Synthesis of tetraazacalix[2]arene[2]-triazines: Tuning the cavity by the substituents on the bridging nitrogen atoms

Article abstract of DOI:10.1021/ol062441e

(Chemical Equation Presented) A number of tetraazacalix[2]arene[2]triazines bearing different substituents on the bridging nitrogen atoms were synthesized efficiently using a fragment coupling strategy. The N-arylation of the parent azacalix[2]arene[2]tri

Full text of DOI:10.1021/ol062441e

ORGANIC
LETTERS
2006
Vol. 8, No. 26
5967-5970
Synthesis of Tetraazacalix[2]arene[2]-
triazines: Tuning the Cavity by the
Substituents on the Bridging Nitrogen
Atoms
Qi-Qiang Wang, De-Xian Wang, Hong-Wei Ma, and Mei-Xiang Wang*
Beijing National Laboratory for Molecular Sciences, Laboratory of Chemical Biology,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China
mxwang@iccas.ac.cn
Received October 4, 2006
ABSTRACT
A number of tetraazacalix[2]arene[2]triazines bearing different substituents on the bridging nitrogen atoms were synthesized efficiently using
a fragment coupling strategy. The N-arylation of the parent azacalix[2]arene[2]triazine afforded tetra(arylaza)calix[2]arene[2]triazine in 91%
yield. The introduction of different substituents on the bridging positions led to the regulation of the cavity of the resulting macrocyclic
molecules.
There is an increasing interest in heteroatom-bridged
calix(hetero)aromatics.1-4 Compared with calixarenes and
calixheteroarenes such as calixpyrroles,5 calixpyridines,6 and
other calixaromatics7 in which the (hetero)arene units are
linked by methylenes, introduction of heteroatoms into the
bridging positions would lead to a wide variety of macro-
cyclic molecules. Because of the electronic nature of
(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: (a) Kumagai, H.; Hasegawa, M.; Miyanari,
S.; Sugawa, Y.; Sato, Y.; Hori, T.; Ueda, S.; Kamiyama, H.; Miyano, S.
Tetrahedron Lett. 1997, 38, 3971. (b) Iki, H.; Kabuto, C.; Fukushima, T.;
Kumagai, H.; Takeya, H.; Miyanari, S.; Miyashi, T.; Miyano, S. Tetrahedron
2000, 56, 1437. (c) Akdas, H.; Bringel, L.; Graf, E.; Hosseini, M. W.; Mislin,
G.; Pansanel, J.; De Cian, A.; Fischer, J. Tetrahedron Lett. 1998, 39, 2311.
(d) Lhotak, P. Eur. J. Org. Chem. 2004, 1675.
(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) Maes, W.; Van
Rossom, W.; Van Hecke, K.; Van Meervelt, L.; Dehaen, W. Org. Lett.
2006, 8, 4161. (f) Hao, E.; Fronczek, F. R.; Vicente, M. G. H. J. Org.
Chem. 2006, 71, 1233. (g) 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. (h) 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. (i) Li, X. H.; Upton, T. G.; Gibb, C. L. D.; Gibb, B.
C. J. Am. Chem. Soc. 2003, 125, 650. (j) 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.
(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.; Zhang, X.-H.; Wang, D.-X.; Ma, H.-W.; Zheng, Q.-Y.; Wang, M.-X.
Chem.-Eur. J. 2006, 12, in press. (f) Gong, H.-Y.; Zheng, Q.-Y.; Zhang,
X.-H.; Wang, D.-X.; Wang, M.-X. Org. Lett. 2006, 8, 4895. (g) Tsue, H.;
Ishibashi, K.; Takahashi, H.; Tamura, R. Org. Lett. 2005, 7, 11. (h)
Fukushima, W.; Kanbara, T.; Yamamoto, T. Synlett 2005, 19, 2931. (i)
Selby, T. D.; Blackstock, S. C. Org. Lett. 1999, 1, 2053. (j) Suzuki, Y.;
Yanagi, T.; Kanbara, T.; Yamamoto, T. Synlett 2005, 2, 263.
(5) For reviews of calixpyrroles, see: (a) Gale, P. A.; Anzenbacher, P.;
Sessler, J. L. Coord. Chem. ReV. 2001, 222, 57. (b) Sliwa, W. Heterocycles
2002, 57, 169.
(6) (a) Kra´l, V.; Gale, P. A.; Anzenbacher, P.; Jursikova´, K.; Lynch, V.;
Sessler, J. L. Chem. Commun. 1998, 9. (b) Sessler, J. L.; Cho, W.-S.; Lynch,
V.; Kra´l, V. Chem.-Eur. J. 2002, 8, 1134. (c) Newkome, G. R.; Joo, Y. J.;
Fronczek, F. R. J. Chem. Soc., Chem. Commun. 1987, 854.
10.1021/ol062441e CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/21/2006

