Helical-Shaped Bis-1,4-benzoxathiines through an Inverse-Electron-Demand Hetero-Diels–Alder Reaction of ortho-Thioquinones

Article abstract of DOI:10.1002/ejoc.201600850

The reaction of transient ortho-thioquinones, which act as electron-poor dienes, with properly designed bis-dienophiles leads to the formation of helical-shaped bis-benzoxathiine cycloadducts with complete control of the regiochemistry and the relative stereochemistry. Bis-benzoxathiines were the result of two consecutive inverse-electron-demand cycloaddition processes with stereospecific approach of the diene anti to the bis-dienophile. The helical-shaped structure of the final products was demonstrated spectroscopically and confirmed by single-crystal X-ray analysis.

Full text of DOI:10.1002/ejoc.201600850

A Journal of
Accepted Article
Title: Helical shaped bis-1,4-benzoxathiines through the inverse electron demand
hetero Diels-Alder reaction of ortho-thioquinones
Authors: Stefano Menichetti; Caterina Viglianisi; Sara Piantini; Lorenzo Tofani
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600850
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European Journal of Organic Chemistry
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Helical shaped bis-1,4-benzoxathiines through the inverse
electron demand hetero Diels-Alder reaction of ortho-
thioquinones
Caterina Viglianisi,* Stefano Menichetti, Sara Piantini, Lorenzo Tofani*
Abstract: The reaction of transient ortho-thioquinones, acting as
electron-poor dienes, with proper designed bis-dienophiles leads to
the formation of helical shaped bis-benzoxathiine cycloadducts with
complete control of the regiochemistry and the relative
stereochemistry. Bis-benzoxathiines were the result of two
consecutive inverse electron demand cycloaddition processes with
the diene stereospecifically approaching anti the bis-dienophile. The
helical shaped structure of final products was demonstrated
spectroscopically and confirmed by single crystal X-ray analysis.
Diels-Alder reactions with several electron-rich dienophiles
affording 1,4-benzo[b]oxathiine cycloadducts like 3 (Scheme 1).
Due to the structural features of these benzofused heterocycles,
and the simplicity of the procedure, the chemistry reported in
Scheme 1 found application for the synthesis of biologically
active compounds including very potent chain breaking multi-
8
defence antioxidants.
Following
our
recent
interest
in
sulfur
containing
9
heterohelicenes, in this paper we report the preparation of
helical shaped benzoxathiine cycloadducts using the chemistry
reported in Scheme 1.
Introduction
Results and Discussion
Helicenes and heterohelicenes are challenging chiral structures
that continuously stimulate new interest and find new
Diels-Alder reactions are among the procedure of choice for the
1
applications. From just a chemical curiosity, their inherent
10
11
preparation of helicenes and heterohelicenes. Due to the
structural features of the [4+2] cycloaddition of ortho-
thioquinones 1, we envisaged to build-up helical shaped
cycloadducts through two consecutive [4+2] processes with a
proper electron-rich bis-dienophile possessing, for example, the
2
chirality, is now commonly used in asymmetric synthesis,
3
4
material science and medicinal chemistry. During the last 20
years we developed and applied the chemistry of ortho-
thioquinones of general structure 1 (Scheme 1). These reagents
can be generated in solution under mild conditions from ortho-
hydroxy-N-thiophthalimides 2 using a weak base (typically a
tertiary amine) to promote the 1,4-elimination at sulfur of the
1,2,7,8-tetrahydrophenanthrene skeleton.
Such structural requirement was satisfied preparing 5,6-
dimethyl- and 5,6-dimethoxy-3,8-dihydropyrano[3,2-f]chromene
5
phthalimide anion. Compounds 2, in turn, are easily prepared
4
a and 4b, which were synthesized as described in Scheme 2.
Thus, commercially available, 2,3-dimethylhydroquinone, and
,3-dimethoxyhydroquinone, prepared by oxidation of 2,3-
dimethoxyphenol (see Experimental section), were classically
by regioselective ortho-sulfenylation of electron-rich phenols with
the phthalimidesulfenyl chloride, PhtNSCl, Pht
= phthaloyl
2
5
,6
(
Scheme 1).
1
2
propargylated to give ethers 5a and 5b which were cyclized to
the required chromenes 4a and 4b using a catalytic amounts of
Au(I) complex Ph
3
PAuNTf
procedure yet not applied to bis-propargyl derivatives (Scheme
).
2
, exploiting a recently described
1
3
2
Scheme 1. General procedure for the generation of ortho-thioquinones 1 and
formation of benzoxathiine cycloadducts 3.
Scheme 2. Synthesis of 3,8-dihydropyrano[3,2-f]chromenes 4a and 4b.
7
Thioquinones 1 are sulfur electrophiles, and can act as
electron-poor dienes in [4+2] inverse electron demand hetero
Using 2,3-disubstituted hydroquinones as starting materials we
avoided the ring closure of regioisomeric chromenes, building-up
a bis-dienophile with two electron-rich double bonds in the right
position for the possible construction of a helical shaped bis-
cycloadduct. We studied the reaction of 4a and 4b with ortho-
thioquinones 1a-d (see Scheme 1) deriving from the
corresponding ortho-hydroxy-N-thiophthalimides 2a-d reported
in Figure 1.
C. Viglianisi, S. Menichetti, S. Piantini, L. Tofani
Department of Chemistry “U. Schiff” - University of Florence.
Via della Lastruccia, 3-13, 50019 Sesto Fiorentino – (FI) – Italy
E-mail: caterina.viglianisi@unifi.it; URL: macromad.jimdo.com
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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bis-adduct was very similar and we isolated helical shaped bis-
benzoxathiine 7aa in 13% yield, since several fractions eluted
with tiny amount of mono-adduct 6aa. Actually, this trend was
quite general and helical shaped bis-adducts 7 were isolated as
single regio- and stereoisomers albeit in modest yields (Table 1).
