Synthesis of isoxazolopyridobicyclooxacalix[4]arenes: A new family of heteracalixarene systems

Article abstract of DOI:10.1002/ejoc.200800714

A new family of isoxazolopyridobicyclooxacalix[4]arenes was obtained by reaction of dichloroisoxazolopyridines with phloroglucinol. X-ray crystallography and density functional calculations were used for their structural determination and evaluation of their chemical properties. Their role as metal chelators was studied by mass spectrometry. This new family of heteracalixarenes is of potential interest for host-guest interactions. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800714

FULL PAPER
DOI: 10.1002/ejoc.200800714
Synthesis of Isoxazolopyridobicyclooxacalix[4]arenes: A New Family of
Heteracalixarene Systems
Serena Ferrini,[a] Stefania Fusi,[a] Gianluca Giorgi,[a] and Fabio Ponticelli*[a]
Keywords: Calixarenes / Cage compounds / Density functional calculations / X-ray diffraction
A new family of isoxazolopyridobicyclooxacalix[4]arenes was
obtained by reaction of dichloroisoxazolopyridines with
phloroglucinol. X-ray crystallography and density functional
calculations were used for their structural determination and
evaluation of their chemical properties. Their role as metal
chelators was studied by mass spectrometry. This new family
of heteracalixarenes is of potential interest for host–guest in-
teractions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
tem with an isoxazole moiety increases the mobility of chlo-
rine atoms, which allows easy substitution by suitable nu-
cleophiles. In addition, it is possible to increase the struc-
tural diversity of the final products by well-known thermal
and/or photochemical modifications of the five-membered
nucleus.[9]
Introduction
Calixarenes[1] are a particularly interesting class of
macrocyclic compounds that continue to receive a large de-
gree of attention as a result of their wide ranging and prac-
tically useful features. Host–guest properties of these com-
pounds towards cations, anions and neutral species are use-
ful for analytical purposes,[2] as well as for the preparation
of new catalytic systems.[3] In addition, a biological role of
calixarene-containing structures was recently evidenced due
to their ability to simulate supramolecular cavities of active
sites.[4] Among this class of compounds, calixarenes con-
taining heterocyclic systems, that is, heteracalixarenes, are
of great interest as a consequence of both their increased
functionality and wide molecular diversity. Such a variety
derives from the nature and the position of the heteroatoms,
the dimensions of the ring systems and the nature of the
substituents that afford inner cavities that are easily tune-
able in both their structural and electronic properties. In this
way, modulation of the physicochemical properties of the
macromolecule can be achieved.[5] Conformational aspects
are also important: cone, partial cone and alternate struc-
tures have been described previously.[6] Recently, during an
investigation of oxacalixarenes[7] the synthesis and structure
of some heterobicyclooxacalix[4]arenes were described, and
these compounds were found to be conformationally re-
stricted analogues of oxacalixarenes with a cage-like struc-
ture of high symmetry.[8] This prompted us to design
calixarene structures based on aromatic isoxazolopyridines,
a class of molecules that we previously considered from a
synthetic, structural and chemical behaviour (namely, pho-
tochemical) point of view. Condensation of a pyridine sys-
Results and Discussion
Reaction of 4,6-dichloro-3-methylisoxazolo[4,5-c]pyr-
idine (1)[10] with phloroglucinol in the presence of DBU al-
lowed the preparation of the compounds reported in
Scheme 1. Careful selection of both reagent ratio and reac-
tion temperature (Entry a, b or c) allowed isolation of each
compound.
When the reaction was carried out according to the con-
ditions described in Entry a (Scheme 1), diether 3 was ob-
tained in 70% yield. A 1:1:1 molar ratio of reagents was
insufficient, and this compound was only formed in 40%
yield with the corresponding amount of starting material 1
recovered. Only a trace amount of monosubstituted com-
pound 2 was evidenced in the crude reaction mixture by
electrospray ionization mass spectrometry (ESI-MS), which
shows the corresponding very-low intensity protonated
molecule. Probably, the increased acidity of compound 2
owing to the heteroaryl substituent causes this compound
to be more reactive than phloroglucinol towards dichloro
derivative 1.