heteroatoms which is different from that of carbon, the
heteroatom-bridged calix(hetero)aromatics exhibit interesting
structure and molecular recognition properties.1-4 For ex-
ample, we3a,4d-f have shown that, due to the intrinsic nature
of nitrogen which can adopt sp2 and/or sp3 electronic
configurations to form or not to form conjugation with its
adjacent aromatic rings, azacalix[n]pyridines and azacalix-
[m]arene[n]pyridines are able to preorganize into different
conformational and cavity structures to interact with metal
ions,4f anions,4e fullerenes,4d,e and other small neutral mol-
ecules.
Scheme 1. Synthesis of Linear Trimers
The control of conformational structures, particularly the
fine-tuning of the cavity size of the macrocyclic rings, is
essential for the design of tailor-made host molecules. We3a
have previously shown that the cavity of oxygen- and/or
nitrogen-bridged calix[2]arene[2]triazines, which ranges from
4.724 to 6.928 Å, was determined by the combined effect
of bridging oxygen and nitrogen atoms. We envisioned that
the presence of the different substituents on the bridging
nitrogen atoms would lead to the tuning of the cavity of the
calix[2]arene[2]triazines because the electronic and steric
effects of different substituents might perturbate the elec-
tronic configuration and conjugation states of the bridging
nitrogen atoms. We report herein the highly efficient
synthesis of various bridge-N-substituted calix[2]arene[2]-
triazines and the regulation of their cavity through the
introduction of different numbers of aliphatic and/or aromatic
groups on the bridging nitrogen atoms.
phenylenediamine and 3a-c was facilitated at an elevated
temperature to produce tetraazacalix[2]arene[2]triazines in
good yields (Table 1). Intramolecular cyclization of the linear
intermediates 6bb and 6bc in refluxing acetone led to the
formation of macrocyclic molecules 5bb and 5bc efficiently
(Scheme 3). It was noticeable that N,N′-di(p-methoxyphenyl)-
1,3-phenylenediamine did not interact with intermediates 3,
and no reaction at all was observed even under more forceful
conditions (Table 1).
The results summarized in Table 1 provided us with the
guidelines to construct calix[2]arene[2]triazines from the
macrocyclic coupling reaction between the linear trimer and
To synthesize tetraazacalix[2]arene[2]triazines bearing the
desired substituents on the bridging nitrogen atoms, the
condensation reaction of 1,3-phenylenediamine derivatives
1 with cyanuric acid chloride was first performed. In the
presence of di(isopropyl)ethylamine, diamines 1 reacted with
2 equiv of cyanuric acid chloride 2 at 0 °C to give
intermediates 3a-c in good yields (Scheme 1). Macrocyclic
coupling reaction of 3a-c with 1,3-phenylenediamine pro-
ceeded smoothly at ambient temperature to furnish the
corresponding tetraazacalix[2]arene[2]triazines 5aa-ac
(Scheme 2) in the yield of 43-61%. The reaction time was
shortened and the chemical yields were improved when the
reaction was carried out in refluxing acetone (Table 1). At
room temperature, the reaction between 3a-c and N,N′-
dibenzyl-1,3-phenylenediamine was very slow. For example,
it took 3 days for N,N′-dibenzyl-1,3-phenylenediamine to
react with 3a to form 5ab in 13% yield, whereas the reaction
with 3b or 3c at room temperature gave mainly the linear
products 6bb and 7bb or 6bc and 7bc, respectively. The
macrocyclic coupling reaction between N,N′-dibenzyl-1,3-
Scheme 2. Synthesis of Azacalix[2]arene[2]triazines
(7) For recent examples, see: (a) Guillard, J.; Meth-Cohn, O.; Rees, C.
W.; White, A. J. P.; Williams, D. J. Chem. Commun. 2002, 232. (b) Vogel,
E.; Pohl, M.; Herrmann, A.; Wiss, T.; Ko¨nig, C.; Lex, J.; Gross, M.;
Gisselbrecht, J. P. Angew. Chem., Int. Ed. Engl. 1996, 35, 1520. (c) St, C.;
Black, D.; Craig, D. C.; Rezaie, R. Chem. Commun. 2002, 810. (d) Sessler,
J. L.; Cho, W.-S.; Lynch, V.; Kra´l, V. Chem.-Eur. J. 2002, 8, 1134. (e)
Cafeo, G.; Kohnke, F. H.; La Torre, G. L.; White, A. J. P.; Williams, D. J.
Angew. Chem.. Int. Ed. 2000, 39, 1496. (f) Cafeo, G.; Kohnke, F. H.; La
Torre, G. L.; Parisi, M. F.; Nascone, R. P.; White, A. J. P.; Williams, D. J.
Chem.-Eur. J. 2002, 8, 3148. (g) Cafeo, G.; Garozzo, D.; Kohnke, F. H.;
Pappalardo, S.; Parisi, M. F.; Nascone, R. P.; Williams, D. J. Tetrahedron
2004, 60, 1895. (h) Kumar, S.; Paul, D.; Singh, H. AdV. Heterocycl. Chem.
2005, 89, 65.
5968
Org. Lett., Vol. 8, No. 26, 2006

