Generation and trapping of o-thioquinones on solid support: Synthesis of hydroxylated 4-thiaflavans

Article abstract of DOI:10.1080/10426500902856339

The generation and trapping of o-thioquinones was successfully applied to the synthesis of hydroxy-4-thiaflavans on solid support using commercially available carboxy and aminomethylated polystyrene resins. These valuable cycloadducts are obtained as pure

Full text of DOI:10.1080/10426500902856339

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Generation and Trapping of o-
Thioquinones on Solid Support:
Synthesis of Hydroxylated 4-
Thiaflavans
Stefano Menichetti a & Caterina Viglianisi a
a Dipartimento di Chimica Organica and Laboratorio
di Progettazione Sintesi e Studio di Eterocicli
Biologicamente Attivi (HeteroBioLab), Polo
Scientifico e Tecnologico, Università di Firenze,
Sesto Fiorentino, Italy
Published online: 28 Apr 2009.
To cite this article: Stefano Menichetti & Caterina Viglianisi (2009): Generation and
Trapping of o-Thioquinones on Solid Support: Synthesis of Hydroxylated 4-Thiaflavans,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:5, 1233-1246
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Phosphorus, Sulfur, and Silicon, 184:1233–1246, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902856339
Generation and Trapping of o-Thioquinones on Solid
Support: Synthesis of Hydroxylated 4-Thiaflavans
Stefano Menichetti and Caterina Viglianisi
Dipartimento di Chimica Organica and Laboratorio di Progettazione
Sintesi e Studio di Eterocicli Biologicamente Attivi (HeteroBioLab), Polo
Scientifico e Tecnologico, Universita` di Firenze, Sesto Fiorentino, Italy
The generation and trapping of o-thioquinones was successfully applied to the
synthesis of hydroxy-4-thiaflavans on solid support using commercially available
carboxy and aminomethylated polystyrene resins. These valuable cycloadducts are
obtained as pure compounds without any intermediate purification, in better overall
yields than the solution phase procedure.
Keywords Antioxidants; phthalimidesulfenyl chloride; solid phase synthesis; 4-
thiaflavans; o-thioquinones
INTRODUCTION
Mono-o-thioquinones appeared in the literature for the first time in the
1971,1 and for many years they did not find any practical synthetic
application, mainly because of the harsh reaction conditions required
for their generation.2 The situation changed when an effective method-
ology for their formation, under very mild reaction conditions, was
discovered in our group.3 The key starting materials for the generation
of o-thioquinones are the corresponding o-hydroxy-N-thiophthalimides,
in turn obtained in good yields, as indefinitely stable crystalline com-
pounds, by reacting electron-rich phenols with the phthalimidesulfenyl
Received 7 January 2008; accepted 24 January 2008.
Dedicated to Professor Marian Mikolꢀajczyk, CBMiM PAN in Lꢀ o´dz´, Poland, on the
occasion of his 70th birthday.
Financial support from MIUR (Research project “Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni,” contract 2005035330) is gratefully acknowledged. We also
wish to thank Mrs. Brunella Innocenti for elemental analysis.
Address correspondence to Stefano Menichetti, Dipartimento di Chimica Organica,
and Laboratorio di Progettazione Sintesi e Studio di Eterocicli Biologicamente Attivi
(HeteroBioLab), Polo Scientifico e Tecnologico, Universita` di Firenze, Via della Lastruccia
13, 50019 Sesto Fiorentino (FI), Italy. E-mail: stefano.menichetti@unifi.it
1233

