Synthesis and properties of a new member of the calixnaphthalene family: A C2-Symmetrical endo-calix[4]naphthalene

Article abstract of DOI:10.1021/jo026045v

The synthesis of a new endo-calix[4]naphthalene is described. The reaction sequence involves the cyclocondensation of a key bisnaphthylmethane intermediate (8) with formaldehyde. This key intermediate (8) is formed using a modified Suzuki-Miyaura Pd-catalyzed crosscoupling reaction between bromomethylnaphthyl (6) and naphthylboronic acid (7), both of which can be derived from 2-hydroxynaphthoic acid.

Full text of DOI:10.1021/jo026045v

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Syn th esis a n d P r op er ties of a New Mem ber
of th e Ca lixn a p h th a len e F a m ily: A
C2-Sym m etr ica l en d o-Ca lix[4]n a p h th a len e
Sultan Chowdhury and Paris E. Georghiou*
Department of Chemistry, Memorial University of
Newfoundland, St. J ohn’s, Newfoundland and Labrador
A1B 3X7, Canada
parisg@mun.ca
Received J une 11, 2002
Abstr a ct: The synthesis of a new endo-calix[4]naphthalene
is described. The reaction sequence involves the cyclocon-
densation of a key bisnaphthylmethane intermediate (8)
with formaldehyde. This key intermediate (8) is formed
using a modified Suzuki-Miyaura Pd-catalyzed cross-
coupling reaction between bromomethylnaphthyl (6) and
naphthylboronic acid (7), both of which can be derived from
2-hydroxynaphthoic acid.
F IGURE 1. Cone conformer of endo-calix[4]naphthalene (1)
as determined by molecular modeling.
route includes the use of directed ortho metalation
conditions and a modified8 Suzuki-Miyaura9 Pd-cata-
lyzed cross-coupling reaction to produce key intermedi-
ates.
Calix[n]arenes constitute an important class of com-
pounds that have been widely used as “molecular bas-
kets” in supramolecular complexation studies and in a
variety of other applications.1,2 In general, the depth of
the basket or cavity in a cone conformer of an unsubsti-
tuted calix[4]arene as measured from the phenolic oxygen
atom to the distal hydrogen atom on the para hydrogen
atom is approximately 5.3 Å. In an analogous unsubsti-
tuted endo-calix[4]naphthalene such as 1, however, the
comparable distance is 7.5 Å (Figure 1).3 Calix[4]-
naphthalenes such as 1 can therefore be thought of as
deeper and electron-richer “molecular baskets” than the
corresponding calix[4]arenes. Such calixnaphthalenes
have been shown to be capable of complexing4 with C60
and also of forming a dimer in the solid state.5
A simple retrosynthetic approach can be envisioned for
a convergent synthesis of 2 (or its derivatives) via a “2 +
2” cross-coupling of synthons such as 3 (or 3a ) with 4
and/or 4a (Scheme 1) using different metal-assisted or
catalyzed carbon-carbon bond-forming methodologies, in
particular, the modified Suzuki-Miyaura coupling reac-
tion.8,9 We have previously demonstrated that it is
possible to achieve Pd-catalyzed cross-coupling between
phenyl- or naphthylboronic acids and benzyl bromides,
iodides, or bromomethylnaphthalenes to form methylene-
bridged products in synthetically useful yields.8 However,
until now, this methodology had not been tested for the
“2 + 2” cross-coupling reactions between diboronic acids
such as 3 (or 3a ), with 4 and/or 4a , as envisioned, for
example, in Scheme 1.
To date, there have only been a few calix[n]naphtha-
lenes that have been reported.5-7 In this paper, we report
the synthesis of the newest member of the calix[4]-
naphthalene family, the C2-symmetrical endo-calix[4]-
naphthalene 2 and its alkoxy derivatives. The synthetic
Both synthons 3 (or 3a ) and 4 (or 4a ) can be derived
from the common intermediates bis(2-methoxy-3-naph-
thyl)methane (5) or its O-methoxymethyl analogue, 5a .
