Efficient synthesis of amino-protected calix[4]arenes selectively functionalized with iron chelator ICL670 designed as platform for iron recognition

Article abstract of DOI:10.1016/j.tet.2011.02.059

The development of selective electrochemical iron sensor is still a challenging task. One promising possibility is to use organically functionalized inorganic particles, for instance silica, as sensitive element. Herein, we report on the design and synthesis of calix[4]arene-based platforms modified with ICL670 iron chelator and alkylamino chain(s). These new molecular edifices could be easily grafted on silica particles. The strategy relies on selective calix[4]arenes functionalizations by alkylamino chains at the lower rim, in partial-cone or 1,3-alternate conformations. The different synthesis routes are presented and discussed.

Full text of DOI:10.1016/j.tet.2011.02.059

Tetrahedron 67 (2011) 2916e2924
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of amino-protected calix[4]arenes selectively functionalized
with iron chelator ICL670 designed as platform for iron recognition
,
,
,
,d
Pascal Rouge a d, Mathieu Becuwe b d, Alexandra Dassonville-Klimpt a d, Sophie Da Nascimento a
,
Jean-Franc¸ ois Raimbert a d, Dominique Cailleu c d, Emmanuel Baudrin a d, Pascal Sonnet a
UMR-CNRS 6219, Laboratoire des Glucides, Faculte de Pharmacie, Universite de Picardie Jules Verne, 1 rue des Louvels, 80039 Amiens Cedex, France
Laboratoire de Reactivite et Chimie des Solides, UMR CNRS 6007, Universite de Picardie Jules Verne, 33 Rue Saint Leu, 80039 Amiens Cedex, France
Plate-forme analytique, Universite de Picardie Jules Verne, 80039 Amiens Cedex, France
,
,
,
,d,
*
a
ꢀ
ꢀ
b
c
ꢀ
ꢀ
ꢀ
ꢀ
d
ꢀ
Institut de Chimie de Picardie, FR3085 CNRS, Universite de Picardie Jules Verne, 33 Rue Saint Leu, 80039 Amiens Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of selective electrochemical iron sensor is still a challenging task. One promising
possibility is to use organically functionalized inorganic particles, for instance silica, as sensitive element.
Herein, we report on the design and synthesis of calix[4]arene-based platforms modified with ICL670
iron chelator and alkylamino chain(s). These new molecular edifices could be easily grafted on silica
particles. The strategy relies on selective calix[4]arenes functionalizations by alkylamino chains at the
lower rim, in partial-cone or 1,3-alternate conformations. The different synthesis routes are presented
and discussed.
Received 3 December 2010
Received in revised form 17 February 2011
Accepted 21 February 2011
Available online 26 February 2011
Keywords:
Calix[4]arene
Lower-rim functionalization
ICL670
Ó 2011 Elsevier Ltd. All rights reserved.
Iron sensor
1. Introduction
of ionic surface equilibriums.4 The surface of inorganic sensitive
materials in contact with the electrolyte to analyze can thus be seen
Understanding the iron metabolism has become important be-
cause of its vital biological role. It is not an easy task and necessi-
tates the development of new tools enabling the selective detection
of specific ions, ideally in situ. Besides these biological applications,
such systems could also be profitably deciding for environmental
control, allowing continuous on-line detection.1 Fe3þ is a major
transition metal for all organisms and present only as trace
amounts in its ligand-free form. It is an essential element for the
critical steps of the cellular metabolism, such as cell progression,
growth, and division, including DNA synthesis.2 For the specific
medicinal applications, the developed ion sensors should be ideally
integrated in miniaturized systems. For such a case, electro-
chemical detection is one of the simplest and cheapest type of
measurements, and more specifically the potentiometric detection.
Very few Fe3þ sensors have been reported so far3 and thus sensing
and quantification of Fe3þ is still a challenging task. We are now
following a bottom-up approach for the specific development of
sensitive materials, which can be used in electrochemical sensor.
This comes from the knowledge that the sensing mechanism of
most of the sensitive materials used so far lies in the establishment
as an assembly of complexing sites, initially present or formed
during an aging step, and which can be more or less specific for the
ions to detect. Thus, it was attempting to synthesize directly such
a system. Formation of silica, selected as matrix, can be easily
controlled (formation of films, mesostructures, nanoparticles,.)
and functionalized for the development of different sensor types.5
For the development of iron sensor, the key is to use macrocycles,
which could efficiently and specifically bind iron and furthermore
which can be easily grafted onto the matrix. The present work aims
at preparing calix[4]arene-based platforms modified with iron
chelators and which could be considered as good candidates for
such purpose.
The prepared platforms should be selective for the Fe3þ com-
plexation and thus minimizing chelation with other important bi-
ologically cations present in the serum, such as Zn2þ and Cu2þ. The
thermodynamic stability of Fe3þ complexes (iron octahedral envi-
ronment) can be maximized by incorporating the six coordinating
atoms into a single macromolecular structure thereby creating
a hexadentate ligand.6 Among three molecules that are presently
used in therapeutics, we have chosen to use the orally active tri-
dentate ICL670 (4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]
benzoic acid, deferasirox Fig. 1).7 To its advantage, this compound
can be easily synthesized (two steps), and can to be grafted onto the
* Corresponding author. E-mail address: pascal.sonnet@u-picardie.fr (P. Sonnet).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.059

P. Rouge et al. / Tetrahedron 67 (2011) 2916e2924
2917
O
O
O
HN
HO
O
NH
N
N
HN
N
N
N
NH
N
N
HO
N
N
O
N
N
O
HO
O
N
O
OH
OH
O
HO
O
HO
HO
O
OH
N
N
O
N
OH O
O
O
HO
O
OH
inorganic matrix-HN
NH-inorganic matrix
NH-inorganic matrix
ICL670
ICL670-modified calix[4]arenes
Fig. 1. ICL670 and ICL670-modified calix[4]arenes for the formation of hybrid material.
multivalent calix[4]arene platform through the carboxylic function,
which is not involved in the Fe3þ chelation. Calix[4]arenes (C4R),
which have been largely reported for the sensitive and selective
recognition of various metal ions,8 were chosen as an ideal platform
for the preorganization of the ICL670 iron chelator. The possibility
of selective functionalization at the lower rim (iron chelator and
inorganic matrix grafting group) together with different possible
C4R conformations (partial-cone, 1,2- or 1,3-alternate or cone) bring
a useful versatility to these macromolecules.
In this work, we present below the routes to prepare new se-
lectively amino-protected calix[4]arenes. These orthogonally
amino protections allowed us to synthesize the key C4R in-
termediates substituted at the lower rim by ICL670 as the iron
chelator and by an alkylamino spacer that could be used for the
grafting with a halogenopropyl modified silica-matrix (Fig. 1).
carbonate. A first selective deprotection of the phthalimide groups
allowed the incorporation of the iron chelator (ICL670), which was
then followed by a second deprotection step or by a reduction
leading to calixarenes 6 and 7. The obtained amino-calixarenes
6and 7 (from nitrile or carbamate) will give us the opportunity, by
an SN reaction, to graft the iron ligand-based platform onto the
inorganic matrix.
The unsubstituted calixarene 1, used as starting material, was
prepared according to a two-steps synthesis developed by Gutsche
from p-tertbutylphenol.10 For the reaction with this calixarene 1,
the iodo compound 8 can be synthesized by two routes from the
same intermediate 10, obtained by aminoprotection of hydrox-
yethyloxyethylamine 9 in quantitative yield (Scheme 1). The first
(route A) is a one-step reaction, known as GarreggeSamuelsson’s
reaction,11 which uses as halogenating reagent PPh3I2 in the pres-
ence of imidazole. The iodo compound 8 was obtained with a 68%
yield but two disadvantages would limit the use of this method for
large scale; (i) distillation of large quantities of pyridine and toluene
and (ii) purification of substantial quantities of triphenylphosphine
oxide. Another route (route B) was then preferred via the mesylate
11 to obtain the compound 8 in two steps with a global yield of 78%.
