Flavonoid derivatives as organometallic bioprobes

Article abstract of DOI:10.1016/S0022-328X(02)02146-0

The synthesis of organoiron derivatives of biologically active flavonoids is described. Lithium enolates of functionalised protected acetophenones and metallated derivatives of substituted aromatic rings have been employed as nucleophiles in combination with tricarbonyl(η⁵-cyclohexadienyl)iron electrophiles. Products have been converted into flavonoid and chalcone derivatives. Enolates generated from protected flavanones have also been used in nucleophile addition reactions, and a one-pot in situ protection, nucleophile addition, deprotection sequence is reported.

Full text of DOI:10.1016/S0022-328X(02)02146-0

Journal of Organometallic Chemistry 668 (2003) 101ꢀ122
/
www.elsevier.com/locate/jorganchem
Flavonoid derivatives as organometallic bioprobesꢀ
Christopher E. Anson a,1, Colin S. Creaser b,*, Andrej V. Malkov a,2, Ljubica Mojovic a,3,
G. Richard Stephenson a,*
a Wolfson Materials and Catalysis Centre, School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK
b School of Science and Interdisciplinary Biomedical Research Centre, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK
Received 9 October 2002; accepted 26 November 2002
Abstract
The synthesis of organoiron derivatives of biologically active flavonoids is described. Lithium enolates of functionalised protected
acetophenones and metallated derivatives of substituted aromatic rings have been employed as nucleophiles in combination with
tricarbonyl(h5-cyclohexadienyl)iron electrophiles. Products have been converted into flavonoid and chalcone derivatives. Enolates
generated from protected flavanones have also been used in nucleophile addition reactions, and a one-pot in situ protection,
nucleophile addition, deprotection sequence is reported.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Flavonoids; Root nodulation; Rhizobium; Gene induction; Signal molecules; Organometalcarbonyl groups; Tricarbonyliron; Synthesis;
Bioprobes
1. Introduction
signals, and organometalcarbonyl groups have intense
IR vibrational bands that can be observed in a window
in the water background spectrum [12]. These bands are
narrow, so several can be observed in a single experi-
ment [2,11,13], and respond to changes in solvation
environment [1], providing the basis for our molecular
scale sensors and bioprobes. Over the past few years, we
have established many of the essential features needed
for such applications. Principal component analysis of
FTIR spectra has been used to differentiate responses to
different solvents [1] and mixtures of solvents [1,2],
different ions associated with crown ethers [3], and
changes in pH [4]. The method can detect p-stacking [5]
Bioprobes are functional molecules or devices that
provide information about biological systems. They can
operate on a macroscopic, microscopic, or submicro-
scopic scale (bionanometrology and molecular scale
observation of biological systems). Our recent work in
Nottingham and Norwich has been developing proce-
dures for such sensing molecules based on novel analysis
of spectroscopic responses from organometalcarbonyl
groups [1ꢀ11]. Organometal structures are rare in
/
nature, so there is no cross-talk with background
and ionic recognition [6] in the hostꢀguest chemistry of
/
ꢀ Presented as a Keynote Lecture at ISBOMC’02 (the first
International Symposium on BioOrganoMetallic Chemistry, Paris,
charged heteroaromatic compounds, and differentiate
18ꢀ
* Corresponding author. Tel.: ꢁ
592003.
E-mail
Stephenson).
/
20 July, 2002)
between barbituate structures by subtle changes in
/
44-1603-592019; fax: ꢁ
/
44-1603-
Richard
hydrogen bonding to hostꢀguest receptors [7]. The
/
organometalcarbonyl groups have been attached to
proteins [8] to allow ionisation changes on protein
surface groups to be studied [9]. Supported organome-
tallics have been used in combination with ATR
elements [10] and fibre optics [11] to facilitate sampling.
The methods established in this way should be suitable
for use with FTIR microscopy [14] and FTIR imaging
[15] technologies. Improvements in methodologies for
address:
g.r.stephenson@uea.ac.uk (G.
1
Present address: Institut fur Anorganische Chemie II, Universitat
¨
¨
Karlsruhe, Engesserstrasse Geb. 30.45, 76128 Karlsruhe, Germany.
2
Present address: Department of Chemistry, Joseph Black
Building, University of Glasgow, Glasgow G12 8QQ, UK.
3
Present address: IRCOF, Laboratoire de Chimie Organique Fine
et He´te´rocyclique, UPRES-A 6014, INSA B.P. 08, 76131 Mont St.
Aignan Cedex, France.
0022-328X/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-328X(02)02146-0

102
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ122
/
synthetic chemistry are now needed to prepare more
advanced and optimised organometalcarbonyl deriva-
tives for use in combination with our FTIR procedures,
and this is becoming a major focus for the development
of new organometallic bioprobes. Our first explorations
in this direction with bioflavonoids have been the
subject of a preliminary communication [16]. The
synthesis of bioflavonoids bearing organometallic
groups should provide a series of valuable spectroscopic
probes. Since the pioneering preparation [17] of orga-
nometallic derivatives of estradiols by the Jaouen group,
and the demonstration of their retained biological
activity [18], it has become clear that the introduction
of additional organometal-bearing substituents does not
preclude retained binding ability with the natural
biological receptors. Since then, prospects for novel
applications of organometallic chemistry in biology
have been reviewed by Ryabov [19] and Beck [20],
significant advances have been made through develop-
ments in the CMIA technique [21], and a variety of
organometalcarbonyl-tagged natural products have
control of root nodulation [27], a prerequisite for
nitrogen fixation in plants. Induction of nodulation
(nod) gene expression in symbiotic Rhizobium bacteria is
a crucial event in the early stages of legume root
nodulation, and plant-derived flavonoid signal mole-
cules such as naringenin (1) and eriodictyol (2) effect the
gene induction process. These biological processes are
summarised in Fig. 1. It has been shown that OH groups
must be present on both A and B-rings for efficient
biological activity. In recent years, the molecular
signalling that controls root nodulation (Fig. 1a) has
been the subject of sustained research effort, culminat-
ing in the identification [28] and total synthesis [29] of
NodRm-IV factors (sulfated lipooligosaccharides), the
Rhizobium nodulation signal molecules that are released
by the bacteria as a response to the presence of flavonoid
nod gene inducing compounds originating from le-
gumes. For some time, it has also been known from
experiments with mutant Rhizobium strains that the
constitutive nodD gene is essential for nod gene induc-
tion (Fig. 1b) that leads to the production of the
NodRm-IV factors [30], giving rise to the proposal
that recognition of plant-derived flavonoids by binding
to the gene-product NodD initiates the production of
the bacterial nodulation signal molecules, which, in
turn, effect changes in legume root cells that lead to
root-hair deformation [31] and the onset of root
nodulation by infestation by Rhizobium. The objective
of our work has been to prepare organometallic
flavonoid derivatives which retain their capacity to
induce nod gene expression, in preparation for their
use in an FTIR investigation of the organometalcarbo-
nyl probe in the presence of protein-containing fractions
of lysed cells from nodDꢁ and nodDꢂ strains of
been prepared for spectroscopic investigation [17,22ꢀ
/
26]. This growing focus on the prospects for novel
applications of organometallic systems in biology has
recently culminated in the first International Sympo-
sium on Bio-organometallic Chemistry (ISBOMC’02)
which marks the beginning of a wider interest in these
procedures that will take this area of chemistry beyond
the domain of specialised research groups into the wider
chemical, biological chemistry, and biochemical com-
munities.
In our present work, we have been addressing the
synthesis of organometalcarbonyl derivatives of a series
of A/B-ring oxygenated flavonoids that are active in the
Fig. 1. Cartoon to illustrate signalling (a) and nod gene induction events (b) at the first stage of root nodulation in legumes.

C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
103
Rhizobium. The practicality of FTIR observation of this
class of compounds at biologically relevant concentra-
tions (50 mM) has been established [16] in the presence of
lysed cells of Rhizobium leguminosarum (8400pRL1)
carrying nodD on pIJ1518, and an isogenic strain
lacking nodD. The prime objective now is the search
for flavonoid derivatives with substantial residual bio-
logical activity, so that differences between the IR
2. Results and discussion
2.1. Synthetic strategies for B-ring substitution
Since the electrophilic substitution of oxygenated
flavanones occurs readily at ring A, intact flavanones
were the logical starting point for the preparation of A-
ring substituted derivatives (Fig. 3a), and commercially-
available compounds were convenient for this purpose
[32]. It follows, however, that if the organometallic
substituent is required on the B-ring, it should be
attached to the aromatic ring before the formation of
the flavanone (Fig. 3b). A number of metallation
strategies could be chosen for this purpose, and at the
start of our investigations towards the B-ring series, we
compared several metallated derivatives to establish
their suitability in combination with tricarbonyl(h5-
cyclohexadienyl)iron electrophiles. Metallation next to
OMe groups is well known [33], and since the required
building block is a benzaldehyde derivative, an acetal-
protected benzaldehyde with an ether substituent was
spectra in the carbonylmetal vibrational region (2040ꢀ
/
1900 cmꢂ1) can be used to prove that the flavonoid
binds to the NodD protein, and reveal details of the
nature of the putative binding site. Our approach is to
prepare a representative set of flavonoids (Fig. 2) with
the organometallic moiety attached at the A-, B- or C-
rings, and to compare their activity in a screen for nod
gene induction.
The introduction of the A-ring substituent proved
straight-forward by direct reaction between the flava-
none and a tricarbonyl(h5-cyclohexadienyl)iron com-
plex, and full details of these procedures have already
been reported [32] (direct introduction of electrophilic
carbonylcobalt alkyne complexes to natural products
with oxygenated aromatic rings has also been reported
[25]). We now describe details of progress towards the
more challenging synthetic routes needed for the B and
C-ring derivatives that will complete the set of structures
required (Fig. 2) for the initial biological evaluation.
evaluated first, but without success (Table 1: entries 1ꢀ
/
3). Metallation of the ethanediol acetal of 4-methox-
ybenzaldehyde with n-butyllithium, followed by at-
tempted reaction of the resulting aryllithium reagent
with the tricarbonyliron complex 4 was the starting
point for this work, but no products corresponding to
Fig. 2. Labelling strategies to explore the point of attachment of tricarbonyl(h5-cyclohexadienyl) iron groups around the periphery of bioactive
flavanoids.

104
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ122
/
Fig. 3. Disconnections to illustrate reterosynthetic strategies for the A (a), B (b) and C (c) ring substitution patterns.
nucleophile addition to the dienyl salt were obtained. In
a protracted series of experiments, variation of the
phenol protecting group (methyl, t-butyldimethylsilyl,
allyl) the metallating agent (n-butyllithium, s-butyl-
lithium, t-butyllithium and n-butyllithium/potassium
tert-butoxide) and solvent (ether, tetrahydrofuran
(THF), dichloromethane, and hexane in the case of the
Schlosser base) were all examined. Attention turned next
(Scheme 1) to the oxazoline derivative 3 which was
prepared from 4-methoxybenzoyl chloride by the litera-
ture procedure [34]. This approach proved far more
successful. Metallation of 3 with s-butyllithium in ether
[35], and addition of the electrophile 4 to the resulting
aryllithium reagent, now afforded the expected adduct 5
in 76% yield (Table 1: entry 4). When this reaction was
repeated with the less reactive electrophile 7, the
corresponding adduct 8 was again obtained, but in a
reduced yield (Table 1: entry 5). Conversion of the
oxazoline into the aldehyde is possible by quaternisation
and hydride reduction. This reaction was attempted first
with the metal complex 5. Reaction with methyl iodide,
lysed hydrolysis of the heterocyclic ring, afforded the
required benzaldehyde derivative 6, but in only 20%
yield, and then as a 1:1 mixture with recovered starting
material. Product 6 was tentatively identified from an
NMR spectrum of the mixture of products. The reaction
was repeated with the adduct 8, but none of the
corresponding benzaldehyde adduct was obtained. In
view of these problems, further attempts at optimisation
of the production of 6 and further characterisation of
this compound was not attempted.
A new approach was based on lithium-for-halogen
exchange which provided an alternative procedure for
the generation of the aryllithium reagents, and two B-
ring substitution patterns were addressed (Schemes 2
and 3) starting from either 3-bromophenol by formyla-
tion, protection and metallation, or from 4-hydroyx-
benzaldehyde by bromination, protection, and
metallation. Formylation of 3-bromophenol (Scheme
2) using the ReimerꢀTiemann conditions as described
/
by Hodgson [36] gave the known 2-bromo-4-hydroxy-
benzaldehyde which was purified by column chromato-
graphy. Silylation with t-butyldimethylsilyl chloride
followed by reduction with L-selectride and acid-cata-

