Synthesis and click cycloaddition reactions of tetramethoxy- and tetrapropoxy-2-(ω-azidoalkyl)calix[4]arenes

Article abstract of DOI:10.1016/j.tet.2011.07.022

2-(ω-Chloroalkyl)tetramethoxycalix[4]arenes are converted to 2-(ω-azidoalkyl)tetramethoxy- and cone-2-(ω-azidoalkyl) tetrapropoxycalix[4]arenes, the former by substitution and the latter by demethylation to 2-(ω-chloroalkyl)tetrahydroxycalix[4]arenes, whi

Full text of DOI:10.1016/j.tet.2011.07.022

Tetrahedron 67 (2011) 7027e7034
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and ‘click’ cycloaddition reactions of tetramethoxy- and
tetrapropoxy-2-(u-azidoalkyl)calix[4]arenes
Michael J. Hardman a, Ashley M. Thomas a, Louise T. Carroll a, Linus C. Williams a, Sean Parkin b,
,
Jordan L. Fantini a
*
a Department of Chemistry and Biochemistry, Ebaugh Laboratories, Denison University, Granville, OH 43023, USA
b Department of Chemistry, University of Kentucky, Lexington, KY 40536, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2011
Received in revised form 8 July 2011
Accepted 8 July 2011
Available online 19 July 2011
2-(
2-(
to 2-(
u
u
-Chloroalkyl)tetramethoxycalix[4]arenes are converted to 2-(
-azidoalkyl)tetrapropoxycalix[4]arenes, the former by substitution and the latter by demethylation
-chloroalkyl)tetrahydroxycalix[4]arenes, which are O-propylated before substitution of azide for
u-azidoalkyl)tetramethoxy- and cone-
u
chloride. The azide-terminated calixarenes undergo Cu(I)-catalyzed 1,3-cycloaddition to terminal alkynes
to give 1,4-disubstituted 1,2,3-triazoles, demonstrating the potential to couple calixarenes from a tether
at the 2-position (methylene bridge) to substrates that bear a terminal alkyne group. The cone confor-
mation of cone-2-(4-chlorobutyl)tetrapropoxycalix[4]arene has been confirmed by X-ray diffraction.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Atropisomerism
Azides
Calixarenes
Click chemistry
1. Introduction
of atropisomers because the bulk of the propyl group prevents aryl
group rotation through the annulus of the calixarene.6
Calix[n]arenes are cyclic oligomers obtained from the base-
catalyzed condensation of para-substituted alkyl phenols (typi-
cally p-tert-butylphenol) with formaldehyde, where n denotes the
number of repeating units in the molecules.1 The preferred con-
formation of tetrahydroxy-p-tert-butylcalix[4]arene (1, Fig. 1)2 is
the so-called cone conformation, stabilized by intramolecular hy-
drogen bonds3 of the phenolic groups at the narrow rim (or lower
rim). The C-alkyl groups occupy the wide rim (or upper rim). O-
Alkylation of the phenols imparts comparable stability to the con-
formations shown in Fig. 1dthe partial cone (paco), 1,2-alternate
(1,2-alt), and 1,3-alternate (1,3-alt).4
In the series of tetra(alkyl)calixarenes 2-R, accessed by O-al-
kylation of 1 (Fig. 2), the rate of interconversion of atropisomers
depends on the size of the alkyl group. Interconversion is swift for
2-Me, occurs at elevated temperatures for 2-Et, and is effectively
prohibited for 2-Pr (and similar species with larger R groups).5 For
this project, we studied calixarene derivatives where in-
terconversion would either be facile (derivatives of 2-Me) or not
occur at all (derivatives of 2-Pr). Syntheses of derivatives of 2-Pr by
tetrapropylation of a tetrahydroxycalixarene can lead to mixtures
Calixarene-forming condensation works with formaldehyde and
no other aldehydes and is only high-yielding with p-tert-butylphe-
nol.7 As a result, a rich body of chemistry has developed around the
modification of 1. Typical transformations at the upper rim involve
electrophilic aromatic substitution, for example, dealkylation8 or ni-
tration9 of the aryl ring. Entry to modifications at the lower rim often
start with O-alkylation of the phenolic groups.10 The chemistry of the
methylene group linking the calixarene aromatic rings is much less
developed even though selective substitution at that position could
alter calixarene solubility or flexibility and provide a point for con-
nection to surfaces and other molecules. Early efforts to incorporate
alkyl groups at one or more bridge positions were by a ‘fragment-
condensation’ pathway in which smaller unitsdat least one bearing
a bridge substituentdwere independently synthesized then brought
together by condensation.11 In contrast, our research has centered on
the direct, selective installation of a single substituent at the
methylene-bridge position of the calix[4]arene by
a depro-
tonationealkylation sequence.12 Our first report detailed the in-
stallation of an alkyl or carboxy group at the 2-position of
tetramethoxycalix[4]arene.12a Recently we have described the syn-
thesis and characterization of a series of functional group tether cal-
ixarenesdcompounds with a 3e6 methylene chain terminating in
a functional group (chloro, iodo, alkyl or aryl amine) starting from
* Corresponding author. Tel.: þ1 740 587 6491; fax: þ1 740 587 6673; e-mail
tetramethoxycalix[4]arene and a 1-bromo-u
-chloroalkane.12b Other
addresses: s.parkin@uky.edu (S. Parkin), fantinij@denison.edu (J.L. Fantini).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.022

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M.J. Hardman et al. / Tetrahedron 67 (2011) 7027e7034
Fig. 1. The four major conformations of p-tert-butylcalix[4]arenes (1: R¼H).
as described below. The preparation of rigid tetrapropoxy bridge-
substituted calixarenes (8) was complicated by the failure of direct
deprotonationealkylation of 2-Pr, which yielded no C-alkylated
products. The products recovered when 2-Pr in THF was treated with
a solution of n-butyllithium in hexanes followed by attempted al-
kylation with MeI were ca. 95% 2-Pr and ca. 5% cone-25,26,27-
tripropoxy-28-hydroxy-p-tert-butylcalix[4]arene (3).25 The conver-
sion of 2-Pr to 3 increased to 81% (19% unreacted 2-Pr) when the re-
action was carried out in hexanes. The appearance of 3 in these
reactions likely begins with formation of the bridge-lithiated calix-
Fig. 2. Alkylation of tetrahydroxy-p-tert-butylcalix[4]arene (1) with excess alkyl halide
(methyl or 1ꢁ) and strong base (e.g., NaH) yields tetraalkylcalix[4]arenes. Mixtures of
atropisomers are possible for RsMe.
arene, followed by intramolecular b-elimination (Fig. 4). Modifica-
tions to the solvent or base were not likely to prevent this undesired
reaction, thus we prepared bridge-substituted tetrapropoxycalixar-
enes by an O-dealkylationerealkylation sequence on bridge-
substituted tetramethoxycalixarenes.
reactions that install groups at the bridge position include the anionic
ortho-Fries rearrangement,13 addition to a spirodienone calixarene
derivative,14 and tetrabromination15 followed by nucleophilic sub-
stitution.16 The bridge position can alsobeoxidized to a ketone,17 then
further transformed by an addition reaction at that site.18
2.1. Lower-rim reactions of (chloroalkyl)calixarenes
The Huisgen19 1,3-dipolar cycloaddition of azides and terminal
alkynes to give 1,2,3-triazoles is widely considered the prototypical
‘click’ reaction.20 The cycloaddition is regiospecific when catalyzed
by Cu(I), affording 1,4-substituted triazoles under mild condi-
tions.21 Calixarenes with upper- or lower- rim azide22 and alkyne23
groups have been employed in this click reaction. In this paper we
extend calixarene click chemistry to the methylene bridge with the
synthesis of flexible (tetramethoxy) and rigid (cone-tetrapropoxy)
To prepare bridge-substituted tetrapropoxycalixarenes from
analogous tetramethoxycalixarenes requires that the bridge sub-
stituent react with neither the reagents for O-dealkylation (strong
Lewis acid)26 nor the reagents for ether synthesis (strong Brønsted
base).8 The alkyl chloride tether 4 was expected to fulfill these
conditions as shown in Fig. 5.
