Formation and conformational conversion of flattened partial cone oxygen bridged calix[2]arene[2]triazines

Article abstract of DOI:10.1021/ol0710008

A stepwise fragment coupling reaction starting with substituted dichlorotriazine and resorcinol derivatives gave rise to thermodynamically favored 1,3-altemate tetraoxacalix[2]arene[2]triazines and kinetically controlled flattened partial cone tetraoxacal

Full text of DOI:10.1021/ol0710008

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2847-2850
Formation and Conformational
Conversion of Flattened Partial Cone
Oxygen Bridged Calix[2]arene[2]triazines
Qi-Qiang Wang, De-Xian Wang, Qi-Yu Zheng, and Mei-Xiang Wang*
National Laboratory for Molecular Sciences, Laboratory of Chemical Biology,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China
mxwang@iccas.ac.cn
Received April 29, 2007
ABSTRACT
A stepwise fragment coupling reaction starting with substituted dichlorotriazine and resorcinol derivatives gave rise to thermodynamically
favored 1,3-alternate tetraoxacalix[2]arene[2]triazines and kinetically controlled flattened partial cone tetraoxacalix[2]arene[2]triazines. The flattened
partial cone conformer, which was stable due to the steric effect, converted into the 1,3-alternate conformer via ether bond cleavage upon
treatment with an inorganic base.
There is a growing interest in the chemistry of heteroatom-
bridged calixaromatics.1-4 Being different from conventional
calixarenes5 in which the aromatic rings are linked by meth-
ylene units, heteroatom-bridged calixaromatics have been
shown to exihibit different structure characteristics and
unique molecular recognition properties. The nitrogen-
bridged calix[n]pyridines4d-f and their protonated macro-
cycles,4g for instance, are able to self-regulate their confor-
mation and cavity in order to achieve the strongest interaction
with guest species, because the bridging nitrogen atoms can
adopt different electronic configurations and form various
degrees of conjugation with their adjacent pyridine rings.
In 2004, we3a reported the efficient and high-yielding
synthesis of the oxygen- and/or nitrogen-bridged calix[2]-
arene[2]triazines from cyanuric chloride and various 1,3-
bisnucleophiles based on a fragment coupling strategy. By
reacting 1,3-dihydroxybenzenes with reactive 1,5-difluoro-
2,4-dinitrobenzene, Katz3b in 2005 reported a very useful
one-pot synthesis of symmetric tetraoxacalix[4]arenes. The
chemical yield was dramatically improved in comparison to
the reaction with 1,5-dichloro-2,4-dinitrobenzene.6 Since then
a number of tetraoxacalix[4]aromatics have been prepared
in either a one-pot synthesis fashion3c-j or a [3+1] fragment
coupling approach3k,l with use of activated 1,3-dihalogenated
(1) For a useful overview of heteroatom-bridged calixarenes, see: Ko¨nig,
B.; Fonseca, M. H. Eur. J. Inorg. Chem. 2000, 2303.
(2) For thiacalixarenes, see: Morohashi, N.; Narumi, F.; Iki, N.; Hattori,
T.; Miyano, S. Chem. ReV. 2006, 106, 5291.
10.1021/ol0710008 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/21/2007