Table 1
Nucleophile addition reactions with tricarbonyl(h5-cyclohexadienyl)iron(1ꢁ
) electrophiles
/
a
Entry Nucleophile
Metal
Electrophile Product
R
Type
Derived from: [Structure]
%
Type
1
ꢀ
ꢀ/
ꢀ/
3
3
9
/
Metallated arene
Metallated arene
Metallated arene
Metallated arene
Metallated arene
Metallated arene
Metallated arene
Metallated arene
Metallated arene
Metallated arene
Arene [41: Xꢃ
Arene [41: Xꢃ
Arene [41: Xꢃ
Arene [41: Xꢃ
Arene [41: Xꢃ
Bromoarene [41: Xꢃ
Bromoarene [41: Xꢃ
Bromoarene [41: Xꢃ
Aryllithium reagent from bromoarene [41: Xꢃ
Aryllithium reagent from bromoarene [41: Xꢃ
Enolate from acetophenone derivative [42: Xꢃ
Enolate from acetophenone derivative [42: Xꢃ
Enolate from acetophenone derivative [42: Xꢃ
Enolate from flavanone derivative [43: XꢃYꢃ
Acetophenone derivative [42: XꢃYꢃOMe]
Acetophenone derivative [42: XꢃCH2OMe, Yꢃ
Flavanone derivative [43: XꢃYꢃ
Flavanone derivative [43: XꢃYꢃ
Flavanone derivative [43: XꢃYꢃ
Flavanone derivative [43: XꢃYꢃ
Flavanone derivative [43: XꢃYꢃ
/
OMe, Yꢃ
OSiMe2t-Bu, Yꢃ
OCH2CHꢁCH2, Yꢃ
C(ꢁNꢀCMe2ꢀCH2Oꢀ
C(ꢁNꢀCMe2ꢀCH2Oꢀ
CH(ꢀOꢀCH2ꢀCH2Oꢀ
OMe, YꢃCH(ꢀOꢀCH2ꢀ
OMe, YꢃCH(ꢀOꢀCH2ꢀ
/
CH(ꢀ
/
Oꢀ
CH(ꢀ
CH(ꢀ
), Y ꢃ
), YꢃOMe]
), Yꢃ
CH2Oꢀ
CH2Oꢀ
/
CH2ꢀ
/
CH2Oꢀ
CH2ꢀCH2Oꢀ
OꢀCH2ꢀCH2Oꢀ
OMe]
/
)]
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
Mꢃ
/
Li
4
4
4
4
7
4
4
7
4
7
7
7
7
4
4
7
4
4
7
4
7
4
4
4
4
7
7
H
ꢀ
ꢀ/
ꢀ/
5
/
0
ꢀ
ꢀ/
ꢀ/
/
2
/
/
/
Oꢀ
/
/
/)]
/Li
H
0
3
/
/
/
/
/
/
/)]
/Li
H
0
4
/
/
/
/
/
/
/Li
H
76
38
Arene derivative
Arene derivative
5
/
/
/
/
/
/
/Li
OMe
H
8
b
6
/
/
/
/
/
/
OSiMe2t-Bu]
/Li
10
11
12
11
12
18
22
7
9
Arene derivative
Arene derivative
b
7
ꢀ/
ꢀ/
ꢀ/
ꢀ/
/
/
/
/
/
/)]
/Li
H
b
b
b
8
/
/
/
/
/
/)]
/Li
OMe
H
15
57
67
60
72
0
Arene derivative
Arene derivative
9
/
OMe, Yꢃ
/
CH(ꢀ
/
Oꢀ
/
CH2ꢀ
/
CH2Oꢀ
/
)]
)]
/
(CuLi)/2
(CuLi)/2
SiMe3
SiMe3
SiMe3
SiMe3
Li
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
/OMe, Yꢃ
/
CH(ꢀ
/
Oꢀ
/
CH2ꢀ
/
CH2Oꢀ
/
/
OMe
OMe
OMe
OMe
H
Arene derivative
Acetophenone derivative
Acetophenone derivative
17 Silylenol ether
21 Silylenol ether
26 Silylenol ether
31 Silylenol ether
23 Lithium enolate
28 Lithium enolate
32 Lithium enolate
35 Lithium enolate
/Yꢃ
/H]
/
/Yꢃ
/OMe]
/
/Yꢃ
/OSiMe3]
/
ꢀ/
ꢀ/
30
24
ꢀ/
ꢀ/
/
/OSiMe3]
/
0
b
/
/
/
H
53
73
0
Acetophenone derivative
Acetophenone derivative
c
/
/OSiMe3]
/Li
OMe
H
/
/OSiMe3]
/Li
ꢀ/
ꢀ/
/
/
OMe]
/Li
H
36, 37 64, 23 Flavanone and chalcone
c
b
ꢀ/
ꢀ/
ꢀ/
Lithium enolate
Lithium enolate
Lithium enolate
/
/OH]
/Li
OMe
H
40
39
40
20
24
/
8
Flavanone
Flavanone
c
b
b
/
/OH]
/Li
20
31
90
72
0
d
/
/OH]
/Li
OMe
H
Flavanone
Acetophenone derivative
Acetophenone derivative
19 Copper-mod. enolate Enolate from acetophenone derivative [42: Xꢃ
25 Copper-mod. enolate Enolate from acetophenone derivative [42: Xꢃ
27 Copper-mod. enolate Flavanone derivative [42: Xꢃ
33 Copper-mod. enolate Flavanone derivative [43: Xꢃ
Copper-mod. enolate Flavanone derivative [43: Xꢃ
Sodium enolate Flavanone derivative [43: Xꢃ
/Yꢃ
/OH]
/
(CuLi)/2
(CuLi)/2
(CuLi)/2
(CuLi)/2
(CuLi)/2
Na
/Yꢃ
/OMe]
/
H
/
Yꢃ
Yꢃ
Yꢃ
Yꢃ
/
OSiMe3]
OSiMe3]
OMe]
/
H
ꢀ/
ꢀ/
/
/
/
H
ꢀ/
38
38
0
/
/
/
OMe
OMe
28
23
Chalcone
Chalcone
/
/OMe]
/
a
Generalised structures of nucleophiles:
.
b
c
Yield after in situ removal of protecting groups.
In situ protection by SiMe3 groups.
In situ protection by CH2OMe groups.
d

106
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
Scheme 1.
introduced a bulky protecting group at the phenolic
oxygen, chosen to minimise possible complications
through migration [37] of the site of metallation of the
aromatic ring. Conversion into the acetal, as before,
afforded the protected bromoarene 9. Lithium-for-
bromine exchange with n-butyllithium followed by
addition of the cyclohexadienyliron complex 4 and
hydrolysis of the product in aqueous acid, led directly
to the formation of the adduct 10 of the silyloxybenzal-
dehyde, but in only 7% yield (Table 1: entry 6). The
efficiency of addition of aryllithium reagents to
tricarbonyl(h5-cyclohexadienyl)iron complexes is clearly
very sensitive to the nature of substituents on the
aromatic ring, and in the case of 9 the combination of
acetal and TBDMS ether is far less desirable than the
oxazoline/methyl ether pairing in 3. Fortunately, the
alternative of bromination of 4-hydroxybenzaldehyde
proved more successful (Scheme 3). A small ether
protecting group was chosen, and after acetalisation,
lithium-for-bromine exchange with n-butyllithium af-
forded the aryllithium reagent which was employed as a
nucleophile with salts 4 and 7 using an acidic work-up,
as before, to give direct access to the derivatised
benzaldehydes. The products 11 and 12 were obtained
in this way in slightly improved yields in the range 9ꢀ
/
15% (Table 1: entries 7, 8). Further improvement was
Scheme 2.

C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
107
Scheme 3.
obtained by conversion of the aryllithium reagent into
an organocuprate [37,38]. In this way, yields of 11 and
12 were raised to 57 and 67%, respectively, (Table 1:
entries 9, 10). The adduct 12 was taken on to the
flavanone (Scheme 4). Condensation of 12 with the
partially protected [39] trihydroxyacetophenone 13 af-
forded 14. Removal of the MOM protecting groups with
acid, afforded the chalcone derivative 15 in 20% yield.
Since flavanone and chalcone species are likely to
interconvert under biological conditions, this product
might itself be suitable for biological evaluation, and
was fully characterised. Although well precedented [40],
Scheme 4.

108
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ122
/
cyclisation of orthohydroxychalcones to flavanones can
be a difficult procedure, but none-the-less, 15 was
successfully taken through to provide enough of the
flavanone 16 for it to be used in the biological assay for
nod gene induction. Product 16 was identified by NMR,
IR and FAB mass spectrometry, but the high-mass ions
in the FAB spectrum, in this case, were of too low an
intensity to permit accurate mass confirmation of the
structure. Since it is formed by the known cyclisation
reaction of the characterised chalcone precursor 15, high
field NMR and low resolution FAB characterisation is
sufficient to allow the unambiguous assignment of
structure 16 to the product of the cyclisation step.
of our current studies, this final step proved unneces-
sary, as the required adducts were successfully obtained
in sufficient quantities for screening by the alternative
direct reaction of the flavonoids with electrophilic
cyclohexadienyliron complexes, but the preparation of
30 by the stepwise sequence shown in Scheme 6 is
important because it provides the key intermediate
needed for a higher yielding strategy to gain access to
specific C-ring products in future work.
The investigation of the intact flavonoid series began
(Scheme 7) with the examination of the tetra(trimethyl-
silyl)naringenin derivative 31. By means of low tem-
perature conditions, this was successfully prepared in
79% yield, but unlike 18 and 20, reaction with the
tricarbonyl(h5-cyclohexadienyl)iron complex 4 proved
unsuccessful (Table 1: entry 14). The use of the lithium
enolate 32 of the tris(trimethysilyloxy)flavanone deriva-
tive (Table 1: entry 17), and a copper-modified reagent
33 obtained from the unprotected flavanone using LDA
2.2. Synthetic strategies for C-ring substitution
A similar approach (Fig. 3c) can yield a C-ring
derivative by introduction of the tricarbonyliron com-
plex prior to formation of the flavonoid, but in
principle, direct functionalisation of the intact flavonoid
could also provide the required structure. The problem
with this direct alternative, however, is that both
protection of the flavonoid OH groups, and develop-
ment of the C-ring enolate, requires great care in order
to avoid the opening of the labile central ring. The use of
silylenol ethers as nucleophiles with cyclohexadienyliron
complexes, on the other hand, is well established [41],
and in preliminary model studies (Scheme 5), we tested
enol ethers 17 and copper-modified enolates 19 with the
cyclohexadienyliron electrophiles 7 and 4 to form 18 and
20 (Table 1: entries 11, 22). The copper-modified enolate
gave particularly good results. Similarly, trimethoxy-
acetophenone derivatives were successfully converted
into the corresponding organoiron products 22 and 24,
using either electrophile 4, or the methoxy-substituted
counterpart 7 (Table 1: entries 12, 16, 23). Trimethylsi-
lylenol ethers 21, lithium enolates 23 and copper-
modified enolates 25 were all found to be suitable for
the purpose, and the products 22 and 24 were isolated in
better than 70% yield in each case. Again, however,
these reactions were found to be sensitive to the exact
substitution pattern on the nucleophilic reagent, and the
corresponding tetra- and tris-trimethylsilyl nucleophiles
26 and 27 gave no isolable products from reactions with
7 and 4 (Table 1: entries 13, 24). Selective bis protection
of 2,4,6-trihydroxyacetophenone is possible (Scheme 4),
and the bis-MOM product 13 [39] was further protected
with a trimethylsilyl group and converted without
isolation into the lithium enolate 28 (Scheme 6). Addi-
tion of the cyclohexadienyliron electrophile 7 to form
29, and a hydrolytic work-up, afforded the required
trihydroxyacetophenone derivative 30 (Table 1: entry
15), which should be suitable for the completion of the
stepwise route (Fig. 3c) to C-ring adducts, using the
same procedures shown in Scheme 4. In fact, for the
purpose of initial biological evaluation which is the goal
and CuBr×
/
Me2S (Table 1: entry 25) were similarly
unsuccessful. The 4?,5,7-trimethoxy derivative 34 [42]
was also prepared (Scheme 8) using dimethyl sulfate and
potassium carbonate in acetone. This was converted into
the lithium enolate 35 and reaction with 4 gave the
flavanone adduct 36 in 64% yield, together with the
chalcone 37 (Table 1: entry 18). The opening of the
central ring could not be completely prevented in this
case. Finally (Scheme 9), a practical though relatively
low yielding one-pot procedure was developed, in which
protection of the phenolic OH groups, deprotonation to
generate the enolate, reaction with the tricarbonyliron
complex, and deprotection were all performed in single
sequence (Table 1: entries 19ꢀ21), affording the flava-
/
none derivatives 39 and 40 directly in the form needed
for biological evaluation. In situ protection with tri-
methylsilyl chloride and MOM chloride was compared,
and the latter was found to give the better results. The
product 40 was obtained in 31% overall yield for the
four steps.
3. Conclusions
The the A-ring products from our previous paper [32],
and 16, 39, and 40, described here, are the first
tricarbonyliron derivatives of flavanones to be prepared
[43]. Commercially-available hydroxyflavanones can be
converted into organometallic derivatives by convenient,
direct, one-pot procedures (using 3 equivalents of
sodium hydride to generate the triphenolate for the A-
ring substitution [32], and the in situ protection, enolate
generation and deprotection described above for ring C)
to afford sufficient material for biological evaluation in
screens for nodulation gene induction. Where the
flavonoid must be prepared from hydroxyarene compo-
nents, the alternative of formation of the organometallic

C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
109
Scheme 5.
adduct prior to introduction of the B-, C-ring system
looks promising, and has successfully yielded the B-ring
adduct 16. Biological testing reported elsewhere [16] has
shown that significant residual biological activity is
retained in the some of the organometallic products at
20 mM concentrations. Despite the bulk of the addi-
tional metal-bearing ring, the metal-tagged product
must still be capable of participating in the binding
events that underpin the mechanism of the gene induc-
tion process. The B- and C-ring adducts described in this

110
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
Scheme 6.
paper are an improvement on the A-ring series reported
earlier [16,32], as they also show significant nod gene
induction activity [16] at 2 mM levels (e.g. compound
40).
In the development of synthetic strategies for these B-
and C-ring derivatives, a wide selection of examples of
nucleophilic addition to tricarbonyl(h5-cyclohexadieny-
l)iron electrophiles have been examined (Table 1), and in
contrast to results typical of simple systems [44], the use
of highly functionalised intermediates needed for the
construction of oxygenated flavonoids has shown that
the efficiency of nucleophile addition can be profoundly
influenced by the precise nature of substituents, and the
choice of protecting group strategies. In this work, we
have identified simple procedures (lithium counterions
in dichloromethane) for the use of enolates of aceto-
Scheme 7.

C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
111
Scheme 8.
phenones, and have demonstrated that the nucleophile
4. Experimental
addition step is sufficiently fast to intercept flavanone-
derived enolates prior to C-ring fragmentation. Metal-
lated aromatic rings have also been employed as
nucleophiles. Metallation adjacent to an oxazoline
substituent, followed by trapping of the nucleophile
with the organometallic electrophile proved effective,
and lithium-for-halogen exchange next to an ether
substituent also proved to be an effective strategy to
gain access to suitable metallated nucleophilic precur-
sors. In this way, a series of differently substituted
aromatic rings carrying organometallic reporting groups
have been prepared, and taken together with work
described earlier [32], clear methodologies have been
established for the selective attachment of organome-
talcarbonyl groups to either the rings A, B or C of the
flavonoid skeleton.
All reactions involving tricarbonyliron complexes
were performed under an atmosphere of dry, oxygen-
free nitrogen in oven-dried glassware twice evacuated
and filled with the nitrogen. All solvents for the
reactions were of reagent grade and were dried and
distilled immediately before use as follows: diethyl ether
(ether, Et2O) and THF from sodium/benzophenone;
dichloromethane and acetonitrile from calcium hydride.
All reagents were purchased at highest commercial
quality and used without further purification. Column
chromatography was performed using Merck silica gels.
TLC analyses were carried out on Merck aluminium-
backed silica gel plates. Low resolution EI mass spectro-
metry (Kratos MS25 mass spectrometer) and elemental
analyses were performed at the University of East

