Synthesis of upper rim N-formamido and isocyanocalix[4]arenes: Adaptation of Ugi-4-CR on calix[4]arenes towards peptide-like architectures

Article abstract of DOI:10.1016/j.tet.2012.05.023

Methods are described for the selective diametrical functionalization of calix[4]arenes at the upper rim by formamide and isocyanide functional groups. The adaptation of Ugi-4-CR to calix[4]arenes leading to α- acylaminocarboxamide derivatives is also dis

Full text of DOI:10.1016/j.tet.2012.05.023

Tetrahedron 68 (2012) 6323e6328
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Synthesis of upper rim N-formamido and isocyanocalix[4]arenes: adaptation
of Ugi-4-CR on calix[4]arenes towards peptide-like architectures
*
Anupriya Savithri, Sreeja Thulasi, Luxmi Varma
Organic Chemistry Section, Chemical Sciences and Technology Division, National Institute for Interdisciplinary Science and Technology (CSIR), Trivandrum 695 019, Kerala, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Methods are described for the selective diametrical functionalization of calix[4]arenes at the upper rim
by formamide and isocyanide functional groups. The adaptation of Ugi-4-CR to calix[4]arenes leading to
Received 22 January 2012
Received in revised form 4 May 2012
Accepted 6 May 2012
a
-acylaminocarboxamide derivatives is also discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 19 May 2012
Keywords:
Calix[4]arene
Upper rim functionalization
Multicomponent reactions
Ugi-4-CR
1. Introduction
describe a firsthand report of a facile methodology for the synthesis
of upper rim disubstituted N-formamide and isocyanide derivatives
of calix[4]arene.
Calixarenes, which are probably the world’s most readily avail-
able synthetic molecular baskets enjoy considerable reputation of
being applied in diverse areas.1 The incredible development of calix
[4]arenes as molecular receptors is related to many possible struc-
tural and functional modifications of their core molecular architec-
ture,2 which constitutes a hollow cavity flanked by a hydrophobic
upper rim and a hydrophilic lower rim. Introduction of multifunc-
tional groups at the upper rim of calix[4]arenes reflects a current
trend, aiming towards ‘smart’ materials, informationally rich mo-
lecular devices, and nanofabrication.3 Regioselective modification of
the upper rim can be achieved through partial or total de-tert-bu-
tylation of p-tert-butylcalix[4]arenes followed by the appropriate
derivatization.4 To date, various approaches towards the construc-
tion of multivalent calixarenes,4a such as peptidocalixarenes5,13 and
glycocalixarenes6 have been reported in literatute.7 The use of
peptidocalixarenes as hosts is attractive because of the chirality and
range of functional groups provided by them.5,13 The syntheses of
such calixarenes involve selective protection of the lower rim and
then multi steps including established techniques for the formation
of peptide and glycoside bonds. Rapid and direct access to calix[4]
arenes with peptide-like linkage on the upper rim, which is partic-
ularly attractive and effective, are not reported. Herein we report
a facile and efficient route to libraries of such multifunctionalized
calix[4]arenes involving Ugi-4-component reaction. We also
Multicomponent reactions8 (MCRs) have become an important
component of the combinatorial chemistry, as a great number of
compounds can be produced in a rapid parallel synthetic program.
The high atom economy, convergent character, operational sim-
plicity, structural diversity and complexity of molecules are the
major advantages associated with the MCRs. Multicomponent re-
actions are also emerging as a powerful tool in the synthesis of
biologically active compounds, which have recently attracted the
attention of several academic and industrial researchers, since
accessing diversity is of paramount importance in search of new
biologically active candidates. Large portion of MCR chemistry has
developed from isocyanides. Isocyanide based multicomponent
reactions (IMCRs) are of great importance among MCRs.8a IMCRs
allow for the synthesis of the largest number of different scaffolds.
The outstanding position of IMCRs can be traced back to the ex-
ceptional reactivity of the isocyanide functional group. The in-
troduction of isocyanide group on to the calixarene scaffold makes
it highly functionalizable, which ensures construction of libraries of
multi-functionalised derivatives using IMCR. A large number of
multicomponent reactions are possible on these newly introduced
isocyanide group, which ensures the construction of libraries of
highly functionalized calixarene derivatives. Among the isocyanide
based multicomponent reactions, Ugi-4-component reaction9 oc-
cupies a leading position since it represents a valuable method to
access peptide-like moiety, such as
a-acylaminocarboxamide in
* Corresponding author. E-mail address: lux_varma@rediffmail.com (L. Varma).
a straight forward manner by coupling isocyanides with carbonyl
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.023

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A. Savithri et al. / Tetrahedron 68 (2012) 6323e6328
Table 1
compounds, primary amines and carboxylic acids. Calixarene
chemistry has been relatively untouched by the concept of multi-
component reactions. Our interest in this area stemmed from
a need to synthesize multiply functionalized calix[4]arenes from
isocyanide derivatized calix[4]arene.
Ugi-4-CR of diisocyanocalix[4]arene 3
2. Results and discussion
The basic precursor of our investigation, diaminocalix[4]arene 1
was prepared in good yield using previously reported synthetic
procedures.10 Preliminary endeavours towards transformation of
diaminocalix[4]arene 1 to its N-formamide counterpart focused on
optimizing the utility of various formylating agents available. In an
original work, Shargi and co-workers employed formic acid sup-
ported on non-toxic, inexpensive and bio-compatible ZnO as the
formylating agent.11 When we applied this procedure to 1, the re-
action furnished N-formamide derivatized calix[4]arene 2 as a 1:1
mixture of cis/trans isomer in 90% yield (Scheme 1) (See SI).
Entry R1
R2
5a, (4-CH3)C6H5e 6b, (4-OCH3)C6H5e 7aab, 65
5b, C6H5CH2e 6b, (4-OCH3)C6H5e 7abb, 61
5c, (4-OCH3)C6H5e 6b, (4-OCH3)C6H5e 7acb, 60
5d, (6-CH3)Pye 6b, (4-OCH3)C6H5e 7adb, 63
R3
Yield of 7 (%)
1
2
3
4
5
6
7
4a, C6H5e
4a, C6H5e
4a, C6H5e
4a, C6H5e
4b, (3-CI)C6H5e 5a, (4-CH3)C6H5e 6b, (4-OCH3)C6H5e 7bab, 60
4c, (4-NO2)C6H5e 5a, (4-CH3)C6H5e 6b, (4-OCH3)C6H5e 7cab, 61
4d, CH3e
5a, (4-CH3)C6H5e 6b, (4-OCH3)C6H5e 7dab, 62
Scheme 1. Synthesis of N-formamide 2 and isocyanide 3.
The N-formamide 2 was effortlessly converted into the required
isocyanide 3 in quantitative yield by its reaction with POCl3 and
Et3N in 1 h (Scheme 1). In contrast to the obnoxious odour, which is
characteristic of isocyanides, the diisocyanocalix[4]arene 3 was
odourless.