1234
S. Menichetti and C. Viglianisi
chloride 1 (PhtNSCl, Pht Phthaloyl).3 The reaction of o-hydroxy-N-
thiophthalimides with weak bases, such as triethylamine, causes depro-
tonation of the hydroxy group followed by elimination of the phthalim-
ide anion and formation of the o-thioquinone species. Once generated,
these short-lived reactive intermediates can be trapped as dienophiles,4
across the carbon-sulfur double bond, or, more conveniently, as hetero-
dienes in an inverse electron-demand hetero Diels–Alder reaction, with
a large number of electron-rich alkenes acting as dienophiles, providing
benzoxathiin cycloadducts.3,5 In all cases tested, this [4+2] cycloaddi-
tion afforded a single regioisomeric 1,4-benzoxathiin, deriving from the
interaction of the oxygen of the thione with the more electron-rich car-
bon of the alkene (Scheme 1).
EDG
O
S
O
S
EDG
OH
OH
Base
PhtNSCl
R
R
R
R
-
- PhtN
SNPht
O
N
PhtN
O
SCHEME 1 General procedure for the solution phase generation and trapping
of o-thioquinones.
Using styrenes as dienophiles, the above reaction affords cy-
cloadducts with the 4-thiaflavan skeleton that showed very promising
biological activities.6,7 In particular, when properly substituted with
hydroxy groups, these heterocyclic derivatives are able to mimic the
antiradical activity of either flavonoids, bearing a catechol group on
the B ring like catechin, and/or tocopherols, like α-tocopherol or Vita-
min E, due to the presence of the hydroxy-thiachromane moiety (A and
C fused rings, Figure 1).
As a matter of fact, these 4-thiaflavans showed effective in vitro pro-
tection against DNA oxidative damage caused by either hydroperoxides
or hydroxyl radicals obtained by Fenton chemistry.8 Consequently, they
possess what we call a “multidefence”9 antioxidant activity, combining
the abilities of the two more important families of natural antioxidants.
RESULTS AND DISCUSSION
Our original synthetic procedure is currently well established
in solution phase.7b For example using resorcinol (2) or 2,6-

Synthesis of Hydroxylated 4-Thiaflavans
1235
OR
OR
OH
B
RO
O
S
HO
O
C
S
OH
+
A
OR
OH
4-thiaflavans
OH
HO
B
HO
O
OH
A
C
O
OH
OH
α-tocopherol
(+/-)-catechin
FIGURE 1 Structural similarities of hydroxy-4-thiaflavans with (+/−)-
catechin and α-tocopherol.
dihydroxynaphthalene (3) as starting model phenols and 4-
methoxystyrene (4) as model dienophile, four steps, each entailing a
flash chromatography purification (see experimental section), are nec-
essary to isolate benzoxathiins 5 and 6 with overall yields ranging from
25% to 40% as depicted in Scheme 2.
HO
OH
HO
TBDMSO
HO
OH
3
2
a, b
a, b
TBDMSO
OH
OH
SNPht
c, d
SNPht
c, d
2b
3b
OMe
HO
O
O
S
S
5
6
OMe
Reagents and condition: a) TBDMSCl, dry DMF, Imidazole, Flash Chromatography; 2a, 3a
b) PhtNSCl (1), CHCl3, rt, 1.5h, Flash Chromatography; 2b, 3b
c) 4-methoxystyrene (4), CHCl3, 60 °C, 23h, Flash Chromatography; 2c, 3c
d) TBAF.3H2O, THF, 0 °C, 0.5h, Flash Chromatography; 5, 6
SCHEME 2 Solution phase synthesis of 4-thiaflavans 5 and 6.

