Development of functionalized cyclotriveratrylene analogues: Introduction of withdrawing and π-conjugated groups

Article abstract of DOI:10.1021/jo301183b

Cyclotriveratrylene analogues (CTVs) are supramolecular bowl-shaped molecules known for their ability to complex organic and organometallic guests, to form liquid crystals, polymers, or nanostructures. In this Article, we report the synthesis of new cyclotriveratrylene analogues with fluorescence properties in which various electron-withdrawing or π-extended conjugated groups are appended to the wide rim ortho to the methoxy-donating groups. Synthetically, these functionalized CTVs cannot be obtained as CTVs with electron-rich functions by the typical method (i.e., the trimerization of the corresponding benzyl alcohol) but are prepared from a common key intermediate, the C ₃-triiodocyclotriveratrylene (CTV-I₃), in good yields. Despite the synthetic difficulties encountered due to the presence of three reactive centers, we have demonstrated the possibility of performing Sonogashira coupling and Huisgen cycloaddition reactions directly to the CTV core for the first time. CTVs with π-extended conjugated groups reveal interesting fluorescence profiles. More broadly, this study utilizes CTV-I₃ to introduce novel functionalities into CTVs to keep exploring their potential applications.

Full text of DOI:10.1021/jo301183b

Article
pubs.acs.org/joc
Development of Functionalized Cyclotriveratrylene Analogues:
Introduction of Withdrawing and π‑Conjugated Groups
Lisa Peyrard,† Marie-Laurence Dumartin,† Sabine Chierici,† Sandra Pinet,† Gediminas Jonusauskas,‡
Pierre Meyrand,§ and Isabelle Gosse*,†
†Institut des Sciences Molec
Av. Pey Berland, 33607 Pessac, France
‡Centre de Physique Molec
ulaire Optique et Hertzienne, Universite
Talence, France
§Institut des Maladies Neurodeg
́
ulaires UMR CNRS 5525, Groupe Nanosystem
̀
es analytiques, Universite
de Bordeaux, UMR 5798, 351 cours de la liber
de Bordeaux, 351 cours de la liberation, 33405 Talence, France
́
de Bordeaux, Site ENSCBP, 16
́
́
́
ation, 33400
́
en
́
er
́
atives UMR 5293, Universite
́
́
S
* Supporting Information
ABSTRACT: Cyclotriveratrylene analogues (CTVs) are supramolec-
ular bowl-shaped molecules known for their ability to complex organic
and organometallic guests, to form liquid crystals, polymers, or
nanostructures. In this Article, we report the synthesis of new
cyclotriveratrylene analogues with fluorescence properties in which
various electron-withdrawing or π-extended conjugated groups are
appended to the wide rim ortho to the methoxy-donating groups.
Synthetically, these functionalized CTVs cannot be obtained as CTVs
with electron-rich functions by the typical method (i.e., the
trimerization of the corresponding benzyl alcohol) but are prepared
from a common key intermediate, the C3-triiodocyclotriveratrylene (CTV-I3), in good yields. Despite the synthetic difficulties
encountered due to the presence of three reactive centers, we have demonstrated the possibility of performing Sonogashira
coupling and Huisgen cycloaddition reactions directly to the CTV core for the first time. CTVs with π-extended conjugated
groups reveal interesting fluorescence profiles. More broadly, this study utilizes CTV-I3 to introduce novel functionalities into
CTVs to keep exploring their potential applications.
or formation of byproduct during the trimerization process is
observed. Thus, most of the synthesized CTVs bear electron-
rich functions on their wide rim, in particular, ethers (R1 and R2
= alkyl ether, Figure 1), and only few examples of CTVs with
aromatic or electron-withdrawing groups have been reported in
the literature.7,14,15 However, the latter are of interest to widen
the family of CTVs and to access, in particular, extended-cavity
CTVs with properties other than those with ether side-arms.