aroamtic compounds. It is interesting to note that, except
for only one case,3j all of the tetraoxacalix[4]aromatics
reported to date have been shown to adopt the 1,3-alternate
conformation.3a-n To explore their applications in molecular
recognition and molecular assembly, however, it is highly
challenging and desirable to construct tetraoxacalix[4]-
aromatics of different conformations. Our ongoing project3l,4d-h
to study the functionalizations of heteroatom bridged calix-
aromatics has led us to obtain accidentally the oxygen-
bridged calix[2]arene[2]triazines of partial cone conforma-
tion. Here we report their synthesis, structure, and confor-
mational conversion into 1,3-alternate conformers.
Scheme 1. Synthesis of Functionalized
Tetraoxacalix[2]arene[2]triazine 5
Initially, we targeted the synthesis of functionalized tetra-
oxacalix[2]arene[2]triazines with hydroxyl groups attached
to the lower rim. Following our previously established
method,3a,l we prepared tetraoxacalix[2]arene[2]triazine 4
readily starting from methyl 4-benzoxy-3,5-dihydroxyben-
zoate 1 and cyanuric chloride. To obtain the desired dichloro-
dihydroxy-tetraoxacalix[2]arene[2]triazine, we tried a number
of well-established methods to remove the benzyl protecting
groups of 4. Unfortunately, no deprotection reaction was
observed. Only under conditions that used a large amount
of AlCl3 (30 equiv) in toluene did the reaction proceed to
afford 75% yield of 5, a product containing both two free
hydroxy groups at the low rim of the benzene rings and the
two p-tolyl groups of the upper rim of the triazine rings
(Scheme 1).
p-tolyl and O-benzyl groups with the intention of further
mechanistic study. As summarized in Table 1, the reaction
between 1 and 7 was strongly influenced by the base and
the solvent used. No reaction was observed when a mixture
of 1 and 7 was heated at reflux in THF or 1,4-dioxane in
the presence of DIPEA as a base. The use of acetone or
acetonitrile as a solvent gave rise to a moderate yield of
product 8a and a very small amount of a second product
8b. Interestingly, on the basis of mass spectroscopy and
microanalysis, both products 8a and 8b have identical
chemical constitutions. The combination of triethylamine as
a base and acetonitrile as a solvent led to a slight increase
of the chemical yield of product 8b. When an inorganic base
such as K2CO3 or Cs2CO3 was used, the reaction afforded
exclusively 8a in excellent yields (entries 8-10 in Table 1).
The NMR spectra of 8a and 8b (Figure 1), which showed
only marginal differences, did not give conclusive evidence
for the assignment of their structures. Fortunately, both 8a
and 8b gave high-quality single crystals which allowed us
to determine their structures unambiguously. Surprisingly,
the X-ray crystallography revealed that products 8a and 8b
are actually a pair of conformers. As illustrated in Figure 2,
compound 8a, the major product from the reaction, adopted
a 1,3-alternate conformation. However, it is worth noting
that, compared to the structure of 4 (see Figure S1 in the
Supporting Information), the introduction of two p-tolyl
groups caused the upper rim of triazine rings and the lower
rim of benzene rings to get closer, generating a cavity formed
by four benzene rings (Figure 2). In contrast to 8a, product
8b gave a flattened partial cone (u, uo, d, uo) conformation.7
To the best of our knowledge, such a flattened partial cone
Intrigued by the deprotection-arylation reaction, we
prepared tetraoxacalix[2]arene[2]triazine 8 bearing both
(3) For recent examples of oxygen-bridged calixarene derivatives, see:
(a) Wang, M.-X.; Yang, H.-B. J. Am. Chem. Soc. 2004, 126, 15412. (b)
Katz, J. L.; Feldman, M. B.; Conry, R. R. Org. Lett. 2005, 7, 91. (c) Katz,
J. L.; Selby, K. J.; Conry, R. R. Org. Lett. 2005, 7, 3505. (d) Katz, J. L.;
Geller, B. J.; Conry, R. R. Org. Lett. 2006, 8, 2755. (e) Katz, J. L.; Geller,
B. J.; Foster, P. D. Chem. Commun. 2007, 1026. (f) Maes, W.; Van Rossom,
W.; Van Hecke, K.; Van Meervelt, L.; Dehaen, W. Org. Lett. 2006, 8,
4161. (g) Hao, E.; Fronczek, F. R.; Vicente, M. G. H. J. Org. Chem. 2006,
71, 1233. (h) Yang, F.; Yan, L.-W.; Ma, K.-Y.; Yang, L.; Li, J.-H.; Chen,
L.-J.; You, J.-S. Eur. J. Org. Chem. 2006, 1109. (i) Zhang, C.; Chen, C.-F.
J. Org. Chem. 2007, 72, 3880. (j) Konishi, H.; Tanaka, K.; Teshima, Y.;
Mita, T.; Morikawa, O.; Kobayashi, K. Tetrahedron Lett. 2006, 47, 4041.
(k) Konishi, H.; Mita, T.; Morikawa, O.; Kobayashi, K. Tetrahedron Lett.
2007, 48, 3029. (l) Yang, H.-B.; Wang, D.-X.; Wang, Q.-Q.; Wang, M.-X.
J. Org. Chem. 2007, 72, 3757. (m) Chambers, R. D.; Hoskin, P. R.; Khalil,
A.; Richmond, P.; Sandford, G.; Yufit, D. S.; Howard, J. A. K. J. Fluorine
Chem. 2002, 116, 19. (n) Chambers, R. D.; Hoskin, P. R.; Kenwright, A.
R.; Khalil, A.; Richmond, P.; Sandford, G.; Yufit, D. S.; Howard, J. A. K.
Org. Biomol. Chem. 2003, 2137. (o) Li, X. H.; Upton, T. G.; Gibb, C. L.
D.; Gibb, B. C. J. Am. Chem. Soc. 2003, 125, 650.
(4) For recent examples of nitrogen-bridged calixarene derivatives, see:
(a) Ito, A.; Ono, Y.; Tanaka, K. New J. Chem. 1998, 779. (b) Ito, A.; Ono,
Y.; Tanaka, K. J. Org. Chem. 1999, 64, 8236. (c) Miyazaki; Kanbara, T.;
Yamamoto, T. Tetrahedron Lett. 2002, 43, 7945. (d) Wang, M.-X.; Zhang,
X.-H.; Zheng, Q.-Y. Angew. Chem., Int. Ed. 2004, 43, 838. (e) Gong,
H.-Y.; Zheng, Q.-Y.; Zhang, X.-H.; Wang, D.-X.; Wang, M.-X. Org. Lett.
2006, 8, 4895. (f) Gong, H.-Y.; Zhang, X.-H.; Wang, D.-X.; Ma, H.-W.;
Zheng, Q.-Y.; Wang, M.-X. Chem. Eur. J. 2007, 13, in press. (g) Gong,
H.-Y.; Zhang, X.-H.; Wang, D.-X.; Ma, H.-W.; Zheng, Q.-Y.; Wang,
M.-X. Chem. Eur. J. 2006, 12, 9262. (h) Wang, Q.-Q.; Wang, D.-X.; Ma,
H.-W.; Wang, M.-X. Org. Lett. 2006, 8, 5967. (i) Tsue, H.; Ishibashi, K.;
Takahashi, H.; Tamura, R. Org. Lett. 2005, 7, 11. (j) Fukushima, W.;
Kanbara, T.; Yamamoto, T. Synlett 2005, 19, 2931. (k) Selby, T. D.;
Blackstock, S. C. Org. Lett. 1999, 1, 2053. (l) Suzuki, Y.; Yanagi, T.;
Kanbara, T.; Yamamoto, T. Synlett 2005, 2, 263.
(5) (a) Gutsche, C. D. Calixarenes; The Royal Society of Chemistry:
Cambridge, UK, 1989. (b) Gutsche, C. D. Calixarenes ReVisited; The Royal
Society of Chemistry: Cambridge, UK, 1998.
(6) (a) Sommer, N.; Staab, H. A. Tetrahedron Lett. 1966, 2837. (b)
Lehmann, F. P. A. Tetrahedron 1974, 30, 727.
2848
Org. Lett., Vol. 9, No. 15, 2007