2.2. Demethylation of tetramethoxy(chloroalkyl)calixarenes
u
-azidoalkyl calixarenes. Calixarenes with azide tethers provide
the potential for anchoring a calixarene to a solid support, attaching
a chromophore or reactive species, or a complementary element at
a position that does not occupy the upper or lower rims. The azide
element is ‘orthogonal’ to many chemical transformations,20 and
should allow for modifications at the calixarene. We demonstrate
The tetramethoxycalixarene 4 was demethylated by treatment
with the strong Lewis acid BBr3 (CH2Cl2, ꢀ78 ꢁC).26 Colorless, mi-
crocrystalline tetrahydroxycalixarenes with chloroalkyl chain
lengths of 3e5 (5aec) were obtained after workup and re-
crystallization from methanol. The NMR spectra (CDCl3) of 5a to 5c
were consistent with the expected cone conformation, which is
stabilized preferentially by intramolecular hydrogen bonding,3
with the tether group in an equatorial position.27 Two signals,
rather than four, are observed for the tert-butyl groups, indicating
molecular Cs symmetry. (In some bridge-substituted calixarenes,
the signals for all the tert-butyl groups are accidentally equivalent.)
The equatorial disposition of the tether is confidently inferred by
the 1H NMR signal of the methyne hydrogen residing on the same
carbon. The tether occupies the equatorial position in all of the cone
calixarenes described herein. These calixarenes have very similar
NMR signals arising from the calixarene moiety, but distinctions are
the cycloaddition of u-azidoalkyl calixarenes with terminal alkynes
to give 1,4-substituted 1,2,3-triazoles as shown in Fig. 3.
In this system, the attachment of the tether, whose length is
easily varied, is accomplished without taking up a position on the
upper or lower rims of the calixarene. At the methylene-bridge
position, the tether is not expected to appreciably perturb the
conformation of a calixarene vis a vis its unsubstituted analog.24
2. Results and discussion
The flexible
u-azidoalkyl calixarenes (6) were prepared by routine
transformationsatthe
u-carbonofthemethylene-bridgesubstituent,
noted for signals from the tether, especially at the u
-position.12b
Fig. 3. Desired
u-azidoalkyl calixarenes and expected reaction products from Cu(I)-catalyzed cycloaddition to terminal alkynes.

M.J. Hardman et al. / Tetrahedron 67 (2011) 7027e7034
7029
Fig. 4. The deprotonation of tetrapropoxy-p-tert-butylcalix[4]arene (2-Pr) generates a lithium-stabilized carbanion, which intramolecularly attacks a lower rim substituent. The net
result is a selective single dealkylation at the lower rim.
Fig. 5. Dealkylation of the calix[4]arene 4, followed by realkylation with sodium hydride and propyl iodide gives a tetrapropoxycalixarene with a cone conformation and the tether
in the equatorial position. The letter indicates the length of the alkyl chain (a: n¼3; b: n¼4; c: n¼5).
2.3. Tetrapropylation of tetrahydroxy(chloroalkyl)calixarenes
Exhaustive alkylation of a tetrahydroxycalix[4]arene with pro-
pyl iodide can give different atropisomers because the propyl group
is too large to fit through the annulus of the calixarene.6 Literature
precedent for direct and selective synthesis of the cone atropisomer
of 2-Pr is inconsistent. For example, Reinhoudt28 reported 100%
selectivity for the cone atropisomer while Shinkai25 obtained
a 55:45 paco/cone mixture under ostensibly similar conditions. We
attempted propylations of 5aec using a literature procedure for the
propylation of 25,26,27,28-tetrahydroxycalix[4]arene (no para tert-
butyl groups), which yields the cone atropisomer of 25,26,27,28-
tetrapropoxycalix[4]arene.8 In our hands, this procedure for alkyl-
ation applied to 5aec gave predominantly the cone atropisomer of
6aec with variable amounts (10e30%) of other atropisomers, as
judged by the signals in the 1H NMR spectra of the products. The
major signals were consistent with the Cs-symmetric cone atro-
Fig. 6. Thermal ellipsoid plot (50% probability) of 6b. Hydrogen atoms, minor com-
ponents of disordered groups, and chloroform solvent of crystallization molecules are
omitted to enhance clarity.
pisomer with an equatorial tether. (Percent cone atropisomer was
estimated by integrations of signals in the aromatic region of the 1H
NMR spectra of the products.) Because the cone conformation of
calix[4]arenes is templated by the Naþ ion,29 we modified the lit-
erature protocol, adding 2 equiv of Naþ (from NaCl) to the reaction
mixture prior to the addition of calixarene. Percent cone atro-
pisomer of tetrapropoxycalix[4]arenes 6aec increased from
75e92% without extra Naþ to 92e95% cone with extra Naþ. Prod-
ucts obtained with the modified process were carried forward in
syntheses. No products arising from intramolecular O-alkylation
with the alkyl chloride tether moiety were detected. The tetra-
propoxy compounds are colorless powders obtained by pre-
2.4. 2-(5-Iodopentyl)tetrapropoxy-p-tert-butylcalixarene (7)
Although the chloroalkyl compounds 4 and 6 are well suited for
substitution at the chloride position, as described below, it will be
advantageous in future work to have a better leaving group in place
of the chloride at the tether’s end. As an example, the 1ꢁ iodo
compound 2-(5-iodopentyl)tetrapropoxy-p-tert-butylcalix[4]arene
(7) was prepared from the corresponding chloroalkyl species 6c by
the Finkelstein reaction.30 As expected from the similar reactions
cipitation from
a DMF/methanol solvent mixture; samples
recrystallized from methanol/dichloromethane were not further
enriched in cone atropisomer.
on
u
-chloroalkyltetramethoxycalixarenes,12b treatment of 6c with
As described above, the cone conformation for 6aec was infer-
red from 1H and 13C NMR spectra; it was verified for 6b by a single
crystal X-ray diffraction structure determination (Fig. 6). The crystal
structure of 6b exhibits substantial disorder of tert-butyl groups
and of the chlorobutyl group with chloroform solvent molecules.
Because of this disorder, manifest in poor observation of high-angle
reflections, little confidence is placed on individual bond lengths or
angles in the structure solution. Nevertheless, the connectivity and
gross geometry (cone conformation) of 6b is unequivocally con-
firmed by the X-ray crystal structure.
excess NaI in 2-butanone gave 7 in 61% yield after workup and
recrystallization (Fig. 7).
2.5. (u-Azidoalkyl)calixarenes
(u
-Azidoalkyl)calixarenes are easily obtained by treatment of
the corresponding (u-chloroalkyl)calixarenes with NaN3 and NaI in
warm DMF (ca. 90e120 ꢁC; ca. 14 h; Fig. 8). The azide compounds
are obtained as colorless microcrystalline solids in good yields.

