Fused azacalix[4]arenes

Article abstract of DOI:10.1002/ejoc.201301509

The synthesis of unprecedented fused azacalixarenes (dimers and trimer) through successive nucleophilic aromatic substitutions is described. Absorption spectrophotometric and theoretical studies demonstrated that these oligomers share common phenyl moieties that enable conjugation of the whole π-system and a multiconcave geometry with aligned cavities because of the high flexibility of these macrocycles.

Full text of DOI:10.1002/ejoc.201301509

FULL PAPER
DOI: 10.1002/ejoc.201301509
Fused Azacalix[4]arenes
Rose Haddoub,[a] Mounia Touil,[a] Zhongrui Chen,[a] Jean-Manuel Raimundo,[a]
Philippe Marsal,[a] Mourad Elhabiri,[b] and Olivier Siri*[a]
Keywords: Macrocycles / Structure elucidation / Nucleophilic substitution / Calixarenes
The synthesis of unprecedented fused azacalixarenes (di-
mers and trimer) through successive nucleophilic aromatic
substitutions is described. Absorption spectrophotometric
and theoretical studies demonstrated that these oligomers
share common phenyl moieties that enable conjugation of
the whole π-system and a multiconcave geometry with
aligned cavities because of the high flexibility of these
macrocycles.
Introduction
The design of host molecules for guest binding has gener-
ated continuous interest in areas such as highly selective
and/or multimodal detection.[1] Among them, calix[4]arenes
1 have been widely studied for decades as hosts due to their
unique three-dimensional structures and versatile complex-
ation properties.[2] As such, they have found widespread
application in sensing, selective metal extraction, recogni-
tion, catalysis, and host–guest interactions.[3] These com-
plexation abilities are closely related to the conformational
properties of calix[4]arene, which depend on the substitu-
ents at the intra-annular positions.[3] Thus, they can adopt
four distinct conformations: cone, partial cone, 1,2-alter-
nate, and 1,3-alternate. The latter is of peculiar interest, be-
cause it furnishes a distinctive concave molecular architec-
ture that is favorable for selective complexation according
to the concept of concave reagents.[4]
The design and preparation of multicalixarene com-
pounds with precise length and constitution is now at-
tracting major interest in light of their potential applica-
tions in the field of material sciences.[5] For example, bis-
(calixarenes) have been extensively studied, because they
have the potential to complex two different guests using two
cavities independently or a single guest using two cavities
cooperatively. In most cases, multiple calixarene molecules
of type 2 were obtained by assembling calixarene subunits
either in a covalent or noncovalent manner.[6] For instance,
many research groups have reported on the synthesis of
multicalixarene molecules covalently Csp3-bridged by a
variety of linkers.[7] It was shown that the length and nature
of the bridges between the calixarene units played an im-
portant role in the conformation of the binding sites and
thus directly affect the binding properties.[8]
However, to take full advantage of these multicalixarene
arrays, it appears important that individual components in
such an array can interact with each other through suitable
linkers. Such internal cooperation, for instance through
electronic conjugation throughout the whole array and/or
additive geometry, is expected to bring novel properties that
go beyond the sum of each component’s property.[9] In re-
cent years it was found that substitution of the methylene
bridges by nitrogen afforded azacalix[4]arenes[10–12] and the
related azacalix[4]pyridines[13] or azacalix[2]arene[2]tri-
azines.[14] As a new member in the calixarene family, aza-
calix[4]arenes attracted much attention by providing sites
for functionalization not only on the phenyl units[10] but
also on the bridging nitrogen atoms.[11] We recently re-
ported on the synthesis of azacalix[4]arenes of type 3 and
related macrocycles with 1,3-alternate conformations.[12]
The synthetic strategy, based on catalyst-free, stepwise nu-
cleophilic aromatic substitutions (SNAr), allowed easy ac-
cess to new macrocycles that could be subjected to further
[a] CINaM, UMR 7325 CNRS, Aix-Marseille Université
Campus de Luminy, case 913, 13288 Marseille Cedex 09, France
E-mail: olivier.siri@univ-amu.fr
http://www.cinam.univ-mrs.fr
[b] Laboratoire de Chimie Moléculaire, UMR 7509 CNRS – UdS,
Equipe de Chimie Bioorganique et Médicinale, ECPM,
Université de Strasbourg
25, rue Becquerel, 67200 Strasbourg, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301509
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O. Siri et al.
