Narrow-rim functionalization of calix[4]arene through Ugi-4CR: Synthesis of a series of calix[4]arene peptoids

Article abstract of DOI:10.1021/jo4025732

Adaptation of Ugi-4CR for the narrow-rim modification of calix[4]arene toward the synthesis of a series of tripeptoid and tetrapeptoid calix[4]arenes is described. The metal ion/organic cation binding properties of the newly synthesized peptoid calix[4]arenes were also investigated.

Full text of DOI:10.1021/jo4025732

Article
pubs.acs.org/joc
Narrow-Rim Functionalization of Calix[4]arene through Ugi-4CR:
Synthesis of a Series of Calix[4]arene Peptoids
Anupriya Savithri,† Sreeja Thulasi,† and Ramavarma Luxmi Varma*,†,‡
‡
†Chemical Sciences and Technology Division and Academy of Scientific and Innovative Research (AcSIR), National Institute for
Interdisciplinary Science and Technology (NIIST)-CSIR, Trivandrum 695019, India
S
* Supporting Information
ABSTRACT: Adaptation of Ugi-4CR for the narrow-rim modification of calix[4]arene toward the synthesis of a series of
tripeptoid and tetrapeptoid calix[4]arenes is described. The metal ion/organic cation binding properties of the newly synthesized
peptoid calix[4]arenes were also investigated.
conformation by retaining two hydrogen bonds at the lower rim.
A number of 1,3-diconjugates of calix[4]arene are known in the
literature for their ion and molecular recognition.6
INTRODUCTION
■
Calixarenes, which are probably the most readily available
synthetic molecular baskets, enjoy a considerable reputation
for being applied in diverse areas.1 The incredible development
of calix[4]arenes as molecular receptors is related to the many
possible structural and functional modifications of their core
molecular architecture,2 which constitutes a hollow cavity
flanked by a hydrophobic upper rim and a hydrophilic lower
rim. The introduction of suitable donor groups at the lower rim
and upper rim of calixarenes produces powerful and selective
ionophores, particularly for spherical metal ions.
Among the various calix[4]arene derivatives, those adorned
with multivalent groups such as peptides or peptide-like motifs
are attractive in host−guest chemistry, since they provide a
variety of functional groupshydrophobic, polar, and charged
groupsthat can interact with other molecules through
hydrogen-bonding, electrostatic, and van der Waals interactions.
In addition, amino acid units introduce chirality and afford the
potential for stereoselective recognition.3,4 The most widely
investigated peptidocalixarenes are those bearing amino acids
at the lower rim,5 particularly due to their ability to bind small
molecules and metals. The synthesis of such calixarenes involves
selective protection of the lower rim followed by multiple steps
using established techniques for the formation of peptide bonds.
Among narrow-rim functionalizations of calix[4]arenes,
1,3-disubstitution at the lower rim has become more attractive
due to the presence of two phenolic OH groups (which provide
extra coordination sites) and its ability to maintain a cone
As part of our general interest in calixarene chemistry, we have
been involved in working out the potential for functionalizing
calix[4]arene with multivalent groups using a multicomponent
strategy. We have successfully demonstrated the synthetic utility
of the multicomponent methodology toward the synthesis of a
series of upper-rim-substituted peptoid derivatives of calix[4]-
arene through the Ugi-4-component reaction (Ugi-4CR) of
diisocyano and diamino calix[4]arenes.7 The Ugi-4CR8a occupies
a leading position among isocyanide-based multicomponent
reactions (IMCR),8b since it represents a valuable method to
access a peptide-like moiety, such as α-acylaminocarboxamide, in
a straightforward manner by coupling isocyanides with carbonyl
compounds, primary amines, and carboxylic acids. The conjuga-
tion of multivalent groups at the lower rim of calixarenes involves
many steps. Since the lower-rim-functionalized calix[4]arene
can provide preorganized binding cores suitable for various ions
and molecular species, we were interested in implementing a
multicomponent strategy at the lower rim of calix[4]arenes, as it
enables the rapid functionalization with promising complexity
and diversity by a simple one-pot reaction with great efficiency.
Here, we demonstrate a versatile synthesis of the lower-
rim-substituted calix[4]arene peptoids based on the Ugi-4CR
Received: November 21, 2013
Published: February 5, 2014
© 2014 American Chemical Society
1683
dx.doi.org/10.1021/jo4025732 | J. Org. Chem. 2014, 79, 1683−1689

The Journal of Organic Chemistry
Article
of calix[4]arene diametrically substituted with benzaldehyde
groups.
13C NMR, and HRMS spectroscopic data are in agreement with
the proposed structures.
To understand the conformational preferences and rigidity of
these new compounds, as a representative example, compound
5baa was subjected to a variable-temperature H NMR study,
RESULTS AND DISCUSSION
■
1
We commenced our investigation on the feasibility of the Ugi
reaction at the narrow rim with a 1,3-disubstituted aldehyde
functionalized calix[4]arene in the hope that this method
would enrich the chemical repertoire of calix[4]arene, because
the method provides easy access to tripeptoids.8c The required
starting material 1 was synthesized in good yields using
previously reported synthetic procedures.9,10
The dialdehyde 1 was then reacted with benzoic acid (2a),
toluidine (3a) and cyclohexyl isocyanide (4a) by simply
combining the four components in 2,2,2-trifluoroethanol (TFE).