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M.J. Hardman et al. / Tetrahedron 67 (2011) 7027e7034
Fig. 7. The Finkelstein reaction was used to produce 2-(5-iodopentyl)tetrapropoxy-p-tert-butylcalix[4]arene (7).
Fig. 8. Preparation of
u
-azidoalkyl calixarenes by substitution. The letter indicates the length of the alkyl chain (a: n¼3; b: n¼4; c: n¼5).
The NMR spectra of 8 and 9 (1H and 13C) are similar to those
from the starting ( -chloroalkyl)calixarenes. The progress and
typically 40e70%; the exceptionally low yield for 11a reflects ma-
terial loss during recrystallization. The products and yields are
summarized in Fig. 9. The 1H NMR spectra of 10e13 show signals
indicative of molecular Cs symmetry and the presence of the tri-
azole ring with a characteristic signal for the 5-hydrogen around
u
completion of this reaction (and other transformations at the
u
u
-
-
position) are judged by the 1H NMR signals of the protons on the
carbon. The reactant (8) and product (9) calixarenes show virtually
identical behavior in thin layer chromatography.
d 7.9 ppm.
2.6. Click reactions of (
u-azidoalkyl)calixarenes
3. Conclusion/summary
The -azidocalixarenes 8 and 9 are easily converted to triazoles
u
The utility of alkyl-tethered functional groups at a single
methylene bridge of a calix[4]arene has been extended to include
by the Cu(I)-catalyzed Staudinger ligation with both aryl and alkyl
terminal alkynes. Calixarenes 8 and 9 showed adequate solubility in
a tert-butyl alcoholewater mixture (4:1) at 75 ꢁC so that the re-
action catalyzed by Cu(I) (generated from Cu powder and CuSO4)
proceeded smoothly and was complete in about 16 h. Despite the
elevated temperature used to dissolve the calixarene, only the 1,4-
disubstituted triazole was detected by 1H NMR spectroscopy. The
triazoles were reluctant to crystallize and were usually obtained
and purified by trituration with methanol. The yields were fair,
the
(u-azido)alkyl group on tetramethoxy- and cone-
tetrapropoxycalixarenes, thus broadening the scope of how
a bridge tether can be used. Tether calixarenes with all upper- and
lower-rim sites available for elaboration will allow for connection
to a solid support or to various biologically relevant molecules
functionalized with an alkyne group. By virtue of the ‘orthogonal
nature’ of the azide group, these azido-terminated species will al-
low for a range of transformations at the other reactive sites on the
Fig. 9. Copper(I)-catalyzed 1,3-cycloaddition of calixarene azides to terminal alkynes yields 1,4-substituted 1,2,3-triazoles. The letter indicates the length of the alkyl chain (a: n¼3;
b: n¼4; c: n¼5).

M.J. Hardman et al. / Tetrahedron 67 (2011) 7027e7034
7031
calixarene before the azide group engages in a ‘click’ reaction with
(100 MHz), CDClC NMR (100 MHz, CDCl3)
d
146.8, 146.7, 144.5,
a terminal alkyne. The potential utility of these species has been
demonstrated with representative click couplings of the (u-azido)
alkylcalixarenes with both aryl and alkyl terminal alkynes.
4. Experimental section
144.3, 130.8, 127.7, 127.5, 127.4, 125.9, 125.3, 121.7, 44.7, 35.5, 34.2,
34, 32.8, 32.7, 32.5, 31.5, 31.4(2), 25.3; HRMS calculated for
C48H63ClNaO4 [MþNa]þ: 761.4313, found 761.3788.
4.2.3. 2-(5-Chloropentyl)tetrahydroxy-p-tert-butylcalix[4]arene
(5c). Reagents: 4c (3.66 g, 4.52 mmol); BBr3 (2.8 mL, 30 mmol).
4.1. General considerations
Yield: 2.96 g (86.9%); 1H NMR (400 MHz, CDCl3)
d 10.28 (s, 4H), 7.09
(d, J¼2.2 Hz, 2H), 7.07 (d, J¼2.4 Hz, 2H), 7.05 (d, J¼2.4 Hz, 2H), 6.99
(d, J¼2.2 Hz, 2H), 4.48 (t, J¼7.8 Hz, 1H), 4.26 (d, J¼13.9 Hz, 1H), 4.24
(d, J¼13.9 Hz, 2H), 3.51 (t, J¼6.7 Hz, 2H), 3.47 (d, J¼13.8 Hz, 3H), 2.19
(‘quartet’, J¼7.7 Hz, 2H), 1.77 (‘quintet’, J¼7.1 Hz, 2H), 1.56e1.46 (m,
2H,), 1.39e1.30 (m, 2H), 1.22 (s, 18H), 1.20 (s, 18H); 13C NMR
Compounds 7e13 were synthesized under ambient atmosphere
while compounds 5 and 6 were synthesized using standard Schlenk
techniques. The solvents and reagents were purchased from com-
mercial suppliers and used as received. CD3CN and CDCl3 (with
0.03% SiMe4) were purchased from Aldrich or Fisher and used as
received. 1H and 13C NMR data were obtained on a 400 MHz Bruker
Avance NMR spectrometer at ambient temperature. NMR spectra of
tetramethoxycalixarenes 1, 8aec, 10aec, and 12aec were obtained
using a mixture of CDCl3/CD3CN (3:1) containing NaI (1 g per 80 mL
solution). NMR spectra of other calixarenes were obtained in CDCl3.
1H NMR shifts are given relative to SiMe4 (0.00 ppm) and 13C NMR
shifts are given relative to CDCl3 (77.0 ppm). High resolution time-
of-flight or quadrupole mass spectra were obtained using electro-
spray ionization by the Campus Chemical Instrument CenterdMass
Spectrometry & Proteomics Facility at The Ohio State University.
Electrospray samples were prepared by dissolving the calixarene in
methanol and, in some cases, adding an NaI internal standard.
The X-ray structure determination was performed at the University
of Kentucky. cone-Tetrapropoxy-p-tert-butylcalix[4]arene,8 and
chloroalkyltetramethoxycalix[4]arenes12b were prepared as pre-
viously reported.
(100 MHz, CDCl3)
d 146.8, 146.7, 144.4, 144.3, 131.1, 127.8, 127.5,
127.3,126.0,125.9,125.2,121.7, 45.0, 35.5, 34.2, 34.0, 32.8, 32.7, 32.4,
32.1, 31.4, 27.3, 26.8; HRMS calculated for C49H65ClNaO4 [MþNa]þ:
775.4469, found 775.4442.
4.3. General procedure for the synthesis of 2-(
u-chloroalkyl)
tetrapropoxy-p-tert-butylcalix[4]arenes (6aec)8
A Schlenk vessel (typically 125 mL size to accommodate foam-
ing) was charged with 5 and a 60% dispersion of NaH in mineral oil
(10.4 equiv) under an inert atmosphere. To remove the mineral oil,
the NaH was washed with three portions of hexanes. To the vessel
was added DMF (ca. 4 mL per mmol calixarene) and NaCl (2 equiv).
After the resulting slurry was cooled to 0 ꢁC, 1-iodopropane was
added (10.3 equiv) to the mixture, followed by additional DMF (ca.
4 mL per mmol calixarene). After at least 14 h stirring at ambient
temperature the reaction mixture was vented and the excess NaH
was quenched by the slow addition of 2 M HCl (ca. 16 mL per mmol
calixarene). The crude product precipitated from the reaction
mixture, was collected by filtration, and washed with water (ca.
15 mL per mmol calixarene). Pure 6 was obtained after trituration
with methanol and filtration.
