Microwave-assisted synthesis of a nitro-m-xylylenedioxycalix[6]arene building block functionalized at the upper rim

Article abstract of DOI:10.1002/ejoc.201000954

Microwave-assisted synthesis represents a new methodology to obtain calix[6]arene building blocks. The synthesis of compounds 1 and 2 is described. These compounds are A,D-m-xylylenedioxy-bridged calix[6]arenes in cone conformation, functionalized with potential amino groups in the lower rim spacer (5-position) and amino groups or their precursors in A,D-para positions at the upper rim. A conformational study has been performed for all newly synthesized compounds. New methodology involving the use ofmicrowave irradiation has allowed calix[6]arene building blocks to be obtained. The synthesis of compounds 1 and 2 is described. These compounds are A,D-m-xylylenedioxy-bridged calix[6]arenes in cone conformation, functionalized with potential amino groups in the lower rim spacer (5-position) and amino or their precursors in A,D-para positions at the upper rim. Copyright

Full text of DOI:10.1002/ejoc.201000954

FULL PAPER
DOI: 10.1002/ejoc.201000954
Microwave-Assisted Synthesis of a Nitro-m-xylylenedioxycalix[6]arene Building
Block Functionalized at the Upper Rim
Hitos Galán,[a][‡] Javier de Mendoza,[a][‡‡] and Pilar Prados*[a]
Keywords: Calixarenes / Microwave chemistry / Supramolecular chemistry / Macrocycles
Microwave-assisted synthesis represents a new methodology
to obtain calix[6]arene building blocks. The synthesis of com-
pounds 1 and 2 is described. These compounds are A,D-m-
xylylenedioxy-bridged calix[6]arenes in cone conformation,
functionalized with potential amino groups in the lower rim
spacer (5-position) and amino groups or their precursors in
A,D-para positions at the upper rim. A conformational study
has been performed for all newly synthesized compounds.
calix[6]arenes in a cone conformation, with ethyl groups in
the remaining phenol groups and functionalized with
amino group precursors at the 5-position of the spacer. To
use these macrocycles as building blocks, a new methodol-
ogy to introduce two new functional groups at the para po-
sitions of two opposite (A, D) rings was necessary (Fig-
ure 1).
Introduction
The design of platforms such as calix[6]arenes for supra-
molecular chemistry requires both efficient control of their
conformational flexibility[1] and the formation of multifunc-
tionalized macrocycles at the upper and lower rims.
Although the cone conformation can be occasionally ob-
tained for calix[6]arenes,[2] it is not the general case, as rota-
tion of the rings can also take place by the passage of the
para substituent (i.e., the tert-butyl group) through the cav-
ity.[2c,3] A common way to prevent this rotation is to bridge
two or three phenol rings with appropriate spacers.[4] Most
often, the bridge links two opposite (A,D) rings.[5] Spacers
such as m-xylylene or 2,6-lutidinedinyl can better keep the
A and D rings in syn orientation, although the relative di-
rection of the remaining four rings depends on their O-sub-
stituents.[6] It has been demonstrated that O-ethyl groups
facilitate a cone conformation of A,D-m-xylylenedioxyca-
lix[6]arenes.[6d,6f] Moreover, the use of the m-xylylene spacer
allows the introduction of an additional function at the 5-
position, thus enabling linkage of the calixarene to other
platforms. Thus, these macrocycles may serve as molecular
building blocks for the construction of more complex struc-
tures such as dendrimeric endoreceptors.[7]
Here we report on the benefits of using microwave
(MW)-assisted synthesis to prepare branching units 1 and
2, which are constituted by bridged A,D-m-xylylenedioxy-
Figure 1. Compounds 1 and 2.
[a] Departamento de Química Orgánica (C-I),
Facultad de Ciencias, Universidad Autónoma de Madrid,
28049 Madrid, Spain
The general strategy to selectively obtain para-function-
alization in calix[6]arenes is based on the well-established
differences in reactivity between anisole and phenol.[1] O-
Benzylation of the A and D phenol rings, followed by meth-
ylation of the remaining rings and deprotection of the
benzyl groups affords the desired substitution
pattern.[2c,8,9a] However, to the best of our knowledge, only
a few examples have been published for this reaction se-
quence.[9] In order to link the A and D rings, which are
Fax: +34-91-4973966
E-mail: pilar.prados@uam.es
[‡] Current address: Centro de Investigaciones Energéticas,
Medioambientales y Tecnológicas (CIEMAT),
Avda. Complutense 22, Madrid 28040, Spain
[‡‡]Current address: Institute of Chemical Research of Catalonia
(ICIQ),
43007 Tarragona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000954.
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H. Galán, J. de Mendoza, P. Prados
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previously functionalized in the para positions, we have es-
In fact, ethyl groups were only introduced successfully
tablished a new strategy based on the use of MW irradia- when MW irradiation was employed, and compound 5 was
tion.
obtained almost pure in 89% yield. Debenzylation of 5 was
carried out by hydrogenolysis. Treatment of 6 with a mix-
ture of nitric and sulfuric acids (1:1) in dichloromethane
afforded nitro derivative 7 in 65% yield (Scheme 1).
