Versatile synthesis of tunable N,S-bridged-[1.1.1.1]-cyclophanes promoted by ester functions

Article abstract of DOI:10.1016/j.tet.2016.08.034

We report herein a powerful and highly adaptable metal-free organic synthetic route to functionalized N,S- bridged-[1.1.1.1]-cyclophanes using an ester-promoted macrocyclisation step. The newly synthesized cyclophanes are obtained in good yields exhibitin

Full text of DOI:10.1016/j.tet.2016.08.034

Accepted Manuscript
Versatile synthesis of tunable N,S-bridged-[1.1.1.1]-cyclophanes promoted by ester
functions
Volodymyr Malytskyi, Vinicius Demetrio da Silva, Olivier Siri, Michel Giorgi, Jean-
Manuel Raimundo
PII:
S0040-4020(16)30801-8
10.1016/j.tet.2016.08.034
TET 28015
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 April 2016
Revised Date: 10 August 2016
Accepted Date: 11 August 2016
Please cite this article as: Malytskyi V, da Silva VD, Siri O, Giorgi M, Raimundo J-M, Versatile synthesis
of tunable N,S-bridged-[1.1.1.1]-cyclophanes promoted by ester functions, Tetrahedron (2016), doi:
10.1016/j.tet.2016.08.034.
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Volodymyr Malytskyi, Vinicius Demetrio da Silva, Olivier Siri, Michel Giorgi and Jean-Manuel Raimundo

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1
Tetrahedron
journal homepage: www.elsevier.com
Versatile synthesis of tunable N,S-bridged-[1.1.1.1]-cyclophanes promoted by
ester functions
a
a
a
b
Volodymyr Malytskyi, † Vinicius Demetrio da Silva, † Olivier Siri, Michel Giorgi and Jean-Manuel
Raimundo *
a,
a
Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix-Marseille Université, CNRS UMR 7325, 163 Ave de Luminy case 913, 13288 Marseille
Cedex 09, France. Email: jean-manuel.raimundo@univ-amu.fr
b
Spectropole FR 1739, Aix Marseille Université, Campus scientifique de Saint Jérôme, 13397 Marseille France.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report herein a powerful and highly adaptable metal-free organic synthetic route to
functionalized N,S- bridged-[1.1.1.1]-cyclophanes using an ester-promoted macrocyclisation
step. The newly synthesized cyclophanes are obtained in good yields exhibiting (i) high
solubility, allowing the possibility to enlarge the scope and chemistry for such macrocycles, (ii)
Available online
a tunable cavity and (iii) orthogonal functional groups.
2
015 Elsevier Ltd. All rights reserved.
Keywords: Organic synthesis, Macrocycles, SNAr
[1.1.1.1]-Cyclophanes
1
. Introduction
and efficiency of these reactions led us to extend this strategy by
widening it to innovative molecular scaffolds that could
overcome those drawbacks. For this purpose, aromatic rings
substituted with carbonyl groups (C=O); such as ketones,
aldehydes, esters and so on; could be envisioned as interesting
alternatives. Surprisingly, solely one example, based on a diketo
substituted benzene, has been described for the synthesis of
1
Cyclophanes are natural or synthetic strained cage-like
structures that play a prominent role in host-guest chemistry and
supramolecular
encompass among others, pillararenes and calixarenes
derivatives. They are widely used in a variety of applications
including analytical detection or sensing, catalysis, medicine
assemblies.
Cyclophanes
architectures
2
3
4
5
6
10
soluble symmetrical thiacalix[n]arenes. Moreover, the scarcity
7
and materials technology. Although these macrocycles can be
readily obtained in good yields from commercially available
starting materials, their synthesis suffer oftenly of a lack of
compatibility with functionalized monomers due to the harsh
synthetic conditions used. Indeed, in several cases, it appears
difficult to avoid the formation of by-products that render their
of functional groups on these macrocycles can limit considerably
their uses. Therefore, the insertion of orthogonal functional
groups or atoms either on the aromatic subunits or in the bridges
is of great of importance and interest. For all of these reasons, we
turned out our attention on the use of the diethyl 4,6-
dibromoisophthalate 2 derivative that fulfills all required criteria
for the well-established synthetic pathway. Furthermore, to the
best of our knowledge, this molecule is hitherto unknown in the
macrocyclic chemistry field.
8
purifications somewhat tricky and tedious. Therefore, a peculiar
attention has to be paid in order to develop efficient synthetic
protocols leading to cyclophanes with high yields and under mild
conditions.
