From simple phenols to potent chain-breaking antioxidants by transposition of benzo[1,4]oxathiines to benzo[b]thiophenes

Article abstract of DOI:10.24820/ark.5550190.p011.037

Simple phenols, including food stock recycled derivatives, were used for the synthesis of 1,4-benzooxathiine intermediates, with limited or no antioxidant activity. Depending upon their substitution pattern, these compounds, through an acid promoted transposition, can be converted into o-hydroxydihydrobenzo[b]thiophenes or o-hydroxy-benzo[b]thiophenes as a new class of potent chain-breaking antioxidants, showing, in the reaction with alkyl peroxyl radicals, kinetic rate constants (kinh) comparable to that of α?tocopherol, the more potent natural lipophilic phenolic antioxidant.

Full text of DOI:10.24820/ark.5550190.p011.037

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Arkivoc 2019, part ii, 0-0
Organic Chemistry
to be inserted by editorial office
From simple phenols to potent chain-breaking antioxidants by transposition of
benzo[1,4]oxathiines to benzo[b]thiophenes
a
a
a
b
a
Caterina Viglianisi,* Leonardo Di Pietro, Valentina Meoni, Riccardo Amorati, Stefano Menichetti
aDepartment of Chemistry “U. Schiff”, University of Firenze,
Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
Department of Chemistry “G. Ciamician”, University of Bologna, Via San Giacomo 11, 40126 Bologna, Italy
b
Email: caterina.viglianisi@unifi.it
th
Dedicated to Professor Lorenzo Testaferri in the occasion of his 75 birthday
Received 08-01-2019
Accepted 08-29-2019
Published on line 09-24-2019
Abstract
Simple phenols, including food stock recycled derivatives, were used for the synthesis of 1,4-benzooxathiine
intermediates, with limited or no antioxidant activity. Depending upon their substitution pattern, these
compounds, through an acid promoted transposition, can be converted into o-hydroxy-
dihydrobenzo[b]thiophenes or o-hydroxy-benzo[b]thiophenes as a new class of potent chain-breaking
antioxidants, showing, in the reaction with alkyl peroxyl radicals, kinetic rate constants (kinh) comparable to
that of −tocopherol, the more potent natural lipophilic phenolic antioxidant.
Keywords: Antioxidant, transposition, sulfur heterocycle, benzo[b]thiophenes, phenols
DOI: https://doi.org/10.24820/ark.5550190.p011.037
Page 1
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
Introduction
Reactive Oxygen Species (ROS) and other free radicals are natural by-products of the human metabolism
playing an important role in cell signalling, homeostasis and biochemical transformations.1 On the other
hand, they can also be formed through a variety of exogenous events such as exposure to UV light and ionizing
radiation, smoking, air pollution and inflammation. Indeed, an anomalous high concentration of ROS in tissues
is strictly related to oxidative stress, in turn cause and effect of several diseases and aging itself.4
Our endogenous antioxidant defense systems have the function to control ROS level in order to conserve
their biological benefits avoiding risky high concentrations and preventing oxidative stress and related
diseases such as neurodegeneration, cardiovascular injury, mutation of healthy cells into cancerous ones,
etcetera.4
-3
-11
-11
On the other hand, many substances, taken with diet, are able to control oxidative processes acting as
exogenous antioxidants. In particular, natural and synthetic phenols have the ability to prevent auto-oxidation
acting as chain breaking antioxidant a process that is crucial for the protection of cell membranes and LDL.
Phenols (ArOH) are known to reduce the rates of oxidation of organic materials by transferring an H atom
•
•
12-14
(
H ) from their OH groups to the more common chain-carrying species i.e. peroxyl radicals (ROO ).
1
5-17
18,19
Polyphenols as flavonoids
such natural antioxidants.
(vitamin P) and tocopherols
(vitamin E) are the more important examples of
Recently, we focused our attention on some sulfur containing phenols, namely, o-hydroxy-
2
0
21
dihydrobenzo[b]thiophenes and benzo[b]thiophenes as efficient multi-defense antioxidants.
In particular, we have settled out new acid-catalysed transpositions that allow, in few steps with reasonably
good overall yields, to transform easily accessible benzo[1,4]oxathiines2
0-28
into 7-hydroxy-
dihydrobenzo[b]thiophenes or 7-hydroxy-benzo[b]thiophenes (Figure 1). These benzofused phenolic systems
showed antioxidant activities similar to that of α-tocopherol (α-TOH), the main component of vitamin E and
•
the more potent lipophilic antioxidant know in nature, showing in the reaction with ROO kinetic constants
6
-1 -1
(kinh) as high as 3.2x10 M s .
Figure 1. Structure and kinetic constants (kinh) of model phenolic compounds discussed in this study.
Page 2
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
Moving from a 6-hydroxychromane (like in α-TOH) to a 5-hydroxydihydrobenzo[b]furane the kinh slightly
increases since the five-membered ring is almost coplanar with the aromatic ring, hence one of the lone pairs
of the endocyclic O atom lays parallel to the aromatic π orbitals allowing an optimal stabilization of the
•
29
phenoxyl radical (ArO ). On the other hand 5-hydroxybenzo[b]furane, despite its complete planarity, showed
a ten time reduced hydrogen transfer ability due to the aromatization that, involving the lone pair of
•
29
endocyclic O atom, reduces its electron donating ability and ArO stability. We demonstrated that,
considering the corresponding sulfur heterocycles, moving from 7-hydoxydihydrobenzo[b]thiophenes to 7-
2
1
hydoxybenzo[b]thiophenes there is an overall increasing (up to three times) of the kinh
.
The (weak)
intramolecular H-bond stabilization of the ArOH, and the electron donating effect stabilization of sulfur
•
moieties on ArO do not allow to rationalize this unexpected result of kinh increasing with aromatization. We
have suggested that the extra stabilization of the phenoxyl radical in the benzothiophene compound is due to
3
0-35
the contribution of a chalcogen-bond effect,
namely the interaction between the high electron density
•
around the oxygen centered radical of ArO and the sulfur σ-hole of the thiophene that ensures an overall
●
increasing of the H transfer attitude.
We applied this observation preparing a couple of super vitamin-E like phenolic antioxidants bearing a
benzo[b]thiophene residue (Figure 1) perfectly suitable for studying the role of chain breaking activity in
2
1
biological environments.
In this paper, we report the scope and limitation of the transformation of different phenols (1), with
limited antioxidant activity, through benzo[b]oxathiines 4 (typically without any pendant OH , hence without
any antioxidant activity), into o-hydroxy benzothiophene systems 5, 6 showing a remarkable chain breaking
antioxidant ability (Scheme 1).
Scheme 1. The synthetic transformations considered in this study.
Results and Discussion
Synthesis of N-thiophthalimide derivatives 2
Our research group has developed the synthesis of benzo[1,4]oxathiine derivatives that exploits the reactivity
of ortho-hydroxy-N-thiophthalimides 2 in turn obtained by reaction of phthalimidesulfenyl chloride (PhtNSCl,
Pht = Phthaloyl) with phenols containing at least one additional electron donor group (EDG).2 o-Hydroxy-N-
2-28
thiophthalimides 2 are the result of an electrophilic aromatic substitution (S
E
Ar) that occurs without any
catalyst under mild conditions. The sulfenylation with PhtNSCl proved to be highly ortho-hydroxy-
Page 3
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
regioselective and, typically, affords a mono-sulfenylated derivative. In fact, after the first substitution, the
thiophthalimide group deactivates the aromatic ring toward further S Ar. Phenols 1a-g used as substrates and
E
N-thiophthalimides 2a-g prepared are depicted in table 1. Phenol 1a was synthesized through a Wolff-Kishner
reduction starting from 2-hydroxy-5-methoxybenzaldehyde as previously reported.20 Derivative 1b is
commercially available and tyrosol 1c is a natural phenolic antioxidant present in a variety of natural sources.
Saturated cardanol 1d is obtained from anacardic acid, the main component of cashew nutshell liquid (CNSL),
a by-product of cashew nut processing. Derivatives 1e and 1f were prepared by alkylation of commercially
available 2-methyl- and 2-tert-butyl-hydroquinone (see experimental). The bromide used for alkylation was
chosen to obtain derivatives 1e and 1f bearing a long saturated tail like in Tocopherols.