For example, aryl-extended rigid CTVs (R1 = OMe, R2 = Ar,
Figure 1) have much larger and deeper cavities and more
appropriate shapes to form nanotubes or to interact with
C60.7,14 We also recently showed that CTVs presenting
electron-withdrawing groups near donating ones (R1 = OMe,
R2 = PO(OH)2, OPO(OLi)Bu, Figure 1) led to fluorescent
CTVs of interest as fluorescent probes.10,16
INTRODUCTION
■
Since the discovery of the bowl-shaped cyclotriveratrylene
macrocycle a century ago, its analogues have attached much
attention1,2 for their complexing properties (for metals,3−6
fullerenes,7−9 and small organic molecules guests10) and as
materials to form liquid crystals,11 gelators,12 dendrimers,13 or
nanostructures.14,15 Like the cyclotriveratrylene parent, which is
prepared from veratryl alcohol, cyclotriveratrylene analogues
(hereafter designed CTVs) are typically synthesized by
aromatic electrophilic substitution of appropriate benzyl
alcohols. This reaction is really efficient when two electron-
donating groups are present in meta and para positions of the
benzyl alcohol (R1, R2 in Figure 1). Nevertheless, this strategy
has some limitations as soon as these positions are substituted
by either deactivating electron-withdrawing groups or aromatic
groups. Indeed, in such cases, the trimerization is not efficient,
In this context, to extend the CTV family, the trihalogenated
CTVs (R1 = OMe, R2 = Br, I, Figure 1), the syntheses of which
were reported a few years ago,17−19 are attractive intermediates.
In particular, the cavitands with rigid arms (R1 = OMe, R2 = Py,
Ar, Figure 1) have been obtained via Suzuki−Miyaura coupling
reactions7,14 from the C3-tribromoyclotriveratrylene, CTV-
Figure 1. Typical synthesis and structure of cyclotriveratrylene
analogues.
Received: June 19, 2012
Published: July 30, 2012
© 2012 American Chemical Society
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Br317,18 (R1 = OMe, R2 = Br, Figure 1). In the present work, we
have focused our attention on the iodo analogue C3-
triiodocylotriveratrylene CTV-I3 (R1 = OMe, R2 = I, Figure
the aryl iodides using the Rosenmund−von Bran reaction
(Scheme 1). The reaction in DMF as solvent was proved
efficient, and the cyanylated CTV 3 was obtained in an
excellent yield of 85%. Next, we explored CTV-I3 in cross-
coupling Sonogashira reactions (Scheme 2). Classical con-
19
1). Indeed, iodo aryl groups are expected to be better substrates
than bromo aryl ones, especially in cross-coupling reac-
tions.20,21 In a recent report, we have reconsidered the
synthesis of CTV-I3, and with 47% overall yield in only three
steps, we can now prepare this intermediate in gram scale,16 as
compared to the synthesis of CTV-Br3, which is described in
only 10% overall yield.17,18 We have also shown that it could be
efficiently used in an Arbusov−Michaelis reaction to prepare a
phosphorylated CTV, CTV-(PO(OH)2)3 (R1 = OMe, R2 =
PO(OH)2, Figure 1). To date, this CTV-I3 has been underused,
and only one example (R1 = OMe, R2 = CHO) has been
reported in the literature.15 In this work, we propose then to
further exploit the reactivity of the aryl iodides of CTV-I3 to
synthesize CTVs that cannot be obtained by direct
trimerization of the corresponding benzyl alcohol derivatives,
that is, CTVs substituted by electron-withdrawing and π-
extended conjugated groups ortho to the methoxy-donating
ones. Through various examples reported herein, this study
highlights the potential of CTV-I3 as a key intermediate in the
chemistry of CTVs to introduce novel functionalities.
Scheme 2. Sonogashira Couplings from CTV-I3
ditions for Sonogashira couplings using ethynylbenzene or
trimethyl-silylacetylene as alkynylated reagents were employed.