The first type of amino protecting groups was introduced by a se-
lective alkylation of the calix[4]arene 1 with 4 equiv of iodo com-
pound 8 in the presence of 2 equiv of K2CO3 as a base, in refluxing
acetonitrile for 7 days (Scheme 2). This alkylation led selectively in
74% yield to the diametrically substituted calixarene 12 in the cone
conformation, as indicated by the 1H NMR spectrum. A typical AB
pattern was observed for the methylene bridge ArCH2Ar protons
(J¼12.9 Hz) at 3.06 ppm for the equatorial protons and 3.97 ppm for
the axial protons. In order to maintain the 1,3-alternate conformation
for the final calix[4]arene, the second etherification was achieved
with an excess of Cs2CO3 as a base.12 Thus, calixarene 12 was engaged
2. Results and discussion
9
€
Recently, Bohmer et al. reported on the synthesis of calix[4]
arenes fixed in the 1,3-alternate conformation and substituted se-
lectively by precursors of amino groups (
u-bromonitrile and
u
-bromophthalimide). For the present investigation, we have
chosen to synthesize such calixarene locked in the 1,3-alternate (or
partial cone) conformation as it allows a selective functionalization
of both sides of the molecule (namely iron chelators on one side
and the inorganic matrix on the other one). The reactional sequence
used to prepare the key calixarenes, before the grafting onto in-
organic matrix, is depicted in Fig. 2. A first O-alkylation of the calix
[4]arene 1 was accomplished using a iodoalkylphthalimide to ob-
tain an intermediate syn-1,3-diether, which was converted into
a mixed tetra-ether 2e5 fixed in the 1,3-alternate or partial cone
conformation after a second alkylation in the presence of cesium
NPht
NPht
NPht
NHR3
NHR3
NPht
NHR3
NHR3
O
O
O
O
O
OR
O
O
O
O
OH
O
OH
OH
HO
or
O
O
O
O
1
O
OH
O
O
or
O
O
O
O
O
R
1
R
R
R2
R2
R2
6
7
O
R1 = CH2CH2CH2CN, R = CN (4)
R1 = H, R = NHBoc (5)
R = CN (2)
R = NHBoc (3)
N
N
R2 = NH2, CH2NH2, R3 =
N
HO
OH
Fig. 2. Reactional sequence used to synthesize the key calixarenes as a preliminary step for the formation of the hybrid material.

2918
P. Rouge et al. / Tetrahedron 67 (2011) 2916e2924
PPh3 I2, imidazole
toluene/pyridine (1/1)
I
O
68%
route A
NPht
8
OH
phtalic anhydride
OH
toluene, reflux
NaI, acetone, reflux
82%
O
O
100%
NH2
NPht
9
10
OMs
route B
MsCl, Et3N, CH2Cl2
96%
O
NPht
11
Scheme 1. Synthesis of the iodo arm spacer.
NPht
NPht
8, K2CO3,
CH3CN, reflux
74%
O
HO
O
OH
OH
HO
OH
OH
O
O
12
1
γ-bromobutyronitrile
Cs2CO3, DMF, 50°C
NPht
NPht
NH2
NPht
NH2
NH2
O
NPht
O
NH2
CN
CN
O
O
O
O
O
O
Hydrazine
EtOH, reflux
98%.
O
Hydrazine
EtOH, reflux
87%.
O
O
O
O
O
O
O
O
O
O
+
O
O
O
O
O
CN
CN
CN
NC
NC
CN
14
2 : 38%
4 : 48%
13
ICL670, EDCI/HOBt
CH2Cl2
ICL670, EDCI/HOBt
CH2Cl2
81 %
45 %
O
O
O
O
NH
CN
HN
NH
HN
N
N
N
N
N
N
N
N
N
N
N
N
O
O
OH
O
HO
O
OH
HO
O
O
OH
HO
HO
OH
O
O
O
O
O
O
CN
16
15
CN
No reduction
NC
No reduction
Scheme 2. Synthesis of the mono or dinitrilealkyl diICL calix[4]arenes in partial cone or in 1,3-alternate conformation.

P. Rouge et al. / Tetrahedron 67 (2011) 2916e2924
2919
in reaction with 10 equiv of
g
-bromobutyronitrile and 10 equiv
NMR analysis of the compound 5, as for the compound 4, indicates
two pair of doublets at 3.09 ppm (d, J 13.2 Hz)/4.10 ppm and at
3.72 ppm/4.01 ppm, connected to, respectively, the carbon at
30.59 ppm and 37.56 ppm, confirming the partial cone conforma-
tion. For the compound 5, there are seven kinds of aromatic protons
for the calixarene part; three triplets and four doublets.
The phthalimide groups of the Boc-protected calixarenes 3 and
5 were removed using an excess of hydrazine in boiling ethanol to
lead, respectively, to 17 (60% yield) and 18 (66% yield). The peptidic
coupling reactions between the tridentate iron(III) chelator ICL670
and these diamino free calixarenes 17 and 18 gave the hexadentate
calixarenes 19 and 20 in 14% and 56% yield, respectively. Finally, the
deprotection of the carbamate groups was afforded with success in
TFA to obtain the expected calix[4]arenes 6 (1,3-alternate) and 7
(partial cone) in 65% and 100% yield, respectively.
For the calixarene 6, the NMR analysis indicate one AB system,
include in the massif at 3.60 ppm, lied with one methylene carbon
at 37.72 ppm. For the compound 7, two pairs of doublet again are
found, which are connected to the two different methylene carbons
(30.62 ppm and 37.93 ppm). NMR spectra for compounds 19 and 6,
which are in 1,3-alternate conformation and for compounds 20 and
7, which are in partial cone conformation show the same kind of
signal that respectively compounds 3 and 17 (one AB system, 1,3-
alternate conformation) and compounds 5 and 18 (two AB systems,
partial cone conformation).
As a first step, to check if the formed platforms present indeed
sensing properties toward iron (III) species, we undertook a first
potentiometric test. To realize these measurements, the calixarene
derivative 7 was grafted onto silica particles through a nucleophilic
substitution between the free amino group included in the struc-
ture and a chloropropyl functionalized silica’s nanoparticle. The
coupling was performed in dry acetonitrile under reflux for 36 h.
The corresponding solid-state NMR spectra of the recovered
washed particles confirm the grafting process (Fig. 3).
Indeed, the calixarene derivative is clearly observed on the
spectrum of the hybrid material. On the basis of the liquid 13C NMR
spectrum of the platform, the different component of the ICL670
chelator, i.e., the carbonyl and phenolic quaternary carbon, triazole
fragment resonance, and the different aromatic carbon, are ob-
served at 170e152 ppm, 146e138 ppm, and 136e113 ppm, re-
spectively. Furthermore, additional peaks corresponding to the
alkyl chain (32 ppm) and also to the eCH2eO carbon (65e74 ppm)
are present and confirm the well-introduction of the organo-
chelator onto the silica nanoparticles. A thorough description of the
synthesis and characterization of this hybrid material will be
published in a forthcoming paper.
The new hybrid material was then incorporated in a PVDF-HFP
matrix to form an electrode according to Belcore’s technology as
reported previously.18 The potential of the porous plastic electrode
obtained containing the hybrid material as a sensing element was
measured against a classical saturated calomel electrodes (SCE) as
a function of the dissolved iron (III) concentration (FeCl3 from
Acros) (Fig. 4).