Before O-alkylation of 7 with bridging reagent 12, it was
necessary to differentiate the amino precursor of the upper
rim from the one at the lower rim. Therefore, both nitro
groups of compound 7 were converted into protected amino
groups after protection of the phenol groups as a result of
the easy oxidation of aminophenols. Acetylation of 7 and
subsequent reduction of 8 with SnCl2·2H2O/NaBH4 in a
mixture of AcOEt/tBuOH (9:1) gave diamine 9 in 54%
overall yield. Finally, protection of these functional groups
with phthalic anhydride gave derivative 10 in 75% yield
(Scheme 2).
Results and Discussion
Reaction of 3[2b] with sodium hydride and ethyl or propyl
iodide yielded complex reaction mixtures, and compound 4
was only obtained in a 65% yield when allyl bromide was
employed (Scheme 1). These results suggest that the phenol
groups are buried into the cavity, disabling O-alkylation,
which is favored by a more reactive halogen derivative.[10]
The selective hydrolysis of the acetyl groups under acidic
or basic conditions resulted in complex reaction mixtures.
Indeed, mass spectrometry showed that partial hydrolysis
of the phthalimido groups had occurred.
Reduction of the nitro groups in compound 7 with
SnCl2·2H2O/NaBH4, or with hydrazine and Pd/C in etha-
nol for prolonged reaction times, gave complex reaction
mixtures in which only minor amounts of the amino deriva-
tives were found, probably due to oxidation of the ami-
nophenols, thus indicating that the amino groups should be
protected in situ. Therefore, a fast and quantitative re-
duction method was necessary. Once again, after testing nu-
merous experimental conditions and reduction reagents,
only MW conditions gave satisfactory results. Compound 7
was reduced by using hydrazine and Pd/C in ethanol at
130 °C under pressure (6 bar) followed by treatment with
phthalic anhydride to give 11 in 60% overall yield
(Scheme 2).
Reaction of 11 with difunctional derivative 12 was again
successful when MW irradiation was used, and 1 was ob-
Scheme 1. Synthesis of compounds 4–7.
Scheme 2. Synthesis of compounds 8–11, 1, and 2.
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A Nitro-m-xylylenedioxycalix[6]arene Building Block
tained in 48% yield. Deprotection of the amino groups in ter) and the observed ROESY peaks, we conclude that an
1 was carried out with hydrazine in ethanol to give 2 in equilibrium between several 1,2,3-alternate conformations
69% yield (Scheme 2).
of lower symmetry operates, as a result of the inclusion of
1
The H NMR spectra of compounds 4–11 are broad at the two opposite rings carrying alkyl groups that are more
room temperature, revealing a flexible structure for all of shielded than the remaining rings. Similar results were pre-
them. In most cases, variable-temperature (188–298 K) viously reported by us for p-unsubstituted calix[6]arenes.[10]
studies showed complex spectra at 188 K. Ethyl or allyl sig-
Single crystals were obtained for 4 from tetrachloroeth-
nals appear at abnormally high fields, indicating that at le- ane. In the solid state, a uudddu conformation is displayed,
ast some of these substituents are inside the cavity. Never- with the allyl groups oriented inside the cavity and in agree-
theless, some differences could be observed depending on ment with low-temperature studies in solution (Figure 3).
the substitution at the A and D rings.
Compounds 4 and 5, which have two p-methylbenzyl
groups in opposite rings, displayed similar 1H NMR
(CD2Cl2, 238 K) behavior: three AB systems are observed
for the calixarene methylene bridges (ArCH2Ar) in a 1:1:1
ratio, as well as six signals for the aromatic calixarene pro-
tons. Remarkably, ethyl or allyl chains appeared as two
well-separated groups of signals, one strongly shielded, indi-
cating inclusion of the chain into the cavity. These results
indicate that compounds 4 and 5 are in a conformation dis-
playing only one element of symmetry (Figure 2).
To have better insight into the conformation of these ca-
lix[6]arenes, 2D NMR experiments (HSQC, COSY, and
ROESY) were recorded at 238 K. In the HSQC spectrum
of 4, three signals are visible for the calixarene methylene
bridges, which correspond to the three AB systems in the
1H NMR spectrum, two at ca. 29 ppm and the other one
at ca. 33 ppm. In compound 5, two of these carbon signals
are present at ca. 29 ppm (which correlates with the AB
systems) and at ca. 34 ppm (which correlates with a singlet).
Figure 3. X-ray structure of compound 4.
Although the observed values (ca. 33 ppm) are away from
When variable-temperature (188–298 K) experiments
the 37 ppm standard shift to confirm an anti arrangement were performed with compounds 6, 7, and 11, which bear
1
of the bridged aromatic rings,[11] it has been reported (for free OH groups, complex H NMR spectra were observed.
calix[4]arenes) that large deviations from the usual 31 and The spectrum of compound 6 was indeed too complex to
37 ppm values for “pure” syn or anti arrangements, respec- conclude anything about its conformation. Compound 7
tively, may be interpreted either as a distorted conformation showed two nonsymmetrical conformers (CD2Cl2, hydro-
or as a fast equilibrium between syn and anti forms.[12]
gen-bonding patterns at the 188 K), whereas for 11 only one
A ROESY experiment of compounds 4 and 5 (238 K, could be observed (CD2Cl2, 188 K). These results could be
CD2Cl2) revealed exchange peaks between similar protons. explained by taking into account the lower rim and the na-
Considering the symmetry of the compound (inversion cen- ture of the substituent at the para position. For instance,
1
Figure 2. H NMR spectra of compounds 4 and 5.
