Novel reaction products from the hypervalent iodine oxidation of hydroxylated stilbenes and isoflavones

Article abstract of DOI:10.1039/b510240e

Novel reaction pathways for the hypervalent iodine-mediated oxidation of bioactive phenols containing extended conjugated π-systems are described. Oxidation of 4-hydroxystilbenes in methanol using a hypervalent iodine-based oxidant led to the formal 1,2-a

Full text of DOI:10.1039/b510240e

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A R T I C L E
Novel reaction products from the hypervalent iodine oxidation of
hydroxylated stilbenes and isoflavones
Cedric J. Lion,a David A. Vasselin,a Carl H. Schwalbe,b Charles S. Matthews,a
Malcolm F. G. Stevensa and Andrew D. Westwell*a
a Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham,
Nottingham, UK NG7 2RD. E-mail: andrew.westwell@nottingham.ac.uk;
Fax: +44 115 9513412; Tel: +44 115 9513404
b School of Life and Health Sciences, Aston University, Birmingham, UK B4 7ET
Received 19th July 2005, Accepted 19th September 2005
First published as an Advance Article on the web 4th October 2005
Novel reaction pathways for the hypervalent iodine-mediated oxidation of bioactive phenols containing extended
conjugated p-systems are described. Oxidation of 4-hydroxystilbenes in methanol using a hypervalent iodine-based
oxidant led to the formal 1,2-addition of methoxy groups across the central stilbene double bond. Treatment of the
structurally related 4-hydroxyisoflavone with di(trifluoroacetoxy)iodobenzene leads to the surprising formation of
2,4ꢀ-dihydroxybenzil. Potential mechanisms for these new reaction pathways are discussed, and the X-ray crystal
structure of 2,4ꢀ-dihydroxybenzil is presented. In contrast, oxidation of the corresponding 3-hydroxystilbenes and
3-hydroxyisoflavone led to conventional dienone oxidation products. The antitumour implications of these oxidation
processes are briefly highlighted; the novel 4-substituted phenolic oxidation products were found to be inactive in
terms of in vitro antitumour cellular activity, whereas the 3-substituted phenol products gave novel agents with potent
and enhanced antitumour activity in the HCT 116 cancer cell line.
As part of our studies on the chemistry associated with
Introduction
antitumour phenolic (E)-stilbenes10 and isoflavones,11 we here
The chemical oxidation of simple para-substituted phenols 1
report our findings on the unusual hypervalent iodine oxidation
to 4,4-disubstituted cyclohexa-2,5-dien-1-ones 2 using a variety
pathways undertaken by para-substituted phenols of these types,
of oxidising agents has previously been well-studied.1 Reagents
and the resulting novel products. The contrasting conventional
used to accomplish this transformation include hypervalent
oxidation products resulting from the chemical oxidation of
iodine oxidants such as diacetoxyiodobenzene (DAIB) and
the corresponding meta-substituted phenols are also presented
di(trifluoroacetoxy)iodobenzene (DTIB),2 thallium(III) nitrate,3
here. The antitumour activity of these new chemical oxidation
peracetic acid,4 and electrochemical5 and photooxidative6 meth-
ods. However, the mechanistic details associated with this simple
synthetic transformation remain to be fully elucidated, with the
products has been studied in two human cancer cell lines.
Results and discussion
nature of the intermediate (3 or 4) dependent on the substituent
group R (Scheme 1).
Use of fluorous hypervalent iodine oxidant
We have prepared previously a series of 4-hydroxystilbenes
(exclusively as (E)-isomers) for the purposes of screening for
antitumour (apoptosis-inducing) activity and examination of
their oxidation chemistry mediated by hypervalent iodine-based
reagents.10 Surprisingly the hydroxylated stilbenes examined
(R = H, F, OMe; where R substituents are on the non-
hydroxylated ring) were found to be unreactive when treated with
the most commonly used hypervalent iodine oxidants DAIB and
DTIB in methanol under ambient conditions.
The initial lack of reactivity of 4-hydroxystilbenes was
solved through the use of a more reactive “fluorous” oxi-
dant, [bis(trifluoroacetoxy)]tridecafluoro-6-iodohexane 7.12 Lit-
erature methods for the preparation of this and related fluorous
oxidants have previously made use of a 90% solution of hydrogen
peroxideinorder topreparethetrifluoroperaceticacid13 required
to oxidise commercially available perfluorohexyl iodide to the
product. The potentially explosive nature of highly concentrated
hydrogen peroxide means that such solutions are no longer
available commercially, and methods to concentrate available
solutions of lower concentration are hazardous. We therefore
devised our own method for the preparation of 7 through the
use of commercially available urea–hydrogen peroxide complex
(UHP) in place of concentrated hydrogen peroxide solution.