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modifications.[11] The versatility of this method prompted SNAr reaction with tetraaminobenzene 7 and a large excess
us to explore the possible preparation of new extended of Hünig’s base at 80 °C. Dimer 8, having two azacalix-
architectures (i.e., multicalix[4]arenes scaffold) sharing a
arenes cavities fused through a shared phenyl subunit, was
common subunit.
then obtained by filtration with a relatively good yield
(54%). Its H NMR spectrum showed signals with unusual
1
high-field chemical shifts of the intra-annular aromatic (Hi)
protons at δ = 4.98 ppm. This observation suggests that the
dimer adopts the 1,3-alternate conformation in which the
Hi protons are located inside the anisotropic shielding cone
of the adjacent aromatic rings, as already observed for
monomer 3.[10,12]
The synthesis of azacalixarene-based trimer was then en-
visaged (Scheme 2). To this end, compounds 3 (R =
CO2Me)[12] and 6 were chosen as starting materials. Indeed,
macrocycle 3 appeared to be a precursor of choice owing
to the presence of four NO2 groups that could be reduced
into four nucleophilic amino functions. However, the direct
reduction of 3 (catalytic hydrogenation) led to the forma-
Herein, we report the synthesis and absorption spectro-
photometric studies of fused azacalixarene oligomers 8, 13
and 16 in which two or three macrocyclic units are fused
together. Unlike the previously described multicalix-
arenes,[6] our approach allows full electronic conjugation tion of the corresponding electron-rich tetraamino deriva-
because of the fused assembly. Theoretical studies revealed tive 9 (not isolated), which, under air, is converted into a
geometries with aligned cavities based on one or two com- very poorly soluble quinoid-type structure 10. This latter
mon phenyl subunits in 8 (and 16) and 13.
could be isolated after precipitation from CH3CN as a
green solid in 25% yield.
1
The H NMR spectrum of 10 revealed the presence of
two resonances at δ = 5.67 and 5.74 ppm that are consistent
Results and Discussion
The synthesis of dimer 8 is summarized in Scheme 1. with nonaromatic protons. Noteworthy, no NMR spectral
Commercially available m-diaminobenzene 4 (1 equiv.) was changes could be observed in the range 300–380 K as ex-
used as the nucleophilic component, and 1,5-difluoro-2,4- pected for 10, which is more rigid than azacalix[4]arenes of
dinitrobenzene (5) was identified as the coupling partner of type 3[11,12] due to the presence of bridging double bonds.
choice owing to the presence of structural elements that Formation of 10 was further supported by electrospray
were suitable for SNAr.[12]
HRMS mass spectrometry, which showed a peak at m/z =
The reaction took place at low temperature, and led to 537.1999 amu in the positive mode corresponding to [10 +
the formation of the [1+2] product 6, which precipitated in H]+. Introduction of N-CH3 substituents was then envis-
EtOH in 90% yield. Compound 6 was then subjected to an aged to prevent the oxidation of the octaamino macrocycle.
Scheme 1. Synthesis of dimer 8.
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Fused Azacalix[4]arenes
in agreement with the resonance of the aromatic protons
located in ortho positions with respect to the nitro groups.
