Synthesis and structural characterization of ferrocenyl-substituted aurones, flavones, and flavonols

Article abstract of DOI:10.1021/om200644e

In the context of our studies on the modification of bioactive molecules with ferrocene, we here report the first examples of ferrocenyl flavonoids, where ferrocene replaces the B ring of the flavonoid skeleton. Ferrocenyl aurones possessing an electron-w

Full text of DOI:10.1021/om200644e

ARTICLE
pubs.acs.org/Organometallics
Synthesis and Structural Characterization of Ferrocenyl-Substituted
Aurones, Flavones, and Flavonols
Keshri Nath Tiwari,†,‡,^ Jean-Philippe Monserrat,†,‡,^ Frꢀederic de Montigny,†,‡ Gꢀerard Jaouen,†,‡
Marie-Noelle Rager,*,§ and Elizabeth Hillard*,†,‡
†Laboratoire Charles Friedel (LCF), ENSCP Chimie ParisTech, 75005 Paris, France
‡CNRS, UMR 7223, 75005 Paris, France
§NMR Facility, ENSCP Chimie ParisTech, 11 Rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
S Supporting Information
b
ABSTRACT: In the context of our studies on the modification
of bioactive molecules with ferrocene, we here report the first
examples of ferrocenyl flavonoids, where ferrocene replaces the
B ring of the flavonoid skeleton. Ferrocenyl aurones possessing
an electron-withdrawing or an electron-donating group in the
50-position were obtained from 50-R-20-hydroxy-3-ferrocenyl
chalcones via 1,5 oxidative exocyclization using Hg(OAc)2 or AgOTf. Treatment of the ferrocenyl aurones with LDA resulted
in a ring opening to form ferrocenyl ynones, which could then be selectively recyclized to the flavone isomer by treatment with
NaOEt. Ferrocenyl flavones were also obtained by isomerization of the aurones with KCN and were hydroxylated in the 3-position
to form ferrocenyl flavonols with oxone in a biphasic reaction. In many cases the reactivity of the ferrocenyl compounds was
significantly different from that of their organic analogues. This reactivity and regioselectivity can be rationalized by ferrocene’s
particular ability to destabilize α-anions in reaction intermediates. Representative examples of ferrocenyl aurones, ynones, and
flavones were characterized by 2D NMR and X-ray crystallography, and the molecules all show a planar arrangement of the organic
skeleton with the cyclopentadienyl ring of the ferrocene group. Putative MLCT bands in the visible region are responsible for the
variety of highly saturated colors observed.
’ INTRODUCTION
of an additional redox-active group might affect the biological
effects of flavonoids. Several coordination complexes with
chalcones16 and other flavonoids17 are known; indeed, the ability
of flavonoids to coordinate metals is considered to be part of their
antioxidant arsenal.18 Examples of organometallic flavonoids, on
the other hand, are rarer. Examples include zerovalent complexes
of Fe, Cr, Mo, and W, where the chalcone is coordinated to the
metal via the enone,19 examples of Fe(CO)3 coordinated through
the A or B ring,20 and a broad series of ferrocenyl chalcones.21
Indeed, ferrocenyl chalcones have been studied since the
1950s,22 and some of their biological activities have more
recently been evaluated.21,23 However, to our knowledge, ferro-
cenyl chalcones have never been exploited for the synthesis of
higher ferrocenyl flavonoids, for which no examples exist.
We have recently shown that aurones wherein ferrocene
replaces the B ring and with halogen substitution on the A ring
(Chart 1) can be obtained in high yield by treating the corre-
sponding 2-hydroxychalcones with AgOTf and NaH.24 We now
report further studies on the synthesis and reactivity of such
compounds, including the sequential synthesis of ferrocenyl
aurones, ynones, flavones, and flavonols. In many cases we find
that the presence of ferrocene significantly changes the reactivity
Flavonoids, such as flavanones, flavones, aurones, and flavo-
nols and their precursor chalcones (Chart 1), are plant-based
dietary polyphenols associated with a wide range of medicinal
activities including beneficial effects against cancer,1 cardiovas-
cular disease,2 inflammation,3 and parasitic4 and viral5 infections.
The salutary effects of flavonoids have often been attributed to
their antioxidant properties,6 although interactions with proteins
and cell signaling pathways have also been revealed.7
The role of ferrocene in medicinal chemistry has received
much attention in the last twenty years,8 primarily due to the
observation that modification of natural products or drugs by the
introduction of ferrocene can have dramatic effects on the
biological activity of such molecules. In one such class of
ferrocenyl compounds, based on the resveratrol skeleton, the nano-
molar antiproliferative activities against cancer cells have been
attributed to the redox behavior of ferrocene.9 More recently, a
report of the modification of SAHA with ferrocene revealed
nanomolar and selective inhibition of histone deacetylases
and low micromolar cancer cytotoxicity in vitro.10 Modification
of curcuminoids,11 indoles,12 oxyindoles,13 and aminoquinolines14
by ferrocene has also been shown to enhance their anticancer
activity.
In the context of our studies in ferrocenyl medicinal
Received: July 18, 2011
Published: September 29, 2011
chemistry,8b,15 we became interested in how the introduction
r
2011 American Chemical Society
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Chart 1. Some of the Principal Classes of Flavonoids
Scheme 1. Synthesis of Ferrocenyl Aurones 2aꢀc via Oxi-
dative Cyclization of 2-Hydroxychalcones 1aꢀca
a R = H (a); R = Br (b); R = OMe (c).
of such molecules compared to their organic analogues. For
example, the ring opening of the aurone to form a ferrocenyl
ynone, which can then be “recyclized” to quantitatively yield the
corresponding flavone, is a sequence of reactions not observed
for organic flavonoids. The reactivity and regioselectivity found
in the ferrocene series is likely due to the particular ability of
ferrocene to stabilize adjacent cations25 and to consequently
destabilize adjacent anions in reaction intermediates. All of these
novel and strongly colored compounds have been obtained in
moderate to high yields and have been characterized by X-ray
crystallography and/or 2D NMR spectroscopy and UV/visible
spectroscopy.
