Nucleophilic Functionalization of the Calix[6]arene Para- and Meta-Position via p-Bromodienone Route

Article abstract of DOI:10.1021/acs.joc.5b00978

It is here demonstrated that the p-bromodienone route, previously reported for calix[4]arenes, is also effective for the functionalization of the calix[6]arene macrocycle. Thus, alcoholic O-nucleophiles can be introduced at the calix[6]arene exo rim. In a

Full text of DOI:10.1021/acs.joc.5b00978

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Note
Nucleophilic Functionalization of the Calix[6]arene
Para- and Meta-Position via p-Bromodienone Route
Margherita De Rosa, Annunziata Soriente, Gerardo
Concilio, Carmen Talotta, Carmine Gaeta, and Placido Neri
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00978 • Publication Date (Web): 17 Jun 2015
Downloaded from http://pubs.acs.org on June 25, 2015
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The Journal of Organic Chemistry
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Nucleophilic Functionalization of the Calix[6]arene
Para- and Meta-Position via p-Bromodienone Route
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Margherita De Rosa,* Annunziata Soriente, Gerardo Concilio, Carmen Talotta,
Carmine Gaeta, and Placido Neri*
Dipartimento di Chimica e Biologia, Università di Salerno, Via Giovanni Paolo II 132, I-84084
Fisciano (Salerno), Italy, e-mail: maderosa@unisa.it; neri@unisa.it
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT. It is here demonstrated that the pꢀbromodienone route, previously reported for
calix[4]arenes, is also effective for the functionalization of the calix[6]arene macrocycle. Thus,
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alcoholic Oꢀnucleophiles can be introduced at the calix[6]arene exo rim. In addition, the reaction of a
calix[6]arene pꢀbromodienone derivative with an actived aromatic substrate, such as resorcinol, led to
the first example of a metaꢀfunctionalized, inherently chiral calix[6]arene derivative.
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Today, many strategies are known for introducing functionalities at the calixarene exo rim,1 which
include several electrophilic aromatic substitutions2 and three classical paths, namely the “Claisen
rearrangement”,3 “pꢀquinoneꢀmethide”,4 and “pꢀchloromethylation”5 routes. However, in the last years,
significant efforts from calixarene chemists have been directed to the search for alternative ways6 to
functionalize the calixarene skeleton with the aim to obtain novel calixareneꢀbased supramolecular
hosts.
Thus, recently, our group has reported the “pꢀbromodienone route”7 as a new synthetic strategy
to introduce nucleophiles at the calix[4]arene upper rim, starting from calixarene pꢀbromodienone
derivatives8 (2 in Scheme 1). These latter, undergo a silverꢀmediated nucleophilic substitution of the
bromine atom with several alcoholic or carboxylic Oꢀnucleophiles,7a then a spontaneous reꢀ
aromatization leads to pꢀalkoxyꢀ or pꢀacyloxyꢀcalix[4]arene derivatives. Subsequently, we
demonstrated7b that the “pꢀbromodienone route” can be also extended to appropriate aromatic substrates,
thus allowing the para or meta functionalization with aryl groups. The metaꢀsubstitution is likely
obtained by rearrangement of the pꢀaryldienone intermediate. Concomitantly, a related procedure was
reported by Varma9 and coꢀworkers in which calixarene spirodienone derivatives are used to introduce
alkoxy groups into the calix[4]arene exo rim.10
Regarding the larger calix[6]arene hosts, recent reports11 have evidenced interesting and peculiar
supramolecular properties ranging from molecular recognition11c−e to the synthesis of interpentrated
architectures.11a,b,f Consequently, an increased interest has been aroused for developing novel and
alternative functionalization procedures of the calix[6]arene macrocycle. Thus, Reinaud6e and coworkers
reported the ipsoꢀchlorosulfonylation of calix[6]arene derivatives in which ꢀSO2Cl groups were
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introduced selectively at their exo rim, while Jabin and coworkers6a,b showed interesting and novel
routes for the functionalization of the calix[6]arene endo rim.
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In order to broaden the synthetic versatility and to define new procedures for the
functionalization of the calix[6]arene macrocycle, we decided to verify the feasibility of the pꢀ
bromodienone route on partially Oꢀalkylated calix[6]arene derivatives and we report here the results of
our studies.
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Scheme 1. The pꢀbromodienone route.7a,b
We first studied the feasibility of the pꢀbromodienone route on pentamethoxyꢀp-tertꢀ
buylcalix[6]areneꢀmonoꢀol derivatives 812 bearing a single oxidable phenol ring. The synthesis of
derivative 8 is presented in Scheme 2 and is based on a protectionꢀdeprotection procedure already
reported by De Mendoza and coworkers.12 Thus, p-tertꢀbutylcalix[6]arene 5 was monoalkylated with
benzylbromide, in presence of K2CO3 as the base, to give 6 in 45% yield, which was exhaustively
methylated with MeI in the presence of Cs2CO3 to give 7 in 80% yield. Finally, 7 was subjected to
hydrogenolysis with Pd/C to give pentamethoxycalix[6]areneꢀmonoꢀol 8 in quantitative yield.
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Scheme 2.
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The H NMR spectrum (400 MHz, CDCl3, 298 K) of 812 shows three sharp singlets due to ArCH2Ar
groups indicating a fast conformational interconversion, which is due to the small dimension of the
methoxy groups at the lower rim of the macrocycle.
In the next step, we decided to perform the oxidation of the phenol ring of monoꢀol 8 to the
corresponding pꢀbromodienone system, under conditions usually adopted for the synthesis of the
corresponding calix[4]arene derivatives.7a Thus, the treatment of 8 (in CH2Cl2 at 25°C) with
trimethylphenylammonium tribromide and a saturated solution of NaHCO3 resulted in the quantitative
formation of the first example of calix[6]arene pꢀbromodienone derivative 11. The structure of 11 was
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assigned by means of spectral analysis. In particular, its ESI(+) mass spectrum revealed the presence of a
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ion peak at 1143 m/z (MNa)+ with a typical bromine isotopic pattern, in accord with the molecular
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formula of 11. The H NMR spectrum of pꢀbromodiene derivative 11 in CDCl3 at 298 K (600 MHz)
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(Figure S5) revealed the presence of 3 singlets in a 2:2:1 ratio at 1.23, 1.16, and 1.11 ppm, respectively,
due to tꢀbutyl groups on anisole rings, while a broad singlet was present at 0.86 ppm due to t-butyl group
on the oxidized pꢀbromodienone ring. In addition, three broad singlets were present at 2.90, 3.11, and
3.25 ppm due to OMe groups, while the ArCH2Ar region showed the presence of two AX systems at
4.20/3.74 ppm (J = 14.6 Hz) and 4.09/3.71 ppm (J = 14.8 Hz) and one AB system at 3.51/3.60 ppm (J =
15.0 Hz) due to ArCH2Ar groups. Regarding the 4ꢀtertꢀbutylꢀ4ꢀbromoꢀ2,5ꢀcyclohexadienone moiety of
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11, a broad singlet at 6.60 ppm due to the dienone Hꢀatoms was observed in the H NMR spectrum,
while in the 13C NMR spectrum the C=O and CꢀBr resonances were present at 183.7 and 71.3 ppm,
respectively.
