Stereoselective synthesis of dithia[3.3]cyclophane S,S'-dioxides with planar and central chirality

Article abstract of DOI:10.1002/ejoc.201301636

5,8-Dimethyl-1,12-dimethylene-2,11-dithia[3.3]cyclophane 2,11-dioxides with planar and central chirality were synthesized in high yields, starting from 2,5-dimethyl-1,4-benzenedimethanethiol, through the formation of suitable transient sulfenic functions

Full text of DOI:10.1002/ejoc.201301636

FULL PAPER
DOI: 10.1002/ejoc.201301636
Stereoselective Synthesis of Dithia[3.3]cyclophane S,SЈ-Dioxides with Planar
and Central Chirality
Anna Barattucci,*[a] Maria Luisa Di Gioia,[b] Antonella Leggio,[b] Lucio Minuti,[c]
Teresa Papalia,[d] Carlo Siciliano,[b] Andrea Temperini,[e] and Paola Bonaccorsi[a]
Keywords: Cyclophanes / Sulfur heterocycles / Chirality / Reactive intermediates
5,8-Dimethyl-1,12-dimethylene-2,11-dithia[3.3]cyclophane and stereochemical insights into the key step of the synthetic
2,11-dioxides with planar and central chirality were synthe-
sized in high yields, starting from 2,5-dimethyl-1,4-benzene-
dimethanethiol, through the formation of suitable transient
sulfenic functions that add to the triple bonds of disubstituted
benzenes. Experimental observations allowed mechanistic
pathway, and NMR experiments were diagnostic for the
structure assignments of the cage-like compounds. The
stereochemical characteristics of the new dithiacyclophane
S,SЈ-dioxides synthesized may be applicable in the field of
organocatalysis.
mimic the stereospecificity of hydrogen transfer in bio-
logical asymmetric reduction with NADH.[5]
Introduction
A number of synthetic strategies have been developed to
obtain planar chiral cyclophanes and heteracyclophanes. In
particular, a general, well-assessed route to thiacyclophanes
is represented by the use, under dilution conditions, of suit-
ably functionalized cyclization partners, for instance bis-
(bromomethyl)benzene and variously substituted benzened-
imethanethiols, as illustrated in Scheme 1.[2] The planar chi-
rality is generated by the introduction of at least one sub-
stituent on one of the aromatic rings, so enhancing the con-
formational barrier related to complete rotation of the sub-
stituted ring.[2d]
Planar chirality plays a main role in determining the
properties and behavior of cyclophanes (CPs) as chiral rea-
gents, backbones of organocatalysts, and a source of func-
tional materials.[1] Therefore, an increasing number of in-
vestigations have been conducted on the relationship be-
tween structure and chemical properties of these molecules,
as examples of compounds without stereogenic centers but
comprising well-defined stereoelectronic characteristics.[2]
A
planar and centrally chiral bicyclic 1,2,4-triazolium salt,
synthesized from [2.2]paracyclophanes, has been shown to
be an efficient catalyst for the asymmetric β-borylation of
acyclic enones, producing β-boryl ketones in high yields and
enantioselectivities.[3] A planar chiral bis(thiourea) catalyst,
based on the pseudo-ortho-substituted [2.2]paracyclophane
skeleton, has been synthesized and found to catalyze a
highly enantioselective Henry reaction, as a result of its
asymmetric environment.[4] Worthy of note is the work con-
ducted on planar chiral ansa-bridge cyclophanes used to
Scheme 1. Synthetic approach to dithia[3.3]paracyclophanes with
planar chirality.
[a] Dipartimento di Scienze chimiche, Università di Messina,
Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy
E-mail: abarattucci@unime.it
Recently, Tanaka and co-workers[6] reported an interest-
ing example of rhodium-catalyzed enantioselective synthe-
sis of planar chiral dithiacyclophanes with up to 50% yield.
