Synthesis and "double-faced" antioxidant activity of polyhydroxylated 4-thiaflavans

Article abstract of DOI:10.1039/b507496g

A simple synthetic methodology, based on the inverse electron demand hetero Diels-Alder reaction of electron-poor dienic o-thioquinones with electron-rich styrenes used as dienophiles, allowed the preparation of several polyhydroxylated 4-thiaflavans. Suc

Full text of DOI:10.1039/b507496g

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A R T I C L E
Synthesis and “double-faced” antioxidant activity of
polyhydroxylated 4-thiaflavans†
Stefano Menichetti,*a Maria Chiara Aversa,b Francesco Cimino,c Alessandro Contini,d
Caterina Viglianisib and Antonio Tomainoc
a Dipartimento di Chimica Organica, Polo Scientifico-Universita` di Firenze, via della Lastruccia
13, 50019, Sesto Fiorentino, Firenze, Italy. E-mail: stefano.menichetti@unifi.it;
Fax: 39-055-4573531; Tel: 39-055-4573535
b Dipartimento di Chimica Organica e Biologica, Universita` di Messina, Salita Sperone 31,
98166, Messina, Italy
c Dipartimento Farmaco-Biologico, Universita` di Messina, Viale SS Annunziata, Messina, Italy
d Istituto di Chimica Organica “A. Marchesini” Universita` di Milano, Via Venezian 21, 20133,
Milano, Italy
Received 26th May 2005, Accepted 20th June 2005
First published as an Advance Article on the web 13th July 2005
A simple synthetic methodology, based on the inverse electron demand hetero Diels–Alder reaction of electron-poor
dienic o-thioquinones with electron-rich styrenes used as dienophiles, allowed the preparation of several
polyhydroxylated 4-thiaflavans. Such compounds, as a function of the nature and position of the substituents on the
aromatic rings, as well as of the oxidation state of the sulfur atom, are able to behave in vitro as efficient antioxidants
mimicking the action of catechol containing flavonoids or/and tocopherols. The possibility of joining together the
potentialities of two relevant families of natural polyphenolic antioxidants appears particularly appealing since an
efficient protection against free radicals and other reactive oxygen species (ROS) depends in vivo upon the synergic
action of different antioxidant derivatives.
Introduction
Formation of free radicals and other reactive oxygen species
(ROS) in the human body is an unavoidable consequence of
metabolism.1 Despite it now being widely recognized that oxygen
centred free radicals are crucially involved in several biochemical
transformations,2 it is even more clear that an anomalously high
concentration of ROS is strictly related to the “oxidative stress”
of tissues and to the origin and consequence of the main part
of the more dangerous diseases and ageing itself.3 Evolution
provided endogenous and exogenous defences for keeping ROS
concentrations under control. For example, the expression of
specific enzymes able to avoid the formation of free radicals
(i.e. super-oxide dismutase, catalase and several oxygenases) is
one of the endogenous answers to this problem.1 On the other
hand, the comsumption of a diet high in small molecules able
to break the chain radical reactions leading to the oxidative
damage is the more simple and efficient exogenous solution.1
A diet rich in antioxidants can have a crucial role on health,
most of all in those countries where the factors in charge of
dangerously increasing ROS concentrations (stress, smoking,
over-alimentation, alcohol and/or drug abuse and pollution)
are frequent components of the style of living.
Fig. 1 Natural phenolic antioxidants catechin (1) and a-tocopherol (2),
containing the chromane skeleton, and 4-thiaflavans 3.
The more important antioxidant small molecules to be
associated with diet are vitamins: ascorbic acid (vitamin C),
b-carotenes and vitamin A, tocopherols (vitamin E), as well
as polyphenolic flavonoids (called vitamin P). These latter
compounds, possessing the 2-phenylchromane skeleton (see
Fig. 1), are almost ubiquitous in vascular plants where, for
example, they provide the colour of flowers and leaves, or supply
protection against insects and micro-organism attack, as well as
UV irradiation.4
polyphenolic species [like ( )-catechin (1), Fig. 1] is generally
considered a healthy habit5 and regarded as a reason for the
unexpectedly low incidence of cardiovascular diseases, stroke
and several types of cancer in those populations that associate
a risky high consumption of animal fats with a high intake
of flavonoids, usually from red wine; the so called “French
paradox”.6 Despite the lack of definitive evidence for their action
in vivo, the powerful in vitro antioxidant ability of flavonoids7 is
indicated as the key reason for the beneficial response of a robust
intake of these polyphenols.8
Owing to their diffusion in edible plants, flavonoids are
commonly present in our diet, with a daily intake ranging
from only a few to hundreds of mg. The consumption of these
On the other hand, a-tocopherol (2) (Fig. 1), the main compo-
nent of vitamin E, is known as the best chain breaking lipophilic
antioxidant and the foremost responsible for protection against
low density lipoprotein (LDL) oxidation in the human body.9
† Electronic supplementary information (ESI) available: full experimen-
tal and spectroscopic data and BDE values for compounds 9, 10, 11 and
12. See http://dx.doi.org/10.1039/b507496g
3 0 6 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 6 6 – 3 0 7 2
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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We recently reported10 that 3ꢀ,4ꢀ-dihydroxy- or/and 7-
hydroxy-4-thiaflavans of type 3 (Fig. 1) show what we called a
“double-faced” antioxidant activity. A thiaflavan 3ꢀ,4ꢀ-dihydroxy
substituted B ring can behave in a similar manner to catechin (1)
and flavonoids containing a catechol moiety, quenching two eq.