In 12, the signal of such protons appears at δ = 6.19 ppm
due to the replacement of the electron-withdrawing NO2
groups by the electron-donating NH2 functions, which exhi-
bit a broad singlet at δ = 4.48 ppm. Finally, 12 was used as
the nucleophilic compound, undertaking an SNAr reaction
with the [2+1] difluorotriaryl product 6 to give 13 after pre-
cipitation in 30% yield. Unfortunately, trimer 13 could not
be characterized in solution due to its low solubility. In con-
trast, its formation was clearly supported by solid-state
NMR spectroscopy, elemental analysis and mass spectrom-
etry, which showed one peak at m/z = 1607.4 amu in the
positive mode corresponding to [13 + Na]+.
We carried out a conformational analysis for 3, 8, and
13 to explore the potential energy surface at the PM6[15]
level. In a second step, we performed geometry optimiza-
tion and frequency calculations on their obtained global
energy minima. To this end, we used the Density Func-
tional Theory (DFT) level, with a 6-31G** split-valence ba-
sis set (Gaussian 03 package),[16] combined to a hybrid po-
tential including both Becke and Hartree–Fock exchange
and Lee, Yang and Parr correlation (B3LYP) in the gas
phase.[17] As expected, the obtained geometrical parameters
show an 1,3-alternate conformation for each oligomer in
Scheme 2. Synthesis of trimer 13.
Thus, N-alkylation of 3 using methyl iodide in N,N-dimeth-
ylformamide (DMF) at 70 °C furnished tetramethylaza-
calixarene 11 as a yellow solid in 87% yield (Scheme 2). Its
reduction in the presence of Pd/C and ammonium formate
(NH4HCO2) afforded 12 as a black solid in 77% yield. The
Figure 1. Geometry optimization of oligomers 3, 8 and 13 (hydro-
1H NMR spectrum of 11 shows a singlet at δ = 8.77 ppm, gen atoms have been omitted for clarity).
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O. Siri et al.
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global minima leading to multiconcave molecules with one,
two or three aligned cavities for 3, 8 and 13, respectively
(Figure 1).
This calculated high flexibility – typical in the calixarene
family – is consistent with experimental data obtained with
8 and 13, and the X-ray analysis of a closely related ana-
logue of 3 for which R = H.[10d]
Although molecules 3, 8 and 13 are not planar because
of the 1,3-alternate conformation, we undertook an absorp-
tion spectrophotometric study of 8 and 13 (that of 3 being
already reported by our group)[11] to highlight a possible
conjugation of the π-system between the macrocyclic sub-
units.[12] For solubility reasons, their absorption spectro-
scopic properties were examined in DMF and compared to
those of model 3 under the same experimental conditions.
Neutral azacalix[4]arenes 3, 8 and 13 are both characterized
by an intense absorption (ε ≈ 5–8ϫ104 m–1 cm–1) in the UV
region (ca. 340–350 nm; Figure 2), together with a shoulder
lying at lower energies (λmax ≈ 400–420 nm). Simulated
spectra based on TD-DFT calculations[17] confirmed ab-
sorption bands in the UV region as expected for a flexible
geometry (1,3-alternate conformation).
These absorption bands originate from π–π* transitions
of the electronically independent 1,5-diamino-2,4-dinitro-
benzene units,[18] those of the para-substituted benzene
rings being centered at much higher energies. The bridging
secondary amines of 3, 8 or 13 can be – in principle – either
protonated or deprotonated, leading to potential positively
and negatively multicharged hosts, respectively. However,
the electron-withdrawing effect of the NO2 groups and the
presence of strong intramolecular NH···O2N hydrogen
bonds[11] prevent easy protonation of the bridging amines.