O N
NO2
EtO C
CO Et
2
2
2
In this respect, nucleophilic aromatic substitution reactions
(SNAr) appeared to be an attractive synthetic approach that has
F
F
Br
Br
been successfully9 applied for the preparation of
heteracalix[4]arenes. The reaction requires two entities namely a
nucleophile and an electron-poor aromatic ring (acting as an
electrophile). A rapid literature survey shows that in most cases,
the involved electrophile corresponds to a triazine ring or an
aromatic ring bearing electron-withdrawing groups such as CN,
SO H or NO . Among them, the dinitrobenzene derivative 1 has
been widely used as electrophile. However the lack of solubility
of the obtained macrocycles prevents the possibility to extend
their scope and chemistry, as they are only soluble in solvent
such as DMF or DMSO. Nevertheless the simplicity, versatility
1
2
Thus, we describe herein a simple intuitive, iterative and modular
synthetic strategy, based on SNAr reactions of 1 and 2, that one
may give easy access to asymmetric structures in which the
orthogonal chemical groups, the sizes cavities and the
heteroatoms positions can be finely controlled. For this aim, we
have focused our work on the synthesis of mixed N,S-[1.1.1.1]-
heteraphanes that are at the cross-road of two major classes of
macrocycles, namely the thia- and aza-[1.1.1.1]-cyclophanes, in
order to combine their concomitant properties.
3
2
9

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2
Tetrahedron
2
. Results and discussion
behavior indicates that esters functions are seemingly suitable to
replace the nitro group in the engineering of novel cyclophanes
even if these intramolecular interactions are slightly weaker
comparing to the nitro counterparts.
2
.1 Synthesis
Diethyl 4,6-dibromoisophthalate 2 was readily synthetized from
m-xylene in three steps according to reported literature
procedures.
11
The key intermediate 2 was then further reacted, in presence of
NaH in DMF, with 2 equiv. of 3-aminothiophenol 6 leading to
the symmetrical triaryl 9 as an off-white solid in 69% yield after
purification by column chromatography over SiO . Similarly,
2
intermediates 10 and 11 have been prepared by condensation of 2
and 2-aminothiophenol 7 or 4-aminothiophenol 8 to furnish 10
and 11 in 66% and 61% yield, respectively (Scheme 1). The ring
closure step was achieved by condensation of the triaryl units 9,
9
10
11
1
0 and 11 with 1,5-difluoro-2,4-dinitrobenzene 1 in CH CN
3
under reflux over 18 h in presence of N(iPr) Et. The target N,S-
Figure 1. ORTEP view of the pre-organized intermediates 9, 10 and 11
2
[
1.1.1.1]-heteraphanes precipitated in the reaction medium and
(black: C; blue: N; green: S and red:O, for clarity H are omitted).
were isolated by filtration as orange-yellow solids in 61-77%. All
1
1
obtained macrocycles have been thoroughly characterized by H
2.3 H NMR analysis
13
NMR, C NMR, mass spectrometry and elemental analysis.
1
In addition, the survey of the H NMR spectra reveals that all
EtO2C
S
CO2Et
S
NH2
EtO2C
S
CO2Et
S
macrocycles 12-14 adopt preferably the 1,3-alternate
conformation as evidenced by the chemical shift observed for the
intra-annular protons Ha and Ha’ (Table 1). Moreover the inner
protons (Ha and Ha’) experiencing the diamagnetic shielding of
the adjacent aromatic rings can act as internal probes for the size
cavity. In addition, the inner proton Ha is slightly outside of the
area of maximum shielding comparatively to the Ha’ protons
located on the nitrogenated part of the N,S-[1.1.1.1]-heteraphanes
6
SH
1
NaH 0 °C DMF
then 50 °C , 18h
DIPEA, CH3CN
reflux 18h
6
9%
NH2 H2N
61%
HN
NH
9
O2N
NO2
1
2
EtO2C
S
CO2Et
S
EtO2C
S
CO2Et
S
H2N
SH
9i, 13
which is in accordance with previous results.
1
7
NaH 0 °C DMF
then 50 °C , 18h
DIPEA, CH3CN
reflux 18h
Table 1. Relative chemical shift (ppm) of the inner and outer protons Ha,
2
3
Ha’ and Hb, Hb’ respectively in CDCl .
6
6%
65%
HN
NH
NH2
H2N
O2N
NO2
1
0
1
3
EtO2C
S
CO2Et
S
H2N
EtO2C
S
CO2Et
S
8
SH
1
DIPEA, CH3CN
reflux 18h
NaH 0 °C DMF
then 50 °C , 18h
6
1%
77%
HN
NH
3 x
Chemical shift δ (ppm) in CDCl of inner and outer H
NH2
NH2
O2N
NO2
11
δ
Ha
δ
Ha’
δ
Hb
δ
Hb’
1
4
1
1
1
2
3
4
6.31
6.34
6.91
4.86
4.96
5.77
8.17
8.67
8.66
8.99
9.25
9.29
Scheme 1. Synthesis of mixed N,S-[1.1.1.1]-heteraphanes 12-14.