of an oxygen centred radical to give a stable and “safe” o-quinone
compound (Scheme 1). We proved that the sulfur atom in the
C ring is poorly involved in such “catechin-like” performance
and it can be oxidized without affecting the radical scavenger
ability.10 On the other hand, a 7-hydroxy-4-thiaflavan can mimic
the behaviour of tocopherol 2 since the sulfur atom ensures
the formation of a stabilized radical intermediate (Scheme 1).
Indeed the “tocopherol-like” behaviour requires sulfide sulfur
in position 4 and oxidation at sulfur strongly depletes the
antioxidant ability.10
Fig.
2
Starting materials for the preparation of polyphenolic
4-thiaflavans.
Scheme 1 “Double-faced” antioxidant activity of 4-thiaflavans.
These preliminary results prompted us to keep investigating
this subject for a number of reasons. First of all we were
interested in investigating the substitution effects on the A
and B rings, as well as the role that sulfur in its different
oxidation states, plays on the antioxidant activity of thiafla-
vans. Moreover, the possibility that both “catechin-like” and
“tocopherol-like” mechanisms could operate together was an
open question. Connecting together the features of different
natural antioxidants is a modern trend in drug discovery.11 In
fact, protection against ROS by small molecules has to face
the problem that any new radical formed, even when stabilized,
retains a pro-oxidant effect,12 i.e. the possibility of damaging
the tissue where it was generated. It is well demonstrated that
an effective protection against ROS requires the synergic action
of different antioxidants, ensuring a cascade of redox reactions
from a highly reactive free radical to a safe molecule.13
Scheme 2 Reagents and conditions: i) PhtNSCl, CHCl3, rt; ii) Et3N,
CHCl3, 60 ◦C; iii) TBAF·3H2O, THF, 0 ◦C.
These efficient electron-poor dienes reacted with electron rich
styrenes 7a–c16 (Fig. 2) to give benzoxathiin cycloadducts 8a–i
(Scheme 2) through an inverse electron demand hetero Diels–
Alder reaction.10,17
This simple procedure allowed the regiocontrolled construc-
tion of a 4-thiaflavan ring and was accomplished by desilylation
of the phenoxy groups using tetrabutylammonium fluoride hy-
drate (TBAF·3H2O) in THF18 to obtain the phenolic derivatives
9a–i (Scheme 2 and Fig. 3).
Derivatives 8a–8b were also oxidized at sulfur with 1 eq. of
m-chloroperoxybenzoic acid (MCPBA) in DCM to obtain the
expected silylated sulfoxides (see Experimental). Desilylation
with TBAF afforded hydroxylated sulfoxides 10a–10b obtained
Therefore, we decided to prepare several hydroxy substituted
thiaflavans 3 and measure their antioxidant activity in vitro
focusing our attention on the effect of substitution on the A
and B rings, the role of the sulfur atom and the actual “double-
faced” character of these molecules.
1
as mixtures of the two possible stereoisomers. Analysis of H
NMR spectra of the crude reaction mixtures, in comparison
with data of similar compounds,19 allowed the attribution of the
relative geometry of diastereoisomeric sulfoxides. Oxathiin ring
3
hydrogen J values indicate a pseudo-equatorial position for
Results and discussion
the 2-aryl group in both isomers (Fig. 4). Coupling constants
and chemical shifts mutually indicate that oxidation affords as
a major isomer (85 : 15 for 10a, 90 : 10 for 10b) the sulfoxide
with the oxygen laying in a pseudo-axial position19,20 (i.e. the
trans-isomers, Fig. 4).