The oxidation of perfluorohexyl iodide using the relatively
stable UHP complex in a mixture of trifluoroacetic acid (TFA)
and trifluoroacetic anhydride (TFAA) affords the target oxidant
Scheme 1
Our research in this area has focussed on the hypervalent
iodine oxidation of bioactive phenols,7,8 which can give rise to
novel products with interesting biological properties, exemplified
by the oxidation of 2-(4-hydroxyphenyl)benzothiazole 5 to the
experimental antitumour agent (6: AW 464) in a single step
(Scheme 2).9
Scheme 2 Reagents and conditions:PhI(OCOCF3)2, TEMPO, CH3CN–
H2O (9 : 1).
3 9 9 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 9 6 – 4 0 0 1
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 3 Reagents and conditions: urea–H2O2 complex, (CF3CO)2O,
CF3CO2H.
7 in a single step through generation of trifluoroperacetic acid
in situ (Scheme 3). The use of UHP in this instance provides
a good alternative to concentrated hydrogen peroxide; the
complex is not only more stable and thus preferred from a safety
perspective, but in addition avoids the use of water, which here
would compromise the solubility of the perfluorinated substrate.
However, special care needs to be taken in the order of addition
of reagents; the exothermic addition of trifluoroacetic anhydride
to a stirred suspension of urea–hydrogen peroxide complex in
trifluoroacetic acid should be carried out slowly, keeping the
reaction temperature below 0 ◦C, followed by dropwise addition
of the perfluorohexyl iodide to form the required hypervalent
oxidant 7.
Scheme 5
Oxidation of 4-hydroxy-(E)-stilbenes
Oxidation of 4-hydroxyisoflavone
Our reasons for testing the fluorous oxidant 7 for oxidation
studies on our 4-hydroxylated stilbenes were two-fold: firstly to
provide a more reactive oxidant following the observed lack of
reactivity using the more conventional hypervalent iodine oxi-
dants DAIB and DTIB in methanol; and secondly to enable the
easy removal of the oxidation reaction by-product tridecafluoro-
6-iodohexane by fluorous extraction techniques, according to
the principles established by Curran and co-workers.14 This
would avoid the normal chromatographic purification required
to remove iodobenzene following conventional hypervalent
iodine-mediated oxidation chemistry.
Hydroxylated isoflavonoids of natural origin such as the
soya-derived trihydroxylated isoflavone genistein are known to
possess a range of biological properties, including anticancer
potential.16 Related chemistry within our group has focussed on
the synthesis and application of novel isoflavones and derivatives
as potential antitumour agents.11 Since 4-hydroxyisoflavone
11 is structurally related (as a cyclic variant) to the 4-
hydroxystilbenes 8a–d, we were interested to explore the hy-
pervalent iodine-mediated oxidation chemistry of 11. However,
unlike the 4-hydroxystilbenes, oxidation of 4-hydroxyisoflavone
could be achieved under conditions analogous to those used
for oxidation of 2-(4-hydroxyphenyl)benzothiazole 5 (DTIB
and 2,2,6,6-tetramethylpiperidinyloxy free radical (TEMPO) in
acetonitrile–water). Once again, oxidation to the corresponding
hydroxycyclohexa-2,5-dienone 12 was not the observed reaction
pathway; instead 11 was converted in 46% yield to the 2,4ꢀ-
dihydroxybenzil 13 (Scheme 6). A possible reaction mechanism
to account for the formation of the benzil product is proposed
in Scheme 7. It is noteworthy that in the absence of TEMPO, the
conversion of 11 to 13 occurs more slowly, and with the forma-
tion of significant by-products leading to a lower yield of product
13. We speculate that TEMPO may in this instance be acting as
a “quench” for radical by-products formed during the oxidation
process, facilitating workup and isolation of 13 in moderate
yield. The role of TEMPO in enhancing the yield of related
phenolic oxidation processes has been previously observed.17
However, the contribution of radical intermediates (not included
in the postulated mechanism outlined in Scheme 7), cannot be
discounted. The true role of TEMPO, itself a known co-oxidant
in the hypervalent iodine oxidation of alcohols,18 remains the
subject of speculation.
Oxidation of 4-hydroxystilbenes 8a–d using the fluorous
oxidant 7 proved to be experimentally very straightforward,
as the perfluorohexyl iodide by-product (bp 140 ◦C) could be
1
removed simply by evaporation in vacuo. However, H NMR
analysis of the resulting product revealed the rather surprising
formal addition of methoxy groups across the central alkene
bond to give the novel products 9a–d (Scheme 4), as opposed
to the formation of a hydroxycyclohexa-2,5-dienone 10, as
is the case with other 4-substituted phenols such as 2-(4-
hydroxyphenyl)benzothiazole 5. The 1,2-addition of methoxy
groups across a stilbene double bond using hypervalent iodine-
based reagents constitutes an unusual synthetic pathway; some
literature precedent for the 1,2-addition of oxygen-bearing
groups has previously been observed, for example in the
formation of a 1,2-diacetate by-product from the manganese
triacetate oxidative lactonisation of resveratrol analogues.15
Scheme 4 Reagents and conditions: (i) C6F13I(OCOCF3)2, MeOH.