2
.2 Crystallographic analysis of intermediates
The macrocyclization step was performed at high concentrated
These data are also consistent with both the presence that limit
the conformation changes at the NMR timescale (electrostatic
solution. As previously demonstrated for mixed
heteracalix[4]arenes, a pre-organized intermediate controlled by
9i
+
12
interactions coming from the S atom (� δ , due to its conjugation
electrostatic interactions between the d orbitals of the sulfur
-
+
with the dinitrobenzene ring) and the oxygen atom ( δ , in the
atom ( δ , due to its conjugation with the diethyl isophthalate
-
adjacent C=O group) and hydrogen bonding coming from the N–
ring) and the p orbitals of the oxygen atom (δ , of the carbonyl in
H----O N intramolecular H-bonds) and
a strong push-pull
2
the adjacent CO Et group), might be formed during the course of
2
conjugation-type effect developed between the bridges (acting as
a donor) and the ester or nitro groups (acceptor part). Indeed the
measured S-C bond lengths (from crystallographic data of the
derivatives 9,10, 11 d(C-S) 1.82Å > d(C-S)o,m,p 1.768-1.778Å > d(C=S)
1.61Å) are comprised between a single and double bond and the
measured angles are nearly about 120° (119.22° < θ < 120.32°)
the reaction, favoring the macrocyclisation step.
This hypothesis is clearly supported in each case by the analysis
of the crystallographic structure of the single crystals of 9, 10 and
1
1 (Figure 1). Indeed, all crystal structures display a non-planar
architecture and the examination of the S--O=C distances
ranging from 2.668 Å < d(S---O=C-OEt) < 2.780 Å) shows that
2
(
suggesting a sp character which induces a quasi-planar geometry
these distances are significantly shorter than the sum of the van
der Waals radii of oxygen and sulfur (3.25 Å) which evidences
the occurrence of strong intramolecular interactions. This
of the bridges. These two effects contribute conjointly to restrict
thermodynamically the internal rotation.

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3
2
.4 Optical and electrochemical properties
3
The optical properties of these new macrocycles 12-14 have been
1
1
investigated by UV-Visible spectroscopy in CHCl (Figure 2,
3
Table 2) and interesting features can be deduced from their
optical spectra. The three novel N,S-[1.1.1.1]-heteraphanes
present the same appearance characterized by three main
absorbance bands that are red-shifted from the ortho to the para-
substituted derivative. Thus, the lowest energy band
corresponding to the charge transfer band, related to the intrinsic
push-pull effect of these structures, is almost centered at the same
wavelenght for all compounds. Indeed, only a slight red-shift is
observed because the push-effect involves only the heteratoms
linked to the electron deficient rings which are the same in all
cases. However, the main bathochromic shift is observed for the
principal π-π* absorbance band originating from the substitution
pattern. Therefore the highest red-shift is observed for the para-
substituted derivative 14. Interestingly, depending on the
substitution pattern, the macrocycles show a more constrained
character resulting in the emergence of a fine vibronic structure.
Hence, the most constrainted macrocycle in this series appears to
be the heteraphane 12 having the smallest cavity.
-
-3
1
2
13
14
-
5
7
-
-9
-
1.75
-0.75
E(V) 0.25
1.25
Figure 3. Cyclic voltammograms for compounds 12, 13 and 14.
-
Table 3. Oxidation and reduction potentials for compounds 12, 13 and 14 10
M in DMF, 0.1 M Bu NPF , Pt (WE) Ag/AgCl v= 100 mV/s.
3
4
6
[a]
[a]
[a]
[a]
E
1/2(ox
1
)
E
1/2(ox
2
)
E
1/2(red
1
)
2
E1/2(red )
1
1
1
2
3
4
0.14
0.13
0.11
0.60
0.51
0.46
-0.92
-0.92
-0.90
-1.42
-1.33
-1.33
2
1
0
.5
[
a]
12
13
14
E (V) vs Ag/AgCl obtained from the deconvulated voltammograms
2
3
. Conclusion
.5
1
In conclusion, we have herein established a powerful and highly
adaptable route to functionalized heteraphanes. Indeed, three
novel mixed N,S-bridged [1.1.1.1]-cyclophanes 12-14 have been
effortlessly synthesized via a simple intuitive and modular
synthesis based on nucleophilic aromatic substitution reactions
.5
(SNAr). Importantly, we have clearly demonstrated that the ester
0
fragment constitutes a very promising alternative relative to the
nitro group, since the newly designed N,S-diethylcarboxlate-
dinitro-heteraphanes compounds are much more soluble
250
300
350
400
450
500
λ(nm)
compared to their tetranitro analogues. As shown, the CO R
2
Figure 2. Optical properties for compounds 12, 13 and 14.