1236
S. Menichetti and C. Viglianisi
This approach is, at least, competitive, regarding number of steps
and overall yields, with the other procedures available for the syn-
thesis of benzoxathiins10; nevertheless, we decided to study a further
improvement considering the possibility to apply it on solid phase. This
would allow an oversimplification of the whole process and, reasonably,
permit avoidance of some of the tedious and poor eco-friendly interme-
diate chromatographic purification procedures.
We have recently demonstrated that α-acylthiones, obtained from a
similar application of the chemistry of phthalimidesulfenyl chloride to
β-dicarbonyls, can be successfully accomplished from solid supported
β-ketoesters.11 Thus we decided to explore the possibility of linking
a phenol moiety on solid support to be used as the scaffold for the
generation of o-thioquinones and for the assembling of the 4-thiaflavan
skeleton on the resin.
Phenols are involved in several solid-phase organic reactions, and
they can be immobilized on resins through a variety of synthetic strate-
gies, including the mono-functionalization of symmetrical derivatives
such as resorcinol (2) or 2,6-dihydroxynaphthalene (3).12 Despite the
fact that silyl modified resins have been described in the literature,13
their use for either the protection or the linkage of the phenols to the
solid support was not feasible and practical enough for the required
improvement of the methodology depicted in Scheme 1. Thus we de-
cided to use easily available carboxylic pending Merrifield resins and
to introduce 2 and 3 through an ester link to give supported mono-
hydroxyesters 7 and 8, respectively (Scheme 3). Clearly the transfor-
mation of one of the O H groups into an O-C(O)R residue causes a
depletion of the electron-rich character of the phenolic ring, hence of
its ability to react with 1 in a SEAr.14 Nevertheless, the availability of
carboxylic modified resins, as well as simple methodologies for ester-
ification and hydrolysis, prompted us to evaluate this possibility. As
depicted in Scheme 3, the esterification step can be carried out either
via the formation of a solid supported acyl chloride15 or by activating
the carboxylic acid with DCC (paths a and a’ respectively).16 Working
on solid phase, it was possible to completely avoid the reaction of both
the hydroxy groups, i.e., one of the drawbacks of the solution phase
methodology (Scheme 2, step a). In both cases we verify the formation
of the required mono-hydroxyesters 7 and 8 by FTIR of the resin after
washing and drying (see the Experimental section). FTIR analysis was
used for problem-solving also to verify the occurrence of the SEAr of
supported phenols with 1 (i.e., the formation of phthalimides 7a and
8a) and of the [4+2] cycloaddition, giving rise to supported benzoxathi-
ins 7b and 8b. In fact, the introduction and the elimination of the

Synthesis of Hydroxylated 4-Thiaflavans
1237
phthaloyl group can be easily monitored by FTIR due to the charac-
teristic imidic C O stretching multiple bands. The actual formation of
4-thiaflavans on solid phase was demonstrated by saponification with
LiOH in THF that allowed the isolation of derivatives 5 and 6 in 46%
and 47% overall yield, respectively, as pure compounds without any
purification procedure as depicted in Scheme 3.
OH
OH
O
O
a
a'
O
O
OH
O
O
O
O
O
O
OH
OH
7
8
b
c
b'
c'
OH
SNPht
8a
7a
SNPht
O
O
O
O
O
S
O
S
OMe
O
O
O
O
O
O
S
S
8b
7b
d
d'
6 (47%)
OMe
5 (46%)
Reagents and condition: a) i) SOCl2, PhMe 60 °C 2h, ii) resorcinol (2), DMAP, Py, CH2Cl2, rt, 24; 7
a' ) 2,6-Dihydroxynaphthalene (3), DCC, DMAP, CH2Cl2, rt, 24h; 8
b, b' ) PhtNSCl (1), CHCl3, rt, 24h; 7a, 8a
c, c' ) 4-methoxystyrene (4), Et3N, CHCl3, 60 °C, 24h; 7b, 8b
d, d' ) LiOH, THF, rt, 3h; 5, 6: NO Flash Chromatography!
SCHEME 3 Solid phase synthesis of 4-thiaflavans 5 and 6.
The above result deserves some additional comment. We have in-
deed verified that the SEAr with the phthalimidesulfenyl chloride (1)
is an efficient process also on solid supported mono-hydroxyester. As
expected it requires longer reaction times (1.5 h vs. 24 h; see Schemes 2