Oxidation of 4-hydroxystilbenes 8a–d using oxidant 7 gave
facile access to diaryl-1,2-dimethoxyethanes 9a–d in moderate
to good yields as mixtures of diastereoisomers (Scheme 4).
Separation by column chromatography gave access to pure
diastereoisomers as racemic mixtures. A possible mechanism to
account for the unusual reaction pathway observed is presented
in Scheme 5.
Scheme 6 Reagents and conditions: (i) PhI(OCOCF3)2, TEMPO,
CH3CN–H2O
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 9 6 – 4 0 0 1
3 9 9 7

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Scheme 7
An X-ray crystal structure determination for the 2,4ꢀ-
dihydroxybenzil 13 (Fig. 119) confirms the disparate hydroxyla-
tion sites. The 2-hydroxy group forms the expected intramolec-
ular hydrogen bond to the nearby carbonyl oxygen atom with
˚
an H · · · O hydrogen bond distance of 1.80 A.
Scheme 8 Reagents and conditions: (i) PhI(OCOCH3)2, MeOH.
Fig. 1 ORTEP19 drawing of the 2,4ꢀ-dihydroxybenzil molecule 13.
Displacement ellipsoids are drawn at the 50% level.
In vitro antitumour activity
Our studies on the generation of novel oxidation products of
bioactive phenols have been stimulated by the potential role of
metabolic oxidation as a bioactivating event underpinning the
biological mechanism of action of antitumour phenols.9,20 For
example, the observation that di- and tri-phenolic tyrphostins
decompose in solution to more active protein tyrosine kinase
inhibitors,21 whereas tyrphostins devoid of hydroxyl groups have
a rapid onset of cellular activity22 is suggestive of bioactivation
via metabolic oxidation.
We have tested the antiproliferative activity of both 4- and 3-
hydroxystilbenes 8a–d and 14a–d plus their respective oxidation
products 9a–d and 15a–d to further test the hypothesis that novel
phenolic oxidation products can possess enhanced antitumour
activity. The hydroxylated stilbenes and their oxidation products
were examined in two human cancer cell lines in vitro – HCT 116
(colorectal) and MDA MB 468 (breast). The mean GI50 results
(concentration required to inhibit growth by 50%) are presented
in Table 1.
Oxidation of 3-hydroxy-(E)-stilbenes
We have previously reported our studies on the synthesis of novel
dienone-based antitumour agents via the hypervalent iodine-
mediated oxidation of 2-(3-hydroxyphenyl)benzothiazoles.8
Chemical oxidation of a series of analogous 3-hydroxy-(E)-
stilbenes 14a–d (bearing substituents corresponding to the 4-
hydroxy series 8a–d) was achieved simply by treating the phe-
nolic stilbenes with DAIB in methanol at ambient temperature.
This simple oxidation process led to the expected substituted
4,4-dimethoxycyclohexa-2,5-dienone oxidation products 15a–d
in moderate yields (45–65%) following column chromatography
(Scheme 8).
Oxidation of 3-hydroxyisoflavone
In contrast to the unusual reaction pathway undertaken by 4-
hydroxyisoflavone 11, the corresponding 3-hydroxyisoflavone 16
was found to undergo a conventional course of oxidation when
treated with DAIB in methanol to give the isoflavone-substituted
dienone 17 in 52% yield (Scheme 8). This expected reaction
pathway was analogous to the chemical oxidation of 3-hydroxy-
(E)-stilbenes.