When operating under the conditions described in En-
try b (Scheme 1), trisubstituted phloroglucinol 4 was ob-
tained as the sole product. Finally, when the reaction tem-
perature was raised to 120 °C and the reaction time to 18 h
(Entry c, Scheme 1), bicyclooxacalix[4]arene isomers 5 and
6 (in a 2.75:1 molar ratio) were obtained and separated by
column chromatography. Proton NMR spectra allowed
structure assignments of these compounds. In fact, for com-
[a] Dipartimento di Chimica, Università degli Studi di Siena,
Via A. Moro, 53100 Siena, Italy
Fax: +39-0577-234254
E-mail: ponticelli@unisi.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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S. Ferrini, S. Fusi, G. Giorgi, F. Ponticelli
FULL PAPER
Scheme 1. Experimental conditions for the synthesis of compounds 3–6.
pound 6 the protons of the phenolic moieties resonate as a
singlet due to equivalent chemical shifts, whereas series of
multiplets is observed for compound 5. Owing to their
scarce polarity, both compounds 5 and 6 do not give any
ESI-MS signal, either as positive or negative ions. In con-
trast, they can be ionized as protonated molecules by atmo-
spheric pressure chemical ionization, which produces in-
tense ions suitable for MS–MS experiments for structural
characterization. The atmospheric pressure chemical ioniza-
tion (APCI) MS–MS spectrum obtained by selecting [5 +
H]+ as the precursor ion is reported in Figure 1. As it is
shown, the main gas-phase decomposition pathways involve
successive loss of HCN and CO, mainly due to the disman-
tling of the isoxazole moieties. It is noteworthy that after
one electron removal neither radical cations of isoxazolo-
pyridines[11,12] nor those of benzisoxazoles[13] show elimi-
Figure 1. APCI MS–MS spectrum of [5 + H]+ (m/z = 643) selected
as the precursor ion.
nation of HCN. In the present case, both the effect of pro-
tonation and the linkage of the isoxazolopyridine moiety in
the calix assembly play crucial roles in driving gas-phase cule. The three nitrogen atoms of the pyridine moieties
decompositions. point into the cavity in a trigonal planar array and the
The structure of compound 6, crystallized as its chloro- N···N distances are 4.81(1) Å. They act as possible nucleo-
form solvate, was confirmed by X-ray analysis (Figure 2). philic sites for interactions with included ligands. The nitro-
¯
It crystallizes in a highly symmetric space group (i.e., R), gen and oxygen atoms of the isoxazole moiety point out
and it shows C3i symmetry with a 1,3-alternate conforma- from the molecule, and they should play an important role
tion, which is also observed in other analogous com- in interactions with species surrounding the calixarene into
pounds.[7a,7b] One third of the atoms constitute the asym- the formed cavity. Conjugation between the bridging oxy-
metric unit, whereas the remaining atoms are generated by gen atoms and the pyridine rings is supported by the signifi-
symmetry. This causes the two phenyl rings to be parallel cantly shorter C–O bond length [1.364(5) Å average bond
and eclipsed with a distance of 4.437(1) Å between their length] versus the O–C phenyl ring carbon atoms
centroids. This arrangement results in an intramolecular π– [1.403(3) Å average bond length]. The three methyl groups
π interaction between the two rings that stabilizes the mole- are cis oriented.
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Synthesis of Isoxazolopyridobicyclooxacalix[4]arenes
Figure 3. Crystal packing views along the x axis of 6·CHCl3.
Figure 2. Two views of the ORTEP drawing of compound 6·CHCl3
(50% probability thermal ellipsoids). The site-occupation factor for
the reported chloroform molecule is 0.55(4). In the bottom view,
the chloroform molecule is omitted for clarity.
The chloroform molecule shows statistical disorder and
three different positions were refined for it with site occupa-
tion factors of 0.56(4), 0.29(4) and 0.16(1), respectively. The
chlorine atoms show intermolecular interactions with O1,
N2 N6 and O10. The crystal packing of 6·CHCl3 is shown
in Figure 3. The different layers of molecules along the bc
Figure 4. Two different views of the energy-minimized structures
[B3LYP/6-31G(d,p)] of compounds 5 and 6.
plane are formed by chloroform and heteracalixarene mole- 6 have almost the same energy (Table 1), which suggests
cules. The heteracalixarene moieties are arranged in a head- that the alternate orientation of the methylisoxazolo moiety
to-head fashion with the methyl groups of the two adjacent does not influence the stability of the entire molecule.
layers oriented on the same side.
Similarly, when compound 4, which represents a possible
Aimed at evaluating the relative stability of both com- intermediate for the formation of the calix systems, was
pounds 5 and 6, density functional theory calculations were treated according to the Entry c (Scheme 1), compounds 5
carried out (Figure 4). Concerning compound 6, the calcu- and 6 were obtained. In any case, careful analysis of the
lations optimized a structure quite close to that obtained crude reaction mixture also allowed monosubstituted ether
from the crystal data.
2 to be isolated from the fractions with low Rf values. Treat-
The intramolecular distance between the nitrogen atoms ment of this fraction with an excess amount of ethereal di-
of the cavity was calculated to be 4.839 Å for both 5 and 6, azomethane (Scheme 2) gave corresponding dimethyl ether
which is close to that determined in the X-ray structure of 7, which was also easily obtained from dichloro derivative
6·CHCl3. All the nitrogen and oxygen atoms in both 5 and 1 and 3,5-dimethoxyphenol.