Scheme 4. Synthesis of Fully N-Arylated
Table 1. Synthesis of Tetraazacalix[2]arene[2]triazines 5
Calix[2]arene[2]triazine
entry
3
R
4
R1
temp
timed
5 (%)
6 (%)
1
2
3
4
5
6
7
3a
3b Bn
3b Bn
3c PMP 4a
3c PMP 4a
H
4a
4a
4a
H
rt
rt
8 + 48 h
5 + 41 h
5aa (58)
5ab (61)
5ab (82)
5ac (43)
5ac (54)
5ab (13)
5ab (70)
-
-
-
-
-
-
-
-
H
H
H
H
reflux 5 + 31 h
rt 5 + 43 h
reflux 5 + 72 h
rt 5 + 72 h
reflux 5 + 58 h
rt 8 + 81 h
reflux 7 + 90 h
3a
3a
H
H
4b Bn
4b Bn
4b Bn
4b Bn
8a 3b Bn
6bb (46)
9b 3b Bn
5bb (60) 6bb (3)
- 6bc (68)
10
11c
12
13
14
15
3c PMP 4b Bn
3c PMP 4b Bn
3c PMP 4b Bn
3a
3b Bn
rt
rt
2 + 94 h
5 + 9 days 5bc (26) 6bc (26)
reflux 4 + 80 h
5bc (67)
-
-
-
-
H
4c PMP reflux 6 days
4c PMP reflux 11 days
-
-
-
3c PMP 4c PMP reflux 10 days
a 7bb was obtained in 23% yield. b 7bb was obtained in 22% yield. c 7bc
was obtained in 27% yield. d The period of mixing reactants + reaction
time.
1,3-phenylenediamine derivatives. The less sterically hin-
dered and more nucleophilic diamines including phenylene-
diamine and N,N′-dibenzylphenylenediamine are reactive
toward all linear trimers, whereas the more sterically hindered
and less nucleophilic diamines such as N,N′-di(p-methoxy-
phenyl)phenylenediamine are inert. For the preparation of
calix[2]arene[2]triazines having two different N-substituents,
it is apparently advantageous to couple diamines bearing two
smaller substituents on amino with the trimers that are
N-substituted with two larger groups. Higher reaction tem-
perature is beneficial to effect cyclization.
depicted in Figures 1 and 2 and Supporting Information
Figures S1-S3, showed that they adopted a 1,3-alternate
conformation with two benzene rings in a face-to-face
position and two triazine rings in an edge-to-edge orientation.
Four bridging nitrogen atoms sat nearly on the same plane.
The bond lengths and bond angles of the bridging nitrogen
Scheme 3. Cyclization of 6
To synthesize tetra(arylaza)calix[2]arene[2]triazine, an
alternative approach was employed starting with parent
macrocyclic ring compound 5aa. The chloro substituents on
the triazine rings of 5aa were first replaced by two di-
methylamino groups. The resulting compound 8 was ef-
ficiently N-arylated by 4-iodoanisole in the presence of CuI
and NaH at 130 °C to afford the desired calix[2]arene[2]-
triazine 9 with four p-methoxyphenyl (PMP) moieties on the
bridging nitrogens in an excellent yield (Scheme 4).
All macrocyclic compounds, which were characterized
with spectroscopic data and microanalysis, were in crystalline
form, and they easily gave X-ray quality single crystals. The
molecular structures of 5 and 9 in the solid state, which are
Figure 1. X-ray structure of 5ab: top and side views.
Org. Lett., Vol. 8, No. 26, 2006
5969