Stirring the mixture at room temperature after 48 h gave the highly
functionalized α-acylaminocarboxamide derivative 5aaa in 52%
yield. When we replaced TFE with a more benign and common
solvent such as methanol at room temperature, the product was
obtained in 58% yield. However, the same reaction at 50 °C
furnished the product 5aaa in 83% yield (Scheme 1).
In order to study the scope of the method, we applied the
same procedure to different acids and amines. In all cases, the
expected products were obtained in good yields (Table 1). When
the reaction was repeated with naphthyl isocyanide as one of
the components under optimal conditions, it failed to give the
desired product. However, a moderate yield of the corresponding
product was obtained when the reaction was conducted in TFE
at room temperature, affording the tripeptoid 5aab (Table 1,
entry 10) in 52% yield.
To increase the scope and utility of this route, we then
incorporated some biologically relevant amino acids such as
N-BOC-gly, N-BOC-L-ala, and N-BOC-L-trp (Table 1, entries
7−9), which would further introduce one more peptoid bond
equivalent at the narrow rim. The synthesis of tetrapeptoid deriva-
tives of calix[4]arene is otherwise very difficult and involves
multiple steps. We also incorporated the biologically important
pyramidine unit as well (Table 1, entry 6). The reaction was
shown to be tolerant to a wide range of substituents on the
different components. That several useful functionalities such as
halo-group-containing substrates capable of undergoing further
manipulation were readily incorporated into the final products
was particularly pleasing. The products have been characterized
and it presented a few significant changes (Figure 1). As the
temperature was lowered from 298 to 223 K, the OH protons,
which were discernible as a multiplet, underwent a profound
downfield shift of about 0.88 ppm and appeared as a broad
singlet. This suggested that a dramatic increase in the intra-
molecular hydrogen bonding occurred. Considerable changes in
the chemical shift values of aromatic protons were also observed.
Moreover, a marginal upfield shift of NH and downfield shift of
CH (at the spiro center) protons occurred with shift values of
0.22 and 0.30 ppm, respectively, which suggested that some sort
of rearrangement in the spatial orientation of compound 5baa
is occurring at lower temperatures (Figure 1).
To get some insights into the intramolecular hydrogen
1
bonding occurring in compound 5baa, the H NMR spectrum
in a polar solvent (acetone-d6) was also obtained (Figure 2). The
proton which appeared at around δ 7.10 ppm was assigned to
the −NH proton on the basis of its correlation with the −CH
proton of the cyclohexyl group in the COSY spectrum (Figure S5,
Supporting Information). Downfield shifts of OH protons
(∼0.81 ppm) and NH protons (∼1.4 ppm) were noticed,
indicating that both the OH and NH groups participate in
significant hydrogen-bonding interactions in nonpolar solvent.
1
Furthermore, the H NMR spectrum of 5baa was recorded in
DMSO-d6 as well, a solvent which is even more competitive for
hydrogen bonds. A more significant downfield shift was found
to occur in this case for −NH protons (∼2.2 ppm) (Figure S6,
Supporting Information). To further prove the occurrence of
intramolecular hydrogen-bonding interactions in 5baa, we also
1
carried out a H NMR titration experiment by adding small
aliquots of acetone (10−50 μL) to a solution of 5baa in CDCl3
(Figure 3). When acetone was added gradually and the spectrum
recorded in each case, it was observed that the chemical shift
values of the −OH and −NH protons underwent gradual
downfield shifts. This indicates the possible rupture of intra-
molecular hydrogen bonds involving NH (probably with the
carbonyl groups in the peptoid framework) and OH protons
and formation of new hydrogen bonds with the acceptor acetone.
We could rule out intermolecular hydrogen bonding of 5baa in
1
by the usual spectroscopic techniques, and their IR, H NMR,
Scheme 1. Ugi Reaction of Compound 1
1684
dx.doi.org/10.1021/jo4025732 | J. Org. Chem. 2014, 79, 1683−1689

The Journal of Organic Chemistry
Article
Table 1. Ugi-4CR of Compound 1
a
The reaction was carried out in TFE at room temperature.
CDCl3, since its 1H NMR spectra recorded at different concentra-
tions did not show any significant changes.
We further investigated the ionic binding ability of these new
tripeptoids. Compounds 5caa, 5daa, and 5gaa were examined.
However, preliminary binding studies toward anions (fluoride,
chloride, bromide, iodide, benzoate, acetate, perchlorate, and
bisulfate) and organic cations (benzylammonium ion) using
1
UV−vis and H NMR spectroscopy indicated no significant
1685
dx.doi.org/10.1021/jo4025732 | J. Org. Chem. 2014, 79, 1683−1689

The Journal of Organic Chemistry
Article
Figure 1. Variable-temperature 500 MHz 1H NMR spectra of 5baa in CDCl3. Full spectra are available in the Supporting Information (Figure S3).
Figure 2. Comparison of 1H NMR spectra of compound 5baa in CDCl3 and acetone-d6.
activity. In a cation binding study with cations as metal
perchlorates (Cr3+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Hg2+,
Ag+, Pb2+, Cd2+, Na+, K+, Ca2+, Al3+) compound 5gaa showed
selective binding affinity toward Cu2+. The core 5gaa showed no
fluorescence, and this may be because the peptide bond quenches
tryptophan fluorescence by excited-state electron transfer
(peptide is an efficient intramolecular quencher).11,12 Moreover,
Cu2+ is a known quencher due to its paramagnetic nature.13
Hence, the binding studies were carried out by UV−vis
spectrophotometric techniques.