The unique properties of the isocyano group, which may
function as both electrophile and nucleophile, have turned these
compounds into indispensable reagents for organic synthesis.12
Taking into account this fact and our interest in the adaptation
of multicomponent reactions to calixarene scaffolds, we attempted
an Ugi-4-component reaction with the hope of preparing highly
functionalized calixarene based macrocycles. Thus when we
reacted the diisocyanide 3 with benzoic acid 4a, toluidine 5a and
cyclopropane carboxaldehyde 6a in 2,2,2-trifluoroethanol (TFE) at
room temperature (Scheme 2) and stirring was continued until the
consumption of the starting material as indicated by TLC. After
16 h, removal of the solvent followed by column chromatography
To expand the scope of scaffold diversity generated by this
versatile reaction, amino derivatives of calix[4]arene was subjected
to Ugi reaction. The diaminocalix[4]arene 1 was reacted with ani-
saldehyde 6b, benzoic acid 4a and cyclohexyl isocyanide 8a in TFE
for 16 h at room temperature to afford the corresponding carbox-
amide derivative 9baa in 60% yield (Scheme 3).
Scheme 3. Ugi reaction of diaminocalix[4]arene 1.
of the residue on alumina afforded the highly functionalized
a-
acylaminocarboxamide derivative 7aaa in 65% yield.
The reaction of diaminocalix[4]arene 1 with various aldehydes,
acids and isocyanides provided the multifunctionalized peptide-
like calix[4]arenes in good yields as outlined in Table 2.
The 1H NMR spectra of products obtained from diaminocalix[4]
arene provide evidence for asymmetric structural features. All of
them presented two pairs of doublets around
d 3.00 and 4.10 ppm
(see SI) that have arisen due to the non-equivalency of protons of
the methylene bridges (AreCH2eAr). Some of the 1H NMR spectra
showed even finer splitting in the case of these signals. As pre-
viously reported in the literature,13 this can be explained by the
presence of chiral substituents at the upper rim. Unlike a-acyla-
minocarboxamide derivatives obtained from amines, the 1H NMR
spectra for compounds derived from the diisocyanocalix[4]arene
showed only a pair of doublets, eventhough they contained a ster-
eocenter. This might probably be due to the fact that the stereo-
center in the latter is one carbon away from the calixarene core
than that in the amine derived carboxamides. Chiral resolution of
Scheme 2. Ugi reaction of diisocyanocalix[4]arene 3.
To further demonstrate the efficiency of the Ugi reaction based
on calix[4]arenes, the scope of the reaction with various aromatic
and aliphatic acids, amines and aldehydes were explored and the
results obtained are summarized in Table 1.

A. Savithri et al. / Tetrahedron 68 (2012) 6323e6328
6325
Table 2
0.75
a)
Ugi-4-CR of diaminocalix[4]arene 1
Ligand
K
0.60
Mg
Fe
Hg
Zn
0.45
0.30
Entry R1
R2
R3
Yield of 9 (%)
1
2
3
4
5
6
7
6c, (2,4-diMe)C6H5- 4a, C6H5-
8a, Cy
8a, Cy
8a, Cy
8a, Cy
9caa, 65
0.15
6d, (2-Me)C6H5-
6e, (4-Me)C6H5-
4a, C6H5-
4a, C6H5-
9daa, 63
9eaa, 62
9faa, 70
6f, (4-OMe)C6H5Py- 4a, C6H5-
0.00
6b, (4-OMe)C6H5-
6b, (4-OMe)C6H5-
6b, (4-OMe)C6H5-
4b, (3-CI)C6H5- 8a, Cy
4a, C6H5-
4a, C6H5-
9bba, 62
240
270
300
330
360
390
420
450
8b, (4-OMe)C6H5- 9bab, 60
8c,
b-Np
9bac, 61
Wavelength (nm)
0.5
b)
these compounds may provide new series of calixarene derivatives,
which are capable of stereo recognition in addition to the ionic and
molecular recognition.
Ligand
Acetate
Nitrate
0.4
0.3
0.2
0.1
0.0
The presence of two pairs of NH donor sites and carbonyl groups
at the upper rim of the newly synthesized receptors prompted us to
investigate their molecular/ion recognition properties. However,
preliminary binding studies using UVevis and 1H NMR spectros-
copy towards anions (fluoride, chloride, bromide, iodide, benzoate,
acetate, perchlorate and bisulphate), cations as metal perchlorates
Bromide
Cyanide
Flouride
Phosphate
Chloride
(Cr3þ, Mn2þ, Fe2þ, Co2þ, Ni2þ, Cu2þ, Zn2þ, Hg2þ, Agþ, Pb2þ, Cd2þ
,
Naþ, Kþ, Ca2þ, Al3þ) and neutral molecules (acetone, methanol)
indicated no significant activity. This could be probably due to the
overcrowding around the binding sites by t-butyl as well as bulky
substituent at the upper rim. Fig. 1.
240
270
300
330
360
390
420
450
3. Conclusion
Wavelength (nm)
In conclusion, we have documented a multicomponent approach
to accesslarge diversities of multifunctionalized calix[4]arenes via Ugi
reaction of aminocalix[4]arenes and novel isocyanocalix[4]arenes.
Fig. 1. (a) UVevis spectra of 9faa upon addition of some of the metal ions used in the
binding studies; (b) anions.
The reaction allows us to make a variety of a-acylaminocarboxamide
derivatives of calix[4]arene with considerable generality and sim-
plicity. Thismethodologyenabledthesynthesisofmultifunctionalized
calixarenes bearing heteroaromatic rings and also chromophoric
groups like naphthyl moeity in the peptoid chain. In contrast to many
otherpeptidocalixarenesreported,thecompoundsobtainedusingthe
current methodology has excellent solubility in non-polar solvents.
Duringthecourseofthepresentstudy,wehavesuccessfullyoptimized
the conditions for attaining N-formamido and diisocyanocalix[4]are-
nes,whichareofgreatsyntheticuse. Recognitionstudiesusingneutral
heterocycles and organic cations are being currently undertaken in
our laboratory and will be duly reported.
HPLC analyses were conducted with a LC9101 Recycling Pre-
parative chromatograph. The IR spectra were taken on Nicolet im-
pact 400d FTIR spectrophotometer. NMR spectra were recorded at
300 and 500 (1H) and 75 and 125 (13C) MHz, respectively, on a Bruker
DPX-300 and 500 MHz FT-NMR spectrophotometer. NMR spectra
were obtained using CDCl3þCCl4 as the solvent. Chemical shifts
are given in
d scale with TMS as internal standard. Abbreviations
used in 1H NMR are s: singlet, bs: broad singlet, d: doublet, t: triplet,
m: multiplet. Mass spectrawere recorded by MALDI technique using
Shimadzu MALDI-TOF mass spectrophotometer. Elemental analysis
was done using Perkin-Elmer-2400 CHNS analyser.
4. Experimental section
4.1. General
4.2. Procedure for the synthesis of upper rim formamidocalix
[4]arene (2)
To a mixture of HCO2H (0.22 mL, 6 mmol) and ZnO (160.0 mg,
2 mmol) in toluene (2 mL) was added the diaminocalix[4]arene 1
(100.0 mg, 0.15 mmol) and the reaction mixture was heated in an
oil bath at 75 ꢀC. The progress of the reaction was monitored by TLC.
After the reaction was complete, dichloromethane was added to the
reaction mixture and ZnO was filtered off. The organic solvent was
washed with H2O (2ꢁ20 mL) and saturated solution of NaHCO3.
