Synthesis and characterization of original calix-salen type ligands

Article abstract of DOI:10.1016/j.tet.2012.09.077

Polycondensation reactions between various modified disalicylaldehyde derivatives and two chiral diamines afforded in each case macrocyclic structures, named calix-salen. Mixtures of oligomers (dimers to pentamers) were qualitatively analyzed by Maldi-Tof

Full text of DOI:10.1016/j.tet.2012.09.077

Tetrahedron 68 (2012) 9954e9961
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and characterization of original calixesalen type ligands
,
b
,
,
,
,
Farah Ibrahim a y, Houssein Nasrallah a y, Xiang Hong a y, Mohamed Mellah a y, Ali Hachem b,
Ghassan Ibrahim b, Nada Jaber b , Emmanuelle Schulz
Equipe de catalyse moleculaire, Univ. Paris-Sud 11, ICMMO, UMR 8182, Orsay 91405, France
,
a,
c
, ,
y
*
*
a
ꢀ
b
ꢀ
ꢀ
ꢀ
Laboratoire de chimie medicinale et des produits naturels, Universite Libanaise, Faculte des Sciences (I) et PRASE-EDST, Hadath, Beyrouth, Lebanon
c CNRS, Orsay 91405, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2012
Received in revised form 14 September 2012
Accepted 16 September 2012
Available online 21 September 2012
Polycondensation reactions between various modified disalicylaldehyde derivatives and two chiral di-
amines afforded in each case macrocyclic structures, named calixesalen. Mixtures of oligomers (dimers
to pentamers) were qualitatively analyzed by Maldi-Tof and 1H NMR DOSY experiments allowed their
easy quantitative investigation. Tuning the reaction conditions and namely the concentration of both
monomeric partners led interestingly to the selective preparation of the dimer or the tetramer as main
products, in diluted or concentrated media, respectively.
Keywords:
Calixesalen
Ó 2012 Elsevier Ltd. All rights reserved.
Chiral macrocyclic ligands
1H NMR DOSY experiment
Oligomers
Polycondensation
1. Introduction
context, some macrocyclic structures have been synthesized through
polycondensation reactions between modified disalicylaldehyde de-
Chiral complexes based on salen ligands are considered privi-
leged and versatile catalysts due to the remarkably wide variety of
reactions they are able to catalyze.1 Among all of them, the most
renown and currently used compound results from the condensa-
tion between 5,50-di-tert-butyl-salicylaldehyde and optically pure
(S,S)-cyclohexane-1,2-diamine. This ligand was described for the
first time by Jacobsen in 1991 associated to manganese salts to
promote the asymmetric epoxidation of alkenes and led to excellent
results in terms of both activity and enantioselectivity, especially for
cis-disubstituted olefins, such as 2,2-dimethyl-2H-chromene de-
rivatives.2 It has then been associated to numerous metals to pro-
mote different transformations with a huge success, leading to the
selective formation of new CeC or C-heteroatom bonds.
More recently, it has been emphasized that some asymmetric
transformations were more efficiently performed through co-
operative bimetallic catalysis, and some efforts have been performed
to describe the synthesis of oligomeric salen-based species, to in-
vestigate their efficiency, associated especially to cobalt or chromium
salts, in enantioselective epoxide ring-opening reactions.3,4 In this
rivatives and various (chiral) diamines, giving rise to cyclic structures
named calixesalen, in analogy to the well-known calixarene de-
rivatives.5 Following the concept of dynamic combinatorial chemis-
try,6 various macrocycles built from imine condensation reactions7
have been described.8
Li and Jablonski have thus reported the synthesis of macrocycles
formed from chiral salen moieties linked together through a meth-
ylene or an ethyleneglycol group. The cyclization was performed in
the presence of Ba(ClO4)2 leading to the preparation of the dimer as
major product but not exempt from the trimer and tetramer ana-
logues.9,10 Cyclic trimeric structures were obtained from [3þ3]
cyclocondensation of trans-1,2-diaminocyclohexane and two
hydroxyl-substituted isophthalic aldehydes without any template
assistance.11 The authors assumed indeed that the driving force of
this transformation relied on the structural predisposition of the
intermediate imine leading to a vase-like structure. Extending the
length of the dialdehyde molecule toa linearone byconnecting their
components via an alkyne or an aromatic moiety still allowed, after
condensation with trans-1,2-diaminocyclohexane, the formation of
chiral large-ring triangular salen ligands.12 Contrarily, when the
dialdehyde was substituted with tert-butyl groups corresponding
linear structures were synthesized with eight to fifteen repeating
units, according to the structure of the chiral diamine, probably due
to a too large steric hindrance for forming macrocycles.13 Worth
* Corresponding authors. E-mail addresses: nada.jaber@ul.edu.lb (N. Jaber),
emmanuelle.schulz@u-psud.fr (E. Schulz).
y
Fax: þ33 169154680.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.077

F. Ibrahim et al. / Tetrahedron 68 (2012) 9954e9961
9955
mentioning is also the use of a diformyl triphenol, which is large
enough for forming a calix-arene-like salen ligand through simple
cyclocondensation.14 Kureshy and co-workers investigated the use
of trigol-bis(aldehyde) for the condensation reaction.15 With this
large, flexible dialdehyde they interestingly demonstrated that the
condensation reaction in the presence of cyclohexyldiamine or
diphenylethylenediamine led to a monomer (simple closing re-
action) or a dimer, according tothe reaction solvent. The preparation
of a dialdehyde linked by a piperazine group afforded in THF a di-
meric macrocyclic salen ligand with onlytraces of the corresponding
monomer.16
Other chiral calixesalen macrocycles have been prepared from
structurally diverse chiral diamines, including readily available
diphenylethylenediamine and binaphthyldiamine together with 2-
hydroxy-5-methyl-benzene-1,3-dicarbaldehyde, in the presence of
metallic salts as templates.17 Varghese and co-workers have further
described a microwave assisted cyclocondensation between vari-
ous dialdehydes and chiral amines, without any template.18,19
According to the structure of the dialdehyde (either a linked spe-
cies or 2,5-dihydroxy-benzene-1,4-dicarbaldehyde) they could
isolate [2þ2] or [3þ3] (dimers or trimers) cyclocondensed macro-
cycles, respectively.
