Easy and selective method for the synthesis of various mono-O- functionalized Calix[4]arenes: De-O-functionalization using TiCl4

Article abstract of DOI:10.1021/jo101319s

An efficient and selective method for the monofunctionalization of p-tert-butylcalix[4]arene is described. A mono-de-O-functionalization of disubstituted p-tert-butylcalix[4]arenes using titanium tetrachloride was developed to synthesize a series of monosubstituted p-tert-butylcalix[4]arenes with the pendant functions being ethoxycarbonylmethyloxy, 3- ethoxycarbonylpropyloxy, cyanomethyloxy, 3-cyanopropyloxy, 4-bromobutyloxy, 3-hydroxypropyloxy, propyloxy, 2-methylpropyloxy, 3-butynyloxy, and 3-cyanopropyloxy groups. The reaction mechanism of the formation of 5,11,17,23-tetra-tert-butyl-26,27,28-trihydroxy-25-(3-ethoxycarbonylpropyloxy) calix[4]arene was studied by ¹H NMR and GC/mass spectroscopy monitoring. Reaction of TiCl₄ with the disubstituted p-tert-butylcalix[4]arene produced the corresponding dioxocalix[4]arene titanium dichloride complex, which undergoes elimination of ethyl 4-chlorobutyrate, leading to a trioxocalix[4]arene titanium dichloride complex and to monosubstituted calix[4]arene after hydrolysis. These two complexes were also synthesized, isolated, and fully characterized.

Full text of DOI:10.1021/jo101319s

pubs.acs.org/joc
Easy and Selective Method for the Synthesis of Various
Mono-O-functionalized Calix[4]arenes: De-O-functionalization
Using TiCl4
Joackim Bois,† Jeff Espinas,†,‡ Ulrich Darbost,† Caroline Felix,† Christian Duchamp,†
Denis Bouchu,† Mostafa Taoufik,*,‡ and Isabelle Bonnamour*,†
†
ꢀ
Institut de Chimie et Biochimie Moleculaires et Supramoleculaires, Equipe CSAp, CNRS, UMR 5246,
Universite de Lyon, Lyon, Universite Lyon 1, Villeurbanne, 43 Boulevard du 11 Novembre 1918, F-69622
ꢀ
ꢀ
ꢀ
‡
ꢀ
Villeurbanne, France, and UMR 5265, C2P2, CNRS-CPE Lyon, Universite de Lyon, Lyon,
ꢀ
Universite Lyon 1, Villeurbanne, 43 Boulevard du11 Novembre 1918, F-69616 Villeurbanne, France
isabelle.bonnamour@univ-lyon1.fr; taoufik@cpe.fr
Received July 5, 2010
An efficient and selective method for the monofunctionalization of p-tert-butylcalix[4]arene is
described. A mono-de-O-functionalization of disubstituted p-tert-butylcalix[4]arenes using titanium
tetrachloride was developed to synthesize a series of monosubstituted p-tert-butylcalix[4]arenes
with the pendant functions being ethoxycarbonylmethyloxy, 3-ethoxycarbonylpropyloxy, cyano-
methyloxy, 3-cyanopropyloxy, 4-bromobutyloxy, 3-hydroxypropyloxy, propyloxy, 2-methylpropyl-
oxy, 3-butynyloxy, and 3-cyanopropyloxy groups. The reaction mechanism of the formation of
5,11,17,23-tetra-tert-butyl-26,27,28-trihydroxy-25-(3-ethoxycarbonylpropyloxy) calix[4]arene was
studied by 1H NMR and GC/mass spectroscopy monitoring. Reaction of TiCl4 with the disubstituted
p-tert-butylcalix[4]arene produced the corresponding dioxocalix[4]arene titanium dichloride com-
plex, which undergoes elimination of ethyl 4-chlorobutyrate, leading to a trioxocalix[4]arene
titanium dichloride complex and to monosubstituted calix[4]arene after hydrolysis. These two
complexes were also synthesized, isolated, and fully characterized.
Introduction
field of macrocyclic and supramolecular chemistry.1-3 With
the constant increase in need for novel supramolecular hosts
based on these macrocycles, chemists have developed new
The p-tert-butylcalix[4]arenes are a major class of organic
macrocyclic compounds and have become inescapable in the
(1) Mandolini, L., Ungaro, R., Eds. Calixarenes in Action; Imperial
College Press: London, 2000.
(3) Gutsche, C. D., Ed. Calixarenes: An Introduction, 2nd ed.; Royal
Society of Chemistry: London, 2008.
(2) Asfari, Z., Bohmer, V., Harrowfield, J., Vicens, J., Eds. Calixarenes
2001; Kluwer: Dordrecht, The Netherlands, 2001.
(4) Tabakci, M.; Memon, S.; Yilmaz, M. Tetrahedron 2007, 63, 6861–
6865.
7550 J. Org. Chem. 2010, 75, 7550–7558
Published on Web 10/20/2010
DOI: 10.1021/jo101319s
r
2010 American Chemical Society

Bois et al.
JOCArticle
synthesis tools for their selective functionalization.4-8
The 1,3-dialkylation of p-tert-butylcalix[4]arenes is well-
described and reproducible, leading selectively to numerous
and diverse 1,3-dialkylated p-tert-butylcalix[4]arenes in high
yield.9-20 However, the elaboration of heterofunctionalized
calixarenes is still particularly difficult, requiring synthesis of
a monoalkylated p-tert-butylcalix[4]arene key intermediate
obtained in low to moderate yields. Direct alkylation of
p-tert-butylcalix[4]arene with alkyl halides in presence of
1 equiv of base often yields a difficult to separate mixture
of mono- and dialkylated calix[4]arenes and unreacted
starting material.21-26 Multistep routes for the preparation
of monoalkylated p-tert-butylcalix[4]arenes have also been
described involving protection and deprotection sequences
of phenoxyl groups of p-tert-butylcalix[4]arene by using silyl
compounds.27,28 The above pathways allow the synthesis of
different heterofunctionalized p-tert-butylcalix[4]arenes
but involve laborious synthesis procedures. Another ap-
proach is to use an oxophilic metallic element as a coordi-
nating template for the selective functionalization of p-tert-
butylcalix[4]arenes. However, this strategy is as yet not well-
studied. Recently, the synthesis of monoalkoxy p-tert-
butylcalix[4]arenes by selective dealkylation of 1,2-dialky-
lated p-tert-butylcalix[4]arenes with aluminum chloride in
benzene has been described.29 The mono-O-methoxy-p-tert-
butylcalix[4]arene was obtained by an original reaction of
dealkylation of one oxygen atom of the 1,3-di-O-methoxy-p-
tert-butylcalix[4]arene precursor. This σ bond destruction
was inherent in the oxophilicity of a titanium tetrachloride
corresponding complex and was interpreted by Floriani30,31
as a Lewis acid assisted cleavage of one ether functionality.
