Calix[4]arene derivatives monosubstituted at all four methylene bridges

Article abstract of DOI:10.1021/jo702474n

(Chemical Equation Presented) The scope of the reaction of the tetrabromocalixarene derivative 2b with alcohols under solvolytic conditions in trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP) was explored. The reaction proceeded readily with MeOH, EtOH, n-PrOH, ethylene glycol and i-PrOH affording preferentially the rccc isomer of the tetrasubstituted product. The methoxy derivative 6a undergoes isomerization upon attempted recrystallization from CHCl₃/MeOH and its rcct and rctt forms were characterized by X-ray crystallography. Incorporation of hydroxy groups on the bridges was accomplished via solvolysis in AcOH, followed by LiAlH₄ reduction of the acetoxy groups. Reaction of the tetra-(2-methylfuranyl)calixarene derivative 11 with benzyne followed by deoxygenation with Me₃SiCl/NaI afforded in low yield the tetra-(4-methylnaphthyl)calix[4]arene derivative 12. Reaction of de-tert-butylated tetrabromo derivative 2a with m-xylene in HFIP followed by methylation of the crude product afforded the tetraxylyl derivative 14.

Full text of DOI:10.1021/jo702474n

Calix[4]arene Derivatives Monosubstituted at All Four Methylene
Bridges
Ishay Columbus*,‡ and Silvio E. Biali*
Department of Organic Chemistry, The Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel
ishayc@iibr.goV.il; silVio@Vms.huji.ac.il
ReceiVed NoVember 18, 2007
The scope of the reaction of the tetrabromocalixarene derivative 2b with alcohols under solvolytic
conditions in trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP) was explored. The reaction proceeded
readily with MeOH, EtOH, n-PrOH, ethylene glycol and i-PrOH affording preferentially the rccc isomer
of the tetrasubstituted product. The methoxy derivative 6a undergoes isomerization upon attempted
recrystallization from CHCl3/MeOH and its rcct and rctt forms were characterized by X-ray crystallography.
Incorporation of hydroxy groups on the bridges was accomplished via solvolysis in AcOH, followed by
LiAlH4 reduction of the acetoxy groups. Reaction of the tetra-(2-methylfuranyl)calixarene derivative 11
with benzyne followed by deoxygenation with Me3SiCl/NaI afforded in low yield the tetra-(4-
methylnaphthyl)calix[4]arene derivative 12. Reaction of de-tert-butylated tetrabromo derivative 2a with
m-xylene in HFIP followed by methylation of the crude product afforded the tetraxylyl derivative 14.
Introduction
and formaldehyde.1 Although numerous modifications of the
calix scaffold have been achieved, the functionalization of the
methylene groups has remained relatively unexplored. Calix-
[4]arene derivatives substituted at one or two methylene bridges
have been prepared by the fragment condensation method,2 by
a spirodienone route,3 by an homologous anionic ortho-Fries
rearrangement4 and via alkylation of a monolithiated tet-
ramethoxy p-tert-butylcalix[4]arene.5 There are only a few
“classical”6 calix[4]arenes derivatives having all four methylene
bridges monofunctionalized which have been reported in the
literature.7 These include the tetrabromo derivatives 2a8 and 2b,9
Calix[n]arenes are macrocyclic compounds easily prepared
in multigram scale by basic condensation of p-tert-butylphenol
‡ On sabbatical leave from the Israel Institute for Biological Research, P. O.
Box 19, Ness Ziona, Israel.
(1) For reviews on calixarenes see: (a) Vicens, J., Bo¨hmer, V., Eds.
Calixarenes, a Versatile Class of Macrocyclic Compounds; Kluwer:
Dordrecht, 1991. (b) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34,
713. (c) Gutsche, C. D. Aldrichimica Acta 1995, 28, 1. (d) Pochini, A.;
Ungaro, R. In ComprehensiVe Supramolecular Chemistry; Vo¨gtle, F., Vol.
Ed.; Pergamon Press: Oxford, UK, 1996; Vol. 2, p 103. (e) Gutsche, C. D.
Calixarenes ReVisited Royal Society of Chemistry, Cambridge, 1998. (f)
Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds. Calixarenes 2001;
Kluwer: Dordrecht, 2001. (g) Bo¨hmer, V. In The Chemistry of Phenols;
Rappoport, Z., Ed.; Wiley: Chichester, 2003; Chapter 19.
(2) (a) Tabatai, M.; Vogt, W.; Bo¨hmer, V. Tetrahedron Lett. 1990,
31, 3295. (b) Sartori, G.; Maggi, R.; Bigi, F.; Arduini, A.; Pastorio, A.;
Porta, C. J. Chem. Soc., Perkin Trans. 1 1994, 1657. (c) Sartori, G.; Bigi,
F.; Porta, C.; Maggi, R.; Mora, R. Tetrahedron Lett. 1995, 36, 2311. (d)
Biali, S. E.; Bo¨hmer, V.; Cohen, S.; Ferguson, G.; Gru¨ttner, C.; Grynszpan,
F.; Paulus, E. F.; Thondorf, I.; Vogt, W. J. Am. Chem. Soc. 1996, 118,
2261. (e) Bergamaschi, M.; Bigi, F.; Lanfranchi, M.; Maggi, R.; Pastorio,
A.; Pellinghelli, M. A.; Peri, F.; Porta, C.; Sartori, G. Tetrahedron 1997,
53, 13037. (f) Tsue, H.; Enyo, K.; Hirao, K. Org. Lett. 2000, 2, 3071. (g)
For a review on the synthesis of calixarenes via the stepwise and
fragment condensation methods see: Bo¨hmer, V. Liebigs Ann./Recl. 1997,
2019.
(3) (a) Agbaria, K.; Biali, S. E. J. Am. Chem. Soc. 2001, 123, 12495.
(b) Simaan, S.; Agbaria, K.; Biali, S. E. J. Org. Chem. 2002, 67, 6136. (c)
Simaan, S.; Biali, S. E. J. Org. Chem., 2003, 68, 3634. (d) Simaan, S.;
Biali, S. E. J. Org. Chem. 2003, 68, 7685. (e) For a review on spirodienone
calixarene derivatives see: Biali, S. E. Synlett 2003, 1.
(4) Middel, O.; Greff, Z.; Taylor, N. J.; Verboom, W.; Reinhoudt, D.
N.; Snieckus, V. J. Org. Chem. 2000, 65, 667.
(5) Scully, P. A.; Hamilton, T. M.; Bennett, J. L. Org. Lett. 2001, 3,
2741.
(6) The term “classical” designates calixarenes possessing bridging
methylene groups connecting the phenol rings as opposed to “thiacalix-
arenes” (which possess sulfur bridges) “azacalixarenes” (nitrogen atoms),
“ketocalixarenes” (carbonyl groups), etc.