Synthesis
Polyhydroxy 4-thiaflavans required for this study were prepared
from easily available phenols 4a–f14 which were sulfenylated with
phthalimidesulfenyl chloride PhtNSCl (Pht = phthaloyl) to the
corresponding o-hydroxythiophthalimides 5a–f obtained with
complete regioselectivity (Fig. 2).15
Flash chromatography allowed the isolation of trans-10a and
both diastereoisomers of 10b. We observed that cis-10b was
unstable in solution. A pure sample of cis-10b, kept in CDCl3
1
Compounds 5 were treated with Et3N in chloroform at
for several hours, showed by H NMR the formation of trans-
60 ◦C to give transient o-thioquinones 6a–f (Scheme 2).
isomer together with styrene 7a. As expected19 oxidation at
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 6 6 – 3 0 7 2
3 0 6 7

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Fig. 3 Thiaflavans 9, 10 and 11 prepared and tested in this study.
Deprotection of silylated sulfones must be carefully controlled
to avoid a base mediated ring opening of the oxathiin ring.
This process causes to the formation of vinyl sulfones 12,
which become the major, or exclusive, products working with an
excess of TBAF at room temperature (Scheme 3).22 Under these
conditions derivative 12h was isolated and used for antioxidant
testing, despite the lack of thiaflavan skeleton.
The whole synthetic procedure has been optimized with
overall yields of sulfenylation, cycloaddition, possible oxidation
and desilylation ranging from 25 to 48%. All thiaflavans 9, trans-
sulfoxides 10 and sulfones 11 were stable compounds, storable
for months without appreciable decomposition either as pure
sample or in solution (acetone or ethanol).
Fig. 4 Relative geometry of cis- and trans-sulfoxides 10a and 10b.
sulfur, and probably also desilylation,21 facilitate a retro Diels–
Alder process with formation of 7a and an o-thioquinone S-
oxide, even at room temperature, which react together to give
the thermodynamically favoured sulfoxide trans-10b.19
The same process probably prevented the isolation of cis-
10a, thus vanishing the possibility of measuring the antioxidant
activity of cis-sulfoxides (vide infra).
The antioxidant activity of these derivatives has been mea-
sured in vitro, as reported in the next section.
Thiaflavans 8a–8b and 8g–8h were oxidized using 2.2 eq. of
MCPBA in DCM to give the corresponding silylated sulfones,
which in turn were reacted with TBAF to obtain hydroxy
sulfones 11a–11b and 11g–11h (Scheme 3, see Experimental).
Antioxidant activity
In our previous report on the antioxidant activity of some 4-
thiaflavans10 we measured their reducing activity (RA) as fading
of the purple colour (k = 515 nm) of a methanolic solution of
the commercially available 2,2-diphenyl-1-picrylhydrazyl radical
(DPPH, Fig. 5) after mixing with an equimolar amount of the
substrate. Despite being simple, well-liked and very practical
from a qualitative point of view,23 this assay did not allow to
quantify the “catechin-like” vs. “tocopherol-like” mechanisms
and, above all, to verify the possibility that both these features
work together.
Scheme 3 Reagents and conditions: i) MCPBA 2.2 eq., DCM, rt; ii)
TBAF·3H2O, THF, 0 ◦C.
Fig. 5 DPPH and trolox (13) structures.
3 0 6 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 6 6 – 3 0 7 2

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Table 1 SC50 values of 4-thiaflavans 9a–i, 10a–b, 11a–b, 11g–h and
sulfone 12h tested in this study
On the other hand, either derivative 11h, with the sulfur atom
oxidized to sulfone, or compound 12h, which despite the opening
of the C ring maintains the cathecol moiety, showed an activity
similar to 9h (and 1), supporting the primary role of the o-
dihydroxy substituted B ring in the “catechin-like” behaviour of
these derivatives. The little improvement moving from 11h to 12h
can be rationalized by considering for the former the additional
effect of the conjugated double bond.30
Entry
Compound
SC50/lM, 8%
A
SF
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Catechin (1)
15
16
23
18
23
19
26
40
1
3.4
3.1
2.2
2.8
2.2
2.7
1.9
1.3
4.1
3.1
6.4
—
—
0.2
—
0.2
3.3
3.8
Trolox (13)
9a
0.9
0.6
0.8
0.6
0.8
0.6
0.4
1.2
0.9
1.9
—
—
0.1
—
0.05
1.0
1.1
9b
9c
More of our efforts were devoted to better understanding the
role of the substitution and the sulfur atom on the “tocopherol-
like” antioxidant mechanism played by the A and C rings.