’ RESULTS AND DISCUSSION
Synthesis and Reactivity of Ferrocenyl Flavonoids. With
the future aim of exploring how the addition of ferrocene can
influence the biological properties of flavonoids, we set out to
synthesize a series of compounds where ferrocene replaces the
B ring of the flavonoid skeleton. This strategy was inspired by
several examples demonstrating that integration of ferrocene
into the skeleton of a bioactive molecule can potentiate the
biological effects. As is common in flavonoid synthesis and
the rule in flavonoid biosynthesis, we began our synthetic
pathway with the chalcone precursor. In this way a variety of
substituted compounds can be obtained, using a range of
commercially available substituted acetophenones. We selec-
ted for this study 20-hydroxychalcones substituted in the
50-position by an electron-withdrawing group (bromido), an
electron-donating group (methoxy), and the standard unsubsti-
tuted compound.
Figure 1. 1H NMR spectrum of the ferrocene region in pyridine-d5 and
Hg(OAc)2. Diamonds = 1b and stars = 2b; (a) after 18 h; (b) after 12 h;
(c) after 1 h.
with AgOTf and NaH in THF resulted in a quantitative conver-
sion (by TLC) to a deep violet compound in about 72% yield
after silica gel column chromatography (Scheme 1). On the
basis of mass, elemental analyses, and 1D 1H NMR spectra, we
initially and erroneously attributed the flavone structure to these
products.24 However, subsequent crystallographic and 2D NMR
characterization of 2b showed that this compound was instead
the aurone isomer (vide infra).
While the AgOTf system gave aurones 2a and 2b after only 10
min at rt, the conversion of the methoxy compound 1c to 2c
using this method was sluggish and accompanied by the forma-
tion of insoluble side products. Subsequently we found that
treatment of 1aꢀc with mercury(II) acetate in pyridine at 80 ꢀC
for 3ꢀ5 h cleanly yielded 2aꢀc in about 73% yield after
purification on silica gel.
An interesting aspect of these reactions is their regioselectivity.
Oxidative cyclizations of 20-hydroxychalcones are rarely selective,
and the mixture of products (aurones, flavones, isoflavones,
flavanones) obtained is highly dependent on the reagents
used.26,27 Flavones have been the major product of oxidative
cyclization of chalcones usingDDQ (often mixed with aurones),27a
palladium lithium chloride (often mixed with flavanones),27b
and thallium(III) nitrate trihydride.27c Conversely, aurones are
the sole product found using Hg(OAc)2 and pyridine in the
organic series.26a
Ferrocenyl Aurones. Ferrocene chalcones 1aꢀc were obtained
by a standard ClaisenꢀSchmidt condensation between ferrocene
carboxaldehyde and 2-hydroxyacetophenone, 2-hydroxy-5-bro-
midoacetophenone, or 2-hydroxy-5-methoxyacetophenone with
NaOH in refluxing EtOH.22 Our first target was the flavanone,
classically formed by the cyclization of the chalcone by a simple
acid- or base-catalyzed 1,4-nucleophilic attack. However, in our
hands, treatment of the ferrocenyl chalcones with common
flavanone-forming reagents such as AcOH, pyridine, L-proline, or
various bases led to only decomposition products.
Oxidative cyclization of 20-hydroxychalcones is a common
methodology for the synthesis of the aurone or flavone scaffold.
We therefore investigated the reactivity of the ferrocene chalcone
with a variety of metal salts and found that treatment of 1a and 1b
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ARTICLE
Scheme 2. Synthesis of Ferrocenyl Flavones 4aꢀc via Iso-
merization of Aurones 2aꢀc and Hydroxylation of 4a,b to
Flavonols 5a,ba
Scheme 3. Selective Synthesis of Ferrocenyl Flavones 4aꢀc
via Cyclization of Ynones 3aꢀca
a R = H (a); R = Br (b); R = OMe (c).
Previous work suggests that [HgOAc]+ forms complexes with
the phenolate and double bond, leading eventually to a four-
centered pericyclic addition of ArO and HgOAc over the double
bond;26b,c it is not immediately obvious if AgOTf plays the same
role as Hg(OAc)2. The reaction with AgOTf being very rapid, we
1
attempted to follow the reaction of 1b with Hg(OAc)2 by H
a Conditions: (i) LDA in THF, ꢀ78 ꢀC; (ii) NaOEt in EtOH.
NMR in pyridine-d5 at rt over 18 h. As shown in Figure 1, at t = 1 h,
a 2/1 proportion of chalcone to aurone signals was observed. Over
time, those signals corresponding to the chalcone diminished and
those corresponding to the aurone increased. No signals of any
intermediate or other product were observed.
of the phenolateꢀmetalꢀolefin complex, in that a silver atom
with a weakly coordinating anion would be expected to strongly
complex to the chalcone and hinder cyclization. Accordingly, in
our hands, silver salts with PF6, BF4, and ClO4 did not yield any
aurone product, according to TLC analysis. Trifluoroacetate
would be expected to make a stronger ion pair with silver, thus
activating the OꢀAgꢀolefin complex, and an aurone product
was indeed obtained with this reagent.
However, while the use of Hg(OAc)2 to obtain aurones is well
known in the organic series,26aꢀd reactions of organic 20-hydro-
xychalcones with AgOTf yielded only intractable mixtures,
strongly implicating the ferrocene group in the mechanism of
cyclization. We originally hypothesized that a one-electron
oxidation of the ferrocene group by AgOTf could be the first
step in the reaction. However, reaction with the chalcone 1a and
1b with AgOTf in THF or pyridine gave only a brown,
diamagnetic product that could not be eluted on a TLC plate,
ruling out the likelihood of this mechanism. We next investigated
if an inductive effect by the ferrocene group modified the electronic
In another effort to understand the role of Hg(OAc)2, we
attempted to prevent cyclization by using a protected chalcone.