The corresponding CTVs 4 and 5 were obtained in 64% and
73%, respectively (after hydrolysis of the silyl groups in case of
5). These are the first examples of Sonogashira couplings on a
CTV scaffold, and the good yields obtained attest to the
efficiency of this kind of organometallic cross coupling from
CTV-I3.
Diverse CTVs could be further obtained by Sonogashira
couplings from CTV-I3 by using a variety of alkynes and
aromatic alkynes diversily substituted. CTVs with π-conjugation
extension as in 4 could be of interest in particular for their
fluorescence properties. CTV 5 or its silylated precursor could
also be employed as intermediates in additional organometallic
couplings or in alkyne-based chemistry. As an example, we
engaged CTV 5 in a copper(I)-mediated alkyne−azide
cycloaddition (CuAAC) reaction with phenylazide as a
prototype of organic azides (Scheme 3). CTV 6 was obtained
RESULTS AND DISCUSSION
CTV-I3 was first employed to access CTVs 1 and 2, bearing
carboxyl or ketone functions (Scheme 1). To get the CTV 1
■
Scheme 1. Synthesis of CTVs Bearing Withdrawing Groups
Scheme 3. Example of Cu(I)-Catalyzed Huisgen 1,3-Dipolar
Cycloaddition from 5
with three carboxyl groups, CTV-I3 was engaged in a halogen
metal exchange with n-BuLi at low temperature. The
organolithium intermediate formed reacted with ethylchlo-
roformate in THF to give, after ester hydrolysis, CTV 1 with
54% yield. The yield is similar to those reported in the literature
using DMF as electrophile (R1 = OMe, R2 = CHO, Figure 1),
confirming the potential of the iodinated intermediate to
introduce electrophilic substituents on the CTV core.15
Moreover, by taking advantage of the carboxyl group
functionalization, CTV 1 appears as an interesting precursor
to append diverse side-arms to the wide rim of CTVs.
CTV 2 with ketone arms was synthesized in 69% yield via a
Friedel−Crafts reaction after reduction of the CTV-I3 by
lithium aluminum chloride.19 Obviously in this last case, we do
not take direct advantage of the reactivity of the iodo aryl
groups of CTV-I3 because they are reduced before the
electrophilic substitution. The interest of CTV-I3 is indirect
and lies in the easy access to the hydrogenated CTV
intermediate, CTV-H3, that can be subjected to efficient
Friedel−Crafts substitutions thanks to its methoxy activating
groups and thus lead to new functionalized CTVs.
in 40% yield using the classical combination of sodium
ascorbate and CuSO4 as Cu(I) source in a mixture of water/
dimethylsulfoxyde to dissolve the starting material 5. This
example shows the feasibility of using “click chemistry” to
functionalize CTVs directly onto their aromatic core, and thus
the possibility of taking advantage of the versatility of this
chemoselective ligation to introduce different entities on the
CTV core. Moreover, the 1,2,3-triazole-1,4-diyl entity formed
in the CuAAC has been recently studied and proved as a π-
linker.22 Using “click chemistry” from 5 is also a way to extend
the conjugation in the CTV core, as do the Sonogashira
couplings using aryl acetylenes.
In our research group, we are interested in developing
fluorescent CTVs. Therefore, we wanted to investigate the
spectroscopic properties of the CTVs 1−3 with electron-
withdrawing conjugated groups and the CTVs 4 and 6 with π-
extended conjugated groups (Table 1). This study was
performed in DMSO.
To test the reactivity of CTV-I3 in transition metal-catalyzed
cross-coupling reactions, we first performed the cyanation of
It is noteworthy that CTV-I3 that absorbs light with a
maximum at 300 nm (ε = 12 × 104 M−1 cm−1) is not
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Article
with donating groups could overcome this weakness and is
under investigation.