As expected, compound 9a (entry 3), with a 6-OH substitu-
tion, was less active than trolox. To our surprise, compound 9b,
showing the sulfur atom conjugated with the 7-OH group, was
more active than 9a and only little less active than trolox (13)
(entry 4). A rational explanation could be related to the ability of
the sulfur atom to stabilize the phenoxyl radical formed by the
reaction with DPPH, an aptitude claimed to be better than that
of the oxygen.31 However, it must be considered that literature
data are quite puzzling with regard to the role of sulfur. For
example, synthetic thiatocopherol was reported to show a slight
reduction of the antioxidant activity compared with vitamin
E,32 while the passing from oxygen to sulfur produced a weak
increase of 2,3-dihydrobenzo[b]thiophene-5-ol activity.33
We reported that sulfur oxidation on the C ring does not
play any role in the “catechin-like” mechanism expressed by the
3ꢀ,4ꢀ-dihydroxy substituted B ring, while it strongly influences
the “tocopherol-like” activity.10 The SC50 values obtained for
sulfoxides 10a–b and sulfones 11a–b are shown in Table 1, entries
12–15. In any case, the sulfur oxidation produces a dramatic
decrease of radical scavenger capability. This can be explained if
it is taken into account that the transformation of a sulfide sulfur
into a sulfoxide, or sulfone, introducing an electron withdrawing
group on the A ring, increases the bond dissociation enthalpy
(BDE) values of the OH group (vide infra).30 Moreover, in
compounds 10b and 11b the oxidation modifies the electronic
characteristics of the sulfur atom directly conjugated to the
potential radical centre31 and resulted in 11b being significantly
less active than 11a.
As already mentioned, sulfoxides 10a–b were tested as pure
trans-isomers. In our opinion, the sulfoxide geometry is also re-
lated with their very low antioxidant ability. It has been reported
that the stability of p-alkoxy substituted phenoxyl radicals
depends upon the possibility that one of the oxygen lone pairs
of the alkoxy group is parallel to the aromatic p-orbitals.9,33,34
On this basis, the higher activity of 2,3-dihydrobenzo[b]furan-
5-ol, with respect to the corresponding 6-hydroxychromanes,
was explained by taking into account that in the more rigid five-
member ring one of the lone pairs of the furan oxygen is forced in
an orthogonal localization to the aromatic ring.9,33,34 As reported
in Fig. 4, trans-sulfoxides 10a–b bear the oxygen–sulfur bond in
a pseudo-axial position, i.e. the free sulfur lone pair is almost
perpendicular to the aromatic p-orbitals and hence is unable
to stabilize the phenoxyl radical by conjugation. Unfortunately
the instability of cis-sulfoxides did not allow us to verify this
hypothesis by measuring SC50 for the minor isomers. On the
other hand, at the moment we have no rational explanation for
the small increase of activity observed moving from sulfoxide
10a to sulfone 11a.
9d
9e
9f
9g
12
16
8
9h
9i
10a
10b
11a
11b
11g
11h
12h
Nda
Nda
210
Nda
301
15
13
a Quenching of 50% DPPH was higher than 300 lM.
In this paper we measured the SC50 of derivatives 9, 10, 11 and
12h as the lM concentration of substrate required to quench
50% of a 100 lM solution of DPPH in methanol.24 In order
to compare results of our substrates with those of two well
known and highly efficient radical scavenger derivatives, which
undoubtedly operate by one of the mechanisms proposed for thi-
aflavans, the SC50 values were also determined for ( )-catechin
(1) and trolox (13) (Fig. 5), commonly used as a tocopherol
substitute for antioxidant measurements in polar media.
Collected data are reported in Table 1. Column A shows the
thiaflavan SC50 values, normalized by considering unitary the
value measured for the catechin (1). Column SF (stoichiometric
factor) indicates the number of reduced DPPH radicals per
antioxidant molecule: SF = C/2SC50, where C is the initial
DPPH concentration (100 lM).
Chain breaking antioxidant polyphenols effect their activity
in reactions with ROS, typically peroxyl radicals (ROO•), by
hydrogen transfer and formation of stabilized phenoxyl radicals
(ArO•).1,7,9 The measures performed with DPPH stand exactly
on the same mechanism. Thus, we can consider that hydroxy
4-thiaflavans (ThFlav–OH) react with purple DPPH radicals
by hydrogen transfer, with the formation of a phenoxyl radical
(ThFlav–O•) and the colourless species DPPH–H.
The ability of a generic phenol to react with DPPH strongly
depends upon the reaction conditions used to carry out the
experiment. For example, the solvent, or pH, chosen has an effect
on the antioxidant activity measured for hydroxyphenols.25–27
However, the ability as a radical scavenger of a phenolic
species can be easily related to the whole skeleton of the
compound.28 Since our goal was to study the characteristics
of the thiaflavan structure with a maximized “catechin-like”
or/and “tocopherol-like” radical scavenger ability, we decided
to test our derivatives in comparison with catechin (1) and trolox
(13) and to address the data merged from the measurements in
terms of effect of the substituents on antioxidant ability.
