Synthesis and reactivity of functionalized bridged m-xylylenedioxycalix[6] arenes

Article abstract of DOI:10.1021/jo8009769

(Chemical Equation Presented) The synthesis of A,D-m-xylylene-bridged calix[6]arenes 1-8 functionalized at position 5 of the spacer arm is described. The cone conformation of the new bridged calix[6]arenes has been established by ¹H and ¹³C NMR. The X-ray structure of compound 6 confirmed the cone conformation also in the solid state. Compounds 9 and 10, which are branched-like structures, were obtained by reductive amination of 5-amino-A,D-m-xylylene-bridged-B,C,E,F-tetra-O-ethylcalix[6]arene 7 with diformyl calix[4]arene and CTV derivatives 22 and 24, respectively.

Full text of DOI:10.1021/jo8009769

Synthesis and Reactivity of Functionalized Bridged
m-Xylylenedioxycalix[6]arenes
Hitos Gala´n, Alex Fragoso,† Javier de Mendoza,‡ and Pilar Prados*
Departamento de Qu´ımica Orga´nica UniVersidad Auto´noma de Madrid, Cantoblanco,
E-28049 Madrid, Spain
pilar.prados@uam.es
ReceiVed May 6, 2008
The synthesis of A,D-m-xylylene-bridged calix[6]arenes 1-8 functionalized at position 5 of the spacer
1
arm is described. The cone conformation of the new bridged calix[6]arenes has been established by H
and 13C NMR. The X-ray structure of compound 6 confirmed the cone conformation also in the solid
state. Compounds 9 and 10, which are branched-like structures, were obtained by reductive amination of
5-amino-A,D-m-xylylene-bridged-B,C,E,F-tetra-O-ethylcalix[6]arene 7 with diformyl calix[4]arene and
CTV derivatives 22 and 24, respectively.
Introduction
two or three phenol rings by appropriate spacers,3 and several
examples have been reported with xylylene,4 9,10-anthrylene,4a
durylene,4a or pyridine5 spacers. Spacers derived from m-
xylylene or 2,6-lutidinediyl have been found to better keep the
A and D rings in a syn orientation, although the relative direction
of the remaining four rings depends on their O-substitution.
Whereas the free phenols favor a cone conformation due to
The development of receptors based on calixarenes requires
an efficient control of the conformational flexibility of these
cyclic phenol oligomers.1 Different strategies have been used
aimed at restricting the mobility of calix[6]arenes, since
inversion of the rings can also take place by rotation of the
para-substituent (even a tert-butyl group) through the annulus.2
The most common method to prevent these rotations is to bridge
(3) For general reviews see: (a) Ikeda, A.; Shinkai, S. Chem. ReV. 1997, 97,
1713–1734. (b) Chen, Y.; Gong, S. J. Inclusion Phenom. Macrocyclic Chem.
2003, 45, 165–184, and references therein.
† Current address: Department of Chemical Engineering, Universitat Rovira
i Virgili, E-43007 Tarragona, Spain.
(4) (a) Kanamathareddy, S.; Gutsche, C. D. J. Am. Chem. Soc. 1993, 115,
6572–6579. (b) Otsuka, H.; Araki, K.; Shinkai, S. J. Org. Chem. 1994, 59, 1542–
1547. (c) Otsuka, H.; Araki, K.; Matsumoto, H.; Harada, T.; Shinkai, S. J. Org.
Chem. 1995, 60, 4862–4867. (d) Lu¨ning, U.; Ross, H.; Thondorf, I. J. Chem.
Soc., Perkin Trans. 2 1998, 1313–1317. (e) Saiki, T.; Akine, S.; Goto, K.;
Tokitoh, N.; Kawashima, T.; Okazaki, R. Bull. Chem. Soc. Jpn. 2000, 73, 1893–
1902. (f) Akine, S.; Goto, K.; Kawashima, T. J. Inclusion Phenom. Macrocyclic
Chem. 2000, 36, 119–124. (g) Akine, S.; Goto, K.; Kawashima, T. Bull. Chem.
Soc. Jpn. 2001, 74, 2167–2174. (h) Akine, S.; Goto, K.; Kawashima, T.
Tetrahedron Lett. 2003, 44, 1171–1174. (i) Gala´n, H.; de Mendoza, J.; Prados,
P. Eur. J. Org. Chem. 2005, 4093–4097.
‡ Current address: Institute of Chemical Research of Catalonia (ICIQ),
E-43007 Tarragona, Spain.
(1) (a) Calixarenes: A Versatile Class of Macrocyclic Compounds; Vicens,
J., Bo¨hmer, V., Eds.; Kluwer Academic Publishers: Dordrecht, 1991. (b) Gutsche
C. D. In Calixarenes ReVisited (Monographs in Supramolecular Chemistry);
Stoddart, J. F., Ed.; Royal Society: Cambridge, 1998; Vol. 1. (c) Calixarenes in
Action; Mandolini, L., Ungaro, R., Eds.; Imperial College Press: London, 2000.
(d) Lu¨ning, U.; Lo¨ffler, F.; Eggert, J. In Calixarenes 2001; Asfari, Z., Bo¨hmer,
V.,Harrowfield, J. M. J., Vicens, J., Eds.; Kluwer Academic Publishers:
Dordrecht, 2001.
(2) (a) Otsuka, H.; Araki, K.; Shinkai, S. Chem. Express. 1993, 8, 479–482.
(b) Duynhoven, J. P. M.; Janssen, R. G.; Verboom, W.; Franken, S. M.; Casnati,
A.; Pochini, A.; Ungaro, R.; de Mendoza, J.; Nieto, P. M.; Prados, P.; Reinhoudt,
D. N. J. Am. Chem. Soc. 1994, 116, 5814–5822.
(5) (a) Ross, H.; Lu¨ning, U. Angew. Chem., Int. Ed. Engl. 1995, 34, 2555–
2557. (b) Ross, H.; Lu¨ning, U. Liebigs Ann. 1996, 1367–1373. (c) Eggert,
J. P. W.; Harrowfield, J.; Lu¨ning, U.; Skelton, B. W.; White, A. H.; Lo¨ffler, F.;
Konrad, S. Eur. J. Org. Chem. 2005, 1348–1353.
7124 J. Org. Chem. 2008, 73, 7124–7131
10.1021/jo8009769 CCC: $40.75 2008 American Chemical Society
Published on Web 08/14/2008

Functionalized Bridged m-Xylylenedioxycalix[6]arenes
SCHEME 1. Synthesis of Compounds 1-3
SCHEME 2. Synthesis of Compound 14
hydrogen bonding, small substituents such as OMe result in a
flexible structure in all cases.4c However, introduction of OEt
groups does not seem to have the same effect, since a cone
conformation is obtained with the m-xylylene spacer,4g and
mixtures of conformations result with p-xylylene and 2,6-
lutidinediyl spacers.5b On the other hand, the presence of bulky
substituents such as a bromine in position 2 of the spacer
disfavors the cone because it does not fit well inside the
cavity.4f,g,6 The use of the m-xylylene spacer to link opposite
rings allows the introduction of an additional function in position
5, facilitating the attachment to other calixarene or cyclotriv-
eratrylene (CTV) platforms. Use of these building blocks might
be an efficient strategy to construct dendrimeric structures that
possess definite cavities if a concave rigid platform is employed
to direct the calix[6]arene arms to the same side of the plane.