Disappointingly, we were unable to increase the yield of 7, or the
bis/mono ratio, neither modifying the reaction conditions
(
temperature, solvent, concentration, see Table SI-1 in the
Supporting Information) nor carrying out the reaction in two
steps by reacting 1 with fractions of cycloadducts enriched in
1
4
Figure 1. o-Hydroxy-N-thiophthalimides 2a-d used in this study.
mono-adducts 6.
As noted, the reactions of 1 with 4 and, above all, with 6 were
very slow even at high temperature. This implies a certain
decomposition of ortho-thioquinones 1 and also of chromenes 4
as demonstrated in an independent experiment settled out to
verify their thermal stability. The yields of 7 are, however, the
result of three consecutive reactions occurring in solution: i) the
generation of ortho-thioquinones 1 from 2, ii) the first [4+2]
cycloaddition of 1 with 4, iii) the second cycloaddition of 1 with 6.
Derivatives 2a-d are the result of the ortho-regiospecific
electrophilic aromatic substitution of PhtNSCl with 3-
methoxyphenol,
2,4-dimethylphenol,
sesamol
and
3-
acetoxyphenol respectively. Noteworthy, for this chemistry,
ortho-hydroxy-N-thiophthalimides 2a-d can be used without any
purification for the generation of the corresponding ortho-
a
thioquinones 1 obtained with 1 equiv of Et
0 °C. We started studying the reaction of 2a (2 equiv, i.e. 1
equiv for each double bond of the bis-dienophile) and 4a carried
out at 60 °C in CDCl in a NMR tube. We in fact verified the
3
N in dry chloroform at
Table 1. Synthesis of helical shaped benzoxathiines 7.
6
b
c
Entry
Diene
1a
1b
1c
1d
Dienophile 7/6 (yield)
bis-Adduct 7
7aa (13%)
7ba (14%)
7ca (14%)
7da (16%)
7ab (22%)
7bb (25%)
1
2
3
4
5
6
a
4a
4a
4a
4a
4b
4b
5/1 (23%)
3/1 (21%)
6/1 (24%)
2/1 (25%)
3/1 (49%)
2/1 (48%)
3
formation of mono-cycloadduct 6aa bearing a benzoxathiine ring
and a chromene unit on the same skeleton, followed by the slow
comparison of a set of signals indicating the formation of bis-
adduct 7aa (Scheme 3).
1a
1b
Reactions carried out in chloroform at 60 °C using
4 equiv of the
corresponding N-thiophthalimide 2 (2 equiv for each dienophilic double bond)
b
3
added in small portions and 2 equiv of Et N. bis-Adduct 7/mono-adduct 6 ratio
1
measured by H NMR on the crude reaction mixtures. Yields refer to the sum
c
of mono- and bis-cyclodducts. Isolated yield of pure bis-cycloadducts 7.
In more details, the cycloaddition yield increases using bis-
dienophile 4b (see entries 5-6 vs entries 1-4). Reasonably, in
bis-dienophile 4b the para-methoxy groups ensure a higher
reactivity of dienophilic double bonds increasing the yields of
cycloadducts. However, the steric hindrance on the exa-
substituted phenyl ring, prevents the planarity of the Ar-O-CH
3
residues, limiting the conjugation and the ED effect of the para
methoxy groups in 4b is lower than it could be expected.
Spectroscopic data of derivatives 7 confirmed that both the
cycloadditions occurred with complete control of the
regiochemistry. In fact, the oxygen of ortho-thioquinones 1 links
to the benzylic carbon of 4 that is the more electron-poor in the
dienophilic double bond. In fact, chemical shifts of the former
olefinic protons, in the cycloadducts range from 5.16 to 5.35
ppm for the oxygen substituted benzylic protons, and from 3.66
to 3.77 ppm for the sulfur substituted ones. Additionally, both the
Scheme 3. Synthesis of helical shaped benzoxathiine 7aa.
The first and, above all, the second cycloaddition demonstrated
to be very slow and the signals of N-thiophthalimide 2a
disappeared when mono-derivative 6aa was still the more
abundant cycloaddition product. Thus, we operated using an
excess of 2a (4 equiv, i.e. 2 equiv for each double bond of the
bis-dienophile) added in small portions during 12h. The reaction
cycloadditions occurred with formation of
a
cis-fused
cycloadduct due to the concerted [4+2] mechanism operative in
the closure of the benzoxathiine ring. In this case, is the value of
was then kept at 60 °C until the complete disappearance of 2a
3
1
J coupling constants among the above mentioned protons,
(
roughly 24h). After a trivial work-up, the H NMR analysis of the
ranging from 2.0 to 2.4 Hz, that clear indicated an axial-
crude reaction mixture allowed to point out bis-adduct 7aa and
mono-adduct 6aa in a 5/1 ratio (Table 1).
The inclusive yield of cycloadducts (7aa plus 6aa) was 23%
1
13
equatorial relationship (i.e. a cis-fusion). H and C spectra of
bis-cycloadducts 7 stated the formation of a single stereoisomer
showing a half of the expected signals. This can be possible if
(
Table 1), however the chromatographic behaviour of mono- and
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European Journal of Organic Chemistry
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the two dienic thiones 1 approached the dienophile (4 and 6) Conclusions
from the same side (syn) affording a meso derivative 7
containing a plane of symmetry, or through an anti approach
with the two thiones attacking 4 and 6 from opposite sides
affording a racemic C symmetric helical shaped derivative. As
2
In conclusion, we have described the synthesis of several new
helical-shaped bis-benzoxathiines prepared by the cycloaddition
of ortho-thioquinones with proper designed electron-rich bis-
dienophiles. Despite the modest final yields (yet roughly an
average yield ranging from 63% to 52% for each of the three
consecutive reactions), this one-pot procedure represents a
useful tools for the regio- and stereocontrolled preparation of a
new family of helical shaped benzofused heterocycles.
