Synthesis and antiproliferative effects of [3]ferrocenophane transposition products and pinacols obtained from McMurry cross-coupling reactions

Article abstract of DOI:10.1021/om300382h

We here report the synthesis and antiproliferative activities of two new series of ferrocenophanes obtained from McMurry cross-coupling reactions of [3]ferrocenophan-1-one with benzophenone, 4-hydroxybenzophenone, 4,4′-dihydroxybenzophenone, and 4,4′-diacetylaminobenzophenone. In addition to the main formation of olefins at reflux, tetrahedral transposition products, resulting from a pinacolic rearrangement, were also isolated in about 10% yields. Lowering the temperature of the reaction to 0 °C allowed the isolation of pinacols, which could be transformed into transposition compounds in good yields. Three ferrocenophane compounds have been characterized by X-ray crystallography: 1-(p-hydroxyphenyl)-1-phenyl-2-oxo[4]ferrocenophane (7b), 1,1-diphenyl-2-oxo[4]ferrocenophane (7c), and 1-hydroxy-1-[1-hydroxy-1-[3] ferrocenophanyl][3]ferrocenophane (12) crystallize in monoclinic P2 ₁/n, triclinic P1, and monoclinic P2₁/c space groups, respectively. The antiproliferative effects on hormone-independent breast cancer cells (MDA-MB-231) of the transposition compounds are generally lower than those of their corresponding butene analogues (IC₅₀ values in micromolar versus nanomolar range). In contrast and quite surprisingly, the pinacol complexes are significantly cytotoxic (IC₅₀ in the nanomolar range), among the most cytotoxic ferrocene compounds prepared so far. This antiproliferative activity may be linked to their oxidative cleavage.

Full text of DOI:10.1021/om300382h

Article
pubs.acs.org/Organometallics
Synthesis and Antiproliferative Effects of [3]Ferrocenophane
Transposition Products and Pinacols Obtained from McMurry Cross-
Coupling Reactions
Meral Gormen,†,‡ Pascal Pigeon,†,‡ Elizabeth A. Hillard,†,‡ Anne Vessieres,†,‡ Michel Huche,†,‡
̀
́
̈
Marie-Aude Richard,†,‡ Michael J. McGlinchey,§ Siden Top,*,†,‡ and Gerard Jaouen*,†,‡
́
†ENSCP Chimie ParisTech, Laboratoire Charles Friedel (LCF), 75005 Paris, France
‡CNRS, UMR 7223, 75005 Paris, France
§UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
S
* Supporting Information
ABSTRACT: We here report the synthesis and antiprolifer-
ative activities of two new series of ferrocenophanes obtained
from McMurry cross-coupling reactions of [3]ferrocenophan-
1-one with benzophenone, 4-hydroxybenzophenone, 4,4′-
dihydroxybenzophenone, and 4,4′-diacetylaminobenzophe-
none. In addition to the main formation of olefins at reflux,
tetrahedral transposition products, resulting from a pinacolic
rearrangement, were also isolated in about 10% yields.
Lowering the temperature of the reaction to 0 °C allowed
the isolation of pinacols, which could be transformed into
transposition compounds in good yields. Three ferroceno-
phane compounds have been characterized by X-ray
crystallography: 1-(p-hydroxyphenyl)-1-phenyl-2-oxo[4]ferrocenophane (7b), 1,1-diphenyl-2-oxo[4]ferrocenophane (7c), and
1-hydroxy-1-[1-hydroxy-1-[3]ferrocenophanyl][3]ferrocenophane (12) crystallize in monoclinic P2 /n, triclinic P1, and
̅
1
monoclinic P21/c space groups, respectively. The antiproliferative effects on hormone-independent breast cancer cells (MDA-
MB-231) of the transposition compounds are generally lower than those of their corresponding butene analogues (IC50 values in
micromolar versus nanomolar range). In contrast and quite surprisingly, the pinacol complexes are significantly cytotoxic (IC50 in
the nanomolar range), among the most cytotoxic ferrocene compounds prepared so far. This antiproliferative activity may be
linked to their oxidative cleavage.
(IC50 values of 20 and 30 μM, respectively), rendering them
not viable at the therapeutic level.10,11 We have therefore
worked to adjust these levels via organometallic modification,
and following a suitable formulation of 2a, encouraging in vivo
results have been obtained on implanted tumors in rat (9L
gliosarcoma).12
It seems likely that the presence of the redox-active ferrocene
group favors the generation of quinone methides in cancer cells,
possibly leading to cell death via interaction with nucleophiles
such as glutathione and proteins.13,14 In addition to electro-
chemical experiments, this hypothesis has been supported by
the observation that the [ferrocene-conjugated spacer-p-
phenol] motif seems to be crucial for strong antiproliferative
effects, and a change in the position of either the hydroxyl
group or the ferrocene results in weakening of the
antiproliferative effect.15,16 This behavior, first observed with
INTRODUCTION
■
Within the recent research activity in bioinorganic chemistry,
the topic of medicinal organometallic chemistry is now a
particularly fertile field.1−6 This domain can be defined as the
synthesis and evaluation of organometallic compounds for
diagnostic and therapeutic applications, as well as investigation
into their mode of action.7
We have recently shown that, in certain favorable cases, the
biological properties of organic polyphenols can be substantially
modified by substitution of a ferrocenyl entity in place of an
aryl group on the molecular skeleton. The organic diphenol 1,
ferrocenyl diphenol 2a, resveratrol 3, hydroxytamoxifen 4, and
ferrocifen 5 (Chart 1) are all known to interact with the
estrogen receptors (ER) present in MCF-7 cells. This leads, at
low concentration, to an estrogenic (proliferative) effect for 1,
2a, and 3 and to an antiestrogenic (antiproliferative) effect for 4
and 5 due to specific interactions of the hormone-receptor
complex with DNA. Interestingly, the ferrocenyl derivatives 2a
and 5 produce a powerful antiproliferative effect on MDA-MB-
231 cells, which lack the ER (IC50 around 0.5 μM). Indeed, on
this cell line 3 and 4 show only a weak antiproliferative effect
Special Issue: Organometallics in Biology and Medicine
Received: May 7, 2012
Published: July 5, 2012
© 2012 American Chemical Society
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Chart 1. Tamoxifen and Related Molecules
Scheme 1. General Trends in the Reactivity of the Pinacolate 9 Formed by [3]Ferrocenophan-1-one and Benzophenones in the
Presence of Low-Valent Titanium
MDA-MB-231 cells, pertains to other types of cancer cells as
well (prostate, colon, glioma, and melanoma, inter alia).
Importantly, healthy cells are not affected at these concen-
trations (1 μM).17−20
tetrahedral carbon core, does not apparently lend itself to the
ferrocene-mediated formation of quinone methides, thought to
be the key to the antiproliferative effects of 2 and 6, the
antiproliferative activities of 7a−d are nonetheless in the low
micromolar range. We therefore became interested in the
competitive synthesis of 6 and 7, as well as the examination of
the importance of pinacols of type 8 (Scheme 1) in their
generation. The antiproliferative effects on MDA-MB-231
cancer cells are reported for 7, 8, and some related molecules;
to our knowledge, this is the first communication concerning
the anticancer activity of organometallic pinacols.
These promising results were further elaborated through
discovery of new structures with even greater efficacy in vitro
and by a successful transition in vivo. We have already obtained
some success in vitro by changing the substituent (e.g., OH for
NH2) in series 221,22 and in formulating 2a for in vivo
administration.18,23,24 Furthermore, a cyclic series (Chart
1),25−28 for which diphenol 6a is the archetypal example, is
about 2−4 times more active than 2a in the NCI 60 cell line
panel, particularly against melanoma, leukemia, CNS cancer,
and renal cancer.28
RESULTS AND DISCUSSION
■
Synthesis. The McMurry cross-coupling reaction between
[3]-ferrocenophan-1-one31 and a disubstituted benzophenone
(Scheme 1) yielded the olefin 6 and/or the transposition
product 7, depending on the reaction conditions (Table 1).