This elegant pathway was successfully reused by Radius32 for
the synthesis of mono-O-R-tert-butylcalix[4]arene (R = Bn
and Si(Me)3). Among all of these published examples, the
monofunctionalization of p-tert-butylcalix[4]arene corre-
sponds mainly to the incorporation of an alkyl group. Only
a few papers26,33,34 describe the synthesis of monofunctio-
nalized calix[4]arenes with different kinds of functions as
alcohol, nitrile, and ester. Moreover, reported methods do
not always match with fragile functions as ester, bromide, or
terminal alkyne derivatives. There is clearly a lack of a
general method for the synthesis of various classes of mono-
functionalized p-tert-butylcalix[4]arenes. On the basis of our
recent work35 on p-tert-butylcalix[4]arenes-Ti complexes,
and the expectation that the titanium coordination chemistry
could lead to a key intermediate orienting the reaction
toward the selective mono-O-defunctionalization, we under-
took the in-depth investigation of the behavior of such Ti
complexes. As a result, we propose a simple and reproducible
procedure allowing the preparation of a range of monofunc-
tionalized p-tert-butylcalix[4]arenes. Moreover, thanks to a
complete characterization of the reaction intermediates and
a careful monitoring of the byproduct, we demonstrated the
mechanism of this titanium-driven-force pathway.
(5) Boyko, V. I.; Yakovenko, A. V.; Matvieiev, Y. I.; Kalchenko, O. I.;
Shishkin, O. V.; Shishkina, S. V.; Kalchenko, V. I. Tetrahedron 2008, 64,
7567–7573.
(6) Bois, J.; Bonnamour, I.; Duchamp, C.; Parrot-Lopez, H.; Darbost,
U.; Felix, C. New J. Chem. 2009, 33, 2128–2135.
(7) Boyko, V. I.; Matvieiev, Y. I.; Klyachina, M. A.; Yesypenko, O. A.;
Shishkina, S. V.; Shishkin, O. V.; Kalchenko, V. I. Tetrahedron 2009, 65,
4220–4227.
(8) Da Silva, E.; Memmi, L.; Coleman, A. W.; Rather, B.; Zaworotko,
M. J. J. Supramol. Chem. 2002, 1, 135–138.
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M.; Ferguson, G.; Harris, S. J. J. Chem. Soc., Perkin Trans. 1 1991, 3137–
3142.
Results and Discussion
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Macrocyclic Chem. 2009, 64, 317–324.
(11) Zhang, W. C.; Huang, Z. T. Synthesis 1997, 1073–1076.
(12) Chawla, H. M.; Pant, N.; Srivastava, B. Tetrahedron Lett. 2005, 46,
7259–7262.
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J. R.; Maxwell, J.; Hoye, T. R.; Mayo, K. H. J. Med. Chem. 2006, 49, 7754–
7765.
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Toftlund, H. Tetrahedron 2006, 62, 9066–9071.
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Du, A.-L.; Wei, M. J. Org. Chem. 1999, 64, 3572–3584.
(16) Scheerder, J.; Fochi, M.; Engbersen, J. F. J.; Reinhoudt, D. N.
J. Org. Chem. 1994, 59, 7815–7820.
(17) Yakovenko, A. V.; Boyko, V. I.; Kalchenko, V. I.; Baldini, L.;
Casnati, A.; Sansone, F.; Ungaro, R. J. Org. Chem. 2007, 72, 3223–3231.
(18) Halouani, H.; Dumazet-Bonnamour, I.; Perrin, M.; Lamartine, R.
J. Org. Chem. 2004, 69, 6521–6527.
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Boyd, P. D. W. J. Am. Chem. Soc. 2006, 128, 15903–15913.
(20) Kenis, P. J. A.; Noordman, O. F. J.; Schonherr, H.; Kerver, E. G.;
Snellink-Ruel, B. H. M.; van Hummel, G. J.; Harkema, S.; van der Vorst, C.
P. J. M.; Hare, J.; Picken, S. J.; Engbersen, J. F. J.; van Hulst, N. F.; Vancso,
G. J.; Reinhoudt, D. N. Chem.;Eur. J. 1998, 4, 1225–1234.
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(22) Alekseeva, E. A.; Mazepa, A. V.; Gren, A. I. Russ. J. Gen. Chem.
2001, 71, 1786–1792.
Synthesis and Characterization. With the aim to synthesize
a series of monofunctionalized p-tert-butylcalix[4]arenes, we
have selected a panel of different functions such as alkyl,
ester, alcohol, nitrile, or bromide. With this goal in mind, we
first undertook the classical difunctionalization of the p-tert-
butylcalix[4]arene in acetonitrile with an excess of the
corresponding bromo derivative. Once obtained, the result-
ing disubstituted calix[4]arenes (1a-10a) were then totally
converted into monosubstituted p-tert-butylcalix[4]arenes
(1b-10b) by refluxing with titanium tetrachloride in toluene,
followed by acidic hydrolysis (Scheme 1). This original
procedure allows an efficient and selective access to mono-
functionalized p-tert-butylcalix[4]arenes 1b-10b with var-
ious substituents as ester (1b,26 2b), nitrile (3b,33 4b, 10b),
halogen (5b), alcohol (6b), alkyl (7b,25 8b), and alkynyl (9b)
groups (Table 1) and isolated with moderate to high yields
(from 53 to 85% except for the monoester 1b (15%)).
(29) Matvieiev, Y. I.; Boyko, V. I.; Podoprigorina, A. A.; Kalchenko,
V. I. J. Inclusion Phenom. Macrocyclic Chem. 2008, 61, 89–92.
(30) Floriani, C.; Floriani-Moro, R. Adv. Organomet. Chem. 2001, 47,
167–233.
(23) Shu, C.-M.; Chung, W.-S.; Wu, S.-H.; Ho, Z.-C.; Lin, L.-G. J. Org.
Chem. 1999, 64, 2673–2679.
(24) Arnaud-Neu, F.; Caccamese, S.; Fuangswasdi, S.; Pappalardo, S.;
Parisi, M. F.; Petringa, A.; Principato, G. J. Org. Chem. 1997, 62, 8041–8048.
(25) Iwamoto, K.; Araki, K.; Shinkai, S. Tetrahedron 1991, 47, 4325–
4342.
(26) Groenen, L. C.; Ruel, B. H. M.; Casnati, A.; Verboom, W.; Pochini,
A.; Ungaro, R.; Reinhoudt, D. N. Tetrahedron 1991, 47, 8379–8384.