Table 1. Spectroscopic Characterizations of the CTVs
ε (104
a
b
λabs max
(nm)
M−1
λem max Δλ
ΦF
CTV
cm−1
)
(nm) (nm) (%) τ (ns)
CONCLUSION
■
CTV 1
CTV 2
CTV 3
CTV 4
CTV 6
302
318
310
320
302
297
5.1
7.4
6.4
4.9
3.2
7.1
348
520
334
355
377
317
46
183
24
8
<1
16
1
In summary, through this work, we enhance the CTV family
with new CTVs functionalized by electron-withdrawing and π-
extended conjugated groups. These groups are directly attached
onto the CTV aromatic core, enabling one to keep the very
interesting rigid and stable structure of CTVs. All of the
compounds are prepared in maximum three steps from the
CTV-I3 intermediate with good yields considering that for each
step three reaction sites are present on the CTV squeleton. In
terms of fluorescence properties, CTVs with π-extended
conjugated groups are the most promising ones. More broadly,
this study proves the potential of CTV-I3 as a key intermediate
in the chemistry of CTVs to introduce novel functionalities and
thus to keep exploring the interest of CTVs in many
applications. In particular, the opportunity to perform
Sonogashira couplings and Huisgen cycloadditions, two
reactions with wide scopes, opens new routes toward
functionalized CTVs.
0.09
2
35
63
1.5
0.9
2.7
75
<1
13.5
c
CTV(PO(OH)2)3
20
a
b
Δλ = Stokes shift. Relative quantum yields are measured using 7-
methoxycoumarin-4-acetic acid as a reference (ΦF = 0.18 in
methanol).23 This compound, previously described,18 is studied
c
here in DMSO.
fluorescent. The fact that nonradiative pathways of de-
excitation are very strong when aromatic groups are substituted
by heavy atoms like iodine atoms is consistent with this
observation.24
For the CTVs 1−3, if the nature of the electron-withdrawing
groups introduced on the CTV core has only a minor influence
on the absorption properties, it affects more significantly the
emission properties. Indeed, 2 shows only a faint emission,
while CTVs 1 and 3 are fluorescent with moderate fluorescent
quantum yields of 16% and 8% respectively. Concerning the
maximum emission wavelength (λem), both 1 and 3 show
longer values than CTV-(PO(OH)2)3, attesting an effect of the
relative strength of the electron-withdrawing groups on the
bathochromic shift of the λem. Nevertheless, CTV 1 with λem at
348 nm and Stokes displacement of 46 nm is the most
interesting one considering further applications as probes.
Indeed, its λem and its fluorescent quantum yield, although it is
moderate, are retained in aqueous buffer at neutral pH.
Therefore, we evaluated the complexing properties of 1 toward
ammonium species in phosphate buffer, and the preliminary
results showed a slight preference of 1 for acetylcholine (Figure
S1, Supporting Information).
CTV 2 bearing ketone groups is a special case with a high
bathochromic shift associated with a very low fluorescent
quantum yield. Similar behaviors for aromatic ketones are
mentioned in the literature and are correlated to low-lying
n−π* transition states of weak energy that induce red-shifted
emissions and strengthen the intersystem crossing and the
nonradiative pathways of de-excitation, quenching the
fluorescence.24
In CTVs 4 and 6, by extending π conjugation, we expected a
shift of the absorption and emission maxima to longer
wavelengths and better fluorescence quantum yields than
CTVs 2 and 3. This is the case for CTV 4 prepared by
Sonogashira coupling. This one absorbs at 320 nm, and
presents a higher red-shift (λem at 355 nm) and a superior
quantum yield of 63%, as compared to the moderate ones
obtained for CTVs 1 and 2. Concerning CTV 6 with triazole
units, it shows the longest-wavelength emission of this series
(about 20 nm bathochromically shifted as compared to 4). The
very low quantum yield obtained for 6 does not question the
ability of the triazole to act as a π-linker and its potential to get
fluorescent CTVs. Indeed, by exploring the literature about the
fluorescence properties of some triazole clicked compounds, it
seems that the value of quantum yield is very dependent on the
electron-donor or -withdrawing character of the clickable azido
and alkyne subunits.25,26 In our case, the use of phenylazides
EXPERIMENTAL SECTION
■
General Experimental Details. Commercially available reagents
were used without purification. Dichloromethane was freshly distilled
from CaH2 and tetrahydrofuran from sodium benzophenone ketyl
under nitogen atmosphere. Anhydrous N,N-dimethylformamide was
kept under argon atmosphere and used without further purification.