The dihydrobenzofuranol 1g was prepared in one-step starting from 2-t-butyl-5-methyl hydroquinone, 2-
methyl-2-propen-1-ol and p-toluensulfonic acid (PTSA). The steric hindrance of tert-butyl group allowed the
complete control of the regiochemistry giving 1g as the unique phenol isolated in 74% (see experimental).
The synthesis of N-thiophthalimide derivatives 2 (Table 1), was carried out following our standard
procedure. To a 0.1M solution of each phenol in chloroform a 0.1M solution of phthalimidesulfenyl chloride in
chloroform was added dropwise keeping the reaction mixture at 0°C. Then the mixture was kept under stirring
at room temperature until complete consumption of the starting phenol. The expected o-hydroxy-N-
thiophthalimide derivatives 2a-g were obtained after a trivial aqueous work-up and solvent evaporation and
typically used without further purification (Table 1).
Table 1. Synthesis of N-thiophthalimide derivatives 2
Entry
1
2
3
4
5
6
7
1g
Phenol
1
c
1d
1
a
a
1b
1
e
1
f
Product
(yield)
2
c (16%)
2d (≥99%)
2
2b (63%)
2
e (≥99%)
2
f (≥99%)
2g (≥99%)
Synthesis of benzo[1,4]oxathiine cycloadducts 4
2
0-28
In the last three decades
a-g with a base, such as triethylamine, allows the formation of the corresponding o-thioquinones as the
result of ArOH deprotonation and 1-4 elimination at sulfur of the phthalimide anion from the phenate ion
scheme 2). o-Thioquinones are transient intermediates, very efficient as electron-poor dienes in inverse
we demonstrated that the reaction of o-hydroxy-N-thiophthalimide derivatives
2
(
electron demand hetero Diels-Alder reactions with a plethora of electron-rich alkenes (3, Figure 2) acting as
dienophiles to afford of benzo[1,4]oxathiine cycloadducts 4 under mild conditions (Scheme 2).
Page 4
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
Scheme 2. Access to benzo[1,4]oxathiines 4 from o-hydroxy-N-thiophthalimides 2 via o-thioquinones.
Noteworthy, the high polarization of the hetero-diene36,37 ensures, in all cases, the formation of a single
regioisomeric cycloadduct in which the oxygen atom of the thioquinone is bounded to the more electron-poor
carbon atom of the dienophile (Scheme 2). Electron-rich dienophiles 3 used for this study are depicted in
Figure 2. All dienophiles used are commercially available, apart from 4-methoxy-α-methylstyrene (3c), which
was prepared through a Wittig olefination from 4-methoxy-acetophenone and methyltriphenylphosphonium
2
0
bromide as previously reported.
Figure 2. Electron-rich alkenes used as dienophiles in this study.
The cycloaddition reactions were carried out as following: to a (roughly) 0.1 M solution of the o-hydroxyl-
N-thiophthalimide derivative 2 in chloroform, an excess (2-5 equiv) of the dienophile 3 was added followed by
freshly distilled triethylamine (1 equiv). The mixture was kept under magnetic stirring at 60 °C until complete
consumption of starting o-hydroxy-N-thiophthalimide. The crude obtained after an aqueous work-up was
purified by column chromatography on silica gel to afford the desired benzo[1,4]oxathiine 4 as depicted in
Table 2.
The use of an excess of dienophile was decided to speed up the cycloaddition allowing a relative fast
consumption of the o-thioquinone. The reaction with styrene 3d was carried out in dichloroethane at 80 °C
since the lack of EDG decreases its ability as dienophile.
The cycloaddition reactions were indeed completely regiocontrolled allowing the isolation of a single
regioisomeric cycloadduct where the oxygen atom of the thioquinones binds to the more electron-poor
carbon atom of the dienophile. Additionally, the cycloaddition occurs with retention of the alkene geometry,
as expected for a concerted [4+2] process. Thus, reacting alkene 3f, commercially available as a 72:28 trans:cis
mixture, allowed the isolation of cycloadduct 4df as 72:28 trans:cis mixture of diastereoisomers (Table 2, entry
7
), while reactions carried out with trans-anethole 3b gave trans-benzo[b][1,4]oxathiines 4eb and 4fb as single
diastereoisomers (Table 2, entries 9, 11).
Page 5
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
Table 2. Synthesis of benzo[1,4]oxathiine cycloadducts 4
Entry o-hydroxy-N-thiophthalimide Dienophile
Product (Yield)
1
2a
3c
4
ac1
2
2a
3d
4
ad (30%)
3
4
5
6
7
8
2a
2b
2c
2d
2d
2e
3e
3a
3a
3a
3f
4
ae (64%)
4
ba (71%)
4
ca (57%)
4
da (62%)
4
df
(
cis-trans mixture)
3a
4
ea (36%)
Page 6
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
9
2e
2e
2f
3b
3e
3b
4
eb (37%)
1
0
1
4
ee (53%)
1
1
4
fb (33%)
2
2g
3a
4
ga (59%)
Page 7
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
Acid mediated transposition of benzo[1,4]oxathiines 4 to dihydrobenzo[b]thiophenes 5 and
benzo[b]thiophenes 6
Having in hand a variety of different substituted benzoxathiine cycloadducts 4 (Table 2) we had the
opportunity to study and rationalize the limitation and scope of their transformation into 7-hydroxy-
2
0
21
dihydrobenzo[b]thiophenes 5, and/or 7-hydroxybenzo[b]thiophenes 6, using the better condition for both
processes, i.e. chloroform as solvent and BF .OEt or triflic acid (TfOH) as acid promoters. The mechanism we
3
2
propose is depicted in Scheme 3 using derivative 4ac as model substrate.
Scheme 3. Acid promoted transformation of benzoxathiines 4 into dihydrobenzo[b]thiophene 5 and
benzo[b]thiophenes 6.
Thus, benzoxathiine 4ac, under acid conditions gives ring opening of the benzo-fused heterocyclic ring
with formation of a benzylic carbocation which, through an internal electrophilic alkylation (i-S Ar) gives rise to
E
ring closure and formation of dihydrobenzo[b]thiophene 5ac. This first part of the process is directly related
with the well-known chromane-indene acid catalysed transposition despite occurring under milder
conditions.3 In fact, using benzoxathiine as starting materials, the intermediate carbocation is stabilized by
8-44
2
0
the anchimeric assistance of the sulfur atom and formation of a thiiranium ion. Once derivative 5ac is
formed and under harsh acid conditions, we postulated the possibility of a retro-alkylation (r-S Ar), via
protonation of aromatic ring and elimination, in the case of 5ac, of anisole. The new cyclic carbocation formed
E
2
1
easily deprotonate to give the aromatic benzo[b]thiophene 6a (Scheme 3).
Keeping this mechanism in mind, we studied the behaviour of derivatives 4 as reported in Table 3.
.
Benzoxathiine 4ac reacts smoothly with BF
3
2
Et O (3.0 equiv) giving 5ac in 66% yield. Indeed, the benzylic
carbocation formed from 4ac is stabilized by the 4’-methoxy group on the aryl ring and by the methyl group on
the benzylic carbon. Actually, the formation of high stabilized tertiary carbocation plays a crucial role in both
processes since 4ac is the only derivative that allowed the isolation of the corresponding benzo[b]thiophene
.
6
a (16%) just under BF
3
2
Et O catalysis (Table 3, entry 1). As a matter of fact, reacting 4ac with 1 equiv. of TfOH,
Page 8
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
6
a becomes the only product observed in the crude mixture, and isolated in 46% yield (Table 3, entry 2),
indicating an easy and fast transformation of 5ac into 6a facilitated by the stability of the cyclic tertiary
carbocation formed after anisole elimination (Scheme 3). The critical role of carbocation stability in both
processes (i-S
E
Ar and r-S Ar) depicted in Scheme 3 is boosted by the result obtained with derivative 4ab. In
E
fact, in the absence of a 4’-metoxy group and alkyl substituents on benzylic carbon, the reaction does not take
.
place with 3 equiv of BF
3
2
Et O at 60°C being the starting material stable under these conditions for more than
1
2h. Repeating the reaction under drastic acid conditions, 5 equiv of TfOH at 60 °C, for 6.5h, we were able to
isolate dihydrobenzo[b]thiophene 5ad albeit in low yield, 25%, while analysis of the crude pointed out a large
amount of unreacted starting material without any trace of the corresponding benzo[b]thiophene.