fragment is able to promote macrocyclisation in high
concentrated medium due to the presence of intramolecular
interactions. Finally, following the adopted strategy,
unprecedented mixed -heteraphanes, associated with various
functional groups have been obtained. The methodology has been
shown to be valuable and worth to be pursued with the
emergence of a novel class of mixed N,S-heterophanes.
Undoubtedly this feature opens new perspectives in cyclophane’s
chemistry and chemical modifications on esters and nitro
functions are now under investigations.
Table 2. Absorption maximum (λabs, nm) and molar extinction coefficient
-1
-1
(
log (ε) L.mol .cm ) of compounds 12-14 in CHCl
3
.
1
2
13
14
λ
abs
Log ε
λ
abs
Log ε
λ
abs
Log ε
3
3
2
97
12
79
3.95
4.44
4.40
398
330
277
3.99
4.56
4.48
403
340
301
4.06
4.64
4.51
4
. Experimental section
.1 General
Analysis of the cyclic voltammograms (CV) of macrocycles 12-
4 has revealed similar characteristics. They display two
4
1
irreversible one-electron reduction redox system corresponding
to the formation of the radical anion on each electron poor rings
present on the molecular scaffold (Figure 3 - Table 3). All
compounds exhibit close values for E (red ) and E (red ) as
All commercially available products and reagents were
purchased from Alfa Aesar (mercaptoaniline derivatives;
acetonitrile;
N,N-diisopropylethylamine) or Sigma-Aldrich
(NaH (60% in mineral oil); anhydrous dimethylformamide;
ethanol, cyclohexane, ethylacetate) and used as received.
Mercaptoaniline derivatives may be hazardous; handle with
care and read the MSDS. Reactions were performed in air
unless otherwise specified. TLC analysis was performed on
E. Merck silica gel 60 F254 precoated plates (0.25 mm) and
flash chromatography was performed with the indicated
solvent systems using silica gel grade 60 (230-400 mesh).
1/2
1
1/2
2
well as for E (ox ) and E (ox ) suggesting that both geometric
1/2
1
1/2
2
and/or steric parameters as well as the nature of the heteroatoms
contribute to these small changes. Indeed, the small variations
observed for the reduction potentials can be correlated to the
angle formed between the two aromatic rings bearing the ester
and nitro electron withdrawing groups. These features are also in
agreement with the spectral behaviors.
1
13
All spectra H and C NMR spectra were recorded at 21°C
in the indicated solvent with a Jeol spectrometer, operating

ACCEPTED MANUSCRIPT
4
Tetrahedron
+
+
-
at 400 and 101 MHz, respectively. Chemical shifts are
reported in δ units, in parts per million (ppm) and the
486.1 ([M+NH ] ), 491.1 ([M+Na] ); ESI-MS(-): 467.1 ([M-H] ),
4
-
527.0 ([M+Ac] ). EA calc. (%): C 61.52, H 5.16, N 5.98, S 13.69;
found (%): C 61.22, H 5.16, N 5.73, S 12.94.
1
13
resonance multiplicity in the H and C NMR were
described as s (singlet), d (doublet), t (triplet), m (multiplet).
Elemental and MS analyses were performed at the
Bis-1,3-(4-phenyleneamino sulphide) 4,6-diethylisophthalate
(11). 4-aminothiophenol 8 0.550 g (4.40 mmol) was dissolved in
10 mL of dry DMF under an argon atmosphere. To the ice-cooled
solution was added portionwise 0.176 g (4.40 mmol) of sodium
hydride (60% in mineral oil). The solution was further stirred 10
min. and 0.760 g (2.00 mmol) of diethyl 4,6-dibromoisophthalate
2 was added in one portion. The reaction was allowed to warm
up to room temperature and then heated at 50°C for 18 hours
(brownish solution). Then the solvent was removed under
reduced pressure to afford a brownish residue. The latter was
Spectropole of Marseille. Compound
three steps as follow: the first step has consisted in the
brominating of the m-xylene affording the 1,3-dibromo-
,6-dimethylbenzene in 82% yield as a white solid. The
2 was synthetized in
3
4
4
latter one was successfully oxidized using conventional
methodology with KMnO in a mixture of H O/tert-BuOH
leading to the 4,6-dibromoisophthalic acid
in 69% yield. Finally the obtained 4,6-dibromoisophthalic
acid was esterified following the procedure described by
Wong et al affording diethyl 4,6-dibromoisophthalate in
4
2
5
as a white solid
5
2
taken into CHCl and the organic phase was washed with water.