As previously reported, the synthesis of calix[4]arene pꢀbromodienone 2 (Scheme 1), gives rise
to two stereoisomers, namely the exo and endo ones (referring to the relative orientation of the Brꢀatom
with respect to the calix[4]arene cavity), which were purified by selective precipitation from diethyl
ether. Naturally, an analogous stereoisomerism should be expected for calix[6]arene pꢀbromodienone
11, but its rapid cone-to-cone1 inversion (even with respect to the NMR time scale) led to the mutual
interconversion between exo- and endoꢀ11 stereoisomers (Figure 1). Interestingly, 11 displays
temperatureꢀdependent 1H NMR spectra due to the easy through-the-annulus rotation of the anisole and
pꢀbromodienone rings. In fact, the lowering of the temperature caused a broadening of the ArCH2Ar
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signals followed by decoalescence and resharpening to give at 233 K a very complicated H NMR
spectrum corresponding to the presence of the two exo-/endo-11 stereoisomers in different
conformations.
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Figure 1. The cone-to-cone inversion interconverts the two exoꢀ and endoꢀ11 stereoisomers.
At this point, we tested the feasibility of the nucleophilic substitution of bromine atom on the pꢀ
bromodienone derivative 11 using Oꢀnucleophiles such as methanol and benzylic alcohol. Thus, a
sample of 11 was treated with a cold methanolic solution of AgClO4 (Scheme 2) to give pꢀ
methoxycalix[6]arene 13a in 20% yield, after usual workꢀup. The structure of 13a was confirmed by
means of spectral analysis. In particular, ESI(+) mass spectrum confirmed the molecular formula while
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the Cs molecular symmetry was assigned by pertinent signals in the H and 13C NMR spectra. In
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particular, the presence in the H NMR spectrum of 13a (400 MHz, CDCl3, 298 K) of only three 1:2:2
tertꢀbutyl signals at 0.98, 1.13, and 1.17 ppm were a clear evidence of the displacement of a tꢀBu group
by a methoxyl one, which was corroborated by the presence of four singlets due to OMe groups at 3.02,
3.15, 3.49, and 3.57 ppm in a 2:2:1:1 ratio. Finally, due to the rapid through-the-annulus passage of both
exo and endo rim of 13a, the ArCH2Ar 1H resonances were present as two singlets at 3.81 (4H) and 3.93
(8H) ppm.
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The influence of the alcoholic portion on the reaction outcome was tested by using the bulkier
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benzylic alcohol. Thus, the treatment of pꢀbromodienone derivative 11 with BnOH in the presence of
AgClO4 in DME as solvent (Scheme 2) afforded the expected pꢀbenzyloxycalix[6]arene derivative 13b
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in 30% yield, after usual work up. The H NMR spectrum of 13b (400 MHz, CDCl3, 298 K) showed
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three 1:2:2 tertꢀbutyl singlets at 0.93, 1.08, and 1.10 ppm, respectively, and one singlet at 4.73 ppm due
to OCH2Ph group, which was indicative of the displacement of the tꢀBu group by the benzyloxy one.
The 13C NMR spectrum (100 MHz, CDCl3, 298 K) of 13b confirmed its Cs molecular symmetry by the
presence of three signals due to ArCH2Ar groups at 29.7, 30.3, and 31.2 ppm, three signals due to ꢀ
C(CH3)3 Cꢀatoms at 31.3, 31.4, and 31.6 ppm, and one resonance at 70.2 ppm due to OCH2Ph group.
In a previous study,7b,e we have shown that the pꢀbromodienone route with actived aromatic
substrates (e.g.: resorcinol in Scheme 1) is a valid synthetic method to obtain metaꢀsubstitued inherently
chiral calix[4]arene derivatives13 (e.g.: 4 in Scheme 1). Such chiral calixarene derivatives are interesting
hosts which may find applications in enantiodiscrimination processess14 and asymmetrical catalysis.15 A
survey of the calixarene literature strangely reveals that no synthetic procedures have been so far
reported for the metaꢀfunctionalization of calix[6]arene macrocycle. Prompted by this observation, we
decided to study the reaction of calix[6]arene pꢀbromodienone derivative 11 with resorcinol under
condition previously reported7b for the synthesis of metaꢀsubstituted calix[4]arene 4 (Scheme 1). Thus,
the treatment of 11 with resorcinol and a cold solution of AgClO4 afforded metaꢀsubstituted
calix[6]arene 14 in 30% yield (Scheme 2). 1D and 2D NMR spectra were in agreement with the
asymmetrical structure of 14, in which the resorcinol and tꢀBu groups were, respectively, metaꢀ and
paraꢀlinked to the calixarene phenol ring. In fact, five of the expected six tꢀBu singlets (two accidentally
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isochronous) were present in the H NMR spectrum (CDCl3, 400 MHz, 298 K) of 14 at 1.12, 1.15
(18H), 1.19, 1.21, and 1.33 ppm, while five singlets due to ArCH2Ar groups were present at 3.83, 3.97,
4.07, 4.10 (4H), and 4.12 ppm, which correlates in the HSQC spectrum with carbon resonances at 31.8 ,
32.6, 30.2 (2C), 30.3, and 29.9 ppm. In addition, the 13C NMR spectrum evidenced five signals due to ꢀ
C(CH3)3 atoms at 31.50, 31.51 (2C), 31.54, 31.56, and 31.77 ppm, and four signals due to OMe groups
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at 60.93, 60.98 (2C), 62.27, and 62.34 ppm, which correlates in the HSQC spectrum with singlets at
3.60 (9H), 3.87 and 3.88 ppm. The asymmetric structure of 14 coupled to its threeꢀdimensional nature
makes it inherently chiral and, consequently, it should be formed as a racemic mixture. In contrast to the
conformationally blocked calix[4]arene derivative 4 (Scheme 1), a rapid cone-to-cone inversion (Figure
2) of the calix[6]arene skeleton of 14 leads to the interconversion between the two enantiomers.