It is commonly accepted that the pinacolate 9 is a reactive
intermediate in the McMurry reaction.29,30,32 Depending on the
nature of the reactants and the reaction conditions, the
In performing the reductive cross-coupling29,30 to obtain
series 6 molecules, we have observed that another series of
molecules, 7 (Scheme 1), resulting from a pinacolic rearrange-
ment to a transposition product is also accessible and that the
yield of this secondary product is influenced by the reaction
conditions. Although the transposition geometry, with a
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As seen in Table 1, the fate of the pinacolate is very sensitive
to the reaction temperature, and at 0 °C, evolution toward the
olefin or transposition product is slow enough that hydrolysis at
this temperature allowed us to isolate the pinacols 8b,c in good
yields (80% and 82%, respectively).35,39 Compound 8b exists as
two diastereomers, 8b1 and 8b2, which are separable by HPLC.
Treatment of the isolated pinacols 8b,c with acid generates the
transposition products 7b,c in yields of 98% and 79%,
respectively.
It is interesting to note that the reaction of [3]-
ferrocenophan-1-one in the absence of a benzophenone led
to the pinacol 12 in 53% yield. Only a small amount of the
corresponding olefin 10 or transposition product 11 (Scheme
2) was obtained after H2O hydrolysis, suggesting that the
pinacolate of [3]ferrocenophan-1-one is stable even under
reflux conditions.
Table 1. Yields of 6 and 7 According to Varying Reaction
Conditions
yield (%)
temp
series 6
series 7
reflux (THF)
55 (a)
62 (b)
93 (c)
44 (d)
23 (a)
0 (b)
10 (a)
11 (b)
0 (c)
10 (d)
12 (a)
80 (b)
71 (c)
0 (d)
0 °C
0 (c)
0 (d)
−25 °C
reflux + catechol
19 (a)
0 (a)
33 (a)
13 (a)
0 (b)
19 (b)
0 (c)
12 (c)
33 (d)
In order to study the influence of the aromatic rings on the
generation of such compounds, we examined the reaction
between [3]ferrocenophan-1-one and 4-hydroxybenzaldehyde
at 0 °C (Scheme 3). Acid hydrolysis gave the transposition
products 13 and 14, as well as unreacted starting material.
0 (d)
pinacolate can evolve toward the classic cross-coupling product
6 or toward other products, principally the transposition
product 7.33,34 For example, at THF reflux, we quantitatively
obtained the olefin 6c, while at 0 °C, only the transposition
product 7c was found after acid workup. This result is similar
for the reaction with 4-hydroxybenzophenone, although a small
quantity of the transposition product 7b was also isolated at
reflux. This suggests that the pinocolates 9b,c are quite stable at
0 °C. With 4,4′-dihydroxybenzophenone, the results were not
quite as straightforward: at both reflux and 0 °C we obtained a
mixture of the olefin 6a and the transposition product 7a,
although the ratio of 7a to 6a was improved at lower
temperatures. This indicates that the pinacolate 9a is less stable
than that of 9c, and the low yields of 6a and 7a suggest that the
pinocolate likely evolves toward other unidentified products.35
Lowering the temperature to −25 °C further stabilized 9a and
increased the yield of 7a to 33%. In the case of the
diacetamidobenzophenone, we primarily obtained the olefin
6d under reflux conditions, but at 0 °C no reaction was
observed. This is not surprising, as it is known that McMurry
coupling with aminobenzophenones proceeds relatively
slowly.36
It was recently found that the addition of catechol to the
reaction medium favors the production of the transposition
compound,37,38 by chelating the titanium ion and thus
stabilizing the pinacolate. Indeed, in the presence of catechol,
the reaction of 4,4′-diacetamidobenzophenone at reflux
permitted the isolation of 7d in 33% yield and further
deprotection of 7d by HCl gave access to the diamino
compound 7e. For the other benzophenones, the addition of
catechol blocked olefin formation but did not consistently
increase the yield of the transposition product.
Scheme 3. Cross-Coupling Reaction between
[3]Ferrocenophan-1-one and 4-Hydroxybenzaldehyde
The mechanism of transformation from the pinacolate to the
transposition product is thought to involve the in situ formation
of a carbocation by protonation and subsequent elimination of
H2O, followed by migration of a substituent toward the carbon
atom bearing the positive charge.40 A variant of this mechanism
involves the simultaneous transfer of two electrons and
substituent migration.38 It is interesting to note that all of the
benzophenones give only one type of transposition product,
while the reaction with the hydroxybenzaldehyde yields two
isomers, 13 and 14, resulting from the existence of two
possibilities for substituent migration (Scheme 4).
The identity of the final product strongly depends on where
the initial carbocation is formed. It is known that the ferrocenyl
substituent stabilizes carbocations better than does a phenyl
+
ring, according to the following reported pKR values (going
41
+
from least to most stable): <−17.3 for PhCH2 , −13.3 for
Ph2CH+,42 −5.7 for (4-MeO-C6H4)2CH+,42 −1.28 for
43
44
FcCH2 , and +0.35 for FcCH+Ph. Therefore, a priori, one
+
might anticipate that cation A should be more stable than
Scheme 2. Homocoupling of [3]Ferrocenophan-1-one
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with these observations, quantum mechanical semiempirical
PM3 calculations show that, in the case of the diphenol
compound 7a, the variation of the enthalpy activation energy
(ΔH°*) necessary for the transformation of cation A to
pinacolone C is 95.9 kcal mol−1, while that for the
transformation of cation B to pinacolone D is 26.3 kcal
mol−1. Therefore, the transformation of B to D is the more
favorable process.
Scheme 4. Pinacolic Rearrangement
The migration of the ferrocenyl group instead of the aryl
group may also be favored due to an additional contribution of
strain release by cycle expansion. This would explain the
exclusive formation of the D type compound. In the case of 4-
OH-benzaldehyde, the contribution to the stability of the
cation comes only from one aromatic ring, and thus the role of
these effects on the stability of cations A and B should be
similar. However, compound 13, the ring expansion product, is
the major product in this reaction.
X-ray Structures. Suitable crystals of 7b,c and 12 were
obtained from dichloromethane/hexane or ether. ORTEP
diagrams are shown in Figure 1, crystallographic data are
given in Table S1 in the Supporting Information, and selected
bond distances and bond angles are collected in Table 2.
In the [4]ferrocenophanes 7b,c, the dihedral angle between
the η5-C5H4 ring planes is close to parallel: 6(1) and 7(1)° in
the two independent molecules of 7b and 2.7(2)° in 7c. In 12,
the bis[3]ferrocenophane system, these angles have widened
somewhat to 8.6(1) and 10.2(1)° as a consequence of the
shorter chain connecting the cyclopentadienyl rings. Interest-
ingly, in 7b and 12, the Cp rings are very nearly eclipsed,
whereas in 7c they are almost perfectly staggered. Most of the
bond distances and bond angles of 7b,c are similar. Compound
7b is a racemate, and only the S enantiomer is shown. The
pinacol 12 also crystallizes as a racemic mixture, and the
molecule shown in Figure 1 is the S,S enantiomer; the dihedral
angle between the two hydroxy groups is 46.7°.
cation B in Scheme 4. However, the reactions with the
benzophenones exclusively give molecules of type D: that is,
those proceeding via cation B. Although stabilization of the
cation located β to the ferrocenyl unit has been observed in
cyclic systems, this occurs via a through-space interaction when
the cation is on the bridging carbon.45,46 This is not the case
here; instead, the β-carbon is positioned far from the ferrocenyl
moiety. However, the rigidity of the bridge may impair a
through-space stabilization of cation A with the iron atom,
which is an important contribution to the stability of the cation
[FcCH2]+. Thus, the destabilization of cation A relative to
cation B could be attributable to the lack of a stabilizing
contribution of the iron atom to the α position. Indeed, the
destabilization of the cation in the [3]ferrocenophane series
+
compared to the ferrocene series is reflected by its pKR value
of −3.2 for an α cation of [3]ferrocenophane,47 which is thus
less stable than FcCH2 but still more stable than the Ph2CH+
+
cation.