Quantitative access to enantiopure derivatives and applications
are in due course.
reported in Scheme 3, taking in consideration steric hindrance
and previous results obtained in bis-cycloadditions involving
6b,15
thiones like 1,
we indicated the anti approach as the actual
mode of formation of bis-cycloadducts 7. Eventually, this
hypothesis was confirmed by single crystal X-Ray analysis
obtained for derivatives 7ca and 7ab. As shown in Figure 2 the
single diastereoisomers obtained from these reactions are C
2
symmetric derivatives with an evident helical shaped structure.
Scheme 4. Synthesis of phenolic bis-adduct 8.
Experimental Section
Commercially available reagents and catalysts were purchased
from Aldrich Chemical Company, Alfa Aesar and Acros Organics.
All of the materials were used without further purification. Dry
solvents and anhydrous triethylamine were obtained by standard
8
procedure.
Phthalimidesulfenyl
chloride,
2-Hydroxy-N-
6
17
thiophthalymide 2a, and 3-acetoxyphenol were prepared as
reported elsewhere.
1
Melting points were measured with Melting Point Buchi 510. H
1
3
and C NMR spectra were recorded with Varian Gemini 200
and 50 MHz respectively or Varian Mercury 400 and 100 MHz
Figure 2. Side and front view of helical shaped bis-benzoxathiines 7ca (top)
and 7ab (bottom). Analysis was carried out on racemic derivatives,
P
configuration showed is casual (ellipsoid at 50% probability, H atoms are
omitted for clarity).
respectively. The NMR spectra were obtained in CDCl
3
solutions
using the reference at 7.26 ppm of the residue of chloroform in
1
13
H NMR spectrum and at 77.0 ppm in the C NMR. FTIR
spectra were recorded with FT Infrared Spectrometer 1600
Perkin-Elmer in CDCl solutions or in KBr pellets. GC-MS
spectra were measured with a QMD 1000 Carlo Erba. ESI-MS
spectra were measured with JEOL MStation JMS700.
3
As a matter of fact, racemic helical shaped bis-adduct 7bb was
analytically resolved by HPLC using a column packed with an
amylose-based stationary phase. The optimal enantiomers
separation occurred using hexane/2-propanol 90/10 v/v as
mobile phase, delivered at a flow rate of 1.00 mL/min. Under the
same elution conditions helical bis-adduct 7ab elutes as a single
large peak (see the Supporting Information for chromatographic
details).
a
Elemental analysis was measured with Elemental Analyzer 2400
series II Perkin-Elmer. X-Ray Data Collection: Crystals were
mounted on a glass fiber then they were analyzed using a
Goniometer Oxford Diffraction KM4 Xcalibur2 with a graphite-
monochromated Cu/Kα radiation (40mA/-40KV). The measures
were carried out at 100°K. Structures refinement: The integrated
intensities, measured using the ω scan mode, were corrected for
To further demonstrate the potential utility of the procedure
depicted in Scheme 3 for the preparation of helical-shaped
molecules, bis-ester 7da was quantitatively hydrolyzed to bis-
phenolic derivative 8 (Scheme 4) bearing two phenolic OH
groups in the proper position for its potential use as chiral
1
8
Lorentz and polarization effects. The substantial redundancy in
data allows empirical absorption corrections to be applied using
multiple measurements of symmetry-equivalent reflections.
19
Structures were solved by direct methods of SIR2004 and
2
refined using the full-matrix least squares on F provided by
1
6
20
ligand.
SHELXL-2014/6 (Sheldrick, 2014). The non-hydrogen atoms
were refined anisotropically. In both cases hydrogen atoms were
assigned in calculated positions and all of them were refined as
isotropic. Copies of the data can be obtained, free of charge,
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European Journal of Organic Chemistry
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from CCDC, 12 Union Road, Cambridge, CB2 1EZ UK (e-mail:
deposit@ccdc.cam.ac.uk; internet://www.ccdc.cam.ac.uk) with
the deposition numbers reported below for each compound.
quantity was purified by silica gel column chromatography
(eluent CH
2
Cl
2
:AcOEt = 50:1) to give 2d as a white solid, mp
158-160°C. H NMR (200 MHz, CDCl ) δ 2.27 (s, 3H), 6.62 (dd,
J = 8.4, 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 7.77 – 7.84 (m,
1
3
13
2
(
H), 7.88 (s, 1H), 7.89 – 7.93 (m, 2H), 8.45 (bs, 1H). C NMR
50 MHz, CDCl ) δ 21.0 (1C), 110.3 (1C), 114.2 (1C), 115.9 (1C),
24.2 (2C), 131.9 (2C), 134.9 (2C), 139.2 (1C), 155.7 (1C),
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-
3
1
1
1
-1
60.2 (1C), 168.3 (2C), 168.5 (1C). FT-IR (CDCl
734, 1709, 1282, 1207. MS (ESI) m/z Calcd for C16
3
, cm ) ν 3379,
400 mesh, was used for column chromatography.
5
H11NO S
-
[
M-H] : 328.03; found 328.08. Elemental Analysis Calcd for
S: C 58.35, H 3.37, N 4.25; found C 58.29, H 3.41, N,
16 5
C H11NO
4.40.
General procedure for the synthesis of phthalimidesulfenyl
derivatives 2b-d
Synthesis of 2,3-Dimethoxybenzene-1,4-diol.