3
93% yield as a white solid.
The organic layer was dried over MgSO4, filtered and the solvent
was removed under reduced pressure. The crude solid was
4.2 Synthesis
purified by column chromatography over SiO
2
using
cyclohexane: ethyl acetate to afford 573 mg (61%) as an off-
Bis-1,3-(2-phenyleneamino sulphide) 4,6-diethylisophthalate
9). 2-aminothiophenol 6 0.550 g (4.40 mmol) was dissolved in
0 mL of dry DMF under an argon atmosphere. To the ice-cooled
solution was added portionwise 0.176 g (4.40 mmol) of sodium
hydride (60% in mineral oil). The solution was further stirred 10
min. and 0.760 g (2.00 mmol) of diethyl 4,6-dibromoisophthalate
1
white solid. H NMR (CDCl , δ ppm): 8.59 (s, 1H), 7.02 (d, J =
3
(
1
8
7
.40 Hz, 4H), 6.56 (d, J = 8.40 Hz, 4H), 6.37 (s, 1H), 4.41 (q, J =
.10 Hz, 4H), 1.40 (s, 4H) 1.42 (t, J = 7.10 Hz, 6H). C NMR
13
(
CDCl , δ ppm): 165.88, 137.24, 134.00, 124.01, 121.20, 117.84,
3
1
16.73, 61.37, 14.53. Mp (°C): > 155, decomposition. ESI-
+ +
MS(+): 469.1 ([M+H] ), 491.1 ([M+Na] ); ESI-MS(-): 467.1
2
was added in one portion. The reaction was allowed to warm
-
-
([M-H] ), 527.1 ([M+Ac] ). EA calc. (%): C 61.52, H 5.16, N
up to room temperature and then heated at 50°C for 18 hours.
Then the solvent was removed under reduced pressure and the
5
.98, S 13.69; found (%): C 61.14, H 5.11, N 5.82, S 13.00.
viscous oil obtained was taken up into 100 mL of CHCl and the
organic phase was washed with 100 mL of water. The organic
3
1
,21-dithia-8,14-diaza-10,12-dinitro-23,25-
diethylcarboxylatecyclophane (12). A mixture of 9 (0.200 g,
.42 mmol) and 4,6-difluoro-1,3-dinitrobenzene 1 (0.087 g, 0.42
phase was dried over MgSO affording a 1.10 g of crude solid.
4
0
The crude product was purified by column chromatography over
mmol) in 10 mL of dry CH CN was heated to reflux until
3
SiO using cyclohexane: ethyl acetate (6:4 then 5:5) affording
2
1
complete dissolution of the materials. Then 0.300 mL (2.76
mmol) of N,N-diisopropylethylamine was added dropwise. The
solution became slightly orange and maintained under reflux over
6
8
7
8
48 mg (69%) of an off-white solid. H NMR (CDCl , δ ppm):
3
.65 (s, 1H), 7.14 (dd, J = 7.70, 1.50 Hz, 2H), 7.10 (ddd, J = 8.90,
.60, 1.60 Hz, 2H), 6.56 (td, J = 7.40, 1.10 Hz, 2H), 6.50 (dd, J =
.10, 1.10 Hz, 2H), 6.28 (s, 1H), 4.43 (q, J = 7.10 Hz, 4H), 3.90
4
8h. The reaction mixture was cooled, diluted with
13
dichloromethane, washed with water and brine, dried under
MgSO and the solvents were removed under reduced pressure.
The product was recrystallized from mixture DCM/EtOH,
filtered and dried affording 161 mg of the titled macrocycle (61%
yield) as an orange solid. H NMR (CDCl , δ ppm): 9.00 (s, 2H),
8
(s, 4H), 1.44 (t, J = 7.10 Hz, 6H). C NMR (CDCl , δ ppm):
3
4
1
1
65.84, 149.10, 146.99, 137.21, 134.48, 132.06, 123.13, 122.68,
19.10, 115.90, 112.13, 61.54, 14.53.+ Mp (°C): >193,
+
decomposition. ESI-MS(+): 469.1 ([M+H] ), 491.1 ([M+Na] ),
1
+
-
-
3
5
07.0 ([M+K] ); ESI-MS(-): 467.0 ([M-H] ), 527.1 ([M+Ac] ).