10.1021/jo702474n CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/01/2008
2598
J. Org. Chem. 2008, 73, 2598-2606

Fourfold Functionalized Calixarenes
and calixarenes 3a and 3b, obtained by reduction or reaction
of ketocalix[4]arenes derivatives with LiAlH4 or PhLi, respec-
tively.10,11
FIGURE 1. The four possible isomers of a calix[4]arene possessing
four identically functionalized methylene bridges.
are summarized in Table 1.14 When the macrocycle adopts a
cone conformation, the rccc form is the only one in which the
four substituents at the bridges are located at the sterically
unencumbered equatorial positions. In all the other forms,
necessarily at least one substituent must be located in axial or
isoclinal positions. The parent compounds 1a and 1b exist in
nonpolar solvents as a conformational mixture in which the
partial cone form predominates.15
Radical Bromination of Tetramethoxycalix[4]arene.
The radical brominations of 1a and 1b using different re-
action conditions have been described in the literature. Friedrich-
sen and co-workers reported the bromination of the de-tert-
butylated calixarene 1a using NBS and AIBN.8 A major
product was obtained (2a) that was characterized by X-ray
crystallography as the rccc isomer. X-ray diffraction of single
crystal of 2a indicated that in the crystal the molecule adopts
a cone conformation with all the bromine groups located at
equatorial positions. Two sets of signals in a 83:17 ratio were
observed in the 1H NMR spectrum in CDCl3 at rt. These
signals were ascribed to the cone and partial cone confor-
mers of the molecule. The population ratio between the two
species remained unchanged upon raising the temperature to
80 °C.
We have recently reported that the tetrabromo calixarene
derivatives 2a and 2b can be utilized as synthetic intermediates
for the preparation of calix[4]arenes with all four bridges
monofunctionalized.12 Reaction of these derivatives under
solvolytic (SN1) conditions allows the fourfold replacement of
the bromine atoms by trifluoroethoxy, ethoxy, azido and even
2-methylfuranyl groups. In this article we describe a reinvestiga-
tion of the bromination reaction of 1a and 1b, and a study of
the scope and limitations of the nucleophilic substitution route
in 2b.
Results and Discussion
We conducted the bromination of 1a with NBS in the ab-
1
sence of AIBN but using irradiation. The H NMR of the
Stereochemistry of Fourfold Functionalized Calixarenes.
Four isomers (rccc, rcct, rctt and rtct) (Figure 1) are possible
for a calixarene derivative which is fourfold monosub-
stituted with identical substituents. These forms are configura-
tional isomers that, necessarily, require bond cleavage for their
mutual interconversion. If the four bridges are monosub-
stituted by two types of substituents, the number of isomers
increases.
The possible arrangements of substituents (equatorial, axial
or isoclinal)13 for the four basic conformations of the calix[4]-
arene scaffold (cone, partial cone, 1,2-alternate and 1,3-alternate)
of the four configurational isomers of a tetrasubstituted system
crude product obtained after one recrystallization was identical
to that reported in the literature and displayed two sets of
signals in a ca. 83:17 ratio as reported. However, upon re-
peated recrystallizations from CHCl3/MeOH, the major form
was obtained in pure form. This separation by crystalli-
zation indicates that the mutual interconversion between the two
forms is slow on the human time scale. Thus, either the
interconversion barrier between the cone and partial cone forms
of the rccc form is larger than 25 kcal mol-1, or more likely,
the minor form observed does not correspond to a different
conformer of the rccc form, but rather to a second configura-
tional isomer (e.g., the rcct form) which adopts a partial cone
conformation.
(7) Azacalix[4]arenes substituted at several nitrogen bridges have been
reported. See: (a) Tsue, H.; Ishibashi, K.; Takahashi, H.; Tamura, R. Org.
Lett. 2005, 7, 2165. (b) Ishibashi, K.; Tsue, H.; Tokita, S.; Matsui, K.;
Takahashi, H.; Tamura, R. Org. Lett. 2006, 8, 5991.
(8) Klenke, B.; Na¨ther, C.; Friedrichsen, W. Tetrahedron Lett. 1998, 39,
8967.
(13) If a methylene is connected to two rings oriented anti, the positions
of its protons can be designated as “isoclinal” by analogy to the term utilized
for the pairs of geminal protons that are exchanged by a C2 axis in the
twist form of cyclohexane.
(9) Kumar, S. K.; Chawla, H. M.; Varadarajan, R. Tetrahedron Lett. 2002,
43, 7073.
(10) Go¨rmar, G.; Seiffarth, K.; Schultz, M.; Zimmerman, J.; Fla¨mig, G.
Makromol. Chem. 1990, 191, 81.
(11) Kuno, L.; Seri, N.; Biali, S. E. Org. Lett. 2007, 9, 1577.
(12) Columbus, I.; Biali, S. E. Org. Lett. 2007, 9, 2927.
(14) For a review on calix[4]arene systems functionalized at one or two
bridges see: Simaan, S.; Biali, S. E. J. Phys. Org. Chem. 2004, 17, 752.
(15) (a) Iwamoto, K.; Ikeda, A.; Araki, K.; Harada, T.; Shinkai, S.
Tetrahedron 1993, 49, 9937. (b) See also: van Hoorn, W. P.; Briels, W.
J.; van Duynhoven, J. P. M.; van Veggel, F. C. J. M.; Reinhoudt, D. N. J.
Org. Chem. 1998, 63, 1299.
J. Org. Chem, Vol. 73, No. 7, 2008 2599

Columbus and Biali
TABLE 1. Possible Arrangements of the Substituents in Calix[4]arenes Derivatives Possessing Four Monosubstituted Bridges
isomer
cone
partial conea
1,3-alternate
tetraisoclinal
1,2-alternate
rccc
tetraequatorial
tetraaxial
diequatorial-diisoclinal (I)
diaxial-diisoclinal (II)
axial-equatorial-diisoclinal
rcct
rctt
triequatorial-axial
triaxial-equatorial
diequatorial-isoclinal(I)-isoclinal (II)
equatorial- axial-diisoclinal(II)
tetraisoclinal
tetraisoclinal
diequatorial-diisoclinal
axial-equatorial-diisoclinal
diaxial-diisoclinal
diequatorial-diisoclinal
diaxial-diisoclinal (I)
diequatorial-diaxial
diequatorial-diisoclinal(II)
diaxial-diisoclinal(I)
equatorial-axial-isoclinal(I)-isoclinal(II)
equatorial- axial-isoclinal(I)-isoclinal(II)
rctc
diequatorial-diaxial
tetraisoclinal
equatorial-axial-diisoclinal
a The terms “isoclinal (I)” and “isoclinal (II)” denote arbitrarily the isoclinal positions pointing away or toward the unique ring oriented anti to the rest,
respectively (see ref 14).
atoms or groups via lithiation followed by reaction with
electrophiles (a route analogous to the one developed by Bennett
and co-workers for the monoalkylation of 1b)5 or via reaction
with strong nucleophiles under SN2 conditions. However, since
preliminary experiments conducted with BuLi/MeI or EtONa/
EtOH indicated that the compound underwent decomposition,
we decided to concentrate on the solvolysis reactions of 2b under
SN1 conditions. The reaction was initially attempted in alcohols
(MeOH, EtOH i-PrOH) using a silver salt (AgClO4) as an
electrophilic catalyst.17 Examination of the NMR spectrum of
the crude product indicated the formation of a complex
mixture.18 In the case of isopropanol it was possible to isolate
and purify by crystallization a tetraether product that was
characterized as the rccc form of 6d. When the solvolysis
reactions were conducted by refluxing a solution of 2b in EtOH
in the absence of a silver salt, no reaction took place.