112
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
Scheme 9.
Anglia by Mr A.W.R. Saunders. Other mass spectra
were measured at the EPSRC Mass Spectrometry
Centre at University of Wales, Swansea. IR spectra
residue was treated with SOCl2 (15 ml, 206 mmol) with
vigorous stirring. After the reaction was complete, the
mixture was cooled and poured into ether. The pre-
cipitate was collected by filtration and hydrolysed with
aq. NaOH (20%). The reaction mixture was extracted
were recorded on a PerkinꢀElmer 1720X FTIR spectro-
/
meter as a thin film, unless solvent is specified. NMR
spectra were recorded on Jeol FX270 (1H, 270 MHz), or
Jeol GX400 (1H, 400 MHz) spectrometers. The operat-
ing frequency and solvent are indicated for each set of
data in that order. Reference used was tetramethylsilane
with ether (2ꢄ40 ml) and the extracts were dried over
/
MgSO4. A kugelrohr distillation produced 4.96 g (82%)
of 2-(4?-methoxyphenyl)-4,4-dimethyloxazoline (3) [34]
as a clear oil which was used in step (4.1.1.2) without
further purification. 1H-NMR (270 MHz, CDCl3) d:
1.32 (6H, s, Me2), 3.78 (3H, s, OMe), 4.03 (2H, s,
(dꢃ0.00). Compounds for biological testing were
/
purified by reverse-phase HPLC using a Dynamax C18
column with gradient elution (methanol/water, flow
ꢀ
/
CH2ꢀ
/
), 6.85 (2H, d, Jꢃ8.6 Hz, 3,5-H), 7.84 (2H, d,
/
rate*
100 to 93%, 2ꢀ
25ꢀ27 min 25 to 20%, 27ꢀ
0%, 55ꢀ65 min 0%) and purity was checked by
/
1.5 ml/min; programming (% water), 0ꢀ
8 min 93 to 85%, 8ꢀ25 min 85 to 25%,
50 min 20%, 50ꢀ55 min 20 to
/
2 min
Jꢃ8.6 Hz, 2-H, 6-H).
/
/
/
/
/
/
4.1.1.2. Metallation
[35,45]
and
addition
to
) salts. Following
/
tricarbonyl(cyclohexadienyl)iron(1ꢁ
/
analytical HPLC employing a similar gradient.
the procedure of Meyers [35] a solution of the oxazoline
3 (0.205 g, 1 mmol) in ether was treated with a hexane
4.1. Preparation and use of metallated arenes as
nucleophiles with tricarbonyl(h5-
solution of s-BuLi (0.8 ml, 1 mmol) at ꢂ20 8C. The
/
mixture was stirred for 4 h at 0 8C and then added to a
stirred suspension of tricarbonyl[(1,2,3,4,5-h)-1,3-cy-
cyclohexadienyl)iron(1ꢁ) salts
/
clohexadienyl]iron(1ꢁ
(0.225 g, 0.62 mmol) in dichloromethane cooled to
109 8C. The stirring continued for 2 h then water
(50 ml) was added and the mixture was extracted with
ether (3ꢄ30 ml). The combined extracts were dried over
/
) hexafluorophosphate(1ꢂ) (4)
/
4.1.1. Tricarbonyl{(1,2,3,4-h)-5a-[2?-(4ƒ,4ƒ-
dimethyloxazolin-2ƒ-yl)-5?-methoxyphenyl]-1,3-
cyclohexadiene}iron(0) (5) and tricarbonyl{(1,2,3,4-h)-
2-methoxy-5a-[2?-(4ƒ,4ƒ-dimethyloxazolin-2ƒ-yl)-5?-
methoxyphenyl]-1,3-cyclohexadiene}iron(0) (8)
ꢂ
/
/
MgSO4 and concentrated under reduced pressure.
Column chromatography on silica gel with a mixture
of hexane/ethyl acetate (3:1) as eluent afforded 200 mg
(76%) of tricarbonyl{(1,2,3,4-h)-5a-[2?-(4ƒ,4ƒ-dimethyl-
oxazolin-2ƒ-yl)-5?-methoxyphenyl]-1,3-cyclohexadiene}-
iron(0) (5) as pale yellow oil. IR nmax: 2964, 2917 (CH),
2042, 1967 (FeCO), 1653, 1646, 1607, 1558, 1507, 1282
4.1.1.1. Preparation
of
2-(4?-methoxyphenyl)-4,4-
dimethyloxazoline (3). Following a procedure based
on a combination of literature methods [34], 4-methoxy-
benzoyl chloride (5 g, 29.4 mmol) in dichloromethane
(25 ml) was added dropwise to 2-amino-2-methylpro-
panol (5.24 g, 58.8 mmol) with stirring at 0 8C. The
precipitated solid was removed by filtration and the
solvent was evaporated under reduced pressure. The
cmꢂ1. MS (EI) m/z (relative intensity) 395 (Mꢁ ꢀ
6), 367 (Mꢁ ꢀ2CO, 1), 339 (Mꢁ ꢀ
3CO, 24), 337 (63), 268
(90), 206 (100). Anal. Calc. for C21H21NO5Fe: C 59.6, H
/CO,
/
/

C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
113
1
5.0, N 3.3. Found: C 59.9, H 5.0, N 3.2. H-NMR (270
when used with 8, was unsuccessful, and no products
were isolated.
MHz, CDCl3) d: 1.33 (6H, s, Me, Me), 1.40 (1H, m, 6a-
H), 2.39 (1H, ddd, Jꢃ15.2, 11.2, 3.95 Hz, 6b-H), 3.15
/
(2H, m, 1-H, 4-H), 3.77 (3H, s, OMe), 3.99 (2H, s,
OCH2ꢀ), 4.41 (1H, dt, Jꢃ10.9, 3.95 Hz, 5b-H), 5.44
(2H, m, 2,3-H), 6.64 (1H, dd, Jꢃ8.6, 2.6 Hz, 4?-H), 6.80
(1H, d, Jꢃ2.6 Hz, 6?-H), 7.51 (1H, d, Jꢃ8.6 Hz, 2?-H).
4.1.2. Tricarbonyl[(1,2,3,4-h)-5a-(2?-formyl-5?-t-
butyldimethylsilyloxyphenyl)-1,3-
cyclohexadiene]iron(0) (10)
/
/
/
/
/
Tricarbonyl{(1,2,3,4-h)-2-methoxy-5a-[2?-(4ƒ,4ƒ-di-
methyloxazolin-2ƒ-yl)-5?-methoxyphenyl]-1,3-cyclohexa-
diene}iron(0) (8) was prepared analogously as pale
yellow oil from tricarbonyl[(1,2,3,4,5-h)-2-methoxy-1,3-
4.1.2.1. Preparation of 2-bromo-4-hydroxybenzaldehyde
[46]. Following a modification of the procedure of
Hodgson [36], aq. KOH (30%, 160 ml) was added to 3-
bromophenol (10.04 g, 58 mmol). The mixture was
cyclohexadienyl]iron(1ꢁ
/
) hexafluorophosphate(1ꢂ
/
) (7)
heated to 70ꢀ75 8C and then ethanol (5 ml) was added
/
(0.6 g, 1.52 mmol). Yield: 260 mg (38%). IR nmax: 2962,
2896 (CH), 2041, 1961 (FeCO), 1653, 1607, 1569, 1485,
in one portion followed by dropwise addition of chloro-
form (28 ml, 0.35 mol) during 1 h at 75 8C. The reaction
mixture was stirred for a further 3 h at that temperature.
After cooling to room temperature (r.t.) and acidifica-
tion (10 N HCl), most of the by-products were removed
by steam distillation. The residue was cooled and the
precipitate was separated by filtration. Column chro-
matography of the solid on silica gel with a mixture of
hexane/ethyl acetate (2:1) as eluent afforded 1.75 g
(15%) of 2-bromo-4-hydroxybenzaldehyde. 1H-NMR
1226 cmꢂ1. MS (EI) m/z (relative intensity) 425 (Mꢁ ꢀ
/
CO, 10), 397 (Mꢁ ꢀ
Calc. for MꢃC22H23NO6Fe.
425.0926. Found: 425.0930. 1H-NMR (270 MHz,
CDCl3) d: 1.32 (6H, s, Me,Me), 1.52 (1H, ddd, Jꢃ
14.85, 3.95, 2.9 Hz, 6a-H), 2.40 (1H, ddd, Jꢃ14.85,
11.2, 3.95 Hz, 6b-H), 2.77 (1H, dd, Jꢃ6.6, 3.6 Hz, 4-H),
3.38 (1H, m, 1-H), 3.65 (3H, s, 2-OMe), 3.78 (3H, s, 5?-
OMe), 3.98 (2H, s, OCH2-), 4.11 (1H, dt, Jꢃ10.9, 3.6
Hz, 5b-H), 5.20 (1H, dd, Jꢃ6.6, 2.3 Hz, 3-H), 6.64 (1H,
dd, Jꢃ8.6, 2.6 Hz, 4?-H), 6.78 (1H, d, Jꢃ2.6 Hz, 6?-H),
7.51 (1H, d, Jꢃ8.6 Hz, 2?-H).
/
2CO, 3), 367 (100). HRMS (EI)
/
M
ꢁ ꢀ
/
CO requires:
/
/
/
/
(270 MHz, acetone-d6) d: 6.89 (1H, ddd, Jꢃ
1.0 Hz, 5-H), 7.11 (1H, d, Jꢃ2.3 Hz, 3-H), 7.76 (1H, d,
Jꢃ8.6 Hz, 6-H), 9.56 (1H, br s, OH), 10.12 (d, Jꢃ1.0
Hz, CHO).
/
8.6, 2.3,
/
/
/
/
/
/
/
4.1.2.2. Protection of the hydroxy and aldehyde functions
based on combinations of literature procedures for related
compounds [47,48]. A solution of 4-hydroxybenzalde-
hyde (0.46 g, 3.77 mmol), t-BuMe2SiCl (0.70 g, 4.64
mmol), and imidazole (0.8 g, 11.75 mmol) in DMF (20
ml) [47] was stirred at 65 8C for 6 h. Water was added
4.1.1.3. Attempted removal of the oxazoline protecting
group from 5 and 8. A solution of the complex 5 (200 mg,
0.47 mmol) and methyl iodide (710 mg, 5 mmol) in
acetone (20 ml) was heated at reflux until TLC showed
no sign of the starting material (ca. 4 h). The volatiles
were removed under reduced pressure and the residue
was re-dissolved in dichloromethane (20 ml). The
followed by extraction with ether (3ꢄ30 ml). The
/
combined extracts were dried over MgSO4 and concen-
trated under reduced pressure. Column chromatography
on silica gel eluted with a mixture of hexane/ethyl
acetate (5:1) afforded 525 mg (42%) of the target
compound. (Unreacted starting material (430 mg) was
also recovered.) This product (0.52 g, 1.65 mmol) was
then heated at reflux with 1,2-dihydroxyethane (0.49 g,
7.9 mmol) in benzene (30 ml) in the presence of p-
toluene sulfonic acid (0.1 g) for 6 h in an apparatus fitted
with a Dean-Stark adapter [48]. The reaction mixture
was concentrated, washed with an aq. sodium hydrogen
carbonate solution and water, dried over MgSO4 and
solution was cooled to ꢂ
(0.6 ml, 0.6 mmol) was added. The stirring continued for
1 h. The mixture was allowed to warm to ꢂ10 8C,
/
50 8C and then
L-selectride
/
ethanol solution of HCl (5 ml) was added and the
mixture was stirred for an additional 1 h. After dilution
with water (50 ml) and extraction with ether (3ꢄ30 ml),
/
the combined extracts were dried over MgSO4 and
concentrated under reduced pressure. Column chroma-
tography on silica gel eluted with a mixture of hexane/
ethyl acetate (3:1) afforded an inseparable mixture (60
mg) of the desired product, tricarbonyl[(1,2,3,4-h)-5a-
(2? - formyl - 5? - methoxyphenyl) - 1,3 - cyclohexadiene]-
iron(0) (6), with the starting oxazoline complex (3:2).
then passed through a short silica gel column (3ꢄ2 cm)
/
using hexane/ethyl acetate mixture (5:1) as eluent to
afford 0.6 g (98%) of the desired product 9 as a light oil.
1H-NMR (60 MHz, CDCl3) d: 0.18 (6H, s, Me2Si), 0.98
(9H, s, t-BuSi), 4.05 (4H, m, -OCH2CH2O-), 6.02 (1H, s,
1
Calculated yield of the product is 20% based on H-
1
NMR (taken in mixture with 5): H-NMR (270 MHz,
CDCl3) d: 1.48 (1H, dm, Jꢃ
ddd, Jꢃ15.5, 11.2, 3.95 Hz, 6b-H), 3.15 (2H, m, 1-H, 4-
H), 3.84 (3H, s, OMe), 4.43 (1H, dt, Jꢃ11.2, 3.6 Hz, 5b-
H), 5.46 (2H, m, 2-H, 3-H), 6.77 (1H, dd, Jꢃ8.6, 2.6
Hz, 4?-H), 6.89 (1H, d, Jꢃ2.6 Hz, 6?-H), 7.66 (1H, d,
Jꢃ8.6 Hz, 2?-H), 10.00 (1H, s, CHO). This procedure,
/
15.5 Hz, 6a-H), 2.46 (1H,
/
O2CHꢀ
/
), 6.76 (1H, dd, Jꢃ
/
8.4, 2.4 Hz, 5-H), 7.08 (1H,
8.4 Hz, 6-H).
/
d, Jꢃ2.4 Hz, 3-H), 7.45 (1H, d, Jꢃ
/
/
/
/
4.1.2.3. Metallation [49] and addition to the
tricarbonyl(cyclohexadienyl)iron(1ꢁ) salt. A solution
/
/