Cs2CO3 in DMFat 50 ꢀC for 2 weeks. A mixture of calixarene in the 1,3-
alternate 2 and in the partial cone 4 conformation was obtained in 76%
yield. Both conformers were separated by chromatography and their
structure was confirmed though analysis of their 1H NMR spectrum.
Due to the different ether group in 2, the methylene protons are not
identical and appear as a pair of doublet (AB system, J¼16.1 Hz) at
3.70 ppm and 3.78 ppm (connected to C at 38.19 ppm). This small
difference of chemical shift (Dd¼0.08 ppm) confirms the 1,3-alternate
conformation. The NMR analysis of the partial cone conformer 4
shows two different AB systems (1H NMR); one pair of doublet
(J¼13.3 Hz)at2.91 ppm and 3.90 ppm liedwiththeC at30.3 ppm and
another pair of doublet (J¼13.4 Hz) at 3.49 ppm and 3.68 ppm con-
nected to the C at 36.74 ppm. Moreover the 1H NMR displays four
different doublets (ArH protons) at 6.35 ppm, 6.77 ppm, 6.99 ppm,
and 7.21 ppm, which confirm the partial cone conformation. Each
conformer was functionalized separately, in two steps, by two ICL670
in order to form the corresponding hexadentate iron chelators
(Scheme 2). The phthalimido deprotections of 2 or 4, was realized
with hydrazine in boiling ethanol leading to the corresponding ali-
phatic diamines, 13 or 14 with good yields without reduction of the
nitrile functions. These deprotected calixarenes were then function-
alized, using a peptidic coupling reaction, with the well known tri-
dentate iron(III) chelator ICL670, whichwaspreviouslysynthesized in
two steps according to the procedure of Steinhauser et al.13 The best
peptidic coupling was obtained with the use of EDCI/HOBt in DCM
leading to 1,3-alternate calixarene 15 (81% yield) or partial cone cal-
ixarene 16 (45% yield). At last, the reduction of the nitrile groups is
necessary to form the corresponding amino iron chelator calix[4]
arenes, which could then be coupled to the inorganic matrix by
classical SN reaction. For this, various reaction conditions have been
tried; (i) by several hydrogenation conditions with Nickel9 or Palla-
dium catalysts and (ii) with different hydrides, such as sodium bo-
rohydride,14 lithiumaluminiumhydrideorBH3$Me2S.15 Thecomplete
conversion of the starting material was observed only with lithium
aluminium hydride in boiling THF or with BH3$Me2S in refluxing THF.
However, because ofa lack of selectivity, these kinds ofhydrides led to
complex and inseparable mixtures.
Since the promising orthogonal protection of amines with
phthalimide and nitrile had failed, we decided to try another al-
ternative strategy using a carbamate (Boc) as amino protecting
groups in place of nitrile. To the best of our knowledge, few
examples of O-alkylation of calixarene with Boc-protected halo-
genoalkylamine are described in the literature.16 The N-Boc bro-
mopropylamine, which can easily be synthesized in quantitative
yield from the bromopropylamine hydrobromide,17 was chosen as
precursor for arm spacer between the calixarene and the
inorganic matrix. The synthesis of the Boc-protected calixarenes 3
and 5 were initially considered by using the same procedure de-
scribed for 2 and 4 (calixarene 12 with 10 equiv of N-Boc bro-
mopropylamine and 10 equiv Cs2CO3 in DMF at 50 ꢀC for 2 weeks).
Unfortunately, a complex mixture of products inseparable by
chromatography was obtained. To solve this problem, the reaction
temperature was decreased (0 ꢀC for 2 h then rt for 4 days vs
50 ꢀC). With these new conditions (Scheme 3), the two desired
monoBoc or diBoc-protected calixarenes were isolated, after
chromatography purification, in 22% yield for 3 (1,3-alternate
conformation) and in 30% yield for 5 (partial cone conformation).
Interestingly, the calixarene 5 can be obtained in 63% yield by
reducing the base quantity by half.
The concentration was changed by decades and leads to well
defined voltage plateau. In similar conditions, a chloropropyl-
modified silica based electrode did not show any evolution of the
equilibrium voltage when the concentration was modified. This is
thus a clear proof of the specific interaction of iron(III) with the
platform, which most likely occurs through the formation of
a hexadentate complex.
The 1,3-alternate conformation of the compound 3 was con-
firmed by NMR analysis. As for the compound 2, the methylene
protons display one AB system with a small difference of chemical
shifts (3.70 ppm and 3.78 ppm). The methylene carbons appear at
36.93 ppm. For the compound 3, there are four kinds of aromatic
protons for the calixarene part; two triplets and two doublets. The
3. Conclusion
The selective functionalization of calix[4]arenes by alkylamino
chains at the lower rim, in partial-cone or 1,3-alternate conforma-
tions, was examined. The orthogonally amino protections allowed

2920
P. Rouge et al. / Tetrahedron 67 (2011) 2916e2924
NPht
NPht
NPht
O
NPht
NPht
NPht
O
O
O
N-Bocbromopropylamine
O
O
Cs2CO3, DMF
0°C to RT
O
O
O
OH
O
O
OH
HO
O
+
O
O
O
12
BocHN
5 : 30%
NHBoc
NHBoc
NH2
3 : 22%
Hydrazine
EtOH, reflux
Hydrazine
EtOH, reflux
66%
NH2
60%
NH2
NH2
O
O
O
O
O
OH
O
O
O
O
O
O
NHBoc
NHBoc
BocHN
18
17
ICL670, EDCI, HOBt
ICL670, EDCI/HOBt
56%
14%
O
O
O
HN
O
NH
O
N
HN
N
N
N
N
NH
N
N
N
N
OH
HO
N
N
O
N
HO
O
O
HO
OH
OH
O
OH
OH
O
O
HO
O
O
O
O
BocHN
NHBoc
NHBoc
O
19
20
TFA, CH2Cl2
65%
TFA, CH2Cl2
100%
O
O
O
HN
NH
HN
N
N
NH
N
N
N
N
N
N
N
N
O
N
OH
HO
N
O
HO
O
OH
HO
O
OH
O
OH
HO
O
O
OH
O
O
O
O
NH2
NH2
H2N
6
7
Scheme 3. Synthesis of the mono or diaminoalkyl diICL calix[4]arenes in 1,3-alternate 6 or in partial cone 7 conformation.
us to synthesize in four steps, from the key diphtalimido calixarene
12, the monoamino or diaminoalkyl calixarenes 6 (1,3-alternate)
and 7 (partial cone). They are substituted, at the lower rim, by two
iron(III) chelators ICL670 and by one or two alkylamino chain(s).
We prove here that such calixarene-based platforms modified with
iron chelators can be successfully used as building block for the
formation iron sensors. For that purpose, the calixarenes 6 and 7
can be grafted by nucleophilic substitution reaction to a modified
silica-matrix. We are actually pursuing this route and better char-
acterizing the formed systems.
4. Experimental
4.1. General remarks
Column chromatography was performed on Kielselgel 60
(40e63 m) ASTM (Merck). Reactions were analyzed on pre-
m
coated silica gel 60 F254 plates (Merck) and the compounds were
visualized with a UV lamp (254 nm) and phosphomolybdic acid
in EtOH. Melting points were determined on a Stuart SMP3 ap-
paratus and reported uncorrected. 1H and 13C NMR spectra were

P. Rouge et al. / Tetrahedron 67 (2011) 2916e2924
2921
Fig. 3. Solid-state 13C NMR spectra of the hybrid material including the new organochelator entities.