Figure 4 shows the result of the absorption titration of 5gaa
with Cu2+ in CH3CN. Without cations, 5gaa showed an intense
absorption band centered at 282 nm (ε = 33052 M−1 cm−1).
Upon gradual addition of Cu2+, the 282 nm band decreased and
a new band appeared at 472 nm which reached a maximum
intensity (ε = 17263 M−1 cm−1) on addition of 30 equiv of Cu2+.
1686
dx.doi.org/10.1021/jo4025732 | J. Org. Chem. 2014, 79, 1683−1689

The Journal of Organic Chemistry
Article
Figure 3. 1H NMR spectra of 5baa in CDCl3 upon gradual addition of acetone (10−50 μL). Full spectra are available in the Supporting Information
(Figure S4).
Figure 4. (a) Change in absorption spectra of 5gaa (50 μM) in CH3CN upon addition of 0−30 equiv of Cu2+. The inset shows the color change of the
solution upon Cu2+ addition: (i) 5gaa alone; (ii) 5gaa + Cu2+. (b) UV−vis spectra of 5gaa (50 μM) in CH3CN in the presence of Cu2+ ion and
miscellaneous cations including Cr3+, Mn2+, Fe2+, Co2+, Ni2+, Hg2+, Zn2+, Ag+, Pb2+, Cd2+, Na+, K+, Ca2+, and Al3+ (40 equiv) in CH3CN.
As shown in the inset picture (Figure 4a), the solution color
changed gradually from colorless to orange upon incremental
addition of Cu2+.
miscellaneous competitive cations, compound 5gaa still showed
a UV band shift as well as a color change from colorless to orange,
indicating that the wavelength shift of absorbance resulting from
the addition of the Cu2+ ion is not influenced by any subsequent
addition of miscellaneous cations. All of these experiments
imply that the selectivity of 5gaa for the Cu2+ ion over other
competitive cations is remarkably high.
The distinctive color change of a ligand on complexation with
certain metal ions has an important role in a possible sensing
system. Therefore, it is worth mentioning that the colorimetric
detection of Cu2+ by 5gaa is unaffected even in the presence of
40 equiv of many other cations. Thus, the ligand 5gaa enables
selective detection of Cu2+.
A detailed investigation of the titration results revealed that an
isosbestic point existed at 296 nm in the range of 0−4 equiv of
Cu2+ (Figure S1, Supporting Information). On further addition
of Cu2+ (4−30 equiv) (Figure S2, Supporting Information),
a new peak began to appear at 274 nm. The complex band at
474 nm continuously increased, and the orange color became
more intense. Addition of Cu2+ beyond this concentration did
not lead to any further spectral changes. These changes suggest
some sequential binding of Cu2+ with the ligand 5gaa.14 ESI-MS
analysis of a CH3CN solution containing ligand and Cu2+ did
not show any clear mass assigned to the complex, and a clear
stoichiometry also could not be assigned, as a Job plot was not
obtained. These may be due to the low stability of the complex
formed.14
UV−vis spectral changes (Figure 4b) of 5gaa in competitive
metal ion complexation were also observed in the presence of
Cr3+, Mn2+, Fe2+, Co2+, Ni2+, Hg2+, Zn2+, Ag+, Pb2+, Cd2+, Na+,
K+, Ca2+, and Al3+ in CH3CN (perchlorate counteranion). It may
be mentioned that these cations as such did not lead to any
significant changes in the visible region. In the presence of these
CONCLUSION
■
In conclusion, we have successfully introduced an operationally
simple multicomponent synthetic route at the lower rim of
calix[4]arene toward a new series of peptoid derivatives of
calix[4]arene which accommodate rich multivalent groups that
could find potential applications in supramolecular chemistry. We
incorporated biologically relevant amino acids such as N-BOC-
gly, N-BOC-L-ala, and N-BOC-L-trp and the pyramidine unit as
well. Several useful functionalities such as halo-group-containing
1687
dx.doi.org/10.1021/jo4025732 | J. Org. Chem. 2014, 79, 1683−1689

The Journal of Organic Chemistry
Article
4H), 6.90 (m, ArH, 2H), 6.85 (m, ArH, 8H), 6.61 (t, J = 8.0 Hz, ArH,
2H), 6.12 (m, CH, 2H), 5.78 (m, NH, 2H), 4.34 (m, OCH2, 4H), 4.23
(d, J = 13.0 Hz, ArCH2Ar, 4H), 4.10 (m, OCH2, 4H), 3.84 (m, CH, 2H),
3.33 (d. J = 13.0 Hz, ArCH2Ar, 4H), 2.32 (m, CH2, 4H), 1.93 (m, CH2,
4H), 1.61 (m, CH2, 4H), 1.34 (m, CH2, 4H), 1.24 (m, t-Bu, CH2, 20H),
1.08 (m, CH2, 6H), 1.00 (m, t-Bu, 18H); 13C NMR (125 MHz, CDCl3)
δ 171.0 (CO), 168.6 (CO), 159.0, 150.6, 149.4, 147.2, 142.1,
141.7, 139.2, 135.9, 135.8, 132.7, 131.7, 131.6, 130.2, 129.5, 128.5, 128.4,
127.7, 126.5, 125.6, 125.1, 114.6, 92.7, 72.7, 64.6, 48.9, 48.8, 34.0, 33.8,
32.8, 31.7, 31.0, 29.9, 25.5, 24.9, 24.8, 21.0; HRMS (ESI-MS) calcd for
C104H118I2N4O10 [M + H]+ 1837.7015, found 1837.6958.
