Synthesis of aza-bridged calix(4-methoxy)triazines toward flattened π-conjugated macrocycles

Article abstract of DOI:10.3987/COM-08-S(D)24

Calixtriazines containing a 4-alkoxy-1,3,5-triazine backbone were efficiently synthesized by sequential fragment coupling started from 4-alkoxy-2,6-dichrolo-1,3,5-triazine. These macrocycles tend to form flattened conformations, leading to a stable π-conjugated system, presumably due to the electronic features of the alkoxy-substituent on the triazine rings.

Full text of DOI:10.3987/COM-08-S(D)24

HETEROCYCLES, Vol. 79, 2009
609
HETEROCYCLES, Vol. 79, 2009, pp. 609 - 616. © The Japan Institute of Heterocyclic Chemistry
Received, 17th September, 2008, Accepted, 27th November, 2008, Published online, 1st December, 2008.
DOI: 10.3987/COM-08-S(D)24
SYNTHESIS OF AZA-BRIDGED CALIX(4-METHOXY)TRIAZINES
TOWARD FLATTENED π-CONJUGATED MACROCYCLES
Hiroyuki Tanaka,1 Ayako Wada,2 Motoo Shiro,4 Kazuhito Hioki,2,3 Daiki
Morisaki,1 and Munetaka Kunishima1,3*
1Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and
Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192,
2
Japan. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3
Minatojima Chuo-ku, Kobe 655-8586, Japan. 3Life Science Center, Kobe Gakuin
University, 1-1-3 Minatojima Chuo-ku, Kobe 655-8586, Japan. 4Rigaku
Corporation, 3-9-12 Matsubara, Akishima, Tokyo 196-8666, Japan. E-mail:
kunisima@p.kanazawa-u.ac.jp
Abstract – Calixtriazines containing a 4-alkoxy-1,3,5-triazine backbone were
efficiently synthesized by sequential fragment coupling started from
4-alkoxy-2,6-dichrolo-1,3,5-triazine. These macrocycles tend to form flattened
conformations, leading to a stable π-conjugated system, presumably due to the
electronic features of the alkoxy-substituent on the triazine rings.
INTRODUCTION
Calixarenes are metacyclophane-type cyclic oligomers formed by condensation between formaldehyde
and phenol. They present a unique cavity depending on their specific conformations (cone, partial cone,
and alternates), which recognizes various guests in specific ways.1 To improve selectivity for the wide
variety of guests, an array of calixarene analogues have been developed in supramolecular chemistry. In
the process of evolution, calixfurans,2 calixpyrrols,3 calixindoles,4 and calixpyridines,5 which consist of
heteroaromatics instead of phenols, and aza-,6 oxo-,7 and thia-8 calixarenes, in which the carbon linkage
between aromatic rings are replaced by heteroatoms, have been synthesized.
1,3,5-Triazines have been thoroughly studied and have resulted in extensive applications as
pharmaceuticals, polymers, and other chemicals. Recent applications include proton acceptors9 and metal
ligands10 that act as building blocks in the field of supramolecular chemistry and condensation reagents
for organic synthesis.11,12