114
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ122
/
of the protected compound 9 (0.59 g, 1.64 mmol) in
ether (10 ml) was treated with a hexane solution of n-
product [51] (2.15 g, 10 mmol) was then heated at reflux
with 1,2-dihydroxyethane (2.2 g, 36 mmol) in benzene
(60 ml) in the presence of p-toluene sulfonic acid (0.1 g)
for 6 h in an apparatus fitted with a Dean-Stark adapter
[52]. The reaction mixture was concentrated, washed
with aq. sodium hydrogen carbonate, and sodium
bisulfate solutions (30%), and water, dried over
MgSO4, and then passed through a short silica gel
BuLi (1 ml, 1.55 mmol) at ꢂ
stirred for 1 h and then added to a stirred suspension of
tricarbonyl[(1,2,3,4,5-h)-1,3-cyclohexadienyl]iron(1ꢁ
hexafluorophosphate(1ꢂ) (4) (0.364 g, 1 mmol) in
dichloromethane (20 ml), cooled to ꢂ78 8C. The
/
78 8C. The mixture was
/
)
/
/
stirring continued for 2 h. When the IR spectrum of
the reaction mixture showed no sign of the starting salt,
ethanolic HCl (5 ml) was added and the mixture was
stirred at r.t. for an additional 0.5 h, diluted with water
column (3ꢄ2 cm) using a hexane/ethyl acetate mixture
/
(5:1) with few drops of triethylamine as eluent to afford
1
1.66 g (64%) of the diprotected product. H-NMR (270
MHz, CDCl3) d: 3.85 (3H, s, OMe), 4.02 (4H, m,
(50 ml) and extracted with ether (3ꢄ
/
30 ml). The
combined extracts were dried over MgSO4 and concen-
trated under reduced pressure. Column chromatography
on silica gel with a mixture of hexane/ethyl acetate (5:1)
as eluent afforded 30 mg (7%) of tricarbonyl[(1,2,3,4-
h)-5a-(2?-formyl-5?-t-butyldimethylsilyloxyphenyl)-1,3-
cyclohexadiene]iron(0) (10) as a light-yellow viscous
oil. IR nmax: 2929, 2858 (CH), 2046, 1972 (FeCO), 1696
(formyl), 1598, 1561, 1490, 1258 cmꢂ1. MS (EI) m/z
-OCH2CH2O-), 5.69 (1H, s, -O2CHꢀ
8.6 Hz, 5-H), 7.33 (1H, dd, Jꢃ8.25, 2.0 Hz, 6-H), 7.63
(1H, d, Jꢃ2.0, 2-H).
/
), 6.84 (1H, d, Jꢃ
/
/
/
4.1.3.3. Metallation [53], addition to tricarbonyl-
(cyclohexadienyl)iron(1ꢁ) salts, and deprotection. A
solution of the diprotected compound (0.52 g, 2 mmol)
/
in THF (20 ml) was treated with a hexane solution of n-
(relative intensity) 398 (Mꢁ ꢀ
/
2CO, 12), 270 (Mꢁ ꢀ
/
3CO,
38), 368 (100), 345 (19), 343 (19), 314 (8), 259 (37), 257
BuLi (1.5 ml, 2 mmol) at ꢂ
stirred for 1 h, allowed to warm to ꢂ
CuBr×Me2S (0.206 g, 1 mmol) was added. The mixture
was stirred for 1 h at ꢂ30 8C and after the solid
dissolved, the solution was cooled to ꢂ78 8C and
tricarbonyl[(1,2,3,4,5-h)-1,3-cyclohexadienyl]iron(1ꢁ
hexafluorophosphate(1ꢂ) (4) (0.3 g, 0.82 mmol) was
added in one portion. The stirring continued for 2 h.
The mixture was allowed to warm to ꢂ10 8C. An
/
78 8C. The mixture was
/
40 8C and then
(36). HRMS (EI) Calc. for Mꢃ
/
C22H26O5FeSi. Mꢁ ꢀ
/
/
2CO requires: 398.1001. Found: 398.1001. 1H-NMR
/
(270 MHz, CDCl3) d: 0.24 (6H, s, SiMe2), 0.97 (9H, s,
/
Siꢀ
11.2, 3.95 Hz, 6b-H), 3.09 and 3.16 (2ꢄ
4-H), 4.41 (1H, dt, Jꢃ10.9, 3.6 Hz, 5b-H), 5.46 (2H, m,
2-H, 3-H), 6.71 (1H, dd, Jꢃ8.6, 2.3 Hz, 4?-H), 6.81 (1H,
d, Jꢃ2.3 Hz, 6?-H), 7.59 (1H, d, Jꢃ8.6 Hz, 2?-H), 10.01
(1H, s, CHO).
/
t-Bu), 1.50 (1H, m, 6a-H), 2.46 (1H, ddd, Jꢃ
/
15.2,
/
)
/
1H, 2ꢄm, 1-H,
/
/
/
/
/
/
/
ethanol solution of HCl (5 ml) was added and the
mixture was stirred for an additional 0.5 h. After
dilution with water (50 ml) and extraction with ether
4.1.3. Tricarbonyl[(1,2,3,4-h)-5a-(5?-formyl-2?-
methoxyphenyl)-1,3-cyclohexadiene]iron(0) (11) and
tricarbonyl[(1,2,3,4-h)-2-methoxy-5a-(5?-formyl-2?-
methoxyphenyl)-1,3-cyclohexadiene]iron(0) (12)
(3ꢄ30 ml), the combined extracts were dried over
/
MgSO4 and concentrated under reduced pressure.
Column chromatography on silica gel eluted with a
mixture of hexane/ethyl acetate (5:1) afforded a mixture
of the desired product and the starting material. The
latter was removed by kugelrohr distillation (100 8C,
0.1 Torr). The residue was repeatedly chromatographed
to give 165 mg (57%) of tricarbonyl[(1,2,3,4-h)-5a-(5?-
formyl-2?-methoxyphenyl)-1,3-cyclohexadiene]iron(0)
(11) as a light-yellow viscous oil. IR nmax: 2961, 2929,
4.1.3.1. Preparation of 3-bromo-4-hydroxybenzaldehyde.
Using a modification of an established procedure [50], to
a solution of 4-hydroxybenzaldehyde (6.84, 56 mmol) in
dichloromethane/THF (80 ml, 3:1) at 0 8C, a solution
of bromine (2.82 ml, 5.5 mmol) in dichloromethane (40
ml) was added dropwise during 2 h. The mixture then
was stirred for 2 h at r.t. and left overnight. Work-up
included subsequent washing with aq. sodium thiosul-
fate solution, water, drying over MgSO4 and crystal-
lisation from hexane/ethanol. Yield: 7.3 g (65%).
2855 (CH), 2043, 1967 (FeCO), 1685 (Cꢁ
1511, 1259 cmꢂ1. MS (EI) m/z (relative intensity) 354
(Mꢁ, 2), 326 (Mꢁ ꢀCO, 7.5), 298 (Mꢁ ꢀ
2CO, 93), 253
/O), 1599, 1578,
/
/
(100). HRMS (EI) Calc. for C17H14O5Fe: 354.0191.
1
Found: 354.0191. H-NMR (270 MHz, CDCl3) d: 1.46
(1H, dt, Jꢃ
11.2, 3.95 Hz, 6b-H), 3.09 and 3.15 (2ꢄ
H), 3.74 (1H, dt, Jꢃ11.2, 3.6 Hz, 5b-H), 3.85 (3H, s,
OMe), 5.48 (2H, m, 2-H, 3-H), 6.86 (1H, d, Jꢃ8.25 Hz,
5?-H), 7.64 (dd, Jꢃ8.25, 1.98 Hz, 1H, 6?-H), 7.71 (1H, d,
Jꢃ2.0 Hz, 2?-H), 9.82 (1H, s, CHO).
/
15.2, 3.6 Hz, 6a-H), 2.37 (1H, ddd, Jꢃ
/
15.2,
4.1.3.2. Protection of the hydroxy and aldehyde func-
tions. A solution of 3-bromo-4-hydroxybenzaldehyde
(2.0 g, 10 mmol), (MeO)2SO2 (3.7 g, 30 mmol), and
K2CO3 (9.2 g, 70 mmol) in acetone (50 ml) was refluxed
for 6 h. The solid was separated by filtration and then
/
1H, 2ꢄm, 1,4-
/
/
/
/
/
water was added followed by extraction with ether (3ꢄ
30 ml). The combined extracts were dried over MgSO4
and concentrated under reduced pressure. The crude
/
Tricarbonyl[(1,2,3,4-h)-2-methoxy-5a-(5?-formyl-2?-
methoxyphenyl)-1,3-cyclohexadiene]iron(0) (12) was
prepared analogously as pale yellow oil from tricarbon-

C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
115
yl[(1,2,3,4,5-h) - 2 - methoxy - 1,3 - cyclohexadienyl]iron-
(1ꢁ)hexafluorophosphate(1ꢂ) (7) (0.3 g, 0.76 mmol).
Yield: 195 mg (67%). IR nmax: 2960, 2930 (CH), 2041,
1961 (FeCO), 1690 (CꢁO), 1597, 1487, 1458, 1255
cmꢂ1. MS (EI) m/z (relative intensity) 384 (Mꢁ, 1),
356 (Mꢁ ꢀCO, 7), 328 (Mꢁ ꢀ2CO, 45), 300 (Mꢁ ꢀ
{tricarbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-h)-2ƒ-methoxy-1ƒ,3ƒ-cyclo-
hexadien-5ƒa-yl]iron(0)}chalcone (14) as a yellow
viscous oil. IR nmax: 3400 (OH), 2928 (CH), 2041,
/
/
/
1962 (FeCO), 1623 (Cꢁ
/
O), 1583, 1558, 1486, 1424,
1346, 1253, 1222, 1149, 1111, 1082, 1059, 1021 cmꢂ1
.
/
/
/
HRMS (FAB) Calc. for Mꢃ
C30H30O11Fe. MHꢁ
/
3CO, 34), 215 (100). HRMS (EI) Calc. for
C18H16O6Fe: 384.0296. Found: 384.0296. 1H-NMR
requires: 623.1215. Found: 623.1199. 1H-NMR (270
MHz, CDCl3) d: 1.62 (1H, m, 6ƒb-H), 2.36 (1H, m,
(270 MHz, CDCl3) d: 1.56 (1H, ddd, Jꢃ
2.3 Hz, 6a-H), 2.38 (1H, ddd, Jꢃ14.85, 11.22, 3.96
Hz, 6b-H), 2.69 (1H, dd, Jꢃ6.60, 3.63 Hz, 4-H), 3.39
(1H, m, 1-H), 3.53 (1H, dt, Jꢃ11.2, 3.6 Hz, 5b-H),
3.66 (3H, s, 2-OMe), 3.85 (3H, s, 2?-OMe), 5.24 (1H,
dd, Jꢃ6.6, 2.0 Hz, 3-H), 6.85 (1H, d, Jꢃ8.25 Hz, 3?-
H), 7.64 (1H, dd, Jꢃ8.25, 2.0 Hz, 4?-H), 7.70 (1H, d,
Jꢃ2.0 Hz, 6?-H), 9.83 (1H, s, CHO).
/14.85, 3.6,
6ƒa-H), 2.70 (1H, dd, Jꢃ
/
6.6, 3.6 Hz, 4ƒ-H), 3.41 (1H,
/
m, 1ƒ-H), 3.45, 3.51, 3.65, and 3.81 (4ꢄ
OMe), 3.55 (1H, m, 5ƒb-H), 5.16 and 5.27 (2ꢄ
OCH2O), 5.20 (1H, dd, Jꢃ
(2ꢄ1H, 2ꢄd, Jꢃ2.6 Hz, 3-H, 5-H), 6.78 (1H, d, Jꢃ
8.2 Hz, 5?-H), 7.36 (1H, d, Jꢃ2.3 Hz, 2?-H), 7.40 (1H,
dd, Jꢃ8.25, 2.3, 6?-H), 7.77 (2H, m, ꢀCHꢁCHꢀ), 13.93
(1H, s, OH).
/
3H, 4ꢄ
/s,
/
/
2H, 2ꢄ
/s,
/
/
6.6, 2.3, 3ƒ-H), 6.21 and 6.29
/
/
/
/
/
/
/
/
/
/
/
/
/
Use of the organolithium procedure as described in
Section 4.1.2.3 gave the same products 11 and 12 but the
yields were reduced to 9 and 15%, respectively.
4.1.5. 2,4,6-Trihydroxy-4?-methoxy-3?-
{tricarbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-h)-2ƒ-methoxy-1ƒ,3ƒ-
cyclohexadien-5ƒa-yl]iron(0)}chalcone (15)
4.1.4. 6-Hydroxy-4?-methoxy-2,4-bis-
The chalcone (105 mg, 0.17 mmol) prepared as
described in Section 4.1.4 was dissolved in ethanol (15
ml) and 4% H2SO4 in THF (20 ml) was added. The
mixture was stirred for 4 h at r.t. Work-up as above
followed by column chromatography on silica gel eluted
with a mixture of hexane/ethyl acetate (2:1 to 1:1)
afforded 64 mg (71%) of 2,4,6-trihydroxy-4?-methoxy-
3?-{tricarbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-h)-2ƒ-methoxy-1ƒ,3ƒ-cy-
clohexadien-5ƒa-yl]iron(0)}chalcone (15) as a yellow
solid. IR nmax: 3307 (OH), 2929, 2856 (CH), 2041,
(methoxymethyloxy)-3?-{tricarbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-h)-2ƒ-
methoxy-1ƒ,3ƒ-cyclohexadien-5ƒa-yl]iron(0)}chalcone 14
(a) Preparation of 6-hydroxy-2,4-bis-(methoxymethy-
loxy)acetophenone (13) [39]: By a method based on a
combination of literature procedures [39], 2,4,6-trihy-
droxyacetophenone monohydrate (0.93 g, 5 mmol), t-
BuOK (2.5 g, 22 mmol) and 18-crown-6 (0.2 g) were
stirred in acetonitrile (30 ml) at r.t. Methoxymethyl
chloride (2.3 ml, 30 mmol) was added in portions during
3 h. The mixture was stirred at r.t. for a further 3 h, and
then water (20 ml) was added. The mixture was
1964, 1950 (FeCO), 1624 (Cꢁ
/
O), 1600, 1559, 1509, 1560,
1351, 1253, 1222, 1171, 1115, 1079, 1029 cmꢂ1. HRMS
extracted with dichloromethane (3ꢄ/30 ml). The com-
(FAB) Calc. for Mꢃ
/
C26H22O9Fe. MHꢁ requires:
1
535.0691. Found: 535.0710. H-NMR (270 MHz, ace-
bined dichloromethane extracts were dried over MgSO4
and concentrated under reduced pressure. Column
chromatography on silica gel with a mixture of hex-
ane/ethyl acetate (3:1) as eluent afforded 0.72 g (56%) of
the diprotected product (13). 1H-NMR (270 MHz,
tone-d6) d: 1.58 (1H, m, 6ƒb-H), 2.36 (1H, ddd, Jꢃ
11.2, 4.0 Hz, 6ƒa-H), 2.79 (1H, dd, Jꢃ6.6, 3.6 Hz, 4ƒ-
H), 3.41 (1H, m, 1ƒ-H), 3.50 (1H, dt, Jꢃ11.2, 3.6 Hz,
5ƒb-H), 3.71 and 3.82 (2ꢄ3H, 2ꢄs, 2ƒ-OMe, 4?-OMe),
5.59 (1H, dd, Jꢃ6.6, 2.3 Hz, 3ƒ-H), 5.92 (2H, m, 6-H, 8-
H), 6.92 (2H, d, Jꢃ8.5 Hz, 5?-H), 7.47 (1H, dd, Jꢃ8.5,
2.0 Hz, 6?-H), 7.55 (1H, d, Jꢃ2.0 Hz, 2? H), 7.62 and
8.11 (2ꢄ1H, 2ꢄd, Jꢃ15.95 Hz, ꢀCHꢁCHꢀ), 14.02
(1H, s, OH).
/
14.9,
/
/
/
/
CDCl3) d: 2.61 (3H, s, MeCO), 3.42 and 3.45 (2ꢄ
2ꢄs, 2ꢄMeO), 5.22 and 5.25 (2ꢄ2H, 2ꢄ
CH2Oꢀ), 6.36 (2H, s, 3-H, 5-H), 14.05 (s, 1H, OH).
(b) Condensation with the benzaldehyde derivative:
/3H,
/
/
/
/
/s,
/
/
ꢀ
/
/
/
/
/
/
/
/
/
To a stirred solution of tricarbonyl[(1,2,3,4-h)-2-meth-
oxy-5a-(5?-formyl-2?-methoxyphenyl)-1,3-cyclohexadie-
ne]iron(0) 12 (230 mg, 0.6 mmol) and 6-hydroxy-2,4-bis-
(dimethoxymethyloxy)acetophenone 13 (150 mg, 0.6
mmol) in 95% aq. ethanol (40 ml) at r.t. was added
NaOH (750 mg, 19 mmol). The reaction mixture was
heated at reflux for 2 h, stirred for further 3 h at r.t., and
left overnight without stirring. Acidification with 0.1 N
4.1.5.1. 5,7-Dihydroxy-4?-methoxy-3?-
{tricarbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-h)-2ƒ-methoxy-1ƒ,3ƒ-
cyclohexadien-5ƒa-yl]iron(0)}flavanone (16). The de-
protected chalcone 15 (60 mg, 0.11 mmol) prepared as
described in Section 4.1.5 was dissolved in 80% aq.
ethanol (20 ml) and pH of the solution was adjusted to 9
with ca. 0.1 mg of NaOH. The mixture was stirred for 6
h at r.t. Work-up as above was followed by column
chromatography on silica gel eluted with mixtures of
hexane/ethyl acetate (2:1 to 1:1) to afford 15 mg (25%) of
5,7-dihydroxy-4?-methoxy-3?-{tricarbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-
h)-2ƒ-methoxy-1ƒ,3ƒ-cyclohexadien-5ƒa-yl]iron(0)}fla-
aq. HCl and extraction with ether (3ꢄ30 ml) afforded
/
extracts which were dried over MgSO4 and concentrated
under reduced pressure. Column chromatography of the
residue on silica gel eluted with mixtures of hexane/ethyl
acetate (4:1 to 1:1) afforded 105 mg (28%) of 6-hydroxy-
4 ?-methoxy-2, 4-bis-(methoxymethyloxy)-3 ?-