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H. Galán, J. de Mendoza, P. Prados
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1
Figure 4. H NMR spectra of compounds 7 and 11. Signals for different conformations are highlighted.
compound 11, which has stronger hydrogen bonds than 6,
and a bulkier group in the para position than 7, shows the
Conclusions
The synthesis of A,D-m-xylylene-bridged calix[6]arenes 1
most defined conformation at 188 K (Figure 4).
COSY and ROESY experiments were performed at
188 K for 11. Analysis of the COSY spectra proved the
presence of four different ethyl groups, and at least two of
them are diastereotopic. Nevertheless, its conformation
could not be determined due to the large number of cross-
peaks in the ROESY experiment.
Single crystals were obtained for 11 from CH3CN/
CH2Cl2. In the solid state, a uudddu conformation is dis-
played, with the phenol groups oriented inside the cavity
(Figure 5).
and 2, functionalized in the 5-position of the spacer and in
the upper rim with amino groups or amino precursors has
been described. It was found that these compounds adopt
a cone conformation. These building blocks contain func-
tional groups that pave the way toward more complex
branched structures. The new methodology described here
is useful to obtain calix[6]arenes functionalized at both the
lower and upper rims, and the use of microwave-assisted
synthesis was the key in most cases to obtain the desired
products.
Experimental Section
General: Unless otherwise reported, all reactions were carried out
under a dry and deoxygenated argon atmosphere. Solvents were
freshly distilled and dried before use by standard methods. All
chemicals were used as purchased. Reported melting points were
measured in open capillaries with a Gallenkamp Melting Point ap-
paratus. NMR experiments (1H,13C{1H}, and ROESY) were car-
ried out at 500 (125) MHz and reported chemical shifts (δ) are ex-
ternally referenced to solvent residual signal. Mass spectra were
performed with a REFLEX spectrometer by using the MALDI-
TOF method, with the use of dithranol as matrix and NaI as addi-
tive. Elemental analyses were performed with a LECO CHN 932
microanalyzer, indicated inclusion of solvent molecules for nearly
Figure 5. X-ray structure of compound 11.
1
At 188 K, compounds 8, 9, and 10 (acetyl groups in the
lower rim) still show complex NMR spectra, accounting for
the importance of hydrogen bonding in the conformational
rigidity.
all calixarene products and were supported by separate H NMR
spectroscopic studies. TLC was performed on silica gel Alugram Sil
G/UV254 (Macherey-Nagel) sheets. Microwaves-assisted synthesis
was performed with a Discover microwave (S-Class), cooling by
nitrogen current. Reactions under ultrasound were performed with
a Selecta “Ultrasons-H” (40 kHz).
Conformations of bridged calix[6]arenes 1 and 2 were es-
1
tablished by a full set of 1D H or 13C NMR techniques.
The NMR spectra of these compounds (CDCl3, 298 K) 37,38,40,41-Tetraallyloxy-5,11,17,23,29,35-hexa-tert-butyl-39,42-
bis(4-methylbenzyloxy)calix[6]arene (4): A mixture of 3[2b]
(100.0 mg, 0.085 mmol) and NaH (60% suspension in mineral oil,
showed signals corresponding to molecules with two planes
of symmetry: two AX systems in a 2:1 ratio for the methyl-
27.1 mg, 0.678 mmol) in dry DMF (5.0 mL) was heated at 80 °C
ene protons (ArCH2Ar) and the corresponding two signals
under an argon atmosphere for 1 h. Then, allyl bromide (59.0 μL,
in the 13C NMR spectra at δ = 30.2 and 29.7 ppm, indicat-
0.678 mmol) was added, and the mixture was kept under the same
ing that the macrocycles display cone conformations. A
conditions for 24 h. Once cooled, MeOH was added, and the sol-
ROESY (CDCl3, room temperature) experiment with 1
shows cross-peaks that are in agreement with those pre-
vent was eliminated under reduced pressure. The residue obtained
was partitioned between CHCl3 and HCl (1 m). The organic phase
viously reported for bridged A,D-m-xylylenedioxycalix[6]-