These latter intermediates, in turn, could be synthesized
in 89% and 79% yields, respectively, using the modified
Suzuki-Miyaura Pd-catalyzed reaction between 3-bro-
momethyl-2-methoxynaphthalene (6)5 and naphthylbo-
ronic acids 7 or 7a . To efficiently produce the correspond-
ing diboronic acid synthon 3 or 3a , however, the alkoxy
groups in 5 or 5a , respectively, needed to first be removed
(Scheme 2). This was achieved using BBr3 in CH2Cl2 to
afford 8 in 95% yield. Bromination with Br2 in acetic acid
formed 9, which was then converted to the MOM-
protected compound 9a , both steps affording near-
quantitative yields. Double ortho-lithiation using n-BuLi
(2.2 equiv) in THF at -78 °C followed by the in situ
addition of trimethyl borate and subsequent hydrolysis
furnished the desired diboronic acid synthon 3a . The
second required synthon, 4, was synthesized from 5 by
reaction with aqueous formaldehyde in HBr-acetic acid
solution in 77% yield.
(1) For a recent review, see: Gutsche, C. D. In Calixarenes 2001;
Asfari, Z., Bohmer, V., Harrowfield, J ., Vicens, J ., Eds.; Kluwer
Academic Publishers: Dordrecht, The Netherlands, 2001.
(2) Calixarenes in Action; Mandolini, L., Ungaro, R., Eds.; Imperial
College Press: London, England, 2000.
(3) Molecular modeling calculations were performed using the PC
SPARTAN Pro program from Wavefunction, Inc., Irvine, CA.
(4) Georghiou, P. E.; Mizyed, S.; Chowdhury, S. Tetrahedron Lett.
1999, 40, 611. Mizyed, S.; Georghiou, P. E.; Ashram, M. J . Chem. Soc.,
Perkin Trans. 2 2000, 277. For complexation studies of C60 with the
related hexahomotrioxacalix[3]naphthalenes, see: Mizyed, S.; Miller,
D. O.; Georghiou, P. E. J . Chem. Soc., Perkin Trans. 1 2001, 1916.
(5) Georghiou, P. E.; Ashram, M.; Clase, H. J .; Bridson, J . N. J . Org.
Chem. 1998, 63, 1819.
(6) (a) Georghiou, P. E.; Ashram, M.; Li, Z.; Chaulk, S. G. J . Org.
Chem. 1995, 60, 7284 and references therein. (b) For an earlier
reference to the synthesis of 1, see also: Andreetti, G. D.; Bo¨hmer, V.;
J ordon, J . G.; Tabatabai, M.; Ugozzoli, F.; Vogt, W.; Wolff, A. J . Org.
Chem. 1993, 58, 4023. (c) See also Ashram, M.; Mizyed, S.; Georghiou,
P. E. J . Org. Chem. 2001, 66, 1473 for references to some other
calixnaphthalenes.
(7) For examples of a recently reported different class of calixnaph-
thalene: (a) Shorthill, B. J .; Granucci, R. G.; Powell, D. R.; Glass, T.
E. J . Org. Chem. 1998, 63, 3748. (b) Shorthill, B. J .; Glass, T. E. Org.
Lett. 2000, 2, 577.
(8) Chowdhury, S.; Georghiou, P. E. Tetrahedron Lett. 1999, 40,
7599.
(9) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
10.1021/jo026045v CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/29/2002
6808
J . Org. Chem. 2002, 67, 6808-6811

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
SCHEME 1
During the course of this study, all of our attempts to
effect cross-coupling between synthons 3 (or 3a ) and 4
or 4a as envisioned in Scheme 1 using the modified
Suzuki-Miyaura conditions under various conditions
including using different halides, solvent, reaction times,
and temperatures failed to produce the desired target
product(s). The use of the Neighishi,10 or Stille,11 proce-
dure also failed to produce the desired products. It was
concluded that the di-ortho-substituted and bulkier bis-
naphthylmethyl substrates might not have been able to
adequately form an essential Pd-catalytic intermediate
required for the cross-coupling, resulting instead in
competitive deboronation.