However, the rearrangement process is not controlled solely
by the identity of the initially generated cation. The different
abilities of the competing fragments to undergo migration can
also be a dominant factor. McGlinchey et al. have isolated a
pinacolic rearrangement product from a McMurry homocou-
pling of (η5-acetylcyclopentadienyl)cobalt(η4-tetraphenylcyclo-
butadiene) (Scheme 5).40
The preferential migration of the cobalt sandwich moiety
rather than a methyl group is rationalized in terms of the
enhanced migratory aptitude of the organometallic moiety in
such a way that the positive charge can be delocalized onto the
metal center in the transition state. The ferrocenyl moiety
should likewise possess this migration capacity. In agreement
Antiproliferative Activities. The antiproliferative effects
of all the new compounds against hormone-independent MDA-
MB-231 breast cancer cells were evaluated (Table 3).
In general, the transposition compounds are not very active,
with IC50 values between 9.38 and 20.1 μM. Compound 7b,
with one hydroxy group, is the exception, with an IC50 value of
1.45 μM. Compound 13, which possesses only one
hydroxyphenyl group, is completely inactive. However,
compound 14, which also possesses one hydroxyphenyl
group has activity comparable to that of 7b, evidently due to
the presence of an aldehyde group.
Most remarkably, the pinacols 8 are all very active, and the
isomer 8b1 has the best activity with an IC50 value of 0.06 μM.
This is one of the most antiproliferative compounds prepared
to date in our laboratory. In this series, it is clear that the
phenol group does not play an important role, as 8c, which
lacks this function, is one of the most active compounds with an
IC50 value of 0.17 μM. Finally, the pinacol 12 has only
moderate activity, which may be a consequence of the low
accessibility to the OH group that is sterically blocked by bulky
neighboring groups.
Scheme 5. Proposed Rearrangement Mechanism for a
Cobalt Sandwich Complex
Reactivity Studies. We next turned our attention to
possible chemical transformations that could be involved in the
toxicity of these molecules. An interesting observation was
made from the mass spectrum of 7a (Supporting Information).
In chemical ionization mode, using NH3 as a vector gas, the
following ions were detected: m/z 456 [M + NH4]+, 439 [M +
H]+, and 345 [M − C6H5OH]+. The last peak corresponds to
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Figure 1. ORTEP diagrams of 7b,c and 12.
Table 2. Selected Bond Distances (Å) and Bond Angles (deg) for 7b,c and 12
7b
7c
12
Fe1−CCp
CCp−CCp
C1−C11
C11−C12
C11−C21
C12−C13
O1−C12
C6−C14
O2−C24
C13−C14
2.030(8)−2.095(4)
1.383(18)−1.442(7)
1.549(6)
2.056(19)−2.081(16)
1.419(4)−1.448(2)
1.556(2)
Fe1−CCp
Fe2−CCp
2.0162(16)−2.047(17)
2.0088(15)−2.058(17)
1.414(3)−1.434(2)
1.416(2)−1.434(2)
1.576(2)
C
Cp-CCp(Fe1)
1.562(5)
1.568(2)
C
Cp-CCp(Fe2)
1.549(5)
1.554(2)
C11−C26
C11−O1
C26−O2
C1−C11
C11−C12
C12−C13
1.518(7)
1.530(2)
1.4291(19)
1.231(5)
1.222(2)
1.4371(19)
1.508(7)
1.520(3)
1.515(2)
1.371(5)
1.543(2)
1.531(6)
1.544(3)
1.532(2)
C13−C6
1.496(2)
C1−C11−C12
C12−C11−C15
C12−C11−C21
C11−C12−C13
O1−C12−C13
O1−C12−C11
102.0(3)
111.8(3)
112.7(3)
120.0(4)
120.3(4)
119.7(4)
107.53(13)
107.52(13)
110.72(13)
118.40(14)
119.34(16)
122.23(15)
C1−C11−C12
C1−C11−C26
C1−C11−O1
C12−C11−C26
111.53(13)
113.25(13)
105.98(12)
109.77(12)
the loss of a C6H5OH group to generate the cation 7a′ (Scheme
6). The same process was observed when NH3 was replaced by
ND3. The mass spectrum of the diamine 7e shows this
fragmentation pattern as well.
process cannot be entirely discounted. It should also be
mentioned that the activation energies for 7a,b are the same,
while their biological activities are very different, suggesting that
their activity cannot be explained solely in terms of chemical
transformations.
In the case of pinacols 8b,c their activities cannot be
obviously linked with quinone methide formation, as the
presence of a phenol group is not a major factor in their
activity. These pinacols easily evolve to transposition products
in acidic medium. As transposition products have considerably
lower activity than the pinacols themselves, it is clear that the
transposition compounds are not their active metabolites. One
might postulate that the activity of pinacols is linked to the
reaction of the cation intermediate generated with any
nucleophile present in the medium. We have investigated this
reaction by using methanol as a nucleophile and have shown
that this type of reaction is instantaneous.48
We have also examined the fragmentation observed in mass
spectrometry by a theoretical approach. The potential energy
curves for the displacement of one phenol group of 7aH+ and
7bH+ (protonated ketones) and for the displacement of one
aniline group of 7eH+ were calculated using semiempirical PM3
methods. The calculations were carried out by starting to
protonate the oxygen atom, and then the phenyl bond to be
broken was gradually lengthened from 1.517 to 5.517 Å (in 81
steps). Figure 2 shows the calculated curve of energy versus
bond distance for 7aH+.