Presumably, the ionizing power of the EtOH is not sufficient
to result in an appreciable reaction rate at the normal reflux
temperature. Increasing the reaction temperature to 130 °C (Parr
pressure reactor) afforded the tetraether 6b, but as a mixture of
the rccc, rcct and rctt isomers, as indicated by 1H NMR
spectroscopy.
Bromination of Tetramethoxy-p-tert-butylcalix[4]arene.
The bromination of 1b was described recently by Varadarajan
and co-workers.9 Initially we conducted the photochemical
bromination of 1b as reported in the literature procedure, using
a large excess of NBS (14 equiv) and refluxing the mixture for
24 h. Examination of the crude product by NMR indicated the
formation of a complex mixture. Recrystallization of the crude
product from hexane afforded a product that, on the basis of its
1H NMR spectrum (which displayed a 8:2 integration ratio
between the aromatic and methine protons) and 13C NMR
spectrum (which displayed signals at 41.2 and 66.9 ppm
characteristic of C-Br and CBr2 units, respectively), was
characterized as the hexabromo derivative 4. This compound
proved to be quite labile, and upon attempted crystallization
from CHCl3/MeOH, yielded the dibromo dioxo derivative 5,
resulting from hydrolysis of the gem-dibromomethyl groups.16
Since the bromination utilizing the literature reaction condi-
tions proceeded beyond the tetrabromo stage, we examined next
the photochemical bromination of 1b using nearly stoichiometric
(4-4.2 equiv) amounts of NBS. The product displayed single
signals (sharp singlets) for the tert-butyl, methoxy, methine and
1
aromatic protons in the H NMR spectrum. This spectrum is
Reaction in TFE or HFIP Media. Before attempting the
reaction in the absence of an electrophilic catalyst, using instead
a mixture of a nucleophile (e.g., an aliphatic alcohol) and a
solvent of high ionizing power such as trifluoroethanol (TFE)
or hexafluoroisopropanol (HFIP), some control experiments
were conducted. The reaction involves a competition between
the nucleophile and the ionizing solvent with the putative
carbocation intermediate generated by dissociation of a C-Br
bond. If the reaction proceeds under kinetic control, a low
nucleophilicity of the ionizing solvent (which is present in a
larger concentration than the nucleophile in the medium) is
desirable to ensure the formation of the product with the four
bridges substituted by the nucleophile. A control experiment
consistent with an rccc configuration pattern of the stereocenters.
The conformation in the crystal is similar to the one reported
for 2a: the calix macrocycle adopts a cone conformation with
the four bromines located at equatorial positions.12 The NMR
spectrum of the isolated 2b is markedly different from the one
reported in the literature.9 It was reported that multiplets were
observed for the aromatic, methine and methoxy signals.
Surprisingly, no carbon signal in the 44 ppm region (charac-
teristic of a Csp -Br unit) was reported in the 13C NMR
3
spectrum. It may be possible that the compound reported in the
literature corresponds to a mixture of tetrabromo isomers or
products possessing different numbers of bromine atoms.
Initial Attempts To Replace the Bromine Atoms of 2b. In
principle, the bromine atoms of 2b could be replaced by other
(17) (a) Zavada, J.; Pankova, M.; Arnold, Z. Collect. Czech. Chem.
Commun. 1976, 41, 1777. (b) See also: Simaan, S.; Siegel, J. S.; Biali, S.
E. J. Org. Chem. 2003, 68, 3699.
(16) A preliminary X-ray structure analysis of the molecule corroborated
this structural assignment.
(18) Apparently, a mixture of isomers is obtained.
2600 J. Org. Chem., Vol. 73, No. 7, 2008

Fourfold Functionalized Calixarenes
was conducted by refluxing a solution of 2b in TFE for 2 h.
The reaction afforded the tetrakis(trifluoroethoxy) derivative 6e,
previously characterized on the basis of its NMR spectrum
(which resembled that of 2b) as the rccc isomer.12,19 HFIP was
therefore used for reactions with weak nucleophiles such as
m-xylene (see below), but for nucleophiles stronger than TFE
the latter was chosen due to its significantly lower cost.
Cleavage of the C-OCH2CF3 Bond. We next addressed
the question whether the C-OCH2CF3 bonds formed after
reaction of the carbocations with TFE can be cleaved in TFE
under the reaction conditions (reflux for ca. 2 h). It has been
shown by Mayr and co-workers that dissolution of p-methoxy-
benzyl trifluroethyl ether and mesitylene in TFE at 20 °C affords
quantitatively after 1 h the substituted diphenylmethane
(eq 1).20
FIGURE 2. Crystal structure of one enantiomer of the tetraisopropoxy
derivative 6d viewed along the N-C axis of the acetonitrile molecule
included in the cavity.
To test whether 6e can dissociate appreciably in TFE, a
solution of the compound was refluxed for 1 h in TFE in the
presence of NaN3. Only unreacted 6e was obtained, although
under such reaction conditions 2b is transformed into the
corresponding tetraazido derivative 6g.12 Since the cleavage of
the C-OCH2CF3 bond might be catalyzed by the HBr released
in the medium in the solvolysis reactions of 2b, the reaction of
6e with azide was attempted also after adding two drops of 48%
aq HBr. Again, no reaction was observed, indicating that the
C-OCH2CF3 bond is not cleaved in TFE. From a practical point
of view, the experiments described above indicate that reactions
of 2b can be conducted in TFE only with nucleophiles more
nucleophilic than the fluorinated solvent (e.g., with π nucleo-
philes possessing a N nucleophilic parameter larger than the N1
parameter of TFE).20
tive. Examination of the NMR spectrum of the crude products
indicated that a major product was formed, ascribed to the rccc
form (as indicated by the single signal observed for the methine
signal at ca. 6 ppm). The molecular structure of the tetraiso-
propoxy derivative 6d (grown from acetonitrile) was determined
by X-ray crystallography (Figure 2). The molecule adopts a cone
conformation with the substituents on the bridges arranged in
the rccc, all-equatorial disposition. The H-C(bridge)-O-C
atoms are all oriented in an identical gauche conformation.
The preparation of the tetrasubstituted derivative 6f by
reaction of 2b with ethylene glycol is of interest, since the
presence of the hydroxy groups at the end of the side chains
may allow further modification of the substituents at the bridges.
To avoid oligomeric products (resulting from ethylene glycol
molecules reacting with two calixarene systems), a large excess
of the diol was used. Heating 2b to reflux in a 1:1 mixture of
ethylene glycol and TFE yielded a mixture of products
substituted by both OCH2CH2OH and OCH2CF3 groups at the
bridges, as shown by 1H NMR spectroscopy.21 The reaction of
2b with ethylene glycol was therefore conducted in HFIP to
avoid reaction with the ionizing solvent. As observed for the
reaction with other alcohols, the rccc form of 6f was obtained
as the main product (22% yield after recrystallization).
Reaction of 2b with Alcohols. The reactions were conducted
by refluxing a mixture of 2b, TFE and the appropriate alcohol.