An example has been recently reported with a flat platform as
the linker between calixarenes.7 We describe herein the synthesis
of compounds 1-4, with different spacers functionalized in
position 5, and compounds 5-8, where all rings contain O-alkyl
groups. The conformational study demonstrates that these
compounds display rigid cone conformations. Finally, we have
studied the reactivity of 7 with carboxylic acids and aldehydes
giving rise to branched structures 9 and 10.
Dibromides 129 and 1310are known compounds, and deriva-
tive 14 was obtained from dimethyl 5-iodo-isophthalate by a
Sonogashira coupling reaction,11 followed by reduction and
bromination of the resulting alcohols (Scheme 2).
O-Alkylation of 1 with 2,3-bis(bromomethyl)naphthalene12
or ethyl iodide gave compounds 5 and 6 in 30% and 68% yields,
respectively. Similarly, O-alkylation of 184e with ethyl iodide
gave 8 in good yield.
Compounds 1, 2, 5, and 6 possess a nitro group as a precursor
of an amine, whereas 8 possesses a bromine atom as a precursor
of a carboxylic acid. These functionalities allow an easy growth
of the structure by covalently attaching several calixarenes
through amide or urea linkers.
Reduction of 1 with hydrazine in 2-propanol resulted in the
hydrogenolysis product 11 instead of the desired amine, whereas
the reaction proceeds as expected from the tetra-O-ethyl
compound 6, producing 7 in a 74% yield. It is likely that in
this case the presence of the ethyl groups hinder the access of
the reagent to the benzyl positions, preventing the hydrogenoly-
sis. The alternative reduction of 1 and 6 with SnCl2 in 2-propanol
gave the expected amines 4 (87%) and 7 (78%), respectively.
Attempts to reduce the nitro group in 5 under the same
(6) Saiki, T.; Goto, K.; Okazaki, R. Chem. Lett. 1996, 993–994.
(7) Eggert, J. P. W.; Lu¨ning, U. Eur. J. Org. Chem. 2007, 6046–6052.
(8) Gutsche, C. D.; Dhawan, B.; Leonis, M.; Tewart, D. Org. Synth. 1989,
68, 238–242.
(9) Resing, S.; Arendt, M.; Springer, A.; Grawe, T.; Schrader, T. J. Org.
Chem. 2001, 66, 5814–5821.
Results and Discussion
(10) (a) Momenteau, M.; Mispelter, J.; Loock, B.; Lhoste, J.-M. J. Chem.
Soc. Perkin Trans. I 1985, 61–70. (b) Fuller, A.-M.; Leigh, D. A.; Lusby, P. J.;
Oswald, I. D. H.; Parsons, S.; Walker, D. B. Angew. Chem., Int. Ed. 2004, 43,
3914–3918.
(11) Chinchilla, R.; Na´jera, C. Chem. ReV. 2007, 107, 874–922.
(12) Futamura, S.; Zong, Z. M. Bull. Chem. Soc. Jpn. 1992, 65, 345–348.
Synthesis. Compounds 1-3 were obtained in good yields
by O-alkylation of p-tert-butylcalix[6]arene 118 with dibromides
12-14, respectively, in the presence of NaH and a THF-DMF
(9:1) mixture (Scheme 1).
J. Org. Chem. Vol. 73, No. 18, 2008 7125

Gala´n et al.
TABLE 1. NMR (500 MHz, CDCl3, 298 K) of Compounds 1-8
13C NMR (ppm) 1H NMR (ppm) AX systems 1H NMR (ppm) ArH
SCHEME 3. Synthesis of Compound 21
(ArCH2Ar)
(ArCH2Ar)
(H-2 of spacer)
1
2
3
4
5
6
7
8
33.1 and 32.8
4.25 and 3.53 (8H)
4.28 and 3.35 (4H)
4.31 and 3.52 (8H)
4.19 and 3.35 (4H)
4.19 and 3.44 (8H)
4.08 and 3.26 (4H)
4.32 and 3.47 (8H)
4.18 and 3.31 (4H)
4.52 and 3.65 (8H)
4.22 and 3.01 (4H)
4.47 and 3.45 (8H)
4.31 and 3.24 (4H)
4.45 and 3.44 (8H)
4.36 and 3.25 (4H)
4.44 and 3.44 (8H)
4.34 and 3.25 (4H)
8.87
33.2 and 33.0
32.1 and 31.9
33.2 and 33.0
32.2 and 30.5
30.2 and 28.7
30.2 and 29.7
30.2 and 29.7
8.58
8.79
7.92
6.54
5.66
4.76
5.27
conditions failed, however, presumably due to the protection
of the aromatic walls of the outer spacers toward the access of
any reagent.
On the other hand, treatment of 8 with tert-butyllithium
followed by addition of CO2 gave rise to a complex mixture
where the starting material was the major product (mass
spectrometry analysis). This illustrates again the hindering effect
of the O-ethyl groups. This was further corroborated by the
unsuccessful attempts to form an amide by reaction of amine 7
with p-methoxybenzoic acid or with carboxylic acids 1913a and
2013b under a variety of coupling conditions (oxalyl chloride,
EDC, or PyBOP). In all cases the starting material was recovered
or a complex reaction mixture was obtained.
presence of NaBH(AcO)3 gave diamine 9 in 70% yield. An
attempt to perform a similar reaction with tetraaldehyde 2314
yielded, after 10 days, a mixture of compounds where up to
three or even four calix[6]arene units, in various reduction states,
had been incorporated (mass spectrometry analysis). These
results point to steric hindrance as the major cause for reaction
failure or incompletion.
The rigid, C3V-symmetric CTV-derived trialdehyde 2415 was
chosen next considering its more open shape compared with
calix[4]arenes in cone conformation.16 The reaction between
2415 and a large excess of amine 7 gave compound 10 in 12%
yield after 11 days reaction. The low yield was partly due to
difficulties in isolation in the presence of the excess amine
employed, which caused overlap between compounds of similar
molecular weight in size exclusion chromatography columns,
the most effective method found for the isolation of 10.
Conformational Analysis. The conformations of the new
bridged calix[6]arenes were established by a full set of 1D and
2D 1H or 13C NMR techniques. The NMR spectra of compounds
1-8 (CDCl3, 300 K) showed the signals corresponding to
molecules with two planes of symmetry: two AX systems in a
2:1 ratio for the methylene protons (ArCH2Ar) and the corre-
sponding two signals in 13C NMR around 28-33 ppm, indicat-
ing that the macrocycles display cone conformations in all cases
(Table 1).17 Furthermore, these spectra remain invariable even
if the temperature is raised up to 403 K (C2D2Cl4).
The aromatic proton H-2 of the m-xylylene spacer in O-alkyl
compounds (5-8) is abnormally shielded (∆δ ∼3.00 ppm) with
respect to those who have the free phenols (1-4). In addition,
the shifts found in their 13C NMR spectra for the methylene
groups (ArCH2Ar) appear at higher fields relative to the
analogue compounds 1-4 (e.g., 33.1 and 32.8 ppm for 1 and
30.2 and 28.7 ppm for 6) (Table 1). These effects could be the
result of the O-alkylation that promotes both the introduction
of the aromatic ring of the m-xylylene spacer into the cavity
and the loss of the hydrogen bonding network, which orient
To overcome these difficulties, the formation of imines
was tested, taking advantage of the greater reactivity of
aldehydes with respect to carboxylic acids. Thus, the model
imine 21 was obtained quantitatively from amine 7 and
benzaldehyde (Scheme 3).