Among the limited number of approaches achieved by in-
tramolecular cyclization of functionalized disubstituted
aromatics, the synthesis of a series of ansa-bridge [n]paracy-
clophanediols (n = 8–12) has been reported by samarium-
catalyzed pinacol coupling, with yields ranging from 14 to
64%.[7] Previously, we disclosed a new synthetic route to a
series of dithiacyclophane S,SЈ-dioxides and their tris-
bridged analogues, through the generation of suitable tran-
sient sulfenic acids in situ and their completely regioselec-
http://www.unime.it/dipartimenti/chimica
[b] Dipartimento di Farmacia e Scienze della Salute e della
Nutrizione, Università della Calabria,
Edificio Polifunzionale, 87030 Arcavacata di Rende, Italy
[c] Dipartimento di Chimica, Università di Perugia,
Via Elce di Sotto 8, 06123 Perugia, Italy
[d] Dipartimento di Scienze del Farmaco e Prodotti per la Salute,
Università di Messina,
Villaggio SS. Annunziata, 98168 Messina, Italy
[e] Dipartimento di Chimica e Tecnologia del Farmaco, Università
di Perugia,
Via del Liceo 1, 06123 Perugia, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301636.
Eur. J. Org. Chem. 2014, 2099–2104
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A. Barattucci et al.
FULL PAPER
Scheme 2. A typical synthetic approach to dithia[3.3]paracyclophane S,SЈ-dioxides via transient sulfenic acids.
Scheme 3. Synthetic procedure to dithiacyclophane S,SЈ-dioxides 4–6 with planar and central chirality.
tive and stereocontrolled addition onto the triple bonds of
Results and Discussion
di- and tri-ethynylbenzenes (Scheme 2).[8]
Herein, we describe a consistent approach to new dithia-
Our synthetic approach to dithiacyclophane S,SЈ-diox-
cyclophane S,SЈ-dioxides showing both planar and central ides 4–6, with planar and central chirality, is reported in
chirality. The cage skeleton of dithiacyclophanes 4–6 Scheme 3.
(Scheme 3) with the coexistence of two different sources of
2,5-Dimethyl-1,4-benzenedimethanethiol (1), already
chirality – chiral sulfinyl groups and planar chirality – ob- possessing the elements required for induction of planar
tained through the introduction of two methyl groups on chirality in the cage-like compounds, was applied in the nu-
both sides of one of the rings, to provide an equal steric cleophilic addition of the two sulfur functions onto the ter-
bias, represents a model system to enhance the structure/ minal electrophilic carbon atom of methyl acrylate, to ob-
chirality relationship of these molecules. The synthetic tain disulfide 2, which, in turn, underwent controlled oxi-
methodology adopted for their preparation employs a new dation to disulfoxide 3. Thermolysis of the latter generates
sulfenic acid precursor 3 and guarantees higher yields with transient sulfenic acid functionalities that can add to the
respect to published procedures,[2,6–8] allowing mechanistic triple bonds of meta- and para-diethynylbenzene[9] in a
insights into the sulfenic acid chemistry that can offer stim- completely regio- and stereocontrolled process. The elec-
ulating stereochemical applications.
tronic nature of the substituents, located β to the sulfur
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Stereoselective Synthesis of Dithia[3.3]cyclophane S,SЈ-Dioxides
atoms, is crucial for the generation of the bis-sulfenic acid stereochemical outcomes observed above. Compounds 4–6
from disulfoxide 3. Methyl acrylate was recognized as the were obtained with long reaction times but without decom-
best partner[10] of the nucleophilic disulfide addition in the position products. We suggest that, under these conditions,
presence of Triton B (benzyltrimethylammonium hydrox- the slow formation of one sulfenic function from disulfox-
ide).[11] Disulfoxide 3 generates the sulfenic functions at ide 3 is accomplished when sulfenic acid precursor and un-
83 °C in 1,2-dichloroethane (DCE), has a good shelf-life, saturated acceptor are near in space. It is immediately fol-
and can be easily handled. Furthermore, yields of the new lowed by sulfenic acid 7/triple bond addition, which ap-
dithiacyclophane S,SЈ-dioxides 4–6 range from 70 to 82%, pears to be the fastest process. This pathway gives rise to
thus representing a significant improvement with respect to the formation of intermediates 8 and 9, without appreciable
previously reported analogues[8] (see for example Scheme 2) amounts of sulfenic acid self-condensation byproducts. The
and is an example of a generally applicable synthetic ap- generation of a second sulfenic function and its intramolec-
proach to this class of molecule. Dithiacyclophane S,SЈ-di- ular syn-addition to the remaining triple bond could be
oxides 4–6 were obtained under dilution conditions, with a governed by the favorable geometrical contiguity of the two
1:1 ratio between the sulfenic acid precursor 3 and diethyn- reactive centers due to the interactions between the two aro-
ylbenzene, and could be easily purified and separated by matic rings. This would be consistent with the short reac-
column chromatography as racemic mixtures. It should be tion time observed when compounds 8 or 9 were separately
noted that no traces of sulfenic acid self-condensation prod- thermolyzed, compared to the long reaction time recorded
ucts were isolated.[12]
The appearance and disappearance of spots on the TLC towards cyclophane derivatives 4–6 (Scheme 3).