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Figure 2. The cone-to-cone inversion interconverts the two enantiomers of 14.
In order to extend the generality of the pꢀbromodienone route on calix[6]arene macrocycle, we
synthesized calix[6]arene pꢀbromodienone 12 bearing hexyloxy chains at the endo rim. The synthesis of
12 was very similar to that of its methoxy analogue 11, as outlined in Scheme 2. The monoꢀbenzylated
calix[6]arene 6 was exhaustively alkylated by treatment with Cs2CO3 and 1ꢀiodohexane in acetone as
solvent, to give derivative 9 in 80% yield. Successively, the benzyl group at the endo rim of 9 was
removed by hydrogenolysis (H2 and Pd/C) to give pentahexyloxyꢀmonoꢀol 10 in 91% yield. In contrast
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to pentamethoxyꢀmonoꢀol 8 bearing smaller groups at the endo rim, the H NMR spectrum (400 MHz,
CDCl3) of 10 displays broad signals for the methylene protons, which sharpened at 383 K into 3 singlets
at 3.71, 3.73, and 3.75 ppm.
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Treatment of pentahexyloxycalix[6]areneꢀmonoꢀol 10 under conditions analogous to the
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synthesis of 11, led to the formation of derivative 12 in 96% yield. Its ESI(+) mass spectrum confirmed
the molecular formula of 12 by the presence of a ion peak at 1494 (MNa+) with a typical bromine
isotopic pattern, while the presence of bromine was further corroborated by the ready precipitation of
AgBr upon treatment with alcoholic AgNO3. The 1H NMR spectrum of 12 in TCDE at 298 K showed 4
broad singlets due to to tꢀbutyl groups at 0.71 (9H), 0.99 (18H), 1.13 (9H), and 1.31 (18H) ppm, while
broad signals were presents in the methylene region indicating a slow conformational interconversion on
the NMR time scale. Analogously to pꢀbromodienone 11, lowering the temperature caused a
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decoalescence and resharpening to give at 243 K a very complicated H NMR spectrum corresponding
to the presence of the two exo/endoꢀ12 stereoisomers in different conformations. Upon increasing the
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temperature, the TCDE solution of 12 darkens progressively and the resulting H NMR spectra showed
a number of signals not in agreement with its molecular symmetry. The successive temperature lowering
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back at 298 K did not return to the original H NMR spectrum, indicating that calix[6]arene pꢀ
bromodienone 12 irreversibly decomposes at high temperatures, in accordance with previously observed
data.7
Analogously to pꢀbromodienone derivative 11, the treatment of 12 with a methanolic solution of
AgClO4 (Scheme 2) afforded pꢀmethoxycalix[6]arene 15a in 15% yield, while its treatment benzylic
alcohol (Scheme 2) afforded derivative 15b in 17% yield.
As previously demonstrated,7a,c the pꢀbromodienone route can also be exploited for introducing
chirality into the calixarene framework by appending appropriate chiral substituents. With this aim in
mind, calix[6]arene pꢀbromodienone 12 was treated with a racemic mixture of (±)ꢀ2ꢀphenylꢀ1ꢀpropanol
in the presence of AgClO4 (Scheme 2) to give the corresponding derivative 15c in 15% yield.
In conclusion, we have here demonstrated that the pꢀbromodienone route is also effective for the
functionalization of the calix[6]arene macrocycle. Therefore, through this route it is possible to
introduce alcoholic Oꢀnucleophiles at the calix[6]arene exo rim. In addition, the pꢀbromodienone route
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with activated aromatic substrates allowed the first example of metaꢀfunctionalization of a calix[6]arene
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macrocycle giving rise to an unprecedented metaꢀsubstituted inherently chiral calix[6]arene derivative.
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Experimental Section
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General: ESI(+)−MS measurements were performed on a quadrupole mass spectrometer equipped with
electrospray ion source, using a mixture of H2O/CH3CN (1:1) and 5% HCOOH as solvent. Flash
chromatography was performed on silica gel (40ꢀ63 ꢀm). All chemicals were reagent grade and were
used without further purification. When necessary compounds were dried in vacuo over CaCl2. Reaction
temperatures were measured externally. Reactions were monitored by TLC on silica gel plates (0.25
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mm) and visualized by UV light or by spraying with H2SO4ꢀCe(SO4)2. H NMR spectra were recorded
at 300, 400, or 600 MHz, and 13C NMR spectra were recorded at 75, 100, or 150 MHz. Chemical shifts
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are reported due to to the residual solvent peak. Oneꢀdimensional H and 13C spectra, and twoꢀ
dimensional COSYꢀ45, and heteronuclear single quantum correlation (HSQC) were used for NMR peak
assignment. COSYꢀ45 spectra were taken using a relaxation delay of 2 seconds with 30 scans and 170
increments of 2048 points each. HSQC spectra were performed with gradient selection, sensitivity
enhancement, and phaseꢀsensitive mode using Echo/AntiechoꢀTPPI procedure. A typical experiment
comprised 20 scans with 113 increments of 2048 points each. Derivatives 8 was synthesized according
to a literature procedure.12
Synthesis of Derivative 9. Cs2CO3 (9.8 g, 30 mmol) was added, under stirring, to a solution of
compound 612 (1.18 g, 1.11 mmol) in dry acetone (60 mL) and the mixture was heated at reflux. After
30 min, 1ꢀiodohexane (14.8 g, 10.3 mL, 69.8 mmol) was added and the resulting mixture was kept at
reflux under stirring for 48 h. The reaction was allowed to cool at room temperature and the solvent
removed under reduced pressure. The crude product was solubilized in CH2Cl2, washed with aqueous
1N HCl, brine, and then dried over Na2SO4. The solvent was evaporated to dryness and the product was
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crystallized from MeOH/CH2Cl2 to give 9 as a pale yellow solid (1.32 g, 80% yield). Mp: 245ꢀ248 °C.