In contrast, addition of base (NaOH) leads to significant
spectral changes with bathochromic shifts of the main ab-
sorption bands (Δλmax = 57, 64 and 66 nm for 3, 8 and 13,
respectively), and simultaneous formation of new and less
intense absorption bands in the visible region (λmax
≈
500 nm, ε500 ≈ 2–6ϫ104 m–1 cm–1; Figure 2). These spectral
features for 8 and 13 suggest that each macrocycle subunit
does not behave independently but accounts for an unprece-
dented internal cooperation through electronic conjugation
compared with 3. However, it is noteworthy that the degree
of conjugation between each macrocycle subunit in 8 and
13 is clearly limited by the high flexibility of the oligomers,
which prevents a full overlap of the p-orbitals (a more
planar geometry would have led to a more significant
Figure 2. UV/Vis absorption titration of dimer 8 by (top) NaOH
or (middle) HClO4, and (bottom) electronic absorption spectra of
the neutral (a) and deprotonated (b) forms of oligomers 3, 8 and
13. The inset in the top shows the variation of the absorbance at
330 and 480 nm of dimer 8 upon addition of the base. Solvent:
DMF; T = 25.0(2) °C. NaOH titration: [8]0 = 1.43ϫ10–5 m; (1)
[NaOH]0/[8]0 = 0; (2) [NaOH]0/[8]0 = 88. HClO4 titration: [8]0
=
1.43ϫ10–5 m; (1) [HClO4]0/[8]0 = 0; (2) [HClO4]0/[8]0 = 4055. In the
presence of base, the absorption spectrophotometric data have been
processed and allowed an apparent deprotonation constant to be
Kapp
n–4
bathochromic shift as observed in the more rigid fused measured according to the equilibrium: LHn
+ OH–
i
n–5
oligoporphyrins).[9]
LHn–1 + H2O. For 3, logKapp = 4.2(1); for 8, logKapp = 3.8(2);
for 3, logKapp = 3.5(2).
To gain further insight into the structure–activity rela-
tionships of these oligomeric systems, modulation of the
cavity of the dimer could be also envisaged by alternating
the position of the two NH2 groups in the substituted phen- aminobenzene 7 in CH3CN (10–2 m) heated to reflux led to
ylene precursor while keeping a constant number of benz- the formation of dimer 16 in 25% yield (Scheme 3). The
ene moieties.
formation of 16 instead of 17 could be fully demonstrated
By analogy with the synthesis of 8, compound 5 was sub- by condensation between 15 and 18 (1 equiv.) in dimethyl
jected to a step of aromatic substitution with o-di- sulfoxide (DMSO), which gave 16 as a yellow solid in 63%
aminobenzene (14) (0.5 equiv.), affording the [2+1] products yield. Compound 18 could be obtained in one step by SNAr
15 (91% yield; see Scheme 3). Macrocyclization with tetra- reaction between 15 and tetraaminobenzene 7 (1 equiv.) in
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Fused Azacalix[4]arenes
79% yield without protection of the amino groups. This
high selectivity can be explained by the higher nucleophilic
character of the NH2 group in meta position with respect
to the first amino group that reacted [the two other NH2
groups in the ortho and para position are “deactivated” by
the mesomeric effect (+M)]. Similar to 8, the 1H NMR
spectrum of 16 showed high-field signals of the intra-annu-
lar aromatic protons (Hi) at δ = 5.88 ppm, suggesting that
16 adopted an 1,3-alternate conformation in solution in
which the Hi protons are located inside the anisotropic
shielding cone of the adjacent aromatic rings.
Figure 3. Geometry optimization of dimers 8 and 16 (hydrogen
atoms have been omitted for clarity).
Conclusions
The synthesis of fused azacalixarenes (dimers 8, 16 and
trimer 13) has been achieved through successive SNAr reac-
tions. These macrocycles share common structural proper-
ties with an 1,3-alternate conformation, which allows align-
ment of two or three concave cavities for the dimers and the
trimer, respectively. These novel receptors with multipoint
recognition sites are thus expected to exhibit new physico-
chemical properties that are distinct from simple azacalix-
[4]arenes (for instance 3) owing to their larger dimension
and higher degree of flexibility. In addition, 8, 16 and 13,
possess cavities that can be easily and highly functionalized
and will thus constitute useful and valuable building blocks
for the construction of higher orders of multicavity macro-
cycles. We also described a new class of conjugated macro-
cycles (10) in which the presence of quinoid subunits opens
new perspectives in color chemistry (as new acidichromes)
or coordination chemistry (as new ligands) by analogy with
related 12π-electron quinones[19] and a new class of macro-
cycles named azacalixphyrins.[20]
Scheme 3. Synthesis of dimer 16.