Fig. 4. Potentiometric response of the new electrode toward iron (III) aqueous solution over a range from 10ꢁ1 mol/L to 10ꢁ4 mol/L.
recorded on
a
Bruker 600, 500 or 300 spectrometers. The
4.2. Synthesis
chemical shifts are reported in parts per million (d) and the
signals are quoted as s (singlet), br s (broad singlet), d (doublet),
br d (broad doublet), dd (doublet of doublet), dt (doublet of
trilplet), t (triplet), br t (broad triplet), q (quartet), br q (broad
quartet), m (multiplet). J values are given in Hertz. Signal as-
signment was made using HMBC, HSQC, COSY, and NOESY ex-
periments when necessary. Mass spectra and high resolution
mass spectra (electrospray in positive modedESIþ) were recor-
ded on a Waters Q-TOF Ultima apparatus. The 13C solid-state
NMR spectra were obtained on a Bruker AVANCE 500 spec-
4.2.1. 2-[2-(2-Hydroxyethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 10.
A solution of phthalic anhydride (74 g, 500 mmol) and 2-(2-
hydroxyethyl)ethanolamine (52.5 g, 500 mmol) in toluene (450 mL)
was heated under reflux in a three-necked round bottom flask fitted
with a DeaneStark apparatus. After 24 h, toluene was removed
under reduce pressure and the oily residue is left at rt overnight to
crystallize. White solid (116.7 g) was obtained. Yield: 100%,
mp¼63e64 ꢀC; IR (ATR, cmꢁ1): 3540, 1766, 1701; 1H NMR (CDCl3,
500 MHz)
d
3.53 (t, J¼4.6 Hz, 2H), 3.61 (t, J¼4.6 Hz, 2H), 3.67 (t,
trometer with
a
4 mm probe and executive frequencies of
J¼5.6 Hz, 2H), 3.83 (t, J¼5.6 Hz, 2H), 7.55 (dd, J¼5.5, 3.1 Hz, 2H), 7.60
100.62 MHz. The experiments were performed with a magic
angle spinning frequency set to 5 kHz, a contact time of 3 ms
and using a CPTOSS sequence to suppress rotating bands. All
commercially available products were used without further pu-
rification unless otherwise specified.
(dd, J¼5.5, 3.2 Hz, 2H); 13C NMR (CDCl3, 125 MHz)
d 37.92, 62.00,
68.63, 72.63, 123.64, 132.38, 134.38, 168.76. ESIþ-MS: 258 [MNa]þ.
4.2.2. 2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethyl
methanesulfonate 11. Methanesulfonyl chloride (34.6 mL) was

2922
P. Rouge et al. / Tetrahedron 67 (2011) 2916e2924
slowly added to a cold solution of alcohol 10 (70 g, 298 mmol)
and Et3N (84 mL, 596 mmol) in CH2Cl2 (250 mL). The reaction
mixture was stirred at rt for 5 h. After that, the reaction mixture
was diluted with CH2Cl2 (500 mL) and then filtrated. The organic
phase was washed successively with 1 M HCl (2ꢂ75 mL), satu-
rated solution of NaHCO3 (75 mL), and brine. The organic phase
was dried over Na2SO4, filtered, and the CH2Cl2 was evaporated
under reduced pressure to yield compound 11 (91 g, 96%) as
a light orange solid. Mp¼96e98 ꢀC; IR (ATR) nmax cmꢁ1: 1769,
alternate conformer 2 (2.2 g, 38%) as white gum and the partial cone
conformer 4 (2.8 g, 48%) as a white gum.
4.2.6. 25,27-Bis-(1-(2-(2-phthalimidoethoxy)ethoxy))-26,28-bis-(1-
(3-cyanopropoxy))-calix[4]arene, 1,3-alternate 2. IR(ATR)vmax cmꢁ1
:
2871, 2239, 1769, 1704; 1H NMR (CDCl3, 500 MHz)
d
1.66 (t, J¼6.9 Hz,
4H),1.92 (t, J¼7.4 Hz, 4H), 3.07 (t, J¼6.3 Hz, 4H), 3.51 (t, J¼6.3 Hz, 4H),
3.55 (t, J¼5.8 Hz, 4H), 3.59 (t, J¼6.4 Hz, 4H), 3.70 (d, J¼16.1 Hz, 4H),
3.78 (d, J¼16.1 Hz, 4H), 3.83 (t, J¼5.8 Hz, 4H), 6.81 (t, J¼7.3 Hz, 2H),
6.84 (t, J¼7.1 Hz, 2H), 7.00 (d, J¼7.5 Hz, 4H), 7.03 (d, J¼7.5 Hz, 4H), 7.67
(dd, J¼5.5, 3.1 Hz, 4H), 7.80 (dd, J¼5.4, 3.1 Hz, 4H); 13C NMR (CDCl3,
1702; 1H NMR (CDCl3, 300 MHz)
d
2.99 (s, 3H), 3.72e3.77 (m, 4H),
3.90 (t, J¼5.4 Hz, 2H), 4.29e4.32 (m, 2H), 7.70e7.74 (m, 2H),
7.83e7.86 (m, 2H); 13C NMR (CDCl3, 75 MHz)
d
37.26, 37.52, 68.16,
125 MHz) d 13.83, 26.24, 37.87, 38.19, 67.84, 68.16, 68.88, 69.09,
68.63, 72.63, 123.64, 132.38, 134.38, 168.76. ESIþ-MS: 336 [MNa]þ,
ESIþ-HRMS [MNa]þ: calculated for [C13H15NSO6Na]þ: 336.0518.
Found: 336.0526.
120.32, 122.79, 123.26, 123.61, 129.65, 130.07, 132.54, 133.91, 134.34,
134.53, 156.50, 156.75, 168.58. ESIþ-MS: 1015 [MNa]þ. ESIþ-HRMS
[MNa]þ: calculated for C60H56N4O10Na:1015.3894. Found:1015.3875.
4.2.3. 2-[2-(2-Iodoethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 8. NaI
(62.7 g, 427 mmol) was added to a solution of mesylate 11 (89 g,
284 mmol) in acetone (150 mL). The reaction mixture was stirred
to reflux for 20 h. The solvent was removed under vacuum. The
oily residue was dissolved in CH2Cl2 (300 mL) and washed with
10% (m/m) aqueous Na2SO3 then with water. The organic phase
was dried over Na2SO4 and the CH2Cl2 was evaporated under re-
duced pressure to yield compound 8 (81 g, 82%) as white crystals.