Derivative 9h (Table 1, entry 10), where only the B ring can
act as radical scavenger, showed a SC50 value similar to that of
catechin (1). Several papers address the relationship between
the structure of flavonoids and their antioxidant activity.7,29
However, strictly considering their ability as radical scavengers,
the presence of a 1,2-dihydroxy moiety on the B ring and the
planarity of the three rings of the flavan skeleton30 represent the
crucial requirements.
Compounds 9c and 9d (Table 1, entries 5 and 6) gave results
similar to those of 9a and 9b and, in fact, a single OH group
on the B ring plays a marginal role on the whole antioxidant
activity.
Moreover, we tried to evaluate the effect of an extended
conjugation by testing derivatives 9e and 9f. The obtained data
(Table 1, entries 7 and 8) seem to indicate that, surprisingly, the
effect of an additional condensed aromatic ring is quite poor. On
the contrary, the effect of extra electron donating group (EDG)
substituents on the A ring is significant. Entry 9 reports the SC50
value of compound 9g with a 5,7-dihydroxy substituted A ring,
Our data are in agreement with such observations. In fact,
derivative 9h, with any other hydroxy group neither on the A
ring nor on position 3 of the C ring, gave the same result as that
obtained with the racemic catechin.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 6 6 – 3 0 7 2
3 0 6 9

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whose ability as radical scavenger was higher than for trolox
and catechin, indicating the substantial effect of the additional
5-OH group. Also for 9g, oxidation at sulfur causes a dramatic
decrease of the radical scavenger aptitude, as indicated by SC50
value of sulfone 11g (Table 1, entry 16).
To our pleasure, derivative 9i showed a SC50 similar to the sum
of that of trolox and catechin (Table 1, entry 11). This result
indicates that the 5,7,3ꢀ,4ꢀ-tetrahydroxy substitution provides
to this thiaflavan the ability of working as a “double-faced”
antioxidant polyphenol, where both the “catechin-like” and
“tocopherol-like” mechanisms are operative.
calculations36 for 9i, catechin and trolox, compared those
obtained by considering the additive contribution of the sub-
stituents on the phenolic ring as reported by Wright and co-
workers.28,37 In Table 3 we also report the BDE values recently
calculated by Zhang et al. for catechin38 and 9i.39 Despite semi-
empirical calculation seeming to underestimate all the O–H
bond energies,40 the calculated and estimated BDE values are in
agreement with the SC50 measurements for these species.36 The
possibility that 9i can behave as a “double-faced” antioxidant
is corroborated by the efficiency of the catechol moiety on the
B ring38 and the ability of the 5,7-dihydroxy substituted A ring
coupled with sulfide sulfur on the C ring. In fact, BDE values
for 7-OH and 5-OH 4-thiaflavans (with the latter OH group
claimed to play an unexpected role in such activity38) are similar
to those calculated for trolox36 or experimentally measured for
2,2,5,7,8-pentamethylchromane (BDE = 78.25 Kcal mol−1).41
The calculated BDE values for all prepared thiaflavans36
parallel the general trend merged from SC50 measurements.†
Thus, oxidation at sulfur leads to higher BDE values above all
for directly conjugated 7-OH groups. However, our data are not
completely homogeneous and, for example, calculations invert
the lowest activity between sulfoxides and sulfones. This can be
ascribed to the calculation level and/or to the lack of suitable
parameters for the sulfur substituents at the different oxidation
states; a problem which would probably deserve a dedicated
further investigation.
Recently, Litwinienko and Ingold25 and Foti et al.26 reported
for phenols an abnormal solvent effect on hydrogen atom
abstraction by DPPH working in alcohol solvents. This is due
to the role played by a single electron transfer (SET) mechanism
from the phenoxy anion ArO− to the DPPH radical that is very
fast in alcohols and leads to overestimate the reaction kinetics
in such solvents (Scheme 4).
Scheme 4 The two mechanisms operative in the reaction of phenols
with DPPH radicals.
Conclusions
This seems to be confirmed by the kinetic measurements
carried out on thiaflavans 9g–i, which are reported in Table 2.
Parameter n, indicating the number of DDPH moles reduced by
one mole of thiaflavan, is in accord with the SF values reported
in Table 1 and suggests a rather complex mechanism operatiing
in solution between the several radical species formed.35 Both
n and kinetic constant k values are in agreement with those
measured under the same conditions for cathecol containing
natural antioxidants26 and used to verify the SET mechanism.
However, as Litwinienko and Ingold underline,25 the use of
DPPH for “titration” of total antioxidant ability of phenolic
compounds in methanol or ethanol remains a perfectly valid
procedure, since the direct hydrogen transfer or the sequence,
deprotonation–SET–protonation, have the same stoichiometry
(Scheme 4). Indeed, kinetic parameters perfectly match the trend
of SC50 values for the same compounds 9g–i.