Melting points were measured using a melting point bench and are
uncorrected. NMR spectra were recorded on a 400 MHz (1H
frequency) spectrometer. Chemical shifts are reported using
tetramethylsilane or the residual solvent peak as internal reference
for 1H or for 13C. Infrared spectra were recorded on a FT-IR
spectrometer in the range 4000−1000 cm−1. UV/vis and fluorescence
spectra were recorded in DMSO at 298 K. Molar extinction
coefficients were obtained in the range of 10−4−10−7 M in DMSO.
The data curve absorbance versus concentration was fitted with a
linear curve-fitting equation (with interception at 0 for x = 0)
implemented within Origin. The fluorescence quantum yields were
obtained by using 7-methoxycoumarin-4-acetic acid in methanol as a
reference (ϕref = 0.18). Time-resolved fluorescence experiments were
performed using a frequency-tripled Nd:YAG laser (355 nm, 8 ns
pulse) for excitation. Right-angle detection was used to collect the
luminescence spectra using a gated CCD camera and spectrograph at
variable delays.
3,8,13-Trimethoxy-10,15-dihydro-5H-tribenzo[a,d,g]-
15
cyclononene-2,7,12-tricarboxylic Acid (1). CTV-I3 (400 mg, 0.54
mmol) was dissolved in 25 mL of dried THF under argon atmosphere.
The reaction mixture was cooled to −80 °C, and then butyllithium
(1.95 mL of 2.5 M in hexane solution, 4.9 mmol, 9 equiv) was added
slowly. The reaction was allowed to warm to 0 °C for 1 h, and then to
room temperature for 1 h. The reaction was cooled to −80 °C again
before the addition of ethyl chloroformate (2 mL, 20.8 mmol, 39
equiv). Next, the reaction was allowed to warm to room temperature.
After 3 h at room temperature, the reaction mixture was cooled to 0
°C, and 80 mL of saturated NH4Cl(aq) was added slowly. The crude
mixture was extracted with ethyl acetate (3 × 100 mL). Next, the
organic phases were washed with water, before being dried over
anhydrous magnesium sulfate and concentrated under vacuum. The
residue was finally purified by column chromatography on silica gel
(dichloromethane/ethyl acetate first from 0 to 25% ethyl acetate). The
intermediate ester CTV was obtained as a white solid (170 mg, 55%
yield): mp 130 °C; δH (400 MHz, CDCl3) 7.83 (s, 3H), 6.97 (s, 3H),
4.77 (d, J = 13.6 Hz, 3H), 4.29 (m, 6H), 3.88 (s, 9H), 3.73 (d, J = 13.6
Hz, 3H), 1.33 (t, J = 6.8 Hz, 9H); δC (100 MHz, CDCl3) 165.8, 158.3,
145.4, 133.6, 130.2, 119.1, 113.7, 60.8, 56.3, 36.5, 14.4; νmax (neat)/
cm−1 2977, 2932, 2901, 2859, 2832, 1723, 1692, 1609, 1503, 1403,
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1389, 1244, 1196, 1110, 1058, 1020; HRMS (ESI, positive mode)
calcd for C33H36O9, Na adduct 599.2258, found 599.2275. This
intermediate (60 mg, 0.1 mmol) was dissolved in 6 mL of THF. A 5 M
sodium hydroxide solution (4 mL, 20 mmol, 200 equiv) was added,
and the solution was allowed to react at 50 °C for 24 h. The reaction
mixture was cooled to room temperature, and the THF was removed
under vacuum. A 37% HCl solution was added to the crude to reach
pH < 1. The precipitate formed was collected and rinsed twice with 0.1
M HCl, followed by 0.01 M HCl. The solid obtained was dried under
vacuum at 50 °C overnight. The CTV 1 was obtained as a beige solid
(50 mg, 98% yield): mp decomposition from 255 °C; δH (400 MHz,
DMSO-d6) 12.38 (s, 3H), 7.848 (s, 3H), 7.23 (s, 3H), 4.84 (d, J = 13.2
Hz, 3H), 3.78 (d, J = 13.2 Hz, 3H), 3.77 (s, 9H); δC (100 MHz,
DMSO-d6) 166.9, 156.7, 145.1, 132.5, 130.8, 119.9, 113.7, 55.9, 34.9;
νmax (neat)/cm−1 3490, 3231, 2925, 2859, 2839, 1709, 1602, 1492,
1458, 1406, 1334, 1317, 1285, 1155, 1055, 983; HRMS (ESI, TOF,
negative mode) calcd for C27H23O9, 491.1347, found 491.1356.