plates before completion (almost four days) of the reactions Complete stereoselectivity was observed when disulfox-
for the overall thermolysis step of the synthetic pathway
of disulfoxide 3 with meta- or para-diethynylbenzene sug- ide 3 was thermolyzed in the presence of para-diethyn-
gested to us the possible stepwise formation of the transient ylbenzene, providing, as a unique product of the reaction,
sulfenic functions and, therefore, a parallel or alternative dithiacyclophane S,SЈ-dioxide 4 in high yield (71%). With
synthetic pathway compared to that outlined in Scheme 2 meta-diethynylbenzene, the reaction (84% overall yield) ap-
for which the generation of 1,4-benzenedimethanesulfenic peared to be more complex and less stereoselective; in this
acid is shown.[8] To confirm this, the final step of the syn- case, dithiacyclophane S,SЈ-dioxides 5a and 5b, differing in
thetic procedure was stopped after 24 h; the results are the configuration of the chiral plane, were obtained in a
shown in Scheme 4.
1:1:3 ratio with respect to dithiacyclophane S,SЈ-dioxide 6,
Compounds 8 and 9, still possessing a 2-(methoxycarb- analogous to 4 and was the dominant product formed in
onyl)ethylsulfinyl function on one of the two arms, were the process. Suitable computational studies could clarify
isolated in similar yields as diastereomeric mixtures, to- this significant aspect of the formation of the dithiacyclo-
gether with the corresponding dithiacyclophane S,SЈ-diox- phane S,SЈ-dioxides.
ides 5, 6 or 4 and unreacted disulfoxide 3. Furthermore,
The 1H NMR spectra with NOESY experiments were
the two open-chain intermediates 8 and 9 were subjected, diagnostic for the structure assignment of dithiacyclophane
1
separately, to a new thermolysis in DCE, under the dilution S,SЈ-dioxides 4–6. In the H NMR spectra of 5a and 5b
conditions used before; in this case, within 4 h dithiacyclo- (Table 1) the methyl groups linked to the (1,4)-bridged aro-
phane S,SЈ-dioxides 4–6 were obtained with the same matic ring appear as one sharp singlet, and one singlet is
Scheme 4. Isolation of the intermediates in the synthesis of dithiacyclophane S,SЈ-dioxides 4–6.
Eur. J. Org. Chem. 2014, 2099–2104
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A. Barattucci et al.
FULL PAPER
Figure 1. Graphical description of the proposed benzene ring disposition for 4–6 and diagnostic NOESY experiments conducted on the
methyl groups in 6 (the two shaded spheres).
recorded for the two aryl protons (6,9-H) of the same aro- Table 2. Most significant chemical shifts (δ) in 1H NMR spectra of
dithiacyclophane S,SЈ-dioxides 4 and 6.
matic ring. Moreover one AB system is observed for the
[a]
two methylene protons (3,10-H2) adjacent to the (1,4)-
bridged ring, one multiplet pertains to three of the four pro-
tons of the (1,3)-bridged aromatic ring, and a tiny triplet is
observed for the highfield shifted aromatic inner proton
(18-H). The simplicity of such spectra allows the assump-
tion that molecules 5a and 5b adopt, as preferred, an almost
orthogonal edge-to-face (EtF) disposition (Figure 1),[2d]
with the presence of a symmetry C2-axis perpendicular to
the (1,4)-bridged aromatic ring and bisecting protons in the
15- and 18-positions of the meta-disubstituted benzene.
Variable-temperature NMR (VTNMR) experiments, per-
formed on a sample of 5a (see the Supporting Information)
support this assumption, but the possibility of flipping of
the (1,3)-bridged aromatic ring from one side to the other
of the (1,4)-bridged aromatic ring on the NMR time-scale,
cannot be ruled out.[2e]
5,8-Me2
3-H2 and 10-H2
4
6
1.96; 2.47
1.88; 2.31
3.63 and 4.59; 4.02 and 4.33
3.34 and 4.94; 3.86 and 4.64
[a] Two AB systems.