116
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ122
/
vanone (16) as a pale-yellow viscous oil. Mixture of
two diastereomers (1:1): IR nmax: 3360 (OH), 2924,
2854 (CH), 2042, 1969 (FeCO), 1728, 1640, 1604,
1486, 1463, 1378, 1260, 1159, 1088, 1022 cmꢂ1. MS
was removed by filtration, washed with diethyl ether
(3ꢄ30 ml) and the combined filtrate and washings were
/
concentrated under vacuum. 1-[2?,4?,6?-Tris(trimethyl-
silyloxy)phenyl]-1-(trimethylsilyloxy)ethene (26) was
obtained as a pale yellow oil. Yield: 2.13 g (99%). IR
nmax: 2960, 1597, 1568, 1423, 1297, 1253, 1200, 1167,
1100, 1028 cmꢂ1. MS (EI) m/z (relative intensity) 456
(Mꢁ, 26), 441 (99), 367 (75), 147 (21), 73 (100). Anal.
Calc. for C20H40O4Si4: C, 52.63, H, 8.77. Found: C,
52.83, H, 8.98. 1H-NMR (60 MHz, CDCl3) d: 0.23
(FAB) m/z (relative intensity) 535 (MHꢁ, 2), 478
1
(Mꢁ ꢀ
/
2CO, 4), 450 (Mꢁ ꢀ
/
3CO, 3), 391 (4). H-NMR
(270 MHz, acetone-d6) d: 1.60 (2ꢄ
2.34 (2ꢄ1H, ddd, Jꢃ14.85, 11.2, 3.6 Hz, 6ƒa-H),
2.70 and 2.72 (2ꢄ1H, dd, Jꢃ17.2, 3.3 Hz, 3a-H),
2.77 and 2.78 (2ꢄ1H, 2ꢄdd, Jꢃ6.6, 3.6 Hz, 4ƒ-H),
3.15 and 3.16 (2ꢄ1H, 2ꢄdd, Jꢃ17.2, 12.5 Hz, 3b-
H), 3.41 (2ꢄ1H, m, 1ƒ-H), 3.52 (2ꢄ1H, m, 5ƒb-H),
3.68 and 3.69 (2ꢄ3H, 2ꢄs, 2ƒ-OMe), 3.79 (2ꢄ3H, s,
4?-OMe), 5.43 and 5.44 (2ꢄ1H, 2ꢄdd, Jꢃ12.5, 2.95
Hz, 2-H), 5.56 (2ꢄ1H, m, 3ƒ-H), 5.90 and 5.93 (2ꢄ
2H, 2ꢄm, 6-H, 8-H), 6.91 (2ꢄ1H, d, Jꢃ8.2 Hz, 5?-
H), 7.30 (2ꢄ1H, dd, Jꢃ8.35, 2.0 Hz, 6?-H), 7.39 and
7.40 (2ꢄ1H, 2ꢄd, Jꢃ2.0 Hz, 2?-H), 12.13 (2ꢄ1H,
s, 5-OH).
/
1H, m, 6ƒb-H),
/
/
/
/
/
/
/
/
/
/
(36H, s, SiMe3), 4.20 and 4.57 (2ꢄ
6.03 (2H, s, 3?-H, 5?-H).
/
1H, 2ꢄ
/
s, ꢁ/CH2),
/
/
/
/
/
/
/
/
4.2.1.2. Preparation of 1-(2?,4?,6?-trimethoxyphenyl)-1-
(trimethylsilyloxy)ethene (21). Using the procedures
described in Section 4.2.1.1b, 2,4,6-trimethoxyacetophe-
none [54] (1.05 g, 5 mmol) was converted into 1.4 g
(99%) of 1-(2?,4?,6?-trimethoxyphenyl)-1-(trimethylsily-
loxy)ethene [55] as a colourless oil. IR nmax: 2958, 2839,
2360, 1696, 1605, 1496, 1465, 1414, 1340, 1280, 1251,
1227, 1206, 1187, 1159, 1130, 1014 cmꢂ1. MS (EI) m/z
(relative intensity) 282 (Mꢁ, 22), 267 (71), 251 (37), 237
(16), 210 (23), 195 (100), 180 (7), 165 (5), 152 (5), 137 (6),
109 (4), 89 (5), 73 (36). Anal. Calc. for C14H22O4Si: C,
59.57, H, 7.80. Found: C, 59.53, H, 7.92. 1H-NMR (270
MHz, CDCl3) d: 0.11 (9H, s, SiMe3), 3.80 (9H, s, OMe),
/
/
/
/
/
/
/
/
/
/
/
4.2. Alkylation of tricarbonyl(h5-cyclohexadienyl)iron
salts with acetophenone derivatives
4.2.1. Preparation of trimethylsilylenol ethers
4.2.1.1. Preparation
of
1-[2?,4?,6?-tris(trimethyl-
silyloxy)phenyl]-1-(trimethylsilyloxy)ethene (26). (a)
To a stirred solution of 2,4,6-trihydroxyacetophenone
monohydrate (2.79 g, 15 mmol) and triethylamine (11
ml, 80 mmol) in Et2O (300 ml) was added dropwise
trimethylsilyl chloride (10 ml, 80 mmol). A heavy white
precipitate was formed immediately, accompanied by a
rise in temperature. The mixture was then heated at
reflux for 7 h and allowed to stand overnight at r.t. The
precipitate of the ammonium salt was removed by
filtration and the filtrate was dried over MgSO4.
Removal of solvent at reduced pressure afforded 5.34
g (93%) of 2,4,6-tris(trimethylsilyloxy)acetophenone as a
pale yellow oil. IR nmax: 2960, 1700, 1569, 1419, 1255,
1167, 1105, 1025 cmꢂ1. MS (EI) m/z (relative intensity)
384 (Mꢁ, 3), 369 (100), 297 (17), 147 (3), 73 (23). Anal.
Calc. for C17H32O4Si3: C, 53.13, H, 8.33. Found: C,
53.12, H, 8.62. 1H-NMR (60 MHz, CDCl3) d: 0.22
4.28 and 4.72 (2ꢄ
5?-H).
/
1H, 2ꢄ
/
s, ꢁCH2), 6.11 (2H, s, 3?-H,
/
4.2.2. General procedure for the use of trimethylsilylenol
ethers with tricarbonyl(h5-cyclohexadienyl)iron(1ꢁ
salts
To a stirred solution of the silylenol ether (1ꢀ
in acetonitrile (5ꢀ10 ml) at r.t. was added the tricarbo-
nyl(cyclohexadienyl)iron salt 4 or 7 (0.5ꢀ1 mmol). The
/)
/2 mmol)
/
/
reaction mixture was stirred for 48 h at r.t. and then aq.
ammonium chloride (20 ml) was added. The mixture
was shaken vigorously for 5 min and then extracted with
ether (3ꢄ30 ml). The combined extracts were dried over
/
MgSO4 and concentrated under reduced pressure. The
crude products were purified by column chromatogra-
phy on silica gel with mixtures of hexane/ethyl acetate
(9:1 to 4:1) as eluent.
(27H, s, 3ꢄ
/
SiMe3), 2.35 (3H, s, Me), 5.95 (2H, s, 3-H,
5-H).
4.2.3. General procedure for the preparation and use of
lithium enolates with tricarbonyl(h5-
(b) The solution of this tris-trimethylsilyl derivative
(1.81 g, 4.71 mmol) in THF (10 ml) was added dropwise
via syringe to a solution of lithium diisopropylamide in
THF (50 ml) prepared from 8 mmol of each n-BuLi (1.6
M in hexane) and diisopropylamine, and cooled to
cyclohexadienyl)iron(1ꢁ
To a solution of the acetophenone derivative (4
mmol) in Et2O (10 ml) at ꢂ78 8C via syringe was
/
) salts
/
added a solution of LiN(SiMe3)2 (4 mmol) in THF. The
mixture was stirred for 1 h at that temperature and then
added to a dichloromethane suspension (20 ml) of a
ꢂ
/
78 8C. The resulting solution was stirred for 1.5 h at
ꢂ
/
78 8C, then trimethylsilyl chloride (1.2 ml, 9.4 mmol)
was added and the mixture was stirred for a further 1.5 h
tricarbonyl(cyclohexadienyl)iron salt 4 or 7 (0.5ꢀ
/
1
at ꢂ78 8C. Evaporation of the solvent under reduced
/
mmol) at ꢂ78 8C. The reaction mixture was stirred
/
pressure gave a mixture of a yellow viscous liquid and a
white precipitate of the ammonium salt. The precipitate
for 1.5 h, allowed to warm to 0 8C and then water (20
ml) was added. The mixture was extracted with ether

C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
117
(3ꢄ
/
30 ml). The combined extracts were dried over
206 (11), 195 (53). Anal. Calc. for C21H22O8Fe: C 55.02,
1
H 4.80. Found: C 54.82, H 4.70. H-NMR (270 MHz,
MgSO4 and concentrated under reduced pressure.
Column chromatography on silica gel with mixtures of
hexane/ethyl acetate (9:1 to 4:1) as eluent afforded a
mixture of the target complex with the starting acet-
ophenone. The latter was removed using kugelrohr and
the product was once more purified by column chro-
matography.
CDCl3) d: 1.34 (1H, ddd, Jꢃ
2.05 (1H, ddd, Jꢃ14.85, 10.1, 4.05 Hz, 6a-H), 2.42 (1H,
m, 5b-H), 2.50 (1H, dd, Jꢃ15.2, 8.15 Hz, ꢀCHH ꢀ),
2.65 (1H, dd, Jꢃ5.2, 5.6 Hz, ꢀCHH ꢀ), 2.73 (1H, dd,
Jꢃ6.6, 3.3 Hz, 4-H), 3.26 (1H, m, 1-H), 3.58 (3H, s, 2-
OMe), 3.72 (6H, s, 2?-OMe, 6?-OMe), 3.77 (3H, s, 4?-
OMe), 4.99 (1H, dd, Jꢃ6.6, 2.3 Hz, 3-H), 6.04 (2H, s,
3?-H, 5?-H).
/
14.85, 2.65, 2.3 Hz, 6b-H),
/
/
/
/
/
/
/
/
/
4.2.4. General procedure for the preparation and use of
copper-modified enolates with tricarbonyl(h5-
Tricarbonyl[(1,2,3,4-h)-5a-(2?,4?,6?-trimethoxybenz-
oylmethyl)-1,3-cyclohexadiene]iron(0) (24). Light-yel-
low solid. IR nmax: 3005, 2938, 2845 (CH), 2042, 1964
cyclohexadienyl)iron(1ꢁ
CuBr×Me2S (410 mg, 2 mmol) was added in one
/) salts
/
portion to a stirred solution of corresponding lithium
reagent (4 mmol) prepared as described in Section 4.2.3,
except that THF was used as solvent instead of ether.
The mixture was stirred for 1.5 h at ꢂ
then added to a suspension of organoiron salts (0.5ꢀ
mmol) in THF at ꢂ50 8C. Stirring continued for 1 h
allowing the reaction mixture to warm to ꢂ10 8C.
Work-up followed, as described above.
(FeCO), 1694 (Cꢁ
/
O), 1607, 1589, 1495, 1458 cmꢂ1. MS
(CI) m/z (relative intensity) 429 (MHꢁ, 6), 391 (74), 289
(21). HRMS (CI) Calc. for Mꢃ
C20H20O7Fe. MHꢁ
/
/
15 to 0 8C and
requires: 429.0637. Found: 429.0637. 1H-NMR (270
/
1
MHz, CDCl3) d: 1.26 (1H, m, 6b-H), 2.07 (1H, m, 6a-
/
H), 2.60 (3H, m, 5b-H, ꢀ
/
CH2ꢀ
/
), 3.02 (1H, m, 1-H), 3.15
/
(m, 1H, 4-H), 3.71 (6H, s, 2?,6?-OMe), 3.77 (3H, s, 4?-
OMe), 5.20 and 5.32 (2ꢄ1H, 2ꢄm, 2-H, 3-H), 6.09
(2H, s, 3?,5?-H).
/
/
The following complexes were obtained by these
procedures (see also Table 1):
Tricarbonyl[(1,2,3,4-h)-5a-benzoylmethyl-1,3-cyclo-
hexadiene]iron(0) (18). Light-yellow viscous oil. IR
nmax: 3059, 2936, 2849 (CH), 2043, 1961 (FeCO), 1685
4.2.5. Preparation of tricarbonyl[(1,2,3,4-h)-2-
methoxy-5a-(2?,4?,6?-trihydroxybenzoylmethyl)-1,3-
cyclohexadiene]iron(0) (30) using the lithium enolate
method
(Cꢁ
intensity) 339 (MHꢁ, 0.8), 311 (MHꢁ ꢀ
HRMS (CI) Calc. for Mꢃ
C17H14O4Fe. MHꢁ requires:
339.0320. Found: 339.0320. 1H-NMR (270 MHz,
CDCl3) d: 1.22 (1H, dm, Jꢃ15.2 Hz, 6b-H), 2.14
(1H, ddd, Jꢃ15.2, 10.1, 3.8 Hz, 6a-H), 2.68 (1H, m,
5b-H), 2.76 (1H, dd, Jꢃ16.2, 7.6 Hz, CHH ꢀ), 2.88 (1H,
dd, Jꢃ16.2, 5.6 Hz, ꢀCHHꢀ), 3.01 (1H, m, 1-H), 3.11
(1H, m, 4-H), 5.23 and 5.34 (2ꢄ1H, 2ꢄm, 2-H, 3-H),
7.39 (2H, m, 3?-H, 5?-H), 7.50 (1H, m, 4?-H), 7.85 (2H, d,
Jꢃ7.25 Hz, 2?-H, 6?-H).
/
O), 1597, 1581, 1448 cmꢂ1. MS (CI) m/z (relative
/CO, 0.6).
A solution of the bis-MOM derivative 13 [39]
prepared as described in Section 4.1.4a (0.2 g, 0.8
/
mmol) in dry THF (20 ml) at ꢂ78 8C was treated
/
/
with LiN(SiMe3)2 in THF (0.8 ml, 0.8 mmol) and after
10 min with trimethylsilyl chloride (0.2 ml, 1.5 mmol).
The resulting solution was stirred for 0.5 h, then solvent
was removed under reduced pressure and ether (10 ml)
was added to the residue. The mixture was cooled to
/
/
/
/
/
/
/
/
ꢂ
/
78 8C. LiN(SiMe3)2 in THF (0.8 ml, 0.8 mmol) was
added and the mixture was stirred for 1 h at ꢂ78 8C.
The resulting suspension was first diluted with dichlor-
omethane (50 ml) keeping temperature at ꢂ78 8C and
then tricarbonyl[(1,2,3,4,5-h)-2-methoxy-1,3-cyclohexa-
dienyl]iron(lꢁ) hexafluorophosphate(lꢂ) (7) (0.25 g,
/
/
Tricarbonyl[(1,2,3,4-h)-2-methoxy-5a-benzoylmethyl-
1,3-cyclohexadiene]iron(0) (20). Light-yellow viscous
/
oil. IR nmax: 2043, 1967 (FeCO), 1685 (Cꢁ
1268, 1222 cmꢂ1. MS (EI) m/z (relative intensity) 368
(Mꢁ, 1), 340 (Mꢁ ꢀCO, 4), 312 (Mꢁ ꢀ
2CO, 35), 284
(Mꢁ ꢀ
3CO, 100), 269 (31), 254 (15), 221 (15), 176 (45),
/O), 1376,
/
/
/
/
0.63 mmol) was added in one portion. The mixture was
stirred for 2 h and the allowed to warm to r.t. A solution
of HCl in methanol (1 N, 15 ml) was added and stirring
continued for 0.5 h. Then water (50 ml) was added and
/
164 (39), 133 (80), 105 (78), 77 (48). Anal. Calc. for
C18H16O5Fe: C, 58.70, H, 4.35. Found: C, 58.51, H,
1
4.24. H-NMR (270 MHz, CDCl3) d: 1.38 (1H, m, 6b-
the mixture was extracted with ether (3ꢄ30 ml). The
/
H), 2.18 (1H, m, 6a-H), 2.56 (1H, m, 5b-H), 2.81 (3H,
combined extracts were dried over MgSO4 and concen-
trated under reduced pressure. Column chromatography
on silica gel with a mixture of hexane/ethyl acetate (3:1)
as eluent afforded 0.14 g (53%) of tricarbonyl[(1,2,3,4-h)-
2-methoxy-5a-(2?,4,?6?-trihydroxybenzoylmethyl)-1,3-
cyclohexadiene]iron(0) (30) as a light-yellow viscous
oil. IR nmax: 3325 (OH), 2936 (CH), 2043, 1965
m, ꢀ
OMe), 5.05 (1H, m, 3-H), 7.44ꢀ
5?-H), 7.89 (2H, m, 2?-H, 6?-H).
/
CH2ꢀ
/
and 1-H), 3.30 (1H, m, 4-H), 3.63 (3H, s,
/
7.55 (3H, m, 3?-H, 4?-H,
Tricarbonyl[1,2,3,4-h)-2-methoxy-5a-(2?,4?,6?-tri-
methoxybenzoylmethyl)-1,3-cyclohexadiene]iron(0)
(22). Light-yellow solid, m.p. 122ꢀ
2942, 2841 (CH), 2039, 1962 (FeCO), 1696 (Cꢁ
1589, 1457, 1413 cmꢂ1. MS (EI) m/z (relative intensity)
402 (Mꢁ ꢀ2CO, 3), 374 (Mꢁ ꢀ
3CO, 7), 266 (9), 219 (10),
/
123 8C. IR nmax
:
/O), 1607,
(FeCO), 1636 (Cꢁ
MS (EI) m/z (relative intensity) 360 (Mꢁ ꢀ
332 (Mꢁ ꢀ
3CO, 1), 279 (5), 260 (4), 206 (11), 168 (36).
/
O), 1605, 1525, 1486, 1458 cmꢂ1
2CO, 1),
.
/
/
/
/