However, when amine 7 was reacted with dialdehyde 22,13a
the resulting imine was easily hydrolyzed during the isolation
process. Also, reaction with tetraaldehyde 2314 gave rise to a
complex mixture from which the target compound could not
be isolated. In this case, the steric hindrance caused by the
incorporation of the bulky calix[6]arene on the calix[4]arene
platform is likely the reason for the reaction not be completed.
Secondary amine formation (through reductive amination)
was then considered in order to establish if imines could not be
obtained due to either steric hindrance or hydrolysis during
purification. Reaction of amine 7 with dialdehyde 2213a in the
(15) Arduini, A.; Calzavacca, F.; Demuru, D.; Pochini, A.; Secchi, A. J.
Org. Chem. 2004, 69, 1386–1388.
(16) The size of the cavity is defined by the angle δ between the aromatic
rings and the plane formed by the carbon atoms of the methylene bridges. In
CTVs δ ) 132° (Collet, A. In ComprehensiVe Supramolecular Chemistry;
MacNicol, D. D., Toda, F., Bishop, R., Eds.; Pergamon: Oxford, 1996; Vol. 6)
and in calix[4]arene δ ) 115° (Arduini, A.; Nachtigall, F. F.; Pochini, A.; Secchi,
A.; Ugozzoli, F. Supramol. Chem. 2000, 12, 273-291).
(17) (a) Kanamathareddy, S.; Gutsche, C. D. J. Org. Chem. 1994, 59, 3871–
3879. For the 13C NMR rule in calix[4]arenes, see: (b) Jaime, C.; de Mendoza,
J.; Prados, P.; Nieto, P. M.; Sa´nchez, C. J. Org. Chem. 1991, 56, 3372–3376.
(13) (a) Arduini, A.; Fabbi, S.; Mantovani, M.; Mirone, L.; Pochini, A.;
Secchi, A.; Ungaro, R. J. Org. Chem. 1995, 60, 1454–1457. (b) Sansone, F.;
Barboso, S.; Casnati, A.; Fabbi, M.; Pochini, A.; Ugozzoli, F.; Ungaro, R. Eur.
J. Org. Chem. 1998, 897–905.
(14) Dondoni, A.; Marra, A.; Scherrmann, M.-C.; Casnati, A.; Sansone, F.;
Ungaro, R. Chem. Eur. J. 1997, 3, 1774–1782.
7126 J. Org. Chem. Vol. 73, No. 18, 2008

Functionalized Bridged m-Xylylenedioxycalix[6]arenes
FIGURE 1. ROESY contacts observed for compounds (a) 1-4 and (b) 5-8.
FIGURE 2. X-ray structure of compound 6: (a) general view and (b) partial view along the m-xylylene bridge in which tert-butyl and ethoxy
groups have been removed for clarity.
the aromatic rings (B, C, E and F) toward the cavity, thus
affecting aromatic proton H-2.
the temperature is raised to 403 K. ROESY experiments confirm
this conformation. Thus, contacts were observed between the
axial proton of the methylene group (ArCH2Ar) with OH and
one of the propyl methylene protons, whereas the equatorial
proton showed contacts with the aromatic protons of the
calix[4]arene core.
The latter hypothesis was confirmed by ROESY experiments.
Contacts were observed between the tert-butyl groups (B, C,
E, and F) and some of the protons at the central bridge (i.e.,
H-2 of spacer and benzyl CH2 protons), indicating that at least
one of these groups is sequentially folded inside the cavity,
whereas analogous contacts are not displayed by the more rigid
compounds 1-4, with free OH (Figure 1). In addition, these
experiments indicate that all of the aromatic rings are in a syn
disposition.
Crystals of 6 suitable for X-ray analysis were grown by slow
evaporation of a tetrachloroethane/dichloromethane solution. The
overall structure of the molecule has an elliptical-cage confor-
mation where the calix[6]arene backbone shows a highly
distorted cone shape. Five aromatic rings of the calixarene
framework are pointing outward with respect to the reference
plane defined by the calixarene methylene carbons. The sixth
aromatic ring is oriented toward the cavity, showing a CH-π
interaction with the aromatic proton H-2 (2.807 Å) of the spacer
and 2.505 Å away from the tert-butyl group of this aromatic
ring, in good agreement with the NMR data (Table 1). On the
other hand, each one of the methylene groups of the linker are
oriented in opposite directions. Therefore, the X-ray structure
of 6 demonstrates that the cone conformation is also maintained
in the solid state, in good agreement with the conclusions
obtained in solution where the aromatic rings are folded into
the cavity (Figure 2).
Molecular mechanics were employed to evaluate the
overall shape of the structures. An almost perfect agreement
between the calculated and the X-ray structures of compound
6 was found when using InsightII/Discovery (cvff, in vacuo,
see Supporting Information), so the same method was used
for compounds 9 and 10. Calculations afforded at least three
energy minima for compound 9, all displaying open structures
without a defined cavity, whereas 10 presents a more compact
shape at the top, similar to dendrimers of a higher generation
number (Figure 3).
Conclusions
The synthesis of functionalized A,D-m-xylylene-bridged
calix[6]arenes in position 5 of the spacer has been described. It
was found that all compounds adopt a cone conformation. These
macrocycles show a new mode of functionalization which paves
the way to more complex, branched structures, such as 9 and
10. Although in this case the branches have been connected to
the core by a flexible spacer (CH2N) and it is not possible to
control the inside space of the final resulting structure, we have
described a new methodology that can be useful to prepare
dendrimeric structures based on rigid calixarenes, by function-
alization of the calix[6]arene moieties in para positions. The
1D and 2D NMR spectra of 9 showed that the calix[4]arene
core was in a pinched cone conformation (δ ArCH2Ar 31.6
ppm).17 In addition, these spectra remained invariable even if
J. Org. Chem. Vol. 73, No. 18, 2008 7127

Gala´n et al.
FIGURE 3. Side and top views of the energy optimized structures of amines 9 (a) and 10 (b). Only one conformer is shown for 9. Hydrogen atoms
have been removed for clarity. See Supporting Information for details.
) 13.6 Hz, 2H, ArCH2Ar), 4.25 (d, 2J ) 13.5 Hz, 4H, ArCH2Ar),
5.36 (s, 4H, ArOCH2), 7.12 (s, 8H, ArH), 7.15 (s, 4H, ArH), 8.05
(s, 2H, ArH), 8.79 (s, 4H, ArOH), 8.87 (s, 1H, ArH); 13C NMR
(CDCl3, 125 MHz, DEPT) δ 31.3, 31.7 [C(CH3)3], 32.8, 33.1
(ArCH2Ar), 34.0, 34.4, [C(CH3)3], 76.0 (ArCH2O), 120.4, 125.4,
126.1, 126.7 (ArH), 127.1, 127.6 (Ar), 129.3 (ArH), 132.1, 140.4,
142.9, 147.7, 148.4, 149.69, 149.73 (Ar); MS (MALDI-TOF,
dithranol + NaI) m/z 1142.5 [(M + Na)+, 100%]. Anal. Calcd for
C74H89NO8 ·1/2EtOH: C, 78.77; H, 8.11; N, 1.22. Found: C, 78.59;
H, 8.68; N, 1.35.
results of our efforts in this direction will be reported
independently.