1-(7,12-Diacetyl-3,8,13-trimethoxy-10,15-dihydro-5H-tribenzo-
[a,d,g]cyclononen-2-yl)-1-ethanone (2). CTV-I3 was reduced by
LiAlH4 using the reported procedure.2 The reduced CTV-H3 (1.07 g,
2.97 mmol) was dissolved in 107 mL of dried dichloromethane under
nitrogen atmosphere, at 0 °C. The aluminum chloride (2.14 mg, 16.05
mmol, 5.4 equiv) and acetyl chloride (3.15 mL, 44.5 mmol, 15 equiv)
were added. After 20 min at 0 °C, the reaction was allowed to warm to
room temperature. After 4 h at room temperature, 210 mL of HCl 1
M, which has been cooled to 0 °C, was added to the reaction mixture.
The crude was extracted with dichloromethane (3 × 120 mL). Next,
the organic phases were washed with distilled water up to neutrality of
the water phase. The organic phase was dried with anhydrous
magnesium sulfate and concentrated under vacuum. The solid was
rinsed with diethyl ether and dried under vacuum. Finally, the solid
obtained was purified by column chromatography on silica gel, using
dichloromethane/ethyl acetate (9/1) as eluent, to give CTV 2 as a
white solid (1.0 g, 70% yield): mp decomposition over 265 °C; δH
(400 MHz, CDCl3) 7.82 (s, 3H), 6.97 (s, 3H), 4.73 (d, J = 13.6 Hz,
3H), 3.88 (s, 9H), 3.75 (d, J = 13.6 Hz, 3H), 2.52 (s, 9H); δC (100
MHz, CDCl3) 198.9, 158.4, 146.0, 132.4, 130.5, 126.7, 113.2, 56.9,
36.5, 32.1; νmax (neat)/cm−1 2997, 2918, 2849, 2835, 1664, 1599,
1492, 1392, 1262, 1231, 1151, 1048, 1004; HRMS (FAB with NBA
matrix) calcd for C31H30O6, 487.212, found 487.211.
white powder (114 mg, 64% yield): mp decomposition over 253 °C;
δH (400 MHz, CDCl3) 7.53 (br, 6H), 7.46 (s, 3H), 7.31 (br, 9H), 6.87
(s, 3H), 4.69 (d, J = 13.6 Hz, 3H), 3.91 (s, 9H), 3.62 (d, J = 13.6 Hz,
3H); δC (100 MHz, CDCl3) 159.0, 141.5, 135.0, 131.8, 131.0, 128.4,
128.2, 123.8, 112.6, 111.6, 93.2, 85.8, 56.3, 36.7; νmax (neat)/cm−1
3033, 2969, 2937, 2851, 2822, 1591, 1502, 1481, 1441, 1391,
1295,1242, 1199, 1071, 1003; HRMS (ESI, TOF, positive mode) calcd
for C48H36O3, Na adduct 683.2565, found 683.2556.