The dithiaparacyclophane S,SЈ-dioxide 4 shows a pattern
of signals similar those of 6 (Table 2), suggesting in this case
a parallel offset disposition[2d] of the two para-disubstituted
aromatic rings, with the sulfinyl functions analogously
pointing outside.
Conclusions
We have described a significant improvement, in terms
of yields, of a three-step synthesis of dithiacyclophane S,SЈ-
dioxides, that can now be regarded as an efficient route to
this kind of molecule. The isolation of an intermediate in
the process, which had previously[8] been considered an al-
most synchronous concerted syn-addition of the two
sulfurated functions of a bis-sulfenic acid onto the two tri-
ple bonds of a diethynylbenzene, provides mechanistic in-
sights into the generation and reactivity of sulfenic acids.
The most relevant characteristic of reported 5,8-dimethyl-
1,12-dimethylene-2,11-dithia[3.3]cyclophane 2,11-dioxides
is the coexistence in the same structure of different elements
of chirality (plane and centers) that appear to be a promis-
ing feature for their use as organocatalysts. For this reason,
it would clearly be desirable to obtain these dithiacyclo-
phane S,SЈ-dioxides in enantiomerically pure form.
1
Table 1. Chemical shifts (δ) in H NMR spectra of dithiacyclo-
phane S,SЈ-dioxides 5a and 5b.
[a]
[b]
5,8-Me2 3,10-H2
C=CH2
18-H 6,9-H 14–16-H
5a
5b
1.99
2.13
4.02, 4.53 5.98; 6.17 6.15
3.61, 4.82 5.99; 6.10 5.97
6.64
6.46
7.15–7.26
7.22–7.26
[a] AB system. [b] Two singlets.
On the other hand, the complexity of the 1H NMR spec-
trum of dithiacyclophane S,SЈ-dioxide 6, showing signal
doubling for all the resonances (Table 2), allows the assign-
ment of rel-RS,SS configuration and suggests that the mole-
cule does not adopt a symmetric conformation, but instead,
the two aromatic rings adopt a tilted EtF disposition with
the two oxygen atoms analogously pointing outside. The
attribution of the structure of compound 6 was confirmed
by NOESY experiments. As an example, the methyl protons
linked to the (1,4)-bridged aromatic ring in 6 resonate as
two distinct singlets, one (δ = 2.31 ppm) close in space to
the olefin protons of one of the two ethenyl moieties and
to the inner proton 18-H of the (1,3)-bridged aromatic ring
(δ = 6.11 ppm), whereas the second (δ = 1.88 ppm) is close
in space to the three protons of the meta-disubstituted
benzene and located in its shielding cone.
Experimental Section
General Methods and Materials: All commercial reagents and sol-
vents (AR, LabScan Ltd., SpS, Romil Ltd.) were used without fur-
ther purification. All syntheses were carried out under open atmo-
spheric conditions unless otherwise noted. Analytical TLC was per-
formed on Aldrich silica gel 60 F 254 plates. Products were visual-
ized by UV or vanillin [1 g dissolved in MeOH (60 mL) and conc.
H2SO4 (0.6 mL)]. Column chromatography was performed on Ald-
rich 60 silica gel (40–63 mm). 1H and 13C NMR measurements
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Stereoselective Synthesis of Dithia[3.3]cyclophane S,SЈ-Dioxides
were performed in CDCl3 solutions at 300.1 and 75.5 MHz or at
500.1 and 125.7 MHz, respectively. All chemical shifts are reported
in parts per million (δ, ppm), downfield to tetramethylsilane
(Me4Si) as an internal standard (δ = 0.00 ppm), or referenced to
residual solvent CHCl3 (1H NMR 7.27 ppm and 13C NMR
77.0 ppm); coupling constants J are given in Hertz. Multiplicities
are reported as: s = singlet, br. s = broad singlet, t = triplet, m
= multiplet. NMR peak assignments were based on homonuclear
(COSY, COrrelationSpectroscopY) and heteronuclear correlation
(1H-13C) spectra. Phase sensitive 1H 2D-NOESY (Nuclear Over-
hauser Effect SpectroscopY) experiments were acquired by using a
standard pulse sequence with mixing times of 350 ms. 1H-13C
HSQC (Heteronuclear Single Quantum Coherence) correlation ex-
periments were also performed for several compounds, and were
recorded in a gradient-selected phase-sensitive mode. Melting
points were determined with a Kofler hot-stage apparatus and are
uncorrected.