To
a solution of the appropriate phenol (0.80 mmol) in
To a solution of 2,3-dimethoxyphenol (304 mg, 1.97 mmol) in
toluene (25 mL), 5% sodium acetate aq. solution (25 mL) and
Fremy’s salt (2147 mg, 8.00 mmol) were added. The reaction
mixture was left under magnetic stirring at room temperature for
anhydrous chloroform (1 mL) Phthalimidesulfenyl chloride (0.88
mmol), dissolved in the minimum volume of anhydrous
chloroform, was added dropwise. The solution was left under
magnetic stirring at room temperature until complete
consumption of the starting material as monitored by TLC. The
2
4h, then it was extracted with diethyl ether and collected
organic phases were washed with saturated solution of NaHCO
The organic layer was dried over Na SO and concentrated in
vacuum, yielding pure 2,3-Dimethoxy-[1,4]benzoquinone. To a
solution of the quinone (202 mg, 1.20 mmol) in MeOH-H O (12
mL, 5:1) at 0 °C was added NaBH (54 mg, 1.43 mmol). The
mixture was stirred at 0 °C for 5 min before being diluted with
O (5 mL) and slowly acidified with 2M HCl. The mixture was
extracted with AcOEt (3x20 mL) and the combined organic
phases dried over anhydrous Na SO before the solvent was
3
.
mixture was then diluted with CH
0% aq. solution of NaHCO (3x40 mL) and H
organic layer was dried over anhydrous Na
2
Cl
2
(80 mL) and washed with a
O (3x40 mL). The
SO and
2
4
1
3
2
2
4
2
concentrated in vacuum. The crude was used in the next step
without further purification for the generation of the
corresponding ortho-thioquinones 1.
4
H
2
2-(2-Hydroxy-3,5-dimethyl-phenylsulfanyl)-isoindole-1,3-dione
2
4
(
2b). The reaction carried out following the general procedure
removed in vacuum to give 2,3-Dimethoxybenzene-1,4-diol as a
using 98 mg of 2,4-dimethylphenol. After 2h at room
temperature and work-up the crude was used in the next step
without further purification and just a little quantity was purified
brown oil that didn’t require any further purification (204 mg, 1.20
1
mmol, 61%). H NMR (200 MHz, CDCl
2
(
1
3
) δ 3.92 (s, 6H), 5.30 (bs,
) δ 60.8 (2C), 109.8
13
H), 6.60 (s, 2H). C NMR (50 MHz, CDCl
2C), 139.6 (2C), 142.6 (2C). IR (CDCl , cm ) ν 3542, 2945,
622, 1493. MS (EI) m/z (rel. int. %): 170 (M , 100), 155 (7).
Elemental Analysis Calcd for C : C 56.47, H 5.92; found C
6.61, H 5.85.
3
by silica gel column chromatography (eluent CH
2
Cl
2
) to give 2b
) δ
.20 (s, 3H), 2.22 (s, 3H), 7.03-7.04 (m, 1H), 7.48-7.49 (m, 1H),
-1
•+
1
3
as a white solid, mp 188-190 °C. H NMR (400 MHz, CDCl
2
7
3
8 10 4
H O
13
.74 - 7.76 (m, 2H), 7.88 - 7.90 (m, 2H), 8.19 (s, 1H). C NMR
) δ 16.4 (1C), 20.0 (1C), 117.3 (1C), 124.1 (2C),
26.0 (1C), 129.2 (1C), 131.9 (2C), 134.7 (2C), 135.5 (1C),
36.7 (1C), 154.9 (1C), 168.5 (2C). FT-IR (CDCl
925, 1731, 1282. MS (EI) m/z (rel. int. %): 299 (M , 13), 124
S: C
5
(
100 MHz, CDCl
3
1
1
2
-
1
General procedure for the synthesis of propargyl
derivatives 5a-b.
3
, cm ) ν 3404,
•+
(
100), 91 (43). Elemental Analysis Calcd for C16
H13NO
3
2 3
Propargyl bromide (4.07 mmol) and anhydrous K CO (6.57
mmol) were added to a solution of the appropriate 1,4-
hydroquinone (1.21 mmol) in anhydrous acetone (2.5 mL). The
reaction mixture was left under magnetic stirring at reflux for 24h,
then it was cooled to room temperature. The suspension was
64.20, H 4.38, N 4.68; found C 64.07, H 4.51, N 4.73.
2-(6-Hydroxybenzo[1,3]dioxol-5-ylsulfanyl)-isoindole-1,3-dione
(
2c). The reaction carried out following the general procedure
using 110 mg of 3,4-(Methylenedioxy)phenol. After 0.5h at room
temperature and work-up the crude was used in the next step
without further purification and just a little quantity was purified
then diluted with water (100 mL) and extracted with CH
2
Cl
2
(
3x70 mL). Collected organic phases were washed with a
saturated solution of NH
organic layer was dried over anhydrous Na
4
Cl (3x80 mL) and brine (3x80 mL). The
SO and
suspending in CHCl
3
to give 2c as a yellow solid, m.p. 185°C
dec.). H NMR (200 MHz, CDCl ) δ 5.91 (s, 2H), 6.52 (s, 1H),
.23 (s, 1H), 7.44 – 7.87 (m, 2H), 7.88 – 7.93 (m, 2H), 8.21 (bs,
1
2
4
(
7
1
3
concentrated in vacuum. The crude was purified by silica gel
column chromatography to yield the desired propargyl derivative.
13
3
H). C NMR (50 MHz, CDCl ) δ 98.2 (1C), 101.8 (1C), 108.7
(
1C), 115.4 (1C), 124.2 (2C), 131.9 (2C), 134.8 (2C), 141.0 (1C),
-1
2
,3-Dimethyl-1,4-bis-prop-2-ynyloxybenzene (5a). The reaction
1
1
1
5
53.1 (1C), 156.3 (1C), 168.4 (2C). FT-IR (CDCl , cm ) ν 3374,
3
•+
carried out following the general procedure using 167 mg of 2,3-
dimethylhydroquinone. After 24h at reflux and work-up the crude
was purified by silica gel column chromatography (eluent
petroleum ether:AcOEt = 10:1) to give 5a as a yellow solid (122
mg, 0.57 mmol, 47%), mp 50-52 °C. H NMR (200 MHz, CDCl
729, 1473, 1281. MS (EI) m/z (re. int. %): 315 (M , 1), 169 (6),
47 (81), 103 (100). Elemental Analysis Calcd for C15
7.14, H 2.88, N 4.44; found C 57.18, H 2.71, N 4.57.