2,7,12-Triethynyl-3,8,13-trimethoxy-10,15-dihydro-5H-tribenzo-
[a,d,g]cyclononene (5). CTV-I3 (300 mg, 0.406 mmol) and
trimethylsilylacetylene (509 μL, 3.65 mmol, 9 equiv) were dissolved
in 12 mL of toluene under argon atmosphere. After 20 min of argon
sparging, copper iodide (46.4 mg, 0.24 mmol, 0.6 equiv), bis-
(triphenylphosphine)palladium(II) dichloride (171 mg, 0.24 mmol,
0.6 equiv), and dried triethylamine 3 mL were added, and the solution
was heated to 40 °C under argon atmosphere. After 48 h, the solution
was cooled to room temperature and evaporated under vacuum. The
crude was purified by chromatography on silica gel, using cyclohexane/
dichloromethane (7/3) as eluent, to give trimethyl(2-{3,8,13-
trimethoxy-7,12-bis[2-(trimethylsilyl)ethynyl]-10,15-dihydro-5H-
tribenzo[a,d,g]cyclononen-2-yl}ethynyl)silane as a white powder (200
mg, 77% yield). This intermediate (200 mg, 0.308 mmol) was
dissolved in 10 mL of dried THF under nitrogen atmosphere.
Tetrabutylammonium fluoride (4.62 mL of 1 M in THF, 4.62 mmol,
15 equiv) was added, and the solution was allowed to react at 25 °C
under argon atmosphere overnight. The THF was evaporated under
vacuum, and distilled water (150 mL) was added to the crude. This
one was extracted three times (100 mL) with dichloromethane. The
organic phases were washed with water, dried with anhydrous
magnesium sulfate, and concentrated under vacuum. The solid
obtained was rinsed with diethyl ether and dried under vacuum.
CTV 5 was obtained as a white powder (127 mg, 95% yield): mp
decomposition over 200 °C; δH (400 MHz, DMSO-d6) 7.64 (s, 3H),
7.19 (s, 3H), 4.75 (d, J = 13.2 Hz, 3H), 4.12 (s, 9H), 3.78 (d, J = 13.2
Hz, 3H), 3.66 (s, 3H); δH (100 MHz, DMSO-d6) 158.8, 142.4, 135.0,
131.2, 112.6, 109.2, 83.9, 80.1, 55.9, 34.9; νmax (neat)/cm−1 3276,
2929, 2847, 2098, 1606, 1559 1492, 1463, 1388, 1199, 1134, 1074;
HRMS (ESI, TOF, positive mode) calcd for C30H24O3, Na adduct
455.1617, found 455.1637.
3,8,13-Trimethoxy-10,15-dihydro-5H-tribenzo[a,d,g]-
cyclononene-2,7,12-tricarbonitrile (3). CTV-I3 (250 mg, 0.34 mmol)
was dissolved in 12 mL of dried DMF under nitrogen atmosphere, and
copper cyanide (250 mg, 5.6 mmol, 17 equiv) was added. The reaction
was warmed to 130 °C. After 24 and 48 h, 250 mg of copper cyanide
was added again to the mixture. After 3 days, the reaction was allowed
to cool to room temperature. The crude was poured into 250 mL of 1
M HCl. The precipitate formed was filtered and washed with 200 mL
of 1 M HCl, followed by saturated NH4Cl(aq) up to neutrality of the
water phase, and then with ether. The solid obtained was dissolved in
hot dichloromethane and filtered through silica gel. After evaporation
under vacuum of the dichloromethane, CTV 3 was obtained as a white
solid (125 mg, 85% yield): mp decomposition over 265 °C; δH (400
MHz, DMSO-d6) 8.08 (s, 3H), 7.46 (s, 3H), 4.88 (d, J = 13.6 Hz, 3H),
3.90 (s, 9H), 3.775 (d, J = 13.6 Hz, 3H); δC (100 MHz, DMSO-d6)
159.6, 147.2, 135.4, 131.4, 113.5, 99.1, 56.7, 34.9; νmax (neat)/cm−1
2933, 2851, 2223, 1605, 1566, 1498, 1459, 1391, 1309, 1274, 1209,
1138, 1074, 1002; MALDI-MS (with a dithranol + AgTFA matrix)
calcd for C27H21N3O3, Ag adduct 542.06, found 542.02.