4.2. General procedure for the synthesis of 2-(
u-chloroalkyl)
tetrahydroxy-p-tert-butylcalix[4]arenes26 (5aec)
To a solution of 4 in CH2Cl2 (ca. 20 mL per mmol of calixarene)
cooled to ꢀ78 ꢁC under a nitrogen or argon atmosphere, BBr3, neat,
or as a 1 M solution in CH2Cl2 (6.5 equiv) was added by disposable
plastic syringe. The resulting mixture was kept at ꢀ78 ꢁC for
30e90 min then at ambient temperature for 14e20 h. The mixture
was quenched with saturated NaHCO3 (ca. 20 mL per mmol calix-
arene). The organic phase was washed with saturated NaHCO3
(1ꢂ10 mL per mmol calixarene), water (2ꢂ15 mL per mmol calix-
arene), then dried over MgSO4 and concentrated under reduced
pressure to obtain 5, which was recrystallized from methanol as
colorless microcrystals.
4.3.1. 2-(3-Chloropropyl)tetrapropoxy-p-tert-butylcalix[4]arene
(6a). Reagents: 5a (1.30 g, 1.79 mmol), NaH, 60% in oil (0.806 g,
33.6 mmol), NaCl (0.211 g, 3.61 mmol), 16 mL DMF total, 1-
iodopropane (1.8 mL, 18 mmol). Yield: 1.313 g (82.0%); 1H NMR
(400 MHz, CDCl3)
d
6.780 (d, J¼2.4 Hz, 2H), 6.777 (s, 4H), 6.76 (d,
J¼2.4 Hz, 2H), 4.78 (t, J¼8.1 Hz, 1H), 4.39 (d, J¼12.4 Hz, 3H), 3.9e3.7
(m, 8H), 3.63 (t, J¼6.4 Hz, 2H), 3.12 (d, J¼12.5 Hz, 2H), 3.10 (d,
J¼12.5 Hz, 1H), 2.16e2.08 (m, 2H), 2.08e1.98 (m, 8H), 1.98e1.88 (m,
2H),1.08 (s,18H),1.07 (s,18H),1.03 (t, J¼7.4 Hz, 6H), 0.99 (t, J¼7.4 Hz,
4.2.1. 2-(3-Chloropropyl)tetrahydroxy-p-tert-butylcalix[4]arene
(5a). Reagents: 4a (3.15 g, 4.03 mmol); BBr3 (2.48 mL, 26.2 mmol).
Yield: 2.07 g (70.8%); 1H NMR (400 MHz, CDCl3)
d
10.28 (s, 4H), 7.11
6H).13C NMR (100 MHz, CDCl3)
d 153.72,153.67,144.26,144.19,136.3,
(d, J¼1.9 Hz, 2H), 7.07 (d, J¼2.2 Hz, 2H), 7.05 (d, J¼2.1 Hz, 2H), 7.00 (d,
J¼2.0 Hz, 2H), 4.51 (t, J¼7.8 Hz, 1H), 4.25 (d, J¼13.9 Hz, 1H), 4.24 (d,
J¼13.9 Hz, 2H), 3.59 (t, J¼6.3 Hz, 2H), 3.48 (d, J¼13.9 Hz, 3H), 2.36
(‘quartet’, J¼7.6 Hz, 2H),1.85e1.76 (m, 2H),1.22 (s,18H),1.20 (s,18H).
133.9, 133.73, 133.70, 124.9, 124.82, 124.75, 121.7, 77.2, 76.9, 45.4,
35.6, 34.0, 33.8, 31.71, 31.66, 31.51, 31.47, 31.17, 31.09, 23.5, 23.3,10.4,
10.3; HRMS calculated for C59H85ClNaO4 [MþNa]þ: 915.6034, found
915.6041.
13C NMR (100 MHz, CDCl3)
d 146.8, 146.7, 144.6, 144.4, 130.5, 127.7,
127.5, 127.4, 126.0, 125.4, 121.7, 45.0, 35.0, 34.2, 34.0, 32.7, 32.7, 31.4,
31.4, 31.1, 29.4; HRMS calculated for C47H62ClO4 [MþH]þ: 725.4337;
for C47H61ClNaO4 [MþNa]þ: 747.4156, found 725.4344; 747.4141.
4.3.2. 2-(4-Chlorobutyl)tetrapropoxy-p-tert-butylcalix[4]arene
(6b). Reagents: 5b (0.750 g, 1.02 mmol), NaH, 60% in oil (0.80 g,
33 mmol), NaCl (0.142 g, 2.43 mmol), 9 mL DMF total, 1-
iodopropane (1.0 mL, 10 mmol). Yield: 0.601 g (65%); 1H NMR
4.2.2. 2-(4-Chlorobutyl)tetrahydroxy-p-tert-butylcalix[4]arene
(5b). Reagents: 4b (1.072 g, 1.348 mmol); 1 M BBr3 in CH2Cl2
(10 mL, 10 mmol). Yield: 0.502 g (50.4%); 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d
6.78 (d, J¼2.8 Hz, 2H), 6.77 (d, J¼2.8 Hz, 2H),
6.76 (d, J¼2.4 Hz, 2H), 6.75 (d, J¼2.4 Hz, 2H), 4.76 (t, J¼8.1 Hz, 1H),
4.39 (d, J¼12.4 Hz, 3H), 3.9e3.7 (m, 8H), 3.56 (t, J¼6.8 Hz, 2H), 3.11
(d, J¼12.5 Hz, 2H), 3.10 (d, J¼12.4 Hz, 1H), 2.11e1.94 (m, 10H), 1.88
(‘quintet’, 2H), 1.64e1.56 (m, 2H), 1.08 (s, 18H), 1.06 (s, 18H), 1.03 (t,
J¼7.6 Hz, 6H), 1.00 (t, J¼7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
10.28 (s, 4H), 7.09 (d, J¼2.2 Hz, 2H), 7.07 (d, J¼2.4 Hz, 2H), 7.05 (d,
J¼2.3 Hz, 2H), 7.00 (d, J¼2.2 Hz, 2H), 4.49 (t, J¼7.8 Hz, 1H), 4.26 (d,
J¼13.9 Hz, 1H), 4.24 (d, J¼13.9 Hz, 2H), 3.52 (t, J¼6.7 Hz, 2H), 3.48
(d, J¼13.8 Hz, 3H), 2.21 (‘quartet’, J¼7.7 Hz, 2H), 1.85 (‘quintet’,
J¼7.1 Hz, 2H), 1.52e1.42 (m, 2H), 1.22 (s, 18H), 1.20 (s, 18H). 13C NMR
d
153.71, 153.66, 144.2(2), 136.6, 133.9, 133.8, 133.7, 124.9, 124.8,
124.6, 121.7, 77.2, 77.0, 44.9, 36.2, 33.9, 33.8, 33.6, 33.0, 31.51, 31.47,

7032
M.J. Hardman et al. / Tetrahedron 67 (2011) 7027e7034
31.1, 31.0, 25.8, 23.5, 23.3, 10.4, 10.3; HRMS calculated for
CD3CN/NaI) d 150.0, 148.1, 147.9, 136.9, 133.91, 133.86, 133.8, 125.4,
C60H87ClNaO4 [MþNa]þ: 929.6191, found 929.6183.
125.3, 125.2, 124.5, 121.5, 64.2, 63.9, 50.5, 34.5, 33.6, 33.5, 30.19,
30.18, 30.1, 29.1, 28.9, 27.4; HRMS calculated for C51H69N3NaO4
[MþNa]þ: 810.5186, found 810.5186.