1238
S. Menichetti and C. Viglianisi
O
O
a
NH2
N
H
O
OH
9
b, c
O
d
O
6 (65%)
N
H
O
O
9b
S
OMe
Reagents and condition: a) i) Succinic Anhydride, Py, rt, 24h;
ii) 2,6-Dihydroxynaphthalene (3), DCC, DMAP, DMF/CH2Cl2, rt, 24h; 9
b) PhtNSCl (1), CHCl3, rt, 24h; 9a
c) 4-methoxystyrene (4), Et3N, CHCl3, 60 °C, 24h; 9b
d) LiOH, THF, rt, 3h; 6: NO Flash Chromatography!
SCHEME 4 Improved solid phase synthesis of 4-thiaflavan 6.
and 3), but it occurs with the same regiospecificity observed in solution
phase.
On the other hand, the generation and trapping of o-thioquinones
works very well on solid phase under the same reaction conditions used
in solution phase, allowing the isolation of valuable 4-thiaflavans with-
out flash chromatography purification and with better overall yields.
This relevant result indicates that the sulfenylation and the cycload-
dition reactions occurred in an almost quantitative yield on the solid
supported phenols. In any other events the 4-thiaflavan cycloadducts
would have been contaminated with the by-products deriving from the
basic hydrolysis of residual solid supported phenols and o-hydroxy-N-
thiophthalimides.
Before verifying the applicability of this new procedure for the
preparation of a wide pool17 of hydroxy-4-thiaflavans, we reasoned
that, perhaps, using an appropriate linker to increase the distance
between the resin and the phenol could produce a further improve-
ment of the methodology. Indeed, by reacting a commercially available
aminomethylated polystyrene resin with succinic anhydride, we pre-
pared a solid support bearing a more sterically available carboxylic
acid.18 To our satisfaction, using this modified resin and following the
previously reported synthetic sequence, 4-thiaflavan 6 was isolated in
65% overall yield after a simple acidic work-up of the resin washing
solvents, without any chromatographic purification, since, as expected,

Synthesis of Hydroxylated 4-Thiaflavans
1239
the amidic bond revealed to be stable under the basic conditions used
for the releasing of the cycloadduct from the resin (Scheme 4).
CONCLUSION
Biologically valuable 4-thiaflavans can be efficiently obtained by hetero
Diels–Alder reaction of solid supported o-thioquinones. The whole pro-
cess optimized on solid phase gave, at least with the two model phenols
chosen, better overall yields and higher simplicity than the procedure
in solution. The applicability of this methodology for the preparation of
a pool17 of biologically active 4-thiaflavans is under study.
EXPERIMENTAL
General
1H and 13C NMR spectra were recorded on a Varian Mercury 200 spec-
trometer at 200 and 50 MHz, respectively, in CDCl3 using residual
CHCl3 at δH = 7.26 ppm and the central line of CDCl3 at δC = 77.0 ppm
as references. FTIR spectra were recorded on a Perkin-Elmer 1600.
Toluene, THF, CH3Cl, DCM, DMF, and TEA were dried following stan-
dard procedures. All commercial reagents were used without further
purification as obtained from freshly opened containers. Phthalim-
idesulfenyl chloride (1) was prepared as reported elsewhere.19
Solution Phase Synthesis7b
General Procedure for the Mono-silylation Reaction (Step a in
Scheme 2)
To a solution of phenol and IMI (1 eq.) in anhydrous DMF, a solution
of TBDMSCl (0.5 eq.) in anhydrous DMF was added dropwise. The
reaction mixture was stirred at room temperature under argon atmo-
sphere and monitored by TLC until the disappearance of the starting
phenol. The crude reaction mixture was diluted with petroleum ether,
and washed with saturated NH4Cl and water. The organic phase was
dried over anhydrous NaSO4 and evaporated to dryness. Purification of
the residue by flash chromatography on silica gel afforded the required
products.
3-(tert-Butyl-dimethyl-silyloxy)-phenol (2a)
The compound was obtained as colorless oil by flash chromatography
on silica gel with dichloromethane:methanol 50:1 as eluent, 61% yield.