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ESI(+) MS: m/z = 1485 (MH+), 1507 ( MNa+), 1522 (MK+). H NMR (300 MHz, TCDE, 383 K):
δ
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0.77 [broad, O(CH2)5CH3, 15H], 0.94 [s, ꢀC(CH3), 9H], 0.95 [s, ꢀC(CH3), 18H], 1.04 [s, ꢀC(CH3), 27H],
1.10−1.25 (overlapped, OCH2CH2CH2CH2CH2CH3, 30H), 1.35−1.60 (overlapped,
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OCH2CH2CH2CH2CH2CH3, 10H), 3.28 (broad, OCH2CH2CH2CH2CH2CH3, 4H), 3.39 (broad,
OCH2CH2CH2CH2CH2CH3, 4H), 3.48 (t, OCH2CH2CH2CH2CH2CH3, J = 6.5 Hz, 2H), 3.79 (broad s,
ArCH2Ar, 12H), 4.67 (s, OCH2Ph, 2H), 6.77 (s, ArH, 2H), 6.83 (s, ArH, 4H), 6.90 (s, ArH, 4H), 6.94 (s,
ArH, 2H), 7.16−7.21 (overlapped, OCH2C6H5, 3H), 7.30ꢀ 7.35 (m, OCH2C6H5, 2H). 13C NMR (75
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MHz, TCDE, 383 K):
δ 12.2, 20.8, 24.2, 28.1, 28.3, 28.4, 28.9, 29.7, 30.0, 32.1, 71.7, 73.0, 123.7,
123.9, 124.3, 124.6, 124.8, 125.6, 126.4, 131.1, 131.2, 136.5, 143.1, 143.6, 150.9, 151.6, 152.0. Anal.
Calcd. for C103H150O6: C, 83.35: H, 10.19. Found: C, 83.25; H, 10.27.
Synthesis of Derivative 10. A solution of 9 (1.32 g, 0.89 mmol) in CHCl3 (80 mL ) was added of Pd/C
and stirred for 12 h under H2 at 25 °C. The catalyst was filtered on a celite pad and the filtrate was
evaporated under vacuum. Precipitation of the residue from methanol gave pure 10 as a yellow solid
1
(1.13 g, 91% yield). Mp: 200ꢀ203 °C. ESI(+) MS: m/z = 1417 ( MNa+), 1434 (MK+). H NMR (300
MHz, TCDE, 383 K):
1.12 [s, ꢀC(CH3), 18H], 1.15 [s, ꢀC(CH3), 18H], 1.06ꢀ1.40 (overlapped, OCH2CH2CH2CH2CH2CH3,
30H), 1.59−1.70 (overlapped, OCH2CH2CH2CH2CH2CH3, 10H), 3.09 (broad t,
δ 0.70 [s, ꢀC(CH3), 9H], 0.77 [broad, O(CH2)5CH3, 15H], 0.94 [s, ꢀC(CH3), 9H],
OCH2CH2CH2CH2CH2CH3, 4H), 3.60 (t, OCH2CH2CH2CH2CH2CH3, J = 7.2 Hz, 2H), 3.71−3.76
(overlapped, ArCH2Ar + OCH2CH2CH2CH2CH2CH3, 16H), 6.41, (br s, ArH, 2H), 6.54 (br s, ArH, 2H),
6.57 (br s, OH, 1H), 6.77 (s, ArH, 2H), 6.91 (s, ArH, 2H), 6.96 (br s, ArH, 2H), 7.00 (br s, ArH, 2H).
13C NMR (75 MHz, TCDE, 383 K):
δ 11.9, 12.0, 20.6, 20.9, 24.0, 27.9, 28.4, 28.6, 29.5, 29.6, 29.8,
30.0, 32.0, 32.1, 71.7, 122.7, 123.0, 124.4, 124.5, 125.3, 130.2, 131.2, 131.8, 140.1, 142.6, 143.0, 143.1,
144.0, 149.3, 149.9, 151.7, 152.4. Anal. Calcd. for C96H144O6: C, 82.70; H, 10.41. Found: C, 82.61; H,
10.40.
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General Procedure for the Synthesis of p-Bromodienone Derivatives 11 and 12. A solution of
phenyltrimethylammonium tribromide (0.13 g, 0.36 mmol) in CH2Cl2 (5 mL) was added dropwise over
15 min to a stirred solution at 0 °C of the appropriate pentaalkoxyꢀcalix[6]areneꢀmonoꢀol 8 or 10 (0.24
mmol) in CH2Cl2 (24 mL). Then, 25 mL of a saturated aqueous solution of NaHCO3 was added and the
resulting mixture was stirred for 15 min at room temperature. The organic phase was separated and
washed with an aqueos solution of Na2SO3 (10% w.t.) and H2O. The organic phase was dried over
Na2SO4, filtered and the solvent removed under reduced pressure, to give the corresponding
calix[6]arene pꢀbromodienone derivative 11 or 12 in quantitative yield.
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Derivative 11 (0.26 g, 99%). Mp: > 175 °C dec. ESI(+) MS: m/z = 1143 (MNa+), 1159 (MK+). 1H NMR
(600 MHz, CDCl3, 298 K):
δ 0.86 [s, ꢀC(CH3)3, 9H], 1.11 [s, C(CH3)3, 9H], 1.16 [s, ꢀC(CH3)3, 18H],
1.23 [s, C(CH3)3, 18H], 2.90 (br s, OCH3, 6H), 3.11 (br s, OCH3, 6H), 3.25 (br s, OCH3, 3H), 3.51 and
3.60 (AB, ArCH2Ar, J = 15.0 Hz, 4H), 3.71 and 4.09 (AB, ArCH2Ar, J = 14.8 Hz, 4H), 3.74 and 4.20
(AX, ArCH2Ar, J = 14.6 Hz, 4H), 6.60 (s, C=CH, 2H), 6.91 (br s, ArH, 2H), 7.03 (br s, ArH, 2H), 7.07
13
(br s, ArH, 4H), 7.11 (br s, ArH, 2H). C NMR (150 MHz, CDCl3, 298 K):
δ 26.3, 30.0, 30.2, 30.8,
31.59, 31.6, 31,7, 34.3, 34.4, 39.5, 60.1, 60.4, 60.6, 71.3, 125.5, 125.9, 126.4, 126.8, 127.0, 130.0,
131.3, 133.4, 133.7, 133.8, 134.0, 137.0, 143.5, 145.8, 145.9, 146.2, 146.2, 154.0, 154.3, 183.7. Anal.