6 have negative atomic charges; the nitrogen atoms are ori-
Results obtained from syntheses carried out at 20 or
ented in towards the cavity and the oxygen atoms bridging 60 °C (Entries a or b, Scheme 1) strongly suggest that the
the phenyl and the pyridine moieties have the most negative formation of compound 2 arises from cleavage of 3 and/or
charges. It was determined by calculations that both 5 and 4. After elution of compounds 5 and 6, further chromato-
Eur. J. Org. Chem. 2008, 5407–5413
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5409

S. Ferrini, S. Fusi, G. Giorgi, F. Ponticelli
FULL PAPER
Table 1. Energy values for the minimized structures of compounds 5 and 6.
Compound
B3LYP/6-31G(d,p)[a]
ZPVE[b]
SCF + ZPVE[a]
∆E (SCF+ZPVE)[c]
5
6
–2273.784290
–2273.784624
0.449097
0.449129
–2273.335193
–2273.335495
+0.19
0
[a] Units of Hartree. [b] Zero-point vibrational energies corrected by 0.9613,[16] units of Hartreeparticle–1. [c] Units of kcalmol–1.
ions at m/z = 771 are due to the mixed-metal complex [M +
Ag + Na – H]+, whose overall monopositive charge requires
deprotonation of the calixarene moiety. Alkaline metal ions
and CuII did not produce detectable complexes. These re-
sults are very useful to verify the progress of the synthetic
procedure and suggest potential use of these heteracalixar-
enes as selective metal chelators.
Scheme 2. Synthesis of dimethoxy derivative 7. Reagents and con-
ditions: (a) 3,5-dimethoxyphenol, DBU, DMSO, r.t.; (b) excess di-
azomethane, methanol.
graphic elution showed, when submitted to electrospray
negative-ion analysis, the presence of ions with m/z = 511,
which corresponds to both oxacalixarenes 8 and 9 (Fig-
ure 5).
Figure 5. Structures of calixarenes 8 and 9.
Attempts to separate these compounds were unsuccessful
due to their very similar chromatographic behaviour and
limited quantities. However, the NMR spectrum of the mix-
ture confirmed the postulated structures.
The versatility of compounds 5 and 6 as metal-ion chela-
tors was initially tested by ESI-MS analysis, a very useful
“ion-fishing” technique. Owing to their affinity for metal
Figure 6. Electrospray spectra (positive mode) obtained by mixing
5 with NiCl2 (a) or AgNO3 (b).
ions such as silver and nickel, compounds 5 and 6 form
stable complexes that yield intense positive ions when sub-
mitted to electrospray ionization (Figure 6). By mixing 5
Catalytic hydrogenation of both compounds 5 and 6 al-
with NiCl2, the ESI(+) spectrum reported in Figure 6a was lowed the preparation in quantitative yield of the corre-
obtained. The most abundant ions are due to [M + NiII
+
sponding modified bicyclooxacalix[4]arenes 10 and 11
Cl]+ (m/z = 735), in which one coordination site of the (Scheme 3), which show a major degree of functionalization
metal is constituted by chlorine, so the overall complex has on the outside rim. In this way it is expected that these
a charge of +1. In addition, ions at m/z = 755 are attribut- compounds will exhibit greater solubility in polar solvents
able to [M + NiII – 3H]+. When 5 is mixed with AgNO3, and in acidic or basic systems. In addition, further chemical
2
abundant ions at m/z = 751 due to [M + Ag]+, in agreement modifications could be achieved on the enamino and pyr-
with their isotopic cluster, are formed (Figure 6b). Other idone moieties.
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Eur. J. Org. Chem. 2008, 5407–5413

Synthesis of Isoxazolopyridobicyclooxacalix[4]arenes
atroomtemperaturefor0.5 h.4,6-Dichloro-3-methylisoxazolo[4,5-c]-
pyridine (1) in different molar ratios (2 mmol, 406 mg or 3 mmol,
609 mg or 1.5 mmol, 305 mg; Scheme 1) was dissolved in DMSO
(5 mL) and added to the solution. The final solution was heated at
different temperatures (20, 60, 120 °C) for different times (14, 3,
18 h) according to Scheme 1. The reaction mixture was poured into
an ice–water mixture and repeatedly extracted with ethyl acetate
(3ϫ20 mL), washed with water and dried with Na2SO4; the sol-
vents were then evaporated under vacuum. The residue was puri-
fied by flash chromatography to give compounds 2–6 and 8 and 9.
5-(6-Chloro-3-methylisoxazolo[4,5-c]pyridine-4-yloxy)benzene-1,3-
diol (2): Obtained according to Entry c (Scheme 1) after purifica-
tion by column chromatography (petroleum ether/EtOAc, 2:1) and
recrystallization from cyclohexane. Yield: 25 mg (9%). White solid.