Initial experiments were conducted by refluxing a 1:10 mixture
1
of EtOH and TFE containing 2b. The H NMR spectrum of
the crude product displayed two signals in the methine region
assigned to CHOCH2CF3 and CHOEt groups, indicating that
the bromine atoms on the bridges were replaced by both ethoxy
and trifluoroethoxy groups.12 TFE is less nucleophilic than the
common aliphatic alcohols such as MeOH, EtOH and i-PrOH,
but it is present in the reaction mixture in large quantities and
therefore successfully competes with the EtOH molecules.
However, when the solution consisted of a ca. 1:1 v/v TFE/
EtOH mixture, the major product was the tetraethoxy deriva-
tive.12 The reaction was also conducted in the presence of
1-propanol, 2-propanol and t-BuOH. With the exception of
t-BuOH, substitution of the bromine atoms at the bridges was
observed and the product obtained was the tetraalkoxy deriva-
Isomerization of 6a. Reaction of 2b with ca. 2:1 TFE/MeOH
yielded mainly, as indicated by 1H and 13C NMR spectroscopy
of the crude product, the rccc isomer of 6a as the major product.
Surprisingly, attempts to obtain this product in pure form proved
unsuccessful. Recrystallization of the crude product from CHCl3/
MeOH afforded, as shown by NMR analysis, a mixture of the
rccc, rcct and rctt forms, indicating that isomerization took
place. The isomerization of the rccc form is apparently solvent
(19) A single crystal of 6e was grown from acetonitrile and submitted
to X-ray crystallography. Although the structure could be refined only to a
relatively high R factor (18 %), the structure corroborated the assigned rccc
configuration of the macrocycle. The molecule adopts a cone conformation
with the substituents located at equatorial positions and an acetonitrile
molecule included in the cavity.
(20) (a) Hofmann, M.; Hampel, N.; Kanzian, T.; Mayr, H. Angew. Chem.,
Int. Ed. 2004, 43, 5402. See also: (b) Mayr, H.; Kempf, B.; Ofial, A. R.
Acc. Chem. Res. 2003, 36, 66. (c) Minegishi, S.; Kobayashi, S.; Mayr, H.
J. Am. Chem. Soc. 2004, 126, 5174.
(21) It is interesting to note that, although reflux of 2b in a 1:1 TFE/
EtOH mixture yields exclusively 6b, heating in a 1:1 TFE/ethylene glycol
mixture affords products containing both trifluoroethoxy and 2-hydroxy-
ethoxy groups at the bridges. The lower relative nucleophilicity of the
ethylene glycol molecules (as compared to that of EtOH) may be connected
to the presence of inter- and intramolecular hydrogen bonds, as well as to
the larger viscosity of the mixture.
J. Org. Chem, Vol. 73, No. 7, 2008 2601

Columbus and Biali
FIGURE 3. X-ray structure of a mixture of the rcct and rctt isomers of 6a. Only an average structure was found. One methoxy group is disordered
betwen two positions (O8-Me and O8a-Me, see arrows) situated cis and trans relative to the reference substituent.
SCHEME 1
indicated the presence of a major product (23% yield after
recrystallization), ascribed to the rccc isomer of the tetraacetoxy
derivative (8). LiAlH4 reduction of 8 proceeded readily and
afforded the rccc isomer of the tetraalcohol 9 (Scheme 2). The
1H NMR spectrum of 9 in acetone-d6 displays a pair of mutually
coupled doublets (J ) 4.3 Hz) at δ 6.33 and 4.32 for the methine
and OH protons, indicating a gauche conformation of the HCOH
units at the bridges.
Reaction with Thiocyanate. We have shown that the cationic
intermediate formed in the solvolysis of 2b can be trapped by
the azide nucleophile, yielding the tetraazido derivative 6g.12
To test whether also sulfur-containing nucleophiles can be
attached to the calix scaffold, we conducted the reaction of 2b
dependent, and it is relatively fast in CHCl3/MeOH and slow
in CHCl3/CH3CN. We have observed previously the thermal
isomerization of the trans -thiomethoxy methylene-functional-
ized calixarene (7-trans). Upon heating in solution the com-
pound isomerized to its most stable cis-form (7-cis) (Scheme
1).22 The methoxy-substituted derivative appears to be the more
labile of all the alkoxy methylene-functionalized calixarenes
studied.
Slow evaporation of the mixture of isomers in a CHCl3/CH3-
CN solution afforded two types of crystals of different morphol-
ogy (prisms and plates). X-ray analysis of the prisms indicated
cocrystallization of a mixture of the rcct and rctt isomers of
6a. The macrocyclic ring of the rcct and rctt forms adopts the
partial cone conformation with one methoxy group disordered
between two positions (O8 and O8a) (Figure 3). According to
the crystal structure, in the rcct and rctt forms the substituents
are located in diequatorial and diisoclinal positions. As observed
in all structures so far, the substituents avoid the axial positions
of the macrocycle.
1
with KSCN in HFIP. Judging from the H NMR spectrum, a
mixture of stereoisomers products was formed, with the rccc
isomer 10 being the major form (Scheme 3).23 In principle,
thiocyanate ion (an ambident nucleophile) can attack the
carbocation via its N or S atoms. The presence of HC-SCN
bonds in the product can be concluded from the 13C NMR
spectrum, which displays a signal at 111.4 ppm, characteristic
of the thiocyanate group.24 It is interesting to note that the only
two cases observed in which the reaction with a nucleophile in
fluorinated alcohols proceeded with poor stereoselectivity and
did not yield nearly exclusively the rccc form were in the
reaction with azide and thiocyanate. In both cases, the reaction
involved small and highly reactive charged nucleophiles.
Aryl Substituents at the Bridges. (a) Modification of the
2-Methylfuranyl Functionalities. In principle, reaction of the
tetrabromo derivatives with aromatic compounds under sol-
volytic Friedel Crafts conditions may afford calixarenes sub-
stituted at all bridges by aromatic groups. We have previously
reported the preparation of a tetrakis(2-methylfuranyl)calix[4]-
arene derivative of 2a by this route.12 The furan ring is an
attractive substituent since it can provide an entry into other
aromatic substituents via Diels-Alder reaction with benzyne
followed by deoxygenation of the resulting 1,4-endoxide
(Scheme 4).25
Solvolysis of 2b in Acetic Acid. Incorporation of OH
Groups at the Bridges. Initial attempts to prepare the tetrahy-
droxy derivative by solvolysis of 2b in TFE in the presence of
NaOH indicated that only decomposition products were formed.
To introduce hydroxyl groups into the bridges we therefore
resorted to the acetoxy group that can be viewed as a “masked”
hydroxyl group.
Initial experiments were conducted by refluxing a mixture
of 2b, TFE and NaOAc, but only decomposition products were
obtained. We therefore attempted the direct acetolysis of 2b.
(23) When the reaction was conducted in TFE, a different isomeric
mixture was obtained, the major form corresponding to the rctt isomer.
(24) The SCN carbon of ethyl thiocyanate resonates at 112 ppm, while
in isothiocyanates the carbon resonance is about ca. 20 ppm shifted
downfield. See: Ben-Efraim, D. A. In The Chemistry of Cyanates and their
Thio DeriVatiVes, Part 1; Patai, S., Ed., Wiley: Chichester, 1977; Chapter
5, p 227.