Together with the role of carbocation stability, the substitution pattern on the oxathiine benzofused aryl
ring demonstrated to be crucial as well. In fact, when derivatives 4ba, 4ca, 4da and 4df, able to generate
.
stabilized carbocations, were reacted with either BF
3
2
Et O or TfOH at 60 °C any benzothiophene was observed
yet, typically, an extensive decomposition of the starting materials was experienced (Table 3, entries 4-7). In
all these compounds the position in the aromatic ring ortho to the sulfur atom is less nucleophilic due to the
lack of the alkoxy group in ortho’ position, a structural feature that demonstrated to be mandatory for the
success of the procedure. This prevented the possibility to transform stock recycled phenols, like tirosol and
cardanol, into potent chain breaking antioxidants. In perfect agreement with previous observations,
.
benzoxathiines 4ea and 4eb easily reacted with BF
3
2
Et O to give dihydrothiophenes 5ea and 5eb in 53% and
6
3% yield respectively (Table 3, entries 8 and 9). For these derivatives the one-pot formation of
benzothiophenes 6 from 4 was poor effective. However, benzo[b]thiophenes 6b and 6c were obtained in 48%
and 50% yield respectively carrying out the process in two steps by reacting the corresponding
dihydrobenzo[b]thiophenes 5ea and 5eb with 0.5 equiv of TfOH (Table 3, entries 10 and 11).
As a matter of fact, benzo[b]thiophene 6b was also prepared reacting benzoxathiine 4ee with 0.5 equiv. of
TfOH. In this case, the transposition was very fast and, in just a hour, thiophene 6b was the unique product of
the reaction, while no trace of residual starting material or intermediate dihydrobenzo[b]thiophene were
1
detected by TLC and H NMR analysis of the crude mixture (Table 3, entry 12). Derivative 4ee was obtained
using ethyl vinyl ether as dienophile (see Table 2 entry 10). Taking in consideration the mechanism depicted in
Scheme 3 we can suggest that the first carbocation, obtained by oxathiine ring opening, is stabilized by the
adjacent ethoxy group, while the aromatization process of the corresponding 3-ethoxy-
dihydrobenzo[b]thiophene foresees and easy elimination of ethanol (see scheme 3). In other words, once the
structural features required for both processes are maintained, the transformation occurs independently upon
the presence of a p-methoxyaryl group on C2 of benzoxathiine.
As a further demonstration that a fine tuning of the substitution pattern is mandatory to achieve either
dihydro- and benzo[b]thiophenes, compound 4fb was simply transformed into dihydrobenzo[b]thiophene 5fb
in 45% yield using BF
3
.Et O (Table 3, entry 13), however, all the attempts to push the reaction to the
2
corresponding benzo[b]thiophenes using TfOH as promoter, from 4fb or 5fb as starting materials, failed while
we observed extensive de-terbutylation and decomposition.
Eventually, we tested derivative 4ga, a benzo[1,4]oxathiine with a dihydrobenzofuranic moiety and no
free nucleophilic positions on the benzofused aromatic ring (see Table 2 entry 14). Indeed, we used similar
2
1
compounds for the preparation of the benzo[b]thiophenes containing the α-TOH skeleton (Figure 1)
exploiting a TfOH promoted de-terbutylation since to liberate the required nucleophilic position ortho to the
sulfur atom. However, in this case the dimethyl-dihydrobenzofuranic ring proved to be poor stable under acid
condition and de-terbutylation occurred together with rings opening preventing the thiophene ring formation
(Table 3, entry 14).
Page 9
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
Table 3. Access to dihydrobenzo[b]thiophenes 5 and benzo[b]thiophenes 6
Entry
Substrate
Acid (equiv)
Product (Yield)
1
BF .
3
2
Et O (3.0)
4
ac
5
ac (66%)
6a (16%)
2
3
4ac
CF
3
SO
3
H (1.0)
6
a (46%)
No products
BF .
CF SO
Et
O (3.0)
3
2
4
ad
3
3
H (5.0)
5
ad (25%)
4
5
BF .
3
Et
Et
2
2
O (3.0)
O (3.0)
-
4
ba
BF .
CF
3
-
-
3
SO
3
H (1.0)
4
ca
BF .
Et
O (3.0)
3
2
6
7
CF SO
3
3
H (1.0)
4
da
BF .
CF SO
Et
O (3.0)
3
2
-
4
df
4
3
3
H (1.0)
8
9
BF .
3
Et
Et
2
2
O (3.0)
ea
5
ea (53%)
eb (63%)
BF .
O (3.0)
3
4
eb
5
1
0
CF
3
SO H (0.5)
3
6
b (48%)
5
ea
Page 10
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
1
1
1
2
CF
CF
3
3
SO
3
3
H (0.5)
H (0.5)
6
c (50%)
5
eb
SO
4
ee
6b (23%)
1
1
3
4
BF .
3
Et
Et
2
2
O (3.0)
O (3.0)
4
fb
5
fb (45%)
BF .
CF
3
-
3
SO
3
H (1.0)
4
ga
Chain-breaking antioxidant activity of dihydrobenzo[b]thiophenes 5 and benzo[b]thiophenes 6
The antioxidant activity of the dihydrobenzo[b]thiophenes 5 and benzo[b]thiophenes 6 was
assessed by studying the inhibition of the thermally initiated autoxidation of styrene (R=styrene,
5
0% v/v in chlorobenzene), used as reference hydrocarbon, under controlled conditions.
Autoxidation of styrene is a radical chain reaction (see Equations 1-6) carried on mainly by
alkylperoxyl radicals (ROO˙) which are representative of the reactive oxygen species responsible
for the oxidation of natural lipids and man-made materials under air. The initiator is represented
by azobis(isobutyronitrile) (AIBN), whose decomposition at 30°C originates a constant flux of free
radicals (initiation rate, Ri). The reaction was followed by measuring the oxygen consumption by
an automatic oxygen uptake recording apparatus, build in our laboratory, based on a differential
4
5-48
pressure transducer.
In the absence of antioxidants, the O
2
consumption is fast and linear, whereas in the presence of an
antioxidant, the O consumption is retarded or completely inhibited for a period that depends on its
2
Page 11
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
concentration. The number of radicals trapped by each antioxidant molecule (n) is related to the length of the
inhibited period τ through Equation (7), in which the initiation rate Ri can be determined by using a reference
antioxidant. The rate constant of the reaction of the antioxidant with ROO˙ radicals (kinh, see Equation 5) was
calculated by using Equation (8): A plot of Δ[O ]t vs ln(1-t/ τ) gives a straight line of slope kp [styrene]/kinh
2
−1 −1 48,49
from which kinh is obtained by using the known kp value at 30°C of styrene, that is, 41 M s .
obtained by using this method are reported in Table 4 and compared with that of α-TOH.
The results
Table 4. Kinh and n values of derivatives 5 and 6 compared with those of α-tocopherol
-
1 -1
Entry
Compound
k
inh M s
n
1
3
.2e6
2
α-Tocopherol
2
3
4
(
1.800.4)e6
1.80.1
5
5
ea
(
(
1.63±0.06)e6 1.86±0.06
1.22±0.02)e6 1.92±0.14
eb
5
fb
5
6
7
(
3.90±1.3)e6 1.83±0.07
6
a
(
5.24±0.36)e6 1.86±0.11
6
b
(
6.29±0.71)e6 1.78±0.24
6
c
From Table 4 we observe that the products tested have a rate inhibition constant of the same order of
magnitude of α-TOH, indicating they are all potent chain breaking antioxidants. The number of peroxyl radicals
Page 12
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
trapped by each antioxidant (n) is approximately 2 demonstrating that the mechanism of neutralization of
radicals is also analogous to that of α-TOH.
In more details it is confirmed also that moving from dihydrobenzo[b]thiophenes 5 (Table 4 entries 2-4) to
dihydrobenzo[b]thiophenes 6 (Table 4 entries 5-7) there is a solid increasing of kinh that allowed to consider a
benzo[b]thiophene ring as the more efficient residue to insert in ortho position to OH group for increasing the
chain breaking antioxidant activity of a phenolic compound.