Enthalpies of activation (ΔH°*) of 50.3, 50.8, and 80.5 kcal
mol−1 and variations of the enthalpy of the reaction (ΔrH°) of
−32.3, −32.5, and −108.3 kcal mol−1 were obtained for 7a,b,e,
respectively. While these exothermic reactions indicate that the
formation of the cations 7a′,b′,e′ are thermodynamically
favorable, the high activation energies needed to lose the aryl
ring seem to preclude this transformation under biological
conditions, although the involvement of enzymes in such a
When concentrated H2SO4 was added to the solution of 8c
in methanol (Scheme 7), only the formation of 7c was
observed with no trace of the methoxy compound 15,
indicating that the pinacolic rearrangement is faster than the
reaction of methanol and suggesting that migration and loss of
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Having ruled out a carbocation species as the active
intermediate, we turned our attention to the pinacolate and
its interaction with electrophiles. The pinacolate was prepared
by addition of sodium hydride to a THF solution of 8c
(Scheme 8). Addition of iodomethane to the pinacolate
suspension led to the formation of ferrocenophanone and
benzophenone with no trace of 16, thus revealing an oxidation
process. The oxidation of pinacol is a well-known reaction and
has been extensively studied. It has been found that several
metals,49 O2,50,51 H2O2,52 and N-iodosuccinimide53 can oxidize
pinacol to radicals which undergo cleavage to ketones. We
found that addition of H2O2 or N-bromosuccinimide to a THF
solution of 8c led to the formation of benzophenone with
complete disappearance of starting material. Ferrocenophanone
was only detected in small amounts (5%) in the case of NBS
addition. The very low yield of ferrocenophanone may be
attributed to its sensitivity toward oxidizing reagents, and the
antiproliferative activity of pinacols may also be linked to these
oxidative cleavage properties. The involvement of redox
systems in cells which are not present in normal cells has
been exemplified with hydroxyferrocifen and related species18,54
and with aminoferrocenyl-based prodrugs.58 This is in agree-
ment with the observed antiproliferative effects. Moreover, in
this case, quinone methides have been isolated.14
Table 3. IC50 Values (μM) of Compounds on Breast Cancer
Cells (MDA-MB-231)
CONCLUSIONS
■
Scheme 6. Mass Fragmentation of 7a
We have described the synthesis and antiproliferative activities
of two new series of ferrocenophanes obtained from the
McMurry cross-coupling reaction between [3]ferrocenophan-1-
one and benzophenone derivatives and have also studied the
conditions of their production. The first series concerns
transposition compounds 7a−d, resulting from a pinacolic
rearrangement occurring within the reaction. The second series
comprises the intermediate pinacols that could be isolated from
the reaction. The antiproliferative effects of transposition
compounds are moderate, while the monophenol 7b is at
least 10 times more active than diphenyl (7c), diphenol (7a),
and dianiline (7e). Surprisingly, the pinacol series is very active;
compounds 8b,c are almost as active as 6a−d and are far more
active than 7a−e. We suggest that this excellent activity is
probably linked to the oxidation of pinacols. This work will be
continued in order to gain insight into the mechanism of action
of pinacols.
water are synchronous processes. When HBF4·Et2O was added
to a yellow solution of 8c in anhydrous dichloromethane and
cooled to −70 °C, the solution immediately became blue,
characteristic of cation generation. Likewise, addition of EtONa
or HOCH2CH2SNa to the cation solution produced only
transposition compound 7c. It is clear that the pinacolic
rearrangement is a fast process and rules out a link between the
reactivity of pinacol and its cation intermediate.
Figure 2. Calculated energy versus bond distance curve for 7aH+.
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Scheme 7. Reactivity of 8c
Scheme 8. Reaction of Iodomethane on Pinacolate and Oxidation of 8c
1,1-Bis(p-hydroxyphenyl)-2-oxo[4]ferrocenophane (7a): zinc
powder (2.86 g, 43.7 mmol), titanium tetrachloride (3.43 mL, 31.2
mmol), [3]ferrocenophan-1-one (1.5 g, 6.25 mmol), p,p-dihydrox-
ybenzophenone (1.34 g, 6.25 mmol), time 2 days, T = −25 °C.
Recrystallization from acetonitrile/water gave 7a as yellow crystals
EXPERIMENTAL SECTION
■
General Remarks. All reactions were carried out under an argon
atmosphere using standard Schlenk techniques. Anhydrous THF was
obtained by distillation from sodium/benzophenone. The preparative
HPLC separations were performed on a Shimadzu apparatus with a
Nucleodur C18 column (length of 25 cm, diameter of 3.2 cm, and
particle size of 10 μm) using acetonitrile as the eluent. The analytical
HPLC controls were performed on a Shimadzu apparatus with a
Nucleodur C18 column (length of 15 cm, diameter of 0.46 cm, and
particle size of 5 μm) using acetonitrile or methanol/water as the
eluent. Infrared spectra were obtained on an IRFT BOMEM
Michelson-100 spectrometer equipped with a DTGS detector as a
1
(0.90 g, 33% yield). Mp: 230 °C dec. H NMR (300 MHz, acetone-
d6): δ 2.72−2.81 (m, 2H, CH2), 3.07−3.16 (m, 2H, CH2), 4.08 (t, J =
1.7 Hz, 2H, C5H4), 4.21 (t, J = 1.7 Hz, 2H, C5H4), 4.29 (s, 4H, C5H4),
6.74 (d, J = 8.8 Hz, 4H, C6H4), 7.04 (d, J = 8.8 Hz, 4H, C6H4), 8.24 (s,
2H, OH). 13C NMR (75.4 MHz, acetone-d6): δ 28.0 (CH2), 44.6
(CH2), 69.0 (2CH, C5H4), 69.2 (2CH, C5H4), 70.3 (C), 72.7 (2CH,
C5H4), 74.2 (2CH, C5H4), 88.6 (Cip), 93.9 (Cip), 115.9 (2 × 2CH,
C6H4), 132.1 (2 × 2CH, C6H4), 137.2 (2C, C6H4), 157.2 (2C, C6H4),
205.5 (CO). IR (KBr, ν, cm−1): 3380 (OH), 3010, 2914, 2856 (CH2),
1681 (CO). MS (CI, NH3): m/z 439 [M + H]+, 456 [M + NH4]+.
HRMS (ESI, C26H22FeNaO3 [M + Na]+): calcd 461.081 18, found
461.081 76. Anal. Calcd for C26H22FeO3·H2O: C, 68.43; H, 5.30.
Found: C, 67.93; H, 5.16.
1
KBr plate. H and 13C NMR spectra were recorded on a 300 MHz
Bruker spectrometer. Mass spectrometry was performed with a
Nermag R 10-10C spectrometer. HRMS measurements were
performed on a Thermo Fischer LTQ-Orbitrap XL apparatus
equipped with an electrospray source by the Institut Parisien de
́ ́
Chimie Moleculaire (UMR 7201), Universite Pierre et Marie Curie,
1-(p-Hydroxyphenyl)-1-phenyl-2-oxo[4]ferrocenophane (7b):
zinc powder (0.95 g, 14.6 mmol), titanium tetrachloride (1.14 mL,
10.4 mmol), [3]ferrocenophan-1-one (0.5 g, 2.08 mmol), p-
hydroxybenzophenone (0.41 g, 2.08 mmol), time 2 h, T = 0 °C.
Concentrated HCl (10.2 mL, 125.0 mmol) was added, and the mixture
was stirred for 1 h at 0 °C. Recrystallization from diethyl ether gave 7b
as orange crystals (0.70 g, 80% yield). 1H NMR (300 MHz, CDCl3): δ
2.78−2.85 (m, 2H, CH2), 3.11−3.16 (m, 2H, CH2), 4.05 (s, 2H,
C5H4), 4.20 (s, 2H, C5H4), 4.27 (s, 2H, C5H4), 4.31 (s, 2H, C5H4),
4.82 (s, 1H, OH), 6.70 (d, J = 8.7, 2H, C6H4), 7.08 (d, J = 8.7, 2H,
C6H4), 7.13−7.26 (m, 5H, C6H5). 13C NMR (75.4 MHz, CDCl3): δ
26.9 (CH2), 43.9 (CH2), 67.7 (2CH, C5H4), 67.8 and 67.9 (2CH,
C5H4), 69.9 (C), 71.3 and 71.4 (2CH, C5H4), 72.7 (2CH, C5H4), 86.2
(Cip), 92.7 (Cip), 114.8 (2CH, C6H4), 126.4 (CH, C6H5), 127.9 (2CH,
C6H4), 129.3 (2CH, C6H5), 130.6 (2CH, C6H5), 136.2 (C, C6H4),
144.2 (C, C6H4), 154.1 (C, C6H4), 204.9 (CO). IR (KBr, ν, cm−1):
3311.2 (OH), 3021, 2969, 2917, 2859 (CH2), 1678 (CO). MS (EI, 70
eV): m/z 422 [M]•+, 394 [M − CO]•+. HRMS (ESI, C26H22FeNaO2
[M + Na]+): calcd 445.086 26, found 445.086 14. Anal. Calcd for
C26H22FeO2: C, 73.94; H, 5.47. Found: C, 73.36; H, 5.47.