EA calc. (%): C 61.52, H 5.16, N 5.98, S 13.69; found (%): C
2.29, H 5.47, N 5.72, S 12.83.
.99 (s, 1H), 8.17 (s, 1H), 7.70 (dd, J = 7.60, 1.50 Hz, 2H), 7.37
(
(
td, J = 7.60, 1.50 Hz, 2H), 7.30 (td, J = 7.70, 1.40 Hz, 2H), 7.19
d, J = 7.70 Hz, 2H), 6.31 (s, 1H), 4.86 (s, 1H), 4.37 (q, J = 7.10
6
13
Hz, 4H), 1.41 (t, J = 7.10 Hz, 6H). C NMR (CDCl , δ ppm):
1
1
3
Bis-1,3-(3-phenyleneamino sulphide) 4,6-diethylisophthalate
10). 3-aminothiophenol 7 0.550 g (4.40 mmol) was dissolved in
0 mL of dry DMF under an argon atmosphere. To the ice-cooled
65.21, 147.91, 144.39, 141.47, 138.98, 133.12, 131.64, 131.59,
31.38, 129.23, 128.18, 125.34, 124.98, 99.02, 62.03, 14.37. Mp
(
1
+
(°C): > 175, decomposition. ESI-MS(+): 633.1 ([M+H] ), 650.1
solution was added portionwise 0.176 g (4.40 mmol) of sodium
hydride (60% in mineral oil). The solution was further stirred 10
min. and 0.760 g (2.00 mmol) of diethyl 4,6-dibromoisophthalate
+
-
([M+NH ] ); ESI-MS(-): 631.1 ([M-H] ). EA calc. (%): C 56.95,
4
H 3.82, N 8.86, S 10.14; found (%): C 56.46, H 3.81, N 8.73, S
9
cm , 1701 cm , 1624 cm , 1570 cm , 1288 cm , 1077 cm .
UV-vis (CHCl ): λ = 312 nm, ε = 2.8·10 L·mol ·cm .
-
1
-1
-1
-1
.71. FTIR: 3348 cm , 2982 cm , 2930 cm , 2361 cm , 2324
2
was added in one portion. The reaction was allowed to warm
-1 -1 -1 -1 -1 -1
up to room temperature and then heated at 50°C for 18 hours.
Then the solvent was removed under reduced pressure and the
4
-1
-1
3
max
viscous oil obtained was taken up into 100 mL of CHCl and the
organic phase was washed with 100 mL of water. The organic
3
1
,19-dithia-7,13-diaza-9,11-dinitro-21,23-
diethylcarboxylatecyclophane (13). A mixture of 10 (0.200 g,
.42 mmol) and 4,6-difluoro-1,3-dinitrobenzene 1 (0.087 g, 0.42
phase was dried over MgSO affording a 1.10 g of crude solid.
4
0
The crude product was purified by column chromatography over
mmol) in 10 mL of dry CH CN was heated to reflux until
3
SiO using cyclohexane: ethyl acetate (6:4 then 5:5) affording
2
1
complete dissolution of the materials. Then 0.300 mL (2.76
mmol) of N,N-diisopropylethylamine was added dropwise. The
solution became slightly orange and maintained under reflux over
18h (after 1 hour a yellow precipitate started to form in the
medium). The solution was cooled in the fridge and then filtered
off, washed with 20 mL of hot water followed by 30 mL of
6
8
4
20 mg (66%) of an off-white solid. H NMR (CDCl , δ ppm):
3
.59 (s, 1H), 6.99 (t, J = 7.70 Hz, 2H), 6.62 (m, 6H), 6.42 (s, 1H),
.41 (q, J = 7.20 Hz, 4H), 2.30 (s, 4H), 1.43 (t, J = 7.20 Hz, 6H).
1
3
C NMR (CDCl , δ ppm): 165.79, 149.30, 147.45, 133.74,
3
1
30.78, 130.47, 125.69, 124.97, 121.75, 116.85, 61.48, 14.52.
+
Mp (°C): >170, decomposition. ESI-MS(+): 469.1 ([M+H] ),

ACCEPTED MANUSCRIPT
5
Wiley-VCH, 2004; j) Davis, F.; Higson, S. eds., Macrocycles :
ethanol. The obtained solid was dried affording 176 mg of the
1
construction, chemistry and nanotechnology applications, Wiley,
Hoboken, N.J., 2011; k) Marsault, E.; Peterson, M. L. J. Med. Chem.,
011, 54, 1961-2004; l) Wessjohann, L. A.; Ruijter, E.; Garcia-Rivera,
titled macrocycle (65 % yield) as a yellow solid. H NMR
CDCl , δ ppm): 9.25 (s, 1H), 9.19 (s, 2H), 8.67 (s, 1H), 7.47 (d,
(
3
2
J = 7.80 Hz, 2H), 7.39 (t, J = 7.80 Hz, 2H), 7.30 (t, J = 1.60 Hz,
H), 7.14 (d, J = 7.90 Hz, 2H), 6.34 (s, 1H), 4.96 (s, 1H), 4.44 (q,
D.; Brandt, W. Mol. Diversity, 2005, 9, 171–186.