Compound 5baa: 0.035 g, 77% yield; Rf = 0.56 (35/65 EtOAc/
hexane); white solid; mp 133−135 °C; IR (KBr) νmax 3338, 2929, 2857,
1682, 1640, 1511, 1483, 1246 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.71
(m, OH, 2H), 7.11 (m, ArH, 6H), 7.06 (s, ArH, 4H), 7.02 (m, ArH, 2H),
6.87 (m, ArH, 6H), 6.79 (m, ArH, 8H), 6.71 (m, ArH, 4H), 6.16 (m,
CH, 2H), 5.70 (m, NH, 2H), 4.32 (m, OCH2, 4H), 4.21 (m, ArCH2Ar,
4H), 4.10 (m, OCH2, 4H), 3.84 (m, CH, 2H), 3.33 (m, ArCH2Ar, 4H),
2.34 (s, CH3, 6H), 2.29 (m, CH2, 4H), 2.10 (s, CH3, 6H), 1.92 (m, CH2,
4H), 1.61 (m, CH2, 4H), 1.34 (m, t-Bu, CH2, 24H), 1.10 (m, CH2, 6H),
1.00 (s, t-Bu, 18H); 13C NMR (125 MHz, CDCl3) δ 170.9 (CO),
168.6 (CO), 158.9, 150.6, 149.4, 147.3, 141.7, 137.3, 137.1, 135.8,
132.8, 132.7, 132.6, 131.7, 129.8, 128.9, 128.7, 127.9, 127.7, 126.7, 125.7,
125.2, 122.1, 114.5, 72.7, 64.9, 64.6, 48.8, 34.0. 33.8, 32.9, 32.8, 31.7,
31.0, 29.9, 25.5, 24.9, 24.8, 20.9, 19.4; HRMS (ESI-MS) calcd for
C108H126Br2N4O10 [M + H]+ 1797.7919, found 1797.7896.
Compound 5aca: 0.034 g, 80% yield; Rf = 0.23 (35/65 EtOAc/
hexane); white solid; mp 179−181 °C; IR (KBr) νmax 3329, 2955, 2928,
2856, 1678, 1632, 1510, 1484 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.75
(m, OH, 2H), 7.29 (m, ArH, 6H), 7.17 (m, ArH, 10H), 7.05 (s, ArH,
4H), 6.86 (m, ArH, 6H), 6.80 (m, ArH, 4H), 6.47 (m, ArH, 4H), 6.16 (s,
CH, 2H), 5.86 (m, NH, 2H), 4.34 (m, OCH2, 4H), 4.25 (m, ArCH2Ar,
4H), 4.11 (m, OCH2, 4H), 3.84 (m, CH, 2H), 3.61 (s, OCH3, 6H), 3.35
(m, ArCH2Ar, 4H), 2.30 (m, CH2, 4H), 1.94 (m, CH2, 4H), 1.62 (m,
CH2, 4H), 1.33 (m, CH2, 4H), 1.27 (s, t-Bu, 18H), 1.09 (m, CH2, 6H),
1.01 (s, t-Bu, 18H); 13C NMR (125 MHz, CDCl3) δ 171.4 (CO),
168.9 (CO), 158.8, 158.1, 150.6, 149.4, 147.2, 141.7, 136.4, 132.7,
131.7, 129.7, 129.1, 128.4, 127.7, 127.6, 126.9, 125.6, 125.1, 114.6, 114.4,
113.3, 72.8, 64.6, 60.4, 55.1, 48.7, 34.0, 33.8, 32.8, 31.7, 31.0, 29.9, 25.5,
24.9, 24.8; HRMS (ESI-MS) calcd for C106H124N4O12, [M + H]+
1645.9294, found 1645.9249.
Compound 5caa: 0.035 g, 74% yield; Rf = 0.46 (35/65 EtOAc/
hexane); light yellow solid; mp 73−75 °C; IR (KBr) νmax 3326,
2955, 2924, 2854, 1655, 1607, 1534, 1512, 1483, 1249 cm−1; 1H NMR
(500 MHz, CDCl3) δ 8.05 (m, ArH, 2H), 7.75 (m, OH, 2H), 7.55 (d, J =
8.0 Hz, ArH, 2H), 7.32 (d, J = 8.0 Hz, ArH, 2H), 7.14 (m, ArH, 6H), 7.05
(s, ArH, 4H), 6.87 (m, ArH, 6H), 6.80 (m, ArH, 4H), 6.71 (m, ArH,
4H), 6.19 (m, CH, 2H), 5.86 (m, NH, 2H), 4.33 (m, OCH2, 4H), 4.23
(m, ArCH2Ar, 4H), 4.10 (m, OCH2, 4H), 3.86 (m, CH, 2H), 3.33 (d, J =
13.0 Hz, ArCH2Ar, 4H), 2.30 (m, CH2, 4H), 2.08 (s, CH3, 6H), 1.95 (m,
CH2, 4H), 1.65 (m, CH2, 4H), 1.30 (m, CH2, t-Bu, 24H), 1.09 (m, CH2,
6H), 1.00 (m, t-Bu, 18H); 13C NMR (125 MHz, CDCl3) δ 168.3 (C
O), 166.9 (CO), 159.0, 150.6, 149.4, 147.2, 145.4, 138.1, 136.5, 132.7,
132.3, 131.9, 130.9, 129.7, 129.5, 129.4, 129.0, 128.2, 127.7, 127.1, 125.6,
125.2, 122.4, 115.3, 114.5, 72.8, 65.0, 64.6, 60.4, 34.0, 33.8, 32.8, 31.7,
31.0, 29.9, 25.5, 24.9, 21.0, 20.1; HRMS (ESI-MS) calcd for
C106H120Br2N6O14 [M + H]+ 1859.7307, found 1859.7253.