arenes, indicating that all of the aromatic rings are in a syn
orientation.[7a]
was washed sequentially with brine (3 ϫ15 mL) and water, and
then it was dried (MgSO4). The solvent was eliminated under re-
duced pressure, and the residue obtained was triturated with
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A Nitro-m-xylylenedioxycalix[6]arene Building Block
MeOH. Finally, the precipitate obtained was purified by crystalli-
2.081 mmol) in dry CH2Cl2 (1.2 mL, 0.61 m) stirred at room tem-
zation (CHCl3/MeOH) to give 4 as a white solid (73.8 mg, 65%). perature was added a freshly prepared mixture of 65% HNO3 and
1
M.p. 245–247 °C. H NMR (500 MHz, C2D2Cl4, 403 K): δ = 7.43
concentrated H2SO4 (1:1, 260.0 μL). The mixture was heated at
30 °C for 3 h and, once cooled, water was added. The aqueous
3
3
(d, JH,H = 7.6 Hz, 4 H, ArH), 7.19 (s, 4 H, ArH), 7.15 (d, JH,H
= 7.7 Hz, 4 H, ArH), 7.07 (s, 4 H, ArH), 6.95 (s, 4 H, ArH), 5.55– solution was extracted with CH2Cl2, and the organic phase was
5.35 (m, 4 H, CH=), 4.87 (s, 4 H, ArOCH2Ph), 4.68–4.55 (m, 8 H, washed with water (until neutral pH) and then dried (MgSO4). The
2
CH2=), 4.53–4.44 (m, 8 H, ArOCH2), 4.20 (d, JH,H = 13.1 Hz 4
H, ArCH2Ar), 3.88–3.78 (m, 2 H, ArCH2Ar), 3.62–3.42 (m, 6 H,
ArCH2Ar), 2.34 (s, 6 H, ArCH3), 1.16 [s, 18 H, C(CH3)3], 1.10 [s,
solvent was eliminated under reduced pressure, and the residue ob-
tained was triturated with acetonitrile/H2O to give 7 as a yellowish
solid (431.1 mg, 65 %). M.p. Ͼ258 °C (decomp.). 1H NMR
36 H, C(CH3)3] ppm. 13C NMR (125 MHz, C2D2Cl4, 373 K, (500 MHz, C2D2Cl4, 373 K): δ = 8.67 (s, 2 H, ArOH), 7.81 (s, 4 H,
DEPT): δ = 153.5, 153.2, 145.9, 145.7, 137.7, 135.5 (Ar), 133.8
(CH=), 133.4, 133.3, 133.1 (Ar), 129.4, 128.5, 127.9, 126.3, 125.0
(ArH), 117.9 (CH2=), 74.8, 74.2 (OCH2), 34.4, 34.2 [C(CH3)3],
31.8, 31.7 [C(CH3)3], 30.0, 29.8 (ArCH2Ar), 21.3 (ArCH3) ppm.
ArH), 6.94 (s, 4 H, ArH), 6.88 (s, 4 H, ArH), 3.75 (s, 4 H, Ar-
CH2Ar), 3.74 (s, 8 H, ArCH2Ar), 3.55–3.45 (m, 8 H, Ar-
OCH2CH3), 0.97 [s, 36 H, C(CH3)3], 0.99–0.96 (m, 12 H, Ar-
OCH2CH3) ppm. 13C NMR (125 MHz, C2D2Cl4, 373 K, DEPT):
MS (MALDI-TOF+, NaI): m/z (%) = 1363.6 (100) [M + Na]+. δ = 158.5, 151.7, 147.3, 140.6, 133.8, 130.9, 128.8 (Ar), 127.1, 126.1,
C94H116O6·MeOH (1374.0): calcd. C 83.05, H 8.80; found C 83.16,
H 8.84.
124.0 (ArH), 69.8 (ArOCH2CH3), 34.0 [C(CH3)3], 31.6, 31.2 (Ar-
CH2Ar), 31.1 [C(CH3)3], 14.7 (ArOCH2CH3) ppm. MS (MALDI-
T O F + , N a I ) : m / z ( % ) = 1 0 8 5 . 6 ( 1 0 0 ) [ M + N a ] +
.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,40,41-tetraethoxy-39,42-
bis(4-methylbenzyloxy)calix[6]arene (5): A suspension of 3[2b]
(500.0 mg, 0.421 mmol) and NaH (60% suspension in mineral oil,
118.5 mg, 2.947 mmol) in dry DMF (17.5 mL, 25 mm) was pre-
pared in a 35-mL MW container. Ethyl iodide (550.0 μL,
6.876 mmol) was added, and the vessel was sealed and introduced
into the MW oven. The reaction was programmed at 120 °C for
25 min by using a 5-min temperature ramp and a maximum power
of 50 W. Then, H2O and HCl (1 m) were added, and the mixture
was stirred at room temperature for 40 min. The precipitate formed
was filtered, and the solid obtained was triturated with MeOH to
give 5 as a whitish solid (487.3 mg, 89%). M.p. 302–304 °C. 1H
C66H82N2O10·H2O (1081.4): calcd. C 73.31, H 7.83, N 2.59; found
C 73.54, H 7.74, N 2.60.
39,42-Diacetoxy-5,17,23,35-tetra-tert-butyl-37,38,40,41-tetra-
ethoxy-11,29-dinitrocalix[6]arene (8): To a solution of 7 (1.495 g,
1.406 mmol) and NaH (60% suspension in mineral oil, 562.0 mg,
14.059 mmol) in dry THF (140 mL, 0.01 m) under an argon atmo-
sphere at 60 °C was added acetyl chloride (1.40 mL, 19.7 mmol).
The mixture was kept under the same conditions for 24 h. Solvent
was eliminated under reduced pressure, and the residue obtained
was partitioned between CH2Cl2/HCl (1 m). The organic phase was
washed with water (until neutral pH) and dried (MgSO4). The sol-
vent was eliminated under reduced pressure, and the solid obtained
was triturated with Et2O to give 8 as a yellowish solid (1.4 g, 85%).