(rel-RS,SS,Rp)-5,8-Dimethyl-1,12-dimethylene-2,11-dithia[3.3]para-
cyclophane 2,11-Dioxide (4): Following the general procedure, com-
pound 4 was prepared from 1,4-diethynylbenzene and disulfoxide
3, and isolated, after chromatography purification (acetone/hexane,
2:8), as a white solid (0.25 g, 0.70 mmol, 71%) that decomposed
before melting (Ͼ 170 °C); Rf = 0.54 (acetone/hexane, 5:5). 1H
NMR: δ = 7.40 and 7.24, and 6.88 and 6.79 (two split AB systems,
4
3Jortho = 8.1 Hz, Jmeta = 1.8 Hz, 4 H, 14,15-H and 17,18-H), 6.86,
6.19, 6.16, 6.13, and 6.12 (5ϫ s, 6 H, 6,9-H and 2ϫ =CH2), 4.59
2
and 3.63, and 4.33 and 4.02 (two AB systems, Jgem = 11.8 Hz, 4
H, 3,10-H2), 2.47 and 1.96 (2ϫ s, 6 H, 2ϫ CH3) ppm. 13C NMR:
δ = 152.5 and 152.1 (C-1,12), 136.1, 135.2, 135.1, 134.2, 129.0,
128.6 (C-4,5,7,8,13,16), 135.9 and 131.6 (C-6,9), 127.5, 126.1,
125.3, 124.5 (C-14,15,17,18), 115.3 and 115.2 (2ϫ =CH2), 64.0 and
60.3 (C-3,10), 19.8 and 19.0 (2ϫ CH3) ppm. C20H20O2S2 (356.50):
calcd. C 67.38, H 5.65; found C 67.30, H 5.66.
(rel-RS,RS,Rp)- or (rel-RS,RS,Sp)-5,8-Dimethyl-1,12-dimethylene-
2,11-dithia[3.3]parametacyclophane 2,11-Dioxide (5a) (more mobile
by chromatography): Racemate 5a was prepared, together with its
diastereoisomer 5b and compound 6, from 1,3-diethynylbenzene
and disulfoxide 3 by following the general procedure. Compound
5a was isolated after chromatographic purification (ethyl acetate/
hexane, 2:8) as a white solid (0.06 g, 17%); Rf = 0.47 (ethyl acetate/
hexane, 8:2) that decomposed before melting (Ͼ 170 °C). 1H NMR:
δ = 7.26–7.15 (m, 3 H, 14–16-H), 6.64 (s, 2 H, 6,9-H), 6.17 and
Dimethyl 3,3Ј-[(2,5-Dimethyl-1,4-phenylene)bis(methylenethio)]di-
propanoate (2): To a solution of 1 (0.50 g, 2.5 mmol) in anhydrous
THF (6 mL), under an argon atmosphere at –78 °C, Triton B solu-
tion (40 wt.-% in MeOH, 0.68 mL, 1.5 mmol) was added. After
5 min stirring at –78 °C, methyl acrylate (0.57 mL, 6.3 mmol) was
added and the reaction (monitored by TLC every 5 min) was al-
lowed to proceed until completion (ca. 30 min). The reaction mix-
ture was concentrated in vacuo and the crude residue was purified
by flash column chromatography (ethyl acetate/hexane, 2:8) to pro-
vide disulfide 2 (0.75 g, 80%) as a transparent oil; Rf = 0.60 (ethyl
acetate/hexane, 4:6). 1H NMR: δ = 6.99 (s, 2 H, ArH), 3.69 (s, 6
H, 2ϫ OCH3), 3.68 (s, 4 H, 2ϫ ArCH2), 2.74 and 2.58 (2ϫ t, 3Jvic
= 7.0 Hz, 8 H, 2ϫ CH2CH2), 2.32 (s, 6 H, 2ϫ ArCH3) ppm. 13C
NMR: δ = 172.3 (2ϫ CO), 134.6 and 134.0 (C-1,2,4,5), 132.0 (C-
3,6), 51.8 (2ϫ OCH3), 34.5 (2ϫ CH2CH2CO2CH3), 34.1 (2ϫ
ArCH2), 26.8 (2ϫ CH2CO2CH3), 18.5 (2ϫ ArCH3) ppm.