(27) Shang, S.; Khasnis, D. V.; Burton, J. M.; Santini, C. J.; Fan, M.;
Small, A. C.; Lattman, M. Organometallics 1994, 13, 5157–5159.
(28) Casnati, A.; Arduini, A.; Ghidini, E.; Pochini, A.; Ungaro, R.
Tetrahedron 1991, 47, 2221–2228.
(31) Zanotti-Gerosa, A.; Solari, E.; Giannini, L.; Floriani, C.; Re, N.;
Chiesi-Villa, A.; Rizzoli, C. Inorg. Chim. Acta 1998, 270, 298–311.
(32) Friedrich, A.; Radius, U. Eur. J. Inorg. Chem. 2004, 4300–4316.
(33) Santoyo-Gonzalez, F.; Torres-Pinedo, A.; Sanchez-Ortega, A.
J. Org. Chem. 2000, 65, 4409–4414.
(34) Gong, S.; Wang, W.; Chen, Y.; Meng, L.; Wan, T. New J. Chem.
2002, 26, 1827–1830.
(35) Espinas, J.; Darbost, U.; Pelletier, J.; Jeanneau, E.; Duchamp, C.;
Bayard, F.; Boyron, O.; Broyer, J. P.; Thivolle-Cazat, J.; Basset, J. M.;
Taoufik, M.; Bonnamour, I. Eur. J. Inorg. Chem. 2010, 1349–1359.
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SCHEME 1a
aReagents and conditions: (i) R1-X, K2CO3, acetonitrile, reflux; (ii) TiCl4(THF)2, toluene, reflux, 48 h; (iii) 1 M HCl, room temperature.
TABLE 1. Yields and Overall Yields of Monofunctionalized p-tert-
Butylcalix[4]arenes
When the difunctionalization step was taken into account,
overall yields range from 37 to 64%, except for the mono-
ester 1b (10%). The reaction of compounds 11a and 12a in
the same conditions as compounds 1a-10a did not yield the
targeted monosubstituted compounds, and a total defunc-
tionalization occurs, leading to the formation of p-tert-
butylcalix[4]arene.
R
R1
compounds yield (%) overall yield (%)
t-Bu CH2COOEt
t-Bu (CH2)3COOEt
t-Bu CH2CN
t-Bu (CH2)3CN
t-Bu (CH2)4Br
t-Bu (CH2)3OH
t-Bu (CH2)2CH3
t-Bu CH2CH(CH3)2
t-Bu (CH2)2CCH
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
15
75
58
60
85
70
77
57
78
53
10
64
37
44
60
63
47
47
63
40
The 1H NMR spectra of all of these monosubstituted
calix[4]arenes exhibit two signals for phenolic protons in the
range of of 8.6-10.3 ppm, integrating, respectively, 2:1, a W
plan coupling (J ∼ 2.5 Hz) for the aromatic protons of the
phenolic units close to the substituted one, two pairs of AB-
type signals between 4.2 and 4.6 ppm and between 3.3 and 3.6
ppm (J ∼ 13 Hz) corresponding to the two sets of ArCH2Ar
protons (see Supporting Information). The 13C NMR spec-
tra display signals between 32 and 35 ppm attributed to the
methylene bridge (ArCH2Ar), consistent with the calixarene
being in cone conformation.36 All of the NMR spectra are
given in the Supporting Information (Figures S1-S39).
Mechanism Study. According to the results obtained in the
literature with the monomethoxy calixarene,31,32 we ex-
pected that the mechanism of the reaction involves the
formation of the two successive titana-calix[4]arenes com-
plexes (13 and 14) (Scheme 2). During the reaction, two
distinct colors of the mixture were clearly observed: A first
dark red one appears at room temperature just after the
addition of the titanium tetrachloride into the disubstituted
calix[4]arene solution. After refluxing the mixture, a second
orange coloration of the solution is observed. We assumed
that the first coloration was the result of the formation of the
bis-O-functionalized titana-calix[4]arene complex 13; this
complex then probably undergoes the defunctionalization of
one of the oxygen atoms, leading to the resulting mono-O-
functionalized titana-calix[4]arene complex 14. After an
acidic hydrolysis, 14 would lead to the corresponding mono-
O-functionalized calix[4]arene.
H
CH2CN
the second time, we investigated, by 1H NMR monitoring of
the reaction, the formation of the different species. In order
to detect the fragment of defunctionalization, GC/MS anal-
ysis was also realized.
Synthesis of Titanium Complexes. 1,3-Dioxotitanium
complex 2a-Ti was synthesized by stirring the calixarene
diester derivative 2a with titanium tetrachloride in dry
toluene for more than 1 h at 40 °C and then isolating the
complex (Scheme 3a). This titanium complex 2a-Ti, by
refluxing in dry toluene for more than 50 h, evolves into
trioxotitanium complex 2b-Ti (Scheme 3b).
Characterization. In order to determine the conformation
of the different species 2a, 2b, 2a-Ti, and 2b-Ti, an exhaustive
1H NMR study was realized (spectra a-d, Figure 1). Com-
pared to the free ligands 2a and 2b, the 1H NMR spectra of
the corresponding Ti complexes 2a-Ti and 2b-Ti display
1
several relevant differences (Figure 1). H NMR spectra of
2a and 2a-Ti (Figure 1c,d) show an AB system for the
bridging CH2 protons (JH-H ∼ 13 Hz) characteristic of a C2v
symmetry, consistent with the calixarene being in cone confor-
mation. However, in the case of complex 2a-Ti, compared with
2a, it should be emphasized that axial CH2 (4.78 ppm) is
downfield shifted (Δδ = þ0.41 ppm) and equatorial CH2
(3.25 ppm) is upfield shifted (Δδ = -0.11 ppm). This different
NMR signature is probably due to a rearrangement of the
calixarene skeleton. Indeed, to coordinate the metallic Ti center,
the oxygen atoms of 2a-Ti are attracted toward the central axis
of the cavity, consequently constraining the calixarene structure
in a more flattened cone conformation. This phenomenon has
clearly been demonstrated by the X-ray structures of parent Ti
complexes in the literature.30,32,35
With the aim to demonstrate this postulate, we undertook
the study of the reaction mechanism through the synthesis of
compound 2a. At first, we synthesized, isolated, and char-
acterized titanium complexes 2a-Ti and 2b-Ti (Scheme 3). In
(36) Jaime, C.; De Mendoza, J.; Prados, P.; Nieto, P. M.; Sanchez, C.