M.p. Ͼ330 °C (decomp.). 1H NMR (500 MHz, C2D2Cl4, 373 K): δ
3
NMR (500 MHz, C2D2Cl4, 398 K): δ = 7.54 (d, JH,H = 7.9 Hz, 4
H, ArH), 7.30–7.20 (m, 8 H, ArH), 7.13 (s, 4 H, ArH), 6.97 (s, 4
2
H, ArH), 4.95 (s, 4 H, ArOCH2), 4.27 (d, JH,H = 14.0 Hz, 4 H,
2
4
ArCH2Ar), 4.00–3.80 (m, 4 H, ArCH2Ar), 3.64 (d, JH,H
=
= 7.89 (s, 4 H, ArH), 7.02 (d, JH,H = 2.4 Hz, 4 H, ArH), 6.98 (d,
4JH,H = 2.4 Hz, 4 H, ArH), 3.92 (s, 4 H, ArCH2Ar), 3.79 (s, 8 H,
ArCH2Ar), 3.38 (s, 8 H, ArOCH2CH3), 2.29 (s, 6 H, ArOCOCH3),
13.8 Hz, 4 H, ArCH2Ar), 3.10–2.85 (m, 8 H, ArOCH2CH3), 2.42
(s, 6 H, ArCH3), 1.22 [s, 36 H, C(CH3)3], 1.15 [s, 18 H, C(CH3)3],
0.80–0.55 (m, 12 H, CH3) ppm. 13C NMR (125 MHz, C2D2Cl4,
373 K, DEPT): δ = 153.6, 152.8, 145.9, 145.5, 137.7, 135.6, 133.5,
133.4, 133.1 (Ar), 129.4, 128.5, 127.7 (ArH), 74.7, 68.6 (ArOCH2),
34.3, 34.2 [C(CH3)3], 31.8, 31.7 [C(CH3)3], 30.1 (ArCH2Ar), 21.3
(ArCH3), 15.7 (ArOCH2CH3) ppm. MS (MALDI-TOF+, NaI):
m/z (%) = 1316.7 (100) [M + Na]+. C90H116O6·H2O (1311.9): calcd.
C 82.40, H 9.07; found C 82.23, H 8.98.
3
1.20 [s, 36 H, C(CH3)3], 0.82 (t, JH,H = 6.8 Hz, 12 H, Ar-
OCH2CH3) ppm. 13C NMR (125 MHz, C2D2Cl4, 373 K, DEPT):
δ = 167.7 (CO), 153.1, 151.8, 146.5, 145.6, 136.3, 133.6, 130.5 (Ar),
127.2, 125.8, 123.3 (ArH), 68.6 (ArOCH2CH3), 34.1 [C(CH3)3],
31.7, 30.8 (ArCH2Ar), 31.3 [C(CH3)3], 20.5 (ArOCOCH3), 15.1
(ArOCH2CH3) ppm. MS (MALDI-TOF+, NaI): m/z (%) = 1169.7
(100) [M + Na]+. C70H86N2O12·0.5CHCl3 (1207.2): calcd. C 70.15,
H 7.22, N 2.32; found C 69.70, H 7.30, N 2.56.
5,11,17,23,29,35-Hexa-tert-butyl-37,38,40,41-tetraethoxy-39,42-di-
hydroxycalix[6]arene (6): To a mixture of 5 (3.800 g, 2.939 mmol)
and 10% Pd/C (200.0 mg) in CH2Cl2/iPrOH (8.5:1.5, 220.0 mL)
was passed a flow of hydrogen for 30 min, and the mixture was
stirred under a hydrogen atmosphere at room temperature for 4 h.
Then, the mixture was filtered through Celite, and the solvent was
eliminated under reduced pressure. The residue obtained was tritu-
rated with MeOH to give 6 as a whitish solid (3.05 g, 96%). M.p.