9 5
H NO S: C
1
3
)
Acetic
acid
4-(1,3-dioxo-1,3-dihydroisoindo-2-ylsulfanyl)-3-
δ 2.20 (s, 6H), 2.51 (t, J = 2.2 Hz, 2H), 4.66 (d, J = 2.2 Hz, 4H),
hydroxyphenyl ester (2d). The reaction carried out following the
general procedure using 122 mg of Acetic acid 3-hydroxy-phenyl
ester. After 12h at room temperature and work-up the crude was
used in the next step without further purification and just a little
1
3
6.80 (s, 2H). C NMR (50 MHz, CDCl
3
) δ 12.3 (2C), 56.9 (2C),
74.9 (2C), 79.3 (2C), 110.2 (2C), 127.8 (2C), 150.7 (2C). IR (KBr,
-1
cm ) ν 3266, 2925, 2108, 1599, 1480, 1207. MS (EI) m/z (rel.
int. %): 215 (2), 214 (M , 15), 175 (44), 39 (100). Elemental
•+
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European Journal of Organic Chemistry
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Analysis Calcd for C14
H
14
O
2
: C 78.48, H 6.59; found C 78.50, H
by TLC. The solution was then cooled to room temperature,
6
.63.
diluted with CH
NH Cl (3x30 mL) and H
dried over anhydrous Na
crude was purified by silica gel column chromatography to yield
the desired helical shaped bis-benzoxathiine 7.
2
Cl
2
(50 mL), washed with a saturate solution of
O (3x30 mL). The organic layer was
SO and concentrated in vacuum. The
4
2
2,3-Dimethoxy-1,4-bis-prop-2-ynyloxybenzene
(5b).
The
2
4
reaction carried out following the general procedure using 206
mg of 2,3-dimethoxy-benzene-1,4-diol. After 24h at reflux and
work-up the crude was purified by silica gel column
chromatography (eluent petroleum ether:AcOEt = 3:1) to give 5b
bis-Benzoxathiine 7aa. The reaction carried out following the
general procedure using 54 mg of 4a and 303 mg of 2a. After
18h at 60 °C and work-up the crude was purified by silica gel
column chromatography (eluent petroleum ether:AcOEt = 12:1)
1
as a yellow oil (195 mg, 0.79 mmol, 65%). H NMR (200 MHz,
CDCl
Hz, 4H), 6.75 (s, 2H). C NMR (50 MHz, CDCl
1.3 (2C), 75.5 (2C), 78.9 (2C), 110.0 (2C), 144.6 (2C), 146.7
2C). IR (CDCl , cm-1) ν 3307, 2939, 2125, 1600, 1488. MS (EI)
m/z (rel. int. %): 246 (M•+, 100), 207 (91). Elemental Analysis
Calcd for C : C 68.28, H 5.73; found C 68.33, H 5.85.
3
) δ 2.51 (t, J = 2.2 Hz, 2H), 3.91 (s, 6H), 4.70 (d, J = 2.2
13
3
) δ 57.7 (2C),
6
(
to give 7aa as a yellow solid (17 mg, 0.033 mmol, 13%), mp
1
3
163 °C (dec.). H NMR (400 MHz, CDCl
3
) δ 2.16 (s, 6H), 3.67 (s,
6H), 3.68 – 3.77 (m, 2H), 4.27 – 4.34 (m, 4H), 5.34 – 5.35 (m,
2H), 6.37 (d, J = 2.8 Hz, 2H), 6.52 (dd, J = 8.8, 2.8 Hz, 2H), 6.96
8
10 4
H O
13
(
3
(
d, J = 8.8 Hz, 2H). C NMR (100 MHz, CDCl
5.5 (2C), 55.4 (2C), 64.8 (2C), 66.4 (2C), 104.0 (2C), 107.1
2C), 109.9 (2C), 115.3 (2C), 127.0 (2C), 128.4 (2C), 146.0 (2C),
3
) δ 12.2 (2C),
General procedure for the synthesis of chromenes 4a-b
-1
1
1
5
51.0 (2C), 158.2 (2C). FT-IR (CDCl
3
, cm ) ν 2926, 1604, 1574,
The appropriate propargyl derivative (2.96 mmol) was dissolved
in anhydrous dichloromethane (6 mL), then Ph PAuNTf (0.1
3 2
mol%) was added and the reaction mixture was left under
magnetic stirring at room temperature until complete
consumption of the starting material as monitored by TLC. After
488, 1247, 1161. MS (EI) m/z (re. int. %): 524 (4), 523 (10),
•+
22 (M , 31), 368 (36), 213 (100). Elemental Analysis Calcd for
: C 64.35, H 5.01; found C 64.21, H 5.17.
28 26 6 2
C H O S
bis-Benzoxathiine 7ba. The reaction carried out following the
general procedure using 54 mg of 4a and 300 mg of 2b. After 5h
at 60 °C and work-up the crude was purified by silica gel column
24h the solvent was concentrated in vacuum. The crude was
purified by silica gel column chromatography to yield the desired
chromene derivative.
chromatography (eluent petroleum ether:Et
2
O = 10:1) to give
7
ba as a yellow solid (18 mg, 0.035 mmol, 14%), mp 185 °C
5
,6-Dimethyl-3,8-dihydropyrano[3,2-f]chromene
(4a).