1
After reflux of a solution of 2b in AcOH, H NMR analysis
(22) Simaan, S.; Agbaria, K.; Biali, S. E. J. Org. Chem. 2002, 67, 6136.
2602 J. Org. Chem., Vol. 73, No. 7, 2008

Fourfold Functionalized Calixarenes
SCHEME 2
SCHEME 3
SCHEME 5
SCHEME 4
Reaction of 2b with 2-methylfuran/TFE/1,2-butylene oxide26
afforded a tetra-(2-methylfuranyl) calix[4]arene derivative.27 The
1H NMR spectrum of this product displayed a signal pattern
similar that of its de-tert-butylated derivative (previously
characterized by X-ray crystallography as the rccc isomer).12
On the basis of this similarity, we ascribe also a rccc config-
uration to the tetrafuranyl calix[4]arene derivative 11. Reaction
of 11 with excess benzyne (generated from benzenediazonium
2-carboxylate hydrochloride) afforded a product which displayed
a complex NMR spectrum.28 The mixture was deoxygenated
by reaction with trimethylsilyl iodide (generated in situ from
Me3SiCl/NaI)29 to yield the tetranaphthyl derivative 12 in low
yield (Scheme 5). Although cleavage of the O-Me bonds in
p-tert-butylcalix[4]arenes tetramethyl ether can be achieved by
treatment with Me3SiI in CHCl3,30 no Me-O cleavage was
observed in the deoxygenation step. An rccc configuration of
the stereocenters at the bridges is assigned to this product, since
the rccc configuration of the starting material 11 should not be
affected by the Diels-Alder reaction/deoxygenation reaction
sequence. The molecule displays in the 1H NMR a signal pattern
indicating that all the groups at the bridges are symmetry
equivalent, but two types of methoxy, t-Bu and phenyl groups
are present in the macrocycle. This is consistent with a pinched
cone conformation which is “frozen” on the NMR time scale.
(b) Reaction with m-Xylene. Preliminary experiments
conducted with anisole/HFIP indicated that, although fourfold
Friedel-Crafts reaction takes place with the aromatic compound
as indicated by NMR and MS analysis, a complex product
mixture is obtained, apparently resulting from the different
combinations of ortho/para substitution of the aromatic rings
attached to the bridges. We therefore decided to study the
reaction of m-xylene since it undergoes electrophilic substitution
preferentially at a single unique position. The studies of Mayr
and co-workers were not encouraging, since although they
showed that a reaction proceeds readily between 4-methoxy-
benzyl cation (cf. eq 1) and mesitylene, no reaction occurs
between diphenylmethyl cation (a better model for the cation-
(s) generated by ionization of 2a/2b) and m-xylene in TFE.20
Initial attempts conducted by reflux of a mixture of 2b and
a 10:1 TFE/m-xylene under reaction conditions similar to those
used for the preparation of 11 did not afford an arylated product.
Probably since m-xylene is less nucleophilic than 2-methylfuran,
it cannot compete with the TFE. We therefore conducted the
reaction of 2a in HFIP. Inspection of the 1H NMR spectrum of
(25) For selected examples of this transformation in macrocyclic rings
see: (a) Hart, H.; Takehira, Y. J. Org. Chem. 1982, 47, 4370. (b) Kohnke,
F. H.; Parisi, M. F.; Raymo, F. M.; O’Neil, P. A.; Williams, D. J.
Tetrahedron 1984, 50, 9113.
(26) For uses of propylene oxide as an HBr scavenger see: de la Vega,
F.; Sasson, Y. J. Chem. Soc., Chem. Commun. 1989, 653.
(27) Without 1,2-butylene oxide an intractable mixture of products was
obtained.
(28) The complexity of the spectrum may be due to the presence of
configurational isomers of the tetraaduct that adopt different conformations.
(29) Jung, K.; Koreeda, M. J. Org. Chem. 1989, 64, 5667.
(30) Casnati, A.; Arduini, A.; Ghidini, E. W.; Pochini, A.; Ungaro, R.
Tetrahedron 1991, 47, 2221.
J. Org. Chem, Vol. 73, No. 7, 2008 2603

Columbus and Biali
SCHEME 6
TABLE 2. Calculated (MM3) Steric Energies (in kcal mol-1) of
the crude product obtained indicated that indeed four m-xylyl
moieties were incorporated into the bridges, but unexpectedly,
the reaction product was the trimethoxy derivative 13 (Scheme
6).31 Apparently, the HBr released by the Friedel-Crafts
reaction cleaves one of the methoxy groups of the calix
skeleton.32 The crude 13 was methylated (MeI/NaH) to afford
14. The NMR of the tetraxylyl derivative 14 displayed a signal
pattern indicating that all rings at the bridges are equivalent,
while two types of rings are present in the calix macrocycle.
By analogy to 11 and 12, and on the basis of the symmetry
indicated by the NMR pattern, we ascribed to 14 the rccc
configuration with the macrocyclic ring adopting a frozen (on
the NMR time scale) pinched cone conformation.
Cone/Partial Cone Energy Gap. In all the calixarenes
monofunctionalized at four bridges in rccc fashion studied so
far by X-ray crystallography (with bromine, isopropoxy and
2-methylfuranyl substituents at the bridges), the calix macrocycle
adopted in the crystal a cone or pinched cone conformation. In
contrast, a partial cone conformation was present in the crystal
structures of the rcct and rctt forms of 6a and the rcct form of
6g. To assess whether indeed for a given substituent a change
in the configuration of the bridges can modify the conforma-
tional preferences of the calix macrocycle we resorted to
molecular mechanics (MM3) calculations.33,34 MM3 calculations
conducted by Shinkai and co-workers indicated that the lowest
energy conformation of the parent 1a and 1b is the partial cone
form, with the cone conformation lying 1.3-1.5 kcal mol-1 (for
1b) or 0.3 kcal mol-1 (for 1a) above it.35 The cone/partial cone
conformational equilibrium of the tetramethoxycalix[4]arene 1a
is strongly influenced by the solvent polarity. In general, the
population of the more polar cone form increases with the
solvent polarity.36,37
the Cone and Partial Cone Conformations of the Stereoisomers of
15a
conformation
isomer
cone
partial cone
rccc
34.4 [0.0] (tetraequatorial)
38.8 [4.4](diequatorial-
diisoclinal (I))
rcct
rctt
38.3 [0.5] (triequatorial-
axial)
42.3 [4.9] (diequatorial-
diaxial)
37.8 [0.0] (diequatorial-
isoclinal (I)-isoclinal(II))b
37.4 [0.0] (diequatorial-
diisoclinal (II))
38.0 [0.6] (diequatorial-
diisoclinal (II))c
a Numbers in brackets are energy differences between a conformation
and the lowest calculated conformer of a given isomer. b Conformation
analogous to the one found in the crystal structure of rcct 6a. c Conformation
analogous to the one found in the crystal structure of rctt 6a. The two
calculated partial cone conformations of the rctt form differ in the orientation
of the methoxy groups on the bridges.
MM3 calculations were conducted on the de-tert-butylated
model compound 15. Calculations on the rccc form indicate
that, as expected in the cone form, the tetraequatorial conforma-
tion is of lower energy than the tetraaxial form (Table 2). For
the partial cone form, the diequatorial-diisoclinal(I) conformer
is of lower energy than the diaxial-diisoclinal(II) form, but is
4.4 kcal mol-1 higher than the tetraequatorial cone form.