Table 1. Synthesis of Tetraoxacalix[2]arene[2]triazine 8a
Figure 2. X-ray structure of 8a: side views.
dicular to the plane formed by the two triazine rings (Figure
3). As indicated by the bond lengths (Figures S2 and S3,
entry
solvent
base
time
8a (%)b
17
8b (%)b
1
2
3
acetone
acetone
THF
DIPEA 53 h
DIPEA 6 days 31
DIPEA 6 days no reaction
n.d.
6
4
1,4-dioxane DIPEA 7 days no reaction
5
6
7c
8
9c
10
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DIPEA 1 day
53
3
5
14
0
0
Et3N
2 days 49
Figure 3. X-ray structure of 8b: side views.
Et3N
7 h
42
91
92
88
K2CO3
K2CO3
20 h
12 h
Cs2CO3 16 h
0
Supporting Information), the bridging oxygen atoms conju-
gated with their neighboring triazine rings rather than
benzene rings in both conformational structures 8a and 8b.
To understand the formation of different conformers from
the reaction, the mutual conversions of two isomers 8a and
8b were investigated. The 1,3-alternate tetraoxacalix[2]arene-
[2]triazine 8a was very stable, and no transformation was
effected when it was treated with either DIPEA in acetone
or K2CO3 in acetonitrile under heating. The partial cone
tetraoxacalix[2]arene[2]triazine 8b was stable too. For
example, it did not undergo change under neutral conditions
even at an elevated temperature. Only a small portion of 8b
was converted into the 1,3-alternate conformer 8a within 16
days, when 8b was heated at reflux with DIPEA in acetone.
However, heating 8b at reflux in acetonitrile in the presence
of K2CO3 (the conditions for exclusive formation of 8a from
the reaction between 1 and 7 [entries 8 and 9 in Table 1])
resulted in the complete transformation of 8b into 8a rapidly
(within 15 min). These outcomes indicated convincingly that
8a was a thermodynamically controlled product whereas 8b
was the kinetic product from the reaction of 7 with 1.
Although the exact mechanism needs more study, the
conversion of 8b into 8a likely proceeds through ether bond
scission.
a 1 (1 mmol) and 7 (1 mmol) were added at the same rate to a mixture
of an organic base (2.5 mmol) or inorganic base (1.25 mmol) in solvent.
For the reaction procedure, see the Supporting Information. b Isolated yield.
c Starting materials were mixed and heated.
structure was only noted once in a substituted tetraoxacalix-
[4]arene derivative.3j More interestingly, two triazine rings
located on the same plane and were orientated outward,
whereas the benzene rings were anti-positioned and perpen-
(7) For the nomenclature, see ref 5b, pp 41-46.
The stability of the flattened partial cone conformation in
the case of 8b is intriguing. We rationalized that the stability
most probably originates from the steric effect of the
substitutents on the aromatic rings. In other words, bulky
groups such as p-tolyl and benzyloxy prohibit the free
rotation of the benzene and triazine rings around the meta-
meta axes or through the annulus, and therefore inhibit
Figure 1. 1H NMR of 8a, 8b, 12a, and 12b in CDCl3. The insets
are expansions.
Org. Lett., Vol. 9, No. 15, 2007
2849