the substituents on the bridging positions. As tabulated in
Table 2, dupper benzene values varied from 3.514 to 7.392 Å
Table 2. Cavity of Azacalix[2]arene[2]triazinesa
dupper
dlower
dupper
dlower
5
substituent
R ) R1 ) H
benzene
benzene
triazine
triazine
5aa
5ab
5acb
5acb
5bb
5bc
9
7.392
5.993
6.763
7.245
4.031
4.269
3.514
4.217
4.404
4.480
4.366
4.650
4.572
4.776
9.050
9.474
9.690
9.483
9.344
9.863
9.621
4.632
4.727
4.684
4.678
4.816
5.095
4.830
R ) Bn, R1 ) H
R ) PMP, R1 ) H
R ) PMP, R1 ) H
R ) R1 ) Bn
R ) PMP, R1 ) Bn
R ) R1 ) PMP
a The distances were given in Å. b Two discrete molecules of slightly
different cavity sizes crystallized in the solid state.
depending on both the number and the nature of the
N-substituents. For example, the cavity decreased in the order
of 5aa (7.392 Å), 5ac (7.245, 6.763 Å), 5ab (5.993 Å), 5bc
(4.269 Å), 5bb (4.031 Å), and 9 (3.514 Å) with an increase
of the number and bulkiness of the substituents.
In summary, we have shown an efficient fragment
coupling approach for the synthesis of calix[2]arene[2]-
triazines bearing different N-substituents. The cross-coupling
reaction of tetraazacalix[2]arene[2]triazine with aryl iodide
afforded fully N-arylated azacalix[2]arene[2]triazine in ex-
cellent yield. The synthetic methods are useful for the
functionalization of calix[2]arene[2]triazines on the bridging
positions. We have also demonstrated that by introducing
different numbers and different substituents on the bridging
nitrogen atoms the cavity of the resulting macrocyclic
molecules can be regulated. This might open a new avenue
to the tailor-made cavity host molecules.
Figure 2. X-ray structure of 9: top and side views.
atoms indicated that four linking nitrogen atoms adopted an
sp2 configuration, and each of them formed a conjugation
with their neighboring triazine ring. The cavity of calix[2]-
arene[2]triazines can be viewed as resulting from cyclic
arrangement of two isolated benzene units and two diamino-
conjugated triazine segments in an alternate fashion. It is
very interesting to note that the cavity or the cleft size of
the molecule, defined by the distance between two benzene
rings at the upper rim (dupper benzene) (Figure 1), is tuned by
Acknowledgment. The project was supported by the
grants from NNSFC, MOST, and CAS.
1
Supporting Information Available: H NMR spectra and
X-ray structures of 5 and 9 (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL062441E
5970
Org. Lett., Vol. 8, No. 26, 2006