C18H26O4S2 (370.52): calcd. C 58.35, H 7.07; found C 58.42, H
7.05.
4
5.98 (2ϫ s, 4 H, 2ϫ =CH2), 6.15 (t, Jmeta = 1.5 Hz, 1 H, 18-H),
2
4.53 and 4.02 (AB system, Jgem = 12.3 Hz, 4 H, 3,10-H2), 1.99 (s,
6 H, 2ϫ CH3) ppm. 13C NMR: δ = 152.1 (C-1,12), 134.9, 134.6,
and 129.3 (C-4,5,7,8,13,17), 132.7 (C-6,9), 127.7 and 127.0 (C-
14,15,16), 122.9 (C-18), 117.9 (2ϫ =CH2), 60.7 (C-3,10), 19.8 (2ϫ
CH3) ppm. C20H20O2S2 (356.50): calcd. C 67.38, H 5.65; found C
67.40, H 5.67.
(rel-RS,RS,Rp)- or (rel-RS,RS,Sp)-5,8-Dimethyl-1,12-dimethylene-
2,11-dithia[3.3]parametacyclophane-2,11-dioxide (5b) (less mobile by
chromatography): Racemate 5b was prepared, together with its dia-
stereoisomer 5a and compound 6, from 1,3-diethynylbenzene and
disulfoxide 3 by following the general procedure. Compound 5b
was isolated after chromatographic purification (ethyl acetate/hex-
ane, 2:8) as a white solid (0.06 g, 17%) that decomposed before
melting (Ͼ 170 °C); Rf = 0.45 (ethyl acetate/hexane, 8:2). 1H NMR:
δ = 7.26–7.22 (m, 3 H, 14–16-H), 6.46 (s, 2 H, 6,9-H), 6.10 and
5.99 (2ϫ s, 4 H, 2ϫ =CH2), 5.97 (br. s, 1 H, 18-H), 4.82 and 3.61
Dimethyl 3,3Ј-[(2,5-Dimethyl-1,4-phenylene)bis(methylenesulfinyl)]-
dipropanoate (3): A solution of 2 (0.33 g, 0.89 mmol) in CH2Cl2
(9 mL) was stirred at –78 °C and a solution of m-CPBA (Ͻ 77%,
0.40 g, 1.8 mmol) in CH2Cl2 (13 mL) was slowly added. The reac-
tion was monitored by TLC and appeared to be complete by the
end of the oxidant addition. The mixture was quenched by adding
aqueous Na2S2O3 (10 wt.-%) and the combined organics were
washed twice with a satd. NaHCO3 solution and twice with brine,
dried (Na2SO4), filtered, and concentrated to give 3 (0.36 g) in al-
most quantitative yield as a white solid diastereomeric racemate
mixture; Rf = 0.10 (acetone/hexane, 7:3); m.p. 120–122 °C. 1H
NMR: δ = 7.09 (s, 2 H, ArH), 4.01 (AB m, 4 H, 2ϫ ArCH2), 3.71
(s, 6 H, 2ϫ OCH3), 3.08–2.82 (m, 8 H, 2ϫ CH2CH2), 2.35 (s, 6
H, 2ϫ ArCH3) ppm. 13C NMR: δ = 171.7 (2ϫ CO), 135.5 (C-2,5),
133.7 (C-3,6), 129.7 (C-1,4), 57.0 (2ϫ ArCH2), 52.2 (2ϫ OCH3),
46.3 (2ϫ CH2CH2CO2CH3), 26.6 (2ϫ CH2CO2CH3), 19.4 (2ϫ
ArCH3) ppm. C18H26O6S2 (402.52): calcd. C 53.71, H 6.51; found
C 53.85, H 6.53.
2
(AB system, Jgem = 12.3 Hz, 4 H, 3,10-H2), 2.13 (s, 6 H, 2 ϫ
CH3) ppm. 13C NMR: δ = 152.2 (C-1,12), 134.8, 134.6 and 129.3
(C-4,5,7,8,13,17), 132.1 (C-6,9), 127.8 and 127.4 (C-14,15,16), 122.6
(C-18), 117.7 (2 ϫ =CH2), 63.4 (C-3,10), 19.1 (2 ϫ CH3) ppm.