M.p. 179–180 °C. Rf = 0.10 (petroleum ether/EtOAc, 2:1). 1H
NMR (400 MHz, CD3OD): δ = 2.51 (s, 3 H), 6.16 (s, 2 H), 6.19 (s,
1 H), 7.34 (s, 1 H) ppm. 13C NMR (100 MHz, CD3OD): δ = 11.29,
95.98, 101.23, 102.24, 108.81, 150.29, 155.45, 155.68, 158.30,
160.37, 172.93 ppm. ESI-MS: m/z = 291/293 [M – H]– .
C13H9ClN2O4 (292.67): calcd. C 53.35, H 3.10, N 9.57; found C
53.12, H 3.07, N 9.74.
Scheme 3. Catalytic hydrogenation of bicyclooxacalix[4]arenes.
Reagents and conditions: (a) H2, 10% Pd on carbon, ethyl acetate,
60 psi, r.t.; (b) from 5; (c) from 6.
3,5-Bis(6-chloro-3-methylisoxazolo[4,5-c]pyridin-4-oxy)phenol (3):
Obtained according to Entry a (Scheme 1) after purification by col-
umn chromatography (petroleum ether/EtOAc, 4:1). Yield: 320 mg
(70%). White solid. M.p. 220–222 °C. Rf = 0.28 (petroleum ether/
Conclusions
The synthetic strategy described herein offers efficient ac-
cess to bicyclooxacalix[4]arenes of potential interest for
host–guest interactions. By operating under different condi-
tions, some reaction intermediates were isolated and fully
characterized. X-ray crystallography was successfully used
for the determination of the structural and conformational
parameters of one major compound. Density functional
calculations showed that the orientation of the isoxazolo-
pyridine moiety has only a minor effect on the stability of
the molecule. Chelating properties towards metal ions, in
particular AgI and NiII, were studied by mass spectrometry.
Catalytic hydrogenation gives access to differently function-
alized heteracalixarene systems.
1
EtOAc, 4:1). H NMR (200 MHz): δ = 2.65 (s, 6 H), 6.51–6.61 (m,
3 H), 7.15 (s, 2 H) ppm. 13C NMR (50 MHz, CDCl3/CD3OD): δ
= 11.16, 101.56, 105.77, 106.36, 107.65, 148.90, 153.39, 154.16,
156.36, 158.72, 171.34 ppm. ESI-MS: m/z = 457/459 [M – H]–.
C20H12Cl2N4O5 (459.24): calcd. C 52.31, H 2.63, N 12.20; found C
52.09, H 2.74, N 12.39.
1,3,5-Tris(6-chloro-3-methylisoxazolo[4,5-c]pyridin-4-yloxy)benzene
(4): Obtained according to Entry b (Scheme 1) after purification
by column chromatography (petroleum ether/EtOAc, 4:1). Yield:
345 mg (55%). Very electrostatic white solid. M.p. Ͼ 270 °C. Rf =
1
0.28 (petroleum ether/EtOAc, 4:1). H NMR (400 MHz): δ = 2.72
(s, 9 H), 7.16 (s, 3 H), 7.23 (s, 3 H) ppm. 13C NMR (100 MHz):
δ = 11.45, 29.69, 102.15, 112.53, 148.94, 153.29, 154.04, 155.89,
1 7 1 . 6 0 p p m . E S I - M S : m / z = 6 2 5 / 6 2 7 / 6 2 9 [ M + H ] +
.
C27H15Cl3N6O6 (625.80): calcd. C 51.82, H 2.42, N 13.43; found C
51.63, H 2.31, N 13.57.
Experimental Section
General Information: 1H and 13C NMR spectra were recorded at
27 °C (CDCl3), unless otherwise stated, with a Bruker AC200 in-
strument operating at 200.13 and 50.33 MHz, respectively, or with
7,22,34-Trimethyl-4,9,13,19,24,28,31,36,40-nonaoxa-8,23,35,41,
43,45-hexa-azadecacyclo[14.14.10.13,29.15,12.114,18.120,27.132,39
.
06,10.021,25.033,37]pentatetraconta-1,3(42),5,7,10,12(45),14,15,17,20,
22,25,27(43),29,32,34,37,39(41)octadecaene (5): Obtained accord-
ing to Entry c (Scheme 1) after separation from compound 6 by
column chromatography (petroleum ether/EtOAc, 9:1) and
recrystallization from cyclohexane. Yield: 141 mg (22%). White so-
lid. M.p. Ͼ 270 °C. Rf = 0.68 (petroleum ether/EtOAc, 9:1). 1H
NMR (400 MHz): δ = 2.62 (s, 9 H), 6.53–6.55 (m, 3 H), 6.59–6.62
(m, 3 H), 6.68 (s, 3 H) ppm. 13C NMR (100 MHz): δ = 11.32,
84.94, 85.02, 103.37, 115.32, 115.40, 115.78, 115.88, 153.53, 153.64,
153.79, 153.87, 154.96, 155.09, 156.62, 163.51, 173.02 ppm. APCI-
MS: m/z = 643 [M + H]+. C33H18N6O9 (642.53): calcd. C 61.69, H
2.82, N 13.08; found C 61.81, H 2.74, N 13.36.