substrates capable of undergoing further manipulation also were
readily incorporated into the final products. We observed that,
among the new calix[4]arene derivatives synthesized, compound
5gaa showed a selective change in UV absorption and color
toward the Cu2+cation in CH3CN. Competition experiments and
the visual changes in 5gaa give a solid foundation for the design of
an optimal host molecule for Cu(II) ion which can be applied to
industrial and environmental fields.
EXPERIMENTAL SECTION
■
All the chemicals were of the best grade commercially available and were
used without further purification. All of the solvents were purified
according to standard procedures; dry solvents were obtained according
to the literature methods and stored over molecular sieves. Analytical
thin-layer chromatography was performed on glass plates coated with
silica gel containing calcium sulfate binder. Gravity column chromatog-
raphy was performed using neutral alumina, and hexane−ethyl acetate
mixtures were used for elution. The perchlorate salts of Cr(II), Mn(II),
Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Hg(II), Ag(I), Pb(II), Cd(II),
Na(I), K(I), and Ca(II) used in this study were purchased from Aldrich.
Melting points were determined on a melting point apparatus and are
uncorrected. Proton nuclear magnetic resonance (1H NMR) and
1H−1H correlation spectra (COSY) were recorded on a 500 MHz
NMR spectrophotometer (CDCl3 as solvent unless otherwise stated).
Chemical shifts for 1H NMR spectra are reported as δ units of parts per
million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal
of chloroform-d (δ 7.25, singlet). Multiplicities are given as follows: s
(singlet); d (doublet); dd (doublet of doublets); t (triplet); bs (broad
singlet). Coupling constants are reported as J values in Hz.
Carbon nuclear magnetic resonance spectra (13C NMR) are reported
as δ in units of parts per million (ppm) downfield from SiMe4 (δ 0.0)
and relative to the signal of chloroform-d (δ 77.03, triplet).
Mass spectra were recorded under ESI/HRMS at 60000 resolution
using a mass spectrometer (analyzer type: orbitrap). IR spectra were
recorded on FT-IR spectrometer.
General Procedure for the Synthesis of α-Acyloxycarbox-
amidocalixarene (5) by the U-4CR (except 5aab). Compound 1
(0.0257 mmol), amine 2 (0.1027 mmol), carboxylic acid 3 (0.1284
mmol), and isocyanide 4 (0.1027 mmol) were taken up in 1 mL of
methanol, and the reaction mixture was heated at 50 °C for 48 h. The
solvent was removed in vacuo. The product was purified by column
chromatography on neutral alumina (hexane/EtOAc).
Procedure for the Synthesis of Derivative 5aab. Compound 1
(0.0257 mmol) and amine 2a (0.1027 mmol) were stirred in 1 mL of
TFE for 2 h. Then, carboxylic acid 3a (0.1284 mmol) and naphthyl
isocyanide 4b (0.1027 mmol) were added and the reaction mixture was
stirred for 48 h at room temperature. The solvent was removed in vacuo.
The product was purified by column chromatography on neutral
alumina (hexane/EtOAc).
Compound 5aaa: 0.034 g, 83% yield; Rf = 0.36 (35/75 EtOAc/
hexane); white solid; mp 103−105 °C; IR (KBr) νmax 3327, 2955, 2928,
2857, 1679, 1636, 1511, 1484, 1246 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.75 (m, OH, 2H), 7.29 (d, J = 8.0 Hz, ArH, 4H), 7.17 (m, ArH, 6H),
7.11 (m, ArH, 4H), 7.05 (s, ArH, 4H), 6.87 (m, ArH, 4H), 6.80 (m, ArH,
8H), 6.75 (m, ArH, 4H), 6.10 (s, CH, 2H), 5.88 (m, NH, 2H), 4.29 (m,
OCH2, ArCH2Ar, 4H), 4.11 (m, OCH2, 4H), 3.85 (m, CH, 2H), 3.32
(d, J = 12.5 Hz, ArCH2Ar, 4H), 2.30 (m, CH2, 4H), 2.12 (s, CH3, 6H),
1.91 (m, CH2, 4H), 1.60 (m, CH2, 4H), 1.33 (m, CH2, 4H), 1.27 (m,
CH2, t-Bu, 22H), 1.11 (m, CH2, 4H), 1.01 (m, t-Bu, 18H); 13C NMR
(125 MHz, CDCl3) δ 171.3 (CO), 168.8 (CO), 158.8, 150.6,
149.4, 141.7, 138.6, 136.7, 136.4, 132.7, 131.6, 130.0, 129.9, 129.2, 128.9,
128.5, 127.7, 127.5, 127.0, 125.6, 125.1, 114.4, 72.8, 65.9, 64.6, 48.7,
34.0, 33.8, 32.9, 32.8, 31.7, 31.0, 29.9, 25.5, 24.9, 24.8, 20.9; HRMS (ESI-
MS) calcd for C106H124N4O10 [M + H]+ 1613.9395, found 1613.9361.