The
1
(
2
(
dec.). H NMR (400 MHz, CDCl
.18 (s, 6H), 3.68 (ddd, J = 12.0, 4.8, 2.4 Hz, 2H), 4.27 – 4.38
m, 4H), 5.27 (dd, J = 2.4, 1.6 Hz, 2H), 6.64 – 6.65 (m, 2H), 6.70
3
) δ 2.06 (s, 6H), 2.17 (s, 6H),
reaction carried out following the generale procedure using 633
mg of 5a. After 24h at room temperature and work-up the crude
was purified by silica gel column chromatography (eluent
petroleum ether:AcOEt = 15:1) to give 4a as a yellow solid (285
mg, 1.33 mmol, 45%), mp 90-92 °C. H NMR (200 MHz, CDCl
13
–
3
6.71 (m, 2H). C NMR (100 MHz, CDCl ) δ 12.2 (2C), 16.1
1
(2C), 20.5 (2C), 35.7 (2C), 65.0 (2C), 65.6 (2C), 115.4 (2C),
3
)
116.0 (2C), 124.0 (2C), 127.4 (2C), 128.0 (2C), 128.2 (2C),
δ 2.11 (s, 6H), 4.67 (dd, J = 3.8, 1.8 Hz, 4H), 5.87 (dt, J = 9.8,
-1
1
3
131.2 (2C), 145.9 (2C), 146.1 (2C). FT-IR (CDCl
3
, cm ) ν 2926,
3
.8 Hz, 2H), 6.65 (dt, J = 9.8, 1.8 Hz, 2H). C NMR (50 MHz,
CDCl ) δ 11.8 (2C), 64.6 (2C), 115.6 (2C), 121.0 (2C), 122.0
2C), 124.8 (2C), 146.0 (2C). FT-IR (CDCl , cm-1) ν 2926, 2838,
600, 1458, 1240, 1101. MS (EI): m/z (rel. int. %): 215 (13), 214
•+
1
3
593, 1580, 1473, 1245. MS (EI) m/z (rel. int. %): 518 (M , 11),
66 (23), 214 (74), 213 (72), 32 (100). Elemental Analysis Calcd
: C 69.47, H 5.83; found C 69.52, H 5.99.
3
(
1
3
30 4 2
for C30H O S
•+
(
M , 95), 213 (100), 199 (42). Elemental Analysis Calcd for
: C 78.48, H 6.59; found C 78.52, H 6.63.
bis-Benzoxathiine 7ca. The reaction carried out following the
general procedure using 54 mg of 4a and 317 mg of 2c. After
14 14 2
C H O
1
8h at 60 °C and work-up the crude was purified by silica gel
column chromatography (petroleum ether:Et O = 5:1 as eluent)
to give 7ca as a white solid (19 mg, 0.035 mmol, 14%), mp
5
,6-Dimethoxy-3,8-dihydropyrano[3,2-f]chromene (4b).
The
2
reaction carried out following the generale procedure using 729
mg of 5b. After 24h at room temperature and work-up the crude
was purified by silica gel column chromatography (eluent
1
170 °C (dec.). H NMR (400 MHz, CDCl
3
) δ 2.15 (s, 6H), 3.73
(
ddd, J = 10.7, 6.2, 2.4 Hz, 2H), 4.29 – 4.32 (m, 4H), 5.16-5.17
petroleum ether:Et
2
O = 2:1) to give 4b as a white solid (430 mg,
13
1
(m, 2H), 5.84-5.86 (m, 4H), 6.36 (s, 2H), 6.53 (s, 2H). C NMR
100 MHz, CDCl ) δ 12.2 (2C), 35.9 (2C), 64.9 (2C), 66.6 (2C),
100.8 (2C), 101.2 (2C), 105.5 (2C), 107.6 (2C), 115.1 (2C),
1
3
4
.75 mmol, 59%), mp 149-151 °C. H NMR (200 MHz, CDCl
.89 (s, 6H), 4.72 (dd, J = 4.0, 1.8 Hz, 4H), 5.86 (dt, J = 10.0,
.0 Hz, 2H), 6.60 (dt, J = 10.0, 1.8 Hz, 2H). C NMR (50 MHz,
) δ 61.3 (2C), 64.8 (2C), 114.5 (2C), 120.4 (2C), 121.8
3
) δ
(
3
1
3
128.4 (2C), 143.2 (2C), 145.1 (2C), 145.8 (2C), 146.2 (2C). FT-
CDCl
3
-1
-1
3
IR (CDCl , cm ) ν 2960, 1472, 1265, 1252. MS (EI) m/z (rel.
int. %): 382 (4), 213 (100), 212 (100). Elemental Analysis Calcd
for C28 : C 61.08, H 4.03; found C 61.23, H 3.75.
(
2C), 141.4 (2C), 141.8 (2C). IR (CDCl
3
, cm ) ν 2972, 2940,
2848, 1585, 1431, 1129. MS (EI) m/z (rel. int. %): 247 (100), 246
•+
22 8 2
H O S
(
5
M , 56). Elemental Analysis Calcd for C14
.73; found C 68.11, H 5.89.
14 4
H O : C 68.28, H
Crystallographic data for 7ca:
C
28
H
22
O
8
S
2
,
M=550.57,
Monoclinic, space group P 21/c, a=17.354(1), b=15.289(1),
General procedure for the synthesis of bis-adducts 7a-d.
3
c=8.874(1)Å, β=100.735(2) V=2313.38(9)Å , Z=4

D
c
=1.581,
=2.577 mm , F(000)=1144. 5030 reflections were collected
with a 5.18872.023 range with a completeness to theta
9,1%; 2183 were independent, the parameters were 685 and
-1
Anhydrous TEA (51 mg, 0.50 mmol) was added to a solution of
the appropriate bis-dienophile (0.25 mmol) in anhydrous
9
chloroform
(2
mL),
then
the
appropriate
ortho-
the final R index was 0.0428 for reflections having I2I.