11 or 11a in 58% and 43% yields, respectively. These are
relatively lower yields than those observed for other
products obtained using this method.8 Attempts at ef-
fecting a cyclocondensation with formaldehyde at the free
1- and 1′-positions in 11 or 11a (Scheme 3); however,
failed to produce the desired calix[4]naphthalenes 2a or
2b in any appreciable amounts, affording only resinous
products. Similarly, in an another attempt at effecting a
cyclocondensation with formaldehyde, the tetranaphthyl
product 12 obtained in 23% yield from reaction between
4 and 2-methoxy-1-naphthaleneboronic acid 13, also
failed to produce cyclized calix[4]naphthalene 2a (Scheme
3).
SCHEME 2a
SCHEME 3
a
Reagents and conditions: (i) BBr3, CH2Cl2, rt; (ii) Br2, AcOH,
rt; NaH, dry THF, MOMCl; (iv) n-BuLi (2.2 equiv), dry THF, -78
°C, B(OCH3)3, H3O+; (v) aq 30% (CH2O)n, HBr, AcOH, rt.
A modified version of Scheme 1 was evaluated using
3-methoxy-2-naphthylboronic acid (7) or 3-O-methoxy-
methyl-2-naphthylboronic acid (7a ), both of which could
be formed in high yields, using a modification of a
procedure employed by Biehl.12 Coupling of 7 (or 7a ) with
the bisnaphthyl compound 106a using our Suzuki-
Miyaura conditions formed the tetranaphthyl products
Despite the failure of the attempts described above,
calix[4]naphthalene 2 was synthesized using the bis-
naphthylmethane intermediate 8 in a different approach
(Scheme 4). The reaction of 8 using aqueous 37% form-
(10) Negishi, E.; Matsushita, H.; Okukado, N. Tetrahedron Lett.
1981, 22, 2715.
(11) Stille, J . K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434.
(12) Biehl, E. R.; Deshmukh, A. R.; Dutta, M. Synthesis 1993, 885.
J . Org. Chem, Vol. 67, No. 19, 2002 6809

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
SCHEME 4
F IGURE 2. 1H NMR spectrum of 14a showing the splitting
patterns of the methylene bridge protons linking the four
naphthalene units and also of the diastereotopic methylene
protons of the butyloxy groups, which are R to the ether oxygen
atoms.
aldehyde in ethanol-dioxane and concentrated HCl
afforded a brown, sparingly soluble, solid crude product
in 81% yield. This product could not be easily purified
since it was found to be insoluble in all but DMF,
pyridine, or DMSO. Two singlets at δ 4.61 and 5.19 in
constants of J ) 12.9, 15.2, 12.9, and 15.2 Hz, respectively
(and correlated by COSY), are due to the protons of the
methylene bridges linking the four naphthalene units.
Two sets of overlapped multiplets appear at δ 4.03-4.07
and 4.11-4.16 ppm, revealing the diastereotopicity of the
methylene protons of the n-butyl groups R to the oxygen
atoms (Figure 2).
NOED measurements on 14a also confirmed that the
molecule is in a “pinched” or “flattened” cone (see Figure
3): saturation of the methylene signals at δ 3.67 en-
hanced the signals at δ 4.73, 7.08, and 7.36 by 14%, 3%,
and 7%, respectively, and saturation of the signal at δ
4.90 enhanced the signals at δ 4.50 and 8.48 by 18% and
12%, respectively. The 13C NMR spectrum is in good
agreement with the structure proposed; in particular, the
two signals at δ 21.9 and 32.2 due to the two groups of
equivalent methylene bridge carbons confirm that the
butyl groups are distal to each other.
1
its H NMR (pyridine-d5) were indicative of the presence
of two methylene groups in a cyclized product, however,
and a (+)-FAB MS showed the presence of the expected
molecular ion peak at m/z ) 624. Initial experiments
aimed at purifying this product involved conversion to
the chromatographically separable alkoxy ethers (Scheme
4). The low yields of the alkoxy products that could be
isolated and characterized as described below indicated
that 2 was only present in minor amounts in the acid-
mediated formaldehyde cyclocondensation crude product.