After the removal of the solvent, the pure product was obtained as
a mixture of cis and trans isomers.
All reactions were conducted in oven dried glassware. Solvents
used for the experiments were distilled or dried as specified. An-
alytical thin layer chromatography was performed on glass plates
coated with silica gel (E-Merck) containing 13% CaSO4 as binder.
Column chromatography was done using 100e200 mesh silica gel
and appropriate mixture of petroleum ether and ethyl acetate for
elution. The solvents were removed using Buchi E.L. rotary
evaporator.

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A. Savithri et al. / Tetrahedron 68 (2012) 6323e6328
4.2.1. Formamidocalix[4]arene (2). Yield: 90% as white solid. Rf:
0.09 (15:85 EtOAc/Hexane). Mp:> 250 ꢀC. IR (KBr) ymax: 3279, 3011,
CDCl3):
d
8.29 (s, OH, 2H), 7.83 (s, NH, 2H), 7.31 (d, J¼7 Hz, ArH, 4H),
7.19 (m, ArH,10H), 7.12 (m, ArH, 4H), 6.97 (d, J¼4.5 Hz, ArH, 4H), 6.82
(s, ArH, 8H), 6.76 (d, J¼8.5 Hz, ArH, 4H), 6.29 (s, CH, 2H), 4.30 (m,
ArCH2Ar, 4H), 3.98 (t, J1¼6.5 Hz, J2¼7 Hz, OCH2, 4H), 3.75 (s, OCH3,
6H), 3.32 (m, ArCH2Ar, 4H), 2.17 (s, ArCH3, 6H), 2.06 (m, CH2, 4H),1.68
(m, CH2, 4H),1.12 (m, t-Bu,18H),1.07(t, J1¼7.5 Hz, J2¼7.5 Hz, CH3, 6H).
2961, 1688, 1483, 1252, 1215, 1101, 756, 665 cmꢂ1 1H NMR:
d 8.56 (s,
CHO, 2H), 8.40 (s, NH, 2H), 8.36 (dd, J¼3.5 Hz, J¼11.5 Hz, CHO, 2H),
8.25 (d, J¼1.5 Hz, NH, 2H), 7.56 (broad s, OH, 4H), 7.21 (s, ArH, 2H),
7.00 (d, J¼2.0 Hz, ArH, 2H), 6.98 (s, ArH, 2H), 6.97 (s, ArH, 2H), 6.95
(d, J¼2.0 Hz, ArH, 4H), 6.77 (d, J¼2.5 Hz, ArH, 4H), 4.32 (m, ArCH2Ar,
8H), 3.99 (m, ꢂOCH2, 8H), 3.33 (m, ArCH2Ar, 8H), 2.08 (m, ꢂCH2,
13C NMR (125 MHz, CDCl3):
d 171.54 (C]O), 167.42 (C]O), 159.57,
159.3, 149.83, 138.5, 137.07, 136.05, 132.98, 131.4, 129.9, 129.5, 129.2,
128.06,127.6,126.6,125.8,120.4,113.81 (AreC), 76.56 (eOCH2) 66.6,
55.2, 34.2, 32.1, 31.1, 29.7, 20.1, 19.3, 14.1 (ArCH2Ar, t-Bu, ArCH3, CH3,
CH2, OCH3). Anal. Calcd for C90H96N4O10: C, 77.56; H, 6.94; N, 4.02.
Found: C, 77.43; H, 7.01; N, 4.13.
8H), 1.71 (m, ꢂCH2, 8H), 1.13 (s, t-Bu, 36H), 1.09 (m, ꢂCH3, 12H). 13
C
NMR:
d
168.2 (ꢂCHO), 158.5 (ꢂCHO),151.4, 150.2, 147.7, 133.3, 132.8,
132.6, 130.0, 129.8, 129.1, 128.5, 127.7, 126.0, 125.7, 121.1, 120.5, 76.3
(ꢂOCH2), 32.1, 31.9, 31.7, 31.3, 29.7, 29.4, 19.3, 14.1, (t-Bu,
AreCH2eAr, ꢂCH2, ꢂCH3). Anal. Calcd for C46H58N2O6: C, 75.17; H,
7.95; N, 3.81. Found: C, 75.23; H, 7.89; N, 3.76.
4.4.3. Compound 7abb. Yield: 61% as a white solid. Rf: 0.33 (45:55
EtOAc/Hexane). Mp: 100e102 ꢀC. IR (KBr) nmax: 3308, 2958, 2930,
4.3. Procedure for the synthesis of calix[4]arene isocyanide (3)
2871, 1687, 1613, 1512, 1251 cmꢂ1 1H NMR (500 MHz, CDCl3):
d 7.46
(m, ArH, 4H), 7.31 (m, ArH, OH, NH, 10H), 7.16 (m, ArH, 8H), 7.08 (m,
ArH, 6H), 6.96 (d, J¼9 Hz, ArH, 6H), 6.79 (d, 6H. J¼8.5 Hz, ArH, 6H),
5.67 (s, CH, 2H), 4.73 (d, J¼16.5 Hz, ArCH2, 2H), 4.49 (m, ArCH2, 2H),
4.29 (d, J¼12.5 Hz, ArCH2Ar, 4H), 3.97 (m, OCH2, 4H), 3.76 (s, OCH3,
6H), 3.29 (d, J¼13 Hz, ArCH2Ar, 4H), 2.06 (m, CH2, 4H), 1.68 (m, CH2,
4H), 1.12 (s, t-Bu, 18H), 1.07 (t, J1¼J2¼7.5 Hz, CH3, 6H). 13C NMR
To
a solution of formamidocalix[4]arene 2 (136.0 mg,
0.19 mmol) in dichloromethane (5 mL), was added triethyl amine
(11 equiv) and POCl3 (5.5 equiv) at 0 ꢀC under nitrogen. After being
stirred for 1 h, the reaction mixture was poured into 10% aqueous
Na2CO3 solution. The reaction mixture was worked up with
dichloromethane-water mixture. The solvent was removed under
reduced pressure, and the residue was purified by column chro-
matography on silica gel (hexaneseethyl acetate in 95:5).
(125 MHz, CDCl3):
d 173.4 (C]O), 167.2 (C]O), 160.9, 159.8, 150.3,
149.9, 147.4, 136.2, 133.0, 130.9, 129.9, 128.8, 128.75, 128.4, 127.8,
126.97, 126.8, 126.7, 125.8, 120.4, 114.25 (AreC), 76.59 (OCH2), 55.3
(OCH3), 34.2, 32.1, 31.9, 31.7, 31.3, 29.7, 29.4, 22.7, 19.3, 14.1 (CH2,
CH3, t-Bu, ArCH2Ar). Anal. Calcd for C90H96N4O10: C, 77.56; H, 6.94;
N, 4.02. Found: C, 77.62; H, 7.02; N, 4.17.