The 4- and 3-hydroxystilbene starting materials display mod-
erate growth inhibitory activity in the two cell lines examined,
and are markedly more active in the MDA MB 468 cell line.10 Ox-
idation of 4-hydroxystilbenes 8a–d to the 1,2-dimethoxyethane
derivatives has a dramatic dyschemotherapeutic effect, and
the resulting oxidation products 9a–d display essentially no
antiproliferative activity. On the other hand, oxidation of
3 9 9 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 9 6 – 4 0 0 1

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Table 1 Cell growth inhibitory (GI50) activity of substituted (E)-hydroxystilbenes and their oxidation products in HCT 116 and MDA MB 468 cell
lines (tested in triplicate, mean values presented)
GI50/lM
GI50/lM
Phenol
R
HCT 116
MDA MB 468
Oxidation product
HCT 116
MDA MB 468
8a
H
3-OMe
4-F
3-F
H
3-OMe
4-F
3-F
39.6
37.4
21.0
40.3
57.4
62.0
58.0
44.2
13.0
7.2
8.1
7.7
7.8
3.1
4.7
2.1
9a
> 100
> 100
> 100
> 100
0.62
>100
>100
>100
>100
2.5
8b
9b
8c
8d
14a
14b
14c
14d
9c
9d
15a
15b
15c
15d
2.1
1.1
0.46
3.3
2.2
0.98
the corresponding 3-hydroxystilbenes 14a–d produces dienone
products 15a–d with greatly enhanced activity in the colon HCT
116 cell line (around 30–100-fold enhancement). However, no
significant increase in antiproliferative activity is seen in the
MDA MB 468 cell line. Preliminary findings concerning the in
vitro antitumour activity of hydroxylated isoflavones and their
oxidation products are not indicative of enhancement of activity
following chemical oxidation (results not shown).
addition (Caution: the reaction is exothermic and potentially
explosive). Stirring was continued at this temperature for 30 min.
Perfluorohexyl iodide (6.48 mL, 30 mmol) was then added
dropwise, with continuous stirring. The reaction mixture was left
to stir at 0 ◦C for 2 h, then allowed to reach room temperature
and left overnight. The excess TFA was rem◦oved in vacuo to give
7
12 (28.2 mmol, 94%) as a white solid, mp 67 C (decomposition);
dF (CD3OD) −77.8 (6F, m, 2 × OCOCF3), −81.3 (2F, m, CF2I),
−82.8 (3F, m, CF3), −117.0 (2F, m, CF2), −123.1 (2F, m, CF2),
−124.11 (2F, m, CF2), −127.7 (2F, m, CF2); IR m/cm−1 1744
Conclusions
+
=
(C O). m/z 673 (M + 1).
In conclusion, we have demonstrated in this report that hyper-
valent iodine-mediated oxidation of bioactive phenols such as
simple hydroxylated stilbenes and isoflavones can lead to novel
and interesting reaction pathways and products. Further studies
in this area will help to clarify the rules governing reaction
pathways for phenolic compounds with extended conjugated p-
electron systems using hypervalent iodine-based oxidants, and
should shed light on the mechanistic details underpinning this
interesting and novel chemistry. We have further tested our hy-
pothesis that phenolic oxidation can lead to novel products with
enhanced antitumour activity. In this case the non-conventional
oxidation products 9a–d from 4-hydroxystilbenes were inactive
in the models examined; whereas the conventional hypervalent
iodine-mediated 3-hydroxystilbene oxidation products 15a–d
displayed potent (low to submicromolar) activity in the colon-
derived HCT 116 cell line. Further studies concerning the
antitumour potential of dienone products 15a–d will be reported
in due course.
General method for the oxidation of substituted
4-hydroxy-(E)-stilbenes
The substituted 4-hydroxy-(E)-stilbene 8a–d (3.0 mmol) was
dissolved in methanol. [Bis(trifluoroacetoxy)]tridecafluoro-6-
iodohexane 7 was added as one portion at room temperature,
and the mixture was left to stir for 10 min. The solution was
concentrated in vacuo, to give the oxidation product as a mixture
of diastereoisomers. Purification by flash column chromatogra-
phy (hexane–EtOAc 80 : 20) afforded pure diastereoisomers as
crystalline white solid products.
1-(4-Hydroxyphenyl)-1,2-dimethoxy-2-phenylethane (9a).
Fraction 1. Yield 34%; mp 144–146 ◦C; dH (CDCl3) 7.27 (3H,
m, ArH), 7.17 (2H, m, ArH), 7.04 (2H, d, J 8.5 Hz, ArH), 6.75
(2H, d, J 8.5 Hz, ArH), 4.98 (1H, s, ArOH), 4.31 (1H, d, J
5.5 Hz, ArCHOMe), 4.26 (1H, d, J 5.5 Hz, ArCHOMe), 3.16
(3H, s, OCH3), 3.14 (3H, s, OCH3). dC (CD3OD) d 158.5 (COH),
139.9 (ArC), 130.6 (ArCH), 130.3 (ArC), 129.5 (ArCH), 129.3
(ArCH), 129.1 (ArCH), 116.1 (ArCH), 89.5 (CHOMe), 89.0
(CHOMe), 57.5 (OCH3), 57.2 (OCH3). IR m/cm−1 3274 (OH),
2964 (CH), 2834 (CH), 1267, 1117, 1091; m/z (EI) 259 (M+ +
1), 227 (M+ − OMe). Anal. (C16H18O3) %C: calcd 74.40, found
74.06; %H: calcd 7.02, found 6.80.