Conclusions
In this paper we reported a study dedicated to elucidating the scope of the acid promoted transposition of
benzoxathiines into dihydrobenzo[b]thiophenes and benzo[b]thiophenes, the latter obtainable directly from
oxathiines or from the dihydro- derivatives. The structural features on both C2 and benzofused aromatic ring
of benzoxathiines required to allow the first and the second transposition have been clarified and exploited for
the preparation of potent phenolic chain breaking antioxidants. The peculiar ability of the benzothiophene
●
●
sulfur atom in promoting the H atom transfer process from the ortho OH group to a peroxyl radical (ROO )
●
has been confirmed. In fact, derivatives 5 and 6 showed kinetic constants (kinh) in the reaction with ROO
similar or superior to that of α-TOH, the more potent natural lipophilic antioxidant known.
We are now applying these results for the preparation of benzoxathiine derivatives to be used as a
"
reservoir" of potent antioxidants being unreactive towards oxidant radical species under neutral or basic
conditions, but very reactive under acid conditions. The aim is to exploit these derivatives in peculiar
physiologic conditions such as those cancer cells experiencing a hypoxic and low pH environment.
Experimental Section
General. H and 13C NMR spectra were recorded with Varian Mercury Plus 400, using CDCl
1
as solvent.
3
1
13
Residual CHCl
3
at 7.26 ppm and central line of CDCl at 77.00 ppm were used as the reference of H and C
3
NMR spectra respectively. FT-IR spectra were recorded with Spectrum Two FT-IR Spectrometer. GC-MS
spectra were recorded with a QMD 100 Carlo Erba. ESI-MS spectra were recorded with a JEOL MStation
JMS700. Melting points were measured with Stuart SMP50 Automatic Melting Point Apparatus. All the
reactions were monitored by TLC on commercially available precoated plates (silica gel 60 F 254) and the
products were visualized with acidic vanillin solution. Silica gel 60 (230–400 mesh) was used for column
chromatography. Dry solvents were obtained by The PureSolv Micro Solvent Purification System. Chloroform
was washed with water several times and stored over calcium chloride. Pyridine and TEA were freshly distilled
over KOH. Phthalimide sulfenyl chloride was prepared from the corresponding commercially available disulfide
(purchased from Chemper snc) as reported elsewhere. Reagents were purchased at the highest commercial
quality and used without further purification, unless otherwise stated.
General cycloaddition procedure for the synthesis of derivatives 4. To a solution of derivatives 2 in CHCl (0.1
3
M), was added the dienophile 3 (3 eq.) and triethylamine (1 eq.). The reaction mixture was left stirring at 60 °C
until TLC analysis indicated complete consumption of the starting material, then was diluted with CH Cl
, filtered and
2
2
,
washed once with a saturated solution of NH
4
Cl. The organic layer was dried over Na
2
SO
4
evaporated in vacuo.
Page 13
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
4
ad. From 2a (571 mg, 1.81 mmol). The crude was purified by silica gel column
chromatography, using a mixture of petroleum ether and CH
obtained as pale yellow solid (150 mg, 30% yield) mp 93-95 °C. H NMR (400 MHz, CDCl
2
Cl
2
2:1 as eluent. The purified product was
) δ 7.60 – 7.29 (m, 5H),
1
3
6
.52 (s, 2H), 5.15 (bd, J 9.4 Hz, 1H), 3.75 (s, 3H), 3.25 (dd, J 12.9, 9.4 Hz, 1H), 3.11 (dd, J 12.9, 1.6 Hz, 1H), 2.22
1
3
(s, 3H). C NMR (100 MHz, CDCl
3
) δ 153.3, 144.6, 140.7, 128.9, 128.7, 128.2, 125.8, 117.1, 114.0, 108.4, 76.2,
S: C 70.56, H 5.92; found C 70.64, H 5.97.
5
5.6, 32.3, 16.5. Elemental Analysis Calcd for C16
H O
16 2
4
ae. From 2a (446 mg, 1.42 mmol). The crude was purified by silica gel column chromatography,
using a mixture of petroleum ether and CH
solid (216 mg, yield 64%) mp 34-38°C. H NMR (400 MHz, CDCl
2
Cl
2
1:7 as eluent. The purified product was obtained as light brown
) δ 6.55 – 6.39 (m, 2H), 5.35 (dd, J 5.0, 2.3 Hz,
), 3.14 (dd, J 12.7, 2.3 Hz, 1H), 3.00 (dd, J 12.7, 5.0 Hz, 1H),
.19 (s, 3H), 1.25 (t, J 7.1 Hz, 3H). C NMR (100 MHz, CDCl ) δ 153.4, 141.7, 128.9, 117.9, 114.1, 108.4, 94.7,
4.1, 55.5, 29.6, 16.3, 15.0. Elemental Analysis Calcd for C12 S: C 59.98, H 6.71; found C 59.84, H 6.85.
1
3
1
2
6
H), 4.07 – 3.81 (m, 1H), 3.79 – 3.60 (s+m, 4H, -OCH
3
13
3
H
O
16 3
4
ba. From 2a (411 mg, 1.38 mmol). The crude was purified by silica gel column
chromatography, using a mixture of petroleum ether and CH
obtained as white solid (280 mg, yield 71%) mp 94-96 °C. H NMR (400 MHz, CDCl
2
Cl
2
3:1 as eluent. The purified product was
) δ 7.38 – 7.35 (m, 2H), 6.98
1
3
–
1
1
6.93 (m, 2H), 6.87 (d, J 8.4 Hz, 1H), 6.71 (d, J 8.4 Hz, 1H), 5.15 (dd, J 9.6, 2.0 Hz, 1H), 3.84 (s, 3H), 3.21 (dd, J
1
3
3.2, 9.6 Hz, 1H) 3.06 (dd, J 13.2, 2.0 Hz, 1H), 2.23 (s, 3H), 2.14 (s, 3H). C NMR (100 MHz, CDCl
50.2, 134.2, 133.3, 127.3, 127.0, 126.2, 123.8, 122.7, 114.0, 76.4, 55.3, 32.0, 19.8, 11.8. Elemental Analysis
S: C 71.30, H 6.34; found C 69.84, H 6.15.
3
) δ 159.5,
Calcd for C17
H O
18 2
4
ca. From 2c (144 mg, 0.46 mmol). The crude was purified by silica gel column
chromatography, using a mixture of CH
colouless oil (79 mg, 57% yield). H-NMR (400 MHz, CDCl3) δ 2.77 (t, J 2.0 Hz, 2H), 3.04 (dd, J 6.3, 1.0 Hz, 1H),
2
Cl and AcOEt 20:1 as eluent. The purified product was obtained as
2
1
3
6
1
.27 (dd, J 6.3, 4.8 Hz, 1H), 3.78-3.86 (m, 5H), 5.1 (dd, J 4.8, 1.0 Hz, 1H), 6.85-6.89 (m, 2H), 6.92-6.96 (m, 2H),
.97-6.99 (m, 1H), 7.31-7.34 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ: 31.7, 38.2, 55.3, 63.6, 114.1, 117.2, 118.8,
26.2, 127.3, 127.4, 131.6, 132.4, 151.2, 159.7. Elemental Analysis Calcd for C17
H
18
3
O S: C 67.52, H 6.00; found
C 67.58, H 6.05.
4
da. From 2d (103 mg, 0.38 mmol). The crude was purified by silica gel column
chromatography, using a mixture of petroleum ether and CH
obtained as colouless oil (110 mg, 62% yield). H-NMR (400 MHz, CDCl3) δ 0.85-0.93 (m, 3H), 1.22-1.35 (m,
2
Cl 6:1 as eluent. The purified product was
2
1
2
6
C
6H), 2.45-2.57 (at, 2H), 3.03 (dd, J 13.1, 2.0 Hz, 1H), 3.27 (dd, J 13.1, 9.6 Hz, 1H), 5.14 (dd, J 9.6, 2.0 Hz, 1H),
.65-6.80 (m, 2H), 6.90-6.98 (m, 2H), 7.02 (d, J 6.0 Hz, 1H), 7.30-7.40 (m, 2H). Elemental Analysis Calcd for
30
H
44
2
O S: C 76.87, H 9.46; found C 76.90, H 9.51.