118
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ122
/
HRMS Calc. for Mꢃ
quires: 360.0296. Found: 360.0296. 1H-NMR (270
MHz, acetone-d6) d: 1.43 (1H, dt, Jꢃ14.85, 2.65 Hz,
6b-H), 2.10 (1H, m, 6a-H), 2.53 (1H, m, 5b-H), 2.88
(1H, dd, Jꢃ6.6, 3.3 Hz, 4-H), 2.89 (1H, dd, Jꢃ16.5,
8.25 Hz, ꢀCHHꢀ), 3.12 (1H, dd, Jꢃ16.5, 5.6 Hz,
CHHꢀ), 3.37 (1H, m, 1-H), 3.69 (3H, s, 2-OMe),
5.39 (1H, dd, Jꢃ6.6, 2.3 Hz, 3-H), 5.92 (2H, s, 3?-H,
5?-H).
/
C18H16O8Fe. Mꢁ ꢀ
/
2CO re-
The following complexes were obtained by this
procedure (see also Table 1):
/
Chalcone (35). Yellow-orange crystals: m.p. 160ꢀ
162 8C. IR nmax: 3430 (OH), 2925, 2846 (CH), 2038,
O), 1605, 1559, 1511
/
/
/
1964, 1950 (FeCO), 1627 (Cꢁ
/
/
/
/
cmꢂ1. Anal. Calc. for C27H24O8Fe: C 60.89, H 4.55.
Found: C 61.05, H 4.41. 1H-NMR (90 MHz, CDCl3) d:
1.87 (2H, m, 6ƒ-CH2), 2.91 (1H, m, 1ƒ-H), 3.15 (1H, m,
ꢀ
/
/
/
4ƒ-H), 3.80, 3.84, and 3.88 (3ꢄ
OMe, 4?-OMe), 3.96 (1H, m, 5ƒb-H), 5.36 (2H, m, 2ƒ-H,
3ƒ-H), 5.90 (1H, s, 3-H), 6.87 (2H, d, Jꢃ8.8 Hz, 3?-H,
5?H), 7.50 (2H, d, Jꢃ8.8 Hz, 2?-H, 6?-H), 7.69 (2H, s,
CHꢁCHꢀ), 14.22 (1H, s, OH).
Flavanone (36). Pale-yellow viscous oil. Mixture of
two diastereoisomers (1:1): IR nmax: 3007, 2937, 2842
(CH), 2043, 1963 (FeCO), 1735 (CꢁO), 1670, 1608,
1575, 1514, 1457 cmꢂ1. HRMS (FAB) Calc. for Mꢃ
C27H24O8Fe. Mꢁꢁ
Na requires: 555.0718. Found:
555.0704. 1H-NMR (270 MHz, CDCl3) d: 1.55 and
1.65 (2ꢄ1H, 2ꢄdm, Jꢃ15.3 Hz, 6ƒb-H), 1.87 and 2.19
(2ꢄ1H, 2ꢄddd, Jꢃ15.2, 10.55, 3.95 Hz, 6ƒa-H), 2.45
(2ꢄ1H, m, 3-H), 2.51 and 2.63 (2ꢄ1H, 2ꢄm, 5ƒb-H),
2.85, 3.02, 3.05, and 3.23 (4ꢄ1H, 4ꢄm, 1ƒ-H, 4ƒ-H),
3.67, 3.71 (2ꢄ3H, 2ꢄs, 5-OMe), 3.75, 3.76, 3.77, and
3.79 (4ꢄ3H, 4ꢄs, 4?-OMe, 7-OMe), 5.32 (2ꢄ2H, m,
2ƒ-H, 3ƒ-H), 5.33 and 5.59 (2ꢄ1H, 2ꢄm, 2-H), 5.95
and 5.98 (2ꢄ1H, 2ꢄd, Jꢃ2.3 Hz, 6-H), 6.05 (2ꢄ1H,
m, 8-H), 6.73 and 6.75 (2ꢄ2H, 2ꢄd, Jꢃ8.9 Hz, 3?-H,
5?-H), 7.11 and 7.17 (2ꢄ2H, 2ꢄd, Jꢃ8.9 Hz, 2?-H, 6?-
H).
/
3H, 3ꢄ/s, 2-OMe, 4-
4.3. Alkylation of tricarbonyl(h5-cyclohexadienyl)iron
salts with trimethoxyflavanone derivatives
/
/
ꢀ
/
/
/
4.3.1. Preparation of 4?,5,7-trimethoxyflavanone 34
By a combination of literature methods [56] a mixture
of 4?,5,7-trihydroxyflavanone [57] (2.18 g, 8 mmol),
dimethyl sulfate (10 ml, 0.1 mol) and potassium
carbonate (27.6 g, 0.2 mol) in acetone (100 ml) was
heated at reflux for 24 h. The solid was separated by
filtration. The filtrate was evaporated and water (50 ml)
was added to the residue, which was extracted with ether
/
/
/
/
/
/
/
/
/
/
/
/
(3ꢄ30 ml). The combined extracts were dried over
/
/
/
MgSO4 and concentrated under reduced pressure.
Column chromatography on silica gel with a mixture
of hexane/ethyl acetate (2:1) as eluent afforded 1.91 g
(76%) of 4?,5,7-trimethoxyflavanone (34) [42,57] as a
/
/
/
/
/
/
/
/
/
/
/
pale-yellow solid, m.p. 123ꢀ
/
125 8C ([57] 128 8C; [58]
125 8C) H-NMR (270 MHz, CDCl3) d: 2.71 (1H, dd,
Jꢃ16.5, 2.95 Hz, 3b-H), 2.99 (1H, dd, Jꢃ16.5, 13.2
Hz, 3b-H), 3.76 and 3.78 (2ꢄ3H, 2ꢄs, 5-OMe, 7-
OMe), 3.84 (3H, s, 4?-OMe), 5.30 (1H, dd, Jꢃ13.2, 2.95
Hz, 2-H), 6.04 and 6.09 (2ꢄ1H, 2ꢄd, Jꢃ2.3 Hz, 6-H,
8-H), 6.89 (2H, d, Jꢃ8.6 Hz, 3?-H, 5?-H), 7.34 (2H, d,
Jꢃ8.6 Hz, 2?-H, 6?-H).
/
/
/
1
/
/
/
/
/
/
/
When the reaction of the lithium enolate of 4?,5,7-
trimethoxyflavanone with organoiron salt 7 was carried
/
/
/
/
out at ꢂ78 8C, the only product isolated was chalcone
/
/
38 (yield 10%). For characterisation of 38, see Section
4.3.3.
/
4.3.2. Addition to the
tricarbonyl(cyclohexadienyl)iron(1ꢁ
procedure A (lithium enolate method)
To a stirred solution of 4?,5,7-trimethoxyflavanone
[42] (0.48 g, 1.5 mmol) cooled to ꢂ110 8C, a THF
4.3.3. Addition to the
tricarbonyl(cyclohexadienyl)iron(1ꢁ) salt: general
procedure B (copper-modified enolate method)
/
) salt: general
/
The solution of 4?,5,7-trimethoxyflavanone [42] (0.63
g, 2.0 mmol) in THF (5 ml) was added dropwise via
syringe to a solution of lithium diisopropylamide in
THF (20 ml) prepared from 2.1 mmol of each n-BuLi
(1.5 M in hexane) and diisopropylamine, and cooled to
/
solution of LiN(SiMe3)2 (1.5 ml, 1.5 mmol) was added.
The mixture was stirred for 1 h, and then tricarbonyl-
[(1,2,3,4,5-h)-1,3-cyclohexadienyl]iron(lꢁ
/
) hexafluoro-
phosphate(lꢂ) (4) (0.25 g, 0.69 mmol) was added in
/
ꢂ
/
78 8C. The mixture was stirred for 15 min. After-
wards CuBr×Me2S (0.208 g, 1 mmol) was added in one
portion and stirring continued for further 1 h at
78 8C. Then tricarbonyl[(1,2,3,4,5-h)-2-methoxy-1,3-
cyclohexadienyl]iron(lꢁ) hexafluorophosphate(1ꢂ) (7)
one portion. The stirring continued for 2 h, and then
water (20 ml) was added. The mixture was extracted
/
with ether (3ꢄ/30 ml). The combined extracts were dried
ꢂ
/
over MgSO4 and concentrated under reduced pressure.
Column chromatography on silica gel with mixtures of
hexane/ethyl acetate (4:1 to 2:1) as eluent afforded in
order of elution 90 mg (23%) of 2,4,4?-trimethoxy-6-
hydroxy-5-{tricarbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-h)-1ƒ,3ƒ-cyclohex-
adien-5ƒa-yl]iron(0)}chalcone (37) and 250 mg (65%)
of 4,5,7-trimethoxy-3-{tricarbonyl[1ƒ,2ƒ,3ƒ,4ƒ-h)-1ƒ,3ƒ-
cyclohexa-5ƒa-dienyl]iron(0)}flavanone (36).
/
/
(0.2 g, 0.5 mmol) was added also in one portion and the
mixture was gently warmed to r.t. After 1 h, aq.
ammonium chloride (20 ml) was added. The mixture
was extracted with ether (3ꢄ30 ml). The combined
/
extracts were dried over MgSO4 and concentrated under
reduced pressure. Column chromatography on silica gel
with the dichloromethane as eluent afforded in order of