Experimental
Commercial reagents and solvents were used as received,
unless otherwise specified. Melting points were recorded on a
1
Gallenkamp melting point apparatus, and are uncorrected. H
NMR spectra were recorded on a Bruker Avance 400 MHz
spectrometer in solvents as specified, with tetramethylsilane as
internal standard. Low resolution mass spectra were recorded
on a Micromass Platform (AP+, ES+). High resolution mass
spectrometry (HRMS) was carried out by the services provided
by the School of Chemistry, University of Nottingham and
EPSRC National Mass Spectrometry Service Centre, Swansea,
UK. Silica gel TLC was performed on 60F–254 pre-coated sheets
(Merck). Elemental analyses were carried out by the microanal-
ysis service, School of Chemistry, University of Nottingham. X-
Ray diffraction data were collected on an Enraf-Nonius CAD4
diffractometer (Mo–Kairradiation at 293 K). The structure was
solved by direct methods and refined by full-matrix least squares.
Fraction 2. Yield 29%; mp 165–167 ◦C; dH (CDCl3) 7.30 (3H,
m, ArH), 7.18 (2H, m, ArH), 7.09 (2H, d, J 8.5 Hz, ArH), 6.77
(2H, d, J 8.5 Hz, ArH), 5.37 (1H, s, ArOH), 4.28 (1H, d, J
7.7 Hz, ArCHOMe), 4.26 (1H, d, J 7.7 Hz, ArCHOMe), 3.25
(3H, s, OCH3), 3.23 (3H, s, OCH3); IR m/cm−1 3397 (OH), 2898
(CH), 2847 (CH), 1284, 1125, 1054; m/z (EI) 259 (M+ + 1), 227
(M+ − OMe). Accurate m/z (ES−) found: 257.1170; C16H18O3
requires 257.1178.
1-(4-Hydroxyphenyl)-1,2-dimethoxy-2-
(3-methoxyphenyl)ethane (9b).
◦
Fraction 1. Yield 19%; mp 85 C; dH (CDCl3) 7.22 (1H, t, J
8.0 Hz, ArH), 7.08 (2H, d, J 8.5 Hz, ArH), 6.86 (5H, m, ArH),
6.59 (1H, s, ArOH), 4.39 (1H, d, J 5.5 Hz, ArCHOMe), 4.31
(1H, d, J 5.5 Hz, ArCHOMe), 3.75 (3H, s, ArOCH3), 3.20 (3H, s,
OCH3), 3.18 (3H, s, OCH3); IR m/cm−1 3347 (OH), 2944 (CH),
2826 (CH), 1272, 1226, 1161, 1091; m/z (EI) 288 (M+ + 1). Anal.
(C17H20O4) %C: calcd 70.81, found 70.45; %H: calc 6.99, found
6.96.
[Bis(trifluoroacetoxy)]tridecafluoro-6-iodohexane (7)
Trifluoroacetic anhydride (4.2 mL, 30 mmol) was added very
slowly to a stirred suspension of urea–hydrogen peroxide
complex (2.82 g, 30 mmol) in TFA (60 mL) at −5 ◦C, maintaining
the temperature of the solution below 0 ◦C throughout the
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 9 6 – 4 0 0 1
3 9 9 9

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Fraction 2. Yield 28%; mp 160 ◦C; dH (CDCl3) 7.10 (1H, t, J
8.2 Hz, ArH), 6.93 (2H, d, J 8.5 Hz, ArH), 6.71 (5H, m, ArH),
5.19 (1H, s, ArOH), 4.27 (2H, s, 2 × ArCHOMe), 3.72 (3H, s,
ArOCH3), 3.29 (3H, s, OCH3), 3.27 (3H, s, OCH3); IR m/cm−1
3277 (OH), 2990 (CH), 2872 (CH), 1281, 1214, 1083, 1050;
m/z (EI) 288 (M+ + 1). Accurate m/z (ES−) found: 287.1302;
C17H20O4 requires 287.1284.
calculations. The final R1 and wR2 were 0.0435 and 0.1113 (for
I > 2r(I)), and 0.0700 and 0.1268 (for all data).
CCDC reference number 279000. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b510240e.
General method for the oxidation of substituted
3-hydroxy-(E)-stilbenes
The substituted 3-hydroxy-(E)-stilbene 14a–d (1 mmol) was dis-
solved in methanol. Diacetoxyiodobenzene (3 mmol) was added
as one portion at room temperature, and the mixture was left to
stir for 10 min. The solvent was then removed in vacuo and the
residue purified by flash chromatography (CHCl3) to afford the
product 15a–d as a pale yellow to orange oil.
