, 11.2 mmol), dry THF (40 mL), [5]ferrocenophanꢀ1ꢀone (0.5 g,
1.9 mmol), 4ꢀhydroxybenzophenone (0.74 g, 3.7 mmol), reflux time: 17 hours. After cooling
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to room temperature, the mixture was stirred with water and dichloromethane. The crude
product was chromatographed on silica gel column, with a mixture of pentane/ethyl acetate
(5:1) as an eluent. 11 was obtained as a yellowꢀorange powder of Z/E isomers mixture (120
1
mg, 15 % yield, major/minor 73/27). Major isomer, H NMR (300 MHz, acetoneꢀd6): δ 1.86ꢀ
1.96 (m, 2H, CH2CH2CH2CH2C=), 2.21ꢀ2.31 (m, 2H, CH2CH2CH2CH2C=), 2.45ꢀ2.49 (m,
2H, CH2CH2CH2CH2C=), 2.62ꢀ2.65 (m, 2H, CH2CH2CH2CH2C=), 3.83 (t, J = 1.9 Hz, 2H,
C5H4), 3.97 (t, J = 1.9 Hz, 2H, C5H4), 4.04 (t, J = 1.9 Hz, 2H, C5H4), 4.08 (t, J = 1.9 Hz, 2H,
C5H4), 6.68 (d, J = 8.6 Hz, 2H, C6H4), 6.86 (d, J = 8.6 Hz, 2H, C6H4), 7.14ꢀ7.26 (m, 3H,
C6H5), 7.34 (t, J = 7.3 Hz, 2H, C6H5), 8.24 (s, 1H, OH). 13C NMR (75 MHz, acetoneꢀd6): δ
24.5 (CH2CH2CH2CH2C=), 25.8 (CH2CH2CH2CH2C=), 26.3 (CH2CH2CH2CH2C=), 32.4
(CH2CH2CH2CH2C=), 67.5 (2CH, C5H4), 68.0 (2CH, C5H4), 69.8 (2CH, C5H4), 70.9 (2CH,
C5H4), 86.4 (C, C5H4), 88.7 (C, C5H4), 115.7 (2CH, C6H4), 126.6 (CH, C6H5), 128.8 (2CH,
C6H5), 129.7 (2CH, C6H5), 131.2 (2CH, C6H4), 134.8 (C, CH2C=C), 136.7 (C, C=CꢀC, C6H4),
1
139.9 (C, CH2C=C), 146.0 (C, C=CꢀC, C6H5), 156.4 (C, CꢀOH, C6H4). Minor isomer, H
NMR (300 MHz, acetoneꢀd6): δ 1.86ꢀ1.96 (m, 2H, CH2CH2CH2CH2C=), 2.21ꢀ2.31 (m, 2H,
CH2CH2CH2CH2C=), 2.51ꢀ2.56 (m, 2H, CH2CH2CH2CH2C=), 2.62ꢀ2.65 (m, 2H,
CH2CH2CH2CH2C=), 3.76 (t, J = 1.9 Hz, 2H, C5H4), 4.04 (t, J = 1.9 Hz, 2H, C5H4), 3.96 (t, J
= 1.9 Hz, 2H, C5H4), 4.08 (t, J = 1.9 Hz, 2H, C5H4), 6.81 (d, J = 8.5 Hz, 2H, C6H4), 7.00ꢀ7.36
(m, 7H, C6H4 + C6H5), 8.31 (s, 1H, OH). 13C NMR (75 MHz, acetoneꢀd6): δ 24.5
(CH2CH2CH2CH2C=), 25.9 (CH2CH2CH2CH2C=), 26.3 (CH2CH2CH2CH2C=), 32.2
(CH2CH2CH2CH2C=), 67.5 (2CH, C5H4), 68.0 (2CH, C5H4), 69.8 (2CH, C5H4), 70.9 (2CH,
C5H4), 86.4 (C, C5H4), 88.7 (C, C5H4), 115.7 (2CH, C6H4), 126.5 (CH, C6H5), 128.7 (2CH,
C6H5), 130.1 (2CH, C6H5), 130.9 (2CH, C6H4), 135.1 (C, CH2C=C), 136.6 (C, C=CꢀC, C6H4),
139.9 (C, CH2C=C), 146.1 (C, C=CꢀC, C6H5), 156.5 (C, CꢀOH, C6H4). MS (CI, NH3): m/z
435.1 [M+H]+. HRMS (ESI, C28H26FeO: [M]+•) calcd: 434.13276, found: 434.13261.