J. Org. Chem. 1991, 56, 3372–3376.
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SCHEME 2. Proposed Mechanism for the Formation of Monosubstituted Calix[4]arenes
SCHEME 3. Synthesis of Titanium Complexes 2a-Ti and 2b-Ti
1
1
Moreover, compared with the H NMR spectra of free
ligand 2a, the spectra of 2a-Ti show a significant downfield
shift (Δδ) of the R protons (Ar-OCH2) of the alkoxy chains
(Δδ = þ1.21 ppm), indicating that the two oxygen atoms of
the alkoxy chains participate as ancillary ligands in the
coordination with the titanium atom. An upfield shift of
CH2CO protons (Δδ = -1.22 ppm) is also observed, which
can be attributed to both the electron-attracting nature of
the titanium atom and the anisotropic effect due to the
calixarene cavity and the chlorine atoms, as observed in a
recently reported study.35 1H NMR spectra of 2b and 2b-Ti
(Figure 1a,b) show two AB systems for the bridging CH2
protons (JH-H ∼ 13 Hz) typical of a Cs cone conformation.
In the case of the complex 2b-Ti, the strong flattening of the
calixarene core induces a significant downfield shift (Δδ =
þ0.52 ppm) for one of the AB systems of the bridging axial
CH2 protons. Compared with the free ligand 2b, the H
NMR spectra of 2b-Ti show, as observed between 2a and 2a-
Ti, a significant downfield shift (Δδ) of the R protons (Ar-
OCH2) of the alkoxy chain (Δδ = þ0.49 ppm) and an upfield
shift of CH2CO protons (Δδ = -0.57 ppm). As confirmed
by the value of the shift (chemical-induced shift), the elec-
tron-attracting nature of the titanium is conducted through
the carbon chain and is experienced by the terminal protons
of the ester group (Δδ = -0.2 and -0.08 ppm for OCH2 of
2a-Ti and 2b-Ti, respectively, and Δδ = -0.09 and -0.05
ppm for OCH2CH3 of 2a-Ti and 2b-Ti, respectively). These
original electronic features were recently reported for Ti
complexes.35
NMR Monitoring. To highlight the formation of the two
1
complexes 2a-Ti and 2b-Ti during the reaction, H NMR
monitoring was undertaken (Figure 2) in toluene-d8. The
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FIGURE 1. 1H NMR spectra of compounds 2b-Ti (a), 2b (b), 2a-Ti (c), 2a (d): data were collected on a 300 MHz spectrometer using toluene-d8
as a solvent.
FIGURE 2. 1H NMR monitoring of the reaction: data were collected on a 300 MHz spectrometer using toluene-d8 as a solvent: proton peaks of
compounds (2) 2a, (f) 2a-Ti, (9) 2b-Ti, and (b) 2b.
previous experiments of characterization allowed us to care-
fully attribute all of the 1H NMR signals from each species.
In the first minutes of the reaction and before heating, the
complex 2a-Ti appears spontaneously (Figure 2b). After 10
min of refluxing, the ligand 2a has disappeared and the
complexes 2a-Ti and 2b-Ti coexist with compound 2b
(Figure 2c). After 24 h, 2a-Ti has completely disappeared
and only the mono-O-alkylated products 2b-Ti and 2b are
present in solution (Figure 2g), consistent with the total
conversion of the complex 2a-Ti in the complex 2b-Ti
through defunctionalization under reflux conditions.
1
During the H NMR monitoring, we also observed the
appearance of ethyl 4-chlorobutyrate signals corresponding
to the elimination product (Figure 3a). A GC/MS analysis of
the reaction mixture after 24 h heating confirms the presence
of this compound (Figure 3b). The formation of the chloro-
ester during the reaction is consistent with the proposed
mechanism of monodefunctionalization.
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FIGURE 3. (a) 1H NMR monitoring of the ethyl 4-chlorobutyrate formation. Data were collected on a 300 MHz spectrometer using toluene-
d8 as a solvent. (b) GC/MS analysis after 24 h refluxing.
Discussion. Complete characterizations of each ligand and
complex allow identification with certitude of the formation
and the disappearance of each species during the reaction
process. In the presence of titanium tetrachloride, compound
2a leads spontaneously to the complex 2a-Ti. This MO2Cl2-
(OR)2-type complex displays a sterically strained structure in
which the tetrahedral Ti is coordinated by four L ligands
(two oxygens and two chlorine atoms) and two ancillary
ligands (OR). When the mixture is heated under toluene
reflux, it has clearly been demonstrated that complex 2a-Ti
undergoes a σ bond metathesis between a Ti-Cl and an
O-R bond with R-Cl evolution and consequently leads to
the more constrained MO3Cl(OR)1 complex 2b-Ti due to the
proximity between the pendant groups and the titanium
center imposed by the calixarene core. In these conditions,
the system possesses enough energy to pass the highly
instable transition state and lead to a more electronically
stable complex 2b-Ti, a species less favored than 2a-Ti in a
conformational point of view. This behavior clearly empha-
sizes that the driving force is the coordination of the metal
and particularly the oxophilic feature of titanium. This
oxophilic feature of titanium can also explain the low yield
of compound 1b. It seems that the presence of oxygen atoms
of ethoxycarbonylmethyloxy groups, which are very close
to other phenolic oxygens, obstructs the reaction. This is
probably due to the stabilization of the bis-O-ethoxycarbo-
nylmethyloxy titana-calix[4]arene complex by two bonds
between the titanium center and the carbonyl groups, pre-
venting the de-O-alkylation. Moreover, in the case of the
reaction of compounds 11a and 12a, bearing, respectively,
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benzyl and 2-naphthylmethyloxy pendant groups, a com-
plete defunctionalization is observed and p-tert-butylcalix-
[4]arene is quantitatively obtained. This is probably due to
the higher reactivity of the OCH2Ph and OCH2(2-naphthyl)
carbon atoms compared to the other OCH2 carbon atoms of
pendant groups used, leading to the complete de-O-functio-
nalization rather than the mono-de-O-functionalization. It
should be emphasized that TiCl4 could also be used as
reagents for complete de-O-benzylation of calixarene.
found 775.4697; IR (FTIR) ν = 3411, 3320, 2955, 2869, 2123,
2050, 1485, 1194, 1032, 869 cm-1
General Procedure for the Preparation of Monofunctionalized
.
Calix[4]arene Derivatives. Corresponding di-O-substituted
calixarene (1 equiv) and TiCl4 2THF (1.5 equiv) were refluxed
3
for 2 days in dry toluene. After cooling to room temperature, the
reaction mixture was quenched with 1 M HCl for 2-10 h.
The organic layer was washed with water and dried with
MgSO4. After evaporation of the solvent, the remaining crude
product was taken up in MeOH or was purified by column
chromatography.