4.3.3. 2-(5-Chloropentyl)tetrapropoxy-p-tert-butylcalix[4]arene
(6c). Reagents: 5c (3.753 g, 4.988 mmol), NaH, 60% in oil (2.564 g,
107 mmol), NaCl (0.705 g, 12.1 mmol), 42 mL DMF total, 1-
iodopropane (4.9 mL, 50 mmol). Yield: 3.455 g (75.2%); 1H NMR
4.5.2. 2-(4-Azidobutyl)tetramethoxy-p-tert-butylcalix[4]arene
(8b). Reagents: 4b (3.825 g, 4.808 mmol), NaI (1.436 g,
9.580 mmol), NaN3 (0.627 g, 9.64 mmol), 60 mL DMF. Yield:
(400 MHz, CDCl3)
d
6.78 (d, J¼2.7 Hz, 2H), 6.773 (d, J¼2.7 Hz, 2H),
6.770 (d, J¼2.3 Hz, 2H), 6.75 (d, J¼2.3 Hz, 2H), 4.75 (t, J¼8.1 Hz, 1H),
4.40 (d, J¼12.4 Hz, 3H), 3.90e3.64 (m, 8H), 3.53 (t, J¼6.7 Hz, 2H), 3.11
(d, J¼12.5 Hz, 2H), 3.10 (d, J¼12.4 Hz, 1H), 2.11e1.94 (m, 10H),
1.85e1.75 (m, 2H), 1.64e1.50 (m, 4H), 1.08 (s, 18H), 1.06 (s, 18H), 1.03
(t, J¼7.4 Hz, 6H), 1.00 (t, J¼7.4 Hz, 6H). 13C NMR (100 MHz, CDCl3)
2.88 g (74.7%); 1H NMR (400 MHz, CDCl3/CD3CN/NaI)
d 7.24 (d,
J¼2.4 Hz, 2H), 7.23 (s, 4H), 7.22 (d, J¼2.2 Hz, 2H), 4.66 (t, J¼8.3 Hz,
1H), 4.27 (d, J¼12.4 Hz, 3H), 4.15 (s, 6H), 4.14 (s, 6H), 3.47 (d,
J¼12.4 Hz, 2H), 3.46 (d, J¼12.4 Hz, 1H), 3.31 (t, J¼6.8 Hz, 2H),
2.21e2.14 (m, 2H), 1.70 (‘quintet’, J¼7.2, 2H), 1.44e1.39 (m, 2H),
1.208 (s, 18H), 1.206 (s, 18H); 13C NMR (100 MHz, CDCl3/CD3CN/
d
153.74,153.67,144.15,144.12,136.8,133.9,133.8,133.6,124.9,124.8,
124.5,121.7, 77.1, 76.9, 45.1, 36.1, 34.2, 33.9, 33.8, 32.6, 31.5, 31.2, 31.0,
27.8, 27.3, 23.5, 23.3, 10.4, 10.3; HRMS calculated for C61H89ClNaO4
[MþNa]þ: 943.6347, found 943.6364.
NaI) d 150.0, 148.1, 148.0, 137.2, 133.9, 133.8, 125.4, 125.0, 121.6,
64.1, 63.9, 50.2, 34.9, 33.6, 33.5, 32.6, 30.23, 30.19, 29.1, 29.0, 28.1,
25.2; HRMS calculated for C52H71N3NaO4 [MþNa]þ: 824.5342,
found 824.5275.
4.4. cone-2-(5-Iodopentyl)tetrapropoxy-p-tert-butylcalix[4]
arene (7)
4.5.3. 2-(5-Azidopentyl)tetramethoxy-p-tert-butylcalix[4]arene
(8c). Reagents: 4c (2.026 g, 2.502 mmol), NaI (0.504 g, 3.36 mmol),
NaN3 (0.325 g, 5.00 mmol), 100 mL DMF. Yield: 0.935 g (45.8%); 1H
Sodium iodide (0.692 g, 4.616 mmol) and 6c (2.128 g,
2.308 mmol) were combined in 2-butanone (75 mL) in a round-
bottom flask. The resulting mixture was heated under reflux for 7
days after which the volatiles were removed under reduced pres-
sure and the reaction mixture was partitioned between water and
dichloromethane. The organic phase was washed with water (2ꢂ),
dried over MgSO4, and evaporated to dryness under reduced
pressure. Recrystallization from methanol afforded a colorless mi-
crocrystalline powder, dried in vacuo to recover 1.438 g of 7 (61.5%).
NMR (400 MHz, CDCl3/CD3CN/NaI)
d
7.24 (d, J¼2.2 Hz, 2H), 7.23 (s,
4H), 7.21 (d, J¼2.2 Hz, 2H), 4.65 (t, J¼8.2 Hz, 1H), 4.27 (d, J¼12.4 Hz,
3H), 4.15 (s, 6H), 4.13 (s, 6H), 3.47 (d, J¼12.4 Hz, 2H), 3.46 (d,
J¼12.5 Hz, 1H), 3.27 (t, J¼6.8 Hz, 2H), 2.29e2.10 (m, 2H), 1.61
(‘quintet’, J¼7.1, 2H), 1.53e1.43 (m, 2H), 1.42e1.33 (m, 2H), 1.206 (s,
36H); 13C NMR (100 MHz, CDCl3/CD3CN/NaI)
d 150.0, 148.0, 147.9,
137.3, 133.9, 133.8, 125.4, 125.0, 121.6, 64.1, 63.9, 50.4, 34.8, 33.0,
29.1, 29.0, 27.7, 27.6, 26.0; HRMS calculated for C53H73N3NaO4
[MþNa]þ: 838.5499, found 838.5480.
1H NMR (400 MHz, CDCl3)
d
6.78 (d, J¼2.7 Hz, 2H), 6.773 (d,
J¼2.7 Hz, 2H), 6.766 (d, J¼2.7 Hz, 2H), 6.75 (d, J¼2.3 Hz, 2H), 4.74 (t,
J¼8.1 Hz, 1H), 4.40 (d, J¼12.4 Hz, 3H), 3.90e3.70 (m, 8H), 3.19 (t,
J¼7.0 Hz, 2H), 3.11 (d, J¼12.4 Hz, 2H), 3.10 (d, J¼12.5 Hz, 1H),
2.11e1.92 (m, 10H), 1.85 (‘quintet’, J¼7.0, 2H), 1.53e1.43 (m, 4H),
1.08 (s, 18H), 1.07 (s, 18H), 1.03 (t, J¼7.5 Hz, 6H), 0.99 (t, J¼7.5 Hz,
4.5.4. 2-(3-Azidopropyl)tetrapropoxy-p-tert-butylcalix[4]arene
(9a). Reagents: 6a (3.005 g, 3.36 mmol), NaI (1.007 g, 6.718 mmol),
NaN3 (0.434 g, 6.68 mmol), 60 mL DMF. Yield: 1.485 g (49.1%); 1H
NMR (400 MHz, CDCl3)
d
6.78 (s, 4H), 6.77 (s, 4H), 4.77 (t, J¼8.2 Hz,
6H); 13C NMR (100 MHz, CDCl3)
d
153.75, 153.68, 144.15, 144.13,
1H), 4.39 (d, J¼12.4 Hz, 3H), 3.80 (m, 8H), 3.36 (t, J¼6.7 Hz, 2H), 3.12
(d, J¼12.6 Hz, 2H), 3.10 (d, J¼12.5 Hz, 1H), 2.10e1.98 (m, 10H),
1.79e1.72 (m, 2H), 1.08 (s, 18H), 1.07 (s, 18H), 1.03 (t, J¼7.6 Hz, 6H),
136.8, 133.9, 133.8, 133.6, 124.9, 124.8, 124.6, 121.7, 77.14, 76.9, 36.2,
34.2, 33.9, 33.8, 33.5, 31.55, 31.47, 31.2, 31.1, 31.0, 27.5, 23.5, 23.3,
10.5, 10.3, 7.0; HRMS calculated for C61H89INaO4 [MþNa]þ:
1035.5703, found 1035.5699.