a
Bruker Avance 400 instrument operating at 400.13 and
100.62 MHz, respectively. The chemical shifts are reported in ppm
on the δ scale by using the solvent peak as a reference value. Data
are reported as follows: s = singlet, d = doublet, t = triplet, q =
quartet, dd = doublet of doublet, m = multiplet, br. = broad. Mass
spectra were recorded as positive ions or negative ions with a LCQ-
DECA Thermo instrument by using electrospray or APCI. GC–
MS experiments were carried out with a Saturn 2000 ion trap (EI,
70 eV) coupled with a Varian 3800 gas chromatograph (Varian,
Walnut Creek, CA, USA) equipped with a J&W DB5-MS column
(30 mϫ0.25 mm ID, 0.25 µm film thickness). All solvents were pre-
viously dried according to standard procedures. Analytical TLC
was performed on silica gel 60 F254 plates. Flash column
chromatography was carried out on silica gel (0.040–0.063 mm).
7,25,34-Trimethyl-4,9,13,19,23,28,31,36,40-nonaoxa-8,24,35,
41,43,45-hexaaza-decacyclo[14.14.10.13,29.15,12.114,18.120,27.132,39
.
06,10.022,26.033,37]pentatetraconta-1,3 (42),5,7,10,12(45),14,15,17,20,
22(26),24,27(43),29,32,34,37,39(41)octadecaene (6): Obtained ac-
cording to Entry c (Scheme 1) after separation from compound 5
by column chromatography (petroleum ether/EtOAc, 9:1) and
recrystallization from cyclohexane. Yield: 51 mg (8%). White solid.
General Procedure for the Reactions of Phloroglucinol with 4,6-
Dichloro-3-methylisoxazolo[4,5-c]pyridine: A solution of phloroglu-
cinol (1 m, 126 mg) in DMSO (5 mL) and different amounts of
DBU (2 mmol, 0.3 mL or 3 mmol, 0.45 mL; Scheme 1) was stirred
Eur. J. Org. Chem. 2008, 5407–5413
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S. Ferrini, S. Fusi, G. Giorgi, F. Ponticelli
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1
M.p. Ͼ 270 °C. Rf = 0.72 (petroleum ether/EtOAc, 9:1). H NMR
6,20,27-Triethanimidoyl-4,10,16,22,25,31-hexaoxa-32,34,36-
triazaheptacyclo[11.11.7.13,23.15,9.111,15.117,21.126,30]hexatriaconta-
(400 MHz): δ = 2.62 (s, 9 H), 6.47 (s, 3 H), 6.66 (s, 6 H) ppm. 13C
NMR (100 MHz): δ = 11.33, 85.11, 103.29, 115.25, 115.99, 153.75, 1,3(33),5,8,11(35),12,14,17,20,23,26,29-dodecaene-7,19,28-trione
154.81, 156.55, 163.54, 173.03 ppm. APCI-MS: m/z = 643 [M +
H]+. C33H18N6O9 (642.53): calcd. C 61.69, H 2.82, N 13.08; found
C 61.59, H 2.97, N 12.83.
(11): Rf = 0.25 (ethyl acetate/petroleum ether, 4:1). M.p. 124–
126 °C. H NMR (400 MHz, [D6]DMSO): δ = 2.47 (s, 9 H), 5.52
1
(m, 3 H), 5.95 (exch. br., 3 H), 6.23 (s, 3 H), 6.55 (s, 3 H), 6.64
(exch. br., 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 25.32,
92.16, 94.29, 98.43, 115.38, 115.68, 153.73, 154.20, 164.83,165.77,
177.28, 182.93 ppm. ESI-MS: m/z = 753/755 [M – 2H + Ag]–.
C33H24N6O9 (648.58): calcd. C 61.11, H 3.73, N 12.96; found C
61.32, H 3.59, N 13.12.
6-Chloro-4-(3,5-dimethoxyphenoxy)-3-methylisoxazolo[4,5-c]pyr-
idine (7): A solution of 3,5-dimethoxyphenol (0.154 g, 1 m) in
DMSO (3 mL) and DBU (1 m) was stirred at room temperature
for 0.5 h. 4,6-Dichloro-3-methylisoxazolo[4,5-c]pyridine (1; 0.203 g,
1 m) dissolved in DMSO (3 mL) was added, and the solution was
kept at room temperature for 3 h. The reaction mixture was poured
into an ice–water mixture and repeatedly extracted with ethyl ace-
tate, washed with water and dried with Na2SO4; the solvents were
then evaporated under vacuum to give compound 7 (288 mg, 90%)
as a white solid that was purified by recrystallization from cyclo-
X-ray Crystallography: Single crystals of 6·CHCl3 were obtained by
dissolving a few milligrams of powder in chloroform and allowing
the solution to concentrate at room temperature. A Siemens P4
four-circle diffractometer with graphite-monochromated Mo-Kα
radiation (λ = 0.71073 Å) and the ω scan technique were used for
data collection. The structure was solved by direct methods im-
plemented in the SHELXS-97 program.[14] The refinement was car-
ried out by full-matrix anisotropic least-squares methods on F2 for
all reflections for non-hydrogen atoms by using the SHELXL-97
program.[15] The cocrystallized chloroform molecule shows statisti-
cal disorder with three different positions, whose site occupancy
factors were refined to 0.55(4), 0.29(4), and 0.16(1), respectively.