isolated yield. The synthesis of the corresponding boronic ester 2
formerly succeeded by combining the procedures described by
NoceraeYang23 and DiMauroeVitullo24 through the use of bis-
(pinacolato)diboron and diphenylphosphinoferrocene (dppf) pal-
ladium dichloride as a catalyst under microwave activation. Com-
pound 2 was isolated in a low but reproducible yield of 33%.22 This
methodology could nonetheless be optimized by varying the
structure and amount of base, and in the presence of potassium
acetate and a reduced amount of Pd as catalyst, a one to one mix-
ture of bromide 1 and bis-(pinacolato)diboron delivered 2 in 76%
isolated yield after 3 h at 120 ꢀC (Scheme 1). Corresponding 2-
hydroxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzal-
dehyde 3, lacking the tert-butyl substituent, was accordingly pre-
pared from commercially available 5-bromo-2-hydroxy-
benzaldehyde.
CHO
1. Br2, AcOH, RT
Br
OH
Bu
OH
Bu
2. (CH2O)n, MgCl2
Et3N, THF, 70 °C, 34 h
t
t
1
82 %
We have been recently involved in the preparation of chiral
thiophene-modified salen complexes, for their use as monomers
towards the synthesis of insoluble polymeric species by anodic
electrochemical oxidation.20 These catalysts were proved to be ef-
ficient promoters for different asymmetric transformations and
could be interestingly reused in successive catalytic runs.21 In some
cases, however, the heterogeneous catalysts were less efficient
particularly in terms of selectivity compared to their homogeneous
counterparts, particularly for transformations that are known to be
promoted through mechanisms involving bimetallic catalysis.21d
We assumed that our electrogenerated catalysts, possessing a lin-
ear structure, were not flexible enough to allow this specific sites
arrangement for high selectivities. We have thus prepared their
O
O
O
B
O
KOAc
3% Pd(dppf)Cl2
dioxanne
B
CHO
OH
CHO
O
O
O
B
B
OH
O
2
3
t
Bu
76 %
Scheme 1. Synthesis of boronic esters 2 (and 3), as key intermediates.
The chosen strategy was then to follow the synthesis of different
salen-derived macrocycles according to the structure of the aro-
matic spacers. A series of dialdehydes was thus prepared through
a Suzuki cross-coupling methodology, involving the boronic esters
2 or 3 and various commercially available aromatic dihalides
(Scheme 2). Optimized reaction conditions were discovered by
using 6 mol % Pd(PPh3)4 in the presence of 1 equiv of K2CO3 as base
in a 5/1 mixture of DME/H2O at 100 ꢀC.
analogues, through
a condensation reaction between a dis-
alicylaldehyde with a thiophene linker and (S,S)-cyclohexane-1,2-
diamine. The resulting polymeric compound was demonstrated
to own a cyclic structure possessing from 2 to 5 repetitive units.22 In
the presence of chromium(II) salts it led to the preparation of
a chiral catalyst was used to promote the nucleophilic epoxides ring
opening under heterogeneous conditions. Targeted products were
obtained in high yields and with selectivity values improved,
compared to those obtained using analogous linear polymers. The
catalyst could be successfully recycled, as the first use of cal-
ixesalen complexes under heterogeneous catalytic conditions.
In this context, we report here the synthesis of other structurally
varied polysalen ligands obtained by condensation reactions be-
tween different disalicylaldehyde derivatives and cyclohexane-1,2-
diamine or diphenylethylenediamine, aiming at controlling the
rules that lead to the formation of targeted linear or cyclic
structures.
CHO
OH
OHC
HO
CHO
OH
O
O
Br Ar Br
Ar
B
K2CO3
6 mol% Pd(PPh3)4
DME/H2O, 100 °C, 24 h
R
R
R
2 or 3
4 to 10, 34 - 90%
Scheme 2. Synthesis of a variety of dialdehydes by a Suzuki cross-coupling.
This procedure was previously successfully reported for the
synthesis of derivative 4, possessing one thiophene unit as spacer,22
delivering the targeted dialdehyde in a high yield of 82% (Table 1,
entry 1). Using a dimeric spacer, such as 4,40-dibromo-dithienyl
afforded the diaromatic spacer 5 with a high isolated yield of 80%
(Table 1, entry 2). Similarly, compound 6 obtained from 1,4-
dibromobenzene was isolated in a quantitative yield (>99%, Table
1, entry 3). The use of the corresponding dimeric spacer 4,40-
dibromo-biphenyl, however, led to the recovery of a lower yield of
the expected compound 7, due to the poor solubility of this fully
conjugated tetra-aromatic dialdehyde (Table 1, entry 4). Dialdehyde
8 was instead prepared in a very high yield due to enhanced sol-
ubility (Table 1, entry 5). Similar trends were observed for the
synthesis of dialdehydes 9 and 10 from the non-substituted boronic
derivative 3 (Table 1, entries 6e7).
2. Results and discussion
2.1. Synthesis of disalicylaldehyde derivatives
We previously reported a procedure for the preparation of
a disalicylaldehyde containing a thiophene spacer that delivered
the expected compound with high yield.22 This synthetic strategy
based on Suzuki couplings was thus again followed for preparing
various dimeric aldehydes possessing different aromatic structures
and starting from boronic ester 2 as key intermediate. The synthesis
of 5-bromo-3-tert-butyl-2-hydroxybenzaldehyde 1 is straightfor-
ward from commercially available 2-tert-butyl-phenol by selective
bromination in acetic acid and subsequent formylation in up to 82%

9956
F. Ibrahim et al. / Tetrahedron 68 (2012) 9954e9961
Table 1
Suzuki bis(coupling) of dibromo aromatic derivatives with boronic esters 2 or 3
Entry
1
BreAreBr
R
Product
Yield %
tBu
4
82
Br
Br
S
S
2
tBu
5
80
Br
Br
S
3
4
5
tBu
tBu
tBu
6
7
8
99
34
90
Br
Br
Br
Br
Br
O
O
Br
6
7
H
H
9
45
88
Br
Br
10
Br
Br
2.2. Synthesis of calixesalen derivatives
Scheme 3. Synthesis of a variety of calixesalen derivatives.