4.3.1. calix[4]arene isocyanide (3). Yield: 99% as white solid. Rf :
0.65 (15:85 EtOAc/Hexane). Mp: 53e55 ꢀC. IR (KBr) ymax: 3277,
2961, 2932, 2119, 1476, 1362, 1196, 995 cmꢂ1 1H NMR:
d 8.73 (s, OH,
2H), 7.09 (s, ArH, 4H), 6.91 (s, ArH, 4H), 4.24 (d, J¼13.0 Hz, ArCH2Ar,
4H), 3.98 (t, J¼5.0 Hz, ꢂOCH2, 4H), 3.33 (d, J¼13.5 Hz, ArCH2Ar, 4H),
2.03 (m, ꢂCH2, 4H), 1.72 (m, ꢂCH2, 4H), 1.09 (s, t-Bu, 18H), 0.87 (m,
4.4.4. Compound 7acb. Yield: 60% as a white solid. Rf: 0.23 (45:55
EtOAc/Hexane). Mp: 120e124 ꢀC. IR (KBr) nmax: 3304, 2957, 2924,
2854, 1681, 1632, 1513, 1253 cmꢂ1 1H NMR (500 MHz, CDCl3):
d 8.28
ꢂCH3, 6H). 13C NMR:
d
161.1, (NC) 154.2, 149.9, 148.2, 131.7, 130.8,
(s, OH, 2H), 7.70 (s, NH, 2H), 7.30 (d, J¼7 Hz, ArH, 4H), 7.18 (m, ArH,
10H), 7.12 (m, ArH, 4H), 6.97 (d, J¼9 Hz, ArH, 4H), 6.84 (bs, ArH, 4H),
6.76 (d, J¼9 Hz, ArH, 4H), 6.52 (d, J¼9 Hz, ArH, 4H), 6.36 (s, CH, 2H),
4.30 (m, ArCH2Ar, 4H), 3.98 (t, J1¼6.5 Hz, J2¼7 Hz, OCH2, 4H), 3.76 (s,
OCH3, 6H), 3.65 (s, OCH3, 6H), 3.32 (m, ArCH2Ar, 4H), 2.06 (m, CH2,
4H), 1.68 (m, CH2, 4H), 1.11 (d, J¼3.5 Hz, t-Bu, 18H), 1.09 (t, J1¼7.5 Hz,
129.3, 128.8, 126.2, 117.8, 115.9 (AreC), 64.9 (ꢂOCH2), 34.2, 32.2,
31.9, 31.6, 29.7, 22.7, 19.4 (t-Bu, AreCH2eAr, CH2, CH3). MS (MALDI-
TOF): Calcd for C46H54N2O4, [MþNa]þ: 721.4084; Found: 721.4254.
4.4. General procedure for the synthesis of a-
acylaminocarboxamidocalix[4]arene (7) by the U-4CR
J2¼7 Hz, CH3, 6H). 13C NMR (125 MHz, CDCl3):
d 171.66 (C]O), 167.5
(C]O), 159.6, 158.4, 150.3, 149.8, 136.1, 132.97, 131.7, 131.6, 129.3,
128.5, 127.6, 126.4, 125.8, 120.4, 113.8, 113.5 (AreC), 76.56 (OCH2),
55.21 (OCH3), 55. 19 (OCH3), 34.2, 32.1, 31.3, 29.7, 19.3, 14.1
(ArCH2Ar, t-Bu, CH2, CH3). Anal. Calcd for C90H96N4O12: C, 75.82; H,
6.79; N, 3.93. Found: C, 75.69; H, 6.83; N, 4.03.
Amine 5a (0.0534 mmol) and aldehyde 6a (0.0534 mmol) were
stirred in 0.5 mL TFE for 2 h. Then, carboxylic acid 4a (0.1335 mmol)
and diisocyanocalix[4]arene 3 (20 mg, 0.0267 mmol) were added
and the reaction mixture was stirred for 16 h at room temperature.
The solvent was removed in vacuo. Product was purified by column
chromatography on neutral alumina (Hexane/EtOAc).
4.4.5. Compound 7adb. Yield: 62% as a white solid. Rf: 0.13 (60:40
EtOAc/Hexane). Mp: 115e119 ꢀC. IR (KBr) nmax: 3340, 2924, 2854,
4.4.1. Compound 7aaa. Yield: 65% as white solid. Rf : 0.50 (35:75
EtOAc/Hexane). Mp: 123e126 ꢀC. IR (KBr) nmax: 3327, 2957, 2927,
1659, 1642 cmꢂ1 1H NMR (500 MHz, CDCl3):
d
8.29 (d, J¼2.5 Hz, OH,
2H), 7.79 (s, NH, 2H), 7.43 (m, ArH, 2H), 7.29 (m, ArH, 6H), 7.20 (m,
ArH, 2H), 7.15 (m, ArH, 10H), 6.95 (m, ArH, 4H), 6.84 (d, J¼5 Hz, ArH,
2H), 6.75 (d, J¼8.5 Hz, ArH, 4H), 6.44 (s, CH, 2H), 4.30 (m, ArCH2Ar,
4H), 3.98 (t, J1¼7 Hz, J2¼6.5 Hz, OCH2, 6H), 3.75 (s, OCH3, 6H), 3.32
(m, ArCH2Ar, 4H), 2.36 (s, ArCH3, 6H), 2.06 (m, CH2, 4H), 1.69 (m,
CH2, 4H),1.11 (d, J¼2.5 Hz, t-Bu,18H),1.08 (t, J1¼7 Hz, J2¼7.5 Hz, CH3,
2870, 1692, 1628, 1511, 1249 cmꢂ1 1H NMR (500 MHz, CDCl3):
d 8.56
(s, NH, 2H), 8.39 (s, OH, 2H), 7.43 (s, ArH, 2H), 7.24 (m, ArH, 4H), 7.20
(m, ArH, 4H), 7.11 (m, ArH, 4H), 7,04 (m, ArH, 2H), 7.00 (m, ArH, 6H),
6.94 (m, ArH, 4H), 4.44 (d, J¼10.5 Hz, CH, 2H), 4.32 (d, J¼12.5 Hz,
ArCH2Ar, 4H), 3.99 (t, J1¼7 Hz, J2¼6.5 Hz, OCH2, 4H), 3.34 (d,
J¼13.0 Hz, ArCH2Ar, 4H), 2.23 (s, ArCH3, 6H), 2.08 (m, CH2, 4H), 1.71
(m, CH2, 4H), 1.11 (m, t-Bu, CH3, 24H), 0.87 (m, CH2, 4H), 0.78 (m,
6H). 13C NMR (125 MHz, CDCl3):
d 171.5 (C]O), 167.3 (C]O), 159.9,
150.3, 150.0, 147.4, 135.5, 133.0, 132.9, 132.8, 131.7, 129.7, 129.3,
129.2, 129.1, 120.5, 128.5, 127.9, 125.85, 125.76, 122.75, 120.6, 114.2
(AreC), 76.58 (OCH2), 55.2, 34.2, 32.1, 31.76, 31.57, 31.3, 29.7, 19.3,
14.1 (ArCH2Ar, CH2, CH3, OCH3). Anal. Calcd for C88H94N6O10: C,
75.73; H, 6.79; N, 6.02. Found: C, 75.78; H, 6.88; N, 6.16.