Page 14
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
4
df. From 2d (589 mg, 1.22 mmol). The cis and trans products (cis-4df + trans-4df 60% yield)
were isolated after silica-gel column chromatography using a mixture of CH
2
2
Cl and petroleum ether 1:3 as
eluent.
1
cis-4df white solid, mp 41-44°C. H-NMR (400 MHz, CDCl
3
) δ: 0.85-0.93 (m, 3H), 1.17-1.34 (m, 29H), 1.37 (d, J
3
1
2
.4 Hz, 3H), 2.45-2.55 (pt, 2H), 3.36 (qd, J 3.4, 1.0 Hz, 1H), 3.72 (dq, J 5.1, 3.5 Hz, 1H), 3.93 (dq, J 5.1, 3.5 Hz,
1
3
H), 5.17 (d, J 1.0 Hz), 6.68-6.72 (m, 2H), 6.90-6.94 (m, 1H). C-NMR (100 MHz, CDCl ) δ 14.1, 15.0, 15.4, 22.7,
3
9.2, 29.3, 29.5, 29.6 (2C), 29.7 (5C), 31.2, 31.9, 35.3, 36.2, 64.5, 97.1, 114.4, 118.2, 122.0, 126.6, 140.8, 148.5.
1
trans-4df white solid, mp 41-42°C. H-NMR (400 MHz, CDCl
3
) δ: 0.85-0.93 (m, 3H), 1.18-1.34 (m, 29H), 1.37 (d,
J 3.4 Hz, 3H), 2.45-2.55 (pt, 2H), 3.36 (dq, J 2.1, 3.4 Hz, 1H), 3.72 (dq, J 5.0, 3.6 Hz, 1H), 3.93 (dq, J 5.0, 3.6 Hz,
1
3
1
2
H), 5.17 (d, J 2.1 Hz), 6.68-6.72 (m, 2H), 6.92-6.96 (m, 1H) C-NMR (100 MHz, CDCl
3
) δ: 14.1, 15.0, 15.4, 22.7,
9.2, 29.3, 29.5, 29.6 (2C), 29.7 (5C), 31.2, 31.9, 35.3, 36.2, 64.5, 97.1, 114.4, 118.2, 122.0, 126.6, 140.8, 148.5.
4
ea. From 2e (101 mg, 0.20 mmol). The crude product was purified by silica-gel column
chromatography with a mixture of petroleum ether : CH
2
Cl = 3 : 1. The purified product was obtained as oil
2
1
(37 mg, 36% yield). H NMR (400 MHz, CDCl
3
) δ 7.35 (d, J 8.8 Hz, 2H), 6.94 (d, J 8.8 Hz, 2H), 6.49 (s, 2H), 5.08
(
1
dd, J 9.6, 1.8 Hz, 1H), 3.87 (t, J 6.6 Hz, 2H), 3.83 (s, 3H), 3.22 (dd, J 12.9, 9.6 Hz, 1H), 3.05 (dd, J 12.9, 1.9 Hz,
1
3
H), 2.17 (s, 3H), 1.77 – 1.70 (m, 2H), 1.44 – 1.39 (m, 2H), 1.35 – 1.26 (m, 20H), 0.88 (t, J 6.6 Hz, 3H). C NMR
) δ 159.5, 152.8, 144.6, 133.0, 128.8, 127.0, 117.0, 114.5, 114.0, 109.2, 68.5, 55.3, 32.3, 31.9,
0.9, 29.7, 29.6, 29.4, 29.3 (4 signals for 9 non-equivalent CH groups), 26.0, 22.7, 16.4, 14.1. Elemental
S: C 74.33, H 9.15; found C 74.38, H 9.19.
(100 MHz, CDCl
3
3
2
Analysis Calcd for C30
H O
44 3
4
eb. From 2e (100 mg, 0.20 mmol). The crude product was purified by silica-gel flash
chromatography with a mixture of petroleum ether : CH
2
Cl
) δ 7.28 (d, J 8.6 Hz, 2H), 6.94 (d, J 8.6 Hz, 2H), 6.48
2
= 3 : 1 as eluent. The purified product was
1
obtained as oil (37 mg 37% yield). H NMR (400 MHz, CDCl
3
(
s, 2 H), 4.61 (d, J 8.6 Hz, 1H), 3.87 (t, J 6.6 Hz, 2H), 3.84 (s, 3H), 3.46 – 3.38 (m, 1H), 2.12 (s, 3H), 1.78 – 1.71
1
3
(m, 2H), 1.45 – 1.40 (m, 2H), 1.33 – 1.28 (m, 20H), 1.09 + 1.07 (s, 3H), 0.91 – 0.88 (m, 3H). C NMR (100 MHz,
CDCl3) δ 159.6, 152.9, 144.7, 131.3, 128.4, 128.3, 118.9, 114.2, 113.9, 108.7, 82.5, 68.5, 55.2, 38.9, 31.9, 29.7,
2
9.6, 29.4 (3 signals for 9 non-equivalent CH
2
groups), 26.0, 22.7, 17.6, 16.5, 14.1. Elemental Analysis Calcd for
C
31
H O
46 3
S: C 74.65, H 9.30; found C 74.70, H 9.34.
4
ee. From 2e (150 mg, 0.30 mmol). The crude product was purified by silica-gel column
chromatography with a mixture of petroleum ether and CH
obtained as a pale yellow oil (37 mg, 53% yield). H NMR (400 MHz, CDCl
2
Cl
2
3 : 1 as eluent. The purified product was
) δ 6.49 – 6.45 (m, 2H), 5.34 (dd, J
1
3
5
.0, 2.2 Hz, 1H), 3.97 – 3.89 (m, 1H), 3.45 (t, J 6.6 Hz, 2H), 3.75 – 3.68 (m, 1H), 3.14 (dd, J 12.7, 2.2 Hz, 1H), 3.00
(
dd, J 12.7, 5.0 Hz, 1H), 2.18 (s, 3H), 1.76 – 1.69 (m, 2H), 1.44 – 1.40 (m, 2H), 1.34 – 1.24 (m, 23H), 0.88 (t, J 6.6
13
Hz, 3H). C NMR (100 MHz, CDCl
2
3
) δ 153.0, 141.6, 128.8, 120.7, 117.8, 114.8, 109.2, 94.8, 68.4, 64.1, 31.9,
groups), 26.0, 22.7, 16.3, 15.0, 14.1. Elemental Analysis
9.6, 29.4, 29.3 (3 signals for 9 non-equivalent CH
2
Calcd for C25
H
42
O
3
S: C 71.04, H 10.02; found C 71.07, H 10.04.
Page 15
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
4
fb. From 2f (206 mg, 0.40 mmol). The crude product was purified by silica-gel column
chromatography using a mixture of CH
obtained as yellow oil (70 mg, 37%). H NMR (400 MHz, CDCl
2
Cl
2
and petroleum ether 1:1 as eluent. The purified product was
) δ 7.28 (d, J 8.8 Hz, 2H), 6.93 (d, J 8.8 Hz, 2H),
1
3
6
9
3
6
1
.60 (d, J 2.9 Hz, 1H), 6.50 (d, J 2.9 Hz, 1H), 4.40 (d, J 9.1 Hz, 1H), 3.87 (t, J 6.6 Hz, 2H), 3.84 (s, 3H), 3.56 (dd, J
.1, 6.6 Hz, 1H), 1.77 – 1.73 (m, 2H), 1.46 – 1.42 (m, 2H), 1.36 – 1.27 (m, 22H), 1.24 (s, 9H), 0.88 (t, J 6.6 Hz,
1
3
H). C NMR (100 MHz, CDCl
8.4, 55.2, 39.8, 35.0, 31.9, 30.9, 29.7, 29.6, 29.4 (2 signals for 9 non-equivalent CH
4.1. MS m/z (Irel, %): 419 (31.29); 148 (100.00). Elemental Analysis Calcd for C34
3
) δ 159.6, 153.2, 145.9, 141.0, 131.0, 128.3, 120.8, 113.9, 111.2, 107.7, 82.4,
groups), 26.1, 22.7, 17.9,
S: C 75.51, H 9.69; found
2
H O
52 3
C 75.57, H 9.74.