However, after these alkylation reactions were conducted
and established unequivocally that 2 was indeed formed
and could be characterized, pure 2 was obtained as a
brown solid, in 54% yield, from the base-induced con-
densation reaction of 8 with 2 molar equiv of aqueous
37% formaldehyde solution in boiling DMF for 48 h. A
stoichiometric amount of Cs2CO3 was employed as the
base (Scheme 4). The 1H NMR spectrum of 2 in pyridine-
d5 showed the same two signals at δ 4.61 and 5.19, which
were seen in the crude product derived earlier using the
acidic conditions. HETCOR NMR clearly revealed signals
at δ 23.3 and 34.4 that correspond to the methylene
carbons and are correlated with the proton signals at δ
4.61 and 5.19, respectively. The molecular mass of the
assigned structure 2 was also confirmed by CI MS
Di-n-propyl and diisopropyl ethers 14b and 14c, re-
spectively, were obtained in a similar manner from the
crude product (crude calix[4]naphthalene 2): 1,3-di-O-
propylcalix[4]naphthalene 14b was obtained in 4% yield
with 1-iodopropane, and 1,3-di-O-isopropylcalix[4]naph-
thalene 14c was obtained in 6% yield with 2-iodopropane.
The structures of 14b and 14c were confirmed on the
1
basis of their H NMR spectra, which are similar to that
analysis showing the expected molecular ion peak M+
1 at m/z ) 625.
+
of 14a , also demonstrating similar diastereotopicity of
the protons on the alkoxy group carbon atoms, which are
R to the oxygen atoms. Similarly, 1,3-di-O-ethyl ether 14d
was also obtained in 8% yield from the crude calix[4]-
Alkylation of the crude calix[4]naphthalene 2, de-
scribed above (“crude product”), with various 1-alkyl
halides under basic conditions afforded products that
could now be chromatographically purified. With 1-bro-
mobutane, the linear hexanaphthyl-formaldehyde con-
densation product 14 was isolated in 18% yield. The only
other component that could be isolated was 1,3-di-O-n-
butyloxycalix[4]naphthalene 14a in 3% yield. (+)-FAB
MS showed the expected molecular ion peak at m/z )
1
naphthalene 2 with 1-iodoethane. Its H NMR spectrum
in CDCl3 was similar to those of the other ethers;
however, with 14d , suitable crystals for X-ray crystal-
lography were obtained. The X-ray crystal structure
(Figure 3) clearly showed that the two naphthalene units
bearing the ethyl groups are nearly parallel to each other,
while the other two naphthalene units are pushed
outward to give a “pinched cone” (or flattened cone)
1
736, and its H NMR spectrum clearly indicates it to be
1
conformationally fixed. The four sets of doublets centered
conformation, predicted by the H NMR analysis. Fur-
at δ 3.67, 4.50, 4.73, and 4.90 having geminal coupling
thermore, the crystal structure also reveals the presence
6810 J . Org. Chem., Vol. 67, No. 19, 2002

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
F IGURE 3. Stereoview of single-crystal X-ray structure of clathrate of 14d showing a “pinched cone” conformation with two
molecules of toluene in the cavity.
formaldehyde solution (0.79 mL, 28.6 mmol) followed by con-
centrated HCl (0.72 mL, 8.6 mmol) at rt under argon. The brown
solution was stirred at rt for 24 h, during which time a brown
precipitate formed. The solid was filtered off, washed several
times with water and finally with dioxane to remove any
unreacted starting material, and dried under vacuum to afford
a brown solid “crude product 2” (0.73 g, 81%). The solid could
not be purified due to its poor solubility and was used directly
for the alkylation reactions described in Scheme 4.