Conclusion
Synthesis of 5,11,17,23-Tetra-tert-butyl-25-ethoxycarbonyl-
methyloxy-26,27,28-trihydroxycalix[4]arene (1b). Column chro-
matography of the crude (heptane/ethyl acetate 8:2) gave 1b
(15%) as a white solid: mp 248-250 °C; H NMR (300 MHz,
The synthesis of a range of monofunctionalized calix[4]arene
derivatives and two titanium calixarene complexes has been
achieved in honorable yields. H NMR and GC-mass spec-
1
1
CDCl3) δ 1.21 (s, 9H, tBu), 1.22 (s, 18H, tBu), 1.25 (s, 9H, tBu),
1.41 (t, 3H, J = 7.2 Hz, CH2CH3), 3.44 (d, 4H, J = 13.6 Hz,
CH2), 4.32 (d, 2H, J = 13.6 Hz, CH2), 4.42 (q, 2H, J = 7.2 Hz,
OCH2CH3), 4.50 (d, 2H, J = 13.2 Hz, CH2), 4,90 (s, 2H, OCH2),
7.00 (d, 2H, J = 2.3 Hz, H-Ar), 7.07 (m, 4H, H-Ar), 7.11 (s, 2H,
H-Ar), 9.27 (s, 2H, OH), 10.24 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3) δ 14.3, 30.9, 31.3, 31.6, 32.6, 33.0, 34.0, 34.1, 34.3, 62.0,
72.1, 125.7, 125.8, 125.9, 126.7, 127.8, 128.1, 128.1, 133.4, 143.3,
143.6, 147.8, 148.2, 148.5, 150.1, 169.7; LRMS (ESþ) m/z 735.3
([M þ H]þ); HRMS (ESþ) for C48H62O6Naþ, calcd 757,4446,
found 757.4446; IR (FTIR) ν = 3349, 2955, 2865, 17404, 1484,
troscopy monitoring of the reaction has allowed us to clearly
establish the reaction mechanism. The impressive force of the
oxophilic nature of titanium has been used here as an efficient
synthesis tool for the preparation of seven new monosubsti-
tuted calix[4]arenes. These series of monofunctionalized
p-tert-butylcalix[4]arenes with different kinds of functions
such as haloalkane, nitrile, alcohol, ester, and alkyne are
key intermediates for the elaboration of heterofunctionalized
calixarenes.
1191, 1065, 872, 784 cm-1
.
Experimental Section
Synthesis of 5,11,17,23-Tetra-tert-butyl-26,27,28-trihydroxy-
25-(3-ethoxycarbonylpropyloxy)calix[4]arene (2b). The crude
product was triturated in methanol to give 2b (83%) as a white
solid: mp 200-202 °C (dec.); 1H NMR (300 MHz, CDCl3) δ 1.19
(s, 9H, tBu), 1.21 (s, 18H, tBu), 1.23 (s, 9H, tBu), 1.30 (t, 3H, J =
7.2 Hz, CH2CH3), 2.40-2.50 (m, 2H, CH2-CH2-CH2), 2.83 (t,
2H, J = 7.2 Hz, CH2CO), 3.42 (d, 2H, J = 13.0 Hz, CH2), 3.44
(d, 2H, J = 13.7 Hz, CH2), 4.17 (t, 2H, J = 6.3 Hz, OCH2), 4.21
(q, 2H, J = 7.2 Hz, OCH2CH3), 4.27 (d, 2H, J = 13.7 Hz, CH2),
4.32 (d, 2H, J = 13.0 Hz, CH2), 6.99 (d, 2H, J = 2.6 Hz, H-Ar),
7.05 (s, 2H, H-Ar), 7.06 (d, 2H, J = 2.6 Hz, H-Ar), 7.08 (s, 2H,
H-Ar), 9.50 (s, 2H, OH), 10.12 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3) δ 14.4, 25.4, 30.8, 31.4, 31.6, 31.6, 32.3, 33.1, 34.1, 34.2,
34.4, 60.7, 76.2, 125.8, 125.8, 125.9, 126.6, 127.6, 128.1, 128.5,
133.6, 143.3, 143.8, 147.8, 148.4, 148.6, 149.2, 173.3; LRMS
(ESþ) m/z 785.4 ([M þ Na]þ); HRMS (ESþ) for C50H66O6Naþ,
calcd 785.4757, found 785.4757; IR (FTIR) ν = 3331, 3174,
Materials. Solvents were purified and dried by standard meth-
ods prior to use. All reactions were carried out under nitrogen.
Column chromatography was performed using silica gel
(0.040-0.063 nm). Reactions were monitored by TLC on silica
gel plates and visualized by UV light. H and 13C NMR spectra
1
were recorded at 300 and 75 MHz (CDCl3). Mass spectra were
acquired on a LCQ Advantage ion trap instrument, detecting
positive ions (þ) or negative ions (-) in the ESI mode. Samples
(in methanol-dichloromethane-water, 45: 40: 15, v/v/v) were in-
fused directly into the source (5 mL.min-1) using a syringe pump.
The following source parameters were applied: spray voltage
3.0-3.5 kV, nitrogen sheath gas flow 5-20 arbitrary units. The
heated capillary was held at 200 °C. Compounds 1a,9 2a,17 3a9 4a,13
5a,15 6a,19 7a,12 8a,20 10a,18 11a,37 12a38 were prepared according to
literature procedures.
Synthesis of 5,11,17,23-Tetra-tert-butyl-25,26-bis(but-3-
ynyloxy)-27,28-dihydroxycalix[4]arene (9a). To a suspension of
tetra-tert-butylcalix[4]arene (2.5 g, 3.85 mmol) and potassium
carbonate (1.330 g, 9.62 mmol) in dry acetonitrile (70 mL) was
added 4-bromobut-1-yne (2.138 g, 16.2 mmol), and the reaction
mixture was refluxed for 17 h. After cooling, the solvent was
removed and the colorless suspension was quenched with HCl
(2 M, 30 mL) and extracted with dichloromethane (2 ꢀ 40 mL).
The organic layer was washed with water (2 ꢀ 40 mL) and brine
(50 mL) and then dried over anhydrous MgSO4. Column
chromatography of the crude (heptane/ethyl acetate 8:2) gave
9a (49%) as a white solid: mp 228-230 °C; 1H NMR (300 MHz,
CDCl3) δ 0.97 (s, 18H, tBu), 1.31 (s, 18H, tBu), 2.08 (t, 2H, J =
2.6 Hz, CCH), 2.90 (td, 4H, J1 = 2.6 Hz, J2 = 7.1 Hz, CH2-
CCH), 3.33 (d, 4H, J = 13.0 Hz, CH2), 4.13 (t, 4H, J = 7.1 Hz,
O-CH2), 4.32 (d, 4H, J = 13.0 Hz, CH2), 6.80 (s, 4H, Ar-H), 7.07
(s, 4H, Ar-H), 7.08 (s, 2H, OH); 13C NMR (75 MHz, CDCl3) δ
20.3, 31.4, 32.1, 32.1, 34.2, 34.3, 70.7, 74.2, 80.9, 125.5, 126.0,
128.2, 132.9, 141.9, 147.4, 149.9, 151.0; LRMS (ESþ) m/z 775.4
([M þ Na]þ); HRMS (ESþ) for C50H66O6Naþ, calcd 775.4702,
2961, 1740, 1482, 1179, 1006, 871 cm-1
.