Compound 5aba: 0.037 g, 79% yield; Rf = 0.38 (35/75 EtOAc/
hexane); white solid; mp 110−112 °C; IR (KBr) νmax 3329, 2956, 2929,
2857, 1678, 1648, 1512, 1481, 1247 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.74 (m, OH, 2H), 7.34 (bs, ArH, 2H), 7.29 (d, J = 7.5 Hz, ArH, 4H),
7.24 (m, ArH, 2H), 7.20 (m, ArH, 2H), 7.13 (m, ArH, 8H), 7.05 (s, ArH,
Compound 5daa: 0.036 g, 75% yield; Rf = 0.46 (35/65 EtOAc/
hexane); white solid; mp 106−108 °C; IR (KBr) νmax 3331, 2926, 2854,
1655, 1609, 1541, 1511, 1248 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.33
(m, ArH, 2H), 7.71 (m, OH, 2H), 7.11 (m, ArH, 4H), 7.05 (s, ArH, 6H),
6.86 (s, ArH, 6H), 6.79 (d, J = 7.0 Hz, ArH, 4H), 6.75 (m, ArH, 4H),
6.18 (d, J = 15 Hz, CH, 2H), 5.87 (dd, J1 = 18.5 Hz, J2 = 8 Hz, NH, 2H),
4.30 (m, OCH2, 4H), 4.23 (m, ArCH2Ar, 4H), 4.10 (m, OCH2, 4H),
3.87 (m, CH, 2H), 3.33 (d, J = 12.5 Hz, ArCH2Ar, 4H), 2.43 (s, CH3,
6H), 2.30 (m, CH2, 4H), 2.13 (s, CH3, 6H), 1.97 (m, CH2, 2H), 1.89
(m, CH2, 4H), 1.61 (m, CH2, 4H), 1.36 (m, CH2, 4H), 1.27 (s, t-Bu,
18H), 1.14 (m, CH2, 6H), 1.00 (s, t-Bu, 18H); 13C NMR (125 MHz,
CDCl3) δ 170.6 (CO), 167.7 (CO), 165.3, 161.3, 159.1, 158.9,
150.6, 149.4, 147.2, 138.6, 134.7, 132.7, 131.8, 130.3, 128.9, 127.7, 125.7,
1688
dx.doi.org/10.1021/jo4025732 | J. Org. Chem. 2014, 79, 1683−1689

The Journal of Organic Chemistry
Article
125.6, 125.2, 114.4, 110.9, 72.8, 64.6, 63.9, 48.8, 34.0, 33.8, 33.2, 32.8,
31.8, 31.0, 29.9, 25.5, 24.9, 24.8, 21.1, 14.3; HRMS (ESI-MS) calcd for
C104H122Br2N8O10S2, [M + H]+ 1865.7170, found 1865.7154.
amounts of analytes were added to the acetonitrile. Titration plots were
generated by using Origin 6.0 (Microcal software).
Compound 5eca: 0.034 g, 76% yield; Rf = 0.35 (40/60 EtOAc/
hexane); white solid; mp 230−232 °C; IR (KBr) νmax 3291, 2956, 2928,
2856, 1715, 1652, 1610, 1510, 1245 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.70 (s, OH, 2H), 7.59 (bs, ArH, 2H), 7.05 (s, ArH, 4H), 6.96 (d, J = 8.5
Hz, ArH, 4H), 6.86 (s, ArH, 4H), 6.76 (m, ArH, 6H), 6.51 (bs, ArH, 2H),
6.37 (bs, ArH, 2H), 5.98 (s, CH, 2H), 5.59 (d, J = 8.0 Hz, NH, 2H), 5.43
(bs, NH, 2H), 4.30 (m, OCH2, 4H), 4.21 (m, ArCH2Ar, 4H), 4.09 (m,
OCH2, 4H), 3.78 (m, CH, 2H), 3.70 (s, OCH3, 6H), 3.57 (m, CH2, 4H),
3.32 (d, J = 13.0 Hz, ArCH2Ar, 4H), 2.29 (m, CH2, 4H), 1.92 (m, CH2,
2H), 1.79 (m, CH2, 2H), 1.61 (m, CH2, 8H), 1.40 (s, t-Bu, 18H), 1.31 (m,
CH2, 4H), 1.27 (s, t-Bu, 18H), 1.09 (m, CH2, 4H), 1.00 (s, t-Bu, 18H); 13C
NMR (125 MHz, CDCl3) δ 169.7 (CO), 168.6 (CO), 159.4 (CO),
158.9, 155.7, 150.6, 149.4, 147.2, 141.7, 132.7, 131.8, 131.5, 130.5, 127.7,
126.2, 125.6, 125.1, 114.4, 114.3, 79.4, 72.8, 64.6, 64.5, 55.3, 48.8, 43.7, 34.0,
33.8, 32.8, 31.7, 31.0, 29.9, 28.3, 25.5, 24.9, 24.8; HRMS (ESI-MS) calcd for
C106H138N6O16 [M + H]+ 1752.0247, found 1752.0186.