Ͼ280 °C (decomp.). 1H NMR (500 MHz, C2D2Cl4, 403 K): δ =
7.25 (s, 4 H, ArH), 6.96 (s, 8 H, ArH), 6.84 (s, 2 H, ArOH), 3.87 (s,
4 H, ArCH2Ar), 3.82 (s, 8 H, ArCH2Ar), 3.57 (q, 3JH,H = 7.0 Hz, 8
H, ArOCH2CH3), 1.18 [s, 18 H, C(CH3)3], 1.10 [s, 36 H,
39,42-Diacetoxy-11,29-diamino-5,17,23,35-tetra-tert-butyl-
37,38,40,41-tetraethoxycalix[6]arene (9): A mixture of 8 (651.0 mg,
0.567 mmol) and SnCl2·2H2O (1.456 g, 5.675 mmol) in AcOEt/
tBuOH (9:1, 65.0 mL) under an argon atmosphere was heated at
80 °C for 1 h. Then, a suspension of NaBH4 (21.6 mg, 0.567 mmol)
in AcOEt (2.0 mL) was added in small portions. The mixture was
kept at 70 °C for 2 h. The solvent was eliminated under reduced
pressure and cold water was added. The solution was basified with
5% NaHCO3 and extracted with AcOEt (2ϫ20 mL). The organic
phase was washed with water and dried (MgSO4). The solvent was
eliminated under reduced pressure, and the residue was triturated
with hexane/Et2O. The resulting precipitate was purified by column
chromatography (silica gel; hexane/THF, 8:1) to give 9 as a white
solid (389 mg, 63 %). M.p. Ͼ280 °C (decomp.). 1H NMR
(500 MHz, C2D2Cl4, 408 K): δ = 7.15–7.10 (m, 4 H, ArH), 6.94 (d,
4JH,H = 2.5 Hz, 4 H, ArH), 5.70–5.60 (m, 4 H, ArH), 4.10–4.00
(m, 4 H, ArCH2Ar) 3.73–3.69 (m, 8 H, ArOCH2CH3), 3.64 (s, 8
H, ArCH2Ar), 2.32 (s, 6 H, ArOCOCH3), 1.26 [s, 36 H,
3
C(CH3)3], 0.93 (t, JH,H = 7.0 Hz, 12 H, ArOCH2CH3) ppm. 13C
NMR (75 MHz, CDCl3, 298 K, DEPT): δ = 151.8, 149.9, 146.3,
141.7, 132.8, 132.2, 126.9 (Ar), 126.1, 125.9, 124.9 (ArH), 69.5 (Ar-
OCH2CH3), 34.0, 33.8 [C(CH3)3], 31.5, 31.3 [C(CH3)3], 30.9 (Ar-
CH2Ar), 14.9 (ArOCH2CH3) ppm. MS (MALDI-TOF+, NaI): m/z
(%) = 1107.7 (100) [M + Na]+. C74H100O6·H2O (1103.6): calcd. C
80.54, H 9.32; found C 80.57, H 9.23.
3
5,17,23,35-Tetra-tert-butyl-37,38,40,41-tetraethoxy-39,42-di-
hydroxy-11,29-dinitrocalix[6]arene (7): To a solution of 6 (673.0 mg,
C(CH3)3], 1.15 (t, JH,H = 6.6 Hz, 12 H, ArOCH2CH3) ppm. 13C
NMR (125 MHz, C2D2Cl4, 408 K, DEPT): δ = 169.2 (CO), 154.1,
Eur. J. Org. Chem. 2010, 7005–7011
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7009

H. Galán, J. de Mendoza, P. Prados
FULL PAPER
146.2, 145.7, 138.1, 133.2, 131.8 (Ar), 126.8, 125.9, 114.3 (ArH),
5,17,23,35-Tetra-tert-butyl-37,38,40,41-tetraethoxy-39,42-[5-nitro-
68.7 (ArOCH2CH3), 34.0 [C(CH3)3], 31.5 [C(CH3)3], 30.7 (Ar-
1,3-phenylenebis(methyleneoxy)]-11,29-bis(1,3-dioxo-1,3-dihydroiso-
CH2Ar), 20.4 (ArOCOCH3), 15.7 (ArOCH2CH3) ppm. MS indol-2-yl)calix[6]arene (1): A solution of 11 (15.0 mg, 0.012 mmol)
(MALDI-TOF+, NaI): m/z (%) = 1109.7 (38) [M + Na]+, 1087.7
and NaH (60% suspension in mineral oil, 2.0 mg, 0.047 mmol) in
(100) [M + H]+. C70H90N2O8·0.5(CHCl3·H2O) (1156.2): calcd. C dry THF/DMF (9:1, 2.0 mL, 5ϫ10–3 m) was prepared in a 10-mL
73.24, H 7.98, N 2.42; found C 73.16, H 8.17, N 2.50.
MW vessel and stirred for 5 min under an argon atmosphere. Then,
a solution of 12 (4.6 mg, 0.015 mmol) in THF/DMF (9:1, 0.5 mL,
5ϫ10–3 m) was added, and the vessel was sealed and introduced in
the MW oven. The reaction was programmed at 130 °C for 30 min
by using a 5-min temperature ramp and a maximum power of
180 W. Then, H2O and HCl (1 m) were added, and the mixture was
stirred at room temperature for 30 min. The solvent was eliminated
under reduced pressure, and the solid obtained was filtered, tritu-
rated with MeOH, and purified by thin-layer chromatography (sil-
ica gel; CH2Cl2/hexane, 3:1Ǟ5:1). Finally, the solid was triturated
with MeOH to give 1 as a white solid (8.0 mg, 48%). M.p. Ͼ300 °C