As we previously described, compound 4 was engaged in
subsequent condensation step with (S,S)-cyclohexane-1,2-
a
The condensation of a dialdehyde containing a longer spacer, such
as in 11 or 13, afforded analogous results, both in terms of yield and
structural characterization. Consequently, the potential influence of
the sterically strongly hindering tert-butyl groups on the course of
the transformation was studied, but dialdehyde 10 lacking these
substituents once more delivered high yielding cyclic compounds
14. Finally, structural variations on the diamine linker were evalu-
ated, and dialdehyde 6 was reacted with an equimolar amount of
(S,S)-1,2-diphenyl-ethane-1,2-diamine. Under the reported re-
action conditions, the cyclic calixesalen structure 15 was also
identified by SEC analyses and isolated in 50% yield.
diamine leading to the formation of a calixesalen derivative, as
a mixture of differently sized macrocycles. This mixture could be
further analyzed by Maldi-Tof spectroscopy indicating indeed un-
ambiguously the presence of different oligomers possessing 2, 3, 4
or 5 salen units, with a molecular mass of 514 g molꢁ1 for the re-
petitive units (with the loss of a supplementary water molecule),
confirming the cyclization.22
Soluble aldehydes 5, 6, 8 and 10 were thus engaged in a similar
procedure to study the influence of their structure, i.e., the nature of
the aromatic spacer, its size, or the presence or absence of the tert-
butyl substituent, on the formation of the corresponding oligomers.
Furthermore, two different chiral diamines, (S,S)-cyclohexane-1,2-
diamine and (S,S)-1,2-diphenyl-ethane-1,2-diamine were used for
the polycondensation reaction, as structurally privileged chiral
backbones usually and successfully involved in asymmetric catal-
ysis (Scheme 3).
All the transformations were performed by mixing a 1/1 amount
of each monomer in refluxing THF (8.75 mmol/L) for 24 h in the
presence of molecular sieves, and the resulting oligomers were
isolated after filtration and simple removal of the solvent.25
Delightfully, all reactions led to the high yield formation of
macrocyclic salen derivatives that could be characterized by Maldi-
Tof analyses.26 Contrarily to the observation made by Punniya-
murthy13 in our case, the presence of the tert-butyl groups did not
hinder the formation of cyclic structures. Specifically, the reaction
2.3. Characterization of calixesalen derivativesd2D 1H NMR
studies
Calix derivatives 11e15 were easily solubilized in CDCl3 and
their structures were further analyzed by NMR spectroscopy. For all
compounds, no remaining signals characteristic for aldehyde or
amine functionalities could be detected, but different specific peaks
for imine groups were almost present. This pattern seems fur-
thermore obvious for the OH-groups and for the hydrogen atoms of
the cyclohexyl group in the a-position of the nitrogen atoms. More
precise information could be obtained by Diffusion-Ordered Spec-
troscopy (DOSY) experiments with 12 as probe (see Fig. 2). DOSY
experiments provide an easy way to analytically separate com-
pounds in a mixture based on their different translation diffusion
coefficients, derived from their varying size and shape. The test was
conducted in CDCl3, with a 0.049 M mixture. Under these condi-
tions, the 2D DOSY spectrum undoubtedly distinguished three
types of signals groups, each of them containing a specific singlet in
the imine region, and also characteristic protons in the high field
region. Considering thus their diffusion coefficient and the repre-
sentative 1H NMR spectrum, each group could be attributed to
a specific macrocycle, according to their size. The compound pos-
sessing the highest coefficient is therefore the dimeric form of
between dialdehyde
6 and (S,S)-cyclohexane-1,2-diamine led
analogously to the preparation of a cyclic oligomeric salen structure
12 in a good isolated yield of 74%, indicating that the formation of
such macrocycles is not only privileged by the presence of a thio-
phenic ring. SEC experiments performed with compound 12 in-
dicated the formation of dimers to pentamers derivatives.26 This
analysis was confirmed by qualitative Maldi-Tof analyses that
showed a repetitive mass unit of 508.7 g molꢁ1 for the cyclic
structures (see Fig. 1).

Fig. 1. Maldi-Tof analysis of the calixesalen mixture 12.
Fig. 2. 1H NMR and DOSY experiment for the calixesalen mixture 12 in CDCl3.

9958
F. Ibrahim et al. / Tetrahedron 68 (2012) 9954e9961
calixesalen 12, with the imine protons present as a single signal at
7.9 ppm. The identified trimer may be characterized by its imine
signal at 8.2 ppm, and the remaining group represents the tetramer.
Gratifying, this practical analytic methodology led thus to the
quantitative estimation of each macrocycle in the mixture through
the comparison of each imine signal integration. For 12, and under
the reaction conditions described above, the dimer represented
thus 47% of the whole mixture, the trimer 16%, and the tetramer the
remaining 37%.
Furthermore, dihedral angles between the aromatic groups are
very small while values close to 30ꢀ should be achieved. In the case
of the trimer derivative calculated from 12, this strain is slightly
released and the aromatic rings are brought into line. Finally, the
dimer’s optimized structure allows respecting non strained di-
hedral angles with aligned phenyl groups. These rough modelisa-
tion studies are nevertheless in complete accordance with the
preferential formation of the more stable dimeric calixesalen de-
rivative for 12, possessing indeed conformationally strained linkers
between the chelating salen units.
2.4. Synthesis of calixesalen derivativesdvariation of the
reaction conditions
3. Conclusion
As a simple 1H NMR spectrum allowed the characterization of
a complex calixesalen mixture, variations in reaction conditions
were undertaken, aiming at a better control of the calixesalen size.