1240
S. Menichetti and C. Viglianisi
1H NMR: δ = 0.20 (s, 6H), 0.99 (s, 9H), 5.46 (bs, 1H), 6.37–6.38 (m,
1H), 4.43–6.44 (m, 1H), 4.43–6.47 (m, 2H), 7.07 (t, J = 8.2 Hz, 1H). 13
NMR: δ = −4.6, 18.1, 25.6, 107.7, 108.7, 112.5, 129.9, 156.5, 156.7.
C
6-(tert-Butyl-dimethyl-silyloxy)-naphthalen-2-ol (3a)
The compound was obtained as a colorless oil by flash chromatogra-
phy on silica gel with dichloromethane:methanol 50:1 as eluent, 74%
1
yield. H NMR: δ = 0.25 (s, 6H), 1.03 (s, 9H), 7.02–7.16 (m, 4H), 7.52–
7.62 (m, 2H). 13C-NMR: δ = −4.3, 18.3, 27.8, 109.5, 115.0, 117.9, 122.7,
127.5, 128.4, 129.8, 130.1, 151.6, 151.7.
General Procedure for the Sulfenylation Reaction (Step b in
Scheme 2)
A solution of phthalimidesulfenyl chloride 1 (1 eq.) in dry chloroform
was added to a solution of the mono-silylated phenol in chloroform
kept at 0◦C. The reaction mixture was heated to room temperature and
stirred until complete disappearance of the starting product monitored
by TLC (1.5 h). The crude mixture was diluted with ethyl acetate, and
washed with saturated NaHCO3 and water. The organic phase was
dried over anhydrous NaSO4 and evaporated to dryness. Purification of
the residue by flash chromatography on silica gel afforded the required
product.
2-[4-(tert-Butyl-dimethyl-silyloxy)-2-hydroxy-
phenylsulfanyl]-isoindole-1,3-dione (2b)
The compound was isolated after work-up as a white solid not re-
1
quiring further purification, mp 180–183◦C, 96% yield. H NMR δ =
0.19 (s, 6H), 0.94 (s, 9H), 6.35 (dd, J = 8.4, 2.4 Hz, 1H), 6.47 (d, J =
2.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.75–7.92 (m, 4H), 8.30 (s, 1H).
13C-NMR: δ = −4.5, 18.1, 25.4, 107.7, 110.8, 113.2, 124.1, 131.8, 134.7,
139.4, 160.4, 161.6, 168.5.
2-[6-(tert-Butyl-dimethyl-silyloxy)-2-hydroxy-
naphthalen-1-sulfanyl]-isoindole-1,3-dione (3b)
The compound was obtained as a white solid by flash chromatogra-
phy on silica gel using dichloromethane as eluent, mp 182–186◦C, 44%
1
yield. H NMR: δ = 0.23 (s, 6H), 1.01 (s, 9H), 7.10 (d, 1H,J = 2.2 Hz),
7.21 (d, 1H,J = 8.8 Hz), 7.24–7.32 (m, 1H), 7.68–7.79 (m, 3H), 7.83–7.92
(m, 2H), 9.04 (d, 1H,J = 8.8 Hz), 9.06 (s, 1H).