Paris, France. Elemental analyses were performed by the microanalysis
services of the ICSN (Gif sur Yvette, France). Due to the presence of
water or crystallization solvents, compounds 7a,d,e, 8b, and 12 did not
provide satisfactory elemental analyses. For these compounds 1H
NMR spectra are given in the Supporting Information as proof of their
purity. Melting points were measured with a Kofler device.
Determination of the cytotoxicity of the complexes was performed
at the IMAGIF (ICSN, Gif sur Yvette, France).
General Synthesis for 7a−c, 13, and 14. Zinc powder was
suspended in anhydrous THF at room temperature, and titanium
tetrachloride was slowly added via a syringe while stirring. The
reaction mixture was refluxed for 2 h and then cooled to 0 or −25 °C
(see below), after which a THF solution containing [3]ferrocenophan-
1-one and the appropriate benzophenone were added. After the
reaction was complete (see below), the reaction mixture was poured
into water and extracted with dichloromethane. The organic layer was
washed with water, dried over magnesium sulfate, and filtered, and the
solvent was evaporated. The oil was purified by HPLC. Recrystalliza-
tions were performed from convenient solvent systems.
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1,1-Diphenyl-2-oxo[4]ferrocenophane (7c): zinc powder (0.95 g,
14.6 mmol), titanium tetrachloride (1.14 mL, 10.4 mmol), [3]-
ferrocenophan-1-one (0.5 g, 2.08 mmol), benzophenone (0.38 g, 2.1
mmol), time 2 h, T = 0 °C. The solvent was then evaporated, the oily
reaction mixture was dissolved in CH2Cl2 and cooled to 0 °C, and
concentrated HCl (38.5 mL, 468.6 mmol) was added portion by
portion and then the mixture was stirred for 1 day at room
temperature. Recrystallization from hexane/dichloromethane gave 7c
purified by HPLC. Recrystallization was performed in hexane/
dichloromethane. Compound 7d was obtained as yellow crystals
(0.17 g, 33% yield). Mp: 286 °C dec. H NMR (300 MHz, DMSO-
1
d6): δ 1.99 (s, 6H, CH3), 2.67−2.71 (m, 2H, CH2), 3.08−3.12 (m, 2H,
CH2), 4.05 (s, 2H, C5H4), 4.18−4.20 (m, 4H, C5H4), 4.32 (s, 2H,
C5H4), 7.05 (d, J = 8.7, 4H, C6H4), 7.40 (d, J = 8.7, 4H, C6H4), 9.88
(s, 2H, NH). 13C NMR (75.4 MHz, DMSO-d6): δ 23.8 (2CH3), 26.3
(CH2), 42.9 (CH2), 67.2 (2CH, C5H4), 67.4 (2CH, C5H4), 69.0 (C),
70.6 (2CH, C5H4), 71.8 (2CH, C5H4), 86.2 (Cip), 92.7 (Cip), 118.2 (2
× 2CH, C6H4), 129.0 (2 × 2CH, C6H4), 137.1 (2C, C6H4), 139.1 (2C
C6H4), 168.1 (2CONH), 203.7 (CO). IR (KBr, ν, cm−1): 3289, 3247
(NH), 3111, 3058 (CH3, CH2), 1698 (CO), 1663 (CO). MS (EI, 70
eV): m/z 520 [M]+., 492 [M − CO]+., 400, 357, 179. HRMS (ESI,
C30H28FeN2NaO3 [M + Na]+): calcd 543.134 30, found 543.133 04.
Anal. Calcd for C30H28FeN2O3: C, 69.23; H, 5.42; N, 5.38. Found: C,
68.74; H, 5.65; N, 5.62.
1
as orange crystals (0.6 g, 71% yield). Mp: 177 °C. H NMR (300
MHz, CDCl3): δ 2.81−2.85 (m, 2H, CH2), 3.13−3.17 (m, 2H, CH2),
4.04 (t, J = 1.7, 2H, C5H4), 4.20 (t, J = 1.7, 2H, C5H4), 4.27 (t, J = 1.7,
2H, C5H4), 4.33 (t, J = 1.7, 2H, C5H4), 7.12−7.20 (m, 2H, C6H5), 7.22
(s, 5H, C6H5), 7.23 (s, 3H, C6H5). 13C NMR (75.4 MHz, CDCl3): δ
26.9 (CH2), 44.0 (CH2), 67.7 (2CH, C5H4), 67.9 (2CH, C5H4), 70.5
(C), 71.3 (2CH, C5H4), 72.7 (2CH, C5H4), 83.3 (Cip), 92.9 (Cip),
126.5 (2 × 1CH, C6H5), 127.9 (2 × 2CH, C6H5), 129.4 (2 × 2CH,
C6H5), 144.2 (2 × 1C C6H5), 204.2 (CO). IR (KBr, ν, cm−1): 2926
(CH2), 1698 (CO). MS (EI, 70 eV): m/z 406 [M]•+, 378 [M −
CO]•+, 301, 228, 165. Anal. Calcd for C26H22FeO: C, 76.85; H, 5.45.
Found: C, 76.81; H, 5.38.
1,1-Bis(p-aminophenyl)-2-oxo[4]ferrocenophane (7e). 1,1-
Bis(p-acetamidophenyl)-2-oxo[4]ferrocenophane (7d; 0.23 g, 0.44
mmol) was dissolved in ethanol, and concentrated hydrochloric acid
(8.7 mL, 106 mmol) was added. The solution was refluxed for 3 days.
After it was cooled to room temperature, the solution was poured into
a saturated NaHCO3 solution portion by portion. Water was added,
the solution was extracted with dichloromethane, the solvent was
removed under reduced pressure, and the product was purified by
column flash chromatography (diethyl ether/petroleum ether 2/1).