Calcd. for C71H93BrO6: C, 75.98; H, 8.35; Br, 7.12. Found: C, 76.07; H, 8.27; Br, 7.21.
1
Derivative 12 (0.34 g, 96%). Mp: > 168 °C dec. ESI(+) MS: m/z = 1494 (MNa+). H NMR
(
300 MHz,
TCDE, 298 K):
1.13 [s, ꢀC(CH3)3, 9H], 1.16−1.19 (overlapped, OCH2CH2CH2CH2CH2CH3, 30H), 1.31 [s, ꢀC(CH3)3,
18H], 1.52−1.98 (overlapped, OCH2CH2CH2CH2CH2CH3, 10H), 2.92−2.95 (broad,
δ 0.71 [broad, ꢀC(CH3)3, 9H], 0.89 [br s, O(CH2)5CH3, 15H], 0.99 [s, ꢀC(CH3)3, 18H],
OCH2CH2CH2CH2CH2CH3, 2H), 2.98−3.46 (overlapped, ArCH2Ar + OCH2CH2CH2CH2CH2CH3,
14H), 4.28−4.34 (overlapped, ArCH2Ar, 6H), 6.61−7.07 (overlapped, ArH+ C=CH, 12H). 13C NMR
(150 MHz, CDCl3, 298 K):
δ 14.4, 14.5, 22.8, 22.9, 26.0, 26.2, 29.7, 29.9, 30.5, 30.7, 31.7, 31.8, 32.1,
32.3, 34.3, 38.9, 83.9, 74.2, 126.7, 126.2, 126.5, 127.0, 127.6, 131.1, 132.8, 133.2, 134.1, 136.6, 144.3,
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145.1, 145.5, 153.5, 154.1, 183.7. Anal. Calcd. for C96H143BrO6: C, 78.27; H, 9.78; Br, 5.42. Found: C,
78.36; H, 9.69; Br, 5.31.
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General Procedure for the Synthesis of Derivatives 13a-b. A solution of AgClO4 (0.048 g, 0.23
mmol) in the appropriate alcohol (1.6 mL of methanol or benzylic alchol) was cooled at 0 °C and added
to solid 11 (0.13 g, 0.12 mmol). The reaction mixture was allowed to warm at room temperature and
stirred in the dark overnight. The solvent was removed under reduced pressure and the residue was
solubilized in CH2Cl2 (10 mL). The organic phase was washed 3 times with water, dried on Na2SO4,
filtered and the solvent was removed under reduced pressure.
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Derivative 13a. The crude product was purified by preparative thinꢀlayer chromatography, eluent n-
hexane/diethyl ether/methanol 80/20/1, v/v, to give 13a as a white solid, 0.025 g, yield 20%. Mp: 188ꢀ
191 °C. ESI(+) MS: m/z = 1017 (MH+). 1H NMR (400 MHz, CDCl3, 298 K):
δ 0.98 [s, ꢀC(CH3)3, 9H],
1.13 [s, ꢀC(CH3)3, 18H], 1.17 [s, ꢀC(CH3)3, 18H], 3.02 (s, OCH3, 6H), 3.15 (s, OCH3, 6H), 3.49 (s,
OCH3, 3H), 3.57 (s, OCH3, 3H), 3.81 (s, ArCH2Ar, 4H), 3.93 (br s, ArCH2Ar, 8H), 6.44 (s, ArH, 2H),
13
6.87 ( s, ArH, 2H), 6.92 ( s, ArH, 2H), 7.00 ( s, ArH, 2H), 7.06 ( s, ArH, 4H), 7.27 (s, OH, 1H). C
NMR (CDCl3, 100 MHz, 298 K):
δ 30.5, 31.4, 31.5, 31.7, 34.2, 34.3, 55.3, 60.6, 60.9, 113.2, 125.6,
126.3, 126.5, 129.0, 132.5, 133.2, 133.4, 133.6, 133.8, 145.4, 145.8, 145.9, 146.7, 152.6, 153.2, 154.1,
154.4. Anal. Calcd. for C68H88O7: C, 80.27; H, 8.72. Found: C, 80.36; H, 8.81.
Derivative 13b. The crude product was purified by column chromatography on silica gel using CHCl3/
nꢀhexane (96/4, v/v) as eluent to give 13b as a colourless solid, 0.040 g, 30% yield. Mp: 188ꢀ191 °C.
ESI(+) MS: m/z = 1093 ( MH+). 1H NMR (600 MHz, CDCl3, 298 K):
δ 0.93 [s, ꢀC(CH3)3, 9H], 1.08 [s,
ꢀC(CH3)3, 18H], 1.10 [s, C(CH3)3, 18H], 2.95 (s, OCH3, 6H), 3.09 (s, OCH3, 6H), 3.41 (s, OCH3, 3H),
3.73 (s, ArCH2Ar, 4H), 3.85 (bs, ArCH2Ar, 8H), 4.73 (s, OCH2Ph, 2H), 6.47 (s, ArH, 2H), 6.81 (s, ArH,
2H), 6.87 and 7.01 (AB, ArH, J =2.04 Hz, 4H), 6.93 and 6.96 (AB, ArH, J =2.04 Hz, 4H), 7.18ꢀ7.21
(overlapped, OCH2C6H5 + OH, 6H). 13C NMR (150 MHz, CDCl3, 298 K):
δ 29.7, 30.3, 31.2, 31.3,
31.4, 31.6, 31.9, 34.05, 34.1, 60.3, 60.7, 70.2, 114.2, 125.4, 125.7, 125.9, 126.1, 126.4, 127.5, 127.7,
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128.4, 128.6, 128.7, 132.2, 133.0, 133.2, 133.4, 133.6, 133.7, 137.4, 145.2, 145.6, 146,0, 146.5, 151.8,
153.0, 154.0, 154.3. Anal. Calcd. for C74H92O7: C, 81.28; H, 8.48. Found: C, 81.37; H, 8.56.
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Synthesis of derivative 14. To a solution of pꢀbromodienone 11 (0.52 g, 0.47 mmol) in DME (3 mL) at
0 °C was added a solution of AgClO4 (0.19 g, 0.93 mmol) and resorcinol (0.52 g, 4.7 mmol) in DME (4
mL). The reaction mixture was allowed to warm at room temperature and stirred in the dark overnight.