Experimental Section
General Procedure for O-Alkylation of p-tert-Butylcalix[6]arene
(11) with Dialkylating Agents. A suspension of 118 and NaH (60%
on a dispersion oil) in dry THF-DMF (9:1) was heated at 50-60
°C under argon, and a solution of the appropriate alkylating agent
in THF-DMF (9:1) was added dropwise while the temperature
was raised. The reaction mixture was stirred at specific conditions
(temperature, time) for each case under study.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,40,41-tetrahydroxy-39,42-
[5-(4-nitrophenylethynyl)-1,3-phenylenebis(methyleneoxy)]calix[6]-
arene (2). Obtained from 118 (70.7 mg, 0.073 mmol), NaH (18.25
mg, 0.455 mmol), THF-DMF (7.1 mL), and 14 (37.0 mg, 0.091
mmol) in THF-DMF (1.8 mL). The temperature was 50 °C
overnight. The mixture was quenched with MeOH and an excess
of 1 N HCl. The solid was filtered, washed with water, dried,
triturated in EtOH-H2O, and crystallized in CHCl3-MeOH to give
5,11,17,23,29,35-Hexa-tert-butyl-37,38,40,41-tetrahydroxy-39,42-
[5-nitro-1,3-phenylenebis(methyleneoxy)]calix[6]arene (1). Obtained
from 118 (500.0 mg, 0.514 mmol), NaH (128.5 mg, 3.213 mmol),
THF-DMF (25.0 mL), and 129 (198.5 mg, 0.643 mmol) in
THF-DMF (5.0 mL). The temperature was kept at 40-50 °C for
1.5 h and at room temperature for 15 h. The mixture was quenched
with MeOH and concentrated in vacuo. The residue was partitioned
between CHCl3 and 1 N HCl. The organic layer was washed with
brine and water, dried (MgSO4) and evaporated to dryness The
residue was purified by trituration in MeOH, and the solid obtained
was crystallized in CHCl3-EtOH, to give 1 as a white solid (440.0
1
2 as a white solid (62.0 mg, 70%). Mp > 280 °C (dec). H NMR
(CDCl3, 500 MHz) δ 1.22 [s, 18H, C(CH3)3], 1.29 [s, 36H,
2
2
C(CH3)3], 3.35 (d, J ) 13.8 Hz, 2H, ArCH2Ar), 3.52 (d, J )
2
13.5 Hz, 4H, ArCH2Ar), 4.19 (d, J ) 13.7 Hz, 2H, ArCH2Ar),
4.31 (d, 2J ) 13.4 Hz, 4H, ArCH2Ar), 5.30 (s, 4H, ArOCH2), 7.13
1
3
mg, 75%). Mp 212-214 °C. H NMR (CDCl3, 500 MHz) δ 1.21
(s, 8H, ArH), 7.15 (s, 4H, ArH), 7.38 (s, 2H, ArH), 7.68 (d, J )
3
[s, 18H, C(CH3)3], 1.28 [s, 36H, C(CH3)3], 3.35 (d, 2J ) 13.6 Hz,
8.9 Hz, 2H, ArH), 8.23 (d, J ) 8.9 Hz, 1H, ArH), 8.58 (s, 1H,
2
2
2H, ArCH2Ar), 3.53 (d, J ) 13.5 Hz, 4H, ArCH2Ar), 4.18 (d, J
ArH), 8.94 (s, 4H, ArOH); 13C NMR (CDCl3, 75 MHz, DEPT) δ
7128 J. Org. Chem. Vol. 73, No. 18, 2008

Functionalized Bridged m-Xylylenedioxycalix[6]arenes
31.3, 31.7 [C(CH3)3], 33.0, 33.2, (ArCH2Ar), 34.0, 34.3 [C(CH3)3],
76.5 (ArCH2OAr), 88.1, 93.9 (Ct C), 122.1 (Ar), 123.7, 124.7,
125.3, 126.1, 126.5 (ArH), 127.2, 127.6 (Ar), 129.0 (ArH), 130.0,
132.3 (Ar), 132.4 (ArH), 138.9, 142.8, 147.2, 148.2, 149.90, 149.94
(Ar); MS (MALDI-TOF, dithranol + NaI) m/z 1242.7 [(M + Na)+,
100%]; HRMS (MALDI) m/z (M + Na)+ calcd for C82H93NO8Na
1242.68396, found 1242.67934.
mg, 0.044 mmol), Pd(C) 10% (5 mg), hydrazine (0.21 mL, 4.413
mmol), and 2-propanol (5 mL). Yield (36.0 mg, 74%). Compound
7 was also obtained following method B of the general procedure
from 6 (296.0 mg, 0.240 mmol), SnCl2 ·2H2O (1.80 g, 6.007 mmol),
1
and 2-propanol (30 mL). Yield (226.0 mg, 78%). Mp 185 °C. H
3
NMR (CDCl3, 500 MHz) δ 0.91 [s, 36H, C(CH3)3], 1.14 (t, J )
7.1 Hz, 12H, CH3), 1.44 [s, 18H, C(CH3)3], 3.25 (d, 2J ) 13.9 Hz,
2
2H, ArCH2Ar), 3.44 (d, J ) 15.4 Hz, 4H, ArCH2Ar), 3.66-3.56
5,11,17,23,29,35-Hexa-tert-butyl-37,38,40,41-tetrahydroxy-39,42-
[3,5-pyridinylbis(methyleneoxy)]calix[6]arene (3). Obtained from
118 (56.4 mg, 0.060 mmol), NaH (14.5 mg, 0.362 mmol) in
THF-DMF (5.0 mL), and 1310 in THF-DMF (2.0 mL). The
reaction was maintained at room temperature for 24 h. The mixture
was quenched with water and stirred for an additional 30 min, and
then CHCl3 was added. The organic layer was washed with water
and dried (MgSO4). The solvent was evaporated to dryness, and
the remaining solid was triturated in CH2Cl2-MeOH-H2O to give
(m, 8H, OCH2), 4.13 (s, 4H, ArOCH2), 4.36 (d, 2J ) 14.1 Hz, 2H,
ArCH2Ar), 4.45 (d, 2J ) 15.4 Hz, 4H, ArCH2Ar), 4.76 (s, 1H, ArH),
6.53 (s, 2H, ArH), 6.81 (s, 4H, ArH), 6.89 (s, 4H, ArH), 7.34 (s,
4H, ArH); 13C NMR (CDCl3, 125 MHz, DEPT) δ 15.6
(ArOCH2CH3), 29.7, 30.2 (ArCH2Ar), 31.3, 31.7 [C(CH3)3], 34.0,
34.3 [C(CH3)3], 68.8 (ArOCH2CH3), 71.7 (ArOCH2), 109.6, 113.3,
124.1, 125.1, 128.1 (ArH), 132.8, 132.9, 133.4, 139.3, 145.0, 152.3,
152.7 (Ar); MS (MALDI-TOF, dithranol + NaI) m/z 1224.8 [(M
+ Na)+, 95%], 1202.8 [(M + H)+, 100%], 1146.7 [(M + 2H -
t-Bu]+, 35%]. Anal. Calcd for C82H107NO6 ·1/2CHCl3: C, 78.49;
H, 8.58; N, 1.11. Found: C, 78.65; H, 8.87; N, 1.22.