We have shown that a new class of polyphenolic antioxidants,
possessing the 4-thiaflavan skeleton, can be prepared through
a simple hetero Diels–Alder reaction of o-thioquinones used as
electron-poor dienes. As a consequence of substitution on the A
and B aromatic rings and the oxidation state of the sulfur atom
on the C ring, such thiaflavans are able to imitate the mechanisms
operative in the two more valuable families of natural polyphe-
nolic antioxidants: flavonoids and tocopherols. The synthesis of
a derivative with both the structural requirements allowed the
availability of a compound showing the sum of the activities of
catechin and trolox in vitro.
The feasibility of the synthetic procedure allows foreseeing
stimulating modifications to our 4-thiaflavans, currently under
development in our laboratories, together with in vivo testing of
these new antioxidants.
The aptitude to give a hydrogen transfer reaction depends
upon the ionization potential (IP) of the whole molecule and
the BDE of the specific OH group involved in the transfer
reaction. Table 3 shows BDE values achieved by semi-empirical
Experimental
General: H and 13C NMR spectra were recorded on a Varian
1
Mercury 300 spectrometer at 300 and 75 MHz respectively, in
CDCl3 for silylated compounds and acetone-d6 for hydroxy
thiaflavans, unless otherwise specified, using signals of resid-
ual non-deuterated solvents as reference lines. Melting points
are uncorrected. CHCl3, DCM, THF, DMF and Et3N were
dried following standard procedures. All the other commercial
reagents were used as obtained from freshly opened containers.
Silylated phenols 4a–d and 4f were prepared by reaction of
the commercially available hydroxy arenes with TBDMSCl and
imidazole in dry DMF. Styrenes 7a–b were obtained from
3-hydroxy- and 3,4-dihydroxy-benzaldehyde by silylation and
subsequent Wittig reaction.17 PhtNSCl and N-thiophthalimides
5 were prepared as reported elsewhere.15,17 SC50 values24 and
kinetic parameters26,40 n and k have been obtained following
literature methods. General procedures for the cycloaddition,
oxidation and desilylation and spectroscopic data of derivatives
8a, 10a and 11a are given as an example. Full experimental and
spectroscopic data, including calculated BDE, for compounds
8, 9, 10, 11 and 12 are available as supplementary information.†
Table 2 Kinetic parameters k and n for selected thiaflavans 9g–i
Compound
k/mol−1s−1
n
9g
9h
9i
2129 116
1954 99
5383 250
3.03 0.28
2.97 0.30
6.37 0.54
Table 3 Calculated and estimated O–H BDE (Kcal mol−1) values for
thiaflavan 9i, catechin (1) and trolox (13)
O–H BDE O–H BDE
O–H BDE
Compound Radical
calculated35 estimated28,36 lit. data
9i
4ꢀ-O•
3ꢀ-O•
7-O•
5-O•
4ꢀ-O•
3ꢀ-O•
7-O•
5-O•
6-O•
72.26
72.49
77.07
76.36
72.11
72.35
77.94
76.89
73.50
75.35
77.45
79.95
79.65
75.35
77.45
83.55
84.05
76.15
78.1838
83.3538
79.3538
71.9337
1
Cycloaddition reactions. General procedure
To a solution of thiophthalimides 5 in dry CHCl3 (roughly
0.1 M), styrenes 7 (1 eq.) and freshly distilled Et3N (1 eq.) were
13
3 0 7 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 6 6 – 3 0 7 2

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added in sequence, the reaction mixtures heated at 60 ◦C and
monitored either by H NMR or TLC until the disappearance
of 5. Evaporation of the solvent and flash chromatography on
silica gel allowed the isolation of cycloadducts 8. Spectroscopic
data of silylated derivative 8a are as follows.
Desilylation reactions. General procedure
1
To a solution of compounds 8, 10ꢀ and 11ꢀ, in dry THF (0.04 M)
at 0 ◦C, a solution of TBAF·3H2O in DCM (1 eq. for each
TBDMSO group) was added and the reaction monitored by
TLC until the disappearance of the silylated starting products.
The crude mixture was diluted with ethyl acetate, washed with
saturated NH4Cl and water. The organic phase was dried over
anhydrous Na2SO4 and evaporated to dryness. Purification of
the residue by flash chromatography on silica gel afforded the
required products 9, 10 and 11. Spectroscopic data are as follows.