Synthesis of 5,11,17,23-Tetra-tert-butyl-25-cyanomethyloxy-
26,27,28-trihydroxycalix[4]arene (3b). Column chromatography
of the crude (heptane/ethyl acetate 8:2) gave 3b (58%) as a white
solid: mp 252-254 °C (dec.); 1H NMR (300 MHz, CDCl3) δ 1.18
(s, 9H, tBu), 1.22 (s, 18H, tBu), 1.22 (s, 9H, tBu), 3.46 (d, 2H, J =
13.8 Hz, CH2), 3.53 (d, 2H, J = 13.4 Hz, CH2), 4.24 (d, 2H, J =
13.8 Hz, CH2), 4.33 (d, 2H, J = 13.4 Hz, CH2), 5.00 (s, 2H,
CH2CN), 7.02 (d, 2H, J = 2.4 Hz, H-Ar), 7.05 (s, 2H, H-Ar),
7.07 (d, 2H, J = 2.5 Hz, H-Ar), 7.11 (s, 2H, H-Ar), 8.67 (s, 2H,
OH), 9.75 (s, 1H, OH); 13C NMR (75 MHz, CDCl3) 31.2, 31.6,
31.6, 32.5, 32.9, 34.1, 34.2, 34.5, 60.4, 114.9, 125.8, 125.9, 126.2,
127.3, 127.5, 127.5, 128.2, 133.0, 143.6, 143.9, 147.5, 148.4,
149.8; LRMS (ESþ) m/z 688.2 ([M þ H]þ); HRMS (ESþ) for
C45H57NO4Naþ, calcd 710,4185, found 710.4185; IR (FTIR)
ν = 3260, 2953, 2901, 2865, 1483, 1362, 1203, 1006, 872,
782 cm-1
.
Synthesis of 5,11,17,23-Tetra-tert-butyl-26,27,28-trihydroxy-
25-(3-cyanopropyloxy)calix[4]arene (4b). Column chromatogra-
phy of the crude (heptane/ethyl acetate 9:1) gave 4b (60%) as a
white solid: mp 171-173 °C (dec.); 1H NMR (300 MHz, CDCl3)
t
t
t
δ 1.18 (s, 9H, Bu), 1.21 (s, 18H, Bu), 1.22 (s, 9H, Bu),
2.36-2.46 (m, 2H, CH2-CH2-CH2), 3.05 (t, 2H, J = 6.9 Hz,
CH2CN), 3.44 (d, 2H, J= 13.8 Hz, CH2), 3.47 (d, 2H, J= 12.9 Hz,
(37) Gutsche, C. D.; Reddy, P. A. J. Org. Chem. 1991, 56, 4783–4791.
(38) Stoikov, I. I.; Khrustalev, A. A.; Antipin, I. S.; Konovalov, A. I.
Dokl. Akad. Nauk 2000, 374, 202–205.
7556 J. Org. Chem. Vol. 75, No. 22, 2010

Bois et al.
JOCArticle
CH2), 4.23 (t, 2H, J = 6.1 Hz, OCH2), 4.25 (d, 2H, J = 14.3 Hz,
CH2), 4.26 (d, 2H, J = 13.2 Hz, CH2), 7.00 (d, 2H, J = 2.3 Hz,
H-Ar), 7.05 (s, 2H, H-Ar), 7.07 (d, 2H, J = 2.5 Hz, H-Ar), 7.09 (s,
2H, H-Ar), 9.36 (s, 2H, OH), 10.02 (s, 1H, OH); 13C NMR
(75 MHz, CDCl3) δ 14.6, 26.3, 31.3, 31.6, 31.6, 32.2, 33.0, 34.0,
34.2, 34.4, 74.4, 119.4, 125.8, 125.9, 126.0, 126.8, 127.4, 127.9, 128.4,
133.4, 143.5, 143.9, 147.5, 148.5, 148.7, 148.8; LRMS (ESþ) m/z
716.2 ([M þ H]þ); HRMS (ESþ) for C48H61NO4Naþ, calcd
738.4498, found 738.4499; IR (FTIR) ν=3260, 2957, 2901, 2856,
O-CH2), 4.31 (d, 2H, J = 13.8 Hz, CH2), 4.39 (d, 2H, J = 13.0 Hz,
CH2), 7.02 (d, 2H, J = 2.5 Hz, H-Ar), 7.08 (s, 2H, H-Ar), 7.10 (d,
2H, J = 2.5 Hz, H-Ar), 7.11 (s, 2H, H-Ar), 9.57 (s, 2H, OH), 10.19
(s, 1H, OH); 13C NMR (75 MHz, CDCl3) δ 19.9, 29.3, 31.4, 31.6,
31.7, 32.2, 33.2, 34.0, 34.2, 34.4, 84.5, 125.8, 125.8, 125.9, 126.6,
127.5, 128.2, 128.6, 133.5, 143.2, 143.8, 147.8, 148.1, 148.8, 149.6;
LRMS (ESþ) m/z 727.4 ([M þ Na]þ); HRMS (ESþ) for
C48H65O4þ, calcd 705.4877, found 705.4864; IR (FTIR) ν =
3306, 3184, 2953,2870, 1482,1203, 1006, 906, 872, 731 cm-1
.
1483, 1201 cm-1
.