The solvent was removed under reduced pressure and the residue was solubilized in CH2Cl2 (15 mL)
and washed with aqueous 1 N HCl and successively with water, dried on Na2SO4, filtered and the
solvent was removed under reduced pressure. The crude product was purified by column
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chromatography on silica gel (CH2Cl2) to give derivative 14 (0.16 g, 30% yield) as a white solid. Mp: >
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190 °C dec. ESI(+) MS: m/z = 1152 (MH+). H NMR (600 MHz, CDCl3, 298 K):
δ 1.12 [s, ꢀC(CH3)3,
9H], 1.15 [bs, ꢀC(CH3)3, 18H], 1.19 [s, ꢀC(CH3)3, 9H], 1.21 [s, ꢀC(CH3)3, 9H], 1.33 [s, ꢀC(CH3)3, 9H],
3.60 (s, OCH3, 9H), 3.83 (s, ArCH2Ar, 2H), 3.88 (bs, OCH3, 6H), 3.97 (s, ArCH2Ar, 2H), 4.07 (s,
ArCH2Ar, 2H), 4.10 (bs, ArCH2Ar, 4H), 4.12 (s, ArCH2Ar, 2H), 4.76 (s, OH, 1H), 5.03 (s, OH, 1H),
6.34 (m, ArH, 1H), 6.36 (bs, ArH, 1H), 6.52 (m, ArH, 1H), 6.55 (m, ArH, 1H), 6.88−6.97 (overlapped,
ArH, 3H), 7.10−7.14 (overlapped, ArH, 3H), 7.24−7.32 (overlapped, ArH, 3H), 7.81 (s, ArH, 1H), 8.55
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(s, OH, 1H). C NMR (150 MHz, CDCl3, 298 K):
δ 29.9, 30.2, 30.3, 31.50, 31.51, 31.54, 31.56, 31.8,
32.6, 34.37, 34.41, 34.51, 34.54, 60.93, 60.98, 62.27, 62.34, 104.1, 104.8, 107.5, 108.6, 119.9, 120.1,
125.3, 125.6, 125.7, 125.9, 126.0, 126.1, 126.4, 126.5, 127.1, 127.2, 127.3, 127.7, 131.0, 132.0, 132.3,
132.4, 132.5, 133.2, 133.3, 133.4, 133.5, 133.6, 144.2, 146.3, 146.6, 148.1, 148.3, 152.0, 152.1, 154.6,
154.7, 155.2, 155.7, 155.8, 156.8. Anal. Calcd. for C77H98O8: C, 80.31; H, 8.58. Found: C, 80.24; H,
8.66.
General Procedure for the Synthesis of Derivatives 15a-c. A solution of AgClO4 (0.048 g, 0.23
mmol) in the appropriate alcohol a-c in Scheme 2 (1.6 mL) at 0 °C was added to the solid pꢀ
bromodienone derivative 12 (0.18 g, 0.12 mmol). The reaction mixture was allowed to warm at room
temperature and stirred in the dark overnight. The solvent was removed under reduced pressure and the
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residue was solubilized in CH2Cl2 (10 mL). The organic phase was washed 3 times with water, dried on
Na2SO4, filtered and the solvent was removed under reduced pressure.
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Derivative 15a. The crude product was purified by column chromatography on silica gel using CHCl3/
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nꢀhexane 96/4 as eluent to give 15a as a white solid, 0.025 g, 15% yield. Mp: 176ꢀ179 °C. ESI(+) MS:
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m/z = 1369 (MH+), 1391 (MNa+). H NMR (300 MHz, TCDE, 393 K):
δ 0.79 [broad, O(CH2)5CH3,
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15H], 0.87 [s, ꢀC(CH3)3, 18H], 0.99 [s, ꢀC(CH3)3, 9H], 1.14 [s, ꢀC(CH3)3, 18H], 1.14−1.73 (overlapped,
OCH2CH2CH2CH2CH2CH3, 40H), 3.17 (br t, OCH2CH2CH2CH2CH2CH3, 2H), 3.60−3.80 (overlapped,
ArCH2Ar + OCH2CH2CH2CH2CH2CH3, 20H), 3.70 (bs, OCH3, 3H), 6.63 (bs, ArH, 2H), 6.70 (bs, ArH,
13
2H), 6.82 (s, ArH, 2H), 6.94 (bs, ArH, 2H), 7.03 (bs, ArH, 4H). C NMR (75 MHz, TCDE, 393 K):
δ
11.9, 20.5, 20.8, 21.4, 23.9, 24.1, 27.8, 27.9, 29.0, 29.5, 29.7, 32.1, 71.4, 109.4, 127.7, 123.1, 123.3,
123.8, 125.1, 125.2, 127.9, 129.6, 130.2, 131.2, 131.6, 143.0, 143.2, 144.0, 144.4, 150.2, 150.7, 151.6,
152.3. Anal. Calcd. for C93H138O7: C, 81.65; H, 10.17. Found: C, 81.73; H, 10.25.
Derivative 15b. The crude product was purified by column chromatography on silica gel using CHCl3/
nꢀhexane 40/60 as eluent to give 15b as a pale yellow solid, 0.031 g, 17% yield. Mp: 183ꢀ186 °C.
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ESI(+) MS: m/z = 1466 (MNa+), 1483 (MK+). H NMR (300 MHz, TCDE, 393 K):
δ 0.77ꢀ0.80
[overlapped, O(CH2)5CH3 + C(CH3)3, 33H], 0.98 [s, ꢀC(CH3)3, 9H], 1.12 [s, ꢀC(CH3)3, 18H], 1.08−1.62
(overlapped, OCH2CH2CH2CH2CH2CH3, 40H), 3.16 (br t, OCH2CH2CH2CH2CH2CH3, 2H), 3.49ꢀ 3.79
(overlapped, ArCH2Ar + OCH2CH2CH2CH2CH2CH3, 20H), 4.53 (bs, OH, 1H), 4.82 (s, OCH2Ph, 2H),
6.50−6.64 (overlapped, ArH, 6H), 6.80 (bs, ArH, 2H), 6.93 (s, ArH, 2H), 6.99 (s, ArH, 2H), 7.16−7.23
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(overlapped, OCH2C6H5, 5H). C NMR (75 MHz, TCDE, 393 K):
δ 17.0, 25.8, 29.1, 33.0, 33.3, 33.7,
34.0, 34.6, 35.0, 37.1, 74.5, 119.6, 127.9, 128.4, 130.1, 130.5, 131.5, 132.8, 134.0, 134.9, 135.4, 136.7,
148.2, 149.1, 155.9, 156.8, 157.4. Anal. Calcd. for C99H142O7: C, 82.33; H, 9.91. Found: C, 82.26; H,
9.99.