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Elemental analysis: Calcd for C28H26FeO(H2O)0.1: C, 77.10; H, 6.05. Found: C, 76.90; H,
6.01.
Synthesis of 1ꢀ[bisꢀ(4ꢀhydroxyphenyl)methylidene]ꢀ[3]ruthenocenophane, 13
The synthetic procedure of 13 is similar to that of 8. Titanium (IV) chloride (0.23 mL, 2.15
mmol), zinc powder (0.279 g, 4.3 mmol), THF: 5 mL. [3]ruthenocenophanꢀ1ꢀone (0.100 g,
0.43 mmol), 4,4’ꢀdihydroxybenzophenone (0.184 g, 0.86 mmol), THF: 5 mL. After cooling to
room temperature, the mixture was poured into water, acidified with diluted hydrochloric acid
and extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water, dried
over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product
was chromatographed on silica gel column using diethyl ether:petroleum ether 1:1 as an
eluent. Compound 13 was obtained as a beige solid (0.155 g, 77%). 13 was crystallized from
1
acetone:heptane (mp = 270°C). H NMR (300 MHz, acetoneꢀd6): δ 2.19 (m, 2H, CH2), 2.35
(m, 2H, CH2), 4.32 (m, 2H, C5H4), 4.45 (m, 4H, C5H4), 4.61 (m, 2H, C5H4), 6.61 (d, J = 8.7
Hz, 2H, C6H4), 6.80 (d, J = 8.7 Hz, 2H, C6H4), 6.94 (d, J = 8.7 Hz, 2H, C6H4), 7.00 (d, J = 8.7
Hz, 2H, C6H4), 8.22 (s, 1H, OH), 8.35 (s, 1H, OH). 13C NMR (75 MHz, acetoneꢀd6): δ 29.4
(CH2), 44.6 (CH2), 72.3 (2x2CH, C5H4), 72.7 (2CH, C5H4), 73.1 (2CH, C5H4), 85.2 (C, C5H4),
88.4 (C, C5H4), 115.0 (2CH, C6H4), 115.7 (2CH, C6H4), 131.1 (2CH, C6H4), 132.5 (2CH,
C6H4), 135.9 and 142.4 (1C, 1C, C=C), 156.6 and 157.1 (1C, 1C, CꢀOH). MS (CI, NH3):
469.10 [M+H]+. HRMS (ESI, C26H22RuO2: [M]+•) calcd: 468.06578, found: 468.06579.
Elemental analysis: C26H22RuO2. Calc.: C, 66.79; H, 4.74. Found : C, 66.26; H, 4.39.
Synthesis of 1,3ꢀbisꢀ[bisꢀ(4ꢀhydroxyphenyl)methylidene]ꢀ[5]ferrocenophane, 14
The synthetic procedure of 14 is similar to that of 8. Titanium (IV) chloride (2.79 mL, 25.5
mmol), zinc powder (3.33 g, 51 mmol), THF: 30 mL. [5]ferrocenocenophanꢀ1,5ꢀdione (0.240
g, 0.85 mmol), 4,4’ꢀdihydroxybenzophenone (1.82 g, 8.5 mmol), THF: 15 mL. Reflux time:
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1.5 h. After cooling to room temperature, the mixture was poured into water (100 mL). The
solution was acidified with diluted HCl solution and extracted with ethyl acetate (3 x 50 mL).