1
3 as a white solid (44.0 mg, 70%). Mp > 196 °C (dec). H NMR
(CDCl3, 500 MHz) δ 1.12 [s, 18H, C(CH3)3], 1.20 [s, 36H,
2
2
C(CH3)3], 3.26 (d, J ) 13.7 Hz, 2H, ArCH2Ar), 3.44 (d, J )
2
13.4 Hz, 4H, ArCH2Ar), 4.08 (d, J ) 13.7 Hz, 2H, ArCH2Ar),
General Procedure for Tetra-O-alkylation of A,D-m-xylylene-
dioxycalix[6]arenes with Monoalkylating Agents. Method A. A
suspension of the corresponding A,D-m-xylylenedioxycalix[6]-
arene derivative and NaH (60% on a dispersion oil, 4 equiv/OH)
in dry DMF was heated under argon at 60 °C for 30 min, and then
ethyl iodide (2 equiv/OH) was added. The reaction was stirred at
50-60 °C for 3 days. The mixture was quenched with an excess
of MeOH and concentrated under reduced pressure. The residue
was partitioned between CHCl3 and 1 N HCl, and the organic layer
was washed with brine and water and dried (MgSO4). The solvent
was removed under reduced pressure, and the residue was triturated
in MeOH and then crystallized in CHCl3-MeOH. Method B. A
mixture of A,D-m-xylylenedioxycalix[6]arene derivative and NaH
(60% on a dispersion oil, 4 equiv/OH) in dry DMF was heated in
a sealed tube for 30 min at 50 °C, under argon. The reaction was
allowed to reach room temperature, then ethyl iodide was added
(2 equiv/OH), and the mixture was heated for 2 days at 80 °C. The
mixture was quenched with MeOH and worked up similarly as for
method A.
4.19 (d, 2J ) 13.4 Hz, 4H, ArCH2Ar), 5.25 (s, 1H, ArOCH2), 7.04
(s, 8H, ArH), 7.06 (s, 4H, ArH), 8.40 (s, 2H, ArH), 8.79 (s, 1H,
ArH), 8.83 (s, 4H, ArOH); 13C NMR (CDCl3, 125 MHz, DEPT) δ
30.3, 30.6 [C(CH3)3], 31.9, 32.1 (ArCH2Ar), 32.9, 33.3 [C(CH3)3],
73.2 (ArCH2OAr), 124.3, 125.0, 125.5 (ArH), 126.1, 126.5 (Ar),
130.7 (ArH), 131.2, 132.4, 141.8 (Ar), 146.1 (ArH), 147.3, 148.6,
148.7 (Ar); MS (MALDI-TOF, dithranol + NaI) m/z 1098.6 [(M
+ Na)+, 100%], 1076.6 [(M + H)+, 66.7%]. Anal. Calcd for
C73H89NO6 ·1/2CHCl3: C, 77.70; H, 7.94; N, 1.23. Found: C, 77.35;
H, 8.27; N, 1.72.
General Procedure for Reduction of Nitro A,D-m-Xylylene-
dioxycalix[6]arene Derivatives. Method A. A suspension of the
corresponding nitro derivative (1 equiv), a catalytic amount of Pd(C)
10%, and hydrazine (100 equiv) in 2-propanol (9 × 10-3 M) was
heated at 70 °C for 16 h, under argon. The mixture was filtered on
Celite, and the solvent was evaporated to dryness. The residue was
partitioned between CHCl3 and water, and the aqueous layer was
extracted with CHCl3. The organic layers were joined, washed with
water, and dried (MgSO4). The solvent was removed under reduced
pressure, and the remaining solid was purified by trituration in
MeOH. Method B. A suspension of the corresponding nitro
derivative and SnCl2 ·2H2O (25 equiv/NO2) in 2-propanol (8 × 10-3
M) was heated at 70 °C under argon for 20 h. The mixture was
quenched with 10% NaOH until basic pH and filtered on Celite,
and the solid was washed with CH2Cl2. The organic layer was
washed with water and dried (MgSO4). The solvent was removed
under reduced pressure, and the residue was purified by trituration
in EtOH-H2O.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,40,41-tetraethyloxy-39,42-
[5-nitro-1,3-phenylenebis(methyleneoxy)]calix[6]arene (6). This
compound was obtained following method A of the general
procedure by reaction of 1 (400.0 mg, 0.353 mmol), NaH (225.9
mg, 5.650 mmol), DMF (20 mL) with ethyl iodide (0.226 mL, 2.824
mmol). Yield (195.0 mg, 45%). In addition, 6 was also prepared
following method B of the general procedure by reaction of 1 (200.0
mg, 0.178 mmol), NaH (114.2 mg, 2.850 mmol), DMF (10 mL)
with ethyl iodide (0.114 mL, 1.412 mmol). Yield (149.5 mg, 68%).
Mp > 274 °C (dec). 1H NMR (CDCl3, 500 MHz) δ 0.92 [s, 36 H,
3
C(CH3)3], 1.07 (t, J ) 6.8 Hz, 12H, ArOCH2CH3), 1.46 [s, 18H,
39,42-[5-Amino-1,3-phenylenebis(methyleneoxy)]-5,11,17,23,
29,35-hexa-tert-butyl-37,38,40,41-tetrahydroxycalix[6]arene (4).
Obtained following method B of the general procedure from 1
(200.0 mg, 0.178 mmol), SnCl2 ·2H2O (1.020 g, 4.461 mmol), and
2-propanol (20 mL). Yield (170.0 mg, 87%). Mp > 224 °C (dec).
1H NMR (CDCl3, 500 MHz) δ 1.19 [s, 18H, C(CH3)3], 1.27 [s,
2
2
C(CH3)3], 3.24 (d, J ) 14.0 Hz, 2H, ArCH2Ar), 3.45 (d, J )
15.3 Hz, 4H, ArCH2Ar), 3.69-3.58 (m, 8H, ArOCH2CH3), 4.23
2
(s, 4H, ArOCH2Ar), 4.31 (d, J ) 14.0 Hz, 2H, ArCH2Ar), 4.47
2
(d, J ) 15.3 Hz, 4H, ArCH2Ar), 5.66 (s, 1 H, ArH), 6.85 (s, 4H,
ArH), 6.89 (s, 4H, ArH), 7.38 (s, 4H, ArH), 8.16 (s, 2H, ArH); 13
C
2
2
NMR (CDCl3, 125 MHz, DEPT) δ 15.4 (ArOCH2CH3), 28.7, 30.2
(ArCH2Ar), 31.3, 31.7 [C(CH3)3], 34.0, 34.4 [C(CH3)3], 68.7
(ArOCH2CH3), 70.7 (ArOCH2Ar), 118.3, 124.2, 125.0, 128.0, 129.0
(ArH), 132.7, 132.8, 133.4, 140.6, 145.2, 146.4, 147.5, 152.2 (Ar);
MS (MALDI-TOF, dithranol + NaI) m/z 1254.8 (MNa+, 100%).
Anal. Calcd for C82H105NO8: C, 79.90; H, 8.59; N, 1.14. Found: C
79,68; H 8,87; N 1,25.