Similar to 8, TD-DFT geometry optimization and fre-
quency calculations on 16 also show an 1,3-alternate con-
formation but revealed smaller aligned cavities (Figure 3).
This observation can be explained by the ortho substitution
of two phenyl rings in 16, which increases the strength of
the macrocyclic cavities (the angle between the o-di-
aminobenzene subunit and the molecular plane is smaller
than in 8).
Experimental Section
General Remarks: All solvents for the syntheses were of analytic
grade; spectroscopic measurements were carried out with spectro-
scopic-grade solvents. NMR spectra were recorded at room temp.
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O. Siri et al.
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with a Bruker AC250 spectrometer operated at 250, 62.5, and
stirred at room temperature under air for 24 h. After slow evapora-
1
235 MHz for H, 13C, and 19F nuclei, respectively. Data are listed
tion of the solvent, macrocycle 10 was isolated as a green solid
1
in parts per million (ppm) and are reported relative to tetramethyl-
silane (1H and 13C); residual solvent peaks of the deuterated sol-
vents were used as an internal standard. NMR spectra were re-
corded in CDCl3, [D6]acetone or [D6]DMSO. Chemical shifts are
reported in delta (δ) units, expressed in parts per million (ppm)
using the residual protonated solvent as an internal standard
[CDCl3: δ = 7.26 ppm; [D6]DMSO: δ = 2.50 ppm; [D6]acetone: δ =
2.05 ppm]. Splitting patterns are described as s (singlet), br.
(broad), d (doublet), m (multiplet). Elemental and MS analyses
were performed by Marseille Spectropole. ESI MS analyses were
recorded with a 3200 QTRAP (Applied Biosystems SCIEX) mass
spectrometer. HRMS MS analysis was performed with a QStar El-
ite (Applied Biosystems SCIEX) mass spectrometer.
(40 mg, 25%). H NMR (250 MHz, [D6]DMSO): δ = 3.77 (br. s, 6
H, OCH3), 5.67 (s, 2 H, olefinic H), 5.74 (s, 2 H, olefinic H), 6.90
(br. s, 2 H, ArH), 7.13 (m, 4 H, ArH), 7.80 (br. s, 8 H, NH and
NH2) ppm. HRMS: calcd. for [M + H]+ 537.1993; found 537.1999.
Synthesis of 11: To a solution of 3 (1 g, 1.51 mmol) and dried
K2CO3 (2.5 g, 18 equiv.) in DMF (20 mL) was added MeI (1 mL,
12 equiv.) under argon. After stirring at 70 °C for 12 h, the crude
reaction mixture was filtered, DMF was then evaporated under re-
duced pressure, and the residue was taken up in water. Successive
extractions with EtOAc and washing with brine afforded 11 (87%)
as an orange solid. 1H NMR (250 MHz, CDCl3): δ = 3.16 (s, 12
H, NCH3), 3.94 (s, 6 H, OCH3), 6.39 (t, J = 2.2 Hz, 2 H, ArH),
6.52 (s, 2 H, MeN-C-CH=C-NMe), 7.44 (d, J = 2.2 Hz, 4 H, ArH),
8.77 (s, 2 H, O2N-C-CH=C-NO2) ppm. 13C NMR (62 MHz,
CDCl3): δ = 40.6 (N-CH3), 52.1 (OCH3), 114.3, 117.7, 121.9, 128.1,
133.2, 134.66, 146.6, 146.7 (ArC), 165.5 (C=O) ppm.
C32H28N8O12·5/4EtOAc (826.25): calcd. C 54.48, H 4.76, N 13.92;
found C 54.66, H 4.73, N 13.91. MS (ESI): calcd. for [M + H]+
717.1; found 717.1.