The synthesis of 12 was thus renewed under diluted conditions
(two times, each monomer at 3.7 mM), that delivered a cyclic
mixture with, as expected, an enhanced proportion in the dimer
derivative. In that case indeed, the dimer represented up to 65% of
the total amount of the mixture. Using a five times diluted prepa-
ration (1.7 mM) compared to the initial procedure led only to
a slight increase of this value up to 68% in favour of the dimeric
structure of 12. Contrarily, working in very concentrated solution
(i.e., 0.2 M), reversed the tendency and delivered principally the
tetramer that was then easily isolated with 80% yield. Preparative
thin layer chromatography in an eluent cyclohexaneeethylacetate
(93/7) afforded a clean separation of the dimer and the trimer from
the mixture and they were then further fully characterized.26
Polycondensation reactions between aromatic bridged dis-
alicylaldehydes and enantiopure diamines have been performed
leading to the synthesis of new macrocyclic structures of salen
derivatives. Neither the steric hindrance of the aldehyde (bearing
tert-butyl groups or not) or the structure/length of the spacer in-
fluence the course of the reaction. The cyclic oligomers prepared
from both (S,S)-cyclohexane-1,2-diamine or (S,S)-1,2-diphenyl-
ethane-1,2-diamine are isolated in moderate to high yield,
depending on their solubility. These new salen derivatives could be
characterized by Maldi-Tof analyses proving undoubtedly their
cyclic nature. Detailed analyses were performed with compound 12
and SEC experiments confirmed the presence of dimers to pen-
tamers. DOSY experiments were further conducted that allowed
a more precise quantitative analysis from the 1H NMR Spectrum.
NMR signals corresponding to the imine protons of the salen
moieties could be indeed easily differentiated and assigned to each
macrocycle according to their size. Reaction conditions were then
optimized and different dilutions favoured either the isolation of
the pure dimeric species or the recovery of the tetrameric one.
These new calixesalen derivatives are promising chiral co-
ordinating structures for transition metals and asymmetric catal-
ysis. Work towards this aim is in progress in our laboratory and will
be reported in due course.
2.5. Characterization of calixesalen derivativesdmodelisa-
tion studies
Apart from simple explanations resulting from dilution con-
siderations to describe these selectivities in the macrocycles for-
mation, molecular mechanics calculation (MMþ method within the
Hyperchem 5.11 Standard package)27 was carried out for a direct
comparison of the calixesalen structure. After optimization of the
structure for the tetrameric species from 12, tensions between the
successive aromatic rings are clearly detectable (see Fig. 3). Their
rotation axis should indeed be aligned but it is undoubtedly bent.
4. Experiment
4.1. General information
All reactions were conducted in glassware with magnetic stir-
ring. THF was distillated from sodium/benzophenone and DCM was
distillated from CaH2 before use. 1H NMR spectra and 13C NMR
spectra were recorded on either a Bruker AM 360 (360 MHz), AM
300 (300 MHz) or AM 250 (250 MHz) instrument with samples
dissolved in CDCl3 and data are reported in parts per million with
the solvent signal as reference (7.24 ppm for 1H NMR and 77 ppm
for 13C NMR). IR spectra were recorded as KBr disks using a Per-
kineElmer spectrometer. UVevis spectra were obtained using
a Bio-TEK UNIKON XL spectrometer. Optical rotations were mea-
sured on a PerkineElmer 241 digital polarimeter with a sodium
(489 nm) lamp. Mass spectra were recorded on a Finnigan MAT 95 S
spectrometer. Elemental analyses were performed by the National
analytical Centre of Scientific Research in Solaize. MALDI-Tof anal-
yses were performed by the service of masse spectrometry of the
Institut de Chimie des Substances Naturelles, Gif sur Yvette, on
a Voyager DE-SFR spectrometer with a solution of dithranol in THF
(10 g/L) as matrix. The polymer molar masses were determined
using size exclusion chromatography (SEC) with tetrahydrofuran as
eluent (1 mL minꢁ1) at room temperature. This apparatus was
equipped with a refractive index detector (Waters 410) and two
mixed-bed ViscoGELÔ columns (7.8ꢂ300 mm, type GMHH R-H)
provided by Viscotek. The molar masses were determined using
a calibration curve based on polystyrene standards. The hardware
and software for data acquisition and treatment were supplied
Fig. 3. MMþ calculation for the dimeric, trimeric and tetrameric structure of 12.

F. Ibrahim et al. / Tetrahedron 68 (2012) 9954e9961
9959
from hs GmbH Ober-Hilbersheim (Germany). Compound 1,28 324
and 422 were prepared according to reported procedures.
the expected product (34%, 52 mg, 0.102 mmol) as a white yel-
lowish solid. 1H NMR (250 MHz, CDCl3)
11.80 (s, 2H), 9.97 (s, 2H),
7.81 (d, J¼2.3 Hz, 2H), 7.72 (d, J¼8.7 Hz, 4H) 7.66e7.63 (m, 6H), 1.47
(s, 18H). 13C NMR (62.5 MHz, CDCl3)
197.4, 161.0, 139.6, 139.4,
d
4.2. Synthesis of disalicylaldehyde derivatives
d
139.1, 133.2, 132.1, 130.1, 127.7, 127.3, 121.0, 35.3, 29.5. HRMS (ESI)
4.2.1. Synthesis of boronic ester 2. A schlenk tube charged with
bis(pinacolato)diboron (2 g, 7.9 mmol), Pd(dppf)Cl2 (200 mg,
0.24 mmol) and KOAc (2 g, 20 mmol) was maintained under argon
by successive vacuum-argon cycles. Thoroughly degassed 1,4-
dioxane (9 mL) was introduced in the schlenk and the mixture
was stirred for 10 min. Then 5-bromo-3-tert-butyl-2-hydroxy-
benzaldehyde 1 (1.8 g, 7.1 mmol) diluted in 9 mL of degassed 1,4-
dioxane was introduced. The mixture was heated at 120 ꢀC for
3 h. The suspension was filtered on Celite, washed with CH2Cl2 and
the solvents were removed under reduced pressure. The residue
was purified by silica gel chromatography (pentane/ether 95/5) to
afford the expected product (76%, 1.65 g, 5.4 mmol) as a white solid.
calcd for C33H33O4 (MꢁH) 505.2384, found 505.2371. MS (ESI neg):
505.36 (MꢁH) (100), 252.21 (76), 239.08 (45). IR (KBr,
n
(cmꢁ1))
3436, 2961, 1646, 1443. Mp 260 ꢀC.