36H, C(CH3)3], 3.31 (d, J ) 13.9 Hz, 2H, ArCH2Ar), 3.47 (d, J
) 13.5 Hz, 4H, ArCH2Ar), 4.18 (d, 2J ) 13.9 Hz, 2H, ArCH2Ar),
4.32 (d, 2J ) 13.5 Hz, 4H, ArCH2Ar), 5.17 (s, 4H, ArOCH2), 6.46
(s, 2H, ArH), 7.10 (s, 8H, ArH), 7.12 (s, 4H, ArH), 7.92 (s, 1H,
ArH), 9.03 (s, 4H, ArOH); 13C NMR (CDCl3, 125 MHz, DEPT) δ
31.3, 31.7 [C(CH3)3], 33.0, 33.2 (ArCH2Ar), 33.9, 34.3 [C(CH3)3],
77.2 (ArOCH2), 112.5, 114.2, 125.3, 126.0, 126.4 (ArH), 127.4,
127.6, 132.4, 139.3, 142.5, 147.8, 150.0, 150.1 (Ar); MS (MALDI-
TOF, dithranol + NaI) m/z 1112.7 [(M + Na)+, 100%), 1090.7
[(M + H)+, 50%], 1034.7 [(M + H - t-Bu)+, 19%]. Anal. Calcd
for C74H91NO6 ·1/2(H2O.MeOH): C, 80.21; H, 8.49; N, 1.26. Found:
C, 79.92; H, 8.57; N, 1.30.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,40,41-tetraethyloxy-39,42-
[5-bromo-1,3-phenylenebis(methyleneoxy)]calix[6]arene (8). This
compound was obtained following method A of the general
procedure by reaction of 184e (450.0 mg, 0.389 mmol), NaH (250.0
mg, 6.237 mmol), DMF (40 mL) with ethyl iodide (0.25 mL, 3.112
1
39,42-[5-Amino-1,3-phenylenebis(methyleneoxy)]-5,11,17,23,
29,35-hexa-tert-butyl-37,38,40,41-tetraethyloxycalix[6]arene (7).
Obtained following method A of the general procedure from 6 (50.0
mmol). Yield (390.0 mg, 80%). Mp > 160 °C (dec). H NMR
(CDCl3, 500 MHz) δ 0.91 [s, 36H, C(CH3)3], 1.14 (t, 3J ) 6.9 Hz,
2
12H, ArOCH2CH3), 1.45 [s, 18H, C(CH3)3], 3.25 (d, J ) 14.1
J. Org. Chem. Vol. 73, No. 18, 2008 7129

Gala´n et al.
Hz, 2H, ArCH2Ar), 3.44 (d, 2J ) 15.4 Hz, 4H, ArCH2Ar),
3.71-3.63 (m, 8H, ArOCH2CH3), 4.16 (s, 4H, ArOCH2Ar), 4.34
(d, 2J ) 14.3 Hz, 2H, ArCH2Ar), 4.44 (d, 2J ) 15.4 Hz, 4H,
ArCH2Ar), 5.27 (s, 1H, ArH), 6.82 (s, 4H, ArH), 6.89 (s, 4H, ArH),
7.35 (s, 6H, ArH); 13C NMR (CDCl3, 125 MHz, DEPT) δ 15.5
(ArOCH2CH3), 29.7, 30.2 (ArCH2Ar), 31.3, 31.7 [C(CH3)3], 34.0,
34.3 [C(CH3)3], 68.8 (ArOCH2CH3), 70.9 (ArOCH2CH3), 120.8
(Ar), 121.1, 124.1, 125.0, 125.7, 128.0 (ArH), 132.7, 132.8, 133.4,
140.7, 145.1, 146.1, 152.2, 152.4 (Ar); MS (MALDI-TOF, dithranol
+ NaI) m/z 1289.8 [(M + Na)+, 100%] 1210.9 ([M + Na - Br]+,
15%]. Anal. Calcd for C82H105BrO6 ·H2O: C, 76.67; H, 8.40. Found:
C, 76.32; H, 8.21.
the reaction was quenched at room temperature with brine and
neutralized with 3 M HCl until pH ) 7, and the mixture was further
stirred at room temperature for 1 h. The organic solvent was
eliminated under reduced pressure, and the aqueous solution was
extracted with Et2O. The organic layer was washed with brine and
dried (MgSO4). The solvent was removed under reduced pressure
and the residue was purified by trituration in hexane-CH2Cl2 to
give 17 as a pale yellow solid (203.5 mg, 81%). Mp > 192 °C
1
(dec). H NMR (CD3OD, 300 MHz) δ 4.66 (s, 4H, ArCH2OH),
3
7.44 (s, 1H, ArH), 7.50 (s, 2H, ArH), 7.77 (d, J ) 8.9 Hz, 2H,
ArH), 8.29 (d, 3J ) 9.0 Hz, 2H, ArH); 13C NMR (CD3OD, 75 MHz,
DEPT) δ 64.5 (ArCH2OH), 88.1, 95.3 (Ct C), 123.5 (Ar), 124.8,
127.4, 129.9 (ArH), 131.3 (Ar), 133.5 (ArH), 143.8, 148.5 (Ar);
MS (EI) m/z 283.0 (M+, 100%), 252.0 [(M - CH2OH)+, 15%].
Anal. Calcd for C16H13NO4 ·(H2O·CH2Cl2): C, 52.87; H, 4.44; N
3.63. Found: C, 52.90; H, 4.04; N, 3.89.
5,11,17,23,29,35-Hexa-tert-butyl-37,38;40,41-bis[naphthalene-2,3-
diylbis(methyleneoxy)]-39,42-[5-nitro-1,3-phenylenebis(methylene-
oxy)]calix[6]arene (5). A mixture of 1 (100.0 mg, 0.081 mmol) and
NaH 60% (127.3 mg, 3.181 mmol, 2 equiv/OH) in dry DMF (18
mL) was heated at 40 °C for 10 min under argon. Then a solution
of 2,3-bis(bromomethyl)naphthalene12 (56.0 mg, 0.178 mmol, 2.2
equiv) in DMF (2 mL) was slowly added. The reaction was heated
for 3 h at 40 °C. The mixture was quenched with water and 1 N
HCl, stirred for another 30 min and extracted with CHCl3. The
organic layer was washed sequentially with 1 N HCl (5 × 15 mL),
brine, and water and dried (MgSO4). The solvent was eliminated
under reduced pressure, and the residue was triturated in MeOH.
The obtained solid was purified by column chromatography (silica
gel, hexane-CHCl3, 8:2) to give 5 as a white solid (23.5 mg, 30%).
1,3-Bis(bromomethyl)-5-(4-nitrophenylethynyl)benzene (14). A
mixture of 17 (50.0 mg, 0.176 mmol), CBr4 (269.2 mg, 0.812
mmol), and triphenyl phosphine (212.9 mg, 0.812 mmol) in dry
CH2Cl2 (10 mL) was heated at 40 °C for 1 day. The solvent was
removed under reduced pressure, and the residue was triturated in
diethyl ether. The filtrate was eliminated under reduced pressure,
and the residue was purified by column chromatography (silica gel,
hexane-CHCl3, 2:1) to give 14 as a white solid (87.0 mg, 69%).
1
Mp 115-118 °C. H NMR (CDCl3, 300 MHz) δ 4.59 (s, 4H,
3
ArCH2OH), 7.44 (s, 1H, ArH), 7.55 (s, 2H, ArH), 7.67 (d, J )
9.0 Hz, 2H), 8.23 (d, 3J ) 8.8 Hz, 4H); 13C NMR (CDCl3, 75 MHz,
DEPT) δ 45.1 (ArOCH2Br), 88.4, 93.3 (C≡C), 123.3 (Ar), 123.7,
129.4 (ArH), 129.7 (Ar) 131.7, 132.4 (ArH), 138.6, 147.2 (Ar);
MS (EI) m/z 411.0 [(M + 4)+, 24%), 409.0 [(M + 2)+, 45%], 407.0
(M+, 24%), 330.1 [(M - Br)+, 100%], 249.1 [(M - 2Br)+, 50%];
HRMS (EI) m/z M+ calcd for C16H11Br2NO2 406.9157, found
406.9165.