Absorption Spectrophotometric Studies: For solubility reasons, the
acido-basic properties of systems 3, 8 and 13 were examined in
DMF (Prolabo, AnalaR Normapur), which was further deoxy-
genated by using CO2- and O2-free argon prior to use (Sigma Ox-
iclear cartridge). All the stock solutions were prepared by weighing
solid products with an AG 245 Mettler Toledo analytical balance
(precision 0.01 mg). The complete dissolution of the ligands was
achieved by using an ultrasonic bath (Bandelin Sonorex RK102).
The effects of acid (HClO4, 10–1 m from Sigma–Aldrich, ca. 70%,
99.999% trace metals basis) and base (NaOH, 10–1 m from NaOH,
BdH, AnalaR) on compounds 3, 8 and 13 was probed by absorp-
tion spectrophotometry (250–800 nm) with a Varian Cary 50 spec-
trophotometer.
Synthesis of 12: A solution of 11 (300 mg, 0.42 mmol) in CH3OH/
THF (1:1, 300 mL) was reduced in the presence of catalytic Pd/C
(10%) and azeotropically (toluene) dried ammonium formate
(530 mg, 20 equiv.) for 12 h. The mixture was then filtered through
Celite, and the filtrate was concentrated under reduced pressure.
The residue was taken up in EtOAc, and washed with water. The
organic phase was then concentrated in vacuo to give 12 (192 mg,
1
Synthesis of 6: To a stirred solution of 1,5-difluoro-2,4-dinitro-
benzene (5) (100 mg, 0.49 mmol, 2 equiv.) in THF (10 mL) placed
at 0 °C under nitrogen, was added dropwise a mixture of NiPr2Et
(DIPEA; 0.73 mmol, 3 equiv.) and 4 (40 mg, 1 equiv.) in THF
(5 mL). The mixture was allowed to warm to room temp. for 12 h,
then the crude mixture was concentrated and taken up in EtOH.
The obtained precipitate was isolated by filtration, washed with hot
water and Et2O, and dried to afford 6 (118 mg, 90%). 1H NMR
(250 MHz, [D6]acetone): δ = 10.27 (s, 2 H, 2 NH), 9.08–9.05 (d, J
= 7.5 Hz, 2 H), 8.07 (dd, J = 0.5, 1.75 Hz, 2 H), 7.98 (dt, J = 0.25,
2.0 Hz, 1 H), 7.26–7.20 (d, J = 14.0 Hz, 2 H), 3.93 (s, 3 H) ppm.
13C NMR (62 MHz, [D6]acetone): δ = 166.8 (C=O), 163.4 (J =
267 Hz, C-F), 149.9 (J = 13 Hz), 141.5, 135.6, 130.9, 129.3, 129.0,
127.1 (ArCH), 106.1 (J = 25 Hz, CH-CF), 54.0 (CH3-O) ppm.
HRMS: calcd. for [M + NH4]+ 552.0921; found 552.0926.
77%) as a black-green solid. H NMR (250 MHz, [D6]DMSO): δ
= 2.95 (br. s, 12 H, NCH3), 3.82 (s, 6 H, OCH3), 4.48 (s, 8 H,
NH2), 5.61 (t, J = 2.2 Hz, 2 H, ArH), 6.04 (s, 2 H, MeN-C-CH=C-
NMe), 6.19 (s, 2 H, H2N-C-CH=C-NH2), 6.72 (d, J = 2.2 Hz, 4
H, ArH) ppm. 13C APT NMR (62 MHz, [D6]DMSO): δ = 167.9,
150.9, 144.5, 131.0, 127.1, 123.4, 104.2, 101.9, 101.3, 52.3,
40.7 ppm. HRMS: calcd. for [M + Ag]+ 703.1905; found 703.1910.