1
hexane. M.p. 109–111 °C. H NMR (200 MHz): δ = 2.68 (s, 3 H),
3.78 (s, 6 H), 6.37, 6.39 (m, 3 H), 7.18 (s, 1 H) ppm. 13C NMR
(50 MHz): δ = 11.28, 55.49, 97.99, 99.96, 101.40, 107.89, 149.00,
153.64, 154.13, 161.30, 171.43 ppm. GC–MS: m/z = 320/322 [M]+·.
C15H13ClN2O4 (320.73): calcd. C 56.17, H 4.09, N 8.73; found C
56.46, H 4.23, N 8.46.
The same compound (identical m.p. and spectroscopic data) was
obtained in quantitative yield by reaction of 5-(6-chloro-3-methyl-
isoxazolo[4,5-c]pyridine-4-yloxy)benzene-1,3-diol (2) with an excess
amount of diazomethane in ether.
CCDC-668972 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
11,26-Dimethyl-2,8,13,17,23,28-hexaoxa-12,27,31,33-tetra-
azaheptacyclo[22.6.1.13,7.19,16.118,22.010,14.025,29]tetratriaconta-
1(31),3(34),4,6,9,11,14,16(33),18(32),19,21,24,26,29-tetradecaene-
5,20-diol 8 and 11,29-Dimethyl-2,8,13,17,23,27-hexaoxa-
Theoretical Calculations: Density functional theory calculations
were carried out for compounds 5 and 6 by using Gaussian 03[16]
implemented on a IBM SP RS/6000 Power 5 supercomputer at Ci-
neca in Bologna (Italy). All geometries were fully optimized with-
out any constraints at the Becke 3LYP (B3LYP)[17] method with
the 6-31G(d,p) level of theory. The final lowest-energy geometries
were confirmed as a minimum on the potential energy surface by
normal-mode vibrational frequency calculations that produced all
real frequencies. Zero-point energies and statistical thermodynamic
properties at 298.15 K and 1 atm were calculated at the B3LYP/6-
31G(d,p) level of theory. A scaling factor of 0.9613 was used for
zero-point energies.[18]
12,28,31,33-tetraazaheptacyclo[22.6.1.13 , 7 .19 , 1 6 .11 8 , 2 2
.
010,14.026,30]tetratria-conta-1(30),3(34),4,6,9,11,14,16(33),18(32),
19,21,24(31),25,28-tetradecaene-5,20-diol (9): Obtained according
to Entry c (Scheme 1) after separation from compound 2 by col-
umn chromatography (petroleum ether/EtOAc, 2:1) as a single
chromatographic fraction. Yield: 50 mg (10%). White solid. Rf =
0.08 (petroleum ether/EtOAc, 2:1). 1H NMR (400 MHz, CD3OD):
δ = 2.58 (s, 6 H, 2 CH3), 6.03 (t, 2 H, CHPh), 6.12 (t, 2 H, CHPh),
6.21 (d, 4 H, CHPh), 6.25 (t, 2 H, CHPh), 6.30 (t, 2 H, CHPh),
6.36 (d, 4 H, CHPh), 6.69 (s, 2 H, CHPyr), 6.71 (s, 2 H, CHPyr)
ppm. 13C NMR (50 MHz, CD3OD): δ = 11.27, 86.36, 86.82, 96.73,
104.78, 106.94, 107.14, 107.63, 107.93, 108.20, 108.57, 155.14,
155.37, 156.82, 157.85, 160.19, 160.49, 164.83, 165.42, 174.26 ppm.
ESI-MS: m/z = 511 [M – H]–. C26H16N4O8 (512.43): calcd. C 60.94,
H 3.15, N 10.93; found C 61.09, H 3.10, N 10.64.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic characterization of compounds 2–11.
Acknowledgments
Catalytic Hydrogenation of Compounds 5 and 6: A mixture of com-
pound 5 or 6 (50 mg) and 10 % Pd/C (10 mg) in ethyl acetate
(50 mL) was shaken in a Parr apparatus under hydrogen pressure
(60 psi) for 1 h. The catalyst was removed by filtration through Ce-
lite, and the solvent was evaporated in vacuo to give compounds
10 and 11, respectively, in quantitative yield.