1-(4-Hydroxyphenyl)-1,2-dimethoxy-2-(4-fluorophenyl)ethane
(9c).
Fraction 1. Yield 31%; mp 139–140 ◦C; dH (CDCl3) 7.15 (2H,
m, ArH), 7.02 (4H, m, ArH), 6.75 (2H, d, J 8.5 Hz, ArH), 5.69
(1H, s, ArOH), 4.34 (1H, d, J 5.3 Hz, ArCHOMe), 4.29 (1H, d,
J 5.3 Hz, ArCHOMe), 3.19 (3H, s, OCH3), 3.17 (3H, s, OCH3);
IR m/cm−1 3359 (OH), 2940 (CH), 2828 (CH), 1337 (C–F), 1218,
1104, 1013; m/z (EI) 277 (M+ + 1). Anal. (C16H17FO3) %C: calcd
69.55, found 69.53; %H: calc 6.20, found 6.31.
4,4-Dimethoxy-3-styrylcyclohexa-2,5-dien-1-one (15a). Or-
ange oil. Yield 65%. 1H NMR (CDCl3) d 7.60 (1H, d, J 16.0 Hz,
=
CH CH), 7.54 (2H, m, ArH), 7.35 (3H, m, ArH), 6.88 (1H,
Fraction 2. Yield 28%; mp 166 ◦C; dH (CDCl3) 7.01 (3H, m,
ArH), 6.86 (3H, m, ArH), 6.70 (2H, d, J 8.6 Hz, ArH), 5.28
(1H, s, ArOH), 4.32 (1H, d, J 7.7 Hz, ArCHOMe), 4.26 (1H, d,
J 7.7 Hz, ArCHOMe), 3.27 (3H, s, OCH3), 3.26 (3H, s, OCH3);
IR m/cm−1 3271 (OH), 2901 (CH), 2872 (CH), 1358 (C–F), 1231,
1083, 1062; m/z (EI) 277 (M+ + 1). Accurate m/z (ES−) found:
275.1073; C16H17FO3 requires 275.1084.
=
d, J 16.0 Hz, CH CH), 6.71 (1H, d, J 10.0 Hz, H-2), 6.54
(1H, d, J 1.6 Hz, H-3), 6.50 (1H, dd, J 10.0, 1.6 Hz, H-1), 3.23
13
=
(6H, s, 2 × OMe); C NMR (CD3OD) d 185.5 (C O), 151.8,
144.2, 137.7, 136.2, 132.4, 129.3 (×2), 128.8, 128.3, 127.5 (×2),
122.8, 96.3 (Cq(OCH3)2), 51.3 (2 × OCH3); IR m/cm−1 1668
=
=
(C O), 1584 (aromatic C C), 1291 (C–O), 1107 (C–O), 967
=
(trans C C). Accurate m/z (ES−) found 256.1106; C16H16O3
requires 256.1099. Anal. (C16H16O3) %C: calcd 74.98, found
75.35; %H: calcd 6.29, found 6.36.
1-(-Hydroxyphenyl)-1,2-dimethoxy-2-(3-fluorophenyl)ethane
(9d).
Fraction 1. Yield 31%; mp 122–123 ◦C; dH (CDCl3) 7.27 (1H,
m, ArH), 7.04 (2H, d, J 8.5 Hz, ArH), 6.92 (3H, m, ArH), 6.76
(2H, d, J 8.5 Hz, ArH), 4.74 (1H, s, ArOH), 4.29 (1H, d, J
5.5 Hz, ArCHOMe), 4.25 (1H, d, J 5.5 Hz, ArCHOMe), 3.19
(3H, s, OCH3), 3.16 (3H, s, OCH3); IR m/cm−1 3381 (OH), 2935
(CH), 2886 (CH), 1332 (C–F), 1251, 1097; m/z (EI) 277 (M+ +
1). Anal. (C16H17FO3) %C: calcd 69.55, found 69.71; %H: calcd
6.20, found 6.40.