Mp¼79e81 ꢀC; IR (ATR) nmax cmꢁ1: 1769, 1697; 1H NMR (CDCl3,
4.2.7. 25,27-Bis-(1-(2-(2-phthalimidoethoxy)ethoxy))-26,28-bis-(1-
(3-cyanopropoxy))-calix[4]arene, partial cone 4. IR (ATR) vmax cmꢁ1
:
2920, 2873, 2242, 1709; 1H NMR (CDCl3, 500 MHz)
d 1.61 (q,
J¼7.5 Hz, 2H), 1.99e2.06 (m, 2H), 2.23 (m, 4H), 2.91 (d, J¼13.3 Hz,
2H), 3.21 (t, J¼7.2 Hz, 2H), 3.45 (t, J¼6.5 Hz, 2H), 3.49 (d, J¼13.7 Hz,
2H), 3.68 (d, J¼13.4 Hz, 2H), 3.69e3.76 (m, 8H), 3.78e3.82 (m, 2H),
3.88e3.96 (m, 8H), 6.35 (d, J¼7.4 Hz, 2H), 6.45 (t, J¼7.5 Hz, 2H), 6.77
(d, J¼7.0 Hz, 2H), 6.86 (t, J¼7.4 Hz, 1H), 6.99 (m, 3H), 7.21 (d,
J¼7.5 Hz, 2H), 7.59e7.62 (m, 4H), 7.71e7.73 (m, 4H); 13C NMR
500 MHz)
d
3.18 (t, J¼6.7 Hz, 2H), 3.69e3.76 (m, 4H), 3.90 (t,
(CDCl3, 125 MHz) d 14.01, 14.09, 25.37, 27.21, 30.30, 36.74, 37.95,
J¼5.7 Hz, 2H), 7.69e7.72 (m, 2H), 7.83e7.86 (m, 2H); 13C NMR
68.10, 69.63, 70.43, 72.08, 73.17, 120.03, 121.46, 122.30, 123.29,
123.47, 123.63, 129.20, 129.43, 129.48, 131.33, 132.37, 132.93, 134.12,
134.17, 134.33, 136.75, 155.16, 156.54, 157.23, 168.56. ESIþ-MS: 1015
[MNa]þ. ESIþ-HRMS [MNa]þ: calculated for C60H56N4O10Na:
1015.3894. Found: 1015.3833.
(CDCl3, 125 MHz)
d 2.78, 37.32, 67.50, 71.19, 123.31, 132.15, 133.99,
168.28. ESIþ-MS: 368 [MNa]þ(100), 713 [M2Na]þ. ESIþ-HRMS
[MNa]þ: calculated for [C12H12NO3INa]þ: 367.9760. Found:
367.9775.
4.2.8. 25,27-Bis-(1-(2-(2-phthalimidoethoxy)ethoxy))-26,28-bis-(1-
(3-(tert-butyloxycarbonyl) aminopropyloxy))calix[4]arene. A solu-
tion of N-Boc bromopropylamine (555 mg, 2.33 mmol) in anhydrous
DMF (4 mL) was added at 0 ꢀC under Argon atmosphere to a slurry of
calix[4]arene 12 (200 mg, 0.233 mmol), and anhydrous Cs2CO3
(762 mg, 2.33 mmol) in anhydrous DMF (5 mL). The reaction mix-
ture was stirred at 0 ꢀC for 2 h then at rt for 4 days. After this time,
0.1 M HCl aqueous (50 mL) was added. This aqueous phase was
extracted with ethyl acetate (2ꢂ40 mL). The combined organic layers
were washed successively with 0.1 M HCl aqueous (10 mL), water
(10 mL), and brine. The organic layer was dried over Na2SO4, filtered,
and the solvent was removed under reduced pressure. The crude
product was purified by chromatography (CH2Cl2/AcOEt 8:2) to yield
1,3-alternate conformer 3 (60 mg, 22%) as a white solid and partial
cone conformer 5 (70 mg, 30%) as a white foam.
4.2.4. 25,27-Bis-(1-(2-(2-phthalimidoethoxy)ethoxy))-26,28-dihy-
droxycalix[4]arene, cone 12. A slurry of calix[4]arene 1 (10 g,
23.6 mmol), anhydrous K2CO3 (6.5 g, 47.2 mmol), and iodide 8
(32.5 g, 94.4 mmol) in dry CH3CN (150 mL) was heated to reflux
for 1 week. After removal of CH3CN, the residue was dissolved
with CH2Cl2 (250 mL). The organic phase was washed successively
with water (30 mL), 1 M HCl (2ꢂ20 mL), H2O (20 mL), and brine.
The mixture was dried over Na2SO4, filtered, and the solvent was
evaporated under reduced pressure. The crude product was pu-
rified by crystallization in CH2Cl2/MeOH (2:3; v/v) to yield com-
pound 12 (14.9 g, 74%) as white crystals. Mp¼199e200 ꢀC; IR
(ATR) vmax cmꢁ1: 3320, 1773, 1709; 1H NMR (CDCl3, 500 MHz)
d
3.06 (d, J¼12.9 Hz, 4H), 3.97 (d, J¼12.8 Hz, 4H), 4.02e4.07 (m,
16H), 6.47 (t, J¼7.4 Hz, 2H), 6.65 (t, J¼7.6 Hz, 2H), 6.79 (d,
J¼7.5 Hz, 4H), 6.82 (d, J¼7.6 Hz, 4H), 7.40 (m, 4H), 7.48 (m, 4H),
7.88 (s, 2H); 13C NMR (CDCl3, 125 MHz)
d 31.43, 38.53, 68.98,
4.2.9. 25,27-Bis-(1-(2-(2-phthalimidoethoxy)ethoxy))-26,28-bis-(1-
(3-(tert-butyloxycarbonyl) aminopropyloxy))calix[4]arene, 1,3-alter-
nate 3. Mp¼156e158 ꢀC; IR (ATR) vmax cmꢁ1: 3417, 2978, 2930,
70.44, 75.66, 119.3, 123.12, 125.71, 128.54, 128.62, 129.14, 132.24,
133.89, 134.24, 151.88, 153.06, 168.89. ESIþ-MS: 881 [MNa]þ. ESIþ-
HRMS [MNa]þ: calculated for [C52H46N2O10Na]þ: 881.3050.
Found: 881.3008.
2902, 2869, 1708; 1H NMR (CDCl3, 300 MHz)
d 1.52 (s, 18H), 1.64 (br
t, 4H), 2.99e3.01 (m, 4H), 3.35e3.37 (m, 4H), 3.47 (m, 4H),
3.59e3.73 (m, 16H), 3.92 (t, J¼5.7 Hz, 4H), 4.82 (br s, 2H), 6.70 (t,
J¼7.4 Hz, 2H), 6.79 (t, J¼7.4 Hz, 2H), 6.97 (d, J¼7.5 Hz, 4H), 7.01 (d,
J¼7.5 Hz, 4H), 7.68e7.71 (m, 4H), 7.82e7.85 (m, 4H); 13C NMR
4.2.5. 25,27-Bis-(1-(2-(2-phthalimidoethoxy)ethoxy))-26,28-bis-(1-
(3-cyanopropoxy))-calix[4]arene. A slurry of calixarene 12 (5 g,
5.83 mmol) and dry Cs2CO3 (19 g, 58.3 mmol) in 80 mL of dry DMF
was heated at 50 ꢀC under argon atmosphere for 1 h 30 min. After
(CDCl3, 75 MHz)
d 28.56, 30.58, 36.93, 37.54, 37.86, 67.84, 69.21,
69.57, 79.03, 122.11, 122.30, 123.22, 129.47, 129.85, 132.17, 133.38,
133.89, 134.04, 156.07, 156.16, 156.45, 168.23. ESIþ-MS: 1195
[MNa]þ. ESIþ-HRMS [MNa]þ: calculated for C68H76N4O14Na:
1195.5256. Found: 1195.5255.
this, a solution of g-bromobutyronitrile (5.8 mL, 58.3 mmol) was
introduced and the reaction mixture was stirred at 50 ꢀC under
argon atmosphere for 5 days. After cooling to rt, water was added
(200 mL). Aqueous phase was extracted with AcOEt (2ꢂ100 mL).