Methylation of the phenol group of 1b was effected with MeI/
NaH in THF at room temperature after 6 h. The new compound,
(E)-1-(50-bromido-20-methoxyphenyl)-3-ferrocenylprop-2-en-
1-one, was dissolved in pyridine-d5, and an excess of Hg(OAc)2
was added and monitored by 1H NMR over 13 h. No change in
the spectrum was observed, suggesting Hg does not simply add
over the double bond of the enone. Finally, the interaction of 1b
and Hg(OAc)2 was examined in the absence of base. Likewise, no
reaction was observed via 1H NMR in MeOD over 12 h. Other
experiments monitored by TLC also demonstrated the necessity
of an external base, the replacement of pyridine with a stronger
base considerably enhancing the reaction rate.
These results support a mechanism of cyclization involving
initial coordination of HgOAc to the oxygen atom of the
phenolate. This could very well be followed by the addition of
ArO-HgOAc over the double bond to form a metalated inter-
mediate, as previously proposed for the organic series.26b,c The
partial negative charge on the carbon would be destabilized by
the adjacent ferrocene group, promoting rapid β-elimination.
This interpretation explains why the mercurated intermediate
was observed in the organic series but not in the ferrocene series.
The reaction with AgOTf could, a priori, proceed similarly.
This type of reaction should be strongly dependent on the nature
structure of the α,β-unsaturated ketone in order to promote a
1
nucleophilic attack in the 3-position. On the basis of H and 13
C
NMR of 1b (Supporting Information), while the double bond is less
polarized in the ferrocene chalcone than in the analogous organic
chalcone, the differences are too small to alone drive 5-exocycliza-
tion. Therefore, if the silver reagents act similarly to Hg(OAc)2, the
ferrocene group may then be involved in the elimination step. As a
one-electron oxidant, a radical reaction or homolytic elimination of
Ag cannot be ruled out, and this will be the subject of a future study.
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ARTICLE
Table 1. Crystal Data for a Representative Aurone, Ynone,
and Flavone
Z-2b
3a
4b
C19H13BrFeO2
409.06
C19H14FeO2
330.17
C19H13BrFeO2
409.06
M
cryst syst
space group
a (Å)
monoclinic
P21/a
monoclinic
P21/c
monoclinic
P21/c
7.5434(7)
14.7364(17)
13.8726(8)
99.146(8)
1522.5(2)
4
9.8786(6)
13.7386(7)
10.6891(6)
95.745(5)
1443.42(14)
4
7.3599(2)
15.1457(5)
27.5266(8)
90.2090(10)
3068.39(16)
8
b (Å)
c (Å)
β (deg)
V (Å3)
Z
T (K)
200
200
200
no. reflns
no. indep reflns
Rint
21 523
13 536
36 796
3471
4177
9784
0.059
0.000
0.037
2θ (deg)
R1 (all data)
wR2 (all data)
R1 (with cutoff)
wR2 (with cutoff)
52.8
54.6
61.1
0.0644
0.0622
0.0365
0.0506
0.0526
0.0610
0.0322
0.0502
0.0624
0.0655
0.0388
0.0556
(LDA) in THF yielded, after workup, deep red solids, which were
identified as 1-(20-hydroxyphenyl)-3-ferrocenylprop-2-yn-1-one
derivatives (Scheme 3). Presumably, deprotonation of the vinyl
proton creates an anion, which is destabilized by the adjacent
ferrocene, resulting in a rapid rearrangement and ring opening,
yielding the ynones 3aꢀc as the sole products in about 70%
purified yield. Interestingly, it has been previously observed that
organic aurones do not react readily with LDA, although in some
cases, a minor amount of ynone product has been detected.29 This
clearly demonstrates the destabilizinginfluence of ferroceneon the
adjacent anion, which promotes rapid ynone formation.
With the ferrocenyl ynones 3aꢀc in hand, we investigated
their base-catalyzed cyclization. Treatment of 3aꢀc with NaOEt
in EtOH at room temperature gave a single orange product that
was identified as having the flavone structure with 65ꢀ70%
purified yield (Scheme 3). Conversely, such reactions of organic
ynones usually give a mixture of flavones and aurones,30 often
with the aurone isomer predominating.31 The presence of
ferrocene, however, exclusively favors attack on C3 (the 4-posi-
tion of the enone). In line with our previous argumentation, the
production of ferrocenyl aurones should not be favored, because
it requires an unstable α-ferrocenyl anion as an intermediate.
Conversely, an attack on C3 places the anion on C2, further from
the ferrocene group, thus yielding an equilibrium favoring
evolution to the flavone. We have previously seen that treatment
of ferrocenyl aurones with LDA rapidly generates the ynone,
suggesting that the lifetime of the aurone anion is very short.
Ferrocenyl Flavonols. Organic flavonols can directly be pre-
pared from chalcones, via the AlgarꢀFlynnꢀOyamada reaction,
involving an oxidative cyclization and treatment with hydrogen
peroxide in basic media.32 Once again, however, this reaction led
only to decomposition of the ferrocenyl chalcone. Another
method to form flavonols involves flavone hydroxylation with
DMDO33 or with LDA followed by H2O2.30 Nonetheless, in the
ferrocenyl flavone series, these methods failed to give any of the desired
product. However, dissolution of 4a,b in a 2/1 dichloromethane/
Figure 2. Asymmetric units for Z-2b, 3a, and 4b grown from a
CH2Cl2/pentane solution. Thermal ellipsoids are shown at the 50%
probability level.
Ferrocenyl Flavones. The standard method of forming fla-
vones is via 1,6-oxidative cyclization of chalcones. However,
treatment of ferrocenyl chalcones 1aꢀc with reagents known to
effect this transformation, such as I2, DDQ, SeO2, and Br2,
produced only intractable mixtures with no trace of flavone
visible in TLC. 1H NMR spectra of these mixtures furthermore
suggest the loss of the ferrocene group.
Direct isomerization of aurones to flavones is known to occur
in basic media and in the presence of KCN.28 Isomerization of 2
to 4 was not observed during the formation of 2 in the presence
of NaH or pyridine. However, treatment of isolated 2a with
KOtBu in EtOH slowly yielded the flavone 4a along with
decomposition products. The use of KCN gave better results:
treatment of aurones 2aꢀc with KCN in refluxing EtOH allowed
an effective isomerization to flavones 4aꢀc, complete after 2 h
with isolated yields of 75ꢀ80% (Scheme 2). The mechanism of
isomerization is very likely enhanced by the presence of ferro-
cene. The attack of the cyanide on C10 (the 4-position of the
enone) would be expected to generate an unstable negative
charge on this position adjacent to the ferrocene, after proton
migration. This unstable anion would be expected to rearrange
following either a 1,2-migration of the phenolic oxygen to
generate the more stable enolate or a ring opening to the
phenolate. An attack of the phenolate on C10 and ejection of
the cyanide would yield the flavone structure.