C20H20O2S2 (356.50): calcd. C 67.38, H 5.65; found C 67.45, H
5.65.
(rel-RS,SS,Rp)-5,8-Dimethyl-1,12-dimethylene-2,11-dithia[3.3]para-
metacyclophane 2,11-Dioxide (6): Compound 6 was prepared, to-
gether with compounds 5a and 5b, from 1,3-diethynylbenzene and
disulfoxide 3 by following the general procedure. Compound 6 was
isolated after chromatographic purification (ethyl acetate/hexane,
2:8) as a white solid (0.18 g, 0.50 mmol, 50%) that decomposed
before melting (Ͼ 170 °C); Rf = 0.44 (ethyl acetate/hexane, 8:2). 1H
NMR δ = 7.20 (t, 3Jortho = 7.6 Hz, 1 H, 15-H), 6.99 (m, 2 H, 14,16-
H), 6.82 and 6.26 (2ϫ s, 2 H, 6,9-H), 6.24, 6.19, 5.98 and 5.92 (4ϫ
Thermolysis of Disulfoxide 3 in the Presence of Diethynylbenzene.
General Procedure: A solution of disulfoxide 3 (0.40 g, 0.99 mmol)
and commercial diethynyl acceptor (0.13 g, 1.0 mmol) in DCE
(100 mL) was heated at reflux temp. (83 °C) until the reaction ap-
peared to be complete (TLC; disappearance of starting sulfoxide
and intermediate products 8/9), the solvent was removed under re-
duced pressure and the crude material was purified by column
chromatography on silica gel to give dithiacyclophane S,SЈ-dioxides
4–6.
4
s, 4 H, 2ϫ =CH2), 6.11 (t, Jmeta = 1.8 Hz, 1 H, 18-H), 4.94 and
2
3.34, and 4.64 and 3.86 (two AB systems, Jgem = 12.0 Hz, 4 H,
3,10-H2), 2.31 and 1.88 (2ϫ s, 6 H, 2ϫ CH3) ppm. 13C NMR: δ =
153.5 and 152.2 (C-1,12), 136.4, 135.0, 134.5, 134.1, 130.6, 129.5
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A. Barattucci et al.
FULL PAPER
(C-4,5,7,8,13,17), 133.0 and 131.0 (C-6,9), 128.1, 128.0, 127.3 and
127.0 (C-14–16,18), 117.6 and 117.3 (2ϫ =CH2), 65.6 and 61.6 (C-
3,10), 19.9 and 18.9 (2ϫ CH3) ppm. C20H20O2S2 (356.50): calcd. C
67.38, H 5.65; found C 67.26, H 5.66.
Acknowledgments
The authors thank the Ministero dell’Università e della Ricerca
(MIUR) for financial support (PRIN 20109Z2XRJ_010).
Methyl (rel-RS,RS)- and (rel-RS,SS)-3-{(2,5-Dimethyl-1,4-phenyl-
ene)-1-(methylenesulfinyl)-4-([1-(3-ethynylphenyl)ethenyl]sulfinyl-
methylene)}propanoate (8): A solution of disulfoxide 3 (0.40 g,
0.99 mmol) and 1,3-diethynylbenzene (0.13 g, 1.0 mmol) in DCE
(100 mL) was heated to reflux temp. (83 °C). After 24 h, the solvent
was removed under reduced pressure and the crude material was
purified by flash column chromatography on silica gel (acetone/
hexane, 2:8), giving, together with the expected dithiacyclophane
S,SЈ-dioxides 5 and 6 (31% overall yield) and the starting disulfox-
ide 3 (60% yield), compound 8 (0.04 g, 0.09 mmol, 9%), as a low-
melting solid; Rf = 0.43 (acetone/hexane, 5:5). 1H NMR: δ = 7.51–
7.35 (m, 4 H, 2Ј,4Ј,5Ј,6Ј-H), 7.00 and 6.92 (2ϫ s, 2 H, 3,6-H), 6.09
and 6.06 (2ϫ s, 2 H, =CH2), 4.11–3.68 (m, 4 H, 2ϫ ArCH2), 3.72
and 3.71 (2ϫ s, 3 H, OCH3), 3.14 (s, 1 H, ϵCH), 3.05–2.84 (m, 4
H, CH2CH2), 2.30, 2.18 and 2.17 (3ϫ s, 6 H, 2ϫ ArCH3) ppm.