4.2.5. Synthesis of disalicylaldehyde derivative 8. The same pro-
cedure was performed with (100 mg, 0.33 mmol), bis(4-
2
bromophenyl)ether (43.1 mg, 0.13 mmol), Pd(PPh3)4 (9 mg,
0.008 mmol) and K2CO3 (27 mg, 0.19 mmol). The residue was pu-
rified by column on silica gel (cyclohexane/diethylether 95/5) to
afford the expected product (90%, 62 mg, 0.12 mmol) as a yellow
foam. 1H NMR (360 MHz, CDCl3)
d 11.78 (s, 2H), 9.94 (s, 2H), 7.73 (d,
J¼2.3 Hz, 2H), 7.56 (d, J¼2.3 Hz, 2H), 7.52 (d, J¼8.7 Hz, 4H), 7.12 (d,
1H NMR (250 MHz, CDCl3):
d
12.00 (s, 1H), 9.91 (s, 1H), 7.93e7.89
J¼8.7 Hz, 4H), 1.40 (s, 18H). 13C NMR (90 MHz, CDCl3)
d 197.3, 160.7,
(m, 2H),1.44 (s, 9H),1.36 (s,12H); 13C NMR (90 MHz, CDCl3):
163.6, 140.0, 139.9, 137.4, 120.4, 83.9, 34.8, 29.2, 24.8.
d
197.5,
156.8, 139.1, 135.7, 133.2, 132.0, 129.9, 128.3, 121.0, 119.5, 35.3, 29.5.
HRMS (ESI neg) calcd for C34H33O5 (MꢁH) 521.2333, found
521.2324. IR (KBr,
n
(cmꢁ1)) 2961, 2868.4, 1651, 1505.3. Mp 92 ꢀC.
4.2.2. Synthesis of 5,50-di(3-tert-butyl-2-hydroxy-benzaldehyde)-
2,20-bithiophene 5. To a stirred solution of 5,50-dibromo-2,20-
bithiophene (1 g, 3.09 mmol), 2 (2.35 g, 7.73 mmol) and tetrakis-
(triphenylphosphine)palladium (535 mg, 0.46 mmol) in degassed
DME (12 mL) at room temperature under argon was added a solu-
tion of sodium carbonate (983 mg, 9.27 mmol) in degassed water
(4 mL). The mixture was heated at reflux for 16 h under argon,
cooled, and then partitioned between water (50 mL) and
dichloromethane (50 mLꢂ3). The combined extracts were dried
over Na2SO4 and evaporated in vacuum. Chromatography was
performed with gradient elution using 5e10% of ether in pentane to
eliminate the impurities, and then pure toluene to get the targeted
product (1.61 g, 80%) as a yellow powder. 1H NMR (250 MHz, CDCl3)
4.2.6. Synthesis of disalicylaldehyde derivative 9. The same pro-
cedure was performed with 3 (140 mg, 0.56 mmol), 4,40-dibromo-
diphenyl (70.13 mg, 0.23 mmol), Pd(PPh3)4 (15.58 mg, 0.014 mmol)
and K2CO3 (46.6 mg, 0.34 mmol). The residue was purified by col-
umn on silica gel (cyclohexane/dichloromethane 2/3) to afford the
expected product (45%, 40 mg, 0.101 mmol) as a white solid. 1H
NMR (250 MHz, CDCl3)
d
11.02 (s, 2H), 9.99 (s, 2H), 7.82 (d, J¼7.3 Hz,
4H), 7.73 (d, J¼8.2 Hz, 4H) 7.65 (d, J¼8.5 Hz, 4H), 7.1 (d, J¼9.1 Hz,
2H). MS (ESI neg) 393.1125 (MꢁH) (100), 255.2328 (10), 152.9179
(1). HRMS (ESI neg) calcd for C26H17O4 (MꢁH) 393.1205, found
393.1129. Mp >260 ꢀC.
d
11.81 (s, 2H), 9.92 (s, 2H), 7.73 (d, 2H, J¼1.8 Hz), 7.58 (d, 2H,
4.2.7. Synthesis of disalicylaldehyde derivative 10. The same pro-
cedure was performed with 3 (110.7 mg, 0.42 mmol), bis(4-
J¼1.8 Hz), 7.15 (s, 4H),1.45 (s,18H). 13C NMR (90 MHz, CDCl3)
d
197.1,
161.0, 142.1, 139.2, 136.2, 131.7, 128.6, 125.6, 124.5, 123.3, 120.7, 35.1,
29.2. HRMS (ESI): calcd for C30H29O4S2 517.1513, found 517.1548. IR
bromophenyl)ether (58.3 mg, 0.18 mmol), Pd(PPh3)4 (12 mg,
0.010 mmol) and K2CO3 (49 mg, 0.35 mmol). The recovered residue
was purified by column on silica gel (cyclohexane/dichloromethane
2/3) to afford the expected product (88%, 64 mg, 0.156 mmol) as
(KBr, n
(cmꢁ1)) 3068, 2955, 2837, 2371, 1646, 1610, 1465, 1433, 1393,
1336, 1270, 1239, 1160, 1040, 808, 765, 747. Mp 215 ꢀC.