Ferrocenyl flavones were also synthesized via another route
involving an ynone intermediate, which has been isolated. Treat-
ment of ferrocenyl aurones 2aꢀc with lithium diisopropylamide
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Table 2. Selected 1H and 13C NMR and IR Spectroscopic Data for Aurones 2aꢀc and Flavones 4aꢀca
δ (Hvinyl)/ppm
δ (CHvinyl)/ppm
δ (Cq vinyl)/ppm
νmax (CdO)/cmꢀ1
νmax (CdC)/cmꢀ1
2a
6.90
116.6
117.6
116.4
105.9
105.8
105.1
+11 ( 1
146.1
146.5
146.6
168.3
168.8
167.9
ꢀ22 ( 1
1698
1642
2b
6.91
1701
1639
2c
6.88
1689
1632
4a
6.48
1631
1605
4b
6.47
1643
1612
4c
6.47
1627
ca. 1612 (sh)
+28 ( 9
Δδ or ν
+0.43 ( 0.02
+62 ( 9
a Locations of the vinyl proton and vinyl carbon atoms under discussion are marked with an asterisk.
acetone solution in carbonate buffer as a biphasic medium and
addition of oxone solution in water provided the flavonols as orange
solids in 78ꢀ80% yields (Scheme 2).34
Table 3. UV/Vis Spectroscopic Data
λmax (nm)
ε
λmax (nm)
ε
Structural Characterization. The aurones, flavones, and
ynones reported here are all structural isomers and thus cannot
be differentiated by mass spectrometry or elemental analysis
alone. The ynones 3aꢀc could be identified by IR and 1H NMR
spectroscopy, but the structural similarity between aurones and
flavones made the structural attribution nontrivial. Indeed, some
mischaracterizations and subsequent corrections can be found in
the literature.35
1a
1b
1c
2a
2b
2c
5a
526
342
535
344sh
526
351
545
386
559
392
545
400
483
348
1740
6720
2570
9690
1790
7690
2140
7600
2710
10040
2020
4720
2150
12410
3a
3b
3c
4a
4b
4c
5b
497
317
477
368
497
399
466
362sh
475
369
463
364sh
494
352
1730
8840
3180
5340
2027
5170
622
1330
935
Crystals of 2b, 3a, and 4b suitable for X-ray diffraction were
obtained from slow evaporation of dichloromethane/pentane
solutions. Ortep diagrams are shown in Figure 2, and crystal-
1800
979
1
lographic data are given in Table 1. Consistent with H NMR
data, 2b exists as the Z isomer in the X-ray structure, with a quasi-
planar arrangement of the benzofuranone moiety with the C5H4
ring of the ferrocene, the angle created by the planes being 8.5ꢀ.
The bond distances are normal, and there is no significant
distortion of the ferrocene, with an angle created by the iron
atom and the cyclopentadienyl centroids of 177ꢀ. Likewise,
for 3a, the phenol ring is almost coplanar with the C5H4 ring
of the ferrocene (8.6ꢀ), and no distortion of the ferrocene
(CpcentroidꢀFeꢀCpcentroid = 179ꢀ) was observed. For 4b, two
molecules make up the asymmetric unit. Here it appears that
repulsions between the Cp α proton and that of C3 (according to
Scheme 2) are minimized by the ferrocene twisting out of the
benzopyrone plane by an average angle of 18.3ꢀ.
3360
3190
14190
The 2D NMR experiments furthermore allowed the full
1
attribution of the H and 13C spectra of all molecules. The
chemical shifts of the vinyl proton, vinyl carbon, and quaternary
carbon adjacent to the oxo group clearly differentiate 2aꢀc from
4aꢀc (Table 2). In the aurone, the vinyl proton and carbon are in
the 4-position of the ketone and thus are deshielded compared to
the flavone structure, where these atoms are in the 3-position of
the ketone. Similarly, the quaternary carbon is in the shielded
3-position in the aurone and the deshielded 4-position in the
flavone. While substitution on the phenyl ring of the benzofurone
or benzopyrone groups only slightly influences the chemical
shifts of characteristic peaks, a given structural isomer can be
easily identified by the large difference in chemical shifts.
Likewise, characteristic absorption frequencies in the IR allow
the differentiation between the two isomers (Table 2). Con-
tributions of mesomeric canonical structures in the flavone result
in CdO and CdC bond orders of less than 2. Therefore, in the
flavone geometry, the CdO and CdC stretching frequencies are
expected at lower energy than those found in the aurones, which
is exactly what is observed.
The bulk solids of representative aurones, flavones, and
flavonols were furthermore structurally characterized by 2D
HMQC and HMBC (Supporting Information). For 2b, the
HMBC experiment showed vinylic proton (H10) correlations
with the ketone carbon (C3) and Cα of C5H4, indicating an
aurone structure. For 4b, we observed correlations involving the
vinylic H3 with C5H4ꢀCipso and aromatic C10 and weaker
correlations with the aromatic C5, consistent with a flavone
structure. The flavonols were differentiated from isoflavanols by
the chemical shifts of the CdC group; C2 was observed at around
150 ppm and C3 at around 135 ppm. In the case of the
isoflavonol, C2 would be expected to appear around 180 ppm,
due to the influence of the OH group, while C3 should appear
around 100 ppm.36
UVꢀVisible Spectroscopy. One of the most attractive fea-
tures of these molecules is their strong colors. The prefix “flavo”
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comes from the Latin “flavus” (yellow), and indeed, with the
exception of the anthocyanidins, most organic flavonoids are
yellow to orange in color, due to π f π* transitions. The
addition of ferrocene gives rise to a gamut of colors: in solution
ferrocenyl chalcones are red-violet, ferrocenyl aurones are indigo-
violet, ferrocenyl ynones are red, and ferrocenyl flavones and
flavonols are red-orange. The relatively large extinction coeffi-
cients and previous studies on donorꢀacceptor complexes of
ferrocene37 suggest that the transition in the visible region has the
nature of a MLCT transition, that is, from a molecular orbital
based primarily on ferrocene to one involving the π* orbitals of
the ligand (Table 3). It is likely that the substituted Cp ring
contributes significantly to the frontier orbitals, in that the molar
absorptivity of this transition is lower in the flavone series,
consistent with the X-ray structure that shows the ferrocene
being twisted out of the plane created by the ligand. In general,
electron-withdrawing groups decrease the energy of λmax relative
to the unsubstituted molecule. This is likely due to a stabilization
of the π* molecular orbital by electron-withdrawing groups,
consistent with previous theoretical calculations for organic
chalcones.38 The higher energy bands are similar in energy to
those found in organic chalcones and can be attributed to π f π*
transitions on the ligand.