The organic layer was washed with water, dried over magnesium sulfate, filtered and
evaporated under reduced pressure. The crude product was dissolved in acetone, then, diethyl
ether was added. 187 mg of 4,4’ꢀdihydroxybenzophenone precipitated from the solution. The
solution, separated from the solid, was successively chromatographed three times on silica gel
column with diethyl ether as eluent. The fraction containing the product was purified with
preparative HPLC, using silica gel column and diethyl ether as eluent. 28 mg of the product,
containing about 20 % of another compound, was isolated. A second purification with
preparative HPLC, using C18 reverse phase column and acetonitrile as eluent, gave 10 mg of
pure 14 as a red solid (2% yield). 1H NMR (300 MHz, acetoneꢀd6): δ 2.35 (m, 2H, CH2), 2.61
(m, 4H, 2CH2), 3.94 (m, 4H, C5H4), 3.97 (m, 4H, C5H4), 6.58, 6.74, 6.77, and 6.99 (4d, 16H,
2x2 C6H4), 8.11 (s, 2OH), 8.22 (s, 2OH). 13C NMR (75 MHz, acetoneꢀd6): δ 29.5 (CH2), 32.9
(2CH2), 67.9 (2x2CH, C5H4), 71.1 (2x2CH, C5H4), 90.4 (2C, C5H4), 115.3 (2x2CH, C6H4),
115.6 (2x2CH, C6H4), 131.1 (2x2CH, C6H4), 131.8 (2x2CH, C6H4), 134.7 (2C), 136.6 (2C),
136.8 (C), 141.0 (C), 156.3 (2C), 156.6 (2C). HRMS (ESI, C41H34O4Fe+•) calcd: 646.1806,
found: 646.1794.
Synthesis of 1,3ꢀbisꢀ[bisꢀ(4ꢀhydroxyphenyl)methylidene]ꢀ[5]ruthenocenophane, 15
The synthetic procedure of 15 is similar to that of 8. Titanium (IV) chloride (0.16 mL, 1.5
mmol), zinc powder (195 mg, 3 mmol), THF: 5 mL. [5]ruthenocenophanꢀ1,5ꢀdione (85 mg,
0.25 mmol), 4,4’ꢀdihydroxybenzophenone (214 mg, 1 mmol), THF: 8 mL. Reflux time: 3 h.
After cooling to room temperature, the mixture was poured into water (60 mL). The solution
was acidified with diluted HCl solution and extracted with ethyl acetate (2 x 50 mL). The
organic layer was washed with water, dried over magnesium sulfate, filtered and evaporated
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under reduced pressure. The crude product was chromatographed on silica gel column using
ethyl acetate:petroleum ether 1:1 as eluent. First fraction, 71 mg, contains mainly the
remaining 4,4’ꢀdihydroxybenzophenone, and small amounts of [5]ruthenocenophaneꢀ1,5ꢀ
dione and the monocoupling compound. Second fraction, 69 mg, corresponds to the
dicoupling compound 15, with small amount of the homo coupling dihydroxybenzophenone
compounds. A second purification by silica gel column, using diethyl ether 4:1 as eluent, gave
1
15 as white powder (49 mg, 28%). H NMR (300 MHz, acetoneꢀd6): δ 2.18 (m, 2H, CH2),
2.37 (t, J = 6.6 Hz, 4H, 2CH2), 4.29 (t, J = 1.6 Hz, 4H, C5H4), 4.41 (t, J = 1.6 Hz, 4H, C5H4),
6.62, 6.73, 6.83, and 6.93 (4d, 16H, 2x2C6H4), 8.16 (s, 2x2OH). 13C NMR (75 MHz, acetoneꢀ
d6): δ 30.0 (CH2), 33.9 (2CH2), 69.6 (2x2CH, C5H4), 74.1 (2x2CH, C5H4), 94.5 (2C, C5H4),
115.3 (2x2CH, C6H4), 115.6 (2x2CH, C6H4), 130.9 (2x2CH, C6H4), 131.9 (2x2CH, C6H4),
134.0 (2C), 136.5 (2C), 136.7 (C), 141.1 (C), 156.4 (2C), 156.7 (2C). HRMS (ESI,
C41H34O4Ru+•) calcd: 692.1501, found: 692.1524.
Typical procedure of oxidation with Ag2O
Substrate (around 20 mg, 1 equiv.) was dissolved in 1 mL of acetoneꢀd6. Freshly prepared
silver oxide (5 equiv.) was added and the mixture was sonicated for 1ꢀ2h until total
conversion of the starting material. Silver oxide was removed by centrifugation (6 min., 3500
rpm) and the solution was transferred immediately into an NMR tube.