39,42-Diacetoxy-5,17,23,35-tetra-tert-butyl-37,38,40,41-tetra-
ethoxy-11,29-bis(1,3-dioxo-1,3-dihydroisoindol-2-yl)calix[6]arene
(10): To a suspension of 9 (210.0 mg, 0.193 mmol), phthalic anhy-
dride (77.2 mg, 0.521 mmol), and molecular sieves (3 Å, powder) in
dry toluene (5.2 mL) under an argon atmosphere was added Et3N
(150.0 μL). The mixture was heated at 100 °C for 20 h. After being
filtered, the solvent was eliminated under reduced pressure. The
residue was triturated with acetonitrile to give 10 as a white solid
(194.0 mg, 75%). M.p. Ͼ296 °C (decomp.). 1H NMR (500 MHz,
C2D2Cl4, 403 K): δ = 7.93–7.90 (m, 4 H, ArHphthal), 7.76–7.74 (m,
1
(decomp.). H NMR (500 MHz, CDCl3, 298 K): δ = 8.26 (s, 2 H,
4
4 H, ArHphthal), 7.35 (s, 4 H, ArH), 7.00 (d, JH,H = 2.3 Hz, 4 H,
ArHm-xylylenyl), 8.09–8.05 (m, 4 H, ArHphthal), 7.89–7.86 (m, 4 H,
ArHphthal), 7.53 (s, 4 H, ArH), 7.00 (s, 4 H, ArH), 6.99 (s, 4 H,
ArH), 6.97 (d, 4JH,H = 2.3 Hz, 4 H, ArH), 3.94 (s, 4 H, ArCH2Ar),
3
3.82 (s, 8 H, ArCH2Ar), 3.47 (q, JH,H = 6.9 Hz, 8 H, Ar-
2
ArH), 5.70 (s, 1 H, ArHm-xylylenyl), 4.59 (d, JH,H = 15.3 Hz, 4 H,
OCH2CH3), 2.08 (s, 6 H, ArOCOCH3), 1.16 [s, 36 H, C(CH3)3],
2
ArCH2Ar), 4.37 (d, JH,H = 14.8 Hz, 2 H, ArCH2Ar), 4.32 (s, 4 H,
3
0.96 (t, JH,H = 6.9 Hz, 12 H, ArOCH2CH3) ppm. 13C NMR
2
ArOCH2Ar), 3.75–3.66 (m, 8 H, ArOCH2CH3), 3.55 (d, JH,H
=
(125 MHz, C2D2Cl4, 373 K, DEPT): δ = 168.5, 166.5 (CO), 153.2,
145.7, 134.9, 133.1 (Ar), 134.1 (ArH), 132.1, 131.3, 129.3 (Ar),
126.5, 126.1, 125.7, 123.5 (ArH), 68.7 (ArOCH2CH3), 34.0
[C(CH3)3], 31.4 [C(CH3)3], 31.0 (ArCH2Ar), 20.6 (ArOCOCH3),
15.3 (ArOCH2CH3) ppm. MS (MALDI-TOF+, NaI): m/z (%) =
1369.7 (100) [M + Na]+. C86H94N2O12·0.5H2O (1356.7): calcd. C
76.14, H 7.06, N 2.06; found C 75.86, H 7.17, N 2.14.
15.0 Hz, 4 H, ArCH2Ar), 3.29 (d, 2JH,H = 14.0 Hz, 2 H, ArCH2Ar),
1.14 (t, JH,H = 7.0 Hz, 12 H, ArOCH2CH3), 1.03 [s, 36 H,
3
C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3, 298 K, DEPT): δ =
167.4 (CO), 152.1, 145.7, 135.2 (Ar), 134.3 (ArH), 132.7, 132.1,
132.0 (Ar), 129.2, 129.0 (ArH), 127.0 (Ar), 125.2, 124.3, 123.8,
118.6 (ArH), 70.9 (ArOCH2Ar), 68.7 (ArOCH2CH3), 34.2
[C(CH3)3], 31.3 [C(CH3)3], 30.2, 29.7 (ArCH2Ar), 15.4 (Ar-
OCH2CH3) ppm. MS (MALDI-TOF+, NaI): m/z (%) = 1433.8
(100) [M + Na]+. C90H95N3O12·0.5CHCl3 (1470.4): calcd. C 73.92,
H 6.55, N 2.86; found C 73.66, H 7.31, N 2.60.
5,17,23,35-Tetra-tert-butyl-37,38,40,41-tetraethoxy-39,42-di-
hydroxy-11,29-bis(1,3-dioxo-1,3-dihydroisoindol-2-yl)calix[6]arene
(11): A suspension of 7 (343.0 mg, 0.323 mmol) and Pd/C (10%,
20.0 mg) in EtOH (13.5 mL) was prepared in a 35-mL MW vessel.
Hydrazine monohydrate was added (630.0 μL, 6.450 mmol), and
the vessel was sealed and introduced in the MW oven. The reaction
was programmed at 120 °C for 20 min by using a 5-min tempera-
ture ramp and a maximum power of 125 W.
11,29-Diamino-5,17,23,35-tetra-tert-butyl-37,38,40,41-tetraethoxy-
39,42-[5-nitro-1,3-phenylenebis(methyleneoxy)]calix[6]arene (2): To
a sonicated suspension of 1 (55.0 mg, 0.039 mmol) in EtOH
(3.0 mL) was added hydrazine monohydrate (300.0 μL,
3.899 mmol), and the mixture was heated at 80 °C for 48 h. The
solvent was eliminated under reduced pressure, and the residue was
dissolved in CH2Cl2. The organic solution was washed with water
and dried (MgSO4). The solvent was eliminated under reduced
pressure. The resulting solid was dissolved in CHCl3/MeOH (2:1),
and the solvent was again removed in vacuo (the procedure was
repeated several times) to give 2 as a white solid (31.0 mg, 69%).