CH2, 2H), 0.52 (m, CH2, 4H). 13C NMR (125 MHz, CDCl3):
d 172.1 (C]
O), 167.8 (C]O), 150.3, 149.6, 147.4, 137.5, 135.7, 133.04, 129.98,
129.56, 129.1, 128.4, 127.6, 125.9, 119.95, 119.86, (AreC), 76.56
(OCH2), 66.63, 34.2, 31.4, 29.7, 22.7, 21.0, 19.3, 14.1, 10.4, 5.9, 4.2
(ArCH2Ar,, t-Bu, CH, ArCH3, CH2). MS (MALDI-TOF): Calcd for
C82H92N4O8, [MþNa]þ: 1283.6915; Found: 1283.6469.
4.4.6. Compound 7bab. Yield: 65% as a white solid. Rf: 0.36 (45:55
EtOAc/Hexane). Mp: 117e121 ꢀC. IR (KBr) nmax: 3305, 2923, 2853,1680,
4.4.2. Compound 7aab. Yield: 65% as white solid. Rf: 0.25 (35:75
EtOAc/Hexane). Mp: 118e120 ꢀC. IR (KBr) nmax: 3318, 2957, 2931,
2871,2931, 1693, 1632, 1511, 1483, 1250 cmꢂ1 1H NMR (500 MHz,
1632, 1511, 1252 cmꢂ1 1H NMR (500 MHz, CDCl3):
OH, 2H), 7.55 (s, NH, 2H), 7.35 (s, ArH, 2H), 7.16 (m, ArH, 12H), 7.03 (m,
d
8.30 (d, J¼1.5 Hz,
ArH, 2H), 6.97(m, ArH, 4H), 6.83(s, ArH, 8H), 6.76(d, J¼8.5 Hz, ArH, 4H),

A. Savithri et al. / Tetrahedron 68 (2012) 6323e6328
6327
6.28 (s, CH, 2H), 4.30 (m, ArCH2Ar, 4H), 3.98 (t, J1¼7Hz, J2¼6.5 Hz, OCH2,
4H), 3.75 (s, OCH3, 6H), 3.32 (m, ArCH2Ar, 4H), 2.18 (s, CH3, 6H), 2.06(m,
CH2, 4H),1.68 ( m, CH2, 4H),1.12 (s, t-Bu,18H),1.07 (t, J1¼J2¼7.5 Hz, CH3,
(OCH2), 55.2, 48.6, 33.8, 32.9, 32.8, 32.2, 31.2, 25.6, 24.8, 24.7, 19.3,
14.07 (ArCH2Ar, CH2, CH3, t-Bu, OCH3). MS (MALDI-TOF): Calcd for
C88H104N4O10 [MþNa]þ: 1399.7752; Found: 1399.7487.
6H). 13C NMR (125 MHz, CDCl3):
d 169.95 (C]O), 167.20 (C]O), 159.7,
150.3, 149.9, 147.4, 137.8, 137.4, 133.7, 133.0, 131.6, 130.0, 129.5, 129.3,
128.8, 128.7, 126.6, 126.2, 125.8, 120.4, 113.9 (AreC),76.57 (OCH2), 66.4,
55.2, 34.2, 32.1, 31.6, 31.3, 20.99, 19.3, 14.1 (ArCH2Ar, t-Bu, CH2, ArCH3,
CH3, OCH3). Anal. Calcd for C90H94Cl2N4O10: C, 73.91; H, 6.48; N, 3.83.
Found: C, 73.81; H, 6.59; N, 3.75.
4.5.2. Compound 9caa. Yield: 65% as a white solid. Rf: 0.54 (45:55
EtOAc/Hexane). Mp: 97e101 ꢀC. IR (KBr) nmax: 3318, 2953, 2930,
2856, 1680, 1636, 1515, 1251 cmꢂ1 1H NMR (500 MHz, CDCl3):
d 7.42
(s, OH, 2H), 7.38 (m, ArH, 4H), 7.29 (bs, ArH, 2H), 7.16 (m, ArH, 2H),
7.05 (m, ArH, 6H), 6.96 (s, ArH, 4H), 5.96 (bs, CH, 2H), 5.50 (m, NH,
2H), 3.99 (m, ArCH2Ar, 4H), 3.82 (m, OCH2, CH, 6H), 3.19 (d,
J¼13.5 Hz, ArCH2Ar, 2H), 2.89 (m, ArCH2Ar, 2H), 2.29 (s, CH3, 6H),
2.23 (s, CH3, 6H), 1.90 (m, CH2, 8H), 1.56 (m, CH, OCH2, 4H), 1.33 (m,
CH2, 6H), 1.09 (m, CH2, 6H), 1.00 (m, CH3, 6H), 0.792 (m, t-Bu, 18H).
4.4.7. Compound 7cab. Yield: 60% as a light yellow solid. Rf: 0.35
(45:55 EtOAc/Hexane). Mp: 122e124 ꢀC. IR (KBr) nmax: 3312, 2958,
2931, 2871, 1690, 1634, 1512, 1483, 1252 cmꢂ1 1H NMR (500 MHz,
CDCl3):
d
8.33 (d, J¼3.5 Hz, OH, 2H), 7.98 (d, J¼9 Hz, ArH, 4H), 7.46
13C NMR (125 MHz, CDCl3):
d 170.8 (C]O), 168.6 (C]O), 152.5,
150.5, 146.9, 137.97, 137.2, 136.2, 131.7, 131.5, 130.4, 129.5, 129.1,
128.7, 128.2, 127.5, 127.1, 125.2, 125.11 (AreC), 76.5 (OCH2), 48.7,
33.8, 32.8, 32.1, 31.5, 31.2, 25.1, 24.9, 21.06, 19.5, 19.3, 14.0 (ArCH2Ar,
(d, J¼8.5 Hz, ArH, 4H), 7.28 (s, NH, 2H), 7.15 (m, ArH, 8H), 6.97 (m,
ArH, 4H), 6.78 (m, ArH,12H), 6.33 (s, CH, 2H), 4.29 (m, ArCH2Ar, 4H),
3.98 (t, J1¼7 Hz, J2¼6.5 Hz, OCH2, 4H), 3.76 (s, OCH3, 6H), 3.22 (m,
ArCH2Ar, 4H), 2.17 (s, ArCH3, 6H), 2.07 (m, CH2, 4H), 1.68 (m, CH2,
4H), 1.12 (d, J¼4 Hz, t-Bu, 18H), 1.07 (t, J1¼7 Hz, J2¼7.5 Hz, CH3, 6H).
t-Bu, CH2, CH3). MS (MALDI-TOF): Calcd for C90H108N4O10
[MþNa]þ: 1395.8167; Found: 1395.9396.
,
13C NMR (125 MHz, CDCl3):
d 169.3 (C]O), 166.9 (C]O), 159.9,
150.3,149.48,147.7,142,56,137.9,133.06,133.00,131.81,113.3,129.4,
129.2, 129.1, 125.9, 125.8, 122.9, 120.5, 114.0 (AreC), 76.60 (OCH2),
65.91, 55.2, 34.2, 32.1, 31.3, 21.0, 19.3, 14.1 (ArCH2Ar, ArCH3, CH2,
CH3, OCH3). Anal. Calcd for C90H94N6O14: C, 72.85; H, 6.39; N, 5.66.
Found: C, 72.94; H, 6.48; N, 5.73.