Derivative 15c. The crude product was purified by column chromatography on silica gel using CH2Cl2/
petroleum ether, 60/40 as eluent to give 15c as a pale yellow solid, 0.026 g, 15% yield. Mp: > 185 °C
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1
dec. ESI(+) MS: m/z = 1472 (MH+). H NMR (300 MHz, TCDE, 393 K):
δ 0.77−0.87 [overlapped,
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5
O(CH2)5CH3, 15H], 0.87 [overlapped, ꢀC(CH3)3, 18H], 0.99 [s, ꢀC(CH3)3, 9H], 1.13 [overlapped, ꢀ
C(CH3)3, 18H], 1.18−1.31 (overlapped, OCH2CH2CH2CH2CH2CH3+CalixꢀOCH2CH(CH3)Ph, 33H),
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1.57−1.70 (overlapped, OCH2CH2CH2CH2CH2CH3 + CalixꢀOCH2CH(CH3)Ph,
11H), 3.21 (t,
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OCH2CH2CH2CH2CH2CH3, J = 6.9 Hz, 2H), 3.53−3.81 (overlapped, OCH2CH2CH2CH2CH2CH3 +
ArCH2Ar + CalixꢀOCH2CH(CH3)Ph, 22H), 6.34 (br s, ArH, 5H), 6.63 and 6.70 (AB, ArH, J = 1.7 Hz,
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4H), 6.83 (s, ArH, 4H), 6.93 and 7.00 (AB, ArH, J = 2.3 Hz, 4H). 13C NMR (75 MHz, TCDE, 393 K):
δ
11.9, 12.0, 20.5, 20.6, 20.8, 23.9, 24.0, 24.1, 28.0, 28.2, 28.6, 29.1, 29.6, 29.7, 29.9, 32.1, 113.9, 117.4,
123.1, 123.4, 123.6, 124.9, 126.5, 129.7, 130.5, 131.2, 131.4, 131.6, 143.2, 144.1, 145.3, 146.5, 150.4,
151.7, 152.2; Anal. Calcd. for C101H146O7: C, 82.40; H, 10.01. Found: C, 82.47; H, 9.91.
Acknowledgements
We thank the Italian MIUR (PRIN 20109Z2XRJ_006) for financial support and the Centro di
Tecnologie Integrate per la Salute (Project PONa3_00138), Università di Salerno, for the 600 MHz
NMR instrumental time. Thanks are due to Dr. Patrizia Iannece and to Dr. Patrizia Oliva (Dipartimento
di Chimica e Biologia, Università di Salerno) for ESIꢀMS and NMR spectral measurements,
respectively.
Supporting Information: 1D and 2D NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
REFERENCES
1 (a) Gutsche, C. D. Calixarenes, An Introduction; Royal Society of Chemistry: Cambridge, UK, 2008.
(b) Calixarenes 2001; Asfari, Z.; Böhmer, V.; Harrowfield, J.; Vicens J.; Eds.; Kluwer: Dordrecht,
2001. (c) Böhmer, V. In The Chemistry of Phenols; Rappoport, Z., Ed.; Wiley: Chichester, UK, 2003;
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Chapter 19. (d) Calixarenes in the Nanoworld; Vicens J.; Harrowfield, J.; Eds.; Springer, Dordrecht,
1
2
3
2007.
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2 For general reviews see ref. 1, while for representative or recent examples of electrophilic aromatic
substitutions, see. Sulfonation: (a) Shinkai, S.; Koreishi, H.; Ueda, K.; Arimura, T.; Manabe, O. J. Am.
Chem. Soc. 1987, 109, 6371−6376. (b) Gaeta, C.; Caruso, T.; Mincolelli, M.; Troisi, F.; Vasca, E.; Neri,
P. Tetrahedron 2008, 64, 5370−5378. Acylation: (c) Gutsche, C. D.; Lin, L.ꢀG. Tetrahedron 1986, 42,
1633−1640. Nitration: (d) Verboom, W.; Durie, A.; Egberink, R. J. M.; Asfari, Z.; Reinhoudt, D. N. J.
Org. Chem. 1992, 57, 1313−1316. Halogenation: (e) Gutsche, C. D.; Pagoria, P. F. J. Org. Chem. 1985,
50, 5795−5802. Formylation: (f) Arduini, A.; Fanni, S.; Manfredi, G.; Pochini, A.; Ungaro, R.; Sicuri,
A. R.; Ugozzoli, F. J. Org. Chem. 1995, 60, 1448−1453.
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3 Gutsche, C. D.; Levine, J. J. Am. Chem. Soc. 1982, 104, 2652−2653.
4 Gutsche, C. D.; Nam, K. C. J. Am. Chem. Soc. 1988, 110, 6153−6162.
5 Almi, M.; Arduini, A.; Casnati, A.; Pochini, A.; Ungaro, R. Tetrahedron 1989, 45, 2177−2182.
6 (a) Danjou, P.ꢀE.; De Leener, G.; Cornut, D.; Moerkerke, S.; Mameri, S.; Lascaux, A.; Wouters, J.;
Brugnara. A.; Colasson, B.; Reinaud, O.; Jabin, I. J. Org. Chem. 2015, 80, 5084–5091. (b)
Lavendomme, R.; Leroy, A.; Luhmer, M.; Jabin, I. J. Org. Chem. 2014, 79, 6563−6570. (c) Columbus,
I.; Biali, S. E. Org. Lett. 2007, 9, 2927−2929. (d) Troisi, F.; Mogavero, L.; Gaeta, C.; Gavuzzo, E.;
Neri, P. Org. Lett. 2007, 9, 915−918. (e) Coquière, D.; Cadeau, H.; Rondelez, Y.; Giorgi, M.; Reinaud,
O. J. Org. Chem. 2006, 11, 4059−4065. (f) Gaeta, C.; Martino, M.; Gregoli, L.; Neri, P. Tetrahedron
Lett. 2002, 43, 9521−9525.