1
Mp > 269 °C (dec). H NMR (CDCl3, 500 MHz) δ 0.95 [s, 36H,
C(CH3)3], 1.47 [s, 18H, C(CH3)3], 3.01 (d, 2J ) 14.0 Hz, 2H,
2
2
ArCH2Ar), 3.65 (d, J ) 15.1 Hz, 4H, ArCH2Ar), 4.22 (d, J )
2
13.9 Hz, 2H, ArCH2Ar), 4.41 (s, 4H, ArOCH2Ar), 4.52 (d, J )
3
15.0 Hz, 4H, ArCH2Ar), 4.79 (d, J ) 11.4 Hz, 4H, ArOCH2Ar),
3
5.05 (d, J ) 11.4 Hz, 4H, ArOCH2Ar), 6.54 (s, 1H, ArH), 6.90
(s, 8H, ArH), 7.41-7.45 (m, 8H, ArH), 7.59 (s, 4H, ArH),
7.63-7.73 (m, 4H, ArH), 7.81 (s, 2H, ArH); 13C NMR (CDCl3,
125 MHz, DEPT) δ 30.5, 32.2, (ArCH2Ar), 31.2, 31.7 [C(CH3)3],
34.0, 34.5 [C(CH3)3], 70.5, 75.0 (ArOCH2Ar), 117.2, 124.7, 125.6,
126.6, 127.4, 127.8, 129.6 (ArH), 132.7, 133.2, 133.6, 133.8, 134.2,
141.2, 146.0, 147.0, 151.9, 152.2 (Ar); MS (MALDI-TOF, dithranol
+ NaI) m/z 1446.8 [(M + Na)+, 100%]. Anal. Calcd for
C98H105NO8 ·CHCl3: C, 77.00; H, 6.92; N, 0.91. Found: C, 76.90;
H, 7.14; N, 1.16.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,40,41-tetraethyloxy-39,42-
[5-benzylideneamine-1,3-phenylenebis(methyleneoxy)]calix[6]arene
(21). A solution of amine 7 (25.0 mg, 0.021 mmol) and benzalde-
hyde (2.0 µL, 0.021 mmol) in dry CH2Cl2 (3 mL) was stirred at 50
°C for 1 h. Solvent was eliminated under reduced pressure to give
21 as a white solid (26.3 mg, 98%). Mp > 197 °C (dec). 1H NMR
(500 MHz, CDCl3) δ 0.98 [s, 36H, C(CH3)3], 1.15 (t, 3J ) 6.9 Hz,
2
12H, ArOCH2CH3), 1.50 [s, 18 H, C(CH3)3], 3.31 (d, J ) 14.2
Hz, 2H, ArCH2Ar), 3.51 (d, 2J ) 15.5 Hz, 4H, ArCH2Ar),
3.64-3.71 (m, 8H, ArOCH2CH3), 4.31 (s, 4H, ArOCH2Ar), 4.41
(d, 2J ) 14.2 Hz, 2H, ArCH2Ar), 4.54 (d, 2J ) 15.4 Hz, 4H,
ArCH2Ar), 5.31 (s, 1H, ArH), 6.89 (s, 4H, ArH), 6.96 (s, 4H, ArH),
7.20 (s, 2H, ArH), 7.42 (s, 4H, ArH), 7.52-7.54 (m, 2H, ArH),
7.67-8.00 (m, 2H, ArH), 8.16 (d, 3J ) 7.4 Hz, 1H, ArH), 8.63 (s,
1H, CHdN); 13C NMR (125 MHz, CDCl3, DEPT) δ 15.6
(ArOCH2CH3), 28.8, 30.2, (ArCH2Ar), 31.3, 31.7 [C(CH3)3], 34.3,
34.0 [C(CH3)3], 68.8 (ArOCH2CH3), 71.5 (ArOCH2Ar), 115.3,
120.4, 124.1, 125.1, 128.1, 128.7 (ArH), 129.0, 129.8 (Ar), 130.2,
131.0 (ArH), 132.8, 132.9, 133.5, 136.7, 139.5, 145.0, 146.0, 150.4,
152.3, 152.6 (Ar), 158.9 (CHdN); MS (MALDI-TOF, dithranol
+ NaI) m/z 1312.4 [(M + Na)+, 100%], 1290.4 [(M + H)+, 33%].
Anal. Calcd for C89H111NO6 ·1/2(CH2Cl2 ·H2O): C, 80.08; H, 8.49;
N, 1.04. Found: C, 80.00; H, 8.80; N, 1.12.
General Procedure To Obtain Secondary Amines by Reduc-
tive Amination. Glacial acetic acid (1 equiv/CHO) was added at
room temperature under argon to a suspension of amine 7 (2.5
equiv/CHO), the corresponding aldehyde (1 equiv), and NaB-
H(AcO)3 (1.5 equiv/CHO) in 1,2-dicloroethane, keeping [aldehyde]/
n ) 22 mM, where n is the number of imine groups to be reduced.
The mixture was heated at 60-70 °C for a specified time and then
1 M NaOH was added until a basic pH was reached. The mixture
was extracted with CH2Cl2, and the organic layer was washed with
water and dried (MgSO4). The solvent was eliminated under reduced
pressure, and the residue was triturated in CH2Cl2-MeOH.
Compound 9. Prepared from 7 (200.0 mg, 0.166 mmol),
dialdehyde 2213a (18.8 mg, 0.033 mmol), 1,2-dichloroethane (3 mL),
Dimethyl 5-(4-nitrophenylethynyl)isophthalate (16). A suspen-
sion of dimethyl 5-iodo-isophthalate (500.0 mg, 1.562 mmol),
Pd(PPh3)2Cl2 (27.4 mg, 0.025 equiv) and CuI (7.5 mg, 0.025 equiv)
in dry DIPEA (15 mL) was stirred at room temperature for 30 min.
Compound 1518 (276.0 mg, 1.874 mmol) was then added, and the
mixture was stirred at 50-70 °C for 18 h. The reaction mixture
was diluted with water, the solution was extracted with ethyl acetate,
and the organic layer was dried (MgSO4) and filtered on Celite.
The solvent was removed under reduced pressure, and the residue
was purified by column chromatography (silica gel, hexane-AcOEt
9.5:0.5) to give 16 as a yellow solid (403.6 mg, 76%). Mp 134-137
1
°C. H NMR (CDCl3, 300 MHz) δ 3.98 (s, 6 H, ArOCH3), 7.70
3
3
(d, J ) 8.7 Hz, 2H, ArH), 8.25 (d, J ) 8.9 Hz, 2H, ArH), 8.40
4
4
(d, J ) 1.5 Hz, 2H, ArH), 8.68 (t, J ) 1.5 Hz, 1H, ArH); 13C
NMR (CDCl3, 75 MHz, DEPT) δ 52.6 (ArOCH3), 89.1, 92.2
(Ct C), 123.1 (Ar), 123.7 (ArH), 129.3 (Ar), 130.9 (ArH), 131.2
(Ar), 132.5, 136.7 (ArH), 147.4 (Ar), 165.3 (CO); MS (EI) m/z
339.1 (M+, 100%), 308.1 [(M - OCH3)+, 70%]. Anal. Calcd for
C18H13NO6: C, 63.72; H, 3.86; N, 4.13. Found: C, 63.27; H, 3.98;
N, 4.20.
1,3-Bis(hydroxymethyl)-5-(4-nitrophenylethynyl)benzene (17).