Recrystallization from dichloromethane/hexane gave 7e as orange-
1-(p-Hydroxyphenyl)-2-oxo[4]ferrocenophane (13) and 1-(p-
Hydroxyphenyl)-1-formyl[3]ferrocenophane (14): zinc powder
(0.95 g, 14.6 mmol), titanium tetrachloride (1.14 mL, 10.4 mmol),
[3]ferrocenophan-1-one (0.5 g, 2.08 mmol), p-hydroxybenzaldehyde
(0.76 g, 6.20 mmol), T = 0 °C, time one night. Concentrated HCl
(10.3 mL, 125.0 mmol) was added, and the mixture was stirred for 4 h
at 0 °C. The crude product was subjected to column chromatography
with diethyl ether/petroleum ether as eluent. Two fractions were
collected. Recrystallization of the first fraction from dichloromethane/
pentane gave 13 as orange crystals (0.19 g, 27% yield, mp 212 °C). 1H
NMR (300 MHz, acetone-d6): δ 2.49−2.71 (m, 2H, CH2), 2.88−3.06
(m, 2H, CH2), 3.90−4.06 (m, 6H, C5H4), 4.08−4.10 (m, 1H, C5H4),
4.14−4.16 (m, 1H, C5H4), 4.99 (s, 1H, CH), 6.55 (d, J = 8.4 Hz, 2H,
C6H4), 6.95 (d, J = 8.4 Hz, 2H, C6H4), 8.02 (s, 1H, OH). 13C NMR
(75.4 MHz, acetone-d6): δ 25.7 (CH2), 42.8 (CH2), 53.5 (CH), 68.5
(CH, C5H4), 69.0 (2CH, C5H4), 69.2 (CH, C5H4), 69.3 (CH, C5H4),
69.6 (CH, C5H4), 69.9 (CH, C5H4), 70.3 (CH, C5H4), 81.9 (Cip), 87.7
(Cip), 115.3 (2CH, C6H4), 130.4 (2CH, C6H4), 132.3 (C, C6H4),
157.0 (C, C6H4), 207.7 (CO). MS (CI, NH3): m/z 347 [M + H]+, 364
[M + NH4]+. Anal. Calcd for C20H18FeO2: C, 69.38; H, 5.24. Found:
C, 69.61; H, 5.23. Recrystallization of the second fraction from
dichloromethane/pentane gave 14 as orange crystals (0.04 g, 7%, mp
1
yellow crystals (0.06 g, 32%). Mp: 216 °C dec. H NMR (300 MHz,
CDCl3): δ 2.75−2.79 (m, 2H, CH2), 3.07−3.11 (m, 2H, CH2), 3.58
(broad s, 4H, NH2), 4.02 (s, 2H, C5H4), 4.16 (s, 2H, C5H4), 4.21 (s,
2H, C5H4), 4.27 (s, 2H, C5H4), 6.55 (d, J = 7.5, 4H, C6H4), 6.95 (d, J
= 7.5, 4H, C6H4). 13C NMR (75.4 MHz, CDCl3): δ 26.8 (CH2), 43.5
(CH2), 67.6 (2CH, C5H4), 67.7 (2CH, C5H4), 68.9 (C), 71.3 (2CH,
C5H4), 72.9 (2CH, C5H4), 86.7 (Cip), 92.2 (Cip), 114.5 (2 × 2CH
C6H4), 130.3 (2 × 2CH, C6H4), 134.4 (2C, C6H4), 144.6 (2C, C6H4),
205.5 (CO). IR (KBr, ν, cm−1): 3351, 3218 (NH2), 3089, 3080, 3026,
2923 (CH2), 1687 (CO). MS (CI, NH3): m/z 437 [M + H]+, 344,
223. Anal. Calcd for C26H24FeN2O: C, 71.55; H, 5.55; N, 6.42. Found:
C, 68.98; H, 5.58; N, 6.19 (the NMR spectrum shows the presence of
dichloromethane and hexane).
General Synthesis for 8b,c. Zinc powder was suspended in THF
at room temperature, and titanium tetrachloride was slowly added via a
syringe with stirring. The reaction mixture was heated at reflux for 2 h
and then cooled to 0 °C, after which time a THF solution containing
[3]ferrocenophan-1-one and the appropriate amount of benzophe-
none were added. The mixture was stirred at 0 °C for 2 h. The
reaction mixture was poured into water and extracted with
dichloromethane. The organic layer was washed with water, dried
over magnesium sulfate, and filtered, and the solvent was evaporated.
The crude product was purified by flash chromatography and/or
HPLC to give the pinacol.
1-Hydroxy-1-(hydroxydiphenylmethyl)[3]ferrocenophane (8c):
zinc powder (0.95 g, 14.6 mmol), titanium tetrachloride (1.14 mL,
10.4 mmol), [3]ferrocenophan-1-one (0.5 g, 2.08 mmol), and
benzophenone (0.38 g, 2.08 mmol). The crude product was purified
by column flash chromatography with petroleum ether as eluent
followed by HPLC (acetonitrile/water 85/15). Pinacol 8c was
obtained as orange-yellow crystals (0.72 g, 82%). 1H NMR (300
MHz, CDCl3): δ 1.95−2.30 (m, 4H, CH2), 2.52 (s broad, 1H, OH),
2.86 (s broad, 1H, OH), 3.65 (s, 1H, C5H4), 3.87 (s, 1H, C5H4), 3.89
(s, 1H, C5H4), 3.95 (s, 3H, C5H4), 4.08 (s, 1H, C5H4), 4.18 (s, 1H,
C5H4), 7.11−7.23 (m, 6H, C6H5), 7.49−7.56 (m, 4H, C6H5). 13C
NMR (75.4 MHz, CDCl3): δ 19.4 (CH2), 42.9 (CH2), 67.5 (CH,
C5H4), 67.7 (CH, C5H4), 67.9 (CH, C5H4), 68.3 (CH, C5H4), 69.0
(CH, C5H4), 69.2 (CH, C5H4), 69.4 (CH, C5H4), 71.8 (CH, C5H4),
77.3 (C), 82.4 (C), 86.7 (Cip), 88.7 (Cip), 127.1 (2CH, C6H5), 127.3
(2CH, C6H5), 127.6 (2CH, C6H5), 128.5 (2CH, C6H5), 128.7 (2CH,
C6H5), 144.3 (2C). IR (KBr, ν, cm−1): 3572, 3557 (OH), 2957, 2923,
2888 (CH2). MS (EI, 70 eV): m/z 424 [M]+., 241 [C13H13FeO]+, 213,
199. MS (CI, NH3): m/z 425 [M + H]+, 407 [M + H − H2O]+, 241
[C13H13FeO]+, 199. HRMS (ESI, C26H24FeO2: [M]•+): calcd 424.112
1
166.5 °C). H NMR (300 MHz, acetone-d6): δ 2.14−2.27 (m, 1H,
CH2), 2.34−2.56 (m, 2H, CH2), 2.83−3.01 (m, 1H, CH2), 3.90−3.92
(m, 1H, C5H4), 3.98−4.00 (m, 1H, C5H4), 4.02−4.04 (m, 1H, C5H4),
4.08−4.11 (m, 2H, C5H4), 4.15−4.17 (m, 1H, C5H4), 4.18−4.21 (m,
1H, C5H4), 4.52−4.55 (m, 1H, C5H4), 6.81 (d, J = 8.7 Hz, 2H, C6H4),
7.21 (d, J = 8.7 Hz, 2H, C6H4), 8.49 (s, 1H, OH), 9.54 (s, 1H, CHO).
13C NMR (75.4 MHz, acetone-d6): δ 22.2 (CH2), 41.2 (CH2), 54.6
(C), 68.9 (CH, C5H4), 69.1 (2CH, C5H4), 69.2 (CH, C5H4), 69.3
(CH, C5H4), 69.7 (CH, C5H4), 70.0 (CH, C5H4), 71.6 (CH, C5H4),
87.6 (Cip), 89.0 (Cip), 116.2 (2CH, C6H4), 130.8 (C, C6H4), 130.9
(2CH, C6H4), 157.5 (C, C6H4), 198.7 (CO). MS (CI, NH3): m/z 347
[M + H]+, 364 [M + NH4]+, 318 [M − CHO]+. HRMS (ESI,
C20H18FeO2: [M]•+): calcd 346.065 07, found 346.065 15. Anal. Calcd
for C20H18FeO2·0.5H2O: C, 68.61; H, 5.39. Found: C, 68.11; H, 5.31.
1,1-Bis(p-acetamidophenyl-2-oxo[4]ferrocenophane (7d).
Zinc powder (0.93 g, 14.2 mmol) was suspended in THF at room
temperature, and titanium tetrachloride (1.1 mL, 10.1 mmol) was
slowly added via a syringe with stirring. The reaction mixture was
heated at reflux for 2 h and then cooled to room temperature. o-
Dihydroxybenzene (catechol; 1.12 g, 10.1 mmol) was added, and the
reaction mixture was stirred for 20 min at room temperature. The
reaction mixture was heated to reflux, after which a THF solution
containing [3]ferrocenophan-1-one (0.49 g, 2.03 mmol) and p,p-
diacetylaminobenzophenone (0.3 g, 1.01 mmol)55 were added. The
mixture was refluxed for 3 days. The reaction mixture was poured into
water, acidified with HCl, and extracted with dichloromethane. The
organic layer was washed with water, dried over magnesium sulfate,
and filtered, and the solvent was evaporated. The obtained oil was
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02, found 424.111 71. Anal. Calcd for C26H24FeO2·0.5H2O: C, 72.07;
H, 5.82. Found: C, 72.06; H, 5.83.