The combined organic layers were washed successively with 0.2 N
HCl (2ꢂ10 mL), water (10 mL), and brine (25 mL). The organic layer
was dried over Na2SO4 and evaporated. The crude product was
purified by chromatography (CH2Cl2/AcOEt 9:1) to yield the 1,3-
4.2.10. 25,27-Bis-(1-(2-(2-phthalimidoethoxy)ethoxy))-26-(1-(3-
(tert-butyloxycarbonyl) aminopropyloxy))-28-hydroxycalix[4]arene,
partial cone 5. 1H NMR (CDCl3, 300 MHz)
d
1.40 (s, 9H),1.49 (m, 2H),
2.65 (m, 2H), 2.88 (m, 2H), 3.09 (d, J¼13.2 Hz, 2H), 3.72e4.01 (m,

P. Rouge et al. / Tetrahedron 67 (2011) 2916e2924
2923
22H), 6.54 (t, J¼7.4 Hz, 1H), 6.72 (t, J¼7.5 Hz, 2H), 6.84 (d, J¼7.6 Hz,
2H), 6.86 (dd, J¼7.5, 1.5 Hz, 2H), 6.93 (dd, J¼7.5, 1.5 Hz, 2H), 7.01
(t, J¼7.5 Hz, 1H), 7.28e7.31 (d, J¼7.5 Hz, 2H), 7.61e7.67 (m, 4H),
cone 18. Chromatography over silica gel (CH2Cl2/MeOH/NH4OH
37% 90:10:2). Yield 66%; white gum; IR (ATR) vmax cmꢁ1: 3329,
2980, 2929, 2892, 2871, 1698; 1H NMR (CDCl3, 300 MHz)
d 1.36 (s,
7.70e7.76 (m, 4H); 13C NMR (CDCl3, 75 MHz)
d
27.84, 28.52, 30.59,
9H), 1.65 (br t, 2H), 2.95 (m, 2H), 3.26 (d, J¼13.2 Hz, 2H), 3.32 (br t,
2H), 3.61e3.93 (m, 17H), 4.16e4.26 (m, 5H), 6.67 (t, J¼7.4 Hz, 1H),
6.76 (t, J¼7.4 Hz, 2H), 6.85e6.86 (d, J¼7.0 Hz, 2H), 7.00 (dd, J¼7.2,
1.3 Hz, 2H), 7.05 (d, J¼7.4 Hz, 2H), 7.10 (t, J¼7.4 Hz, 1H), 7.37 (d,
37.56, 37.70, 37.91, 68.28, 69.45, 70.17, 72.71, 78.51, 118.67, 122.32,
123.04, 123.23, 123.83, 128.06, 128.24, 129.02, 129.28, 130.85,
132.03, 133.72, 133.94, 134.00, 152.51, 154.30, 155.72, 156.47, 168.28.
ESIþ-MS: 1039 [MNa]þ. ESIþ-HRMS [MNa]þ: calculated for
C60H61N3O12Na: 1038.4153. Found: 1038.4170.
J¼7.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz)
d 28.49, 30.30, 30.62, 37.68,
38.31, 69.15, 70.54, 72.57, 78.66, 119.49, 122.97, 124.23, 128.03,
128.59, 129.38, 129.66, 131.20, 133.47, 133.69, 133.81, 152.12, 153.68,
155.78, 156.53. ESIþ-MS: 756 [MH]þ. ESIþ-HRMS [MH]þ: calculated
for C44H58N3O8: 756.4224. Found: 756.4214.
4.3. General procedure for deprotection of the phthalimido
group of calix[4]arenes 13e14 and 17e18
A 35% aqueous solution of hydrazine (10 mmol) was added to
slurry of phthalimidocalixarene (1 mmol) in absolute EtOH
(50 mL). The reaction mixture was heated to reflux for 7 h. Solvents
were removed under reduced pressure. The residue was manipu-
lated in ethyl acetate (50 mL). The resulting precipitate was filtered
and washed with small volumes of AcOEt. The combined organic
phases were washed successively with a 2 M NaOH aqueous, water,
and brine. The organic phase was dried over Na2SO4 and concen-
trated by rotary evaporation.
4.4. General coupling procedure for the peptidic coupling
with ICL670: synthesis of calix[4]arenes 6 and 7
A solution of carboxylic acid (1.1 equiv/equiv NH2 group), HOBt
(1.1 equiv/equiv NH2 group), and EDCI (1.1 equiv/equiv NH2 group)
in CH2Cl2 (10 mL) was stirred at rt for 15 min. Aminocalixarene
(1 mmol) was added and the reaction medium was stirred at rt
overnight. The reaction mixture was diluted with CH2Cl2 (100 mL)
and this organic phase was washed successively with 1 M HCl
aqueous, saturated NaHCO3 aqueous, water, and brine. The organic
phase was dried over Na2SO4 then evaporated by rotary evapora-
tion. The crude product was purified by chromatography.
4.3.1. 25,27-Bis-(1-(2-(2-aminoethoxy)ethoxy))-26,28-bis-(1-(3-cy-
anopropoxy))calix[4]arene, 1,3-alternate 13. Manipulation in Et2O.
Yield 87%; white gum; IR (ATR) vmax cmꢁ1: 3369, 2920, 2875, 2326,
2246; 1H NMR (CDCl3, 500 MHz)
d
1.71 (br q, J¼6.6 Hz, 4H), 1.97 (t,
4.4.1. 25,27-Bis-(1-(2-(2-[4-(3,5-bis-(2-hydroxyphenyl)-1,2,4-tri-
azol-1-yl)phenyl]carbamoyl ethoxy)ethoxy))-26,28-bis-(1-(3-cyano-
propoxy))calix[4]arene, 1,3-alternate 15. Chromatography (CH2Cl2/
MeOH 98:2). Yield 81%; beige solid; mp¼162e168 ꢀC; IR (ATR) vmax
cmꢁ1: 3259, 2920, 2873, 1647, 1621, 1610, 1586; 1H NMR (CDCl3,
J¼7.2 Hz, 4H), 2.86 (br s, 4H), 3.08 (br t, J¼6.0 Hz, 4H), 3.40 (br t,
4H), 3.61 (br t, J¼6.1 Hz, 4H), 3.65 (br t, J¼6.1 Hz, 4H), 3.78 (d,
J¼16.0 Hz, 4H), 3.86 (d, J¼16.0 Hz, 4H), 6.85 (t, J¼7.5 Hz, 2H), 6.89 (t,
J¼7.3 Hz, 2H), 7.06 (d, J¼7.4 Hz, 4H), 7.10 (d, J¼7.4 Hz, 2H); 13C NMR
(CDCl3, 125 MHz)
d
13.88, 26.29, 38.17, 42.29, 68.00, 68.90, 69.35,
500 MHz)
d
1.66 (br q, 4H), 1.97 (t, J¼7.3 Hz, 4H), 3.23 (t, J¼5.3 Hz,
73.72, 120.25, 122.82, 123.16, 129.70, 130.03, 133.94, 134.45, 156.61,
156.80. ESIþ-MS: 733 [MH]þ. ESIþ-HRMS [MH]þ: calculated for
C44H53N4O6: 733.3965. Found: 733.3938.
4H), 3.35e3.45 (m, 6H), 3.50e3.70 (m, 10H), 3.77 (d, J¼16.3 Hz, 4H),
3.85 (d, J¼16.4 Hz, 4H), 6.62 (t, J¼7.3 Hz, 2H), 6.79 (t, J¼7.5 Hz, 2H),
6.87 (m, 18H), 7.23e7.37 (m, 6H), 7.52 (d, J¼8.4 Hz, 4H), 7.97 (d,
J¼8.4 Hz, 4H), 8.06 (d, J¼8.0 Hz, 2H), 9.66 (s, 2H); 13C NMR (CDCl3,
4.3.2. 25,27-Bis-(1-(2-(2-aminoethoxy)ethoxy))-26,28-bis-(1-(3-cy-
anopropoxy))calix[4]arene, partial cone 14. Yield 98%; white gum;
IR (ATR) vmax cmꢁ1: 3371, 2919, 2868, 2244, 2159; 1H NMR (CDCl3,
125 MHz) d 13.45, 25.68, 37.95, 40.30, 67.58, 69.37, 69.48, 69.61,
110.33, 113.20, 117.13, 118.31, 119.11, 119.81, 119.94, 122.66, 122.82,
125.98, 127.61, 127.84, 128.82, 129.58, 129.72, 131.84, 133.01, 133.78,
134.02, 135.72, 140.53, 152.08, 156.34, 156.47, 157.84, 159.64, 166.41.