Deposition number at the Cambridge Crystallographic Data
Center: CCDC 1491666. Asymmetric unit contains half molecule,
hydroxythiophthalimide (1.00 mmol) was added in small portions.
The reaction mixture was left under magnetic stirring at 60 °C
until complete consumption of the starting material as monitored
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European Journal of Organic Chemistry
10.1002/ejoc.201600850
FULL PAPER
the other is reported by symmetry along b-axis;no relevant
hydrogen bond has been detected.
NMR (100 MHz, CDCl
(2C), 65.0 (2C), 65.2 (2C), 114.8 (2C), 115.2 (2C), 124.0 (2C),
3
) δ 16.1 (2C), 20.4 (2C), 35.4 (2C), 61.3
1
1
1
27.4 (2C), 128.4 (2C), 131.4 (2C), 142.2 (2C), 143.1 (2C),
-1
1
45.9 (2C). IR (CDCl
3
, cm ) ν 2940, 1596, 1471, 1430, 1141,
Mono cycloadduct 6ca. White solid, mp 160 °C (d). H NMR
122. Elemental Analysis Calcd for C30
H
30
O
6
S
2
: C 65.43, H 5.49;
(
400 MHz, CDCl
3
) δ 2.12 (s,3H), 2.13 (s, 3H), 3.69 (ddd, J =
2.2, 4.4, 2.6 Hz, 1H), 4.22-4.32 (m, 2H), 4.66-4.78 (m, 2H),
.85-4.86 (m, 1H), 5.89-5.93 (m, 3H), 6.52 (s, 1H), 6.58 (s, 1H),
.61 (dt, J = 10.0, 1.6 Hz, 1H). C NMR (100 MHz, CDCl
1.96, 12.00, 37.0, 64.8, 65.1, 67.2, 101.1, 101.2, 105.4, 108.9,
11.9, 118.7, 120.9, 122.7, 125.7, 127.4, 143.3, 145.7, 146.0,
found C 65.29, H 5.33.
1
4
6
1
1
1
1
3
1
3
) δ
Mono cycloadducts 6bb: White solid, mp 180-182 °C. H NMR
(400 MHz, CDCl ) δ 2.17 (s, 3H), 2.22 (s, 3H), 3.70 (ddd, J =
3
11.8, 4.8, 2.4 Hz, 1H), 3.90 (s, 3H), 3.93 (s, 3H), 4.28-4.38 (m,
2H), 4.73-4.84 (m, 2H), 4.85-4.86 (m, 1H), 5.89 (dt, J = 10.0, 3.8
-
1
46.2, 146.3. FT-IR (CDCl
3
, cm ) ν 2929, 1472, 1248. MS (EI)
1
3
m/z (rel. int. %): 216 (17), 215 (100), 214 (29). Elemental
Analysis Calcd for C21 S: C 65.95, H 4.74; found C 66.09, H
.81.
Hz, 1H), 6.60 (dt, J = 10.0, 1.8 Hz, 1H), 6.73-6.78 (m, 2H).
NMR (100 MHz, CDCl ) δ 15.8, 20.5, 37.0, 61.31, 61.34, 64.9,
65.2, 66.1, 111.3, 117.1, 117.7, 120.4, 122.4, 123.9, 127.9,
3
28.1, 131.7, 141.5, 141.6, 142.6, 143.2, 147.1. FT-IR (CDCl ,
C
H
18
O
5
3
4
1
-1
cm ) ν 2939, 1468, 1431, 1143, 1126. Elemental Analysis Calcd
for C22 S: C 66.31, H 5.56; found C 66.23, H 5.72.
bis-Benzoxathiine 7da. The reaction carried out following the
general procedure using 54 mg of 4a and 328 mg of 2d. After
22 5
H O
18h at 60 °C and work-up the crude was purified by silica gel
column chromatography (eluent petroleum ether:AcOEt = 10:1)
to give 7da as a white solid (23 mg, 0.040 mmol, 16%), mp
bis-Benzoxathiine 8. To a suspension of 7da (12 mg, 0.021
mmol) in methanol (1 mL), CH Cl was added dropwise until
complete dissolution. Anhydrous K CO (7 mg, 0.051 mmol) was
then added and the mixture was left under magnetic stirring at
room temperature until complete consumption of the starting
material as monitored by TLC. After 1h the solution was diluted
with water (30 mL) and acidified with aqueous HCl 0.1N to pH 6,
then it was extracted with DCM (3x30 mL) and the recollected
2
2
1
2
6
5
2
10 °C (dec.). H NMR (400 MHz, CDCl
3
) δ 2.15 (s, 6H), 2.24 (s,
2
3
H), 3.70 (ddd, J = 11.6, 5.2, 2.0 Hz, 2H), 4.26 – 4.34 (m, 4H),
.33 -5.34 (m, 2H), 6.61 (d, J = 2.4 Hz, 2H), 6.67 (dd, J = 8.4,
13
.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H). C NMR (100 MHz,
) δ 12.2 (2C), 21.1 (2C), 35.0 (2C), 64.7 (2C), 65.8 (2C),
12.1 (2C), 113.2 (2C), 115.3 (2C), 116.1 (2C), 126.9 (2C),
28.6 (2C), 145.9 (2C), 148.5 (2C), 150.0 (2C), 169.2 (2C). FT-
CDCl
1
1
3
organic phases were washed with H
layer was dried over anhydrous Na
vacuum to give 8 as a white solid (10 mg, 0.020 mmol, 96%),
2
O (3x40 mL). The organic
-1
IR (CDCl
3
, cm ) ν 2933. 1757, 1481, 1213. MS (EI) m/z (rel.
2
SO and concentrated in
4
•+
int. %): 578 (M , 3), 395 (19), 212 (100). Elemental Analysis
Calcd for C30 : C 62.27, H 4.53; found C 62.40, H 4.61.