C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
119
elution 453 mg (72%) of 2,4,4?-trimethoxy-6-hydroxy-
chalcone and 78 mg (28%) 2,4,4?-trimethoxy-6-hydroxy-
5-{tricarbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-h)-2ƒ-methoxy-1ƒ,3ƒ-cyclo-
hexa-5ƒa-dienyl]iron(0)}chalcone (38).
4.4. Alkylation of tricarbonyl(h5-cyclohexadienyl)iron
salts with tris(trimethylsilyloxy)flavanone derivatives
4.4.1. Preparation of 4,4?,5,7-tetra(trimethylsilyloxy)-
3,4-didehydroflavanane (31)
The following products were obtained by this proce-
A stirred solution of 4?,5,7-trihydroxyflavanone (1)
(0.41 g, 1.5 mmol) in THF (20 ml) was treated with THF
dure (see also Table 1):
2,4,4?-Trimethoxy-6-hydroxychalcone [59]. Orange
solution of LiN(SiMe3)2 (6 ml, 6 mmol) at ꢂ
thick suspension was stirred for 1.5 h at ꢂ
/
78 8C. The
78 8C.
crystals: m.p. 110ꢀ
/
112 8C ([57] 113ꢀ114 8C). IR nmax:
/
/
3055, 2987, 2306, 1624, 1561, 1512, 1423, 1344, 1266,
1218, 1173, 1159, 1114, 1033 cmꢂ1. MS (EI) m/z
(relative intensity) 314 (Mꢁ, 2), 290 (3), 262 (7), 234
(35), 220 (6), 205 (4), 164 (100), 135 (92), 108 (17), 92
(13), 77 (30). Anal. Calc. for C18H18O5: C 68.79, H 5.73.
Trimethylsilyl chloride (1 ml, 7.9 mmol) was added
and the mixture was stirred for a further 1.5 h at
ꢂ78 8C. Volatiles were removed under reduced pres-
/
sure. The residue was redissolved in diethyl ether, dried
over MgSO4 and concentrated under vacuum. 4,4?,5,7-
Tetra(trimethylsilyloxy)-3,4-didehydroflavanane (31)
1
Found: C 68.65, H 5.62. H-NMR (270 MHz, CDCl3)
d: 3.80, 3.84 and 3.88 (3ꢄ
OMe), 5.92 and 6.07 (2ꢄ1H, 2ꢄ
H), 6.90 (2H, d, Jꢃ8.60 Hz, 3?-H, 5?-H), 7.53 (2H, d,
Jꢃ8.6 Hz, 2?-H, 6?-H), 7.77 (2H, s, ꢀCHꢁCHꢀ), 14.47
(1H, s, OH).
2,4,4?-Trimethoxy-6-hydroxy-5-
/
3H, 3ꢄ
/
s, 2-OMe, 4-OMe, 4?-
was obtained as an orange oil (0.67 g, 79%). IR nmax
:
/
/
d, Jꢃ/2.0 Hz, 3-H, 5-
2961, 2902, 1560, 1510, 1255, 1168, 1097, 1021 cmꢂ1
MS (EI) m/z (relative intensity) 560 (Mꢁ, 0.3), 545 (3),
488 (12), 473 (15), 416 (49), 296 (10), 251 (14), 224 (14),
192 (52), 179 (100), 147 (88), 73 (73). Anal. Calc. for
C27H44O5Si4: C, 57.86, H, 7.86. Found: C, 58.15, H,
7.61. 1H-NMR (60 MHz, CDCl3) d: 0.25 (36H, s,
/
/
/
/
/
{tricarbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-h)-2ƒ-methoxy-lƒ,3ƒ-cyclo-
hexadien-5??a-yl]iron(0)}chalcone (38). Orange viscous
SiMe3), 6.02 (2H, s, 6-H, 8-H), 6.67ꢀ/7.50 (6H, m, 2-H,
oil. IR nmax: 2939, 2037, 1960 (FeCO), 1606 (Cꢁ
/O),
3-H, 2?-H, 3?-H, 5?-H, 6?-H).
1561, 1512, 1487, 1466, 1423, 1326, 1305, 1290, 1256,
1222, 1173, 1120, 1073, 1026 cmꢂ1. HRMS (FAB) Calc.
4.4.2. Attempted use of the trimethylsilylenol ether
method with the flavanone derivative
for Mꢃ
C28H26O9Fe. MHꢁ requires: 563.1004. Found:
/
563.1004. Anal. Calc. for C28H26O9Fe: C 59.79, H 4.63.
Found: C 60.02, H 4.61. 1H-NMR (90 MHz, CDCl3) ?d:
2.03 (2H, m, 6ƒ-CH2), 2.56 (1H, m, 4ƒ-H), 3.40 (1H, m,
1ƒ-H), 3.59 (3H, s, 2ƒ-OMe), 3.75 (1H, m, 5ƒb-H), 3.83,
To a stirred solution of the trimethylsilylenol ether
(31) (0.56 g, 1 mmol) in acetonitrile (20 ml) at r.t. was
added the tricarbonyl(cyclohexadienyl)iron salt 4 or 7
(0.5ꢀ1 mmol). The reaction mixture was stirred for 48 h
/
3.87, and 3.92 (3ꢄ
5.09 (1H, m, 3ƒ-H), 5.93 (1H, s, 3-H), 6.90 (2H, d, Jꢃ
8.7 Hz, 3?-H, 5?-H), 7.53 (2H, d, Jꢃ8.7 Hz, 2?,6?-H),
7.73 (2H, s, CHꢃCHꢀ), 14.31 (1H, s, OH).
/
3H, 3ꢄ
/
s, 2-OMe, 4-OMe, 4?-OMe),
at r.t. and then aq. ammonium chloride (20 ml) was
added. The mixture was shaken vigorously for 5 min
/
/
and then extracted with ether (3ꢄ30 ml). The combined
/
/
/
extracts were dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by
column chromatography on silica gel with mixtures of
hexane/ethyl acetate (4:1 to 2:1) as eluent. Only the
starting flavanone 1 was recovered in either case.
4.3.4. Addition to the
tricarbonyl(cyclohexadienyl)iron(1ꢁ
procedure C (sodium enolate method)
To a solution of 4?,5,7-trimethoxyflavanone (0.746 g,
2.4 mmol) in THF (50 ml) cooled to ꢂ78 8C was added
NaH (68 mg, 2.9 mmol) in one portion. The mixture was
stirred for 1 h at ꢂ78 8C and then tricarbon-
yl[(1,2,3,4,5-h)-2-methoxy-1,3-cyclohexadienyl]iron(lꢁ
hexafluorophosphate(1ꢂ) (7) (0.946 g, 2.4 mmol) was
added also in one portion. After 15 min at ꢂ78 8C, the
/) salt: general
4.4.3. One-pot protection, enolate generation, reaction
with the tricarbonyl(cyclohexadienyl)iron(1ꢁ
/
) salt, and
/
deprotection
/
4.4.3.1. Using trimethylsilyl protecting groups. A stirred
suspension of 4?,5,7-trihydroxyflavanone (1) (0.545 g, 2
mmol) in THF (20 ml) was treated with a THF solution
/
)
/
/
of LiN(SiMe3)2 (6 ml, 6 mmol) at ꢂ78 8C. A thick
/
mixture was gently warmed to r.t. Stirring continued
overnight. The reaction mixture was worked up as
described in Section 4.4.3. Column chromatography
on silica gel with the dichloromethane as eluent afforded
this time only 2,4,4?-trimethoxy-6-hydroxy-5-(tri-
carbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-h)-2ƒ-methoxy-1ƒ,3ƒ-cyclohexa-
dien-5ƒa-yl]iron(0)}chalcone (38). Yield 306 mg (23%).
Spectroscopic details as shown in Section 4.3.3.
precipitate was formed. After 0.5 h, trimethylsilyl
chloride (0.7 g, 6.5 mmol) was added to form a thinner
suspension. The mixture was stirred for an additional
0.5 h and then volatiles were removed under reduced
pressure to afford the crude tri-protected derivative [60].
The residue was re-suspended in dichloromethane (30
ml) and cooled to ꢂ
/
10 8C. A THF solution of
LiN(SiMe3)2 (2 ml, 2 mmol) was added. The mixture

120
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ122
/
was stirred for 0.5 h, and then tricarbonyl[(1,2,3,4,5-h)-
1,3-cyclohexadienyl]iron(lꢁ) hexafluorophosphate(lꢂ
mmol) at ꢂ
stirred for 1.5 h ꢂ
/
78 8C to form a thick slurry, which was
/
/
)
/
78 8C. The mixture was warmed to
(4) (0.25 g, 0.69 mmol) was added in one portion. The
stirring continued for 2 h allowing the mixture to warm
to r.t. The mixture was treated with 1 N HCl in MeOH/
H2O (10:1, 3 ml) at r.t. for 20 min and then water (20 ml)
was added. The resulting mixture was extracted with
0 8C and methoxymethyl chloride (2 ml, 26.3 mmol)
was added dropwise. Stirring continued for 2 h at r.t.
and then volatiles were removed under reduced pressure.
Water (20 ml) was added to the residue which was
extracted with ether (3ꢄ30 ml). Combined extracts
/
ether (3ꢄ
/
30 ml). The combined extracts were dried over
were dried over MgSO4. Column chromatography on
silica gel with a mixture of hexane/ethyl acetate (4:1) as
eluent afforded 0.7 g (43%) of 4?,5,7-tris(methoxymethy-
loxy)flavanone as a light yellow solid. 1H-NMR (90
MgSO4 and concentrated under reduced pressure.
Column chromatography on silica gel with mixtures of
hexane/ethyl acetate (4:1 to 2:1) as eluent afforded 65
mg
(20%)
of
4?,5,7-trihydroxy-3-{tricarbonyl-
MHz, CDCl3) d: 2.64 (1H, dd, Jꢃ
3.00 (1H, dd, Jꢃ16.7, 12.1 Hz, 3b-H), 3.43, 3.44, and
3.45 (3ꢄ3H, 3ꢄs, 4?-OMe, 5-OMe, 7-OMe), 5.13, 5.15,
and 5.16 (3ꢄ2H, 3ꢄs, ꢀOCH2Oꢀ), 5.33 (1H, dd, Jꢃ
12.1, 3.95 Hz, 2-H), 6.37 (2H, m, 6-H, 8-H), 7.03 (2H, d,
Jꢃ8.55 Hz, 3?-H, 5?-H), 7.34 (2H, d, Jꢃ8.6 Hz, 2?-H,
6?-H). This product was used in the next step without
further purification.
4.4.3.2.2. Enolate generation, addition to the
/
16.7, 3.95 Hz, 3a-H),
[(1ƒ,2ƒ,3ƒ,4ƒ-h)-1ƒ,3ƒ-cyclohexa-5ƒa-dienyl]iron(0)}-
flavanone (39) as a pale-yellow viscous oil. Mixture of
two diastereoisomers (5:4): IR nmax: 3390 (OH), 2927
(CH), 2045, 1967 (FeCO), 1701, 1636, 1629, 1602, 1517,
/
/
/
/
/
/
/
/
1457 cmꢂ1. HRMS (FAB) Calc. for Mꢃ
ꢁ ꢀ3CO requires: 406.0503. Found: 406.0493. 1H-
NMR (270 MHz, acetone-d6) d: 1.38 and 1.58 (2ꢄ
1H, 2ꢄdm, Jꢃ15.5 Hz, 6ƒb-H), 1.68 and 1.85(2ꢄ
1H, 2ꢄm, 6ƒa-H), 2.29 and 2.41 (2ꢄ1H, 2ꢄm, 5ƒb-
H), 2.62 and 2.75 (2ꢄ1H, 2ꢄm, 3-H), 2.88, 2.95, 3.01,
and 3.09 (4ꢄ1H, 4ꢄm, 1ƒ-H, 4ƒ-H), 4.95, 5.28, 5.32,
and 5.34 (4ꢄ1H, 4ꢄm, 2ƒ-H,3ƒ-H), 5.60 (2ꢄ1H, m, 2-
H), 5.91, 5.93, 5.98, and 6.03 (4ꢄ1H, 4ꢄd, Jꢃ2.0 Hz,
6-H, 8-H), 6.85 and 6.88 (2ꢄ2H, 2ꢄd, Jꢃ8.6 Hz, 3?-
H, 5?-H), 7.26 and 7.31 (2ꢄ2H, 2ꢄd, Jꢃ8.6 Hz, 2?-H,
6?-H), 12.24 and 12.27 (1H, s, 5-OH).
/C27H24O8Fe.
/
/
M
/
/
/
/
/
/
/
/
tricarbonyl(cyclohexadienyl)iron(1ꢁ) salt, and depro-
/
/
/
tection. To a stirred solution of the crude 4?,5,7-
tris(methoxymethyloxy)flavanone (0.467 g, 1.16 mmol)
/
/
/
/
/
prepared as described above, and cooled to ꢂ109 8C, a
/
/
/
/
THF solution of LiN(SiMe3)2 (1.2 ml, 1.2 mmol) was
added. The mixture was stirred for 1 h, and then
tricarbonyl[(1,2,3,4,5 - h) - 2 - methoxy - 1,3 - cyclohexa-
/
/
/
/
/
/
dienyl]iron(lꢁ
/
) hexafluorophosphate(lꢂ) (7) (0.3 g, 0.76
/
4?,5,7-Trihydroxy-3-{tricarbonyl[(1ƒ,2ƒ,3ƒ,4ƒ-h)-2ƒ-
methoxy-lƒ,3ƒ-cyclohexadien-5ƒa-yl]iron(0)}flavanone
(40) was prepared analogously as pale-yellow oil from
tricarbonyl[(1,2,3,4,5-h) - 2 - methoxy - 1,3 - cyclohexa-
mmol) was added in one portion. The stirring continued
for 2 h, and then water was added. The mixture was
extracted with ether (3ꢄ30 ml). The combined extracts
/
were dried over MgSO4 and concentrated under reduced
pressure. Column chromatography on silica gel with
mixtures of hexane/ethyl acetate (4:1 to 2:1) as eluent
afforded 198 mg (40%) of an intermediate which was
treated with 1 N HCl in MeOH/H2O (10:1, 3 ml) at r.t.
for 20 min. Then water was added. The resulting
dienyl]iron(lꢁ
/
) hexafluorophosphate(lꢂ) (7) (0.25 g,
/
0.63 mmol). Yield: 25 mg (8%). Mixture of two
diastereoisomers (1:1): IR nmax: 3384 (OH), 2927 (CH),
2044, 1964 (FeCO), 1701, 1636, 1620, 1597, 1518, 1485
cmꢂ1. HRMS (FAB) Calc. for Mꢃ
/
C25H20O9Fe. MHꢁ
requires: 521.0534. Found: MHꢁ 521.0500. H-NMR
mixture was extracted with ether (3ꢄ30 ml). The
/
1
(270 MHz, acetone-d6) d: 1.72 and 1.90 (2ꢄ
ddd, Jꢃ14.9, 3.95, 2.3 Hz, 6ƒb-H), 1.86 and 2.16 (2ꢄ
1H, 2ꢄm, 6ƒa-H), 2.43 and 2.57 (2ꢄ1H, 2ꢄm, 5ƒb-
H), 2.59 (1H, m, 3-H), 2.69 and 2.82 (2ꢄ1H, 2ꢄdd,
Jꢃ6.3, 3.6 Hz, 4ƒ-H), 3.29 (2ꢄ1H, 2ꢄm, 1ƒ-H), 3.59
and 3.66 (2ꢄ3H, 2ꢄs, 2ƒ-OMe), 5.03 and 5.47 (2ꢄ
H, 2ꢄdd, Jꢃ6.6, 2.3 Hz, 3ƒ-H), 5.45 and 5.78 (2ꢄ1H,
2ꢄd, Jꢃ4.6 and 4.3 Hz, respectively, 2-H), 5.81, 5.85,
5.89, and 5.90 (4ꢄ1H, 4ꢄm, 6-H, 8-H), 6.74 (4H, d,
Jꢃ8.6 Hz, 3?,5?-H), 7.14 and 7.17 (2ꢄ2H, 2ꢄd, Jꢃ
8.59 Hz, 2?,6?-H), 11.93 and 12.06 (2ꢄ1H, 2ꢄs, 5-OH).
/
1H, 2ꢄ
/
combined extracts were dried over MgSO4 and concen-
trated under reduced pressure. Column chromatography
on silica gel with mixtures of hexane/ethyl acetate (4:1 to
2:1) as eluent afforded 122 mg (77 or 31% by calculation
based on the starting organoiron salt) of 4?,5,7-trihy-
droxy-3-[tricarbonyl[(1?,2?,3?,4?-h)-2?-methoxy-1?,3?-
cyclohexadien-5?a-yl]iron(0)}flavanone (40). Spectro-
scopic details are shown in Section 4.4.3.1.
/
/
/
/
/
/
/
/
/
/
/
/
/
1
/
/
/
/
/
/
/
/
/
/
/
/
/
Acknowledgements
4.4.3.2. Using methoxymethyloxy protecting groups in a
two step sequence.
We thank the BBSRC for financial support, and we
acknowledge the EPSRC Mass Spectrometry Service
(Swansea) for CI and FAB mass spectrometric measure-
ments and accurate mass determinations. We thank Dr
J.A. Downie (John Innes Centre, Norwich) for his
assistance and advice on root nodulation and Rhizobium
4.4.3.2.1. Preparation of 4?,5,7-tris(methoxymethy-
loxy)flavanone. A stirred suspension of 4?,5,7-trihydrox-
yflavanone (1.09 g, 4 mmol) in THF (200 ml) was
treated with a THF solution of LiN(SiMe3)2 (12 ml, 12