4.5.3. Compound 9daa. Yield: 63% as a white solid. Rf: 0.57 (45:55
EtOAc/Hexane). Mp: 98e100 ꢀC. IR (KBr) nmax: 3341, 2928, 2855,
1691, 1642, 1534, 1275 cmꢂ1 1H NMR (500 MHz, CDCl3):
d 7.47 (s,
OH, 2H), 7.39 (m, ArH, 6H), 7.10 (m, ArH, 14H), 6.42 (m, ArH, 6H),
6.09 (bs, CH2, 2H), 5.50 (m, NH, 2H), 3.89 (m, OCH2, ArCH2Ar, CH,
10H), 3.15 (d, J¼13.5 Hz, ArCH2Ar, 2H), 2.89 (d, J¼13.5 Hz, ArCH2Ar,
2H), 2.32 (s, ArCH3, 6H), 1.95 (m, CH2, 4H), 1.87 (m, CH2, 4H), 1.66
(m, CH2, 4H), 1.56 (m, CH2, 6H), 1.35 (m, CH2, 4H), 1.10 (m, CH2, 6H),
0.99 (m, CH3, 6H), 0.81 (m, t-Bu, 18H). 13C NMR (125 MHz, CDCl3):
4.4.8. Compound 7dab. Yield: 60% as a white solid. Rf: 0.23 (35:75
EtOAc/Hexane). Mp: 106e108 ꢀC. IR (KBr) nmax: 3309, 2958, 2933,
2871, 1689, 1640, 1512, 1483, 1251 cmꢂ1 1H NMR (500 MHz, CDCl3):
d
8.18 (s, OH, 2H), 7.56 (d, J¼3.5 Hz, NH, 2H), 7.17 (m, ArH, 4H), 7.06
d 170.9 (C]O), 168.6 (C]O), 152.6, 150.06, 146.9, 137.5, 136.19,
(d, 4H, J¼8.56 Hz, 4H), 6.99 (d, J¼6.5 Hz, ArH, 4H), 6.93 (m, ArH, 6H),
6.69 (m, ArH, 6H), 6.23 (s, CH, 2H), 4.23 (m, ArCH2Ar, 2H), 3.96 (t,
J1¼6.5 Hz, J2¼7 Hz, OCH2, 4H), 3.73 (s, OCH3, 6H), 3.30 (m, ArCH2Ar,
4H), 2.23 (s, ArCH3, 6H), 2.04 (m, CH2, 4H), 1.86 (s, O]CeCH3, 6H),
1.68 (m, CH2, 4H), 1.098 (m, t-Bu, 18H), 1.08 (t, J1¼J2¼8 Hz, CH3, 6H).
133.46, 131.8, 131.46, 129.8, 129.5, 129.3, 128.7, 128.4, 128.0, 127.5,
126.3, 125.4 (AreC), 76.3 (OCH2), 48.8, 33.8, 32.8, 32.1, 31.6, 31.3,
31.0, 25.5, 24.8, 19.6, 19.25, 14.0 (ArCH2Ar, CH2, CH3, t-Bu). MS
(MALDI-TOF): Calcd for C88H104N4O10, [MþNa]þ: 1367.7854; Found:
1367.7379.
13C NMR (125 MHz, CDCl3):
d 171.66 (C]O), 167.52 (C]O), 159.52,
150.25, 149.8, 147.3, 138.0, 137.8, 132.8, 131.85, 129.91, 129.6, 129.4,
129.0, 126.3, 125.8, 120.2, 113.6 (AreC), 76.5 (OCH2), 64.4, 55.16,
34.22, 32.13, 23.2, 21.1, 19.3, 14.07 (ArCH2Ar, O]CeCH3, t-Bu,
ArCH3, CH3, CH2, OCH3). Anal. Calcd for C80H92N4O10: C, 75.68; H,
7.30; N, 4.41. Found: C, 75.63; H, 7.46; N, 4.29.
4.5.4. Compound 9eaa. Yield: 62% as white solid. Rf: 0.57 (45:55
EtOAc/Hexane). Mp: 100e102 ꢀC. IR (KBr) nmax: 3319, 2954, 2929,
2855, 1679,1634, 1479, 1250 cmꢂ1 1H NMR (500 MHz, CDCl3):
d 7.56
(d, J¼5 Hz, OH, 2H), 7.40 (d, J¼7.5 Hz, ArH, 4H), 7.29 (d, J¼7.5 Hz, ArH,
4H), 7.14 (m, ArH, 6H), 7.07 (m, ArH, 6H), 6.62 (s, ArH, 2H), 6.55 (m,
ArH, 2H), 6.41 (m, ArH, 2H), 5.84 (d, J¼8 Hz, NH, 2H), 5.53 (s, CH, 2H),
4.09 (dd, J1¼3 Hz, J2¼13 Hz, ArCH2Ar, 2H), 3.98 (m, ArCH2Ar, 2H),
3.85 (m, OCH2, CH, 6H), 3.18 (dd, J1¼6.5 Hz, J2¼13.5 Hz, ArCH2Ar, 2H),
2.99 (m, ArCH2Ar, 2H), 2.34 (s, ArCH3, 6H),1.91 (m, CH2, 8H),1.63 (m,
CH2, 8H), 1.35 (m, CH2, 6H), 1.12 (m, CH2, 6H), 1.02 (m, CH3, 6H),
4.5. General procedure for the synthesis of a-
acylaminocarboxamidocalix[4]arene (9) by the U-4CR
Diaminocalix[4]arene 1 (30.0 mg, 0.044 mmol) and aldehyde 6b
(0.088 mmol) were stirred in 1 mL TFE for 2 h. Then, carboxylic acid
4a (0.176 mmol) and isocyanide 8a (0.132 mmol) were added and
the reaction mixture was stirred for 16 h at room temperature. The
solvent was removed in vacuo. Product was purified by column
chromatography on neutral alumina (Hexane/EtOAc).
0.83 (m, t-Bu,18H). 13C NMR (125 MHz, CDCl3):
d 170.6 (C]O),168.6
(C]O), 152.6, 149.96, 147.1, 137.99, 136.1, 13.5, 131.66, 131.60, 129.64,
129.39, 128.80, 128.42, 127.53, 125.42, 125.19 (AreC), 76.30 (OCH2),
48.64, 33.88, 32.86, 32.80, 32.17, 31.18, 26.9, 25.56, 24.76, 21.20,19.3,
14.07 (ArCH2Ar, CH2, ArCH3, CH3, t-Bu). Anal. Calcd for C88H104N4O8:
C, 78.54; H, 7.79; N, 4.16. Found: C, 78.69; H, 7.92; N, 4.21.