This work was financially supported by the University of Siena as
a PAR Project 2006 and PRIN 2006. The authors wish to thank
the “Centro di Analisi e Determinazioni Strutturali” of the Univer-
sity of Siena for MS spectra and X-ray data collection.
[1] For recent general reviews, see: a) V. Böhmer in The Chemistry
of Phenols: Calixarenes (Ed.: Z. Rappoport), J. Wiley & Sons,
New York, 2003, pp. 1370–1383; b) G. Mc Mahon, S. O’Mal-
ley, K. Nolan, Arkivoc 2003, 23–31; c) M.-Z. Asfari, V. Böhmer,
J. Harrowfield, J. Vicens (Eds.), Calixarenes 2001, Kluwer Aca-
demic, Dordrecht, 2001; d) L. Mandolini, R. Ungaro (Eds.),
Calixarenes in Action, Imperial College Press, London, 2000;
e) C. D. Gutsche in Calixarene Revisited (Ed.: J. F. Stoddart),
The Royal Society of Chemistry, Cambridge, 1998.
[2] a) G. J. Lumetta, R. D. Rogers, A. S. Gopalan (Eds.), Calixar-
enes for Separations, ACS Symposium Series 757, American
Chemical Society, Washington, DC, 2000; b) J. L. Sessler, D. E.
Gross, W.-S. Cho, V. M. Lynch, F. P. Schmidtchen, G. W. Bates,
6,18,27-Triethanimidoyl-4,10,16,22,25,31-hexaoxa-32,34,36-tri-
azaheptacyclo[11.11.7.13,23.15,9.111,15.117,21.126,30]hexatriaconta-
1,3(33),5,8,11(35),12,14,17,20,23,26,29-dodecaene-7,19,28-trione
(10): Rf = 0.45 (ethyl acetate/petroleum ether, 4:1). M.p. 122–
1
123 °C. H NMR (200 MHz, [D6]DSMO): δ = 2.49 (s, 9 H), 5.52
(m, 3 H), 6.38 (m, 3 H), 6.41 (m, 3 H), 5.92, 6.27, 6.51 (exch. br.,
6 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 25.38, 92.26,
94.30, 98.42, 115.52, 115.60, 153.70, 154.21, 156.77, 163.45, 164.89,
174.60, 177.40, 182.94 ppm. ESI-MS: m/z = 753/755 [M – 2H +
Ag]–. C33H24N6O9 (648.58): calcd. C 61.11, H 3.73, N 12.96; found
C 60.95, H 3.68, N 13.06.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5407–5413

Synthesis of Isoxazolopyridobicyclooxacalix[4]arenes
M. E. Light, P. A. Gale, J. Am. Chem. Soc. 2006, 128, 12281–
12288; c) K. A. Nielsen, W.-S. Cho, J. Lyskawa, E. Levillain,
V. M. Lynch, J. L. Sessler, J. O. Jeppesen, J. Am. Chem. Soc.
2006, 128, 2444–2451; d) J.-Y. Park, B.-C. Kim, S.-M. Park,
Anal. Chem. 2007, 79, 1890–1896.
W. V. Rossom, W. Maes, L. Kishore, M. Ovaere, L. Van Meerv-
elt, W. Dehaen, Org. Lett. 2008, 10, 585–588; W. Maes, W. V.
Rossom, K. Van Hecke, L. Van Meervelt, W. Dehaen, Org.
Lett. 2006, 8, 4161–4164.
[8] J. L. Katz, K. J. Selby, R. R. Conry, Org. Lett. 2005, 7, 3505–
[3] a) F. Haffner, M. Marquez, C. Gonzalez, J. Phys. Chem. A
2007, 111, 268–272; b) R. Cacciapaglia, A. Casnati, A. L. Man-
dolini, D. N. Reinhoudt, R. Salvio, A. Sartori, R. Ungaro, J.
Am. Chem. Soc. 2006, 128, 12322–12330; c) R. Cacciapaglia, A.
Casnati, L. Mandolini, D. N. Reinhoudt, R. Salvio, A. Sartori,
3507.
[9] a) D. Donati, S. Fusi, F. Ponticelli, Tetrahedron Lett. 2002, 43,
9527–9530; b) D. Donati, S. Ferrini, S. Fusi, F. Ponticelli, Syn-
thesis 2003, 2518–2524; c) D. Donati, S. Ferrini, S. Fusi, F.
Ponticelli, J. Heterocycl. Chem. 2004, 41, 761–766.
A. R. Ungaro, J. Org. Chem. 2005, 70, 624–630; d) S. Shimizu, [10] G. Adembri, A. Camparini, F. Ponticelli, P. Tedeschi, J. Chem.
S. Shirakawa, T. Suzuki, Y. Sasaki, Tetrahedron 2001, 57, 6169–
6173.
Soc. Perkin Trans. 1 1975, 2190–2194.