Synthesis of 13: To a solution of 6 (71 mg, 0.13 mmol, 2 equiv.) in
CH3CN (5ϫ10–2 m) in the presence of DIPEA (2.6 mmol,
20 equiv.), was added 12 (40 mg, 0.067 mmol, 1 equiv.) at room
temp. under nitrogen. After stirring and heating to reflux for 72 h,
the obtained precipitate was isolated by filtration and washed with
water, MeOH, EtOH, and MeCN to afford the desired product
(32 mg, 30%) as a red solid. Solid-state 13C NMR: δ = 165.4, 148.9,
144.3, 140.2, 132.4, 127.3, 103.9, 52.2, 38.8, 30.2, 18.1 ppm.
C72H56N20O24·2C2H5OH·CH3OH (1078.49): calcd. C 54.10, H
4.25, N, 16.39; found C 54.30, 4.22, 16.35. MALDI-TOF: calcd.
for [M + Na]+ 1607.4; found 1607.4.
Synthesis of 8: To a solution of 6 (150 mg, 0.28 mmol, 2 equiv.) in
CH3CN (5ϫ10–2 m) in the presence of DIPEA (0.39 mL), was
added tetraaminobenzene tetrahydrochloride 7·4HCl (0.14 mmol,
1 equiv.) at room temp. under nitrogen. After stirring and heating
to reflux for 48 h, the obtained precipitate was isolated by filtration
and washed with water, methanol, ethanol, and CH3CN to afford
the desired product (85 mg, 54%) as a brown solid. 1H NMR
(250 MHz, [D6]DMSO): δ = 9.94 (s, 2 H), 9.33 (s, 2 H), 9.02 (s, 2
H), 7.66 (br. s, 4 H), 7.38 (s, 1 H), 5.70 (s, 1 H), 3.72 (s, 3 H) ppm.
Solid-state 13C NMR: δ = 164.7, 147.2, 140.6, 133.9, 126.1, 98.7,
52.5 ppm. C46H30N16O20·3/2CH3OH·1/2C2H5OH (1197.48): calcd.
C 48.63, H 3.28, N 18.71; found C 48.69, H 2.99, N 18.27.
MALDI-TOF: calcd. for [M]+· 1126.2; found 1126.2.
Synthesis of 15: Compound 5 (2.52 g, 12.35 mmol) was dissolved
in THF, and the solution was cooled with an ice/water bath. A
solution of 14 (0.66 g, 6.16 mmol) in THF (50 mL) was added
dropwise, and the mixture was stirred at 0 °C for 3 h and at room
temperature for 48 h. The progress of the reaction was monitored
by TLC (silica; EtOAc/cyclohexane, 50:50). After evaporation of
the solvent under reduced pressure, acetone was added, leading to
a suspension that was isolated by filtration, washed with EtOH,
1
and dried under vacuum to give 15 (2.66 g, 5.58 mmol, 91%). H
NMR (250 MHz, [D6]DMSO): δ = 6.98 (d, J = 14.0 Hz, 2 H,
Synthesis of 10: A solution of 3 (200 mg, 0.30 mmol) in CH3OH/ C=CH-CF), 77.58 (m, 4 H, ArH), 8.82 (d, J = 8.0 Hz, 2 H,
EtOAc (2:1, v/v) was hydrogenated (60 bars) in the presence of Pd/
C (5%) for 24 h. After filtration of the reaction mixture through
Celite, which was washed with methanol, the filtrate was concen-
trated under reduced pressure, and the solid in suspension was iso-
lated by filtration. This solid was then taken up in CH3CN and
O2NC=CH-CNO2), 10.15 (br. s, 2 H, NH) ppm. 13C APT NMR
(62 MHz, [D6]DMSO): δ = 160.6 (d, J = 263 Hz, C-F), 147.7 (d, J
= 13 Hz, FC-C-NO2), 134.0 (NHC-C-NO2), 129.0 (ArCH), 128.5
(ArCH), 128.1 (C-NH), 126.8 (NO2C-CH), 126.3 (d, J = 10 Hz,
FC-C-NH), 104.4 (d,
J
=
27 Hz, NHC-CH-CF) ppm.
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Fused Azacalix[4]arenes
[4]
[5]
U. Lüning, Top. Curr. Chem. 1995, 175, 57 and references cited
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C18H10F2N6O8 (476.05): calcd. C 45.39, H 2.12, N 17.64; found C
45.92, H 2.21, N 17.13. ESI-MS (positive mode): m/z = 494.0 [M
+ NH4]+.