4H, CH2), 3.83−3.90 (m, 6H, C5H4), 3.90−3.93 (m, 2H, C5H4),
3.94−3.97 (m, 2H, C5H4), 4.07−4.11 (m, 4H, C5H4), 4.18−4.21 (m,
4H, OH + C5H4). 13C NMR (75.4 MHz, DMSO-d6): δ 19.2 (2CH2),
41.8 (2CH2), 66.6 (2CH, C5H4), 67.2 (2CH, C5H4), 67.3 (2CH,
C5H4), 67.4 (2CH, C5H4), 67.5 (2CH, C5H4), 68.4 (2CH, C5H4),
68.5 (2CH, C5H4), 71.4 (2CH, C5H4), 73.9 (2C), 86.6 (2Cip), 89.2
(2Cip). MS (EI, 70 eV): m/z 482 [M]+., 242, 199. HRMS (ESI,
C26H26Fe2O2: [M]•+): calcd 482.062 62, found 482.061 61. Anal.
Calcd for C26H26Fe2O2·0.5H2O: C, 63.57; H, 5.54. Found: C, 63.53;
H, 5.46.
Reaction of Pinacol 8c with Methanol. Compound 8c (30 mg)
was dissolved in methanol (2 mL), and 10 drops of concentrated
H2SO4 were added. After it was stirred for 1 h, the mixture was poured
into water and extracted with diethyl ether. The NMR spectrum of the
crude product obtained showed mainly the presence of 7c.
1-Hydroxy-1-(hydroxy-p-hydroxyphenylphenylmethyl)[3]-
ferrocenophane (8b): zinc powder (0.95 g, 14.6 mmol), titanium
tetrachloride (1.14 mL, 10.4 mmol), [3]ferrocenophan-1-one (0.5 g,
2.08 mmol) and 4-hydroxybenzophenone (0.41 g, 2.1 mmol). The oil
was purified by column flash chromatography (diethyl ether/
petroleum ether 1/2) followed by HPLC (acetonitrile/water 80/20).
Two diastereoisomers were obtained. Recrystallizations of the two
diastereomers were performed from ether/hexane (0.44 g, 48% and
1
0.30 g, 32%). Data for diastereomer 1 are as follows. H NMR (300
MHz, acetone-d6): δ 2.05−2.30 (m, 2H, CH2), 2.45 (s broad, 2H,
CH2), 3.45 (s, 1H, OH), 3.89 (s, 1H, C5H4), 3.94 (s, 2H, C5H4), 3.99
(s, 1H, C5H4), 4.03 (s, 1H, C5H4), 4.14 (s, 1H, C5H4), 4.19 (s, 1H,
C5H4), 4.37 (s, 1H, C5H4), 4.38 (s, 1H, OH), 6.60 (d, J = 8.7, 2H,
C6H4), 7.18−7.29 (m, 3H, C6H5), 7.46 (d, J = 8.7, 2H, C6H4), 7.78 (d,
J = 7.2, 2H, C6H5). 8.09 (s, 1H, OH). 13C NMR (75.4 MHz, acetone-
d6): δ 20.8 (CH2), 44.8 (CH2), 68.4 (CH, C5H4), 68.7 (CH, C5H4),
68.9 (CH, C5H4), 69.8 (2CH, C5H4), 70.3 (CH, C5H4), 70.9 (CH,
C5H4), 73.0 (CH, C5H4), 78.3 (C), 83.3 (Cip), 88.4 (C), 91.7 (Cip),
115.0 (2CH, C6H4), 127.8 (CH, C6H5), 128.5 (2CHarom), 130.5
(2CHarom), 131.5 (2CHarom), 138.4 (C), 148.1 (C), 157.3 (C). IR
(KBr, ν, cm−1): 3538, 3501, 3328 (OH), 2948, 2920, 2851 (CH2).
HRMS (ESI, C26H24FeNaO3 [M + Na]+): calcd 463.096 84, found
463.095 77. Anal. Calcd for C26H24FeO3: C, 70.92; H, 5.49. Found: C,
Reaction of Pinacol 8c with EtONa or HOCH2CH2SNa.
Compound 8c (42 mg, 0.1 mmol) was dissolved in 2 mL of
anhydrous CH2Cl2. The solution was cooled to −70 °C, and when
HBF4·Et2O (0.1 mL, 0.7 mmol) was added, the solution turned blue.
After 5 min, EtONa (50 mg, 0.7 mmol) was added, and after it was
stirred for 15 min, the mixture was poured into water and extracted
with diethyl ether. CCM of the crude product showed only the
presence of 7c. The analogous reaction with HOCH2CH2SNa,
prepared from 2-mercaptoethanol and NaH, gave the same result.
Reaction of Pinacol 8c with Iodomethane. 8c (42 mg, 0.1
mmol) was dissolved in 2 mL of anhydrous THF to which NaH (15
mg, 0.6 mmol) was added. After the mixture was stirred for 30 min,
iodomethane (141 mg, 1 mmol) was added and the stirring was
maintained for 1 h. The mixture was then poured into water and
extracted with diethyl ether. HPLC of the crude product obtained
showed only the presence of ferrocenophanone and benzophenone in
a 50/50 ratio.
Reaction of Pinacol 8c with Hydrogen Peroxide. Compound
8c (21 mg, 0.05 mmol) was dissolved in 1 mL of anhydrous THF. A
0.2 mL portion of hydrogen peroxide (30 wt % solution in water) was
added. The reaction was monitored by TLC and HPLC. 8c
progressively disappeared, with formation of benzophenone and two
other compounds. After 1 h of stirring, 8c completely disappeared.
Reaction of Pinacol 8c with N-Bromosuccinimide. Compound
8c (21 mg, 0.05 mmol) was dissolved in 1 mL of anhydrous THF. N-
Bromosuccinimide (9 mg, 0.05 mmol) was added. The reaction was
monitored by TLC. After 5 min of stirring 8c almost disappeared with
formation of ferrocenophanone and benzophenone. HPLC showed
the presence of ferrocenophanone and benzophenone in a 5/95 ratio.
X-ray Crystal Structure Determinations for 7b,c and 12.
Crystal data were collected at 200 K with a Kappa-CCD Enraf-Nonius
diffractometer with Mo Kα radiation. The structures were solved by
direct methods and refined by full-matrix least-squares techniques on F
using the CRYSTALS programs.56,57 All non-hydrogen atoms were
refined with anisotropic displacement parameters. All hydrogen atoms
were located with geometrical restraints in riding mode. Crystallo-
graphic data for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publications CCDC 886312−886314. Copies of this
information may be obtained free of charge from The Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax, +44-1223-
336033; e-mail, deposit@ccdc.cam.ac.uk; web, http://www.ccdc.cam.
ac.uk).