(C9), 123.1 (C5), 124.6 (C4), 136.2 (C6), 146.1 (C2), 165.5 (C8),
183.0 (C3).
(Z)-5-Bromido-2-(ferrocenylidene)benzofuran-3-one, 2b.
Violet solid, 142 mg, 71%, Rf = 0.33 (silica gel, hexanes/EtOAc, 3/1). 1H
NMR (400 MHz; acetone-d6): δ 4.24 (s, 5H, C5H5), 4.64 (t, 2H, 3J = 1.7
Hz, Hβ), 4.97 (t, 2H, 3J = 1.7 Hz, Hα), 6.91 (s, 1H, H10), 7.48 (d, 1H, 3J =
8.6 Hz, H7), 7.86 (d, 1H, 4J = 2.0 Hz, H4), 7.89 (dd, 1H, 3J = 8.6 Hz, 4J =
2.0 Hz, H6). 13C NMR (100 MHz; acetone-d6): δ 70.6 (C5H5), 72.4
(C5H4ꢀCα), 72.7 (C5H4ꢀCβ), 75.6 (C5H4ꢀCipso), 116.1 (C7), 116.2
(C5,), 117.6 (C10), 125.1 (C9), 127.0 (C4), 139.4 (C6), 146.5 (C2),
164.7 (C8), 181.0 (C3).
(Z)-5-Methoxy-2-(ferrocenylidene)benzofuran-3-one, 2c.
Violet solid, 160 mg, 80%, mp 142 ꢀC, Rf = 0.31 (silica gel, hexanes/
EtOAc, 3/1). IR νmax/cmꢀ1 1689 (CdO), 1632 (CdC). 1H NMR (300
MHz; CDCl3): δ 3.83 (s, 3H, OMe), 4.17 (s, 5H, C5H5), 4.54 (t, 2H,
3J=1.8Hz, Hβ), 4.85 (t, 2H, 3J=1.8Hz, Hα), 6.88 (s, 1H, H10), 7.21ꢀ7.25
(m, 3H, H4, H6, H7). 13C NMR (75 MHz; CDCl3): δ 55.8 (OMe), 69.8
(C5H5), 71.3 (C5H4ꢀCα), 71.6 (C5H4ꢀCβ), 75.0 (C5H4ꢀCipso),
104.8 (C4), 113.6 (C7), 116.4 (C10) 122.5 (C9), 125.4 (C6), 146.6
(C2), 155.7 (C5), 160.3 (C8), 182.9 (C3). MS (CI NH3): m/z 361.0
(MH+). HRMS (ESI): calcd for C20H16FeO3Na+ 383.03466, found
383.03411.
Synthesis and Characterization of Ferrocenyl Ynones 3aꢀc.
Ferrocene aurone 2 (100 mg) was dissolved in THF and cooled in
an acetone/liquid nitrogen bath. Lithium diisopropylamide (1.1 equiv,
2 M in THF) was added, and the solution color changed from deep
violet to pale red. The solution was allowed to return to rt, poured into
H2O and 12 M HCl, extracted with EtOAc, and washed with water.
The organic phase was dried over MgSO4, filtered, and evaporated.
The product was purified using a silica gel column, using petroleum
ether/dichloromethane, 1/1, as an eluent.
’ EXPERIMENTAL SECTION
General Remarks. All reactions were carried out under argon. THF
was distilled over sodium/benzophenone, and all other chemical
reagents and solvents were used without further purification. Silica gel
chromatography was performed with Merck 60 (40ꢀ63 μm) silica. 1H
and 13C NMR spectra were recorded with a 300 or 400 MHz Bruker
Avance spectrometer, and δ are given in ppm and referenced to the
residual solvent peaks (1H, δ 7.26 and 13C{1H}, δ 77.1 for CDCl3 and
1H, δ 2.05 and 13C{1H}, δ 29.7 for acetone-d6). Mass spectra were
measured on a Thermoscientific ITQ1100 spectrometer using the direct
1-(20-Hydroxyphenyl)-3-ferrocenylprop-2-yn-1-one, 3a.
Red solid, 78 mg, 78%, mp 130 ꢀC, Rf = 0.39 (silica gel, hexanes/EtOAc,
3/1). IR: νmax/cmꢀ1 2175 (CtC), 1612 (CdO). 1H NMR (400 MHz;
CDCl3): δ 4.30 (s, 5H, C5H5), 4.47 (t, 2H, 3J = 1.7 Hz, C5H4), 4.71 (t,
3
3
0
0
2H, J = 1.7 Hz, C5H4), 6.96ꢀ7.02 (m, 2H, H3 , H5 ), 7.52 (td, 1H, J =
8.2 Hz, J = 1.3 Hz, H4 ), 8.05 (dd, 1H, J = 8.2 Hz, J = 1.3 Hz, H6 ). 13C
4
3
4
ꢀ
0
0
exposure probe method by the mass spectrometry service at the Ecole
NMR (100 MHz; CDCl3): δ 59.8 (C5H4ꢀCipso), 70.7 (C5H5), 71.3
Nationale Supꢀerieure de Chimie de Paris. High-resolution mass spectra
were obtained by ESI/ESCI-TOF using a Waters LCT Premier XE or a
Thermo Fischer LTQ-Orbitrap XL. Melting points were determined
using an Electrothermal 9100 apparatus. IR data were collected on a
JASCO FT/IR-4100 using a KBr pellet.