ESIþ-MS: 1466 [MNa]þ. ESIþ-HRMS [MNa]þ: calculated for
C86H78N10O12Na: 1465.5698. Found: 1465.5739.
500 MHz)
d
1.79 (br q, J¼7.2 Hz, 2H), 2.12 (br q, J¼6.9 Hz, 2H), 2.32
(m, 4H), 2.93 (br s, 4H), 3.11 (d, J¼13.2 Hz, 2H), 3.56e3.64 (m, 10H),
3.75 (br s, 4H), 3.81e3.87 (m, 4H), 3.98e4.02 (m, 2H), 4.12 (d,
J¼13.2 Hz, 2H), 6.47 (d, J¼7.4 Hz, 2H), 6.55 (t, J¼7.5 Hz, 2H), 6.88 (d,
J¼7.1 Hz, 2H), 6.96 (t, J¼7.4 Hz, 1H), 7.06 (t, J¼7.4 Hz, 1H), 7.13 (d,
J¼7.5 Hz, 2H), 7.36 (d, J¼7.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz)
4.4.2. 25,27-Bis-(1-(2-(2-[4-(3,5-bis-(2-hydroxyphenyl)-1,2,4-tri-
azol-1-yl)phenyl]carbamoyl ethoxy)ethoxy))-26,28-bis-(1-(3-cyano-
propoxy))calix[4]arene, partial cone 16. Chromatography (CH2Cl2/
MeOH 98:2). Yield 45%; beige solid; mp¼148e149 ꢀC; IR (ATR)
vmax cmꢁ1: 3295, 3052, 2923, 2864, 1740, 1649, 1621, 1611, 1587;
d
14.10, 14.55, 25.66, 27.22, 30.56, 36.80, 42.32, 69.79, 70.62, 72.36,
73.60, 73.71, 119.97, 121.39, 122.41, 123.16, 123.71, 129.34, 129.58,
131.38, 132.99, 134.00, 134.42, 136.73, 155.42, 156.72, 157.41. ESIþ-
MS: 733 [MH]þ. ESIþ-HRMS [MH]þ: calculated for C44H53N4O6:
733.3965. Found: 733.3985.
1H NMR (CDCl3, 500 MHz)
d 1.85e1.90 (m, 2H), 2.05e2.15 (m, 2H),
2.30e2.40 (m, 4H), 3.09 (d, J¼13.2 Hz, 2H), 3.44 (br t, 2H),
3.60e3.67 (m, 4H), 3.75e3.95 (m, 16H), 4.02e4.15 (m, 4H), 6.45 (d,
J¼7.4 Hz, 2H), 6.55 (t, J¼7.4 Hz, 2H), 6.66 (t, J¼7.5 Hz, 2H),
6.90e6.98 (m, 8H), 7.04e7.09 (m, 6H), 7.15 (d, J¼8.2 Hz, 4H),
7.32e7.40 (m, 6H), 7.46 (d, J¼8.2 Hz, 4H), 7.91 (d, J¼8.2 Hz, 4H),
8.15 (d, J¼7.2 Hz, 2H), 9.65 (s, 2H), 11.29 (s, 2H); 13C NMR (CDCl3,
4.3.3. 25,27-Bis-(1-(2-(2-aminoethoxy)ethoxy))-26,28-bis-(1-(3-
(tert-butyloxycarbonyl) aminopropyloxy))calix[4]arene, 1,3-alternate
17. Chromatography (CH2Cl2/MeOH/NH4OH 37% 80:20:3). Yield
60%; white gum; IR (ATR) vmax cmꢁ1: 3359, 2922, 2866, 1697; 1H
NMR (CDCl3, 600 MHz)
d
1.51 (s, 18H), 1.65e1.72 (m, 4H), 2.87e2.95
125 MHz) d 14.14, 14.68, 25.58, 27.19, 30.48, 36.88, 40.68, 69.81,
(m, 4H), 2.98e3.08 (m, 4H), 3.38e3.48 (m, 4H), 3.49e3.60 (m, 8H),
3.68 (d, J¼14.8 Hz, 2H), 3.70e3.80 (m, 10H), 6.79 (t, J¼7.5 Hz, 2H),
6.83 (t, J¼7.5 Hz, 2H), 7.02 (d, J¼7.5 Hz, 4H), 7.10 (d, J¼7.6 Hz, 4H);
70.09, 70.81, 72.10, 73.37, 110.42, 113.64, 117.53, 118.80, 119.51,
119.79, 120.38, 121.84, 122.57, 123.00, 123.91, 126.47, 128.07, 128.91,
129.20, 129.42, 129.69, 131.22, 132.27, 132.77, 133.43, 133.97,
134.45, 136.20, 136.66, 140.73, 152.56, 155.15, 156.59, 156.89,
157.47, 158.42, 159.95, 166.57. ESIþ-MS: 1466 [MNa]þ. ESIþ-HRMS
[MNa]þ: calculated for C86H78N10O12Na: 1465.5698. Found:
1465.5717.
13C NMR (CDCl3, 150 MHz)
d 28.54, 30.55, 36.91, 37.85, 41.50, 69.42,
69.55, 70.16, 72.61, 79.08, 122.24, 122.46, 129.69, 129.99, 133.59,
133.91, 156.06, 156.17, 156.56. ESIþ-MS: 913 [MH]þ. ESIþ-HRMS
[MH]þ: calculated for C52H73N4O10: 913.5327. Found: 913.5300.
4.3.4. 25,27-Bis-(1-(2-(2-aminoethoxy)ethoxy))-26-(1-(3-(tert-bu-
tyloxycarbonyl)amino propyloxy))-28-hydroxycalix[4]arene, partial
4.4.3. 25,27-Bis-(1-(2-(2-[4-(3,5-bis-(2-hydroxyphenyl)-1,2,4-tri-
azol-1-yl)phenyl]carbamoyl ethoxy)ethoxy))-26,28-bis-(1-(3-(tert-

2924
P. Rouge et al. / Tetrahedron 67 (2011) 2916e2924
butyloxycarbonyl)aminopropyloxy))calix[4]arene, 1,3-alternate 19.