7 (a) Troisi, F.; Pierro, T.; Gaeta, C.; Neri, P. Org. Lett. 2009, 11, 697−700. (b) Troisi, F.; Pierro, T.;
Carratù, M.; Gaeta, C.; Neri, P. Tetrahedron Lett. 2009, 50, 4416−4419. (c) Talotta, C.; Gaeta, C.;
Troisi, F.; Monaco, G.; Zanasi, R.; Mazzeo, G.; Rosini, C.; Neri, P. Org. Lett. 2010, 12, 2912−2915.
(d) Chena, S.; Webster, R. D.; Talotta, C.; Troisi, F.; Gaeta, C.; Neri, P. Electrochim. Acta 2010, 55,
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7036–7043. (e) Gaeta, C.; Troisi, F.; Talotta, C.; Pierro, T.; Neri, P. J. Org. Chem. 2012, 77,
3634−3639. (f) Gaeta, C.; Talotta, C.; Neri, P. J. Incl. Phenom. Macrocycl. Chem. 2014, 79, 23–46. (f)
Swager, T. M.; Moslin, R. M. Synfacts 2009, 4, 387–387.
1
2
3
4
5
6
7
8
9
8 Gaeta, C.; Martino, M.; Neri, P. Tetrahedron Lett. 2003, 44, 9155−9159.
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21
22
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25
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50
51
52
53
54
55
56
57
58
59
60
9 (a) Thulasi, S.; Bhagavathy, G. V.; Eliyan, J.; Varma, L. R. Tetrahedron Lett. 2009, 50, 770−772. (b)
Thulasi, S.; Babu, J.; Babukuttannair, A.; Sreemathi, V.; Varma, L. R. Tetrahedron 2010, 66,
5270−5276.
10 Litwak, A. M.; Biali, S. E. J. Org. Chem. 1992, 57, 1943−1945.
11 (a) Talotta, C.; De Simone, N. A.; Gaeta, C.; Neri, P. Org. Lett. 2015, 17, 1006−1009. (b) Gaeta, C.;
Talotta, C.; Neri, P. Chem. Commun. 2014, 50, 9917−9920. (c) Brunetti, E.; Inthasot, A.; Keymeulen,
F.; Reinaud, O.; Jabin, I.; Bartik, K. Org. Biomol. Chem. 2015, 13, 2931−2938. (d) Brunetti, E.; Picron,
J.ꢀF.; Flidrova, K.; Bruylants, G.; Bartik, K.; Jabin, I. J. Org. Chem. 2014, 79, 6179−6188. (e) Rat, S.;
Gout, J.; Bistri, O.; Reinaud, O. Org. Biomol. Chem. 2015, 13, 3194−3197. (f) Semeraro, M.; Secchi,
A.; Silvi, S.; Venturi, M.; Arduini, A.; Credi, A. Inorg. Chim. Acta 2014, 417, 258−262.
12 de Mendoza, J.; Carramolino, M.; Cuevas, F.; Manule Nieto, P.; Reinhoudt, D. N.; Verboom, W.;
1
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Ungaro, R.; Casnati, A. Synthesis 1994, 47−50. For completeness, we report here the H and C NMR
data of compound 8: 1H NMR (400 MHz, CDCl3, 298 K):
δ
0.91 [0.91 [s, ꢀC(CH3), 9H], 1.12 [s, ꢀ
C(CH3), 9H], 1.16 [s, ꢀC(CH3), 18H], 1.19 [s, ꢀC(CH3), 18H], 3.05 (s, OCH3, 6H), 3.08 (s, OCH3, 6H),
3.50 (s, OCH3, 3H), 3.81 (s, ArCH2Ar, 4H), 3.93 (s, ArCH2Ar, 4H), 3.96 (s, ArCH2Ar, 4H), 6.81 (s,
ArH, 2H), 6.89 (s, ArH, 2H), 7.01−7.10 (overlapped, ArH, 8H), 7.32 (s, OH, 1H). 13C NMR (100 MHz,
CDCl3, 298 K):
δ 30.6, 31.6, 31.63, 34.0, 34.2, 34.3, 34.4, 60.66, 60.7, 60.9, 124.9, 125.6, 126.9, 126.3,
126.5, 126.6, 127.2, 132.8, 133.5, 133.6, 133.6, 133.8, 142.2, 145.4, 145.9, 146.7, 149.7, 153.2, 154.2,
154.6. Anal. Calcd. for C71H94O6: C, 81.72: H, 9.08. Found: C, 81.63; H, 9.17.
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For reviews on inherently chiral calixarenes, see: (a) Böhmer, V.; Kraft, D.; Tabatabai, M. J.
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2
3
4
5
6
7
8
9
Inclusion Phenom. Mol. Recognit. 1994, 19, 17−39. (b) Otsuka, H.; Shinkai, S. Supramol. Sci. 1996, 3,
189−205. (c) Vysotsky, M.; Schmidt, C.; Böhmer, V. Adv. Supramol. Chem. 2000, 7, 139−233. (d)
Zsumma, A. Chem. Soc. Rev. 2010, 39, 4274−4285. For recent reports on the synthesis of metaꢀ
substituted inherently chiral calixarenes, see: (e) Slavik, P.; Dudic, M.; Flidrova, K.; Sykora, J.;
Cisarova, I.; Böhm, S.; Lhotak, P. Org. Lett. 2012, 14, 3628−3631. (f) Flidrova, K.; Böhm, S.;
Dvorakova, H.; Eigner, V.; Lhotak, P. Org. Lett. 2014, 16, 138−141. (g) Slavik, P.; Flidrova, K.;
Dvorakova, H.; Eigner, V.; Lhotak, P. Org. Biomol. Chem. 2013, 11, 5528−5534. (h) Flidrova, K.;
Slavik, P.; Eigner, V.; Dvorakova, H.; Lhotak, P. Chem. Commun. 2013, 49, 2798−2800.
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49
50
51
52
53
54
55
56
57
58
59
60
14 (a) Shirakawa, S.; Moriyama, A.; Shimizu, S. Eur. J. Org. Chem. 2008, 5957−5964. (b) Shirakawa,
S.; Shimizu, S. Eur. J. Org. Chem. 2009, 1916−1924.
15 (a) Luo, J.; Zheng, Q.ꢀY.; Chen, C.ꢀF.; Huang, Z.ꢀT. Tetrahedron 2005, 61, 8517−8528. (b) Gaeta,
C.; De Rosa, M.; Fruilo, M.; Soriente, A.; Neri, P. Tetrahedron Asymmetry 2005, 16, 2333−2340.
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