4
ga. From 2g (140 mg, 0.34 mmol). The crude was purified by silica-gel column
chromatography, using a mixture of petroleum ether and CH
obtained an incolor oil (80 mg, 59% yield). H NMR (400 MHz, CDCl
2
Cl
2
2:1 as eluent. The purified product was
) δ 7.36 (d, J 8.7 Hz, 2H), 6.93 (d, J 8.7 Hz,
1
3
2
2
1
H), 5.19 (dd, J 9.2, 3.6 Hz, 1H), 3.83 (s, 3H), 3.08 (dd, J 12.9, 3.6 Hz, 1H), 2.99 (dd, J 12.9, 9.2 Hz, 1H), 2.84 (s,
1
3
H), 2.05 (s, 3H), 1.58 (s, 9H), 1.45 (s, 3H), 1.44 (s, 3H). C NMR (100 MHz, CDCl
27.2, 126.1, 125.9, 122.8, 119.0, 113.9, 84.2, 77.9, 55.3, 41.9, 37.7, 34.6, 31.7, 28.3, 13.4. Elemental Analysis
S: C 72.33, H 7.59; found C 72.37, H 9.63.
3
) δ 159.4, 151.3, 145.8, 133.8,
Calcd for C24
H O
30 3
General procedure for transposition. A solution of 4 or 5 and acid (BF
was left under magnetic stirring at r.t. or 60 °C until complete consumption of the starting material as
monitored by TLC. The solution was then diluted with CH Cl (30 mL) and washed with a saturated solution of
NaHCO (2x30 mL) and H O (2x30 mL). The organic layer was dried over anhydrous Na SO and concentrated
3
.OEt
2
or CF
3
SO
3
H) in dry CHCl (0.03 M)
3
2
2
3
2
2
4
in vacuum. The crude was purified by silica gel column chromatography to yield the desired
dihydrobenzo[b]thiophene 5 or benzothiophene 6.
5
ac. The reaction carried out following the general procedure from 4ac (40 mg, 0.13 mmol) using
BF
3
Et
2
O (3 equiv.) at 60°C for 30 min. The crude was purified by silica gel column chromatography (CH Cl as
2
2
eluent) to yield the desired product 5ac as light orange solid mp 111-113 °C (27 mg, yield 66%) and 16%
1
benzo[b]thiophene 6a. H NMR (400 MHz, CDCl
(
3
) δ 7.19 – 7.17 (m, 2H), 6.82 – 6.80 (m, 2H), 6.41 (s, 1H), 3.78
1
3
s, 3H), 3.50 – 3.40 (m, 5H), 2.25 (s, 3H), 1.85 (s, 3H). C NMR (100 MHz, CDCl ) δ 157.9, 150.5, 142.2, 138.8,
3
-
1
1
3
C
32.7, 129.3, 127.0, 124.2, 113.3, 111.7, 56.0, 55.8, 55.2, 50.0, 24.9, 15.9. FT-IR (CCl
572, 3000, 2934, 2834, 1717, 1610, 1583, 1511, 1484, 1464, 1400, 1248, 1182. Elemental Analysis Calcd for
S: C 68.33, H 6.37; found C 68.47, H 6.51.
4
0.05M, cm ) ν 3615,
18
H O
20 3
Page 16
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
6
a. The reaction carried out following the general procedure from 4ac (51 mg, 0.16 mmol) using
H (1 equiv.) at 60°C for 20 min. The crude was purified by silica gel column chromatograph (petroleum
ether:CH Cl 1:1 as eluent) and the second, on the mixed fraction containing the desired product, using a
mixture of petroleum ether and CH
CF
3
SO
3
2
2
2
Cl
2
1:1. The purified product was obtained as brown oil (15 mg, yield 46%).
-
1
1
IR (CCl
4
0.05M, cm ) ν 3614, 3590, 2925, 2845, 1655, 1614, 1529, 1485, 1464, 1173. H NMR (400 MHz, CDCl
3
)
1
3
δ 6.80 (d, J 1.2 Hz, 1H), 6.51 (s, 1H), 4.46 (bs, 1H), 3.85 (s, 3H), 2.56 (d, J 1.2 Hz, 3H), 2.35 (s, 3H). C NMR (100
MHz, CDCl ) δ 150.9, 141.7, 134.1, 131.2, 129.2, 119.2, 117.6, 108.3, 55.9, 17.3, 15.6. Elemental Analysis Calcd
S: C 63.44, H 5.81; found C 63.49, H 5.85.
3
for C11
H
O
12 2
5
ad. The reaction carried out following the general procedure from 4ad (25 mg, 0.09 mmol) using
CF
ether:CH
CDCl
3
SO
3
H (5 equiv.) at 60°C for 7h. The crude was purified by silica gel column chromatography (petroleum
1
2
Cl
2
1:1 as eluent) to yield the desired product as a brown oil (6 mg, yield 25%). H NMR (400 MHz,
3
) δ 7.28 – 7.05 (m, 5H), 6.31 (s, 1H), 4.74 (dd, J 8.5, 2.1 Hz, 1H), 4.10 (s, 1H), 3.97 – 3.78 (m, 1H), 3.50 (s,
1
3
3
1
2
7
H), 3.22 (dd, J 11.1, 2.1 Hz, 1H), 2.18 (s, 3H). C NMR (100 MHz, CDCl
28.3, 127.1, 126.7, 124.5, 110.6, 55.9, 50.7, 42.9, 16.0. IR (CCl 0.025M, cm ) ν 3614, 3576, 3063, 3028, 3001,
932, 2854, 2833, 1602, 1593, 1490, 1464, 1453, 1405, 1186, 1034. Elemental Analysis Calcd for C16
0.56, H 5.92; found C 70.61, H 5.97.
3
) δ 150.2, 142.7, 142.2, 129.6, 128.6,
-
1
4
H
16
2
O S: C
5
ea. The reaction carried out following the general procedure from 4ea (30 mg, 0.06 mmol) using
O (3 equiv.) at 60°C for 3h. The crude product was purified by silica-gel column chromatography
Cl
1:2 as eluent) obtaining the purified product 5ea as a beige oil (15 mg, yield 53%). 1
) δ 7.16 (d, J 8.6 Hz, 2H), 6.78 (d, J 8.6 Hz, 2H), 6.34 (s, 1H), 4.76 (dd, J 8.5, 2.8 Hz, 1H),
.18 (s, 1H), 3.92 (dd, J 11.1, 8.5 Hz, 1H), 3.81 – 3.75 (m, 1H), 3.76 (s, 3H), 3.66 – 3.60 (m, 1H), 3.26 (dd, J 11.1,
BF
3
Et
2
(petroleum ether:CH
2
2
H
NMR (400 MHz, CDCl
4
2
3
1
3
.8 Hz, 1H), 2.23 (s, 3H), 1.52 – 1.45 (m, 2H), 1.30 – 1.17 (m, 22H), 0.88 (t, J 6.62 Hz, 3H). C NMR (100 MHz,
) δ 158.3, 149.6, 142.0, 135.4, 130.0, 129.2, 128.1, 124.3, 113.6, 111.5, 68.5, 55.2, 50.3, 42.7, 31.9, 29.71,
CDCl
3
-
1
2
2
9.70, 29.68, 29.66, 29.63, 29.55, 29.4, 29.3, 29.2, 25.8, 22.7, 16.0, 14.1. IR (CDCl
855, 1609, 1511, 1487, 1468, 1407, 1245, 1179. Elemental Analysis Calcd for C30
3
, 0.05M, cm ) ν 3603, 2927,
H O
44 3
S: C 74.33, H 9.15;
found C 74.37, H 9.18.
5
eb. The reaction carried out following the general procedure from 4eb (35 mg, 0.07 mmol) using
O (3 equiv.) at 60°C for 1h. The crude product was purified by silica-gel column chromatography
petroleum ether:CH Cl 1:2 as eluent) obtaining the purified product 5eb as light orange oil (22 mg, yield
BF
(
3
.Et
2
2
2
Page 17
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
6
4
3%).