610
HETEROCYCLES, Vol. 79, 2009
In terms of the synthesis of the calixtriazines, which consisted of 1,3,5-triazines as aromatic backbones,
thiacalix[3]triazine 113 (in 1966) and azacalix[2]arene[2]triazines 2, 314 (in 1973) were initially reported.
However these macrocycles received little attention over the course of two decades despite the electronic
feature of π-acidic aromatics, and aromatic nitrogen, which acts as a donor for metal ions and hydrogen
bonding as melamine derivatives.15 Recently, investigation has begun on the synthesis and binding
activities of the oxo- or aza-oxo-mixed bridged calix[2]arene[2]triazines16 and the other macrocycles
containing 1,3,5-triazines.17 We report here the preparation of a variety of azacalixtriazines 4-6 based on
the use of 4-methoxy-1,3,5-triazines as a building block, wherein co-planarity between the adjacent
triazine and phenyl group, lead to an interconversion to more stable π-conjugated macrocycle.
H
N
N
OMe
Ph
N
HN
NH
Y
Y
N
N
N
N
N
N
N
N
N
N
X
N
N
X
NH
HN
N
S
N
S
N
MeO
N
N
N
N
HN
NH
H
N
N
HN
NH
Ph
S
Ph
2: X = Cl, Y = CH
N
N
OMe
1
3: X = NR1R2, Y = CH
4: X = OMe, Y = CH
5: X = OMe, Y = N
6
Figure 1. Various types of calixtriazines. R1 and R2 indicate alkyl groups or hydrogen.
RESULTS AND DISCUSSION
The synthesis of 4-alkylamino calixtriazines 3 was carried out by the SNAr reaction of calixtriazine 2 with
primary or secondary amines under basic conditions.14,16a,16b Although calix[2]arene[2](4-methoxy)triazine
4 seems to be readily obtained by the substitutions of 2 with methanol under basic conditions, the reaction
cannot proceed because of the lower nucleophilicity of alcohols compared with that of amines.16c We
successfully achieved the synthesis of azacalix(4-methoxy)triazines 4-6 by the macrocyclization based on
the sequential SNAr reaction of 2,6-dichrolo-4-methoxytriazine (7) (Scheme 1).18
Mono methoxy substituted triazine 7 was selectively and quantitatively obtained by the treatment of
cyanuric chloride with methanol at 0 ˚C. Of the 4-arene derivatives, acyclic trimer 9 was initially
synthesized from 1,3-phenylenediamine (8) and two equivalent of 7 by the SNAr reaction at ambient
temperature (98% yield); then azacalix[2]arene[2](4-methoxy)triazines 4 were obtained in 68% yield by
heating a 1:1 mixture of 8 and the trimer 9 at 100 ˚C for 72 hrs in a sealed tube. The synthesis of
calix[2]pyridine[2](4-methoxy)triazine 5 was carried out the same way as that of 4 except for the use of
2,6-diaminopyridine (10) and a trimer 11 instead of 8 and 9, respectively. The lower nucleophilicity of
pyridylamine, however, caused longer reaction time (48 h) and reduction in yield (65%). To make

HETEROCYCLES, Vol. 79, 2009
611
Cl
N
Cl
Cl
N
Cl
a
b
2
4
N
N
N
N
Cl
OMe
cyanuric chloride
7
H
N
H
N
Cl
N
N
Cl
H3N
NH2
d
c
7 (2 eq.)
4
N
N
N
N
OMe
OMe
8 (1 eq.)
9
H
N
H
N
Cl
N
N
N
Cl
H2N
N
NH2
e
7 (2 eq.)
N
N
N
N
OMe
OMe
10 (1 eq.)
11
H
N
H
N
H
N
Cl
N
N
N
N
NH2
f
5
N
N
N
N
OMe
OMe
NH2
12
H
N
H
N
H2N
N
g
h
7
(1 eq.)
8 (2 eq.)
N
N
OMe
13
H
N
N
N
OMe
N
OMe
HN
N
N
N
NH
HN
N
N
MeO
NH
HN
N
N
MeO
NH
N
N
H
N
H
N
H
N
N
N
NH
HN
N
N
OMe
N
N
OMe
14
6
Scheme 1. Synthesis of aza-calix(4-methoxy)triazines 4-6. (a) MeOH, iPr2NEt, reflux; (b) MeOH,
NaHCO3, H2O, 0 °C, 2.5 h, 98%; (c) iPr2NEt, THF, rt, 50 min, 98%; (d) 8, iPr2NEt, THF, 100 °C, 72 h,
68%; (e) iPr2NEt, THF, rt, 48 h, 65%; (f) 10, iPr2NEt, THF, 130 °C, 120 h, (g) iPr2NEt, THF, 60 °C, 48 h,
55%; (h) 9, iPr2NEt, THF, 100 °C, 72 h, 57%.
matters worse, only a small amount (less than 7%) of calixpyridyltriazine 5 was obtained as a mixture
with acyclic tetramer 12 (determined by ESI-MS and 1H-NMR; data not shown) despite longer reaction
time at higher temperature (130 ˚C, 120 h).
Toward the synthesis of aza-calix[3]arene[3](4-methoxy)triazine 6, bis-phenylenediamine inverse trimer
13 was prepared by substitution of 7 with two equivalents of 8 at 60 ˚C for 48 h. Even for a large