(31) When the reaction was conducted with 2b, a mixture of trimethoxy
and dimethoxy tetraxylyl derivatives was obtained. Since we were unable
to fully methylate this mixture, we performed the reaction with the de-tert-
butylated derivative 2a.
(32) Preliminary experiments indicate that reaction of 1b with excess
HBr (50%) in HFIP (2 h reflux) affords the monodemethylated derivative
(i.e., the trimethyl ether of p-tert-butylcalix[4]arene), while in TFE the
demethylation proceeds further, and a mixture of the monomethyl ether
and tetrahydroxycalixarene is obtained.
(33) Alchemy 2000; Tripos Inc.: St. Louis, MO 63144, 2000.
(34) Molecular mechanics calculations of 2a have been reported by
Friedrichsen and coworkers (ref 8). These calculations were conducted
assuming that each of the four forms (rccc, rcct, rctt, rctc) adopts a cone
conformation. However, it was not examined whether in some substitution
patterns the preferred conformation is different from cone.
(35) (a) Iwamoto, K.; Araki, K.; Shinkai, S. J. Org. Chem. 1991, 56,
4955. (b) Harada, T.; Rudzinski, J. M.; Shinkai, S. J. Chem. Soc., Perkin
Trans. 2 1992, 2109. (c) For a review on the conformation and stereody-
namics of calixarenes see: Thondorf, I. in ref 1f, Chapter 15.
(36) Iwamoto, K.; Ikeda, A.; Araki, K.; Harada, T.; Shinkai, S.
Tetrahedron 1993, 49, 9937.
For the rcct form, calculations indicate that the triequatorial-
axial form is of lower energy than the triaxial-equatorial, but
this form is about 0.5 kcal mol-1 higher in energy than the
partial cone form with diequatorial-isoclinal(I)-isoclinal(II)
disposition of substituents. For the rctt isomer, the energy gap
between the cone form (diequatorial-diaxial) and the preferred
partial cone form (diequatorial-diisoclinal(II)) is larger (4.9 kcal
mol-1). To summarize, the calculations suggest that, whereas
the rccc form prefers the tetraequatorial cone form, the rcct and
rctt forms prefer the partial cone conformers with diequatorial-
(37) (a) van Hoorn, W. P.; Briels, W. J.; van Duynhoven, J. P. M.; van
Veggel, F. C. J. M.; Reinhoudt, D. N. J. Org. Chem. 1998, 63, 1299. (b)
See also ref 3d.
2604 J. Org. Chem., Vol. 73, No. 7, 2008

Fourfold Functionalized Calixarenes
TABLE 3. Summary of the Reactions Involving the Fourfold
Replacement of the Bromine Atoms
conducted as described for 2b using 0.31 g of 1b (0.43 mmol), 1.1
g of NBS (6.2 mmol) and 30 mL of CCl4. Recrystallization from
hexane afforded 0.11 g (22%) of 4, mp 245 °C (dec).
calixarene
nucleophilic reagent
solvent
TFE
TFE
TFE
TFE
TFE
TFE
TFE or HFIP
TFE or HFIP
HFIP
acetic acid
HFIP
product
6e
6a
6b
1H NMR (400 MHz, CDCl3) δ 8.21 (d, J ) 2.2 Hz, 4H), 7.87
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2a
2a
TFE
MeOH
EtOH
n-PrOH
i-PrOH
2-methylfuran
NaN3
(d, J ) 2.2 Hz, 4H), 6.29 (s, 2H), 3.33 (s, 12H), 1.38 (s, 36H). 13
C
NMR (100 MHz, CDCl3) δ 149.7, 145.7, 137.6, 134.3, 128.4, 127.6,
66.9, 60.3, 41.2, 34.8, 31.4. MALDI MS, m/z 1098.9 (M - Br).
General Procedure for the Reaction of 2b with Alcohols. A
solution of 2b (0.10 g, 0.10 mmol) in a mixture of 10 mL of TFE
and 10 mL of of the appropriate alcohol (5 mL in the case of
MeOH) was refluxed for 1-2 h (until the solution is clear). The
solvent was evaporated and the residue recrystallized from CHCl3/
MeOH or CHCl3/acetonitrile.
6c
6d
11 (12)a
6g
KSCN
10
6f
ethylene glycol
acetic acid
m-xylene
2-methylfuran
8 (9)b
13 (14)c
6 (in ref 12)
5,11,17,23-Tetra-tert-butyl-2,8,14,20,25,26,27,28-octameth-
oxycalix[4]arene (6a). The rccc, rcct and rctt forms were not
TFE
a Diels-Alder reaction of the product 11 with benzyne followed by
deoxygenation with Me3SiCl/NaI yielded 12. b LiAlH4 reduction of the
product 8 afforded the tetraalcohol 9. c Methylation of the product 13
afforded 14.
1
separated. The signals in the H NMR spectrum were assigned to
the different isomers on the basis of their symmetry pattern.
rccc form: 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 8H), 5.78 (s,
4H), 3.92 (s, 12H), 3.49 (s, 12H), 1.08 (s, 36H). rcct form: 1H
NMR (400 MHz, CDCl3) δ 7.79 (d, J ) 2.4 Hz, 1H), 7.44 (d, J )
2.4 Hz, 1H), 7.42 (d, J ) 2.4 Hz, 1H), 7.36 (d, J ) 2.4 Hz, 1H),
7.29 (d, J ) 2.4 Hz, 1H), 7.01 (d, J ) 2.4 Hz, 1H), 6.92 (d, J )
2.4 Hz, 1H), 6.75 (d, J ) 2.4 Hz, 1H), 5.53 (s, 1H), 5.49 (s, 1H),
5.13 (s, 1H), 5.01 (s, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 3.63 (s, 3H),
3.55 (s, 3H), 3.45 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H), 2.91 (s, 3H),
1.31 (s, 9H), 1.16 (s, 9H), 1.09 (s, 9H), 1.07 (s, 9H). rctt form:
1H NMR (400 MHz, CDCl3) δ 7.69 (s, 2H), 7.17 (d, J ) 2.4 Hz,
2H), 7.15 (s, 2H), 7.12 (d, J ) 2.4 Hz, 2H), 5.61 (s, 2H), 5.09 (s,
2H), 3.62 (s, 3H), 3.45 (s, 6H), 3.44 (s, 3H), 3.43 (s, 6H), 3.42 (s,
3H), 3.41 (s, 3H), 1.44 (s, 18H), 1.17 (s, 18H). MALDI MS, m/z
863.36 (M + K)+.
isoclinal(I)-isoclinal(II) and diequatorial-diisoclinal(II) dis-
positions of substituents, respectively. Apparently, conforma-
tions avoiding axial dispositions of substituents are favored.
Conclusions
The tetrabromo derivatives readily react with alcohol nu-
cleophiles, azide, thiocyanate, acetoxy and aromatic compounds
under solvolytic conditions, to afford calixarenes which are
functionalized fourfold at the bridges (Table 3). In most cases
examined, the reaction proceeds with high stereoselectivity,
yielding the rccc product. The tetramethoxy derivative 6a is
configurationally labile in CHCl3/MeOH solutions. The 2-me-
thylfuranyl substituents at the bridges can be further function-
alized.