1H NMR (400 MHz, CDCl
3
) δ 7.12 (d, J 8.7 Hz, 2H), 6.77 (d, J 8.7 Hz, 2H), 6.35 (s, 1H), 4.32 (d, J 3.1 Hz, 1H),
.16 (bs, 1H), 3.80 – 3.70 (m, 2H), 3.76 (s, 3H), 3.63 – 3.57 (m, 1H), 2.23 (s, 3H), 1.53 + 1.52 (s, 3H), 1.48 – 1.41
1
3
(m, 2H), 1.31 – 1.12 (m, 22H), 0.89 (t, J 6.6 Hz, 3H). C NMR (100 MHz, CDCl ) δ 158.3, 150.1, 142.1, 135.1,
3
1
2
1
28.8, 128.3, 128.1, 124.2, 113.6, 111.7, 68.6, 58.9, 55.2, 54.8, 31.9, 29.71, 29.70, 29.68, 29.66, 29.65, 29.55,
9.36, 29.34, 29.23, 25.8, 23.7, 22.7, 16.0, 14. IR (CDCl
3
, 0.05M, cm-1 ν 3571, 2928, 2856, 1610, 1511, 1488,
)
-
468, 1408, 1304, 1245, 1178, 1108, 1036. MS (ESI): m/z 497.3 [M-H] . Elemental Analysis Calcd for C31
H
46
3
O S:
C 74.65, H 9.30; found C 74.68, H 9.35.
6
b. The reaction carried out following the general procedure from 4ee (20 mg, 0.047 mmol) using
H (0.5 equiv.) at room temperature for 30 min, was gradually heated to 30 °C (3h) and then to 60 °C
1h). The crude was purified by silica gel column chromatography, using a mixture of petroleum ether and
CH Cl 1:2 as eluent. The purified product was obtained as a light brown oil (4 mg, yield 23%). IR (CDCl
.05M, cm ) ν 3602, 2928, 2856, 1466, 1409, 1262, 1099. MS (ESI): m/z 375.2 [M-H] . H NMR (400 MHz,
CDCl ) δ 7.44 (d, J 5.8 Hz, 1H), 7.25 (d, J 5.8 Hz, 1H), 6.54 (s, 1H), 4.54 (bs, 1H), 4.04 (t, J 6.5 Hz, 2H), 2.36 (s,
CF
3
SO
3
(
2
2
3
,
-
1
- 1
0
3
1
3
3
1
H), 1.87 – 1.80 (m, 2H), 1.52 – 1.46 (m, 2H), 1.26 (bs, 20H), 0.90 – 0.86 (m, 3H). C NMR (100 MHz, CDCl
48.6, 141.7, 135.0, 134.7, 123.8, 121.4, 117.8, 109.0, 68.9, 31.9, 29.7, 29.6, 29.4 (3 signals for 9 non-
groups), 26.2, 22.7, 15.7, 14.1. Elemental Analysis Calcd for C23 S: C 73.35, H 9.64; found C
3
) δ
equivalent CH
3.38, H 9.69.
2
H
O
36 2
7
6
c. The reaction carried out following the general procedure from 5eb (18 mg, 0.036 mmol) using
CF
3
SO
3
H (0.5 equiv.) at 60°C for 2h. The crude product was purified by silica-gel column chromatography
1
(petroleum ether:CH
2
Cl
2
1:1 as eluent) obtaining a light brown oil (7 mg, yield 50%). H NMR (400 MHz, CDCl
3
)
δ 7.08 (s, 1H), 6.50 (s, 1H), 4.45 (bs, 1H), 4.00 (t, J 6.5 Hz, 2H), 2.56 (s, 3H), 2.33 (s, 3H), 1.85 – 1.78 (m, 2H),
13
1
1
.52 – 1.45 (m, 2H), 1.35 – 1.26 (m, 20H), 0.88 (t, J 6.7 Hz, 3H). C NMR (100 MHz, CDCl3) δ 147.8, 141.3,
38.4, 131.1, 129.2, 119.0, 117.0, 109.2, 68.9, 31.9, 29.7, 29.6, 29.5, 29.4 (4 signals for 9 non-equivalent CH
2
groups), 26.2, 22.7, 16.1, 15.7, 14.1. IR (CDCl
MS (ESI): m/z 389.3 [M-H] . Elemental Analysis Calcd for C24
3
, 0.05M, cm-1) ν 3602, 2928, 2856, 1469, 1277, 1229, 1139, 1039.
S: C 73.80, H 9.81; found C 73.84, H 9.87.
-
H O
38 2
5
fb. The reaction carried out following the general procedure from 4fb (34 mg, 0.063 mmol, 0.001
.Et O (3 equiv.) at 60°C for 22h after was added more BF .Et O (3 equiv.) and the reaction was left
for additional 8h at 60°C. The crude was purified by silica-gel column chromatography using before a mixture
M) using BF
3
2
3
2
of petroleum ether and CH
2
Cl 8:1 as eluent to 1:1 to obtain the desired product as an orange solid (15 mg,
2
1
yield 45%). H NMR (400 MHz, CDCl3) δ 7.13 (d, J 8.6 Hz, 2H), 6.79 (d, J 8.6 Hz, 2H), 6.51 (s, 1H), 4.32 (d, J 3.7
Hz, 1H), 4.06 (s, 1H), 3.80 – 3.75 (m, 2H), 3.76 (s, 3H), 3.63 – 3.58 (m, 1H), 1.53 + 1.51 (s, 3H), 1.47- 1.43 (m,
1
3
2
1
H), 1.40 (s, 9H), 1.32 – 1.14 (m, 22H), 0.88 (t, J 6.6 Hz, 3H). C NMR (100 MHz, CDCl3) δ 158.3, 149.7, 142.5,
36.9, 135.0, 129.7, 128.6, 128.3, 113.6, 109.0, 68.7, 59.2, 55.2, 55.1, 34.9, 31.9, 29.7, 29.6, 29.4 (2 signals for
Page 18
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
9
7
non-equivalent CH
5.55, H 9.71.
2
), 25.8, 23.2, 22.7, 14.1. Elemental Analysis Calcd for C34
H
52
O
3
S: C 75.51, H 9.69; found C
Acknowledgements
We thank MIUR-Italy ("Progetto Dipartimenti di Eccellenza 2018-2022" allocated to Department of Chemistry
Ugo Schiff" and “Funding for basic activities related to research FFABR 2018“.
"
Supplementary Material
Synthetic procedures and NMR spectra are available as supplementary material of this article.
References
1
2
3
4
. Stubbe, J.; van Der Donk, W. A. Chem. Rev. 1998, 98, 705.
https://doi.org/10.1021/cr9400875
. Hensley, K.; Robinson, K. A.; Gabbita, S. P.; Salsman, S.; Floyd, R. A. Free Radic. Biol. Med. 2000, 28, 1456.
https://doi.org/10.1016/S0891-5849(00)00252-5
. Stubbe, J. J. Chem. Commun. 2003, 2511.
https://doi.org/10.1039/b307617m
Halliwell, B.; Gutteridge, J. M. C. Antioxidants in Nutrition, Health, and Disease, Oxford University Press
Inc., New York 1996.
5
6
7
Halliwell, B.; Encyclopedia of life sciences, 2001, Nature Publishing Group, 1-7.
Vroegop, S. M.; Decker, D. E.; Buxser, S. E. Free Radic. Biol. Med. 1995, 18, 141.
Breen, A.P.; Murphy, J. A. Free Radic. Biol. Med. 1995, 18, 1033.
https://doi.org/10.1016/0891-5849(94)00209-3
8
9
1
1
Pace, G. W.; Leaf, C. D. Free Radic. Biol. Med. 1995, 19, 523.
https://doi.org/10.1016/0891-5849(95)00047-2
Aruoma, O. I. Free Radic. Biol. Med. 1996, 20, 675.
https://doi.org/10.1016/0891-5849(95)02110-8
0 Schwarz, K. B. Free Radic. Biol. Med. 1996, 21, 641.
https://doi.org/10.1016/0891-5849(96)00131-1
1 Viglianisi, C.; Menichetti, S.; Morelli, P.; Baschieri, A.; Amorati, A. Heteroatom Chemistry 2018, e21466.
https://doi.org/10.1002/hc.21466
https://doi.org/10.1002/hc.21466
1
1
1
2 Ingold, K. U. Chem. Rev. 1961, 61, 563.
https://doi.org/10.1021/cr60214a002
3 Finkel, T.; Holbrook N. J., Nature, 2000, 408, 239.
https://doi.org/10.1038/35041687
4 Lucarini, M.; Pedulli, G. F. Chem. Soc. Rev. 2010, 39, 2106.
https://doi.org/10.1039/b901838g
Page 19
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
1
1
1
1
1
2
2
2
2
2
5 Middleton Jr, E.; Kandaswarni, C. in The Flavonoids Advances in Research Since 1986, (Ed. J. B. Harborne),
Chapman & Hall, London, 1994, pp. 619–645.