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Synthesis of 16. Method 1: Compound 15 (168 mg, 0.353 mmol)
was dissolved in DMSO (5 mL), and the solution was degassed
with argon in an ultrasonic bath for 20 min. DIPEA (0.49 mL) and
tetraaminobenzene 7·4HCl (50 mg, 0.176 mmol) were added under
argon, and the mixture was heated at 80 °C for 24 h. The progress
of the reaction was monitored by TLC. The obtained suspension
was cooled to room temperature, and EtOH was added. The re-
sulting solid was collected by filtration and washed with EtOH and
acetonitrile. Product 16 (43.8 mg, 0.043 mmol, 25%) was obtained
after washing with hot acetone. Method 2: Compounds 18 (52 mg,
0.091 mmol) and 15 (43 mg, 0.090 mmol) were dissolved in DMSO
(5 mL), and DIPEA (40 μL) was added. The solution was then
heated at 75 °C for 24 h, then anhydrous EtOH was added to this
hot suspension. The resulting suspension was filtered, the residue
washed with EtOH, and then dried under vacuum to give 16
[6]
[7]
[8]
1
(57 mg, 0.056 mmol, 63%). H NMR (250 MHz, [D6]DMSO): δ =
5.88 (s, 4 H, CH-C=CNO2), 7.19 (s, 2 H, NHC=CH-CNH), 7.33
(m, 8 H, ArH), 8.96 (s, 4 H, NO2C=CH-CNO2), 9.11 (br. s, 4 H,
NH), 9.81 (br. s,
4
H, NH) ppm. C42H26N16O16·4/5DMSO
(1072.58): calcd. C 48.79, H 2.89, N 20.88, S 2.39; found C 48.79,
H 3.03, N 20.50; S 1.95. ESI-MS (positive mode): m/z = 1011.2 [M
+ H]+.
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Synthesis of 18: In a 100 mL flask, 15 (417 mg, 0.875 mmol) was
dissolved in MeCN (25 mL), and tetraaminobenzene 7·4HCl
(251 mg, 0.884 mmol) was then added under argon. The mixture
was heated at 50 °C and DIPEA (1.25 mL) was added dropwise.
The obtained red solution was heated to reflux for 22 h, then EtOH
was added to the hot suspension, and the solution was cooled to
room temperature. The orange solid was collected by filtration,
washed with EtOH and Et2O, and finally dried under vacuum to
[11]
[12]
1
give the desired product 18 (393 mg, 0.684 mmol, 79%). H NMR
(250 MHz, [D6]DMSO): δ = 4.99 (br. s, 4 H, NH2), 5.62 (s, 2 H,
CH-C=CNO2), 6.03 (s, 1 H, NH2C=CH-CNH2), 6.46 (s, 1 H
NHC=CH-CNH), 7.35–7.26 (m, 4 H, ArH), 8.82 (br. s, 2 H, NH),
8.94 (s, 2 H, NO2C=CH-CNO2), 9.53 (br. s, 2 H, NH) ppm.
C24H18N10O8·1/3EtOH·2/3H2O (601.49): calcd. C 49.23, H 3.57, N
23.17; found C 49.39, H 3.27, N 23.19. ESI-MS (positive mode):
m/z = 575.0 [M + H]+.
[13]
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all key intermediates and final
products, theoretical data of the calculated geometries.
Acknowledgments
[14]
This work was supported by the Centre National de la Recherche
Scientifique, the Ministère de l’Enseignement Supérieur et de la
Recherche, and the Agence Universitaire de la Francophonie
(AUF) agency (grant for M. T.).
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Received: October 4, 2013
Published Online: November 22, 2013
752
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 745–752