a brown solid. 1H NMR (250 MHz, CDCl3)
d
10.98 (s, 2H), 9.96 (s, 2H),
7.80e7.76 (m, 4H), 7.52 (d, J¼8.4 Hz, 4H), 7.12 (d, J¼8.4 Hz, 4H),
7.08e7.04 (m, 2H). 13C NMR (62.5 MHz, CDCl3)
196.8, 161.0, 158.9,
135.7, 134.9, 132.8, 131.8, 128.2, 120.9, 119.6, 118.4. HRMS (ESI neg)
4.2.3. Synthesis of disalicylaldehyde derivative 6. A schlenk tube
charged with 3-tert-butyl-2-hydroxy-5-(4,4,5,5,-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzaldehyde
d
2 (219 mg, 0.72 mmol), 1,4-
dibromobenzene (68 mg, 0.29 mmol), Pd(PPh3)4 (20 mg,
0.017 mmol) and K2CO3 (79.6 mg, 0.57 mmol) was maintained
under argon by successive vacuum-argon cycles. Thoroughly
degassed DME (3 mL) and degassed water (0.6 mL) were in-
troduced with a cannula in the schlenk. The mixture was heated at
100 ꢀC for 24 h. Water (10 mL) was added and the aqueous layer
was extracted with CH2Cl2. The organic layer was dried over MgSO4
and the solvents were removed under reduced pressure. The resi-
due was purified by column on silica gel (cyclohexane/ethyl acetate
95/5) to afford the expected product (quantitative yield, 125 mg,
calcd for C26H17O5 (MꢁH) 409.1081, found 409.1076. IR (KBr,
n
(cmꢁ1)) 3365, 2925, 1687, 1670, 1477.
4.3. Synthesis of calixesalen derivativesdstandard
conditions
4.3.1. Synthesis of calixesalen 11. A solution of disalicylaldehyde 5
(673 mg, 1.3 mmol) and (S,S)-cyclohexane-1,2-diamine (148 mg,
1.3 mmol) in a mixture of toluene (30 mL) and dry ethanol (30 mL)
was stirred at 60 ꢀC for 20 h. After solvents removal under reduced
pressure, the targeted product (800 mg, 99%) 11 was obtained as an
orange solid. 1H NMR (250 MHz, CDCl3) was performed as a mixture
0.29 mmol) as a white solid. 1H NMR (250 MHz, CDCl3)
2H), 9.97 (s, 2H), 7.79 (d, J¼2.2 Hz, 2H), 7.65e7.61 (m, 6H), 1.47 (s,
18H). 13C NMR (62.5 MHz, CDCl3)
197.4, 160.9, 139.1, 133.2, 132.1,
131.5, 130.1, 128.4, 120.9, 35.3, 29.5. HRMS (ESI neg) calcd for
d 11.80 (s,
d
of macrocycles (see a copy in S.D.). IR (KBr, n
(cmꢁ1), mixture) 3419,
3066, 2934, 2861, 2361, 2347, 1731, 1625, 1465, 1449, 1433, 1390,
1360, 1273, 1167, 1031, 791, 728, 697. Maldi-Tof (m/z): 1194.4 (n¼2),
1790.6 (n¼3), 2387.2 (n¼4), 2984.1 (n¼5), 3580.9 (n¼6).
C28H29O4 (MꢁH) 429.2071, found 429.2067. IR (KBr,
n
(cmꢁ1)) 2924,
2854, 1645, 1438. Mp 266 ꢀC.
4.2.4. Synthesis of disalicylaldehyde derivative 7. The same pro-
cedure was performed with 2 (232 mg, 0.76 mmol), 4,40-dibromo-
diphenyl (95.2 mg, 0.305 mmol), Pd(PPh3)4 (21.15 mg, 0.018 mmol)
and K2CO3 (63.25 mg, 0.46 mmol). The recovered residue was pu-
rified by column on silica gel (cyclohexane/CH2Cl2: 30/70) to afford
4.3.2. Synthesis of calixesalen 12. (S,S)-Cyclohexane-1,2-diamine
(24 mg, 0.21 mmol) was added to a solution of dialdehyde 6
(90.5 mg, 0.21 mmol) in THF (24 mL) with continuous stirring, and
the mixture was heated at 70 ꢀC for 24 h. The reaction was cooled at
room temperature, THF was partially evaporated and methanol was

9960
F. Ibrahim et al. / Tetrahedron 68 (2012) 9954e9961
added. A solid precipitated, was filtered and washed with cold
126.1, 118.0, 69.9, 35.1, 32.4, 29.5, 24.2. HRMS (ESI positive) calcd for
methanol to afford the product as a yellow powder (74%, 79 mg,
C
68H80O4N4Na (MþNa) 1039.6072, found 1039.6019. IR (KBr,
n
0.15 mmol). 1H NMR (250 MHz, CDCl3) was performed as a mixture
(cmꢁ1)) 2933, 2360, 2346, 1626, 1440. [
a]
20 þ133.1 (c 0.06, CHCl3).
D
20
of macrocycles (see a copy in S.D.). [
a
]
ꢁ150 (c 0.2, CHCl3 as
Mp >230 ꢀC.
D
a mixture). Maldi-Tof (m/z): 1017.6 (n¼2), 1525.9 (n¼3), 2035.3
Trimer 1H NMR (250 MHz, CDCl3):
d 8.25 (s, 6H), 7.65e7.56 (m,
(n¼4). IR (KBr,
n
(cmꢁ1), mixture)¼3431, 2959, 2863, 1627, 1439. Mp
4H), 7.54e7.38 (m, 6H), 7.36e7.32 (m, 10H), 7.16e7.08 (m, 4H),
3.42e3.22 (m, 6H), 2.21e2.08 (m, 8H), 1.96e1.84 (m, 12H), 1.50 (s,
>260 ꢀC. SEC analysis, Mn¼1690 g molꢁ1, Mw/Mn¼2.
54H), 1.52e1.27 (m, 4H). 13C NMR (62.5 MHz, CDCl3)
d 166.4, 159.9,
4.3.3. Synthesis of calixesalen 13. (S,S)-Cyclohexane-1,2-diamine
(15 mg, 0.13 mmol) was added to a solution of dialdehyde 8
(70 mg, 0.13 mmol) in THF (24 mL) with continuous stirring, and
the mixture was heated at 70 ꢀC for 24 h. The reaction was cooled at
room temperature, THF was partially evaporated and methanol was
added. A solid precipitated, was filtered and washed with cold
methanol to afford the product as a yellow powder (94%, 76 mg,
0.127 mmol). 1H NMR (250 MHz, CDCl3) was performed as a mix-
139.2, 137.6, 130.5, 128.4, 126.8, 118.5, 69.9, 35.1, 32.4, 29.5, 24.2.