0.99 (t, J¼7.5 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 153.70, 153.65,
144.26, 144.18, 136.3, 133.9, 133.7, 124.9, 124.8, 124.8, 121.6, 51.74,
35.89, 33.95, 33.81, 31.49, 31.46, 31.41, 31.1, 31.0, 28.0, 23.5, 23.3,
10.4, 10.3. Mp 179e184 ꢁC. HRMS calculated for C59H85N3NaO4
[MþNa]þ: 922.6438, found 922.6396.
4.5. General procedure for the synthesis of 2-(u-azidoalkyl)
tetraalkoxy-p-tert-butylcalix[4]arenes (8aec and 9aec)
A reaction mixture of 4 or 6 (1 equiv), NaI (2 equiv), and NaN3
(2 equiv) was prepared in DMF (ca. 20e65 mL per mmol calixarene)
and heated at ca. 90e120 ꢁC for 24 h in a round-bottom flask. After
completion of the reaction, as judged by 1H NMR spectrometry, the
reaction mixture was cooled to room temperature, diluted with
diethyl ether (ca. 10 mL per mmol calixarene), and washed with
saturated ammonium chloride (3ꢂ; ca.10 mL per mmol calixarene).
The aqueous extracts were back-extracted with diethyl ether (2ꢂ;
ca. 10 mL per mmol calixarene) after which all organic fractions
were combined, dried over MgSO4, and evaporated under reduced
pressure to afford the crude product. Recrystallization from
methanol yielded colorless, microcrystalline 8 or 9.
4.5.5. 2-(4-Azidobutyl)tetrapropoxy-p-tert-butylcalix[4]arene
(9b). Reagents: 6b (0.139 g, 0.153 mmol), NaI (0.0615 g,
0.410 mmol), NaN3 (0.0321 g, 0.494 mmol), 10 mL DMF. Yield:
0.067 g (47.9%); 1H NMR (400 MHz, CDCl3)
d 6.78 (br, 4H), 6.76 (s,
4H), 4.76 (t, J¼7.8 Hz, 1H), 4.39 (d, J¼12.5 Hz, 3H), 3.90e3.70 (m,
8H), 3.28 (t, J¼7.1 Hz, 2H), 3.11 (d, J¼12.4 Hz, 2H), 3.10 (d,
J¼12.6 Hz, 1H), 2.10e1.96 (m, 10H), 1.75e1.68 (m, 2H), 1.52 (br s,
2H), 1.08 (s, 18H), 1.07 (s, 18H), 1.03 (t, J¼7.5 Hz, 6H), 0.99 (t,
J¼7.5 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 153.7, 153.6, 144.2,
136.6, 133.9, 133.73, 133.66, 124.9, 124.8, 124.6, 121.6, 77.2, 76.9,
51.3, 36.1, 33.9, 33.8, 31.49, 31.46, 31.1, 31.0, 29.1, 25.7, 23.5, 23.3,
10.4, 10.3; HRMS calculated for C60H87N3NaO4 [MþNa]þ:
936.6594, found 936.6525.
4.5.1. 2-(3-Azidopropyl)tetramethoxy-p-tert-butylcalix[4]arene
(8a). Reagents: 4a (2.373 g, 3.036 mmol), NaI (0.910 g, 6.07 mmol),
NaN3 (0.397 g, 6.11 mmol), 50 mL DMF. Yield: 1.68 g (70.1%); 1H
4.5.6. 2-(5-Azidopentyl)tetrapropoxy-p-tert-butylcalix[4]arene
(9c). Reagents: 6c (2.415 g, 2.623 mmol), NaI (0.783 g, 5.22 mmol),
NaN3 (0.348 g, 5.35 mmol), 120 mL DMF. Yield: 1.804 g (74.1%); 1H
NMR (400 MHz, CDCl3/CD3CN/NaI)
d
7.25 (d, J¼2.3 Hz, 2H), 7.24 (s,
4H), 7.23 (d, J¼2.3 Hz, 2H), 4.67 (t, J¼8.4 Hz, 1H), 4.27 (d, J¼12.4 Hz,
3H), 4.15 (s, 6H), 4.14 (s, 6H), 3.48 (d, J¼12.5 Hz, 2H), 3.47 (d,
J¼12.4 Hz, 1H), 3.38 (t, J¼6.6 Hz, 2H), 2.28e2.19 (m, 2H), 1.68e1.59
(m, 2H), 1.21 (s, 18H), 1.20 (s, 18H); 13C NMR (100 MHz, CDCl3/
NMR (400 MHz, CDCl3)
d
6.78 (d, J¼2.5 Hz, 2H), 6.77 (d, J¼2.5 Hz,
2H), 6.76 (d, J¼2.4 Hz, 2H), 6.75 (d, J¼2.4 Hz, 2H), 4.75 (t, J¼8.1 Hz,
1H), 4.40 (d, J¼12.4 Hz, 3H), 3.89e3.71 (m, 8H), 3.26 (t, J¼6.9 Hz,
2H), 3.11 (d, J¼12.5 Hz, 2H), 3.10 (d, J¼12.5 Hz, 1H), 2.11e1.96 (m,

M.J. Hardman et al. / Tetrahedron 67 (2011) 7027e7034
7033
10H), 1.66e1.60 (m, 2H), 1.08 (s, 18H), 1.07 (s, 18H), 1.03 (t, J¼7.6 Hz,
4H), 1.20 (s, 18H), 1.19 (s, 18H); 13C NMR (100 MHz, CDCl3/CD3CN/
NaI) 150.0, 148.2,148.1, 146.6, 137.4, 137.1, 134.0, 133.8,128.8, 127.4,
125.5, 125.1, 124.7, 121.8, 120.2, 119.1, 64.0, 63.8, 49.5, 35.0, 33.7,
33.6, 33.0, 30.33, 30.28, 29.9, 29.3, 29.2, 29.0, 27.7, 25.9, 20.3; HRMS
calculated for C62H81N3NaO4 [MþNa]þ: 954.6125, found 954.6109.
6H), 0.99 (t, J¼7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
153.74,
d
153.67, 144.15, 144.13, 136.8, 133.9, 133.8, 133.6, 124.9, 124.8, 124.6,
121.7, 77.1, 76.9, 51.5, 36.2, 34.3, 33.9, 33.8, 31.52, 31.47, 31.2, 31.1,
28.9, 28.1, 27.1, 23.5, 23.3, 10.4, 10.3; HRMS calculated for
C61H89N3NaO4 [MþNa]þ: 950.6751, found 950.6720.