13C NMR: δ = 171.4 (CO), 152.2 (C=CH2), 135.2–126.8 (C-
1,1Ј,2,2Ј,3,4,4Ј,5,5Ј,6,6Ј), 123.2 (C-3Ј), 118.1 (=CH2), 82.5
(CϵCH), 78.5 (ϵCH), 58.2 and 56.9 (2ϫ ArCH2), 52.2 (OCH3),
46.0 and 26.9 (CH2CH2), 19.2 and 19.1 (2 ϫ ArCH3) ppm.
C24H26O4S2 (442.59): calcd. C 65.13, H 5.92; found C 65.23, H
5.93.
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Methyl (rel-RS,RS)- and (rel-RS,SS)-3-{(2,5-Dimethyl-1,4-phenyl-
ene)-1-(methylenesulfinyl)-4-([1-(4-ethynylphenyl)ethenyl]sulfinyl-
methylene)}propanoate (9): A solution of disulfoxide 3 (0.40 g,
0.99 mmol) and 1,4-diethynylbenzene (0.13 g, 1.0 mmol) in DCE
(100 mL) was heated at reflux temp. (83 °C). After 24 h, the solvent
was removed under reduced pressure and the crude material was
purified by flash column chromatography on silica gel (ethyl acet-
ate/hexane, 3:7), giving, together with the expected dithiacyclo-
phane S,SЈ-dioxide 4 (28% yield) and the starting disulfoxide 3
(64% yield), compound 9 (0.03 g, 0.08 mmol, 8%) as a low-melting
solid; Rf = 0.38 (ethyl acetate/hexane, 8:2). 1H NMR: δ = 7.50 and
7.37 (AB system, 3Jortho = 8.3 Hz, 4 H, 2Ј,3Ј,5Ј,6Ј-H), 7.01 and 6.89
(2ϫ s, 2 H, 3,6-H), 6.09 and 6.06 (2ϫ s, 2 H, =CH2), 4.05–3.69
(m, 4 H, ArCH2), 3.71 (s, 3 H, OCH3), 3.18 (s, 1 H, ϵCH), 3.03–
[9] M. C. Aversa, P. Bonaccorsi, P. Giannetto, S. M. A. Jafari,
D. N. Jones, Tetrahedron: Asymmetry 1992, 3, 701–704.
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2.82 (m, 4 H, CH2CH2), 2.29, 2.28 and 2.19 (3 ϫ s, 6 H, 2 ϫ [11] a) M. C. Aversa, A. Barattucci, P. Bonaccorsi, F. Marino-
ArCH3) ppm. 13C NMR: δ = 171.7 (CO), 152.5 (C=CH2), 135.1
and 134.4 (C-2,5), 133.8 and 133.1 (C-3,6), 132.8 (C-3Ј,5Ј), 129.5
and 128.7 (C-1,1Ј,4), 126.4 (C-2Ј,6Ј), 123.3 (C-4Ј), 118.1 (=CH2),
82.7 (CϵCH), 79.0 (ϵCH), 58.3 and 56.9 (2 ϫ ArCH2), 52.2
(OCH3), 46.0 and 26.9 (CH2CH2), 19.2 (2 ϫ ArCH3) ppm.
C24H26O4S2 (442.59): calcd. C 65.13, H 5.92; found C 65.05, H
5.94.
Merlo, A. Mastino, M. T. Sciortino, Bioorg. Med. Chem. 2009,
17, 1456–1463; b) P. Bonaccorsi, F. Marino-Merlo, A. Ba-
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A. Mastino, Bioorg. Med. Chem. 2012, 20, 3186–3195.
[12] Thermolysis of disulfoxide 3 with para-diethynylbenzene was
performed in 1,4-dioxane (100 °C) and in benzene (80 °C). In
the first case, we obtained only sulfenic acid self-condensation
products, in the second case, results similar to those of the reac-
tion performed in DCE were obtained. Thus, the thermolysis
temperature appears to be crucial for the formation of dithiacy-
clophane S,SЈ-dioxides.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all key intermediates
Received: October 31, 2013
Published Online: February 3, 2014
and final products and NOESY spectra for compound 6.
2104
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Eur. J. Org. Chem. 2014, 2099–2104