1
70.92; H, 5.51. Data for diastereomer 2 are as follows. H NMR (300
MHz, acetone-d6): δ 2.05−2.35 (m, 2H, CH2), 2.33 (s broad, 2H,
CH2), 3.44 (s, 1H, OH), 3.71 (s broad, 2H, C5H4), 3.75 (s, 1H,
C5H4), 3.82 (s, 1H, C5H4), 3.86 (s, 1H, C5H4), 4.02 (s, 2H, C5H4),
4.17 (s, 1H, C5H4), 4.41 (s, 1H, OH), 6.57 (d, J = 8.8, 2H, C6H4),
6.87−7.00 (m, 3H, C6H5), 7.36−7.51 (m, 4H, C6H4 + C6H5), 8.03 (s,
1H, OH). 13C NMR (75.4 MHz, acetone-d6): δ 20.7 (CH2), 44.7
(CH2), 68.3 (CH, C5H4), 68.7 (CH, C5H4), 68.9 (CH, C5H4), 69.8
(2CH, C5H4), 70.3 (CH, C5H4), 70.9 (CH, C5H4), 73.0 (CH, C5H4),
78.2 (C), 83.3 (Cip), 88.5 (C), 91.6 (Cip), 115.4 (2CH, C6H4), 127.5
(CH, C6H5), 128.1 (2CHarom), 130.2 (2CHarom), 131.7 (2CHarom),
138.4 (C), 147.9 (C), 157.5 (C). IR (KBr, ν, cm−1): 3539, 3457, 3365,
(OH), 2976, 2945, 2904 (CH2). HRMS (ESI, C26H24FeO3, [M]•+):
calcd 440.106 94, found 440.106 49. Anal. Calcd for C26H24FeO3: C,
70.92; H, 5.49. Found: C, 70.34; H, 5.24.
Synthesis of 7c from 8c. To a solution of 8c (50 mg, 0.12 mmol)
in CH2Cl2 was added concentrated HCl (2.3 mL, 28.8 mmol) portion
by portion at 0 °C, and the mixture was stirred for 1 day at room
temperature. The reaction mixture was poured into water and
extracted with dichloromethane. The organic layer was washed with
water, dried over magnesium sulfate, and filtered, and the solvent was
evaporated. The crude product was purified by column flash
chromatography (petroleum ether) to give 7c (38 mg, 79%).
Synthesis of 7b from 8b. To a solution of 8b (50 mg, 0.11
mmol) in THF was added concentrated H2SO4 (0.07 mL, 1.32 mmol)
portion by portion at 0 °C. Then, the mixture was stirred for 1 h at
room temperature. The reaction mixture was poured into water and
extracted with dichloromethane. The organic layer was washed with
water, dried over magnesium sulfate, and filtered, and the solvent was
evaporated. The crude product was purified by column flash
chromatography (diethyl ether/petroleum ether), giving 7b (47 mg,
98%).
1-Hydroxy-1-[1-hydroxy-1[3]ferrocenophanyl][3]-
ferrocenophane (12). Zinc powder (0.49 g, 7.5 mmol) was
suspended in THF at room temperature, and titanium tetrachloride
(0.55 mL, 5.0 mmol) was added slowly via a syringe with stirring. The
reaction mixture was refluxed for 2 h, after which a THF solution
containing [3]ferrocenophan-1-one (0.3 g and 1.25 mmol) was added,
and the mixture was refluxed for 2 h. The reaction mixture was poured
into water and extracted with dichloromethane. The organic layer was
washed with water, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified
by flash column chromatography and recrystallized from dichloro-
Cell Culture and Cell Proliferation Assay. The breast
adenocarcinoma cell line MDA-MB-231 was obtained from ATCC.
Cells were grown in RPMI medium supplemented with 10% fetal calf
serum, in the presence of penicillin, streptomycin, and fungizone in a
75 cm2 flask under 5% CO2. Cells were plated in 96-well tissue culture
plates in 200 μL of medium and treated 24 h later with 2 μL stock
solutions of compounds dissolved in DMSO using a Biomek 3000
instrument (Beckman-Coulter). Controls received the same volume of
DMSO (1% final volume). After 72 h of exposure, MTS reagent
(Promega) was added and incubated for 3 h at 37 °C: the absorbance
was monitored at 490 nm and results expressed as the inhibition of cell
proliferation calculated as the ratio (1 − (OD490 treated/OD490
1
methane/hexane. Pinacol 12 was obtained (0.16 g, 53%). H NMR
(300 MHz, DMSO-d6): δ 1.82−2.03 (m, 4H, CH2), 2.11−2.35 (m,
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Organometallics
Article
control)) × 100 in triplicate experiments. For IC50 determination
(50% inhibition of cell proliferation), cells were incubated for 72 h
following the same protocol with compound concentrations ranging
from 5 nM to 100 μM in separate duplicate experiments.
Theoretical Calculations. Theoretical calculations were per-
formed with Spartan’4 software (Wavefunction Inc., 18401 Von
Karman Ave., Suite 370, Irvine, CA 92612). A geometry optimization
was performed on each molecule to find the absolute energetic
minimum using the semiempirical PM3 Hamiltonian.
(18) Allard, E.; Passirani, C.; Garcion, E.; Pigeon, P.; Vessier
Jaouen, G.; Benoit, J. P. J. Controlled Release 2008, 130, 146−153.
̀
(19) Michard, Q.; Jaouen, G.; Vessieres, A.; Bernard, B. A. J. Inorg.
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es, A.;
Biochem. 2008, 102, 1980−1985.
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es, A.;
Pigeon, P.; Gref, R.; Legrand, P.; Jaouen, G.; Renoir, J.-M. Int. J.
Pharm. 2008, 347, 128−135.
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Bunz, H.; Jaouen, G. Dalton Trans. 2009, 4318−4326.
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́ ́
Plamont, M. A.; Buriez, O.; Labbe, E.; Huche,
ASSOCIATED CONTENT
* Supporting Information
̀
■
́
̈
S
A table, figures, and CIF files giving crystallographic data and
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
́
̀
es, A.;
Jaouen, G.; Benoît, J. P.; Passirani, C. Pharm. Res. 2011, 28, 3189−
3198.
(24) Allard, E.; Huynh, N. T.; Vessier
Benoit, J.-P.; Passirani, C. Int. J. Pharm. 2009, 379, 317−323.
́
(25) Plazuk, D.; Vessieres, A.; Hillard, E. A.; Buriez, O.; Labbe, E.;
̀
es, A.; Pigeon, P.; Jaouen, G.;
AUTHOR INFORMATION
Corresponding Author
*G.J.: tel, 33 1 43 26 95 55; e-mail, gerard-jaouen@chimie-
paristech.fr. S.T.: tel, 33 1 44 27 66 99; e-mail. siden-top@
chimie-paristech.fr.
■
̀
Pigeon, P.; Plamont, M. A.; Amatore, C.; Zakrzewski, J.; Jaouen, G., A
J. Med. Chem. 2009, 52, 4964−4967.
(26) Gormen, M.; Pigeon, P.; Hillard, E. A.; Plamont, M. A.; Plazuk,
̇
D.; Top, S.; Vessier
120.
(27) Gormen, M.; Pigeon, P.; Top, S.; Vessier
̀
es, A.; Jaouen, G. Tetrahedron Lett. 2010, 51, 118−
Notes
The authors declare no competing financial interest.
̀
es, A.; Plamont, M.-A.;
̈
Hillard, E.; Jaouen, G. MedChemComm 2010, 1, 149−151.
(28) Gormen, M.; Pigeon, P.; Top, S.; Hillard, E. A.; Huche,
́
M.;
es, A.;
̈
ACKNOWLEDGMENTS
We thank the Agence Nationale de la Recherche for financial
support (ANR 2010 BLAN 7061 blanc “Mecaferol”) and the
Ministere des Affaires Etrangeres for a doctoral fellowship
̀ ̀
(M.G.). We thank P. Herson for crystal structure determi-
nations and T. Crestiel for tests on cancer cells.
■
Hartinger, C. G.; de Montigny, F.; Plamont, M.-A.; Vessier
Jaouen, G. ChemMedChem 2010, 5, 2039−2050.
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