4.6.4. 2-(3-((4-p-Tolyl)-1H-1,2,3-triazolyl)propyl)tetrapropoxy-p-
tert-butylcalix[4]arene (11a). Reagents: 9a (0.746 g, 0.830 mmol), 4-
ethynyltoluene (0.10 g, 0.11 mL, 0.89 mmol), Cu (0.211 g,
3.32 mmol), CuSO4 (0.202 g, 0.830 mmol), 45 mL solvent. Yield:
4.6. General procedure for the cycloaddition of 8 and 9 with
ethynyltoluene or 1-hexyne. (10e13)
A reaction mixture of 8 or 9 (1 equiv), Cu powder (4 equiv),
CuSO4 (1 equiv) was prepared in a 4:1 tert-butanol/water mixture
(20e40 mL per mmol calixarene). The alkyne (ethynyltoluene or 1-
hexyne; 1 equiv) was added by syringe, and the reaction mixture
was heated at ca. 75 ꢁC for 16e24 h. After completion of the re-
action, as judged from 1H NMR spectra, the reaction mixture was
filtered through Celite and the volatiles were removed under re-
duced pressure. The residue was partitioned between water (ca.
25 mL per mmol calixarene) and dichloromethane (ca. 25 mL per
mmol calixarene), and the organic layer was washed with water
(2ꢂ; ca. 20 mL per mmol calixarene). The aqueous portions were
combined and washed with CH2Cl2 (ca. 20 mL per mmol calixarene)
then all organic portions were combined, dried over MgSO4, and
concentrated under reduced pressure to give a glass or oil. Solid
product was obtained from trituration with methanol (10c and 11a
crystallized from 50:50 methanol/acetonitrile).
0.079 g (9.4%); 1H NMR (400 MHz, CDCl3)
d
7.694 (d, J¼8.0 Hz, 2H),
7.690 (s, 1H), 7.22 (d, J¼7.8 Hz, 2H), 6.80e6.69 (m, 8H), 4.80 (t,
J¼7.3 Hz, 1H), 4.48 (t, J¼6.6 Hz, 2H), 4.38 (d, J¼12.5 Hz, 1H), 4.37 (d,
J¼12.4 Hz, 2H), 3.92e3.59 (m, 8H), 3.11 (d, J¼12.4 Hz, 2H), 3.10 (d,
J¼12.4 Hz, 1H), 2.34 (s, 3H), 2.13e1.95 (m, 12H), 1.07 (s, 18H), 1.05 (s,
18H),1.00 (t, J¼7.4 Hz, 6H), 0.98 (t, J¼7.4 Hz, 6H) 13C NMR (100 MHz,
CDCl3)
d 153.7, 153.6, 147.9, 144.3, 144.2, 137.9, 136.0, 133.9, 133.8,
133.6, 129.4, 125.6, 124.9, 124.8, 123.1, 121.3, 118.8, 77.2, 76.9, 50.7,
35.9, 33.9, 33.8, 31.7, 31.5, 31.4, 31.3, 31.1, 31.0, 29.7, 23.4, 23.2, 21.2,
10.4, 10.2; HRMS calculated for C68H93N3NaO4 [MþNa]þ:
1038.7064, found 1038.7097.
4.6.5. 2-(3-((4-Butyl)-1H-1,2,3-triazolyl)propyl)tetramethoxy-p-tert-
butylcalix[4]arene (12a). Reagents: 8a (0.700 g, 0.888 mmol), 1-
hexyne (0.073 g, 0.10 mL, 0.89 mmol), Cuꢁ (0.226 g, 3.55 mmol),
CuSO4 (0.222 g, 0.888 mmol), 35 mL solvent. Yield: 0.488 g (63.1%);
1H NMR (400 MHz, CDCl3/CD3CN/NaI)
d 7.42 (s, 1H), 7.23 (s, 4H),
4.6.1. 2-(3-((4-p-Tolyl)-1H-1,2,3-triazolyl)propyl)tetramethoxy-p-
tert-butylcalix[4]arene (10a). Reagents: 8a (0.700 g, 0.888 mmol),
4-ethynyltoluene (0.10 g, 0.11 mL, 0.89 mmol), Cu (0.226 g,
3.55 mmol), CuSO4 (0.222 g, 0.888 mmol), 35 mL solvent. Yield:
7.22 (d, J¼2.3 Hz, 2H), 7.15 (d, J¼2.3 Hz, 2H), 4.68 (t, J¼8.3 Hz, 1H),
4.41 (t, J¼6.8 Hz, 2H), 4.26 (d, J¼12.4 Hz, 3H), 4.14 (s, 6H), 4.13 (s,
6H), 3.47 (d, J¼12.4 Hz, 2H), 3.46 (d, J¼12.4 Hz, 1H), 2.68 (‘t’,
J¼7.7 Hz, 2H), 2.20e2.11 (m, 2H), 2.00e1.85 (m, 2H), 1.64 (‘quintet’,
J¼7.6, 2H), 1.43e1.30 (m, 2H), 1.20 (s, 18H), 1.19 (s, 18H), 0.93 (t,
0.566 g (70.5%); 1H NMR (400 MHz, CDCl3/CD3CN/NaI)
d 7.98 (s,1H),
7.70 (d, J¼8.1 Hz, 2H), 7.26e7.20 (m, 8H), 7.17 (d, J¼2.3 Hz, 2H), 4.70
(t, J¼8.2 Hz, 1H), 4.51 (t, J¼6.8 Hz, 2H), 4.26 (d, J¼12.4 Hz, 3H), 4.14
(s, 6H), 4.13 (s, 6H), 3.47 (d, J¼12.4 Hz, 2H), 3.46 (d, J¼12.4 Hz, 1H),
2.38 (s, 3H), 2.27e2.17 (m, 2H), 2.04e1.95 (m, 2H), 1.20 (s, 18H), 1.17
J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3/CD3CN/NaI)
d 150.0, 148.2,
148.0, 147.4, 136.7, 134.0, 133.93, 133.89, 125.42, 125.40, 125.3, 121.5,
120.2, 64.3, 63.9, 49.1, 34.4, 33.7, 33.5, 30.8, 30.4, 30.2, 29.9, 29.1,
29.0, 28.8, 24.5, 21.4, 12.9; HRMS calculated for C57H80N3O4
[MþH]þ: 870.6149, found 870.6097.
(s,18H); 13C NMR (100 MHz, CDCl3/CD3CN/NaI)
d 150.0,148.2,148.0,
146.7, 136.9, 136.7, 133.89, 133.85, 133.83, 128.6, 128.2, 125.4, 125.3,
125.2, 124.7, 121.4, 119.1, 64.2, 63.9, 49.3, 34.3, 33.6, 33.4, 30.2, 29.8,
29.1, 28.9, 28.8, 20.1; HRMS calculated for C60H77N3NaO4 [MþNa]þ:
926.5812, found 926.5728.