1ꢀ([2,5ꢀDienꢀ4ꢀoxoꢀcyclohexanilidenyl]phenyl)methylꢀ1,4ꢀ(ferroceneꢀ1,1’ꢀdiyl)ꢀbutꢀ1ꢀene,
23
1H NMR (400 MHz, acetoneꢀd6): δ 2.14ꢀ2.16 (m, 2H, CH2CH2CH=), 2.73ꢀ2.78 (m, 2H,
CH2CH2CH=), 4.05 (t, J = 1.8 Hz, 2H, C5H4), 4.10 (t, J = 1.8 Hz, 2H, C5H4), 4.11 (s, 4H,
C5H4), 6.16 (t, J = 8.6 Hz, 1H, CH2CH2CH=), 6.29 (dd, J = 10 and 2.1 Hz, 1H, C6H4), 6.38
(dd, J = 10 and 2.1 Hz, 1H, C6H4), 7.25 (dd, J = 10 and 2.1 Hz, 1H, C6H4), 7.39ꢀ7.40 (m, 5H,
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C6H5), 7.81 (dd, J = 10 and 2.1 Hz, 1H, C6H4). 13C NMR (100.6 MHz, acetoneꢀd6): δ 21.8
(CH2CH2CH=), 29.4 (CH2CH2CH=), 69.7 (2CH, C5H4), 69.9 (2CH, C5H4), 70.4 (2CH, C5H4),
71.1 (2CH, C5H4), 86.2 (C, C5H4), 82.7 (C, C5H4), 128.6 (2CH, C6H4), 128.9 (2CH, C6H5),
129.1 (CH, C6H4), 129.6 (C, C6H4), 130.4 (CH, C6H5), 132.1 (2CH, C6H5), 138.2 (C, CH=C),
138.9 (CH, CH=C), 139.1 (C, C6H5), 139.7 (CH, C6H4), 140.0 (CH, C6H4), 162.7 (C, =Cꢀ
C6H5), 186.8 (CO). MS (CI, NH3): m/z = 419.06 [M+H]+.
1ꢀ([2,5ꢀDienꢀ4ꢀoxoꢀcyclohexanilidenyl]phenyl)methylꢀ1,5ꢀ(ferroceneꢀ1,1’ꢀdiyl)ꢀpentꢀ1ꢀ
ene, 24
1H NMR (400 MHz, acetoneꢀd6): δ 1.84 (qint, J = 6.4 Hz, 2H, CH2CH2CH2CH=), 2.5 (t, J =
6.4 Hz, 2H, CH2CH2CH2CH=), 2.80 (bd, 2H, CH2CH2CH2CH=), 4.13 (m, 3H, C5H4), 4.19
(m, 1H, C5H4), 5.92 (t, J = 8.8 Hz, 1H, CH2CH2CH2CH=), 6.25 (dd, 1H, C6H4), 6.31 (large d,
J = 10 Hz, 1H, C6H4), 7.17 (dd, 1H, C6H4), 7.34ꢀ7.36 (m, 2H, C6H5), 7.39ꢀ7.42 (m, 3H,
C6H5), 7.78 (large d, J = 10 Hz, 1H, C6H4). 13C NMR (100.6 MHz, acetoneꢀd6): δ 23.2
(CH2CH2CH2CH=), 23.5 (CH2CH2CH2CH=), 26.2 (CH2CH2CH2CH=), 68.3 (2CH, C5H4),
68.5 (2CH, C5H4), 69.0 (2CH, C5H4), 71.7 (2CH, C5H4), 85.5 (C, C5H4), 87.0 (C, C5H4),
128.4 (2CH, C6H4), 128.8 (2CH, C6H5), 128.9 (CH, C6H5), 129.3 (C, C6H4), 130.2 (CH,
C6H5), 131.9 (2CH, C6H5), 138.5 (C, CH=C), 139.7 (C + 2CH, CH=C + C6H5 + C6H4), 163.7
(C, =CꢀC6H5), 186.7 (CO). MS (CI, NH3): m/z = 433.10 [M+H]+.
Acknowledgements
24

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DOI: 10.1039/C6DT01640E
Authors acknowledge B. McGlinchey for linguistic help and the Agence Nationale de la
Recherche (grant number ANRꢀ10ꢀBLANꢀ706; Mecaferrol) for financial support. M. B.
thanks the PGG foundation for financial support.
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Graphical Abstract
HO
M
R1
OH
MDA-MB-231 cells
Structure Activity
Relationship
R2
M
3
n
OH
R3
M = Fe, Ru n = 1, 2, 3
R = H, Me
R1, R2 = H, OH
3
HO
[n]ferrocenophane and [n]ruthenocenophane derivatives with n = 3, 4, 5 have been
synthesized and their antiproliferative activity evaluated against MDAꢀMBꢀ231 cells.
Compounds with M = Fe, n = 3 are the most active ones.
28