612
HETEROCYCLES, Vol. 79, 2009
macrocycle, cyclocoupling between the trimers 11 and 13 produced a satisfactory high yield (57%) under
the same conditions as those employed for 4. Surprisingly, in the NMR spectrum of the obtained
macrocycle, there were two pairs of dissymmetrical NH groups and aromatic protons equally separated.
This spectrum suggested three pairs of adjacent triazine-phenol rings in 6 were converted to π-conjugated
isomer, which led to a more stable conjugated macrocycle 14. Thermal interconversion between 14 and 6
was not observed at temperatures up to 100 ˚C in DMSO-d6 on an NMR analysis. Since this type of
conjugation was not observed on either calix[2]arene[2]triazines 2-4 or aza-calix[3]arene[3](4-
alkylamino)triazines,17c this isomerization probably arose not only from the larger ring size of the 6-arene
compared to that of the 4-arenes, which allows it to form the conjugated structure without increase in the
ring strain, but also from an electronic feature of the alkoxy group at the 4-position of 1,3,5-triazine rings.
In solid state, 4 forms 1,3-altanate in a relatively flattened conformation as compared with 4-chloro or
4-amino calixtriazines (Figure 2 and Table 1).16a,19 In the crystal structure, hydrogen bonding between
oxygen in THF and hydrogen of the bridged NH groups was observed (distances between O3-N13 is 2.98
Å, and O4-N8 is 2.89 Å in Figure 2). By contrast, an absolutely flat conformation of the macrocycle 14
was observed in the crystallographic structure, which supports the existence of a π-conjugated
macrocycle as noted above (Figure 3).20 Regardless of the flat conjugated system of 14, neither stacking
between calixtriazines nor a layered structure was observed since solvent molecules (acetone and hexane,
which were omitted from the figure) were packed between the macrocycles.
Figure 2. Crystal structure of 4･2THF: top view (a) and side views (b and c). Hydrogen atoms are
excluded for clarity.
Distances for 4
4.577
9.612
Distances for 2a
4.648
9.035
N5-N10
C17-C27
C20-C30
C23-C33
4.255
8.572
4.217
7.392
a
Table 1. Distances between atoms on upper/lower rims in aromatic rings. The data was cited from ref
16a.

HETEROCYCLES, Vol. 79, 2009
613
Figure 3. Crystal structure of 14: (a) top view and (b) side views. Hydrogen atoms and solvents are
excluded for clarity.
In conclusion, we were able to develop an efficient and convenient preparation of 4-alkoxy-1,3,5-
triazines-based calixtriazines by application of sequential SNAr reactions on triazine rings without any
protection on the nitrogen linker. Although the final step for the construction of macrocycles 4 or 6 may
involve macrocyclization of the linear tetramer or hexamer, the reactions proceeded with satisfactory
yields. A chief characteristic of our calixtriazines is their flattened conformation compared to that of
others reported previously; indicating that the nature of substituents at the 4-position of 1,3,5-triazine is
an important factor determining the conformational structure of calixtriazines.
EXPERIMENTAL
General
All melting points were measured by Yanagimoto melting point apparatus and the temperatures were
uncorrected. NMR spectra were recorded using BRUKER DPX400 spectrometers (δ given in ppm,
internal Me4Si). IR spectra on JEOL JIR-100 FT-IR spectrometer, EI-MS spectra on HITACHI M-2000
Mass spectrometer, and ESI-MS were taken on Micromass ZQ2000 spectrometer. TLC and
chromatography was performed on silica gel (Kieselgel 60 F254 for TLC, Wakogel 75-150 mesh for
column chromatography). Solvents and reagents were purchased from Aldrich, Nacalai Tesque, and
Wako Chemicals and dried according to usual procedures.
2,4-Dichloro-6-methoxy-1,3,5-triazine 7.
Cyanuric chloride (300 g, 1.63 mol) was added to a mixture of MeOH (1.6 L), water (156 mL) and
NaHCO3 (273 g, 3.25 mol) at 0 °C. After stirring for 2.5 h, iced water (1.5 L) was added, then the
resulting precipitate was collected by filtration. The solid was washed with water followed by
lyophilyzation to give 7 (287 g, 98%) as a white solid, mp 88-89 °C; IR (KBr) 1545, 1486, 1391, 847
cm-1; 1H NMR (CDCl3) δ 4.13 (s, 3H).