5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetramethoxy-2,8,14,-
1
20-tetrapropoxycalix[4]arene (rccc form) (6c): H NMR (400
MHz, CDCl3) δ 7.09 (s, 8H), 5.87 (s, 4H), 3.90 (s, 12H), 3.53 (t,
J ) 6.8 Hz, 8H), 1.71 (m, 8H), 1.08 (s, 36H), 1.00 (t, J ) 7.4 Hz,
12H). 13C NMR (100 MHz, CDCl3) δ 153.4, 145.4, 134.4, 122.1,
72.5, 70.9, 61.4, 34.2, 31.3, 23.3, 11.0. Mp 220-225 °C. MALDI
MS, m/z 959.54 (M + Na)+.
5,11,17,23-Tetra-tert-butyl-2,8,14,20-tetraisopropoxy-25,26,-
27,28-tetramethoxycalix[4]arene (rccc form) (6d): 1H NMR (400
MHz, CDCl3) δ 7.09 (s, 8H), 6.09 (s, 4H), 3.92 (s, 12H), 3.79 (h,
J ) 6.1 Hz, 4H), 1.28 (d, J ) 6.1 Hz, 24H), 1.08 (s, 36H). 13C
NMR (100 MHz, CDCl3) δ 153.3, 145.3, 134.6, 122.4, 69.3, 68.5,
61.5, 34.2, 31.3, 22.3. Mp 220-225 °C. MALDI MS, m/z 959.56
(M + Na)+.
Experimental Section
2,8,14,20-Tetrabromo-25,26,27,28-tetramethoxycalix[4]-
arene (rccc form) (2a). A mixture of 1a38 (8.0 g, 16.7 mmol),
NBS (13.3 g, 74.7 mmol) and CCl4 (300 mL) was refluxed while
irradiated with a spotlight (100 W). After 4 h, a second portion of
NBS (7.2 g, 40.5 mmol) was added. Reflux was continued for an
additional 18 h. After cooling, the solvent was washed once with
aq Na2SO3 and twice with water. The organic phase was dried
(MgSO4) and evaporated to yield 5.0 g (38%) of 2a. The crude
material is usually pure enough to be used in subsequent reactions.
If needed, recrystallization can be conducted from acetone or
CHCl3/MeOH, mp 260-265 °C (lit8 265-270 °C). 1H NMR (400
MHz, CDCl3) δ 7.10 (d, J ) 7.8 Hz, 8H), 6.78 (t, J ) 7.8 Hz,
4H), 6.70 (s, 4H), 3.99 (s, 12H).
2,8,14,20-Tetrabromo-5,11,17,23-tetra-tert-butyl-25,26,27,28-
tetramethoxycalix-[4]arene (rccc form) (2b). A mixture of 1b38
(15.3 g, 21.7 mmol), NBS (15.6 g, 87.6 mmol) and CCl4 (600 mL)
was refluxed for 22 h while irradiated with a spotlight (100 W).
The solvent was washed once with aq Na2SO3 and twice with water.
The organic phase was dried (MgSO4) and evaporated. The crude
product was recrystallized from CHCl3/MeOH to yield 6.0 g (27%)
of 2b, mp 290 °C (dec).
5,11,17,23-Tetra-tert-butyl-2,8,14,20-tetrakis(2′-hydroxyethoxy)-
25,26,27,28-tetramethoxycalix[4]arene (rccc form) (6f). A mix-
ture of 0.1 g of 2b, 10 mL of HFIP and 5 mL of ethylene glycol
was refluxed for 2 h. The solvent was evaporated, and the residue
was dissolved in chloroform. The organic phase was washed twice
with water and then dried and evaporated. After recrystallization
of the residue from CHCl3/MeOH 20 mg (22%) of 6f was obtained,
mp 285-288 °C.
1H NMR (400 MHz, CDCl3) δ 7.07 (s, 8H), 5.94 (s, 4H), 3.92
(s, 12H), 3.84 (m, 8H), 3.73 (m, 8H), 2.10 (t, J ) 5.5 Hz, 4H,
OH), 1.09 (s, 36H). 13C NMR (100 MHz, CDCl3) δ 153.2, 145.9,
134.0, 122.2, 73.3, 70.8, 62.1, 61.7, 34.2, 31.3. MALDI MS, m/z
967.7 (M + Na)+.
2,8,14,20-Tetraacetoxy-5,11,17,23-tetra-tert-butyl-25,26,27,28-
tetramethoxycalix[4]arene (8). A solution of 1.0 g of 2b in 150
mL of acetic acid was refluxed for 18 h. After cooling, the solvent
was evaporated and the residue recrystallized from CHCl3/MeOH
to yield 215 mg of tetraacetoxy 8 (23%), mp 345-348 °C (dec).
1H NMR (400 MHz, CDCl3) δ 7.40 (s, 4H), 7.02 (s, 8H), 3.99
(s, 12H), 2.18 (s, 12H), 1.09 (s, 36H). 13C NMR (100 MHz, CDCl3)
δ 169.9, 152.6, 145.6, 133.1, 122.3, 67.3, 61.9, 34.2, 31.3, 21.3.
MALDI MS, m/z 959.4 (M + Na+).
1H NMR (400 MHz, CDCl3) δ 7.27 (s, 8H), 6.71 (s, 4H), 3.99
(s, 12H), 1.11 (s, 36H). 13C NMR (100 MHz, CDCl3) δ 150.3,
146.6, 134.0, 125.7, 61.3, 44.1 (CBr), 34.4, 31.2. MALDI MS, m/z
1042.99 (M + Na)+, m/z 1058.96 (M + K)+.
2,2,8,14,14,20-Hexabromo-5,11,17,23-tetra-tert-butyl-25,26,-
27,28-tetramethoxycalix[4]arene (cis form) (4). The reaction was
5,11,17,23-Tetra-tert-butyl-2,8,14,20-tetrahydroxy-25,26,27,-
28-tetramethoxycalix[4]arene (9). To an ice-cold solution of 8
(38) Gutsche, C. D.; Dhawan, B.; Levine, J. A.; No, K. H.; Bauer, L. J.
Tetrahedron 1983, 39, 409.
J. Org. Chem, Vol. 73, No. 7, 2008 2605

Columbus and Biali
(290 mg, 0.31 mmol) in 15 mL of dry THF was added LiAlH4
(100 mg, 2.63 mmol) under an inert atmosphere, and the mixture
was stirred for 10 min. Ethyl acetate was added to quench the excess
LiAlH4, and the solution was washed with water, and then with 1
M aq HCl. After drying (MgSO4) the organic phase was filtered
and evaporated. Recrystallization from acetone gave 50 mg of 9
(21%), mp 322-325 °C (dec).
NMR spectrum. The mixture was dissolved in 9 mL of dry CH3-
CN, and Me3SiCl (110 mg, 1 mmol) and NaI (150 mg, 1 mmol)
were added. The mixture was refluxed under nitrogen for 1 h. A
10-mL sample of 5% aq Na2SO3 was added, and the mixture was
extracted with ether. The insoluble solid from the ether extraction
was filtered and recrystallized from CHCl3/MeOH to yield 10 mg
of 12 (>90% purity), mp 320 °C (dec).