6-(tert-Butyl-dimethyl-silanyloxy)-2,3-dihydro-2-(4-methoxy-
phenyl)-1,4-benzoxathiin (8a)
Compound 8a was obtained as a white solid by flash chromatog-
raphy on s◦ilica gel with petroleum ether–DCM, 4 : 1, as eluent;
mp 89–90 C, (67%). 1H NMR d: 0.17 (s, 6H), 0.97 (s, 9H), 3.01
(dd, J = 13.0, 1.8 Hz, 1H), 3.28 (dd, J = 13.0, 9.6 Hz, 1H), 3.82
(s, 3H), 5.05 (dd, J = 9.6, 1.8 Hz, 1H), 6.51 (dd, J = 8.7, 2.7 Hz,
1H), 6.61 (d, J = 2.7 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.93–6.95
(m, 2H), 7.32–7.35 (m, 2H); 13C NMR d: −4.5 (q, 2C), 18.1 (s,
1C), 25.6 (q, 3C), 31.8 (t, 1C), 55.2 (q, 1C), 76.1 (d, 1C), 114.0
(d, 2C), 117.3(d, 1C), 117.6 (1s, 1d, 2C), 119.1 (d, 1C), 127.3 (d,
2C), 132.6 (s, 1C), 147.0 (s, 1C), 149.7 (s, 1C), 159.6 (s, 1C).
2,3-Dihydro-2-(4-methoxy-phenyl)-1,4-benzoxathiin-6-ol (9a)
Compound 9a was obtained as a white solid by flash chromatog-
raphy on◦silica gel with DCM–ethyl acetate, 20 : 1, as eluent; mp
110–111 C, (95%). 1H NMR d: 3.12 (dd, J = 13.2, 2.1 Hz, 1H),
3.25 (dd, J = 13.2, 9.3 Hz, 1H), 3.80 (s, 3H), 5.02 (dd, J = 9.3,
2.1 Hz, 1H), 6.51 (dd, J = 8.7, 3.0 Hz, 1H), 6.57 (d, J = 3.0 Hz,
1H), 6.71 (d, J = 8.7 Hz, 1H), 6.93–6.98 (m, 2H), 7.37–7.42
(m, 2H), 8.01 (br s, 1H); 13C NMR d: 32.1 (t, 1C), 55.5 (q, 1C),
76.8 (d, 1C), 113.3 (d, 1C), 113.6 (d, 1C), 114.7 (d, 2C), 118.9
(s, 1C), 120.0 (d, 1C), 128.3 (d, 2C), 133.8 (s, 1C), 146.7 (s, 1C),
152.5 (s, 1C), 160.6 (s, 1C). Found: C, 65.71; H, 5.17%. Calc. for
C15H14O3S: C, 65.67; H, 5.14%.
Oxidation reactions to silylated sulfoxides (indicated as 10aꢀ and
10bꢀ). General procedure
To a solution of cycloadduct 8a or 8b, in DCM (0.04 M) kept at
0 ◦C, a solution of MCPBA (1 eq.) in DCM was added and the
reactions monitored by TLC until the disappearance of sulfide 8
(30–40 min). The mixtures was diluted with DCM, washed with
10% Na2S2O3, saturated NaHCO3 and water. The organic phase
was dried over anhydrous Na2SO4 and evaporated to dryness.
1H NMR of the crude mixture allowed the attribution of the
cis–trans ratio, purification by flash chromatography on silica
gel allowed the isolation of trans-10aꢀ and cis- and trans-10bꢀ.
trans-2,3-Dihydro-2-(4-methoxy-phenyl)-4-oxo-1,4-
benzoxathiin-6-ol (trans-10a)
Compound trans-10a was obtained as a white solid by flash
chromatography on silica gel with ethyl acetate–DCM, 2 : 1, as
eluent; mp 178 ◦C dec., (65%). 1H NMR (DMSO-d6) d: 3.26 (dd,
J = 14.5, 1.2 Hz, 1H), 3.47 (dd, J = 14.5, 12.0 Hz, 1H), 3.77 (s,
3H), 5.38 (br d, J = 11.1 Hz, 1H), 6.94–7.02 (m, 5H), 7.44–7.48
(m, 2H), 9.56 (br s, 1H); 13C NMR (DMSO-d6, 75 MHz) d: 48.4
(t, 1C), 55.2 (q, 1C), 67.1 (d, 1C), 114.0 (d, 2C), 116.5 (d, 1C),
119.8 (d, 1C), 122.0 (d, 1C), 123.1 (s 1C), 128.5 (d, 2C), 130.9 (s,
1C), 145.5 (s, 1C), 151.3 (s, 1C), 159.5 (s, 1C). Found: C, 62.25;
H, 4.69%. Calc. for C15H14O4S: C, 62.05; H, 4.86%.