614
HETEROCYCLES, Vol. 79, 2009
Compound 9.
A solution of 1,3-phenylenediamine 8 (3.00 g, 27.8 mmol) in THF (30 mL) was slowly added to a
solution of 7 (10.0 g, 55.6 mmol) and iPr2NEt (10.8 g, 83.4 mmol) in THF (70 mL) at 0 °C, then stirred at
rt for 50 min. The solvents were removed in vacuo, and the residue was separated between EtOAc (200
mL) and 0.1 N HCl (150 mL). The organic layer was washed with water (100 mL x 2), dried over MgSO4,
filtrated and evaporated to give 9 (10.8 g, 98%) as a white solid, mp 179-182°C; IR (KBr) 3353, 1565,
1
1483, 1366 cm-1; H NMR (CD3OD) δ 4.02 (s, 6H), 7.32 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H),
8.07 (brs, 1H); ESIMS [MeOH/H2O (1/1)] m/z 395 (M+H+), 417 (M+Na+); Anal. Calcd for
C14H12Cl2N8O2: C, 42.55; H, 3.06; N, 28.35. Found: C 42.64; H, 3.29; N, 28.13.
Tetraaza-calix[2]arene[2](4-methoxy)triazine 4.
A solution of 1,3-phenylenediamine 8 (0.54 g, 5.00 mmol), 9 (1.98 g, 5.00 mmol) and iPr2NEt (1.62 g,
12.5 mmol) in THF (100 mL) was stirred for 72 h under N2 at 100 °C in sealed tube. After removal of the
solvents, the residue was suspended in 1N HCl (50 mL), then filtrated, and dried to give 4 (1.46 g, 68%)
1
as a white powder, mp >280 °C; IR (KBr) 1592, 1468, 1358 cm-1; H NMR (DMSO-d6) δ 3.88 (s, 6H),
6.75 (dd, J = 8.0, 2.0 Hz, 4H), 7.16 (t, J = 8.0 Hz, 2H), 7.76 (t, J = 2.0 Hz, 2H), 9.41 (s, 4H); ESIMS
[MeOH/H2O (1/1)] m/z 431 (M+H+), 453 (M+Na+); Anal. Calcd for C20H18N10O2·1/2H2O: C, 54.67; H,
4.36; N, 31.87. Found: C 54.40; H, 4.19; N, 31.83.
Synthesis of 11.
A solution of 2,6-diaminopyridine 10 (1.52 g, 13.9 mmol) in THF (20 mL) was slowly added to a solution
of 7 (5.00 g, 27.8 mmol) and iPr2NEt (5.39 g, 41.7 mmol) in THF (30 mL), then the mixture was stirred
for 48 h at rt. After removal of the solvents, the residue was separated between EtOAc (200 mL) and 0.1
N HCl (150 mL). The organic layer was washed with water (150 mL x 3), dried over MgSO4, filtrated and
concentrated. The crude residue was purified by a column chromatography [SiO2, CHCl3/MeOH (98/2)]
1
to give 11 (3.58 g, 65%) as a white solid, mp 188-191°C; IR (KBr) 1592, 1462, 1353, 1284 cm-1; H
NMR (CDCl3) δ 4.07 (s, 6H), 7.84 (t, J = 8.1 Hz 2H), 8.04 (d, J = 8.1 Hz, 2H), 8.88 (brs, 2H); ESIMS
[MeOH/H2O(1/1)] m/z 396 (M+H+), 418 (M+Na+); Anal. Calcd for C13H11Cl2N9O2·1/2H2O: C, 38.53; H,
2.99; N, 31.11. Found: C, 38.51; H, 3.15; N, 30.98.
Compound 13.
A solution of 1,3-phenylenediamine 8 (1.32 g, 12.2 mmol) in THF (20 mL) was slowly added to a
solution of 7 (1.00 g, 5.56 mmol) and iPr2NEt (2.15 g, 16.7 mmol) in THF (60 mL), then stirred at 60 °C
for 48 h. The reaction mixture was poured into EtOAc (150 mL) and water (100 mL). The organic layer
was washed with water (100 mL x 2), dried over MgSO4, filtrated and evaporated. The residue was
purified by a column chromatography [SiO2, hexane/EtOAc (8/2)] to give 13 (0.99 g, 55%) as a white
1
solid; mp 143-146 °C; IR (KBr) 3370, 1582, 1453, 1382, 1356 cm-1; H NMR (CD3OD) δ 3.96 (s, 3H),