C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ
/122
121
[19] A.D. Ryabov, Angew Chem. Int. Ed. Engl. 30 (1991) 931.
[20] K. Severin, R. Bergs, W. Beck, Angew Chem. Int. Ed. Engl. 37
(1998) 1635.
genetics, Ms K.E. Wilson (John Innes Centre, Norwich)
for preliminary screening [16,30] of the organometallic
flavanone derivatives for nod gene induction activity,
and Dr O. Egyed for FTIR measurements [16].
[21] (a) M. Salmain, A. Vessie`res, I.S. Butler, G. Jaouen, Bioconjugate
Chem. 2 (1991) 13;
(b) M. Salmain, A. Vessie`res, G. Jaouen, I.S. Butler, Analytical
Chem. 63 (1991) 2323;
(c) M. Salmain, A. Vessie`res, P. Brossier, I.S. Butler, G. Jaouen, J.
Immunological Methods 148 (1992) 65;
References
(d) M. Salmain, A. Vessie`res, P. Brossier, G. Jaouen, Analytical.
Biochem. 208 (1993) 177;
[1] C.S. Creaser, M.A. Fey, G.R. Stephenson, Spectrochim. Acta
50A (1994) 1295.
(e) V. Philomin, A. Vessie`res, G. Jaouen, J. Immunological
Methods 171 (1994) 201;
[2] C.S. Creaser, W.E. Hutchinson, G.R. Stephenson, The Analyst
126 (2001) 647.
(f) A. Varrene, A. Vessie`res, M. Salmain, P. Brossier, G. Jaouen,
J. Immunological Methods 186 (1995) 195.
[3] C.E. Anson, C.S. Creaser, G.R. Stephenson, Chem. Commun.
(1994) 2175.
[22] Oligonucleotides: Z. Wang, B.A. Roe, K.M. Nicholas, R.L.
White, J. Am. Chem. Soc., 115 (1993) 4399.
[4] C.E. Anson, T.J. Baldwin, C.S. Creaser, M.A. Fey, G.R.
Stephenson, Organometallics 15 (1996) 1451.
[23] Peptides and proteins: F. Le Borgne, J.P. Beaucourt, Tetrahedron
Lett., 29 (1988) 5649; N.A. Sasaki, P. Potier, M. Savignac, G.
Jaouen, Tetrahedron Lett., 29 (1988) 5761; A. Varenne, M.
Salmain, C. Brisson, G. Jaouen, Bioconjugate Chem., 3 (1992)
447; M. Salmain, M. Gunn, A. Gorfti, S. Top, G. Jaouen,
Bioconjugate Chem., 4 (1993) 425; J.A. Carver, B. Fates, L.A.P.
Kane-Maguire, Chem. Commun., 1 (1993) 928; A. Hess, N.
Metzler-Nolte, Chem. Commun., (1999) 885. See also refs. [8] and
[9].
[5] C.E. Anson, C.S. Creaser, G.R. Stephenson, Spectrochim. Acta
52 (1996) 1183.
[6] Selective binding of diquat using an organometalcarbonyl deri-
vative of Stoddart’s large ring crown ether host has been studied
by PCA: C.E. Anson, C.S. Creaser, G.R. Stephenson, unpub-
lished results; for the crown system on which this method was
based, see: H.M. Colquhoun, E.P. Goodings, J.M. Maud, J.F.
Stoddart, J.B. Wolstenholm, D.J. Williams, J. Chem. Soc., Perkin
Trans., 2 (1985) 607.
[24] Micotoxins: M. Gruselle, P. Deprez, A. Vessie`res, S. Greenfield,
G. Jaouen, J.-P. Laure, D. Thouvenot, J. Organometal. Chem.,
359 (1989) C53.
[7] C.E. Anson, C.S. Creaser, G.R. Stephenson, unpublished results;
for the host architecture on which this method was based, see: S.-
K. Chang, D. Van Engen, E. Fan, A.D. Hamilton, J. Am. Chem.
Soc., 113 (1991) 7640.
[25] Resorcylic acids: M. Gruselle, J.-L. Rossignol, A. Vessie`res, G.
Jaouen, J. Organometal. Chem., 328 (1987) C12.
[26] M. Salmain, A. Vessie`res, I.S. Butler, G. Jaouen, Bioconjugate
Chem. 2 (1991) 13.
[8] C.E. Anson, C.S. Creaser, O. Egyed, M.A. Fey, G.R. Stephenson,
Chem. Commun. 1 (1994) 39.
[27] (a) J.L. Firmin, K.E. Wilson, L. Rossen, A.W.B. Johnston,
Nature 324 (1986) 90;
[9] C.E. Anson, C.S. Creaser, O. Egyed, G.R. Stephenson, Spectro-
chim. Acta 53 (1997) 1867.
(b) C.A. Shearman, L. Rossen, A.W.B. Johnston, J.A. Downie,
EMBO 5 (1986) 647;
[10] C.S. Creaser, W.E. Hutchinson, G.R. Stephenson, Applied
Spectroscopy 54 (2000) 1624.
(c) S.A.J. Zaat, J. Schripsema, C.A. Wijffelman, A.N. van
Brussel, B.J.J. Lugtenberg, Plant Mol. Biol. 13 (1989) 175.
[28] (a) P. Lerouge, P. Roche, C. Faucher, F. Maillet, G. Truchet, J.C.
Prome, J. Dearie, Nature 344 (1990) 781;
[11] C.S. Creaser, W.E. Hutchinson, G.R. Stephenson, Sensors
Actuators 82B (2002) 150.
[12] (a) G. Jaouen, A. Vessie`res, Pure Appl. Chem. 61 (1989) 565;
(b) A. Vessie`res, S. Top, A.A. Ismail, I.S. Butler, M. Louer, G.
Jaouen, Biochemistry 27 (1988) 6659;
(b) M. Schultze, B. Quilet-Sire, E. Kondorosi, H. Virelizier, J.N.
Glushka, G. Endre, S.D. Gero, A. Kondorosi, Proc. Natl. Acad.
Sci. USA 89 (1992) 192.
(c) G. Jaouen, A. Vessie`res, S. Top, A.A. Ismail, I.S. Butler, J.
Am. Chem. Soc. 107 (1985) 4778.
[29] K.C. Nicolaou, N.J. Bocovich, D.R. Caranague, C.W. Hummel,
L.F. Even, J. Am. Chem. Soc. 114 (1992) 8701.
[30] L. Rossen, C.A. Shearman, A.W.B. Johnston, J.A. Downie,
EMBO 4 (1985) 3369.
[13] (a) A. Varenne, A. Vessie`res, M. Salmain, P. Brossier, G. Jaouen,
Immunoanal. Biol. Spe´c. 9 (1994) 205;
(b) M. Salmain, A. Vessie`res, P. Brossier, G. Jaouen, Anal.
Biochem. 208 (1993) 117;
[31] (a) L. Rossen, A.W.B. Johnston, J.A. Downie, Nucleic Acids Res.
12 (1984) 9497;
(c) A. Varenne, A. Vessie`res, M. Salmain, S. Durand, P. Brossier,
G. Jaouen, Anal. Biochem. 242 (1996) 172;
(b) J.A. Downie, C.D. Knight, A.W.B. Johnston, L. Rossen, Mol.
Gen. Genet. 198 (1985) 225.
(d) M. Salmain, A. Vessie`res, A. Varenne, P. Brossier, G. Jaouen,
J. Organometal. Chem. 589 (1999) 92.
[32] A.V. Malkov, L. Mojovic, G.R. Stephenson, A.T. Turner, C.S.
Creaser, J. Organometal. Chem. 589 (1999) 103.
[33] (a) S. Harder, J. Boersma, L. Brandsma, G.P.M. van Mier, J.A.
Kanters, J. Organomet. Chem. 364 (1989) 1;
[14] D.L. Wetzel, J.A. Reffner, Chem. Ind. 8 (2000) 313.
[15] S. Kazarian, J. Higgins, Chem. Ind. 20 (2002) 21.
[16] C.E. Anson, C.S. Creaser, J.A. Downie, O. Egyed, A.V. Malkov,
L. Mojovic, G.R. Stephenson, A.T. Turner, K.E. Wilson, Bioorg.
Med. Chem. Lett. 8 (1998) 3549.
(b) S. Mutti, C. Daubie, F. Decalogne, R. Fournier, P. Rossi,
Tetrahedron Lett. 37 (1996) 3125.
[17] (a) G. Jaouen, A. Vessie`res, S. Top, A.A. Ismail, I.S. Butler, C.R.
Acad. Sci. Ser. 2 298 (1984) 683;
[34] (a) J.C. Clinet, E. Dunach, K.P.C. Vollhardt, J. Am. Chem. Soc.
105 (1983) 6710;
(b) H. El Amouri, A. Vessie`res, D. Vichard, S. Top, M. Grusselle,
G. Jaouen, J. Med. Chem. 35 (1992) 3130.
(b) R. Mohan, J.A. Katzenellenbogen, J. Org. Chem. 49 (1984)
1238;
[18] (a) S. Top, A. Vessie`res, G. Jaouen, J. Labled Comp. 24 (1987)
1257;
(c) D.S. Clarke, R. Wood, Synth. Commun. 26 (1996) 1335;
(d) G.K. Jnaneswhara, V.H. Deshpande, M. Lalithambika, T.
Ravindranathan, A.V. Bedekar, Tetrahedron Lett. 39 (1998) 459.
[35] (a) A.I. Meyers, B.E. Williams, Tetrahedron Lett. (1978) 223;
(b) A.I. Meyers, K. Lutomski, Synthesis (1983) 105.
(b) A. Vessie`res, S. Tondu, G. Jaouen, S. Top, A.A. Ismail, G.
Teutsch, M. Moguilewsky, Inorg. Chem. 27 (1988) 1850;
(c) A. Vessie`res, S. Top, C. Vaillant, D. Osella, J.-P. Mornon, G.
Jaouen, Angew Chem. Int. Ed. Engl. 31 (1992) 753.

122
C.E. Anson et al. / Journal of Organometallic Chemistry 668 (2003) 101ꢀ122
/
[36] H.H. Hodgson, T.A. Jenkinson, J. Chem. Soc. (1927) 3041.
[37] S.T. Astley, G.R. Stephenson, J. Chem. Soc. Perkin Trans. 1
(1993) 1953.
[48] G. Sabitha, R.S. Babu, E.V. Reddy, J.S. Yadav, Chem. Lett.
(2000) 1074.
[49] R.J.K. Taylor, S.M. Turner, D.C. Horwell, Chem. Commun.
(1990) 406.
[38] (a) S.T. Astley, G.R. Stephenson, Synlett (1992) 507;
(b) G.R. Stephenson, I.M. Palotai, W.J. Ross, D.E. Tupper,
Synlett (1991) 586;
[50] J. Zhu, R. Beugelmans, A. Bigot, G.P. Singh, M. Bois-Choussy,
Tetrahedron Lett. 34 (1993) 7401.
[51] A. McKillop, B. Bromley, E.C. Taylor, J. Org. Chem. 37 (1972)
88.
(c) A. McKillop, G.R. Stephenson, M. Tinkl, J. Chem. Soc.
Perkin Trans. 1 (1993) 1827.
[52] M. Sulzbacher, E. Bergmann, E.R. Pariser, J. Am. Chem. Soc. 70
(1948) 2827.
[39] (a) T. Kumazawa, T. Minatogawa, S. Matsuba, S. Sato, J.
Onodera, Carbohydr. Res. 329 (2000) 507;
[53] For examples of lithium-for-bromine exchange next to an OMe
group, see: (n-BuLi/ambient) S. Harder, J. Boersma, L.
Brandsma, G.P.M. van Mier, J.A. Kanters, J. Organomet.
Chem., 364 (1989) 1; (n-BuLi/20 8C) W.G. Klumpp, M.J.
(b) Y.-J. Choi, P.J. Shim, K.S. Ko, H.-D. Kim, Heterocycles 43
(1996) 1223;
(c) T. Patonay, D. Molnar, Z. Muranyi, Bull. Soc. Chim. Fr. 132
(1995) 233;
Sinnige, Tetrahedron Lett., 27 (1986) 2247; (t-BuLi/ꢀ78 8C) T.
/
(d) G. Makrandi, Indian J. Chem. Sect. B 15 (1977) 752.
[40] A. Cisak, C. Mielczarek, J. Chem. Soc. Perkin Trans. 2 (1992)
1603.
Oshiki, T. Imamoto, Bull. Chem. Soc. Jpn, 63 (1990) 3719; (n-
BuLi/0 8C) S. Mutti, C. Daubie, F. Decalogne, R. Fournier, P.
Rossi, Tetrahedron Lett., 37 (1996) 3125.
[41] A.J. Birch, L.F. Kelly, A.S. Narula, Tetrahedron 38 (1982) 1813.
[42] R. von Narasimhachari, Can. J. Chem. 40 (1962) 1123.
[43] For a report of an organochromium flavone derivative, see: M.R.
Detty, L.W. McGarry, J. Org. Chem. 53 (1988) 1203.
[44] G.R. Stephenson, in: M. Lautens (Ed.), Houben-Weyl Science of
[54] C. Eneback, Acta Chem. Scand. 11 (1957) 895.
¨
[55] S.M. Mazza, K. Lal, R.G. Salomon, J. Org. Chem. 53 (1988)
3681.
[56] (a) B. Haley, J. Am. Pharm. Assoc. 40 (1951) 111;
(b) A.C. Jain, N.K. Nayyar, B.N. Sharma, Indian J. Chem. Sect.
B 23 (1984) 1211.
Synthesis, vol. 1, Thieme, Stuttgart, 2001, pp. 787ꢀ789.
/
[45] D.L. Boger, R.J. Mathvink, J. Org. Chem. 57 (1992) 1429.
[46] S. Kobayashi, M. Azekawa, H. Morita, Chem. Pharm. Bull. 17
(1969) 89.
[57] R. Bernini, E. Mincione, M. Cortese, G. Aliotta, A. Oliva, R.
Saladino, Tetrahedron Lett. 42 (2001) 5401.
[58] K. Khare, Indian J. Chem. 12 (1974) 1134.
[59] S.M. Ali, M. Ilyas, J. Org. Chem. 51 (1986) 5415.
[60] (a) S. Esaki, K. Nishiyama, N. Sugiyama, R. Nakajima, Y.
Takao, S. Kamiya, Biosci. Biotechnol. Biochem. 58 (1994)
1479;
[47] (a) M. Watanabe, K. Kawanishi, R. Akiyoshi, S. Furukawa,
Chem. Pharm. Bull. 39 (1991) 3123;
(b) T. Hirano, R. Negishi, M. Yamaguchi, F.Q. Chen, Y.
Ohmiya, F.I. Tsuji, M. Ohashi, Tetrahedron 53 (1997) 12903;
(c) M.R. Tremblay, V. Luu-The, G. Leblanc, P. Noeel, E. Breton,
F. Labrie, D. Poirier, Bioorg. Med. Chem. 7 (1999) 1013.
(b) M. Ahmad, N. Jain, M. Kamil, M. Ilyas, J. Chem. Res.
Miniprint 5 (1991) 901.