2,7,12-Trimethoxy-3,8,13-tris(2-phenylethynyl)-10,15-dihydro-
5H-tribenzo[a,d,g]cyclononene (4). CTV-I3 (200 mg, 0.27 mmol)
and ethynylbenzene (267 μL, 2.4 mmol, 9 equiv) were dissolved in 8
mL of toluene and 2 mL of dried triethylamine, under argon
atmosphere. After 20 min of argon sparging, copper iodide (30.8 mg,
0.016 mmol, 0.6 equiv) and bis(triphenylphosphine)palladium(II)
dichloride (114 mg, 0.16 mmol, 0.6 equiv) were added, and the
solution was heated to 40 °C under argon atmosphere. After 60 h, the
solution was cooled to room temperature and was evaporated under
vacuum. The crude was purified by chromatography on silica gel, using
cyclohexane/dichloromethane (1/1) as eluent, to give CTV 4 as a
1-Phenyl-4-[3,8,13-trimethoxy-7,12-bis(1-phenyl-1H-1,2,3-tria-
zol-4-yl)-10,15-dihydro-5H-tribenzo[a,d,g]cyclononen-2-yl]-1H-
1,2,3-triazole (6). CTV 5 (30 mg, 0.069 mmol) and 1-azidobenzene
(74.4 mg, 0.062 mmol, 9 equiv) were dissolved in 5 mL of DMSO/
water (2/3) under argon atmosphere. After 20 min of argon sparging,
copper sulfate (17 mg, 0.014 mmol, 1.5 equiv) and sodium ascorbate
(41 mg, 0.02 mmol, 3 equiv) were added, and the solution was heated
to 50 °C under argon atmosphere. After 48 h, the solution was cooled
to room temperature, and 50 mL of distilled water was added. The
crude was extracted with dichloromethane. The organic phases were
dried with anhydrous magnesium sulfate and concentrated under
vacuum. The solid was rinsed with diethyl ether and then dried under
vacuum at 40 °C overnight. CTV 6 was obtained as a yellow powder
(22 mg, 40% yield): mp decomposition over 265 °C; δH (400 MHz,
CDCl3) 8.48 (s, 3H), 8.32 (s, 3H), 7.77 (d, J = 7.4 Hz, 6H), 7.5 (t, J =
7.4 Hz, 6H), 7.4 (t, J = 7.4 Hz, 3H) ; δC (100 MHz, CDCl3) 154.8,
143.8, 141.2, 137.4, 131.6, 129.8, 129.0, 128.5, 120.7, 120.5, 117.7,
112.6, 55.98, 36.8; νmax (neat)/cm−1 2919, 2851, 1595, 1495, 1463,
1420, 1378, 1256, 1235, 1149, 1113, 1031; HRMS (ESI, TOF, positive
mode) calcd for C48H39N9O3, Na adduct 812.3068, found 812.3053.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of the 1H and 13C NMR spectra for all new compounds,
and fluorescence titration data of 1 in the presence of choline
and acetylcholine. This material is available free of charge via
the Internet at http://pubs.acs.org.
7026
dx.doi.org/10.1021/jo301183b | J. Org. Chem. 2012, 77, 7023−7027

The Journal of Organic Chemistry
Article
AUTHOR INFORMATION
Corresponding Author
*E-mail: gosse@enscbp.fr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the “Minister
the “Centre National de Recherche Scientifique”, and the
■
̀
e de la Recherche”,
́
“Region Aquitaine”.
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