HETEROCYCLES, Vol. 79, 2009
615
6.45 (ddd, J = 7.9, 2.2, 1.0 Hz, 2H), 6.85 (brs, 2H), 7.03 (t, J = 8.0 Hz, 2H), 7.27 (brs, 2H); HRMS (EI)
calcd for C16H17N7O 323.1495; found 323.1515.; Anal. Calcd for C16H17N7O·1/4AcOEt: C, 59.12; H, 5.54;
N, 28.39; found C, 58.76; H, 5.43; N, 28.55.
Macrocycle 14.
A solution of 9 (198 mg, 0.50 mmol), 13 (162 mg, 0.50 mmol) and iPr2NEt (162 mg, 1.25 mmol) in THF
(10 mL) was stirred for 72 h under N2 at 100 °C in sealed tube. After cooling, the precipitate was
collected to give product 14 (184.1 mg, 57%) as a pale yellow powder; mp >280 °C; IR (KBr) 1620, 1561,
1482, 1446, 1407, 1342 cm-1; 1H NMR (DMSO-d6) δ 3.98 (s, 9H), 6.94 (dd, J = 8.2, 1.2 Hz, 3H), 7.28 (t,
J = 8.2 Hz, 3H), 8.29 (dd, J = 8.2, 1.4 Hz, 3H), 8.51 (s, 3H), 8.77 (s, 3H), 9.94 (s, 3H); ESIMS
[MeOH/H2O (1/1)] m/z 646 (M+H+), 668 (M+Na+).
REFERENCES AND NOTES
1. Recent reviews for calixarenes: (a) S. Shinkai, Tetrahedron, 1993, 40, 8933; (b) V. Böhmer, Angew.
Chem., Int. Ed. Engl., 1995, 34, 713; (c) M. Takeshita and S. Shinkai, Bull. Chem. Soc. Jpn., 1995,
68, 1088; (d) A. Ikeda and S. Shinkai, Chem. Rev., 1997, 97, 1713; (e) C. D. Gutsche, ‘Calixarenes:
Monographs in Supramolecular Chemistry’, (Ed. J. F. Stoddart), The Royal Society of Chemistry:
Cambridge, 1989.
2. R. M. Musau and A. Whiting, J. Chem. Soc., Perkin Trans. 1, 1994, 2881.
3. P. A. Gale, J. L. Sessler, V. Král, and V. Lynch, J. Am. Chem. Soc., 1996, 118, 5140.
4. D. StC. Black, D. C. Craig, N. Kumar, and D. B. McConnell, Tetrahedron Lett., 1996, 37, 241.
5. V. Král, P. A. Gale, P. Jr. Anzenbacher, K. Jursíková, V. Lynch, and J. L. Sessler, Chem. Commun.,
1998, 9.
6. H. Takemura, K. Yoshimura, I. U. Khan, T. Shinmyozu, and T. Inazu, Tetrahedron Lett., 1992, 33,
5775.
7. B. Dhawan and C. D. Gutsche, J. Org. Chem., 1983, 48, 1536.
8. T. Sone, Y. Ohba, K. Moriya, H. Kumada, and K. Ito, Tetrahedron, 1997, 53, 10689.
9. V. Paraschiv, M. Crego-Calama; R. H. Fokkens, C. J. Padberg, P. Timmerman, and D. N. Reinhoudt,
J. Org. Chem., 2001, 66, 8297.
10. M. Fujita, K. Umemoto, M. Yoshizawa, N. Fujita, T. Kusukawa, and K. Biradha, Chem. Commun.,
2001, 509.
11. M. Kunishima, C. Kawachi, F. Iwasaki, K. Terao, and S. Tani, Tetrahedron Lett., 1999, 40, 5327.
12. For a recent review of applications of 2,4,6-trichloro-1,3,5-triazine and its derivatives in organic
synthesis, see G. Blotny, Tetrahedron, 2006, 62, 9507.
13. G. A. Loughran, G. F. L. Ehlers, and J. L. Burkett, J. Heterocycl. Chem., 1966, 3, 143.