1H NMR (400 MHz, acetone-d6) δ 7.20 (s, 8H), 6.33 (d, J )
4.3 Hz, 4H), 4.32 (d, J ) 4.3 Hz, 4H), 3.92 (s, 12 H), 1.09 (s, 36
H). 13C NMR (100 MHz, acetone-d6) δ 152.6, 144.4, 137.1, 121.4,
64.5, 61.6, 33.9, 30.9. MALDI MS, m/z 791.4 (M + Na+).
2,8,14,20-Tetrathiocyanato-5,11,17,23-tetra-tert-butyl-25,26,-
27,28-tetramethoxycalix[4]arene (10). A mixture of 2b (200 mg),
KSCN (90 mg) and 12 mL of HFIP was refluxed for 1 h. The
solvent was evaporated, chloroform was added to the residue, and
the insoluble material was filtered. The residue obtained after
evaporation of the filtrate was recrystallized from CHCl3/MeOH
1H NMR (400 MHz, CDCl3, rt) δ 8.27 (d, J ) 7.9 Hz, 4H),
8.03 (d, J ) 7.9 Hz, 4H), 7.57-7.45 (m, 16H), 6.89 (s, 4H), 6.68
(s, 4H), 6.46 (s, 4H), 4.74 (s, 6H), 3.13 (s, 6H), 2.70 (s, 12H), 0.95
(s, 18H), 0.72 (s, 18H). 13C NMR (CDCl3, 100 MHz) δ 155.7,
153.9, 145.2, 143.5, 139.4, 137.1, 133.4, 132.8, 132.6 (double
intensity), 127.1, 126.7, 126.3, 126.0, 124.8, 124.7, 124.6, 122.6,
62.4, 59.8, 40.6, 34.0, 33.9, 31.4, 31.3. MALDI MS, m/z 1288.7
(M + Na+).
2,8,14,20-tetra(m-xylyl)-25,26,27,28-tetramethoxycalix[4]-
arene (14). A mixture of 280 mg of 2a and m-xylene (6 mL) in 80
mL of HFIP was refluxed for 24 h to give a clear-red solution.
After cooling, the solvent was evaporated, and the residue recrystal-
lized from CHCl3/MeOH to get 180 mg of material, which
1
to yield 45 mg of the crude product. H NMR analysis indicated
that the product consisted of 75% of the rccc form and 25% of a
mixture of the other forms. A second recrystallization afforded the
pure rccc form, mp 280-282 °C (dec).
1
according to the H NMR spectrum consisted mainly (>90%) of
1H NMR (400 MHz, CDCl3) δ 7.17 (s, 8H), 6.35 (s, 4H), 4.05
(s, 12H), 1.12 (s, 36H). 13C NMR (100 MHz, CDCl3) δ 152.9,
147.6, 131.2, 124.4, 111.4, 62.6, 45.1, 34.5, 31.1. MALDI MS,
m/z 955.2 (M + Na+).
the trimethoxy tetraxylyl derivative 13. This product (165 mg) was
dissolved in dry THF, and to the solution were added 100 mg of
NaH (60% in oil) and 0.4 g of MeI. After reflux for 30 min under
an inert atmosphere the mixture was cooled, MeOH was added to
quench the excess NaH, and the solvent was evaporated. To the
residue was added CHCl3 and brine, and the organic phase was
evaporated to yield 110 mg of crude product. After two crystal-
lizations, 47 mg of the tetraxylyl tetramethoxy derivative 14 was
obtained, ca. 95% purity, mp 270-275 °C (dec).
5,11,17,23-Tetra-tert-butyl-2,8,14,20-tetra(2-methylfuranyl)-
25,26,27,28-tetramethoxycalix[4]arene (11). A mixture of 1.0 g
of 2b (1.0 mmol), 8 mL of 1,2-butylene oxide, 1.65 g (2.01 mmol)
of 2-methylfuran in 100 mL of TFE was refluxed for 2 h to afford
a clear, bluish solution. After cooling, the solvent was partially
evaporated, and the solid that precipitated was filtered. After two
crystallizations from CHCl3/MeOH pure 11 (145 mg, 14%) was
obtained, mp 285-288 °C (dec).
1H NMR (400 MHz, CDCl3, rt) δ 7.15 (d, J ) 7.8 Hz, 4H),
7.02 (s, 4H), 6.31 (d, J ) 7.3 Hz, 4H), 6.70 (t, J ) 7.6 Hz, 2H),
6.48 (d, J ) 7.7 Hz, 4H), 6.45 (t, J ) 7.7 Hz, 2H), 6.17 (s, 4H),
6.12 (d, J ) 7.6 Hz, 4H), 4.17 (s, 6H), 3.03 (s, 6H), 2.34 (s, 12H),
2.29 (s, 12H). 13C NMR (100 MHz, CDCl3) δ 158.2, 157.1, 139.9,
137.1, 136.5, 135.6, 135.4, 131.2, 129.4, 129.0, 126.2, 125.8, 123.2,
122.2, 61.7, 60.3, 40.4, 20.9, 20.4. MALDI MS, m/z 919.9 (M +
Na+).
1H NMR (400 MHz, CDCl3, rt) δ 6.71 (s, 8H), 5.99 (s, 4H),
5.94 (d, J ) 2.5 Hz, 4H), 5.88 (d, J ) 2.5 Hz, 4H), 3.87 (s, 12H),
2.27 (s, 12H), 1.01 (s, 36H). 13C NMR (CDCl3, 100 MHz) δ 155.3,
154.3, 151.1, 144.6, 134.4, 123.7, 109.1, 105.5, 61.9, 37.8, 34.0,
31.3, 13.6. MALDI MS, m/z 1047.4 (M + Na+)
5,11,17,23-Tetra-tert-butyl-2,8,14,20-tetra(4-methylnaphthyl)-
25,26,27,28-tetramethoxycalix[4]arene (12). A mixture of 150 mg
of 11 (0.15 mmol), 0.5 mL of butylene oxide, 115 mg of
benzenediazonium-2-carboxylate hydrochloride39 (0.62 mmol) and
10 mL of dichloroethane was refluxed for 90 min. After cooling,
the clear-orange solution was evaporated to dryness. The crude
residue was recrystallized from CHCl3/MeOH to yield 110 mg (0.08
Acknowledgment. We thank Dr. Shmuel Cohen for the
crystal structure determinations. This research was supported
by the Israel Science Foundation (Grant No. 934/04).
Supporting Information Available: Crystallographic data for
6a and 6d (CIF), NMR spectra of 2a, 4, 6a, 6c, 6d, 6f, 8-12 and
14 and minimized coordinates (MM3) of the cone and partial cone
conformers of 15. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
mmol) of a mixture of Diels-Alder adducts according to the H
(39) Adams, R.; Johnson, J. R.; Wilcox, C. F., Jr. Laboratory Experiments
in Organic Chemistry, 6th ed.; Macmillan: London, 1970; p 452.
JO702474N
2606 J. Org. Chem., Vol. 73, No. 7, 2008