Synthesis of 5,11,17,23-Tetra-tert-butyl-26,27,28-trihydroxy-
25-(3-butynyloxy)calix[4]arene (9b). The crude product was
crystallized from methanol to give 9b (78%) as a white solid:
mp 154-156 °C (dec.); 1H NMR (300 MHz, CDCl3) δ 1.20 (s,
9H, tBu), 1.22 (s, 18H, tBu), 1.23 (s, 9H, tBu), 2.16 (t, 1H, J = 2.3
Hz, CCH), 3.04 (m, 2H, CH2-CCH), 3.43 (d, 4H, J = 13.4 Hz,
CH2), 4.27 (d, 2H, J = 13.5 Hz, CH2), 4.29 (t, 2H, J = 6.1 Hz,
O-CH2) 4.32 (d, 2H, J = 12.9 Hz, CH2), 7.00 (d, 2H, J = 2.5 Hz,
H-Ar), 7.05 (s, 2H, H-Ar), 7.06 (d, 2H, J = 2.5 Hz, H-Ar), 7.09
(s, 2H, H-Ar), 9.27 (s, 2H, OH), 10.07 (s, 1H, OH); 13C NMR (75
MHz, CDCl3) δ 20.2, 31.4, 31.6, 31.7, 32.4, 33.2, 34.2, 34.1,
34.43, 71.0, 74.4, 80.4, 125.8, 125.9, 126.0, 126.7, 127.8, 128.1,
128.5, 133.6, 143.3, 143.8, 147.9, 148.5, 148.6, 149.2; LRMS
(ESþ) m/z 723.4 ([M þ Na]þ); HRMS (ESþ) for C48H60O4Naþ,
calcd 723.4389, found 723.4387; IR (FTIR) ν = 3311, 2954,
Synthesis of 5,11,17,23-Tetra-tert-butyl-26,27,28-trihydroxy-
25-(4-bromobutyloxy)calix[4]arene (5b). Column chromatogra-
phy of the crude (heptane/ethyl acetate 9:1) gave 5b (85%) as a
white solid: mp 168-171 °C; 1H NMR (300 MHz, CDCl3) δ 1.20
(s, 9H, tBu), 1.22 (s, 18H, tBu), 1.24 (s, 9H, tBu), 2.27-2.38 (m,
4H, CH2-CH2-CH2-CH2), 3.44 (d, 2H, J = 13.0 Hz, CH2), 3.46
(d, 2H, J = 13.8 Hz, CH2), 3.65 (t, 2H, J = 6.1 Hz, CH2Br), 4.17
(t, 2H, J = 6.1 Hz, OCH2), 4.28 (d, 2H, J = 13.8 Hz, CH2), 4.33
(d, 2H, J = 13.0 Hz, CH2), 7.00 (d, 2H, J = 2.3 Hz, H-Ar), 7.06
(s, 2H, H-Ar), 7.07 (d, 2H, J = 2.5 Hz, H-Ar), 7.10 (s, 2H, H-
Ar), 9.52 (s, 2H, OH), 10.13 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3) δ 28.6, 29.2, 31.4, 31.6, 31.6, 32.4, 33.1, 33.6, 34.0, 34.2,
34.4, 76.1, 125.8, 125.9, 125.9, 126.6, 127.7, 128.1, 128.4, 133.5,
143.3, 143.8, 147.8, 148.4, 148.6, 149.3; LRMS (ESþ) m/z 783.4
([M þ H]þ); HRMS (ESþ) for C48H63BrO4Naþ, calcd 805.3809,
found 805.3809; IR (FTIR) ν = 3296, 2955, 2901, 2865, 1483,
2901, 2865, 1483, 1361, 1203, 1021, 871 cm-1
.
Synthesis of 26,27,28-trihydroxy-25-(3-cyanopropyloxy)calix-
[4]arene (10b). Column chromatography of the crude (heptane/
ethyl acetate 9:1) gave 10b (53%) as a white solid: 1H NMR
(300 MHz, CDCl3) δ 2.39-2.49 (m, 2H, CH2-CH2-CH2), 3.08 (t,
2H, J = 6.9 Hz, CH2CN), 3.49 (d, 2H, J = 13.8 Hz, CH2), 3.52 (d,
2H, J = 13.2 Hz, CH2), 4.25 (d, 2H, J = 13.4 Hz, CH2), 4.25 (t, 2H,
OCH2, 6.2 Hz), 4.28 (d, 2H, J = 13.0 Hz, CH2), 6.67-6.73 (m, 3H,
H-Ar), 6.86-7.11 (m, 9H, H-Ar), 9.17 (s, 2H, OH), 9.52 (s, 1H,
OH); 13C NMR (75 MHz, CDCl3) δ 14.6, 26.3, 31.5, 31.9, 74.5,
119.3, 121.2, 122.4, 126.8, 128.6, 128.9, 129.1, 129.7, 128.1, 128.3,
128.7, 133.9, 148.9, 150.7, 150.9; LRMS (ES-) m/z 492.2 ([M þ
H]þ); HRMS (ESþ) for C32H29NO4Naþ, calcd 514.1994, found
514.1995; IR (FTIR) ν = 3282, 2921, 2876, 1594, 1450, 1190, 1034,
1362, 1200, 872, 782 cm-1
.
Synthesis of 5,11,17,23-Tetra-tert-butyl-26,27,28-trihydroxy-
25-(3-hydroxypropyloxy)calix[4]arene (6b). Column chromatog-
raphy of the crude (heptane/ethyl acetate 7:3) gave 6b (70%) as a
white solid: mp 98-100 °C (dec.); 1H NMR (300 MHz, CDCl3)
t
t
δ 1.19 (s, 9H, tBu), 1.22 (s, 18H, Bu), 1.23 (s, 9H, Bu),
2.24-2.32 (m, 4H, CH2-CH2-CH2), 3.46 (d, 4H, J = 13.4 Hz,
CH2), 3.54 (t, 1H, J = 5.0 Hz, -OH), 4.17 (m, 2H, CH2OH), 4.27
(d, 2H, J = 13.4 Hz, CH2), 4.28 (t, 2H, J = 6.0 Hz, O-CH2), 4.31
(d, 2H, J = 12.8 Hz, CH2), 7.00 (d, 2H, J = 2.3 Hz, H-Ar), 7.06
(s, 2H, H-Ar), 7.08 (d, 2H, J = 2.4 Hz, H-Ar), 7.09 (s, 2H, H-
Ar), 9.77 (s, 2H, OH), 10.25 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3) δ 31.4, 31.6, 31.6, 31.9, 32.3, 33.1, 34.1, 34.2, 34.4, 58.9,
73.9, 125.9, 125.96, 126.7, 127.6, 128.1, 128.4, 133.5, 143.6,
143.9, 147.6, 148.2, 148.5, 149.0; LRMS (ESþ) m/z 729.5 ([M
þ Na]þ); HRMS (ESþ) for C48H64O5Naþ, calcd 729.4495,
found 729.4496; IR (FTIR) ν = 3188, 2953, 2869, 1483, 1362,
752 cm-1
.