Compound 5fca: 0.034 g, 74% yield; Rf = 0.41 (40/60 EtOAc/
hexane); white solid; mp 124−126 °C; IR (KBr) νmax 3327, 2953, 2932,
2856, 1716, 1654, 1610, 1510, 1487, 1247 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.76 (m, OH, 2H), 7.59 (m, ArH, 2H), 7.04 (s, ArH, 4H), 6.96
(m, ArH, 4H), 6.87 (s, ArH, 4H), 6.74 (m, ArH, 6H), 6.58 (m, ArH,
4H), 6.09 (m, CH, 2H), 5.63 (m, NH, 2H), 5.28 (m, NH, 2H), 4.25 (m,
OCH2, ArCH2Ar, 8H), 4.11 (m, OCH2, 4H), 3.82 (m, CH, 2H), 3.71
(m, OCH3, 6H), 3.32 (m, ArCH2Ar, 4H), 2.29 (m, CH2, 4H), 1.88 (m,
CH2, 4H), 1.63 (m, CH2, CH, 6H), 1.43 (m, t-Bu, 18H), 1.35 (m, CH2,
6H), 1.26 (m, t-Bu, CH2, 20H), 1.18 (m, CH2, 4H), 1.09 (m, CH3, 6H),
1.01 (s, t-Bu, 18H); 13C NMR (125 MHz, CDCl3) δ 173.9 (CO),
168.8 (CO), 168.3 (CO), 160.3, 159.2, 158.8, 150.6, 149.4, 147.2,
141.6, 132.7, 131.9, 131.8, 131.4, 131.0, 127.7, 126.2, 125.6, 125.1, 79.3,
72.8, 64.6, 55.3, 48.8, 47.6, 34.0, 33.8, 33.1, 32.9, 32.8, 31.7, 31.0, 29.9,
28.3, 25.5, 24.9, 19.1, 18.6; HRMS (ESI-MS) calcd for C108H142N6O16
[M + H]+ 1780.0560, found 1780.0488.
Compound 5gaa: 0.036 g, 72% yield; Rf = 0.29 (40/60 EtOAc/
hexane); white solid; mp 78−80 °C; IR (KBr) νmax 3333, 2924, 2855,
1654, 1609, 1511, 1364, 1246, 1175 cm−1; 1H NMR (500 MHz, CDCl3) δ
8.19 (m, NH, 2H), 7.79 (m, OH, 2H), 7.38 (m, ArH, 4H), 7.22 (m, ArH,
6H), 7.05 (m, ArH, 10H), 6.88 (m, ArH, 8H), 6.75 (m, ArH, 4H), 6.60
(m, ArH, 2H), 6.49 (bs, ArH, 2H), 5.91 (m, CH, 2H), 5.13 (m, NH, 2H),
4.54 (m, CH, 2H), 4.29 (m, OCH2, ArCH2Ar, 8H), 4.10 (m, OCH2, 4H),
3.80 (m, CH, 2H), 3.31 (m, ArCH2Ar, 4H), 3.12 (m, indolyl-CH, 2H),
2.88 (m, indolyl-CH, 2H), 2.25 (m, CH2, CH3, 10H), 1.88 (m, CH2, 4H),
1.63 (m, CH2, 6H), 1.34 (m, t-Bu, CH2, 40H), 1.05 (m, t-Bu, CH2, 24H);
13C NMR (125 MHz, CDCl3): 172.8 (CO), 168.8 (CO), 168.4
(CO), 158.7, 158.5, 155.0, 150.6, 149.4, 147.2, 141.8, 137.9, 136.1,
132.6, 131.8, 130.3, 129.6, 128.2, 127.7, 125.7, 125.2, 123.5, 121.6, 118.9,
114.2, 113.9, 111.3, 110.9, 79.4, 72.7, 64.7, 52.1, 48.8, 48.7, 34.0, 33.9, 33.8,
32.8, 31.7, 31.0, 29.9, 29.7, 28.3, 25.5, 24.9, 21.1, 21.0; HRMS (ESI-MS)
calcd for C124H152N8O14 [M + H]+ 1978.1506, found 1978.1467.
Compound 5aab: 0.023 g, 52% yield; Rf = 0.42 (35/65 EtOAc/
hexane); red solid; mp 100−102 °C; IR (KBr) νmax 3313, 3054, 2957,
2925, 2857, 1699, 1628, 1555, 1510, 1485, 1390, 1283, 1052 cm−1; 1H
NMR (500 MHz, CDCl3) δ 8.20 (m, OH, 2H), 7.68 (m, ArH, 8H), 7.36
(s, ArH, 10H), 7.24 (m, ArH, 8H), 7.18 (d, J = 21 Hz, CH, 2H), 7.12 (m,
ArH, 2H), 7.04 (m, ArH, 4H), 6.84 (m, ArH, 12H), 6.78 (m, ArH, 4H),
6.27 (m, NH, 2H), 4.36 (m, OCH2, 4H), 4.23 (m, ArCH2Ar, 4H), 4.08
(m, OCH2, 4H), 3.30 (m, ArCH2Ar, 4H), 2.31 (m, CH2, 4H), 2.13 (s,
ArCH3, 6H), 1.26 (m, t-Bu, 18H), 0.99 (m, t-Bu, 18H); 13C NMR (125
MHz, CDCl3) δ 171.6 (CO), 168.5 (CO), 159.0, 150.6, 149.4,
147.2, 141.6, 138.3, 137.0, 135.9, 135.3, 133.8, 131.7, 131.6, 130.6,
130.1, 129.5, 129.1, 128.7,128.6, 128.5, 127.7, 127.6, 127.4, 126.4, 126.2,
125.6, 125.1, 124.8, 120.2, 116.8, 114.6, 72.7, 65.2, 64.7, 34.0, 33.8, 31.9,
31.7, 31.0, 29.7, 24.9, 22.7; HRMS (ESI-MS) calcd for C114H116N4O10
[M + H]+ 1700.8769, found 1700.8645.