Synthesis of Hydroxylated 4-Thiaflavans
1241
General Procedure for the Cycloaddition Reaction (Step c in
Scheme 2)
To a solution of the o-hydroxy-N-thiophthalimide derivatives in dry
CH3Cl (roughly 0.1 M), p-methoxystyrene (4) (1.5 eq.) and Et3N (1 eq.)
were added in sequence, and the reaction mixture was heated at 60◦C
and monitored, either by 1H NMR or TLC, until the disappearance
of the starting thiophthalimide (23 h). Evaporation of the solvent and
flash chromatography on silica gel allowed the isolation of the silylated
cycloadducts.
7-(tert-Butyl-dimethyl-silanyloxy)-2,3-dihydro-2-
(4-methoxy-phenyl)-1,4-benzoxathiin (2c)
The compound was obtained as a colorless oil by flash chromatogra-
phy on silica gel using petroleum ether:dichloromethane 3:1 as eluent,
1
63% yield. H NMR: δ = 0.20 (s, 6H), 0.99 (s, 9H), 3.02 (dd, J = 13.2,
1.8 Hz, 1H), 3.25 (dd, J = 13.2, 9.6 Hz, 1H), 3.84 (s, 3H), 5.15 (dd, J =
9.6, 1.8 Hz, 1H), 6.44–6.49 (m, 2H), 6.93–6.98 (m, 3H), 7.34–7.36 (m,
2H). 13C NMR: δ = −4.5, 18.1, 25.6, 31.6, 55.3, 76.6, 108.7, 110.4, 114.0,
114.3, 127.3, 127.5, 132.5, 152.9, 153.8, 159.7.
8-(tert-Butyl-dimethyl-silyloxy)-2,3-dihydro-3-
(4-methoxy-phenyl)-naphth[2,1-b][1,4]-oxathiin (3c)
The compound was obtained as a white solid by flash chromatogra-
phy on silica gel using petroleum ether:ethyl acetate 10:1 as eluent,
mp 113–115◦C, 75% yield. 1H NMR: δ = 0.25 (s, 6H), 1.03 (s, 9H), 3.21
(dd, J = 14.0, 2.6 Hz, 1H), 3.64 (dd, J = 14.0, 9.2 Hz, 1H), 3.84 (s, 3H),
5.23 (dd, J = 9.2, 2.6 Hz, 1H), 6.94–6.98 (m, 3H), 7.06–7.15 (m, 2H),
7.37–7.43 (m, 3H), 7.79 (d, J = 8.6 Hz, 1H). 13C NMR (CDCl3, 75 MHz):
δ = –4.4, 18.2, 25.7, 31.5, 55.2, 76.1, 110.3, 114.1, 115.8, 120.3, 122.0,
123.9, 124.5, 127.3, 130.5, 132.5, 148.7, 152.2, 159.7.
General Procedure for the Desilylation Reaction (Step d in
Scheme 2)
To a solution of the silylated cycloadducts in dry THF (0.04 M) kept at
0◦C, a solution of TBAF.3H2O in THF (1eq.) was added, and the reac-
tion mixture monitored by TLC until the disappearance of the reagents
(0.5 h). The crude mixture was diluted with ethyl acetate, and 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
4-thiaflavans 5 and 6.

1242
S. Menichetti and C. Viglianisi
2,3-Dihydro-2-(4-metoxy-phenyl)-1,4-benzoxathiin-7-ol (5)
The compound was obtained as a colorless glassy solid by flash chro-
matography on silica gel with dichloromethane:ethyl acetate 20:1 as
1
eluent, 96% yield. H NMR: δ = 3.06–3.23 (m, 2H), 3.79 (s, 3H), 5.13
(dd, J = 9.0, 2.4 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), 6.46 (dd, J = 8.5, 2.5
Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.93–6.97 (m, 3H), 7.36–7.39 (m, 2H),
8.32 (br s, 1H). 13C NMR: δ = 31.8, 55.5, 77.5, 106.2, 107.5, 110.5, 114.6,
128.3, 128.5, 133.5, 154.0, 156.5, 160.5. Anal: Calcd for C15H14O3S: C,
65.67, H, 5.14. Found C, 65.81; H, 5.05%.
2,3-Dihydro-3-(4-metoxy-phenyl)-naphth[2,1-b][1,4]
oxathiin-8-ol (6)
The compound was obtained as a white solid by flash chromatogra-
phy on silica gel using dichloromethane:ethyl acetate 20:1 as eluent,
mp 160–163◦C, 32% yield.1H NMR: δ = 3.34–3.35 (m, 2H), 3.82 (s, 3H),
5.22 (dd, J = 6.8, 4.4 Hz, 1H), 6.97–7.03 (m, 3H), 7.15–7.18 (m, 2H),
7.40–7.48 (m, 3H), 7.71–7.73 (m, 1H), 8.53 (br s, 1H). 13C NMR: δ =
31.6, 55.6, 76.8, 111.0, 111.3, 114.7, 119.1, 121.1, 124.6, 124.9, 126.4,
128.4, 131.8, 133.6, 149.0, 155.0, 160.7. Anal: Calcd for C19H16O3S: C,
70.35; H, 4.97. Found C, 70.55; H, 5.12%.
Solid Phase Synthesis
Carboxy polystyrene resin was purchased from Novabiochem as a 1%
cross-linked divinylbenzene-styrene copolymer of 100–200 mesh with
a loading of 1.4 mmol/g. Aminomethylated polystyrene resin was pur-
chased from Novabiochem as a copolymer of 100–200 mesh with a
loading of 1.2 mmol/g. Solid phase reactions were carried out in se-
curely sealed vials and the resin suspensions transferred by plastic
pipettes. Solid phase work-up was carried out by means of the plas-
tic syringe technique. Flat-bottom PE syringes were equipped with
sintered Teflon filters, Teflon tubing, and valves, which allow suc-
tion to be applied to the syringe from below. The resins were washed
with the solvent used for the reaction and sequentially with DCM,
MeOH, diethyl ether, and again DCM, and the shrunken beads were
dried under vacuum over KOH before further transformations and
analyses.
The purity of final cycloadducts 5 and 6 was verified by comparison
with an authentic sample obtained by solution phase synthesis.