4.5.1. Compound 9baa. Yield: 60% as a white solid. Rf: 0.43 (45:55
EtOAc/Hexane). Mp: 110e112 ꢀC. IR (KBr) nmax:3332, 2929, 2855,
4.5.5. Compound 9faa. Yield: 70% as a light yellow solid. Rf: 0.29
(45:55 EtOAc/Hexane). Mp: 118e120 ꢀC. IR (KBr) nmax: 3289, 2929,
2854, 1669, 1651, 1515, 1479, 1452, 1251 cmꢂ1 1H NMR (500 MHz,
1665, 1637, 1512, 1479, 1251 cmꢂ1 1H NMR (500 MHz, CDCl3):
d 7.61
(d, J¼5 Hz, OH, 2H), 7.39 (d, J¼7 Hz, ArH, 4H), 7.31 (d, J¼8 Hz, ArH,
4H), 7.13 (m, ArH, 2H), 7.07 (m, ArH, 6H), 6.84 (d, J¼8.5 Hz, ArH, 4H),
6.59 (s, ArH, 2H), 6.54 (m, ArH, 2H), 6.43 (m, ArH, 2H), 5.79 (d,
J¼8 Hz, CH, 2H), 5.59 (bs, NH, 2H), 4.09 (dd, J1¼4 Hz, J2¼13.5 Hz,
ArCH2Ar, 2H), 3.99 (dd, J1¼2.5 Hz, J2¼13.5 Hz, ArCH2Ar, 2H), 3.86
(m, CH, OCH2, 6H), 3.80 (s, OCH3, 6H), 3.18 (dd, J1¼6 Hz, J2¼13 Hz,
ArCH2Ar, 2H), 2.99 (dd, J1¼4 Hz, J2¼13 Hz, ArCH2Ar, 2H), 1.91 (m,
CH2, 8H), 1.62 (m, CH2, 8H), 1.36 (m, CH2, 4H), 1.13 (m, CH2, 8H), 1.02
(m, CH3, 6H), 0.83 (m, t-Bu, 18H). 13C NMR (125 MHz, CDCl3): 170.6
(C]O), 168.7 (C]O), 159.5, 152.6, 149.9, 147.2, 147.1, 136.1, 131.6,
131.0, 129.6, 128.8, 128.3, 127.5, 125.4, 125.2, 113.9 (AreC), 76.36
CDCl3):
d
8.71 (d, J¼7.5 Hz, OH, 2H), 7.89 (m, NH, ArH, 6H), 7.74 (m,
ArH, 2H), 7.59 (d, J¼8 Hz, ArH, 2H), 7.52 (d, J¼7.5 Hz, 2H), 7.46 (d,
J¼7.5 Hz, ArH, 4H), 7.24 (s, ArH, 2H), 7.12 (m, ArH, 2H), 7.06 (m, ArH,
4H), 6.99 (d, J¼8.5 Hz, ArH, 4H), 6.84 (m, ArH, 2H), 6.66 (d, J¼14 Hz,
ArH, 2H), 6.45 (d, J¼14 Hz, ArH, 2H), 5.59 (s, CH, 2H), 4.14 (d, J¼13 Hz,
ArCH2Ar, 2H), 4.05 (d, J¼13 Hz, ArCH2Ar, 2H), 3.87 (m, OCH2, OCH3,
CH,12H), 3.25 (m, ArCH2Ar, 2H), 3.07 (m, ArCH2Ar, 2H),1.92 (m, CH2,
6H), 1.81 (m, CH2, 2H), 1.66 (m, CH2, 6H), 1.52 (m, CH2, 4H), 1.21 (m,
CH2, 10H), 1.04 (m, CH3, 6H), 0.81 (m, t-Bu, 18H). 13C NMR (125 MHz,
CDCl3): d 170.3 (C]O),166.6 (C]O),156.12,155.5,152.6,149.9,147.2,

6328
A. Savithri et al. / Tetrahedron 68 (2012) 6323e6328
137.99, 135.8, 131.7, 131.4, 129.8, 128.9, 128.6, 128.3, 128.0, 127.5,
125.5, 125.3, 118.1, 114.1 (AreC), 76.3 (OCH2), 55.4, 48.3, 33.9, 33.0,
32.8, 32.2, 31.2, 29.7, 25.6, 25.4, 24.6, 19.4, 14.06 (ArCH2Ar, CH2, CH3,
t-Bu, OCH3). Anal. Calcd for C98H110N6O10: C, 76.83; H, 7.24; N, 5.49.
Found: C, 76.97; H, 7.41; N, 5.62.
of the receptors in the presence of analytes were recorded as in-
creasing amounts of analytes were added to the acetonitrile. Titra-
tion plots were generated by using Origin 6.0 (Microcal software).
Acknowledgements
4.5.6. Compound 9bba. Yield: 62% as a white solid. Rf: 0.48 (45:55
EtOAc/Hexane). Mp: 112e114 ꢀC. IR (KBr) nmax: 3315, 2925, 2856,
The authors thank the Network Project 0023, Council of Scien-
tific and Industrial Research, New Delhi for financial assistance. S.T.
and A.S. thank UGC and CSIR, New Delhi for the award of research
fellowships. We also acknowledge Dr. G. Vijay Nair for useful dis-
cussions. The authors would like to thank Mrs. S. Viji, Mrs. Soumini
Shoji and Mr. Adarsh B. for spectral analysis.
1660,1642,1513,1479,1252 cmꢂ1 1H NMR (500 MHz, CDCl3):
d 8.059
(bs, OH, 2H), 7.30 (m, ArH, 4H), 7.187 (m, ArH, 4H), 6.19 (m, ArH, 4H),
6.83 (d, J¼10 Hz, ArH, 6H), 6.65 (bs, ArH, 2H), 6.56 (bs, ArH, 2H), 6.501
(bs, ArH, 2H), 5.66 (m, CH, 2H), 5.53 (bs, NH, 2H), 4.14 (dd, J1¼5 Hz,
J2¼13 Hz, ArCH2Ar, 2H), 4.02 (dd, J1¼5 Hz, J2¼13 Hz, ArCH2Ar, 2H),
3.87(m, CH, OCH2, 6H), 3.80 (s, OCH3, 6H), 3.23(m, ArCH2Ar, 2H), 3.03
(m, ArCH2Ar, 2H), 1.94 (m, CH2, 8H), 1.65 (m, CH2, 8H), 1.35 (m, CH2,
6H),1.11 (m, CH2, 6H),1.04 (m, CH3, 6H), 0.828 (m, t-Bu,18H).13C NMR
Supplementary data
Supplementary data associated with this article: characteriza-
tion datas of the prepared compounds and the UVevis spectra of
the compound 9faa. Supplementary data associated with this ar-
ticle can be found in the online version, at doi:10.1016/
j.tet.2012.05.023. These data include MOL files and InChIKeys of the
most important compounds described in this article.
(125 MHz, CDCl3):
d 168.7(C]O), 168.4 (C]O), 159.56, 152.8, 149.8,
147.3, 137.65, 133.76, 131.8, 131.14, 131.01, 129.69, 129.27, 128.94,
128.59, 127.29, 126.89, 125.62, 125.2, 114.06 (AreC), 76.47 (OCH2),
55.21, 48.7, 33.8, 32.86, 31.38, 31.29, 31.11, 25.55, 24.77, 19.3, 14.09
(ArCH2Ar, CH2, CH3, t-Bu, OCH3). Anal. Calcd for C88H102Cl2N4O10: C,
73.06; H, 7.11; N, 3.87. Found: C, 73.14; H, 7.30; N, 3.74.
4.5.7. Compound 9bab. Yield: 60% as a red solid. Rf: 0.22 (45:55
EtOAc/Hexane). Mp: 118e120 ꢀC. IR (KBr) nmax: 3313, 2956, 1928,
References and notes
2871, 1680, 1620, 1247 cmꢂ1 1H NMR (500 MHz, CDCl3):
d 7.87 (s,
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3. (a) Mammen, M.; Chio, S.-K.; Whitesides, G. M. Angew. Chem., Int. Ed. 1998, 37,
2755e2794; (b) Zhang, S.; Marini, D. M.; Hwang, W.; Santoso, S. Curr. Opin.