1
H
26
O
8
S
2
mp 105 °C (dec.). H NMR (400 MHz, CDCl
3
) δ 2.15 (s, 6H),
.69 - 3.73 (m, 2H), 4.29 – 4.31 (m, 4H), 4.92 (bs, 2H), 5.29 -
.30 (m, 2H), 6.31 (d, J = 2.8 Hz, 2H), 6.43 (dd, J = 8.4, 2.8 Hz,
3
5
2
bis-Benzoxathiine 7ab. The reaction carried out following the
general procedure using 62 mg of 4b and 301 mg of 2a. After
1
3
3
H), 6.91 (d, J = 8.4 Hz, 2H). C NMR (100 MHz, CDCl ) δ 12.2
(
2C), 35.4 (2C), 64.8 (2C), 66.3 (2C), 105.9 (2C), 107.3 (2C),
2
4h at 60 °C and work-up the crude was purified by silica gel
column chromatography (eluent CH Cl :Et O = 50:1) to give 7ab
as a white solid (31 mg, 0.056 mmol, 22%), mp 198 °C (dec.). H
NMR (400 MHz, CDCl ) δ 3.68 (s, 6H), 3.71-3.76 (m, 2H), 3.92
s, 6H), 4.29-4.41 (m, 4H), 5.31-5.32 (m, 2H), 6.38 (d, J = 2.8 Hz,
1
1
1
4
10.7 (2C), 115.3 (2C), 127.2 (2C), 128.4 (2C), 146.0 (2C),
2
2
2
-1
1
50.9 (2C), 154.0 (2C). FT-IR (CDCl
296. MS (ESI) m/z Calcd for C26
3
, cm ): 3595. 2959, 2928,
-
H
22
O
6
S
2
[M-H] : 493.08, found
93.51, [2M-H] 987.16, found 987.04. Elemental Analysis Calcd
: C 63.14, H 4.48; found C 63.27, H 4.31.
3
-
(
13
22 6 2
for C26H O S
2
H), 6.53 (dd, J = 8.8, 2.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H).
) δ 35.1 (2C), 55.4 (2C), 61.3 (2C), 64.9
2C), 65.9 (2C), 104.0 (2C), 106.8 (2C), 110.1 (2C), 114.3 (2C),
C
NMR (100 MHz, CDCl
(
3
Experimental HPLC
1
27.1 (2C), 142.4 (2C), 143.4 (2C), 150.7 (2C), 158.3 (2C). IR
-1
(
CDCl
Analysis Calcd for C28
H 4.61. Crystallographic data for 7ab: C28
Monoclinic, space group P 21/c, a=15.994(1), b=20.773(1),
3
, cm ) ν 2941, 1605, 1488, 1298, 1143. Elemental
: C 60.63, H 4.73; found C 60.77,
, M=554.61,
Analytical (250*4.6, 5 μm particle size) column packed with
Chiralpak IA stationary phase was obtained from Chiral
Technologies Europe. The HPLC resolution was performed
using a Gilson HPLC system equipped with a Rheodyne model
26 8 2
H O S
26 8 2
H O S
3
c=15.890(1)Å, β=108.440(1) V=5008.3(5)Å , Z=4
D
c
=1.471,
=2.381 mm , F(000)=2320. 27743 reflections were collected
with a 4.02672.274 range with a completeness to theta
9,5%; 9592 were independent, the parameters were 685 and
7010 5 μL loop injector, a Model 302 and Model 305 Gilson
-1

HPLC pumps and a spectrophotometer UV Model 116 Gilson.
9
the final R index was 0.0482 for reflections having I2I.
Deposition number at the Cambridge Crystallographic Data
Center: CCDC 1491667. Asymmetric unit contains two
independent molecules and no relevant hydrogen bond has
been detected.
Acknowledgements
Authors are indebted with ITT (Istituto Toscano Tumori) for a
grant to SP and to dr. Cristina Faggi for X-ray analyses.
bis-Benzoxathiine 7bb. The reaction carried out following the
general procedure using 62 mg of 4b and 300 mg of 2b. After
Keywords: helical shaped compounds • cycloadditions • sulfur
heterocycles • stereoselectivity • ortho-thioquinones
2
0h at 60 °C and work-up the crude was purified by silica gel
column chromatography (eluent CH Cl :petroleum ether = 50:1)
to give 7bb as a white solid (35 mg, 0.063 mmol, 25%), mp
2
2
[1]
Selected Review: (a) R. H. Martin, Angew. Chem. Int. Ed. Eng. 1974,
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1
6
5
89 °C (dec.). H NMR (400 MHz, CDCl
3
) δ 2.08 (s, 6H), 2.18 (s,
H), 3.67-3.72 (m, 2H), 3.95 (s, 6H), 4.34-4.37 (m, 4H), 5.23-
1
3
.24 (m, 2H), 6.655-6.660 (m, 2H), 6.709-6.714 (m, 2H).
C
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600850
FULL PAPER
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European Journal of Organic Chemistry
10.1002/ejoc.201600850
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Helical shaped heterocycles,
Cycloadditions
Caterina Viglianisi,* Stefano Menichetti,
Sara Piantini, Lorenzo Tofani*
Page No. – Page No.
Helical shaped bis-benzoxathiines were obtained through two inverse electron
demand cycloadditions using transient ortho-thioquinones as electron-poor dienes.
The process occurs with complete control of the regio- and relative stereochemistry
Helical shaped bis-1,4-benzoxathiines
through the inverse electron demand
hetero Diels-Alder reaction of ortho-
thioquinones
affording exclusively C
2
symmetric bis-cycloadducts. Helicity of final products was
confirmed by single crystal X-ray analysis.
*one or two words that highlight the emphasis of the paper or the field of the study
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