2
2. a) Ogoshi, T. ; Kanai, S. ; Fujinami, S. ; Yamagishi, T. A. ; Nakamoto,
Y. J. Am. Chem. Soc., 2008, 130, 5022–5023 ; b) Cao, D.; Meier, H.
Asian J. Org. Chem., 2014, 3, 244 -262.
13
J = 7.00 Hz, 4H), 1.44 (t, J = 7.20 Hz, 6H). C NMR (CDCl , δ
3
ppm): 165.55, 148.94, 148.57, 139.37, 136.49, 134.28, 132.54,
3
.
a) Gutsch, C. D.; Muthukrishnan, R. J. Org. Chem.
,
1978, 43, 4905-
906; b) Kappe, T. J. Incl. Phenom. Macrocycl. Chem., 1994, 19, 3-
5; c) Gutsche. C. D. Calixarenes : an introduction; The Royal
1
1
31.34, 131.07, 128.53, 125.04, 122.92, 122.26, 99.01, 61.80,
4.49. Mp (°C): > 280, decomposition. ESI-MS(+): 633.1
4
1
+
+
+
(
6
[M+H] ), 650.1 ([M+NH ] ), 655.0 ([M+Na] ); ESI-MS(-):
4
-
Society of Chemsitry: London, 2001; d) Guo, D. S. ; Liu, Y. Chem.
Soc. Rev., 2012, 41, 5907-5921.
31.1 ([M-H] ). EA calc. (%): C 56.95, H 3.82, N 8.86, S 10.14;
-1
found (%): C 56.79, H 3.76, N 8.86, S 10.20. FTIR: 3359 cm (δ
N-H), 2981 cm (δ C-H), 2360 cm , 2334 cm , 1707 cm , 1628
cm , 1569 cm , 1292 cm , 1074 cm . UV-vis (CHCl ): λ
3
4. a) Kim, D. S.; Sessler, J. L. Chem. Soc. Rev., 2015, 44, 532-546; b)
-
1
-1
-1
-1
Ghasemabadi, P. G.; Yao, T.; Graham, G. J. Chem. Soc. Rev., 2015
44, 6494-6518; c) Han, Y.; Jiang, Y.; Chen, C.-F. Tetrahedron 2015
1, 503-522; d) Tashiro, S. ; Shionoya, M. Bull. Chem. Soc. Japan
,
,
,
,
-
1
-1
-1
-1
=
,
3
max
4
-1
-1
7
2
4
30 nm, ε = 3.7·10 L·mol ·cm .
014, 87, 643-654 ; e) Ghale, G. ; Nau, W. M. Acc. Chem. Res., 2014
7, 2150-2159.
1
,17-dithia-6,12-diaza-8,10-dinitro-19,21-
5
. a) Camacho, D. H. ; Salo, E. V. ; Guan, Z. Org. Lett.
, 2004, 6, 865-
diethylcarboxylatecyclophane (14). A mixture of 10 (0.200 g,
.42 mmol) and 4,6-difluoro-1,3-dinitrobenzene 1 (0.087 g, 0.42
8
68 ; b) Wang, L. ; Chen, Z. ; Ma, M. ; Duan, W. ; Song, C. ; Ma, Y.
0
Org. Biomol. Chem., 2015, 13, 10691-10698 ; c) Stemper, J. ; Isaac,
K. ; Pastor, J. ; Frison, G. ; Retailleau, P. ; Voituriez, A. ; Betzer, J.-
F. ; Marinetti, A. Adv. Synth. Cat., 2013, 355, 3613-3624.
mmol) in 10 mL of dry CH CN was heated to reflux until
3
complete dissolution of the materials. Then 0.300 mL (2.76
mmol) of N,N-diisopropylethylamine was added dropwise. The
solution became slightly orange and maintained under reflux over
6. a) Baran P. S. ; Burns, N. Z. J. Am. Chem. Soc.
b) Garrido, L. ; Zubia, E. ; Ortega, M. J. ; Salva, J. J. Org. Chem.
003 293-299 ; c) Cameron, K. S. ; Fielding, L. ; Mason, R. ;
Muir, A. W. ; Rees, D. C. ; Thorn, S. ; Zhang, M. Bioorg. Med.