HRMS: (ESI positive) calcd for C102H121O6N6 (MþH) 1525.9342,
found 1526.9283. IR (KBr,
n
(cmꢁ1))¼3439, 2959, 2869, 1626, 1439.
[a
]
20 ꢁ36 (c 0.07, CHCl3). Mp >230 ꢀC.
D
Synthesis of Calixesalen 12 in diluted medium (i.e., 5ꢂ diluted
than the initial value) dialdehyde 6 (100 mg, 0.23 mmol) and MS
4 Ǻ were added to a solution of (S,S)-cyclohexane-1,2-diamine
(28 mg, 0.25 mmol) in THF (142 mL) with continuous stirring, and
the mixture was heated at 70 ꢀC for 24 h. The reaction was cooled at
room temperature; the solution was filtrated to eliminate the MS.
THF was evaporated. A yellow solid (77%, 97 mg, 0.191 mmol) is
obtained. Repartition of macrocycle in the mixture is: dimer (68%),
trimer (12%), tetramer and other structure (20%).
ture of macrocycles (see a copy in S.D.). [
a]
20 þ81.6 (c 0.5, CHCl3 as
D
a mixture). Maldi-Tof (m/z): 1201.7 (n¼2), 1803.0 (n¼3), 2403.4
(n¼4). IR (KBr,
>260 ꢀC.
n
(cmꢁ1), mixture)¼3538, 2962, 2861, 1627, 1504. Mp
4.3.4. Synthesis of calixesalen 14. (S,S)-Cyclohexane-1,2-diamine
(8.3 mg, 0.073 mmol) was added to a solution of dialdehyde 10
(30 mg, 0.073 mmol) in THF (10 mL) with continuous stirring, and
the mixture was heated at 70 ꢀC for 24 h. The reaction was cooled at
room temperature, THF was partially evaporated and methanol was
added. A solid precipitated, was filtered and washed with cold
methanol to afford the product as a yellow powder (99%, 40 mg,
0.081 mmol). 1H NMR (250 MHz, CDCl3) was performed as a mix-
ture of macrocycles (see a copy in S.D.). Maldi-Tof (m/z): 977.4
(n¼2), 1465.6 (n¼3), 1954.8 (n¼4), 2443.0 (n¼5), 2931 (n¼6). IR
Synthesis of Calixesalen 12 in concentrated medium (i.e., 26.5ꢂ
concentrated than the initial value) (S,S)-cyclohexane-1,2-diamine
(28 mg, 0.25 mmol) and dialdehyde 6 (100 mg, 0.25 mmol) and MS
4 Ǻ were mixed under argon. 1 mL of THF was added with con-
tinuous stirring, and the mixture was heated at 70 ꢀC for 24 h. The
reaction was cooled at room temperature; the solution was filtrated
to eliminate the MS. THF was evaporated. A yellow-brown solid
(79%, 100 mg, 0.196 mmol) is obtained, exclusively as the tetramer
species.
Tetramer 1H NMR (250 MHz, CDCl3)
d 14.06 (br s, 8H), 8.41 (s,
(KBr,
n
(cmꢁ1), mixture) 3429.8, 2930, 2857, 1630, 1484. Mp
8H), 7.57e7.51 (m, 24H), 7.33e7.31 (m, 8H), 3.42e3.24 (m, 8H),
>260 ꢀC.
2.16e1.66 (m, 24H), 1.45 (s, 72H), 1.42e1.24 (m, 8H). 13C NMR
(62.5 MHz, CDCl3)
d 165.9, 160.1, 139.4, 137.8, 130.7, 128.5, 128.2,
4.3.5. Synthesis of calixesalen 15. (S,S)-1,2-Diphenylethylendiamine
(42 mg, 0.20 mmol) was added to a solution of dialdehyde 6
(85 mg, 0.20 mmol) in THF (10 mL) with continuous stirring, and the
mixture was heated at 70 ꢀC for 24 h. The reaction was cooled at
room temperature, THF was partially evaporated and methanol was
added. A solid precipitated, was filtered and washed with cold
methanol afford the product as a yellow powder (50%, 60 mg,
127.1,118.9, 72.6, 35.1, 33.3, 29.6, 24.2. HRMS: (ESI positive) calcd for
C136H161O8N8 (MþH) 2035.7827, found 2035.2360. IR (KBr,
n
20
(cmꢁ1))¼2932, 2869, 16,267, 1439. [
>230 ꢀC.
a
]
ꢁ175 (c 0.2, CHCl3). Mp
D
Acknowledgements
0.10 mmol). 1H NMR (250 MHz, CDCl3) was performed as a mixture
ꢁ
ꢀ
The CNRS, the Ministere de l’Enseignement Superieur et de la
20
ꢁ
ꢁ
of macrocycles (see a copy in S.D.). [
a
]
þ80.5 (c 0.5, CHCl3, as
Recherche, the Ministere des Affaires Etrangeres (Eiffel Scholar-
D
(cmꢁ1), mixture)¼3439, 2959, 2869,1626,1439.
ꢀ
a mixture). IR (KBr,
n
ship), the Direction des Relations Internationales de l’Universite
Mp >260 ꢀC. SEC analysis, Mn¼2000 g molꢁ1, Mw/Mn¼1.5.