trans-6-(tert-Butyl-dimethyl-silanyloxy)-2,3-dihydro-2-(4-
methoxy-phenyl)-1,4-benzoxathiin 4-oxide (trans-10aꢀ)
Compound trans-10aꢀ was obtained as a white solid by flash
chromatography on silica gel with petroleum ether–ethyl acetate,
2 : 1, as eluent; mp 139 ◦C dec., (65%). 1H NMR d: 0.20 (s, 6H),
0.99 (s, 9H), 3.07 (dd, J = 14.4, 12.0 Hz, 1H), 3.24 (dd, J = 14.4,
1.5 Hz, 1H), 3.84 (s, 3H), 5.61 (br d, 1H), 6.94–6.98 (m, 4H),
7.13–7.14 (m, 1H), 7.40–7.45 (m, 2H); 13C NMR d: −4.5 (q, 2C),
18.1 (s, 1C), 25.6 (q, 3C), 49.8 (t, 1C), 55.3 (q, 1C), 67.4 (d, 1C),
114.2 (d, 2C), 120.2 (d, 1C), 122.1 (d, 1C), 122.4 (s, 1C), 126.9
(d, 1C), 127.9 (d, 2C), 130.6 (s, 1C), 147.7 (s, 1C), 149.7 (s, 1C),
160.1 (s, 1C).
2,3-Dihydro-2-(4-methoxy-phenyl)-4,4-dioxo-1,4-benzoxathiin-
6-ol (11a)
Compound 11a was obtained as a white solid by flash chro-
matography on silica gel with DCM–ethyl acet◦ate, 1 : 1, (or
1
DCM–methanol, 6 : 1) as eluent; mp 201–206 C, (79%). H
NMR d: 3.63 (dd, J = 14.1, 1.5 Hz, 1H), 3.83 (s, 3H), 3.94 (dd,
J = 14.1, 12.1 Hz, 1H), 5.65 (dd, J = 12.1, 1.5 Hz, 1H), 6.95 (d,
J = 9.0 Hz, 1H), 6.00–7.08 (m, 3H), 7.17 (d, J = 2.7 Hz, 1H),
7.54–7.56 (m, 2H), 8.71 (br s, 1H); 13C NMR d: 55.6 (q, 1C), 55.8
(t, 1C), 78.3 (d, 1C), 108.6 (d, 1C), 114.9 (d, 2C), 121.0 (d, 1C),
123.3 (d, 1C), 127.0 (s, 1C), 129.1 (d, 2C), 130.8 (s, 1C), 147.4
(s, 1C), 152.8 (s, 1C), 161.3 (s, 1C). Found: C, 58.97; H, 4.69%.
Calc. for C15H14O5S: C, 58.81; H, 4.61%.
Oxidation reactions to silylated sulfones (indicated as 11aꢀ, 11bꢀ,
11gꢀ, 11hꢀ). General procedure
To a solution of cycloadducts 8, in DCM (0.04 M) at rt, a
solution of MCPBA (2.2 eq.) in DCM was added and the
reactions monitored by TLC until the disappearance of sulfides
8 (4–8 h). The mixtures were diluted with DCM, washed with
10% Na2S2O3, saturated NaHCO3 and water. The organic phase
was dried over anhydrous Na2SO4 and evaporated to dryness
to give sulfones 11ꢀ, which did not require purification before
desilylation.
Acknowledgements
Work carried out in the framework of the National Project
“Stereoselezione in Sintesi Organica. Metodologie ed Appli-
cazioni”, supported by MIUR (Ministero Istruzione Universita`
e Ricerca) and Universities of Firenze and Messina.
6-(tert-Butyl-dimethyl-silanyloxy)-2,3-dihydro-2-(4-methoxy-
phenyl)-1,4-benzoxathiin 4,4-dioxide (11aꢀ)
References
Compound 11aꢀ was obtained as a white solid; mp 93–96 ◦C,
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1.5 Hz, 1H), 3.71 (dd, J = 14.1, 12.0 Hz, 1H), 3.84 (s, 3H), 5.70
(dd, J = 12.0, 1.5 Hz, 1H), 6.91–6.99 (m, 4H), 7.24–7.26 (m,
1H), 7.36–7.40 (m, 2H); 13C NMR d: −4.5 (q, 2C), 18.1 (s, 1C),
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114.5 (d, 2C), 120.0 (d, 1C), 125.5 (s, 1C), 127.1 (d, 1C), 127.7
(d, 2C), 129.3 (s, 1C), 147.6 (s, 1C), 150.5 (s, 1C), 160.5 (s, 1C).
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A
−1. A complete list of BDE values for compounds 9–12
˚
is available as supplementary information†.
37 The contribution to BDE value due to the presence of an S-
alkyl moiety has not been parameterized. On the basis of literature
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solvent, or with CsF in methanol.
3 0 7 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 0 6 6 – 3 0 7 2