Chem. Lett. 2002 753-755 ; d) Ettmayer, P. ; Billich, A. ; Hecht,
P. ; Rosenwirth, B. ; Gstach, H. J. Med. Chem. 1996 17 3291-3299 ;
, 2006, 12, 3908-3909 ;
2
, 2,
1
8h (after 30 min a yellow precipitate starts to form in the
medium). The reaction mixture was cooled down with an ice bath
then filtered off. The obtained yellow solid was washed several
,
, 5,
,
,
,
times with ethanol and dried affording 0.210 g of the expected
1
e) Osmani, R. A. M.; Bhosale, R. R. ; Hani, U. ; Vaghela, R. ;
Kulkarni, P. K. Curr. Drug Ther., 2015, 10, 3-19 ; f) Yu, G. ; Jie, K. ;
Huang, F. Chem. Rev. 2015, 115, 7240-7303; g) Zafar, N. ; Fessi, H. ;
Elaissari, A. Int. J. Pharm., 2014, 46, 351-366 ; h) Jie, K. ; Zhou, Y. ;
Yao, Y. ; Huang, F. Chem. Soc. Rev., 2015, 44, 3568-3587.
macrocycle (77% yield) as a yellow solid. H NMR (CDCl , δ
3
ppm): 9.32 (s, 2H), 9.29 (s, 1H), 8.66 (s, 1H), 7.53 (d, J = 8.40
Hz, 4H), 7.15 (d, J = 8.40 Hz, 4H), 6.91 (s, 1H), 5.77 (s, 1H),
13
4
.45 (q, J = 7.10 Hz, 4H), 1.46 (t, J = 7.10 Hz, 6H). C NMR
(
1
CDCl , δ ppm): 147.52, 138.48, 136.34, 128.95, 125.39, 61.86,
4.51. Mp (°C): > 300, decomposition. ESI-MS(+): 633.1
+ + +
7. See some recent references: a) Marrocchi, A. ; Tomasi, I. ; Vaccaro,
L. Israel J. Chem., 2012, 52, 41-52 ; b) Berville, M. ; Karmazin, L. ;
Wytko, J. A. ; Weiss, J. Chem. Commun., 2015, 51, 15772-15775 ; c)
El Nashar, R. M. ; Wagdy, H. A. A. ; Aboul-Enein, H. Y. ; Hassan,
Y., Curr. Anal. Chem., 2009, 5, 249-270 ; d) Kothur, R. R. ; Patel, B.
3
(
6
[M+H] ), 650.1 ([M+NH ] ), 655.0 ([M+Na] ); ESI-MS(-):
4
-
31.1 ([M-H] ). EA calc. (%): C 56.95, H 3.82, N 8.86, S 10.14;
-1
found (%): C 56.92, H 3.75, N 8.92, S 10.14. FTIR: 3300 cm (δ
N-H), 2985 cm , 2354 cm , 2329 cm , 1696 cm , 1624 cm ,
1
-
1
-1
-1
-1
-1
A. ; Cragg, P. J. Science Jet
D. Chem. Soc. Rev., 2013, 42, 143-155 ; f) Dolbier, W. R. ; Duan, J. -
X. ; Roche, A. J. Org. Lett. 2000, 2, 1867- 1869.
. a) Ohseto, F. ; Murakami, H. ; Araki, K.; Shinkai, S. Tetrahedron Lett.
992, 33, 1217-1220; b) Van Gelder, J. M.; Aleksiuk, O.; Biali, S. E.
, 2015, 4, 72/1-72/8 ; e) Meier, H. ; Cao,
-
1
-1
-1
-1
577 cm , 1560 cm , 1276 cm , 1071 cm . UV-vis (CHCl ):
3
4 -1 -1
,
λmax = 338 nm, ε = 4.4·10 L·mol ·cm .
8
9
1
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This work was supported by the Centre National de la Recherche
Scientifique, the Ministère de l’Enseignement Supérieur et de la
Recherche (MESR) and Aix-Marseille Université throughout
their financial support. V.D.S. thanks also the Conselho Nacional
de Desenvolvimento Científico e Tecnológico (National Council
of Technological and Scientific Development) CNPq for its
doctoral financial support (CNPq 202734/2011-0).
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1
7
,
,
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Supplementary data
,
Supplementary data (Tables of crystallographic data for 9, 10 and
1
in the online version at http://dx.doi.org/xx.xxxx/j.tet.xx.xx.xxx.
1. Copies of NMR spectra) related to this article can be found,
,
4
Notes and references
1
†
1
VM and VDS contributed equally in the present work.
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