Chem. Biol. 2002, 6, 865e871; (c) Xia, Y.; Rogers, J. A.; Paul, K. E.; Whitesides, G.
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Whitesides, G. M. Perspect. Supramol. Chem. 1999, 4, 1e46.
OH, 2H), 7.70 (s, NH, 2H), 7.41 (m, ArH, 12H), 7.17 (m, ArH, 2H), 7.08
(m, ArH, 6H), 6.88 (d, J¼8.5 Hz, ArH, 4H), 6.83 (d, J¼9 Hz, ArH, 4H),
6.64 (s, ArH, 2H), 6.55 (m, ArH, 2H), 6.46 (m, ArH, 2H), 5.73 (bs, CH,
2H), 4.09 (m, ArCH2Ar, 2H), 4.01 (m, ArCH2Ar, 2H), 3.87 (m, OCH2,
4H), 3.82 (s, OCH3, 6H), 3.78 (s, OCH3, 6H), 3.19 (m, ArCH2Ar, 2H),
3.02 (m, ArCH2Ar, 2H), 1.91 (m, CH2, 4H), 1.63 (m, CH2, 4H), 1.04 (m,
CH3, 6H), 0.83 (m, t-Bu, 18H). 13C NMR (125 MHz, CDCl3):
d 170.82
(C]O), 167.8 (C]O), 159.7, 156.5, 152.86, 146.97, 147.2, 135.7, 131.6,
131.56, 131.01, 130.9, 129.9, 128.9, 128.6, 127.6, 127.1, 125.4, 125.1,
121.9, 114.2 (AreC), 76.33, 55.5, 55.3, 33.9, 32.2, 31.4, 31.2, 29.7, 19.4,
14.1 (ArCH2Ar, OCH2, OCH3, CH2, CH3). MS (MALDI-TOF): Calcd for
C90H96N4O12, [MþNa]þ: 1447.7025; Found: 1447.7314.
4. (a) Arduini, A.; Fanni, S.; Manfredi, G.; Pochini, A.; Ungaro, R.; Sicuri, A. R.;
Ugozzoli, F. J. Org. Chem. 1995, 60, 1448e1453; (b) Arora, V.; Chawla, H. M.;
Santra, A. Tetrahedron 2002, 58, 5591e5597.
5. Sansone, F.; Barboso, S.; Casnati, A.; Fabbi, M.; Pochini, A.; Ugozzoli, F.; Ungaro,
R. Eur. J. Org. Chem. 1998, 897e905.
4.5.8. Compound 9bac. Yield: 61% as light red solid. Rf: 0.46 (45:55
EtOAc/Hexane). Mp: 120e123 ꢀC. IR (KBr) nmax: 3284, 2823, 2852,
6. (a) Marra, A.; Scherrmann, M.-C.; Dondoni, A.; Casnati, A.; Minari, P.; Ungaro, R.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2479e2481; (b) Dondoni, A.; Marra, A.;
Scherrmann, M.-C.; Casnati, A.; Sansone, F.; Ungaro, R. Chem.dEur. J. 1997, 3,
1774e1782; (c) Dondoni, A.; Marra, A. Chem. Rev. 2010, 110, 4949e4977.
7. Casnati, A.; Sansone, F.; Ungaro, R. Acc. Chem. Res. 2003, 36, 246e254.
8. Selected reviews on MCRs: (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000,
39, 3168e3210; (b) Ugi, I.; Hech, S. Comb. Chem. High Throughput Screening
2001, 4, 1e34; (c) Ugi, I. Pure Appl. Chem. 2001, 73, 187e191; (d) Orru, R. V. A.;
de Greef, M. Synthesis 2003, 1471e1499; (e) Nair, V.; Rajesh, C.; Vinod, A. U.;
Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. B. Acc. Chem. Res. 2003, 36,
899e907; (f) von Wangelin, A. J.; Neumann, H.; Gordes, D.; Kaus, S.; Strubing,
D.; Beller, M. Chem.dEur. J. 2003, 9, 4286e4294; (g) Zhu, J. Eur. J. Org. Chem.
2003, 1133e1144.
1661, 1643, 1589, 1120 cmꢂ1 1H NMR (500 MHz, CDCl3):
d 8.27 (s,
ArH, 2H), 8.24 (s, OH, 2H), 7.75 (m, ArH, 8H), 7.42 (m, ArH, 14H), 1.17
(m, ArH, 2H), 7.10 (m, ArH, 6H), 6.91 (d, J¼9 Hz, ArH, 4H), 6.67 (s,
ArH, 2H), 6.57 (bs, NH, 2H), 6.46 (m, ArH, 2H), 5.81 (bs, CH, 2H), 4.10
(m, ArCH2Ar, 2H), 4.03 (m, ArCH2Ar, 2H), 3.86 (m, OCH2, OCH3,10H),
3.20 (m, ArCH2Ar, 2H), 3.02 (d, J¼13 Hz, ArCH2Ar, 2H), 1.90 (m, CH2,
4H), 1.63 (m, CH2, 4H), 1.03 (t, J1¼7 Hz, J2¼7.5 Hz, CH3, 6H), 0.84 (m,
t-Bu, 18H). 13C NMR (125 MHz, CDCl3):
d 170.9 (C]O), 168.1 (C]O),
159.8, 152.9, 144.97, 147.2, 136.6, 135.3, 133.88, 131.5, 130.0, 129.0,
128.6, 127.6, 126.9, 126.4, 125.4, 125.3, 124.09, 120.1, 116.7, 114.28
(AreC), 76.35 (OCH2), 55.28 (OCH3), 33.88, 32.2, 31.27, 29.69, 19.36,
14.06 (ArCH2Ar, CH2, CH3, t-Bu). MS (MALDI-TOF): Calcd for
C96H96N4O10, [MþNa]þ: 1487.7126; Found: 1487.8248.
€
9. Ugi, I.; Meyer, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem. 1959, 71, 386.
10. (a) Gutsche, C. D.; Dhawan, B.; Levine, J. A.; No, K. H.; Bauer, L. Tetrahedron 1983,
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1997, 38, 421e424; (c) Creaven, B. S.; Gernon, T. L.; McGinley, J.; Moore, A.-M.;
Toftlund, H. Tetrahedron 2006, 62, 9066e9071.
11. Sarvari, M. H.; Shargi, H. J. Org. Chem. 2006, 71, 6652e6654.
12. For a general review, see: Suginome, M.; Ito, Y. In; Murahashi, S.-I., Ed. Science
of Synthesis; Thieme: Stuttgart, 2004; vol. 19, pp 445e530.
Titration with Analytes: Because of the poor solubility of metal
perchlorates in chloroform, all the UV-visible experiments reported
in this work were carried out in acetonitrile. The UV-visible spectra
13. Lazzaroto, M.; Sansone, F.; Baldini, L.; Casnati, A.; Cozzini, P.; Ungaro, R. Eur. J.
Org. Chem. 2001, 595e602.