DIBAL-H (3.6 mL, 3.625 mmol, 1 M in CH2Cl2) was added
dropwise under argon at -13 °C to a solution of 16 (300.0 mg,
0.884 mmol) in dry CH2Cl2 (30 mL), and the mixture was stirred
for 3 h in the same conditions. CH2Cl2 (30 mL) was added, and
(18) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis
1980, 627–630.
7130 J. Org. Chem. Vol. 73, No. 18, 2008

Functionalized Bridged m-Xylylenedioxycalix[6]arenes
acetic acid (3.8 µL), and NaBH(AcO)3 (21.0 mg, 0.100 mmol) for
6 days at 70 °C. Purification was achieved by repeated crystalliza-
tion in CH2Cl2-MeOH giving 9 as a white solid (68.0 mg, 70%).
CH2Cl2-MeOH gave 10 as a white solid (9.2 mg, 12%). Mp >
170 °C (dec). 1H NMR (500 MHz, CDCl3) δ 0.91 [s, 108H,
3
C(CH3)3], 1.07 (t, J ) 6.9 Hz, 36H, ArOCH2CH3), 1.44 [s, 54H,
1
C(CH3)3], 3.25 (d, 2J ) 14.2 Hz, 6H, ArCH2Arcalix[6]arene), 3.41-3.44
(m, 16H, ArCH2Arcalix[6]arene, ArCH2ArCTV), 3.46-3.58 (m, 33H,
ArOCH2CH3, ArOCH3), 3.70 (s, 6H, ArCH2NH), 4.14 (s, 12H,
ArOCH2Ar), 4.34-4.46 (m, 21H, ArCH2Arcalix[6]arene, ArCH2ArCTV),
4.66 (s, 3H, ArH), 6.58 (s, 6H, ArH), 6.72 (s, 3H, ArHCTV), 6.81
(s, 12H, ArHcalix[6]arene), 6.89 (bs, 18H, ArH, ArHcalix[6]arene), 6.93
Mp > 229 °C (dec). H NMR (500 MHz, CDCl3, COSY) δ 0.93
3
[s, 72H, C(CH3)3], 1.11 (t, J ) 6.9 Hz, 3H, ArOCH2CH2CH3),
1.16 (t, 3J ) 6.8 Hz, 24H, ArOCH2CH3), 1.34 (t, 3J ) 7.3 Hz, 3H,
ArOCH2CH2CH3), 1.46 [s, 36H, C(CH3)3], 2.07-2.14 (m, 4H,
ArOCH2CH2CH3), 3.28 (d, 2J ) 14.2 Hz, 4H, ArCH2Arcalix[6]arene),
3.39 (d, 2J ) 12.9 Hz, 4H, ArCH2Arcalix[4]arene), 3.46 (d, 2J ) 15.5
Hz, 8H, ArCH2Arcalix[6]arene), 3.58-3.71 (m, 16H, ArOCH2CH3),
4.00 (t, 3J ) 6.1 Hz, 4H, ArOCH2CH2CH3), 4.15 (s, 4H,
3
(s, 3H, ArHCTV), 7.19 (d, J ) 8.4 Hz, 6H, ArH), 7.34 (s, 12H,
ArHcalix[6]arene); 13C NMR (125 MHz, CDCl3, DEPT) δ 15.9 (CH3),
29.1, 30.4 (ArCH2Arcalix[6]arene), 31.5, 32.0 [C(CH3)3], 34.0, 34.3
[C(CH3)3], 36.6 (ArCH2ArCTV), 53.9 (ArCH2NHAr), 56.4
(ArOCH3), 69.0 (ArOCH2CH3), 72.3 (ArOCH2Ar), 107.4, 111.7,
114.5, 117.6, 124.4, 125.4, 128.4, 128.5 (ArH), 133.1, 133.2, 133.7,
133.8, 139.5, 145.2, 146.0, 148.2, 152.6, 153.1 (Ar); MS (MALDI-
TOF, dithranol + NaI) m/z 4364.1 [(M + Na + HAcO)+, 100%];
2
ArCH2NHAr), 4.16 (s, 8H, ArOCH2Ar), 4.35 (d, J ) 12.3 Hz,
4H, ArCH2Arcalix[4]arene), 4.39 (d, 2J
)
14.1 Hz, 4H,
ArCH2Arcalix[6]arene), 4.48 (d, 2J ) 15.5 Hz, 8H, ArCH2Arcalix[6]arene),
3
4.75 (s, 2H, ArH), 6.50 (s, 4H, ArH), 6.79 (t, J ) 7.6 Hz, 2H,
ArHcalix[4]arene), 6.83 (s, 8H, ArHcalix[6]arene), 6.91 (s, 8H,
3
ArHcalix[6]arene), 6.98 (d, J ) 7.6 Hz, 4H, ArHcalix[4]arene), 7.08 (s,
HRMS (MALDI) m/z (M
293H361N3O26Na 4360.6909, found 4360.7085.
+ Na +
HAcO)+ calcd for
4H, ArHcalix[4]arene), 7.36 (s, 8H, ArHcalix[6]arene), 8.36 (s, 2H, OH);
13C NMR (125 MHz, CDCl3, DEPT, HMQC) δ 10.9, 15.7 (CH3),
23.5 (ArOCH2CH2CH3), 28.8, 30.2 (ArCH2Arcalix[6]arene), 31.3
[C(CH3)3], 31.5 (ArCH2Arcalix[4]arene), 31.7 [C(CH3)3], 34.0, 34.3
[C(CH3)3], 48.7 (ArCH2NHAr), 68.8 (ArOCH2CH3), 71.9
(ArOCH2Ar), 78.4 (ArOCH2CH2CH3), 107.4, 112.2, 124.1, 125.0,
125.4, 127.8, 128.1 (ArH), 128.2 (Ar), 129.0 (ArH), 130.3, 132.8,
132.9, 133.4, 133.6, 139.1, 144.9, 145.7, 147.6, 152.0, 152.3, 152.5,
152.8 (Ar); MS (MALDI-TOF, dithranol + NaI) m/z 2960.9 [(M
+ Na)+, 100%]. Anal. Calcd for C200H250N2O16 ·1/2CH2Cl2: C,
80.79; H, 8.49; N, 0.94. Found: C, 80.90; H, 8.66; N, 0.99.
Compound 10. Prepared from 7 (100.0 mg, 0.083 mmol),
trialdehyde 2415 (13.3 mg, 0.018 mmol), 1,2-dichloroethane (2.5
mL), acetic acid (3.2 µL), and NaBH(AcO)3 (17.6 mg, 0.083 mmol)
for 11 days at 70 °C. Purification was achieved by gel permeation
chromatography using Bio-Beads SX-1 as stationary phase and
toluene as eluent, followed by repeated crystallization in
C
Acknowledgment. Financial support was provided by CYCIT
(projects CTQ2005-08948-C02-02 and Consolider Ingenio 2010,
grant CSD2006-0003). H.G. acknowledges Ministerio de Edu-
cacio´n y Ciencia of Spain for a fellowship.
Supporting Information Available: Spectral characterization
data (1-10, 14, 16, 17, and 21); ROESY spectra of compounds
1-9; VT 1H NMR spectra (403-298 K) of compounds 1, 3, 4,
6, 8, and 9; X-ray crystallographic data of compounds 6; HRMS
of compound 10. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO8009769
J. Org. Chem. Vol. 73, No. 18, 2008 7131