Chromatography (CH2Cl2/MeOH 95:5). Yield 14%; beige solid;
mp¼114e116 ꢀC; IR (ATR) vmax cmꢁ1: 3327, 3068, 2924, 2864,
hydroxycalix[4]arene, partial cone 7. Yield 100%; white gum; IR
(ATR) vmax cmꢁ1: 3271, 3065, 2917, 2872, 1649, 1611, 1588; 1H NMR
(CDCl3, 600 MHz)
d
1.43 (br t, 2H), 3.16e3.18 (d, J¼13.2 Hz, 2H), 3.28
1692, 1647, 1621, 1611, 1587; 1H NMR (CDCl3, 300 MHz)
d
1.50 (s,
(br t, 2H), 3.55e3.60 (m, 6H), 3.66e3.71 (m, 6H), 3.85e3.93 (m, 6H),
4.06e4.13 (m, 4H), 6.67 (t, J¼7.5 Hz,1H), 6.74e6.77 (m, 3H), 6.83 (br
d, J¼7.4 Hz, 2H), 6.96e7.09 (m, 11H), 7.12 (dd, J¼7.9, 1.5 Hz, 2H),
7.29e7.34 (m, 9H), 7.37 (dt, J¼7.7, 1.7 Hz, 2H), 7.56 (br t, 2H), 7.75 (d,
J¼8.5 Hz, 4H), 8.15 (dd, J¼7.8, 1.7 Hz, 2H); 13C NMR (CDCl3,
18H), 1.57e1.63 (m, 4H), 2.95e3.02 (m, 4H), 3.41e3.79 (m, 28H),
4.95 (br s, 2H), 6.63e6.73 (m, 4H), 6.83 (t, J¼7.3 Hz, 2H), 6.97e7.07
(m, 14H), 7.29e7.37 (m, 6H), 7.49 (br d, J¼8.1 Hz, 4H), 7.95 (br d,
J¼8.0 Hz, 4H), 8.08 (dd, J¼8.7, 2.4 Hz, 2H), 9.75 (s, 2H); 13C NMR
(CDCl3, 75 MHz)
d
28.53, 30.41, 37.21, 37.74, 40.29, 69.06, 69.65,
150 MHz) d 30.62, 31.95, 37.93, 39.08, 40.12, 69.83, 69.91, 69.94,
69.77, 70.19, 79.09, 110.68, 113.28, 117.13, 118.13, 119.20, 119.88,
122.18, 122.55, 125.68, 127.54, 128.08, 128.80, 129.77, 131.75,
132.93, 133.78, 133.84, 135.54, 140.43, 152.04, 156.13, 156.21,
156.51, 156.76, 157.61, 159.65, 166.38. ESIþ-MS: 1647 [MNa]þ. ESIþ-
HRMS [MNa]þ: calculated for C94H98N10O16Na: 1645.7060. Found:
1645.7091.
72.36, 111.63, 113.50, 117.18, 117.88, 119.23, 119.81, 120.42, 122.53,
124.28,124.92,127.46,128.55,128.58,128.63,128.67,129.45,129.58,
130.60, 131.65, 132.85, 133.33, 133.85, 134.00, 134.90, 140.51, 151.74,
152.12, 153.72, 156.68, 156.70, 157.26, 159.91, 166.64. ESIþ-MS: 1366
[MH]þ. ESIþ-HRMS [MH]þ: calculated for C81H76N9O12: 1366.5613.
Found: 1366.5615.
4.4.4. 25,27-Bis-(1-(2-(2-[4-(3,5-bis-(2-hydroxyphenyl)-1,2,4-tri-
azol-1-yl)phenyl]carbamoyl ethoxy)ethoxy))-26-(1-(3-(tert-butylox-
ycarbonyl)aminopropyloxy))-28-hydroxy calix[4]arene, partial cone
20. Chromatography (CH2Cl2/MeOH 95:5). Yield 56%; beige solid;
mp¼146e148 ꢀC; IR (ATR) vmax cmꢁ1: 3283, 3060, 2916, 2871,
Acknowledgements
ꢀ
This work was supported by Region Picardie (TsFer project). P.R.
was the recipient of a grant from the Region Picardie.
ꢀ
1702, 1648, 1621, 1612, 1587; 1H NMR (CDCl3, 300 MHz)
d 1.40 (s,
9H), 1.47e1.50 (m, 2H), 2.75e2.77 (m, 2H), 3.24e3.28 (m, 4H),
3.57e3.92 (m, 17H), 4.11e4.19 (m, 5H), 6.65 (t, J¼7.4 Hz),
6.69e6.83 (m, 4H), 6.90e7.17 (m, 14H), 7.25e7.45 (m, 11H),
7.71e7.81 (m, 6H), 8.15 (dd, J¼7.4, 1.6 Hz, 2H), 9.94 (s, 2H), 10.86
References and notes
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(s, 2H); 13C NMR (CDCl3, 75 MHz)
d 28.51, 30.19, 30.49, 37.80,
38.00, 40.14, 69.64, 69.98, 72.36, 78.76, 111.34, 113.47, 117.20,
118.02, 119.40, 119.85, 120.25, 122.35, 124.39, 125.02, 127.50,
128.42, 128.63, 128.78, 129.49, 129.72, 130.75, 131.69, 132.93,
133.35, 133.64, 134.04, 134.75, 140.56, 151.94, 152.07, 153.58,
155.81, 156.65, 156.76, 157.19, 159.86, 166.55. ESIþ-MS: 1488
[MNa]þ. ESIþ-HRMS [MNa]þ: calculated for C86H83N9O14Na:
1488.5957. Found: 1488.5928.
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groups: synthesis of calix[4]arenes 6 and 7
€
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A solution of carbamate calix[4]arene (1 mmol) in CH2Cl2/TFA
10:1 (20 mL) was stirred at rt overnight. The solvent was removed
by evaporation then the residue was dissolved in ethyl acetate or
CH2Cl2 (100 mL). This organic phase was washed successively with
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€
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azol-1-yl)phenyl]carbamoyl
ethoxy)ethoxy))-26,28-bis-(amino-
propyloxy)calix[4]arene, 1,3-alternate 6. Chromatography (CH2Cl2/
MeOH/NH4OH 37% 80:20:3 to 70:30:3). Yield 65%; beige solid;
mp¼168e170 ꢀC; IR (ATR) vmax cmꢁ1: 3261, 3063, 2923, 2864, 1645,
€
€
1611, 1587; 1H NMR (CDCl3, 600 MHz)
d 1.68e1.80 (m, 4H),
2.58e2.76 (m, 4H), 3.40e4.00 (m, 28H), 6.55e6.68 (m, 4H), 6.72 (t,
J¼7.8 Hz, 2H), 6.87e7.10 (m, 14H), 7.20e7.40 (m, 6H), 7.48 (br d,
J¼7.1 Hz, 4H), 7.87 (br d, J¼7.1 Hz, 4H), 8.03 (br d, J¼7.1 Hz, 2H); 13C
15. (a) Halouani, H.; Dumazet-Bonnamour, I.; Perrin, M.; Lamartine, R. J. Org. Chem.
NMR (CDCl3, 150 MHz)
d 29.71, 37.72, 40.18, 69.60, 69.68, 111.70,
ꢀꢁ
€
€
2004, 69, 6521; (b) Mikulasek, L.; Gruner, B.; Dordea, C.; Rudzevich, V.; Bohmer,
ꢁ
ꢀ
ꢀ
ꢀ
V.; Haddaoui, J.; Hubscher-Bruder, V.; Arnaud-Neu, F.; Caslavsky, J.; Selucky, P.
113.42, 117.16, 118.08, 118.93, 119.85, 122.90, 125.12, 125.54, 127.46,
128.60, 128.72, 130.00, 131.71, 132.84, 133.73, 134.13, 135.26, 140.50,
152.28, 156.27, 156.51, 156.60, 157.85, 159.89, 166.51. ESIþ-HRMS
[MH]þ: calculated for C84H83N10O12: 1423.6191. Found: 1422.6213.
Eur. J. Org. Chem. 2007, 13, 4772.
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ꢂ
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4.5.2. 25,27-Bis-(1-(2-(2-[4-(3,5-bis-(2-hydroxyphenyl)-1,2,4-tri-
azol-1-yl)phenyl]carbamoyl ethoxy)ethoxy))-26-aminopropyloxy-28-
18. Le Poul, N.; Baudrin, E.; Morcrette, M.; Gwizdala, S.; Masquelier, C.; Tarascon, J.-
M. Solid State Ionics 2003, 159, 149.