4,4-Dimethoxy-3-[2-(3-methoxyphenyl)vinyl]cyclohexa-2,5-
1
dien-1-one (15b). Yellow oil. Yield 45%. H NMR (CDCl3)
=
d 7.59 (1H, d, J 16.35 Hz, CH CH), 7.28 (1H, t, J 8.0 Hz,
ArH), 7.18 (1H, d, J 7.7 Hz, ArH), 7.08 (1H, m, ArH), 6.95
=
(1H, m, ArH), 6.88 (1H, d, J 16.35 Hz, CH CH), 6.73 (1H,
d, J 10.2 Hz, H-2), 6.56 (1H, d, J 1.95 Hz, H-3), 6.51 (1H,
dd, J 10.2, 1.9 Hz, H-1), 3.86 (3H, s, OMe), 3.26 (6H, s, 2 ×
OMe); 13C NMR (CD3OD) d 185.4 (C O), 159.8, 151.7, 144.1,
=
Fraction 2. Yield 34%; mp 178 ◦C; dH (CDCl3) 7.14 (1H, m,
ArH), 6.90 (2H, d, J 8.5 Hz, ArH), 6.79 (3H, m, ArH), 6.67 (2H,
d, J 8.5 Hz, ArH), 4.73 (1H, s, ArOH), 4.30 (1H, d, J 5.2 Hz,
ArCHOMe), 4.25 (1H, d, J 5.2 Hz, ArCHOMe), 3.29 (3H, s,
OCH3), 3.26 (3H, s, OCH3); IR m/cm−1 3254 (OH), 2938 (CH),
2794 (CH), 1358 (C–F), 1276, 1215, 1117; m/z (EI) 277 (M+ +
1). Accurate m/z (ES−) found: 275.1108; C16H17FO3 requires
275.1084.
137.6, 137.4, 132.3, 129.7, 127.6, 123.0, 120.1, 115.2, 112.3,
96.3 (Cq(OCH3)2), 55.2 (OCH3), 51.2 (2 × OCH3); IR m/cm−1
=
=
1664 (C O), 1575 (C C), 1215 (C–O), 1108 (C–O), 973 (trans
C C). Accurate m/z (ES−) found 286.1209; C17H18O4 requires
=
286.1205.
4,4-Dimethoxy-3-[2-(4-fluorophenyl)vinyl]cyclohexa-2,5-dien-
1-one (15c). Orange oil. Yield 54%. 1H NMR (CDCl3) d 7.56
=
(1H, d, J 16.0 Hz, CH CH), 7.53 (2H, m, ArH), 7.10 (2H, t, J
8.1 Hz, ArH), 6.78 (1H, d, J 17.0 Hz, CH CH), 6.71 (1H, d,
2,4ꢀ-Dihydroxybenzil (13). A solution of DTIB (0.65 g,
1.50 mmol) in acetonitrile (5 mL) was added slowly to a
stirred suspension of TEMPO (0.031 g, 0.20 mmol) and 3-(4-
hydroxyphenyl)-4H-1-benzopyranone 11 (0.238 g, 1.00 mmol)
in a 1 : 1 mixture of acetonitrile and water (40 mL). The solution
volume was immediately reduced in vacuo to approximately
20 mL, then water (50 mL) and ethyl acetate (50 mL) were
added. The organic phase was separated and washed with
saturated aqueous potassium carbonate (50 mL). The aqueous
layer was then neutralised using 1 M HCl and extracted using
20% MeOH–CH2Cl2 (2 × 200 mL), and the combined organic
layers were dried (MgSO4) and concentrated in vacuo. The
crude product was recrystallised from methanol to give 2,4ꢀ-
dihydroxybenzil (0.167 g, 46%) as a yellow solid, mp 160–163 ◦C;
dH (CDCl3) 11.44 (1H, s, ArOH), 7.92 (1H, d, J 10.0 Hz,
ArH, 7.52 (2H, m, ArH), 7.14 (1H, m, ArH), 6.93 (3H, m,
=
J 10.0 Hz, H-2), 6.52 (1H, d, J 2.0 Hz, H-3), 6.50 (1H, dd, J
10.0, 2.0 Hz, H-1), 3.23 (6H, s, 2 × OMe); 13C NMR (CD3OD)
=
d 185.9 (C O), 162.0 (1C, d, J 239.3 Hz), 152.1, 144.5, 136.9,
132.8, 129.7 (2C, d, J 8.2 Hz), 127.9, 116.4 (2C, d, J 21.8 Hz),
96.7 (Cq(OCH3)2), 51.7 (2 × OCH3); IR m/cm−1 1666 (C O),
=
=
=
1582 (aromatic C C), 1215 (C–O), 978 (trans C C). Accurate
m/z (ES−) found 274.1009; C16H15FO3 requires 274.1005.