[11] F. Ponticelli, D. Giomi, S. Papaleo, P. Tedeschi, Org. Mass
Spectrom. 1993, 28, 451–454.
[12] G. Giorgi, F. Ponticelli, G. Czira, K. Vékey, J. Am. Soc. Mass
Spectrom. 1995, 6, 962–971.
[13] G. Giorgi, L. Salvini, F. Ponticelli, J. Am. Soc. Mass Spectrom.
2004, 15, 1005–1013.
[14] G. Sheldrick, SHELXS-97: A Program for Automatic Solution
of Crystal Structures, Release 97-2, University of Göttingen,
Germany, 1997.
[15] G. Sheldrick, SHELXL-97: A Program for Crystal Structure
Refinement, Release 97-2, University of Göttingen, Germany,
1997.
[16] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr., T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morok-
uma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzew-
ski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K.
Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V.
Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B.
Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.
Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A.
Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian 03, Re-
vision D.02, Gaussian, Inc., Wallingford, CT, 2004.
[17] A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[4] a) V. Paquet, A. Zumbuehl, A. E. M. Carreira, Bioconjugate
Chem. 2006, 17, 1460–1463; b) S. Safi, Z. Asfari, L. Ehret-
Sabatier, M. Leroy, A. Hagege, Bioconjugate Chem. 2006, 17,
1346–1350; c) S. Cherenok, A. Vovk, I. Muravyova, A. Shivan-
yuk, V. Kukhar, J. Lipkowski, V. Kalchenko, Org. Lett. 2006,
8, 549–552; d) R. Nishiyabu, P. Anzenbacher, J. Am. Chem.
Soc. 2005, 127, 8270–8271.
[5] a) S. Kumar, D. Paul, H. Singh in Advances in Heterocyclic
Chemistry (Ed. A. R. Katritzky), Elsevier, Amsterdam, 2005,
vol. 89, pp. 65–73; b) W. Sliwa, Chem. Heterocycl. Compd.
2004, 40, 683–700; c) A. F. Danil de Namor, M. Shehab, I.
Abbas, M. V. Withams, J. Zvietcovich-Guerra, J. Phys. Chem.
B 2006, 110, 12653–12659; d) T. V. Shishkanova, D. Sýkora,
J. L. Sessler, V. Král, Anal. Chim. Acta 2007, 587, 247–253; e)
R. Nishiyabu, M. A. Palacios, W. Dehaen, P. Anzenbacher, J.
Am. Chem. Soc. 2006, 128, 11496–11504; f) A. F.
Danil de Namor, I. Abbas, H. H. Hammud, J. Phys. Chem. B
2006, 110, 2142–2149; g) W. Chen, W. Z.-R. Li, D. Wu, Y. Li,
C.-C. Sun, F. L. Gu, Y. Aoki, J. Am. Chem. Soc. 2006, 128,
1072–1073; h) A. F. Danil de Namor, A. Aguilar-Cornejo, R.
Soualhi, M. Shehab, K. B. Nolan, N. Ouazzani, N. L. Mandi,
J. Phys. Chem. B 2005, 109, 14735–14741; i) C.-H. Lee, J.-S.
Lee, H.-K. Na, D.-W. Yoon, H. Miyaji, W.-S. Cho, J. L. Sessler,
J. Org. Chem. 2005, 70, 2067–2074; j) M.-X. Wang, H.-B. Yang,
J. Am. Chem. Soc. 2004, 126, 15412–15422.
[6] a) C. Aleman, D. Zanuy, J. Casanovas, J. Org. Chem. 2006,
71, 6952–6957; b) Y. Tokunaga, H. Sakon, H. Kanefusa, Y.
Shimomura, K. Suzuki, Arkivoc 2003, 135–143; c) R. D. Cham-
bers, P. R. Hoskin, A. R. Kenwright, A. Khalil, P. Richmond,
G. Sandford, D. S. Yufit, J. A. K. Howard, Org. Biomol. Chem.
2003, 1, 2137–2147.
[7] a) J. L. Katz, B. J. Geller, P. D. Foster, Chem. Commun. 2007, [18] M. P. Callahan, B. Crews, A. Abo-Riziq, L. Grace, M. S.
1026–1028; b) J. L. Katz, M. B. Feldman, R. R. Conry, Org.
Lett. 2005, 7, 91–94; c) J. L. Katz, B. J. Geller, R. R. Conry,
Org. Lett. 2006, 8, 2755–2758; d) H. Konishi, T. Mita, O. Mori-
kawa, K. Kobayashi, Tetrahedron Lett. 2007, 48, 3029–3032; e)
de Vries, Z. Gengeliczki, T. M. Holmes, G. A. Hill, Phys. Chem.
Chem. Phys. 2007, 9, 4587–4591.
Received: July 18, 2008
Published Online: October 9, 2008
Eur. J. Org. Chem. 2008, 5407–5413
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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