ꢁ
ꢀ ꢀ
Paris Sud, the ‘Groupement de Recherche Synthese et Procedes
ꢀ
Durables pour une Chimie eco-Compatible’ du CNRS and the Sup-
4.4. Synthesis of calixesalen derivativesddifferent dilution
port of Research Grant Program at the Lebanese University are ac-
conditions
knowledged for financial support. Jean-Pierre Baltaze is sincerely
ꢀ ꢀ
thanked for his help in DOSY experiments and Dr. Benedicte Lep-
Synthesis of calixesalen 12 in diluted conditions (i.e., 2ꢂ diluted
than the initial value) dialdehyde 6 (500 mg, 1.2 mmol) and MS 4 Ǻ
were added to a solution of (S,S)-cyclohexane-1,2-diamine (131 mg,
1.2 mmol) in THF (368 mL) with continuous stirring, and the mix-
ture was heated at 70 ꢀC for 24 h. The reaction was cooled to room
temperature; the solution was filtrated to eliminate the MS. THF
was partially evaporated and methanol was added. A solid pre-
cipitated, was filtered and washed with cold methanol to afford the
product as a yellow powder (70%, 427 mg, 0.84 mmol). Repartition
oittevin for SEC analyses. We also express our gratitude to Lei Yang
for technical assistance.
Supplementary data
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.09.077.
References and notes
of
dimer
(65%),
trimer
(18%),
mixture
(tetramerþ
1. Cozzi, P. G. Chem. Soc. Rev. 2004, 33, 410.
2. Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc.
1991, 113, 7063.
3. (a) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 2687; (b) Ready, J. M.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41, 1374; (c) White, D. E.; Jacobsen, E.
N. Tetrahedron: Asymmetry 2003, 14, 3633.
4. Liu, Y.; Rawlson, J.; Swann, A. T.; Takatani, T.; Sherrill, C. D.; Ludovice, P. J.; Weck,
M. Chem. Sci. 2011, 2, 429.
pentamerþhexamer) (17%). The mixture of macrocycle was sepa-
rated on silica gel (cyclohexane/ethylacetate: 93/7). The dimer was
isolated in 32% yield. The trimer was isolated in 40% yield.
Dimer 1H NMR (250 MHz, CDCl3)
d 7.89 (s, 4H), 7.52 (br s, 4H),
7.03 (s, 8H), 6.62 (br s, 4H), 3.35e3.16 (m, 4H), 2.40e2.25 (m, 4H),
2.05e1.85 (m, 8H), 1.59 (s, 36H), 1.52e1.45 (m, 4H). 13C NMR
(62.5 MHz, CDCl3)
d
167.3, 159.9, 138.1, 137.6, 130.0, 128.3, 126.8,
5. Baldini, L.; Casnati, A.; Sansone, F.; Ungaro, R. Chem. Soc. Rev. 2007, 36, 254.

F. Ibrahim et al. / Tetrahedron 68 (2012) 9954e9961
9961
6. Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.; Wietor, J. L.; Sanders, J. K. M.; Otto,
S. Chem. Rev. 2006, 106, 3652.
18. Srimurungan, S.; Viswanathan, B.; Varadarajan, T. K.; Varghese, B. Tetrahedron
Lett. 2005, 46, 1351.
7. (a) Tanaka, K.; Hachiken, S. Tetrahedron Lett. 2008, 49, 2533; (b) Savoia, D.;
19. Srimurungan, S.; Viswanathan, B.; Varadarajan, T. K.; Varghese, B. Org. Biomol.
Gualandi, A.; Stoeckli-Evans, H. Org. Biomol. Chem. 2010, 8, 3992; (c) Gualandi,
A.; Grilli, S.; Savoia, D.; Kwit, M.; Gawronski, J. Org. Biomol. Chem. 2011, 9, 4234.
Chem. 2006, 4, 3044.
ꢀ
20. Voituriez, A.; Mellah, M.; Schulz, E. Synth. Met. 2006, 156, 166.
21. (a) Mellah, M.; Ansel, B.; Patureau, F.; Voituriez, A.; Schulz, E. J. Mol. Catal. A:
Chem. 2007, 272, 20; (b) Zulauf, A.; Mellah, M.; Guillot, R.; Schulz, E. Eur. J. Org.
Chem. 2008, 2118; (c) Zulauf, A.; Mellah, M.; Schulz, E. J. Org. Chem. 2009, 74,
2242; (d) Zulauf, A.; Mellah, M.; Schulz, E. Chem. Commun. 2009, 6574.
22. Zulauf, A.; Mellah, M.; Schulz, E. Chem.dEur. J. 2010, 16, 11108.
23. Yang, J. Y.; Nocera, D. G. J. Am. Chem. Soc. 2007, 129, 8192.
24. DiMauro, E. F.; Vitullo, J. R. J. Org. Chem. 2006, 71, 3959.
25. Except for compound 11, which was synthesized in a toluene/ethanol mixture
for solubility reasons.
8. Srimurugan, S.; Suresh, P.; Babu, B.; Pati, H. N. Mini-Reviews in Organic Chemistry
2008, 5, 228.
9. Li, Z.; Jablonski, C. Chem. Commun. 1999, 1531.
10. Li, Z.; Jablonski, C. Inorg. Chem. 2000, 39, 2456.
11. Kwit, M.; Gawronski, J. Tetrahedron: Asymmetry 2003, 14, 1303.
12. Kwit, M.; Zabicka, B.; Gawronski, J. Dalton Trans. 2009, 6783.
13. Sakthivel, S.; Punniyamurthy, T. Tetrahedron: Asymmetry 2010, 21, 2834.
14. Zhu, C.; Yuan, C.; Lv, Y. Synlett 2006, 1221.
15. Kureshy, R. I.; Das, A.;Khan, N. u. H.; Abdi, S. H. R.; Bajaj, H. C. ACS Catal. 2011,1,1529.
16. Kureshy, R. I.; Prathap, K. J.; Kumar, M.; Bera, P. K.; Khan, N. u. H.; Abdi, S. H. R.;
Bajaj, H. C. Tetrahedron 2011, 67, 8300.
26. See experimental part and Supplementary data for more details.
27. Hyperchem 5.11 (Standard); Hypercube: Gainesville, FL, 1996.
28. Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org. Chem.
1994, 59, 1939.
17. Gao, J.; Reibenspies, J. H.; Zingaro, R. A.; Woolley, F. R.; Martell, A. E.; Clearfield,
A. Inorg. Chem. 2005, 44, 232.