4,4-Dimethoxy-3-[2-(3-fluorophenyl)vinyl]cyclohexa-2,5-dien-
1-one (15d). Orange oil. Yield 54%. 1H NMR (CDCl3) d 7.55
=
(1H, d, J 16.3 Hz, CH CH), 7.35 (3H, m, ArH), 7.06 (1H,
m, ArH), 6.86 (1H, d, J 16.3 Hz, CH CH), 6.74 (1H, d, J
=
10.2 Hz, H-2), 6.54 (1H, d, J 1.8 Hz, H-3), 6.50 (1H, dd, J
10.2, 1.8 Hz, H-1), 3.26 (6H, s, 2 × OMe); 13C NMR (CD3OD)
=
d 185.4 (C O), 165.0 (1C, d, J 246.1 Hz), 151.4, 144.1, 138.7
(1C, d, J 8.0 Hz), 136.4 (1C, d, J 2.7 Hz), 132.4, 130.3 (1C, d,
J 8.3 Hz), 128.1, 124.1, 123.5 (1C, d, J 2.7 Hz), 116.2 (1C, d, J
21.4 Hz), 113.8 (1C, d, J 21.9 Hz), 96.4 (Cq(OCH3)2), 51.3 (2 ×
=
ArH), 5.75 (1H, br s, ArOH); dC (CDCl3) 200.0 (C O), 191.2
=
(C O), 163.8 (ArC), 162.5 (ArC), 138.5 (ArCH), 133.5 (ArCH),
133.0 (ArCH), 126.3 (ArC), 120.1 (ArCH), 119.1 (ArCH), 117.1
OCH3); IR m/cm−1 1664 (C O), 1582 (aromatic C C), 1106
=
=
(ArC), 116.4 (ArCH); IR m/cm−1 3369 (OH), 1629 (C O), 1599,
=
=
(C–O), 979 (trans C C). Accurate m/z (ES−) found 274.1008;
1575, 1514, 1485, 1452; m/z (EI) 242 (M+). Accurate m/z (ES−)
C16H15FO3 requires 274.1005.
found: 242.0571; C14H10O4 requires 242.0579.
Crystal data. Compound 13. C14H10O4, M = 242.22, mon-
3-(6,6-Dimethoxy-3-oxocyclohexa-1,4-dienyl-4H-1-benzopyran-
4-one (17). A solution of bis(trifluoroacetoxy)iodobenzene
(0.13 g, 0.30 mmol) in methanol (1 mL) was added dropwise
to a solution of 3-hydroxyisoflavone 16 (0.05 g, 0.21 mmol)
in methanol (10 mL). The solution was then concentrated in
˚
˚
˚
oclinic, a = 17.771(5) A, b = 10.833(2) A, c = 15.115(4) A,
◦
3
˚
b = 124.564(18) , U = 2396.3(10) A , T = 293(2) K, space
group C2/c, Z = 8, l(MoKa) = 0.71073 mm−1, 4305 reflections
measured, 1456 unique (Rint = 0.0610) which were used in all
4 0 0 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 9 6 – 4 0 0 1

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vacuo and the residue partitioned between dichloromethane
(20 mL) and saturated aqueous potassium carbonate (20 mL).
The separated organic layer was washed with water (20 mL),
then dried (MgSO4) and concentrated in vacuo. The crude
product was purified by flash column chromatography (15 : 85
hexane–ethyl acetate) to give the dienone ◦product 17 (0.031 g,
52%) as a pale yellow solid, mp 167–170 C; dH (CDCl3) 9.00
(1H, s, H-2), 8.29 (1H, dd, J 8.0, 1.6 Hz, ArH), 7.71 (2H, m,
5 A. Nilsson, A. Ronla´n and V. D. Parker, Tetrahedron Lett., 1975, 16,
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46, 532–541.
10 C. J. Lion, C. S. Matthews, M. F. G. Stevens and A. D. Westwell,
J. Med. Chem., 2005, 48, 1292–1295.
11 D. A. Vasselin, PhD Thesis, University of Nottingham, UK, 2003.
12 T. Umemoto, Y. Kuriu, H. Shuyama, O. Miyano and S. Nakayama,
J. Fluorine Chem., 1982, 20, 695–698.
=
ArH and C CH), 7.49 (2H, m, ArH), 6.73 (1H, d, J 10.0 Hz,
=
=
HC CH), 6.54 (1H, dd, J 10.0, 2.0 Hz, HC CH), 3.27 (6H, s,
OCH3); IR m/cm−1 1728 (C O), 1672 (C O), 1647, 1617, 1565,
1266; m/z (EI) 298 (M+). Anal. (C17H14O5) %C: calcd 68.45,
found 68.12; %H: calcd 4.73, found 5.10.
=
=
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Acknowledgements
This work was supported by a Programme Grant to the Cancer
Research UK Experimental Cancer Chemotherapy Research
Group. The authors are grateful to Marloes Technologies and
the EPSRC for financial support to C.J.L., and to the University
of Nottingham and Cancer Research UK for financial support
to D.A.V.
17 A. McKillop, L. McLaren, R. J. Watson, R. J. K. Taylor and N.
Lewis, Tetrahedron Lett., 1993, 34, 5519.
18 A. DeMico, R. Margarita, L. Parlanti, A. Vescovi and G. Piancatelli,
J. Org. Chem., 1997, 62, 6974.
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 9 6 – 4 0 0 1
4 0 0 1