Synthesis of 5,11,17,23-Tetra-tert-butyl-25,27-dioxo-26,28-di-(3-
ethoxycarbonylpropyloxy)calix[4]arene titanium(IV) dichloride
(2a-Ti). A slurry of compound 2a (0.302 g, 0.344 mmol) and
TiCl4 2THF (0.115 g, 0.344 mmol) in 10 mL of dry toluene was
3
1203, 1047, 872, 782 cm-1
.
stirred over 1 h at 40 °C. After evaporation of the volatiles, the
Synthesis of 5,11,17,23-Tetra-tert-butyl-25-propyloxy-26,27,
28-trihydroxycalix[4]arene (7b). Column chromatography of the
crude (heptane/ethyl acetate 95:5) gave 7b (77%) as a white
solid: mp 228-230 °C (dec.); 1H NMR (300 MHz, CDCl3) δ 1.20
(s, 9H, tBu), 1.22 (s, 18H, tBu), 1.23 (s, 9H, tBu), 1.26 (t, 3H, J =
4.4 Hz, CH3), 2.13-2.26 (m, 2H, CH2-CH2-CH3), 3.42 (d, 2H,
J = 13.0 Hz, CH2), 3.45 (d, 2H, J = 13.8 Hz, CH2), 4.11 (t, 2H,
J = 7.0 Hz, O-CH2), 4.29 (d, 2H, J = 13.7 Hz, CH2), 4.37 (d,
2H, J = 13.0 Hz, CH2), 7.00 (d, 2H, J = 2.5 Hz, H-Ar), 7.06 (s,
2H, H-Ar), 7.07 (d, 2H, J = 2.5 Hz, H-Ar), 7.10 (s, 2H, H-Ar),
9.62 (s, 2H, OH), 10.21 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3) δ 10.8, 23.4, 31.4, 31.6, 31.6, 32.4, 33.2, 34.1, 34.1,
34.4, 79.0, 125.8, 125.8, 125.9, 126.5, 127.8, 128.3, 128.5, 133.7,
143.2, 143.7, 147.9, 148.2, 148.6, 149.5; LRMS (ESþ) m/z 713.5
([M þ Na]þ); HRMS (EI) for C47H62O4þ, calcd 690.4648, found
690.4648; IR (FTIR) ν = 3324, 3169, 2956, 2870, 1484, 1362,
residue was washed with pentane (5 þ 3 mL) and dried under
1
vacuum to provide a dark red solid (0.315 g, 92%): H NMR
(300 MHz, CD2Cl2) δ 1.17 (s, 18H, tBu), 1.20 (t, 6H, J = 7.2 Hz,
OCH2CH3), 1.30 (s, 18H, tBu), 2.24-2.40 (m, 8H, CH2-CH2-CH2
þ CH2CO), 3.41 (d, 4H, J = 13.5 Hz, CH2), 4.07 (q, 4H, J =
7.2 Hz, OCH2CH3), 4.49 (d, 4H, J = 13.4 Hz, CH2), 4.94 (m, 4H,
OCH2), 7.10 (s, 4H, H-Ar), 7.11 (s, 4H, H-Ar); 13CNMR (75MHz,
CDCl3) δ 14.5, 23.9, 30.4, 31.7, 31.9, 34.9, 35.1, 61.2, 85.2, 125.2,
128.3, 129.9, 132.6, 145.9, 150.7, 156.1, 165.7, 172.6; LRMS (ESþ)
m/z 1015.1 ([M þ Na]þ); HRMS (ESþ) for C56H74O8TiCl2Na,
calcd 1015.4138, found 1015.4139.
Synthesis of 5,11,17,23-Tetra-tert-butyl-25,26,27-trioxo-28-
(3-ethoxycarbonylpropyloxy)calix[4]arene titanium(IV) chloride
(2b-Ti). Compound 2a-Ti (0.150 g, 0.151 mmol) in 5 mL of
toluene was refluxed for 50 h. After evaporation of the volatiles, the
residue was washed with pentane (3 þ 3 mL) to provide an orange
solid (0.085 g, 70%): 1H NMR (300 MHz, CD2Cl2) δ 1.15 (s, 9H,
tBu), 1.16 (s, 9H, tBu), 1.22 (t, 3H, J = 7.2 Hz, CH2CH3), 1.26 (s,
18H, tBu), 2.25-2.36 (m, 2H, CH2-CH2-CH2), 2.63 (t, 2H, J = 7.0
Hz, CH2CO), 3.35 (d, 4H, J = 13.8 Hz, CH2), 4.11 (q, 2H, J = 7.2
Hz, OCH2CH3), 4.36 (d, 2H, J = 12.6 Hz, CH2), 4.48 (t, 2H, J =
6.8 Hz, OCH2), 4.70 (d, 2H, J = 13.0 Hz, CH2), 7.05 (s, 2H, H-Ar),
7.07 (s, 2H, H-Ar), 7.11 (d, 2H, J = 2.3 Hz, H-Ar), 7.12 (d, 2H, J =
2.3 Hz, H-Ar); 13C NMR (75 MHz, CDCl3) δ 14.5, 25.1, 31.5, 31.7,
1203, 872, 782 cm-1
.
Synthesis of 5,11,17,23-Tetra-tert-butyl-26,27,28-trihydroxy25-
(2-methylpropyloxy)calix[4]arene (8b). Column chromatography
of the crude (heptane/ethyl acetate 95:5) gave 8b (57%) as a white
solid: mp 154-156 °C (dec.); 1H NMR (300 MHz, CDCl3) δ 1.22
(s, 9H,tBu), 1.25 (s, 18H, tBu), 1.26 (s, 9H, tBu), 1,30 (d, 6H, J=6.6
Hz), 2.45-2.59 (m, 1H, CH-(CH3)2), 3.44 (d, 2H, J = 13.0 Hz,
CH2), 3.47 (d, 2H, J = 13.8 Hz, CH2), 3.91 (d, 2H, J = 6.6 Hz,
J. Org. Chem. Vol. 75, No. 22, 2010 7557

Bois et al.
JOCArticle
31.8, 31.9, 33.8, 34.3, 34.6, 34.7, 34.8, 61.9, 79.4, 124.5, 125.6, 125.7,
126.3, 127.9, 130.8, 131.4, 132.9, 146.9, 147.1, 149.0, 152.1, 161.1,
163.3, 174.6; LRMS (EIþ) m/z 842 ([M]þ); HRMS (EI) for
C50H63O6TiClþ, calcd 842.3799, found 842.3799.
Acknowledgment. This work was supported by the French
Government through the “MATCALCAT” ANR Project
(Contract ANR 07-CP2D-21-02) and the pole of competi-
tiveness AXELERA “Chemistry and Environment”.
GC/MS Analysis of the Ethyl 4-chlorobutyrate Formation. To
a solution of 2a (0.502 g, 0.572 mmol) in dry toluene (50 mL) was
added TiCl4 2THF (0,250 g, 0,751 mmol). The reaction mixture
Supporting Information Available: NMR spectra of all new
compounds and complexes (Figures S1-S39); GC/MS analysis
(Figure S40). This material is available free of charge via the
Internet at http://pubs.acs.org.
3
was refluxed for 24 h and then distillated to collect toluene and other
volatile compounds. Distillate is then analyzed by GC/MS. Details
of the GC/MS method are available in Supporting Information.
7558 J. Org. Chem. Vol. 75, No. 22, 2010