ASSOCIATED CONTENT
* Supporting Information
Figures giving spectroscopic characterization data for the
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail for R.L.V.: lux_varma@rediffmail.com.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Network Project 0023, Council of
Scientific and Industrial Research, New Delhi, India, for financial
assistance. A.S. and S.T. thank the UGC and CSIR, New Delhi,
India, for the award of research fellowships. We also acknowledge
Dr. G. Vijay Nair for useful discussions. The authors thank Mrs. S.
Viji, Mrs. Soumini Shoji, and Mr. Saran P. R. for spectral analysis.
REFERENCES
■
(1) (a) Gutsche, C. D. In Calixarenes; Stoddart, J. F., Ed.; The Royal
Society of Chemistry: Cambridge, U.K., 1989; Monographs in
Supramolecular Chemistry. (b) Gutsche, C. D. In Calixarenes Revisited;
Stoddart, J. F., Ed.; The Royal Society of Chemistry: Cambridge, U.K.,
1998; Monographs in Supramolecular Chemistry.
(2) (a) Hwang, G. T.; Kim, B. H. Tetrahedron 2002, 58, 9019−9028.
(b) Lhotak, P.; Zieba, R.; Hromadko, V.; Stibor, I.; Sykora, J.
Tetrahedron Lett. 2003, 44, 4519−4522. (c) Dondoni, A.; Kleban, M.;
Hu, X.; Marra, A.; Banks, H. D. J. Org. Chem. 2002, 67, 4722−4733.
(3) Sansone, F.; Barboso, S.; Casnati, A.; Fabbi, M.; Pochini, A.;
Ugozzoli, F.; Ungaro, R. Eur. J. Org. Chem. 1998, 897−905.
(4) Lazzaroto, M.; Sansone, F.; Baldini, L.; Casnati, A.; Cozzini, P.;
Ungaro, R. Eur. J. Org. Chem. 2001, 595−602.
(5) Brewster, R. E.; Caran, K. L.; Sasine, J. S.; Shuker, S. B. Curr. Org.
Chem. 2004, 8, 867−881.
(6) (a) Joseph, R.; Rao, C. P. Ion and Molecular Recognition by Lower
Rim 1,3-Di-conjugates of Calix[4]arene as Receptors. Chem. Rev. 2011,
111, 4658−4702. (b) Chang, K.-C.; Su, I.-H.; Senthilvelan, A.; Chung,
W.-S. Org. Lett. 2007, 9, 3363−3366. (c) Chang, K.-C.; Su, I.-H.; Lee, G.-
H.; Chung, W.-S. Tetrahedron Lett. 2007, 48, 7274−7278.
(7) Savithri, A.; Thulasi, S.; Varma, R. L. Tetrahedron 2012, 68, 6323−
6328.
(8) (a) Ugi, I.; Meyer, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
̈
1959, 71, 386. (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168−3210. (c) Mangunuru, H. P. R.; Yang, H.; Wang, G. Chem.
Commun. 2013, 49, 4489−4491.
(9) Li, Z.-T.; Ji, G.-Z.; Zhao, C.-X.; Yuan, S.-D.; Ding, H.; Huang, C.;
Du, A.-L.; Wei, M. J. Org. Chem. 1999, 64 (10), 3572−3584.
(10) Chawla, H. M.; Sahu, S. N.; Shrivastava, R. Tetrahedron Lett. 2007,
48, 6054−6058.
(11) Adams, P. D.; Chen, Y.; Ma, K.; Zagorski, M. G.; Sonnichsen, F.
̈
D.; McLaughlin, M. L.; Barkley, M. D. J. Am. Chem. Soc. 2002, 124,
9278−9286.
(12) Chen, Y.; Liu, B.; Yu, H.-T.; Barkley, M. D. J. Am. Chem. Soc. 1996,
118, 9271−9278.
(13) (a) Kim, H. J.; Park, S. Y.; Yoon, S.; Kim, J. S. Tetrahedron 2008,
64, 1294. (b) Kim, H. J.; Hong, J.; Hong, A.; Ham, S.; Lee, J. H.; Kim, J.
S. Org. Lett. 2008, 10, 1963. (c) Lin, W.; Yuan, L.; Tan, W.; Feng, J.;
Long, L. Chem. Eur. J. 2009, 15, 1030. (d) Zheng, Y.; Gattas
M.; Konka, V.; Leblanc, R. M. Chem. Commun. 2002, 2350.
(14) Wang, D.; Shiraishi, Y.; Hirai, T. Tetrahedron Lett. 2010, 51,
2545−2549.
́
-Asfura, K.
Titration with Analytes. Because of the poor solubility of metal
perchlorates in chloroform, all of the UV−visible experiments reported
in this work were carried out in acetonitrile. The UV−visible spectra of
the receptors in the presence of analytes were recorded as increasing
1689
dx.doi.org/10.1021/jo4025732 | J. Org. Chem. 2014, 79, 1683−1689