Synthesis and Characterization of Ferrocenyl Chalcones
1aꢀc. The synthesis and characterization of compounds 1aꢀc have
been previously described.24,39
Synthesis and Characterization of Ferrocenyl Aurones
2aꢀc. Ferrocene chalcone 1 (200 mg) was dissolved in pyridine. After
stirring for 5 min at room temperature, Hg(OAc)2 (2.5 equiv) was
added, and the mixture was stirred at reflux until the starting chalcone
was consumed (2ꢀ3 h). The reaction mixture was poured into H2O and
12 M HCl, extracted with CH2Cl2, and washed with water. The organic
phase was dried over MgSO4, filtered, and evaporated. The product was
purified using a silica gel column, with petroleum ether/dichloro-
methane, 1/1, as an eluent. Compounds 2a and 2b were previously
synthesized using AgOTf;24 here the yields of these compounds
synthesized by the above method are reported with their fully attributed
1H and 13C NMR spectra.
(Z)-2-(Ferrocenylidene)benzofuran-3-one, 2a. Violet solid,
150 mg, 75%, Rf = 0.36 (silica gel, hexanes/EtOAc, 3/1). 1H NMR (400
MHz; CDCl3): δ 4.19 (s, 5H, C5H5), 4.56 (t, 2H, 3J = 2.0 Hz, Hβ), 4.88
(t, 2H, 3J = 2.0 Hz, Hα), 6.90 (s, 1H, H10), 7.18ꢀ7.22 (m, 1H, H5), 7.30
(d, 1H, 3J = 7.8 Hz, H7), 7.62ꢀ7.66 (m, 1H, H6), 7.81 (d, 1H, 3J = 7.8 Hz,
H4). 13C NMR (100 MHz; CDCl3): δ 70.0 (C5H5), 71.6 (C5H4ꢀCα),
71.9 (C5H4ꢀCβ), 75.1 (C5H4ꢀCipso), 113.0 (C7), 116.6 (C10,), 122.7
0
0
(C5H4), 73.4 (C5H4), 84.5 (C2), 100.2 (C3), 118.2 (C3 ), 119.4 (C5 ),
0
0
0
0
121.0 (C1 ), 132.9 (C6 ), 136.7 (C4 ), 162.8 (C2 ), 181.9 (C1),. MS (CI
NH3): m/z 330 (MH+). HRMS (ESI): calcd for C19H14FeO2
+
330.03432, found 330.03377.
1-(50-Bromido-20-hydroxyphenyl)-3-ferrocenylprop-2-yn-
1-one, 3b. Red solid, 65 mg, 65%, mp 132 ꢀC, Rf = 0.36 (silica gel,
hexanes/EtOAc, 3/1). IR: νmax/cmꢀ1 2179 (CtC), 1619 (CdO). 1H
NMR (400 MHz; CDCl3): δ 4.32 (s, 5H, C5H5), 4.50 (t, 2H, 3J = 1.8 Hz,
3
3
0
C5H4), 4.74 (t, 2H, J = 1.8 Hz, C5H4), 6.90 (d, 1H, J = 8.9 Hz, H3 ),
3
4
4
0
0
7.58 (dd, 1H, J = 8.9 Hz, J = 2.5 Hz, H4 ), 8.13 (d, 1H, J = 2.5 Hz, H6 ).
13C NMR (100 MHz; CDCl3): δ 59.3, (C5H4ꢀCipso), 70.7 (C5H5),
0
71.5 (C5H4), 73.5 (C5H4), 84.2 (C2), 101.8 (C3), 110.8 (C5 ), 120.3
0
0
0
0
0
(C3 ), 122.2 (C1 ), 134.9 (C6 ), 139.3 (C4 ), 161.7 (C2 ), 180.6 (C1). MS
+
(CI NH3): m/z 409.04 (MH+). HRMS (ESI): calcd for C19H13BrFeO2
407.9448 and 409.9428, found 407.9482 and 409.9530.
1-(50-Methoxy-20-hydroxyphenyl)-3-ferrocenylprop-2-yn-
1-one, 3c. Red solid, 73 mg, 73%, mp 120 ꢀC, Rf = 0.33 (silica gel,
hexanes/EtOAc, 3/1). IR: νmax/cmꢀ1 2179 (CtC), 1731 (CdO), 1H
NMR (400 MHz; acetone-d6): δ 3.91 (s, 3H, OMe), 4.37 (s, 5H, C5H5),
4.59 (t, 2H, 3J = 1.9 Hz, C5H4), 4.84 (t, 2H, 3J = 1.9 Hz, C5H4), 6.94 (d,
3
3
4
0
0
1H, J = 9.1 Hz, H3 ), 7.26 (dd, 1H, J = 9.1 Hz, J = 3.1 Hz, H4 ), 7.58 (d,
4
1H, J = 3.1 Hz, H6 ). 13C NMR (100 MHz; acetone-d6): δ 56.0 (OMe),
0
60.1 (C5H4ꢀCipso), 71.3 (C5H5), 72.2 (C5H4), 74.0 (C5H4), 84.6 (C2),
0
0
0
0
100.9 (C3), 114.8 (C6 ), 119.7 (C3 ), 121.0 (C1 ), 125.9 (C4 ), 153.1
+
0
0
(C5 ), 157.8 (C2 ), 181.8 (C1). MS (CI NH3): m/z 361.11 (MH ).
HRMS (ESI): calcd for C20H16FeO3+ 360.04489, found 360.04422.
5429
dx.doi.org/10.1021/om200644e |Organometallics 2011, 30, 5424–5432

Organometallics
ARTICLE
Synthesis and Characterization of Ferrocenyl Flavones
4aꢀc. From Ynone. Ferrocene ynone 3 (40 mg) was dissolved in
EtOH. NaOEt (excess) was added, and the solution was stirred at rt for
24 h, with a color change from red to orange. The reaction mixture was
poured into H2O and 12 M HCl, extracted with CH2Cl2, and washed
with water. The organic phase was dried over MgSO4, filtered, and
evaporated. The crude product was purified using a silica gel column,
using petroleum ether/dichloromethane, 1/1, as an eluent and was
isolated as an orange solid. Yields after purification: 68% (4a), 65% (4b),
and 63% (4c).