Table 2. Synthesis of Tetraoxacalix[2]arene[2]triazine 12a
Figure 4. X-ray structure of 12a (left) and 12b (right). The disorder
of tert-butyl groups has been omitted for clarity.
as 8b. Only under the conditions such as heating 12b with
an inorganic base in acetonitrile did a flattened partial cone
conformation convert into a 1,3-alternate conformation.
In summary, we have shown that the introduction of
sterically bulky groups on the aromatic rings in the [1+3]
fragment coupling reaction can lead to the formation of both
thermodynamically favored 1,3-alternate and kinetically
controlled flattened partial cone tetraoxacalix[2]arene[2]-
triazines. The flattened partial cone conformer, which was
very stable under neutral conditions due to the steric effect,
underwent conversion to 1,3-alternate conformer via the ether
bond cleavage upon treatment of an inorganic base. The study
of the conformation control and the molecular recognition
property of the functionalized heteroatom bridged calixaro-
matics is in progress and will be reported in due course.
entry
solvent
base
time
12a (%)b
12b (%)b
1
2
3
4
5
acetone
MeCN
MeCN
MeCN
MeCN
DIPEA
K2CO3
Cs2CO3
DIPEA
Et3N
4 days
12 h
9 h
12 h
12 h
no reaction
87
82
0
0
17
10
7
trace
a 9 (0.5 mmol), 11 (0.5 mmol), and an organic base (1.25 mmol) or
inorganic base (0.63 mmol) were used. For the reaction procedure, see the
Supporting Information. b Isolated yield.
conversion of the flattened partial cone conformation into
the 1,3-alternate conformation without breaking the ether
bond linkage. To test our hypothesis of steric effects on the
conformations, we then synthesized the tetraoxacalix[2]arene-
[2]triazines bearing tertiary butyl groups on the aromatic
rings from the reaction of 9 and 11 (Table 2). Although the
reaction yielded the thermodynamically favored 1,3-alternate
product 12a (Figure 4, left) with use of an inorganic base
(entries 2 and 3 in Table 2), the flattened partial cone
conformational product 12b (Figure 4, right) was indeed
obtained as the major product, albeit in a low yield, under
the kinetically controlled conditions (entries 4 and 5 in Table
2). Product 12b showed the same conformational stability
Acknowledgment. The project was supported by grants
from NNSFC, MOST, and CAS.
Supporting Information Available: Synthesis and char-
acterization of tetraoxacalix[2]arene[2]triazines, 1H and 13
C
NMR spectra of all new compounds, and X-ray structures
of 4, 8a, 8b, 12a, and 12b (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0710008
2850
Org. Lett., Vol. 9, No. 15, 2007