Synthesis of Hydroxylated 4-Thiaflavans
1243
2,3-Dihydro-2-(4-metoxy-phenyl)-1,4-benzoxathiin-7-ol (5)
(Step a in Scheme 3)
i) Commercial carboxy polystyrene resin (500 mg, loading 1.4 mmol/g,
0.7 mmol) was swelled in dry toluene (3 mL) for 30 min, then SOCl2
(300 µL, 3.5 mmol) was added, and the mixture was heated at 60◦C
for 2 h to afford the solid supported acyl chloride. IR (KBr): ν = 1768
+ 1734 (C O stretch), 870 (C-Cl stretch) cm−1. ii) The acyl chloride
resin (0.7 mmol) was swelled in dry CH2Cl2 (10 mL). After 30 min
at room temperature resorcinol (231 mg, 2.1 mmol), DMAP (15 mg,
0.12 mmol) and Py (113 µL, 1.4 mmol) were added in sequence and
the mixture swelled for 24 h at room temperature to afford the solid
supported mono-hydroxyester 7. IR (KBr): ν = 3428 (OH stretch),1734
(C O stretch) cm−1
.
Step b in Scheme 3
The phenol resin 7 (0.7 mmol) was swelled in CHCl3 (6 mL). After 30
min at room temperature, PhtNSCl 1 (450 mg, 2.1 mmol) was added
and the mixture swelled for 24 h at room temperature to afford the
solid supported o-hydroxy-N-thiophthalimide 7a. IR (KBr): ν = 3373
(OH stretch), 1779 + 1734 + 1701 (PhtN, C O stretch) cm−1
.
Step c in Scheme 3
The o-hydroxythiophthalimide resin 7a (0.7 mmol) was swelled in
CHCl3 (4 mL). After 30 min at room temperature, 4-methoxystyrene
(4) (281 mg, 2.1 mmol) and TEA (212 mg, 2.1 mmol) were added in se-
quence and the mixture was heating at 60◦C for 24 h to afford the solid
supported 4-thiaflavan 7b. IR (KBr): ν = 1737 (C O stretch) cm−1
.
Step d in Scheme 3
The 4-thiaflavan functionalized resin 7b (0.7 mmol) was swelled in
THF (5 mL). After 30 min at room temperature, a solution of LiOH
(51 mg, 2.1 mmol) in H2O (2 mL) was added, and the mixture swelled
for 3 h at room temperature. The resin was filtered and washed with
CH2Cl2 (3 × 15 mL), the collected organic phase washed with saturated
NH4Cl (2 × 30 mL), H2O (50 mL) and dried over Na2SO4. Evaporation
of the solvent under reduced pressure gave the cycloadduct 5 as pure
compound, overall yield 46%.