From Aurone. Alternatively, ferrocenyl aurone (30 mg) and potas-
sium cyanide (1.5 equiv) were dissolved in ethanol (25 mL) and stirred
at reflux for 2 h; the solution color changed from deep violet to deep red.
The solution was then allowed to return to rt before being poured into
an aqueous solution of 1 M NaOH (100 mL). The mixture was extracted
with EtOAc (3 ꢁ 50 mL) and washed with water. The organic phase was
dried over MgSO4, filtered, and evaporated, and the crude product was
purified using a silica gel column, using petroleum ether/ethyl acetate,
60/40, as an eluent and was isolated as an orange solid. Yields after
purification: 88% (4a), 75% (4b), and 78% (4c).
2-Ferrocenylchromen-4-one, 4a. Mp 110 ꢀC, Rf = 0.24 (silica
gel, hexanes/EtOAc, 3/1). IR: νmax/cmꢀ1 1631 (CdO), 1605 (CdC).
1H NMR (400 MHz; CDCl3): δ 4.18 (s, 5H, C5H5), 4.54 (t, 2H, 3J = 1.8
Hz, C5H4), 4.88 (t, 2H, 3J = 1.8 Hz, C5H4), 6.48 (s, 1H, H3), 7.39 (td,
1H, 3J = 7.9 Hz, 4J = 1.1 Hz, H6), 7.51 (dd, 1H, 3J = 7.2 Hz, 4J = 1.1 Hz,
H8), 7.63ꢀ7.69 (m, 1H, H7), 8.21 (dd, 1H, 3J = 7.9 Hz, 4J = 1.6 Hz, H5).
13C NMR (100 MHz; CDCl3): δ 67.6 (C5H4), 70.3 (C5H5), 71.5
(C5H4), 75.1 (C5H4ꢀCipso), 105.9 (C3), 117.8 (C8), 124.3 (C10),
125.1(C6), 125.8 (C5), 133.4 (C7), 156.3 (C9), 168.3 (C2), 177.6 (C4).
MS (CI NH3): m/z 330.1 (MH+). HRMS (ESI): calcd for C19H14FeO2-
Na+ 353.02409, found 353.02354.
3-Hydroxy-2-ferrocenylchromen-4-one, 5a. Orange solid,
33 mg, 80%, mp 160 ꢀC, Rf = 0.28 (silica gel, hexanes/EtOAc, 3/1).
IR: νmax/cmꢀ1 3247 (OH), 1731 (CdO), 1608 (CdC). 1H NMR (400
MHz; CDCl3): δ 4.17 (s, 5H, C5H5), 4.54 (t, 2H, 3J = 1.8 Hz, C5H4),
5.19 (t, 2H, 3J = 1.8 Hz, C5H4), 7.40 (td, 1H, 3J = 8.0 Hz, 4J = 1.1 Hz,
H6), 7.54 (d, 1H, 3J = 7.2 Hz, H8), 7.65ꢀ7.70 (m, 1H, H7), 8.24 (dd, 1H,
4
3J = 8.0 Hz, J = 1.6 Hz, H5). 13C NMR (100 MHz; CDCl3): δ 68.7
(C5H4), 70.0 (C5H5), 71.0 (C5H4), 74.2 (C5H4ꢀCipso), 118.1 (C8),
121.3 (C10), 124.5 (C5 or C6), 125.4 (C5 or C6), 132.9 (C7), 136.9 (C3),
150.5 (C2), 155.4 (C9), 171.5 (C4). MS (CI NH3): m/z 347.1 (MH+).
HRMS (ESI): calcd for C19H14FeO3+ 346.0292, found 346.0286.
6-Bromido-3-hydroxy-2-ferrocenylchromen-4-one, 5b.
Orange solid, 31 mg, 76%, mp 178 ꢀC, Rf = 0.25 (silica gel, hexanes/
EtOAc, 3/1). IR: νmax/cmꢀ1 3309 (OH), 1739 (CdO), 1604 (CdC).
1H NMR (400 MHz; CDCl3): δ 4.16 (s, 5H, C5H5), 4.55 (t, 2H, 3J = 1.8
Hz, C5H4), 5.17 (t, 2H, 3J = 1.8 Hz, C5H4), 7.43 (d, 1H, 3J = 8.8 Hz, H8),
7.74 (dd, 1H, 3J = 8.8 Hz, 4J = 2.3 Hz, H7), 8.36 (d, 1H, 4J = 2.3 Hz, H5).
13C NMR (100 MHz; CDCl3): δ 68.8 (C5H4), 70.1 (C5H5), 71.2
(C5H4), 73.7 (C5H4ꢀCipso), 117.8 (C6), 120.0 (C8), 122.7 (C10), 127.9
(C5), 135.8 (C7), 137.0 (C3), 151.2 (C2), 154.1 (C9), 170.2 (C4). MS
(CI NH3): m/z 425.1 (MH+). HRMS (ESI): calcd for C19H13BrFeO3
+
423.9397 and 425.9377, found 423.9392 and 425.9371.
’ CONCLUSIONS
The sequential synthesis of the first ferrocenyl aurones, flavones,
and flavonols has been achieved, making use of ferrocenyl chalcones
and ferrocenyl ynones as starting materials. Although these are
common precursors in flavonoid chemistry, the ferrocenyl species
did not always act similarly to organic flavonoids. For example,
treatment of ferrocenyl chalcones with known flavanone, flavone, or
flavonol-forming reagents typically resulted in the formation of
intractable mixtures. From the starting point of the chalcone, we
were however able to selectively obtain ferrocenyl Z-aurones
possessing electron-withdrawing or electron-donating substituents
via the known method using Hg(OAc)2 in pyridine. No inter-
mediate could be observed in the reaction with Hg(OAc)2, possibly
due to fast β elimination due to the destabilizing influence of the
adjacent ferrocene group. A new, very rapid method, applicable only
to the formation of ferrocenyl aurones, was also discovered. The
specificity of AgOTf for the ferrocenyl chalcones is still not well
understood and may involve a radical reaction or elimination.