4.6.6. 2-(4-((4-Butyl)-1H-1,2,3-triazolyl)butyl)tetramethoxy-p-tert-
butylcalix[4]arene (12b). Reagents: 8b (1.25 g, 1.56 mmol), 1-
hexyne (0.10 g, 0.18 mL, 1.6 mmol), Cu (0.396 g, 6.24 mmol),
CuSO4 (0.390 g, 1.56 mmol), 35 mL solvent. Yield: 0.684 g (49.7%);
4.6.2. 2-(4-((4-p-Tolyl)-1H-1,2,3-triazolyl)butyl)tetramethoxy-p-
tert-butylcalix[4]arene (10b). Reagents: 8b (1.25 g, 1.56 mmol), 4-
ethynyltoluene (0.18 g, 0.20 mL, 1.56 mmol), Cu (0.396 g,
6.24 mmol), CuSO4 (0.390 g, 1.56 mmol), 35 mL solvent. Yield:
1H NMR (400 MHz, CDCl3/CD3CN/NaI)
d 7.37 (s, 1H), 7.23 (s, 4H),
7.22 (d, J¼2.3 Hz, 2H), 7.21 (d, J¼2.3 Hz, 2H), 4.62 (t, J¼8.2 Hz, 1H),
4.33 (t, J¼7.1 Hz, 2H), 4.26 (d, J¼12.4 Hz, 3H), 4.14 (s, 6H), 4.10 (s,
6H), 3.47 (d, J¼12.4 Hz, 3H), 2.65 (‘t’, J¼7.7 Hz, 2H), 2.22e2.12 (m,
2H), 2.02e1.96 (m, 2H), 1.60 (‘quintet’, J¼7.6, 2H), 1.41e1.30 (m,
4H), 1.20 (s, 36H), 0.93 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz,
0.691 g (48.5%); 1H NMR (400 MHz, CDCl3/CD3CN/NaI)
d 7.91 (s,1H),
7.68 (d, J¼8.0 Hz, 2H), 7.27e7.18 (m, 10H), 4.64 (t, J¼8.2 Hz,1H), 4.42
(t, J¼7.1 Hz, 2H), 4.26 (d, J¼12.4 Hz, 1H), 4.25 (d, J¼12.4 Hz, 2H), 4.14
(s, 6H), 4.10 (s, 6H), 3.46 (d, J¼12.4 Hz, 3H), 2.38 (s, 3H), 2.25e2.16
(m, 2H), 2.11e1.97 (m, 2H), 1.48e1.36 (m, 2H), 1.20 (s, 18H), 1.19 (s,
CDCl3/CD3CN/NaI)
d 150.0, 148.1, 148.1, 147.3, 137.1, 133.91, 133.89,
133.8, 125.4, 125.1, 121.6, 120.1, 64.1, 63.9, 49.0, 34.8, 33.6, 33.5,
32.5, 30.7, 30.25, 30.20, 29.7, 29.1, 29.0, 25.1, 24.4, 21.4, 12.9;
HRMS calculated for C58H81N3NaO4 [MþNa]þ: 906.6125, found
906.6122.
18H); 13C NMR (100 MHz, CDCl3/CD3CN/NaI)
d 150.0, 148.1, 148.0,
146.6, 137.1, 137.0, 133.91, 133.89, 133.78, 128.7, 127.2, 125.4, 124.7,
121.6, 119.0, 64.1, 63.9, 49.2, 34.9, 33.6, 33.5, 32.4, 30.23, 30.20, 29.6,
29.1, 29.0, 25.1, 20.2; HRMS calculated for C61H79N3NaO4 [MþNa]þ:
940.5968, found 940.5991.
4.6.7. 2-(5-((4-Butyl)-1H-1,2,3-triazolyl)pentyl)tetramethoxy-p-tert-
butylcalix[4]arene (12c). Reagents: 8c (1.00 g, 1.23 mmol), 1-hexyne
(0.10 g, 0.14 mL, 1.2 mmol), Cu (0.313 g, 4.92 mmol), CuSO4 (0.307 g,
1.23 mmol), 35 mL solvent. Yield: 0.462 g (41.8%); 1H NMR
4.6.3. 2-(5-((4-p-Tolyl)-1H-1,2,3-triazolyl)pentyl)tetramethoxy-p-
tert-butylcalix[4]arene (10c). Reagents: 8c (1.00 g, 1.23 mmol), 4-
ethynyltoluene (0.15 g, 0.16 mL, 1.2 mmol), Cu (0.313 g,
4.92 mmol), CuSO4 (0.307 g, 1.23 mmol), 35 mL solvent. Yield:
(400 MHz, CDCl3/CD3CN/NaI)
d 7.40 (s, 1H), 7.23 (s, 4H), 7.22 (d,
J¼2.3 Hz, 2H), 7.21 (d, J¼2.3 Hz, 2H), 4.63 (t, J¼8.2 Hz, 1H), 4.30 (t,
J¼7.1 Hz, 2H), 4.27 (d, J¼12.3 Hz, 3H), 4.15 (s, 6H), 4.12 (s, 6H), 3.47
(d, J¼12.4 Hz, 3H), 2.67 (‘t’, J¼7.7 Hz, 2H), 2.17e2.09 (m, 2H), 1.88
(‘quintet’, J¼6.9, 2H), 1.68e1.58 (m, 2H), 1.48e1.31 (m, 6H), 1.203 (s,
18H), 1.198 (s, 18H), 0.93 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz,
0.691 g (48.5%); 1H NMR (400 MHz, CDCl3/CD3CN/NaI)
d 7.88 (s,1H),
7.70 (d, J¼8.2 Hz, 2H), 7.26e7.17 (m, 10H), 4.63 (t, J¼8.2 Hz,1H), 4.38
(t, J¼7.0 Hz, 2H), 4.26 (d, J¼12.3 Hz, 1H), 4.25 (d, J¼12.4 Hz, 2H), 4.13
(s, 6H), 4.10 (s, 6H), 3.46 (d, J¼12.5 Hz, 1H), 3.45 (d, J¼12.5 Hz, 2H),
2.38 (s, 3H), 2.20e2.07 (m, 2H), 2.05e1.88 (m, 2H), 1.52e1.32 (m,
CDCl3/CD3CN/NaI)
d 150.0, 148.0, 147.9, 147.2, 137.3, 133.9, 133.7,
125.3, 125.0, 121.6, 120.2, 64.1, 63.9, 49.1, 34.8, 33.6, 33.4, 32.9, 30.7,

7034
M.J. Hardman et al. / Tetrahedron 67 (2011) 7027e7034
30.23, 30.17, 29.2, 29.1, 28.9, 27.6, 25.8, 24.4, 21.3, 12.8; HRMS cal-
the Denison University Research Foundation is gratefully
acknowledged.
culated for C59H83N3NaO4 [MþNa]þ: 920.6281, found 920.6256.
4.6.8. 2-(3-((4-Butyl)-1H-1,2,3-triazolyl)propyl)tetrapropoxy-p-tert-
butylcalix[4]arene (13a). Reagents: 9a (0.661 g, 0.734 mmol), 1-
hexyne (0.06 g, 0.08 mL, 0.7 mmol), Cu (0.186 g, 2.94 mmol),
CuSO4 (0.183 g, 0.734 mmol), 40 mL solvent. Yield: 0.392 g (54.4%);
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.07.022.
1H NMR (400 MHz, CDCl3)
d 7.23 (s, 1H), 6.77 (s, 4H), 6.76 (d,
J¼2.4 Hz, 2H), 6.69 (d, J¼2.3 Hz, 2H), 4.78 (t, J¼7.6 Hz, 1H), 4.41 (t,
J¼7.0 Hz, 2H), 4.38 (d, J¼12.4 Hz, 1H), 4.37 (d, J¼12.5 Hz, 2H),
3.90e3.75 (m, 6H), 3.72e3.63 (m, 2H), 3.11 (d, J¼12.6 Hz, 2H), 3.10
(d, J¼12.5 Hz, 1H), 2.70 (‘t’, J¼7.7 Hz, 2H), 2.10e1.94 (m, 12H),
1.68e1.58 (m, 2H), 1.43e1.32 (m, 6H), 1.07 (s, 18H), 1.05 (s, 18H), 1.01
(t, J¼7.5 Hz, 6H), 0.98 (t, J¼7.3 Hz, 6H), 0.92 (t, J¼7.3 Hz, 3H); 13C
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Acknowledgements
We thank Drs. Thomas A. Evans and Joseph J. Reczek for helpful
comments. Support for this research by the Denison University and
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