1244
S. Menichetti and C. Viglianisi
2,3-Dihydro-3-(4-metoxy-phenyl)naphth[2,1-b][1,4]oxathiin-8-
ol (6)
Commercially available carboxy polystyrene resin (400 mg, loading
1.4 mmol/g, 0.56 mmol) was swelled in dry DCM (3 mL). After 30 min
at room temperature DCC (346 mg, 1.68 mmol), DMAP (205 mg, 1.68
mmol) and 2,6-dihydroxynaphthalene (269 mg, 1.68 mmol) were added
in sequence and the mixture swelled for 24 h at room temperature to
afford the solid supported mono-hydroxyester 8. IR (KBr): ν = 3443
(OH stretch), 1737 (C O stretch) cm−1
.
Steps bꢀ, cꢀ) and dꢀ) in Scheme 3
Solid supported o-hydroxy-N-thiophthalimide 8a. IR (KBr): ν = 3444
(OH stretch), 1781 + 1736 + 1701 (PhtN, C O stretch) cm−1. Solid
supported 4-thiaflavan 8b. IR (KBr): ν = 1736 (C O stretch) cm−1. After
washing and work-up, 4-thiaflavan 6 was isolated as pure compound in
47% overall yield.
Optimized Synthesis of 2,3-Dihydro-3-(4-
metoxy-phenyl)naphth[2,1-b][1,4]oxathiin-8-ol (6)
Step a in Scheme 4
i) Commercially available aminomethylated polystyrene resin (3.0
g, loading 1.2 mmol/g, 3.6 mmol) was pre-swelled in dry Py (35 mL).
A solution of succinic anhydride (1.08 g, 10.8 mmol) in dry Py (12
mL) was added to this suspension, and the mixture was swelled
for 24 h at room temperature. The resin was filtered, washed with
Py, DMF, DCM, and EtOH (3 × 20 mL each), and then dried un-
der reduced pressure over KOH pellets. This procedure was repeated
again to afford the desired succinic acid mono-amide pending resin.
IR (KBr): ν = 3500–2500 (C(O)O-H + C(O)N-H stretch), 1718 + 1654
(C O stretch) cm−1. ii) The succinic acid resin (926 mg, loading 1.08
mmol/g, 1 mmol) was swelled in dry DMF:DCM (4:1, 15 mL). Af-
ter 1 h at room temperature, DCC (620 mg, 3 mmol), DMAP (430
mg, 3.5 mmol), and 2,6-dihydroxynaphthalene (3) (480 mg, 3 mmol)
were added in sequence and the mixture swelled for 24 h at room
temperature. After classical washing, the mono-hydroxyester resin 9
was dried in vacuum. IR (KBr): ν = 3313 (O-H stretch), 1757 + 1654
(C O stretch) cm−1
.

Synthesis of Hydroxylated 4-Thiaflavans
1245
Step b in Scheme 4
The phenol resin 9 (1 mmol) was swelled in CHCl3 (10 mL). After 1 h,
PhtNSCl 1 (639 mg, 3 mmol) was added, and the mixture swelled for
24 h at room temperature to afford the solid supported o-hydroxy-N-
thiophthalimide 9a. IR (KBr): ν = 3400 (OH stretch), 1781 + 1737 +
1703 (PhtN, C O stretch) cm−1
.
Step c in Scheme 4
The o-hydroxy-N-thiophthalimide resin 9a (1 mmol) was swelled in
CHCl3 (4 mL). After 30 min at room temperature, styrene 4 (402 mg,
3 mmol) and TEA (301 mg, 3 mmol) were added in sequence, and the
mixture was heated at 60◦C for 24 h to afford the solid supported 4-
thiaflavan 9b. IR (KBr): ν = 1731 + 1675 (C O stretch) cm−1
.
Step d in Scheme 4
The 4-thiaflavan functionalized resin 9b (1 mmol) was swelled in
THF (5 mL). After 30 min at room temperature, a solution of LiOH
(72 mg, 3 mmol) in H2O (2 mL) was added, and the mixture was swelled
for 3 h at room temperature. The resin was filtered and washed with
CH2Cl2 (3 × 15 mL), the collected organic phases washed with satu-
rated NH4Cl (2 × 30 mL) and H2O (50 mL), and dried over Na2SO4.
Evaporation of the solvent under reduced pressure gave the cycloadduct
6 as pure compound in 65% overall yield.
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