M.p. Ͼ215 °C (decomp.). 1H NMR (500 MHz, CDCl3, 298 K): δ
= 8.18 (s, 2 H, ArHm-xylylenyl), 6.96 (s, 4 H, ArH), 6.94 (s, 4 H,
ArH), 6.76 (s, 4 H, ArH), 5.70 (s, 1 H, ArHm-xylylenyl), 4.44 (d,
CAUTION! HIGH PRESSURE, OPEN CAREFULLY AFTER
COOLING.
The mixture was filtered through Celite, and the solvent was elimin-
ated under reduced pressure. A suspension of the solid obtained
without further purification, phthalic anhydride (143.4 mg,
0.967 mmol), and molecular sieves (4 Å, in powder) in dry toluene
(16.0 mL) was prepared under an argon atmosphere. Et3N
(300.0 μL) was added, and the mixture was heated at 90 °C for
20 h. After being filtered, the solvent was eliminated under reduced
pressure. The residue obtained was purified by column chromatog-
raphy (silica gel; CH2Cl2/hexane, 5:1) and finally triturated with
Et2O to give 11 as a white solid (240.0 mg, 60%). M.p. Ͼ340 °C.
1H NMR (500 MHz, C2D2Cl4, 388 K): δ = 8.00–7.98 (m, 2 H,
ArHphthal), 7.90–7.88 (m, 2 H, ArHphthal), 7.87–7.84 (m, 2 H,
ArHphthal), 7.74–7.72 (m, 2 H, ArHphthal), 7.56 (s, 2 H, ArOH), 7.10
2
2JH,H = 15.5 Hz, 4 H, ArCH2Ar), 4.32 (d, JH,H = 14.6 Hz, 2 H,
ArCH2Ar), 4.20 (s, 4 H, ArOCH2Ar), 3.66–3.63 (m, 8 H, Ar-
2
OCH2CH3), 3.37 (d, JH,H = 14.7 Hz, 4 H, ArCH2Ar), 3.27 (d,
2JH,H = 13.5 Hz, 2 H, ArCH2Ar), 1.17–1.05 (m, 12 H, ArCH2CH3),
1.00 [s, 36 H, C(CH3)3] ppm. 13C NMR (125 MHz, CDCl3, 298 K,
DEPT): δ = 152.1, 147.4, 145.2, 142.1, 135.0, 132.6 (Ar), 129.0,
125.0, 124.2, 118.3, 117.7 (ArH), 71.0 (ArOCH2Ar), 68.6 (Ar-
OCH2CH3), 34.1 [C(CH3)3], 31.4 [C(CH3)3], 30.2, 29.7 (ArCH2Ar),
15.4 (ArOCH2CH3) ppm. MS (MALDI-TOF+, NaI): m/z (%) =
1150. 8 (100) [M + H]+, 1172.7 (60) [M + Na]+. HRMS (MALDI):
calcd. for C74H91N3O8 [M]+ 1149.68007; found 1149.67810.
C74H91N3O8·2(CHCl3·H2O) (1425.3): calcd. C 64.04, H 6.86, N
2.95; found C 64.03, H 6.95, N 3.04.
4
4
(s, 4 H, ArH), 7.03 (d, JH,H = 2.0 Hz, 4 H, ArH), 6.98 (d, JH,H
3
= 2.1 Hz, 4 H, ArH), 3.91 (s, 12 H, ArCH2Ar), 3.68 (q, JH,H
=
=
6.8 Hz, 8 H, ArOCH2CH3), 1.13 [s, 36 H, C(CH3)3], 1.01 (t, 3JH,H
6.8 Hz, 12 H, ArOCH2CH3) ppm. 13C NMR (125 MHz, C2D2Cl4,
388 K): δ = 167.1, 163.3 (CO), 152.3, 152.1, 146.7 (Ar), 135.0, 133.8
(ArH), 133.4, 132.4, 131.9, 130.3, 128.4 (Ar), 126.4, 126.2, 126.0,
124.3, 123.2 (ArH), 69.5 (ArOCH2CH3), 34.0 [C(CH3)3], 31.5, 31.4
(ArCH2Ar), 31.3 [C(CH3)3], 14.9 (ArOCH2CH3) ppm. MS
(MALDI-TOF+, NaI): m/z (%) = 1301.6 (20) [M + K]+, 1285.6
(100) [M + Na]+. C82H90N2O10·0.5H2O (1272.6): calcd. C 77.39, H
7.21, N 2.20; found C 77.23, H 7.22, N 2.40.
CCDC-777050 (for 4) and -777051 (for 11) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
7010
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 7005–7011

A Nitro-m-xylylenedioxycalix[6]arene Building Block
U. Lüning, B. W. Skelton, A. H. White, F. Löffler, S. Konrad,
Eur. J. Org. Chem. 2005, 1348–1353; d) B. Guan, S. Gong, X.
Wu, Y. Chen, Tetrahedron Lett. 2005, 46, 6041–6044; e) S. Kon-
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Boswell, Tetrahedron Lett. 2006, 47, 7081–7084.
Supporting Information (see footnote on the first page of this arti-
cle): Spectral characterization data (1, 2, 4–11) and VT-1H NMR
spectra (188–298 K) and 2D NMR experiments at low temperature.
Acknowledgments
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Received: July 6, 2010
Published Online: November 17, 2010
Eur. J. Org. Chem. 2010, 7005–7011
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7011