6 Bohm, B. A. Introduction to Flavonoids, Harwood Academic Publishers, Amsterdam, 1998 and references
cited therein.
7 Dixon, R. A.; Ferreira, D. Phytochemistry 2002, 60, 205.
https://doi.org/10.1016/S0031-9422(02)00116-4
8 Burton, G. W.; Ingold, K. U. Acc. Chem. Res. 1986, 19, 194.
https://doi.org/10.1021/ar00127a001
9 Jiang, Q. Free Rad. Biol. Med. 2014, 72, 76.
https://doi.org/10.1016/j.freeradbiomed.2014.03.035
0 Viglianisi, C.; Amorati, R.; Di Pietro, L.; Menichetti, S. Chem. Eur. J. 2015, 21, 16639.
https://doi.org/10.1002/chem.201502650
1 Menichetti, S.; Amorati, R.; Meoni, V.; Tofani, L.; Caminati, G.; Viglianisi, C. Org. Lett. 2016, 18, 5464.
https://doi.org/10.1021/acs.orglett.6b02557
2 Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C. J. Org. Chem. 1997, 62, 2611.
https://doi.org/10.1021/jo962014m
3 Capozzi, G.; Lo Nostro, P.; Menichetti, S.; Nativi, C.; Sarri, P. Chem. Commun. 2001, 551.
https://doi.org/10.1039/b100359n
4 Menichetti, S.; Aversa, M. C., Cimino, F.; Contini, A.; Viglianisi, C.; Tomaino, A. Org. Biomol. Chem. 2005, 3,
3
066.
https://doi.org/10.1039/b507496g
2
2
5 Lodovici, M.; Menichetti, S.; Viglianisi, C.; Caldini, S.; Giuliani, E. Bioorg. Med. Chem. Lett. 2006, 16, 1957.
https://doi.org/10.1016/j.bmcl.2005.12.078
6 Amorati, R.; Cavalli, A.; Fumo, M. G.; Masetti, M.; Menichetti, S.; Pagliuca, C.; Pedulli, G. F.; Viglianisi, C.
Chem. Eur. J. 2007, 13, 8223.
https://doi.org/10.1002/chem.200700309
2
2
7 Amorati, R.; Catarzi, F.; Menichetti, S.; Pedulli, G. F.; Viglianisi, C. J. Am. Chem. Soc. 2008, 130, 237.
https://doi.org/10.1021/ja075554h
8 Menichetti, S.; Amorati, R.; Bartolozzi, M. G.; Pedulli, G. F.; Salvini, A.; Viglianisi, C. Eur. J. Org. Chem. 2010,
2
218.
https://doi.org/10.1002/ejoc.200901493
2
9 Zahalka, H. A.; Robillard, B.; Hughes, L.; Lusztyk, J.; Burton, G. W.; Janzen, E. G.; Kotake, Y.; Ingold, K. U. J.
Org. Chem. 1988, 53, 3739.
https://doi.org/10.1021/jo00251a014
3
3
0 Politzer, P.; Murray, J. S.; Clark, T. Phys. Chem. Chem. Phys. 2013, 15, 11178.
https://doi.org/10.1039/c3cp00054k
1 Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.; Meanwell, N. A. J. Med. Chem. 2015, 58,
4
383.
https://doi.org/10.1021/jm501853m
3
3
2 Fick, R. J.; Kroner, G. M.; Nepal, B.; Magnani, R.; Horowitz, S.; Houtz, R. L.; Scheiner, S.; Trievel, R. C. ACS
Chem. Biol. 2016, 11, 748.
https://doi.org/10.1021/acschembio.5b00852
3 Turbiez, M.; Frere, P.; Allain, M.; Videlot, C.; Ackermann, J.; Roncali, J. Chem. Eur. J. 2005, 11, 3742−3752.
https://doi.org/10.1002/chem.200401058
Page 20
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Viglianisi, C. et al.
3
4 Fanfrlik, J.; Prada, A.; Padelkova, Z.; Pecina, A.; Machacek, J.; Lepsik, M.; Holub, J.; Ruzicka, A.; Hnyk, D.;
Hobza, P. Angew. Chem., Int. Ed. 2014, 53, 10139.
https://doi.org/10.1002/anie.201405901
3
3
3
3
3
4
4
4
5 Nziko, V. de P. N.; Scheiner, S. J. Org. Chem. 2015, 80, 2356.
https://doi.org/10.1021/acs.joc.5b00012
6 Viglianisi, C.; Marcantoni, E.; Carapacchi, V.; Menichetti, S.; Marsili, L. Eur. J. Org. Chem. 2014, 6405.
https://doi.org/10.1002/ejoc.201402894
7 Viglianisi, C.; Vasa, K.; Tanini, D.; Capperucci, A.; Amorati, R.; Valgimigli, L.; Baschieri, A.; Menichetti, S.
Chem. Eur. J. 2019, 25, 9108.
8 Anchel, M.; Blatt, A. H. J. Am. Chem. Soc. 1941, 63, 1948.
https://doi.org/10.1021/ja01852a045
9 Loudon, J. D.; Razdan, R. K. J. Chem. Soc. 1954, 4299.
https://doi.org/10.1039/jr9540004299
0 Anastasis, P.; Brown, P. E. J. Chem. Soc. Perkin Trans. 1 1982, 2013.
https://doi.org/10.1039/p19820002013
1 Bellamy, D. Chazan, J. B.; Ou, K. Tetrahedron 1983, 39, 2803.
https://doi.org/10.1016/S0040-4020(01)82450-9
2 Tanaka, T.; Miyaguchi, M.; Mochisuki, R. K.; Tanaka, S.; Okamoto, M.; Kitajima, Y.; Miyazaki, T. Heterocycles
1
987, 25, 463.
https://doi.org/10.3987/S-1987-01-0463
4
3 Levy, J.-N.; Latham, C. M.; Roisin, L.; Kandziora, N.; Di Fruscia, P.; White, A. J. P.; Woodward, S.; Fuchter,
M. J. Org. Biomol. Chem. 2012, 10, 512
https://doi.org/10.1039/C1OB06780J
4
4
4 Killander, D.; Sterner, O. Eur. J. Org. Chem. 2014, 6507.
https://doi.org/10.1002/ejoc.201402722
5 Burton, G. W.; Doba, T.; Gabe, E. J.; Hughes, L.; Lee, F. L.; Prasad, L., Ingold, K. U. J. Am. Chem. Soc. 1985,
1
07, 7053.
https://doi.org/10.1021/ja00310a049
4
4
6 Lucarini, M.; Pedulli, G. F. Chem. Soc. Rev., 2010, 39, 2106.
https://doi.org/10.1039/b901838g
7 Nam, T-g.; Rector, C. L.; Kim, Hye-y.; Sonnen, A. F.-P. Meyer, R.; Nau, W. M.; Atkinson, J.; Rintoul, G.; Pratt,
D. A.; Porter, N. A. J. Am. Chem. Soc. 2007, 129, 10211.
https://doi.org/10.1021/ja072371m
4
4
8 Amorati, R.; Baschieri, A. Valgimigli, L. J. Chem. 2017, 6369358.
https://doi.org/10.1155/2017/6369358
9 Viglianisi, C.; Bartolozzi, M. G.; Pedulli, G. F.; Amorati, R.; Menichetti, S. Chem. Eur. J. 2011, 17, 12396.
https://doi.org/10.1002/chem.201101146
Page 21
©ARKAT USA, Inc