616
HETEROCYCLES, Vol. 79, 2009
14. V. F. Borodkin, V. A. Gnedina, and I. A. Grukova, Izv. Vyssh. Uchebn. Zaved., Khim. Khim.
Tekhnol., 1973, 16, 1722.
15. (a) H. Graubaum, G. Lutze, F. Tittelbach, and M. Bartoszek, J. prakt. Chem., 1995, 337, 401; (b) M.
Mascal, J. L. Richardson, A. J. Blake, and W.-S. Li, Tetrahedron Lett., 1997, 43, 7639; (c) H.
Graubaum, B. Costisella, and R. Dambowsky, J. prakt. Chem., 1998, 340, 165.
16. (a) M.-X. Wang and H.-B. Yang, J. Am. Chem. Soc., 2004, 126, 15412; (b) Q.-Q. Wang, D.-X.
Wang, H.-W. Ma, and M.-X. Wang, Org. Lett., 2006, 8, 5967; (c) H.-B. Yang, D.-X. Wang, Q.-Q.
Wang, and M.-X. Wang, J. Org. Chem., 2007, 72, 3757; (d) Q.-Q. Wang, D.-X. Wang, Q.-Y. Zheng,
and M.-X. Wang, Org. Lett., 2007, 9, 2847; (e) B.-Y. Hou, Q.-Y. Zheng, D.-X. Wang, and M.-X.
Wang, Tetrahedron, 2007, 63, 10801.
17. (a) D. W. P. M. Löwik and C. R. Lowe, Tetrahedron Lett., 2000, 41, 1837; (b) D. W. P. M. Löwik
and C. R. Lowe, Eur. J. Org. Chem., 2001, 2825; (c) X. Yang and C. R. Lowe, Tetrahedron Lett.,
2003, 44, 1359; (d) C. Zhang and C.-F. Chen, J. Org. Chem., 2007, 72, 3880.
18. P. de Hoog, P. Gamez, W. L. Driessen, and J. Reedijk, Tetrahedron Lett., 2002, 43, 6783.
19. Crystal data for tetraaza-calix[2]arene[2](4-methoxy)triazine 4·2THF crystallized from a
tetrahydrofurane-acetone-hexane mixed solvent: colorless platelets of C28H34N10O4, dimensions 0.15
x 0.10 x 0.03 mm3, orthorhombic, space group Pbca (# 61), a = 7.815(5), b = 21.28(1), c = 33.31(2)
Å, V = 5539 (5) Å3, Z = 8, Dcalcd = 1.378 g/cm3. Data collected on a Rigaku RAXIS-RAPID
diffractometer with MoKα radiation (λ = 0.71075 Å) at T = -180±1 ºC, 2θmax = 60.1°, Rint = 0.076, μ
(MoKα) = 0.97 cm-1. R1 = 0.045, wR2 = 0.117.
20. Crystal data for macrocycle 14·acetone·hexane crystallized from a tetrahydrofurane-acetone-hexane
mixed solvent: colorless block of C39H47N15O4, dimensions 0.15 x 0.12 x 0.07 mm3, triclinic, space
group P-1 (# 2), a = 12.95 (2), b = 14.77 (2), c = 21.46 (2) Å, V = 3902 (9) Å3, Z = 4, Dcalcd = 1.344
g/cm3. Data collected on a Rigaku RAXIS-RAPID diffractometer with MoKα radiation (λ = 0.7107
Å) at T = -180±1ºC, 2θmax = 26.0°, Rint = 0.074, μ (MoKα) = 0.99 cm-1. R1 = 0.077, wR2 = 0.196.