(b) Ba sic Con d ition s. To a solution of bis(2-hydroxy-3-
naphthyl)methane (8) (0.48 g, 1.6 mmol) in anhydrous DMF (50
mL) were added aqueous 37% formaldehyde (0.080 mL, 2.8
mmol) and Cs2CO3 (0.52 g, 1.6 mmol) in H2O (1.0 mL). The
yellow solution was heated at reflux for 48 h and cooled to rt,
and the solvent was evaporated under reduced pressure. The
residue was redissolved in CH2Cl2, washed with aqueous 10%
HCl, and dried over MgSO4. After the solvent was evaporated,
the product (0.45 g) was purified by flash column chromatog-
raphy over silica gel, eluting with ethyl acetate-hexane 20:80
to recover 30 mg of the pure product. After further the column
was further eluted with CHCl3, a light brown solid (0.32 g) was
obtained that showed the presence of two spots on TLC. The
solid was washed several times with CHCl3 to afford 2 as a
colorless solid (0.276 g, 54%): mp >360 °C; 1H NMR (500 MHz,
pyridine-d5) δ 4.61 (s, 4H), 5.19 (s, 4H), 7.04 (t, J ) 7.4 Hz, 4H),
7.26 (t, J ) 7.4 Hz, 4H), 7.47 (d, J ) 7.9 Hz, 4H), 7.71 (s, 4H),
8.45 (br, 4H, OH), 8.49 (d, J ) 8.6 Hz, 4H); 13C (125 MHz,
pyridine-d5) δ 23.3, 34.3, 120.2, 122.7, 126.0, 129.0, 129.7, 133.2,
133.9, 135.5, 136.3, 155.0; MS m/z 625 (M+ + 1, 8), 624 (M+,
17), 606 (10), 588 (5), 437 (4), 325 (35), 312 (M/2, 100), 300 (23),
281 (8); HRMS M+ 624.2352, calcd for C44H32O4 624.2300.
of two toluene molecules situated within the cavity and
is therefore a 1:2 host-guest clathrate having C2 sym-
metry.13 The methyl groups of each of the two toluene
guest molecules suggest the presence of π-CH3 interac-
tions with the distal naphthalene units on which the
ethoxy groups are located. Formation of a clathrate with
two molecules of toluene appears to be unique to this
endo-calix[4]naphthalene system. In one of the earliest
X-ray structures determined of calix[4]arene, a single
toluene molecule only was contained within the cavity
of the calixarene,14 and in general, solvent molecule-
containing clathrates formed from various derivatives of
tert-butylcalix[4]arene are usually 1:1 complexes.
Although “2 + 2” cross-coupling of 3 (or 3a ) with 4 and/
or 4a using the modified Suzuki-Miyaura coupling
reaction conditions failed to produce 2 or 2a , the impor-
tant intermediates 5 and 5a were synthesized in high
yields using this procedure. The C2-symmetrical endo-
calix[4]naphthalene (2) and was synthesized using 8,
which was derived from 5 and 5a . The alkoxy derivatives
14a -d were synthesized from 2, and their structures
were confirmed by NMR studies. X-ray crystallography
of 14d confirmed its conformation in the solid state,
which was consistent also with its conformation in
solution.
Exp er im en ta l Section
Ack n ow led gm en t. This work was supported by
NSERC and Memorial University of Newfoundland. We
thank Dr. Bob McDonald, University of Alberta, for the
X-ray data collection and Mr. David O. Miller of the
X-ray Crystallographic Unit, Memorial University of
Newfoundland.
6H,14H,22H,30H-5,31:7,13:15,21:23,29-Tetr a m eth en otet-
r a ben zo[a ,f,m ,r ]cyclotetr a cosen e-33,34,35,36-tetr ol (en d o-
Ca lix[4]n a p h th a len e) (2). (a ) Acid ic Con d ition s. To a
solution of bis(2-hydroxy-3-naphthyl)methane (8) (0.86 g, 2.86
mmol) in dioxane/ethanol(1:2, 60 mL) was added aqueous 37%
(13) Atomic coordinates for 14d have been deposited with the
Cambridge Crystallographic Centre. The coordinates can be obtained
from the Director, Cambridge Crystallographic Centre, 12 Union Road,
Cambridge, CB2 1EZ, U.K.
(14) Andreetti, G. D.; Ugozzoli, F.; Ungaro, R.; Pochini, A. In
Inclusion Compounds; Atwood, J . L., Davies, J . E. D., MacNicol, D.
D., Eds.; Oxford University Press: Oxford, 1991; Vol. 4, p 64 and
references therein.
Su p p or tin g In for m a tion Ava ila ble: Experimental condi-
tions for the synthesis of compounds 4-14a -d and the 1H and
13C NMR spectra of all of the new compounds reported herein.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O026045V
J . Org. Chem, Vol. 67, No. 19, 2002 6811