Ferrocenyl flavones were obtained directly from isomerization of
ferrocenyl aurones, as previously observed in the organic series, and,
originally, via a ferrocenyl ynone intermediate. Production of this
intermediate is probably assisted by the destabilizing influence of the
ferrocene on the anion resulting from deprotonation of the aurone,
while 1,6-cyclization is likewise favored by the greater stability of the
anion in the 3-position. Thus, in general, contrary to what is
observed in organic flavonoid chemistry, these reactions are all
very selective, giving only the desired product in high yield.
Ferrocenyl flavonols were further obtained via hydroxylation of
the 3-position of the α,β-unsaturated ketone of the flavones in a
biphasic reaction with oxone.
6-Bromido-2-ferrocenylchromen-4-one, 4b. Mp 177 ꢀC, Rf =
0.22 (silica gel, hexanes/EtOAc, 3/1). IR: νmax/cmꢀ1 1643 (CdO),
1612 (CdC). 1H NMR (400 MHz; CDCl3): δ 4.18 (s, 5H, C5H5), 4.56
(t, 2H, 3J = 1.9 Hz, C5H4), 4.87 (t, 2H, 3J = 1.9 Hz, C5H4), 6.47 (s, 1H,
H3), 7.40 (d, 1H, 3J = 8.8 Hz, H8), 7.75 (dd, 1H, 3J = 8.8 Hz, 4J = 2.4 Hz,
H7), 8.34 (d, 1H, 4J = 2.4 Hz, H5). 13C NMR (100 MHz; CDCl3): δ 67.6
(C5H4), 70.4 (C5H5), 71.8 (C5H4), 74.6 (C5H4ꢀCipso), 105.8 (C3),
118.5 (C6), 119.8 (C8), 125.7 (C10), 128.5 (C5), 136.3 (C7), 155.1 (C9),
168.8 (C2), 176.0 (C4). MS (CI NH3): m/z 408.9ꢀ410.9 (MH+).
+
HRMS (ESI): calcd for C19H13BrFeO2 430.93460 and 432.93256,
found 430.93406 and 432.93201.
6-Methoxy-2-ferrocenylchromen-4-one, 4c. Mp 140 ꢀC, Rf =
0.20 (silica gel, hexanes/EtOAc, 3/1). IR: νmax/cmꢀ1 1627 (CdO),
1
ca. 1612(sh) (CdC). H NMR (300 MHz; CDCl3): δ 3.91 (s, 3H,
OMe), 4.17 (s, 5H, C5H5), 4.52 (t, 2H, 3J = 1.7 Hz, C5H4), 4.87 (t, 2H,
3J = 1.7 Hz, C5H4), 6.47 (s, 1H, H3), 7.26 (dd, 1H, 3J = 9.1 Hz, 4J = 3.0
Hz, H7), 7.44 (d, 1H, 3J = 9.1 Hz, H8), 7.59 (d, 1H, 4J = 3.0 Hz, H5). 13
C
NMR (75 MHz; CDCl3): δ 55.9 (OMe), 67.4 (C5H4), 70.2 (C5H5),
71.3 (C5H4), 75.0 (C5H4ꢀCipso), 104.9 (C5), 105.1 (C3), 119.1 (C8),
123.1 (C7), 124.7 (C10), 151.0 (C9), 156.8 (C6), 167.9 (C2), 177.3 (C4).
+
MS (CI NH3): m/z 361.0 (MH+). HRMS (ESI): calcd for C20H16FeO3
383.03466, found 383.03411.
Synthesis and Characterization of Ferrocenyl Flavanols
5a,b. Carbonate buffer (15 mL) was added to a solution of ferrocenyl flavone
4 (40 mg) in CH2Cl2/acetone (2:1, 10 mL) and stirred vigorously at rt. A
5 mL aqueous solution of oxone (0.6 g) was added in four portions every 10
min, and the pH of the solution was checked to ensure that it remained alkaline
(pH 9). The consumption of starting material was followed by TLC. After the
reaction was complete, the two phases were separated and the aqueous phase
was extracted with CH2Cl2 (3 ꢁ 50 mL). The combined organic layer was
washed with sodium thiosulfate solution, dried with MgSO4, filtered, and
evaporated. The crude product was purified using a silica gel column with
petroleum ether/ethyl acetate (80:20) as eluent.
Full structural characterization of representative molecules of
each class was undertaken by 2D NMR and/or X-ray crystal-
lography experiments. Aurones and flavones can easily be
distinguished by the chemical shifts of their vinyl protons, vinyl
carbon, and quaternary carbon peaks, as well as by the stretching
frequencies of the CdC and CdO groups. The color of the
compounds is a result of a transition occurring between 450 and
600 nm, which can be attributed to a charge transfer from the
ferrocene to the planar π* system.
5430
dx.doi.org/10.1021/om200644e |Organometallics 2011, 30, 5424–5432

Organometallics
ARTICLE
The biological properties of these compounds are currently
being studied and will be reported in due course.
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Supporting Information. HMBC NMR spectra for 2b
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and 4b; selected chemical shifts for 1aꢀc and the organic
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with the CDCC, Nos. 787468, 823195, and 823196. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
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*(M.N.R.) Tel: +33 1 44 27 66 96. Fax: +33 1 44 27 66 96. E-mail:
marie-noelle.rager@chimie-paristech.fr. (E.A.H.) Tel: +33 1 44
27 66 98. Fax: +33 1 43 26 00 61. E-mail: elizabeth-hillard@
chimie-paristech.fr.
Author Contributions
^These authors contributed equally to the work.
’ ACKNOWLEDGMENT
We thank P. Herson for crystallographic characterization and
Cꢀeline Fosse for mass spectrometry experiments. K.N.T. thanks
Association pour la Recherche sur le Cancer for the award
of a postdoctoral fellowship; J.P.M. thanks the Ministꢁere de
l0Enseignement Supꢀerieur et de la Recherche for support of his
studies.
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